N: September 12, 2013 Food and Drug Administration Center for Drug Evaluation and Research Central Document Room Drug Master File Staff Ammendale Road Beltsville, MD 20705-1266 Re: DMF 027320 Holder: MeKesson Specialty Health (McKesson) DMF Subject: Transmueosal Immediate Release Fentanyl (TIRF) Access Program Re: REMS Shared Program DMF Type: DMF Submission Information: Clinical/Clinical Information REMS Submission Identi?er: Assessment Sequence Number: 0003 Dear Drug Master File Staff: This Type DMF contains the Risk Evaluation and Mitigation Strategy (REMS) for Transmucosal Immediate Release Fentanyl for the Shared System REMS program. As agreed upon during the Agency?s teleconference held on July 31, 2013, the final historical document for the REMS Assessment 1 at 6 months would be submitted as a separate sequence (0003). McKesson states that information provided in this Master File is current and assures that the material furnished will meet the specifications described herein. McKesson also con?rms that the Holder obligations are observed. We request that all information in this file be treated as con?dential commercial information to the Food and Drug Administration pursuant to 21 C.F.R. ?20.61, and that no information from this file be provided to any unauthorized persons without written consent. If you have any questions or concerns, please do not hesitate to contact ann Kochel, US. Agent for McKesson, at 610-535?6500, ext. 5572 or alternatively Via email at jann.a.kochel@accenture.com. Sincerely, A. Kochel, US. Agent Accenture, LLP 585 East Swedesford Road Wayne, PA 19087 Attachments: Table of Contents for the submission Electronic Submission Speci?cations DMF #027320; Sequence 0003 Shared System REMS Table of Contents Page 1 of 1 Assessment – 6 Month Module Section Description 1.2 Cover Letter Cover Letter w/ Attachments 1.16 – Risk Management Plans REMS History REMS Assessment – 6 Month FDA_2 Electronic Submission Specifications This submission is compliant with FDA's Guideline for Industry: Providing Regulatory Submissions in Electronic Format - Human Pharmaceutical Product Applications and Related Submissions Using the eCTD Specifications (June 2008). All files were checked and verified to be free of viruses prior to transmission through the electronic submission gateway. This eCTD has been generated by Accenture, LLP (formerly Octagon Research Solutions Inc.), who has filed an acceptable eCTD pilot with the Center (Pilot Number 900777). Anti-Virus Program Program Version Virus Definition Date Submission Size Symantec Endpoint Protection Edition 11.0.5002.333 09/04/2013 rev. 3 Approx. 1 MB The IT point of contact for this submission is: Name Phone Number Email Address Matt Francis 610-535-6500 ext. 5665 Matthew.p.francis@accenture.com FDA_3 DMF #027320; Sequence 0003 Shared System REMS Modification Date Approved Documents Affected No. 1 June 5, 2012 x REMS x Prescriber Program Overview x Education Program x Prescriber Enrollment Form x Patient Provider Agreement Form x Patient and Caregiver Overview x Dear Healthcare Provider Letter x Outpatient Pharmacy Overview x Chain Pharmacy Overview x Inpatient Pharmacy Overview x Outpatient Pharmacy Enrollment Form x Chain Pharmacy Enrollment Form x Inpatient Pharmacy Enrollment form x Outpatient Pharmacy Letter x Inpatient Pharmacy Letter x Dear Distributor Letter x Distributor Enrollment Form x Supporting Document N/A N/A Assessment Report 1 – due 06/28/2012 REMS History Page 1 of 1 Overview of Modification Sequence 0002: Edits to Patient-Prescriber Agreement Form, the addition of the Closed System Pharmacy Enrollment Form*, the addition of the newly approved TIRF product, Subsys (fentanyl sublingual spray) and minor editorial changes. *The Closed System Pharmacy Enrollment Form was not formally submitted through the Gateway but was submitted via email on May 18, 2012 and included in the June 5, 2012 FDA approval letter. Sequence 0003: Assessment report covering 12/28/2011 to 04/27/2012 FDA_4 Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies. June 2012 6-month REMS Assessment Report Title: Transmucosal Immediate Release Fentanyl (TIRF) Risk Evaluation and Mitigation Strategy (REMS) Access Program 6-month Assessment Report Document Number: Version 1.0 FINAL Product Name: Transmucosal Immediate Release Fentanyl Sponsor: TIRF REMS Industry Group (TRIG) of Companies: Archimedes Pharma US Inc. Cephalon, Inc. (a wholly-owned subsidiary of Teva Pharmaceuticals) Insys Therapeutics Inc. Meda Pharmaceuticals Mallinckrodt Inc. (a Covidien Company) Par Pharmaceutical, Inc. ProStrakan, Inc.   Confidentiality Statement The information contained herein is confidential and the proprietary property of the TRIG of Companies and its affiliates, and any unauthorized use or disclosure of such information without the prior written authorization of the TRIG is expressly prohibited. Page 1 of 70 FDA_5 Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies. June 2012 6-month REMS Assessment Report TABLE OF CONTENTS Pg LIST OF TABLES ................................................................................................................... 4  LIST OF FIGURES ................................................................................................................. 5  LIST OF ABBREVIATIONS ................................................................................................. 6  EXECUTIVE SUMMARY ..................................................................................................... 7  1  BACKGROUND .......................................................................................................... 9  1.1  2  Reporting Period ..................................................................................................... 10  REMS GOALS ........................................................................................................... 11  2.1  3  The TIRF REMS Access Program Transition Plan: From Individual to Shared REMS ...................................................................................................................... 11  2.1.1  Prescribers ........................................................................................................ 11  2.1.2  Inpatient Pharmacies ........................................................................................ 12  2.1.3  Outpatient Pharmacies ..................................................................................... 12  2.1.4  Patients ............................................................................................................. 12  2.1.5  Distributors ...................................................................................................... 13  SUPPORTING INFORMATION ON PROPOSED REMS ELEMENTS ........... 13  3.1  Additional Elements ................................................................................................ 13  3.1.1  Medication Guide ............................................................................................ 13  3.1.2  Letters to Healthcare Professionals.................................................................. 13  3.2  Elements to Assure Safe Use (ETASU) .................................................................. 14  3.2.1  Prescription Verification .................................................................................. 15  3.3  Implementation System........................................................................................... 16  3.3.1  Wholesaler/Distribution Enrollment and Fulfillment ...................................... 16  3.3.2  The TIRF REMS Access Program Compliance .............................................. 16  3.3.3  TIRF REMS Access Program Call Center ...................................................... 16  4  REMS ASSESSMENT PLAN METHODS ............................................................. 16  4.1  Data Sources ........................................................................................................... 17  4.1.1  TIRF REMS Access Program Outreach .......................................................... 17  4.1.2  The TIRF REMS Access Program and Product Utilization Statistics ............. 17  4.1.3  Program Infrastructure and Performance ......................................................... 18  4.1.4  Safety Surveillance .......................................................................................... 19  4.2  TIRF REMS Access Program Non-Compliance Plan ............................................ 19  4.2.1  Corrective Action Measures ............................................................................ 20  5  RESULTS ................................................................................................................... 20  5.1  TIRF REMS Access Program Outreach ................................................................. 20  5.1.1  Dear Healthcare Professional Letters [Metric 1-4] .......................................... 20  5.2  REMS Program Utilization ..................................................................................... 21  5.2.1  Independent TIRF REMS Program Transitioned Stakeholders ...................... 21  Page 2 of 70 FDA_6 Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies. 5.2.2  5.2.3  5.2.4  5.2.5  5.2.6  5.2.7  June 2012 6-month REMS Assessment Report Patient Enrollment [Metric 5 and 6] ................................................................ 22  Prescriber Enrollment, Inactivation, and Education [Metric 7, 8, 9] ............... 25  Pharmacy Enrollment, Inactivation, and Education [Metric 10, 11, 12] ......... 30  Dispensing Activity [Metric 13 and 14] .......................................................... 35  Wholesaler/Distributor Enrollment [Metric 15 and 16] .................................. 37  Barriers or Delays in Patient Access [Metric 17 and 18] ................................ 38  5.3  Program Infrastructure and Performance [Metrics 19, 20, 21, 22, 23, 24] ............. 42  5.3.1  Pharmacy Management Systems [Metric 19] .................................................. 42  5.3.2  Backup System for Prescription Validation [Metric 20] ................................. 43  5.3.3  REMS Call Center [Metric 21a, b] .................................................................. 43  5.4  System Errors and Corrective Actions [Metric 22] ................................................ 46  5.4.1  Lack of Enrolled Prescribers and/or Pharmacies for Patients [Metric 23] ...... 48  5.4.2  Delays after Prescription Denial [Metric 24] ................................................... 48  5.5  Unintended System Interruptions [Metrics 25, 26, 27, 28] ..................................... 48  5.5.1  Inadvertent Enrollment Deactivations [Metric 25] .......................................... 48  5.5.2  Reports of False Positives [Metric 26] ............................................................ 48  5.5.3  Failure of Re-enrollment Notifications [Metric 27] ........................................ 48  5.5.4  Reports of False Negatives [Metric 28] ........................................................... 48  5.6  Audits ...................................................................................................................... 48  5.6.1  Periodic Surveys of Stakeholders .................................................................... 49  6  TIRF REMS ACCESS NON-COMPLIANCE........................................................ 49  7  SAFETY SURVEILLANCE ..................................................................................... 54  7.1  Adverse Events ....................................................................................................... 54  7.2  8  American Association of Poison Control Centers (AAPCC) ................................. 54  FDA COMMUNICATIONS ..................................................................................... 59  9  POST-APPROVAL STUDIES AND CLINICAL TRIALS ................................... 59  10  OVERALL CONCLUSIONS ................................................................................... 60  11  APPENDICES ............................................................................................................ 61  11.1  Medical Dictionary for Drug Regulatory Activities (MedDRA) Preferred Terms . 62  11.2  AAPCC LISTINGS................................................................................................. 67  Page 3 of 70 FDA_7 Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies. June 2012 6-month REMS Assessment Report LIST OF TABLES Table 1:  TIRF Medicines ............................................................................................................10  Table 2:  Number of Mailed Dear Healthcare Professional and Distributor Letters Current Reporting Period: 28 December 2011 to 27 April 2012 ...............................................21  Table 3:  Transition Enrollment Statistics by Stakeholder Type: 28 December 2011 to 27 April 2012 ................................................................................................................22  Table 4:  Patient Enrollment and Geographic Distribution ..........................................................23  Table 5:  Prescriber Enrollment ...................................................................................................25  Table 6:  Prescriber Inactivations .................................................................................................29  Table 7:  Enrolled Prescriber Completed Knowledge Assessments and Number of Attempts to Complete ...................................................................................................................29  Table 8:  Pharmacy Enrollment ....................................................................................................31  Table 9:  Enrolled Authorized Pharmacist/Pharmacy Knowledge Assessments and Attempts Needed to Complete ......................................................................................................34  Table 10:  Authorized Prescriptions Dispensed from Outpatient Pharmacies ...............................35  Table 11:  Total Number of Prescriptions Rejected for Safety ......................................................36  Table 12:  Wholesaler/Distributor Enrollment ...............................................................................37  Table 13:  Submission of Patient-Prescriber Agreements to the REMS Program .........................39  Table 14:  Prescriptions Dispensed During the First 10 Days after Patient Enrollment ................41  Table 15:  Configuration of Pharmacy Management System (PMS).............................................43  Table 16:  Reasons and Frequency for Contacting the Call Center ...............................................44  Table 17:  Site of Call and Site of Exposure, Human Exposure Cases Associated with TIRF Medicines: 28 December 2011 to 27 April 2012 .........................................................55  Table 18:  Age and Gender Distribution of Human Exposures Associated with TIRF Medicines: 28 December 2011 to 27 April 2012 .........................................................56  Table 19:  Number of Substances Involved in Human Exposure Cases Associated with TIRF Medicines or a Fentanyl and included Oral Inhalation Route of Exposure: 28 December 2011 to 27 April 2012 ..................................................................................56  Table 20:  Reason for Human Exposure Cases Associated with TIRF Medicines: 28 December 2011 to 27 April 2012 .............................................................................57  Table 21:  Distribution of Reason for Exposure by Age Associated with TIRF Medicines: 28 December 2011 to 27 April 2012 .............................................................................57  Table 22:  Route of Exposure for Human Exposure Cases: 28 December 2011 to 27 April 2012 ...............................................................................................................................58  Table 23:  Medical Outcome of Human Exposure Cases by Patient Age: 28 December 2011 to 27 April 2012 ............................................................................................................58  Table 24:  Medical Outcome by Reason for Exposure in Human Exposuresa: 28 December 2011 to 27 April 2012 ...................................................................................................59  Page 4 of 70 FDA_8 Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies. June 2012 6-month REMS Assessment Report LIST OF FIGURES Figure 1:  PPAF Receipt by Time Since Patient Enrollment. ....................................................... 40  Figure 2:  Number of Patients Dispensed a Prescription During the First 10 Days After Patient Enrollment. ................................................................................................................... 42    Page 5 of 70 FDA_9 Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies. June 2012 6-month REMS Assessment Report LIST OF ABBREVIATIONS AAPCC AERS American Association of Poison Control Centers Adverse Event Reporting System BTP CSR DEA ETASU FDA MedDRA Breakthrough Pain Center Service Representative Drug Enforcement Administration Elements to Assure Safe Use Food and Drug Administration Medical Dictionary for Drug Regulatory Activities NCPDP NDC NPI NRCT PMS PPAF REMS REMS edits SOP SOW TIRF National Council for Prescription Drug Program National Drug Code National Provider Identifier Non-Compliance Review Team Pharmacy Management System Patient-Prescriber Agreement Form Risk Evaluation and Mitigation Strategy Pass all checks to confirm that TIRF REMS Access program requirements were met. Standard Operating Procedure Scope of Work Transmucosal Immediate Release Fentanyl TIRF Medicines Transmucosal Immediate Release Fentanyl product(s) TIRF REMS Access REMS program for TIRF medicines TIRF Sponsors The group of sponsors that are submitting this REMS TRIG TIRF REMS Industry Group UBC United BioSource Corporation US United States Page 6 of 70 FDA_10 Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies. June 2012 6-month REMS Assessment Report EXECUTIVE SUMMARY The Transmucosal Immediate Release Fentanyl (TIRF) Risk Evaluation Mitigation Strategy (REMS) Access program was approved by the Food and Drug Administration (FDA) on 28 December 2011 for ABSTRAL®, ACTIQ®, FENTORA®, LAZANDA®, ONSOLIS® and generic versions of these TIRF medicines. On 04 January 2012, the FDA approved the inclusion of SUBSYS™ to the TIRF REMS Access program. The TIRF REMS Access program was successfully launched on 12 March 2012, approximately 11 weeks after REMS approval. Prior to the launch of the TIRF REMS Access program, 5,855 letters of notification were sent to Pharmacies and Prescribers already enrolled in an individual TIRF REMS program and 83,390 Dear Healthcare Professional letters were mailed to targeted prescribers and outpatient and inpatient pharmacies. Of these mailings, a total of 338 letters or e-mails were returned. As of 12 March 2012, records for patients, prescribers, pharmacies, and distributors actively enrolled in independent TIRF REMS programs (i.e., enrollments were completed) were transitioned into the TIRF REMS Access program. Combined stakeholder enrollment (new and transitioned) in the TIRF REMS Access program during the current reporting period included 6,747 prescribers, 35,407 outpatient pharmacies, and 42 wholesaler/distributors. Additionally, 7,783 patients were enrolled who had prescription activity during the current reporting period. Implementation of the TIRF REMS Access program for closed system pharmacies (integrated healthcare systems with outpatient pharmacy management systems [PMS] unable to support the electronic transmission for required validation and claims), has been deferred to 30 June 2012. Therefore, this assessment report does not include data from the closed system pharmacies. No patients, inpatient or outpatient pharmacies, or wholesaler/distributor enrollments were inactivated during the reporting period. A total of 199 prescribers were inactivated with 98.0% due to expiration of enrollment period. Among 2,423 newly enrolled prescribers who attempted and completed the knowledge assessments most prescribers passed the knowledge assessments on the first (43.5%) or second attempt (32.9%). Of the 2,183 enrolled authorized pharmacies, the majority completed the knowledge assessments on the first (37.6%) or the second attempt (38.8%). There were 60 incomplete prescriber enrollment forms received (multiple forms may have been submitted for the same prescriber). The majority of incomplete forms were incomplete due to missing physician signature date (66.7%), missing signature (66.7%), and missing e-mail (33.3%). There were 75 incomplete pharmacy enrollments attempts via Web, mostly due to missing Drug Enforcement Administration (DEA) number (16.0%), invalid DEA (13.3%), missing National Provider Identifier (NPI; 9.3%), and invalid NPI (6.7%). There were no incomplete forms received from wholesalers/distributors. A total of 5,799 patient-prescriber agreement forms (PPAFs) were submitted to the REMS program; the majority was submitted via the Web. Page 7 of 70 FDA_11 Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies. June 2012 6-month REMS Assessment Report At total of 14,175 prescriptions were authorized and 94.3% of those authorized prescriptions were adjudicated for safety and approved for dispensing. No patient had more than 3 prescribers in a 6 month period. A total of 8,668 prescriptions were dispensed to 7,148 patients during the first 10 days after patient enrollment (i.e., enrollment occurred when first prescription was filled). There were a greater number of patients who had their first prescription filled in the first 10 days without a PPAF compared with those patients with a PPAF (83.0% vs. 9.0%). For patients without a PPAF, the majority of patients (83.0%) received only 1 fill. Of 2,188 outpatient pharmacies that attempted to configure a PMS, 96.3% successfully reconfigured their systems in a mean of 0.9 days to configure (min/max; 0.0001 days/42 days). A total of 11,808 prescription claims were rejected for safety reasons (meaning the transaction failed to meet REMS requirements for prescriber and/or patient and/or pharmacy). A single prescription may have been submitted and rejected multiple times. The majority of safety reasons were due to prescriber ID not in the TIRF REMS Access database (46.8%), PPAF incomplete (23.6%), pharmacy not enrolled (17.9%), patient zip code missing from claim (14.5%), or prescriber last name did not match name registered (10.0%). The TIRF REMS Access Call Center was contacted most frequently for the following reasons: enrollment status inquiry (18.7%), claim rejection due to pharmacy REMS edit (12.4%), claim rejection due to prescriber REMS edit (10.7%), PPAF inquiry (8.8%), and PPAF follow up (7.9%). There were no reports from patients of inability to find an enrolled pharmacy. One prescriber reported that his/her local pharmacies were not enrolled; however, TIRF REMS Access program records showed that there were enrolled pharmacies in the area. There were no reports from patients of an inability to find an enrolled prescriber. No reports of inadvertent enrollment deactivations were identified; 10 reports concerning confirmed or potential non-compliant activity; and 5 issues were identified as system errors. During the current reporting period, no FDA Adverse Event Reporting System (AERS) cases were reported. There were 9 cases of known exposure to oral fentanyl immediate-release medicines and 8 cases of exposure to unknown fentanyl reported to the American Association of Poison Control Centers (AAPCC) during the current reporting period. One death was reported in an unknown fentanyl case (indirect report). There were 3 pediatric exposures reported for TIRF medicines, including one minor effect, one moderate effect, and one no follow-up/non toxic effect. Over all, the TIRF REMS Access program has adequately addressed its goals for the current reporting period. Page 8 of 70 FDA_12 Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies. 1 June 2012 6-month REMS Assessment Report BACKGROUND Opioids remain the mainstay of treatment of moderate to severe pain, but their safe use requires careful consideration of proper patient selection and treatment characteristics in order to mitigate any inherent health risks. Opioids are formulated as both extended release and immediate release products. Extended release or long acting opioid products are designed to provide extended analgesic activity to control persistent pain. Fentanyl, an opioid agonist and a Schedule II controlled substance, is approximately 100-fold more potent than morphine as an analgesic. 1 Secondary effects of fentanyl on central nervous system, respiratory and gastrointestinal functions are typical of opioid analgesics and are considered to be an effect. 2 Transmucosal immediate release fentanyl products (“TIRF medicines”) and short-acting opioid products have a rapid onset and short duration of action and are designed for the treatment of acute episodes of pain that ‘break through’ the chronic pain control (breakthrough pain, BTP). All the TIRF medicines are short acting fentanyl products. As with all high-potency opioid analgesics, there are significant potential risks associated with the use and misuse of TIRF medicines, including acute respiratory depression which may lead to death. With appropriate clinical use in opioid-tolerant patients these risks have been shown to be low. However, instances of diversion, overdose and prescribing to opioid-non-tolerant patients have led to serious and on occasion fatal, adverse events demonstrating that shortacting fentanyl products can pose a health risk if not used appropriately. The FDA has determined that a REMS is required to mitigate the risk of misuse, abuse, addiction, overdose, and serious complications due to medication errors with the use of TIRF medicines. The TIRF REMS Access program was approved by the FDA on 28 December 2011 for ABSTRAL®, ACTIQ®, FENTORA®, LAZANDA®, ONSOLIS® and generic versions of these TIRF medicines. On 04 January 2012, the FDA approved the inclusion of SUBSYS™ to the TIRF REMS. The group of Sponsors that are submitting this REMS (Archimedes Pharma US Inc., Cephalon, Inc. [a wholly-owned subsidiary of Teva Pharmaceuticals], Insys Therapeutics Inc., Meda Pharmaceuticals, Mallinckrodt Inc. [a Covidien Company], Par Pharmaceutical, Inc., and ProStrakan, Inc.) are hereafter referred to as the TIRF Sponsors. The TIRF REMS Access program is administered by McKesson Specialty Health and RelayHealth. This report is prepared by United BioSource Corporation (UBC). 1 Biedrzycki OJ, Bevan D, Lucas S, Fatal overdose due to prescription fentanyl patches in a patient with sickle cell/beta- thalassemia and acute chest syndrome: A case report and review of the literature. Am J Forensic Med Pathol. 2009 Jun; 30(2): 188-90 2 Simpson DM, Messina J, Xie F, Hale M. Fentanyl buccal tablet for the relief of breakthrough pain in opioid-tolerant adult patients with chronic neuropathic pain: a multicenter, randomized, double-blind, placebo-controlled study. Clin Ther. 2007 Apr; 29(4):588-601. Page 9 of 70 FDA_13 Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies. June 2012 6-month REMS Assessment Report The TIRF medicines that are the subject of this TIRF REMS are shown in Table 1 below. Table 1: TIRF Medicines Product Name (active ingredient)/formulation NDA 022510, ABSTRAL® (fentanyl) sublingual tablets NDA 020747, ACTIQ® (fentanyl citrate) oral transmucosal lozenge NDA 021947, FENTORA® (fentanyl citrate) buccal tablet NDA 022569, LAZANDA® (fentanyl) nasal spray NDA 022266, ONSOLIS® (fentanyl), buccal soluble film NDA 202788, SUBSYS™ (fentanyl sublingual spray) ANDA 077312, fentanyl citrate oral transmucosal lozenge ANDA 078907, fentanyl citrate oral transmucosal lozenge The TIRF REMS Access program addresses the current requirements set forth by the FDA provided to TIRF Sponsors. The program will be monitored over time and modified when and where appropriate. 1.1 Reporting Period The initial REMS was approved on 28 December 2011 and went live on 12 March 2012. FDA requires an initial report 6 months after initial approval. For this reporting period the cut-off date was 27 April 2012 thereby allowing 60 days to prepare the report for the FDA, which is due on 28 June 2012. Data cutoffs include all data/information available from the start of the reporting period up to the end of each reporting period to allow for programming, analysis, and report writing. Reports are scheduled for completion according to the following schedule: Reports Reporting Interval Date Sent to FDA 6 months REMS Assessment 12/28/2011 - 04/27/2012 06/28/2012 12 months REMS Assessment 04/28/2012 - 10/28/2012 12/28/2012 24 months REMS Assessment* 10/29/2012 - 10/28/2013 12/28/2013 *Annually thereafter Page 10 of 70 FDA_14 Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies. 2 June 2012 6-month REMS Assessment Report REMS GOALS The goals of the TIRF REMS Access program are to mitigate the risk of misuse, abuse, addiction, overdose and serious complications due to medication errors by: 1. Prescribing and dispensing TIRF medicines only to appropriate patients, which includes use only in opioid-tolerant patients. 2. Preventing inappropriate conversion between TIRF medicines. 3. Preventing accidental exposure to children and others for whom it was not prescribed. 4. Educating prescribers, pharmacists, and patients on the potential for misuse, abuse, addiction, and overdose of TIRF medicines. 2.1 The TIRF REMS Access Program Transition Plan: From Individual to Shared REMS Upon launch of the TIRF REMS Access program on 12 March 2012, all stakeholders enrolled in an individual TIRF REMS program were transitioned to the TIRF REMS Access program. From this point onward, all new stakeholders will be required to enroll in the TIRF REMS Access program. All distributors, pharmacies, and prescribers already enrolled in an individual TIRF REMS program were sent by mail the TIRF REMS Access program Distributor Letter, Pharmacy Letter or Dear Healthcare Provider Letter, respectively. Web sites, Call Centers, and enrollment forms for individual TIRF REMS programs were redirected to the TIRF REMS Access program. Historical data from all individual TIRF REMS programs was referenced to determine the date of last prescription so that the TIRF REMS Access program could accurately calculate 6 months of prescription activity for each patient. Prescribers, inpatient and outpatient pharmacies, and distributors are required to re-enroll and successfully complete the enrollment requirements of the TIRF REMS Access program every 2 years from their last enrollment in the individual TIRF REMS program. Independent TIRF REMS program bridging reports for individual TIRF REMS programs will capture the transitioned data (prior to launch of TIRF REMS Access program on 12 March 2012). 2.1.1 Prescribers Enrollment data for each enrolled prescriber were transferred from the individual TIRF REMS program to the TIRF REMS Access program database. After this transfer, these prescribers were then able to prescribe any TIRF medicine within the TIRF REMS Access program. Page 11 of 70 FDA_15 Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies. June 2012 6-month REMS Assessment Report Healthcare providers were guided to review the educational program for the TIRF REMS Access program but were not tested on these materials. 2.1.2 Inpatient Pharmacies Enrollment data for each enrolled inpatient pharmacy were automatically transferred from the individual TIRF REMS program to the TIRF REMS Access program database. After this transfer, inpatient pharmacies were then able to order and dispense any TIRF medicine within the TIRF REMS Access program to inpatients. 2.1.3 Outpatient Pharmacies Enrollment data on all outpatient pharmacies in an individual TIRF REMS program were automatically transitioned to the new TIRF REMS Access program. However, chain pharmacies were required to execute a TIRF REMS Access program contract with their switch provider before they could order and dispense all TIRF medicines. (A switch provider provides information to pharmacists at point-of-dispensing via their pharmacy terminals. Their secure connectivity network provides a single point of access between pharmacies and the TIRF REMS Access program so that transactions are routed through the program for evaluation of the eligibility rules.) Chain pharmacies that had not executed a TIRF REMS Access program contract with their switch provider were still able to dispense those TIRF medicines with an individual TIRF REMS program(s), in which they previously enrolled, for up to 6 months from 12 March 2012 (launch of the TIRF REMS Access program). If chain pharmacies do not execute a TIRF REMS Access program contract with their switch provider within six months, they will no longer be able to order or dispense any TIRF medicine. Independent pharmacies must agree to the shared program terms and conditions before they could order and dispense all TIRF medicines. Independent pharmacies that had not agreed to the shared program terms and conditions were still able to dispense those TIRF medicines with an individual TIRF REMS program(s), in which they previously enrolled, for up to 6 months from availability of the TIRF REMS Access program. If independent pharmacies do not sign the new terms and conditions within six months, they will no longer be able to order or dispense any TIRF medicine. 2.1.4 Patients Enrollment data for patients were automatically transferred from the individual TIRF REMS program to the TIRF REMS Access program database. Patients who were enrolled in an individual TIRF REMS and had completed a PPAF could be prescribed/receive any TIRF medicine within the TIRF REMS Access program. Patients are only required to complete a new PPAF for the TIRF REMS Access program every 2 years from the date of their last PPAF submission. Page 12 of 70 FDA_16 Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies. 2.1.5 June 2012 6-month REMS Assessment Report Distributors Enrollment data for distributors were transferred from the individual TIRF REMS programs to the TIRF REMS Access program database. 3 SUPPORTING INFORMATION ON PROPOSED REMS ELEMENTS The TIRF Sponsors are executing the TIRF REMS Access program to ensure the appropriate use of TIRF medicines and proper patient selection. All stakeholders subject to the TIRF REMS Access program including patients, prescribers, pharmacists and distributors were to be enrolled in the TIRF program, educated on the requirements of the program and required to document that they understood and would abide by the “elements to assure safe use.” Provisions were made to transition stakeholders from individual TIRF REMS programs into the TIRF REMS Access program (see Section 2.1). Program materials are provided on the TIRF medicines in addition to product-specific materials. The Educational Program and Knowledge Assessment components of the program contain both TIRF medicine class and product-specific components. All program tools, including enrollment forms, PPAF, stakeholder letters, and overview documents containing program information specific to the TIRF REMS Access program, are available through the www.TIRFREMSACCESS.com Web site. The program procedures are monitored for adherence and were modified as necessary to ensure optimal effectiveness (see Section 5.4, System Error #5). The TIRF Sponsors will continue to conduct ongoing and retrospective analysis as necessary to comply with all mandates and to maximize the safe use of the TIRF medicines. 3.1 3.1.1 Additional Elements Medication Guide The product-specific TIRF Medication Guide should be dispensed with each TIRF medicine prescription. Every TIRF medicine has a unique Medication Guide. 3.1.2 Letters to Healthcare Professionals A Communication Plan for the TIRF REMS was not required. However, TIRF Sponsors sent materials to targeted stakeholders to support implementation of the TIRF REMS Access program. These communications included Dear Healthcare Provider and Dear Pharmacy letters, and informed prescribers and authorized pharmacists on the risks associated with the use of TIRF medicines, the procedures and requirements of the TIRF REMS Access program and means of reporting adverse events. The target audience for the Dear Healthcare Provider letter included pain management specialists (comprised of anesthesiologists, physical medicine and rehabilitation physicians and primary care physicians), oncologists, oncology nurse practitioners who treat breakthrough pain in patients with cancer, and other appropriately licensed healthcare professionals who prescribe TIRF medicines. Page 13 of 70 FDA_17 Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies. June 2012 6-month REMS Assessment Report Separate Dear Pharmacy Letters were sent to inpatient pharmacies and outpatient pharmacies. The target audience for the letter included outpatient and inpatient pharmacies that may be involved in dispensing TIRF medicines. 3.2 Elements to Assure Safe Use (ETASU) Because of the significant potential health risks associated with prescribing TIRF medicines to opioid non-tolerant patients, it is important that prescribers are aware of the procedures for appropriate patient selection and appropriate dosing and titration. This was achieved by prescriber’s enrollment through a review of the TIRF REMS Access Education Program including the TIRF medicine’s Full Prescribing Information, successful completion of the Knowledge Assessment, and completion of the enrollment form. TIRF medicines are only to be available through the TIRF REMS Access program to reduce the risks of inappropriate patient selection and ensure appropriate dosing and administration of TIRF medicines. To ensure that TIRF medicines were only dispensed to appropriate patients, pharmacies are enrolled into the TIRF REMS Access program. There was a different set of enrollment requirements for outpatient pharmacies (e.g. retail, mail order, institutional outpatient pharmacies that dispense for outpatient use) and inpatient pharmacies (e.g. hospitals that dispense for inpatient use only). For Long-Term Care and Hospice patients whose prescriptions were obtained through an outpatient pharmacy setting, the pharmacy, patient, and prescriber were enrolled in the TIRF REMS Access program. Implementation of the TIRF REMS Access program for closed system pharmacies, which are integrated healthcare systems that dispense for outpatient use with pharmacy management systems unable to support the process of electronically transmitting the validation and claim information required, has been deferred to 30 June 2012. Therefore, this assessment report does not include data from the closed system pharmacies. Outpatient pharmacy enrollment required an authorized pharmacist at the pharmacy to undergo enrollment through review of the TIRF REMS Access Education Program and successful completion of the Knowledge Assessment on behalf of the pharmacy and submission of a completed and signed TIRF REMS Access program enrollment form. The authorized pharmacist ensured the pharmacy enabled their pharmacy management system (PMS) to support communication with the TIRF REMS Access program using established telecommunication standards. This required standardized validation test transactions to validate the system enhancements. The authorized pharmacist was responsible for educating all pharmacy staff who participated in dispensing TIRF medicines on the risks associated with TIRF medicines and the requirements of the TIRF REMS Access program. This training was documented and subject to audit. For inpatient pharmacy enrollment, the authorized pharmacist underwent the TIRF REMS Access Education Program, successfully completed the Knowledge Assessment, and submitted a completed and signed enrollment form on behalf of the pharmacy. The authorized inpatient pharmacist acknowledged that they understood that outpatient pharmacies within their facility were to be separately enrolled. Page 14 of 70 FDA_18 Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies. June 2012 6-month REMS Assessment Report For chain pharmacies, an authorized chain pharmacy representative completed enrollment. The authorized chain pharmacy representative acknowledged that training would occur for all pharmacy staff involved in the dispensing of TIRF medicines. Once the TIRF REMS Access Education Program and Knowledge Assessment were completed, the authorized chain pharmacy representative, on behalf of the chain, was required to acknowledge their understanding of the appropriate use of TIRF medicines and to agree to adhere to the TIRF REMS Access program requirements by submitting a completed and signed enrollment form. Patients were enrolled in the TIRF REMS Access program when their first prescription was processed at the pharmacy. A completed PPAF needed to be sent to the TIRF REMS Access program by the prescriber within 10 working days from the processing date of the patient’s first prescription for a TIRF medicine. A maximum of three prescriptions were allowed within 10 working days from when the patient had their first prescription filled. No further prescriptions were dispensed after the 10 working day window until a completed PPAF was received. A patient’s healthcare provider can submit a copy of the PPAF to the TIRF REMS Access program via the Web site, fax, or US mail. Data regarding the receipt of PPAFs from individual TIRF REMS programs were transitioned into the TIRF REMS Access program (see Section 2.1.4). In some cases, a PPAF may never be received if the patient received only one prescription without a PPAF and never attempted to fill another prescription, the patient is deceased, or they changed residence. 3.2.1 Prescription Verification Following initial patient enrollment on processing of a patient’s first TIRF medicine prescription, pharmacies verified for all subsequent prescriptions that both the prescriber and patient were enrolled in the TIRF REMS Access program prior to dispensing. Prescription verification was not required for inpatient use of TIRF medicines. Prescription verification occurs through a model that uses a pharmacy billing claim and engages a switch provider in the validation process. On receipt of a prescription for a TIRF medicine at an enrolled pharmacy, the pharmacist entered the prescription details in their PMS and sent the transaction to the TIRF REMS Access program via a switch provider. The TIRF REMS Access program used this transaction data to automatically transfer patient details into the TIRF REMS Access database for enrollment. For all prescriptions, the REMS database was then interrogated, via the switch provider, to validate the REMS edits (i.e., met the TIRF REMS Access program requirements). In the case of a valid prescription, a billing request was sent to the payer by the switch provider. Once the payer authorized payment the switch provider then authorized the pharmacy to dispense the TIRF medicine as with a normal prescription, returning an authorization number which was captured by the TIRF REMS Access program. If the prescription was not valid (e.g. one of the stakeholders was not enrolled), the TIRF REMS Access program rejected the claim (prior to the claim being forwarded to the payer) and the pharmacy received a rejection notice from the switch provider. This automated feedback Page 15 of 70 FDA_19 Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies. June 2012 6-month REMS Assessment Report indicated the reason for rejection, instructed the pharmacist not to dispense the TIRF medicine, and notified the pharmacist to contact the TIRF REMS Access program Call Center for further information. 3.3 Implementation System The Implementation System and its components are described in the following sections. 3.3.1 Wholesaler/Distribution Enrollment and Fulfillment Wholesalers/distributors who distribute TIRF medicines must be enrolled in the TIRF REMS Access program before they are allowed to distribute TIRF medicines. For the purpose of the TIRF REMS Access program, the term distributor refers to wholesaler, distributor, and/or chain pharmacy distributor. TIRF medicine distributors received a Dear Distributor Letter describing the TIRF REMS Access program and the requirements to purchase TIRF medicines from TIRF Sponsors and sell TIRF medicines to pharmacies. The distributor’s authorized representative reviewed the distributor program materials. The distributor’s authorized representative must complete and sign the Distributor Enrollment Form and faxed it to the TIRF REMS Access program. TIRF Sponsors did not ship TIRF medicines to any distributor who had not completed and signed the enrollment form. 3.3.2 The TIRF REMS Access Program Compliance TIRF Sponsors monitored prescriber, inpatient and outpatient pharmacy, and wholesaler/distributor activities for compliance with TIRF REMS Access program requirements. Corrective action (e.g., re-education, additional monitoring, process revision, stakeholder inactivation) was instituted by the TIRF Sponsors as appropriate if noncompliance was found. Based on monitoring and evaluation of the elements to ensure safe use, TIRF Sponsors worked to improve implementation of these elements and to ensure compliance with the TIRF REMS Access program requirements, as applicable. 3.3.3 TIRF REMS Access Program Call Center The TIRF REMS Access program included a Call Center component. The Call Center was staffed by qualified and trained specialists, who provided TIRF REMS Access program support to patients, prescribers, pharmacies, and distributors. 4 REMS ASSESSMENT PLAN METHODS The aim of the TIRF REMS Access program’s evaluation was to assess the effectiveness of the mitigation strategies in meeting the goals of the TIRF REMS Access program to ensure safe use, proper prescribing, and appropriate distribution of TIRF medicines. Findings from these evaluations were used in an effort to improve the processes, as needed. Page 16 of 70 FDA_20 Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies. 4.1 June 2012 6-month REMS Assessment Report Data Sources Data were collected from the following main sources as described in detail below: a) the TIRF REMS Access program outreach (Section 4.1.1), b) TIRF REMS Access product and program utilization statistics (Section 4.1.2), c) program infrastructure and performance (Section 4.1.3), and d) safety surveillance (Section 4.1.4). All programmed source tables and histograms, as well as source data for TIRF REMS Access program outreach and transition stakeholder statistics are on file at UBC and available upon request. The individual metrics for each main data source are provided below with a direct link to the results sections of the report. 4.1.1 TIRF REMS Access Program Outreach The following metrics were tabulated for this reporting period to assess program outreach efforts (Section 5.1.1): 1. 2. 3. 4. 4.1.2 Number of Dear HCP letters mailed to prescribers (by date) Number of returned mailings of Dear HCP letters to prescribers. Number of Pharmacist letters mailed to pharmacies (by date) Number of returned mailings of Pharmacist letters to pharmacies The TIRF REMS Access Program and Product Utilization Statistics For the assessment of enrollment, utilization, and discontinuation statistics for prescribers, pharmacies, patients, and wholesalers, the following metrics were tabulated for this reporting period and cumulatively: 5. Number of new patients enrolled by state (Section 5.2.2) 6. Number of patients inactivated (Section 5.2.2) 7. Number of attempts needed for prescribers to successfully complete Knowledge Assessments (Section 5.2.3) o Method of completion 8. Number of new prescribers enrolled by state (Section 5.2.3) o Method of enrollment o Number of incomplete forms and, to extent possible, a brief description of the reason for incomplete data fields 9. Number of prescribers who are inactivated (Section 5.2.3) 10. Number of new pharmacies enrolled by type (inpatient or outpatient), by state (Section 5.2.4) o Method of enrollment o Number of incomplete forms and, to extent possible, a brief description of the reason for incomplete data fields 11. Number of pharmacies that are inactivated by type (inpatient or outpatient) (Section 5.2.4) Page 17 of 70 FDA_21 Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies. June 2012 6-month REMS Assessment Report 12. Number of attempts needed for pharmacies to successfully complete Knowledge Assessments (Section 5.2.4) 13. Dispensing activity for enrolled outpatient pharmacies (Section 5.2.5) o Total number of prescriptions authorized o Total number of prescriptions rejected for safety (description of safety issues and any interventions or corrective actions taken) 14. Summary of cases identified where a patient received prescriptions for a TIRF medicine from multiple prescribers within an overlapping time frame (description of any investigations and the outcome) (Section 5.2.5) 15. Number of wholesalers/distributors inactivated, total (Section 5.2.6) 16. Number of new wholesalers/distributors enrolled (Section 5.2.6) o Method of enrollment o Number of incomplete forms 17. Number of days between enrollment and receipt of a PPAF (Section 5.2.7) o Method of PPAF submission 18. Number of prescriptions dispensed per patient during the first 10 days after patient enrollment with and without a PPAF in place. (Section 5.2.7) o A histogram of the number of days between passive enrollment and receipt of a PPAF. Stratify by the method of PPAF submission o A histogram of the number of prescriptions dispensed per patient during the first 10 days after patient passive enrollment stratified by whether there is a PPAF in place. 4.1.3 Program Infrastructure and Performance The following metrics on program infrastructure performance were tabulated for this reporting period and cumulatively: 19. Assessment of process for pharmacies to upgrade their PMS (mean, maximum, and minimum time needed, number of pharmacies that attempted and failed to upgrade their systems) (Section 5.3.1) 20. Number of times a backup system was used to validate a prescription, with reason for each instance (pharmacy level problem, switch problem, or REMS database problem) (Section 5.3.2) 21. Call center report (Section 5.3.3) a. Summary of frequently asked questions b. Problems reported 22. Description of corrective actions taken to address program/system problems (Section 5.4) Page 18 of 70 FDA_22 Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies. June 2012 6-month REMS Assessment Report 23. Number of reports of lack of enrolled prescribers and/or pharmacies in a patient’s area (Section 5.4.1) 24. Delays after original prescriptions are denied by pharmacy and brief summary to include characterization of delays (Section 5.4.2) The following reports for unintended system interruptions were provided for this reporting period: 25. Reports identified of inadvertent enrollment deactivations (Section 5.5.1) 26. Reports of false positives (e.g., all entities not enrolled but system generated a prescription authorization code) (Section 5.5.2) 27. Reports of failure of re-enrollment notifications to reach stakeholders (Section 5.5.3) 28. Reports of false negatives (e.g., all entities enrolled but the system generated a prescription rejection notice), including brief summary of reason for rejection (Section 5.5.4) 4.1.4 Safety Surveillance TIRF Sponsors processed adverse event reports related to their specific products and reported to the FDA according to current regulations outlined in 21 CFR 314.80 and the sponsor’s respective Standard Operating Procedures. Surveillance data from the following sources are included in the REMS Assessment Reports: o FDA adverse event reporting system (AERS) database using signal detection methods for TIRF medicines to identify outcomes of death, overdose, misuse, abuse, addiction, inappropriate prescribing, medication errors, and accidental exposures/ingestion period. See Appendix 11.1 for list of Medical Dictionary for Drug Regulatory Activities (MedDRA) Preferred Terms used. o AAPCC (Appendix 11.2) data for TIRF medicines and unknown fentanyl products with inhalation or ingestion as routes of exposure. All source data are on file at UBC and available upon request. 4.2 TIRF REMS Access Program Non-Compliance Plan The TIRF REMS Access program is in place to ensure the safe and appropriate use of TIRF medications. The goal of the non-compliance plan is to ensure that TRIG monitors the functioning of TIRF REMS Access program and identifies and investigates deviations and non compliance with TIRF REMS requirements in order to ensure patient safety and continuously improve the program. A TIRF REMS Access program Non-Compliance Review Team (NCRT) will be created and a detailed plan for compliance monitoring will be created and implemented. The team will have membership from the companies of the TRIG. A detailed plan for the TIRF REMS Access Page 19 of 70 FDA_23 Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies. June 2012 6-month REMS Assessment Report program will be created and implemented by the team. The NCRT will regularly review the following data sources for non-compliance or deviation from program procedures. Those potential sources include: • TIRF REMS Assessment reports • REMS database activity • TIRF REMS Access program Call Center • Data Requests and Audits Until the NCRT is instituted, all potential non-compliance events are reviewed individually by the TIRF REMS Access program to determine appropriate corrective action, if any. 4.2.1 Corrective Action Measures Stakeholders that fail to comply with one or more elements of the TIRF REMS Access program will be subject to corrective action. Corrective actions resulting from non-compliance will be determined by the TIRF REMS Access program according to the severity of the action. 5 RESULTS 5.1 5.1.1 TIRF REMS Access Program Outreach Dear Healthcare Professional Letters [Metric 1-4] Prior to the launch of the TIRF REMS Access program, letters were sent to pharmacies and prescribers already enrolled in an individual TIRF REMS program. The first mailing for transition stakeholders occurred on 21 February 2012 and 22 February 2012 and the second mailing to a broader targeted stakeholder population occurred over a 10-day timeframe from 27 February 2012 through 09 March 2012. For the transition mailing there were a total of 5,855 Dear Healthcare Professional letters mailed: 4158 letters were mailed to prescribers, 1593 letters were mailed to outpatient pharmacies, 88 letters were mailed to inpatient pharmacies, and 16 were mailed to distributors (see Table 2). For the targeted mailing there were a total of 83,390 Dear Healthcare Professional letters mailed: 16,713 were mailed to prescribers, 60,737 were mailed to outpatient pharmacies, and 5,912 letters were mailed to inpatient pharmacies. Distributor letters were e-mailed to 28 distributors. Over all the mailings, a total of 338 letters and e-mails were returned: 304 letters in March, 22 letters in April, and 10 letters in May (number of letters returned or reasons for the returns were not tracked by stakeholder). Two distributor letters that were sent via e-mail bounced back, one on 14 February 2012 and the second on 20 February 2012. In each case, alternate e-mail addresses were obtained and the e-mails were resent on the same day. Page 20 of 70 FDA_24 Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies. Table 2: June 2012 6-month REMS Assessment Report Number of Mailed Dear Healthcare Professional and Distributor Letters Current Reporting Period: 28 December 2011 to 27 April 2012 Number of Letters Mailed N Transition Stakeholder Dear HCP Mailinga Prescriber Outpatient Pharmacy Inpatient Pharmacy Distributor 4158 1593 88 16 Total 5,855 Target Stakeholder Dear HCP Mailingb Prescriber Outpatient Pharmacy Inpatient Pharmacy Distributor Total 16,713 60,737 5,912 28 83,390 Total Returned Mailings 338 a Transition Stakeholder Dear Healthcare Professional letters were mailed on 21 February 2012 and 22 February 2012. Transition Distributor letters were mailed between 14 February 2012 and 21 February 2012. b Target Stakeholder Dear Healthcare Professional letters were mailed between 27 February 2012 and 09 March 2012. Target Stakeholder Distributor letters were e-mailed between 14 February 2012 and 21 February 2012. Source: Data on file. 5.2 REMS Program Utilization The total number and geographic distribution is described below of all enrolled stakeholders (prescribers, patients, distributors, outpatient independent and inpatient pharmacies, corporate chain pharmacy offices and chain pharmacy stores), stakeholder enrollment and inactivations, dispensing activities, and barriers or delays in patient access. 5.2.1 Independent TIRF REMS Program Transitioned Stakeholders As of 12 March 2012, records for patients, prescribers, pharmacies, and distributors actively enrolled in independent TIRF REMS programs (i.e., enrollments were completed) were transitioned into the TIRF REMS Access program. The numbers of enrolled, transitioned stakeholders are shown below by stakeholder type (Table 3). Page 21 of 70 FDA_25 Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies. Table 3: June 2012 6-month REMS Assessment Report Transition Enrollment Statistics by Stakeholder Type: 28 December 2011 to 27 April 2012 Stakeholder Type Transition Enrollment Statistics Prescribers 4,530 Patients 506 Distributors 22 Outpatient Independent Pharmacies 216 Inpatient Pharmacies 131 Corporate Chain Pharmacy Offices 52 Chain Pharmacy Stores 26,493 Source: Data on file. Where applicable, these stakeholders are included in the metrics reported for the TIRF REMS Access program. 5.2.2 Patient Enrollment [Metric 5 and 6] During the current reporting period, there were 7,783 patients from all 50 states, the District of Columbia and Puerto Rico who were enrolled in the REMS program, i.e., they had prescription activity during the current reporting period or transitions from individual TIRF REMS programs (Table 4). The following states had the highest proportion of enrolled patients: California (10.7%), Florida (5.8%), New Jersey (5.4%), Texas (5.4%), New York (4.6%), and Pennsylvania (3.1%). For 30.4% of patients, state/territory was unknown. Location is not reported for all patients who transitioned into the TIRF REMS Access program because it was not available for all patients from all independent TIRF REMS programs. Additionally, patients enrolled in the TIRF REMS Access program who sign the PPAF provide consent for data use in reporting; therefore, location cannot be reported on enrolled patients who do not have a PPAF on file. For patients who submitted more than one PPAF, the location is recorded from the first completed PPAF received. There were no patients inactivated during the reporting period (not shown in Table 3; Data Sources: Table 6c: MCK_UBC_TIRF_FDA_Reporting_Enrollment_050420121711.txt; MCK_UBC_TIRF_FDA_Reporting_Enrollment_Status_History_050420121711.txt). Page 22 of 70 FDA_26 Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies. Table 4: June 2012 6-month REMS Assessment Report Patient Enrollment and Geographic Distribution Current Reporting Perioda Cumulativea,b 28DEC2011 to 27APR2012 28DEC2011 to 27APR2012 N (%) N (%) Parameter Number of Newly Enrolled Patientsc 7,783 State/Territory of Patient Primary Addressd Unknown Alabama Alaska Arizona Arkansas California Colorado Connecticut Delaware Florida Georgia Hawaii Idaho Illinois Indiana Iowa Kansas Kentucky Louisiana Maine Maryland Massachusetts Michigan Minnesota Mississippi Missouri Montana Nebraska 2,367 (30.4%) 78 (1.0%) 19 (0.2%) 109 (1.4%) 21 (0.3%) 830 (10.7%) 175 (2.3%) 91 (1.2%) 40 (0.5%) 448 (5.8%) 143 (1.8%) 12 (0.2%) 17 (0.2%) 171 (2.2%) 97 (1.3%) 19 (0.2%) 56 (0.7%) 47 (0.6%) 26 (0.3%) 10 (0.1%) 137 (1.8%) 51 (0.7%) 167 (2.2%) 25 (0.3%) 23 (0.3%) 66 (0.9%) 8 (0.1%) 19 (0.2%) 7,783 2,367 (30.4%) 78 (1.0%) 19 (0.2%) 109 (1.4%) 21 (0.3%) 830 (10.7%) 175 (2.3%) 91 (1.2%) 40 (0.5%) 448 (5.8%) 143 (1.8%) 12 (0.2%) 17 (0.2%) 171 (2.2%) 97 (1.3%) 19 (0.2%) 56 (0.7%) 47 (0.6%) 26 (0.3%) 10 (0.1%) 137 (1.8%) 51 (0.7%) 167 (2.2%) 25 (0.3%) 23 (0.3%) 66 (0.9%) 8 (0.1%) 19 (0.2%) (continued) Page 23 of 70 FDA_27 Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies. Table 4: June 2012 6-month REMS Assessment Report Patient Enrollment and Geographic Distribution Parameter Nevada New Hampshire New Jersey New Mexico New York North Carolina North Dakota Ohio Oklahoma Oregon Pennsylvania Rhode Island South Carolina South Dakota Tennessee Texas Utah Vermont Virginia Washington West Virginia Wisconsin Wyoming District of Columbia Guam Puerto Rico Virgin Islands Current Reporting Perioda Cumulativea,b 28DEC2011 to 27APR2012 28DEC2011 to 27APR2012 N (%) N (%) 47 (0.6%) 47 (0.6%) 12 (0.2%) 12 (0.2%) 420 (5.4%) 420 (5.4%) 12 (0.2%) 12 (0.2%) 355 (4.6%) 355 (4.6%) 161 (2.1%) 161 (2.1%) 9 (0.1%) 9 (0.1%) 141 (1.8%) 141 (1.8%) 84 (1.1%) 84 (1.1%) 52 (0.7%) 52 (0.7%) 239 (3.1%) 239 (3.1%) 15 (0.2%) 15 (0.2%) 49 (0.6%) 49 (0.6%) 3 (0.0%) 3 (0.0%) 120 (1.5%) 120 (1.5%) 422 (5.4%) 422 (5.4%) 94 (1.2%) 94 (1.2%) 1 (0.0%) 1 (0.0%) 100 (1.3%) 100 (1.3%) 101 (1.3%) 101 (1.3%) 14 (0.2%) 14 (0.2%) 41 (0.5%) 41 (0.5%) 15 (0.2%) 15 (0.2%) 3 (<0.1%) 3 (<0.1%) 0 0 1 (<0.1%) 1 (<0.1%) 0 0 a Includes patients that transitioned into the TIRF REMS Access program from other independent TIRF REMS programs. b Cumulative patients from the end of prior period may differ from last period's report due to reconciliation of duplicate patients. c Patients enrolled in this time period and were still enrolled at the end of the time period. d Patients are classified by state based on 5-digit zip code provided on PPAF Data Source: Table 1c: MCK_UBC_TIRF_FDA_Reporting_Patient_050420121711.txt; MCK_UBC_TIRF_FDA_Reporting_Enrollment_050420121711.txt Page 24 of 70 FDA_28 Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies. 5.2.3 June 2012 6-month REMS Assessment Report Prescriber Enrollment, Inactivation, and Education [Metric 7, 8, 9] During the current reporting period, there were 6,750 prescribers from all 50 states, the District of Columbia, and Puerto Rico who were enrolled in the TIRF REMS program (Table 5). The majority of these enrolled prescribers (64.1%) transitioned from other independent TIRF REMS programs (i.e., one-time file upload); prescribers who were first enrolled after 12 March 2012 enrolled using the Web-based enrollment system (33.7%) and manually by fax (2.2%). The highest enrolling state was California (12.0%), followed by Florida (6.8%), Texas (6.5%), New York (6.0%), Pennsylvania (5.9%), and New Jersey (5.7%); all other states had enrollment of <4.5%. There were 60 incomplete prescriber enrollment forms received for prescribers who enrolled via fax. Multiple forms may have been submitted for the same prescriber, and a form may be incomplete for more than one reason. The majority of incomplete forms were incomplete due to missing physician signature date (66.7%), missing signature (66.7%), and missing e-mail (33.3%), invalid DEA (26.7%), and provided DEA does not have correct schedule for drug (26.7%). Prescribers who enroll via Web do not submit forms. They move through a series of enrollment modules and, at any given time in the process, one or more modules may be incomplete. A prescriber cannot enroll via Web unless all modules and requirements are completed. Of prescribers who initiated enrollment via the Web and had not completed enrollment as of the last date of the current reporting period (27 April 2012; data on file), the reasons for incomplete enrollment that represented at least 80.0% of those enrolling via Web were no attestation (469, 84.81%) and training not complete (469, 84.81%). Table 5: Prescriber Enrollment Parameter Current Reporting Perioda Cumulativea,b 28DEC2011 to 27APR2012 28DEC2011 to 27APR2012 N (%) N (%) Number of Newly Enrolled Prescribersc 6,747d 6,747d Method of Successful New Enrollmentse Web Fax One-time file upload 2,274 (33.7%) 147 (2.2%) 4,326 (64.1%) 2,274 (33.7%) 147 (2.2%) 4,326 (64.1%) (continued) Page 25 of 70 FDA_29 Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies. Table 5: June 2012 6-month REMS Assessment Report Prescriber Enrollment Parameter State/Territory of Prescriber Primary Addressf Alabama Alaska Arizona Arkansas California Colorado Connecticut Delaware Florida Georgia Hawaii Idaho Illinois Indiana Iowa Kansas Kentucky Louisiana Maine Maryland Massachusetts Michigan Minnesota Mississippi Missouri Montana Nebraska Nevada New Hampshire New Jersey New Mexico New York Current Reporting Perioda Cumulativea,b 28DEC2011 to 27APR2012 28DEC2011 to 27APR2012 N (%) N (%) 102 (1.5%) 15 (0.2%) 203 (3.0%) 47 (0.7%) 811 (12.0%) 153 (2.3%) 103 (1.5%) 23 (0.3%) 458 (6.8%) 191 (2.8%) 10 (0.2%) 13 (0.2%) 238 (3.5%) 199 (3.0%) 17 (0.3%) 49 (0.7%) 61 (0.9%) 76 (1.1%) 17 (0.3%) 253 (3.7%) 95 (1.4%) 171 (2.5%) 63 (0.9%) 31 (0.5%) 99 (1.5%) 15 (0.2%) 29 (0.4%) 49 (0.7%) 33 (0.5%) 385 (5.7%) 16 (0.2%) 403 (6.0%) 102 (1.5%) 15 (0.2%) 203 (3.0%) 47 (0.7%) 811 (12.0%) 153 (2.3%) 103 (1.5%) 23 (0.3%) 458 (6.8%) 191 (2.8%) 10 (0.2%) 13 (0.2%) 238 (3.5%) 199 (3.0%) 17 (0.3%) 49 (0.7%) 61 (0.9%) 76 (1.1%) 17 (0.3%) 253 (3.7%) 95 (1.4%) 171 (2.5%) 63 (0.9%) 31 (0.5%) 99 (1.5%) 15 (0.2%) 29 (0.4%) 49 (0.7%) 33 (0.5%) 385 (5.7%) 16 (0.2%) 403 (6.0%) (continued) Page 26 of 70 FDA_30 Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies. Table 5: June 2012 6-month REMS Assessment Report Prescriber Enrollment Current Reporting Perioda Cumulativea,b 28DEC2011 to 27APR2012 28DEC2011 to 27APR2012 N (%) N (%) 294 (4.3%) 294 (4.3%) 7 (0.1%) 7 (0.1%) 215 (3.2%) 215 (3.2%) 68 (1.0%) 68 (1.0%) 62 (0.9%) 62 (0.9%) 395 (5.9%) 395 (5.9%) 13 (0.2%) 13 (0.2%) 60 (0.9%) 60 (0.9%) 4 (0.1%) 4 (0.1%) 226 (3.4%) 226 (3.4%) 438 (6.5%) 438 (6.5%) 98 (1.5%) 98 (1.5%) 4 (0.1%) 4 (0.1%) 165 (2.5%) 165 (2.5%) 129 (1.9%) 129 (1.9%) 28 (0.4%) 28 (0.4%) 96 (1.4%) 96 (1.4%) 5 (0.1%) 5 (0.1%) Parameter North Carolina North Dakota Ohio Oklahoma Oregon Pennsylvania Rhode Island South Carolina South Dakota Tennessee Texas Utah Vermont Virginia Washington West Virginia Wisconsin Wyoming District of Columbia Guam Puerto Rico Virgin Islands Distribution of Reasons for Incomplete Prescriber Enrollment Forms Received for Fax-Enrolled Prescribersg, h Missing Physician Signature Date Missing Signature Missing Email 13 (0.2%) 0 1 (<0.1%) 0 13 (0.2%) 0 1 (<0.1%) 0 60i 60i 40 (66.7%) 40 (66.7%) 20 (33.3%) 40 (66.7%) 40 (66.7%) 20 (33.3%) (continued) Page 27 of 70 FDA_31 Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies. Table 5: June 2012 6-month REMS Assessment Report Prescriber Enrollment Parameter Invalid DEA Provided DEA does not have Correct Schedule for this Drug Invalid NPI Missing NPI Number Missing State Medical License Number Missing DEA Number Missing Fax Number Current Reporting Perioda Cumulativea,b 28DEC2011 to 27APR2012 28DEC2011 to 27APR2012 N (%) N (%) 16 (26.7%) 16 (26.7%) 16 (26.7%) 16 (26.7%) 8 (13.3%) 6 (10.0%) 6 (10.0%) 2 (3.3%) 1 (1.7%) 8 (13.3%) 6 (10.0%) 6 (10.0%) 2 (3.3%) 1 (1.7%) Note: Percentages are based on the total number (N) of prescribers for the period except for counts of incomplete forms. a The table reflects only enrolled prescribers who completed enrollment via fax. b Cumulative is defined as sum of consecutive reporting periods. c Prescribers enrolled in this time period and still enrolled at the end of the time period. New Prescriber is defined as having passed Knowledge Assessment and completed enrollment form and does not include prescriber re-enrollments. d Includes prescribers who transitioned into the TIRF REMS Access program from other independent TIRF REMS programs. e Percentage is based on the number of prescribers new to the TIRF REMS Access program, including prescribers that transitioned from other independent TIRF REMS programs. f Enrolled prescribers are classified by their primary address as recorded on the Prescriber Enrollment Form. g Percentage is based on the total number of incomplete forms received in the reporting period. Forms may be incomplete for more than one reason and more than one incomplete form received for a unique prescriber. h Some stakeholders may have attempted enrollment via the Web. i Does not include prescribers who transitioned into the TIRF REMS Access program from other independent TIRF REMS programs. Data Sources: Table 1a: MCK_UBC_TIRF_FDA_Reporting_Enrollment_050420121711.txt; MCK_UBC_TIRF_FDA_Reporting_Enrollment_Status_History_050420121711.txt; MCK_UBC_TIRF_FDA_Prescriber_Location_050420121711.txt Prescribers who take 6 attempts to complete the Knowledge Assessment are “suspended” in the TIRF REMS Access program until a representative from the Call Center can conduct outreach to provide additional educational assistance. A total of 199 prescribers were inactivated during the current reporting period with 195 transitioned prescribers (98.0%) inactivated due to expiration of enrollment period, 2 (1.0%) prescribers were deceased, and 2 (1.0%) opted out of the program (Table 6). Page 28 of 70 FDA_32 Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies. Table 6: June 2012 6-month REMS Assessment Report Prescriber Inactivations Current Reporting Perioda Cumulativeb 28DEC2011 to 27APR2012 28DEC2011 to 27APR2012 N (%) N (%) Parameter Number of Inactivated Prescribers Reason(s) For Inactivationc Enrollment Expired Deceased Program Opt-Out 199 199 195 (98.0%) 2 (1.0%) 2 (1.0%) 195 (98.0%) 2 (1.0%) 2 (1.0%) Note: Percentages are based on the total number (N) for the relevant stakeholder/period. a Prescribers whose status is 'inactive' at least once during the period. b Cumulative is sum of consecutive reporting period totals. c Percentages are based on the total number (N) of inactivated prescribers. A prescriber may have more than one reason for inactivation. Data Sources: Table 6a: MCK_UBC_TIRF_FDA_Reporting_Enrollment_050420121711.txt; MCK_UBC_TIRF_FDA_Reporting_Enrollment_Status_History_050420121711.txt Among 2,423 newly enrolled prescribers who attempted and completed the knowledge assessments, 90.5% completed them via the Web and 9.5% completed them via fax (Table 7). Most prescribers passed the knowledge assessments on the first attempt (43.5%) or second attempt (32.9%). Seventy-eight (3.2%) prescribers enrolled during this assessment period required more than 4 attempts to successfully complete the knowledge assessments. Table 7: Enrolled Prescriber Completed Knowledge Assessments and Number of Attempts to Complete Parameter Current Reporting Period 28DEC2011 to 27APR2012 N (%) Cumulativea 28DEC2011 to 27APR2012 N (%) 2,423 2,423 2,193 (90.5%) 230 (9.5%) 2,193 (90.5%) 230 (9.5%) Number of Enrolled Prescribers Successfully Completing Knowledge Assessment (KA) Method of KA Completion The Web Fax (continued) Page 29 of 70 FDA_33 Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies. Table 7: June 2012 6-month REMS Assessment Report Enrolled Prescriber Completed Knowledge Assessments and Number of Attempts to Complete Parameter Number of Prescribers with One or More Attempts to Successfully Complete Knowledge Assessmentb One attempt Two attempts Three attempts Four attempts Five attempts Six attempts Greater than six attempts Current Reporting Period 28DEC2011 to 27APR2012 N (%) Cumulativea 28DEC2011 to 27APR2012 N (%) 1,054 (43.5%) 797 (32.9%) 380 (15.7%) 114 (4.7%) 46 (1.9%) 24 (1.0%) 8 (0.3%) 1,054 (43.5%) 797 (32.9%) 380 (15.7%) 114 (4.7%) 46 (1.9%) 24 (1.0%) 8 (0.3%) Note: Percentages are based on the total number (N) of prescribers successfully enrolled in the period. a Cumulative stakeholders from the end of prior period may differ from last period's report due to reconciliation of duplicate stakeholders. b Limited to successfully enrolled prescribers completing a Knowledge Assessment. Data Sources: Table 2a: MCK_UBC_TIRF_FDA_Reporting_KA_050420121711.txt; MCK_UBC_TIRF_FDA_Reporting_Enrollment_050420121711.txt 5.2.4 Pharmacy Enrollment, Inactivation, and Education [Metric 10, 11, 12] Implementation of the TIRF REMS Access program for closed system pharmacies has been deferred to 30 June 2012. Therefore, this assessment report does not include any data from the closed system pharmacies. During the current reporting period, there were 35,407 outpatient pharmacies from all 50 states, as well as the District of Columbia, Guam, Puerto Rico, and the Virgin Islands that were enrolled in the REMS program including corporate pharmacy stores (89.1%), independent outpatient pharmacies (9.6%), inpatient pharmacies (1.1%), and corporate pharmacy headquarters (0.2%) (Table 8). The states where pharmacies had the highest proportion of enrolled pharmacies included California (9.7%), Florida (8.1%), Texas (6.5%), New York (5.9%), Pennsylvania (5.2%), Ohio (4.3%), Illinois (4.0%), Georgia (3.8%), Michigan (3.8%), New Jersey (3.4%), North Carolina (3.2%); all other states had enrollment ≤2.8%. As shown in Table 8, the method of enrollment for the majority of pharmacies was via their corporate chain (89.7%; i.e., enrollment occurred via file enrollment upload), followed by those that enrolled via the Web (10.1%), or manually by fax (0.2%). Page 30 of 70 FDA_34 Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies. June 2012 6-month REMS Assessment Report There were 75 incomplete pharmacy enrollment forms received for pharmacies that enrolled via fax and the reasons most often reported for incompleteness were missing DEA number (16.0%), invalid DEA number (13.3%), missing NPI number (9.3%), and invalid NPI (6.7%). It should be noted that each form may have multiple reasons and could have been submitted multiple times. As described for prescribers, pharmacies that enroll via Web do not submit forms, but instead move through a series of modules. At any given time in the process, one or more modules may be incomplete. Pharmacies cannot enroll via Web unless all modules/requirements are completed. There were a number of outpatient (N=1303) and inpatient pharmacies (N=61) who initiated enrollment via the Web but did not complete enrollment as of the last date of the current reporting period (27 April 2012; data on file). The major reasons for incomplete enrollment of outpatient pharmacies (representing at least 80.0% of all incomplete reasons) were as follows: not agreed to terms and conditions (625, 47.97%), pending test transaction verification (369, 28.32%), and no attestation (311, 23.87%). The single reason for incomplete enrollment of inpatient pharmacies that represented at least 80.0% of incomplete reasons was no attestation (53, 86.89%). There were no inpatient or outpatient pharmacies deactivated during this reporting period (not shown in Table 8; Data Sources: Table 6b: MCK_UBC_TIRF_FDA_Reporting_Enrollment_050420121711.txt; MCK_UBC_TIRF_FDA_Reporting_Enrollment_Status_History_050420121711.txt). Table 8: Pharmacy Enrollment Current Reporting Period 28DEC2011 to 27APR2012 N (%) Cumulativea 28DEC2011 to 27APR2012 N (%) Number of Enrolled Pharmaciesb Independent Outpatient Corporate Pharmacy Headquarters Corporate Pharmacy Stores Inpatient 35,407 c 3,386 (9.6%) 79 (0.2%) 31,545 (89.1%) 397 (1.1%) 35,407 c 3,386 (9.6%) 79 (0.2%) 31,545 (89.1%) 397 (1.1%) Method of Successful Enrollmentsd The Web Fax File (file enrollment upload) 3,574 (10.1%) 79 (0.2%) 31,754 (89.7%) 3,574 (10.1%) 79 (0.2%) 31,754 (89.7%) Parameter (continued) Page 31 of 70 FDA_35 Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies. Table 8: June 2012 6-month REMS Assessment Report Pharmacy Enrollment Parameter State/Territory of Pharmacy Primary Addresse Alabama Alaska Arizona Arkansas California Colorado Connecticut Delaware Florida Georgia Hawaii Idaho Illinois Indiana Iowa Kansas Kentucky Louisiana Maine Maryland Massachusetts Michigan Minnesota Mississippi Missouri Montana Nebraska Nevada New Hampshire New Jersey New Mexico New York North Carolina Current Reporting Period 28DEC2011 to 27APR2012 N (%) Cumulativea 28DEC2011 to 27APR2012 N (%) 596 (1.7%) 52 (0.2%) 789 (2.2%) 216 (0.6%) 3,416 (9.7%) 551 (1.6%) 457 (1.3%) 147 (0.4%) 2,852 (8.1%) 1,326 (3.8%) 95 (0.3%) 152 (0.4%) 1,423 (4.0%) 835 (2.4%) 209 (0.6%) 259 (0.7%) 471 (1.3%) 463 (1.3%) 154 (0.4%) 739 (2.1%) 858 (2.4%) 1,347 (3.8%) 525 (1.5%) 252 (0.7%) 544 (1.5%) 93 (0.3%) 176 (0.5%) 305 (0.9%) 172 (0.5%) 1,190 (3.4%) 161 (0.5%) 2,098 (5.9%) 1,139 (3.2%) 596 (1.7%) 52 (0.2%) 789 (2.2%) 216 (0.6%) 3,416 (9.7%) 551 (1.6%) 457 (1.3%) 147 (0.4%) 2,852 (8.1%) 1,326 (3.8%) 95 (0.3%) 152 (0.4%) 1,423 (4.0%) 835 (2.4%) 209 (0.6%) 259 (0.7%) 471 (1.3%) 463 (1.3%) 154 (0.4%) 739 (2.1%) 858 (2.4%) 1,347 (3.8%) 525 (1.5%) 252 (0.7%) 544 (1.5%) 93 (0.3%) 176 (0.5%) 305 (0.9%) 172 (0.5%) 1,190 (3.4%) 161 (0.5%) 2,098 (5.9%) 1,139 (3.2%) (continued) Page 32 of 70 FDA_36 Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies. Table 8: June 2012 6-month REMS Assessment Report Pharmacy Enrollment Parameter North Dakota Ohio Oklahoma Oregon Pennsylvania Rhode Island South Carolina South Dakota Tennessee Texas Utah Vermont Virginia Washington West Virginia Wisconsin Wyoming District of Columbia Guam Puerto Rico Virgin Islands Number of Incomplete Pharmacy Enrollment Forms Received for Fax Enrolled Pharmaciesf Missing DEA Number Invalid DEA Missing NPI Number Invalid NPI Invalid NCPDP Missing NCPDP Number Missing Email Current Reporting Period 28DEC2011 to 27APR2012 N (%) 44 (0.1%) 1,529 (4.3%) 336 (1.0%) 385 (1.1%) 1,830 (5.2%) 157 (0.4%) 630 (1.8%) 46 (0.1%) 833 (2.4%) 2,317 (6.5%) 275 (0.8%) 78 (0.2%) 984 (2.8%) 750 (2.1%) 284 (0.8%) 575 (1.6%) 63 (0.2%) 84 (0.2%) 1 (<0.1%) 142 (0.4%) 2 (<0.1%) Cumulativea 28DEC2011 to 27APR2012 N (%) 44 (0.1%) 1,529 (4.3%) 336 (1.0%) 385 (1.1%) 1,830 (5.2%) 157 (0.4%) 630 (1.8%) 46 (0.1%) 833 (2.4%) 2,317 (6.5%) 275 (0.8%) 78 (0.2%) 984 (2.8%) 750 (2.1%) 284 (0.8%) 575 (1.6%) 63 (0.2%) 84 (0.2%) 1 (<0.1%) 142 (0.4%) 2 (<0.1%) 75g 75g 12 (16.0%) 10 (13.3%) 7 (9.3%) 5 (6.7%) 4 (5.3%) 4 (5.3%) 3 (4.0%) 12 (16.0%) 10 (13.3%) 7 (9.3%) 5 (6.7%) 4 (5.3%) 4 (5.3%) 3 (4.0%) (continued) Page 33 of 70 FDA_37 Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies. Table 8: June 2012 6-month REMS Assessment Report Pharmacy Enrollment Parameter Missing State License Number Missing Fax Number Current Reporting Period 28DEC2011 to 27APR2012 N (%) 2 (2.7%) 1 (1.3%) Cumulativea 28DEC2011 to 27APR2012 N (%) 2 (2.7%) 1 (1.3%) Note: Percentages are based on the total number (N) for stakeholders for the period. a Cumulative stakeholders from the end of prior period may differ from last period's report due to reconciliation of duplicate records. b Pharmacies that are enrolled in this time period and were still enrolled at the end of the time period. c Includes pharmacies that transitioned into the TIRF REMS Access program from other independent TIRF REMS programs. d Method Definitions: Web – enrollment occurred via program Web site; Fax – enrollment occurred via fax sent to the Call Center; File – enrollment occurred via custom file load (e.g. chain stores). e Pharmacies are classified by the primary address for the Pharmacist in Charge as recorded on the enrollment form. f Percentage is based on the total number of incomplete forms received in the reporting period. Forms may be incomplete for more than one reason. g Does not include pharmacies that transitioned into the TIRF REMS Access program from other independent TIRF REMS programs. Data Sources: Table 1b: MCK_UBC_TIRF_FDA_Reporting_Pharmacy_050420121711.txt; MCK_UBC_TIRF_FDA_Reporting_Enrollment_050420121711.txt; MCK_UBC_TIRF_FDA_Reporting_Enrollment_Status_History_050420121711.txt A total of 2,183 enrolled authorized pharmacies completed the knowledge assessments (Table 9). The majority of pharmacies completed the knowledge assessments on the first attempt (37.6%) or the second attempt (38.8%). There were 7.5% of pharmacies that required four or more attempts to successfully complete the knowledge assessment. Table 9: Enrolled Authorized Pharmacist/Pharmacy Knowledge Assessments and Attempts Needed to Complete Current Reporting Perioda Cumulativea,b 28DEC2011 to 27APR2012 28DEC2011 to 27APR2012 N (%) N (%) Parameter Number of Authorized Pharmacists/Pharmacy Representatives Successfully Completing Knowledge Assessment Number of Authorized Pharmacists with One or More Attempts to Successfully Complete Knowledge Assessmentc One attempt Two attempts Three attempts 2,183 821 (37.6%) 846 (38.8%) 353 (16.2%) 2,183 821 (37.6%) 846 (38.8%) 353 (16.2%) (continued) Page 34 of 70 FDA_38 Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies. Table 9: June 2012 6-month REMS Assessment Report Enrolled Authorized Pharmacist/Pharmacy Knowledge Assessments and Attempts Needed to Complete Current Reporting Perioda Cumulativea,b 28DEC2011 to 27APR2012 28DEC2011 to 27APR2012 N (%) N (%) 112 (5.1%) 112 (5.1%) 37 (1.7%) 37 (1.7%) 10 (0.5%) 10 (0.5%) 4 (0.2%) 4 (0.2%) Parameter Four attempts Five attempts Six attempts Greater than six attempts Note: Percentages are based on the total number (N) of pharmacists for the period. a Includes pharmacies that transitioned into the TIRF REMS Access program from other independent TIRF REMS programs. b Cumulative from the end of prior period may differ from last period's report due to reconciliation of duplicates. c Limited to successfully enrolled pharmacists. Data Sources: Table 2b: MCK_UBC_TIRF_FDA_Reporting_KA_050420121711.txt ; MCK_UBC_TIRF_FDA_Reporting_Enrollment_050420121711.txt 5.2.5 Dispensing Activity [Metric 13 and 14] At total of 14,175 prescriptions were authorized in the current reporting period. To be authorized, the prescriber must be enrolled, the pharmacy must be enrolled, and the outpatient can receive up to 3 fills without a PPAF in 10 days. Of those authorized prescriptions, 94.3% were dispensed (meaning authorized for dispensing by insurance or paid for in cash) (Table 10). Patients with prescriptions from multiple prescribers within an overlapping time frame were assessed, and no patient had more than 3 prescribers in a 6 month period (not shown in Table 9; Source Table 3b, Data Source: RHP_UBC_TIRF_FDA_Network_Data_04282012.txt). Table 10: Authorized Prescriptions Dispensed from Outpatient Pharmacies Current Reporting Perioda Cumulativea 28DEC2011 to 27APR2012 28DEC2011 to 27APR2012 N (%) N (%) Parameter Number of Authorized Prescriptionsb Number of Authorized Prescriptions Dispensedc 14,175 14,175 13,371 (94.3%) 13,371 (94.3%) Note: Percentages are based on the total number (N) of authorized prescriptions for the period. a Includes authorizations from pharmacies that transitioned into the TIRF REMS Access program from other independent TIRF REMS programs. b Prescription successfully adjudicated for safety (i.e., successful REMS edit). c Indicates number of prescriptions that were adjudicated for safety (i.e., successful REMS edit) and authorized for dispensing by insurance or paid for in cash. Data Source: Table 3a, RHP_UBC_TIRF_FDA_Network_Data_04282012.txt Page 35 of 70 FDA_39 Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies. June 2012 6-month REMS Assessment Report A total of 11,808 prescription claims were rejected for safety reasons (meaning the transaction failed to meet REMS requirements for prescriber and/or patient and/or pharmacy). A single prescription may have been submitted and rejected multiple times. The majority of safety reasons were due to prescriber ID not in TIRF REMS Access database (46.8%), PPAF incomplete (23.6%), patient zip code missing from claim (14.5%), or prescriber last name did not match name registered (10.0%). Upon receiving an inbound call from a pharmacy provider, the TIRF REMS Access program Call Center Service Representative (CSR) worked to resolve the rejected transaction and to provide instructions on the corrective action needed to successfully process the transaction. CSR resolution process included asking a series of questions to determine the reason for the rejected claim and looking up the rejected transaction to view the actual data submitted on the transaction. Quick Reference Guides were used to provide specific instruction for correcting a rejected message. Corrective action included outreach and education to remedy rejected transaction processing. Table 11: Total Number of Prescriptions Rejected for Safety Current Reporting Perioda Cumulativea 28DEC2011 to 27APR2012 28DEC2011 to 27APR2012 N (%) N (%) Parameter Number of Prescription Claims Rejected for Safety Reasons For Rejectionb Pharmacy not enrolled Pharmacy enrollment incomplete or expired System unavailable due to maintenance Prescriber ID not submitted on claim Prescriber ID not in TIRF REMS Access database Prescriber last name did not match name registered Prescriber enrollment incomplete or expired Prescriber enrollment incomplete or expired and prescriber last name mismatch DOB missing from claim Patient first name missing from claim Patient last name missing from claim Patient zip code missing from claim Multiple patients found 11,808 11,808 2,119 (17.9%) 344 (2.9%) 5 (<0.1%) 104 (0.9%) 5,529 (46.8%) 1,175 (10.0%) 213 (1.8%) 22 (0.2%) 2,119 (17.9%) 344 (2.9%) 5 (<0.1%) 104 (0.9%) 5,529 (46.8%) 1,175 (10.0%) 213 (1.8%) 22 (0.2%) 9 (0.1%) 71 (0.6%) 26 (0.2%) 1,712 (14.5%) 1 (<0.1%) 9 (0.1%) 71 (0.6%) 26 (0.2%) 1,712 (14.5%) 1 (<0.1%) (continued) Page 36 of 70 FDA_40 Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies. Table 11: June 2012 6-month REMS Assessment Report Total Number of Prescriptions Rejected for Safety Parameter Prescriber decision to deactivate patient Patient inactive > 6 months and must resubmit PPAF Patient deceased Database failure PPAF Incomplete PPAF Terminated Current Reporting Perioda Cumulativea 28DEC2011 to 27APR2012 28DEC2011 to 27APR2012 N (%) N (%) 0 0 0 0 0 0 0 0 2,790 (23.6%) 2,790 (23.6%) 14 (0.1%) 14 (0.1%) Note: Percentages are based on the total number (N) of rejected prescriptions for the relevant period. Rejected for Safety is defined in this table to mean the prescription did not pass REMS edits a Includes patients that transitioned into the TIRF REMS Access program from other independent TIRF REMS programs. b A prescription may be rejected for more than one reason. Data Source: Table 3c: RHP_UBC_TIRF_FDA_Network_Data_04282012.txt 5.2.6 Wholesaler/Distributor Enrollment [Metric 15 and 16] During the current reporting period, 42 wholesalers/distributors were enrolled in the REMS program, and all were enrolled by fax (100.0%) (Table 12). There were no incomplete forms received from wholesalers/distributors (Table 12), and no wholesaler/distributor enrollments had been inactivated (data not shown in Table 11; Data Sources Table 6d: MCK_UBC_TIRF_FDA_Reporting_Enrollment_050420121711.txt; MCK_UBC_TIRF_FDA_Reporting_Enrollment_Status_History_050420121711.txt). Table 12: Wholesaler/Distributor Enrollment Parameter Current Reporting Perioda 28DEC2011 to 27APR2012 N (%) Cumulativea,b 28DEC2011 to 27APR2012 N (%) 42 42 42 (100.0%) 42 (100.0%) Number of Wholesalers/Distributors Enrolled Method of Enrollment Fax (continued) Page 37 of 70 FDA_41 Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies. Table 12: June 2012 6-month REMS Assessment Report Wholesaler/Distributor Enrollment Parameter Number of Incomplete Wholesaler/ Distributor Enrollment Forms Received Current Reporting Perioda 28DEC2011 to 27APR2012 N (%) 0 Cumulativea,b 28DEC2011 to 27APR2012 N (%) 0 Note: Percentages are based on the total number (N) for the relevant Wholesalers/Distributors for the period. a Includes Wholesalers/Distributors that transitioned into the TIRF REMS Access program from other independent TIRF REMS programs. b Cumulative Wholesalers/Distributors from the end of prior period may differ from last period's report due to reconciliation of duplicate Wholesalers/Distributors. Data Source: Table 1d: MCK_UBC_TIRF_FDA_Reporting_Distributor_050420121711.txt; MCK_UBC_TIRF_FDA_Reporting_Enrollment_050420121711.txt 5.2.7 Barriers or Delays in Patient Access [Metric 17 and 18] A total of 5,799 PPAFs were submitted to the REMS program either via the Web (72.4%), by fax (16.6%), or forms were transitioned into the REMS program via other independent TIRF REMS programs (i.e., one time file upload; 11.0%). Most PPAFs (45.0%) were received on the same day as patient enrollment (31.1%) or between 1 and 10 days (13.9%); however 28.3% of forms were received between 21 and 30 days and 13.4% of forms were received greater than 30 days after enrollment (Table 13 and Figure 1). There are 637 PPAFs received via file upload for transitioned patients, and 506 enrolled patients transitioned from independent TIRF REMS programs (see Section 5.2.1). Only one completed PPAF was transitioned per a unique patient from the independent TIRF REMS programs. Not all transitioned PPAFs are necessarily associated with an enrolled patient. PPAFs may be on file for patients who have not enrolled (i.e., not filled at least one prescription). PPAFs for 200 enrolled patients had not been received as of the cutoff date for this report. No receipt of PPAF for an enrolled patient may indicate that the patient received one filled prescription without a PPAF and then never attempted to receive another prescription, the patient is deceased, changed residence, or opted out of the program. Page 38 of 70 FDA_42 Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies. Table 13: June 2012 6-month REMS Assessment Report Submission of Patient-Prescriber Agreements to the REMS Program Current Reporting Perioda Cumulativea 28DEC2011 to 27APR2012 28DEC2011 to 27APR2012 N (%) N (%) Parameter Number of Patient-Prescriber Agreement Forms Submitted to REMS Program Method of PPAF Submission The Web Fax One-time file upload Number of Forms Received by Days Elapsed between Patient Enrollment and Receipt of Patient-Prescriber Agreement by REMS Program Form Received Same Day Form Received between 1 and 10 days Form Received between 11 and 15 days Form Received between 16 and 20 days Form Received between 21 and 30 days Form Received >30 days after Patient Enrollment PPAF not yet received 5,799 5,799 4,200 (72.4%) 962 (16.6%) 637 (11.0%) 4,200 (72.4%) 962 (16.6%) 637 (11.0%) 1,802 (31.1%) 804 (13.9%) 275 (4.7%) 303 (5.2%) 1,641 (28.3%) 774 (13.4%) 1,802 (31.1%) 804 (13.9%) 275 (4.7%) 303 (5.2%) 1,641 (28.3%) 774 (13.4%) 200 (3.5%) 200 (3.5%) Note: Percentages are based on the total number (N) of forms for the period. a Includes patients that transitioned into the TIRF REMS Access program from other independent TIRF REMS programs. Data Sources: Table 4a: MCK_UBC_TIRF_FDA_Reporting_PPAF_050420121711.txt; MCK_UBC_TIRF_FDA_Reporting_Enrollment_050420121711.txt Page 39 of 70 FDA_43 Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies. Figure 1: June 2012 6-month REMS Assessment Report PPAF Receipt by Time Since Patient Enrollment. Figure Source: Table 4a: MCK_UBC_TIRF_FDA_Reporting_PPAF_050420121711.txt; MCK_UBC_TIRF_FDA_Reporting_Enrollment_050420121711.txt A total of 8,668 prescriptions were dispensed to a total of 7,148 patients during the first 10 days after patient enrollment (Table 14 and Figure 2 below). There were a greater number of patients who had one prescription filled in the first 10 days without a PPAF compared with those patients with a PPAF (83.0% vs. 9.0%); however, a patient is eligible to receive up to 3 fills in the first 10 days after enrollment without a PPAF. For patients without a PPAF, the majority of patients (83.0%) received only 1 fill compared with 10.5% of patients who received more than 1 fill. There were 29 patients who received more than 3 fills without a PPAF on file in a 10-day period. Root cause analysis on these transaction data is underway to determine which data elements permitted the transaction to pass through the REMS edits. The results of this investigation are ongoing and will be reported in the next reporting cycle. Page 40 of 70 FDA_44 Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies. Table 14: June 2012 6-month REMS Assessment Report Prescriptions Dispensed During the First 10 Days after Patient Enrollment Current Reporting Period Cumulativea 28DEC2011 to 27APR2012 28DEC2011 to 27APR2012 N (%) N (%) Parameter Number of prescriptions dispensed to patients during the first 10 days after patient enrollment 8,668 8,668 Number of patients dispensed a prescription during the first 10 days after patient enrollment 7,148 7,148 644 (9.0%) 126 (1.8%) 22 (0.3%) 10 (0.1%) 644 (9.0%) 126 (1.8%) 22 (0.3%) 10 (0.1%) 5,931 (83.0%) 610 (8.5%) 115 (1.6%) 29 (0.4%) 5,931 (83.0%) 610 (8.5%) 115 (1.6%) 29 (0.4%) With PPAFb 1 Fill 2 Fills 3 Fills >3 Fills Without a PPAFb, c 1 Fill 2 Fills 3 Fills >3 Fills a Cumulative data from the end of the prior period may differ from the last period's report due to reconciliation of duplicate stakeholders. b Percentages are based on the total number of patients (N=7,148) for the period. Sum of percentages may be greater than 100 due to patients receiving prescriptions with and without a PPAF during the grace period. c A patient may receive up to 3 fills in the first 10 days after enrollment without a PPAF. Data Source: Table 4b: RHP_UBC_TIRF_FDA_Network_Data_04282012.txt Page 41 of 70 FDA_45 Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies. Figure 2: June 2012 6-month REMS Assessment Report Number of Patients Dispensed a Prescription During the First 10 Days After Patient Enrollment. Figure Source: Table 4b: RHP_UBC_TIRF_FDA_Network_Data_04282012.txt 5.3 5.3.1 Program Infrastructure and Performance [Metrics 19, 20, 21, 22, 23, 24] Pharmacy Management Systems [Metric 19] Table 15 summarizes the time it took enrolled outpatient pharmacies to configure their PMS to communicate with the REMS program. Of 2,188 outpatient pharmacies that attempted to configure a PMS, 96.3% successfully reconfigured their systems and 3.7% did not complete configuration of their PMS within the reporting period. It took a mean of 0.9 days to configure, with a minimum of 0.0001 days and a maximum of approximately 42 days. Page 42 of 70 FDA_46 Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies. Table 15: June 2012 6-month REMS Assessment Report Configuration of Pharmacy Management System (PMS) Parameter Current Reporting Period 28DEC2011 to 27APR2012 N (%) Cumulative 28DEC2011 to 27APR2012 N (%) 2,188 2,188 81 (3.7%) 81 (3.7%) 2,107 (96.3%) 2,107 (96.3%) 0.9205 0.0001 42.187 0.9205 0.0001 42.187 Number of Outpatient Pharmacies Attempting to Configure PMS Number of Pharmacies with Incomplete Configuration of PMSa Number of Outpatient Pharmacies Successfully Completing Configuration of PMSb Time Required to Complete Configurationc Mean Minimum Maximum a Defined as number of pharmacies with less than 3 dates of test transfers in the reporting period. Percentages are based on the total number (N) of pharmacies attempting to configure their PMS for the relevant period. For chain pharmacies, this refers to their corporate office(s), not individual locations. c Time measured in days from 1st transaction attempt to final transaction success. Data Source: Table 5: RHP_UBC_TIRF_FDA_Network_Data_04282012.txt b 5.3.2 Backup System for Prescription Validation [Metric 20] During this reporting period there were no instances in which a backup system was used to validate a prescription due to pharmacy level problems, switch problems, or REMS database problems. 5.3.3 REMS Call Center [Metric 21a, b] Table 16 below shows reasons for contacting the REMS Call Center by frequency (%). For presentation in the report, the table cut-off is at least 80% of the total cumulative frequency of contact reasons. The most frequent reasons classified under the call reason were enrollment status inquiry (18.7%), claim rejection due to pharmacy REMS edit (12.4%), claim rejection due to prescriber REMS edit (10.7%), PPAF inquiry (8.8%), and PPAF follow up (7.9%). The call reasons listed below in Table 16 represent 83.80% of calls to the Call Center for the current reporting period. Page 43 of 70 FDA_47 Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies. Table 16: June 2012 6-month REMS Assessment Report Reasons and Frequency for Contacting the Call Center Current Reporting Period 28DEC2011 to 27APR2012 Cumulative 28DEC2011 to 27APR2012 Frequency Percenta Cumulative Frequency Cumulative Percent Enrollment Status Inquiry 4729 18.66 4729 18.66 Claim Rejection Due to Pharmacy REMS Edit 3145 12.41 3145 12.41 Claim Rejection Due to Prescriber REMS Edit 2722 10.74 2722 10.74 PPAF Inquiry 2228 8.79 2228 8.79 PPAF Follow Up 2010 7.93 2010 7.93 General Program Questions 1684 6.65 1684 6.65 Claim Rejection Due to Patient REMS Edit 1628 6.43 1628 6.43 Enrollment Follow Up 1575 6.22 1575 6.22 b 1511 5.96 1511 5.96 Contact Reason Other/Misc a The total percentage presented in the table is 83.80% of all reasons for contacting the Call Center. Other/misc include: request to change or update current information; transfers for pharmacy technical support; wrong number/hang-up/no one on the line; and, general REMS questions – non-TIRF specific. Source: Data on file (The FREQ Procedure). b Problems or complaints that were reported to the REMS Call Center for review by the TIRF REMS Access program are summarized below: ID#1 Issue: Several patients complained regarding inability to find enrolled prescriber in program because their prescriber is refusing to enroll and will no longer prescribe TIRF medicines. Resolution: The TIRF REMS Access program Call Center reviewed options with callers. A call guideline will be created and an offer made to contact patient's prescriber. The original prescriber will be advised of other prescribers enrolled in the TIRF REMS Access program to potentially provide to and refer the patient. ID #2 Issue: Patient frustrated with delay in receiving medication due to no PPAF on file. Three outbound PPAF reminder calls placed to prescriber from 17 March 2012 – 13 April 2012. Patient requested to file a complaint about the requirements of a PPAF. The patient stated she feels the requirement of a PPAF is a “threat” because program mandates that she does have to sign a PPAF, but also states that she will not receive medication until she does so. Page 44 of 70 FDA_48 Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies. June 2012 6-month REMS Assessment Report Resolution: Case was reviewed and complaints will continue to be monitored. No further escalations were received from patient. ID #3 Issue: Identified two examples of small institutions with multiple outpatient pharmacies where pharmacies share identifiers. The TIRF REMS Access program requires unique identifiers to enroll and process claims. Resolution: At one institution, three outpatient pharmacies are located at different addresses. The pharmacies share the same pharmacy system, and no attempt had been made to request separate identifiers. Subsequently, all three of the pharmacy locations were successfully enrolled as outpatient pharmacies and are dispensing TIRF medicines. At the other institution, no outpatient pharmacy has been enrolled. ID #4 Issue: Several Prescribers complained that the TIRF REMS program was contacting the office too often to follow-up on the status of missing PPAFs. An office can receive multiple calls for multiple patients each week. Resolution: TRIG evaluated the option to reduce number of outbound calls, however, felt it was important during the post launch period to follow-up often and reinforce the PPAF requirement with prescriber offices. No changes will be made at this time to reduce the number of outbound calls for missing PPAFs. ID #5 Issue: Several pharmacist complaints were received regarding the process to change an authorized pharmacist or what is known as the ‘designee’. When a change to the authorized pharmacist is needed, the new pharmacist is asked to complete and fax a completed enrollment form and Knowledge Assessment as an outpatient pharmacy. New authorized pharmacists were requesting that a change of name be completed without the need to send in new forms Resolution: Current process will remain unchanged. New pharmacist in charge must attest to the REMS requirements. Modifications to the ‘change in designee’ process may be considered in the future. Additional Call Center issues that met the definition of non-compliance are presented in Section 6, Report #1, #2, and Report #10. Page 45 of 70 FDA_49 Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies. 5.4 June 2012 6-month REMS Assessment Report System Errors and Corrective Actions [Metric 22] A brief summary of issues identified as system errors and their corrective actions is presented below. Additional system errors that met the definition of non-compliance are presented in Section 6, Reports # 5, 6, 7, 8, and 9. System Error #1 Description: Customers were reporting issues logging into TIRF REMS Access program Web site related to their inability to use the ‘forgot password’ function. This was due to not transitioning some of the stakeholders’ existing passwords over to TIRF REMS Access program from the independent TIRF REMS programs. Root Cause: Record conversion issue from independent TIRF REMS programs into TIRF REMS Access program (insufficient test case). Correction: The TIRF REMS Access program moved training records for affected records into TIRF REMS Access program database, and developed fax template to respond to the inquiries with instructions to transition stakeholders on how to register and create a new user name and password in the TIRF REMS Access program Web site. System Error #2 Description: TIRF REMS Access program Web site URL not found when using search function on Bing. Root Cause: Bing search engine link to TIRF REMS Access program was pointing to the coming soon link: http://www.tirfremsaccess.com/TirfUISplashWeb/index.html. Once program went live on 12 March 2012, this page was no longer available. Correction: Removed http://www.tirfremsaccess.com/TirfUISplashWeb/index.html page from Web site to force a refresh for this search engine. System Error #3 Description: Scope of Work (SOW) message is displaying for stakeholders who are already enrolled and accepted the SOW conditions. Users need to click OK to move past the message. Root Cause: Defect in application that checked status of SOW completion, not found during QA; insufficient test case. Correction: Interim solution communicated to Call Center representatives on 12 March 2012 that by clicking the OK button on the SOW screen, stakeholders can move into the dashboard and access appropriate functionality. The program was permanently fixed on 12 March 2012 so that for stakeholders who are already enrolled and have accepted the SOW conditions the SOW message is not displayed. Page 46 of 70 FDA_50 Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies. June 2012 6-month REMS Assessment Report System Error #4 Description: The TIRF REMS Access program forecasted 550 activities per day based on independent TIRF REMS program volumes and projected additional activities. Upon implementation, the TIRF REMS Access program volume accelerated to 1500 inbound calls and 250 faxes per day and the reasons appeared to be related to the following: trouble-shooting rejected claims; high volume of new enrollments and program inquiry calls; Web enrollment inquiries; assisting pharmacy callers with updating their terms and conditions. Root Cause: Underestimated Call Center activities Correction: The following corrective actions were implemented: increased and trained 19 additional agents to handle Call Center activities; implemented voice mail during business hours (updated call flow); created fax templates to respond to callers frequently asked questions; postponed outbound call activity for incomplete enrollments; and instituted daily operation checkpoint meetings to monitor activities. System Error #5: PPAFs specific to the individual TIRF REMS programs were received by TIRF REMS Access program after go-live date of 12 March 2012 for new patients. In response, the TIRF REMS Access program allowed prescribers to submit PPAFs for newly enrolled patients using forms from individual TIRF REMS programs for 60-days from 12 March 2012 in order to allow patient access. During this time educational outreach was conducted to prescribers instructing on the use of the new PPAF form for the TIRF REMS Access program. System Error #6: Effective 12 March 2012, all prescription claims transmitted to the TIRF REMS Access program with an national drug code (NDC) code for a TIRF medicine are subject to REMS edits. However, the TIRF REMS Access program logic did not include an exclusion for processing claims with a Date of Service that predated 12 March 2012. After the go-live date of 12 March 2012, the TIRF REMS Access program continued to receive transactions with a Date of Service (DOS) dated prior to 12 March 2012 and these claims were rejected due to pharmacy REMS edits. During the assessment period of 12 March 2012 thru 27 April 2012, there were 42 transactions that were impacted by this issue with DOS prior to March 12 and rejected. The TIRF REMS Access program developed a manual process that would allow transactions with a DOS prior to the 12 March 2012 to bypass all REMS edits on a case-by-case basis, and the list was placed into production on 15 March 2012. The exclusion list is tailored to only allow transactions with a DOS prior to 12 March 2012 to bypass the REMS network. Prior to bypassing the REMS network, TIRF REMS Access program conducts outreach to the pharmacy to confirm that the prescription was dispensed prior to 12 March 2012. Once confirmation has been received, the Service Provider ID, prescription number, and DOS are manually added to the exclusion list. The transaction is then re-processed by the pharmacy and sent to the Third Party Administrator for payment. This error delayed payment processing but did not have any Page 47 of 70 FDA_51 Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies. June 2012 6-month REMS Assessment Report impact on patient access to TIRF medicines, and only applied to NDC codes that were not part of an individual TIRF REMS program. 5.4.1 Lack of Enrolled Prescribers and/or Pharmacies for Patients [Metric 23] During the current reporting period, no reports of lack of enrolled pharmacies were received. 5.4.2 Delays after Prescription Denial [Metric 24] The prescription conversion time or length of time delay is defined as the length of time between the initial reject on a claim to when it successfully passes all the REMS business rules/edits and is sent to the payer of adjudication. For the current assessment period: • The mean prescription conversion time was 0 days, 7.759 hours. • The median prescription conversion time was 0 days, 1.101 hours. • The minimum prescription conversion was 0 days, 0.001 hours. • The maximum prescription conversion time was 29 days, 17.482 hours. 5.5 5.5.1 Unintended System Interruptions [Metrics 25, 26, 27, 28] Inadvertent Enrollment Deactivations [Metric 25] There were no reports indentified of inadvertent enrollment deactivations. 5.5.2 Reports of False Positives [Metric 26] A summary of two false positive reports (Report #3 and Report #4) are presented in Section 6. 5.5.3 Failure of Re-enrollment Notifications [Metric 27] A total of 248 distinct prescribers were scheduled to receive re-enrollment reminders this reporting period. Overall, a total of 313 re-enrollment notification faxes were sent since program inception, including reminders. Of the 248 unique prescribers, 225 successfully received a fax notification for re-enrollment. There were a total of 23 unique physicians outstanding who have not had a successful re-enrollment notification received: 19 of the 23 had 1 fax attempt and 4 had 2 unsuccessful fax attempts. 5.5.4 Reports of False Negatives [Metric 28] A summary of one false negative report System Error #11 is presented in Section 5.4. 5.6 Audits No audits were conducted during the current reporting period. Page 48 of 70 FDA_52 Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies. 5.6.1 June 2012 6-month REMS Assessment Report Periodic Surveys of Stakeholders No surveys of prescribers, inpatient pharmacists, or patients were planned or conducted during the current reporting period. Knowledge, Attitude, and, Behavior surveys will be conducted for the 12 months assessment report. 6 TIRF REMS Access Non-Compliance During the current reporting period, instances of potential stakeholder non-compliance with the TIRF REMS Access program were reviewed and investigated. The following is a list of resolved and pending potential reports of non-compliance. Report No. Report Description Report Status Call Center reported: Office staff completing or initiating enrollment on prescriber's behalf without prescriber's knowledge. 1 2 Closed Call Center reported: Three examples of prescriber modification to attestation language on PPAF form for independent TIRF REMS program and TIRF REMS Access program PPAF (e.g., crossed out opioid tolerance confirmation and replaced with "Pt not on an around-the-clock med but has been using fentanyl without side effects for some time"; "my patient is intolerant of all opioid analgesics except TIRF medicines and understand this is an off-label use"). Closed Outcome/Resolution Outreach was conducted with prescriber. Enrollment was deactivated at prescriber's request so enrollment could be reinitiated; the Knowledge Assessment was unsuspended to allow prescriber to re-take the assessment. The TIRF REMS Access program Call Center will track deactivation and Knowledge Assessment suspension in program database for reporting, as needed. In all cases, prescriber was contacted and advised the PPAF cannot be accepted with changes to the attestation language. The following information has been confirmed: • Prescriber #1 – Resubmitted a new / clean PPAF with no language crossed out on the form, and patient received TIRF medicine. • Prescriber #2 – Did not resubmit PPAF; however, a subsequent prescriber resubmitted a new/clean PPAF, and patient received TIRF medicine. This case will be referred to the NCRT for monitoring and potential future action. • Prescriber #3 – No updated PPAF received; confirmed no prescription filled for the patient. (continued) Page 49 of 70 FDA_53 Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies. Report No. 3 4 Report Description On 15 March 2012, it was discovered that an update was run that was originally developed for transition activities to move the data from independent TIRF REMS program to the TIRF REMS Access program. The update allowed 39 prescriber records to transition in an enrolled status into the TIRF REMS Access program in error. Of the 39 prescriber records enrolled in error, the TIRF REMS Access program identified that 10 prescriptions were authorized in error representing 6 unique prescriber records. Root Cause: The Standard Operating Procedure (SOP) requires code review and updates to be run in test environment prior to release to production. Because this SOP contains wording that certain steps can be skipped if the update has been previously tested and validated, the developer did not perform these steps. However, because this update was used for a different purpose than it was originally tested for, it should have been treated and tested as a new update. A chain pharmacy was incorrectly flagged as having completed both their SOW and Vendor Verification and became enrolled. This chain had 102 associated stores. Of those 102 stores, some were marked as trained by the chain. As a result, there was one instance of a prescription authorized in error. Root cause: Inadequate process documented. June 2012 6-month REMS Assessment Report Report Status Outcome/Resolution Enrollment records were voided, enrollment status was corrected in the TIRF REMS Access program system, a complete analysis was performed to determine the fills against the invalid records, and SOP clarifications and modifications were made. Closed The chain pharmacy record was updated and 102 chain store records were corrected. The TIRF REMS Access program deleted all of the store enrollments. Closed (continued) Page 50 of 70 FDA_54 Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies. Report No. 5 6 Report Description System Error: On 21 March 2012, (b) (4) (a switch provider) discovered that NDC codes for Actiq and Fentora were not routing to TIRF REMS Access program and that claims processed during this time period for these medicines did not pass through all of the REMS edits prior to dispensing. As a result, there were 234 prescriptions that were not sent from (b) (4) to the TIRF REMS Access program for REMS edits from 12 March 2012 until 21 March 2012. It was discovered that (b) (4) had not put the correct start date (12 March 2012) for claims for these NDC codes to start routing to the TIRF REMS Access program. System Error: On 09 April 2012, (b) (4) discovered that claims for retail stores were not routed to the TIRF REMS Access program from 12 March 2012 until 09 April 2012 and claims for TIRF medicines did not pass through all of the REMS edits prior to dispensing. As a result, there were 11 prescription claims that did not pass through the REMS edits during this period. June 2012 6-month REMS Assessment Report Report Status Outcome/Resolution (b) (4) corrected the issue within 24 hours of discovery and the NDC codes for these products were subsequently properly routed properly to the TIRF REMS Access program for the REMS edits. Closed Closed Of the 234 claims affected during this time period, 155 would have successfully passed REMS edits if they had been properly routed through the TIRF REMS Access program. The remaining 79 claims would have been rejected: 11 due to both pharmacy and prescriber REMS edits, 25 due to pharmacy REMS edits, and 43 due to prescriber REMS edits. Educational outreach was conducted to the affected pharmacies and prescribers to the extent feasible. In the future, additional documentation will be requested from (b) (4) Quality Management to confirm proper processing of new NDC codes. (b) (4) corrected the issue on the same day (09 April 2012) and all subsequent claims were routed properly to the TIRF REMS Access program for REMS edits. Of the 11 claims affected during this time period, 7 would have successfully passed the REMS edits if properly routed through the TIRF REMS Access program. The remaining 4 claims would have been rejected: 1 due to both pharmacy and prescriber REMS edits, and 3 due to prescriber REMS edits. Outreach was conducted to the affected pharmacies and prescribers to the extent feasible. As a result, (b) (4) instituted revised rules to limit ability to alter NDC routing for TIRF medicines. (continued) Page 51 of 70 FDA_55 Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies. Report No. 7 8 Report Description System Error: On 27 March 2012, it was discovered that one TIRF program NDC code was incorrectly communicated to the switch providers (b) (4) and (b) (4) Claims for this NDC code sent through (b) (4) from 12 March 2012 until 27 March 2012 and from (b) (4) 12 March 2012 until 28 March 2012 were not routed to the TIRF REMS Access program and did not pass through all of the REMS edits prior to dispensing. As a result, there were 2 prescription claims that did not pass through all of the REMS edits prior to dispensing. System Error: On 12 March 2012, (b) (4) stores were temporarily deactivated from the TIRF REMS Access program from 12:01AM EST until approximately 1:30AM EST to allow for customization of REMS rejection errors reported back to (b) (4) locations. During this window, one transaction was transmitted by an unenrolled (b) (4) location and, as a result, did not process through the TIRF REMS Access program. June 2012 6-month REMS Assessment Report Report Status Outcome/Resolution The error was corrected by (b) (4) on 27 March 2012 and by (b) (4) on 28 March 2012. Closed Closed The single prescription would have been rejected due to pharmacy not enrolled if properly routed. Both of these prescriptions would have been rejected due to prescriber REMS edits if properly routed through the TIRF REMS Access program. Outreach was conducted to the affected pharmacies and prescribers to the extent feasible. On 25 April, 2012, the TIRF REMS access program instituted a process to validate the correct NDC codes before providing to switch providers. On 12 March 2012, The TIRF REMS Access program conducted outreach and enrolled the (b) (4) pharmacy location in the TIRF REMS program. The enrollment was completed on 12 March 2012. After completion of the enrollment, the prescription claim was reversed and reprocessed through the REMS edits on 12 March 2012 where it successfully passed all REMS validation checks. (b) (4) confirmed that the patient received proper counseling upon dispensing of the medication. This instance occurred during the launch window for the TIRF REMS Access program. Future customization requirements will follow specific guidelines for change requests. (continued) Page 52 of 70 FDA_56 Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies. Report No. 9 10 Report Description System Error: On 05 April 2012, it was discovered that all transactions for TIRF medicines were not being routed to the TIRF REMS Access program. Upon investigation, it was discovered that data aggregators and pharmacy software vendors have direct connections to payers and do not require the usage of a traditional switch provider to send claims for payment. By not sending the claim through a traditional switch provider, the claim will not pass through the REMS edits prior to dispensing. Received pharmacist complaint regarding lack of weekend coverage at TIRF REMS Access program Call Center. Pharmacist reported that the prescriber for a prescription was unaware of PPAF requirement and that the patient was in pain. Pharmacist was unable to resolve rejected claim provided the patient with 3 tablets to carry the patient through the weekend. June 2012 6-month REMS Assessment Report Report Status Closed Pending Outcome/Resolution Beginning on 24 April 2012, the TIRF REMS Access program initiated outreach to all contracted vendors and data aggregators to identify those that have direct connections to payers that allow them to bypass a traditional switch network. As of the close of the reporting period, 2 vendors were identified as having direct connections to payers. One vendor confirmed that they are now sending all TIRF medicines to the TIRF REMS Access program. The TIRF REMS Access program is currently working with the second vendor to establish an amendment and to route all TIRF medicines to the TIRF REMS Access program for REMS edits. The TIRF REMS Access program also requested that (b) (4) perform the same outreach to vendors and data aggregators that are directly connected to (b) (4) for traditional switching services. As of the close of this reporting period, (b) (4) has identified 1 data aggregator with direct connections to payers that require amendment. The data aggregator has confirmed that they are now sending all TIRF medicines to (b) (4) There is no live coverage for the TIRF REMS Access program over the weekend. Stakeholders are able to leave a voice mail message after Call Center operation hours, including during the weekends. Live Call Center coverage is available Monday through Friday 8am-8pm EST. (The Call Center was not open seven days a week for independent TIRF REMS programs.) The TIRF REMS Access program Call Center will continue to monitor trends of calls and complaints. As part of standard procedures, this case was forwarded as an adverse event to the appropriate Sponsor for further research and follow up. Additional investigation is ongoing to confirm the “3 tablets dispensed” were a TIRF medicine. (continued) Page 53 of 70 FDA_57 Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies. Report No. 11 Report Description Two scenarios reported where the Pharmacist submitted original claim and received a reject for “prescriber not enrolled.” The Pharmacist re-submitted the claim for the same prescription with prescriber that was enrolled. Prescribers were not in the same facility. Prescriber requesting that patient be disassociated from his profile. June 2012 6-month REMS Assessment Report Report Status Outcome/Resolution Closed Outreached to Pharmacist in charge to discuss data submitted on paid claim. Pharmacist in charge at (b) (4) store did not want patient to experience withdrawal symptoms so the prescription was switched to a Prescriber that was enrolled. Patient has since switched to another medication. All prescribers involved were contacted. This case will be referred to the NCRT for monitoring and potential future action. On 5/24/12, (b) (4) provided the following response to this issue: “This is an isolated situation and the store has received education on the proper procedures for handling TIRF REMS medications. The patient is seeing a doctor now who is enrolled in the program.” Source: Data on file. 7 7.1 SAFETY SURVEILLANCE Adverse Events During the current reporting period, an analysis of the FDA AERS reporting database released in the fourth quarter of 2011 did not identify any reports that met the inclusion criteria for the TIRF REMS Access program Assessment Report. Data for the first quarter of 2012 was not available at the time of this report. 7.2 American Association of Poison Control Centers (AAPCC) The AAPCC database is monitored to identify reports of misuse, abuse, and overdose. The AAPCC database includes all 57 poison centers in the US. Reports were requested from AAPCC on calls related to the aggregated data for the class of immediate-release transmucosal fentanyls (no manufacturer names or brand names are provided). The search also included reports of unknown manufacturer oral immediate release fentanyl products, and "unknown fentanyls" with oral and/or inhalation/nasal route(s) of exposure. AAPCC listings of reports for TIRF medicines and unknown fentanyl are presented in Appendix 11.2. In future reports, data will be compared across reporting periods. The AAPCC received reports for 9 cases of known exposure to oral fentanyl immediate-release medicines during the current reporting period. The 9 cases had medical outcomes of 1 major effect, 1 moderate effect, 5 minor effects, 1 unable to follow/judged as potentially toxic exposure, and 1 not followed/judged as non toxic exposure. “Effect” is defined as sign, Page 54 of 70 FDA_58 Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies. June 2012 6-month REMS Assessment Report symptom, or laboratory abnormality and described as minor, moderate, major, or death (See Appendix 11.2 for effect definitions). Eight cases of exposure to unknown fentanyl were reported to the AAPCC during the current reporting period. The cases had medical outcomes of 1 death (indirect report), 2 major effects, 1 moderate effect, 3 unable to follow/judged as potentially toxic exposure, and 1 not followed/minimal clinical effect possible. The following tables (Tables 17-24) include reports for exposures to TIRF medicines received between 28 December 2011 and 27 April 2012. The tables do not include reports for unknown fentanyls. Human Exposure Cases: Site of Call/Site of Exposure As shown in Table 17, of the 9 human exposures associated with TIRF medicines reported, 4 call sites were from a residence (own or other) but there were 8 cases where the site of exposure actually occurred at a residence (own or other). Another 4 calls were made from a health care facility and 1 from “other.” Beyond residences, 1 exposure occurred in a public area. Table 17: Site of Call and Site of Exposure, Human Exposure Cases Associated with TIRF Medicines: 28 December 2011 to 27 April 2012 Site Health Care Facility Other Other Residence Own Residence Public Area Restaurant/food service School Unknown Workplace Total Source: AAPCC Database Table 2. Site of Caller Site of Exposure Case Count 4 1 0 4 0 0 0 0 0 9 Case Count 0 0 0 8 1 0 0 0 0 9 Human Exposure Cases: Age and Gender Distribution The age and gender distribution of human exposures associated with TIRF medicines is outlined in Table 18. Children <2 years of age were involved in 3 exposures. Another 6 exposures were reported in adults ≥20 years of age. Page 55 of 70 FDA_59 Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies. Table 18: June 2012 6-month REMS Assessment Report Age and Gender Distribution of Human Exposures Associated with TIRF Medicines: 28 December 2011 to 27 April 2012 Age (yr) Male Female Unknown Total 1 1 1 0 2 2 0 1 0 1 3-19 0 0 0 0 20-29 1 1 0 2 30-39 1 0 0 1 40-49 0 2 0 2 50-59 0 0 0 0 60-69 1 0 0 1 Total 4 5 0 9 Source: AAPCC Database Table 3A. All fatalities – All Ages and Gender No fatalities were reported in the AAPCC data associated with TIRF medicines (AAPCC Database Table 4). There was one fatality reported for exposure to an unknown fentanyl product. Human Exposure Cases: Number of Substances As shown in Table 19, a single substance was implicated in 6 reported human exposures, and 3 patients were exposed to two or more drugs or products. There were no exposure- related fatalities. For cases that involved multiple substances, the route of exposure is only captured for one of the substances; therefore, the reported case may include fentanyls that are not oral or inhalation formulations and may not be limited to the class of immediate-release fentanyls. Table 19: Number of Substances Involved in Human Exposure Cases Associated with TIRF Medicines or a Fentanyl and included Oral Inhalation Route of Exposure: 28 December 2011 to 27 April 2012 Number of Substances 1 2 3 4 5 Total Source: AAPCC Database Table 5. Case Count Fatality Case Count 6 1 1 0 1 9 0 0 0 0 0 0 Page 56 of 70 FDA_60 Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies. June 2012 6-month REMS Assessment Report Reason for Exposure The reasons for both unintentional (general and misuse) and intentional (abuse, suspected suicide, and unknown) human exposures associated with TIRF medicines are shown in Table 20. Table 20: Reason for Human Exposure Cases Associated with TIRF Medicines: 28 December 2011 to 27 April 2012 Reason Category Case Count Unintentional Unintentional General Unintentional Misuse Intentional Intentional Abuse Intentional Suspected Suicide Intentional Unknown Total Source: AAPCC Database Table 6A. 3 1 2 2 1 9 Therapeutic Errors There were no reports of therapeutic errors associated with TIRF medicines in the current reporting period (AAPCC Database Table 6B). Reason of Exposure by Age Intentional and unintentional exposures by age are shown in Table 21. Adults >19 years of age accounted for 6 human exposures, 5 intentional and 1 unintentional. There were 3 unintentional exposures in children <6 years of age. Table 21: Distribution of Reason for Exposure by Age Associated with TIRF Medicines: 28 December 2011 to 27 April 2012 0 0 Unknown Child 0 0 Unknown Adult 0 0 0 0 0 Reason <6 6-12 13-19 >19 Unknown Unintentional Intentional 3 0 0 0 0 0 1 5 0 6 Total 3 0 Source: AAPCC Database Table 7. Missing 0 0 0 Reason of Exposure by Age for Fatalities There were no reports of unintentional fatalities from exposure to TIRF medicines (AAPCC Database Table 8). Page 57 of 70 FDA_61 Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies. June 2012 6-month REMS Assessment Report Route of Exposure Ingestion was the route of exposure in 7 of 9 cases associated with TIRF medicines (Table 22), followed in frequency by parenteral (n=1) and dermal (n=1). Each exposure case may have more than one route Table 22: Route of Exposure for Human Exposure Cases: 28 December 2011 to 27 April 2012 Route Human Exposures Fatal Exposures 7 1 1 9 0 0 0 0 Ingestion Parenteral Dermal Total Source: AAPCC Database Table 9. Medical Outcome Table 23 displays the medical outcome of human exposure cases associated with TIRF medicines distributed by age. A greater number of severe medical outcomes was observed in the older age groups. Table 23: Outcome Medical Outcome of Human Exposure Cases by Patient Age: 28 December 2011 to 27 April 2012 <6 yr No effect Minor effect Moderate effect Major effect Death No follow-up, nontoxic No follow-up, minimal toxicity No follow-up, potentially toxic Unrelated effect Confirmed nonexposure Death, indirect report Total Source: AAPCC Database Table 11. 0 1 1 0 0 1 0 0 0 0 0 3 6-12 yr 13-19 yr >19 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 4 0 1 0 0 0 1 0 0 0 6 Unknown Child 0 0 0 0 0 0 0 0 0 0 0 0 Unknown Adult 0 0 0 0 0 0 0 0 0 0 0 0 Table 24 compares medical outcome and reason for exposure and shows a comparable frequency of serious outcomes in intentional (n=5) versus unintentional exposures (n=4). Page 58 of 70 FDA_62 Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies. Table 24: Medical Outcome by Reason for Exposure in Human Exposuresa: 28 December 2011 to 27 April 2012 Outcome Death Death, indirect report Major effect Minor effect Moderate effect No effect No follow-up, nontoxic No follow-up, minimal toxicity No follow-up, potentially toxic Unrelated effect Total Source: AAPCC Database Table 12. 8 June 2012 6-month REMS Assessment Report Unintentional Intentional 0 0 0 2 1 0 1 0 0 0 4 0 0 1 3 0 0 0 0 1 0 5 FDA COMMUNICATIONS FDA communicated with TRIG on 16 March 2012 regarding consumer inquiries about long phone hold times when contacting the TRIG Access program Call Center. Metrics regarding call volume and operations were provided to the agency on 16 March 2012, and the proposed action plan was implemented by 23 March 2012. (See System Error #4, Section 5.4 for additional details.) FDA requested information on the geographic distribution of pharmacies enrolled in the TIRF REMS Access program in the Kansas City, MO metropolitan area because the agency received a complaint from a prescriber that the two pharmacies in his/her local area were not enrolled. On 08 May 2012, the TIRF REMS Access program responded that there were enrolled pharmacies in the area in question. FDA acknowledged that the pharmacies within this area may have been enrolled in the TIRF REMS Access program but that pharmacy staff may not have been educated on the program or aware that their pharmacy was enrolled. 9 POST-APPROVAL STUDIES AND CLINICAL TRIALS FDA should refer to the most recent annual report for each TIRF sponsor for updated information on post-approval studies and/or clinical trials. Page 59 of 70 FDA_63 Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies. June 2012 6-month REMS Assessment Report 10 OVERALL CONCLUSIONS The TIRF REMS Access program was successfully launched on 12 March 2012, approximately 11 weeks after REMS approval. Prescribers, patients, and pharmacies were transitioned from independent TIRF REMS programs and, subsequent to 12 March and through the end of this reporting period, many additional stakeholders successfully enrolled in the TIRF REMS Access program. The REMS goal of educating prescribers and pharmacists on the potential for misuse, abuse, addiction, and overdose is being documented through the implementation of the Knowledge Assessment, which is required for enrollment. Patient education is completed through the PPAFs, and most PPAFs received within this reporting period were within the required time frame. With an overall volume of more than 14,000 prescriptions authorized for REMS edits, there were few reports of patients unable to gain access to TIRF medicines or reports of system issues. The TIRF REMS Access program system continues to be monitored for issues and, where appropriate, corrective actions instituted. Only a few instances of un-enrolled physicians prescribing TIRF medicines, un-enrolled pharmacies dispensing, and un-enrolled patients receiving product were identified. A thorough investigation is applied to all of these instances, and, where complete, corrective actions have been documented. Sponsors remain vigilant in monitoring spontaneous reports and external data sources, such as AAPCC, to identify safety risks. Surveillance methods using FDA AERS and AAPCC data identified few exposures. There were three pediatric exposures reported in AAPCC data for TIRF medicines, including one minor effect, one moderate effect, and one no follow-up/non toxic effect. There were no fatalities reported for exposure to TIRF medicines. There was one fatality reported for exposure to an unknown fentanyl. Over all, the TIRF REMS Access program has adequately addressed its goals for the current reporting period. Page 60 of 70 FDA_64 Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies. June 2012 6-month REMS Assessment Report 11 APPENDICES Page 61 of 70 FDA_65 Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies. June 2012 6-month REMS Assessment Report 11.1 Medical Dictionary for Drug Regulatory Activities (MedDRA) Preferred Terms Page 62 of 70 FDA_66 Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies. June 2012 6-month REMS Assessment Report Primary SOC lHigh Level Groupl High Level Term Preferred Term Overdose Injury. Oisoning and Medication eirors Overdoses Accidental overdose procedural complications Injury. 015?)ng and Medication eirors Overdoses Intentional overdose procedural complications Injury. Oisonnig and Medication eirors Overdoses Multiple drug overdose procedural complications Injury. Oisoning and Medication eirors Overdoses Multiple drug overdose procedural complications acc1dental Injury. Oisoning and Medications eirors Overdoses Multiple drug overdose procedural complications mtentional Injury. 0150111113 and Medication eirors Overdoses Overdose procedural complications Death General disorders and administration site Fatal outcomes Death and sudden death Accidental death conditions Nervous system disorders Cortical dysfiuiction NEC Brain death Cardiac disorders Cardiac Ventricular and Cardiac death cardiac anest General disorders and administration site conditions Fatal outcomes Death and sudden death Death General disorders and administrations site conditions Fatal outcomes Death and sudden death Death neonatal General disorders and administration site Fatal outcomes Death and sudden death Sudden cardiac death conditions . . Cardiac Ventricular airh hniias and Cardiac disorders . . YT Sudden death cardiac anest General disorders and administration site Fatal outcomes Death and sudden death Agonal death snuggle conditions General disorders and Generals stein General si is and administration site g1 Apparent death conditions disorders NEC NBC Social Family Issues Bereavement Death of companion or relative General disorders and administration site conditions Fatal outcomes Death and sudden death Sudden. unexplained death in epilepsy Page 63 of 70 Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies. J1me 2012 6-month REMS Assessment Report Primary SOC High Level Group High Level Term Preferred Term Respiratory. thoracic and Respiratory . . . . me dias tinal disorders disorders NEC Breathing abnormalities Cardio respiratory arrest Cardiac Ventricular and Cardiac disorders Cardiac arrest cardiac arrest Respiratory. thoracic and Respiratory . . . . . mediastinal disorders disorders NEC Breathing abnormalities Respnatory arrest Misuse disorders Substance-related disorders Intentional drug misuse disorders NEC Drug abuse dependence and withdrawal SMQ (Standardized Query) Abuse . . . - disorders disorders NE Substance-related disorders Drug abuse Social circumstances Lifestyle issues Drug and chemical abuse Drug abuser . . . - disorders disorders NE Substance-related disorders Substance abuse Social circumstances Lifestyle issues Drug and chemical abuse Substance abuser Social circumstances Lifestyle issues Drug and chemical abuse Ex-drug abuser Drug abuse dependence and withdrawal SMQ (Standardized Query) Inappropriate Injury. poisoning and procedural complications Medication errors Maladrninistrations Drug administered at inappropriate site Injury. poisoning and procedural complications Medication errors Maladrninistrations Inappropriate schedule of drug administration Surgical and Therapeutic procedures and Therapeutic procedures Off label use procedures . . NEC supportive care In'r . oisonin and . . . . . Dru administered to atient Juy .g . Medication errors Maladrninistrations . . procedural complications of inappropriate age Medication Error In'r . oisonin and . . . . . . rry .g . Medication errors Medication errors NEC Intercepted rnedrcatron error procedural complications In'i . oisonin and . . . . . . rry .g . Medication errors Medication errors NEC Medication error procedural complications 11111113, porsoning and Medication errors Maladrninistrations drug procedural complications Injury. orsonmig and Medication errors Maladrninistrations Drug administration error procedural complications Injury. (?50ng and Medication errors Maladrninistrations Drug dose omission procedural complications Page 64 of 70 Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies. Primary SOC High Level Group High Level Term Preferred Term Maladministrations Expired drug administered Medication errors Maladministrations Incorrect dose administered Medication errors Maladministrations Medication errors Maladministrations Medication errors Maladministrations Medication errors Maladministrations Medication errors Maladministrations Medication errors Maladministrations Medication errors Maladministrations Underdose Therapeutic and nontherapeutic effects Therapeutic and nontherapeutic responses Therapy naive Medication errors Maladministrations Wrong drug administered Medication errors Maladministrations Wrong technique in drug usage process Medication errors Medication errors NEC Drug dispensing error Medication errors Medication errors NEC Drug label confusion Medication errors Medication errors NEC Drug name confusion Medication errors Medication errors NEC Drug prescribing error Medication errors Medication errors NEC Incorrect storage of drug Medication errors Medication errors NEC Medication errors Medication errors NEC Injury, poisoning and Medication errors procedural complications Injury, poisoning and procedural complications Injury, poisoning and procedural complications Injury, poisoning and procedural complications Injury, poisoning and procedural complications Injury, poisoning and procedural complications Injury, poisoning and procedural complications Injury, poisoning and procedural complications Injury, poisoning and procedural complications General disorders and administrative sites Injury, poisoning and procedural complications Injury, poisoning and procedural complications Injury, poisoning and procedural complications Injury, poisoning and procedural complications Injury, poisoning and procedural complications Injury, poisoning and procedural complications Injury, poisoning and procedural complications Injury, poisoning and procedural complications Injury, poisoning and procedural complications Injury, poisoning and procedural complications Injury, poisoning and procedural complications June 2012 6-month REMS Assessment Report Medication errors Medication errors Medication monitoring errors Medication monitoring errors Page 65 of 70 Incorrect drug administration duration Incorrect drug administration rate Incorrect drug dosage form administered Incorrect route of drug administration Poor quality drug administered Inappropriate schedule of drug administration Intercepted drug dispensing error Intercepted drug medication error Labeled drug-disease interaction medication error Labeled drug-drug interaction medication error FDA_69 Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies. Primary SOC High Level Group High Level Term June 2012 6-month REMS Assessment Report Preferred Term Injury. poisoning and procedural complications Medication errors Maladrninistrations Drug administered to patient of inappropriate age Injury. poisoning and procedural complications Medication errors Medication errors due to accidental exposures Accidental drug intake by child Accidental Injury. poisoning and procedural complications Medication errors Medication errors due to accidental exposures Accidental drug intake by child Injury. poisoning and procedural complications Medication errors Medication errors due to accidental exposures Accidental exposure Injury. poisoning and procedural complications Medication errors Overdoses Accidental overdose Injury. poisoning and procedural complications Chemical injury and poisoning Poisoning and toxicity Accidental poisoning Injury. poisoning and procedural complications Chemical injury and poisoning Poisoning and toxicity Toxicity to various agents Injury. porsoning and Medication errors Over doses Multiple drug overdose procedural complications accrdental Dependence . . . . disorders disorders NEC Substance-related disorders Dependence . . . . . disorders disorders NEC Substance-related disorders Drug dependence Pregnancy. puerperiurn Foetal Foetal conditions due to Drug dependence. and perinatal conditions complications maternal conditions . . . . Drug dependence. disorders disorders NE Substance-related disorders postparttun . . . . disorders disorders NE Substance-related disorders Polysubstance dependence . . . - . - disorders disorders NE Substance-related disorders Withdrawal Drug Diversion Social circumstances Legal issues Criminal activity Drug diversion Surgical and medical procedures Therapeutic procedures and supportive care NEC Therapeutic procedures NEC Off label use Respiratory Depression Acute central respiratory depression SMQ (Standardized Query) Page 66 of 70 Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies. June 2012 6-month REMS Assessment Report 11.2 AAPCC LISTINGS The following definitions are used to characterize data in the attached listings of TIRF medicines fentanyl exposures and unknown exposures which were derived AAPCC annual report: Bronstein AC, Spyker DA, Cantilena LR et al. 2010 annual report of the American Association of Poison Control Centers’ National Poison Data System (NPDS): 28th annual report. Clinical Toxicology. 2011;49:910-941. No effect: The patient did not develop any signs or symptoms as a result of the exposure. Minor effect: The patient developed some signs or symptoms as a result of the exposure, but they were minimally bothersome and generally resolved rapidly with no residual disability or disfigurement. A minor effect is often limited to the skin or mucus membranes (e.g., self-limited gastrointestinal symptoms, drowsiness, skin irritation, first-degree dermal burn, sinus tachycardia without hypotension, and transient cough). Moderate effect: The patient exhibited signs or symptoms as a result of the exposure that were more pronounced, more prolonged, or more systemic in nature than minor symptoms. Usually, some form of treatment is indicated. Symptoms were not life-threatening, and the patient had no residual disability or disfigurement (e.g., corneal abrasion, acid-base disturbance, high fever, disorientation, hypotension that is rapidly responsive to treatment, and isolated brief seizures that respond readily to treatment). Major effect: The patient exhibited signs or symptoms as a result of the exposure that were lifethreatening or resulted in significant residual disability or disfigurement (e.g., repeated seizures or status epilepticus, respiratory compromise requiring intubation, ventricular tachycardia with hypotension, cardiac or respiratory arrest, esophageal stricture, and disseminated intravascular coagulation). Death: The patient died as a result of the exposure or as a direct complication of the exposure. Page 67 of 70 FDA_71 Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies. June 2012 6-month REMS Assessment Report A statement on AAPCC data must be included in all publications referencing AAPCC data. The AAPCC maintains the national database of information logged by the country's 57 poison control centers. Case records in this database are from self-reported calls: they reflect only information provided when the public or healthcare professionals report an actual or potential exposure to a substance (e.g., an ingestion, an inhalation, or a topical exposure, etc.), or request information/educational materials. Exposures do not necessarily represent a poisoning or overdose. The AAPCC is not able to completely verify the accuracy of every report made to member centers. Additional exposures may go unreported to PCCs and data referenced from the AAPCC should not be construed to represent the complete incidence of national exposures to any substance(s). All data produced from the AAPCCs databases during the year in which the exposures occur is considered preliminary. Changes occur in only a small number of cases each year. This is because it is possible that a poison center may update a case anytime during that year if new data is obtained. In the fall of each year the data for the previous year is locked and no changes are permitted. At that time the data for a year is considered closed. Page 68 of 70 FDA_72 Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies. June 2012 6-month REMS Assessment Report Listing of TRIG TIRF Immediate-Release Medicines Subject 1 2 3 Start Date Public Case Number Age Gender Substance Rank No of Substances 6 7 8 Solid (tablets / capsules / caplets) Solid (tablets / capsules / caplets) 1/1/12 9983173722012 22 Male 1 2 1/1/12 9983173722012 22 Male 2 2 1/2/12 30122033582012 30 Male 1 1 Liquid 5 Solid (tablets / capsules / caplets) 1/17/12 1407423672012 49 Female 5 Solid (tablets / capsules / caplets) Quantity 14 2 NULL 275 Unknown mcg tabs / pills / capsules 1407423672012 49 Female 1 5 1/17/12 1407423672012 49 Female 2 5 1/17/12 1407423672012 49 Female 3 5 1/17/12 1407423672012 49 Female 4 5 1/18/12 20124953322012 21 Female 1 1 Solid (tablets / capsules / caplets) 600 mg 2/22/12 3409573352012 14 Female 1 1 Other NULL Unknown 3 Solid (tablets / capsules / caplets) 3/11/12 17653713532012 66 Male 1 Solid (tablets / capsules / caplets) Solid (tablets / capsules / caplets) Solid (tablets / capsules / caplets) 30 Quantity Unit tabs / pills / capsules tabs / pills / capsules 1/17/12 4 5 Formulation 2 2 45 1.2 tabs / pills / capsules tabs / pills / capsules tabs / pills / capsules mg 3/11/12 17653713532012 66 Male 2 3 Solid (tablets / capsules / caplets) 120 mg 3/11/12 17653713532012 66 Male 3 3 Solid (tablets / capsules / caplets) 20 mg 3/17/12 26199563612012 45 Female 1 1 Patch 1 taste / lick / drop 4/6/12 18509453282012 20 Male 1 1 Solid (tablets / capsules / caplets) NULL Unknown 9 Major Category Fentanyl Benzodiazepines Reason For Exposure Intentional Unknown Intentional Unknown 728291893052012 2 Female 1 1 Other Page 69 of 70 1 taste / lick / drop Minor effect Minor effect Fentanyl Intentional - Abuse Major effect Fentanyl Intentional Suspected suicide Minor effect Intentional Suspected suicide Minor effect Other Types of Sedative/Hypnotic/ Anti-Anxiety or AntiPsychotic Drug Carisoprodol (Formulated Alone) Acetaminophen with Hydrocodone Acetaminophen with Oxycodone Fentanyl Intentional Suspected suicide Intentional Suspected suicide Intentional Suspected suicide Intentional - Abuse Fentanyl Fentanyl Oxycodone Alone or in Combination (Excluding Combination Products with Acetaminophen or Acetylsalicylic Acid) Methadone Fentanyl Fentanyl Unintentional General Intentional Suspected suicide Intentional Suspected suicide Intentional Suspected suicide Unintentional Misuse Unintentional General Fentanyl 4/13/12 Medical Outcome Unintentional General Minor effect Minor effect Minor effect Unable to follow, judged as a potentially toxic exposure Moderate effect Minor effect Minor effect Minor effect Minor effect Minor effect Not followed, judged as nontoxic exposure (clinical effects not expected) FDA_73 Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies. June 2012 6-month REMS Assessment Report Listing of TRIG TIRF Immediate-Release Medicines Subject Start Date Public Case Number Age Gender Substance Rank No of Substances Formulation Quantity Quantity Unit Major Category Reason For Exposure 1 1/15/12 23666153092012 25 Male 1 1 Patch 1 each (e.g. bites / stings) 2 2/15/12 7896563442012 NULL Female 1 3 Solid (tablets / capsules / caplets) 5 tabs / pills / capsules Acetaminophen with Oxycodone Intentional - Misuse 2/15/12 7896563442012 NULL Female 2 3 Solid (tablets / capsules / caplets) 1 tabs / pills / capsules Methadone Intentional - Misuse 2/15/12 7896563442012 NULL Female 3 3 Other 2 each (e.g. bites / stings) Fentanyl Intentional - Misuse 3 3/2/12 19455103222012 NULL Male 1 1 Solid (tablets / capsules / caplets) NULL Unknown Fentanyl Intentional - Abuse 4 3/16/12 5079873332012 37 Female 1 1 Patch NULL Unknown Fentanyl Intentional Suspected suicide Major effect 5 3/18/12 20752222375201 2 30 Male 1 1 Solid (tablets / capsules / caplets) 2 each (e.g. bites / stings) Fentanyl Intentional Suspected suicide Unable to follow, judged as a potentially toxic exposure 6 3/28/12 4109423642012 36 Male 1 4 Cream / lotion / gel NULL Unknown Fentanyl Intentional - Abuse Death, indirect report Solid (tablets / capsules / caplets) NULL Unknown Benzodiazepines Intentional - Abuse Death, indirect report 7 8 Fentanyl Intentional Unknown Medical Outcome Unable to follow, judged as a potentially toxic exposure Not followed, minimal clinical effects possible (no more than minor effect possible) Not followed, minimal clinical effects possible (no more than minor effect possible) Not followed, minimal clinical effects possible (no more than minor effect possible) Unable to follow, judged as a potentially toxic exposure 3/28/12 4109423642012 36 Male 2 4 3/28/12 4109423642012 36 Male 3 4 Unknown NULL Unknown Cocaine Intentional - Abuse Death, indirect report NULL Unknown Benzodiazepines Intentional - Abuse Death, indirect report 3/28/12 4109423642012 36 Male 4 4 Solid (tablets / capsules / caplets) 4/14/12 30352563582012 21 Female 1 4 Powder / granules NULL Unknown Fentanyl 4/14/12 30352563582012 21 Female 2 4 Solid (tablets / capsules / caplets) NULL Unknown Hydromorphone NULL Unknown Other Types of Sedative/Hypnotic/ Anti-Anxiety or AntiPsychotic Drug NULL Unknown Benzodiazepines NULL Unknown Hydromorphone 4/14/12 30352563582012 21 Female 3 4 4/14/12 30352563582012 21 Female 4 4 4/18/12 10170303722012 34 Female 1 3 Solid (tablets / capsules / caplets) Solid (tablets / capsules / caplets) Solid (tablets / capsules / caplets) Page 70 of 70 Intentional Suspected suicide Intentional Suspected suicide Intentional Suspected suicide Intentional Suspected suicide Intentional Suspected suicide Major effect Major effect Major effect Major effect Moderate effect FDA_74 a: .- September 18, 2013 Food and Drug Administration Center for Drug Evaluation and Research Central Document Room Drug Master File Staff Ammendale Road Beltsville, MD 20705?1266 Re: DMF 027320 Holder: McKesson Specialty Health (McKesson) DMF Subject: Transmucosal Immediate Release Fentanyl (TIRF) Access Program Re: REMS Shared Program DMF Type: DMF Submission Information: Clinical/Clinical Information REMS Submission Identi?er: Assessment Sequence Number: 0005 Dear Drug Master File Staff: This Type DMF contains the Risk Evaluation and Mitigation Strategy (REMS) for Transmucosal Immediate Release Fentanyl for the Shared System REMS program. As agreed upon during the Agency?s teleconference held on July 31, 2013, the final historical document for the REMS Assessment 2 at 12 months would be submitted as a separate sequence (0005). McKesson states that information provided in this Master File is current and assures that the material furnished will meet the speci?cations described herein. McKessou also con?rms that the Holder obligations are observed. We request that all information in this ?le be treated as con?dential commercial information to the Food and Drug Administration pursuant to 21 C.F.R. ?20.61, and that no information from this ?le be provided to any unauthorized persons without written consent. If you have any questions or concerns, please do not hesitate to contact Jann Kochel, US. Agent for McKesson, at 610?535?6500, ext. 5572 or alternatively via email at jann.a.kochel@accenture.com. (?Mg?Sincerely, {Llano A. Kochel, US. Agent Accenture, LLP 585 East Swedesford Road Wayne, PA 19087 Attachments: Table of Contents for the submission Electronic Submission Speci?cations DMF #027320; Sequence 0005 Shared System REMS Table of Contents Page 1 of 1 Assessment – 12 Months Module Section Description 1.2 Cover Letter Cover Letter w/ Attachments Administrative Information Page 1.16 – Risk Management Plans REMS History REMS Assessment – 12 Months FDA_76 Electronic Submission Specifications This submission is compliant with FDA's Guideline for Industry: Providing Regulatory Submissions in Electronic Format - Human Pharmaceutical Product Applications and Related Submissions Using the eCTD Specifications (June 2008). All files were checked and verified to be free of viruses prior to transmission through the electronic submission gateway. This eCTD has been generated by Accenture, LLP (formerly Octagon Research Solutions Inc.), who has filed an acceptable eCTD pilot with the Center (Pilot Number 900777). Anti-Virus Program Program Version Virus Definition Date Submission Size Symantec Endpoint Protection Edition 11.0.5002.333 09/11/2013 rev. 4 Approx. 1 MB The IT point of contact for this submission is: Name Phone Number Email Address Matt Francis 610-535-6500 ext. 5665 Matthew.p.francis@accenture.com FDA_77 ADMINISTRATIVE INFORMATION Holder’s Name: McKesson Specialty Health (McKesson) Holder’s Address: 4343 N. Scottsdale Road Suite 150 Scottsdale, AZ 85251 Holder’s Contact Person: Laura Baloun Contact’s Address: 4343 N. Scottsdale Road Suite 150 Scottsdale, AZ 85251 Contact’s Phone: 480-663-4009 Contact’s Fax: 480-663-4973 Contact’s Email address: laura.baloun@mckesson.com Statement of Commitment: Attached, please find a signed statement of commitment. The statement certifies that the DMF is current and that McKesson will comply with the statements made in it. Agent’s Name: Accenture, LLP Agent’s Address: 585 East Swedesford Road Wayne, PA 19087 Agent’s Contact Person: Jann A. Kochel Contact’s Address 585 East Swedesford Road Wayne, PA 19087 Contact’s Phone: 610-535-6500, ext. 5572 Contact’s Fax: 610-535-6515 Contact’s E-mail address: jann.a.kochel@accenture.com FDA_78 DMF #027320; Sequence 0005 Shared System REMS Modification Date Approved Documents Affected No. 1 June 5, 2012 x REMS x Prescriber Program Overview x Education Program x Prescriber Enrollment Form x Patient Provider Agreement Form x Patient and Caregiver Overview x Dear Healthcare Provider Letter x Outpatient Pharmacy Overview x Chain Pharmacy Overview x Inpatient Pharmacy Overview x Outpatient Pharmacy Enrollment Form x Chain Pharmacy Enrollment Form x Inpatient Pharmacy Enrollment form x Outpatient Pharmacy Letter x Inpatient Pharmacy Letter x Dear Distributor Letter x Distributor Enrollment Form x Supporting Document N/A N/A Assessment Report 1 at 6 months – due 06/28/2012 2 Approval Draft Documents Pending submitted on or before REMS History Page 1 of 2 Overview of Modification Sequence 0002: Edits to Patient-Prescriber Agreement Form, the addition of the Closed System Pharmacy Enrollment Form*, the addition of the newly approved TIRF product, Subsys (fentanyl sublingual spray) and minor editorial changes. *The Closed System Pharmacy Enrollment Form was not formally submitted through the Gateway but was submitted via email on May 18, 2012 and included in the June 5, 2012 FDA approval letter. Sequence 0003: Assessment report covering 12/28/2011 to 04/27/2012 Sequence 0004: Modification proposed to: FDA_79 DMF #027320; Sequence 0005 Shared System REMS N/A N/A REMS History Page 2 of 2 09/28/2012 x Chain Pharmacy Enrollment Form x Outpatient Pharmacy Enrollment Form x Closed System Pharmacy Overview x Education Program x Frequently Asked Questions (FAQ) x Outpatient Pharmacy Letter x REMS x Supporting Document Assessment Report 2 at 1 year – due 12/28/2012 x Incorporate closed system pharmacies into the TIRF REMS Access Program x Correct minor inconsistencies between the FDA provided versions and the current PDF versions of REMS materials Sequence 0005: Assessment report covering 04/28/2012 to 10/28/2012 FDA_80 Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies. December 2012 12-month REMS Assessment Report Title: Transmucosal Immediate Release Fentanyl (TIRF) Risk Evaluation and Mitigation Strategy (REMS) Access Program 12-month Assessment Report Document Number: Final Version 1.0 Product Name: Transmucosal Immediate Release Fentanyl Sponsor: TIRF REMS Industry Group (TRIG) of Companies: Archimedes Pharma US Inc. Cephalon, Inc. (a wholly-owned subsidiary of Teva Pharmaceutical Industries, Ltd.) Insys Therapeutics Inc. Meda Pharmaceuticals Mallinckrodt Inc. (the Pharmaceuticals Business of Covidien) Par Pharmaceutical, Inc. ProStrakan, Inc.   Confidentiality Statement The information contained herein is confidential and the proprietary property of the TRIG of Companies and its affiliates, and any unauthorized use or disclosure of such information without the prior written authorization of the TRIG is expressly prohibited. FDA_81 Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies. December 2012 12-month REMS Assessment Report TABLE OF CONTENTS Pg LIST OF TABLES ................................................................................................................... 5  LIST OF FIGURES ................................................................................................................. 6  LIST OF ABBREVIATIONS ................................................................................................. 7  EXECUTIVE SUMMARY ..................................................................................................... 8  1  BACKGROUND ........................................................................................................ 11  1.1  Reporting Period ..................................................................................................... 12  REMS GOALS ........................................................................................................... 13  2.1  The TIRF REMS Access Program Transition Plan: From Individual to Shared REMS ...................................................................................................................... 13  SUPPORTING INFORMATION ON PROPOSED REMS ELEMENTS ........... 13  2  3  3.1  Additional Elements ................................................................................................ 14  3.1.1  Medication Guide ............................................................................................ 14  3.1.2  Letters to Healthcare Professionals.................................................................. 14  3.2  Elements to Assure Safe Use (ETASU) .................................................................. 14  3.2.1  Prescription Verification .................................................................................. 15  3.3  Implementation System........................................................................................... 16  3.3.1  Wholesaler/Distribution Enrollment and Fulfillment ...................................... 16  3.3.2  The TIRF REMS Access Program Compliance .............................................. 16  3.3.3  TIRF REMS Access Program Call Center ...................................................... 17  4  REMS ASSESSMENT PLAN METHODS ............................................................. 17  4.1  Data Sources ........................................................................................................... 17  4.1.1  TIRF REMS Access Program Outreach .......................................................... 17  4.1.2  The TIRF REMS Access Program and Product Utilization Statistics ............. 17  4.1.3  Program Infrastructure and Performance ......................................................... 18  4.1.4  Safety Surveillance .......................................................................................... 19  4.2  TIRF REMS Access Program Non-Compliance Plan ............................................ 20  4.2.1  Corrective Action Measures ............................................................................ 20  5  RESULTS ................................................................................................................... 20  5.1  TIRF REMS Access Program Outreach ................................................................. 20  5.1.1  Dear Healthcare Professional Letters [Metric 1-4] .......................................... 20  5.2  REMS Program Utilization ..................................................................................... 20  5.2.1  Patient Enrollment [Metric 5 and 6] ................................................................ 20  5.2.2  Prescriber Enrollment, Inactivation, and Education [Metric 7, 8, 9] ............... 27  5.2.3  Pharmacy Enrollment, Inactivation, and Education [Metric 10, 11, 12] ......... 32  5.2.4  Dispensing Activity [Metric 13 and 14] .......................................................... 38  5.2.5  Wholesaler/Distributor Enrollment [Metric 15 and 16] .................................. 40  5.2.6  Barriers or Delays in Patient Access [Metric 17 and 18] ................................ 41  FDA_82 Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies. December 2012 12-month REMS Assessment Report 5.3  Program Infrastructure and Performance [Metrics 19, 20, 21, 22, 23, 24] ............. 46  5.3.1  Pharmacy Management Systems [Metric 19] .................................................. 46  5.3.2  Backup System for Prescription Validation [Metric 20] ................................. 48  5.3.3  REMS Call Center [Metric 21a, b] .................................................................. 48  5.4  System Errors and Corrective Actions [Metric 22] ................................................ 50  5.4.1  Lack of Enrolled Prescribers and/or Pharmacies for Patients [Metric 23] ...... 53  5.4.2  Delays after Prescription Denial [Metric 24] ................................................... 53  5.5  Unintended System Interruptions [Metrics 25, 26, 27, 28] ..................................... 53  5.5.1  Inadvertent Enrollment Deactivations [Metric 25] .......................................... 53  5.5.2  Reports of False Positives [Metric 26] ............................................................ 54  5.5.3  Failure of Re-enrollment Notifications [Metric 27] ........................................ 54  5.5.4  Reports of False Negatives [Metric 28] ........................................................... 54  5.6  6  Audits ...................................................................................................................... 54  TIRF REMS ACCESS PROGRAM NON-COMPLIANCE ................................. 54  7  SAFETY SURVEILLANCE ..................................................................................... 56  7.1  Adverse Events ....................................................................................................... 56  7.2  American Association of Poison Control Centers (AAPCC) ................................. 60  PERIODIC SURVEYS OF STAKEHOLDERS ..................................................... 71  8  8.1  Patient KAB Survey ................................................................................................ 71  8.1.1  Survey Statistics ............................................................................................... 71  8.1.2  Demographics and Respondent Characteristics ............................................... 72  8.1.3  TIRF Educational Materials............................................................................. 72  8.1.4  Patient Survey Results ..................................................................................... 72  8.1.4.1  Key Risk Message 1 .................................................................................... 72  8.1.4.2  Key Risk Message 2 .................................................................................... 72  8.1.4.3  Key Risk Message 3 .................................................................................... 73  8.1.4.4  Key Risk Message 4 .................................................................................... 73  8.1.4.5  Key Risk Message 5 .................................................................................... 73  8.1.4.6  Key Risk Message 6 .................................................................................... 73  8.1.5  Additional Safety Questions about TIRF Medicines Safety ............................ 74  8.2  Pharmacy KAB Survey ........................................................................................... 74  8.2.1  Survey Statistics ............................................................................................... 74  8.2.2  Demographic and Respondent Characteristics ................................................ 75  8.2.3  TIRF Educational Materials............................................................................. 75  8.2.4  Pharmacy Survey Results ................................................................................ 75  8.2.4.1  Key Risk Message 1 .................................................................................... 76  8.2.4.2  Key Risk Message 2 .................................................................................... 76  8.2.4.3  Key Risk Message 3 .................................................................................... 76  8.2.4.4  Key Risk Message 4 .................................................................................... 76  8.2.5  Additional Safety Questions about TIRF Medicines Safety ............................ 77  8.2.6  Pharmacist Activities When Dispensing TIRF Medicines .............................. 77  8.3  Prescriber KAB Survey ........................................................................................... 77  FDA_83 Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies. December 2012 12-month REMS Assessment Report 8.3.1  Survey Statistics ............................................................................................... 77  8.3.2  Demographics and Respondent Characteristics ............................................... 78  8.3.3  TIRF Educational Materials............................................................................. 78  8.3.4  Prescriber Survey Results ................................................................................ 79  8.3.4.1  Key Risk Message 1 .................................................................................... 79  8.3.4.2  Key Risk Message 2 .................................................................................... 79  8.3.4.3  Key Risk Message 3 .................................................................................... 79  8.3.4.4  Key Risk Message 4 .................................................................................... 79  8.3.5  Additional Questions About TIRF Medicines Safety ...................................... 80  8.3.6  Prescriber Activities When Prescribing TIRF Medicines................................ 80  8.4  9  Overall Conclusions for KAB Results .................................................................... 80  FDA COMMUNICATIONS ..................................................................................... 81  10  POST-APPROVAL STUDIES AND CLINICAL TRIALS ................................... 81  11  OVERALL CONCLUSIONS ................................................................................... 81  APPENDICES ........................................................................................................................ 84  11.1  Medical Dictionary for Drug Regulatory Activities (MedDRA) Preferred Terms . 85  11.2  AAPCC LISTINGS................................................................................................. 90  11.3  TRIG AERS Safety Surveillance Analysis Report ................................................. 96  11.4  Periodic Stakeholder Surveys ...............................................................................115  11.4.1  Patient KAB Survey.......................................................................................116  11.4.2  Pharmacy KAB Survey ..................................................................................303  11.4.3  Prescriber KAB Survey .................................................................................427  FDA_84 Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies. December 2012 12-month REMS Assessment Report LIST OF TABLES Table 1:  Table 2:  Table 3:  Table 4:  Table 5:  Table 6:  TIRF Medicines ............................................................................................................12  Patient Enrollment and Geographic Distribution ..........................................................21  Patient Enrollment by State According to 2010 US Census .........................................24  Prescriber Enrollment ...................................................................................................28  Prescriber Inactivations .................................................................................................31  Enrolled Prescriber Completed Knowledge Assessments and Number of Attempts to Complete ...................................................................................................................32  Table 7:  Pharmacy Enrollment ....................................................................................................33  Table 8:  Reasons for Pharmacy Inactivations .............................................................................37  Table 9:  Enrolled Authorized Pharmacist/Pharmacy Knowledge Assessments and Attempts Needed to Complete ......................................................................................................38  Table 10:  Authorized Prescriptions Dispensed from Outpatient Pharmacies ...............................39  Table 11:  Total Number of Prescriptions Rejected for Safety ......................................................40  Table 12:  Wholesaler/Distributor Enrollment ...............................................................................41  Table 13:  Submission of Patient-Prescriber Agreements to the REMS Program .........................42  Table 14:  Prescriptions Dispensed During the First 10 Days after Patient Enrollment ................44  Table 15:  Configuration of Pharmacy Management System (PMS).............................................47  Table 16:  Reasons and Frequency for Contacting the Call Center ...............................................48  Table 17:  Pending/Open Reports from Prior Reporting Period: 28 December 2011 to 27 April 2012 .....................................................................................................................54  Table 18  Reports in the Current Reporting Period: 28 April 2012 to 28 October 2012 .............55  Table 19:  Count of Reported Events of Interest Grouped by TRIG Category: Second Quarter 2012 ...............................................................................................................................57  Table 20:  Site of Call and Site of Exposure, Human Exposure Cases Associated with TIRF Medicines: 28 April 2012 to 28 October 2012..............................................................61  Table 21:  Age and Gender Distribution of Human Exposures Associated with TIRF Medicines: 28 April 2012 to 28 October 2012..............................................................62  Table 22:  Number of Substances Involved in Human Exposure Cases Associated with TIRF Medicines or a Fentanyl with Oral or Inhalation as Route of Exposure: 28 April 2012 to 28 October 2012 ...............................................................................................63  Table 23:  Reason for Human Exposure Cases Associated with TIRF Medicines: 28 April 2012 to 28 October 2012 ...............................................................................................64  Table 24:  Distribution of Therapeutic Errorsa by Age Associated with TIRF Medicines: 28 April 2012 to 28 October 2012 .....................................................................................65  Table 25:  Distribution of Reason for Exposure by Age Associated with TIRF Medicines: 28 April 2012 to 28 October 2012 .....................................................................................67  Table 26:  Route of Exposure for Human Exposure Cases: 28 April 2012 to 28 October 2012 ..68  Table 27:  Medical Outcome of Human Exposure Cases by Patient Age: 28 April 2012 to 28 October 2012 .................................................................................................................69  Table 28:  Medical Outcome by Reason for Exposure in Human Exposures: 28 April 2012 to 28 October 2012 ............................................................................................................70  FDA_85 Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies. December 2012 12-month REMS Assessment Report LIST OF FIGURES Figure 1:  PPAF Receipt by Time Since Patient Enrollment (28APR2012 to 28OCT2012) ....... 43  Figure 2:  Number of Patients Dispensed a Prescription During the First 10 Days After Patient Enrollment (28APR2012 to 28OCT2012). ................................................................... 45    FDA_86 Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies. December 2012 12-month REMS Assessment Report LIST OF ABBREVIATIONS AAPCC AERS American Association of Poison Control Centers Adverse Event Reporting System BTP CSR DEA ETASU KAB FDA MedDRA Breakthrough Pain Center Service Representative Drug Enforcement Administration Elements to Assure Safe Use Knowledge, Attitude, and Behavior Food and Drug Administration Medical Dictionary for Drug Regulatory Activities NCPDP NDC NPI NCRT PMS PPAF REMS REMS edits SMQ SOP TIRF National Council for Prescription Drug Program National Drug Code National Provider Identifier Non-Compliance Review Team Pharmacy Management System Patient-Prescriber Agreement Form Risk Evaluation and Mitigation Strategy Checks conducted by the TIRF REMS Access program to confirm that all safety requirements were met Standardized MedDRA Query Standard Operating Procedure Transmucosal Immediate Release Fentanyl TIRF Medicines Transmucosal Immediate Release Fentanyl product(s) TIRF REMS Access REMS program for TIRF medicines TIRF Sponsors The group of sponsors that are submitting this REMS TRIG TIRF REMS Industry Group UBC United BioSource Corporation US United States FDA_87 Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies. December 2012 12-month REMS Assessment Report EXECUTIVE SUMMARY The Transmucosal Immediate Release Fentanyl (TIRF) Risk Evaluation Mitigation Strategy (REMS) Access program was approved by the Food and Drug Administration (FDA) on 28 December 2011 for ABSTRAL®, ACTIQ®, FENTORA®, LAZANDA®, ONSOLIS® and generic versions of these TIRF medicines. On 04 January 2012, the FDA approved the inclusion of SUBSYS® to the TIRF REMS Access program. The TIRF REMS Access program was successfully launched on 12 March 2012, approximately 11 weeks after REMS approval. The initial REMS Assessment report was submitted on 28 June 2012 (cut-off date of 27 April 2012). This second REMS Assessment report covers the period from 27 April 2012 to 28 October 2012. Upon launch of the TIRF REMS Access program, stakeholders (distributors, pharmacies, and prescribers) that had been enrolled in an individual REMS program were transitioned to the TIRF REMS Access program. The opportunity to transition into the TIRF REMS Access program from an individual REMS program ended on 12 September 2012. There were no new “Dear Healthcare Professional Letter” mailings in this reporting period; however, 42 letters were returned that had been mailed during the initial reporting period including 7 Dear Healthcare Professional letters and 35 Pharmacist letters (33 outpatient and 2 inpatient pharmacies). Stakeholder enrollment (transitioned and newly enrolled) in the TIRF REMS Access program during the current reporting period included 1,862 prescribers and 2,595 pharmacies. No wholesaler/distributors enrolled during the current reporting period. Additionally, 4,290 patients were enrolled who had prescription activity during the current reporting period. Implementation of the TIRF REMS Access program for closed system pharmacies (integrated healthcare systems with outpatient pharmacy management systems [PMS] unable to support the electronic transmission for required validation and claims), was launched on 30 June 2012. No wholesalers/distributors were inactivated during the reporting period. A total of 6 pharmacies were inactivated due to opting out of the TIRF REMS Access program (2 inpatient, 33.3%; 4 outpatient, 66.7%). A total of 445 prescribers were inactivated with 98.7% due to expiration of enrollment period. There were 143 incomplete prescriber enrollment forms received. The majority of incomplete forms were incomplete due to missing physician signature date (45.5%), missing signature (45.5%), and missing e-mail (18.2%). There were 61 incomplete pharmacy enrollments attempts via fax, mostly due to invalid Drug Enforcement Administration (DEA) number (4.9%), missing DEA number (3.3%), invalid National Provider Identifier (NPI; 1.6%), invalid National Council for Prescription Drug Program (NCPDP; 1.6%), and missing state license number (1.6%). Of 658 outpatient pharmacies that attempted to configure a PMS, 96.5% successfully configured their systems in a mean of 2.49 days (min/max; 0.0002 days/189.97 days). FDA_88 Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies. December 2012 12-month REMS Assessment Report A total of 54,614 prescriptions were adjudicated for safety by the TIRF REMS Access program and 96.3% of those prescriptions were subsequently approved for dispensing. There were 505 patients who had 3 or more prescribers in a rolling 6-month period. Patients may have multiple prescribers for various reasons such as patient relocation, prescriber relocation/retirement/death, or patient is seen at a single practice with multiple prescribers. A total of 7,444 prescriptions were dispensed to 4,244 patients during the first 10 days after patient enrollment (i.e., enrollment occurred when first prescription was filled). There were a greater number of patients who had their first prescription filled in the first 10 days without a Patient-Prescriber Agreement Form (PPAF) compared with those patients with a PPAF (71.4% vs. 14.2%). For patients without a PPAF, the majority of patients (80.0%) received only 1 fill. A total of 11,313 prescription claims were rejected because the claim failed to meet REMS requirements for prescriber and/or patient and/or pharmacy. A single prescription may have been submitted and rejected multiple times. The majority of rejection reasons were due to prescriber not enrolled or prescriber ID entered was not found in the TIRF REMS Access database (44.8%), PPAF incomplete (22.2%), patient zip code missing from claim (17.3%), prescriber last name did not match name registered (15.2%), and pharmacy not enrolled (8.3%). The TIRF REMS Access program Call Center was contacted most frequently for the following reasons: pharmacy:pharmacy claim rejection (15.1%), enrollment status inquiry (14.1%), prescriber:pharmacy claim rejection (11.7%), PPAF follow up or status inquiry (20.9%). There were no reports from patients of inability to find an enrolled pharmacy. There were no reports from patients of an inability to find an enrolled prescriber. No reports of inadvertent enrollment deactivations were identified; 2 reports concerning confirmed or potential noncompliant activity; and 7 issues were identified as system errors. During the current reporting period, 36 FDA Adverse Event Reporting System (AERS) case reports in the United States (US) were associated with a TIRF medicine exposure. Twentyseven (27) of the cases included one of the individual Preferred Terms (PT) of Interest for the TIRF REMS or at least one PT from the Medical Dictionary for Drug Regulatory Activities (MedDRA) standardized MedDRA Query (SMQ), Acute Central Respiratory Depression. There were 11 cases of exposure to known oral fentanyl immediate-release medicines reported to the American Association of Poison Control Centers (AAPCC) during the current reporting period. No deaths were reported for exposures to TIRF medicines. There were 3 pediatric exposures reported for TIRF medicines, including 1 minor effect and 1 no effect in children <6 years of age, and a moderate effect in a teenager who was 13 to 19 years of age. Twelve cases of exposure to unknown fentanyl were reported to the AAPCC during the current reporting period. The cases had medical outcomes of 7 deaths (indirect reports), 2 moderate effects, 1 minor effect, 1 unable to follow/judged as potentially toxic exposure, and 1 no effect. There were no pediatric exposures. The patient Knowledge, Attitude, and Behavior (KAB) survey showed that the ongoing patientoriented educational process is meeting its objectives in that the majority of patients completing the survey were aware of the key safety issues related to their use of a TIRF medication. FDA_89 Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies. December 2012 12-month REMS Assessment Report In the prescriber and pharmacist KABs, a minority of prescribers and pharmacists correctly indicated that patients considered opioid tolerant are those who are taking regular opioid therapy for one week or longer (12.6% pharmacists and 7.9% prescribers). Few prescribers and pharmacists correctly indicated patients not currently taking opioid therapy but who have unknown intolerance or hypersensitivity to fentanyl are not considered opioid tolerant (15.6%, for prescribers and pharmacists). Because both pharmacists and prescribers had low correct response rates for both of these questions, and because the high correct response rates for the other related risk messages, including other questions about opioid tolerance, this may possibly indicate a challenge in understanding the questions and not a knowledge issue. Additional research will be conducted to explore these results. The outcome of the research will be included in the next assessment report, and, based on the outcome, appropriate action may be taken. Across the surveys for all key risk messages both pharmacists and prescribers demonstrated a high level of understanding that TIRF medicines are contraindicated in opioid non-tolerant patients, are only indicated for the management of breakthrough pain in adult patients with cancer, contain fentanyl with abuse liability similar to other opioid analgesics, and are not interchangeable with each other regardless of route of administration. FDA_90 Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies. 1 December 2012 12-month REMS Assessment Report BACKGROUND Opioids remain the mainstay of treatment of moderate to severe pain, but their safe use requires careful consideration of proper patient selection and treatment characteristics in order to mitigate any inherent health risks. Opioids are formulated as both extended release and immediate release products. Extended release or long acting opioid products are designed to provide extended analgesic activity to control persistent pain. Transmucosal immediate release fentanyl products (“TIRF medicines”) and short-acting opioid products have a rapid onset and short duration of action and are designed for the treatment of acute episodes of pain that ‘break through’ the chronic pain control (breakthrough pain, BTP). All the TIRF medicines are short acting fentanyl products. Fentanyl, an opioid agonist and a Schedule II controlled substance, is approximately 100-fold more potent than morphine as an analgesic. 1 Secondary effects of fentanyl on central nervous system, respiratory and gastrointestinal functions are typical of opioid analgesics and are considered to be an effect. 2 As with all high-potency opioid analgesics, there are significant potential risks associated with the use and misuse of TIRF medicines, including acute respiratory depression which may lead to death. With appropriate clinical use in opioid-tolerant patients these risks have been shown to be low. However, instances of diversion, overdose and prescribing to opioid-non-tolerant patients have led to serious and on occasion fatal, adverse events demonstrating that shortacting fentanyl products can pose a health risk if not used appropriately. The FDA has determined that a REMS is required to mitigate the risk of misuse, abuse, addiction, overdose, and serious complications due to medication errors with the use of TIRF medicines. The TIRF REMS Access program was approved by the FDA on 28 December 2011 for ABSTRAL, ACTIQ, FENTORA, LAZANDA, ONSOLIS and generic versions of these TIRF medicines. On 04 January 2012, the FDA approved the inclusion of SUBSYS to the TIRF REMS. The group of Sponsors that are submitting this REMS (Archimedes Pharma US Inc., Cephalon, Inc. [a wholly-owned subsidiary of Teva Pharmaceutical Industries, Ltd.], Insys Therapeutics Inc., Meda Pharmaceuticals, Mallinckrodt Inc. [the Pharmaceuticals Business of Covidien], Par Pharmaceutical, Inc., and ProStrakan, Inc.) are hereafter referred to as the TIRF Sponsors. At the time of protocol development for the Knowledge, Attitude, and Behavior (KAB) surveys, Sandoz was also a member of the group of TIRF Sponsors; however Sandoz 1 Biedrzycki OJ, Bevan D, Lucas S, Fatal overdose due to prescription fentanyl patches in a patient with sickle cell/beta- thalassemia and acute chest syndrome: A case report and review of the literature. Am J Forensic Med Pathol. 2009 Jun; 30(2): 188-90 2 Simpson DM, Messina J, Xie F, Hale M. Fentanyl buccal tablet for the relief of breakthrough pain in opioid-tolerant adult patients with chronic neuropathic pain: a multicenter, randomized, double-blind, placebo-controlled study. Clin Ther. 2007 Apr; 29(4):588-601. FDA_91 Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies. December 2012 12-month REMS Assessment Report terminated their involvement in the TIRF REMS Access program, effective 15 September 2012. The TIRF REMS Access program is administered by McKesson Specialty Health and RelayHealth. This report is prepared by United BioSource Corporation (UBC). The TIRF medicines that are the subject of this TIRF REMS are shown in Table 1 below. Table 1: TIRF Medicines Product Name (active ingredient)/formulation NDA 022510, ABSTRAL (fentanyl) sublingual tablets NDA 020747, ACTIQ (fentanyl citrate) oral transmucosal lozenge and its authorized generic NDA 021947, FENTORA (fentanyl citrate) buccal tablet NDA 022569, LAZANDA (fentanyl) nasal spray NDA 022266, ONSOLIS (fentanyl), buccal soluble film NDA 202788, SUBSYS (fentanyl sublingual spray) ANDA 077312, fentanyl citrate oral transmucosal lozenge ANDA 078907, fentanyl citrate oral transmucosal lozenge The TIRF REMS Access program addresses the current requirements set forth by the FDA provided to TIRF Sponsors. The program will be monitored over time and modified when and where appropriate. 1.1 Reporting Period The initial REMS was approved on 28 December 2011 and went live on 12 March 2012. FDA requires an initial report 6 months after initial approval; therefore, the first report was submitted on 28 June 2012 with a cut-off date of 27 April 2012. For this 12-month reporting period the cut-off date was 28 October 2012 thereby allowing 60 days to prepare this report for the FDA, which is due on 28 December 2012. Data cutoffs include all data and information available from the start of the reporting period up to the end of each reporting period to allow for programming, analysis, and report writing. Reports are scheduled for completion according to the following schedule: Reports Reporting Interval Date Sent to FDA 6 months REMS Assessment 12/28/2011 - 04/27/2012 06/28/2012 12 months REMS Assessment 04/28/2012 - 10/28/2012 12/28/2012 24 months REMS Assessment* 10/29/2012 - 10/28/2013 12/28/2013 *Annually thereafter FDA_92 Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies. 2 December 2012 12-month REMS Assessment Report REMS GOALS The goals of the TIRF REMS Access program are to mitigate the risk of misuse, abuse, addiction, overdose and serious complications due to medication errors by: 1. Prescribing and dispensing TIRF medicines only to appropriate patients, which includes use only in opioid-tolerant patients. 2. Preventing inappropriate conversion between TIRF medicines. 3. Preventing accidental exposure to children and others for whom it was not prescribed. 4. Educating prescribers, pharmacists, and patients on the potential for misuse, abuse, addiction, and overdose of TIRF medicines. 2.1 The TIRF REMS Access Program Transition Plan: From Individual to Shared REMS Upon launch of the TIRF REMS Access program on 12 March 2012, all stakeholders (distributors, pharmacies, and prescribers) enrolled in an individual TIRF product REMS program were transitioned to the TIRF REMS Access program. From this point onward, all new stakeholders were required to enroll in the TIRF REMS Access program. Pharmacies enrolled in individual REMS programs were required to re-new their Terms & Conditions as part of enrolling in the TIRF REMS Access program. Pharmacies that did not complete this action by 12 September 2012 were not transitioned into the TIRF REMS Access program. Metrics that include transitioned stakeholders are so noted within this report. As of 12 September 2012, all stakeholders were required to enroll in the TIRF REMS Access program and could no longer transition into the TIRF REMS Access program from individual REMS programs. 3 SUPPORTING INFORMATION ON PROPOSED REMS ELEMENTS The TIRF Sponsors are executing the TIRF REMS Access program to ensure the appropriate use of TIRF medicines and proper patient selection. All stakeholders subject to the TIRF REMS Access program including patients, prescribers, pharmacists and distributors must be enrolled in the TIRF program, educated on the requirements of the program and required to document that they understood and would abide by the “elements to assure safe use.” Program materials are provided on the TIRF medicines in addition to product-specific materials. The Educational Program and Knowledge Assessment components of the program contain both TIRF medicine class and product-specific components. All program tools, including enrollment forms, PPAF, stakeholder letters, and overview documents containing program information specific to the TIRF REMS Access program, are available through the www.TIRFREMSACCESS.com Web site. FDA_93 Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies. December 2012 12-month REMS Assessment Report The program procedures are monitored for adherence and the TIRF Sponsors will continue to conduct ongoing and retrospective analysis as necessary to comply with all mandates and to maximize the safe use of the TIRF medicines. 3.1 3.1.1 Additional Elements Medication Guide The product-specific TIRF Medication Guide should be dispensed with each TIRF medicine prescription. Every TIRF medicine has a unique Medication Guide. 3.1.2 Letters to Healthcare Professionals A Communication Plan for the TIRF REMS was not required. However, TIRF Sponsors sent materials to targeted stakeholders to support implementation of the TIRF REMS Access program at the time of program launch. These communications included Dear Healthcare Provider and Dear Pharmacy letters, and informed prescribers and authorized pharmacists on the risks associated with the use of TIRF medicines, the procedures and requirements of the TIRF REMS Access program and means of reporting adverse events. In this reporting period, there were no mailings of either the Dear Healthcare Provider or Dear Pharmacy letters. 3.2 Elements to Assure Safe Use (ETASU) Because of the significant potential health risks associated with prescribing TIRF medicines to opioid non-tolerant patients, it is important that prescribers are aware of the procedures for appropriate patient selection and appropriate dosing and titration. This was achieved by prescriber’s enrollment through a review of the TIRF REMS Access Education Program including the TIRF medicine’s full Prescribing Information, successful completion of the Knowledge Assessment, and completion of the enrollment form. TIRF medicines are only to be available through the TIRF REMS Access program to reduce the risks of inappropriate patient selection and ensure appropriate dosing and administration of TIRF medicines. To ensure that TIRF medicines were only dispensed to appropriate patients, pharmacies are enrolled into the TIRF REMS Access program. There was a different set of enrollment requirements for outpatient pharmacies (e.g. retail, mail order, institutional outpatient pharmacies that dispense for outpatient use) and inpatient pharmacies (e.g. hospitals that dispense for inpatient use only). For Long-Term Care and Hospice patients whose prescriptions were obtained through an outpatient pharmacy setting, the pharmacy, patient, and prescriber were enrolled in the TIRF REMS Access program. Implementation of the TIRF REMS Access program for closed system pharmacies was launched on 30 June 2012. Closed System Pharmacies are integrated healthcare systems that dispense for outpatient use with pharmacy management systems unable to support the process of electronically transmitting the validation and claim information required. Outpatient pharmacy enrollment required an authorized pharmacist at the pharmacy to undergo enrollment through review of the TIRF REMS Access Education Program and successful FDA_94 Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies. December 2012 12-month REMS Assessment Report completion of the Knowledge Assessment on behalf of the pharmacy and submission of a completed and signed TIRF REMS Access program enrollment form. The authorized pharmacist ensured the pharmacy enabled their pharmacy management system (PMS) to support communication with the TIRF REMS Access program using established telecommunication standards. This required standardized validation test transactions to validate the system enhancements. The authorized pharmacist was responsible for educating all pharmacy staff who participated in dispensing TIRF medicines on the risks associated with TIRF medicines and the requirements of the TIRF REMS Access program. This training was to be documented and is subject to an audit. For inpatient pharmacy enrollment, the authorized pharmacist underwent the TIRF REMS Access Education program, successfully completed the Knowledge Assessment, and submitted a completed and signed enrollment form on behalf of the pharmacy. The authorized inpatient pharmacist acknowledged that they understood that outpatient pharmacies within their facility were to be separately enrolled. For chain pharmacies, an authorized chain pharmacy representative completed enrollment. The authorized chain pharmacy representative acknowledged that training would occur for all pharmacy staff involved in the dispensing of TIRF medicines. Once the TIRF REMS Access Education program and Knowledge Assessment were completed, the authorized chain pharmacy representative, on behalf of the chain, was required to acknowledge their understanding of the appropriate use of TIRF medicines and to agree to adhere to the TIRF REMS Access program requirements by submitting a completed and signed enrollment form. Patients were enrolled in the TIRF REMS Access program when their first prescription was processed at the pharmacy. A completed PPAF needed to be sent to the TIRF REMS Access program by the prescriber within 10 working days from the processing date of the patient’s first prescription for a TIRF medicine. A maximum of three prescriptions were allowed within 10 working days from when the patient had their first prescription filled. No further prescriptions were dispensed after the 10 working day window until a completed PPAF was received. A patient’s healthcare provider can submit a copy of the PPAF to the TIRF REMS Access program via the Web site, fax, or US mail. In some cases, a PPAF may never be received if the patient received only one prescription without a PPAF and never attempted to fill another prescription, or the patient subsequently died 3.2.1 Prescription Verification Following initial patient enrollment on processing of a patient’s first TIRF medicine prescription, pharmacies verified for all subsequent prescriptions that both the prescriber and patient were enrolled in the TIRF REMS Access program prior to dispensing. Prescription verification was not required for inpatient use of TIRF medicines. Prescription verification occurs through a model that uses a pharmacy billing claim and engages a switch provider in the validation process. On receipt of a prescription for a TIRF medicine at an enrolled pharmacy, the pharmacist entered the prescription details in their PMS and sent the transaction to the TIRF REMS Access FDA_95 Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies. December 2012 12-month REMS Assessment Report program via a switch provider. The TIRF REMS Access program used this transaction data to automatically transfer patient details into the TIRF REMS Access database for enrollment. For all prescriptions, the REMS database was then interrogated, via the switch provider, to validate the REMS edits (i.e., met the TIRF REMS Access program requirements). In the case of a valid prescription, a billing request was sent to the payer by the switch provider. Once the payer authorized payment the switch provider then authorized the pharmacy to dispense the TIRF medicine as with a normal prescription, returning an authorization number which was captured by the TIRF REMS Access program. If the prescription was not valid (e.g. one of the stakeholders was not enrolled), the TIRF REMS Access program rejected the claim (prior to the claim being forwarded to the payer) and the pharmacy received a rejection notice from the switch provider. This automated feedback indicated the reason for rejection, instructed the pharmacist not to dispense the TIRF medicine, and notified the pharmacist to contact the TIRF REMS Access program Call Center for further information. 3.3 Implementation System The Implementation System and its components are described in the following sections. 3.3.1 Wholesaler/Distribution Enrollment and Fulfillment Wholesalers/distributors who distribute TIRF medicines must be enrolled in the TIRF REMS Access program before they are allowed to distribute TIRF medicines. For the purpose of the TIRF REMS Access program, the term distributor refers to wholesaler, distributor, and/or chain pharmacy distributor. TIRF medicine distributors received a Dear Distributor Letter describing the TIRF REMS Access program and the requirements to purchase TIRF medicines from TIRF Sponsors and sell TIRF medicines to pharmacies. The distributor’s authorized representative reviewed the distributor program materials. The distributor’s authorized representative must complete and sign the Distributor Enrollment Form and faxed it to the TIRF REMS Access program. TIRF Sponsors did not ship TIRF medicines to any distributor who had not completed and signed the enrollment form. 3.3.2 The TIRF REMS Access Program Compliance TIRF Sponsors monitored prescriber, inpatient and outpatient pharmacy, and wholesaler/distributor activities for compliance with TIRF REMS Access program requirements. Corrective action (e.g., re-education, additional monitoring, process revision, stakeholder inactivation) was instituted by the TIRF Sponsors as appropriate if noncompliance was found. FDA_96 Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies. 3.3.3 December 2012 12-month REMS Assessment Report TIRF REMS Access Program Call Center The TIRF REMS Access program included a Call Center component. The Call Center was staffed by qualified and trained specialists, who provided TIRF REMS Access program support to patients, prescribers, pharmacies, and distributors. 4 REMS ASSESSMENT PLAN METHODS The aim of the TIRF REMS Access program’s evaluation was to assess the effectiveness of the mitigation strategies in meeting the goals of the TIRF REMS Access program to ensure safe use, proper prescribing, and appropriate distribution of TIRF medicines. Findings from these evaluations were used in an effort to improve the processes, as needed. 4.1 Data Sources Data were collected from the following main sources as described in detail below: a) the TIRF REMS Access program outreach (Section 4.1.1), b) TIRF REMS Access product and program utilization statistics (Section 4.1.2), c) program infrastructure and performance (Section 4.1.3), and d) safety surveillance (Section 4.1.4). All programmed source tables and histograms, as well as source data are on file at UBC and available upon request. The individual metrics for each main data source are provided below with a direct link to the results sections of the report. 4.1.1 TIRF REMS Access Program Outreach The following metrics were tabulated for this reporting period to assess program outreach efforts (Section 5.1.1): 1. 2. 3. 4. 4.1.2 Number of Dear HCP letters mailed to prescribers (by date) Number of returned mailings of Dear HCP letters to prescribers. Number of Pharmacist letters mailed to pharmacies (by date) Number of returned mailings of Pharmacist letters to pharmacies The TIRF REMS Access Program and Product Utilization Statistics For the assessment of enrollment, utilization, and discontinuation statistics for prescribers, pharmacies, patients, and wholesalers, the following metrics were tabulated for this reporting period and cumulatively: 5. Number of new patients enrolled by state (Section 5.2.1) 6. Number of patients inactivated (Section 5.2.1) 7. Number of attempts needed for prescribers to successfully complete Knowledge Assessments (Section 5.2.2) o Method of completion 8. Number of new prescribers enrolled by state (Section 5.2.2) o Method of enrollment FDA_97 Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies. December 2012 12-month REMS Assessment Report o Number of incomplete forms and, to extent possible, a brief description of the reason for incomplete data fields 9. Number of prescribers who are inactivated (Section 5.2.2) 10. Number of new pharmacies enrolled by type (inpatient or outpatient), by state (Section 5.2.3) o Method of enrollment o Number of incomplete forms and, to extent possible, a brief description of the reason for incomplete data fields 11. Number of pharmacies that are inactivated by type (inpatient or outpatient) (Section 5.2.3) 12. Number of attempts needed for pharmacies to successfully complete Knowledge Assessments (Section 5.2.3) 13. Dispensing activity for enrolled outpatient pharmacies (Section 5.2.4) o Total number of prescriptions authorized o Total number of prescriptions rejected for safety (description of safety issues and any interventions or corrective actions taken) 14. Summary of cases identified where a patient received prescriptions for a TIRF medicine from multiple prescribers within an overlapping time frame (description of any investigations and the outcome) (Section 5.2.4) 15. Number of wholesalers/distributors inactivated, total (Section 5.2.5) 16. Number of new wholesalers/distributors enrolled (Section 5.2.5) o Method of enrollment o Number of incomplete forms, to extent possible, a brief description of the reason for incomplete data fields 17. Number of days between enrollment and receipt of a PPAF (Section 5.2.6) o Method of PPAF submission 18. Number of prescriptions dispensed per patient during the first 10 days after patient enrollment with and without a PPAF in place. (Section 5.2.6) o A histogram of the number of days between passive enrollment and receipt of a PPAF. Stratify by the method of PPAF submission o A histogram of the number of prescriptions dispensed per patient during the first 10 days after patient passive enrollment stratified by whether there is a PPAF in place. 4.1.3 Program Infrastructure and Performance The following metrics on program infrastructure performance were tabulated for this reporting period and cumulatively: FDA_98 Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies. December 2012 12-month REMS Assessment Report 19. Assessment of process for pharmacies to upgrade their PMS (mean, maximum, and minimum time needed, number of pharmacies that attempted and failed to upgrade their systems) (Section 5.3.1) 20. Number of times a backup system was used to validate a prescription, with reason for each instance (pharmacy level problem, switch problem, or REMS database problem) (Section 5.3.2) 21. Call center report (Section 5.3.3) a. Summary of frequently asked questions b. Problems reported 22. Description of corrective actions taken to address program/system problems (Section 5.4) 23. Number of reports of lack of enrolled prescribers and/or pharmacies in a patient’s area (Section 5.4.1) 24. Delays after original prescriptions are denied by pharmacy and brief summary to include characterization of delays (Section 5.4.2) The following reports for unintended system interruptions were provided for this reporting period: 25. Reports identified of inadvertent enrollment deactivations (Section 5.5.1) 26. Reports of false positives (e.g., all entities not enrolled but system generated a prescription authorization code) (Section 5.5.2) 27. Reports of failure of re-enrollment notifications to reach stakeholders (Section 5.5.3) 28. Reports of false negatives (e.g., all entities enrolled but the system generated a prescription rejection notice), including brief summary of reason for rejection (Section 5.5.4) 4.1.4 Safety Surveillance TIRF Sponsors processed adverse event reports related to their specific products and reported to the FDA according to current regulations outlined in 21 CFR 314.80 and the sponsor’s respective Standard Operating Procedures. Surveillance data from the following sources are included in the REMS Assessment Reports: o FDA adverse event reporting system (AERS) database using signal detection methods for TIRF medicines to identify outcomes of death, overdose, misuse, abuse, addiction, inappropriate prescribing, medication errors, and accidental exposures/ingestion period. See Appendix 11.1 for list of Medical Dictionary for Drug Regulatory Activities (MedDRA) Preferred Terms used. o AAPCC (Appendix 11.2) data for TIRF medicines and unknown fentanyl products with inhalation or ingestion as routes of exposure. FDA_99 Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies. 4.2 December 2012 12-month REMS Assessment Report TIRF REMS Access Program Non-Compliance Plan The TIRF REMS Access program is in place to ensure the safe and appropriate use of TIRF medications. The goal of the non-compliance plan is to ensure that TRIG monitors the functioning of TIRF REMS Access program and identifies and investigates deviations and noncompliance with TIRF REMS requirements in order to ensure patient safety and continuously improve the program. A TIRF REMS Access program Non-Compliance Review Team (NCRT) was created from the companies of the TRIG on 19 October 2012. The NCRT reviews reports of suspected non-compliance with respect to the TIRF REMS Access program requirements. 4.2.1 Corrective Action Measures Stakeholders that fail to comply with one or more elements of the TIRF REMS Access program will be subject to corrective action. Corrective actions resulting from non-compliance will be determined by the TIRF REMS Access program according to the severity of the action. 5 RESULTS 5.1 5.1.1 TIRF REMS Access Program Outreach Dear Healthcare Professional Letters [Metric 1-4] There were no new mailings in this reporting period; however, 42 letters were returned that had been mailed during the previous reporting period including 7 Dear Healthcare Professional letters (Metric 2) and 35 Pharmacist letters (33 outpatient and 2 inpatient pharmacies; Metric 4). 5.2 REMS Program Utilization Described below is the total number and geographic distribution of all enrolled stakeholders (prescribers, patients, distributors, outpatient independent and inpatient pharmacies, corporate chain pharmacy offices and chain pharmacy stores), as well as stakeholder enrollment and inactivations, dispensing activities, and barriers or delays in patient access. 5.2.1 Patient Enrollment [Metric 5 and 6] During the current reporting period, there were 4,290 patients from 49 states (Vermont had no patients enrolled), the District of Columbia and Puerto Rico who were enrolled in the REMS program, i.e., they had prescription activity during the current reporting period (Table 2). The following states had the highest proportion of enrolled patients: California (10.4%), Florida (6.5%), Texas (6.4%), New York (4.1%), New Jersey (3.6%), Alabama (3.2%, and Pennsylvania (2.6%). For 31.6% of patients, state/territory was unknown. Patients enrolled in the TIRF REMS Access program provide consent for data use in reporting then they sign the PPAF; therefore, location cannot be reported on enrolled patients who do not have a PPAF on file. For patients FDA_100 Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies. December 2012 12-month REMS Assessment Report who submitted more than one PPAF, the location is recorded from the first completed PPAF received. There were no patients inactivated during the reporting period (not shown in Table 3; Data Sources: Table 6c: MCK_UBC_TIRF_FDA_Reporting_Enrollment_ Status_ History_110220121036.txt. Table 2: Parameter Patient Enrollment and Geographic Distribution Current Reporting Perioda Cumulativea,b 28APR2012 to 28OCT2012 28DEC2011 to 28OCT2012 N (%) N (%) Number of Newly Enrolled Patientsc State/Territory of Patient Primary Addressd Unknown Alabama Alaska Arizona Arkansas California Colorado Connecticut Delaware Florida Georgia Hawaii Idaho Illinois Indiana Iowa Kansas Kentucky Louisiana Maine Maryland Massachusetts Michigan 4,290 1,357 (31.6%) 138 (3.2%) 6 (0.1%) 55 (1.3%) 32 (0.8%) 446 (10.4%) 66 (1.5%) 39 (0.9%) 8 (0.2%) 278 (6.5%) 80 (1.9%) 3 (0.1%) 5 (0.1%) 72 (1.7%) 48 (1.1%) 6 (0.1%) 27 (0.6%) 17 (0.4%) 16 (0.4%) 1 (<0.1%) 56 (1.3%) 30 (0.7%) 100 (2.3%) 12,071 2,143 (17.8%) 237 (2.0%) 31 (0.3%) 187 (1.6%) 63 (0.5%) 1,507 (12.5%) 280 (2.3%) 148 (1.2%) 52 (0.4%) 898 (7.4%) 266 (2.2%) 18 (0.2%) 24 (0.2%) 288 (2.4%) 176 (1.5%) 31 (0.3%) 97 (0.8%) 75 (0.6%) 52 (0.4%) 12 (0.1%) 222 (1.8%) 95 (0.8%) 322 (2.7%) (continued) FDA_101 Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies. December 2012 12-month REMS Assessment Report Table 2: Patient Enrollment and Geographic Distribution Current Reporting Perioda Cumulativea,b 28APR2012 to 28OCT2012 28DEC2011 to 28OCT2012 Parameter N (%) N (%) Minnesota 7 (0.2%) 34 (0.3%) Mississippi 26 (0.6%) 54 (0.5%) Missouri 47 (1.1%) 133 (1.1%) Montana 5 (0.1%) 17 (0.1%) Nebraska 8 (0.2%) 32 (0.3%) Nevada 20 (0.5%) 84 (0.7%) New Hampshire 3 (0.1%) 25 (0.2%) New Jersey 153 (3.6%) 654 (5.4%) New Mexico 1 (<0.1%) 16 (0.1%) New York 177 (4.1%) 619 (5.1%) North Carolina 91 (2.1%) 313 (2.6%) North Dakota 2 (0.1%) 12 (0.1%) Ohio 86 (2.0%) 268 (2.2%) Oklahoma 43 (1.0%) 156 (1.3%) Oregon 16 (0.4%) 82 (0.7%) Pennsylvania 113 (2.6%) 407 (3.4%) Rhode Island 15 (0.4%) 36 (0.3%) South Carolina 41 (1.0%) 108 (0.9%) South Dakota 1 (<0.1%) 4 (<0.1%) Tennessee 60 (1.4%) 216 (1.8%) Texas 273 (6.4%) 866 (7.2%) Utah 67 (1.6%) 192 (1.6%) Vermont 0 1 (<0.1%) Virginia 46 (1.1%) 184 (1.5%) Washington 75 (1.8%) 198 (1.6%) West Virginia 4 (0.1%) 33 (0.3%) Wisconsin 10 (0.2%) 66 (0.6%) Wyoming 11 (0.3%) 30 (0.3%) (continued) FDA_102 Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies. December 2012 12-month REMS Assessment Report Table 2: Patient Enrollment and Geographic Distribution Current Reporting Perioda Cumulativea,b 28APR2012 to 28OCT2012 28DEC2011 to 28OCT2012 Parameter N (%) N (%) District of Columbia 2 (0.1%) 5 (<0.1%) Guam 0 0 Puerto Rico 1 (<0.1%) 2 (<0.1%) Virgin Islands 0 0 a Includes patients that transitioned into the TIRF REMS Access program from other individual REMS programs. Cumulative patients from the end of prior period may differ from last period's report due to reconciliation of duplicate patients. c Patients enrolled in this time period and were still enrolled at the end of the time period. d Patients are classified by state based on 5-digit zip code provided on PPAF. If the zip code is invalid, the patient’s self-reported state is used if available. b Data Source: Table 1 c: MCK UBC TIRF FDA Reporting Enrollment 110220121036.txt MCK_UBC_TIRF_FDA_Reporting_Patient_111420121036.txt Based upon FDA request, this report includes the proportion of states’ populations enrolled as a TIRF REMS patient, as calculated using the number of new patients in that state divided by the total population of that state as per the latest US census data. The number of newly enrolled patients in the TIRF REMS Access program is shown in the table below for the reporting period from 28 April 2012 to 28 October 2012 and cumulatively from 28 April 2012 to 28 October 2012. In addition, the proportion of these patients enrolled by state population using data from the United States Census of 2010 is presented (Table 3). The highest proportion of patients enrolled according to state population were in the states of New Jersey (0.0074%), Utah (0.0069%), Delaware (0.0058%), Colorado (0.0056%), Wyoming (0.0053%), Alabama (0.0050%), and Florida (0.0048%). FDA_103 Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies. Table 3: December 2012 12-month REMS Assessment Report Patient Enrollment by State According to 2010 US Census State\Territory of Current Reporting Period Patient 28APR2012 to Primary Addressa 28OCT2012b Total 4,290 Unknown 1,357 Alabama 138 Alaska 6 Arizona 55 Arkansas 32 California 446 Colorado 66 Connecticut 39 Delaware 8 Florida 278 Georgia 80 Hawaii 3 Idaho 5 Illinois 72 Indiana 48 Iowa 6 Kansas 27 Kentucky 17 Louisiana 16 Maine 1 Cumulative 28DEC2011 to 28OCT2012b 12,071 2,143 237 31 187 63 1,507 280 148 52 898 266 18 24 288 176 31 97 75 52 12 Population Derived from 2010 US Census Datac 312,471,327 N/A 4,779,736 710,231 6,392,017 2,915,918 37,253,956 5,029,196 3,574,097 897,934 18,801,310 9,687,653 1,360,301 1,567,582 12,830,632 6,483,802 3,046,355 2,853,118 4,339,367 4,533,372 1,328,361 Percentage of Population Enrolled in TIRF REMS Accessd 0.00004% N/A 0.0050% 0.0044% 0.0029% 0.0022% 0.0040% 0.0056% 0.0041% 0.0058% 0.0048% 0.0027% 0.0013% 0.0015% 0.0022% 0.0027% 0.0010% 0.0034% 0.0017% 0.0011% 0.0009% Rate of Persons Enrolled (Per 100,000)d 0.04 N/A 5.0 4.4 2.9 2.2 4.0 5.6 4.1 5.8 4.8 2.7 1.3 1.5 2.2 2.7 1.0 3.4 1.7 1.1 0.9 (continued) FDA_104 Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies. Table 3: December 2012 12-month REMS Assessment Report Patient Enrollment by State According to 2010 US Census State\Territory of Current Reporting Period Patient 28APR2012 to Primary Addressa 28OCT2012b Maryland 56 Massachusetts 30 Michigan 100 Minnesota 7 Mississippi 26 Missouri 47 Montana 5 Nebraska 8 Nevada 20 New Hampshire 3 New Jersey 153 New Mexico 1 New York 177 North Carolina 91 North Dakota 2 Ohio 86 Oklahoma 43 Oregon 16 Pennsylvania 113 Rhode Island 15 South Carolina 41 South Dakota 1 Cumulative 28DEC2011 to 28OCT2012b 222 95 322 34 54 133 17 32 84 25 654 16 619 313 12 268 156 82 407 36 108 4 Population Derived from 2010 US Census Datac 5,773,552 6,547,629 9,883,640 5,303,925 2,967,297 5,988,927 989,415 1,826,341 2,700,551 1,316,470 8,791,894 2,059,179 19,378,102 9,535,483 672,591 11,536,504 3,751,351 3,831,074 12,702,379 1,052,567 4,625,364 814,180 Percentage of Population Enrolled in TIRF REMS Accessd 0.0038% 0.0015% 0.0033% 0.0006% 0.0018% 0.0022% 0.0017% 0.0018% 0.0031% 0.0019% 0.0074% 0.0008% 0.0032% 0.0033% 0.0018% 0.0023% 0.0042% 0.0021% 0.0032% 0.0034% 0.0023% 0.0005% Rate of Persons Enrolled (Per 100,000)d 3.8 1.5 3.3 0.6 1.8 2.2 1.7 1.8 3.1 1.9 7.4 0.8 3.2 3.3 1.8 2.3 4.2 2.1 3.2 3.4 2.3 0.5 (continued) FDA_105 Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies. Table 3: Patient Enrollment by State According to 2010 US Census Cumulative 28DEC2011 to 28OCT2012b 216 866 192 1 184 198 33 66 30 Population Derived from 2010 US Census Datac 6,346,105 25,145,561 2,763,885 625,741 8,001,024 6,724,540 1,852,994 5,686,986 563,626 Percentage of Population Enrolled in TIRF REMS Accessd 0.0034% 0.0034% 0.0069% 0.0002% 0.0023% 0.0029% 0.0018% 0.0012% 0.0053% Rate of Persons Enrolled (Per 100,000)d 3.4 3.4 6.9 0.2 2.3 2.9 1.8 1.2 5.3 2 5 601,723 0.0008% 0.8 1 2 3,725,789 0.0001% 0.1 State\Territory of Current Reporting Period Patient 28APR2012 to Primary Addressa 28OCT2012b Tennessee 60 Texas 273 Utah 67 Vermont 0 Virginia 46 Washington 75 West Virginia 4 Wisconsin 10 Wyoming 11 District of Columbia Puerto Rico December 2012 12-month REMS Assessment Report N/A = not applicable a Patients are classified by state based on 5-digit zip code provided on PPAF. b Patients enrolled in this time period and were still enrolled at the end of the time period. c Based on 2010 US Census Data d Rates are based on Cumulative enrollment. Source: Table 1.e: MCK_UBC_TIRF_FDA_Reporting_Enrollment_110220121036.txt MCK_UBC_TIRF_FDA_Reporting_Patient_111420121036.txt FDA_106 Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies. 5.2.2 December 2012 12-month REMS Assessment Report Prescriber Enrollment, Inactivation, and Education [Metric 7, 8, 9] During the current reporting period, there were 1,862 prescribers from all 50 states, the District of Columbia, and Puerto Rico who were newly enrolled in the TIRF REMS Access program (Table 4). The majority of these enrolled prescribers (86.5%) enrolled using the Web-based enrollment system. Almost all the other prescribers completed their enrollment manually and submitted it by fax (13.4%). One prescriber (0.1%) who previously transitioned into the TIRF REMS Access program with an incomplete enrollment subsequently completed enrollment during the current reporting period. This prescriber appears as “one-time file upload” (i.e., transitioned from other individual REMS programs) in the table below. The highest enrolling state was California (14.7%), followed by New York (8.2%), Texas (7.9%), Pennsylvania (5.9%), and Florida (5.3%); all other states had enrollment of ≤4.3%. There were 143 incomplete prescriber enrollment forms received for prescribers who enrolled via fax. Multiple forms may have been submitted for the same prescriber, and a form may be incomplete for more than one reason. The majority of incomplete forms were incomplete due to missing physician signature date (45.5%), missing signature (45.5%), missing e-mail (18.2%), invalid DEA number (5.6%), and DEA number did not have correct schedule for drug (4.9%). Prescribers who enroll via Web do not submit forms. They move through a series of enrollment modules and, at any given time in the process, one or more modules may be incomplete. A prescriber cannot enroll via Web unless all modules and requirements are completed. Of 339 prescribers who initiated enrollment via the Web and had not completed enrollment as of the last date of the current reporting period (28 October 2012; data on file), the reasons for incomplete enrollment that represented at least 80.0% of those enrolling via Web were no attestation (292, 86.14%) and training not complete (270, 79.65%). FDA_107 Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies. Table 4: December 2012 12-month REMS Assessment Report Prescriber Enrollment Current Reporting Perioda 28APR2012 to 28OCT2012 N (%) Cumulativea,b 28DEC2011 to 28OCT012 N (%) Number of Newly Enrolled Prescribersc 1,862d 8,115d Method of Successful New Enrollmentse Web Fax One-time file upload 1,611 (86.5%) 250 (13.4%) 1 (0.1%) 3,881 (47.8%) 396 (4.9%) 3,838 (47.3%) Parameter State/Territory of Prescriber Primary Addressf Alabama Alaska Arizona Arkansas California Colorado Connecticut Delaware Florida Georgia Hawaii Idaho Illinois Indiana Iowa Kansas Kentucky Louisiana Maine Maryland Massachusetts Michigan Minnesota Mississippi 13 (0.7%) 5 (0.3%) 56 (3.0%) 13 (0.7%) 274 (14.7%) 44 (2.4%) 22 (1.2%) 8 (0.4%) 98 (5.3%) 31 (1.7%) 4 (0.2%) 8 (0.4%) 80 (4.3%) 30 (1.6%) 9 (0.5%) 10 (0.5%) 12 (0.6%) 13 (0.7%) 3 (0.2%) 58 (3.1%) 45 (2.4%) 48 (2.6%) 18 (1.0%) 7 (0.4%) 108 (1.3%) 20 (0.3%) 247 (3.0%) 59 (0.7%) 1,015 (12.5%) 188 (2.3%) 109 (1.3%) 28 (0.4%) 501 (6.2%) 189 (2.3%) 14 (0.2%) 19 (0.2%) 290 (3.6%) 220 (2.7%) 26 (0.3%) 59 (0.7%) 64 (0.8%) 81 (1.0%) 19 (0.2%) 283 (3.5%) 139 (1.7%) 208 (2.6%) 79 (1.0%) 36 (0.4%) (continued) FDA_108 Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies. Table 4: December 2012 12-month REMS Assessment Report Prescriber Enrollment Parameter Missouri Montana Nebraska Nevada New Hampshire New Jersey New Mexico New York North Carolina North Dakota Ohio Oklahoma Oregon Pennsylvania Rhode Island South Carolina South Dakota Tennessee Texas Utah Vermont Virginia Washington West Virginia Wisconsin Wyoming District of Columbia Guam Puerto Rico Virgin Islands Current Reporting Perioda 28APR2012 to 28OCT2012 N (%) 26 (1.4%) 3 (0.2%) 26 (1.4%) 26 (1.4%) 6 (0.3%) 54 (2.9%) 8 (0.4%) 153 (8.2%) 59 (3.2%) 4 (0.2%) 37 (2.0%) 14 (0.8%) 26 (1.4%) 109 (5.9%) 3 (0.2%) 21 (1.1%) 2 (0.1%) 44 (2.4%) 147 (7.9%) 25 (1.3%) 2 (0.1%) 32 (1.7%) 77 (4.1%) 3 (0.2%) 28 (1.5%) 8 (0.4%) 9 (0.5%) 0 1 (0.1%) 0 Cumulativea,b 28DEC2011 to 28OCT012 N (%) 116 (1.4%) 18 (0.2%) 54 (0.7%) 70 (0.9%) 30 (0.4%) 428 (5.3%) 24 (0.3%) 540 (6.7%) 318 (3.9%) 11 (0.1%) 242 (3.0%) 82 (1.0%) 88 (1.1%) 482 (5.9%) 16 (0.2%) 77 (1.0%) 6 (0.1%) 240 (3.0%) 573 (7.1%) 123 (1.5%) 6 (0.1%) 195 (2.4%) 200 (2.5%) 30 (0.4%) 113 (1.4%) 13 (0.2%) 17 (0.2%) 0 2 (0.0%) 0 (continued) FDA_109 Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies. Table 4: December 2012 12-month REMS Assessment Report Prescriber Enrollment Parameter Distribution of Reasons for Incomplete Prescriber Enrollment Forms Received for Fax-Enrolled Prescribersg, h Missing Physician Signature Date Missing Signature Missing Email Invalid DEA Number Provided DEA Number does not have Correct Schedule for this Drug Invalid NPI Number Missing State Medical License Number Missing NPI Number Missing DEA Number Missing Fax Number Current Reporting Perioda 28APR2012 to 28OCT2012 N (%) 143i Cumulativea,b 28DEC2011 to 28OCT012 N (%) 203i 65 (45.5%) 65 (45.5%) 26 (18.2%) 8 (5.6%) 7 (4.9%) 120 (59.1%) 120 (59.1%) 50 (24.6%) 29 (14.3%) 28 (13.8%) 9 (6.3%) 11 (7.7%) 5 (3.5%) 5 (3.5%) 3 (2.1%) 20 (9.9%) 18 (8.9%) 12 (5.9%) 8 (3.9%) 4 (2.0%) Note: Percentages are based on the total number (N) of prescribers for the period except for counts of incomplete forms. a The table reflects only enrolled prescribers who completed enrollment via fax. b Cumulative is defined as sum of consecutive reporting periods. c Prescribers enrolled in this time period and still enrolled at the end of the time period. New Prescriber is defined as having passed Knowledge Assessment and completed enrollment form and does not include prescriber re-enrollments. d Includes prescribers who transitioned into the TIRF REMS Access program from other individual REMS programs. e Percentage is based on the number of prescribers new to the TIRF REMS Access program, including prescribers that transitioned from other individual REMS programs. f Enrolled prescribers are classified by their primary address as recorded on the Prescriber Enrollment Form. g Percentage is based on the total number of incomplete forms received in the reporting period. Forms may be incomplete for more than one reason and more than one incomplete form received for a unique prescriber. h Reflects only enrolled prescribers who completed enrollment via fax. Some stakeholders may have attempted enrollment via the Web. i Does not include prescribers who transitioned into the TIRF REMS Access program from other individual REMS programs. Data Sources: Table 1a: MCK_UBC_TIRF_FDA_Prescriber_Location_110220121036.txt MCK_UBC_TIRF_FDA_Reporting_Enrollment_Status_History_110220121036.txt A total of 445 prescribers were inactivated at some point during the current reporting period, and the majority (439, 98.7%) was due to expiration of enrollment period. Of those 439 prescribers whose enrollment period expired at some point during the current reporting period, 409 (93.2%) of these prescribers’ statuses were expired at the close of the reporting period (Table 5). It should be noted that a prescriber is required to enroll every 2 years within the TIRF REMS Access program. Some of these 439 prescribers likely include prescribers who originally enrolled within an individual REMS program and subsequently transitioned to the FDA_110 Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies. December 2012 12-month REMS Assessment Report TIRF REMS Access program. Enrollment reminders are sent to prescribers at 60-days and 30days prior to their enrollment expiry date. Table 5: Prescriber Inactivations Parameter Current Reporting Perioda Cumulativeb 28APR2012 to 28OCT2012 28DEC2011 to 28OCT2012 N (%) N (%) Number of Inactivated Prescribers Reason(s) For Inactivationc Deceased Program Opt-Out Expired Expired at end of periodd 445 642 2 (0.5%) 4 (0.9%) 439 (98.7%) 409 (93.2%) 4 (0.6%) 6 (0.9%) 632 (98.4%) 584 (92.4%) Note: Percentages are based on the total number (N) for the relevant stakeholder/period. a Prescribers whose status is 'inactive' at least once during the period. b Cumulative is sum of consecutive reporting period totals. c Percentages are based on the total number (N) of inactivated prescribers. A prescriber may have more than one reason for inactivation. d Prescribers whose status is 'Inactive - Expired' at the end of the period. Percentages are based on the total number (N) of prescribers with 'Inactivate - Expired' status at least once. Data Sources: Table 6a: MCK_UBC_TIRF_FDA_Reporting_Enrollment_Status_History_110220121036.txt MCK_UBC_TIRF_FDA_Reporting_Enrollment_110220121036.txt Among 1,843 newly enrolled prescribers who attempted and completed the knowledge assessments, 82.2% completed the assessments via the Web and 17.9% completed them via fax (Table 6). Most prescribers passed the knowledge assessments on the first attempt (49.5%) or second attempt (32.6%). Forty-eight (2.6%) prescribers enrolled during this assessment period required more than 4 attempts to successfully complete the knowledge assessments. FDA_111 Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies. December 2012 12-month REMS Assessment Report Prescribers who take 6 attempts to complete the Knowledge Assessment are “suspended” in the TIRF REMS Access program until a representative from the Call Center can conduct outreach to provide additional educational assistance. Table 6: Parameter Enrolled Prescriber Completed Knowledge Assessments and Number of Attempts to Complete Current Reporting Period Cumulativea 28APR2012 to 28OCT2012 28DEC2011 to 28OCT2012 N (%) N (%) Number of Enrolled Prescribers Successfully Completing Knowledge Assessment (KA) Method of KA Completion Web Fax Number of Prescribers with One or More Attempts to Successfully Complete Knowledge Assessmentb One attempt Two attempts Three attempts Four attempts Five attempts Six attempts Greater than six attempts 1,843 4,296 1,514 (82.1%) 329 (17.9%) 3,729 (86.8%) 567 (13.2%) 912 (49.5%) 600 (32.6%) 210 (11.4%) 73 (4.0%) 30 (1.6%) 12 (0.7%) 6 (0.3%) 1,983 (46.2%) 1,405 (32.7%) 593 (13.8%) 189 (4.4%) 76 (1.8%) 36 (0.8%) 14 (0.3%) Note: Percentages are based on the total number (N) of prescribers successfully enrolled in the period. a Cumulative stakeholders from the end of prior period may differ from last period's report due to reconciliation of duplicate stakeholders. b Limited to successfully enrolled prescribers completing a Knowledge Assessment. Data Sources: Table 2a: MCK_UBC_TIRF_FDA_Reporting_KA_110220121036.txt 5.2.3 Pharmacy Enrollment, Inactivation, and Education [Metric 10, 11, 12] During the current reporting period, there were 2,595 newly enrolled pharmacies from all 50 states, as well as the District of Columbia, Guam, Puerto Rico, and the Virgin Islands. These included independent outpatient pharmacies (45.4%), corporate pharmacy stores (41.7%), inpatient pharmacies (12.6%), and corporate pharmacy headquarters (0.4%) (Table 7). The states where pharmacies had the highest proportion of enrolled pharmacies included California (10.5%), Florida (8.7%), Texas (8.7%), New York (6.6%), Pennsylvania (4.4%), FDA_112 Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies. December 2012 12-month REMS Assessment Report North Carolina (4.4%), New Jersey (4.1%), Missouri (3.7%), and Maryland (3.2%); all other states had enrollment ≤2.8%. As shown in Table 7, the method of enrollment for the majority of pharmacies was via the Web (51.1%), their corporate chain (45.3%; i.e., enrollment occurred via file enrollment upload), or manually by fax (3.6%). There were 61 incomplete pharmacy enrollment forms received for pharmacies that enrolled via fax. The reasons most often reported for incompleteness were invalid DEA number (4.9%), missing DEA number (3.3%), invalid NPI (1.6%), invalid NCPDP (1.6%), and missing state license number (1.6%). It should be noted that each form may have multiple reasons and could have been submitted multiple times. As described for prescribers, pharmacies that enroll via Web do not submit forms, but instead move through a series of modules. At any given time in the process, one or more modules may be incomplete. Pharmacies cannot enroll via Web unless all modules/requirements are completed. There were a number of outpatient (N=198), inpatient pharmacies (N=35), and corporate pharmacy headquarter/stores (N=47) who initiated enrollment via the Web but did not complete enrollment as of the last date of the current reporting period (28 October 2012; data on file). The major reasons for incomplete enrollment of outpatient pharmacies were as follows: no attestation (98, 49.5%), pending test transaction verification (97, 49.0%), and training not complete (87, 43.9%). The major reasons for incomplete enrollment of inpatient pharmacies were no attestation (35, 100.0%) and invalid DEA number (8, 22.9%). The major reasons for incomplete enrollment of corporate pharmacy stores were training not complete (47, 100.0%), and invalid DEA number (6, 12.8%). Table 7: Pharmacy Enrollment Current Reporting Period 28APR2012 to 28OCT2012 N (%) Cumulativea 28DEC2011 to 28OCT2012 N (%) Number of Enrolled Pharmaciesb Independent Outpatient Corporate Pharmacy Headquarters Corporate Pharmacy Stores Inpatient 2,595 c 1,177 (45.4%) 10 (0.4%) 1,081 (41.7%) 327 (12.6%) 37,968 c 4,537 (12.0%) 89 (0.2%) 32,622 (85.9%) 720 (1.9%) Method of Successful Enrollmentsd The Web Fax File (file enrollment upload) 1,326 (51.1%) 94 (3.6%) 1,175 (45.3%) 4,882 (12.9%) 170 (0.5%) 32,916 (86.7%) (continued) Parameter FDA_113 Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies. Table 7: December 2012 12-month REMS Assessment Report Pharmacy Enrollment Parameter State/Territory of Pharmacy Primary Addresse Alabama Alaska Arizona Arkansas California Colorado Connecticut Delaware Florida Georgia Hawaii Idaho Illinois Indiana Iowa Kansas Kentucky Louisiana Maine Maryland Massachusetts Michigan Minnesota Mississippi Missouri Montana Nebraska Nevada New Hampshire New Jersey New Mexico New York Current Reporting Period 28APR2012 to 28OCT2012 N (%) 42 (1.6%) 2 (0.1%) 26 (1.0%) 33 (1.3%) 273 (10.5%) 50 (1.9%) 26 (1.0%) 7 (0.3%) 225 (8.7%) 65 (2.5%) 22 (0.9%) 4 (0.2%) 72 (2.8%) 42 (1.6%) 13 (0.5%) 13 (0.5%) 25 (1.0%) 60 (2.3%) 5 (0.2%) 83 (3.2%) 22 (0.9%) 64 (2.5%) 18 (0.7%) 57 (2.2%) 96 (3.7%) 9 (0.4%) 11 (0.4%) 22 (0.9%) 4 (0.2%) 107 (4.1%) 8 (0.3%) 171 (6.6%) Cumulativea 28DEC2011 to 28OCT2012 N (%) 637 (1.7%) 54 (0.1%) 815 (2.2%) 249 (0.7%) 3,685 (9.7%) 601 (1.6%) 483 (1.3%) 154 (0.4%) 3,076 (8.1%) 1,391 (3.7%) 117 (0.3%) 156 (0.4%) 1,494 (3.9%) 877 (2.3%) 222 (0.6%) 272 (0.7%) 496 (1.3%) 523 (1.4%) 159 (0.4%) 820 (2.2%) 880 (2.3%) 1,410 (3.7%) 543 (1.4%) 309 (0.8%) 633 (1.7%) 102 (0.3%) 187 (0.5%) 327 (0.9%) 176 (0.5%) 1,297 (3.4%) 169 (0.5%) 2,269 (6.0%) (continued) FDA_114 Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies. Table 7: December 2012 12-month REMS Assessment Report Pharmacy Enrollment Parameter North Carolina North Dakota Ohio Oklahoma Oregon Pennsylvania Rhode Island South Carolina South Dakota Tennessee Texas Utah Vermont Virginia Washington West Virginia Wisconsin Wyoming District of Columbia Guam Puerto Rico Virgin Islands Number of Incomplete Pharmacy Enrollment Forms Received for Fax Enrolled Pharmaciesf Missing DEA Number Invalid DEA Number Missing NPI Number Invalid NPI Number Not Agreed to Terms and Conditions Invalid NCPDP Number Missing NCPDP Number Missing Email Current Reporting Period 28APR2012 to 28OCT2012 N (%) 115 (4.4%) 5 (0.2%) 72 (2.8%) 26 (1.0%) 34 (1.3%) 113 (4.4%) 4 (0.2%) 44 (1.7%) 7 (0.3%) 53 (2.0%) 226 (8.7%) 29 (1.1%) 1 (<0.1%) 64 (2.5%) 40 (1.5%) 14 (0.5%) 37 (1.4%) 7 (0.3%) Cumulativea 28DEC2011 to 28OCT2012 N (%) 1,254 (3.3%) 48 (0.1%) 1,599 (4.2%) 362 (1.0%) 416 (1.1%) 1,942 (5.1%) 161 (0.4%) 674 (1.8%) 52 (0.1%) 885 (2.3%) 2,541 (6.7%) 303 (0.8%) 79 (0.2%) 1,048 (2.8%) 785 (2.1%) 298 (0.8%) 612 (1.6%) 70 (0.2%) 16 (0.6%) 0 10 (0.4%) 1 (<0.1%) 100 (0.3%) 1 (<0.1%) 152 (0.4%) 3 (<0.1%) 61g 131g 2 (3.3%) 3 (4.9%) 0 1 (1.6%) 0 1 (1.6%) 0 0 21 (16.0%) 16 (12.2%) 9 (6.9%) 7 (5.3%) 7 (5.3%) 6 (4.6%) 4 (3.1%) 3 (2.3%) (continued) FDA_115 Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies. Table 7: December 2012 12-month REMS Assessment Report Pharmacy Enrollment Parameter Missing State License Number Missing Fax Number Missing Pharmacist Phone Number Current Reporting Period 28APR2012 to 28OCT2012 N (%) 1 (1.6%) 0 0 Cumulativea 28DEC2011 to 28OCT2012 N (%) 3 (2.3%) 1 (0.8%) 1 (0.8%) Note: Percentages are based on the total number (N) for stakeholders for the period. a Cumulative stakeholders from the end of prior period may differ from last period's report due to reconciliation of duplicate records. b Pharmacies that are enrolled in this time period and were still enrolled at the end of the time period. c Includes pharmacies that transitioned into the TIRF REMS Access program from other individual REMS programs. d Method Definitions: Web – enrollment occurred via program Web site; Fax – enrollment occurred via fax sent to the Call Center; File – enrollment occurred via custom file load (e.g. chain stores). e Pharmacies are classified by the primary address for the Pharmacist in Charge as recorded on the enrollment form. f Percentage is based on the total number of incomplete forms received in the reporting period. Forms may be incomplete for more than one reason. g Does not include pharmacies that transitioned into the TIRF REMS Access program from other individual REMS programs. Data Sources: Table 1b: MCK_UBC_TIRF_FDA_Reporting_Pharmacy_110220121036.txt MCK_UBC_TIRF_FDA_Reporting_Enrollment_Status_History_110220121036.txt MCK_UBC_TIRF_FDA_Reporting_Enrollment_110220121036.txt FDA_116 Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies. December 2012 12-month REMS Assessment Report There were 2 (33.3%) inpatient pharmacies and 4 (66.7%) outpatient pharmacies inactivated at least once during this reporting period. The reason for all 6 inactivations was due to the pharmacy opting out of the program. Table 8: Reasons for Pharmacy Inactivations Current Reporting Period 28APR2012 to 28OCT2012 N (%) Cumulativeb 28DEC2011 to 28OCT2012 N (%) Number of Inactivated Pharmacies Inpatient Outpatient 6 2 (33.3%) 4 (66.7%) 6 2 (33.3%) 4 (66.7%) Reason(s) for Inpatient Inactivationc Program Opt-Out 2 (100.0%) 2 (100.0%) Reason(s) for Outpatient Inactivationd Program Opt-Out 4 (100.0%) 4 (100.0%) a Parameter a Pharmacies with 'inactive' status at least once during the period. Cumulative is sum of 'reporting period' totals. c Percentages are based on the total number (N) of inactivated inpatient pharmacies. An inpatient pharmacy may have more than one reason for inactivation. d Percentages are based on the total number (N) of inactivated outpatient pharmacies. An outpatient pharmacy may have more than one reason for inactivation. Data Source: MCK_UBC_TIRF_FDA_Reporting_Enrollment_Status_History_110220121036.txt b Of the 2595 newly enrolled pharmacies in this reporting period, a total of 890 authorized pharmacists/pharmacy representatives completed the knowledge assessment (Table 9). The majority of authorized pharmacists/completed the knowledge assessment on the first attempt (43.0%) or the second attempt (37.3%). There were 6.9% authorized pharmacists/that required four or more attempts to successfully complete the knowledge assessment. Authorized pharmacists who take 6 attempts to complete the knowledge assessment are “suspended” in the TIRF REMS Access program until a representative from the Call Center can conduct outreach to provide additional educational assistance. The number of authorized pharmacists is lower than the number of enrolled pharmacies since pharmacies that were transitioned from an individual REMS program were not required to complete the TIRF REMS Access program knowledge assessment. Also, an authorized pharmacist/pharmacy representative may have been in charge of more than one store. Additionally, the TIRF REMS Access program does not manage the education of the chain pharmacy stores; this is done by the corporate chain headquarters. However, training and education data are available to the TIRF REMS Access program via audit. FDA_117 Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies. Table 9: Parameter December 2012 12-month REMS Assessment Report Enrolled Authorized Pharmacist/Pharmacy Knowledge Assessments and Attempts Needed to Complete Current Reporting Perioda Cumulativea,b 28APR2012 to 28OCT2012 28DEC2011 to 28OCT2012 N (%) N (%) Number of Authorized Pharmacists/Pharmacy Representatives Successfully Completing Knowledge Assessment Number of Authorized Pharmacists with One or More Attempts to Successfully Complete Knowledge Assessmentd One attempt Two attempts Three attempts Four attempts Five attempts Six attempts Greater than six attempts 890c 3,173 383 (43.0%) 332 (37.3%) 114 (12.8%) 36 (4.0%) 14 (1.6%) 7 (0.8%) 4 (0.5%) 1,254 (39.5%) 1,210 (38.1%) 476 (15.0%) 151 (4.8%) 53 (1.7%) 21 (0.7%) 8 (0.3%) Note: Percentages are based on the total number (N) of pharmacists for the period. a Includes pharmacies that transitioned into the TIRF REMS Access program from other individual REMS programs. b Cumulative from the end of prior period may differ from last period's report due to reconciliation of duplicates. c For chain pharmacies, the results only reflect completion by the corporate headquarters and may not include individual retail locations. Corporate pharmacies are required to certify outlets will complete all applicable assessments to participate in the program. d Limited to successfully enrolled pharmacists. Data Sources: Table 2b: MCK_UBC_TIRF_FDA_Reporting_KA_110220121036.txt MCK_UBC_TIRF_FDA_Reporting_Enrollment_Status_History_110220121036.txt 5.2.4 Dispensing Activity [Metric 13 and 14] A total of 54,614 prescriptions were adjudicated for safety by the TIRF REMS Access program in the current reporting period. Of those adjudicated by the TIRF REMS Access program, 96.3% of those prescriptions were subsequently approved for dispensing (meaning authorized for dispensing by insurance or paid for in cash) (Table 10). FDA_118 Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies. Table 10: December 2012 12-month REMS Assessment Report Authorized Prescriptions Dispensed from Outpatient Pharmacies Parameter Number of Authorized Prescriptionsb Number of Authorized Prescriptions Dispensedc Current Reporting Perioda Cumulativea 28APR2012 to 28OCT2012 28DEC2011 to 28OCT2012 N (%) N (%) 54,614 68,781 52,606 (96.3%) 65,977 (95.9%) Note: Percentages are based on the total number (N) of authorized prescriptions for the period. a Includes authorizations from pharmacies that transitioned into the TIRF REMS Access program from other individual REMS programs. b Prescription successfully adjudicated for safety (i.e., successful REMS edit). c Indicates number of prescriptions that were adjudicated for safety (i.e., successful REMS edit) and authorized for dispensing by insurance or paid for in cash. Data Source: Table 3a, RHP_UBC_TIRF_FDA_Network_Data_10282012.txt A total of 11,313 prescription claims were rejected because they failed to meet REMS requirements for prescriber and/or patient and/or pharmacy. A single prescription may have been submitted and rejected multiple times. The majority of rejection reasons were due to prescriber ID not enrolled or prescriber ID enterers was not found in TIRF REMS Access database (44.8%), PPAF incomplete (22.2%), patient zip code missing from claim (17.3%), prescriber last name did not match name registered (15.2%), or pharmacy was not enrolled (8.3%). Upon receiving an inbound call from a pharmacy provider, the TIRF REMS Access program Call Center Service Representative (CSR) worked to resolve the rejected transaction and to provide instructions on the corrective action needed to successfully process the transaction. Corrective action included outreach and education to remedy rejected transaction processing. Patients with prescriptions from multiple prescribers within an overlapping time frame were assessed, and 505 patients had 3 or more prescribers in a rolling 6-month period (data not shown, which represents approximately 4% of all enrolled patients (N=12,071); Data Source: Table 3b. RHP_UBC_TIRF_FDA_Network_Data_10282012.txt). Patients may have multiple prescribers for various reasons such as patient relocation, prescriber relocation/retirement/death, or patient is seen at a single practice with multiple prescribers. Attempts are made to research reports of patients with prescriptions from 3 or more prescribers in a rolling 6-month period. Outcomes from this research will be included in subsequent reports. FDA_119 Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies. Table 11: December 2012 12-month REMS Assessment Report Total Number of Prescriptions Rejected for Safety Current Reporting Period 28APR2012 to 28OCT2012 N (%) Cumulativea 28DEC2011 to 28OCT2012 N (%) 11,313 23,121 934 (8.3%) 87 (0.8%) 3 (<0.1%) 129 (1.1%) 5,065 (44.8%) 1,714 (15.2%) 135 (1.2%) 5 (<0.1%) 3,053 (13.2%) 431 (1.9%) 8 (<0.1%) 233 (1.0%) 10,594 (45.8%) 2,889 (12.5%) 348 (1.5%) 27 (0.1%) 18 (0.2%) 104 (0.9%) 27 (0.2%) 1,952 (17.3%) 12 (0.1%) 0 0 0 0 2,513 (22.2%) 28 (0.2%) 27 (0.1%) 175 (0.8%) 53 (0.2%) 3,664 (15.8%) 13 (0.1%) 0 0 0 0 5,303 (22.9%) 42 (0.2%) a Parameter Number of Prescription Claims Rejected for Safety Reasons For Rejectionb Pharmacy not enrolled Pharmacy enrollment incomplete or expired System unavailable due to maintenance Prescriber ID not submitted on claim Prescriber ID not in TIRF REMS Access database Prescriber last name did not match name registered Prescriber enrollment incomplete or expired Prescriber enrollment incomplete or expired and prescriber last name mismatch DOB missing from claim Patient first name missing from claim Patient last name missing from claim Patient zip code missing from claim Multiple patients found Prescriber decision to deactivate patient Patient inactive >= 6mos and must resubmit PPAF Patient deceased Database failure PPAF Incomplete PPAF Terminated Note: Percentages are based on the total number (N) of rejected prescriptions for the relevant period. Rejected for Safety is defined in this table to mean the prescription did not pass REMS edits a Includes patients that transitioned into the TIRF REMS Access program from other individual REMS programs. b A prescription may be rejected for more than one reason. Data Source: Table 3c: RHP_UBC_TIRF_FDA_Network_Data_10282012.txt 5.2.5 Wholesaler/Distributor Enrollment [Metric 15 and 16] During the current reporting period, no wholesalers/distributors were newly enrolled in the REMS program (Table 12). FDA_120 Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies. December 2012 12-month REMS Assessment Report No wholesalers/distributors were inactivated (data not shown in Table 11; Data Sources Table 6d: MCK_UBC_TIRF_FDA_Reporting_Enrollment_Status_ History_110220121036.txt Table 12: Parameter Wholesaler/Distributor Enrollment Current Reporting Perioda 28APR2012 to 28OCT2012 N (%) Number of Wholesalers/Distributors Enrolled Method of Enrollment Fax File Number of Incomplete Wholesaler/ Distributor Enrollment Forms Received Cumulativea,b 28DEC2011 to 28OCT2012 N (%) 0 40 0 0 0 18 (45.0%) 22 (55.0%) 0 Note: Percentages are based on the total number (N) for the relevant Wholesalers/Distributors for the period. a Includes Wholesalers/Distributors that transitioned into the TIRF REMS Access program from other individual REMS programs. b Cumulative Wholesalers/Distributors from the end of prior period may differ from last period's report due to reconciliation of duplicate Wholesalers/Distributors. Data Source: Table 1d: MCK_UBC_TIRF_FDA_Reporting_Enrollment_Status_History_110220121036.txt 5.2.6 Barriers or Delays in Patient Access [Metric 17 and 18] A total of 4,437 PPAFs were submitted to the REMS program either via the Web (75.5%) or by fax (24.5%). At least 36.4% of PPAFs were received the same day or within 10 days (25.6% on the same day and 10.8% between 1 and 10 days) (Table 13 and Figure 1). FDA_121 Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies. Table 13: December 2012 12-month REMS Assessment Report Submission of Patient-Prescriber Agreements to the REMS Program Parameter Number of Patient-Prescriber Agreement Forms Submitted to REMS Program Method of PPAF Submission The Web Fax One-time file upload Number of Forms Received by Days Elapsed between Patient Enrollment and Receipt of Patient-Prescriber Agreement by REMS Program Form Received Same Day Form Received between 1 and 10 days Form Received between 11 and 15 days Form Received between 16 and 20 days Form Received between 21 and 30 days Form Received >30 days after Patient Enrollment Current Reporting Period Cumulativea, b 28APR2012 to 28OCT2012 28DEC2011 to 28OCT2012 N (%) N (%) 4,437 10,127 3,349 (75.5%) 1,088 (24.5%) 0 7,313 (72.2%) 2,205 (21.8%) 609 (6.0%) 1,134 (25.6%) 478 (10.8%) 241 (5.4%) 164 (3.7%) 872 (19.7%) 1,548 (34.9%) 3,066 (30.3%) 1,294 (12.8%) 511 (5.1%) 464 (4.6%) 2,524 (24.9%) 2,268 (22.4%) Note: Percentages are based on the total number (N) of forms for the period. a Includes patients that transitioned into the TIRF REMS Access program from other individual REMS programs. b Cumulative total from the end of prior reporting period may differ from current period's report due to reconciliation of patients with completed enrollment. Data Sources: Table 4a: MCK_UBC_TIRF_FDA_Reporting_PPAF_110220121036.txt MCK_UBC_TIRF_FDA_Reporting_Enrollment_110220121036.txt FDA_122 Transmucosal Immediate Release Fentanyl (TIRF) December 2012 TIRF REMS Industry Group (TRIG) of Companies. 12-month REMS Assessment Report Figure 1: PPAF Receipt by Time Since Patient Enrollment (28APR2012 to 280CT2012) PPAF Receipt by Time Since Patient Enrollment Current Reporting Period 1,800 1,600 1.548 1,400 ~l?I l" 8 800 Number of PPAFs 600 400 200 Same Day 1 10 Days 11 15 Days 16 20 Days 21 30 Days 30 Days Days Between Enrollment and PPAF Reciept Figure Source: Table 4a: 10220121036.txt A total of 7,444 prescriptions were dispensed to a total of 4,244 patients during the ?rst 10 days after patient enrollment (Table 14 and Figm?e 2 below). There were a greater number of patients who had their ?rst prescription ?lled in the ?rst 10 days without a PPAF compared with those patients with a PPAF (71.4% vs. For patients without a PPAF, the majority of patients received only I ?ll. It was observed that 1 patient received more than 3 ?lls in a lO-day period Without a PPAF on ?le. This report will be investigated and the outcome of this research will be reported in next assessment report. Additionally, the TIRF REMS Access program is exploring the root cause for these events to identify possible system enhancements. 23 Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies. Table 14: Parameter December 2012 12-month REMS Assessment Report Prescriptions Dispensed During the First 10 Days after Patient Enrollment Current Reporting Period Cumulativea 28APR2012 to 28OCT2012 28DEC2011 to 28OCT2012 N (%) N (%) Number of prescriptions dispensed to patients during the first 10 days after patient enrollment 4,960 12,796 Number of patients dispensed a prescription during the first 10 days after patient enrollment 4,442 11,000 760 (17.1%) 78 (1.8%) 13 (0.3%) 2 (<0.1%) 1,417 (12.9%) 222 (2.0%) 34 (0.3%) 12 (0.1%) 3,566 (80.3%) 184 (4.1%) 19 (0.4%) 1 (<0.1%) 8,978 (81.6%) 704 (6.4%) 112 (1.0%) 10 (0.1%) With PPAFb 1 Fill 2 Fills 3 Fills >3 Fills Without a PPAFb, c 1 Fill 2 Fills 3 Fills >3 Fills a Cumulative data from the end of the prior period may differ from the last period's report due to reconciliation of duplicate stakeholders. b Percentages are based on the total number of patients for the period. Sum of percentages may be greater than 100 due to patients receiving prescriptions with and without a PPAF during the grace period. c A patient may receive up to 3 fills in the first 10 days after enrollment without a PPAF. Data Source: Table 4b: RHP_UBC_TIRF_FDA_Network_Data_10282012.txt FDA_124 Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies. December 2012 12-month REMS Assessment Report Figure 2: Number of Patients Dispensed a Prescription During the First 10 Days After Patient Enrollment (28APR2012 to 280CT2012). Dlspensed Du ring the ?rst 10 Days after Patlent Enrollment (Stratified by PPAF Status) Current Reporting Period 100% 760 3,566 90With PPAF 5 40V 9; Without PPAF Fill 2 Fills 3 Fills 3 Fills Patient Prescriptions Filled During the First 10 Days Figure Source: Table 4b: It was previously reported to FDA that 29 patients received more than 3 ?lls without a PPAF on ?le in a 10-day period. Upon additional research, 13 of the 29 patients did have a PPAF on ?le prior to receiving the 4th prescription. These 13 patients were incorrectly reported as not having a PPAF on ?le in the previous assessment report. The remaining 16 patient transactions were reviewed in detail and the outcomes of this research are reported below: 0 Pharmacy data entry errors: Ten (10) of the 16 patients were identi?ed as receiving more than 3 prescriptions within a lO-day grace period due to data entry errors made by 16 pharmacies. When patient prescriptions are processed by the TIRF REMS, the patient is passively enrolled in the program. In order for passive enrolhnent to occur, a communication is completed with the REMS Administrator to obtain a unique patient identi?er. In this scenario, patient prescriptions are submitted for the same patient with different information. When the prescription was sent to the REMS Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies. December 2012 12-month REMS Assessment Report Administrator, the patient was issued a new patient identifier (although they had already been previously enrolled). The system was unable to identify that this patient was the same patient because it relies on exact data. These 16 pharmacies were able to receive approval from the TIRF REMS system because the patient data were different between the claims to appear as if the transaction was for a new patient. All of these reports will be further investigated to identify any issues of non-compliance and updates will be provided in the next report. As of 11 December 2012, 8 of the 10 patients now have a PPAF on file. As mentioned above, the TIRF REMS Access program is exploring system and program enhancements to mitigate the possibility for these events in the future. • Duplicate patient records: Six (6) of the 16 patients were identified as receiving more than 3 prescriptions within the 10 day grace period due to the pharmacy process that was used to transmit the paid claims. The pharmacy submitted multiple prescriptions subseconds apart, which did not allow the TIRF REMS the ability to process the enrollment for the patient. When multiple prescriptions are submitted simultaneously, TIRF REMS will create two patient records that are not immediately identified as being the same patient. These instances are automatically investigated in real-time and resolved as duplicate records. As of 11 December 2012, all 6 patients now have a PPAF on file. TIRF REMS currently performs outreach to prescribers to obtain a PPAF. TIRF REMS has performed additional outreach to the prescribers to obtain a PPAF for the remaining 2 patients. 5.3 5.3.1 Program Infrastructure and Performance [Metrics 19, 20, 21, 22, 23, 24] Pharmacy Management Systems [Metric 19] Table 15 summarizes the time it took enrolled outpatient pharmacies to configure their PMS to communicate with the REMS program. Of 682 outpatient pharmacies that attempted to configure a PMS, 96.5% successfully reconfigured their systems and 3.5% did not complete configuration of their PMS within the reporting period. It took a mean of 2.49 days to configure, with a minimum of 0.0002 days and a maximum of approximately 189.97 days. FDA_126 Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies. Table 15: December 2012 12-month REMS Assessment Report Configuration of Pharmacy Management System (PMS) Parameter Number of Outpatient Pharmacies Attempting to Configure PMS Number of Pharmacies with Incomplete Configuration of PMSa Number of Outpatient Pharmacies Successfully Completing Configuration of PMSb Time Required to Complete Configurationc Mean Minimum Maximum Current Reporting Period 28APR2012 to 28OCT2012 N (%) Cumulative 28DEC2011 to 28OCT2012 N (%) 682 2,816 24 (3.5%) 51 (1.8%) 658 (96.5%) 2,765 (98.2%) 2.4920 0.0002 189.97 0.8239 0.0001 189.97 a Defined as number of pharmacies with less than 3 dates of test transfers in the reporting period. Percentages are based on the total number (N) of pharmacies attempting to configure their PMS for the relevant period. For chain pharmacies, this refers to their corporate office(s), not individual locations. c Time measured in days from 1st transaction attempt to final transaction success. Data Source: Table 5: RHP_UBC_TIRF_FDA_Network_Data_10282012.txt b In the previous reporting period, (28 December 2011 to 27 April 2012), it was reported that 81 pharmacies did not complete configuration of their PMS. Of these 81 pharmacies, 8 pharmacies were considered chain pharmacies and inadvertently enrolled as independent pharmacies. These 8 chain pharmacies are now currently enrolled in the TIRF REMS Access program. Of the 73 independent pharmacies pending system configuration: • • 19 have successfully completed their pharmacy system configuration 35 were identified as independent pharmacies transitioned to the TIRF REMS Access program from a previous independent REMS program for a TIRF medicine who inadvertently began the pharmacy system configuration process again o This step was not a requirement for enrollment as it was completed at the time of enrollment in the independent program. The only requirement necessary for these transitioned pharmacies to become enrolled in the TIRF REMS Access program was to acknowledge the updated terms and conditions for the program. FDA_127 Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies. • • 5.3.2 December 2012 12-month REMS Assessment Report o This step was completed and confirmed for these 35 independent pharmacies and they are actively enrolled in the program 10 have chosen to “opt out” of the program 9 have not configured their system as of the end of the reporting period. Backup System for Prescription Validation [Metric 20] During this reporting period there were no instances in which a backup system was used to validate a prescription due to pharmacy level problems, switch problems, or REMS database problems. 5.3.3 REMS Call Center [Metric 21a, b] Table 16 below shows reasons for contacting the REMS Call Center by frequency (%). For presentation in the report, the table cut-off is at least 80% of the total cumulative frequency of contact reasons. The most frequent reasons classified under the call reason were pharmacy:pharmacy claim rejection (15.11%), enrollment status inquiry (14.06%), prescriber:pharmacy claim rejection (11.73%), and PPAF follow up or status inquiry (20.92%). The call reasons listed below in Table 16 represent 81.01% of calls to the Call Center for the current reporting period. Table 16: Reasons and Frequency for Contacting the Call Center Current Reporting Period 28APR2012 to 28OCT2012 Frequency Percenta Cumulative Percent Pharmacy: Pharmacy Claim Rejection 2594 15.11 15.11 Enrollment Status Inquiry 2414 14.06 29.17 Prescriber: Pharmacy Claim Rejection 1952 11.73 40.54 PPAF Status Inquiry or Follow-up 3592 20.92 61.46 Patient: Pharmacy Claim Rejection 1246 7.26 68.72 General Program Questions 1056 6.15 74.87 Enrollment Follow Up 1053 6.13 81.01 Contact Reason a The total percentage presented in the table is 81.01% of all reasons for contacting the Call Center.Source: Data on file (The FREQ Procedure). Problems or complaints that were reported to the REMS Call Center for review by the TIRF REMS Access program are summarized below. Additional Call Center issues that met the definition of non-compliance are presented in Section 6, Report #12. FDA_128 Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies. December 2012 12-month REMS Assessment Report ID #1: Open [Patient Access] Issue: On 23 August 2012, a complaint letter was received from a prescriber regarding attestation language in the PPAF. The prescriber complained that the TIRF REMS requirement regarding opioid tolerance does not allow the physician to provide “best possible pain management to patients” and possibly requires ”over-prescribing of pain medication.” Resolution: A copy of the letter was submitted to FDA. This prescriber is currently enrolled in the TIRF REMS Access program and has prescribed TIRF medicines. There was one paid claim recorded in the TIRF REMS Access program for this prescriber. ID #2: Closed [Patient Access] Issue: On 10 September 2012, a pharmacy and a prescriber attempted to enroll with a shared DEA. The prescriber is a physician and also the owner of outpatient pharmacy. The pharmacy was successfully enrolled in April 2012. The prescriber attempted to enroll in September 2012 using the same DEA number as used by the pharmacy; however, the REMS application did not allow the prescriber to enroll because the DEA number was already in use. Resolution: An outreach was conducted to the DEA office that governs the prescriber’s area (New York). The DEA office confirmed the legitimacy of the prescriber and approved the outpatient pharmacy and prescriber to enroll in the TIRF REMS and share the same DEA number so long as both records were enrolled with the same address. The prescriber was successfully enrolled on 26 October 2012. ID #3: Open [Patient Access] Issue: On 03 October 2012, a prescriber submitted a written complaint over PPAF attestation language. The TIRF REMS received a modified PPAF from the prescriber because the patient is not on around-the-clock opioid medication. The call center advised the prescriber that an altered PPAF could not be processed and requested the prescriber resubmit the PPAF. The same PPAF was re-submitted with letter of explanation from the patient's physician describing the patient’s condition (i.e., not on ATC opioids). The PPAF was not processed because it was an altered PPAF and therefore did not meet the TIRF REMS requirements. Resolution: An email was sent to FDA requesting a teleconference. ID #4: Closed Issue: Seven (7) escalations have been reported for cases identified within this reporting period where a TIRF REMS Access program call center agent conducted outreach to prescribers' offices to obtain a PPAF for an enrolled patient, and the offices all confirmed the patient was not a patient of the prescribers’ office. The issue was identified as a result of pharmacies selecting the incorrect patient profiles within their pharmacy management systems. Upon FDA_129 Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies. December 2012 12-month REMS Assessment Report investigation, the pharmacies all confirmed that they immediately reversed the claim and resubmitted the claim by selecting the correct patient profile. As a result of the incorrect patient being submitted on the initial transaction, the patient enrollment record was created in the TIRF REMS Access database but later removed when the pharmacy error was confirmed. Resolution: The patient enrollment records that were created as result of this error have been removed from the TIRF REMS database. 5.4 System Errors and Corrective Actions [Metric 22] A brief summary of issues identified as system errors and their corrective actions is presented below. Additional system errors that met the definition of non-compliance are presented in Section 6. System Error #1 Description: Part of the TIRF REMS networking software, a Passive Patient Queue, was not submitting some updates to the TIRF REMS Access program for passive patient enrollment between 16 May 2012 and 23 May2012. This resulted in 136 unique patients not being passively enrolled in TIRF REMS. The passive patient enrollment is designed to determine if there are more than 3 prescriptions received in a 10-day grace period because a Prescriber Patient Agreement Form is required if this count is exceeded. A total of 168 transactions were impacted by the queuing issue with 136 unique patients not passively enrolled. However, there were no patients that received more than 3 scripts in a 10-day grace period and all effected patients have been passively enrolled in TIRF REMS. Root Cause: Part of the TIRF REMS networking software, a Passive Patient Queue, was not submitting some updates to the TIRF REMS. Correction: The connection to the Passive Patient Queue was updated on 24 May2012 and 136 new patient records were sent to TIRF REMS for passive enrollment. TIRF REMS patient IDs were updated in TIRF REMS History database as well as updated in all reporting tools designed for TIRF REMS. The failed patient queue is now monitored daily and an email alert is sent to the support team when web service calls are not delivered or have failed. System Error #2 (b) (4) Description: On 04 June 2012, one switch provider, experienced a spontaneous server incident where one TIRF REMS claim bypassed the TIRF REMS validation process. During the period of interruption, the prescription was dispensed without being validated or authorized by the TIRF REMS Access program and was sent directly to the payer for payment. It was verified that only one transaction was not validated by TIRF REMS at time of dispense. The pharmacy and the prescriber were enrolled at the time the prescription was transmitted. FDA_130 Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies. December 2012 12-month REMS Assessment Report Root Cause: Switch provider server interruption. Correction: On 02 October 2012, the switch provider informed TIRF REMS that a server fix (b) (4) was implemented for future spontaneous interruptions. updated their servers from 24 September 2012 and 28 September 2012. System Error #3 (b) (4) Description: On 28 June 2012, pharmacy chain attempted to enroll in TIRF REMS under the chain enrollment umbrella. When the chain attempted to complete the enrollment, they transmitted the incorrect chain ID in their vendor certification transactions, which resulted in an enrollment error. When the transactions were submitted incorrectly, a web service call failure was generated which triggered an email alert to the TIRF REMS Access program. As per (b) (4) current standards, TIRF REMS should have performed an outreach to to correct the issue with their enrollment. Upon investigation, it was determined on 30 August 2012 that the issue with the pharmacy chain completing the enrollment was still open and TIRF REMS Access program had not contacted the chain to correct the enrollment error. Root Cause: TIRF REMS Access program did not follow-up on a failed enrollment message . (b) (4) Correction: successfully enrolled on 30 August 2012. Standard Operating Procedures (SOP) were written to clarify actions needed when a REMS web service failure occurs. Training on the SOP for TIRF REMS team was completed on 18 September 2012. System Error #4 (b) (4) Description: stores initiated inbound calls to the TIRF REMS call center because (b) (4) they were receiving rejections of “M/I Prescriber Last Name.” sent the claims back to TIRF REMS for validation, but should have sent them directly to a payer or re-submitted them (b) (4) to the TRIF REMS without removing the prescriber’s last name, per specifications. TIRF REMS transactions were correctly validated. There were a total of 1,457 transactions rerouted to TIRF REMS that received the rejection of “M/I Prescriber Last Name,” of which 617 were unique prescriptions. This resulted in the rejection of these transactions, and (b) (4) pharmacies were unable to dispense the TIRF REMS medication at the time the rejection was received. (b) (4) Root Cause: discovered that they made switch channel updates between 29 August 2012 and 07 September 2012, which resulted in TIRF REMS transactions being (b) (4) rerouted for a second validation check. should not route any transactions to TIRF REMS that were sent to them by TIRF REMS. (b) (4) Correction: On 12 September 2012, was notified by TIRF REMS of the issue and (b) (4) (b) (4) begin to research the routing problem on their end. immediately added FDA_131 Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies. December 2012 12-month REMS Assessment Report additional logic to the TIRF REMS set up so that claims originating from TIRF REMS would be routed to the payer for payment. On 13 September 2012, the TIRF REMS identified that the (b) (4) issue is resolved and the TIRF REMS call center contacted all stores that reported (b) (4) the problem to ensure that all stores were able to process. On 18 September 2012, advised the TIRF REMS program of internal organizational updates to mitigate this risk going forward. System Error #5 Description: On 19 October 2012, TIRF REMS had a hardware problem (conversion network adapter overheat) that resulted in TIRF REMS transactions to reject due to the TIRF REMS engine not being able to perform a validation check on stakeholder records. The rejection that was sent to the pharmacies was “System Unavailable. Please Try Again Later.” There were 461 transactions impacted, of which there was 111 unique prescriptions. Root Cause: TIRF REMS Access Program had a conversion network adapter overheat that resulted in TIRF REMS transactions to reject due to the TIRF REMS engine not being able to perform a validation check on stakeholder records. Correction: TIRF REMS Access program identified the issue on 19 October 2012 and fixed the hardware and any data-related issues. Upon investigation, all 111 unique prescriptions were reprocessed correctly. System Error #6 Description: On 07 May 2012, during an override validation confirmation process, it was discovered that the TIRF REMS Access program inadvertently validated 7 identifiers in error by overriding the identifiers submitted on 6 stakeholders’ enrollment submissions. Three (3) of the prescribers were enrolled once the identifiers were incorrectly validated. Three (3) prescribers never completed the enrollment process after the identifiers were validated. Root cause: The TIRF REMS Access program was validating invalid identifiers without benefit of a Work Instruction. Correction: A Work Instruction was completed, approved, and trained on 24 April 2012. It was determined that the 3 prescribers were inadvertently enrolled for approximately 90-days. Two files were corrected on 28 June 28 2012 and the third file corrected on 29 June 2012. The TIRF REMS Access program identified there was one (1) paid claim by one of the inadvertently enrolled stakeholders. The TIRF REMS Access program contacted all three inadvertently enrolled prescribers and advised them that their enrollment status was changed to incomplete because the program could not validate their DEA number with Schedule II eligibility. One of the 6 prescribers enrolled on 09 July 2012 and all identifiers are confirmed as valid. FDA_132 Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies. December 2012 12-month REMS Assessment Report System Error #7 Description: Five prescribers were inadvertently enrolled in the TIRF REMS Access program as a result of the prescribers enrolling in the program with facility DEA numbers. The 5 prescribers were notified of the error, and their status was changed to an incomplete status to allow the impacted prescribers to enroll with an eligible individual DEA number. Root Cause: Prescribers were enrolling in the program with facility DEA numbers. Correction: It was confirmed that there were no dispensed TIRF prescriptions as a result of the 5 inadvertent prescriber enrollments. 5.4.1 Lack of Enrolled Prescribers and/or Pharmacies for Patients [Metric 23] During the current reporting period, no reports of lack of enrolled pharmacies were received. 5.4.2 Delays after Prescription Denial [Metric 24] The prescription conversion time or length of time delay is defined as the length of time between the initial reject on a claim to when it successfully passes all the REMS business rules/edits and is sent to the payer of adjudication. For the assessment period, 28 April 2012 through 28 October 2012: • The mean prescription conversion time is 0 days, 11.410 hours. • The median prescription conversion time is 0 days, 0.194 hours. • The minimum prescription conversion is 0 days, 0.001 hours. • The maximum prescription conversion time is 173 days, 3.001 hours. There was one outlier that impacted the maximum prescription conversion time of 173 days and 3.001 hours. On 12 April 2012, one independent outpatient pharmacy transmitted a TIRF REMS prescription that did not pass the REMS edits. This transaction rejected for invalid date of birth. On 02 October 2012 (173 days later), the pharmacy resubmitted the prescription, the transaction passed the REMS edits, and was paid. 5.5 5.5.1 Unintended System Interruptions [Metrics 25, 26, 27, 28] Inadvertent Enrollment Deactivations [Metric 25] Enrollment Deactivation #1: During this reporting period there were a total of 3 inadvertent prescriber deactivations encompassing one incident. This was as a result of incorrect enrollment effective dates assigned to transitioned prescribers. Upon identification of the deactivations, the 3 prescribers records were reverted back to an enrolled status, and all prescribers were notified FDA_133 Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies. December 2012 12-month REMS Assessment Report of current status. There were no claims impacted during the time the prescribers were inadvertently deactivated. 5.5.2 Reports of False Positives [Metric 26] During this reporting period, there were no reports of a false positive incident. 5.5.3 Failure of Re-enrollment Notifications [Metric 27] Re-enrollment notifications were sent to a total of 396 prescribers this reporting period. Of these, 374 prescribers successfully received a notification for re-enrollment via fax. Two prescribers were successfully notified of re-enrollment via email. By the end of the reporting period, there were a total of 22 unique prescribers who have not yet had a successful reenrollment notification received via fax in spite of multiple attempts. 5.5.4 Reports of False Negatives [Metric 28] During the reporting period, there were no reports of a false negative transaction. 5.6 Audits No audits were conducted during the current reporting period and no reasons were identified to conduct a for-cause audit. 6 TIRF REMS Access Program Non-Compliance During the current reporting period, instances of potential stakeholder non-compliance with the TIRF REMS Access program were reviewed and investigated. The following tables list resolved and pending potential reports of non-compliance, respectively. Table 17: Pending/Open Reports from Prior Reporting Period: 28 December 2011 to 27 April 2012 Report No. Report Description 10 Received pharmacist complaint regarding lack of weekend coverage at TIRF REMS Access program Call Center. Pharmacist reported that the prescriber for a prescription was unaware of PPAF requirement and that the patient was in pain. Pharmacist was unable to resolve rejected claim provided the patient with 3 tablets to carry the patient through the weekend. Live Call Center coverage is available Monday through Friday 8am-8pm EST. (The Call Center was not open seven days a week for individual REMS programs.) Report Status Outcome/Resolution This case was forwarded as an adverse event to the appropriate Sponsor for further research and follow up. Additional investigation is ongoing to confirm the “3 tablets dispensed” were a TIRF medicine. Closed Update: This case was forwarded to the Manufacturer’s Product Safety group however no further investigation was completed as it was not deemed to be a potential safety issue. FDA_134 Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies. Table 18 Report No.1 12 13 December 2012 12-month REMS Assessment Report Reports in the Current Reporting Period: 28 April 2012 to 28 October 2012 Report Description Call Center: On 30 May 2012, a pharmacy dispensed a TIRF medicine without successfully processing the claim through REMS edits. A pharmacy received a claim reject reason of “prescriber not enrolled” and contacted the call center. A follow-up call was placed to the prescriber to notify of the enrollment requirement before patient could receive the prescription. The pharmacy advised that the insurance would pay for the prescription so the pharmacy processed the transaction as cash and the medication was dispensed without processing through the REMS edits. Closed System Pharmacy: The TIRF REMS Access program administrator identified that the program had not received any prescription authorizations since the Closed System Pharmacy effective day of 01 July2012. Following multiple outreach attempts to the Veteran’s Administration (VA), the program received contact from the VA Authorized Representative on November 15th confirming that there had been TIRF prescriptions dispensed without obtaining an authorization to dispense from the Closed System Program. (CAPA 341) Report Status Open Open Outcome/Resolution Resolution: . The Non-Compliance Team investigated this report and was able to confirm that the patient received a TIRF medicine on 30 May 2012, but there is no evidence of additional attempts to reprocess a claim. The prescriber in question is not enrolled as of the close of this reporting period. The TIRF REMS Access program has made multiple attempts to contact the prescriber. In addition, as of the close of the reporting period the patient still does not have a passive enrollment in TIRF REMS; thus, it appears the patient has not sought out another prescriber. A Non-compliance Notice Letter was sent to the pharmacist in charge at the pharmacy involved. The VA conducted a thorough search across the entire VA system and confirmed that there were TIRF prescriptions dispensed between July 1st and the current date that impacted 15 closed system outpatient VA pharmacies. The VA was only able to provide the number of locations and unable to provide the number of dispenses/prescriptions, only the number of locations. The VA confirmed that they have reeducated these 15 locations and ensured that the processes are being followed for receipt of authorization numbers prior to dispensing prescriptions. The re-education will occur across all locations, but they started specifically with the 15 identified above since they have active patients in these locations. The VA is actively working on obtaining all of the data elements the TIRF REMS Access program requested for each of the dispenses that occurred and they stated this unfortunately takes time and a number of rounds of clearance before they are authorized to send it. They anticipate it will be available by the end of November. The VA confirmed that they are working on this as a priority request. The full outcome of this investigation will be reported in the next REMS Assessment Report. 1 For tracking purposes across TIRF REMS Access program assessment reports, noncompliance reports are numbered consecutively and continuously from the first TIRF REMS Access program assessment report. Source: Data on file. FDA_135 Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies. 7 7.1 December 2012 12-month REMS Assessment Report SAFETY SURVEILLANCE Adverse Events The following summary was produced from the 2012 Q2 release of the FDA’s Freedom of Information Act (FOIA) Adverse Event Reporting System (AERS) database which was made publicly available by the FDA in early October, 2012 (See Appendix 11.3 for full report). The AERS database comprises 3,778,243 cumulative case reports, including 181,428 new reports in the 2012 Q2 quarterly release. Of these case reports, 46 reference a TIRF product covered by the FDA REMS for TIRF medicines, with an event date on or after 28 December 2011. Thirty-six (36) of these case reports specify United States as the Country of Origin, and 26 of these US cases also include one of the individual MedDRA Preferred Terms (PT) of Interest for the TIRF REMS described in the TRIG AERS Safety Surveillance Plan. These MedDRA Preferred Terms of Interest are grouped into the following broad Categories of Interest (TRIG Categories) for aggregate reporting: o Death o Overdose (fatal and non-fatal) o Misuse, abuse, addiction, and diversion o Inappropriate o Medication errors o Accidental In addition, 1 report includes at least one Preferred Term from the MedDRA Standardized MedDRA Query (SMQ: Broad) Acute Central Respiratory Depression, which is included in the AERS analysis as a possible symptom related to the TRIG Categories above. None of the individual Preferred Terms from this SMQ is a TRIG Preferred Term of interest; instead counts of reports listing any PT from this SMQ will be summarized into an aggregate count for the entire SMQ and reported separately. The following table summarizes the reported adverse event Terms and Categories of Interest that were reported on the case reports for TIRF products that met the selection criteria for this analysis. A total of 36 PTs of Interest for this study were reported across 26 case reports selected for TIRF products that contained a PT of Interest. The most commonly reported Term is “Off label use” (n=18) followed by “Drug prescribing error” (n=7). One (1) additional case report contained a Preferred Term from the MedDRA SMQ Acute central respiratory depression. These counts of the reported PTs and categories are summarized in the table below: FDA_136 Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies. 12-month REMS Assessment Report December 2012 Table 19: Count of Reported Events of Interest Grouped by TRIG Category: Second Quarter 2012 Total Events by Category Q2 2012 to Date Overdose 0 0.0% 0 0.0% Accidental overdose 0 0.0% Intentional overdose 0 0.0% Multiple drug overdose 0.0% Multiple drug overdose accidental 0.0% Multiple drug overdose intentional 0 0.0% Overdose 0 0.0% Death 0 0.0% 0 0.0% Accidental death 0 0.0% Agonal death struggle 0 0.0% Apparent death 0 0.0% Brain death 0 0.0% Cardiac airest 0.0% Cardiac death 0 0.0% Cardio-respiratory arrest 0 0.0% Death 0 0.0% Death neonatal 0 0.0% Death of companion 0 0.0% Death of relative 0 0.0% Respiratory airest 0 0.0% Sudden cardiac death 0 0.0% Sudden death 0 0.0% Sudden lulexplained death in epilepsy 0.0% Misuse 0 0.0% 0 0.0% Intentional Drug Misuse 0 0.0% Medication overuse headache 0 0.0% Drug abuse dependence and withdrawal SMQ 6 Abuse 0 0.0% 0 0.0% Drug abuse 0 0.0% Drug abuser 0 0.0% Ex-dmg abuser 0.0% (continued) 37 Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies. 12-month REMS Assessment Report December 2012 Table 19: Count of Reported Events of Interest Grouped by TRIG Category: Second Quarter 2012 Total Events by Category Q2 2012 to Date Substance abuse 0 0.0% Substance abuser 0 0.0% Substance-induced mood disorder 0 0.0% Substance-induced disorder 0 0.0% Drug abuse dependence and withdrawal SMQ 6 Inappropriate 18 50.0% 18 50.0% Drug administered at inappropriate site 0 0.00% Drug administered to patient of inappropriate age 0.00% Inappropriate schedule of drug administration 0.00% Off label use 18 50.0% Medication Error 12 33.3% 12 33.3% Accidental drug intake by child 0 0.0% Counterfeit drug administered 0 0.0% Drug administered to patient of inappropriate age 0 0.0% Drug administration error 1 2.8% Drug dispensing error 1 2.8% Drug dose omission 1 2.8% Drug label confusion 0 0.0% Drug name confusion 0 0.0% Drug prescribing error 7 19.4% Expired drug administered 1 2. 8% Inappropriate schedule of drug administration 0 0.0% Incorrect dose administered 0 0.0% Incorrect drug administration duration 0 0.0% Incorrect drug administration rate 0 0.0% Incorrect drug dosage form administered 0 0.0% Incorrect route of drug administration 0 0.0% Incorrect storage of drug 0 0.0% Intercepted drug dispensing error 0 0.0% Intercepted drug prescribing error 0 0.0% Intercepted medication error 0 0.0% Labelled drug-disease interaction medication error 0 0.0% (continued) 38 Transmucosal Immediate Release Fentanyl (TIRF) December 2012 TIRF REMS Industry Group (TRIG) of Companies. 12-month REMS Assessment Report Table 19: Count of Reported Events of Interest Grouped by TRIG Category: Second Quarter 2012 Total Events by Category Q2 2012 to Date Labelled drug-drug interaction medication error 0 0.0% Medication error 0 0.0% Multiple use of single-use product 0 0.0% Poor quality drug administered 0 0.0% Therapy na'r've 0 0.0% Underdose 0 0.0% Wrong drug administered 0 0.0% Wrong technique in drug usage process 1 2.8% Accidental 0 0.0% 0 0.0% Accidental drug intake by child 0 0.0% Accidental exposure 0 0.0% Accidental overdose 0 0.0% Accidental poisoning 0.0% Multiple drug overdose accidental 0 0.0% Toxicity to various agents 0 0.0% Dependence 6 16.7% 6 14.3% Dependence 0 0.0% Drug dependence 0 0.0% Drug dependence. antepartlun 0 0.0% Drug dependence. postpartum 0 0.0% Drug Withdrawal 3 8.3% Polysubstance dependence 0 0.0% Withdrawal 3 8.3% Drug Diversion 8 50.0% 1 8 50.0% Drug diversion 0 0.0% Off label use 18 50% Respiratory Depression 1 1 Acute central respiratonf depression SMQ 1 A data mining (disproportionality) analysis was also performed on the selected AERS cases, using the entire AERS database as the background denominator. Not sruprisingly, relatively robust signals of disproportionate reporting were generated for the PTs of Interest: ?Off label Use? and ?Drug prescribing error. A weaker signal was generated for the PT of Interest ?Drug withdrawal These are known adverse events for TIRF medicines, and are the 39 Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies. December 2012 12-month REMS Assessment Report subject of the TIRF REMS Access program. When analyzed according to TRIG Categories of Interest, relatively robust signals were also generated for “Inappropriate use,” “Drug diversion,” “Medication error,” and “Drug dependence.” When examined by MedDRA SMQ, the SMQ “Drug abuse, dependence and withdrawal” generated a somewhat weak signal of disproportionate reporting. Data mining results for these adverse events will continue to be monitored over time to understand the impact of the REMS program on the overall reporting rates for these events of interest. 7.2 American Association of Poison Control Centers (AAPCC) The AAPCC database is monitored to identify reports of misuse, abuse, and overdose. The AAPCC database includes all 57 poison centers in the US. Reports were requested from AAPCC on calls related to the aggregated data for the class of immediate-release transmucosal fentanyls (no manufacturer names or brand names are provided). The search also included reports of unknown manufacturer oral immediate release fentanyl products, and "unknown fentanyls" with oral and/or inhalation/nasal route(s) of exposure. AAPCC listings of reports for TIRF medicines and unknown fentanyl are presented in Appendix 11.2. In the prior reporting period (28 December 2011 to 27 April 2012), the AAPCC received reports for 9 cases of known exposure to oral fentanyl immediate-release medicines during the current reporting period. The 9 cases had medical outcomes of 1 major effect, 1 moderate effect, 5 minor effects, 1 unable to follow/judged as potentially toxic exposure, and 1 not followed/judged as non toxic exposure. “Effect” is defined as sign, symptom, or laboratory abnormality and described as minor, moderate, major, or death (See Appendix 11.2 for effect definitions). Eight cases of exposure to unknown fentanyl were reported to the AAPCC during the previous reporting period. The cases had medical outcomes of 1 death (indirect report), 2 major effects, 1 moderate effect, 3 unable to follow/judged as potentially toxic exposure, and 1 not followed/minimal clinical effect possible. In the current reporting period (28 April 2012 to 28 October 2012), the AAPCC received reports for 11 cases of known exposure to oral fentanyl immediate-release medicines during the current reporting period. The 11 cases had medical outcomes of 1 major effect, 1 moderate effect, 3 minor effects, 2 no follow-up minimal toxicity, and 3 no effects. Twelve cases of exposure to unknown fentanyl were reported to the AAPCC during the current reporting period. The cases had medical outcomes of 7 deaths (indirect reports), 2 moderate effects, 1 minor effect, 1 unable to follow/judged as potentially toxic exposure, and 1 no effect. Of the 7 deaths, 6 were intentional abuse and 1 had an unknown reason for exposure. The 2 moderate reports were characterized as intentional suspected suicide and the 1 minor event was intentional. The other 2 reports were unintentional FDA_140 Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies. December 2012 12-month REMS Assessment Report The following tables (Tables 20-26) include reports for exposures to TIRF medicines received between 28 April 2012 and 28 October 2012. The tables do not include reports for unknown fentanyls. Human Exposure Cases: Site of Call/Site of Exposure As shown in Table 20 for the current reporting period, of the 11 human exposures associated with TIRF medicines reported, 4 call sites were from a residence (own or other) but there were 10 cases where the site of exposure actually occurred at a residence (own or other). Another 5 calls were made from a health care facility and 2 from “other.” Beyond residences, 1 exposure occurred in a school. Table 20: Site of Call and Site of Exposure, Human Exposure Cases Associated with TIRF Medicines: 28 April 2012 to 28 October 2012 Site of Caller Case Count Site of Exposure Case Count Health Care Facility 5 0 Other 2 0 Other Residence 0 1 Own Residence 4 9 Public Area 0 0 Restaurant/food service 0 0 School 0 1 Unknown 0 0 Workplace 0 0 Total 11 11 Site Source: AAPCC Table 2 Human Exposure Cases: Age and Gender Distribution The age and gender distribution of human exposures associated with TIRF medicines is outlined in Table 21. Children ≤2 years of age were involved in 2 exposures and children aged 3 to 19 were involved in 1 exposure. Another 8 exposures were reported in adults ≥30 years of age. FDA_141 Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies. Table 21: December 2012 12-month REMS Assessment Report Age and Gender Distribution of Human Exposures Associated with TIRF Medicines: 28 April 2012 to 28 October 2012 Male N (%) Female N (%) Unknown N (%) Total N (%) 1 0 1 (16.7%) 0 1 (9.1%) 2 0 1 (16.7%) 0 1 (9.1%) 3-19 1 (20.0%) 0 0 1 (9.1%) 20-29 0 0 0 0 30-39 1 (20.0%) 0 0 1 (9.1%) 40-49 1 (20.0%) 1 (16.7%) 0 2 (18.2%) 50-59 2 (40.0%) 3 (50.0%) 0 5 (45.5%) 60-69 0 0 0 0 Total 5 (45.5%) 6 (54.5%) 0 11 (100.0%) Age (yr) Source: AAPCC Table 3a All fatalities – All Ages and Gender No fatalities were reported in the AAPCC data associated with TIRF medicines (AAPCC Database Table 4). Human Exposure Cases: Number of Substances As shown in Table 22, a single substance was implicated in 6 reported human exposures, and 5 patients were exposed to two or more drugs or products including 1 patient who was exposed to 9 substances. There were no exposure- related fatalities. For cases that involved multiple substances, the route of exposure is only captured for one of the substances; therefore, the reported case may include fentanyls that are not oral or inhalation formulations and may not be limited to the class of immediate-release fentanyls. FDA_142 Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies. Table 22: December 2012 12-month REMS Assessment Report Number of Substances Involved in Human Exposure Cases Associated with TIRF Medicines or a Fentanyl with Oral or Inhalation as Route of Exposure: 28 April 2012 to 28 October 2012 Case Count N (%) Fatality Case Counta N (%) 1 6 (54.5%) 0 2 1 (9.1%) 0 3 2 (18.2%) 0 4 0 0 5 1 (9.1%) 0 6 0 0 7 0 0 8 0 0 9 1 (9.1%) 0 11 (100.0%) 0 Number of Substances Total a Includes cases with relative contribution to fatality of 1-Undoubtedly responsible, 2-Probably responsible, or 3-Contributory. This excludes reports with outcome of Death INDIRECT. Source: AAPCC Table 5 FDA_143 Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies. December 2012 12-month REMS Assessment Report Reason for Exposure The reasons for both unintentional (general and misuse) and intentional (abuse, suspected suicide, and unknown) human exposures associated with TIRF medicines are shown in Table 23. Table 23: Reason for Human Exposure Cases Associated with TIRF Medicines: 28 April 2012 to 28 October 2012 Reason Category Case Count N (%) Unintentional Unintentional - General 2 (50.0%) Unintentional - Therapeutic error 2 (50.0%) Subtotal 4 (36.4%) Intentional Intentional - Abuse 1 (14.3%) Intentional - Misuse 2 (28.6%) Intentional - Suspected suicide 3 (42.9%) Intentional - Unknown 1 (14.3%) Subtotal 7 (63.6%) Total 11 (100.0%) Source: AAPCC Table 6a. Therapeutic Errors There were 2 reports of therapeutic errors associated with TIRF medicines in the current reporting period (AAPCC Database Table 6B) as shown in Table 24. The therapeutic errors included incorrect dosing route and wrong medication taken/given in patients >19 years of age. FDA_144 Transmucosal Immediate Release Fentanyl (TTRF) TIRF REMS Industry Group (TRIG) of Companies. December 2012 12-month REMS Assessment Report Table 24: Distribution of Therapeutic Errorsa by Age Associated with TIRF Medicines: 28 April 2012 to 28 October 2012 Unknown Unknown <6 years 6-12 years 13-19 years >19 years Child Adult Unknown Scenario (Row (Row (Row o/o) (Row (Row (Row (Row Total Incorrect Dosing Route 0 0 0 1 (100.0%) 0 0 0 Dispensing Cup Error 10-Fold Dosing Error Inadvertently Took/Given Someone Else's Medication Inadvertently Took/Given Medication Twice Incorrect Formulation or Concentration Given Incorrect Formulation or Concentration Dispensed Wrong Medication Taken/Given 0 0 0 1 (100.0%) 0 0 0 1 Health Professional Iatrogenic Error Exposure Through Breast Milk More Than One Product Containing Same Ingredient Medication Doses Given/1' aken Too Close Together Confused Units Of Measure Other Incorrect Dose Drug Interaction Other/Unknown Therapeutic Error All cases with a scenario category of therapeutic error regardless of reason. Source: AAPCC Table 6b. 45 Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies. December 2012 12-month REMS Assessment Report Reason of Exposure by Age Intentional and unintentional exposures by age are shown in Table 25. Adults >19 years of age accounted for 8 human exposures, 6 intentional and 2 unintentional. There was 1 intentional exposure in a teenager 13 to 19 years of age, and 2 unintentional exposures in children <6 years of age. FDA_146 Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies. Table 25: December 2012 12-month REMS Assessment Report Distribution of Reason for Exposure by Age Associated with TIRF Medicines: 28 April 2012 to 28 October 2012 <6 years 6-12 years 13-19 years >19 years Unintentional 2 0 0 2 0 0 Intentional 0 0 1 6 0 Total 2 0 1 8 0 Reason Unknown Unknown Unknown Child Adult Age Missing Total 0 0 4 0 0 0 7 0 0 0 11 Source: AAPCC Table 7 FDA_147 Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies. December 2012 12-month REMS Assessment Report Reason of Exposure by Age for Fatalities There were no reports of unintentional fatalities from exposure to TIRF medicines (AAPCC Database Table 8). Route of Exposure Ingestion was the route of exposure in 11 of 11 cases associated with TIRF medicines (Table 26). Each exposure case may have more than one route Table 26: Route of Exposure for Human Exposure Cases: 28 April 2012 to 28 October 2012 Human Exposures Fatal Exposuresa Ingestion 11 0 Totalb 11 0 Route a Includes cases with relative contribution to fatality of 1-Undoubtedly responsible, 2-Probably responsible, or 3-Contributory. This excludes reports with outcome of Death INDIRECT. b Each exposure case may have more than one route. Source: AAPCC Table 9 Medical Outcome Table 27 displays the medical outcome of human exposure cases associated with TIRF medicines distributed by age. A greater number of severe medical outcomes was observed in the older age groups. Table 28 compares medical outcome and reason for exposure and shows a higher frequency of serious outcomes in intentional (n=7) versus unintentional exposures (n=4). FDA_148 Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies. Table 27: December 2012 12-month REMS Assessment Report Medical Outcome of Human Exposure Cases by Patient Age: 28 April 2012 to 28 October 2012 Outcome <6 years N (%) 6-12 years N (%) 13-19 years N (%) >19 years N (%) Unknown Child N (%) Unknown Adult N (%) Unknown Age N (%) Total N (%) No effect 1 (50.0%) 0 0 2 (25.0%) 0 0 0 3 (27.3%) Minor effect 1 (50.0%) 0 0 3 (37.5%) 0 0 0 4 (36.4%) Moderate effect 0 0 1 (100.0%) 0 0 0 0 1 (9.1%) Major effect 0 0 0 1 (12.5%) 0 0 0 1 (9.1%) Death 0 0 0 0 0 0 0 0 No follow-up, nontoxic 0 0 0 0 0 0 0 0 No follow-up, minimal toxicity 0 0 0 2 (25.0%) 0 0 0 0 No follow-up, potentially toxic 0 0 0 0 0 0 0 0 Unrelated effect 0 0 0 0 0 0 0 0 Confirmed nonexposure 0 0 0 0 0 0 0 0 Death, indirect report 0 0 0 0 0 0 0 0 2 (18.2%) 0 1 (9.1%) 8 (72.7%) 0 0 0 11 (100.0%) Total Source: AAPCC Table 11 FDA_149 Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies. Table 28: December 2012 12-month REMS Assessment Report Medical Outcome by Reason for Exposure in Human Exposures: 28 April 2012 to 28 October 2012 Outcome Unintentional N (%) Intentional N (%) Other N (%) Unknown N (%) Total N (%) No effect 2 (50.0%) 1 (14.3%) 0 0 3 (27.3%) Minor effect 1 (25.0%) 3 (42.9%) 0 0 4 (36.4%) Moderate effect 0 1 (14.3%) 0 0 1 (9.1%) Major effect 0 1 (14.3%) 0 0 1 (9.1%) Death 0 0 0 0 0 No follow-up, nontoxic 0 0 0 0 0 No follow-up, minimal toxicity 1 (25.0%) 1 (14.3%) 0 0 2 (18.2%) No follow-up, potentially toxic 0 0 0 0 0 Unrelated effect 0 0 0 0 0 Confirmed nonexposure 0 0 0 0 0 Death, indirect report 0 0 0 0 0 4 (36.4%) 7 (63.6%) 0 0 11 (100.0%) Total Source: AAPCC Table 12 FDA_150 Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies. 8 December 2012 12-month REMS Assessment Report PERIODIC SURVEYS OF STAKEHOLDERS An important component of the TIRF REMS assessment is the conduct of quantitative evaluation surveys to assess patients’ and caregivers,’ pharmacists, and prescribers knowledge, attitudes, and behavior (KAB) regarding the safe use of TIRF medicines as described in the educational materials of all stakeholders, enrollment form (pharmacists and prescribers only) and Prescribing Information (pharmacists and prescribers only) of each product. The protocols describe the administration of the individual surveys that were conducted among patients, pharmacists, and prescribers who are treated with TIRF medicines, or their caregivers (see Appendix 11.4.1, 11.4.2, and 11.4.3, respectively, for the patient, pharmacist, and prescriber survey protocols). Data from the surveys, together with other REMS evaluation metrics, will be used to determine whether changes need to be made to the REMS processes or educational materials to make them more effective in achieving the goals of the REMS. The surveys are implemented so that data are available for inclusion in the REMS Assessment Reports 12 months after approval of the TIRF REMS and annually thereafter. 8.1 8.1.1 Patient KAB Survey Survey Statistics Based on the number of prescriptions filled during the 90 days prior to 12 September 2012, the national pharmacy chain network partner identified 1112 possible participants among patients and caregivers. All of these possible participants were sent a survey invitation letter. A total of 899 follow up letters were sent to non-responders on 08 October 2012. Of the 1112 possible participants, 198 respondents indicated interest in the survey and were screened for eligibility to participate and 192 respondents met eligibility criteria and completed the survey. Of these 192 respondents, 112 (56.6%) completed the survey online, and 80 (40.4%) completed it by telephone. Although, the survey had a target of 300 eligible completed responders, the initial population of 1112 possible participants was small. The response of 192 completed surveys is within the expected response rate (10%) to mailed invitations. To increase participation in the survey, recruitment methodology and inclusion criteria will be evaluated in future survey waves. Of the 198 respondents, the screening procedure identified 192 eligible participants (including 190 patients and 2 caregivers) all of whom completed the survey. Due to the small number of caregivers participating in the survey, the majority of results are reported for patients and caregivers combined. FDA_151 Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies. 8.1.2 December 2012 12-month REMS Assessment Report Demographics and Respondent Characteristics The majority of respondents were above the age of 40 years (88.0%), female (63.0%), and had at least some college or Associate’s degree or higher education (153, 79.7%). Participants were largely from the Midwest (32.3%) or South (39.6%) with the Northeast accounting for 13.5% and the West 14.0% of the respondents. 8.1.3 TIRF Educational Materials Most respondents, 173 (90.1%), reported they received a Medication Guide for the TIRF medicine prescribed to them. Of these 173 respondents, 158 (91.3%) received the Medication Guide from the pharmacy; 167 (96.5%) read the Medication Guide of those who read it, 109 (65.3%) read all of it and 41 (24.6%) most of it. From these 167 respondents, 96 (57.5%) understood all of the Medication Guide and 58 (34.7%) most of it. When asked if they had received, read, and understood the Patient-Prescriber Agreement Form (PPAF), 134 (69.8%) respondents confirmed that someone at the doctor’s office offered to explain the PPAF to them, and that 113 (84.3%) of them understood all of it and 19 (14.2%) understood most of it. The PPAF was signed by 144 (75.0%) respondents; of these 144 responders, 113 reported receiving a copy of the signed PPAF. 8.1.4 Patient Survey Results The specific goals of the TIRF medicines patient KAB survey were to evaluate the level of knowledge and assess the attitudes and behavior of patients and caregivers regarding TIRF medicines. The focus of the survey included the potential for life-threatening breathing problems that can lead to death, the need for patients to take TIRF medicines if they are opioidtolerant and strictly follow the directions of the HCP, the caution that patients should not switch from a TIRF medicine to another medicine that contains fentanyl without talking to an HCP, the requirements that patients should not give TIRF medicines to anyone else even if they have the same symptoms, and that TIRF medicines should be stored in a safe place away from children and properly disposed. 8.1.4.1 Key Risk Message 1 Key Risk Message 1 refers to the patient’s knowledge that TIRF medicines can cause lifethreatening breathing problems that can lead to death. Analysis of responses to Question 12d for Key Risk Message 1 showed that 90.1% of the respondents were aware of the risk of life-threatening breathing problems with TIRF medicines. 8.1.4.2 Key Risk Message 2 Key Risk Message 2 refers to the respondents’ knowledge that they should not take TIRF Medicines if they are not opioid tolerant. Three questions define this key risk message. FDA_152 Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies. December 2012 12-month REMS Assessment Report In response to the statement in Question 10 that TIRF medicines should only be taken by patients who are opioid tolerant, 90.6% respondents gave the correct (true) response. The majority of respondents understood that opioid tolerant means that a patient is already taking other opioid pain medicines around the clock and their body is used to these medicines (91.7%), and the majority also understood that it is not okay for patients to take TIRF medicines for headache pain (70.8%). Evidence of understanding this key risk information is further supported by the average number of 2.5 out of a possible 3 correct responses. 8.1.4.3 Key Risk Message 3 Key Risk Message 3 refers to the patient’s knowledge that TIRF medicines should be taken exactly as prescribed by the healthcare provider. Three questions define this key risk message). Less than half (42.7%) of respondents understood that if a patient stops taking around-the-clock opioid pain medicine, they must also stop taking the TIRF medicine. However, all patients (100%) understood that TIRF medicines should be taken exactly as prescribed by the doctor and 82.3% of respondents knew that is not OK to take TIRF medicines for short-term pain that will go away in a few days. Evidence of understanding this key risk information is further supported by the average number of 2.3 out of a possible 3 correct responses. 8.1.4.4 Key Risk Message 4 Key Risk Message 4 refers to the patient’s knowledge that they must not switch TIRF medicines without talking to a healthcare provider. The majority of respondents (96.9%) understood that it is not safe to switch to another medicine that contains fentanyl without talking to a healthcare provider first. 8.1.4.5 Key Risk Message 5 Key Risk Message 5 refers to the patient’s knowledge that TIRF medicines should not be given to anyone else even if they have the same symptoms. All (100%) respondents understood that a patient may not give TIRF medicines to another person if they have the same symptoms as the patient, and 97.9% understood that selling or giving away TIRF medicines is against the law. Evidence of understanding this key risk information is further supported by the average number of 2.0 out of a possible 2 correct responses. 8.1.4.6 Key Risk Message 6 Key Risk Message 6 refers to the patient’s knowledge that TIRF medicines should be stored in a safe place away from children and properly disposed. FDA_153 Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies. December 2012 12-month REMS Assessment Report All (100%) respondents understood that TIRF medicines should be stored in a safe place out of the reach of children. The majority of respondents understood that TIRF medicines must be disposed of as described in the specific product’s Medication Guide (95.8%); a TIRF medicine can cause an overdose and death in any child who takes it (90.6%); and that they should get emergency help right way (89.1%) when asked, “What should you do if an adult who has not been prescribed a TIRF medicine takes a TIRF medicine?” Evidence of understanding this key risk information is further supported by the average number of 3.8 out of a possible 4 correct responses. 8.1.5 Additional Safety Questions about TIRF Medicines Safety Respondents answered additional questions beyond those associated with the key risk messages. These questions assessed whether the patient had been informed of the risks and possible side effects, indications, usage, and storage, and the availability of TIRF medicines through the TIRF REMS Access program. Most respondents (67.7% to 89.6%) were aware of the clinical conditions for using TIRF medicines; however, the awareness was low regarding use in chronic non-cancer pain with only 24.5% of respondents correctly responding false. The majority of patients were told by their doctor, nurse, or other healthcare provider how to use their TIRF medicine (93.8%) and how to properly store the medicine (80.7%). Half (50.5%) of all patients understood that TIRF medicines are only available through the TIRF REMS Access program. 8.2 8.2.1 Pharmacy KAB Survey Survey Statistics A total of 7236 pharmacists were invited to participate in this survey. Of those invited to participate, 6286 were outpatient pharmacists, 650 were inpatient pharmacists, and 300 were pharmacists practicing in Closed System Pharmacies (CSPs). In order to increase the total overall response, 98 out bound calls were made from 09 October 2012 to 11 October 2012. Reminder invitations were sent to potential participants to reduce volunteer bias. Some pharmacists received more than 1 reminder. In all, a total of 302 pharmacists met eligibility criteria and completed the survey. Of these 302 pharmacists, 286 (94.7%) completed the survey online, and 16 (5.3%) completed it by telephone. From the 302 respondents, 304 surveys were collected. It was identified that 2 respondents completed the survey twice. Only the first completed survey was included in the analysis for FDA_154 Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies. December 2012 12-month REMS Assessment Report each respondent. Of the 302 pharmacists who completed the survey, 6 were CSP pharmacists, 16 were inpatient pharmacists, and 280 were outpatient pharmacists. A total of 348 pharmacists agreed to participate in this survey and 304 of these pharmacists worked in pharmacies that were enrolled in the TIRF REMS. Of the 348 total respondents, 44 were ineligible to participate in the survey because they worked in pharmacies that were not enrolled or they did not know whether their pharmacy was enrolled in the TIRF REMS. Of the 304 respondents who reported that their pharmacies were enrolled in the TIRF REMS Access Program, one respondent was ineligible for the survey because the respondent, or an immediate family member, had worked for a TRIG company in the past, and one respondent did not know whether he/she or an immediate family member had worked for a TRIG company, UBC, Specialty Care Solutions, RelayHealth, or FDA in the past. 8.2.2 Demographic and Respondent Characteristics The majority of eligible respondents who completed the survey were male (66.9%). Respondents from the South, Northeast, and Midwest reflected 34.4%, 26.5%, and 21.5% of total respondents, respectively, while respondents from the Western region of the US composed 17.2%, of the total survey population. The proportion of eligible completed pharmacists within each geographic region was similar to the overall proportion of pharmacists (37,480 pharmacists enrolled in the TIRF REMS Access Program as of 15 August 2012) in each geographic region. Almost half (48.0%) had been a practicing pharmacist for more than 15 years. The majority of pharmacists (82.1%) functioned as the pharmacist in charge for the TIRF REMS Access Program where they worked. Most pharmacists (74.2%) had dispensed a TIRF medicine zero to 2 times per month within the past 6 months, and had dispensed Actiq or generic Actiq most frequently within the 6 months prior to taking the survey (76.7%). 8.2.3 TIRF Educational Materials Pharmacists were asked about their access to educational materials for TIRF medicines, specifically the Full Prescribing Information and the Medication Guide. Most respondents reported they received or had access to the Full Prescribing Information and the Medication Guide (97.7% and 97.0%, respectively). Of those with access to these materials, 75.3% and 82.9%, respectively, indicated that they had read the Full Prescribing Information and the Medication Guide. 8.2.4 Pharmacy Survey Results The TIRF medicines pharmacist KAB survey is a systematic approach to measuring knowledge, attitudes, and behaviors associated with the prescribing of TIRF medicines and risks associated with its use. FDA_155 Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies. December 2012 12-month REMS Assessment Report 8.2.4.1 Key Risk Message 1 Key Risk Message 1 refers to the pharmacist’s knowledge of the specific contraindications for TIRF medicines in patients. Analysis of responses to components of Question 6 for Key Risk Message 1 showed that a high percentage of pharmacists know that TIRF medicines are contraindicated in opioid non-tolerant patients (86.1%) and that death has occurred in opioid non-tolerant patients treated with some fentanyl products (92.1%). Most pharmacists were aware patients just starting a TIRF medicine must begin with titration from the lowest available dose for that product (78.5%) and that TIRF medicines may not be used to treat opioid non-tolerant patients (78.5%). Evidence for understanding of this key risk information is further supported by the average number of 3.4 out of 4 correct responses. 8.2.4.2 Key Risk Message 2 Key Risk Message 2 refers to the pharmacist’s knowledge of the approved indications for prescribing TIRF medicines to opioid tolerant patients. Responses to components of Question 8 for Key Risk Message 2 indicate that most pharmacists were aware TIRF medicines are prescribed for adult opioid-tolerant patients with breakthrough pain from cancer (83.4%) and not for patients with acute or postoperative pain (78.1%), headache or migraine pain (89.1%), or dental pain (94.7%). Evidence for understanding of this key risk information is further supported by an average number of 3.5 out of 4 correct responses. 8.2.4.3 Key Risk Message 3 Key Risk Message 3 refers to the pharmacist’s knowledge of the risk factors and signs and symptoms of opioid abuse in patients who take TIRF medicines. Responses to components of Questions 6, 7, and 9 for Key Risk Message 3 showed that a high percentage of pharmacists were aware that it is important to monitor for signs of abuse and addiction in patients who take TIRF medicines (97.7%), a personal history of past or current alcohol or drug abuse or family history of drug and alcohol abuse is a risk factor for opioid abuse (99.7%), and that TIRF medicines can be abused in a manner similar to other opioid agonists (90.4%). More than half of pharmacists were aware that a personal history of psychiatric illness is a risk factor for opioid abuse (66.6%). Evidence for understanding of this key risk information is further supported by an average number of 3.5 out of 4 correct responses. 8.2.4.4 Key Risk Message 4 Key Risk Message 4 refers to the pharmacist’s knowledge that TIRF medicines are not interchangeable regardless of the route of administration. . FDA_156 Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies. December 2012 12-month REMS Assessment Report Responses to components of Question 9 for Key Risk Message 4 showed that a high percentage of pharmacists understood TIRF medicines are not interchangeable with each other regardless of the route of administration (95.0%), the conversion of one TIRF medicine to another may result in a fatal overdose (92.7%), and dosing of TIRF medicines is not equivalent on a microgram-to-microgram basis (92.4%). Evidence for understanding of this key risk information is further supported by an average number of 2.8 correct responses out of 3. 8.2.5 Additional Safety Questions about TIRF Medicines Safety Despite the high proportion of pharmacists responding correctly to the questions around Key Risk Message 1 (i.e., that patients must be opioid tolerant), only 12.6% of pharmacists correctly indicated that patients considered opioid tolerant are those who are taking regular opioid therapy for 1 week or longer. Additionally, 15.6% correctly indicated that patients not currently taking opioid therapy but who have no known intolerance or hypersensitivity to fentanyl are not considered opioid tolerant. In contrast a high percentage (80.1%) correctly indicated patients not currently taking opioid therapy but who had taken opioid therapy before are not considered opioid tolerant. Because the results for the 2 components of Question 5 are discrepant from the other pharmacist results around opioid tolerance, it is possible that these results reflect a misunderstanding of the question rather than a lack of understanding of the important safety information. Additional research will be conducted to explore pharmacists’ interpretation and understanding of all 3 components of Question 5. The outcome of the research will be included in the next assessment report, and action proposed, if appropriate. 8.2.6 Pharmacist Activities When Dispensing TIRF Medicines More than half of the pharmacists indicated they always give patients (or their caregivers) the Medication Guide for TIRF medicine (90.1%), instruct the patient (or their caregivers) not to share TIRF medicines (66.9%), counsel patients (or their caregivers) that accidental exposure to TIRF medicines by a child may be fatal (62.9%), instruct patients (or their caregivers) to keep TIRF medicines out of reach of children (68.9%), and instruct patients (or their caregivers) about proper disposal of any unused or partially used TIRF medicines (57.0%). Almost half (48.3%) always ask patients (or their caregivers) about the presence of children in the home, but 22.5% ask only with the first prescription. 8.3 8.3.1 Prescriber KAB Survey Survey Statistics A total of 5330 prescribers were sent letters inviting them to participate in this survey. An additional 3505 reminder letters were sent. Prescribers may have received more than 1 reminder letter. In all, a total of 302 prescribers met the eligibility criteria, and completed the survey. Of these 302 prescribers, 293 (97.0%) completed the survey online, and 9 (3.0%) completed it by telephone. FDA_157 Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies. December 2012 12-month REMS Assessment Report A total of 358 prescribers agreed to participate in this survey and of those 315 prescribers were enrolled in the TIRF REMS Access program; 43 prescribers were ineligible because they were not enrolled in the program or they did not know whether they were enrolled. Eleven respondents were ineligible for the survey because they, or an immediate family member, had worked for UBC or a TRIG company in the past, or did not know whether they, or an immediate family member, had worked for a TRIG company, UBC, RelayHealth, McKesson Specialty Care Solutions, or FDA in the past, and 2 prescribers preferred not to answer. 8.3.2 Demographics and Respondent Characteristics The majority of respondents were male (59.6%). Respondents from the South, West, and Northeast included 31.1%, 26.8%, and 25.2% of the survey population, respectively; while respondents from the Midwest region of the US composed 16.9%, of the total survey population. The proportion of eligible completed prescribers within each geographic region was similar to the overall proportion of prescribers (7701 prescribers enrolled in the TIRF REMS Access program as of 15 August 2012) in each geographic region. The most common healthcare degree was an MD (57.0%), and the most common medical specialties were pain management (50.7%) and oncology (22.5%). Of respondents who were medical doctors, most respondents (50.7%) had practiced medicine for more than 15 years. Of prescribers who described their medical specialty as ‘other,’ the majority (5.0%) stated their medical specialty was General Medicine, followed by Neurology and Rehabilitation (5% each). Nearly half (46.7%) of the prescribers prescribed TIRF medicines 1 to 2 times a month within the past 6 months, and Actiq or generic Actiq was most frequently prescribed TIRF medicine (79.6% of prescribers). 8.3.3 TIRF Educational Materials Prescribers were asked about their awareness of educational materials for TIRF medicines, specifically the Full Prescribing Information, the Medication Guide, and the PPAF. Most respondents received or had access to the Full Prescribing Information and the Medication Guide (94.4% and 90.4%, respectively). Of those with access to these materials, 80.0% and 89.0%, respectively, indicated that they had read the Full Prescribing Information and the Medication Guide. Additionally, most prescribers review the PPAF with each patient or their caregiver (88.1%), and, following review, the majority of those prescribers (94.0%) sign and have the patient/caregiver sign the form, and 82.5% give a copy of the PPAF to the patient or their caregiver. FDA_158 Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies. 8.3.4 December 2012 12-month REMS Assessment Report Prescriber Survey Results 8.3.4.1 Key Risk Message 1 Key Risk Message 1 assesses the prescriber’s knowledge of the specific contraindications for TIRF medicines in patients. Analysis of responses to components of Question 6 for Key Risk Message 1 showed that a high percentage of prescribers know that TIRF medicines are contraindicated in opioid non-tolerant patients because life-threatening respiratory depression could occur (87.4%) and that death has occurred in opioid non-tolerant patients treated with some fentanyl products (95.7%). Most prescribers were aware patients just starting a TIRF medicine must begin with titration from the lowest available dose for that product (83.1%) and that TIRF medicines may not be used to treat opioid non-tolerant patients (82.5%). This is further supported by an average number of correct responses of 3.5 out of 4. 8.3.4.2 Key Risk Message 2 Key Risk Message 2 assesses the prescriber’s knowledge of the approved indications for prescribing TIRF Medicines to opioid tolerant patients. Responses to components of Question 8 for Key Risk Message 2 indicate that a high percentage of prescribers were aware TIRF medicines are prescribed for adult opioid-tolerant patients with breakthrough pain from cancer (95.4%) and not for patients with acute or postoperative pain (86.4%), headache or migraine pain (86.8%),or dental pain (96.0%). This is further supported by an average number of correct responses of 3.6 out of 4. 8.3.4.3 Key Risk Message 3 Key Risk Message 3 assesses the prescriber’s knowledge of the risk factors and signs and symptoms of opioid abuse in patients who take TIRF medicines. Responses to components of Questions 6, 7, and 9 for Key Risk Message 3 showed that a high percentage of prescribers were aware that it is important to monitor for signs of abuse and addiction in patients who take TIRF medicines (99.7%), a personal history of psychiatric illness is a risk factor for opioid abuse (82.5%), a personal history of past or current alcohol or drug abuse or family history of drug and alcohol abuse is a risk factor for opioid abuse (99.3%), and that TIRF medicines can be abused in a manner similar to other opioid agonists (97.7%). This is further supported by an average number of correct responses of 3.8 out of 4. 8.3.4.4 Key Risk Message 4 Key Risk Message 4 assesses the prescriber’s knowledge that TIRF medicines are not interchangeable regardless of the route of administration. . Responses to components of Question 9 for Key Risk Message 4 showed that a high percentage of prescribers understood TIRF medicines are not interchangeable with each other regardless of FDA_159 Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies. December 2012 12-month REMS Assessment Report the route of administration (95.7%), the conversion of one TIRF medicine to another may result in a fatal overdose (94.7%), and dosing of TIRF medicines is not equivalent on a microgram-tomicrogram basis (90.4%). This is further supported by an average number of correct responses of 2.8 out of 3. 8.3.5 Additional Questions About TIRF Medicines Safety Despite the high proportion of physicians responding correctly to the questions around Key Risk Message 1 (i.e. that patients must be opioid tolerant), only 7.9% of prescribers correctly indicated that patients considered opioid tolerant are those who are taking regular opioid therapy for one week or longer. Additionally, 15.6% correctly indicated patients not currently taking opioid therapy but who have no known intolerance or hypersensitivity to fentanyl are not considered opioid tolerant. In contrast a high percentage (88.7%) correctly indicated patients not currently taking opioid therapy but who had taken opioid therapy before are not considered opioid tolerant. Because the results for the 2 components of Question 5 are discrepant from the other prescriber results around opioid tolerance, it is possible that these results reflect a misunderstanding of the question rather than a lack of understanding of the educational materials. Additional research will be conducted with survey respondents to explore their interpretation and understanding of all 3 components of Question 5. The outcome of the research will be included in the next assessment report, and based on the outcome appropriate action may be taken, such as rephrasing Question 5. 8.3.6 Prescriber Activities When Prescribing TIRF Medicines Prescribers were asked about specific activities performed when prescribing TIRF medicines. More than half of prescribers indicated they always ask patients (or their caregivers) about the presence of children in the home (57.9%), instruct patients (or their caregivers) not to share TIRF medicines (79.1%), counsel patients (or their caregivers) that accidental exposure to TIRF medicines by a child may be fatal (65.9%), instruct patients (or their caregivers) to keep TIRF medicines out of the reach of children (72.8%), instruct patients (or their caregivers) about proper disposal of any unused or partially used TIRF medicines (60.9%). Less than half of prescribers (40.4%) always give patients (or their caregivers) the Medication Guide for their TIRF medicine, but 42.4% give their patients (or their caregivers) the Medication Guide for their TIRF medicine with the first prescription. 8.4 Overall Conclusions for KAB Results Patients: The analyses of responses to questions defining each of the six key risk messages demonstrated that most respondents were well informed about the risks and safe use criteria associated with TIRF medicines. FDA_160 Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies. December 2012 12-month REMS Assessment Report Overall, this patient survey shows that the ongoing patient-oriented educational process is meeting its objectives in that the majority of patients completing the survey were aware of the key issues related to their use of a TIRF medication. Pharmacists and Prescribers: Among responses to all questions about the safe use of TIRF medicines, there were two questions relating to the definition of a non-opioid tolerant patient that had low correct response rates for both pharmacist and prescribers. A minority of prescribers and pharmacists correctly indicated that patients considered opioid tolerant are those who are taking regular opioid therapy for one week or longer (12.6% pharmacists and 7.9% prescribers). Few prescribers and pharmacists correctly indicated patients not currently taking opioid therapy but who have unknown intolerance or hypersensitivity to fentanyl are not considered opioid tolerant (15.6%, for prescribers and pharmacists). Because both pharmacists and prescribers had low correct response rates for both of these questions, and because the high correct response rates for the other related risk messages, including other questions about opioid tolerance, this may possibly indicate a challenge in understanding the questions and not a knowledge issue. Additional research will be conducted to explore these results. The outcome of the research will be included in the next assessment report, and, based on the outcome, appropriate action may be taken. Across the surveys for all key risk messages both pharmacists and prescribers demonstrated a high level of understanding that TIRF medicines are contraindicated in opioid non-tolerant patients, are only indicated for the management of breakthrough pain in adult patients with cancer, contain fentanyl with abuse liability similar to other opioid analgesics, and are not interchangeable with each other regardless of route of administration. 9 FDA COMMUNICATIONS During this reporting period, 2 letters and multiple modified PPAFs were received by the TIRF REMS Access program (see Section 6, ID#1). The TRIG shared this feedback from prescribers with the FDA. 10 POST-APPROVAL STUDIES AND CLINICAL TRIALS FDA should refer to the most recent annual report for each TIRF sponsor for updated information on post-approval studies and/or clinical trials. 11 OVERALL CONCLUSIONS The TIRF REMS Access program was successfully launched on 12 March 2012, approximately 11 weeks after REMS approval. Between 27 April 2012 and 28 October 2012, prescribers, FDA_161 Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies. December 2012 12-month REMS Assessment Report patients, and pharmacies were transitioned from individual REMS programs and 8747 additional stakeholders successfully enrolled in the TIRF REMS Access program. With an overall volume of more than 54,614 prescriptions authorized for REMS edits, there were few reports of patients unable to gain access to TIRF medicines or reports of system issues. Only a few instances of un-enrolled physicians prescribing TIRF medicines, un-enrolled pharmacies dispensing, or un-enrolled patients receiving product were identified. A thorough investigation is applied to all of these instances, and, where complete, corrective actions have been documented. The TIRF REMS Access program system continues to be monitored for issues and, where appropriate, corrective actions instituted. Sponsors remain vigilant in monitoring spontaneous reports and external data sources, such as AAPCC, to identify safety risks. The REMS goal of educating prescribers and pharmacists on the potential for misuse, abuse, addiction, and overdose is being documented through the implementation of the Knowledge Assessment, which is required for enrollment. Additional information obtained through the pharmacy and prescriber KAB surveys shows that both pharmacists and prescribers demonstrated a high level of understanding that TIRF medicines are contraindicated in opioid non-tolerant patients, are only indicated for the management of breakthrough pain in adult cancer patients, contain fentanyl with abuse liability similar to other opioid analgesics, and are not interchangeable with each other regardless of route of administration. Additional research will be conducted to understand challenges in comprehension of questions with low correct response rates for prescribers and pharmacists. The outcome of this research will be included in the next assessment report, and, based on the outcome, appropriate action may be taken. Patient education is completed through healthcare provider counseling and completion of a PPAF. The patient KAB survey results showed that the ongoing patient-oriented educational process is meeting its objectives in that the majority of patients completing the survey were aware of the key issues related to their use of a TIRF medication (i.e., not sharing TIRF medicines, taking TIRF medicines as prescribed, and proper disposal of TIRF medicines). Surveillance methods using AAPCC data identified few reported exposures to poison centers. There were 12 cases of exposure to unknown fentanyl reported to the AAPCC during the current reporting period, including 7 fatalities. There were 11 cases of exposure to known oral fentanyl immediate-release medicines reported to the AAPCC, including 3 pediatric exposures. There were no fatalities reported for exposure to TIRF medicines. In the US, 36 FDA AERS case reports were associated with a TIRF medicine exposure, of which 27 of the cases included one of the individual PT of Interest for the TIRF REMS or at least one PT from the MedDRA SMQ, Acute Central Respiratory Depression. Not surprisingly, relatively robust signals were generated for the PT of Interest: “Off label Use” and “Drug prescribing error.” These are known adverse events for TIRF medicines. The FDA AERS FDA_162 Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies. December 2012 12-month REMS Assessment Report database will be monitored to understand the impact of the TIRF REMS Access program on the rates of these Preferred Terms of Interest. FDA_163 Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies. December 2012 12-month REMS Assessment Report APPENDICES FDA_164 Transmucosal Immediate Release Fentanyl (TIRF) December 2012 REMS Industry Group (TRIG) of Companies. 12-month REMS Assessment Report 11.1 Medical Dictionary for Drug Regulatory Activities Preferred Terms Primary SOC High Level Group High Level Term Preferred Term Overdose Injury. orsonmg and Medication errors Overdoses Accidental overdose procedural complications Injury. porsonnrg and Medication errors Overdoses Intentional overdose procedural complications Injury. orsonmg and Medication errors Overdoses Multiple drug overdose procedural complications Injury. poisoning and Multiple drug overdose . . Medication errors Overdoses . procedural complications accrdental In'u . oisonin and . . Multi 1e dru overdose ry .g . Medications errors Overdoses p. .g procedural complications mtentronal Injury. orsonmg and Medication errors Overdoses Overdose procedural complications Death General disorders and administration site Fatal outcomes Death and sudden death Accidental death conditions Nervous stem disorders Neurological Cortical s?mction NEC Brain death disorders NEC Ventricular and . Cardiac death cardiac arrest Cardiac disorders Cardiac General disorders and administration site Fatal outcomes Death and sudden death Death conditions General disorders and administrations site Fatal outcomes Death and sudden death Death neonatal conditions General disorders and administration site Fatal outcomes Death and sudden death Sudden cardiac death conditions . . . . tn' 1 1 ardrac disorders Cardiac en cu ar arr 1yt mnas an Sudden death cardiac arrest General disorders and administration site Fatal outcomes Death and sudden death Agonal death struggle conditions General disorders and . administration site General system General and Apparent death . . disorders NEC NEC conditions Social Circumstances Family Issues Bereavement issues Death of companion Social Circrunstances Family Issues Bereavement issues Death of relative 65 Transmucosal Immediate Release Fentanyl (TIRF) REMS Industry Group (TRIG) of Companies. 12-month REMS Assessment Report December 2012 Primary SOC High Level Group High Level Term Preferred Term General disorders and administration site conditions Fatal outcomes Death and sudden death Sudden unexplained death in epilepsy Respiratory. thoracic and mediastinal disorders Respiratory disorders NEC Breathing abnormalities ardio respiratory arrest Cardiac disorders Cardiac Ventricular and cardiac arrest Cardiac arrest Respiratory. thoracic and mediastinal disorders Respiratory disorders NEC Breathing abnormalities Respiratory arrest Misuse General disorders and administration site conditions Therapeutic and nontherapeutic e?ects (excl toxicity) Withdrawal and rebound effects Medication overuse headache disorders disorders NEC Substance-related disorders Intentional drug misuse Drug abuse dependence and withdrawal SMQ (Standardized Query) Abuse disorders disorders NEC Substance-related disorders Drug abuse Social circrunstances Lifestyle issues Drug and chemical abuse Drug abuser disorders disorders NEC Substance-related disorders Substance abuse Social circrunstances Lifestyle issues Drug and chemical abuse Substance abuser Social circrunstances Lifestyle issues Drug and chemical abuse Ex-drug abuser Injury. poisoning and procedural complications Exposures. chemical injuries and poisoning Poisoning and toxicity Substance-induced mood disorder Injury. poisoning and procedural complications Exposures. chemical injuries and poisoning Poisoning and toxicity Substance-induced disorder Drug abuse dependence and withdrawal SMQ (Standardized Query) Inappropriate Injury. poisoning and Drug administered at procedures supportive care . . Medication errors Maladrninistrations . . . procedural complications mapproprrate srte Injury. orsonmg and Medication errors Maladrninistrations Inap rop rrate schedule 0f drug procedural complications administration . . Therapeutic Sur real and medical . procedures and Therapeutic procedures NEC Off label use Injury. poisoning and Medication errors Maladrninistrations Drug administered to patient of 66 Transmucosal Immediate Release Fentanyl (TIRF) REMS Industry Group (TRIG) of Companies. December 2012 12-month REMS Assessment Report Primary SOC High Level Group High Level Term Preferred Term procedural complications inappropriate age Medication Error Injury. orsonmg and Medication errors Medication errors NEC Intercepted medication error procedural complications Injury. poisoning and procedural complications Medication errors Medication errors NEC Intercepted drug prescribing error Injury. poisoning and procedural complications Medication errors Medication errors NEC Medication error pril?jel 23:18 Medication errors Maladrninistrations Counterfeit drug administered In'u . oisonin and . . . . . . . . pro cjedfirzil cornpl a tions Medication errors Maladmmistratrons Drug error In'u . oisonin and . . . . . . . pro clecliirzil cornpl a tions Medication errors Drug dose onussron In'u . oisonin and . . . . . . . . pro (i511; compligcations Medication errors Expired drug 1gc :3ng Medication errors Incorrect dose adnmustered In'u . oisonin and . . . . . Incorrect dru administration ry . Medication errors . procedural complications duration In'u . oisonin and . . . . . Incorrect dru administration ry . Medication errors procedural complications rate In'u . oisonin and . . . . . Incorrect dru dosa form ry .g . Medication errors . procedural complications In'u . oisonin and . . . . . Incorrect route of dru ry .g . Medication errors . . . procedural complications admnustratron In'u . oisonin and . . . . . . . . pro $51151 compl 1gc a tions Medication errors Poor quality drug In'u . oisonin and . . . . . Ina ro riate schedule of dru ry . Medication errors pp . . . procedural complications In'u . oisonin and . . . . . pro decliirzil cornpl 1gc ations Medication errors Maladmmistratrons Underdose . Thera eutic and Thera eutic and . General disorders and . . Therapy naive administrative sites nontherapeutrc effects nontherapeutrc responses In'u . oisonin and . . . . . . . pro $51151 compl 1gc a tions Medication errors Wrong drug administered In'u . oisonin and . . . . . Wron teclmi ue in dru usa ry Medication errors procedural complications process Injury. poisoning and procedural complications Medication errors Medication errors NEC Drug dispensing error Injury. poisoning and procedural complications Medication errors Medication errors NEC Drug label confusion Injury. poisoning and procedural complications Medication errors Medication errors NEC Drug name confusion 67 Transmucosal Immediate Release Fentanyl (TIRF) REMS Industry Group (TRIG) of Companies. December 2012 12-month REMS Assessment Report procedural complications Injury. poisoning and procedural complications Medication errors Medication monitoring errors Primary SOC High Level Group High Level Term Preferred Term Injury. (?80ng and Medication errors Medication errors NEC Drug prescribing error procedural complications Injury. 0150111118 and Medication errors Medication errors NEC Incorrect storage of drug procedural complications Injury. porsoning and Medication errors Medication errors NE Intercepted drug Labelled drug?disease interaction medication error Injury. poisoning and procedural complications Medication errors Medication monitoring errors Labelled drug-drug interaction medication error Injury. poisoning and procedural complications Medication errors Maladministrations Drug administered to patient of inappropriate age Injury. poisoning and procedural complications Medication errors Medication errors due to accidental exposures Accidental drug intake by child Injury. poisoning and procedural complications Medication errors Maladministrations Multiple use of a single use product Accidental Injury. poisoning and procedural complications Medication errors Medication errors due to accidental exposures Accidental drug intake by child Injury. poisoning and procedural complications Medication errors Medication errors due to accidental exposures Accidental exposure Injury. poisoning and procedural complications Medication errors Overdoses Accidental overdose Injury. poisoning and procedural complications Chemical injury and poisoning Poisoning and toxicity Accidental poisoning Injury. poisoning and procedural complications Chemical injury and poisoning Poisoning and toxicity Toxicity to various agents Injury. poisoning and Medication errors Overdoses Multiple drug overdose procedural complications accidental Dependence . . . disorders . disorders NE Substance-related disorders Dependence disorders Substance-related disorders Drug dependence Pregnancy. puerperium and perinatal conditions Foetal complications Foetal conditions due to maternal conditions Drug dependence. anteparnun disorders disorders NEC Substance-related disorders Drug dependence. postpartum disorders disorders NEC Substance-related disorders Polysubstance dependence disorders disorders NEC Substance-related disorders Withdrawal disorders disorders NEC Substance-related disorders Drug withdrawal 68 Transmucosal Immediate Release Fentanyl (TIRF) December 2012 TIRF REMS Industry Group (TRIG) of Companies. 12-month REMS Assessment Report Primary SOC I High Level Group High Level Term I Preferred Term Drug Diversion Social circumstances Legal issues Criminal activity Drug diversion . 1 d' 1 Therapeutic urg 1ca a; me 1ca procedures and Therapeutic procedures NEC Off label use proc ures supportive care NEC Respiratory Depression Acute central respiratory depression SMQ (Standardized Query) 69 Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies. December 2012 12-month REMS Assessment Report 11.2 AAPCC LISTINGS The following definitions are used to characterize data in the attached listings of TIRF medicines fentanyl exposures and unknown exposures which were derived AAPCC annual report: Bronstein AC, Spyker DA, Cantilena LR et al. 2010 annual report of the American Association of Poison Control Centers’ National Poison Data System (NPDS): 28th annual report. Clinical Toxicology. 2011;49:910-941. No effect: The patient did not develop any signs or symptoms as a result of the exposure. Minor effect: The patient developed some signs or symptoms as a result of the exposure, but they were minimally bothersome and generally resolved rapidly with no residual disability or disfigurement. A minor effect is often limited to the skin or mucus membranes (e.g., self-limited gastrointestinal symptoms, drowsiness, skin irritation, first-degree dermal burn, sinus tachycardia without hypotension, and transient cough). Moderate effect: The patient exhibited signs or symptoms as a result of the exposure that were more pronounced, more prolonged, or more systemic in nature than minor symptoms. Usually, some form of treatment is indicated. Symptoms were not life-threatening, and the patient had no residual disability or disfigurement (e.g., corneal abrasion, acid-base disturbance, high fever, disorientation, hypotension that is rapidly responsive to treatment, and isolated brief seizures that respond readily to treatment). Major effect: The patient exhibited signs or symptoms as a result of the exposure that were lifethreatening or resulted in significant residual disability or disfigurement (e.g., repeated seizures or status epilepticus, respiratory compromise requiring intubation, ventricular tachycardia with hypotension, cardiac or respiratory arrest, esophageal stricture, and disseminated intravascular coagulation). Death: The patient died as a result of the exposure or as a direct complication of the exposure. FDA_170 Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies. December 2012 12-month REMS Assessment Report A statement on AAPCC data must be included in all publications referencing AAPCC data. The AAPCC maintains the national database of information logged by the country's 57 poison control centers. Case records in this database are from self-reported calls: they reflect only information provided when the public or healthcare professionals report an actual or potential exposure to a substance (e.g., an ingestion, an inhalation, or a topical exposure, etc.), or request information/educational materials. Exposures do not necessarily represent a poisoning or overdose. The AAPCC is not able to completely verify the accuracy of every report made to member centers. Additional exposures may go unreported to PCCs and data referenced from the AAPCC should not be construed to represent the complete incidence of national exposures to any substance(s). All data produced from the AAPCCs databases during the year in which the exposures occur is considered preliminary. Changes occur in only a small number of cases each year. This is because it is possible that a poison center may update a case anytime during that year if new data is obtained. In the fall of each year the data for the previous year is locked and no changes are permitted. At that time the data for a year is considered closed. FDA_171 Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies. December 2012 12-month REMS Assessment Report AAPCC Listing of Exposures to Known TRIG TIRF Immediate-Release Oral Medicines Subject 1 Start Date Public Case Number Age (yrs) Gender Substance Rank No of Substances Formulation Quantity Quantity Unit Major Category 5/3/12 31874263522012 55 Female 3 3 Solid (tablets / capsules / caplets) NULL Unknown Fentanyl Intentional Suspected suicide Intentional Suspected suicide No effect 5/3/12 31874263522012 55 Female 1 3 Solid (tablets / capsules / caplets) 10.8 g Other Types of Anticonvulsant (Excluding Barbiturates) 5/3/12 31874263522012 55 Female 2 3 Solid (tablets / capsules / caplets) 19 mg Benzodiazepines Reason For Exposure Intentional Suspected suicide 2 3 6 No effect No effect 7/9/12 1488183362012 59 Female 1 1 Other 1 each (e.g. bites / stings) Fentanyl Intentional Misuse Not followed, minimal clinical effects possible (no more than minor effect possible) 7/13/12 19228193742012 45 Male 1 1 Solid (tablets / capsules / caplets) 16 tabs / pills / capsules Fentanyl Intentional Misuse Minor effect 2 tabs / pills / capsules Fentanyl Unintentional Therapeutic error 4 5 Medical Outcome 7/19/12 22802523012012 32 Male 1 3 Solid (tablets / capsules / caplets) 7/19/12 22802523012012 32 Male 2 3 Solid (tablets / capsules / caplets) 2 tabs / pills / capsules Beta Blockers (Including All Propranolol Cases) Unintentional Therapeutic error 7/19/12 22802523012012 32 Male 3 3 Solid (tablets / capsules / caplets) 2 tabs / pills / capsules Nitroglycerin Unintentional Therapeutic error 7/26/12 729172193542012 2 Female 1 1 Other 100 mcg Fentanyl 7/29/12 4724053302012 57 Male 3 9 Other NULL Unknown Fentanyl 7/29/12 4724053302012 57 Male 1 9 Solid (tablets / capsules / caplets) NULL Unknown Colchicine 7/29/12 4724053302012 57 Male 2 9 Solid (tablets / capsules / caplets) NULL Unknown Acetylsalicylic Acid Alone, Adult Formulations 7/29/12 4724053302012 57 Male 4 9 NULL Unknown Long-Acting Nitrates 7/29/12 4724053302012 57 Male 5 9 NULL Unknown Thiazide Solid (tablets / capsules / caplets) Solid (tablets / capsules / caplets) Not followed, minimal clinical effects possible (no more than minor effect possible) Not followed, minimal clinical effects possible (no more than minor effect possible) Not followed, minimal clinical effects possible (no more than minor effect possible) Unintentional General Intentional Suspected suicide Intentional Suspected suicide Minor effect Intentional Suspected suicide Minor effect Intentional Suspected suicide Intentional Suspected suicide No effect Minor effect Minor effect Minor effect FDA_172 Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies. December 2012 12-month REMS Assessment Report AAPCC Listing of Exposures to Known TRIG TIRF Immediate-Release Oral Medicines Subject 7 8 9 10 11 Start Date Public Case Number Age (yrs) Gender Substance Rank No of Substances Formulation Quantity Quantity Unit Major Category Angiotensin Converting Enzyme Inhibitors Other Types of Gamma Aminobutyric Acid Anticonvulsant Reason For Exposure Medical Outcome Intentional Suspected suicide Minor effect Intentional Suspected suicide Minor effect 7/29/12 4724053302012 57 Male 6 9 Solid (tablets / capsules / caplets) NULL Unknown 7/29/12 4724053302012 57 Male 7 9 Solid (tablets / capsules / caplets) NULL Unknown 7/29/12 4724053302012 57 Male 8 9 Solid (tablets / capsules / caplets) NULL Unknown Tramadol Intentional Suspected suicide Minor effect 7/29/12 4724053302012 57 Male 9 9 Solid (tablets / capsules / caplets) NULL Unknown Beta Blockers (Including All Propranolol Cases) Intentional Suspected suicide Minor effect 8/6/12 10270173702012 52 Male 1 1 Solid (tablets / capsules / caplets) 1 tabs / pills / capsules Fentanyl Unintentional Therapeutic error No effect 8/16/12 19757193222012 16 Male 2 2 Unknown NULL Unknown Fentanyl Intentional - Abuse Moderate effect 8/16/12 19757193222012 16 Male 1 2 Other 1 each (e.g. bites / stings) Buprenorphine Intentional - Abuse Moderate effect 8/30/12 24226833092012 50 Female 5 5 8/30/12 24226833092012 50 Female 1 5 8/30/12 24226833092012 50 Female 2 5 8/30/12 24226833092012 50 Female 3 5 8/30/12 24226833092012 50 Female 4 5 9/29/12 729692973262012 17 Female 1 10/23/1 2 23049223012012 44 Female 1 Solid (tablets / capsules / caplets) Solid (tablets / capsules / caplets) Solid (tablets / capsules / caplets) Solid (tablets / capsules / caplets) NULL Unknown Fentanyl NULL Unknown Tapentadol NULL Unknown Morphine Other Types of Antidepressant Other Types of Sedative/Hypnotic/Ant i-Anxiety or AntiPsychotic Drug NULL Unknown Solid (tablets / capsules / caplets) NULL Unknown 1 Solid (tablets / capsules / caplets) 1 tabs / pills / capsules Fentanyl 1 Patch NULL Unknown Fentanyl Intentional Suspected suicide Intentional Suspected suicide Intentional Suspected suicide Intentional Suspected suicide Intentional Suspected suicide Unintentional General Intentional Unknown Major effect Major effect Major effect Major effect Major effect Minor effect Minor effect FDA_173 Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies. December 2012 12-month REMS Assessment Report AAPCC Listing of Exposures to Unknown Fentanyl Subject Start Date Public Case Number Age Gender Substance Rank No of Substances Formulation Quantity Quantity Unit Major Category Reason For Exposure Medical Outcome 1 5/11/12 4169283642012 44 Male 1 4 Unknown NULL Unknown Fentanyl Intentional - Abuse Death, indirect report 5/11/12 4169283642012 44 Male 2 4 Unknown NULL Unknown Methamphetamines Intentional - Abuse Death, indirect report NULL Unknown Benzodiazepines Intentional - Abuse Death, indirect report NULL Unknown Methadone Intentional - Abuse Death, indirect report NULL Unknown Fentanyl Intentional - Abuse Death, indirect report Intentional - Abuse Death, indirect report 2 3 5/11/12 4169283642012 44 Male 3 4 5/11/12 4169283642012 44 Male 4 4 5/12/12 4170313642012 23 Female 1 3 6 Unknown 5/12/12 4170313642012 23 Female 2 3 Solid (tablets / capsules / caplets) NULL Unknown Other Types of Skeletal Muscle Relaxant 5/12/12 4170313642012 23 Female 3 3 Solid (tablets / capsules / caplets) NULL Unknown Benzodiazepines Intentional - Abuse Death, indirect report 5/12/12 4170373642012 42 Female 1 3 Unknown NULL Unknown Fentanyl Unknown reason Death, indirect report NULL Unknown Tramadol Unknown reason Death, indirect report NULL Unknown Acetaminophen with Hydrocodone Unknown reason 5/12/12 4170373642012 42 Female 2 3 5/12/12 4170373642012 42 Female 3 3 4 5 Solid (tablets / capsules / caplets) Solid (tablets / capsules / caplets) Solid (tablets / capsules / caplets) Solid (tablets / capsules / caplets) Death, indirect report Unable to follow, judged as a potentially toxic exposure Unable to follow, judged as a potentially toxic exposure 7/15/12 30564603582012 22 Male 1 2 Solid (tablets / capsules / caplets) 40 tabs / pills / capsules Acetaminophen with Hydrocodone Intentional - Abuse 7/15/12 30564603582012 22 Male 2 2 Powder / granules 1 each (e.g. bites / stings) Fentanyl Intentional - Abuse 7/18/12 4264843642012 51 Female 1 5 Unknown NULL Unknown Fentanyl Intentional - Abuse Death, indirect report NULL Unknown Tramadol Intentional - Abuse Death, indirect report Ethanol (Beverages) Intentional - Abuse Death, indirect report 7/18/12 4264843642012 51 Female 2 5 Solid (tablets / capsules / caplets) 7/18/12 4264843642012 51 Female 3 5 Liquid NULL Unknown 7/18/12 4264843642012 51 Female 4 5 Solid (tablets / capsules / caplets) NULL Unknown Benzodiazepines Intentional - Abuse Death, indirect report Diphenhydramine Alone (Unknown if Over the Counter or Prescription) Intentional - Abuse Death, indirect report Fentanyl Intentional - Abuse Death, indirect report Intentional - Abuse Death, indirect report Intentional - Abuse Death, indirect report 7/18/12 4264843642012 51 Female 5 5 Solid (tablets / capsules / caplets) NULL Unknown 8/2/12 4286983642012 36 Male 1 5 Unknown NULL Unknown 8/2/12 4286983642012 36 Male 2 5 Unknown NULL Unknown 8/2/12 4286983642012 36 Male 3 5 Solid (tablets / capsules / caplets) NULL Unknown Acetaminophen with Hydrocodone Other Types of Skeletal Muscle Relaxant FDA_174 Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies. December 2012 12-month REMS Assessment Report AAPCC Listing of Exposures to Unknown Fentanyl Subject 7 8 9 Start Date Public Case Number Age Gender Substance Rank No of Substances Formulation Quantity 8/2/12 4286983642012 36 Male 4 5 Solid (tablets / capsules / caplets) NULL 8/2/12 4286983642012 36 Male 5 5 Solid (tablets / capsules / caplets) NULL 8/5/12 30611853582012 65 Male 1 3 8/5/12 30611853582012 65 Male 2 3 8/5/12 30611853582012 65 Male 3 3 8/6/12 4292223642012 52 Female 1 2 8/6/12 4292223642012 52 Female 2 2 8/11/12 4299653642012 35 Female 1 4 8/11/12 4299653642012 35 Female 2 4 8/11/12 4299653642012 35 Female 3 4 Powder / granules Solid (tablets / capsules / caplets) Solid (tablets / capsules / caplets) 28 130 Quantity Unit Unknown Unknown each (e.g. bites / stings) tabs / pills / capsules 12 Other Antihistamines Alone (Excluding Cough and Cold Preparations) Other Types of Antidepressant Fentanyl Methadone Death, indirect report Intentional Suspected suicide Intentional Suspected suicide Intentional Suspected suicide Moderate effect Moderate effect Unknown Fentanyl Intentional - Abuse Death, indirect report Solid (tablets / capsules / caplets) NULL Unknown Diphenhydramine Alone (Unknown if Over the Counter or Prescription) Intentional - Abuse Death, indirect report Unknown NULL Unknown Fentanyl Intentional - Abuse Death, indirect report NULL Unknown Benzodiazepines Intentional - Abuse Death, indirect report NULL Unknown Phenothiazines Intentional - Abuse Death, indirect report Intentional - Abuse Death, indirect report Intentional - Abuse Minor effect Intentional - Abuse Minor effect Solid (tablets / capsules / caplets) Solid (tablets / capsules / caplets) Diphenhydramine Alone (Unknown if Over the Counter or Prescription) Oxycodone Alone or in Combination (Excluding Combination Products with Acetaminophen or Acetylsalicylic Acid) 4 4 Solid (tablets / capsules / caplets) NULL Unknown 10/8/12 10480443722012 43 Female 1 2 Solid (tablets / capsules / caplets) 2 tabs / pills / capsules 10/8/12 10480443722012 43 Female 2 2 Other NULL Unknown 1 Solid (tablets / capsules / caplets) 8 each (e.g. bites / stings) Fentanyl 1 Intentional - Abuse NULL Female Male Death, indirect report Unknown 35 74 Intentional - Abuse Benzodiazepines 4299653642012 10491743722012 Medical Outcome Unknown 8/11/12 10/15/1 2 10/24/1 2 10/24/1 2 Reason For Exposure NULL 10 11 Major Category Fentanyl 19960333472012 56 Female 1 2 Unknown NULL Unknown Atypical Antipsychotics 19960333472012 56 Female 2 2 Unknown NULL Unknown Fentanyl Unintentional Therapeutic error Intentional Suspected suicide Intentional Suspected suicide Moderate effect No effect Moderate effect Moderate effect FDA_175 Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies. December 2012 12-month REMS Assessment Report 11.3 TRIG AERS Safety Surveillance Analysis Report FDA_176 FDA AERS Safety Surveillance Analysis Report AERS Data Release Date: 2012 Q2 Product: Transmucosal immediate-release fentanyl products (TIRF) Sponsor: TIRF REMS Industry Group (TRIG) of Companies Date: 14 December 2012 Status: Final Version: 1.0 FDA_177 Table of Contents Overview ................................................................................................................................. 3 Analysis Results ........................................................................................................................ 4 AERS Reports: Quarterly and Cumulative Summary Statistics ...................................... 4 Outcomes of Interest - Cumulative and Quarterly Summary Statistics .......................... 12 Signals of Disproportionate Reporting ........................................................................... 16 Patient Case Listing ........................................................................................................ 18 FDA_178 14Dec2012 Overview The following Quarterly Analysis report was produced from the 2012 Q2 release of the FDA’s Freedom of Information Act (FOIA) Adverse Event Reporting System (AERS) database which was made publicly available by the FDA in early October, 2012. The AERS database comprises 3,778,243 cumulative case reports, including 181,428 new reports in the 2012 Q2 quarterly release. Of the case reports submitted in Q2 2012, forty-six (46) cases reference a transmucosal immediate-release fentanyl (TIRF) product covered by the FDA Risk Evaluation and Mitigation Strategy (REMS) for TIRF products, with an event date on or after December 28, 2011. Thirty-seven (37) of these TIRF product case reports with an event date after December 28, 2011 also specify United States as the Country of Origin and are included in the analysis results described below. Twenty-six (26) of the 37 cases selected for analysis include at least one of the individual MedDRA Preferred Terms of Interest specified in the TRIG AERS Safety Surveillance Plan. These Preferred Terms of Interest are grouped into the following broad Categories of Interest (TRIG Categories) for aggregate reporting: o Death o Overdose (fatal and non-fatal) o Misuse, abuse, addiction, and diversion o Inappropriate o Medication errors o Accidental In addition, one (1) of the 37 cases selected also specifies at least one Preferred Term from the MedDRA SMQ (Broad) Acute Central Respiratory Depression, which is included in this analysis as a possible symptom related to the events included in the TRIG Categories above. None of the individual Preferred Terms from this SMQ is a TRIG Preferred Term of interest; instead counts of reports listing any PT from this SMQ will be summarized into an aggregate count for the entire SMQ and reported separately. The analysis protocol and assumptions that were used to guide this quarterly analysis are documented in the TRIG AERS Safety Surveillance Plan (TRIG AERS Safety Surveillance Plan 14Dec2012 V3 Final.docx). This analysis report summarizes the reporting characteristics of the AERS case reports for TIRF products covered by the FDA REMS for the TRIG companies. The results are presented in 4 sections and an additional optional section: • • AERS Reports - Cumulative and Quarterly Summary Statistics: this section provides summary characteristics of the reports comprising the entire AERS database which can be used to provide additional context for interpreting results of the TIRF analysis TIRF Product Reports – Cumulative and Quarterly Summary Statistics: this section TRIG Q2 2012 AERS Safety Surveillance Report Page 3 FDA_179 14Dec2012 provides the summary report characteristics of case reports which were selected for the TRIG quarterly analysis, that also include a PT or SMQ of interest 0 Outcomes of Interest Cumulative and Quarterly Summary Statistics: this section provides counts for each individual Preferred Term of Interest, as well as for the TRIG event categories Overdose, Death, Abuse, Misuse, Inappropriate, Medication Error, Accidental, Dependence, and Drug Diversion. In addition, counts for the SMQs Drug Abuse Dependence and Withdrawal, and Acute Central Respiratory Depression are also included. 0 Signal Detection: This section provides signal detection results for TRIG individual Preferred Terms of interest, for each TRIG event category, and for the 2 of interest. 0 Case Details (optional upon request): At the request of a TRIG sponsor, AERS case reports can be provided for any or all of the TIRF cases described in this report. These cases will be provided without product name/identi?ers or Manufacturer Analysis Results AERS Reports: Quarterly and Cumulative Summary Statistics The tables below provide a descriptive summary of the 2012 Q2AERS database. These tables include cumulative totals as well as totals for the current and prior quarter: 0 Table 1: AERS Overall Case Report Counts 0 Table 2, Figure l: AERS Gender Summary 0 Table 3, Figure 2: AERS Age Summary 0 Table 4: AERS Report Type 0 Table 5: AERS Initial and Follow up Reports 0 Table 6: AERS Outcome Type 0 Table 7: AERS Submission Type 0 Table 8: AERS Report Source Type 0 Table 9, AERS Reporter Occupation 0 Table 10: AERS Country of Origin Table Overall Case Report Countsl Overall Database Current Cumulative Total Prior uarter Quarter Reports 3,778,243 181,428 187,557 From Q41997 through Q2 2012 Q2 2012 AERS Safety Surveillance Report Page 4 80 l4Dec2012 Table 2 AERS Gender Summary Gender Cumulative Total Current Quarter Prior Quarter Female 2,099,382 101,568 109,432 Male 1,359,594 62,352 64,362 Other/ Unknown 319,267 17,508 13,763 Total 3,778,243 181,428 187,557 Figure Gender Summary, Current and Prior Quarter 120,000 100,000 30,000 60000 IC?urrent Quarter I Quarter 40,000 20,000 0 1 ale Male 0th Unkn Table 3 AERS Age Summary Age Cumulative Total Current Quarter Prior Quarter Age 0-2 34,306 1,223 813 Age 3-5 17,797 661 592 Age 6-10 34,726 1,583 1,070 Age 11-18 83,699 3,444 3,868 Age 19-25 116,640 5,023 6,708 Age 26-35 232,644 9,953 12,522 Age 36-64 1,203,086 57,673 63,700 Age 65+ 789,151 39,277 37,526 Not Reported 1,266,194 62,591 60,758 Total 3,778,243 181,428 187,557 Q2 2012 AERS Safety Surveillance Report Page 5 81 l4Dec2012 Figure 2 AERS Age Summary, Current and Prior Quarter 70.000 60.000 40,000 I Cu rre nt Quarte 20.000 7 Prior Quarter p3Table 4 Report Type Report Type Cumulative Total Current Quarter Prior Quarter Direct 325,185 7,015 6,975 Expedited 1,951,963 106,095 105,189 Periodic 1,501,095 68,318 75,393 Total 3,778,243 181,428 187,557 Table 5 Initial Follow-up Reports Initial/Follow-Up Cumulative Total Current Quarter Prior Quarter Follow-Up 981,680 51,010 46,367 Initial 2,796,296 130,418 141,190 Unspeci?ed 267 - - Total 3,778,243 181,428 187,557 Q2 2012 AERS Safety Surveillance Report Page 6 82 l4Dec2012 Table 6 AERS Outcome Type Outcome Type Cumulative Total Current Quarter Prior Quarter Congenital Anomaly 20,745 1,412 1,304 Death 413,431 19,764 22,689 Disability 131,279 7,445 4,438 Hospitalization 1,072,018 52,097 51,308 Life-Threatening 169,218 5,787 5,868 Other 1,381,924 71,097 67,804 Required Intervention 120,023 965 1,112 Total 3,308,638 158,567 154,523 Table 7 AERS Submission Type Submission Type Cumulative Total Current Quarter Prior Quarter Electronic 2,011,634 158,713 162,022 Other 1,132,302 22,715 25,535 Unspeci?ed 634,307 - - Total 3,778,243 181,428 187,557 Table 8 AERS Report Source Type* Report Source Type Cumulative Total Current Quarter Prior Quarter Foreign 346,172 4,876 4,275 Study 99,818 1,234 925 Literature 106,909 2,745 2,962 Consumer 602,433 5,456 7,247 Health Professional 846,333 12,995 14,206 User Facility 3,715 87 64 Company Representative 142,931 1,381 2,210 Distributor 11,138 150 59 Other 283,120 5,278 4,876 Unspecified 2,320,745 164,567 166,782 Total 4,763,314 198,769 203,606 *One report may have zero, one, or multiple report sources Q2 2012 AERS Safety Surveillance Report Page 7 83 14Dec201 2 Table 9 AERS Reporter Occupation Reporter Occupation Cumulative Total Current Quarter Prior Quarter Consumer 1,102,847 79,279 87,762 Lawyer 96,675 7,867 6,078 Other Health Professional 498,131 33,131 32,377 Pharmacist 194,271 9,187 8,065 Physician 811,278 46,401 47,072 Unspeci?ed 1,075,041 5,583 6,203 Total 3,778,243 181,428 187,557 Table 10 AERS Country of Origin Country of Origin Cumulative Total Current Quarter Prior Quarter United States 1,819,621 125,542 136,654 Unspeci?ed 1,241,581 1,496 617 Other 717,041 54,390 50,286 Total 3,778,243 181,428 187,557 Q2 2012 AERS Safety Surveillance Report Page 8 84 14Dec2012 TIRF Product Reports: Quarterly and Cumulative Summary Statistics The tables below provide descriptive analyses of AERS case reports for TIRF products that met the selection criteria as defined in the Quarterly Surveillance Plan, and also contain a TRIG Preferred Term or SMQ of interest. Results are summarized for the current quarter; prior quarter and cumulative results are included for comparison. The 2012 Q1 data release was the first AERS quarterly release covered by the REMS, however there were no cases for TIRF products that met the case selection criteria in that prior release so that information is omitted from this quarterly report. The case selection criteria used for this analysis includes the following: • Brand Name:: Case reports with specified TIRF brand names • Generic Fentanyl: Case Reports referencing the generic ingredient Fentanyl, with case selection restricted to specified routes of administration and TRIG Manufacturer IDs AERS case report selection is further restricted to only include reports for adverse events occurring on or after December 28, 2011 with United States designated as the Country of Origin. Cases with an unspecified Event Date or Country of Origin are not selected for analysis. Of the thirty-seven (37) reports that meet all TIRF selection criteria as described above, twentysix (26) of these reports also include a MedDRA Preferred Term of Interest for this study. In addition, one (1) report includes a MedDRA Preferred Term from the SMQ Acute central respiratory depression SMQ. Although the reported Preferred Term from this SMQ is not a TRIG Preferred Terms of interest, this SMQ was included as a potential symptom of the outcomes of interest and report counts are included in aggregate for this SMQ. The twenty seven (27) reports that reference a PT or SMQ of interest are further characterized in this section of the report. A majority of the reports are for female patients, aged 36 to 64. Consumer is the most commonly reported Occupation, reported on nearly 74% (20 of 27) of the reports. Additionally, on 81% (22 of 27) of the reports, the TIRF product is reported as the primary suspect drug. Characteristics of these 27 reports are further described in the tables below: • • • • • • • • • Table 11: Table 12: Table 13: Table 14: Table 15: Table 16: Table 17: Table 18: Table 19: Patient counts for case reports referencing TIRF Products Gender summary for TIRF case reports containing Events of Interest Age summary for TIRF case reports containing Events of Interest Reported Outcomes for TIRF case reports containing Events of Interest Submission Type for TIRF case reports containing Events of Interest Report Source for TIRF case reports containing Events of Interest Reporter Occupation for TIRF case reports containing Events of Interest Role of TIRF Product Report Type of TIRF Products TRIG Q2 2012 AERS Safety Surveillance Report Page 9 FDA_185 l4Dec2012 Table 11 Patient Counts for TIRF case reports containing Events of Interest Total Patient Counts 2012 Q2 to Date All Reports for TIRF Drugs with event date after 12/28/2012 46 46 US Reports Only 37 37 Reports meeting TRIG selection criteria and containing Term of Interest 26 26 Reports meeting TRIG selection criteria and matching Acute Central Respiratory 1 1 Depression SMQ Table 12 Gender Summary for TIRF case reports containing Events of Interest Total Gender 2012 Q2 to Date Males 6 6 Females 20 20 Unknown 1 1 Table 13 Age Summary for TIRF case reports containing Events of Interest Total Age 2012 0?2 to Date Age 0Age 6-10 0 0 Age 11-18 0 0 Age 19-25 0 0 Age 26-35 1 1 Age 36-Unknown Age 7 7 .Table 14 Reported outcomes for TIRF case reports containing Events of Interest* Total Outcome 2012 Q2 to Date Congenital Anomaly 0 0 Death 1 1 Disability 0 0 Hospitalization 4 4 Life Threatening 0 0 Requires Intervention 0 0 Other 9 9 Not Specified 13 13 *Cases may have 0, or multiple outcomes speci?ed TRIG Q2 2012 AERS Safety Surveillance Report Page 10 86 14Dec2012 Table 15 Submission type for case reports referencing TIRF products Total submission Type 2012 Q2 to Date Electronic 27 27 Other 0 0 Unspecified 0 0 Table 16 Report source for TIRF case reports containing Events of Interest Total Report Source 2012 Q2 to Date Foreign 0 0 Study 0 0 Literature 0 0 Consumer 0 0 Health Professional 0 0 User Facility 0 0 Company Representative 0 0 Distributor 0 0 Other 0 0 Unspecified 27 27 Table 17 Reporter occupation for TIRF case reports containing Events of Interest Total Reporter Occupation 2012 02 to Date Consumer 20 20 Lawyer 0 0 Other Health Professional 5 5 Pharmacist 0 0 Physician 1 1 Unspecified 1 1 Table 18 Role code for TIRF products Total Role Code 2012 Q2 to Date Primary Suspect 22 22 Concomitant 5 5 Table 19 Report Type for TIRF case reports containing Events of Interest Total Report Type 2012 02 to Date Expedited 9 9 Periodic 18 19 Q2 2012 AERS Safety Surveillance Report Page 11 87 l4Dec2012 Outcomes of Interest - Cumulative and Quarterly Summary Statistics The following tables summarize the TRIG Preferred Terms of Interest that were reported on the case reports for TIRF products that met the selection criteria for this analysis. Each case report may include one or more Preferred Terms. A total of 36 Preferred Terms of Interest for this study are reported across 26 case reports selected for TIRF products that contain at least 1 TRIG Preferred Term of Interest. The most commonly reported Term is ?Off label use? (18) followed by ?Drug prescribing error? (7). In addition, one (1) Case report includes a term from the SMQ Acute central respiratory depression. The tables below summarize the reported terms: 0 Table 20: Count of reported TRIG Preferred Terms of interest 0 Table Count of reported Preferred Terms by TRIG Category Table 20 Count of reported TRIG Preferred Terms of Interest Total Unique Preferred Term 2012 Q2 to Date 96 Brand Name Analysis Accidental death 0 0.0% 0 0.0% Accidental drug intake by child 0 0.0% 0 0.0% Accidental exposure 0 0.0% 0 0.0% Accidental overdose 0 0.0% 0 0.0% Accidental poisoning 0 0.0% 0 0.0% Agonal death struggle 0 0.0% 0 0.0% Apparent death 0 0.0% 0 0.0% Brain death 0 0.0% 0 0.0% Cardiac arrest 0 0.0% 0 0.0% Cardiac death 0 0.0% 0 0.0% Cardio-respiratory arrest 0 0.0% 0.0% Counterfeit drug administered 0 0.0% 0 0.0% Death 0 0.0% 0 0.0% Death neonatal 0.0% 0 0.0% Death of companion 0 0.0% 0 0.0% Death of relative 0 0.0% 0 0.0% Dependence 0 0.0% 0 0.0% Drug abuse 0 0.0% 0 0.0% Drug abuser 0 0.0% 0 0.0% Drug administered at inappropriate site 0 0.0% 0 0.0% Drug administered to patient of inappropriate age 0 0.0% 0 0.0% Drug administration error 1 2.8% 1 2.8% Drug dependence 0 0.0% 0 0.0% Drug dependence, antepartum 0 0.0% 0 0.0% Drug dependence, postpartum 0 0.0% 0 0.0% Drug dispensing error 1 2.8% 1 2.8% Drug diversion 0 0.0% 0 0.0% Drug dose omission 1 2. 8% 1 2. 8% Drug label confusion 0 0.0% 0.0% TRIG Q2 2012 AERS Safety Surveillance Report Page 12 88 l4Dec2012 Drug name confusion 0 0.0% 0 0.0% Drug prescribing error 7 19. 4% 8 19.4% Drug Withdrawal 3 8.3% 3 8.3% Ex-drug abuser 0 0.0% 0 0.0% Expired drug administered 1 2. 8% 1 2.8% Inappropriate schedule of drug administration 0 0.0% 0 0.0% Incorrect dose administered 0 0.0% 0 0.0% Incorrect drug administration duration 0 0.0% 0 0.0% Incorrect drug administration rate 0 0.0% 0 0.0% Incorrect drug dosage form administered 0 0.0% 0 0.0% Incorrect route of drug administration 0 0.0% 0 0.0% Incorrect storage of drug 0 0.0% 0 0.0% Intentional drug misuse 0 0.0% 0 0.0% Intentional overdose 0 0.0% 0 0.0% Intercepted drug dispensing error 0 0.0% 0 0.0% Intercepted drug prescribing error 0 0.0% 0 0.0% Intercepted medication error 0 0.0% 0 0.0% Labelled drug-disease interaction medication error 0 0.0% 0 0.0% Labelled drug-drug interaction medication error 0 0.0% 0 0.0% Medication error 0 0.0% 0 0.0% Medication overuse headache 0 0.0% 0 0.0% Multiple drug overdose 0 0.0% 0 0.0% Multiple drug overdose accidental 0 0.0% 0 0.0% Multiple drug overdose intentional 0 0.0% 0 0.0% Multiple use of single-use product 0 0.0% 0 0.0% Off label use 18 50.0% 18 50% Overdose 0 0.0% 0 0.0% Polysubstance dependence 0 0.0% 0 0.0% Poor quality drug administered 0 0.0% 0 0.0% Respiratory arrest 0 0.0% 0 0.0% Substance abuse 0 0.0% 0 0.0% Substance abuser 0 0.0% 0 0.0% Substance-induced mood disorder 0 0.0% 0 0.0% Su bstance-induced disorder 0 0.0% 0 0.0% Sudden cardiac death 0 0.0% 0 0.0% Sudden death 0 0.0% 0 0.0% Sudden unexplained death in epilepsy 0 0.0% 0 0.0% Therapy naive 0 0.0% 0 0.0% Toxicity to various agents 0 0.0% 0 0.0% Underdose 0 0.0% 0 0.0% Withdrawal 3 8.3 3 8.3% Wrong drug administered 0 0.0% 0 0.0% Wrong technique in drug usage process 1 2.8% 1 2.8% Total Number of Preferred Terms Reported 36 100% 36 100% TRIG Q2 2012 AERS Safety Surveillance Report Page 13 89 l4Dec2012 Table 21 Count of reported Events of Interest grouped by TRIG Category Total Q2 2012 to Date Events by Category Overdose 0 0.0% 0 0.0% Accidental overdose 0 0.0% Intentional overdose 0 0.0% Multiple drug overdose 0 0.0% Multiple drug overdose accidental 0 0.0% Multiple drug overdose intentional 0 0.0% Overdose 0 0.0% Death 0 0.0% 0.0% Accidental death 0 0.0% Agonal death struggle 0 0.0% Apparent death 0 0.0% Brain death 0 0.0% Cardiac arrest 0 0.0% Cardiac death 0 0.0% Cardio-respiratory arrest 0 0.0% Death 0 0.0% Death neonatal 0 0.0% Death of companion 0 0.0% Death of relative 0 0.0% Respiratory arrest 0 0.0% Sudden cardiac death 0 0.0% Sudden death 0 0.0% Sudden unexplained death in epilepsy 0 0.0% Misuse 0.0% 0.0% Intentional Drug Misuse 0 0.0% Medication overuse headache 0 0.0% Drug abuse dependence and withdrawal SMQ 6 Abuse 0 0.0% 0.0% Drug abuse 0 0.0% Drug abuser 0 0.0% Ex-drug abuser 0 0.0% Substance abuse 0 0.0% Substance abuser 0 0.0% Substance-induced mood disorder 0 0.0% Substance-induced disorder 0 0.0% Drug abuse dependence and withdrawal SMQ 6 Inappropriate 18 50.0% 18 I 50.0% Drug administered at inappropriate site 0 0.00% Drug administered to patient of inappropriate age 0 0.00% Inappropriate schedule of drug administration 0 0.00% Off label use 18 50.0% Medication Error 12 33.3% 12 33.3% Accidental drug intake by child 0 0.0% Counterfeit drug administered 0 0.0% Drug administered to patient of inappropriate age 0 0.0% TRIG Q2 2012 AERS Safety Surveillance Report Page 14 90 l4Dec2012 Drug administration error 1 2.8% Drug dispensing error 1 2.8% Drug dose omission 1 2.8% Drug label confusion 0 0.0% Drug name confusion 0 0.0% Drug prescribing error 7 19.4% Expired drug administered 1 2. 8% Inappropriate schedule of drug administration 0 0.0% Incorrect dose administered 0 0.0% Incorrect drug administration duration 0 0.0% Incorrect drug administration rate 0 0.0% Incorrect drug dosage form administered 0 0.0% Incorrect route of drug administration 0 0.0% Incorrect storage of drug 0 0.0% Intercepted drug dispensing error 0 0.0% Intercepted drug prescribing error 0 0.0% Intercepted medication error 0 0.0% Labelled drug-disease interaction medication error 0 0.0% Labelled drug-drug interaction medication error 0 0.0% Medication error 0 0.0% Multiple use of single-use product 0 0.0% Poor quality drug administered 0 0.0% Therapy nai?ve 0 0.0% Underdose 0 0.0% Wrong drug administered 0 0.0% Wrong technique in drug usage process 1 2.8% Accidental 0.0% 0.0% Accidental drug intake by child 0 0.0% Accidental exposure 0 0.0% Accidental overdose 0 0.0% Accidental poisoning 0 0.0% Multiple drug overdose accidental 0 0.0% Toxicity to various agents 0 0.0% Dependence 6 16.7% 6 14.3% Dependence 0 0.0% Drug dependence 0 0.0% Drug dependence, antepartum 0 0.0% Drug dependence, postpartum 0 0.0% Drug Withdrawal 3 8.3% Polysubstance dependence 0 0.0% Withdrawal 3 8.3% Drug Diversion 18 50.0% 18 I 50.0% Drug diversion 0 0.0% Off label use 18 50% Respiratory Depression 1 1 I Acute central respiratory depression SMQ 1 TRIG Q2 2012 AERS Safety Surveillance Report Page 15 91 14Dec2012 Signals of Disproportionate Reporting Data mining signal detection was carried out for the 37 TIRF cases selected by TRIG case selection criteria, using the AERS database as the background. In a data mining analysis using a spontaneous reporting database such as AERS, a traditional “denominator” (e.g. the number of patients exposed to a particular drug and/or how long they’ve been exposed) is not known. To overcome this limitation, data mining methods produce a ratio of disproportionate reporting, comparing the number of reports for a particular Drug / Adverse Event (AE) combination to the number of reports for that AE across all of the other drugs in the AERS database. A disporportionality ratio of 1 indicates that that the AE is being reported for the drug of interest at the same rate as it is being reported for all other drugs in the background; a ratio of 2 means that it is being reported at twice the background rate. There are several commonly used algorithms that produce disproportionality statistics. Three of the most common algorithms were utilized in this analysis. Each of these algorithms also includes a measure of confidence: • Proportional Reporting Ratio (PRR), Chi Square • Reporting Ratio (RR), Statistical Unexpectedness (1/P) • Multi-gamma poisson shrinker (MGPS), lower bounds of the 95% confidence interval (EB05) There is no single international standard for signal detection thresholds based on AERS and other spontaneous report databases. The CIOMS VIII Working Group (CIOMS Geneva 2010) dedicates a chapter (VII) to “more complex quantitative signal detection methods”, and provides thoughtful perspectives on the role of statistical analysis in the setting of pharmacovigilance. Despite a lack of standards, signaling is commonly defined by the following thresholds: • PRR: PRR>2, Chi Square >4, and number of reports>3 – considered to be more sensitive but not as specific • MGPS: EB05>2 (lower bounds of the 95% confidence interval of EBGM) – considered to be more specific, but not as sensitive. • RR: RR>1, Statistical Unexpectedness (1/P-value) >system calculated, Bonferroni corrected threshold – considered to have intermediate sensitivity / specificity1 A Drug / AE combination that crosses a data mining signal threshold is not necessarily indicative that the drug is the cause of that adverse event. For instance, many adverse events that produce high disproportionality scores are related to the reported drug’s indication. Therefore, disproportionality results should be interpreted in the context of other information known about the drug. 1 Hochberg AM, Hauben M, Pearson RK, O'Hara DJ, Reisinger SJ, Goldsmith DI, Gould AL, Madigan D., An evaluation of three signal-detection algorithms using a highly inclusive reference event database. Drug Saf. 2009;32(6):509-25. doi: 10.2165/00002018-200932060-00007. TRIG Q2 2012 AERS Safety Surveillance Report Page 16 FDA_192 l4Dec2012 Only terms that cross the signaling threshold for at least one of the three data mining algorithms utilized for the analysis are included in the tables below (note that MGPS scores are only calculated when the total number of case reports for the drug and the total number of case reports for the adverse event both exceed one hundred (100), so these scores are not included in the tables below for this quarter). The following tables describe the results of data mining signal detection carried out for the TIRF cases of interest, using the AERS database as the background: 0 Table 22 Signals of Disproportionate Reporting, Preferred Terms of Interest 0 Table 23 Signals of Disproportionate Reporting, TRIG Categories of Interest 0 Table 24 Signals of Disproportionate Reporting, SMQS of Interest Table 22 Signals of Disproportionate Reporting, Preferred Terms of Interest Reports Reports with Drug with Reporting Statistical Chi AdverseEvent 8: Event Event Ratio Unexpectedness PRR Square Brand Name Analysis Off label use 18 12,535 146.63 34.41 146.84 2468.16 Drug prescribing error 7 3.367 212.30 14.35 212.74 1269.54 Withdrawal 3 5,510 55.60 4.63 55.63 111.05 Table 23 Signals 0f Disproportionate Reporting, TRIG Categories of Interest Reports with Reports Reporting Statistical Chi AdverseEvent Drug 81 Event with Event Ratio Unexpectedness PRR Square inappropriate 18 21,189 86.75 30.32 86.82 1449.24 Diversion 18 12,944 141.45 34.13 141.65 2380.03 Medication Error 12 130,192 9.41 8.63 9.41 84.93 Dependence 6 42,746 14.33 5.44 14.34 62.39 Table 24 Signals 0f Disproportionate Reporting, of Interest Reports with Drug Reports Reporting Statistical Chi AdverseEvent Event with Event Ratio Unexpectedness PRR Square Drug abuse, dependence and 6 173846 3.52 2.19 3.52 8.88 withdrawal Not surprisingly, relatively robust signals were generated for the Preferred Terms of Interest: ?Off label Use? and ?Drug prescribing error?. A weaker signal was generated for the Preferred Term of Interest ?Drug withdrawal These are known adverse events for TRIG products, and are the subject of the TIRF REMS program. When analyzed according to TRIG Categories of Interest, relatively robust signals were also generated for ?Inappropriate use?, ?Drug diversion", ?Medication error?, and ?Drug dependence?. When examined by SMQ, the SMQ ?Drug abuse, dependence and withdrawal? generated a somewhat weak signal of disproportionate reporting. Q2 2012 AERS Safety Surveillance Report Page 17 93 14Dec2012 Data mining results for these adverse events will continue to be monitored over time to understand the impact of the REMS program on the overall reporting rates for these events of interest. Patient Case Listing Case Details (optional upon request): At the request of a TRIG sponsor, AERS case reports can be provided for any or all of the TIRF cases described in this report. These cases will be provided without product name/identifiers or Manufacturer ID’s. TRIG Q2 2012 AERS Safety Surveillance Report Page 18 FDA_194 Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies. December 2012 12-month REMS Assessment Report 11.4 Periodic Stakeholder Surveys FDA_195 Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies. December 2012 12-month REMS Assessment Report 11.4.1 Patient KAB Survey FDA_196 Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Title: December 2012 Patient KAB Assessment Report Transmucosal Immediate Release Fentanyl (TIRF) REMS Assessment Quantitative Testing of Patient Knowledge, Attitudes, and Behavior (KAB) about TIRF Products Safety and Use Information Document Number Final Wave 1, Version 1.0 Product Name: Transmucosal Immediate Release Fentanyl Sponsor: TIRF REMS Industry Group (TRIG) of Companies: Archimedes Pharma US Inc. Cephalon, Inc. (a wholly-owned subsidiary of Teva Pharmaceutical Industries, Ltd.) Insys Therapeutics Meda Pharmaceuticals Mallinckrodt (the Pharmaceuticals Business of Covidien) Par Pharmaceutical, Inc. ProStrakan, Inc. Date: 14 December 2012 Confidentiality Statement The information contained herein is confidential and the proprietary property of the TRIG of Companies and its affiliates, and any unauthorized use or disclosure of such information without the prior written authorization of the TRIG is expressly prohibited. Page 1 of 52 FDA_197 Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies TABLE OF CONTENTS December 2012 Patient KAB Assessment Report PAGE TABLE OF CONTENTS ......................................................................................................... 2  LIST OF INTEXT TABLES .................................................................................................... 4  LIST OF APPENDICES .......................................................................................................... 5  LIST OF ABBREVIATIONS .................................................................................................. 6  1.  PATIENT SURVEY BACKGROUND ................................................................... 7  2.  PATIENT SURVEY OBJECTIVES ....................................................................... 8  3.  SURVEY METHODOLOGY.................................................................................. 8  3.1  Survey Sample ......................................................................................................... 8  3.2  3.2.1  3.2.2  3.2.3  3.2.4  3.2.5  3.2.6  Questions and Statements on Key Risk Messages ................................................... 9  Key Risk Message 1 ............................................................................................... 10  Key Risk Message 2 ............................................................................................... 10  Key Risk Message 3 ............................................................................................... 11  Key Risk Message 4 ............................................................................................... 11  Key Risk Message 5 ............................................................................................... 12  Key Risk Message 6 ............................................................................................... 12  4.  STATISTICAL METHODS .................................................................................. 13  4.1  4.1.1  4.1.2  4.1.2.1  4.1.2.2  4.1.3  Study Population .................................................................................................... 13  Primary Analysis Population ................................................................................. 13  Sub-populations of Interest .................................................................................... 13  Primary Analyses ................................................................................................... 14  Secondary Analyses ............................................................................................... 14  Patient Report of Adverse Event, Product Complaint, or Medical Information Request during Survey ....................................................................... 14  5.  RESULTS .............................................................................................................. 14  5.1  5.1.1  5.2.1  5.2.2  5.2.3  Survey Participants ................................................................................................ 14  Survey Participant Administration Results ............................................................ 14  Patient/Caregiver Demographics ........................................................................... 19  TIRF Medicines Educational Materials ................................................................. 22  Patient-Prescriber Agreement Form....................................................................... 28  5.3  5.3.1  5.3.1.1  5.3.1.2  KAB Survey Objectives ......................................................................................... 29  Key Risk Message Results ..................................................................................... 29  Key Risk Message 1 ............................................................................................... 29  Key Risk Message 2 ............................................................................................... 30  Page 2 of 52 FDA_198 Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies December 2012 Patient KAB Assessment Report 5.3.1.3  5.3.1.4  5.3.1.5  5.3.1.6  5.3.2  5.3.2.1  5.3.3  Key Risk Message 3 ............................................................................................... 32  Key Risk Message 4 ............................................................................................... 34  Key Risk Message 5 ............................................................................................... 35  Key Risk Message 6 ............................................................................................... 36  Other Survey Questions ......................................................................................... 38  Additional Questions About TIRF Medicines Safety ............................................ 38  Analyses of Subpopulations ................................................................................... 40  5.4  Spontaneous Reporting of Adverse Events, Product Complaints, or Medical Information Requests ............................................................................... 41  5.5  Discussion, Conclusions, and Recommendations .................................................. 42  Listing 1  CATEGORIZATION OF VERBATIM RESPONSES TO QUESTION 21 (Most recent time receiving Medication Guide for the TIRF medicine from the pharmacy) ......................................................................................................... 47  Listing 2  CATEGORIZATION OF VERBATIM RESPONSES TO QUESTION 26 (Other person offering explanation of the Medication Guide) .............................. 48  Listing 3  CATEGORIZATION OF VERBATIM RESPONSES TO QUESTION 29 (Questions about the information in the Medication Guide) ................................. 49  Listing 4  CATEGORIZATION OF REPORTED SAFETY EVENTS OR PRODUCT COMPLAINTS .................................................................................. 50  Page 3 of 52 FDA_199 Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies December 2012 Patient KAB Assessment Report LIST OF INTEXT TABLES Table 1.  Survey Participant Administration Results...............................................15  Table 2.  Survey Participant Screening Results ....................................................... 16  Table 3.  Time to Complete Survey .........................................................................19  Table 4.  Demographic Characteristics of Eligible Patients/Caregivers..................20  Table 5.  Responses to Questions About TIRF Medication Guides ........................ 23  Table 6.  Categorized Responses To Question 21 (Most recent time receiving Medication Guide for the TIRF medicine from the pharmacy) .................................................................................................27  Table 7.  Categorized Responses To Question 26 (Other person offering explanation of the Medication Guide) ......................................................27  Table 8.  Categorized Responses To Question 29 (Questions about the information in the Medication Guide) ......................................................28  Table 9.  Responses to Questions About the Patient-Prescriber Agreement Form..........................................................................................................28  Table 10.  Key Risk Message 1: TIRF Medicines Can Cause LifeThreatening Breathing Problems That Can Lead To Death .....................30  Table 11.  Key Risk Message 2: Patients Should Not Take TIRF Medicines If They Are Not Opioid Tolerant .................................................................31  Table 12.  Risk Message 3: TIRF Medicines Should Be Taken Exactly As Prescribed By The Healthcare Provider ................................................... 33  Table 13.  Risk Message 4: Patients Should Not Switch From A TIRF Medicine To Another Medicine That Contains Fentanyl Without Talking To A Healthcare Provider ........................................................... 35  Table 14.  Key Risk Message 5: Patients Should Not Give TIRF Medicines ToAnyone Else Even If They Have The Same Symptoms ......................36  Table 15.  Key Risk Message 6: TIRF Medicines Should Be Stored In A Safe Place Away From Children And Properly Disposed ................................37  Table 16.  Responses to Additional Questions about the Safe Use of TIRF Medicines..................................................................................................39  Table 17.   Respondent Report of Adverse Events, Product Complaints, or Medical Information Requests During Survey .........................................41  Table 18.   Categorized Reported Adverse Events,Product Complaints, or Medical Information Requests.................................................................. 42  Page 4 of 52 FDA_200 Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies December 2012 Patient KAB Assessment Report LIST OF APPENDICES Appendix A Patient Survey Protocol ............................................................................ 44  Appendix B Patient Survey Listings and Subanalyses Tables ......................................45  Page 5 of 52 FDA_201 Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies December 2012 Patient KAB Assessment Report LIST OF ABBREVIATIONS CI Confidence Interval ETASU Elements to Assure Safe Use FDA Food and Drug Administration HCP Healthcare Professional KAB Knowledge, Attitudes and Behavior PPAF Patient-Prescriber Agreement Form REMS Risk Evaluation and Mitigation Strategy TIRF Transmucosal Immediate Release Fentanyl TIRF Medicines Transmucosal Immediate Release Fentanyl products TIRF REMS Access Program REMS program for TIRF medicines TRIG TIRF REMS Industry Group SAP Statistical Analysis Plan SERP Safety Event Report Planning UBC United BioSource Corporation US United States USPS United States Postal Service Page 6 of 52 FDA_202 Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies 1. December 2012 Patient KAB Assessment Report PATIENT SURVEY BACKGROUND Transmucosal Immediate Release Fentanyl (TIRF) medicines are a class of immediate-release opioid analgesics that are indicated only for the management of breakthrough pain in cancer patients 18 years of age or older (16 or older for Actiq® [fentanyl citrate oral transmucosal lozenge] and equivalent generics) who are already receiving and already tolerant to opioid therapy for their underlying persistent cancer pain. The TIRF medicines include Abstral®, Actiq®, Fentora®, Lazanda®, Onsolis®, Subsys®, and generic versions of any of these brands. The TIRF Risk Evaluation and Mitigation Strategy (REMS) Industry Group (TRIG) includes Archimedes Pharma United States (US) Inc., Cephalon, Inc. (a wholly-owned subsidiary of Teva Pharmaceutical Industries, Ltd.), Insys Therapeutics, Meda Pharmaceuticals, Mallinckrodt (a Pharmaceuticals Business of Covidien), Par Pharmaceutical, Inc., and ProStrakan, Inc. At the time of protocol development for the Knowledge, Attitude, and Behavior (KAB) surveys, Sandoz was also a member of the TRIG; however, Sandoz terminated their involvement in the TIRF REMS Access program, effective 15 September 2012. The Food and Drug Administration (FDA) has determined that a class-wide REMS is required to mitigate the risk of misuse, abuse, addiction, overdose, and serious complications due to medication errors with the use of TIRF medicines. The TIRF REMS Access Program (hereafter referred to as TIRF REMS) was approved by the FDA on 28 December 2011. The TIRF REMS consists of a Medication Guide, Elements to Assure Safe Use (ETASU), an Implementation System, and a timetable for submission of assessments of the REMS. The goals of the TIRF REMS are to mitigate the risk of misuse, abuse, addiction, overdose and serious complications due to medication errors bythe following: 1. Prescribing and dispensing TIRF medicines only to appropriate patients, which includes use only in opioid-tolerant patients. 2. Preventing inappropriate conversion between TIRF medicines. 3. Preventing accidental exposure to children and others for whom it was not prescribed. 4. Educating prescribers, pharmacists, and patients on the potential for misuse, abuse, addiction, and overdose of TIRF medicines. An important component of the TIRF REMS assessment is the conduct of quantitative evaluation surveys to assess patients’ and caregivers’ knowledge, attitudes, and behavior (KAB) regarding the safe use of TIRF medicines as described in the educational materials. The protocol describes the administration of the surveys that will be conducted among patients who are treated with TIRF medicines, or their caregivers. Page 7 of 52 FDA_203 Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies December 2012 Patient KAB Assessment Report Data from the surveys, together with other REMS evaluation metrics, will be used to determine whether changes need to be made to the REMS processes or educational materials to make them more effective in achieving the goals of the REMS. Results from the surveys will be submitted to the FDA at 12 months after approval of the TIRF REMS and annually thereafter. 2. PATIENT SURVEY OBJECTIVES The evaluation survey uses a questionnaire to document the level of knowledge and assess the attitudes and behavior of patients regarding the following key information and risk messages communicated through the REMS: 1. TIRF medicines can cause life-threatening breathing problems that can lead to death. 2. Patients should not take TIRF medicines if they are not opioid tolerant. 3. TIRF medicines should be taken exactly as prescribed by the healthcare provider. 4. Patients should not switch from a TIRF medicine to another medicine that contains fentanyl without talking to a healthcare provider. 5. Patients should not give TIRF medicines to anyone else even if they have the same symptoms. 6. TIRF medicines should be stored in a safe place away from children and properly disposed. The survey also includes questions about whether patients received, read, and understood the product-specific Medication Guide and Patient-Prescriber Agreement Form (PPAF). 3. SURVEY METHODOLOGY This section summarizes the survey design and the questions that were constructed to test patient understanding of the key risk messages of the REMS. Full details of the survey design are in the protocol, which can be found in Appendix A. 3.1 Survey Sample This survey was conducted among patients who had a prescription filled for a TIRF medicine within the 90 days prior 12 September 2012. A target sample of 300 patients treated with TIRF medicines were to be surveyed in this first KAB survey conducted from 24 September 2012 to 30 October 2012. Subject recruitment was performed via a direct letter Page 8 of 52 FDA_204 Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies December 2012 Patient KAB Assessment Report program, and some subjects were also invited through a national pharmacy chain network partner. Patients 18 years of age or older and caregivers 18 years of age or older who cared for patients unable to take the survey for themselves were eligible to participate in the survey. Respondents or their immediate family members who had ever worked for any of the TRIG companies, McKesson Specialty Care Solutions, RelayHealth, United BioSource Corporation (UBC), or the FDA were not eligible to participate in this survey. Respondents who participated in the first wave of the TIRF survey will not be eligible to participate in subsequent survey waves. Potential participants were recruited via a letter of invitation sent through the United States Postal Service (USPS). The required number of completed surveys was not achieved; therefore, a second mailing was sent to non-respondents through USPS mail with subsequent follow-up to maximize participation. In the second mailing, reminder letters were sent to those patients who had not yet responded. In the third mailing, invitations were sent out to patients not included in the original mailing. Patients were given the option of taking the survey by telephone via the Survey Coordinating Center or online via a secure website. All participating patients were offered a $25 gift card for a completed survey. The survey was estimated to take approximately 20 minutes to complete. 3.2 Questions and Statements on Key Risk Messages The questions and statements comprising the knowledge survey were constructed to test the patients’ understanding of the key risk messages of the REMS. The questions were to be answered either by selecting options from multiple-choice lists that include statements of the specific key risk messages or by choosing “Yes” or “True,” “No” or “False,” or “I Don’t Know” regarding statements about TIRF medicines. For statements or questions that had “True” or “Yes” vs. “False” or “No” response options, the desired response for key risk messages was generally “True” or “Yes” indicating knowledge of, or behavior in accordance with, the objectives of the REMS. However, some questions were formatted to have the respondent disagree with the statement as written by providing response options of “False” or “No” to avoid having the same affirmative answer for all desired responses. REMS statements, corresponding questions, and desired responses covering the key risk messages are identified below and can be found in the complete survey questionnaire (Appendix A). Page 9 of 52 FDA_205 Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies 3.2.1 December 2012 Patient KAB Assessment Report Key Risk Message 1 Key Risk Message 1 refers to the patient’s knowledge that TIRF medicines can cause lifethreatening breathing problems. Key Risk Message 1: TIRF medicines can cause life-threatening breathing problems that can lead to death. Question No. Desired response Please answer True, False, or I don’t know for each statement about the TIRF medicine that was most recently prescribed for you. 12d 3.2.2 Question TIRF medicines can cause life-threatening breathing problems that can lead to death. True Key Risk Message 2 Key Risk Message 2 refers to the patient’s awareness that TIRF medicines should be taken only by opioid-tolerant adult patients. Key Risk Message 2: Patients should not take TIRF medicines if they are not opioid tolerant. Question No. Question Desired response Please answer True, False, or I don’t know for the following statement: 10 TIRF medicines should only be taken by patients who are opioid tolerant. True Opioid tolerant means that a patient is already taking other opioid pain medicines around the clock and their body is used to these medicines. True 11a Please answer True, False, or I don’t know for each statement about the TIRF medicine that was most recently prescribed for you. 12b It is OK for patients to take TIRF medicines for headache pain. False Page 10 of 52 FDA_206 Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies 3.2.3 December 2012 Patient KAB Assessment Report Key Risk Message 3 Key Risk Message 3 refers to the patient’s knowledge that TIRF medicines should be taken exactly as prescribed by the healthcare provider. Key Risk Message 3: TIRF medicines should be taken exactly as prescribed by the healthcare provider. Question No. Question Desired response Please answer “True,” “False,” or “I don’t know” for each statement about TIRF medicines. If a patient stops taking around-the-clock opioid pain medicine, they must also stop taking the TIRF medicine. 11b True Please answer True, False, or I don’t know for each statement about the TIRF medicine that was most recently prescribed for you. 12c TIRF medicines should be taken exactly as prescribed by the doctor. True 16b It is OK to take TIRF medicines for short-term pain that will go away in a few days. False 3.2.4 Key Risk Message 4 Key Risk Message 4 refers to the patient’s knowledge of the interchangeability of TIRF medicines. Key Risk Message 4: Patients should not switch from a TIRF medicine to another medicine that contains fentanyl without talking to a healthcare provider. Question No. Question Desired response Please answer “True,” “False,” or “I don’t know” for each statement about TIRF medicines. 11c It is safe to switch to another medicine that contains fentanyl without talking to a healthcare provider first. False Page 11 of 52 FDA_207 Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies 3.2.5 December 2012 Patient KAB Assessment Report Key Risk Message 5 Key Risk Message 5 refers to the patient’s awareness that TIRF medicines should not be given to anyone else even if they have the same symptoms. Key Risk Message 5: Patients should not give TIRF medicines to anyone else even if they have the same symptoms. Question No. Question Desired response Please answer True, False, or I don’t know for each of the following statements. A patient may give TIRF medicines to another person if they have the same symptoms as the patient. 11d False Please answer True, False, or I don’t know for each statement about the TIRF medicine that was most recently prescribed for you. Selling or giving away TIRF medicines is against the law. 16a 3.2.6 True Key Risk Message 6 Key Risk Message 6 refers to the patient’s knowledge that TIRF medicines should be stored in a safe place away from children and properly disposed. Key Risk Message 6: TIRF medicines should be stored in a safe place away from children and properly disposed. Question No. Question Desired response Please answer True, False, or I don’t know for each statement about the TIRF medicine that was most recently prescribed for you. 12a TIRF medicines should be stored in a safe place out of the reach of children. True 16c TIRF medicines must be disposed of as described in the specific product’s Medication Guide. True 16e A TIRF medicine can cause an overdose and death in any child who takes it. True 13 What should you do if an adult who has not been prescribed a TIRF medicine takes a TIRF medicine? (Please select one.) Get emergency help right away. Page 12 of 52 FDA_208 Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies 4. STATISTICAL METHODS 4.1 Study Population 4.1.1 Primary Analysis Population December 2012 Patient KAB Assessment Report According to the prospective Statistical Analysis Plan (SAP, the primary population for analysis was all eligible patients who completed the survey. Eligible patients were defined as those respondents who answered Yes to Question 1 (agree to take part in survey), Yes to Question 2 (filled a prescription for a TIRF medicine in the last 3 months) or Yes to Question 3 (Caregiver for someone who had filled a prescription for a TIRF medicine in the last 3 months), No to Question 4 (participated in past survey; not applicable for Wave 1), selected an age group >18 years of age for Question 5 (patient and caregiver), and No to Question 7 (worked for a TRIG company, UBC, or FDA). A completed survey was a survey in which all non-eligibility questions as appropriate were answered. Note that some questions may not been answered because of skip logic in the survey questionnaire. 4.1.2 Sub-populations of Interest The following subgroup analyses were conducted if the subgroup included at least 20 respondents. • Sub-population S-1: Reading Medication Guide (Question 17, 22, and 23) (Patients who received the Medication Guide and read at least most of it or Patients who did not get a Medication Guide or answered “I don’t know” or who got a Medication Guide and read only some of it or answered “I don’t know.”) • Sub-population analysis S-2: Understanding of Medication Guide (Question 24) (Respondents who understood all of it or most of it, Respondents who understood some of it, Respondents who answered None or “I don’t know”, Respondents who answered “I don’t know” to receipt or reading of the Medication Guide.) • Sub-population S-3: Time to complete survey-Internet (<10 min, 10 to <20 min, or ≥20 min); • Sub-population S-4: Time to complete survey-Telephone (<10 min, 10 to <20 min, or ≥20 min); • • Sub-population S-5: Modality to complete survey (Internet or telephone) • Sub-population S-7: Age group of respondents (Question 5) (18 to 39, 40 to 49, 50 to 59, 60 or older) Sub-population S-6: Highest level of education (Question 36) (less than, some, or High School graduate/GED, or prefer not to answer, Some college or associated degree, Bachelor’s degree or Master’s degree, or Professional or Doctoral degree) Page 13 of 52 FDA_209 Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies 4.1.2.1 December 2012 Patient KAB Assessment Report Primary Analyses Primary analyses were done for all key risk messages. The primary analysis for a key risk message evaluated the number and percentage of each correct responses for each individual question/item defined by the key risk message. The correct response to each question/item is included in the body of the risk message table (Section 3.2). 4.1.2.2 Secondary Analyses Secondary analyses evaluated the number and percentages of correct responses and the average of correct responses within the risk message overall to assess understanding of the comprehensive key risk message. 4.1.3 Patient Report of Adverse Event, Product Complaint, or Medical Information Request during Survey A patient may have reported an adverse event or other safety event while taking a TIRF product either in free text fields in the survey or while in conversation with the Survey Coordinating Center. If the event was mentioned to a Survey Coordinating Center Associate, the Associate documented the safety event and the respondent’s contact information. The respondent was also informed that a representative from the appropriate TIRF medicine manufacturer might contact them to obtain additional information about the safety event. The Internet surveys were monitored for any comments recorded in the free text fields. Information on all reports (Internet or phone) that constituted an adverse event or other safety event was forwarded to the appropriate TIRF medicine manufacturer for processing within 1 business day of awareness of the event as outlined in the Safety Event Reporting Plan (SERP). 5. RESULTS Results of the patient responses to questions in the KAB survey are summarized in this section. 5.1 Survey Participants 5.1.1 Survey Participant Administration Results Based on the number of prescriptions filled during the 90 days prior to 12 September 2012, the national pharmacy chain network partner identified 1112 possible participants among patients and caregivers. All of these possible participants were sent a survey invitation letter. A total of 899 follow up letters were sent to non-responders on 08 October 2012. Of the 1112 possible participants, 198 respondents indicated interest in the survey and were screened for eligibility to participate and 192 respondents met eligibility criteria and completed the survey (Table 1). Of these 192 respondents, 112 (56.6%) completed the survey online, and 80 (40.4%) completed it by telephone. Although, the survey had a target of 300 eligible completed responders, the initial population of 1112 possible participants was small. The response of 192 completed surveys is within the Page 14 of 52 FDA_210 Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies expected response rate to mailed invitations. To increase participation in the s1nvey, recruitment methodology and inclusion criteria will be evaluated in future smvey waves. December 2012 Patient KAB Assessment Report Table 1. Survey Participant Administration Results Screened Patients/Caregivers N=198l All Respondents Summary Statistic Nlunber of invitations issued to patients/caregivers 1112 Number of reminder letters issued to 899 patients/caregivers Nlunber of patients/caregivers screened for 1981 part1c1pat10n Ntunber of patients/caregivers eligible for participation 192 Nlunber of patients/caregivers completing the smvey 192 97.0 By telephone 80 40.4 By intemet 112 56.6 1 This is the denominator for the percentages in this table Page 15 of 52 1 December 2012 Patient KAB Assessment Report Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Of the 198 respondents, the screening procedlu?e identi?ed 192 eligible participants (including 190 patients and 2 caregivers) all of whom completed the s1uvey (Table 2). Due to the small munber of caregivers participating in the smvey, the majority of results are reported for patients and caregivers combined. Table 2. Survey Participant Screening Results Eligible and Complete All Respondents Respondents Question N=l98 N=l92 5.2 Question 1: Do you agree to participate in this survey? Yes 197 99.5 192 100.0 No1 1 0.5 generic versions of any of these brands. Question 2: Within the last 3 months, have you ?lled a prescription for yourself for a transmucosal immediate release fentanyl medicine (known as medicines?)? TIRF medicines include Abstral?, Actiq?, Fentora?, Lazanda?, 0nsolis?, Subsys?, and the Yes 191 96-5 190 99don?t know 1 0.5 Question not asked2 1 0.5 Question 3: Are you a caregiver for someone who has ?lled a prescription for a TIRF medicine within the last 3 months? As a reminder, TIRF medicines include Abstral?, Actiq?, Fentora?, Lazanda?, 0nsolis?, Subsys?, and the generic versions of any of these Page 16 of 52 brandsdon?t know1 0.0 Question not asked 2 192 97.0 190 99.0 (continued) 2 Transmucosal Immediate Release Fentanyl (TIRF) December 2012 TIRF REMS Industry Group (TRIG) of Companies Patient KAB Assessment Report Table 2. Survey Participant Screening Results Eligible and Complete All Respondents Respondents Question N=l92 Question 4: Have you ever taken part in a survey about a TIRF medicine before185 93.4 184 95.8 I don?t know 6 3.0 6 3.1 Question not asked 2 5 2.5 Question 5: Which of the following groups best describes your age? Under 181 24.7 49 25.5 50 59 73 36.9 72 37.5 60 69 40 20.2 40 20.8 70 or older 8 4.0 8 4.2 Prefer not to answer1 0 0.0 Question not asked2 5 2.5 Question 6: Which of the following groups best describes the patient?s age? (Caregivers, only) Under older 0 0.0 Prefer not to answer 0 0.0 Question not asked2 196 99.0 190 99.0 (continued) Page 17 of 52 Transmucosal Immediate Release Fentanyl (TIRF) December 2012 TIRF REMS Industry Group (TRIG) of Companies Patient KAB Assessment Report Table 2. Survey Participant Screening Results Eligible and Complete All Respondents Respondents Question N=l92 Question 7: Have you or any of your immediate family members ever worked for any of the following companies or agencies? Please select all that apply.3 Anesta LLC.1 0 0.0 Archimedes Pharma US Inc. 1 0 0.0 ephalon. Inc. (a wholly-owned 0 0.0 subsidiary of Teva Phannaceutical Industries. Ltd.) 1 Endo Phannaceuticals Inc. 1 0 0.0 Insys Therapeutic s1 0 0.0 Mallinckrodt (a Phannaceuticals Business 1 0.5 of Covidien)l Meda Pharmaceuticals1 0 0.0 Par Phannaceutical. Inc.1 0 0.0 ProStrakan. Inc.1 0 0.0 Sandoz Inc.1 0 0.0 cha Phannaccuticals. Ltd.1 0 0.0 United BioSom?ce C01poration1 0 0.0 McKesson Specialty Care Solutions1 0 0.0 RelayHealth1 0 0.0 0 0.0 No4 192 97.0 192 100.0 I don?t know1 0 0.0 Question not asked2 5 2.5 Ineligible to participate in the survey. Question not asked due to a previous question elimination More than 1 response can be selected. so percentages may not sum to 100% Ineligible if selected in addition to another response Page 18 of 52 Transmucosal Immediate Release Fentanyl (TIRF) December 2012 TIRF REMS Industry Group (TRIG) of Companies Patient KAB Assessment Report Of the 192 patient/caregivers, 112 completed the survey online, and 80 completed it by telephone (Table 3). Those taking the smvey online took an average of 17.5 minutes to complete it, while those taking it by telephone took an average of 13.7 minutes. Table 3. Time to Complete Survey Time to Complete Survey for Completers (Minutes) Summary Statistic Telephone Internet Total1 80 1 1 2 1 92 Mean (Standard Deviation) 17.5 (4.69) 13.7 (6.86) 15.3 (6.32) Minimum 10 5 5 Median 16.5 11.6 14.9 Maximum 38 42 42 Category 0 <5 Minutes 0 0 0 5?<10 Minutes 1 37 38 10 <15 Minutes 21 40 61 15 <20 Minutes 40 21 61 20 <25 Minutes 13 6 19 25 <30 Minutes 2 30 Minutes or More 3 4 1 Number of eligible respondents completing the survey (See Table 1). 5.2.1 Patient/Caregiver Demographics The demographic characteristics of respondents are shown in Table 4. The majority of respondents were above the age of 40 years female and had at least some college or Associate?s degree or higher education(153, Participants were largely from the Midwest or South with the No?heast acc01mting for 13.5% and the West 14.0% of the respondents. Page 19 of 52 Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies December 2012 Patient KAB Assessment Report Table 4. Demographic Characteristics of Eligible Patients/Caregivers Patients Caregivers Patients Caregivers Question n=l90 n=2 Question 5: Which of the following groups best describes your age50.0 17 8.9 40?49 49 25.8 0 49 25.5 50 59 72 37.9 0 72 37.5 60 69 39 20.5 1 50.0 40 20.8 70 or older 8 4.2 0 8 4.2 Question 35: What is your gender? Male 70 36.8 1 0.0 71 37.0 Female 120 63.2 1 50.0 121 63.0 Prefer not to answer 0 0 0 0 0.0 Question 36: What is the highest level of education you have completed? Less than high school 2 1.1 0 0 1.0 Some high school 2 1.1 0 0 1.0 High School graduate/GED 34 17.9 0 0 34 17.7 Some college/Associate?s degree 80 42.1 0 0 80 41.7 Bachelor?s degree 37 19.5 1 50.0 38 19.8 Master?s degree 27 14.2 1 50.0 28 14.6 Professional or Doctoral dc gree Prefer not to answer 1 0.5 0 0 1 0.5 (continued) Page 20 of 52 6 Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies December 2012 Patient KAB Assessment Report Table 4. Demographic Characteristics of Eligible Patients/Caregivers Patients Caregivers Patients Caregivers Question n=l90 n=2 N=l921 Question 37 2 What is the main language you speak at home? (Please select only one.) English 189 99.5 2 100.0 191 99.5 French 0 0 0 0 0 0.0 Spanish 0 0 0 0 0 0.0 Portuguese 0 0 0 0 0 0.0 Italian 0 0 0 0 0 0.0 Gennan 0 0 0 0 0 0.0 Chinese 0 0 0 0 0 0.0 Japanese 0 0 0 0 0 0.0 Korean 0 0 0 0 0 0.0 Other 0 0 0 0 0 0.0 Prefer not to answer 1 0.5 0 0 1 0.5 Question 38: Are you Hispanic or Latino186 97.9 2 100.0 188 97.9 Prefer not to answer 0 0 0 0 0 0.0 Question 38: For informational purposes only, indicate which of the following US. census categories best describes your race? American Indian or Alaska Native 5 2.6 5 2.6 Asian (origins of Far East. 1 0.5 1 0.5 Southeast Asia or the Indian subcontinent) Black or A?ican American 8 4.2 4.2 Native Hawaiian or Other Paci?c 0 0 0.0 Islander White 170 89.5 100.0 172 89.6 Other 4 2.1 0 4 2.1 Prefer not to answer 2 1.1 0 2 1.0 (continued) Page 21 of 52 7 Transmucosal Immediate Release Fentanyl (TIRF) December 2012 TIRF REMS Industry Group (TRIG) of Companies Patient KAB Assessment Report Table 4. Demographic Characteristics of Eligible Patients/Caregivers Patients Caregivers Patients . Caregivers Question n=l90 n=2 Geographic Distribution (based on Question 40 State or US Territory)2 Northeast 26 13.7 0 0.0 26 13.5 Midwest 62 32.6 0 0.0 62 32.3 South 74 38.9 2 100.0 76 39.6 West 28 14.7 0 0.0 28 14.6 Other 0 0.0 0 0.0 0 0.0 Prefer not to answer Number of eligible respondents completing the survey (See Table 1). 2 US. Census Bureau. last revised Friday. 27-Jul-2001 12:59:43 EDT.. Geography Division. Northeast includes CT. MA. ME. NH. NJ. NY. PA. RI. and VT. Midwest includes IA. IL. IN. KS. MI. l\/1N. MO. ND. NE. OH. SD. and W1. South includes AL. AR. DC. DE. FL. GA. KY. LA. MD. MS. NC. OK. SC. TN. TX. VA. and WV. West includes AK. AZ. CA. CO. HI. ID. MT. NM. NV. OR. UT. WA. and WY. The following US territories are categorized as Other: Puerto Rico. Northern Mariana Islands. US Virgin Islands. American Samoa. and Guam. 5.2.2 TIRF Medicines Educational Materials Respondents were asked about their awareness of educational materials for TIRF medicines, speci?cally the Medication Guide (Table 5), and the Patient-Prescriber Agreement Form (Table 9). Most respondents (173, reported they had received a Medication Guide for the TIRF medicine prescribed to them. Of these 173 respondents, 158 received the Medication Guide from the pharmacy; 167 read the Medication Guide; of those who read it, 109 read all of it and 41 read most of it. From these 167 respondents, 96 reported that they rmderstood all of the Medication Guide and 58 reported that they understood most of it. There were 104 of the 173 respondents who indicated that someone had offered to explain the Medication Guide to them. Page 22 of 52 Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies December 2012 Patient KAB Assessment Report Table 5. Responses to Questions About TIRF Medication Guides Patients Caregivers Patients Caregivers Question n=l90 n=2 Question 17: Have you you or the patient ever received a Medication Guide for the TIRF medicine that was prescribed for you/the patient? Yes 172 90.5 1 50.0 173 90.1 N0 7 3.7 1 50.0 8 4.2 I don?t know 11 5.8 0 0.0 11 5.7 Question 18: Did you receive the Medication Guide from the doctor who prescribed the TIRF medicine or someone in the doctor?s of?ce?2 Yes 86 50.0 0 0.0 86 49.7 No 75 43.6 1 100.0 76 43.9 I don?t know 11 6.4 0 0.0 11 6.4 (answered know to Question 17) Question 19: When was the Medication Guide given to you? 2 At the ?rst appointment with 59 68,6 0 0.0 59 68.6 the doctor who prescn'bed the TIRF medicine At the last appointment with the doctor who prescribed the TIRF medicine I don?t remember 24 27.9 0 0.0 24 27.9 (answered 106 know to Question 17 or No or I don?t know to Question 18) Question 20: Did you receive the Medication Guide from the pharmacy? 2 Yes 157 91.3 1 100.0 158 91don?t know 4 2.3 0 0.0 4 2.3 (answered know to Question 17) (continued) Page 23 of 52 9 Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies December 2012 Patient KAB Assessment Report Table 5. Responses to Questions About TIRF Medication Guides Patients Caregivers Patients Caregivers Question n=l90 n=2 N=l92l Question 21: When was the most recent time that you received a Medication Guide for the TIRF medicine at the pharmacy? 2 Only with the ?rst ?lled 5 3. 2 1 100.0 6 3.8 prescription Each time a prescription is 139 88_ 5 0 0,0 139 88.0 ?lled Other3 4.5 0.0 7 4.4 I don?t know 6 3.8 0.0 6 3.8 (answered know to Question 17 or No or I don?t know to Question 20) Question 22: Did you read the Medication Guide? 2 Yes 166 96.5 1 100.0 167 96don?t know 0 0.0 0 0.0 0 0.0 (answered know to Question 17) Question 23: How much did you read? 2 All of it 109 65.7 0 0.0 109 65.3 MOSI Ofit 40 24.1 1 100.0 41 24.6 Some of it 17 10.2 0 0.0 17 10.2 I don?t know 0 0.0 0 0.0 0 0.0 (answered know to Question 17 or No or I don?t know to Question 22) (continued) Page 24 of 52 Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies December 2012 Patient KAB Assessment Report Table 5. Responses to Questions About TIRF Medication Guides Patients Caregivers Patients Caregivers Question n=l90 n=2 N=l92l Question 24: How much of the Medication Guide did you understand?2 All of it 96 57.8 0 0.0 96 57.5 Most of it 57 34.3 1 100.0 58 34.7 Some 7.8 None don?t know 0.0 0 0.0 0.0 (answered know to Question 17 or No or I don?t know to Question 22) Question 25: Did someone offer to explain the Medication Guide to you?2 Yes 104 60.5 0 0.0 104 60.1 N0 53 30.8 1 100.0 54 31.2 I don?t know 15 8.7 0 0.0 15 8.7 (answered know to Question 17) Question 26: Who offered to explain the Medication Guide to you? (Select all that apply.)2 The doctor or another 64 61 _5 0 0.0 64 61.5 healthcare professional in the doctor?s of?ce The pharmacist where the 93 89_4 0 0,0 93 89.4 TIRF medicine prescription was ?lled Someone else (specify the 8 7.7 0 0,0 8 7.7 type of person but not his/her name)4 (answered know to Question know to Question 25) (continued) Page 25 of 52 Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies December 2012 Patient KAB Assessment Report Table 5. Responses to Questions About TIRF Medication Guides Patients Caregivers Patients Caregivers Question n=l90 N=l92l Question 27: Did you accept the offer to have the Medication Guide explained to you?2 Yes 53 51.0 0 0.0 53 51.0 No 48 46.2 0 0.0 48 46.2 I don?t know 3 2.9 0 0.0 3 2.9 (answered know to Question 17 or No or I don?t know to Question 25) Question 28: How much of the explanation did you understand? 2 All of it 44 83.0 0 0.0 44 83.0 Most ofit 8 15.1 0 0.0 8 15.1 Some 1.9 None don?t ICIIOW 0 0 0 0.0 0.0 (answered 139 know to Question know to Question know to Question 27) Question 29: Did you or do you have any questions about the information in the Medication Guide? Yes5 163 94.8 0 0.0 163 94.2 I don?t know 2 1.2 1 100.0 3 1.7 (answered know to Question 17) 1 Nlunber of eligible respondents completing the smvey (See Table 2 Percentages are calculated based on the sample presented with this question because of skip logic in the survey. 3 Verbatim texts for other time receiving Medication Guide (Question 21) from the pharmacy are presented in Listing 1 4 Verbatim texts for other persons offering to explain the Medication Guide (Question 26) are presented in Listing 2 5 Questions about the information in the Medication Guide (Question 29) are presented in Listing 3 Page 26 of 52 December 20 12 Patient KAB Assessment Report Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies The categorized responses to Question 21, 26 and 29 referenced in Table 5 are shown in Table 6, Table 7, and Table 8, respectively. Table 6. Categorized Responses To Question 21 (Most recent time receiving Medication Guide for the TIRF medicine from the pharmacy) Patients Caregivers CPatlents 2] areglvers Response (Categorized Type) I 11?190 11-2 N=l921 Sometimes Ntunber of eligible respondents completing the survey (See Table 1). 2 Categorization scheme of the verbatim responses is shown in Listing 1. 3 Each category is only counted once per patient Table 7. Categorized Responses To Question 26 (Other person offering explanation of the Medication Guide) Patients Caregivers 223:;21: Response (Categorized Type) [21 N=l90 N=l921 N3 N3 N3 Family 3 1.6 0.0 3 1.6 Pharmaceutical Rep 4 2,1 0.0 4 2. 1 Pharmacy 0.5 0.0 0.5 I Number of eligible respondents completing the survey (See Table 1). 2 Categorization scheme of the verbatim responses is shown in Listing 2. 3 Each category is only counted once per patient Page 27 of 52 Transrnucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies December 2012 Patient KAB Assessment Report Table 8. Categorized Responses To Question 29 (Questions about the information in the Medication Guide) . . Patients t1 . Response (Categorized Type) 2 a en areglvers Caregivers n=l90 n=2 1 N?l92 Education 2 1 .0 0 0.0 2 1.0 Side Effects 1 0.5 0.0 1 0.5 Placement of medication 1 0.5 0 0.0 1 0.5 Oral Side Effects 1 0.5 0 0.0 1 0.5 Disposal Ntunber of eligible respondents completing the sru'vey (See Table 1). 2 Categorization scheme of the verbatim responses is shown in Listing 3. 3 Each category is only counted once per patient 5.2.3 Patient-Prescriber Agreement Form After respondents were asked the questions regarding the key risk messages, they were asked if they had received, read, and rmderstood the PPAF. A total of 134 respondents indicated that someone at the doctor?s of?ce had offered to explain the PPAF to them, and that 113 of them lmderstood all of it and 19 lmderstood most of it. The PPAF was signed by 144 respondents; of these 144 responders, 113 reported receiving a copy of the signed PPAF. Table 9. Responses to Questions About the Patient-Prescriber Agreement Form Patients Caregivers Patients Caregivers Question n=l90 n=2 Question 31: Did the doctor or someone in the doctor?s of?ce explain the Patient-Prescriber Agreement Form to you? Yes 134 70.5 0 0.0 134 69.8 N0 33 17.4 2 100.0 35 18.2 I don?t know 23 12.1 0 0.0 23 12.0 (continued) Page 28 of 52 Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies December 2012 Patient KAB Assessment Report Table 9. Responses to Questions About the Patient-Prescriber Agreement Form Patients Caregivers Patients Caregivers Question n=l90 n=2 N=192l Question 32: How much of the explanation did you understand?2 All ofit 113 84.3 0 0.0 113 84.3 Most of it 19 14.2 0 0.0 19 14.2 Some 1.5 None ofit 0.0 0 0.0 0 0.0 I don?t know 0 0.0 0 0.0 0 0.0 (answered know to Question 31) Question 33: Did you sign a Patient-Prescriber Agreement Form? Yes 144 75.8 0 0.0 144 75.0 N0 13 6.8 1 50.0 14 7.3 I don?t know 33 17.4 1 50.0 34 17.7 Question 34: Did the doctor or someone in the doctor?s of?ce give you a copy of the signed Patient? Prescriber Agreement Form?2 Yes 113 78.5 0 0.0 113 789.7 Idon?tknow 17 11.8 0 0.0 17 11.8 (answered No or I 46 2 48 don?t know to Question 33) Nlunber of eligible respondents completing the sm'vey (See Table 1). 2 Percentages are calculated based on the sample presented with this question because of skip logic in the sm'vey. The focus of this section of the docmnent is on the ?ndings for the total respondent 5.3 KAB Survey Objectives 5.3.1 Key Risk Message Results population. 5.3.1.1 Key Risk Message 1 Key Risk Message 1 refers to the patient?s knowledge that TIRF medicines can cause life- tln'eatening breathing problems that can lead to death. Page 29 of 52 Transmucosal Immediate Release Fentanyl (TIRF) December 2012 TIRF REMS Industry Group (TRIG) of Companies Patient KAB Assessment Report Analysis of responses to Question 12d for Key Risk Message 1 showed that 90.1% of the respondents were aware of the risk of life-threatening breathing problems with TIRF medicines (Table 10). Table 10. Key Risk Message 1: TIRF Medicines Can Cause Life-Threatening Breathing Problems That Can Lead To Death Patients Caregivers Patients Caregivers ti n=19o n=2 N=192l ues on (95% CD3 (95% (95% Question 12: Please answer True, False, or I don?t know for each statement about the TIRF medicine that was most recently prescribed for you the patient. 12d: TIRF medicines can cause life-threatening breathing problems that can lead to death. Truez 172 90.5 1 50.0 173 90.1 (85.4. 94.3) (1.3. 98.7) (85.0. 93.9) False don?t know 13 6.8 1 50.0 14 7.3 Nrunber of eligible respondents completing the survey (See Table 1). 2 Indicates the correct response(s) to each question or item within a question. 3 All con?dence intervals are exact binomial 95% con?dence intervals. 5.3.1.2 Key Risk Message 2 Key Risk Message 2 refers to the respondents? knowledge that they should not take TIRF Medicines if they are not opioid tolerant. Three (3) questions de?ne this key risk message (Table 11). In response to the statement in Question 10 that TIRF medicines should only be taken by patients who are opioid tolerant, 90.6% respondents gave the correct (true) response. The majority of respondents understood that opioid tolerant means that a patient is ah?eady taking other opioid pain medicines arormd the clock and their body is used to these medicines and the majority also rmderstood that it is not okay for patients to?take TIRF medicines for headache pain Evidence of rmderstanding this key risk information is further supported by the average number of 2.5 out of a possible 3 correct responses. Page 30 of 52 Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies December 2012 Patient KAB Assessment Report Table 11. Key Risk Message 2: Patients Should Not Take TIRF Medicines If They Are Not Opioid Tolerant Patients Caregivers Patients n=l90 n=2 Caregivers Question CI) Question 10: Please answer True, False, or I don?t know for the following statement: TIRF medicines should only be taken by patients who are opioid tolerant. Tmez 172 90.5 2 100.0 174 90.6 (85.4. 94.3) (15.8. 100.0) (85.6. 94.3) False don?t know 13 6.8 0 0.0 13 6.8 Question 11: Please answer True, False, or I don?t know for the following statements: 11a: Opioid tolerant means that a patient is already taking other opioid pain medicines around the clock and their body is used to these medicines. Tl'lle2 174 91.6 2 100.0 176 91.7 (86.7. 95.1) (15.8. 100.0) (86.8. 95.2) False don?t know 9 4.7 0 0.0 9 4.7 Question 12: Please answer True, False, or I don?t know for each statement about the TIRF medicine that was most recently prescribed for you the patient. 12b: It is OK for patients to take TIRF medicines for headache pain. True 17 8.9 0 0.0 17 8.9 False2 134 70.5 2 100.0 136 70.8 (63.5. 76.9) (15.8. 100.0) (63.9. 77.2) I don?t know 39 20.5 0 0.0 39 20.3 (continued) Page 31 of 52 Transrnucosal Immediate Release Fentanyl (TIRF) December 2012 TIRF REMS Industry Group (TRIG) of Companies Patient KAB Assessment Report Table 11. Key Risk Message 2: Patients Should Not Take TIRF Medicines If They Are Not Opioid Tolerant Patients Caregivers Patients _190 n?2 Caregivers n- Question 3 3 3 (95% CI) (95% CI) (95% CI) Secondary Analyses: Demonstrated Understanding 0 correct responses correct response correct responses 61 32.1 0 0.0 61 31.8 3 correct responses 116 61.1 2 100.0 118 61.5 Average number of 2.5 (2.3. 3.0)4 3.0 (1.0. 3.0)4 2.5 (2.3. 3.0)4 correct responses 1 Number of eligible respondents completing the survey (See Table 1). 2 Indicates the correct response(s) to each question or item within a question. 3 All con?dence intervals are exact binomial 95% con?dence intervals. 4 One-sided 95 con?dence interval using the normal approximation to the Poisson distribution. 5.3.1.3 Key Risk Message 3 Key Risk Message 3 refers to the patient?s knowledge that TIRF medicines should be taken exactly as prescribed by the healthcare provider. Three (3) questions de?ne this key risk message. (Table 12). Less than half of respondents rmderstood that if a patient stops taking around-the- clock opioid pain medicine, they must also stop taking the TIRF medicine. However, all patients (100%) understood that TIRF medicines should be taken exactly as prescribed by the doctor and 82.3% of respondents knew that is not OK to take TIRF medicines for short-term pain that will go away in a few days. Evidence of lmderstanding this key risk information is further supported by the average nmnber of 2.3 out of a possible 3 correct responses. Page 32 of 52 Transmucosal Immediate Release Fentanyl (TIRF) December 2012 TIRF REMS Industry Group (TRIG) of Companies Patient KAB Assessment Report Table 12. Risk Message 3: TIRF Medicines Should Be Taken Exactly As Prescribed By The Healthcare Provider Patients Caregivers Patients Caregivers . n=190 n=2 N=192l Question 11 (95% (95% (95% CD3 Question 11: Please answer True, False, or I don?t know for each of the following statements. 11b: If a patient stops taking around-the-clock opioid pain medicine, they must also stop taking the TIRF medicine. Trucz 82 43.2 0 0.0 82 42.7 (36.0. 50.5) (35.6. 50.0) False 47 24.7 0 0.0 47 24.5 IdOIl?t know 61 32.1 2 100.0 63 32.8 Question 12: Please answer True, False, or I don?t know for each statement about the TIRF medicine that was most recently prescribed for you the patient. 12c: TIRF medicines should be taken exactly as prescribed by the doctor. Tmez 190 100.0 2 100.0 192 100.0 (98.1. 100.0) (15.8. 100.0) (98.1. 100.0) False don?t know 0 0.0 0 0.0 0 0.0 Question 16: Please answer True, False, or I don?t know for each statement about the TIRF medicine that was most recently prescribed for you the patient. 16b: It is OK to take TIRF medicines for short-term pain that will go away in a few days. True 10 5.3 0 0.0 10 5.2 False2 157 82.6 1 50.0 158 82.3 (76.5. 87.7) (1.3. 98.7) (76.1. 87.4) I don?t know 23 12.1 1 50.0 24 12.5 (continued) Page 33 of 52 Transmucosal Immediate Release Fentanyl (TIRF) December 2012 TIRF REMS Industry Group (TRIG) of Companies Patient KAB Assessment Report Table 12. Risk Message 3: TIRF Medicines Should Be Taken Exactly As Prescribed By The Healthcare Provider Patients Caregivers Patients Caregivers n=l90 n=2 N=192l Question 11 (95% (95% (95% Secondary Analysis: Demonstrated Understanding 0 correct responses correct response 26 13.7 1 50.0 27 14.1 2 correct responses 89 46.8 1 50.0 90 46.9 3 correct responses 75 39.5 0 0.0 75 39.1 Average munber 0f 2.3 (2.1. 3.0)4 1.5 (0.1. 3.0)4 2.3 (2.1. 3.0)4 correct responses 1 Number of eligible respondents completing the survey (See Table 1). 2 Indicates the correct response(s) to each question or item within a question. 3 All con?dence intervals are exact binomial 95% con?dence intervals. 4 One-sided 95 con?dence interval using the nomial approximation to the Poisson distribution. 5.3.1.4 Key Risk Message 4 Key Risk Message 4 refers to the patient?s knowledge that they must not switch TIRF medicines Without talking to a healthcare provider. (Table 13) The majority of respondents imderstood that it is not safe to switch to another medicine that contains fentanyl without talking to a healthcare provider ?rst. Page 34 of 52 December 2012 Patient KAB Assessment Report Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Table 13. Risk Message 4: Patients Should Not Switch From A TIRF Medicine To Another Medicine That Contains Fentanyl Without Talking To A Healthcare Provider Patients Caregivers Patients Caregivers n=l90 n=2 N=192l Question CI) Question 11: Please answer True, False, or I don?t know for each of the following statements. llc: It is safe to switch to another medicine that contains fentanyl without talking to a healthcare provider ?rst True 1 0.5 0 0.0 1 0.5 False2 185 97.4 1 50.0 186 96.9 (94.0. 99.1) (1.3. 98.7) (93.3. 98.8) I don?t know 4 2.1 1 50.0 5 2.6 1 Number of eligible respondents completing the survey (See Table 2 Indicates the correct response(s) to each question or item within a question. 3 All con?dence intervals are exact binomial 95% con?dence intervals. 5.3.1.5 Key Risk Message 5 Key Risk Message 5 refers to the patient?s knowledge that TIRF medicines should not be given to anyone else even if they have the same (Table 14). All (100%) respondents 1mderstood that a patient may not give TIRF medicines to another person if they have the same as the patient, and 97.9% Imderstood that selling or giving away TIRF medicines is against the law. Evidence of lmderstanding this key risk inf01mation is fluther supported by the average mnnber of 2.0 out of a possible 2 con?ect responses. Page 35 of 52 Transmucosal Immediate Release Fentanyl (TIRF) December 2012 TIRF REMS Industry Group (TRIG) of Companies Patient KAB Assessment Report Table 14. Key Risk Message 5: Patients Should Not Give TIRF Medicines To Anyone Else Even If They Have The Same Patients Caregivers Patients Caregivers n=l90 n=2 N=192l Question (95% (95% (95% CD3 Question 11: Please answer True, False, or I don?t know for each of the following statements. 11d: A patient may give TIRF medicines to another person if they have the same as the patient. True 0 0.0 0 0.0 0 0.0 False2 190 100.0 2 100.0 192 100.0 (98.1. 100.0) (15.8. 100.0) (98.1. 100.0) I don?t know 0 0.0 0 0.0 0 0.0 Question 16: Please answer True, False, or I don?t know for each statement about the TIRF medicine that was most recently prescribed for you the patient. 16a: Selling or giving away TIRF medicines is against the law. True2 186 97.9 2 100.0 188 97.9 (94.7. 99.4) (15.8. 100.0) (94.8. 99.4) False don?t know 1 0.5 0 0.0 1 0.5 Secondary Analysis: Demonstrated Understanding 0 correct responses correct response correct responses 186 97.9 2 100.0 188 97.9 32:22:3221? 2.0 (1.8. 2.0)4 2.0 (0.4. 2.0)4 2.0 (1.8. 2.0)4 1 Number of eligible respondents completing the smw?ey (See Table 1). 2 Indicates the correct response(s) to each question or item Within a question. 3 All con?dence intervals are exact binomial 95% con?dence intervals. 4 One-sided 95 con?dence interval using the nonnal approximation to the Poisson distribution. 5.3.1.6 Key Risk Message 6 Key Risk Message 6 refers to the patient?s knowledge that TIRF medicines should be stored in a safe place away from children and properly disposed (Table 15). All (100%) respondents imderstood that TIRF medicines should be stored in a safe place out of the reach of children. The majority of respondents imderstood that TIRF medicines must be Page 36 of 52 December 2012 Patient KAB Assessment Report Transrnucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies disposed of as described in the speci?c product?s Medication Guide a TIRF medicine can cause an overdose and death in any child who takes it and that they should get emergency help right way when asked, ?What should you do if an adult who has not been prescribed a TIRF medicine takes a TIRF medicine?? Evidence of lurderstanding this key risk information is ?uther supported by the average number of 3.8 out of a possible 4 correct responses. Table 15. Key Risk Message 6: TIRF Medicines Should Be Stored In A Safe Place Away From Children And Properly Disposed Patients Caregivers Patients Caregivers n=l90 n=2 N=r92l Question 11 (95% c1)3 (95% (95% Question 12: Please answer True, False, or I don?t know for each statement about the TIRF medicine that was most recently prescribed for you the patient. 12a: TIRF medicines should be stored in a safe place out of the reach of children. Tmeg 190 100.0 2 100.0 192 100.0 (98.1. 100.0) (15.8. 100.0) (98.1. 100.0) False don?t know 0 0.0 0 0.0 0 0.0 Question 16: Please answer True, False, or I don?t know for each statement about the TIRF medicine that was most recently prescribed for you the patient. 16c: TIRF medicines must be disposed of as described in the speci?c product?s Medication Guide. Truez 182 95.8 2 100.0 184 95.8 (91.9. 98.2) (15.8. 100.0) (92.0. 98.2) False don?t know 6 3.2 0 0.0 6 3.1 l6e: A TIRF medicine can cause an overdose and death in any child who takes it. Truez 173 91.1 1 50.0 174 90.6 (86.1. 94.7) (1.3. 98.7) (85.6. 94.3) False don?t know 13 6.8 50.0 14 7.3 (continued) Page 37 of 52 Transmucosal Immediate Release Fentanyl (TIRF) December 2012 TIRF REMS Industry Group (TRIG) of Companies Patient KAB Assessment Report Table 15. Key Risk Message 6: TIRF Medicines Should Be Stored In A Safe Place Away From Children And Properly Disposed Patients Caregivers Patients Caregivers n=19o n=2 N=192l Question (95% (95% (95% Question 13: What should you do if an adult who has not been prescribed a TIRF medicine takes a TIRF medicine? (Please select one.) Get emergency help 1 70 89.5 1 50.0 171 89.1 right away2 (84.2. 93.5) (1.3. 98.7) (83.8. 93.1) Do nothing 0 0.0 0 0.0 0 0.0 Wait an horn and see if 6 3.2 0 0.0 6 3.1 the person is OK I don't know 14 7.4 1 50.0 15 7.8 Secondary Analyses: Demonstrated Understanding 0 correct responses correct response correct responses 6 3.2 1 50.0 7 3.6 3 con'ect responses 33 17.4 0 0.0 33 17.2 4 correct responses 151 79.5 1 50.0 152 79.2 Average number of 3.8 (3.5. 4.0)4 3.0 (1.0. 4.0)4 3.8 (3.5. 4.0)4 Ol?l?CCl 1 Number of eligible respondents completing the Sim'ey (See Table 2 Indicates the correct response(s) to each question or item within a question. 3 All con?dence intervals are exact binomial 95% con?dence intervals. 4 One-sided 95 con?dence interval using the normal approximation to the Poisson distribution. 5.3.2 Other Survey Questions 5.3.2.1 Additional Questions About TIRF Medicines Safety Table 16 summarizes the respondents? answers to additional questions beyond those associated with the key risk messages. These questions assessed whether the patient had been informed of the risks and possible side effects, indications, usage, and storage, and the availability of TIRF medicines through the TIRF REMS Access Program. Respondents were aware of the risks associated with TIRF medicines regarding side effects Page 38 of 52 Transmucosal Immediate Release Fentanyl (TIRF) December 2012 TIRF REMS Industry Group (TRIG) of Companies Patient KAB Assessment Report Most respondents (67.7% to 89.6%) were aware of the clinical conditions for using TIRF medicines; however, the awareness was low regarding use in chronic non-cancer pain with only 24.5% of respondents correctly responding false. The majority of patients were told by their doctor, nlu?se, or other healthcare provider how to use their TIRF medicine and how to properly store the medicine Half of all patients understood that TIRF medicines are only available through the TIRF REMS Access program. Table 16. Responses to Additional Questions about the Safe Use of TIRF Medicines Patients Caregivers 35mm.? areglvers Question ll=l90 ll=2 N=l921 Question 8: Did the doctor, nurse, or other healthcare professional in the doctor?s of?ce ever talk to you about the risks and possible side effects of the TIRF medicine that was most recently prescribed for you? TIRF medicines include Abstral?, Actiq?, Fentora?, Lazanda?, 0nsolis?, Subsys?, and the generic versions of these brands. Yes 165 86.8 0 0.0 165 85.9 No 21 11.1 2 100.0 23 12.0 I don?t know 4 2.1 0 0.0 4 2.1 Question 9: For which of the following conditions should I use a TIRF medicine? 9a: Headache or migraine pain Yes 29 15.3 0 0.0 29 15.1 No2 138 72.6 2 100.0 140 72.9 I don?t know 23 12.1 0 0.0 23 12.0 9b: Breakthrough pain from cancer Yes2 132 69.5 2 100.0 134 69.8 No 52 27.4 0 0.0 52 27.1 I don?t know 6 3.2 0 0.0 6 3.1 9c: Dental pain Yes 3 1.6 0 0.0 3 1.6 No2 170 89.5 2 100.0 172 89.6 I don?t know 17 8.9 0 0.0 17 8.9 (continued) Page 39 of 52 Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies December 2012 Patient KAB Assessment Report Table 16. Responses to Additional Questions about the Safe Use of TIRF Medicines Patients Caregivers 323;:efs Question n=l90 n=2 9d: Acute or post?operative pain Yes 38 20.0 100.0 40 20.8 No2 130 68.4 0 0.0 130 67.7 I don?t know 22 11.6 0 0.0 22 11.5 9e: Chronic non-cancer pain Yes 136 71.6 0 0.0 136 70.8 No2 45 23.7 2 100.0 47 24.5 I don?t know 9 4.7 0 0.0 9 4.7 Question 14: Did the doctor, nurse, or other healthcare professional in the doctor?s of?ce ever tell you how to use the TIRF medicine that was most recently prescribed for you? Yes 179 94.2 1 50.0 180 93.8 No 11 5.8 1 50.0 12 6.3 I don?t know 0 0.0 0 0.0 0 0.0 Question 15: Did the doctor, nurse, or other healthcare professional in the doctor?s of?ce ever tell you how to store or keep the TIRF medicine that was most recently prescribed for you? Yes 155 81.6 0 0.0 155 80.7 No 31 16.3 2 100.0 33 17.2 Idon?t know 4 2.1 0 0.0 4 2.1 16d: TIRF medicines are only available to patients through a special program (called the TIRF REMS Access program). True2 97 51.1 0 0.0 97 50.5 False 23 12.1 0 0.0 23 12.0 I don?t know 70 36.8 2 100.0 72 37.5 1 Number of eligible respondents completing the survey (See Table 1Indicates the correct response(s) to each question or item Within a question. 5.3.3 Analyses of Subpopulations To assess further patients? understanding of key risk messages, subgroup analyses as described in Section 4.1.2 were conducted. All results are similar to the results in the primary population, and no trends are evident. The full set of subgroup analysis tables is provided in Appendix B. Page 40 of 52 Transrnucosal Immediate Release Fentanyl (TIRF) December 2012 TIRF REMS Industry Group (TRIG) of Companies Patient KAB Assessment Report 5.4 Spontaneous Reporting of Adverse Events, Product Complaints, or Medical Information Requests Among all sruvey respondents 15 patients reported an adverse event, product complaint, and or medical information requests associated with the use of TIRF medicines dru'ing phone completions of this sruvey (Appendix B: Listing 4). A total of 7 adverse events were reported as follows: 3 patients, oral side effects affecting the mouth or teeth and gruns; 1 patient, dependency on TIRF medication followed by withdrawal 1 patient cancer (site not speci?ed) since using TIRF medication (dru?ation of exposru?e not provided); 1 patient Imusual side effects (details not available) for which the patient had contacted the manufactru?er; and 1 patient, using TIRF medicine for pain but not for breakthrough pain. No reports of adverse events, product complaints, and or medical information requests were reported in the free text fields of sruveys completed online by respondents Table 17. Respondent Report of Adverse Events, Product Complaints, or Medical Information Requests During Survey Patients Patients Care 'vers ti n=l921 nil Caregivers Ques on N=l981 Respondent spontaneously reported an adverse event, product complaint, or medical information request during the course of this survey. Yes2 181 92.3 2 100.0 183 92.4 1 All respondents who took the srn'vey regardless of eligibility. 2 There were 7 adverse events. 1 product complaint. and 7 medical information requests. Verbatim text of adverse events or product complaints is given in Appendix B. Listing 4. Page 41 of 52 Transrnucosal Immediate Release Fentanyl (TIRF) December 2012 TIRF REMS Industry Group (TRIG) of Companies Patient KAB Assessment Report Table 18. Categorized Reported Adverse Events, Product Complaints, or Medical Information Requests All Respondents Response (Categorized Type) 2 N=l98l N3 Cancer. Pain 1 0.5 Abuse 1 0.5 Disposal 1 0.5 Education 2 1 .0 Oral side effects 4 2.0 Pain 1 0.5 Placement of medication 1 0.5 Side effects 1 0.5 Unusual side effects 1 0.5 Product complaint 1 0.5 Death 1 0.5 lAll respondents who took the survey regardless of eligibility. 2 Categorization scheme of the verbatim responses is shown in Appendix B. Listing 4. 3 Each category is only cormted once per patient/caregiver 5.5 Discussion, Conclusions, and Recommendations The speci?c goals of the TIRF medicines patient KAB sruvey were to evaluate the level of knowledge and assess the attitudes and behavior of patients and caregivers regarding TIRF medicines. The focus of the survey included the potential for life-threatening breathing problems that can lead to death, the need for patients to take TIRF medicines if they are opioid-tolerant and strictly follow the directions of the HC P, the caution that patients should not switch from a TIRF medicine to another medicine that contains fentanyl without talking to an HC P, the requirements that patients should not give TIRF medicines to anyone else even if they have the same and that TIRF medicines should be stored in a safe place away from children and properly disposed. The survey also included questions about whether patients received, read, and rmderstood the product-speci?c Medication Guide and the PPAF. Based on the number of prescriptions ?lled during the 90 days prior to 12 September 2012, the national pharmacy chain network partner identi?ed 1112 possible participants. All of these participants were sent a survey invitation letter. The screening criteria determined that 192 of the responders were eligible for participation in this sruvey; all 192 responders completed the sruvey. Although, the survey had a target of 300 Page 42 of 52 Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies December 2012 Patient KAB Assessment Report completed responders, the pool of 1112 patients/caregivers, who were mailed the invitation, was small. The response of 192 completed surveys from this limited pool is within the expected response rate to mailed invitations. To maximize participation in the survey, additional recruitment methodology and or inclusion criteria will be evaluated and considered in future survey waves. Several questions tested respondents’ level of awareness of conditions for which TIRF medicines may be used. Most respondents were aware of permitted conditions for use of TIRF medicines. However, 70.8% of respondents were unaware that use in non-cancer pain is not a recommended indication. Use in headache pain was correctly identified by 136 (70.8%) patients as not to be appropriate. Lastly, the majority of respondents were aware that TIRF medicines should only be taken by patients who are opioid-tolerant. A series of questions probed respondents’ understanding of how to take TIRF medications. Although 100% of respondents understood that TIRF medicines should be taken exactly as prescribed, only 82 (42.7%) responders were aware that if a patient stopped taking round-theclock opioid pain medication, they also needed to stop taking TIRF medicines. Most respondents (96.9%) were aware that it is not safe to switch to another medicine containing fentanyl without consulting with their HCP. All (100%) respondents knew they were not to share TIRF medicines with another person. All (100%) respondents were aware of the need for safely storing TIRF medicines. The analyses of responses to questions defining each of the 6 key risk messages demonstrated that most respondents were well informed about the risks and safe use criteria associated with use of TIRF medicines. Overall, this survey shows that the ongoing patient-oriented educational process is meeting its objectives in that the majority of patients completing the survey were aware of the key issues related to their use of a TIRF medication. Page 43 of 52 FDA_239 Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Appendix A December 2012 Patient KAB Assessment Report Patient Survey Protocol Page 44 of 52 FDA_240 TIRF REMS Industry Group (TRIG) Transmucosal Immediate Release Fentanyl (TIRF) Products Patient/Caregiver KAB Survey Protocol Version 3.0 10 September 2012 PROTOCOL TITLE: Quantitative Testing of Patient/Caregiver Knowledge, Attitudes, and Behavior about Transmucosal Immediate Release Fentanyl (TIRF) Products Safety and Use Information SPONSOR: TIRF REMS Industry Group (TRIG) Archimedes Pharma US Inc., Cephalon, Inc., Endo Pharmaceuticals Inc., Insys Therapeutics, Meda Pharmaceuticals, Mallinckrodt (a Covidien Company), Par Pharmaceutical, Inc., ProStrakan, Inc., and Sandoz Inc. VERSION: 3.0 DATE: 10 SEP 2012 APPROVED: 07 SEP 2012 1 of 40 FDA_241 TIRF REMS Industry Group (TRIG) Transmucosal Immediate Release Fentanyl (TIRF) Products Patient/Caregiver KAB Survey Protocol Version 3.0 10 September 2012 TABLE OF CONTENTS TABLE OF CONTENTS ......................................................................................................... 2  1.  LIST OF ABBREVIATIONS .................................................................................. 3  2.  BACKGROUND ..................................................................................................... 4  3.  OBJECTIVES OF THE EVALUATION SURVEY ............................................... 5  4.  METHODS .............................................................................................................. 5  4.1  4.1.1  4.1.2  4.1.3  Survey Design .......................................................................................................... 5  Qualitative Research on the Survey ......................................................................... 6  Questions and Statements on REMS Goals ............................................................. 6  Additional Questions.............................................................................................. 11  4.2  4.2.1  Subject Recruitment ............................................................................................... 11  Measures to Minimize Bias in the Sample............................................................. 12  5.  5.1.1  5.1.2  5.1.3  STUDY POPULATION ........................................................................................ 12  Sample Size ............................................................................................................ 12  Inclusion Criteria.................................................................................................... 13  Exclusion Criteria .................................................................................................. 13  6.  SURVEY PROCESS ............................................................................................. 14  6.1  6.1.1  6.1.2  Screening and Survey Administration ................................................................... 14  Telephone ............................................................................................................... 14  Internet ................................................................................................................... 14  6.2  Measures to Minimize Bias in the Survey Process ................................................ 14  7.  ANALYSIS ............................................................................................................ 15  8.  SAFETY EVENT REPORTING ........................................................................... 16  9.  PRIVACY PROTECTION AND CONFIDENTIALITY...................................... 16  LIST OF APPENDICES APPENDIX A Screening and Main Questionnaire..............................................................18  APPENDIX B Sample Patient Letter of Invitation ..............................................................39  2 of 40 FDA_242 TIRF REMS Industry Group (TRIG) Transmucosal Immediate Release Fentanyl (TIRF) Products Patient/Caregiver KAB Survey Protocol 1. Version 3.0 10 September 2012 LIST OF ABBREVIATIONS CATI CI EDC ETASU FDA HIPAA IRB KAB PBM PPAF REALM REMS SERP TIRF TRIG UBC Computer-Assisted Telephone Interviewing Confidence Interval Electronic Data Capture Elements to Assure Safe Use Food and Drug Administration Health Insurance Portability and Accountability Act Institutional Review Board Knowledge, Attitudes and Behavior Pharmacy Benefits Manager Patient-Prescriber Agreement Form Rapid Estimate of Adult Literacy in Medicine Risk Evaluation and Mitigation Strategy Safety Event Reporting Plan Transmucosal Immediate Release Fentanyl TIRF REMS Industry Group United BioSource Corporation 3 of 40 FDA_243 TIRF REMS Industry Group (TRIG) Transmucosal Immediate Release Fentanyl (TIRF) Products Patient/Caregiver KAB Survey Protocol 2. Version 3.0 10 September 2012 BACKGROUND Transmucosal Immediate Release Fentanyl (TIRF) medicines include the class of immediaterelease opioid analgesics, which are indicated only for the management of breakthrough pain in cancer patients 18 years of age or older (16 or older for Actiq® and equivalent generics) who are already receiving and already tolerant to opioid therapy for their underlying persistent cancer pain. The TIRF medicines include Abstral®, Actiq®, Fentora®, Lazanda®, Onsolis®, Subsys™, and the generic versions of any of these brands. The TIRF REMS Industry Group (TRIG) includes Archimedes Pharma US Inc., Cephalon, Inc., Endo Pharmaceuticals Inc., Insys Therapeutics, Meda Pharmaceuticals, Mallinckrodt (a Covidien Company), Par Pharmaceutical, Inc., ProStrakan, Inc., and Sandoz Inc. The Food and Drug Administration (FDA) has determined that a Risk Evaluation and Mitigation Strategy (REMS) is required to mitigate the risks of misuse, abuse, addiction, overdose and serious complications due to medication errors with the use of TIRF medicines. The TIRF REMS Access Program (hereafter referred to as TIRF REMS) was approved by the FDA on December 28, 2011. The TIRF REMS consists of a Medication Guide, Elements to Assure Safe Use (ETASU), an Implementation System, and a timetable for submission of assessments of the REMS. The goals of the TIRF REMS are to mitigate the risk of misuse, abuse, addiction, overdose and serious complications due to medication errors by: 1. Prescribing and dispensing TIRF medicines only to appropriate patients, which includes use only in opioid-tolerant patients 2. Preventing inappropriate conversion between TIRF medicines 3. Preventing accidental exposure to children and others for whom it was not prescribed 4. Educating prescribers, pharmacists, and patients on the potential for misuse, abuse, addiction, and overdose of TIRF medicines An important component of the TIRF REMS assessment is the conduct of quantitative evaluation surveys to assess patients’ and caregivers’ knowledge, attitudes, and behavior (KAB) regarding the safe use of TIRF medicines, as described in the product-specific Medication Guide. This protocol will describe the administration of the surveys that will be conducted among patients who are treated with TIRF medicines, or their caregivers. Data from the surveys, together with other REMS evaluation metrics, will be used to determine whether changes need to be made to the REMS processes and/or educational materials to make them more effective in achieving the goals of the REMS. The surveys will be implemented so that data will be available for inclusion in the REMS Assessment Reports that will be submitted to the FDA at 12 months after approval of the TIRF REMS and annually thereafter. 4 of 40 FDA_244 TIRF REMS Industry Group (TRIG) Transmucosal Immediate Release Fentanyl (TIRF) Products Patient/Caregiver KAB Survey Protocol 3. Version 3.0 10 September 2012 OBJECTIVES OF THE EVALUATION SURVEY The evaluation survey will use a questionnaire to document the level of knowledge and assess the attitudes and behavior of patients around the following key information and risk messages communicated through the REMS: 1) TIRF medicines can cause life-threatening breathing problems that can lead to death. 2) Patients should not take TIRF medicines if they are not opioid tolerant. 3) TIRF medicines should be taken exactly as prescribed by the healthcare provider. 4) Patients should not switch from a TIRF medicine to another medicine that contains fentanyl without talking to a healthcare provider. 5) Patients should not give TIRF medicines to anyone else even if they have the same symptoms. 6) TIRF medicines should be stored in a safe place away from children and properly disposed. The survey will also include questions about whether patients received, read, and understood the product-specific Medication Guide and Patient-Prescriber Agreement Form (PPAF). 4. METHODS The survey was designed in collaboration between the TRIG and United BioSource Corporation (UBC), and will be administered by UBC. 4.1 Survey Design This survey will be conducted among a sample of patients who have filled a prescription for a TIRF medicine within the past 3 months prior to survey launch and their caregivers. Respondents who have participated in a previous wave of the TIRF REMS KAB survey will not be eligible to participate in subsequent survey waves. The survey will be administered using the following modalities: • Self-administered, online through a secure website • Telephone surveys facilitated by a trained interviewer from the Survey Coordinating Center using a computer-assisted telephone interviewing (CATI) program The survey will begin with screening questions to confirm respondent eligibility to participate in the survey. Completion of the entire survey is expected to take approximately 20 minutes. 5 of 40 FDA_245 TIRF REMS Industry Group (TRIG) Transmucosal Immediate Release Fentanyl (TIRF) Products Patient/Caregiver KAB Survey Protocol Version 3.0 10 September 2012 The survey included in Appendix B is written to reflect wording for both methods of survey administration: Internet-based and telephone administration. 4.1.1 Qualitative Research on the Survey In order to effectively evaluate the patient/caregiver survey prior to fielding the surveys, qualitative research will be performed on the survey with a sample of patients. The qualitative research assesses comprehension among participants of the words and phrases used in the survey questions and response options. Qualitative research will be performed with eight (8) patients who meet pre-determined eligibility criteria for participation in the qualitative research interviews. The purpose of the qualitative research is to identify any terms, questions, or topics in the survey that require clarification or revision based on any areas of confusion or miscomprehension by participants interviewed. Participants are primarily recruited through a database of patients at a research facility who are interested in being included in market research. To ensure the appropriateness of the survey for all literacy levels, attempts are made to recruit at least half of the participants to have less than or equal to a 12th grade education. As part of the overall interview, participants are administered a REALM® (Rapid Estimate of Adult Literacy in Medicine 1) to assess health literacy level. Participants are also recruited to represent a mix of race and gender. 4.1.2 Questions and Statements on REMS Goals The KAB items of the questionnaire are made up of multiple-choice, closed-ended statements or questions (the majority of which use true/false or yes/no dichotomous response options), and open-ended questions. These will evaluate current knowledge, attitudes, and behavior regarding the key risk messages noted in Section 3. The survey is written to follow principles of health literacy and readability. Questionnaire items will be presented in several formats: • Statements or questions asking the respondent to indicate whether a statement or question is true or false, or if they do not know the answer (there is a similar set of statements and questions that use “yes,” “no,” or “I don’t know” as potential response options); • Statements or questions asking the respondent to choose from a defined list of possible statements or answers; and 1 Davis TC, Long SW, Jackson RH, Mayeaux EJ, George RB, Murphy PW, Crouch MA. Rapid estimate of adult literacy in medicine: a shortened screening instrument. Fam Med. 1993 Jun;25(6):391-5. 6 of 40 FDA_246 TIRF REMS Industry Group (TRIG) Transmucosal Immediate Release Fentanyl (TIRF) Products Patient/Caregiver KAB Survey Protocol • Version 3.0 10 September 2012 Questions allowing for the respondent to provide information about when, where and from whom they obtained a Medication Guide, as well as to list questions about information in the Medication Guides. Questionnaires will be analyzed to determine patient understanding of each key risk message. For statements or questions that use “true” or “yes” vs. “false” or “no” response options, the desired response for key risk messages is generally “true” or “yes” indicating knowledge of, or behavior in accordance with, the objectives of the REMS. However, some questions are formatted to have the respondent disagree with the statement as written by providing response options of “false” or “no” to avoid having the same affirmative answer for all desired responses. REMS statements, corresponding questions, and desired responses covering the key risk messages are identified below and can be found in the complete survey questionnaire (Appendix A). Key Risk Message 1: TIRF medicines can cause life-threatening breathing problems that can lead to death. Question No. Question Desired response Please answer True, False, or I don’t know for each statement about the TIRF medicine that was most recently prescribed for you. 12d TIRF medicines can cause life-threatening breathing problems that can lead to death. 7 of 40 TRUE FDA_247 TIRF REMS Industry Group (TRIG) Transmucosal Immediate Release Fentanyl (TIRF) Products Patient/Caregiver KAB Survey Protocol Version 3.0 10 September 2012 Key Risk Message 2: Patients should not take TIRF medicines if they are not opioid tolerant. Question No. Question Desired response Please answer True, False, or I don’t know for the following statement: 10 TIRF medicines should only be taken by patients who are opioid tolerant. TRUE Please answer True, False, or I don’t know for each of the following statements. 11a Opioid tolerant means that a patient is already taking other opioid pain medicines around the clock and their body is used to these medicines. TRUE Please answer True, False, or I don’t know for each statement about the TIRF medicine that was most recently prescribed for you. 12b It is OK for patients to take TIRF medicines for headache pain. 8 of 40 FALSE FDA_248 TIRF REMS Industry Group (TRIG) Transmucosal Immediate Release Fentanyl (TIRF) Products Patient/Caregiver KAB Survey Protocol Version 3.0 10 September 2012 Key Risk Message 3: TIRF medicines should be taken exactly as prescribed by the healthcare provider. Question No. Question Desired response Please answer True, False, or I don’t know for each of the following statements. 11b If a patient stops taking around-the-clock opioid pain medicine, they must also stop taking the TIRF medicine. TRUE Please answer True, False, or I don’t know for each statement about the TIRF medicine that was most recently prescribed for you. 12c TIRF medicines should be taken exactly as prescribed by the doctor. TRUE 16b It is OK to take TIRF medicines for short-term pain that will go away in a few days. FALSE Key Risk Message 4: Patients should not switch from a TIRF medicine to another medicine that contains fentanyl without talking to a healthcare provider. Question No. Question Desired response Please answer True, False, or I don’t know for each of the following statements. 11c It is safe to switch to another medicine that contains fentanyl without talking to a healthcare provider first. 9 of 40 FALSE FDA_249 TIRF REMS Industry Group (TRIG) Transmucosal Immediate Release Fentanyl (TIRF) Products Patient/Caregiver KAB Survey Protocol Version 3.0 10 September 2012 Key Risk Message 5: Patients should not give TIRF medicines to anyone else even if they have the same symptoms. Question Question No. Desired response Please answer True, False, or I don’t know for each of the following statements. 11d A patient may give TIRF medicines to another person if they have the same symptoms as the patient. FALSE Please answer True, False, or I don’t know for each statement about the TIRF medicine that was most recently prescribed for you. 16a Selling or giving away TIRF medicines is against the law. TRUE Key Risk Message 6: TIRF medicines should be stored in a safe place away from children and properly disposed. Question Question No. Desired response Please answer True, False, or I don’t know for each statement about the TIRF medicine that was most recently prescribed for you. 12a TIRF medicines should be stored in a safe place out of the reach of children. TRUE 16c TIRF medicines must be disposed of as described in the specific product’s Medication Guide. TRUE 16e A TIRF medicine can cause an overdose and death in any child who takes it. TRUE 10 of 40 FDA_250 TIRF REMS Industry Group (TRIG) Transmucosal Immediate Release Fentanyl (TIRF) Products Patient/Caregiver KAB Survey Protocol 13 4.1.3 What should you do if an adult who has not been prescribed a TIRF medicine takes a TIRF medicine? (Please select one.) Version 3.0 10 September 2012 Get emergency help right away. Additional Questions Questions about the requirements of the TIRF REMS, and receipt and understanding of the Medication Guides and Patient-Prescriber Agreement Form will be asked after the key risk message questions, and will be followed by the collection of demographic information at the completion of the survey. 4.2 Subject Recruitment Patients will be recruited through a direct letter program. Patients will be invited through a national pharmacy chain network partner or pharmacy benefits management (PBM) partner, which each have broad demographic coverage and include patients in 49 states. Leveraging one or more of these partners, a list will be created of patients who have filled a prescription for a TIRF medicine within 3 months prior to survey launch (first prescriptions and refills). Patients in this list will be invited to participate in the survey through an invitation letter (Appendix B) mailed directly to the patients on the pharmacy or PBM’s letterhead at the corporate level via the US Postal Service. The invitation will indicate that participants will receive a $25 gift card for completing the survey. Each invitation will also include a unique ID code and directions for accessing the survey either via the Internet or by telephone through an interviewer at the Survey Coordinating Center. The unique ID code will be used to identify the manufacturer of the most recent TIRF prescription that the patient filled. A random sample of patients who have filled a prescription for a TIRF medicine within the last 90 days will be chosen from the pharmacy partner’s database. This sampling approach will be used to create several batches of survey invitations. The overall number of unique patients and the duration of the survey period will dictate the size and number of invitation batches. If the required number of completed surveys is not achieved within approximately 10 business days after the first mailing, a second mailing will be sent to non-respondents from the original batch mailing and initial invitations will be sent to patients in the second batch. If the required number of completed surveys is not achieved within 10 additional business days, reminder letters will be sent to the patients in the second batch and initial invitations will be sent to the third batch of patients. If these efforts do not result in the required number of surveys within another 10 days, then a new random sample of patients may be selected. The 10 day intervals described above will be condensed as necessary based on the actual rate of survey accrual relative to the proximity of the target survey close date. All respondents who complete the survey and who provide their contact information will be mailed a $25 gift card to thank them for their participation. The mailing will include a thank you letter, a copy of the product-specific Medication Guide, and a copy of the correct answers to the key risk message questions. 11 of 40 FDA_251 TIRF REMS Industry Group (TRIG) Transmucosal Immediate Release Fentanyl (TIRF) Products Patient/Caregiver KAB Survey Protocol 4.2.1 Version 3.0 10 September 2012 Measures to Minimize Bias in the Sample The sample of participating patients will be self-selected since respondents will voluntarily respond to the invitation to participate; however, the survey recruitment strategies are intended to recruit a heterogeneous sample of patients for participation. Respondents will be offered online or telephone options for completing the survey. Multiple modalities for survey data collection allow for wider survey access to a more heterogeneous population. Respondents will be provided a unique code during the recruitment process and will be asked to provide the unique code to gain access to the online survey or when calling the Survey Coordinating Center. The code will be deactivated after use to minimize the possibility for fraud. 5. STUDY POPULATION 5.1.1 Sample Size A sample of 300 patients treated with TIRF medicines is proposed for the first survey wave. The size of the sample was determined based on both practical and statistical considerations. There is no target comprehension rate specified a priori. A sample of 300 completed surveys will allow estimation of the comprehension rate for each key risk message with a moderately high degree of precision. The table below shows the precision of the estimates for level of understanding using two-sided 95% confidence intervals (CIs) obtained with the sample size of 300 completed surveys. The noted CIs are used to indicate that for any survey-estimated rate of understanding, the true population rate of understanding is at least as high as the lower limit of the 95% CI and may be as high as the upper limit of the 95% CI. 12 of 40 FDA_252 TIRF REMS Industry Group (TRIG) Transmucosal Immediate Release Fentanyl (TIRF) Products Patient/Caregiver KAB Survey Protocol Version 3.0 10 September 2012 Precision of Estimated Rates of Understanding with a Sample Size of 300 (2-sided 95% Confidence Interval) Estimated Rate of Understanding 50% 5.1.2 Estimated Confidence Interval 44.2% 55.8% 55% 49.2% 60.7% 60% 54.2% 65.6% 65% 59.3% 70.4% 70% 64.5% 75.1% 75% 69.7% 79.8% 80% 75.0% 84.4% 85% 80.4% 88.8% 90% 86.0% 93.2% 95% 91.9% 97.2% Inclusion Criteria The following respondents are eligible to participate in the survey: • Patients who are 18 years of age or older • Patients who have filled a TIRF medicine prescription within the past 3 months prior to survey launch • Caregivers 18 years of age or older who care for patients who are unable to take the survey for themselves • Patients or caregivers who are able to complete the survey in English 5.1.3 Exclusion Criteria The following respondents are not eligible to participate in the surveys: • Patients who have previously participated in the TIRF REMS KAB survey (this exclusion applies to the second and subsequent waves only) 13 of 40 FDA_253 TIRF REMS Industry Group (TRIG) Transmucosal Immediate Release Fentanyl (TIRF) Products Patient/Caregiver KAB Survey Protocol • Version 3.0 10 September 2012 Patients or their immediate family members who have ever worked for Anesta LLC, Archimedes Pharma US Inc., Cephalon, Inc., Endo Pharmaceuticals Inc., Insys Therapeutics, Meda Pharmaceuticals, Mallinckrodt (a Covidien Company), Par Pharmaceutical, Inc., ProStrakan, Inc., Sandoz Inc., United BioSource Corporation, Teva Pharmaceuticals, Ltd., McKesson Specialty Care Solutions, RelayHealth, or the FDA. 6. SURVEY PROCESS 6.1 Screening and Survey Administration The questionnaire will begin with a screening module with five questions to confirm patient eligibility. The entire survey is expected to take approximately 20 minutes to complete. Depending on the answers to the screening questions, survey participation could either be terminated or continued. If ineligible, respondents are immediately notified with a thank you message that survey participation has ended. If eligible, respondents are allowed to continue survey participation. The electronic data capture (EDC) system that is used for both methods of survey administration has been validated and is secure for receiving and storing survey data. An Internet-based data repository will be used to store survey data and other relevant program information. The system is 21 CFR Part 11 and Health Insurance Portability and Accountability Act (HIPAA) compliant. Patient-identifying information will be stored separately from survey data. 6.1.1 Telephone The telephone survey is facilitated by a trained interviewer from the Survey Coordinating Center using a CATI program. The respondent will be required to provide a unique code to access the survey. Working from a CATI script, the interviewer will read questions or statements to the respondent and enter the responses into the EDC system. Screening and main elements of the questionnaire will be administered sequentially during the same telephone call. Telephone interviewing allows participation of respondents who do not have Internet access, or prefer to complete the survey in this manner. 6.1.2 Internet An Internet-based survey system will also be used for conducting the KAB surveys. If respondents select to participate in the survey online, they will be directed to a secured website and instructed to enter a unique code to access the survey. An Internet survey will be convenient for respondents to participate since they can complete the questionnaire at any convenient time and location during the specified survey time period. 6.2 Measures to Minimize Bias in the Survey Process A number of controls will be in place to ensure the survey is conducted in a controlled and professional manner and to minimize bias. For example, a unique code will be given to each 14 of 40 FDA_254 TIRF REMS Industry Group (TRIG) Transmucosal Immediate Release Fentanyl (TIRF) Products Patient/Caregiver KAB Survey Protocol Version 3.0 10 September 2012 survey participant and the code will be inactivated after use to minimize fraud. Telephone interviewers are highly trained and use a standardized script to administer interviews. All questions will be programmed to ensure that questions are asked in the appropriate sequence. Skip patterns will be clearly indicated. Respondents cannot go back to a question once the question has been answered and cannot skip ahead. All questions must be answered in order to complete the survey. Response options presented in a list will be randomized to minimize positional bias. Programming will be reviewed by quality control and simulated users (User Acceptance Testing) prior to implementing the survey. 7. ANALYSIS Information obtained from the survey will be reported as descriptive statistics for the survey administration, study population, and the survey questions. Any free text fields will be grouped into applicable categories. Verbatim text from open-ended questions will be displayed when appropriate. The following will be reported as part of this analysis: • The number of invitations issued • The number of respondents screened for participation • The number of respondents eligible for participation • The number of respondents who completed the survey • Description of survey participants, including: • − Type of respondent (patient/caregiver) − Age (patient/caregiver) − Gender (respondent) − Educational level (respondent) − Main language spoken at home (respondent) − Ethnicity (respondent) − Race (respondent) − Geographic region (respondent) Frequency distribution of responses to each question (the number of respondents who give each answer to each question) 15 of 40 FDA_255 TIRF REMS Industry Group (TRIG) Transmucosal Immediate Release Fentanyl (TIRF) Products Patient/Caregiver KAB Survey Protocol • Version 3.0 10 September 2012 Percent of respondents selecting desired response to each question relating to each key risk message and 95% confidence interval Measurement of understanding will be computed for each question of the key risk message individually. A secondary analysis will be conducted to determine the number of respondents who answered all items correctly for the key risk message. Behavior questions will be summarized on a question by question basis and are not included in the analysis by key risk message. Additional analyses may be performed as needed. 8. SAFETY EVENT REPORTING The survey will be conducted via the Internet and by telephone. It is possible that a respondent may report an adverse event or other safety event experienced while taking TIRF medicines either in free text fields of the survey or while in conversation with the Survey Coordinating Center. If an event is mentioned to a Survey Coordinating Center Associate, the Associate will document the safety event and the respondent’s contact information. The respondent will also be informed that a representative from the appropriate TIRF medicine manufacturer may contact him/her if there are questions about the survey. The Internet-based questionnaires will be monitored for any comments recorded in free text fields. Information on all comments that may constitute an adverse event or other safety event will be forwarded to the appropriate TIRF medicine manufacturer as described in the Safety Event Reporting Plan (SERP). Additional detail regarding processes for adverse event reporting will be specified in the SERP. 9. PRIVACY PROTECTION AND CONFIDENTIALITY All data collected during the survey will be held confidential. The EDC system used for data collection encrypts all identifiable information and respondent identifiers are stored separately from the survey responses. Respondent names and addresses are collected in order to mail a $25 gift card, a Thank You Letter, a product-specific Medication Guide, and correct survey responses to key risk message questions after the survey is completed. Respondent contact information is also needed in the event a safety event is reported and a TIRF medicine manufacturer must obtain follow-up information. A respondent may be contacted only if clarification or follow-up is needed regarding a possible safety event that was mentioned to the interviewer or recorded in free text fields of the online survey. Respondents will be informed when they access the survey that they may be contacted if there are any questions about their survey responses. Respondents will be informed that their answers to the survey questions will not affect their ability to receive TIRF medicines. 16 of 40 FDA_256 TIRF REMS Industry Group (TRIG) Transmucosal Immediate Release Fentanyl (TIRF) Products Patient/Caregiver KAB Survey Protocol Version 3.0 10 September 2012 This protocol and survey will be reviewed and approved by a central Institutional Review Board (IRB) before administration of the survey. 17 of 40 FDA_257 TIRF REMS Industry Group (TRIG) Transmucosal Immediate Release Fentanyl (TIRF) Products Patient/Caregiver KAB Survey Protocol Version 3.0 10 September 2012 APPENDIX A Screening and Main Questionnaire Survey Legend • [PROGRAMMER] is used to indicate directions to the programmer and is set in bold, red, uppercase letters between square brackets. [PATIENT] indicates text applicable to a patient when it differs from survey text for caregivers, parents and legal guardians. [PARENT/CAREGIVER/LEGAL GUARDIAN] indicates text applicable to parents, caregivers, and legal guardians when it differs from survey text for patients. • (INTERVIEWER) is used to indicate directions to the phone interviewer and is set in bold, blue, text between parentheses. This text appears when content is to be administered by phone only (for example, spontaneous adverse event reporting). • [ONLINE] indicates a question is worded specifically for administering the survey online. [PHONE] indicates a question is worded specifically to be read by a phone interviewer and differs from the online text. • [BEGIN ONLINE/PHONE SURVEY CONTENT] and [END SURVEY CONTENT] are used to indicate to the programmer the type of survey administration and the beginning and end of the survey or sections within the survey content, for example, [BEGIN ADVERSE EVENT/PRODUCT COMPLAINT] and [END ADVERSE EVENT/PRODUCT COMPLAINT]. • [TERMINATE] is displayed next to responses that should cause the survey to end. The following termination language will be programmed into the survey or read by the interviewer unless different language is specified with the question. Thank you very much for your time today. Based on your answer, you are not eligible to take this survey. We appreciate your interest in the survey. • [RANDOMIZE LIST] is inserted before questions to indicate to the programmer that the responses should be randomized. Responses such as “I don’t know,” “Prefer not to answer” or “None of the above” will always appear at the end of the randomized responses. • [GO TO Ax] (Skip logic) is inserted after a response to indicate to the programmer that the survey should skip to the indicated question (for example, [GO TO Q17] skips to question 17). If no skip logic is indicated the survey continues to the next question in the sequence. 18 of 40 FDA_258 TIRF REMS Industry Group (TRIG) Transmucosal Immediate Release Fentanyl (TIRF) Products Patient/Caregiver KAB Survey Protocol Version 3.0 10 September 2012 Survey Legend • [MULTILINE INPUT] indicates to the programmer that multiple lines should be provided for data entry (for example, two address lines or a free-text response). • [DROP-DOWN LIST INPUT WITH STATES TABLE] indicates to the programmer that the response should be a drop-down list containing the states in the table below. Alabama Georgia Massachusetts New York Tennessee Alaska Guam Michigan North Carolina Texas American Samoa Hawaii Minnesota North Dakota Idaho Mississippi Arizona Illinois Missouri Arkansas Indiana Montana Northern Mariana Islands US Virgin Islands California Iowa Nebraska Colorado Kansas Nevada Connecticut Kentucky New Hampshire Delaware Louisiana New Jersey District of Columbia Maine New Mexico Utah Vermont Ohio Virginia Oklahoma Washington Oregon West Virginia Pennsylvania Wisconsin Puerto Rico Wyoming Rhode Island Maryland Florida South Carolina South Dakota • The following is used to categorize survey populations into standard geographic regions but it is not displayed in the survey. Geographic Distribution (based on address) 1: Northeast, Midwest, South, and West regions Northeast Region − New England Division - ME, NH, VT, MA, RI, CT − Middle Atlantic Division - NY, NJ, PA Midwest Region − East North Central Division - OH, IN, IL, MI, WI − West North Central Division - MN, IA, MO, ND, SD, NE, KS South Region − South Atlantic Division - DE, MD, DC, VA, WV, NC, SC, GA, FL − East South Central Division - KY, TN, AL, MS − West South Central Division - AR, LA, OK, TX West 19 of 40 FDA_259 TIRF REMS Industry Group (TRIG) Transmucosal Immediate Release Fentanyl (TIRF) Products Patient/Caregiver KAB Survey Protocol Version 3.0 10 September 2012 Survey Legend − Mountain Division - MT, ID, WY, CO, NM, AZ, UT, NV − Pacific Division WA, OR, CA, AK, HI • The following US territories are categorized as Other: Puerto Rico, Northern Mariana Islands, US Virgin Islands, American Samoa, and Guam. 1 U.S. Census Bureau, last revised Friday, 27-Jul-2001 12:59:43 EDT. 20 of 40 FDA_260 TIRF REMS Industry Group (TRIG) Transmucosal Immediate Release Fentanyl (TIRF) Products Patient/Caregiver KAB Survey Protocol Version 3.0 10 September 2012 [BEGIN ONLINE/PHONE SURVEY CONTENT] [PREAMBLE 1] Before you begin, we would like to share some important information about this survey. The survey is being conducted by the makers of Abstral®, Actiq®, Fentora®, Lazanda®, Onsolis®, Subsys™ and the generic versions of any of these brands. These are Transmucosal Immediate Release Fentanyl medicines, also known as rapid onset opioids (INTERVIEWER: Please pause briefly) (and sometimes called “fast acting fentanyls”) or TIRF medicines. (INTERVIEWER: Pronounce “TIRF,” then spell out T-I-R-F). The information collected will help the makers of TIRF medicines know if patients and their caregivers understand important information about taking these medicines. The survey will take about 20 minutes. There are no known risks to you in taking this survey. You may refuse to take part or withdraw at any time without penalty or loss of benefits to which you are otherwise entitled. Your answers to the questions or your decision to take part in the survey will not affect your ability to receive or take TIRF medicines. [ONLINE ONLY]How We Use Your Information [PHONE ONLY] Now I would like to tell you about how your contact information will be used. Your answers to the survey questions will be combined with answers given by other people taking the survey. All answers will be put together and reported in anonymous form to manufacturers of TIRF medicines. Your name will not be used in any report. If you are eligible to take the survey, complete all the questions, and provide your contact information, you will receive a $25 gift card for your time. Your name and address will be used only to send you the gift card, a Thank You Letter, a product-specific Medication Guide, and a copy of the correct answers to key risk message questions, after you complete the survey. Providing a telephone number is optional. Your telephone number will be used only if there are any questions about your answers. [ONLINE ONLY] How We Protect Your Privacy [PHONE ONLY]Now I would like to tell you about how we protect your privacy. We respect that the privacy of your personal information is important to you. You will not be contacted for marketing purposes based on your personal information or your answers to the survey. Neither the manufacturers of TIRF medicines nor their contractors will sell, transfer, 21 of 40 FDA_261 TIRF REMS Industry Group (TRIG) Transmucosal Immediate Release Fentanyl (TIRF) Products Patient/Caregiver KAB Survey Protocol Version 3.0 10 September 2012 or rent your information. Your answers will be kept strictly confidential. Your privacy will be protected; however, research survey records may be inspected by the FDA (Food and Drug (b) (4) Administration) and a company called which is the Institutional Review Board (IRB). Your choice to allow the manufacturers of TIRF medicines to use your information is entirely voluntary, but necessary to take part in this survey. [ONLINE ONLY] How to Learn More About Transmucosal Immediate Release Fentanyl Medicines [ONLINE ONLY] If you have questions about the survey, or have any problems with the survey, please contact the Survey Coordinating Center at 1-877-379-3297. [PHONE ONLY] Please feel free to ask me to repeat any questions or statements as we go through the survey. Once you have answered a question and moved on, you cannot go back and change your answers. If you have questions about your rights as a research participant or related concerns, you may (b) (4) contact the IRB at . [ONLINE ONLY] Be sure to write down this telephone number; it will not be displayed again. The information in this survey should not take the place of talking with your doctor or health care professional. If you have any questions about your condition or treatment or that of the person you care for, or if you would like more information about TIRF medicines, talk to your doctor, pharmacist, or other health care professional. Thank you for your participation in this survey. [END PREAMBLE 1] 22 of 40 FDA_262 TIRF REMS Industry Group (TRIG) Transmucosal Immediate Release Fentanyl (TIRF) Products Patient/Caregiver KAB Survey Protocol 1. 2. 3. 4. Version 3.0 10 September 2012 Do you agree to take part in this survey? ○ Yes ○ No [TERMINATE] Within the last 3 months, have you filled a prescription for yourself for a transmucosal immediate release fentanyl medicine (known as “TIRF medicines”)? TIRF medicines include Abstral®, Actiq®, Fentora®, Lazanda®, Onsolis®, Subsys™, and the generic versions of any of these brands. ○ Yes [GO TO Q4] ○ No ○ I don’t know Are you a caregiver for someone who has filled a prescription for a TIRF medicine within the last 3 months? As a reminder, TIRF medicines include Abstral®, Actiq®, Fentora®, Lazanda®, Onsolis®, Subsys™, and the generic versions of any of these brands. ○ Yes ○ No [TERMINATE] ○ I don’t know [TERMINATE] Have you ever taken part in a survey about a TIRF medicine before? ○ Yes [TERMINATE ONLY IN ALL SUBSEQUENT WAVES] ○ No ○ I don’t know [TERMINATE ONLY IN ALL SUBSEQUENT WAVES] 23 of 40 FDA_263 TIRF REMS Industry Group (TRIG) Transmucosal Immediate Release Fentanyl (TIRF) Products Patient/Caregiver KAB Survey Protocol 5. 6. 7. Version 3.0 10 September 2012 Which of the following groups best describes your age? ○ Under 18 [TERMINATE] ○ 18 – 29 ○ 30 – 39 ○ 40 – 49 ○ 50 – 59 ○ 60 – 69 ○ 70 or older ○ Prefer not to answer [TERMINATE] [CAREGIVER ONLY] Which of the following groups best describes the patient’s age? ○ Under 16 ○ 16 – 29 ○ 30 – 39 ○ 40 – 49 ○ 50 – 59 ○ 60 – 69 ○ 70 or older ○ Prefer not to answer Have you or any of your immediate family members ever worked for any of the following companies or agencies? Please select all that apply. ○ Anesta LLC [TERMINATE] ○ Archimedes Pharma US Inc.[TERMINATE] ○ Cephalon, Inc. [TERMINATE] ○ Endo Pharmaceuticals Inc. [TERMINATE] 24 of 40 FDA_264 TIRF REMS Industry Group (TRIG) Transmucosal Immediate Release Fentanyl (TIRF) Products Patient/Caregiver KAB Survey Protocol ○ Insys Therapeutics[TERMINATE] ○ Mallinckrodt (a Covidien Company) [TERMINATE] ○ Meda Pharmaceuticals [TERMINATE] ○ Par Pharmaceutical, Inc.[TERMINATE] ○ ProStrakan, Inc. [TERMINATE] ○ Sandoz Inc. [TERMINATE] ○ Teva Pharmaceuticals, Ltd. [TERMINATE] ○ United BioSource Corporation[TERMINATE] ○ McKesson Specialty Care Solutions[TERMINATE] ○ RelayHealth[TERMINATE] ○ FDA (Food and Drug Administration) [TERMINATE] ○ No [IF SELECTED IN ADDITION TO OTHER RESPONSES, TERMINATE] ○ I don’t know [TERMINATE] Version 3.0 10 September 2012 [PREAMBLE 2] [PATIENT]Please answer the following questions based on information about the TIRF medicine that was most recently prescribed for you. TIRF medicines include Abstral®, Actiq®, Fentora®, Lazanda®, Onsolis®, Subsys™, and the generic versions of these brands. Please think of the information that you read or that was provided to you by a doctor, nurse, or other healthcare professional. If you don’t know the answer to any of the following questions please respond “I don’t know” instead of guessing the correct response. [CAREGIVER]Please answer the following questions based on information about the TIRF medicine that was most recently prescribed for the patient. TIRF medicines include Abstral®, Actiq®, Fentora®, Lazanda®, Onsolis®, Subsys™, and the generic versions of these brands. Please think of the information that you read or that was provided to you or to the patient by a doctor, nurse, or other healthcare professional. If you don’t know the answer to any of the following questions please respond “I don’t know” instead of guessing the correct response. 25 of 40 FDA_265 TIRF REMS Industry Group (TRIG) Transmucosal Immediate Release Fentanyl (TIRF) Products Patient/Caregiver KAB Survey Protocol 8. Version 3.0 10 September 2012 [PATIENT] Did the doctor, nurse, or other healthcare professional in the doctor’s office ever talk to you about the risks and possible side effects of the TIRF medicine that was most recently prescribed for you? TIRF medicines include Abstral®, Actiq®, Fentora®, Lazanda®, Onsolis®, Subsys™, and the generic versions of these brands. [CAREGIVER] Did the doctor, nurse, or other healthcare professional in the doctor’s office ever talk to you about the risks and possible side effects of the TIRF medicine that was most recently prescribed to the patient? TIRF medicines include Abstral®, Actiq®, Fentora®, Lazanda®, Onsolis®, Subsys™, and the generic versions of these brands. 9. ○ Yes ○ No ○ I don’t know [PATIENT] For which of the following conditions should I use a TIRF medicine? [CAREGIVER] For which of the following conditions should the person I take care of use a TIRF medicine? [RANDOMIZE LIST] Yes No I don’t know 9a. Headache or migraine pain ○ ○ ○ 9b. Breakthrough pain from cancer ○ ○ ○ 9c. Dental pain ○ ○ ○ 9d. Acute or post-operative pain ○ ○ ○ 9e. Chronic non-cancer pain ○ ○ ○ 10. Please answer True, False, or I don’t know for the following statement: TIRF medicines should only be taken by patients who are opioid tolerant. ○ True ○ False ○ I don’t know 26 of 40 FDA_266 TIRF REMS Industry Group (TRIG) Transmucosal Immediate Release Fentanyl (TIRF) Products Patient/Caregiver KAB Survey Protocol 11. Version 3.0 10 September 2012 Please answer True, False, or I don’t know for each of the following statements. True False I don’t know 11a. Opioid tolerant means that a patient is already taking other opioid pain medicines around the clock and their body is used to these medicines. ○ ○ ○ 11b. If a patient stops taking around-the-clock opioid pain medicine, they must also stop taking the TIRF medicine. ○ ○ ○ 11c. It is safe to switch to another medicine that contains fentanyl without talking to a healthcare provider first. ○ ○ ○ 11d. A patient may give TIRF medicines to another person if they have the same symptoms as the patient. ○ ○ ○ [RANDOMIZE LIST] 12. [PATIENT] Please answer True, False, or I don’t know for each statement about the TIRF medicine that was most recently prescribed for you. [CAREGIVER] Please answer True, False, or I don’t know for each statement about the TIRF medicine that was most recently prescribed for the patient. True False I don’t know 12a. TIRF medicines should be stored in a safe place out of the reach of children. ○ ○ ○ 12b. It is OK for patients to take TIRF medicines for headache pain. ○ ○ ○ 12c. TIRF medicines should be taken exactly as prescribed by the doctor. ○ ○ ○ 12d. TIRF medicines can cause life-threatening breathing problems that can lead to death. ○ ○ ○ [RANDOMIZE LIST] 27 of 40 FDA_267 TIRF REMS Industry Group (TRIG) Transmucosal Immediate Release Fentanyl (TIRF) Products Patient/Caregiver KAB Survey Protocol 13. Version 3.0 10 September 2012 What should you do if an adult who has not been prescribed a TIRF medicine takes a TIRF medicine? (Please select one.) [RANDOMIZE LIST] 14. ○ Wait an hour and see if the person is OK. ○ Get emergency help right away. ○ Do nothing. ○ I don’t know [PATIENT] Did the doctor, nurse, or other healthcare professional in the doctor’s office ever tell you how to use the TIRF medicine that was most recently prescribed for you? [CAREGIVER] Did the doctor, nurse, or other healthcare professional in the doctor’s office ever tell you how to use the TIRF medicine that was most recently prescribed for the patient? 15. ○ Yes ○ No ○ I don’t know [PATIENT] Did the doctor, nurse, or other healthcare professional in the doctor’s office ever tell you how to store or keep the TIRF medicine that was most recently prescribed for you? [CAREGIVER] Did the doctor, nurse, or other healthcare professional in the doctor’s office ever tell you how to store or keep the TIRF medicine that was most recently prescribed for the patient? ○ Yes ○ No ○ I don’t know 28 of 40 FDA_268 TIRF REMS Industry Group (TRIG) Transmucosal Immediate Release Fentanyl (TIRF) Products Patient/Caregiver KAB Survey Protocol 16. Version 3.0 10 September 2012 [PATIENT] Please answer True, False, or I don’t know for each statement about the TIRF medicine that was most recently prescribed for you. [CAREGIVER] Please answer True, False, or I don’t know for each statement about the TIRF medicine that was most recently prescribed for the patient. [RANDOMIZE LIST] True False I don’t know 16a. Selling or giving away TIRF medicines is against the law. ○ ○ ○ 16b. It is OK to take TIRF medicines for short-term pain that will go away in a few days. ○ ○ ○ 16c. TIRF medicines must be disposed of as described in the specific product’s Medication Guide. ○ ○ ○ 16d. TIRF medicines are only available to patients through a special program (called the TIRF REMS Access program). ○ ○ ○ 16e. A TIRF medicine can cause an overdose and death in any child who takes it. ○ ○ ○ [PREAMBLE 3] [PATIENT] The next set of questions is about the Medication Guide for the TIRF medicine that was most recently prescribed for you. [CAREGIVER] The next set of questions is about the Medication Guide for the TIRF medicine that was most recently prescribed for the patient. [BOTH] A Medication Guide is a paper handout that contains important information about the risks associated with the use of a TIRF medicine and how to use it safely. Medication Guides always include the title “Medication Guide” followed by the name of the medicine and its pronunciation. The Medication Guide usually has a section titled “What is the most important information I should know?” The Medication Guide is in a question-and-answer format and may be given to you by your pharmacist or doctor. [END PREAMBLE 3] 29 of 40 FDA_269 TIRF REMS Industry Group (TRIG) Transmucosal Immediate Release Fentanyl (TIRF) Products Patient/Caregiver KAB Survey Protocol 17. Version 3.0 10 September 2012 [PATIENT] Have you ever received a Medication Guide for the TIRF medicine that was prescribed for you? [CAREGIVER] Have you or the patient ever received a Medication Guide for the TIRF medicine that was prescribed for the patient? 18. ○ Yes ○ No [GO TO PREAMBLE 4] ○ I don’t know [GO TO PREAMBLE 4] [PATIENT] Did you receive the Medication Guide from the doctor who prescribed the TIRF medicine or someone in the doctor’s office? [CAREGIVER] Did you or the patient receive the Medication Guide from the doctor who prescribed the TIRF medicine or someone in the doctor’s office? 19. ○ Yes ○ No [GO TO Q20] ○ I don’t know [GO TO Q20] [PATIENT] When was the Medication Guide given to you? [CAREGIVER] When was the Medication Guide given to you or the patient? ○ At the first appointment with the doctor who prescribed the TIRF medicine ○ At the last appointment with the doctor who prescribed the TIRF medicine ○ I don’t remember 30 of 40 FDA_270 TIRF REMS Industry Group (TRIG) Transmucosal Immediate Release Fentanyl (TIRF) Products Patient/Caregiver KAB Survey Protocol 20. Version 3.0 10 September 2012 [PATIENT] Did you receive the Medication Guide for the TIRF medicine from the pharmacy? [CAREGIVER] Did you or the patient receive the Medication Guide for the TIRF medicine from the pharmacy? 21. ○ Yes ○ No [GO TO Q22] ○ I don’t know [GO TO Q22] [PATIENT] When was the most recent time that you received a Medication Guide for the TIRF medicine at the pharmacy? [CAREGIVER] When was the most recent time that you or the patient received a Medication Guide for the TIRF medicine at the pharmacy? 22. 23. ○ Only with the first filled prescription ○ Each time a prescription is filled ○ Other (please specify): _____________________________ ○ I don’t know Did you read the Medication Guide? ○ Yes ○ No [GO TO Q25] ○ I don’t know [GO TO Q25] How much did you read? ○ All of it ○ Most of it ○ Some of it ○ I don’t know 31 of 40 FDA_271 TIRF REMS Industry Group (TRIG) Transmucosal Immediate Release Fentanyl (TIRF) Products Patient/Caregiver KAB Survey Protocol 24. 25. 26. Version 3.0 10 September 2012 How much of the Medication Guide did you understand? ○ All of it ○ Most of it ○ Some of it ○ None of it ○ I don’t know Did someone offer to explain the Medication Guide to you? ○ Yes ○ No [GO TO Q29] ○ I don’t know [GO TO Q29] Who offered to explain the Medication Guide to you? (Select all that apply.) ○ The doctor or another healthcare professional in the doctor’s office ○ The pharmacist where the TIRF medicine prescription was filled ○ Someone else (specify the type of person but not his/her name) ____________________________________________________________ 27. Did you accept the offer to have the Medication Guide explained to you? ○ Yes ○ No [GO TO Q29] ○ I don’t know [GO TO Q29] 32 of 40 FDA_272 TIRF REMS Industry Group (TRIG) Transmucosal Immediate Release Fentanyl (TIRF) Products Patient/Caregiver KAB Survey Protocol 28. 29. 30. Version 3.0 10 September 2012 How much of the explanation did you understand? ○ All of it ○ Most of it ○ Some of it ○ None of it ○ I don’t know Did you or do you have any questions about the information in the Medication Guide? ○ Yes ○ No [GO TO PREAMBLE 4] ○ I don’t know [GO TO PREAMBLE 4] What are your questions? [MULTILINE INPUT] [PREAMBLE 4] The next set of questions is about the Patient-Prescriber Agreement Form for TIRF medicines. As a reminder, TIRF medicines include Abstral®, Actiq®, Fentora®, Lazanda®, Onsolis®, Subsys™, and the generic versions of any of these brands. The Patient-Prescriber Agreement is a form that is signed by the doctor and the patient or their caregiver. This form may also be referred to as the Prescriber-Patient Agreement. [END PREAMBLE 4] 31. Did the doctor or someone in the doctor’s office explain the Patient-Prescriber Agreement Form to you? ○ Yes ○ No [GO TO Q33] ○ I don’t know [GO TO Q33] 33 of 40 FDA_273 TIRF REMS Industry Group (TRIG) Transmucosal Immediate Release Fentanyl (TIRF) Products Patient/Caregiver KAB Survey Protocol 32. 33. Version 3.0 10 September 2012 How much of the explanation did you understand? ○ All of it ○ Most of it ○ Some of it ○ None of it ○ I don’t know [PATIENT] Did you sign a Patient-Prescriber Agreement Form? [CAREGIVER] Did you or the person you are caring for sign a Patient-Prescriber Agreement Form? 34. ○ Yes ○ No [GO TO DEMOGRAPHICS PREAMBLE] ○ I don’t know [GO TO DEMOGRAPHICS PREAMBLE] Did the doctor or someone in the doctor’s office give you a copy of the signed Patient-Prescriber Agreement Form? ○ Yes ○ No ○ I don’t know [DEMOGRAPHICS PREAMBLE] There are just a few more questions to help us combine your answers with other answers we have received. 35. What is your gender? ○ Male ○ Female ○ Prefer not to answer 34 of 40 FDA_274 TIRF REMS Industry Group (TRIG) Transmucosal Immediate Release Fentanyl (TIRF) Products Patient/Caregiver KAB Survey Protocol 36. 37. Version 3.0 10 September 2012 What is the highest level of education you have completed? ○ Less than high school ○ Some high school ○ High school graduate/GED ○ Some college/Associate’s degree ○ Bachelor’s degree ○ Master’s degree ○ Professional or Doctoral degree ○ Prefer not to answer What is the main language you speak at home? (Please select only one.) ○ English ○ French ○ Spanish ○ Portuguese ○ Italian ○ German ○ Chinese ○ Japanese ○ Korean ○ Other ○ Prefer not to answer 35 of 40 FDA_275 TIRF REMS Industry Group (TRIG) Transmucosal Immediate Release Fentanyl (TIRF) Products Patient/Caregiver KAB Survey Protocol 38. 39. 40. Version 3.0 10 September 2012 Are you Hispanic or Latino? ○ Yes ○ No ○ Prefer not to answer For informational purposes only, which of the following U.S. census categories best describes your race? (Please select only one.) ○ American Indian or Alaska Native ○ Asian (origins of Far East, Southeast Asia or the Indian subcontinent) ○ Black or African American ○ Native Hawaiian or Other Pacific Islander ○ White ○ Other ○ Prefer not to answer In which state do you live? [DROP-DOWN LIST INPUT WITH STATES TABLE WITH “Prefer not to answer” AT END] 36 of 40 FDA_276 TIRF REMS Industry Group (TRIG) Transmucosal Immediate Release Fentanyl (TIRF) Products Patient/Caregiver KAB Survey Protocol Version 3.0 10 September 2012 [PHONE ONLY: ADVERSE EVENT/PRODUCT COMPLAINT] (INTERVIEWER: Please record if respondent spontaneously reported an adverse event or product complaint during the course of this interview.) ○ Yes ○ No [GO TO CLOSING 1] Enter Safety Adverse Event Verbatim [MULTILINE INPUT] (INTERVIEWER: Indicate to the respondent that someone may call back to ask more questions about the adverse event or product complaint that was reported.) [END ADVERSE EVENT/PRODUCT COMPLAINT] [CLOSING 1] You are eligible to receive a $25 gift card for your time completing the survey. In order to receive the gift card, we need to collect your name and address so that we can mail it to you. If you do not provide your name and address you will not receive the gift card for your time taking the survey. 41. Do you agree to give us your name and mailing address so we can send your payment? ○ Yes ○ No [SKIP TO CLOSING 2] FIRST NAME: _______________________________________________ LAST NAME: _______________________________________________ ADDRESS: [MULTILINE INPUT] CITY: _____________________________________ STATE: [DROP-DOWN LIST INPUT WITH STATES TABLE] ZIP: ___________ 37 of 40 FDA_277 TIRF REMS Industry Group (TRIG) Transmucosal Immediate Release Fentanyl (TIRF) Products Patient/Caregiver KAB Survey Protocol Version 3.0 10 September 2012 [CLOSING 2] We would also like to ask for your telephone number. Providing your telephone number is optional and it will be used to contact you only if there are questions about your survey responses.  42. Do you want to provide your telephone number? ○ Yes ○ No [SKIP TO CLOSING 3] Telephone: ________________________________ [CLOSING 3] This is the end of the survey. If you have questions about the survey, please contact the Survey Coordinating Center at 1-877-379-3297. Thank you again for your help. [END OF SURVEY CONTENT] 38 of 40 FDA_278 TIRF REMS Industry Group (TRIG) Transmucosal Immediate Release Fentanyl (TIRF) Products Patient/Caregiver KAB Survey Protocol Version 3.0 10 September 2012 APPENDIX B Sample Patient Letter of Invitation PAT_FIRST_NAME] [PAT_LAST_NAME] [CURR_DATE] [PAT_STREET_ADDR] [PAT_CITY], [PAT_STATE] [PAT_ZIP] Dear [PAT_FULL_NAME]: Thank you for choosing [PHARMACY] for your prescription needs. We are contacting you to invite you to participate in a survey being conducted by the manufacturers of Transmucosal Immediate Release Fentanyl medicines (TIRF medicines), as required by the FDA. The purpose of the survey is to find out if patients and/or their caregivers understand important information related to taking these medicines. The TIRF medicines include Abstral®, Actiq®, Fentora®, Lazanda®, Onsolis®, Subsys™, and the generic versions of any of these brands. The survey is being administered by United BioSource Corporation, on behalf of the manufacturers of TIRF medicines: Archimedes Pharma US Inc., Cephalon, Inc., Endo Pharmaceuticals Inc., Insys Therapeutics, Meda Pharmaceuticals, Mallinckrodt (a Covidien Company), Par Pharmaceutical, Inc., ProStrakan, Inc., and Sandoz Inc. Survey participants must be 18 years of age or older. A caregiver may complete the survey on behalf of patients who are unable to take the survey for themselves. Eligible individuals who complete the survey will be sent a $25 gift card to thank them for their time. The survey will take about 20 minutes. If you are interested in participating and want to find out if you are eligible, • • Go to www.XXX.com* any time, or Call 1-877-379-3297, 8 a.m. to 10 p.m. Eastern Time, Monday through Friday. Please have this letter with you when you take the survey. You will be asked to give this unique code prior to starting the survey: [CODE_ID]. The survey asks questions about the type of information you received about your TIRF medication and where you get your medication information. You do not have to take part in this survey; the decision to participate is entirely yours. Your privacy will be strictly guarded. Your answers to the survey questions will be combined with answers given by others, and your name will not be used in any written report or publication. Neither taking the survey nor your answers to the questions will affect your ability to receive or take a TIRF medicine. 39 of 40 FDA_279 TIRF REMS Industry Group (TRIG) Transmucosal Immediate Release Fentanyl (TIRF) Products Patient/Caregiver KAB Survey Protocol Version 3.0 10 September 2012 Thank you in advance for your help with this important survey. Sincerely, [PHARMACY] * We recommend that you take the survey on a desktop or laptop computer. Taking the survey on mobile devices, such as smart phones, tablets, and e-notebooks, is not supported. 40 of 40 FDA_280 Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Appendix B December 2012 Patient KAB Assessment Report Patient Survey Listings and Subanalyses Tables Page 45 of 52 FDA_281 Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies December 2012 Patient KAB Assessment Report Patient Listings Page 46 of 52 FDA_282 Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies December 2012 Patient KAB Assessment Report Listing 1 CATEGORIZATION OF VERBATIM RESPONSES TO QUESTION 21 (Most recent time receiving Medication Guide for the TIRF medicine from the pharmacy) Verbatim Response Categorized Response Every 3 or 4 months Sometimes Occasionnally but not every time Sometimes Depends 011 pharmacist. Get them almost eveiy time. Sometimes Eveiy couple of months Sometimes I have received the Medication Guide more than once but not Sometimes each time a prescription is ?lled. They ask if I need one and occasionally I will take one. Sometimes I believe I received it a few times but i don't think I get one Sometimes each time Page 47 of 52 Transmucosal Immediate Release Fentanyl December 2012 TIRF REMS Industry Group (TRIG) of Companies Patient KAB Assessment Report Listing 2 CATEGORIZATION OF VERBATIM RESPONSES TO QUESTION 26 (Other person offering explanation of the Medication Guide) Verbatim Response Categorized Response Her son Family My husband Family Person from company on phone Phannaceutical Rep Pharmaceutical representative Pharmaceutical Rep phannacy tech Pharmacy The drug rep who solicited this medication to the practice Pharmaceutical Rep The manufacturer contacted me by phone when I started taking Pharmaceutical Rep Actiq The patient's wife is a nurse Family Page 48 of 52 Transmucosal Immediate Release Fentanyl (TIRE) TIRF REMS Industry Group (TRIG) of Companies December 2012 Patient KAB Assessment Report Listing 3 CATEGORIZATION OF VERBATIM RESPONSES TO QUESTION 29 (Questions about the information in the Medication Guide) Verbatim Response Categorized Response Is there any ARTIFICIAL SUGAR in the Education product? Exactly 110w much sugar is in the product? A?er reading about absorption only about 40%-60% of actual medicine is absorbed into person body through mucosa of the cheek? Are there serious side effects? Side e?ects Exact placement of tab in mouth Placement of medication How is Actiq still on the market when it has been shown to distroy peoples teeth even with proper dental care and you admit that even in the medication guide? Oral side effects How to understand the actual chemical structure diagram symbols. I am not a chemist. but would like to know what the chemical symbols mean. Education I currently do not have questions but on begiiming the medication both my wife and I had questions and concerns that where addressed at that time. Question regarding proper disposal of container(s) holding buccal tablets. Disposal Page 49 of 52 Transrnucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies December 2012 Patient KAB Assessment Report Listing 4 PRODUCT COMPLAINTS CATEGORIZATION OF REPORTED SAFETY EVENTS OR Verbatim Response Categorized Response I got put on the medication because I shattered my jaw in a accident. I have a hard time chewing because of my facial injury. I have developed cancer since being 011 the medication." Cancer. Pain I was hooked on this medication. Withdrawal was tenible. I became a mean and hateful person without it. It was a horrible experience. My son took the medications away from me. Abuse I'm taking it for breakthrough pain but not cancer pain. Pain My dentist bill is crazy from taking the medicine my mouth looks like a junkyard. Oral side effects Patient has had this teeth decaying for a while. He was told by his doctor that this is normal due to the sugar in the medication. Oral side effects That lollypop is rotting my teeth and gums. Oral side effects This patient completed her survey without mentioning an adverse event(s). Once the survey was completed. PT asked if she could ask me a question. PT asked how/to whom she would report unusual side effects to her TIRF medication. Since the survey had been completed. I directed PT to her doctor. PT stated that she has called her doctor with these side effects and was told that they would be reported to the manufacturer. PT also stated that she called the manufacturer about these side effects and received a return call that 'gee. we've never heard that before'. PT inquired whether she should contact the FDA with this information. Unusual side effects Is there any ARTIFICIAL SUGAR in the product? Exactly 110w much sugar is in the product? After reading about absorption only about of actual medicine is absorbed into person body through mucosa of the cheek? Education Are there serious side effects? Side Effects Exact placement of tab in mouth Placement of medication Page 50 of 52 Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies December 2012 Patient KAB Assessment Report Verbatim Response Categorized Response How is Actiq still on the market when it has been shown to distroy peoples teeth even with proper dental care and you admit that even in the medication guide? Oral Side Effects How to understand the actual chemical structure diagram symbols. I am not a chemist. but would like to know what the chemical symbols mean. Education Question regarding proper disposal of container(s) holding buccal tablets. Disposal After I had been on the medication for several years Product Complaint $25.00 for 20 minutes. That?s not a lot. The only reason I called is because I thought I could ?ll out the survey for my husband because he died.? Death Page 51 of 52 Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies December 2012 Patient KAB Assessment Report Patient Subanalysis Tables Page 52 of 52 FDA_288 TABLE 6.1.1 PRIMARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #1 KEY RISK MESSAGE l: TIRF MEDICINES CAN CAUSE LIFE-THREATENING BREATHING PROBLEMS THAT CAN LEAD TO DEATH. SUBGROUP ANALYSIS 1: READING MEDICATION GUIDE (QUESTION 15, 16 AND 17) S-la - Respondents who got the Medication Guide and read at least most of it S-lb - Respondents who did not get a Medication Guide or answered don?t know? or who got a Medication Guide and read only some of it or answered don?t know?. la S?lb Read most 6f Med Guide Read some or none of Med Guide Question (95% CI) (95% CI) Question 12: Please answer True, False, or I don?t know for each statement about the TIRF medicine that was most recently prescribed for you. 12d: TIRF medicines can cause life?threatening breathing problems that can lead to death. Con'ect response True 138 92.0 35 83.3 (86.4. 95.8) (68.6. 93.0) Incouect response False 3 2.0 2 4.8 I don't know 9 6.0 5 11.9 Client: TRIG Project: TIRF KAB Report Run Date and Time: 11/12/2012 12:38 PM Page 1 of 1 TABLE 7.1.1 PRIMARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #2 KEY RISK MESSAGE 2: PATIENTS SHOULD NOT TAKE TIRF MEDICINES IF THEY ARE NOT OPIOID TOLERANT. SUBGROUP ANALYSIS 1: READING MEDICATION GUIDE (QUESTION 15, 16 AND 17) S-la - Respondents who got the Medication Guide and read at least most of it S-lb - Respondents who did not get a Medication Guide or answered don?t know? or who got a Medication Guide and read only some of it or answered don?t know?. S-la Read most of Med Guide Read somg?ggne Of Med Question (95% CI) (95% CI) Question 10: Please answer True, False, or I don?t know for the following statement: TIRF medicines should only be taken by patients who are opioid tolerant. Correct response Tme 140 93.3 34 81.0 (88.1. 96.8) (65.9. 91.4) Incorrect response False 3 2.0 2 4.8 I don't know 7 4.7 6 14.3 Question 11: Please answer True, False, or I don?t know for the following statements: 11a: Opioid tolerant means that a patient is already taking other opioid pain medicines around the clock and their body is used to these medicines. Correct response True 141 94.0 35 83.3 (88.9. 97.2) (68.6. 93.0) Incorrect response False 6 4.0 1 2.4 I don't know 3 2.0 6 14.3 Client: TRIG Project: TIRF KAB Report Run Date and Time: 11/12/2012 12:38 PM Page 1 of 2 la S?lb Read most at Med Guide Read some or none of Med Guide Question (95% Cl) (95% CI) Question 12: Please answer True, False, or I don?t know for each statement about the TIRF medicine that was most recently prescribed for you. 12b: It is OK for patients to take TIRF medicines for headache pain. Con?ect response False 110 73.3 26 61.9 (65.5. 80.2) (45.6. 76.4) Incorrect response True 14 9.3 3 7.1 I don't know 26 17.3 13 31.0 Client: TRIG Project: TIRF KAB Report Run Date and Time: 11/12/2012 12:38 PM Page 2 of 2 TABLE 7.2.1 SECONDARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #2 KEY RISK MESSAGE 2: PATIENTS SHOULD NOT TAKE TIRF MEDICINES IF THEY ARE NOT OPIOID TOLERANT. SUBGROUP ANALYSIS 1: READING MEDICATION GUIDE (QUESTION 15, 16 AND 17) S-la - Respondents who got the Medication Guide and read at least most of it S-lb - Respondents who did not get a Medication Guide or answered don?t know? or who got a Medication Guide and read only some of it or answered don?t know?. S-la S-lb Read most of Med Read some or none of Guide Med Guide Demonstrated Understanding (95% CI) (95% CI) 0 correct responses 0 0.0 7.1 1 correct response 5 3.3 - 11.9 2 correct responses 49 32.7 12 28.6 3 correct responses 96 64.0 22 52.4 Average number of c01rect responses 2.6 (2.4. 3.0) 2.3 (1.9. 3.0) Client: TRIG Project: TIRF KAB Report Run Date and Time: 11/12/2012 12:16 PM Page 1 of TABLE 8.1.1 PRIMARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #3 RISK MESSAGE 3: TIRF MEDICINES SHOULD BE TAKEN EXACTLY AS PRESCRIBED BY THE HEALTHCARE PROVIDER. SUBGROUP ANALYSIS 1: READING MEDICATION GUIDE (QUESTION 15, 16 AND 17) S-la - Respondents who got the Medication Guide and read at least most of it S-lb - Respondents who did not get a Medication Guide or answered don?t know? or who got a Medication Guide and read only some of it or answered don?t know?. S-la S-lb Read most of Med Guide Read Williams?? Of Med Question (95% CI) (95% CI) Question 11: Please answer True, False, or I don?t know for the following statements: 11b: If a patient stops taking around-the-clock opioid pain medicine, they must also stop taking the TIRF medicine. Con'ect response Tme 70 46.7 12 28.6 (38.5. 55.0) (15.7. 44.6) Incorrect response False 39 26.0 8 19.0 I don't know 41 27.3 22 52.4 Question 12: Please answer True, False, or I don?t know for each statement about the TIRF medicine that was most recently prescribed for you. 12c: TIRF medicines should be taken exactly as prescribed by the doctor. Cou'ect response Tme 150 100.0 42 100.0 (97.6. 100.0) (91.6. 100.0) Inconect response False 0 0.0 0 0.0 I don't know 0 0.0 0 0.0 Client: TRIG Project: TIRF KAB Report Run Date and Time: 11/12/2012 12:18 PM Page 1 of 2 la S?lb Read most 61- Med Guide Read some or none of Med Guide Question (95% CI) (95% CI) Question 16: Please answer True, False, or I don?t know for each statement about the TIRF medicine that was most recently prescribed for you. 16b: It is OK to take TIRF medicines for short-term pain that will go awav in a few davs. Con'ect response False 130 86.7 28 66.7 (80.2. 91.7) (50.5. 80.4) Incorrect response Tnle 7 4. 7 3 7.1 I don't know 13 8.7 11 26.2 Client: TRIG Project: TIRF KAB Report Run Date and Time: 11/12/2012 12:18 PM Page 2 of 2 TABLE 8.2.1 SECONDARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #3 KEY RISK MESSAGE 3: TIRF MEDICINES SHOULD BE TAKEN EXACTLY AS PRESCRIBED BY THE HEALTHCARE PROVIDER. SUBGROUP ANALYSIS 1: READING MEDICATION GUIDE (QUESTION 15, 16 AND 17) S-la - Respondents who got the Medication Guide and read at least most of it S-lb - Respondents who did not get a Medication Guide or answered don?t know? or who got a Medication Guide and read only some of it or answered don?t know?. S-la S-lb Read most of Med Read some or none Guide of Med Guide Demonstrated Understanding (95% (95% CI) CI) 0 correct responses 0 0.0 0 0.0 1 con?ect response 14 9.3 13 31.0 2 correct responses 72 48.0 18 42.9 3 correct responses 64 42.7 11 26.2 Average number of correct responses 2.3 (2.1. 3.0) 2.0 (1.6. 3.0) Client: TRIG Project: TIRF KAB Report Run Date and Time: 11/12/2012 12:20 PM Page 1 of TABLE 9.1.1 PRIMARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #4 RISK MESSAGE 4: PATIENTS SHOULD NOT SWITCH FROM A TIRF MEDICINE TO ANOTHER MEDICINE THAT CONTAINS FENTANY WITHOUT TALKING TO A HEALTHCARE PROVIDER. SUBGROUP ANALYSIS 1: READING MEDICATION GUIDE (QUESTION 15, 16 AND 17) S-la - Respondents who got the Medication Guide and read at least most of it S-lb - Respondents who did not get a Medication Guide or answered don?t know? or who got a Medication Guide and read only some of it or answered don?t know?. la S-lb Read most 6" Med Guide Read some or none of Med Guide Question (95% CI) (95% CI) Question 11: Please answer True, False, or I don?t know for the following statements: 11c: It is safe to switch to another medicine that contains fentanyl without talking to a healthcare provider ?rst Con?ect response False 148 98.7 38 90.5 (95.3. 99.8) (77.4. 97.3) Inconect response T1116 1 0.7 0 0.0 I don't know 1 0.7 4 9.5 Client: TRIG Project: TIRF KAB Report Run Date and Time: 11/12/2012 12:22 PM Page 1 of 1 TABLE 10.1.1 PRIMARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #5 KEY RISK MESSAGE 5: PATIENTS SHOULD NOT GIVE TIRF MEDICINES TO ANYONE ELSE EVEN IF THEY HAVE THE SAME SUBGROUP ANALYSIS 1: READING MEDICATION GUIDE (QUESTION 15, 16 AND 17) S-la - Respondents who got the Medication Guide and read at least most of it S-lb - Respondents who did not get a Medication Guide or answered don?t know? or who got a Medication Guide and read only some of it or answered don?t know?. la $41) Read most Med Guide Read some or none of Med Guide Question (95% CI) (95% CI) Question 11: Please answer True, False, or I don?t know for the following statements: 11d: A patient may give TIRF medicines to another person if they have the same as the patient. Correct response False 150 100.0 42 100.0 (97.6. 100.0) (91.6. 100.0) Incorrect response True 0 0.0 0 0.0 I don't know 0 0.0 0 0.0 Question 16: Please answer True, False, or I don?t know for each statement about the TIRF medicine that was most recently prescribed for you. 16a: Selling or giving away TIRF medicines is against the law. Correct response True 147 98.0 41 97.6 (94.3. 99.6) (87.4. 99.9) Incorrect response False 3 2.0 0 0.0 I don't know 0 0.0 1 2.4 Client: TRIG Project: TIRF KAB Report Run Date and Time: 11/12/2012 12:25 PM Page 1 of 1 TABLE 10.2.1 SECONDARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #5 KEY RISK MESSAGE 5: PATIENTS SHOULD NOT GIVE TIRF MEDICINES TO ANYONE ELSE EVEN IF THEY HAVE THE SAME SUBGROUP ANALYSIS 1: READING MEDICATION GUIDE (QUESTION 15, 16 AND 17) S-la - Respondents who got the Medication Guide and read at least most of it S-lb - Respondents who did not get a Medication Guide or answered don?t know? or who got a Medication Guide and read only some of it or answered don?t know?. S-la S-lb Read most of Med Read some or none Guide of Med Guide Demonstrated Understanding (95% (95% CI) CI) 0 correct responses 0 0.0 0 0.0 1 correct response 3 2.0 2.4 2 correct responses 147 98.0 41 97.6 Average number of correct responses 2.0 (1.8. 2.0) 2.0 (1.6. 2.0) Client: TRIG Project: TIRFKAB Report Run Date and Time: 11/12/2012 12:27 PM Page 1 ofl TABLE 11.1.1 PRIMARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #6 KEY RISK MESSAGE 6: TIRF MEDICINES SHOULD BE STORED IN A SAFE PLACE AWAY FROM CHILDREN AND PROPERLY DISPOSED. SUBGROUP ANALYSIS 1: READING MEDICATION GUIDE (QUESTION 15, 16 AND 17) S-la - Respondents who got the Medication Guide and read at least most of it S-lb - Respondents who did not get a Medication Guide or answered don?t know? or who got a Medication Guide and read only some of it or answered don?t know?. S-la S-lb Read most of Med Guide Read someg?ggne Of Med Question (95% CI) (95% CI) Question 12: Please answer True, False, or I don?t know for each statement about the TIRF medicine that was most recently prescribed for you. 12a: TIRF medicines should be stored in a safe place out of the reach of children. Con'ect response Tme 150 100.0 42 100.0 (97.6. 100.0) (91.6. 100.0) Incorrect response False 0.0 0.0 I don't know 0.0 0.0 Client: TRIG Project: TIRFKAB Report Run Date and Time: 11/12/2012 12:31 PM Page 1 of 2 Question S?lb S?la Read most of Med Guide Read some or. none of Med Gmde (95% CI) (95% CI) Question 16: Please answer True, False, or I don?t know for each statement about the TIRF medicine that was most recently prescribed for you. 16c: TIRF medicines must be dis osed of as described in the speci?c product?s Medication Guide. correct response Tme 147 98.0 37 88.1 (94.3. 99.6) (74.4. 96.0) Inconect response False 1 0.7 1 I don't know 2 1.3 4 16e: A TIRF medicine can cause an overdose and death in any child who takes it. Cou'ect response Tme 140 93.3 34 81.0 (88.1. 96.8) (65.9. 91.4) Inconect response False 2 1.3 2 4.8 I don't know 8 5.3 6 14.3 Question 13: What should you do if an adult who has not been prescribed a TIRF medicine takes a TIRF medicine? (Please select one.) correct response Get emergency help right away. 138 92.0 33 78.6 (86.4. 95.8) (63.2. 89.7) Incorrect response Do nothing. 0 0.0 0 0.0 Wait an hour and see if the - 3.3 1 2.4 person is OK. I don't know 7 4.7 8 19.0 Client: TRIG Project: TIRFKAB Report Run Date and Time: 11/12/2012 12:31 PM Page 2 of 2 TABLE 11.2.1 SECONDARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #6 KEY RISK MESSAGE 6: TIRF MEDICINES SHOULD BE STORED IN A SAFE PLACE AWAY FROM CHILDREN AND PROPERLY DISPOSED. SUBGROUP ANALYSIS 1: READING MEDICATION GUIDE (QUESTION 15, 16 AND 17) S-la - Respondents who got the Medication Guide and read at least most of it S-lb - Respondents who did not get a Medication Guide or answered don?t know? or who got a Medication Guide and read only some of it or answered don?t know?. S-la S-lb Read most of Med Read some or none of Guide Med Guide Demonstrated Understanding (95% CI) (95% CI) 0 correct responses 0 0.0 0 0.0 1 correct response 0 0.0 0 0.0 2 correct responses 3 2.0 4 9.5 3 correct responses 19 12.7 14 33.3 4 correct responses 128 85.3 24 57.1 Average number of correct responses 3.8 (3.6. 4.0) 3.5 (3.0. 4.0) Client: TRIG Project: TIRFKAB Report Run Date and Time: 11/12/2012 12:34 PM Page 1 of TABLE 6.1.2 PRIMARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #1 KEY RISK MESSAGE 1: TIRF MEDICINES CAN CAUSE BREATHING PROBLEMS THAT CAN LEAD TO DEATH. SUBGROUP ANALYSIS 2: UNDERSTANDING OF MEDICATION GUIDE (QUESTION 24) Medication Guide. S-2a - Respondents who understood all of it or most of it S-2b Respondents who understood some of it S-2c Respondents who answered None or don?t know? S-2d - Respondents who answered don?t know? to receipt or reading of the Question S?2a S?2c Sid Understood All 8?21, None/I don?t Mt or Understood Some Read Medication 0r Most know . N=l3 Gmde (95% (95% (95% (95% CI) CI) C1) C1) Question 12: Please answer True, False, or I don?t know for each statement about the TIRF medicine that was most recently prescribed for you. 12d: TIRF medicines can cause life-threatening breathing problems that can lead to death. Tme 143 92.9 9 69.2 0 0.0 21 84.0 (87.6. (38.6. (63.9. 96.4) 90.9) 95.5) False 4.0 Idon't know 8 5.2 3 23.1 0 0.0 3 12.0 Client: TRIG Project: TIRFKAB Report Run Date and Time: 11/19/2012 10:34 ANI Page 1 of 1 TABLE 7.1.2 PRIMARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #2 KEY RISK MESSAGE 2: PATIENTS SHOULD NOT TAKE TIRF MEDICINES IF THEY ARE NOT OPIOID TOLERANT. SUBGROUP ANALYSIS 2: UNDERSTANDING OF MEDICATION GUIDE (QUESTION 24) Medication Guide. S-2a - Respondents who understood all of it or most of it S-2b Respondents who understood some of it S-2c - Respondents who answered None or don?t know? S-2d - Respondents who answered don?t know? to receipt or reading of the S?2a S?2d Understood All Or S-2b S-2c Did not Get or Most Undergotlig Some None/I know Read get?llication . Question (95% (95% (95% (95% CI) CI) CI) CI) Question 10: Please answer True, False, or I don?t know for the following statement: TIRF medicines should only be taken by patients who are opioid tolerant. correct response True 144 93.5 10 76.9 0 0.0 20 80.0 (88.4. (46.2. (59.3. 96.8) 95.0) 93.2) False don't know 7 4.5 2 15.4 0 0.0 4 16.0 Client: TRIG Project: TIRFKAB Report Run Date and Time: 11/19/2012 2:22 PM Page 1 of 2 Question S?2a S?2b S?2c Did not Get or Understood All Or Understood Some None/I don?t know Read Medication Most . N=l3 Guide (95% (95% (95% (95% C1) C1) CI) CI) Question 11: Please answer True, False, or I don?t know for the following statements: 11a: Opioid tolerant means that a patient is already taking other opioid pain medicines around the clock and their bodv is used to these medicines. COITCCI response True 144 93.5 12 92.3 0 0.0 20 80.0 (88.4. (64.0. (59.3. 96.8) 99.8) 93.2) Incorrect response False don't know 20.0 Question 12: Please answer True, False, or I don?t know for each statement about the TIRF medicine that was most recently prescribed for you. 12b: It is OK for patients to take TIRF medicines for headache pain. False 112 72.7 9 69.2 0 0.0 15 60.0 (65.0. (38.6. (38.7. 79.6) 90.9) 78.9) Incorrect response True don't know 28 18.2 3 23.1 0 0.0 8 32.0 Client: TRIG Project: TIRFKAB Report Run Date and Time: 11/19/2012 2:22 PM Page 2 of 2 TABLE 7.2.2 SECONDARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #2 KEY RISK MESSAGE 2: PATIENTS SHOULD NOT TAKE TIRF MEDICINES IF THEY ARE NOT OPIOID TOLERANT. SUBGROUP ANALYSIS 2: UNDERSTANDING OF MEDICATION GUIDE (QUESTION 24) S-2a - Respondents who understood all of it or most of it S-2b Respondents who understood some of it S-2c Respondents who answered None or don?t know? 0 S-2d - Respondents who answered don?t know? to receipt or reading of the Medication Guide. S-2d S-2a S-2b S-2c Did not Get Understood Understood None/I don?t or Read All Or Most Some know Medication Demonstrated Understanding N=l3 Guide (95% (95% (95% (95% CI) CI) CI) CI) 0 correct responses correct response 16.0 2 correct responses 49 31.8 6 46.2 0 0.0 6 24.0 3 correct responses 99 64.3 6 46.2 0 0.0 13 52.0 Average number of correct 2.6 (2.4. 2.4 (1.7. 0 (0.0. 2.2 (1.7. responses 3.0) 3.0) 3 .0) 3.0) Client: TRIG Project: TIRF KAB Report Run Date and Time: 11/12/2012 4:09 PM Page 1 of 1 TABLE 8.1.2 PRIMARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #3 RISK MESSAGE 3: TIRF MEDICINES SHOULD BE TAKEN EXACTLY AS PRESCRIBED BY THE HEALTHCARE PROVIDER. SUBGROUP ANALYSIS 2: UNDERSTANDING OF MEDICATION GUIDE (QUESTION 24) Medication Guide. S-2a - Respondents who understood all of it or most of it S-2b Respondents who understood some of it S-2c Respondents who answered None or don?t know? S-2d - Respondents who answered don?t know? to receipt or reading of the S-2a . Sid Understood All Or S-2b S-2c not Get or Most Some None/I :12: know Read adedlication . Question (95% (95% (95% (95% CI) CI) CI) CI) Question 11: Please answer True, False, or I don?t know for the following statements: 11b: If a patient stops taking around-the-clock opioid pain medicine, they must also stop taking the TIRF medicine. Correct response True 72 46.8 2 15.4 0 0.0 8 32.0 (38.7. (1.9. (14.9. 55.0) 45.4) 53.5) Incorrect response False 40 26.0 2 15.4 0 0.0 5 20.0 I don't know 42 27.3 9 69.2 0 0.0 12 48.0 Client: TRIG Project: TIRFKAB Report Run Date and Time: 11/20/2012 1:50 PM Page 1 of 2 S?2d S?2a S?2b S?Understood Some None/I don?t know Read Medication . N=l3 Guide Question (95% (95% (95% (95% CI) CI) C1) C1) Question 12: Please answer True, False, or I don?t know for each statement about the TIRF medicine that was most recently prescribed for you. 12c: TIRF medicines should be taken exactlv as prescribed by the doctor. correct response True 154 100.0 13 100.0 0 0.0 25 100.0 (97.6. (75.3. (86.3. 100.0) 100.0) 100.0) Inconect response False don?t know 0.0 Question 16: Please answer True, False, or I don?t know for each statement about the TIRF medicine that was most recently prescribed for you. 16b: It is OK to take TIRF medicines for short?term pain that will go away in a few days. False 132 85.7 10 76.9 0 0.0 16 64.0 (79.2. (46.2. (42.5. 90.8) 95.0) 82.0.0 Idon'tknow 13 8.4 2 15.4 0 0.0 9 36.0 Client: TRIG Project: TIRFKAB Report Run Date and Time: 11/20/2012 1:50 PM Page 2 of 2 TABLE 8.2.2 SECONDARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #3 KEY RISK MESSAGE 3: TIRF MEDICINES SHOULD BE TAKEN EXACTLY AS PRESCRIBED BY THE HEALTHCARE PROVIDER. SUBGROUP ANALYSIS 2: UNDERSTANDING OF MEDICATION GUIDE (QUESTION 24) Medication Guide. S-2a - Respondents who understood all of it or most of it S-2b Respondents who understood some of it S-2c Respondents who answered None or don?t know? S-2d - Respondents who answered don?t know? to receipt or reading of the S-2d S-2a S-2b S-2c Did not Get Understood Understood None/I don?t or Read All Or Most Some know Medication Demonstrated Understanding N=l3 Guide (95% (95% (95% (95% CI) CI) C1) C1) 0 correct responses correct response 16 10.4 3 23.1 0 0.0 8 32.0 2 correct responses 72 46.8 8 61.5 0 0.0 10 40.0 3 correct responses 66 42.9 2 15.4 0 0.0 7 28.0 Average number of correct 2.3 (2.1. 1.9 (1.3. 0 (0.0. 2.0 (1.5. responses 3.0) 3.0) 3.0) 3.0) Client: TRIG Project: TIRFKAB Report Run Date and Time: 11/12/2012 4:17 PM Page 1 of 1 TABLE 9.1.2 PRIMARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #4 RISK MESSAGE 4: PATIENTS SHOULD NOT SWITCH FROM A TIRF MEDICINE TO ANOTHER MEDICINE THAT CONTAINS FENTANY WITHOUT TALKING TO A HEALTHCARE PROVIDER. SUBGROUP ANALYSIS 2: UNDERSTANDING OF MEDICATION GUIDE (QUESTION 24) Medication Guide. S-2a - Respondents who understood all of it or most of it S-2b Respondents who understood some of it S-2c Respondents who answered None or don?t know? S-2d - Respondents who answered don?t know? to receipt or reading of the S?2a . Understood All Or S?2b S?2c Did not Get or Most Understood Some None/I don?t know Read Medication Question N43 Eff; (95% (95% (95% (95% CD CD CD CD Question 11: Please answer True, False, or I don?t know for the following statements: 11c: It is safe to switch to another medicine that contains fentanyl without talking to a healthcare provider ?rst False 153 99.4 11 84.6 0 0.0 22 88.0 (96.4. (54.6. (68.8. 100.0) 98.1) 97.5) Incorrect response True don't know 1 0.6 7.7 0 0.0 3 12.0 Client: TRIG Project: TIRFKAB Report Run Date and Time: 12/14/2012 1:29 PM Page 1 of 1 TABLE 10.1.2 PRIMARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #5 KEY RISK MESSAGE 5: PATIENTS SHOULD NOT GIVE TIRF MEDICINES TO ANYONE ELSE EVEN IF THEY HAVE THE SAME SYNIPTOMS. SUBGROUP ANALYSIS 2: UNDERSTANDING OF MEDICATION GUIDE (QUESTION 24) Medication Guide. S-2a - Respondents who understood all of it or most of it S-2b Respondents who understood some of it S-2c Respondents who answered None or don?t know? S-2d - Respondents who answered don?t know? to receipt or reading of the S?2d S?2a . Understood All None/I don?t Mt Get or Understood Some Read Medication 0r Most know Guide Question (95% (95% (95% (95% CI) CI) CI) CI) Question 11: Please answer True, False, or I don?t know for the following statements: 11d: A patient may give TIRF medicines to another person if they have the same as the patient. Con?ect response False 154 100.0 13 100.0 0 0.0 25 100.0 (97.6. (75.3. (86.3. 100.0) 100.0) 100.0) Incorrect response Tme don't know 0.0 Client: TRIG Project: TIRFKAB Report Run Date and Time: 11/20/2012 12:41 PM Page 1 of 2 0 S?2d S?2a S?2c . Understood All S_2b None/I don?t Did Mt Get or Understood Some Read Medication 0r Most know Guide Question (95% (95% (95% (95% CI) CI) CI) CI) Question 16: Please answer True, False, or I don?t know for each statement about the TIRF medicine that was most recently prescribed for you. 16a: Selling or giving awav TIRF medicines is against the law. correct response T1116 151 98.1 13 100.0 0 0.0 24 96.0 (94.4. (75.3. (79.6. 99.6) 100.0) 99.9) Incorrect response False don't know 4.0 Client: TRIG Project: TIRFKAB Report Run Date and Time: 11/20/2012 12:41 PM Page 2 of 2 1 TABLE 10.2.2 SECONDARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #5 KEY RISK MESSAGE 5: PATIENTS SHOULD NOT GIVE TIRF MEDICINES TO ANYONE ELSE EVEN IF THEY HAVE THE SAME SYNIPTOMS. SUBGROUP ANALYSIS 2: UNDERSTANDING OF MEDICATION GUIDE (QUESTION 24) Medication Guide. S-2a - Respondents who understood all of it or most of it S-2b Respondents who understood some of it S-2c Respondents who answered None or don?t know? S-2d - Respondents who answered don?t know? to receipt or reading of the S-2d S-2a S-2b S-2c Did not Get Understood Understood None/I don?t or Read All Or Most Some know Medication Demonstrated Understanding Guide (95% (95% (95% (95% CI) CI) CI) CI) 0 conect responses con?ect response correct responses 151 98.1 13 100.0 0 0.0 24 96.0 Average number of correct 2.0 (1.8. 2.0 (1.4. 0 (0.0. 2.0 (1.5. responses 2.0) 2.0) 2.0) 2.0) Client: TRIG Project: TIRFKAB Report Run Date and Time: 11/12/2012 4:34 PM Page 1 of 1 2 TABLE 11.1.2 PRIMARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #6 KEY RISK MESSAGE 6: TIRF MEDICINES SHOULD BE STORED IN A SAFE PLACE AWAY FROM CHILDREN AND PROPERLY DISPOSED. SUBGROUP ANALYSIS 2: UNDERSTANDING OF MEDICATION GUIDE (QUESTION 24) Medication Guide. S-2a - Respondents who understood all of it or most of it S-2b Respondents who understood some of it S-2c Respondents who answered None or don?t know? S-2d - Respondents who answered don?t know? to receipt or reading of the 2a S?2d Understood All Or 5?2? 5-20 Did not Get or Most Understood Some None/I don?t know Read Medication Question N=l3 Guide (95% (95% (95% (95% CD C1) C1) CI) Question 12: Please answer True, False, or I don?t know for each statement about the TIRF medicine that was most recently prescribed for you. 12a: TIRF medicines should be stored in a safe place out of the reach of children. Correct response True 154 100.0 13 100.0 0 0.0 25 100.0 (97.6. (75.3. (86.3. 100.0) 100.0) 100.0) Incorrect response False don't know 0.0 Client: TRIG Project: TIRFKAB Report Run Date and Time: 11/20/2012 1:36 PM Page 1 of 3 3 S?2a S?2d S?2b S?2c Did not Get or 0r Some None/I 11311:]? know Read gledlkation Question (95% (95% (95% (95% C1) C1) C1) CI) Question 16: Please answer True, False, or I don?t know for each statement about the TIRF medicine that was most recently prescribed for you. 16c: TIRF medicines must be disposed of as described in the speci?c product?s Medication Guide. Tme 149 96.8 11 84.6 0 0.0 24 96.0 (92.6. (54.6. (79.6. 98.9) 98.1) 99.9) Incorrect response False don't know 3 1.9 2 15.4 0 0.0 1 4.0 l6e: A TIRF medicine can cause an overdose and death in any child who takes it. Correct response Tme 145 94.2 11 84.6 0 0.0 18 72.0 (89.2. (54.6. (50.6. 97.3) 98.1) 87.9) Incorrect response False 1 0.6 2 15.4 0 0.0 1 4.0 I don't know 24.0 Client: TRIG Project: TIRFKAB Report Run Date and Time: 11/20/2012 1:36 PM Page 2 of 3 4 Question S?2d S?2a S?2b S?2c Did not Get or Understood All Or Understood Some None/I don?t know Read Medication Most . N=l3 Guide (95% (95% (95% (95% C1) C1) CI) CI) Question 13: What should you do if an adult who has not been prescribed a TIRF medicine takes a TIRF medicine? (Please select one.) Get emergency help 140 90.9 10 76.9 0 0.0 21 84.0 right away. (85.2. (46.2. (63.9. 94.9) 95.0) 95.5) Incorrect response Do nothing0.0 Wait an hour and the person is OK. I don't know 8 5.2 3 23.1 0 0.0 4 16.0 Client: TRIG Project: TIRFKAB Report Run Date and Time: 11/20/2012 1:36 PM Page 3 of 3 5 TABLE 11.2.2 SECONDARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #6 KEY RISK MESSAGE 6: TIRF MEDICINES SHOULD BE STORED IN A SAFE PLACE AWAY FROM CHILDREN AND PROPERLY DISPOSED. SUBGROUP ANALYSIS 2: UNDERSTANDING OF MEDICATION GUIDE (QUESTION 24) Medication Guide. S-2a - Respondents who understood all of it or most of it S-2b Respondents who understood some of it S-2c - Respondents who answered None or don?t know? S-2d - Respondents who answered don?t know? to receipt or reading of the S-2d S-2a S-2b S-2c Did not Get Understood Understood None/I don?t or Read All Or Most Some know Medication Demonstrated Understanding Guide (95% (95% (95% (95% C1) C1) CI) CI) 0 correct responses correct response 0correct responses 3 1.9 2 15.4 0 0.0 2 8.0 3 correct responses 22 14.3 3 23.1 0 0.0 8 32.0 4 correct responses 129 83.8 8 61.5 0 0.0 15 60.0 Average number of correct 3.8 (3.6. 3.5 (2.6. 0 (0.0. 3.5 (2.9. responses 4.0) 4.0) 4.0) 4.0) Client: TRIG Project: TIRFKAB Report Run Date and Time: 11/12/2012 4:42 PM Page 1 of 1 6 TABLE 6.1.3 PRIMARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #1 KEY RISK MESSAGE l: TIRF MEDICINES CAN CAUSE LIFE-THREATENING BREATHING PROBLEMS THAT CAN LEAD TO DEATH. SUB-GROUP ANALYSIS 3: TIME TO COMPLETE SURVEY - INTERNET: S-3a - <10 min 0 S-3b - 10 to<20 min 0 S-3c - 220 min Question S?3a S?3b S?min (95% CI) (95% CI) (95% CI) Question 12: Please answer True, False, or I don?t know for each statement about the TIRF medicine that was most recently prescribed for you. 12d: TIRF medicines can cause life?threatening breathing problems that can lead to death. True 38 80.9 51 98.1 12 92.3 (66.7. (89.7. (64.0. 90.9) 100.0) 99.8) Incorrect response False 3 6.4 0.0 1 7.7 I don't know 6 12.8 1 1.9 0.0 Client: TRIG Project: TIRFKAB Report Run Date and Time: 11/12/2012 5:05 PM Page 1 ofl 7 TABLE 7.1.3 PRIMARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #2 KEY RISK MESSAGE 2: PATIENTS SHOULD NOT TAKE TIRF MEDICINES IF THEY ARE NOT OPIOID TOLERANT. SUB-GROUP ANALYSIS 3: TIME TO COMPLETE SURVEY - INTERNET: S-3a - <10 min 0 S-3b - 10 to<20 S-3c - 220 min min Question S-3a S?3b S-min N=l3 (95% CI) (95% CI) (95% CI) Question 10: Please answer True, False, or I don?t know for the following statement: TIRF medicines should only be taken by patients who are opioid tolerant. ICSPOIISC Tme 40 85.1 52 100.0 13 100.0 (71.7. (93.2. (75.3. 93.8) 100.0) 100.0) Incorrect response False don't know 6 12.8 0 0.0 0 0.0 Question 11: Please answer True, False, or I don?t know for the following statements: 11a: Opioid tolerant means that a patient is already taking other opioid pain medicines around the clock and their mm 1' is used to these medicines. True 39 83.0 49 94.2 13 100.0 (69.2. (84.1. (75.3. 92.4) 98.8) 100.0) Inc01rect response False don't know 4 8.5 1 1.9 0 0.0 Client: TRIG Project: TIRFKAB Report Run Date and Time: 11/12/2012 5:06 PM Page 1 of 2 8 Question S?3a S?3b S?min N=l3 (95% CI) (95% CI) (95% CI) Question 12: Please answer True, False, or I don?t know for each statement about the TIRF medicine that was most recently prescribed for you. 12b: It is OK for patients to take TIRF medicines for headache pain. False 36 76.6 32 61.5 9 69.2 (62.0. (47.0. (38.6. 87.7) 74.7) 90.9) Incorrect response True 2 4.3 8 15.4 3 23.1 I don't know 9 19.1 12 23.1 1 7.7 Client: TRIG Project: TIRFKAB Report Run Date and Time: 11/12/2012 5:06 PM Page 2 of2 9 TABLE 7.2.3 SECONDARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #2 KEY RISK MESSAGE 2: PATIENTS SHOULD NOT TAKE TIRF MEDICINES IF THEY ARE NOT OPIOID TOLERANT. SUB-GROUP ANALYSIS 3: TIME TO COMPLETE SURVEY - INTERNET: 0 8?33 - <10 min 0 S-3b - 10 to<20 min 0 S-3c - 220 min S-3a S-3b S-Demonstrated Understandmg (95% (95% (95% CI) Cl) CI) 0 correct responses 2 4.3 0.0 0 0.0 1 correct response 6.4 3.8 0 0.0 2 correct responses 14 29.8 19 36.5 4 30.8 3 correct responses 28 59.6 31 59.6 9 69.2 Average number of correct responses 2.4 (2.1. 2.6 (2.2. 2.7 (1.9. 3.0) 3.0) 3.0) Client: TRIG Project: TIRFKAB Report Run Date and Time: 11/12/2012 5:08 PM Page 1 of TABLE 8.1.3 PRIMARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #3 RISK MESSAGE 3: TIRF MEDICINES SHOULD BE TAKEN EXACTLY AS PRESCRIBED BY THE HEALTHCARE PROVIDER. SUB-GROUP ANALYSIS 3: TIME TO COMPLETE SURVEY - INTERNET: S-3a - <10 min 0 S-3b - 10 to<20 min 0 S-3c - 220 min Question S?3a S?3b S?min N=l3 (95% CI) (95% CI) (95% CI) Question 11: Please answer True, False, or I don?t know for the following statements: 11b: If a patient stops taking around-the-clock opioid pain medicine, they must also stop taking the TIRF medicine. Correct response True 18 38.3 32 61.5 6 46.2 (24.5. (47.0. (19.2. 53.6) 74.7) 74.9) Incorrect response False 12 25.5 9 17.3 3 23.1 Idon't know 17 36.2 11 21.2 4 30.8 Question 12: Please answer True, False, or I don?t know for each statement about the TIRF medicine that was most recently prescribed for you. 12c: TIRF medicines should be taken exactly as prescribed by the doctor. True 47 100.0 52 100.0 13 100.0 (92.5. (93.2. (75.3. 100.0) 100.0) 100.0) Incorrect response False don't know 0 0.0 0 0.0 0 0.0 Client: TRIG Project: TIRFKAB Report Run Date and Time: 11/12/2012 5:11 PM Page 1 of 2 Question S?3a S?3b S?min N=l3 (95% CI) (95% CI) (95% CI) Question 16: Please answer True, False, or I don?t know for each statement about the TIRF medicine that was most recently prescribed for you. 16b: It is OK to take TIRF medicines for short-term pain that will go away in a few days. False 40 85.1 46 88.5 10 76.9 (71.7. (76.6. (46.2. 93.8) 95.6) 95.0) Incorrect response True 1 2.1 2 3.8 2 15.4 I don't know 6 12.8 4 7.7 1 7.7 Client: TRIG Project: TIRFKAB Report Run Date and Time: 11/12/2012 5:11 PM Page 2 of2 TABLE 8.2.3 SECONDARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #3 KEY RISK MESSAGE 3: TIRF MEDICINES SHOULD BE TAKEN EXACTLY AS PRESCRIBED BY THE HEALTHCARE PROVIDER. SUB-GROUP ANALYSIS 3: TIME TO COMPLETE SURVEY - INTERNET: S-3a - <10 min 0 S-3b - 10 to<20 min 0 S-3c - 220 min S-3a S-3b S-Demonstrated Understandmg (95% (95% (95% CI) CI) CI) 0 correct responses 0.0 0 0.0 0 0.0 1 correct response 12.8 3 5.8 2 15.4 2 correct responses 24 51.1 20 38.5 6 46.2 3 correct responses 17 36.2 29 55.8 5 38.5 Average number of correct responses 2.2 (1.9. 2.5 (2.1. 2.2 (1.5. 3.0) 3.0) 3.0) Client: TRIG Project: TIRF KAB Report Run Date and Time: 11/12/2012 5:13 PM Page 1 of TABLE 9.1.3 PRIMARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #4 RISK MESSAGE 4: PATIENTS SHOULD NOT SWITCH FROM A TIRF MEDICINE TO ANOTHER MEDICINE THAT CONTAINS FENTANY WITHOUT TALKING TO A HEALTHCARE PROVIDER. SUB-GROUP ANALYSIS 3: TIME TO COMPLETE SURVEY - INTERNET: 0 8?33 - <10 min 0 S-3b - 10 to<20 min 0 S-3c - 220 min Question S?3a S?3b S?min N=l3 (95% CI) (95% CI) (95% CI) Question 11: Please answer True, False, or I don?t know for the following statements: 11c: It is safe to switch to another medicine that contains fentanyl without talking to a healthcare provider ?rst False 45 95.7 52 100.0 13 100.0 (85.5. (93.2. (75.3. 99.5) 100.0) 100.0) Incorrect response True don't know 2 4.3 0 0.0 0 0.0 Client: TRIG Project: TIRFKAB Report Run Date and Time: 11/12/2012 5:15 PM Page 1 of TABLE 10.1.3 PRIMARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #5 KEY RISK MESSAGE 5: PATIENTS SHOULD NOT GIVE TIRF MEDICINES TO ANYONE ELSE EVEN IF THEY HAVE THE SAME SUB-GROUP ANALYSIS 3: TIME TO COMPLETE SURVEY - INTERNET: S-3a - <10 min 0 S-3b - 10 to<20 min 0 S-3c - 220 min Question S?3a S?3b S?min N=l3 (95% CI) (95% CI) (95% CI) Question 11: Please answer True, False, or I don?t know for the following statements: 11d: A patient may give TIRF medicines to another person if they have the same as the patient. Correct response False 47 100.0 52 100.0 13 100.0 (92.5. (93.2. (75.3. 100.0) 100.0) 100.0) Incorrect response True don't know 0 0.0 0 0.0 0 0.0 Question 16: Please answer True, False, or I don?t know for each statement about the TIRF medicine that was most recently prescribed for you. 16a: Selling or giving awav TIRF medicines is against the law. correct response True 46 97.9 52 100.0 12 92.3 (88.7. (93.2. (64.0. 99.9) 100.0) 99.8) Incorrect response False don't know 1 2.1 0 0.0 0 0.0 Client: TRIG Project: TIRFKAB Report Run Date and Time: 11/12/2012 5:18 PM Page 1 of TABLE 10.2.3 SECONDARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #5 KEY RISK MESSAGE 5: PATIENTS SHOULD NOT GIVE TIRF MEDICINES TO ANYONE ELSE EVEN IF THEY HAVE THE SAME SUB-GROUP ANALYSIS 3: TIME TO COMPLETE SURVEY - INTERNET: S-3a - <10 min 0 S-3b - 10 to<20 min 0 S-3c - 220 min S-3a S-3b S-Demonstrated Understandmg (95% (95% (95% CI) CI) CI) 0 correct responses correct response correct responses 46 97.9 52 100.0 12 92.3 Average nlunber of correct responses 2.0 (1.6. 2.0 (1.7. 1.9 (1.3. 2.0) 2.0) 2.0) Client: TRIG Project: TIRF KAB Report Run Date and Time: 11/12/2012 5:21 PM Page 1 of TABLE 11.1.3 PRIMARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #6 KEY RISK MESSAGE 6: TIRF MEDICINES SHOULD BE STORED IN A SAFE PLACE AWAY FROM CHILDREN AND PROPERLY DISPOSED. SUB-GROUP ANALYSIS 3: TIME TO COMPLETE SURVEY - INTERNET: S-3a - <10 min S-3b - 10 to<20 min S-3c - 220 min S?3a S?3b S?min Question N=l3 (95% CI) (95% CI) (95% CI) Question 12: Please answer True, False, or I don?t know for each statement about the TIRF medicine that was most recently prescribed for you. 12a: TIRF medicines should be stored in a safe place out of the reach of children. True 47 100.0 52 100.0 13 100.0 (92.5. (93.2. (75.3. 100.0) 100.0) 100.0) Incorrect response False 0.0 0.0 0.0 I don't know 0 0.0 0 0.0 0 0.0 Client: TRIG Project: TIRFKAB Report Run Date and Time: 11/12/2012 5:23 PM Page 1 of2 S?3a S?3b S?min Question N=l3 (95% CI) (95% CI) (95% CI) Question 16: Please answer True, False, or I don?t know for each statement about the TIRF medicine that was most recently prescribed for you. 16c: TIRF medicines must be disposed of as described in the speci?c product?s Medication Guide. Con?ect response True 45 95.7 49 94.2 13 100.0 (85.5. (84.1. (75.3. 99.5) 98.8) 100.0) Incorrect response False don't know 2 4.3 3 5.8 0 0.0 l6e: A TIRF medicine can cause an overdose and death in any child who takes it. Correct response True 44 93.6 46 88.5 12 92.3 (82.5. (76.6. (64.0. 98.7) 95.6) 99.8) Incorrect response False don't know 1 2.1 6 11.5 1 7.7 Question 13: What should you do if an adult who has not been prescribed a TIRF medicine takes a TIRF medicine? (Please select one.) Get emergency help 40 85.1 48 92.3 11 84.6 right away. (71.7. (81.5. (54.6. 93.8) 97.9) 98.1) Incorrect response Do nothing. 0 0.0 0 0.0 0 0.0 Wait an hour and see if 1 2.1 1 1.9 1 7.7 the person is OK. I don't know 6 12.8 3 5.8 1 7.7 Client: TRIG Project: TIRFKAB Report Run Date and Time: 11/12/2012 5:23 PM Page 2 of 2 TABLE 11.2.3 SECONDARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #6 KEY RISK MESSAGE 6: TIRF MEDICINES SHOULD BE STORED IN A SAFE PLACE AWAY FROM CHILDREN AND PROPERLY DISPOSED. SUB-GROUP ANALYSIS 3: TIME TO COMPLETE SURVEY - INTERNET: S-3a - <10 min 0 S-3b - 10 to<20 min 0 S?3c - 220 min S-3a S-3b S-Demonstrated (95% (95% (95% CI) CI) CI) 0 correct responses correct response 0 0.0 0 0.0 0.0 2 correct responses correct responses 4 8.5 11 21.2 1 7.7 4 correct responses 39 83.0 40 76.9 11 84.6 Average number of correct responses 3.7 (3.3. 3.8 (3.3. 3.8 (2.9. 4.0) 4.0) 4.0) Client: TRIG Project: TIRF KAB Report Run Date and Time: 11/12/2012 5:26 PM Page 1 of TABLE 6.1.4 PRIMARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #1 KEY RISK MESSAGE l: TIRF MEDICINES CAN CAUSE LIFE-THREATENING BREATHING PROBLEMS THAT CAN LEAD TO DEATH. SUB-GROUP ANALYSIS 4: TIME TO COMPLETE SURVEY - TELEPHONE S-4a - <10 min 0 S-S-4c - 220 min S?4a S?4b S?min Question (95% CI) (95% CI) (95% CI) Question 12: Please answer True, False, or I don?t know for each statement about the TIRF medicine that was most recently prescribed for you. 12d: TIRF medicines can cause life?threatening breathing problems that can lead to death. Correct response True 2 100.0 56 90.3 14 87.5 (15.8. (80.1. (61.7. 100.0) 96.4) 98.4) Incorrect response False don't know 0 0.0 5 8.1 2 12.5 Client: TRIG Project: TIRF KAB Report Run Date and Time: 11/19/2012 10:54 ANI Page 1 of TABLE 7.1.4 PRIMARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #2 KEY RISK MESSAGE 2: PATIENTS SHOULD NOT TAKE TIRF MEDICINES IF THEY ARE NOT OPIOID TOLERANT. SUB-GROUP ANALYSIS 4: TIME TO COMPLETE SURVEY - TELEPHONE S-4a - <10 min 0 S-S-4c - 220 min S?4a S?4b S?min Question (95% CI) (95% CI) (95% CI) Question 10: Please answer True, False, or I don?t know for the following statement: TIRF medicines should onlv be taken bV patients who are opioid tolerant. True 2 100.0 52 83.9 15 93.8 (15.8. (72.3. (69.8. 100.0) 92.0) 99.8) Incorrect response False don't know 0 0.0 6 9.7 1 6.3 Question 11: Please answer True, False, or I don?t know for the following statements: 11a: Opioid tolerant means that a patient is already taking other opioid pain medicines around the clock and their bodv is used to these medicines. Con?ect response True 2 100.0 58 93.5 15 93.8 (15.8. (84.3. (69.8. 100.0) 98.2) 99.8) Inconect response False 0.0 1 1.6 0.0 I don't know 0 0.0 3 4.8 1 6.3 Client: TRIG Project: TIRFKAB Report Run Date and Time: 11/19/2012 10:54 ANI Page 1 of 2 Question S?4a S?4b S?min N=l6 (95% CI) (95% CI) (95% CI) Question 12: Please answer True, False, or I don?t know for each statement about the TIRF medicine that was most recently prescribed for you. 12b: It is OK for patients to take TIRF medicines for headache pain. False 2 100.0 45 72.6 12 75.0 (15.8. (59.8. (47.6. 100.0) 83.1) 92.7) Incorrect response True don't know 0 0.0 14 22.6 3 18.8 Client: TRIG Project: TIRFKAB Report Run Date and Time: 11/19/2012 10:54 AM Page 2 of2 TABLE 7.2.4 SECONDARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #2 KEY RISK MESSAGE 2: PATIENTS SHOULD NOT TAKE TIRF MEDICINES IF THEY ARE NOT OPIOID TOLERANT. SUB-GROUP ANALYSIS 4: TIME TO COMPLETE SURVEY - TELEPHONE S-4a - <10 min 0 S-S-4c - 220 min S?4a S-4b S-Demonstrated (95% (95% (95% CI) CI) CI) 0 correct responses 0 0.0 1 1.6 0.0 1 correct response 0 0.0 5 8.1 0.0 2 correct responses 0 0.0 18 29.0 37.5 3 correct responses 2 100.0 38 61.3 10 62.5 Average number of correct responses 3.0 (1.0. 2.5 (2.2. 2.6 (2.0. 3.0) 3.0) 3.0) Client: TRIG Project: TIRFKAB Report Run Date and Time: 11/19/2012 10:57 ANI Page 1 of TABLE 8.1.4 PRIMARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #3 RISK MESSAGE 3: TIRF MEDICINES SHOULD BE TAKEN EXACTLY AS PRESCRIBED BY THE HEALTHCARE PROVIDER. SUB-GROUP ANALYSIS 4: TIME TO COMPLETE SURVEY - TELEPHONE S-4a - <10 min 0 S-S-4c - 220 min Question S?4a S?4b S?min (95% CI) (95% CI) (95% CI) Question 11: Please answer True, False, or I don?t know for the following statements: 11b: If a patient stops taking around-the-clock opioid pain medicine, they must also stop taking the TIRF medicine. Cou'ect response True 1 50.0 22 35.5 3 18.8 (1.3. 98.7) (23.7. (4.0. 45.6) 48.7) Incouect response False 1 50.0 17 27.4 5 31.3 Idon't know 0 0.0 23 37.1 8 50.0 Question 12: Please answer True, False, or I don?t know for each statement about the TIRF medicine that was most recently prescribed for you. 12c: TIRF medicines should be taken exactly as prescribed by the doctor. correct response True 2 100.0 62 100.0 16 100.0 (15.8. (94.2. (79.4. 100.0) 100.0) 100.0) Incorrect response False don't know 0 0.0 0 0.0 0 0.0 Client: TRIG Project: TIRFKAB Report Run Date and Time: 11/19/2012 10:57 ANI Page 1 of 2 Question S?4a S?4b S?min N=l6 (95% CI) (95% CI) (95% CI) Question 16: Please answer True, False, or I don?t know for each statement about the TIRF medicine that was most recently prescribed for you. 16b: It is OK to take TIRF medicines for short-term pain that will go away in a few days. False 1 50.0 49 79.0 12 75.0 (1.3. 98.7) (66.8. (47.6. 88.3) 92.7) True 1 50.0 4 6.5 0 0.0 I don't know 0 0.0 9 14.5 4 25.0 Client: TRIG Project: TIRFKAB Report Run Date and Time: 11/19/2012 10:57 AM Page 2 of2 TABLE 8.2.4 SECONDARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #3 KEY RISK MESSAGE 3: TIRF MEDICINES SHOULD BE TAKEN EXACTLY AS PRESCRIBED BY THE HEALTHCARE PROVIDER. SUB-GROUP ANALYSIS 4: TIME TO COMPLETE SURVEY - TELEPHONE S-4a - <10 min 0 S-S-4c - 220 min S?4a S-4b S?N=l6 Demonstrated Understandmg (95% (95% (95% CI) CI) CI) 0 correct responses correct response 0 0.0 12 19.4 4 25.0 2 correct responses 2 100.0 29 46.8 9 56.3 3 correct responses 0 0.0 21 33.9 3 18.8 Average number of correct responses 2.0 (0.4. 2.1 (1.8. 1.9 (1.4. 3.0) 3.0) 3.0) Client: TRIG Project: TIRF KAB Report Run Date and Time: 11/19/2012 10:54 ANI Page 1 of TABLE 9.1.4 PRIMARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #4 RISK MESSAGE 4: PATIENTS SHOULD NOT SWITCH FROM A TIRF MEDICINE TO ANOTHER MEDICINE THAT CONTAINS FENTANY WITHOUT TALKING TO A HEALTHCARE PROVIDER. SUB-GROUP ANALYSIS 4: TIME TO COMPLETE SURVEY - TELEPHONE S-4a - <10 min 0 S-S-4c - 220 min Question S?4a S?4b S?min (95% CI) (95% CI) (95% CI) Question 11: Please answer True, False, or I don?t know for the following statements: 11c: It is safe to switch to another medicine that contains fentanyl without talking to a healthcare provider ?rst False 2 100.0 59 95.2 15 93.8 (15.8. (86.5. (69.8. 100.0) 99.0) 99.8) Incorrect response True don't know 0 0.0 3 4.8 0 0.0 Client: TRIG Project: TIRFKAB Report Run Date and Time: 11/19/2012 10:56 ANI Page 1 of TABLE 10.1.4 PRIMARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #5 KEY RISK MESSAGE 5: PATIENTS SHOULD NOT GIVE TIRF MEDICINES TO ANYONE ELSE EVEN IF THEY HAVE THE SAME SUB-GROUP ANALYSIS 4: TIME TO COMPLETE SURVEY - TELEPHONE S-4a - <10 min 0 S-S-4c - 220 min Question S-min N=l6 (95% CI) (95% CI) (95% CI) Question 11: Please answer True, False, or I don?t know for the following statements: 11d: A patient may give TIRF medicines to another person if they have the same as the patient. Correct response False 2 100.0 62 100.0 16 100.0 (15.8. (94.2. (79.4. 100.0) 100.0) 100.0) Incorrect response True don't know 0 0.0 0 0.0 0 0.0 Question 16: Please answer True, False, or I don?t know for each statement about the TIRF medicine that was most recently prescribed for you. 16a: Selling or giving away TIRF medicines is against the law. correct response True 2 100.0 60 96.8 16 100.0 (15.8. (88.8. (79.4. 100.0) 99.6) 100.0) Incorrect response False don't know 0 0.0 0 0.0 0 0.0 Client: TRIG Project: TIRFKAB Report Run Date and Time: 11/19/2012 10:55 ANI Page 1 of 1 TABLE 10.2.4 SECONDARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #5 KEY RISK MESSAGE 5: PATIENTS SHOULD NOT GIVE TIRF MEDICINES TO ANYONE ELSE EVEN IF THEY HAVE THE SAME SUB-GROUP ANALYSIS 4: TIME TO COMPLETE SURVEY - TELEPHONE S-4a - <10 min 0 S-S-4c - 220 min S-4b S-Demonstrated Understandmg (95% (95% (95% CI) CI) CI) 0 correct responses 0 0.0 0 0.0 0.0 1 correct response 0 0.0 2 3.2 0.0 2 correct responses 100.0 60 96.8 16 100.0 Average nlunber of correct responses 2.0 (0.4. 2.0 (1.7. 2.0 (1.4. 2.0) 2.0) 2.0) Client: TRIG Project: TIRFKAB Report Run Date and Time: 11/19/2012 10:56 AM Page 1 of TABLE 11.1.4 PRIMARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #6 KEY RISK MESSAGE 6: TIRF MEDICINES SHOULD BE STORED IN A SAFE PLACE AWAY FROM CHILDREN AND PROPERLY DISPOSED. SUB-GROUP ANALYSIS 4: TIME TO COMPLETE SURVEY - TELEPHONE S-4a - <10 min 0 S?S-4c - 220 min S-4a S?4b S?min Question N=l6 (95% CI) (95% CI) (95% CI) Question 12: Please answer True, False, or I don?t know for each statement about the TIRF medicine that was most recently prescribed for you. 12a: TIRF medicines should be stored in a safe place out of the reach of children. Correct response True 2 100.0 62 100.0 16 100.0 (15.8. (94.2. (79.4. 100.0) 100.0) 100.0) Incorrect response False 0.0 0.0 0.0 I don't know 0 0.0 0 0.0 0 0.0 Client: TRIG Project: TIRFKAB Report Run Date and Time: 11/19/2012 10:55 ANI Page 1 of2 S?4a S?4b S?min Question N=l6 (95% CI) (95% CI) (95% CI) Question 16: Please answer True, False, or I don?t know for each statement about the TIRF medicine that was most recently prescribed for you. 16c: TIRF medicines must be disposed of as described in the speci?c product?s Medication Guide. Correct response True 2 100.0 59 95.2 16 100.0 (15.8. (86.5. (79.4. 100.0) 99.0) 100.0) Incorrect response False don't know 0 0.0 1 1.6 0 0.0 l6e: A TIRF medicine can cause an overdose and death in any child who takes it. Correct response True 2 100.0 56 90.3 14 87.5 (15.8. (80.1. (61.7. 100.0) 96.4) 98.4) Incorrect response False don't know 0 0.0 5 8.1 1 6.3 Question 13: What should you do if an adult who has not been prescribed a TIRF medicine takes a TIRF medicine? (Please select one.) Correct response Get emergency help 2 100.0 54 87.1 16 100.0 right away. (15.8. (76.1. (79.4. 100.0) 94.3) 100.0) Incorrect response Do nothing. 0 0.0 0 0.0 0 0.0 Wait an hour and see if 0 0.0 3 4.8 0 0.0 the person is OK. I don't know 0 0.0 5 8.1 0 0.0 Client: TRIG Project: TIRFKAB Report Run Date and Time: 11/19/2012 10:55 AM Page 2 of 2 TABLE 11.2.4 SECONDARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #6 KEY RISK MESSAGE 6: TIRF MEDICINES SHOULD BE STORED IN A SAFE PLACE AWAY FROM CHILDREN AND PROPERLY DISPOSED. SUB-GROUP ANALYSIS 4: TIME TO COMPLETE SURVEY - TELEPHONE S-4a - <10 min 0 S-S-4c - 220 min S-4a S-4b S?Demonstrated Understanding (95% (95% (95% CI) CI) CI) 0 correct responses 0 0.0 0.0 0 0.0 1 correct response correct responses correct responses 0 0.0 15 24.2 2 12.5 4 correct responses 2 100.0 46 74.2 14 87.5 Average number of correct responses 4.0 (1.7. 3.7 (3.3. 3.9 (3.1. 4.0) 4.0) 4.0) Client: TRIG Project: TIRF KAB Report Run Date and Time: 11/19/2012 10:56 ANI Page 1 of TABLE 6.1.5 PRIMARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #1 KEY RISK MESSAGE l: TIRF MEDICINES CAN CAUSE LIFE-THREATENING BREATHING PROBLEMS THAT CAN LEAD TO DEATH. SUB-GROUP ANALYSIS 5: MODALITY TO COMPLETE SURVEY - Internet 0 S-5b - Telephone S?5a Internet Telephone Question N=l 2 (95% C1) (95% CI) Question 12: Please answer True, False, or I don?t know for each statement about the TIRF medicine that was most recently prescribed for you. 12d: TIRF medicines can cause life?threatening breathing problems that can lead to death. Correct response True 101 90.2 72 90.0 (83.1. 95.0) (81.2. 95.6) Incorrect response False 4 3.6 1 1.3 I don?t know 7 6.3 7 8.8 Client: TRIG Project: TIRF KAB Report Run Date and Time: 11/9/2012 2:03 PM Page 1 of 1 TABLE 7.1.5 PRIMARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #2 KEY RISK MESSAGE 2: PATIENTS SHOULD NOT TAKE TIRF MEDICINES IF THEY ARE NOT OPIOID TOLERANT. SUB-GROUP ANALYSIS 5: MODALITY TO COMPLETE SURVEY - Internet 0 Telephone Question Internet Telephone (95% CI) (95% CI) Question 10: Please answer True, False, or I don?t know for the following statement: TIRF medicines should only be taken by patients who are opioid tolerant. correct response Tnle 105 93.8 69 86.3 (87.5. 97.5) (76.7. 92.9) Incorrect response False 0.9 4 5.0 I don't know 6 5.4 7 8.8 Question 11: Please answer True, False, or I don?t know for the following statements: 11a: Opioid tolerant means that a patient is already taking other opioid pain medicines around the clock and their body is used to these medicines. correct response Tnle 101 90.2 75 93.8 (83.1. 95.0) (86.0. 97.9) Incorrect response False 6 5.4 1 1.3 I don't know 5 4.5 4 5.0 Client: TRIG Project: TIRFKAB Report Run Date and Time: 11/9/2012 2:08 PM Page 1 of2 Question Internet Telephone (95% CI) (95% CI) Question 12: Please answer True, False, or I don?t know for each statement about the TIRF medicine that was most recently prescribed for you. 12b: It is OK for patients to take TIRF medicines for headache pain. False 77 68.8 59 73.8 (59.3. 77.2) (62.7. 83.0) Incorrect response Tme 13 11.6 4 5.0 I don't know 22 19.6 17 21.3 Client: TRIG Project: TIRFKAB Report Run Date and Time: 11/9/2012 2:08 PM Page 2 of 2 TABLE 7.2.5 SECONDARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #2 KEY RISK MESSAGE 2: PATIENTS SHOULD NOT TAKE TIRF MEDICINES IF THEY ARE NOT OPIOID TOLERANT. SUB-GROUP ANALYSIS 5: MODALITY TO COMPLETE SURVEY 0 8-521 - Internet 0 S-5b Telephone S-5a S-5b Internet Telephone . Demonstrated Understanding (95% (95% CI) CI) 0 correct responses 2 1.8 1.3 1 con?ect response 5 4.5 5 6.3 2 correct responses 37 33.0 24 30.0 3 correct responses 68 60.7 50 62.5 Average munber of correct responses 2.5 (2.3. 3.0) 2.5 (2.2. 3.0) Client: TRIG Project: TIRF KAB Report Run Date and Time: 11/9/2012 2:47 PM Page 1 of TABLE 8.1.5 PRIMARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #3 RISK MESSAGE 3: TIRF MEDICINES SHOULD BE TAKEN EXACTLY AS PRESCRIBED BY THE HEALTHCARE PROVIDER. SUB-GROUP ANALYSIS 5: MODALITY TO COMPLETE SURVEY - Internet 0 S-5b Telephone S?5b Internet Telephone Question N=l 1 2 (95% CI) (95% CI) Question 11: Please answer True, False, or I don?t know for the following statements: 11b: If a patient stops taking around?the-clock opioid pain medicine, they must also stop taking the TIRF medicine. Correct response Tme 56 50.0 26 32.5 (40.4. 59.6) (22.4. 43.9) Incorrect response False 24 21.4 23 28.8 I don't know 32 28.6 31 38.8 Question 12: Please answer True, False, or I don?t know for each statement about the TIRF medicine that was most recently prescribed for you. 12c: TIRF medicines should be taken exactly as prescribed by the doctor. Correct response Tme 112 100.0 80 100.0 (96.8. 100.0) (95.5. 100.0) Incorrect response False 0 0.0 0 0.0 I don't know 0 0.0 0 0.0 Client: TRIG Project: TIRF KAB Report Run Date and Time: 11/9/2012 2:15 PM Page 1 of 2 S?5b Internet Telephone Question N=l 1 2 (95% CI) (95% CI) Question 16: Please answer True, False, or I don?t know for each statement about the TIRF medicine that was most recently prescribed for you. 16b: It is OK to take TIRF medicines for short-term pain that will go away in a few days. Con?ect response False 96 85.7 62 77.5 (77.8. 91.6) (66.8. 86.1) Incorrect response True 5 4.5 5 6.3 I don't know 11 9.8 13 16.3 Client: TRIG Project: TIRF KAB Report Run Date and Time: 11/9/2012 2:15 PM Page 2 of 2 TABLE 8.2.5 SECONDARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #3 KEY RISK MESSAGE 3: TIRF MEDICINES SHOULD BE TAKEN EXACTLY AS PRESCRIBED BY THE HEALTHCARE PROVIDER. SUB-GROUP ANALYSIS 5: MODALITY TO COMPLETE SURVEY - Internet 0 S-5b Telephone Internet Telephone Demonstrated Understanding (95% (95% CI) CI) 0 correct responses 0 0.0 0 0.0 1 correct response 11 9.8 16 20.0 2 correct responses 50 44.6 40 50.0 3 correct responses 51 45.5 24 30.0 Average number of correct responses 2.4 (2.1. 3.0) 2.1 (1.8. 3.0) Client: TRIG Project: TIRF KAB Report Run Date and Time: 11/9/2012 2:16 PM Page 1 of 1 TABLE 9.1.5 KEY RISK MESSAGE #4 PRIMARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO RISK MESSAGE 4: PATIENTS SHOULD NOT SWITCH FROM A TIRF MEDICINE TO ANOTHER MEDICINE THAT CONTAINS FENTANY WITHOUT TALKING TO A HEALTHCARE PROVIDER. SUB-GROUP ANALYSIS 5: MODALITY TO COMPLETE SURVEY - Internet 0 Telephone Question S-5b Internet Telephone (95% CI) (95% CI) Question 11: Please answer True, False, or I don?t know for the following statements: provider ?rst 11c: It is safe to switch to another medicine that contains fentanyl without talking to a healthcare correct response False 110 98.2 76 95.0 (93.7. 99.8) (87.7. 98.6) Incouect response True 0 0.0 1 1.3 I don't know 2 1.8 3 3.8 Client: TRIG Project: TIRFKAB Report Run Date and Time: 11/9/2012 2:19 PM Page 1 of 1 TABLE 10.1.5 PRIMARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #5 KEY RISK MESSAGE 5: PATIENTS SHOULD NOT GIVE TIRF MEDICINES TO ANYONE ELSE EVEN IF THEY HAVE THE SAME SUB-GROUP ANALYSIS 5: MODALITY TO COMPLETE SURVEY S-5a - Internet 0 - Telephone S?5a S?5b Internet Telephone Question N=l 2 (95% CI) (95% CI) Question 11: Please answer True, False, or I don?t know for the following statements: 11d: A patient may give TIRF medicines to another person if they have the same as the patient. Correct response False 112 100.0 80 100.0 (96.8. 100.0) (95.5. 100.0) Incorrect response True 0 0.0 0 0.0 I don't know 0 0.0 0 0.0 Question 16: Please answer True, False, or I don?t know for each statement about the TIRF medicine that was most recently prescribed for you. 16a: Selling or giving away TIRF medicines is against the law. C01rect response True 110 98.2 78 97.5 (93.7. 99.8) (91.3. 99.7) Incorrect response False 1 0.9 2 2.5 I don't know 1 0.9 0 0.0 Client: TRIG Project: TIRF KAB Report Run Date and Time: 11/9/2012 2:24 PM Page 1 of 1 TABLE 10.2.5 SECONDARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #5 KEY RISK MESSAGE 5: PATIENTS SHOULD NOT GIVE TIRF MEDICINES TO ANYONE ELSE EVEN IF THEY HAVE THE SAME SUB-GROUP ANALYSIS 5: MODALITY TO COMPLETE SURVEY - Internet S-5b - Telephone S-5a S-5b Internet Telephone Demonstrated Understanding A: (95% (95% CI) CI) 0 correct responses 0 0.0 0 0.0 1 correct response 2 1.8 2 2.5 2 correct responses 110 98.2 78 97.5 Average number of correct responses 2.0 (1.8. 2.0) 2.0 (1.7. 2.0) Client: TRIG Project: TIRFKAB Report Run Date and Time: 11/9/2012 2:27 PM Page 1 of TABLE 11.1.5 PRIMARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #6 KEY RISK MESSAGE 6: TIRF MEDICINES SHOULD BE STORED IN A SAFE PLACE AWAY FROM CHILDREN AND PROPERLY DISPOSED. SUB-GROUP ANALYSIS 5: MODALITY TO COMPLETE SURVEY - Internet 0 Telephone S-5a S?5b Internet Telephone Question (95% CI) (95% CI) Question 12: Please answer True, False, or I don?t know for each statement about the TIRF medicine that was most recently prescribed for you. 12a: TIRF medicines should be stored in a safe place out of the reach of children. Correct response True 112 100.0 80 100.0 (96.8. 100.0) (95.5. 100.0) Incouect response False 0 0.0 0 0.0 I don't know 0 0.0 0 0.0 Question 16: Please answer True, False, or I don?t know for each statement about the TIRF medicine that was most recently prescribed for you. 16c: TIRF medicines must be disposed of as described in the specific product?s Medication Guide. correct response Tme 107 95.5 77 96.3 (89.9. 98.5) (89.4. 99.2) Inconect response False 0 0.0 2 2.5 I don't know 5 4.5 1 1.3 l6e: A TIRF medicine can cause an overdose and death in any child who takes it. ICSPOIISC Tme 102 91.1 72 90.0 (84.2. 95.6) (81.2. 95.6) Incorrect response False 2 1.8 2 2.5 I don't know 8 7.1 6 7.5 Client: TRIG Project: TIRF KAB Report Run Date and Time: 11/9/2012 3:02 PM Page 1 of 2 Internet Telephone Question (95% CI) (95% CI) Question 13: What should you do if an adult who has not been prescribed a TIRF medicine takes a TIRF medicine? (Please select one.) Correct response Get emergency help right away. 99 88.4 72 90.0 (81.0. 93.7) (81.2. 95.6) Incorrect response Do nothing. 0 0.0 0 0.0 Wait an hour and see if the 3 2.7 3 3.8 person is OK. I don't know 10 8.9 5 6.3 Client: TRIG Project: TIRFKAB Report Run Date and Time: 11/9/2012 3:02 PM Page 2 of2 TABLE 11.2.5 SECONDARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #6 KEY RISK MESSAGE 6: TIRF MEDICINES SHOULD BE STORED IN A SAFE PLACE AWAY FROM CHILDREN AND PROPERLY DISPOSED. SUB-GROUP ANALYSIS 5: MODALITY TO COMPLETE SURVEY - Internet 0 S-5b - Telephone S-5b Internet Telephone Demonstrated Understanding ?y /o (95% (95% CI) CI) 0 correct responses 0 0.0 0 0.0 1 correct response 0 0.0 0 0.0 2 correct responses 6 5.4 1.3 3 correct responses 16 14.3 17 21.3 4 correct responses 90 80.4 62 77.5 Average number of correct responses 3.8 (3.5. 4.0) 3.8 (3.4. 4.0) Client: TRIG Project: TIRF KAB Report Run Date and Time: 11/19/2012 11:22 ANI Page 1 of TABLE 6.1.6 PRIMARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #1 KEY RISK MESSAGE l: TIRF MEDICINES CAN CAUSE LIFE-THREATENING BREATHING PROBLEMS THAT CAN LEAD TO DEATH. SUB-GROUP ANALYSIS 6: HIGHEST LEVEL OF EDUCATION (QUESTION 36): S-6a Less than, Some, or High school graduate/GED or prefer not to answer S-6b - Some college or associate degree S-6c - Bachelor?s degree or Master?s degree S-6d - Professional or Doctoral degree S?6a S?b Baclsne?r or S-6d High School Some college Doctoral degree Mas? Question (95% (95% (95% (95% C1) C1) CI) CI) Question 12: Please answer True, False, or I don?t know for each statement about the TIRF medicine that was most recently prescribed for you. 12d: TIRF medicines can cause life-threatening breathing problems that can lead to death. correct response Tme 35 89.7 72 90.0 59 89.4 7 100.0 (75.8. (81.2. (79.4. (59.0. 97.1) 95.6) 95.6) 100.0) Incouect response False don't know 4 10.3 6.3 5 7.6 0 0.0 Client: TRIG Project: TIRFKAB Report Run Date and Time: 11/9/2012 3:18 PM Page 1 of 1 TABLE 7.1.6 PRIMARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #2 KEY RISK MESSAGE 2: PATIENTS SHOULD NOT TAKE TIRF MEDICINES IF THEY ARE NOT OPIOID TOLERANT. SUB-GROUP ANALYSIS 6: HIGHEST LEVEL OF EDUCATION (QUESTION 36): S-6a Less than, Some, or High school graduate/GED or prefer not to answer S-6b - Some college or associate degree S-6c - Bachelor?s degree or Master?s degree S-6d - Professional or Doctoral degree 8?61! S?6b BaclsleIzr or ?d High School Some college Doctoral degree Mas? Question (95% (95% (95% (95% CI) CI) CI) CI) Question 10: Please answer True, False, or I don?t know for the following statement: TIRF medicines should only be taken by patients who are opioid tolerant. Con?ect response True 32 82.1 74 92.5 61 92.4 7 100.0 (66.5. (84.4. (83.2. (59.0. 92.5) 97.2) 97.5) 100.0) Inconect response False 2don't know 6 15.4 3 3.8 4 6.1 0 0.0 Question 11: Please answer True, False, or I don?t know for the following statements: 11a: Opioid tolerant means that a patient is already taking other opioid pain medicines around the clock and their bodv is used to these medicines. True 37 94.9 72 90.0 61 92.4 6 85.7 (82.7. (81.2. (83.2. (42.1. 99.4) 95.6) 97.5) 99.6) Inconect response False don't know 1 2.6 6.3 3.0 1 14.3 Client: TRIG Project: TIRFKAB Report Run Date and Time: 11/9/2012 3:23 PM Page 1 of 2 S?6c S?6b Bachelor or High School Some college Doctoral degree Mas? Question (95% (95% (95% (95% CI) CI) C1) C1) Question 12: Please answer True, False, or I don?t know for each statement about the TIRF medicine that was most recently prescribed for you. 12b: It is OK for patients to take TIRF medicines for headache pain. Con?ect response False 28 71.8 57 71.3 46 69.7 5 71.4 (55.1. (60.0. (57.1. (29.0. 85.0) 80.8) 80.4) 96.3) True 4 10.3 7 8.8 5 7.6 1 14.3 I don't know 7 17.9 16 20.0 15 22.7 1 14.3 Client: TRIG Project: TIRFKAB Report Run Date and Time: 11/9/2012 3:23 PM Page 2 of 2 TABLE 7.2.6 SECONDARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #2 KEY RISK MESSAGE 2: PATIENTS SHOULD NOT TAKE TIRF MEDICINES IF THEY ARE NOT OPIOID TOLERANT. SUB-GROUP ANALYSIS 6: HIGHEST LEVEL OF EDUCATION (QUESTION 36): S-6a Less than, Some, or High school graduate/GED or prefer not to answer S-6b - Some college or associate degree S-6c - Bachelor?s degree or Master?s degree S-6d - Professional or Doctoral degree 8- 6a S-6b S-6c S-6d . Bachelor or Doctoral High School Some college =80 aster degree Demonstrated Understanding (95% (95% (95% (95% CI) C1) C1) CI) 0 correct responses correct response 14.3 2 correct responses 14 35.9 28 35.0 18 27.3 1 14.3 3 correct responses 22 56.4 48 60.0 43 65.2 5 71.4 Average number of correct 2.5 (2.1. 2.5 (2.2. 2.5 (2.2. 2.6 (1.6. responses 3.0) 3.0) 3.0) 3.0) Client: TRIG Project: TIRFKAB Report Run Date and Time: 11/9/2012 3:27 PM Page 1 of TABLE 8.1.6 PRIMARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #3 RISK MESSAGE 3: TIRF MEDICINES SHOULD BE TAKEN EXACTLY AS PRESCRIBED BY THE HEALTHCARE PROVIDER. SUB-GROUP ANALYSIS 6: HIGHEST LEVEL OF EDUCATION (QUESTION 36): S-6a Less than, Some, or High school graduate/GED or prefer not to answer S-6b - Some college or associate degree S-6c - Bachelor?s degree or Master?s degree S-6d - Professional or Doctoral degree S-6a 8?61) or High School Some college Doctoral degree Mas? Question (95% (95% (95% (95% CI) CI) CI) CI) Question 11: Please answer True, False, or I don?t know for the following statements: 11b: If a patient stops taking around-the-clock opioid pain medicine, they must also stop taking the TIRF medicine. Con'ect response Tme 12 30.8 39 48.8 27 40.9 4 57.1 (17.0. (37.4. (29.0. (18.4. 47.6) 60.2) 53.7) 90.1) Incorrect response False 10 25.6 19 23.8 16 24.2 2 28.6 I don?t know 17 43.6 22 27.5 23 34.8 1 14.3 Question 12: Please answer True, False, or I don?t know for each statement about the TIRF medicine that was most recently prescribed for you. 12c: TIRF medicines should be taken exactlv as prescribed bV the doctor. True 39 100.0 80 100.0 66 100.0 7 100.0 (91.0. (95.5. (94.6. (59.0. 100.0) 100.0) 100.0) 100.0) Incorrect response False don't know 0 0.0 0 0.0 0 0.0 0.0 Client: TRIG Project: TIRFKAB Report Run Date and Time: 11/9/2012 3:43 PM Page 1 of 2 S?6c S?6a 8?61) Bachelor or 84? High School Some college Doctoral degree Mas? Question (95% (95% (95% (95% CD CD CD CD Question 16: Please answer True, False, or I don?t know for each statement about the TIRF medicine that was most recently prescribed for you. 16b: It is OK to take TIRF medicines for short?term pain that will go away in a few days. Correct response False 29 74.4 70 87.5 54 81.8 5 71.4 (57.9. (78.2. (70.4. (29.0. 87.0) 93.8) 90.2) 96.3) Incorrect response Tme don't know 8 20.5 8.8 10.6 2 28.6 Client: TRIG Project: TIRFKAB Report Run Date and Time: 11/9/2012 3:43 PM Page 2 of 2 TABLE 8.2.6 SECONDARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #3 KEY RISK MESSAGE 3: TIRF MEDICINES SHOULD BE TAKEN EXACTLY AS PRESCRIBED BY THE HEALTHCARE PROVIDER. SUB-GROUP ANALYSIS 6: HIGHEST LEVEL OF EDUCATION (QUESTION 36): S-6a Less than, Some, or High school graduate/GED or prefer not to answer S-6b - Some college or associate degree S-6c - Bachelor?s degree or Master?s degree S-6d - Professional or Doctoral degree S- 6a S- 6b S-6c S-6d High School Some college Bachelor or Doctoral =80 Master degree Demonstrated Understanding (95% (95% (95% (95% CI) CI) CI) CI) 0 correct responses correct response 8 20.5 8 10.0 9 13.6 2 28.6 2 correct responses 21 53.8 35 43.8 33 50.0 1 14.3 3 correct responses 10 25.6 37 46.3 24 36.4 4 57.1 Average number of correct 2.1 (1.7. 2.4 (2.1. 2.2 (1.9. 2.3 (1.3. responses 3 .0) 3.0) 3.0) 3.0) Client: TRIG Project: TIRFKAB Report Run Date and Time: 11/9/2012 3:42 PM Page 1 of 1 TABLE 9.1.6 PRIMARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #4 RISK MESSAGE 4: PATIENTS SHOULD NOT SWITCH FROM A TIRF MEDICINE TO ANOTHER MEDICINE THAT CONTAINS FENTANY WITHOUT TALKING TO A HEALTHCARE PROVIDER. SUB-GROUP ANALYSIS 6: HIGHEST LEVEL OF EDUCATION (QUESTION 36): S-6a Less than, Some, or High school graduate/GED or prefer not to answer S-6b - Some college or associate degree S-6c - Bachelor?s degree or Master?s degree S-6d - Professional or Doctoral degree S-6c 8-63 Bachelor or High School Some college Doctoral degree Mam" Question (95% (95% (95% (95% C1) C1) CI) CI) Question 11: Please answer True, False, or I don?t know for the following statements: 11c: It is safe to switch to another medicine that contains fentanyl without talking to a healthcare provider ?rst Con?ect response False 36 92.3 78 97.5 65 98.5 7 100.0 (79.1. (91.3. (91.8. (59.0. 98.4) 99.7) 100.0) 100.0) True don't know 0.0 Client: TRIG Project: TIRFKAB Report Run Date and Time: 11/9/2012 3:49 PM Page 1 of 1 TABLE 10.1.6 PRIMARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #5 KEY RISK MESSAGE 5: PATIENTS SHOULD NOT GIVE TIRF MEDICINES TO ANYONE ELSE EVEN IF THEY HAVE THE SAME SYNIPTOMS. SUB-GROUP ANALYSIS 6: HIGHEST LEVEL OF EDUCATION (QUESTION 36): S-6d - Professional or Doctoral degree S-6a Less than, Some, or High school graduate/GED or prefer not to answer S-6b - Some college or associate degree S-6c - Bachelor?s degree or Master?s degree S?6a S?6b mass; or S?6d High School Some college Doctoral degree Mas?" Question (95% (95% (95% (95% CI) CI) CI) CI) Question 11: Please answer True, False, or I don?t know for the following statements: 11d: A patient may give TIRF medicines to another person if they have the same as the patient. Con'ect response False 39 100.0 80 100.0 66 100.0 7 100.0 (91.0. (95.5. (94.6. (59.0. 100.0) 100.0) 100.0) 100.0) Incorrect response True don't know 0 0.0 0.0 0.0 0.0 Question 16: Please answer True, False, or I don?t know for each statement about the TIRF medicine that was most recently prescribed for you. 16a: Selling or giving away TIRF medicines is against the law. Correct response True 39 100.0 78 97.5 64 97.0 7 100.0 (91.0. (91.3. (89.5. (59.0. 100.0) 99.7) 99.6) 100.0) Inc01rect response False don't know 0.0 Client: TRIG Project: TIRF KAB Report Run Date and Time: 11/9/2012 3:53 PM Page 1 of 1 TABLE 10.2.6 SECONDARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #5 KEY RISK MESSAGE 5: PATIENTS SHOULD NOT GIVE TIRF MEDICINES TO ANYONE ELSE EVEN IF THEY HAVE THE SAME SYNIPTOMS. SUB-GROUP ANALYSIS 6: HIGHEST LEVEL OF EDUCATION (QUESTION 36): S-6a Less than, Some, or High school graduate/GED or prefer not to answer S-6b - Some college or associate degree S-6c - Bachelor?s degree or Master?s degree S-6d - Professional or Doctoral degree 8- 6a S-6b S-6c S-6d . Bachelor or Doctoral School Some college Master de ree Demonstrated Understandin (95% (95% (95% (95% CI) CI) CI) CI) 0 correct responses correct response correct responses 39 100.0 78 97.5 64 97.0 7 100.0 Average number of correct 2.0 (1.6. 2.0 (1.7. 2.0 (1.7. 2.0 (1.1. responses 2.0) 2.0) 2.0) 2.0) Client: TRIG Project: TIRFKAB Report Run Date and Time: 11/9/2012 3:56 PM Page 1 of 1 TABLE 11.1.6 PRIMARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #6 KEY RISK MESSAGE 6: TIRF MEDICINES SHOULD BE STORED IN A SAFE PLACE AWAY FROM CHILDREN AND PROPERLY DISPOSED. SUB-GROUP ANALYSIS 6: HIGHEST LEVEL OF EDUCATION (QUESTION 36): S-6a Less than, Some, or High school graduate/GED or prefer not to answer 0 S-6b - Some college or associate degree 0 S-6c - Bachelor?s degree or Master?s degree 0 S-6d - Professional or Doctoral degree S?6a S?6b or S?6d High School Some college Doctoral degree Master . Question N46 (95% (95% (95% (95% CD CD CD CD Question 12: Please answer True, False, or I don?t know for each statement about the TIRF medicine that was most recently prescribed for you. 12a: TIRF medicines should be stored in a safe place out of the reach of children. True 39 100.0 80 100.0 66 100.0 7 100.0 (91.0. (95.5. (94.6. (59.0. 100.0) 100.0) 100.0) 100.0) 111C 1 1651301186 False don't know 0.0 Question 16: Please answer True, False, or I don?t know for each statement about the TIRF medicine that was most recently prescribed for you. 16c: TIRF medicines must be disposed of as described in the speci?c product?s Medication Guide. correct response True 38 97.4 79 98.8 61 92.4 6 85.7 (86.5. (93.2. (83.2. (42.1. 99.9) 100.0) 97.5) 99.6) Client: TRIG Project: TIRF KAB Report Run Date and Time: 11/12/2012 12:21 PM Page 1 of 2 S?6c S?6a S?6b Bachelor or High School Some college Doctoral degree Master Question N456 (95% (95% (95% (95% CD CD CD CD Incorrect response False don't know 1 2.6 1.3 3 4.5 1 14.3 l6e: A TIRF medicine can cause an overdose and death in any child who takes it. C01rect response True 35 89.7 75 93.8 57 86.4 7 100.0 (75.8. (86.0. (75.7. (59.0. 97.1) 97.9) 93.6) 100.0) Incorrect response False don't know 3 7.7 4 5.0 7 10.6 0 0.0 Question 13: What should you do if an adult who has not been prescribed a TIRF medicine takes a TIRF medicine? (Please select one.) ICSPOIISC Get emergency 34 87.2 74 92.5 56 84.8 7 100.0 help right away. (72.6. (84.4. (73.9. (59.0. 95.7) 97.2) 92.5) 100.0) Incouect response Do nothing0.0 Wait an horn and the person is OK. I don't know 3 7.7 5 6.3 7 10.6 0 0.0 Client: TRIG Project: TIRFKAB Report Run Date and Time: 11/12/2012 12:21 PM Page 2 of TABLE 11.2.6 LINKED TO KEY RISK MESSAGE #6 SECONDARY ANALYSIS OF RESPONSES TO QUESTIONS KEY RISK MESSAGE 6: TIRF MEDICINES SHOULD BE STORED IN A SAFE PLACE AWAY FROM CHILDREN AND PROPERLY DISPOSED. SUB-GROUP ANALYSIS 6: HIGHEST LEVEL OF EDUCATION (QUESTION 36): S-6a Less than, Some, or High school graduate/GED or prefer not to answer 0 S-6b - Some college or associate degree 0 S-6c - Bachelor?s degree or Master?s degree 0 S-6d - Professional or Doctoral degree S-6a S-6b 8'6? High School Some college Bachelor or Doctoral Master degree Demonstrated Understanding (95% (95% (95% (95% CI) CI) CI) CI) 0 correct responses correct response correct responses 0correct responses 10 25.6 10 12.5 12 18.2 1 14.3 4 correct responses 29 74.4 69 86.3 48 72.7 6 85.7 Average number of correct 3.7 (3.2. 3.9 (3.5. 3.6 (3.3. 3.9 (2.6. responses 4.0) 4.0) 4.0) 4.0) Client: TRIG Project: TIRFKAB Report Run Date and Time: 11/12/2012 11:21 ANI Page 1 of TABLE 6.1.7 PRIMARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #1 KEY RISK MESSAGE l: TIRF MEDICINES CAN CAUSE LIFE-THREATENING BREATHING PROBLEMS THAT CAN LEAD TO DEATH. SUB-GROUP ANALYSIS 7: AGE GROUP OF RESPONDENT (QUESTION 5): S-7a 18 to 39 S-7b 40 to 49 S-7c 50 to 59 S-7d 60 or older S-7a S?7b S?7c S?older Question =48 (95% (95% (95% (95% CI) CI) CI) CI) Question 12: Please answer True, False, or I don?t know for each statement about the TIRF medicine that was most recently prescribed for you. 12d: TIRF medicines can cause life?threatening breathing problems that can lead to death. Tme 21 91.3 44 89.8 66 91.7 42 87.5 (72.0. (77.8. (82.7. (74.8. 98.9) 96.6) 96.9) 95.3) Incorrect response False don't know 1 4.3 5 10.2 4 5.6 4 8.3 Client: TRIG Project: TIRFKAB Report Run Date and Time: 11/9/2012 4:17 PM Page 1 of TABLE 7.1.7 PRIMARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #2 KEY RISK MESSAGE 2: PATIENTS SHOULD NOT TAKE TIRF MEDICINES IF THEY ARE NOT OPIOID TOLERANT. SUB-GROUP ANALYSIS 7: AGE GROUP OF RESPONDENT (QUESTION 5): S-7a 18 to 39 S-7b 40 to 49 S?7c 50 to 59 S-7d 60 or older S-7a S-7b S-7c S-older Question (95% (95% (95% (95% CI) CI) CI) CI) Question 10: Please answer True, False, or I don?t know for the following statement: TIRF medicines should only be taken by patients who are opioid tolerant. Con?ect response True 21 91.3 45 91.8 65 90.3 43 89.6 (72.0. (80.4. (81.0. (77.3. 98.9) 97.7) 96.0) 96.5) Incorrect response False don't know 10.4 Question 11: Please answer True, False, or I don?t know for the following statements: 11a: Opioid tolerant means that a patient is already taking other opioid pain medicines around the clock and their body is used to these medicines. correct response True 21 91.3 47 95.9 67 93.1 41 85.4 (72.0. (86.0. (84.5. (72.2. 98.9) 99.5) 97.7) 93.9) False don't know 10.4 Client: TRIG Project: TIRFKAB Report Run Date and Time: 11/9/2012 4:22 PM Page 1 of2 S?7a S?7b S?7c S?older Question (95% (95% (95% (95% CI) CI) CI) CI) Question 12: Please answer True, False, or I don?t know for each statement about the TIRF medicine that was most recently prescribed for you. 12b: It is OK for patients to take TIRF medicines for headache pain. False 18 78.3 32 65.3 55 76.4 31 64.6 (56.3. (50.4. (64.9. (49.5. 92.5) 78.3) 85.6) 77.8) Incorrect response True 1 4.3 7 14.3 5 6.9 4 8.3 I don't know 4 17.4 10 20.4 12 16.7 13 27.1 Client: TRIG Project: TIRFKAB Report Run Date and Time: 11/9/2012 4:22 PM Page 2 of 2 TABLE 7.2.7 SECONDARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #2 KEY RISK MESSAGE 2: PATIENTS SHOULD NOT TAKE TIRF MEDICINES IF THEY ARE NOT OPIOID TOLERANT. SUB-GROUP ANALYSIS 7: AGE GROUP OF RESPONDENT (QUESTION 5): S-7a 18 to 39 S-7b 40 to 49 S-7c 50 to 59 S-7d 60 or older S-7a S-7b S-7c S-older . Demonstrated Understanding (95% (95% (95% (95% CI) CI) CI) Cl) 0 correct responses correct response correct responses 6 26.1 17 34.7 20 27.8 18 37.5 3 correct responses 16 69.6 29 59.2 48 66.7 25 52.1 Average number of correct 2.6 (2.1. 2.5 (2.2. 2.6 (2.3. 2.4 (2.0. responses 3.0) 3.0) 3.0) 3.0) Client: TRIG Project: TIRFKAB Report Run Date and Time: 11/9/2012 4:24 PM Page 1 of TABLE 8.1.7 PRIMARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #3 KEY RISK MESSAGE 3: TIRF MEDICINES SHOULD BE TAKEN EXACTLY AS PRESCRIBED BY THE HEALTHCARE PROVIDER. SUB-GROUP ANALYSIS 7: AGE GROUP OF RESPONDENT (QUESTION 5): S-7a 18 to 39 S-7b 40 to 49 S-7c 50 to 59 S-7d 60 or older S-7a S-7b S-7c S-older Question (95% (95% (95% (95% CI) CI) CI) CI) Question 11: Please answer True, False, or I don?t know for the following statements: 11b: If a patient stops taking around-the-clock opioid pain medicine, they must also stop taking the TIRF medicine. Cou'ect response True 12 52.2 18 36.7 36 50.0 16 33.3 (30.6. (23.4. (38.0. (20.4. 73.2) 51.7) 62.0) 48.4) Incorrect response False 5 21.7 16 32.7 10 13.9 16 33.3 I don't know 6 26.1 15 30.6 26 36.1 16 33.3 Question 12: Please answer True, False, or I don?t know for each statement about the TIRF medicine that was most recently prescribed for you. 12c: TIRF medicines should be taken exactlv as prescribed bV the doctor. Con'ect response True 23 100.0 49 100.0 72 100.0 48 100.0 (85.2. (92.7. (95.0. (92.6. 100.0) 100.0) 100.0) 100.0) Incorrect response False don't know 0.0 Client: TRIG Project: TIRF KAB Report Run Date and Time: 11/15/2012 2:22 PM Page 1 of 2 S?7a S?7b S?7c S?older Question (95% (95% (95% (95% CI) CI) CI) CI) Question 16: Please answer True, False, or I don?t know for each statement about the TIRF medicine that was most recently prescribed for you. 16b: It is OK to take TIRF medicines for short-term pain that will go away in a few days. False 19 82.6 43 87.8 62 86.1 34 70.8 (61.2. (75.2. (75.9. (55.9. 95.0) 95.4) 93.1) 83.0) Incorrect response Tnle 3 13don't know 1 4.3 5 10.2 9.7 11 22.9 Client: TRIG Project: TIRFKAB Report Run Date and Time: 11/15/2012 2:22 PM Page 2 of 2 TABLE 8.2.7 SECONDARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #3 KEY RISK MESSAGE 3: TIRF MEDICINES SHOULD BE TAKEN EXACTLY AS PRESCRIBED BY THE HEALTHCARE PROVIDER. SUB-GROUP ANALYSIS 7: AGE GROUP OF RESPONDENT (QUESTION 5): S-7a 18 to 39 S-7b 40 to 49 S-7c 50 to 59 S-7d 60 or older S-7a S-7b S-7c S-older . Demonstrated (95% (95% (95% (95% CI) CI) CI) CI) 0 correct responses correct response 3 13.0 4 8.2 11.1 12 25.0 2 correct responses 9 39.1 29 59.2 30 41.7 22 45.8 3 correct responses 11 47.8 16 32.7 34 47.2 14 29.2 Average number of correct 2.4 (1.8. 2.2 (1.9. 2.4 (2.1. 2.0 (1.7. responses 3 .0) 3.0) 3.0) 3.0) Client: TRIG Project: TIRFKAB Report Run Date and Time: 11/15/2012 3:04 PM Page 1 of TABLE 9.1.7 PRIMARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #4 RISK MESSAGE 4: PATIENTS SHOULD NOT SWITCH FROM A TIRF MEDICINE TO ANOTHER MEDICINE THAT CONTAINS FENTANY WITHOUT TALKING TO A HEALTHCARE PROVIDER. SUB-GROUP ANALYSIS 7: AGE GROUP OF RESPONDENT (QUESTION 5): S-7a 18 to 39 S-7b 40 to 49 S-7c 50 to 59 S-7d 60 or older S-7a S-7b S-7c S-older Question (95% (95% (95% (95% CI) CI) C1) C1) Question 11: Please answer True, False, or I don?t know for the following statements: 11c: It is safe to switch to another medicine that contains fentanyl without talking to a healthcare provider ?rst Conect response False 23 100.0 47 95.9 71 98.6 45 93.8 (85.2. (86.0. (92.5. (82.8. 100.0) 99.5) 100.0) 98.7) Incorrect response True don't know 4.2 Client: TRIG Project: TIRFKAB Report Run Date and Time: 11/9/2012 4:46 PM Page 1 of TABLE 10.1.7 PRIMARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #5 KEY RISK MESSAGE 5: PATIENTS SHOULD NOT GIVE TIRF MEDICINES TO ANYONE ELSE EVEN IF THEY HAVE THE SAME SYNIPTOMS. SUB-GROUP ANALYSIS 7: AGE GROUP OF RESPONDENT (QUESTION 5): S-7a 18 to 39 S-7b 40 to 49 S-7c 50 to 59 S-7d 60 or older S-7a S-7b S-7c S-older Question (95% (95% (95% (95% CI) CI) CI) CI) Question 11: Please answer True, False, or I don?t know for the following statements: 11d: A patient may give TIRF medicines to another person if they have the same as the patient. Correct response False 23 100.0 49 100.0 72 100.0 48 100.0 (85.2. (92.7. (95.0. (92.6. 100.0) 100.0) 100.0) 100.0) Incorrect response True don't know 0.0 Question 16: Please answer True, False, or I don?t know for each statement about the TIRF medicine that was most recently prescribed for you. 16a: Selling or giving away TIRF medicines is against the law. ICSPOIISC True 21 91.3 49 100.0 70 97.2 48 100.0 (72.0. (92.7. (90.3. (92.6. 98.9) 100.0) 99.7) 100.0) Incorrect response False don't know 0.0 Client: TRIG Project: TIRFKAB Report Run Date and Time: 12/10/2012 2:40 PM Page 1 of TABLE 10.2.7 SECONDARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #5 KEY RISK MESSAGE 5: PATIENTS SHOULD NOT GIVE TIRF MEDICINES TO ANYONE ELSE EVEN IF THEY HAVE THE SAME SYNIPTOMS. SUB-GROUP ANALYSIS 7: AGE GROUP OF RESPONDENT (QUESTION 5): S-7a 18 to 39 S-7b 40 to 49 S-7c 50 to 59 S-7d 60 or older S-7 a S-7b S-7c S-older . Demonstrated (95% (95% (95% (95% CI) CI) CI) CI) 0 correct responses correct response correct responses 21 91.3 49 100.0 70 97.2 48 100.0 Average number of correct 1.9 (1.4. 2.0 (1.7. 2.0 (1.7. 2.0 (1.7. responses 2.0) 2.0) 2.0) 2.0) Client: TRIG Project: TIRFKAB Report Run Date and Time: 11/9/2012 4:52 PM Page 1 of 1 TABLE 11.1.7 PRIMARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #6 KEY RISK MESSAGE 6: TIRF MEDICINES SHOULD BE STORED IN A SAFE PLACE AWAY FROM CHILDREN AND PROPERLY DISPOSED. SUB-GROUP ANALYSIS 7: AGE GROUP OF RESPONDENT (QUESTION 5): S-7a 18 to 39 S-7b 40 to 49 S-7c 50 to 59 S-7d 60 or older Question S-7a S-7b S-7c S-older (95% (95% (95% (95% CI) CI) C1) C1) Question 12: Please answer True, False, or I don?t know for each statement about the TIRF medicine that was most recently prescribed for you. 12a: TIRF medicines should be stored in a safe place out of the reach of children. ICSPOIISC Tnle 23 100.0 49 100.0 72 100.0 48 100.0 (85.2. (92.7. (95.0. (92.6. 100.0) 100.0) 100.0) 100.0) Incorrect response False don't know 0 0.0 0.0 0 0.0 0 0.0 Client: TRIG Project: TIRFKAB Report Run Date and Time: 11/12/2012 11:46 ANI Page 1 of 3 S?7a S?7b S?7c S?older ti Ques on (95% (95% (95% (95% C1) C1) C1) C1) Question 16: Please answer True, False, or I don?t know for each statement about the TIRF medicine that was most recently prescribed for you. 16c: TIRF medicines must be disposed of as described in the speci?c product?s Medication Guide. correct response Tme 23 100.0 48 98.0 67 93.1 46 95.8 (85.2. (89.1. (84.5. (85.7. 100.0) 99.9) 97.7) 99.5) Incorrect response False don't know 0 0.0 2.0 4 5.6 1 2.1 16e: A TIRF medicine can cause an overdose and death in any child who takes it. C01rect response T1116 21 91.3 47 95.9 64 88.9 42 87.5 (72.0. (86.0. (79.3. (74.8. 98.9) 99.5) 95.1) 95.3) Incorrect response False don't know 10.4 Client: TRIG Project: TIRFKAB Report Run Date and Time: 11/12/2012 11:46 ANI Page 2 of S?7a S?7b S?7c S?older ti Ques on (95% (95% (95% (95% CI) C1) C1) C1) Question 13: What should you do if an adult who has not been prescribed a TIRF medicine takes a TIRF medicine? (Please select one.) Get emergency 21 91.3 46 93.9 65 90.3 39 81.3 help right away. (72.0. (83.1. (81.0. (67.4. 98.9) 98.7) 96.0) 91.1) Incorrect response Do nothing0.0 Wait an hour and the person is OK. I don't know 16.7 Client: TRIG Project: TIRFKAB Report Run Date and Time: 11/12/2012 11:46 AM Page 3 of 3 TABLE 11.2.7 SECONDARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #6 KEY RISK MESSAGE 6: TIRF MEDICINES SHOULD BE STORED IN A SAFE PLACE AWAY FROM CHILDREN AND PROPERLY DISPOSED. SUB-GROUP ANALYSIS 7: AGE GROUP OF RESPONDENT (QUESTION 5): S-7a 18 to 39 S-7b 40 to 49 S-7c 50 to 59 S-7d 60 or older S-7a S-7b S-7c S-older . Demonstrated Understandmg (95% (95% (95% (95% CD CD CD CD 0 correct responses correct response correct responses correct responses 2 8.7 6 12.2 14 19.4 11 22.9 4 correct responses 20 87.0 43 87.8 55 76.4 34 70.8 Average number of correct 3.8 (3.2. 3.9 (3.4. 3.7 (3.3. 3.6 (3.2. responses 4.0) 4.0) 4.0) 4.0) Client: TRIG Project: TIRF KAB Report Run Date and Time: 11/12/2012 11:54 ANI Page 1 of Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies. December 2012 12-month REMS Assessment Report 11.4.2 Pharmacy KAB Survey FDA_383 Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Title: December 2012 Pharmacy KAB Assessment Report Transmucosal Immediate Release Fentanyl (TIRF) REMS Assessment Quantitative Testing of Pharmacist Knowledge, Attitudes, and Behavior (KAB) about TIRF Products Safety and Use Information Document Number Final Wave 1, Version 1.0 Product Name: Transmucosal Immediate Release Fentanyl Sponsor: TIRF REMS Industry Group (TRIG) of Companies: Archimedes Pharma US, Inc. Cephalon, Inc. (a wholly-owned subsidiary of Teva Pharmaceutical Industries, Ltd.) Insys Therapeutics Meda Pharmaceuticals Mallinckrodt (the Pharmaceuticals Business of Covidien) Par Pharmaceutical, Inc. ProStrakan, Inc. Date: 14 December 2012 Confidentiality Statement The information contained herein is confidential and the proprietary property of the TRIG of Companies and its affiliates, and any unauthorized use or disclosure of such information without the prior written authorization of the TRIG is expressly prohibited. Page 1 of 46 FDA_384 Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies TABLE OF CONTENTS December 2012 Pharmacy KAB Assessment Report PAGE TABLE OF CONTENTS ......................................................................................................... 2  LIST OF APPENDICES .......................................................................................................... 4  LIST OF INTEXT TABLES .................................................................................................... 5  LIST OF ABBREVIATIONS .................................................................................................. 7  1.  PHARMACIST SURVEY BACKGROUND.......................................................... 8  2.  PHARMACIST SURVEY OBJECTIVES .............................................................. 9  3.  SURVEY METHODOLOGY.................................................................................. 9  3.1  Survey Sample ......................................................................................................... 9  3.2  3.2.1  3.2.2  3.2.3  3.2.4  Questions and Statements on Key Risk Messages ................................................. 10  Key Risk Message 1 ............................................................................................... 11  Key Risk Message 2 ............................................................................................... 11  Key Risk Message 3 ............................................................................................... 12  Key Risk Message 4 ............................................................................................... 12  3.3  Additional Questions.............................................................................................. 13  4.  STATISTICAL METHODS .................................................................................. 13  4.1  4.1.1  4.1.2  4.1.2.2  4.1.2.3  4.1.3  Study Population .................................................................................................... 13  Primary Analysis Population ................................................................................. 13  Sub-populations of Interest .................................................................................... 13  Primary Analyses ................................................................................................... 14  Secondary Analyses ............................................................................................... 14  Pharmacist Report of Adverse Event, Product Complaint, or Medical Information Request During Survey ...................................................................... 14  5.  RESULTS .............................................................................................................. 15  5.1  5.1.1  5.1.2  5.1.3  Survey Participants ................................................................................................ 15  Survey Participant Administration Results ............................................................ 15  Pharmacist Demographic and TIRF Product Dispensing Characteristics ............. 18  TIRF Medicines Educational Materials ................................................................. 21  5.2  5.2.1  5.2.1.1  5.2.1.2  5.2.1.3  5.2.1.4  5.2.2  KAB Survey Objectives ......................................................................................... 23  Key Risk Message Results ..................................................................................... 23  Key Risk Message 1 ............................................................................................... 23  Key Risk Message 2 ............................................................................................... 25  Key Risk Message 3 ............................................................................................... 27  Key Risk Message 4 ............................................................................................... 29  Other Survey Questions ......................................................................................... 31  Page 2 of 46 FDA_385 Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies December 2012 Pharmacy KAB Assessment Report 5.2.2.1  5.2.2.2  5.2.3  Additional Questions About TIRF Medicines Safety ............................................ 31  Pharmacist Activities When Dispensing TIRF Medicines .................................... 34  Analyses of Subpopulations ................................................................................... 38  5.3  Spontaneous Reporting of Adverse Events, Product Complaints, or Medical Information Requests ............................................................................... 38  5.4  Discussion, Conclusions, and Recommendations .................................................. 39  Listing 1  CATEGORIZATION OF VERBATIM RESPONSES TO QUESTION 21 (Questions about the information in the Full Prescribing Information or Medication Guide) ................................................................................................. 44  Listing 2  CATEGORIZATION OF VERBATIM RESPONSES TO REPORTED SAFETY EVENTS OR PRODUCT COMPLAINTS ........................................... 45  Page 3 of 46 FDA_386 Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies December 2012 Pharmacy KAB Assessment Report LIST OF APPENDICES Appendix A Pharmacy Survey Protocol ....................................................................... 42  Appendix B Pharmacy Survey Listings and Subanalysis Tables .................................43  Page 4 of 46 FDA_387 Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies December 2012 Pharmacy KAB Assessment Report LIST OF INTEXT TABLES Table 1.  Survey Participant Administration Results...............................................15  Table 2.  Survey Participant Screening Results ....................................................... 16  Table 3.  Time to Complete Survey for Completers (Minutes) ............................... 18  Table 4.  Demographic Characteristics of Eligible Pharmacists ............................. 19  Table 5.  Characteristics of Respondents Completing the Survey...........................20  Table 6.  Responses to Questions About TIRF Medicines Educational Materials ...................................................................................................21  Table 7.  Categorized Responses To Question 21 (Questions About the Information in the Full Prescribing Information or Medication Guide) .......................................................................................................22  Table 8.  Responses Linked to Key Risk Message 1: TIRF Medicines Are Contraindicated in Opioid Non-Tolerant Patients .................................... 24  Table 9.  Responses Linked to Key Risk Message 2: TIRF Medicines Are Only Indicated for the Management of Breakthrough Pain in Adult Cancer Patients 18 Years of Age and Older (16 Years of Age and Older for Actiq® Brand and Generic Equivalents) Who Are Already Receiving and Who Are Tolerant to Around-The-Clock Opioid Therapy for Their Underlying Persistent Cancer Pain ................. 26  Table 10.  Responses Linked to Key Risk Message 3: TIRF Medicines Contain Fentanyl, an Opioid Agonist and a Schedule II Controlled Substance, With Abuse Liability Similar to Other Opioid Analgesics. ................................................................................................ 28  Table 11.  Responses Linked to Key Risk Message 4: TIRF Medicines Are Not Interchangeable with Each Other, Regardless of Route of Administration. .........................................................................................30  Table 12.  Responses to Additional Questions About the Safe Use of TIRF Medicines..................................................................................................32  Table 13.  Responses to Additional Questions About the Safe Use of TIRF Medicines: Question asked of Inpatient Pharmacists, Only ....................34  Table 14.  Responses to All Questions About Activities When Dispensing TIRF Medicines ........................................................................................ 35  Table 15.  Responses to All Questions About Activities When Dispensing TIRF Medicines: Asked of Inpatient Pharmacies, Only..........................37  Table 16.  Responses to All Questions About Activities When Dispensing TIRF Medicines: Outpatient Pharmacists, Only...................................... 37  Page 5 of 46 FDA_388 Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies December 2012 Pharmacy KAB Assessment Report Table 17.  Responses to All Questions About Activities When Dispensing TIRF Medicines: Closed System Pharmacy Outpatient Pharmacists, Only .....................................................................................38  Table 18.  Respondent Report of Adverse Event, Product Complaint, or Medical Information Request During Survey ..........................................39  Table 19.  Categorized Reported Adverse Events, Product Complaints, or Medical Information Request ...................................................................39  Page 6 of 46 FDA_389 Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies December 2012 Pharmacy KAB Assessment Report LIST OF ABBREVIATIONS CSP Closed System Pharmacy ETASU Elements to Assure Safe Use FDA Food and Drug Administration KAB Knowledge, Attitudes, and Behavior PI Prescribing Information REMS Risk Evaluation and Mitigation Strategy SAP Statistical Analysis Plan SERP Safety Event Reporting Plan TIRF Transmucosal Immediate Release Fentanyl TIRF medicines Transmucosal Immediate Release Fentanyl products TIRF REMS Access program REMS program for TIRF medicines TRIG TIRF REMS Industry Group UBC United BioSource Corporation US United States Page 7 of 46 FDA_390 Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies 1. December 2012 Pharmacy KAB Assessment Report PHARMACIST SURVEY BACKGROUND Transmucosal Immediate Release Fentanyl (TIRF) medicines are a class of immediate-release opioid analgesics that are indicated only for the management of breakthrough pain in cancer patients 18 years of age or older (16 or older for Actiq ® [fentanyl citrate oral transmucosal lozenge] and equivalent generics) who are receiving and already tolerant to opioid therapy for their underlying persistent cancer pain. The TIRF medicines include Abstral®, Actiq®, Fentora®, Lazanda®, Onsolis®, Subsys®, and their generic equivalents. The TIRF Risk Evaluation and Mitigation Strategy (REMS) Industry Group (TRIG) includes Archimedes Pharma United States (US) Inc., Cephalon, Inc. (a wholly-owned subsidiary of Teva Pharmaceutical Industries, Ltd.), Insys Therapeutics, Meda Pharmaceuticals, Mallinckrodt (the Pharmaceuticals Business of Covidien), Par Pharmaceutical, Inc., and ProStrakan, Inc. At the time of protocol development for the Knowledge, Attitude, and Behavior (KAB) surveys, Sandoz was also a member of the TRIG; however Sandoz terminated their involvement in the TIRF REMS Access program, effective 15 September 2012. The Food and Drug Administration (FDA) has determined that a class-wide REMS is required to mitigate the risk of misuse, abuse, addiction, overdose, and serious complications due to medication errors with the use of TIRF medicines. The TIRF REMS Access program (hereafter referred to as TIRF REMS) was approved by the FDA on 28 December 2011. The TIRF REMS consists of a Medication Guide, Elements to Assure Safe Use (ETASU), an Implementation System, and a timetable for submission of assessments of the REMS. The goals of the TIRF REMS are to mitigate the risk of misuse, abuse, addiction, overdose, and serious complications due to medication errors by the following: 1. Prescribing and dispensing TIRF medicines only to appropriate patients, which includes use only in opioid-tolerant patients. 2. Preventing inappropriate conversion between TIRF medicines. 3. Preventing accidental exposure to children and others for whom it was not prescribed. 4. Educating prescribers, pharmacists, and patients on the potential for misuse, abuse, addiction, and overdose of TIRF medicines. An important component of the TIRF REMS assessment is the conduct of quantitative evaluation surveys to assess pharmacists’ understanding and knowledge of the safe use and appropriate prescribing of TIRF medicines as described in the TIRF REMS educational materials, enrollment form, and Prescribing Information (PI) of each product. The protocol describes the administration of these surveys among pharmacists who are enrolled in the TIRF REMS Access program. Page 8 of 46 FDA_391 Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies December 2012 Pharmacy KAB Assessment Report Data from the surveys, together with other REMS evaluation metrics, will be used to determine whether changes need to be made to the REMS processes or educational materials to make them more effective in achieving the goals of the REMS. Results from the surveys will be submitted to the FDA at 12 months after approval of the TIRF REMS and annually thereafter. 2. PHARMACIST SURVEY OBJECTIVES The evaluation survey uses a questionnaire to document the level of knowledge and assess the attitudes and behavior of pharmacists regarding the following key information and risk messages communicated through the REMS: 1. TIRF medicines are contraindicated in opioid non-tolerant patients. 2. TIRF medicines are only indicated for the management of breakthrough pain in adult cancer patients 18 years of age and older (16 or older for Actiq® and equivalent generics) who are already receiving and who are tolerant to around-the-clock opioid therapy for their underlying persistent cancer pain. 3. TIRF medicines contain fentanyl, an opioid agonist and a Schedule II controlled substance, with abuse liability similar to other opioid analgesics. 4. TIRF medicines are not interchangeable with each other, regardless of route of administration. 5. Patients and their caregivers must be instructed that TIRF medicines contain a medicine in an amount that can be fatal in children, in individuals for whom it is not prescribed, and in those who are not opioid tolerant. The survey also collects data on behaviors, such as receipt and use of educational materials and compliance with REMS requirements. 3. SURVEY METHODOLOGY This section summarizes the survey design and the questions that were constructed to test pharmacist understanding of the key risk messages of the REMS. Full details of the survey design are in the protocol, which can be found in Appendix A. 3.1 Survey Sample This survey was conducted among pharmacists who were enrolled in the TIRF REMS Access program as of 15 August 2012. A target sample of 300 pharmacists who dispense TIRF products and were known to have received the REMS educational materials were surveyed in Page 9 of 46 FDA_392 Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies December 2012 Pharmacy KAB Assessment Report this first KAB survey conducted from 24 September 2012 to 01 November 2012. The size of the sample was determined based on both practical and statistical considerations. Subject recruitment was from a random sample of pharmacists from pharmacies that were enrolled in the TIRF REMS Access program. Any pharmacist who worked at an enrolled pharmacy was eligible to participate. Respondents or respondents’ immediate family members who had ever worked for the any of the TRIG companies, McKesson Specialty Care Solutions, RelayHealth, United BioSource Corporation (UBC), or the FDA were not eligible to participate. Respondents who participated in the first wave of the TIRF survey will not be eligible to participate in subsequent survey waves. Potential subjects were recruited via a letter sent through the United States Postal Service, faxed, and additionally outbound calls were made (see Section 5.1.1 for more detail). The required number of completed surveys from the initial mailing was not achieved as expected within approximately 10 days after the first mailing. A second mailing was sent to non-respondents from the original sample with subsequent fax, email, or telephone follow-up to maximize participation. These efforts did not result in the required number of surveys within approximately 21 days, and an additional sample of potential subjects was randomly selected. Pharmacists were given the option of taking the survey by telephone via the Survey Coordinating Center or online via a secure website. All participating pharmacists were offered an honorarium of $50 for a completed survey. The survey was estimated to take approximately 20 minutes to complete. 3.2 Questions and Statements on Key Risk Messages The questions and statements comprising the knowledge survey were constructed to test the pharmacists’ understanding of the key risk messages of the REMS. The questions were to be answered either by selecting options from multiple-choice lists that include statements of the specific key risk messages or by choosing “Yes” or “True,” “No” or “False,” or “I Don’t Know” regarding statements about TIRF medicines. For statements or questions that had “True” or “Yes” vs. “False” or “No” response options, the desired response for key risk messages was generally “True” or “Yes” indicating knowledge of, or behavior in accordance with, the objectives of the REMS. However, some questions were formatted to have the respondent disagree with the statement as written by providing response options of “False” or “No” to avoid having the same affirmative answer for all desired responses. REMS statements, corresponding questions, and desired responses covering the key risk messages are identified below and can be found in the complete survey questionnaire (Appendix A). Page 10 of 46 FDA_393 Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies 3.2.1 December 2012 Pharmacy KAB Assessment Report Key Risk Message 1 Key Risk Message 1 referred to the pharmacist’s knowledge of the specific contraindications for TIRF medicines in opioid non-tolerant patients. Key Risk Message 1: TIRF medicines are contraindicated in opioid non-tolerant patients. Question No. Question Desired response 6 Please answer “True,” “False,” or “I don’t know” for each statement about TIRF medicines. 6a TIRF medicines are contraindicated in opioid non-tolerant patients because life-threatening respiratory depression could occur at any dose. True 6b Death has occurred in opioid non-tolerant patients treated with some fentanyl products. True 6c TIRF medicines may be used to treat opioid non-tolerant patients. False 6d Prescribers starting a patient on a TIRF medicine must begin with titration from the lowest dose available for that specific product, even if the patient has previously taken another TIRF medicine. True 3.2.2 Key Risk Message 2 Key Risk Message 2 referred to the pharmacist’s knowledge of the indications for prescribing TIRF medicines for the management of breakthrough pain in opioid-tolerant adult cancer patients. Key Risk Message 2: TIRF medicines are only indicated for the management of breakthrough pain in adult cancer patients 18 years of age and older (16 years of age and older for Actiq® brand and generic equivalents) who are already receiving and who are tolerant to around-the-clock opioid therapy for their underlying persistent cancer pain. Question No. Question Desired response 8 For which of the following indications can TIRF medicines be prescribed to opioid tolerant patients? Please answer “Yes,” “No,” or “I don’t know” for each option. 8a Acute or postoperative pain No 8b Headache or migraine pain No 8c Dental pain No 8d Breakthrough pain from cancer Yes Page 11 of 46 FDA_394 Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies 3.2.3 December 2012 Pharmacy KAB Assessment Report Key Risk Message 3 Key Risk Message 3 referred to the pharmacist’s knowledge of the risk factors and signs and symptoms of opioid abuse in patients who take TIRF medicines. Key Risk Message 3: TIRF medicines contain fentanyl, an opioid agonist and a Schedule II controlled substance, with abuse liability similar to other opioid analgesics. Question No. Question Desired response 6 Please answer “True,” “False,” or “I don’t know” for each statement about TIRF medicines. 6e It is important to monitor for signs of abuse and addiction in patients who take TIRF medicines. 7 Which of the following are risk factors for opioid abuse? Please answer “Yes,” “No,” or “I don’t know” for each option. 7a A personal history of psychiatric illness Yes 7b A personal history of past or current alcohol or drug abuse, or a family history of illicit drug use or alcohol abuse Yes 9 Please answer “True,” “False,” or “I don’t know” for each statement about TIRF medicines. 9a TIRF medicines can be abused in a manner similar to other opioid agonists. 3.2.4 True True Key Risk Message 4 Key Risk Message 4 referred to the pharmacist’s knowledge of the interchangeability of TIRF medicines based on route of administration, pharmacokinetic absorption, and dosage. Key Risk Message 4: TIRF medicines are not interchangeable with each other, regardless of route of administration. Question No. Question Desired response 9 Please answer “True,” “False,” or “I don’t know” for each statement about TIRF medicines. 9b TIRF medicines are interchangeable with each other regardless of route of administration. False 9c The conversion of one TIRF medicine for another TIRF medicine may result in a fatal overdose because of differences in the pharmacokinetics of fentanyl absorption. True 9d Dosing of TIRF medicines is not equivalent on a microgram-tomicrogram basis. True Page 12 of 46 FDA_395 Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies 3.3 December 2012 Pharmacy KAB Assessment Report Additional Questions The survey also contained questions about the requirements of the TIRF REMS Access program and receipt and understanding of the TIRF educational materials. The following question about behaviors was asked after the key risk message questions: Question: How frequently do you perform the following activities when dispensing TIRF medicines? Ask patients (or their caregivers) about the presence of children in the home Instruct patients (or their caregivers) not to share TIRF medicines with anyone else Counsel patients (or their caregivers) that accidental exposure to TIRF medicines by a child may be fatal Instruct patients (or their caregivers) to keep TIRF medicines out of the reach of children to prevent accidental exposure Instruct patients (or their caregivers) about proper disposal of any unused or partially used TIRF medicines 4. STATISTICAL METHODS 4.1 Study Population 4.1.1 Primary Analysis Population According to the prospective Statistical Analysis Plan (SAP), the primary population for analysis was all eligible pharmacists who completed the survey. Eligible pharmacists were defined as those respondents who answered Yes to Question 1 (agree to take part in survey), and Question 3 (work at a pharmacy that is enrolled in the TIRF REMs Access program), and No to Question 2 (participated in past survey; not applicable for Wave 1) and Question 4 (worked for a TRIG company, UBC, or FDA). A completed survey was a survey in which all non-eligibility questions as appropriate were answered. Some questions may not have been answered because of skip logic in the survey questionnaire. 4.1.2 Sub-populations of Interest The following subgroup analyses were conducted if the subgroup included at least 20 respondents. • a) Subpopulation S-1: Pharmacists who received and read the TIRF medicine educational materials (Yes for Question 17 [Full Prescribing Information], or Yes for Question 19 [Medication Guide]). Page 13 of 46 FDA_396 Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies b) December 2012 Pharmacy KAB Assessment Report Pharmacists who did not read the full prescribing information for the TIRF medicine educational materials (No or I don’t know for Question 17 [Full Prescribing Information], or No or I don’t know for Question 19 [Medication Guide]). • Subpopulation S-2: Time to complete survey-Internet (<10 min, 10 to <20 min, or ≥20 min); • Sub-population S-3: Time to complete survey-Telephone (<10 min, 10 to <20 min, or ≥20 min); • • Subpopulation S-4: Modality to complete survey (Internet or Telephone) • Subpopulation S-6: Number of times per month dispensing TIRF medicines within the last 6 months (None, 1-2 times, 3-5 times, or more than 5 times a month for Question 23). Subpopulation S-5: Time practicing as a pharmacist (less than 3 years, 3 to 5 years, 6 to 15 years, or more than 15 years for Question 26) 4.1.2.2 Primary Analyses Primary analyses were done for all key risk messages. The primary analysis for a key risk message evaluated the number and percentage of correct responses for each individual question/item defined by the key risk message. The correct response to each question/item was identified in the body of the risk message table (Section 3.2). 4.1.2.3 Secondary Analyses Secondary analyses evaluated the number and percentages of correct responses and the average number of correct responses within the risk message overall to assess understanding of the comprehensive key risk message. 4.1.3 Pharmacist Report of Adverse Event, Product Complaint, or Medical Information Request During Survey A pharmacist may have reported an adverse event or other safety event experienced by their patients while taking a TIRF product either in free text fields in the survey or while in conversation with the Survey Coordinating Center. If the event was mentioned to a Survey Coordinating Center Associate, the Associate documented the safety event and the pharmacist’s contact information if provided. The pharmacist was also informed that a representative from the appropriate TIRF medicine manufacturer might contact them to obtain additional information about the safety event. The Internet surveys were monitored for any comments recorded in the free text fields. Information on all reports (Internet or Telephone) that constituted an adverse event or other safety event was forwarded to the appropriate TIRF medicine manufacturer for processing within 1 business day of awareness of the event as outlined in the Safety Event Reporting Plan (SERP). Page 14 of 46 FDA_397 Transrnucosal Immediate Release Fentanyl (TIRF) December 2012 TIRF REMS Industry Group (TRIG) of Companies Pharmacy KAB Assessment Report 5. RESULTS Results of the pharmacist responses to questions in the KAB survey are summarized in this section. 5.1 Survey Participants 5.1.1 Survey Participant Administration Results A total of 7236 pharmacists were invited to participate in this survey (Table 1). Of those invited to participate, 6286 were outpatient pharmacists, 650 were inpatient pharmacists, and 300 were pharmacists practicing in Closed System Pharmacies (C SPs). In order to increase the total overall response, 98 out bormd calls were made from 09 October 2012 to 11 October 2012. Reminder invitations were sent to potential participants to reduce volrmteer bias. Some pharmacists received more than 1 reminder. In all, a total of 302 pharmacists met eligibility criteria and completed the sruvey. Of these 302 pharmacists, 286 completed the survey online, and 16 completed it by telephone (Table 3). From the 302 respondents, 304 surveys were collected. It was identi?ed that 2 respondents completed the survey twice. Only the ?rst completed survey was included in the analysis for each respondent. Of the 302 pharmacists who completed the survey, 6 were SP pharmacists, 16 were inpatient pharmacists, and 280 were outpatient pharmacists (Table 14). Table 1. Survey Participant Administration Results Screened Pharmacists All Respondents Summary Statistic Number of invitations issued to pharmacists 7236 Number of reminder letters issued to pharmacists 11607 Nlunber of pharmacists screened for participation 3481 Nlunber of pharmacists eligible for participation 302 Number of pharmacists completing the survey 302 86.8 By telephone 16 4.6 By intemet 286 82.2 1 This is the denominator for the percentages in this table Page 15 of 46 Transrnucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies December 20 12 Pharmacy KAB Assessment Report As shown in Table 2, a total of 348 pharmacists agreed to participate in this sruvey and 304 of these pharmacists worked in pharmacies that were em?olled in the TIRF REMS. Of the 348 total respondents, 44 were ineligible to participate in the smvey because they worked in pharmacies that were not enrolled or they did not know whether their pharmacy was enrolled in the TIRF REMS. Of the 304 respondents who reported that their pharmacies were enrolled in the TIRF REMS Access program, 1 respondent was ineligible for the sru'vey because the respondent, or an family member, had worked for a TRIG company in the past, and respondent did not know whether he/ she or an immediate family member had worked for a TRIG company, UBC, Specialty Care Solutions, RelayHealth, or FDA in the past. Table 2. Survey Participant Screening Results All Respondents Completed Pharmacists Question Question 1: Do you agree to participate in this survey? Yes 348 100.0 302 100.0 No1 0 0.0 Question 2: Have you ever taken part in this survey about TIRF medicines before? TIRF medicines include Abstral?, Actiq?, Fentora?, Lazanda?, Onsolis?, Subsys? and generic versions of any of these brands Yes 4 1.1 4 1.3 NO 338 97.1 293 97.0 I don?t know 6 1.7 5 1.7 Question not asked 2 0 0.0 Question 3: Do you work in a pharmacy that is enrolled in the TIRF REMS Access program? Yes 304 87.4 302 100.0 No1 15 4.3 I don?t know1 29 8.3 Question not asked 2 0 0.0 (continued) Page 16 of 46 Transmucosal Immediate Release Fentanyl (TIRF) December 2012 TIRF REMS Industry Group (TRIG) of Companies Pharmacy KAB Assessment Report Table 2. Survey Participant Screening Results All Respondents Completed Pharmacists Question Question 4: Have you or any of your immediate family members ever worked for any of the following companies or agencies? Please select all that apply.3 Anesta LLC. 1 1 0.3 Archimedes Phanna US Inc. 1 1 0.3 Cephalon. Inc. (a wholly-owned 1 0.3 subsidiary of Teva Pharmaceutical Industries. Ltd.) 1 Endo Phannaceuticals Inc. 1 1 0.3 Insys Therapeutics1 1 0.3 McKesson Specialty Care 1 0.3 Solutions1 Mallinckrodt (the 1 0.3 Pharmaceuticals Business of ovidien)1 Meda Pharmaceuticals1 1 0.3 Par Phannaceutical. Inc.1 1 0.3 ProStrakan. Inc. 1 1 0.3 Sandoz Inc. 1 1 0.3 Teva Pharmaceuticals. Ltd.1 1 0.3 RelayHealth1 1 0.3 United BioSom?ce Comorationl 0 0.0 FDA1 0 0.0 None of these apply4 302 86.8 302 100.0 I don?t know1 1 0.3 Prefer not to answer1 0 0.0 Question not asked2 44 12.6 1 Ineligible to participate in the survey. 2 Question not asked due to a previous question elimination. 3 More than 1 response can be selected. so percentages may not sum to 100%. 4 Ineligible if selected in addition to another response. Those taking the smvey online took an average of 12.2 minutes to complete it. while those taking it by telephone took an average of 16.6 minutes. Page 17 of 46 Transrnucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies December 2012 Pharmacy KAB Assessment Report Table 3. Time to Complete Survey for Completers (Minutes) Summary Statistic Telephone Internet Total 1 16 286 302 Mean (Standard Deviation) 16.6 (4.34) 12.2 (6.54) 12.4 (6.51) Minimum 11 4 4 Median 15.9 10.7 10.9 Maximum 2 8 5 1 5 1 Category 0 <5 Minutes 0 2 2 5 <10 Minutes 0 130 130 10 <15 Minutes 8 87 95 15 <20 Minutes 6 43 49 20 <25 Minutes 1 12 13 25 <30 Minutes 1 6 7 30 Minutes or More 0 6 6 1 Number of eligible pharmacists completing the survey (See Table 1). 5.1.2 Pharmacist Demographic and TIRF Product Dispensing Characteristics The demographic characteristics of pharmacists who completed the srnvey are shown in Table 4, and their experience with prescribing TIRF medicines is summarized in Table 5. The majority of pharmacists who completed the srnvey were male Respondents from the South, Northeast, and Midwest re?ected 34.4%, 26.5%, and 21.5% of total respondents, respectively, while respondents from the Western region of the US composed 17.2% of total respondents. The proportion of respondents who completed the srnvey within each geographic region was similar to the overall proportion of pharmacists (37,480 pharmacists em'olled in the TIRF REMS Access program as of 15 August 2012) in each geographic region (Table 4). Almost half had been a practicing pharmacist for more than 15 years. The majority of pharmacists as the pharmacist in charge for the TIRF REMS Access program where they worked. Most pharmacists had dispensed a TIRF medicine zero to 2 times per month within the past 6 months, and the most frequently dispensed TIRF medicine within the 6 months prior to taking the survey was Actiq or generic Actiq Foru? pharmacists indicated that they dispensed Onsolis dru?ing the 6 months prior to taking the sru'vey, which would be after March 23, 2012. However, Onsolis was not available to any pharmacy at that time. The last Onsolis provided to patients was in May 2011. Page 18 of 46 Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies December 2012 Pharmacy KAB Assessment Report Table 4. Demographic Characteristics of Eligible Pharmacists Eligible Completed Pharmacists Question N=302l Question 25: What is your gender? Male 202 66.9 Female 95 3 1 .5 Prefer not to answer 5 1.7 Question 26: In total, how many years have you been a practicing pharmacist Less than 3 years 25 8.3 3-5 years 41 13.6 6-10 years 51 16.9 11-15 years 37 12.3 More than 15 years 145 48.0 Prefer not to answer 3 1.0 Question 27: In which state do you practice?2 Enrolled in TIRF REMS Eligible and Complete Access Program on Respondents 15AU62012 Geographic Region] Northeast 80 26.5 7362 21.0 Midwest 65 21.5 7874 19.6 South 104 34.4 14574 38.9 West 52 17.2 7516 20.1 Other 0 0.0 154 0.4 Prefer not to answer 1 0.3 1 Number of eligible pharmacists completing the sruvey (See Table 1). 2 According to the 2001 Geographic Area Regions set by the US Census Bureau. Geography Division. Northeast includes CT. MA. ME. NH. NJ. NY. PA. RI. and VT. Midwest includes IA. IL. IN. KS. MI. MN. MO. ND. NE. OH. SD. and W1. South includes AL. AR. DC. DE. FL. GA. KY. LA. MD. MS. NC. OK. SC. TN. TX. VA. and WV. West includes AK. AZ. CA. 0. HI. II). MT. NM. NV. OR. UT. WA. and WY. Other includes Puerto Rico. Northern Mariana Islands. US Virgin Islands. American Samoa. and Guam. Page 19 of 46 Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies December 2012 Pharmacy KAB Assessment Report Table 5. Characteristics of Respondents Completing the Survey Question Eligible Completed Pharmacists Question 22: Are you the Pharmacist in Charge for the TIRF REMS Access program where you work? Yes 248 82.1 No 47 15.6 I don?t know 7 2.3 Question 23: On average, how many times per month have you dispensed the TIRF medicines within the last 6 months None 122 40.4 1-2 times per month 102 33.8 3-5 times per month 29 9.6 More than 5 times per month 23 7.6 I don?t remember 26 8.6 Question 24: Please select the TIRF medicines that you have dispensed within the last 6 months (select all that apply):2 Abstra1? 1 6.1 Actiq? or generic Actiq? 138 76. 7 Fcntora? 70 38.9 Lazanda? 5 .0 Onsolis? 2.2 Subsys? 18 10.0 (answered None to 122 Question 23) lNlunber of eligible pharmacists completing the survey (See Table 1). 2 Percentages are calculated based 011 the sample presented with this question because of skip logic in the srm?ey. Page 20 of 46 Transrnucosal Immediate Release Fentanyl (TIRF) December 2012 TIRF REMS Industry Group (TRIG) of Companies Pharmacy KAB Assessment Report 5.1.3 TIRF Medicines Educational Materials Pharmacists were asked about their access to educational materials for TIRF medicines, speci?cally the Full Prescribing Information and the Medication Guide (Table 6). Most respondents reported they had received or had access to the F1111 Prescribing Information and the Medication Guide (97.7% and 97.0%, respectively). Of those with access to these materials, 75.3% and 82.9%, respectively, indicated that they had read the Full Prescribing Information and the Medication Guide. Table 6. Responses to Questions About TIRF Medicines Educational Materials Eligible Completed Pharmacists Question N=302l Question 16: Did you receive or do you have access to the Full Prescribing Information for the TIRF medicine that you dispense? Yes 295 97.7 No 1 0.3 I don?t know 6 2.0 Question 17: Did you read the Full Prescribing Information for the TIRF medicine that you dispense?? Yes 222 75.3 No 59 20.0 I don?t know 14 4.7 (answered No or I don?t 7 know to Question 16) Question 18: Did you receive or do you have access to the Medication Guide for the TIRF medicine that you dispense? Yes 293 97.0 No 4 1.3 I don?t know 5 1.7 (continued) Page 21 of 46 Transmucosal Immediate Release Fentanyl (TIRF) December 2012 TIRF REMS Industry Group (TRIG) of Companies Pharmacy KAB Assessment Report Table 6. Responses to Questions About TIRF Medicines Educational Materials Question 19: Did you read the Medication Guide for the TIRF medicine that you dispense?2 Yes 243 82.9 No 39 13.3 I don?t know 11 3.8 (answered No or I don?t 9 know to Question 18) Question 20: Did you or do you have any questions about the information in the Full Prescribing Information or Medication Guide? Yes3 15 5.0 No 266 88.1 I don?t know 21 7.0 1 Number of eligible phannacists completing the survey (See Table 1). 2 Percentages are calculated based on the sample presented with this question because of skip logic in the sm'vey. 3 Verbatim text for questions about the information in the Full Prescribing Information are presented in Listing 1. There were 15 respondents who typed a response into the ??ee text ?eld for Question 21. These responses are categorized in Table 7 (see verbatim responses shown in Appendix B, Listing 1). Six of the responses questions categorized as ?generalized response? were primarily statements that respondents had no questions at the time of the smvey or they meant to answer ?no? on a previous question. Table 7. Categorized Responses To Question 21 (Questions About the Information in the Full Prescribing Information or Medication Guide) Eligible Completed Pharmacists Response (Categorized Type) 2 1 3 Abuse monitoring 1 0.3 Dosage, Side Effects 1 0.3 Medication Guide distribution 1 0.3 Medication Guide distribution/ format 1 0.3 Prescribing Information request 1 0.3 (continued) Page 22 of 46 Transrnucosal Immediate Release Fentanyl (TIRF) December 2012 TIRF REMS Industry Group (TRIG) of Companies Pharmacy KAB Assessment Report Table 7. Categorized Responses To Question 21 (Questions About the Information in the Full Prescribing Information or Medication Guide) Eligible Completed Pharmacists Response (Categorized Type) 2 3 REMS process 2 0.7 General responses (speci?c questions not asked) 6 1.9 1 Number of eligible pharmacists completing the sru'vey (See Table 1). 2 Categorization scheme of the verbatim responses is shown in Appendix B. Listing 1. 3 Each category is only cormted once per pharmacist. 5.2 KAB Survey Objectives 5.2.1 Key Risk Message Results The focus of this section of the document is on the fmdings for the total eligible respondent population that completed the sruvey. A summary of results by subgroup is provided in a separate section of the docrunent, Section 5.2.3. 5.2.1.1 Key Risk Message 1 Key Risk Message 1 refers to the pharmacist?s knowledge of the speci?c contraindications for TIRF medicines in patients. Analysis of responses to components of Question 6 for Key Risk Message 1 showed that a high percentage of pharmacists knew that TIRF medicines are contraindicated in opioid non- tolerant patients and that death has occru?red in opioid non-tolerant patients treated with some fentanyl products Most pharmacists were aware that dose titration for patients starting a TIRF medicine must begin with the lowest available dose for that product and that TIRF medicines may not be used to treat opioid non-tolerant patients (Table 8). Evidence of rmderstanding of this key risk information is ?uther supported by the average number of 3.4 out of a possible 4 correct responses. Page 23 of 46 Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies December 2012 Pharmacy KAB Assessment Report Table 8. Responses Linked to Key Risk Message 1: TIRF Medicines Are Contraindicated in Opioid Non-Tolerant Patients Eligible Completed Pharmacists N=302l Question (95% Question 6: Please answer ?True,? ?False,? or don?t know? for each statement about TIRF medicines. 6a: TIRF medicines are contraindicated in opioid non-tolerant patients because life-threatening respiratory depression could occur at any dose. Tme 2 260 86.1 (81.7. 89.8) False 24 7.9 I don?t know 18 6.0 6b: Death has occurred in opioid non-tolerant patien ts treated with some fentanyl products. True 2 278 92.1 (88.4. 94.8) False 5 1.7 I don?t know 19 6.3 6c: TIRF medicines maybe used in opioid non-tolerant patients. Tme 48 15.9 False2 237 78.5 (73.4. 83.0) I don?t know 17 5.6 6d: Prescribers starting a patient on a TIRF medicine must begin with titration from the lowest dose available for that speci?c product, even if the patient has previously taken another TIRF medicine. Tme 2 237 78.5 (73.4. 83.0) False 46 15.2 I don?t know 19 6.3 (continued) Page 24 of 46 Transrnucosal Immediate Release Fentanyl (TIRF) December 2012 TIRF REMS Industry Group (TRIG) of Companies Pharmacy KAB Assessment Report Table 8. Responses Linked to Key Risk Message 1: TIRF Medicines Are Contraindicated in Opioid Non-Tolerant Patients Eligible Completed Pharmacists Question 3 (95% CI) Secondary Analysis: Demonstrated Understanding 0 correct responses 2 0.7 1 correct response 13 4.3 2 correct responses 34 11.3 3 correct responses 81 26.8 4 correct responses 172 57.0 Average nmnber of correct responses 3.4 (3.2. 4.0) 4 1 Nlunber of eligible pharmacists completing the survey (See Table 1). 2 Indicates the correct response(s) to each question or item within a question. 3 All con?dence intervals are exact binomial 95% con?dence intervals. 4 One-sided 95 con?dence interval using the normal approximation to the Poisson distribution. 5.2.1.2 Key Risk Message 2 Key Risk Message 2 refers to the pharmacist?s knowledge of the approved indications for prescribing TIRF medicines to opioid tolerant patients. Responses to components of Question 8 for Key Risk Message 2 indicate that most pharmacists were aware TIRF medicines are prescribed for adult opioid-tolerant patients with breakthrough pain from cancer and not for patients with acute or postoperative pain headache or migraine pain dental pain (Table 9). Evidence of tmderstanding of this key risk information is further supported by an average number of 3.5 out of a possible 4 correct responses. Page 25 of 46 Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies December 2012 Pharmacy KAB Assessment Report Table 9. Responses Linked to Key Risk Message 2: TIRF Medicines Are Only Indicated for the Management of Breakthrough Pain in Adult Cancer Patients 18 Years of Age and Older (16 Years of Age and Older for Actiq? Brand and Generic Equivalents) Who Are Already Receiving and Who Are Tolerant to Around-The-Clock Opioid Therapy for Their Underlying Persistent Cancer Pain Question N=302l Eligible Completed Pharmacists (95% CI) 3 Question 8: For which of the following indications can TIRF medicines be prescribed to opioid tolerant patients? Please answer ?Yes,? or don?t know? for each option. 8a: Acute or postoperative pain Yes 52 17.2 No2 236 78.1 (73.1. 82.7) I don?t know 14 4.6 SD: Headache or migraine pain Yes 12 4.0 No2 269 89.1 (850.924) I don?t know 21 7.0 8c: Dental pain Yes 6 2.0 N02 286 94.7 (91.5. 96.9) I don?t know 10 3.3 8d: Breakthrough pain from cancer Yes 2 252 83.4 (78.8. 87.5) No 46 15.2 I don?t know 4 1.3 (continued) Page 26 of 46 Transrnucosal Immediate Release Fentanyl (TIRF) December 2012 TIRF REMS Industry Group (TRIG) of Companies Pharmacy KAB Assessment Report Table 9. Responses Linked to Key Risk Message 2: TIRF Medicines Are Only Indicated for the Management of Breakthrough Pain in Adult Cancer Patients 18 Years of Age and Older (16 Years of Age and Older for Actiq? Brand and Generic Equivalents) Who Are Already Receiving and Who Are Tolerant to Around-The-Clock Opioid Therapy for Their Underlying Persistent Cancer Pain Eligible Completed Pharmacists N=302l Question 11 (95% CI) 3 Secondary Analysis: Demonstrated Understanding 0 correct responses 2 0.7 1 correct response 11 3.6 2 correct responses 19 6.3 3 correct responses 86 28.5 4 correct responses 184 60.9 Average number of correct responses 3.5 (3.3. 4.0) 4 1 Number of eligible pharmacists completing the sun'ey (See Table 1). 2 Indicates the correct response(s) to each question or item Within a question. 3 All con?dence intervals are exact binomial 95% con?dence intervals. 4 One-sided 95 con?dence interval using the normal approximation to the Poisson distribution. 5.2.1.3 Key Risk Message 3 Key Risk Message 3 refers to the pharmacist?s knowledge of the risk factors and signs and of opioid abuse in patients who take TIRF medicines. Responses to components of Questions 6, 7. and 9 for Key Risk Message 3 showed that a high percentage of pharmacists were aware that it is important to monitor for signs of abuse and addiction in patients who take TIRF medicines a personal history of past or current alcohol or ding abuse or family history of drug and alcohol abuse is a risk factor for opioid abuse and TIRF medicines can be abused in a manner similar to other opioid agonists More than half of pharmacists were aware that a personal history of illness is a risk factor for opioid abuse (Table 10). Evidence of rmderstanding of this key risk information is fluther supported by an average munber? of 3.5 out of a possible 4 correct responses. Page 27 of 46 Transmucosal Immediate Release Fentanyl (TIRF) December 2012 TIRF REMS Industry Group (TRIG) of Companies Pharmacy KAB Assessment Report Table 10. Responses Linked to Key Risk Message 3: TIRF Medicines Contain Fentanyl, an Opioid Agonist and a Schedule II Controlled Substance, With Abuse Liability Similar to Other Opioid Analgesics. Eligible Completed Pharmacists N=302l uestion (95% CI) 2' Question 6: Please answer ?True,? ?False,? or don?t know? for each statement about TIRF medicines. 6e: It is important to monitor for signs of abuse and addiction in patients who take TIRF medicines. Tme 2 295 97.7 (95.3. 99.1) False 5 1.7 I don?t know 2 0.7 Question 7: Which of the following are risk factors for opioid abuse? Please answer ?Yes,? or don?t know? for each option. 7a: A personal history of illness Yes 2 201 66.6 (60.9. 71.9) No 62 20.5 I don?t know 39 12.9 7b: A personal history of past or current alcohol or drug abuse, or a family history of illicit drug use or alcohol abuse Yes 2 301 99.7 (98.2. 100.0) No 0 0.0 I don?t know 1 0.3 Question 9: Please answer ?True,? ?False,? or don?t know? for each statement about TIRF medicines. 9a: TIRF medicines can be abused in a manner similar to other opioid agonists. rme2 273 90.4 (86.5. 93.5) False 19 6.3 I don?t know 10 3.3 (continued) Page 28 of 46 1 Transrnucosal Immediate Release Fentanyl (TIRF) December 2012 TIRF REMS Industry Group (TRIG) of Companies Pharmacy KAB Assessment Report Table 10. Responses Linked to Key Risk Message 3: TIRF Medicines Contain Fentanyl, an Opioid Agonist and a Schedule II Controlled Substance, With Abuse Liability Similar to Other Opioid Analgesics. Eligible Completed Pharmacists Question 3 (95% CI) Secondary Demonstrated Understanding 0 correct responses 1 0.3 1 correct response 0 0.0 2 correct responses 13 4.3 3 correct responses 108 35.8 4 correct responses 180 59.6 Average number of correct responses 3.5 (3.4. 4.0) 4 1 Number of eligible pharmacists completing the sru'vey (See Table 1). 2 Indicates the correct response(s) to each question or item within a question. 3 All con?dence intervals are exact binomial 95% con?dence intervals. 4 One-sided 95 con?dence interval using the nomial approximation to the Poisson distribution. 5.2.1.4 Key Risk Message 4 Key Risk Message 4 refers to the pharmacist?s knowledge that TIRF medicines are not interchangeable regardless of the route of administration. . Responses to components of Question 9 for Key Risk Message 4 showed that a high percentage of pharmacists rmderstood TIRF medicines are not interchangeable with each other regardless of the route of administration the conversion of 1 TIRF medicine to another may result in a fatal overdose and dosing of TIRF medicines is not equivalent on a microgram-to-microgram basis (Table 11). Evidence of rmder'standing of this key risk information is ?uther supported by an average number of 2.8 out of a possible 3 correct responses. Page 29 of 46 Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies December 2012 Pharmacy KAB Assessment Report Table 11. Responses Linked to Key Risk Message 4: TIRF Medicines Are Not Interchangeable with Each Other, Regardless of Route of Administration. Eligible Completed Pharmacists 1 (95% CI) 3 Question 9: Please answer ?True,? ?False,? or don?t know? for each statement about TIRF medicines. 9b: TIRF medicines are interchangeable with each other regardless of route of administration. True 9 3.0 False2 287 95.0 (91.9. 97.2) I don?t know 6 2.0 9c: The conversion of one TIRF medicine for another TIRF medicine may result in a fatal overdose because of differences in the pharmacokinetics of fentanyl absorption. T1ue2 280 92.7 (89.2. 95.4) False 10 3.3 I don?t know 12 4.0 9d: Dosing of TIRF medicines is not equivalent on a microgram-to-microgram basis. Tiue2 279 92.4 (88.8. 95.1) False 10 3.3 I don?t know 13 43 Secondary Analysis: Demonstrated Understanding 0 con?ect responses 3 1.0 1 correct response 5 1.7 2 con'ect responses 41 13.6 3 correct responses 253 83.8 Average number of correct responses 2.8 (2.6. 3.0) 4 Nlunber of eligible pharmacists completing the sm'vey (See Table 2 Indicates the correct response(s) to each question or item within a question. 3 All con?dence intervals are exact binomial 95% con?dence intervals. 4 One-sided 95 con?dence interval using the normal approximation to the Poisson distribution. Page 30 of 46 3 Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies 5.2.2 Other Survey Questions 5.2.2.1 Additional Questions About TIRF Medicines Safety December 2012 Pharmacy KAB Assessment Report Table 12 summarizes the pharmacists’ responses to additional questions about the safe use of TIRF medicines beyond those associated with the key risk messages. Responses to these additional questions confirmed the pharmacists’ understanding of the safety issues and the risks associated with taking TIRF medicines. A high percentage of pharmacists correctly indicated that TIRF medicines may not be sold, loaned, or transferred to another pharmacy (86.8%); pharmacy staff who dispense TIRF medicines must be educated on the requirements of the TIRF REMS Access program (92.7%); and that TIRF medicines with the same route of administration cannot be substituted with each other (95.7%). The majority of inpatient pharmacists correctly indicated that it is not OK to dispense TIRF medicines from the inpatient pharmacy inventory to an outpatient for home use (87.5%; Table 13). Despite the high proportion of pharmacists responding correctly to the questions around Key Risk Message 1 (i.e., that patients must be opioid tolerant), only 12.6% of pharmacists correctly indicated that patients considered opioid tolerant are those who are taking regular opioid therapy for 1 week or longer. Additionally, 15.6% correctly indicated that patients not currently taking opioid therapy but who have no known intolerance or hypersensitivity to fentanyl are not considered opioid tolerant. In contrast a high percentage (80.1%) correctly indicated patients not currently taking opioid therapy but who had taken opioid therapy before are not considered opioid tolerant. Because the results for the 2 components of Question 5 are discrepant from the other pharmacist results around opioid tolerance, it is possible that these results reflect a misunderstanding of the question rather than a lack of understanding of the important safety information. Additional research will be conducted to explore pharmacists’ interpretation and understanding of all 3 components of Question 5. The outcome of the research will be included in the next assessment report, and action proposed, if appropriate. Page 31 of 46 FDA_414 Transmucosal Immediate Release Fentanyl (TIRF) December 2012 TIRF REMS Industry Group (TRIG) of Companies Pharmacy KAB Assessment Report Table 12. Responses to Additional Questions About the Safe Use of TIRF Medicines Eligible Completed Pharmacists Question N=302l Question 5: Please answer ?True,? ?False,? or don?t know? for each of the following. According to the labeling, patients considered opioid?tolerant are those: 5a: Who are taking regular opioid therapy for underlying persistent cancer pain for one week or longer. True 2 38 12.6 False 255 84.4 I don?t know 9 3.0 5b: Who are not currently taking opioid therapy, but have taken opioid therapy before. True 46 15.2 False2 242 80.1 I don?t know 14 4.6 5c: Who are not currently taking opioid therapy, but with no known intolerance or hypersensitivity to the drug fentanyl True 242 80.1 False2 47 15.6 I don?t know 13 4.3 Question 7: Which of the following are risk factors for opioid abuse? Please answer ?Yes,? or don?t know? for each option. 7c: A family history of asthma Yes 26 8.6 No2 251 83.1 I don't know 25 8.3 (continued) Page 32 of 46 5 Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies December 2012 Pharmacy KAB Assessment Report Table 12. Responses to Additional Questions About the Safe Use of TIRF Medicines Eligible Completed Pharmacists Question N=302l Question 8: For which of the following indications can TIRF medicines be prescribed to opioid tolerant patients? Please answer ?Yes,? or don?t know? for each option. 8e: Chronic non?cancer pain Yes 194 64.2 No2 90 29.8 I don't know 18 6.0 Question 11: Please answer ?True,? ?False,? or don?t know? for each statement about TIRF medicines. 11a: TIRF medicines maybe sold, loaned, or transferred to another pharmacy. True 14 4.6 False2 262 86.8 I don?t know 26 8.6 11b: All pharmacy staff that dispenses TIRF medicines must be educated on the requirements of the TIRF REMS Access program. Tme 2 280 92.7 False 12 4.0 I don?t know 10 3.3 11c: TIRF medicines with the same route of administration can be substituted with each other if the pharmacy is out of stock for one product. True 5 1.7 False2 289 95.7 I don?t know 8 2.6 1 Number of eligible pharmacists completing the sun'ey (See Table Indicates the correct response(s) to each question or item w1tlm1 a question. Page 33 of 46 6 Transrnucosal Immediate Release Fentanyl (TIRF) December 2012 TIRF REMS Industry Group (TRIG) of Companies Pharmacy KAB Assessment Report Table 13. Responses to Additional Questions About the Safe Use of TIRF Medicines: Question asked of Inpatient Pharmacists, Only Eligible Completed Inpatient . Pharmacists Question N=l6l Question 15: Please answer ?True,? ?False,? or don?t know? for the following statement about TIRF medicines. (Inpatient pharmacists, only) It is OK to dispense TIRF medicines from the inpatient pharmacy inventory to an outpatient for use at home.3 True 2 12.5 False2 14 87.5 I don?t know 0 0.0 1 Question asked of inpatient pharmacists only. 2 Indicates the correct response(s) to each question or item within a question. 3 This question is presented only to a subgroup of pharmacists. Percentages are based on the number of pharmacists to whom this question was presented. 5.2.2.2 Pharmacist Activities When Dispensing TIRF Medicines Pharmacists were asked about speci?c activities performed when dispensing TIRF medicines (Table 14). More than half of the pharmacists indicated they always give patients (or their caregivers) the Medication Guide for TIRF medicine instruct the patient (or their caregivers) not to share TIRF medicines cormsel patients (or their caregivers) that accidental exposru?e to TIRF medicines by a child may be fatal instruct patients (or their caregivers) to keep TIRF medicines out of reach of children and instruct patients (or their caregivers) about proper disposal of any rmused or partially used TIRF medicines Ahnost half of the pharmacists always ask their patients (or their caregivers) about the presence of children in the home, with 22.5% asking only with the ?st prescription. Page 34 of 46 7 Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies December 2012 Pharmacy KAB Assessment Report Table 14. Responses to All Questions About Activities When Dispensing TIRF Medicines Question Eligible Completed Pharmacists 1 Question 10: How frequently do you perform the following activities when dispensing TIRF medicines? Please answer ?Always,? ?Only with the ?rst prescription,? ?Sometimes,? ?Never,? or don?t know.? 10a: Ask patients (or their caregivers) about the presence of children in the home. Always 146 48.3 Only with the ?st prescription 68 22.5 Sometimes 54 1 7.9 Never 28 9.3 I don?t know 6 2.0 10b: Instruct patients (or their caregivers) not to share TIRF medicines with anyone else. Always 202 66.9 Only with the ?st prescription 54 17,9 Sometimes 26 8.6 Never 15 5.0 I don?t know 5 1.7 10c: Counsel patients (or their caregivers) that accidental exposure to TIRF medicines by a child may be fatal. Always 190 62.9 Only with the ?st 63 20.9 Sometimes 29 9.6 Never 13 4.3 I don?t know 7 2.3 (continued) Page 35 of 46 8 Transrnucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies December 2012 Pharmacy KAB Assessment Report Table 14. Responses to All Questions About Activities When Dispensing TIRF Medicines Eligible Completed Pharmacists Question 10d: Instruct patients (or their caregivers) to keep TIRF medicines out of the reach of children to prevent accidental exposure. Always 208 68.9 Only with the ?st prescription 56 18. 5 Sometimes 21 7.0 Never 12 4.0 I don?t know 5 1.7 10e: Instruct patients (or their caregivers) about proper disposal of any unused or partially used TIRF medicines. Always 172 57.0 Only with the ?rst prescription 76 25, 2 Sometimes 34 1 1.3 Never 13 4.3 I don?t know 7 2.3 10f: Give patients (or their caregivers) the Medication Guide for their TIRF medicine. Always 272 90.1 Only with the ?st prescription 17 5.6 Sometimes 5 1 .7 Never 3 1.0 I don?t know 5 1.7 1 Number of eligible pharmacists completing the survey (See Table 1). 2 This question is presented only to a subgroup of phamracists. Percentages are based on the number of phamracists to whom this question was presented. Speci?c pharmacy types (inpatient, outpatient, and closed system pharmacy pharmacies) were each asked a single different question regarding pharmacy systems and processes. Question 12 was presented only to pharmacy respondents from inpatient pharmacies (N =16) as identi?ed through the access code entered by the respondent (Table 15). Fifty percent of these respondents reported their pharmacy has processes to ensru'e compliance with the TIRF REMS Access program requirements. Page 36 of 46 Transmucosal Immediate Release Fentanyl (TIRF) December 2012 TIRF REMS Industry Group (TRIG) of Companies Pharmacy KAB Assessment Report Table 15. Responses to All Questions About Activities When Dispensing TIRF Medicines: Asked of Inpatient Pharmacies, Only Eligible Completed Inpatient Pharmacists Question N=l6 Question 12: Does the inpatient pharmacy where you work have an established system, order sets, protocols and/or other measures to help ensure appropriate patient selection and complziance with the requirements of the TIRF REMS Access program? [Inpatient pharmacists, only] Yes 8 50.0 No 6 37.5 I don't know 2 12.5 1 Number of eligible inpatient pharmacists completing the survey. 2 This question is presented only to a subgroup of pharmacists. Percentages are based on the number of pharmacists to whom this question was presented. Question 13 was presented only to pharmacy respondents from outpatient phaimacies (N =280) as identi?ed through the access code entered by the respondent. This sub-population did not include respondents from SPs (Table 16). The majority of these respondents reported their pharmacy processes prescriptions for TIRF medicines through their pharmacy management system. Table 16. Responses to All Questions About Activities When Dispensing TIRF Medicines: Outpatient Pharmacists, Only Eligible Completed Outpatient Pharmacists Question 1 Question 13: Does the outpatient or retail pharmacy where you work process all TIRF medicine prescriptions, regardless of method of payment, through the pharmacy management system? [Outpatient pharmacists, only] 2 Yes 235 83.9 No 7 2.5 I don't know 38 13.6 1 Number of eligible outpatient pharmacists completing the survey. 2 This question is presented only to a subgroup of pharmacists. Percentages are based on the number of pharmacists to whom this question was presented. Page 37 of 46 Transrnucosal Immediate Release Fentanyl (TIRF) December 2012 TIRF REMS Industry Group (TRIG) of Companies Pharmacy KAB Assessment Report Question 14 was presented only to pharmacy respondents from SPs as identi?ed through the access code entered by the respondent (Table 17). The majority of SP respondents reported their pharmacy processes all prescriptions for TIRF medicines through the TIRF REMS Access Call Center. Table 17. Responses to All Questions About Activities When Dispensing TIRF Medicines: Closed System Pharmacy Outpatient Pharmacists, Only Eligible Completed CSP Pharmacists Question Question 14: Does the pharmacy where you work process all TIRF medicine prescriptions, regardless of method of payment, through the TIRF REMS Access Call Center? Outpatient pharmacists, only] 2 Yes 5 83.3 No 0 0.0 I don?t know 1 16.7 1 Number of eligible CSP outpatient pharmacists completing the survey. 2 This question is presented only to a subgroup of pharmacists. Percentages are based on the number of pharmacists to whom this question was presented. 5.2.3 Analyses of Subpopulations To fruther assess pharmacist rmderstanding of key risk messages, subgroup analyses as described in Section 4.1.2 were conducted. All results are similar to the results in the primary analysis population, and no trends are evident. The full set of subgroup analysis tables is provided in Appendix B. 5.3 Spontaneous Reporting of Adverse Events, Product Complaints, or Medical Information Requests Among all sruvey respondents no pharmacists reported an adverse event, product complaint, or requested medical information associated with the use of TIRF medicines dru'ing phone completions of this smvey. Five reports of adverse events, product complaints, and/or medical information requests were reported in the ??ee text ?elds of sruveys completed online by pharmacists (Table 18; Appendix B: Listing 2). Adverse event, product complaint, or medical information request reports were categorized as described in Table 19. Page 38 of 46 Transrnucosal Immediate Release Fentanyl (TIRF) December 2012 TIRF REMS Industry Group (TRIG) of Companies Pharmacy KAB Assessment Report Table 18. Respondent Report of Adverse Event, Product Complaint, or Medical Information Request During Survey All Respondents Question N=348l Respondent spontaneously reported an adverse event, product complaint, or medical information request during the course of this survey. Yes 2 5 1.4 NO 343 98.6 1 All respondents who took the survey regardless of eligibility. 2 Verbatim text of adverse events. product complaints. or medical information requests is given in Appendix B. Listing 2. Table 19. Categorized Reported Adverse Events, Product Complaints, or Medical Information Request All Respondents Response (Categon Type)2 N=348l 3 Abuse monitoring 1 0.3 Dosage. Side Effects 1 0.3 REMS process 1 0.3 Prescribing Information request 1 0.3 Medication Guide distribution/ format 1 0.3 1 All respondents who took the survey regardless of eligibility. 2 Categorization scheme of the verbatim responses is shown in Appendix B. Listing 2. 3 Each category is only counted once per pharmacist. 5.4 Discussion, Conclusions, and Recommendations The speci?c goals of the TIRF medicines pharmacist KAB sruvey were to assess pharmacist understanding of the risks associated with TIRF medicine use, of the speci?c indications for treatment with TIRF medicines, and that TIRF medicines are contraindicated in opioid non- tolerant patients. The sruvey invited 7236 pharmacists (based on TIRF REMS enrolhnent records), of whom 302 met the inclusion criteria for the survey. The majority of respondents were male Respondents from the South, Northeast, and Midwest re?ected 34.4%, 26.5%, and 21.5% of total respondents, respectively, while respondents from the Western region of the US Page 39 of 46 Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies December 2012 Pharmacy KAB Assessment Report composed 17.2%, of the total survey population. The proportion of eligible completed pharmacists within each geographic region was similar to the overall proportion of pharmacists (37,480 pharmacists enrolled in the TIRF REMS Access program as of 10 August 2012) in each geographic region. Almost half (48.0%) of eligible respondents who completed the survey had been a practicing pharmacist for more than 15 years. The majority of respondents (82.1%) self-identified themselves as the pharmacist in charge for the TIRF REMS Access program where they worked. Most respondents received or had access to the Full Prescribing Information and the Medication Guide (97.7% and 97.0%, respectively). Of those with access to these materials, 75.3% and 82.9%, claimed to have read the Full Prescribing Information and the Medication Guide, respectively. There were 4 key risk messages included in the survey. Pharmacists demonstrated a high level of understanding of each key risk message. There was a correct response rate of greater than 78% for all components of Key Risk Messages 1, 2, and 4, with the exception of a correct response rate of 66% for Key Risk Message 3, which included questions that assessed the pharmacist’s understanding that a personal history of psychiatric illness is a risk factor for opioid abuse. Analysis of responses to components of Question 6 for Key Risk Message 1 (TIRF medicines are contraindicated in opioid non-tolerant patients) showed that a high percentage of pharmacists knew that TIRF medicines are contraindicated in opioid non-tolerant patients (86.1%) and that death has occurred in opioid non-tolerant patients treated with some fentanyl products (92.1%). Most pharmacists were aware that dose titration for patients starting a TIRF medicine must begin with the lowest available dose for that product (78.5%) and that TIRF medicines may not be used to treat opioid non-tolerant patients (78.5%). Responses to components of Question 8 for Key Risk Message 2 indicate that most pharmacists were aware TIRF medicines are prescribed for adult opioid-tolerant patients with breakthrough pain from cancer (83.4%) and not for patients with acute or postoperative pain (78.1%), headache or migraine pain (89.1%), or dental pain (94.7%). Responses to components of Questions 6, 7, and 9 for Key Risk Message 3 showed that a high percentage of pharmacists were aware that it is important to monitor for signs of abuse and addiction in patients who take TIRF medicines (97.7%); a personal history of past or current alcohol or drug abuse or family history of drug and alcohol abuse is a risk factor for opioid abuse (99.7%); and TIRF medicines can be abused in a manner similar to other opioid agonists (90.4%). Responses to components of Question 9 for Key Risk Message 4 showed that a high percentage of pharmacists understood TIRF medicines are not interchangeable with each other regardless of the route of administration (95.0%); the conversion of 1 TIRF medicine to another may result in a fatal overdose (92.7%); and dosing of TIRF medicines is not equivalent on a microgram-to-microgram basis (92.4%). Additional analyses of the key risk messages did not demonstrate any notable differences between subgroups of pharmacists. Page 40 of 46 FDA_423 Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies December 2012 Pharmacy KAB Assessment Report Among responses to all questions about the safe use of TIRF medicines, there were 2 components of Question 5 relating to the definition of a non-opioid tolerant patient that had low response rates. Despite the high proportion of pharmacists responding correctly to the questions around Key Risk Message 1 (i.e., that patients must be opioid tolerant), only 12.6% of pharmacists correctly indicated that patients considered opioid tolerant are those who are taking regular opioid therapy for 1 week or longer. In addition, 15.6% of pharmacists also correctly indicated that patients not currently taking opioid therapy but who have no known intolerance or hypersensitivity to fentanyl are not considered opioid tolerant. Because the results to Question 5 are discrepant from the other pharmacist results around opioid tolerance (e.g., Questions 6 and 8), it is possible that these results reflect a misunderstanding of the question rather than a lack of understanding of the important safety information. Additional research will be conducted to explore pharmacists’ interpretation and understanding of all 3 components of Question 5. The outcome of the research will be included in the next assessment report, and appropriate action may be taken based on the outcome. Across the 4 key risk messages, pharmacists demonstrated a high level of understanding that TIRF medicines are contraindicated in opioid non-tolerant patients, are only indicated for the management of breakthrough pain in adult cancer patients, contain fentanyl with abuse liability similar to other opioid analgesics, and are not interchangeable with each other regardless of route of administration. Page 41 of 46 FDA_424 Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Appendix A December 2012 Pharmacy KAB Assessment Report Pharmacy Survey Protocol Page 42 of 46 FDA_425 PROTOCOL TITLE: Quantitative Testing of Pharmacist Knowledge, Attitudes, and Behavior about Transmucosal Immediate Release Fentanyl (TIRF) Products Safety and Use Information SPONSOR: TIRF REMS Industry Group (TRIG) Archimedes Pharma US Inc. Cephalon, Inc. Endo Pharmaceuticals Inc. Insys Therapeutics Meda Pharmaceuticals Mallinckrodt (a Covidien Company) Par Pharmaceutical, Inc. ProStrakan, Inc. Sandoz, Inc. VERSION: 3.0 DATE: 10 SEP 2012 APPROVED: 07 SEP 2012 FDA_426 TIRF REMS Industry Group (TRIG) Transmucosal Immediate Release Fentanyl (TIRF) Products Pharmacist KAB Survey Protocol TABLE OF CONTENTS Version 3.0 10 September 2012 PAGE TABLE OF CONTENTS ......................................................................................... 2  1.  LIST OF ABBREVIATIONS .................................................................................. 3  2.  BACKGROUND ..................................................................................................... 4  3.  OBJECTIVES OF THE EVALUATION SURVEY ............................................... 5  4.  METHODS .............................................................................................................. 5  4.1  4.1.1  4.1.2  Survey Design .......................................................................................................... 5  Questions and Statements on REMS Goals ............................................................. 6  Additional Questions................................................................................................ 8  4.2  4.2.1  Participant Recruitment............................................................................................ 9  Measures to Minimize Bias in the Sample............................................................... 9  5.  5.1.1  5.1.2  5.1.3  STUDY POPULATION ........................................................................................ 10  Sample Size ............................................................................................................ 10  Inclusion Criteria.................................................................................................... 11  Exclusion Criteria .................................................................................................. 11  6.  SURVEY PROCESS ............................................................................................. 12  6.1  6.1.1  6.1.2  Screening and Survey Administration ................................................................... 12  Telephone ............................................................................................................... 12  Internet ................................................................................................................... 12  6.2  Measures to Minimize Bias in the Survey Process ................................................ 12  7.  7.1.1  7.1.2  7.1.3  ANALYSIS ............................................................................................................ 13  Description of Primary Analyses ........................................................................... 13  Description of Secondary Analyses ....................................................................... 13  Analysis Population ............................................................................................... 13  8.  SAFETY EVENT REPORTING ........................................................................... 14  9.  PRIVACY PROTECTION AND CONFIDENTIALITY...................................... 14  LIST OF APPENDICES Appendix A Pharmacist Questionnaire ......................................................................... 15  Appendix B Sample Pharmacist Invitation Letter ........................................................ 30  2 of 30 FDA_427 TIRF REMS Industry Group (TRIG) Transmucosal Immediate Release Fentanyl (TIRF) Products Pharmacist KAB Survey Protocol 1. Version 3.0 10 September 2012 LIST OF ABBREVIATIONS CATI EDC ETASU FDA HIPAA IRB ISI KAB REALM REMS SERP TIRF TRIG UBC Computer-Assisted Telephone Interviewing Electronic Data Capture Elements to Assure Safe Use Food and Drug Administration Health Insurance Portability and Accountability Act Institutional Review Board Important Safety Information Knowledge, Attitudes and Behavior Rapid Estimate of Adult Literacy in Medicine Risk Evaluation and Mitigation Strategy Safety Event Reporting Plan Transmucosal Immediate Release Fentanyl TIRF REMS Industry Group United BioSource Corporation 3 of 30 FDA_428 TIRF REMS Industry Group (TRIG) Transmucosal Immediate Release Fentanyl (TIRF) Products Pharmacist KAB Survey Protocol 2. Version 3.0 10 September 2012 BACKGROUND Transmucosal Immediate Release Fentanyl (TIRF) medicines include the class of immediaterelease opioid analgesics that are indicated only for the management of breakthrough pain in cancer patients 18 years of age or older (16 or older for Actiq® and equivalent generics) who are already receiving and already tolerant to opioid therapy for their underlying persistent cancer pain. The TIRF medicines include Abstral®, Actiq®, Fentora®, Lazanda®, Onsolis®™, Subsys™, and generic versions of any of these brands. The TIRF REMS Industry Group (TRIG) includes Archimedes Pharma US Inc., Cephalon, Inc., Endo Pharmaceuticals Inc., Insys Therapeutics, Meda Pharmaceuticals, Mallinckrodt (a Covidien Company), Par Pharmaceutical, Inc., ProStrakan, Inc., and Sandoz Inc. The Food and Drug Administration (FDA) has determined that a Risk Evaluation and Mitigation Strategy (REMS) is required to mitigate the risk of misuse, abuse, addiction, overdose, and serious complications due to medication errors with the use of TIRF medicines. The TIRF REMS Access Program (hereafter referred to as TIRF REMS) was approved by the Food and Drug Administration (FDA) on December 28, 2011. The TIRF REMS consists of a Medication Guide, Elements to Assure Safe Use (ETASU), an Implementation System, and a timetable for submission of assessments of the REMS. The goals of the TIRF REMS are the following to mitigate the risk of misuse, abuse, addiction, overdose and serious complications due to medication errors by: 1. Prescribing and dispensing TIRF medicines only to appropriate patients, which includes use only in opioid-tolerant patients. 2. Preventing inappropriate conversion between TIRF medicines. 3. Preventing accidental exposure to children and others for whom it was not prescribed. 4. Educating prescribers, pharmacists, and patients on the potential for misuse, abuse, addiction, and overdose of TIRF medicines. An important component of the TIRF REMS is the conduct of quantitative evaluation surveys to assess pharmacists’ understanding and knowledge of the safe use and appropriate prescribing of TIRF medicines as described in the TIRF REMS educational materials, enrollment form, and Prescribing Information (PI). This protocol will describe the administration of the surveys that will be conducted among pharmacists who are enrolled in the TIRF REMS Access Program. Data from the surveys, together with other REMS evaluation metrics, will be used to determine whether changes need to be made to the REMS processes or educational materials to make them more effective in achieving the goals of the REMS. 4 of 30 FDA_429 TIRF REMS Industry Group (TRIG) Transmucosal Immediate Release Fentanyl (TIRF) Products Pharmacist KAB Survey Protocol Version 3.0 10 September 2012 The surveys will be implemented so that data will be available for inclusion in the REMS Assessment Reports that will be submitted to the FDA at 12 months after approval of the TIRF REMS and annually thereafter. 3. OBJECTIVES OF THE EVALUATION SURVEY The evaluation survey will use a questionnaire to document the level of knowledge and assess the attitudes and behavior of pharmacists around the following key information and risk messages communicated through REMS: 1. TIRF medicines are contraindicated in opioid non-tolerant patients. 2. TIRF medicines are only indicated for the management of breakthrough pain in adult cancer patients 18 years of age and older (16 or older for Actiq® and equivalent generics) who are already receiving and who are tolerant to around-the-clock opioid therapy for their underlying persistent cancer pain. 3. TIRF medicines contain fentanyl, an opioid agonist and a Schedule II controlled substance, with abuse liability similar to other opioid analgesics. 4. TIRF medicines are not interchangeable with each other, regardless of route of administration. 5. Patients and their caregivers must be instructed that TIRF medicines contain a medicine in an amount that can be fatal in children, in individuals for whom it is not prescribed, and in those who are not opioid tolerant. The survey will also collect data on behaviors, such as receipt and use of educational materials and compliance with REMS requirements. 4. METHODS The survey was designed in collaboration between the TRIG and United BioSource Corporation (UBC), and will be administered by UBC. 4.1 Survey Design This survey will be conducted among a sample of pharmacists who are enrolled in the TIRF REMS Access Program. Respondents who have participated in the first wave of the TIRF survey will not be eligible to participate in subsequent survey waves. The survey will be administered using the following modalities: • Self-administered via the Internet through a secure website 5 of 30 FDA_430 TIRF REMS Industry Group (TRIG) Transmucosal Immediate Release Fentanyl (TIRF) Products Pharmacist KAB Survey Protocol • Version 3.0 10 September 2012 Telephone surveys facilitated by a trained interviewer from the Survey Coordinating Center using a computer-assisted telephone interviewing (CATI) program The survey will begin with screening questions to confirm respondent eligibility to participate in the survey. Completion of the entire survey is expected to take up to 20 minutes. The survey included in Appendix A is written to reflect wording for both methods of survey administration: Internet-based and telephone. All respondents who complete the survey and who provide their contact information will be mailed a $50 honorarium for their time. 4.1.1 Questions and Statements on REMS Goals The KAB questionnaire is made up of multiple-choice, close-ended statements or questions (the majority of which use true/false or yes/no dichotomous response options), and one openended question. These will evaluate current knowledge, attitudes, and behavior regarding the key risk messages noted in Section 3. Questions will be presented in several formats: • Statements or questions asking the respondent to indicate whether a statement or question is true or false, or if they do not know the answer (there is a similar set of statements and questions that use “yes” or “no” as potential response options); • Statements or questions asking the respondent to choose from a defined list of possible statements or answers; and • One question allowing for the respondent to list questions or comments. Questionnaires will be analyzed to determine pharmacist understanding of each key risk message. For statements or questions that use “true” or “yes” vs. “false” or “no” response options, the desired response for key risk messages is generally “true” or “yes” indicating knowledge of, or behavior in accordance with, the objectives of the REMS. However, some questions are formatted to have the respondent disagree with the statement as written by providing response options of “false” or “no” to avoid having the same affirmative answer for all desired responses. REMS statements, corresponding questions, and desired responses covering the key risk messages are identified below and can be found in the complete survey questionnaire (Appendix A). 6 of 30 FDA_431 TIRF REMS Industry Group (TRIG) Transmucosal Immediate Release Fentanyl (TIRF) Products Pharmacist KAB Survey Protocol Version 3.0 10 September 2012 Key Risk Message 1: TIRF medicines are contraindicated in opioid non-tolerant patients. Question No. 6 6a 6b 6c 6d Question Desired response Please answer “True,” “False,” or “I don’t know” for each statement about TIRF medicines. TIRF medicines are contraindicated in opioid nontolerant patients because life-threatening respiratory TRUE depression could occur at any dose. Death has occurred in opioid non-tolerant patients TRUE treated with some fentanyl products. TIRF medicines may be used in opioid non-tolerant FALSE patients. Prescribers starting a patient on a TIRF medicine must begin with titration from the lowest dose TRUE available for that specific product, even if the patient has previously taken another TIRF medicine. Key Risk Message 2: TIRF medicines are only indicated for the management of breakthrough pain in adult cancer patients 18 years of age and older (16 years of age and older for Actiq® brand and generic equivalents) who are already receiving and who are tolerant to around-the-clock opioid therapy for their underlying persistent cancer pain. Question No. 8 8a 8b 8c 8d Question Desired response For which of the following indications can TIRF medicines be prescribed to opioid tolerant patients? Please answer “Yes,” “No,” or “I don’t know” for each option. Acute or postoperative pain NO Headache or migraine pain NO Dental pain NO Breakthrough pain from cancer YES 7 of 30 FDA_432 TIRF REMS Industry Group (TRIG) Transmucosal Immediate Release Fentanyl (TIRF) Products Pharmacist KAB Survey Protocol Version 3.0 10 September 2012 Key Risk Message 3: TIRF medicines contain fentanyl, an opioid agonist and a Schedule II controlled substance, with abuse liability similar to other opioid analgesics. Question No. 6 6e 7 7a 7b 9 9a Question Desired response Please answer “True,” “False,” or “I don’t know” for each statement about TIRF medicines. It is important to monitor for signs of abuse and addiction in patients who take TIRF TRUE medicines. Which of the following are risk factors for opioid abuse? Please answer "Yes,” “No,” or “I don’t know” for each option. A personal history of psychiatric illness YES A personal history of past or current alcohol or drug abuse, or a family history of YES illicit drug use or alcohol abuse. Please answer “True," “False,” or “I don’t know” for each statement about TIRF medicines. TIRF medicines can be abused in a manner TRUE similar to other opioid agonists. Key Risk Message 4: TIRF medicines are not interchangeable with each other, regardless of route of administration. Question No. 9 9b 9c 9d 4.1.2 Question Desired response Please answer “True,” “False,” or “I don’t know” for each statement about TIRF medicines. TIRF medicines are interchangeable with each other regardless of route of FALSE administration. The conversion of one TIRF medicine for another TIRF medicine may result in a fatal TRUE overdose because of differences in the pharmacokinetics of fentanyl absorption. Dosing of TIRF medicines is not equivalent TRUE on a microgram-to-microgram basis. Additional Questions Questions about the requirements of the TIRF REMS Access Program, receipt and understanding of the TIRF educational materials, and behaviors will be asked after the key 8 of 30 FDA_433 TIRF REMS Industry Group (TRIG) Transmucosal Immediate Release Fentanyl (TIRF) Products Pharmacist KAB Survey Protocol Version 3.0 10 September 2012 risk message questions. The following question about behaviors will be asked after the key risk message questions. Question: How frequently do you perform the following activities when dispensing TIRF medicines? Ask patients (or their caregivers) about the presence of children in the home Instruct patients (or their caregivers) not to share TIRF medicines with anyone else Counsel patients (or their caregivers) that accidental exposure to TIRF medicines by a child may be fatal Instruct patients (or their caregivers) to keep TIRF medicines out of the reach of children to prevent accidental exposure Instruct patients (or their caregivers) about proper disposal of any unused or partially used TIRF medicines 4.2 Participant Recruitment A random sample of “pharmacists in charge” from pharmacies that are enrolled in the TIRF REMS Access Program will be invited to participate via an invitation letter. Any pharmacist who works at an enrolled pharmacy may participate. The text of the sample written invitation to pharmacists can be found in Appendix B. If the required number of completed surveys is not achieved within the expected timeframe of approximately one to two weeks after the first mailing, reminder letters will be sent to nonrespondents from the original sample with subsequent fax, e-mail follow-up to maximize participation. The distribution within the mailing to the second sample will be adjusted in accordance with the allocation in the original sample. If these efforts do not result in the required number of surveys within two to three weeks, then a new sample of pharmacists will be randomly selected. The unique code provided in the invitation letter will be linked to the type of pharmacy (inpatient or outpatient) in which the pharmacist works, based on the information provided as part of the TIRF REMS Access Program enrollment. All respondents who complete the survey and who provide their contact information will be mailed a $50 honorarium to thank them for their participation. The mailing will include a Thank You Letter, a copy of the Important Safety Information (ISI), and a copy of the correct answers to key risk message questions. 4.2.1 Measures to Minimize Bias in the Sample The sample of participating pharmacists will be self-selected since respondents will voluntarily respond to the invitation to participate; however, the survey recruitment strategies are intended to recruit a heterogeneous sample of pharmacies (e.g., chain and independent store) for participation. 9 of 30 FDA_434 TIRF REMS Industry Group (TRIG) Transmucosal Immediate Release Fentanyl (TIRF) Products Pharmacist KAB Survey Protocol Version 3.0 10 September 2012 Pharmacists will be offered an Internet-based or telephone options for completing the survey. Multiple modalities for survey data collection allow for wider survey access to a more heterogeneous population. Respondents will be provided a unique code during the recruitment process and will be asked to provide the unique code to gain access to the Internet-based survey or when calling the Survey Coordinating Center. The code will be deactivated after use to minimize the possibility for fraud. 5. STUDY POPULATION 5.1.1 Sample Size A sample of 300 pharmacists who are enrolled in the TIRF REMS Access Program is proposed for the first survey wave. The size of the sample was determined based on both practical and statistical considerations. There is no target comprehension rate specified a priori. A sample of 300 completed surveys will allow estimation of the comprehension rate for each risk message with a moderately high degree of precision. The table below shows the precision of the estimates for level of understanding using two-sided 95% confidence intervals (CIs) obtained with the sample size of 300 completed surveys. The noted CIs are used to indicate that for any survey-estimated rate of understanding, the true population rate of understanding is at least as high as the lower limit of the 95% CI and may be as high as the upper limit of the 95% CI. 10 of 30 FDA_435 TIRF REMS Industry Group (TRIG) Transmucosal Immediate Release Fentanyl (TIRF) Products Pharmacist KAB Survey Protocol Version 3.0 10 September 2012 Precision of Estimated Rates of Understanding with a Sample Size of 300 (2-sided 95% Confidence Interval) Estimated Rate of Understanding 50% 5.1.2 Estimated Confidence Interval 44.2% 55.8% 55% 49.2% 60.7% 60% 54.2% 65.6% 65% 59.3% 70.4% 70% 64.5% 75.1% 75% 69.7% 79.8% 80% 75.0% 84.4% 85% 80.4% 88.8% 90% 86.0% 93.2% 95% 91.9% 97.2% Inclusion Criteria Pharmacists who work at pharmacies that are enrolled in the TIRF REMS Access Program are eligible to participate in this survey, with the exceptions noted below. 5.1.3 Exclusion Criteria The following respondents are not eligible to participate in the surveys: • Pharmacists who have previously participated in the TIRF REMS KAB survey (this exclusion only applies to all subsequent waves). • Pharmacists or their immediate family members who have ever worked for Anesta LLC, Archimedes Pharma US Inc., Cephalon, Inc., Endo Pharmaceuticals Inc., Insys Therapeutics, Meda Pharmaceuticals, Mallinckrodt (a Covidien Company), Par Pharmaceutical, Inc., ProStrakan, Inc., Teva Pharmaceuticals, Ltd., Sandoz Inc., United BioSource Corporation, McKesson Specialty Care Solutions, RelayHealth, or the FDA 11 of 30 FDA_436 TIRF REMS Industry Group (TRIG) Transmucosal Immediate Release Fentanyl (TIRF) Products Pharmacist KAB Survey Protocol 6. Version 3.0 10 September 2012 SURVEY PROCESS The survey will begin with screening questions to confirm respondent eligibility to participate in the survey. Completion of the entire survey is expected to take approximately 15-20 minutes. 6.1 Screening and Survey Administration The questionnaire will begin with a screening module with questions to confirm pharmacist eligibility. Depending on the answers to the screening questions, survey participation could either be terminated or continued. If ineligible, the respondent is immediately notified with a “thank you” message that survey participation has ended. If eligible, the respondent is allowed to continue survey participation. The data entry system used for both methods of survey administration has been validated and is secure for receiving and storing survey data. An Internet-based data repository will be used to store survey data and other relevant program information. The system is 21 CFR Part 11 and HIPAA compliant. Pharmacist-identifying information will be stored separately from survey data. 6.1.1 Telephone A trained interviewer from the Survey Coordinating Center will conduct the telephone interviews using a CATI program. The screening and main elements of the questionnaire will be administered sequentially during the same telephone call. Telephone interviewing allows participation of pharmacists who do not have Internet access or prefer taking the survey over the phone. It will also be convenient for pharmacists to participate since they can call in and be interviewed at their convenience during the specified time period when the Survey Coordinating Center is available. 6.1.2 Internet An Internet-based survey system will also be used for conducting the KAB surveys. If the pharmacist selects to participate in the survey via the Internet, he/she will be directed to a secured website where he/she will be instructed to complete screening questions. An Internetbased survey will be convenient for respondents to participate since they can complete the questionnaire at any convenient time and location during the specified time period when the Survey Coordinating Center is available. 6.2 Measures to Minimize Bias in the Survey Process A number of controls will be in place to ensure the survey is conducted in a controlled and professional manner and to minimize bias. For example, a unique code will be given to each survey participant and the code will be inactivated after use to minimize fraud. Telephone interviewers are highly trained and use a standardized script to administer interviews. 12 of 30 FDA_437 TIRF REMS Industry Group (TRIG) Transmucosal Immediate Release Fentanyl (TIRF) Products Pharmacist KAB Survey Protocol Version 3.0 10 September 2012 All questions will be programmed to ensure that questions are asked in the appropriate sequence. Skip patterns will be clearly indicated. Respondents cannot go back to a question once the question has been answered and cannot skip ahead. All questions must be answered in order to complete the survey. Response options presented in a list will be randomized to minimize positional bias. Programming will be reviewed by quality control and simulated users (User Acceptance Testing) prior to implementing the survey. 7. ANALYSIS Information obtained from the survey will be reported as descriptive statistics for the survey administration, study population, and the survey questions. The data from the sample population will be reported using frequency distributions of responses to all questions. The following will be reported as part of this analysis: • The number of invitations issued to pharmacists • The number of respondents screened for participation • The number of respondents eligible for participation • The number of respondents who completed the survey • Representativeness of pharmacists based on geography 7.1.1 Description of Primary Analyses Primary analyses are done for all key risk messages. The primary analysis for a key risk message evaluates the rate for each correct response to each individual question/item defined by the key risk message. The specific correct response to each question/item is identified in the body of the risk message table. 7.1.2 Description of Secondary Analyses Secondary analyses are done only for those key risk messages that contain multiple questions/items. The secondary analysis entails a frequency distribution of the number of respondents who got 0, 1, etc. correct responses across the total number of items for the given key risk message. 7.1.3 Analysis Population The analysis population will be based on eligible pharmacists who completed the survey. 13 of 30 FDA_438 TIRF REMS Industry Group (TRIG) Transmucosal Immediate Release Fentanyl (TIRF) Products Pharmacist KAB Survey Protocol 8. Version 3.0 10 September 2012 SAFETY EVENT REPORTING The term ‘Safety Event’ is defined as any information reported by a survey respondent that meets the criteria of an Adverse Event, Product Complaint, or Medical Information Request. While it is not the intention of the survey to solicit the report of information that meets the criteria of a Safety Event, it is possible that a respondent may spontaneously report information that meets this criteria in free text fields of the survey (Internet-based administration) or while in conversation with the Survey Coordinating Center (telephonebased administration). The Internet-based questionnaires will be monitored for any comments recorded in the free text fields. If an event is mentioned to a Survey Coordinating Center Associate, the Associate will document the safety event and the respondent’s contact information. Respondents will also be informed that a representative from the appropriate TIRF medicine manufacturer may contact them if they have questions about the survey. Information on all reports (Internet or phone) that may constitute an adverse event or other safety event will be forwarded to the appropriate TIRF medicine manufacturer as described in the Safety Event Reporting Plan (SERP). Additional detail regarding processes for adverse event reporting will be specified in the SERP. 9. PRIVACY PROTECTION AND CONFIDENTIALITY All data collected during the survey will be held confidential. The electronic data capture (EDC) system used for data collection encrypts all identifiable information, and respondent identifiers are stored separately from the survey responses. Respondent names and addresses are collected in order to mail the $50 honorarium, a Thank You Letter, correct survey responses to key risk message questions, and the ISI after the survey is completed. Respondent contact information is also needed in the event that a safety event is reported and a TIRF medicine manufacturer must obtain follow-up information (see Section 8 above). Respondents will be informed when they access the survey that they may be contacted if there are any questions about their survey responses. Respondents will be informed that their answers to the survey questions will not affect their ability to dispense TIRF medicines. 14 of 30 FDA_439 TIRF REMS Industry Group (TRIG) Transmucosal Immediate Release Fentanyl (TIRF) Products Pharmacist KAB Survey Protocol Appendix A Version 3.0 10 September 2012 Pharmacist Questionnaire Survey Legend • [PROGRAMMER] is used to indicate directions to the programmer and is set in bold, red, uppercase letters between square brackets. • (INTERVIEWER) is used to indicate directions to the phone interviewer and is set in bold, blue, text between parentheses. This text appears when content is to be administered by phone only (for example, spontaneous adverse event reporting). • [ONLINE] indicates a question is worded specifically for administering the survey online. [PHONE] indicates a question is worded specifically to be read by a phone interviewer and differs from the online text. • [BEGIN ONLINE/PHONE SURVEY CONTENT] and [END SURVEY CONTENT] are used to indicate to the programmer the type of survey administration and the beginning and end of the survey or sections within the survey content, for example, [BEGIN ADVERSE EVENT/PRODUCT COMPLAINT] and [END ADVERSE EVENT/PRODUCT COMPLAINT]. • [TERMINATE] is displayed next to responses that should cause the survey to end. The following termination language will be programmed into the survey or read by the interviewer unless different language is specified with the question. Thank you very much for your time today. Based on your answer, you are not eligible to take this survey. We appreciate your interest in the survey. • [RANDOMIZE LIST] is inserted before questions to indicate to the programmer that the responses should be randomized. Responses such as “I don’t know,” “Prefer not to answer” or “None of the above” will always appear at the end of the randomized responses. • [GO TO Qx] (skip logic) is inserted after a response to indicate to the programmer that the survey should skip to the indicated question (for example, [GO TO Q17] skips to question 17). If no skip logic is indicated the survey continues to the next question in the sequence. • [MULTILINE INPUT] indicates to the programmer that multiple lines should be provided for data entry (for example, two address lines or a free-text response). 15 of 30 FDA_440 TIRF REMS Industry Group (TRIG) Transmucosal Immediate Release Fentanyl (TIRF) Products Pharmacist KAB Survey Protocol Version 3.0 10 September 2012 Survey Legend • [DROP-DOWN LIST INPUT WITH STATES TABLE] indicates to the programmer that the response should be a drop-down list containing the states in the table below. Alabama Georgia Massachusetts New York Tennessee Alaska Guam Michigan North Carolina Texas American Samoa Hawaii Minnesota North Dakota Idaho Mississippi Arizona Illinois Missouri Arkansas Indiana Montana Northern Mariana Islands US Virgin Islands California Iowa Nebraska Colorado Kansas Nevada Connecticut Kentucky New Hampshire Delaware Louisiana New Jersey District of Columbia Maine New Mexico Utah Vermont Ohio Virginia Oklahoma Washington Oregon West Virginia Pennsylvania Wisconsin Puerto Rico Wyoming Rhode Island Maryland Florida South Carolina South Dakota • The following is used to categorize survey populations into standard geographic regions but it is not displayed in the survey. Geographic Distribution (based on address) 1: Northeast, Midwest, South, and West regions Northeast Region − New England Division - ME, NH, VT, MA, RI, CT − Middle Atlantic Division - NY, NJ, PA Midwest Region − East North Central Division - OH, IN, IL, MI, WI − West North Central Division - MN, IA, MO, ND, SD, NE, KS South Region − South Atlantic Division - DE, MD, DC, VA, WV, NC, SC, GA, FL − East South Central Division - KY, TN, AL, MS West South Central Division - AR, LA, OK, TX West − Mountain Division - MT, ID, WY, CO, NM, AZ, UT, NV 16 of 30 FDA_441 TIRF REMS Industry Group (TRIG) Transmucosal Immediate Release Fentanyl (TIRF) Products Pharmacist KAB Survey Protocol Version 3.0 10 September 2012 Survey Legend − Pacific Division WA, OR, CA, AK, HI • The following US territories are categorized as Other: Puerto Rico, Northern Mariana Islands, US Virgin Islands, American Samoa, and Guam. 1 U.S. Census Bureau, last revised Friday, 27-Jul-2001 12:59:43 EDT. [BEGIN ONLINE/PHONE SURVEY CONTENT] [PREAMBLE 1] Before you begin, we would like to share some important information about this survey. The manufacturers of Transmucosal Immediate Release Fentanyl medicines are conducting this survey, as required by the FDA, to assess pharmacists’ understanding of the safe use and dispensing of these medicines. These medicines are known as rapid onset opioids and referred to in this survey as “TIRF medicines.” (INTERVIEWER: Say “TIRF” then spell out T-IR-F) The TIRF medicines include Abstral®, Actiq®, Fentora®, Lazanda®, Onsolis®, Subsys™, and generic versions of any of these brands. The manufacturers of these medicines include Archimedes Pharma US Inc., Cephalon, Inc., Endo Pharmaceuticals Inc., Insys Therapeutics, Meda Pharmaceuticals, Mallinckrodt (a Covidien Company), Par Pharmaceutical, Inc., ProStrakan, and Sandoz Inc. The survey will take 15-20 minutes. There are no known risks to you in taking this survey. You may refuse to take part or withdraw at any time. Your answers to the questions or your decision to take part in the survey will not affect your ability to dispense TIRF medicines. [ONLINE ONLY]How We Use Your Information [PHONE ONLY] Now I would like to read some information about how your contact information will be used. Your answers to the survey questions will be combined with answers given by other pharmacists taking the survey. All answers will be put together and reported in anonymous form to the manufacturers of TIRF medicines. Your name will not be used in any report. If you are eligible to take the survey, complete all the questions, and provide your contact information, you will receive a $50 honorarium for your time and participation. Your name and address will be used to send you the honorarium after you complete the survey. Your personal information will also be used if we have questions about your survey or if we are required to use your information to comply with a federal or state law or regulation. Providing a telephone number is optional. Your phone number will be used only if there are any questions about your survey responses. 17 of 30 FDA_442 TIRF REMS Industry Group (TRIG) Transmucosal Immediate Release Fentanyl (TIRF) Products Pharmacist KAB Survey Protocol Version 3.0 10 September 2012 [ONLINE ONLY] How We Protect Your Privacy [PHONE ONLY]Now I would like to tell you some information about how we protect your privacy. We respect that the privacy of your personal information is important to you. You will not be contacted for marketing purposes based on your personal information or your answers to the survey. Neither the manufacturers of TIRF medicines nor their contractors will sell, transfer, or rent your information. Your answers will be kept strictly confidential. Your privacy will be protected; however, research survey records may be inspected by the FDA. Your choice to allow manufacturers of TIRF medicines to use your information is entirely voluntary but necessary to take part in this survey. [ONLINE ONLY] How to Learn More about This Survey [ONLINE ONLY] If you have questions about the survey, or problems with the survey, please contact the Survey Coordinating Center at 1-877-379-3297. Be sure to write down this telephone number; it will not be displayed again. [PHONE ONLY]Now I will tell you how you can learn more about this survey. Please have a pen or pencil ready to write down a telephone number you can call should you have any questions about the survey. If you have questions about the survey, please ask me at any time. If you have questions at a later time, please contact the Survey Coordinating Center at 1-877379-3297. Please feel free to ask me to repeat any questions or statements as we go through the survey. Once you have answered a question and moved on, you cannot go back and change your answers. Thank you for your participation in this survey. [ONLINE ONLY] Taking the Survey [ONLINE ONLY] Once you have answered a question and moved on, you cannot go back and change your answers. [ONLINE ONLY] Thank you for your participation in this survey. [END PREAMBLE 1] 18 of 30 FDA_443 TIRF REMS Industry Group (TRIG) Transmucosal Immediate Release Fentanyl (TIRF) Products Pharmacist KAB Survey Protocol Version 3.0 10 September 2012 [BEGIN INCLUSION/EXCLUSION QUESTIONS] 1. Your agreement to participate in this survey confirms mutual understanding in connection with completion of the survey and the fair market value of the payment to be rendered in connection with those services. Do you agree to participate in this survey? 2. 3. 4. ○ Yes ○ No [TERMINATE] Have you ever taken part in this survey about TIRF medicines before? TIRF medicines include Abstral®, Actiq®, Fentora®, Lazanda®, Onsolis®, Subsys™, and generic versions of any of these brands. ○ Yes [ONLY TERMINATE AFTER WAVE 1] ○ No ○ I don’t know [ONLY TERMINATE AFTER WAVE 1] Do you work in a pharmacy that is enrolled in the TIRF REMS Access program? ○ Yes ○ No [TERMINATE] ○ I don’t know [TERMINATE] Have you or any of your immediate family members ever worked for any of the following companies or agencies? Please select all that apply. ○ Anesta LLC [TERMINATE] ○ Archimedes Pharma US Inc.[TERMINATE] ○ Cephalon, Inc. [TERMINATE] ○ Endo Pharmaceuticals Inc. [TERMINATE] ○ Insys Therapeutics[TERMINATE] ○ McKesson Specialty Care Solutions[TERMINATE] 19 of 30 FDA_444 TIRF REMS Industry Group (TRIG) Transmucosal Immediate Release Fentanyl (TIRF) Products Pharmacist KAB Survey Protocol Version 3.0 10 September 2012 ○ Mallinckrodt (a Covidien Company) [TERMINATE] ○ Meda Pharmaceuticals [TERMINATE] ○ Par Pharmaceutical, Inc.[TERMINATE] ○ ProStrakan, Inc. [TERMINATE] ○ Teva Pharmaceuticals, Ltd. [TERMINATE] ○ Sandoz Inc. [TERMINATE] ○ RelayHealth [TERMINATE] ○ United BioSource Corporation[TERMINATE] ○ FDA [TERMINATE] ○ None of these apply [IF SELECTED IN ADDITION TO OTHER RESPONSES, TERMINATE] ○ I don’t know [TERMINATE] ○ Prefer not to answer [TERMINATE] [END INCLUSION/EXCLUSION QUESTIONS] 20 of 30 FDA_445 TIRF REMS Industry Group (TRIG) Transmucosal Immediate Release Fentanyl (TIRF) Products Pharmacist KAB Survey Protocol 5. Version 3.0 10 September 2012 Please select “True,” “False,” or “I don’t know” for each of the following. According to the labeling, patients considered opioid-tolerant are those: [RANDOMIZE LIST] 5a. Who are taking regular opioid therapy for underlying persistent cancer pain for one week or longer 5b. Who are not currently taking opioid therapy, but have taken opioid therapy before 5c. Who are not currently taking opioid therapy, but with no known intolerance or hypersensitivity to the drug fentanyl 6. True False I don’t know ○ ○ ○ ○ ○ ○ ○ ○ ○ Please answer “True,” “False,” or “I don’t know” for each statement about TIRF medicines. [RANDOMIZE LIST] 6a. TIRF medicines are contraindicated in opioid nontolerant patients because life-threatening respiratory depression could occur at any dose. 6b. Death has occurred in opioid non-tolerant patients treated with some fentanyl products. 6c. TIRF medicines may be used in opioid non-tolerant patients. 6d. Prescribers starting a patient on a TIRF medicine must begin with titration from the lowest dose available for that specific product, even if the patient has previously taken another TIRF medicine. 6e. It is important to monitor for signs of abuse and addiction in patients who take TIRF medicines. 21 of 30 True False I don’t know ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ FDA_446 TIRF REMS Industry Group (TRIG) Transmucosal Immediate Release Fentanyl (TIRF) Products Pharmacist KAB Survey Protocol 7. Version 3.0 10 September 2012 Which of the following are risk factors for opioid abuse? Please answer “Yes,” “No,” or “I don’t know” for each option. [RANDOMIZE LIST] Yes No I don’t know ○ ○ ○ ○ ○ ○ ○ ○ ○ 7a. A personal history of psychiatric illness 7b. A personal history of past or current alcohol or drug abuse, or a family history of illicit drug use or alcohol abuse 7c. A family history of asthma 8. For which of the following indications can TIRF medicines be prescribed to opioid tolerant patients? Answer “Yes,” “No,” or “I don’t know” for each option. [RANDOMIZE LIST] 8a. 8b. 8c. 8d. 8e. 9. No I don’t know ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ Acute or postoperative pain Headache or migraine pain Dental pain Breakthrough pain from cancer Chronic non-cancer pain Please answer “True,” “False,” or “I don’t know” for each statement about TIRF medicines. [RANDOMIZE LIST] 9a. TIRF medicines can be abused in a manner similar to other opioid agonists. 9b. TIRF medicines are interchangeable with each other regardless of route of administration. 9c. The conversion of one TIRF medicine for another TIRF medicine may result in a fatal overdose because of differences in the pharmacokinetics of fentanyl absorption. 9d. Dosing of TIRF medicines is not equivalent on a microgram-to-microgram basis. 10. Yes True False I don’t know ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ How frequently do you perform the following activities when dispensing TIRF 22 of 30 FDA_447 TIRF REMS Industry Group (TRIG) Transmucosal Immediate Release Fentanyl (TIRF) Products Pharmacist KAB Survey Protocol Version 3.0 10 September 2012 medicines? Please answer “Always,” “Only with the first prescription,” “Sometimes,” “Never,” or “I don’t know.” [RANDOMIZE LIST] 10a. Ask patients (or their caregivers) about the presence of children in the home 10b. Instruct patients (or their caregivers) not to share TIRF medicines with anyone else 10c. Counsel patients (or their caregivers) that accidental exposure to TIRF medicines by a child may be fatal 10d. Instruct patients (or their caregivers) to keep TIRF medicines out of the reach of children to prevent accidental exposure 10e. Instruct patients (or their caregivers) about proper disposal of any unused or partially used TIRF medicines 10f. Give patients (or their caregivers) the Medication Guide for their TIRF medicine 11. Always Only with Sometimes the first prescription Never I don’t know ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ Please answer “True,” “False,” or “I don’t know ” for each statement about TIRF medicines. [RANDOMIZE LIST] 11a. TIRF medicines may be sold, loaned, or transferred to another pharmacy. 11b. All pharmacy staff that dispenses TIRF medicines must be educated on the requirements of the TIRF REMS Access program. 23 of 30 True False I don’t know ○ ○ ○ ○ ○ ○ FDA_448 TIRF REMS Industry Group (TRIG) Transmucosal Immediate Release Fentanyl (TIRF) Products Pharmacist KAB Survey Protocol 11c. TIRF medicines with the same route of administration can be substituted with each other if the pharmacy is out of stock for one product. 12. 13. 14. Version 3.0 10 September 2012 ○ ○ ○ [INPATIENT PHARMACIST]Does the inpatient pharmacy where you work have an established system, order sets, protocols and/or other measures to help ensure appropriate patient selection and compliance with the requirements of the TIRF REMS Access Program? ○ Yes ○ No ○ I don’t know [OUTPATIENT PHARMACIST]Does the outpatient or retail pharmacy where you work process all TIRF medicine prescriptions, regardless of method of payment, through the pharmacy management system? ○ Yes ○ No ○ I don’t know [CSP OUTPATIENT PHARMACIST]Does the pharmacy where you work process all TIRF medicine prescriptions, regardless of method of payment, through the TIRF REMS Access Call Center? ○ Yes ○ No ○ I don’t know 24 of 30 FDA_449 TIRF REMS Industry Group (TRIG) Transmucosal Immediate Release Fentanyl (TIRF) Products Pharmacist KAB Survey Protocol 15. Version 3.0 10 September 2012 [INPATIENT PHARMACIST] Please answer “True,” “False,” or “I don’t know” for the following statement about TIRF medicines. It is OK to dispense TIRF medicines from the inpatient pharmacy inventory to an outpatient for use at home. True False I don’t know ○ ○ ○ [PREAMBLE 3] The next set of questions is about the educational materials for TIRF medicines. As a reminder, the TIRF medicines include Abstral®, Actiq®, Fentora®, Lazanda®, Onsolis®, Subsys™, and generic versions of any of these brands. 16. 17. 18. Did you receive or do you have access to the Full Prescribing Information for the TIRF medicine that you dispense? ○ Yes ○ No [GO TO Q18] ○ I don’t know [GO TO Q18] Did you read the Full Prescribing Information for the TIRF medicine that you dispense? ○ Yes ○ No ○ I don’t know Did you receive or do you have access to the Medication Guide for the TIRF medicine that you dispense? ○ Yes ○ No [GO TO Q20] ○ I don’t know [GO TO Q20] 25 of 30 FDA_450 TIRF REMS Industry Group (TRIG) Transmucosal Immediate Release Fentanyl (TIRF) Products Pharmacist KAB Survey Protocol 19. 20. 21. Version 3.0 10 September 2012 Did you read the Medication Guide for the TIRF medicine that you dispense? ○ Yes ○ No ○ I don’t know Did you or do you have any questions about the information in the Full Prescribing Information or Medication Guide? ○ Yes ○ No [GO TO DEMOGRAPHICS PREAMBLE ] ○ I don’t know [GO TO DEMOGRAPHICS PREAMBLE] What are your questions?[MULTILINE INPUT] [DEMOGRAPHICS PREAMBLE] There are just a few more questions to help us combine your answers with other answers we have received. 22. 23. Are you the Pharmacist in Charge for the TIRF REMS Access Program where you work? ○ Yes ○ No ○ I don’t know On average, how many times per month have you dispensed TIRF medicines within the last 6 months? ○ None [Go to DEMOGRAPHICS PREAMBLE 2] ○ 1 – 2 times per month ○ 3 – 5 times per month 26 of 30 FDA_451 TIRF REMS Industry Group (TRIG) Transmucosal Immediate Release Fentanyl (TIRF) Products Pharmacist KAB Survey Protocol 24. ○ More than 5 times per month ○ I don’t remember Version 3.0 10 September 2012 Please select the TIRF medicines that you have dispensed within the last 6 months (select all that apply): ○ Abstral® ○ Actiq® or generic Actiq® ○ Fentora® or generic Fentora® ○ Lazanda ® ○ Onsolis® ○ Subsys™ [DEMOGRAPHICS PREAMBLE 2] These last few questions are for demographic purposes. 25. 26. What is your gender? ○ Male ○ Female ○ Prefer not to answer In total, how many years have you been a practicing pharmacist? ○ Less than 3 years ○ 3 – 5 years ○ 6 – 10 years ○ 11 – 15 years ○ More than 15 years ○ Prefer not to answer 27 of 30 FDA_452 TIRF REMS Industry Group (TRIG) Transmucosal Immediate Release Fentanyl (TIRF) Products Pharmacist KAB Survey Protocol 27. Version 3.0 10 September 2012 In which state do you practice? [DROP-DOWN LIST INPUT WITH STATES TABLE WITH “Prefer not to answer” AT END] [PHONE ONLY: BEGIN ADVERSE EVENT/PRODUCT COMPLAINT] (INTERVIEWER: Please record if respondent spontaneously reported an adverse event or product complaint during the course of this interview.) ○ Yes ○ No [GO TO CLOSING 1] Enter Safety Adverse Event Verbatim [MULTILINE INPUT] (INTERVIEWER: Indicate to the respondent that someone may call back to ask more questions about the adverse event or product complaint that was reported.) [END ADVERSE EVENT/PRODUCT COMPLAINT] 28 of 30 FDA_453 TIRF REMS Industry Group (TRIG) Transmucosal Immediate Release Fentanyl (TIRF) Products Pharmacist KAB Survey Protocol Version 3.0 10 September 2012 [CLOSING 1] We would like to send you a $50 honorarium within the next few weeks to thank you for your time, but we need your name and address to do so. If you do not provide your name and address you will not receive the honorarium for your time and participation in the survey. Do you agree to give us your name and mailing address so we can send you the honorarium? ○ Yes ○ No [SKIP TO CLOSING 2] FIRST NAME: _______________________________________________ LAST NAME: _______________________________________________ ADDRESS: [MULTILINE INPUT] CITY: _____________________________________ STATE: [DROP-DOWN LIST INPUT WITH STATES TABLE] ZIP: ___________ [CLOSING 2] We would also like to ask for your telephone number. Providing your telephone number is optional and it will be used to contact you only if there are questions about your survey responses.  Do you want to provide your telephone number? ○ Yes ○ No [SKIP TO CLOSING 3] Telephone: ________________________________ [CLOSING 3] That ends the survey. Thank you again for your help. [END OF SURVEY CONTENT] 29 of 30 FDA_454 TIRF REMS Industry Group (TRIG) Transmucosal Immediate Release Fentanyl (TIRF) Products Pharmacist KAB Survey Protocol Appendix B Version 3.0 10 September 2012 Sample Pharmacist Invitation Letter [CURR_DATE] [PHARMACY NAME or NAME OF PHARMACIST IN CHARGE] [STREET_ADDR] [CITY], [STATE] [ZIP] Dear [NAME OF PHARMACIST IN CHARGE]: You were selected to receive this letter because you have enrolled in the TIRF REMS Access Program. We are contacting you to inform you about a survey being conducted by the manufacturers of Transmucosal Immediate Release Fentanyl (TIRF) medicines, as required by the Food and Drug Administration (FDA). The purpose of the survey is to assess pharmacists’ understanding of the safe and appropriate use of these medicines. The TIRF medicines include Abstral®, Actiq®, Fentora®, Lazanda®, Onsolis®, Subsys™, and generic versions of any of these brands. The manufacturers of TIRF medicines include Archimedes Pharma US Inc., Cephalon, Inc., Endo Pharmaceuticals Inc., Insys Therapeutics, Meda Pharmaceuticals, Mallinckrodt (a Covidien Company), Par Pharmaceutical, Inc., ProStrakan, Inc., and Sandoz Inc (collectively referred to as the “TIRF Industry REMS Group”). These manufacturers are looking for 200 pharmacists to complete the survey. Eligible pharmacists who complete the survey will be sent a $50 honorarium to thank them for their time. The survey will take 15-20 minutes. Your answers will be kept strictly confidential and will be combined with the answers from other pharmacists who take this survey. Your name will not be used in the report of this survey and your contact information will only be used to send you a $50 honorarium for the time you took to complete the survey. You are under no obligation to participate in this survey. If you are interested in participating, go to www.XXXXXXXXXX.com anytime or call 1-877-379-3297, 8AM to 10PM Eastern Time Monday through Friday. You will be asked to give this unique code prior to starting the survey: [CODE_ID]. Please have this letter with you at the time you take the survey. Thank you in advance for your help with this important effort. Sincerely, TIRF Industry REMS Group * We recommend that you take the survey on a desktop or laptop computer. Taking the survey on mobile devices, such as smart phones, tablets, and e-notebooks, is not supported. 30 of 30 FDA_455 Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Appendix B December 2012 Pharmacy KAB Assessment Report Pharmacy Survey Listings and Subanalysis Tables Page 43 of 46 FDA_456 Transrnucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies December 2012 Pharmacy KAB Assessment Report Pharmacy Listings Listing 1 CATEGORIZATION OF VERBATIM RESPONSES TO QUESTION 21 (Questions about the information in the Full Prescribing Information or Medication Guide) Verbatim Response Categorized Response How can I trust a prescription is not being abused without a diagnosis code ??orn MD Abuse monitoring How do I take it?? Will it make me tired? Dosage. side effects Why should the pharmacist be liable to dispense a medication guide with each ?ll. Liability and responsibility should be from the prescriber Medication Guide distribution Is there an all inclusive guide to dispensing IIRF REMS meds it seems I have to go to each one separately and it's really inconvenient Medication Guide distribution/fonnat Meant to answer "no" General responses Meant to answer no 011 previous question General responses General responses None General responses Nothing right now in General responses Thanks for sharing these info! General responses I need the prescribing information Prescribing information request How exactly does ?lling a prescription for a patient REMS process who pays for it cash get properly monitored?? (we do process it to REMSCASH) Who is this monitored by? REMS process Page 44 of 46 Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies December 2012 Pharmacy KAB Assessment Report Listing 2 CATEGORIZATION OF VERBATIM RESPONSES TO REPORTED SAFETY EVENTS OR PRODUCT COMPLAINTS Verbatim Response Categorized Response How can I trust a prescription is not being abused without a diagnosis code from MD Abuse monitoring How do I take it?? Will it make me tired? Dosage. Side effects How exactly does ?lling a prescription for a patient who pays for it cash get properly monitored?? (we do process it to REMSCASH) REMS process I need the prescribing information Prescribing Infonnation request Is there an all inclusive guide to dispensing TIRF REMS rneds it seems I have to go to each one separately and it's really inconvenient Medication Guide distribution/fonnat Page 45 of 46 Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies December 2012 Pharmacy KAB Assessment Report Pharmacy Subanalysis Tables Page 46 of 46 FDA_459 TABLE 6.1.2 TO KEY RISK MESSAGE #1 PRIMARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED KEY RISK MESSAGE l: TIRF MEDICINES ARE CONTRAINDICATED IN OPIOID PATIENTS. SUBGROUP ANALYSIS 2: TIME TO COMPLETE SURVEY - INTERNET S?2a <10 min 0 S-2b 10 to <20 min 0 S-2c ?2 20 min Question S?2a <10 min S?2b 10 to <20 min S?2c 20 min (95% CI) (95% CI) (95% CI) Question 6: Please answer ?True,? ?False,? or don?t know? for each statement about TIRF medicines. 6a: TIRF medicines are contraindicated in opioid non?tolerant patients because life?threatening respiratory depression could occur at any dose. True 122 86.5 102 84.3 21 87.5 (79.8. (76.6. (67.6. 91.7) 90.3) 97.3) Incorrect response False 11 7.8 13 10.7 0 0.0 I don't know 8 5.7 6 5.0 3 12.5 6b: Death has occurred in opioid non-tolerant patients treated with some fentanyl products. correct response True 131 92.9 109 90.1 22 91.7 (87.3. (83.3. (73.0. 96.5) 94.8) 99.0) Incorrect response False don't know 7 5.0 10 8.3 2 8.3 Client: TRIG Project: TIRFKAB Report Run Date and Time: 11/13/2012 1:57 PM Page 1 of 2 S-2a - <10 min S-2b - 10 to <20 min S-2c - 20 min N=l4l Question (95% CI) (95% CI) (95% CI) 6c: TIRF medicines may be used in opioid non-tolerant patients. Correct response False 115 81.6 89 73.6 20 83.3 (74.2. (64.8. (62.6. 87.6) 81.2) 95.3) Incorrect response True 19 13.5 25 20.7 2 8.3 I don't know 7 5.0 7 5.8 2 8.3 6d: Prescribers starting a patient on a TIRF medicine must begin with titration from the lowest dose available for that speci?c product, even if the patient has previously taken another TIRF medicine. True 112 79.4 91 75.2 21 87.5 (71.8. (66.5. (67.6. 85.8) 82.6) 97.3) Incorrect response False 21 14.9 22 18.2 2 8.3 I don't know 8 5.7 8 6.6 1 4.2 Client: TRIG Project: TIRFKAB Report Run Date and Time: 11/13/2012 1:57 PM Page 2 of2 TABLE 6.2.2 SECONDARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #1 KEY RISK MESSAGE l: TIRF MEDICINES ARE CONTRAINDICATED IN OPIOID PATIENTS. SUBGROUP ANALYSIS 2: TIME TO COMPLETE SURVEY - INTERNET S?2a <10 min 0 S-2b 10 to <20 min 0 S-2c 20 min S-2a - <10 min S-2b - 10 to <20 min S-2c - 20 min N=l4l 33:22:33.2: (95% (95% (95% CD CD CD 0 correct responses correct response correct responses 12 8.5 21 17.4 1 4.2 3 correct responses 36 25.5 34 28.1 4 16.7 4 correct responses 85 60.3 61 50.4 17 70.8 Av?fage ?lube? 0f 3.4 (3.1. 4.0) 3.2 (3.0. 4.0) 3.5 (2.9. 4.0) conect responses Client: TRIG Project: TIRF KAB Report Run Date and Time: 11/13/2012 2:06 PM Page 1 of TABLE 7.1.2 TO KEY RISK MESSAGE #2 PRIMARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED KEY RISK MESSAGE 2: TIRF MEDICINES ARE ONLY INDICATED FOR THE MANAGEMENT OF BREAKTHROUGH PAIN IN ADULT CANCER PATIENTS 18 YEARS OF AGE AND OLDER (16 YEARS OF AGE AND OLDER FOR BRAND AND GENERIC EQUIVALENTS) WHO ARE ALREADY RECEIVING AND WHO ARE TOLERANT TO AROUND-THE-CLOCK OPIOID THERAPY FOR THEIR UNDERLYING PERSISTENT CANCER PAIN. SUBGROUP ANALYSIS 2: TIME TO COMPLETE SURVEY - INTERNET S-2a <10 min 0 S?2b 10 to <20 min 0 S?2c 20 min Question S?2a <10 min N=l41 S?2b 10 to <20 min S?2c - 20 min (95% CI) (95% CI) (95% CI) Question 8: For which of the following indications can TIRF medicines be prescribed to opioid tolerant patients? Please answer ?Yes,? or don?t know? for each option. 8a: Acute or postoperative pain No 107 75.9 97 80.2 22 91.7 (68.0. (71.9. (73.0. 82.7) 86.9) 99.0) Incorrect response Yes 28 19.9 18 14.9 1 4.2 I don't know 6 4.3 6 5.0 1 4.2 8b: Headache or migraine pain Correct response No 123 87.2 111 91.7 22 91.7 (80.6. (85.3. (73.0. 92.3) 96.0) 99.0) Incorrect response Yes 8 5.7 2 1.7 4.2 I don't know 10 7.1 8 6.6 1 4.2 Client: TRIG Project: TIRFKAB Report Run Date and Time: 11/13/2012 2:09 PM Page 1 of 2 S-2a - <10 min S-2b - 10 to <20 min S-2c - 20 min N=l4l Question (95% CI) (95% CI) (95% CI) 8c: Dental pain Correct response No 132 93.6 115 95.0 23 95.8 (88.2. (89.5. (78.9. 97.0) 98.2) 99.9) Incorrect response Yes 4 2.8 0.8 4.2 I don't know 5 3.5 5 4.1 0 0.0 8d: Breakthrough pain from cancer Correct response Yes 122 86.5 96 79.3 21 87.5 (79.8. (71.0. (67.6. 91.7) 86.2) 97.3) Incorrect response No 18 12.8 23 19.0 2 8.3 I don't know 1 0.7 2 1.7 1 4.2 Client: TRIG Project: TIRFKAB Report Run Date and Time: 11/13/2012 2:09 PM Page 2 of 2 TABLE 7.2.2 SECONDARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #2 KEY RISK MESSAGE 2: TIRF MEDICINES ARE ONLY INDICATED FOR THE MANAGEMENT OF BREAKTHROUGH PAIN IN ADULT CANCER PATIENTS 18 YEARS OF AGE AND OLDER (16 YEARS OF AGE AND OLDER FOR BRAND AND GENERIC EQUIVALENTS) WHO ARE ALREADY RECEIVING AND WHO ARE TOLERANT TO AROUND-THE-CLOCK OPIOID THERAPY FOR THEIR UNDERLYING PERSISTENT CANCER PAIN. SUBGROUP ANALYSIS 2: TIME TO COMPLETE SURVEY - INTERNET S?2a <10 min 0 S?2b 10 to <20 min 0 S?2c 20 min S-2a - <10 min S-2b - 10 to <20 S-2c - 20 min N=l41 min Demonstrated Understanding (95% CI) (95% CI) (95% CI) 0 correct responses correct response correct responses 5 3.5 9 7.4 4.2 3 correct responses 48 34.0 31 25.6 3 12.5 4 correct responses 81 57.4 76 62.8 19 79.2 Average number 0f com? 3 .4 (3.2. 4.0) 3.5 (3 .2. 4.0) 3.7 (3 .0. 4.0) lesponses Client: TRIG Project: TIRF KAB Report Run Date and Time: 11/13/2012 2:11 PM Page 1 of 1 TABLE 8.1.2 PRIMARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #3 KEY RISK MESSAGE 3: TIRF MEDICINES CONTAIN FENTANYL, AN OPIOID AGONIST AND A SCHEDULE II CONTROLLED SUBSTANCE, WITH ABUSE LIABILITY SIMILAR TO OTHER OPIOID ANALGESICS. SUBGROUP ANALYSIS 2: TIME TO COMPLETE SURVEY - INTERNET S-2a - <10 min 0 S-2b 10 to <20 min 0 S?2c 2 20 min S?2a - <10 min S?2b - 10 to <20 min S-2c 20 min N=l4l Question (95% CI) (95% CI) (95% CI) Question 6: Please answer ?True,? ?False,? or don?t know? for each statement about TIRF medicines. 6e: It is important to monitor for signs of abuse and addiction in patients who take TIRF medicines. Con?ect response Tme 138 97.9 118 97.5 24 100.0 (93.9. (92.9. (85.8. 99.6) 99.5) 100.0) Inconect response False don't know 1 0.7 1 0.8 0 0.0 Question 7: Which of the following are risk factors for opioid abuse? Please answer ?Yes,? or don?t know? for each option. 7a: A personal history of illness Yes 99 70.2 76 62.8 17 70.8 (61.9. (53.6. (48.9. 77.6) 71.4) 87,4) No 26 18.4 27 22.3 4 16.7 I don't know 16 11.3 18 14.9 3 12.5 Client: TRIG Project: TIRFKAB Report Run Date and Time: 11/13/2012 2:13 PM Page 1 of2 Question S-2a - <10 min S-2b - 10 to <20 min S-2c - 20 min (95% CI) (95% CI) (95% CI) 7b: A personal history of past or current alcohol or drug abuse, or a family history of illicit drug use or alcohol abuse Yes 141 100.0 120 99.2 24 100.0 (97.4. (95.5. (85.8. 100.0) 100.0) 100.0) Incorrect response don't know 0 0.0 1 0.8 0 0.0 Question 9: Please answer ?True,? ?False,? or don?t know? for each statement about TIRF medicines. 9a: TIRF medicines can be abused in a manner similar to other opioid agonists. True 127 90.1 109 90.1 22 91.7 (83.9. (83.3. (73.0. 94.5) 94.8) 99.0) Incorrect response False don't know 5 3.5 4 3.3 0 0.0 Client: TRIG Project: TIRFKAB Report Run Date and Time: 11/13/2012 2:13 PM Page 2 of 2 TABLE 8.2.2 LINKED TO KEY RISK MESSAGE #3 SECONDARY ANALYSIS OF RESPONSES TO QUESTIONS KEY RISK MESSAGE 3: TIRF MEDICINES CONTAIN FENTANYL, AN OPIOID AGONIST AND A SCHEDULE II CONTROLLED SUBSTANCE, WITH ABUSE LIABILITY SIMILAR TO OTHER OPIOID ANALGESICS. SUBGROUP ANALYSIS 2: TIME TO COMPLETE SURVEY - INTERNET S?2a <10 min 0 S-2b 10 to <20 min 0 S-2c 20 min S-2a - <10 min S-2b - 10 to <20 S-2c - 20 min N=l4l min Demonstrated Understanding (95% (95% (95% CI) CI) CI) 0 correct responses correct response correct responses correct responses 49 34.8 45 37.2 7 29.2 4 correct responses 87 61.7 69 57.0 16 66.7 Average number 0f com? 3.6 (3.3. 4.0) 3.5 (3.2. 4.0) 3 .6 (3.0. 4.0) responses Client: TRIG Project: TIRFKAB Report Run Date and Time: 11/13/2012 2:15 PM Page 1 of TABLE 9.1.2 PRIMARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #4 KEY RISK MESSAGE 4: TIRF MEDICINES ARE NOT INTERCHANGEABLE WITH EACH OTHER, REGARDLESS OF ROUTE OF ADMINISTRATION. SUBGROUP ANALYSIS 2: TIME TO COMPLETE SURVEY - INTERNET S?2a <10 min 0 S-2b 10 to <20 min 0 S-2c 20 min S-2a - <10 min S-2b - 10 to <20 min S-(95% CI) (95% CI) (95% CI) TIRF medicines. Question 9: Please answer ?True,? ?False,? or don?t know? for each statement about 9b: TIRF medicines are interchangeable with each other regardless of route of administration. Correct response False 135 95.7 115 95.0 23 95.8 (91.0. (89.5. (78.9. 98.4) 98.2) 99.9) Incorrect response True don't know 4 2.8 1 0.8 0 0.0 9c: The conversion of one TIRF medicine for another TIRF medicine may result in a fatal overdose because of differences in the pharmacokinetics of fentanyl absorption. Correct response True 131 92.9 113 93.4 21 87.5 (87.3. (87.4. (67.6. 96.5) 97.1) 97.3) Incorrect response False don't know 6 4.3 3 2.5 2 8.3 Client: TRIG Project: TIRFKAB Report Run Date and Time: 11/13/2012 2:16 PM Page 1 of 2 S-2a - <10 min S-2b - 10 to <20 min S-2c - 20 min N=l4l Question (95% CI) (95% CI) (95% CI) 9d: Dosing of TIRF medicines is not equivalent on a microgram-to-microgram basis. Correct response True 131 92.9 113 93.4 23 95.8 (87.3. (87.4. (78.9. 96.5) 97.1) 99.9) Incorrect response False don't know 4 2.8 6 5.0 1 4.2 Client: TRIG Project: TIRFKAB Report Run Date and Time: 11/13/2012 2:16 PM Page 2 of2 TABLE 9.2.2 LINKED TO KEY RISK MESSAGE #4 SECONDARY ANALYSIS OF RESPONSES TO QUESTIONS KEY RISK MESSAGE 4: TIRF MEDICINES ARE NOT INTERCHANGEABLE WITH EACH OTHER, REGARDLESS OF ROUTE OF ADMINISTRATION. SUBGROUP ANALYSIS 2: TIME TO COMPLETE SURVEY - INTERNET S?2a <10 min 0 S-2b 10 to <20 min 0 S-2c 2 20 min S-2a - <10 min S-2b - 10 to <20 S?2c - 20 min min Demonstrated Understanding (95% CI) (95% CI) (95% CI) 0 correct responses 1 0.7 0.8 1 4.2 1 correct response correct responses 17 12.1 17 14.0 2 8.3 3 correct responses 120 85.1 102 84.3 21 87.5 Average ?lube? 0f com? 2.8 (2.6. 3.0) 2.8 (2.6. 3.0) 2.8 (2.2. 3.0) responses Client: TRIG Project: TIRFKAB Report Run Date and Time: 11/13/2012 2:17 PM Page 1 of TABLE 6.1.4 PRIMARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #1 KEY RISK MESSAGE l: TIRF MEDICINES ARE CONTRAINDICATED IN OPIOID PATIENTS. SUB-GROUP ANALYSIS 4: MODALITY TO COMPLETE SURVEY: S-4a - Internet 0 S-4b - Telephone S?4a Internet S?4b Telephone ti N=l6 ues on (95% CI) (95% CI) Question 6: Please answer ?True,? ?False,? or don?t know? for each statement about TIRF medicines. 6a: TIRF medicines are contraindicated in opioid non?tolerant patients because life?threatening respiratory depression could occur at any dose. correct response Tnle 245 85.7 15 93.8 (81.1. 89.5) (69.8. 99.8) Inconect response False 24 8.4 0 0.0 I don't know 17 5.9 1 6.3 6b: Death has occurred in opioid non-tolerant patients treated with some fentanyl products. True 262 91.6 16 100.0 (87.8. 94.5) (79.4. 100.0) Incorrect response False 5 1.7 0 0.0 I don?t know 19 6.6 0 0.0 Client: TRIG Project: TIRF KAB Report Run Date and Time: 11/7/2012 4:21 PM Page 1 of 2 S-4a - Internet S-4b - Telephone N=l6 Question (95% CI) (95% CI) 6c: TIRF medicines may be used in opioid non-tolerant patients. Correct response False 224 78.3 13 81.3 (73.1. 83.0) (54.4. 96.0) Incorrect response True 46 16.1 2 12.5 I don't know 16 5.6 1 6.3 6d: Prescribers starting a patient on a TIRF medicine must begin with titration from the lowest dose available for that speci?c product, even if the patient has previously taken another TIRF medicine. Correct response True 224 78.3 13 81.3 (73.1. 83.0) (54.4. 96.0) Incorrect response False 45 15.7 1 6.3 I don't know 17 5.9 2 12.5 Client: TRIG Project: TIRFKAB Report Run Date and Time: 11/7/2012 4:21 PM Page 2 of 2 TABLE 7.1.4 PRIMARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #2 KEY RISK MESSAGE 2: TIRF MEDICINES ARE ONLY INDICATED FOR THE MANAGEMENT OF BREAKTHROUGH PAIN IN ADULT CANCER PATIENTS 18 YEARS OF AGE AND OLDER (16 YEARS OF AGE AND OLDER FOR BRAND AND GENERIC EQUIVALENTS) WHO ARE ALREADY RECEIVING AND WHO ARE TOLERANT TO AROUND-THE-CLOCK OPIOID THERAPY FOR THEIR UNDERLYING PERSISTENT CANCER PAIN. SUB-GROUP ANALYSIS 4: MODALITY TO COMPLETE SURVEY: S-4a - Internet 0 S-4b - Telephone Question S-4a - Internet S?4b - Telephone N=l6 (95% CI) (95% CI) Question 8: For which of the following indications can TIRF medicines be prescribed to opioid tolerant patients? Please answer ?Yes,? or don?t know? for each option. 8a: Acute or postoperative pain correct response No 226 79.0 10 62.5 (73.8. 83.6) (35.4. 84.8) Inconect response Yes 47 16.4 5 31.3 I don't know 13 4.5 1 6.3 8b: Headache or migraine pain Con?ect response No 256 89.5 13 81.3 (85.4. 92.8) (54.4. 96.0) Inconect response Yes 11 3.8 1 6.3 I don't know 19 6.6 2 12.5 Client: TRIG Project: TIRFKAB Report Run Date and Time: 11/8/2012 3:38 PM Page 1 of 2 S-4a - Internet S?4b - Telephone N=l6 Question (95% CI) (95% CI) 8c: Dental pain Correct response No 270 94.4 16 100.0 (91.1. 96.8) (79.4. 100.0) Incorrect response Yes 6 2.1 0 0.0 I don't know 10 3.5 0 0.0 8d: Breakthrough pain from cancer Correct response Yes 239 83.6 13 81.3 (78.8. 87.7) (54.4. 96.0) Incorrect response No 43 15.0 3 18.8 I don't know 4 1.4 0 0.0 Client: TRIG Project: TIRFKAB Report Run Date and Time: 11/8/2012 3:38 PM Page 2 of 2 TABLE 7.2.4 SECONDARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #2 KEY RISK MESSAGE 2: TIRF MEDICINES ARE ONLY INDICATED FOR THE MANAGEMENT OF BREAKTHROUGH PAIN IN ADULT CANCER PATIENTS 18 YEARS OF AGE AND OLDER (16 YEARS OF AGE AND OLDER FOR BRAND AND GENERIC EQUIVALENTS) WHO ARE ALREADY RECEIVING AND WHO ARE TOLERANT TO AROUND-THE-CLOCK OPIOID THERAPY FOR THEIR UNDERLYING PERSISTENT CANCER PAIN. SUB-GROUP ANALYSIS 4: MODALITY TO COMPLETE SURVEY: S-4a - Internet 0 S-4b - Telephone S-4a - Internet S-4b - Telephone Demonstrated Understanding (95% CI) (95% CI) 0 correct responses 2 0.7 0 0.0 I cared response 11 3.8 0 0.0 2 correct responses 15 5.2 4 25.0 3 correct responses 82 28.7 4 25.0 4 correct responses 176 61.5 8 50.0 Average number of correct 3.5 (3.3. 4.0) 3.3 (2.5. 4.0) responses Client: TRIG Project: TIRFKAB Report Run Date and Time: 11/8/2012 2:51 PM Page 1 of TABLE 8.1.4 PRIMARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #3 KEY RISK MESSAGE 3: TIRF MEDICINES CONTAIN FENTANYL, AN OPIOID AGONIST AND A SCHEDULE II CONTROLLED SUBSTANCE, WITH ABUSE LIABILITY SIMILAR TO OTHER OPIOID ANALGESICS. SUB-GROUP ANALYSIS 4: MODALITY TO COMPLETE SURVEY: S-4a - Internet 0 S-4b - Telephone S?4a Internet S?4b Telephone ti N=l6 ues on (95% CI) (95% CI) Question 6: Please answer ?True,? ?False,? or don?t know? for each statement about TIRF medicines. 6e: It is important to monitor for signs of abuse and addiction in patients who take TIRF medicines. Con?ect response True 280 97.9 15 93.8 (95.5. 99.2) (69.8. 99.8) Inconect response False 4 1.4 1 6.3 I don't know 2 0.7 0 0.0 Question 7: Which of the following are risk factors for opioid abuse? Please answer ?Yes,? or don?t know? for each option. 7a: A personal history of illness Con?ect response Yes 192 67.1 9 56.3 (61.4. 72.5) (29.9. 80.2) Inconect response No 57 19.9 5 31.3 I don't know 37 12.9 2 12.5 Client: TRIG Project: TIRF KAB Report Run Date and Time: 11/7/2012 4:31 PM Page 1 of 2 S-4a - Internet S-4b - Telephone N=l6 ues on (95% CI) (95% CI) 7b: A personal history of past or current alcohol or drug abuse, or a family history of illicit drug use or alcohol abuse Con'ect response Yes 285 99.7 16 100.0 (98.1. 100.0) (79.4. 100.0) Incorrect response No 0 0.0 0 0.0 I don't know 1 0.3 0 0.0 Question 9: Please answer ?True,? ?False,? or don?t know? for each statement about TIRF medicines. 9a: TIRF medicines can be abused in a manner similar to other opioid agonists. Correct response True 258 90.2 15 93.8 (86.2. 93.4) (69.8. 99.8) Incorrect response False 19 6.6 0 0.0 I don't know 9 3.1 1 6.3 Client: TRIG Project: TIRF KAB Report Run Date and Time: 11/7/2012 4:31 PM Page 2 of 2 TABLE 8.2.4 SECONDARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #3 KEY RISK MESSAGE 3: TIRF MEDICINES CONTAIN FENTANYL, AN OPIOID AGONIST AND A SCHEDULE II CONTROLLED SUBSTANCE, WITH ABUSE LIABILITY SIMILAR TO OTHER OPIOID ANALGESICS. SUB-GROUP ANALYSIS 4: MODALITY TO COMPLETE SURVEY: S-4a - Internet 0 S-4b - Telephone S?4a - Internet S?4b - Telephone Demonstrated Understanding (95% CI) (95% CI) 0 correct responses 1 0.3 0 0.0 1 correct response 0 0.0 0 0.0 2 correct responses 12 4.2 1 6.3 3 conect responses 101 35.3 7 43.8 4 correct responses 172 60.1 8 50.0 Average number of con'ect responses 3.5 (3.4. 4.0) 3.4 (2.7. 4.0) Client: TRIG Project: TIRF KAB Report Run Date and Time: 11/8/2012 2:51 PM Page 1 of 1 TABLE 9.1.4 PRIMARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #4 KEY RISK MESSAGE 4: TIRF MEDICINES ARE NOT INTERCHANGEABLE WITH EACH OTHER, REGARDLESS OF ROUTE OF ADMINISTRATION. SUB-GROUP ANALYSIS 4: MODALITY TO COMPLETE SURVEY: S-4a - Internet 0 S-4b - Telephone S-4a - Internet S-4b - Telephone N=l6 Question (95% CI) (95% CI) Question 9: Please answer ?True,? ?False,? or don?t know? for each statement about TIRF medicines. 9b: TIRF medicines are interchangeable with each other regardless of route of administration. Correct response False 273 95.5 14 87.5 (92.4. 97.6) (61.7. 98.4) Incorrect response True 8 2.8 1 6.3 I don't know 5 1.7 1 6.3 9c: The conversion of one TIRF medicine for another TIRF medicine may result in a fatal overdose because of differences in the pharmacokinetics of fentanyl absorption. Conect response True 265 92.7 15 93 .8 (89.0. 95.4) (69.8. 99.8) Incorrect response False 10 3.5 0 0.0 I don't know 11 3.8 1 6.3 Client: TRIG Project: TIRFKAB Report Run Date and Time: 11/7/2012 4:35 PM Page 1 of 2 S-4a - Internet S-4b - Telephone N=l6 Question (95% CI) (95% CI) 9d: Dosing of TIRF medicines is not equivalent on a microgram-to-microgram basis. Correct response True 267 93.4 12 75.0 (89.8. 96.0) (47.6. 92.7) Incorrect response False 8 2.8 2 12.5 I don't know 11 3.8 2 12.5 Client: TRIG Project: TIRFKAB Report Run Date and Time: 11/7/2012 4:35 PM Page 2 of 2 TABLE 9.2.4 LINKED TO KEY RISK MESSAGE #4 SECONDARY ANALYSIS OF RESPONSES TO QUESTIONS KEY RISK MESSAGE 4: TIRF MEDICINES ARE NOT INTERCHANGEABLE WITH EACH OTHER, REGARDLESS OF ROUTE OF ADMINISTRATION. SUB-GROUP ANALYSIS 4: MODALITY TO COMPLETE SURVEY: S-4a - Internet 0 S-4b - Telephone S-4a - Internet S-4b - Telephone Demonstrated Understanding (95% CI) (95% CI) 0 correct responses 1.0 0 0.0 1 con?ect response 4 1.4 1 6.3 2 correct responses 36 12.6 5 31.3 3 correct responses 243 85.0 10 62.5 Average number of correct responses 2.8 (2.7. 3.0) 2.6 (1.9. 3.0) Client: TRIG Project: TIRF KAB Report Run Date and Time: 11/8/2012 2:51 PM Page 1 of TABLE 6.1.5 PRIMARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #1 KEY RISK MESSAGE l: TIRF MEDICINES ARE CONTRAINDICATED IN OPIOID PATIENTS. SUBGROUP ANALYSIS 5: TIME PRACTICING AS A PHARMACIST (QUESTION 26) S?5a Less than 3 years 3 to 5 years 0 S-5c 5 to 15 years 0 More than 15 years S?5a Less than 3 851? More than 15 years 3 to 5 years 6 to 15 years years Question 45 (95% CI) (95% CI) (95% CI) (95% CI) Question 6: Please answer ?True,? ?False,? or don?t know? for each statement about TIRF medicines. 6a: TIRF medicines are contraindicated in opioid non-tolerant patients because life-threatening respiratory depression could occur at any dose. ICSPOIISC True 24 96.0 38 92.7 76 86.4 119 82.1 (79.6. (80.1. (77.4. (74.8. 99.9) 98.5) 92.8) 87.9) Incouect response False 10.3 I don't know 7.6 Client: TRIG Project: TIRFKAB Report Run Date and Time: 11/13/2012 1:37 PM Page 1 of 2 Question Less than 3 More than 15 years 3 to 5 years 6 to 15 years years N=2s (95% CI) (95% CI) (95% CI) (95% CI) 6b: Death has occurred in opioid non-tolerant patients treated with some fentanyl products. correct response True 24 96.0 40 97.6 77 87.5 134 92.4 (79.6. (87.1. (78.7. (86.8. 99.9) 99.9) 93.6) 96.2) Incorrect response False don't know 1 4.0 1 2.4 9 10.2 8 5.5 6c: TIRF medicines may be used in opioid non?tolerant patients. Con'ect response False 22 88.0 35 85.4 72 81.8 105 72.4 (68.8. (70.8. (72.2. (64.4. 97.5) 94.4) 89.2) 79.5) Incorrect response True 2 8.0 3 7.3 11 12.5 32 22.1 I don't know 5.5 6d: Prescribers starting a patient on a TIRF medicine must begin with titration from the lowest dose available for that speci?c product, even if the patient has previously taken another TIRF medicine. correct response True 19 76.0 33 80.5 72 81.8 112 77.2 (54.9. (65.1. (72.2. (69.5. 90.6) 91.2) 89.2) 83.8) Incorrect response False 3 12.0 8 19.5 11 12.5 24 16.6 I don't know 3 12.0 0 0.0 5 5.7 9 6.2 Client: TRIG Project: TIRFKAB Report Run Date and Time: 11/13/2012 1:37 PM Page 2 of 2 TABLE 6.2.5 SECONDARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #1 KEY RISK MESSAGE l: TIRF MEDICINES ARE CONTRAINDICATED IN OPIOID PATIENTS. SUB-GROUP ANALYSIS 5: TIME PRACTICING AS A PHARMACIST (QUESTION 26): S-5a - Less than 3 years 0 S-5b - 3 to 5 years 0 S-5c - 6 to 15 years 0 S-5d - More than 15 years S-5a S-5b S-5c S-5d Less than 3 3 to 5 years 6 to 15 years More than 15 years years Demonstrated Understanding (95% (95% (95% (95% CI) CI) CI) CI) 0 correct responses correct response correct responses 15.2 3 correct responses 7 28.0 11 26.8 20 22.7 41 28.3 4 c01rect responses 16 64.0 27 65.9 54 61.4 74 51.0 Average number of 3.6 (2.9. 4.0) 3.6 (3.1.4.0) 3.4 (3.1.4.0) 3.2 (3.0.4.0) correct responses Client: TRIG Project: TIRF KAB Report Run Date and Time: 11/9/2012 12:36 PM Page 1 of 1 TABLE 7.1.5 PRIMARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #2 KEY RISK MESSAGE 2: TIRF MEDICINES ARE ONLY INDICATED FOR THE MANAGEMENT OF BREAKTHROUGH PAIN IN ADULT CANCER PATIENTS 18 YEARS OF AGE AND OLDER (16 YEARS OF AGE AND OLDER FOR BRAND AND GENERIC EQUIVALENTS) WHO ARE ALREADY RECEIVING AND WHO ARE TOLERANT TO AROUND-THE-CLOCK OPIOID THERAPY FOR THEIR UNDERLYING PERSISTENT CANCER PAIN. SUB-GROUP ANALYSIS 5: TIME PRACTICING AS A PHARMACIST (QUESTION 26): - Less than 3 years 0 S-5b - 3 to 5 years 0 - 6 to 15 years 0 S-5d - More than 15 years Less than 3 85" More than 15 years 3 to 5 years 6 to 15 years years Question N=4l (95% CI) (95% CI) (95% CI) (95% CI) Question 8: For which of the following indications can TIRF medicines be prescribed to opioid tolerant patients? Please answer ?Yes,? or don?t know? for each option. 8a: Acute or postoperative pain correct response No 22 88.0 33 80.5 72 81.8 107 73.8 (68.8. (65.1. (72.2. (65.8. 97.5) 91.2) 89.2) 80.7) Yes 2 8.0 7 17.1 13 14.8 29 20.0 Idon'tknow 6.2 Client: TRIG Project: TIRF KAB Report Run Date and Time: 11/9/2012 12:39 PM Page 1 of 2 ?a Less than 3 More than 15 years 3 to 5 years 6 to 15 years years (95% CI) (95% CI) (95% CI) (95% CI) 8b: Headache or migraine pain Correct response No 25 100.0 39 95.1 78 88.6 124 85.5 (86.3. (83.5. (80.1. (78.7. 100.0) 99.4) 94.4) 90.8) Incorrect response Yes don't know 9.7 8c: Dental pain Correct response No 25 100.0 40 97.6 82 93.2 136 93.8 (86.3. (87.1. (85.7. (88.5. 100.0) 99.9) 97.5) 97.1) Incorrect response Yes don't know 5.5 8d: Breakthrough pain from cancer Correct response Yes 23 92.0 34 82.9 72 81.8 121 83.4 (74.0. (67.9. (72.2. (76.4. 99.0) 92.8) 89.2) 89.1) Incorrect response No 2 8.0 7 17.1 14 15.9 22 15.2 I don't know 1.4 Client: TRIG Project: TIRF KAB Report Run Date and Time: 11/9/2012 12:39 PM Page 2 of 2 TABLE 7.2.5 SECONDARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #2 KEY RISK MESSAGE 2: TIRF MEDICINES ARE ONLY INDICATED FOR THE MANAGEMENT OF BREAKTHROUGH PAIN IN ADULT CANCER PATIENTS 18 YEARS OF AGE AND OLDER (16 YEARS OF AGE AND OLDER FOR BRAND AND GENERIC EQUIVALENTS) WHO ARE ALREADY RECEIVING AND WHO ARE TOLERANT TO AROUND-THE-CLOCK OPIOID THERAPY FOR THEIR UNDERLYING PERSISTENT CANCER PAIN. SUB-GROUP ANALYSIS 5: TIME PRACTICING AS A PHARMACIST (QUESTION 26): S-5a - Less than 3 years 0 S-5b - 3 to 5 years 0 S-5c - 6 to 15 years 0 S-5d - More than 15 years S-5a S-5b Less than 3 3 to 5 years 6 to 15 years More than 15 years years Demonstrated N=l45 Understanding (95% (95% (95% (95% CI) CI) CI) CI) 0 correct responses correct response correct responses correct responses 5 20.0 13 31.7 19 21.6 47 32.4 4 correct responses 20 80.0 26 63.4 57 64.8 80 55.2 Average number of (3.2. (3.1. correct responses 3.8 4.0) 3.6 40) 3.5 (3.1.4.0) 3.4 (3.1. 4.0) Client: TRIG Project: TIRFKAB Report Run Date and Time: 11/9/2012 12:46 PM Page 1 of TABLE 8.1.5 PRIMARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #3 KEY RISK MESSAGE 3: TIRF MEDICINES CONTAIN FENTANYL, AN OPIOID AGONIST AND A SCHEDULE II CONTROLLED SUBSTANCE, WITH ABUSE LIABILITY SIMILAR TO OTHER OPIOID ANALGESICS. SUB-GROUP ANALYSIS 5: TIME PRACTICING AS A PHARMACIST (QUESTION 26): S-5a - Less than 3 years - 3 to 5 years S-5c - 6 to 15 years - More than 15 years Question S?5c Less than 3 years 3 to 5 years 6 to 15 years More than 15 years N=4l N=l45 (95% (95% (95% (95% CI) C1) C1) C1) Question 6: Please answer ?True,? ?False,? or don?t know? for each statement about TIRF medicines. 6e: It is important to monitor for signs of abuse and addiction in patients who take TIRF medicines. True 25 100.0 41 100.0 83 94.3 143 98.6 (86.3. (91.4. (87.2. (95.1. 100.0) 100.0) 98.1) 99.8) Incorrect response False don't know 0.7 Client: TRIG Project: TIRFKAB Report Run Date and Time: 11/9/2012 12:52 PM Page 1 of 2 Question S?5a S-5b Less than 3 years 3 to 5 years 6 to 15 years More than 15 years N=4l (95% (95% (95% (95% CI) CI) C1) C1) Question 7: Which of the following are risk factors for opioid abuse? Please answer ?Yes,? or don?t know? for each option. 7a: A personal history of illness Yes 16 64.0 31 75.6 57 64.8 94 64.8 (42.5. (59.7. (53.9. (56.5. 82.0) 87.6) 74.7) 72.6) No 6 24.0 6 14.6 22 25.0 28 19.3 Idon'tknow 3 12.0 4 9.8 9 10.2 23 15.9 7b: A personal history of past or current alcohol or drug abuse, or a family history of illicit drug use or alcohol abuse correct response Yes 25 100.0 41 100.0 87 98.9 145 100.0 (86.3. (91.4. (93.8. (97.5. 100.0) 100.0) 100.0) 100.0) Incorrect response don't know 0.0 Question 9: Please answer ?True,? ?False,? or don?t know? for each statement about TIRF medicines. 9a: TIRF medicines can be abused in a manner similar to other opioid agonists. correct response Due 22 88.0 35 85.4 78 88.6 135 93.1 (68.8. (70.8. (80.1. (87.7. 97.5) 94.4) 94.4) 96.6) False 3 12.0 5 12.2 5 5.7 6 4.1 Idon'tknow 2.8 Client: TRIG Project: TIRFKAB Report Run Date and Time: 11/9/2012 12:52 PM Page 2 of 2 TABLE 8.2.5 SECONDARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #3 KEY RISK MESSAGE 3: TIRF MEDICINES CONTAIN FENTANYL, AN OPIOID AGONIST AND A SCHEDULE II CONTROLLED SUBSTANCE, WITH ABUSE LIABILITY SIMILAR TO OTHER OPIOID ANALGESICS. SUB-GROUP ANALYSIS 5: TIME PRACTICING AS A PHARMACIST (QUESTION 26): S-5a - Less than 3 years 0 - 3 to 5 years 0 S-5c - 6 to 15 years 0 - More than 15 years S-5a S-5c S-5d Less than 3 3 to 5 years 6 to 15 years More than 15 years years Demonstrated Understanding (95% (95% (95% (95% CI) CI) CI) CI) 0 correct responses 0con?ect response 0correct responses correct responses 10 40.0 12 29.3 33 37.5 53 36.6 4 correct responses 14 56.0 27 65.9 49 55.7 87 60.0 ?Page number 0f 3.5 (2.9.4.0) 3.6 (3.1.4.0) 3.5 (3.1.4.0) 3.6 (3.3.4.0) conect responses Client: TRIG Project: TIRFKAB Report Run Date and Time: 11/9/2012 1:02 PM Page 1 of 1 TABLE 9.1.5 PRIMARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #4 KEY RISK MESSAGE 4: TIRF MEDICINES ARE NOT INTERCHANGEABLE WITH EACH OTHER, REGARDLESS OF ROUTE OF ADMINISTRATION. SUB-GROUP ANALYSIS 5: TIME PRACTICING AS A PHARMACIST (QUESTION 26): S-5a - Less than 3 years - 3 to 5 years S-5c - 6 to 15 years - More than 15 years S-5d S-5a Less than 3 years 3 to 5 years 6 to 15 years 15 Question N=l45 (95% CI) (95% CI) (95% CI) (95% c1) Question 9: Please answer ?True,? ?False,? or don?t know? for each statement about TIRF medicines. 9b: TIRF medicines are interchangeable with each other regardless of route of administration. correct response False 25 100.0 40 97.6 82 93.2 137 94.5 (86.3. (87.1. (85.7. (89.4. 100.0) 99.9) 97.5) 97.6) Incorrect response True don't know 2.8 Client: TRIG Project: TIRF KAB Report Run Date and Time: 11/9/2012 1:04 PM Page 1 of 2 S-5d S-5a S-5b S-5c Less than 3 years 3 to 5 years 6 to 15 years 15 Question N=l45 (95% CI) (95% CI) (95% CI) (95% c1) 9c: The conversion of one TIRF medicine for another TIRF medicine may result in a fatal overdose because of differences in the pharmacokinetics of fentanyl absorption. Correct response True 24 96.0 41 100.0 76 86.4 137 94.5 (79.6. 99.9) (91.4. (77.4. (89.4. 100.0) 92.8) 97.6) Incorrect response False don't know 3.4 9d: Dosing of TIRF medicines is not equivalent on a microgram-to-microgram basis. Correct response True 25 100.0 37 90.2 84 95.5 130 89.7 (86.3. (76.9. (88.8. (83.5. 100.0) 97.3) 98.7) 94.1) Incorrect response False don't know 5.5 Client: TRIG Project: TIRF KAB Report Run Date and Time: 11/9/2012 1:04 PM Page 2 of 2 TABLE 9.2.5 SECONDARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #4 KEY RISK MESSAGE 4: TIRF MEDICINES ARE NOT INTERCHANGEABLE WITH EACH OTHER, REGARDLESS OF ROUTE OF ADMINISTRATION. SUB-GROUP ANALYSIS 5: TIME PRACTICING AS A PHARMACIST (QUESTION 26): S-5a - Less than 3 years 0 S-5b - 3 to 5 years 0 S-5c - 6 to 15 years 0 S-5d - More than 15 years S-5a S-5c S-5d Less than 3 3 to 5 years 6 to 15 years More than 15 years years Demonstrated Understanding (95% (95% (95% (95% CI) CI) CI) CI) 0 correct responses correct response correct responses 1 4.0 5 12.2 14 15.9 20 13.8 3 correct responses 24 96.0 36 87.8 71 80.7 120 82.8 Average number of 3.0 (2.4.3.0) 2.9 (2.4.3.0) 2.8 (2.5.3.0) 2.8 (2.6.3.0) correct responses Client: TRIG Project: TIRFKAB Report Run Date and Time: 11/9/2012 1:05 PM Page 1 of 1 TABLE 6.1.6 PRIMARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #1 KEY RISK MESSAGE 1: TIRF MEDICINES ARE CONTRAINDICATED IN OPIOID NON-TOLERANT PATIENTS. SUBGROUP ANALYSIS 6: NUMBER OF TIMES PER MONTH DISPENSING TIRF MEDICINES WITHIN THE LAST 6 MONTHS S-6a None S-6b 1 - 2 times per month S-6c - 3 - 5 times per month S-6d - More than 5 times per month S-6a S-6b S-6c S-6d None 1 2 3 5 More than 5 ti ues on (95% (95% (95% (95% CI) CI) CI) CI) Question 6: Please answer ?True,? ?False,? or don?t know? for each statement about TIRF medicines. 6a: TIRF medicines are contraindicated in opioid non-tolerant patients because life-threatening respiratory depression could occur at any dose. Conect response True 110 90.2 85 83.3 24 82.8 20 87.0 (83.4. (74.7. (64.2. (66.4. 94.8) 90.0) 94.2) 97.2) Incorrect response False 5 4.1 15 14.7 0 0.0 3 13.0 I don't know 7 5.7 2 2.0 5 17.2 0 0.0 Client: TRIG Project: TIRFKAB Report Run Date and Time: 11/14/2012 4:31 PM Page 1 of 2 Question S-6a S-6b S-6c S-6d None 3 5 More than 5 (95% (95% (95% (95% CI) CI) CI) CI) 6b: Death has occurred in opioid non-tolerant patients treated with some fentanyl products. correct response Tme 117 95.9 93 91.2 26 89.7 21 91.3 (90.7. (83.9. (72.6. (72.0. 98.7) 95.9) 97.8) 98.9) Incorrect response False don't know 3 2.5 6 5.9 3 10.3 2 8.7 6c: TIRF medicines may be used in opioid non?tolerant patients. Con'ect response False 101 82.8 77 75.5 21 72.4 19 82.6 (74.9. (66.0. (52.8. (61.2. 89.0) 83.5) 87.3) 95.0) Incorrect response True 15 12.3 17 16.7 7 24.1 4 17.4 I don't know 0.0 6d: Prescribers starting a patient on a TIRF medicine must begin with titration from the lowest dose available for that speci?c product, even if the patient has previously taken another TIRF medicine. correct response True 104 85.2 73 71.6 23 79.3 19 82.6 (77.7. (61.8. (60.3. (61.2. 91.0) 80.1) 92.0) 95.0) Incorrect response False 13 10.7 21 20.6 5 17.2 3 13.0 I don't know 4.3 Client: TRIG Project: TIRFKAB Report Run Date and Time: 11/14/2012 4:31 PM Page 2 of 2 TABLE 6.2.6 SECONDARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #1 KEY RISK MESSAGE l: TIRF MEDICINES ARE CONTRAINDICATED IN OPIOID PATIENTS. SUBGROUP ANALYSIS 6: NUMBER OF TIMES PER MONTH DISPENSING TIRF MEDICINES WITHIN THE LAST 6 MONTHS S-6a None 0 S-6b - 2 times per month 0 S-6c - 3 - 5 times per month 0 S-6d - More than 5 times per month S-6a S-6b S-6c S-6d None 1 - 2 3 - 5 More than 5 Demonstrated Understanding (95% (95% (95% (95% CI) CI) CI) CI) 0 correct responses correct response 3 2.5 6 5.9 3 10.3 0 0.0 2 correct responses 9 7.4 16 15.7 2 6.9 2 8.7 3 correct responses 29 23.8 30 29.4 9 31.0 5 21.7 4 correct responses 81 66.4 50 49.0 15 51.7 15 65.2 Aver?a number of (3.3. (2.9. (2.7. (2.8. correctgresponses 3'5 4.0) 3'2 4.0) 3'2 4.0) 3'4 4.0) Client: TRIG Project: TIRFKAB Report Run Date and Time: 11/17/2012 12:27 PM Page 1 of TABLE 7.1.6 TO KEY RISK MESSAGE #2 KEY RISK MESSAGE 2: TIRF MEDICINES ARE ONLY INDICATED FOR THE MANAGEMENT OF BREAKTHROUGH PAIN IN ADULT CANCER PATIENTS 18 YEARS OF AGE AND OLDER (16 YEARS OF AGE AND OLDER FOR BRAND AND GENERIC EQUIVALENTS) WHO ARE ALREADY RECEIVING AND PRIMARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED WHO ARE TOLERANT TO AROUND-THE-CLOCK OPIOID THERAPY FOR THEIR UNDERLYING PERSISTENT CANCER PAIN. SUBGROUP ANALYSIS 6: NUMBER OF TIMES PER MONTH DISPENSING TIRF MEDICINES WITHIN THE LAST 6 MONTHS S-6a None 0 S-6b 1 - 2 times per month 0 S-6c - 3 - 5 times per month 0 S-6d - More than 5 times per month S?6b S?6c S?6d None 1 - 2 3 - 5 More than 5 Question (95% (95% (95% (95% CD CD CD CD Question 8: For which of the following indications can TIRF medicines be prescribed to opioid tolerant patients? Please answer ?Yes,? or don?t know? for each option. 8a: Acute or postoperative pain Correct response No 99 81.1 85 83.3 18 62.1 17 73.9 (73.1. (74.7. (42.3. (51.6. 87.7) 90.0) 79.3) 89.8) Incorrect response Yes 19 15.6 14 13.7 10 34.5 4 17.4 I don't know 8.7 Client: TRIG Project: TIRF KAB Report Run Date and Time: 11/14/2012 4:37 PM Page 1 of 2 S-6a S-6b S-6c S-6d None 1 - 2 3 - 5 More than 5 Question (95% (95% (95% (95% C1) C1) C1) C1) 8b: Headache or migraine pain Correct response No 111 91.0 95 93.1 22 75.9 22 95.7 (84.4. (86.4. (56.5. (78.1. 95.4) 97.2) 89.7) 99.9) Incorrect response Yes 3 2.5 2 2.0 4 13.8 0 0.0 I don't know 8 6.6 5 4.9 3 10.3 1 4.3 8c: Dental pain Correct response No 119 97.5 98 96.1 27 93.1 23 100.0 (93.0. (90.3. (77.2. (85.2. 99.5) 98.9) 99.2) 100.0) Incorrect response Yes don't know 0.0 8d: Breakthrough pain from cancer Correct response Yes 104 85.2 89 87.3 23 79.3 14 60.9 (77.7. (79.2. (60.3. (38.5. 91.0) 93.0) 92.0) 80.3) Incorrect response No 17 13.9 13 12.7 5 17.2 8 34.8 I don't know 4.3 Client: TRIG Project: TIRFKAB Report Run Date and Time: 11/14/2012 4:37 PM Page 2 of 2 TABLE 7.2.6 SECONDARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #2 KEY RISK MESSAGE 2: TIRF MEDICINES ARE ONLY INDICATED FOR THE MANAGEMENT OF BREAKTHROUGH PAIN IN ADULT CANCER PATIENTS 18 YEARS OF AGE AND OLDER (16 YEARS OF AGE AND OLDER FOR BRAND AND GENERIC EQUIVALENTS) WHO ARE ALREADY RECEIVING AND WHO ARE TOLERANT TO AROUND-THE-CLOCK OPIOH) THERAPY FOR THEIR UNDERLYING PERSISTENT CANCER PAIN. SUBGROUP ANALYSIS 6: NUMBER OF TIMES PER MONTH DISPENSING TIRF MEDICINES WITHIN THE LAST 6 MONTHS S-6a None 0 S-6b 1 - 2 times per month 0 S-6c - 3 - 5 times per month 0 S-6d - More than 5 times per month S-6a S-6b S-6c S-6d None 1 - 2 3 - 5 More than 5 Understanding (95% (95% (95% (95% C1) C1) CI) CI) 0 correct responses correct response correct responses 6 4.9 3 2.9 3 10.3 3 13.0 3 correct responses 34 27.9 26 25.5 13 44.8 10 43.5 4 correct responses 79 64.8 70 68.6 11 37.9 10 43.5 Average number of correct (3.3. (3.3. (2.6. (2.7. responses 3'5 4.0) 3'6 4.0) 3'1 4.0) 3'3 4.0) Client: TRIG Project: TIRF KAB Report Run Date and Time: 11/14/2012 4:41 PM Page 1 of TABLE 8.1.6 PRIMARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #3 KEY RISK MESSAGE 3: TIRF MEDICINES CONTAIN FENTANYL, AN OPIOID AGONIST AND A SCHEDULE II CONTROLLED SUBSTANCE, WITH ABUSE LIABILITY SIMILAR TO OTHER OPIOID ANALGESICS. SUBGROUP ANALYSIS 6: NUMBER OF TIMES PER MONTH DISPENSING TIRF MEDICINES WITHIN THE LAST 6 MONTHS S-6a None 0 S-6b - 2 times per month 0 S-6c - 3 - 5 times per month 0 S-6d - More than 5 times per month Question S?a S?6b S?6c S-6d None 1 - 2 3 5 More than 5 (95% (95% (95% (95% CI) C1) C1) C1) Question 6: Please answer ?True,? ?False,? or don?t know? for each statement about TIRF medicines. 6e: It is important to monitor for signs of abuse and addiction in patients who take TIRF medicines. correct response True 121 99.2 99 97.1 29 100.0 23 100.0 (95.5. (91.6. (88.1. (85.2. 100.0) 99.4) 100.0) 100.0) Incorrect response False don't know 0.0 Client: TRIG Project: TIRFKAB Report Run Date and Time: 11/14/2012 4:44 PM Page 1 of 2 Question S-6a S-6b S-6c S-6d None 1 - 2 3 5 More than 5 (95% (95% (95% (95% C1) C1) CI) CI) Question 7: Which of the following are risk factors for opioid abuse? Please answer ?Yes,? or don?t know? for each option. 7a: A personal history of illness Yes 78 63.9 73 71.6 17 58.6 16 69.6 (54.7. (61.8. (38.9. (47.1. 72.4) 80.1) 76.5) 86.8) No 30 24.6 16 15.7 6 20.7 5 21.7 Idon'tknow 14 11.5 13 12.7 6 20.7 2 8.7 7b: A personal history of past or current alcohol or drug abuse, or a family history of illicit drug use or alcohol abuse Correct response Yes 122 100.0 102 100.0 29 100.0 23 100.0 (97.0. (96.4. (88.1. (85.2. 100.0) 100.0) 100.0) 100.0) Incorrect response don't know 0.0 Question 9: Please answer ?True,? ?False,? or don?t know? for each statement about TIRF medicines. 9a: TIRF medicines can be abused in a manner similar to other opioid agonists. Conect response Tme 110 90.2 94 92.2 26 89.7 22 95.7 (83.4. (85.1. (72.6. (78.1. 94.8) 96.6) 97.8) 99.9) Inconect response False don't know 0.0 Client: TRIG Project: TIRFKAB Report Run Date and Time: 11/14/2012 4:44 PM Page 2 of 2 TABLE 8.2.6 SECONDARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #3 KEY RISK MESSAGE 3: TIRF MEDICINES CONTAIN FENTANYL, AN OPIOID AGONIST AND A SCHEDULE II CONTROLLED SUBSTANCE, WITH ABUSE LIABILITY SIMILAR TO OTHER OPIOID ANALGESICS. SUBGROUP ANALYSIS 6: NUMBER OF TIMES PER MONTH DISPENSING TIRF MEDICINES WITHIN THE LAST 6 MONTHS S-6a None 0 S-6b - 2 times per month 0 S-6c - 3 - 5 times per month 0 S-6d - More than 5 times per month S-6a S-6b S-6c S-6d None 1 - 2 3 - 5 More than 5 Demonstrated Understanding (95% (95% (95% (95% CI) CI) CI) CI) 0 correct responses correct response correct responses correct responses 43 35.2 32 31.4 15 51.7 8 34.8 4 correct responses 72 59.0 66 64.7 14 48.3 15 65.2 Average number of (3.3. (3.3. (2.9. (3.0. correct responses 3'5 4.0) 3'6 4.0) 3'5 4.0) 3'7 4.0) Client: TRIG Project: TIRF KAB Report Run Date and Time: 11/14/2012 4:45 PM Page 1 of 1 TABLE 9.1.6 PRIMARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #4 KEY RISK MESSAGE 4: TIRF MEDICINES ARE NOT INTERCHANGEABLE WITH EACH OTHER, REGARDLESS OF ROUTE OF ADMINISTRATION. SUBGROUP ANALYSIS 6: NUMBER OF TIMES PER MONTH DISPENSING TIRF MEDICINES WITHIN THE LAST 6 MONTHS (QUESTION 23) S-6a None 0 S-6b - 2 times per month 0 S-6c - 3 - 5 times per month 0 S-6d - More than 5 times per month S-6a S-6b S-6c S-6d None 1 2 3 - 5 More than 5 Question (95% (95% (95% (95% CI) C1) C1) C1) Question 9: Please answer ?True,? ?False,? or don?t know? for each statement about TIRF medicines. 9b: TIRF medicines are interchangeable with each other regardless of route of administration. Con?ect response False 119 97.5 94 92.2 29 100.0 23 100.0 (93.0. (85.1. (88.1. (85.2. 99.5) 96.6) 100.0) 100.0) Inconect response Tme don't know 0.0 Client: TRIG Project: TIRFKAB Report Run Date and Time: 11/19/2012 10:47 ANI Page 1 of 2 S-6a S-6b S-6c S-6d None 1 2 3 - 5 More than 5 Question (95% (95% (95% (95% CI) CI) CI) CI) 9c: The conversion of one TIRF medicine for another TIRF medicine may result in a fatal overdose because of differences in the pharmacokinetics of fentanyl absorption. Correct response True 111 91.0 96 94.1 29 100.0 22 95.7 (84.4. (87.6. (88.1. (78.1. 95.4) 97.8) 100.0) 99.9) Incorrect response False don't know 0.0 9d: Dosing of TIRF medicines is not equivalent on a microgram-to-microgram basis. Correct response True 117 95.9 92 90.2 25 86.2 21 91.3 (90.7. (82.7. (68.3. (72.0. 98.7) 95.2) 96.1) 98.9) Incorrect response False 1 0.8 5 4.9 3 10.3 1 4.3 I don't know 4.3 Client: TRIG Project: TIRFKAB Report Run Date and Time: 11/19/2012 10:47 AM Page 2 of 2 TABLE 9.2.6 SECONDARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #4 KEY RISK MESSAGE 4: TIRF MEDICINES ARE NOT INTERCHANGEABLE WITH EACH OTHER, REGARDLESS OF ROUTE OF ADMINISTRATION. SUBGROUP ANALYSIS 6: NUMBER OF TIMES PER MONTH DISPENSING TIRF MEDICINES WITHIN THE LAST 6 MONTHS (QUESTION 23) S-6a None 0 S-6b - 2 times per month 0 S-6c - 3 - 5 times per month 0 S-6d - More than 5 times per month S-6a S-6b S-6c S-6d None 1 - 2 3 - 5 More than 5 Understanding (95% (95% (95% (95% CI) CI) CI) CI) 0 correct responses correct response correct responses 13 10.7 14 13.7 4 13.8 3 13.0 3 correct responses 107 87.7 83 81.4 25 86.2 20 87.0 Average number of correct (2.6. (2.5. (2.3. (2.3. responses 2'8 3.0) 2'8 3.0) 2'9 3.0) 2'9 3.0) Client: TRIG Project: TIRFKAB Report Run Date and Time: 11/19/2012 10:47 ANI Page 1 of Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies. December 2012 12-month REMS Assessment Report 11.4.3 Prescriber KAB Survey FDA_507 Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Title: December 2012 Prescriber KAB Assessment Report Transmucosal Immediate Release Fentanyl (TIRF) REMS Assessment Quantitative Testing of Prescriber Knowledge, Attitudes, and Behavior (KAB) about TIRF Products Safety and Use Information Document Number Final Wave 1, Version 1.0 Product Name: Transmucosal Immediate Release Fentanyl Sponsor: TIRF REMS Industry Group (TRIG) of Companies: Archimedes Pharma US, Inc. Cephalon, Inc. (a wholly-owned subsidiary of Teva Pharmaceutical Industries, Ltd.) Insys Therapeutics Meda Pharmaceuticals Mallinckrodt (the Pharmaceuticals Business of Covidien) Par Pharmaceutical, Inc. ProStrakan, Inc. Date: 14 December 2012 Confidentiality Statement The information contained herein is confidential and the proprietary property of the TRIG of Companies and its affiliates, and any unauthorized use or disclosure of such information without the prior written authorization of the TRIG is expressly prohibited. Page 1 of 54 FDA_508 Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies TABLE OF CONTENTS December 2012 Prescriber KAB Assessment Report PAGE TABLE OF CONTENTS ......................................................................................................... 2  LIST OF APPENDICES .......................................................................................................... 4  LIST OF INTEXT TABLES .................................................................................................... 5  LIST OF ABBREVIATIONS .................................................................................................. 7  1.  PRESCRIBER SURVEY BACKGROUND ........................................................... 8  2.  PRESCRIBER SURVEY OBJECTIVES ................................................................ 9  3.  SURVEY METHODOLOGY.................................................................................. 9  3.1  Survey Sample ......................................................................................................... 9  3.2  3.2.1  3.2.2  3.2.3  3.2.4  Questions and Statements on Key Risk Messages ................................................. 10  Key Risk Message 1 ............................................................................................... 11  Key Risk Message 2 ............................................................................................... 11  Key Risk Message 3 ............................................................................................... 12  Key Risk Message 4 ............................................................................................... 12  3.3  Additional Questions.............................................................................................. 13  4.  STATISTICAL METHODS .................................................................................. 13  4.1  4.1.1  4.1.2  4.1.2.2  4.1.2.3  4.1.3  Study Population .................................................................................................... 13  Primary Analysis Population ................................................................................. 13  Subpopulations of Interest ..................................................................................... 13  Primary Analyses ................................................................................................... 14  Secondary Analyses ............................................................................................... 14  Prescriber Report of Adverse Event, Product Complaint, or Medical Information Request During Survey ...................................................................... 14  5.  RESULTS .............................................................................................................. 15  5.1  5.1.1  5.1.2  5.1.3  Survey Participants ................................................................................................ 15  Survey Participant Administration Results ............................................................ 15  Prescriber Demographic and TIRF Product Prescribing Characteristics ............... 18  TIRF Medicines Educational Materials ................................................................. 22  5.2  5.2.1  5.2.1.1  5.2.1.2  5.2.1.3  5.2.1.4  5.2.2  KAB Survey Objectives ......................................................................................... 26  Key Risk Message Results ..................................................................................... 26  Key Risk Message 1 ............................................................................................... 26  Key Risk Message 2 ............................................................................................... 27  Key Risk Message 3 ............................................................................................... 29  Key Risk Message 4 ............................................................................................... 31  Other Survey Questions ......................................................................................... 33  Page 2 of 54 FDA_509 Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies December 2012 Prescriber KAB Assessment Report 5.2.2.1  5.2.2.2  5.2.3  Additional Questions About TIRF Medicines Safety ............................................ 33  Prescriber Activities When Prescribing TIRF Medicines ...................................... 41  Analyses of Subpopulations ................................................................................... 43  5.3  Spontaneous Reporting of Adverse Events, Product Complaints, or Medical Information Requests ............................................................................... 44  5.4  Discussion, Conclusions, and Recommendations .................................................. 44  Listing 1  CATEGORIZATION OF VERBATIM RESPONSES TO QUESTION 22 (Questions about the information in the Full Prescribing Information or Medication Guide) ................................................................................................. 49  Listing 2  CATEGORIZATION OF VERBATIM RESPONSES TO REPORTED SAFETY EVENTS OR PRODUCT COMPLAINTS ........................................... 51  Listing 3  CATEGORIZATION OF VERBATIM RESPONSES TO QUESTION 33 (OTHER MEDICAL SPECIALTY) ...................................................................... 53  Page 3 of 54 FDA_510 Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies December 2012 Prescriber KAB Assessment Report LIST OF APPENDICES Appendix A Prescriber Survey Protocol ....................................................................... 47  Appendix B Prescriber Survey Listings and Subanalysis Tables ................................. 48  Page 4 of 54 FDA_511 Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies December 2012 Prescriber KAB Assessment Report LIST OF INTEXT TABLES Table 1.  Survey Participant Administration Results...............................................15  Table 2.  Survey Participant Screening Results ....................................................... 16  Table 3.  Time to Complete Survey for Completers Only (Minutes) ...................... 18  Table 4.  Demographic Characteristics of Eligible Prescribers ............................... 19  Table 5.  Categorized Responses for Respondents Who Answered “Other” to Question 32...........................................................................................21  Table 6.  Characteristics of Respondents Completing the Survey...........................22  Table 7.  Responses to Questions About TIRF Medicines Educational Materials and the TIRF Patient-Prescriber Agreement Form ...................23  Table 8.  Categorized Responses To Question 22 (Questions about the Information in the Full Prescribing Information or Medication Guide) .......................................................................................................25  Table 9.  Responses Linked to Key Risk Message 1: TIRF Medicines Are Contraindicated in Opioid Non-Tolerant Patients .................................... 26  Table 10.  Responses Linked to Key Risk Message 2: TIRF Medicines Are Only Indicated for the Management of Breakthrough Pain in Adult Cancer Patients 18 Years of Age and Older (16 Years of Age and Older for Actiq® Brand and Generic Equivalents) Who Are Already Receiving and Who Are Tolerant to Around-The-Clock Opioid Therapy for Their Underlying Persistent Cancer Pain ................. 28  Table 11.  Responses Linked to Key Risk Message 3: TIRF Medicines Contain Fentanyl, an Opioid Agonist and a Schedule II Controlled Substance, With Abuse Liability Similar to Other Opioid Analgesics. ................................................................................................ 30  Table 12.  Responses Linked to Key Risk Message 4: TIRF Medicines Are Not Interchangeable With Each Other, Regardless of Route of Administration. .........................................................................................32  Table 13.  Responses to Additional Questions About the Safe Use of TIRF Medicines..................................................................................................34  Table 14.  Responses to All Questions About What to Advise if Breakthrough Pain is Not Sufficiently Relieved ......................................41  Table 15.  Responses to All Questions About Activities When Prescribing TIRF Medicines ........................................................................................ 42  Table 16.   Respondent Report of Adverse Event, Product Complaint, or Medical Information Request During Survey ..........................................44  Page 5 of 54 FDA_512 Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Table 17.   December 2012 Prescriber KAB Assessment Report Categorized Reported Adverse Events, Product Complaints, or Medical Information Requests.................................................................. 44  Page 6 of 54 FDA_513 Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies December 2012 Prescriber KAB Assessment Report LIST OF ABBREVIATIONS ETASU Elements to Assure Safe Use FDA Food and Drug Administration KAB Knowledge, Attitudes, and Behavior PI Prescribing Information REMS Risk Evaluation and Mitigation Strategy SAP Statistical Analysis Plan SERP Safety Event Reporting Plan TIRF Transmucosal Immediate Release Fentanyl TIRF medicines Transmucosal Immediate Release Fentanyl product(s) TIRF REMS Access program REMS program for TIRF medicines TRIG TIRF REMS Industry Group UBC United BioSource Corporation US United States Page 7 of 54 FDA_514 Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies 1. December 2012 Prescriber KAB Assessment Report PRESCRIBER SURVEY BACKGROUND Transmucosal Immediate Release Fentanyl (TIRF) medicines are a class of immediate-release opioid analgesics that are indicated only for the management of breakthrough pain in cancer patients 18 years of age or older (16 or older for Actiq® [fentanyl citrate oral transmucosal lozenge] and equivalent generics) who are receiving and already tolerant to opioid therapy for their underlying persistent cancer pain. The TIRF medicines include Abstral®, Actiq®, Fentora®, Lazanda®, Onsolis®, Subsys®, and their generic equivalents. The TIRF Risk Evaluation and Mitigation Strategy (REMS) Industry Group (TRIG) includes Archimedes Pharma United States (US) Inc., Cephalon, Inc. (a wholly-owned subsidiary of Teva Pharmaceutical Industries, Ltd.), Insys Therapeutics, Meda Pharmaceuticals, Mallinckrodt (the Pharmaceuticals Business of Covidien), Par Pharmaceutical, Inc., and ProStrakan, Inc. At the time of protocol development for the Knowledge, Attitude, and Behavior (KAB) surveys, Sandoz was also a member of the TRIG; however Sandoz terminated their involvement in the TIRF REMS Access program, effective 15 September 2012. The Food and Drug Administration (FDA) has determined that a class-wide REMS is required to mitigate the risk of misuse, abuse, addiction, overdose, and serious complications due to medication errors with the use of TIRF medicines. The TIRF REMS Access program (hereafter referred to as TIRF REMS) was approved by the FDA on 28 December 2011. The TIRF REMS consists of a Medication Guide, Elements to Assure Safe Use (ETASU), an Implementation System, and a timetable for submission of assessments of the REMS. The goals of the TIRF REMS are to mitigate the risk of misuse, abuse, addiction, overdose and serious complications due to medication errors by the following: 1. Prescribing and dispensing TIRF medicines only to appropriate patients, which includes use only in opioid-tolerant patients. 2. Preventing inappropriate conversion between TIRF medicines. 3. Preventing accidental exposure to children and others for whom it was not prescribed. 4. Educating prescribers, pharmacists, and patients on the potential for misuse, abuse, addiction, and overdose of TIRF medicines. An important component of the TIRF REMS assessment is the conduct of quantitative evaluation surveys to assess prescribers’ understanding and knowledge of the safe use and appropriate prescribing of TIRF medicines as described in the TIRF REMS educational materials, enrollment form, and Prescribing Information (PI) of each product. The protocol describes the administration of the surveys that will be conducted among prescribers who are enrolled in the TIRF REMS Access program. Page 8 of 54 FDA_515 Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies December 2012 Prescriber KAB Assessment Report Data from the surveys, together with other REMS evaluation metrics, will be used to determine whether changes need to be made to the REMS processes or educational materials to make them more effective in achieving the goals of the REMS. Results from the surveys will be submitted to the FDA at 12 months after approval of the TIRF REMS and annually thereafter. 2. PRESCRIBER SURVEY OBJECTIVES The evaluation survey uses a questionnaire to document the level of knowledge and assess the attitudes and behavior of prescribers regarding the following key information and risk messages communicated through the REMS: 1. TIRF medicines are contraindicated in opioid non-tolerant patients. 2. TIRF medicines are only indicated for the management of breakthrough pain in adult cancer patients 18 years of age and older (16 or older for Actiq® and equivalent generics) who are receiving and who are tolerant to around-the-clock opioid therapy for their underlying persistent cancer pain. 3. TIRF medicines contain fentanyl, an opioid agonist and a Schedule II controlled substance, with abuse liability similar to other opioid analgesics. 4. TIRF medicines are not interchangeable with each other, regardless of route of administration. 5. Patients and their caregivers must be instructed that TIRF medicines contain a medicine in an amount that can be fatal in children, in individuals for whom it is not prescribed, and in those who are not opioid tolerant. The survey also collects data on behaviors, such as receipt and use of educational materials and compliance with REMS requirements. 3. SURVEY METHODOLOGY This section summarizes the survey design and the questions that were constructed to test prescriber understanding of the key risk messages of the REMS. Full details of the survey design are in the protocol, which can be found in Appendix A. 3.1 Survey Sample This survey was conducted among prescribers who were enrolled in the TIRF REMS Access program as of 15 August 2012. A target sample of 300 prescribers who were enrolled in the TIRF REMS Access program were surveyed from 24 September 2012 to 30 October 2012. The size of the sample was determined based on both practical and statistical considerations. Page 9 of 54 FDA_516 Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies December 2012 Prescriber KAB Assessment Report Subject recruitment was from a random sample of prescribers who were enrolled in the TIRF REMS Access program. Respondents or respondents’ immediate family members who had ever worked for any of the TRIG companies, RelayHealth, McKesson Specialty Care Solutions, United BioSource Corporation (UBC), or the FDA were not eligible to participate. Respondents who participated in the first wave of the TIRF survey will not be eligible to participate in subsequent survey waves. Potential subjects were recruited via a letter sent through the United States Postal Service, and email (see Section 5.1.1 for more detail). The required number of completed surveys was not achieved within approximately 10 days after the first mailing, a second mailing was sent to non-respondents from the original sample with subsequent email, or mail to maximize participation. If these efforts did not result in the required number of surveys within 21 days, then an additional sample of potential subjects was randomly selected. Prescribers were given the option of taking the survey by telephone via the Survey Coordinating Center or online via a secure website. All participating prescribers were offered an honorarium of $125 for a completed survey. The survey was estimated to take approximately 20 minutes to complete. 3.2 Questions and Statements on Key Risk Messages The questions and statements comprising the knowledge survey were constructed to test the prescribers’ understanding of the key risk messages of the REMS. The questions were to be answered either by selecting options from multiple-choice lists that include statements of the specific key risk messages or by choosing “Yes” or “True,” “No” or “False,” or “I Don’t Know” regarding statements about TIRF medicines. For statements or questions that use “True” or “Yes” vs. “False” or “No” response options, the desired response for key risk messages is generally “True” or “Yes” indicating knowledge of, or behavior in accordance with, the objectives of the REMS. However, some questions were formatted to have the respondent disagree with the statement as written by providing response options of “False” or “No” to avoid having the same affirmative answer for all desired responses. REMS statements, corresponding questions, and desired responses covering the key risk messages are identified below and can be found in the complete survey questionnaire (Appendix A). Page 10 of 54 FDA_517 Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies 3.2.1 December 2012 Prescriber KAB Assessment Report Key Risk Message 1 Key Risk Message 1 referred to the prescriber’s knowledge of the specific contraindications for TIRF medicines opioid non-tolerant patients. Key Risk Message 1: TIRF medicines are contraindicated in opioid non-tolerant patients. Question No. Question Desired response 6 Please answer “True,” “False,” or “I don’t know” for each statement about TIRF medicines. 6a TIRF medicines are contraindicated in opioid non-tolerant patients because life-threatening respiratory depression could occur at any dose. True 6b Death has occurred in opioid non-tolerant patients treated with some fentanyl products. True 6c TIRF medicines may be used to treat opioid non-tolerant patients. False 6d Prescribers starting a patient on a TIRF medicine must begin with titration from the lowest dose available for that specific product, even if the patient has previously taken another TIRF medicine. True 3.2.2 Key Risk Message 2 Key Risk Message 2 referred to the prescriber’s knowledge of the indications for prescribing TIRF medicines for the management of breakthrough pain in opioid-tolerant adult cancer patients. Key Risk Message 2: TIRF medicines are only indicated for the management of breakthrough pain in adult cancer patients 18 years of age and older (16 years of age and older for Actiq® brand and generic equivalents) who are already receiving and who are tolerant to around-the-clock opioid therapy for their underlying persistent cancer pain. Question No. Question Desired response 8 For which of the following indications do you prescribe TIRF medicines to opioid tolerant patients? Please answer “Yes,” “No,” or “I don’t know” for each option. 8a Acute or postoperative pain No 8b Headache or migraine pain No 8c Dental pain No 8d Breakthrough pain from cancer Yes Page 11 of 54 FDA_518 Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies 3.2.3 December 2012 Prescriber KAB Assessment Report Key Risk Message 3 Key Risk Message 3 referred to the prescriber’s knowledge of the risk factors and signs and symptoms of opioid abuse in patients who take TIRF medicines. Key Risk Message 3: TIRF medicines contain fentanyl, an opioid agonist and a Schedule II controlled substance, with abuse liability similar to other opioid analgesics. Question No. Question Desired response 6 Please answer “True,” “False,” or “I don’t know” for each statement about TIRF medicines. 6e It is important to monitor for signs of abuse and addiction in patients who take TIRF medicines. 7 Which of the following are risk factors for opioid abuse? Please answer “Yes,” “No,” or “I don’t know” for each option. 7a A personal history of psychiatric illness Yes 7b A personal history of past or current alcohol or drug abuse, or a family history of illicit drug use or alcohol abuse Yes 9 Please answer “True,” “False,” or “I don’t know” for each statement about TIRF medicines. 9a TIRF medicines can be abused in a manner similar to other opioid agonists. 3.2.4 True True Key Risk Message 4 Key Risk Message 4 referred to the prescriber’s knowledge of the interchangeability of TIRF medicines based on route of administration, pharmacokinetic absorption, and dosage. Key Risk Message 4: TIRF medicines are not interchangeable with each other, regardless of route of administration. Question No. Question Desired response 9 Please answer “True,” “False,” or “I don’t know” for each statement about TIRF medicines. 9b TIRF medicines are interchangeable with each other regardless of route of administration. False 9c The conversion of one TIRF medicine for another TIRF medicine may result in a fatal overdose because of differences in the pharmacokinetics of fentanyl absorption. True 9d Dosing of TIRF medicines is not equivalent on a microgram-tomicrogram basis. True Page 12 of 54 FDA_519 Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies 3.3 December 2012 Prescriber KAB Assessment Report Additional Questions The survey also contained questions about the requirements of the TIRF REMS Access program and receipt and understanding of the TIRF educational materials and the PatientPrescriber Agreement Form. The following question about behaviors was asked after the key risk message questions: Question : How frequently do you perform the following activities when prescribing TIRF medicines? Ask patients (or their caregivers) about the presence of children in the home. Instruct patients (or their caregivers) not to share TIRF medicines with anyone else. Counsel patients (or their caregivers) that accidental exposure to TIRF medicines by a child may be fatal. Instruct patients (or their caregivers) to keep TIRF medicines out of the reach of children to prevent accidental exposure. Instruct patients (or their caregivers) about proper disposal of any unused or partially used TIRF medicines. 4. STATISTICAL METHODS 4.1 Study Population 4.1.1 Primary Analysis Population According to the prospective Statistical Analysis Plan (SAP), the primary population for analysis was all eligible prescribers who completed the survey. Eligible prescribers were defined as those respondents who answered Yes to Question 1 (agree to take part in survey), and Question 3 (enrolled in the TIRF REMS Access program), and No to Question 2 (participated in past survey; not applicable for Wave 1) and Question 4 (worked for a TRIG company, UBC, RelayHealth, McKesson Specialty Care Solutions, or FDA). A completed survey was a survey from an eligible prescriber in which all non-eligibility questions as appropriate were answered. Note that some questions may not be answered because of skip logic in the survey questionnaire. 4.1.2 Subpopulations of Interest The following subgroup analyses were conducted if the subgroup included at least 20 respondents. • Subpopulation S-1: Page 13 of 54 FDA_520 Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies a) December 2012 Prescriber KAB Assessment Report Prescribers who received and read the TIRF medicine educational materials (Yes for Question 18 [Full Prescribing Information], or Yes for Question 20 [Medication Guide]). Prescribers who did not read the full prescribing information for the TIRF medicine educational materials (No or I don’t know for Question 18 [Full Prescribing Information], or No or I don’t know for Question 20 [Medication Guide]). b) • Subpopulation S-2: Medical degree (MD, DO, Nurse Practitioner or Physician Assistant for Question 29); • Subpopulation S-3: Time to complete survey-Internet (<10 min, 10 to <20 min, or ≥20 min); • Subpopulation S-4: Time to complete survey-Telephone (<10 min, 10 to <20 min, or ≥20 min); • • Subpopulation S-5: Modality to complete survey (Internet or Telephone) • Subpopulation S-7: Number of times per month prescribing TIRF medicines with the last 6 months (None, 1-2 times, 3-5 times, or more than 5 times a month for Question 26). Subpopulation S-6: Time practicing medicine (less than 3 years, 3 to 5 years, 6 to 15 years, or more than 15 years for Question 30); 4.1.2.2 Primary Analyses Primary analyses were done for all key risk messages. The primary analysis for a key risk message evaluated the number and percentage of correct responses for each individual question/item defined by the key risk message. The correct response to each question/item was identified in the body of the risk message table (Section 3.2). 4.1.2.3 Secondary Analyses Secondary analyses evaluated the number and percentages of correct responses and the average number of correct answers within the risk message to assess demonstrated understanding of the comprehensive key risk message. 4.1.3 Prescriber Report of Adverse Event, Product Complaint, or Medical Information Request During Survey A prescriber may have reported an adverse event or other safety event experienced by their patients while taking a TIRF product either in free text fields on the survey or while in conversation with the Survey Coordinating Center. If the event was mentioned to a Survey Coordinating Center Associate, the Associate documented the safety event and the respondent’s contact information, if provided. The prescriber was also informed that a representative from the appropriate TIRF medicine manufacturer might contact them to obtain additional information about the safety event. The Internet surveys were monitored for any comments recorded in the free text fields. Information on all reports (Internet or Telephone) that constituted an adverse event or other safety event was forwarded to the appropriate TIRF Page 14 of 54 FDA_521 Transrnucosal Immediate Release Fentanyl (TIRF) December 2012 TIRF REMS Industry Group (TRIG) of Companies Prescriber KAB Assessment Report medicine manufactlu?er for processing within 1 business day of awareness of the event as outlined in the Safety Event Reporting Plan (SERP). 5. RESULTS Results of the prescriber responses to questions in the KAB srnvey are summarized in this section. 5.1 Survey Participants 5.1.1 Survey Participant Administration Results A total of 5330 prescribers were sent letters inviting them to participate in this survey (Table 1). An additional 3505 reminder letters were sent. Prescribers may have received more than 1 reminder letter. In all, a total of 302 prescribers expressed interest in the sruvey, met the eligibility criteria, and completed the sruvey. Of these 302 prescribers, 293 completed the sruvey online, and 9 completed it by telephone (Table 3). From the 302 respondents, 303 surveys were collected. It was identi?ed that respondent completed the sruvey twice. Only the fast completed sruvey was included in the analysis for this respondent. Based on the TRIG Sponsors interpretation of state laws regarding prescriber reimbtu?sement, respondents from Massachusetts (MA), Vermont (VT), and Minnesota (MN) were not eligible to receive the $125 honorarilun. Letters were sent to prescribers in these states, and 2 respondents from these states (MA and MN) chose to participate, but were not paid. Table 1. Survey Participant Administration Results Screened Prescribers All Respondents Summary Statistic 0/0 Number of invitations issued to prescribers 5330 Number of reminder letters issued to prescribers 3505 Ntunber of prescribers screened for participation 358l Ntunber of prescribers eligible for participation 302 Number of prescribers completing the smvey 302 84.4 By telephone 9 2.5 By intemet 293 81.8 1 This is the denominator for the percentages in this table 58). Page 15 of 54 December 2012 Prescriber KAB Assessment Report Transrnucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies As shown in Table 2, a total of 358 prescribers agreed to participate in this survey and of those 315 prescribers were em?olled in the REMS Access program; 43 prescribers were ineligible because they were not em?olled in the program or they did not know whether they were em?olled. Eleven respondents were ineligible for the sruvey because they, or an immediate family member, had worked for UBC or a TRIG company in the past, or did not know whether they, or an inrrnediate family member, had worked for a TRIG company, UBC, RelayHealth, McKesson Specialty Care Solutions, or FDA in the past, and 2 prescribers preferred not to answer and thus were considered ineligible. Of note, following the close of the survey, the Sruvey Coordinating Center received information that a nurse had completed the survey as if she were a TIRF medicines prescriber in the of?ce in which she works, answered Male as gender and DO as medical degree). Since the sruvey was ah'eady closed, this respondent remained in the data as of the 302 eligible and completed prescribers. Table 2. Survey Participant Screening Results Eligible All Respondents Completed Question Prescribers Question 1: Do you agree to participate in this survey? Yes 358 100.0 302 100.0 No1 0 0.0 Question 2: Have you ever taken part in this survey about TIRF medicines before? TIRF medicines include Abstral?, Actiq?, Fentora?, Lazanda?, Onsolis?, Subsys?, and generic versions of any of these brands Yes 8 2.2 5 1.7 No 331 92.5 283 93.7 I don?t know 19 5.3 14 4.6 Question not asked2 0 0.0 Question 3: Are you enrolled in the TIRF REMS Access program? Yes 315 88.0 302 100.0 No1 15 4.2 I don?t know1 28 7.8 Question not asked 2 0.0 (continued) Page 16 of 54 Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies December 2012 Prescriber KAB Assessment Report Table 2. Survey Participant Screening Results Question Eligible All Respondents Completed Prescribers Question 4: Have you or any of your immediate family members ever worked for any of the following companies or agencies? Please select all that apply.3 Anesta LLC.1 0 0.0 Archimedes Phanna US. Inc. 1 0,3 Cephalon. Inc. (a wholly-owned subsidiary 2 0.6 of Teva Pharmaceutical Industries. Ltd.)1 Endo Phannaceuticals. Inc. 1 1 03 Insys Therapeutics1 3 0,8 McKesson Specialty Care Solutions1 0 00 Mallinckrodt (the Pharmaceuticals 0 00 Business of Covidien)1 Meda Pharmaceuticals1 0 0.0 Par Phannaceutical. Inc. 1 0 00 ProStrakan. Inc. 1 0 0.0 Sandoz. Inc. 1 0 0.0 Teva Phannaceuticals. Ltd.1 1 0,3 RelayHealth1 0 0.0 United BioSoru'ce Corporation1 1 0.3 FDA 1 0 0.0 None of these apply4 302 84.4 302 100.0 I don?t know1 7 2.0 Prefer not to answer1 2 0.6 Question not asked2 43 12.0 1 Ineligible to participate in the surveyQuestion not asked due to a previous question elimination. 3 More than 1 response can be selected. so percentages may not $11111 to 100%. 4 Ineligible if selected in addition to another response. Page 17 of 54 Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies December 2012 Prescriber KAB Assessment Report Those taking the s1uvey online took a mean of 17.2 minutes to complete, while those taking it by telephone took a mean of 24.2 minutes. Table 3. Time to Complete Survey for Completers Only (Minutes) Summary Statistic Telephone Internet Total 1 9 293 302 Mean (Standard Deviation) 24.2 (5.80) 17.2 (8.49) 17.5 (8.50) Minimum 13 6 6 Median 24.7 14.8 14.9 Maximum 34 64 64 Category 0 <5 Minutes 0 0 0 5 ?<10 Minutes 0 35 35 10?<15 Minutes 1 116 117 15 <20 Minutes 0 65 65 20 <25 Minutes 5 28 33 25 <30 Minutes 2 28 30 30 Minutes or More 1 21 22 Nmnber of eligible prescribers completing the sun?ey (See Table 1). 5.1.2 Prescriber Demographic and TIRF Product Prescribing Characteristics The demographic characteristics of em?olled prescribers are shown in Table 4. The majority of respondents were male Respondents ?'om the South, West, and Northeast included 31.1%, 26.8%, and 25.2% of the suivey population, respectively; while respondents from the Midwest region of the US composed 16.9%, of the total suwey population. The proportion of eligible completed prescribers within each geographic region was similar to the overall proportion of prescribers (7701 prescribers em'olled in the TIRF REMS Access program as of 15 August 2012) in each geographic region (Table 4). The most common healthcare degree was an MD and the most common medical specialties were pain management and oncology Of respondents who were medical doctors, half of the respondents had practiced medicine for more than 15 years. Page 18 of 54 Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies December 2012 Prescriber KAB Assessment Report Table 4. Demographic Characteristics of Eligible Prescribers Eligible Completed Prescribers Question N=302l Question 28: What is your gender? Male 180 59.6 Female 1 16 3 8.4 Prefer not to answer 6 20 Question 29: What is your medical degree? MD 172 57.0 DO 26 8.6 Nurse Practitioner 55 18.2 Physician?s Assistant 46 15.2 Prefer not to answer 3 10 Question 30: In total, how many years have you been practicing medicine, since completing your post-graduate education?2 Less than 3 years 12 6.0 3-5 years 14 7.0 6-10 years 36 17.9 11-15 years 36 17.9 More than 15 years 102 50.7 Prefer not to answer 1 0.5 Question 32: What is your medical specialty? Oncology 68 22.5 Primary Care 46 15.2 Pain Management 153 50.7 Other (please specify)3 35 11.6 Page 19 of 54 (continued) Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies December 20 12 Prescriber KAB Assessment Report Table 4. Demographic Characteristics of Eligible Prescribers Eligible Completed Prescribers Question N=302l Question 31: In which state or US Territory do you practice?4 Enrolled in TIRF REMS Eligible Completed Access Program on . . Respondents Geographic Region Northeast 76 25.2 1643 21.3 Midwest 51 16.9 1352 17.6 South 94 31.1 2811 36.5 West 81 26.8 1893 24.6 Other 0 0.0 2 0.03 Prefer not to answer 0 0.0 1 Number of eligible prescribers completing the survey (See Table 1). 2 This question is presented only to a sub-group of prescribers. Percentages are based 011 the munber of prescribers to whom this question was presented. 3 Other medical specialties are presented in Appendix B. Listing 3. 4 According to the 2001 Geographic Area Regions set by the US Census Bureau. Geography Division. Northeast includes CT. MA. ME. NH. NJ. NY. PA. RI. and VT. Midwest includes LA. IL. IN. KS. MI. MN. MO. ND. NE. OH. SD. and W1. South includes AL. AR. DC. DE. FL. GA. KY. LA. MD. MS. NC. OK. SC. TN. TX. VA. and WV. West includes AK. AZ. CA. CO. HI. ID. MT. NM. NV. OR. UT. WA. and WY. Other includes Puerto Rico. Northern Mariana Islands. US Virgin Islands. American Samoa. and Guam. Page 20 of 54 Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies December 2012 Prescriber KAB Assessment Report Of prescribers who described their medical specialty as ?other? (see Table 4), 5.0% stated their medical specialty was General Medicine, followed by Nelu?ology and Rehabilitation each), (Table 5). Table 5. Categorized Responses for Respondents Who Answered ?Other? to Question 32 Eligible Completed Prescribers Response (Categorized Type) 2 N=302l 3 General Medicine 15 5.0% Neurology 5 Rehabilitation 5 1 Emergency Medicine 2 0.7% 2 0.7% Anesthesiology 1 0.3% Gerontology 1 0.3% Oncology - Gynecology 1 0.3% Oncology - Hematology 1 0.3% Oncology - Radiology 1 0.3% Rheumatology 1 0.3% 1 Number of eligible prescribers completing the smwey (See Table 1). 2 Categorization scheme of the verbatim responses is shown in Appendix B. Listing 3. 3 Each category is only counted once per prescriber. Page 21 of 54 Transmucosal Immediate Release Fentanyl (TIRF) December 2012 TIRF REMS Industry Group (TRIG) of Companies Prescriber KAB Assessment Report Prescribers and their experience with prescribing TIRF medicines are smmnarized in Table 6. Nearly half of the prescribers prescribed TIRF medicines 1 to 2 times a month within the past 6 months. and Actiq or generic Actiq was the most frequently prescribed TIRF medicine (79.6% of prescribers). Seventeen (l7) prescribers indicated that they prescribed Onsolis dining the 6 months prior to taking the sulvey, which would be after 11 March 2012. However, Onsolis was not available to any pharmacy at that time. Therefore, none of these prescription could have been ?lled. The last Onsolis provided to patients was in May 2011. Table 6. Characteristics of Respondents Completing the Survey Eligible Completed Prescribers Question N=302l Question 26: On average, how many times per month have you prescribed the TIRF medicines within the last 6 months None 42 13.9 1-2 times per month 141 46.7 3-5 times per month 71 23.5 More than 5 times per month 37 12.3 I don?t remember 11 3.6 Question 27: Please select the TM medicines that you have prescribed within the last 6 months (select all that apply): 2 Abstral? 16 6.2 Actiq? or generic Actiq? 207 79.6 Fentora? 152 58.5 Lazanda? 24 9.2 Onsolis? l7 6. 5 Subsys? 49 8.8 (answered None to Question 42 26) 1 Number of eligible prescribers completing the survey (See Table 1). 2 Percentages are calculated based on the sample presented with this question because of skip logic in the survey. 5.1.3 TIRF Medicines Educational Materials Prescribers were asked about their awareness of educational materials for TIRF medicines, speci?cally the Full Prescribing Information, the Medication Guide, and the Patient-Prescriber Page 22 of 54 Transmucosal Immediate Release Fentanyl (TIRF) December 2012 TIRF REMS Industry Group (TRIG) of Companies Prescriber KAB Assessment Report Agreement F01m (PPAF) (Table 7). Most respondents had received or had access to the Full Prescribing Information and the Medication Guide (94.4% and 90.4%, respectively). Of those with access to these materials, 80.0% and 89.0%, respectively, indicated that they had read the Prescribing Information and the Medication Guide. Additionally, most prescribers reported reviewing the PPAF with each patient or their caregiver signing the PPAF and having the patient/caregiver sign the PPAF and giving a copy of the PPAF to the patient Table 7. Responses to Questions About TIRF Medicines Educational Materials and the TIRF Patient-Prescriber Agreement Form Eligible Completed Prescribers Question N=302l Question 17: Did you receive or do you have access to the Full Prescribing Information for the TIRF medicine that you prescribe? Yes 285 94.4 No 7 2.3 I don?t know 10 3.3 Question 18: Did you read the Full Prescribing Information for the TIRF medicine that you prescribe?2 Yes 228 80.0 No 47 16.5 I don?t know 10 3. 5 (answered No or I don?t 17 know to Question 17) Question 19: Did you receive or do you have access to the Medication Guide for the TIRF medicine that you prescribe? Yes 273 90.4 No 9 3.0 I don?t know 20 6.6 (continued) Page 23 of 54 Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies December 2012 Prescriber KAB Assessment Report Table 7. Responses to Questions About TIRF Medicines Educational Materials and the TIRF Patient-Prescriber Agreement Form Question 20: Did you read the Medication Guide for the TIRF medicine that you prescribe?2 Yes 243 89.0 No 22 8.1 I don?t know 8 2.9 (answered No or I don?t 29 know to Question 19) Question 21: Did you or do you have any questions about the information in the Full Prescribing Information or Medication Guide? Yes3 31 10.3 No 253 83.8 I don?t know 18 6.0 Question 23: Do you review the Patient-Prescriber Agreement Form with each of your patients for whom you prescribe TIRF medicines or their caregiver? Yes 266 88.1 No 26 8.6 I don?t know 10 3.3 Question 24: Do you and the patient or their caregiver sign the Patient?Prescriber Agreement Form for TIRF medicines after you have reviewed it with him/her?2 Yes 250 94.0 No 10 3.8 I don?t know 6 2.3 (answered No or I don?t 36 know to Question 23) Question 25: Do you give a copy of the Patient?Prescriber Agreement Form for medicines to the patient or their caregiver? Yes 249 82.5 No 35 11.6 I don?t know 18 6.0 1 Number of eligible prescribers completing the survey (See Table 1). 2 Percentages are calculated based on the sample presented with this question because of skip logic in the survey. 3 Verbatim text for questions about the information in the Full Prescribing Information are presented in Appendix B. Listing 1. Page 24 of 54 Transmucosal Immediate Release Fentanyl (TIRF) December 2012 TIRF REMS Industry Group (TRIG) of Companies Prescriber KAB Assessment Report There were 31 respondents who typed a response into the ??ee text ?eld for Question 21. These responses are categorized in Table 8 (see verbatim responses shown in Appendix B, Listing 1). There were 3 questions about dose titration and 2 questions each about indication and request for additional education Eight (8) of the responses were categorized as ?general responses? and were primarily statements that questions had ah'eady been answered, or that respondents had no questions at the time of the smvey. Table 8. Categorized Responses To Question 22 (Questions about the Information in the Full Prescribing Information or Medication Guide) Eligible Completed Prescribers Response (Categorized Type) 2 N=302l 3 Bioavailability 1 0.3% Dose modi?cations 1 0.3% Dose titration. Treatment failure 1 0.3% Drug interactions 1 0.3% Fonnulary. Insurance coverage 1 0.3% Insurance coverage 1 0.3% Metabolism 1 0.3% Patient compliance monitoring 1 0.3% Prescribing Infonnation/Medication Guide access 1 0.3% Request for Prescribing Infonnation/Medication Guide 2 0.6% Request for Prescribing Infonnation/Medication Guide. REMS enrollment 1 0.3% Simpli?cation of Prescribing Information/Medication Guide 1 0.3% TIRF medicine equivalences. 1 0.3% TIRF medicine conversion. Insurance coverage 1 0.3% Indication 2 0.7% Request for additional education 2 0.7% Dose titration 3 1.0% General responses (speci?c questions not asked) 8 2.6% 1 Number of eligible prescribers completing the survey (See Table 1). 2 Categorization scheme of the verbatim responses is shown in Appendix B. Listing 1. 3 Each category is only counted once per prescriber. Page 25 of 54 Transrnucosal Immediate Release Fentanyl (TIRF) December 2012 TIRF REMS Industry Group (TRIG) of Companies Prescriber KAB Assessment Report 5.2 KAB Survey Objectives 5.2.1 Key Risk Message Results The focus of this section of the docrunent is on the ?ndings for the total eligible respondent population who completed the survey. A surmnary of results by subgroup are described in a separate section of the document, Section 5.2.3. 5.2.1.1 Key Risk Message 1 Key Risk Message 1 assesses the prescriber?s knowledge of the speci?c contraindications for TIRF medicines in patients. Analysis of responses to components of Question 6 for Key Risk Message 1 showed that a high percentage of prescribers know that TIRF medicines are contraindicated in opioid non- tolerant patients because life-threatening respiratory depression could occru? and that death has occurred in opioid non-tolerant patients treated with some fentanyl products Most prescribers were aware patients just starting a TIRF medicine must begin with titration from the lowest available dose for that product and that TIRF medicines may not be used to treat opioid non-tolerant patients (Table 9). This is fruther supported by an average number of correct responses of 3.5 out of 4. Table 9. Responses Linked to Key Risk Message 1: TIRF Medicines Are Contraindicated in Opioid Non-Tolerant Patients Eligible Completed Prescribers N=302l Question 11 (95% CI) 3 Question 6: Please answer ?True,? ?False,? or don?t know? for each statement about TIRF medicines. 6a: TIRF medicines are contraindicated in opioid non-tolerant patients because life-threatening respiratory depression could occur at any dose. True 2 264 87.4 (83.1. 90.9) False 35 11.6 I don?t know 3 1.0 6b: Death has occurred in opioid non?tolerant patients treated with some fentanyl products. True 2 289 95.7 (92.8. 97.7) False 4 1.3 I don?t know 9 3.0 (continued) Page 26 of 54 Transmucosal Immediate Release Fentanyl (TIRF) December 2012 TIRF REMS Industry Group (TRIG) of Companies Prescriber KAB Assessment Report Table 9. Responses Linked to Key Risk Message 1: TIRF Medicines Are Contraindicated in Opioid Non-Tolerant Patients Eligible Completed Prescribers ti N=302l ues on (95% CI) 3 6c: TIRF medicines may be used to treat opioid non-tolerant patients. True 45 14.9 False2 249 82.5 (77.7. 86.6) I don?t know 8 2.6 6d: Prescribers starting a patient on a TIRF medicine must begin with titration from the lowest dose available for that speci?c product, even if the patient has previously taken another TIRF medicine. True 2 251 83.1 (78.4. 87.2) False 45 14.9 I don?t know 6 2.0 Secondary Analysis: Demonstrated Understanding 0 correct responses 1 0.3 1 correct response 9 3.0 2 correct responses 27 8.9 3 correct responses 70 23.2 4 correct responses 195 64.6 Average rnunber of correct responses 3 .5 (3.3. 4.0) 4 1 Number of eligible prescribers completing the survey (See Table 1). 2 Indicates the correct response(s) to each question or item within a question. 3 All con?dence intervals are exact binomial 95% con?dence intervals. 4 One-sided 95 con?dence interval using the rromral approximation to the Poisson distribution. 5.2.1.2 Key Risk Message 2 Key Risk Message 2 assesses the prescriber?s knowledge of the approved indications for prescribing TIRF Medicines to opioid tolerant patients. Responses to components of Question 8 for Key Risk Message 2 indicate that a high percentage of prescribers were aware TIRF medicines are prescribed for adult opioid-tolerant patients with breakthrough pain from cancer and not for patients with acute or Page 27 of 54 Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies December 2012 Prescriber KAB Assessment Report postoperative pain headache or migraine pain dental pain (Table 10). This is fluther supported by an average nlunber of correct responses of 3.6 out of 4. Table 10. Responses Linked to Key Risk Message 2: TIRF Medicines Are Only Indicated for the Management of Breakthrough Pain in Adult Cancer Patients 18 Years of Age and Older (16 Years of Age and Older for Actiq? Brand and Generic Equivalents) Who Are Already Receiving and Who Are Tolerant to Around-The-Clock Opioid Therapy for Their Underlying Persistent Cancer Pain Question N=302l Eligible Completed Prescribers (95% CI) 3 Question 8: For which of the following indications do you prescribe TIRF medicines to opioid tolerant patients? Please answer ?Yes,? or don?t know? for each option. 8a: Acute or postoperative pain Yes 38 12.6 No2 261 86.4 (82.0. 90.1) I don?t know 3 1.0 8b: Headache or migraine pain Yes 38 12.6 No2 262 86.8 (82.4. 90.4) I don?t know 2 0.7 8c: Dental pain Yes 7 2.3 No2 290 96.0 (93.2. 97.9) I don?t know 5 1.7 8d: Breakthrough pain from cancer Yes 2 288 95.4 (92.3. 97.4) No 14 4.6 I don?t know 0 0.0 (continued) Page 28 of 54 Transrnucosal Immediate Release Fentanyl (TIRF) December 2012 TIRF REMS Industry Group (TRIG) of Companies Prescriber KAB Assessment Report Table 10. Responses Linked to Key Risk Message 2: TIRF Medicines Are Only Indicated for the Management of Breakthrough Pain in Adult Cancer Patients 18 Years of Age and Older (16 Years of Age and Older for Actiq? Brand and Generic Equivalents) Who Are Already Receiving and Who Are Tolerant to Around-The-Clock Opioid Therapy for Their Underlying Persistent Cancer Pain Eligible Completed Prescribers N=302l Question 11 (95% CI) 3 Secondary Analysis: Demonstrated Understanding 0 correct responses 0 0.0 1 correct response 7 2.3 2 correct responses 16 5.3 3 correct responses 54 17.9 4 correct responses 225 74.5 Average number of correct responses 3.6 (3.5. 4.0) 4 1 Number of eligible prescribers completing the survey (See Table 1). 2 Indicates the correct response(s) to each question or item Within a question. 3 All con?dence intervals are exact binomial 95% con?dence intervals. 4 One-sided 95 con?dence interval using the normal approximation to the Poisson distribution. 5.2.1.3 Key Risk Message 3 Key Risk Message 3 assesses the prescriber?s knowledge of the risk factors and signs and of opioid abuse in patients who take TIRF medicines. Responses to components of Questions 6, 7, and 9 for Key Risk Message 3 showed that a high percentage of prescribers were aware that it is important to monitor for signs of abuse and addiction in patients who take TIRF medicines a personal history of illness is a risk factor for opioid abuse a personal history of past or current alcohol or drug abuse or family history of drug and alcohol abuse is a risk factor for opioid abuse and that TIRF medicines can be abused in a manner similar to other opioid agonists (Table 11). This is fluther supported by an average number of correct responses of 3.8 out of 4. Page 29 of 54 Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies December 2012 Prescriber KAB Assessment Report Table 11. Responses Linked to Key Risk Message 3: TIRF Medicines Contain Fentanyl, an Opioid Agonist and a Schedule II Controlled Substance, With Abuse Liability Similar to Other Opioid Analgesics. Question Eligible Completed Prescribers N=302l (95% CI) 3 Question 6: Please answer ?True,? ?False,? or don?t know? for each statement about TIRF medicines. 6e: It is important to monitor for signs of abuse and addiction in patients who take TIRF medicines. Tnle 2 301 99.7 (98.2. 100.0) False 1 0.3 I don?t know 0 0.0 Question 7: Which of the following are risk factors for opioid abuse? Please answer ?Yes,? or don?t know? for each option. 7a: A personal history of illness Yes 2 249 82.5 (77.7. 86.6) No 37 12.3 I don?t know 16 5.3 7b: A personal history of past or current alcohol or drug abuse, or a family history of illicit drug use or alcohol abuse Yes 2 300 99.3 (97.6. 99.9) No 1 0.3 I don?t know 1 0.3 Question 9: Please answer ?True,? ?False,? or don?t know? for each statement about TIRF medicines. 9a: TIRF medicines can be abused in a manner similar to other opioid agonists. Tme? 295 97.7 (95.3. 99.1) False 6 2.0 I don?t know 1 0.3 (continued) Page 30 of 54 Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies December 2012 Table 11. Responses Linked to Key Risk Message 3: TIRF Medicines Contain Fentanyl, an Opioid Agonist and a Schedule II Controlled Substance, With Abuse Liability Similar to Other Opioid Analgesics. Prescriber KAB Assessment Report Eligible Completed Prescribers Question 3 (95% CI) Secondary Analysis: Demonstrated Understanding 0 correct responses 0 0.0 1 conect response 0.0 2 correct responses 3 1.0 3 correct responses 57 18.9 4 correct responses 242 80.1 Average number of correct responses 3.8 (3.6. 4.0) 4 1 Number of eligible prescribers completing the survey (See Table 1). 2 Indicates the correct response(s) to each question or item within a question. 3 All con?dence intervals are exact binomial 95% con?dence intervals. 4 One-sided 95 con?dence interval using the normal approximation to the Poisson distribution. 5.2.1.4 Key Risk Message 4 Key Risk Message 4 assesses the prescriber?s knowledge that TIRF medicines are not interchangeable regardless of the route of administration. . Responses to components of Question 9 for Key Risk Message 4 showed that a high percentage of prescribers Imderstood TIRF medicines are not interchangeable with each other regardless of the route of administration the conversion of TIRF medicine to another may result in a fatal overdose and dosing of TIRF medicines is not equivalent on a microgram-to-microgram basis (Table 12). This is ?nther supported by an average munber of correct responses of 2.8 out of 3. Page 31 of 54 Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies December 2012 Prescriber KAB Assessment Report Table 12. Responses Linked to Key Risk Message 4: TIRF Medicines Are Not Interchangeable With Each Other, Regardless of Route of Administration. Eligible Completed Prescribers N=302l Question 11 (95% CI) Question 9: Please answer ?True,? ?False,? or don?t know? for each statement about TIRF medicines. 9b: TIRF medicines are interchangeable with each other regardless of route of administration. Tlue 9 3.0 False? 289 95.7 (92.8. 97.7) I don?t know 4 1.3 9c: The conversion of one TIRF medicine for another TIRF medicine may result in a fatal overdose because of differences in the pharmacokinetics of fentanyl absorption. T111623 286 94.7 (91.5. 96.9) False 5 1.7 I don?t know 11 3.6 9d: Dosing of TIRF medicines is not equivalent on a microgram-to-microgram basis. T111623 273 90.4 (86.5. 93.5) False 12 4.0 I don?t know 17 5.6 Secondary Analysis: Demonstrated Understanding 0 correct responses 3 1.0 1 correct response 7 2.3 2 correct responses 35 11.6 3 correct responses 257 85.1 Average munber of correct responses 4 2.8 (2.6. 3.0) 1 Number of eligible prescribers completing the survey (See Table 1Indicates the con?ect response(s) to each question or item Within a question. 3 All con?dence intervals are exact binomial 95% con?dence intervals. 4 One-sided 95 con?dence interval using the normal approximation to the Poisson distribution. Page 32 of 54 Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies 5.2.2 Other Survey Questions 5.2.2.1 Additional Questions About TIRF Medicines Safety December 2012 Prescriber KAB Assessment Report Table 13 summarizes the prescribers’ responses to additional questions about the safety of TIRF medicines beyond those associated with the key risk messages. Responses to the additional questions listed in Table 14 confirmed the prescribers’ understanding of the safety and the risks of taking TIRF medicines. More than half of the prescribers (54.3%) correctly indicated TIRF medicines cannot be prescribed for chronic non-cancer pain; however, 44.4% indicated that they do prescribe TIRF medicines for chronic non cancer pain. The majority of prescribers correctly answered that a TIRF medicine for breakthrough pain is indicated for an adult patient with advanced lung cancer currently receiving fentanyl for cancer pain (85.1%), for an adult patient with advanced prostate cancer currently receiving morphine for bone metastasis (80.5%), an adult patient with advanced sarcoma currently taking hydromorphone (70.2%). Over 50% of responders correctly indicated that a TIRF medicine for breakthrough pain is not indicated for an adult patient with localized breast cancer following mastectomy (54.3%). The majority of prescribers knew when switching the patient to a different TIRF medicine, they could not safely convert to the equivalent dosage of the new TIRF medicine (88.7%), they must not convert from the equivalent TIRF medicine dose to another TIRF medicine because this could result in fentanyl overdose (75.5%), they must not convert to the new TIRF medicine at half the dose (62.9%), or base the starting dose of the newly prescribed TIRF medicine on the dose of the opioid medicine used for underlying persistent cancer pain (57.9%). Additionally, most prescribers correctly indicated that for a patient starting titration with a TIRF medicine, an appropriate dose is not based on the dose of opioid medicine used for underlying persistent cancer pain (62.9%), the dose is not based on the prescribers assessment based on their clinical experience (79.5%), or the median available dose (94.0%), and is based on the lowest available dose, unless the Full Prescribing Information provides specific guidance (91.4%). Many prescribers also knew that taking erythromycin, a CYP3A4 inhibitor, at the same time as a TIRF medication is allowed (54.6%), and the majority understood that use of a TIRF inhibitor with erythromycin may require dosage adjustment and the patient needs to be carefully monitored for opioid toxicity, otherwise such use may be fatal (86.6%), and there is the possibility of drug interaction between CYP3A4 inhibitors and TIRF medicines (81.1%). Less than half (40.7%) correctly identified that the dose of the TIRF medicine should not be reduced by one half if a CYP3A4 inhibitor is prescribed in the same patient. Finally, a high percentage of prescribers correctly indicated TIRF medicines contain fentanyl in an amount that could be fatal to children and those who are not opioid tolerant (99.0%), that they should inform patients that TIRF medicines must not be used for any short term pain (91.7%), that if patients stop taking their around-the-clock opioid medicine they cannot continue to take their TIRF medicine (68.5%), and that they instruct patients never to share their TIRF medicine with anyone else (99.3%). Page 33 of 54 FDA_540 Transrnucosal Immediate Release Fentanyl (TIRF) December 2012 TIRF REMS Industry Group (TRIG) of Companies Prescriber KAB Assessment Report Despite the high proportion of prescribers responding correctly to the questions around Key Risk Message 1 that patients must be opioid tolerant), only 7.9% of prescribers correctly indicated that patients considered opioid tolerant are those who are taking regular opioid therapy for 1 week or longer. Additionally, 15.6% correctly indicated that patients not crnrently taking opioid therapy but who have no known intolerance or hypersensitivity to fentanyl are not considered opioid tolerant. In contrast a high percentage correctly indicated patients not currently taking opioid therapy but who had taken opioid therapy before are not considered opioid tolerant. Because the results to Question 5 are discrepant from the other pr?escr?iber? results ar?omrd opioid tolerance, it is possible that these results re?ect a misrmderstanding of the question rather than a lack of understanding of the important safety information. Additional research will be conducted to explore prescribers? interpretation and understanding of all 3 components of Question 5. The outcome of the research will be included in the next assessment report, and based on the outcome appropriate action may be taken, such as rephrasing Question 5. Table 13. Responses to Additional Questions About the Safe Use of TIRF Medicines Eligible Completed Prescribers Question N=302l Question 5: Please answer ?True,? ?False,? or don?t know? for each of the following. According to the labeling, patients considered opioid-tolerant are those: 5a: Who are taking regular opioid therapy for underlying persistent cancer pain for one week or longer. True 2 24 7.9 False 271 89.7 I don?t know 7 2.3 5b: Who are not currently taking opioid therapy, but have taken opioid therapy before. True 25 8.3 False2 268 88.7 I don?t know 9 3.0 (continued) Page 34 of 54 Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies December 2012 Table 13. Responses to Additional Questions About the Safe Use of TIRF Medicines Eligible Completed Prescribers Question 5c: Who are not currently taking opioid therapy, but with no known intolerance or hypersensitivity to the drug fentanyl. Tine 251 83.1 False2 47 15.6 I don?t know 4 1.3 Question 7: Which of the following are risk factors for opioid abuse? Please answer ?Yes,? or don?t know? for each option. 7c: A family history of asthma Yes 20 6.6 No2 268 88.7 I don't know 14 4.6 Question 8: For which of the following indications do you prescribe TIRF medicines to opioid tolerant patients? Please answer ?Yes,? or don?t know? for each option. 8e: Chronic non?cancer pain Yes 134 44.4 No2 164 54.3 I don't know 4 1.3 Question 11: The following patients described are experiencing breakthrough pain. According to the labelling, a TIRF medicine is not appropriate for one of them. Please answer ?Yes,? or don?t know? as to whether each patient should receive a TIRF medicine. 11a: Adult male with advanced lung cancer; underlying persistent cancer pain managed with 25 mcg/hour transdermal fentanyl patches for the past two months12.6 I don't know 7 2.3 (continued) Page 35 of 54 Prescriber KAB Assessment Report Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies December 2012 Prescriber KAB Assessment Report Table 13. Responses to Additional Questions About the Safe Use of TIRF Medicines Eligible Completed Prescribers Question N=302l 11b: Adult female with localized breast cancer; just completed a mastectomy and reconstructive surgery; persistent cancer pain managed with 30 mg oral morphine daily for the past 6 weeks. Yes 126 41.7 No2 164 54.3 I don't know 12 4.0 11c: Adult male patient with advanced prostate cancer who, over the last 2 weeks, has been prescribed 100 mg oral morphine daily for pain due to bone metastasis. Yes 2 243 80.5 No 51 16.9 I don't know 8 2.6 11d: Adult female with advanced sarcoma who has been taking a daily dose of 12 mg oral hydromorphone for the last 3 weeks. Yes 2 212 70.2 No 79 26.2 I don't know 11 3.6 Question 12: A patient is already taking a TIRF medicine but wants to change their medicine. The doctor decides to prescribe a different TIRF medicine (that is not a bioequivalent generic version of a branded product) in its place. How should the prescriber proceed? For each of the following scenarios, please indicate if it is a correct action for the prescriber by answering ?Yes,? or don?t know.? 12a: The prescriber can safely convert to the equivalent dosage of the new TIRF medicine as it has the same effect as other TIRF medicines. Yes 25 8.3 No 2 268 88.7 I don't know 9 3 .0 (continued) Page 36 of 54 Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies December 2012 Prescriber KAB Assessment Report Table 13. Responses to Additional Questions About the Safe Use of TIRF Medicines Eligible Completed Prescribers Question N=302l fentanyl overdose. 12b: The prescriber must not convert from the equivalent TIRF medicine dose to another TIRF medicine because they have different absorption properties and this could result in a Yes 2 228 75.5 No 66 21.9 I don't know 8 2.6 12c: Convert from the other TIRF medicine to the new TIRF medicine at half of the dose. Yes 84 27.8 No2 190 62.9 I don't know 28 9.3 12d: The prescriber should base the starting dose of the newly prescribed TIRF medicine on the dose of the opioid medicine used for their underlying persistent cancer pain. Yes 114 37.7 No2 175 57.9 I don't know 13 4.3 scenarios. Question 13: A patient is starting titration with a TIRF medicine. What dose must they start with? Please indicate ?Yes,? or don?t know? for each of the following dosing persistent cancer pain. 13a: An appropriate dose based on the dose of the opioid medicine used for underlying Page 37 of 54 Yes 100 33.1 No2 190 62.9 I don't know 12 4.0 13b: The dose that the prescriber believes is appropriate based on their clinical experience. Yes 56 18.5 No2 240 79.5 I don't know 6 2.0 (continued) Transrnucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies December 2012 Table 13. Responses to Additional Questions About the Safe Use of TIRF Medicines Eligible Completed Prescribers Question N=302l provides product-speci?c guidance. 13c: The lowest available dose, unless individual product Full Prescribing Information Yes 2 276 91.4 No 19 6.3 I don't know 7 2.3 13d: The median available dose. Yes 8 2.6 No2 284 94.0 I don't know 10 3.3 each of the following statements. Question 15: A patient is taking a TIRF medicine and the doctor would like to prescribe a CYP3A4 inhibitor. Please select ?True,? ?False,? or don?t know? for TIRF medicine could be fatal. 15a: The patient can?t be prescribed because using it at the same time as a True 52 17.2 False2 165 54.6 I don't know 85 28.1 fatal respiratory depression. 15b: Use of a TIRF medicine with a CYP3A4 inhibitor may require dosage adjustment; carefully monitor the patient for opioid toxicity, otherwise such use may cause potentially Page 38 of 54 True 2 262 86.8 False 11 3.6 I don't know 29 9.6 15c: There is no possible drug interaction between CYP3A4 inhibitors and TIRF medicines. True 8 2.6 False2 245 81.1 I don't know 49 16.2 (continued) Prescriber KAB Assessment Report December 2012 Prescriber KAB Assessment Report Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Table 13. Responses to Additional Questions About the Safe Use of TIRF Medicines Eligible Completed Prescribers Question N=302l 15d: The dose of the TIRF medicine must be reduced by one half if a CYP3A4 inhibitor is prescribed in the same patient. True 71 23.5 False2 123 40.7 I don't know 108 35.8 Question 16: Before initiating treatment with a TIRF medicine, prescribers must review the Medication Guide with the patient. Please select ?True,? ?False,? or don?t know? for each of the following counselling statements. 16a: TIRF medicines contain fentanyl in an amount that could be fatal to children of all ages, in individuals for whom they were not prescribed, and in those who are not opioid tolerant. True2 299 99.0 False 1 0.3 I don?t know 2 0.7 16b: Inform patients that TIRF medicines must not be used for acute or postoperative pain, pain from injuries, headache/migraine, or any other short?term pain. True2 277 91.7 False 16 5.3 I don?t know 9 3.0 16c: Instruct patients that, if they stop taking their around -the?clock opioid medicine, they can continue to take their TIRF medicine. True 63 20.9 False2 207 68.5 I don?t know 32 10.6 (continued) Page 39 of 54 Transrnucosal Immediate Release Fentanyl (TIRF) December 2012 TIRF REMS Industry Group (TRIG) of Companies Prescriber KAB Assessment Report Table 13. Responses to Additional Questions About the Safe Use of TIRF Medicines Eligible Completed Prescribers Question N=302l 16d: Instruct patients to never share their TIRF medicine with anyone else, even if that person has the same True2 300 99.3 False 1 0.3 I don?t know 1 0.3 1 Number of eligible prescribers completing the survey (See Table 1). 2 Indicates the correct response(s) to each question or item within a question. Responses to questions on managing breakthrough pain that is not suf?ciently relieved are provided in Table 14. In the TIRF REMS Prescriber educational materials, this question is asked with a choice to select the best option in multiple choice format However, due to the logistics of conducting a survey Via telephone administration, this question required a ?yes,? or don?t know? response for each question and did not permit the respondent to compare the response options to each other to identify the best answer. The responses to Question 14 in Table 14 are not assessed as correct or incorrect because the correct or incorrect answer depends on the prescribing information for the particular TIRF medicine. The majority of prescribers indicated that when a patient has started titration of the lowest dose of a TIRF medicine and after 30 minutes breakthrough pain has not been suf?ciently relieved, they would not advise the patient to take another identical dose of the TIRF medicine immediately to take a dose of an alternative rescue medicine or to double the dose and take immediately The minority of prescribers responded they should not provide guidance based on the product speci?c Medication Guide because the instructions are not the same for each TIRF medicine When these questions are presented based on TIRF medicine prescribed, no trends in responses are evident (see Table 3-3, Appendix B). Page 40 of 54 Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Table 14. Pain is Not Sufficiently Relieved December 2012 Prescriber KAB Assessment Report Responses to All Questions About What to Advise if Breakthrough Question Eligible Completed Prescribers N=302l Question 14: A prescriber has started titrating a patient with the lowest dose of a TIRF medicine. However, after 30 minutes the breakthrough pain has not been suf?ciently relieved. What should they advise the patient to do? Please answer ?Yes,? or don?t know? for each of the scenarios described. 14a: Take another (identical) dose of the TIRF medicine immediately. Yes 91 30.1 No 199 65.9 I don't know 12 4.0 14b: Take a dose of an alternative rescue medicine. Yes 59 19.5 No 232 76.8 I don't know 11 3.6 14c: Provide guidance based on the product?specific Medication Guide because the instructions are not the same for all TIRF medicines. Yes 273 90.4 No 21 7.0 I don't know 8 2.6 14d: Double the dose and take immediately. Yes 4 1.3 No 290 96.0 I don't know 8 2.6 1 Number of eligible prescribers completing the survey (See Table 1). 5.2.2.2 Prescriber Activities When Prescribing TIRF Medicines Prescribers were asked about speci?c activities perfonned when prescribing TIRF medicines (Table 15). More than half of prescribers indicated they always ask patients (or their caregivers) about the presence of children in the home instruct patients (or their caregivers) not to share TIRF medicines counsel patients (or their caregivers) that accidental exposure to TIRF medicines by a child may be fatal instruct patients (or their caregivers) to keep Page 41 of 54 Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies December 2012 Prescriber KAB Assessment Report TIRF medicines out of the reach of children instruct patients (or their caregivers) about proper disposal of any Imused or partially used TIRF medicines Less than half of prescribers always give patients (or their caregivers) the Medication Guide for their TIRF medicine, but 42.4% give their patients (or their caregivers) the Medication Guide for their TIRF medicine with the ?rst prescription. Table 15. Responses to All Questions About Activities When Prescribing TIRF Medicines Eligible Completed Prescribers Question N=302l Question 10: How frequently do you perform the following activities when prescribing TIRF medicines? Please answer ?Always,? ?Only with the ?rst prescription,? ?Sometimes,? ?Never,? or don?t know.? 10a: Ask patients (or their caregivers) about the presence of children in the home. Always 175 57.9 Only with the ?st prescription 76 25.2 Sometimes 44 14.6 Never 5 1.7 I don?t know 2 0.7 10b: Instruct patients (or their caregivers) not to share TIRF medicines with anyone else. Always 239 79.1 Only with the ?st prescription 36 11.9 Sometimes 24 7.9 Never 1 0.3 I don?t know 2 0.7 10c: Counsel patients (or their caregivers) that accidental exposure to TIRF medicines by a child may be fatal. Always 199 65.9 Only with the ?st prescription 59 19,5 Sometimes 34 1 1.3 Never 8 2.6 I don?t know 2 0.7 (continued) Page 42 of 54 Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies December 2012 Prescriber KAB Assessment Report Table 15. Responses to All Questions About Activities When Prescribing TIRF Medicines Eligible Completed Prescribers Question children to prevent accidental exposure. 10d: Instruct patients (or their caregivers) to keep TIRF medicines out of the reach of Always 220 72.8 Only with the fn?st prescription 51 16.9 Sometimes 25 8.3 Never 4 1.3 I don?t know 2 0.7 partially used TIRF medicines. 10e: Instruct patients (or their caregivers) about proper disposal of any unused or Always 184 60.9 Only with the fn?st prescription 75 24,8 Sometimes 37 12.3 Never 4 1.3 I don?t know 2 0.7 10f: Give patients (or their caregivers) the Medication Guide for their TIRF medicine. Always 122 40.4 Only with the ?st prescription 128 424 Sometimes 28 9.3 Never 20 6.6 I don?t know 4 1.3 1 Number of eligible prescribers completing the survey (See Table 1). 5.2.3 Analyses of Subpopulations To further assess prescriber lmderstanding of key risk messages, subgroup analyses as described in Section 4.1.2 were conducted. All results are similar to the results in the primary population, and no trends are evident. The full set of subgroup analysis tables is provided in Appendix B. Page 43 of 54 Transmucosal Immediate Release Fentanyl (TIRF) December 2012 TIRF REMS Industry Group (TRIG) of Companies Prescriber KAB Assessment Report 5.3 Spontaneous Reporting of Adverse Events, Product Complaints, or Medical Information Requests Among all survey respondents no prescribers reported an adverse event, product complaint, and/or medical information request associated with the use of TIRF medicines dru?ing phone completions of this sruvey. Twenty-one (21) reports of product complaints, and/or medical information requests were reported in the free text ?elds of surveys completed online by prescribers (Table 16; Appendix B, Listing 2). Adverse event, product complaint, or medical information request reports were categorized as described in Table 17. Table 16. Respondent Report of Adverse Event, Product Complaint, or Medical Information Request During Survey All Respondents Question N=358l Respondent spontaneously reported an adverse event, product complaint, or medical information request during the course of this survey. Yes2 21 5.9 N0 337 94.1 1 All respondents who took the survey regardless of eligibility. 2 Verbatim text of adverse events. product complaints. or medical infonnation requests is given in Appendix B. Listing 2. Table 17. Categorized Reported Adverse Events, Product Complaints, or Medical Information Requests All Respondents Response (Categorized Type) 2 N=358l 3 Adverse Event 0 0 Product Complaint 1 0.3% Medical Information Request 20 5.6% 1 All respondents who took the sruvey regardless of eligibility. 2 Categorization scheme of the verbatim responses is shown in Appendix B. Listing 2. 3 Each category is only counted once per prescriber. 5.4 Discussion, Conclusions, and Recommendations The speci?c goals of the TIRF medicines prescriber KAB sruvey were to assess prescriber rmderstanding of the risks associated with TIRF medicine use, of the speci?c indications for Page 44 of 54 Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies December 2012 Prescriber KAB Assessment Report treatment with TIRF medicines, that TIRF medicines are contraindicated in opioid nontolerant patients. Of the 5330 prescribers invited to participate, a total of 302 prescribers met eligibility criteria and completed the survey. The majority of respondents were male (59.6%). Respondents from the South, West, and Northeast included 31.1%, 26.8%, and 25.2% of the respondents, respectively; while respondents from the Midwest regions of the US composed 16.9%, of the total survey population. The most common healthcare degree was an MD (57.0%), and the most common medical specialties were pain management (50.7%) and oncology (22.5%). Of respondents who were medical doctors, half of the respondents (50.7%) had practiced medicine for more than 15 years. Most respondents received or had access to the Full Prescribing Information and the Medication Guide (94.4% and 90.4%, respectively). Of those with access to these materials, 80.0% and 89.0%, respectively, claimed to have read the Full Prescribing Information and the Medication Guide. Additionally, most prescribers review the Patient-Prescriber Agreement Form with each patient or their caregiver (88.1%), and following review; the majority of those prescribers (94.0%) sign and have the patient/caregiver sign the form, and 82.5% give a copy of the Patient-Prescriber Agreement Form to the patient or their caregiver. There were 4 key risk messages included in the survey. Prescriber demonstrated a high level of understanding of the 4 key risk messages, as there was a correct response rate of greater than 82% for all components of the key risk message questions. Analysis of responses to Key Risk Message 1 showed that a high percentage of prescribers know that TIRF medicines are contraindicated in opioid non-tolerant patients (87.4%) and that death has occurred in opioid non-tolerant patients treated with some fentanyl products (95.7%). Most prescribers were aware that patients just starting a TIRF medicine must begin with titration from the lowest available dose for that product (83.1%) and that TIRF medicines may not be used to treat opioid non-tolerant patients (82.5%). Responses to Key Risk Message 2 indicate that a high percentage of prescribers were aware TIRF medicines are prescribed for adult opioid-tolerant patients with breakthrough pain from cancer (95.4%) and not for patients with acute or postoperative pain (86.4%), headache or migraine pain (86.8%), or dental pain (96.0%). Responses to Key Risk Message 3 showed that a high percentage of prescribers were aware that it is important to monitor for signs of abuse and addiction in patients who take TIRF medicines (99.7%), a personal history of psychiatric illness is a risk factor for opioid abuse (82.5%), a personal history of past or current alcohol or drug abuse or family history of drug and alcohol abuse is a risk factor for opioid abuse (99.3%), and that TIRF medicines can be abused in a manner similar to other opioid agonists (97.7%). Responses to Key Risk Message 4 showed that a high percentage of prescribers understood TIRF medicines are not interchangeable with each other regardless of the route of administration (95.7%), the conversion of one TIRF medicine to another may result in a fatal Page 45 of 54 FDA_552 Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies December 2012 Prescriber KAB Assessment Report overdose (94.7%), and dosing of TIRF medicines is not equivalent on a microgram-tomicrogram basis (90.4%). Additional analyses of the key risk messages did not demonstrate any notable differences between subgroups of prescribers and no trends were evident. Among responses to all questions about the safe use of TIRF medicines, there were 2 questions relating to the definition of a non-opioid tolerant patient that had low response rates. Despite the high proportion of prescribers responding correctly to the questions around Key Risk Message 1 (i.e., that patients must be opioid tolerant), only 7.9% of prescribers correctly indicated that patients considered opioid tolerant are those who are taking regular opioid therapy for 1 week or longer. In addition, 15.6% correctly indicated that patients not currently taking opioid therapy but who have no known intolerance or hypersensitivity to fentanyl are not considered opioid tolerant. Because the results to Question 5 are discrepant from the other prescriber results around opioid tolerance (e.g., Questions 6a, 6b, and 6c), it is possible that these results reflect a misunderstanding of the question rather than a lack of understanding of the important safety information. Additional research will be conducted to explore prescribers’ interpretation and understanding of all 3 components of Question 5. The outcome of the research will be included in the next assessment report, and appropriate action may be taken based on the outcome. Across the 4 key risk messages, prescribers demonstrated a high level of understanding that TIRF medicines are contraindicated in opioid non-tolerant patients, are only indicated for the management of breakthrough pain in adult cancer patients, contain fentanyl with abuse liability similar to other opioid analgesics, and are not interchangeable with each other regardless of route of administration. Page 46 of 54 FDA_553 Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Appendix A December 2012 Prescriber KAB Assessment Report Prescriber Survey Protocol Page 47 of 54 FDA_554 PROTOCOL TITLE: Quantitative Testing of Prescriber Knowledge, Attitudes, and Behavior about Transmucosal Immediate Release Fentanyl (TIRF) Products Safety and Use Information SPONSOR: TIRF REMS Industry Group (TRIG) Archimedes Pharma US Inc. Cephalon, Inc. Endo Pharmaceuticals Inc. Insys Therapeutics Meda Pharmaceuticals Mallinckrodt (a Covidien Company) Par Pharmaceutical, Inc. ProStrakan, Inc. Sandoz, Inc. VERSION: 3.0 DATE: 10 SEP 2012 APPROVED: 07 SEP 2012 FDA_555 TIRF REMS Industry Group (TRIG) Transmucosal Immediate Release Fentanyl (TIRF) Products Prescriber KAB Survey Protocol TABLE OF CONTENTS Version 3.0 10 September 2012 PAGE TABLE OF CONTENTS ......................................................................................... 2  1.  LIST OF ABBREVIATIONS .................................................................................. 3  2.  BACKGROUND ..................................................................................................... 4  3.  OBJECTIVES OF THE EVALUATION SURVEY ............................................... 5  4.  METHODS .............................................................................................................. 5  4.1  4.1.1  4.1.2  Survey Design .......................................................................................................... 5  Questions on REMS Goals ...................................................................................... 6  Additional Questions................................................................................................ 9  4.2  4.2.1  Participant Recruitment............................................................................................ 9  Measures to Minimize Bias in the Sample............................................................... 9  5.  5.1.1  5.1.2  5.1.3  STUDY POPULATION ........................................................................................ 10  Sample Size ............................................................................................................ 10  Inclusion Criteria.................................................................................................... 11  Exclusion Criteria .................................................................................................. 11  6.  SURVEY PROCESS ............................................................................................. 12  6.1  6.1.1  6.1.2  Screening and Survey Administration ................................................................... 12  Telephone ............................................................................................................... 12  Internet ................................................................................................................... 12  6.2  Measures to Minimize Bias in the Survey Process ................................................ 12  7.  7.1.1  7.1.2  7.1.3  ANALYSIS ............................................................................................................ 13  Description of Primary Analyses ........................................................................... 13  Description of Secondary Analyses ....................................................................... 13  Analysis Population ............................................................................................... 14  8.  SAFETY EVENT REPORTING ........................................................................... 14  9.  PRIVACY PROTECTION AND CONFIDENTIALITY...................................... 14  LIST OF APPENDICES Appendix A Prescriber Questionnaire........................................................................... 15  Appendix B Sample Prescriber Invitation Letter .......................................................... 33  2 of 33 FDA_556 TIRF REMS Industry Group (TRIG) Transmucosal Immediate Release Fentanyl (TIRF) Products Prescriber KAB Survey Protocol 1. Version 3.0 10 September 2012 LIST OF ABBREVIATIONS CATI EDC ETASU FDA HIPAA IRB ISI KAB REALM REMS SERP TIRF TRIG UBC Computer-Assisted Telephone Interviewing Electronic Data Capture Elements to Assure Safe Use Food and Drug Administration Health Insurance Portability and Accountability Act Institutional Review Board Important Safety Information Knowledge, Attitudes and Behavior Rapid Estimate of Adult Literacy in Medicine Risk Evaluation and Mitigation Strategy Safety Event Reporting Plan Transmucosal Immediate Release Fentanyl TIRF REMS Industry Group United BioSource Corporation 3 of 33 FDA_557 TIRF REMS Industry Group (TRIG) Transmucosal Immediate Release Fentanyl (TIRF) Products Prescriber KAB Survey Protocol 2. Version 3.0 10 September 2012 BACKGROUND Transmucosal Immediate Release Fentanyl (TIRF) medicines include the class of immediaterelease opioid analgesics that are indicated only for the management of breakthrough pain in cancer patients 18 years of age or older (16 or older for Actiq® and equivalent generics) who are already receiving and already tolerant to opioid therapy for their underlying persistent cancer pain. The TIRF medicines include Abstral®, Actiq®, Fentora®, Lazanda®, Onsolis®, Subsys™, and generic versions of any of these brands. The TIRF REMS Industry Group (TRIG) includes Archimedes Pharma US Inc., Cephalon, Inc., Endo Pharmaceuticals Inc., Insys Therapeutics, Meda Pharmaceuticals, Mallinckrodt (a Covidien Company), Par Pharmaceutical, Inc., ProStrakan, Inc., and Sandoz Inc. The Food and Drug Administration (FDA) has determined that a Risk Evaluation and Mitigation Strategy (REMS) is required to mitigate the risk of misuse, abuse, addiction, overdose, and serious complications due to medication errors with the use of TIRF medicines. The TIRF REMS Access Program (hereafter referred to as TIRF REMS) was approved by the Food and Drug Administration (FDA) on December 28, 2011. The TIRF REMS consists of a Medication Guide, Elements to Assure Safe Use (ETASU), an Implementation System, and a timetable for submission of assessments of the REMS. The goals of the TIRF REMS are to mitigate the risk of misuse, abuse, addiction, overdose and serious complications due to medication errors bythe following: 1. Prescribing and dispensing TIRF medicines only to appropriate patients, which includes use only in opioid-tolerant patients. 2. Preventing inappropriate conversion between TIRF medicines. 3. Preventing accidental exposure to children and others for whom it was not prescribed. 4. Educating prescribers, pharmacists, and patients on the potential for misuse, abuse, addiction, and overdose of TIRF medicines. An important component of the TIRF REMS assessment is the conduct of quantitative evaluation surveys to assess prescribers’ understanding and knowledge of the safe use and appropriate prescribing of TIRF medicines as described in the TIRF REMS educational materials, enrollment form, and Prescribing Information (PI) of each product. This protocol will describe the administration of the surveys that will be conducted among prescribers who are enrolled in the TIRF REMS Access Program. Data from the surveys, together with other REMS evaluation metrics, will be used to determine whether changes need to be made to the REMS processes or educational materials to make them more effective in achieving the goals of the REMS. 4 of 33 FDA_558 TIRF REMS Industry Group (TRIG) Transmucosal Immediate Release Fentanyl (TIRF) Products Prescriber KAB Survey Protocol Version 3.0 10 September 2012 The surveys will be implemented so that data will be available for inclusion in the REMS Assessment Reports that will be submitted to the FDA at 12 months after approval of the TIRF REMS and annually thereafter. 3. OBJECTIVES OF THE EVALUATION SURVEY The evaluation survey will use a questionnaire to document the level of knowledge and assess the attitudes and behavior of prescribers around the following key information and risk messages communicated through REMS: 1. TIRF medicines are contraindicated in opioid non-tolerant patients. 2. TIRF medicines are only indicated for the management of breakthrough pain in adult cancer patients 18 years of age and older (16 or older for Actiq® and equivalent generics) who are already receiving and who are tolerant to around-the-clock opioid therapy for their underlying persistent cancer pain. 3. TIRF medicines contain fentanyl, an opioid agonist and a Schedule II controlled substance, with abuse liability similar to other opioid analgesics. 4. TIRF medicines are not interchangeable with each other, regardless of route of administration. 5. Patients and their caregivers must be instructed that TIRF medicines contain a medicine in an amount that can be fatal in children, in individuals for whom it is not prescribed, and in those who are not opioid tolerant. The survey will also collect data on behaviors, such as receipt and use of educational materials and compliance with REMS requirements. 4. METHODS The survey was designed in collaboration between the TRIG and United BioSource Corporation (UBC) and will be administered by UBC. 4.1 Survey Design This survey will be conducted among a sample of prescribers who are enrolled in the TIRF REMS Access Program. Respondents who participate in the first wave of the TIRF survey will not be eligible to participate in subsequent survey waves. The survey will be administered using the following modalities: • Self-administered, online through a secure website 5 of 33 FDA_559 TIRF REMS Industry Group (TRIG) Transmucosal Immediate Release Fentanyl (TIRF) Products Prescriber KAB Survey Protocol • Version 3.0 10 September 2012 Telephone surveys facilitated by a trained interviewer from the Survey Coordinating Center using a computer-assisted telephone interviewing (CATI) program The survey will begin with screening questions to confirm respondent eligibility to participate in the survey. Completion of the entire survey is expected to take approximately 20 minutes. The survey included in Appendix A is written to reflect wording for both methods of survey administration: Internet-based and telephone. All respondents who complete the survey and who provide their contact information will be mailed a $125 honorarium for their time. 4.1.1 Questions on REMS Goals The KAB questionnaire is made up of multiple-choice, close-ended statements or questions (the majority of which use true/false or yes/no dichotomous response options), and one openended question. These will evaluate current knowledge, attitudes, and behavior regarding the key risk messages noted in Section 3. Questions will be presented in several formats: • Statements or questions asking the respondent to indicate whether a statement or question is true or false, or if they do not know the answer (there is a similar set of statements and questions that use “yes” or “no” as potential response options); • Statements or questions asking the respondent to choose from a defined list of possible statements or answers; and • One question allowing for the respondent to list questions about the products or comments. Questionnaires will be analyzed to determine prescriber understanding of each key risk message. For statements or questions that use “true” or “yes” vs. “false” or “no” response options, the desired response for key risk messages is generally “true” or “yes” indicating knowledge of, or behavior in accordance with, the objectives of the REMS. However, some questions are formatted to have the respondent disagree with the statement as written by providing response options of “false” or “no” to avoid having the same affirmative answer for all desired responses. REMS statements, corresponding questions, and desired responses covering the key risk messages are identified below and can be found in the complete survey questionnaire (Appendix A). 6 of 33 FDA_560 TIRF REMS Industry Group (TRIG) Transmucosal Immediate Release Fentanyl (TIRF) Products Prescriber KAB Survey Protocol Version 3.0 10 September 2012 Key Risk Message 1: TIRF medicines are contraindicated in opioid non-tolerant patients. Question No. 6 6a 6b 6c 6d Question Desired response Please answer “True,” “False,” or “I don’t know” for each statement about TIRF medicines. TIRF medicines are contraindicated in opioid nontolerant patients because life-threatening respiratory TRUE depression could occur at any dose. Death has occurred in opioid non-tolerant patients TRUE treated with some fentanyl products. TIRF medicines may be used to treat opioid nonFALSE tolerant patients. Prescribers starting a patient on a TIRF medicine must begin with titration from the lowest dose TRUE available for that specific product, even if the patient has previously taken another TIRF medicine. Key Risk Message 2: TIRF medicines are only indicated for the management of breakthrough pain in adult cancer patients 18 years of age and older (16 years of age and older for Actiq® brand and generic equivalents) who are already receiving and who are tolerant to around-the-clock opioid therapy for their underlying persistent cancer pain. Question No. 8 8a 8b 8c 8d Question Desired response For which of the following indications do you prescribe TIRF medicines to opioid tolerant patients? Please answer “Yes,” “No,” or “I don’t know” for each option. Acute or postoperative pain NO Headache or migraine pain NO Dental pain NO Breakthrough pain from cancer YES 7 of 33 FDA_561 TIRF REMS Industry Group (TRIG) Transmucosal Immediate Release Fentanyl (TIRF) Products Prescriber KAB Survey Protocol Version 3.0 10 September 2012 Key Risk Message 3: TIRF medicines contain fentanyl, an opioid agonist and a Schedule II controlled substance, with abuse liability similar to other opioid analgesics. Question No. 6 6e 7 7a 7b 9 9a Question Desired response Please answer “True,” “False,” or “I don’t know” for each statement about TIRF medicines. It is important to monitor for signs of abuse and addiction in patients who take TIRF TRUE medicines. Which of the following are risk factors for opioid abuse? Please answer “Yes,” “No,” or “I don’t know” for each option. A personal history of psychiatric illness YES A personal history of past or current alcohol or drug abuse, or a family history of YES illicit drug use or alcohol abuse Please answer “True,” “False,” or “I don’t know” for each statement about TIRF medicines. TIRF medicines can be abused in a manner TRUE similar to other opioid agonists. Key Risk Message 4: TIRF medicines are not interchangeable with each other, regardless of route of administration. Question No. 9 9b 9c 9d Question Desired response Please answer “True,” “False,” or “I don’t know” for each statement about TIRF medicines. TIRF medicines are interchangeable with each other regardless of route of FALSE administration. The conversion of one TIRF medicine for another TIRF medicine may result in a fatal TRUE overdose because of differences in the pharmacokinetics of fentanyl absorption. Dosing of TIRF medicines is not equivalent TRUE on a microgram-to-microgram basis. 8 of 33 FDA_562 TIRF REMS Industry Group (TRIG) Transmucosal Immediate Release Fentanyl (TIRF) Products Prescriber KAB Survey Protocol 4.1.2 Version 3.0 10 September 2012 Additional Questions Questions about the requirements of the TIRF REMS Access Program and receipt and understanding of the TIRF educational materials and the Patient-Prescriber Agreement Form. The following question about behaviors will be asked after the key risk message questions: Question : How frequently do you perform the following activities when prescribing TIRF medicines? Ask patients (or their caregivers) about the presence of children in the home. Instruct patients (or their caregivers) not to share TIRF medicines with anyone else. Counsel patients (or their caregivers) that accidental exposure to TIRF medicines by a child may be fatal. Instruct patients (or their caregivers) to keep TIRF medicines out of the reach of children to prevent accidental exposure. Instruct patients (or their caregivers) about proper disposal of any unused or partially used TIRF medicines. Demographic information will be collected at the end of the survey. 4.2 Participant Recruitment A random sample of prescribers who are enrolled in the TIRF REMS Access Program will be invited to participate via an invitation letter. The text of the sample written invitation to prescribers can be found in Appendix BIf the required number of completed surveys is not achieved within the expected timeframe of approximately one to two weeks after the first mailing, reminder letters will be sent to non-respondents from the original sample with subsequent fax, e-mail follow-up to maximize participation. The distribution within the mailing to the second sample will be adjusted in accordance with the allocation in the original sample. If these efforts do not result in the required number of surveys within two to three weeks, then a new sample of prescribers will be randomly selected. All respondents who complete the survey and who provide their contact information will be mailed a $125 honorarium to thank them for their participation, except for prescribers from Vermont, Massachusetts, or Minnesota. Participants will be informed that prescribers from these states will not receive compensation for their participation. The mailing will include a Thank You Letter, the honorarium, a copy of the Important Safety Information (ISI), and a copy of the correct answers to key risk message questions. 4.2.1 Measures to Minimize Bias in the Sample The sample of prescribers who are invited to participate will be a random sample of all enrolled prescribers. The sample of participating prescribers will be self-selected since respondents will voluntarily respond to the invitation to participate; however, the survey 9 of 33 FDA_563 TIRF REMS Industry Group (TRIG) Transmucosal Immediate Release Fentanyl (TIRF) Products Prescriber KAB Survey Protocol Version 3.0 10 September 2012 recruitment strategies are intended to recruit a heterogeneous sample of prescribers for participation. Prescribers will be offered an online or telephone options for completing the survey. Multiple modalities for survey data collection allow for wider survey access to a more heterogeneous population. Respondents will be provided a unique code during the recruitment process and will be asked to provide the unique code to gain access to the online survey or when calling the Survey Coordinating Center. The code will be deactivated after use to minimize the possibility for fraud. 5. STUDY POPULATION 5.1.1 Sample Size A sample of 300 healthcare providers who are enrolled in the TIRF REMS Access Program is proposed for the first survey wave. The size of the sample was determined based on both practical and statistical considerations. There is no target comprehension rate specified a priori. A sample of 300 completed surveys will allow estimation of the comprehension rate for each risk message with a moderately high degree of precision. The table below shows the precision of the estimates for level of understanding using two-sided 95% confidence intervals (CIs) obtained with the sample size of 300 completed surveys. The noted CIs are used to indicate that for any survey-estimated rate of understanding, the true population rate of understanding is at least as high as the lower limit of the 95% CI and may be as high as the upper limit of the 95% CI. 10 of 33 FDA_564 TIRF REMS Industry Group (TRIG) Transmucosal Immediate Release Fentanyl (TIRF) Products Prescriber KAB Survey Protocol Version 3.0 10 September 2012 Precision of Estimated Rates of Understanding with a Sample Size of 300 (2-sided 95% Confidence Interval) Estimated Rate of Understanding 50% 5.1.2 Estimated Confidence Interval 44.2% 55.8% 55% 49.2% 60.7% 60% 54.2% 65.6% 65% 59.3% 70.4% 70% 64.5% 75.1% 75% 69.7% 79.8% 80% 75.0% 84.4% 85% 80.4% 88.8% 90% 86.0% 93.2% 95% 91.9% 97.2% Inclusion Criteria All prescribers who are enrolled in the TIRF REMS Access Program are eligible to participate in this survey, with the exceptions noted below. 5.1.3 Exclusion Criteria The following respondents are not eligible to participate in the surveys: • Prescribers who have previously participated in the TIRF REMS KAB survey (this exclusion only applies to all subsequent waves). • Prescribers or their immediate family members who have ever worked for Anesta LLC, Archimedes Pharma US Inc., Cephalon, Inc., Endo Pharmaceuticals Inc., Insys Therapeutics, Meda Pharmaceuticals, Mallinckrodt (a Covidien Company), Par Pharmaceutical, Inc., ProStrakan, Inc., Sandoz Inc., Teva Pharmaceuticals, Ltd., United BioSource Corporation, McKesson Specialty Care Solutions, RelayHealth, or the FDA. 11 of 33 FDA_565 TIRF REMS Industry Group (TRIG) Transmucosal Immediate Release Fentanyl (TIRF) Products Prescriber KAB Survey Protocol 6. Version 3.0 10 September 2012 SURVEY PROCESS The survey will begin with screening questions to confirm respondent eligibility to participate in the survey. Completion of the entire survey is expected to take approximately 20 minutes. 6.1 Screening and Survey Administration The questionnaire will begin with a screening module with questions to confirm prescriber eligibility. Depending on the answers to the screening questions, survey participation could either be terminated or continued. If ineligible, the respondent is immediately notified with a “thank you” message that survey participation has ended. If eligible, the respondent is allowed to continue survey participation. The data entry system used for both methods of survey administration has been validated and is secure for receiving and storing survey data. An Internet-based data repository will be used to store survey data and other relevant program information. The system is 21 CFR Part 11 and HIPAA compliant. Prescriber-identifying information will be stored separately from survey data. 6.1.1 Telephone A trained interviewer from the Survey Coordinating Center will conduct the telephone interviews using a CATI program. The screening and main elements of the questionnaire will be administered sequentially during the same telephone call. Telephone interviewing allows participation of prescribers who do not have Internet access. It will also be convenient for prescribers to participate since they can call in and be interviewed at their convenience during the specified time period when the Survey Coordinating Center is available. 6.1.2 Internet An Internet-based survey system will also be used for conducting the KAB surveys. If the prescriber selects to participate in the survey online, he/she will be directed to a secured website to complete screening questions. An Internet survey will be convenient for respondents to participate since they can complete the questionnaire at any convenient time and location during the specified time period when the Survey Coordinating Center is available. 6.2 Measures to Minimize Bias in the Survey Process A number of controls will be in place to ensure the survey is conducted in a controlled and professional manner and to minimize bias. For example, a unique code will be given to each survey participant and the code will be inactivated after use to minimize fraud. Telephone interviewers are highly trained and use a standardized script to administer interviews. All questions will be programmed to ensure that questions are asked in the appropriate sequence. Skip patterns will be clearly indicated. Respondents cannot go back to a question 12 of 33 FDA_566 TIRF REMS Industry Group (TRIG) Transmucosal Immediate Release Fentanyl (TIRF) Products Prescriber KAB Survey Protocol Version 3.0 10 September 2012 once the question has been answered and cannot skip ahead. All questions must be answered in order to complete the survey. Response options presented in a list will be randomized to minimize positional bias. Programming will be reviewed by quality control and simulated users (User Acceptance Testing) prior to implementing the survey. 7. ANALYSIS Information obtained from the survey will be reported as descriptive statistics for the survey administration, study population, and the survey questions. The data from the sample population will be reported using frequency distributions of responses to all questions. The following will be reported as part of this analysis: • The number of invitations issued to prescribers • The number of respondents screened for participation • The number of respondents eligible for participation • The number of respondents who complete the survey • Representativeness of prescribers based on geography • Description of survey participants, including: 7.1.1 − Medical degree of respondent: MD, DO, NP, PA − Medical specialty − Years of professional experience − How many times per month TIRF medicines prescribed in the last 6 months − Geographic region of practice Description of Primary Analyses Primary analyses are done for all key risk messages. The primary analysis for a key risk message evaluates the rate for each correct response to each individual question/item defined by the key risk message. The specific correct response to each question/item is identified in the body of the risk message table. 7.1.2 Description of Secondary Analyses Secondary analyses are done only for those key risk messages that contain multiple questions/items. The secondary analysis entails a frequency distribution of the number of 13 of 33 FDA_567 TIRF REMS Industry Group (TRIG) Transmucosal Immediate Release Fentanyl (TIRF) Products Prescriber KAB Survey Protocol Version 3.0 10 September 2012 respondents who got 0, 1, etc. correct responses across the total number of items for the given key risk message. 7.1.3 Analysis Population The analysis population will be based on eligible prescribers who completed the survey. 8. SAFETY EVENT REPORTING The term ‘Safety Event’ is defined as any information reported by a survey respondent that meets the criteria of an Adverse Event, Product Complaint, or Medical Information Requests. While it is not the intention of the survey to solicit the report of information that meets the criteria of a Safety Event, it is possible that a respondent may spontaneously report information that meets this criteria in free text fields of the survey (Internet-based administration) or while in conversation with the Survey Coordinating Center (telephonebased administration). The Internet-based questionnaires will be monitored for any comments recorded in the free text fields. If an event is mentioned to a Survey Coordinating Center Associate, the Associate will document the safety event and the respondent’s contact information. Respondents will also be informed that a representative from the appropriate TIRF medicine manufacturer may contact them if there are questions about the survey. Information on all reports (Internet or phone) that may constitute an adverse event or other safety event will be forwarded to the appropriate TIRF medicine manufacturer as described in the Safety Event Reporting Plan (SERP). Additional detail regarding processes for adverse event reporting will be specified in the SERP. 9. PRIVACY PROTECTION AND CONFIDENTIALITY All data collected during the survey will be held confidential. The electronic data capture (EDC) system used for data collection encrypts all identifiable information, and respondent identifiers are stored separately from the survey responses. Respondent names and addresses are collected in order to mail the $125 honorarium, a Thank You Letter, the correct responses to key risk messages, and the ISI after the survey is completed. Respondent contact information is also needed when necessary to comply with a federal or state law or regulation, including without limitation, reporting payments made to physicians under the federal physician payment sunshine provisions in addition to instances where a safety event is reported and a TIRF medicine manufacturer must obtain follow-up information (see Section 8 above). Respondents will be informed when they access the survey that they may be contacted if there are any questions about their survey responses. Respondents will be informed that their answers to the survey questions will not affect their ability to prescribe TIRF medicines. 14 of 33 FDA_568 TIRF REMS Industry Group (TRIG) Transmucosal Immediate Release Fentanyl (TIRF) Products Prescriber KAB Survey Protocol Appendix A Version 3.0 10 September 2012 Prescriber Questionnaire Survey Legend • [PROGRAMMER] is used to indicate directions to the programmer and is set in bold, red, uppercase letters between square brackets. • (INTERVIEWER) is used to indicate directions to the phone interviewer and is set in bold, blue, text between parentheses. This text appears when content is to be administered by phone only (for example, spontaneous adverse event reporting). • [ONLINE] indicates a question is worded specifically for administering the survey online. [PHONE] indicates a question is worded specifically to be read by a phone interviewer and differs from the online text. • [BEGIN ONLINE/PHONE SURVEY CONTENT] and [END SURVEY CONTENT] are used to indicate to the programmer the type of survey administration and the beginning and end of the survey or sections within the survey content, for example, [BEGIN ADVERSE EVENT/PRODUCT COMPLAINT] and [END ADVERSE EVENT/PRODUCT COMPLAINT]. • [TERMINATE] is displayed next to responses that should cause the survey to end. The following termination language will be programmed into the survey or read by the interviewer unless different language is specified with the question. Thank you very much for your time today. Based on your answer, you are not eligible to take this survey. We appreciate your interest in the survey. • [RANDOMIZE LIST] is inserted before questions to indicate to the programmer that the responses should be randomized. Responses such as “I don’t know,” “Prefer not to answer” or “None of the above” will always appear at the end of the randomized responses. • [GO TO Qx] (skip logic) is inserted after a response to indicate to the programmer that the survey should skip to the indicated question (for example, [GO TO Q17] skips to question 17). If no skip logic is indicated the survey continues to the next question in the sequence. • [MULTILINE INPUT] indicates to the programmer that multiple lines should be provided for data entry (for example, two address lines or a free-text response). 15 of 33 FDA_569 TIRF REMS Industry Group (TRIG) Transmucosal Immediate Release Fentanyl (TIRF) Products Prescriber KAB Survey Protocol Version 3.0 10 September 2012 Survey Legend • [DROP-DOWN LIST INPUT WITH STATES TABLE] indicates to the programmer that the response should be a drop-down list containing the states and US territories in the table below. Alabama Georgia Massachusetts New York Tennessee Alaska Guam Michigan North Carolina Texas American Samoa Hawaii Minnesota North Dakota Idaho Mississippi Arizona Illinois Missouri Arkansas Indiana Montana Northern Mariana Islands US Virgin Islands California Iowa Nebraska Colorado Kansas Nevada Connecticut Kentucky New Hampshire Delaware Louisiana New Jersey District of Columbia Maine New Mexico Utah Vermont Ohio Virginia Oklahoma Washington Oregon West Virginia Pennsylvania Wisconsin Puerto Rico Wyoming Rhode Island Maryland Florida South Carolina South Dakota • The following is used to categorize survey populations into standard geographic regions but it is not displayed in the survey. Geographic Distribution (based on address) 1: Northeast, Midwest, South, and West regions Northeast Region − New England Division - ME, NH, VT, MA, RI, CT − Middle Atlantic Division - NY, NJ, PA Midwest Region − East North Central Division - OH, IN, IL, MI, WI − West North Central Division - MN, IA, MO, ND, SD, NE, KS South Region − South Atlantic Division - DE, MD, DC, VA, WV, NC, SC, GA, FL − East South Central Division - KY, TN, AL, MS − West South Central Division - AR, LA, OK, TX 16 of 33 FDA_570 TIRF REMS Industry Group (TRIG) Transmucosal Immediate Release Fentanyl (TIRF) Products Prescriber KAB Survey Protocol Version 3.0 10 September 2012 Survey Legend West − Mountain Division - MT, ID, WY, CO, NM, AZ, UT, NV − Pacific Division WA, OR, CA, AK, HI • The following US territories are categorized as Other: Puerto Rico, Northern Mariana Islands, US Virgin Islands, American Samoa, and Guam. 1 U.S. Census Bureau, last revised Friday, 27-Jul-2001 12:59:43 EDT. [BEGIN ONLINE/PHONE SURVEY CONTENT] [PREAMBLE 1] Before you begin, we would like to share some important information about this survey. The manufacturers of Transmucosal Immediate Release Fentanyl medicines are conducting this survey, as required by the FDA, to assess prescribers’ understanding of the safe use and prescribing of these medicines. These medicines are known as rapid onset opioids and referred to in this survey as “TIRF medicines.” (INTERVIEWER: Say “TIRF” then spell out T-IR-F) The TIRF medicines include Abstral®, Actiq®, Fentora®, Lazanda®, Onsolis®, Subsys™, and generic versions of any of these brands. The manufacturers of these medicines include Archimedes Pharma US Inc., Cephalon, Inc., Endo Pharmaceuticals Inc., Insys Therapeutics, Meda Pharmaceuticals, Mallinckrodt (a Covidien Company), Par Pharmaceutical, Inc., ProStrakan, and Sandoz Inc. The survey will take approximately 20 minutes. There are no known risks to you in taking this survey. You may refuse to take part or withdraw at any time. Your answers to the questions or your decision to take part in the survey will not affect your ability to prescribe TIRF medicines. [ONLINE ONLY]How We Use Your Information [PHONE ONLY] Now I would like to read some information about how your contact information will be used. Your answers to the survey questions will be combined with answers given by other healthcare professionals taking the survey. All answers will be put together and reported in anonymous form to the manufacturers of TIRF medicines. Your name will not be used in any report. If you are eligible to take the survey, complete all the questions, and provide your contact information, you will receive a $125 honorarium for your time and participation. This compensation represents the fair value for your services in connection with completion of the survey. The amount of the compensation was not determined in any manner that takes into account the volume or value of any referrals or business otherwise generated by you. 17 of 33 FDA_571 TIRF REMS Industry Group (TRIG) Transmucosal Immediate Release Fentanyl (TIRF) Products Prescriber KAB Survey Protocol Version 3.0 10 September 2012 Your name and address will be used to send you the honorarium after you complete the survey. Your personal information will also be used if we have questions about your survey or if we are required to use your information to comply with a federal or state law or regulation, including without limitation, reporting payments made to physicians under the federal physician payment sunshine provisions. Physicians who practice in Vermont, Massachusetts, or Minnesota should be aware that they will not be permitted to receive payment for survey completion and may elect not to complete the survey. Providing a telephone number is optional. Your phone number will be used only if there are any questions about your survey responses. [ONLINE ONLY] How We Protect Your Privacy [PHONE ONLY]Now I would like to tell you some information about how we protect your privacy. We respect that the privacy of your personal information is important to you. You will not be contacted for marketing purposes based on your personal information or your answers to the survey. Neither the manufacturers of TIRF medicines nor their contractors will sell, transfer, or rent your information. Your answers will be kept strictly confidential. Your personal information will not be used in a manner inconsistent with this document. Your privacy will be protected; however, research survey records may be inspected by the FDA. Your choice to allow manufacturers of TIRF medicines to use your information is entirely voluntary but necessary to take part in this survey. [ONLINE ONLY] How to Learn More about This Survey [ONLINE ONLY] If you have questions about the survey, or problems with the survey, please contact the Survey Coordinating Center at 1-877-379-3297. Be sure to write down this telephone number; it will not be displayed again. [PHONE ONLY]Now I will tell you how you can learn more about this survey. Please have a pen or pencil ready to write down a telephone number you can call should you have any questions about the survey. If you have questions about the survey, please ask me at any time. If you have questions at a later time, please contact the Survey Coordinating Center at 1-877379-3297. Please feel free to ask me to repeat any questions or statements as we go through the survey. Once you have answered a question and moved on, you cannot go back and change your answers. Thank you for your participation in this survey. [ONLINE ONLY] Taking the Survey [ONLINE ONLY] Once you have answered a question and moved on, you cannot go back and change your answers. [ONLINE ONLY] Thank you for your participation in this survey. [END PREAMBLE 1] 18 of 33 FDA_572 TIRF REMS Industry Group (TRIG) Transmucosal Immediate Release Fentanyl (TIRF) Products Prescriber KAB Survey Protocol Version 3.0 10 September 2012 [BEGIN INCLUSION/EXCLUSION QUESTIONS] 1. Your agreement to participate in this survey confirms mutual understanding in connection with completion of the survey and the fair market value of the payment to be rendered in connection with those services. Do you agree to participate in this survey? 2. 3. 4. ○ Yes ○ No [TERMINATE] Have you ever taken part in this survey about TIRF medicines before? TIRF medicines include Abstral®, Actiq®, Fentora®, Lazanda®, Onsolis®, Subsys™, and generic versions of any of these brands. ○ Yes [ONLY TERMINATE AFTER WAVE 1] ○ No ○ I don’t know [ONLY TERMINATE AFTER WAVE 1] Are you enrolled in the TIRF REMS Access program? ○ Yes ○ No [TERMINATE] ○ I don’t know [TERMINATE] Have you or any of your immediate family members ever worked for any of the following companies or agencies? Please select all that apply. ○ Anesta LLC [TERMINATE] ○ Archimedes Pharma US Inc.[TERMINATE] ○ Cephalon, Inc. [TERMINATE] ○ Endo Pharmaceuticals Inc. [TERMINATE] ○ Insys Therapeutics[TERMINATE] 19 of 33 FDA_573 TIRF REMS Industry Group (TRIG) Transmucosal Immediate Release Fentanyl (TIRF) Products Prescriber KAB Survey Protocol Version 3.0 10 September 2012 ○ McKesson Specialty Care Solutions[TERMINATE] ○ Mallinckrodt (a Covidien Company) [TERMINATE] ○ Meda Pharmaceuticals [TERMINATE] ○ Par Pharmaceutical, Inc.[TERMINATE] ○ ProStrakan, Inc. [TERMINATE] ○ Sandoz Inc. [TERMINATE] ○ Teva Pharmaceuticals, Ltd. [TERMINATE] ○ RelayHealth[TERMINATE] ○ United BioSource Corporation[TERMINATE] ○ FDA [TERMINATE] ○ None of these apply [IF SELECTED IN ADDITION TO OTHER RESPONSES, TERMINATE] ○ I don’t know [TERMINATE] ○ Prefer not to answer [TERMINATE] [END INCLUSION/EXCLUSION QUESTIONS] 20 of 33 FDA_574 TIRF REMS Industry Group (TRIG) Transmucosal Immediate Release Fentanyl (TIRF) Products Prescriber KAB Survey Protocol 5. Version 3.0 10 September 2012 Please select “True,” “False,” or “I don’t know” for each of the following. According to the labeling, patients considered opioid-tolerant are those: [RANDOMIZE LIST] 5a. Who are taking regular opioid therapy for underlying persistent cancer pain for one week or longer 5b. Who are not currently taking opioid therapy, but have taken opioid therapy before 5c. Who are not currently taking opioid therapy, but with no known intolerance or hypersensitivity to the drug fentanyl 6. True False I don’t know ○ ○ ○ ○ ○ ○ ○ ○ ○ Please answer “True,” “False,” or “I don’t know” for each statement about TIRF medicines. [RANDOMIZE LIST] TIRF medicines are contraindicated in opioid nontolerant patients because life-threatening respiratory depression could occur at any dose. 6b. Death has occurred in opioid non-tolerant patients treated with some fentanyl products. 6c. TIRF medicines may be used to treat opioid non-tolerant patients. 6d. Prescribers starting a patient on a TIRF medicine must begin with titration from the lowest dose available for that specific product, even if the patient has previously taken another TIRF medicine. 6e. It is important to monitor for signs of abuse and addiction in patients who take TIRF medicines. True False I don’t know ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ 6a. 7. Which of the following are risk factors for opioid abuse? Please answer “Yes,” “No,” or “I don’t know” for each option. 21 of 33 FDA_575 TIRF REMS Industry Group (TRIG) Transmucosal Immediate Release Fentanyl (TIRF) Products Prescriber KAB Survey Protocol [RANDOMIZE LIST] 7a. 7b. 7c. 8. A personal history of psychiatric illness A personal history of past or current alcohol or drug abuse, or a family history of illicit drug use or alcohol abuse A family history of asthma Version 3.0 10 September 2012 Yes No I don’t know ○ ○ ○ ○ ○ ○ ○ ○ ○ For which of the following indications do you prescribe TIRF medicines to opioid tolerant patients? Please answer “Yes,” “No,” or “I don’t know” for each option. [RANDOMIZE LIST] Yes No I don’t know ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ 8a. 8b. 8c. 8d. 8e. Acute or postoperative pain Headache or migraine pain Dental pain Breakthrough pain from cancer Chronic non-cancer pain 9. Please answer “True,” “False,” or “I don’t know” for each statement about TIRF medicines. [RANDOMIZE LIST] 9a. TIRF medicines can be abused in a manner similar to other opioid agonists. 9b. TIRF medicines are interchangeable with each other regardless of route of administration. 9c. The conversion of one TIRF medicine for another TIRF medicine may result in a fatal overdose because of differences in the pharmacokinetics of fentanyl absorption. 9d. Dosing of TIRF medicines is not equivalent on a microgram-to-microgram basis. 10. True False I don’t know ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ How frequently do you perform the following activities when prescribing TIRF medicines? Please answer “Always,” “Only with the first prescription,” “Sometimes,” “Never,” or “I don’t know.” 22 of 33 FDA_576 TIRF REMS Industry Group (TRIG) Transmucosal Immediate Release Fentanyl (TIRF) Products Prescriber KAB Survey Protocol [RANDOMIZE LIST] 10a. Ask patients (or their caregivers) about the presence of children in the home 10b. Instruct patients (or their caregivers) not to share TIRF medicines with anyone else 10c. Counsel patients (or their caregivers) that accidental exposure to TIRF medicines by a child may be fatal 10d. Instruct patients (or their caregivers) to keep TIRF medicines out of the reach of children to prevent accidental exposure 10e. Instruct patients (or their caregivers) about proper disposal of any unused or partially used TIRF medicines 10f. Give patients (or their caregivers) the Medication Guide for their TIRF medicine 11. Always Version 3.0 10 September 2012 Only with Sometimes the first prescription Never I don’t know ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ The following patients described are experiencing breakthrough pain. According to the labeling, a TIRF medicine is not appropriate for one of them. Please answer “Yes,” “No,” or “I don’t know” as to whether each patient should receive a TIRF medicine. [RANDOMIZE LIST] Adult male with advanced lung cancer; underlying persistent cancer pain managed with 25 mcg/hour transdermal fentanyl patches for the past two months. 11b. Adult female with localized breast cancer; just completed a mastectomy and reconstructive surgery; persistent cancer pain managed with 30 mg oral morphine daily for the past 6 weeks. 11c. Adult male patient with advanced prostate cancer who, over the last 2 weeks, has been prescribed 100 mg oral morphine daily for pain due to bone metastasis. Yes No I don’t know ○ ○ ○ ○ ○ ○ ○ ○ ○ 11a. 23 of 33 FDA_577 TIRF REMS Industry Group (TRIG) Transmucosal Immediate Release Fentanyl (TIRF) Products Prescriber KAB Survey Protocol 11d. Adult female with advanced sarcoma who has been taking a daily dose of 12 mg oral hydromorphone for the last 3 weeks. 12. Version 3.0 10 September 2012 ○ ○ ○ A patient is already taking a TIRF medicine but wants to change their medicine. The doctor decides to prescribe a different TIRF medicine (that is not a bioequivalent generic version of a branded product) in its place. How should the prescriber proceed? For each of the following scenarios, please indicate if it is a correct action for the prescriber by answering “Yes,” “No,” or “I don’t know.” [RANDOMIZE LIST] The prescriber can safely convert to the equivalent dosage of the new TIRF medicine as it has the same effect as other TIRF medicines. 12b. The prescriber must not convert from the equivalent TIRF medicine dose to another TIRF medicine because they have different absorption properties and this could result in a fentanyl overdose. 12c. Convert from the other TIRF medicine to the new TIRF medicine at half of the dose. 12d. The prescriber should base the starting dose of the newly prescribed TIRF medicine on the dose of the opioid medicine used for their underlying persistent cancer pain. Yes No I don’t know ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ 12a. 13. A patient is starting titration with a TIRF medicine. What dose must they start with? Please indicate “Yes,” “No,” or “I don’t know” for each of the following dosing scenarios. [RANDOMIZE LIST] 13a. An appropriate dose based on the dose of the opioid medicine used for underlying persistent cancer pain. 13b. The dose that the prescriber believes is appropriate based on their clinical experience. 13c. The lowest available dose, unless individual product Full Prescribing Information provides product-specific guidance. 13d. The median available dose. 24 of 33 Yes No I don’t know ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ FDA_578 TIRF REMS Industry Group (TRIG) Transmucosal Immediate Release Fentanyl (TIRF) Products Prescriber KAB Survey Protocol 14. A prescriber has started titrating a patient with the lowest dose of a TIRF medicine. However, after 30 minutes the breakthrough pain has not been sufficiently relieved. What should they advise the patient to do? Please answer “Yes,” “No,” or “I don’t know” for each of the scenarios described. [RANDOMIZE LIST] 14a. Take another (identical) dose of the TIRF medicine immediately. 14b. Take a dose of an alternative rescue medicine. 14c. Provide guidance based on the product-specific Medication Guide because the instructions are not the same for all TIRF medicines. 14d. Double the dose and take immediately. 15. Version 3.0 10 September 2012 Yes No I don’t know ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ A patient is taking a TIRF medicine and the doctor would like to prescribe erythromycin, a CYP3A4 inhibitor. Please select “True,” “False,” or “I don’t know” for each of the following statements. [RANDOMIZE LIST] The patient can’t be prescribed erythromycin, because using it at the same time as a TIRF medicine could be fatal. 15b. Use of a TIRF medicine with a CYP3A4 inhibitor may require dosage adjustment; carefully monitor the patient for opioid toxicity, otherwise such use may cause potentially fatal respiratory depression. 15c. There is no possible drug interaction between CYP3A4 inhibitors and TIRF medicines. 15d. The dose of the TIRF medicine must be reduced by one half if a CYP3A4 inhibitor is prescribed in the same patient. True False I don’t know ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ 15a. 25 of 33 FDA_579 TIRF REMS Industry Group (TRIG) Transmucosal Immediate Release Fentanyl (TIRF) Products Prescriber KAB Survey Protocol 16. Version 3.0 10 September 2012 Before initiating treatment with a TIRF medicine, prescribers must review the Medication Guide with the patient. Please select “True,” “False,” or “I don’t know” for each of the following counseling statements. [RANDOMIZE LIST] TIRF medicines contain fentanyl in an amount that could be fatal to children of all ages, in individuals for whom they were not prescribed, and in those who are not opioid tolerant. 16b. Inform patients that TIRF medicines must not be used for acute or postoperative pain, pain from injuries, headache/migraine, or any other short-term pain. True False I don’t know ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ 16a. 16c. Instruct patients that, if they stop taking their around the-clock opioid medicine, they can continue to take their TIRF medicine. 16d. Instruct patients to never share their TIRF medicine with anyone else, even if that person has the same symptoms. [PREAMBLE 2] The next set of questions is about the educational materials for TIRF medicines and the TIRF Patient-Prescriber Agreement. As a reminder, the TIRF medicines include Abstral®, Actiq®, Fentora®, Lazanda®, Onsolis®, Subsys™, and generic versions of any of these brands. 17. Did you receive or do you have access to the Full Prescribing Information for the TIRF medicine that you prescribe? ○ Yes ○ No [GO TO Q19] ○ I don’t know [GO TO Q19] 26 of 33 FDA_580 TIRF REMS Industry Group (TRIG) Transmucosal Immediate Release Fentanyl (TIRF) Products Prescriber KAB Survey Protocol 18. 19. 20. 21. 22. Version 3.0 10 September 2012 Did you read the Full Prescribing Information for the TIRF medicine that you prescribe? ○ Yes ○ No ○ I don’t know Did you receive or do you have access to the Medication Guide for the TIRF medicine that you prescribe? ○ Yes ○ No [GO TO Q21] ○ I don’t know [GO TO Q21] Did you read the Medication Guide for the TIRF medicine that you prescribe? ○ Yes ○ No ○ I don’t know Did you or do you have any questions about the information in the Full Prescribing Information or Medication Guide? ○ Yes ○ No [GO TO Q23] ○ I don’t know [GO TO Q23] What are your questions?[MULTILINE INPUT] 27 of 33 FDA_581 TIRF REMS Industry Group (TRIG) Transmucosal Immediate Release Fentanyl (TIRF) Products Prescriber KAB Survey Protocol 23. 24. 25. Version 3.0 10 September 2012 Do you review the Patient-Prescriber Agreement Form with each of your patients for whom you prescribe TIRF medicines or their caregiver? ○ Yes ○ No [GO TO Q25] ○ I don’t know [GO TO Q25] Do you and the patient or their caregiver sign the Patient-Prescriber Agreement Form for TIRF medicines after you have reviewed it with him/her? ○ Yes ○ No ○ I don’t know Do you give a copy of the Patient-Prescriber Agreement Form for TIRF medicines to the patient or their caregiver? ○ Yes ○ No ○ I don’t know 28 of 33 FDA_582 TIRF REMS Industry Group (TRIG) Transmucosal Immediate Release Fentanyl (TIRF) Products Prescriber KAB Survey Protocol Version 3.0 10 September 2012 [DEMOGRAPHICS PREAMBLE] There are just a few more questions to help us combine your answers with other answers we have received. 26. 27. On average, how many times per month have you prescribed the TIRF medicines within the last 6 months? ○ None [GO TO DEMOGRAPHICS PREAMBLE 2] ○ 1 – 2 times per month ○ 3 – 5 times per month ○ More than 5 times per month ○ I don’t remember Please select the TIRF medicines that you have prescribed within the last 6 months: (select all that apply) ○ Abstral® ○ Actiq® or generic Actiq® ○ Fentora® or generic Fentora® ○ Lazanda® ○ Onsolis® ○ Subsys™ [DEMOGRAPHICS PREAMBLE 2]These last few questions are for demographic purposes. 28. What is your gender? ○ Male ○ Female ○ Prefer not to answer 29 of 33 FDA_583 TIRF REMS Industry Group (TRIG) Transmucosal Immediate Release Fentanyl (TIRF) Products Prescriber KAB Survey Protocol 29. 30. 31. Version 3.0 10 September 2012 What is your medical degree? ○ MD ○ DO ○ Nurse Practitioner [Go to Q31] ○ Physician Assistant [Go to Q31] ○ Prefer not to answer In total, how many years have you been practicing medicine, since completing your post-graduate education? ○ Less than 3 years ○ 3 – 5 years ○ 6 – 10 years ○ 11 – 15 years ○ More than 15 years ○ Prefer not to answer In which state do you practice? [DROP-DOWN LIST INPUT WITH STATES TABLE WITH “Prefer not to answer” at END] 32. What is your medical specialty? ○ Oncology ○ Primary care ○ Pain management ○ Other (please specify): _____________________ [PHONE ONLY: BEGIN ADVERSE EVENT/PRODUCT COMPLAINT] (INTERVIEWER: Please record if respondent spontaneously reported an adverse event or product complaint during the course of this interview.) 30 of 33 FDA_584 TIRF REMS Industry Group (TRIG) Transmucosal Immediate Release Fentanyl (TIRF) Products Prescriber KAB Survey Protocol ○ Yes ○ No [GO TO CLOSING 1] Version 3.0 10 September 2012 Enter Safety Adverse Event Verbatim [MULTILINE INPUT] (INTERVIEWER: Indicate to the respondent that someone may call back to ask more questions about the adverse event or product complaint that was reported.) [END ADVERSE EVENT/PRODUCT COMPLAINT] [CLOSING 1] We would like to send you a $125 honorarium within the next few weeks to thank you for your time, but we need your name and address to do so. If you do not provide your name and address you will not receive the honorarium for your time and participation in the survey. As a reminder, physicians who practice in Vermont, Massachusetts, or Minnesota should be aware that they will not be permitted to receive payment for survey completion. Do you agree to give us your name and mailing address so we can send you the honorarium? ○ Yes ○ No [SKIP TO CLOSING 2] FIRST NAME: _______________________________________________ LAST NAME: _______________________________________________ ADDRESS: [MULTILINE INPUT] CITY: _____________________________________ STATE: [DROP-DOWN LIST INPUT WITH STATES TABLE] ZIP: ___________ [CLOSING 2] 31 of 33 FDA_585 TIRF REMS Industry Group (TRIG) Transmucosal Immediate Release Fentanyl (TIRF) Products Prescriber KAB Survey Protocol Version 3.0 10 September 2012 We would also like to ask for your telephone number and NPI number. Providing your telephone number and NPI number is optional. Your telephone number will be used to contact you only if there are questions about your survey responses.  Do you want to provide your telephone number? ○ Yes ○ No [SKIP TO NPI NUMBER QUESTION] Telephone: ________________________________ [NEW PAGE] Do you want to provide your NPI number? ○ Yes ○ No [SKIP TO CLOSING 3] NPI #: ________________________________ [CLOSING 3] That ends the survey. Thank you again for your help. [END OF SURVEY CONTENT] 32 of 33 FDA_586 TIRF REMS Industry Group (TRIG) Transmucosal Immediate Release Fentanyl (TIRF) Products Prescriber KAB Survey Protocol Appendix B Version 3.0 10 September 2012 Sample Prescriber Invitation Letter [CURR_DATE] [PRESCRIBER NAME] [STREET_ADDR] [CITY], [STATE] [ZIP] Dear [PRESCRIBER NAME]: You were selected to receive this letter because you have enrolled in the TIRF REMS Access Program. We are contacting you to invite you to participate in a survey being conducted by the manufacturers of Transmucosal Immediate Release Fentanyl (TIRF) medicines, as required by the Food and Drug Administration (FDA). The purpose of the survey is to assess prescribers’ understanding of the safe and appropriate use of these medicines. The TIRF medicines include Abstral®, Actiq®, Fentora®, Lazanda®, Onsolis®, Subsys™, and generic versions of any of these brands. The manufacturers of TIRF medicines include Archimedes Pharma US Inc., Cephalon, Inc., Endo Pharmaceuticals Inc., Insys Therapeutics, Meda Pharmaceuticals, Mallinckrodt (a Covidien Company), Par Pharmaceutical, Inc., ProStrakan, Inc., and Sandoz Inc (collectively referred to as the “TIRF Industry REMS Group”). These manufacturers are looking for 300 prescribers to complete the survey. Eligible prescribers who complete the survey will be sent a $125 honorarium to thank them for their time. The survey will take 15-20 minutes. Your answers will be kept strictly confidential and will be combined with the answers from other prescribers who take this survey. Your name will not be used in the report of this survey and your contact information will only be used to send you a $125 honorarium for the time you took to complete the survey and if required to comply with a federal or state law or regulation, including without limitation, reporting payments made to physicians under the federal physician payment sunshine provisions. Physicians who practice in Vermont, Massachusetts, or Minnesota should be aware that they will not be permitted to receive payment for survey completion and may elect not to complete the survey. You are under no obligation to participate in this survey. If you are interested in participating, go to www.XXXXXXXXXX.com anytime or call 1-877-379-3297, 8AM to 10PM Eastern Time Monday through Friday. You will be asked to give this unique code prior to starting the survey: [CODE_ID]. Please have this letter with you at the time you take the survey. Thank you in advance for your help with this important effort. Sincerely, TIRF REMS Industry Group * We recommend that you take the survey on a desktop or laptop computer. Taking the survey on mobile devices, such as smart phones, tablets, and e-notebooks, is not supported. 33 of 33 FDA_587 Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Appendix B December 2012 Prescriber KAB Assessment Report Prescriber Survey Listings and Subanalysis Tables Page 48 of 54 FDA_588 Transrnucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies December 20 12 Prescriber KAB Assessment Report Prescriber Listings Listing 1 CATEGORIZATION OF VERBATIM RESPONSES TO QUESTION 22 (Questions about the information in the Full Prescribing Information or Medication Guide) Verbatim Response Categorized Response Ah'eady answered by rep. General response Can they be simpli?ed for quick read? Simpli?cation of Prescribing Information/Medication Guide Clari?cation of some conversions. insurance coverage TIRF medicine conversion. insm?ance coverage Could I work with our palliative care doctors to come up with an "optimal" oral pain medication regimen prior to trying the TIRF medications? General Question Dosage changes for side effects Dose modi?cations Formulary questions Coverage Formulary. Insurance coverage Frequency. guidelines [sic] on possible drug interactions etc. Drug interactions Highlighted 011 this sruvey! General response How best to monitor patient compliance and ef?cacy of prescribed meds. taking into accormt dosing schedules. laboratory vagaries. comorbid conditions and potential interactions with newly added diugs in changing treatment protocols? Patient compliance monitoring How can I get a copy to keep 011 ?le in the of?ce? Request for Prescribing Infonnation/Medication Guide I had speci?c questions regarding escalating doses. Dose titration I need a con?rmation email that I am a TIRF prescriber. Also. I would appreciate the info 011 all TIRF meds Request for Prescribing Infonnation/Medication Guide. REMS enrolhnent Page 49 of 54 Transrnucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies December 2012 Prescriber KAB Assessment Report Verbatim Response Categorized Response I need fruther education regarding the prescribing of these medications. I'm a primary care physician and I never initiate these medications. I have one patient 011 a long acting fentanyl. I never adjust her dosage but I feel I need more education regarding these medications. Request for additional education I often have questions about bioavailability Bioavailability I would like extra copies to keep at the nursing station Request for Prescribing Information/Medication Guide Is it appropriate in OPD Indication Metabolism Metabolism General response None General response Questions regarding treatment failru'e and titration Dose titration. treatment failrn?e Questions were already answered General response Rationale of using in chronic pain conditions. Indication Rep arranged for me to speak with someone from the company phannacy department when I had a quest. I have no request now General response Rough equivalence of products. Absorption characteristics. TIRF medicine equivalences. absorption Titrating regimen Dose titration Titrations Dose titration Unclear General response Where can I access the medication guide? Prescribing Information/Medication Guide access Where can I ?nd whether the medication will be covered readily? Insurance coverage Why have I not been made more aware of the TIRF options Request for additional education Page 50 of 54 Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies December 2012 Prescriber KAB Assessment Report Listing 2 CATEGORIZATION OF VERBATIM RESPONSES TO REPORTED SAFETY EVENTS OR PRODUCT COMPLAINTS Verbatim Response Categorized Response Can they be simpli?ed for quick read? Product complaint Clari?cation of some conversions. insurance coverage Medical information request Could I work with our palliative care doctors to come up with an ?optimal" oral pain medication regimen prior to trying the TIRF medications? Medical information request Dosage changes for side effects Medical information request Formulary questions Coverage Medical information request Frequency. guidelines on possible drug interactions etc. Medical information request How best to monitor patient compliance and ef?cacy of prescribed meds. taking into account dosing schedules. laboratory vagaries. comorbid conditions and potential interactions with newly added drugs in changing treatment protocols? Medical information request How can I get a copy to keep on ?le in the of?ce? Medical information request I had speci?c questions regarding escalating doses. Medical information request I need a con?nnation email that I am a TIRF prescriber. Also. I would appreciate the info 011 all TIRF rneds Medical information request I need further education regarding the prescribing of these medications. I'm a primary care physician and I never initiate these medications. I have one patient 011 a long acting fentanyl. I never adjust her dosage but I feel I need more education regarding these medications. Medical information request I often have questions about bioavailability Medical information request I would like extra copies to keep at the nursing station Medical information request Page 51 of 54 Transrnucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies December 2012 Prescriber KAB Assessment Report Verbatim Response Categorized Response Is it appropriate in Medical information request Metabolism Medical infonnation request Rationale of using in chronic pain conditions. Medical information request Rough equivalence of products. Absorption characteristics. Medical information request Titrating regimen Medical information request Titrations Medical information request Where can I access the medication guide? Medical information request Where can I ?nd whether the medication will be covered readily? Medical information request Page 52 of 54 December 2012 Prescriber KAB Assessment Report Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Listing 3 CATEGORIZATION OF VERBATIM RESPONSES TO QUESTION 33 (OTHER MEDICAL SPECIALTY) Verbatim Response Categorized Response Hospice and Palliative Medicine General Medicine Neurology Neurology Palliative care General Medicine Palliative medicine General Medicine Rehabilitation Rhemnatology Rhetunatology BOIIC marrow transplant Oncology - Hematology oncology Oncology - Gynecology Emergency medicine Emergency Medicine Hospice palliative medicine General Medicine Physical Medicine and Rehabilitation Rehabilitation Adult trauma Emergency Medicine Geriatric/Pain management Gerontology Physical medicine rehabilitation Rehabilitation Radiation oncology Oncology - Radiology General practice General Medicine Anesthesiology Anesthesiology PM&R/pain Rehabilitation Page 53 of 54 Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies December 2012 Prescriber KAB Assessment Report Prescriber Subanalysis Tables Page 54 of 54 FDA_594 TABLE 3.3 SUFFICIENTLY RELIEVED BY TIRF MEDICINES PRESCRIBED RESPONSES TO THE QUESTION ABOUT WHAT TO ADVISE IF BREAKTHROUGH PAIN IS NOT Question 0nsolis?, Fentora<.? or Abstral?, generic an d/or Actiq? or Fentora? or $311313: Lazanda? Abstral? generic generic Lazanda? Onsolis? one and at least N=l6 Actiq? Fentora? N=l7 additional one additional TIRF TIRF medicine medicine Question 14: A prescriber has started titrating a patient with the lowest dose of a TIRF medicine. However, after 30 minutes the breakthrough pain has not been suf?ciently relieved. What should they advise the patient to do? Please answer ?Yes,? or don?t know? for each of the scenarios described. 14a: Take another (identical) dose of the TIRF medicine immediately. Yes 6 37.5 67 32.4 55 36.2 3 12.5 4 23.5 26 53.1 45 37.2 11 29.7 No 10 62.5 133 64.3 93 61.2 21 87.5 13 76.5 23 46.9 74 61.2 26 70.3 Idon't know 0.0 14b: Take a dose of an alternative rescue medicine. Yes 6 37.5 42 20.3 26 17.1 6 25.0 8 47.1 14 28.6 22 18.2 11 29.7 No 10 62.5 159 76.8 122 80.3 18 75.0 8 47.1 35 71.4 98 81.0 25 67.6 Idon't know 2.7 Client: TRIG Project: TIRFKAB Report Run Date and Time: 12/10/2012 2:38 PM Page 1 of2 Fentora? or 0nsolis?, eneric Abstral?, antora? and/or Actiq? or Fentora? or and at least Lazanda? Abstral? generic generic Lazanda? Onsolis? one and at least Question Actiq? Fentora? N=l7 additional one additional TIRF . . TIRF medicine medicine 14c: Provide guidance based on the product?speci?c Medication Guide because the instructions are not the same for all TIRF medicines. Yes 14 87.5 187 90.3 138 90.8 23 95.8 16 94.1 41 83.7 110 90.9 34 91.9 No 2 1210.2 6 5.0 3 8.1 I don't know 0.0 14d: Double the dose and take immediately. Yes 2 1281.3 198 95.7 148 97.4 23 95.8 16 94.1 48 98.0 118 97.5 34 91.9 I don't know 0.0 2.7 Note: A Prescriber can prescribe more than one TIRF Medicines. Therefore, the number of prescribed TIRF Medicines may not sum up to the number of prescribers. Client: TRIG Project: TIRFKAB Report Run Date and Time: 12/10/2012 2:38 PM Page 2 of2 TABLE 6.1.1 PRIMARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #1 KEY RISK MESSAGE l: TIRF MEDICINES ARE CONTRAINDICATED IN OPIOID NON-TOLERANT PATIENTS. SUB-GROUP ANALYSIS 1: READING MEDICATION GUIDE OR FULL PRESCRIBING INFORMATION (QUESTIONS 18 AND 20): S?la Respondents who got read the Full Prescribing Information for the TIRF medicine that they prescribe 01' who read the Medication Guide. 0 S?lb Respondents who did not read the Full Prescribing Information for the TIRF medication that they prescribe (answered ?No? or don?t know? to Question 18) and did not read the Medication Guide for the TIRF medicine that they prescribe (answered ?No? or don?t know? to Question 20). S?la S?lb Read Medication Guide or Did not read Medication . Prescribing Info Guide or Prescribing Info Question (95% CI) (95% CI) Question 6: Please answer ?True,? ?False,? or don?t know? for each statement about TIRF medicines. 6a: TIRF medicines are contraindicated in opioid non?tolerant patients because life?threatening respiratory depression could occur at any dose. True 231 87.8 33 84.6 (83.3. 91.5) (69.5. 94.1) Incorrect response False 29 11.0 6 15.4 I don't know 3 1.1 0 0.0 6b: Death has occurred in opioid non-tolerant patients treated with some fentanyl products. correct response Tme 250 95.1 39 100.0 (91.7. 97.3) (91.0. 100.0) Inconect response False 4 1.5 0 0.0 I don't know 9 3.4 0 0.0 Client: TRIG Project: TRF Wave 1 Report Run Date and Time: 11/9/2012 2:36 PM Page 1 of 2 S-la Read Medication Guide or S-lb Did not read Medication Prescribing Info Guide or Prescribing Info Question 0 0 (950;: CI) (950;: CI) 6c: TIRF medicines may be used to treat opioid non-tolerant patients. C01rect response False 221 84.0 28 71.8 (79.0. 88.2) (55.1. 85.0) Incorrect response True 36 13.7 9 23.1 I don't know 6 2.3 2 5.1 6d: Prescribers starting a patient on a TIRF medicine must begin with titration from the lowest dose available for that speci?c product, even if the patient has previously taken another TIRF medicine. C01rect response True 220 83.7 31 79.5 (78.6. 87.9) (63.5. 90.7) Incorrect response False 37 14.1 8 20.5 I don't know 6 2.3 0 0.0 Client: TRIG Project: TIRF Wave 1 Report Run Date and Time: 11/9/2012 2:36 PM Page 2 of 2 TABLE 6.2.1 SECONDARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #1 KEY RISK MESSAGE l: TIRF MEDICINES ARE CONTRAINDICATED IN OPIOID NON-TOLERANT PATIENTS. SUB-GROUP ANALYSIS 1: READING MEDICATION GUIDE OR FULL PRESCRIBING INFORMATION (QUESTIONS 18 AND 20): S?la Respondents who got read the Full Prescribing Information for the TIRF medicine that they prescribe, or who read the Medication Guide. 0 S-lb - Respondents who did not read the Full Prescribing Information for the TIRF medication that they prescribe (answered ?No? or don?t know? to Question 18) and did not read the Medication Guide for the TIRF medicine that they prescribe (answered ?No? or don?t know? to Question 20). S-la S-lb Read Medication Did not read Guide or Medication Guide Prescribing Info or Prescribing Info Demonstrated Understanding (95% (95% CI) CI) 0 correct responses 1 0.4 0 0.0 1 correct response 7 2.7 2 5.1 2 correct responses 23 8.7 4 10.3 3 correct responses 59 22.4 11 28.2 4 correct responses 173 65.8 22 56.4 Average number of correct responses 3.5 (3.3. 4.0) 3.4 (2.9. 4.0) Client: TRIG Project: THIF Wave 1 Report Run Date and Time: 11/9/2012 2:04 PM Page 1 of 1 TABLE 7.1.1 TO KEY RISK MESSAGE #2 KEY RISK MESSAGE 2: TIRF MEDICINES ARE ONLY INDICATED FOR THE MANAGEMENT OF BREAKTHROUGH PAIN IN ADULT CANCER PATIENTS 18 YEARS OF AGE AND OLDER (16 YEARS OF AGE AND OLDER FOR BRAND AND GENERIC EQUIVALENTS) WHO ARE ALREADY RECEIVING AND WHO ARE TOLERANT TO AROUND- THE-CLOCK OPIOID THERAPY FOR THEIR UNDERLYING PERSISTENT CANCER PAIN. SUB-GROUP ANALYSIS 1: READING MEDICATION GUIDE OR FULL PRESCRIBING INFORMATION (QUESTIONS 18 AND 20): PRIMARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED S-la - Respondents who got read the Full Prescribing Information for the TIRF medicine that they prescribe or who read the Medication Guide. 0 S?lb Respondents who did not read the Full Prescribing Information for the TIRF medication that they prescribe (answered ?No? or don?t know? to Question 18) and did not read the Medication Guide for the TIRF medicine that they prescribe (answered ?No? or don?t know? to Question 20). Question S?la S?lb Read Medication Guide or Did not read Medication Guide Prescribing Info or Prescribing Info (95% CI) (95% CI) Question 8: For which of the following indications can TIRF medicines be prescribed to opioid tolerant patients? Please answer ?Yes,? or don?t know? for each option. 8a: Acute or postoperative pain ICSPOIISC No 229 87.1 32 82.1 (82.4. 90.9) (66.5. 92.5) Incorrect response Yes 32 12.2 6 15.4 I don't know 2 0.8 1 2.6 Client: TRIG Project: TRF Wave 1 Report Run Date and Time: 11/9/2012 2:05 PM Page 1 of 2 Read Medication Guide or Did not read ?izication Guide Prescribing Info or Prescribing Info Question (953: CI) (9500/? C1) 8b: Headache or migraine pain Correct response No 234 89.0 28 71.8 (84.5. 92.5) (55.1. 85.0) Incorrect response Yes 28 10.6 10 25.6 I don't know 1 0.4 1 2.6 8c: Dental pain Correct response No 254 96.6 36 92.3 (93.6. 98.4) (79.1. 98.4) Incorrect response Yes 5 1.9 2 5.1 I don't know 4 1.5 1 2.6 8d: Breakthrough pain from cancer Correct response Yes 252 95.8 36 92.3 (92.6. 97.9) (79.1. 98.4) Incorrect response No 11 4.2 7.7 I don't know 0 0.0 0 0.0 Client: TRIG Project: THIF Wave 1 Report Run Date and Time: 11/9/2012 2:05 PM Page 2 of 2 TABLE 7.2.1 SECONDARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #2 KEY RISK MESSAGE 2: TIRF MEDICINES ARE ONLY INDICATED FOR THE MANAGEMENT OF BREAKTHROUGH PAIN IN ADULT CANCER PATIENTS 18 YEARS OF AGE AND OLDER (16 YEARS OF AGE AND OLDER FOR BRAND AND GENERIC EQUIVALENTS) WHO ARE ALREADY RECEIVING AND WHO ARE TOLERANT TO AROUND- THE-CLOCK OPIOID THERAPY FOR THEIR UNDERLYING PERSISTENT CANCER PAIN. SUB-GROUP ANALYSIS 1: READING MEDICATION GUIDE OR FULL PRESCRIBING INFORMATION (QUESTIONS 18 AND 20): S-la - Respondents who got read the Full Prescribing Information for the TIRF medicine that they prescribe, or who read the Medication Guide. 0 S?lb Respondents who did not read the Full Prescribing Information for the TIRF medication that they prescribe (answered ?No? or don?t know? to Question 18) and did not read the Medication Guide for the TIRF medicine that they prescribe (answered ?No? or don?t know? to Question 20). S-la S-lb Read Medication Did not read Guide or Medication Guide Prescribing Info or Prescribing Info Demonstrated Understanding (95% (95% CI) CI) 0 correct responses 0 0.0 0 0.0 1 correct response 4 1.5 3 7.7 2 correct responses 13 4.9 3 7.7 3 correct responses 45 17.1 9 23.1 4 correct responses 201 76.4 24 61.5 Average number of con'ect responses 3.7 (3.5. 4.0) 3.4 (2.9. 4.0) Client: TRIG Project: TRF Wave 1 Report Run Date and Time: 11/9/2012 2:05 PM Page 1 of 1 TABLE 8.1.1 TO KEY RISK MESSAGE #3 RISK MESSAGE 3: TIRF MEDICINES CONTAIN FENTANYL, AN OPIOID AGONIST AND A SCHEDULE II CONTROLLED SUBSTANCE, WITH ABUSE LIABILITY SIMILAR TO OTHER OPIOID ANALGESICS. SUB-GROUP ANALYSIS 1: READING MEDICATION GUIDE OR FULL PRESCRIBING INFORMATION (QUESTIONS 18 AND 20): S?la - Respondents who got read the Full Prescribing Information for the TIRF medicine that they prescribe or who read the Medication Guide. 0 S-lb - Respondents who did not read the Full Prescribing Information for the TIRF medication that they prescribe (answered ?No? or don?t know? to Question 18) and did not read the Medication Guide for the TIRF medicine that they prescribe (answered ?No? or don?t know? to Question 20). PRIMARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED Question S?la S?lb Read Medication Guide or Did not read Medication Prescribing Info Guide or Prescribing Info (95% CI) (95% CI) Question 6: Please answer ?True,? ?False,? or don?t know? for each statement about TIRF medicines. 6e: It is important to monitor for signs of abuse and addiction in patients who take TIRF medicines. ICSPOIISC True 262 99.6 39 100.0 (97.9. 100.0) (91.0. 100.0) Incouect response False 1 0.4 0 0.0 I don't know 0 0.0 0 0.0 Client: TRIG Project: THIF Wave 1 Report Run Date and Time: 11/9/2012 2:06 PM Page 1 of 2 Question S-la S-lb Read Medication Guide or Did not read Medication Prescribing Info Guide or Prescribing Info (95% CI) (95% CI) Question 7: Which of the following are risk factors for opioid abuse? Please answer ?Yes,? or don?t know? for each option. 7a: A personal history of illness Yes 218 82.9 31 79.5 (77.8. 87.2) (63.5. 90.7) Incorrect response No 33 12.5 4 10.3 I don't know 12 4.6 4 10.3 7b: A personal history of past or current alcohol or drug abuse, or a family history of illicit drug use or alcohol abuse correct response Yes 262 99.6 38 97.4 (97.9. 100.0) (86.5. 99.9) Incorrect response No 1 0.4 0 0.0 I don't know 0 0.0 1 2.6 Question 9: Please answer ?True,? ?False,? or don?t know? for each statement about TIRF medicines. 9a: TIRF medicines can be abused in a manner similar to other opioid agonists. True 257 97.7 38 97.4 (95.1. 99.2) (86.5. 99.9) Incorrect response False 6 2.3 0 0.0 I don't know 0 0.0 1 2.6 Client: TRIG Project: TRF Wave 1 Report Run Date and Time: 11/9/2012 2:06 PM Page 2 of 2 TABLE 8.2.1 SECONDARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #3 KEY RISK MESSAGE 3: TIRF MEDICINES CONTAIN FENTANYL, AN OPIOID AGONIST AND A SCHEDULE II CONTROLLED SUBSTANCE, WITH ABUSE LIABILITY SIMILAR TO OTHER OPIOID ANALGESICS. SUB-GROUP ANALYSIS 1: READING MEDICATION GUIDE OR FULL PRESCRIBING INFORMATION (QUESTIONS 18 AND 20): S?la Respondents who got read the Full Prescribing Information for the TIRF medicine that they prescribe, or who read the Medication Guide. 0 S-lb - Respondents who did not read the Full Prescribing Information for the TIRF medication that they prescribe (answered ?No? or don?t know? to Question 18) and did not read the Medication Guide for the TIRF medicine that they prescribe (answered ?No? or don?t know? to Question 20). S-la S-lb Read Medication Did not read Guide or Medication Guide Prescribing Info or Prescribing Info Demonstrated Understanding (95% (95% CI) CI) 0 correct responses 0 0.0 0 0.0 1 correct response 0 0.0 0 0.0 2 correct responses 2 0.8 2.6 3 correct responses 49 18.6 8 20.5 4 correct responses 212 80.6 30 76.9 Average number of con'ect responses 3.8 (3.6. 4.0) 3.7 (3.2. 4.0) Client: TRIG Project: THIF Wave 1 Report Run Date and Time: 11/9/2012 2:07 PM Page 1 of 1 TABLE 9.1.1 TO KEY RISK MESSAGE #4 PRIMARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED RISK MESSAGE 4: TIRF MEDICINES ARE NOT INTERCHANGEABLE WITH EACH OTHER, REGARDLESS OF ROUTE OF ADMINISTRATION. SUB-GROUP ANALYSIS 1: READING MEDICATION GUIDE OR FULL PRESCRIBING INFORMATION (QUESTIONS 18 AND 20): S?la - Respondents who got read the Full Prescribing Information for the TIRF medicine that they prescribe, or who read the Medication Guide. 0 S-lb - Respondents who did not read the Full Prescribing Information for the TIRF medication that they prescribe (answered ?No? or don?t know? to Question 18) and did not read the Medication Guide for the TIRF medicine that they prescribe (answered ?No? or don?t know? to Question 20). Question S?la Read Medication Guide or Did not read Medication Guide Prescribing Info or Prescribing Info (95% CI) (95% CI) Question 9: Please answer ?True,? ?False,? or don?t know? for each statement about TIRF medicines. 9b: TIRF medicines are interchangeable with each other regardless of route of administration. COITCCI response False 253 96.2 36 92.3 (93.1. 98.2) (79.1. 98.4) Incorrect response True 7 2.7 2 5.1 I don't know 3 1.1 1 2.6 9c: The conversion of one TIRF medicine for another TIRF medicine may result in a fatal overdose because of differences in the pharmacokinetics of fentanyl absorption. ICSPODSC True 248 94.3 38 97.4 (90.8. 96.8) (86.5. 99.9) Incorrect response False 5 1.9 0 0.0 I don't know 10 3.8 1 2.6 Client: TRIG Project: TRF Wave 1 Report Run Date and Time: 11/9/2012 2:08 PM Page 1 of 2 Question S-la Read Medication Guide or S-lb Did not read Medication Guide Prescribing Info or Prescribing Info (95% CI) (95% CI) 9d: Dosing of TIRF medicines is not equivalent on a microgram-to-microgra1n basis. C01rect response 241 91.6 32 82.1 (87.6. 94.7) (66.5. 92.5) Incorrect response 11 4.2 1 2.6 I don't know 11 4.2 6 15.4 Client: TRIG Project: TIRF Wave 1 Report Run Date and Time: 11/9/2012 2:08 PM Page 2 of2 TABLE 9.2.1 SECONDARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #4 KEY RISK MESSAGE 4: TIRF MEDICINES ARE NOT INTERCHANGEABLE WITH EACH OTHER, REGARDLESS OF ROUTE OF ADMINISTRATION. SUB-GROUP ANALYSIS 1: READING MEDICATION GUIDE OR FULL PRESCRIBING INFORMATION (QUESTIONS 18 AND 20): S?la Respondents who got read the Full Prescribing Information for the TIRF medicine that they prescribe, or who read the Medication Guide. 0 S?lb Respondents who did not read the Full Prescribing Information for the TIRF medication that they prescribe (answered ?No? or don?t know? to Question 18) and did not read the Medication Guide for the TIRF medicine that they prescribe (answered ?No? or don?t know? to Question 20). S-la S-lb Read Medication Did not read Guide or Medication Guide Prescribing Info or Prescribing Info Demonstrated Understanding (95% (95% CI) CI) 0 correct responses 2 0.8 2.6 1 correct response 7 2.7 0 0.0 2 correct responses 27 10.3 8 20.5 3 correct responses 227 86.3 30 76.9 Average number of correct responses 2.8 (2.7. 3.0) 2.7 (2.3. 3.0) Client: TRIG Project: THIF Wave 1 Report Run Date and Time: 11/9/2012 2:09 PM Page 1 of 1 TABLE 6.1.2 PRIMARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #1 KEY RISK MESSAGE l: TIRF MEDICINES ARE CONTRAINDICATED IN OPIOID NON-TOLERANT PATIENTS. SUB-GROUP ANALYSIS 2: MEDICAL DEGREE OF RESPONDENTS (QUESTION 29): S-2a - MD 0 S-2b - DO 0 S-2c - Nurse Practitioner S-2d - Physician Assistant Question S-2c S-2d if]: 8?53) Nurse Physician Practitioner Assistant N=l72 4 6 (95% (95% (95% (95% CI) CI) C1) C1) Question 6: Please answer ?True,? ?False,? or don?t know? for each statement about TIRF medicines. 6a: TIRF medicines are contraindicated in opioid non-tolerant patients because life-threatening respiratory depression could occur at any dose. Con'ect response Tme 152 88.4 21 80.8 47 85.5 41 89.1 (82.6. (60.6. (73.3. (76.4. 92.8) 93.4) 93.5) 96.4) Inconect response False 18 10.5 5 19.2 7 12.7 5 10.9 I don't know 0.0 Client: TRIG Project: TRF Wave 1 Report Run Date and Time: 11/9/2012 12:16 PM Page 1 of2 S-2c S-2d if]: 8?53) Nurse Physician Practitioner Assistant Question (95% (95% (95% (95% C1) C1) C1) C1) 6b: Death has occurred in opioid non-tolerant patients treated with some fentanyl products. Tme 167 97.1 24 92.3 49 89.1 46 100.0 (93.3. (74.9. (77.8. (92.3. 99.0) 99.1) 95.9) 100.0) Incorrect response False don't know 0.0 6c: TIRF medicines may be used to treat opioid non-tolerant patients. Correct response False 138 80.2 22 84.6 44 80.0 42 91.3 (73.5. (65.1. (67.0. (79.2. 85.9) 95.6) 89.6) 97.6) Incorrect response Tme 29 16.9 3 11.5 10 18.2 3 6.5 I don't know 2.2 6d: Prescribers starting a patient on a TIRF medicine must begin with titration from the lowest dose available for that speci?c product, even if the patient has previously taken another TIRF medicine. Conect response Tnle 142 82.6 17 65.4 47 85.5 43 93.5 (76.0. (44.3. (73.3. (82.1. 87.9) 82.8) 93.5) 98.6) Incorrect response False 25 14.5 8 30.8 8 14.5 3 6.5 I don't know 0.0 Client: TRIG Project: THIF Wave 1 Report Run Date and Time: 11/9/2012 12:16 PM Page 2 of 2 0 Table 6.2.2 TO KEY RISK MESSAGE #1 SECONDARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED KEY RISK MESSAGE l: TIRF MEDICINES ARE CONTRAINDICATED IN OPIOID NON-TOLERANT PATIENTS. SUB-GROUP ANALYSIS 2: MEDICAL DEGREE OF RESPONDENTS (QUESTION 29): - MD - DO S-2c - Nurse Practitioner - Physician Assistant S-2a S-2b 8'2? Nurse MD DO Practitioner Assistant Demonstrated N=l72 Understandin N46 (95% (95% (95% (95% CD CD CD CD 0 c01rect responses con?ect response correct responses 13 7.6 3 11.5 8 14.5 3 6.5 3 correct responses 41 23.8 11 42.3 11 20.0 6 13.0 4 correct responses 111 64.5 11 42.3 34 61.8 37 80.4 Average number of correct 3.5 (3.2. 3.2 (2.7. 3.4 (3.0. 3.7 (3.3. responses 4.0) 4.0) 4.0) 4.0) Client: TRIG Project: THIF Wave 1 Report Run Date and Time: 11/9/2012 12:16 PM Page 1 ofl 1 TABLE 7.1.2 PRIMARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #2 KEY RISK MESSAGE 2: TIRF MEDICINES ARE ONLY INDICATED FOR THE MANAGEMENT OF BREAKTHROUGH PAIN IN ADULT CANCER PATIENTS 18 YEARS OF AGE AND OLDER (16 YEARS OF AGE AND OLDER FOR BRAND AND GENERIC EQUIVALENTS) WHO ARE ALREADY RECEIVING AND WHO ARE TOLERANT TO AROUND- THE-CLOCK OPIOID THERAPY FOR THEIR UNDERLYING PERSISTENT CANCER PAIN. SUB-GROUP ANALYSIS 2: MEDICAL DEGREE OF RESPONDENTS (QUESTION 29): S?2a - MD 0 S-2b - DO 0 S-2c - Nurse Practitioner S-2d - Physician Assistant Question S?2a S?2b urse ys1c1an Practitioner Assistant (95% (95% (95% (95% CI) CI) CI) CI) Question 8: For which of the following indications can TIRF medicines be prescribed to opioid tolerant patients? Please answer ?Yes,? or don?t know? for each option. 8a: Acute or postoperative pain ICSPODSC No 151 87.8 22 84.6 44 80.0 42 91.3 (81.9. (65.1. (67.0. (79.2. 92.3) 95.6) 89.6) 97.6) Yes 19 11.0 4 15.4 10 18.2 4 8.7 Idon't know 0.0 Client: TRIG Project: TRF Wave 1 Report Run Date and Time: 11/9/2012 12:16 PM Page 1 of2 2 S-2b D0 Nurse Physician 6 Practitioner Assistant Question (95% (95% (95% (95% CI) C1) C1) CI) 8b: Headache or migraine pain Correct response No 149 86.6 21 80.8 49 89.1 41 89.1 (80.6. (60.6. (77.8. (76.4. 91.3) 93.4) 95.9) 96.4) Incorrect response Yes 21 12.2 5 19.2 6 10.9 5 10.9 I don't know 0.0 8c: Dental pain Con?ect response No 166 96.5 25 96.2 52 94.5 44 95.7 (92.6. (80.4. (84.9. (85.2. 98.7) 99.9) 98.9) 99.5) Incorrect response Yes don't know 0.0 8d: Breakthrough pain from cancer Correct response Yes 161 93.6 25 96.2 54 98.2 45 97.8 (88.8. (80.4. (90.3. (88.5. 96.8) 99.9) 100.0) 99.9) Incorrect response don't know 0.0 Client: TRIG Project: THIF Wave 1 Report Run Date and Time: 11/9/2012 12:16 PM Page 2 of 2 3 TABLE 7.2.2 SECONDARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #2 KEY RISK MESSAGE 2: TIRF MEDICINES ARE ONLY INDICATED FOR THE MANAGEMENT OF BREAKTHROUGH PAIN IN ADULT CANCER PATIENTS 18 YEARS OF AGE AND OLDER (16 YEARS OF AGE AND OLDER FOR BRAND AND GENERIC EQUIVALENTS) WHO ARE ALREADY RECEIVING AND WHO ARE TOLERANT TO AROUND- THE-CLOCK OPIOID THERAPY FOR THEIR UNDERLYING PERSISTENT CANCER PAIN. SUB-GROUP ANALYSIS 2: MEDICAL DEGREE OF RESPONDENTS (QUESTION 29): . S?2a - MI) 0 S-2b - DO 0 S-2c - Nurse Practitioner S-2d - Physician Assistant S-2a S-2b 8'2? Nurse MD DO Practitioner Assistant Demonstrated 172 Understanding N46 (95% (95% (95% (95% CI) CI) CI) CI) 0 correct responses 0 0.0 0.0 0.0 0.0 1 correct response 5 2.9 0.0 0.0 4.3 2 correct responses 7 4.1 7.7 10.9 0.0 3 correct responses 32 18.6 26.9 16.4 13.0 4 correct responses 128 74.4 65.4 40 72.7 82.6 Average number of correct 3.6 (3.4. 3.6 (3.0. 3 6 (3.2. 3.7 (3.3. responses 4.0) 4.0) 4.0) 4.0) Client: TRIG Project: THIF Wave 1 Report Run Date and Time: 11/9/2012 12:16 PM Page 1 of 1 4 TABLE 8.1.2 PRIMARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #3 RISK MESSAGE 3: TIRF MEDICINES CONTAIN FENTANYL, AN OPIOID AGONIST AND A SCHEDULE II CONTROLLED SUBSTANCE, WITH ABUSE LIABILITY SIMILAR TO OTHER OPIOID ANALGESICS. SUB-GROUP ANALYSIS 2: MEDICAL DEGREE OF RESPONDENTS (QUESTION 29): S-2a - MD S-2b - DO S-2c - Nurse Practitioner S-2d - Physician Assistant S?2a S?2b 13'2? MI) D0 Wm? N=l72 6 Practitioner Question (95% (95% (95% (95% CD CD CD CD Question 6: Please answer ?True,? ?False,? or don?t know? for each statement about TIRF medicines. 6e: It is important to monitor for signs of abuse and addiction in patients who take TIRF medicines. Con'ect response Tme 171 99.4 26 100.0 55 100.0 46 100.0 (96.8. (86.8. (93.5. (92.3. 100.0) 100.0) 100.0) 100.0) Inconect response False don't know 0.0 Client: TRIG Project: TIRF Wave 1 Report Run Date and Time: 11/9/2012 12:15 PM Page 1 of3 5 Question S?2a S?2b 13'2? Phs?? urse N832 N936 Practitioner Assistant (95% (95% (95% (95% CD CD CD CD Question 7: Which of the following are risk factors for opioid abuse? Please answer ?Yes,? or don?t know? for each option. 7a: A personal history of illness correct response Yes 141 82.0 24 92.3 42 76.4 39 84.8 (75.4. (74.9. (63.0. (71.1. 87.4) 99.1) 86.8) 93.7) Inconect response No 23 13.4 2 7.7 9 16.4 3 6.5 I don't know personal history of past or current alcohol or drug abuse, or a family history of illicit drug use or alcohol abuse response Yes 172 100.0 26 100.0 54 98.2 45 97.8 (97.9. (86.8. (90.3. (88.5. 100.0) 100.0) 100.0) 99.9) Inconect response don't know 2.2 Client: TRIG Project: TIRF Wave 1 Report Run Date and Time: 11/9/2012 12:15 PM Page 2 of 3 6 S?2a S?2b S?2c S?2d Ml) Nurse Physician N=l72 6 Practitioner Assistant Question (95% (95% (95% (95% CD CD CD CD Question 9: Please answer ?True,? ?False,? or don?t know? for each statement about TIRF medicines. 9a: TIRF medicines can be abused in a manner similar to other opioid agonists. Tme 168 97.7 25 96.2 55 100.0 44 95.7 (94.2. (80.4. (93.5. (85.2. 99.4) 99.9) 100.0) 99.5) Inconect response False don't know 0.0 1 3.8 0 0.0 0 0.0 Client: TRIG Project: TIRF Wave 1 Report Run Date and Time: 11/9/2012 12:15 PM Page 3 of3 7 TABLE 8.2.2 SECONDARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #3 KEY RISK MESSAGE 3: TIRF MEDICINES CONTAIN FENTANYL, AN OPIOID AGONIST AND A SCHEDULE II CONTROLLED SUBSTANCE, WITH ABUSE LIABILITY SIMILAR TO OTHER OPIOID ANALGESICS. SUB-GROUP ANALYSIS 2: MEDICAL DEGREE OF RESPONDENTS (QUESTION 29): . S-2a - MD . S-2b - DO 0 S-2c - Nurse Practitioner S-2d - Physician Assistant S-2a S-2b 8?2? Nurse MD DO Practitioner Assistant Demonstrated N=l72 Understandin (95% (95% (95% (95% CD CD CD CD 0 correct responses correct response correct responses correct responses 36 20.9 3 11.5 12 21.8 6 13.0 4 correct responses 136 79.1 23 88.5 42 76.4 38 82.6 Average number of correct 3.8 (3.5. 3.9 (3.2. 3.7 (3.3. 3.8 (3.3. responses 4.0) 4.0) 4.0) 4.0) Client: TRIG Project: THIF Wave 1 Report Run Date and Time: 11/9/2012 12:15 PM Page 1 of 8 Table 9.1.2 KEY RISK MESSAGE #4 PRIMARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO RISK MESSAGE 4: TIRF MEDICINES ARE NOT INTERCHANGEABLE WITH EACH OTHER, REGARDLESS OF ROUTE OF ADMINISTRATION. SUB-GROUP ANALYSIS 2: MEDICAL DEGREE OF RESPONDENTS (QUESTION 29): S-2a - MD 0 S-2b - DO 0 S-2c - Nurse Practitioner S-2d - Physician Assistant Question S?2a S?2b PhS?2t1 urse ys1c1an Practitioner Assistant (95% (95% (95% (95% Question 9: Please answer ?True,? ?False,? or don?t know? for each statement about TIRF medicines. 9b: TIRF medicines are interchangeable with each other regardless of route of administration. COITCCT TCSPODSC False 161 93.6 24 92.3 55 100.0 46 100.0 (88.8. (74.9. (93.5. (92.3. 96.8) 99.1) 100.0) 100.0) Incorrect response True don't know 0.0 Client: TRIG Project: THIF Wave 1 Report Run Date and Time: 11/9/2012 12:15 PM Page 1 of 2 9 Question S-2a S-2b 13-26 Pins-ea N32 N226 Practitioner Assistant (95% (95% (95% (95% CD C1) C1) CI) 9c: The conversion of one TIRF medicine for another TIRF medicine may result in a fatal overdose because of differences in the pharmacokinetics of fentanyl absorption. Con?ect response True 164 95.3 23 88.5 50 90.9 46 100.0 (91.0. (69.8. (80.0. (92.3. 98.0) 97.6) 97.0) 100.0) Incorrect response False don't know 5 2.9 3 11.5 3 5.5 0 0.0 9d: Dosing of TIRF medicines is not equivalent on a microgram?to-microgram basis. Con'ect response True 156 90.7 23 88.5 46 83.6 45 97.8 (85.3. (69.8. (71.2. (88.5. 94.6) 97.6) 92.2) 99.9) Incorrect response False don't know 7 4.1 3 11.5 6 10.9 1 2.2 Client: TRIG Project: TIRF Wave 1 Report Run Date and Time: 11/9/2012 12:15 PM Page 2 of 2 TABLE 9.2.2 SECONDARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #4 KEY RISK MESSAGE 4: TIRF MEDICINES ARE NOT INTERCHANGEABLE WITH EACH OTHER, REGARDLESS OF ROUTE OF ADMINISTRATION. SUB-GROUP ANALYSIS 2: MEDICAL DEGREE OF RESPONDENTS (QUESTION 29): S?2a - NII) S?2b - DO S-2c - Nurse Practitioner - Physician Assistant S-2a S-2b 5'2? Nurse MD D0 Practitioner Assistant Demonstrated N=l72 Understanding N46 (95% (95% (95% (95% CD CD CD CD 0 con'ect responses con?ect response correct responses 23 13.4 3 11.5 14.5 1 2.2 3 c01rect responses 144 83.7 21 80.8 44 80.0 45 97.8 Average number of correct 2.8 (2.6. 2.7 (2.2. 2.7 (2.4. 3.0 (2.6. responses 3.0) 3.0) 3.0) 3.0) Client: TRIG Project: THIF Wave 1 Report Run Date and Time: 11/9/2012 12:16 PM Page 1 ofl TABLE 6.1.3 TO KEY RISK MESSAGE #1 PRIMARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED KEY RISK MESSAGE l: TIRF MEDICINES ARE CONTRAINDICATED IN OPIOID NON-TOLERANT PATIENTS. SUB-GROUP ANALYSIS 3: TIME TO COMPLETE SURVEY - INTERNET S-3a - <10 min 0 S-3b - 10 to <20 min S-3c - 20 min Question S-3a S-3b S-(95% CI) (95% CI) (95% CI) Question 6: Please answer ?True,? ?False,? or don?t know? for each statement about TIRF medicines. 6a: TIRF medicines are contraindicated in opioid non-tolerant patients because life-threatening respiratory depression could occur at any dose. correct response True 42 85.7 154 89.5 61 84.7 (72.8. (84.0. (74.3. 94.1) 93.7) 92.1) Incorrect response False 5 10.2 17 9.9 11 15.3 I don't know 2 4.1 1 0.6 0 0.0 6b: Death has occurred in opioid non-tolerant patients treated with some fentanyl products. COITCCI True 47 95.9 166 96.5 67 93.1 (86.0. (92.6. (84.5. 99.5) 98.7) 97.7) Incorrect response False don't know 1 2.0 4 2.3 4 5.6 Client: TRIG Project: THIF Wave 1 Report Run Date and Time: 11/20/2012 11:24 AM Page 1 of 2 S-3a S-3b S-min Question N=l72 (95% CD (95% CD (95% CI) 6c: TIRF medicines may be used to treat opioid non-tolerant patients. Con?ect response False 36 73.5 144 83.7 62 86.1 (58.9. (77.3. (75.9. 85.1) 88.9) 93.1) Incorrect response True 11 22.4 23 13.4 9 12.5 I don't know 2 4.1 5 2.9 1 1.4 6d: Prescribers starting a patient on a TIRF medicine must begin with titration from the lowest dose available for that speci?c product, even if the patient has previously taken another TIRF medicine. COITCCT ICSPODSC True 42 85.7 147 85.5 56 77.8 (72.8. (79.3. (66.4. 94.1) 90.4) 86.7) Incorrect response False 7 14.3 20 11.6 15 20.8 I don't know 0 0.0 5 2.9 1 1.4 Client: TRIG Project: TIRF Wave 1 Report Run Date and Time: 11/20/2012 11:24 AM Page 2 of 2 TABLE 6.2.3 LINKED TO KEY RISK MESSAGE #1 SECONDARY ANALYSIS OF RESPONSES TO QUESTIONS KEY RISK MESSAGE MEDICINES ARE CONTRAINDICATED IN OPIOID NON-TOLERANT PATIENTS. SUB-GROUP ANALYSIS 3: TIME TO COMPLETE SURVEY - INTERNET S-3a - <10 min 0 S-S-3c - 20 min S-3a S-3b S-min Demonstrated Understanding (95% CI) (95% CI) (95% CI) 0 correct responses con?ect response correct responses 5 10.2 15 8.7 5 6.9 3 correct responses 16 32.7 35 20.3 16 22.2 4 correct responses 27 55.1 118 68.6 46 63.9 Average mum)? 0f cone? 3 .4 (3.0. 4.0) 3 .6 (3.3. 4.0) 3 .4 (3.1. 4.0) responses Client: TRIG Project: TIRF Wave 1 Report Run Date and Time: 11/20/2012 11:23 AM Page 1 of TABLE 7.1.3 PRIMARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #2 KEY RISK MESSAGE 2: TIRF MEDICINES ARE ONLY INDICATED FOR THE MANAGEMENT OF BREAKTHROUGH PAIN IN ADULT CANCER PATIENTS 18 YEARS OF AGE AND OLDER (16 YEARS OF AGE AND OLDER FOR BRAND AND GENERIC EQUIVALENTS) WHO ARE ALREADY RECEIVING AND WHO ARE TOLERANT TO AROUND-THE-CLOCK OPIOID THERAPY FOR THEIR UNDERLYING PERSISTENT CANCER PAIN. SUB-GROUP ANALYSIS 3: TIME TO COMPLETE SURVEY - INTERNET S-3a - <10 min S-S-3c - 20 min S-3a S-3b S-min Question (95% CI) (95% CI) (95% CI) Question 8: For which of the following indications do you prescribe TIRF medicines to opioid tolerant patients? Please answer ?Yes,? or don?t know? for each option. 8a: Acute or postoperative pain N0 43 87.8 148 86.0 62 86.1 (75.2. 95.4) (80.0. 90.9) (75.9. 93.1) Inconect response Yes 4 8.2 23 13.4 10 13.9 I don't know 2 4.1 1 0.6 0 0.0 Client: TRIG Project: THIF Wave 1 Report Run Date and Time: 11/20/2012 11:24 AM Page 1 of 2 S-3a S-3b S-min Question (95% CI) (95% CI) (95% CI) 8b: Headache or migraine pain Correct response No 46 93.9 148 86.0 61 84.7 (83.1. 98.7) (80.0. 90.9) (74.3. 92.1) Incorrect response Yes 2 4.1 24 14.0 11 15.3 I don't know 1 2.0 0 0.0 0 0.0 8c: Dental pain C01rect response No 46 93.9 167 97.1 68 94.4 (83.1. 98.7) (93.3. 99.0) (86.4. 98.5) Incorrect response Yes don't know 3 6.1 0.6 1 1.4 8d: Breakthrough pain from cancer Correct response Yes 48 98.0 165 95.9 67 93.1 (89.1. 99.9) (91.8. 98.3) (84.5. 97.7) Incorrect response don't know 0 0.0 0 0.0 0 0.0 Client: TRIG Project: TIRF Wave 1 Report Run Date and Time: 11/20/2012 11:24 AM Page 2 of 2 TABLE 7.2.3 SECONDARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #2 KEY RISK MESSAGE 2: TIRF MEDICINES ARE ONLY INDICATED FOR THE MANAGEMENT OF BREAKTHROUGH PAIN IN ADULT CANCER PATIENTS 18 YEARS OF AGE AND OLDER (16 YEARS OF AGE AND OLDER FOR BRAND AND GENERIC EQUIVALENTS) WHO ARE ALREADY RECEIVING AND WHO ARE TOLERANT TO AROUND-THE-CLOCK OPIOID THERAPY FOR THEIR UNDERLYING PERSISTENT CANCER PAIN. SUB-GROUP ANALYSIS 3: TIME TO COMPLETE SURVEY - INTERNET S-3a - <10 min S-S-3c - 20 min S-3a S-3b S-min Demonstrated N=l 72 Understanding (95% (95% (95% CI) CI) CI) 0 correct responses correct response correct responses correct responses 8 16.3 35 20.3 9 12.5 4 correct responses 39 79.6 126 73.3 54 75.0 Average number 0f com? 3.7 (3.3. 4.0) 3.7 (3.4. 4.0) 3.6 (3.2. 4.0) responses Client: TRIG Project: THIF Wave 1 Report Run Date and Time: 11/20/2012 11:24 AM Page 1 of TABLE 8.1.3 TO KEY RISK MESSAGE #3 PRIMARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED RISK MESSAGE 3: TIRF MEDICINES CONTAIN FENTANYL, AN OPIOID AGONIST AND A SCHEDULE II CONTROLLED SUBSTANCE, WITH ABUSE LIABILITY SIMILAR TO OTHER OPIOID ANALGESICS. SUB-GROUP ANALYSIS 3: TIME TO COMPLETE SURVEY - INTERNET S-3a - <10 min S-S-3c - 20 min Question S?3a <10 min S?3b 10 to <20 min S?3c 20 min (95% CI) (95% CI) (95% CI) Question 6: Please answer ?True,? ?False,? or don?t know? for each statement about TIRF medicines. 6e: It is important to monitor for signs of abuse and addiction in patients who take TIRF medicines. COITCCI response True 49 100.0 171 99.4 72 100.0 (92.7. 100.0) (96.8. 100.0) (95.0. 100.0) Inconect response False don't know 0 0.0 0 0.0 0 0.0 Question 7: Which of the following are risk factors for opioid abuse? Please answer ?Yes,? or don?t know? for each option. 7a: A personal history of illness correct response Yes 46 93.9 136 79.1 60 83.3 (83.1. 98.7) (72.2. 84.9) (72.7. 91.1) Incorrect response No 3 6.1 23 13.4 9 12.5 I don't know 0 0.0 13 7.6 3 4.2 Client: TRIG Project: TRF Wave 1 Report Run Date and Time: 11/12/2012 2:36 PM Page 1 of 2 Question S?3a - <10 min S-3b - 10 to <20 min S-3c - 20 min (95% CI) (95% CI) (95% CI) 7b: A personal history of past or current alcohol or drug abuse, or a family history of illicit drug use or alcohol abuse Yes 49 100.0 171 99.4 72 100.0 (92.7. 100.0) (96.8. 100.0) (95.0. 100.0) Incorrect response don't know 0 0.0 1 0.6 0 0.0 Question 9: Please answer ?True,? ?False,? or don?t know? for each statement about TIRF medicines. 9a: TIRF medicines can be abused in a manner similar to other opioid agonists. True 46 93.9 170 98.8 70 97.2 (83.1. 98.7) (95.9. 99.9) (90.3. 99.7) Incorrect response False don't know 0 0.0 1 0.6 0 0.0 Client: TRIG Project: TIRF Wave 1 Report Run Date and Time: 11/12/2012 2:36 PM Page 2 of 2 TABLE 8.2.3 SECONDARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #3 KEY RISK MESSAGE 3: TIRF MEDICINES CONTAIN FENTANYL, AN OPIOID AGONIST AND A SCHEDULE II CONTROLLED SUBSTANCE, WITH ABUSE LIABILITY SIMILAR TO OTHER OPIOID ANALGESICS. SUB-GROUP ANALYSIS 3: TIME TO COMPLETE SURVEY - INTERNET S-3a - <10 min 0 S-S-3c - 20 min S-3a - <10 min S-3b - 10 to <20 S-3c - 20 min min Demonstrated Understanding (95% CI) (95% CI) (95% CI) 0 correct responses correct response correct responses correct responses 4 8.2 38 22.1 14 19.4 4 correct responses 44 89.8 133 77.3 58 80.6 Average mm)? 0f com? 3.9 (3.4. 4.0) 3.8 (3.5.4.0) 3.8 (3.4.4.0) responses Client: TRIG Project: TIRF Wave 1 Report Run Date and Time: 11/12/2012 2:38 PM Page 1 of TABLE 9.1.3 PRIMARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #4 RISK MESSAGE 4: TIRF MEDICINES ARE NOT INTERCHANGEABLE WITH EACH OTHER, REGARDLESS OF ROUTE OF ADMINISTRATION. SUB-GROUP ANALYSIS 3: TIME TO COMPLETE SURVEY - INTERNET S-3a - <10 min S-S-3c - 20 min S-3a - <10 min S-3b - 10 to <20 min S-3c - 20 min N=l72 ues on (95% CI) (95% Cl) (95% CI) Question 9: Please answer ?True,? ?False,? or don?t know? for each statement about TIRF medicines. 9b: TIRF medicines are interchangeable with each other regardless of route of administration. Cou'ect response False 44 89.8 166 96.5 70 97.2 (77.8. 96.6) (92.6. 98.7) (90.3. 99.7) Incorrect response True don't know 1 2.0 3 1.7 0 0.0 9c: The conversion of one TIRF medicine for another TIRF medicine may result in a fatal overdose because of differences in the pharmacokinetics of fentanyl absorption. Con?ect response True 46 93.9 164 95.3 67 93.1 (83.1. 98.7) (91.0. 98.0) (84.5. 97.7) Incorrect response False don't know 2 4.1 5 2.9 4 5.6 Client: TRIG Project: THIF Wave 1 Report Run Date and Time: 11/12/2012 2:40 PM Page 1 of 2 S-3a - <10 min S-3b - 10 to <20 min S-3c - 20 min N=l72 Question (95% CI) (95% CI) (95% CI) 9d: Dosing of TIRF medicines is not equivalent on a microgl'am-to-microgram basis. Correct response True 44 89.8 154 89.5 68 94.4 (77.8. 96.6) (84.0. 93.7) (86.4. 98.5) Incorrect response False don't know 3 6.1 12 7.0 2 2.8 Client: TRIG Project: TIRF Wave 1 Report Run Date and Time: 11/12/2012 2:40 PM Page 2 of2 TABLE 9.2.3 SECONDARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #4 KEY RISK MESSAGE 4: TIRF MEDICINES ARE NOT INTERCHANGEABLE WITH EACH OTHER, REGARDLESS OF ROUTE OF ADMINISTRATION. SUB-GROUP ANALYSIS 3: TIME TO COMPLETE SURVEY - INTERNET S-3a - <10 min S-3b - 10 to <20 min S-3c - 20 min S-3a - <10 min S-3b - 10 to <20 min S-3c - 20 min Demonstrated Understanding (95% CI) (95% CI) (95% CI) 0 correct responses cared response conect responses 5 10.2 19 11.0 9 12.5 3 correct responses 41 83.7 147 85.5 62 86.1 Average mum)? 0f ?mm 2.7 (2.4. 3.0) 2.8 (2.6. 3.0) 2.9 (2.5. 3.0) lesponses Client: TRIG Project: TIRF Wave 1 Report Run Date and Time: 11/19/2012 11:24 AM Page 1 of TABLE 6.1.5 PRIMARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #1 KEY RISK MESSAGE l: TIRF MEDICINES ARE CONTRAINDICATED IN OPIOID NON-TOLERANT PATIENTS. SUB-GROUP ANALYSIS 5: MODALITY TO COMPLETE SURVEY Internet 0 S-5b - Telephone Question S?5a Internet Telephone (95% CI) (95% CI) Question 6: Please answer ?True,? ?False,? or don?t know? for each statement about TIRF medicines. 6a: TIRF medicines are contraindicated in opioid non-tolerant patients because life-threatening respiratory depression could occur at any dose. Correct response True 257 87.7 7 77.8 (83.4. 91.2) (40.0. 97.2) Incorrect response False 33 11.3 2 22.2 I don't know 3 1.0 0 0.0 6b: Death has occurred in opioid non-tolerant patients treated with some fentanyl products. True 280 95.6 9 100.0 (92.5. 97.6) (66.4. 100.0) Incorrect response False 4 1.4 0 0.0 I don't know 9 3.1 0 0.0 Client: TRIG Project: THIF Wave 1 Report Run Date and Time: 11/9/2012 9:58 AM Page 1 of 2 Internet Telephone Question 0 0 (950/? CI) 6c: TIRF medicines may be used to treat opioid non-tolerant patients. C01rect response False 242 82.6 7 77.8 (77.8. 86.8) (40.0. 97.2) Incorrect response True 43 14.7 2 22.2 I don?t know 8 2.7 0 0.0 6d: Prescribers starting a patient on a TIRF medicine must begin with titration from the lowest dose available for that speci?c product, even if the patient has previously taken another TIRF medicine. C01rect response True 245 83.6 6 66.7 (78.9. 87.7) (29.9. 92.5) Incorrect response False 42 14.3 3 33.3 I don't know 6 2.0 0 0.0 Client: TRIG Project: TIRF Wave 1 Report Run Date and Time: 11/9/2012 9:58 AM Page 2 of2 TABLE 6.2.5 LINKED TO KEY RISK MESSAGE #1 SECONDARY ANALYSIS OF RESPONSES TO QUESTIONS KEY RISK MESSAGE MEDICINES ARE CONTRAINDICATED IN OPIOID NON-TOLERANT PATIENTS. SUB-GROUP ANALYSIS 5: MODALITY TO COMPLETE SURVEY - Internet 0 - Telephone S-5b Internet Telephone Demonstrated Understanding (95% (95% CI) CI) 0 correct responses 1 0.3 0 0.0 1 correct response 9 3.1 0 0.0 2 correct responses 25 8.5 2 22.2 3 correct responses 67 22.9 3 33.3 4 correct responses 191 65.2 4 44.4 Average number of correct responses 3.5 (3.3. 4.0) 3.2 (2.2. 4.0) Client: TRIG Project: THIF Wave 1 Report Run Date and Time: 11/19/2012 10:41 AM Page 1 of TABLE 7.1.5 TO KEY RISK MESSAGE #2 PRIMARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED KEY RISK MESSAGE 2: TIRF MEDICINES ARE ONLY INDICATED FOR THE MANAGEMENT OF BREAKTHROUGH PAIN IN ADULT CANCER PATIENTS 18 YEARS OF AGE AND OLDER (16 YEARS OF AGE AND OLDER FOR BRAND AND GENERIC EQUIVALENTS) WHO ARE ALREADY RECEIVING AND WHO ARE TOLERANT TO AROUND-THE-CLOCK OPIOID THERAPY FOR THEIR UNDERLYING PERSISTENT CANCER PAIN. SUB-GROUP ANALYSIS 5: MODALITY TO COMPLETE SURVEY Internet 0 - Telephone S?5a - Internet Telephone Question (95% CI) (95% CI) Question 8: For which of the following indications do you prescribe TIRF medicines to opioid tolerant patients? Please answer ?Yes,? or don?t know? for each option. 8a: Acute or postoperative pain correct response No 253 86.3 8 88.9 (81.9. 90.1) (51.8. 99.7) Incorrect response Yes 37 12.6 1 11.1 I don't know 3 1.0 0 0.0 SD: Headache or migraine pain Con'ect response No 255 87.0 7 77.8 (82.6. 90.7) (40.0. 97.2) Incouect response Yes 37 12.6 1 11.1 I don't know 1 0.3 1 11.1 Client: TRIG Project: THIF Wave 1 Report Run Date and Time: 11/9/2012 11:50 AM Page 1 of 2 S-5a - Internet - Telephone Question (95% CI) (95% CI) 8c: Dental pain Correct response No 281 95.9 9 100.0 (93.0. 97.9) (66.4. 100.0) Incorrect response Yes 7 2.4 0 0.0 I don?t know 5 1.7 0 0.0 8d: Breakthrough pain from ca Correct response Yes 280 95.6 8 88.9 (92.5. 97.6) (51.8. 99.7) Incorrect response No 13 4.4 1 11.1 I don't know 0 0.0 0 0.0 Client: TRIG Project: TIRF Wave 1 Report Run Date and Time: 11/9/2012 11:50 AM Page 2 of 2 TABLE 7.2.5 SECONDARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #2 KEY RISK MESSAGE 2: TIRF MEDICINES ARE ONLY INDICATED FOR THE MANAGEMENT OF BREAKTHROUGH PAIN IN ADULT CANCER PATIENTS 18 YEARS OF AGE AND OLDER (16 YEARS OF AGE AND OLDER FOR BRAND AND GENERIC EQUIVALENTS) WHO ARE ALREADY RECEIVING AND WHO ARE TOLERANT TO AROUND-THE-CLOCK OPIOID THERAPY FOR THEIR UNDERLYING PERSISTENT CANCER PAIN. SUB-GROUP ANALYSIS 5: MODALITY TO COMPLETE SURVEY - Internet 0 - Telephone S-5b Internet Telephone Demonstrated Understandmg (95% (95% CI) CI) 0 correct responses 0 0.0 0 0.0 1 correct response 7 2.4 0 0.0 2 correct responses 15 5.1 1 11.1 3 correct responses 52 17.7 2 22.2 4 correct responses 219 74.7 6 66.7 Average number of correct responses 3.6 (3.5. 4.0) 3.6 (2.5. 4.0) Client: TRIG Project: THIF Wave 1 Report Run Date and Time: 11/19/2012 10:41 AM Page 1 of 1 Table 8.1.5 KEY RISK MESSAGE #3 PRIMARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO RISK MESSAGE 3: TIRF MEDICINES CONTAIN FENTANYL, AN OPIOID AGONIST AND A SCHEDULE II CONTROLLED SUBSTANCE, WITH ABUSE LIABILITY SIMILAR TO OTHER OPIOID ANALGESICS. SUB-GROUP ANALYSIS 5: MODALITY TO COMPLETE SURVEY Internet 0 - Telephone Question Internet Telephone (95% CI) (95% CI) Question 6: Please answer ?True,? ?False,? or don?t know? for each statement about TIRF medicines. 6e: It is important to monitor for signs of abuse and addiction in patients who take TIRF medicines. correct response Tnle 292 99.7 9 100.0 (98.1. 100.0) (66.4. 100.0) Inconect response False 1 0.3 0 0.0 I don?t know 0 0.0 0 0.0 Question 7: Which of the following are risk factors for opioid abuse? Please answer ?Yes,? or don?t know? for each option. 7a: A personal history of illness correct response Yes 242 82.6 7 77.8 (77.8. 86.8) (40.0. 97.2) Incon'ect response No 35 11.9 2 22.2 I don?t know 16 5.5 0 0.0 Client: TRIG Project: TRF Wave 1 Report Run Date and Time: 11/9/2012 10:03 AM Page 1 of 2 Question Internet Telephone (95% CI) (95% CI) 7b: A personal history of past or current alcohol or drug abuse, or a family history of illicit drug use or alcohol abuse Yes 292 99.7 8 88.9 (98.1. 100.0) (51.8. 99.7) Incorrect response No 0 0.0 1 1.1 I don't know 1 0.3 0 0.0 Question 9: Please answer ?True,? ?False,? or don?t know? for each statement about TIRF medicines. 9a: TIRF medicines can be abused in a manner similar to other opioid agonists. correct response Tnle 286 97.6 9 100.0 (95.1. 99.0) (66.4. 100.0) Incorrect response False 6 2.0 0 0.0 I don't know 1 0.3 0 0.0 Client: TRIG Project: THIF Wave 1 Report Run Date and Time: 11/9/2012 10:03 AM Page 2 of 2 TABLE 8.2.5 SECONDARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #3 KEY RISK MESSAGE 3: TIRF MEDICINES CONTAIN FENTANYL, AN OPIOID AGONIST AND A SCHEDULE II CONTROLLED SUBSTANCE, WITH ABUSE LIABILITY SIMILAR TO OTHER OPIOID ANALGESICS. SUB-GROUP ANALYSIS 5: MODALITY TO COMPLETE SURVEY - Internet 0 - Telephone Internet Telephone Demonstrated Understandmg (95% (95% CI) CI) 0 correct responses 0 0.0 0 0.0 1 correct response 0 0.0 0 0.0 2 correct responses 2 0.7 1 11.1 3 correct responses 56 19.1 1 11.1 4 correct responses 235 80.2 7 77.8 Average number of correct responses 3.8 (3.6. 4.0) 3.7 (2.6. 4.0) Client: TRIG Project: THIF Wave 1 Report Run Date and Time: 11/19/2012 10:41 AM Page 1 of TABLE 9.1.5 PRIMARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #4 RISK MESSAGE 4: TIRF MEDICINES ARE NOT INTERCHANGEABLE WITH EACH OTHER, REGARDLESS OF ROUTE OF ADMINISTRATION. SUB-GROUP ANALYSIS 5: MODALITY TO COMPLETE SURVEY 0 8-53 Internet 0 S-5b - Telephone Question S-5a S-5b Internet Telephone (95% CI) (95% CI) Question 9: Please answer ?True,? ?False,? or don?t know? for each statement about TIRF medicines. 9b: TIRF medicines are interchangeable with each other regardless of route of administration. COITCCI ICSPODSC False 280 95.6 9 100.0 (92.5. 97.6) (66.4. 100.0) Incorrect response True 9 3 .1 0 0.0 I don't know 4 1.4 0 0.0 9c: The conversion of one TIRF medicine for another TIRF medicine may result in a fatal overdose because of ditferences in the pharmacokinetics of fentanyl absorption. correct response True 277 94.5 9 100.0 (91.3. 96.8) (66.4. 100.0) Incorrect response False 5 1.7 0 0.0 I don't know 11 3.8 0 0.0 Client: TRIG Project: THIF Wave 1 Report Run Date and Time: 11/9/2012 10:03 AM Page 1 of 2 S-5a Internet Telephone Question 0 0 (950/? CI) Cl) 9d: Dosing of TIRF medicines is not equivalent on a microgram-to-microgram basis. Correct response True 266 90.8 7 77.8 (86.9. 93.8) (40.0. 97.2) Incorrect response False 10 3.4 2 22.2 I don't know 17 5.8 0 0.0 Client: TRIG Project: TIRF Wave 1 Report Run Date and Time: 11/9/2012 10:03 AM Page 2 of2 TABLE 9.2.5 SECONDARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #4 KEY RISK MESSAGE 4: TIRF MEDICINES ARE NOT INTERCHANGEABLE WITH EACH OTHER, REGARDLESS OF ROUTE OF ADMINISTRATION. SUB-GROUP ANALYSIS 5: MODALITY TO COMPLETE SURVEY - Internet 0 - Telephone S-5b Internet Telephone . Demonstrated Understanding (95% (95% CI) CI) 0 correct responses 3 1.0 0 0.0 1 correct response 7 2.4 0 0.0 2 correct responses 33 11.3 2 22.2 3 correct responses 250 85.3 7 77.8 Average number of correct responses 2.8 (2.6. 3.0) 2.8 (1.9. 3.0) Client: TRIG Project: THIF Wave 1 Report Run Date and Time: 11/19/2012 10:42 AM Page 1 of TABLE 6.1.6 PRIMARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #1 KEY RISK MESSAGE l: TIRF MEDICINES ARE CONTRAINDICATED IN OPIOID NON-TOLERANT PATIENTS. SUB-GROUP ANALYSIS 6: TIME PRACTICING MEDICINE (PHYSICIANS, ONLY, QUESTION 30) S-6a - Less than 3 years S-6b - 3 to 5 years S-6c - 6 to 15 years S-6d - More than 15 years S-6a S-6d Less than 3 S?6b More than 15 3 5 years 6 to 15 years years N=l4 years (95% (95% (95% (95% C1) C1) C1) CI) Question 6: Please answer ?True,? ?False,? or don?t know? for each statement about TIRF medicines. 6a: TIRF medicines are contraindicated in opioid non-tolerant patients because life?threatening respiratory depression could occur at any dose. Con'ect response True 11 91.7 12 85.7 59 81.9 93 91.2 (61.5. (57.2. (71.1. (83.9. 99.8) 98.2) 90.0) 95.9) Incorrect response False 1 8.3 2 14.3 11 15.3 9 8.8 I don't know 0.0 Client: TRIG Project: THIF Wave 1 Report Run Date and Time: 11/17/2012 1:16 PM Page 1 of 2 Question S-6a S-6d S?6b S?6c Le?eg? 3 3 5 years 6 to 15 years 15 (95% (95% (95% (95% C1) C1) CI) CI) 6b: Death has occurred in opioid non-tolerant patients treated with some fentanyl products. True 11 91.7 14 100.0 70 97.2 98 96.1 (61.5. (76.8. (90.3. (90.3. 99.8) 100.0) 99.7) 98.9) Incorrect response False don't know 2.9 6c: TIRF medicines may be used to treat opioid non-tolerant patients. Correct response False 12 100.0 13 92.9 57 79.2 80 78.4 (73.5. (66.1. (68.0. (69.2. 100.0) 99.8) 87.8) 86.0) Incorrect response True 0 0.0 1 7.1 12 16.7 19 18.6 I don't know 2.9 6d: Prescribers starting a patient on a TIRF medicine must begin with titration from the lowest dose available for that speci?c product, even if the patient has previously taken another TIRF medicine. Correct response True 10 83.3 13 92.9 55 76.4 83 81.4 (51.6. (66.1. (64.9. (72.4. 97.9) 99.8) 85.6) 88.4) hlcorrect response False 2 16.7 1 7.1 12 16.7 18 17.6 I don't know 1.0 Client: TRIG Project: TIRF Wave 1 Report Run Date and Time: 11/17/2012 1:16 PM Page 2 of2 TABLE 6.2.6 SECONDARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #1 KEY RISK MESSAGE MEDICINES ARE CONTRAINDICATED IN OPIOID NON-TOLERANT PATIENTS. SUB-GROUP ANALYSIS 6: TIME PRACTICING MEDICINE (PHYSICIANS, ONLY, QUESTION 30) S-6a - Less than 3 years 0 S-6b - 3 to 5 years 0 S-6c - 6 to 15 years 0 S-6d - More than 15 years S-6a S-6b S-6c S-6d Less than 3 3 - 5 years 6 to 15 years More than 15 years N=l4 years Demonstrated N=l02 Understanding (95% (95% (95% (95% CI) CI) CI) CI) 0 correct responses correct response correct responses 1 8.3 0 0.0 8 11.1 7 6.9 3 correct responses 2 16.7 4 28.6 15 20.8 31 30.4 4 correct responses 9 75.0 10 71.4 44 61.1 61 59.8 Average number of (2.8. (2.9. (3.0. (3.2. correct responses 3?7 4.0) 3'7 4.0) 3?3 4.0) 3'5 4.0) Client: TRIG Project: THIF Wave 1 Report Run Date and Time: 11/17/2012 1:17 PM Page 1 of 1 TABLE 7.1.6 TO KEY RISK MESSAGE #2 PRIMARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED KEY RISK MESSAGE 2: TIRF MEDICINES ARE ONLY INDICATED FOR THE MANAGEMENT OF BREAKTHROUGH PAIN IN ADULT CANCER PATIENTS 18 YEARS OF AGE AND OLDER (16 YEARS OF AGE AND OLDER FOR BRAND AND GENERIC EQUIVALENTS) WHO ARE ALREADY RECEIVING AND WHO ARE TOLERANT TO AROUND-THE-CLOCK OPIOID THERAPY FOR THEIR UNDERLYING PERSISTENT CANCER PAIN. SUB-GROUP ANALYSIS 6: TIME PRACTICING MEDICINE (PHYSICIANS, ONLY, QUESTION 30) S-6a - Less than 3 years 0 S-6b - 3 to 5 years 0 S-6c - 6 to 15 years 0 S-6d - More than 15 years Question S-6a S-6d Less than 3 8?6b More than 15 years 3 5 years 6 to 15 years years N=l4 (95% (95% (95% (95% C1) C1) C1) CI) Question 8: For which of the following indications do you prescribe TIRF medicines to opioid tolerant patients? Please answer ?Yes,? or don?t know? for each option. 8a: Acute or postoperative pain Con?ect response No 10 83.3 12 85.7 65 90.3 88 86.3 (51.6. (57.2. (81.0. (78.0. 97.9) 98.2) 96.0) 92.3) Incorrect response Yes 2 16.7 2 14.3 6 8.3 13 12.7 I don't know 1.0 Client: TRIG Project: THIF Wave 1 Report Run Date and Time: 11/19/2012 10:55 AM Page 1 of 2 S-6a S-6b S-6c S-6d Less than 3 More than 15 years 3 5 years 6 to 15 years years Question N=l4 (95% (95% (95% (95% CI) CI) CI) CI) 8b: Headache or migraine pain Correct response No 11 91.7 12 85.7 62 86.1 87 85.3 (61.5. (57.2. (75.9. (76.9. 99.8) 98.2) 93.1) 91.5) Incorrect response Yes 1 8.3 2 14.3 10 13.9 13 12.7 I don't know 2.0 8c: Dental pain Correct response No 11 91.7 14 100.0 69 95.8 99 97.1 (61.5. (76.8. (88.3. (91.6. 99.8) 100.0) 99.1) 99.4) Incorrect response Yes don't know 0 0.0 0.0 1 1.4 1 1.0 8d: Breakthrough pain from cancer Correct response Yes 12 100.0 13 92.9 70 97.2 93 91.2 (73.5. (66.1. (90.3. (83.9. 100.0) 99.8) 99.7) 95.9) Incorrect response don't know 0.0 Client: TRIG Project: THIF Wave 1 Report Run Date and Time: 11/19/2012 10:55 AM Page 2 of 2 TABLE 7.2.6 SECONDARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #2 KEY RISK MESSAGE 2: TIRF MEDICINES ARE ONLY INDICATED FOR THE MANAGEMENT OF BREAKTHROUGH PAIN IN ADULT CANCER PATIENTS 18 YEARS OF AGE AND OLDER (16 YEARS OF AGE AND OLDER FOR BRAND AND GENERIC EQUIVALENTS) WHO ARE ALREADY RECEIVING AND WHO ARE TOLERANT TO AROUND-THE-CLOCK OPIOID THERAPY FOR THEIR UNDERLYING PERSISTENT CANCER PAIN. SUB-GROUP ANALYSIS 6: TIME PRACTICING MEDICINE (PHYSICIANS, ONLY, QUESTION 30) S-6a - Less than 3 years 0 S-6b - 3 to 5 years 0 S-6c - 6 to 15 years 0 S-6d - More than 15 years S-6a S-6b S-6c S-6d Less than 3 3 - 5 years 6 to 15 years More than 15 years years Demonstrated Understanding (95% (95% (95% (95% CI) CI) CI) CI) 0 correct responses correct response correct responses correct responses 2 16.7 3 21.4 10 13.9 24 23.5 4 correct responses 9 75.0 10 71.4 57 79.2 71 69.6 Average number of (2.8. (2.8. (3.3. (3.3. correct responses 3'7 4.0) 3'6 4.0) 3'7 4.0) 3?6 4.0) Client: TRIG Project: THIF Wave 1 Report Run Date and Time: 11/17/2012 1:18 PM Page 1 of 1 TABLE 8.1.6 PRIMARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #3 RISK MESSAGE 3: TIRF MEDICINES CONTAIN FENTANYL, AN OPIOID AGONIST AND A SCHEDULE II CONTROLLED SUBSTANCE, WITH ABUSE LIABILITY SIMILAR TO OTHER OPIOID ANALGESICS. SUB-GROUP ANALYSIS 6: TIME PRACTICING MEDICINE (PHYSICIANS, ONLY, QUESTION 30) S-6a - Less than 3 years 0 S-6b - 3 to 5 years 0 S-6c - 6 to 15 years 0 S-6d - More than 15 years S?6a S?6b S-6c S?6d Less than 3 More than 15 3 - 5 years 6 to 15 years years years Question (95% (95% (95% (95% CI) CI) C1) C1) Question 6: Please answer ?True,? ?False,? or don?t know? for each statement about TIRF medicines. 6e: It is important to monitor for signs of abuse and addiction in patients who take TIRF medicines. Con'ect response Tme 12 100.0 14 100.0 72 100.0 101 99.0 (73.5. (76.8. (95.0. (94.7. 100.0) 100.0) 100.0) 100.0) Incouect response False don't know 0.0 Client: TRIG Project: THIF Wave 1 Report Run Date and Time: 11/17/2012 1:20 PM Page 1 of2 Question S-6a S?6d Less than 3 S-6b S-6c More than 15 years 3 5 years 6 to 15 years years (95% (95% (95% (95% CD CD CD CD Question 7: Which of the following are risk factors for opioid abuse? Please answer ?Yes,? or don?t know? for each option. 7a: A personal history of illness correct response Yes 8 66.7 13 92.9 63 87.5 83 81.4 (34.9. (66.1. (77.6. (72.4. 90.1) 99.8) 94.1) 88.4) Incorrect response No 4 33.3 0 0.0 7 9.7 14 13.7 I don't know personal history of past or current alcohol or drug abuse, or a family history of illicit drug use or alcohol abuse Con?ect response Yes 12 100.0 14 100.0 72 100.0 102 100.0 (73.5. (76.8. (95.0. (96.4. 100.0) 100.0) 100.0) 100.0) Incorrect response don't know 0.0 Question 9: Please answer ?True,? ?False,? or don?t know? for each statement about TIRF medicines. 9a: TIRF medicines can be abused in a manner similar to other opioid agonists. Con?ect response True 11 91.7 14 100.0 72 100.0 98 96.1 (61.5. (76.8. (95.0. (90.3. 99.8) 100.0) 100.0) 98.9) Inconect response False don't know 1.0 Client: TRIG Project: TRF Wave 1 Report Run Date and Time: 11/17/2012 1:20 PM Page 2 of 2 TABLE 8.2.6 SECONDARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #3 KEY RISK MESSAGE 3: TIRF MEDICINES CONTAIN FENTANYL, AN OPIOID AGONIST AND A SCHEDULE II CONTROLLED SUBSTANCE, WITH ABUSE LIABILITY SIMILAR TO OTHER OPIOID ANALGESICS. SUB-GROUP ANALYSIS 6: TIME PRACTICING MEDICINE (PHYSICIANS, ONLY, QUESTION 30) S-6a - Less than 3 years S-6b - 3 to 5 years S-6c - 6 to 15 years S-6d - More than 15 years S-6a S-6b S-6c S-6d Less than 3 3 - 5 years 6 to 15 years More than 15 years N=l4 years Demonstrated Understanding (95% (95% (95% (95% CI) CI) CI) CI) 0 correct responses correct response correct responses correct responses 5 41.7 1 7.1 9 12.5 24 23.5 4 correct responses 7 58.3 13 92.9 63 87.5 78 76.5 Average number of (2.7. (3.1. (3.5. (3.4. correct responses 3'6 4.0) 3'9 4.0) 3'9 4.0) 3'8 4.0) Client: TRIG Project: THIF Wave 1 Report Run Date and Time: 11/17/2012 1:21 PM Page 1 of TABLE 9.1.6 PRIMARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #4 RISK MESSAGE 4: TIRF MEDICINES ARE NOT INTERCHANGEABLE WITH EACH OTHER, REGARDLESS OF ROUTE OF ADMINISTRATION. SUB-GROUP ANALYSIS 6: TIME PRACTICING MEDICINE (PHYSICIANS, ONLY, QUESTION 30) S-6a - Less than 3 years 0 S-6b - 3 to 5 years 0 S-6c - 6 to 15 years 0 S-6d - More than 15 years S-6a S-6d Less than 3 8.61) More than 15 years 3 5 years 6 to 15 years years Question N=l4 (95% (95% (95% (95% C1) C1) C1) C1) Question 9: Please answer ?True,? ?False,? or don?t know? for each statement about TIRF medicines. 9b: TIRF medicines are interchangeable with each other regardless of route of administration. Con?ect response False 11 91.7 14 100.0 65 90.3 97 95.1 (61.5. (76.8. (81.0. (88.9. 99.8) 100.0) 96.0) 98.4) Inconect response Tme don't know 1.0 Client: TRIG Project: THIF Wave 1 Report Run Date and Time: 11/17/2012 1:22 PM Page 1 of 2 Question S-6a S-6d Less than 3 8.61) More than 15 years 3 5 years 6 to 15 years years N=l4 (95% (95% (95% (95% C1) C1) C1) C1) 9c: The conversion of one TIRF medicine for another TIRF medicine may result in a fatal overdose because of differences in the pharmacokinetics of fentanyl absorption. correct response Tme 11 91.7 13 92.9 68 94.4 97 95.1 (61.5. (66.1. (86.4. (88.9. 99.8) 99.8) 98.5) 98.4) Incorrect response False don't know 1 8.3 7.1 3 4.2 3 2.9 9d: Dosing of TIRF medicines is not equivalent on a microgram?to-microgram basis. Correct response True 11 91.7 11 78.6 65 90.3 94 92.2 (61.5. (49.2. (81.0. (85.1. 99.8) 95.3) 96.0) 96.6) Incorrect response False don't know 1 8.3 21.4 2 2.8 3.9 Client: TRIG Project: THIF Wave 1 Report Run Date and Time: 11/17/2012 1:22 PM Page 2 of2 TABLE 9.2.6 SECONDARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #4 KEY RISK MESSAGE 4: TIRF MEDICINES ARE NOT INTERCHANGEABLE WITH EACH OTHER, REGARDLESS OF ROUTE OF ADMINISTRATION. SUB-GROUP ANALYSIS 6: TIME PRACTICING MEDICINE (PHYSICIANS, ONLY, QUESTION 30) S-6a - Less than 3 years S-6b - 3 to 5 years S-6c - 6 to 15 years S-6d - More than 15 years S-6a S-6b S-6c S-6d Less than 3 3 - 5 years 6 to 15 years More than 15 years N=l4 years Demonstrated Understanding (95% (95% (95% (95% CD CD CD CD 0 correct responses correct response correct responses 0 0.0 4 28.6 10 13.9 12 11.8 3 correct responses 11 91.7 10 71.4 59 81.9 87 85.3 Average number of (2.0. (2.0. (2.4. (2.5. correct responses 2'8 3.0) 2'7 3.0) 2'8 3.0) 2'8 3.0) Client: TRIG Project: THIF Wave 1 Report Run Date and Time: 11/17/2012 1:23 PM Page 1 of TABLE 6.1.7 PRIMARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #1 KEY RISK MESSAGE l: TIRF MEDICINES ARE CONTRAINDICATED IN OPIOID NON-TOLERANT PATIENTS. SUB-GROUP ANALYSIS 7: NUMBER OF TIMES PER MONTH PRESCRIBING TIRF MEDICINES WITHIN THE LAST 6 MONTHS (QUESTION 26): S-7a - None 0 S-7b - 1-2 times a month 0 S-7c - 3 - 5 times a month 0 S-7d - More than 5 times a month Question S?7a SJC Mort?:1?? 5 None 1 2? times 3 5_times times N?l4l N?7l (95% (95% (95% (95% C1) C1) C1) C1) Question 6: Please answer ?True,? ?False,? or don?t know? for each statement about TIRF medicines. 6a: TIRF medicines are contraindicated in opioid non-tolerant patients because life?threatening respiratory depression could occur at any dose. correct response Tme 37 88.1 120 85.1 62 87.3 35 94.6 (74.4. (78.1. (77.3. (81.8. 96.0) 90.5) 94.0) 99.3) Incorrect response False 5 11.9 19 13.5 8 11.3 2 5.4 I don?t know 0.0 Client: TRIG Project: THIF Wave 1 Report Run Date and Time: 11/12/2012 12:33 PM Page 1 of2 S?7a qu ch 5 None 1 2 times 3 5 times times Question N=7l (95% (95% (95% (95% C1) C1) C1) C1) 6b: Death has occurred in opioid non-tolerant patients treated with some fentanyl products. COITCCI response True 42 100.0 133 94.3 66 93.0 37 100.0 (91.6. (89.1. (84.3. (90.5. 100.0) 97.5) 97.7) 100.0) Incorrect response False don't know 0.0 6c: TIRF medicines may be used to treat opioid non-tolerant patients. Correct response False 31 73.8 118 83.7 56 78.9 34 91.9 (58.0. (76.5. (67.6. (78.1. 86.1) 89.4) 87.7) 98.3) Incorrect response True 9 21.4 19 13.5 13 18.3 3 8.1 I don't know 0.0 6d: Prescribers starting a patient on a TIRF medicine must begin with titration from the lowest dose available for that speci?c product, even if the patient has previously taken another TIRF medicine. Correct response True 37 88.1 115 81.6 58 81.7 31 83.8 (74.4. (74.2. (70.7. (68.0. 96.0) 87.6) 89.9) 93.8) Incorrect response False 5 11.9 20 14.2 13 18.3 6 16.2 I don't know 0.0 Client: TRIG Project: THIF Wave 1 Report Run Date and Time: 11/12/2012 12:33 PM Page 2 of 2 TABLE 6.2.7 SECONDARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #1 KEY RISK MESSAGE MEDICINES ARE CONTRAINDICATED IN OPIOID NON-TOLERANT PATIENTS. SUB-GROUP ANALYSIS 7: NUMBER OF TIMES PER MONTH PRESCRIBING TIRF MEDICINES WITHIN THE LAST 6 MONTHS (QUESTION 26): S-7a - None S-7b - 1-2 times a month S-7c - 3 - 5 times a month S-7d - More than 5 times a month S-7a S?7b S-7c 37? . More than 5 None 1 2 times 3 5 times times Demonstrated Understandin (95% (95% (95% (95% CI) CI) CI) CI) 0 correct responses correct response correct responses 3 7.1 15 10.6 8 11.3 1 2.7 3 correct responses 9 21.4 35 24.8 17 23.9 9 24.3 4 correct responses 28 66.7 87 61.7 43 60.6 27 73.0 Average number of correct 3.5 (3.0. 4.0) 3.4 (3.2. 4.0) 3.4 (3.0. 4.0) 3.7 (3.2.4.0) responses Client: TRIG Project: THIF Wave 1 Report Run Date and Time: 11/12/2012 12:33 PM Page 1 of 1 TABLE 7.1.7 PRIMARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #2 KEY RISK MESSAGE 2: TIRF MEDICINES ARE ONLY INDICATED FOR THE MANAGEMENT OF BREAKTHROUGH PAIN IN ADULT CANCER PATIENTS 18 YEARS OF AGE AND OLDER (16 YEARS OF AGE AND OLDER FOR BRAND AND GENERIC EQUIVALENTS) WHO ARE ALREADY RECEIVING AND WHO ARE TOLERANT TO AROUND- THE-CLOCK OPIOID THERAPY FOR THEIR UNDERLYING PERSISTENT CANCER PAIN. SUB-GROUP ANALYSIS 7: NUMBER OF TIMES PER MONTH PRESCRIBING TIRF MEDICINES WITHIN THE LAST 6 MONTHS (QUESTION 26): S-7a - None 0 S-7b - 1-2 times a month 0 S-7c - 3 - 5 times a month 0 S-7d - More than 5 times a month S-7d 7 -7 lieu: SZZibmes 3 SS ticrnes More than 5 tim Question (95% (95% (95% (95% CI) C1) C1) C1) Question 8: For which of the following indications can TIRF medicines be prescribed to opioid tolerant patients? Please answer ?Yes,? or don?t know? for each option. 8a: Acute or postoperative pain Con?ect response No 34 81.0 122 86.5 62 87.3 33 89.2 (65.9. (79.8. (77.3. (74.6. 91.4) 91.7) 94.0) 97.0) Incorrect response Yes 7 16.7 17 12.1 9 12.7 4 10.8 I don't know 0.0 Client: TRIG Project: TRF Wave 1 Report Run Date and Time: 11/12/2012 12:33 PM Page 1 of2 S-7d S?7a qu ch More than 5 None 1 2 times 3 5 times times . N=l4l N=7l Question (95% (95% (95% (95% CI) C1) C1) C1) 8b: Headache or migraine pain Correct response No 38 90.5 122 86.5 60 84.5 31 83.8 (77.4. (79.8. (74.0. (68.0. 97.3) 91.7) 92.0) 93.8) Incorrect response Yes 3 7.1 19 13.5 10 14.1 6 16.2 I don't know 0.0 Sr: Dental pain Correct response No 40 95.2 136 96.5 68 95.8 35 94.6 (83.8. (91.9. (88.1. (81.8. 99.4) 98.8) 99.1) 99.3) Incorrect response Yes don't know 0.0 8d: Breakthrough pain from cancer Correct response Yes 41 97.6 133 94.3 66 93.0 37 100.0 (87.4. (89.1. (84.3. (90.5. 99.9) 97.5) 97.7) 100.0) Incorrect response don't know 0.0 Client: TRIG Project: THIF Wave 1 Report Run Date and Time: 11/12/2012 12:33 PM Page 2 of 2 SECONDARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #2 TABLE 7.2.7 KEY RISK MESSAGE 2: TIRF MEDICINES ARE ONLY INDICATED FOR THE MANAGEMENT OF BREAKTHROUGH PAIN IN ADULT CANCER PATIENTS 18 YEARS OF AGE AND OLDER (16 YEARS OF AGE AND OLDER FOR BRAND AND GENERIC EQUIVALENTS) WHO ARE ALREADY RECEIVING AND WHO ARE TOLERANT TO AROUND-THE-CLOCK OPIOID THERAPY FOR THEIR UNDERLYING PERSISTENT CANCER PAIN. SUB-GROUP ANALYSIS 7: NUMBER OF TIMES PER MONTH PRESCRIBING TIRF MEDICINES WITHIN THE LAST 6 MONTHS (QUESTION 26): S-7a - None S-7b - 1-2 times a month S-7c - 3 - 5 times a month S-7d - More than 5 times a month S?7c Morse?:1?? 5 None 1 2 times 3 5 times times Demonstrated Understandin (95% (95% (95% (95% CI) CI) CI) CI) 0 correct responses con?ect response correct responses correct responses 5 11.9 25 17.7 17 23.9 6 16.2 4 correct responses 33 78.6 104 73.8 49 69.0 29 78.4 Mirage ?umber 0f 3.6 (3.2. 4.0) 3.6 (3.4. 4.0) 3.6 (3.2. 4.0) 3.7 (3.2. 4.0) conect responses Client: TRIG Project: THIF Wave 1 Report Run Date and Time: 11/12/2012 12:32 PM Page 1 of Table 8.1.7 KEY RISK MESSAGE #3 PRIMARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO RISK MESSAGE 3: TIRF MEDICINES CONTAIN FENTANYL, AN OPIOID AGONIST AND A SCHEDULE II CONTROLLED SUBSTANCE, WITH ABUSE LIABILITY SIMILAR TO OTHER OPIOID ANALGESICS. SUB-GROUP ANALYSIS 7: NUMBER OF TIMES PER MONTH PRESCRIBING TIRF MEDICINES WITHIN THE LAST 6 MONTHS (QUESTION 26): S-7a - None 0 S-7b - 1-2 times a month 0 S-7c - 3 - 5 times a month 0 S-7d - More than 5 times a month Question S?7a S-7b S?7c S-7d None 1 2 times 3 5 times More than 5 times N=l4l N=7l (95% (95% (95CI) Question 6: Please answer ?True,? ?False,? or don?t know? for each statement about TIRF medicines. 6e: It is important to monitor for signs of abuse and addiction in patients who take TIRF medicines. True 42 100.0 140 99.3 71 100.0 37 100.0 (91.6. (96.1. (94.9. (90.5. 100.0) 100.0) 100.0) 100.0) Incorrect response False 0don't know 0.0 Client: TRIG Project: THIF Wave 1 Report Run Date and Time: 11/12/2012 12:32 PM Page 1 of2 Question S-7a S-7b S-7c S?7d None 1 2 times 3 5 times More than 5 times N=l4l N=7l (95% (95% (95CI) Question 7: Which of the following are risk factors for opioid abuse? Please answer ?Yes,? or don?t know? for each option. 7a: A personal history of illness Con?ect response Yes 32 76.2 116 82.3 56 78.9 36 97.3 (60.5. (74.9. (67.6. (85.8. 87.9) 88.2) 87.7) 99.9) Inc01rect response No 9 21.4 14 9.9 13 18.3 1 2.7 I don't know personal history of past or current alcohol or drug abuse, or a family history of illicit drug use or alcohol abuse correct response Yes 42 100.0 139 98.6 71 100.0 37 100.0 (91.6. (95.0. (94.9. (90.5. 100.0) 99.8) 100.0) 100.0) Incorrect response don't know 0.0 Question 9: Please answer ?True,? ?False,? or don?t know? for each statement about TIRF medicines. 9a: TIRF medicines can be abused in a manner similar to other opioid agonists. correct response Tule 41 97.6 140 99.3 67 94.4 37 100.0 (87.4. (96.1. (86.2. (90.5. 99.9) 100.0) 98.4) 100.0) Incorrect response False don't know 0.0 Client: TRIG Project: THIF Wave 1 Report Run Date and Time: 11/12/2012 12:32 PM Page 2 of2 TABLE 8.2.7 SECONDARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #3 KEY RISK MESSAGE 3: TIRF MEDICINES CONTAIN FENTANYL, AN OPIOID AGONIST AND A SCHEDULE II CONTROLLED SUBSTANCE, WITH ABUSE LIABILITY SIMILAR TO OTHER OPIOID ANALGESICS. SUB-GROUP ANALYSIS 7: NUMBER OF TIMES PER MONTH PRESCRIBING TIRF MEDICINES WITHIN THE LAST 6 MONTHS (QUESTION 26): S-7a - None S-7b - 1-2 times a month S-7c - 3 - 5 times a month S-7d - More than 5 times a month S?7a S?7b S?7c 5?7? . More than 5 None 1 2 tunes 3 5 tlmes times Demonstrated Understandin (95% (95% (95% (95% CI) C1) C1) CI) 0 correct responses correct response correct responses correct responses 11 26.2 25 17.7 17 23.9 1 2.7 4 correct responses 31 73.8 114 80.9 53 74.6 36 97.3 Average number of (3.2. (3.4. (3.4. correct responses 3'7 4.0) 3'8 4'0) 3'7 4.0) 4'0 4.0) Client: TRIG Project: THIF Wave 1 Report Run Date and Time: 11/12/2012 12:33 PM Page 1 of TABLE 9.1.7 PRIMARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #4 RISK MESSAGE 4: TIRF MEDICINES ARE NOT INTERCHANGEABLE WITH EACH OTHER, REGARDLESS OF ROUTE OF ADMINISTRATION. SUB-GROUP ANALYSIS 7: NUMBER OF TIMES PER MONTH PRESCRIBING TIRF MEDICINES WITHIN THE LAST 6 MONTHS (QUESTION 26): S-7a - None 0 S-7b - 1-2 times a month 0 S-7c - 3 - 5 times a month 0 S-7d - More than 5 times a month Question S?7a S?7c Mari?Zlfan 5 None 1 2 times 3 5 times times N=l41 N=7l (95% (95% (95% (95% C1) C1) C1) C1) TIRF medicines. Question 9: Please answer ?True,? ?False,? or don?t know? for each statement about 9b: TIRF medicines are interchangeable with each other regardless of route of administration. ICSPOIISC False 40 95.2 138 97.9 69 97.2 33 89.2 (83.8. (93.9. (90.2. (74.6. 99.4) 99.6) 99.7) 97.0) Incouect response True don?t know 0 0.0 3 2.1 0 0.0 2.7 Client: TRIG Project: THIF Wave 1 Report Run Date and Time: 11/12/2012 12:33 PM Page 1 of2 Question S-7d ch More than 5 None 1 2 times 3 5 times times N=l4l N=7l (95% (95% (95% (95% C1) C1) C1) C1) 9c: The conversion of one TIRF medicine for another TIRF medicine may result in a fatal overdose because of differences in the pharmacokinetics of fentanyl absorption. True 41 97.6 131 92.9 67 94.4 37 100.0 (87.4. (87.3. (86.2. (90.5. 99.9) 96.5) 98.4) 100.0) Incorrect response False don't know 0.0 9d: Dosing of TIRF medicines is not equivalent on a microgram-to-microgram basis. Con?ect response True 38 90.5 126 89.4 65 91.5 35 94.6 (77.4. (83.1. (82.5. (81.8. 97.3) 93.9) 96.8) 99.3) Incorrect response False don't know 3 7.1 10 7.1 2 2.8 2.7 Client: TRIG Project: TIRF Wave 1 Report Run Date and Time: 11/12/2012 12:33 PM Page 2 of2 TABLE 9.2.7 SECONDARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #4 KEY RISK MESSAGE 4: TIRF MEDICINES ARE NOT INTERCHANGEABLE WITH EACH OTHER, REGARDLESS OF ROUTE OF ADMINISTRATION. SUB-GROUP ANALYSIS 7: NUMBER OF TIMES PER MONTH PRESCRIBING TIRF MEDICINES WITHIN THE LAST 6 MONTHS (QUESTION 26): S-7a - None S-7b - 1-2 times a month S-7c - 3 - 5 times a month S-7d - More than 5 times a month S-More than 5 None 1 2 times 3 5 times times Demonstrated N=7l Understandin (95% (95% (95% (95% CI) CI) CI) CI) 0 correct responses correct response correct responses 7 16.7 12 8.5 8 11.3 6 16.2 3 correct responses 35 83.3 122 86.5 61 85.9 31 83.8 Average number of (2.4. (2.5. correct responses 2.8 3.0) 2.8 (2.6. 3.0) 2.8 3.0) 2.8 (2.4. 3.0) Client: TRIG Project: THIF Wave 1 Report Run Date and Time: 11/12/2012 12:33 PM Page 1 of 5:340. 2"?151?2 we if. 2.: December 27, 2013 Food and Drug Administration Center for Drug Evaluation and Research Central Document Room Drug Master File Staff 590l?-B Ammendaie Road Beltsville, MD 20705?1266 Re: DMF 027320 Holder: McKesson Specialty Health (McKesson) DMF Subject: Transmucosal Immediate Release Fentanyi (TIRF) Access Program Re: REMS Shared Program DMF Type: DMF Submission Information: Clinical/Clinical Information REMS Submission Identi?er: Assessment Sequence Number: 0907 Dear Drug Master File Staff: This Type DMF contains the Risk Evaluation and Mitigation Strategy (REMS) for Transmucosal Immediate Release Fentanyl for the Shared System REMS program. Included in this submission, please ?nd the REMS Assessment 3 at 24 months. McKesson states that information provided in this Master File is current and assures that the material furnished will meet the speci?cations described herein. McKesson also con?rms that the Holder obligations are observed. We request that all information in this ?le be treated as con?dential commercial information to the Food and Drug Administration pursuant to 21 C.F.R. ?20.61, and that no information from this ?le be provided to any unauthorized persons without written consent. if you have any questions or concerns, please do not hesitate to contact Jann Kochel, US. Agent for McKesson, at 610-535?6500, ext. 5572 or alternatively via email atjann.a.kochel@accenture.com. Sincerely, km?, v' a A. Kochel, US. Agent Aeoenture, LLP 585 East Swedesford Road Wayne, PA 19087 Attachments: Table of Contents for the submission Electronic Submission Speci?cations DMF #027320; Sequence 0007 Shared System REMS Table of Contents Page 1 of 1 Assessment – 24 Months Module Section Description 1.2 Cover Letter Cover Letter w/ Attachments Administrative Information Page 1.16 – Risk Management Plans REMS History REMS Assessment – 24 Months FDA_671 Electronic Submission Specifications This submission is compliant with FDA's Guideline for Industry: Providing Regulatory Submissions in Electronic Format - Human Pharmaceutical Product Applications and Related Submissions Using the eCTD Specifications (June 2008). All files were checked and verified to be free of viruses prior to transmission through the electronic submission gateway. This eCTD has been generated by Accenture, LLP (formerly Octagon Research Solutions Inc.), who has filed an acceptable eCTD pilot with the Center (Pilot Number 900777). Anti-Virus Program Program Version Virus Definition Date Submission Size Symantec Endpoint Protection Edition 11.0.5002.333 12/18/2013 rev. 23 Approx. 1 MB The IT point of contact for this submission is: Name Phone Number Email Address Matt Francis 610-535-6500 ext. 5665 Matthew.p.francis@accenture.com FDA_672 ADMINISTRATIVE INFORMATION Holder’s Name: McKesson Specialty Health (McKesson) Holder’s Address: 4343 N. Scottsdale Road Suite 150 Scottsdale, AZ 85251 Holder’s Contact Person: Laura Baloun Contact’s Address: 4343 N. Scottsdale Road Suite 150 Scottsdale, AZ 85251 Contact’s Phone: 480-663-4009 Contact’s Fax: 480-663-4973 Contact’s Email address: laura.baloun@mckesson.com Statement of Commitment: Attached, please find a signed statement of commitment. The statement certifies that the DMF is current and that McKesson will comply with the statements made in it. Agent’s Name: Accenture, LLP Agent’s Address: 585 East Swedesford Road Wayne, PA 19087 Agent’s Contact Person: Jann A. Kochel Contact’s Address 585 East Swedesford Road Wayne, PA 19087 Contact’s Phone: 610-535-6500, ext. 5572 Contact’s Fax: 610-535-6515 Contact’s E-mail address: jann.a.kochel@accenture.com FDA_673 DMF #027320; Sequence 0007 Shared System REMS Modification Date Approved Documents Affected No. 1 June 5, 2012 x REMS x Prescriber Program Overview x Education Program x Prescriber Enrollment Form x Patient Provider Agreement Form x Patient and Caregiver Overview x Dear Healthcare Provider Letter x Outpatient Pharmacy Overview x Chain Pharmacy Overview x Inpatient Pharmacy Overview x Outpatient Pharmacy Enrollment Form x Chain Pharmacy Enrollment Form x Inpatient Pharmacy Enrollment form x Outpatient Pharmacy Letter x Inpatient Pharmacy Letter x Dear Distributor Letter x Distributor Enrollment Form x Supporting Document N/A N/A Assessment Report 1 at 6 months – due 06/28/2012 2 November 7, Draft Documents REMS History Page 1 of 3 Overview of Modification Sequence 0002: Edits to Patient-Prescriber Agreement Form, the addition of the Closed System Pharmacy Enrollment Form*, the addition of the newly approved TIRF product, Subsys (fentanyl sublingual spray) and minor editorial changes. *The Closed System Pharmacy Enrollment Form was not formally submitted through the Gateway but was submitted via email on May 18, 2012 and included in the June 5, 2012 FDA approval letter. Sequence 0003: Assessment report covering 12/28/2011 to 04/27/2012 Sequence 0004: FDA_674 DMF #027320; Sequence 0007 Shared System REMS 2013 N/A N/A 2 November 7, 2013 REMS History Page 2 of 3 submitted on or before 09/28/2012 x Chain Pharmacy Enrollment Form x Outpatient Pharmacy Enrollment Form x Closed System Pharmacy Overview x Education Program x Frequently Asked Questions (FAQ) x Outpatient Pharmacy Letter x REMS x Supporting Document Assessment Report 2 at 1 year – due 12/28/2012 Amendment to 09/28/2012 supplement: x Chain Outpatient Pharmacy Enrollment Form x Independent Outpatient Pharmacy Enrollment Form x Closed System Outpatient Pharmacy Enrollment Form x Inpatient Pharmacy Enrollment Form x Distributor Enrollment Form x Prescriber Enrollment Form x Patient Provider Agreement Form x Chain Outpatient Modification proposed to: x Incorporate closed system pharmacies into the TIRF REMS Access Program x Correct minor inconsistencies between the FDA provided versions and the current PDF versions of REMS materials Sequence 0005: Assessment report covering 04/28/2012 to 10/28/2012 Sequence 0006: Modification proposed to: x Revised terminology, processes, and definitions for outpatient pharmacies x Revised attestations for physicians and patients to address concerns regarding patient access x Revised Program Overview and Frequently Asked Questions to improve clarity and content x Updated REMS materials to reflect the completion of the transition phase for the TIRF REMS Access Program FDA_675 DMF #027320; Sequence 0007 Shared System REMS N/A N/A REMS History Page 3 of 3 Pharmacy Overview x Independent Outpatient Pharmacy Overview x Closed System Outpatient Pharmacy Overview x Inpatient Pharmacy Overview x Patient and Caregiver Overview x Prescriber Overview x Education Program x Knowledge Assessment x Frequently Asked Questions (FAQ) x Dear Outpatient Pharmacy Letter x Dear Inpatient Pharmacy Letter x Dear Healthcare Provide Letter x Dear Distributor Letter x REMS x Supporting Document x Website Landing Page Assessment Report 3 at 2 years – due 12/28/2013 Sequence 0007: Assessment report covering 10/29/2012 to 10/28/2013 FDA_676 24-month REMS Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies. Page 1 of 131 Title: Transmucosal Immediate-Release Fentanyl (TIRF) Risk Evaluation and Mitigation Strategy (REMS) Access Program 24-month Assessment Report Reporting Timeframe: 29OCT2012 to 28OCT2013 Document Number: Final v1.0 – 18DEC2013 Product Name: Transmucosal Immediate-Release Fentanyl Sponsor: TIRF REMS Industry Group (TRIG) of Companies: Cephalon, Inc. (a wholly-owned subsidiary of Teva Pharmaceutical Industries, Ltd.) Depomed, Inc. Galena Biopharma, Inc. Insys Therapeutics Inc. Mallinckrodt Pharmaceuticals Meda Pharmaceuticals, Inc. Mylan, Inc. Par Pharmaceutical, Inc.   Confidentiality Statement The information contained herein is confidential and the proprietary property of the TRIG of Companies and its affiliates, and any unauthorized use or disclosure of such information without the prior written authorization of the TRIG is expressly prohibited. FDA_677 24-month REMS Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies. Page 2 of 131 TABLE OF CONTENTS Pg LIST OF TABLES ................................................................................................................... 5  LIST OF FIGURES ................................................................................................................. 7  LIST OF ABBREVIATIONS ................................................................................................. 8  EXECUTIVE SUMMARY ..................................................................................................... 9  1  BACKGROUND ........................................................................................................ 13  2  REMS GOALS ........................................................................................................... 14  3  SUPPORTING INFORMATION ON PROPOSED REMS ELEMENTS ........... 15  3.1  Additional Elements ................................................................................................ 15  3.1.1  Medication Guide ............................................................................................ 15  3.1.2  Letters to Healthcare Professionals.................................................................. 15  3.2  Elements to Assure Safe Use (ETASU) .................................................................. 15  3.2.1  Prescription Verification .................................................................................. 17  3.3  Implementation System........................................................................................... 18  3.3.1  Wholesaler/Distribution Enrollment and Fulfillment ...................................... 18  3.3.2  The TIRF REMS Access Program Compliance .............................................. 18  3.3.3  TIRF REMS Access Program Call Center ...................................................... 18  4  REMS ASSESSMENT PLAN METHODS ............................................................. 18  4.1  Data Sources ........................................................................................................... 19  4.1.1  TIRF REMS Access Program Outreach .......................................................... 19  4.1.2  The TIRF REMS Access Program and Product Utilization Statistics ............. 19  4.1.3  Program Infrastructure and Performance ......................................................... 21  4.1.4  Safety Surveillance .......................................................................................... 22  4.2  TIRF REMS Access Program Non-Compliance Plan ............................................ 23  4.2.1  Corrective Action Measures ............................................................................ 24  5  RESULTS ................................................................................................................... 26  5.1  TIRF REMS Access Program Outreach ................................................................. 26  5.1.1  Dear Healthcare Professional Letters [Metric 1-4] .......................................... 26  5.2  REMS Program Utilization ..................................................................................... 26  5.2.1  Patient Enrollment [Metric 5 and 6] ................................................................ 26  5.2.2  Prescriber Enrollment, Inactivation, and Education [Metric 7, 8, 9] ............... 32  5.2.3  Pharmacy Enrollment, Inactivation, and Education [Metric 10, 11, 12] ......... 37  5.2.4  Dispensing Activity [Metric 13 and 14] .......................................................... 49  5.2.5  Wholesaler/Distributor Enrollment [Metric 15 and 16] .................................. 55  5.2.6  Barriers or Delays in Patient Access [Metric 17 and 18] ................................ 56  5.3  Program Infrastructure and Performance [Metrics 19, 20, 21, 22, 23, 24] ............. 63  5.3.1  Pharmacy Management Systems [Metric 19] .................................................. 63  FDA_678 24-month REMS Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies. 5.3.2  5.3.3  Page 3 of 131 Backup System for Prescription Validation [Metric 20] ................................. 64  REMS Call Center [Metric 21a, b] .................................................................. 64  5.4  System Errors and Corrective Actions [Metric 22] ................................................ 67  5.4.1  Lack of Enrolled Prescribers and/or Pharmacies for Patients [Metric 23] ...... 69  5.4.2  Delays after Prescription Denial [Metric 24] ................................................... 69  5.5  Unintended System Interruptions [Metrics 25, 26, 27, 28] ..................................... 70  5.5.1  Inadvertent Enrollment Deactivations [Metric 25] .......................................... 70  5.5.2  Reports of False Positives [Metric 26] ............................................................ 70  5.5.3  Failure of Re-enrollment Notifications [Metric 27] ........................................ 70  5.5.4  Reports of False Negatives [Metric 28] ........................................................... 70  5.5.5  Duplicate Stakeholder Records ........................................................................ 70  5.6  6  Audits ...................................................................................................................... 71  TIRF REMS ACCESS PROGRAM NON-COMPLIANCE ................................. 71  7  SAFETY SURVEILLANCE ..................................................................................... 80  8  7.1  Adverse Events ....................................................................................................... 80  7.2  American Association of Poison Control Centers (AAPCC) ................................. 84  PERIODIC SURVEYS OF STAKEHOLDERS ..................................................... 95  8.1  Patient KAB Survey ................................................................................................ 95  8.1.1  Survey Statistics ............................................................................................... 95  8.1.2  Demographics and Respondent Characteristics ............................................... 96  8.1.3  TIRF Educational Materials............................................................................. 96  8.1.4  Patient Survey Results ..................................................................................... 96  8.1.4.1  Key Risk Message 1 .................................................................................... 96  8.1.4.2  Key Risk Message 2 .................................................................................... 97  8.1.4.3  Key Risk Message 3 .................................................................................... 97  8.1.4.4  Key Risk Message 4 .................................................................................... 97  8.1.4.5  Key Risk Message 5 .................................................................................... 98  8.1.4.6  Key Risk Message 6 .................................................................................... 98  8.1.5  Additional Safety Questions about TIRF Medicines Safety ............................ 98  8.1.6  Analysis of Sub-populations ............................................................................ 99  8.2  Pharmacy KAB Survey ......................................................................................... 100  8.2.1  Survey Statistics ............................................................................................. 100  8.2.2  Demographic and Respondent Characteristics .............................................. 101  8.2.3  TIRF Educational Materials........................................................................... 101  8.2.4  Pharmacy Survey Results .............................................................................. 101  8.2.4.1  Key Risk Message 1 .................................................................................. 101  8.2.4.2  Key Risk Message 2 .................................................................................. 102  8.2.4.3  Key Risk Message 3 .................................................................................. 102  8.2.4.4  Key Risk Message 4 .................................................................................. 102  8.2.5  Additional Safety Questions about TIRF Medicines Safety .......................... 103  8.2.6  Pharmacist Activities When Dispensing TIRF Medicines ............................ 103  FDA_679 24-month REMS Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies. Page 4 of 131 8.3  Prescriber KAB Survey ......................................................................................... 103  8.3.1  Survey Statistics ............................................................................................. 103  8.3.2  Demographics and Respondent Characteristics ............................................. 104  8.3.3  TIRF Educational Materials........................................................................... 104  8.3.4  Prescriber Survey Results .............................................................................. 105  8.3.4.1  Key Risk Message 1 .................................................................................. 105  8.3.4.2  Key Risk Message 2 .................................................................................. 105  8.3.4.3  Key Risk Message 3 .................................................................................. 105  8.3.4.4  Key Risk Message 4 .................................................................................. 106  8.3.5  Additional Questions about TIRF Medicines Safety ..................................... 106  8.3.6  Prescriber Activities When Prescribing TIRF Medicines.............................. 107  8.3.7  Analyses of Sub-populations ......................................................................... 107  8.4  9  Overall Conclusions for KAB Results .................................................................. 108  FDA COMMUNICATIONS ................................................................................... 110  10  POST-APPROVAL STUDIES AND CLINICAL TRIALS ................................. 110  11  OVERALL CONCLUSIONS ................................................................................. 110  12  APPENDICES .......................................................................................................... 113  12.1  Medical Dictionary for Drug Regulatory Activities (MedDRA) Preferred Terms ............................................................................................................................... 114  12.2  AAPCC LISTINGS............................................................................................... 118  12.3  TRIG AERS Safety Surveillance Analysis Report ............................................... 127  12.4  Periodic Stakeholder Surveys ............................................................................... 128  12.4.1  Patient KAB Survey....................................................................................... 129  12.4.2  Pharmacy KAB Survey .................................................................................. 130  12.4.3  Prescriber KAB Survey ................................................................................. 131  FDA_680 24-month REMS Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies. Page 5 of 131 LIST OF TABLES Table 1:  Table 2:  Table 3:  Table 4:  TIRF Medicines ...........................................................................................................14  TIRF REMS Access Program Outreach Metrics .........................................................19  Currently Approved Metrics and New Metrics – Utilization Statistics .......................20  Currently Approved Metrics and New Metrics-Program Infrastructure and Performance ..................................................................................................................21  Table 5:  New Metrics ..................................................................................................................22  Table 6:  Additional Metrics Requested by the FDA ...................................................................22  Table 7  Non-Compliance Activity Monitoring .........................................................................23  Table 8:  Corrective Action Guideline .........................................................................................25  Table 9:  Patient Enrollment and Geographic Distribution ..........................................................26  Table 10:  Patient Enrollment by State According to 2010 US Census .........................................29  Table 11:  Reasons for Incomplete Prescriber Web Enrollment ....................................................32  Table 12:  Prescriber Enrollment ...................................................................................................33  Table 13:  Prescriber Inactivations .................................................................................................35  Table 14:  Enrolled Prescriber Completed Knowledge Assessments and Number of Attempts Needed to Complete ......................................................................................................37  Table 15:  Reasons for Incomplete Pharmacy Web Enrollment ....................................................39  Table 16:  Pharmacy Enrollment ....................................................................................................40  Table 17:  Pharmacy Inactivations .................................................................................................45  Table 18:  Enrolled Authorized Pharmacist/Pharmacy Representatives Successfully Completing Knowledge Assessments and Attempts Needed to Successfully Complete Knowledge Assessment ................................................................................48  Table 19:  Prescriptions Authorized for Dispensing from Outpatient Pharmacies ........................50  Table 20  Reasons for Prescriptions Not Meeting REMS Edit Requirement ...............................51  Table 21:  Total Number of Prescriptions Rejected for Safety ......................................................52  Table 22:  Wholesaler/Distributor Enrollment ...............................................................................55  Table 23:  Wholesaler/Distributor Inactivations ............................................................................56  Table 24  Submission of Patient-Prescriber Agreement Forms to the REMS Program ...............56  Table 25:  Prescriptions Dispensed During the First 10 Days after Passive Patient Enrollment ...59  Table 26:  Prescriptions Dispensed Beyond the First 10 Days after Passive Patient Enrollment ..62  Table 27:  Configuration of Pharmacy Management System (PMS).............................................64  Table 28:  Reasons and Frequency for Contacting the Call Center ...............................................65  Table 29  Non-Compliance Activity Reports by Stakeholder in the Current Reporting Period: 29 October 2012 to 28 October 2013 ............................................................................72  Table 30  Follow-up From the 12 Month Assessment Report ......................................................73  Table 31  Reports in the Current Reporting Period: 29 October 2012 to 28 October 2013 .........74  Table 32:  Site of Call and Site of Exposure, Human Exposure Cases Associated with TIRF Medicines: 29 October 2012 to 28 October 2013 .........................................................86  Table 33:  Age and Gender Distribution of Human Exposures Associated with TIRF Medicines: 29 October 2012 to 28 October 2013 .........................................................86  Table 34:  Number of Substances Involved in Human Exposure Cases Associated with TIRF Medicines or a Fentanyl with Oral or Inhalation as Route of Exposure: 29 October 2012 to 28 October 2013 ...............................................................................................88  FDA_681 24-month REMS Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies. Page 6 of 131 Table 35:  Reason for Human Exposure Cases Associated with TIRF Medicines: 29 October 2012 to 28 October 2013 ...............................................................................................88  Table 36:  Distribution of Therapeutic Errorsa by Age Associated with TIRF Medicines: 29 October 2012 to 28 October 2013 .................................................................................90  Table 37:  Distribution of Reason for Exposure by Age Associated with TIRF Medicines: 29 October 2012 to 28 October 2013 .................................................................................91  Table 38:  Route of Exposure for Human Exposure Cases: 29 October 2012 to 28 October 2013 ...............................................................................................................................91  Table 39:  Medical Outcome of Human Exposure Cases by Patient Age: 29 October 2012 to 28 October 2013 ............................................................................................................93  Table 40:  Medical Outcome by Reason for Exposure in Human Exposures: 29 October 2012 to 28 October 2013 ........................................................................................................94  FDA_682 24-month REMS Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies. Page 7 of 131 LIST OF FIGURES Figure 1:  PPAF Receipt by Time Since Patient Enrollment (29OCT2012 to 28OCT2013) ....... 57  Figure 2:  Number of Patients Dispensed a Prescription During the First 10 Days After Patient Enrollment (29OCT2012 to 28OCT2013). .................................................................. 61    FDA_683 24-month REMS Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies. Page 8 of 131 LIST OF ABBREVIATIONS AAPCC AERS American Association of Poison Control Centers Adverse Event Reporting System ANDA Abbreviated New Drug Application BTP CSR DEA ETASU FAERS FDA KAB MedDRA Breakthrough Pain Call Center Service Representative Drug Enforcement Administration Elements to Assure Safe Use FDA Adverse Event Reporting System Food and Drug Administration Knowledge, Attitude, and Behavior Medical Dictionary for Drug Regulatory Activities NC Non-Compliant NCPDP NDA NDC NPI NCRT PMS PPAF PT REMS REMS edits SMQ SOP TIRF National Council for Prescription Drug Program New Drug Application National Drug Code National Provider Identifier Non-Compliance Review Team Pharmacy Management System Patient-Prescriber Agreement Form Preferred Terms Risk Evaluation and Mitigation Strategy Checks conducted by the TIRF REMS Access program to confirm that all safety requirements were met Standardized MedDRA Query Standard Operating Procedure Transmucosal Immediate-Release Fentanyl TIRF Medicines Transmucosal Immediate-Release Fentanyl product(s) TIRF REMS Access REMS program for TIRF medicines TIRF Sponsors The group of sponsors that are submitting this REMS TRIG TIRF REMS Industry Group UBC United BioSource Corporation US United States FDA_684 24-month REMS Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies. Page 9 of 131 EXECUTIVE SUMMARY The Transmucosal Immediate-Release Fentanyl (TIRF) Risk Evaluation and Mitigation Strategy (REMS) Access Program was approved by the Food and Drug Administration (FDA) on 28 December 2011 for ABSTRAL®, ACTIQ®, FENTORA®, LAZANDA®, ONSOLIS® and generic versions of these TIRF medicines. On 04 January 2012, the FDA approved the inclusion of SUBSYS® to the TIRF REMS Access Program. The TIRF REMS Access Program was successfully launched on 12 March 2012, approximately 11 weeks after REMS approval. The initial REMS Assessment report was submitted on 28 June 2012 (cut-off date of 27 April 2012). The second REMS Assessment Report covered the period from 27 April 2012 to 28 October 2012. This third REMS Assessment Report (24 months) covers the period from 29 October 2012 to 28 October 2013. Prescribers Prescriber enrollment in the TIRF REMS Access Program during the current reporting period totaled 2,001 newly enrolled prescribers and 938 re-enrollments. A total of 1,259 prescribers were inactivated in this reporting period, with 99.8% due to expiration of their enrollment period and 0.2% because the prescribers were deceased. As part of the REMS requirements, prescribers must re-enroll every 2 years. During the reporting period, a total of 325 incomplete Prescriber Enrollment Forms were received. The majority of incomplete forms were due to missing physician signature and date (86.8%). Pharmacies During the current reporting period, 22,762 pharmacies including 22,744 non-closed system pharmacies and 18 closed system pharmacy locations enrolled in the TIRF REMS Access Program. Of the non-closed system pharmacy enrollments, 1,944 were new enrollments and 20,800 were re-enrollments. For closed system pharmacies, all were newly enrolled. As part of the REMS requirements, pharmacies must re-enroll every 2 years. A total of 184 incomplete Pharmacy Enrollment Forms were received. Forms were received both via fax and via Web. The most frequently reported reasons for incomplete faxed enrollment forms were Knowledge Assessment Failure (n=16, 8.7%), invalid National Counsel for Prescription Drug Programs (NCPDP) number (n=6, 3.3%), pending test transaction verification (n=6, 3.3%). Other reasons for incomplete enrollment forms include invalid Drug Enforcement Agency (DEA) number (n=5, 2.7%), invalid National Provider Identifier (NPI) number (n=5, 2.7%). It should be noted that each form may have multiple reasons and could have been submitted multiple times. A total of 2,493 non-closed system pharmacies were inactivated due to expiration of their enrollment period in the TIRF REMS Access Program, representing 21 inpatient pharmacies, (0.8%), 2,470 outpatient pharmacies (99.1%), and 2 chain pharmacies (0.1%). There were 675 outpatient pharmacies that attempted to configure a pharmacy management system (PMS) to electronically submit prescriptions to REMS edits. Of these, 645 (95.6%) successfully configured their systems in this reporting period; the mean number of days to FDA_685 24-month REMS Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies. Page 10 of 131 successfully configure their systems was 0.61 days (min/max; 0.0001 days/203.85 days). The 203.85 day outlier for the PMS configuration was an independent outpatient pharmacy that submitted their first PMS test transaction on 18 December 2012 and completed the last PMS test transaction on 10 July 2013 due to the pharmacy’s decision to delay enrollment in the TIRF REMS Access Program. Wholesalers/Distributors In addition, 13 wholesaler/distributors enrolled during the current reporting period including 9 wholesaler/distributors that re-enrolled. There were 4 wholesalers/distributors inactivated during the reporting period due to expiration of enrollment but 2 had re-enrolled by the end of the reporting period. Patients During the current reporting period, 7,767 patients were enrolled in the TIRF REMS Access Program. Because patients are passively enrolled with their first prescription, they are not required to re-enroll at any point. Instead, prescribers must renew a patient PPAF every 2 years. No patients were inactivated from the TIRF REMS Access Program during this reporting period. A total of 111,104 prescriptions were adjudicated for safety by the TIRF REMS Access Program in the current reporting period including 110,170 prescriptions from non-closed system pharmacies and 934 from closed system pharmacies. Of the total prescriptions, 94.0% were subsequently approved for dispensing (meaning authorized for dispensing by insurance or cash bin). There were 1,140 patients who received prescriptions for a TIRF medicine from 3 or more prescribers in a rolling 6-month period. Patients may have multiple prescribers for various reasons such as patient relocation, prescriber relocation/retirement/death, or patient is seen at a single practice with multiple prescribers. A total of 8,256 prescriptions were dispensed to 7,064 patients during the first 10 days after patient enrollment (i.e., enrollment occurred when first prescription was filled). There were a greater number of patients who had their initial prescription filled in the first 10 days without a Patient-Prescriber Agreement Form (PPAF) compared with those patients with a PPAF (77.2% vs. 20.0%). For patients without a PPAF, the majority of patients (77%) received only 1 fill. A total of 15,536 prescription claims were rejected due to failure to meet REMS requirements for the prescriber and/or patient and/or pharmacy. A single prescription may have been submitted and rejected multiple times. The majority of rejection reasons were due to the prescriber not enrolled or the prescriber ID not being found in the TIRF REMS Access database (43.6%), patient zip code missing from claim (18.8%), PPAF incomplete (15.2%), prescriber last name did not match name registered (14.5%), and pharmacy not enrolled (7.8%). Definitions are provided in Section 5.2.4. The TIRF REMS Access Program Call Center was contacted most frequently for the following reasons: inquiring about a pharmacy claim rejection (15.99%), enrollment status inquiry (14.19%), PPAF status inquiry (12.75%), and general program questions (8.01%). During the current reporting period, the TIRF REMS Access Program received 1 report of difficulty accessing an enrolled prescriber. This situation occurred as a result of an enrolled FDA_686 24-month REMS Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies. Page 11 of 131 prescriber assisting a patient who was relocating and needed to identify an enrolled prescriber in his/her new location. FDA Adverse Event Reporting System Since the last TIRF REMS Assessment Report, 16 FDA Adverse Event Reporting System (FAERS) case reports in the United States (US) were associated with a TIRF medicine exposure. Eight (8) of the cases included one of the individual Preferred Terms (PT) of Interest for the TIRF REMS or at least one PT from the Medical Dictionary for Drug Regulatory Activities (MedDRA) standardized MedDRA Query (SMQ), Acute Central Respiratory Depression. American Association of Poison Control Centers There were 17 cases of exposure to known oral fentanyl immediate-release medicines reported to the American Association of Poison Control Centers (AAPCC) during the current reporting period. Two deaths were reported for exposures to TIRF medicines. There was 1 pediatric/adolescent exposure (age 16) reported for TIRF medicines with a medical outcome of minor effect. Twenty cases of exposure to unknown fentanyl were reported to the AAPCC during the current reporting period. The cases had medical outcomes of 2 deaths (indirect reports), 3 major effects, 8 moderate effects, 3 minor effects, 3 unable to follow/judged as potentially toxic exposure, and 1 no effect. Both cases with the outcome of death were classified as intentional abuse. There were 4 reports characterized as intentional suspected suicide, all of these patients survived. No pediatric exposures in children under 16 years of age were reported. In compliance with the FDA’s request in January 2013, the TIRF Sponsors will provide the AAPCC fatality abstracts for the 7 deaths reported in the 12-Month Assessment Report as soon as they are available. AAPCC fatality abstracts are generally available in the 3rd or 4th quarter following the year of interest. The TIRF Sponsors will share these fatality abstracts with FDA via email at the earliest date possible. The TIRF Sponsors will share information on the deaths reported in this assessment report when they become available in 2014. Knowledge, Attitudes, and Behavior (KAB) Surveys During the 12-month reporting period TRIG determined that a correct response rate of 65% or greater would be considered to represent adequate understanding of each concept or key risk message. The same criterion was applied to the 24-month KAB surveys. The purpose of establishing this threshold was to assist TRIG in tracking and monitoring the level of understanding of key risk messages across each wave to determine if the goals of the REMS are being met and if any modification to the REMS is required. In the 24-month patient survey, 2 concepts had correct response rates of less than 65% which include the need to stop taking TIRF medicines if around-the-clock opioid medications are stopped and the approved indication for TIRF medicines for patients. The first concept of stopping a TIRF medicine if an around the clock opioid is discontinued was also a low scoring item in the prescriber survey. The TRIG is exploring options to increase awareness of this important safety message. FDA_687 24-month REMS Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies. Page 12 of 131 Overall, given the results of the remaining items/questions throughout the 6 key risk messages this survey indicates that patients are knowledgeable about the safe use and storage of TIRF medicines. The higher level of understanding in patients who read most or all of the Medication Guide demonstrates effective communication of the key risk messages, which may also be reinforced by prescribers and pharmacists. The consistent high level of patient understanding of key risk messages between the 12-month and 24-month surveys indicates that the REMS goals are being met with the tools currently in place. As demonstrated in appended KAB report there were no important differences in the correct response rates for most the key risk messages between the 12-month and 24-month assessments. In the 24-month pharmacist survey, only one item was identified as having a low level of understanding among pharmacists (TIRF medicines are not indicated for chronic non-cancer pain; 47.0% responded correctly). However, it should be noted that there was a marked improvement in the Pharmacist’s correct response rate for this concept from the 12-month KAB survey to the 24-month KAB survey. It should also be noted that recognition of uses for which TIRF medicines are not indicated is not a goal of the TIRF REMS for pharmacists. The overall high level of understanding of all other items that comprise the 4 key risk messages indicates that the current education program for pharmacists is meeting the REMS goals. The vast improvement in the correct response rate between the 12-month assessment and 24-month assessment provides further evidence that the educational program has been effective at significantly increasing pharmacists’ knowledge regarding safe use of TIRF medicines. Thus, no changes to the pharmacist education program are required at this time. In the 24-month prescriber survey, there were no significant differences in correct response rates for most questions in each of the key risk messages between the 12-month and 24-month assessments. The 2 questions that elicited higher rates of correct responses in the 24-month survey were added as key risk message questions for the 24-month survey. These Questions (found in appended KAB report) are related to the concept of opioid-tolerant patients. The concept that a patient must discontinue a TIRF medicine when they stop taking their aroundthe-clock opioid, while not a key risk message for the prescribers, received a low correct response rate. Prescribers are educated on this concept in the Education Program and in the PPAF. Prescribers low understanding of this concept is likely to have affected the level of understanding of respondents in the patient survey. The overall higher level of understanding of the remaining items/questions throughout the 4 key risk messages indicates that prescribers are knowledgeable about the safe of TIRF medicines. The consistent high level of prescribers’ understanding of key risk messages between the 12month and 24-month surveys indicates that the Prescriber Education Program is meeting the goals of the TIRF REMS Access Program with the tools currently in place. FDA_688 24-month REMS Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies. 1 Page 13 of 131 BACKGROUND Opioids remain the mainstay of treatment of moderate to severe pain, but their safe use requires careful consideration of proper patient selection and treatment characteristics in order to mitigate any inherent health risks. Opioids are formulated as both extended release and immediate-release products. Extendedrelease or long acting opioid products are designed to provide extended analgesic activity to control persistent pain. Transmucosal immediate-release fentanyl products (“TIRF medicines”) and short-acting opioid products have a rapid onset and short duration of action and are designed for the treatment of acute episodes of pain that ‘break through’ the chronic pain control (breakthrough pain, BTP). All the TIRF medicines are short-acting fentanyl products. As with all high-potency opioid analgesics, there are significant potential risks associated with the use and misuse of TIRF medicines, including acute respiratory depression which may lead to death. With appropriate clinical use in opioid-tolerant patients these risks have been shown to be low. However, instances of diversion, overdose and prescribing to opioid-non-tolerant patients have led to serious and on occasion fatal, adverse events demonstrating that short-acting fentanyl products can pose a health risk if not used appropriately. The FDA has determined that a REMS is required to mitigate the risk of misuse, abuse, addiction, overdose, and serious complications due to medication errors with the use of TIRF medicines. The TIRF REMS Access Program was approved by the FDA on 28 December 2011. The group of Sponsors that are submitting this REMS includes (Cephalon, Inc. [a wholly-owned subsidiary of Teva Pharmaceutical Industries, Ltd.], Depomed, Inc., Galena Biopharma, Inc., Insys Therapeutics Inc., Mallinckrodt Pharmaceuticals, Meda Pharmaceuticals, Mylan, Inc. and Par Pharmaceutical, Inc.) are hereafter referred to as the TIRF Sponsors. During this reporting period, Depomed, Inc. acquired the New Drug Application (NDA) for LAZANDA from Archimedes Pharma US, Inc., who is no longer a TIRF Sponsor. In addition, Galena Biopharma, Inc., acquired the NDA for ABSTRAL from Prostrakan Inc. and is now a TIRF Sponsor (as of 01 May 2013) whereas ProStrakan subsequently exited the group. Additionally, Mylan became a TIRF Sponsor on 29 May 2013 due to a pending Abbreviated New Drug Application (ANDA). The TIRF REMS Access Program is administered by McKesson Specialty Health and RelayHealth. This report is prepared by United BioSource Corporation (UBC). FDA_689 24-month REMS Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies. Page 14 of 131 The TIRF medicines that are the subject of this TIRF REMS are shown in Table 1 below. Table 1: TIRF Medicines Product Name (active ingredient)/formulation NDA 022510, ABSTRAL (fentanyl) sublingual tablets NDA 020747, ACTIQ (fentanyl citrate) oral transmucosal lozenge and its authorized generic NDA 021947, FENTORA (fentanyl buccal tablet) NDA 022569, LAZANDA (fentanyl) nasal spray NDA 022266, ONSOLIS (fentanyl), buccal soluble film NDA 202788, SUBSYS (fentanyl sublingual spray) ANDA 077312, fentanyl citrate oral transmucosal lozenge ANDA 078907, fentanyl citrate oral transmucosal lozenge The TIRF REMS Access Program addresses the current requirements set forth by the FDA and provided to TIRF Sponsors. The program will be monitored over time and modified when and where appropriate. The initial REMS was approved on 28 December 2011 and went live on 12 March 2012. The FDA required an initial report 6 months after REMS approval; therefore, the first report was submitted on 28 June 2012 with a cut-off date of 27 April 2012. The 12-month report was submitted on 28 December 2012 with a cut-off date of 28 October 2012. For this reporting period the cut-off date was 28 October 2013 thereby allowing 60 days to prepare this report for the FDA, which is due on 28 December 2013. 2 REMS GOALS The goals of the TIRF REMS Access Program are to mitigate the risks of misuse, abuse, addiction, overdose and serious complications due to medication errors by: 1. Prescribing and dispensing TIRF medicines only to appropriate patients, which includes use only in opioid-tolerant patients. 2. Preventing inappropriate conversion between TIRF medicines. 3. Preventing accidental exposure to children and others for whom it was not prescribed. 4. Educating prescribers, pharmacists, and patients on the potential for misuse, abuse, addiction, and overdose of TIRF medicines. FDA_690 24-month REMS Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies. 3 Page 15 of 131 SUPPORTING INFORMATION ON PROPOSED REMS ELEMENTS The TIRF Sponsors are executing the TIRF REMS Access Program to ensure the appropriate use of TIRF medicines and proper patient selection. All stakeholders subject to the TIRF REMS Access Program including patients, prescribers, pharmacies and distributors must be enrolled in the TIRF REMS Access Program, educated on the requirements of the program and required to document that they understand and will abide by the “elements to assure safe use.” Program materials are provided on the TIRF medicines in addition to product-specific materials. The Education Program and Knowledge Assessment components of the program contain both TIRF medicine class and product-specific components. All program tools, including enrollment forms, PPAFs, stakeholder letters, and overview documents containing program information specific to the TIRF REMS Access Program, are available through www.TIRFREMSACCESS.com. The program procedures are monitored for adherence and the TIRF Sponsors will continue to conduct ongoing and retrospective analyses as necessary to comply with all mandates and to maximize the safe use of the TIRF medicines. 3.1 Additional Elements 3.1.1 Medication Guide The product-specific TIRF Medication Guide should be dispensed with each TIRF medicine prescription. Every TIRF medicine has a unique Medication Guide. 3.1.2 Letters to Healthcare Professionals A Communication Plan for the TIRF REMS was not required. However, TIRF Sponsors sent materials to targeted stakeholders to support implementation of the TIRF REMS Access Program at the time of program launch. These communications included Dear Healthcare Provider and Dear Pharmacy letters, and informed prescribers and authorized pharmacists on the risks associated with the use of TIRF medicines, the procedures and requirements of the TIRF REMS Access Program and means of reporting adverse events. In this reporting period, there were no mailings of either the Dear Healthcare Provider or Dear Pharmacy letters. 3.2 Elements to Assure Safe Use (ETASU) Because of the significant potential health risks associated with prescribing TIRF medicines to opioid non-tolerant patients, it is important that prescribers are aware of the procedures for appropriate patient selection and appropriate dosing and titration. This is achieved by each prescriber’s enrollment through a review of the TIRF REMS Access Education Program including the TIRF medicine’s Full Prescribing Information, successful completion of the Knowledge Assessment, and completion of the enrollment form. TIRF medicines are only available through the TIRF REMS Access Program to reduce the risks of inappropriate patient selection and ensure appropriate dosing and administration of TIRF medicines. To ensure that TIRF medicines are only dispensed to appropriate patients, pharmacies that dispense TIRF medicines must be enrolled into the TIRF REMS Access Program. There are FDA_691 24-month REMS Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies. Page 16 of 131 different enrollment requirements for outpatient pharmacies (e.g., retail, mail order, institutional outpatient pharmacies that dispense for outpatient use) and inpatient pharmacies (e.g., hospitals that dispense for inpatient use only). For Long-Term Care and Hospice patients whose prescriptions were obtained through an outpatient pharmacy setting, the pharmacy, patient, and prescriber must be enrolled in the TIRF REMS Access Program. Implementation of the TIRF REMS Access Program for closed system pharmacies was launched on 30 June 2012. Closed system pharmacies are integrated healthcare systems that dispense for outpatient use but their pharmacy management systems are unable to support the process of electronically transmitting the validation and claim information. Outpatient pharmacy enrollment requires an authorized pharmacist at the pharmacy to review of the TIRF REMS Access Education Program, successfully complete the Knowledge Assessment and submit a completed and signed TIRF REMS Access Program enrollment form. The authorized pharmacist ensures that their PMS is able to support communication with the TIRF REMS Access Program using established telecommunication standards. This requires submitting standardized validation test transactions to validate the system enhancements. The authorized pharmacist is also responsible for educating all pharmacy staff who participate in dispensing TIRF medicines on the risks associated with TIRF medicines and the requirements of the TIRF REMS Access Program. This training is documented by the pharmacy. For inpatient pharmacy enrollment, the authorized pharmacist is required to review the TIRF REMS Access Education Program, successfully complete the Knowledge Assessment, and submit a completed and signed enrollment form on behalf of the pharmacy. The authorized inpatient pharmacist is required to acknowledge that they understand that outpatient pharmacies within their facility must be enrolled separately. For chain pharmacies, an authorized chain pharmacy representative completes the enrollment process on behalf of all individual store locations associated with that chain. The authorized chain pharmacy representative acknowledges that training has been provided to all pharmacy staff involved in the dispensing of TIRF medicines. Once the TIRF REMS Access Education Program and Knowledge Assessment have been completed, the authorized chain pharmacy representative, on behalf of the chain, is required to acknowledge their understanding of the appropriate use of TIRF medicines and agree to adhere to the TIRF REMS Access Program requirements by submitting a completed and signed enrollment form. The reasons and description for stakeholder incomplete enrollments are described in Section 5.2.2 and Section 5.2.3. Patients are passively enrolled in the TIRF REMS Access Program when their first prescription is processed by a pharmacy. A completed PPAF should be sent to the TIRF REMS Access Program by the prescriber within 10 working days from the processing date of the patient’s first prescription for a TIRF medicine. A maximum of 3 prescriptions are allowed within 10 working days from the date that the patient had their first prescription filled. No further prescriptions are to be dispensed after the 10 working day window until a completed PPAF is received. A patient’s healthcare provider can submit a copy of the PPAF to the TIRF REMS Access Program via the Web site, fax, or US mail. FDA_692 24-month REMS Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies. 3.2.1 Page 17 of 131 Prescription Verification Following initial patient enrollment upon processing of a patient’s first TIRF medicine prescription, pharmacies verify for all subsequent prescriptions that both the prescriber and patient are enrolled in the TIRF REMS Access Program and that all REMS requirements are met prior to dispensing. Prescription verification is not required for inpatient use of TIRF medicines. Specific reasons why a prescription would not meet a REMS edit are described in Section 5.2.4. Non-Closed System Pharmacies Prescription verification occurs through a model that uses a pharmacy billing claim and engages a switch provider in the validation process. Upon receipt of a prescription for a TIRF medicine at an enrolled pharmacy, the prescription details are entered into their PMS and a transaction is sent to the TIRF REMS Access Program via a switch provider. If the patient is not enrolled and this is their first prescription, the TIRF REMS Access Program uses this transaction data to automatically transfer patient details into the TIRF REMS Access database for passive enrollment. For all prescriptions, the REMS database is then interrogated, via the switch provider, to validate the REMS edits (i.e., confirm that all TIRF REMS Access Program requirements are met). In the case where a prescription passes all REMS edits, a billing request is then sent to the payer by the switch provider. Once the payer authorizes payment, the switch provider then authorizes the pharmacy to dispense the TIRF medicine as with a normal prescription, returning an authorization number which is captured by the TIRF REMS Access Program. If the prescription does not pass all REMS edits (e.g., one of the stakeholders was not enrolled), the TIRF REMS Access Program rejects the claim prior to the claim being forwarded to the payer and the pharmacy receives a rejection notice from the switch provider. This automated feedback indicates the reason for rejection, instructs the pharmacist not to dispense the TIRF medicine, and notifies the pharmacist to contact the TIRF REMS Access Program Call Center for further information. Closed System Outpatient Pharmacies Upon receipt of a prescription for a TIRF medicine at an enrolled closed system outpatient pharmacy, a pharmacy staff member will contact the TIRF REMS Access Program via phone or fax to provide prescription details for verification. The TIRF REMS Access Program then validates the enrollment status for the patient, prescriber and pharmacy. If the patient is not enrolled, the TIRF REMS Access Program will use this transaction information to automatically transfer patient details into the TIRF REMS Access database for passive enrollment. If all three stakeholders are enrolled (i.e. passes all REMS edits), the closed system outpatient pharmacy is given an authorization number which is captured by the TIRF REMS Access Program. If the prescription does not pass all REMS edits (e.g., one of the stakeholders is not enrolled), the TIRF REMS Access Program will not provide an authorization number and the closed system outpatient pharmacy will receive a rejection notice. This feedback will be provided to the closed system outpatient pharmacy via phone or fax and will include the reason for rejection, FDA_693 24-month REMS Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies. Page 18 of 131 information on how the rejection may be resolved and instructions to not dispense the TIRF prescription until resolution is reached. 3.3 Implementation System The Implementation System and its components are described in the following sections. 3.3.1 Wholesaler/Distribution Enrollment and Fulfillment Wholesalers/distributors who distribute TIRF medicines must be enrolled in the TIRF REMS Access Program before they are allowed to distribute TIRF medicines. For the purpose of the TIRF REMS Access Program, the term distributor refers to wholesaler, distributor, and/or chain pharmacy distributor. TIRF medicine distributors received a Dear Distributor Letter describing the TIRF REMS Access Program and the requirements to purchase TIRF medicines from TIRF Sponsors and sell TIRF medicines to pharmacies upon FDA approval of the program. To enroll, the distributor’s authorized representative must review the distributor program materials, complete and sign the Distributor Enrollment Form and fax it to the TIRF REMS Access Program. TIRF Sponsors have processes in place to prevent shipping TIRF medicines to any distributor who has not completed and signed the enrollment form. 3.3.2 The TIRF REMS Access Program Compliance The TIRF REMS Access Program Non-Compliance Review Team (NCRT) was created by the TRIG on 19 October 2012 and is tasked with reviewing reports of suspected non-compliance with the TIRF REMS Access Program requirements. The NCRT is composed of membership from all TRIG sponsors. There are currently 23 individuals across the 8 sponsors; the functional areas or specialties represented by the members include Regulatory, Medical Affairs, REMS Specialist, Legal, Quality and Drug Safety. TIRF Sponsors monitor prescriber, inpatient and outpatient pharmacy, and wholesaler/distributor activities for compliance with TIRF REMS Access Program requirements. Corrective actions (e.g., re-education, additional monitoring, process revision, stakeholder inactivation) are instituted by the TIRF Sponsors as appropriate if non-compliance is confirmed. The Non-Compliance Plan is described in Section 4.2 and results of noncompliance investigations are included in Section 6 of this report. 3.3.3 TIRF REMS Access Program Call Center The TIRF REMS Access Program includes a Call Center component. The Call Center is staffed by qualified and trained specialists, who provide TIRF REMS Access Program support to patients, prescribers, pharmacies, and distributors. 4 REMS ASSESSMENT PLAN METHODS The aim of the TIRF REMS Access Program’s evaluation is to assess the effectiveness of the mitigation strategies in meeting the goals of the TIRF REMS Access Program to ensure safe use, FDA_694 24-month REMS Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies. Page 19 of 131 proper prescribing, and appropriate distribution of TIRF medicines. Findings from these evaluations are used to identify ways to improve the processes, as needed. Based on communications between TRIG and the FDA, new metrics were proposed by the FDA on 19 September 2013. Some of the metrics require further evaluation and clarification with the FDA prior to implementation. Those metrics that had been provided to the FDA in the 10 October 2013 communication from the TRIG are included in this report. Many of these metrics were the same as those provided in the 12-month report, but were stratified by closed system and non-closed system pharmacy. One metric is indicated as new. The metrics cross referenced to the FDA’s 9/19/2013 list are shown in Tables 2 through 6. 4.1 Data Sources Data were collected from the following main sources as described in detail below: a) the TIRF REMS Access Program outreach (Section 4.1.1), b) TIRF REMS Access product and program utilization statistics (Section 4.1.2), c) program infrastructure and performance (Section 4.1.3), and d) safety surveillance (Section 4.1.4). All programmed source tables and histograms, as well as source data are on file at UBC and available upon request. The individual metrics for each main data source are provided below with a direct link to the results sections of the report. 4.1.1 TIRF REMS Access Program Outreach The following metrics were tabulated for this reporting period to assess program outreach efforts (Section 5.1.1): Table 2: TIRF REMS Access Program Outreach Metrics Metric Number Indicated in FDA Assessment Plan 9/19/2013 1.a Number of Dear HCP letters mailed to prescribers (by date) 2. 1.b. Number of returned mailings of Dear HCP letters to prescribers. 3. 1.c. Number of Pharmacist letters mailed to pharmacies (by date) 4. 1.d. Number of returned mailings of Pharmacist letters to pharmacies Metric Number Indicated in RSD 1. 4.1.2 Metric The TIRF REMS Access Program and Product Utilization Statistics For the assessment of enrollment, utilization, and discontinuation statistics for prescribers, pharmacies, patients, and wholesalers, the following metrics were tabulated for this reporting period and cumulatively: FDA_695 24-month REMS Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies. Table 3: Page 20 of 131 Currently Approved Metrics and New Metrics – Utilization Statistics Metric Number Indicated in RSD 5. Metric Number Indicated in FDA Assessment Plan 9/19/2013 n/a 6. n/a 7. n/a 8. n/a 9. n/a 10. 2.c.i 11. 2.c.iii 12. n/a 13. 2.e 14. n/a 15. 2.d.ii 16. 2.d.i 17. n/a 18. 2f 2.g. Metric Number of new patients enrolled by state (Section 5.2.1) Number of patients inactivated (Section 5.2.1) Number of attempts needed for prescribers to successfully complete Knowledge Assessments (Section 5.2.2) • Method of completion Number of new prescribers enrolled by state (Section 5.2.2) • Method of enrollment • Number of incomplete forms and, to extent possible, a brief description of the reason for incomplete data fields Number of prescribers who are inactivated (Section 5.2.2) Number of new pharmacies enrolled by type, by state (Section 5.2.3) • Method of enrollment • Number of incomplete forms and, to extent possible, a brief description of the reason for incomplete data fields Number of pharmacies that are inactivated by type (Section 5.2.3) Number of attempts needed for pharmacies to successfully complete Knowledge Assessments (Section 5.2.3) Dispensing activity for enrolled outpatient pharmacies (Section 5.2.4) • Total number of prescriptions authorized • Total number of prescriptions rejected for safety (description of safety issues and any interventions or corrective actions taken) Summary of cases identified where a patient received prescriptions for a TIRF medicine from multiple prescribers within an overlapping time frame (description of any investigations and the outcome) (Section 5.2.4) Number of wholesalers/distributors inactivated, total (Section 5.2.5) Number of new wholesalers/distributors enrolled (Section 5.2.5) • Method of enrollment • Number of incomplete forms, to extent possible, a brief description of the reason for incomplete data fields Number of days between enrollment and receipt of a PPAF (Section 5.2.6) • Method of PPAF submission Number of prescriptions dispensed per patient during the first 10 days after patient enrollment with and without a PPAF in place stratified by open and closed system pharmacies. (Section 5.2.6) • A histogram of the number of days between passive enrollment and receipt of a PPAF. Stratify by the method of PPAF submission FDA_696 24-month REMS Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies. Table 3: Page 21 of 131 Currently Approved Metrics and New Metrics – Utilization Statistics Metric Number Indicated in RSD Metric Number Indicated in FDA Assessment Plan 9/19/2013 Metric • A histogram of the number of prescriptions dispensed per patient during the first 10 days after patient passive enrollment stratified by whether there is a PPAF in place. • (new) The number of prescriptions dispensed after 10 days without a PPAF in place stratified by open and closed system pharmacies n/a indicates metric is not included in the 9/19/2013 FDA Assessment Plan. 4.1.3 Program Infrastructure and Performance The following metrics on program infrastructure performance were tabulated for this reporting period and cumulatively: Table 4: Currently Approved Metrics and New Metrics-Program Infrastructure and Performance Metric Number Indicated in RSD 19. Metric Number Indicated in FDA Assessment Plan 9/19/2013 Metric n/a Assessment of process for pharmacies to upgrade their PMS (mean, maximum, and minimum time needed, number of pharmacies that attempted and failed to upgrade their systems) (Section 5.3.1) 20. 3.a. Number of times a backup system was used to validate a prescription, with reason for each instance (pharmacy level problem, switch problem, or REMS database problem) (Section 5.3.2) 21. 3.c.ii. Call center report (Section 5.3.3) 3.c.iii. • Summary of frequently asked questions • Problems reported 22. 3.d. Description of corrective actions taken to address program/system problems (Section 5.4) 23. n/a Number of reports of lack of enrolled prescribers and/or pharmacies in a patient’s area (Section 5.4.1) 24. n/a Delays after original prescriptions are denied by pharmacy and brief summary to include characterization of delays (Section 5.4.2) n/a indicates metric is not included in the 19 September 2013 FDA Assessment Plan. The following reports for unintended system interruptions were provided for this reporting period: FDA_697 24-month REMS Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies. Table 5: Page 22 of 131 New Metrics Metric Number Indicated in RSD Metric Number Indicated in FDA Assessment Plan 9/19/2013 25. n/a 26. n/a Metric Reports identified of inadvertent enrollment deactivations (Section 5.5.1) Reports of false positives (e.g., all entities not enrolled but system generated a prescription authorization code) (Section 5.5.2) 27. n/a Reports of failure of re-enrollment notifications to reach stakeholders (Section 5.5.3) 28. n/a Reports of false negatives (e.g., all entities enrolled but the system generated a prescription rejection notice), including brief summary of reason for rejection (Section 5.5.4) n/a indicates metric is not included in the 9/19/2013 FDA Assessment Plan. Table 6: Additional Metrics Requested by the FDA Metric Number Indicated in RSD Metric Number Indicated in FDA Assessment Plan 9/19/2013 Metric n/a 3.e.i. The number of duplicate prescribers, patients, and pharmacies identified in the system. n/a 3.e.ii Why the duplications were not originally detected. n/a 3.e.iii. The corrective actions taken to assure minimization of future duplicative data entries 4.1.4 Safety Surveillance TIRF Sponsors processed adverse event reports related to their specific products and reported to the FDA according to current regulations outlined in 21 CFR 314.80 and the respective sponsors’ Standard Operating Procedures (SOPs). Surveillance data from the following sources are included in the REMS Assessment Report: o FDA Adverse Event Reporting System (FAERS) database using signal detection methods for TIRF medicines to identify outcomes of death, overdose, misuse, abuse, addiction, inappropriate prescribing, medication errors, and accidental exposures/ingestion. See Appendix 12.1 for list of MedDRA Preferred Terms used. o AAPCC (Appendix 12.2) data for TIRF medicines and unknown fentanyl products with inhalation or ingestion as routes of exposure. FDA_698 24-month REMS Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies. 4.2 Page 23 of 131 TIRF REMS Access Program Non-Compliance Plan The TIRF REMS Access Program is in place to ensure the safe and appropriate use of TIRF medications. The goal of the Non-Compliance Plan is to help TRIG identify and investigate deviations from and non-compliance with TIRF REMS requirements in order to ensure patient safety and continuously improve the program. A confirmed non-compliant (NC) event is when the information collected through investigation of the potential NC event clearly indicates that a program deviation has occurred and/or evidence of the program goals not being met through stakeholder actions is identified. The TIRF REMS Access Program routinely monitors stakeholder activity to identify potential incidents of non-compliance with program requirements. The TIRF REMS Access Program investigates all reports of suspected non-compliance. Routine monitoring of stakeholder activity includes, but is not limited to, the types identified in Table 7. Non-compliance information is collected through standard program reports, spontaneous reports identified via the program’s call center, vendor/sponsor reported events, outreach to relevant stakeholders to validate data/information and solicit further information, investigation of the TIRF REMS Access database. The data are tracked through a NC case that is opened on the stakeholder record in the TIRF REMS Access database. Table 7 indicates each defined non-compliance activity and the method of monitoring. Table 7 Non-Compliance Activity Monitoring Stakeholder Pharmacy # 1 2 3 4 5 6 7 Wholesaler/ Distributor 1 2 Prescriber 1 Scenario Non-Compliance Activity Submission of a claim that did not go through the REMS edits. A TIRF medicine was dispensed without verifying through the TIRF pharmacy management system that the prescriber is enrolled and active, and that the patient is enrolled or has not been inactivated in the program. Dispensing activity for enrolled outpatient pharmacies during reporting period not matching distributor shipment data for that pharmacy. Pharmacy is dispensing TIRF medicine while suspended or deactivated from the TIRF REMS Access Program. [Placeholder for additional scenario if needed] Authorized Inpatient Pharmacy does not comply with the requirements of the TIRF REMS Access Program. Inpatient Pharmacy dispenses for outpatient use Submission of inappropriately altered claim to meet TIRF REMS system requirements (e.g. changing prescriber) Wholesaler/Distributor is suspended or deactivated from the TIRF REMS Access Program and is purchasing or distributing TIRF medicines. Wholesaler/Distributor fills an order for TIRF medicines for a non-enrolled stakeholder. Prescriber is prescribing TIRF medicines while suspended or deactivated from the TIRF REMS Access Program. FDA_699 24-month REMS Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies. Page 24 of 131 Table 7 Non-Compliance Activity Monitoring Stakeholder 2 Closed System Pharmacy Patient 1 All Stakeholders 1 1 Scenario Prescriber failure to submit completed PPAFs in a timely manner (5 or more enrolled patients without a complete PPAF on file, with each patient having greater than 10 working days lapse from initial enrollment date). Dispensing prescriptions outside of the closed system authorization process. The Patient receives prescriptions for TIRF medicines from multiple prescribers within an overlapping time frame that is suggestive of misuse, abuse, or addiction ENROLLMENT MONITORING ONLY: Monitor stakeholders who are not enrolled in TIRF and are associated with non-compliance cases. If a non-compliance event is confirmed, additional investigation is conducted to determine the scope, impact, and root cause of the event. Stakeholders are notified of the investigation via a formal letter from the TIRF REMS Access Program (see section 4.2.1 below) and may also be requested to develop a corrective action plan. All corrective action plans are reviewed and approved by the NCRT. The NCRT will determine if the Non-Compliance Protocol should be modified as the program evolves. Any changes to the plan proposed by the NCRT will be voted upon by the TRIG. 4.2.1 Corrective Action Measures Decisions are made through the NCRT based on the severity of the action as well as the information collected during the investigation. Stakeholders that fail to comply with one or more elements of the TIRF REMS Access Program will be subject to corrective action. Appropriate corrective actions are determined by the TIRF REMS Access Program according to the severity of the event as defined below: • • • Minor - An unintended (e.g., first-time) event. The corrective action typically involves a written notice to the stakeholder and re-education of the program requirements to prevent re-occurrences of the event. Moderate – Multiple occurrences of the same event or a series of distinct, unintended events. Serious - Continued events after retraining has occurred. This level of offense may result in a suspension from the program and possible deactivation. Affected stakeholders are provided written notification of all confirmed non-compliance events. Corrective actions for confirmed events may include a Notice, Warning, Suspension, or Deactivation letter (See Table 8). If deemed necessary, temporary suspension of a prescriber, pharmacist or distributor from the TIRF REMS Access Program may be warranted, prohibiting them from prescribing, dispensing or distributing TIRF medicines for a certain period of time. The most severe consequence of a non-compliance event is deactivation, resulting in the FDA_700 24-month REMS Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies. Page 25 of 131 stakeholder not being able to receive/prescribe/dispense/distribute TIRF medicines and is applicable to all stakeholders including patients. Formal notifications of non-compliance are sent by the TIRF REMS Access Program to the applicable prescriber and/or pharmacy whereas notices for patient non-compliance events are sent to their prescriber. Copies of notices sent to an individual chain pharmacy store are also sent to the chain pharmacy’s headquarters. Table 8: Event Classification Corrective Action Guideline Description • • Notices • • • Warnings • • • • Suspension • • • • Deactivation • • • Patient notices will be sent to a patient's prescriber Minor violations that demonstrate a misunderstanding of the program requirements Notices are intended to re-educate stakeholders 2 Notices in 60 days = Review by Non-Compliance Review Team to determine if escalation to Warning is warranted 2 Warnings in 60 days = Review by Non-Compliance Review Team to determine if escalation to Suspension is warranted >1 Warning in >60 days = Case-by-Case review for Suspension Temporary suspension from the program A suspended pharmacy or distributor may keep existing TIRF inventory but may not purchase or acquire additional TIRF medicines Pharmacies may not dispense TIRF medicines from existing inventory and distributors may not sell/distribute TIRF medicines during suspension If the pharmacy or distributor is part of a larger entity that entity will be notified of the suspension 1 Warning or 2 Notices in Suspension = Review by Non-Compliance Review Team to determine if escalation to Deactivation is warranted 2 Suspensions Within a 12-Month Period = Review by Non-Compliance Review Team to determine if a Deactivation is warranted Deactivation may result from multiple failures to comply with the program elements and/or a non-compliance event for which there is no feasible corrective action Bars stakeholder from providing TIRF medicines for their patients Pharmacies and distributors must return all existing TIRF medicine Patient deactivation will be sent to a patient's prescriber. Patients may only be reinstated into the program by a request from their prescriber FDA_701 24-month REMS Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies. 5 Page 26 of 131 RESULTS 5.1 TIRF REMS Access Program Outreach 5.1.1 Dear Healthcare Professional Letters [Metric 1-4] There were no mailings in this reporting period. 5.2 REMS Program Utilization Described in this section are the total numbers and geographic distribution of all enrolled stakeholders (prescribers, patients, distributors, outpatient independent and inpatient pharmacies, corporate chain pharmacy offices and chain pharmacy stores), as well as stakeholder inactivations, dispensing activities, and barriers or delays in patient access. 5.2.1 Patient Enrollment [Metric 5 and 6] During the current reporting period, there were 7,767 newly enrolled patients. Because patients are passively enrolled with their first prescription there is no patient re-enrollment, but prescribers are required to renew PPAFs with patients every 2 years. There were no patients inactivated during the reporting period. New enrollments represented 49 states (Vermont had no patients enrolled), the District of Columbia and the Virgin Islands (Table 9). The following states had the highest proportion of enrolled patients: California (10.8%), Michigan (7.3%), Florida (7.1%), Texas (6.1%), New Jersey (4.0%), New York (3.9%), Alabama (3.5%), and Pennsylvania (3.0%). For 25.8% of the newly enrolled patients, the territory/state was unknown due to the patient not providing consent for use of this data by the TIRF REMS Access Program or because the patient did not have a PPAF on file. For patients who complete more than one PPAF, the location is recorded from the first completed PPAF received. Table 9: Patient Enrollment and Geographic Distribution Parameter Number of Enrolled Patients State/Territory of Patient Primary Addressd Unknown Alabama Alaska Arizona Arkansas California Current Reporting Period 29OCT2012 to Cumulativea,b 28OCT2013 28DEC2011 to 28OCT2013 N (%) N (%) 7,767c 19,501 2,000 (25.8%) 268 (3.5%) 10 (0.1%) 111 (1.4%) 72 (0.9%) 835 (10.8%) 3,514 (18.0%) 555 (2.9%) 42 (0.2%) 296 (1.5%) 139 (0.7%) 2,391 (12.3%) FDA_702 24-month REMS Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies. Table 9: Page 27 of 131 Patient Enrollment and Geographic Distribution Parameter Colorado Connecticut Delaware Florida Georgia Hawaii Idaho Illinois Indiana Iowa Kansas Kentucky Louisiana Maine Maryland Massachusetts Michigan Minnesota Mississippi Missouri Montana Nebraska Nevada New Hampshire New Jersey New Mexico New York North Carolina North Dakota Ohio Oklahoma Oregon Pennsylvania Rhode Island South Carolina South Dakota Tennessee Current Reporting Period 29OCT2012 to Cumulativea,b 28OCT2013 28DEC2011 to 28OCT2013 N (%) N (%) 117 (1.5%) 395 (2.0%) 81 (1.0%) 235 (1.2%) 13 (0.2%) 66 (0.3%) 548 (7.1%) 1,495 (7.7%) 105 (1.4%) 376 (1.9%) 2 (<0.1%) 20 (0.1%) 22 (0.3%) 46 (0.2%) 61 (0.8%) 341 (1.8%) 71 (0.9%) 252 (1.3%) 3 (<0.1%) 34 (0.2%) 44 (0.6%) 139 (0.7%) 28 (0.4%) 104 (0.5%) 26 (0.3%) 76 (0.4%) 13 (0.2%) 25 (0.1%) 74 (1.0%) 303 (1.6%) 37 (0.5%) 136 (0.7%) 563 (7.3%) 931 (4.8%) 14 (0.2%) 50 (0.3%) 79 (1.0%) 150 (0.8%) 56 (0.7%) 184 (0.9%) 8 (0.1%) 24 (0.1%) 18 (0.2%) 51 (0.3%) 40 (0.5%) 124 (0.6%) 48 (0.6%) 74 (0.4%) 314 (4.0%) 970 (5.0%) 3 (<0.1%) 20 (0.1%) 299 (3.9%) 923 (4.7%) 107 (1.4%) 424 (2.2%) 1 (<0.1%) 13 (0.1%) 163 (2.1%) 445 (2.3%) 90 (1.2%) 245 (1.3%) 28 (0.4%) 115 (0.6%) 229 (3.0%) 633 (3.3%) 69 (0.9%) 109 (0.6%) 76 (1.0%) 185 (1.0%) 3 (<0.1%) 7 (<0.1%) 170 (2.2%) 395 (2.0%) FDA_703 24-month REMS Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies. Table 9: Page 28 of 131 Patient Enrollment and Geographic Distribution Current Reporting Period 29OCT2012 to Cumulativea,b 28OCT2013 28DEC2011 to 28OCT2013 Parameter N (%) N (%) Texas 472 (6.1%) 1,353 (6.9%) Utah 123 (1.6%) 317 (1.6%) Vermont 0 1 (<0.1%) Virginia 80 (1.0%) 266 (1.4%) Washington 135 (1.7%) 338 (1.7%) West Virginia 18 (0.2%) 51 (0.3%) Wisconsin 12 (0.2%) 81 (0.4%) Wyoming 4 (0.1%) 31 (0.2%) District of Columbia 3 (<0.1%) 8 (<0.1%) Puerto Rico 0 2 (<0.1%) Virgin Islands 1 (<0.1%) 1 (<0.1%) a Includes patients that transitioned into the TIRF REMS Access Program from other individual REMS programs. b Cumulative patients from the end of prior period may differ from last period's report due to reconciliation of duplicate patients. c Patients enrolled in this time period and were still enrolled at the end of the time period. d Patients are classified by state based on 5-digit zip code provided on PPAF. If the zip code is invalid, the patient’s self-reported state is used if available. Based upon FDA request, this report includes the proportion of each states’ population enrolled as a TIRF REMS patient, as calculated using the number of patients in that state divided by the total population of that state as per the latest US census data (Table 10). The highest proportion of patients enrolled according to state population were in the states of Alabama (0.0116%), Utah (0.0115%), New Jersey (0.0110%), Rhode Island (0.0104%), Michigan (0.0094%), Florida (0.0080%), Colorado (0.0079%), Delaware (0.0074%), Oklahoma (0.0065%), California (0.0064%), and Tennessee (0.0062%). FDA_704 24-month REMS Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies. Table 10: Page 29 of 131 Patient Enrollment by State According to 2010 US Census State\Territory of Patient Current Reporting Period b a Primary Address 29OCT2012 to 28OCT2013 Total 7,767 Unknown 2,000 Alabama 268 Alaska 10 Arizona 111 Arkansas 72 California 835 Colorado 117 Connecticut 81 Delaware 13 Florida 548 Georgia 105 Hawaii 2 Idaho 22 Illinois 61 Indiana 71 Iowa 3 Kansas 44 Kentucky 28 Louisiana 26 Maine 13 Maryland 74 Massachusetts 37 Michigan 563 Cumulative b 28DEC2011 to 28OCT2013 19,501 3,514 555 42 296 139 2,391 395 235 66 1,495 376 20 46 341 252 34 139 104 76 25 303 136 931 Population Derived from 2010 US Census Datac 312,471,327 N/A 4,779,736 710,231 6,392,017 2,915,918 37,253,956 5,029,196 3,574,097 897,934 18,801,310 9,687,653 1,360,301 1,567,582 12,830,632 6,483,802 3,046,355 2,853,118 4,339,367 4,533,372 1,328,361 5,773,552 6,547,629 9,883,640 Percentage of Population Enrolled in TIRF REMS Accessd 0.00006% N/A 0.0116% 0.0059% 0.0046% 0.0048% 0.0064% 0.0079% 0.0066% 0.0074% 0.0080% 0.0039% 0.0015% 0.0029% 0.0027% 0.0039% 0.0011% 0.0049% 0.0024% 0.0017% 0.0019% 0.0052% 0.0021% 0.0094% Rate of Persons Enrolled (Per 100,000)d 0.06 N/A 11.6 5.9 4.6 4.8 6.4 7.9 6.6 7.4 8.0 3.9 1.5 2.9 2.7 3.9 1.1 4.9 2.4 1.7 1.9 5.2 2.1 9.4 FDA_705 24-month REMS Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies. Table 10: Page 30 of 131 Patient Enrollment by State According to 2010 US Census State\Territory of Patient Current Reporting Period b a Primary Address 29OCT2012 to 28OCT2013 Minnesota 14 Mississippi 79 Missouri 56 Montana 8 Nebraska 18 Nevada 40 New Hampshire 48 New Jersey 314 New Mexico 3 New York 299 North Carolina 107 North Dakota 1 Ohio 163 Oklahoma 90 Oregon 28 Pennsylvania 229 Rhode Island 69 South Carolina 76 South Dakota 3 Tennessee 170 Texas 472 Utah 123 Vermont 0 Virginia 80 Cumulative b 28DEC2011 to 28OCT2013 50 150 184 24 51 124 74 970 20 923 424 13 445 245 115 633 109 185 7 395 1,353 317 1 266 Population Derived from 2010 US Census Datac 5,303,925 2,967,297 5,988,927 989,415 1,826,341 2,700,551 1,316,470 8,791,894 2,059,179 19,378,102 9,535,483 672,591 11,536,504 3,751,351 3,831,074 12,702,379 1,052,567 4,625,364 814,180 6,346,105 25,145,561 2,763,885 625,741 8,001,024 Percentage of Population Enrolled in TIRF REMS Accessd 0.0009% 0.0051% 0.0031% 0.0024% 0.0028% 0.0046% 0.0056% 0.0110% 0.0010% 0.0048% 0.0044% 0.0019% 0.0039% 0.0065% 0.0030% 0.0050% 0.0104% 0.0040% 0.0009% 0.0062% 0.0054% 0.0115% 0.0002% 0.0033% Rate of Persons Enrolled (Per 100,000)d 0.9 5.1 3.1 2.4 2.8 4.6 5.6 11.0 1.0 4.8 4.4 1.9 3.9 6.5 3.0 5.0 10.4 4.0 0.9 6.2 5.4 11.5 0.2 3.3 FDA_706 24-month REMS Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies. Table 10: Patient Enrollment by State According to 2010 US Census Cumulative b 28DEC2011 to 28OCT2013 338 51 81 31 Population Derived from 2010 US Census Datac 6,724,540 1,852,994 5,686,986 563,626 Percentage of Population Enrolled in TIRF REMS Accessd 0.0050% 0.0028% 0.0014% 0.0055% Rate of Persons Enrolled (Per 100,000)d 5.0 2.8 1.4 5.5 3 8 601,723 0.0013% 1.3 0 2 3,725,789 0.0001% 0.1 106,405 0.0009% 0.9 State\Territory of Patient Current Reporting Period b a Primary Address 29OCT2012 to 28OCT2013 Washington 135 West Virginia 18 Wisconsin 12 Wyoming 4 District of Columbia Puerto Rico Page 31 of 131 Virgin Islands 1 1 N/A = not applicable a Patients are classified by state based on 5-digit zip code provided on PPAF. b Patients enrolled in this time period and were still enrolled at the end of the time period. c Based on 2010 US Census Data d Rates are based on Cumulative enrollment. FDA_707 24-month REMS Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies. 5.2.2 Page 32 of 131 Prescriber Enrollment, Inactivation, and Education [Metric 7, 8, 9] During the current reporting period, there were 2,001 newly enrolled prescribers and 938 prescribers who re-enrolled. (Table 12). The majority of these prescribers (71.3%) enrolled using the Web-based enrollment system. All other prescribers completed their enrollment manually and submitted it via fax (28.7%). Enrolled prescribers represented all 50 states, the District of Columbia and Puerto Rico, The highest enrolling state was California (12.0%), followed by New York (10.7%), Florida (7.2%), New Jersey (6.8%), Texas (5.1%), and Pennsylvania (4.7%); all other states had enrollment of less than 4.0% of total prescribers. During this reporting period, 325 incomplete Prescriber Enrollment Forms were received for prescribers who enrolled via fax (Table 13). Multiple forms may have been submitted for the same prescriber, and a form may be incomplete for more than one reason. The most frequent reason for an incomplete form submitted via fax was missing physician signature and date (n=282, 86.8%). Prescribers who enroll via Web are required to complete a series of online modules and, at any given time in the process, one or more modules may be incomplete. A prescriber must complete all modules and requirements to become authorized to prescribe TIRF medicines. Of the 131 prescribers who initiated enrollment via the Web and had not completed enrollment as of the last date of the current reporting period (28 October 2013), the reasons for incomplete Web enrollment were as follows: • no attestation (n=117, 89.3%) • training not complete (n=97, 74.0%) Web enrollment can be incomplete for more than one reason; therefore the total is greater than 100%. Reasons for incomplete Web enrollment and the definitions are below. Table 11: Reasons for Incomplete Prescriber Web Enrollment Reason for Incomplete Enrollment Description Training Not Complete When a stakeholder does not complete the Education Program, they will be incomplete for the reason of “Training Not Complete.” No Attestation When a stakeholder does not attest to their enrollment on the Web, they will be incomplete for the reason of “No Attestation.” Attestation is an e-signature and requires input of the date and checking the attestation check box on the Web. FDA_708 24-month REMS Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies. Table 12: Page 33 of 131 Prescriber Enrollment Parameter Current Reporting Period Cumulativea 29OCT2012 to 28OCT2013 28DEC2011 to 28OCT2013 N (%) N (%) Total Number of Enrolled Prescribers Number of Newly Enrolled Prescribers Number of Re-Enrolled Prescribers 2,939b 2,001 (68.1%) 938 (31.9%) 10,718 c 9,672 (90.2%) 1,046 (9.8%) Method of Successful New Enrollmentsd Web Fax One-time file upload 2,095 (71.3%) 844 (28.7%) 0 5,962 (55.6%) 1,237 (11.5%) 3,519 (32.8%)c 41 (1.4%) 4 (0.1%) 80 (2.7%) 16 (0.5%) 353 (12.0%) 65 (2.2%) 35 (1.2%) 13 (0.4%) 211 (7.2%) 72 (2.5%) 3 (0.1%) 14 (0.5%) 115 (3.9%) 51 (1.7%) 10 (0.3%) 36 (1.2%) 20 (0.7%) 14 (0.5%) 3 (0.1%) 109 (3.7%) 49 (1.7%) 63 (2.1%) 29 (1.0%) 21 (0.7%) 140 (1.3%) 24 (0.2%) 315 (2.9%) 68 (0.6%) 1,359 (12.7%) 248 (2.3%) 147 (1.4%) 38 (0.4%) 694 (6.5%) 270 (2.5%) 17 (0.2%) 34 (0.3%) 397 (3.7%) 264 (2.5%) 35 (0.3%) 90 (0.8%) 83 (0.8%) 99 (0.9%) 23 (0.2%) 379 (3.5%) 180 (1.7%) 257 (2.4%) 107 (1.0%) 56 (0.5%) State/Territory of Prescriber Primary Addresse Alabama Alaska Arizona Arkansas California Colorado Connecticut Delaware Florida Georgia Hawaii Idaho Illinois Indiana Iowa Kansas Kentucky Louisiana Maine Maryland Massachusetts Michigan Minnesota Mississippi FDA_709 24-month REMS Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies. Table 12: Page 34 of 131 Prescriber Enrollment Parameter Missouri Montana Nebraska Nevada New Hampshire New Jersey New Mexico New York North Carolina North Dakota Ohio Oklahoma Oregon Pennsylvania Rhode Island South Carolina South Dakota Tennessee Texas Utah Vermont Virginia Washington West Virginia Wisconsin Wyoming District of Columbia Puerto Rico Distribution of Reasons for Incomplete Prescriber Enrollment Forms Received for Fax-Enrolled Prescribersf,g Missing Physician Signature Date Missing Signature Missing Email Missing NPI Number Missing State License Number Current Reporting Period Cumulativea 29OCT2012 to 28OCT2013 28DEC2011 to 28OCT2013 N (%) N (%) 18 (0.6%) 141 (1.3%) 8 (0.3%) 25 (0.2%) 33 (1.1%) 86 (0.8%) 25 (0.9%) 94 (0.9%) 10 (0.3%) 50 (0.5%) 201 (6.8%) 560 (5.2%) 4 (0.1%) 28 (0.3%) 314 (10.7%) 802 (7.5%) 89 (3.0%) 406 (3.8%) 4 (0.1%) 15 (0.1%) 77 (2.6%) 301 (2.8%) 33 (1.1%) 102 (1.0%) 40 (1.4%) 125 (1.2%) 137 (4.7%) 603 (5.6%) 8 (0.3%) 24 (0.2%) 24 (0.8%) 95 (0.9%) 4 (0.1%) 9 (0.1%) 85 (2.9%) 318 (3.0%) 149 (5.1%) 689 (6.4%) 32 (1.1%) 146 (1.4%) 1 (0.0%) 7 (0.1%) 56 (1.9%) 238 (2.2%) 102 (3.5%) 296 (2.8%) 13 (0.4%) 37 (0.4%) 29 (1.0%) 146 (1.4%) 7 (0.2%) 20 (0.2%) 7 (0.2%) 2 (0.1%) 325h 28 (0.3%) 3 (0.0%) 525h 282 (86.8%) 459 (87.4%) 282 (86.8%) 32 (9.9%) 62 (19.1%) 50 (15.4%) 459 (87.4%) 83 (15.8%) 75 (14.3%) 70 (13.3%) FDA_710 24-month REMS Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies. Table 12: Page 35 of 131 Prescriber Enrollment Current Reporting Period Cumulativea 29OCT2012 to 28OCT2013 28DEC2011 to 28OCT2013 Parameter N (%) N (%) Invalid DEA Number 27 (8.3%) 57 (10.9%) Provided DEA Number does not have Correct 27 (8.3%) 56 (10.7%) Schedule for this Drug Invalid NPI Number 22 (6.8%) 43 (8.2%) Missing DEA Number 33 (10.2%) 41 (7.8%) Note: Percentages are based on the total number (N) of prescribers for the period except for counts of incomplete forms. a Cumulative is defined as sum of consecutive reporting periods. b Includes prescribers enrolled or re-enrolled during the reporting period and were still enrolled at the end of the time period. c Includes prescribers who transitioned into the TIRF REMS Access Program from other individual REMS programs. d Percentage is based on the number of prescribers new to the TIRF REMS Access Program, including prescribers that transitioned from other individual REMS programs. e Enrolled prescribers are classified by their primary address as recorded on the Prescriber Enrollment Form. f Percentage is based on the total number of incomplete forms received in the reporting period. Forms may be incomplete for more than one reason and more than one incomplete form received for a unique prescriber. g Reflects only enrolled prescribers who completed enrollment via fax. Some stakeholders may have attempted enrollment via the Web. h Does not include prescribers who transitioned into the TIRF REMS Access Program from other individual REMS programs. A total of 1,259 prescribers were inactivated at some point during the current reporting period, and the majority of these (1,256, 99.8%) were due to expiration of enrollment period. It should be noted that a prescriber is required to enroll every 2 years within the TIRF REMS Access Program. Of those 1,256 prescribers whose enrollment period expired at some point during the current reporting period, 999 (79.5%) of these prescribers’ statuses remained expired at the close of the reporting period (Table 13). Of these 999 prescribers, 854 (85.5%) had not issued a prescription within six months (May 1, 2013- October 28, 2013). Table 13: Prescriber Inactivations Parameter Number of Inactivated Prescribers Current Reporting Perioda Cumulativeb 29OCT2012 to 28OCT2013 28DEC2011 to 28OCT2013 N (%) N (%) 1,259 1,901 FDA_711 24-month REMS Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies. Table 13: Page 36 of 131 Prescriber Inactivations Parameter Reason(s) For Inactivationc Deceased Program Opt-Out Enrollment Expired Enrollment Expired at End of Periodd Current Reporting Perioda Cumulativeb 29OCT2012 to 28OCT2013 28DEC2011 to 28OCT2013 N (%) N (%) 3 (0.2%) 7 (0.4%) 0 6 (0.3%) 1,256 (99.8%) 1,888 (99.3%) 999 (79.5%) 1,529 (81.0%) Note: Percentages are based on the total number (N) for the relevant stakeholder/period. a Prescribers whose status is 'inactive' at least once during the reporting period. b Cumulative is sum of all reporting period totals. c Percentages are based on the total number (N) of inactivated prescribers. A prescriber may have more than one reason for inactivation. d Prescribers whose status is 'Inactive – Expired” at any time during the enrollment period. e Prescribers whose status is “Inactive – Expired” at the end of the period. Percentages are based on the total number (N) of prescribers with “Inactive – Expired” status at least once. Among 2,949 prescribers who successfully completed the Knowledge Assessment during the reporting period, 68.1% completed the assessments via the Web and 31.9% completed them via fax (Table 14). (Note: Knowledge Assessments and enrollment may not have been completed in the same reporting period. Most prescribers passed the Knowledge Assessment on the first attempt (58.3%) or second attempt (25.7%). Fifty-one (1.8%) prescribers enrolled during this assessment period required more than 4 attempts to successfully complete the Knowledge Assessments. Thirteen prescribers successfully completed the Knowledge Assessment more than once during this reporting period). Prescribers who are unable to successfully complete the Knowledge Assessment after 6 attempts are “suspended” in the TIRF REMS Access Program until a representative from the Call Center can conduct outreach to provide additional educational assistance. Eight prescribers were contacted during the reporting period due to failure to successfully complete the Knowledge Assessment after six attempts. These 8 prescribers have successfully completed the Knowledge Assessment. FDA_712 24-month REMS Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies. Page 37 of 131 Table 14: Enrolled Prescriber Completed Knowledge Assessments and Number of Attempts Needed to Complete Current Reporting Period Cumulativea,b 29OCT2012 to 28OCT2013 28DEC2011 to 28OCT2013 c Parameter N (%) N (%) 2,949 7,255 Method of KA Completion Web Fax 2,008 (68.1%) 941 (31.9%) 5,744 (79.2%) 1,511 (20.8%) Number of Prescribers with One or More Attempts to Successfully Complete Knowledge Assessmente One attempt Two attempts Three attempts Four attempts Five attempts Six attempts Greater than six attempts 1,718 (58.3%) 759 (25.7%) 310 (10.5%) 111 (3.8%) 31 (1.1%) 12 (0.4%) 8 (0.3%) 3,707 (51.1%) 2,168 (29.9%) 903 (12.5%) 300 (4.1%) 107 (1.5%) 48 (0.7%) 22 (0.3%) Total Number of Successfully Completed Knowledge Assessments (KA) by Enrolled Prescribersd Note: Percentages are based on the total number (N) of prescribers successfully enrolled in the period. a Cumulative stakeholders from the end of prior period may differ from last period's report due to reconciliation of duplicate stakeholders. b Cumulative number does not include prescribers transitioned into the TIRF REMS Access Program from the individual REMS programs. c Enrolled prescriber includes newly enrolled prescribers and prescribers who re-enrolled during the current reporting period. d Limited to successfully enrolled prescribers completing a Knowledge Assessment. e Prescribers may have completed more than one Knowledge Assessment. 5.2.3 Pharmacy Enrollment, Inactivation, and Education [Metric 10, 11, 12] There was a total of 22,762 pharmacies newly enrolled or re-enrolled in this reporting period. Of the 1,962 pharmacies that newly enrolled in the TIRF REMS Access Program 1,944 were non-closed system pharmacies and 18 were closed system pharmacy locations. A total of 20,800 pharmacies re-enrolled, all of which were non-closed system pharmacies. Non-closed system pharmacies are comprised of corporate pharmacy stores (93.7%), independent outpatient FDA_713 24-month REMS Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies. Page 38 of 131 pharmacies (5.3%), inpatient pharmacies (0.9%), and corporate pharmacy headquarters (0.2%) and closed system pharmacies (0.1%) (Table 15). The enrolled pharmacies represented all 50 states, as well as the District of Columbia and Puerto Rico. The states that had the highest proportion of total newly enrolled or re-enrolled pharmacies included California (8.5%), Florida (8.3%), New York (7.5%), Texas (5.6%), Illinois (4.5%), Pennsylvania (4.4%), Ohio (3.9%), North Carolina (3.6%), Georgia (3.6%), New Jersey (3.2%), and Michigan (3.2%); all other states had enrollment ≤2.9%. As shown in Table 15, the method of enrollment for the majority of pharmacies was via their corporate chain headquarters (76.0%, i.e., enrollment occurred via file enrollment upload), and the others enrolled via the Web (22.6%), or manually by fax (1.4%). A total of 184 incomplete Pharmacy Enrollment Forms were received. Forms were received both via fax and via Web. The most frequently reported reasons for incomplete faxed enrollment forms were Knowledge Assessment Failure (n=16, 8.7%), invalid National Counsel for Prescription Drug Programs (NCPDP) number (n=6, 3.3%), pending test transaction verification (n=6, 3.3%). Other reasons for incomplete enrollment forms include invalid Drug Enforcement Agency (DEA) number (n=5, 2.7%), invalid National Provider Identifier (NPI) number (n=5, 2.7%). It should be noted that each form may have multiple reasons and could have been submitted multiple times. As described for prescribers, pharmacies that enroll via Web do not submit forms, but instead move through a series of online modules. At any given time in the process, one or more modules may be incomplete. Pharmacists or authorized pharmacy representatives must complete all modules and requirements to become authorized to dispense TIRF medicines. There were a number of outpatient pharmacies (N=198), inpatient pharmacies (N=35), and corporate pharmacy headquarters/stores (N=47) that initiated enrollment via the Web but had not completed enrollment as of the last date of the current reporting period (28 October 2013). The most common reasons for incomplete Web enrollment are shown below. Enrollment can be incomplete for more than one reason therefore the total is greater than 100%. The major reasons for incomplete Web enrollment of outpatient pharmacies (N=198) are listed below: • no attestation (98, 49.5%), • pending test transaction verification (97, 49.0%) • training not complete (87, 43.9%) The major reasons for incomplete Web enrollment of inpatient pharmacies (N=35) were: • no attestation (35, 100.0%) FDA_714 24-month REMS Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies. • Page 39 of 131 invalid DEA number (8, 22.9%) The major reasons for incomplete Web enrollment of corporate pharmacy stores (N=47) were: • training not complete (47, 100.0%) • invalid DEA number (6, 12.8%) Reasons for Web incomplete enrollment and the definition are proved below. Table 15: Reasons for Incomplete Pharmacy Web Enrollment Reason for Incomplete Enrollment Description Training Not Complete When a stakeholder does not complete the Education Program, they will be incomplete for the reason of “Training Not Complete.” No Attestation When a stakeholder does not attest to their enrollment on the Web, they will be incomplete for the reason of “No Attestation.” Attestation is an e-signature and requires input of the date and checking the attestation check box on the Web. Pending Test Transaction When an independent or chain outpatient pharmacy fails to complete the test transactions to enable their pharmacy management system to support communication with the TIRF REMS Access system. Invalid DEA When the enrolling stakeholder is not associated to the DEA number provided or enters an incorrect DEA number. FDA_715 24-month REMS Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies. Table 16: Page 40 of 131 Pharmacy Enrollment Cumulativea,b 28DEC2011 to 28OCT2013 Current Reporting Period 29OCT2012 to 28OCT2013 Parameter Number of Enrolled Pharmaciesb Independent Outpatient Corporate Pharmacy Headquarters Corporate Pharmacy Stores Inpatient Closed System Pharmacies Non-Closed System Pharmacies N (%) Closed System Pharmacies N (%) Total Pharmacies N (%) Non-Closed System Pharmacies N (%) Closed System Pharmacies N (%) Total Pharmacies N (%) 22,744 18 22,762 38,455 c 332 38,787 1,193 (5.3%) N/A 1,193 (5.2%) 4,927 (12.8%) N/A 4,927 (12.7%) 35 (0.2%) N/A 35 (0.2%) 85 (0.2%) N/A 85 (0.2%) 21,305 (93.7%) N/A 21,305 (93.6%) 32,553 (84.7%) N/A 32,553 (83.9%) 211 (0.9%) N/A 211 (0.9%) 890 (2.3%) N/A 890 (2.3%) N/A 18 (100.0%) 18 (0.1%) N/A 332 (100.0%) 332 (0.9%) 20,800 (91.5%) 0 20,800 (91.4%) 20,849 (54.2%) 0 20,849 (53.8%) Independent Outpatient 573 (2.8%) N/A 573 (2.8%) 606 (2.9%) N/A 606 (2.9%) Corporate Pharmacy Headquarters 34 (0.2%) N/A 34 (0.2%) 34 (0.2%) N/A 34 (0.2%) 20,166 (97.0%) N/A 20,166 (97.0%) 20,175 (96.8%) N/A 20,175 (96.8%) 27 (0.1%) N/A 27 (0.1%) 34 (0.2%) N/A 34 (0.2%) Web 5,129 (22.6%) 3 (16.7%) 5,132 (22.6%) 9,348 (24.3%) 27 (8.1%) 9,375 (24.2%) Fax 320 (1.4%) 1 (5.6%) 321 (1.4%) 482 (1.3%) 7 (2.1%) 489 (1.3%) 17,295 (76.0%) 14 (77.8%) 17,309 (76.0%) 28,625 (74.4%) 298 (89.8%) 28,923 (74.6%) Alabama 362 (1.6%) 0 362 (1.6%) 644 (1.7%) 4 (1.2%) 648 (1.7%) Alaska 38 (0.2%) 0 38 (0.2%) 51 (0.1%) 0 51 (0.1%) Arizona 596 (2.6%) 0 596 (2.6%) 811 (2.1%) 2 (0.6%) 813 (2.1%) Arkansas 127 (0.6%) 0 127 (0.6%) 260 (0.7%) 3 (0.9%) 263 (0.7%) California 1,921 (8.5%) 0 1,921 (8.4%) 3,538 (9.2%) 82 (24.7%) 3,620 (9.3%) Colorado 490 (2.2%) 0 490 (2.2%) 577 (1.5%) 30 (9.0%) 607 (1.6%) Connecticut 296 (1.3%) 0 296 (1.3%) 497 (1.3%) 0 497 (1.3%) Delaware 139 (0.6%) 0 139 (0.6%) 160 (0.4%) 1 (0.3%) 161 (0.4%) Number of Re-Enrolled Pharmacies Corporate Pharmacy Stores Inpatient Method of Successful Enrollmentsd File (file enrollment upload) State/Territory of Pharmacy Primary Addresse FDA_716 24-month REMS Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies. Table 16: Page 41 of 131 Pharmacy Enrollment Cumulativea,b 28DEC2011 to 28OCT2013 Current Reporting Period 29OCT2012 to 28OCT2013 Parameter Non-Closed System Pharmacies N (%) Florida 1,877 (8.3%) 0 1,877 (8.3%) 3,079 (8.0%) 18 (5.4%) 3,097 (8.0%) Georgia 816 (3.6%) 2 (11.1%) 818 (3.6%) 1,392 (3.6%) 9 (2.7%) 1,401 (3.6%) Hawaii 29 (0.1%) 0 29 (0.1%) 111 (0.3%) 14 (4.2%) 125 (0.3%) Idaho 98 (0.4%) 0 98 (0.4%) 149 (0.4%) 1 (0.3%) 150 (0.4%) Illinois 1,014 (4.5%) 0 1,014 (4.5%) 1,491 (3.9%) 8 (2.4%) 1,499 (3.9%) Indiana 385 (1.7%) 0 385 (1.7%) 882 (2.3%) 4 (1.2%) 886 (2.3%) Iowa 114 (0.5%) 0 114 (0.5%) 232 (0.6%) 0 232 (0.6%) Kansas 160 (0.7%) 0 160 (0.7%) 288 (0.8%) 0 288 (0.7%) Kentucky 337 (1.5%) 0 337 (1.5%) 501 (1.3%) 3 (0.9%) 504 (1.3%) Louisiana 303 (1.3%) 0 303 (1.3%) 533 (1.4%) 2 (0.6%) 535 (1.4%) Maine 159 (0.7%) 0 159 (0.7%) 204 (0.5%) 0 204 (0.5%) Maryland 469 (2.1%) 2 (11.1%) 471 (2.1%) 796 (2.1%) 20 (6.0%) 816 (2.1%) Massachusetts 485 (2.1%) 0 485 (2.1%) 866 (2.3%) 1 (0.3%) 867 (2.2%) Michigan 738 (3.2%) 0 738 (3.2%) 1,435 (3.7%) 6 (1.8%) 1,441 (3.7%) Minnesota 354 (1.6%) 0 354 (1.6%) 540 (1.4%) 0 540 (1.4%) Mississippi 166 (0.7%) 0 166 (0.7%) 321 (0.8%) 2 (0.6%) 323 (0.8%) Missouri 399 (1.8%) 0 399 (1.8%) 650 (1.7%) 4 (1.2%) 654 (1.7%) Montana 47 (0.2%) 0 47 (0.2%) 97 (0.3%) 2 (0.6%) 99 (0.3%) Nebraska 96 (0.4%) 0 96 (0.4%) 195 (0.5%) 0 195 (0.5%) Nevada 167 (0.7%) 0 167 (0.7%) 314 (0.8%) 3 (0.9%) 317 (0.8%) New Hampshire 151 (0.7%) 0 151 (0.7%) 201 (0.5%) 0 201 (0.5%) New Jersey 719 (3.2%) 3 (16.7%) 722 (3.2%) 1,319 (3.4%) 4 (1.2%) 1,323 (3.4%) New Mexico Closed System Pharmacies N (%) Total Pharmacies N (%) Non-Closed System Pharmacies N (%) Closed System Pharmacies N (%) Total Pharmacies N (%) 125 (0.6%) 0 125 (0.6%) 175 (0.5%) 0 175 (0.5%) 1,707 (7.5%) 0 1,707 (7.5%) 2,582 (6.7%) 5 (1.5%) 2,587 (6.7%) North Carolina 818 (3.6%) 0 818 (3.6%) 1,270 (3.3%) 4 (1.2%) 1,274 (3.3%) North Dakota 31 (0.1%) 0 31 (0.1%) 52 (0.1%) 1 (0.3%) 53 (0.1%) Ohio 897 (3.9%) 0 897 (3.9%) 1,595 (4.2%) 15 (4.5%) 1,610 (4.2%) Oklahoma 158 (0.7%) 0 158 (0.7%) 379 (1.0%) 3 (0.9%) 382 (1.0%) New York FDA_717 24-month REMS Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies. Table 16: Page 42 of 131 Pharmacy Enrollment Cumulativea,b 28DEC2011 to 28OCT2013 Current Reporting Period 29OCT2012 to 28OCT2013 Parameter Non-Closed System Pharmacies N (%) Closed System Pharmacies N (%) Total Pharmacies N (%) Oregon 347 (1.5%) 0 347 (1.5%) 436 (1.1%) 2 (0.6%) 438 (1.1%) Pennsylvania 993 (4.4%) 0 993 (4.4%) 1,938 (5.0%) 12 (3.6%) 1,950 (5.0%) Rhode Island 98 (0.4%) 2 (11.1%) 100 (0.4%) 166 (0.4%) 2 (0.6%) 168 (0.4%) South Carolina 447 (2.0%) 0 447 (2.0%) 676 (1.8%) 3 (0.9%) 679 (1.8%) South Dakota 25 (0.1%) 0 25 (0.1%) 54 (0.1%) 0 54 (0.1%) Tennessee 563 (2.5%) 0 563 (2.5%) 906 (2.4%) 5 (1.5%) 911 (2.4%) Texas 1,270 (5.6%) 8 (44.4%) 1,278 (5.6%) 2,603 (6.8%) 21 (6.3%) 2,624 (6.8%) Utah 150 (0.7%) 0 150 (0.7%) 314 (0.8%) 1 (0.3%) 315 (0.8%) Vermont 87 (0.4%) 0 87 (0.4%) 95 (0.3%) 0 95 (0.2%) Virginia 653 (2.9%) 1 (5.6%) 654 (2.9%) 1,058 (2.8%) 14 (4.2%) 1,072 (2.8%) Washington 605 (2.7%) 0 605 (2.7%) 805 (2.1%) 5 (1.5%) 810 (2.1%) West Virginia 172 (0.8%) 0 172 (0.8%) 292 (0.8%) 4 (1.2%) 296 (0.8%) Wisconsin 364 (1.6%) 0 364 (1.6%) 607 (1.6%) 3 (0.9%) 610 (1.6%) Wyoming 40 (0.2%) 0 40 (0.2%) 68 (0.2%) 2 (0.6%) 70 (0.2%) District of Columbia 30 (0.1%) 0 30 (0.1%) 94 (0.2%) 3 (0.9%) 97 (0.3%) 0 0 0 1 (<0.1%) 0 1 (<0.1%) 112 (0.5%) 0 112 (0.5%) 153 (0.4%) 3 (0.9%) 156 (0.4%) 0 0 0 2 (<0.1%) 1 (0.3%) 3 (<0.1%) 184 g 0 184 317 g 0 317 Guam Puerto Rico Virgin Islands Number of Incomplete Pharmacy Enrollment Forms Received for Fax Enrolled Pharmaciesf Not Agreed to Terms and Conditions Non-Closed System Pharmacies N (%) Closed System Pharmacies N (%) Total Pharmacies N (%) 0 0 0 127 (40.1%) 0 127 (40.1%) Knowledge Assessment Failure - First Attempt 16 (8.7%) 0 16 (8.7%) 44 (13.9%) 0 44 (13.9%) Missing DEA Number 2 (1.1%) 0 2 (1.1%) 25 (7.9%) 0 25 (7.9%) Pending Test Txn Verification 6 (3.3%) 0 6 (3.3%) 24 (7.6%) 0 24 (7.6%) Invalid DEA Number 5 (2.7%) 0 5 (2.7%) 21 (6.6%) 0 21 (6.6%) Missing Pharmacist Signature Date 3 (1.6%) 0 3 (1.6%) 14 (4.4%) 0 14 (4.4%) Missing Signature 3 (1.6%) 0 3 (1.6%) 14 (4.4%) 0 14 (4.4%) FDA_718 24-month REMS Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies. Table 16: Page 43 of 131 Pharmacy Enrollment Cumulativea,b 28DEC2011 to 28OCT2013 Current Reporting Period 29OCT2012 to 28OCT2013 Non-Closed System Pharmacies N (%) Closed System Pharmacies N (%) Total Pharmacies N (%) Non-Closed System Pharmacies N (%) Closed System Pharmacies N (%) Total Pharmacies N (%) Invalid NPI Number 5 (2.7%) 0 5 (2.7%) 13 (4.1%) 0 13 (4.1%) Invalid NCPDP Number 6 (3.3%) 0 6 (3.3%) 12 (3.8%) 0 12 (3.8%) Missing NPI Number 2 (1.1%) 0 2 (1.1%) 11 (3.5%) 0 11 (3.5%) Missing Pharmacy Phone Number 3 (1.6%) 0 3 (1.6%) 6 (1.9%) 0 6 (1.9%) Missing NCPDP Number 1 (0.5%) 0 1 (0.5%) 5 (1.6%) 0 5 (1.6%) Missing State License Number 1 (0.5%) 0 1 (0.5%) 5 (1.6%) 0 5 (1.6%) Missing Address - City 1 (0.5%) 0 1 (0.5%) 4 (1.3%) 0 4 (1.3%) Missing Address - State 1 (0.5%) 0 1 (0.5%) 4 (1.3%) 0 4 (1.3%) Missing Address - Street 1 (0.5%) 0 1 (0.5%) 4 (1.3%) 0 4 (1.3%) 0 0 0 4 (1.3%) 0 4 (1.3%) 1 (0.5%) 0 1 (0.5%) 2 (0.6%) 0 2 (0.6%) 0 0 0 1 (0.3%) 0 1 (0.3%) Parameter Missing Email Missing Fax Number Knowledge Assessment Failure - Second Attempt Missing Pharmacist Phone Number 0 0 0 1 (0.3%) 0 1 (0.3%) Note: Percentages are based on the total number (N) for stakeholders for the period. a Cumulative pharmacies from the end of prior period may differ from last period's report due to reconciliation of duplicate records. b Pharmacies that are enrolled in this time period and were still enrolled at the end of the time period. c Includes pharmacies that transitioned into the TIRF REMS Access Program from other individual REMS programs. d Method Definitions: Web – enrollment occurred via program Web site; Fax – enrollment occurred via fax sent to the Call Center; File – enrollment occurred via custom file load (e.g. chain stores). e Pharmacies are classified by the primary address for the Pharmacist in Charge as recorded on the enrollment form. f Percentage is based on the total number of incomplete forms received in the reporting period. Forms may be incomplete for more than one reason. g Does not include pharmacies that transitioned into the TIRF REMS Access Program from other individual REMS programs. FDA_719 24-month REMS Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies. Page 44 of 131 As shown in Table 17, there were a total of 2,493 non-closed system pharmacies inactivated at least once during the reporting period including 2,470 (99.1%) outpatient pharmacies, 21 (0.8%) inpatient pharmacies, and 2 (0.1%) chain pharmacies. There were no closed system pharmacies inactivated during this reporting period. The reasons for inactivation are described in the table below. FDA_720 24-month REMS Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies. Table 17: Page 45 of 131 Pharmacy Inactivations Cumulativea,b 28DEC2011 to 28OCT2013 Current Reporting Period 29OCT2012 to 28OCT2013 Non-Closed System Pharmacies N (%) Closed System Pharmacies N (%) Total Pharmacies N (%) Non-Closed System Pharmacies N (%) Closed System Pharmacies N (%) Total Pharmacies N (%) 2,493 0 2,493 2,499 0 2,499 21 (0.8%) N/A 21 (0.8%) 23 (0.9%) N/A 23 (0.9%) 2,470 (99.1%) N/A 2,470 (99.1%) 2,474 (99.0%) N/A 2,474 (99.0%) 2 (0.1%) N/A 2 (0.1%) 2 (0.1%) N/A 2 (0.1%) Enrollment Expired 21 (100.0%) N/A 21 (100.0%) 21 (91.3%) N/A 21 (91.3%) Program Opt-Out 0 0 0 2 (8.7%) 0 2 (8.7%) Enrollment Expired 2,400 (97.2%) N/A 2,400 (97.2%) 2,400 (97.0%) N/A 2,400 (97.0%) Program Opt-Out 70 (2.8%) 0 70 (2.8%) 74 (3.0%) 0 74 (3.0%) 2 (100.0%) 0 2 (100.0%) 2 (100.0%) 0 2 (100.0%) Parameter Number of Inactivated Pharmacies Inpatient Outpatient Chain Reason(s) for Inpatient Pharmacy Inactivationc Reason(s) for Outpatient Pharmacy Inactivationd Reason(s) for Chain Pharmacy Inactivatione Enrollment Expired f Reason(s) for CSP Inactivation FDA_721 24-month REMS Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies. Table 17: Page 46 of 131 Pharmacy Inactivations Cumulativea,b 28DEC2011 to 28OCT2013 Current Reporting Period 29OCT2012 to 28OCT2013 Parameter None Non-Closed System Pharmacies N (%) Closed System Pharmacies N (%) Total Pharmacies N (%) Non-Closed System Pharmacies N (%) Closed System Pharmacies N (%) Total Pharmacies N (%) N/A 0 0 N/A 0 0 Note: Closed System Pharmacies refers to integrated healthcare systems that dispense TIRF medicines for outpatient use with pharmacy management systems unable to support the process of electronically transmitting the validation and claim information required by the TIRF REMS Access Program. a Pharmacies with 'inactive' status at least once during the period. b Cumulative is sum of all “reporting period” totals. c Percentages are based on the total number (N) of inactivated inpatient pharmacies. An inpatient pharmacy may have more than one reason for inactivation. d Percentages are based on the total number (N) of inactivated outpatient pharmacies. An outpatient pharmacy may have more than one reason for inactivation. e Percentages are based on the total number (N) of inactivated chain pharmacies. A chain pharmacy may have more than one reason for inactivation. f Percentages are based on the total number (N) of inactivated closed system pharmacies. A closed system pharmacy may have more than one reason for inactivation. FDA_722 24-month REMS Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies. Page 47 of 131 Of the 22,762 pharmacies that completed initial enrollment or re-enrollment during this reporting period, a total of 1,463 authorized pharmacists/pharmacy representatives (including 2 closed system pharmacies) completed the Knowledge Assessment (Table 18). The majority of authorized pharmacists/pharmacy representatives completed the Knowledge Assessment on the first attempt (46.8%) or the second attempt (33.9%). Of the 1,463, 96 authorized pharmacists/pharmacy representatives required four or more attempts to successfully complete the knowledge assessment. Authorized pharmacists/pharmacy representatives who are unable to successfully complete the Knowledge Assessment after 6 attempts are “suspended” in the TIRF REMS Access Program until a representative from the Call Center can conduct outreach to provide additional educational assistance. As of the end of the reporting period, all 6 pharmacists that were unsuccessful after 6 attempts or greater had been contacted and subsequently became enrolled. The number of authorized pharmacists is lower than the number of enrolled pharmacies since pharmacies that were transitioned from an individual REMS program were not required to complete the Knowledge Assessment. Also, an authorized pharmacist/pharmacy representative may have been in charge of more than one store. Additionally, the TIRF REMS Access Program does not manage the education of the chain pharmacy stores; this is done by the corporate chain headquarters. FDA_723 24-month REMS Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies. Page 48 of 131 Table 18: Successfully Complete Knowledge Assessment Enrolled Authorized Pharmacist/Pharmacy Representatives Successfully Completing Knowledge Assessments and Attempts Needed to Current Reporting Period umulative"b 29OCT2012 to 280CT2013 28DEC2011 to 280CT2013 Non?Closed System Closed System Total Non?Closed System Closed System Total Pharmacies Pharmacies Pharmacies Pharmacies Pharmacies Pharmacists Parameter Number of Authorized Pharmacist/Pharmacy 1.461 2 1.463 4.715 8 4.723 Representatives Successfully Completing Knowledge Assessmentc Number of Authorized Pharmacists with One or More Attempts to Successfully Complete Knowledge Assessment?l One attempt 683 2 (100.0%) 685 1.978 6 1.984 Two attempts 496 0 496 1.728 2 1.730 Three attempts 186 0 186 674 0 674 Four attempts 69 0 69 225 0 225 Five attempts 21 0 21 75 0 75 Six attempts 5 0 5 26 0 26 Greater than six attempts I 0 9 0 9 Note: Percentages are based on the total number (N) of pharmacists for the period. Closed system pharmacies refers to integrated healthcare systems that dispense TIRF medicines for outpatient use with pharmacy management systems unable to support the process of electronically transmitting the validation and claim infomlation required by the TIRF REMS Access Program. Includes pharmacies that transitioned into the TIRF REMS Access Program from other individual REMS programs. Cumulative from the end of prior period may differ from last period's report due to reconciliation of duplicates. ?For chain pharmacies. the results only re?ect completion by an authorized pharmacist or pharmacy representative at the corporate headquarters and may not include individual retail locations. Corporate pharmacies are required to attest that authorized pharmacists and/or pharmacy representatives at individual store locations will complete all applicable assessments to participate in the program. dLimited to pharmacists who ultimately successfully completed the Knowledge Assessment. 24-month REMS Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies. 5.2.4 Page 49 of 131 Dispensing Activity [Metric 13 and 14] A total of 111,104 prescriptions were adjudicated for safety by the TIRF REMS Access Program in the current reporting period including 110,170 prescriptions from non-closed system pharmacies and 934 from closed system pharmacies. Of the total prescriptions, 94% were subsequently approved for dispensing (meaning authorized for dispensing by insurance or cash bin). FDA_725 24-month REMS Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies. Table 19: Page 50 of 131 Prescriptions Authorized for Dispensing from Outpatient Pharmacies Cumulativea,b 28DEC2011 to 28OCT2013 Current Reporting Period 29OCT2012 to 28OCT2013 Parameter Number of Authorized Prescriptionsb Number of Authorized Prescriptions Dispensedc Non-Closed System Closed System Pharmacies Pharmacies N (%) N (%) All Pharmacies N (%) Non-Closed System Closed System Pharmacies Pharmacies N (%) N (%) All Pharmacies N (%) 110,170 934 111,104 178,620 1,195 179,815 103,523 (94.0%) 919 (98.4%) 104,442 (94.0%) 167,945 (94.0%) 1,177 (98.5%) 169,122 (94.1%) Note: Percentages are based on the total number (N) of authorized prescriptions for the period. a Includes authorizations from pharmacies that transitioned into the TIRF REMS Access Program from other individual REMS programs. b Prescription successfully adjudicated for safety (i.e., successful REMS edit). c Indicates number of prescriptions that were adjudicated for safety (i.e., successful REMS edit) and authorized for dispensing by insurance or cash bin (bin number). FDA_726 24-month REMS Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies. Page 51 of 131 A total of 15,536 prescription claims were rejected because they failed to meet REMS requirements for prescriber and/or patient and/or pharmacy including 15,321 from non-closed system pharmacies and 215 from closed system pharmacies. Note that prescription claims does not equal the number of hard copy prescriptions presented at TIRF enrolled pharmacies because a single prescription may have been submitted and rejected multiple times. The majority of rejection reasons were due to prescriber not enrolled or prescriber ID not found in TIRF REMS Access database (43.6%), patient zip code missing from claim (18.8%), PPAF incomplete (15.2%), prescriber last name did not match name registered (14.5%), or pharmacy was not enrolled (7.8%). The definitions for the reasons why prescriptions do not meet REMS edit requirements are provided below in Table 20. Table 20 Reasons for Prescriptions Not Meeting REMS Edit Requirement Reason Description Prescriber ID Not Enrolled/ Not Found Found the prescriber last name but not the NPI, DEA or State License Number or both prescriber last name and ID are not found PPAF Incomplete Patient’s PPAF is in an incomplete status; the PPAF is missing information Patient Zip Code Missing Patient’s zip code was not submitted on the transaction Prescriber Last Name Did Not Match Name Registered Prescriber last name on the transaction did not match the prescriber last name associated with the Prescriber ID Pharmacy Not Enrolled Pharmacy is not enrolled; the pharmacy has not completed the enrollment or re-enrollment process Upon receiving an inbound call from a pharmacy provider, the TIRF REMS Access Program Call Center Service Representative (CSR) works to resolve the rejected transaction and to provide instructions on the corrective action needed to successfully process the transaction. Corrective action includes outreach and education to remedy rejected transaction processing. FDA_727 24-month REMS Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies. Table 21: Page 52 of 131 Total Number of Prescriptions Rejected for Safety Current Reporting Perioda 29OCT2012 to 28OCT2013 Cumulativea 28DEC2011 to 28OCT2013 Non-Closed System Pharmacies N (%) Closed System Pharmacies N (%) Total Pharmacies N (%) Non-Closed System Pharmacies N (%) Closed System Pharmacies N (%) Total Pharmacies N (%) 15,321 215 15,536 39,561 318 39,879 1,209 (7.9%) 0 1,209 (7.8%) 4,263 (10.8%) 0 4,263 (10.7%) 161 (1.1%) 2 (0.9%) 163 (1.0%) 590 (1.5%) 7 (2.2%) 597 (1.5%) 9 (0.1%) 0 9 (0.1%) 17 (<0.1%) 0 17 (<0.1%) 209 (1.4%) 1 (0.5%) 210 (1.4%) 442 (1.1%) 1 (0.3%) 443 (1.1%) Prescriber ID not in TIRF REMS Access database 6,634 (43.3%) 134 (62.3%) 6,768 (43.6%) 17,251 (43.6%) 193 (60.7%) 17,444 (43.7%) Prescriber last name did not match name registered 2,233 (14.6%) 27 (12.6%) 2,260 (14.5%) 5,129 (13.0%) 36 (11.3%) 5,165 (13.0%) 483 (3.2%) 6 (2.8%) 489 (3.1%) 828 (2.1%) 9 (2.8%) 837 (2.1%) 15 (0.1%) 0 15 (0.1%) 42 (0.1%) 0 42 (0.1%) DOB missing from claim 10 (0.1%) 0 10 (0.1%) 37 (0.1%) 0 37 (0.1%) Patient first name missing from claim 133 (0.9%) 0 133 (0.9%) 308 (0.8%) 0 308 (0.8%) Patient last name missing from claim 13 (0.1%) 0 13 (0.1%) 66 (0.2%) 0 66 (0.2%) Patient zip code missing from claim 2,901 (18.9%) 15 (7.0%) 2,916 (18.8%) 6,563 (16.6%) 30 (9.4%) 6,593 (16.5%) 1 (<0.1%) 1 (0.5%) 2 (<0.1%) 14 (<0.1%) 1 (0.3%) 15 (<0.1%) Parameter Number of Prescriptions Rejected Reasons For Rejectionb Pharmacy not enrolled Pharmacy enrollment incomplete or expired System unavailable due to maintenance Prescriber ID not submitted on claim Prescriber enrollment incomplete or expired Prescriber enrollment incomplete or expired and prescriber last name mismatch Multiple patients found FDA_728 24-month REMS Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies. Table 21: Page 53 of 131 Total Number of Prescriptions Rejected for Safety Current Reporting Perioda 29OCT2012 to 28OCT2013 Cumulativea 28DEC2011 to 28OCT2013 Non-Closed System Pharmacies N (%) Closed System Pharmacies N (%) Total Pharmacies N (%) Non-Closed System Pharmacies N (%) Closed System Pharmacies N (%) Total Pharmacies N (%) 0 0 0 0 0 0 1 (<0.1%) 0 1 (<0.1%) 1 (<0.1%) 0 1 (<0.1%) Patient deceased 0 0 0 0 0 0 Database failure 1 (<0.1%) 0 1 (<0.1%) 1 (<0.1%) 0 1 (<0.1%) PPAF Incomplete 2,328 (15.2%) 33 (15.3%) 2,361 (15.2%) 7,634 (19.3%) 50 (15.7%) 7,684 (19.3%) PPAF Terminated 340 (2.2%) 2 (0.9%) 342 (2.2%) 383 (1.0%) 2 (0.6%) 385 (1.0%) Parameter Prescriber decision to deactivate patient Patient inactive >= 6mos and must resubmit PPAF Note: Percentages are based on the total number (N) of rejected prescriptions for the relevant period. Rejected for Safety is defined in this table to mean the prescription did not pass REMS edits. a Includes patients that transitioned into the TIRF REMS Access Program from other individual REMS programs. b A prescription may be rejected for more than one reason. FDA_729 24-month REMS Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies. Page 54 of 131 Patients with prescriptions from multiple prescribers within an overlapping time frame were assessed. Patients may have multiple prescribers for various reasons such as patient relocation, prescriber relocation/retirement/death, or patient is seen at a single practice with multiple prescribers. Attempts are made to research reports of patients with prescriptions from 3 or more prescribers in a rolling 6-month period. In this reporting period, there were 671 patients who received prescriptions for a TIRF medicine from 3 or more prescribers with a rolling 6-month period. In the last reporting period, there were 505 patients who had 3 or more prescribers in a rolling 6-month period. A total of 505 cases were investigated and 504 were closed as not a noncompliant event: • • • • 387 patients visited multiple prescribers in the same practice; 108 patients changed practices at some point in their therapy. 5 patients were reviewed with the NCRT for suspected abuse/misuse. The NCRT did not find suspected abuse/misuse after review. 4 patients consistently visited 2 practices, but there were no overlapping prescriptions between the two practices. Per communication with FDA dated 15 May 2013, 1 patient case from the 505 cases investigated could not be ruled out for potential doctor shopping. The patient saw 4 prescribers in different practices. The patient received 28 prescriptions for one branded product (2 different strengths) over a 12 ½ month period. One independent outpatient pharmacy filled all prescriptions. This case was investigated and closed as a potential non-compliance event; however non-compliance could not be confirmed due to patient privacy restrictions. FDA_730 24-month REMS Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies. 5.2.5 Page 55 of 131 Wholesaler/Distributor Enrollment [Metric 15 and 16] During the current reporting period, 4 wholesalers/distributors newly enrolled via fax in the REMS program and 9 (69.2%) re-enrolled. (Table 22). There were 4 wholesalers/distributors inactivated during the current reporting period because the enrollment expired and 2 had not re-enrolled by the end of the reporting period. (Table 23). Table 22: Wholesaler/Distributor Enrollment Parameter Number of Wholesalers/Distributors Enrolled Number of Newly Enrolled Wholesalers/Distributors Number of Re-Enrolled Wholesalers/Distributors Method of Enrollment Fax File Number of Incomplete Wholesaler/ Distributor Enrollment Forms Received Current Reporting Period 29OCT2012 to 28OCT2013 N (%) Cumulativea,b 28DEC2011 to 28OCT2013 N (%) 13 44 4 (30.8%) 35 (79.5%) 9 (69.2%) 9 (20.5%) 13 (100.0%) 0 31 (70.5%) 13 (29.6%) 0 0 Note: Percentages are based on the total number (N) for the relevant Wholesalers/Distributors for the period. a Includes Wholesalers/Distributors that transitioned into the TIRF REMS Access Program from other individual REMS programs. b Cumulative Wholesalers/Distributors from the end of prior period may differ from last period's report due to reconciliation of duplicate Wholesalers/Distributors. FDA_731 24-month REMS Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies. Table 23: Wholesaler/Distributor Inactivations Parameter Current Reporting Perioda 29OCT2012 to 28OCT2013 N (%) Cumulativeb 28DEC2011 to 28OCT2013 N (%) 4 (100%) 4 (100%) Number of Inactivated Wholesalers/Distributors a b Page 56 of 131 Includes Wholesalers/Distributors with “inactive” status at least once during the period. Cumulative is the sum of “reporting period” totals. 5.2.6 Barriers or Delays in Patient Access [Metric 17 and 18] A total of 7,071 PPAFs were submitted to the REMS program either via the Web (64.4%) or by fax (35.7%) during the reporting period. Approximately 49% of PPAFs were received the same day or within 10 days (36.2% on the same day and 12.7% between 1 and 10 days) (Table 24 and Figure 1). Table 24 Submission of Patient-Prescriber Agreement Forms to the REMS Program Parameter Current Reporting Period 29OCT2012 to Cumulativea, b 28OCT2013 28DEC2011 to 28OCT2013 N (%) N (%) 7,071 16,518 Method of PPAF Submission Web Fax One-time file upload 4,549 (64.4%) 2,522 (35.7%) 0 11,331 (68.6%) 4,799 (29.1%) 388 (2.4%) Number of Forms Received by Days Elapsed between Patient Enrollment and Receipt of Patient-Prescriber Agreement by REMS Program Form Received Same Day Form Received between 1 and 10 days Form Received between 11 and 15 days Form Received between 16 and 20 days 2,562 (36.2%) 897 (12.7%) 400 (5.7%) 339 (4.8%) 5,481 (33.2%) 2,117 (12.8%) 886 (5.4%) 779 (4.7%) Number of Patient-Prescriber Agreement Forms Submitted to REMS Program FDA_732 24-month REMS Assessment Report Transmucosal Immediate-Release entanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies. Page 57 of 131 Table 24 Submission of Patient-Prescriber Agreement Forms to the REMS Program Current Reporting Period 29ocr2012 to Cumulative? 280CT2013 28DEC2011 to 280CT2013 Parameter Form Received between 21 and 30 days 656 3.092 Form Received >30 days after Patient 2.217 4.163 Enrollment Note: Percentages are based on the total number (N) of forms for the period. 3 Includes patients that transitioned into the TIRF REMS Access Program from other individual REMS programs. Cumulative total from the end of prior reporting period may differ from current period's report due to reconciliation of duplicates. Figure 1: PPAF Receipt by Time Since Patient Enrollment (290CT2012 to 280CT2013) PPAF Recelpt by Tlme Slnce Patlent En rollment Current Reporting Period 3,000 2,562 2,500 2,000 n. a. Q- 2 1,500 a: a a 2 1,000 500 0 Same Day 1 - 10 Days 11 - 15 Days 16 - 20 Days 21 - 30 Days 30 Days Days Between Enrollment and PPAF Receipt Note: Figure represents number of PPAFs and not unique patients. Within First 10 Days After Patient Enrollment 24-month REMS Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies. Page 58 of 131 Across all pharmacies, a total of 8,256 prescriptions were dispensed to 7,064 patients within the first 10 days after patient enrollment (Table 25 and Figure 2 below). The majority of patients (7,008) were dispensed prescriptions by non-closed system pharmacies (8,180). The majority of patients (77.2%) received only 1 fill without a PPAF. FDA_734 24-month REMS Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies. Table 25: Page 59 of 131 Prescriptions Dispensed During the First 10 Days after Passive Patient Enrollment Current Reporting Period 29OCT2012 to 28OCT2013 Parameter Filled at Non-Closed Filled at System Closed System Pharmacies Pharmacies N (%) N (%) Cumulativea,b 28DEC2011 to 28OCT2013 Filled at Combinedd Pharmacies N (%) Filled at All Pharmacies N (%) Filled at Non-Closed Filled at System Closed System Pharmacies Pharmacies N (%) N (%) Filled at Combinedd Pharmacies N (%) Filled at All Pharmacies N (%) Number of prescriptions dispensed to patients during the first 10 days after patient enrollment 8,180 76 0 8,256 20,364 173 8 20,545 Number of patients dispensed a prescription during the first 10 days after patient enrollment 7,008 56 0 7,064 17,443 145 4 17,592 1 Fill 1,404 (20.0%) 6 (10.7%) 0 1,410 (20.0%) 2,662 (15.3%) 11 (7.6%) 1 (25.0%) 2,674 (15.2%) 2 Fills 194 (2.8%) 0 0 194 (2.7%) 411 (2.4%) 1 (0.7%) 0 412 (2.3%) 3 Fills 26 (0.4%) 0 0 26 (0.4%) 61 (0.3%) 0 0 61 (0.3%) >3 Fills 5 (0.1%) 1 (1.8%) 0 6 (0.1%) 17 (0.1%) 1 (0.7%) 0 18 (0.1%) With PPAFb FDA_735 24-month REMS Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies. Table 25: Page 60 of 131 Prescriptions Dispensed During the First 10 Days after Passive Patient Enrollment Current Reporting Period 29OCT2012 to 28OCT2013 Parameter Filled at Non-Closed Filled at System Closed System Pharmacies Pharmacies N (%) N (%) Cumulativea,b 28DEC2011 to 28OCT2013 Filled at Combinedd Pharmacies N (%) Filled at All Pharmacies N (%) Filled at Non-Closed Filled at System Closed System Pharmacies Pharmacies N (%) N (%) Filled at Combinedd Pharmacies N (%) Filled at All Pharmacies N (%) Without PPAFb,c 1 Fill 5,409 (77.2%) 47 (83.9%) 0 5,456 (77.2%) 13,988 (80.2%) 134 (92.4%) 1 (25.0%) 14,123 (80.3%) 2 Fills 377 (5.4%) 2 (3.6%) 0 379 (5.4%) 1,065 (6.1%) 2 (1.4%) 3 (75.0%) 1,070 (6.1%) 3 Fills 39 (0.6%) 3 (5.4%) 0 42 (0.6%) 152 (0.9%) 4 (2.8%) 0 156 (0.9%) >3 Fills 2 (<0.1%) 0 0 2 (<0.1%) 8 (<0.1%) 0 0 8 (<0.1%) Note: Closed system pharmacies refers to integrated healthcare systems that dispense TIRF medicines for outpatient use with pharmacy management systems unable to support the process of electronically transmitting the validation and claim information required by the TIRF REMS Access Program. *Combined column reflects subjects who obtained prescriptions from both types of pharmacy systems. a Cumulative data from the end of prior period may differ from the last period's report due to reconciliation of duplicate stakeholders. Percentages are based on the total number of patients for the period. Sum of percentages may be greater than 100 due to patients receiving prescriptions with and without a PPAF during the grace period. c A patient may receive up to 3 fills in the first 10 days after enrollment without a PPAF. d A patient who have filled a prescription at both a closed system pharmacy and a non-closed system pharmacy. b FDA_736 24-month REMS Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies. Page 61 of 131 Figure 2: Number of Patients Dispensed a Prescription During the First 10 Days After Patient Enrollment (290CT2012 to 280CT2013). Prescriptions Dispensed During the First 10 Days after Patient Enrollment (Strati?ed by PPAF Status) Current Reporting Period 100With PPAF Without PPAF Percent of Prescriptions Dispensed 1 Fill 2 Fills 3 Fills 3 Fills Patient Prescriptions Filled During the First 10 Days Prescriptions Dispensed Beyond 10 Days After Patient Enrollment The TIRF REMS Access Program requires that each patient have a PPAF submitted to the TIRF REMS Access Program by their prescriber within 10 days of their passive enrolhnent in order to continue to receive a TIRF medicine. The table below shows the number of prescriptions dispensed beyond the ?rst 10 days without a PPAF on ?le. From the inception of the TIRF REMS through the current reporting period, 242 patients have been dispensed at least 1 prescription beyond the ?rst 10 days without a 26 patients were in the current reporting period. However, as discussed below, corrective actions implemented in July 2013 have been effective at preventing any additional occurrences of this non-compliant activity. 24-month REMS Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies. Table 26: Page 62 of 131 Prescriptions Dispensed Beyond the First 10 Days after Passive Patient Enrollment Cumulativea,b 28DEC2011 to 28OCT2013 Current Reporting Period 29OCT2012 to 28OCT2013 Parameter Filled at Filled at Filled at NonClosed Filled at Filled at NonClosed Filled at Closed System System Combinedb Filled at All Closed System System Combinedb Filled at All Pharmacies Pharmacies Pharmacies Pharmacies Pharmacies Pharmacies Pharmacies Pharmacies N (%) N (%) N (%) N (%) N (%) N (%) N (%) N (%) Number of prescriptions dispensed to patients beyond the first 10 days after patient enrollment 12,927 87 61 13,075 146,740 531 1,311 148,582 Number of patients dispensed at least 1 prescription beyond the first 10 days after patient enrollment 2,972 24 7 3,003 11,187 79 98 11,364 25 0 1 26 230 0 12 242 Fills beyond the first 10 days Without PPAFb a b Cumulative data from the end of prior period may differ from the last period's report due to reconciliation of duplicate stakeholders. A patient who have filled a prescription at both a closed system pharmacy and a non-closed system pharmacy. FDA_738 24-month REMS Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies. Page 63 of 131 In the 12-month assessment report there was 1 patient who received more than 3 fills without a PPAF on file within a 10-day period. The TIRF REMS Access Program investigation of the root cause of this event continued into this reporting period. In this reporting period, there were an additional 3 patients who met the same criteria. The investigation included a review of these 4 cases and extended back to the beginning of the program (12 March 2012-28 October 2013), which identified another 3 cases. In each case the root cause was determined to be an insufficient system requirement for patient matching logic to cover changes to patient data elements during prescription processing. On 15 July 2013 the TIRF REMS Access Program finalized the required system enhancements to modify the patient matching in order to prevent patients receiving more than 3 prescriptions without a PPAF. Additionally, during the time when the system enhancement was being implemented, an additional data quality check was instituted to prevent future occurrences. As of 28 October 2013, all 7 patients have a PPAF on file. After the system enhancement was implemented no additional cases of more than 3 fills within the first 10-days in patients without a PPAF were identified, indicating that the corrective action was effective. The investigation described above was also expanded to include patients who received any fills outside of the 10 days without a PPAF on file. The TIRF REMS Access Program investigation of the root cause of this event occurred in this reporting period. The investigation extended back to the beginning of the program identifying a total of 242 cases. In each case the root cause was determined to be the same as that identified for patients receiving more than 3 prescriptions within the first 10 days without a PPAF and the same corrective action was deemed appropriate. Multiple outreach attempts were conducted to the prescribers to obtain the PPAFs, and, as a result of the outreach, 182 patients now have a PPAF on file. Following the implementation of system enhancements on 15 July 2013 no additional cases of patients who received any fill outside of the 10 day grace period without a PPAF on file have been identified, indicating that the corrective action was effective. 5.3 Program Infrastructure and Performance [Metrics 19, 20, 21, 22, 23, 24] 5.3.1 Pharmacy Management Systems [Metric 19] Table 27 summarizes the time it took enrolled outpatient pharmacies to configure their PMS to communicate with the REMS program. Of 675 outpatient pharmacies that attempted to configure a PMS, 95.6% successfully reconfigured their systems and 4.4% did not complete configuration of their PMS within the reporting period. It took a mean of 0.61 days to configure, with a minimum of 0.0001 days and a maximum of approximately 203.85 days. The 203.85 day outlier for the PMS configuration is an independent outpatient pharmacy that submitted their first PMS test transaction on 18 December 2012 and completed the last PMS test transaction on 10 July 2013 due to the pharmacy’s decision to delay enrollment in the TIRF REMS Access Program. FDA_739 24-month REMS Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies. Table 27: Page 64 of 131 Configuration of Pharmacy Management System (PMS) Parameter Number of Outpatient Pharmacies Attempting to Configure PMS Number of Outpatient Pharmacies with Incomplete Configuration of PMSa Number of Outpatient Pharmacies Successfully Completing Configuration of PMSb Current Reporting Period Cumulative 29OCT2012 to 28OCT2013 28DEC2011 to 28OCT2013 N (%) N (%) 675 3,483 30 (4.4%) 73 (2.1%) 645 (95.6%) 3,410 (97.9%) Time Required to Complete Configurationc Mean 0.6146 0.7843 Minimum 0.0001 0.0001 Maximum 203.85 203.85 a Defined as number of pharmacies with less than 3 dates of test transfers in the reporting period. b Percentages are based on the total number (N) of pharmacies attempting to configure their PMS for the relevant period. For chain pharmacies, this refers to their corporate headquarters, not the number of individual store locations. c Time measured in days from 1st transaction attempt to final transaction successful configuration. 5.3.2 Backup System for Prescription Validation [Metric 20] During this reporting period there were no instances in which a backup system was used to validate a prescription due to pharmacy level problems, switch problems, or REMS database problems. 5.3.3 REMS Call Center [Metric 21a, b] Table 28 below shows reasons for contacting the REMS Call Center by frequency (%). For presentation in the report, this table includes at least 80% of the total cumulative frequency. The most frequent reasons classified under the call reason were pharmacy: pharmacy claim rejection (16.0%) which indicated that the prescriber/patient was not enrolled, enrollment status inquiry (14.2%), PPAF status inquiry (12.8%), and general program questions (8.0%). The call reasons listed below in Table 28 represent 82.6% of calls to the Call Center for the current reporting period. FDA_740 24-month REMS Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies. Table 28: Page 65 of 131 Reasons and Frequency for Contacting the Call Center Current Reporting Period 29OCT2012 to 28OCT2013 Frequency Percenta Cumulative Percent Pharmacy: Pharmacy Claim Rejection 3800 16.0% 16.0% Enrollment Status Inquiry 3372 14.2% 30.2% PPAF Status Inquiry 3031 12.8% 43.0% General Program Questions 1904 8.0% 51.0% Other/Miscellaneous 1669 7.0% 58.0% Enrollment Follow Up 1643 6.9% 64.9% PPAF Follow-up 1522 6.4% 71.3% REMS Prescription Authorization Request 995 4.2% 75.5% Enrollment Form 921 3.9% 79.4% Relay Health Transfer-Tier 2 Support 769 3.2% 82.6% Contact Reason a The total percentage presented in the table is 82.6% of all reasons for contacting the Call Center. Problems or complaints related to patient access issues that were reported to the REMS Call Center for review by the TIRF REMS Access Program are summarized below. The cases described begin with cases reported in the 12-month assessment report but whose resolution occurred in this reporting period. In addition, new problems or complaints reported in this time period are described including their resolutions if attained. Any cases that were not resolved in this time period will be included in the 36-month assessment report. Cases Reported in 12-month Assessment Report and Resolved in This Reporting Period ID #1: Closed [Patient Access] Issue: On 23 August 2012, a complaint letter was received from a prescriber regarding attestation language in the PPAF. The prescriber complained that the TIRF REMS requirement regarding opioid tolerance does not allow the physician to provide “best possible pain management to patients” and possibly requires ”over-prescribing of pain medication.” Status reported in 12-month assessment report: A copy of the prescriber’s letter was submitted to FDA. This prescriber is currently enrolled in the TIRF REMS Access Program and has prescribed TIRF medicines. There was one paid claim recorded in the TIRF REMS Access Program for this prescriber. Resolution: No new PPAF was received for this patient. FDA_741 24-month REMS Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies. Page 66 of 131 ID #2: Closed [Patient Access] Issue: On 03 October 2012, a prescriber submitted a written complaint about PPAF attestation language. The TIRF REMS received a modified PPAF from the prescriber because the patient is not on around-the-clock opioid medication. The Call Center advised the prescriber that an altered PPAF could not be processed and requested the prescriber resubmit the PPAF. The same PPAF was re-submitted with letter of explanation from the patient's physician describing the patient’s condition (i.e., not on ATC opioids). The PPAF was not processed because it was an altered PPAF and therefore did not meet the TIRF REMS requirements. Status reported in 12-month assessment report: An email was sent to FDA requesting a teleconference to discuss requests to modify PPAFs. Resolution: A new, unaltered PPAF was received and processed for this patient on 22 January 2013. Cases Reported in This Reporting Period ID #3: Closed Issue: A chain outpatient pharmacy store advised the Call Center they would not process the patient’s prescription until the pharmacy had a copy of the patient’s PPAF. Pharmacist advised this was a corporate headquarters policy. Resolution: TIRF REMS Access Program contacted a corporate headquarter representative. The headquarter representative contacted both pharmacists in the store (who are also the pharmacists in charge) and re-educated them on proper procedures. The patient has received medication. ID #4: Closed Issue: An outpatient pharmacy contacted the TIRF REMS Access Program Call Center to assist with enrolling them as an outpatient pharmacy when they were unable to complete the test transactions. They informed the Call Center that they do not have the ability to transmit claims electronically. The pharmacy (located in a hospital) allows their employees to fill prescriptions on a self-pay basis with themselves acting as the payer. TIRF REMS Access Program has confirmed they are a closed system with no outside access to third parties or other transmissions. There was one patient waiting for the TIRF medication. Resolution: TRIG approved the pharmacy to enroll as a closed system pharmacy. Additional research was conducted to determine if the patient ultimately received drug. The pharmacy was contacted and the pharmacist indicated they referred this patient to a different pharmacy; however, it could not be confirmed if the patient received their TIRF medicine at the alternate pharmacy. FDA_742 24-month REMS Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies. 5.4 Page 67 of 131 System Errors and Corrective Actions [Metric 22] A brief summary of issues identified as system errors and their corrective actions is presented below. Additional system errors that met the definition of non-compliance are presented in Section 6. System Error #1 Re-enrollment Reminders Were Not Sent to Stakeholders Whose Preferred Method was Email Description: Re-Enrollment reminders were not being generated to prescribers and pharmacists where the preferred method of communication was e-mail as indicated on the TIRF REMS Access Program Enrollment Form. Stakeholders whose preferred method of communication was fax were not impacted. There were 6 stakeholders, all prescribers, who did not receive their re-enrollment reminder prior to deactivation. Root Cause: The cause was determined to be insufficient coding logic and test case for this scenario. Correction: Upon identification of this issue on 18 December 2013, the TIRF REMS Access Program generated a query to identify all potentially impacted stakeholders. Once identified, the TIRF REMS Access Program Call Center placed outbound calls to communicate re-enrollment notifications. The calls were completed on 21 January 2013. Any stakeholders unable to be reached via the outbound call were sent a fax notification which was completed on 20 February 2013. Until an automated solution to send re-enrollment notifications via email was implemented, daily reports were run to identify stakeholders who were scheduled to receive their re-enrollment reminders via email, and these stakeholders were informed about the need to re-enroll. The automated solution was implemented on 17 January 2013. Resolution: At the end of this current reporting period, 2 of the 6 prescribers have re-enrolled, 1 is in the process of re-enrolling and the remaining prescribers are in a deactivated state. System Error #2 Closed System Claim Transition Description: On 28 December 2012, a message was received by the REMS Call Center stating that the NDC (National Drug Code) switch was inoperable when attempting to process claims through the closed system pharmacy claim adjudication system in support of the TIRF REMS closed system pharmacies. The issue was resolved on the same day, and four closed system claims were impacted. Root Cause: The application requires a custom rule on the firewall to allow traffic via specific ports to the pharmacy network server. The custom rule was configured on the primary server firewall, but not the secondary server firewall. On 28 December 2012, transactions were routed through the secondary server due to network volume and these transactions failed because the firewall was not configured properly. FDA_743 24-month REMS Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies. Page 68 of 131 Correction: A rule was added to the second firewall to allow traffic to the closed system pharmacy claim adjudication system and the solution was implemented on 28 December 2012. Rule configuration changes were applied to both servers for future installations of this type on 23 January 2013. Resolution: Four impacted claims were processed through the closed system pharmacy claim adjudication system on 31 December 2012. System Error #3 TIRF REMS Access Program Hardware/Connectivity Issue Description: On 08 November 2012 at 4:00pm, the TIRF REMS Access Program experienced a hardware issue which resulted in rerouting some traffic to a secondary router. The impact of the hardware issue caused 53 TIRF REMS transactions to reject back to the pharmacy with a “System Unavailable, Please Try Again Later” rejection. An analysis was performed by the TIRF REMS Access Program to determine the impact of the 53 unique transactions: • 38 of the 53 transactions have been reprocessed by pharmacy and paid by the payer • 11 of the 53 transactions were reprocessed and rejected by the payer/REMS • 4 of the 53 transactions were voided by the pharmacy Root Cause: Faulty network equipment Correction: The TIRF REMS Access Program immediately rerouted some of the traffic to a secondary router to ensure transactions were processing as expected. Resolution: The faulty network equipment was replaced on 11 November 2012. System Error #4 REMS Transaction Bypassed REMS Edits Description: A pharmacy at an academic medical center had an inbound communication line for transaction processing installed in late January. When installed, the REMS Pre- and Post-Edits were not enabled for this interface by the switch provider – therefore, 1 prescription was not submitted to the TIRF REMS Access Program. Root Cause: When installed, the REMS Pre- and Post-Edits were not enabled for this interface. Correction: REMS Pre- and Post-Edits were enabled for this circuit and a query was performed on all inbound circuits to confirm that the REMS Pre- and Post-Edits were properly set. All other circuits were properly set. Resolution: Transaction was reversed from the third party adjudication. Each time a new circuit is installed, an automated email will be delivered to the TIRF REMS Access Program distribution indicating the status of REMS switches. FDA_744 24-month REMS Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies. Page 69 of 131 System Error #5 REMS Communication Line Migrated Without REMS Edits Description: Between 28 May 2013 and 29 May 2013, the TIRF REMS Access Program performed scheduled network maintenance on outbound circuits. During this maintenance, there was a communication line that was migrated to complete the necessary updates required in the maintenance window. After the communication line was migrated, it was not updated to include TIRF REMS edits. There were 2 impacted transaction claims as a result: One transaction was rejected by the payer and not re-processed and 1 transaction was paid without REMS validation. The pharmacy was contacted on 30 May 2013 and requested that they reverse the transaction that had not been validated by the REMS and re-submit. The pharmacy completed this task on 30 May 2013 and the prescription passed all REMS edits. Root cause: Configuration mismatch between primary and backup processes. Correction: All configuration parameters leading to this particular event were reviewed and no other occurrences were found. The code element was removed which eliminated the need for a configuration setting to be used to invoke REMS services any longer. This was completed on 21 October 2013. Resolution: The configuration error was corrected to execute the TIRF REMS Edits. 5.4.1 Lack of Enrolled Prescribers and/or Pharmacies for Patients [Metric 23] During the current reporting period, the TIRF REMS Access Program received 1 report of difficulty accessing an enrolled prescriber. The prescriber reached out to the TIRF REMS Access Program Call Center on behalf of the patient who was moving and in need of a new enrolled TIRF medicines prescriber close to his/her new residence. The TRIF REMS Access Program CSR conducted a search of 6 zip codes which yielded 0 enrolled prescribers. The agent then broadened the search to include city and state and located an enrolled prescriber. No reports of inadvertent enrollment deactivations were identified. 5.4.2 Delays after Prescription Denial [Metric 24] The prescription conversion time or length of time delay is defined as the length of time between the initial reject on a claim to when it successfully passes all the REMS business rules/edits and is sent to the payer of adjudication. For the assessment period, 29 October 2012 through 28 October 2013: • The mean prescription conversion time was 2 days, 2.358 hours. • The median prescription conversion time was 0 days, 0.227 hours. • The minimum prescription conversion was 0 days, 0.001 hours. • The maximum prescription conversion time was 519 days, 22.007 hours. FDA_745 24-month REMS Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies. Page 70 of 131 There was one outlier of 519 days and 22.007 hours that impacted the maximum prescription conversion time. On 11 April 2012, one independent outpatient pharmacy transmitted a TIRF REMS prescription that did not pass the REMS edits. This transaction was rejected for Prescriber Not Enrolled. On 13 September 2013 (519 days later), the pharmacy resubmitted the claim, the transaction passed the REMS edits but was reversed on the same day. 5.5 Unintended System Interruptions [Metrics 25, 26, 27, 28] 5.5.1 Inadvertent Enrollment Deactivations [Metric 25] During this reporting period there were no inadvertent prescriber deactivations. 5.5.2 Reports of False Positives [Metric 26] During this reporting period, there were no reports of a false positive incident. 5.5.3 Failure of Re-enrollment Notifications [Metric 27] Re-enrollment notifications were sent to a total of 1,172 prescribers via fax and 1,424 prescribers via e-mail this reporting period. Of these, 1,086 prescribers successfully received a notification for re-enrollment via fax and 1,406 prescribers via e-mail. By the end of the reporting period, there were a total of 87 unique prescriber re-enrollment notifications that were unable to be delivered via fax and 18 unique prescriber notifications unable to be delivered via e-mail despite multiple attempts. In the event that the prescriber is unable to be contacted via fax, the TIRF REMS Access Program places an outbound call in an attempt to obtain the correct contact information. If updated information is obtained, the re-enrollment notification is resent. 5.5.4 Reports of False Negatives [Metric 28] During the reporting period, there were no reports of a false negative where all entities were enrolled but the system generated a rejection notice. 5.5.5 Duplicate Stakeholder Records In response to the 12-month assessment report, FDA posed a question concerning identification and handling of duplicate reports. As a consequence FDA asked for 3 new metrics which are listed below. 3.e.i. The number of duplicate prescribers, patients, and pharmacies identified in the system. 3.e.ii Why the duplications were not originally detected. 3.e.iii. The corrective actions taken to assure minimization of future duplicative data entries The investigation of duplicate reports identified that records that were classified as “obsolete” had been included in the stakeholder counts reported in the previous assessment reports. FDA_746 24-month REMS Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies. Page 71 of 131 Programming has been updated to ensure that “obsolete” records are excluded from this and future reports. Duplicate Prescriber and Pharmacy Records The system does not allow duplicate records to be created for prescribers and pharmacists due to the unique identifiers required for enrollment (i.e., DEA, NPI, NCPDP). Duplicate Patient Records Patient records are created by the processing of a patient’s first paid TIRF prescription (i.e., passive patient enrollment), or by the receipt of a Patient-Prescriber Agreement Form (PPAF). As a result, the TIRF REMS Access Program has two systematic methods utilized to handle patient duplicates. First, the TIRF REMS Access program systemically identifies and rectifies duplicate records utilizing patient matching logic consisting of key patient identifiers (i.e. Date of Birth, First Name, Last Name, and Zip Code). This occurs as part of the normal course of business when passive patient enrollments and PPAFs are processed; therefore duplicate patient records are not created. Second, the TIRF REMS Access Program systematically identifies potential patient duplicates, which generates a daily report to the TIRF REMS Access Program Call Center to ultimately determine if the record is a valid duplicate. Valid duplicates identified by the TIRF REMS Access Program Call Center are merged into one patient record. A total of 733 duplicate patient records were identified and merged during the 24-month assessment period. Because the system does not allow duplicate records to be created for prescribers and pharmacists due to the unique identifiers required for enrollment TRIG questions the utility of this metric for stakeholders. However, reporting on the number of merged patient records is a metric the TRIG would like to discuss with FDA in January 2014 as a follow-up to the proposed changes to the assessment plan dated 19 September 2013. 5.6 Audits No stakeholder audits were conducted during the current reporting period. 6 TIRF REMS ACCESS PROGRAM NON-COMPLIANCE During the current reporting period, instances of potential stakeholder non-compliance with the TIRF REMS Access program were reviewed and investigated. A summary of the noncompliance activity is presented in Table 29. FDA_747 24-month REMS Assessment Report Transmucosal Irmnediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies. Page 72 of 131 Table 29 29 October 2012 to 28 October 2013 Non-Compliance Activity Reports by Stakeholder in the Current Reporting Period: Stakeholder Non-Compliance Non?Compliant Reason (categorized as Current Reporting Period Activity reported bv the No. of events No. of stakeholders stakeholder) Submission of inappropriately altered claim to meet TIRF Altered RX details for 2 No w/l wt 2 REMS system a REMS authorization requirements changing prescriber) Submission of a claim that did not go through Received reject but 22 No. w/ rpt: 18 Non-Closed the REMS edits. A TIRF dispensed drug NO- rpt: 2 System Pharmacy medicine was dispensed without verifying through aware Of . the TIRF phannacy requirement to process 3 No. rpt. 3 management system that cash claims the prescriber is enrolled Not aware of cash and active. and that the claim and received patient is enrolled or has reject but dispensed 4 NO- ?7/1 rpt: 4 not been inactivated in the drug program. Total 31 29 Dispensing prescriptions . Closed System outside of the closed 2:111) 233:133511 an 2 No /1 t' 2 Pharmacy system authorization authorization rp process. Total 2 2 Prescriber failure to submit completed PPAFs in a timely manner (5 or No reason provided* 8 No. w/ lrpt: 8 more enrolled patients Prescriber without a complete PPAF on ?le. with each patient having greater than 10 working days lapse ?om initial enrollment date). Not aware of PPAF 84 No. w/ 1 rpt: 80 requirement No. w/ 2 rpt: 2 Total 92 90 *No reason provided by stakeholder after multiple outreach attempts. The following tables (Table 30 and Table 31) list resolved and pending potential reports of non- compliance, respectively. 24-month REMS Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies. Table 30 Follow-up From the 12 Month Assessment Report Report No.1 Report Description Page 73 of 131 Report Status Closed System Pharmacy: The TIRF REMS Access Program administrator identified that the program had not received any prescription authorizations from the Veteran’s Administration (VA) since the closed system pharmacy effective day of 01 July 2012. Following multiple outreach attempts to the VA, the program received contact from the VA Authorized Representative on November 15th confirming that there had been TIRF prescriptions dispensed without obtaining an authorization to dispense from the Closed System Program. (CAPA 341) 13 Closed Mitigating Action The VA conducted a thorough search across the entire VA system and confirmed that there were TIRF prescriptions dispensed between 01 July 2012 and 30 November 2012. As stated in the communication sent to FDA on January 25, 2013, there were a total of 85 dispenses from 15 closed system outpatient VA pharmacies for 19 unique patients during this time period. Of the 85 dispense records, 28 dispenses met the safe use conditions and would have received an Rx Authorization if the program was contacted correctly prior to dispense. The remaining 57 dispense records would not have received Rx Authorizations for the following reasons: prescriber not enrolled (38); pharmacy not enrolled (8); PPAF not on file (6); incomplete TIRF medicine NDC (5). Stakeholders affected by the 57 records that did not meet all REMS requirements included: 13 unique prescribers; 3 unique pharmacies; 2 unique patients requiring a PPAF; 2 unique patients with an incomplete NDC on the dispense record. The VA was re-educated on the REMS requirements and issued a formal Notice for Non-Compliance. As of 31 October 2013, 3 additional prescribers have enrolled in the TIRF REMS Access Program bringing the total number of unique stakeholders associated with the VA that are enrolled in the TIRF REMS Access Program to 9. Additionally the VA had a total of 86 prescription authorizations issued as of 31 October 2013. FDA_749 24-month REMS Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies. Table 31 14 15 Page 74 of 131 Reports in the Current Reporting Period: 29 October 2012 to 28 October 2013 ID# 29 (Case #11793909) On 06 November 2012, a prescriber was contacted to request a PPAF for a patient who did not have one on file at least 10 days after enrollment (transaction was submitted on October 19). The prescriber claimed the patient in question was not a patient of his/her practice and a similar scenario with the pharmacy and prescriber had occurred previously in March 2012. The TIRF REMS Access program non-compliance team contacted the pharmacy associated with the REMS authorized prescription for additional information. It was discovered that when an Outpatient Chain Pharmacy Store processed this prescription on 16 March 2012, the pharmacy received a rejection from the TIRF REMS Access Program for the reason “prescriber not enrolled.” The pharmacy then re-processed the prescription, but used another prescriber’s DEA number. This time, the transaction was authorized by the REMS. The pharmacy was contacted on 11 November 2012, re-educated on the TIRF REMS Access Program requirements, and sent a formal Warning for Non-Compliance letter. The pharmacy requested that the TIRF REMS Access Program also directly contact the pharmacy’s chain headquarters to resolve this issue and address any further inquiry. ID# 54 (Case #12146501) On 25 October 2012, the TIRF REMS Access Program contacted a prescriber to obtain a PPAF for a patient who was at least 10 days past enrollment without a PPAF on file. The prescriber reported that he routinely does not submit PPAFs because he only writes one prescription for TIRF medicines for each of his patients. At the time of investigation, 18 patients enrolled by this prescriber did not have a PPAF on file. Closed After re-education, the TIRF REMS Access Program worked with the pharmacy chain headquarters to develop a corrective action plan. An acceptable corrective action plan stating that the chain pharmacy store would dispense TIRF medications only after submitting a claim properly and receiving approval for the claim was received on 04 March 2013 and approved on 08 March 2013 by the NCRT. The chain pharmacy store’s activity was monitored through 19 July 2013, and all activity observed during this period appeared in compliance with program requirements. This is the first confirmed report of non-compliance for this chain pharmacy store to date. The transaction submitted on 19 October 2012 for the patient without a PPAF on file was reversed on October 19, 2012. The original prescriber who wrote the prescription was identified during the investigation and subsequently enrolled in the TIRF REMS Access Program; a PPAF was submitted for the patient. Closed On 12 November 2012, the prescriber was re-educated on the TIRF REMS Access Program requirements and issued a formal Notice for Non-Compliance. The prescriber was unable to provide any PPAFs for these patients. Subsequent to re-education, the prescriber enrolled an additional patient on 19 December 2012 without submitting a PPAF. The prescriber was contacted on 11 January 2013, re-educated again on the requirement to submit PPAFs for enrolled patients, and issued a formal Warning for Non-Compliance letter since the second non-compliant event occurred within 60 days from the initial. The prescriber submitted a corrective action plan stating the prescriber would complete a PPAF at the time when the prescription is written. This corrective FDA_750 24-month REMS Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies. Table 31 Page 75 of 131 Reports in the Current Reporting Period: 29 October 2012 to 28 October 2013 action plan was approved by the NCRT on 23 January 2013. The prescriber activity was monitored through 07 March 2013; no additional patients were enrolled during this period. As of the close of the reporting period, no PPAFs were received for the 19 (total) patients and no additional prescriptions were submitted for these patients. Since closing the non-compliance cases, the prescriber has not enrolled any additional patients in TIRF REMS Access Program. 16 17 ID# 73 (Case #14089142) During regular compliance monitoring, a prescriber was identified as not submitting PPAFs for 36 patients who were at least 10 days past enrollment. The prescriber was contacted on 07 March 2013, re-educated on the TIRF REMS Access Program requirements, and issued a formal Notice for NonCompliance letter. The prescriber submitted PPAFs for 34 of the 36 patients (2 patients were identified as not continuing therapy). The REMS activity for this prescriber was monitored through 07 May 2013 with no additional findings. On 27 June 2013, the prescriber was again identified as not submitting PPAFs for an additional 16 patients who were at least 10 days past enrollment. ID# 89 (Case #14088956) During regular compliance monitoring, a prescriber was identified as not submitting PPAFs for 62 patients who were at least 10 days past enrollment. The prescriber was contacted on 14 March 2013, re-educated on the TIRF REMS Access Program requirements, and issued a formal Notice for NonCompliance letter. The prescriber submitted 27 of the 62 The prescriber was contacted on 11 July 2013, re-educated, and issued a second formal Notice for Non-Compliance letter since this second event was greater than 60 days from the initial noncompliant event. The prescriber provided PPAFs for 3 of these 16 patients identified on 27 June 2013. Closed As of the close of the reporting period, PPAF's have not been received for any of the 15 remaining patients from the noncompliance cases above. Fourteen of the patients have not submitted an additional prescription for a TIRF medicine; 1 of the 15 patients had a rejected claim due to no PPAF on file. Since re-education and closing of the second non-compliance case, the prescriber has no new patients without a PPAF on file outside of the 10-day window. Closed The prescriber was contacted on 26 June 2013, re-educated, and requested to provide PPAFs for these patients. None were provided. TIRF REMS Access Program supported the prescriber over several weeks to maintain compliance with program requirements. During this time, the prescriber enrolled an additional 27 patients and submitted PPAFs for all of these patients. A second formal Notice for Non-Compliance letter was FDA_751 24-month REMS Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies. Table 31 Page 76 of 131 Reports in the Current Reporting Period: 29 October 2012 to 28 October 2013 outstanding PPAFs and confirmed that the remaining 35 patients were identified as not continuing therapy. On 19 June 2013, the prescriber was again identified for not submitting PPAFs for an additional 18 patients. issued on 12 August 2013 since the second event was greater than 60 days from the initial noncompliant event. As of the close of the reporting period, PPAF's have not been received for any of the 53 outstanding patients from the non-compliance cases above. Three of the 53 patients have attempted to have a prescription filled for a TIRF medicine outside of the 10-day window without a completed PPAF on file, however the REMS rejected these prescription attempts due to no PPAF on file. For the remaining 50 patients, no prescriptions have been submitted. Since re-education and closing of the second non-compliance case, the prescriber has no new patients without PPAFs on file outside of the 10-day window. 18 ID# 96 (Case #14089163) During regular compliance monitoring, a prescriber was identified as not submitting PPAFs for 11 patients who were at least 10 days past enrollment. The prescriber was contacted on 09 April 2013, re-educated on the TIRF REMS Access Program requirements, and issued a formal Notice for NonCompliance letter. PPAFs were received for all 11 patients. On 19 June 2013, the prescriber was again identified as not submitting PPAFs for an additional 8 patients who were at least 10 days past enrollment. Closed The prescriber was contacted in July 2013, re-educated, and requested to provide PPAFs for these patients. The prescriber was able to provide PPAFs for 3 of these patients. TIRF REMS Access Program supported the prescriber over several weeks to maintain compliance with program requirements. During this time, one additional patient was enrolled by the prescriber and a PPAF was submitted. A second formal Notice for Non-Compliance letter was issued on 17 August 2013 since this second event was greater than 60 days from the initial noncompliant event. As of the close of the reporting period, PPAFs were received for 3 of the patients. PPAFs were not received for 2 of the 5 patients. These 2 patients have attempted to have a prescription filled for a TIRF medicine; however the REMS rejected these prescription attempts due to no PPAF on file. Since re-education and closing of the second non-compliance case, the prescriber has 0 new patients without PPAFs on file outside of the 10-day window. 19 ID# 102 (Case #15529127) On 12 March 2013, a prescriber was contacted to request Closed The prescriber was contacted on 09 September 2013, re-educated, and requested to provide PPAFs for these patients. The prescriber FDA_752 24-month REMS Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies. Table 31 20 Page 77 of 131 Reports in the Current Reporting Period: 29 October 2012 to 28 October 2013 PPAFs for 18 patients who did not have one on file at least 10 days after enrollment. The prescriber was re-educated on the TIRF REMS Access Program requirements, and issued a formal Notice for Non-Compliance letter. PPAFs were received for 17 of the 18 patients. On 02 September 2013, the prescriber was again identified as not submitting PPAFs for an additional 7 patients who were at least 10 days past enrollment. was able to provide PPAFs for all 7 of these patients. A second formal Notice for Non-Compliance letter was issued on 29 September 2013 since this second event was greater than 60 days from the initial noncompliant event. ID# 121 (Case#) On 09 September 2013, a prescriber was contacted to request PPAFs for 5 patients who did not have one on file at least 10 days after enrollment. The prescriber provided PPAFs for 2 of the patients, but stated that 3 of the patients in question were not from his/her practice. On 10 September 2013, the TIRF REMS Access Program contacted the independent pharmacy associated with the REMS authorized prescriptions for additional information. The pharmacy was unwilling to provide any information on these 3 patients and disconnected the call. All transactions from the pharmacy were reviewed by the NCRT. Seven claims involving 6 patients (including the 3 patients noted above) were identified where the patient’s name was reversed (first name entered as last name, last name entered as first name) after the pharmacy received a rejection from the TIRF REMS Access Program for the reason “no PPAF on file." The pharmacist in charge was contacted on 04 October 2013 and the pharmacist in charge explained that these claims were from electronic prescriptions and processed with the information as it was provided (i.e., names were switched on original prescription). As of the close of the reporting period, a PPAF has not been received for one patient. Since closing the second non-compliance case, the prescriber has 3 new patients without PPAFs on file, all outside of the 10-day window. These 3 patients have not attempted to fill any additional TIRF medicine prescription. A new suspected non-compliance case will be opened if the number of patients without a PPAF outside of the 10-day window reaches the threshold of 5. Open Based on this evidence, the pharmacy was issued a formal Warning for Non-Compliance letter. Additionally, the pharmacy was required to provide a corrective action plan that was approved by the NCRT on 06 November 2013 stating that all pharmacy staff FDA_753 24-month REMS Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies. Table 31 Page 78 of 131 Reports in the Current Reporting Period: 29 October 2012 to 28 October 2013 members have been trained on the program and have been educated on the importance of inputting correct patient data prior to transmitting pharmacy claims. Additionally all TIRF REMS claims will be checked and verified by a pharmacist. Additional monitoring will also occur for a minimum of 1 month to ensure this pharmacy does not continue this non-compliant activity. 21 ID# 127 (Case# 15791475) On 28 January 2013, a prescriber was contacted to request PPAFs for 13 patients who did not have one on file at least 10 days after enrollment. The prescriber was re-educated on the TIRF REMS Access Program requirements, and issued a formal Notice for Non-Compliance letter. The prescriber submitted all 13 outstanding PPAFs. On 17 September 2013, the prescriber was again identified for not submitting PPAFs for an additional 11 patients. The TIRF REMS Access Program made 3 attempts to contact the prescriber, but was advised by the prescriber’s office staff that the prescriber “refused to come to the phone regarding PPAF calls from TIRF REMS Access.” By 21 October 2013, only 1 of the 11 outstanding PPAFs were received, and 3 additional patients were identified who did not have a PPAF on file at least 10 days after enrollment. Open As of the close of the reporting period, PPAFs have not been obtained for any of the 13 patients. Seven new patients have been enrolled without a PPAF on file outside of the 10-day window. To date, the prescriber has a total of 20 patients enrolled without a PPAF. A warning letter requesting a corrective action plan was issued to the prescriber 05 November 2013. FDA_754 24-month REMS Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies. Table 31 22 Page 79 of 131 Reports in the Current Reporting Period: 29 October 2012 to 28 October 2013 ID# 128 (Case# 11744815) On 11 June 2012, the TIRF REMS Access Program contacted a prescriber to obtain a PPAF for a patient who was enrolled in the program on 08 June 2012. The prescriber’s office staff (b) (6) reported the patient in question died in . The pharmacy that processed the prescription confirmed the date of the prescription as 07 June 2012, and verified the pharmacy processed the prescription on 08 June 2012. The TIRF REMS Access Program confirmed that the pharmacy reversed the claim indicating that no TIRF medicine was dispensed. Closed The prescriber was contacted to confirm if the prescription was written after the patient’s death. The prescriber requested, and was provided, a copy of the prescription in question. The prescriber contacted the TIRF REMS Access Program after reviewing the prescription and reported the office has two patients with the same name, one who died and one who was still living, and cited an office error as the source of confusion. Based on this evidence, this case of suspected non-compliance was closed as not a non-compliant event and the details of the case were shared with the sponsor of the product for appropriate follow-up. 1 For tracking purposes across TIRF REMS Access Program assessment reports, noncompliance reports are numbered consecutively and continuously from the first TIRF REMS Access Program Assessment Report. FDA_755 24-month REMS Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies. 7 7.1 Page 80 of 131 SAFETY SURVEILLANCE Adverse Events The following Quarterly Analysis report was produced from the cumulative 2012 Q4 release of the FDA Adverse Event Reporting System (FAERS) database which was made publicly available by the FDA in early October 2013. This Analysis Report focuses on the latest 2 quarters of the AERS data, Q3 and Q4 2012, which are new since the last Quarterly Analysis report was delivered using the Q2 2012 AERS data. As AERS releases are cumulative, the data for both quarters are contained in the most recent Q4 2012 release. The FAERS 2012 Q4 database is comprised of 4,073,790 cumulative case reports, including 232,989 new reports and 115,427 reports from the Q3 2012 quarterly release. Of the cumulative case reports included in this release, seventy-one (71) cases reference a (TIRF medicine covered by this REMS, with an event date on or after December 28, 2011. Fifty-three (53) of these 71 TIRF product case reports with an event date after December 28, 2011 also specify United States as the Country of Origin and are included in the analysis results described below. Sixteen (16) of these 53 domestic cases are new since the last TRIG Surveillance report was produced using the Q2 2012 release of the AERS data for inclusion in the 12 Month TIRF REMS Assessment Report. Thirty-four (34) of the 53 domestic cases include at least one of the TRIG MedDRA Preferred Terms of Interest and are included in the analysis. Eight (8) of these 34 cases with a TRIG MedDRA Preferred Terms of Interest are new since the last TRIG Surveillance Report was produced using the Q2 2012 release of the AERS data for inclusion in the 12 Month TIRF REMS Assessment Report. These MedDRA Preferred Terms of Interest are grouped into the following broad Categories of Interest (TRIG Categories) for aggregate reporting: o Death o Overdose (fatal and non-fatal) o Misuse, abuse, addiction, and diversion o Inappropriate prescribing o Medication errors o Accidental exposure/ingestion In addition, 1 of the 53 cases that specifies at least one Preferred Term from the MedDRA SMQ (Broad) Acute Central Respiratory Depression, (Preferred Terms are located in Appendix FDA_756 24-month REMS Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies. Page 81 of 131 FAERS Safety Surveillance Report) is included in this analysis as it contains a possible symptom related to the events included in the TRIG Categories above. None of the individual Preferred Terms from this SMQ is a TRIG Preferred Term of interest, but counts of reports listing any PT from this SMQ will be summarized into an aggregate count for the entire SMQ and reported separately. The following table summarizes the adverse event Terms and Categories of Interest that were reported in the cases for TIRF products that met the selection criteria for this analysis. A total of 46 PTs of Interest were reported across 34 cumulative case reports that contained a PT of Interest. Ten Preferred Terms were included in the 8 new cases that were submitted since the last AERS Surveillance analysis. Cumulatively, the most commonly reported Term is “Off label use” (23 cumulative / 5 new) followed by “Drug prescribing error” (8 cumulative / 1 new). Three of the 8 new cases contain the Preferred Term “Death” as one of the reported adverse events, representing 30% of all Preferred Terms of Interest reported on new cases. Tallies of the reported PTs and categories are summarized in the table below: Table 31 Q3-Q4 2012 Count of Reported Events of Interest Grouped by TRIG Category : Categories of Interest Q3-Q4 2012 N = 10 PTs Total to Date N = 46 PTs N % N % Overdose 0 0.0% 0 0.0% Accidental overdose 0 0.0% 0 0.0% Intentional overdose 0 0.0% 0 0.0% Overdose 0 0.0% 0 0.0% Death 3 30.0% 3 6.5% Accidental death 0 0.0% 0 0.0% Agonal death struggle 0 0.0% 0 0.0% Apparent death 0 0.0% 0 0.0% Brain death 0 0.0% 0 0.0% Cardiac arrest 0 0.0% 0 0.0% Cardiac death 0 0.0% 0 0.0% Cardio-respiratory arrest 0 0.0% 0 0.0% Death 3 30.0% 3 6.5% Death neonatal 0 0.0% 0 0.0% Death of companion 0 0.0% 0 0.0% Death of relative 0 0.0% 0 0.0% Respiratory arrest 0 0.0% 0 0.0% FDA_757 24-month REMS Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies. Page 82 of 131 Table 31 Count of Reported Events of Interest Grouped by TRIG Category Q3-Q4 2012 2012 tTiiai Categories of Interest 10 PTS :46aPeTs i 0/o Sudden cardiac death 0 0.0% 0 0.0% Sudden death 0 0.0% 0.0% Sudden unexplained death in epilepsy 0 0.0% 0 0.0% Misuse 0 0.0% 0 0.0% Intentional Drug Misuse 0 0.0% 0 0.0% Medication overuse headache 0 0.0% 0 0.0% Drug abuse dependence and withdrawal SMQ 1 7 Abuse 0 0.0% 0 0.0% Drug abuse 0 0.0% 0.0% Drug abuser 0 0.0% 0 0.0% Ex-dmg abuser 0 0.0% 0 0.0% Substance abuse 0 0.0% 0 0.0% Substance abuser 0 0.0% 0 0.0% Substance-induced mood disorder 0 0.0% 0 0.0% Substance-induced disorder 0 0.0% 0 0.0% Drug abuse dependence and withdrawal SMQ 1 7 Inappropriate Prescribing 5 50.0% 23 50.0% Drug administered at inappropriate site 0 0.0% 0 0.0% Drug administered to patient of inappropriate age 0 0.0% 0 0.0% Drug administration monitoring procediu?e incorrectly performed 0 0.0% 0.0% Drug administration monitoring procedlu?e not performed 0 0.0% 0 0.0% Inappropriate schedule of drug administration 0 0.0% 0 0.0% Off label use 5 50.0% 23 50.0% Medication Error 1 10.0% 13 28.3% Accidental drug intake by child 0 0.0% 0 0.0% Comiterfeit drug administered 0 0.0% 0 0.0% Drug administered to patient of inappropriate age 0 0.0% 0.0% Drug administration error 0 0.0% 2.2% Drug dispensing error 0 0.0% 1 2.2% Drug dose omission 0 0.0% 2.2% 24-month REMS Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies. Table 31 Q3-Q4 2012 Page 83 of 131 Count of Reported Events of Interest Grouped by TRIG Category : Q3-Q4 2012 N = 10 PTs Total to Date N = 46 PTs N % N % Drug label confusion 0 0.0% 0 0.0% Drug name confusion 0 0.0% 0 0.0% Drug prescribing error 1 10.0% 8 17.4% Expired drug administered 0 0.0% 1 2.2% Inappropriate schedule of drug administration 0 0.0% 0 0.0% Incorrect dose administered 0 0.0% 0 0.0% Incorrect dosage administered 0 0.0% 0 0.0% Incorrect drug administration duration 0 0.0% 0 0.0% Incorrect drug administration rate 0 0.0% 0 0.0% Incorrect drug dosage form administered 0 0.0% 0 0.0% Incorrect route of drug administration 0 0.0% 0 0.0% Incorrect storage of drug 0 0.0% 0 0.0% Intercepted drug dispensing error 0 0.0% 0 0.0% Intercepted drug prescribing error 0 0.0% 0 0.0% Intercepted medication error 0 0.0% 0 0.0% Labeled drug-disease interaction medication error 0 0.0% 0 0.0% Labeled drug-drug interaction medication error 0 0.0% 0 0.0% Medication error 0 0.0% 0 0.0% Multiple use of single-use product 0 0.0% 0 0.0% Poor quality drug administered 0 0.0% 0 0.0% Prescribed overdose 0 0.0% 0 0.0% Prescribed underdose 0 0.0% 0 0.0% Therapy naïve 0 0.0% 0 0.0% Underdose 0 0.0% 0 0.0% Wrong drug administered 0 0.0% 0 0.0% Wrong technique in drug usage process 0 0.0% 1 2.2% Accidental Exposure 0 0.0% 0 0.0% Accidental drug intake by child 0 0.0% 0 0.0% Accidental exposure to product 0 0.0% 0 0.0% Accidental overdose 0 0.0% 0 0.0% Categories of Interest FDA_759 24-month REMS Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies. Page 84 of 131 Table 31 Count of Reported Events of Interest Grouped by TRIG Category Q3-Q4 2012 2012 tTiiai Categories of Interest 10 PTS :46aPeTs Accidental poisoning 0 0.0% 0 0.0% Toxicity to various agents 0 0.0% 0 0.0% Dependence 1 10.0% 7 15.2% Dependence 0 0.0% 0 0.0% Drug dependence 1 10.0% 1 2.2% Drug dependence. anteparnun 0 0.0% 0 0.0% Drug dependence. postpartum 0.0% 0 0.0% Drug Withdrawal 0 0.0% 3 6.5% Polysubstance dependence 0 0.0% 0 0.0% Withdrawal 0 0.0% 3 6.5% Drug Diversion 5 50.0% 23 50.0% Drug diversion 0 0.0% 0 0.0% Off label use 5 50.0% 23 50.0% Respiratory Depression 0 1 Acute central respiratorv depression SMQ 0 1 A data mining (disproportionality) analysis was also performed on the selected AERS cases, using the entire AERS database as the backgrorurd denominator. Relatively robust signals of disproportionate reporting were generated for the PTs of Interest: ?Off label Use? and ?Drug prescribing error?. A weaker signal was generated for the Preferred Term of Interest ?Drug withdrawal which is a known adverse event for TIRF medicines. When analyzed according to TRIG Categories of Interest, relatively robust signals were also generated for ?Inappropriate use?, ?Drug diversion?, ?Medication error?, and ?Drug dependence?. When examined by SMQ, the SMQ ?Drug abuse, dependence and withdrawal? generated a weaker signal of disproportionate reporting. These results are similar to those seen in the last quarterly analysis, and no additional signals have been identi?ed. 7.2 American Association of Poison Control Centers (AAPCC) The AAPC database is monitored to identify reports of misuse, abuse, and overdose. The AAPC database includes all 57 poison centers in the US. Reports were requested from AAPC on calls related to the aggregated data for the class of immediate-release transmucosal fentanyls (no manufactlu?er names or brand names are provided). The search also included 24-month REMS Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies. Page 85 of 131 reports of unknown manufacturer oral immediate-release fentanyl products, and "unknown fentanyls" with oral and/or inhalation/nasal route(s) of exposure. AAPCC listings of reports for TIRF medicines and unknown fentanyl are presented in Appendix 12.2. In the current reporting period (29 October 2012 to 28 October 2013), the AAPCC received 17 reports of exposure to known oral fentanyl immediate-release medicines. The 17 cases had medical outcomes of 2 deaths, 5 major effects, 4 moderate effects, 2 minor effects, 1 no followup minimal toxicity, and 1 no follow-up potentially toxic. “Effect” is defined as sign, symptom, or laboratory abnormality and described as minor, moderate, major, or death (See Appendix 12.2 for effect definitions). Twenty cases of exposure to unknown fentanyl were reported to the AAPCC during the current reporting period. The cases had medical outcomes of 2 deaths (indirect reports), 3 major effects, 8 moderate effects, 3 minor effects, 3 unable to follow/judged as potentially toxic exposure, and 1 no effect. Both deaths were classified as intentional abuse. Four reports were characterized as intentional suspected suicide, all of these patients survived (Appendix 12.2). Of note, 3 cases included in the AAPCC data were classified as exposures to a TRIF medicine, although the only fentanyl noted in the case was for a patch. When questioned about this report, an AAPCC representative provided this response: “All of the fields are manually coded by the SPI based on self-report information by the caller. I confirmed that all three of these cases are coded specifically to one of the TIRF products’ unique 7-digit Poisindex product identifiers. SPIs make every attempt to code to the exact product involved – they will ask the caller to read off the box/bottle, read the imprint code, etc. to try to determine the exact product, strength and manufacturer. The SPIs then look up the provided information in Poisindex and select the entry that matches the information provided by the caller. When the SPI selects the product involved, the case in their local database is automatically populated with that product’s unique 7-digit Poisindex product identifier. I can’t speak with certainty about what was said on the calls or why the SPIs chose to code the cases as they did, but I will say that Poisindex lists the formulation for the 3 TIRF products in question as “Mucous membrane lozenge/troche”. However, the NPDS Formulation variable does not list this as one of the options for the SPIs to select. There may be confusion on the SPIs part regarding which Formulation option to select in the absence of a “Mucous membrane lozenge/troche” option.” Detailed information on the reports of death will not be available from the AAPCC until December 2014. FDA_761 24-month REMS Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies. Page 86 of 131 The following tables (Tables 20-26) include reports for exposures to TIRF medicines received between 29 October 2012 and 28 October 2013. The tables do not include reports for unknown fentanyl products. Human Exposure Cases: Site of Call/Site of Exposure As shown in Table 32 for the current reporting period, of the 17 human exposures associated with TIRF medicines reported. Of the 17 most of the exposures (n=13) occurred in the patients’ own residences. Beyond residences, 1 exposure occurred in a health care facility, 1 in a public area and 2 exposure sites were unknown. Most of the reports originated from a health care facility (n=14). Table 32: Site of Call and Site of Exposure, Human Exposure Cases Associated with TIRF Medicines: 29 October 2012 to 28 October 2013 Site of Exposure Case Count Site of Caller Case Count Health Care Facility 1 14 Other 0 1 Own Residence 13 2 Public Area 1 0 Unknown 2 0 Total 17 17 Site Human Exposure Cases: Age and Gender Distribution The age and gender distribution of human exposures associated with TIRF medicines is outlined in Table 33. There was one pediatric/adolescent exposure in a male in the age group 3 to 19 (age 16). Another 16 exposures were reported in adults 20 years of age or older, the majority of which were in the 20-29 age group (35.3%). Table 33: Age and Gender Distribution of Human Exposures Associated with TIRF Medicines: 29 October 2012 to 28 October 2013 Male N (%) Female N (%) Unknown N (%) Total N (%) 1 0 0 0 0 2 0 0 0 0 3-19 1 (10.0%) 0 0 1 (5.9%) 20-29 4 (40.0%) 2 (28.6%) 0 6 (35.3%) Age (yr) FDA_762 24-month REMS Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies. Page 87 of 131 Table 33: Age and Gender Distribution of Human Exposures Associated with TIRF Medicines: 29 October 2012 to 28 October 2013 Male N (%) Female N (%) Unknown N (%) Total N (%) 30-39 3 (30.0%) 0 0 3 (17.6%) 40-49 1 (10.0%) 2 (28.6%) 0 3 (17.6%) 50-59 1 (10.0%) 1 (14.3%) 0 2 (11.8%) 60-69 0 0 0 0 70-79 0 1 (14.3%) 0 1 (5.9%) Unknown adult (>=20 yrs) 0 1 (14.3%) 0 1 (5.9%) 10 (58.8%) 7 (41.2%) 0 17 (100.0%) Age (yr) Total All fatalities – All Ages and Gender There were 2 fatalities reported in the AAPCC data associated with known exposures to TIRF medicines: 1 female in the 50 to 59 age group and 1 female in the 70 to 79 age group (AAPCC Database Table 4). Human Exposure Cases: Number of Substances As shown in Table 34, a single substance was implicated in 8 reported human exposures, and 9 patients were exposed to two or more drugs or products. The 2 reports of death involved exposure to 2 or more drugs or products. For cases that involved multiple substances, the route of exposure is only captured for one of the substances; therefore, the reported case may include additional fentanyls that are not oral or inhalation formulations and may not be limited to the class of immediate-release fentanyls. FDA_763 24-month REMS Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies. Page 88 of 131 Table 34: Number of Substances Involved in Human Exposure Cases Associated with TIRF Medicines or a Fentanyl with Oral or Inhalation as Route of Exposure: 29 October 2012 to 28 October 2013 Case Count N (%) Fatality Case Counta N (%) 1 8 (47.1%) 0 2 3 (17.6%) 1 (50.0%) 3 3 (17.6%) 1 (50.0%) 4 3 (17.6%) 0 17 (100.0%) 2 (100.0%) Number of Substances Total a Includes cases with relative contribution to fatality of 1-Undoubtedly responsible, 2-Probably responsible, or 3Contributory. This excludes reports with outcome of Death INDIRECT. Reason for Exposure The reasons for both unintentional (general and misuse) and intentional (abuse, suspected suicide, and unknown) human exposures associated with TIRF medicines are shown in Table 35. There were 3 cases classified as unintentional exposures with 14 classified as intentional exposures including 4 cases of abuse and 5 suspected suicides. Table 35: Reason for Human Exposure Cases Associated with TIRF Medicines: 29 October 2012 to 28 October 2013 Reason Category Case Count N (%) Unintentional Unintentional – General 2 (66.7%) Unintentional - Therapeutic error 1 (33.3%) Subtotal 3 (17.6%) Intentional Intentional – Abuse 4 (28.6%) Intentional – Misuse 1 (7.1%) Intentional - Suspected suicide 5 (35.7%) Intentional – Unknown 2 (14.3%) FDA_764 24-month REMS Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies. Page 89 of 131 Table 35: Reason for Human Exposure Cases Associated with TIRF Medicines: 29 October 2012 to 28 October 2013 Reason Category Case Count N (%) Unknown reason 2 (14.3%) Subtotal 14 (82.4%) Total 17 (100.0%) Therapeutic Errors There was 1 report of a therapeutic error associated with TIRF medicines in the current reporting period (AAPCC Database Table 6B) as shown in Table 36. The therapeutic error was a health professional iatrogenic error in one patient >19 years of age. FDA_765 24-month REMS Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies. Table 36: Page 90 of 131 Distribution of Therapeutic Errorsa by Age Associated with TIRF Medicines: 29 October 2012 to 28 October 2013 <6 years (Row %) 6-12 years (Row %) 13-19 years (Row %) >19 years (Row %) Unknown Child (Row %) Unknown Adult (Row %) Unknown (Row %) Total a Incorrect Dosing Route 0 0 0 0 0 0 0 0 Dispensing Cup Error 0 0 0 0 0 0 0 0 10-Fold Dosing Error 0 0 0 0 0 0 0 0 Inadvertently Took/Given Someone Else's Medication 0 0 0 0 0 0 0 0 Inadvertently Took/Given Medication Twice 0 0 0 0 0 0 0 0 Incorrect Formulation or Concentration Given 0 0 0 0 0 0 0 0 Incorrect Formulation or Concentration Dispensed 0 0 0 0 0 0 0 0 Wrong Medication Taken/Given 0 0 0 0 0 0 0 0 Health Professional Iatrogenic Error 0 0 0 1 (100.0%) 0 0 0 1 Exposure Through Breast Milk 0 0 0 0 0 0 0 0 More Than One Product Containing Same Ingredient 0 0 0 0 0 0 0 0 Medication Doses Given/Taken Too Close Together 0 0 0 0 0 0 0 0 Confused Units Of Measure 0 0 0 0 0 0 0 0 Other Incorrect Dose 0 0 0 0 0 0 0 0 Drug Interaction 0 0 0 0 0 0 0 0 Other/Unknown Therapeutic Error 0 0 0 0 0 0 0 0 Scenario a All cases with a scenario category of therapeutic error regardless of reason. FDA_766 24-month REMS Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies. Page 91 of 131 Reason of Exposure by Age Intentional and unintentional exposures by age are shown in Table 37. Most exposures occurred in adults >19 years of age (n=16) and involved 11 intentional exposures, 3 unintentional exposures, and 2 exposures for an unknown reason. There was 1 intentional exposure in a teenager 13 to 19 years of age. Table 37: Distribution of Reason for Exposure by Age Associated with TIRF Medicines: 29 October 2012 to 28 October 2013 <6 years 6-12 years 13-19 years >19 years Unknown Child Unknown Adult Unknown Age Missing Total Unintentional 0 0 0 3 0 0 0 0 3 Intentional 0 0 1 10 0 1 0 0 12 Unknown reason 0 0 0 2 0 0 0 0 2 Total 0 0 1 15 0 1 0 0 17 Reason Route of Exposure Ingestion was the route in 10 of 20 exposures associated with TIRF medicines (Table 38). Each exposure case may have more than one route. Table 38: Route of Exposure for Human Exposure Cases: 29 October 2012 to 28 October 2013 Human Exposures Fatal Exposuresa Ingestion 10 0 Unknown 5 4 Parenteral 3 0 Inhalation/nasal 2 0 20b 4c Route Total a Includes cases with relative contribution to fatality of 1-Undoubtedly responsible, 2-Probably responsible, or 3Contributory. This excludes reports with outcome of Death INDIRECT. b Each exposure case may have more than one route listed and patients may have multiple exposures to differing types of fentanyl products. Each exposure and its route(s) counted in this table. c Two patients each had an exposure to 2 different types of fentanyl products. The medical outcome for all exposures was “death.” Each exposure is counted in the table. FDA_767 24-month REMS Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies. Page 92 of 131 Medical Outcome Table 39 displays the medical outcome of human exposure cases associated with TIRF medicines distributed by age. A greater number of severe medical outcomes (major, 5; death 2) was observed in the age group >19 years. Table 40 compares medical outcome and reason for exposure and shows a higher frequency of serious outcomes in intentional (n=12) versus unintentional exposures (n=3). FDA_768 24-month REMS Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies. Table 39: Page 93 of 131 Medical Outcome of Human Exposure Cases by Patient Age: 29 October 2012 to 28 October 2013 Outcome <6 years N (%) 6-12 years N (%) 13-19 years N (%) >19 years N (%) Unknown Child N (%) Unknown Adult N (%) Unknown Age N (%) Total N (%) No effect 0 0 0 0 0 0 0 0 Minor effect 0 0 1 (100.0%) 2 (13.3%) 0 0 0 3 (17.6%) Moderate effect 0 0 0 4 (26.7%) 0 0 0 4 (23.5%) Major effect 0 0 0 5 (33.3%) 0 0 0 5 (29.4%) Deatha 0 0 0 2 (13.3%) 0 0 0 2 (11.8%) No follow-up, nontoxic 0 0 0 0 0 0 0 0 No follow-up, minimal toxicity 0 0 0 1 (6.7%) 0 0 0 1 (5.9%) No follow-up, potentially toxic 0 0 0 1 (6.7%) 0 1 (100.0%) 0 2 (11.8%) Unrelated effect 0 0 0 0 0 0 0 0 Confirmed nonexposure 0 0 0 0 0 0 0 0 Death, indirect report 0 0 0 0 0 0 0 0 Total 0 0 1 (5.9%) 15 (88.2%) 0 1 (5.9%) 0 17 (100.0%) a Two patients each had an exposure to 2 different types of fentanyl products. The medical outcome for all exposures was “death.” Each patient is only counted once in the table. FDA_769 24-month REMS Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies. Table 40: Page 94 of 131 Medical Outcome by Reason for Exposure in Human Exposures: 29 October 2012 to 28 October 2013 Outcome Unintentional N (%) Intentional N (%) Other N (%) Unknown N (%) Total N (%) No effect 0 0 0 0 0 Minor effect 0 3 (25.0%) 0 0 3 (17.6%) Moderate effect 1 (33.3%) 3 (25.0%) 0 0 4 (23.5%) Major effect 1 (33.3%) 4 (33.3%) 0 0 5 (29.4%) Deatha 0 0 0 2 (100.0%) 2 (11.8%) No follow-up, nontoxic 0 0 0 0 0 No follow-up, minimal toxicity 0 1 (8.3%) 0 0 1 (5.9%) No follow-up, potentially toxic 1 (33.3%) 1 (8.3%) 0 0 2 (11.8%) Unrelated effect 0 0 0 0 0 Confirmed nonexposure 0 0 0 0 0 Death, indirect report 0 0 0 0 0 3 (17.6%) 12 (70.6%) 0 2 (11.8%) 17 (100.0%) Total a Two patients each had an exposure to 2 different types of fentanyl products. The medical outcome for all exposures was “death.” Each patient is counted once in the table. FDA_770 24-month REMS Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies. 8 Page 95 of 131 PERIODIC SURVEYS OF STAKEHOLDERS An important component of the TIRF REMS assessment is the conduct of quantitative evaluation surveys to assess patients’ and caregivers’, pharmacists’, and prescribers’ knowledge, attitudes, and behavior (KAB) regarding the safe use of TIRF medicines as described in the educational materials for all stakeholders, enrollment form (pharmacists and prescribers only), Full Prescribing Information (pharmacists and prescribers only) and medication guides (prescribers and patients) of each product and the PPAF (prescribers and patients only). The protocols describe the administration of the individual surveys that were conducted among patients, prescribers, and pharmacists who are treated with TIRF medicines, or their caregivers (see Appendix 12.4.1, 12.4.2, and 12.4.3, respectively, for the patient, pharmacist, and prescriber survey protocols). Data from the surveys, together with other REMS evaluation metrics, will be used to determine whether changes need to be made to the REMS processes or educational materials to make them more effective in achieving the goals of the REMS. 8.1 Patient KAB Survey 8.1.1 Survey Statistics Patients were recruited through a pharmacy network partner and a PBM. Physician recruitment of patients did not result in any completed surveys. Based on the number of prescriptions filled during the 120 days prior to survey implementation (16 September 2013), the national pharmacy chain network partner identified 1,450 possible participants and the PBM identified 453 possible participants among patients and caregivers. All of these possible participants were sent a survey invitation letter. A total of 2,454 follow up letters were sent to non-responders (some potential participants received more than one reminder letter). Of the 1,903 possible participants, 347 respondents accessed the survey and were screened for eligibility; 302 of the 347 (87.0%) respondents met eligibility criteria and completed the survey; 175 (58.0%) completed the survey online, and 127 (42.1%) completed it by telephone. From the 302 respondents, 303 surveys were collected. It was identified that one respondent completed the survey twice. Only the first completed survey was included in the analysis for this report. Of the 347 respondents, the screening procedure identified 302 eligible participants (including 301 patients and 1 caregiver) all of whom completed the survey. Due to the small (n=1) number of caregivers participating in the survey, the majority of results are reported for patients and caregivers combined. A total of 346 patients/caregivers agreed to participate in this survey. The screening process found 44 respondents were not eligible to participate: 16 (4.6%) respondents were ineligible because they had previously participated in a survey about TIRF medicines; 11 (3.2%) because they did not know if they had previously participated; 15 (4.3%) said “No” when asked if they were caregivers for someone who has filled a prescription for a TIRF medicine within the FDA_771 24-month REMS Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies. Page 96 of 131 preceding 4 months; 1 (0.3%) respondent because he/she, or an immediate family member, had worked for a TRIG company in the past, and 1 (0.3%) did not know whether he/she, or an immediate family member, had worked for a TRIG company, United BioSource Corporation, RelayHealth, McKesson Specialty Care Solutions, or the FDA in the past and thus were considered ineligible. Thus, there were 302 eligible participants (including one caregiver), all of whom completed the survey. Those taking the survey online took an average of 14.7 minutes to complete it, while those taking it by telephone took an average of 20.1 minutes. 8.1.2 Demographics and Respondent Characteristics Most (n=126; 41.7%) respondents were in the 50 – 59 years age group; 184 (60.9%) were females, and 243 (80.5%) respondents had at least some college or Associate’s degree or higher education. Most prescriptions filled in the 4 months preceding the survey included 117 (38.7%) for Actiq® (including generic versions), 107 (35.4%) for Fentora®, and 88 (29.1%) for Subsys®. Participants were largely from the Northeast (n=113; 37.4%) and 133 (44.0%) from the South regions of the US. 8.1.3 TIRF Educational Materials Of the 302 respondents, 283 (93.7%), reported they had received the Medication Guide for the TIRF medicine prescribed to them; 150 (53.0%) reported receiving the Medication Guide from their doctor with 117 (78.0%) receiving it at the first appointment with the prescribing doctor; 254 (89.8%) respondents received it from their pharmacy; 228 (89.8%) respondents recollected receiving the Medication Guide each time a prescription was filled. Most (n=268; 94.7%) recollected reading the Medication Guide; 170 (63.0%) read all of it with 126 (46.7%) of them understanding all or most (n=125; 46.3%) of the Medication Guide. The pharmacist (n=147; 84.5%) or the prescriber (n=114; 65.5%) offered to explain the Medication Guide to respondents. After respondents were asked the questions regarding the key risk messages, they were asked if they had received, read, and understood the Patient-Prescriber Agreement Form (PPAF). A total of 223 (73.8%) respondents indicated that someone at the doctor’s office had offered to explain the PPAF to them, and that 175 (78.5%) of them understood all of it and 42 (18.8%) understood most of it. The PPAF was signed by 222 (73.5%) respondents; of these 222 responders, 151 (68.0%) reported receiving a copy of the signed PPAF. 8.1.4 Patient Survey Results 8.1.4.1 Key Risk Message 1 Key Risk Message 1 refers to the patient’s knowledge that TIRF medicines can cause lifethreatening breathing problems that can lead to death. Analysis of a question for Key Risk Message 1 showed that 272 (90.1%) of the 302 eligible respondents were aware of the risk of life-threatening breathing problems with TIRF medicines. FDA_772 24-month REMS Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies. Page 97 of 131 8.1.4.2 Key Risk Message 2 Key Risk Message 2 refers to the respondents’ knowledge that they should not take TIRF Medicines if they are not opioid tolerant. Three questions defined this key risk message. In response to the statement that TIRF medicines should only be taken by patients who are opioid tolerant, 277 (91.7%) respondents gave the correct (True) response. The majority (n=267; 88.4%) of respondents understood that opioid tolerant means that a patient is already taking other opioid pain medicines around-the-clock and their body is used to these medicines. Two-hundred-and-six respondents (68.2%) knew that it is not okay for patients to take TIRF medicines for headache pain, while 75 (24.8%) respondents selected the “I don’t know” option. Of the 206 respondents who answered false to “It is OK for patients to take TIRF medicines for headache pain”, 176 respondents had read most of the Medication Guide and 30 respondents had read some or none of it. Overall, evidence of understanding of the comprehensive key risk message is further supported by the average number of correct responses identified as 2.5 (CI 2.3, 3.0) out of a possible 3. 8.1.4.3 Key Risk Message 3 Key Risk Message 3 refers to the patient’s knowledge that TIRF medicines should be taken exactly as prescribed by the healthcare provider. Three questions define this key risk message. A total of 103 (34.1%) respondents understood that if a patient stops taking around-the-clock opioid pain medicine, they must also stop taking the TIRF medicine while 112 (37.1%) selected the “I don’t know” option. Of the 103 respondents who gave the correct response, 95 (92.2%) read most of the Medication Guide while 8 (7.8%) read some or none of the Medication Guide. Of the 87 respondents who answered this question incorrectly, 74 (85.1%) had read most of the Medication Guide and of the 112 (37.1%) respondents who selected the “I don’t know” response, 79 (70.5%) had read the Medication Guide. Responding to Question 13c, 301 (99.7%) understood that TIRF medicines should be taken exactly as prescribed by the doctor, and 252 (83.4%) knew that is not all right to take TIRF medicines for short-term pain that will go away in a few days. Overall, evidence of understanding of the comprehensive key risk message is further supported by the average number of correct responses identified as 2.2 (CI 2.0, 3.0) out of a possible 3. 8.1.4.4 Key Risk Message 4 Key Risk Message 4 refers to the patient’s knowledge that they must not switch from a TIRF medicine to another medicine that contains fentanyl without talking to a healthcare provider. Of the 302 respondents, 285 (94.4%) respondents understood that it is not safe to switch to another medicine that contains fentanyl without talking to a healthcare provider first. FDA_773 24-month REMS Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies. Page 98 of 131 8.1.4.5 Key Risk Message 5 Key Risk Message 5 refers to the patient’s knowledge that TIRF medicines should not be given to anyone else even if they have the same symptoms. A total of 296 (98.0%) respondents understood that a patient may not give TIRF medicines to another person if they have the same symptoms as the patient, and 297 (98.3%) understood that selling or giving away TIRF medicines is against the law. Overall, evidence of understanding of the comprehensive key risk message is further supported by the average number of correct responses identified as 2.0 (CI 1.8, 2.0) out of a possible 2. 8.1.4.6 Key Risk Message 6 Key Risk Message 6 refers to the patient’s knowledge that TIRF medicines should be stored in a safe place away from children and properly disposed. All 302 respondents selected the correct response regarding TIRF medicines being stored in a safe place out of the reach of children. Of the 302 respondents, 285 (94.4%) understood that TIRF medicines must be disposed of as described in the specific product’s Medication Guide. Most (n=275; 91.1%) respondents understood that a TIRF medicine can cause an overdose and death in any child who takes it; and that they should get emergency help right away (n=264; 87.4%) (What should you do if an adult who has not been prescribed a TIRF medicine takes a TIRF medicine?). Overall, evidence of understanding of the comprehensive key risk message is further supported by the average number of correct responses identified as 3.7 (CI 3.5, 4.0) out of a possible 4. 8.1.5 Additional Safety Questions about TIRF Medicines Safety Additional questions were asked to assess whether the patient had been informed of the risks and possible side effects, indications, usage, and storage, and the availability of TIRF medicines through the TIRF REMS Access Program. This section summarizes the respondents' answers to some components associated with key risk messages and additional survey questions not associated with key risk messages. An HCP from the doctor’s office discussed the risks and possible side effects of the prescribed TIRF medicine with 259 (85.8%) of respondents while 36 (11.9%) respondents did not recall having this conversation. Most respondents understood that TIRF medicines should not be used for headache or migraine pain (n=234; 77.5%), dental pain (n=264; 87.4%), and pain after surgery (n=207; 68.5%). Only 66 (21.9%) respondents were aware that TIRF medicines are not indicated for long-lasting painful conditions not caused by cancer. Whereas, 194 (64.2%) respondents knew that TIRF medicines might be used for BTP from cancer. FDA_774 24-month REMS Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies. Page 99 of 131 Most (n=281; 93.0%) respondents recollected that someone in the doctor’s office explained the proper way of using the prescribed TIRF medicines while 241 (79.8%) respondents were educated by someone in the doctor’s office regarding the proper storage of the prescribed TIRF medicines. Most (n=285; 94.4%) respondents were aware of the proper way to dispose of TIRF medicines as described in the prescribed product’s Medication Guide. However, the awareness that TIRF medicines are only available through the TIRF REMS Access Program was low with 147 (48.7%) selecting the correct response. Most respondents (n=275; 91.1%) understood that a TIRF medicine might cause overdose and death in any child who takes it. Overall, the results indicate that respondents were aware of most of the precautions needed to ensure safe use of TIRF medicines. Taking into account the percentage of incorrect and “I don’t know” responses, patients/caregivers scored somewhat less with regard to the need to stop taking TIRF medicines if the around-the-clock opioid is stopped and the approved indication for TIRF medicines. 8.1.6 Analysis of Sub-populations To assess further patients’ understanding of key risk messages, sub-group analyses with more than 20 respondents were conducted. Of the 248 respondents who read most of the Medication Guide (sub-group S-1a), 234 (94.4%) understood Key Risk Message 1 (TIRF medicines can cause life-threatening breathing problems that can lead to death) compared with 38 of the 54 (70.4%) who read some or none of the Medication Guide (sub-group S-1b). In the case of Key Risk Message 2, 230 (92.7%) respondents who read most of the Medication Guide and 47 (87.0%) of respondents who read some or none of the Medication Guide were aware that TIRF medicines should only be taken by patients who are opioid tolerant. In addition, 221 (89.1%) respondents who read most of the Medication Guide (sub-group S-1a) and 46 (85.2%) of sub-group S-1b respondents understood the meaning of the term opioid tolerant. Most (n=176; 71.0%) respondents of sub-group S-1a correctly answered that TIRF medicines are not recommended for headache pain compared with 30 of 54 (55.6%) of sub-group S-1b respondents. Of the three questions/statements under Key Risk Message 3, 95 (38.3%) of sub-group S-1a and 8 (14.8%) sub-group S-1b respondents gave the correct response to Question 12b (If a patient stops taking around-the-clock opioid pain medicine, they must also stop taking the TIRF medicine). Almost all (n=247; 99.6%) of sub-group S-1a and 54 (100.0%) of sub-group S-1b respondents correctly identified with the statement that TIRF medicines should be taken exactly as prescribed by the doctor; and 214 (86.3%) of sub-group S-1a and 38 (70.4%) of sub-group S1b disagreed with the statement that it is okay to take TIRF medicines for short-term pain that will go away in a few days. FDA_775 24-month REMS Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies. Page 100 of 131 There was high understanding for Key Risk Message 4 Question 12c (It is safe to switch from a TIRF medicine to another medicine that contains fentanyl without talking to a healthcare provider first) because 233 (94.0%) of sub-group S-1a and 52 (96.3%) of sub-group S-1b responded correctly. Almost all respondents understood Key Risk Message 5 that patients should not give TIRF medicines to anyone else even if they have the same symptoms. Respondents demonstrated a high level of understanding for Key Risk Message 6 that TIRF medicines should be stored in a safe place away from children and properly disposed. Overall, the results indicate that respondents who read all or most of the Medication Guide were better informed regarding the safe use of TIRF medicines. Therefore, the Medication Guide is an effective tool to help patients understand the key risk messages based on the goals of the TIRF REMS. All other sub-group analyses showed that the results are similar to the results in the primary population, and no sub-group-related trends were evident. 8.2 Pharmacy KAB Survey 8.2.1 Survey Statistics A total of 7,167 pharmacists were invited to participate in this survey. Of those invited to participate, 5,982 were outpatient pharmacists, 860 were inpatient pharmacists, and 325 were pharmacists practicing in Closed System Pharmacies (CSPs). Some pharmacists received more than one reminder. From the total 403 respondents, 300 pharmacists met eligibility criteria and completed the survey. Of these 300 pharmacists, 291 (97.0%) completed the survey online, and 9 (3.0%) completed it by telephone. Of the 300 pharmacists who completed the survey, 4 were CSP pharmacists, 15 were inpatient pharmacists, and 281 were outpatient pharmacists. A total of 371 pharmacists agreed to participate in this survey, 339 of these pharmacists stated they had not taken part in the survey about TIRF medicines before, and 304 of these pharmacists worked in pharmacies that were enrolled in the TIRF REMS. Of the 372 total respondents, 68 were ineligible to participate in the survey because they either did not agree to participate, indicated they had participated in or did not know whether they participated in a survey about TIRF medicines before, or worked in pharmacies that were not enrolled or they did not know whether their pharmacy was enrolled in the TIRF REMS. Of the 304 respondents who reported that their pharmacies were enrolled in the TIRF REMS Access Program, 1 respondent was ineligible for the survey because the respondent, or an immediate family member, had worked for a TRIG company in the past, 1 was ineligible because the respondent or an immediate family member, had worked for the FDA in the past, and 2 respondents preferred not to answer the question. FDA_776 24-month REMS Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies. Page 101 of 131 Those taking the survey online took an average of 14.3 minutes to complete it, while those taking it by telephone took an average of 18.0 minutes. 8.2.2 Demographic and Respondent Characteristics The majority of pharmacists who completed the survey were male (183, 61.0%), and out of 300 eligible pharmacists, 157 (52.3%) had been a practicing pharmacist for more than 15 years. Respondents from the South, Northeast, and Midwest reflected 32.3%, 26.0%, and 24.0% of total respondents, respectively, while respondents from the Western region of the US composed 17.3% of total respondents. The proportion of respondents who completed the survey within each geographic region was similar to the overall proportion of pharmacies enrolled in the TIRF REMS Access Program as of 10 October 2013 in each geographic region. There were no respondents from Puerto Rico, Northern Mariana Islands, US Virgin Islands, American Samoa, and Guam. Most pharmacists (242, 80.7%) functioned as the pharmacist-in-charge for the TIRF REMS Access Program where they worked, and a majority of pharmacists (235, 78.3%) had dispensed a TIRF medicine zero to 2 times per month within the past 6 months. The most frequently dispensed TIRF medicine within the 6 months prior to taking the survey was Actiq® or generic Actiq (120 pharmacists, 77.4%). 8.2.3 TIRF Educational Materials Pharmacists were asked about their access to educational materials for TIRF medicines, specifically the Full Prescribing Information and the Medication Guide. Almost all pharmacists reported they had received or had access to the Full Prescribing Information and the Medication Guide (291, 97.0%; and 297, 99.0%, respectively). Of those with access to these materials, 76.6% and 84.2%, respectively, indicated that they had read the Full Prescribing Information and the Medication Guide. There were 18 respondents who typed a response into the free text field for Question 22 (Did you or do you have any questions about the information in the Full Prescribing Information or Medication Guide?). Of the 18 responses, 13 were requests for medical information and 5 were indications the free text field was not applicable or they had no questions. 8.2.4 Pharmacy Survey Results 8.2.4.1 Key Risk Message 1 Key Risk Message 1 refers to the pharmacist’s knowledge of the specific contraindications for TIRF medicines. Analysis of responses to components of Key Risk Message 1 showed that a high percentage of pharmacists knew that patients with cancer who are considered opioid-tolerant are those who are taking around-the-clock opioid therapy for cancer pain for one week or longer (271, 90.3%), and are those who are currently taking opioid therapy (242, 80.7%). Somewhat less understood was FDA_777 24-month REMS Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies. Page 102 of 131 cancer patients with no known contraindications to the drug fentanyl, but who are not currently taking around-the-clock opioid therapy are not considered opioid tolerant (228, 76.0%). A high percentage of pharmacists knew that TIRF medicines are contraindicated in opioid nontolerant patients (86.0%) and that death has occurred in opioid non-tolerant patients treated with some fentanyl products (93.7%). Similarly, 248 (82.7%) pharmacists were aware that dose titration for patients starting a TIRF medicine must begin with the lowest available dose for that product, and that TIRF medicines may not be used to treat opioid non-tolerant patients (82.0%). Overall, evidence of understanding of this key risk information is further supported by the average number of correct responses identified as 5.9 (CI 5.7, 7.0) out of a possible 7. 8.2.4.2 Key Risk Message 2 Key Risk Message 2 refers to the pharmacist’s knowledge of the approved indications for prescribing TIRF medicines to opioid tolerant patients. Responses to components of Key Risk Message 2 indicate that 268 (89.3%) pharmacists were aware that TIRF medicines are indicated for opioid-tolerant patients with BTP from cancer and not for patients with acute or postoperative pain (84.7%), headache or migraine pain (92.3%), or dental pain (96.7%). Only 47.0% of pharmacists correctly responded that TIRF medicines are not indicated for chronic non-cancer pain. Overall, evidence of understanding of this key risk information is further supported by the average number of correct responses identified as 4.1(CI 3.9, 5.0) out of a possible 5. 8.2.4.3 Key Risk Message 3 Key Risk Message 3 refers to the pharmacist’s knowledge of the risk factors and signs and symptoms of opioid abuse in patients who take TIRF medicines. Responses to components of Key Risk Message 3 showed that 290 (96.7%) pharmacists were aware that it is important to monitor for signs of abuse and addiction in patients who take TIRF medicines; a personal history of past or current alcohol or drug abuse or family history of drug and alcohol abuse is a risk factor for opioid abuse (99.0%); and TIRF medicines can be abused in a manner similar to other opioid agonists (94.0%). Somewhat less understood was that a personal history of psychiatric illness is a risk factor for opioid abuse (72.0%). Overall, evidence of understanding of this key risk information is further supported by the average number of correct responses identified as 3.6 (CI 3.4, 5.0) out of a possible 4. 8.2.4.4 Key Risk Message 4 Key Risk Message 4 refers to the pharmacist’s knowledge that TIRF medicines are not interchangeable regardless of the route of administration. Responses to questions tied to Key Risk Message 4 showed that 284 pharmacists understood TIRF medicines are not interchangeable with each other regardless of the route of administration (94.7%); the conversion of 1 TIRF medicine to another may result in a fatal overdose (92.0%); and dosing of TIRF medicines is not equivalent on a microgram-to-microgram basis (91.3%). FDA_778 24-month REMS Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies. Page 103 of 131 Overall, evidence of understanding of this key risk information is further supported by the average number of correct responses identified as 2.8 (CI 2.6, 3.0) out of a possible 3. 8.2.5 Additional Safety Questions about TIRF Medicines Safety Additional questions about TIRM Medicines generally confirmed the pharmacists’ understanding of the safety issues and the risks associated with taking TIRF medicines. Question 6 was added for this 24-month KAB survey to assist in determining the pharmacist understanding of around-the-clock usage, and 65.3% of pharmacists correctly indicated that a cancer patients should not started on a TIRF medicine and an around-the-clock opioid at the same time, and 74.7% understood a cancer patient who had been on an around-the-clock opioid for 1 day should not start taking a TIRF medicine for BTP. Overall, greater than 70% of pharmacists correctly identified an opioid drug/dose regimen that when taken by the patient, identifies patients as opioid tolerant according to the labeling for TIRF medicines. However, fewer understood that an equianalgesic dose of another oral opioid could also meet the definition of opioid tolerant (correct response 59.0%). Pharmacists correctly indicated that TIRF medicines may not be sold, loaned, or transferred to another pharmacy (91.3%); pharmacy staff who dispense TIRF medicines must be educated on the requirements of the TIRF REMS Access Program (94.0%); and that TIRF medicines with the same route of administration cannot be substituted with each other (96.3%). Thirteen (86.7%) inpatient pharmacists correctly indicated that it is not appropriate to dispense TIRF medicines from the inpatient pharmacy inventory to an outpatient for home use.  8.2.6 Pharmacist Activities When Dispensing TIRF Medicines Pharmacists were asked about specific activities performed when dispensing TIRF medicines Of the 300 eligible pharmacists, 167 (55.7%) responded they always ask their patients (or a patient’s caregiver) about the presence of children in the home; 18.0% responded they ask only with the first prescription. Additionally, 69.3% responded they always instruct the patient (or their caregivers) not to share TIRF medicines, 66.0% responded they always counsel patients (or their caregivers) that accidental exposure to TIRF medicines by a child may be fatal, 74.3% responded they always instruct patients (or their caregivers) to keep TIRF medicines out of reach of children, 66.0% responded they always instruct patients (or their caregivers) about proper disposal of any unused or partially used TIRF medicines, and 91.3% responded they always give patients (or their caregivers) the Medication Guide for TIRF medicine(s). 8.3 Prescriber KAB Survey 8.3.1 Survey Statistics A total of 5,108 prescribers were sent letters inviting them to participate in this survey. An additional 11,986 reminder letters were sent. Some prescribers may have received more than 1 reminder letter. FDA_779 24-month REMS Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies. Page 104 of 131 In all, a total of 425 prescribers expressed interest in the survey and were screened for eligibility. The number of respondents found eligible for participating in the survey was 302, all of whom completed the survey. Of the 302 respondents, 289 (95.7%) completed the survey online, and 13 (4.3%) completed it by telephone. There were no duplicate respondents. Based on the TRIG Sponsors interpretation of state laws regarding prescriber reimbursement, respondents from Massachusetts (MA), Vermont (VT), and Minnesota (MN) were eligible to participate in the survey; however, were not eligible to receive the $125 honorarium. Letters were sent to prescribers in these states, and 2 respondents from MA chose to participate despite receiving no honorarium. A total of 425 prescribers agreed to participate in this survey and of those 302 prescribers were enrolled in the TIRF REMS Access program; 49 (11.5%) prescribers were ineligible because they were not enrolled in the program or they did not know whether they were enrolled. Seventeen (4.0%) respondents were ineligible because they had previously taken part in the survey about TIRF medicines and 49 (11.5%) respondents did not know if they had participated; therefore, they were considered ineligible. Five respondents were ineligible for the survey because they, or an immediate family member, had worked for UBC or a TRIG company in the past, or did not know whether they, or an immediate family member, had worked for a TRIG company, UBC, RelayHealth, McKesson Specialty Care Solutions, or the FDA in the past, and 1 prescriber preferred not to answer and thus was considered ineligible. Those taking the survey online took a mean of 17.0 minutes to complete, while those taking it by telephone took a mean of 27.0 minutes. 8.3.2 Demographics and Respondent Characteristics The survey included 27.5% respondents from the Northeast, 15.2% from the Midwest, 33.1% from the South, and 23.5% from the Western region of the US. The proportion of eligible completed prescribers within each geographic region was similar to the overall proportion of prescribers (9,042 prescribers enrolled in the TIRF REMS Access Program as of 19 October 2013) in each geographic region. There were no respondents from Puerto Rico, Northern Mariana Islands, US Virgin Islands, American Samoa, and Guam. The most common healthcare degree was an MD (60.3%), and the most common medical specialties were pain management (49.0%) and oncology (22.8%). Of respondents who were medical doctors, 117 of the respondents (38.7%) had practiced medicine for more than 15 years. The survey results showed that 173 (57.3%) of the prescribers recalled prescribing TIRF medicines 1 to 2 times a month within the 6 months preceding the survey, and Actiq® or generic Actiq were the most frequently prescribed TIRF medicine (74.2% of prescribers) followed by Fentora® at 58.5% of prescribers.   8.3.3 TIRF Educational Materials Prescribers were asked about their awareness of educational materials for TIRF medicines, specifically the Full Prescribing Information the Medication Guide, and the Patient-Prescriber FDA_780 24-month REMS Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies. Page 105 of 131 Agreement Form (PPAF). Most (n=282; 93.4%) respondents had received or had access to the Full Prescribing Information and 273 (90.4%) to the Medication Guide. Of those with access to these materials, 86.2% and 90.1%indicated that they had read the Full Prescribing Information and the Medication Guide, respectively. Additionally, most prescribers reported reviewing the PPAF with each patient or their caregiver (86.8%); signing the PPAF and having the patient/caregiver sign the PPAF (92.4%); and giving a copy of the PPAF to the patient (80.5%). 8.3.4 Prescriber Survey Results 8.3.4.1 Key Risk Message 1 Key Risk Message 1 assesses the prescriber’s knowledge of the specific contraindications for TIRF medicines in patients. Analysis of responses to questions tied to Key Risk Message 1 showed that a high percentage of prescribers understand that TIRF medicines are contraindicated in opioid non-tolerant patients because life-threatening respiratory depression could occur (n=265; 87.7%) and that death has occurred in opioid non-tolerant patients treated with some fentanyl products (n=283; 93.7%). Most prescribers were aware patients just starting a TIRF medicine must begin with titration from the lowest available dose for that product (n=244; 80.8%) and that TIRF medicines may not be used to treat opioid non-tolerant patients (n=242; 80.1%). Overall, evidence of understanding of the comprehensive key risk message is further supported by the average number of correct responses identified as 6.0 (CI 5.8, 7.0) out of 7. 8.3.4.2 Key Risk Message 2 Key Risk Message 2 assesses the prescriber’s knowledge of the approved indications for prescribing TIRF Medicines to opioid tolerant patients. Responses to components of Key Risk Message 2 indicate that a high percentage of respondents prescribe TIRF medicines for the approved indication of treatment of breakthrough cancer pain in opioid-tolerant patients (n=279; 92.4%) and not for patients with acute or postoperative pain (5.6%), headache or migraine pain (6.6%), or dental pain (1.7%). Respondents were presented with descriptions of 4 patients experiencing BTP and asked them to select the case that should not receive a TIRF medicine. The correct response was given by 199 (65.9%) prescribers. 8.3.4.3 Key Risk Message 3 Key Risk Message 3 assesses the prescriber’s knowledge of the risk factors and signs and symptoms of opioid abuse in patients who take TIRF medicines. Key Risk Message 3 showed that a high percentage of prescribers were aware that it is important to monitor for signs of abuse and addiction in patients who take TIRF medicines (99.0%), a personal history of psychiatric illness is a risk factor for opioid abuse (82.8%), a personal history of past or current alcohol or drug abuse or family history of drug and alcohol abuse is a risk factor for opioid abuse (99.0%), and that TIRF medicines can be abused in a manner similar to FDA_781 24-month REMS Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies. Page 106 of 131 other opioid agonists (96.4%). Overall, evidence of understanding of the comprehensive key risk message is further supported by the average number of correct responses identified as 3.8 (CI 3.6, 4.0) out of 4. 8.3.4.4 Key Risk Message 4 Key Risk Message 4 assesses the prescriber’s knowledge that TIRF medicines are not interchangeable regardless of the route of administration. Majority of prescribers (279, 92.4%) understood that TIRF medicines are not interchangeable with each other regardless of the route of administration, that the conversion of 1 TIRF medicine to another may result in a fatal overdose (n=286; 94.7%), and that dosing of TIRF medicines is not equivalent on a microgram-to-microgram basis (n=274; 90.7%). A large number of prescribers (225, 74.5%) correctly responded that conversion must not be done on a microgramto-microgram basis. Overall, evidence of understanding of the comprehensive key risk message is further supported by the average number of correct responses identified as 3.5 (CI 3.3, 4.0) out of 4. 8.3.5 Additional Questions about TIRF Medicines Safety Over half of the (n=183; 60.6%) prescribers correctly identified that a cancer patient should not be started on a TIRF medicine and an around-the-clock opioid at the same time, while 105 (34.8%) prescribers believe such a combination is acceptable; 196 (64.9%) of prescribers correctly indicated that a cancer patient who has been on an around-the-clock opioid for 1 day should not start taking a TIRF medicine for BTP; 160 (53.0%) responded that patients should not continue to take TIRF medicines if they stopped taking their around-the-clock opioid medicine. A majority of prescribers correctly identified the description of opioid-tolerant patients by the listed opioid preparations and corresponding doses as 8 mg oral hydromorphone/day (68.5%), 60 mg oral morphine/day (89.1%), 30 mg/day oral oxycodone (76.2%), 25 mcg transdermal fentanyl/hour (80.8%), 25 mg/day oral oxymorphone (69.9%), and an equianalgesic dose of another oral opioid (65.9%). Most prescribers (n=254; 84.1%) correctly indicated that for a patient starting titration with a TIRF medicine, an appropriate dose is the lowest available dose, unless the Full Prescribing Information provides specific guidance (84.1%). When a prescriber has started titrating a patient with the lowest dose of a TIRF medicine, and, after 30 minutes, the BTP has not been sufficiently relieved, 205 (67.9%) prescribers correctly pointed out that guidance should be based on the product-specific Medication Guide because the instructions are not the same for all TIRF medicines. Response to Question 17 demonstrates that the majority (225, 74.5%) of prescribers have a high level of understanding pertaining to the safe use of a TIRF medicine with a CYP3A4 inhibitor and the need for monitoring the dosage for their patient. Further, this data reflects that the prescribers clearly understand the need to carefully monitor the patient for opioid toxicity to avoid any potential cause for fatal respiratory depression. FDA_782 24-month REMS Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies. Page 107 of 131 Of the 302 respondents who completed the survey, 199 (65.9%) correctly stated that a patient who had a mastectomy and reconstructive surgery for localized breast cancer with persistent cancer pain managed with 30 mg/day oral morphine for 6 weeks should not receive TIRF medicines because the patient does not meet the definition of opioid tolerant. Furthermore, the majority (225, 74.5%) of prescribers correctly indicated that the prescriber must not convert a patient to another TIRF medicine on a microgram-per-microgram basis because these medicines have different absorption properties which could result in a fentanyl overdose. Nearly all prescribers surveyed (n=298; 98.7%) understood that TIRF medicines contain fentanyl in an amount that could be fatal for children of all ages, for individuals for whom they were not prescribed, and for those who are not opioid tolerant. Two hundred and seventy-eight (92.1%) prescribers were aware that patients must be informed that TIRF medicines should not be used for acute or postoperative pain, pain from injuries, headache/migraine, or any other short-term pain. One hundred and seventy-five (57.9%) prescribers understood that patients should be instructed not to continue their TIRF medicines if they stop taking their around-the-clock opioid medicine; 299 (99.0%) agreed that patients must be instructed not to share their TIRF medicine with anyone else, even if that person has the same symptoms; and 160 (53.0%) indicated that if patients stop taking their around-the-clock opioid pain medicine, they must stop taking their TIRF medicine. 8.3.6 Prescriber Activities When Prescribing TIRF Medicines More than one-half of prescribers (56.3%) indicated they always ask patients (or their caregivers) about the presence of children in the home. Prescribers take care to instruct patients (or their caregivers) not to share TIRF medicines (n=239; 79.1%). When asked about counseling patients/caregivers that accidental exposure to TIRF medicines by a child might be fatal, 197 (65.2%) prescribers selected “always”, 63 (20.9%) responded “only with first prescription”, and 31 (10.3%) answered “sometimes”. In response to the question about instructing patients/caregivers to keep TIRF medicines out of the reach of children, 220 (72.8%) selected “always,” 46 (15.2%) selected “only with the first prescription”, and 28 (9.3%) selected “sometimes.” With regard to instructing patients/caregivers about proper disposal of any unused or partially used TIRF medicines, 187 (61.9%) answered “always,” 62 (20.5%) answered “only with the first prescription,” and 37 (12.3%) responded “sometimes.” Less than one-half of prescribers (47.0%) always give patients/caregivers the Medication Guide for their TIRF medicine, and 35.8% give their patients/caregivers the Medication Guide for their TIRF medicine with the first prescription. 8.3.7 Analyses of Sub-populations Of the 13 respondents who completed the survey via telephone, the correct response rate when asked to identify patients with cancer who are considered opioid-tolerant was 53.8% (n=7) by selecting the “False” response: “Who are not currently taking opioid therapy, but have taken opioid therapy before”(Key Risk Message 1) compared with the correct response rate of 89.6% for those who used the Internet. Likewise, 7 (53.8%) telephone respondents correctly selected the “False” response: “Who have no known contraindications to the drug fentanyl, but are not FDA_783 24-month REMS Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies. Page 108 of 131 currently taking around-the-clock opioid therapy” (Key Risk Message 1) compared with 83.4% in the sub-group that used the Internet. Of the 35 prescribers who had not read the Medication Guide or Full Prescribing Information, 24 (68.6%) were aware that TIRF medicines may not be used in opioid non-tolerant patients (Question 7c; Key Risk Message 1) compared with 218 (81.6%) prescribers who read the Medication Guide or PI. Of the 35 respondents, 23 (65.7%) had not read the Medication Guide or the Full Prescribing Information correctly identified “a personal history of psychiatric illness” as a risk factor for opioid abuse (Question 8a, Key Risk Message 1) compared with 85.0% among those who had read the Medication Guide or PI). Respondents who completed the survey in less than 10 minutes had a low correct response rate of 57.4% when asked about prescribing an alternate TIRF medicine that is not a bioequivalent generic version of the branded product (Question 14, Key Risk Message 4) compared with the more than 75% correct response rate among those who longer to complete the survey. 8.4 Overall Conclusions for KAB Results During the 12-month reporting period TRIG established a threshold for each response rate of <65%. The purpose of this threshold was to assist TRIG in tracking and monitoring the data for each key risk message across each wave ultimately providing direction in determining which area(s) would require improvement to ensure the patient/caregiver, pharmacist and prescriber KAB surveys were meeting the goals of the REMS. Patients: The specific goal of the TIRF medicines patient KAB survey was to evaluate the level of understanding by patients and caregivers of the risks associated with use of TIRF medicines, the importance of being opioid tolerant before starting a TIRF medicine, strictly following the directions of the HCP, not switching from one TIRF medicine to another medicine that contains fentanyl without talking to an HCP, the importance of patients not giving TIRF medicines to anyone else even if they have the same symptoms, and storing TIRF medicines in a safe place away from children and proper disposal of unused medicine. Revisions were made to the 24-month survey based on feedback received from the FDA on the 12-month assessment. The one item that scored noticeably lower on the 24-month assessment was the concept that patients should stop taking a TIRF medicine if they stop their around the clock opioid. The TRIG is exploring options to increase awareness of this important safety message, which is discussed in the current PPAF and medication guides for each product. While not a key risk message in the prescriber survey, this concept was also a low scoring item for prescribers even though it is conveyed in the Prescriber Education Program as a patient counseling message. The overall higher level of understanding of the remaining items/questions throughout the 6 key risk messages indicates that patients are knowledgeable about the safe use and storage of TIRF medicines. The higher level of understanding in patients who read most or all of the medication FDA_784 24-month REMS Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies. Page 109 of 131 guide demonstrates effective communication of the key risk messages, which may also be reinforced by prescribers and pharmacists. The consistent high level of patient understanding of key risk messages between the 12-month and 24-month surveys indicates that the REMS goals are being met with the tools currently in place. Pharmacists: The specific goal of the TIRF REMS pharmacist KAB survey was to assess pharmacist understanding of the risks associated with TIRF medicine use, the specific indications for treatment with TIRF medicines, and that TIRF medicines are contraindicated in opioid nontolerant patients. Based on FDA feedback from the 12-month assessment, revisions were made to the 24-month pharmacist survey. Prior to the 24-month survey, the questions were revised based on the QR results to improve understanding of the questions/items being tested. In addition, there were 22,762 (59%) pharmacies that enrolled or re-enrolled during this reporting period by successfully completing the education program, thereby reinforcing the educational message of the shared system REMS. In the 24-month survey, only one item was identified as having a low level of understanding among pharmacists (TIRF medicines are not indicated for chronic non-cancer pain; 47.0%). However, it should be noted that there was a marked improvement in the Pharmacist’s correct response rate for this concept from the 12-month KAB survey to the 24-month KAB survey. It should also be noted that recognition of uses for which TIRF medicines are not indicated is not a goal of the TIRF REMS for pharmacists. Because a majority of the pharmacists surveyed demonstrated a high level of understanding of all but one item out of the 4 key risk messages, the TRIG has determined that the Pharmacist Education Program is meeting the goals of the TIRF REMS. Therefore, no changes to the education program for pharmacists are required at this time. Prescribers: The prescriber KAB survey included responses from 302 TIRF medicine prescribers invited from a random sample of all prescribers enrolled in the REMS. The specific goal of the prescriber KAB survey was to assess prescribers’ understanding of the risks associated with TIRF medicine use, the selection of appropriate patients for treatment with TIRF medicines, preventing inappropriate conversion between TIRF medicines, and ensuring safe use of TIRF medicines while preventing exposure to children and others for whom TIRF medicines were not prescribed. Following the 12 March 2013 FDA feedback on the 12-month TIRF REMS Access Program Assessment Report, the survey questionnaire was modified. The concept that a patient must discontinue a TIRF medicine when they stop taking their aroundthe-clock opioid, while not a key risk message for the prescribers, received a low correct response rate. Prescribers are educated on this concept in the educational program and in the PPAF. Prescriber’s low understanding of this concept is likely to have affected the level of FDA_785 24-month REMS Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies. Page 110 of 131 understanding of respondents in the patient survey. The TRIG is exploring options to increase awareness of this important safety message. The overall higher level of understanding of the remaining items/questions throughout the 4 key risk messages indicates that prescribers are knowledgeable about the safe of TIRF medicines. The consistent high level of prescribers’ understanding of key risk messages between the 12month and 24-month surveys indicates that the prescriber education program is meeting the goals of the TIRF REMS with the tools currently in place. 9 FDA COMMUNICATIONS In the first quarter of calendar year 2013, the TRIG companies responded to several FDA information requests concerning the 12-month assessment report, with a focus on the metrics for the closed system pharmacies. Submission of REMS Modification 2 and the establishment of the Drug Master File for the TIRF REMS was completed on 21 October 2013. Modification 2 for the TIRF REMS consisted of the following: • Revised terminology, processes, and definitions for outpatient pharmacies; • Revised attestations for physicians and patients to address concerns regarding patient access; • Revised Program Overview and Frequently Asked Questions to improve clarity and content; and, • Updated REMS materials to reflect the completion of the transition phase for the TIRF REMS Access Program, The proposed changes to the TIRF REMS, including the appended REMS materials, were approved on 07 November 2013.  10 POST-APPROVAL STUDIES AND CLINICAL TRIALS FDA should refer to the most recent periodic safety report from each TIRF sponsor for updated information on post-approval studies and/or clinical trials. 11 OVERALL CONCLUSIONS The TIRF REMS Access program was approved on 28 December 2011 and successfully launched on 12 March 2012, approximately 11 weeks after approval. This 24-month assessment report covers the timeframe between 29 October 2012 and 28 October 2013. With an overall volume of more than 111,104 prescriptions authorized for REMS edits during this reporting period and only 1 report of a patient having difficulty accessing an enrolled FDA_786 24-month REMS Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies. Page 111 of 131 prescriber, the program does not appear to present a significant barrier to access of these important medications. The TIRF REMS Access program continues to monitor the electronic systems and stakeholder reports for issues and, where appropriate, corrective actions or system improvements are instituted. The REMS goal of educating prescribers and pharmacists on the potential for misuse, abuse, addiction, and overdose is being documented through the completion of the Knowledge Assessment, which is required for enrollment. Effectiveness of the educational program is evaluated through the pharmacy and prescriber KAB surveys that are performed prior to each assessment report. Results of the 24-month surveys indicate that the educational program has increased the understanding of safe use of TIRF medicines by pharmacists and prescribers. Key risk messages that are important for these stakeholders to understand include the fact that TIRF medicines are contraindicated in opioid non-tolerant patients, are only indicated for the management of breakthrough pain in adult cancer patients, contain fentanyl with abuse liability similar to other opioid analgesics, and are not interchangeable with each other on a mcg-to-mcg basis regardless of route of administration. Due to the high level of understanding of these concepts by pharmacists and prescribers, no modifications to the educational programs or Knowledge Assessment are recommended at this time. Patient education is completed through healthcare provider counseling and completion of a PPAF. The patient KAB survey results indicate that the patient-oriented educational materials including the PPAF and Medication Guide for each product are effective tools at communicating safe use messages to patients, including the importance of not sharing TIRF medicines, taking TIRF medicines as prescribed, and properly disposing unused TIRF medicines. One identified area of potential improvement is patient understanding of the need to stop taking TIRF medicines if around-the-clock opioid therapy is stopped. The TRIG is exploring options to increase awareness of this important safety issue, which is discussed in the current PPAF and Medication Guide for each product. Surveillance data was obtained from AAPCC and FDA AERS for inclusion in this 24-month assessment report as it had been in the previous two assessment reports submitted to FDA. The AAPCC data included no reports of pediatric exposure to TIRF medicines and only one exposure in an adolescent 16 years of age with a minor outcome. Four fatalities were included in the AAPCC data, 2 related to exposure to TIRF medicines and 2 related to exposure to unknown fentanyl products. TRIG is unable to evaluate safety signals based upon these reports at this time. Abstracts or full narratives of all 4 fatalities will be available from the AAPCC in late 2014 at the earliest and will be sent to the FDA as soon as they are received. FDA AERS data encompassing Q3 and Q4 2012 were the most recent data available for this 24month assessment report. Sixteen new case reports associated with TIRF medicine exposure were identified in the data set. Eight of the cases included one of the individual PT of Interest for the TIRF REMS or at least one PT from the MedDRA SMQ, Acute Central Respiratory Depression. Consistent with the 12 month TIRF REMS Assessment report, signals continue to be seen for the PT of Interest: “Off label Use”, “Drug prescribing error” and “Drug withdraw syndrome”. When analyzed according to TRIG categories of interest, signals were also FDA_787 24-month REMS Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies. Page 112 of 131 generated for inappropriate use, drug diversion, medication error, and drug dependence. Realizing the limitations and incompleteness of data in the FDA AERS database, and the resulting difficulty in identifying true safety signals from this database alone, FDA has requested that TRIG sponsors provide complete listings of adverse event reports in CIOMS II Line Listing format for this and future assessment reports. In addition, FDA requested MedWatch forms for all cases involving addiction, overdose and death. FDA and TRIG sponsors agreed that this data will be submitted by each individual company no later than the end of January 2014. FDA AERS data will not be included in future TIRF REMS assessment reports. Based on the data provided in this report the TRIG concludes that the REMS is meeting its established goals. The improvement in knowledge demonstrated by pharmacists and prescribers and the continued high level of awareness of most key risk messages by patients provides evidence that the current tools are effectively communicating the important safety messages to key stakeholders. Based on our analysis of the data for this 24-month assessment, the TRIG is recommending no REMS modifications at this time. FDA_788 24-month REMS Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies. 12 Page 113 of 131 APPENDICES FDA_789 24-month REMS Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies. Page 114 of 131 12.1 Medical Dictionary for Drug Regulatory Activities Preferred Terms Primary SOC I High Level Group I High Level Term Preferred Term I0verdose Injury. porsonmg and Medication errors Overdoses Accidental overdose procedural complications Injury. orsonmg and Medication errors Overdoses Intentional overdose procedural complications Injury. orsonmg and Medication errors Overdoses Multiple drug overdose procedural complications Injury. poisoning and Medication errors Over doses Multiple drug overdose procedural complications accidental Injury. poisoning and Medications errors Over doses Multiple drug overdose procedural complications intentional Injury. orsonmg and Medication errors Overdoses Overdose procedural complications Death General disorders and administration site conditions Fatal outcomes Death and sudden death Accidental death Nervous system disorders Neurological disorders NBC Cortical dysfunction NEC Brain death Cardiac disorders Cardiac Ventricular and cardiac arrest Cardiac death General disorders and administration site conditions Fatal outcomes Death and sudden death Death General disorders and administrations site conditions Fatal outcomes Death and sudden death Death neonatal General disorders and administration site Fatal outcomes Death and sudden death Sudden cardiac death conditions disorders NEC NEC conditions . . . . Ve itricular arrh lnnias a 1d ardrac disorders Cardiac I . yt I Sudden death cardiac arrest General disorders and administration site Fatal outcomes Death and sudden death Agonal death struggle conditions General disorders and General 5 stem General si IS and 1 toms administration site g! yr Apparent death Social Circumstances Family Issues Bereavement issues Death of companion Social Family Issues Bereavement issues Death of relative General disorders and administration site conditions Fatal outcomes Death and sudden death Sudden unexplained death in epilepsy 24-month REMS Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies. Page 115 of 131 Primary SOC High Level Group High Level Term Preferred Term Respiratory. thoracic and Respiratory disorders . . . . . mediastinal disorders NE Breathing abnormalities ardio respiratory arrest Cardiac disorders Cardiac Ventricular and cardiac arrest Cardiac arrest Respiratory. thoracic and mediastinal disorders Respiratory disorders NEC Breathing abnormalities Respiratory arrest Misuse General disorders and administration site Therapeutic and nontherapeutic effects Withdrawal and rebound Medication overuse headache . . . . effects conditions (excl tox1c1ty) . . . Ps chiatric disorders . . . disorders NE Substance-related disorders Intentional drug nususe Drug abuse dependence and withdrawal SMQ (Standardized Query) Abuse disorders disorders NEC Substance-related disorders Drug abuse Social circrunstances Lifestyle issues Drug and chemical abuse Drug abuser disorders disorders NEC Substance-related disorders Substance abuse Social circrunstances Lifestyle issues Drug and chemical abuse Substance abuser Social circrunstances Lifestyle issues Drug and chemical abuse Ex-drug abuser Injury. poisoning and procedural complications Exposures. chemical injuries and poisoning Poisoning and toxicity Substance-induced mood disorder Injury. poisoning and procedural complications Exposures. chemical injuries and poisoning Poisoning and toxicity Substance-induced disorder Drug abuse dependence and Withdrawal SMQ (Standardized Query) Inappropriate Injury. poisoning and Drug administered at . . Medication errors Maladministrations . . . procedural complications inappropriate srte In'u . oisonin and . . . . . Ina ro riate schedule of dru ry . Medication errors pp . . . procedural complications administration . . Therapeutic Sur ical and medical . procedures and Therapeutic procedures NBC Off label use procedures supportive care Injury. poisoning and procedural complications Medication errors Maladministrations Drug administered to patient of inappropriate age Medication Error Injury. poisoning and procedural complications Medication errors Medication errors NEC Intercepted medication error 24-month REMS Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies. Primary SOC Injury, poisoning and procedural complications Injury, poisoning and procedural complications Injury poisoning and procedural complications Injury, poisoning and procedural complications Injury, poisoning and procedural complications Injury, poisoning and procedural complications Injury, poisoning and procedural complications Injury, poisoning and procedural complications Injury, poisoning and procedural complications Injury, poisoning and procedural complications Injury, poisoning and procedural complications Injury, poisoning and procedural complications Injury, poisoning and procedural complications Injury, poisoning and procedural complications Page 116 of 131 High Level Group High Level Term Medication errors Medication errors NEC Medication errors Medication errors NEC Medication error Medication errors Maladministrations Counterfeit drug administered Medication errors Maladministrations Drug administration error Medication errors Maladministrations Drug dose omission Medication errors Maladministrations Expired drug administered Medication errors Maladministrations Incorrect dose administered Medication errors Maladministrations Medication errors Maladministrations Medication errors Maladministrations Medication errors Maladministrations Medication errors Maladministrations Poor quality drug administered Medication errors Maladministrations Inappropriate schedule of drug administration Medication errors Maladministrations Underdose Therapeutic and nontherapeutic responses Therapy naive Maladministrations Wrong drug administered Maladministrations Wrong technique in drug usage process Medication errors NEC Drug dispensing error Medication errors NEC Drug label confusion Medication errors NEC Drug name confusion Medication errors NEC Drug prescribing error Medication errors NEC Incorrect storage of drug Medication errors NEC Intercepted drug dispensing error Therapeutic and General disorders and nontherapeutic effects administrative sites Injury, poisoning and Medication errors procedural complications Injury, poisoning and Medication errors procedural complications Injury, poisoning and Medication errors procedural complications Injury, poisoning and Medication errors procedural complications Injury, poisoning and Medication errors procedural complications Injury, poisoning and Medication errors procedural complications Injury, poisoning and Medication errors procedural complications Injury, poisoning and Medication errors procedural complications Preferred Term Intercepted drug prescribing error Incorrect drug administration duration Incorrect drug administration rate Incorrect drug dosage form administered Incorrect route of drug administration FDA_792 24-month REMS Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies. Page 117 of 131 Preferred Term Labeled drug-disease interaction medication error Labeled drug-drug interaction medication error Primary SOC Injury. poisoning and procedural complications High Level Group High Level Term Medication errors Medication monitoring errors Injury. poisoning and procedural complications Medication monitoring errors Medication errors Drug administered to patient of inappropriate age Injury. poisoning and . . Maladministrations procedural complications Medication errors Medication errors due to accidental exposures Injury. poisoning and procedural complications Accidental drug intake by child Medication errors Multiple use of a single use product Injury. poisoning and procedural complications Accidental Injury. poisoning and procedural complications Medication errors Medication errors due to . Accidental drug intake by child accrderrtal exposures Medication errors Medication errors due to accidental exposures Injury. poisoning and . . Accidental ex osure procedural Medication errors Injury. poisoning and . . Accidental overdose procedural complications Medication errors Overdoses Injury. poisoning and procedural complications Chemical injury and poisoning Poisoning and toxicity Accidental poisoning Injury. poisoning and procedural Chemical injluy and poisoning Poisoning and toxicity Toxicity to various agents Injury. poisoning and Multiple drug overdose Medication errors Overdoses procedural complications accidental Dependence disorders Substance-related disorders Dependence disorders Substance-related disorders Drug dependence Foetal conditions due to maternal conditions Pregnancy. puerperium and perinatal conditions Drug dependence. antepartrun Foetal complications disorders NEC disorders NEC disorders NEC disorders NEC disorders Substance-related disorders Drug dependence. postpartum disorders Substance-related disorders Polysubstance dependence disorders Substance-related disorders Withdrawal disorders Substance-related disorders Drug Withdrawal Drug Diversion Social circrunstances Legal issues Criminal activity Drug diversion Therapeutic procedures and supportive care NEC Surgical and medical Off label use procedures Therapeutic procedures NBC Respiratory Depression Acute central respiratory depression SMQ (Standardized Query) 24-month REMS Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies. 12.2 Page 118 of 131 AAPCC LISTINGS The following definitions are used to characterize data in the attached listings of TIRF medicines fentanyl exposures and unknown exposures which were derived AAPCC annual report: Bronstein AC, Spyker DA, Cantilena LR et al. 2010 annual report of the American Association of Poison Control Centers’ National Poison Data System (NPDS): 28th annual report. Clinical Toxicology. 2011;49:910-941. No effect: The patient did not develop any signs or symptoms as a result of the exposure. Minor effect: The patient developed some signs or symptoms as a result of the exposure, but they were minimally bothersome and generally resolved rapidly with no residual disability or disfigurement. A minor effect is often limited to the skin or mucus membranes (e.g., self-limited gastrointestinal symptoms, drowsiness, skin irritation, first-degree dermal burn, sinus tachycardia without hypotension, and transient cough). Moderate effect: The patient exhibited signs or symptoms as a result of the exposure that were more pronounced, more prolonged, or more systemic in nature than minor symptoms. Usually, some form of treatment is indicated. Symptoms were not life-threatening, and the patient had no residual disability or disfigurement (e.g., corneal abrasion, acid-base disturbance, high fever, disorientation, hypotension that is rapidly responsive to treatment, and isolated brief seizures that respond readily to treatment). Major effect: The patient exhibited signs or symptoms as a result of the exposure that were lifethreatening or resulted in significant residual disability or disfigurement (e.g., repeated seizures or status epilepticus, respiratory compromise requiring intubation, ventricular tachycardia with hypotension, cardiac or respiratory arrest, esophageal stricture, and disseminated intravascular coagulation). Death: The patient died as a result of the exposure or as a direct complication of the exposure. FDA_794 24-month REMS Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies. Page 119 of 131 A statement on AAPCC data must be included in all publications referencing AAPCC data. The AAPCC maintains the national database of information logged by the country's 57 poison control centers. Case records in this database are from self-reported calls: they reflect only information provided when the public or healthcare professionals report an actual or potential exposure to a substance (e.g., an ingestion, an inhalation, or a topical exposure, etc.), or request information/educational materials. Exposures do not necessarily represent a poisoning or overdose. The AAPCC is not able to completely verify the accuracy of every report made to member centers. Additional exposures may go unreported to PCCs and data referenced from the AAPCC should not be construed to represent the complete incidence of national exposures to any substance(s). All data produced from the AAPCCs databases during the year in which the exposures occur is considered preliminary. Changes occur in only a small number of cases each year. This is because it is possible that a poison center may update a case anytime during that year if new data is obtained. In the fall of each year the data for the previous year is locked and no changes are permitted. At that time the data for a year is considered closed. FDA_795 24-month REMS Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies. Page 120 of 131 AAPCC Listing of Exposures to Known TRIG TIRF Immediate-Release Oral Medicines Subject 1 2 3 4 5 6 7 Start Date 11/4/12 7:52 PM 12/25/1 2 8:50 PM 12/25/1 2 8:50 PM 12/28/1 2 1:04 AM Public Case Number Age (yrs) Gender Substance Rank No of Substances Formulation Quantity Quantity Unit Major Category Reason For Exposure Medical Outcome 18482383142012 16 Male 1 1 Aerosol / mist / spray / gas NULL Unknown Fentanyl Intentional - Abuse Minor effect 321244603432012 42 Male 2 2 Patch 2 each (e.g. bites / stings) Fentanyl Intentional Unknown Moderate effect 321244603432012 42 Male 1 2 Solid (tablets / capsules / caplets) 90 each (e.g. bites / stings) Gabapentin Intentional Unknown Moderate effect 21038373392012 23 Female 1 1 Solid (tablets / capsules / caplets) 1600 mcg Fentanyl Intentional - Abuse Minor effect 2/11/13 8:49 PM 10165673472013 35 Male 1 1 Unknown NULL Unknown Fentanyl Unintentional General 2/12/13 12:11 AM 21130043392013 29 Male 1 1 Solid (tablets / capsules / caplets) NULL Unknown Fentanyl Intentional Misuse 1709933672013 38 Male 1 1 Solid (tablets / capsules / caplets) NULL Unknown Fentanyl Intentional Suspected suicide Major effect 10760983722013 78 Female 3 3 Patch NULL Unknown Fentanyl Unknown reason Death 10760983722013 78 Female 2 3 Unknown NULL Unknown Hydromorphone Unknown reason Death 10760983722013 78 Female 1 3 Solid (tablets / capsules / caplets) NULL Unknown Fentanyl Unknown reason Death Female 3 3 Solid (tablets / capsules / caplets) 7 tabs / pills / capsules Other Antihistamines Alone (Excluding Cough and Cold Preparations) Intentional Suspected suicide Unable to follow, judged as a potentially toxic exposure Female 1 3 Solid (tablets / capsules / caplets) 8 tabs / pills / capsules Fentanyl Intentional Suspected suicide Unable to follow, judged as a potentially toxic exposure 3/23/13 10:11 PM 3/28/13 10:27 AM 3/28/13 10:27 AM 3/28/13 10:27 AM 8 3/31/13 1:00 AM 731011543052013 3/31/13 1:00 AM 731011543052013 Unkn own adult (>=2 0 yrs) Unkn own adult (>=2 0 yrs) Unable to follow, judged as a potentially toxic exposure Not followed, minimal clinical effects possible (no more than minor effect possible) FDA_796 24-month REMS Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies. Page 121 of 131 AAPCC Listing of Exposures to Known TRIG TIRF Immediate-Release Oral Medicines Subject 9 10 Start Date Public Case Number 3/31/13 1:00 AM 731011543052013 4/18/13 11:44 PM 5/31/13 7:34 AM 5/31/13 7:34 AM Age (yrs) Unkn own adult (>=2 0 yrs) Gender Substance Rank No of Substances Formulation Quantity Quantity Unit Major Category Female 2 3 Liquid 3 ounces 12 13 14 6/15/13 2:22 AM 6/15/13 2:22 AM 6/15/13 2:22 AM 7/15/13 12:40 PM 7/15/13 12:40 PM 7/15/13 12:40 PM 7/15/13 12:40 PM 7/23/13 3:16 PM 9/1/13 6:34 AM 9/1/13 6:34 AM Medical Outcome Codeine Intentional Suspected suicide Unable to follow, judged as a potentially toxic exposure Intentional - Abuse Major effect 18882943192013 24 Male 1 1 Aerosol / mist / spray / gas NULL Unknown Fentanyl 1507423622013 28 Male 2 2 Liquid NULL Unknown Lidocaine 1507423622013 28 Male 1 2 Liquid NULL Unknown Fentanyl 11 6/15/13 2:22 AM Reason For Exposure Intentional Unknown Intentional Unknown Major effect Major effect 18762153532013 31 Male 2 4 Solid (tablets / capsules / caplets) NULL Unknown Oxycodone Alone or in Combination (Excluding Combination Products with Acetaminophen or Acetylsalicylic Acid) 18762153532013 31 Male 1 4 Patch 3 each (e.g. bites / stings) Fentanyl 18762153532013 31 Male 4 4 Unknown NULL Unknown Cocaine 18762153532013 31 Male 3 4 Unknown NULL Unknown Heroin Unintentional General Major effect Intentional Suspected suicide Intentional Suspected suicide Intentional Suspected suicide Intentional Suspected suicide Moderate effect Moderate effect Moderate effect Moderate effect 21416763322013 48 Female 3 4 Liquid 500 mg Other or Unknown Local and/or Topical Anesthetic 21416763322013 48 Female 1 4 Liquid 160 mg Fentanyl Unintentional General Major effect 21416763322013 48 Female 4 4 Liquid 120 mg Other Analgesics Unintentional General Major effect 21416763322013 48 Female 2 4 Liquid 240 mg Morphine Unintentional General Major effect 19690023742013 25 Male 1 1 Aerosol / mist / spray / gas NULL Unknown Fentanyl Intentional - Abuse Minor effect 4132843842013 23 Female 4 4 Patch NULL Unknown Fentanyl 4132843842013 23 Female 1 4 Solid (tablets / capsules / caplets) NULL Unknown Amitriptyline Intentional Suspected suicide Intentional Suspected suicide Moderate effect Moderate effect FDA_797 24-month REMS Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies. Page 122 of 131 AAPCC Listing of Exposures to Known TRIG TIRF Immediate-Release Oral Medicines Subject Start Date 9/1/13 6:34 AM 9/1/13 6:34 AM 15 16 17 9/9/13 7:17 PM 9/9/13 7:17 PM 9/13/13 12:23 PM 10/4/13 4:12 PM 10/4/13 4:12 PM 10/4/13 4:12 PM Public Case Number Age (yrs) Gender Substance Rank No of Substances Formulation Quantity Quantity Unit Major Category Reason For Exposure Intentional Suspected suicide 4132843842013 23 Female 2 4 Solid (tablets / capsules / caplets) NULL Unknown Benzodiazepines 4132843842013 23 Female 3 4 Solid (tablets / capsules / caplets) NULL Unknown Unknown Dietary Supplements or Homeopathic Agents Intentional Suspected suicide Moderate effect 11037533722013 59 Female 1 2 Other NULL Unknown Fentanyl Unknown reason Death 11037533722013 59 Female 2 2 Patch NULL Unknown Fentanyl Unknown reason Death 1688063622013 58 Male 1 1 Liquid 1100 mcg Fentanyl Unintentional Therapeutic error Moderate effect 732404693602013 41 Female 2 3 Solid (tablets / capsules / caplets) 20 tabs / pills / capsules Benzodiazepines 732404693602013 41 Female 1 3 Unknown NULL Unknown Fentanyl 732404693602013 41 Female 3 3 Solid (tablets / capsules / caplets) NULL Unknown Trazodone Intentional Suspected suicide Intentional Suspected suicide Intentional Suspected suicide Medical Outcome Moderate effect Major effect Major effect Major effect FDA_798 24-month REMS Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies. Page 123 of 131 AAPCC Listing of Exposures to Unknown Fentanyl Subject 1 Start Date 12/4/12 8:54 AM 12/4/12 8:54 AM 12/4/12 8:54 AM 12/4/12 8:54 AM 2 Public Case Number Age Gender Substance Rank No of Substances Formulation Quantity Quantity Unit 4448603642012 56 Male 1 10 Solid (tablets / capsules / caplets) NULL Unknown 4448603642012 56 Male 2 10 Solid (tablets / capsules / caplets) NULL Unknown 4448603642012 56 Male 3 10 Unknown NULL Unknown 4448603642012 56 Male 4 10 Solid (tablets / capsules / caplets) NULL Unknown Reason For Exposure Medical Outcome Intentional - Abuse Death, indirect report Intentional - Abuse Death, indirect report Fentanyl Intentional - Abuse Death, indirect report Pentazocine Intentional - Abuse Death, indirect report Intentional - Abuse Death, indirect report Intentional - Abuse Death, indirect report Major category Acetaminophen with Hydrocodone Oxycodone Alone or in Combination (Excluding Combination Products with Acetaminophen or Acetylsalicylic Acid) Short or Intermediate Acting Barbiturates Other Types of Sedative/Hypnotic/ Anti-Anxiety or AntiPsychotic Drug 12/4/12 8:54 AM 4448603642012 56 Male 5 10 Solid (tablets / capsules / caplets) NULL Unknown 12/4/12 8:54 AM 4448603642012 56 Male 6 10 Solid (tablets / capsules / caplets) NULL Unknown 12/4/12 8:54 AM 4448603642012 56 Male 7 10 Solid (tablets / capsules / caplets) NULL Unknown Amitriptyline Intentional - Abuse Death, indirect report Intentional - Abuse Death, indirect report Intentional - Abuse Death, indirect report Intentional - Abuse Death, indirect report Intentional - Abuse Moderate effect 12/4/12 8:54 AM 4448603642012 56 Male 8 10 Unknown NULL Unknown Other Dextromethorphan Preparations 12/4/12 8:54 AM 4448603642012 56 Male 9 10 Solid (tablets / capsules / caplets) NULL Unknown Propoxyphene 12/4/12 8:54 AM 4448603642012 56 Male 10 10 Solid (tablets / capsules / caplets) NULL Unknown 20593943782012 23 Female 1 2 2 tabs / pills / capsules Diphenhydramine Alone (Unknown if Over the Counter or Prescription) Acetaminophen with Hydrocodone 20593943782012 23 Female 2 2 NULL Unknown Fentanyl Intentional - Abuse Moderate effect 267253202012 Unkn own adult (>=2 0 yrs) Unknown Oxycodone Alone or in Combination (Excluding Combination Products with Acetaminophen or Other - Withdrawal Unable to follow, judged as a potentially toxic exposure 12/4/12 5:53 PM 12/4/12 5:53 PM 3 12/5/12 9:28 PM Male 1 3 Solid (tablets / capsules / caplets) Solid (tablets / capsules / caplets) Solid (tablets / capsules / caplets) NULL FDA_799 24-month REMS Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies. Page 124 of 131 AAPCC Listing of Exposures to Unknown Fentanyl Subject Start Date Public Case Number Age Gender Substance Rank No of Substances Formulation Quantity Quantity Unit Major category Reason For Exposure Medical Outcome Acetylsalicylic Acid) 4 5 6 7 8 9 10 11 12/5/12 9:28 PM 267253202012 12/5/12 9:28 PM 267253202012 1/9/13 12:07 PM 1/23/13 12:22 PM 2/11/13 9:20 PM 2/12/13 11:42 PM 2/12/13 11:42 PM 2/17/13 10:10 AM 2/28/13 8:25 PM 3/11/13 3:34 PM 3/11/13 3:34 PM 3/23/13 6:20 AM 3/23/13 6:20 AM Unkn own adult (>=2 0 yrs) Unkn own adult (>=2 0 yrs) Male 2 3 Unknown NULL Unknown Fentanyl Other - Withdrawal Unable to follow, judged as a potentially toxic exposure Male 3 3 Unknown NULL Unknown Other or Unknown Narcotics Other - Withdrawal Unable to follow, judged as a potentially toxic exposure 20668103782013 52 Male 1 1 Solid (tablets / capsules / caplets) NULL Unknown Fentanyl Intentional - Abuse Minor effect 30984613582013 33 Male 1 1 Powder / granules 1 each (e.g. bites / stings) Fentanyl Intentional - Abuse Moderate effect 11442423862013 78 Male 1 1 Other 1 each (e.g. bites / stings) Fentanyl Adverse reaction Drug Minor effect Unable to follow, judged as a potentially toxic exposure Unable to follow, judged as a potentially toxic exposure 5383243332013 42 Male 1 2 Solid (tablets / capsules / caplets) 4 tabs / pills / capsules Fentanyl Intentional Suspected suicide 5383243332013 42 Male 2 2 Solid (tablets / capsules / caplets) 14 tabs / pills / capsules Benzodiazepines Intentional Suspected suicide 20754553782013 61 Female 1 1 Other NULL Unknown Fentanyl Intentional Suspected suicide Moderate effect 20781363782013 51 Male 1 1 Solid (tablets / capsules / caplets) 1 each (e.g. bites / stings) Fentanyl Intentional - Misuse Moderate effect 4560653642013 31 Female 1 2 Unknown NULL Unknown Fentanyl Intentional - Abuse Death, indirect report 4560653642013 31 Female 2 2 Unknown NULL Unknown Benzodiazepines Intentional - Abuse Death, indirect report 20830413782013 19 Male 1 3 Solid (tablets / capsules / caplets) 12 tabs / pills / capsules Benzodiazepines Intentional - Abuse Moderate effect Unknown Energy Drinks: Caffeine Only (Without Guarana, Kola Nut, Tea, Yerba Mate, Intentional - Abuse Moderate effect 20830413782013 19 Male 2 3 Liquid NULL FDA_800 24-month REMS Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies. Page 125 of 131 AAPCC Listing of Exposures to Unknown Fentanyl Subject Start Date Public Case Number Age Gender Substance Rank No of Substances Formulation Quantity Quantity Unit Reason For Exposure Medical Outcome Fentanyl Intentional - Abuse Moderate effect Fentanyl Intentional - Abuse Major effect Major category Cocoa, etc) 12 3/23/13 6:20 AM 5/1/13 8:15 PM 19 Male 3 3 Other 2 20919503782013 37 Male 1 1 Solid (tablets / capsules / caplets) 1 21032643782013 Unkn own adult (>=2 0 yrs) Male 1 1 Other 1 each (e.g. bites / stings) Fentanyl Unintentional General Unable to follow, judged as a potentially toxic exposure 4094523842013 34 Male 1 1 Other 1 each (e.g. bites / stings) Fentanyl Intentional - Abuse Moderate effect 321711553432013 28 Male 1 2 Other NULL Unknown Fentanyl Intentional - Abuse Minor effect 321711553432013 28 Male 2 2 Other NULL Unknown Hallucinogenic Amphetamines Intentional - Abuse Minor effect 21161483782013 18 Male 1 2 Liquid NULL Unknown Fentanyl 21161483782013 18 Male 2 2 40 mg Hydromorphone NULL Unknown Acetaminophen with Oxycodone NULL Unknown Fentanyl NULL Unknown Benzodiazepines 13 6/17/13 10:19 PM 14 15 16 17 7/22/13 9:44 PM 7/31/13 10:54 AM 7/31/13 10:54 AM 8/12/13 7:35 PM 8/12/13 7:35 PM 8/13/13 1:55 PM 8/13/13 1:55 PM 8/13/13 1:55 PM 8/13/13 1:55 PM 18 18 8/29/13 1:35 PM 8/29/13 1:35 PM 8/29/13 1:35 PM 9/16/13 12:33 PM 9/16/13 12:33 each (e.g. bites / stings) each (e.g. bites / stings) 20830413782013 Solid (tablets / capsules / caplets) Solid (tablets / capsules / caplets) Solid (tablets / capsules / caplets) Solid (tablets / capsules / caplets) 21583013392013 79 Female 1 4 21583013392013 79 Female 2 4 21583013392013 79 Female 3 4 21583013392013 79 Female 4 4 Solid (tablets / capsules / caplets) NULL Unknown Diphenhydramine Alone (Over the Counter) 321773193432013 54 Female 1 3 Other 2 each (e.g. bites / stings) Fentanyl 321773193432013 54 Female 2 3 321773193432013 54 Female 3 3 321811983432013 54 Female 1 2 321811983432013 54 Female 2 2 Solid (tablets / capsules / caplets) Solid (tablets / capsules / caplets) Acetaminophen with Oxycodone Acetaminophen Alone, Adult Intentional Suspected suicide Intentional Suspected suicide Intentional Suspected suicide Intentional Suspected suicide Intentional Suspected suicide Major effect Intentional Suspected suicide Major effect Intentional Unknown Intentional Unknown Intentional Unknown No effect No effect Major effect Major effect Major effect NULL Unknown NULL Unknown Solid (tablets / capsules / caplets) 100 tabs / pills / capsules Hydromorphone Intentional Unknown Moderate effect Other 1 each (e.g. bites / stings) Fentanyl Intentional Unknown Moderate effect Major effect Major effect FDA_801 24-month REMS Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies. Page 126 of 131 AAPCC Listing of Exposures to Unknown Fentanyl Subject Start Date PM 20 10/5/13 3:59 AM Public Case Number Age Gender Substance Rank No of Substances Formulation Quantity Quantity Unit Major category Reason For Exposure Medical Outcome 21279543782013 21 Male 1 1 Solid (tablets / capsules / caplets) NULL Unknown Fentanyl Intentional - Abuse Moderate effect FDA_802 24-month REMS Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies. 12.3 Page 127 of 131 TRIG AERS Safety Surveillance Analysis Report FDA_803 FDA FAERS Safety Surveillance Analysis Report FAERS Data Release Date: 2012 Q4 Product: Transmucosal Immediate-Release Fentanyl (TIRF) Sponsor: TIRF Risk Evaluation Mitigation Strategy (REMS) Industry Group (TRIG) of Companies Date: 18 December 2013 Status: Final Version: 1.0 FDA_804 FDA FAERS Safety Surveillance Analysis Report, 2012 Q4 Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies. Page 2 of 24 Table of Contents Overview ...................................................................................................................................3  FDA Adverse Event Reporting System (FAERS) ............................................................. 3  MedDRA Version 16.1 ...................................................................................................... 3  Summary of Analysis ........................................................................................................ 4  Analysis Results ........................................................................................................................ 5  AERS Reports: Quarterly and Cumulative Summary Statistics ...................................... 5  Preferred Terms of Interest – Q4 2012 and Cumulative Summary Statistics ................. 13  Signals of Disproportionate Reporting ........................................................................... 20  Appendix 1. Specific Preferred Terms in the Standard MedDRA Query for Acute Central Respiratory Depression ...................................................................... 23  FDA_805 FDA FAERS Safety Surveillance Analysis Report, 2012 Q4 Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies. Page 3 of 24 Overview The following Quarterly Analysis report was produced from the cumulative 2012 Q4 release of the FDA’s Freedom of Information Act (FOIA) FDA Adverse Event Reporting System (FAERS) database which was made publicly available by the FDA in early October, 2013. This Analysis Report focuses on the latest 2 quarters of the AERS data, Q3 and Q4 2012, which are new since the last Quarterly Analysis report was delivered using the Q2 2012 AERS data. As AERS releases are cumulative, the data for both quarters are contained in the most recent Q4 2012 release. FDA Adverse Event Reporting System (FAERS) Q4 2012 is the first release of the FDA data using the upgraded FAERS system; prior data releases were produced using the legacy AERS system. There are several notable changes/differences under this new system, including: • FAERS transitioned from an Individual Safety Report Number based system to a Primary ID based system. Cases are now identified with a PrimaryID, CaseID, and CaseVersion. • Some fields were removed, including Image ID, Confidential [identity of the reporter], and Death Date • Serious cases and those with an outcome of death are prioritized for inclusion in the FAERS data • Drug names for new cases are more standardized The 2012 Q4 issue of the FAERS data was released approximately six (6) months behind schedule and contains data through December 2012. The FDA has not communicated a plan to release 2013 issues of the FAERS data, which have also been delayed. MedDRA Version 16.1 The FAERS 2012 Q4 data utilizes MedDRA Version 16.1 for adverse event coding. Therefore, this TRIG FAERS Surveillance analysis also includes an assessment of the TRIG outcomes of interest in order to identify any new Preferred Terms (PTs) of Interest, or existing PTs of interest that may be obsolete under MedDRA 16.1. As a result of this analysis, seven (7) new PTs have been added to the TRIG PTs of interest; 5 PT’s have been demoted (rendered obsolete) and cases for these demoted PTs are cross-referenced with existing PTs in MedDRA 16.1. In total, seventy-four (74) Preferred Terms in MedDRA 16.1 represent a TRIG outcome of interest. Table 20 lists these 74 PTs and also includes a summary of the additions and modifications to the PT list as a result of the upgrade to MedDRA 16.1. These 74 Preferred Terms of Interest are grouped into the following broad Categories of Interest (TRIG Categories) for aggregate reporting: o Death FDA_806 FDA FAERS Safety Surveillance Analysis Report, 2012 Q4 Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies. Page 4 of 24 o Overdose (fatal and non-fatal) o Misuse, abuse, addiction, and diversion o Inappropriate prescribing o Medication errors o Accidental exposure/ingestion Table 21 lists the PTs associated with each TRIG category above and provides detailed and aggregate results for each category and PT. Summary of Analysis The FAERS 2012 Q4 database is comprised of 4,073,790 cumulative case reports, including 232,989 new reports and 115,427 reports from the Q3 2012 quarterly release. Of the cumulative case reports included in this release, seventy-one (71) cases reference a transmucosal immediaterelease fentanyl (TIRF) product covered by the FDA Risk Evaluation and Mitigation Strategy (REMS) for TIRF products, with an event date on or after December 28, 2011. Fifty-three (53) of these 71 TIRF product case reports with an event date after December 28, 2011 also specify United States as the Country of Origin and are included in the analysis results described below. Sixteen (16) of these 53 domestic cases are new since the last TRIG Surveillance report was produced using the Q2 2012 release of the AERS data for inclusion in the 12 Month TIRF REMS Assessment Report. Thirty-four (34) of the 53 domestic cases includeat least one of the TRIG MedDRA Preferred Terms of Interest and are included in the analysis. Eight (8) of these 34 cases with a TRIG MedDRA Preferred Terms of Interest are new since the last TRIG Surveillance Report was produced using the Q2 2012 release of the AERS data for inclusion in the 12 Month TIRF REMS Assessment Report. In addition, one (1) of the 53 cases that specifies at least one Preferred Term from the MedDRA SMQ (Broad) Acute Central Respiratory Depression, is included in this analysis as it contains a possible symptom related to the events included in the TRIG Categories above. The terms included in the SMQ are attached as Appendix 1. None of the individual Preferred Terms from this SMQ is a TRIG Preferred Term of interest; instead counts of reports listing any PT from this SMQ will be summarized into an aggregate count for the entire SMQ and reported separately. The analysis protocol and assumptions that were used to guide this quarterly analysis are documented in the TRIG AERS Safety Surveillance Plan. This analysis report summarizes the reporting characteristics of the FAERS case reports for TIRF products covered by the shared system REMS. The results are presented in 4 sections as described below. • AERS Reports - Cumulative and Quarterly Summary Statistics: this section provides summary characteristics of the reports comprising the entire AERS database which can be used to provide additional context for interpreting results of the TIRF analysis FDA_807 FDA FAERS Safety Surveillance Analysis Report, 2012 Q4 Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies. Page 5 of 24 TIRF Product Reports Cumulative and Quarterly Summary Statistics: this section provides the srunmary report characteristics of case reports which were selected for the TRIG quarterly analysis and that also include a PT or SMQ of interest 0 Outcomes of Interest Cumulative and Quarterly Summary Statistics: this section provides cormts for each individual Preferred Term of Interest and event categories of Overdose, Death, Abuse, Misuse, Inappropriate Prescribing, Medication Error, Accidental Exposure/Ingestion, Dependence, and Drug Diversion. In addition, cormts for the SMQs Drug Abuse, Dependence and Withdrawal, and Acute Central Respiratory Depression are also included. 0 Signal Detection: This section provides signal detection results for TRIG individual Preferred Terms of interest, for each TRIG event category, and for the 2 of interest. Analysis Results AERS Reports: Quarterly and Cumulative Summary Statistics The tables below provide a descriptive srunmary of the 2012 Q4 FAERS database. These tables include crunulative totals as well as totals for the current (2012 Q4) and prior (2012 Q3) quarter for the overall FAERS database: 0 Table 1: Total FAERS Overall Case Report Counts 0 Table 2: Figure 1: Total FAERS Gender Surmnary 0 Table 3: Figure 2: Total FAERS Age Summary 0 Table 4: Total FAERS Report Type 0 Table 5: Total FAERS Initial and Follow 11p Reports 0 Table 6: Total FAERS Outcome Type 0 Table 7: Total FAERS Submission Type 0 Table 8: Total FAERS Report Soru'ce Type 0 Table 9: Total FAERS Reporter Occupation 0 Table 10: Total FAERS Country of Origin Table 1 Total FAERS Overall Case Report Countsl Overall Database Current Cumulative Total Quarter (Q4 gt er 2012) (Q Reports 4,073,790 232,989 115,427 I From Q4 1997 through December 2012 FDA FAERS Safety Surveillance Analysis Report, 2012 Q4 Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies. Page 6 of 24 Table 2 Total FAERS Gender Summaryl Gender Cumulative Current Quarter Prior Quarter Total (Q4 2012) (Q3 2012) Female 2.262.393 131,898 62,408 Male 1.461344 80.858 38,307 Other/Unknown 350.053 20.233 14.712 Total 4,073,790 232,989 115,427 ?From Q4 1997 through December 2012 Figure 1 Total FAERS Gender Summary, Current and Prior Quarter 140,000 120,000 100,000 80,000 60,000 40,000 - 20,000 - Female Current Quarter Male Other/Unknown I Prior Quarter FDA FAERS Safety Surveillance Analysis Report, 2012 Q4 Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industly Group (TRIG) of Companies. Page 7 of 24 Table 3 Total FAERS Age Summaryl Cumulative Total Current Quarter (Q4 2012) Prior Quarter (Q3 2012) _Age 0?2 35.877 1.279 484 _Age 3-5 18.702 711 349 _Age 6?10 36.362 1.324 624 _Age 11-18 87.997 3.666 1.905 Age 19?25 123.593 5.597 3.088 _Age 26?35 247.039 11.375 6.257 Age 36-64 1.288.400 68.110 36.143 _Age 65+ 841.229 40.606 23.258 _Age Not Reported 1.394.591 100.321 43.319 Total 4,073,790 232,989 115,427 lFrom Q4 1997 through December 2012 Figure 2 Total FAERS Age Summary, Current and Prior Quarter1 120,000 100,000 80,000 60,000 40,000 20,000 0 o! o3 67?, 0%?0 ?35"?015" I Current Quarter Prior Quarter 0 FDA FAERS Safety Sluveillance Analysis Report. 2012 Q4 Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industiy Group (TRIG) of Companies. Page 8 of 24 Table4 Total FAERS Report Type1 Cumulative Total Current Quarter (Q4 2012) Prior Quarter (Q3 2012) Direct 338.900 9.476 4.464 Expedited 2.121.933 139.023 68.918 Periodic 1.612.95 7 84.490 42.045 Total 4,073,790 232,989 115,427 1From Q4 1997 through December 2012 Table 5 Total FAERS Initial Follow-up Reportsl Cumulative Total Current Quarter (Q4 2012) Prior Quarter (Q3 2012) Follow?Up 1.065.536 53.606 37.492 Initial 3.007.986 179.383 77.935 Unspecified 268 - - Total 4,703,790 232,989 115,427 1From Q4 1997 through December 2012 Table 6 Total FAERS Outcome Typel Cumulative Total Current Quarter (Q4 2012) Prior Quarter (Q3 2012) Congenital Anomaly 22.354 1.263 796 Death 456.701 37.116 12.066 Disability 138.522 4.980 4.009 Hospitalization 1.141.879 57.250 33.710 Life?Threatening 177.258 6.535 3.589 Required Intervention 121.840 1.23 643 Other 1.479.513 78.481 44.206 Total 3,538,067 186,856 99,019 I From Q4 1997 through December 2012 1 FDA FAERS Safety Sluyeillance Analysis Report, 2012 Q4 Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industly Group (TRIG) of Companies. Page 9 of 24 Table 7 Total FAERS Submission Typel Cumulative Total Current Quarter (Q4 2012) Prior Quarter (Q3 2012) Electronic 2.281.457 212.452 106.478 Other 1.158.176 20.537 8.949 Unspeci?ed 634.157 - - Total 4,073,790 232,989 115,427 1From Q4 1997 through December 2012 Table 8 Total FAERS Report Source Type*, 1 . Current . Cumulative Prior Quarter (Q3 Total Quart" 2012) (Q4 2012) Foreign 351.770 4.713 1.987 Study 100.467 599 340 Literature 110.871 2.968 1.356 Consumer 605.490 3.677 951 Health Professional 860.114 11.996 3.451 User Facility 3.865 141 16 Company 143.710 871 379 Representative Distributor 11.259 113 15 Other 283.330 32 1.182 Unspeci?ed 2.599.886 217.277 110.960 Total 5,070,762 242,387 120,637 *One report may have zero. one. or multiple report som?ce types lFrom Q4 1997 through December 2012 2 FDA FAERS Safety Sruveillance Analysis Report, 2012 Q4 Transmucosal Irmnediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies. Page 10 of 24 Table 9 Total FAERS Reporter Occupationl Cumulative Total Current Quarter (Q4 2012) Prior Quarter (Q3 2012) Consumer 1.240.996 103.270 55.151 Lawyer 100.308 3.251 3.612 Other Health Professional 546.345 37.960 19.289 Pharmacist 207.686 9.968 5.186 Physician 894.010 70.153 28.806 Nurse 838 838 - Sales 2 2 - Unspeci?ed 1.083.605 7547 3.383 Total 4.073.790 232.989 115.427 1 From Q4 1997 through December 2012 Table 10 Total FAERS Country of Origin1 Cumulative Total Current Quarter (Q4 2012) Prior Quarter (Q3 2012) United States 2.026.097 160.051 78.472 Unspecified 1.241.744 - 276 Other 805.949 72.938 36.679 Total 4,073,790 232,989 115,427 TIRF Product Reports: Quarterly and Cumulative Summary Statistics The tables below provide descriptive analyses of thirty-four (34) cumulative FAERS case reports, including eight (8) new reports in this quarter for TIRF products that met the selection criteria as de?ned in the Quarterly Sluveillance Plan and which also contain a TRIG Preferred Term or SMQ of interest. Results are summarized for both the current quarter as well as the cumulative to-date results. A majority of both the cumulative and new reports containing a PT of interest are for female patients. The new cases are of a older age group 65+) than that of the cumulative cases age 36-64; 18%, age The most common report soru?ce of the new cases is a physician and comparatively, this report source constitutes only 14% of the cumulative TIRF reports to date. Additionally, 75% of the new reports and 88.2% (n=30) of the crunulative reports showed the TIRF product as the primary suspect drug. Notably, of the 8 new cases submitted since that last FAERS Surveillance analysis, foru' (4) reported an outcome of death, representing 50% of outcomes on the newly submitted cases. In 2 of these cases, fentanyl is the drug that is suspected of causing the adverse event whereas it is listed as a concomitant medication in the other 2 cases. Additional characteristics of these 34 reports are further summarized in the following tables: 3 FDA FAERS Safety Sruveillance Analysis Report, 2012 Q4 Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies. Page 11 of 24 0 Table 11: Patient Counts for Case Reports Referencing TIRF Products 0 Table 12: Gender Srunrnary for TIRF Case Reports Containing Events of Interest 0 Table 13: Age Summary for TIRF Case Reports Containing Events of Interest 0 Table 14: Reported Outcomes for TIRF Case Reports Containing Events of Interest 0 Table 15: Submission Type for TIRF Case Reports Containing Events of Interest 0 Table 16: Report Soru?ce for TIRF Case Reports Containing Events of Interest 0 Table 17: Reporter Occupation for TIRF Case Reports Containing Events of Interest 0 Table 18: Role of TIRF Product 0 Table 19: Report Type of TIRF Products Table 11 Patient Counts for TIRF Case Reports Containing Events of Interest Patient Counts 2012 Q2 20132403" 53:; All Reports for TIRF Drugs with event date after 12/28/2011 46* 26 71 US Reports Only 37 16 53 Reports meeting TRIG selection criteria and containing 26 8 34 Temr of Interest Reports meeting TRIG selection criteria and matching Acute 1 0 1 Central Respiratory Depression SMQ *One case dropped between releases,? the event date changed in follow?up report and did not meet RIG date cuto? Table 12 Gender Summary for TIRF Case Reports Containing Events of Interest 2012 3? Total to Date Gender 8 geperis 34 Reports Males 2 7 Females 6 26 Unknown 0 1 Table 13 Age Summary for TIRF Case Reports Containing Events of Interest 2012 Total to Date Age 8 Reports 34 Reports Age 0Age 6-10 0 0 Age 11?18 0 0 Age 19?25 0 0 Age 26?35 1 2 Age 36?Unknown Age 1 8 4 FDA FAERS Safety Surveillance Analysis Report, 2012 Q4 Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industly Group (TRIG) of Companies. Page 12 of 24 Table 14 Reported Outcomes for TIRF Case Reports Containing Events of Interest* Outcome 2012 Q3-Q4 Total to Date 8 Reports 34 Reports Congenital Anomaly 0 0 Death 4 4 Disability 0 0 Hospitalization 1 5 Life Threatening 0 Requires Intervention 0 0 Other 2 1 Not Specified 1 14 *Cases may have 0. 1 or multiple outcomes speci?ed Table 15 Submission Type for Case Reports Referencing TIRF products Submission Type 2012 Q3-Q4 Total to Date 8 Reports 34 Reports Electronic 8 34 Other 0 0 Unspeci?ed 0 0 Table 16 Report Source for TIRF Case Reports Containing Events of Interest Report Source 2012 Q3-Q4 Total to Date 8 Reports 34 Reports Foreign 0 0 Study 0 0 Literature 0 0 Consumer 0 0 Health Professional 0 0 User Facility 0 0 Company Representative 0 0 Distributor 0 0 Other 0 0 Unspecified 8 34 Table 17 Reporter Occupation for TIRF Case Reports Containing Events of Interest Reporter Occupation 2012 Q3-Q4 Total to Date 8 Reports 34 Reports Consumer 4 23 Lawyer 0 0 Other Health Professional 0 4 Pharmacist 0 0 Physician 4 5 Unspecified 0 2 5 FDA FAERS Safety Sruveillance Analysis Report, 2012 Q4 Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies. Page 13 of 24 Table 18 Role Code for TIRF Products Role Code 2012 Q3-Q4 Total to date 8 Reports 34 Reports Primary Suspect 6 75% 30 88.2% Concomitant 2 25% 4 11.8% Table 19 Report Type for TIRF Case Reports Containing Events of Interest Report Type 2012 03?04 Total to Date 8 Reports 34 Reports Expedited 6 14 Periodic 2 20 Preferred Terms of Interest Q4 2012 and Cumulative Summary Statistics The following tables summarize the TRIG Preferred Terms of Interest that were reported on the case reports for TIRF products that met the selection criteria for this analysis. Each case report may include one or more Preferred Terms. A total of 46 Preferred Terms of Interest for this study are reported across the 34 cumulative case reports selected for TIRF products. Ten Preferred Terms are reported on the 8 new cases that were submitted since the last AERS Surveillance analysis. runulatively, the most commonly reported Term is ?Off label use? (23 cumulative 5 new) followed by ?Drug prescribing error? (8 crunulative/ 1 new). Three of the 8 new cases contain the Preferred Term ?Death? as one of the reported adverse events, representing 30% of all Preferred Terms of Interest reported on new cases. The tables below the reported terms: 0 Table 20: ormt of Reported TRIG Preferred Terms of Interest 0 Table 21: Count of Reported Preferred Terms by TRIG Category Table 20 Count of Reported TRIG Preferred Terms of Interest1 2012 Total to Date Unique Preferred Term 10 PTs 46 PTs 16.1 Version Accidental death 0 0.0% 0 0.0% New PT Accidental exposure to product by child 0 0.0% 0.0% Obsolete PT: Accidental drug intake by child New PT Accidental exposure to product 0 0.0% 0.0% Obsolete PT: Accidental exposure 6 FDA FAERS Safety Surveillance Analysis Report, 2012 Q4 Transmucosal Irmnediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies. Page 14 of 24 Table 20 Count of Reported TRIG Preferred Terms of Interest1 2012 Total to Date Unique Preferred Term 10 PTs 46 PTs 16.1 Version Accidental overdose 0 0.0% 0 0.0% 8:23;:t:epATcic::elggli 1e Drug Accidental poisoning 0 0.0% 0 0.0% Agonal death struggle 0 0.0% 0 0.0% Apparent death 0 0.0% 0 0.0% Brain death 0 0.0% 0 0.0% Cardiac arrest 0 0.0% 0 0.0% Cardiac death 0 0.0% 0 0.0% Cardio-respiratory arrest 0 0.0% 0 0.0% Counterfeit drug administered 0 0.0% 0 0.0% Death 3 30.0% 3 6.5% Death neonatal 0 0.0% 0 0.0% Death of companion 0 0.0% 0 0.0% Death of relative 0 0.0% 0 0.0% Dependence 0 0.0% 0 0.0% Drug abuse 0 0.0% 0 0.0% Drug abuser 0 0.0% 0 0.0% Drug administered at inappropriate site 0 0.0% 0 0.0% gillg adnmustered to patient of inappropriate 0 0. 0% 0 0. 0% Drug administration error 0 0.0% 2.2% 312(1): (iinonitoring procedure monitoring procedure Drug dependence 1 10.0% 1 2.2% Drug dependence. antepamun 0 0.0% 0 0.0% Drug dependence. postpartum 0 0.0% 0 0.0% Drug dispensing error 0 0.0% 2.2% Drug diversion 0 0.0% 0 0.0% Drug dose omission 0 0.0% 1 2.2% Drug label confusion 0 0.0% 0 0.0% Drug name confusion 0 0.0% 0 0.0% Drug prescribing error 1 10.0% 8 17.4% Drug Withdrawal 0 0.0% 3 6.5% Ex-dmg abuser 0 0.0% 0 0.0% Expired drug administered 0 0.0% 2.2% Inappropriate schedule of drug administration 0 0.0% 0 0.0% 7 FDA FAERS Safety Sluveillance Analysis Report, 2012 Q4 Transmucosal Ilmnediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies. Page 15 of 24 Table 20 Count of Reported TRIG Preferred Terms of Interest1 2012 Total to Date Unique Preferred Term 10 PTs 46 PTs 16.1 Version Incorrect dose administered 0 0.0% 0.0% Incorrect drug administration duration 0 0.0% 0 0.0% Incorrect drug administration rate 0 0.0% 0 0.0% Incorrect dosage administered 0 0.0% 0 0.0% New PT Incorrect drug dosage form administered 0 0.0% 0 0.0% Incorrect route of drug administration 0 0.0% 0.0% Incorrect storage of drug 0 0.0% 0 0.0% Intentional drug misuse 0 0.0% 0 0.0% Intentional overdose 0 0.0% 0 0.0% Drug Intercepted drug dispensing error 0 0.0% 0 0.0% Intercepted drug prescribing error 0 0.0% 0 0.0% Intercepted medication error 0 0.0% 0 0.0% :rarlgeled drug-disease interaction medication 0 0' 0% 0 0' 0% izgeled drug-drug mteraction medication 0 0. 0% 0 0. 0% Medication eiror 0 0.0% 0 0.0% Medication overuse headache 0 0.0% 0 0.0% Multiple use of single-use product 0 0.0% 0 0.0% Off label use 5 50.0% 23 50.0% Overdose 0 0.0% 0 0.0% 83:33:? Multiple Polysubstance dependence 0 0.0% 0 0.0% Poor quality drug administered 0 0.0% 0 0.0% Prescribed overdose 0 0.0% 0 0.0% New PT Prescribed lulderdose 0 0.0% 0 0.0% New PT Respiratory arrest 0 0.0% 0 0.0% Substance abuse 0 0.0% 0 0.0% Substance abuser 0 0.0% 0 0.0% Substance-induced mood disorder 0 0.0% 0 0.0% Substance-induced disorder 0 0.0% 0.0% Sudden cardiac death 0 0.0% 0 0.0% Sudden death 0 0.0% 0 0.0% Sudden unexplained death in epilepsy 0 0.0% 0 0.0% Therapy naive 0.0% 0.0% 8 FDA FAERS Safety Surveillance Analysis Report, 2012 Q4 Transmucosal Ilmnediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies. Page 16 of 24 Table 20 Count of Reported TRIG Preferred Terms of Interest1 2012 Total to Date Unique Preferred Term 10 PTs 46 PTs 16.1 Version Toxicity to various agents 0 0.0% 0 0.0% Underdose 0 0.0% 0 0.0% Withdrawal 0 0.0% 3 6.5% Wrong drug administered 0 0.0% 0 0.0% Wrong technique in drug usage process 0 0.0% 2.2% Total PTs reported 10 100.0% 46 100.0% 1 A report may have one or more PTs 9 FDA FAERS Safety Sluyeillance Analysis Report, 2012 Q4 Transmucosal Iimnediate-Release Fentanyl (TIRF) TIRF REMS Industiy Group (TRIG) of Companies. Page 17 of 24 Table 21 Count of Reported Events of Interest Grouped by TRIG Category 1 Q3-Q4 2012 Total 10 PTs ?0 Date Categories of Interest 46 PTs Overdose 0 0.0% 0 0.0% Accidental overdose 0 0.0% 0 0.0% Intentional overdose 0 0.0% 0 0.0% Overdose 0.0% 0 0.0% Death 3 30.0% 3 6.5% Accidental death 0 0.0% 0 0.0% Agonal death struggle 0 0.0% 0 0.0% Apparent death 0 0.0% 0 0.0% Brain death 0 0.0% 0 0.0% Cardiac airest 0 0.0% 0 0.0% Cardiac death 0 0.0% 0 0.0% Cardio-respiratory arrest 0 0.0% 0 0.0% Death 3 30.0% 3 6.5% Death neonatal 0 0.0% 0 0.0% Death of companion 0.0% 0 0.0% Death of relative 0 0.0% 0 0.0% Respiratory airest 0 0.0% 0 0.0% Sudden cardiac death 0 0.0% 0 0.0% Sudden death 0 0.0% 0 0.0% Sudden Imexplained death in epilepsy 0 0.0% 0 0.0% Misuse 0 0.0% 0 0.0% Intentional Misuse 0.0% 0 0.0% Medication overuse headache 0 0.0% 0 0.0% Drug abuse dependence and withdrawal SMQ 1 7 Abuse 0 0.0% 0 0.0% Drug abuse 0 0.0% 0 0.0% Drug abuser 0 0.0% 0 0.0% Ex-dmg abuser 0 0.0% 0 0.0% Substance abuse 0 0.0% 0 0.0% Substance abuser 0 0.0% 0 0.0% FDA FAERS Safety Sluyeillance Analysis Report, 2012 Q4 Transmucosal Irmnediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies. Page 18 of 24 Table 21 Count of Reported Events of Interest Grouped by TRIG Category 1 Q3-Q4 2012 Tm" 10 PTs ?0 Date Categories of Interest 46 PTs Substance-induced mood disorder 0 0.0% 0 0.0% Substance-induced disorder 0 0.0% 0 0.0% Drug abuse dependence and withdrawal SMQ 1 7 Inappropriate Prescribing 5 50.0% 23 50.0% Drug administered at inappropriate site 0 0.0% 0 0.0% Drug administered to patient of inappropriate age 0 0.0% 0 0.0% Drug administration monitoring procedure incorrectly performed 0 0.0% 0 0.0% Drug administration monitoring procedru?e not performed 0 0.0% 0 0.0% Inappropriate schedule of drug administration 0 0.0% 0 0.0% Off label use 5 50.0% 23 50.0% Medication Error 1 10.0% 13 28.3% Accidental intake by child 0 0.0% 0 0.0% Counterfeit drug administered 0 0.0% 0.0% Drug administered to patient of inappropriate age 0 0.0% 0 0.0% Drug administration error 0 0.0% 1 2.2% Drug dispensing error 0 0.0% 1 2.2% Drug dose omission 0 0.0% 2.2% Drug label confusion 0 0.0% 0 0.0% Drug name con?rsion 0.0% 0 0.0% Drug prescribing error 1 10.0% 8 17.4% Expired drug administered 0 0.0% 1 2.2% Inappropriate schedule of drug administration 0 0.0% 0 0.0% Incorrect dose administered 0 0.0% 0 0.0% Incorrect dosage administered 0 0.0% 0 0.0% Incorrect drug administration duration 0 0.0% 0 0.0% Incorrect drug administration rate 0 0.0% 0 0.0% Incorrect drug dosage form administered 0 0.0% 0 0.0% Incorrect route of ding administration 0 0.0% 0.0% Incorrect storage of drug 0 0.0% 0.0% Intercepted drug dispensing error 0 0.0% 0 0.0% Intercepted drug prescribing error 0 0.0% 0 0.0% Intercepted medication error 0 0.0% 0 0.0% FDA FAERS Safety Sluyeillance Analysis Report, 2012 Q4 Transmucosal hmnediate-Release Fentanyl (TIRF) TIRF REMS Industiy Group (TRIG) of Companies. Page 19 of 24 Table 21 Count of Reported Events of Interest Grouped by TRIG Category 1 Q3-Q4 2012 Tm" 10 PTs ?0 Date Categories of Interest 46 PTs Labeled drug-disease interaction medication error 0 0.0% 0 0.0% Labeled drug-drug interaction medication cum 0 0.0% 0 0.0% Medication error 0 0.0% 0.0% Multiple use of single-use product 0 0.0% 0.0% Poor quality drug administered 0 0.0% 0.0% Prescribed overdose 0 0.0% 0 0.0% Prescribed underdose 0 0.0% 0 0.0% Therapy naive 0.0% 0 0.0% Underdose 0 0.0% 0 0.0% Wrong drug administered 0 0.0% 0.0% Wrong technique in drug usage process 0 0.0% 1 2.2% Accidental Exposure 0 0.0% 0 0.0% Accidental drug intake by child 0 0.0% 0 0.0% Accidental exposure to product 0 0.0% 0 0.0% Accidental overdose 0 0.0% 0 0.0% Accidental poisoning 0 0.0% 0 0.0% Toxicity to various agents 0 0.0% 0 0.0% Dependence 1 10.0% 7 15.2% Dependence 0.0% 0 0.0% Drug dependence 1 10.0% 1 2.2% Drug dependence. antepartlun 0.0% 0.0% Drug dependence. postpartum 0 0.0% 0 0.0% Drug Withdrawal 0 0.0% 3 6.5% Polysubstance dependence 0 0.0% 0 0.0% Withdrawal 0 0.0% 3 6. 5% Drug Diversion 5 50.0% 23 50.0% Drug diversion 0 0.0% 0 0.0% Off label use 5 50.0% 23 50.0% Respiratory Depression 0 1 Acute central respiraton' depression SMQ 0 1 I A report may have more than one PT FDA FAERS Safety Surveillance Analysis Report, 2012 Q4 Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies. Page 20 of 24 Signals of Disproportionate Reporting Data mining signal detection was carried out for the 53 cumulative TIRF cases selected by TRIG case selection criteria, using the AERS database as the background. In a data mining analysis using a spontaneous reporting database such as AERS, a traditional “denominator” (e.g. the number of patients exposed to a particular drug and/or how long they’ve been exposed) is not known. To overcome this limitation, data mining methods produce a ratio of disproportionate reporting, comparing the number of reports for a particular Drug / Adverse Event (AE) combination to the number of reports for that AE across all of the other drugs in the AERS database. A disproportionality ratio of 1 indicates that the AE is being reported for the drug of interest at the same rate as it is being reported for all other drugs in the background; a ratio of 2 means that it is being reported at twice the background rate. There are several commonly used algorithms that produce disproportionality statistics. Three of the most common algorithms were utilized in this analysis. Each of these algorithms also includes a measure of confidence: • Proportional Reporting Ratio (PRR), Chi Square • Reporting Ratio (RR), Statistical Unexpectedness (1/P) • Multi-gamma Poisson shrinker (MGPS), lower bounds of the 95% confidence interval (EB05) There is no single international standard for signal detection thresholds based on AERS and other spontaneous report databases. The CIOMS VIII Working Group (CIOMS Geneva 2010) dedicates a chapter (VII) to “more complex quantitative signal detection methods”, and provides thoughtful perspectives on the role of statistical analysis in the setting of pharmacovigilance. Despite a lack of standards, signaling is commonly defined by the following thresholds: • PRR: PRR>2, Chi Square >4, and number of reports>3 – considered to be more sensitive but not as specific • MGPS: EB05>2 (lower bounds of the 95% confidence interval of EBGM) – considered to be more specific, but not as sensitive. • RR: RR>1, Statistical Unexpectedness (1/P-value) >system calculated, Bonferroni corrected threshold – considered to have intermediate sensitivity / specificity 1 A Drug / AE combination that crosses a data mining signal threshold is not necessarily indicative that the drug is the cause of that adverse event. For instance, many adverse events that produce high disproportionality scores are related to the reported drug’s indication. Therefore, disproportionality results should be interpreted in the context of other information known about 1 Hochberg AM, Hauben M, Pearson RK, O'Hara DJ, Reisinger SJ, Goldsmith DI, Gould AL, Madigan D., An evaluation of three signal-detection algorithms using a highly inclusive reference event database. Drug Saf. 2009;32(6):509-25. doi: 10.2165/00002018-200932060-00007. FDA_823 FDA FAERS Safety Surveillance Analysis Report, 2012 Q4 Transmucosal Irmnediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies. Page 21 of 24 the drug. Only terms that cross the signaling threshold for at least one of the three data mining algorithms utilized for the analysis are included in the tables below (note that MGPS scores are only calculated when the total number of case reports for the drug and the total number of case reports for the adverse event both exceed one (100), so these scores are not included in the tables below for this quarter). The following tables describe the results of data mining signal detection carried out for the TIRF cases of interest, using the AERS database as the background: 0 Table 22 Signals of Disproportionate Reporting, Preferred Terms of Interest 0 Table 23 Signals of Disproportionate Reporting, TRIG Categories of Interest 0 Table 24 Signals of Disproportionate Reporting, SMQs of Interest Table 22 Signals of Disproportionate Reporting, Preferred Terms of Interest Reports with Reports Reporting Statistical Chi Adverse Event Drug Event with Event Ratio Unexpectedness PRR Square Off label use 23 17933 98.58 39.46 98.71 2134.53 Drug prescribing error 3901 157.63 15.22 157.95 1094.44 Withdrawal 6243 36.94 4.10 36.95 72.14 Table 23 Signals of Disproportionate Reporting, TRIG Categories of Interest Reports Reports with Drug with Reporting Statistical Chi Adverse Event Event Event Ratio Unexpectedness PRR Square Inappropriate prescribing 23 28049 63.03 35.02 63.08 1351.99 Diversion 23 18442 95.86 39.18 95.98 2074.65 Medication error 13 146589 6.82 7.43 6.82 61.03 Dependence 7 44773 12.02 5.72 12.02 60.78 Table 24 Signals of Disproportionate Reporting, of Interest Reports with Drug Reports Reporting Statistical Chi Adverse Event Event with Event Ratio Unexpectedness PRR Square Drug abuse. dependence and 7 181778 2.96 2.05 2.96 7.57 withdrawal Relatively robust signals continue to be seen for the Preferred Terms of Interest: ?Off label Use? and ?Drug prescribing error?. A weaker signal was generated for the Preferred Term of Interest ?Drug withdrawal These are known adverse events for TRIG products. When analyzed according to TRIG Categories of Interest, relatively robust signals were also generated for ?Inappropriate use?, ?Drug diversion?, ?Medication error?, and ?Drug dependence?. When FDA FAERS Safety Surveillance Analysis Report, 2012 Q4 Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies. Page 22 of 24 examined by MedDRA SMQ, the SMQ “Drug abuse, dependence and withdrawal” generated a somewhat weak signal of disproportionate reporting. These results are similar to those seen in the last quarterly analysis, and no additional signals have appeared. FDA_825 FDA FAERS Safety Surveillance Analysis Report, 2012 Q4 Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies. Page 23 of 24 Appendix 1. Specific Preferred Terms in the Standard MedDRA Query for Acute Central Respiratory Depression Respiratory Depression Acute respiratory distress syndrome Acute respiratory failure Apnoea Apnoea neonatal Apnoeic attack Bradypnoea Breath holding Breath sounds abnormal Breath sounds absent Cardio-respiratory distress Central-alveolar hypoventilation Hypopnoea Hypoventilation Neonatal respiratory depression Postoperative respiratory failure Respiratory arrest Respiratory depression Respiratory depth decreased Respiratory failure Respiratory paralysis Respiratory rate decreased Severe acute respiratory syndrome Alveolar oxygen partial pressure abnormal Alveolar oxygen partial pressure decreased Anoxia Asphyxia Blood gases abnormal Blood pH abnormal Blood pH decreased Capnogram abnormal Cardiac arrest Cardiac arrest neonatal Cardiopulmonary failure Cardio-respiratory arrest Cardio-respiratory arrest neonatal Cheyne-Stokes respiration Cyanosis Cyanosis central Death neonatal Dyspnoea End-tidal CO2 abnormal FDA_826 FDA FAERS Safety Surveillance Analysis Report, 2012 Q4 Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies. Page 24 of 24 End-tidal CO2 decreased Hypercapnia Hypercapnic coma Hypoxia Neonatal anoxia Neonatal asphyxia Neonatal hypoxia Neonatal respiratory acidosis Neonatal respiratory arrest Neonatal respiratory distress syndrome Neonatal respiratory distress syndrome prophylaxis Orthopnoea Oxygen saturation abnormal Oxygen saturation decreased Oxygen supplementation PCO2 abnormal PCO2 decreased PO2 abnormal PO2 decreased Respiration abnormal Respiratory acidosis Respiratory disorder Respiratory disorder neonatal Respiratory distress Respiratory fume inhalation disorder Respiratory gas exchange disorder Sleep apnoea syndrome Venous oxygen partial pressure abnormal Venous oxygen partial pressure decreased Venous oxygen saturation abnormal Venous oxygen saturation decreased FDA_827 24-month REMS Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies. 12.4 Page 128 of 131 Periodic Stakeholder Surveys FDA_828 24-month REMS Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies. Page 129 of 131 12.4.1 Patient KAB Survey FDA_829 Patient KAB Assessment Report Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Title: Page 1 of 54 Transmucosal Immediate Release Fentanyl (TIRF) REMS Assessment Quantitative Testing of Patient Knowledge, Attitudes, and Behavior (KAB) about TIRF Products’ Safety and Use Information Document Number Wave 2, 24-month REMS Assessment; Version 1.0 Survey Time Period 16 September 2013 to 17 October 2013 Product Name: Transmucosal Immediate Release Fentanyl Sponsor: TIRF REMS Industry Group (TRIG) of Companies: Cephalon, Inc. (a wholly-owned subsidiary of Teva Pharmaceutical Industries, Ltd.) Depomed, Inc Galena Biopharma, Inc. Insys Therapeutics Meda Pharmaceuticals Mallinckrodt Pharmaceuticals Mylan, Inc. Par Pharmaceutical, Inc. Date: 18 December 2013 Confidentiality Statement The information contained herein is confidential and the proprietary property of the TRIG of Companies and its affiliates, and any unauthorized use or disclosure of such information without the prior written authorization of the TRIG is expressly prohibited. FDA_830 Patient KAB Assessment Report Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies TABLE OF CONTENTS Page 2 of 54 PAGE TABLE OF CONTENTS .........................................................................................................2  LIST OF TABLES.................................................................................................................... 3  LIST OF APPENDICES .......................................................................................................... 4  LIST OF ABBREVIATIONS .................................................................................................. 5  1.  PATIENT SURVEY BACKGROUND ..............................................................6  2.  PATIENT SURVEY OBJECTIVES .................................................................. 7  3.  SURVEY METHODOLOGY ............................................................................ 7  3.1  Survey Development ...........................................................................................7  3.2  Survey Sample ....................................................................................................9  3.2.1  Eligibility ............................................................................................................9  3.2.2  Recruitment .........................................................................................................9  3.2.2.1  Direct Letter Program ....................................................................................... 10  3.2.2.2  Physician Recruitment of Patients .................................................................... 10  3.3  Questions and Statements on Key Risk Messages ............................................10  3.3.1  Key Risk Message 1.......................................................................................... 11  3.3.2  Key Risk Message 2.......................................................................................... 11  3.3.3  Key Risk Message 3.......................................................................................... 11  3.3.4  Key Risk Message 4.......................................................................................... 12  3.3.5  Key Risk Message 5.......................................................................................... 12  3.3.6  Key Risk Message 6.......................................................................................... 13  4.  Statistical Methods ............................................................................................ 13  4.1  Study Population ............................................................................................... 13  4.1.1  Primary Analysis Population ............................................................................ 13  4.1.2  Sub-groups of Interest ....................................................................................... 13  4.1.2.1  Primary Analyses .............................................................................................. 15  4.1.2.2  Secondary Analyses .......................................................................................... 15  4.1.3  Patient Report of an Adverse Event, Product Complaint, or Medical Information Request during the Survey ............................................................15  5.  RESULTS ......................................................................................................... 15  FDA_831 Patient KAB Assessment Report Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 3 of 54 5.1  Survey Participants ...........................................................................................15  5.1.1  Survey Participant Administration Results .......................................................15  5.1.2  Patient/Caregiver Demographics ......................................................................20  5.1.3  TIRF Medicines Education Materials ............................................................... 23  5.1.4  Patient-Prescriber Agreement Form..................................................................28  5.2  KAB Survey Objectives .................................................................................... 30  5.2.1  Key Risk Message Results ................................................................................ 30  5.2.1.1  Key Risk Message 1.......................................................................................... 30  5.2.1.2  Key Risk Message 2.......................................................................................... 30  5.2.1.3  Key Risk Message 3.......................................................................................... 32  5.2.1.4  Key Risk Message 4.......................................................................................... 34  5.2.1.5  Key Risk Message 5.......................................................................................... 35  5.2.1.6  Key Risk Message 6.......................................................................................... 36  5.2.1.7  Summary of Understanding of Key Risk Messages ......................................... 38  5.2.2  Other Survey Questions .................................................................................... 40  5.2.2.1  Additional Questions about TIRF Medicines Safety ........................................ 40  5.2.3  Analyses of Sub-populations ............................................................................ 46  5.2.3.1  Effectiveness of Medication Guide ................................................................... 46  5.3  Spontaneous Reporting of Adverse Events, Product Complaints, or Medical Information Requests .......................................................................... 49  6.  DISCUSSION, CONCLUSIONS, AND RECOMMENDATIONS ................. 49  LIST OF TABLES Table 1.  Survey Participant Administration Results.....................................................16  Table 2.  Survey Participant Screening Results ............................................................. 17  Table 3.  Time to Complete Survey ...............................................................................20  Table 4.  Demographic Characteristics of Eligible Patients/Caregivers........................21  Table 5.  Responses to Questions About TIRF Medication Guides ..............................24  Table 6.  Responses to Questions About the Patient-Prescriber Agreement Form .......29  Table 7.  Key Risk Message 1: TIRF Medicines Can Cause Life-Threatening Breathing Problems That Can Lead to Death .................................................30  FDA_832 Patient KAB Assessment Report Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 4 of 54 Table 8.  Key Risk Message 2: Patients Should Not Take TIRF Medicines If They Are Not Opioid Tolerant .......................................................................31  Table 9.  Key Risk Message 3: TIRF Medicines Should Be Taken Exactly As Prescribed By The Healthcare Provider ......................................................... 33  Table 10.  Risk Message 4: Patients Should Not Switch From a TIRF Medicine to Another Medicine That Contains Fentanyl Without Talking to a Healthcare Provider ........................................................................................ 35  Table 11.  Key Risk Message 5: Patients Should Not Give TIRF Medicines to Anyone Else Even if They Have the Same Symptoms ..................................36  Table 12.  Key Risk Message 6: TIRF Medicines Should be Stored in a Safe Place Away From Children and Properly Disposed .......................................37  Table 13.  Summary of Understanding of Key Risk Messages .......................................39  Table 14  Responses to All Questions about the Safe Use of TIRF Medicines ............. 41  Table 15  Correct Responses and Response Rates to Key Risk Message Questions Based on Extent of Reading of Medication Guide ........................ 48  Table 16   Correct Response Rate in the 24-Month KAB Survey Compared with the 12-Month KAB Survey in Key Risk Message Questions Modified Between the Two Versions ............................................................................. 50  LIST OF APPENDICES Appendix A  Patient Survey Protocol ..................................................................................52  Appendix B  Patient Survey Listings and Sub-group Analyses Tables ............................... 53  Appendix C  Patient Survey Protocol Track Change Document: Comparison of 12month Survey to 24-month Survey .................................................................54  FDA_833 Patient KAB Assessment Report Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 5 of 54 LIST OF ABBREVIATIONS AE/PC PSP Adverse Event/Product Complaint Project Specific Procedure ANDA Abbreviated New Drug Application CCA Survey Coordinating Center Associate CI Confidence Interval ETASU Elements to Assure Safe Use FDA Food and Drug Administration HCP Healthcare Professional KAB Knowledge, Attitudes and Behavior NDA New Drug Application PPAF Patient-Prescriber Agreement Form PBM Pharmacy Benefits Manager REMS Risk Evaluation and Mitigation Strategy SCC Survey Coordinating Center TIRF Transmucosal Immediate Release Fentanyl TIRF Medicines Transmucosal Immediate Release Fentanyl products TIRF REMS Access Program REMS Program for TIRF medicines TRIG TIRF REMS Industry Group SAP Survey Analysis Plan UBC United BioSource Corporation US United States USPS United States Postal Service FDA_834 Patient KAB Assessment Report Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies 1. Page 6 of 54 PATIENT SURVEY BACKGROUND Transmucosal Immediate Release Fentanyl (TIRF) medicines are a class of immediate-release opioid analgesics that are indicated only for the management of breakthrough pain in cancer patients 18 years of age or older (16 or older for Actiq® [fentanyl citrate oral transmucosal lozenge] and equivalent generics) who are already receiving and already tolerant to opioid therapy for their underlying persistent cancer pain. The TIRF medicines include Abstral®, Actiq®, Fentora®, Lazanda®, Onsolis®, Subsys®, and generic versions of any of these brands. The TIRF Risk Evaluation and Mitigation Strategy (REMS) Industry Group (TRIG) includes Cephalon, Inc. (a wholly-owned subsidiary of Teva Pharmaceutical Industries, Ltd.), Depomed, Inc., Galena Biopharma, Inc., Insys Therapeutics, Meda Pharmaceuticals, Mallinckrodt Pharmaceuticals, Mylan, Inc., and Par Pharmaceutical, Inc. At the time of protocol finalization for the Knowledge, Attitude, and Behavior (KAB) surveys, Depomed, Inc. acquired the New Drug Application (NDA) for Lazanda (29 July 2013) from Archimedes Pharma US, Inc., who is no longer a TIRF Sponsor. In addition, Galena Biopharma acquired the NDA for Abstral from ProStrakan Inc., and is now a TIRF Sponsor (as of 01 May 2013) whereupon ProStrakan exited the group. Additionally, Mylan became a TIRF Sponsor on 29 May 2013 due to a pending Abbreviated New Drug Application (ANDA). The Food and Drug Administration (FDA) has determined that a shared system REMS is required to mitigate the risk of misuse, abuse, addiction, overdose, and serious complications due to medication errors with the use of TIRF medicines. The TIRF REMS Access Program (hereafter referred to as TIRF REMS) was approved by the FDA on 28 December 2011. The TIRF REMS consists of a Medication Guide, Elements to Assure Safe Use (ETASU), an Implementation System, and a Timetable for Submission of Assessments of the REMS. The goals of the TIRF REMS are to mitigate the risk of misuse, abuse, addiction, overdose, and serious complications due to medication errors by the following: 1. Prescribing and dispensing TIRF medicines only to appropriate patients, which includes use only in opioid-tolerant patients. 2. Preventing inappropriate conversion between TIRF medicines. 3. Preventing accidental exposure to children and others for whom it was not prescribed. 4. Educating prescribers, pharmacists, and patients on the potential for misuse, abuse, addiction, and overdose of TIRF medicines. An important component of the TIRF REMS assessment is the conduct of quantitative evaluation surveys to assess patients’ and caregivers’ knowledge, attitudes, and behavior (KAB) regarding the safe use of TIRF medicines as described in the educational materials. The protocol describes the administration of the surveys conducted among patients who are treated with TIRF medicines, or their caregivers. FDA_835 Patient KAB Assessment Report Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 7 of 54 Data from the surveys, together with other REMS evaluation metrics, will be used to determine whether changes need to be made to the REMS processes or educational materials to make them more effective in achieving the goals of the REMS. This report describes the results from the patient surveys conducted for the 24-month TIRF REMS Access Program Assessment. The 24-month KAB survey launched on 16 September 2013 and closed on 17 October 2013. 2. PATIENT SURVEY OBJECTIVES The evaluation survey uses a questionnaire to document the level of knowledge and assess the attitudes and behavior of patients regarding the following key information and risk messages communicated through the REMS: 1. TIRF medicines can cause life-threatening breathing problems that can lead to death. 2. Patients should not take TIRF medicines if they are not opioid tolerant. 3. TIRF medicines should be taken exactly as prescribed by the healthcare provider. 4. Patients should not switch from a TIRF medicine to another medicine that contains fentanyl without talking to a healthcare provider. 5. Patients should not give TIRF medicines to anyone else even if they have the same symptoms. 6. TIRF medicines should be stored in a safe place away from children and properly disposed. The survey also includes questions about whether patients received, read, and understood the product-specific Medication Guide and Patient-Prescriber Agreement Form (PPAF). 3. SURVEY METHODOLOGY This section summarizes the survey design and the questions that were constructed to test patient understanding of the key risk messages of the REMS. Full details of the survey design are in the protocol, which can be found in Appendix A. 3.1 Survey Development Qualitative research was conducted on a draft of the patient survey prior to implementation of the survey for the 12-month REMS Assessment Report. Qualitative research was not conducted on the survey prior to implementation of the survey for the 24-month REMS Assessment Report. FDA_836 Patient KAB Assessment Report Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 8 of 54 On 12 March 2013, FDA provided feedback on the 12-month TIRF REMS Access Program Assessment Report that included the recommendation for modification to the patient survey as shown below: • “For the patient survey, we are concerned that the terms used in question 9 [For which of the following conditions should I use a TIRF medicine? Headache or migraine pain; Breakthrough pain from cancer; Dental pain; Acute or post-operative pain; Chronic non-cancer pain] may be too advanced for most patients. Thus for future survey, please conduct the survey using the terms referred to in the Medication Guides. Specifically, please change “acute or postoperative pain” to “pain after surgery,” and change “chronic non-cancer pain” to “long-lasting painful conditions not caused by cancer.” The survey was updated and re-submitted to the FDA for review prior to implementation. After this review, on 01 August 2013 FDA provided feedback that included additional recommendations for modification to the patient survey: • Move the link (page 19) of “How to learn more about transmucosal immediate release fentanyl medicines” from the online survey preamble to after respondents complete the survey because the link quoted above may include information that educates or influences a respondent’s ability to answer subsequent survey questions. This change was made to the survey preamble • Add one question to ask which specific TIRF medicine has the patient taken after Question #3. For example, “Please specify which TIRF medicine that you or the person you take care of have filled within the last 3 months. (select from a drop-down list of TIRF medicines)(Select all that apply)”. This questions was added as Q#4 and the responses are shown in Table 2 • Include in analyses all eligible surveys that are completed. This information was incorporated in the 12-month survey and in all subsequent surveys. Thus, based on FDA feedback Question 9 was reworded and included in the 24-month survey as Question 10 under “Additional Questions about TIRF Medicines Safety” (Section 5.2.2.1). Besides, the FDA recommended to add one question "Please specify which TIRF medicine that you or the person you take care of have filled within the last 3 months” with a drop-down list from which to make the selection. This was implemented for the 24-month survey as Question 4 (Section 5.1.2, Table 4). The FDA also recommended including in the analyses all eligible surveys that are completed. FDA_837 Patient KAB Assessment Report Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies 3.2 Page 9 of 54 Survey Sample This survey was conducted among patients who had a prescription filled for a TIRF medicine within the 120 days prior to the survey launch date. A target sample of 300 patients treated with TIRF medicines was to be surveyed in this KAB survey. The survey was administered using the following modalities: Self-administered, online through a secure website; Telephone surveys facilitated by a Survey Coordinating Center Associate (CCA) trained in using a computer-assisted telephone interviewing (CATI) program. The survey began with screening questions to confirm respondent eligibility to participate in the survey. Completion of the entire survey was expected to take approximately 20 minutes. The survey included in Appendix A is written to reflect wording for both methods of survey administration: Internet-based and telephone administration. 3.2.1 Eligibility Eligibility criteria included patients, 18 years of age or older, and caregivers, 18 years of age or older, who cared for patients who were unable to take the survey for themselves. Respondents (or respondents whose immediate family members) who had ever worked for any of the TRIG companies, McKesson Specialty Care Solutions, RelayHealth, United BioSource Corporation (UBC), or the FDA were not eligible to participate in this survey. Respondents who participated in the first wave of the TIRF KAB survey (12-month TIRF REMS Access Program Assessment) were not eligible to participate in subsequent survey waves. 3.2.2 Recruitment The two methods adopted for recruitment of patients were via a direct letter program and through prescribers who had prescribed TIRF medicines. Patients’ invitation letters (Appendix A) informed patients that participants who completed the survey and who provided their contact information would be mailed a $50 gift card to thank them for their participation. The thank you letter included the correct answers to key risk message questions, and a copy of the product-specific Medication Guide. Recruitment efforts for the 12-month survey had failed to yield the target of 300 completed patient surveys. Therefore, to maximize participation in the 24-month survey, additional recruitment methodology and inclusion criteria were implemented as outlined below: • The expansion of the network of pharmacies to include a pharmacy network partner and a PBM; • Recruitment of patients who filled a prescription 120 days prior to survey launch increased from 90 days in the 12-month survey; FDA_838 Patient KAB Assessment Report Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 10 of 54 • An increased honorarium from $25 to $50; and • Outbound calls to physician offices to request their support with patient recruitment among their patients who were prescribed a TIRF medicine (Section 3.2.2.2); however, this process did not yield any completed surveys. Based on the number of prescriptions filled during the 120 days prior to 16 September 2013, the national pharmacy chain network partner and the PBM combined identified all patients filling a prescription and invited all 1903 patients to participate. Of the 347 respondents screened, 302 (87.0%; Table 1 and Table 2) respondents met the eligibility criteria (Section 3.2.1) and completed the survey. It is important to note that once the target of eligible respondents was met, the survey was closed. 3.2.2.1 Direct Letter Program Subject recruitment was performed via a direct letter program, through a national pharmacy chain network partner and a pharmacy benefits manager (PBM). A sample of patients who had filled a prescription for a TIRF medicine in the 120 days prior to survey implementation were recruited via a letter of invitation sent through the United States Postal Service (USPS). The required number of completed surveys was not achieved within approximately 10 days after the first mailing; therefore, subsequent mailings were sent to non-respondents from the original sample to maximize participation. 3.2.2.2 Physician Recruitment of Patients Additionally, a random sample of 250 prescribers with at least 5 patients who had filled prescriptions in the 120 days prior to survey implementation were contacted via phone to request their support with patient recruitment. These prescribers were asked to inform their patients who were prescribed a TIRF medicine about the opportunity to participate in the survey by directly handing out or mailing an invitation. Following up on these outbound calls, 204 information packets with patient invitations were mailed to prescribers who expressed willingness to participate in recruiting patients. However, this effort did not result in any completed patient surveys. Prescribers did not receive any compensation for this recruitment effort. 3.3 Questions and Statements on Key Risk Messages The questions and statements comprising the knowledge survey were constructed to test the patients’ understanding of the key risk messages of the REMS. The questions were to be answered either by selecting options from multiple-choice lists that include statements of the specific key risk messages or by choosing “Yes” or “True,” “No” or “False,” or “I don’t know” regarding statements about TIRF medicines. For statements or questions that had “True” or “Yes” vs. “False” or “No” response options, the desired response for key risk messages was generally “True” or “Yes” indicating knowledge of, or behavior in accordance with, the objectives of the REMS. However, some questions were formatted to have the respondent disagree with the statement as written by providing response options of “False” or “No” to avoid having the same affirmative answer for all desired responses. FDA_839 Patient KAB Assessment Report Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 11 of 54 REMS statements, corresponding questions, and desired responses covering the key risk messages are identified below and can be found in the complete survey questionnaire (Appendix A). 3.3.1 Key Risk Message 1 Key Risk Message 1 refers to the patient’s knowledge that TIRF medicines can cause lifethreatening breathing problems. Key Risk Message 1: TIRF medicines can cause life-threatening breathing problems that can lead to death. Question No. Question Desired response 13 Please answer True, False, or I don’t know for each statement about the TIRF medicine that was most recently prescribed for you. 13d TIRF medicines can cause life-threatening breathing problems that can lead to death. 3.3.2 True Key Risk Message 2 Key Risk Message 2 refers to the patient’s awareness that TIRF medicines should be taken only by opioid-tolerant adult patients. Key Risk Message 2: Patients should not take TIRF medicines if they are not opioid tolerant. Question No. Question Desired response Please answer True, False, or I don’t know for the following statement: 11 12 TIRF medicines should only be taken by patients who are opioid tolerant. True Please answer True, False, or I don’t know for each of the following statements. 12a Opioid tolerant means that a patient is already taking other opioid pain medicines around the clock and their body is used to these medicines. 13 Please answer True, False, or I don’t know for each statement about the TIRF medicine that was most recently prescribed for you. 13b It is OK for patients to take TIRF medicines for headache pain. 3.3.3 True False Key Risk Message 3 Key Risk Message 3 refers to the patient’s knowledge that TIRF medicines should be taken exactly as prescribed by the healthcare provider. FDA_840 Patient KAB Assessment Report Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 12 of 54 Key Risk Message 3: TIRF medicines should be taken exactly as prescribed by the healthcare provider. Question No. Question Desired response 12 Please answer True, False, or I don’t know for each of the following statements. 12b If a patient stops taking around-the-clock opioid pain medicine, they must also stop taking the TIRF medicine. 13/17 13c 17b 3.3.4 True Please answer True, False, or I don’t know for each statement about the TIRF medicine that was most recently prescribed for you. TIRF medicines should be taken exactly as prescribed by the doctor. It is OK to take TIRF medicines for short-term pain that will go away in a few days. True False Key Risk Message 4 Key Risk Message 4 refers to the patient’s knowledge of the interchangeability of TIRF medicines. Key Risk Message 4: Patients should not switch from a TIRF medicine to another medicine that contains fentanyl without talking to a healthcare provider. Question No. Question Desired response 12 12c 3.3.5 Please answer True, False, or I don’t know for each of the following statements. It is safe to switch to another medicine that contains fentanyl without talking to a healthcare provider first. False Key Risk Message 5 Key Risk Message 5 refers to the patient’s awareness that TIRF medicines should not be given to anyone else even if they have the same symptoms. Key Risk Message 5: Patients should not give TIRF medicines to anyone else even if they have the same symptoms. Question No. Question Desired response 12 12d 17 17a Please answer True, False, or I don’t know for each of the following statements. A patient may give TIRF medicines to another person if they have the same symptoms as the patient. False Please answer True, False, or I don’t know for each statement about the TIRF medicine that was most recently prescribed for you. Selling or giving away TIRF medicines is against the law. True FDA_841 Patient KAB Assessment Report Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies 3.3.6 Page 13 of 54 Key Risk Message 6 Key Risk Message 6 refers to the patient’s knowledge that TIRF medicines should be stored in a safe place away from children and properly disposed. Key Risk Message 6: TIRF medicines should be stored in a safe place away from children and properly disposed. Question No. Question Desired response Please answer True, False, or I don’t know for each statement about the TIRF medicine that was most recently prescribed for you. 13/17 TIRF medicines should be stored in a safe place out of the reach of children. 13a True TIRF medicines must be disposed of as described in the specific product’s Medication Guide. 17c True A TIRF medicine can cause an overdose and death in any child who takes it. 17e True 14 What should you do if an adult who has not been prescribed a TIRF medicine takes a TIRF medicine? (Please select one.) 4. STATISTICAL METHODS 4.1 Study Population 4.1.1 Primary Analysis Population Get emergency help right away. The primary population for analysis was all eligible patients who completed the survey. Eligible patients were defined as those respondents who answered Yes to Question 1 (agree to take part in survey), Yes to Question 2 (filled a prescription for a TIRF medicine in the last 4 months) or Yes to Question 3 (Caregiver for someone who had filled a prescription for a TIRF medicine in the last 4 months), No to Question 5 (participated in past survey), selected an age group ≥18 years of age for Question 6 (patient and caregiver), and No to Question 8 (worked for a TRIG company, UBC, or FDA). A completed survey was a survey in which all questions as appropriate were answered. Note that some questions may not have been answered due to skip logic in the survey questionnaire. 4.1.2 Sub-groups of Interest The following sub-group analyses were conducted if the sub-group included at least 20 respondents. Sub-group analysis 1: Reading Medication Guide (Question 18, Question 23, and Question 24): • S-1a - Respondents who got the Medication Guide and read at least most of it • S-1b - Respondents who did not get a Medication Guide or answered, “I don’t know” or who got a Medication Guide and read only some of it or answered, “I don’t know.” FDA_842 Patient KAB Assessment Report Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 14 of 54 Sub-group analysis 2: Understanding of Medication Guide (Question 25): • S-2a - Respondents who understood all of it or most of it • S-2b - Respondents who understood some of it • S-2c - Respondents who answered None or “I don’t know” • S-2d - Respondents who answered, “I don’t know” to receipt or reading of the Medication Guide. Sub-group analysis 3: Time to complete survey - Internet: • S-3a - <10 min • S-3b - 10 to<20 min • S-3c - ≥20 min Sub-group analysis 4: Time to complete survey - Telephone: • S-4a - <10 min • S-4b - 10 to <20 min • S-4c - ≥20 min Sub-group analysis 5: Modality to complete survey: • S-5a - Internet • S-5b – Telephone Sub-group analysis 6: Highest level of education (Question 37): • S-6a – Less than, Some, or High school graduate/GED or prefer not to answer • S-6b - Some college or associate’s degree • S-6c - Bachelor’s degree or Master’s degree • S-6d - Professional or Doctoral degree Sub-group analysis 7: Age group of respondent (Question 6): • S-7a – 18 to 39 • S-7b – 40 to 49 • S-7c – 50 to 59 • S-7d – 60 or older Results of sub-group analyses performed are provided in Appendix B, Tables 6.1, 7.1, 7.2, 8.1, 8.2, 9.1, 10.1, 10.2, 11.1, and 11.2. Answers from caregivers and answers from patients will be combined for the sub-group analysis. FDA_843 Patient KAB Assessment Report Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies 4.1.2.1 Page 15 of 54 Primary Analyses Primary analyses were done for all key risk messages. The primary analysis for a key risk message evaluated the number and percentage of each correct response for each individual question/item defined by the key risk message. The correct response to each question/item is included in the body of the risk message table (Section 3.3). 4.1.2.2 Secondary Analyses Secondary analyses evaluated the number and percentages of correct responses and the average of correct responses within the risk message overall to assess understanding of the comprehensive key risk message. A correct response rate of 65% or greater was considered to represent adequate understanding of each concept or key risk message. 4.1.3 Patient Report of an Adverse Event, Product Complaint, or Medical Information Request during the Survey A patient may have reported an adverse event or product complaint while taking the online survey in the free text field of the Internet-based survey. Patients/caregivers who opted for the telephone-based survey may have reported an adverse event or a product complaint while in conversation with the CCA. If the event was mentioned to the CCA, the CCA documented the adverse event or product complaint, the verbatim response, and the respondent’s contact information, if provided. The respondent was informed that a representative from the appropriate TIRF medicine manufacturer might contact them to obtain additional information about the adverse event or product complaint. Internet surveys were monitored for any comments recorded in the free text field. Information on all reports (Internet or telephone) that constituted an adverse event or product complaint was forwarded to the appropriate TIRF medicine manufacturer for processing within one business day of awareness of the event as outlined in the Adverse Event/Product Complaint Project Specific Procedure (AE/PC PSP). 5. RESULTS Results of the patient responses to questions in the KAB survey are summarized in this section, and a full set of responses can be found in Appendix B. 5.1 Survey Participants 5.1.1 Survey Participant Administration Results Patients were recruited through a pharmacy network partner and a PBM, as well as through physician recruitment. Physician recruitment of patients did not result in any completed surveys (Section 3.2.2.2). Based on the number of prescriptions filled during the 120 days prior to survey implementation (16 September 2013), the national pharmacy chain network partner identified 1,450 possible participants and the PBM identified 453 possible participants among patients and caregivers. All of these possible participants were sent a survey invitation letter. A total of 2,454 follow up letters were sent to non-responders (some potential participants received more than one reminder letter). Of the 1,903 possible participants, 347 FDA_844 Patient KAB Assessment Report Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 16 of 54 respondents accessed the sruvey and were screened for eligibility; 302 of the 347 respondents met eligibility criteria and completed the sruvey (Table 127 completed the sruvey by telephone, and 175 completed it on the Internet. From the 302 respondents, 303 surveys were collected. It was identi?ed that one respondent completed the survey twice. Only the ?st completed sruvey was included in the analysis for this report. Table 1. Survey Participant Administration Results Screened Patients/Caregivers N=347l All Respondents Summary Statistic Nrunber of invitations issued to patients/caregivers 1903 Number of reminder letters issued to patients/caregivers 2454 Nrunber of patients/caregivers screened for 3471 Nrunber of patients/caregivers eligible for participation 302 Nrunber of eligible patient/caregivers eligible for 302 Nrunber of eligible respondents completing the survey 302 87 .01 Method of Sruvey Completion Nrunber of surveys completed by telephone 127 42.12 Number of surveys completed by intemet 175 58,02 1 The denominator for the percentages of eligible patients/caregivers is the number of screened patients/caregivers 2 . . . . The denommator for percentages completed by telephone or Internet rs the number of patients/caregivers who completed the survey Of the 347 respondents, the screening procedure identi?ed 302 eligible participants (including 301 patients and 1 caregiver) all of whom completed the sruvey (Table 2). Due to the small nrunber of caregivers participating in the sruvey, the majority of results are reported for patients and caregivers combined. As shown in Table 2, a total of 346 patients/caregivers agreed to participate in this sruvey. The screening process formd 44 respondents were not eligible to participate: Patient KAB Assessment Report Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 17 of 54 16 respondents were ineligible because they had previously participated in a Sluvey about TIRF medicines; 11 because they did not know if they had previously participated: 15 said ?No? when asked if they were caregivers for someone who has ?lled a prescription for a TIRF medicine within the preceding 4 months; 1 respondent because he/she, or an immediate family member, had worked for a TRIG company in the past, and 1 did not know whether he/she, or an immediate family member, had worked for a TRIG company, UBC, RelayHealth, McKesson Specialty Care Solutions, or the FDA in the past and thus were considered ineligible. Thus, there were 302 eligible participants (including one caregiver), all of whom completed the Sluvey (Table 2). Table 2. Survey Participant Screening Results Screened and Complete . . espondents Patients/Caregivers Question Question 1: Do you agree to participate in this survey? Yes 346 99.7 302 100.0 No1 1 0.3 generic versions of any of these brands. Question 2: Within the last 4 months, have you ?lled a prescription for yourself for a transmucosal immediate release fentanyl medicine (known as medicines?)? TIRF medicines include Abstral?, Actiq?, Fentora?, Lazanda?, Onsolis?, Subsys?, and the Yes 330 95.1 301 99don?t know 2 0.6 0 0.0 Question not asked2 1 0.3 0.0 Question 3: Are you a caregiver for someone who has ?lled a prescription for a TM medicine within the last 4 months? As a reminder, TIRF medicines include Abstral?, Actiq?, Fentora?, Lazanda?, Onsolis?, Subsys?, and the generic versions of any of these brandsdon?t know1 0 0.0 Question not asked 2 331 95.4 Patient KAB Assessment Report Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 18 of 54 Table 2. Survey Participant Screening Results Question Panengga?gegwers Question 5: Have you ever taken part in a survey about a TIRF medicine before? Yesl 16 4.6 No 304 87.6 302 100.0 I don?t know1 11 3.2 Question not asked 2 16 4.6 Question 6: Which of the following groups best describes your age? Under 181 20.2 70 23 .2 50?59 126 36.3 126 41.7 60?69 60 17.3 59 19.5 70 or older 15 4.3 15 5.0 Prefer not to answer1 0 0.0 Question not asked2 43 12.4 Question 7: Which of the following groups best describes the patient?s age? (Caregivers, only) Under older 0 0.0 0 0.0 Prefer not to answer 0 0.0 Question not asked2 346 99. 7 Patient KAB Assessment Report Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 19 of 54 Table 2. Survey Participant Screening Results Screened and Complete - espondents Pauents/Careglvers Question Question 8: Have you or any of your immediate family members ever worked for any of the following companies or agencies? Please select all that apply.3 Anesta LLC.1 0 0.0 Archimedes Pharma US Inc. 1 0 0.0 ephalon. Inc. (a wholly-owned 0 subsidiary of Teva Pharmaceutical Industries. Ltd.) 1 Endo Phannaceuticals Inc. 1 0 0.0 Galena Biophaima1 0 0.0 Insys Therapeutic s1 0 0.0 0 0.0 McKesson Specialty Care Solutions1 0 0.0 Meda Phannaceuticalsl 0 0.0 Par Pharmaceutical. Inc.1 0 0.0 ProStrakan. Inc.1 0 0.0 RelayHealth1 0 0.0 Teva Pharmaceuticals. Ltd.1 0 0.0 United BioSom?ce C01poration1 1 0.3 FDA1 0 0.0 No4 302 87.0 302 100.0 I don?t know1 1 0.3 Question not asked2 43 12.4 1 Ineligible to participate in the sm'veyQuestion not asked due to prevrous question elmmiation. 3 More than 1 response can be selected. so percentages may not $11111 to 100%. 4 Ineligible if selected in addition to another response. Patient KAB Assessment Report Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 20 of 54 Of the 302 patient/caregivers, 175 completed the sruvey online, and 127 completed it by telephone (Table 3). Those taking the smvey online took an average of 14.7 minutes to complete it, while those taking it by telephone took an average of 20.1 minutes. Of the 302 participants, 147 online participants required less than 20 minutes to complete the smvey, while the other 28 online participants required 20 minutes or more. In the case of telephone participants, 80 required less than 20 minutes and 47 (15.6) took 20 minutes or longer (Table 3). Table 3. Time to Complete Survey Time to Complete Survey for Completers (Minutes) Summary Statistic Telephone Internet Total1 127 175 302 Mean (Standard Deviation) 20.1 (5.20) 14.7 (8.37) 17.0 (7.68) Minimum 13 6 6 Median 18.6 12.2 16.5 Maximum 44 71 71 Category 0 <5 Minutes 0 0 5 <10 Minutes 0 47 47 10 <15 Minutes 5 70 75 15 <20 Minutes 75 30 105 20 <25 Minutes 32 15 47 25 <30 Minutes 9 6 15 30 Minutes or More 6 7 13 1 Number of eligible respondents completing the survey (Table 1). 5.1.2 Patient/Caregiver Demographics The demographic characteristics of respondents who completed the survey are shown in Table 4. The largest number of (n=126; 41.7%) respondents were in the 50 59 years age group; 184 were females, and 243 respondents had at least some college or an Associate?s degree or higher education. Most prescriptions ?lled in the 4 months preceding the sruvey included 117 for Actiq (including generic versions), 107 for Fentora, and 88 for Subsys. Participants were largely from the Northeast (n=113; 37.4%) and South (n=133; 44.0%) regions of the United States (US). There were no Patient KAB Assessment Report Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 21 of 54 participants from Puerto Rico, Northern Mariana Islands, US Virgin Islands, American Samoa, and Guam identi?ed as ?Other? in Table 4. Table 4. Demographic Characteristics of Eligible Patients/Caregivers Patients Caregivers Patients . =301 n=1 Caregivers Question Question 4: For which TIRF medicines have you filled a prescription in the last 4 months. Please select all that apply. Actiq. including generic versions 117 38-9 0 0-0 117 38-7 of Actiq Lazanda 2 0.7 0 0.0 2 0.7 01150115 0 0.0 0 0.0 0 0.0 Subsys 87 28.9 1 100.0 88 29.1 Other 13 4.3 0 0.0 13 4.3 Question 6: Which of the following groups best describes your age23.3 0 0.0 70 23.2 50?59 126 41.9 0 0.0 126 41.7 60 ?69 58 19.3 1 100.0 59 19.5 70 or older 15 5.0 0 0.0 15 5.0 Question 36: What is your gender? Male 116 38.5 1 100.0 117 38.7 Female 184 61.1 0 0.0 184 60.9 Prefer not to answer 1 0.3 0 0.0 1 0.3 Patient KAB Assessment Report Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 22 of 54 Table 4. Demographic Characteristics of Eligible Patients/Caregivers Patients Caregivers $233233; Question n=301 n=1 Question 37: What is the highest level of education you have completed? Less than high school 2 0.7 0 0.0 2 0.7 Some high school 6 2.0 0 0.0 6 2.0 High School graduate/GED 50 16.6 0 0.0 50 16.6 Some college/Associate?s degree 140 46.5 1 100.0 141 46.7 Bachelor?s degree 53 17.6 0 0.0 53 17.5 Master?s degree 29 9.6 0 0.0 29 9.6 Professional or Doctoral degree 20 6.6 0 0.0 20 6.6 Prefer not to answer 1 0.3 0 0.0 1 0.3 Question 38: What is the main language you speak at home? (Please select only one) English 299 99.3 1 100.0 300 99.3 French 0 0.0 0 0.0 0 0.0 Spanish 0 0.0 0 0.0 0 0.0 Pomlguese 0 0.0 0 0.0 0 0.0 Italian 0 0.0 0 0.0 0 0.0 German 0 0.0 0 0.0 0 0.0 Chinese 0 0.0 0 0.0 0 0.0 Japanese 0 0.0 0 0.0 0 0.0 Korean 0 0.0 0 0.0 0 0.0 Other 1 0.3 0 0.0 1 0.3 Prefer not to answer 1 0.3 0 0.0 1 0.3 Question 39: Are you Hispanic or Latino290 96.3 1 100.0 291 96.4 Prefer not to answer 6 2.0 0 0.0 6 2.0 Patient KAB Assessment Report Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 23 of 54 Table 4. Demographic Characteristics of Eligible Patients/Caregivers Patients Caregivers Patients . =301 n=1 Caregivers Question 11 Question 40: For informational purposes only, indicate which of the following US. census categories best describes your race? American Indian or Alaska Native 5 1.7 0 0.0 5 1.7 Asian (origins of Far EastSoutheast Asia or the Indian subcontinent) Black or African American 13 4.3 0 0.0 13 4.3 Native Hawaiian or Other Paci?c 0 0.0 0 0.0 0 Islander White 266 88.4 1 100.0 267 88.4 Other 4 1.3 0 0.0 4 1.3 Prefer not to answer 9 3.0 0 0.0 9 3.0 Geographic Distribution (based on Question 40 State or US Territory)2 Northeast 113 37.5 0 0.0 113 37.4 Midwest 24 8.0 0 0.0 24 7.9 South 132 43.9 1 100.0 133 44.0 West 31 10.3 0 0.0 31 10.3 Other 0 0.0 0 0.0 0 0.0 Prefer not to answer Number of eligible respondents completing the survey (See Table 1). 2 US. Census Bureau. last revised Friday. 27-Jul-2001 12:59:43 EDT.. Geography Division. Northeast includes CT. MA. ME. NH. NJ. NY. PA. RI. and VT. Midwest includes IA. IL. IN. KS. MI. MN. MO. ND. NE. OH. SD. and WI. South includes AL. AR. DC. DE. FL. GA. KY. LA. MD. MS. NC. OK. SC. TN. TX. VA. and WV. West includes AK. AZ. CA. CO HI. ID. MT. NM. NV. OR. UT. WA. and WY. The following US territories are categorized as Other: Puerto Rico. Northern Mariana Islands. US Virgin Islands. American Samoa. and Guam. 5.1.3 TIRF Medicines Education Materials Respondents were asked about their awareness of educational materials for TIRF medicines. speci?cally the Medication Guide (Table 5). and the Patient-Prescriber Agreement Form (Table 6). Patient KAB Assessment Report Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 24 of 54 Of the 302 respondents, 283 reported they had received the Medication Guide for the TIRF medicine prescribed to them; 150 reported receiving the Medication Guide from their doctor with 117 receiving it at the ?rst appointment with the prescribing doctor; 254 respondents received it from their pharmacy; 228 respondents recollected receiving the Medication Guide each time a prescription was ?lled. Most (11:268; 94.7%) recollected reading the Medication Guide; 170 read all of it with 126 of them understanding all or most (n=125; 46.3%) of the Medication Guide. The respondent also identi?ed that either the pharmacist (n=147:_ 84.5%) or the prescriber (n=114; 65.5%) offered to explain the Medication Guide. Table 5. Responses to Questions About TIRF Medication Guides Patients Caregivers Patients Caregivers Question ll=301 ll=1 Question 18: Have you ever received a Medication Guide for the TIRF medicine that was prescribed for you? Yes 282 93.7 1 100.0 283 93don?t know 12 4.0 0.0 12 4.0 Question 19: Did you receive the Medication Guide from the doctor who prescribed the TIRF medicine or someone in the doctor?s office?2 Yes 149 52.8 1 100.0 150 53.0 No 115 40.8 0 0.0 115 40.6 I don?t know 18 6.4 0 0.0 18 6.4 (answered know to Question 18) Question 20: When was the Medication Guide given to you? 2 At the ?rst appointment 1 16 77.9 1 100_() 117 78.0 with the doctor who prescribed the TIRF medicine At the last appointment 24 16.1 0 0,0 24 16.0 with the doctor who prescribed the TIRF medicine I don?t remember 22 14.8 0 0.0 22 14.7 Patient KAB Assessment Report Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 25 of 54 Table 5. Responses to Questions About TIRF Medication Guides Patients Caregivers Patients Caregivers Question n=301 N=302l (answered know to Question know to Question 19) Question 21: Did you receive the Medication Guide from the pharmacy? 2 Yes 253 89.7 1 100.0 254 89don?t know 5 1.8 0 0.0 5 1.8 (answered know to Question 18) Question 22: When was the most recent time that you received a Medication Guide for the TIRF medicine at the pharmacy? 2 Only with the ?rst ?lled 12 4.7 0 0.0 12 4_7 prescn'ption Each time a prescription is 227 89.7 1 100.0 228 89.8 ?lled Other3 don?t know 8 3.2 0 0.0 8 3.1 (answered know to Question know to Question 21) Question 23: Did you read the Medication Guide? Yes 267 94.7 1 100.0 268 94don?t know 2 0.7 0 0.0 2 0.7 (answered know to Question 18) Patient KAB Assessment Report Transniucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 26 of 54 Table 5. Responses to Questions About TIRF Medication Guides Patients Caregivers Patients Caregivers Question n=301 N=302l Question 24: How much did you read? 2 All of it 169 62.8 1 100.0 170 63.0 Most of it 78 29.0 0 0.0 78 28.9 Some don?t know 3 1.1 0 0.0 3 1.1 (answered know to Question know to Question 23) Question 25: How much of the Medication Guide did you understand?2 All of it 126 46.8 0 0.0 126 46.7 Most of it 124 46.1 1 100.0 125 46.3 Some 6.7 None don?t know 0 0.0 0 0.0 0 0.0 (answered know to Question know to Question 23) Question 26: Did someone offer to explain the Medication Guide to you?2 Yes 173 61.3 1 100.0 174 61.5 N0 96 34.0 0 0.0 96 33.9 I don?t know 13 4.6 0 0.0 13 4.6 (answered know to Question 18) Patient KAB Assessment Repo? Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industiy Group (TRIG) of Companies Page 27 of 54 Table 5. Responses to Questions About TIRF Medication Guides Patients Caregivers Patients Caregivers Question n=301 N=302l Question 27: Who offered to explain the Medication Guide to you? (Select all that apply.)2 The doctor or another 113 65.3 1 100.0 114 65.5 healthcare professional in the doctor?s of?ce The pharmacist Where the 146 84.4 1 1000 147 84.5 TIRF medicine prescription was ?lled Someone else (specify the 10 5.8 0 0.0 10 57 type of person but not his/her name)4 (answered know to Question know to Question 26) Question 28: Did you accept the offer to have the Medication Guide explained to you?2 Yes 110 63.6 1 100.0 111 63.8 No 61 35.3 0 0.0 61 35.1 I don?t know 2 1.2 0 0.0 2 1.1 (answered know to Question know to Question 26) Question 29: How much of the explanation did you understand? 2 All of it 81 73.6 0 0.0 81 73.0 Most of it 27 24.5 1 100.0 28 25.2 Some 1.8 None don?t know 0 0.0 0 0.0 0 0.0 Patient KAB Assessment Report Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 28 of 54 Table 5. Responses to Questions About TIRF Medication Guides . . Patients Patients Careglvers Caregivers Question n=301 N=302l (answered know to Question know to Question know to Question 28) Questiop 30: Did you or do you have any questions about the information in the Medication Guide? Yes5 266 94.3 1 100.0 267 94.3 I don?t know 1 0.4 0 0.0 1 0.4 (answered know to Question 18) Niunber of eligible respondents completing the survey (See Table 1). 2 Percentages are calculated based on the sample presented with this question and thus may not re?ect the entire sample because of skip logic in the survey. 3 Verbatim texts for ?Other? selection with regard to the question asking about the most recent time when Medication Guide (Question 22) was received from the pharmacy are presented in Listing 1. 4 Verbatim texts for other persons offering to explain the Medication Guide (Question 27) are presented in Listing 2. 5 Questions about the information in the Medication Guide (Question 30) are presented in Listing 3. The responses to Questions 22, 27 and 30 are listed in Listing 1, Listing 2, and Listing 3, respectively. 5.1.4 Patient-Prescriber Agreement Form After respondents were asked the questions regarding the key risk messages, they were asked if they had received, read, and Imderstood the PPAF. A total of 223 respondents indicated that someone at the doctor?s of?ce had offered to explain the PPAF to them, and that 175 of them lmderstood all of it and 42 lmderstood most of it. The PPAF was signed by 222 respondents; of these 222 responders, 151 reported receiving a copy of the signed PPAF (Table 6). Patient KAB Assessment Repo? Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industiy Group (TRIG) of Companies Page 29 of 54 Table 6. Responses to Questions About the Patient-Prescriber Agreement Form Patients Caregivers Patients Caregivers Question n=301 Question 32: Did the doctor or someone in the doctor?s of?ce explain the Patient?Prescriber Agreement Form to you? Yes 222 73.8 1 100.0 223 73.8 No 43 14.3 0 0.0 43 14.2 I don?t know 36 12.0 0 0.0 36 11.9 Question 33: How much of the explanation did you understand?2 All of it 174 78.4 1 100.0 175 78.5 Most of it 42 18.9 0 0.0 42 18.8 Some 1.8 None don?t know 1 0.5 0 0.0 1 0.4 (answered know to Question 32) Question 34: Did you sign a Patient-Prescriber Agreement Form? Yes 221 73.4 1 100.0 222 73don?t know 65 21.6 0 0.0 65 21.5 Question 35: Did the doctor or someone in the doctor?s of?ce give you a copy of the signed Patient-Prescriber Agreement Form?2 Yes 150 67.9 1 100.0 151 68.0 No 38 17.2 0 0.0 38 17.1 I don?t know 33 14.9 0 0.0 33 14.9 (answered know to Question 34) 1 Number of eligible respondents completing the sm'vey (See Table 2 Percentages are calculated based on the sample presented with this question because of skip logic in the Siu'vey. Patient KAB Assessment Report Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 30 of 54 5.2 KAB Survey Objectives 5.2.1 Key Risk Message Results The focus of this section of the document is on the ?ndings for the total respondent population (patients plus caregivers). 5.2.1.1 Key Risk Message 1 Key Risk Message 1 refers to the patient?s knowledge that TIRF medicines can cause life- threatening breathing problems that can lead to death. Analysis of responses to Question 13d for Key Risk Message 1 showed that 272 of the 302 eligible respondents were aware of the risk of life-threatening breathing problems with TIRF medicines (Table 7). Table 7. Key Risk Message 1: TIRF Medicines Can Cause Life-Threatening Breathing Problems That Can Lead to Death Patients Caregivers Patients Caregivers . n=301 n=l N=302l Question 11 (95% CD3 (95% (95% Question 13: Please answer True, False, or I don?t know for each statement about the TM medicine that was most recently prescribed for you the patient. 13d: TIRF medicines can cause life-threatening breathing problems that can lead to death. 2 90.0 100.0 90.1 True 271 (86.1. 93.2) 1 (2.5. 100.0) 272 (86.1. 93.2) False don?t know 30 10.0 0 0.0 30 9.9 1 Number of eligible respondents completing the sru'vey (See Table 1Indicates the correct response(s) to each question or item Withm a question. 3 All con?dence intervals are exact binomial 95% con?dence intervals. 5.2.1.2 Key Risk Message 2 Key Risk Message 2 refers to the respondents? knowledge that they should not take TIRF Medicines if they are not opioid tolerant. Three questions de?ned this key risk message (Table 8). In response to the statement in Question 11 that TIRF medicines should only be taken by patients who are opioid tolerant, 277 respondents gave the correct (True) response. Patient KAB Assessment Repon Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 31 of 54 The majority (n=267; 88.4%) of respondents lmderstood that opioid tolerant means that a patient is ah'eady taking other opioid pain medicines ar01md-the-clock and their body is used to these medicines (Question 12a). In response to Question 13b, 206 knew that it is not okay for patients to?take TIRF medicines for headache pain, while 75 respondents selected the don?t know? option. Of the 206 respondents who answered Question 13b ("It is OK for patients to take IRF medicines for headache pain) correctly, 176 respondents had read most of the Medication Guide and 30 respondents had read some or none of it. Overall, evidence of understanding of the comprehensive key risk message is fmther suppo?ed by the average number of correct responses identi?ed as 2.5 (one-sided 95% I 2.3, 3.0) out of a possible 3 (Table 8). Table 8. Key Risk Message 2: Patients Should Not Take TIRF Medicines If They Are Not Opioid Tolerant Patients Caregivers Patients Caregivers n=301 n=1 N=302l Question 3 3 3 (95% CI) (95% CI) (95% CI) Question 11: Please answer True, False, or I don?t know for the following statement: TIRF medicines should only be taken by patients who are opioid tolerant. 91.7 100.0 91.7 2 me 276 (88.0. 94.6) 1 (2.5. 100.0) 277 (88.0. 94.6) False don?t know 20 6.6 0 0.0 20 6.6 Question 12: Please answer True, False, or I don?t know for the following statements: 12a: Opioid tolerant means that a patient is already taking other opioid pain medicines around the clock and their body is used to these medicines. 88.4 100.0 88.4 2 me 266 (842.918) 1 (2.5. 100.0) 267 (84.3. 91.8) False don?t know 23 7.6 0 0.0 23 7.6 Question 13: Please answer True, False, or I don?t know for each statement about the TIRF medicine that was most recently prescribed for you. 13b: It is OK for patients to take TIRF medicines for headache pain. True 21 7.0 0 0.0 21 7.0 68.1 100.0 68(62.5. 73.3) 1 (2.5. 100.0) 206 (62.6. 73.4) Idon?t know 75 24.9 0 0.0 75 24.8 Patient KAB Assessment Report Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 32 of 54 Table 8. Key Risk Message 2: Patients Should Not Take TIRF Medicines If They Are Not Opioid Tolerant Patients Caregivers Patients Caregivers n=301 n=1 N=302l Question 11 (95% (95% (95% Secondary Analyses: Demonstrated Understanding 0 correct responses correct response correct responses 95 31.6 0 0.0 95 31.5 3 correct responses 179 59.5 1 100.0 180 59.6 Average number of 2.5 (2.3. 3.0)4 3.0 (0.2. 3.0)4 2.5 (2.3. 3.0)4 correct responses 1 Number of eligible respondents completing the survey (See Table 1). 2 Indicates the correct response(s) to each question or item within a question. 3 All con?dence intervals are exact binomial 95% con?dence intervals. 4 One-sided 95 con?dence interval using the normal approximation to the Poisson distribution. 5.2.1.3 Key Risk Message 3 Key Risk Message 3 refers to the patient?s knowledge that TIRF medicines should be taken exactly as prescribed by the healthcare provider. Three questions de?ne this key risk message (Table 9). In response to Question 12b, 103 respondents rmderstood that if a patient stops taking arormd-the-clock opioid pain medicine, they must also stop taking the TIRF medicine while 87 answered incorrectly and 112 selected the don?t know? option. Of the 103 respondents who gave the correct response, 95 read most of the Medication Guide while 8 read some or none of the Medication Guide. Of the 87 respondents who answered this question incorrectly, 74 had read most of the Medication Guide and of the 112 respondents who selected the don?t know? response, 79 had read the Medication Guide. Responding to Question 13c. 301 rmderstood that TIRF medicines should be taken exactly as prescribed by the doctor, and 252 knew that is not all right to take TIRF medicines for short-term pain that will go away in a few days (Question 17b). Overall. evidence of rmderstanding of the comprehensive key risk message is further supported by the average nrunber of correct responses identi?ed as 2.2 (one-sided 95% CI 2.0, 3.0) out of a possible 3 (Table 9). Patient KAB Assessment Repo? Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industly Group (TRIG) of Companies Page 33 of 54 Table 9. Key Risk Message 3: TIRF Medicines Should Be Taken Exactly As Prescribed By The Healthcare Provider Patients Caregivers Patients Caregivers . n=301 n=1 N=302l Question 11 (95% (95% (95% Question 12: Please answer True, False, or I don?t know for each of the following statements. 12b: If a patient stops taking around-the-clock opioid pain medicine, they must also stop taking the TIRF medicine. 33.9 100.0 34.1 2 me 102 (28.6. 39.5) 1 (2.5. 100.0) 103 (28.8. 39.8) False 87 28.9 0 0.0 87 28.8 Idon?t know 112 37.2 0 0.0 112 37.1 Question 13: Please answer True, False, or I don?t know for each statement about the TIRF medicine that was most recently prescribed for you. 13c: TIRF medicines should be taken exactly as prescribed by the doctor. 99.7 100.0 99.7 2 me 300 (98.2. 100.0) 1 (2.5. 100.0) 301 (98.2. 100.0) False don?t know 1 0.3 0 0.0 0.3 Question 17: Please answer True, False, or I don?t know for each statement about the TIRF medicine that was most recently prescribed for you the patient. 17b: It is OK to take TIRF medicines for short-term pain that will go away in a few days. T1116 15 5.0 0 0.0 15 5.0 83.4 100.0 83.4 False2 2?1 (78.7. 87.4) 1 (2.5. 100.0) 2? 2 (78.8. 87.5) Idon?t know 35 11.6 0 0.0 35 11.6 Patient KAB Assessment Report Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 34 of 54 Table 9. Key Risk Message 3: TIRF Medicines Should Be Taken Exactly As Prescribed By The Healthcare Provider Patients Caregivers Patients Caregivers n=301 n=l N=302l Question 11 (95% (95% cry" (95% Secondary Analysis: Demonstrated Understanding 0 correct responses correct response 40 13.3 0 0.0 40 13.2 2 correct responses 167 55.5 0 0.0 167 55.3 3 correct responses 93 30.9 1 100.0 94 31.1 Average number of 2.2 (2.0. 3.0)4 3.0 (0.2. 3.0)4 2.2 (2.0. 3.0)4 correct responses 1 Number of eligible respondents completing the survey (See Table 1). 2 Indicates the correct response(s) to each question or item Within a question. 3 All con?dence intervals are exact binomial 95% con?dence intervals. 4 One-sided 95 con?dence interval using the normal approximation to the Poisson distribution. 5.2.1.4 Key Risk Message 4 Key Risk Message 4 refers to the patient?s knowledge that they must not switch from a TIRF medicine to another medicine that contains fentanyl without talking to a healthcare provider (Table 10). Of the 302 respondents, 285 respondents lmderstood that it is not safe to switch to another medicine that contains fentanyl without talking to a healthcare provider fn?st. Patient KAB Assessment Report Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 35 of 54 Table 10. Risk Message 4: Patients Should Not Switch From a TIRF Medicine to Another Medicine That Contains Fentanyl Without Talking to a Healthcare Provider Patients Caregivers Patients Caregivers n=301 n=1 N=302l Question 11 (95% (95% (95% cn? Question 12: Please answer True, False, or I don?t know for each of the following statements. 12c: It is safe to switch to another medicine that contains fentanyl without talking to a healthcare provider ?rst True 8 2.7 0 0.0 8 2.6 94.4 100.0 94.4 1 2 5 a 56 284 (91.1. 96.7) 1 (2.5. 100.0) 28 (91.1. 96.7) I don?t know Number of eligible respondents completing the survey (See Table 2 Indicates the correct response(s) to each question or item within a question. 3 All con?dence intervals are exact binomial 95% con?dence intervals. 5.2.1.5 Key Risk Message 5 Key Risk Message 5 refers to patients? knowledge that TIRF medicines should not be given to anyone else even if they have the same (Table 11). Response to Question 12d, 296 respondents Imderstood that a patient may not give TIRF medicines to another person if they have the same as the patient, and 297 understood that selling or giving away TIRF medicines is against the law (Question 17a). Overall, evidence of understanding of the comprehensive key risk message is further supported by the average munber of correct responses identi?ed as 2.0 (one-sided 95% I 1.8, 2.0) out of a possible 2 (Table 11). Patient KAB Assessment Report Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 36 of 54 Table 11. Key Risk Message 5: Patients Should Not Give TIRF Medicines to Anyone Else Even if They Have the Same Patients Caregivers Patients Caregivers n=301 n=1 N=302l Question 11 (95% (95% (95% Question 12: Please answer True, False, or I don?t know for each of the followin statements. 12d: A patient may give TIRF medicines to another person if they have the same as the patient. True 5 1.7 0 0.0 5 1.7 98.0 100.0 98.0 2 5 a se 29 (95.7. 99.3) 1 (2.5. 100.0) 296 (95.7. 99.3) I don?t know 1 0.3 0 0.0 1 0.3 Question 17: Please answer True, False, or I don?t know for each statement about the TIRF medicine that was most recently prescribed for you. 17a: Selling or giving away TIRF medicines is against the law. ?"62 296 (96.93395) 1 297 (96.93395) False don?t know 3 1.0 0 0.0 3 1.0 Secondary Analysis: Demonstrated Understanding 0 correct responses correct response correct responses 290 96.3 1 100.0 291 96.4 Average number of 2.0 (1.8. 2.0)4 2.0 (-0.3. 2.0)4 2.0 (1.8. 2.0)4 correct responses 1 Number of eligible respondents completing the survey (See Table 1). 2 Indicates the correct response(s) to each question or item within a question. 3 All con?dence intervals are exact binomial 95% con?dence intervals. 4 One-sided 95 con?dence interval using the normal approximation to the Poisson distribution. 5.2.1.6 Key Risk Message 6 Key Risk Message 6 refers to the patient?s knowledge that TIRF medicines should be stored in a safe place away from children and properly disposed (Table 12). Patient KAB Assessment Report Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 37 of 54 Question 13a elicited the correct (True) response from all 302 (100.0%) respondents who were knowledgeable that TIRF medicines should be stored in a safe place out of the reach of children. Of the 302 respondents, 285 understood that TIRF medicines must be disposed of as described in the speci?c product?s Medication Guide (Question 17c). Whereas, most (n=2 75; 91.1%) respondents imderstood that a TIRF medicine can cause an overdose and death in any child who takes it (Question 17e); and that they should get emergency help right way (n=264;_ 87.4%) in response to Question 14 (What should you do if an adult who has not been prescribed a TIRF medicine takes a TIRF medicine?) Overall, evidence of imderstanding of the comprehensive key risk message is fmther supported by the average number of correct responses identi?ed as 3.7 (one-sided 95% I 3.5, 4.0) out of a possible 4 (Table 12). Table 12. Key Risk Message 6: TIRF Medicines Should be Stored in a Safe Place Away From Children and Properly Disposed Patients Caregivers Patients Caregivers . n=301 n=l Question 11 (95% (95% CD3 (95% Question 13: Please answer True, False, or I don?t know for each statement about the TIRF medicine that was most recently prescribed for you. 13a: TIRF medicines should be stored in a safe place out of the reach of children. 100.0 100.0 100.0 2 me 301 (98.8. 100.0) 1 (2.5. 100.0) 302 (98.8.1000) False don?t know 0 0.0 0 0.0 0.0 Question 17: Please answer True, False, or I don?t know for each statement about the TIRF medicine that was most recently prescribed for you. 17c: TIRF medicines must be disposed of as described in the speci?c product?s Medication Guide. Tmez 284 (91.95367) 1 (2.51.0?000) 285 (91.93367) False 0 0.0 0.0 0 0.0 I don?t know 17 5.6 0 0.0 17 5.6 l7e: A TIRF medicine can cause an overdose and death in any child who takes it. Tmez 274 (87.9340) 1 275 (8729140) False don?t know 25 8.3 0 0.0 25 8.3 Patient KAB Assessment Report Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 38 of 54 Table 12. Key Risk Message 6: TIRF Medicines Should be Stored in a Safe Place Away From Children and Properly Disposed Patients Caregivers Patients Caregivers . n=301 n=l Question 11 (95% (95% (95% Question 14: What should you do if an adult who has not been prescribed a TIRF medicine takes a TIRF medicine? (Please select one.) Get emergency help 263 87.4 1 100.0 264 87.4 right away2 (83.1. 90.9) (2.5. 100.0) (83.1. 90.9) Do nothing 17 5.6 0 0.0 17 5.6 Wart an hour and see if 2 0.7 0 0.0 2 0.7 the person rs OK I don't know 19 6.3 0 0.0 19 6.3 Secondary Analyses: Demonstrated Understandin 0 correct responses correct response correct responses correct responses 50 16.6 0 0.0 50 16.6 4 correct responses 236 78.4 1 100.0 237 78.5 Average number of 3.7 (3.5. 4.0)4 4.0 (0.7. 4.0)4 3.7 (3.5. 4.0)4 correct responses 1 Number of eligible respondents completing the sru'vey (See Table 1Indrcates the correct response(s) to each questron or rtem a questron. 3 All con?dence intervals are exact binomial 95% con?dence intervals. 4 One-sided 95 con?dence interval using the normal approximation to the Poisson distribution. 5.2.1.7 Summary of Understanding of Key Risk Messages The of correct responses to questions detailing the 6 key risk messages is presented in Table 13 below and showed that of the 14 questions, the correct response rates were 70% or higher in respect to 12 of the questions. The correct response rate for Question 13b (It is OK for patients to take medicines for headache pain) was 68.2% and for Question 12b (If a patient stops taking aronnd-the-c/ock opioid pain medicine, they must also stop taking the TIRF medicine) was 34.1%. Patient KAB Assessment Report Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Table 13. Page 39 of 54 Summary of Understanding of Key Risk Messages Key Risk Message 1: TIRF medicines can cause life-threatening breathing problems that can lead to death. Question No. 13d Question TIRF medicines can cause lifethreatening breathing problems that can lead to death. Desired response N True 272 % (95% CI) 90.1 (86.1, 93.2) Key Risk Message 2: Patients should not take TIRF medicines if they are not opioid tolerant. 11 TIRF medicines should only be taken by patients who are opioid tolerant True 277 91.7 (88.0, 94.6) 12a Opioid tolerant means that a patient is already taking other opioid pain medicines around the clock and their body is used to these medicines True 267 88.4 (84.3, 91.8) 13b It is OK for patients to take TIRF medicines for headache pain False 206 68.2 (62.6, 73.4) Key Risk Message 3: TIRF medicines should be taken exactly as prescribed by the healthcare provider. 12b If a patient stops taking around-theclock opioid pain medicine, they must also stop taking the TIRF medicine True 103 34.1 (28.8, 39.8) 13c TIRF medicines should be taken exactly as prescribed by the doctor True 301 99.7 (98.2, 100.0) 17b It is OK to take TIRF medicines for short-term pain that will go away in a few days False 252 83.4 (78.8, 87.5) Key Risk Message 4: Patients should not switch from a TIRF medicine to another medicine that contains fentanyl without talking to a healthcare provider. 12c It is safe to switch to another medicine that contains fentanyl without talking to a healthcare provider first 94.4 False 285 (91.1, 96.7) FDA_868 Patient KAB Assessment Report Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 40 of 54 Key Risk Message 5: Patients should not give TIRF medicines to anyone else even if they have the same symptoms. Question No. Desired response N 12d A patient may give TIRF medicines to another person if they have the same symptoms as the patient False 296 98.0 (95.7, 99.3) 17a Selling or giving away TIRF medicines is against the law True 297 98.3 (96.2, 99.5) Question % (95% CI) Key Risk Message 6: TIRF medicines should be stored in a safe place away from children and properly disposed 13a TIRF medicines should be stored in a safe place out of the reach of children True 302 100.0 (98.8, 100.0) 17c TIRF medicines must be disposed of as described in the specific product’s Medication Guide True 285 94.4 (91.1, 96.7) 17e A TIRF medicine can cause an overdose and death in any child who takes it True 275 91.1 (87.3, 94.0) 14 What should you do if an adult who has not been prescribed a TIRF medicine takes a TIRF medicine? (Please select one.) Get emergency help right away 264 87.4 (83.1, 90.9) 5.2.2 Other Survey Questions 5.2.2.1 Additional Questions about TIRF Medicines Safety With the intention of collating responses to survey questions dealing with safety aspects of TIRF medicines and obtain a one-table view, Table 14 was created. The table below summarizes the respondents' answers to some components associated with key risk messages and additional survey questions not associated with key risk messages. These questions assessed whether the patient has been informed of the risks and possible side effects, indications, usage, storage, and the availability of TIRF medicines through the TIRF REMS Access Program. FDA_869 Patient KAB Assessment Report Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 41 of 54 An HC from the doctor?s of?ce discussed the risks and possible side effects of the prescribed TIRF medicine with 259 respondents while 36 respondents did not recall having this conversation. Most respondents rmderstood that TIRF medicines should not be used for headache or migraine pain (n=234; dental pain (n=264; and pain after surgery (n=207; Only 66 respondents were aware that TIRF medicines are not indicated for long-lasting painful conditions not caused by cancer. Whereas, 194 of the 302 respondents knew that TIRF medicines might be used for breakthrough pain from cancer. Most (281; 93.0%) respondents recollected that someone in the doctor?s of?ce explained the proper way of using the prescribed TIRF medicines while 241 respondents were educated by someone in the doctor?s of?ce regarding the proper storage of the prescribed TIRF medicines. Most (285; 94.4%) respondents were aware of the proper way to dispose of TIRF medicines as described in the product?s Medication Guide. However, the awareness that TIRF medicines are only available through the TIRF REMS Access Program scored less than expected with 147 selecting the correct response. Fruther, most respondents (275; 91.1%) rmderstood that a TIRF medicine might cause overdose and death in any child who takes it. On an overall basis, the results presented in Table 14 indicate that respondents were aware of most of the precautions needed to ensure safe use of TIRF medicines. Taking into account the percentage of incorrect and don?t know? responses, patients/caregivers scored somewhat less with regard to the need to stop taking TIRF medicines if the aromrd-the-clock opioid is stopped and the approved indication for TIRF medicines. Table 14 Responses to All Questions about the Safe Use of TIRF Medicines Patients Caregivers 5:23:21 Question N=l Question 9: Did the doctor, nurse, or other healthcare professional in the doctor?s of?ce ever talk to you about the risks and possible side effects of the TIRF medicine that was most recently prescribed for you? TIRF medicines include Abstral?, Actiq?, Fentora?, Lazanda?, 0nsolis?, Subsys?, and the generic versions of these brands. Yes 258 85.7 1 100.0 259 85.8 No 36 12.0 0 0.0 36 11.9 Idon't know 7 2.3 0 0.0 7 2.3 Patient KAB Assessment Repo? Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industly Group (TRIG) of Companies Page 42 of 54 Table 14 Responses to All Questions about the Safe Use of TIRF Medicines Question Patients Caregivers Patients &1 N=l Caregivers Question 10: For which of the following conditions should I use a TIRF medicine? 10a: Headache or migraine pain Yes 25 8.3 0 0.0 25 8.3 No2 233 77.4 1 100.0 234 77.5 I don't know 43 14.3 0 0.0 43 14.2 10b: Breakthrough pain from cancer Yes2 193 64.1 1 100.0 194 64.2 No 90 29.9 0 0.0 90 29.8 I don't know 18 6.0 0 0.0 18 6.0 10c: Dental pain Yes 9 3.0 0 0.0 49 3.0 No2 263 87.4 1 100.0 264 87.4 I don't know 29 9.6 0 0.0 29 9.6 10d: Pain after surgery Yes 52 17.3 0 0.0 52 17.2 No2 206 68.4 1 100.0 207 68.5 I don't know 43 14.3 0 0.0 43 14.2 10e: Long-lasting painful conditions not caused by cancer Yes 210 69.8 0 0.0 210 69.5 No 2 65 21.6 1 100.0 66 21.9 I don't know 26 8.6 0 0.0 26 8.6 Question 11: Please answer True, False, or I don?t know for the following statement: TIRF medicines should only be taken by patients who are opioid tolerant? Tine2 276 91.7 1 100.0 277 91.7 False don't know 20 6.6 0 0.0 20 6.6 Patient KAB Assessment Repo? Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industly Group (TRIG) of Companies Page 43 of 54 Table 14 Responses to All Questions about the Safe Use of TIRF Medicines Question Patients Caregivers Patients &1 N=l Caregivers Question 12: Please answer True, False, or I don?t know for the following statements: 12a: Opioid tolerant means that a patient is already taking other opioid pain medicines around? the-clock and their body is used to these medicines3 True2 266 88.4 1 100.0 267 88.4 False don't know 23 7.6 0 0.0 23 7.6 12b: If a patient stops taking around-the-clock opioid pain medicine, they must also stop taking the TIRF medicine3 Tme2 102 33.9 1 100.0 103 34.1 False 87 28.9 0 0.0 87 28.8 Idon't know 112 37.2 0 0.0 112 37.1 12c: It is safe to switch to another medicine that contains fentanyl without talking to a healthcare provider ?rst3 Due 48 2.7 0 0.0 8 42.6 False2 284 94.4 1 100.0 285 94.4 I don't know 9 3.0 0 0.0 9 3.0 12d: A patient may give TIRF medicines to another person if they have the same as the patient3 True 5 1.7 0 0.0 5 1.7 False2 295 98.0 1 100.0 296 98.0 I don't know 1 0.3 0 0.0 1 0.3 Question 13: Please answer True, False, or I don?t know for each statement about the TIRF medicine that was most recently prescribed for you. 13a: TIRF medicines should be stored in a safe place out of the reach of children3 Tme2 301 100.0 1 100.0 302 100.0 False don't know 0 0.0 0 0.0 0 0.0 Patient KAB Assessment Report Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 44 of 54 Table 14 Responses to All Questions about the Safe Use of TIRF Medicines Patients Caregivers Patients &1 Question Ca;:231;;rs 13b: It is OK for patients to take TIRF medicines for headache pain3 Tme 21 7.0 0 0.0 21 7.0 False2 205 68.1 1 100.0 206 68.2 I don't know 75 24.9 0 0.0 75 24.8 13c: TIRF medicines should be taken exactly as prescribed by the doctor3 True2 300 99.7 1 100.0 301 99.7 False don't know 1 0.3 0 0.0 1 0.3 13d: TIRF medicines can cause life-threatening breathing problems that can lead to death3 True2 271 90.0 1 100.0 272 90.1 False don't know 30 10.0 0 0.0 30 9.9 Question 14: What should you do if an adult who has not been prescribed a TIRF medicine takes a TIRF medicine? (Please select one.) 3 Get emergency help right away2 263 87?4 1 100'0 264 87'4 Wait an hour and see if the person nothing don't know 19 6.3 0 0.0 19 6.3 Question 15: Did the doctor, nurse, or other healthcare professional in the doctor?s of?ce ever tell you how to use the TIRF medicine that was most recently prescribed for? Yes 280 93.0 1 100.0 281 93don't know 2 0.7 0 0.0 2 0.7 Patient KAB Assessment Report Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 45 of 54 Table 14 Responses to All Questions about the Safe Use of TIRF Medicines Question Patients Caregivers Patients &1 N=l Caregivers Question 16: Did the doctor, nurse, or other healthcare professional in the doctor?s of?ce ever tell you how to store or keep the TIRF medicine that was most recently prescribed for you? Yes 240 79.7 1 100.0 241 79.8 No 52 17.3 0 0.0 52 17.2 I don't know 9 3.0 0 0.0 9 3.0 Question 17: Please answer True, False, or I don?t know for each statement about the TIRF medicine that was most recently prescribed for you. 17a: Selling or giving away TIRF medicines is against the law} True2 296 98.3 1 100.0 297 98.3 False don't know 3 1.0 0 0.0 3 1.0 17b: It is OK to take TIRF medicines for short?term pain that will go away in a few days3 True 15 5.0 0 0.0 15 5.0 False2 251 83.4 1 100.0 252 83.4 Idon't know 35 11.6 0 0.0 35 11.6 17c: TIRF medicines must be disposed of as described in the speci?c product?s Medication Guide. True2 284 94.4 1 100.0 285 94.4 False don't know 17 5.6 0 0.0 17 5.6 17d: TIRF medicines are only available to patients through a special program (called the TIRF REMS Access program). True2 147 48.8 0 0.0 147 48.7 False 33 11.0 0 0.0 33 10.9 I don't know 121 40.2 1 100.0 122 40.4 Patient KAB Assessment Report Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 46 of 54 Table 14 Responses to All Questions about the Safe Use of TIRF Medicines Patients Caregivers Patients &1 Caregivers Question N401 N?l l7e: A TIRF medicine can cause an overdose and death in any child who takes it. True2 274 91.0 1 100.0 275 91.1 False don't know Number of eligible respondents completing the sm'vey (See Table 1). 2 Indicates the correct response(s) to each question or item within a question 3 Questions taken from key risk messages 5.2.3 Analyses of Sub-populations To assess further patients? Imderstanding of key risk messages, sub-group analyses with more than 20 respondents were conducted and outlined in Section 4.1.2. Sub-groups that were not analyzed because they had less than 20 respondents included: 0 Sub-group 2b Respondents who understood some of the Medication Guide; 0 Sub-group Note: The for sub-group 2c (Respondents who answered don?t know?) was 0; therefore, a column for sub-group 2c was not included in the above Table Respondents who answered None or don?t know?) to Question 25 (How much of the Medication Guide did you understand Sub-group 4a Time to complete smvey (Telephone) <10 minutes. 5.2.3.1 Effectiveness of Medication Guide The correct response rates for questions detailing the 6 key risk messages are presented in Table 15 by respondents who got the Medication Guide and read at least most of it (sub-group S-la) and by respondents who did not get a Medication Guide or answered, don?t know? or who got a Medication Guide and read only some of it or answered don?t know? (sub-group S-lb). Of the 248 respondents who read most of the Medication Guide (sub-group S-la), 234 lmderstood Key Risk Message 1 (TIRF medicines can cause life-threatening breathing problems that can lead to death) compared with 38 of the 54 who read some or none of the Medication Guide (sub-group S-lb). In the case of Key Risk Message 2, 230 respondents who read most of the Medication Guide and 47 of respondents who read some or none of the Medication Guide were Patient KAB Assessment Report Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 47 of 54 aware that TIRF medicines should only be taken by patients who are opioid tolerant. In addition, 221 (89.1%) respondents who read most of the Medication Guide (sub-group S-1a) and 46 (85.2%) of sub-group S-1b respondents understood the meaning of the term opioid tolerant. Most (n=176; 71.0%) respondents of sub-group S-1a correctly answered that TIRF medicines are not recommended for headache pain compared with 30 of 54 (55.6%) of subgroup S-1b respondents (Table 15). Of the three questions/statements under Key Risk Message 3, 95 (38.3%) of sub-group S-1a and 8 (14.8%) sub-group S-1b respondents gave the correct response to Question 12b (If a patient stops taking around-the-clock opioid pain medicine, they must also stop taking the TIRF medicine). Almost all (n=247; 99.6%) of sub-group S-1a and 54 (100.0%) of sub-group S-1b respondents correctly identified with the statement that TIRF medicines should be taken exactly as prescribed by the doctor; and 214 (86.3%) of sub-group S-1a and 38 (70.4%) of sub-group S-1b disagreed with the statement that it is okay to take TIRF medicines for shortterm pain that will go away in a few days (Table 15). There was high understanding for Key Risk Message 4 Question 12c (It is safe to switch from a TIRF medicine to another medicine that contains fentanyl without talking to a healthcare provider first) because 233 (94.0%) of sub-group S-1a and 52 (96.3%) of sub-group S-1b responded correctly (Table 15). Almost all respondents understood Key Risk Message 5 that patients should not give TIRF medicines to anyone else even if they have the same symptoms (Table 15). Respondents demonstrated a high level of understanding for Key Risk Message 6 that TIRF medicines should be stored in a safe place away from children and properly disposed (Table 15). Overall, the results indicate that respondents who read all or most of the Medication Guide were better informed regarding the safe use of TIRF medicines. Therefore, the Medication Guide is an effective tool to help patients understand the key risk messages based on the goals of the TIRF REMS. All other sub-group analyses showed that the results are similar to the results in the primary population, and no sub-group-related trends were evident. FDA_876 Patient KAB Assessment Report Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 48 of 54 Table 15 Correct Responses and Response Rates to Key Risk Message Questions Based on Extent of Reading of Medication Guide Correct Response Rates 11:3; Read Most of the . . . Message Question Medicatlo: Guide Medication Guide 8 13d: TIRF medicines can cause life- 1 threatening breathing problems that can lead 234 94.4 38 70.4 to death 1 medicmes should only be taken by 230 92-7 47 87.0 patients who are op101d tolerant 12a: Opioid tolerant means that a patient is ah?eady taking other opioid pain medicines . . . 5. 2 ar01md-the-clock and their body 1S used these medicines 13b:.It 1S OK for patients to take TIRF 176 71-0 30 55.6 medrcmes for headache pam 12b: If a patient stops taking around-the-clock opioid pain medicine. they must also stop 95 38.3 8 14.8 taking the TIRF medicine 3 13c: TIRF medicmes should be taken exactly 247 99.6 54 1000 as by the doctor 17b: It is OK to take TIRF medicines for short-term pain that will go away in a few 214 86.3 38 70.4 days 12c: It is safe to switch to another medicine 4 that contains fentanyl without talking to a 233 94.0 52 96.3 healthcare provider ?rst 12d: A patient may give TIRF medicines to another person if they have the same 243 98.0 53 98.1 5 as the patient 17a: Selhng or givmg away TIRF medicmes agamst the law Patient KAB Assessment Report Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 49 of 54 Table 15 Correct Responses and Response Rates to Key Risk Message Questions Based on Extent of Reading of Medication Guide Correct Response Rates 11:: Read Most of the 11153111332231. . . . Message Question Medication Guide Medication Guide l3a: TIRF medicines should be stored in a . . 5 . safe place out of the reach 17c: TIRF medicines must be disposed of as described in the speci?c product?s Medication 241 97.2 44 81.5 Guide 6 . . l7e. A TIRF medicine can cause an overdose 230 92-7 45 83.3 and death n1 any who takes it 14: What should you do if an adult who has not been prescribed a TIRF medicine takes a TIRF medicine? 222 89" 42 77?8 Get emergency help right away The full set of sub-group analysis tables is provided in Appendix B. 5.3 Spontaneous Reporting of Adverse Events, Product Complaints, or Medical Information Requests Among all sruvey respondents Table 1), there were 27 reports of a potential adverse event, product complaint, and/or medical information request associated with the use of TIRF medicines made during smvey collection (Appendix B, Listing 4). Respondents who completed the smvey online had the option to write in any questions they had in the ?'ee-text ?eld. Of the 15 reports made in the free text ?eld of the online smvey, nine were requests for medical information related to adverse events, withdrawal, drug administration, and dosage. The remaining six responses were comments that their questions had been answered by the HC or they had no questions (Appendix B, Listing 3). 6. DISCUSSION, CONCLUSIONS, AND RECOMMENDATIONS The speci?c goal of the TIRF medicines patient KAB survey was to evaluate the level of understanding by patients and caregivers of the risks associated with use of TIRF medicines, the importance of being opioid tolerant before starting a TIRF medicine, strictly following the Patient KAB Assessment Report Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 50 of 54 directions of the HCP, not switching from one TIRF medicine to another medicine that contains fentanyl without talking to an HCP, the importance of patients not giving TIRF medicines to anyone else even if they have the same and storing TIRF medicines in a safe place away from children and proper disposal of unused medicine. Revisions were made to the 24-month s1uvey based on feedback received from the FDA on the 12-month assessment. Table 16 below shows the changes in key risk message questions between the two sruvey versions, and the patients? scores in each version. No improvement in correct response rate was noted for Question 10, which was reworded in the 24-month survey in an attempt to improve patient understanding of the question. The one item that scored noticeably lower on the 24-month assessment was the concept that patients should stop taking a TIRF medicine if they stop their around the clock opioid. The TRIG is exploring options to increase awareness of this important safety message. which is discussed in the current PPAF and medication guides for each product. While not a key risk message in the prescriber sruvey, this concept was also a low scoring item for prescribers even though that it is conveyed in the Prescriber Education Program as a patient cormseling message. Table 16 Correct Response Rate in the 24-Month KAB Survey Compared with the 12-Month KAB Survey in Key Risk Message Questions Modified Between the Two Versions 12?month 24?month lZ-month 24?month Survey Survey Survey Survey Correct Correct Question Question Question as Presented in the 24-month Response Response Number Number Survey 9 10 For which of the following conditions should I use a TIRF medicine? 9a 10a Headache or migraine pain 72.9 77.5 9b 10b Breakthrough pain ?om cancer 69.8 64.2 9c 10c Dental pain 89.6 87.4 9d 10d Pain after surgery 67.7 68.5 9e 10e Long-lasting pamful conditions not caused by 24. 5 21-9 cancer 11 12 Please answer True. False. or I don?t know for each of the following statements. If a patient stops taking arormd-the clock 11b 12b opioid pain medicine. they must also stop 42.7 34.1 taking the TIRF medicine. Patient KAB Assessment Report Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 51 of 54 The overall higher level of understanding of the remaining items/questions throughout the 6 key risk messages indicates that patients are knowledgeable about the safe use and storage of TIRF medicines. The higher level of understanding in patients who read most or all of the medication guide demonstrates effective communication of the key risk messages, which may also be reinforced by prescribers and pharmacists. The consistent high level of patient understanding of key risk messages between the 12-month and 24-month surveys indicates that the REMS goals are being met with the tools currently in place. FDA_880 Patient KAB Assessment Report Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Appendix A Page 52 of 54 Patient Survey Protocol FDA_881 PROTOCOL TITLE: Quantitative Testing of Patient/Caregiver Knowledge, Attitudes, and Behavior about Transmucosal Immediate Release Fentanyl (TIRF) Products Safety and Use Information SPONSOR: TIRF REMS Industry Group (TRIG) Archimedes Pharma US Inc. Cephalon, Inc. (a wholly-owned subsidiary of Teva Pharmaceutical Industries, Ltd.) Endo Pharmaceuticals Inc. Galena Biopharma Insys Therapeutics Mallinckrodt Meda Pharmaceuticals Mylan, Inc. Par Pharmaceutical, Inc. VERSION: 6.0 DATE: 10 Sep 2013 APPROVED: FINAL FDA_882 TIRF REMS Industry Group (TRIG) Transmucosal Immediate Release Fentanyl (TIRF) Products Patient/Caregiver KAB Survey Protocol TABLE OF CONTENTS Version 6.0 10 Sep 2013 PAGE TABLE OF CONTENTS ......................................................................................... 2 1. LIST OF ABBREVIATIONS .................................................................................. 3 2. BACKGROUND ..................................................................................................... 4 3. OBJECTIVES OF THE EVALUATION SURVEY ............................................... 5 4. METHODS .............................................................................................................. 5 4.1 4.1.1 4.1.2 Survey Design .......................................................................................................... 5 Questions and Statements on REMS Goals ............................................................. 6 Additional Questions................................................................................................ 9 4.2 4.2.1 Subject Recruitment ................................................................................................. 9 Measures to Minimize Bias in the Sample............................................................. 10 5. 5.1.1 5.1.2 5.1.3 STUDY POPULATION ........................................................................................ 11 Sample Size ............................................................................................................ 11 Inclusion Criteria.................................................................................................... 12 Exclusion Criteria .................................................................................................. 12 6. SURVEY PROCESS ............................................................................................. 12 6.1 6.1.1 6.1.2 Screening and Survey Administration ................................................................... 12 Telephone ............................................................................................................... 12 Internet ................................................................................................................... 13 6.2 Measures to Minimize Bias in the Survey Process ................................................ 13 7. ANALYSIS ............................................................................................................ 13 8. SAFETY EVENT REPORTING ........................................................................... 14 9. PRIVACY PROTECTION AND CONFIDENTIALITY...................................... 15 LIST OF APPENDICES APPENDIX A Screening and Main Questionnaire........................................................... 16 APPENDIX B Patient Letter of Invitation ........................................................................ 40 2 of 41 FDA_883 TIRF REMS Industry Group (TRIG) Transmucosal Immediate Release Fentanyl (TIRF) Products Patient/Caregiver KAB Survey Protocol 1. Version 6.0 10 Sep 2013 LIST OF ABBREVIATIONS CATI CI EDC ETASU FDA HIPAA IRB KAB PBM PPAF REMS SE/PSP TIRF TIRF REMS TRIG UBC US Computer-Assisted Telephone Interviewing Confidence Interval Electronic Data Capture Elements to Assure Safe Use Food and Drug Administration Health Insurance Portability and Accountability Act Institutional Review Board Knowledge, Attitudes and Behavior Pharmacy Benefits Management Patient-Prescriber Agreement Form Risk Evaluation and Mitigation Strategy Safety Event Project Specific Procedure Transmucosal Immediate Release Fentanyl TIRF REMS Access Program TIRF REMS Industry Group United BioSource Corporation United States 3 of 41 FDA_884 TIRF REMS Industry Group (TRIG) Transmucosal Immediate Release Fentanyl (TIRF) Products Patient/Caregiver KAB Survey Protocol 2. Version 6.0 10 Sep 2013 BACKGROUND Transmucosal Immediate Release Fentanyl (TIRF) medicines include the class of immediaterelease opioid analgesics, which are indicated only for the management of breakthrough pain in cancer patients 18 years of age or older (16 or older for Actiq® and equivalent generics) who are already receiving and already tolerant to opioid therapy for their underlying persistent cancer pain. The TIRF medicines include Abstral®, Actiq®, Fentora®, Lazanda®, Onsolis®, Subsys®, and generic versions of any of these brands. The TIRF REMS Industry Group (TRIG) includes Archimedes Pharma US Inc.; Cephalon, Inc. (a wholly-owned subsidiary of Teva Pharmaceutical Industries, Ltd.); Endo Pharmaceuticals Inc.; Galena Biopharma; Insys Therapeutics; Mallinckrodt; Meda Pharmaceuticals; Mylan, Inc.; and Par Pharmaceutical, Inc. The Food and Drug Administration (FDA) has determined that a class-wide Risk Evaluation and Mitigation Strategy (REMS) is required to mitigate the risks of misuse, abuse, addiction, overdose and serious complications due to medication errors with the use of TIRF medicines. The TIRF REMS Access Program (hereafter referred to as TIRF REMS) was approved by the FDA on December 28, 2011. The TIRF REMS consists of a Medication Guide, Elements to Assure Safe Use (ETASU), an Implementation System, and a timetable for submission of assessments of the REMS. The goals of the TIRF REMS are to mitigate the risk of misuse, abuse, addiction, overdose and serious complications due to medication errors by: 1. Prescribing and dispensing TIRF medicines only to appropriate patients, which includes use only in opioid-tolerant patients 2. Preventing inappropriate conversion between TIRF medicines 3. Preventing accidental exposure to children and others for whom it was not prescribed 4. Educating prescribers, pharmacists, and patients on the potential for misuse, abuse, addiction, and overdose of TIRF medicines An important component of the TIRF REMS assessment is the conduct of quantitative evaluation surveys to assess patients’ and caregivers’ knowledge, attitudes, and behavior (KAB) regarding the safe use of TIRF medicines, as described in the product-specific Medication Guide. This protocol will describe the administration of the surveys that will be conducted among patients who are treated with TIRF medicines, or their caregivers. Data from the surveys, together with other REMS evaluation metrics, will be used to determine whether changes need to be made to the REMS processes and/or educational materials to make them more effective in achieving the goals of the REMS. The surveys will be implemented so that data will be available for inclusion in the REMS Assessment Reports that will be submitted to the FDA at 12 months after approval of the TIRF REMS and annually thereafter. 4 of 41 FDA_885 TIRF REMS Industry Group (TRIG) Transmucosal Immediate Release Fentanyl (TIRF) Products Patient/Caregiver KAB Survey Protocol 3. Version 6.0 10 Sep 2013 OBJECTIVES OF THE EVALUATION SURVEY The evaluation survey will use a questionnaire to document the level of knowledge and assess the attitudes and behavior of patients around the following key information and risk messages communicated through the REMS: 1) TIRF medicines can cause life-threatening breathing problems that can lead to death. 2) Patients should not take TIRF medicines if they are not opioid tolerant. 3) TIRF medicines should be taken exactly as prescribed by the healthcare provider. 4) Patients should not switch from a TIRF medicine to another medicine that contains fentanyl without talking to a healthcare provider. 5) Patients should not give TIRF medicines to anyone else even if they have the same symptoms. 6) TIRF medicines should be stored in a safe place away from children and properly disposed. The survey will also include questions about whether patients received, read, and understood the product-specific Medication Guide and Patient-Prescriber Agreement Form (PPAF). 4. METHODS The survey was designed in collaboration between the TRIG and United BioSource Corporation (UBC), and will be administered by UBC. 4.1 Survey Design This survey will be conducted among a sample of patients who have filled a prescription for a TIRF medicine within the past 4 months prior to survey launch and their caregivers. Respondents who have participated in a previous wave of the TIRF REMS KAB survey will not be eligible to participate in subsequent survey waves. The survey will be administered using the following modalities:  Self-administered, online through a secure website  Telephone surveys facilitated by a trained interviewer from the Survey Coordinating Center using a computer-assisted telephone interviewing (CATI) program The survey will begin with screening questions to confirm respondent eligibility to participate in the survey. Completion of the entire survey is expected to take approximately 20 minutes. 5 of 41 FDA_886 TIRF REMS Industry Group (TRIG) Transmucosal Immediate Release Fentanyl (TIRF) Products Patient/Caregiver KAB Survey Protocol Version 6.0 10 Sep 2013 The survey included in Appendix B is written to reflect wording for both methods of survey administration: Internet-based and telephone administration. 4.1.1 Questions and Statements on REMS Goals The KAB items of the questionnaire are made up of multiple-choice, closed-ended statements or questions (the majority of which use true/false or yes/no dichotomous response options), and open-ended questions. These will evaluate current knowledge, attitudes, and behavior regarding the key risk messages noted in Section 3. The survey is written to follow principles of health literacy and readability. Questionnaire items will be presented in several formats:  Statements or questions asking the respondent to indicate whether a statement or question is true or false, or if they do not know the answer (there is a similar set of statements and questions that use “yes,” “no,” or “I don’t know” as potential response options);  Statements or questions asking the respondent to choose from a defined list of possible statements or answers; and  Questions allowing for the respondent to provide information about when, where and from whom they obtained a Medication Guide, as well as to list questions about information in the Medication Guides. Questionnaires will be analyzed to determine patient understanding of each key risk message. For statements or questions that use “true” or “yes” vs. “false” or “no” response options, the desired response for the key risk messages is generally “true” or “yes” indicating knowledge of, or behavior in accordance with, the objectives of the REMS. However, some questions are formatted to have the respondent disagree with the statement as written by providing response options of “false” or “no” to avoid having the same affirmative answer for all desired responses. REMS statements, corresponding questions, and desired responses covering the key risk messages are identified below and can be found in the complete survey questionnaire (Appendix A). For better readability, the patient questions, only, are presented in the key risk messages tables. Caregiver questions are presented in Appendix A. 6 of 41 FDA_887 TIRF REMS Industry Group (TRIG) Transmucosal Immediate Release Fentanyl (TIRF) Products Patient/Caregiver KAB Survey Protocol Version 6.0 10 Sep 2013 Key Risk Message 1: TIRF medicines can cause life-threatening breathing problems that can lead to death. Question No. Question Desired response 13 Please answer True, False, or I don’t know for each statement about the TIRF medicine that was most recently prescribed for you. 13d TIRF medicines can cause life-threatening breathing problems that can lead to death. TRUE Key Risk Message 2: Patients should not take TIRF medicines if they are not opioid tolerant. Question No. Question Desired response Please answer True, False, or I don’t know for the following statement: 11 12 12a 13 13b TIRF medicines should only be taken by patients TRUE who are opioid tolerant. Please answer True, False, or I don’t know for each of the following statements. Opioid tolerant means that a patient is already taking other opioid pain medicines around-theTRUE clock and their body is used to these medicines. Please answer True, False, or I don’t know for each statement about the TIRF medicine that was most recently prescribed for you. It is OK for patients to take TIRF medicines for FALSE headache pain. 7 of 41 FDA_888 TIRF REMS Industry Group (TRIG) Transmucosal Immediate Release Fentanyl (TIRF) Products Patient/Caregiver KAB Survey Protocol Version 6.0 10 Sep 2013 Key Risk Message 3: TIRF medicines should be taken exactly as prescribed by the healthcare provider. Question No. Question Desired response 12 Please answer True, False, or I don’t know for each of the following statements. 12b If a patient stops taking around-the-clock opioid pain medicine, they must also stop taking the TIRF medicine. 13/17 13c 17b TRUE Please answer True, False, or I don’t know for each statement about the TIRF medicine that was most recently prescribed for you. TIRF medicines should be taken exactly as TRUE prescribed by the doctor. It is OK to take TIRF medicines for short-term FALSE pain that will go away in a few days. Key Risk Message 4: Patients should not switch from a TIRF medicine to another medicine that contains fentanyl without talking to a healthcare provider. Question No. 12 12c Question Desired response Please answer True, False, or I don’t know for each of the following statements. It is safe to switch to another medicine that contains fentanyl without talking to a healthcare FALSE provider first. 8 of 41 FDA_889 TIRF REMS Industry Group (TRIG) Transmucosal Immediate Release Fentanyl (TIRF) Products Patient/Caregiver KAB Survey Protocol Version 6.0 10 Sep 2013 Key Risk Message 5: Patients should not give TIRF medicines to anyone else even if they have the same symptoms. Question Question No. 12 12d 17 17a Desired response Please answer True, False, or I don’t know for each of the following statements. A patient may give TIRF medicines to another person if they have the same symptoms as the FALSE patient. Please answer True, False, or I don’t know for each statement about the TIRF medicine that was most recently prescribed for you. Selling or giving away TIRF medicines is against TRUE the law. Key Risk Message 6: TIRF medicines should be stored in a safe place away from children and properly disposed. Question Question No. 13/17 13a 17c 17e 13 4.1.2 Desired response Please answer True, False, or I don’t know for each statement about the TIRF medicine that was most recently prescribed for you. TIRF medicines should be stored in a safe TRUE place out of the reach of children. TIRF medicines must be disposed of as described in the specific product’s TRUE Medication Guide. A TIRF medicine can cause an overdose TRUE and death in any child who takes it. What should you do if an adult who has not Get emergency help right been prescribed a TIRF medicine takes a away. TIRF medicine? (Please select one.) Additional Questions Questions about the requirements of the TIRF REMS, and receipt and understanding of the Medication Guides and PPAF will be asked after the key risk message questions, and will be followed by the collection of demographic information at the completion of the survey. 4.2 Subject Recruitment Patients will be recruited through a direct letter program. Patients will be invited through a network of national pharmacies and a pharmacy benefits management (PBM) partner, which 9 of 41 FDA_890 TIRF REMS Industry Group (TRIG) Transmucosal Immediate Release Fentanyl (TIRF) Products Patient/Caregiver KAB Survey Protocol Version 6.0 10 Sep 2013 each have broad demographic coverage and include patients in 49 states. Leveraging one or more of these partners, a list will be created of patients who have filled a prescription for a TIRF medicine within 4 months prior to survey launch (first prescriptions and refills). Patients in this list will be invited to participate in the survey through an invitation letter (Appendix B) mailed directly to the patients on the pharmacy or PBM’s letterhead at the corporate level via the United States (US) Postal Service. Additionally, outbound calls will be placed to prescribers to ask for their support in informing patients about the opportunity to participate in the survey by providing an invitation directly to patients who are prescribed a TIRF medicine. A random sample of up to 250 prescribers with at least 5 patients who have filled prescriptions in the 4 months prior to survey implementation will be contacted for this purpose. If a prescriber expresses willingness to support the survey effort, an information packet including invitation letters will be mailed to the prescriber. Prescribers will not receive any compensation for this support. The invitation will indicate that participants will receive a $50 gift card for completing the survey. Each invitation will also include a unique code and directions for accessing the survey either via the Internet or by telephone through an interviewer at the Survey Coordinating Center. The unique code will be used to identify the manufacturer of the most recent TIRF prescription that the patient filled. A random sample of patients who have filled a prescription for a TIRF medicine within the 4 months prior to survey launch will be chosen from the pharmacy partner’s or PBM database. This sampling approach will be used to create several batches of survey invitations. The overall number of unique patients and the duration of the survey period will dictate the size and number of invitation batches. If the required number of completed surveys is not achieved within a reasonable time frame, a second mailing will be sent to non-respondents from the original batch mailing and initial invitations will be sent to patients in the second batch. If the required number of completed surveys is still not achieved within a reasonable time frame, reminder letters will be sent to the patients in the second batch and initial invitations will be sent to the third batch of patients. If these efforts do not result in the required number of surveys within a reasonable time frame, then a new random sample of patients may be selected. The intervals for sending reminder invitations to non-responders and for selecting a new sample will be condensed as necessary based on the actual rate of survey accrual relative to the proximity of the target survey close date. All respondents who complete the survey and who provide their contact information will be mailed a $50 gift card to thank them for their participation. The mailing will include a thank you letter, a copy of the product-specific Medication Guide, and a copy of the correct answers to the key risk message questions. 4.2.1 Measures to Minimize Bias in the Sample The sample of participating patients will be self-selected since respondents will voluntarily respond to the invitation to participate; however, the survey recruitment strategies are intended to recruit a heterogeneous sample of patients for participation. 10 of 41 FDA_891 TIRF REMS Industry Group (TRIG) Transmucosal Immediate Release Fentanyl (TIRF) Products Patient/Caregiver KAB Survey Protocol Version 6.0 10 Sep 2013 Respondents will be offered online or telephone options for completing the survey. Multiple modalities for survey data collection allow for wider survey access to a more heterogeneous population. Respondents will be provided a unique code during the recruitment process and will be asked to provide the unique code to gain access to the online survey or when calling the Survey Coordinating Center. The code will be deactivated after use to minimize the possibility for fraud. 5. STUDY POPULATION 5.1.1 Sample Size A sample of 300 patients treated with TIRF medicines is proposed for the survey wave. The size of the sample was determined based on both practical and statistical considerations. There is no target comprehension rate specified a priori. A sample of 300 completed surveys will allow estimation of the comprehension rate for each key risk message with a moderately high degree of precision. The table below shows the precision of the estimates for level of understanding using two-sided 95% confidence intervals (CIs) obtained with the sample size of 300 completed surveys. The noted CIs are used to indicate that for any survey-estimated rate of understanding, the true population rate of understanding is at least as high as the lower limit of the 95% CI and may be as high as the upper limit of the 95% CI. Table 5.1: Precision of Estimated Rates of Understanding with a Sample Size of 300 Estimated Rate of Understanding 5% 10% 15% 20% 25% 30% 35% 40% 45% 50% 55% 60% 65% 70% 75% 80% 85% 90% 95% Estimated Confidence Interval 2.8% 8.1% 6.8% 14.0% 11.2% 19.6% 15.6% 25.0% 20.2% 30.3% 24.9% 35.5% 29.6% 40.7% 34.4% 45.8% 39.3% 50.8% 44.2% 55.8% 49.2% 60.7% 54.2% 65.6% 59.3% 70.4% 64.5% 75.1% 69.7% 79.8% 75.0% 84.4% 80.4% 88.8% 86.0% 93.2% 91.9% 97.2% 11 of 41 FDA_892 TIRF REMS Industry Group (TRIG) Transmucosal Immediate Release Fentanyl (TIRF) Products Patient/Caregiver KAB Survey Protocol 5.1.2 Version 6.0 10 Sep 2013 Inclusion Criteria The following respondents are eligible to participate in the survey:  Patients who are 18 years of age or older who have filled a prescription for at least one of the TIRF medicines within 4 months prior to survey launch  Caregivers 18 years of age or older who care for patients who have filled a TIRF medicine prescription within the past 4 months prior to survey launch and are unable to take the survey for themselves 5.1.3 Exclusion Criteria The following respondents are not eligible to participate in the surveys:  Patients who have previously participated in the TIRF REMS KAB survey (this exclusion applies to the second and subsequent waves only)  Patients or their immediate family members who have ever worked for Anesta LLC, Archimedes Pharma US Inc.; Cephalon, Inc. (a wholly-owned subsidiary of Teva Pharmaceutical Industries, Ltd.); Endo Pharmaceuticals Inc.; Galena Biopharma; Insys Therapeutics; Mallinckrodt; Meda Pharmaceuticals; Mylan, Inc.; Par Pharmaceutical, Inc.; ProStrakan Inc.; Teva Pharmaceuticals, Ltd.; UBC; McKesson Specialty Care Solutions; RelayHealth; or the FDA. 6. SURVEY PROCESS 6.1 Screening and Survey Administration The questionnaire will begin with a screening module with questions to confirm patient eligibility. The entire survey is expected to take approximately 20 minutes to complete. Depending on the answers to the screening questions, survey participation could either be terminated or continued. If ineligible, respondents are immediately notified with a thank you message that survey participation has ended. If eligible, respondents are allowed to continue survey participation. The electronic data capture (EDC) system that is used for both methods of survey administration has been validated and is secure for receiving and storing survey data. The system is 21 CFR Part 11 and Health Insurance Portability and Accountability Act (HIPAA) compliant. Patient-identifying information will be stored separately from survey data. 6.1.1 Telephone The telephone survey is facilitated by a trained interviewer from the Survey Coordinating Center using a CATI program. The respondent will be required to provide a unique code to access the survey. Working from a CATI script, the interviewer will read questions or statements to the respondent and enter the responses into the EDC system. Screening and main 12 of 41 FDA_893 TIRF REMS Industry Group (TRIG) Transmucosal Immediate Release Fentanyl (TIRF) Products Patient/Caregiver KAB Survey Protocol Version 6.0 10 Sep 2013 elements of the questionnaire will be administered sequentially during the same telephone call. Telephone interviewing allows participation of respondents who do not have Internet access, or prefer to complete the survey in this manner. 6.1.2 Internet An Internet-based survey system will also be used for conducting the KAB surveys. If respondents select to participate in the survey online, they will be directed to a secured website and instructed to enter a unique code to access the survey. An Internet survey will be convenient for respondents to participate since they can complete the questionnaire at any convenient time and location during the specified survey time period. 6.2 Measures to Minimize Bias in the Survey Process A number of controls will be in place to ensure the survey is conducted in a controlled and professional manner and to minimize bias. For example, a unique code will be given to each survey participant and the code will be inactivated after use to minimize fraud. Telephone interviewers are highly trained and use a standardized script to administer interviews. All questions will be programmed to ensure that questions are asked in the appropriate sequence. Skip patterns will be clearly indicated. Respondents cannot go back to a question once the question has been answered and cannot skip ahead. All questions must be answered in order to complete the survey. Response options presented in a list will be randomized to minimize positional bias. Programming will be reviewed by quality control and simulated users (User Acceptance Testing) prior to implementing the survey. 7. ANALYSIS Information obtained from the survey will be reported as descriptive statistics for the survey administration, study population, and the survey questions. Any free text fields will be grouped into applicable categories. Verbatim text from open-ended questions will be displayed when appropriate. The following will be reported as part of this analysis:  The number of invitations issued  The number of reminder letters  The number of respondents screened for participation  The number of respondents eligible for participation  The number of respondents who completed all questions presented to them  Description of survey participants, including:  Type of respondent (patient/caregiver) 13 of 41 FDA_894 TIRF REMS Industry Group (TRIG) Transmucosal Immediate Release Fentanyl (TIRF) Products Patient/Caregiver KAB Survey Protocol   Age (patient/caregiver)  Gender (respondent)  Educational level (respondent)  Main language spoken at home (respondent)  Ethnicity (respondent)  Race (respondent)  Geographic region (respondent) Version 6.0 10 Sep 2013 Data from all respondents who completed all questions presented to them in the survey (“completers”) will be analyzed, including:  Frequency distribution of responses to each key risk message question.  Percent of completers selecting desired response to each question relating to each key risk message and 95% CI. Measurement of understanding will be computed for each question of the key risk message individually. A secondary analysis will be conducted to determine the number of completers who answered all items correctly for the key risk message. Behavior questions will be summarized on a question-by-question basis and are not included in the analysis by key risk message. Additional analyses may be performed as needed. 8. SAFETY EVENT REPORTING The survey will be conducted via the Internet and by telephone. It is possible that a respondent may report an adverse event or other safety event experienced while taking TIRF medicines either in free text fields of the survey or while in conversation with the Survey Coordinating Center. If an event is mentioned to a Survey Coordinating Center Associate, the Associate will document the safety event and the respondent’s contact information. The respondent will also be informed that a representative from the appropriate TIRF medicine manufacturer may contact him/her if there are questions about the survey. The Internet-based questionnaires will be monitored for any comments recorded in free text fields. Information on all comments that may constitute an adverse event or other safety event will be forwarded to the appropriate TIRF medicine manufacturer as described in the Safety Event Project Specific Procedure (SE/PSP). Additional detail regarding processes for adverse event reporting will be specified in the SE/PSP. 14 of 41 FDA_895 TIRF REMS Industry Group (TRIG) Transmucosal Immediate Release Fentanyl (TIRF) Products Patient/Caregiver KAB Survey Protocol 9. Version 6.0 10 Sep 2013 PRIVACY PROTECTION AND CONFIDENTIALITY All data collected during the survey will be held confidential. The EDC system used for data collection encrypts all identifiable information and respondent identifiers are stored separately from the survey responses. Respondent names and addresses are collected in order to mail a $50 gift card, a Thank You Letter, a product-specific Medication Guide, and correct survey responses to key risk message questions after the survey is completed. Respondent contact information is also requested in the event a safety event is reported and a TIRF medicine manufacturer must obtain follow-up information. A respondent may be contacted only if clarification or follow-up is needed regarding a possible safety event that was mentioned to the interviewer or recorded in free text fields of the online survey. Respondents will be informed when they access the survey that they may be contacted if there are any questions about their survey responses. Respondents will be informed that their answers to the survey questions will not affect their ability to receive TIRF medicines. This protocol and survey will be reviewed and approved by a central Institutional Review Board (IRB) before administration of the survey. 15 of 41 FDA_896 TIRF REMS Industry Group (TRIG) Transmucosal Immediate Release Fentanyl (TIRF) Products Patient/Caregiver KAB Survey Protocol Version 6.0 10 Sep 2013 APPENDIX A Screening and Main Questionnaire Survey Legend  [PROGRAMMER] is used to indicate directions to the programmer and is set in bold, red, uppercase letters between square brackets. [PATIENT] indicates text applicable to a patient when it differs from survey text for caregivers, parents and legal guardians. [PARENT/CAREGIVER/LEGAL GUARDIAN] indicates text applicable to parents, caregivers, and legal guardians when it differs from survey text for patients.  (INTERVIEWER) is used to indicate directions to the telephone interviewer and is set in bold, blue, text between parentheses. This text appears when content is to be administered by tlelphone only (for example, spontaneous adverse event reporting).  [ONLINE] indicates a question is worded specifically for administering the survey online. [PHONE] indicates a question is worded specifically to be read by a telephone interviewer and differs from the online text.  [BEGIN ONLINE/PHONE SURVEY CONTENT] and [END SURVEY CONTENT] are used to indicate to the programmer the type of survey administration and the beginning and end of the survey or sections within the survey content, for example, [BEGIN ADVERSE EVENT/PRODUCT COMPLAINT] and [END ADVERSE EVENT/PRODUCT COMPLAINT].  [TERMINATE] is displayed next to responses that should cause the survey to end. The following termination language will be programmed into the survey or read by the interviewer unless different language is specified with the question. Thank you very much for your time today. Based on your answer, you are not eligible to take this survey. We appreciate your interest in the survey.  [RANDOMIZE LIST] is inserted before questions to indicate to the programmer that the responses should be randomized. Responses such as “I don’t know,” “Prefer not to answer” or “None of the above” will always appear at the end of the randomized responses.  [GO TO Ax] (Skip logic) is inserted after a response to indicate to the programmer that the survey should skip to the indicated question (for example, [GO TO Q17] skips to question 17). If no skip logic is indicated the survey continues to the next question in the sequence. 16 of 41 FDA_897 TIRF REMS Industry Group (TRIG) Transmucosal Immediate Release Fentanyl (TIRF) Products Patient/Caregiver KAB Survey Protocol Version 6.0 10 Sep 2013 Survey Legend  [MULTILINE INPUT] indicates to the programmer that multiple lines should be provided for data entry (for example, two address lines or a free-text response).  [DROP-DOWN LIST INPUT WITH STATES TABLE] indicates to the programmer that the response should be a drop-down list containing the states in the table below. Alabama Georgia Massachusetts New York Tennessee Alaska Guam Michigan North Carolina Texas American Samoa Hawaii Minnesota North Dakota Arizona Idaho Mississippi Illinois Missouri Indiana Montana Northern Mariana Islands US Virgin Islands Iowa Nebraska Kansas Nevada Kentucky New Hampshire Louisiana New Jersey Maine New Mexico Arkansas California Colorado Connecticut Delaware District of Columbia Florida Maryland Ohio Oklahoma Oregon Pennsylvania Puerto Rico Rhode Island Utah Vermont Virginia Washington West Virginia Wisconsin Wyoming South Carolina South Dakota  The following is used to categorize survey populations into standard geographic regions but it is not displayed in the survey. Geographic Distribution (based on address) 1: Northeast, Midwest, South, and West regions Northeast Region  New England Division - ME, NH, VT, MA, RI, CT  Middle Atlantic Division - NY, NJ, PA Midwest Region  East North Central Division - OH, IN, IL, MI, WI  West North Central Division - MN, IA, MO, ND, SD, NE, KS South Region  South Atlantic Division - DE, MD, DC, VA, WV, NC, SC, GA, FL  East South Central Division - KY, TN, AL, MS  West South Central Division - AR, LA, OK, TX 17 of 41 FDA_898 TIRF REMS Industry Group (TRIG) Transmucosal Immediate Release Fentanyl (TIRF) Products Patient/Caregiver KAB Survey Protocol Version 6.0 10 Sep 2013 Survey Legend West  Mountain Division - MT, ID, WY, CO, NM, AZ, UT, NV  Pacific Division WA, OR, CA, AK, HI  The following US territories are categorized as Other: Puerto Rico, Northern Mariana Islands, US Virgin Islands, American Samoa, and Guam. 1 U.S. Census Bureau, last revised Friday, 27-Jul-2001 12:59:43 EDT. [BEGIN SURVEY CONTENT] [ONLINE PREAMBLE 1] Before you begin, we would like to share some important information about this survey. The survey is being conducted by the makers of Abstral®, Actiq®, Fentora®, Lazanda®, Onsolis®, Subsys® and the generic versions of any of these brands. These are Transmucosal Immediate Release Fentanyl medicines, also known as rapid onset opioids (and sometimes called “fast acting fentanyls”) or TIRF medicines. The information collected will help the makers of TIRF medicines know if patients and their caregivers understand important information about taking these medicines. The survey will take about 20 minutes. There are no known risks to you in taking this survey. You may refuse to take part or withdraw at any time without penalty or loss of benefits to which you are otherwise entitled. Your answers to the questions or your decision to take part in the survey will not affect your ability to receive or take TIRF medicines. How We Use Your Information Your answers to the survey questions will be combined with answers given by other people taking the survey. All answers will be put together and reported in anonymous form to manufacturers of TIRF medicines. Your name will not be used in any report. If you are eligible to take the survey, complete all the questions, and provide your contact information, you will receive a $50 gift card for your time. Your name and address will be used only to send you the gift card, a Thank You Letter, a product-specific Medication Guide, and a copy of the correct answers to key risk message questions, after you complete the survey. Providing a telephone number is optional. Your telephone number will be used only if there are any questions about your answers. 18 of 41 FDA_899 TIRF REMS Industry Group (TRIG) Transmucosal Immediate Release Fentanyl (TIRF) Products Patient/Caregiver KAB Survey Protocol Version 6.0 10 Sep 2013 How We Protect Your Privacy We respect that the privacy of your personal information is important to you. You will not be contacted for marketing purposes based on your personal information or your answers to the survey. Neither the manufacturers of TIRF medicines nor their contractors will sell, transfer, or rent your information. Your answers will be kept strictly confidential. Your privacy will be protected; however, research survey records may be inspected by the FDA (Food and Drug (b) (4) Administration) and a company called ., which is the Institutional Review Board (IRB). Your choice to allow the manufacturers of TIRF medicines to use your information is entirely voluntary, but necessary to take part in this survey. How to Learn More About This Survey If you have questions about the survey, or have any problems with the survey, please contact the Survey Coordinating Center at 1-877-379-3297. Once you have answered a question and moved on, you cannot go back and change your answers. If you have questions about your rights as a research participant or related concerns, you may (b) (4) contact the IRB at . Be sure to write down this telephone number; it will not be displayed again. The information in this survey should not take the place of talking with your doctor or health care professional. If you have any questions about your condition or treatment or that of the person you care for, or if you would like more information about TIRF medicines, talk to your doctor, pharmacist, or other health care professional. Thank you for your participation in this survey. [END ONLINE PREAMBLE 1] 19 of 41 FDA_900 TIRF REMS Industry Group (TRIG) Transmucosal Immediate Release Fentanyl (TIRF) Products Patient/Caregiver KAB Survey Protocol Version 6.0 10 Sep 2013 [PHONE PREAMBLE 1] Before you begin, we would like to share some important information about this survey. The survey is being conducted by the makers of Abstral®, Actiq®, Fentora®, Lazanda®, Onsolis®, Subsys® and the generic versions of any of these brands. These are Transmucosal Immediate Release Fentanyl medicines, also known as rapid onset opioids (INTERVIEWER: Please pause briefly) (and sometimes called “fast acting fentanyls”) or TIRF medicines. (INTERVIEWER: Pronounce “TIRF,” then spell out T-I-R-F). The information collected will help the makers of TIRF medicines know if patients and their caregivers understand important information about taking these medicines. The survey will take about 20 minutes. There are no known risks to you in taking this survey. You may refuse to take part or withdraw at any time without penalty or loss of benefits to which you are otherwise entitled. Your answers to the questions or your decision to take part in the survey will not affect your ability to receive or take TIRF medicines. Now I would like to tell you about how your contact information will be used. Your answers to the survey questions will be combined with answers given by other people taking the survey. All answers will be put together and reported in anonymous form to manufacturers of TIRF medicines. Your name will not be used in any report. If you are eligible to take the survey, complete all the questions, and provide your contact information, you will receive a $50 gift card for your time. Your name and address will be used only to send you the gift card, a Thank You Letter, a product-specific Medication Guide, and a copy of the correct answers to key risk message questions, after you complete the survey. Providing a telephone number is optional. Your telephone number will be used only if there are any questions about your answers. Now I would like to tell you about how we protect your privacy. We respect that the privacy of your personal information is important to you. You will not be contacted for marketing purposes based on your personal information or your answers to the survey. Neither the manufacturers of TIRF medicines nor their contractors will sell, transfer, or rent your information. Your answers will be kept strictly confidential. Your privacy will be protected; however, research survey records may be inspected by the FDA (Food and Drug (b) (4) Administration) and a company called ., which is the Institutional Review Board (IRB). Your choice to allow the manufacturers of TIRF medicines to use your information is entirely voluntary, but necessary to take part in this survey. Please feel free to ask me to repeat any questions or statements as we go through the survey. 20 of 41 FDA_901 TIRF REMS Industry Group (TRIG) Transmucosal Immediate Release Fentanyl (TIRF) Products Patient/Caregiver KAB Survey Protocol Version 6.0 10 Sep 2013 Once you have answered a question and moved on, you cannot go back and change your answers. If you have questions about your rights as a research participant or related concerns, you may (b) (4) contact the IRB at . The information in this survey should not take the place of talking with your doctor or health care professional. If you have any questions about your condition or treatment or that of the person you care for, or if you would like more information about TIRF medicines, talk to your doctor, pharmacist, or other health care professional. Thank you for your participation in this survey. [END PHONE PREAMBLE 1] 21 of 41 FDA_902 TIRF REMS Industry Group (TRIG) Transmucosal Immediate Release Fentanyl (TIRF) Products Patient/Caregiver KAB Survey Protocol 1. 2. 3. Version 6.0 10 Sep 2013 Do you agree to take part in this survey? ○ Yes ○ No [TERMINATE] Within the last 4 months, have you filled a prescription for yourself for a transmucosal immediate release fentanyl medicine (known as “TIRF medicines”)? TIRF medicines include Abstral®, Actiq®, Fentora®, Lazanda®, Onsolis®, Subsys®, and the generic versions of any of these brands. ○ Yes [GO TO Q4] ○ No ○ I don’t know Are you a caregiver for someone who has filled a prescription for a TIRF medicine within the last 4 months? As a reminder, TIRF medicines include Abstral®, Actiq®, Fentora®, Lazanda®, Onsolis®, Subsys® and the generic versions of any of these brands. ○ Yes ○ No [TERMINATE] ○ I don’t know [TERMINATE] 22 of 41 FDA_903 TIRF REMS Industry Group (TRIG) Transmucosal Immediate Release Fentanyl (TIRF) Products Patient/Caregiver KAB Survey Protocol 4. 5. Version 6.0 10 Sep 2013 [PATIENT] For which TIRF medicines have you filled a prescription in the last 4 months? Please select all that apply. [CAREGIVER] For which TIRF medicines has the person you care for filled a prescription in the last 4 months? Please select all that apply. □ Abstral □ Actiq, including generic versions of Actiq □ Fentora □ Lazanda □ Onsolis □ Subsys □ Other ○ I don’t know [CLEAR ALL OTHER SELECTIONS] Have you ever taken part in a survey about a TIRF medicine before? ○ Yes [TERMINATE] ○ No ○ I don’t know [TERMINATE] 23 of 41 FDA_904 TIRF REMS Industry Group (TRIG) Transmucosal Immediate Release Fentanyl (TIRF) Products Patient/Caregiver KAB Survey Protocol 6. 7. Version 6.0 10 Sep 2013 Which of the following groups best describes your age? ○ Under 18 [TERMINATE] ○ 18 – 29 ○ 30 – 39 ○ 40 – 49 ○ 50 – 59 ○ 60 – 69 ○ 70 or older ○ Prefer not to answer [TERMINATE] [CAREGIVER ONLY] Which of the following groups best describes the patient’s age? ○ Under 16 ○ 16 – 29 ○ 30 – 39 ○ 40 – 49 ○ 50 – 59 ○ 60 – 69 ○ 70 or older ○ Prefer not to answer 24 of 41 FDA_905 TIRF REMS Industry Group (TRIG) Transmucosal Immediate Release Fentanyl (TIRF) Products Patient/Caregiver KAB Survey Protocol 8. Version 6.0 10 Sep 2013 Have you or any of your immediate family members ever worked for any of the following companies or agencies? Please select all that apply. □ Anesta LLC [TERMINATE] □ Archimedes Pharma US Inc. [TERMINATE] □ Cephalon, Inc. (a wholly-owned subsidiary of Teva Pharmaceutical Industries, Ltd.) [TERMINATE] □ □ Endo Pharmaceuticals Inc. [TERMINATE] □ □ Insys Therapeutics [TERMINATE] □ McKesson Specialty Care Solutions [TERMINATE] □ Meda Pharmaceuticals [TERMINATE] □ Mylan, Inc. [TERMINATE] □ Par Pharmaceutical, Inc. [TERMINATE] □ ProStrakan, Inc. [TERMINATE] □ RelayHealth[TERMINATE] □ Teva Pharmaceuticals, Ltd. [TERMINATE] □ United BioSource Corporation [TERMINATE] □ FDA (Food and Drug Administration) [TERMINATE] □ No [IF SELECTED IN ADDITION TO OTHER RESPONSES, TERMINATE] □ I don’t know [TERMINATE] Galena Biopharma [TERMINATE] Mallinckrodt [TERMINATE] [PREAMBLE 2] [PATIENT]Please answer the following questions based on information about the TIRF medicine that was most recently prescribed for you. TIRF medicines include Abstral®, Actiq®, Fentora®, Lazanda®, Onsolis®, Subsys®, and the generic versions of these brands. 25 of 41 FDA_906 TIRF REMS Industry Group (TRIG) Transmucosal Immediate Release Fentanyl (TIRF) Products Patient/Caregiver KAB Survey Protocol Version 6.0 10 Sep 2013 Please think of the information that you read or that was provided to you by a doctor, nurse, or other healthcare professional. If you don’t know the answers to any of the following questions please respond “I don’t know” instead of guessing the correct responses. [CAREGIVER]Please answer the following questions based on information about the TIRF medicine that was most recently prescribed for the patient. TIRF medicines include Abstral®, Actiq®, Fentora®, Lazanda®, Onsolis®, Subsys®, and the generic versions of these brands. Please think of the information that you read or that was provided to you or to the patient by a doctor, nurse, or other healthcare professional. If you don’t know the answers to any of the following questions please respond “I don’t know” instead of guessing the correct responses. 9. [PATIENT] Did the doctor, nurse, or other healthcare professional in the doctor’s office ever talk to you about the risks and possible side effects of the TIRF medicine that was most recently prescribed for you? TIRF medicines include Abstral®, Actiq®, Fentora®, Lazanda®, Onsolis®, Subsys®, and the generic versions of these brands. [CAREGIVER] Did the doctor, nurse, or other healthcare professional in the doctor’s office ever talk to you about the risks and possible side effects of the TIRF medicine that was most recently prescribed to the patient? TIRF medicines include Abstral®, Actiq®, Fentora®, Lazanda®, Onsolis®, Subsys®, and the generic versions of these brands. 10. ○ Yes ○ No ○ I don’t know [PATIENT] For which of the following conditions should I use a TIRF medicine? [CAREGIVER] For which of the following conditions should the person I take care of use a TIRF medicine? Yes No I don’t [RANDOMIZE LIST] know 10a. Headache or migraine pain ○ ○ ○ 10b. Breakthrough pain from cancer ○ ○ ○ 10c. Dental pain ○ ○ ○ 10d. Pain after surgery ○ ○ ○ 10e. Long-lasting painful conditions not caused by cancer ○ ○ ○ 26 of 41 FDA_907 TIRF REMS Industry Group (TRIG) Transmucosal Immediate Release Fentanyl (TIRF) Products Patient/Caregiver KAB Survey Protocol 11. Version 6.0 10 Sep 2013 Please answer True, False, or I don’t know for the following statement: TIRF medicines should only be taken by patients who are opioid tolerant. 12. ○ True ○ False ○ I don’t know Please answer True, False, or I don’t know for each of the following statements. True False I don’t [RANDOMIZE LIST] know 12a. Opioid tolerant means that a patient is already taking other opioid pain medicines around-the-clock and their body is used to these medicines. ○ ○ ○ 12b. If a patient stops taking around-the-clock opioid pain medicine, they must also stop taking the TIRF medicine. ○ ○ ○ 12c. It is safe to switch to another medicine that contains fentanyl without talking to a healthcare provider first. ○ ○ ○ 12d. A patient may give TIRF medicines to another person if they have the same symptoms as the patient. ○ ○ ○ 27 of 41 FDA_908 TIRF REMS Industry Group (TRIG) Transmucosal Immediate Release Fentanyl (TIRF) Products Patient/Caregiver KAB Survey Protocol 13. Version 6.0 10 Sep 2013 [PATIENT] Please answer True, False, or I don’t know for each statement about the TIRF medicine that was most recently prescribed for you. [CAREGIVER] Please answer True, False, or I don’t know for each statement about the TIRF medicine that was most recently prescribed for the patient. I don’t [RANDOMIZE LIST] True False know 13a. TIRF medicines should be stored in a safe place out of the reach of children. ○ ○ ○ 13b. It is OK for patients to take TIRF medicines for headache pain. ○ ○ ○ 13c. TIRF medicines should be taken exactly as prescribed by the doctor. ○ ○ ○ 13d. TIRF medicines can cause life-threatening breathing problems that can lead to death. ○ ○ ○ 14. What should you do if an adult who has not been prescribed a TIRF medicine takes a TIRF medicine? (Please select one.) [RANDOMIZE LIST] ○ Wait an hour and see if the person is OK. ○ Get emergency help right away. ○ Do nothing. ○ I don’t know 28 of 41 FDA_909 TIRF REMS Industry Group (TRIG) Transmucosal Immediate Release Fentanyl (TIRF) Products Patient/Caregiver KAB Survey Protocol 15. Version 6.0 10 Sep 2013 [PATIENT] Did the doctor, nurse, or other healthcare professional in the doctor’s office ever tell you how to use the TIRF medicine that was most recently prescribed for you? [CAREGIVER] Did the doctor, nurse, or other healthcare professional in the doctor’s office ever tell you how to use the TIRF medicine that was most recently prescribed for the patient? 16. ○ Yes ○ No ○ I don’t know [PATIENT] Did the doctor, nurse, or other healthcare professional in the doctor’s office ever tell you how to store or keep the TIRF medicine that was most recently prescribed for you? [CAREGIVER] Did the doctor, nurse, or other healthcare professional in the doctor’s office ever tell you how to store or keep the TIRF medicine that was most recently prescribed for the patient? ○ Yes ○ No ○ I don’t know 29 of 41 FDA_910 TIRF REMS Industry Group (TRIG) Transmucosal Immediate Release Fentanyl (TIRF) Products Patient/Caregiver KAB Survey Protocol 17. Version 6.0 10 Sep 2013 [PATIENT] Please answer True, False, or I don’t know for each statement about the TIRF medicine that was most recently prescribed for you. [CAREGIVER] Please answer True, False, or I don’t know for each statement about the TIRF medicine that was most recently prescribed for the patient. [RANDOMIZE LIST] True False I don’t know 17a. Selling or giving away TIRF medicines is against the law. ○ ○ ○ 17b. It is OK to take TIRF medicines for short-term pain that will go away in a few days. ○ ○ ○ 17c. TIRF medicines must be disposed of as described in the specific product’s Medication Guide. ○ ○ ○ 17d. TIRF medicines are only available to patients through a special program (called the TIRF REMS Access program). ○ ○ ○ 17e. A TIRF medicine can cause an overdose and death in any child who takes it. ○ ○ ○ [PREAMBLE 3] [PATIENT] The next set of questions is about the Medication Guide for the TIRF medicine that was most recently prescribed for you. [CAREGIVER] The next set of questions is about the Medication Guide for the TIRF medicine that was most recently prescribed for the patient. [BOTH] A Medication Guide is a paper handout that contains important information about the risks associated with the use of a TIRF medicine and how to use it safely. Medication Guides always include the title “Medication Guide” followed by the name of the medicine and its pronunciation. The Medication Guide usually has a section titled “What is the most important information I should know?” The Medication Guide is in a question-and-answer format and may be given to you by your pharmacist or doctor. [END PREAMBLE 3] 30 of 41 FDA_911 TIRF REMS Industry Group (TRIG) Transmucosal Immediate Release Fentanyl (TIRF) Products Patient/Caregiver KAB Survey Protocol 18. Version 6.0 10 Sep 2013 [PATIENT] Have you ever received a Medication Guide for the TIRF medicine that was prescribed for you? [CAREGIVER] Have you or the patient ever received a Medication Guide for the TIRF medicine that was prescribed for the patient? 19. ○ Yes ○ No [GO TO PREAMBLE 4] ○ I don’t know [GO TO PREAMBLE 4] [PATIENT] Did you receive the Medication Guide from the doctor who prescribed the TIRF medicine or someone in the doctor’s office? [CAREGIVER] Did you or the patient receive the Medication Guide from the doctor who prescribed the TIRF medicine or someone in the doctor’s office? 20. ○ Yes ○ No [GO TO Q21] ○ I don’t know [GO TO Q21] [PATIENT] When was the Medication Guide given to you? Please select all that apply. [CAREGIVER] When was the Medication Guide given to you or the patient? Please select all that apply. ○ At the first appointment with the doctor who prescribed the TIRF medicine ○ At the last appointment with the doctor who prescribed the TIRF medicine ○ I don’t remember [CLEAR ALL OTHER SELECTIONS] 31 of 41 FDA_912 TIRF REMS Industry Group (TRIG) Transmucosal Immediate Release Fentanyl (TIRF) Products Patient/Caregiver KAB Survey Protocol 21. Version 6.0 10 Sep 2013 [PATIENT] Did you receive the Medication Guide for the TIRF medicine from the pharmacy? [CAREGIVER] Did you or the patient receive the Medication Guide for the TIRF medicine from the pharmacy? 22. ○ Yes ○ No [GO TO Q23] ○ I don’t know [GO TO Q23] [PATIENT] How frequently do you receive a Medication Guide for the TIRF medicine at the pharmacy? [CAREGIVER] How frequently do you or the patient receive a Medication Guide for the TIRF medicine at the pharmacy? 23. 24. ○ Only with the first filled prescription ○ Each time a prescription is filled ○ Other (please specify): _____________________________ ○ I don’t know Did you read the Medication Guide? ○ Yes ○ No [GO TO Q26] ○ I don’t know [GO TO Q26] How much did you read? ○ All of it ○ Most of it ○ Some of it ○ I don’t know 32 of 41 FDA_913 TIRF REMS Industry Group (TRIG) Transmucosal Immediate Release Fentanyl (TIRF) Products Patient/Caregiver KAB Survey Protocol 25. 26. 27. Version 6.0 10 Sep 2013 How much of the Medication Guide did you understand? ○ All of it ○ Most of it ○ Some of it ○ None of it ○ I don’t know Did someone offer to explain the Medication Guide to you? ○ Yes ○ No [GO TO Q30] ○ I don’t know [GO TO Q30] Who offered to explain the Medication Guide to you? (Select all that apply.) □ The doctor or another healthcare professional in the doctor’s office □ The pharmacist where the TIRF medicine prescription was filled □ Someone else (specify the type of person but not his/her name) ____________________________________________________________ 28. Did you accept the offer to have the Medication Guide explained to you? ○ Yes ○ No [GO TO Q30] ○ I don’t know [GO TO Q30] 33 of 41 FDA_914 TIRF REMS Industry Group (TRIG) Transmucosal Immediate Release Fentanyl (TIRF) Products Patient/Caregiver KAB Survey Protocol 29. 30. 31. Version 6.0 10 Sep 2013 How much of the explanation did you understand? ○ All of it ○ Most of it ○ Some of it ○ None of it ○ I don’t know Did you or do you have any questions about the information in the Medication Guide? ○ Yes ○ No [GO TO PREAMBLE 4] ○ I don’t know [GO TO PREAMBLE 4] What are your questions? [MULTILINE INPUT] [PREAMBLE 4] The next set of questions is about the Patient-Prescriber Agreement Form for TIRF medicines. As a reminder, TIRF medicines include Abstral®, Actiq®, Fentora®, Lazanda®, Onsolis®, Subsys®, and the generic versions of any of these brands. The Patient-Prescriber Agreement is a form that is signed by the doctor and the patient or their caregiver. This form may also be referred to as the Prescriber-Patient Agreement. [END PREAMBLE 4] 32. Did the doctor or someone in the doctor’s office explain the Patient-Prescriber Agreement Form to you? ○ Yes ○ No [GO TO Q34] ○ I don’t know [GO TO Q34] 34 of 41 FDA_915 TIRF REMS Industry Group (TRIG) Transmucosal Immediate Release Fentanyl (TIRF) Products Patient/Caregiver KAB Survey Protocol 33. 34. Version 6.0 10 Sep 2013 How much of the explanation did you understand? ○ All of it ○ Most of it ○ Some of it ○ None of it ○ I don’t know [PATIENT] Did you sign a Patient-Prescriber Agreement Form? [CAREGIVER] Did you or the person you are caring for sign a Patient-Prescriber Agreement Form? 35. ○ Yes ○ No [GO TO DEMOGRAPHICS PREAMBLE] ○ I don’t know [GO TO DEMOGRAPHICS PREAMBLE] Did the doctor or someone in the doctor’s office give you a copy of the signed Patient-Prescriber Agreement Form? ○ Yes ○ No ○ I don’t know [DEMOGRAPHICS PREAMBLE] There are just a few more questions to help us combine your answers with other answers we have received. 36. What is your gender? ○ Male ○ Female ○ Prefer not to answer 35 of 41 FDA_916 TIRF REMS Industry Group (TRIG) Transmucosal Immediate Release Fentanyl (TIRF) Products Patient/Caregiver KAB Survey Protocol 37. 38. Version 6.0 10 Sep 2013 What is the highest level of education you have completed? ○ Less than high school ○ Some high school ○ High school graduate/GED ○ Some college/Associate’s degree ○ Bachelor’s degree ○ Master’s degree ○ Professional or Doctoral degree ○ Prefer not to answer What is the main language you speak at home? (Please select only one.) ○ English ○ French ○ Spanish ○ Portuguese ○ Italian ○ German ○ Chinese ○ Japanese ○ Korean ○ Other ○ Prefer not to answer 36 of 41 FDA_917 TIRF REMS Industry Group (TRIG) Transmucosal Immediate Release Fentanyl (TIRF) Products Patient/Caregiver KAB Survey Protocol 39. 40. 41. Version 6.0 10 Sep 2013 Are you Hispanic or Latino? ○ Yes ○ No ○ Prefer not to answer For informational purposes only, which of the following U.S. census categories best describes your race? (Please select only one.) ○ American Indian or Alaska Native ○ Asian (origins of Far East, Southeast Asia or the Indian subcontinent) ○ Black or African American ○ Native Hawaiian or Other Pacific Islander ○ White ○ Other ○ Prefer not to answer In which state do you live? [DROP-DOWN LIST INPUT WITH STATES TABLE WITH “Prefer not to answer” AT END] 37 of 41 FDA_918 TIRF REMS Industry Group (TRIG) Transmucosal Immediate Release Fentanyl (TIRF) Products Patient/Caregiver KAB Survey Protocol Version 6.0 10 Sep 2013 [PHONE ONLY: ADVERSE EVENT/PRODUCT COMPLAINT] (INTERVIEWER: Please record if respondent spontaneously reported an adverse event or product complaint during the course of this interview.) ○ Yes ○ No [GO TO CLOSING 1] Enter Safety Adverse Event Verbatim [MULTILINE INPUT] (INTERVIEWER: Indicate to the respondent that someone may call back to ask more questions about the adverse event or product complaint that was reported.) [END ADVERSE EVENT/PRODUCT COMPLAINT] [CLOSING 1] You are eligible to receive a $50 gift card for your time completing the survey. In order to receive the gift card, we need to collect your name and address so that we can mail it to you. If you do not provide your name and address you will not receive the gift card for your time taking the survey. 42. Do you agree to give us your name and mailing address so we can send your payment? ○ Yes ○ No [SKIP TO CLOSING 2] FIRST NAME: _______________________________________________ LAST NAME: _______________________________________________ ADDRESS: [MULTILINE INPUT] CITY: _____________________________________ STATE: [DROP-DOWN LIST INPUT WITH STATES TABLE] ZIP: ___________ 38 of 41 FDA_919 TIRF REMS Industry Group (TRIG) Transmucosal Immediate Release Fentanyl (TIRF) Products Patient/Caregiver KAB Survey Protocol Version 6.0 10 Sep 2013 [CLOSING 2] We would also like to ask for your telephone number. Providing your telephone number is optional and it will be used to contact you only if there are questions about your survey responses. 43. Do you want to provide your telephone number? ○ Yes ○ No [SKIP TO CLOSING 3] Telephone: ________________________________ [CLOSING 3] This is the end of the survey. If you have questions about the survey, please contact the Survey Coordinating Center at 1-877-379-3297. Thank you again for your help. [END OF SURVEY CONTENT] 39 of 41 FDA_920 TIRF REMS Industry Group (TRIG) Transmucosal Immediate Release Fentanyl (TIRF) Products Patient/Caregiver KAB Survey Protocol Version 6.0 10 Sep 2013 APPENDIX B Patient Letter of Invitation [PAT_FIRST_NAME] [PAT_LAST_NAME [CURR_DATE] [PAT_STREET_ADDR] [PAT_CITY], [PAT_STATE] [PAT_ZIP] Dear [PAT_FULL_NAME]: Thank you for choosing [pharmacy partner or PBM name] for your prescription needs. The purpose of this letter is to inform you about a voluntary research survey being conducted by [COMPANY], the maker of [BRAND_GENERIC]. The survey is part of an FDA requirement to find out if patients and/or their caregivers understand important safety information about [BRAND] and other medicines like it. The first 300 people who complete this 20-minute survey and provide their contact information will receive a $50 [pharmacy partner or PBM name] gift card from [COMPANY] to thank them for their time. You may be eligible to take part if you have taken [BRAND] and are 18 years of age or older. If you are unable to take the survey yourself, a caregiver who is 18 or older may be eligible to take the survey for you. The survey asks questions about the type of information you received about [BRAND] and where you get your medical information. If you are interested in participating and to find out if you are eligible:   Go to www.TIRFREMSsurvey.com any time or Call 877-379-3297, 8 a.m. to 8 p.m. Eastern Time, Monday through Friday Please have this letter with you at the time you take the survey. You will be asked to provide this code prior to starting the survey: [CODE_ID]. *It is recommended that you take the survey on a desktop or laptop computer. Taking the survey on mobile devices, such as smart phones, tablets, and e-notebooks, is not supported. (over, please) 40 of 41 FDA_921 TIRF REMS Industry Group (TRIG) Transmucosal Immediate Release Fentanyl (TIRF) Products Patient/Caregiver KAB Survey Protocol Version 6.0 10 Sep 2013 You are not required to take part in this survey. If you choose to take part, please be assured that your contact information and your individual responses will be kept strictly confidential. You will not be asked to identify yourself to participate in the survey. However, if you wish to receive the $50 gift card from [COMPANY], you must provide your name and contact information for delivery. Your answers to the survey questions will be combined with answers given by others, and your name will not be used in any written report or publication. Neither taking the survey nor your answers to the questions will affect your ability to receive or take [BRAND]. Sincerely, [Pharmacy partner or PBM name] [COMPANY] funded the cost of the gift card, the cost of mailing this letter and paid a fee to [pharmacy partner or PBM name]. The research study is not being conducted by [pharmacy partner or PBM name]. No information that can identify you, your medication, or your health condition will be provided by [pharmacy partner or PBM name] to [COMPANY]. This letter provides information about a drug prescribed by your doctor and is not a recommendation by [pharmacy partner or PBM name] to use a particular drug for your condition. Call [pharmacy partner or PBM name] toll free at xxx-xxx-xxxx if you do not wish to continue receiving mailings about [BRAND] from [pharmacy partner or PBM name]. 41 of 41 FDA_922 Patient KAB Assessment Report Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Appendix B Page 53 of 54 Patient Survey Listings and Sub-group Analyses Tables FDA_923 Listing 1 VERBATIM RESPONSES TO QUESTION 22 (How frequently do you receive a Medication Guide for the TIRF medicine at the pharmacy?) Verbatim Response not all the time 7- 8 times year Yearly or dosage change Every 3 months. There is one in each box received in the mail I have only ?lled 1 perscription Client: TRIG Project: TIRF Wave 2 Report Run Date and Time: 11/14/2013 10:16:00 AM Page 1 of Listing 2 VERBATIM RESPONSES TO QUESTION 27 (Other person offering explanation of the Medication Guide) Verbatim Response drug rep Husband 111anufactiu?er on the phone My husband is a Phannacist my mom she is a nurse. Nurse Practitioner in Doctors Of?doctor and daughter is Subsys ding Rep the manufacturer's rep Wife Client: TRIG Project: Report Run Date and Time: 11/11/2013 12:56:00 PM Page 1 of Listing 3 VERBATIM RESPONSES TO QUESTION 30 (Questions about the information in the Medication Guide) Verbatim Response Allergic reactions and safety instructions are there withdrawal 110w to get off in a safe manner I asked questions about going off of the medication and was it safe to only use prescribed (4) a day I don't remember at this point. I would have to reread the medication guide to be able to answer this question with my questions that I have. I wondered over time. will it rot me teeth? In the guide it has section that has long term side effects it has dental. It does not explain the dental. my one question was on how long it should take a Actiq to dissolve in your mouth My questions have been subsequently worked out with my prescribing healthcare of?cials. My questions were answered by the doctor after I read the Guide. Safety. and 110w it would affect me with relation to the other pain meds I am taking. None answered incorrectly. I had a question in regard to my fentanyl patch. the med guide said not to I was wondering how the transdermal patch would be effected by the sun or heat from the sun the questions were answered by the doctor Was it possible to only spray half of the container? What happens if I can?t dissolve the medicine in 20min? If the ?rst sucker doesn't not relieve the pain how soon can I take the second one? Client: TRIG Project: TIRF Wave 2 Report Run Date and Time: 11/11/2013 12:59:00 PM Page 1 of Listing 4 REPORTED ADVERSE EVENTS, PRODUCT COMPLAINTS, or Requests for Medical Information Verbatim Response "I'm Sorry. I'm just getting over a cold." "Sometimes I break out from the lollipop. is there latex in it?" "What I have had is 5 back fusions. 3 Lumbar and 2 Cervical. I have nerve damage in my back. I can only take Fentanyl cause I am allergic to everything else." Bigger print I can hardly read it. It is too complicated. Could I say something to pass 011 to the people who made these drugs? They are too damn expensive. Even the generic is too expensive. And now I won't even be able to get these suckers anymore because the FDA won't let you have them rmless you have cancer. I got ?agged at the pharmacy and they called my doctor. When they found out that they were for pain after my truck accident they told my doctor that he couldn't prescribe it for me anymore. This is my last month. These things worked great for me and I don't know what I'm going to do now. For me. I am not using for cancer pain. I am using for long term pain relief. I broke my left leg. I broke my tibia in 5 places on July 15th. When I took the SUBSYS the medicine worked It took the pain from about a 12 to a 2. Especially in a broke leg I feel like it's a good product especially for a broke leg. It helped get me through the first few weeks. I do take the medication for long term pain but it is not because of cancer. I dont take it for cancer pain. I'm opioid tolerant. I had surgery for spinal stenous spinal stenosishalf hour surgery. I have COPD. I have breathing problems. I have breakthrough pain from RSV that's why I'm taking the medication. I don't have cancer. I had to have Actiq lollipop for dental pain. I had my teeth cut out and that's why I had the Actiq. I have nerve damage from an accident that is way I take the medication. I use my generic Actiq for breakthrough pain for prior surgeries. I am a chronic pain sufferer after 16 operations. I?ve got a cold. My ear is stopped up. I believe it has to do with the change of seasons. Long lasting painful conditions not caused by cancer: Yes. That' 5 what I use it for. I'm just an old guy with a really bad back. Yes. but I don't have cancer. Allergic reactions and safety instructions are there withdrawal how to get off in a safe manner I wondered over time. will it rot me teeth? Client: TRIG Project: TIRF Wave 2 Report Run Date and Time: 11/11/2013 1:41:00 PM Page 1 of 2 Verbatim Response my one question was on how long it should take a Actiq to dissolve in your mouth answered incorrectly. I had a question in regard to my fentanyl patch. the med guide said not to I was wondering how the transdennal patch would be effected by the sun or heat from the sun Was it possible to only spray half of the container? What happens if I can't dissolve the medicine in 20min? If the ?rst sucker doesn't not relieve the pain how soon can I take the second one? I've been really sick and back problems. I go back and forth from the Dr. and some of the medications make me sick. Fentora makes me too sick to my stomach. received this letter about Subsys. I can?t take that any more I am allergic to it.? received this letter about Subsys. I can?t take that any more I am allergic to it.? Client: TRIG Project: TIRF Wave 2 Report Run Date and Time: 11/11/2013 1:41:00 PM Page 2 of 2 TABLE 1.1 SURVEY ADNIINISTRATION STATISTICS Question The number of invitations issued to . .. 1903 The number of reminder letters . . 2454 malled to prescribers The nlunber? of respondents screened . . . 347 for The number of respondents eligible for 302 participation The number of respondents eligible for participation who completed the 302 87.0 sruvey By Telephone 127 36.6 By Internet 175 50.4 This is the denominator for the percentages in this table Client: TRIG Project: TIRF Wave 2 Report Run Date and Time: 11/14/2013 10:28:00 AM Page 1 of TABLE 1.2 TIME TO COMPLETE SURVEY (COMPLETERS ONLY) Time to Complete Survey Summary Statistic Telephone Internet Total 12 7 1 75 302 Mean (SD) 20.1 (5.20) 14.7 (8.37) 17.0 (7.68) Minimlun 1 3 6 6 Median 18.6 12.2 16.5 Maximum 44 7 1 7 1 Category Telephone Internet Total 0 to <5 Minutes 0 0 0 5 to <10 Minutes 0 47 47 10 to <15 Minutes 5 70 75 15 to <20 Minutes 75 30 105 20 to <25 Minutes 32 15 47 25 - <30 Minutes 9 6 15 30 Minutes 01' More 6 7 13 Client: TRIG Project: Report Run Date and Time: 11/11/2013 11:58:00 AM Page 1 of TABLE 1.3 SURVEY PARTICIPANT SCREENING RESULTS Eligible and Complete Respondents Question Question 1: Do you agree to take part in this survey? Yes 346 99.7 302 100.0 No ?1 1 0.3 Question 2: Within the last 4 months, have you ?lled a prescription for yourself for a transmucosal immediate release fentanyl medicine (known as medicines?)? TIRF medicines include Abstral?, Actiq?, Fentora?, Lazanda?, Onsolis?, Subsys?, and the generic versions of any of these brands. Yes 330 95.1 301 99don't know 2 0.6 0 0.0 Question not asked 1 0.3 0 0.0 Question 3: Are you a caregiver for someone who has ?lled a prescription for a TIRF medicine within the last 4 months? As a reminder, TIRF medicines include Abstral?, Actiq?, Fentora?, Lazanda?, Onsolis?, Subsys?, and the generic versions of any of these brandsdon't know 0 0.0 Question not asked 331 95.4 Question 5: Have you ever taken part in a survey about a TIRF medicine before? Yes ?1 16 4.6 No 304 87.6 302 100.0 I don't know 11 3.2 Question not asked 16 4.6 Client: TRIG Project: TIRF Wave 2 Report Run Date and Time: 11/11/2013 4:18:00 PM Page 1 of 3 All Respondents and Complete Res ondents Question 13:3? Question 6: Which of the following groups best describes your age? Under 20.2 70 23.2 50?59 126 36.3 126 41.7 60? 69 60 17.3 59 19.5 70 or older 15 4.3 15 5.0 Prefer not to answer 0 0.0 Question not asked 43 12.4 Question 7: Which of the following groups best describes the patient?s age? (Caregivers, only) Under older 0 0.0 0 0.0 Prefer not to answer 0 0.0 Question not asked 346 99.7 Client: TRIG Project: TIRF Wave 2 Report Run Date and Time: 11/11/2013 4:18:00 PM Page 2 of 3 All Res ondents Eligible and Complete N=p347 Respondents Question Question 8: Have you or any of your immediate family members ever worked for any of the following companies or agencies? Please select all that apply!? Anesta LLC ?1 0 0.0 Archimedes Phaima US Inc? 0 0.0 Cephalon. Inc. (a wholly-owned 0 0.0 subsidiary of Teva [lilliannaceutical Industries. Ltd.) Endo Phannaceuticals Inc. 0 0.0 Galena BioPhanna 0 0.0 Insys Therapeutics 0 0.0 Mallinckrodtm 0 0.0 McKesson Specialty Care 0 0.0 Solutions Meda Pharmaceuticals 0 0.0 Mylan. Inc.[? 0 0.0 Par Pharmaceutical. Inc.? 0 0.0 ProStrakan. Inc. ?1 0 0.0 RelayHealth 0 0.0 Teva Phannaceuticals. Ltd. 1 0.3 United BioSource Corporation 0 0.0 FDA (Food and 0 0.0 Administration) No [41 302 87.0 302 100.0 I don?t know 1 0.3 Ineligible to participate in the smvey. Question not asked due to a previous question elimination. More than one response can be selected. so percentages may not sum to 100%. Ineligible if selected in addition to another response. Client: TRIG Project: TIRF WaveZ Report Run Date and Time: 11/11/2013 4:18:00 PM Page 3 of 3 TABLE 2 DESCRIPTION OF SURVEY COMPLETERS Patients Caregivers Question N=l Question 4: For which TIRF medicines have you ?lled a prescription in the last 4 months? Please select all that apply. Abstral 2 0.7 0 0.0 2 0.7 Actiq. including 117 38.9 0 0.0 117 38.7 generic versions of Actiq Fentora 107 35.5 0 0.0 107 35.4 Lazanda 2 0.7 0 0.0 2 0.7 Onsolis 0 0.0 0 0.0 0 0.0 Subsys 87 28.9 1 100.0 88 29.1 Other don?t know 2 0.7 0 0.0 2 0.7 Question 6: Which of the following groups best describes your age1.7 30?23.3 0 0.0 70 23.2 50?59 126 41.9 0 0.0 126 41.7 60?69 58 19.3 1 100.0 59 19.5 70 or older 15 5.0 0 0.0 15 5.0 Question 36: What is your gender? Male 116 38.5 1 100.0 117 38.7 Female 184 61.1 0 0.0 184 60.9 Prefer not to answer 1 0.3 0 0.0 1 0.3 Client: TRIG Project: TIRF Wave2 Report Run Date and Time: 11/12/2013 10:24:00 AM Page 1 of 3 Patients Patients Caregivers . Caregivers Question N-301 N?l Question 37: What is the highest level of education you have completed? Less than high school 2 0.7 0 0.0 2 0.7 Some high school 6 2.0 0 0.0 6 2.0 High school 50 16.6 0 0.0 50 16.6 graduate/GED Some 140 46.5 1 100.0 141 46.7 college/Associate?s degree Bachelor?s degree 53 17.6 0 0.0 53 17.5 Master?s degree 29 9.6 0 0.0 29 9.6 Professional or 20 6.6 0 0.0 20 6.6 Doctoral degree Prefer not to answer 1 0.3 0 0.0 1 0.3 Question 38: What is the main language you speak at home? (Please select only one.) English 299 99.3 1 100.0 300 99.3 French 0 0.0 0 0.0 0 0.0 Spanish 0 0.0 0 0.0 0 0.0 Portuguese 0 0.0 0 0.0 0 0.0 Italian 0 0.0 0 0.0 0 0.0 German 0 0.0 0 0.0 0 0.0 Chinese 0 0.0 0 0.0 0 0.0 Japanese 0 0.0 0 0.0 0 0.0 Korean 0 0.0 0 0.0 0 0.0 Other 1 0.3 0 0.0 1 0.3 Prefer not to answer 1 0.3 0 0.0 1 0.3 Question 39: Are you Hispanic or Latino290 96.3 1 100.0 291 96.4 Prefer not to answer 6 2.0 0 0.0 6 2.0 Client: TRIG Project: TIRF Wave2 Report Run Date and Time: 11/12/2013 10:24:00 AM Page 2 of 3 Patients Caregivers Patients 8:1] . N=l Caregivers Question Question 40: For informational purposes only, which of the following US. census categories best describes your race? (Please select only one.) American Indian or 5 1.7 0 0.0 5 1.7 Alaska Native Asian (origins 1.3 East. Southeast Asia or the Indian subcontinent) Black or African 13 4.3 0 0.0 13 4.3 American Native Hawaiian or 0 0.0 0 0.0 0 0.0 Other Paci?c Islander White 266 88.4 1 100.0 267 88.4 Other 4 1.3 0 0.0 4 1.3 Prefer not to answer 9 3.0 0 0.0 9 3.0 Geographic Distribution (based on Question 41 State or US Territory) Northeast 113 37.5 0 0.0 113 37.4 Midwest 24 8.0 0 0.0 24 7.9 South 132 43.9 1 100.0 133 44.0 West 31 10.3 0 0.0 31 10.3 Other 0 0.0 0 0.0 0 0.0 Prefer not to answer 1 0.3 0 0.0 1 0.3 Number of eligible respondents completing the survey (See Table Census Bureau. last revised Friday. 27-Jul-2001 12:59:43 EDT.. Geography Division. Northeast includes CT. MA. ME. NH. NJ. NY. PA. RI. and VT. Midwest includes IA. IL. IN. KS. MI. MN. MO. ND. NE. OH. SD. and W1. South includes AL. AR. DC. DE. FL. GA. KY. LA. MD. MS. NC. OK. SC. TN. TX. VA. and WV. West includes AK. AZ. CA. CO HI. ID. MT. NM. NV. OR. UT. WA. and WY. The following US territories are categorized as Other: Puerto Rico. Northern Mariana Islands. US Virgin Islands. American Samoa. and Guam. Client: TRIG Project: TIRF Wave 2 Report Run Date and Time: 11/12/2013 10:24:00 AM Page 3 of 3 TABLE 3 RESPONSES TO ALL QUESTIONS ABOUT THE SAFE USE OF TIRF MEDICINES Patients Caregivers Patients 8{1] . N=l Caregivers Question Subsys?, and the generic versions of these brands. Question 9: Did the doctor, nurse, or other healthcare professional in the doctor?s of?ce ever talk to you about the risks and possible side effects of the TIRF medicine that was most recently prescribed for you? TIRF medicines include Abstral?, Actiq?, Fentora?, Lazanda?, 0nsolis?, Yes 258 85.7 1 100.0 259 85.8 No 36 12.0 0 0.0 36 11.9 I don't know 7 2.3 0 0.0 7 2.3 Question 10: For which of the following conditions should I use a TIRF medicine? 10a: Headache or migraine pain No [21 233 77.4 1 100.0 234 77don't know 43 14.3 0 0.0 43 14.2 10b: Breakthrough pain from cancer Yes [21 193 64.1 1 100.0 194 64.2 No 90 29.9 0 0.0 90 29.8 I don't know 18 6.0 0 0.0 18 6.0 10c: Dental pain No [21 263 87.4 1 100.0 264 87don't know 29 9.6 0 0.0 29 9.6 10d: Pain after surgery No [21 206 68.4 1 100.0 207 68.5 Yes 52 17.3 0 0.0 52 17.2 I don't know 43 14.3 0 0.0 43 14.2 Client: TRIG Project: TIRF Wave 2 Report Run Date and Time: 11/12/2013 11:58:00 AM Page 1 of 5 Patients Caregivers Patients 8:1] - N=l Caregivers Question 10e: Long?lasting painful conditions not caused by cancer No [21 65 21.6 1 100.0 66 21.9 Yes 210 69.8 0 0.0 210 69.5 I don't know 26 8.6 0 0.0 26 8.6 Question 11: Please answer True, False, or I don?t know for the following statement: TIRF medicines should only be taken by patients who are opioid tolerant. True [21 276 91.7 1 100.0 277 91.7 False don't know 20 6.6 0 0.0 20 6.6 Question 12: Please answer True, False, or I don?t know for the following statements: 12a: Opioid tolerant means that a patient is already taking other opioid pain medicines around? the-clock and their body is used to these medicines. True [21 266 88.4 1 100.0 267 88.4 False don't know 23 7.6 0 0.0 23 7.6 12b: If a patient stops taking around-the-clock opioid pain medicine, they must also stop taking the TIRF medicine. True [21 102 33.9 1 100.0 103 34.1 False 87 28.9 0 0.0 87 28.8 1 don't know 112 37.2 0 0.0 112 37.1 12c: It is safe to switch to another medicine that contains fentanyl without talking to a healthcare provider ?rst. False [21 284 94.4 1 100.0 285 94.4 True don't know 9 3.0 0 0.0 9 3.0 Client: TRIG Project: TIRF Wave 2 Report Run Date and Time: 11/12/2013 11:58:00 AM Page 2 of 5 Patients Caregivers Patlents 8:1] N=l Caregivers Question 12d: A patient may give TIRF medicines to another person if they have the same as the patient. False ?1 295 98.0 1 100.0 296 98.0 True don't know 1 0.3 0 0.0 1 0.3 Question 13: Please answer True, False, or I don?t know for each statement about the TIRF medicine that was most recently prescribed for you. 13a: TIRF medicines should be stored in a safe place out of the reach of children. True 301 100.0 1 100.0 302 100.0 False don't know 0 0.0 0 0.0 0 0.0 13b: It is OK for patients to take TIRF medicines for headache pain. False ?1 205 68.1 1 100.0 206 68don't know 75 24.9 0 0.0 75 24.8 13c: TIRF medicines should be taken exactly as prescribed by the doctor. True [21 300 99.7 1 100.0 301 99.7 False don't know 1 0.3 0 0.0 1 0.3 13d: TIRF medicines can cause life?threatening breathing problems that can lead to death. True 271 90.0 1 100.0 272 90.1 False don't know 30 10.0 0 0.0 30 9.9 Client: TRIG Project: TIRF Wave2 Report Run Date and Time: 11/12/2013 11:58:00 AM Page 3 of 5 Question Patients Caregivers N=l Patients Caregiversm Question 14: What should you do if an adult who has not been prescribed a TIRF medicine takes a TIRF medicine? (Please select one.) Get emergency help 263 87.4 1 100.0 264 87.4 right away. Wait an hour and see if 17 5.6 0 0.0 17 5.6 the person is OK. Do nothingdon't know 19 6.3 0 0.0 19 6.3 Question 15: Did the doctor, nurse, or other healthcare professional in the doctor?s office ever tell you how to use the TIRF medicine that was most recently prescribed for Yes 280 93.0 1 100.0 281 93don't know 2 0.7 0 0.0 2 0.7 Question 16: Did the doctor, nurse, or other healthcare professional in the doctor?s of?ce ever tell you how to store or keep the TIRF medicine that was most recently prescribed for you? Yes 240 79.7 1 100.0 241 79.8 No 52 17.3 0 0.0 52 17.2 I don't know 9 3.0 0 0.0 9 3.0 Question 17: Please answer True, False, or I don?t know for each statement about the TIRF medicine that was most recently prescribed for you. 17a: Selling or giving away TIRF medicines is against the law. True [21 296 98.3 1 100.0 297 98.3 False don't know 3 1.0 0 0.0 3 1.0 17b: It is OK to take TIRF medicines for short?term pain that will go away in a few days. False ?1 251 83.4 1 100.0 252 83.4 True don't know 35 11.6 0 0.0 35 11.6 Client: TRIG Project: TIRF WaveZ Report Run Date and Time: 11/12/2013 11:58:00 AM Page 4 5 Patients Patients Caregivers . - N=l Caregivers Question 17c: TIRF medicines must be disposed of as described in the speci?c product?s Medication Guide. True [21 284 94.4 1 100.0 285 94.4 False don't know 17 5.6 0 0.0 17 5.6 17d: TIRF medicines are only available to patients through a special program (called the TIRF REMS Access program). True [21 147 48.8 0 0.0 147 48.7 False 33 11.0 0 0.0 33 10.9 I don't know 121 40.2 1 100.0 122 40.4 l7e: A TIRF medicine can cause an overdose and death in any child who takes it. True [21 274 91.0 1 100.0 275 91.1 False don?t know Nmnber of eligible respondents completing the sm'vey (See Table Conect response Client: TRIG Project: Report Run Date and Time: 11/12/2013 11:58:00 AM Page 5 of 5 TABLE 4 RESPONSES TO QUESTIONS ABOUT TIRF MEDICATION GUIDES Patients Caregivers CPatlents areglvers Question N-301 N?l Question 18: Have ever received a Medication Guide for the TIRF medicine that was prescribed for you Yes 282 93.7 1 100.0 283 93don't know 12 4.0 0 0.0 12 4.0 medicine or someone in the doctor?s of?ce? [21 Question 19: Did receive the Medication Guide from the doctor who prescribed the TIRF Yes 149 52.8 1 100.0 150 53.0 No 115 40.8 0 0.0 115 40.6 I don't know 18 6.4 0 0.0 18 6.4 (answered No or I 19 0 19 don?t know to Question 18) Question 20: When was the Medication Guide given to you? Please select all that apply. At the inst 116 77.9 1 100.0 117 78.0 appointment with the doctor who prescribed the TIRF medicine At the last appointment 24 16.1 0 0.0 24 16.0 with the doctor who prescribed the TIRF medicine I don?t remember 22 14.8 0 0.0 22 14.7 (answered No or I 152 0 152 don?t know to Question know to Question 19) Client: TRIG Project: TIRF Wave 2 Report Run Date and Time: 11/12/2013 1:38:00 PM Page 1 of 5 Question Patients Caregivers N=l Patients Caregiversm Question 21: Did you receive the Medication Guide for the TIRF medicine from the pharmacy?? Yes 253 89.7 1 100.0 254 89don't know 5 1.8 0 0.0 5 1.8 (answered No or I 19 0 19 don?t know to Question 1 8) Question 22: How frequently do receive a Medication Guide for the TIRF medicine at the pharmacy? Only with the ?rst 12 4.7 0 0.0 12 4.7 ?lled prescription Each time a 227 89.7 1 100.0 228 89.8 prescription is ?lled Other (please 6 2.4 0 0.0 6 2.4 specify)[3] I don?t know 8 3.2 0 0.0 8 3.1 (answered No or I 48 0 48 don?t know to Question know to Question 21) Question 23: Did you read the Medication Guide? Yes 267 94.7 1 100.0 268 94don't know 2 0.7 0 0.0 2 0.7 (answered No or I 19 0 19 don?t know to Question 1 8) Client: TRIG Project: TIRF WaveZ Report Run Date and Time: 11/12/2013 1:38:00 PM Page 2 5 Patients Caregivers Question N=l Question 24: How much did you read? All ofit 169 62.8 1 100.0 170 63.0 Most of it 78 29.0 0 0.0 78 28.9 Some don't know 3 1.1 0 0.0 3 1.1 (answered No or I 32 0 32 don?t know to Question know to Question 23) Question 25: How much of the Medication Guide did you understand? All of it 126 46.8 0 0.0 126 46.7 Most of it 124 46.1 1 100.0 125 46.3 Some of it 18 6.7 0.0 18 6.7 None don't know 0 0.0 0 0.0 0 0.0 (answered No or I 32 0 32 don?t know to Question know to Question 23) Question 26: Did someone offer to explain the Medication Guide to you? I 1 Yes 173 61.3 1 100.0 174 61.5 No 96 34.0 0 0.0 96 33.9 I don't know 13 4.6 0 0.0 13 4.6 (answered No or I 19 0 19 don?t know to Question 18) Client: TRIG Project: TIRF WaveZ Report Run Date and Time: 11/12/2013 1:38:00 PM Page 3 of 5 Patients Caregivers Patients Caregiversm Question N=l Question 27: Who offered to explain the Medication Guide to you? (Select all that apply.) The doctor or another 113 65.3 1 100.0 114 65.5 healthcare professional in the doctor?s of?ce The pharmacist where 146 84.4 1 100.0 147 84.5 the TIRE medicine prescription was ?lled Someone else (specify 10 5.8 0 0.0 10 5.7 the type of person but not his/her na111e)[4] (answered No or I 128 0 128 don?t know to Question know to Question 26) Question 28: Did you accept the offer to have the Medication Guide explained to you? 2] Yes 110 63.6 1 100.0 111 63.8 No 61 35.3 0 0.0 61 35.1 I don't know 2 1.2 0 0.0 2 1.1 (answered No or I 128 0 128 don?t know to Question know to Question 26) Client: TRIG Project: TIRF Wave2 Report Run Date and Time: 11/12/2013 1:38:00 PM Page 4 of 5 Patients Patients Caregivers Caregiversm Question Question 29: How much of the explanation did you understand? All of it 81 73.6 0 0.0 81 73.0 Most of it 27 24.5 1 100.0 28 25.2 Some 1.8 None don't know 0 0.0 0 0.0 0 0.0 (answered No or I 191 0 191 don?t know to Question know to Question 26 or No or I don?t know to Question 28) Question 30: Did you or do you have any questions about the information in the Medication Guide? ?21 Yesm 266 94.3 1 100.0 267 94.3 I don't know 1 0.4 0 0.0 1 0.4 (answered No or I 19 0 19 don?t know to Question 18) Number of eligible respondents completing the sun'ey (See Table 1). Percentages are calculated based on the sample presented with this question because of skip logic in the sun'ey. Verbatim texts for other time receiving Medication Guide from the pharmacy are presented in Listing 1. Verbatim texts for other persons offering to explain the Medication Guide are presented in Listing 2. 3 Questions about the information in the Medication Guide (Question 30) are presented in Listing . Client: TRIG Project: TIRF Wave2 Report Run Date and Time: 11/12/2013 1:38:00 PM Page 5 of 5 TABLE 5 RESPONSES TO QUESTIONS ABOUT THE PATIENT-PRESCRIBER AGREEMENT FORM Patients Caregivers Patients 8:1] Caregivers Question N-301 N?l Question 32: Did the doctor or someone in your doctor?s of?ce explain the Patient-Prescriber Agreement Form to you? Yes 222 73.8 1 100.0 223 73.8 No 43 14.3 0 0.0 43 14.2 I don't know 36 12.0 0 0.0 36 11.9 Question 33: How much of the explanation did you understand? All of it 174 78.4 1 100.0 175 78.5 Most of it 42 18.9 0 0.0 42 18.8 Some ofit 4 1.8 0 0.0 4 1.8 None don't know 1 0.5 0 0.0 1 0.4 (answered No or I 79 0 79 don?t know to Question 32) Question 34: Did sign a Patient-Prescriber Agreement Form? Yes 221 73.4 1 100.0 222 73don't know 65 21.6 0 0.0 65 21.5 Question 35: Did the doctor or someone in the doctor?s of?ce give you a copy of the signed Patient?Prescriber Agreement Form? Yes 150 67.9 1 100.0 151 68.0 No 38 17.2 0 0.0 38 17.1 I don't know 33 14.9 0 0.0 33 14.9 (answered No or I 80 0 80 don?t know to Question 34) Number of eligible respondents completing the survey (See Table Percentages are calculated based on the sample presented with this question because of skip logic in the sm'vey. Client: TRIG Project: TIRF WaveZ Report Run Date and Time: 11/12/2013 1:52:00 PM Page 1 of TABLE 6.1 PRIMARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #1 KEY RISK MESSAGE 1: TIRF MEDICINES CAN CAUSE LIFE-THREATENING BREATHING PROBLEMS THAT CAN LEAD TO DEATH. Patients Caregivers Patients 8f? N=l Caregivers Question (95% CI) (95% CI) (95% CD Question 13: Please answer True, False, or I don?t know for each statement about the TIRF medicine that was most recently prescribed for you. 13d: TIRF medicines can cause life?threatening breathing problems that can lead to death. 90.0 100.0 90.1 True [21 271 (86.1. 1 (2.5. 272 (86.1. 93.2) 100.0) 93.2) False don't know 30 10.0 0 0.0 30 9.9 Number of eligible respondents completing the sun'ey (See Table 1). Correct Response Client: TRIG Project: Report Run Date and Time: 11/7/2013 4:23:00 PM Page 1 of TABLE 6.1.1 PRIMARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #1 KEY RISK MESSAGE 1: TIRF MEDICINES CAN CAUSE LIFE-THREATENING BREATHING PROBLEMS THAT CAN LEAD TO DEATH. SUB-GROUP ANALYSIS 1: READING MEDICATION GUIDE (QUESTION 18, 23 AND 24) S-la - Respondents who received the Medication Guide and read at least most of it S-lb - Respondents who did not receive a Medication Guide or answered don?t know? or who received a Medication Guide and read only some of it or answered don?t know?. S-la S?lb . Read some or none of Read most of Med Gmde Med Guide Question (95% CI) (95% c1) Question 13: Please answer True, False, or I don?t know for each statement about the TIRF medicine that was most recently prescribed for you. 13d: TIRF medicines can cause life?threatening breathing problems that can lead to death. 94.4 70.4 True 234 (90.7. 96.9) 38 (56.4. 82.0) False 0 0.0 0 0.0 I don't know 14 5.6 16 29.6 COITCCT Client: TRIG Project: TIRF Wave2 Report Run Date and Time: 10/31/2013 12:28:00 PM Page 1 of TABLE 6.1.2 PRIMARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #1 KEY RISK MESSAGE l: TIRF MEDICINES CAN CAUSE LIFE-THREATENING BREATHING PROBLEMS THAT CAN LEAD TO DEATH. SUB-GROUP ANALYSIS 2: UNDERSTANDING OF MEDICATION GUIDE (QUESTION 25) S-2a - Respondents who understood all of it or most of it S-2b Respondents who understood some of it 0 S-2c Respondents who answered None or don?t know? 0 S-2d - Respondents who answered don?t know? to receipt or reading of the Medication Guide. Question S?2d S-2a 2b S-2c Did not Get or Understood All - None/I don't Read Understood Some . . or Most know Medication N=l Guide (95% CI) (95% CI) (95% CI) (95% CI) Question 13: Please answer True, False, or I don?t know for each statement about the TIRF medicine that was most recently prescribed for you. 13d: TIRF medicines can cause life-threatening breathing problems that can lead to death. 94.0 83.3 100.0 62.5 Tm" 236 (90.3. 96.6) 15 (58.6. 96.4) 1 (2.5. 100.0) 20 (43.7. 78.9) False don't know 15 6.0 3 16.7 0 0.0 12 37.5 COITCCI Client: TRIG Project: TIRF Wave2 Report Run Date and Time: 11/11/2013 4:57:00 PM Page 1 of TABLE 6.1.3 PRIMARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #1 KEY RISK MESSAGE l: TIRF NIEDICINES CAN CAUSE LIFE-THREATENING BREATHING PROBLEMS THAT CAN LEAD TO DEATH. SUB-GROUP ANALYSIS 3: TIME TO COMPLETE SURVEY - INTERNET: S-3a - <10 min 0 S-3b - 10 to<20 min 0 S-3c - 220 min S-3a S-3b S-3c <10 min 10 to <20 min 220 min Question (95% CI) (95% CI) (95% CI) Question 13: Please answer True, False, or I don?t know for each statement about the TIRF medicine that was most recently prescribed for you. 13d: TIRF medicines can cause life-threatening breathing problems that can lead to death. 87.2 91.0 92.9 True ?1 41 (74.3. 91 (83.6. 26 (76.5. 95.2) 95.8) 99.1) False 0 0.0 0 0.0 0 0.0 Idon't know 6 12.8 9 9.0 2 7.1 COITCCI Client: TRIG Project: TIRF Wave 2 Report Run Date and Time: 11/8/2013 11:39:00 AM Page 1 of TABLE 6.1.4 PRIMARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #1 KEY RISK MESSAGE l: TIRF NIEDICINES CAN CAUSE LIFE-THREATENING BREATHING PROBLEMS THAT CAN LEAD TO DEATH. SUB-GROUP ANALYSIS 4: TIME TO COMPLETE SURVEY - TELEPHONE: S-4a - <10 min 0 S-4b - 10 to<20 min 0 S-4c - 220 min S-4a s41? S?4c <10 min 10 to <20 min 220 min (95% CI) (95% CI) (95% CI) Question 13: Please answer True, False, or I don?t know for each statement about the TIRF medicine that was most recently prescribed for you. 13d: TIRF medicines can cause life-threatening breathing problems that can lead to death. 87.5 93.6 True ?1 0 0.0 70 (78.2. 44 (82.5. 93.8) 98.7) False don't know 0 0.0 10 12.5 3 6.4 COITCCI Client: TRIG Project: TIRF Wave 2 Report Run Date and Time: 11/11/2013 5:09:00 PM Page 1 of TABLE 6.1.5 PRIMARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #1 KEY RISK MESSAGE l: TIRF NIEDICINES CAN CAUSE LIFE-THREATENING BREATHING PROBLEMS THAT CAN LEAD TO DEATH. SUB-GROUP ANALYSIS 5: MODALITY TO COMPLETE SURVEY: Internet 0 S-5b Telephone Question S?5a S?5b Internet Telephone (95% CI) (95% CI) Question 13: Please answer True, False, or I don?t know for each statement about the TIRF medicine that was most recently prescribed for you. 13d: TIRF medicines can cause life?threatening breathing problems that can lead to death. 90.3 89.8 True 158 (84.9. 94.2) ?4 (83.1. 94.4) False 0 0.0 0 0.0 I don't know 17 9.7 13 10.2 COITCCI Client: TRIG Project: TIRF Wave2 Report Run Date and Time: 11/7/2013 11:09:00 AM Page 1 of TABLE 6.1.6 PRIMARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #1 KEY RISK MESSAGE l: TIRF MEDICINES CAN CAUSE LIFE-THREATENING BREATHING PROBLEMS THAT CAN LEAD TO DEATH. SUB-GROUP ANALYSIS 6: HIGHEST LEVEL OF EDUCATION (QUESTION 37): S-6a - Less than, Some, or High school graduate/GED or prefer not to answer S-6b - Some college or associate degree S-6c - Bachelor?s degree or Master?s degree S-6d - Professional or Doctoral degree Question S-6a S?6b S?6c S?6d High School Some college Bachelor or Master Doctoral degree N=14l (95% CI) (95% Cl) (95% CI) (95% CI) Question 13: Please answer True, False, or I don?t know for each statement about the TIRF medicine that was most recently prescribed for you. 13d: TIRF medicines can cause life-threatening breathing problems that can lead to death. 79.7 92.2 92.7 95.0 me 47 (67.2. 89.0) 130 (86.5. 96.0) 76 (84.8. 97.3) 19 (75.1. 99.9) False 0.0 Idon't know 12 20.3 11 7.8 6 7.3 1 5.0 onect response Client: TRIG Project: TIRF Wave2 Report Run Date and Time: 11/4/2013 4:23:00 PM Page 1 of TABLE 6.1.7 PRIMARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #1 KEY RISK MESSAGE l: TIRF MEDICINES CAN CAUSE LIFE-THREATENING BREATHING PROBLEMS THAT CAN LEAD TO DEATH. SUB-GROUP ANALYSIS 7: AGE GROUP OF RESPONDENT (QUESTION 6): S-7a 18 to 39 S-7b 40 to 49 S-7c 50 to 59 S-7d 60 or older Question S-7a S?7b S?7c S?older (95% CI) (95% CI) (95% CI) (95% CI) Question 13: Please answer True, False, or I don?t know for each statement about the TIRF medicine that was most recently prescribed for you. 13d: TIRF medicines can cause life?threatening breathing problems that can lead to death. 96.9 88.6 90.5 87.8 True 31 (83.8. 99.9) 62 (787.949) 114 (84.0. 95.0) 65 (78.2. 94.3) False don't know 1 3.1 8 11.4 12 9.5 9 12.2 ?1C01Tect response Client: TRIG Project: TIRF WaveZ Report Run Date and Time: 11/4/2013 4:26:00 PM Page 1 of TABLE 7.1 PRIMARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #2 KEY RISK MESSAGE 2: PATIENTS SHOULD NOT TAKE TIRF MEDICINES IF THEY ARE NOT OPIOID TOLERANT. Question Patients Caregivers Patients 8h] N=l Caregivers (95% CI) (95% CI) (95% CI) Question 11: Please answer True, False, or I don?t know for the following statement: TIRF medicines should only be taken by patients who are opioid tolerant. 91.7 100.0 91.7 True [21 276 (88.0. 1 (2.5. 277 (88.0. 94.6) 100.0) 94.6) False don't know 20 6.6 0 0.0 20 6.6 Question 12: Please answer True, False, or I don?t know for the following statements. 12a: Opioid tolerant means that a patient is already taking other opioid pain medicines around? the-clock and their body is used to these medicines. 88.4 100.0 88.4 True [21 266 (84.2. 1 (2.5. 267 (84.3. 91.8) 100.0) 91.8) False don't know 23 7.6 0 0.0 23 7.6 Question 13: Please answer True, False, or I don?t know for each statement about the TIRF medicine that was most recently prescribed for you. 13b: It is OK for patients to take TIRF medicines for headache pain. 68.1 100.0 68.2 False 205 (62.5. 1 (2.5. 206 (62.6. 73.3) 100.0) 73.4) True don't know 75 24.9 0 0.0 75 24.8 Number of eligible respondents completing the snn'ey (See Table 1). Correct response Client: TRIG Project: TIRF Wave2 Report Run Date and Time: 11/12/2013 12:00:00 PM Page 1 of TABLE 7.1.1 PRIMARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #2 KEY RISK MESSAGE 2: PATIENTS SHOULD NOT TAKE TIRF MEDICINES IF THEY ARE NOT OPIOID TOLERANT. SUB-GROUP ANALYSIS 1: READING MEDICATION GUIDE (QUESTION 18, 23 AND 24) S-la - Respondents who received the Medication Guide and read at least most of it S-lb - Respondents who did not receive a Medication Guide or answered don?t know? or who received a Medication Guide and read only some of it or answered don?t know?. S-la S?lb Read most of Med Guide 0f Question =54 ?Vo (95% CI) (95% CI) Question 11: Please answer True, False, or I don?t know for the following statement: TIRF medicines should only be taken by patients who are opioid tolerant. 92.7 87.0 True 230 (88.8. 95.6) 47 (75.1. 94.6) False 5 2.0 0 0.0 I don't know 13 5.2 7 13.0 Question 12: Please answer True, False, or I don?t know for the following statements. 12a: Opioid tolerant means that a patient is already taking other opioid pain medicines around- the-clock and their body is used to these medicines. 89.1 85.2 True 221 (84.6. 92.7) 46 (72.9. 93.4) False 12 4.8 0 0.0 I don't know 15 6.0 8 14.8 Client: TRIG Project: TIRF WaveZ Report Run Date and Time: 11/12/2013 11:59:00 AM Page 1 of 2 Question S?lb S?la Read some or none of Read most of Med Guide . Med Gmde =54 (95% CI) (95% CI) Question 13: Please answer True, False, or I don?t know for each statement about the TIRF medicine that was most recently prescribed for you. 13b: It is OK for patients to take TIRF medicines for headache pain. 71.0 55.6 False 176 (64.9. 76.5) 30 (41.4. 69.1) True 20 8.1 1 1.9 I don't know 52 21.0 23 42.6 Correct response Client: TRIG Project: TIRF Wave2 Report Run Date and Time: 11/12/2013 11:59:00 AM Page 2 of 2 TABLE 7.1.2 PRIMARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #2 KEY RISK MESSAGE 2: PATIENTS SHOULD NOT TAKE TIRF MEDICINES IF THEY ARE NOT OPIOID TOLERANT. SUB-GROUP ANALYSIS 2: UNDERSTANDING OF MEDICATION GUIDE (QUESTION 25) S-2a - Respondents who understood all of it or most of it S-2b Respondents who understood some of it S-2c Respondents who answered None or don?t know? 0 S-2d - Respondents who answered don?t know? to receipt or reading of the Medication Guide. S?2d S-2a 2b S-2c Did not Get or Understood All None/I don't Read Understood Some . . or Most know Medication Question Guide (95% CI) (95% CI) (95% CI) (95% CI) Question 11: Please answer True, False, or I don?t know for the following statement: TIRF medicines should only be taken by patients who are opioid tolerant. 92.8 83.3 100.0 87.5 True ?1 233 (88.9. 15 (58.6. 1 (2.5. 28 (71.0. 95.7) 96.4) 100.0) 96.5) False don't know 13 5.2 3 16.7 0 0.0 4 12.5 Client: TRIG Project: TIRF Wave2 Report Run Date and Time: 11/12/2013 12:01:00 PM Page 1 of 2 Question S-2d S?2a S?2b S?2c Did not Get or Understood All Understood Some None/I don Read. or Most know Medication N=l Guide (95% CI) (95% Cl) (95% Cl) (95% CI) Question 12: Please answer True, False, or I don?t know for the following statements. 12a: Opioid tolerant means that a patient is already taking other opioid pain medicines around-the-clock and their body is used to these medicines. 88.8 83.3 100.0 87.5 True ?1 223 (84.3. 15 (58.6. 1 (2.5. 28 (71.0. 92.5) 96.4) 100.0) 96.5) False don't know 16 6.4 3 16.7 0 0.0 4 12.5 Question 13: Please answer True, False, or I don?t know for each statement about the TIRF medicine that was most recently prescribed for you. 13b: It is OK for patients to take TIRF medicines for headache pain. 70.9 44.4 62.5 False ?1 178 (64.9. 8 (21.5. 0 0.0 20 (43.7. 76.5) 69.2) 78.9) True don't know 53 21.1 9 50.0 1 100.0 12 37.5 Correct response Client: TRIG Project: TIRF Wave2 Report Run Date and Time: 11/12/2013 12:01:00 PM Page 2 of 2 TABLE 7.1.3 PRIMARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #2 KEY RISK MESSAGE 2: PATIENTS SHOULD NOT TAKE TIRF MEDICINES IF THEY ARE NOT OPIOID TOLERANT. SUB-GROUP ANALYSIS 3: TIME TO COMPLETE SURVEY - INTERNET: S-3a - <10 min 0 S-3b - 10 to<20 min 0 S-3c - 220 min S-3a S-3b S-3c <10 min 10 to <20 min 220 min ues?on (95% CI) (95% CI) (95% CI) Question 11: Please answer True, False, or I don?t know for the following statement: TIRF medicines should only be taken by patients who are opioid tolerant. 97.9 91.0 89.3 True 46 (88.7. 91 (83.6. 25 (71.8. 99.9) 95.8) 97.7) False don't know 1 2.1 6 6.0 2 7.1 Question 12: Please answer True, False, or I don?t know for the following statements. 12a: Opioid tolerant means that a patient is already taking other opioid pain medicines around? the?clock and their body is used to these medicines. 95.7 89.0 85.7 True 45 (85.5. 89 (81.2. 24 (67.3. 99.5) 94.4) 96.0) False don't know 1 2.1 7 7.0 2 7.1 Client: TRIG Project: TIRF Wave 2 Report Run Date and Time: 11/12/2013 11:59:00 AM Page 1 of 2 S?3a S?3b S?3c <10 min 10 to <20 min 220 min uestion (95% CI) (95% CI) (95% CI) Question 13: Please answer True, False, or I don?t know for each statement about the TIRF medicine that was most recently prescribed for you. 13b: It is OK for patients to take TIRF medicines for headache pain. 68.1 68.0 71.4 False 32 (52.9. 68 (57.9. 20 (51.3. 80.9) 77.0) 86.8) True don't know 12 25.5 26 26.0 8 28.6 Correct response Client: TRIG Project: TIRF Wave 2 Report Run Date and Time: 11/12/2013 11:59:00 AM Page 2 of 2 TABLE 7.1.4 PRIMARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #2 KEY RISK MESSAGE 2: PATIENTS SHOULD NOT TAKE TIRF MEDICINES IF THEY ARE NOT OPIOID TOLERANT. SUB-GROUP ANALYSIS 4: TIME TO COMPLETE SURVEY - TELEPHONE: S-4a - <10 min 0 S-4b - 10 to<20 min 0 S-4c - 220 min S-4a S-4b S-4c <10 min 10 to <20 min 220 min Question (95% CI) (95% CI) (95% CI) Question 11: Please answer True, False, or I don?t know for the following statement: TIRF medicines should only be taken by patients who are opioid tolerant. 93.8 85.1 True ?1 0 0.0 75 (86.0. 40 (71.7. 97.9) 93.8) False don't know 0 0.0 4 5.0 7 14.9 Question 12: Please answer True, False, or I don?t know for each of the following statements. 12a: Opioid tolerant means that a patient is already taking other opioid pain medicines around? the-clock and their body is used to these medicines. 90.0 78.7 True ?1 0 0.0 72 (81.2. 37 (64.3. 95.6) 89.3) False don't know 0 0.0 6 7.5 7 14.9 Client: TRIG Project: TIRF Wave 2 Report Run Date and Time: 11/11/2013 5:09:00 PM Page 1 of 2 Question S-4a S?4b S?4c <10 min 10 to <20 min 220 min (95% CI) (95% CI) (95% CI) Question 13: Please answer True, False, or I don?t know for each statement about the TIRF medicine that was most recently prescribed for you. 13b: It is OK for patients to take TIRF medicines for headache pain. 71.3 61.7 False ?1 0 0.0 57 (60.0. 29 (46.4. 80.8) 75.5) True 0 0.0 5 6.3 7 14.9 I don't know 0 0.0 18 22.5 11 23.4 Con'ect response Client: TRIG Project: TIRF Wave2 Report Run Date and Time: 11/11/2013 5:09:00 PM Page 2 of 2 TABLE 7.1.5 PRIMARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #2 KEY RISK MESSAGE 2: PATIENTS SHOULD NOT TAKE TIRF MEDICINES IF THEY ARE NOT OPIOID TOLERANT. SUB-GROUP ANALYSIS 5: MODALITY TO COMPLETE SURVEY: S-5a Internet 0 Telephone S?5a Internet Telephone Question (95% CI) (95% CI) Question 11: Please answer True, False, or I don?t know for the following statement: TIRF medicines should only be taken by patients who are opioid tolerant. 92.6 90.6 Tme 162 (87.6. 96.0) 115 (84.1. 95.0) False 4 2.3 1 0.8 I don't know 5.1 11 8.7 Question 12: Please answer True, False, or I don?t know for the following statements. 12a: Opioid tolerant means that a patient is already taking other opioid pain medicines around- the-clock and their body is used to these medicines. 90.3 85.8 True 158 (84.9. 94.2) 109 (78.5. 91.4) False 7 4.0 5 3.9 I don't know 10 5.7 13 10.2 Question 13: Please answer True, False, or I don?t know for each statement about the TIRF medicine that was most recently prescribed for you. 13b: It is OK for patients to take TIRF medicines for headache pain. 68.6 67.7 False 120 (61.1. 75.4) 86 (58.8. 75.7) True 9 5.1 12 9.4 I don't know 46 26.3 29 22.8 Con?ect response Client: TRIG Project: TIRF WaveZ Report Run Date and Time: 11/12/2013 12:01:00 PM Page 1 of TABLE 7.1.6 PRIMARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #2 KEY RISK MESSAGE 2: PATIENTS SHOULD NOT TAKE TIRF MEDICINES IF THEY ARE NOT OPIOID TOLERANT. SUB-GROUP ANALYSIS 6: HIGHEST LEVEL OF EDUCATION (QUESTION 37): S-6a - Less than, Some, or High school graduate/GED or prefer not to answer S-6b - Some college or associate degree S-6c - Bachelor?s degree or Master?s degree S-6d - Professional or Doctoral degree S?6a S-6b S?6c S?6d High School Some college Bachelor or Master Doctoral degree (95% CI) (95% CI) (95% CI) (95% CI) Question 11: Please answer True, False, or I don?t know for the following statement: TIRF medicines should only be taken by patients who are opioid tolerant. 86.4 92.2 93.9 95.0 True 51 (75.0. 94.0) 130 (86.5. 96.0) 77 (86.3. 98.0) 19 (75.1. 99.9) False don't know 8 13.6 9 6.4 2 2.4 1 5.0 Client: TRIG Project: TIRF Wave2 Report Run Date and Time: 11/12/2013 12:00:00 PM Page 1 of 2 Question S?6a S-6b S?6c S-6d High School Some college Bachelor or Master Doctoral degree (95% CI) (95% CI) (95% CI) (95% CI) Question 12: Please answer True, False, or I don?t know for the following statements. 12a: Opioid tolerant means that a patient is already taking other opioid pain medicines around-the-clock and their body is used to these medicines. 83.1 88.7 92.7 85.0 True 49 (71.0. 91.6) 125 (82.2. 93.4) 76 (84.8. 97.3) 17 (62.1. 96.8) False 10.0 I don?t know 7 11.9 11 7.8 4 4.9 1 5.0 Question 13: Please answer True, False, or I don?t know for each statement about the TIRF medicine that was most recently prescribed for you. 13b: It is OK for patients to take TIRF medicines for headache pain. 62.7 64.5 75.6 80.0 False 37 (49.1. 75.0) 91 (56.0. 72.4) 62 (64.9. 84.4) 16 (56.3. 94.3) True don't know 17 28.8 39 27.7 15 18.3 4 20.0 Correct response Client: TRIG Project: TIRF Wave2 Report Run Date and Time: 11/12/2013 12:00:00 PM Page TABLE 7.1.7 PRIMARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #2 KEY RISK MESSAGE 2: PATIENTS SHOULD NOT TAKE TIRF MEDICINES IF THEY ARE NOT OPIOID TOLERANT. SUB-GROUP ANALYSIS 7: AGE GROUP OF RESPONDENT (QUESTION 6): S-7a 18 to 39 S-7b 40 to 49 S-7c 50 to 59 S-7d 60 or older S-7a S?7b S?7c S?older (95% CI) (95% CI) (95% CI) (95% CI) Question 11: Please answer True, False, or I don?t know for the following statement: TIRF medicines should only be taken by patients who are opioid tolerant. 96.9 90.0 93.7 87.8 True 31 (83.8. 99.9) 63 (80.5. 95.9) ?8 (87.9. 97.2) 65 (78.2. 94.3) False don't know 10.8 Client: TRIG Project: TIRF Wave2 Report Run Date and Time: 11/12/2013 12:00:00 PM Page 1 of 2 S-7a S?7b S?7c S?older (95% CI) (95% CI) (95% CI) (95% CI) Question 12: Please answer True, False, or I don?t know for the following statements. 12a: Opioid tolerant means that a patient is already taking other opioid pain medicines around-the-clock and their body is used to these medicines. 93.8 90.0 88.9 83.8 True 30 (79.2. 99.2) 63 (80.5. 95.9) ?2 (82.1. 93.8) 62 (73.4. 91.3) False don?t know 13.5 Question 13: Please answer True, False, or I don?t know for each statement about the TIRF medicine that was most recently prescribed for you. 13b: It is OK for patients to take TIRF medicines for headache pain. 59.4 68.6 65.9 75.7 False 19 (40.6. 76.3) 48 (56.4. 79.1) 83 (56.9. 74.1) 56 (64.3. 84.9) True don't know 11 34.4 20 28.6 32 25.4 12 16.2 Correct response Client: TRIG Project: TIRF Wave 2 Report Run Date and Time: 11/12/2013 12:00:00 PM Page 2 of 2 TABLE 7.2 SECONDARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #2 KEY RISK MESSAGE 2: PATIENTS SHOULD NOT TAKE TIRF MEDICINES IF THEY ARE NOT OPIOID TOLERANT. Patients Caregivers Patients &[l]Caregivers Demonstrated Understanding 0 correct responses correct response correct responses 95 31.6 0 0.0 95 31.5 3 correct responses 179 59.5 1 100.0 180 59.6 Average nlunber of correct responses 2.5 (2.3. 3.0) 3.0 (0.2. 3.0) [21 2.5 (2.3. 3.0) Number of eligible respondents completing the survey (See Table One-sided 95 confidence inten?al using the normal approximation to the Poisson distribution. Client: TRIG Project: TIRF Wave 2 Report Run Date and Time: 11/7/2013 4:24:00 PM Page 1 of TABLE 7.2.1 SECONDARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #2 KEY RISK MESSAGE 2: PATIENTS SHOULD NOT TAKE TIRF MEDICINES IF THEY ARE NOT OPIOID TOLERANT. SUB-GROUP ANALYSIS 1: READING MEDICATION GUIDE (QUESTION 18, 23 AND 24) S-la - Respondents who received the Medication Guide and read at least most of it S-lb - Respondents who did not receive a Medication Guide or answered don?t know? or who received a Medication Guide and read only some of it or answered don?t know?. S-la S-lb Read most of Med Guide Read some or none of Demonstrated Understanding Med Guide 0 correct responses 6 2.4 1 1.9 1 correct response 14 5.6 6 11.1 2 conect responses 71 28.6 24 44.4 3 correct responses 157 63.3 23 42.6 Average number of correct responses 2.5 (2.4. 3.0) 2.3 (1.9. 3.0) One-sided 95 con?dence interval using the normal approximation to the Poisson distribution. Client: TRIG Project: TIRF Wave2 Report Run Date and Time: 11/7/2013 10:55:00 AM Page 1 of TABLE 7.2.2 SECONDARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #2 KEY RISK MESSAGE 2: PATIENTS SHOULD NOT TAKE TIRF MEDICINES IF THEY ARE NOT OPIOID TOLERANT. SUB-GROUP ANALYSIS 2: UNDERSTANDING OF MEDICATION GUIDE (QUESTION 25) S-2a - Respondents who understood all of it or most of it S-2b Respondents who understood some of it S-2c Respondents who answered None or don?t know? 0 S-2d - Respondents who answered don?t know? to receipt or reading of the Medication Guide. S-2a S-2b S-2c S-2d Understood All Understood Some None/I don't Did not Get or or Most know Read Demonstrated Understanding Medication Guide 0 correct responses con?ect response correct responses 72 28.7 11 61.1 1 100.0 11 34.4 3 correct responses 158 62.9 5 27.8 0 0.0 17 53.1 Average number of correct responses 2.5 (2.4. 3.0) "l 2.1 (1.5. 3.0) ?1 2.0 (-0.3. 2.4 (1.9. 3.0) One-sided 95 con?dence interval using the normal approximation to the Poisson distribution. Client: TRIG Project: TIRF Wave2 Report Run Date and Time: 11/8/2013 10:36:00 AM Page 1 of TABLE 7.2.3 SECONDARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #2 KEY RISK MESSAGE 2: PATIENTS SHOULD NOT TAKE TIRF MEDICINES IF THEY ARE NOT OPIOID TOLERANT. SUB-GROUP ANALYSIS 3: TIME TO COMPLETE SURVEY - INTERNET: 0 8-33 - <10 min 0 S-3b - 10 to<20 min 0 S-3c - 220 min S-3a Demonstrated Understanding 10 tloljgomin 0 correct responses correct response correct responses 16 34.0 34 34.0 8 28.6 3 correct responses 30 63.8 57 57.0 17 60.7 Average number of correct responses 2.6 (2.2. 3.0) 2.5 (2.2. 3.0) 2.5 (2.0. 3.0) One-sided 95 con?dence interval using the normal approximation to the Poisson distribution. Client: TRIG Project: TIRF Wave 2 Report Run Date and Time: 11/8/2013 11:40:00 AM Page 1 of TABLE 7.2.4 SECONDARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #2 KEY RISK MESSAGE 2: PATIENTS SHOULD NOT TAKE TIRF MEDICINES IF THEY ARE NOT OPIOID TOLERANT. SUB-GROUP ANALYSIS 4: TIME TO COMPLETE SURVEY - TELEPHONE: 0 8?43 - <10 min 0 S-4b - 10 to<20 min 0 S-4c - 220 min S-4a S-4b S-4c <10 min 10 to <20 min 220 min Demonstrated Understanding 0 correct responses correct response 0 0.0 2 2.5 6 12.8 2 correct responses 0 0.0 23 28.8 14 29.8 3 correct responses 0 0.0 52 65.0 24 51.1 Average number of correct responses 0 (0.0. 3.0) 2.6 (2.3. 2.3 (1.9. 3.0) "1 [ll One-sided 95 con?dence interval using the normal approximation to the Poisson distribution. Client: TRIG Project: TIRF Wave 2 Report Run Date and Time: 11/11/2013 5:11:00 PM Page 1 of TABLE 7.2.5 SECONDARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #2 KEY RISK MESSAGE 2: PATIENTS SHOULD NOT TAKE TIRF MEDICINES IF THEY ARE NOT OPIOID TOLERANT. SUB-GROUP ANALYSIS 5: MODALITY TO COMPLETE SURVEY: S-5a Internet 0 S-5b Telephone S-5a S-5b Demonstrated Understanding 11:23? nglizgne 0 conect responses 1 0.6 6 4.7 1 conect response 12 6.9 8 6.3 2 conect responses 58 33.1 37 29.1 3 conect responses 104 59.4 76 59.8 Average number of con?ect responses 2.5 (2.3. 3.0) 2.4 (2.2. 3.0) "1 One-sided 95 con?dence interval using the normal approximation to the Poisson distribution. Client: TRIG Project: Report Run Date and Time: 11/7/2013 12:49:00 PM Page 1 of TABLE 7.2.6 SECONDARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #2 KEY RISK MESSAGE 2: PATIENTS SHOULD NOT TAKE TIRF MEDICINES IF THEY ARE NOT OPIOID TOLERANT. SUB-GROUP ANALYSIS 6: HIGHEST LEVEL OF EDUCATION (QUESTION 37): S-6a - Less than, Some, or High school graduate/GED or prefer not to answer 0 S-6b - Some college or associate degree 0 S-6c - Bachelor?s degree or Master?s degree 0 S-6d - Professional or Doctoral degree S-6a S-6b S-6c S-6d High School Some college Bachelor or Master Doctoral degree Demonstrated Understanding N=l41 0 correct responses correct response 10.0 2 correct responses 28 47.5 42 29.8 21 25.6 4 20.0 3 correct responses 26 44.1 84 59.6 56 68.3 14 70.0 Average number of correct responses 2.3 (2.0. 3.0) ?1 2.5 (2.2. 3.0) "l 2.6 (2.3. 3.0) 2.6 (2.0. [ll One-sided 95 con?dence interval using the normal approximation to the Poisson distribution. Client: TRIG Project: TIRF WaveZ Report Run Date and Time: 11/7/2013 11:14:00 AM Page 1 of TABLE 7.2.7 SECONDARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #2 KEY RISK MESSAGE 2: PATIENTS SHOULD NOT TAKE TIRF MEDICINES IF THEY ARE NOT OPIOID TOLERANT. SUB-GROUP ANALYSIS 7: AGE GROUP OF RESPONDENT (QUESTION 6): S-7a 18 to 39 S-7b - 40 to 49 S-7c 50 to 59 S-7d 60 or older S-7a S-7b S-7c S-older Demonstrated 0 correct responses correct response 12.2 2 correct responses 14 43.8 23 32.9 43 34.1 15 20.3 3 correct responses 17 53.1 42 60.0 73 57.9 48 64.9 Average number of correct responses 2.5 (2.0. 3.0) "1 2.5 (2.2. 3.0) 2.5 (2.3. 3.0) ?1 2.5 (2.2. 3.0) One-sided 95 con?dence interval using the normal approximation to the Poisson distribution. Client: TRIG Project: TIRF Wave 2 Report Run Date and Time: 11/7/2013 11:17:00 AM Page 1 of TABLE 8.1 PRIMARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #3 RISK MESSAGE 3: TIRF MEDICINES SHOULD BE TAKEN EXACTLY AS PRESCRIBED BY THE HEALTHCARE PROVIDER. Question Patients Caregivers Patients 8h] N=l Caregivers (95% CI) (95% CI) (95% CI) Question 12: Please answer True, False, or I don?t know for the following statements. 12b: If a patient stops taking around-the-clock opioid pain medicine, they must also stop taking the TIRF medicine. 33.9 100.0 34.1 True [21 102 (28.6. 1 (2.5. 103 (28.8. 39.5) 100.0) 39.8) False 87 28.9 0 0.0 87 28.8 I don?t know 112 37.2 0 0.0 112 37.1 Question 13: Please answer True, False, or I don?t know for each statement about the TIRF medicine that was most recently prescribed for you. 13c: TIRF medicines should be taken exactly as prescribed by the doctor. 99.7 100.0 99.7 True [21 300 (98.2. 1 (2.5. 301 (98.2. 100.0) 100.0) 100.0) False don?t know 1 0.3 0 0.0 1 0.3 Question 17: Please answer True, False, or I don?t know for each statement about the TIRF medicine that was most recently prescribed for you. 17b: It is OK to take TIRF medicines for short-term pain that will go away in a few days. 83.4 100.0 83.4 False 121 251 (78.7. 1 (2.5. 252 (78.8. 87.4) 100.0) 87.5) True 15 5.0 0 0.0 15 5.0 Idon?t know 35 11.6 0 0.0 35 11.6 Number of eligible respondents completing the Siu'vey (See Table 1). Correct response Client: TRIG Project: TIRF WaveZ Report Run Date and Time: 11/12/2013 12:01:00 PM Page 1 of TABLE 8.1.1 PRIMARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #3 RISK MESSAGE 3: TIRF MEDICINES SHOULD BE TAKEN EXACTLY AS PRESCRIBED BY THE HEALTHCARE PROVIDER. SUB-GROUP ANALYSIS 1: READING MEDICATION GUIDE (QUESTION 18, 23 AND 24) S-la - Respondents who received the Medication Guide and read at least most of it S-lb - Respondents who did not receive a Medication Guide or answered don?t know? or who received a Medication Guide and read only some of it or answered don?t know?. la S?lb . Read some or none of Read most of Med Guide Med Guide Question (95% CI) (95% c1) Question 12: Please answer True, False, or I don?t know for the following statements. 12b: If a patient stops taking around?the?clock opioid pain medicine, they must also stop taking the TIRF medicine. 38.3 14.8 True 95 (32.2. 44.7) 8 (6.6. 27.1) False 74 29.8 13 24.1 I don't know 79 31.9 33 61.1 Question 13: Please answer True, False, or I don?t know for each statement about the TIRF medicine that was most recently prescribed for you. 13c: TIRF medicines should be taken exactly as prescribed by the doctor. 99.6 100.0 me 247 (97.8.1000) 54 (93.4. 100.0) False 0 0.0 0 0.0 I don't know 1 0.4 0 0.0 Client: TRIG Project: TIRF WaveZ Report Run Date and Time: 11/12/2013 12:04:00 PM Page 1 of Question S?lb S?la Read some or none of Read most of Med Guide . N-2 48 Med Gmde (95% CI) (95% CI) Question 17: Please answer True, False, or I don?t know for each statement about the TIRF medicine that was most recently prescribed for you. 17b: It is OK to take TIRF medicines for short-term pain that will go away in a few days. 86.3 70.4 False 214 (81.4. 90.3) 38 (56.4. 82.0) True 14 5.6 1 1.9 I don't know 20 8.1 15 27.8 Correct response Client: TRIG Project: TIRF Wave2 Report Run Date and Time: 11/12/2013 12:04:00 PM Page 2 of 2 TABLE 8.1.2 PRIMARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #3 RISK MESSAGE 3: TIRF MEDICINES SHOULD BE TAKEN EXACTLY AS PRESCRIBED BY THE HEALTHCARE PROVIDER. SUB-GROUP ANALYSIS 2: UNDERSTANDING OF MEDICATION GUIDE (QUESTION 25) S-2a - Respondents who understood all of it or most of it S-2b Respondents who understood some of it 0 S-2c Respondents who answered None or don?t know? 0 S-2d - Respondents who answered don?t know? to receipt or reading of the Medication Guide. S-2d S-2a S?2b S-2c Did not Get or Understood All None/I don't Read Understood Some . . . or Most know Medication Questlon Guide (95% CI) (95% CI) (95% CI) (95% CI) Question 12: Please answer True, False, or I don?t know for the following statements. 12b: If a patient stops taking around-the-clock opioid pain medicine, they must also stop taking the TIRF medicine. 37.1 27.8 15.6 True 93 (31.1. 43.4) 5 (9.7. 53.5) 0 0'0 5 (5.3. 32.8) False 77 30.7 2 11.1 0 0.0 8 25.0 I don't know 81 32.3 11 61.1 1 100.0 19 59.4 Client: TRIG Project: TIRF Wave2 Report Run Date and Time: 11/12/2013 12:02:00 PM Page 1 2 Question S?2d S?2a S-2b S?2c Did not Get or Understood All None/I don't Read Understood Some . . or Most N-18 know Medication Guide (95% CI) (95% CI) (95% CI) (95% CI) Question 13: Please answer True, False, or I don?t know for each statement about the TIRF medicine that was most recently prescribed for you. 13c: TIRF medicines should be taken exactly as prescribed by the doctor. me 250 (97.2.91 30.0) 18 (8115912000) 1 (2.51.0330) 3?2 False don't know 0.0 Question 17: Please answer True, False, or I don?t know for each statement about the TIRF medicine that was most recently prescribed for you. 17b: It is OK to take TIRF medicines for short?term pain that will go away in a few days. False 216 (81.859101) 14 (52:53.6) 0 0'0 22 (50.038839) True 12 4.8 2 11.1 0 0.0 1 3.1 I don't know 23 9.2 2 11.1 1 100.0 9 28.1 Correct response Client: TRIG Project: TIRF Wave2 Report Run Date and Time: 11/12/2013 12:02:00 PM Page 2 TABLE 8.1.3 PRIMARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #3 RISK MESSAGE 3: TIRF MEDICINES SHOULD BE TAKEN EXACTLY AS PRESCRIBED BY THE HEALTHCARE PROVIDER. SUB-GROUP ANALYSIS 3: TIME TO COMPLETE SURVEY - INTERNET: S-3a - <10 min 0 S-3b - 10 to<20 min 0 S-3c - 220 min Question S-3a S-3b S-3c <10 min 10 to <20 min 220 min (95% CI) (95% CI) (95% CI) Question 12: Please answer True, False, or I don?t know for the following statements. 12b: If a patient stops taking around?the?clock opioid pain medicine, they must also stop taking the TIRF medicine. 42.6 36.0 25.0 True ?1 20 (28.3. 36 (26.6. 7 (10.7. 57.8) 46.2) 44.9) False 9 19.1 29 29.0 10 35.7 Idon't know 18 38.3 35 35.0 11 39.3 Question 13: Please answer True, False, or I don?t know for each statement about the TIRF medicine that was most recently prescribed for you. 13c: TIRF medicines should be taken exactly as prescribed by the doctor. 100.0 100.0 100.0 True ?1 47 (92.5. 100 (96.4. 28 (87.7. 100.0) 100.0) 100.0) False don't know 0 0.0 0 0.0 0 0.0 Client: TRIG Project: TIRF Wave2 Report Run Date and Time: 11/12/2013 12:01:00 PM Page 1 of 2 S?3a S?3b S?3c <10 min 10 to <20 min 220 min uestion (95% CI) (95% CI) (95% CI) Question 17: Please answer True, False, or I don?t know for each statement about the TIRF medicine that was most recently prescribed for you. 17b: It is OK to take TIRF medicines for short?term pain that will go away in a few days. 89.4 87.0 78.6 False ?1 42 (76.9. 87 (78.8. 22 (59.0. 96.5) 92.9) 91.7) True don?t know 4 8.5 12 12.0 4 14.3 Correct response Client: TRIG Project: TIRF Wave 2 Report Run Date and Time: 11/12/2013 12:01:00 PM Page 2 of 2 TABLE 8.1.4 PRIMARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #3 RISK MESSAGE 3: TIRF MEDICINES SHOULD BE TAKEN EXACTLY AS PRESCRIBED BY THE HEALTHCARE PROVIDER. SUB-GROUP ANALYSIS 4: TIME TO COMPLETE SURVEY - TELEPHONE: S-4a - <10 min 0 S-4b - 10 to<20 min 0 S-4c - 220 min Question S-4a S-4b S-4c <10 min 10 to <20 min 220 min (95% CI) (95% CI) (95% CI) Question 12: Please answer True, False, or I don?t know for the following statements. 12b: If a patient stops taking around?the?clock opioid pain medicine, they must also stop taking the TIRF medicine. 35.0 25.5 True ?1 0 0.0 28 (24.7. 12 (13.9. 46.5) 40.3) False 0 0.0 21 26.3 18 38.3 I don't know 0 0.0 31 38.8 17 36.2 Question 13: Please answer True, False, or I don?t know for each statement about the TIRF medicine that was most recently prescribed for you. 13c: TIRF medicines should be taken exactly as prescribed by the doctor. 98.8 100.0 True ?1 0 0.0 79 (93.2. 47 (92.5. 100.0) 100.0) False don't know 0 0.0 1 1.3 0 0.0 Client: TRIG Project: TIRF WaveZ Report Run Date and Time: 11/12/2013 12:02:00 PM Page 1 of 2 S-4a S?4b S?4c <10 min 10 to <20 min 220 min (95% CI) (95% CI) (95% CI) Question 17: Please answer True, False, or I don?t know for each statement about the TIRF medicine that was most recently prescribed for you. 17b: It is OK to take TIRF medicines for short-term pain that will go away in a few days. 81.3 76.6 False ?1 0 0.0 65 (71.0. 36 (62.0. 89.1) 87.7) True 0 0.0 6 7.5 5 10.6 I don't know 0 0.0 9 11.3 6 12.8 Correct response Client: TRIG Project: TIRF Wave 2 Report Run Date and Time: 11/12/2013 12:02:00 PM Page 2 of 2 TABLE 8.1.5 PRIMARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #3 RISK MESSAGE 3: TIRF MEDICINES SHOULD BE TAKEN EXACTLY AS PRESCRIBED BY THE HEALTHCARE PROVIDER. SUB-GROUP ANALYSIS 5: MODALITY TO COMPLETE SURVEY: S-5a Internet 0 Telephone Question S?5b Internet Telephone N=l75 (95% CI) (95% CI) Question 12: Please answer True, False, or I don?t know for the following statements. 12b: If a patient stops taking around-the?clock opioid pain medicine, they must also stop taking the TIRF medicine. 36.0 31.5 Tm" 63 (28.9. 43.6) 40 (23.5. 40.3) False 48 27.4 39 30.7 I don't know 64 36.6 48 37.8 Question 13: Please answer True, False, or I don?t know for each statement about the TIRF medicine that was most recently prescribed for you. 13c: TIRF medicines should be taken exactly as prescribed by the doctor. 100.0 99.2 Tme 175 (97.9. 100.0) 126 (95.7. 100.0) False 0 0.0 0 0.0 I don't know 0 0.0 0.8 Question 17: Please answer True, False, or I don?t know for each statement about the TIRF medicine that was most recently prescribed for you. 17b: It is OK to take TIRF medicines for short-term pain that will go away in a few days. 86.3 79.5 False 151 (80.3. 91.0) 101 (71.5. 86.2) True 4 2.3 11 8.7 Idon't know 20 11.4 15 11.8 Correct response Client: TRIG Project: TIRF WaveZ Report Run Date and Time: 11/12/2013 12:02:00 AM Page 1 of TABLE 8.1.6 PRIMARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #3 RISK MESSAGE 3: TIRF MEDICINES SHOULD BE TAKEN EXACTLY AS PRESCRIBED BY THE HEALTHCARE PROVIDER. SUB-GROUP ANALYSIS 6: HIGHEST LEVEL OF EDUCATION (QUESTION 37): S-6a - Less than, Some, or High school graduate/GED or prefer not to answer 0 S-6b - Some college or associate degree 0 S-6c - Bachelor?s degree or Master?s degree 0 S-6d - Professional or Doctoral degree S?6a S?6b S?6c S?6d High School Some college Bachelor or Master Doctoral degree (95% CI) (95% CI) (95% CI) (95% CI) Question 12: Please answer True, False, or I don?t know for the following statements. 12b: If a patient stops taking around-the-clock opioid pain medicine, they must also stop taking the TIRF medicine. 33.9 39.0 25.6 35.0 True ?1 20 (22.1. 55 (30.9. 21 (16.6. 7 (15.4. 47.4) 47.6) 36.4) 59.2) False 15 25.4 40 28.4 24 29.3 8 40.0 I don't know 24 40.7 46 32.6 37 45.1 5 25.0 Client: TRIG Project: TIRF Wave 2 Report Run Date and Time: 11/12/2013 12:02:00 PM Page 1 of 2 Question S?6a S?6b S?6c S?6d High School Some college Bachelor or Master Doctoral degree N=l4l (95% CI) (95% CI) (95% CI) (95% CI) Question 13: Please answer True, False, or I don?t know for each statement about the TIRF medicine that was most recently prescribed for you. 13c: TIRF medicines should be taken exactly as prescribed by the doctor. 100.0 99.3 100.0 100.0 True ?1 59 (93.9. 140 (96.1. 82 (95.6. 20 (83.2. 100.0) 100.0) 100.0) 100.0) False don't know 0.0 Question 17: Please answer True, False, or I don?t know for each statement about the TIRF medicine that was most recently prescribed for you. 17b: It is OK to take TIRF medicines for short?term pain that will go away in a few days. 78.0 85.8 82.9 85.0 False ?1 46 (65.3. 121 (78.9. 68 (73.0. 17 (62.1. 87.7) 91.1) 90.3) 96.8) True don't know 10 16.9 15 10.6 7 8.5 3 15.0 Correct response Client: TRIG Project: TIRF Wave2 Report Run Date and Time: 11/12/2013 12:02:00 PM Page 2 TABLE 8.1.7 PRIMARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #3 RISK MESSAGE 3: TIRF MEDICINES SHOULD BE TAKEN EXACTLY AS PRESCRIBED BY THE HEALTHCARE PROVIDER. SUB-GROUP ANALYSIS 7: AGE GROUP OF RESPONDENT (QUESTION 6): S-7a 18 to 39 S-7b - 40 to 49 S-7c 50 to 59 S-7d 60 or older S?7a S?7b S?7c S?older (95% CI) (95% CI) (95% CI) (95% CI) Question 12: Please answer True, False, or I don?t know for the following statements. 12b: If a patient stops taking around-the-clock opioid pain medicine, they must also stop taking the TIRF medicine. 37.5 32.9 34.1 33.8 True 12 (21.1. 56.3) 23 (22.1. 45.1) 43 (25.9. 43.1) 25 (23.2. 45.7) False 8 25.0 22 31.4 39 31.0 18 24.3 I don't know 12 37.5 25 35.7 44 34.9 31 41.9 Client: TRIG Project: TIRF Wave 2 Report Run Date and Time: 11/12/2013 12:02:00 PM Page 1 of 2 Question S?7a S?7b S?7c S-older (95% CI) (95% CI) (95% CI) (95% CI) Question 13: Please answer True, False, or I don?t know for each statement about the TIRF medicine that was most recently prescribed for you. 13c: TIRF medicines should be taken exactly as prescribed by the doctor. 100.0 100.0 99.2 100.0 True ?1 32 (89.1. 70 (94.9. 125 (95.7. 74 (95.1. 100.0) 100.0) 100.0) 100.0) False don't know 0.0 Question 17: Please answer True, False, or I don?t know for each statement about the TIRF medicine that was most recently prescribed for you. 17b: It is OK to take TIRF medicines for short?term pain that will go away in a few days. 90.6 87.1 81.7 79.7 False 29 (75.0. 98.0) 61 (77.0. 93.9) 103 (73.9. 88.1) 59 (68.8. 88.2) True don't know 3 9.4 7 10.0 15 11.9 10 13.5 Correct response Client: TRIG Project: TIRF Wave2 Report Run Date and Time: 11/12/2013 12:02:00 PM Page TABLE 8.2 SECONDARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #3 KEY RISK MESSAGE 3: TIRF MEDICINES SHOULD BE TAKEN EXACTLY AS PRESCRIBED BY THE HEALTHCARE PROVIDER. Patients Caregivers Patients Caregivers Demonstrated Understanding 0 correct responses con?ect response 40 13.3 0 0.0 40 13.2 2 correct responses 167 55.5 0 0.0 167 55.3 3 correct responses 93 30.9 1 100.0 94 31.1 Average nlunber of correct responses 2.2 (2.0. 3.0 (0.2. 3.0) [21 2.2 (2.0. 3.0) Number of eligible respondents completing the sm'vey (See Table 1). [210ne-sided 95 con?dence interval using the normal approximation to the Poisson distribution. Client: TRIG Project: TIRF Wave 2 Report Run Date and Time: 11/7/2013 4:24:00 PM Page 1 of TABLE 8.2.1 SECONDARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #3 KEY RISK MESSAGE 3: TIRF MEDICINES SHOULD BE TAKEN EXACTLY AS PRESCRIBED BY THE HEALTHCARE PROVIDER. SUB-GROUP ANALYSIS 1: READING MEDICATION GUIDE (QUESTION 18, 23 AND 24) S-la - Respondents who received the Medication Guide and read at least most of it S-lb - Respondents who did not receive a Medication Guide or answered don?t know? or who received a Medication Guide and read only some of it or answered don?t know?. S-la S-lb Read most of Med Read some or none of Demonstrated Understanding Guide Med Guide 0 conect responses 1 0.4 0 0.0 1 conect response 25 10.1 15 27.8 2 conect responses 135 54.4 32 59.3 3 conect responses 87 35.1 7 13.0 Average number of correct responses 2.2 (2.1. 3.0) 1.9 (1.5. 3.0) ?1 One-sided 95 con?dence interval using the normal approximation to the Poisson distribution. Client: TRIG Project: TIRF Wave 2 Report Run Date and Time: 11/7/2013 11:45:00 AM Page 1 of TABLE 8.2.2 SECONDARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #3 KEY RISK MESSAGE 3: TIRF MEDICINES SHOULD BE TAKEN EXACTLY AS PRESCRIBED BY THE HEALTHCARE PROVIDER. SUB-GROUP ANALYSIS 2: UNDERSTANDING OF MEDICATION GUIDE (QUESTION 25) S-2a - Respondents who understood all of it or most of it S-2b Respondents who understood some of it S-2c Respondents who answered None or don?t know? 0 S-2d - Respondents who answered don?t know? to receipt or reading of the Medication Guide. S-2d S-2a 2b S-2c Did not Get or Understood All None/I don't Read Understood Some . . Demonstrated Understanding or know Medication Guide 0 correct responses correct response 28 11.2 2 11.1 1 100.0 9 28.1 2 correct responses 135 53.8 13 72.2 0 0.0 19 59.4 3 correct responses 87 34.7 3 16.7 0 0.0 4 12.5 Average number of correct responses 2.2 (2.1. 3.0) ?1 2.1 (1.5. 3.0) 1.0 (-0.6. 1.8 (1.4. 3.0) ?1 ll] One-sided 95 con?dence interval using the nomral approximation to the Poisson distribution. Client: TRIG Project: TIRF Wave2 Report Run Date and Time: 11/8/2013 10:45:00 AM Page 1 of TABLE 8.2.3 SECONDARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #3 KEY RISK MESSAGE 3: TIRF MEDICINES SHOULD BE TAKEN EXACTLY AS PRESCRIBED BY THE HEALTHCARE PROVIDER. SUB-GROUP ANALYSIS 3: TIME TO COMPLETE SURVEY - INTERNET: S-3a - <10 min 0 S-3b - 10 to<20 min 0 S-3c - 220 min S-3a S-3b S-3c Demonstrated Understanding 1110:2311 10 23:21:! 0 correct responses correct response 4 8.5 13 13.0 5 17.9 2 correct responses 24 51.1 51 51.0 17 60. 7 3 correct responses 19 40.4 36 36.0 6 21.4 Average number of correct responses 2.3 (2.0. 3.0) 2.2 (2.0. 2.0 (1.6. One-sided 95 con?dence interval using the normal approximation to the Poisson distribution. Client: TRIG Project: TIRF WaveZ Report Run Date and Time: 11/8/2013 11:41:00 AM Page 1 of TABLE 8.2.4 SECONDARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #3 KEY RISK MESSAGE 3: TIRF MEDICINES SHOULD BE TAKEN EXACTLY AS PRESCRIBED BY THE HEALTHCARE PROVIDER. SUB-GROUP ANALYSIS 4: TIME TO COMPLETE SURVEY - TELEPHONE: S?4a - <10 min 0 S-4b - 10 to<20 min 0 S-4c - 220 min S-4a S-4b S-4c <10 min 10 to <20 min 220 min Demonstrated Understanding 0 correct responses correct response 0 0.0 8 10.0 10 21.3 2 correct responses 0 0.0 49 61.3 26 55.3 3 correct responses 0 0.0 22 27.5 11 23.4 Average number of con'ect responses 0 (0.0. 3.0) ?1 2.2 (1.9. 2.0 (1.7. 3.0) [ll One-sided 95 con?dence interval using the normal approximation to the Poisson distribution. Client: TRIG Project: TIRF Wave 2 Report Run Date and Time: 11/11/2013 5:11:00 PM Page 1 of TABLE 8.2.5 SECONDARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #3 KEY RISK MESSAGE 3: TIRF MEDICINES SHOULD BE TAKEN EXACTLY AS PRESCRIBED BY THE HEALTHCARE PROVIDER. SUB-GROUP ANALYSIS 5: MODALITY TO COMPLETE SURVEY: S-5a Internet 0 S-5b Telephone S-5a S-5b Demonstrated Understanding 11:21.35? 0 correct responses 0 0.0 1 0.8 1 correct response 22 12.6 18 14.2 2 correct responses 92 52.6 75 59.1 3 correct responses 61 34.9 33 26.0 Average number of correct responses 2.2 (2.0. 3.0) 2.1 (1.9. 3.0) One-sided 95 con?dence interval using the normal approximation to the Poisson distribution. Client: TRIG Project: Report Run Date and Time: 11/7/2013 12:49:00 PM Page 1 of TABLE 8.2.6 SECONDARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #3 KEY RISK MESSAGE 3: TIRF MEDICINES SHOULD BE TAKEN EXACTLY AS PRESCRIBED BY THE HEALTHCARE PROVIDER. SUB-GROUP ANALYSIS 6: HIGHEST LEVEL OF EDUCATION (QUESTION 37): S-6a - Less than, Some, or High school graduate/GED or prefer not to answer S-6b - Some college or associate degree S-6c - Bachelor?s degree or Master?s degree S-6d - Professional or Doctoral degree S-6a S-6b S-6c S-6d High School Some college Bachelor or Master Doctoral degree Demonstrated Understanding N=l 41 0 correct responses correct response 9 15.3 17 12.1 12 14.6 2 10.0 2 correct responses 34 57.6 70 49.6 51 62.2 12 60.0 3 correct responses 16 27.1 53 37.6 19 23.2 6 30.0 Average number of correct responses 2.1 (1.8. 3.0) 2.2 (2.0. 3.0) "1 2.1 (1.8. 3.0) 2.2 (1.7. 3.0) ?1 [ll One-sided 95 con?dence interval using the normal approximation to the Poisson distribution. Client: TRIG Project: TIRF Wave 2 Report Run Date and Time: 11/7/2013 12:19:00 PM Page 1 of TABLE 8.2.7 SECONDARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #3 KEY RISK MESSAGE 3: TIRF MEDICINES SHOULD BE TAKEN EXACTLY AS PRESCRIBED BY THE HEALTHCARE PROVIDER. SUB-GROUP ANALYSIS 7: AGE GROUP OF RESPONDENT (QUESTION 6): S-7a 18 to 39 S-7b - 40 to 49 S-7c 50 to 59 S-7d 60 or older S-7a S-7b S-7c S-older Demonstrated Understanding 0 correct responses correct response 3 9.4 8 11.4 17 13.5 12 16.2 2 correct responses 17 53.1 40 57.1 70 55.6 40 54.1 3 correct responses 12 37.5 22 31.4 38 30.2 22 29.7 Average number of correct responses 2.3 (1.8. 3.0) "1 2.2 (1.9. 3.0) ?1 2.2 (1.9. 2.1 (1.9. 3.0) [ll One-sided 95 con?dence interval using the normal approximation to the Poisson distribution. Client: TRIG Project: TIRF Wave 2 Report Run Date and Time: 11/7/2013 12:32:00 PM Page 1 of TABLE 9.1 PRIMARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #4 RISK MESSAGE 4: PATIENTS SHOULD NOT SWITCH FROM A TIRF MEDICINE TO ANOTHER MEDICINE THAT CONTAINS FENTANY WITHOUT TALKING TO A HEALTHCARE PROVIDER. Question Patients Caregivers Patients 8:1] N=l Caregivers (95% CI) (95% CI) (95% CI) Question 12: Please answer True, False, or I don?t know for the following statements. 12c: It is safe to switch to another medicine that contains fentanyl without talking to a healthcare provider ?rst. 94.4 100.0 94.4 False [21 284 (91.1. 1 (2.5. 285 (91.1. 96.7) 100.0) 96.7) True don't know 9 3.0 0 0.0 9 3.0 Nlunber of eligible respondents completing the survey (See Table Correct response Client: TRIG Project: TIRF WaveZ Report Run Date and Time: 11/12/2013 12:03:00 PM Page 1 of 000 TABLE 9.1.1 PRIMARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #4 RISK MESSAGE 4: PATIENTS SHOULD NOT SWITCH FROM A TIRF MEDICINE TO ANOTHER MEDICINE THAT CONTAINS FENTANYL WITHOUT TALKING TO A HEALTHCARE PROVIDER. SUB-GROUP ANALYSIS 1: READING MEDICATION GUIDE (QUESTION 18, 23 AND 24) S-la - Respondents who received the Medication Guide and read at least most of it S-lb - Respondents who did not receive a Medication Guide or answered don?t know? or who received a Medication Guide and read only some of it or answered don?t know?. S?la S?lb Read most of Med Guide 0f Question Question 12: Please answer True, False, or I don?t know for the following statements. 12c: It is safe to switch to another medicine that contains fentanyl without talking to a healthcare provider ?rst. 94.0 96.3 False 233 (90.2. 96.6) 52 (87.3. 995) True 7 2.8 1 1.9 I don't know 8 3.2 1 1.9 Correct response Client: TRIG Project: TIRF Wave2 Report Run Date and Time: 11/12/2013 12:03:00 PM Page 1 001 TABLE 9.1.2 PRIMARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #4 RISK MESSAGE 4: PATIENTS SHOULD NOT SWITCH FROM A TIRF MEDICINE TO ANOTHER MEDICINE THAT CONTAINS FENTANY WITHOUT TALKING TO A HEALTHCARE PROVIDER. SUB-GROUP ANALYSIS 2: UNDERSTANDING OF MEDICATION GUIDE (QUESTION 25) S-2a - Respondents who understood all of it or most of it S-2b Respondents who understood some of it S-2c Respondents who answered None or don?t know? S-2d - Respondents who answered don?t know? to receipt or reading of the Medication Guide. S?2d S?2a S-2b S?2c Did not Get or Understood All None/I don't Read Understood Some . . . or Most know Medication Q?estlon Guide (95% CI) (95% CI) (95% CI) (95% CI) Question 12: Please answer True, False, or I don?t know for the following statements. 12c: It is safe to switch to another medicine that contains fentanyl without talking to a healthcare provider ?rst. 94.4 94.4 100.0 93.8 False 237 (90.8. 96.9) 17 (72.7. 99.9) 1 (2.5. 100.0) 30 (792.992) True don't know 3.1 Correct response Client: TRIG Project: TIRF Wave2 Report Run Date and Time: 11/12/2013 12:03:00 PM Page 1 of 002 TABLE 9.1.3 PRIMARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #4 RISK MESSAGE 4: PATIENTS SHOULD NOT SWITCH FROM A TIRF MEDICINE TO ANOTHER MEDICINE THAT CONTAINS FENTANYL WITHOUT TALKING TO A HEALTHCARE PROVIDER. SUB-GROUP ANALYSIS 3: TIME TO COMPLETE SURVEY - INTERNET: 0 5-321 - <10 min 0 S-3b - 10 to<20 min 0 S-3c - 220 min Question S-3a S-3b S-3c <10 min 10 to <20 min 220 min (95% CI) (95% CI) (95% CI) Question 12: Please answer True, False, or I don?t know for the following statements. 12c: It is safe to switch to another medicine that contains fentanyl without talking to a healthcare provider ?rst. 100.0 96.0 92.9 False ?1 47 (92.5. 96 (90.1. 26 (76.5. 100.0) 98.9) 99.1) True 0 0.0 1.0 3.6 I don't know 0 0.0 3 3.0 3.6 Con?eet response Client: TRIG Project: TIRF Wave2 Report Run Date and Time: 11/12/2013 12:03:00 PM Page 1 of 003 TABLE 9.1.4 PRIMARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #4 RISK MESSAGE 4: PATIENTS SHOULD NOT SWITCH FROM A TIRF MEDICINE TO ANOTHER MEDICINE THAT CONTAINS FENTANYL WITHOUT TALKING TO A HEALTHCARE PROVIDER. SUB-GROUP ANALYSIS 4: TIME TO COMPLETE SURVEY - TELEPHONE: S-4a - <10 min 0 S-4b - 10 to<20 min 0 S-4c - 220 min Question S-4a S-4b S-4c <10 min 10 to <20 min 220 min (95% CI) (95% CI) (95% CI) Question 12: Please answer True, False, or I don?t know for the following statements. 12c: It is safe to switch to another medicine that contains fentanyl without talking to a healthcare provider ?rst. 93.8 87.2 False ?1 0 0.0 75 (86.0. 41 (74.3. 97.9) 95.2) True don't know 0 0.0 2 2.5 3 6.4 Conect response Client: TRIG Project: TIRF Wave2 Report Run Date and Time: 11/12/2013 12:03:00 PM Page 1 of 004 TABLE 9.1.5 PRIMARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #4 RISK MESSAGE 4: PATIENTS SHOULD NOT SWITCH FROM A TIRF MEDICINE TO ANOTHER MEDICINE THAT CONTAINS FENTANYL WITHOUT TALKING TO A HEALTHCARE PROVIDER. SUB-GROUP ANALYSIS 5: MODALITY TO COMPLETE SURVEY: 0 8-521 Internet 0 Telephone Question S?5a S-5b Internet Telephone N=l75 (95% CI) (95% CI) Question 12: Please answer True, False, or I don?t know for the following statements. 12c: It is safe to switch to another medicine that contains fentanyl without talking to a healthcare provider ?rst. 96.6 91.3 False 169 (92.7. 98.7) 116 (85.0. 95.6) True 2 1.1 6 4.7 I don't know 4 2.3 5 3.9 Correct response Client: TRIG Project: TIRF WaveZ Report Run Date and Time: 11/12/2013 12:03:00 PM Page 1 of 005 TABLE 9.1.6 PRIMARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #4 RISK MESSAGE 4: PATIENTS SHOULD NOT SWITCH FROM A TIRF MEDICINE TO ANOTHER MEDICINE THAT CONTAINS FENTANY WITHOUT TALKING TO A HEALTHCARE PROVIDER. SUB-GROUP ANALYSIS 6: HIGHEST LEVEL OF EDUCATION (QUESTION 37): S-6a - Less than, Some, or High school graduate/GED or prefer not to answer S-6b - Some college or associate degree S-6c - Bachelor?s degree or Master?s degree S-6d - Professional or Doctoral degree S?6a S?6b S?6c High School Some college Bachelor or Master Doctoral degree Question N=l4l (95% CI) (95% CI) (95% CI) (95% CI) Question 12: Please answer True, False, or I don?t know for the following statements. 12c: It is safe to switch to another medicine that contains fentanyl without talking to a healthcare provider ?rst. 100.0 91.5 93.6 96.3 False 54 (81.3. 97.2) 132 (88.2. 97.0) 79 (89.7. 99.2) 20 (83'7" 100.0) True don't know 0.0 Correct response Client: TRIG Project: TIRF Wave2 Report Run Date and Time: 11/12/2013 12:03:00 PM Page 1 of 006 TABLE 9.1.7 PRIMARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #4 RISK MESSAGE 4: PATIENTS SHOULD NOT SWITCH FROM A TIRF MEDICINE TO ANOTHER MEDICINE THAT CONTAINS FENTANY WITHOUT TALKING TO A HEALTHCARE PROVIDER. SUB-GROUP ANALYSIS 7: AGE GROUP OF RESPONDENT (QUESTION 6): S-7a 18 to 39 S-7b - 40 to 49 S-7c 50 to 59 S-7d 60 or older S?7a S-7b S?7c S?older Question (95% CI) (95% CI) (95% CI) (95% CI) Question 12: Please answer True, False, or I don?t know for each of the following statements. 12c: It is safe to switch to another medicine that contains fentanyl without talking to a healthcare provider first. 100.0 95.7 93.7 91.9 False ?1 32 (89.1. 67 (88.0. 118 (87.9. 68 (83.2. 100.0) 99.1) 97.2) 97.don't know 0 0.0 3 4.3 3.2 2 2.7 Correct response Client: TRIG Project: TIRF Wave2 Report Run Date and Time: 11/7/2013 12:40:00 PM Page 1 of 007 TABLE 10.1 PRIMARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #5 KEY RISK MESSAGE 5: PATIENTS SHOULD NOT GIVE TIRF MEDICINES TO ANYONE ELSE EVEN IF THEY HAVE THE SAME Patients Caregivers CPatlents 8:1] areglvers N?l N-302 Question (95% CI) (95% CI) (95% CI) Question 12: Please answer True, False, or I don?t know for the following statements. 12d: A patient may give TIRF medicines to another person if they have the same as the patient. 98.0 100.0 98.0 False [21 295 (95.7. 1 (2.5. 296 (95.7. 99.3) 100.0) 99.3) True don't know 1 0.3 0 0.0 0.3 Question 17: Please answer True, False, or I don?t know for each statement about the TIRF medicine that was most recently prescribed for you. 17a: Selling or giving away TIRF medicines is against the law. 98.3 100.0 98.3 True [21 296 (96.2. 1 (2.5. 297 (96.2. 99.5) 100.0) 99.5) False don't know 3 1.0 0 0.0 3 1.0 Number of eligible respondents completing the survey (See Table 1). Correct response Client: TRIG Project: TIRF Wave2 Report Run Date and Time: 11/12/2013 12:04:00 PM Page 1 of 008 TABLE 10.1.1 PRIMARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #5 KEY RISK MESSAGE 5: PATIENTS SHOULD NOT GIVE TIRF MEDICINES TO ANYONE ELSE EVEN IF THEY HAVE THE SAME SUB-GROUP ANALYSIS 1: READING MEDICATION GUIDE (QUESTION 18, 23 AND 24) S-la - Respondents who received the Medication Guide and read at least most of it S-lb - Respondents who did not receive a Medication Guide or answered don?t know? or who received a Medication Guide and read only some of it or answered don?t know?. S-la Read most of Med Guide 0f Question (95% 0) (95% CI) Question 12: Please answer True, False, or I don?t know for the following statements. 12d: A patient may give TIRF medicines to another person if they have the same as the patient. 98.0 98.1 False 243 (95.4. 99.3) 53 (90.1. 100.0) True 4 1.6 1 1.9 I don't know 1 0.4 0 0.0 Question 17: Please answer True, False, or I don?t know for each statement about the TIRF medicine that was most recently prescribed for you. 17a: Selling or giving away TIRF medicines is against the law. 98.8 96.3 True 245 (96.5. 99.7) 52 (87.3. 99.5) False 1 0.4 1 1.9 I don't know 2 0.8 1 1.9 Correct response Client: TRIG Project: TIRF WaveZ Report Run Date and Time: 11/12/2013 12:04:00 PM Page 009 TABLE 10.1.2 PRINIARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #5 KEY RISK MESSAGE 5: PATIENTS SHOULD NOT GIVE TIRF MEDICINES TO ANYONE ELSE EVEN IF THEY HAVE THE SAME SUB-GROUP ANALYSIS 2: UNDERSTANDING OF MEDICATION GUIDE (QUESTION 25) S-2a - Respondents who understood all of it or most of it S-2b Respondents who understood some of it S-2c Respondents who answered None or don?t know? 0 S-2d - Respondents who answered don?t know? to receipt or reading of the Medication Guide. S?2d S-2a S-2b S?2c Did not Get or Understood All None/I don't Read Understood Some . . or Most know Medication 0119511011 Guide (95% CI) (95% CI) (95% CI) (95% CI) Question 12: Please answer True, False, or I don?t know for the following statements. 12d: A patient may give TIRF medicines to another person if they have the same as the patient. 98.0 100.0 100.0 96.9 False ?1 246 (95.4. 18 (81.5. 1 (2.5. 31 (83.8. 99.4) 100.0) 100.0) 99.9) True don't know 0.0 Client: TRIG Project: TIRF Wave2 Report Run Date and Time: 11/12/2013 12:04:00 PM Page 1 of 2 17a: Selling or giving away TIRF medicines is against the law. 98.4 100.0 100.0 96.9 True ?1 247 (96.0, 18 (81.5, (2.5, 31 (83.8, 99.6) 100.0) 100.0) 99.9) False 0.4 0.0 0.0 3.1 I don't know 3 1.2 0.0 0.0 0 0.0 Correct response Client: TRIG Project: TIRF Wave 2 Report Run Date and Time: 11/12/2013 12:04:00 PM Page 2 01 1 TABLE 10.1.3 PRIMARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #5 KEY RISK MESSAGE 5: PATIENTS SHOULD NOT GIVE TIRF MEDICINES TO ANYONE ELSE EVEN IF THEY HAVE THE SAME SUB-GROUP ANALYSIS 3: TIME TO COMPLETE SURVEY - INTERNET: S-3a - <10 min 0 S-3b - 10 to<20 min 0 S-3c - 220 min Question S-3a S-3b S-3c <10 min 10 to <20 min 220 min (95% CI) (95% CI) (95% CI) Question 12: Please answer True, False, or I don?t know for the following statements. 12d: A patient may give TIRF medicines to another person if they have the same as the patient. 97.9 100.0 100.0 False ?1 46 (88.7. 100 (96.4. 28 (87.7. 99.9) 100.0) 100.0) True don't know 0 0.0 0 0.0 0 0.0 Question 17: Please answer True, False, or I don?t know for each statement about the TIRF medicine that was most recently prescribed for you. 17a: Selling or giving away TIRF medicines is against the law. 100.0 97.0 100.0 Tme ?1 47 (92.5. 97 (91.5. 28 (87.7. 100.0) 99.4) 100.0) False don't know 0 0.0 2 2.0 0 0.0 Correct response Client: TRIG Project: TIRF Wave2 Report Run Date and Time: 11/12/2013 12:05:00 PM Page 1 of TABLE 10.1.4 PRIMARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #5 KEY RISK MESSAGE 5: PATIENTS SHOULD NOT GIVE TIRF MEDICINES TO ANYONE ELSE EVEN IF THEY HAVE THE SAME SUB-GROUP ANALYSIS 4: TIME TO COMPLETE SURVEY - TELEPHONE: S-4a - <10 min 0 S-4b - 10 to<20 min 0 S-4c - 220 min S-4a s40 S-4c <10 min 10 to <20 min 220 min Question (95% CI) (95% CI) (95% CI) Question 12: Please answer True, False, or I don?t know for the following statements. 12d: A patient may give TIRF medicines to another person if they have the same as the patient. 96.3 95.7 False ?1 0 0.0 77 (89.4. 45 (85.5. 99.2) 99.5) True don't know 0 0.0 1.3 0 0.0 Question 17: Please answer True, False, or I don?t know for each statement about the TIRF medicine that was most recently prescribed for you. 17a: Selling or giving away TIRF medicines is against the law. 97.5 100.0 True ?1 0 0.0 78 (91.3. 47 (92.5. 99.7) 100.0) False don't know 0 0.0 1.3 0 0.0 Correct response Client: TRIG Project: TIRF Wave2 Report Run Date and Time: 11/12/2013 12:05:00 PM Page 1 TABLE 10.1.5 PRIMARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #5 KEY RISK MESSAGE 5: PATIENTS SHOULD NOT GIVE TIRF MEDICINES TO ANYONE ELSE EVEN IF THEY HAVE THE SAME SUB-GROUP ANALYSIS 5: MODALITY TO COMPLETE SURVEY: S-5a Internet 0 Telephone Question S?5a S?5b Internet Telephone (95% CI) (95% CI) Question 12: Please answer True, False, or I don?t know for the following statements. 12d: A patient may give TIRF medicines to another person if they have the same as the patient. [11 99.4 96.1 False 174 (96.9. 100.0) 122 (91.1. 98.7) True 1 0.6 4 3.1 I don't know 0 0.0 1 0.8 Question 17: Please answer True, False, or I don?t know for each statement about the TIRF medicine that was most recently prescribed for you. 17a: Selling or giving away TIRF medicines is against the law. 98.3 98.4 True 172 (95.1. 99.6) 125 (94.4. 99.8) False 1 0.6 1 0.8 I don't know 2 1.1 1 0.8 Correct response Client: TRIG Project: TIRF Wave2 Report Run Date and Time: 11/12/2013 12:05:00 PM Page 1 of TABLE 10.1.6 PRINIARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #5 KEY RISK MESSAGE 5: PATIENTS SHOULD NOT GIVE TIRF MEDICINES TO ANYONE ELSE EVEN IF THEY HAVE THE SAME SUB-GROUP ANALYSIS 6: HIGHEST LEVEL OF EDUCATION (QUESTION 37): S-6a - Less than, Some, or High school graduate/GED or prefer not to answer S-6b - Some college or associate degree S-6c - Bachelor?s degree or Master?s degree S-6d - Professional or Doctoral degree S?6a S?6b S?6c S?6d High School Some college Bachelor or Master Doctoral degree (95% CI) (95% CI) (95% CI) (95% CI) Question 12: Please answer True, False, or I don?t know for the following statements. 12d: A patient may give TIRF medicines to another person if they have the same as the patient. 98.3 96.5 100.0 100.0 False 58 (90.9. 100.0) 136 (91.9. 98.8) 82 (95.6. 100.0) 20 (83.2. 100.0) True don't know 0.0 Client: TRIG Project: TIRF Wave2 Report Run Date and Time: 11/12/2013 12:05:00 PM Page 1 of 2 S?6a S-6b High School Some college Bachelor or Master Doctoral degree (95% CI) (95% CI) (95% CI) (95% CI) Question 17: Please answer True, False, or I don?t know for each statement about the TIRF medicine that was most recently prescribed for you. 17a: Selling or giving away TIRF medicines is against the law. 96.6 99.3 100.0 90.0 True 57 (88.3. 99.6) 140 (96.1. 100.0) 82 (95.6. 100.0) 18 (68.3. 98.8) False don't know 10.0 Correct response Client: TRIG Project: TIRF Wave2 Report Run Date and Time: 11/12/2013 12:05:00 PM Page 2 of TABLE 10.1.7 PRINIARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #5 KEY RISK MESSAGE 5: PATIENTS SHOULD NOT GIVE TIRF MEDICINES TO ANYONE ELSE EVEN IF THEY HAVE THE SAME SUB-GROUP ANALYSIS 7: AGE GROUP OF RESPONDENT (QUESTION 6): S-7a 18 to 39 S-7b - 40 to 49 S-7c 50 to 59 S-7d 60 or older S?7a S?7b S?7c S?older (95% CI) (95% CI) (95% CI) (95% CI) Question 12: Please answer True, False, or I don?t know for the following statements. 12d: A patient may give TIRF medicines to another person if they have the same as the patient. 100.0 100.0 96.0 98.6 False 32 (89.1. 100.0) 70 (94.9. 100.0) 121 (91.0. 98.7) 73 (92.7.1000) True don't know 0.0 Client: TRIG Project: TIRF Wave2 Report Run Date and Time: 11/12/2013 12:05:00 PM Page 1 of 2 S?7a S?7b S?7c S?older (95% CI) (95% CI) (95% CI) (95% CI) Question 17: Please answer True, False, or I don?t know for each statement about the TIRF medicine that was most recently prescribed for you. 17a: Selling or giving away TIRF medicines is against the law. 100.0 100.0 97.6 97.3 True 32 (89.1. 100.0) 70 (94.9. 100.0) 123 (93.2. 99.5) 72 (90.6. 99.7) False don't know 1.4 Correct response Client: TRIG Project: TIRF Wave2 Report Run Date and Time: 11/12/2013 12:05:00 PM Page 2 of 2 TABLE 10.2 SECONDARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #5 KEY RISK MESSAGE 5: PATIENTS SHOULD NOT GIVE TIRF MEDICINES TO ANYONE ELSE EVEN IF THEY HAVE THE SAME Patients Caregivers Patients Caregivers ?1 Demonstrated Understanding 0 correct responses correct response correct responses 290 96.3 1 100.0 291 96.4 Average number of correct responses 2.0 (1.8. 2.0) 2.0 (-0.3. 2.0) 2.0 (1.8. 2.0) '21 Number of eligible respondents completing the sm'vey (See Table 1). One-sided 95 con?dence interval using the normal approximation to the Poisson distribution. Client: TRIG Project: TIRF Wave 2 Report Run Date and Time: 11/7/2013 4:25:00 PM Page 1 of TABLE 10.2.1 SECONDARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #5 KEY RISK MESSAGE 5: PATIENTS SHOULD NOT GIVE TIRF MEDICINES TO ANYONE ELSE EVEN IF THEY HAVE THE SAME SUB-GROUP ANALYSIS 1: READING MEDICATION GUIDE (QUESTION 18, 23 AND 24) S-la - Respondents who received the Medication Guide and read at least most of it S-lb - Respondents who did not receive a Medication Guide or answered don?t know? or who received a Medication Guide and read only some of it or answered don?t know?. S-la S-lb Read most of Med Guide Read some or none of Demonstrated Understanding Med Guide =54 0 correct responses 0 0.0 0 0.0 1 correct response 8 3.2 3 5.6 2 conect responses 240 96.8 51 94.4 Average number of correct responses 2.0 (1.8. 2.0) "1 1.9 (1.6. 2.0) ?1 One-sided 95 con?dence interval using the normal approximation to the Poisson distribution. Client: TRIG Project: TIRF Wave2 Report Run Date and Time: 11/7/2013 12:43:00 PM Page 1 of 020 TABLE 10.2.2 SECONDARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #5 KEY RISK MESSAGE 5: PATIENTS SHOULD NOT GIVE TIRF MEDICINES TO ANYONE ELSE EVEN IF THEY HAVE THE SAME SUB-GROUP ANALYSIS 2: UNDERSTANDING OF MEDICATION GUIDE (QUESTION 25) S-2a - Respondents who understood all of it or most of it S-2b Respondents who understood some of it S-2c Respondents who answered None or don?t know? 0 S-2d - Respondents who answered don?t know? to receipt or reading of the Medication Guide. S-2d S-2a 2b S-2c Did not Get or Understood All None/I don't Read Understood Some . . Demonstrated Understanding or know Medication Guide 0 correct responses con'ect response correct responses 242 96.4 18 100.0 1 100.0 30 93.8 Average number of correct responses 2.0 (1.8. 2.0) "1 2.0 (1.5. 2.0) 2.0 (-0.3. 2.0) ?1 1.9 (1.5. 2.0) ?1 One-sided 95 con?dence inten'al using the normal approximation to the Poisson distribution. Client: TRIG Project: TIRF Wave2 Report Run Date and Time: 11/8/2013 10:51:00 AM Page 1 of 021 TABLE 10.2.3 SECONDARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #5 KEY RISK MESSAGE 5: PATIENTS SHOULD NOT GIVE TIRF MEDICINES TO ANYONE ELSE EVEN IF THEY HAVE THE SAME SUB-GROUP ANALYSIS 3: TIME TO COMPLETE SURVEY - INTERNET: 0 8?33 - <10 min 0 S-3b - 10 to<20 min 0 S-3c - 220 min S-3a S-3b S-3c Demonstrated Understanding <33 10 13:33:11]! 23:15:11 0 correct responses correct response correct responses 46 97.9 97 97.0 28 100.0 Average munber of correct responses 2.0 (1.6. 2.0) 2.0 (1.7. 2.0) [11 2.0 (1.6. 2.0) ?1 One-sided 95 con?dence interval using the normal approximation to the Poisson distribution. Client: TRIG Project: TIRF Wave 2 Report Run Date and Time: 11/8/2013 11:42:00 AM Page 1 of 022 TABLE 10.2.4 SECONDARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #5 KEY RISK MESSAGE 5: PATIENTS SHOULD NOT GIVE TIRF MEDICINES TO ANYONE ELSE EVEN IF THEY HAVE THE SAME SUB-GROUP ANALYSIS 4: TIME TO COMPLETE SURVEY - TELEPHONE: 0 8?43 - <10 min 0 S-4b - 10 to<20 min 0 S-4c - 220 min S-4a S-4b S-4c <10 min 10 to <20 min 220 min Demonstrated Understanding 0 correct responses 0 0.0 0.0 0 0.0 1 correct response correct responses 0 0.0 75 93.8 45 95.7 Average number of correct responses 0 (0.0. 2.0) 1.9 (1.7. 2.0) "1 2.0 (1.6. 2.0) [ll One-sided 95 con?dence interval using the normal approximation to the Poisson distribution. Client: TRIG Project: TIRF Wave 2 Report Run Date and Time: 11/11/2013 5:10:00 PM Page 1 of 023 TABLE 10.2.5 SECONDARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #5 KEY RISK MESSAGE 5: PATIENTS SHOULD NOT GIVE TIRF MEDICINES TO ANYONE ELSE EVEN IF THEY HAVE THE SAME SUB-GROUP ANALYSIS 5: MODALITY TO COMPLETE SURVEY: S-5a Internet 0 S-5b Telephone S-5b Demonstrated Understanding 11:23:17]? T?3112%ne 0 correct responses 0 0.0 0 0.0 1 correct response 4 2.3 7 5.5 2 correct responses 171 97.7 120 94.5 Average number of correct responses 2.0 (1.8. 2.0) ?1 1.9 (1.7. 2.0) ?1 One-sided 95 con?dence interval using the normal approximation to the Poisson distribution. Client: TRIG Project: Report Run Date and Time: 11/7/2013 12:48:00 PM Page 1 of 024 TABLE 10.2.6 SECONDARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #5 KEY RISK MESSAGE 5: PATIENTS SHOULD NOT GIVE TIRF MEDICINES TO ANYONE ELSE EVEN IF THEY HAVE THE SAME SUB-GROUP ANALYSIS 6: HIGHEST LEVEL OF EDUCATION (QUESTION 37): S-6a - Less than, Some, or High school graduate/GED or prefer not to answer S-6b - Some college or associate degree S-6c - Bachelor?s degree or Master?s degree S-6d - Professional or Doctoral degree S-6a S-6b S-6c S-6d High School Some college Bachelor or Master Doctoral degree Demonstrated Understanding N=14l 0 correct responses correct response 10.0 2 correct responses 56 94.9 135 95.7 82 100.0 18 90.0 Average number of correct responses 1.9 (1.7. 2.0) ?1 2.0 (1.8. 2.0) 2.0 (1.7. 2.0) 1.9 (1.4. 2.0) ?1 One-sided 95 con?dence interval using the normal approximation to the Poisson distribution. Client: TRIG Project: TIRF WaveZ Report Run Date and Time: 11/7/2013 12:54:00 PM Page 1 of 025 TABLE 10.2.7 SECONDARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #5 KEY RISK MESSAGE 5: PATIENTS SHOULD NOT GIVE TIRF MEDICINES TO ANYONE ELSE EVEN IF THEY HAVE THE SAME SUB-GROUP ANALYSIS 7: AGE GROUP OF RESPONDENT (QUESTION 6): S-7a 18 to 39 S-7b - 40 to 49 S-7c 50 to 59 S-7d 60 or older S-7a S-7b S-7c S-older Demonstrated Understanding 0 correct responses correct response correct responses 32 100.0 70 100.0 118 93.7 71 95.9 Average number of correct responses 2.0 (1.6. 2.0) 2.0 (1.7. 2.0) 1.9 (1.7. 2.0) 2.0 (1.7. 2.0) "1 One-sided 95 con?dence interval using the normal approximation to the Poisson distribution. Client: TRIG Project: TIRF WaveZ Report Run Date and Time: 11/7/2013 12:58:00 PM Page 1 of 026 TABLE 11.1 PRIMARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #6 KEY RISK MESSAGE 6: TIRF MEDICINES SHOULD BE STORED IN A SAFE PLACE AWAY FROM CHILDREN AND PROPERLY DISPOSED. . . Patients Patients Caregivers Caregiversm N=l N-302 Question (95% CI) (95% CI) (95% CI) Question 13: Please answer True, False, or I don?t know for each statement about the TIRF medicine that was most recently prescribed for you. 13a: TIRF medicines should be stored in a safe place out of the reach of children. 100.0 100.0 100.0 True [21 301 (98.8. 1 (2.5. 302 (98.8. 100.0) 100.0) 100.0) False don't know 0 0.0 0 0.0 0 0.0 Question 17: Please answer True, False, or I don?t know for each statement about the TIRF medicine that was most recently prescribed for you. 17c: TIRF medicines must be disposed of as described in the speci?c product?s Medication Guide. 94.4 100.0 94.4 True [21 284 (91.1. 1 (2.5. 285 (91.1. 96.7) 100.0) 96.7) False don't know 17 5.6 0 0.0 17 5.6 l7e: A TIRF medicine can cause an overdose and death in any child who takes it. 91.0 100.0 91.1 True [21 274 (87.2. 1 (2.5. 275 (87.3. 94.0) 100.0) 94.0) False don't know 25 8.3 0 0.0 25 8.3 Client: TRIG Project: TIRF WaveZ Report Run Date and Time: 11/7/2013 4:25:00 PM Page 2 027 Question Patients Patients Caregivers . Caregivers 1 (95% CI) (95% CI) (95% CI) Question 14: What should you do if an adult who has not been prescribed a TIRF medicine takes a TIRF medicine? (Please select one.) Get emer enc hel 87'4 100'0 87'4 right awag my 263 (83.1. 1 (2.5. 264 (83.1. 3" 90.9) 100.0) 90.9) Wait an hour and see if the person nothingdon't know 19 6.3 0 0.0 19 6.3 Number of eligible respondents completing the survey (See Table 1). Correct response Client: TRIG Project: Report Run Date and Time: 11/7/2013 4:25:00 PM Page 2 of 2 028 TABLE 11.1.1 PRIMARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #6 KEY RISK MESSAGE 6: TIRF MEDICINES SHOULD BE STORED IN A SAFE PLACE AWAY FROM CHILDREN AND PROPERLY DISPOSED. SUB-GROUP ANALYSIS 1: READING MEDICATION GUIDE (QUESTION 18, 23 AND 24) S-la - Respondents who received the Medication Guide and read at least most of it S?lb Respondents who did not receive a Medication Guide or answered don?t know? or who received a Medication Guide and read only some of it or answered don?t know?. S-la S?lb . Read some or none of Read most of Med Guide Med Guide Question (95% CI) (95% CI) Question 13: Please answer True, False, or I don?t know for each statement about the TIRF medicine that was most recently prescribed for you. 13a: TIRF medicines should be stored in a safe place out of the reach of children. 100.0 100.0 True 248 (98.5. 100.0) 54 (93.4. 100.0) False 0 0.0 0 0.0 I don't know 0 0.0 0 0.0 Question 17: Please answer True, False, or I don?t know for each statement about the TIRF medicine that was most recently prescribed for you. 17c: TIRF medicines must be disposed of as described in the speci?c product?s Medication Guide. 97.2 81.5 Tme 241 (94.3. 98.9) 44 (68.6. 90.7) False 0 0.0 0 0.0 I don't know 7 2.8 10 18.5 Client: TRIG Project: TIRF WaveZ Report Run Date and Time: 11/7/2013 1:36:00 PM Page 1 029 S?lb S-la Read some or none of Read most of Med Guide . Med Guide Question (95% CI) (95% CI) l7e: A TIRF medicine can cause an overdose and death in any child who takes it. 92.7 83.3 True 230 (88.8. 95.6) 45 (70.7. 92.1) False 2 0.8 0 0.0 I don't know 16 6.5 9 16.7 Question 14: What should you do if an adult who has not been prescribed a TIRF medicine takes a TIRF medicine? (Please select one.) Get emergency help ?ght away. 89.5 77.8 ?1 222 (85.0. 93.0) 42 (64.4. 88.0) Wait an hour and see person is OK. Do nothing. 2 0.8 0 0.0 I don't know 11 4.4 8 14.8 Correct response Client: TRIG Project: Report Run Date and Time: 11/7/2013 1:36:00 PM Page 2 of 2 030 TABLE 11.1.2 PRIMARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #6 KEY RISK MESSAGE 6: TIRF MEDICINES SHOULD BE STORED IN A SAFE PLACE AWAY FROM CHILDREN AND PROPERLY DISPOSED. SUB-GROUP ANALYSIS 2: UNDERSTANDING OF MEDICATION GUIDE (QUESTION 25) S-2a - Respondents who understood all of it or most of it S-2b Respondents who understood some of it 0 S-2c Respondents who answered None or don?t know? 0 S-2d - Respondents who answered don?t know? to receipt or reading of the Medication Guide. Question S-2d S?2a S-2b S?2c Did not Get or Understood All None/I don't Read Understood Some . . or Most know Medication Guide (95% CI) (95% CI) (95% CI) (95% CI) Question 13: Please answer True, False, or I don?t know for each statement about the TIRF medicine that was most recently prescribed for you. 13a: TIRF medicines should be stored in a safe place out of the reach of children. 100.0 100.0 100 0 100.0 Tmem 251 (98.5. 18 (81.5. 1 (2 5 1000) 32 (89.1. 100.0) 100.0) 100.0) False don't know 0.0 Client: TRIG Project: TIRF Wave2 Report Run Date and Time: 11/8/2013 10:54:00 AM Page 1 of 3 O31 Question S?2d S?2a S-2b S?2c Did not Get or Understood All None/I don't Read Understood Some . . or Most know Medication Guide (95% CI) (95% CI) (95% CI) (95% CI) Question 17: Please answer True, False, or I don?t know for each statement about the TIRF medicine that was most recently prescribed for you. 17c: TIRF medicines must be disposed of as described in the speci?c product?s Medication Guide. True 245 (949979691) 15 (58.85364) 1 (2.51.030) 24 False don't know 6 2.4 3 16.7 0 0.0 8 25.0 l7e: A TIRF medicine can cause an overdose and death in any child who takes it. True 230 (87.95347) 17 (72.93399) 0 0'0 28 (71.207565) False don't know 19 7.6 1 5.6 1 100.0 4 12.5 Client: TRIG Project: TIRF Wave2 Report Run Date and Time: 11/8/2013 10:54:00 AM Page 2 of 3 032 Get emergency help right 88.8 88.9 78.1 away. ?1 223 (84.3, 92.5) 16 (65.3, 98.6) 0'0 25 (60.0, 90.7) Walt an. 119.4 person 1s OK. Do nothingdon't know 12 4.8 11.1 100.0 12.5 Correct response Client: TRIG Project: TIRF Wave 2 Report Run Date and Time: 11/8/2013 10:54:00 AM Page 3 of 033 TABLE 11.1.3 PRIMARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #6 KEY RISK MESSAGE 6: TIRF MEDICINES SHOULD BE STORED IN A SAFE PLACE AWAY FROM CHILDREN AND PROPERLY DISPOSED. SUB-GROUP ANALYSIS 3: TIME TO COMPLETE SURVEY - INTERNET: S-3a - <10 min 0 S-3b - 10 to<20 min 0 S-3c - 220 min Question S-3a S-3b S-3c <10 min 10 to <20 min 220 min (95% CI) (95% CI) (95% CI) Question 13: Please answer True, False, or I don?t know for each statement about the TIRF medicine that was most recently prescribed for you. 13a: TIRF medicines should be stored in a safe place out of the reach of children. 100.0 100.0 100.0 True ?1 47 (92.5. 100 (96.4. 28 (87.7. 100.0) 100.0) 100.0) False don't know 0 0.0 0 0.0 0 0.0 Question 17: Please answer True, False, or I don?t know for each statement about the TIRF medicine that was most recently prescribed for you. 17c: TIRF medicines must be disposed of as described in the speci?c product?s Medication Guide. 95.7 94.0 92.9 True ?1 45 (85.5. 94 (87.4. 26 (76.5. 99.5) 97.8) 99.1) False don't know 2 4.3 6 6.0 2 7.1 17c: A TIRF medicine can cause an overdose and death in any child who takes it. 97.9 90.0 96.4 True ?1 46 (88.7. 90 (82.4. 27 (81.7. 99.9) 95.1) 99.9) False 0 0.0 1.0 0 0.0 Client: TRIG Project: TIRF WaveZ Report Run Date and Time: 11/13/2013 2:27:00 PM Page 1 2 034 S?3a S?3b S?3c <10 min 10 to <20 min 220 min Question (95% CI) (95% CI) (95% CI) I don't know 1 2.1 9 9.0 3.6 Question 14: What should you do if an adult who has not been prescribed a TIRF medicine takes a TIRF medicine? (Please select one.) Get emergency help 93 ?6 86'0 82'] . 44 (82.5. 86 (77.6. 23 (63.1. ?g1? 98.7) 92.1) 93.9) Wait an hour and see if the person nothing. 0 0.0 1.0 3.6 I don't know 2 4.3 8 8.0 4 14.3 Correct response Client: TRIG Project: Report Run Date and Time: 11/13/2013 2:27:00 PM Page 2 of 2 035 TABLE 11.1.4 PRIMARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #6 KEY RISK MESSAGE 6: TIRF MEDICINES SHOULD BE STORED IN A SAFE PLACE AWAY FROM CHILDREN AND PROPERLY DISPOSED. SUB-GROUP ANALYSIS 4: TIME TO COMPLETE SURVEY - TELEPHONE: S-4a - <10 min 0 S-4b - 10 to<20 min 0 S-4c - 220 min Question S-4a S-4b S-4c <10 min 10 to <20 min 220 min (95% CI) (95% CI) (95% CI) Question 13: Please answer True, False, or I don?t know for each statement about the TIRF medicine that was most recently prescribed for you. 13a: TIRF medicines should be stored in a safe place out of the reach of children. 100.0 100.0 True ?1 0 0.0 80 (95.5. 47 (92.5. 100.0) 100.0) False don't know 0 0.0 0 0.0 0 0.0 Question 17: Please answer True, False, or I don?t know for each statement about the TIRF medicine that was most recently prescribed for you. 17c: TIRF medicines must be disposed of as described in the speci?c product?s Medication Guide. 93.8 95.7 True ?1 0 0.0 75 (86.0. 45 (85.5. 97.9) 99.5) False don't know 0 0.0 5 6.3 2 4.3 Client: TRIG Project: TIRF WaveZ Report Run Date and Time: 11/11/2013 5:10:00 PM Page 1 2 036 S?4a S?4b S?4c <10 min 10 to <20 min 220 min (95% CI) (95% CI) (95% CI) l7e: A TIRF medicine can cause an overdose and death in any child who takes it. 91.3 83.0 True ?1 0 0.0 73 (82.8. 39 (69.2. 96.4) 92.4) False 0 0.0 1.3 0 0.0 I don't know 0 0.0 6 7.5 8 17.0 Question 14: What should you do if an adult who has not been prescribed a TIRF medicine takes a TM medicine? (Please select one.) . 88.8 85.1 emelgenfy help right away. 94 93 .8). Wait an hour and see if the person nothingdon't know 0 0.0 2 2.5 3 6.4 Correct response Client: TRIG Project: TIRF Wave2 Report Run Date and Time: 11/11/2013 5:10:00 PM Page 2 of 2 037 TABLE 11.1.5 PRIMARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #6 KEY RISK MESSAGE 6: TIRF MEDICINES SHOULD BE STORED IN A SAFE PLACE AWAY FROM CHILDREN AND PROPERLY DISPOSED. SUB-GROUP ANALYSIS 5: MODALITY TO COMPLETE SURVEY: Internet 0 Telephone Question S?5b Internet Telephone N=l75 (95% CI) (95% CI) Question 13: Please answer True, False, or I don?t know for each statement about the TIRF medicine that was most recently prescribed for you. 13a: TIRF medicines should be stored in a safe place out of the reach of children. 100.0 100.0 True 175 (97.9. 100.0) 127 (97.1. 100.0) False 0 0.0 0 0.0 I don't know 0 0.0 0 0.0 Question 17: Please answer True, False, or I don?t know for each statement about the TIRF medicine that was most recently prescribed for you. 17c: TIRF medicines must be disposed of as described in the speci?c product?s Medication Guide. True 165 (89971-9372) 120 False 0 0.0 0 0.0 I don't know 10 5.7 7 5.5 17c: A TIRF medicine can cause an overdose and death in any child who takes it. me 163 (88330164) 1 12 (81.22.1532) False 0.6 1 0.8 I don't know 11 6.3 14 11.0 Client: TRIG Project: TIRF Wave 2 Report Run Date and Time: 11/13/2013 2:29:00 PM Page 1 of 2 038 Get emergency help right away. 153 87.4 111 87.4 [11 (81.6, 92.0) (80.3, 926) Walt an hour and see 1f the 6 3'4 11 8.7 person 15 OK. Do nothing. 2 1.1 0 0.0 I don't know 14 8.0 3.9 Correct response Client: TRIG Project: Report Run Date and Time: 11/13/2013 2:29:00 PM Page 2 of 2 039 TABLE 11.1.6 PRINIARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #6 KEY RISK MESSAGE 6: TIRF MEDICINES SHOULD BE STORED IN A SAFE PLACE AWAY FROM CHILDREN AND PROPERLY DISPOSED. SUB-GROUP ANALYSIS 6: HIGHEST LEVEL OF EDUCATION (QUESTION 37): S-6a - Less than, Some, or High school graduate/GED or prefer not to answer S-6b - Some college or associate degree S-6c - Bachelor?s degree or Master?s degree S-6d - Professional or Doctoral degree S?6a 86b S?6c S?6d High School Some college Bachelor or Master Doctoral degree (95% CI) (95% CI) (95% CI) (95% CI) Question 13: Please answer True, False, or I don?t know for each statement about the TIRF medicine that was most recently prescribed for you. 13a: TIRF medicines should be stored in a safe place out of the reach of children. 100.0 100.0 100.0 100.0 True ?1 59 (93.9. 141 (97.4. 82 (95.6. 20 (83.2. 100.0) 100.0) 100.0) 100.0) False don't know 0.0 Client: TRIG Project: TIRF Wave2 Report Run Date and Time: 11/7/2013 1:53:00 PM Page 1 of 3 040 Question S?6a S?6b S?6c S?6d High School Some college Bachelor or Master Doctoral degree N=l4l (95% CI) (95% CI) (95% CI) (95% CI) Question 17: Please answer True, False, or I don?t know for each statement about the TIRF medicine that was most recently prescribed for you. 17c: TIRF medicines must be disposed of as described in the speci?c product?s Medication Guide. 89.8 93.6 98.8 95.0 True ?1 53 (79.2. 132 (88.2. 81 (93.4. 19 (75.1. 96.2) 97.0) 100.0) 99.9) False don't know 6 10.2 9 6.4 1 1.2 1 5.0 l7e: A TIRF medicine can cause an overdose and death in any child who takes it. 88.1 91.5 92.7 90.0 True ?1 52 (77.1. 129 (85.6. 76 (84.8. 18 (68.3. 95.1) 95.5) 97.3) 98.8) False don't know 6 10.2 12 8.5 6 7.3 1 5.0 Client: TRIG Project: TIRF WaveZ Report Run Date and Time: 11/7/2013 1:53:00 PM Page 2 of 3 041 Question S-6a S-6b S-6c S-6d High School Some college Bachelor or Master Doctoral degree N=l4l (95% CI) (95% CI) (95% CI) (95% CI) Question 14: What should you do if an adult who has not been prescribed a TIRF medicine takes a TIRF medicine? (Please select one.) Get emer enc hel 84'7 90-8 87-8 70.0 n- In awag my 50 (73.0. 128 (84.7. 72 (78.7. 14 (45.7. y' 92.8) 95.0) 94.0) 88,1) Wait an hour and see if the person nothingdon't know 6 10.2 4 2.8 4 4.9 5 25.0 Correct response Client: TRIG Project: Report Run Date and Time: 11/7/2013 1:53:00 PM Page 3 of 3 042 TABLE 11.1.7 PRINIARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #6 KEY RISK MESSAGE 6: TIRF MEDICINES SHOULD BE STORED IN A SAFE PLACE AWAY FROM CHILDREN AND PROPERLY DISPOSED. SUB-GROUP ANALYSIS 7: AGE GROUP OF RESPONDENT (QUESTION 6): S-7a 18 to 39 S-7b - 40 to 49 S-7c 50 to 59 S-7d 60 or older Question S?7a S?7b S?7c S-older (95% CI) (95% CI) (95% CI) (95% CI) Question 13: Please answer True, False, or I don?t know for each statement about the TIRF medicine that was most recently prescribed for you. 13a: TIRF medicines should be stored in a safe place out of the reach of children. 100.0 100.0 100.0 100.0 True ?1 32 (89.1. 70 (94.9. 126 (97.1. 74 (95.1. 100.0) 100.0) 100.0) 100.0) False don't know 0.0 Client: TRIG Project: TIRF Wave2 Report Run Date and Time: 11/7/2013 1:57:00 PM Page 1 of 2 043 Question S?7a S?7b S?7c S-older (95% CI) (95% CI) (95% CI) (95% CI) Question 17: Please answer True, False, or I don?t know for each statement about the TIRF medicine that was most recently prescribed for you. 17c: TIRF medicines must be disposed of as described in the speci?c product?s Medication Guide. True 3?2 (8913(10000) 65 (84.959916) 121 (9123387) 67 (81.299561) False don't know 9.5 17e: A TIRF medicine can cause an overdose and death in any child who takes it. True 27 (67.34.1347) 64 916.8) ?9 (88.99%.9177) 65 (78.279843) False don't know 4 12.5 5 7.1 7 5.6 9 12.2 Question 14: What should you do if an adult who has not been prescribed a TIRF medicine takes a TIRF medicine? (Please select one.) Get emergency help right 90.6 90.0 85.7 86.5 away. ?1 29 (75.0. 98.0) 63 (80.5. 95.9) 108 (78.4. 91.3) 64 (76.5. 93.3) Wart an hour and see 6.8 pelson 18 OK. Do nothingdon't know Correct response Client: TRIG Project: TIRF Wave2 Report Run Date and Time: 11/7/2013 1:57:00 PM Page 2 of 2 044 TABLE 11.2 SECONDARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #6 KEY RISK MESSAGE 6: TIRF MEDICINES SHOULD BE STORED IN A SAFE PLACE AWAY FROM CHILDREN AND PROPERLY DISPOSED. Patients Caregivers Patients &1Caregivers Demonstrated Understanding Nigoz 0 correct responses correct response correct responses correct responses 50 16.6 0 0.0 50 16.6 4 correct responses 236 78.4 1 100.0 237 78.5 Average number of correct responses 3.7 (3.5. 4.0) 4.0 (0.7. 4.0) 3.7 (3.5. 4.0) ?21 Number of eligible respondents completing the sruvey (See Table 1). One-sided 95 con?dence interval using the normal approximation to the Poisson distribution. Client: TRIG Project: TIRF Wave 2 Report Run Date and Time: 11/7/2013 4:25:00 PM Page 1 of 045 TABLE 11.2.1 SECONDARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #6 KEY RISK MESSAGE 6: TIRF MEDICINES SHOULD BE STORED IN A SAFE PLACE AWAY FROM CHILDREN AND PROPERLY DISPOSED. SUB-GROUP ANALYSIS 1: READING MEDICATION GUIDE (QUESTION 18, 23 AND 24) S-la - Respondents who received the Medication Guide and read at least most of it S-lb - Respondents who did not receive a Medication Guide or answered don?t know? or who received a Medication Guide and read only some of it or answered don?t know?. S-la S-lb Read most of Med Guide Read some or none of Demonstrated Understanding Med Guide 0 correct responses 0 0.0 0 0.0 1 correct response 0 0.0 2 3.7 2 conect responses 7 2.8 6 11.1 3 correct responses 37 14.9 13 24.1 4 correct responses 204 82.3 33 61.1 Average number of correct responses 3.8 (3.6. 4.0) 3.4 (3.0. 4.0) One-sided 95 con?dence interval using the normal approximation to the Poisson distribution. Client: TRIG Project: TIRF Wave2 Report Run Date and Time: 11/7/2013 1:43:00 PM Page 1 of 046 TABLE 11.2.2 SECONDARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #6 KEY RISK MESSAGE 6: TIRF MEDICINES SHOULD BE STORED IN A SAFE PLACE AWAY FROM CHILDREN AND PROPERLY DISPOSED. SUB-GROUP ANALYSIS 2: UNDERSTANDING OF MEDICATION GUIDE (QUESTION 25) S-2a - Respondents who understood all of it or most of it S-2b Respondents who understood some of it S-2c Respondents who answered None or don?t know? 0 S-2d - Respondents who answered don?t know? to receipt or reading of the Medication Guide. S-2d S-2a 2b S-2c Did not Get or Understood All - None/I don't Read Understood Some kn d' . Demonstrated Understanding or ?St lcatlon N=l Guide 0 correct responses con?ect response c01rect responses 6 2.4 5.6 1 100.0 5 15.6 3 c01rect responses 40 15.9 4 22.2 0.0 6 18.8 4 correct responses 204 81.3 13 72.2 0 0.0 20 62.5 Average number of correct responses 3.8 (3.6. 4.0) ?1 3.7 (2.9. 4.0) ?1 2.0 (-0.3. 4.0) "1 3.4 (2.9. 4.0) ?1 One-sided 95 con?dence interval using the normal approximation to the Poisson distribution. Client: TRIG Project: TIRF Wave2 Report Run Date and Time: 11/8/2013 10:55:00 AM Page 1 of 047 TABLE 11.2.3 SECONDARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #6 KEY RISK MESSAGE 6: TIRF MEDICINES SHOULD BE STORED IN A SAFE PLACE AWAY FROM CHILDREN AND PROPERLY DISPOSED. SUB-GROUP ANALYSIS 3: TIME TO COMPLETE SURVEY - INTERNET: S-3a - <10 min 0 S-3b - 10 to<20 min 0 S-3c - 220 min S-3a S-3b S-3c Demonstrated Understanding <11:=:17in 10 t?:1230min 23:2?! 0 correct responses con?ect response correct responses correct responses 4 8.5 14 14.0 4 14.3 4 correct responses 42 89.4 79 79.0 22 78.6 Average number of correct responses 3.9 (3.4. 4.0) 3.7 (3.4. 4.0) 3.7 (3.1. 4.0) One-sided 95 con?dence inten?al using the normal approximation to the Poisson distribution. Client: TRIG Project: TIRF Wave 2 Report Run Date and Time: 11/8/2013 11:43:00 AM Page 1 of 048 TABLE 11.2.4 SECONDARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #6 KEY RISK MESSAGE 6: TIRF MEDICINES SHOULD BE STORED IN A SAFE PLACE AWAY FROM CHILDREN AND PROPERLY DISPOSED. SUB-GROUP ANALYSIS 4: TIME TO COMPLETE SURVEY - TELEPHONE: 0 8?43 - <10 min 0 S-4b - 10 to<20 min 0 S-4c - 220 min S-4a S-4b S-4c <10 min 10 to <20 min 220 min Demonstrated Understanding 0 correct responses 0 0.0 0 0.0 0.0 1 correct response 0 0.0 0 0.0 0.0 2 correct responses correct responses 0 0.0 17 21.3 11 23.4 4 correct responses 0 0.0 61 76.3 33 70.2 Average number of correct responses 0 (0.0. 4.0) 3.7 (3.4. 4.0) 3.6 (3.2. 4.0) "1 One-sided 95 con?dence interval using the normal approximation to the Poisson distribution. Client: TRIG Project: TIRF Wave 2 Report Run Date and Time: 11/11/2013 5:10:00 PM Page 1 of 049 TABLE 11.2.5 SECONDARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #6 KEY RISK MESSAGE 6: TIRF MEDICINES SHOULD BE STORED IN A SAFE PLACE AWAY FROM CHILDREN AND PROPERLY DISPOSED. SUB-GROUP ANALYSIS 5: MODALITY TO COMPLETE SURVEY: S-5a Internet 0 S-5b Telephone S-5a - Internet S-5b - Telephone Demonstrated Understanding 0 correct responses 0 0.0 0 0.0 1 correct response 2 1.1 0 0.0 2 correct responses 8 4.6 5 3.9 3 c01rect responses 22 12.6 28 22.0 4 correct responses 143 81.7 94 74.0 Average number of correct responses 3.7 (3.5. 4.0) ?1 3.7 (3.4. 4.0) "1 One-sided 95 con?dence interval using the normal approximation to the Poisson distribution. Client: TRIG Project: TIRF Wave 2 Report Run Date and Time: 11/7/2013 1:50:00 PM Page 1 of 050 TABLE 11.2.6 SECONDARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #6 KEY RISK MESSAGE 6: TIRF MEDICINES SHOULD BE STORED IN A SAFE PLACE AWAY FROM CHILDREN AND PROPERLY DISPOSED. SUB-GROUP ANALYSIS 6: HIGHEST LEVEL OF EDUCATION (QUESTION 37): S-6a - Less than, Some, or High school graduate/GED or prefer not to answer S-6b - Some college or associate degree S-6c - Bachelor?s degree or Master?s degree S-6d - Professional or Doctoral degree S-6a S-6b S-6c S-6d High School Some college Bachelor or Master Doctoral degree Demonstrated Understanding N=l41 0 correct responses correct response correct responses correct responses 13 22.0 20 14.2 11 13.4 6 30.0 4 correct responses 42 71.2 114 80.9 68 82.9 13 65.0 Average number of correct responses 3.6 (3.2. 4.0) ?1 3.8 (3.5. 4.0) ?1 3.8 (3.4. 4.0) ?1 3.6 (2.9. 4.0) "1 [ll One-sided 95 con?dence interval using the normal approximation to the Poisson distribution. Client: TRIG Project: TIRF Wave 2 Report Run Date and Time: 11/7/2013 1:55:00 PM Page 1 of 051 TABLE 11.2.7 SECONDARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #6 KEY RISK MESSAGE 6: TIRF MEDICINES SHOULD BE STORED IN A SAFE PLACE AWAY FROM CHILDREN AND PROPERLY DISPOSED. SUB-GROUP ANALYSIS 7: AGE GROUP OF RESPONDENT (QUESTION 6): S-7a 18 to 39 S-7b - 40 to 49 S-7c 50 to 59 S-7d 60 or older S-7a S-7b S-7c S-older Demonstrated Understanding 0 correct responses correct response correct responses correct responses 6 18.8 14 20.0 19 15.1 11 14.9 4 correct responses 25 78.1 54 77.1 102 81.0 56 75.7 Average number of correct responses 3.8 (3.2. 4.0) "1 3.7 (3.4. 4.0) ?1 3.8 (3.5. 4.0) "1 3.6 (3.3. 4.0) One-sided 95 con?dence interval using the normal approximation to the Poisson distribution. Client: TRIG Project: TIRF WaveZ Report Run Date and Time: 11/7/2013 1:59:00 PM Page 1 of 052 Patient KAB Assessment Report Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Appendix C Page 54 of 54 Patient Survey Protocol Track Change Document: Comparison of 12month Survey to 24-month Survey FDA_1053 PROTOCOL TITLE: Quantitative Testing of Patient/Caregiver Knowledge, Attitudes, and Behavior about Transmucosal Immediate Release Fentanyl (TIRF) Products Safety and Use Information SPONSOR: TIRF REMS Industry Group (TRIG) Archimedes Pharma US Inc. Cephalon, Inc. (a wholly-owned subsidiary of Teva Pharmaceutical Industries, Ltd.) Endo Pharmaceuticals Inc. Galena Biopharma Insys Therapeutics Mallinckrodt, the Pharmaceuticals Business of Covidien Meda Pharmaceuticals Mylan, Inc. Par Pharmaceutical, Inc. VERSION: 64.0 DATE: 10 Sep22 May 2013 APPROVED: FINAL FDA_1054 TIRF REMS Industry Group (TRIG) Transmucosal Immediate Release Fentanyl (TIRF) Products Patient/Caregiver KAB Survey Protocol TABLE OF CONTENTS Version 64 0 10 Sep22 May 2013 PAGE TABLE OF CONTENTS TABLE OF CONTENTS ......................................................................................................... 2 1. LIST OF ABBREVIATIONS ................................................................................ 43 2. BACKGROUND ................................................................................................... 54 3. OBJECTIVES OF THE EVALUATION SURVEY ............................................. 65 4. METHODS ............................................................................................................ 65 4.1 4.1.1 4.1.2 Survey Design ........................................................................................................ 65 Questions and Statements on REMS Goals ........................................................... 76 Additional Questions.......................................................................................... 1110 4.2 4.2.1 Subject Recruitment ........................................................................................... 1110 Measures to Minimize Bias in the Sample......................................................... 1211 5. 5.1.1 5.1.2 5.1.3 STUDY POPULATION .................................................................................... 1311 Sample Size ........................................................................................................ 1311 Inclusion Criteria................................................................................................ 1312 Exclusion Criteria .............................................................................................. 1412 6. SURVEY PROCESS ......................................................................................... 1413 6.1 6.1.1 6.1.2 Screening and Survey Administration ............................................................... 1413 Telephone ........................................................................................................... 1413 Internet ............................................................................................................... 1413 6.2 Measures to Minimize Bias in the Survey Process ............................................ 1513 7. ANALYSIS ........................................................................................................ 1514 8. SAFETY EVENT REPORTING ....................................................................... 1615 9. PRIVACY PROTECTION AND CONFIDENTIALITY.................................. 1615 LIST OF APPENDICES APPENDIX A Screening and Main Questionnaire....................................................... 1816 APPENDIX B Patient Letter of Invitation .................................................................... 4336 2 of 44 FDA_1055 TIRF REMS Industry Group (TRIG) Transmucosal Immediate Release Fentanyl (TIRF) Products Patient/Caregiver KAB Survey Protocol Version 64 0 10 Sep22 May 2013 3 of 44 FDA_1056 TIRF REMS Industry Group (TRIG) Transmucosal Immediate Release Fentanyl (TIRF) Products Patient/Caregiver KAB Survey Protocol 1. Version 64 0 10 Sep22 May 2013 LIST OF ABBREVIATIONS CATI CI EDC ETASU FDA HIPAA IRB KAB PBM PPAF REMS SE/PSP TIRF TIRF REMS TRIG UBC US Computer-Assisted Telephone Interviewing Confidence Interval Electronic Data Capture Elements to Assure Safe Use Food and Drug Administration Health Insurance Portability and Accountability Act Institutional Review Board Knowledge, Attitudes and Behavior Pharmacy Benefits Management Patient-Prescriber Agreement Form Risk Evaluation and Mitigation Strategy Safety Event Project Specific Procedure Transmucosal Immediate Release Fentanyl TIRF REMS Access Program TIRF REMS Industry Group United BioSource Corporation United States 4 of 44 FDA_1057 TIRF REMS Industry Group (TRIG) Transmucosal Immediate Release Fentanyl (TIRF) Products Patient/Caregiver KAB Survey Protocol 2. Version 64 0 10 Sep22 May 2013 BACKGROUND Transmucosal Immediate Release Fentanyl (TIRF) medicines include the class of immediaterelease opioid analgesics, which are indicated only for the management of breakthrough pain in cancer patients 18 years of age or older (16 or older for Actiq® and equivalent generics) who are already receiving and already tolerant to opioid therapy for their underlying persistent cancer pain. The TIRF medicines include Abstral®, Actiq®, Fentora®, Lazanda®, Onsolis®, Subsys®, and generic versions of any of these brands. The TIRF REMS Industry Group (TRIG) includes Archimedes Pharma US Inc.; Cephalon, Inc. (a wholly-owned subsidiary of Teva Pharmaceutical Industries, Ltd.); Endo Pharmaceuticals Inc.; Galena Biopharma; Insys Therapeutics; Mallinckrodt, the Pharmaceuticals Business of Covidien; Meda Pharmaceuticals; Mylan, Inc.; and Par Pharmaceutical, Inc. The Food and Drug Administration (FDA) has determined that a class-wide Risk Evaluation and Mitigation Strategy (REMS) is required to mitigate the risks of misuse, abuse, addiction, overdose and serious complications due to medication errors with the use of TIRF medicines. The TIRF REMS Access Program (hereafter referred to as TIRF REMS) was approved by the FDA on December 28, 2011. The TIRF REMS consists of a Medication Guide, Elements to Assure Safe Use (ETASU), an Implementation System, and a timetable for submission of assessments of the REMS. The goals of the TIRF REMS are to mitigate the risk of misuse, abuse, addiction, overdose and serious complications due to medication errors by: 1. Prescribing and dispensing TIRF medicines only to appropriate patients, which includes use only in opioid-tolerant patients 2. Preventing inappropriate conversion between TIRF medicines 3. Preventing accidental exposure to children and others for whom it was not prescribed 4. Educating prescribers, pharmacists, and patients on the potential for misuse, abuse, addiction, and overdose of TIRF medicines An important component of the TIRF REMS assessment is the conduct of quantitative evaluation surveys to assess patients’ and caregivers’ knowledge, attitudes, and behavior (KAB) regarding the safe use of TIRF medicines, as described in the product-specific Medication Guide. This protocol will describe the administration of the surveys that will be conducted among patients who are treated with TIRF medicines, or their caregivers. Data from the surveys, together with other REMS evaluation metrics, will be used to determine whether changes need to be made to the REMS processes and/or educational materials to make them more effective in achieving the goals of the REMS. 5 of 44 FDA_1058 TIRF REMS Industry Group (TRIG) Transmucosal Immediate Release Fentanyl (TIRF) Products Patient/Caregiver KAB Survey Protocol Version 64 0 10 Sep22 May 2013 The surveys will be implemented so that data will be available for inclusion in the REMS Assessment Reports that will be submitted to the FDA at 12 months after approval of the TIRF REMS and annually thereafter. 3. OBJECTIVES OF THE EVALUATION SURVEY The evaluation survey will use a questionnaire to document the level of knowledge and assess the attitudes and behavior of patients around the following key information and risk messages communicated through the REMS: 1) TIRF medicines can cause life-threatening breathing problems that can lead to death. 2) Patients should not take TIRF medicines if they are not opioid tolerant. 3) TIRF medicines should be taken exactly as prescribed by the healthcare provider. 4) Patients should not switch from a TIRF medicine to another medicine that contains fentanyl without talking to a healthcare provider. 5) Patients should not give TIRF medicines to anyone else even if they have the same symptoms. 6) TIRF medicines should be stored in a safe place away from children and properly disposed. The survey will also include questions about whether patients received, read, and understood the product-specific Medication Guide and Patient-Prescriber Agreement Form (PPAF). 4. METHODS The survey was designed in collaboration between the TRIG and United BioSource Corporation (UBC), and will be administered by UBC. 4.1 Survey Design This survey will be conducted among a sample of patients who have filled a prescription for a TIRF medicine within the past 43 months prior to survey launch and their caregivers. Respondents who have participated in a previous wave of the TIRF REMS KAB survey will not be eligible to participate in subsequent survey waves. The survey will be administered using the following modalities:  Self-administered, online through a secure website 6 of 44 FDA_1059 TIRF REMS Industry Group (TRIG) Transmucosal Immediate Release Fentanyl (TIRF) Products Patient/Caregiver KAB Survey Protocol  Version 64 0 10 Sep22 May 2013 Telephone surveys facilitated by a trained interviewer from the Survey Coordinating Center using a computer-assisted telephone interviewing (CATI) program The survey will begin with screening questions to confirm respondent eligibility to participate in the survey. Completion of the entire survey is expected to take approximately 20 minutes. The survey included in Appendix B is written to reflect wording for both methods of survey administration: Internet-based and telephone administration. 4.1.1 Questions and Statements on REMS Goals The KAB items of the questionnaire are made up of multiple-choice, closed-ended statements or questions (the majority of which use true/false or yes/no dichotomous response options), and open-ended questions. These will evaluate current knowledge, attitudes, and behavior regarding the key risk messages noted in Section 3. The survey is written to follow principles of health literacy and readability. Questionnaire items will be presented in several formats:  Statements or questions asking the respondent to indicate whether a statement or question is true or false, or if they do not know the answer (there is a similar set of statements and questions that use “yes,” “no,” or “I don’t know” as potential response options);  Statements or questions asking the respondent to choose from a defined list of possible statements or answers; and  Questions allowing for the respondent to provide information about when, where and from whom they obtained a Medication Guide, as well as to list questions about information in the Medication Guides. Questionnaires will be analyzed to determine patient understanding of each key risk message. For statements or questions that use “true” or “yes” vs. “false” or “no” response options, the desired response for the key risk messages is generally “true” or “yes” indicating knowledge of, or behavior in accordance with, the objectives of the REMS. However, some questions are formatted to have the respondent disagree with the statement as written by providing response options of “false” or “no” to avoid having the same affirmative answer for all desired responses. REMS statements, corresponding questions, and desired responses covering the key risk messages are identified below and can be found in the complete survey questionnaire (Appendix A). For better readability, the patient questions, only, are presented in the key risk messages tables. Caregiver questions are presented in Appendix A. 7 of 44 FDA_1060 TIRF REMS Industry Group (TRIG) Transmucosal Immediate Release Fentanyl (TIRF) Products Patient/Caregiver KAB Survey Protocol Version 64 0 10 Sep22 May 2013 Key Risk Message 1: TIRF medicines can cause life-threatening breathing problems that can lead to death. Question No. 1312 13d12d Question Desired response Please answer True, False, or I don’t know for each statement about the TIRF medicine that was most recently prescribed for you. TIRF medicines can cause life-threatening breathing problems that can lead to death. TRUE Key Risk Message 2: Patients should not take TIRF medicines if they are not opioid tolerant. Question No. Question Desired response Please answer True, False, or I don’t know for the following statement: 1110 1211 12a11a 1312 13b12b TIRF medicines should only be taken by patients TRUE who are opioid tolerant. Please answer True, False, or I don’t know for each of the following statements. Opioid tolerant means that a patient is already taking other opioid pain medicines around-theTRUE clock and their body is used to these medicines. Please answer True, False, or I don’t know for each statement about the TIRF medicine that was most recently prescribed for you. It is OK for patients to take TIRF medicines for FALSE headache pain. Key Risk Message 3: TIRF medicines should be taken exactly as prescribed by the healthcare provider. Question No. 1211 Question Desired response Please answer True, False, or I don’t know for each of the following statements. 8 of 44 FDA_1061 TIRF REMS Industry Group (TRIG) Transmucosal Immediate Release Fentanyl (TIRF) Products Patient/Caregiver KAB Survey Protocol 12b11b 13/1712/16 13c12c 17b16b If a patient stops taking around-the-clock opioid pain medicine, they must also stop taking the TIRF medicine. Version 64 0 10 Sep22 May 2013 TRUE Please answer True, False, or I don’t know for each statement about the TIRF medicine that was most recently prescribed for you. TIRF medicines should be taken exactly as TRUE prescribed by the doctor. It is OK to take TIRF medicines for short-term FALSE pain that will go away in a few days. 9 of 44 FDA_1062 TIRF REMS Industry Group (TRIG) Transmucosal Immediate Release Fentanyl (TIRF) Products Patient/Caregiver KAB Survey Protocol Version 64 0 10 Sep22 May 2013 Key Risk Message 4: Patients should not switch from a TIRF medicine to another medicine that contains fentanyl without talking to a healthcare provider. Question No. 1211 12c11c Question Desired response Please answer True, False, or I don’t know for each of the following statements. It is safe to switch to another medicine that contains fentanyl without talking to a healthcare FALSE provider first. Key Risk Message 5: Patients should not give TIRF medicines to anyone else even if they have the same symptoms. Question Question No. 1211 12d11d 1716a 17a16a Desired response Please answer True, False, or I don’t know for each of the following statements. A patient may give TIRF medicines to another person if they have the same symptoms as the FALSE patient. Please answer True, False, or I don’t know for each statement about the TIRF medicine that was most recently prescribed for you. Selling or giving away TIRF medicines is against TRUE the law. 10 of 44 FDA_1063 TIRF REMS Industry Group (TRIG) Transmucosal Immediate Release Fentanyl (TIRF) Products Patient/Caregiver KAB Survey Protocol Version 64 0 10 Sep22 May 2013 Key Risk Message 6: TIRF medicines should be stored in a safe place away from children and properly disposed. Question No. Question 13/1712/16 13a12a 17c16c 17e16e 1313 4.1.2 Desired response Please answer True, False, or I don’t know for each statement about the TIRF medicine that was most recently prescribed for you. TIRF medicines should be stored in a safe TRUE place out of the reach of children. TIRF medicines must be disposed of as described in the specific product’s TRUE Medication Guide. A TIRF medicine can cause an overdose TRUE and death in any child who takes it. What should you do if an adult who has not Get emergency help right been prescribed a TIRF medicine takes a away. TIRF medicine? (Please select one.) Additional Questions Questions about the requirements of the TIRF REMS, and receipt and understanding of the Medication Guides and PPAF will be asked after the key risk message questions, and will be followed by the collection of demographic information at the completion of the survey. 4.2 Subject Recruitment Patients will be recruited through a direct letter program. Patients will be invited through a network of national pharmacies and apharmacy chain network partner or pharmacy benefits management (PBM) partner, which each have broad demographic coverage and include patients in 49 states. Leveraging one or more of these partners, a list will be created of patients who have filled a prescription for a TIRF medicine within 43 months prior to survey launch (first prescriptions and refills). Patients in this list will be invited to participate in the survey through an invitation letter (Appendix B) mailed directly to the patients on the pharmacy or PBM’s letterhead at the corporate level via the United States (US) Postal Service. Additionally, outbound calls will be placed to prescribers to ask for their support in informing patients about the opportunity to participate in the survey by providing an invitation directly to patients who are prescribed a TIRF medicine. A random sample of up to 250 prescribers with at least 5 patients who have filled prescriptions in the 4 months prior to survey implementation will be contacted for this purpose. If a prescriber expresses willingness to support the survey effort, an information packet including invitation letters will be mailed to the prescriber. Prescribers will not receive any compensation for this support. 11 of 44 FDA_1064 TIRF REMS Industry Group (TRIG) Transmucosal Immediate Release Fentanyl (TIRF) Products Patient/Caregiver KAB Survey Protocol Version 64 0 10 Sep22 May 2013 The invitation will indicate that participants will receive a $5025 gift card for completing the survey. Each invitation will also include a unique code and directions for accessing the survey either via the Internet or by telephone through an interviewer at the Survey Coordinating Center. The unique code will be used to identify the manufacturer of the most recent TIRF prescription that the patient filled. A random sample of patients who have filled a prescription for a TIRF medicine within the 43 months prior to survey launch will be chosen from the pharmacy partner’s or PBM database. This sampling approach will be used to create several batches of survey invitations. The overall number of unique patients and the duration of the survey period will dictate the size and number of invitation batches. If the required number of completed surveys is not achieved within a reasonable time frame, a second mailing will be sent to non-respondents from the original batch mailing and initial invitations will be sent to patients in the second batch. If the required number of completed surveys is still not achieved within a reasonable time frame, reminder letters will be sent to the patients in the second batch and initial invitations will be sent to the third batch of patients. If these efforts do not result in the required number of surveys within a reasonable time frame, then a new random sample of patients may be selected. The intervals for sending reminder invitations to non-responders and for selecting a new sample will be condensed as necessary based on the actual rate of survey accrual relative to the proximity of the target survey close date. All respondents who complete the survey and who provide their contact information will be mailed a $5025 gift card to thank them for their participation. The mailing will include a thank you letter, a copy of the product-specific Medication Guide, and a copy of the correct answers to the key risk message questions. 4.2.1 Measures to Minimize Bias in the Sample The sample of participating patients will be self-selected since respondents will voluntarily respond to the invitation to participate; however, the survey recruitment strategies are intended to recruit a heterogeneous sample of patients for participation. Respondents will be offered online or telephone options for completing the survey. Multiple modalities for survey data collection allow for wider survey access to a more heterogeneous population. Respondents will be provided a unique code during the recruitment process and will be asked to provide the unique code to gain access to the online survey or when calling the Survey Coordinating Center. The code will be deactivated after use to minimize the possibility for fraud. 12 of 44 FDA_1065 TIRF REMS Industry Group (TRIG) Transmucosal Immediate Release Fentanyl (TIRF) Products Patient/Caregiver KAB Survey Protocol 5. STUDY POPULATION 5.1.1 Sample Size Version 64 0 10 Sep22 May 2013 A sample of 300 patients treated with TIRF medicines is proposed for the survey wave. The size of the sample was determined based on both practical and statistical considerations. There is no target comprehension rate specified a priori. A sample of 300 completed surveys will allow estimation of the comprehension rate for each key risk message with a moderately high degree of precision. The table below shows the precision of the estimates for level of understanding using two-sided 95% confidence intervals (CIs) obtained with the sample size of 300 completed surveys. The noted CIs are used to indicate that for any survey-estimated rate of understanding, the true population rate of understanding is at least as high as the lower limit of the 95% CI and may be as high as the upper limit of the 95% CI. Table 5.1: Precision of Estimated Rates of Understanding with a Sample Size of 300 Estimated Rate of Understanding 5% 10% 15% 20% 25% 30% 35% 40% 45% 50% 55% 60% 65% 70% 75% 80% 85% 90% 95% 5.1.2 Estimated Confidence Interval 2.8% 8.1% 6.8% 14.0% 11.2% 19.6% 15.6% 25.0% 20.2% 30.3% 24.9% 35.5% 29.6% 40.7% 34.4% 45.8% 39.3% 50.8% 44.2% 55.8% 49.2% 60.7% 54.2% 65.6% 59.3% 70.4% 64.5% 75.1% 69.7% 79.8% 75.0% 84.4% 80.4% 88.8% 86.0% 93.2% 91.9% 97.2% Inclusion Criteria The following respondents are eligible to participate in the survey:  Patients who are 18 years of age or older who have filled a prescription for at least one of the TIRF medicines within 43 months prior to survey launch  Caregivers 18 years of age or older who care for patients who have filled a TIRF medicine prescription within the past 43 months prior to survey launch and are unable to take the survey for themselves 13 of 44 FDA_1066 TIRF REMS Industry Group (TRIG) Transmucosal Immediate Release Fentanyl (TIRF) Products Patient/Caregiver KAB Survey Protocol 5.1.3 Version 64 0 10 Sep22 May 2013 Exclusion Criteria The following respondents are not eligible to participate in the surveys:  Patients who have previously participated in the TIRF REMS KAB survey (this exclusion applies to the second and subsequent waves only)  Patients or their immediate family members who have ever worked for Anesta LLC, Archimedes Pharma US Inc.; Cephalon, Inc. (a wholly-owned subsidiary of Teva Pharmaceutical Industries, Ltd.); Endo Pharmaceuticals Inc.; Galena Biopharma; Insys Therapeutics; Mallinckrodt, the Pharmaceuticals Business of Covidien; Meda Pharmaceuticals; Mylan, Inc.; Par Pharmaceutical, Inc.; ProStrakan Inc.; Teva Pharmaceuticals, Ltd.; UBC; McKesson Specialty Care Solutions; RelayHealth; or the FDA. 6. SURVEY PROCESS 6.1 Screening and Survey Administration The questionnaire will begin with a screening module with questions to confirm patient eligibility. The entire survey is expected to take approximately 20 minutes to complete. Depending on the answers to the screening questions, survey participation could either be terminated or continued. If ineligible, respondents are immediately notified with a thank you message that survey participation has ended. If eligible, respondents are allowed to continue survey participation. The electronic data capture (EDC) system that is used for both methods of survey administration has been validated and is secure for receiving and storing survey data. The system is 21 CFR Part 11 and Health Insurance Portability and Accountability Act (HIPAA) compliant. Patient-identifying information will be stored separately from survey data. 6.1.1 Telephone The telephone survey is facilitated by a trained interviewer from the Survey Coordinating Center using a CATI program. The respondent will be required to provide a unique code to access the survey. Working from a CATI script, the interviewer will read questions or statements to the respondent and enter the responses into the EDC system. Screening and main elements of the questionnaire will be administered sequentially during the same telephone call. Telephone interviewing allows participation of respondents who do not have Internet access, or prefer to complete the survey in this manner. 6.1.2 Internet An Internet-based survey system will also be used for conducting the KAB surveys. If respondents select to participate in the survey online, they will be directed to a secured website and instructed to enter a unique code to access the survey. An Internet survey will be 14 of 44 FDA_1067 TIRF REMS Industry Group (TRIG) Transmucosal Immediate Release Fentanyl (TIRF) Products Patient/Caregiver KAB Survey Protocol Version 64 0 10 Sep22 May 2013 convenient for respondents to participate since they can complete the questionnaire at any convenient time and location during the specified survey time period. 6.2 Measures to Minimize Bias in the Survey Process A number of controls will be in place to ensure the survey is conducted in a controlled and professional manner and to minimize bias. For example, a unique code will be given to each survey participant and the code will be inactivated after use to minimize fraud. Telephone interviewers are highly trained and use a standardized script to administer interviews. All questions will be programmed to ensure that questions are asked in the appropriate sequence. Skip patterns will be clearly indicated. Respondents cannot go back to a question once the question has been answered and cannot skip ahead. All questions must be answered in order to complete the survey. Response options presented in a list will be randomized to minimize positional bias. Programming will be reviewed by quality control and simulated users (User Acceptance Testing) prior to implementing the survey. 7. ANALYSIS Information obtained from the survey will be reported as descriptive statistics for the survey administration, study population, and the survey questions. Any free text fields will be grouped into applicable categories. Verbatim text from open-ended questions will be displayed when appropriate. The following will be reported as part of this analysis:  The number of invitations issued  The number of reminder letters  The number of respondents screened for participation  The number of respondents eligible for participation  The number of respondents who completed all questions presented to themthe survey  Description of survey participants, including:  Type of respondent (patient/caregiver)  Age (patient/caregiver)  Gender (respondent)  Educational level (respondent)  Main language spoken at home (respondent) 15 of 44 FDA_1068 TIRF REMS Industry Group (TRIG) Transmucosal Immediate Release Fentanyl (TIRF) Products Patient/Caregiver KAB Survey Protocol  Ethnicity (respondent)  Race (respondent)  Geographic region (respondent) Version 64 0 10 Sep22 May 2013  Data from all respondents who completed all questions presented to them in the survey (“completers”) will be analyzed, including:  Frequency distribution of responses to each key risk message question. (the number of respondents who give each answer to each question)  Percent of completersrespondents selecting desired response to each question relating to each key risk message and 95% CI. Measurement of understanding will be computed for each question of the key risk message individually. A secondary analysis will be conducted to determine the number of completersrespondents who answered all items correctly for the key risk message. Behavior questions will be summarized on a question-by-question basis and are not included in the analysis by key risk message. Additional analyses may be performed as needed. 8. SAFETY EVENT REPORTING The survey will be conducted via the Internet and by telephone. It is possible that a respondent may report an adverse event or other safety event experienced while taking TIRF medicines either in free text fields of the survey or while in conversation with the Survey Coordinating Center. If an event is mentioned to a Survey Coordinating Center Associate, the Associate will document the safety event and the respondent’s contact information. The respondent will also be informed that a representative from the appropriate TIRF medicine manufacturer may contact him/her if there are questions about the survey. The Internet-based questionnaires will be monitored for any comments recorded in free text fields. Information on all comments that may constitute an adverse event or other safety event will be forwarded to the appropriate TIRF medicine manufacturer as described in the Safety Event Project Specific Procedure (SE/PSP). Additional detail regarding processes for adverse event reporting will be specified in the SE/PSP. 9. PRIVACY PROTECTION AND CONFIDENTIALITY All data collected during the survey will be held confidential. The EDC system used for data collection encrypts all identifiable information and respondent identifiers are stored separately from the survey responses. 16 of 44 FDA_1069 TIRF REMS Industry Group (TRIG) Transmucosal Immediate Release Fentanyl (TIRF) Products Patient/Caregiver KAB Survey Protocol Version 64 0 10 Sep22 May 2013 Respondent names and addresses are collected in order to mail a $5025 gift card, a Thank You Letter, a product-specific Medication Guide, and correct survey responses to key risk message questions after the survey is completed. Respondent contact information is also requested in the event a safety event is reported and a TIRF medicine manufacturer must obtain follow-up information. A respondent may be contacted only if clarification or follow-up is needed regarding a possible safety event that was mentioned to the interviewer or recorded in free text fields of the online survey. Respondents will be informed when they access the survey that they may be contacted if there are any questions about their survey responses. Respondents will be informed that their answers to the survey questions will not affect their ability to receive TIRF medicines. This protocol and survey will be reviewed and approved by a central Institutional Review Board (IRB) before administration of the survey. 17 of 44 FDA_1070 TIRF REMS Industry Group (TRIG) Transmucosal Immediate Release Fentanyl (TIRF) Products Patient/Caregiver KAB Survey Protocol Version 64 0 10 Sep22 May 2013 APPENDIX A Screening and Main Questionnaire Survey Legend  [PROGRAMMER] is used to indicate directions to the programmer and is set in bold, red, uppercase letters between square brackets. [PATIENT] indicates text applicable to a patient when it differs from survey text for caregivers, parents and legal guardians. [PARENT/CAREGIVER/LEGAL GUARDIAN] indicates text applicable to parents, caregivers, and legal guardians when it differs from survey text for patients.  (INTERVIEWER) is used to indicate directions to the telephone interviewer and is set in bold, blue, text between parentheses. This text appears when content is to be administered by tlelphone only (for example, spontaneous adverse event reporting).  [ONLINE] indicates a question is worded specifically for administering the survey online. [PHONE] indicates a question is worded specifically to be read by a telephone interviewer and differs from the online text.  [BEGIN ONLINE/PHONE SURVEY CONTENT] and [END SURVEY CONTENT] are used to indicate to the programmer the type of survey administration and the beginning and end of the survey or sections within the survey content, for example, [BEGIN ADVERSE EVENT/PRODUCT COMPLAINT] and [END ADVERSE EVENT/PRODUCT COMPLAINT].  [TERMINATE] is displayed next to responses that should cause the survey to end. The following termination language will be programmed into the survey or read by the interviewer unless different language is specified with the question. Thank you very much for your time today. Based on your answer, you are not eligible to take this survey. We appreciate your interest in the survey.  [RANDOMIZE LIST] is inserted before questions to indicate to the programmer that the responses should be randomized. Responses such as “I don’t know,” “Prefer not to answer” or “None of the above” will always appear at the end of the randomized responses.  [GO TO Ax] (Skip logic) is inserted after a response to indicate to the programmer that the survey should skip to the indicated question (for example, [GO TO Q17] skips to question 17). If no skip logic is indicated the survey continues to the next question in the sequence. 18 of 44 FDA_1071 TIRF REMS Industry Group (TRIG) Transmucosal Immediate Release Fentanyl (TIRF) Products Patient/Caregiver KAB Survey Protocol Version 64 0 10 Sep22 May 2013 Survey Legend  [MULTILINE INPUT] indicates to the programmer that multiple lines should be provided for data entry (for example, two address lines or a free-text response).  [DROP-DOWN LIST INPUT WITH STATES TABLE] indicates to the programmer that the response should be a drop-down list containing the states in the table below. Alabama Georgia Massachusetts New York Alaska Guam Michigan North Carolina Texas American Samoa Hawaii Minnesota North Dakota Arizona Idaho Mississippi Illinois Missouri Indiana Montana Northern Mariana Islands US Virgin Islands Iowa Nebraska Kansas Nevada Kentucky New Hampshire Louisiana New Jersey Maine New Mexico Arkansas California Colorado Connecticut Delaware District of Columbia Florida Maryland Ohio Oklahoma Oregon Pennsylvania Puerto Rico Rhode Island Tennessee Utah Vermont Virginia Washington West Virginia Wisconsin Wyoming South Carolina South Dakota  The following is used to categorize survey populations into standard geographic regions but it is not displayed in the survey. Geographic Distribution (based on address) 1: Northeast, Midwest, South, and West regions Northeast Region  New England Division - ME, NH, VT, MA, RI, CT  Middle Atlantic Division - NY, NJ, PA Midwest Region  East North Central Division - OH, IN, IL, MI, WI  West North Central Division - MN, IA, MO, ND, SD, NE, KS South Region  South Atlantic Division - DE, MD, DC, VA, WV, NC, SC, GA, FL  East South Central Division - KY, TN, AL, MS  West South Central Division - AR, LA, OK, TX 19 of 44 FDA_1072 TIRF REMS Industry Group (TRIG) Transmucosal Immediate Release Fentanyl (TIRF) Products Patient/Caregiver KAB Survey Protocol Version 64 0 10 Sep22 May 2013 Survey Legend West  Mountain Division - MT, ID, WY, CO, NM, AZ, UT, NV  Pacific Division WA, OR, CA, AK, HI  The following US territories are categorized as Other: Puerto Rico, Northern Mariana Islands, US Virgin Islands, American Samoa, and Guam. 1 U.S. Census Bureau, last revised Friday, 27-Jul-2001 12:59:43 EDT. [BEGIN ONLINE/PHONE SURVEY CONTENT] [PREAMBLE 1] Before you begin, we would like to share some important information about this survey. The survey is being conducted by the makers of Abstral®, Actiq®, Fentora®, Lazanda®, Onsolis®, Subsys® and the generic versions of any of these brands. These are Transmucosal Immediate Release Fentanyl medicines, also known as rapid onset opioids (INTERVIEWER: Please pause briefly) (and sometimes called “fast acting fentanyls”) or TIRF medicines. (INTERVIEWER: Pronounce “TIRF,” then spell out T I R F). The information collected will help the makers of TIRF medicines know if patients and their caregivers understand important information about taking these medicines. The survey will take about 20 minutes. There are no known risks to you in taking this survey. You may refuse to take part or withdraw at any time without penalty or loss of benefits to which you are otherwise entitled. Your answers to the questions or your decision to take part in the survey will not affect your ability to receive or take TIRF medicines. [ONLINE PREAMBLE 1] Before you begin, we would like to share some important information about this survey. The survey is being conducted by the makers of Abstral®, Actiq®, Fentora®, Lazanda®, Onsolis®, Subsys® and the generic versions of any of these brands. These are Transmucosal Immediate Release Fentanyl medicines, also known as rapid onset opioids (and sometimes called “fast acting fentanyls”) or TIRF medicines. The information collected will help the makers of TIRF medicines know if patients and their caregivers understand important information about taking these medicines. The survey will take about 20 minutes. There are no known risks to you in taking this survey. You may refuse to take part or withdraw at any time without penalty or loss of benefits to which you are otherwise entitled. Your answers to the questions or your decision to take part in the survey will not affect your ability to receive or take TIRF medicines. 20 of 44 FDA_1073 Version?4~0 Imurdiate Release Fananyl (TIRE Products Patient/Caregiver KAB Survey Protocol 2013 We Use Your Informatio? Comment [24ml]: please mum mderlinedsmispreseubdonliuua titb oftheprunirle Boldedtextisnotahypa?link Your answers to the survey questions will be combined with answers given by other people taking the survey. All answers will be put together and reported in anonymous form to manufacturers of TIRF medicines. Your name will not be used in any report. If you are eligible to take the survey. complete all the questions. and provide your contact information. you will receive a gift card for your time. Your name and address will be used only to send you the gift card. a Thank You Letter. a product-speci?c Medication Guide. and a copy of the correct answers to key risk message questions. after you complete the survey. Providing a telephone number is optional. Your telephone number will be used only if there are any questions about your answers. We Protect Your Privacyl mm [lezl-?Dk pkuenote?m?n's titb Of?lm Boldedtutisnotahypulink We respect that the privacy of your personal information is important to you. You will not be contacted for marketing purposes based on your personal information or your answers to the survey. Neither the manufacturers of IRF medicines nor their contractors will sell. transfer, or rent your information. Your answers will be kept strictly con?dential. Your privacy will be protected: however. research survey records may be inspected by the FDA (Food and Drug Administration) and a company called mm? which is the Institutional Review Board (IRB). Your choice to allow the manufacturers of TIRF medicines to use your information is entirely voluntary, but necessary to take part in this survey. to Learn More About This Surve Comment FDA: please note?utthis - - title Boldedtactisnotalrypalink WK you have questions about the survey. or have any problems with the survey. please contact the Survey Coordinating Center at 1-877-379-3297. Once you have answered a question and moved on. you cannot go back and change your answers. If you have questions about your rights as a research participant or related concerns. you may contact the IRB at 21 of44 074 TIRF REMS Industry Group (TRIG) Transmucosal Immediate Release Fentanyl (TIRF) Products Patient/Caregiver KAB Survey Protocol Version 64 0 10 Sep22 May 2013 If you have questions about your rights as a research participant or related concerns, you may (b) (4) contact the IRB at . [ONLINE ONLY] Be sure to write down this telephone number; it will not be displayed again. The information in this survey should not take the place of talking with your doctor or health care professional. If you have any questions about your condition or treatment or that of the person you care for, or if you would like more information about TIRF medicines, talk to your doctor, pharmacist, or other health care professional. Thank you for your participation in this survey. [END ONLINE PREAMBLE 1] 22 of 44 FDA_1075 TIRF REMS Industry Group (TRIG) Transmucosal Immediate Release Fentanyl (TIRF) Products Patient/Caregiver KAB Survey Protocol Version 64 0 10 Sep22 May 2013 [PHONE PREAMBLE 1] Before you begin, we would like to share some important information about this survey. The survey is being conducted by the makers of Abstral®, Actiq®, Fentora®, Lazanda®, Onsolis®, Subsys® and the generic versions of any of these brands. These are Transmucosal Immediate Release Fentanyl medicines, also known as rapid onset opioids (INTERVIEWER: Please pause briefly) (and sometimes called “fast acting fentanyls”) or TIRF medicines. (INTERVIEWER: Pronounce “TIRF,” then spell out T-I-R-F). The information collected will help the makers of TIRF medicines know if patients and their caregivers understand important information about taking these medicines. The survey will take about 20 minutes. There are no known risks to you in taking this survey. You may refuse to take part or withdraw at any time without penalty or loss of benefits to which you are otherwise entitled. Your answers to the questions or your decision to take part in the survey will not affect your ability to receive or take TIRF medicines. Now I would like to tell you about how your contact information will be used. Your answers to the survey questions will be combined with answers given by other people taking the survey. All answers will be put together and reported in anonymous form to manufacturers of TIRF medicines. Your name will not be used in any report. If you are eligible to take the survey, complete all the questions, and provide your contact information, you will receive a $50 gift card for your time. Your name and address will be used only to send you the gift card, a Thank You Letter, a product-specific Medication Guide, and a copy of the correct answers to key risk message questions, after you complete the survey. Providing a telephone number is optional. Your telephone number will be used only if there are any questions about your answers. Now I would like to tell you about how we protect your privacy. We respect that the privacy of your personal information is important to you. You will not be contacted for marketing purposes based on your personal information or your answers to the survey. Neither the manufacturers of TIRF medicines nor their contractors will sell, transfer, or rent your information. Your answers will be kept strictly confidential. Your privacy will be protected; however, research survey records may be inspected by the FDA (Food and Drug (b) (4) Administration) and a company called ., which is the Institutional Review Board (IRB). Your choice to allow the manufacturers of TIRF medicines to use your information is entirely voluntary, but necessary to take part in this survey. Please feel free to ask me to repeat any questions or statements as we go through the survey. 23 of 44 FDA_1076 TIRF REMS Industry Group (TRIG) Transmucosal Immediate Release Fentanyl (TIRF) Products Patient/Caregiver KAB Survey Protocol Version 64 0 10 Sep22 May 2013 Once you have answered a question and moved on, you cannot go back and change your answers. If you have questions about your rights as a research participant or related concerns, you may (b) (4) contact the IRB at . The information in this survey should not take the place of talking with your doctor or health care professional. If you have any questions about your condition or treatment or that of the person you care for, or if you would like more information about TIRF medicines, talk to your doctor, pharmacist, or other health care professional. Thank you for your participation in this survey. [END PHONE PREAMBLE 1] 24 of 44 FDA_1077 TIRF REMS Industry Group (TRIG) Transmucosal Immediate Release Fentanyl (TIRF) Products Patient/Caregiver KAB Survey Protocol 1. 2. 3. Version 64 0 10 Sep22 May 2013 Do you agree to take part in this survey? ○ Yes ○ No [TERMINATE] Within the last 43 months, have you filled a prescription for yourself for a transmucosal immediate release fentanyl medicine (known as “TIRF medicines”)? TIRF medicines include Abstral®, Actiq®, Fentora®, Lazanda®, Onsolis®, Subsys®, and the generic versions of any of these brands. ○ Yes [GO TO Q4]Q4] ○ No ○ I don’t know Are you a caregiver for someone who has filled a prescription for a TIRF medicine within the last 43 months? As a reminder, TIRF medicines include Abstral®, Actiq®, Fentora®, Lazanda®, Onsolis®, Subsys® and the generic versions of any of these brands. ○ Yes ○ No [TERMINATE] ○ I don’t know [TERMINATE] 25 of 44 FDA_1078 TIRF REMS Industry Group (TRIG) Transmucosal Immediate Release Fentanyl (TIRF) Products Patient/Caregiver KAB Survey Protocol 4. 4.5. Version 64 0 10 Sep22 May 2013 [PATIENT] For which TIRF medicines have you filled a prescription in the last 4 months? Please select all that apply. [CAREGIVER] For which TIRF medicines has the person you care for filled a prescription in the last 4 months? Please select all that apply. □ Abstral □ Actiq, including generic versions of Actiq □ Fentora □ Lazanda □ Onsolis □ Subsys □ Other ○ I don’t know [CLEAR ALL OTHER SELECTIONS] Have you ever taken part in a survey about a TIRF medicine before? ○ Yes [TERMINATE] ○ No ○ I don’t know [TERMINATE] 26 of 44 FDA_1079 TIRF REMS Industry Group (TRIG) Transmucosal Immediate Release Fentanyl (TIRF) Products Patient/Caregiver KAB Survey Protocol 5.6. 6.7. 7.8. Version 64 0 10 Sep22 May 2013 Which of the following groups best describes your age? ○ Under 18 [TERMINATE] ○ 18 – 29 ○ 30 – 39 ○ 40 – 49 ○ 50 – 59 ○ 60 – 69 ○ 70 or older ○ Prefer not to answer [TERMINATE] [CAREGIVER ONLY] Which of the following groups best describes the patient’s age? ○ Under 16 ○ 16 – 29 ○ 30 – 39 ○ 40 – 49 ○ 50 – 59 ○ 60 – 69 ○ 70 or older ○ Prefer not to answer Have you or any of your immediate family members ever worked for any of the following companies or agencies? Please select all that apply. □ Anesta LLC [TERMINATE] □ Archimedes Pharma US Inc. [TERMINATE] □ Cephalon, Inc. (a wholly-owned subsidiary of Teva Pharmaceutical Industries, Ltd.) [TERMINATE] 27 of 44 FDA_1080 TIRF REMS Industry Group (TRIG) Transmucosal Immediate Release Fentanyl (TIRF) Products Patient/Caregiver KAB Survey Protocol Version 64 0 10 Sep22 May 2013 □ □ Endo Pharmaceuticals Inc. [TERMINATE] □ □ Insys Therapeutics [TERMINATE] □ McKesson Specialty Care SolutionsSolutionsMeda Pharmaceuticals [TERMINATE] □ Meda Pharmaceuticals [TERMINATE] □ Mylan, Inc. [TERMINATE] □ Par Pharmaceutical, Inc. [TERMINATE] □ ProStrakan, Inc. [TERMINATE] □ RelayHealth[TERMINATE] □ Teva Pharmaceuticals, Ltd. [TERMINATE] □ United BioSource Corporation [TERMINATE] □ FDA (Food and Drug Administration) [TERMINATE] □ No [IF SELECTED IN ADDITION TO OTHER RESPONSES, TERMINATE] □ I don’t know [TERMINATE] Galena BiopharmaBioPharma [TERMINATE] Mallinckrodt, the Pharmaceuticals business of Covidien [TERMINATE] [PREAMBLE 2] [PATIENT]Please answer the following questions based on information about the TIRF medicine that was most recently prescribed for you. TIRF medicines include Abstral®, Actiq®, Fentora®, Lazanda®, Onsolis®, Subsys®, and the generic versions of these brands. Please think of the information that you read or that was provided to you by a doctor, nurse, or other healthcare professional. If you don’t know the answers to any of the following questions please respond “I don’t know” instead of guessing the correct responses. [CAREGIVER]Please answer the following questions based on information about the TIRF medicine that was most recently prescribed for the patient. TIRF medicines include Abstral®, 28 of 44 FDA_1081 TIRF REMS Industry Group (TRIG) Transmucosal Immediate Release Fentanyl (TIRF) Products Patient/Caregiver KAB Survey Protocol Version 64 0 10 Sep22 May 2013 Actiq®, Fentora®, Lazanda®, Onsolis®, Subsys®, and the generic versions of these brands. Please think of the information that you read or that was provided to you or to the patient by a doctor, nurse, or other healthcare professional. If you don’t know the answers to any of the following questions please respond “I don’t know” instead of guessing the correct responses. 8.9. [PATIENT] Did the doctor, nurse, or other healthcare professional in the doctor’s office ever talk to you about the risks and possible side effects of the TIRF medicine that was most recently prescribed for you? TIRF medicines include Abstral®, Actiq®, Fentora®, Lazanda®, Onsolis®, Subsys®, and the generic versions of these brands. [CAREGIVER] Did the doctor, nurse, or other healthcare professional in the doctor’s office ever talk to you about the risks and possible side effects of the TIRF medicine that was most recently prescribed to the patient? TIRF medicines include Abstral®, Actiq®, Fentora®, Lazanda®, Onsolis®, Subsys®, and the generic versions of these brands. ○ Yes ○ No ○ I don’t know 9.10. [PATIENT] For which of the following conditions should I use a TIRF medicine? [CAREGIVER] For which of the following conditions should the person I take care of use a TIRF medicine? Yes No I don’t [RANDOMIZE LIST] know 9a.10 Headache or migraine pain ○ ○ ○ 9b.10 Breakthrough pain from cancer ○ ○ ○ 9c.10 Dental pain ○ ○ ○ 9d.10 Pain after surgery ○ ○ ○ 9e.10 Long-lasting painful conditions not caused by cancer ○ ○ ○ 10.11 Please answer True, False, or I don’t know for the following statement: 29 of 44 FDA_1082 TIRF REMS Industry Group (TRIG) Transmucosal Immediate Release Fentanyl (TIRF) Products Patient/Caregiver KAB Survey Protocol Version 64 0 10 Sep22 May 2013 TIRF medicines should only be taken by patients who are opioid tolerant. ○ True ○ False ○ I don’t know 11.12 Please answer True, False, or I don’t know for each of the following statements. True False I don’t [RANDOMIZE LIST] know 11a.1 Opioid tolerant means that a patient is already taking other opioid pain medicines around-the-clock and their body is used to these medicines. ○ ○ ○ 11b.1 If a patient stops taking around-the-clock opioid pain medicine, they must also stop taking the TIRF medicine. ○ ○ ○ 11c.1 It is safe to switch to another medicine that contains fentanyl without talking to a healthcare provider first. ○ ○ ○ 11d.1 A patient may give TIRF medicines to another person if they have the same symptoms as the patient. ○ ○ ○ 12.13 [PATIENT] Please answer True, False, or I don’t know for each statement about the TIRF medicine that was most recently prescribed for you. [CAREGIVER] Please answer True, False, or I don’t know for each statement about the TIRF medicine that was most recently prescribed for the patient. I don’t [RANDOMIZE LIST] True False know 12a.1 TIRF medicines should be stored in a safe place out of the reach of children. ○ ○ ○ 12b.1 It is OK for patients to take TIRF medicines for headache pain. ○ ○ ○ 12c.1 TIRF medicines should be taken exactly as prescribed by the doctor. ○ ○ ○ 12d.1 TIRF medicines can cause life-threatening breathing problems that can lead to death. ○ ○ ○ 30 of 44 FDA_1083 TIRF REMS Industry Group (TRIG) Transmucosal Immediate Release Fentanyl (TIRF) Products Patient/Caregiver KAB Survey Protocol Version 64 0 10 Sep22 May 2013 31 of 44 FDA_1084 TIRF REMS Industry Group (TRIG) Transmucosal Immediate Release Fentanyl (TIRF) Products Patient/Caregiver KAB Survey Protocol Version 64 0 10 Sep22 May 2013 13.14. What should you do if an adult who has not been prescribed a TIRF medicine takes a TIRF medicine? (Please select one.) [RANDOMIZE LIST] ○ Wait an hour and see if the person is OK. ○ Get emergency help right away. ○ Do nothing. ○ I don’t know 14.15 [PATIENT] Did the doctor, nurse, or other healthcare professional in the doctor’s office ever tell you how to use the TIRF medicine that was most recently prescribed for you? [CAREGIVER] Did the doctor, nurse, or other healthcare professional in the doctor’s office ever tell you how to use the TIRF medicine that was most recently prescribed for the patient? ○ Yes ○ No ○ I don’t know 15.16 [PATIENT] Did the doctor, nurse, or other healthcare professional in the doctor’s office ever tell you how to store or keep the TIRF medicine that was most recently prescribed for you? [CAREGIVER] Did the doctor, nurse, or other healthcare professional in the doctor’s office ever tell you how to store or keep the TIRF medicine that was most recently prescribed for the patient? ○ Yes ○ No ○ I don’t know 32 of 44 FDA_1085 TIRF REMS Industry Group (TRIG) Transmucosal Immediate Release Fentanyl (TIRF) Products Patient/Caregiver KAB Survey Protocol Version 64 0 10 Sep22 May 2013 16.17 [PATIENT] Please answer True, False, or I don’t know for each statement about the TIRF medicine that was most recently prescribed for you. [CAREGIVER] Please answer True, False, or I don’t know for each statement about the TIRF medicine that was most recently prescribed for the patient. [RANDOMIZE LIST] True False I don’t know 16a.1 Selling or giving away TIRF medicines is against the law. ○ ○ ○ 16b.1 It is OK to take TIRF medicines for short-term pain that will go away in a few days. ○ ○ ○ 16c.1 TIRF medicines must be disposed of as described in the specific product’s Medication Guide. ○ ○ ○ 16d.1 TIRF medicines are only available to patients through a special program (called the TIRF REMS Access program). ○ ○ ○ 16e.1 A TIRF medicine can cause an overdose and death in any child who takes it. ○ ○ ○ [PREAMBLE 3] [PATIENT] The next set of questions is about the Medication Guide for the TIRF medicine that was most recently prescribed for you. [CAREGIVER] The next set of questions is about the Medication Guide for the TIRF medicine that was most recently prescribed for the patient. [BOTH] A Medication Guide is a paper handout that contains important information about the risks associated with the use of a TIRF medicine and how to use it safely. Medication Guides always include the title “Medication Guide” followed by the name of the medicine and its pronunciation. The Medication Guide usually has a section titled “What is the most important information I should know?” The Medication Guide is in a question-and-answer format and may be given to you by your pharmacist or doctor. [END PREAMBLE 3] 33 of 44 FDA_1086 TIRF REMS Industry Group (TRIG) Transmucosal Immediate Release Fentanyl (TIRF) Products Patient/Caregiver KAB Survey Protocol Version 64 0 10 Sep22 May 2013 17.18 [PATIENT] Have you ever received a Medication Guide for the TIRF medicine that was prescribed for you? [CAREGIVER] Have you or the patient ever received a Medication Guide for the TIRF medicine that was prescribed for the patient? ○ Yes ○ No [GO TO PREAMBLE 4] ○ I don’t know [GO TO PREAMBLE 4] 18.19 [PATIENT] Did you receive the Medication Guide from the doctor who prescribed the TIRF medicine or someone in the doctor’s office? [CAREGIVER] Did you or the patient receive the Medication Guide from the doctor who prescribed the TIRF medicine or someone in the doctor’s office? ○ Yes ○ No [GO TO Q21]Q20] ○ I don’t know [GO TO Q21]Q20] 19.20 [PATIENT] When was the Medication Guide given to you? Please select all that apply. [CAREGIVER] When was the Medication Guide given to you or the patient? Please select all that apply. ○ At the first appointment with the doctor who prescribed the TIRF medicine ○ At the last appointment with the doctor who prescribed the TIRF medicine ○ I don’t remember [CLEAR ALL OTHER SELECTIONS] 34 of 44 FDA_1087 TIRF REMS Industry Group (TRIG) Transmucosal Immediate Release Fentanyl (TIRF) Products Patient/Caregiver KAB Survey Protocol Version 64 0 10 Sep22 May 2013 20.21 [PATIENT] Did you receive the Medication Guide for the TIRF medicine from the pharmacy? [CAREGIVER] Did you or the patient receive the Medication Guide for the TIRF medicine from the pharmacy? ○ Yes ○ No [GO TO Q23]Q22] ○ I don’t know [GO TO Q23]Q22] 21.22 [PATIENT] How frequently do you receive a Medication Guide for the TIRF medicine at the pharmacy? [CAREGIVER] How frequently do you or the patient receive a Medication Guide for the TIRF medicine at the pharmacy? ○ Only with the first filled prescription ○ Each time a prescription is filled ○ Other (please specify): _____________________________ ○ I don’t know 22.23 Did you read the Medication Guide? ○ Yes ○ No [GO TO Q26]Q25] ○ I don’t know [GO TO Q26]Q25] 23.24 How much did you read? ○ All of it ○ Most of it ○ Some of it ○ I don’t know 35 of 44 FDA_1088 TIRF REMS Industry Group (TRIG) Transmucosal Immediate Release Fentanyl (TIRF) Products Patient/Caregiver KAB Survey Protocol Version 64 0 10 Sep22 May 2013 24.25 How much of the Medication Guide did you understand? ○ All of it ○ Most of it ○ Some of it ○ None of it ○ I don’t know 25.26 Did someone offer to explain the Medication Guide to you? ○ Yes ○ No [GO TO Q30]Q29] ○ I don’t know [GO TO Q30]Q29] 26.27 Who offered to explain the Medication Guide to you? (Select all that apply.) □ The doctor or another healthcare professional in the doctor’s office □ The pharmacist where the TIRF medicine prescription was filled □ Someone else (specify the type of person but not his/her name) ____________________________________________________________ 27.28 Did you accept the offer to have the Medication Guide explained to you? ○ Yes ○ No [GO TO Q30]Q29] ○ I don’t know [GO TO Q30]Q29] 36 of 44 FDA_1089 TIRF REMS Industry Group (TRIG) Transmucosal Immediate Release Fentanyl (TIRF) Products Patient/Caregiver KAB Survey Protocol Version 64 0 10 Sep22 May 2013 28.29 How much of the explanation did you understand? ○ All of it ○ Most of it ○ Some of it ○ None of it ○ I don’t know 29.30 Did you or do you have any questions about the information in the Medication Guide? ○ Yes ○ No [GO TO PREAMBLE 4] ○ I don’t know [GO TO PREAMBLE 4] 30.31 What are your questions? [MULTILINE INPUT] [PREAMBLE 4] The next set of questions is about the Patient-Prescriber Agreement Form for TIRF medicines. As a reminder, TIRF medicines include Abstral®, Actiq®, Fentora®, Lazanda®, Onsolis®, Subsys®, and the generic versions of any of these brands. The Patient-Prescriber Agreement is a form that is signed by the doctor and the patient or their caregiver. This form may also be referred to as the Prescriber-Patient Agreement. [END PREAMBLE 4] 31.32 Did the doctor or someone in the doctor’s office explain the Patient-Prescriber Agreement Form to you? ○ Yes ○ No [GO TO Q34]Q33] ○ I don’t know [GO TO Q34]Q33] 37 of 44 FDA_1090 TIRF REMS Industry Group (TRIG) Transmucosal Immediate Release Fentanyl (TIRF) Products Patient/Caregiver KAB Survey Protocol Version 64 0 10 Sep22 May 2013 32.33 How much of the explanation did you understand? ○ All of it ○ Most of it ○ Some of it ○ None of it ○ I don’t know 33.34. [PATIENT] Did you sign a Patient-Prescriber Agreement Form? [CAREGIVER] Did you or the person you are caring for sign a Patient-Prescriber Agreement Form? ○ Yes ○ No [GO TO DEMOGRAPHICS PREAMBLE] ○ I don’t know [GO TO DEMOGRAPHICS PREAMBLE] 34.35. Did the doctor or someone in the doctor’s office give you a copy of the signed Patient-Prescriber Agreement Form? ○ Yes ○ No ○ I don’t know [DEMOGRAPHICS PREAMBLE] There are just a few more questions to help us combine your answers with other answers we have received. 35.36 What is your gender? ○ Male ○ Female ○ Prefer not to answer 38 of 44 FDA_1091 TIRF REMS Industry Group (TRIG) Transmucosal Immediate Release Fentanyl (TIRF) Products Patient/Caregiver KAB Survey Protocol Version 64 0 10 Sep22 May 2013 36.37 What is the highest level of education you have completed? ○ Less than high school ○ Some high school ○ High school graduate/GED ○ Some college/Associate’s degree ○ Bachelor’s degree ○ Master’s degree ○ Professional or Doctoral degree ○ Prefer not to answer 37.38 What is the main language you speak at home? (Please select only one.) ○ English ○ French ○ Spanish ○ Portuguese ○ Italian ○ German ○ Chinese ○ Japanese ○ Korean ○ Other ○ Prefer not to answer 39 of 44 FDA_1092 TIRF REMS Industry Group (TRIG) Transmucosal Immediate Release Fentanyl (TIRF) Products Patient/Caregiver KAB Survey Protocol Version 64 0 10 Sep22 May 2013 38.39 Are you Hispanic or Latino? ○ Yes ○ No ○ Prefer not to answer 39.40 For informational purposes only, which of the following U.S. census categories best describes your race? (Please select only one.) ○ American Indian or Alaska Native ○ Asian (origins of Far East, Southeast Asia or the Indian subcontinent) ○ Black or African American ○ Native Hawaiian or Other Pacific Islander ○ White ○ Other ○ Prefer not to answer 40.41 In which state do you live? [DROP-DOWN LIST INPUT WITH STATES TABLE WITH “Prefer not to answer” AT END] 40 of 44 FDA_1093 TIRF REMS Industry Group (TRIG) Transmucosal Immediate Release Fentanyl (TIRF) Products Patient/Caregiver KAB Survey Protocol Version 64 0 10 Sep22 May 2013 [PHONE ONLY: ADVERSE EVENT/PRODUCT COMPLAINT] (INTERVIEWER: Please record if respondent spontaneously reported an adverse event or product complaint during the course of this interview.) ○ Yes ○ No [GO TO CLOSING 1] Enter Safety Adverse Event Verbatim [MULTILINE INPUT] (INTERVIEWER: Indicate to the respondent that someone may call back to ask more questions about the adverse event or product complaint that was reported.) [END ADVERSE EVENT/PRODUCT COMPLAINT] [CLOSING 1] You are eligible to receive a $5025 gift card for your time completing the survey. In order to receive the gift card, we need to collect your name and address so that we can mail it to you. If you do not provide your name and address you will not receive the gift card for your time taking the survey. 41.42. Do you agree to give us your name and mailing address so we can send your payment? ○ Yes ○ No [SKIP TO CLOSING 2] FIRST NAME: _______________________________________________ LAST NAME: _______________________________________________ ADDRESS: [MULTILINE INPUT] CITY: _____________________________________ STATE: [DROP-DOWN LIST INPUT WITH STATES TABLE] ZIP: ___________ 41 of 44 FDA_1094 TIRF REMS Industry Group (TRIG) Transmucosal Immediate Release Fentanyl (TIRF) Products Patient/Caregiver KAB Survey Protocol Version 64 0 10 Sep22 May 2013 [CLOSING 2] We would also like to ask for your telephone number. Providing your telephone number is optional and it will be used to contact you only if there are questions about your survey responses. 42.43. Do you want to provide your telephone number? ○ Yes ○ No [SKIP TO CLOSING 3] Telephone: ________________________________ [CLOSING 3] This is the end of the survey. If you have questions about the survey, please contact the Survey Coordinating Center at 1-877-379-3297. Thank you again for your help. [END OF SURVEY CONTENT] 42 of 44 FDA_1095 TIRF REMS Industry Group (TRIG) Transmucosal Immediate Release Fentanyl (TIRF) Products Patient/Caregiver KAB Survey Protocol Version 64 0 10 Sep22 May 2013 APPENDIX B Patient Letter of Invitation [PAT_FIRST_NAME] [PAT_LAST_NAME [CURR_DATE] [PAT_STREET_ADDR] [PAT_CITY], [PAT_STATE] [PAT_ZIP] Dear [PAT_FULL_NAME]: Thank you for choosing [pharmacy partner or PBM name] for your prescription needs. The purpose of this letter is to inform you about a voluntary research survey being conducted by [COMPANY], the maker of [BRAND_GENERIC]. The survey is part of an FDA requirement to find out if patients and/or their caregivers understand important safety information about [BRAND] and other medicines like it. The first 300 people who complete this 20-minute survey and provide their contact information will receive a $5025 [pharmacy partner or PBM name] gift card from [COMPANY] to thank them for their time. You may be eligible to take part if you have taken [BRAND] and are 18 years of age or older. If you are unable to take the survey yourself, a caregiver who is 18 or older may be eligible to take the survey for you. The survey asks questions about the type of information you received about [BRAND] and where you get your medical information. If you are interested in participating and to find out if you are eligible:   Go to www.TIRFREMSsurvey.com any time or Call 877-379-3297, 8 a.m. to 8 p.m. Eastern Time, Monday through Friday Please have this letter with you at the time you take the survey. You will be asked to provide this code prior to starting the survey: [CODE_ID]. *It is recommended that you take the survey on a desktop or laptop computer. Taking the survey on mobile devices, such as smart phones, tablets, and e-notebooks, is not supported. (over, please) 43 of 44 FDA_1096 TIRF REMS Industry Group (TRIG) Transmucosal Immediate Release Fentanyl (TIRF) Products Patient/Caregiver KAB Survey Protocol Version 3 2 26 March 2013 You are not required to take part in this survey. If you choose to take part, please be assured that your contact information and your individual responses will be kept strictly confidential. You will not be asked to identify yourself to participate in the survey. However, if you wish to receive the $5025 gift card from [COMPANY], you must provide your name and contact information for delivery. Your answers to the survey questions will be combined with answers given by others, and your name will not be used in any written report or publication. Neither taking the survey nor your answers to the questions will affect your ability to receive or take [BRAND]. Sincerely, [Pharmacy partner or PBM name] [COMPANY] funded the cost of the gift card, the cost of mailing this letter and paid a fee to [pharmacy partner or PBM name]. The research study is not being conducted by [pharmacy partner or PBM name]. No information that can identify you, your medication, or your health condition will be provided by [pharmacy partner or PBM name] to [COMPANY]. This letter provides information about a drug prescribed by your doctor and is not a recommendation by [pharmacy partner or PBM name] to use a particular drug for your condition. Call [pharmacy partner or PBM name] toll free at xxx-xxx-xxxx if you do not wish to continue receiving mailings about [BRAND] from [pharmacy partner or PBM name]. 44 of 44 FDA_1097 Pharmacy KAB Assessment Report Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Title: Page 1 of 47 Transmucosal Immediate Release Fentanyl (TIRF) REMS Assessment Quantitative Testing of Pharmacist Knowledge, Attitudes, and Behavior (KAB) about TIRF Products’ Safety and Use Information Document Number Wave 2, 24-month REMS Assessment; Version 1.0 Survey Time Period 16 September 2013 – 16 October 2013 Product Name: Transmucosal Immediate Release Fentanyl Sponsor: TIRF REMS Industry Group (TRIG) of Companies: Cephalon, Inc. (a wholly-owned subsidiary of Teva Pharmaceutical Industries, Ltd.) Depomed, Inc. Galena Biopharma, Inc. Insys Therapeutics Mallinckrodt Pharmaceuticals Meda Pharmaceuticals Mylan, Inc. Par Pharmaceutical, Inc. Date: 18 December 2013 Confidentiality Statement The information contained herein is confidential and the proprietary property of the TRIG of Companies and its affiliates, and any unauthorized use or disclosure of such information without the prior written authorization of the TRIG is expressly prohibited. FDA_1098 Pharmacy KAB Assessment Report Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies TABLE OF CONTENTS Page 2 of 47 PAGE TABLE OF CONTENTS......................................................................................................... 2  LIST OF TABLES ................................................................................................................... 3  LIST OF APPENDICES .......................................................................................................... 4  LIST OF ABBREVIATIONS .................................................................................................. 5  1.  PHARMACIST SURVEY BACKGROUND ......................................................... 6  2.  PHARMACIST SURVEY OBJECTIVES.............................................................. 7  3.  SURVEY METHODOLOGY ................................................................................. 7  3.1  Survey Development: FDA Feedback and Qualitative Research of Draft Survey Questionnaire .............................................................................................. 7  3.2  Survey Sample ....................................................................................................... 11  3.2.1  Eligibility ............................................................................................................... 11  3.2.2  Recruitment ........................................................................................................... 11  3.3  Questions and Statements on Key Risk Messages ................................................ 12  3.3.1  Key Risk Message 1 .............................................................................................. 12  3.3.2  Key Risk Message 2 .............................................................................................. 13  3.3.3  Key Risk Message 3 .............................................................................................. 14  3.3.4  Key Risk Message 4 .............................................................................................. 14  3.4  Additional Questions ............................................................................................. 15  4.  STATISTICAL METHODS ................................................................................. 15  4.1  Study Population ................................................................................................... 15  4.1.1  Primary Analysis Population ................................................................................. 15  4.1.2  Sub-populations of Interest ................................................................................... 15  4.1.2.1  Primary Analyses .................................................................................................. 16  4.1.2.2  Secondary Analyses .............................................................................................. 17  4.1.3  Pharmacist Report of Adverse Event, Product Complaint, or Medical Information Request During Survey ..................................................................... 17  5.  RESULTS.............................................................................................................. 17  5.1  Survey Participants ................................................................................................ 17  5.1.1  Survey Participant Administration Results ........................................................... 17  FDA_1099 Pharmacy KAB Assessment Report Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 3 of 47 5.1.2  Pharmacist Demographic and TIRF Product Dispensing Characteristics ............. 21  5.1.3  TIRF Medicines Educational Materials ................................................................ 24  5.2  KAB Survey Objectives ........................................................................................ 25  5.2.1  Key Risk Message Results .................................................................................... 25  5.2.1.1  Key Risk Message 1 .............................................................................................. 25  5.2.1.2  Key Risk Message 2 .............................................................................................. 28  5.2.1.3  Key Risk Message 3 .............................................................................................. 30  5.2.1.4  Key Risk Message 4 .............................................................................................. 32  5.2.2  Other Survey Questions......................................................................................... 34  5.2.2.1  Additional Questions About TIRF Medicines Safety ........................................... 34  5.2.2.2  Pharmacist Activities When Dispensing TIRF Medicines .................................... 37  5.2.3  Analyses of Sub-populations ................................................................................. 41  5.3  Spontaneous Reporting of Adverse Events, Product Complaints, or Medical Information Requests .............................................................................. 41  6.  DISCUSSION, CONCLUSIONS, AND RECOMMENDATIONS ..................... 42  LIST OF TABLES Table 1.  Survey Participant Administration Results .................................................... 18  Table 2.  Survey Participant Screening Results ............................................................ 19  Table 3.  Time to Complete Survey for Completers (Minutes) .................................... 20  Table 4.  Demographic Characteristics of Eligible Pharmacists ................................... 21  Table 5.  Characteristics of Respondents Completing the Survey ................................ 23  Table 6.  Responses to Questions About TIRF Medicines Educational Materials ........................................................................................................ 24  Table 7.  Responses Linked to Key Risk Message 1: TIRF Medicines Are Contraindicated in Opioid Non-Tolerant Patients ......................................... 26  Table 8.  Responses Linked to Key Risk Message 2: TIRF Medicines Are Only Indicated for the Management of Breakthrough Pain in Adult Cancer Patients 18 Years of Age and Older (16 Years of Age and Older for Actiq® Brand and Generic Equivalents) Who Are Already Receiving and Who Are Tolerant to Around-The-Clock Opioid Therapy for Their Underlying Persistent Cancer Pain ................................... 29  FDA_1100 Pharmacy KAB Assessment Report Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 4 of 47 Table 9.  Responses Linked to Key Risk Message 3: TIRF Medicines Contain Fentanyl, an Opioid Agonist and a Schedule II Controlled Substance, With Abuse Liability Similar to Other Opioid Analgesics. ........................... 31  Table 10.  Responses Linked to Key Risk Message 4: TIRF Medicines Are Not Interchangeable with Each Other, Regardless of Route of Administration. .............................................................................................. 33  Table 11.  Responses to Additional Questions About the Safe Use of TIRF Medicines ....................................................................................................... 34  Table 12.  Responses to Additional Questions About the Safe Use of TIRF Medicines: Question asked of Inpatient Pharmacists, Only ......................... 37  Table 13.  Responses to All Questions About Activities When Dispensing TIRF Medicines ....................................................................................................... 38  Table 14.  Responses to All Questions About Activities When Dispensing TIRF Medicines: Asked of Inpatient Pharmacies Only.......................................... 40  Table 15.  Responses to All Questions About Activities When Dispensing TIRF Medicines: Outpatient Pharmacists Only...................................................... 40  Table 16.  Responses to All Questions About Activities When Dispensing TIRF Medicines: Closed System Pharmacy Outpatient Pharmacists Only ............ 41  Table 17.  Correct Response Rate in the 24-month KAB Survey Compared with the 12-month KAB Survey in Key Risk Message Questions Modified Between the Two Versions ............................................................................ 42  LIST OF APPENDICES Appendix A Pharmacy Survey Protocol ............................................................................. 44  Appendix B Pharmacy Survey Listings and Sub-analysis Tables ..................................... 45  Appendix C Findings Report: Qualitative Research to Evaluate the Prescriber and Pharmacist 12-month REMS Assessment Surveys for TIRF Medicines ....................................................................................................... 46  Appendix D Pharmacy Survey Protocol Track Change Document: Comparison of 12-month Survey to 24-month Survey........................................................... 47  FDA_1101 Pharmacy KAB Assessment Report Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 5 of 47 LIST OF ABBREVIATIONS AE/PC PSP Adverse Event/Product Complaint Project Specific Procedure ANDA Abbreviated New Drug Application CSP Closed System Pharmacy ETASU Elements to Assure Safe Use FDA Food and Drug Administration KAB Knowledge, Attitudes, and Behavior NDA New Drug Application QR Qualitative Research REMS Risk Evaluation and Mitigation Strategy TIRF Transmucosal Immediate Release Fentanyl TIRF medicines Transmucosal Immediate Release Fentanyl products TIRF REMS Access Program REMS Program for TIRF medicines TRIG TIRF REMS Industry Group UBC United BioSource Corporation US United States USPS United States Postal Service FDA_1102 Pharmacy KAB Assessment Report Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies 1. Page 6 of 47 PHARMACIST SURVEY BACKGROUND Transmucosal Immediate Release Fentanyl (TIRF) medicines are a class of immediaterelease opioid analgesics that are indicated only for the management of breakthrough pain in cancer patients 18 years of age or older (16 or older for Actiq® [fentanyl citrate oral transmucosal lozenge] and equivalent generics) who are receiving and already tolerant to opioid therapy for their underlying persistent cancer pain. The TIRF medicines include Abstral®, Actiq®, Fentora®, Lazanda®, Onsolis®, Subsys®, and their generic equivalents. The TIRF Risk Evaluation and Mitigation Strategy (REMS) Industry Group (TRIG) includes Cephalon, Inc. (a wholly-owned subsidiary of Teva Pharmaceutical Industries, Ltd.), Depomed, Inc., Galena Biopharma, Inc., Insys Therapeutics, Mallinckrodt Pharmaceuticals, Meda Pharmaceuticals, Mylan, Inc., and Par Pharmaceutical, Inc. At the time of protocol finalization for the Knowledge, Attitude, and Behavior (KAB) surveys, Depomed, Inc. acquired the New Drug Application (NDA) for Lazanda (29 July 2013) from Archimedes Pharma US, Inc., who is no longer a TIRF Sponsor. In addition, Galena Biopharma acquired the NDA for Abstral from Prostrakan, Inc. and is now a TIRF Sponsor (as of 01 May 2013) whereupon ProStrakan exited the group. Additionally, Mylan became a TIRF Sponsor on 29 May 2013 due to a pending Abbreviated New Drug Application (ANDA). The Food and Drug Administration (FDA) has determined that a shared system REMS is required to mitigate the risk of misuse, abuse, addiction, overdose, and serious complications due to medication errors with the use of TIRF medicines. The TIRF REMS Access Program (hereafter referred to as TIRF REMS) was approved by the FDA on 28 December 2011. The TIRF REMS consists of a Medication Guide, Elements to Assure Safe Use (ETASU), an Implementation System, and a Timetable for Submission of Assessments of the REMS. The goals of the TIRF REMS are to mitigate the risk of misuse, abuse, addiction, overdose, and serious complications due to medication errors by the following: 1. Prescribing and dispensing TIRF medicines only to appropriate patients, which includes use only in opioid-tolerant patients. 2. Preventing inappropriate conversion between TIRF medicines. 3. Preventing accidental exposure to children and others for whom it was not prescribed. 4. Educating prescribers, pharmacists, and patients on the potential for misuse, abuse, addiction, and overdose of TIRF medicines. An important component of the TIRF REMS assessment is the conduct of quantitative evaluation surveys to assess pharmacists’ understanding and knowledge of the safe use and appropriate prescribing of TIRF medicines as described in the TIRF REMS educational materials, enrollment form, and Prescribing Information of each product. The protocol describes the administration of these surveys among pharmacists who are enrolled in the TIRF REMS Access Program. FDA_1103 Pharmacy KAB Assessment Report Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 7 of 47 Data from the surveys, together with other REMS evaluation metrics, will be used to determine whether changes need to be made to the REMS processes or educational materials to make them more effective in achieving the goals of the REMS. This report describes the results from the pharmacists survey conducted for the 24-month TIRF REMS Access Program Assessment. The 24-month KAB survey launched on 16 September 2013 and closed on 16 October 2013. 2. PHARMACIST SURVEY OBJECTIVES The evaluation survey uses a questionnaire to document the level of knowledge and assess the attitudes and behavior of pharmacists regarding the following key information and risk messages communicated through the REMS: 1. TIRF medicines are contraindicated in opioid non-tolerant patients. 2. TIRF medicines are only indicated for the management of breakthrough pain in adult cancer patients 18 years of age and older (16 or older for Actiq and equivalent generics) who are already receiving and who are tolerant to around-the-clock opioid therapy for their underlying persistent cancer pain. 3. TIRF medicines contain fentanyl, an opioid agonist and a Schedule II controlled substance, with abuse liability similar to other opioid analgesics. 4. TIRF medicines are not interchangeable with each other, regardless of route of administration. 5. Patients and their caregivers must be instructed that TIRF medicines contain a medicine in an amount that can be fatal in children, in individuals for whom it is not prescribed, and in those who are not opioid tolerant. The survey also collects data on behaviors, such as receipt and use of educational materials and compliance with REMS requirements. 3. SURVEY METHODOLOGY This section summarizes the survey design and the questions that were designed to test pharmacist understanding of the key risk messages of the REMS. Full details of the survey design are in the protocol, which can be found in Appendix A. 3.1 Survey Development: FDA Feedback and Qualitative Research of Draft Survey Questionnaire On 12 March 2013, FDA provided feedback on the 12-month TIRF REMS Access Program Assessment Report that included recommendations for modifications to the pharmacist survey, as described below: FDA_1104 Pharmacy KAB Assessment Report Transmucosal Irmnediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 8 of 47 (1) Add the questions, identi?ed below, as key risk messages in the 24-month TIRF REMS Access Program Assessment Report and investigate the cause for low scores to these questions speci?cally relating to the safe use questions that potentially indicate poor rmderstanding of these concepts. The following questions, identified by the FDA, were moved to key risk messages. 12?month 24?month Survey Survey Question Question Question Number Number 5 Please select True. False. or I don?t know for each of the following. According to the labeling, patients considered opioid-tolerant are those: ?a 5a Who are taking regular therapy for rmderlying persistent cancer pain for one week or longer 5b 5b Who are not currently taking opioid therapy. but have taken opioid therapy before 5c 5c Who are not cmrently taking opioid therapy. but with no known intolerance or hypersensitivity to the drug fentanyl For which of the following indications can TIRF medicines be prescribed 8 9 to opioid tolerant patients? Please answer Yes. No. or I don?t know for each option 8e 9e Chronic non-cancer pain (2) Investigate the causes, including conducting a pre-testing of all questions related to key risk messages, prior to yorn? next srnvey to determine the reasons for the poor performance on these questions. If yorn' pie-testing indicates that a re-phrasing of a question is indicated, please also re-test the re-phrased question and then submit the results of both the pre-testing and re-testing. Before implementing the 24-month sruvey, TRIG conducted a Qualitative Research (QR) interview of 7 items from the Pharmacist REMS Assessment Srnvey Questions and 1 new question that was not included in the 12-month srnvey, (see Appendix C). The research rmdertaken in this QR process included: 0 Review of the questions identi?ed by the FDA that had a low correct response rate; 0 Review of 1 new question created to assist in the determining the understanding of the term ?arormd-the-clock usage?; 0 Review of proposed new wording on various questions. 1 05 Pharmacy KAB Assessment Report Transmucosal Irmnediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 9 of 47 The objectives of this research were to: 0 Evaluate clarity and comprehension of questions and answer options used in the 12- month assessment; 0 Identify terms, questions or topics for clari?cation or revision based on any areas of confusion with or misunderstanding for crurent wording; 0 Determine how participants understand speci?c questions and why those questions are answered a particular way; 0 Determine how certain questions might be understood differently and answered more accru'ately if further clari?ed; 0 Evaluate alternative language for these questions. This QR involved individual telephone interviews with 7 pharmacists. Each interview lasted about 45 minutes. All interviews were conducted by the same experienced moderator using a detailed discussion guide that probed into each area of the survey questions identi?ed for ?nther investigation. The strategy used to conduct the 7 telephone interviews was to interview: 0 7 TIRF REMS Access pharmacists who completed the 12-month Pharmacist REMS Assessment Survey and met the de?nition of a ?low performer? based on their incorrect responses items identi?ed by FDA. Based on the outcome of the QR, the following questions were added or reworded for Wave 2. A tracked-change version of the protocol can be found in Appendix D. The following new questions were added to the 24-month REMS Assessment based on QR ?ndings. 24?month Survey Question Question Number 6 Please answer True. False. or I don?t know for each statement based on the labeling for TIRF medicines. 6a A cancer patient can be started 011 a TIRF medicine and an aromid-the-clock opioid at the same time 6b A cancer patient who has been on an arormd-the-clock opioid for 1 day can start taking a TIRF medicine for breakthrough pain 1 06 Pharmacy KAB Assessment Report Transmucosal Iimnediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 10 of 47 he following questions were revised for the TIRF REMS KAB 24-month surrey: 12-month Survey . 24-month 12?month Question Survey Question 24?month Question Question Number Number Please select ?True?. Please select True. False. or I ?False.? or don?t don?t know for each of the know? for each of the following. According to the 5 following. According to 5 labeling for TIRF medicines. the labeling. patients patients with cancer who are considered opioid- considered opioid-tolerant are tolerant are those: those: Who are taking regular Who are taking arormd-the- opioid therapy for clock opioid therapy for 5a lmderlying persistent 5a lmderlying persistent cancer cancer pain for one week pain for one week or longer or longer Who are not currently Who have no known taking opioid therapy. contraindications to the drug 5 but with no known fentanyl. but are not currently - . 5c . intolerance or taking around-the-clock hypersensitivity to the opioid therapy drug fentanyl For which of the Per the approved labeling for following indications TIRF medicines. for which of can TIRF medicines be the following indications can 8 prescribed to opioid 9 TIRF medicines be prescribed tolerant patients? to opioid tolerant patients? Answer ?Yes.? or Please answer Yes. No. or I don?t know? for each don?t know for each option option. 8e Chronic non-cancer pain 9e Chronic non-cancer pain After the initial review and subsequent to QR. the sruvey was updated and re-submitted to the FDA. On 01 August 2013. FDA provided feedback and the following revisions were made (see Appendix A and Appendix B) to the smvey and protocol. as appropriate, to incorporate these requests: 0 Include in analyses all eligible smveys that are completed. This information was incorporated in the 12-month survey and in all subsequent surveys. 1 07 Pharmacy KAB Assessment Report Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 11 of 47 Appendix C includes a copy of the Top-Line Findings Report: Findings Report: Qualitative Research to Evaluate the Prescriber and Pharmacist 12-month REMS Assessment Surveys for TIRF Medicines. 3.2 Survey Sample This survey was conducted among a random sample of pharmacists who were enrolled in the TIRF REMS Access Program as of 15 August 2013. A target sample of 300 pharmacists who dispense TIRF products and were known to have received the REMS educational materials were surveyed in this second KAB survey conducted from 16 September 2013 to 16 October 2013. The size of the sample was determined based on both practical and statistical considerations. 3.2.1 Eligibility Subject recruitment was from a random sample of pharmacists from pharmacies that were enrolled in the TIRF REMS Access Program. (The number of pharmacies enrolled in TIRF REMS Access Program on 10 October 2013 is provided in Table 4). Any pharmacist who worked at an enrolled pharmacy was eligible to participate. Respondents or respondents with immediate family members who had ever worked for any of the TRIG companies, McKesson Specialty Care Solutions, RelayHealth, United BioSource Corporation (UBC), or the FDA were not eligible to participate. Respondents who participated in the first wave of the TIRF KAB survey (12-month TIRF REMS Access Program Assessment) were not eligible to participate. 3.2.2 Recruitment Subject recruitment was performed via a letter sent through the United States Postal Service (USPS), and via fax (see Section 5.1.1 for more detail). The required number of completed surveys was not achieved within approximately 10 days after the first mailing; second and third mailings were sent to non-respondents from the original sample to maximize participation. At the end of the 3rd mailing, the pharmacists had not reached the survey sample target; therefore, a new random sample was selected and invitations were mailed through the USPS or faxed. Each letter of invitation included a unique code needed to complete the survey. There were three categories of pharmacies which were Closed System Pharmacy (CSP), Inpatient Pharmacy and Outpatient Pharmacy. Each type of pharmacy was provided with a unique access code in order to determine which questions were displayed. The code was deactivated after the respondent had initiated the survey (whether or not the survey was completed). Pharmacists were given the option of taking the survey by telephone via the Survey Coordinating Center or online via a secure website. All participating pharmacists were offered an honorarium of $50 for a completed survey. The survey was estimated to take approximately 20 minutes to complete. FDA_1108 Pharmacy KAB Assessment Report Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies 3.3 Page 12 of 47 Questions and Statements on Key Risk Messages The questions and statements comprising the knowledge survey were constructed to test the pharmacists’ understanding of the key risk messages of the REMS. The questions were to be answered either by selecting options from multiple-choice lists that include statements of the specific key risk messages or by choosing “Yes” or “True,” “No” or “False,” or “I Don’t Know” regarding statements about TIRF medicines. For statements or questions that had “True” or “Yes” vs. “False” or “No” response options, the desired response for key risk messages was generally “True” or “Yes” indicating knowledge of, or behavior in accordance with, the objectives of the REMS. However, some questions were formatted to have the respondent disagree with the statement as written by providing response options of “False” or “No” to avoid having the same affirmative answer for all desired responses. REMS statements, corresponding questions, and desired responses covering the key risk messages are identified below and can be found in the complete survey questionnaire (Appendix A). 3.3.1 Key Risk Message 1 Key Risk Message 1 referred to the pharmacist’s knowledge of the specific contraindications for TIRF medicines in opioid non-tolerant patients. Questions in bold face type were added as key risk message questions based on FDA feedback. Key Risk Message 1: TIRF medicines are contraindicated in opioid non-tolerant patients. Question No. 5 5a 5b 5c Question Desired response Please select True, False, or I don’t know for each of the following. According to the labeling for TIRF medicines, patients with cancer who are considered opioid-tolerant are those: Who are taking around-the-clock opioid therapy for underlying True persistent cancer pain for one week or longer Who are not currently taking opioid therapy, but have taken False opioid therapy before Who have no known contraindications to the drug fentanyl, but False are not currently taking around-the-clock opioid therapy FDA_1109 Pharmacy KAB Assessment Report Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 13 of 47 Key Risk Message 1: TIRF medicines are contraindicated in opioid non-tolerant patients. Question No. 7 7a 7b 7c 7d 3.3.2 Desired response Please answer True, False, or I don’t know for each statement based on the labeling for TIRF medicines. TIRF medicines are contraindicated in opioid non-tolerant patients because life-threatening respiratory depression could occur at any True dose. Death has occurred in opioid non-tolerant patients treated with some True fentanyl products. TIRF medicines may be used in opioid non-tolerant patients. False Prescribers starting a patient on a TIRF medicine must begin with titration from the lowest dose available for that specific product, even True if the patient has previously taken another TIRF medicine. Question Key Risk Message 2 Key Risk Message 2 referred to the pharmacist’s knowledge of the indications for prescribing TIRF medicines for the management of breakthrough pain in opioid-tolerant adult cancer patients. Question 9e, identified in bold face type, was added as a key risk message question based on FDA feedback. Key Risk Message 2: TIRF medicines are only indicated for the management of breakthrough pain in adult cancer patients 18 years of age and older (16 years of age and older for Actiq® brand and generic equivalents) who are already receiving and who are tolerant to around-theclock opioid therapy for their underlying persistent cancer pain. Question No. Question Desired response 9 Per the approved labeling for TIRF medicines, for which of the following indications can TIRF medicines be prescribed to opioid tolerant patients? Please answer Yes, No, or I don’t know for each option. 9a Acute or postoperative pain No 9b Headache or migraine pain No 9c Dental pain No 9d Breakthrough pain from cancer Yes 9e Chronic non-cancer pain No FDA_1110 Pharmacy KAB Assessment Report Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies 3.3.3 Page 14 of 47 Key Risk Message 3 Key Risk Message 3 referred to the pharmacist’s knowledge of the risk factors and signs and symptoms of opioid abuse in patients who take TIRF medicines. Key Risk Message 3: TIRF medicines contain fentanyl, an opioid agonist and a Schedule II controlled substance, with abuse liability similar to other opioid analgesics. Question No. Question Desired response 7 Please answer True, False, or I don’t know for each statement about TIRF medicines. 7e It is important to monitor for signs of abuse and addiction in patients who take TIRF medicines. 8 Which of the following are risk factors for opioid abuse? Please answer Yes, No, or I don’t know for each option. 8a A personal history of psychiatric illness Yes 8b A personal history of past or current alcohol or drug abuse, or a family history of illicit drug use or alcohol abuse Yes 10 Please answer True, False, or I don’t know for each statement about TIRF medicines. 10a TIRF medicines can be abused in a manner similar to other opioid agonists. 3.3.4 True True Key Risk Message 4 Key Risk Message 4 referred to the pharmacist’s knowledge of the interchangeability of TIRF medicines based on route of administration, pharmacokinetic absorption, and dosage. Key Risk Message 4: TIRF medicines are not interchangeable with each other, regardless of route of administration. Question No. Question Desired response 10 Please answer True, False, or I don’t know for each statement about TIRF medicines. 10b TIRF medicines are interchangeable with each other regardless of route of administration. False 10c The conversion of one TIRF medicine for another TIRF medicine may result in a fatal overdose because of differences in the pharmacokinetics of fentanyl absorption. True 10d Dosing of TIRF medicines is not equivalent on a microgram-tomicrogram basis. True FDA_1111 Pharmacy KAB Assessment Report Transmucosal Irmnediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 15 of 47 3.4 Additional Questions The srnvey also contained questions (Question 12a-t) about the requirements of the TIRF REMS Access Program and receipt and understanding of the TIRF educational materials. The following questions about behaviors were asked after the key risk message questions: Question No. Question 12 How ?equently do you perform the following activities when dispensing TIRF medicines? 12a Ask patients (or their caregivers) about the presence of children in the home 12b Instruct patients (or their caregivers) not to share TIRF medicines with anyone else Counsel patients (or their caregivers) that accidental exposure to TIRF medicines by a 12c . may be fatal 12d Instruct patients (or their caregivers) to keep TIRF medicines out of the reach of children to prevent accidental exposure Instruct patients (or their caregivers) about proper disposal of any tmused or partially 12c . . used TIRF rnedrcmes 12f Give patients (or their caregivers) the Medication Guide for their TIRF medicine 4. STATISTICAL METHODS 4.1 Study Population 4.1.1 Primary Analysis Population The primary population for analysis was all eligible pharmacists who completed the sruvey. Eligible pharmacists were defmed as those respondents who answered Yes to Question 1 (agree to take part in smvey), and Question 3 (work at a pharmacy that is em?olled in the TIRF REMS Access Program), and No to Question 2 (participated in past sruvey) and Question 4 (worked for a TRIG company, UBC, or FDA). A completed sruvey was a survey in which all non-eligibility questions as appropriate were answered. Some questions may not have been answered because of skip logic in the sruvey questionnaire. 4.1.2 Sub-populations of Interest The following sub-group analyses were conducted if the sub-group included at least 20 respondents. Of note, sub-group analysis 3 was not done since only 9 pharmacists completed the smvey Via telephone. Sub-group analysis 1: Reading Medication Guide or Full Prescribing Information (Questions 18,19, 20 and 21): 1 1 2 Pharmacy KAB Assessment Report Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 16 of 47 • S-1a - Respondents who read the Full Prescribing Information (Question 19) and Medication Guide for the TIRF medicine that they dispense (Question 21). • S-1b - Respondents who responded No or I don’t know to getting and reading the Full Prescribing Information and to getting and reading the Medication Guide for the TIRF medicine that they dispense. Sub-group analysis 2: Time to complete survey - Internet: • S-2a - <10 min • S-2b - 10 to <20 min • S-2c - ≥20 min Sub-group analysis 3: Time to complete survey - Telephone: • S-3a - <10 min • S-3b - 10 to <20 min • S-3c - ≥20 min Sub-group analysis 4: Modality to complete survey: • S-4a - Internet • S-4b – Telephone Sub-group analysis 5: Time practicing as a pharmacist (Question 28): • S-5a - Less than 3 years • S-5b - 3 to 5 years • S-5c - 6 to 15 years • S-5d - More than 15 years Sub-group analysis 6: Number of times per month dispensed TIRF medicines within the last 6 months (Question 25): • S-6a - None • S-6b - 1 - 2 times per month • S-6c - 3 - 5 times per month • S-6d - More than 5 times per month Results of sub-group analyses performed are provided in Appendix B: Tables 6.1 and 6.2, 7.1 and 7.2, 8.1 and 8.2, 9.1 and 9.2. 4.1.2.1 Primary Analyses Primary analyses were done for all key risk messages. The primary analysis for a key risk message evaluated the number and percentage of correct responses for each individual question/item defined by the key risk message. The correct response to each question/item was identified in the body of the risk message table (Section 3.3). FDA_1113 Pharmacy KAB Assessment Report Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies 4.1.2.2 Page 17 of 47 Secondary Analyses Secondary analyses evaluated the number and percentages of correct responses and the average number of correct responses within the risk message overall to assess understanding of the comprehensive key risk message. A correct response rate of 65% or greater was considered to represent adequate understanding of each concept or key risk message. 4.1.3 Pharmacist Report of Adverse Event, Product Complaint, or Medical Information Request During Survey A pharmacist may have reported an adverse event or other event experienced by their patients while taking a TIRF product either in free text fields while taking the online survey or while in conversation with the Survey Coordinating Center Associate. If the event was mentioned to an Associate, the Associate documented the event or complaint, the verbatim response, and the pharmacist’s contact information, if provided. The pharmacist was also informed that a representative from the appropriate TIRF medicine manufacturer may contact them to obtain additional information about the event. The Internet surveys were monitored for any comments recorded in the free text field. Information on all reports (Internet or telephone) that constituted an adverse event or other event was forwarded to the appropriate TIRF medicine manufacturer for processing within 1 business day of awareness of the event as outlined in the Adverse Event/Product Complaint Project Specific Procedure (AE/PC PSP). 5. RESULTS Results of the pharmacist responses to questions in the KAB survey are summarized in this section and a full set of responses can be found in Appendix B. 5.1 Survey Participants 5.1.1 Survey Participant Administration Results A total of 7167 pharmacists were invited to participate in this survey (Table 1). Of those invited to participate, 5,982 were outpatient pharmacists, 860 were inpatient pharmacists, and 325 were pharmacists practicing in CSPs. Some pharmacists received more than 1 reminder. From the total 403 respondents, 300 pharmacists met eligibility criteria and completed the survey. Of these 300 pharmacists, 291 (97.0%) completed the survey online, and 9 (3.0%) completed it by telephone (Table 3). Of the 300 pharmacists who completed the survey, 4 were CSP pharmacists, 15 were inpatient pharmacists, and 281 were outpatient pharmacists. FDA_1114 Pharmacy KAB Assessment Report Transmucosal Irmnediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 18 of 47 Table 1. Survey Participant Administration Results Screened Pharmacists N=372l All Respondents Summary Statistic Number of invitations issued to pharmacists 7167 Number of reminder letters issued to pharmacists 13215 Number of pharmacists screened for participation 3721 Number of pharmacists eligible for participation 300 Number of screened pharmacists eligible for participation who answered all questions presented to 300 80.61 them Method of Sluvey Completion of srnveys completed by telephone 9 3.02 Nrunber of sruveys completed by Internet 291 97 _02 1 The denominator for the percentage of eligible pharmacists is the munber of screened phamracists 72). 2 The denominator for percentages completed by telephone or Internet is the number of eligible pharmacists who completed the survey. As shown in Table 2, a total of 371 pharmacists agreed to participate in this srnvey, 339 of these pharmacists stated they had not taken part in the srnvey about TIRF medicines before, and 304 of these pharmacists worked in pharmacies that were em?olled in the TIRF REMS. Of the 372 total respondents, 68 were ineligible to participate in the smvey because they either did not agree to participate, indicated they had participated in or did not know whether they participated in a smvey about TIRF medicines before, or worked in pharmacies that were not em'olled or they did not know whether their pharmacy was em'olled in the TIRF REMS. Of the 304 respondents who reported that their pharmacies were em?olled in the TIRF REMS Access Program, 1 respondent was ineligible for the sruvey because the respondent, or an immediate family member, had worked for a TRIG company in the past, 1 was ineligible because the respondent or an immediate family member, had worked for the FDA in the past, and 2 respondents preferred not to answer the question. 1 1 5 Pharmacy KAB Assessment Report Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 19 of 47 Table 2. Survey Participant Screening Results Screened Pharmacists Question Question 1: Do you agree to participate in this survey? Yes 371 99.7 300 100.0 No1 1 0.3 Question 2: Have you ever taken part in this survey about TIRF medicines before? TIRF medicines include Abstral", Actti, Fentorao, Lazanda?, Onsoliso, Subsys4D and generic versions of any of these brands Yes1 8 2.2 No 339 91.1 300 100.0 I don?t know1 24 6.5 Question not asked2 1 0.3 Question 3: Do you work in a pharmacy that is enrolled in the TIRF REMS Access Program? Yes 304 81.7 300 100.0 No1 8 2.2 I don?t know1 27 7.3 Question not asked2 33 8.9 Question 4: Have you or any of your immediate family members ever worked for any of the following companies or agencies? Please select all that apply.3 Anesta LLC.1 0 0.0 Archimedes Pharma US Inc.1 0 0.0 Cephalon. Inc. (a wholly-owned subsidiary of Teva 0 0.0 Pharmaceutical Industries. Ltd.)1 Endo Pharmaceuticals Inc.1 1 0.3 Galena Biophanna1 0 0.0 Insys Therapeutics1 0 0.0 0 0.0 McKesson Specialty Care Solutions1 0 0'0 Meda Pharmaceuticals1 0 0.0 Mylan Inc.1 0 0-0 1 1 6 Pharmacy KAB Assessment Report Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 20 of 47 Table 2. Survey Participant Screening Results Screened Pharmacists Question Par Pharmaceutical. Inc.1 0 0.0 ProStrakan. Inc.1 0 0.0 RelayHealthl 0 0.0 Teva Phannaceuticals. Ltd.1 0 0.0 United BioSource Corporation1 0 0.0 FDA1 1 0.3 None of these apply4 300 80.6 300 100.0 I don?t know1 0 0.0 Prefer not to answer1 2 0.5 Question not asked2 68 18.3 Ineligible to participate in the surveyQuestion not asked due to a prenous question elimination. 3 More than 1 response can be selected. so percentages may not sum to 100%. 4 Ineligible if selected in addition to another response. Those taking the smvey online took an average of 14.3 minutes to complete it, while those taking it by telephone took an average of 18.0 minutes. Table 3. Time to Complete Survey for Completers (Minutes) Summary Statistic Telephone Internet Total1 9 291 300 Mean (i SD) 18.0 (1.81) 14.3 (8.75) 14.4 (8.64) 15 4 4 Median 18.0 11.6 11.8 Maximum 20 85 85 Category 0 <5 Minutes 0 1 1 5 <10 Minutes 0 90 90 10 <15 Minutes 0 106 106 15 <20 Minutes 8 47 55 20 <25 Minutes 1 21 22 1 1 7 Pharmacy KAB Assessment Report Transmucosal Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 21 of 47 Table 3. Time to Complete Survey for Completers (lVIinutes) Category 25 <30 Minutes 0 12 12 30 Minutes or More 0 14 14 Nrunber of eligible phanrracists completing the survey (See Table 1). 5.1.2 Pharmacist Demographic and TIRF Product Dispensing Characteristics The demographic characteristics of pharmacists who completed the smvey are shown in Table 4, and their experience with prescribing TIRF medicines is summarized in Table 5. The majority of pharmacists who completed the sruyey were male (183, and out of 300 eligible pharmacists, 157 had been a practicing pharmacist for more than 15 years. Respondents from the South, Northeast, and Midwest re?ected 32.3%, 26.0%, and 24.0% of total respondents, respectively, while respondents from the Western region of the United States (US) composed 17.3% of total respondents. The proportion of respondents who completed the sruvey within each geographic region was similar to the overall proportion of pharmacies em?olled in the TIRF REMS Access Program as of 10 October 2013 in each geographic region (Table 4). There were no respondents from Puerto Rico, Northern Mariana Islands, US Virgin Islands, American Samoa, and Guam identi?ed as ?Other? in Table 4 below. Most pharmacists (242, 80.7%) flurctioned as the pharmacist-in-charge for the TIRF REMS Access Program where they worked, and a majority of pharmacists (235, 78.3%) had dispensed a TIRF medicine zero to 2 times per month within the past 6 months. The most frequently dispensed TIRF medicine within the 6 months prior to taking the srnvey was Actiq or generic Actiq (120 pharmacists, Table 4. Demographic Characteristics of Eligible Pharmacists Eligible Completed Pharmacists Question N=300l Question 27: What is your gender? Male 183 61.0 Female 11 1 37.0 Prefer not to answer 6 2.0 Question 28: In total, how many years have you been a practicing pharmacist Less than 3 years 23 7.7 3-5 years 41 13.7 6-10 years 40 13.3 1 1 8 Pharmacy KAB Assessment Report Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 22 of 47 Table 4. Demographic Characteristics of Eligible Pharmacists Eligible Completed Pharmacists Question N=300l 11-15 years 34 11.3 More than 15 years 157 52.3 Prefer not to answer 5 1_7 Question 29: In which state do you practice?2 Geographic Region2 Eligible and Complete Pharmacies Enrolled in TIRF Respondents REMS Access Program as of 100ct2013 by Region Northeast 78 26.0 7834 20.3 Midwest 72 24.0 8027 20.8 South 97 32.3 15027 38.9 West 52 17.3 7549 19.6 Other 0 0.0 160 0.4 Prefer not to answer 1 0.3 0 0.0 1 Niunber of eligible phannacists completing the survey (See Table 1). 2 According to the 2001 Geographic Area Regions set by the US Census Bureau. Geography Division. Northeast includes CT. MA. ME. NH. NJ. NY. PA. RI. and VT. Midwest includes IA. IL. IN. KS. MI. MN. MO. ND. NE. OH. SD. and WI. South includes AL. AR. DC. DE. FL. GA. KY. LA. MD. MS. NC. OK. SC. TN. TX. VA. and WV. West includes AK. AZ. CA. CO. HI. ID. MT. NM. NV. OR. UT. WA. and WY. Other includes Puerto Rico. Northern Mariana Islands. US Virgin Islands. American Samoa. and Guam. 1 1 9 Pharmacy KAB Assessment Report Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 23 of 47 Table 5. Characteristics of Respondents Completing the Survey Question Eligible Completed Pharmacists Question 24: Are you the Pharmacist in Charge for the TIRF REMS Access Program where you work17.3 I don?t know 6 2.0 Question 25: On average, how many times per month have you dispensed TIRF medicines within the last 6 months None 145 48.3 1-2 times per month 90 30.0 3-5 times per month 32 107 More than 5 times per month 15 5.0 I don?t remember 18 6.0 Question 26: Please select the TIRF medicine(s) that you have dispensed within the last 6 months (select all that apply):2 Abstral? 8 5.2 Actiq? or generic Actiq 120 77.4 Fentora? 57 36.8 Lazanda? 6 3.9 Onsolis? 1 0.6 Subsys? 17 1 .0 (answered None to 145 Question 25) 1Number of eligible pharmacists completing the survey (See Table 1). 2 Percentages are calculated based on the sample presented with this question. which may not re?ect the entire sample because of skip logic in the survey. Not applicable. 1 20 Pharmacy KAB Assessment Report Transmucosal Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 24 of 47 5.1.3 TIRF Medicines Educational Materials Pharmacists were asked about their access to educational materials for TIRF medicines, speci?cally the Full Prescribing Information and the Medication Guide (Table 6). Ahnost all pharmacists reported they had received or had access to the Full Prescribing Information and the Medication Guide (291, 97.0%; and 297, 99.0%, respectively). Of those with access to these materials, 76.6% and 84.2%, respectively, indicated that they had read the Full Prescribing Information and the Medication Guide. Table 6. Responses to Questions About TIRF Medicines Educational Materials Eligible Completed Pharmacists Question N=300l Question 18: Did you receive or do you have access to the Full Prescribing Information for the TIRF medicine(s) that you dispense? Yes 291 97.0 No 1 0.3 I don?t know 8 2.7 Question 19: Did you read the Full Prescribing Information for the TIRF medicine(s) that you dispense?2 Yes 223 76.6 No 61 21.0 I don?t know 7 2.4 (answered No or I don?t 9 know to Question 18) Question 20: Did you receive or do you have access to the Medication Guide for the TIRF medicine(s) that you dispense? Yes 297 99.0 No 1 0.3 I don?t know 2 0.7 Question 21: Did you read the Medication Guide for the TIRF medicine(s) that you dispense?2 Yes 250 84.2 No 39 13.1 I don?t know 8 2.7 (answered No or I don ?t 3 know to Question 20) 121 Pharmacy KAB Assessment Report Transmucosal Irmnediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 25 of 47 Table 6. Responses to Questions About TIRF Medicines Educational Materials Eligible Completed Pharmacists Question N=300l Question 22: Did you or do you have any questions about the information in the Full Prescribing Information or Medication Guide? Yes3 21 7.0 No 259 86.3 I don?t know 20 6.7 1 Number of eligible pharmacists completing the sru'vey (See Table 2 Percentages are calculated based on the sample presented with this question. which may not re?ect the entire sample because of skip logic in the survey. 3 Verbatim text for questions about the information in the Full Prescribing Information are presented in Appendix B. Listing 2. There were 18 respondents who typed a response into the ??ee text ?eld for Question 22 (Did you or do you have any questions about the information in the Full Prescribing Information or Medication Guide These responses are shown in Appendix B, Listing 2. Of the 18 responses, 13 were requests for medical information and 5 were indications the ??ee text ?eld was not applicable or they had no questions. 5.2 KAB Survey Objectives 5.2.1 Key Risk Message Results The focus of this section of the document is on the ?ndings for the total eligible respondent population that completed the sruyey. A summary of results by sub-group is provided in a separate section of the docmnent, Section 5.2.3. 5.2.1.1 Key Risk Message 1 Key Risk Message 1 refers to the pharmacist?s knowledge of the speci?c contraindications for TIRF medicines. Analysis of responses to components of Question 5 for Key Risk Message 1 showed that a high percentage of pharmacists knew that patients with cancer who are considered opioid- tolerant are those who are taking around-the-clock opioid therapy for cancer pain for one week or longer (271, and are those who are crurently taking opioid therapy (242, Somewhat less rmderstood was cancer patients with no known contraindications to the drug fentanyl, but who are not taking arormd-the-clock opioid therapy are not considered opioid tolerant (228, Fluther discussion is provided in Section 6. Analysis of responses to components of Question 7 for Key Risk Message 1 showed that a high percentage of pharmacists knew that TIRF medicines are contraindicated in opioid non- tolerant patients and that death has occurred in opioid non-tolerant patients treated 1 22 Pharmacy KAB Assessment Report Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 26 of 47 with some fentanyl products Similarly, 248 pharmacists were aware that dose titration for patients starting a TIRF medicine must begin with the lowest available dose for that product, and that TIRF medicines may not be used to treat opioid non-tolerant patients (Table 7). Overall, evidence of lurderstanding of this key risk information is ?uther supported by the average munber of correct responses identi?ed as 5.9 out of a possible 7. Table 7. Responses Linked to Key Risk Message 1: TIRF Medicines Are Contraindicated in Opioid Non-Tolerant Patients Eligible Completed Pharmacists N=300l Question 11 (95% Question 5: Please select True, False, or I don?t know for each of the following. According to the labeling for TIRF medicines, patients with cancer who are considered opioid- tolerant are those: 5a: Who are taking around-the-clock opioid therapy for underlying persistent cancer pain for one week or longer Tmez 271 (8633334) False 23 7.7 I don?t know 6 2.0 SD: Who are not currently taking opioid therapy, but have taken opioid therapy before True 41 13.7 ?1562 242 I don?t know 17 57 5c: Who have no known contraindications to the drug fentanyl, but are not currently taking around-the?clock opioid therapy True 52 17.3 76.0 2 False 228 (70.8. 80.7) I don?t know 20 6.7 1 23 Pharmacy KAB Assessment Report Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 27 of 47 Table 7. Responses Linked to Key Risk Message 1: TIRF Medicines Are Contraindicated in Opioid Non-Tolerant Patients Question Eligible Completed Pharmacists N=300l (95% CD3 Question 7: Please answer True, False, or I don?t know for each statement based on the labeling for TIRF medicines. 7a: TIRF medicines are contraindicated in opioid non?tolerant patients because life?threatening respiratory depression could occur at any dose. 86.0 2 5 Tm 2 8 (81.6. 89.7) False 27 9.0 I don?t know 15 5.0 7b: Death has occurred in opioid non-tolerant patients treated with some fentanyl products. ??62 281 (90.239761) False 2 0.7 I don?t know 17 5.7 7c: TIRF medicines may be used in opioid non?tolerant patients.4 True 40 13.3 False? 246 (77.27362) I don?t know 14 4.7 7d: Prescribers starting a patient on a TIRF medicine must begin with titration from the lowest dose available for that speci?c product, even if the patient has previously taken another TIRF medicine. Tmez 248 (77.27.8768) False 38 12.7 I don?t know 14 4.7 Secondary Analysis: Demonstrated Understanding 0 correct responses 2 0.7 1 correct response 2 0.7 1 24 Pharmacy KAB Assessment Report Transmucosal Irmnediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 28 of 47 Table 7. Responses Linked to Key Risk Message 1: TIRF Medicines Are Contraindicated in Opioid Non-Tolerant Patients Eligible Completed Pharmacists Question 3 (95% CI) 2 correct responses 6 2.0 3 correct responses 7 2.3 4 correct responses 22 7.3 5 correct responses 45 15.0 6 correct responses 86 28.7 7 correct responses 130 43.3 Average number of correct responses 5.9 (5.7. 7.0)5 1 Nrunber of eligible pharmacists completing the survey (See Table 2 Indicates the correct response(s) to each question or item within a question. 3 All con?dence intervals are exact binomial 95% con?dence intervals. 4 Question 7c was presented to pharmacists participating in the intemet sru'vey as follows: TIRF medicines may be used in treat opioid non-tolerant patients. The word ?treat? was included in error and was removed for reporting purposes. 5 One-sided 95 con?dence interval using the nonnal approximation to the Poisson distribution. 5.2.1.2 Key Risk Message 2 Key Risk Message 2 refers to the pharmacist?s knowledge of the approved indications for prescribing TIRF medicines to opioid tolerant patients. Responses to components of Question 9 for Key Risk Message 2 indicate that 268 pharmacists were aware that TIRF medicines are indicated for opioid-tolerant patients with breakthrough pain ??om cancer and not for patients with acute or postoperative pain headache or migraine pain or dental pain (Table 8). For Question 9e, only 47.0% of pharmacists correctly responded that TIRF medicines are not indicated for chronic non-cancer pain. Further discussion is provided in Section 6. Overall, evidence of rmderstanding of this key risk information is fruther supported by the average number of correct responses identi?ed as 4.1 out of a possible 5. 1 25 Pharmacy KAB Assessment Report Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 29 of 47 Table 8. Responses Linked to Key Risk Message 2: TIRF Medicines Are Only Indicated for the Management of Breakthrough Pain in Adult Cancer Patients 18 Years of Age and Older (16 Years of Age and Older for Actiq? Brand and Generic Equivalents) Who Are Already Receiving and Who Are Tolerant to Around-The-Clock Opioid Therapy for Their Underlying Persistent Cancer Pain Question Eligible Completed Pharmacists (95% Question 9: Per the approved labeling for TIRF medicines, for which of the following indications can TIRF medicines be prescribed to opioid tolerant patients? Please answer Yes, No, or I don?t know for each option. 9a: Acute or postoperative pain Yes 31 10.3 No2 254 84'7 (80.1. 88.6) I don?t know 15 5.0 9b: Headache or migraine pain Yes 8 2.7 N02 277 (88.95351) I don?t know 15 5.0 9c: Dental pain Yes 3 1.0 N02 290 (94238.4) I don?t know 7 2.3 9d: Breakthrough pain from cancer Yesz 268 (85332.6) No 27 9.0 I don?t know 5 1.7 1 26 Pharmacy KAB Assessment Report Transmucosal Irmnediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 30 of 47 Table 8. Responses Linked to Key Risk Message 2: TIRF Medicines Are Only Indicated for the Management of Breakthrough Pain in Adult Cancer Patients 18 Years of Age and Older (16 Years of Age and Older for Actiq? Brand and Generic Equivalents) Who Are Already Receiving and Who Are Tolerant to Around-The-Clock Opioid Therapy for Their Underlying Persistent Cancer Pain Eligible Completed Pharmacists Question (95% 9e: Chronic non?cancer pain Yes 126 42.0 N02 141 (4137.228) I don?t know 33 11.0 Secondary Analysis: Demonstrated Understanding 0 correct responses 2 0.7 1 correct response 4 1.3 2 correct responses 12 4.0 3 correct responses 47 15.7 4 correct responses 114 38.0 5 correct responses 121 40.3 Average number of correct responses 4.1 (3.9. 5.0)4 1 Nimiber of eligible pharmacists completing the survey (See Table 1). 2 Indicates the correct response(s) to each question or item within a question. 3 All con?dence intervals are exact binomial 95% con?dence intervals. 4 One-sided 95 con?dence interval using the normal approximation to the Poisson distribution. 5.2.1.3 Key Risk Message 3 Key Risk Message 3 refers to the pharmacist?s knowledge of the risk factors and signs and of opioid abuse in patients who take TIRF medicines. Responses to components of Questions 7, 8. and 10 for Key Risk Message 3 showed that 290 pharmacists were aware that it is important to monitor for signs of abuse and addiction in patients who take TIRF medicines; a personal history of past or crurent alcohol or drug abuse or family history of drug and alcohol abuse is a risk factor for opioid abuse and TIRF medicines can be abused in a manner similar to other opioid agonists Somewhat less rmderstood was that a personal history of illness is a risk 1 27 Pharmacy KAB Assessment Report Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 31 of 47 factor for opioid abuse (Table 9). Fru'ther discussion is provided in Section 6. Overall, evidence of rurderstanding of this key risk information is ?uther supported by the average munber of correct responses identi?ed as 3.6 out of a possible 4. Table 9. Responses Linked to Key Risk Message 3: TIRF Medicines Contain Fentanyl, an Opioid Agonist and a Schedule II Controlled Substance, With Abuse Liability Similar to Other Opioid Analgesics. Eligible Completed Pharmacists N=300l ues on (95% Question 7: Please answer True, False, or I don?t know for each statement based on the labeling for TIRF medicines. 7e: It is important to monitor for signs of abuse and addiction in patients who take TIRF medicines. 96.7 2 True 290 (94.0. 98.4) False 5 1.7 I don?t know 5 1.7 Question 8: Which of the following are risk factors for opioid abuse? Please answer Yes, No, or I don?t know for each option. 8a: A personal history of illness 72.0 Yes 216 (66.6. 77.0) No 48 16.0 I don?t know 36 12.0 8b: A personal history of past or current alcohol or drug abuse, or a family history of illicit drug use or alcohol abuse 2 99.0 Yes 297 (97.1. 99.8) No 0 0.0 I don?t know 3 1.0 Question 10: Please answer True, False, or I don?t know for each statement about TIRF medicines. 10a: TIRF medicines can be abused in a manner similar to other opioid agonists. 94.0 2 me 282 (90.7. 96.4) False 10 3.3 1 28 Pharmacy KAB Assessment Report Transmucosal Irmnediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 32 of 47 Table 9. Responses Linked to Key Risk Message 3: TIRF Medicines Contain entanyl, an Opioid Agonist and a Schedule II Controlled Substance, With Abuse Liability Similar to Other Opioid Analgesics. Eligible Completed Pharmacists ti N=3ool ues on (95% I don?t know 8 2.7 Secondary Analysis: Demonstrated Understanding 0 correct responses 0 0.0 1 correct response 3 1.0 2 correct responses 7 2.3 3 correct responses 92 30.7 4 correct responses 198 66.0 Average number of correct responses 3.6 (3 .4. 4.0)4 1 Number of eligible pharmacists completing the survey (See Table 1). 2 Indicates the correct response(s) to each question or item within a question. 3 All con?dence intervals are exact binomial 95% con?dence intervals. 4 One-sided 95 con?dence interval using the normal approximation to the Poisson distribution. 5.2.1.4 Key Risk Message 4 Key Risk Message 4 refers to the pharmacist?s knowledge that TIRF medicines are not interchangeable regardless of the route of administration. Responses to components of Question 10b, c, and for Key Risk Message 4 showed that 284 pharmacists rmderstood TIRF medicines are not interchangeable with each other regardless of the route of administration the conversion of TIRF medicine to another may result in a fatal overdose and dosing of TIRF medicines is not equivalent on a microgram-to-microgram basis (Table 10). Overall, evidence of rmderstanding of this key risk information is ?uther supported by the average number of correct responses identi?ed as 2.8 out of a possible 3. 1 29 Pharmacy KAB Assessment Report Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 33 of 47 Table 10. Responses Linked to Key Risk Message 4: TIRF Medicines Are Not Interchangeable with Each Other, Regardless of Route of Administration. Eligible Completed Pharmacists Question 11 (95% Question 10: Please answer True, False, or I don?t know for each statement based on the labeling for TIRF medicines. 10b: TIRF medicines are interchangeable with each other regardless of route of administration. True 6 2.0 2 94.7 False 284 (91.5. 96.9) I don?t know 10 3.3 10c: The conversion of one TIRF medicine for another TIRF medicine may result in a fatal overdose because of differences in the pharmacokinetics of fentanyl absorption. Tmez 276 (88254.8) False 5 1.7 I don?t know 19 6.3 10d: Dosing of TIRF medicines is not equivalent on a microgram-to-microgram basis. Tmez 274 (87.959343) False 10 3.3 I don?t know 16 5.3 Secondary Analysis: Demonstrated Understanding 0 correct responses 5 1.7 1 correct response 11 3.7 2 correct responses 29 9.7 3 correct responses 255 85.0 Average number of correct responses 2.8 (2.6. 3 .0)4 1 Number of eligible pharmacists completing the sru?vey (See Table 2 hrdicates the correct response(s) to each question or item within a question. 3 All con?dence intervals are exact binomial 95% con?dence intervals. 4 One-sided 95 con?dence interval using the normal approximation to the Poisson distribution. 1 30 Pharmacy KAB Assessment Report Transmucosal Irmnediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 34 of 47 5.2.2 Other Survey Questions 5.2.2.1 Additional Questions About TIRF Medicines Safety Table 11 srunmarizes the pharmacists? responses to additional questions about the safe use of TIRF medicines beyond those associated with the key risk messages. Responses to these additional questions generally confnmed the pharmacists? rmderstanding of the safety issues and the risks associated with taking TIRF medicines. Question 6 (see Table 11) was added for this 24-month KAB sruvey to assist in determining the pharmacist rmderstanding of arormd-the-clock usage, and 65.3% of pharmacists correctly indicated that a cancer patients should not be started on a TIRF medicine and an arormd-the- clock opioid at the same time, and 74.7% understood a cancer patient who had been on an arormd-the-clock opioid for 1 day should not start taking a TIRF medicine for breakthrough pain. Overall, greater than 70% of pharmacists correctly identi?ed an opioid drug/dose regimen that, when taken by the patient, identi?es patients as opioid tolerant according to the labeling for TIRF medicines. However, fewer understood that an equianalgesic dose of another oral opioid could also meet the de?nition of opioid tolerant (correct response 59.0%; Table 11). Pharmacists correctly indicated that TIRF medicines may not be sold, loaned, or transferred to another pharmacy pharmacy staff who dispense TIRF medicines must be educated on the requirements of the TIRF REMS Access Program and that TIRF medicines with the same route of administration cannot be substituted with each other Thirteen inpatient pharmacists correctly indicated that it is not OK to dispense TIRF medicines from the inpatient pharmacy inventory to an outpatient for home use (Table 12). Table 11. Responses to Additional Questions About the Safe Use of TIRF Medicines Eligible Completed Pharmacists Question N=300l Question 6: Please answer True, False, or I don?t know for each statement based on the labeling for TIRF medicines.2 6a: A cancer patient can be started on a TIRF medicine and an around?the?clock opioid at the same time. True 80 26.7 False3 196 65.3 I don?t know 24 8-0 131 Pharmacy KAB Assessment Report Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 35 of 47 Table 11. Responses to Additional Questions About the Safe Use of TIRF Medicines Eligible Completed Pharmacists Question N=300l 6b: A cancer patient who has been on an around-the-clock opioid for 1 day can start taking a TIRF medicine for breakthrough pain. True 50 16. 7 False3 224 74.7 I don?t know 26 8.7 Question 8: Which of the following are risk factors for opioid abuse? Please answer Yes, No, or I don?t know for each option. 8c: A family history of asthma Yes 38 12.7 No3 245 81.7 I don't know 17 5.7 Question 11: Please select True, False, or I don?t know for each of the following. According to the labeling for TIRF medicines, patients considered opioid-tolerant are those who are taking, for one week or longer, at least: 11a: 8 mg oral hydromorphone/day True3 237 79.0 False 29 9-7 I don?t know 34 11-3 11b: 60 mg oral morphine/day True3 255 85.0 False 14 4.7 I don?t know 31 10.3 11c: 30 mg oral oxycodone/day True 3 214 71.3 False 44 14_7 I don?t know 42 14-0 1 32 Phannacy KAB Assessment Report Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industly Group (TRIG) of Companies Page 36 of 47 Table 11. Responses to Additional Questions About the Safe Use of TIRF Medicines Eligible Completed Pharmacists Question N=300l 11d: 25 transdermal fentanyl/hour Tme3 216 72.0 False 45 15.0 I don?t know 39 13.0 lle: 25 mg oral oxymorphone/day Tme3 213 71.0 False 29 9.7 I don?t know 58 19.3 11f: An equianalgesic dose of another oral opioid Tme3 177 59.0 False 61 20.3 I don?t know 62 20.7 Question 13: Please answer True, False, or I don?t know for each statement about TIRF medicines. 13a: TIRF medicines may be sold, loaned, or transferred to another pharmacy. Tnle 8 2.7 False3 274 91.3 I don?t know 18 6.0 13b: All pharmacy staff that dispenses TIRF medicines must be educated on the requirements of the TIRF REMS Access Program. Tme3 282 94.0 False 6 2.0 I don?t know 12 4.0 1 33 Pharmacy KAB Assessment Report Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 37 of 47 Table 11. Responses to Additional Questions About the Safe Use of TIRF Medicines Eligible Completed Pharmacists Question N=300l 13c: TIRF medicines with the same route of administration can be substituted with each other if the pharmacy is out of stock for one product. True 6 2.0 False3 289 96.3 I don?t know 5 1,7 1 Nrunber of eligible phannacists completing the sruvey (See Table 1). 2 Question 6 was presented to phannacists participating in the irrtemet sruyey as follows: Please answer True. False. or I don?t know for each statement based on the labeling TIRF medicines. The word ?for? was excluded in error and was added for reporting purposes 3 Indicates the correct response(s) to each question or item within a question. Table 12. Responses to Additional Questions About the Safe Use of TIRF Medicines: Question asked of Inpatient Pharmacists, Only Eligible Completed Pharmacists Question N=15l Question 17: Please answer True, False, or I don?t know for the following statement about TIRF medicines. (Inpatient pharmacists, only) It is OK to dispense TIRF medicines from the inpatient pharmacy inventory to an outpatient for use at home.3 True 0 0.0 Falsez 13 86.7 I don?t know 2 13.3 1 Question asked of inpatient pharmacists only. 2 Indicates the correct response(s) to each question or item within a question. 3 This question is presented only to a sub-group of pharmacists. Percentages are based on the munber of phamracists to whom this question was presented. 5.2.2.2 Pharmacist Activities When Dispensing TIRF Medicines Pharmacists were asked about speci?c activities performed when dispensing TIRF medicines (Table 13). Of the 300 eligible pharmacists, 167 responded they always ask their patients (or a patient?s caregiver) about the presence of children in the home; 18.0% responded that they 1 34 Pharmacy KAB Assessment Report Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 38 of 47 ask only with the ?rst prescription. Additionally, 69.3% responded they always instruct the patient (or their caregivers) not to share TIRF medicines, 66.0% responded they always counsel patients (or their caregivers) that accidental exposm?e to TIRF medicines by a child may be fatal, 74.3% responded they always instruct patients (or their caregivers) to keep TIRF medicines out of reach of children, 66.0% responded they always instruct patients (or their caregivers) about proper disposal of any unused or partially used TIRF medicines, and 91.3% responded they always give patients (or their caregivers) the Medication Guide for TIRF medicine. Table 13. Responses to All Questions About Activities When Dispensing TIRF Medicines Eligible Completed Pharmacists Question N=300l Question 12: How frequently do you perform the following activities when dispensing TIRF medicines? Please answer Always, Only with the ?rst prescription, Sometimes, Never, or I don?t know. 12a: Ask patients (or their caregivers) about the presence of children in the home. Always 167 55.7 Only with the ?st prescription 54 18.0 Sometimes 54 18.0 Never 13 4.3 I don?t know 12 4.0 12b: Instruct patients (or their caregivers) not to share TIRF medicines with anyone else. Always 208 69.3 Only with the ?st prescription 52 17.3 Sometimes 26 8.7 Never 8 2.7 I don?t know 6 2.0 12c: Counsel patients (or their caregivers) that accidental exposure to TIRF medicines by a child may be fatal. Always 198 66.0 Only with the ?st prescription 57 19.0 Sometimes 29 9.7 Never 8 2.7 I don?t know 8 2.7 1 35 Pharmacy KAB Assessment Report Transmucosal Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 39 of 47 Table 13. Responses to All Questions About Activities When Dispensing TIRF Medicines Eligible Completed Pharmacists Question N=300l 12d: Instruct patients (or their caregivers) to keep TIRF medicines out of the reach of children to prevent accidental exposure. Always 223 74.3 Only with the ?st prescription 44 14.7 Sometimes 23 7.7 Never - 1.7 I don?t know 5 1.7 12e: Instruct patients (or their caregivers) about proper disposal of any unused or partially used TIRF medicines. Always 198 66.0 Only with the fn?st prescription 67 22.3 Sometimes 26 8.7 Never 4 1.3 I don?t know 5 1.7 12f: Give patients (or their caregivers) the Medication Guide for their TIRF medicine. Always 274 91.3 Only with the fn'st prescription 11 3.7 Sometimes 10 3.3 Never 0 0.0 I don?t know 5 1.7 1 Number of eligible pharmacists completing the survey (See Table 1). 2 This question is presented only to a sub-group of phamracists. Percentages are based on the munber of phannacists to whom this question was presented. Speci?c pharmacy types (inpatient, outpatient, and SP pharmacies) were each asked a single different question regarding pharmacy systems and processes. Question 14 was presented only to pharmacy respondents from inpatient pharmacies (N =1 5) as identi?ed through the access code entered by the respondent (Table 14). Of the 15 respondents, 8 reported their pharmacy has processes to ensure compliance with the TIRF REMS Access Program requirements. 1 36 Pharmacy KAB Assessment Report Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 40 of 47 Table 14. Responses to All Questions About Activities When Dispensing TIRF Medicines: Asked of Inpatient Pharmacies Only Eligible Completed Inpatient Pharmacists Question N=15l Question 14: Does the inpatient pharmacy where you work have an established system, order sets, protocols and/or other measures to help ensure appropriate patient selection and compliance with the requirements of the TIRF REMS Access Program? [Inpatient pharmacists only]2 Yes 8 53.3 No 4 26. 7 I don't know 3 20.0 1 Number of eligible inpatient pharmacists completing the sun'ey. 2 This question is presented only to a sub-group of pharmacists. Percentages are based on the rnunber of inpatient pharmacists to whom this question was presented. Question 15 was presented only to pharmacy respondents from outpatient pharmacies (n=281) as identi?ed though the access code entered by the respondent. This sub-population did not include respondents from SPs (Table 15). Of the 281 respondents, 231 reported their pharmacy processes prescriptions for TIRF medicines through their pharmacy management system. Table 15. Responses to All Questions About Activities When Dispensing TIRF Medicines: Outpatient Pharmacists Only Eligible Completed Outpatient Pharmacists Question Question 15: Does the outpatient or retail pharmacy where you work process all TIRF medicine prescriptions, regardless of method of payment, through the pharmacy management system? [Outpatient pharmacists only]2 Yes 231 82.2 No 5 1.8 I don't know 45 16.0 1 Number of eligible outpatient pharmacists completing the survey. 2 This question is presented only to a sub-group of phamracists. Percentages are based on the munber of outpatient pharmacists to whom this question was presented. 1 37 Pharmacy KAB Assessment Report Transmucosal Irmnediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 41 of 47 Question 16 was presented only to pharmacy respondents from SPs (N as identi?ed through the access code entered by the respondent (Table 16). Of the 4 respondents, 2 reported their pharmacy processes all prescriptions for TIRF medicines through the TIRF REMS Access Call Center. Table 16. Responses to All Questions About Activities When Dispensing TIRF Medicines: Closed System Pharmacy Outpatient Pharmacists Only Eligible Completed CSP Pharmacists Question N=4l Question 16: Does the pharmacy where you work process all TIRF medicine prescriptions, regardless of method of payment, through the TIRF REMS Access Call Center? Outpatient pharmacists only]2 Yes 2 50.0 No 0 0.0 I don't know 2 50.0 1 Nrunber of eligible CSP outpatient pharmacists completing the survey. 2 This question is presented only to a sub-group of pharmacists. Percentages are based on the number of CSP phamracists to whom this question was presented. 5.2.3 Analyses of Sub-populations To fruther assess pharmacist rmderstanding of key risk messages, sub-group analyses as described in Section 4.1.2 were conducted. Sub-group analysis of time to complete the survey for telephone respondents was not done since there were less than 20 respondents in this sub-group (telephone respondents; For the remaining sub-group analyses that were performed, all results are similar to the results in the primary analysis population, and no trends are evident. The full set of sub-group analysis tables is provided in Appendix B. 5.3 Spontaneous Reporting of Adverse Events, Product Complaints, or Medical Information Requests Among all survey respondents Table 1), there were no adverse events or product complaints reported. In the Internet sruvey, respondents had the option to write in any questions they had when asked ?What are your questions?? This prompt resulted in 18 individual responses by various completers, of which 13 were requests for medical information and 5 were indications that the free text ?eld was not applicable or they had no questions (Appendix B, Listing 1). Since only medical information requests were received, the same information is reported in Appendix B, Listing 2 (qquestions about the information in the F1111 Prescribing Information or Medication Guide) as described in Section 5.1.3. 1 38 Pharmacy KAB Assessment Report Transmucosal Irmnediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 42 of 47 6. DISCUSSION, CONCLUSIONS, AND RECONIMENDATIONS The speci?c goal of the TIRF REMS pharmacist KAB survey was to assess pharmacist rmderstanding of the risks associated with TIRF medicine use, the speci?c indications for treatment with TIRF medicines, and that TIRF medicines are contraindicated in opioid non- tolerant patients. Based on FDA feedback from the 12-month assessment, revisions were made to the 24- month pharmacist smvey. As presented in Table 17 for changes in key risk message questions, there was a substantial improvement in correct response rate for key risk messages in the 24-month KAB smvey compared with the 12-month KAB sruvey. Additionally, there was improvement in this 24-month KAB survey for Question 8a; this question was also included in Key Risk Message 3 in the l2-month KAB survey. A potential reason for the low performance on the 12-month assessment may be due to the short period of time that the shared system REMS was live prior to the l2-month smvey (6 months). Prior to the 24- month sruvey, the questions were revised based on the QR results to improve understanding of the questions/items being tested. In addition, there were 22,762 pharmacies that em?olled or re-em?olled dru?ing this reporting period by successfully completing the education program, thereby reinforcing the educational message of the shared system REMS. Table 17. Correct Response Rate in the 24-month KAB Survey Compared with the lZ-month KAB Survey in Key Risk Message Questions Modi?ed Between the Two Versions 12?month 24?month lZ-month 24-month Survey Survey Survey Survey Correct Correct Question Question Question as Presented in the 24?month Response Response Number Number Survey Please select True. False. or I don?t know for each of the following. According to the 5 5 labeling for TIRF medicines. patients with cancer who are considered opioid-tolerant are those: Who are taking arormd-the?clock opioid 5a 53 therapy for cancer pam 12.6 903 for one week or longer (Correct Response True) Who have no known contraindications to the SC SC drug fentanyl. but are not crurently taking 1 5.6 76.0 aromid-the-clock opioid therapy (Correct Response False) 1 39 Pharmacy KAB Assessment Report Transmucosal Irmnediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 43 of 47 Table 17. Correct Response Rate in the 24-month KAB Survey Compared with the 12-month KAB Survey in Key Risk Message Questions Modified Between the Two Versions lZ-month 24-month 12-month 24?month Survey Survey Survey Survey Correct Correct Question Question Question as Presented in the 24-month Response Response Number Number Survey Which of the following are risk factors for 7 8 opioid abuse? Please answer Yes. No. or I don?t know for each option. 7a 8a A personal history of illness 66.6 72.0 (Correct Response Yes) Per the approved labeling for TIRF medicines. for which of the following 8 9 indications can TIRF medicines be prescribed to opioid tolerant patients? Please answer Yes. No. or I don?t know for each option: 8e 9e Chronic non-cancer pam 29.8 47-0 (Correct Response No) In this 24-month smvey, only one item was identi?ed as having a low level of understanding among pharmacists (TIRF medicines are not indicated for chronic non-cancer pain; However, it should be noted that there was a marked improvement in the Pharmacist?s correct response rate for this concept from the 12-month KAB survey to the 24-month KAB srnvey. It should also be noted that recognition of uses for which TIRF medicines are not indicated is not a goal of the TIRF REMS for pharmacists. Because a majority of the pharmacists srnveyed demonstrated a high level of rmderstanding of all but one item out of the 4 key risk messages the TRIG has determined that the Pharmacist Education Program is meeting the goals of the TIRF REMS. 1 40 Pharmacy KAB Assessment Report Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Appendix A Page 44 of 47 Pharmacy Survey Protocol FDA_1141 PROTOCOL TITLE: Quantitative Testing of Pharmacist Knowledge, Attitudes, and Behavior about Transmucosal Immediate Release Fentanyl (TIRF) Products Safety and Use Information SPONSOR: TIRF REMS Industry Group (TRIG) Archimedes Pharma US Inc. Cephalon, Inc. (a wholly-owned subsidiary of Teva Pharmaceutical Industries, Ltd.) Endo Pharmaceuticals Inc. Galena Biopharma Insys Therapeutics Mallinckrodt Meda Pharmaceuticals Mylan, Inc. Par Pharmaceutical, Inc. VERSION: 5.0 DATE: 10 Sep 2013 APPROVED: FINAL FDA_1142 TIRF REMS Industry Group (TRIG) Transmucosal Immediate Release Fentanyl (TIRF) Products Pharmacist KAB Survey Protocol TABLE OF CONTENTS Version 5.0 10 Sep 2013 PAGE TABLE OF CONTENTS ......................................................................................... 2 1. LIST OF ABBREVIATIONS .................................................................................. 3 2. BACKGROUND ..................................................................................................... 4 3. OBJECTIVES OF THE EVALUATION SURVEY ............................................... 5 4. METHODS .............................................................................................................. 5 4.1 4.1.1 4.1.2 4.1.3 Survey Design .......................................................................................................... 5 Qualitative Research on the Survey ......................................................................... 6 Questions and Statements on REMS Goals ............................................................. 6 Additional Questions................................................................................................ 9 4.2 4.2.1 Participant Recruitment.......................................................................................... 10 Measures to Minimize Bias in the Sample............................................................. 10 5. 5.1.1 5.1.2 5.1.3 STUDY POPULATION ........................................................................................ 10 Sample Size ............................................................................................................ 10 Inclusion Criteria.................................................................................................... 11 Exclusion Criteria .................................................................................................. 11 6. SURVEY PROCESS ............................................................................................. 12 6.1 6.1.1 6.1.2 Screening and Survey Administration ................................................................... 12 Telephone ............................................................................................................... 12 Internet ................................................................................................................... 12 6.2 Measures to Minimize Bias in the Survey Process ................................................ 12 7. 7.1.1 7.1.1.1 7.1.1.2 ANALYSIS ............................................................................................................ 13 Analysis Population ............................................................................................... 13 Description of Primary Analyses ........................................................................... 13 Description of Secondary Analyses ....................................................................... 14 8. SAFETY EVENT REPORTING ........................................................................... 14 9. PRIVACY PROTECTION AND CONFIDENTIALITY...................................... 14 LIST OF APPENDICES Appendix A Pharmacist Questionnaire ......................................................................... 15 Appendix B Pharmacist Invitation Letter ..................................................................... 32 Appendix C Qualitative Research Report ..................................................................... 34 2 of 34 FDA_1143 TIRF REMS Industry Group (TRIG) Transmucosal Immediate Release Fentanyl (TIRF) Products Pharmacist KAB Survey Protocol 1. Version 5.0 10 Sep 2013 LIST OF ABBREVIATIONS CATI CSP CI EDC ETASU FDA HIPAA ISI KAB PI REMS SE/PSP TIRF TIRF REMS TRIG UBC US Computer-Assisted Telephone Interviewing Closed System Pharmacy Confidence Interval Electronic Data Capture Elements to Assure Safe Use Food and Drug Administration Health Insurance Portability and Accountability Act Important Safety Information Knowledge, Attitudes and Behavior Prescribing Information Risk Evaluation and Mitigation Strategy Safety Event Project Specific Procedure Transmucosal Immediate Release Fentanyl TIRF REMS Access Program TIRF REMS Industry Group United BioSource Corporation United States 3 of 34 FDA_1144 TIRF REMS Industry Group (TRIG) Transmucosal Immediate Release Fentanyl (TIRF) Products Pharmacist KAB Survey Protocol 2. Version 5.0 10 Sep 2013 BACKGROUND Transmucosal Immediate Release Fentanyl (TIRF) medicines include the class of immediaterelease opioid analgesics that are indicated only for the management of breakthrough pain in cancer patients 18 years of age or older (16 or older for Actiq® and equivalent generics) who are already receiving and already tolerant to opioid therapy for their underlying persistent cancer pain. The TIRF medicines include Abstral®, Actiq®, Fentora®, Lazanda®, Onsolis®, Subsys®, and generic versions of any of these brands. The TIRF REMS Industry Group (TRIG) includes Archimedes Pharma US Inc.; Cephalon, Inc. (a wholly-owned subsidiary of Teva Pharmaceutical Industries, Ltd.); Endo Pharmaceuticals Inc.; Galena Biopharma; Insys Therapeutics; Meda Pharmaceuticals; Mallinckrodt; Mylan, Inc.; and Par Pharmaceutical, Inc. The Food and Drug Administration (FDA) has determined that a class-wide Risk Evaluation and Mitigation Strategy (REMS) is required to mitigate the risk of misuse, abuse, addiction, overdose, and serious complications due to medication errors with the use of TIRF medicines. The TIRF REMS Access Program (hereafter referred to as TIRF REMS) was approved by the FDA on December 28, 2011. The TIRF REMS consists of a Medication Guide, Elements to Assure Safe Use (ETASU), an Implementation System, and a timetable for submission of assessments of the REMS. The goals of the TIRF REMS are to mitigate the risk of misuse, abuse, addiction, overdose and serious complications due to medication errors by: 1. Prescribing and dispensing TIRF medicines only to appropriate patients, which includes use only in opioid-tolerant patients 2. Preventing inappropriate conversion between TIRF medicines 3. Preventing accidental exposure to children and others for whom it was not prescribed 4. Educating prescribers, pharmacists, and patients on the potential for misuse, abuse, addiction, and overdose of TIRF medicines An important component of the TIRF REMS is the conduct of quantitative evaluation surveys to assess pharmacists’ understanding and knowledge of the safe use and appropriate prescribing of TIRF medicines as described in the TIRF REMS educational materials, enrollment form, and Prescribing Information (PI). This protocol will describe the administration of the surveys that will be conducted among pharmacists who are enrolled in the TIRF REMS Access Program. Data from the surveys, together with other REMS evaluation metrics, will be used to determine whether changes need to be made to the REMS processes or educational materials to make them more effective in achieving the goals of the REMS. 4 of 34 FDA_1145 TIRF REMS Industry Group (TRIG) Transmucosal Immediate Release Fentanyl (TIRF) Products Pharmacist KAB Survey Protocol Version 5.0 10 Sep 2013 The surveys will be implemented so that data will be available for inclusion in the REMS Assessment Reports that will be submitted to the FDA at 12 months after approval of the TIRF REMS and annually thereafter. 3. OBJECTIVES OF THE EVALUATION SURVEY The evaluation survey will use a questionnaire to document the level of knowledge and assess the attitudes and behavior of pharmacists around the following key information and risk messages communicated through REMS: 1. TIRF medicines are contraindicated in opioid non-tolerant patients. 2. TIRF medicines are only indicated for the management of breakthrough pain in adult cancer patients 18 years of age and older (16 or older for Actiq® and equivalent generics) who are already receiving and who are tolerant to around-the-clock opioid therapy for their underlying persistent cancer pain. 3. TIRF medicines contain fentanyl, an opioid agonist and a Schedule II controlled substance, with abuse liability similar to other opioid analgesics. 4. TIRF medicines are not interchangeable with each other, regardless of route of administration. 5. Patients and their caregivers must be instructed that TIRF medicines contain a medicine in an amount that can be fatal in children, in individuals for whom it is not prescribed, and in those who are not opioid tolerant. The survey will also collect data on behaviors, such as receipt and use of educational materials and compliance with REMS requirements. 4. METHODS The survey was designed in collaboration between the TRIG and United BioSource Corporation (UBC), and will be administered by UBC. 4.1 Survey Design This survey will be conducted among a sample of pharmacists who are enrolled in the TIRF REMS Access Program. Respondents who have participated in the first wave of the TIRF survey will not be eligible to participate in subsequent survey waves. The survey will be administered using the following modalities:  Self-administered via the Internet through a secure website 5 of 34 FDA_1146 TIRF REMS Industry Group (TRIG) Transmucosal Immediate Release Fentanyl (TIRF) Products Pharmacist KAB Survey Protocol  Version 5.0 10 Sep 2013 Telephone surveys facilitated by a trained interviewer from the Survey Coordinating Center using a computer-assisted telephone interviewing (CATI) program The survey will begin with screening questions to confirm respondent eligibility to participate in the survey. Completion of the entire survey is expected to take up to 20 minutes. The survey included in Appendix A is written to reflect wording for both methods of survey administration: Internet-based and telephone. All respondents who complete the survey and who provide their contact information will be mailed a $50 honorarium for their time. 4.1.1 Qualitative Research on the Survey The FDA provided feedback to the TRIG on the KAB survey results for pharmacists included in the 12-month REMS Assessment results. The FDA requested that the TRIG investigate the causes for low correct response rates to specific questions in the survey by conducting research to determine the reasons for the poor performance on these questions, and to assess proposed revised wording to select questions. Qualitative research was performed with 7 pharmacists who were recruited from the list of pharmacists who completed surveys for the 12-month TIRF REMS Assessment and met the definition of “low performer”, i.e., provided an incorrect response on 3 to 5 of the 7 targeted responses/questions from the 12-month TIRF REMS Assessment. Among the pharmacists interviewed, the most notable finding was that their survey responses should be based on (“according to”) the TIRF medicines label. The findings from this research have been incorporated into the survey in Appendix A. The qualitative research report can be found in Appendix C. 4.1.2 Questions and Statements on REMS Goals The Knowledge, Attitudes, and Behaviors (KAB) questionnaire is made up of multiplechoice, close-ended statements or questions (the majority of which use true/false or yes/no dichotomous response options), and one open-ended question. These will evaluate current knowledge, attitudes, and behavior regarding the key risk messages noted in Section 3. Questions will be presented in several formats:  Statements or questions asking the respondent to indicate whether a statement or question is true or false, or if they do not know the answer (there is a similar set of statements and questions that use “yes” or “no” as potential response options);  Statements or questions asking the respondent to choose from a defined list of possible statements or answers; and  One question allowing for the respondent to list questions or comments. 6 of 34 FDA_1147 TIRF REMS Industry Group (TRIG) Transmucosal Immediate Release Fentanyl (TIRF) Products Pharmacist KAB Survey Protocol Version 5.0 10 Sep 2013 Questionnaires will be analyzed to determine pharmacist understanding of each key risk message. For statements or questions that use “true” or “yes” vs. “false” or “no” response options, the desired response for the key risk messages is generally “true” or “yes” indicating knowledge of, or behavior in accordance with, the objectives of the REMS. However, some questions are formatted to have the respondent disagree with the statement as written by providing response options of “false” or “no” to avoid having the same affirmative answer for all desired responses. REMS statements, corresponding questions, and desired responses covering the key risk messages are identified below and can be found in the complete survey questionnaire (Appendix A). Key Risk Message 1: TIRF medicines are contraindicated in opioid non-tolerant patients. Question No. 5 5a 5b 5c 7 7a 7b 7c 7d Question Desired response Please select True, False, or I don’t know for each of the following. According to the labeling for TIRF medicines, patients with cancer who are considered opioid-tolerant are those: Who are taking around-the-clock opioid therapy for underlying persistent cancer pain for one week or TRUE longer Who are not currently taking opioid therapy, but FALSE have taken opioid therapy before Who have no known contraindications to the drug fentanyl, but are not currently taking around-theFALSE clock opioid therapy Please answer True, False, or I don’t know for each statement based on the labeling for TIRF medicines. TIRF medicines are contraindicated in opioid nontolerant patients because life-threatening respiratory TRUE depression could occur at any dose. Death has occurred in opioid non-tolerant patients TRUE treated with some fentanyl products. TIRF medicines may be used in opioid non-tolerant FALSE patients. Prescribers starting a patient on a TIRF medicine must begin with titration from the lowest dose TRUE available for that specific product, even if the patient has previously taken another TIRF medicine. 7 of 34 FDA_1148 TIRF REMS Industry Group (TRIG) Transmucosal Immediate Release Fentanyl (TIRF) Products Pharmacist KAB Survey Protocol Version 5.0 10 Sep 2013 Key Risk Message 2: TIRF medicines are only indicated for the management of breakthrough pain in adult cancer patients 18 years of age and older (16 years of age and older for Actiq® brand and generic equivalents) who are already receiving and who are tolerant to around-theclock opioid therapy for their underlying persistent cancer pain. Question No. 9 9a 9b 9c 9d 9e Question Desired response Per the approved labeling for TIRF medicines, for which of the following indications can TIRF medicines be prescribed to opioid tolerant patients? Please answer Yes, No, or I don’t know for each option. Acute or postoperative pain NO Headache or migraine pain NO Dental pain NO Breakthrough pain from cancer YES Chronic non-cancer pain NO Key Risk Message 3: TIRF medicines contain fentanyl, an opioid agonist and a Schedule II controlled substance with abuse liability similar to other opioid analgesics. Question No. 7 7e 8 8a 8b 10 10a Question Desired response Please answer True, False, or I don’t know for each statement based on the labeling for TIRF medicines. It is important to monitor for signs of abuse and addiction in patients who take TIRF TRUE medicines. Which of the following are risk factors for opioid abuse? Please answer Yes, No, or I don’t know for each option. A personal history of psychiatric illness YES A personal history of past or current alcohol or drug abuse, or a family history of YES illicit drug use or alcohol abuse Please answer True, False, or I don’t know for each statement based on the labeling for TIRF medicines. TIRF medicines can be abused in a manner TRUE similar to other opioid agonists. 8 of 34 FDA_1149 TIRF REMS Industry Group (TRIG) Transmucosal Immediate Release Fentanyl (TIRF) Products Pharmacist KAB Survey Protocol Version 5.0 10 Sep 2013 Key Risk Message 4: TIRF medicines are not interchangeable with each other, regardless of route of administration. Question No. 10 10b 10c 10d 4.1.3 Question Desired response Please answer True, False, or I don’t know for each statement based on the labeling for TIRF medicines. TIRF medicines are interchangeable with each other regardless of route of FALSE administration. The conversion of one TIRF medicine for another TIRF medicine may result in a fatal TRUE overdose because of differences in the pharmacokinetics of fentanyl absorption. Dosing of TIRF medicines is not equivalent TRUE on a microgram-to-microgram basis. Additional Questions The survey includes questions about the requirements of the TIRF REMS Access Program, receipt and understanding of the TIRF educational materials, and behaviors. The following question about behaviors will be asked after the key risk message questions. Question 12: How frequently do you perform the following activities when dispensing TIRF medicines? Please answer Always, Only with the first prescription, Sometimes, Never, or I don’t know. Ask patients (or their caregivers) about the presence of children in the home Instruct patients (or their caregivers) not to share TIRF medicines with anyone else Counsel patients (or their caregivers) that accidental exposure to TIRF medicines by a child may be fatal Instruct patients (or their caregivers) to keep TIRF medicines out of the reach of children to prevent accidental exposure Instruct patients (or their caregivers) about proper disposal of any unused or partially used TIRF medicines Give patients (or their caregivers) the Medication Guide for their TIRF medicine Demographic information will be collected at the end of the survey. 9 of 34 FDA_1150 TIRF REMS Industry Group (TRIG) Transmucosal Immediate Release Fentanyl (TIRF) Products Pharmacist KAB Survey Protocol 4.2 Version 5.0 10 Sep 2013 Participant Recruitment A random sample of “pharmacists in charge” from pharmacies that are enrolled in the TIRF REMS Access Program will be invited to participate via an invitation letter. Any pharmacist who works at an enrolled pharmacy may participate. The text of the sample written invitation to pharmacists can be found in Appendix B. If the required number of completed surveys is not achieved within the expected timeframe of approximately one to two weeks after the first mailing, reminder letters will be sent to nonrespondents from the original sample with subsequent fax, e-mail, or United States (US) Mail follow-up to maximize participation. The distribution within the mailing to the second sample will be adjusted in accordance with the allocation in the original sample. If these efforts do not result in the required number of surveys within two to three weeks, then a new sample of pharmacists will be randomly selected. The unique code provided in the invitation letter will be linked to the type of pharmacy (inpatient, outpatient, or Closed System Pharmacy [CSP]) in which the pharmacist works, based on the information provided as part of the TIRF REMS Access Program enrollment. All respondents who complete the survey and who provide their contact information will be mailed a $50 honorarium to thank them for their participation. The mailing will include a Thank You Letter, a copy of the Important Safety Information (ISI), and a copy of the correct answers to key risk message questions. 4.2.1 Measures to Minimize Bias in the Sample The sample of participating pharmacists will be self-selected since respondents will voluntarily respond to the invitation to participate; however, the survey recruitment strategies are intended to recruit a heterogeneous sample of pharmacies (e.g., chain and independent store) for participation. Pharmacists will be offered Internet-based or telephone options for completing the survey. Multiple modalities for survey data collection allow for wider survey access to a more heterogeneous population. Respondents will be provided a unique code during the recruitment process and will be asked to provide the unique code to gain access to the Internet-based survey or when calling the Survey Coordinating Center. The code will be deactivated after use to minimize the possibility for fraud. 5. STUDY POPULATION 5.1.1 Sample Size A sample of 300 pharmacists who are enrolled in the TIRF REMS Access Program is proposed for each survey wave. The size of the sample was determined based on both practical and statistical considerations. There is no target comprehension rate specified a priori. A sample of 300 completed surveys will allow estimation of the comprehension rate 10 of 34 FDA_1151 TIRF REMS Industry Group (TRIG) Transmucosal Immediate Release Fentanyl (TIRF) Products Pharmacist KAB Survey Protocol Version 5.0 10 Sep 2013 for each risk message with a moderately high degree of precision. The table below shows the precision of the estimates for level of understanding using two-sided 95% confidence intervals (CIs) obtained with the sample size of 300 completed surveys. The noted CIs are used to indicate that for any survey-estimated rate of understanding, the true population rate of understanding is at least as high as the lower limit of the 95% CI and may be as high as the upper limit of the 95% CI. Table 5.1: Precision of Estimated Rates of Understanding with a Sample Size of 300 Estimated Rate of Understanding 5% 10% 15% 20% 25% 30% 35% 40% 45% 50% 55% 60% 65% 70% 75% 80% 85% 90% 95% 5.1.2 Estimated Confidence Interval 2.8% 6.8% 11.2% 15.6% 20.2% 24.9% 29.6% 34.4% 39.3% 44.2% 49.2% 54.2% 59.3% 64.5% 69.7% 75.0% 80.4% 86.0% 91.9% 8.1% 14.0% 19.6% 25.0% 30.3% 35.5% 40.7% 45.8% 50.8% 55.8% 60.7% 65.6% 70.4% 75.1% 79.8% 84.4% 88.8% 93.2% 97.2% Inclusion Criteria Pharmacists who work at pharmacies that are enrolled in the TIRF REMS Access Program are eligible to participate in this survey, with the exceptions noted below. 5.1.3 Exclusion Criteria The following respondents are not eligible to participate in the surveys:  Pharmacists who have previously participated in the TIRF REMS KAB survey.  Pharmacists or their immediate family members who have ever worked for Anesta LLC, Archimedes Pharma US Inc.; Cephalon, Inc. (a wholly-owned subsidiary of Teva Pharmaceutical Industries, Ltd.); Endo Pharmaceuticals Inc.; Galena Biopharma; Insys Therapeutics; Mallinckrodt; Meda Pharmaceuticals; Mylan, Inc.; Par Pharmaceutical, Inc.; ProStrakan, Inc.; Teva Pharmaceuticals, Ltd.; UBC; McKesson Specialty Care Solutions; RelayHealth; or the FDA. 11 of 34 FDA_1152 TIRF REMS Industry Group (TRIG) Transmucosal Immediate Release Fentanyl (TIRF) Products Pharmacist KAB Survey Protocol 6. Version 5.0 10 Sep 2013 SURVEY PROCESS The survey will begin with screening questions to confirm respondent eligibility to participate in the survey. Completion of the entire survey is expected to take approximately 20 minutes. 6.1 Screening and Survey Administration The questionnaire will begin with a screening module with questions to confirm pharmacist eligibility. Depending on the answers to the screening questions, survey participation could either be terminated or continued. If ineligible, the respondent is immediately notified with a “thank you” message that survey participation has ended. If eligible, the respondent is allowed to continue survey participation. The data entry system used for both methods of survey administration has been validated and is secure for receiving and storing survey data. An Internet-based data repository will be used to store survey data and other relevant program information. The system is 21 CFR Part 11 and Health Insurance Portability and Accountability Act (HIPAA) compliant. Pharmacistidentifying information will be stored separately from survey data. 6.1.1 Telephone A trained interviewer from the Survey Coordinating Center will conduct the telephone interviews using a CATI program. The screening and main elements of the questionnaire will be administered sequentially during the same telephone call. Telephone interviewing allows participation of pharmacists who do not have Internet access or prefer taking the survey over the telephone. It will also be convenient for pharmacists to participate since they can call in and be interviewed at their convenience during the specified time period when the Survey Coordinating Center is available. 6.1.2 Internet An Internet-based survey system will also be used for conducting the KAB surveys. If the pharmacist selects to participate in the survey via the Internet, he/she will be directed to a secured website where he/she will be instructed to complete screening questions. An Internetbased survey will be convenient for respondents to participate since they can complete the questionnaire at any convenient time and location during the specified time period when the Survey Coordinating Center is available. 6.2 Measures to Minimize Bias in the Survey Process A number of controls will be in place to ensure the survey is conducted in a controlled and professional manner and to minimize bias. For example, a unique code will be given to each survey participant and the code will be inactivated after use to minimize fraud. Telephone interviewers are highly trained and use a standardized script to administer interviews. All questions will be programmed to ensure that questions are asked in the appropriate sequence. Skip patterns will be clearly indicated. Respondents cannot go back to a question 12 of 34 FDA_1153 TIRF REMS Industry Group (TRIG) Transmucosal Immediate Release Fentanyl (TIRF) Products Pharmacist KAB Survey Protocol Version 5.0 10 Sep 2013 once the question has been answered and cannot skip ahead. All questions must be answered in order to complete the survey. Response options presented in a list will be randomized to minimize positional bias. Programming will be reviewed by quality control and simulated users (User Acceptance Testing) prior to implementing the survey. 7. ANALYSIS Information obtained from the survey will be reported as descriptive statistics for the survey administration, study population, and the survey questions. The data from the sample population will be reported using frequency distributions of responses to all questions. The following will be reported as part of this analysis:  The number of invitations issued to pharmacists  The number of reminder letters issued to pharmacists  The number of respondents screened for participation  The number of respondents eligible for participation  The number of respondents eligible for participation who answered all questions presented to them  Representativeness of pharmacists based on geography  Description of survey participants, including: o Gender o Years of professional experience o How many times per month TIRF medicines dispensed in the last 6 months Additional descriptive statistics may be reported as appropriate. 7.1.1 Analysis Population The analysis population will be based on eligible pharmacists who completed all questions presented to them in the survey (“completers”). 7.1.1.1 Description of Primary Analyses Primary analyses are done for all key risk messages using data from all completers. The primary analysis for a key risk message evaluates the rate for each correct response to each individual question/item defined by the key risk message. The specific correct response to each question/item is identified in the body of the risk message table. 13 of 34 FDA_1154 TIRF REMS Industry Group (TRIG) Transmucosal Immediate Release Fentanyl (TIRF) Products Pharmacist KAB Survey Protocol 7.1.1.2 Version 5.0 10 Sep 2013 Description of Secondary Analyses Secondary analyses are done only for those key risk messages that contain multiple questions/items using data from all completers. The secondary analysis entails a frequency distribution of the number of completers who got 0, 1, etc. correct responses across the total number of items for the given key risk message. 8. SAFETY EVENT REPORTING The term ‘Safety Event’ is defined as any information reported by a survey respondent that meets the criteria of an adverse event or product complaint. While it is not the intention of the survey to solicit the report of information that meets the criteria of a Safety Event, it is possible that a respondent may spontaneously report information that meets this criteria in free text fields of the survey (Internet-based administration) or while in conversation with the Survey Coordinating Center (telephone-based administration). The Internet-based questionnaires will be monitored for any comments recorded in the free text fields. If an event is mentioned to a Survey Coordinating Center Associate, the Associate will document the safety event and the respondent’s contact information. Respondents will also be informed that a representative from the appropriate TIRF medicine manufacturer may contact them if they have questions about the survey. Information on all reports (Internet or telephone) that may constitute an adverse event or other safety event will be forwarded to the appropriate TIRF medicine manufacturer as described in the Safety Event Project Specific Procedure (SE/PSP). Additional detail regarding processes for adverse event reporting will be specified in the SE/PSP. 9. PRIVACY PROTECTION AND CONFIDENTIALITY All data collected during the survey will be held confidential. The electronic data capture (EDC) system used for data collection encrypts all identifiable information, and respondent identifiers are stored separately from the survey responses. Respondent names and addresses are collected in order to mail the $50 honorarium, a Thank You Letter, correct survey responses to key risk message questions, and the ISI after the survey is completed. Respondent contact information is also needed in the event that a safety event is reported and a TIRF medicine manufacturer must obtain follow-up information (see Section 8 above). Respondents will be informed when they access the survey that they may be contacted if there are any questions about their survey responses. Respondents will be informed that their answers to the survey questions will not affect their ability to dispense TIRF medicines. 14 of 34 FDA_1155 TIRF REMS Industry Group (TRIG) Transmucosal Immediate Release Fentanyl (TIRF) Products Pharmacist KAB Survey Protocol Appendix A Version 5.0 10 Sep 2013 Pharmacist Questionnaire Survey Legend  [PROGRAMMER] is used to indicate directions to the programmer and is set in bold, red, uppercase letters between square brackets.  (INTERVIEWER) is used to indicate directions to the telephone interviewer and is set in bold, blue, text between parentheses. This text appears when content is to be administered by telephone only (for example, spontaneous adverse event reporting).  [ONLINE] indicates a question is worded specifically for administering the survey online. [PHONE] indicates a question is worded specifically to be read by a telephone interviewer and differs from the online text.  [BEGIN ONLINE/PHONE SURVEY CONTENT] and [END SURVEY CONTENT] are used to indicate to the programmer the type of survey administration and the beginning and end of the survey or sections within the survey content, for example, [BEGIN ADVERSE EVENT/PRODUCT COMPLAINT] and [END ADVERSE EVENT/PRODUCT COMPLAINT].  [TERMINATE] is displayed next to responses that should cause the survey to end. The following termination language will be programmed into the survey or read by the interviewer unless different language is specified with the question. Thank you very much for your time today. Based on your answer, you are not eligible to take this survey. We appreciate your interest in the survey.  [RANDOMIZE LIST] is inserted before questions to indicate to the programmer that the responses should be randomized. Responses such as “I don’t know,” “Prefer not to answer” or “None of the above” will always appear at the end of the randomized responses.  [GO TO Qx] (skip logic) is inserted after a response to indicate to the programmer that the survey should skip to the indicated question (for example, [GO TO Q17] skips to question 17). If no skip logic is indicated the survey continues to the next question in the sequence.  [MULTILINE INPUT] indicates to the programmer that multiple lines should be provided for data entry (for example, two address lines or a free-text response). 15 of 34 FDA_1156 TIRF REMS Industry Group (TRIG) Transmucosal Immediate Release Fentanyl (TIRF) Products Pharmacist KAB Survey Protocol Version 5.0 10 Sep 2013 Survey Legend  [DROP-DOWN LIST INPUT WITH STATES TABLE] indicates to the programmer that the response should be a drop-down list containing the states in the table below. Alabama Georgia Massachusetts New York Tennessee Alaska Guam Michigan North Carolina Texas American Samoa Hawaii Minnesota North Dakota Arizona Idaho Mississippi Illinois Missouri Indiana Montana Northern Mariana Islands US Virgin Islands Iowa Nebraska Kansas Nevada Kentucky New Hampshire Louisiana New Jersey Maine New Mexico Arkansas California Colorado Connecticut Delaware District of Columbia Florida Maryland Ohio Oklahoma Oregon Pennsylvania Puerto Rico Rhode Island Utah Vermont Virginia Washington West Virginia Wisconsin Wyoming South Carolina South Dakota The following is used to categorize survey populations into standard geographic regions but it is not displayed in the survey. Geographic Distribution (based on address) 1: Northeast, Midwest, South, and West regions Northeast Region   New England Division - ME, NH, VT, MA, RI, CT Middle Atlantic Division - NY, NJ, PA Midwest Region   East North Central Division - OH, IN, IL, MI, WI West North Central Division - MN, IA, MO, ND, SD, NE, KS South Region   South Atlantic Division - DE, MD, DC, VA, WV, NC, SC, GA, FL East South Central Division - KY, TN, AL, MS West South Central Division - AR, LA, OK, TX West  Mountain Division - MT, ID, WY, CO, NM, AZ, UT, NV 16 of 34 FDA_1157 TIRF REMS Industry Group (TRIG) Transmucosal Immediate Release Fentanyl (TIRF) Products Pharmacist KAB Survey Protocol Version 5.0 10 Sep 2013 Survey Legend  Pacific Division WA, OR, CA, AK, HI The following US territories are categorized as Other: Puerto Rico, Northern Mariana Islands, US Virgin Islands, American Samoa, and Guam. 1 U.S. Census Bureau, last revised Friday, 27-Jul-2001 12:59:43 EDT. [BEGIN SURVEY CONTENT] [ONLINE PREAMBLE 1] Before you begin, we would like to share some important information about this survey. The manufacturers of Transmucosal Immediate Release Fentanyl (TIRF) medicines are conducting this survey, as required by the FDA, to assess pharmacists’ understanding of the safe use and dispensing of these medicines. These medicines are known as rapid onset opioids and referred to in this survey as “TIRF medicines.” The TIRF medicines include Abstral®, Actiq®, Fentora®, Lazanda®, Onsolis®, Subsys®, and generic versions of any of these brands. The manufacturers of these medicines include Archimedes Pharma US Inc.; Cephalon, Inc. (a wholly-owned subsidiary of Teva Pharmaceutical Industries, Ltd.); Endo Pharmaceuticals Inc.; Galena Biopharma; Insys Therapeutics; Mallinckrodt; Meda Pharmaceuticals; Mylan, Inc.; and Par Pharmaceutical, Inc. The survey will take 15-20 minutes. There are no known risks to you in taking this survey. You may refuse to take part or withdraw at any time. Your answers to the questions or your decision to take part in the survey will not affect your ability to dispense TIRF medicines. How We Use Your Information Your answers to the survey questions will be combined with answers given by other pharmacists taking the survey. All answers will be put together and reported in anonymous form to the manufacturers of TIRF medicines. Your name will not be used in any report. If you are eligible to take the survey, complete all the questions, and provide your contact information, you will receive a $50 honorarium for your time and participation. Your name and address will be used to send you the honorarium after you complete the survey. Your personal information will also be used if we have questions about your survey or if we are required to use your information to comply with a federal or state law or regulation. Providing a telephone number is optional. Your telephone number will be used only if there are any questions about your survey responses. How We Protect Your Privacy 17 of 34 FDA_1158 TIRF REMS Industry Group (TRIG) Transmucosal Immediate Release Fentanyl (TIRF) Products Pharmacist KAB Survey Protocol Version 5.0 10 Sep 2013 We respect that the privacy of your personal information is important to you. You will not be contacted for marketing purposes based on your personal information or your answers to the survey. Neither the manufacturers of TIRF medicines nor their contractors will sell, transfer, or rent your information. Your answers will be kept strictly confidential. Your privacy will be protected; however, research survey records may be inspected by the FDA. Your choice to allow manufacturers of TIRF medicines to use your information is entirely voluntary but necessary to take part in this survey. How to Learn More about This Survey If you have questions about the survey, or problems with the survey, please contact the Survey Coordinating Center at 1-877-379-3297. Be sure to write down this telephone number; it will not be displayed again. Taking the Survey Once you have answered a question and moved on, you cannot go back and change your answers. Thank you for your participation in this survey. [END ONLINE PREAMBLE 1] 18 of 34 FDA_1159 TIRF REMS Industry Group (TRIG) Transmucosal Immediate Release Fentanyl (TIRF) Products Pharmacist KAB Survey Protocol Version 5.0 10 Sep 2013 [PHONE PREAMBLE 1] Before you begin, we would like to share some important information about this survey. The manufacturers of Transmucosal Immediate Release Fentanyl (TIRF) medicines are conducting this survey, as required by the FDA, to assess pharmacists’ understanding of the safe use and dispensing of these medicines. These medicines are known as rapid onset opioids and referred to in this survey as “TIRF medicines.” (INTERVIEWER: Say “TIRF” then spell out T-IR-F) The TIRF medicines include Abstral®, Actiq®, Fentora®, Lazanda®, Onsolis®, Subsys®, and generic versions of any of these brands. The manufacturers of these medicines include Archimedes Pharma US Inc.; Cephalon, Inc. (a wholly-owned subsidiary of Teva Pharmaceutical Industries, Ltd.); Endo Pharmaceuticals Inc.; Galena Biopharma; Insys Therapeutics; Mallinckrodt; Meda Pharmaceuticals; Mylan, Inc.; and Par Pharmaceutical, Inc. The survey will take 15-20 minutes. There are no known risks to you in taking this survey. You may refuse to take part or withdraw at any time. Your answers to the questions or your decision to take part in the survey will not affect your ability to dispense TIRF medicines. Now I would like to read some information about how your contact information will be used. Your answers to the survey questions will be combined with answers given by other pharmacists taking the survey. All answers will be put together and reported in anonymous form to the manufacturers of TIRF medicines. Your name will not be used in any report. If you are eligible to take the survey, complete all the questions, and provide your contact information, you will receive a $50 honorarium for your time and participation. Your name and address will be used to send you the honorarium after you complete the survey. Your personal information will also be used if we have questions about your survey or if we are required to use your information to comply with a federal or state law or regulation. Providing a telephone number is optional. Your telephone number will be used only if there are any questions about your survey responses. Now I would like to tell you some information about how we protect your privacy. We respect that the privacy of your personal information is important to you. You will not be contacted for marketing purposes based on your personal information or your answers to the survey. Neither the manufacturers of TIRF medicines nor their contractors will sell, transfer, or rent your information. Your answers will be kept strictly confidential. Your privacy will be protected; however, research survey records may be inspected by the FDA. Your choice to allow manufacturers of TIRF medicines to use your information is entirely voluntary but necessary to take part in this survey. Now I will tell you how you can learn more about this survey. Please have a pen or pencil ready to write down a telephone number you can call should you have any questions about the survey. If you have questions about the survey, please ask me at any time. If you have questions at a later time, please contact the Survey Coordinating Center at 1-877-379-3297. 19 of 34 FDA_1160 TIRF REMS Industry Group (TRIG) Transmucosal Immediate Release Fentanyl (TIRF) Products Pharmacist KAB Survey Protocol Version 5.0 10 Sep 2013 Please feel free to ask me to repeat any questions or statements as we go through the survey. Once you have answered a question and moved on, you cannot go back and change your answers. Thank you for your participation in this survey. [END PHONE PREAMBLE 1] 20 of 34 FDA_1161 TIRF REMS Industry Group (TRIG) Transmucosal Immediate Release Fentanyl (TIRF) Products Pharmacist KAB Survey Protocol Version 5.0 10 Sep 2013 [BEGIN INCLUSION/EXCLUSION QUESTIONS] 1. Your agreement to participate in this survey confirms mutual understanding in connection with completion of the survey and the fair market value of the payment to be rendered in connection with those services. Do you agree to participate in this survey? 2. 3. 4. ○ Yes ○ No [TERMINATE] Have you ever taken part in this survey about TIRF medicines before? TIRF medicines include Abstral®, Actiq®, Fentora®, Lazanda®, Onsolis®, Subsys®, and generic versions of any of these brands. ○ Yes [ONLY TERMINATE AFTER WAVE 1] ○ No ○ I don’t know [ONLY TERMINATE AFTER WAVE 1] Do you work in a pharmacy that is enrolled in the TIRF REMS Access program? ○ Yes ○ No [TERMINATE] ○ I don’t know [TERMINATE] Have you or any of your immediate family members ever worked for any of the following companies or agencies? Please select all that apply. □ □ Anesta LLC [TERMINATE] Archimedes Pharma US Inc.[TERMINATE] □ Cephalon, Inc. (a wholly-owned subsidiary of Teva Pharmaceutical Industries, Ltd.) [TERMINATE] □ Endo Pharmaceuticals Inc. [TERMINATE] □ Galena Biopharma [TERMINATE] 21 of 34 FDA_1162 TIRF REMS Industry Group (TRIG) Transmucosal Immediate Release Fentanyl (TIRF) Products Pharmacist KAB Survey Protocol Version 5.0 10 Sep 2013 □ Insys Therapeutics [TERMINATE] □ Mallinckrodt [TERMINATE] □ McKesson Specialty Care Solutions [TERMINATE] □ Meda Pharmaceuticals [TERMINATE] □ Mylan, Inc. [TERMINATE] □ Par Pharmaceutical, Inc. [TERMINATE] □ ProStrakan, Inc. [TERMINATE] □ RelayHealth [TERMINATE] □ Teva Pharmaceuticals, Ltd. [TERMINATE] □ United BioSource Corporation [TERMINATE] □ FDA [TERMINATE] □ None of these apply [IF SELECTED IN ADDITION TO OTHER RESPONSES, TERMINATE] □ I don’t know [TERMINATE] □ Prefer not to answer [TERMINATE] [END INCLUSION/EXCLUSION QUESTIONS] 5. Please select True, False, or I don’t know for each of the following. According to the labeling for TIRF medicines, patients with cancer who are considered opioid-tolerant are those: [RANDOMIZE LIST] Who are taking around-the-clock opioid therapy for underlying persistent cancer pain for one week or longer Who are not currently taking opioid therapy, but have 5b. taken opioid therapy before Who have no known contraindications to the drug 5c. fentanyl, but are not currently taking around-the-clock opioid therapy 5a. 22 of 34 True False I don’t know ○ ○ ○ ○ ○ ○ ○ ○ ○ FDA_1163 TIRF REMS Industry Group (TRIG) Transmucosal Immediate Release Fentanyl (TIRF) Products Pharmacist KAB Survey Protocol Version 5.0 10 Sep 2013 Please answer True, False, or I don’t know for each statement based on the labeling for TIRF medicines. 6. [RANDOMIZE LIST] 6a. A cancer patient can be started on a TIRF medicine and an around-the-clock opioid at the same time. 6b. A cancer patient who has been on an around-the-clock opioid for 1 day can start taking a TIRF medicine for breakthrough pain. True False I don’t know ○ ○ ○ ○ ○ ○ Please answer True, False, or I don’t know for each statement based on the labeling for TIRF medicines. 7. [RANDOMIZE LIST] 7a. TIRF medicines are contraindicated in opioid nontolerant patients because life-threatening respiratory depression could occur at any dose. 7b. Death has occurred in opioid non-tolerant patients treated with some fentanyl products. 7c. TIRF medicines may be used in opioid non-tolerant patients. 7d. Prescribers starting a patient on a TIRF medicine must begin with titration from the lowest dose available for that specific product, even if the patient has previously taken another TIRF medicine. 7e. It is important to monitor for signs of abuse and addiction in patients who take TIRF medicines. 23 of 34 True False I don’t know ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ FDA_1164 TIRF REMS Industry Group (TRIG) Transmucosal Immediate Release Fentanyl (TIRF) Products Pharmacist KAB Survey Protocol 8. Which of the following are risk factors for opioid abuse? Please answer Yes, No, or I don’t know for each option. [RANDOMIZE LIST] 8a. 8b. 8c. 9. Version 5.0 10 Sep 2013 Yes No I don’t know ○ ○ ○ ○ ○ ○ ○ ○ ○ A personal history of psychiatric illness A personal history of past or current alcohol or drug abuse, or a family history of illicit drug use or alcohol abuse A family history of asthma Per the approved labeling for TIRF medicines, for which of the following indications can TIRF medicines be prescribed to opioid tolerant patients? Please answer Yes, No, or I don’t know for each option. [RANDOMIZE LIST] Yes No I don’t know ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ 9a. 9b. 9c. Acute or postoperative pain Headache or migraine pain Dental pain 9d. 9e. Breakthrough pain from cancer Chronic non-cancer pain 10. Please answer True, False, or I don’t know for each statement based on the labeling for TIRF medicines. [RANDOMIZE LIST] 10a. TIRF medicines can be abused in a manner similar to other opioid agonists. 10b. TIRF medicines are interchangeable with each other regardless of route of administration. 10c. The conversion of one TIRF medicine for another TIRF medicine may result in a fatal overdose because of differences in the pharmacokinetics of fentanyl absorption. 10d. Dosing of TIRF medicines is not equivalent on a microgram-to-microgram basis. 24 of 34 True False I don’t know ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ FDA_1165 TIRF REMS Industry Group (TRIG) Transmucosal Immediate Release Fentanyl (TIRF) Products Pharmacist KAB Survey Protocol 11. Version 5.0 10 Sep 2013 Please select True, False, or I don’t know for each of the following. According to the labeling for TIRF medicines, patients considered opioid-tolerant are those who are taking, for one week or longer, at least: [RANDOMIZE LIST] 11a. 11b. 11c. 11d. 11e. 11f. 8 mg oral hydromorphone/day 60 mg oral morphine/day 30 mg oral oxycodone/day 25 mcg transdermal fentanyl/hour 25 mg oral oxymorphone/day An equianalgesic dose of another oral opioid True False I don’t know ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ 12. How frequently do you perform the following activities when dispensing TIRF medicines? Please answer Always, Only with the first prescription, Sometimes, Never, or I don’t know. [RANDOMIZE LIST] 12a Ask patients (or their caregivers) about the presence of children in the home 12b Instruct patients (or their caregivers) not to share TIRF medicines with anyone else 12c Counsel patients (or their caregivers) that accidental exposure to TIRF medicines by a child may be fatal 12d Instruct patients (or their caregivers) to keep TIRF medicines out of the reach of children to prevent accidental exposure 12e Instruct patients (or their caregivers) about proper disposal of any unused or partially used TIRF medicines 12f. Give patients (or their caregivers) the Medication Guide for their TIRF medicine Always Only with the first prescription ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ 25 of 34 Sometimes Never I don’t know FDA_1166 TIRF REMS Industry Group (TRIG) Transmucosal Immediate Release Fentanyl (TIRF) Products Pharmacist KAB Survey Protocol 13. Please answer True, False, or I don’t know for each statement about TIRF medicines. [RANDOMIZE LIST] 13a. TIRF medicines may be sold, loaned, or transferred to another pharmacy. 13b. All pharmacy staff that dispenses TIRF medicines must be educated on the requirements of the TIRF REMS Access program. 13c. TIRF medicines with the same route of administration can be substituted with each other if the pharmacy is out of stock for one product. 14. 15. Version 5.0 10 Sep 2013 True False I don’t know ○ ○ ○ ○ ○ ○ ○ ○ ○ [INPATIENT PHARMACIST] Does the inpatient pharmacy where you work have an established system, order sets, protocols and/or other measures to help ensure appropriate patient selection and compliance with the requirements of the TIRF REMS Access Program? ○ Yes ○ No ○ I don’t know [OUTPATIENT PHARMACIST] Does the outpatient or retail pharmacy where you work process all TIRF medicine prescriptions, regardless of method of payment, through the pharmacy management system? ○ Yes ○ No ○ I don’t know 26 of 34 FDA_1167 TIRF REMS Industry Group (TRIG) Transmucosal Immediate Release Fentanyl (TIRF) Products Pharmacist KAB Survey Protocol 16. 17. Version 5.0 10 Sep 2013 [CSP OUTPATIENT PHARMACIST] Does the pharmacy where you work process all TIRF medicine prescriptions, regardless of method of payment, through the TIRF REMS Access Call Center? ○ Yes ○ No ○ I don’t know [INPATIENT PHARMACIST] Please answer True, False, or I don’t know for the following statement about TIRF medicines. It is OK to dispense TIRF medicines from the inpatient pharmacy inventory to an outpatient for use at home. True False I don’t know ○ ○ ○ [PREAMBLE 3] The next set of questions is about the educational materials for TIRF medicines. As a reminder, the TIRF medicines include Abstral®, Actiq®, Fentora®, Lazanda®, Onsolis®, Subsys®, and generic versions of any of these brands. 18. 19. Did you receive or do you have access to the Full Prescribing Information for the TIRF medicine(s) that you dispense? ○ Yes ○ No [GO TO Q20] ○ I don’t know [GO TO Q20] Did you read the Full Prescribing Information for the TIRF medicine(s) that you dispense? ○ Yes ○ No ○ I don’t know 27 of 34 FDA_1168 TIRF REMS Industry Group (TRIG) Transmucosal Immediate Release Fentanyl (TIRF) Products Pharmacist KAB Survey Protocol 20. 21. 22. 23. Version 5.0 10 Sep 2013 Did you receive or do you have access to the Medication Guide for the TIRF medicine(s) that you dispense? ○ Yes ○ No [GO TO Q22] ○ I don’t know [GO TO Q22] Did you read the Medication Guide for the TIRF medicine(s) that you dispense? ○ Yes ○ No ○ I don’t know Did you or do you have any questions about the information in the Full Prescribing Information or Medication Guide? ○ Yes ○ No [GO TO DEMOGRAPHICS PREAMBLE ] ○ I don’t know [GO TO DEMOGRAPHICS PREAMBLE] What are your questions? [MULTILINE INPUT] [DEMOGRAPHICS PREAMBLE] There are just a few more questions to help us combine your answers with other answers we have received. 24. Are you the Pharmacist in Charge for the TIRF REMS Access Program where you work? ○ Yes ○ No ○ I don’t know 28 of 34 FDA_1169 TIRF REMS Industry Group (TRIG) Transmucosal Immediate Release Fentanyl (TIRF) Products Pharmacist KAB Survey Protocol 25. 26. Version 5.0 10 Sep 2013 On average, how many times per month have you dispensed TIRF medicine within the last 6 months? ○ None [Go to DEMOGRAPHICS PREAMBLE 2] ○ 1 – 2 times per month ○ 3 – 5 times per month ○ More than 5 times per month ○ I don’t remember Please select the TIRF medicine(s) that you have dispensed within the last 6 months (select all that apply): □ Abstral® □ Actiq® or generic Actiq® □ Fentora® □ Lazanda ® □ Onsolis® □ Subsys® [DEMOGRAPHICS PREAMBLE 2] These last few questions are for demographic purposes. 27. What is your gender? ○ Male ○ Female ○ Prefer not to answer 29 of 34 FDA_1170 TIRF REMS Industry Group (TRIG) Transmucosal Immediate Release Fentanyl (TIRF) Products Pharmacist KAB Survey Protocol 28. 29. Version 5.0 10 Sep 2013 In total, how many years have you been a practicing pharmacist? ○ Less than 3 years ○ 3 – 5 years ○ 6 – 10 years ○ 11 – 15 years ○ More than 15 years ○ Prefer not to answer In which state do you practice? [DROP-DOWN LIST INPUT WITH STATES TABLE WITH “Prefer not to answer” AT END] [PHONE ONLY: BEGIN ADVERSE EVENT/PRODUCT COMPLAINT] (INTERVIEWER: Please record if respondent spontaneously reported an adverse event or product complaint during the course of this interview.) ○ Yes ○ No [GO TO CLOSING 1] Enter Safety Adverse Event Verbatim [MULTILINE INPUT] (INTERVIEWER: Indicate to the respondent that someone may call back to ask more questions about the adverse event or product complaint that was reported.) [END ADVERSE EVENT/PRODUCT COMPLAINT] [CLOSING 1] We would like to send you a $50 honorarium within the next few weeks to thank you for your time, but we need your name and address to do so. If you do not provide your name and address you will not receive the honorarium for your time and participation in the survey. 30 of 34 FDA_1171 TIRF REMS Industry Group (TRIG) Transmucosal Immediate Release Fentanyl (TIRF) Products Pharmacist KAB Survey Protocol Version 5.0 10 Sep 2013 Do you agree to give us your name and mailing address so we can send you the honorarium? ○ Yes ○ No [SKIP TO CLOSING 2] [END CLOSING 1] FIRST NAME: _______________________________________________ LAST NAME: _______________________________________________ ADDRESS: [MULTILINE INPUT] CITY: _____________________________________ STATE: [DROP-DOWN LIST INPUT WITH STATES TABLE] ZIP: ___________ [CLOSING 2] We would also like to ask for your telephone number. Providing your telephone number is optional and it will be used to contact you only if there are questions about your survey responses. Do you want to provide your telephone number? ○ ○ Yes No [SKIP TO CLOSING 3] Telephone: ________________________________ [END CLOSING 2] [CLOSING 3] That ends the survey. Thank you again for your help. [END CLOSING 3] [END OF SURVEY CONTENT] 31 of 34 FDA_1172 TIRF REMS Industry Group (TRIG) Transmucosal Immediate Release Fentanyl (TIRF) Products Pharmacist KAB Survey Protocol Appendix B Version 5.0 10 Sep 2013 Pharmacist Invitation Letter [CURR_DATE] [PHARMACY_NAME] [PHARMACY _STREET_ADDR] [PHARMACY_CITY], [PHARMACY _STATE] [PHARMACY _ZIP] [PHARMACY_FAX_NUMBER] Dear [PHARMACIST_IN CHARGE] Your Pharmacy was selected to receive this letter, because of enrollment in the TIRF REMS Access Program. We are contacting you to inform you about a survey being conducted by the manufacturers of Transmucosal Immediate Release Fentanyl (TIRF) medicines, as required by the Food and Drug Administration (FDA). The purpose of the survey is to assess pharmacists’ understanding of the safe and appropriate use of these medicines. The TIRF medicines include Abstral®, Actiq®, Fentora®, Lazanda®, Onsolis®, Subsys®, and generic versions of any of these brands. The manufacturers of TIRF medicines include Archimedes Pharma US Inc.; Cephalon, Inc. (a wholly-owned subsidiary of Teva Pharmaceutical Industries, Ltd.); Endo Pharmaceuticals Inc.; Galena Biopharma; Insys Therapeutics; Meda Pharmaceuticals; Mallinckrodt; Mylan, Inc.; and Par Pharmaceutical, Inc. (collectively referred to as the “TIRF REMS Industry Group”). These manufacturers are looking for 300 pharmacists to complete the survey. Eligible pharmacists who complete the survey will be sent a $50 honorarium to thank them for their time. The survey will take 15-20 minutes. Your answers will be kept strictly confidential and will be combined with the answers from other pharmacists who take this survey. Your name will not be used in the report of this survey and your contact information, if provided, will only be used to send you a $50 honorarium for your time to complete the survey. You are under no obligation to participate in this survey. Only one pharmacist from each enrolled pharmacy can participate. If you are interested in participating and to find out if you are eligible:   Go to www.TIRFREMSsurvey.com any time or Call 1-877-379-3297, 8 a.m. to 8 p.m. Eastern Time, Monday through Friday Please have this letter with you at the time you take the survey. You will be asked to provide this code prior to starting the survey: [CODE_ID]. *We recommend that you take the survey on a desktop or laptop computer. Taking the survey on mobile devices, such as smart phones, tablets, and e-notebooks, is not supported. Neither taking the survey nor your answers to the questions will affect your ability to dispense any of the TIRF medicines identified above. 32 of 34 FDA_1173 TIRF REMS Industry Group (TRIG) Transmucosal Immediate Release Fentanyl (TIRF) Products Pharmacist KAB Survey Protocol Version 5.0 10 Sep 2013 Sincerely, The TIRF REMS Survey Team 1-877-379-3297 www.TIRFREMSsurvey.com 33 of 34 FDA_1174 TIRF REMS Industry Group (TRIG) Transmucosal Immediate Release Fentanyl (TIRF) Products Pharmacist KAB Survey Protocol Appendix C Version 5.0 10 Sep 2013 Qualitative Research Report 34 of 34 FDA_1175 Pharmacy KAB Assessment Report Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Appendix B Page 45 of 47 Pharmacy Survey Listings and Sub-analysis Tables FDA_1176 Listing 1 REPORTED ADVERSE EVENTS, PRODUCT COMPLAINTS, or Requests for Medical Information Verbatim Response r) CAN YOU SEND A COPY OF THE FULL PRESCRIBING IS IT DIFFERENT THAN THE PACKAGE IF NOT. THEN NEED IT. I CAN LOOK AT THE PACKAGE INSERT dose conversions form other narcotics DOSIN RELATED equivalent does.evaluation of pt 011 vely high and multiple pain rx's by 111d I have no questions I just need to go back and read the section about what other opioid doses need to be met before starting this med. I questioned the requirements for opioid use and dose suggestions. They have since been clari?ed. I would like to have a visit ?om a rep. If insurance has lapsed. is there a problem with selling a product out-of-pocket? Making sure the proper dose is used and titrated for the patient based on history n/a na Need alot more speci?c prescribing info 011 these meds need complete guidelines about the products falls under TIRF NONE what is considered opioid tolerant patient? Why do you educate that these medications are only for cancer pain yet they are allowed to be prescribed for non-cancer pain Client: TRIG Project: TIRF Wave 2 Report Run Date and Time: 11/11/2013 2:33:00 PM Page 1 of 1 77 LISTING 2. VERBATIM RESPONSES TO QUESTION 22 (QUESTIONS ABOUT THE INFORMATION IN THE FULL PRESCRIBING INFORMATION OR MEDICATION GUIDE) Verbatim Response r) CAN YOU SEND A COPY OF THE FULL PRESCRIBING IS IT DIFFERENT THAN THE PACKAGE IF NOT. THEN NEED IT. I CAN LOOK AT THE PACKAGE INSERT dose conversions form other narcotics DOSING RELATED equivalent does.evaluation of pt 011 veiy high and multiple pain rx?s by 111d I have no questions I just need to go back and read the section about what other opioid doses need to be met before starting this med. I questioned the requirements for opioid use and dose suggestions. They have since been clari?ed. I would like to have a visit ?om a rep. If insurance has lapsed. is there a problem with selling a product out-of-pocket? Making sure the proper dose is used and titrated for the patient based on history n/a na Need alot more specific prescribing info 011 these meds need complete guidelines about the products falls under TIRF NONE what is considered opioid tolerant patient? Why do you educate that these medications are only for cancer pain yet they are allowed to be prescribed for non-cancer pain Client: TRIG Project: TIRF Wave 2 Report Run Date and Time: 11/11/2013 11:41:00 AM Page 1 of 1 78 TABLE 1.1 SURVEY ADNIINISTRATION STATISTICS Question The number of invitations issued to . 7 167 The number of reminder letters issued . 13 ,2 1 5 to pharmac1sts The munber of respondents screened 372?] for participation The nrunber of respondents eligible for 300 participation The number of respondents eligible for participation who answered all 300 80.6 questions presented to them By Telephone 9 2.4 By Internet 291 78.2 This is the denominator for the percentages in this table 72). Client: TRIG Project: TIRF Wave 2 Report Run Date and Time: 11/14/2013 10:17:00 AM Page 1 of 1 79 TABLE 1.2 TIME TO COMPLETE SURVEY (COMPLETERS ONLY) Time to Complete Survey Summary Statistic Telephone Internet Total 9 291 300 Mean (SD) 18.0 (1.81) 14.3 (8.75) 14.4 (8.64) Minimmn 1 5 4 4 Median 18.0 11.6 11.8 Maximum 20 85 85 Category Telephone Internet Total 0 to <5 Minutes 0 1 1 5 to <10 Minutes 0 90 90 10 to <15 Minutes 0 106 106 15 to <20 Minutes 8 47 55 20 to <25 Minutes 1 21 22 25 to <30 Minutes 0 12 12 30 Minutes 01' More 0 14 14 Client: TRIG Project: Report Run Date and Time: 11/11/2013 10:24:00 AM Page 1 of 1 80 TABLE 1.3 SURVEY PARTICIPANT SCREENING RESULTS All Respondents and Complete . Respondents Question Question 1: Do you agree to participate in this survey? Yes 371 99.7 300 100.0 Noll] 1 0.3 0 0.0 Question 2: Have you ever taken part in this survey about TIRF medicines before? TIRF medicines include Abstral?, Actiq?, Fentora?, Lazanda?, Onsolis?, Subsys?, and generic versions of any of these brands. Yes ?1 8 2.2 No 339 91.1 300 100.0 I don't know 24 6.5 Question not asked 1 0.3 Question 3: Do you work in a pharmacy that is enrolled in the TIRF REMS Access program? Yes 304 81.7 300 100.0 Noll] 8 2.2 I don't knowm 27 7.3 Question not asked 33 8.9 Question 4: Have you or any of your immediate family members ever worked for any of the following companies or agencies? Please select all that apply. Anesta 0 0.0 Archimedes Phanna US Incl? 0 0.0 ephalon. Inc. (a wholly-owned subsidiary of Teva Phannaceutical Industn'es. Client: TRIG Project: TIRF Wave 2 Report Run Date and Time: 11/11/2013 12:40:00 PM Page 1 of 2 1 81 All Rggogdents Question Endo Phaimaceuticals Inc. 0.3 Galena Biopharinall] 0 0.0 Insys Therapeuticsm 0 0.0 Mallinckrodtm 0 0.0 Care 0 0.0 Meda Phamiaceuticalsm 0 0.0 Mylan. 111cm 0 0.0 Par Pharmaceutical. Inc.? 0 0.0 ProStrakan. Inc.[? 0 0.0 RelayHealthm 0 0.0 Teva Phannaceuticals. 0 0.0 United BioSource Corporationm 0 0.0 1 0.3 None of these 300 80.6 300 100.0 I don?t knowm 0 0.0 Prefer not to answerm 2 0.5 Question not asked 68 18.3 Ineligible to participate in the sun'eyQuestion not asked due to a preVious question elimination. More than one response can be selected. so percentages may not sum to 100%. Ineligible if selected in addition to another item. Client: TRIG Project: TIRF Wave 2 Report Run Date and Time: 11/11/2013 12:40:00 PM Page 2 of 2 1 82 TABLE 2 DESCRIPTION OF ELIGIBLE AND COMPLETE RESPONDENTS Pharmacists Question Question 24: Are you the Pharmacist in Charge for the TIRF REMS Access Program where you work? Yes 242 80.7 No 52 1 7.3 I don't know 6 2.0 Question 25: On average, how many times per month have you dispensed TIRF medicine within the last 6 months? None 145 48.3 1 2 times per month 90 30.0 3 5 times per month 32 10.7 More than 5 times per month 15 5.0 I don?t remember 18 6.0 Question 26: Please select the TIRF medicine(s) that you have dispensed within the last 6 months (select all that apply): Abstra1? 8 5.2 Actiq? or generic Actiq? 120 77.4 Fentora? 57 36.8 Lazanda? 6 3.9 Onsolis? 1 0.6 Subsys? 17 1 1.0 (answered None to Question 25) 145 Question 27: What is your gender? Male 183 61.0 Female 111 37.0 Prefer not to answer 6 2.0 Client: TRIG Project: TIRF WaveZ Report Run Date and Time: 11/7/2013 5:00:00 PM Page 1 of 2 1 83 Pharmacists Question Question 28: In total, how many years have you been a practicing pharmacist? Less than 3 years 23 7.7 3 - 5 years 41 13.7 6- 10 years 40 13.3 11 - 15 years 34 11.3 More than 15 years 157 52.3 Prefer not to answer 5 1.7 Client: TRIG Project: TIRF Wave 2 Report Run Date and Time: 11/7/2013 5:00:00 PM Page 2 of 2 1 84 TABLE 2.1 GEOGRAPHIC DISTRIBUTION (BASED ON QUESTION 29 IN WHICH STATE OR US TERRITORY DO YOU PRACTICE) . . Enrolled in TIRF REMS Eligible and Complete Access Pro am on Geographic Region Respondents gr 100ct2013 Northeast 78 26.0 7834 20.3 Midwest 72 24.0 8027 20.8 South 97 32.3 15027 38.9 West 52 17.3 7549 19.6 Other 0 0.0 160 0.4 Prefer not to answer 1 0.3 0 0.0 Census Bureau. last revised Friday. 27-Jul-2001 12:59:43 EDT.. Geography Division. Northeast includes CT. MA. ME. NH. NJ. NY. PA. RI. and VT. Midwest includes IA. IL. IN. KS. MI. MN. MO. ND. NE. OH. SD. and WI. South includes AL. AR. DC. DE. FL. GA. KY. LA. MD. MS. NC. OK. SC. TN. VA. and WV. West includes AK. AZ. CA. CO HI. ID. MT. NM. NV. OR. UT. WA. and WY. The following US territories are categorized as Other: Puerto Rico. Northern Mariana Islands. US Virgin Islands. American Samoa. and Guam. Client: TRIG Project: TIRF Wave 2 Report Run Date and Time: 11/11/2013 11:35:00 AM Page 1 of 1 85 TABLE 3 MEDICINES RESPONSES TO ALL QUESTIONS ABOUT THE SAFE USE OF TIRF Question Pharmacists Question 5: Please select True, False, or I don?t know for each of the following. According to the labeling for TIRF medicines, patients with cancer who are considered opioid- tolerant are those: 5a: Who are taking around?the?clock opioid therapy for underlying persistent cancer pain for one week or longer True ?1 271 90.3 False 23 7.7 I don't know 6 2.0 5b: Who are not currently taking opioid therapy, but have taken opioid therapy before False ?1 242 80.7 True 41 13.7 I don't know 17 5.7 5c: Who have no known contraindications to the drug fentanyl, but are not currently taking around-the-clock opioid therapy False ?1 228 76.0 True 52 17.3 I don't know 20 6.7 Question 6: Please answer True, False, or I don?t know for each statement based on the labeling for TIRF medicines. 6a: A cancer patient can be started on a TIRF medicine and an around-the-clock opioid at the same time. False ?1 196 65.3 True 80 26.7 I don't know 24 8.0 Client: TRIG Project: TIRF Wave 2 Report Run Date and Time: 11/7/2013 5:27:00 PM Page 1 of 7 1 86 Question Pharmacists 6b: A cancer patient who has been on an around-the-clock opioid for 1 day can start taking a TIRF medicine for breakthrough pain. False ?1 224 74.7 Tme 50 16.7 I don't know 26 8.7 Question 7: Please answer True, False, or I don?t know for each statement based on the labeling for TIRF medicines. 7a: TIRF medicines are contraindicated in opioid non-tolerant patients because life-threatening respiratory depression could occur at any dose. True ?1 258 86.0 False 27 9.0 I don't know 15 5.0 7b: Death has occurred in opioid non-tolerant patients treated with some fentanyl products. True ?1 281 93.7 False 2 0.7 I don't know 17 5.7 7c: TIRF medicines may be used in opioid non-tolerant patients. False ?1 246 82.0 True 40 13.3 I don't know 14 4.7 7d: Prescribers starting a patient on a TIRF medicine must begin with titration from the lowest dose available for that specific product, even if the patient has previously taken another TIRF medicine. True ?1 248 82.7 False 38 12.7 I don't know 14 4.7 Client: TRIG Project: TIRF Wave 2 Report Run Date and Time: 11/7/2013 5:27:00 PM Page 2 of 7 1 87 Pharmacists Question 7e: It is important to monitor for signs of abuse and addiction in patients who take TIRF medicines. True ?1 290 96.7 False 5 1.7 I don't know 5 1.7 Question 8: Which of the following are risk factors for opioid abuse? Please answer Yes, No, or I don?t know for each option. 8a: A personal history of illness Yes ?1 216 72.0 No 48 16.0 I don't know 36 12.0 8b: A personal history of past or current alcohol or drug abuse, or a family history of illicit drug use or alcohol abuse Yes ?1 297 99.0 No 0 0.0 I don't know 3 1.0 8c: A family history of asthma No ?1 245 81.7 Yes 38 12.7 I don't know 17 5.7 Question 9: Per the approved labeling for TIRF medicines, for which of the following indications can TIRF medicines be prescribed to opioid tolerant patients? Please answer Yes, No, or I don?t know for each option. 9a: Acute or postoperative pain No 254 84.7 Yes 31 10.3 I don't know 15 5.0 Client: TRIG Project: TIRF Wave 2 Report Run Date and Time: 11/7/2013 5:27:00 PM Page 3 of 7 1 88 Pharmacists Question 9b: Headache or migraine pain No ?1 277 92.3 Yes 8 2.7 I don't know 15 5.0 9c: Dental pain No ?1 290 96.7 Yes 3 1.0 I don't know 7 2.3 9d: Breakthrough pain from cancer Yes ?1 268 89.3 No 27 9.0 I don't know 5 1.7 9e: Chronic non-cancer pain No ?1 141 47.0 Yes 126 42.0 I don't know 33 11.0 Question 10: Please answer True, False, or I don?t know for each statement based on the labeling for TIRF medicines. 10a: TIRF medicines can be abused in a manner similar to other opioid agonists. True ?1 282 94.0 False 10 3.3 I don't know 8 2.7 10b: TIRF medicines are interchangeable with each other regardless of route of administration. False ?1 284 94.7 Tme 6 2.0 I don't know 10 3.3 Client: TRIG Project: TIRF Wave 2 Report Run Date and Time: 11/7/2013 5:27:00 PM Page 4 of 7 1 89 Question Pharmacists 10c: The conversion of one TIRF medicine for another TIRF medicine may result in a fatal overdose because of differences in the pharmacokinetics of fentanyl absorption. True ?1 276 92.0 False 5 1.7 I don't know 19 6.3 10d: Dosing of TIRF medicines is not equivalent on a microgram?to?microgram basis. True ?1 274 91.3 False 10 3 .3 I don't know 16 5.3 Question 11: Please select True, False, or I don?t know for each of the following. According to the labeling for TIRF medicines, patients considered opioid-tolerant are those who are taking, for one week or longer, at least: 11a: 8 mg oral hydromorphone/day True ?1 237 79.0 False 29 9.7 I don't know 34 11.3 11b: 60 mg oral morphine/day True ?1 255 85.0 False 14 4.7 I don't know 31 10.3 11c: 30 mg oral oxycodone/day True ?1 214 71.3 False 44 14.7 I don't know 42 14.0 11d: 25 transdermal fentanyl/hour True ?1 216 72.0 False 45 15.0 I don't know 39 13.0 Client: TRIG Project: TIRF Wave 2 Report Run Date and Time: 11/7/2013 5:27:00 PM Page 5 of 7 1 90 Pharmacists Question lle: 25 mg oral oxymorphone/day True ?1 213 71.0 False 29 9.7 I don't know 58 19.3 11f: An equianalgesic dose of another oral opioid True ?1 177 59.0 False 61 20.3 I don't know 62 20.7 Question 13: Please answer True, False, or I don?t know for each statement about TIRF medicines. 13a: TIRF medicines maybe sold, loaned, or transferred to another pharmacy. False ?1 274 91.3 True 8 2.7 I don't know 18 6.0 13b: All pharmacy staff that dispenses TIRF medicines must be educated on the requirements of the TIRF REMS Access program. True ?1 282 94.0 False 6 2.0 I don't know 12 4.0 13c: TIRF medicines with the same route of administration can be substituted with each other if the pharmacy is out of stock for one product. False ?1 289 96.3 True 6 2.0 I don't know 5 1.7 Client: TRIG Project: TIRF Wave 2 Report Run Date and Time: 11/7/2013 5:27:00 PM Page 6 of 7 191 Question Pharmacists Question 17: Please answer True, False, or I don?t know for the following statement about TIRF medicines. (Inpatient pharmacists, only) It is OK to dispense TIRF medicines from the inpatient pharmacy inventory to an outpatient for use at home. False ?1 13 86.7 True 0 0.0 I don't know 2 13.3 Correct response Client: TRIG Project: TIRF Wave 2 Report Run Date and Time: 11/7/2013 5:27:00 PM Page 7 of 7 1 92 TABLE 4 MATERIALS RESPONSES TO QUESTIONS ABOUT THE EDUCATIONAL Question Pharmacists Question 18: Did you receive or do you have access to the Full Prescribing Information for the TIRF medicine(s) that you dispensedon't know 8 2.7 Question 19: Did you read the Full Prescribing Information for the TIRF medicine(s) that you dispense?? Yes 223 76don't know 7 2.4 (answered No or I don ?t know to Question 18) 9 Question 20: Did you receive or do you have access to the Medication Guide for the TIRF medicine(s) that you dispense? Yes 297 99.0 No 1 0.3 I don't know 2 0.7 Question 21: Did you read the Medication Guide for the TIRF medicine that you dispense? [ll Yes 250 84.2 No 39 3. 1 I don't know 8 2.7 (answered No or I don ?t know to Question 20) 3 Question 22: Did you or do you have any questions about the information in the Full Prescribing Information or Medication Guide? Yesp] 21 7.0 No 259 86.3 I don't know 20 6.7 [11 Percentages are calculated based on the sample presented with this question because of skip logic in the sun'ey. Verbatim texts for questions about the information in the Full Prescribing Information are presented in Listing 2. Client: TRIG Project: TIRF Wave 2 Report Run Date and Time: 11/8/2013 8:32:00 AM Page 1 of 1 93 TABLE 5 DISPENSING TIRF MEDICINES RESPONSES TO QUESTIONS ABOUT ACTIVITIES WHEN Question Pharmacists Never, or I don?t know. Question 12: How frequently do you perform the following activities when dispensing TIRF medicines? Please answer Always, Only with the first prescription, Sometimes, 12a: Ask patients (or their caregivers) about the presence of children in the home Always 167 55.7 Only with the fu?stpresc1iption 54 18.0 Sometimes 54 18.0 Never 13 4.3 I don't know 12 4.0 12b: Instruct patients (or their caregivers) not to share TIRF medicines with anyone else Always 208 69.3 Only with the ?rst prescription 52 17.3 Sometimes 26 8.7 Never 8 2.7 I don't know 6 2.0 may be fatal 12c: Counsel patients (or their caregivers) that accidental exposure to TIRF medicines by a child Always 198 66.0 Only with the ?rst prescription 57 19.0 Sometimes 29 9.7 Never 8 2.7 I don't know 8 2.7 Client: TRIG Project: TIRF Wave 2 Report Run Date and Time: 11/8/2013 8:39:00 AM Page 1 of 3 1 94 Question Pharmacists 12d: Instruct patients (or their caregivers) to keep TIRF medicines out of the reach of children to prevent accidental exposure Always 223 74.3 Only with the ?rst prescription 44 14.7 Sometimes 23 7.7 Never 5 1.7 I don't know 5 1.7 12e: Instruct patients (or their caregivers) about proper disposal of any unused or partially used TIRF medicines Always 198 66.0 Only with the ?rst prescription 67 22.3 Sometimes 26 8.7 Never 4 1.3 I don't know 5 1.7 12f: Give patients (or their caregivers) the Medication Guide for their TIRF medicine Always 274 91.3 Only with the ?rst prescription 11 3.7 Sometimes 10 3.3 Never 0 0.0 I don't know 5 1.7 Question 14: Does the inpatient pharmacy where you work have an established system, order sets, protocols and/or other measures to help ensure appropriate patient selection and compliance with the requirements of the TIRF REMS Access Program? [Inpatient pharmacists, only26.7 I don't know 3 20.0 Client: TRIG Project: TIRF Wave 2 Report Run Date and Time: 11/8/2013 8:39:00 AM Page 2 of 3 1 95 Question Pharmacists Question 15: Does the outpatient or retail pharmacy where you work process all TIRF medicine prescriptions, regardless of method of payment, through the pharmacy management system? [Outpatient pharmacists, onlydon't know 45 16'0 Question 16: Does the pharmacy where you work process all TIRF medicine prescriptions, regardless of method of payment, through the TIRF REMS Access Call Center? Outpatient pharmacists, only] Yes 2 50.0 No 0 0.0 I don't know 2 50.0 This question is presented only to a sub-group of pharmacists. Percentages are based on the number of pharmacists to whom this question was presented. Client: TRIG Project: TIRF Wave 2 Report Run Date and Time: 11/8/2013 8:39:00 AM Page 3 of 3 1 96 TABLE 6.1 PRIMARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #1 KEY RISK MESSAGE 1: TIRF MEDICINES ARE CONTRAINDICATED IN OPIOID NON-TOLERANT PATIENTS. Question Eligible and Complete Respondents (95% CI) [21 Question 5: Please select True, False, or I don?t know for each of the following. According to the labeling for TIRF medicines, patients with cancer who are considered opioid-tolerant are those: 5a: Who are taking around-the-clock opioid therapy for underlying persistent cancer pain for one week or longer 90.3 True 271 (86.4. 93.4) False 23 7.7 I don't know 6 2.0 5b: Who are not currently taking opioid therapy, but have taken opioid therapy before 80.7 False 242 (75.7. 85.0) True 41 13.7 I don't know 17 5.7 5c: Who have no known contraindications to the drug fentanyl, but are not currently taking around-the-clock opioid therapy 76.0 False 228 (70-21 80.7) True 52 17.3 I don't know 20 6.7 Client: TRIG Project: TIRF Wave 2 Report Run Date and Time: 11/6/2013 12:47:00 PM Page 1 of 1 97 Question Eligible and Complete Respondents (95% CI) [21 Question 7: Please answer True, False, or I don?t know for each statement based on the labeling for TIRF medicines. 7a: TIRF medicines are contraindicated in opioid non-tolerant patients because life-threatening respiratmy depression could occur at any dose. 86.0 True 258 (81.6. 89.7) False 27 9.0 I don't know 15 5.0 7b: Death has occurred in opioid non-tolerant patients treated with some fentanyl products. Tm 281 (90.23.9761) False 2 0.7 I don't know 17 5.7 7c: TIRF medicines may be used in opioid non?tolerant patients. False 246 (77.3%362) True 40 13.3 I don't know 14 4.7 Client: TRIG Project: TIRF Wave 2 Report Run Date and Time: 11/6/2013 12:47:00 PM Page 2 of 3 1 98 Question Eligible and Complete Respondents (95% CI) [21 7d: Prescribers starting a patient on a TIRF medicine must begin with titration from the lowest dose available for that speci?c product, even if the patient has previously taken another TIRF medicine. 82.7 True 248 (77.9. 86.8) False 38 12.7 I don't know 14 4.7 Correct response All con?dence intervals are exact binomial 95% con?dence intervals. Client: TRIG Project: TIRF Wave 2 Report Run Date and Time: 11/6/2013 12:47:00 PM Page 3 of 3 1 99 TABLE 6.1.1 PRIMARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #1 KEY RISK MESSAGE l: TIRF MEDICINES ARE CONTRAINDICATED IN OPIOID NON-TOLERANT PATIENTS. SUB-GROUP ANALYSIS 1: READING MEDICATION GUIDE OR FULL PRESCRIBING INFORMATION (QUESTIONS 18, 19, 20 AND 21): S-la-Respondents who read the Full Prescribing Information (Question 19) and Medication Guide for the TIRF medicine that they dispense (Question 21). S-lb-Respondents who responded ?No? or don?t know? to getting and reading the Full Prescribing Information and to getting and reading the Medication Guide for the TIRF medicine that they dispense. S-la S-lb Read Medication Guide or Did Mt read Medication . . Gmde and Full Prescribing ti Full Info Info ues on 262 (95% CI) (95% CI) Question 5: Please select True, False, or I don?t know for each of the following. According to the labeling for medicines, patients with cancer who are considered opioid-tolerant are those: 5a: Who are taking around-the-clock opioid therapy for underlying persistent cancer pain for one week or longer True 241 (8825-850) 30 (62.77%.9904) False 16 6.1 7 18.4 I don't know 5 1.9 1 2.6 5b: Who are not currently taking opioid therapy, but have taken opioid therapy before False 211 (75:92:51) 31 (65871-9623) True 37 14.1 4 10.5 I don't know 14 5.3 3 7.9 Client: TRIG Project: TIRF Wave 2 Report Run Date and Time: 11/6/2013 11:52:00 AM Page 1 of 3 200 Question S-lb S-la . . . Read Medication Guide or Did Mt read Medication . . Guide and Full Full Info 62 Info (95% CI) (95% CI) 5c: Who have no known contraindications to the drug fentanyl, but are not currently taking around?the-clock opioid therapy 77.1 68.4 False 202 (71.5. 82.0) 26 (51.3. 82.5) True 44 16.8 8 21.1 I don't know 16 6.1 4 10.5 Question 7: Please answer True, False, or I don?t know for each statement based on the labeling for TIRF medicines. 7a: TIRF medicines are contraindicated in opioid non?tolerant patients because life? threatening respiratory depression could occur at any dose. 85.1 92.1 True 223 (80.2. 89.2) 35 (78.6. 98.3) False 25 9.5 2 5.3 I don't know 14 5.3 1 2.6 7b: Death has occurred in opioid non-tolerant patients treated with some fentanyl products. True 248 (91.95.9770) 33 False 1 0.4 1 2.6 I don't know 13 5.0 4 10.5 7c: TIRF medicines may be used in opioid non?tolerant patients. False 214 876.2) 32 (68.874.1'9240) True 36 13.7 4 10.5 I don't know 12 4.6 2 5.3 Client: TRIG Project: TIRF WaveZ Report Run Date and Time: 11/6/2013 11:52:00 AM Page 2 of 3 201 Question S-la Read Medication Guide or S-lb Did not read Medication Guide and Full Prescribing Full Prescribing Info 62 Info (95% CI) (95% CI) 7d: Prescribers starting a patient on a TIRF medicine must begin with titration from the lowest dose available for that speci?c product, even if the patient has previously taken another TIRF medicine. 83.6 76.3 Tm 219 (78.5. 87.9) 29 (59.8. 88.6) False 30 11.5 8 21.1 I don't know 13 5.0 1 2.6 Correct response Client: TRIG Project: TIRF Wave2 Report Run Date and Time: 11/6/2013 11:52:00 AM Page 3 of 3 202 TABLE 6.1.2 PRIMARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #1 KEY RISK MESSAGE l: TIRF MEDICINES ARE CONTRAINDICATED IN OPIOID NON-TOLERANT PATIENTS. SUB-GROUP ANALYSIS 2: TIME TO COMPLETE SURVEY INTERNET: S-2a - <10 min 0 S?min Question S?2a S?2b S?min (95% CI) (95% CI) (95% CI) Question 5: Please select True, False, or I don?t know for each of the following. According to the labeling for TIRF medicines, patients with cancer who are considered opioid-tolerant are those: one week or longer 5a: Who are taking around?the?clock opioid therapy for underlying persistent cancer pain for 93.4 89.5 89.4 True ?1 85 (86.2. 137 (83.6. 42 (76.9. 97.5) 93.9) 96.5) False 4 4.4 14 9.2 5 10.6 I don't know 2 2.2 2 1.3 0 0.0 5b: Who are not currently taking opioid therapy, but have taken opioid therapy before 75.8 83.0 85.1 False ?1 69 (65.7. 127 (76.1. 40 (71.7. 84.2) 88.6) 93.8) Tme 16 17.6 19 12.4 4 8.5 I don't know 6 6.6 7 4.6 3 6.4 5c: Who have no known contraindications to the drug fentanyl, but are not currently taking around-the-clock opioid therapy 69.2 80.4 76.6 False ?1 63 (58.7. 123 (73.2. 36 (62.0. 78.5) 86.4) 87.7) True 19 20.9 22 14.4 10 21.3 I don't know 9 9.9 8 5.2 1 2.1 Client: TRIG Project: TIRF WaveZ Report Run Date and Time: 11/6/2013 2:38:00 PM Page 1 2 203 Question S?2a s21) S-min (95% CI) (95% CI) (95% CI) Question 7: Please answer True, False, or I don?t know for each statement based on the labeling for TIRF medicines. 7a: TIRF medicines are contraindicated in opioid non?tolerant patients because life?threatening respiratory depression could occur at any dose. 82.4 86.3 91.5 True ?1 75 (73.0. 132 (79.8. 43 (79.6. 89.6) 91.3) 97.6) False 10 11.0 13 8.5 4 8.5 I don't know 6 6.6 8 5.2 0 0.0 7b: Death has occurred in opioid non-tolerant patients treated with some fentanyl products. 93.4 94.1 91.5 True ?1 85 (86.2. 144 (89.1. 43 (79.6. 97.5) 97.3) 97.6) False 1 1.1 0 0.0 2.1 I don't know 5 5.5 9 5.9 3 6.4 7c: TIRF medicines may be used in opioid non-tolerant patients. 78.0 81.7 91.5 False ?1 71 (68.1. 125 (74.6. 43 (79.6. 86.0) 87.5) 97.6) True 16 17.6 20 13.1 3 6.4 I don't know 4 4.4 8 5.2 2.1 7d: Prescribers starting a patient on a TIRF medicine must begin with titration from the lowest dose available for that speci?c product, even if the patient has previously taken another TIRF medicine. 82.4 81.7 87.2 True ?1 75 (73.0. 125 (74.6. 41 (74.3. 89.6) 87.5) 95.2) False 13 14.3 17 11.1 6 12.8 I don't know 3 3.3 11 7.2 0 0.0 Con?ect response Client: TRIG Project: TIRF Wave2 Report Run Date and Time: 11/6/2013 2:38:00 PM Page 2 of 2 204 TABLE 6.1.4 PRIMARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #1 KEY RISK MESSAGE l: TIRF MEDICINES ARE CONTRAINDICATED IN OPIOID NON-TOLERANT PATIENTS. SUB-GROUP ANALYSIS 4: MODALITY TO COMPLETE SURVEY: S-4a - Internet 0 S?4b - Telephone Question S?4a S?4b Internet Telephone N=29l (95% CI) (95% CI) Question 5: Please select True, False, or I don?t know for each of the following. According to the labeling for TIRF medicines, patients with cancer who are considered opioid-tolerant are those: 5a: Who are taking around-the-clock opioid therapy for underlying persistent cancer pain for one week or longer 90.7 77.8 True 264 (86.8. 93.8) 7 (40.0. 97.2) False 23 7.9 0 0.0 I don't know 4 1.4 2 22.2 5b: Who are not currently taking opioid therapy, but have taken opioid therapy before 81.1 66.7 False 236 (76.1. 85.4) 6 (29.9. 92.5) True 39 13.4 2 22.2 I don't know 16 5.5 1 11.1 5c: Who have no known contraindications to the drug fentanyl, but are not currently taking around?the-clock opioid therapy 111 76.3 66.7 False 222 (71.0. 81.1) 6 (29.9. 92.5) True 51 17.5 1 11.1 I don't know 18 6.2 2 22.2 Client: TRIG Project: TIRF Wave2 Report Run Date and Time: 11/6/2013 11:52:00 AM Page 1 of 2 205 Question S?4a S?4b Internet Telephone N=29l (95% CI) (95% CI) Question 7: Please answer True, False, or I don?t know for each statement based on the labeling for TIRF medicines. 7a: TIRF medicines are contraindicated in opioid non?tolerant patients because life?threatening respiratory depression could oc cur at any dose. 85.9 88.9 me 250 (81.4. 89.7) 8 (51.8. 99.7) False 27 9.3 0 0.0 I don't know 14 4.8 1 11.1 7b: Death has occurred in opioi non?tolerant atients treated with some fentanyl products. 93.5 100.0 True 272 (90.0. 96.0) 9 (66.4. 100.0) False 2 0.7 0 0.0 I don't know 17 5.8 0 0.0 7c: TIRF medicines may be used in opioid non?tolerant patients. 82.1 77.8 False 239 (77.2. 86.4) 7 (40.0. 97.2) True 39 13.4 1 11.1 I don't know 13 4.5 1 11.1 7d: Prescribers starting a patient on a TIRF medicine must begin with titration from the lowest dose available for that speci?c product, even if the patient has previously taken another TIRF medicine. 82.8 77.8 True 241 (78.0. 87.0) 7 (40.0. 97.2) False 36 12.4 2 22.2 I don't know 14 4.8 0 0.0 Correct response Client: TRIG Project: TIRF Wav Report Run Date and Time: 11/6/2 Page 2 of 2 2 013 206 TABLE 6.1.5 PRIMARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #1 KEY RISK MESSAGE l: TIRF MEDICINES ARE CONTRAINDICATED IN OPIOID NON-TOLERANT PATIENTS. SUB-GROUP ANALYSIS 5: TIME PRACTICING AS A PHARMACIST (QUESTION 28): - Less than 3 years 0 S-5b 3 to 5 years 0 S?5c 6 to 15 years 0 More than 15 years S?5a S-5b Less than 3 years 3 to 5 years 6 to 15 years More than 15 years Question N=4l CI) (95?02 CI) CI) (95;:o CI) Question 5: Please select True, False, or I don?t know for each of the following. According to the labeling for TIRF medicines, patients with cancer who are considered opioid-tolerant are those: 5a: Who are taking around-the-clock opioid therapy for underlying persistent cancer pain for one week or longer True 23 38 (80.95.9785) 65 (738279843) 142 (849799146) False don't know 0.6 5b: Who are not currently taking opioid therapy, but have taken opioid therapy before False 20 (66317372) 36 (73.27.9859) 56 (64.732349) 127 (73.299367) True 2 8.7 4 9.8 11 14.9 23 14.6 I don't know 4.5 Client: TRIG Project: TIRF Wave2 Report Run Date and Time: 11/6/2013 11:53:00 AM Page 1 207 S?5a S?5d Less than 3 years 3 to 5 years 6 to 15 years More than 15 years (95% CI) (95% CI) (95% CI) (95% CI) 5c: Who have no known contraindications to the drug fentanyl, but are not currently taking around?the?clock opioid therapy 91.3 92.7 70.3 72.0 False 21 (72.0. 98.9) 38 (80.1. 98.5) 52 (58.5. 80.3) ?3 (64.3. 78.8) True 2 8.7 3 7.3 12 16.2 35 22.3 I don't know 0 0.0 0.0 10 13.5 9 5.7 Question 7: Please answer True, False, or I don?t know for each statement based on the labeling for TIRF medicines. 7a: TIRF medicines are contraindicated in opioid non-tolerant patients because life-threatening respiratory depression could occur at any dose. True 23 39 (839559194) 63 (75%?9123) 129 (752878) False 12.1 I don't know 0 0.0 0.0 5 6.8 9 5.7 7b: Death has occurred in opioid non-tolerant patients treated with some fentanyl products. True 21 (72259989) 39 (839559194) 71 (88.35.9992) 147 (88.95.9669) False don't know 5.7 Client: TRIG Project: TIRF Wave 2 Report Run Date and Time: 11/6/2013 11:53:00 AM Page 2 of 3 208 S?5a Less than 3 years 3 to 5 years 6 to 15 years More than 15 years (95% CI) (95% CI) (95% CI) (95% CI) 7c: TIRF medicines may be used in opioid non?tolerant patients. 100.0 97.6 83.8 75.2 False 23 (85.2.1000) 40 (87.1. 99.9) 62 (73.4. 91.3) ?8 (67.6. 81.7) True 21.7 I don't know 3.2 7d: Prescribers starting a patient on a TIRF medicine must begin with titration from the lowest dose available for that speci?c product, even if the patient has previously taken another TIRF medicine. 87.0 78.0 79.7 84.7 True 20 (66.4. 97.2) 32 (62.4. 89.4) 59 (68.8. 88.2) 133 (78.1. 90.0) False 1 4.3 7 17.1 10 13.5 20 12.7 I don't know 2.5 Correct response Client: TRIG Project: TIRF Wave2 Report Run Date and Time: 11/6/2013 11:53:00 AM Page 3 of 3 209 TABLE 6.1.6 PRIMARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #1 KEY RISK MESSAGE l: TIRF MEDICINES ARE CONTRAINDICATED IN OPIOID NON-TOLERANT PATIENTS. SUB-GROUP ANALYSIS 6: NUMBER OF TIMES PER MONTH DISPENSED TIRF MEDICINES WITHIN THE LAST 6 MONTHS (QUESTION 25): S-6a - None S?6b 2 times per month S-6c - 3 - 5 times per month S-6d - More than 5 times per month Question S-6a S-6b S-6c S?6d None 1 2 3 - 5 More than 5 (95% CI) (95% CI) (95% Cl) (95% CI) Question 5: Please select True, False, or I don?t know for each of the following. According to the labeling for TIRF medicines, patients with cancer who are considered opioid-tolerant are those: 5a: Who are taking around?the?clock opioid therapy for underlying persistent cancer pain for one week or longer 100.0 90.3 91.1 81.3 True 131 (84.3. 94.6) 82 (83.2. 96.1) 26 (63.6. 92.8) 15 (782? 100.0) False 11 7.6 7 7.8 5 15.6 0.0 I don?t know 3 2.1 1 1.1 1 3.1 0.0 Client: TRIG Project: TIRF Wave2 Report Run Date and Time: 11/6/2013 11:52:00 AM Page 1 of 3 S?6a S?6b S?6c S?6d None 1 2 3 5 More than 5 Question N=l45 (953CI) 5b: Who are not currently taking opioid therapy, but have taken opioid therapy before False 121 70 (67:35.9) 28 (71:36.5) 9 (32.?337) True 17 11.7 15 16.7 3 9.4 4 26.7 I don't know 7 4.8 5 5.6 3.1 2 13.3 5c: Who have no known contraindications to the drug fentanyl, but are not currently taking around-the-clock opioid therapy False 1 16 (72.29362) 64 (60.76% $310.2) 25 (60.39107) 9 (3229;37) True 21 14.5 19 21.1 5 15.6 4 26.7 I don't know 13.3 Question 7: Please answer True, False, or I don?t know for each statement based on the labeling for TIRF medicines. 7a: TIRF medicines are contraindicated in opioid non-tolerant patients because life?threatening respiratory depression could occur at any dose. True 129 (82.?336) 76 1.2) 27 (6731347) 10 (38.?2382) False 10 6.9 11 12.2 3 9.4 3 20.0 I don't know 13.3 Client: TRIG Project: TIRF Wave2 Report Run Date and Time: 11/6/2013 11:52:00 AM Page 2 of 3 1 S?6a S?6b S?6c S?6d None 1 2 3 5 More than 5 (95% CI) (95% CI) (95% CI) (95% CI) 7b: Death has occurred in opioid non-tolerant patients treated with some fentanyl products. 93.1 96.7 90.6 93.3 True 135 (87.7. 96.6) 87 (90.6. 99.3) 29 (75.0. 98.0) 14 (68.1. 99.8) False don't know 6.7 7c: TIRF medicines may be used in opioid non-tolerant patients. 89.7 78.9 71.9 53.3 False 130 (83.5. 94.1) 71 (69.0. 86.8) 23 (53.3. 86.3) 8 (26.6. 78.7) True 10 6.9 18 20.0 7 21.9 4 26.7 I don't know 20.0 7d: Prescribers starting a patient on a TIRF medicine must begin with titration from the lowest dose available for that speci?c product, even if the patient has previously taken another TIRF medicine. 83.4 86.7 81.3 66.7 True 121 (76.4. 89.1) 78 (77.9. 92.9) 26 (63.6. 92.8) 10 (38.4. 88.2) False 19 13.1 9 10.0 3 9.4 4 26.7 I don't know 6.7 Correct response Client: TRIG Project: TIRF Wave2 Report Run Date and Time: 11/6/2013 11:52:00 AM Page 3 of 3 TABLE 6.2 SECONDARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #1 KEY RISK MESSAGEI: TIRF MEDICINES ARE CONTRAINDICATED IN OPIOID NON-TOLERANT PATIENTS. Eligible and Complete Respondents Demonstrated Understanding 0 correct responses 2 0.7 1 correct response 2 0.7 2 correct responses 6 2.0 3 correct responses 7 2.3 4 correct responses 22 7.3 5 correct responses 45 15.0 6 correct responses 86 28.7 7 correct responses 130 43.3 Average number of correct responses 5.9 (5.7. 7.0) [ll One-sided 95 con?dence interval using the approximation to the Poisson distribution Client: TRIG Project: Report Run Date and Time: 10/30/2013 1:46:00 PM Page 1 of TABLE 6.2.1 SECONDARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #1 KEY RISK TIRF MEDICINES ARE CONTRAINDICATED IN OPIOID NON-TOLERANT PATIENTS. SUB-GROUP ANALYSIS 1: READING MEDICATION GUIDE OR FULL PRESCRIBING INFORMATION (QUESTIONS 18, 19, 20 AND 21): S-la-Respondents who read the Full Prescribing Information (Question 19) and Medication Guide for the TIRF medicine that they dispense (Question 21). S-lb-Respondents who responded ?No? or don?t know? to getting and reading the Full Prescribing Information and to getting and reading the Medication Guide for the TIRF medicine that they dispense. S-lb S-la Did not read Medication Read Medication Guide or Guide and Full Info 0 correct responses 2 0.8 0 0.0 1 correct response 2 0.8 0 0.0 2 correct responses 5 1.9 1 2.6 3 correct responses 5 1.9 2 5.3 4 correct responses 17 6.5 5 13.2 5 correct responses 38 14.5 7 18.4 6 correct responses 78 29.8 8 21.1 7 correct responses 115 43.9 15 39.5 Average number of correct responses 5.9 (5.7. 7.0) 5.7 (5.0. 7.0) [ll One-sided 95 con?dence interval using the normal approximation to the Poisson distribution Client: TRIG Project: TIRF Wave2 Report Run Date and Time: 10/31/2013 11:26:00 AM Page 1 of TABLE 6.2.2 SECONDARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #1 KEY RISK MESSAGEI: TIRF MEDICINES ARE CONTRAINDICATED IN OPIOID NON-TOLERANT PATIENTS. SUB-GROUP ANALYSIS 2: TIME TO COMPLETE SURVEY INTERNET: S-2a - <10 min 0 S-2b 10 to <20 min S-2c 2 20 min S-2a S-2b S-2c Demonstrated Understanding 10 t;:12;13min >=N2?4rpin 0 correct responses correct response correct responses correct responses correct responses correct responses 17 18.7 21 13.7 6 12.8 6 correct responses 19 20.9 45 29.4 19 40.4 7 correct responses 40 44.0 68 44.4 19 40.4 Average number of correct responses 5.7 (5.3. 7.0) 6.0 (5.6. 7.0) 6.1 (5.5. 7.0) One-sided 95 con?dence inten?al using the normal approximation to the Poisson distribution Client: TRIG Project: TIRF Wave 2 Report Run Date and Time: 10/31/2013 11:26:00 AM Page 1 of 21 5 TABLE 6.2.4 SECONDARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #1 KEY RISK MESSAGEI: TIRF MEDICINES ARE CONTRAINDICATED IN OPIOID NON-TOLERANT PATIENTS. SUB-GROUP ANALYSIS 4: MODALITY TO COMPLETE SURVEY: 0 8-43 - Internet 0 S?4b - Telephone S-4a 54" Internet Telephone Demonstrated Understanding 0 correct responses 2 0.7 0 0.0 1 correct response 2 0.7 0 0.0 2 correct responses 5 1.7 1 11.1 3 correct responses 7 2.4 0 0.0 4 correct responses 21 7.2 1 11.1 5 correct responses 44 15.1 1 11.1 6 correct responses 83 28.5 3 33.3 7 correct responses 127 43.6 3 33.3 Average number of correct responses 5.9 (5.7. 7.0) 5.6 (4.3. 7.0) ll] One-sided 95 con?dence interval using the normal approximation to the Poisson distribution Client: TRIG Project: Report Run Date and Time: 10/30/2013 4:32:00 PM Page 1 of TABLE 6.2.5 SECONDARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #1 KEY RISK MESSAGEI: TIRF MEDICINES ARE CONTRAINDICATED IN OPIOID NON-TOLERANT PATIENTS. SUB-GROUP ANALYSIS 5: TIME PRACTICING AS A PHARMACIST (QUESTION 28): - Less than 3 years 0 3 to 5 years 0 6 to 15 years 0 More than 15 years S-5a S-5b S-5c Demonstrated Less than 3 years 3 to 5 years 6 to 15 years More than 15 years Understanding 0 correct responses correct response correct responses correct responses correct responses 0 0.0 0.0 6 8.1 16 10.2 5 correct responses 21.0 6 correct responses 6 26.1 17 41.5 25 33.8 36 22.9 7 correct responses 15 65.2 20 48.8 31 41.9 63 40.1 Average number of 6.6 (5.7. 7.0) ?1 6.4 (5.7. 7.0) ?1 5.8 (5.3. 7.0) ?1 5.8 (5.5. 7.0) ?1 correct responses One-sided 95 con?dence interval using the normal approximation to the Poisson distribution Client: TRIG Project: TIRF Wave2 Report Run Date and Time: 10/30/2013 4:32:00 PM Page 1 of TABLE 6.2.6 SECONDARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #1 KEY RISK MESSAGEI: TIRF MEDICINES ARE CONTRAINDICATED IN OPIOID NON-TOLERANT PATIENTS. SUB-GROUP ANALYSIS 6: NUMBER OF TIMES PER MONTH DISPENSED TIRF MEDICINES WITHIN THE LAST 6 MONTHS (QUESTION 25): S?6a None 0 S?6b 2 times per month 0 S-6c - 3 - 5 times per month 0 S-6d - More than 5 times per month S-6a S-6b S-6c S-6d None 1 - 2 3 - 5 More than 5 Demonstrated Understanding 0 correct responses correct response correct responses correct responses correct responses correct responses 19 13.1 17 18.9 4 12.5 4 26.7 6 correct responses 41 28.3 25 27.8 9 28.1 4 26.7 7 correct responses 70 48.3 36 40.0 14 43.8 3 20.0 Average number of correct responses 6.1 (5.8. 7.0) 5.9 (5.4. 7.0) 5.8 (5.1. 7.0) 5.0 (4.1. 7.0) One-sided 95 con?dence interval using the normal approximation to the Poisson distribution Client: TRIG Project: TIRF Wave 2 Report Run Date and Time: 10/31/2013 11:27:00 AM Page 1 of 21 8 TABLE 7.1 PRIMARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #2 KEY RISK MESSAGE 2: TIRF MEDICINES ARE ONLY INDICATED FOR THE MANAGEMENT OF BREAKTHROUGH PAIN IN ADULT CANCER PATIENTS 18 YEARS OF AGE AND OLDER (16 YEARS OF AGE AND OLDER FOR BRAND AND GENERIC EQUIVALENTS) WHO ARE ALREADY RECEIVING AND WHO ARE TOLERAN TO AROUND- THE-CLOCK OPIOID THERAPY FOR THEIR UNDERLYING PERSISTENT CANCER PAIN. Question Eligible and Complete Respondents (95% CI) [21 Question 9: Per the approved labeling for TIRF medicines, for which of the following indications can TIRF medicines be prescribed to opioid tolerant patients? Please answer Yes, No, or I don?t know for each option. 9a: Acute or postoperative pain N0 254 (80.85.8786) Yes 31 10.3 I don't know 15 5.0 9b: Headache or migraine pain N0 277 (88.95351) Yes 8 2.7 I don't know 15 5.0 9c: Dental pain N0 290 (94239784) Yes 3 1.0 I don't know 7 2.3 Client: TRIG Project: TIRF Wave 2 Report Run Date and Time: 10/30/2013 1:14:00 PM Page 1 of 2 Eligible and Complete Respondents . Question (95% CI) [21 9d: Breakthrough pain from cancer Yes 268 (85.233326) No 27 9.0 I don't know 5 1.7 9e: Chronic non?cancer pain N0 (4137.228) Yes 126 42.0 I don't know 33 11.0 Correct response All con?dence intervals are exact binomial 95% con?dence intervals. Client: TRIG Project: Report Run Date and Time: 10/30/2013 1:14:00 PM Page 2 of 2 220 TABLE 7.1.1 PRIMARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #2 KEY RISK MESSAGE 2: TIRF MEDICINES ARE ONLY INDICATED FOR THE MANAGEMENT OF BREAKTHROUGH PAIN IN ADULT CANCER PATIENTS 18 YEARS OF AGE AND OLDER (16 YEARS OF AGE AND OLDER FOR BRAND AND GENERIC EQUIVALENTS) WHO ARE ALREADY RECEIVING AND WHO ARE TOLERAN TO AROUND-THE-CLOCK OPIOID THERAPY FOR THEIR UNDERLYING PERSISTENT CANCER PAIN. SUB-GROUP ANALYSIS 1: READING MEDICATION GUIDE OR FULL PRESCRIBING INFORMATION (QUESTIONS l8, 19, 20 AND 21): S-la-Respondents who read the Full Prescribing Information (Question 19) and Medication Guide for the TIRF medicine that they dispense (Question 21). S-lb-Respondents who responded ?No? or don?t know? to getting and reading the Full Prescribing Information and to getting and reading the Medication Guide for the TIRF medicine that they dispense. Question S-la S?lb Read Medication Guide or Did not read Medication . . Gmde and Full Full Prescribing Info Inf? (95% CI) (95% CI) Question 9: Per the approved labeling for TIRF medicines, for which of the following indications can TIRF medicines be prescribed to opioid tolerant patients? Please answer Yes, No, or I don?t know for each option. 9a: Acute or postoperative pain N0 221 33 (71.839856) Yes 27 10.3 4 10.5 I don't know 14 5.3 1 2.6 9b: Headache or migraine pain N0 245 (89.983362) 32 (68.?9240don't know 11 4.2 4 10.5 Client: TRIG Project: TIRF Wave 2 Report Run Date and Time: 10/30/2013 3:11:00 PM Page 1 of 2 221 S?la S?lb . . . Did not read Medication Read Medication Guide or Guide and Full Prescribing ti Full Info Info ues on 262 (95% CI) (95% CI) 9c: Dental pain 96.9 94.7 No 254 (94.1. 98.7) 36 (82.3. 99.don't know 5 1.9 2 5.3 9d: Breakthrough pain from cancer 88.9 92.1 Yes 233 (84.5. 92.5) 35 (78.6. 98.don't know 4 1.5 1 2.6 9e: Chronic non?cancer pain 49.2 31.6 No 129 (43.0. 55.5) 12 (17.5. 48.7) Yes 106 40.5 20 52.6 I don't know 27 10.3 6 15.8 Correct response Client: TRIG Project: TIRF Wave2 Report Run Date and Time: 10/30/2013 3:11:00 PM Page 2 of 2 222 TABLE 7.1.2 PRIMARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #2 KEY RISK MESSAGE 2: TIRF MEDICINES ARE ONLY INDICATED FOR THE MANAGEMENT OF BREAKTHROUGH PAIN IN ADULT CANCER PATIENTS 18 YEARS OF AGE AND OLDER (16 YEARS OF AGE AND OLDER FOR BRAND AND GENERIC EQUIVALENTS) WHO ARE ALREADY RECEIVING AND WHO ARE TOLERAN TO AROUND-THE-CLOCK OPIOID THERAPY FOR THEIR UNDERLYING PERSISTENT CANCER PAIN. SUB-GROUP ANALYSIS 2: TIME TO COMPLETE SURVEY INTERNET: S?2a <10 min 0 S-2b 10 to <20 min 0 S-2c 2 20 min S-2b S-min Question (95% CI) (95% (95% c1) Question 9: Per the approved labeling for TIRF medicines, for which of the following indications can TIRF medicines be prescribed to opioid tolerant patients? Please answer Yes, No, or I don?t know for each option. 9a: Acute or postoperative pain 75.8 88.9 89.4 No ?1 69 (65.7. 136 (82.8. 42 (76.9. 84.2) 93.4) 96.5) Yes 16 17.6 9 5.9 5 10.6 I don't know 6 6.6 8 5.2 0 0.0 9b: Headache or migraine pain 91.2 90.8 97.9 No ?1 83 (83.4. 139 (85.1. 46 (88.7. 96.1) 94.9) 99.don't know 6 6.6 8 5.2 1 2.1 Client: TRIG Project: TIRF Wave 2 Report Run Date and Time: 10/31/2013 8:21:00 AM Page 1 of 2 223 S-2a S?2b S-min (95% CI) (95% CI) (95% CI) 9c: Dental pain 94.5 96.7 100.0 No ?1 86 (87.6. 148 (92.5. 47 (92.5. 98.2) 98.9) 100.don't know 2 2.2 5 3.3 0 0.0 9d: Breakthrough pain from cancer 86.8 88.9 95.7 Yes 79 (78.1. 136 (82.8. 45 (85.5. 93.0) 93.4) 99.5) No 10 11.0 14 9.2 2 4.3 I don't know 2 2.2 3 2.0 0 0.0 9e: Chronic non-cancer pain 41.8 50.3 48.9 No ?1 38 (31.5. 77 (42.1. 23 (34.1. 52.6) 58.5) 63.9) Yes 42 46.2 58 37.9 22 46.8 I don't know 11 12.1 18 11.8 2 4.3 Correct response Client: TRIG Project: Report Run Date and Time: 10/31/2013 8:21:00 AM Page 2 of 2 224 TABLE 7.1.4 PRIMARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #2 KEY RISK MESSAGE 2: TIRF MEDICINES ARE ONLY INDICATED FOR THE MANAGEMENT OF BREAKTHROUGH PAIN IN ADULT CANCER PATIENTS 18 YEARS OF AGE AND OLDER (16 YEARS OF AGE AND OLDER FOR BRAND AND GENERIC EQUIVALENTS) WHO ARE ALREADY RECEIVING AND WHO ARE TOLERAN TO AROUND-THE-CLOCK OPIOID THERAPY FOR THEIR UNDERLYING PERSISTENT CANCER PAIN. SUB-GROUP ANALYSIS 4: MODALITY TO COMPLETE SURVEY: S?4a Internet S-4b - Telephone S-4a S-4b Internet Telephone Question (95% CI) (95% CI) Question 9: Per the approved labeling for TIRF medicines, for which of the following indications can TIRF medicines be prescribed to opioid tolerant patients? Please answer Yes, No, or I don?t know for each option. 9a: Acute or postoperative pain 84.9 77.8 N0 247 (80.2. 88.8) 7 (40.0. 97.2) Yes 30 10.3 1 11.1 I don't know 14 4.8 1 11.1 9b: Headache or migraine pain 92.1 100.0 N0 268 (88.4. 94.9) 9 (66.4. 100.don't know 15 5.2 0 0.0 9c: Dental pain 96.6 100.0 N0 281 (93.8. 98.3) 9 (66.4. 100.don't know 7 2.4 0 0.0 Client: TRIG Project: TIRF WaveZ Report Run Date and Time: 10/31/2013 8:26:00 AM Page 1 of 2 225 S?4a Internet Telephone Question (95% CI) (95% CI) 9d: Breakthrough pain from cancer Yes 260 (85.?326) (51.882.3'9997) No 26 8.9 11.1 I don't know 5 1.7 0.0 9e: Chronic non-cancer pain N0 138 (4117:?) (7.53.3511) Yes 122 41.9 44.4 I don't know 31 10.7 22.2 Correct response Client: TRIG Project: Report Run Date and Time: 10/31/2013 8:26:00 AM Page 2 of 2 226 TABLE 7.1.5 PRIMARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #2 KEY RISK MESSAGE 2: TIRF MEDICINES ARE ONLY INDICATED FOR THE MANAGEMENT OF BREAKTHROUGH PAIN IN ADULT CANCER PATIENTS 18 YEARS OF AGE AND OLDER (16 YEARS OF AGE AND OLDER FOR BRAND AND GENERIC EQUIVALENTS) WHO ARE ALREADY RECEIVING AND WHO ARE TOLERANT TO AROUND-THE-CLOCK OPIOID THERAPY FOR THEIR UNDERLYING PERSISTENT CANCER PAIN. SUB-GROUP ANALYSIS 5: TIME PRACTICING AS A PHARMACIST (QUESTION 28): S?5a - Less than 3 years 3 to 5 years 0 8-51? 6 to 15 years 0 More than 15 years Question S?5b S?5c S-5d Less than 3 years 3 to 5 years 6 to 15 years More than 15 years (95% CI) (95% CI) (95% CI) (95% CI) Question 9: Per the approved labeling for TIRF medicines, for which of the following indications can TIRF medicines be prescribed to opioid tolerant patients? Please answer Yes, No, or I don?t know for each option. 9a: Acute or postoperative pain 111 78.3 92.7 83.8 84.1 No 18 (56.3. 92.5) 38 (80.1. 98.5) 62 (73.4. 91.3) 132 (77.4. 89.12.2 18 11.5 I don't know 3 13.0 1 2.4 3 4.1 7 4.5 Client: TRIG Project: TIRF Wave 2 Report Run Date and Time: 10/31/2013 10:49:00 AM Page 1 227 S?5a S?5b S?5c S?5d Less than 3 years 3 to 5 years 6 to 15 years More than 15 years (95% CI) (95% CI) (95% CI) (95% CI) 9b: Headache or migraine pain 95.7 95.1 89.2 93.0 N0 22 (78.1. 99.9) 39 (83.5. 99.4) 66 (79.8. 95.2) 146 (87.8. 96.don't know 3.8 9c: Dental pain 100.0 100.0 95.9 96.2 No 23 (85.2.1000) 41 (91.4.1000) 71 (88.6. 99.2) 151 (91.9. 98.don't know 2.5 9d: Breakthrough pain from cancer 95.7 92.7 91.9 87.3 Yes 22 (78.1. 99.9) 38 (80.1. 98.5) 68 (83.2. 97.0) 137 (81.0. 92.11.5 I don't know 1.3 Client: TRIG Project: TIRF Wave 2 Report Run Date and Time: 10/31/2013 10:49:00 AM Page 2 228 S?5a S?5b S?5d Less than 3 years 3 to 5 years 6 to 15 years More than 15 years (95% CI) (95% CI) (95% CI) (95% CI) 9e: Chronic non?cancer pain 52.2 48.8 43.2 47.1 N0 12 (30.6. 73.2) 20 (32.9. 64.9) 32 (31.8. 55.3) 74 (39.1. 55.2) Yes 7 30.4 19 46.3 31 41.9 68 43.3 Idon't know 4 17.4 2 4.9 11 14.9 15 9.6 Correct response Client: TRIG Project: TIRF Wave2 Report Run Date and Time: 10/31/2013 10:49:00 AM Page 3 of 3 229 TABLE 7.1.6 PRIMARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #2 KEY RISK MESSAGE 2: TIRF MEDICINES ARE ONLY INDICATED FOR THE MANAGEMENT OF BREAKTHROUGH PAIN IN ADULT CANCER PATIENTS 18 YEARS OF AGE AND OLDER (16 YEARS OF AGE AND OLDER FOR BRAND AND GENERIC EQUIVALENTS) WHO ARE ALREADY RECEIVING AND WHO ARE TOLERANT TO AROUND-THE-CLOCK OPIOID THERAPY FOR THEIR UNDERLYING PERSISTENT CANCER PAIN. SUB-GROUP ANALYSIS 6: NUMBER OF TIMES PER MONTH DISPENSED TIRF MEDICINES WITHIN THE LAST 6 MONTHS (QUESTION 25): S?6a None 0 S?6b 1 2 times per month 0 S?6e 3 5 times per month S?6d More than 5 times per month S?6a S6b S?6c S?6d None 1 - 2 3 5 More than 5 Question N=l45 (95% CI) (95% CI) (95% CI) (95% CI) Question 9: Per the approved labeling for TIRF medicines, for which of the following indications can TIRF medicines be prescribed to opioid tolerant patients? Please answer Yes, No, or I don?t know for each option. 9a: Acute or postoperative pain 86.2 86.7 81.3 66.7 No 125 (79.5. 91.4) 78 (77.9. 92.9) 26 (63.6. 92.8) 10 (38.4. 88.2) Yes 11 7.6 11 12.2 4 12.5 4 26.7 Idon?t know 6.7 Client: TRIG Project: TIRF Wave2 Report Run Date and Time: 10/31/2013 9:12:00 AM Page 1 230 S?6a S?6b S?6c S?6d None 1 2 3 5 More than 5 (95% CI) (95% CI) (95% CI) (95% CI) 9b: Headache or migraine pain 90.3 97.8 90.6 80.0 N0 131 (84.3. 94.6) 88 (92.2. 99.7) 29 (75.0. 98.0) 12 (51.9. 95.13.3 I don't know 6.7 9c: Dental pain 98.6 97.8 90.6 86.7 No 143 (95.1. 99.8) 88 (92.2. 99.7) 29 (75.0. 98.0) 13 (59.5. 98.don't know 6.7 9d: Breakthrough pain from cancer 93.1 91.1 78.1 73.3 Yes 135 (87.7. 96.6) 82 (83.2. 96.1) 25 (60.0. 90.7) 11 (44.9. 92.12.5 4 26.7 I don't know 0.0 Client: TRIG Project: TIRF WaveZ Report Run Date and Time: 10/31/2013 9:12:00 AM Page 2 3 231 S?6a S?6b S?6c S?6d None 1 2 3 5 More than 5 (95% CI) (95% CI) (95% CI) (95% CI) 9e: Chronic non?cancer pain 538 47.8 28.1 33.3 N0 78 (45.3. 62.1) 43 (37.1. 58.6) 9 (13.7. 46.7) 5 (11.8. 61.6) Yes 49 33.8 38 42.2 20 62.5 9 60.0 I don't know 18 12.4 9 10.0 3 9.4 1 6.7 Correct response Client: TRIG Project: TIRF WaveZ Report Run Date and Time: 10/31/2013 9:12:00 AM Page 3 of 3 232 TABLE 7.2 SECONDARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED KEY RISK MESSAGE 2: TIRF MEDICINES ARE ONLY INDICATED FOR THE TO KEY RISK MESSAGE #2 MANAGEMENT OF BREAKTHROUGH PAIN IN ADULT CANCER PATIENTS 18 YEARS OF AGE AND OLDER (16 YEARS OF AGE AND OLDER FOR BRAND AND GENERIC EQUIVALENTS) WHO ARE ALREADY RECEIVING AND WHO ARE TOLERANT TO AROUND- THE-CLOCK OPIOID THERAPY FOR THEIR UNDERLYING PERSISTENT CANCER PAIN. Eligible and Complete Respondents Demonstrated Understanding 0 correct responses 2 0.7 1 correct response 4 1.3 2 correct responses 12 4.0 3 correct responses 47 15.7 4 correct responses 114 38.0 5 correct responses 121 40.3 Average number of correct responses 4.1 (3.9. 5.0) [ll One-sided 95 con?dence interval using the approximation to the Poisson distribution Client: TRIG Project: TIRF Wave 2 Report Run Date and Time: 10/30/2013 1:50:00 PM Page 1 of 233 TABLE 7.2.1 SECONDARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #2 KEY RISK MESSAGE 2: TIRF MEDICINES ARE ONLY INDICATED FOR THE MANAGEMENT OF BREAKTHROUGH PAIN IN ADULT CANCER PATIENTS 18 YEARS OF AGE AND OLDER (16 YEARS OF AGE AND OLDER FOR BRAND AND GENERIC EQUIVALENTS) WHO ARE ALREADY RECEIVING AND WHO ARE TOLERAN TO AROUND-THE-CLOCK OPIOID THERAPY FOR THEIR UNDERLYING PERSISTENT CANCER PAIN. SUB-GROUP ANALYSIS 1: READING MEDICATION GUIDE OR FULL PRESCRIBING INFORMATION (QUESTIONS 18, 19, 20 AND 21): S-la-Respondents who read the Full Prescribing Information (Question 19) and Medication Guide for the TIRF medicine that they dispense (Question 21). S-lb-Respondents who responded ?No? or don?t know? to getting and reading the Full Prescribing Information and to getting and reading the Medication Guide for the TIRF medicine that they dispense. S-lb S-la Did not read Medication Read Medication Guide or Guide and Full Demonstrated Understanding Prescribing Info Prescribing Info 0 con'ect responses 2 0.8 0 0.0 1 correct response 2 0.8 2 5.3 2 correct responses 12 4.6 0 0.0 3 c01rect responses 38 14.5 9 23.7 4 con'ect responses 98 37.4 16 42.1 5 con?ect responses 110 42.0 11 28.9 Average number of con'ect responses 4.1 (3.9. 5.0) 3.9 (3.4. 5.0) One-sided 95 con?dence interval using the normal approximation to the Poisson distribution Client: TRIG Project: TIRF Wave2 Report Run Date and Time: 10/30/2013 3:14:00 PM Page 1 of 234 TABLE 7.2.2 SECONDARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #2 KEY RISK MESSAGE 2: TIRF MEDICINES ARE ONLY INDICATED FOR THE MANAGEMENT OF BREAKTHROUGH PAIN IN ADULT CANCER PATIENTS 18 YEARS OF AGE AND OLDER (16 YEARS OF AGE AND OLDER FOR BRAND AND GENERIC EQUIVALENTS) WHO ARE ALREADY RECEIVING AND WHO ARE TOLERANT TO AROUND-THE-CLOCK OPIOID THERAPY FOR THEIR UNDERLYING PERSISTENT CANCER PAIN. SUB-GROUP ANALYSIS 2: TIME TO COMPLETE SURVEY INTERNET: S?2a - <10 min 0 S?2b 10 to <20 min 0 S-2c 2 20 min S-2a S-2b S-min Demonstrated Understanding 0 correct responses correct response correct responses correct responses 18 19.8 20 13.1 6 12.8 4 correct responses 35 38.5 59 38.6 17 36.2 5 correct responses 29 31.9 66 43.1 23 48.9 Average number of correct responses 3.9 (3.6. 5.0) 4.2 (3.9. 5.0) 4.3 (3.8. 5.0) One-sided 95 con?dence interval using the normal approximation to the Poisson distribution Client: TRIG Project: TIRF Wave 2 Report Run Date and Time: 10/31/2013 8:25:00 AM Page 1 of 235 TABLE 7.2.4 SECONDARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #2 KEY RISK MESSAGE 2: TIRF MEDICINES ARE ONLY INDICATED FOR THE MANAGEMENT OF BREAKTHROUGH PAIN IN ADULT CANCER PATIENTS 18 YEARS OF AGE AND OLDER (16 YEARS OF AGE AND OLDER FOR BRAND AND GENERIC EQUIVALENTS) WHO ARE ALREADY RECEIVING AND WHO ARE TOLERAN TO AROUND-THE-CLOCK OPIOID THERAPY FOR THEIR UNDERLYING PERSISTENT CANCER PAIN. SUB-GROUP ANALYSIS 4: MODALITY TO COMPLETE SURVEY: 0 8?421 Internet 0 S-4b - Telephone S-4a S-4b Internet Telephone Demonstrated Understanding 0 correct responses 2 0.7 0 0.0 1 correct response 4 1.4 0 0.0 2 correct responses 12 4.1 0 0.0 3 correct responses 44 15.1 3 33.3 4 correct responses 111 38.1 3 33.3 5 correct responses 118 40.5 3 33.3 Average number of correct responses 4.1 (3.9. 5.0) 4.0 (2.9. 5.0) [ll One-sided 95 con?dence interval using the normal approximation to the Poisson distribution Client: TRIG Project: TIRF Wave2 Report Run Date and Time: 10/31/2013 11:27:00 AM Page 1 of 236 TABLE 7.2.5 SECONDARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #2 KEY RISK MESSAGE 2: TIRF MEDICINES ARE ONLY INDICATED FOR THE MANAGEMENT OF BREAKTHROUGH PAIN IN ADULT CANCER PATIENTS 18 YEARS OF AGE AND OLDER (16 YEARS OF AGE AND OLDER FOR BRAND AND GENERIC EQUIVALENTS) WHO ARE ALREADY RECEIVING AND WHO ARE TOLERANT TO AROUND-THE-CLOCK OPIOID THERAPY FOR THEIR UNDERLYING PERSISTENT CANCER PAIN. SUB-GROUP ANALYSIS 5: TIME PRACTICING AS A PHARMACIST (QUESTION 28): S?5a - Less than 3 years 3 to 5 years 6 to 15 years More than 15 years S-5b S-5c S-5d Less than 3 years 3 to 5 years 6 to 15 years More than 15 years Demonstrated Understanding 0 correct responses correct response correct responses correct responses 3 13.0 3 7.3 14 18.9 26 16.6 4 correct responses 9 39.1 20 48.8 28 37.8 57 36.3 5 correct responses 10 43.5 17 41.5 28 37.8 63 40.1 Average number of correct responses 4.2 (3.5. 5.0) 4.3 (3.8. 5.0) 4.0 (3.7. 5.0) 4.1 (3.8. 5.0) One-sided 95 con?dence interval using the normal approximation to the Poisson distribution Client: TRIG Project: TIRF Wave2 Report Run Date and Time: 10/31/2013 11:28:00 AM Page 1 of 237 TABLE 7.2.6 SECONDARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #2 KEY RISK MESSAGE 2: TIRF MEDICINES ARE ONLY INDICATED FOR THE MANAGEMENT OF BREAKTHROUGH PAIN IN ADULT CANCER PATIENTS 18 YEARS OF AGE AND OLDER (16 YEARS OF AGE AND OLDER FOR BRAND AND GENERIC EQUIVALENTS) WHO ARE ALREADY RECEIVING AND WHO ARE TOLERANT TO AROUND-THE-CLOCK OPIOID THERAPY FOR THEIR UNDERLYING PERSISTENT CANCER PAIN. SUB-GROUP ANALYSIS 6: NUMBER OF TIMES PER MONTH DISPENSED TIRF MEDICINES WITHIN THE LAST 6 MONTHS (QUESTION 25): S-6a - None 0 S?6b 2 times per month S-6c - 3 - 5 times per month 0 S-6d - More than 5 times per month S-6a S-6b S-6c S-6d None 1 - 2 3 - 5 More than 5 Demonstrated Understanding N=l45 0 correct responses correct response 2 1.4 0.0 0 0.0 2 13.3 2 correct responses correct responses 23 15.9 8 8.9 9 28.1 4 26.7 4 correct responses 44 30.3 46 51.1 10 31.3 5 33.3 5 correct responses 71 49.0 33 36.7 9 28.1 3 20.0 Average number of correct responses 4.2 (3.9. 5.0) 4.2 (3.9. 5.0) 3.7 (3.1. 5.0) 3.4 (2.6. 5.0) One-sided 95 con?dence interval using the normal approximation to the Poisson distribution Client: TRIG Project: TIRF Wave2 Report Run Date and Time: 10/31/2013 11:28:00 AM Page 1 of 238 TABLE 8.1 PRIMARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #3 KEY RISK MESSAGE 3: TIRF MEDICINES CONTAIN FENTANYL, AN OPIOID AGONIST AND A SCHEDULE II CONTROLLED SUBSTANCE, WITH ABUSE LIABILITY SINIILAR TO OTHER OPIOID AN ALGESICS. Eligible and Complete Respondents ti Ques on (95% CI) "1 the labeling for TIRF medicines. Question 7: Please answer True, False, or I don?t know for each statement based on 7e: It is important to monitor for signs of abuse and addiction in patients who take TIRF medicines. 96.7 True 290 (94.0. 98.4) False 5 1.7 I don't know 5 1.7 Yes, No, or I don?t know for each option. Question 8: Which of the following are risk factors for opioid abuse? Please answer 8a: A personal history of illness 72.0 Yes 216 (66.6. 77.0) No 48 16.0 I don't know 36 12.0 drug use or alcohol abuse 8b: A personal histony of past or current alcohol or drug abuse, or a family history of illicit 99.0 Yes 297 (97.1. 99.8) No 0 0.0 I don't know 3 1.0 Client: TRIG Project: TIRF Wave 2 Report Run Date and Time: 10/30/2013 1:26:00 PM Page 1 of 2 239 Eligible and Complete Respondents uestion (95% CI) "1 Question 10: Please answer True, False, or I don?t know for each statement based on the labeling for TIRF medicines. 10a: TIRF medicines can be abused in a manner similar to other opioid agonists. 94.0 True 282 (90.7. 96.4) False 10 3.3 I don't know 8 2.7 Correct response All con?dence intervals are exact binomial 95% con?dence intervals. Client: TRIG Project: TIRF Wave 2 Report Run Date and Time: 10/30/2013 1:26:00 PM Page 2 of 2 240 TABLE 8.1.1 PRIMARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #3 KEY RISK MESSAGE 3: TIRF MEDICINES CONTAIN FENTANYL, AN OPIOID AGONIST AND A SCHEDULE II CONTROLLED SUBSTANCE, WITH ABUSE LIABILITY SIMILAR TO OTHER OPIOID ANALGESICS. SUB-GROUP ANALYSIS 1: READING MEDICATION GUIDE OR FULL PRESCRIBING INFORMATION (QUESTIONS 18, 19, 20 AND 21): S-la-Respondents who read the Full Prescribing Information (Question 19) and Medication Guide for the TIRF medicine that they dispense (Question 21). S-lb-Respondents who responded ?No? or don?t know? to getting and reading the Full Prescribing Information and to getting and reading the Medication Guide for the TIRF medicine that they dispense. S?la S-lb Read Medication Guide or Did Mt read Medication . . Guide and Full Prescribing ti Full Info Info ues on 262 (95% CI) (95% CI) Question 7: Please answer True, False, or I don?t know for each statement based on the labeling for TIRF medicines. 7e: It is important to monitor for signs of abuse and addiction in patients who take TIRF medicines. 96.6 97.4 Tm 253 (93.6. 98.4) 37 (86.2. 99.9) False 4 1.5 1 2.6 I don't know 5 1.9 0 0.0 Question 8: Which of the following are risk factors for opioid abuse? Please answer Yes, No, or I don?t know for each option. 8a: A personal history of illness 73.3 63.2 Yes 192 (67.5. 78.5) 24 (46.0. 78.2) No 39 14.9 9 23.7 Idon't know 31 11.8 5 13.2 Client: TRIG Project: TIRF WaveZ Report Run Date and Time: 10/30/2013 3:18:00 PM Page 1 241 Question S?la Read Medication Guide or S?lb Did not read Medication Full Prescribing Info Guide and Full Prescribing Info (95% CI) (95% CI) 8b: A personal history of past or current alcohol or drug abuse, or a family history of illicit drug use or alcohol abuse 98.9 100.0 Yes 259 (96.7. 99.8) 38 (90.7. 100.don't know 3 1.1 0.0 Question 10: Please answer True, False, or I don?t know for each statement based on the labeling for TIRF medicines. 10a: TIRF medicines can be abused in a manner similar to other opioid agonists. 94.7 89.5 [11 True 248 (91.2. 97.0) 34 (75.2. 97.1) False 7 2.7 3 7.9 I don't know 7 2.7 1 2.6 Conect response Client: TRIG Project: TIRF WaveZ Report Run Date and Time: 10/30/2013 3:18:00 PM Page 2 of 2 242 TABLE 8.1.2 PRIMARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #3 KEY RISK MESSAGE 3: TIRF MEDICINES CONTAIN FENTANYL, AN OPIOID AGONIST AND A SCHEDULE II CONTROLLED SUBSTANCE, WITH ABUSE LIABILITY SIMILAR TO OTHER OPIOID ANALGESICS. SUB-GROUP ANALYSIS 2: TIME TO COMPLETE SURVEY INTERNET: S?2a <10 min S?2b 10 to <20 min S?2c 20 min S?2a S?2b S?min Question (95% CI) (95% CI) (95% CI) Question 7: Please answer True, False, or I don?t know for each statement based on the labeling for TIRF medicines. 7e: It is important to monitor for signs of abuse and addiction in patients who take TIRF medicines. 95.6 96.7 97.9 True ?1 87 (89.1. 148 (92.5. 46 (88.7. 98.8) 98.9) 99.9) False don't know 2 2.2 3 2.0 0 0.0 Question 8: Which of the following are risk factors for opioid abuse? Please answer Yes, No, or I don?t know for each option. 8a: A personal history of illness 76.9 69.9 70.2 Yes ?1 70 (66.9. 107 (62.0. 33 (55.1. 85.1) 77.1) 82.7) No 12 13.2 24 15.7 10 21.3 I don't know 9 9.9 22 14.4 4 8.5 Client: TRIG Project: TIRF Wave 2 Report Run Date and Time: 10/31/2013 10:02:00 AM Page 1 of 2 243 S?2a S-min (95% CI) (95% CI) (95% CI) 8b: A personal history of past or current alcohol or drug abuse, or a family history of illicit drug use or alcohol abuse 97.8 99.3 100.0 Yes ?1 89 (92.3. 152 (96.4. 47 (92.5. 99.7) 100.0) 100.don't know 2 2.2 0.7 0 0.0 Question 10: Please answer True, False, or I don?t know for each statement based on the labeling for TIRF medicines. 10a: TIRF medicines can be abused in a manner similar to other opioid agonists. 93.4 93.5 95.7 True ?1 85 (86.2. 143 (88.3. 45 (85.5. 97.5) 96.8) 99.5) False don't know 3 3.3 4 2.6 2.1 Conect response Client: TRIG Project: TIRF Wave 2 Report Run Date and Time: 10/31/2013 10:02:00 AM Page 2 of 2 244 TABLE 8.1.4 PRIMARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #3 KEY RISK MESSAGE 3: TIRF MEDICINES CONTAIN FENTANYL, AN OPIOID AGONIST AND A SCHEDULE II CONTROLLED SUBSTANCE, WITH ABUSE LIABILITY SIMILAR TO OTHER OPIOID ANALGESICS. SUB-GROUP ANALYSIS 4: MODALITY TO COMPLETE SURVEY: S?4a Internet 0 S-4b - Telephone Question 84a 84b Internet Telephone (95% CI) (95% CI) Question 7: Please answer True, False, or I don?t know for each statement based on the labeling for TIRF medicines. 7e: It is important to monitor for signs of abuse and addiction in patients who take TIRF medicines. 96.6 100.0 True 281 (93.8. 98.3) 9 (66.4. 100.0) False 5 1.7 0 0.0 I don't know 5 1.7 0 0.0 Question 8: Which of the following are risk factors for opioid abuse? Please answer Yes, No, or I don?t know for each option. 8a: A personal history of illness 72.2 66.7 Yes 210 (66.6. 77.2) 6 (29.9. 92.5) No 46 15.8 2 22.2 I don't know 35 12.0 1 11.1 drug use or alcohol abuse 8b: A personal history of past or current alcohol or drug abuse, or a family history of illicit 99.0 100.0 Yes 288 (97.0. 99.8) 9 (66.4. 100.don't know 3 1.0 0 0.0 Client: TRIG Project: TIRF WaveZ Report Run Date and Time: 10/31/2013 10:07:00 AM Page 1 of 2 245 Question S?4a S?4b Internet Telephone (95% CI) (95% CI) Question 10: Please answer True, False, or I don?t know for each statement based on the labeling for TIRF medicines. 10a: TIRF medicines can be abused in a manner similar to other opioid agonists. 93.8 100.0 True 273 (90.4. 96.3) 9 (66.4. 100.0) False 10 3 .4 0 0.0 I don't know 8 2.7 0 0.0 Correct response Client: TRIG Project: TIRF Wave2 Report Run Date and Time: 10/31/2013 10:07:00 AM Page 2 of 2 246 TABLE 8.1.5 PRIMARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #3 KEY RISK MESSAGE 3: TIRF MEDICINES CONTAIN FENTANY L, AN OPIOID AGONIST AND A SCHEDULE II CONTROLLED SUBSTANCE, WITH ABUSE LIABILITY SIMILAR TO OTHER OPIOID ANALGESICS. SUB-GROUP ANALYSIS 5: TIME PRACTICING AS A PHARMACIST (QUESTION 28): - Less than 3 years 0 3 to 5 years 0 S?5c 6 to 15 years 0 More than 15 years Question S?5a S?5c Less than 3 years 3 to 5 years 6 to 15 years More than 15 years N=4l (95% CI) (95% CI) (95% CI) (95% CI) Question 7: Please answer True, False, or I don?t know for each statement based on the labeling for TIRF medicines. 7e: It is important to monitor for signs of abuse and addiction in patients Who take TIRF medicines. 100.0 97.6 94.6 97.5 True 23 (852? 40 (87.1. 99.9) 70 (86.7. 98.5) 153 (93.6. 99.3) 100.0) False don't know 0.6 Client: TRIG Project: TIRF Wave2 Report Run Date and Time: 10/31/2013 10:45:00 AM Page 1 2 247 S?5a S-5c Less than 3 years 3 to 5 years 6 to 15 years More than 15 years (95% CI) (95% CI) (95% CI) (95% CI) Question 8: Which of the following are risk factors for opioid abuse? Please answer Yes, No, or I don?t know for each option. 8a: A personal history of illness 111 73.9 78.0 66.2 73.9 Yes 17 (51.6. 89.8) 32 (62.4. 89.4) 49 (54.3. 76.8) ?6 (66.3. 80.6) No 2 8.7 5 12.2 11 14.9 28 17.8 I don't know 4 17.4 4 9.8 14 18.9 13 8.3 8b: A personal history of past or current alcohol or drug abuse, or a family history of illicit drug use or alcohol abuse 100.0 100.0 100.0 99.4 Yes 23 (852.1000) 41 (91.41000) 74 (951.1000) 156 (96.5.1000don't know 0.6 Question 10: Please answer True, False, or I don?t know for each statement based on the labeling for TIRF medicines. 10a: TIRF medicines can be abused in a manner similar to other opioid agonists. 91.3 95.1 90.5 95.5 True 21 (72.0. 98.9) 39 (83.5. 99.4) 67 (81.5. 96.1) 150 (91.0. 98.2) False don't know 1.9 Correct response Client: TRIG Project: TIRF Wave 2 Report Run Date and Time: 10/31/2013 10:45:00 AM Page 2 of 2 248 TABLE 8.1.6 PRIMARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #3 KEY RISK MESSAGE 3: TIRF MEDICINES CONTAIN FENTANY L, AN OPIOID AGONIST AND A SCHEDULE II CONTROLLED SUBSTANCE, WITH ABUSE LIABILITY SIMILAR TO OTHER OPIOID ANALGESICS. SUB-GROUP ANALYSIS 6: NUMBER OF TIMES PER MONTH DISPENSED TIRF MEDICINES WITHIN THE LAST 6 MONTHS (QUESTION 25): S?6a - None S-6b - - 2 times per month S-6c - 3 - 5 times per month S?6d More than 5 times per month Question S?6a S?6b S-6c S?6d None 1 - 2 3 5 More than 5 N=l45 (95% CI) (95% CI) (95% CI) (95% CI) Question 7: Please answer True, False, or I don?t know for each statement based on the labeling for TIRF medicines. 7e: It is important to monitor for signs of abuse and addiction in patients who take TIRF medicines. 97.2 96.7 96.9 93.3 True 141 (93.1. 99.2) 87 (90.6. 99.3) 31 (83.8. 99.9) 14 (68.1. 99.8) False don't know 6.7 Client: TRIG Project: TIRF Wave2 Report Run Date and Time: 10/31/2013 10:48:00 AM Page 1 of 2 249 S?6a S?6b S-6c S-6d None 1 2 3 5 More than 5 Question N=l45 (953: CI) (95?02 CI) CI) CI) Question 8: Which of the following are risk factors for opioid abuse? Please answer Yes, No, or I don?t know for each option. 8a: A personal history of illness 109 (67.258220) 64 (60.21%02) 22 (50.32.;8839) 7 (21.?7734) No 19 13.1 16 17.8 5 15.6 7 46.7 Idon't know 17 11.7 10 11.1 5 15.6 1 6.7 8b: A personal history of past or current alcohol or drug abuse, or a family history of illicit drug use or alcohol abuse Yes 111 144 (96.391300) 90 32 (89.136000) 14 (68.91? 9398don't know 6.7 Question 10: Please answer True, False, or I don?t know for each statement based on the labeling for TIRF medicines. 10a: TIRF medicines can be abused in a manner similar to other opioid agonists. 95.2 92.2 96.9 93.3 True 138 (90.3. 98.0) 83 (84.6. 96.8) 31 (83.8. 99.9) 14 (68.1. 99.8) False don't know 6.7 Correct response Client: TRIG Project: TIRF Wave2 Report Run Date and Time: 10/31/2013 10:48:00 AM Page 2 of 2 250 TABLE 8.2 SECONDARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #3 KEY RISK MESSAGE 3: MEDICINES CONTAIN FENTANYL, AN OPIOID AGONIST AND A SCHEDULE II CONTROLLED SUBSTANCE, WITH ABUSE LIABILITY SINIILAR TO OTHER OPIOID ANALGESICS. Eligible and Complete Respondents Demonstrated Understanding 0 correct responses 0 0.0 1 correct response 3 1.0 2 correct responses 7 2.3 3 correct responses 92 30.7 4 correct responses 198 66.0 Average number of correct responses 3.6 (3.4. 4.0) [ll One-sided 95 con?dence interval using the normal approximation to the Poisson distn'bution Client: TRIG Project: TIRF Wave 2 Report Run Date and Time: 11/8/2013 9:02:00 AM Page 1 of 251 TABLE 8.2.1 SECONDARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #3 KEY RISK MESSAGE 3: TIRF MEDICINES CONTAIN FENTANYL, AN OPIOID AGONIST AND A SCHEDULE II CONTROLLED SUBSTANCE, WITH ABUSE LIABILITY SIMILAR TO OTHER OPIOID ANALGESICS. SUB-GROUP ANALYSIS 1: READING MEDICATION GUIDE OR FULL PRESCRIBING INFORMATION (QUESTIONS 18, 19, 20 AND 21): S-la-Respondents who read the Full Prescribing Information (Question 19) and Medication Guide for the TIRF medicine that they dispense (Question 21). S-lb-Respondents who responded ?No? or don?t know? to getting and reading the Full Prescribing Information and to getting and reading the Medication Guide for the TIRF medicine that they dispense. S-la S-lb Read Medication Guide or Did not read Medication Full Prescribing Info Guide and Full Prescribing Demonstrated Understanding Info 0 c01rect responses 0 0.0 0 0.0 1 conect response 3 1.1 0 0.0 2 conect responses 6 2.3 1 2.6 3 conect responses 75 28.6 17 44.7 4 c01rect responses 178 67.9 20 52.6 Average number of con'ect responses 3.6 (3.4. 4.0) 3.5 (3.0. 4.0) One-sided 95 con?dence interval using the nonnal approximation to the Poisson distribution Client: TRIG Project: TIRF Wave2 Report Run Date and Time: 11/8/2013 9:04:00 AM Page 1 of 252 TABLE 8.2.2 SECONDARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #3 KEY RISK MESSAGE 3: TIRF MEDICINES CONTAIN FENTANY L, AN OPIOID AGONIST AND A SCHEDULE II CONTROLLED SUBSTANCE, WITH ABUSE LIABILITY SIMILAR TO OTHER OPIOID ANALGESICS. SUB-GROUP ANALYSIS 2: TINIE TO COMPLETE SURVEY INTERNET: S-2a - <10 min 0 S?2b 10 to <20 min 0 S?2c 20 min S-2a S-2b S-min Demonstrated Understanding 0 correct responses correct response correct responses correct responses 24 26.4 50 32.7 15 31.9 4 correct responses 63 69.2 98 64.1 31 66.0 Average number of correct responses 3.6 (3.3. 3.6 (3.3. 3.6 (3.2. One-sided 95 con?dence interval using the normal approximation to the Poisson distribution Client: TRIG Project: TIRF Wave2 Report Run Date and Time: 11/8/2013 9:06:00 AM Page 1 of 1 253 TABLE 8.2.4 SECONDARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #3 KEY RISK MESSAGE 3: TIRF MEDICINES CONTAIN FENTANYL, AN OPIOID AGONIST AND A SCHEDULE II CONTROLLED SUBSTANCE, WITH ABUSE LIABILITY SIMILAR TO OTHER OPIOID ANALGESIC S. SUB-GROUP ANALYSIS 4: MODALITY TO COMPLETE SURVEY: 0 5?421 Internet 0 S-4b - Telephone S-4a S-4b Internet Telephone Demonstrated Understanding 0 correct responses 0 0.0 0 0.0 1 correct response 3 1.0 0 0.0 2 c01rect responses 7 2.4 0.0 3 correct responses 89 30.6 3 33.3 4 correct responses 192 66.0 6 66.7 Average number of correct responses 3.6 (3.4. 4.0) 3.7 (2.6. 4.0) ?1 One-sided 95 con?dence interval using the normal approximation to the Poisson distribution Client: TRIG Project: TIRF WaveZ Report Run Date and Time: 11/8/2013 9:08:00 AM Page 1 of 254 TABLE 8.2.5 SECONDARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #3 KEY RISK MESSAGE 3: TIRF MEDICINES CONTAIN FENTANY L, AN OPIOID AGONIST AND A SCHEDULE II CONTROLLED SUBSTANCE, WITH ABUSE LIABILITY SIMILAR TO OTHER OPIOID ANALGESICS. SUB-GROUP ANALYSIS 5: TIME PRACTICING AS A PHARMACIST (QUESTION 28): S-5a - Less than 3 years 0 S?5b 3 to 5 years 0 6 to 15 years 0 More than 15 years S-5a S?5b S-5d Less than 3 years 3 to 5 years 6 to 15 years More than 15 years Demonstrated Understanding 0 correct responses correct response correct responses correct responses 8 34.8 10 24.4 27 36.5 46 29.3 4 correct responses 15 65.2 30 73.2 43 58.1 108 68.8 Average number of correct responses 3.7 (3.0. 4.0) 3.7 (3.2. 4.0) ?l 3.5 (3.2. 4.0) ?1 3 .7 (3.4. 4.0) One-sided 95 con?dence interval using the normal approximation to the Poisson distribution Client: TRIG Project: TIRF Wave2 Report Run Date and Time: 11/8/2013 9:10:00 AM Page 1 of 255 TABLE 8.2.6 SECONDARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #3 KEY RISK MESSAGE 3: TIRF MEDICINES CONTAIN FENTANY L, AN OPIOID AGONIST AND A SCHEDULE II CONTROLLED SUBSTANCE, WITH ABUSE LIABILITY SIMILAR TO OTHER OPIOID ANALGESICS. SUB-GROUP ANALYSIS 6: NUMBER OF TIMES PER MONTH DISPENSED TIRF MEDICINES WITHIN THE LAST 6 MONTHS (QUESTION 25): S?6a None S-6b - - 2 times per month S-6c - 3 - 5 times per month S?6d - More than 5 times per month S-6a S-6b S-6c S-6d None 1 - 2 3 - 5 More than 5 Demonstrated Understanding 0 correct responses correct response correct responses correct responses 42 29.0 28 31.1 28.1 8 53.3 4 correct responses 100 69.0 58 64.4 22 68.8 6 40.0 Average number of correct responses 3.7 (3.4. 3.6 (3.3. 4.0) 3.6 (3.1. 4.0) 3.3 (2.5. 4.0) ?1 One-sided 95 con?dence interval using the normal approximation to the Poisson distribution Client: TRIG Project: TIRF Wave 2 Report Run Date and Time: 11/8/2013 9:12:00 AM Page 1 of 256 TABLE 9.1 PRIMARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #4 KEY RISK MESSAGE 4: TIRF MEDICINES ARE NOT INTERCHANGEABLE WITH EACH OTHER, REGARDLESS OF ROUTE OF ADMINISTRATION. Eligible and Complete Respondents ti ues on (95% CI) Question 10: Please answer True, False, or I don?t know for each statement based on the labeling for TIRF medicines. 10b: TIRF medicines are interchangeable with each other regardless of route of administration. 94.7 False 284 (91.5. 96.9) True 6 2.0 I don't know 10 3.3 10c: The conversion of one TIRF medicine for another TIRF medicine may result in a fatal overdose because of differences in the pharmacokinetics of fentanyl absorption. 92.0 True 276 (88.3. 94.8) False 5 1.7 I don't know 19 6.3 10d: Dosing of TIRF medicines is not equivale nt on a microgram-to-microgram basis. 91.3 True 274 (87.6. 94.3) False 10 3.3 I don't know 16 5.3 Correct response All con?dence intervals are exact binomial 95% con?dence intervals. Client: TRIG Project: TIRF Wave2 Report Run Date and Time: 10/30/2013 1:30:00 PM Page 1 of 257 TABLE 9.1.1 PRIMARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #4 KEY RISK MESSAGE 4: TIRF MEDICINES ARE NOT INTERCHANGEABLE WITH EACH OTHER, REGARDLESS OF ROUTE OF ADMINISTRATION. SUB-GROUP ANALYSIS 1: READING MEDICATION GUIDE OR FULL PRESCRIBING INFORMATION (QUESTIONS l8, 19, 20 AND 21): S-la-Respondents who read the Full Prescribing Information (Question 19) and Medication Guide for the TIRF medicine that they dispense (Question 21). S-lb-Respondents who responded ?No? or don?t know? to getting and reading the Full Prescribing Information and to getting and reading the Medication Guide for the TIRF medicine that they dispense. S?la S?lb Read Medication Guide or Did Mt read Medication . . Guide and Full Prescribing ti Full Info Info nes on 262 (95% CI) (95% CI) Question 10: Please answer True, False, or I don?t know for each statement based on the labeling for TIRF medicines. 10b: TIRF medicines are interchangeable with each other regardless of route of administration. 95.4 89.5 False 250 (92.1. 97.6) 34 (752.971) True 6 2.3 0 0.0 I don't know 6 2.3 4 10.5 10c: The conversion of one TIRF medicine for another TIRF medicine may result in a fatal overdose because of differences in the pharmacokinetics of fentanyl absorption. 92.4 89.5 True 242 (88.5. 95.3) 34 (75.2. 97.1) False 3 1.1 2 5.3 I don't know 17 6.5 2 5.3 Client: TRIG Project: TIRF Wave2 Report Run Date and Time: 10/30/2013 3:50:00 PM Page 1 of 2 258 S?la Read Medication Guide or Full Prescribing Info S?lb Did not read Medication Guide and Full Prescribing nestion Info 262 (95% CI) (95% CI) 10d: Dosing of TIRF medicines is not equivalent on a microgram?to-microgram basis. 93.5 76.3 True 245 (89.8. 96.2) 29 (59.8. 88.6) False 6 2.3 4 10.5 I don't know 11 4.2 5 13.2 Correct response Client: TRIG Project: TIRF Wave2 Report Run Date and Time: 10/30/2013 3:50:00 PM Page 2 of 2 259 TABLE 9.1.2 PRIMARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #4 KEY RISK MESSAGE 4: TIRF MEDICINES ARE NOT INTERCHANGEABLE WITH EACH OTHER, REGARDLESS OF ROUTE OF ADMINISTRATION. SUB-GROUP ANALYSIS 2: TIME TO COMPLETE SURVEY INTERNET: S-2a - <10 min 0 S?min Question S?2a S?2b S?min (95% CI) (95% CI) (95% CI) Question 10: Please answer True, False, or I don?t know for each statement based on the labeling for TIRF medicines. 10b: TIRF medicines are interchangeable with each other regardless of route of administration. 92.3 96.1 93.6 False ?1 84 (84.8. 147 (91.7. 44 (82.5. 96.9) 98.5) 98.7) True don't know 2 2.2 6 3.9 2 4.3 10c: The conversion of one TIRF medicine for another TIRF medicine may result in a fatal overdose because of differences in the pharmacokinetics of fentanyl absorption. 91.2 92.2 91.5 True ?1 83 (83.4. 141 (86.7. 43 (79.6. 96.1) 95.9) 97.6) False 2 2.2 0.7 2 4.3 I don't know 6 6.6 11 7.2 2 4.3 10d: Dosing of TIRF medicines is not equivalent on a microgram-to-microgram basis. 87.9 95.4 83.0 True ?1 80 (79.4. 146 (90.8. 39 (69.2. 93.8) 98.1) 92.4) False 6 6.6 3 2.0 2.1 I don't know 5 5.5 4 2.6 7 14.9 Correct response Client: TRIG Project: TIRF Wave2 Report Run Date and Time: 10/31/2013 10:57:00 AM Page 1 of 260 TABLE 9.1.4 PRIMARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #4 KEY RISK MESSAGE 4: TIRF MEDICINES ARE NOT INTERCHANGEABLE WITH EACH OTHER, REGARDLESS OF ROUTE OF ADMINISTRATION. SUB-GROUP ANALYSIS 4: MODALITY TO COMPLETE SURVEY: S-4a - Internet 0 S?4b - Telephone S?4a 84" Internet Telephone Question N=29l (95% CI) (95% CI) Question 10: Please answer True, False, or I don?t know for each statement based on the labeling for TIRF medicines. 10b: TIRF medicines are interchangeable with each other regardless of route of administration. 94.5 100.0 False 275 (91.2. 96.8) 9 (66.4. 100.0) True 6 2.1 0 0.0 I don't know 10 3.4 0 0.0 10c: The conversion of one TIRF medicine for another TIRF medicine may result in a fatal overdose because of differences in the pharmacokinetics of fentanyl absorption. True [11 267 (882: 984.6) 9 False 5 1.7 0 0.0 I don't know 19 6.5 0 0.0 10d: Dosing of TIRF medicines is not equivalent on a microgram?to-microgram basis. True 265 (87.92.9141) 9 (66.132800) False 10 3.4 0 0.0 I don't know 16 5.5 0 0.0 Correct response Client: TRIG Project: TIRF Wave 2 Report Run Date and Time: 10/31/2013 11:04:00 AM Page 1 of 261 TABLE 9.1.5 PRIMARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #4 KEY RISK MESSAGE 4: TIRF MEDICINES ARE NOT INTERCHANGEABLE WITH EACH OTHER, REGARDLESS OF ROUTE OF ADMINISTRATION. SUB-GROUP ANALYSIS 5: TIME PRACTICING AS A PHARMACIST (QUESTION 28): - Less than 3 years 3 to 5 years S?5c 6 to 15 years More than 15 years S?5d Less than 3 years 3 to 5 years 6 to 15 years More than 15 years Question (95% CI) (95% CI) (95% CI) (95% Cl) Question 10: Please answer True, False, or I don?t know for each statement based on the labeling for THIF medicines. 10b: TIRF medicines are interchangeable with each other regardless of route of administration. 87.0 92.7 93.2 96.8 False 20 (66.4. 97.2) 38 (80.1. 98.5) 69 (84.9. 97.8) 152 (92.7. 99.0) True don't know 1.9 Client: TRIG Project: TIRF Wave2 Report Run Date and Time: 10/31/2013 11:11:00 AM Page 1 of 2 262 Question Less than 3 years 3 to 5 years 6 to 15 years More than 15 years (95% CI) (95% CI) (95% CI) (95% CI) 10c: The conversion of one TIRF medicine for another TIRF medicine may result in a fatal overdose because of differences in the pharmacokinetics of fentanyl absorption. True 20 (6635-372) 39 (83.95.9194) 64 (76.?333) 149 (90.921.997.23) False don't know 2 8.7 2 4.9 9 12.2 5 3.2 10d: Dosing of TIRF medicines is not equivalent on a microgram?to-microgram basis. True 20 (66.847872) 39 (83:39.4) 65 (723.827.9843) 146 (87.981365) False don't know 3 13.0 2 4.9 5 6.8 5 3.2 Correct response Client: TRIG Project: TIRF Wave 2 Report Run Date and Time: 10/31/2013 11:11:00 AM Page 2 of 2 263 TABLE 9.1.6 PRIMARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #4 KEY RISK MESSAGE 4: TIRF MEDICINES ARE NOT INTERCHANGEABLE WITH EACH OTHER, REGARDLESS OF ROUTE OF ADMINISTRATION. SUB-GROUP ANALYSIS 6: NUMBER OF TIMES PER MONTH DISPENSED TIRF MEDICINES WITHIN THE LAST 6 MONTHS (QUESTION 25): S?6a - None S-6b - - 2 times per month S-6c - 3 - 5 times per month S?6d More than 5 times per month Question S?6a S?6b S-6c S?6d None 1 - 2 3 - 5 More than 5 (95% CI) (95% CI) (95% CI) (95% CI) Question 10: Please answer True, False, or I don?t know for each statement based on the labeling for TIRF medicines. 10b: TIRF medicines are interchangeable with each other regardless of route of administration. 98.9 93.8 96.9 86.7 False 136 (88.5. 97.1) 89 (940' 31 (83.8. 99.9) 13 (59.5. 98.3) 100.0) True don't know 6.7 Client: TRIG Project: TIRF Wave2 Report Run Date and Time: 10/31/2013 11:19:00 AM Page 1 of 2 264 Question S?6a S-6b S?6c S?6d None 1 2 3 5 More than 5 N=l45 (95% CI) (95% CI) (95% CI) (95% CI) 10c: The conversion of one TIRF medicine for another TIRF medicine may result in a fatal overdose because of differences in the pharmacokinetics of fentanyl absorption. True 133 (862)1g57) 85 (87.?382) 31 (83.92399) 12 (51.899357) False don't know 13.3 10d: Dosing of TIRF medicines is not equivalent on a microgram?to-microgram basis. True 133 (86319757) 86 (89259688) 29 (75239680) 12 (51.29357) False 13.3 I don't know 8 5.5 3 3.3 1 3.1 6.7 Correct response Client: TRIG Project: TIRF Wave 2 Report Run Date and Time: 10/31/2013 11:19:00 AM Page 2 of 2 265 TABLE 9.2 SECONDARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #4 KEY RISK MESSAGE 4: TIRF MEDICINES ARE NOT INTERCHANGEABLE WITH EACH OTHER, REGARDLESS OF ROUTE OF ADMINISTRATION. Eligible and Complete Respondents Demonstrated Understanding 0 correct responses 5 1.7 1 correct response 11 3.7 2 correct responses 29 9.7 3 correct responses 255 85.0 Average number of correct responses 2.8 (2.6. 3.0) One-sided 95 con?dence interval using the normal approximation to the Poisson distribution Client: TRIG Project: TIRF Wave 2 Report Run Date and Time: 10/30/2013 1:52:00 PM Page 1 of 266 TABLE 9.2.1 SECONDARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #4 KEY RISK MESSAGE 4: TIRF MEDICINES ARE NOT INTERCHANGEABLE WITH EACH OTHER, REGARDLESS OF ROUTE OF ADMINISTRATION. SUB-GROUP ANALYSIS 1: READING MEDICATION GUIDE OR FULL PRESCRIBING INFORMATION (QUESTIONS l8, 19, 20 AND 21): S-la-Respondents who read the Full Prescribing Information (Question 19) and Medication Guide for the TIRF medicine that they dispense (Question 21). S-lb-Respondents who responded ?No? or don?t know? to getting and reading the Full Prescribing Information and to getting and reading the Medication Guide for the TIRF medicine that they dispense. S-lb S-la Did not read Medication Read Medication Guide or Guide and Full Demonstrated Understanding Full Prescribing Info Prescribing Info 0 correct responses 3 1.1 2 5.3 1 con'ect response 9 3.4 2 5.3 2 correct responses 22 8.4 7 18.4 3 correct responses 228 87.0 27 71.1 Average number of correct responses 2.8 (2.6. 3.0) 2.6 (2.1. 3.0) ll] One-sided 95 con?dence interval using the normal approximation to the Poisson distribution Client: TRIG Project: TIRF WaveZ Report Run Date and Time: 10/31/2013 11:28:00 AM Page 1 of 267 TABLE 9.2.2 SECONDARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #4 KEY RISK MESSAGE 4: TIRF MEDICINES ARE NOT INTERCHANGEABLE WITH EACH OTHER, REGARDLESS OF ROUTE OF ADMINISTRATION. SUB-GROUP ANALYSIS 2: TIIWE TO COMPLETE SURVEY INTERNET: S-2a - <10 min 0 S?min S-2a S-2b S-min Demonstrated Understanding 0 correct responses 2 2.2 1.3 1 2.1 1 correct response correct responses 14 15.4 11 7.2 4 8.5 3 correct responses 72 79.1 136 88.9 38 80.9 Average number of correct responses 2.7 (2.4. 3.0) 2.8 (2.6. 3.0) 2.7 (2.3. 3.0) One-sided 95 con?dence interval using the nomial approximation to the Poisson distribution Client: TRIG Project: TIRF Wave 2 Report Run Date and Time: 10/31/2013 10:58:00 AM Page 1 of 268 TABLE 9.2.4 SECONDARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #4 KEY RISK MESSAGE 4: TIRF MEDICINES ARE NOT INTERCHANGEABLE WITH EACH OTHER, REGARDLESS OF ROUTE OF ADMINISTRATION. SUB-GROUP ANALYSIS 4: MODALITY TO COMPLETE SURVEY: S-4a - Internet 0 S?4b - Telephone S-4a S-4b Internet Telephone Demonstrated Understanding 0 correct responses 5 1.7 0 0.0 1 correct response 11 3.8 0 0.0 2 c01rect responses 29 10.0 0 0.0 3 correct responses 246 84.5 9 100.0 Average number of correct responses 2.8 (2.6. 3.0) 3.0 (2.1. 3.0) ?1 One-sided 95 con?dence interval using the normal approximation to the Poisson distribution Client: TRIG Project: TIRF Wave2 Report Run Date and Time: 10/31/2013 11:05:00 AM Page 1 of 269 TABLE 9.2.5 SECONDARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #4 KEY RISK MESSAGE 4: TIRF MEDICINES ARE NOT INTERCHANGEABLE WITH EACH OTHER, REGARDLESS OF ROUTE OF ADMINISTRATION. SUB-GROUP ANALYSIS 5: TIME PRACTICING AS A PHARMACIST (QUESTION 28): - Less than 3 years 0 S-5b 3 to 5 years 0 S?5c 6 to 15 years 0 More than 15 years S-5a S-5b S-5c Less than 3 years 3 to 5 years 6 to 15 years More than 15 years Demonstrated Understanding 0 correct responses correct response 13correct responses 0 0.0 5 12.2 12 16.2 12 7.6 3 correct responses 19 82.6 35 85.4 57 77.0 140 89.2 Average number of correct responses 2.6 (2.1. 3.0) 2.8 (2.4. 3.0) 2.7 (2.4. 3.0) 2.8 (2.6. 3.0) One-sided 95 con?dence interval using the normal approximation to the Poisson distribution Client: TRIG Project: TIRF WaveZ Report Run Date and Time: 10/31/2013 11:17:00 AM Page 1 of 270 TABLE 9.2.6 SECONDARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #4 KEY RISK MESSAGE 4: TIRF MEDICINES ARE NOT INTERCHANGEABLE WITH EACH OTHER, REGARDLESS OF ROUTE OF ADMINISTRATION. SUB-GROUP ANALYSIS 6: NUMBER OF TIMES PER MONTH DISPENSED TIRF MEDICINES WITHIN THE LAST 6 MONTHS (QUESTION 25): S?6a None S-6b - - 2 times per month S-6c - 3 - 5 times per month S?6d - More than 5 times per month S-6a S-6b S-6c S-6d None 1 - 2 3 - 5 More than 5 Demonstrated Understanding N=l45 0 correct responses correct response 13.3 2 correct responses 19 13correct responses 120 82.8 82 91.1 29 90.6 11 73.3 Average number of correct 2.8 (2.5. 3.0) ?1 2.9 (2.6. 3.0) ?1 2.8 (2.4. 3.0) ?1 2.5 (1.8. 3.0) ?1 responses One-sided 95 con?dence interval using the normal approximation to the Poisson distribution Client: TRIG Project: TIRF Wave 2 Report Run Date and Time: 10/31/2013 11:22:00 AM Page 1 of 271 Pharmacy KAB Assessment Report Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Appendix C Page 46 of 47 Findings Report: Qualitative Research to Evaluate the Prescriber and Pharmacist 12-month REMS Assessment Surveys for TIRF Medicines FDA_1272 Findings Report: Qualitative Research to Evaluate the Prescriber and Pharmacist 12-month REMS Assessment Surveys for Transmucosal Immediate Release Fentanyl (TIRF) Medicines UBC Contacts: 920 Harvest Drive Suite 200 Blue Bell, PA 19422 www.unitedbiosource.com Megan Leone-Perkins, PhD, Research Lead Blythe Vito, Senior Manager 215-390-1385 16 December 2013 Version 3.0 FDA_1273 TABLE OF CONTENTS TABLE OF CONTENTS ....................................................................................................................................... 2 1 INTRODUCTION ........................................................................................................................................ 3 2 RESEARCH OBJECTIVES .......................................................................................................................... 3 3 RESEARCH DESIGN ................................................................................................................................. 4 3.1 Overview .................................................................................................................................... 4 3.2 Eligibility Criteria......................................................................................................................... 5 3.3 Recruitment................................................................................................................................ 5 3.4 Participant Demographics .......................................................................................................... 6 4 INTERVIEW DESIGN .................................................................................................................................. 6 4.1 Prior to the Interview Session .................................................................................................... 6 4.2 During the Interview ................................................................................................................... 7 5 RESEARCH FINDINGS ............................................................................................................................... 8 5.1 Prescribers ................................................................................................................................. 8 5.1.1 Frame of Reference (Questions 8, new 7, NEW 19) .............................................................. 8 5.1.2 Definition of Opioid Tolerance (Questions 5, 11) ................................................................. 10 5.1.3 Risks Associated with TIRF Medicine Conversion (Question 12) ........................................ 13 5.1.4 Risks associated with CYP3A4 Inhibitor (Question 15) ....................................................... 14 5.2 Pharmacists ............................................................................................................................. 15 5.2.1 Frame of Reference (Questions 5, 8, NEW 7) ..................................................................... 15 5.3 Conclusion ............................................................................................................................... 19 6 APPENDIX A: SURVEY QUESTIONS USED IN QUALITATIVE RESEARCH .................................................... 20 TIRF Medicines Prescriber/Pharmacist Qualitative Research Final Report 2 FDA_1274 1 INTRODUCTION The Food and Drug Administration (FDA) has approved a shared risk evaluation and mitigation strategy (REMS) for the class of transmucosal immediate-release fentanyl (TIRF) products. The products in the TIRF REMS Program include ABSTRAL® (fentanyl) sublingual tablets CII, ACTIQ® (fentanyl citrate) oral transmucosal lozenge CII, FENTORA® (fentanyl buccal tablet) CII, LAZANDA® (fentanyl) nasal spray CII, and ONSOLIS® (fentanyl buccal soluble film) CII, SUBSYS® (fentanyl) sublingual spray CII, as well as generic forms of the aforementioned products. The FDA provided feedback to the TIRF REMS Industry Group (TRIG) on the Knowledge, Attitude, and Behavior survey results for prescribers and pharmacists included in the 12-month REMS Assessment results. The FDA requested that the TRIG investigate the causes for low correct response rates to specific questions in the survey by conducting research to determine the reasons for the poor performance on these questions. The research undertaken included review of the questions identified by the FDA that had low correct response rates, as well as two new questions approved by the TRIG. This document describes how this research was conducted, including a description of research participants, and major findings used to inform KAB survey revisions. 2 RESEARCH OBJECTIVES The purpose of this qualitative research was to investigate the causes for low correct response rates to specific prescriber and pharmacist questions used in the survey administered as part of the TIRF REMS Access Program 12-month REMS Assessment. Additionally, this research was conducted to assess proposed revised wording to select questions, as well as to assess comprehension of two additional questions. The questions reviewed during the qualitative research interviews included the following (see Appendix A for full question sets. Readers should note that the survey content that is displayed in blue font represents proposed revised wording.):   Prescribers reviewed: o 10 items from the Prescriber 12-month REMS Assessment Survey Questions: 5a, 5c, 8e, 11b, 12c, 12d, 15a-d o New questions 7 and 19 Pharmacists reviewed: o 7 items from the Pharmacist 12-month REMS Assessment Survey Questions: 5a, 5c, 8 (a-e); o New question 7 TIRF Medicines Prescriber/Pharmacist Qualitative Research Final Report 3 FDA_1275 The objectives of this research were to:  Evaluate clarity and comprehension of questions and answer options used in the 12month assessment;  Identify terms, questions or topics for clarification or revision based on any areas of confusion with or misunderstanding for current wording;  Determine how participants understand specific questions and why those questions are answered a particular way;  Determine how certain questions might be understood differently and answered more accurately if further clarified;  Evaluate alternative language for these questions. 3 RESEARCH DESIGN 3.1 OVERVIEW (b) (4) TIRF Medicines Prescriber/Pharmacist Qualitative Research Final Report 4 FDA_1276 3.2 ELIGIBILITY CRITERIA (b) (4) 3.3 RECRUITMENT (b) (4) TIRF Medicines Prescriber/Pharmacist Qualitative Research Final Report 5 FDA_1277 3.4 PARTICIPANT DEMOGRAPHICS (b) (4) 4 INTERVIEW DESIGN (b) (4) TIRF Medicines Prescriber/Pharmacist Qualitative Research Final Report 6 FDA_1278 279 TIRF Medicines Prescriber/Pharmacist Qualitative Research Final Report 5 RESEARCH FINDINGS (b) (4) TIRF Medicines Prescriber/Pharmacist Qualitative Research Final Report 8 FDA_1280 281 TIRF Medicines Prescriber/Pharmacist Qualitative Research Final Report 282 TIRF Medicines Prescriber/Pharmacist Qualitative Research Final Report 10 283 TIRF Medicines Prescriber/Pharmacist Qualitative Research Final Report 11 284 TIRF Medicines Prescriber/Pharmacist Qualitative Research Final Report 12 285 TIRF Medicines Prescriber/Pharmacist Qualitative Research Final Report 13 286 TIRF Medicines Prescriber/Pharmacist Qualitative Research Final Report 14 287 TIRF Medicines Prescriber/Pharmacist Qualitative Research Final Report 15 288 TIRF Medicines Prescriber/Pharmacist Qualitative Research Final Report 16 289 TIRF Medicines Prescriber/Pharmacist Qualitative Research Final Report 17 290 TIRF Medicines Prescriber/Pharmacist Qualitative Research Final Report 18 5.3 CONCLUSION (b) (4) TIRF Medicines Prescriber/Pharmacist Qualitative Research Final Report 19 FDA_1291 6 APPENDIX A: SURVEY QUESTIONS USED IN QUALITATIVE RESEARCH The following survey questions were studied during the qualitative research interviews. A hard copy was sent to each participant as appropriate by stakeholder and returned to the research facility after the interviews were completed. Readers should note that survey content displayed in blue font represents alternative survey questions/responses developed for this research. APPENDIX A: Survey Questions Used in Qualitative Research FDA_1292 20 TIRF Medicines Prescriber Survey The Moderator will review the enclosed questions with you during the interview. Please do not fill in the answer choices. This document is only meant to guide your discussion with the Moderator. APPENDIX A: Survey Questions Used in Qualitative Research FDA_1293 21 294 APPENDIX A: Survey Questions Used in Qualitative Research 295 APPENDIX A: Survey Questions Used in Qualitative Research 296 APPENDIX A: Survey Questions Used in Qualitative Research 297 APPENDIX A: Survey Questions Used in Qualitative Research 298 APPENDIX A: Survey Questions Used in Qualitative Research 299 APPENDIX A: Survey Questions Used in Qualitative Research 300 APPENDIX A: Survey Questions Used in Qualitative Research TIRF Medicines Pharmacist Survey The Moderator will review the enclosed questions with you during the interview. Please do not fill in the answer choices. This document is only meant to guide your discussion with the Moderator. APPENDIX A: Survey Questions Used in Qualitative Research FDA_1301 29 302 APPENDIX A: Survey Questions Used in Qualitative Research 303 APPENDIX A: Survey Questions Used in Qualitative Research 304 APPENDIX A: Survey Questions Used in Qualitative Research Pharmacy KAB Assessment Report Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Appendix D Page 47 of 47 Pharmacy Survey Protocol Track Change Document: Comparison of 12-month Survey to 24-month Survey FDA_1305 PROTOCOL TITLE: Quantitative Testing of Pharmacist Knowledge, Attitudes, and Behavior about Transmucosal Immediate Release Fentanyl (TIRF) Products Safety and Use Information SPONSOR: TIRF REMS Industry Group (TRIG) Archimedes Pharma US Inc. Cephalon, Inc. (a wholly-owned subsidiary of Teva Pharmaceutical Industries, Ltd.) Endo Pharmaceuticals Inc. Galena Biopharma Insys Therapeutics Mallinckrodt, the Pharmaceuticals Business of Covidien Meda Pharmaceuticals Mylan, Inc. Par Pharmaceutical, Inc. VERSION: 54.0 DATE: 10 Sep22 May 2013 APPROVED: FINAL FDA_1306 TIRF REMS Industry Group (TRIG) Transmucosal Immediate Release Fentanyl (TIRF) Products Pharmacist KAB Survey Protocol TABLE OF CONTENTS Version 54 0 10 Sep21 May 2013 PAGE TABLE OF CONTENTS ......................................................................................... 2 1. LIST OF ABBREVIATIONS .................................................................................. 3 2. BACKGROUND ..................................................................................................... 4 3. OBJECTIVES OF THE EVALUATION SURVEY ............................................... 5 4. METHODS .............................................................................................................. 5 4.1 4.1.1 4.1.2 4.1.3 Survey Design .......................................................................................................... 5 Qualitative Research on the Survey ......................................................................... 6 Questions and Statements on REMS Goals ............................................................. 6 Additional Questions.............................................................................................. 10 4.2 4.2.1 Participant Recruitment.......................................................................................... 11 Measures to Minimize Bias in the Sample............................................................. 11 5. 5.1.1 5.1.2 5.1.3 STUDY POPULATION ........................................................................................ 11 Sample Size ............................................................................................................ 11 Inclusion Criteria.................................................................................................... 12 Exclusion Criteria .................................................................................................. 12 6. SURVEY PROCESS ............................................................................................. 13 6.1 6.1.1 6.1.2 Screening and Survey Administration ................................................................... 13 Telephone ............................................................................................................... 13 Internet ................................................................................................................... 13 6.2 Measures to Minimize Bias in the Survey Process ................................................ 13 7. 7.1.1 7.1.1.1 7.1.1.2 ANALYSIS ............................................................................................................ 14 Analysis Population ........................................................................................... 1413 Description of Primary Analyses ........................................................................... 14 Description of Secondary Analyses ................................................................... 1514 8. SAFETY EVENT REPORTING ........................................................................... 15 9. PRIVACY PROTECTION AND CONFIDENTIALITY.................................. 1514 LIST OF APPENDICES Appendix A Pharmacist Questionnaire ......................................................................... 16 Appendix B Pharmacist Invitation Letter ................................................................. 3432 Appendix C Qualitative Research Report ................................................................. 3634 2 of 36 FDA_1307 TIRF REMS Industry Group (TRIG) Transmucosal Immediate Release Fentanyl (TIRF) Products Pharmacist KAB Survey Protocol 1. Version 54 0 10 Sep21 May 2013 LIST OF ABBREVIATIONS CATI CSP CI EDC ETASU FDA HIPAA ISI KAB PI REMS SE/PSP TIRF TIRF REMS TRIG UBC US Computer-Assisted Telephone Interviewing Closed System Pharmacy Confidence Interval Electronic Data Capture Elements to Assure Safe Use Food and Drug Administration Health Insurance Portability and Accountability Act Important Safety Information Knowledge, Attitudes and Behavior Prescribing Information Risk Evaluation and Mitigation Strategy Safety Event Project Specific Procedure Transmucosal Immediate Release Fentanyl TIRF REMS Access Program TIRF REMS Industry Group United BioSource Corporation United States 3 of 36 FDA_1308 TIRF REMS Industry Group (TRIG) Transmucosal Immediate Release Fentanyl (TIRF) Products Pharmacist KAB Survey Protocol 2. Version 54 0 10 Sep21 May 2013 BACKGROUND Transmucosal Immediate Release Fentanyl (TIRF) medicines include the class of immediaterelease opioid analgesics that are indicated only for the management of breakthrough pain in cancer patients 18 years of age or older (16 or older for Actiq® and equivalent generics) who are already receiving and already tolerant to opioid therapy for their underlying persistent cancer pain. The TIRF medicines include Abstral®, Actiq®, Fentora®, Lazanda®, Onsolis®, Subsys®, and generic versions of any of these brands. The TIRF REMS Industry Group (TRIG) includes Archimedes Pharma US Inc.; Cephalon, Inc. (a wholly-owned subsidiary of Teva Pharmaceutical Industries, Ltd.); Endo Pharmaceuticals Inc.; Galena Biopharma; Insys Therapeutics; Meda Pharmaceuticals; Mallinckrodt; Mylan, Inc.;, the Pharmaceuticals Business of Covidien; and Par Pharmaceutical, Inc. The Food and Drug Administration (FDA) has determined that a class-wide Risk Evaluation and Mitigation Strategy (REMS) is required to mitigate the risk of misuse, abuse, addiction, overdose, and serious complications due to medication errors with the use of TIRF medicines. The TIRF REMS Access Program (hereafter referred to as TIRF REMS) was approved by the FDA on December 28, 2011. The TIRF REMS consists of a Medication Guide, Elements to Assure Safe Use (ETASU), an Implementation System, and a timetable for submission of assessments of the REMS. The goals of the TIRF REMS are to mitigate the risk of misuse, abuse, addiction, overdose and serious complications due to medication errors by: 1. Prescribing and dispensing TIRF medicines only to appropriate patients, which includes use only in opioid-tolerant patients 2. Preventing inappropriate conversion between TIRF medicines 3. Preventing accidental exposure to children and others for whom it was not prescribed 4. Educating prescribers, pharmacists, and patients on the potential for misuse, abuse, addiction, and overdose of TIRF medicines An important component of the TIRF REMS is the conduct of quantitative evaluation surveys to assess pharmacists’ understanding and knowledge of the safe use and appropriate prescribing of TIRF medicines as described in the TIRF REMS educational materials, enrollment form, and Prescribing Information (PI). This protocol will describe the administration of the surveys that will be conducted among pharmacists who are enrolled in the TIRF REMS Access Program. Data from the surveys, together with other REMS evaluation metrics, will be used to determine whether changes need to be made to the REMS processes or educational materials to make them more effective in achieving the goals of the REMS. 4 of 36 FDA_1309 TIRF REMS Industry Group (TRIG) Transmucosal Immediate Release Fentanyl (TIRF) Products Pharmacist KAB Survey Protocol Version 54 0 10 Sep21 May 2013 The surveys will be implemented so that data will be available for inclusion in the REMS Assessment Reports that will be submitted to the FDA at 12 months after approval of the TIRF REMS and annually thereafter. 3. OBJECTIVES OF THE EVALUATION SURVEY The evaluation survey will use a questionnaire to document the level of knowledge and assess the attitudes and behavior of pharmacists around the following key information and risk messages communicated through REMS: 1. TIRF medicines are contraindicated in opioid non-tolerant patients. 2. TIRF medicines are only indicated for the management of breakthrough pain in adult cancer patients 18 years of age and older (16 or older for Actiq® and equivalent generics) who are already receiving and who are tolerant to around-the-clock opioid therapy for their underlying persistent cancer pain. 3. TIRF medicines contain fentanyl, an opioid agonist and a Schedule II controlled substance, with abuse liability similar to other opioid analgesics. 4. TIRF medicines are not interchangeable with each other, regardless of route of administration. 5. Patients and their caregivers must be instructed that TIRF medicines contain a medicine in an amount that can be fatal in children, in individuals for whom it is not prescribed, and in those who are not opioid tolerant. The survey will also collect data on behaviors, such as receipt and use of educational materials and compliance with REMS requirements. 4. METHODS The survey was designed in collaboration between the TRIG and United BioSource Corporation (UBC), and will be administered by UBC. 4.1 Survey Design This survey will be conducted among a sample of pharmacists who are enrolled in the TIRF REMS Access Program. Respondents who have participated in the first wave of the TIRF survey will not be eligible to participate in subsequent survey waves. The survey will be administered using the following modalities:  Self-administered via the Internet through a secure website 5 of 36 FDA_1310 TIRF REMS Industry Group (TRIG) Transmucosal Immediate Release Fentanyl (TIRF) Products Pharmacist KAB Survey Protocol  Version 54 0 10 Sep21 May 2013 Telephone surveys facilitated by a trained interviewer from the Survey Coordinating Center using a computer-assisted telephone interviewing (CATI) program The survey will begin with screening questions to confirm respondent eligibility to participate in the survey. Completion of the entire survey is expected to take up to 20 minutes. The survey included in Appendix A is written to reflect wording for both methods of survey administration: Internet-based and telephone. All respondents who complete the survey and who provide their contact information will be mailed a $50 honorarium for their time. 4.1.1 Qualitative Research on the Survey The FDA provided feedback to the TRIG on the KAB survey results for pharmacists included in the 12-month REMS Assessment results. The FDA requested that the TRIG investigate the causes for low correct response rates to specific questions in the survey by conducting research to determine the reasons for the poor performance on these questions, and to assess proposed revised wording to select questions. Qualitative research was performed with 7 pharmacists who were recruited from the list of pharmacists who completed surveys for the 12-month TIRF REMS Assessment and met the definition of “low performer”, i.e., provided an incorrect response on 3 to 5 of the 7 targeted responses/questions from the 12-month TIRF REMS Assessment. Among the pharmacists interviewed, the most notable finding was that their survey responses should be based on (“according to”) the TIRF medicines label. The findings from this research have been incorporated into the survey in Appendix A. The qualitative research report can be found in Appendix C. 4.1.2 Questions and Statements on REMS Goals The Knowledge, Attitudes, and Behaviors (KAB) questionnaire is made up of multiplechoice, close-ended statements or questions (the majority of which use true/false or yes/no dichotomous response options), and one open-ended question. These will evaluate current knowledge, attitudes, and behavior regarding the key risk messages noted in Section 3. Questions will be presented in several formats:  Statements or questions asking the respondent to indicate whether a statement or question is true or false, or if they do not know the answer (there is a similar set of statements and questions that use “yes” or “no” as potential response options);  Statements or questions asking the respondent to choose from a defined list of possible statements or answers; and  One question allowing for the respondent to list questions or comments. 6 of 36 FDA_1311 TIRF REMS Industry Group (TRIG) Transmucosal Immediate Release Fentanyl (TIRF) Products Pharmacist KAB Survey Protocol Version 54 0 10 Sep21 May 2013 Questionnaires will be analyzed to determine pharmacist understanding of each key risk message. For statements or questions that use “true” or “yes” vs. “false” or “no” response options, the desired response for the key risk messages is generally “true” or “yes” indicating knowledge of, or behavior in accordance with, the objectives of the REMS. However, some questions are formatted to have the respondent disagree with the statement as written by providing response options of “false” or “no” to avoid having the same affirmative answer for all desired responses. REMS statements, corresponding questions, and desired responses covering the key risk messages are identified below and can be found in the complete survey questionnaire (Appendix A). 7 of 36 FDA_1312 TIRF REMS Industry Group (TRIG) Transmucosal Immediate Release Fentanyl (TIRF) Products Pharmacist KAB Survey Protocol Version 54 0 10 Sep21 May 2013 Key Risk Message 1: TIRF medicines are contraindicated in opioid non-tolerant patients. Question No. 5 5a 5b 5c 7 7a 7b 7c 7d Question Desired response Please select True, False, or I don’t know for each of the following. According to the labeling for TIRF medicines, patients with cancer who are considered opioid-tolerant are those: Who are taking around-the-clock opioid therapy for underlying persistent cancer pain for one week or TRUE longer Who are not currently taking opioid therapy, but FALSE have taken opioid therapy before Who have no known contraindications to the drug fentanyl, but are not currently taking around-theFALSE clock opioid therapy Please answer “True, ,” “False,,” or “I don’t know” for each statement based on the labeling for TIRF medicines. TIRF medicines are contraindicated in opioid nontolerant patients because life-threatening respiratory TRUE depression could occur at any dose. Death has occurred in opioid non-tolerant patients TRUE treated with some fentanyl products. TIRF medicines may be used in opioid non-tolerant FALSE patients. Prescribers starting a patient on a TIRF medicine must begin with titration from the lowest dose TRUE available for that specific product, even if the patient has previously taken another TIRF medicine. 8 of 36 FDA_1313 TIRF REMS Industry Group (TRIG) Transmucosal Immediate Release Fentanyl (TIRF) Products Pharmacist KAB Survey Protocol Version 54 0 10 Sep21 May 2013 Key Risk Message 2: TIRF medicines are only indicated for the management of breakthrough pain in adult cancer patients 18 years of age and older (16 years of age and older for Actiq® brand and generic equivalents) who are already receiving and who are tolerant to around-theclock opioid therapy for their underlying persistent cancer pain. Question No. 9 9a 9b 9c 9d 9e Question Desired response Per the approved labeling for TIRF medicines, for which of the following indications can TIRF medicines be prescribed to opioid tolerant patients? Please answer Yes, No, or I don’t know for each option. Acute or postoperative pain NO Headache or migraine pain NO Dental pain NO Breakthrough pain from cancer YES Chronic non-cancer pain NO Key Risk Message 3: TIRF medicines contain fentanyl, an opioid agonist and a Schedule II controlled substance with abuse liability similar to other opioid analgesics. Question No. 7 7e 80 8a 8b 10 10a Question Desired response Please answer “True, ,” “False,,” or “I don’t know” for each statement based on the labeling for TIRF medicines. It is important to monitor for signs of abuse and addiction in patients who take TIRF TRUE medicines. Which of the following are risk factors for opioid abuse? Please answer Yes, No, or I don’t know for each option. A personal history of psychiatric illness YES A personal history of past or current alcohol or drug abuse, or a family history of YES illicit drug use or alcohol abuse Please answer True, False, or I don’t know for each statement based on the labeling for TIRF medicines. TIRF medicines can be abused in a manner TRUE similar to other opioid agonists. 9 of 36 FDA_1314 TIRF REMS Industry Group (TRIG) Transmucosal Immediate Release Fentanyl (TIRF) Products Pharmacist KAB Survey Protocol Version 54 0 10 Sep21 May 2013 Key Risk Message 4: TIRF medicines are not interchangeable with each other, regardless of route of administration. Question No. 10 10b 10c 10d 4.1.3 Question Desired response Please answer True, False, or I don’t know for each statement based on the labeling for TIRF medicines. TIRF medicines are interchangeable with each other regardless of route of FALSE administration. The conversion of one TIRF medicine for another TIRF medicine may result in a fatal TRUE overdose because of differences in the pharmacokinetics of fentanyl absorption. Dosing of TIRF medicines is not equivalent TRUE on a microgram-to-microgram basis. Additional Questions The survey includes questions about the requirements of the TIRF REMS Access Program, receipt and understanding of the TIRF educational materials, and behaviors. The following question about behaviors will be asked after the key risk message questions. Question 12: How frequently do you perform the following activities when dispensing TIRF medicines? Please answer Always, Only with the first prescription, Sometimes, Never, or I don’t know. Ask patients (or their caregivers) about the presence of children in the home Instruct patients (or their caregivers) not to share TIRF medicines with anyone else Counsel patients (or their caregivers) that accidental exposure to TIRF medicines by a child may be fatal Instruct patients (or their caregivers) to keep TIRF medicines out of the reach of children to prevent accidental exposure Instruct patients (or their caregivers) about proper disposal of any unused or partially used TIRF medicines Give patients (or their caregivers) the Medication Guide for their TIRF medicine Demographic information will be collected at the end of the survey. 10 of 36 FDA_1315 TIRF REMS Industry Group (TRIG) Transmucosal Immediate Release Fentanyl (TIRF) Products Pharmacist KAB Survey Protocol 4.2 Version 54 0 10 Sep21 May 2013 Participant Recruitment A random sample of “pharmacists in charge” from pharmacies that are enrolled in the TIRF REMS Access Program will be invited to participate via an invitation letter. Any pharmacist who works at an enrolled pharmacy may participate. The text of the sample written invitation to pharmacists can be found in Appendix B. If the required number of completed surveys is not achieved within the expected timeframe of approximately one to two weeks after the first mailing, reminder letters will be sent to nonrespondents from the original sample with subsequent fax, e-mail, or United States (US) Mail follow-up to maximize participation. The distribution within the mailing to the second sample will be adjusted in accordance with the allocation in the original sample. If these efforts do not result in the required number of surveys within two to three weeks, then a new sample of pharmacists will be randomly selected. The unique code provided in the invitation letter will be linked to the type of pharmacy (inpatient, outpatient, or Closed System Pharmacy [CSP]) in which the pharmacist works, based on the information provided as part of the TIRF REMS Access Program enrollment. All respondents who complete the survey and who provide their contact information will be mailed a $50 honorarium to thank them for their participation. The mailing will include a Thank You Letter, a copy of the Important Safety Information (ISI), and a copy of the correct answers to key risk message questions. 4.2.1 Measures to Minimize Bias in the Sample The sample of participating pharmacists will be self-selected since respondents will voluntarily respond to the invitation to participate; however, the survey recruitment strategies are intended to recruit a heterogeneous sample of pharmacies (e.g., chain and independent store) for participation. Pharmacists will be offered Internet-based or telephone options for completing the survey. Multiple modalities for survey data collection allow for wider survey access to a more heterogeneous population. Respondents will be provided a unique code during the recruitment process and will be asked to provide the unique code to gain access to the Internet-based survey or when calling the Survey Coordinating Center. The code will be deactivated after use to minimize the possibility for fraud. 5. STUDY POPULATION 5.1.1 Sample Size A sample of 300 pharmacists who are enrolled in the TIRF REMS Access Program is proposed for each survey wave. The size of the sample was determined based on both practical and statistical considerations. There is no target comprehension rate specified a priori. A sample of 300 completed surveys will allow estimation of the comprehension rate 11 of 36 FDA_1316 TIRF REMS Industry Group (TRIG) Transmucosal Immediate Release Fentanyl (TIRF) Products Pharmacist KAB Survey Protocol Version 54 0 10 Sep21 May 2013 for each risk message with a moderately high degree of precision. The table below shows the precision of the estimates for level of understanding using two-sided 95% confidence intervals (CIs) obtained with the sample size of 300 completed surveys. The noted CIs are used to indicate that for any survey-estimated rate of understanding, the true population rate of understanding is at least as high as the lower limit of the 95% CI and may be as high as the upper limit of the 95% CI. Table 5.1: Precision of Estimated Rates of Understanding with a Sample Size of 300 Estimated Rate of Understanding 5% 10% 15% 20% 25% 30% 35% 40% 45% 50% 55% 60% 65% 70% 75% 80% 85% 90% 95% 5.1.2 Estimated Confidence Interval 2.8% 6.8% 11.2% 15.6% 20.2% 24.9% 29.6% 34.4% 39.3% 44.2% 49.2% 54.2% 59.3% 64.5% 69.7% 75.0% 80.4% 86.0% 91.9% 8.1% 14.0% 19.6% 25.0% 30.3% 35.5% 40.7% 45.8% 50.8% 55.8% 60.7% 65.6% 70.4% 75.1% 79.8% 84.4% 88.8% 93.2% 97.2% Inclusion Criteria Pharmacists who work at pharmacies that are enrolled in the TIRF REMS Access Program are eligible to participate in this survey, with the exceptions noted below. 5.1.3 Exclusion Criteria The following respondents are not eligible to participate in the surveys:  Pharmacists who have previously participated in the TIRF REMS KAB survey.  Pharmacists or their immediate family members who have ever worked for Anesta LLC, Archimedes Pharma US Inc.; Cephalon, Inc. (a wholly-owned subsidiary of Teva Pharmaceutical Industries, Ltd.); Endo Pharmaceuticals Inc.; Galena Biopharma; Insys Therapeutics; Mallinckrodt, the Pharmaceuticals business of Covidien; Meda Pharmaceuticals; Mylan, Inc.; Par Pharmaceutical, Inc.; ProStrakan, Inc.; Teva Pharmaceuticals, Ltd.; UBC; McKesson Specialty Care Solutions; RelayHealth;or the FDA. 12 of 36 FDA_1317 TIRF REMS Industry Group (TRIG) Transmucosal Immediate Release Fentanyl (TIRF) Products Pharmacist KAB Survey Protocol 6. Version 54 0 10 Sep21 May 2013 SURVEY PROCESS The survey will begin with screening questions to confirm respondent eligibility to participate in the survey. Completion of the entire survey is expected to take approximately 20 minutes. 6.1 Screening and Survey Administration The questionnaire will begin with a screening module with questions to confirm pharmacist eligibility. Depending on the answers to the screening questions, survey participation could either be terminated or continued. If ineligible, the respondent is immediately notified with a “thank you” message that survey participation has ended. If eligible, the respondent is allowed to continue survey participation. The data entry system used for both methods of survey administration has been validated and is secure for receiving and storing survey data. An Internet-based data repository will be used to store survey data and other relevant program information. The system is 21 CFR Part 11 and Health Insurance Portability and Accountability Act (HIPAA) compliant. Pharmacistidentifying information will be stored separately from survey data. 6.1.1 Telephone A trained interviewer from the Survey Coordinating Center will conduct the telephone interviews using a CATI program. The screening and main elements of the questionnaire will be administered sequentially during the same telephone call. Telephone interviewing allows participation of pharmacists who do not have Internet access or prefer taking the survey over the telephone. It will also be convenient for pharmacists to participate since they can call in and be interviewed at their convenience during the specified time period when the Survey Coordinating Center is available. 6.1.2 Internet An Internet-based survey system will also be used for conducting the KAB surveys. If the pharmacist selects to participate in the survey via the Internet, he/she will be directed to a secured website where he/she will be instructed to complete screening questions. An Internetbased survey will be convenient for respondents to participate since they can complete the questionnaire at any convenient time and location during the specified time period when the Survey Coordinating Center is available. 6.2 Measures to Minimize Bias in the Survey Process A number of controls will be in place to ensure the survey is conducted in a controlled and professional manner and to minimize bias. For example, a unique code will be given to each survey participant and the code will be inactivated after use to minimize fraud. Telephone interviewers are highly trained and use a standardized script to administer interviews. All questions will be programmed to ensure that questions are asked in the appropriate sequence. Skip patterns will be clearly indicated. Respondents cannot go back to a question 13 of 36 FDA_1318 TIRF REMS Industry Group (TRIG) Transmucosal Immediate Release Fentanyl (TIRF) Products Pharmacist KAB Survey Protocol Version 54 0 10 Sep21 May 2013 once the question has been answered and cannot skip ahead. All questions must be answered in order to complete the survey. Response options presented in a list will be randomized to minimize positional bias. Programming will be reviewed by quality control and simulated users (User Acceptance Testing) prior to implementing the survey. 7. ANALYSIS Information obtained from the survey will be reported as descriptive statistics for the survey administration, study population, and the survey questions. The data from the sample population will be reported using frequency distributions of responses to all questions. The following will be reported as part of this analysis:  The number of invitations issued to pharmacists  The number of reminder letters issued to pharmacists  The number of respondents screened for participation  The number of respondents eligible for participation  The number of respondents eligible for participation who answered all questions presented to themcompleted the survey  Representativeness of pharmacists based on geography  Description of survey participants, including: o Gender o Years of professional experience o How many times per month TIRF medicines dispensed in the last 6 months Additional descriptive statistics may be reported as appropriate. 7.1.1 Analysis Population The analysis population will be based on eligible pharmacists who completed all questions presented to them in the survey (“completers”). 7.1.2 Description of Primary Analyses Primary analyses are done for all key risk messages using data from all completers. The primary analysis for a key risk message evaluates the rate for each correct response to each individual question/item defined by the key risk message. The specific correct response to each question/item is identified in the body of the risk message table. 14 of 36 FDA_1319 TIRF REMS Industry Group (TRIG) Transmucosal Immediate Release Fentanyl (TIRF) Products Pharmacist KAB Survey Protocol 7.1.3 Version 54 0 10 Sep21 May 2013 Description of Secondary Analyses Secondary analyses are done only for those key risk messages that contain multiple questions/items using data from all completers.. The secondary analysis entails a frequency distribution of the number of completersrespondents who got 0, 1, etc. correct responses across the total number of items for the given key risk message. 7.1.4 Analysis Population The analysis population will be based on eligible pharmacists who completed the survey. 8. SAFETY EVENT REPORTING The term ‘Safety Event’ is defined as any information reported by a survey respondent that meets the criteria of an adverse event or product complaint. While it is not the intention of the survey to solicit the report of information that meets the criteria of a Safety Event, it is possible that a respondent may spontaneously report information that meets this criteria in free text fields of the survey (Internet-based administration) or while in conversation with the Survey Coordinating Center (telephone-based administration). The Internet-based questionnaires will be monitored for any comments recorded in the free text fields. If an event is mentioned to a Survey Coordinating Center Associate, the Associate will document the safety event and the respondent’s contact information. Respondents will also be informed that a representative from the appropriate TIRF medicine manufacturer may contact them if they have questions about the survey. Information on all reports (Internet or telephone) that may constitute an adverse event or other safety event will be forwarded to the appropriate TIRF medicine manufacturer as described in the Safety Event Project Specific Procedure (SE/PSP). Additional detail regarding processes for adverse event reporting will be specified in the SE/PSP. 9. PRIVACY PROTECTION AND CONFIDENTIALITY All data collected during the survey will be held confidential. The electronic data capture (EDC) system used for data collection encrypts all identifiable information, and respondent identifiers are stored separately from the survey responses. Respondent names and addresses are collected in order to mail the $50 honorarium, a Thank You Letter, correct survey responses to key risk message questions, and the ISI after the survey is completed. Respondent contact information is also needed in the event that a safety event is reported and a TIRF medicine manufacturer must obtain follow-up information (see Section 8 above). Respondents will be informed when they access the survey that they may be contacted if there are any questions about their survey responses. Respondents will be informed that their answers to the survey questions will not affect their ability to dispense TIRF medicines. 15 of 36 FDA_1320 TIRF REMS Industry Group (TRIG) Transmucosal Immediate Release Fentanyl (TIRF) Products Pharmacist KAB Survey Protocol Appendix A Version 54 0 10 Sep21 May 2013 Pharmacist Questionnaire Survey Legend  [PROGRAMMER] is used to indicate directions to the programmer and is set in bold, red, uppercase letters between square brackets.  (INTERVIEWER) is used to indicate directions to the telephone interviewer and is set in bold, blue, text between parentheses. This text appears when content is to be administered by telephone only (for example, spontaneous adverse event reporting).  [ONLINE] indicates a question is worded specifically for administering the survey online. [PHONE] indicates a question is worded specifically to be read by a telephone interviewer and differs from the online text.  [BEGIN ONLINE/PHONE SURVEY CONTENT] and [END SURVEY CONTENT] are used to indicate to the programmer the type of survey administration and the beginning and end of the survey or sections within the survey content, for example, [BEGIN ADVERSE EVENT/PRODUCT COMPLAINT] and [END ADVERSE EVENT/PRODUCT COMPLAINT].  [TERMINATE] is displayed next to responses that should cause the survey to end. The following termination language will be programmed into the survey or read by the interviewer unless different language is specified with the question. Thank you very much for your time today. Based on your answer, you are not eligible to take this survey. We appreciate your interest in the survey.  [RANDOMIZE LIST] is inserted before questions to indicate to the programmer that the responses should be randomized. Responses such as “I don’t know,” “Prefer not to answer” or “None of the above” will always appear at the end of the randomized responses.  [GO TO Qx] (skip logic) is inserted after a response to indicate to the programmer that the survey should skip to the indicated question (for example, [GO TO Q17] skips to question 17). If no skip logic is indicated the survey continues to the next question in the sequence.  [MULTILINE INPUT] indicates to the programmer that multiple lines should be provided for data entry (for example, two address lines or a free-text response). 16 of 36 FDA_1321 TIRF REMS Industry Group (TRIG) Transmucosal Immediate Release Fentanyl (TIRF) Products Pharmacist KAB Survey Protocol Version 54 0 10 Sep21 May 2013 Survey Legend  [DROP-DOWN LIST INPUT WITH STATES TABLE] indicates to the programmer that the response should be a drop-down list containing the states in the table below. Alabama Georgia Massachusetts New York Tennessee Alaska Guam Michigan North Carolina Texas American Samoa Hawaii Minnesota North Dakota Arizona Idaho Mississippi Illinois Missouri Indiana Montana Northern Mariana Islands US Virgin Islands Iowa Nebraska Kansas Nevada Kentucky New Hampshire Louisiana New Jersey Maine New Mexico Arkansas California Colorado Connecticut Delaware District of Columbia Florida Maryland Ohio Oklahoma Oregon Pennsylvania Puerto Rico Rhode Island Utah Vermont Virginia Washington West Virginia Wisconsin Wyoming South Carolina South Dakota The following is used to categorize survey populations into standard geographic regions but it is not displayed in the survey. Geographic Distribution (based on address) 1: Northeast, Midwest, South, and West regions Northeast Region   New England Division - ME, NH, VT, MA, RI, CT Middle Atlantic Division - NY, NJ, PA Midwest Region   East North Central Division - OH, IN, IL, MI, WI West North Central Division - MN, IA, MO, ND, SD, NE, KS South Region   South Atlantic Division - DE, MD, DC, VA, WV, NC, SC, GA, FL East South Central Division - KY, TN, AL, MS West South Central Division - AR, LA, OK, TX West  Mountain Division - MT, ID, WY, CO, NM, AZ, UT, NV 17 of 36 FDA_1322 (TRIG) Version?40 Immdiate Releue Fenianyl (FIRE Products Phannadst KAB Survey Protocol 2013 Survey Legend Paci?c Division WA, OR CA, AK HI The following US territories are categorized as Other: Puerto Rico, Northern Mariana Islands, US Virgin Islands, American Samoa, and Guam. 1 US. Census Bureau, last revised Friday, 27-Jul-2001 12:59:43 EDT. WSURVEY WIONLINE PREAIVIBLE 1] Before you begin. we would like to share some important infounation about this survey. The manufacturers of Transmucosal Immediate Release Fentanyl (TIRF) medicines are conducting this survey. as required by the FDA. to assess pharmacists? understanding of the safe use and dispensing of these medicines. These medicines are known as rapid onset opioids and referred to in this survey as medicines.? The TIRF medicines include Abstra1?. Actig?, Fe11tora?. Lazanda'EI. Onsolis?. Subsys?. and generic versions of any of these brands. The manufacturers of these medicines include Archimedes Pharma US Inc. Cephalon: Inc. (a Inc.: Galena Biophanna: Insys Theiapeutics: Mallincklodt: Meda Pharmaceuticals; Mylan Inc. and Par Pharmaceutical. Inc. The survey will take 15-20 minutes. There are no known risks to you in taking this survey. You may refuse to take part or withdraw at any time. Your answers to the questions or your decision to take part in the survey will not affect your ability to dispense TIRF medicines. WHOW We Use Your Information] . . l. 18 of36 WDm?H-?kaleuemtht?iis title of?npreanble 323 (TRIG) Version?40 Immdiate Release Fenianyl (TIRE Products Pharmacist KAB Survey Protocol 2013 Your answers to the survey questions will be combined with answers given by other pharmacists taking the survey. All answers will be put together and reported in anonymous form to the manufacturers of TIRF medicines. Your name will not be used in any report. If you are eligible to take the survey. complete all the questions. and provide your contact information. you will receive a $50 honorarium for your time and participation. Your name and address will be used to send you the honorarium after you complete the survey. Your personal information will also be used if we have questions about your survey or if we are required to use your information to comply with a federal or state law or regulation. Providing a telephone number is optional. Your telephone number will be used only if there are any questions about your survey responses. WHW We Protect Your rivacyl Comment title - ofthepxunble We respect that the privacy of your personal information is important to you. You will not be contacted for marketing purposes based on your personal information or your answers to the survey. Neither the manufacturers of TIRF medicines nor their contractors will sell. transfer. or rent your information. Your answers will be kept strictly con?dential. Your privacy will be protected; however. research survey records may be inspected by the FDA. Your choice to allow manufacturers of TIRF medicines to use your information is entirely voluntary but necessary to take part in this survey. WHOW to Learn More about This Surveyl Comment [24mos3]: mm pleasenotethanhis underlined is planned onlim as a title he.? fthe?ollowmg' you have questions about the survey. or problems with the survey. ofmmi. please contact the Survey Coordinating Center at 1-877-379-3297. Be sure to write down this telephone number: it will not be displayed again. Taking the Survey Once you have answered a question and moved 011. you cannot go back and change your answers. Thank you for your participation in this survey. ONLINE PREANIBLE 1 19 of36 324 TIRF REMS Industry Group (TRIG) Transmucosal Immediate Release Fentanyl (TIRF) Products Pharmacist KAB Survey Protocol Version 54 0 10 Sep21 May 2013 [PHONE PREAMBLE 1] Before you begin, we would like to share some important information about this survey. The manufacturers of Transmucosal Immediate Release Fentanyl (TIRF) medicines are conducting this survey, as required by the FDA, to assess pharmacists’ understanding of the safe use and dispensing of these medicines. These medicines are known as rapid onset opioids and referred to in this survey as “TIRF medicines.” (INTERVIEWER: Say “TIRF” then spell out T-IR-F) The TIRF medicines include Abstral®, Actiq®, Fentora®, Lazanda®, Onsolis®, Subsys®, and generic versions of any of these brands. The manufacturers of these medicines include Archimedes Pharma US Inc.; Cephalon, Inc. (a wholly-owned subsidiary of Teva Pharmaceutical Industries, Ltd.); Endo Pharmaceuticals Inc.; Galena Biopharma; Insys Therapeutics; Mallinckrodt; Meda Pharmaceuticals; Mylan, Inc.; and Par Pharmaceutical, Inc. The survey will take 15-20 minutes. There are no known risks to you in taking this survey. You may refuse to take part or withdraw at any time. Your answers to the questions or your decision to take part in the survey will not affect your ability to dispense TIRF medicines. Now I would like to read some information about how your contact information will be used. Your answers to the survey questions will be combined with answers given by other pharmacists taking the survey. All answers will be put together and reported in anonymous form to the manufacturers of TIRF medicines. Your name will not be used in any report. If you are eligible to take the survey, complete all the questions, and provide your contact information, you will receive a $50 honorarium for your time and participation. Your name and address will be used to send you the honorarium after you complete the survey. Your personal information will also be used if we have questions about your survey or if we are required to use your information to comply with a federal or state law or regulation. Providing a telephone number is optional. Your telephone number will be used only if there are any questions about your survey responses. Now I would like to tell you some information about how we protect your privacy. We respect that the privacy of your personal information is important to you. You will not be contacted for marketing purposes based on your personal information or your answers to the survey. Neither the manufacturers of TIRF medicines nor their contractors will sell, transfer, or rent your information. Your answers will be kept strictly confidential. Your privacy will be protected; however, research survey records may be inspected by the FDA. Your choice to allow manufacturers of TIRF medicines to use your information is entirely voluntary but necessary to take part in this survey. ONLY]Now I will tell you how you can learn more about this survey. Please have a pen or pencil ready to write down a telephone number you can call should you have any questions about the survey. If you have questions about the survey, please ask me at any time. If you have questions at a later time, please contact the Survey Coordinating Center at 1-877-379- 20 of 36 FDA_1325 TIRF REMS Industry Group (TRIG) Transmucosal Immediate Release Fentanyl (TIRF) Products Pharmacist KAB Survey Protocol Version 54 0 10 Sep21 May 2013 3297. Please feel free to ask me to repeat any questions or statements as we go through the survey. Once you have answered a question and moved on, you cannot go back and change your answers. Thank you for your participation in this survey. [ONLINE ONLY] Taking the Survey [ONLINE ONLY] Once you have answered a question and moved on, you cannot go back and change your answers. [ONLINE ONLY] Thank you for your participation in this survey. [END PHONE PREAMBLE 1] 21 of 36 FDA_1326 TIRF REMS Industry Group (TRIG) Transmucosal Immediate Release Fentanyl (TIRF) Products Pharmacist KAB Survey Protocol Version 54 0 10 Sep21 May 2013 [BEGIN INCLUSION/EXCLUSION QUESTIONS] 1. Your agreement to participate in this survey confirms mutual understanding in connection with completion of the survey and the fair market value of the payment to be rendered in connection with those services. Do you agree to participate in this survey? 2. 3. 4. ○ Yes ○ No [TERMINATE] Have you ever taken part in this survey about TIRF medicines before? TIRF medicines include Abstral®, Actiq®, Fentora®, Lazanda®, Onsolis®, Subsys®, and generic versions of any of these brands. ○ Yes [ONLY TERMINATE AFTER WAVE 1] ○ No ○ I don’t know [ONLY TERMINATE AFTER WAVE 1] Do you work in a pharmacy that is enrolled in the TIRF REMS Access program? ○ Yes ○ No [TERMINATE] ○ I don’t know [TERMINATE] Have you or any of your immediate family members ever worked for any of the following companies or agencies? Please select all that apply. □ □ Anesta LLC [TERMINATE] Archimedes Pharma US Inc.[TERMINATE] □ Cephalon, Inc. (a wholly-owned subsidiary of Teva Pharmaceutical Industries, Ltd.) [TERMINATE] □ Endo Pharmaceuticals Inc. [TERMINATE] □ Galena Biopharma [TERMINATE] 22 of 36 FDA_1327 TIRF REMS Industry Group (TRIG) Transmucosal Immediate Release Fentanyl (TIRF) Products Pharmacist KAB Survey Protocol Version 54 0 10 Sep21 May 2013 □ Insys Therapeutics [TERMINATE] □ Mallinckrodt, the Pharmaceuticals Business of Covidien [TERMINATE] □ McKesson Specialty Care Solutions [TERMINATE] □ Meda Pharmaceuticals [TERMINATE] □ Mylan, Inc. [TERMINATE] □ Par Pharmaceutical, Inc. [TERMINATE] □ ProStrakan, Inc. [TERMINATE] □ RelayHealth [TERMINATE] □ Teva Pharmaceuticals, Ltd. [TERMINATE] □ United BioSource Corporation [TERMINATE] □ FDA [TERMINATE] □ None of these apply [IF SELECTED IN ADDITION TO OTHER RESPONSES, TERMINATE] □ I don’t know [TERMINATE] □ Prefer not to answer [TERMINATE] [END INCLUSION/EXCLUSION QUESTIONS] 5. Please select True, False, or I don’t know for each of the following. According to the labeling for TIRF medicines, patients with cancer who are considered opioid-tolerant are those: [RANDOMIZE LIST] Who are taking around-the-clock opioid therapy for underlying persistent cancer pain for one week or longer Who are not currently taking opioid therapy, but have 5b. taken opioid therapy before Who have no known contraindications to the drug 5c. fentanyl, but are not currently taking around-the-clock opioid therapy 5a. True False I don’t know ○ ○ ○ ○ ○ ○ ○ ○ ○ 23 of 36 FDA_1328 TIRF REMS Industry Group (TRIG) Transmucosal Immediate Release Fentanyl (TIRF) Products Pharmacist KAB Survey Protocol 6. Please answer True, False, or I don’t know for each statement based on the labeling for TIRF medicines. [RANDOMIZE LIST] 6a. A cancer patient can be started on a TIRF medicine and an around-the-clock opioid at the same time. 6b. A cancer patient who has been on an around-the-clock opioid for 1 day can start taking a TIRF medicine for breakthrough pain. 7. Version 54 0 10 Sep21 May 2013 True False I don’t know ○ ○ ○ ○ ○ ○ Please answer “True, ,” “False,,” or “I don’t know” for each statement based on the labeling for TIRF medicines. [RANDOMIZE LIST] 7a. TIRF medicines are contraindicated in opioid nontolerant patients because life-threatening respiratory depression could occur at any dose. 7b. Death has occurred in opioid non-tolerant patients treated with some fentanyl products. 7c. TIRF medicines may be used in opioid non-tolerant patients. 7d. Prescribers starting a patient on a TIRF medicine must begin with titration from the lowest dose available for that specific product, even if the patient has previously taken another TIRF medicine. 7e. It is important to monitor for signs of abuse and addiction in patients who take TIRF medicines. True False I don’t know ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ 24 of 36 FDA_1329 TIRF REMS Industry Group (TRIG) Transmucosal Immediate Release Fentanyl (TIRF) Products Pharmacist KAB Survey Protocol 8. Which of the following are risk factors for opioid abuse? Please answer Yes, No, or I don’t know for each option. [RANDOMIZE LIST] 8a. 8b. 8c. 9. Version 54 0 10 Sep21 May 2013 Yes No I don’t know ○ ○ ○ ○ ○ ○ ○ ○ ○ A personal history of psychiatric illness A personal history of past or current alcohol or drug abuse, or a family history of illicit drug use or alcohol abuse A family history of asthma Per the approved labeling for TIRF medicines, for which of the following indications can TIRF medicines be prescribed to opioid tolerant patients? Please answer Yes, No, or I don’t know for each option. [RANDOMIZE LIST] Yes No I don’t know ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ 9a. 9b. 9c. 9d. 9e. Acute or postoperative pain Headache or migraine pain Dental pain Breakthrough pain from cancer Chronic non-cancer pain 10. Please answer True, False, or I don’t know for each statement based on the labeling for TIRF medicines. [RANDOMIZE LIST] 10a. TIRF medicines can be abused in a manner similar to other opioid agonists. 10b. TIRF medicines are interchangeable with each other regardless of route of administration. 10c. The conversion of one TIRF medicine for another TIRF medicine may result in a fatal overdose because of differences in the pharmacokinetics of fentanyl absorption. 10d. Dosing of TIRF medicines is not equivalent on a microgram-to-microgram basis. True False I don’t know ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ 25 of 36 FDA_1330 TIRF REMS Industry Group (TRIG) Transmucosal Immediate Release Fentanyl (TIRF) Products Pharmacist KAB Survey Protocol 11. Please select True, False, or I don’t know for each of the following. According to the labeling for TIRF medicines, patients considered opioid-tolerant are those who are taking, for one week or longer, at least: [RANDOMIZE LIST] 11a. 11b. 11c. 11d. 11e. 11f. 12. Version 54 0 10 Sep21 May 2013 8 mg oral hydromorphone/day 60 mg oral morphine/day 30 mg oral oxycodone/day 25 mcg transdermal fentanyl/hour 25 mg oral oxymorphone/day An equianalgesic dose of another oral opioid True False I don’t know ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ How frequently do you perform the following activities when dispensing TIRF medicines? Please answer Always, Only with the first prescription, Sometimes, Never, or I don’t know. [RANDOMIZE LIST] 12a. Ask patients (or their caregivers) about the presence of children in the home 12b. Instruct patients (or their caregivers) not to share TIRF medicines with anyone else 12c. Counsel patients (or their caregivers) that accidental exposure to TIRF medicines by a child may be fatal 12d. Instruct patients (or their caregivers) to keep TIRF medicines out of the reach of children to prevent accidental exposure 12e. Instruct patients (or their caregivers) about proper disposal of any unused or partially used TIRF medicines 12f. Give patients (or their Always Only with Sometimes the first prescription Never I don’t know ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ 26 of 36 FDA_1331 TIRF REMS Industry Group (TRIG) Transmucosal Immediate Release Fentanyl (TIRF) Products Pharmacist KAB Survey Protocol Version 54 0 10 Sep21 May 2013 caregivers) the Medication Guide for their TIRF medicine 13. Please answer True, False, or I don’t know for each statement about TIRF medicines. [RANDOMIZE LIST] 13a. TIRF medicines may be sold, loaned, or transferred to another pharmacy. 13b. All pharmacy staff that dispenses TIRF medicines must be educated on the requirements of the TIRF REMS Access program. 13c. TIRF medicines with the same route of administration can be substituted with each other if the pharmacy is out of stock for one product. 14. 15. True False I don’t know ○ ○ ○ ○ ○ ○ ○ ○ ○ [INPATIENT PHARMACIST] Does the inpatient pharmacy where you work have an established system, order sets, protocols and/or other measures to help ensure appropriate patient selection and compliance with the requirements of the TIRF REMS Access Program? ○ Yes ○ No ○ I don’t know [OUTPATIENT PHARMACIST] Does the outpatient or retail pharmacy where you work process all TIRF medicine prescriptions, regardless of method of payment, through the pharmacy management system? ○ Yes ○ No ○ I don’t know 27 of 36 FDA_1332 TIRF REMS Industry Group (TRIG) Transmucosal Immediate Release Fentanyl (TIRF) Products Pharmacist KAB Survey Protocol 16. 17. Version 54 0 10 Sep21 May 2013 [CSP OUTPATIENT PHARMACIST] Does the pharmacy where you work process all TIRF medicine prescriptions, regardless of method of payment, through the TIRF REMS Access Call Center? ○ Yes ○ No ○ I don’t know [INPATIENT PHARMACIST] Please answer True, False, or I don’t know for the following statement about TIRF medicines. It is OK to dispense TIRF medicines from the inpatient pharmacy inventory to an outpatient for use at home. True False I don’t know ○ ○ ○ [PREAMBLE 3] The next set of questions is about the educational materials for TIRF medicines. As a reminder, the TIRF medicines include Abstral®, Actiq®, Fentora®, Lazanda®, Onsolis®, Subsys®, and generic versions of any of these brands. 18. 19. Did you receive or do you have access to the Full Prescribing Information for the TIRF medicine(s) that you dispense? ○ Yes ○ No [GO TO Q20] ○ I don’t know [GO TO Q20] Did you read the Full Prescribing Information for the TIRF medicine(s) that you dispense? ○ Yes ○ No ○ I don’t know 28 of 36 FDA_1333 TIRF REMS Industry Group (TRIG) Transmucosal Immediate Release Fentanyl (TIRF) Products Pharmacist KAB Survey Protocol 20. 21. 22. 23. Version 54 0 10 Sep21 May 2013 Did you receive or do you have access to the Medication Guide for the TIRF medicine(s) that you dispense? ○ Yes ○ No [GO TO Q22] ○ I don’t know [GO TO Q22] Did you read the Medication Guide for the TIRF medicine(s) that you dispense? ○ Yes ○ No ○ I don’t know Did you or do you have any questions about the information in the Full Prescribing Information or Medication Guide? ○ Yes ○ No [GO TO DEMOGRAPHICS PREAMBLE ] ○ I don’t know [GO TO DEMOGRAPHICS PREAMBLE] What are your questions? [MULTILINE INPUT] [DEMOGRAPHICS PREAMBLE] There are just a few more questions to help us combine your answers with other answers we have received. 24. Are you the Pharmacist in Charge for the TIRF REMS Access Program where you work? ○ Yes ○ No ○ I don’t know 29 of 36 FDA_1334 TIRF REMS Industry Group (TRIG) Transmucosal Immediate Release Fentanyl (TIRF) Products Pharmacist KAB Survey Protocol 25. 26. Version 54 0 10 Sep21 May 2013 On average, how many times per month have you dispensed TIRF medicine within the last 6 months? ○ None [Go to DEMOGRAPHICS PREAMBLE 2] ○ 1 – 2 times per month ○ 3 – 5 times per month ○ More than 5 times per month ○ I don’t remember Please select the TIRF medicine(s) that you have dispensed within the last 6 months (select all that apply): □ Abstral® □ Actiq® or generic Actiq® □ Fentora® or generic Fentora® □ Lazanda ® □ Onsolis® □ Subsys® [DEMOGRAPHICS PREAMBLE 2] These last few questions are for demographic purposes. 27. What is your gender? ○ Male ○ Female ○ Prefer not to answer 30 of 36 FDA_1335 TIRF REMS Industry Group (TRIG) Transmucosal Immediate Release Fentanyl (TIRF) Products Pharmacist KAB Survey Protocol 28. 29. Version 54 0 10 Sep21 May 2013 In total, how many years have you been a practicing pharmacist? ○ Less than 3 years ○ 3 – 5 years ○ 6 – 10 years ○ 11 – 15 years ○ More than 15 years ○ Prefer not to answer In which state do you practice? [DROP-DOWN LIST INPUT WITH STATES TABLE WITH “Prefer not to answer” AT END] [PHONE ONLY: BEGIN ADVERSE EVENT/PRODUCT COMPLAINT] (INTERVIEWER: Please record if respondent spontaneously reported an adverse event or product complaint during the course of this interview.) ○ Yes ○ No [GO TO CLOSING 1] Enter Safety Adverse Event Verbatim [MULTILINE INPUT] (INTERVIEWER: Indicate to the respondent that someone may call back to ask more questions about the adverse event or product complaint that was reported.) [END ADVERSE EVENT/PRODUCT COMPLAINT] [CLOSING 1] We would like to send you a $50 honorarium within the next few weeks to thank you for your time, but we need your name and address to do so. If you do not provide your name 31 of 36 FDA_1336 TIRF REMS Industry Group (TRIG) Transmucosal Immediate Release Fentanyl (TIRF) Products Pharmacist KAB Survey Protocol Version 54 0 10 Sep21 May 2013 and address you will not receive the honorarium for your time and participation in the survey. Do you agree to give us your name and mailing address so we can send you the honorarium? ○ Yes ○ No [SKIP TO CLOSING 2] [END CLOSING 1] FIRST NAME: _______________________________________________ LAST NAME: _______________________________________________ ADDRESS: [MULTILINE INPUT] CITY: _____________________________________ STATE: [DROP-DOWN LIST INPUT WITH STATES TABLE] ZIP: ___________ [CLOSING 2] We would also like to ask for your telephone number. Providing your telephone number is optional and it will be used to contact you only if there are questions about your survey responses. Do you want to provide your telephone number? ○ ○ Yes No [SKIP TO CLOSING 3] Telephone: ________________________________ [END CLOSING 2] [CLOSING 3] That ends the survey. Thank you again for your help. 32 of 36 FDA_1337 TIRF REMS Industry Group (TRIG) Transmucosal Immediate Release Fentanyl (TIRF) Products Pharmacist KAB Survey Protocol Version 54 0 10 Sep21 May 2013 [END CLOSING 3] [END OF SURVEY CONTENT] 33 of 36 FDA_1338 TIRF REMS Industry Group (TRIG) Transmucosal Immediate Release Fentanyl (TIRF) Products Pharmacist KAB Survey Protocol Appendix B Version 54 0 10 Sep21 May 2013 Pharmacist Invitation Letter [CURR_DATE] [PHARMACY_NAME] [PHARMACY _STREET_ADDR] [PHARMACY_CITY], [PHARMACY _STATE] [PHARMACY _ZIP] [PHARMACY_FAX_NUMBER] Dear [PHARMACIST_IN CHARGE] Your Pharmacy was selected to receive this letter, because of enrollment in the TIRF REMS Access Program. We are contacting you to inform you about a survey being conducted by the manufacturers of Transmucosal Immediate Release Fentanyl (TIRF) medicines, as required by the Food and Drug Administration (FDA). The purpose of the survey is to assess pharmacists’ understanding of the safe and appropriate use of these medicines. The TIRF medicines include Abstral®, Actiq®, Fentora®, Lazanda®, Onsolis®, Subsys®, and generic versions of any of these brands. The manufacturers of TIRF medicines include Archimedes Pharma US Inc.; Cephalon, Inc. (a wholly-owned subsidiary of Teva Pharmaceutical Industries, Ltd.); Endo Pharmaceuticals Inc.; Galena Biopharma; Insys Therapeutics; Meda Pharmaceuticals; Mallinckrodt; Mylan, Inc.;, the Pharmaceuticals Business of Covidien; and Par Pharmaceutical, Inc. (collectively referred to as the “TIRF REMS Industry Group”). These manufacturers are looking for 300 pharmacists to complete the survey. Eligible pharmacists who complete the survey will be sent a $50 honorarium to thank them for their time. The survey will take 15-20 minutes. Your answers will be kept strictly confidential and will be combined with the answers from other pharmacists who take this survey. Your name will not be used in the report of this survey and your contact information, if provided, will only be used to send you a $50 honorarium for your time to complete the survey. You are under no obligation to participate in this survey. Only one pharmacist from each enrolled pharmacy can participate. If you are interested in participating and to find out if you are eligible:   Go to www.TIRFREMSsurvey.com any time or Call 1-877-379-3297, 8 a.m. to 8 p.m. Eastern Time, Monday through Friday Please have this letter with you at the time you take the survey. You will be asked to provide this code prior to starting the survey: [CODE_ID]. *We recommend that you take the survey on a desktop or laptop computer. Taking the survey on mobile devices, such as smart phones, tablets, and e-notebooks, is not supported. Neither taking the survey nor your answers to the questions will affect your ability to dispense any of the TIRF medicines identified above. 34 of 36 FDA_1339 TIRF REMS Industry Group (TRIG) Transmucosal Immediate Release Fentanyl (TIRF) Products Pharmacist KAB Survey Protocol Version 54 0 10 Sep21 May 2013 Sincerely, The TIRF REMS Survey Team 1-877-379-3297 www.TIRFREMSsurvey.com 35 of 36 FDA_1340 TIRF REMS Industry Group (TRIG) Transmucosal Immediate Release Fentanyl (TIRF) Products Pharmacist KAB Survey Protocol Appendix C Version 54 0 10 Sep21 May 2013 Qualitative Research Report 36 of 36 FDA_1341 Prescriber KAB Assessment Report Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Title: Page 1 of 67 Transmucosal Immediate Release Fentanyl (TIRF) REMS Assessment Quantitative Testing of Prescriber Knowledge, Attitudes, and Behavior (KAB) about TIRF Products’ Safety and Use Information Document Number Wave 2, 24-month REMS Assessment Version 1.0 Survey Time Period 16 September 2013 to 17 October 2013 Product Name: Transmucosal Immediate Release Fentanyl Sponsor: TIRF REMS Industry Group (TRIG) of Companies: Cephalon, Inc. (a wholly-owned subsidiary of Teva Pharmaceutical Industries, Ltd.) Depomed, Inc. Galena Biopharma, Inc. Insys Therapeutics Mallinckrodt Pharmaceuticals Meda Pharmaceuticals Mylan, Inc. Par Pharmaceutical, Inc. Date: 18 December 2013 Confidentiality Statement The information contained herein is confidential and the proprietary property of the TRIG of Companies and its affiliates, and any unauthorized use or disclosure of such information without the prior written authorization of the TRIG is expressly prohibited. FDA_1342 Prescriber KAB Assessment Report Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies TABLE OF CONTENTS Page 2 of 67 PAGE TABLE OF CONTENTS......................................................................................................... 2  LIST OF IN-TEXT TABLES .................................................................................................. 3  LIST OF APPENDICES .......................................................................................................... 4  LIST OF ABBREVIATIONS .................................................................................................. 5  1.  PRESCRIBER SURVEY BACKGROUND .......................................................... 6  2.  PRESCRIBER SURVEY OBJECTIVES ............................................................... 7  3.  SURVEY METHODOLOGY................................................................................. 7  3.1  Survey Development: FDA Feedback and Qualitative Research of Draft Survey Questionnaire .............................................................................................. 8  3.1.1  Qualitative Research ............................................................................................. 10  3.2  Survey Sample ...................................................................................................... 14  3.2.1  Eligibility .............................................................................................................. 15  3.2.2  Recruitment ........................................................................................................... 15  3.3  Questions and Statements on Key Risk Messages ................................................ 15  3.3.1  Key Risk Message 1 .............................................................................................. 16  3.3.2  Key Risk Message 2 .............................................................................................. 17  3.3.3  Key Risk Message 3 .............................................................................................. 17  3.3.4  Key Risk Message 4 .............................................................................................. 18  3.4  Additional Questions............................................................................................. 19  4.  STATISTICAL METHODS ................................................................................. 20  4.1  Study Population ................................................................................................... 20  4.1.1  Primary Analysis Population ................................................................................ 20  4.1.2  Sub-populations of Interest ................................................................................... 20  4.1.2.1  Primary Analyses .................................................................................................. 21  4.1.2.2  Secondary Analyses .............................................................................................. 21  4.1.3  Prescriber Report of Adverse Event, Product Complaint, or Medical Information Request during Survey ...................................................................... 22  5.  RESULTS ............................................................................................................. 22  5.1  Survey Participants................................................................................................ 22  FDA_1343 Prescriber KAB Assessment Report Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 3 of 67 5.1.1  Survey Participant Administration Results ........................................................... 22  5.1.2  Demographic Characteristics of Prescribers who Completed the Survey ............ 26  5.1.3  Prescribing Habits of Eligible Prescribers Related to TIRF Products .................. 28  5.1.4  TIRF Medicines Educational Materials ................................................................ 29  5.2  KAB Survey Objectives ........................................................................................ 31  5.2.1  Key Risk Message Results .................................................................................... 31  5.2.1.1  Key Risk Message 1 .............................................................................................. 32  5.2.1.2  Key Risk Message 2 .............................................................................................. 34  5.2.1.3  Key Risk Message 3 .............................................................................................. 37  5.2.1.4  Key Risk Message 4 .............................................................................................. 39  5.2.2  Other Survey Questions ........................................................................................ 41  5.2.2.1  Additional Questions about TIRF Medicines Safety ............................................ 41  5.2.2.2  Prescriber Activities When Prescribing TIRF Medicines ..................................... 52  5.2.3  Analyses of Sub-populations ................................................................................ 54  5.3  Spontaneous Comments or Medical Information Requests .................................. 55  5.4  Summary of Correct Responses for Key Risk Messages ...................................... 55  6.  DISCUSSION, CONCLUSIONS, AND RECOMMENDATIONS ..................... 60  LIST OF IN-TEXT TABLES Table 1.  Survey Participant Administration Results .................................................... 23  Table 2.  Survey Participant Screening Results ............................................................ 24  Table 3.  Time to Complete Survey for Completers Only (Minutes) ........................... 25  Table 4  Demographic Characteristics of Eligible Prescribers .................................... 27  Table 5.  Prescribing Habits of Respondents Completing the Survey .......................... 29  Table 6.  Responses to Questions About the TIRF Medicines Educational Materials and the TIRF Patient-Prescriber-Agreement Form ........................ 30  Table 7.  Responses Linked to Key Risk Message 1: TIRF Medicines Are Contraindicated in Opioid Non-Tolerant Patients ......................................... 32  Table 8.  Responses Linked to Key Risk Message 2: TIRF Medicines Are Only Indicated for the Management of Breakthrough Pain in Adult Cancer Patients 18 Years of Age and Older (16 Years of Age and Older for Actiq® Brand and Generic Equivalents) Who Are Already FDA_1344 Prescriber KAB Assessment Report Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 4 of 67 Receiving and Who Are Tolerant to Around-The-Clock Opioid Therapy for Their Underlying Persistent Cancer Pain ................................... 35  Table 9.  Responses Linked to Key Risk Message 3: TIRF Medicines Contain Fentanyl, an Opioid Agonist, and a Schedule II Controlled Substance, With Abuse Liability Similar to Other Opioid Analgesics. ......... 38  Table 10.  Responses Linked to Key Risk Message 4: TIRF Medicines Are Not Interchangeable With Each Other, Regardless of Route of Administration. .............................................................................................. 40  Table 11.  Responses to Additional Questions About the Safe Use of TIRF Medicines ....................................................................................................... 43  Table 12.  Responses to All Questions About Activities When Prescribing TIRF Medicines ....................................................................................................... 53  Table 13.  Summary of Correct Responses for Key Risk Messages............................... 56  Table 14. Correct Response Rates in the 24-month KAB Survey Compared with the 12-month KAB Survey in Key Risk Message Questions Modified Between the Two Versions ............................................................ 61  LIST OF APPENDICES Appendix A Prescriber Survey Protocol ............................................................................ 64  Appendix B Prescriber Survey Listings and Sub-group Analysis Tables .......................... 65  Appendix C Findings Report: Qualitative Research to Evaluate the Prescriber and Pharmacist 12-month REMS Assessment Surveys for TIRF Medicines ....................................................................................................... 66  Appendix D Prescriber Survey Protocol Track Change Document: Comparison of 12-month Survey to 24-month Survey........................................................... 67  FDA_1345 Prescriber KAB Assessment Report Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 5 of 67 LIST OF ABBREVIATIONS AE/PC/PSP Adverse Event/Product Complaint Project Specific Procedure ANDA Abbreviated New Drug Application ETASU Elements to Assure Safe Use FDA Food and Drug Administration KAB Knowledge, Attitudes, and Behavior NDA New Drug Application PPAF Patient-Prescriber Agreement Form QR Qualitative Research REMS Risk Evaluation and Mitigation Strategy TIRF Transmucosal Immediate Release Fentanyl TIRF medicines Transmucosal Immediate Release Fentanyl product(s) TIRF REMS Access Program REMS Program for TIRF medicines TRIG TIRF REMS Industry Group UBC United BioSource Corporation US United States USPS United States Postal Service FDA_1346 Prescriber KAB Assessment Report Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies 1. Page 6 of 67 PRESCRIBER SURVEY BACKGROUND Transmucosal Immediate Release Fentanyl (TIRF) medicines are a class of immediaterelease opioid analgesics that are indicated only for the management of breakthrough pain in cancer patients 18 years of age or older (16 or older for Actiq® [fentanyl citrate oral transmucosal lozenge] and equivalent generics) who are receiving and already tolerant to opioid therapy for their underlying persistent cancer pain. The TIRF medicines include Abstral®, Actiq®, Fentora®, Lazanda®, Onsolis®, Subsys®, and their generic equivalents. The TIRF Risk Evaluation and Mitigation Strategy (REMS) Industry Group (TRIG) includes Cephalon, Inc. (a wholly-owned subsidiary of Teva Pharmaceutical Industries, Ltd.), Depomed, Inc., Galena Biopharma, Inc., Insys Therapeutics, Meda Pharmaceuticals, Mallinckrodt Pharmaceuticals, Mylan, Inc., and Par Pharmaceutical, Inc. At the time of protocol finalization for the Knowledge, Attitude, and Behavior (KAB) surveys, Depomed, Inc. acquired the New Drug Application (NDA) for Lazanda (29 July 2013) from Archimedes Pharma US, Inc., who is no longer a TIRF Sponsor. In addition, Galena Biopharma acquired the NDA for Abstral from ProStrakan Inc., and is now a TIRF Sponsor (as of 01 May 2013) whereupon ProStrakan exited the group. Additionally, Mylan became a TIRF Sponsor on 29 May 2013 due to a pending Abbreviated New Drug Application (ANDA). The Food and Drug Administration (FDA) has determined that a shared system REMS is required to mitigate the risk of misuse, abuse, addiction, overdose, and serious complications due to medication errors with the use of TIRF medicines. The TIRF REMS Access Program (hereafter referred to as TIRF REMS) was approved by the FDA on 28 December 2011. The TIRF REMS consists of a Medication Guide, Elements to Assure Safe Use (ETASU), an Implementation System, and a Timetable for Submission of Assessments of the REMS. The goals of the TIRF REMS are to mitigate the risk of misuse, abuse, addiction, overdose, and serious complications due to medication errors by the following: 1. Prescribing and dispensing TIRF medicines only to appropriate patients, which includes use only in opioid-tolerant patients. 2. Preventing inappropriate conversion between TIRF medicines. 3. Preventing accidental exposure to children and others for whom it was not prescribed. 4. Educating prescribers, pharmacists, and patients on the potential for misuse, abuse, addiction, and overdose of TIRF medicines. An important component of the TIRF REMS assessment is the conduct of quantitative evaluation surveys to assess prescribers’ understanding and knowledge of the safe use and appropriate prescribing of TIRF medicines as described in the TIRF REMS educational materials, enrollment form, and Prescribing Information of each product. FDA_1347 Prescriber KAB Assessment Report Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 7 of 67 The protocol describes the administration of the surveys conducted among prescribers who are enrolled in the TIRF REMS Access Program. Data from the surveys, together with other REMS evaluation metrics, will be used to determine whether changes need to be made to the REMS processes or educational materials to make them more effective in achieving the goals of the REMS. This report describes the results from the prescriber survey conducted for the 24-month TIRF REMS Access Program Assessment. The 24-month prescriber KAB survey launched on 16 September 2013 and closed on 17 October 2013. 2. PRESCRIBER SURVEY OBJECTIVES The evaluation survey uses a questionnaire to document the level of knowledge and assess the attitudes and behaviors of prescribers regarding the following key information and risk messages communicated through the REMS: 1. TIRF medicines are contraindicated in opioid non-tolerant patients. 2. TIRF medicines are only indicated for the management of breakthrough pain in adult cancer patients 18 years of age and older (16 or older for Actiq and equivalent generics) who are receiving and who are tolerant to around-the-clock opioid therapy for their underlying persistent cancer pain. 3. TIRF medicines contain fentanyl, an opioid agonist, and a Schedule II controlled substance, with abuse liability similar to other opioid analgesics. 4. TIRF medicines are not interchangeable with each other, regardless of route of administration. 5. Patients and their caregivers must be instructed that TIRF medicines contain a medicine in an amount that can be fatal in children, in individuals for whom it is not prescribed, and in those who are not opioid tolerant. The survey also collects data on behaviors, such as receipt and use of educational materials and compliance with REMS requirements. 3. SURVEY METHODOLOGY This section summarizes the survey design and the questions that were constructed to test prescriber understanding of the key risk messages of the REMS. Full details of the survey design are in the protocol, which can be found in Appendix A. FDA_1348 Prescriber KAB Assessment Repo? Transmucosal Iimnediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 8 of 67 3.1 Survey Development: FDA Feedback and Qualitative Research of Draft Survey Questionnaire On 12 March 2013, FDA provided feedback on the 12-month TIRF REMS Access Program Assessment Report that included recommendations for modi?cation to the prescriber smvey, as described below. (1) Add the questions, identi?ed below, as key risk messages in the 24-month TIRF REMS Access Program Assessment Report and investigate the cause for low scores to these questions speci?cally relating to the safe use questions that potentially indicate poor lmderstanding of these concepts. Thefo/lowing questions, identi?ed by the FDA, were moved to key risk messages. 12?month 24?month Survey Survey Question Question Number Number Question Please answer ?Tine.? ?False." or don?t know? for each of the followingAccording to the labeling. patients c01151dered op101d-tolerant are those: 5a 5a Who are taking regular opioid therapy for underlying persistent cancer pain for one week or longer Sb 5b Who are not cmrently taking opioid therapy. but have taken opioid therapy before 5c 5c Who are not cmrently taking opioid therapy. but with no known intolerance or hypersensitivity to the drug fentanyl For which of the following indications do you prescn'ber TIRF medicines to 8 9 opioid tolerant patients? Please answer ?Yes." No.? or don?t know" for each option 8e 9e Chronic non-cancer pain The following patients described are experiencing breaktln'ough pain. According to the labeling. a medicine is not appropriate for one of ll 13 them. Please answer ?Yes.? or don?t know? as to whether each patient should receive a TIRF medicine. A patient is ah'eady taking a TIRF medicine but wants to change their medicine. The doctor decides to prescribe a different TIRF medicine (that 12 14 is not a bioequivalent generic version of a branded product) in its place. How should the prescriber proceed? For each of the following scenarios. please indicate if it is a correct action for the prescriber by answering ?Yes.? or don?t know.? 349 Prescriber KAB Assessment Report Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 9 of 67 (2) Investigate the cause for low scores to speci?c key risk message questions speci?cally relating to the safe use questions outlined below: 12?month 24?month Survey Survey Question Question Number Number Question Please answer ?True." ?False.? or don?t know? for each of the 5 5 following. According to the labeling. patients considered opioid-tolerant are those: 5a 5a Who are taking regular opioid therapy for underlying persistent cancer pain for one week or longer Who are not currently taking opioid therapy. but with no known intolerance or hypersensitivity to the drug fentanyl For which of the following indications do you prescriber TIRF medicines 8 9 to opioid tolerant patients? Please answer ?Yes.? No.? or don?t know? for each option 8e 9e Cln?onic non-cancer pain The following patients described are experiencing breakthrough pain. According to the labeling. a TIRF medicine is not appropriate for one of them. Please answer ?Yes.? or don?t know? as to whether each patient should receive a TIRF medicine ll 13 Adult male with advanced lung cancer; miderlying persistent cancer pain lla 13a managed with 25 mcg/horu? transdermal fentanyl patches for the past two months A patient is ah?eady taking a TIRF medicine but wants to change their medicine. The doctor decides to prescribe a different TIRF medicine (that is not a bioequivalent generic version of a branded product) in its place. How should the prescriber proceed? For each of the following scenarios. please indicate if it is a correct action for the prescriber by answering ?Yes." or don?t know.? 12 14 Convert from the other TIRF medicine to the new TIRF medicine at half 12c 14c of the dose The prescriber should base the starting dose of the newly prescribed TIRF 12d 14d medicine on the dose of the opioid medicine used for their rmderlying persistent cancer pain 350 Prescriber KAB Assessment Report Transmucosal Irmnediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 10 of 67 12-month 24-month Survey Survey Question Question Number Number Question A patient is taking a TIRF medicine and the doctor would like to prescribe 15 17 a CYP3A4 inhibitor. Please select ?True.? ?False.? or don?t know? for each of the following statements The patient can?t be prescribed because using it at the sanre 15" 17a time as a TIRF medicine could be fatal Use of a TIRF medicine with a CYP3A4 inhibitor may require a dosage 15b 17b adjustment: carefully monitor the patient for opioid toxicity. otherwise such use may cause potentially fatal respiratory depression There is no possible drug interaction between CYP3A4 inhibitors and 5 . . 17? TIRFmedrcmes The dose of the TIRF medicine must be reduced by one halfif a CYP3A4 15d 17d inhibitor is prescribed in the same patient (3) Investigate the causes, including conducting a pre-testing of all questions related to all key risk messages prior to the next sruvey, to determine the reasons for the poor performance on these questions. If pre-testing indicates that a rephrasing of a question is indicated, please also re-test the rephrased question and then submit the results of both the pre-testing and re-testing. 3.1.1 Qualitative Research Before implementing the 24-month srnvey, TRIG conducted qualitative research (QR) interviews of 12 items from the Prescriber REMS Assessment Sruvey Questions and 2 new questions that were not included in the 12-month sruvey (see Appendix C). The research rmdertaken in this QR process included: 0 Review of the questions identi?ed by the FDA that had a low correct response rate; 0 Review of two new questions created to assist in determining the rmderstanding of the term ?around-the-clock usage?; 0 Review of proposed new wording on various questions. The objectives of this research were to: 0 Evaluate clarity and comprehension of questions and answer options used in the 12- month assessment; 0 Identify terms, questions or topics for clari?cation or revision based on any areas of confusion with or misunderstanding for crurent wording; 351 Prescriber KAB Assessment Report Transmucosal Irmnediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 11 of 67 0 Determine how participants rmderstand speci?c questions and why those questions are answered a particular way; 0 Determine how certain questions might be lmderstood differently and answered more accm?ately if ?nther clari?ed; 0 Evaluate alternative language for these questions. This QR involved in-depth, individual telephone interviews with 7 prescribers. Each interview lasted about 45 minutes. All interviews were conducted by the same experienced moderator using a detailed discussion guide that probed into each area of the sruvey questions identi?ed for further investigation. The strategy used to conduct the 7 telephone interviews was to interview: 0 7 TIRF REMS Access-em?olled prescribers who completed the 12-month Prescriber REMS Assessment Sruvey and met the de?nition of a ?low performer? based on their incorrect responses to between 3 and 7 of the 10 items identi?ed by FDA. Based on the outcome of the QR, the questions shown below were added or reworded for Wave 2. A track change version of the protocol can be found in Appendix D. The following new questions were added to the 24-month REMS Assessment based on QR ?ndings. 24?month Survey Question Question Number 6 Please answer ?True.? ?False." or don?t know? for each statement about TIRF medicines 6a A cancer patient can be started 011 a TIRF medicine and an around-the-clock opioid at the same time 6b A cancer patient who has been on an around-the-clock opioid for 1 day can start taking TIRF medicines for breakthrough pain 19 Can patients continue to take their TIRF medicine if they stop taking their arormd-the-clock opioid medicine? 352 Prescriber KAB Assessment Report Transmucosal Irmnediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 12 of 67 The following questions were revised for the TIRF REMS KAB 24-month survey: 12?month 24-month Survey Survey Question 12-month Question Question 24?month Question Number Number Please select ?True.? ?False.? or ?1 Please select ?True.? ?False.? or don?t know? for each of the don?t know? for each of the 5 following. According to the labeling 5 following. According to the labeling for TIRF medicines, patients with for TIRF medicines. patients with cancer who are considered opioid- cancer who are considered opioid- tolerant are those: tolerant are those: Who are taking regular opioid therapy Who are taking arormd-the-clock . . . . op101d therapy for 5a f01 cancer pam 5a . . . . pe151$tent cancer pain for one week or for one week or longer longer Who are not crurently taking opioid Who have no known 5c therapy. but with no known ic contraindications to the drug fentanyl. intolerance or hypersensitivity to the but are not cmrently taking around- drug fentanyl the-clock opioid therapy The following patients described are The patients described are expenencmg breaktlnough pain. . . . . . expenencmg breakthrough pam. Accordmg to the labeling. a TIRF . . . . . . According to the labeling. a TIRF medicme 15 not appropriate for one medrcme 15 not approprrate for one of them. Please answer Yes. No. or . . a them. patient should not I don know as to whether each . . . . . receive a TIRF medicme? Please patient should receive a TIRF . . . select one option. med1c1ne. Adult female with localized breast Adult female with localized breast cancer: just completed a mastectomy cancer: just completed a mastectomy 11b and reconstructive surgery: persistent 13b and reconstructive surgery: persistent cancer pain managed with 30 mg oral morphine daily for the past 6 weeks cancer pain managed with 30 mg oral morphine daily for the past 6 weeks. 353 Prescriber KAB Assessment Rep01t Transmucosal Irmnediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 13 of 67 12-mouth 24?month Survey . Survey Question lZ?month Question Question Number Number 24?month Question A patient is already taking a TIRF medicine but wants to change their medicine. The doctor decides to prescribe a different TIRF medicine (that is not a bioequivalent generic version of a branded product) in its A patient is already taking a TIRF medicine but wants to change their medicine. His/her doctor decides to prescribe a different TIRF medicine (that is not a bioequivalent generic version of a branded product) in its 12 place. How should the prescriber 14 place. According to the labeling. how proceed? For each of the following should the prescriber proceed? Please scenarios. please indicate if it is a select one option correct action for the prescriber by answering ?Yes.? or don?t know.? Convert from the other TIRF Convert from the other TIRF 12c medicine to the new TIRF medicine 14c medicine to the new TIRF medicine at half of the dose at half of the dose The prescriber should base the starting dose of the newly prescribed 12d TIRF medicine on the dose of the 14d opioid medicine used for their tmderlying persistent cancer pain The prescriber should base the starting dose of the newly-prescribed TIRF medicine 011 the dose of the opioid medicine used for their lmderlying persistent cancer pain A patient is taking a TIRF medicine and the doctor would like to prescribe a CYP3A4 inhibitor. A patient is taking a TIRF medicine and the doctor would like to prescribe a CYP3A4 inhibitorPlease select ?True.? ?False. or I Please pick the best option of the don?t know? for each of the following scenarios described. statements The patient can?t be prescribed The patient can?t be prescribed 15a because using it at the 17a because using it at the same time as a TIRF medicine could be fatal same time as TIRF medicine could be fatal. Use of a TIRF medicine with a CYP3A4 inhibitor may require dosage adjustment: carefully monitor 15b the patient for opioid toxicity. 17b otherwise such use may cause potentially fatal respiratory depression Use of a TIRF medicine with a CYP3A4 inhibitor may require a dosage adjustment: carefully monitor the patient for opioid toxicity. otherwise such use may cause potentially fatal respiratory depression. There is no possible drug interaction 15c between CYP3A4 inhibitors and 17c TIRF medicines There is no possible drug interaction between CYP3A4 inhibitors and TIRF medicines. 354 Prescriber KAB Assessment Report Transmucosal Irmnediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 14 of 67 12-month 24?month Survey Survey Question 12?month Question Question 24?month Question Number Number The dose of the TIRF medicine The dose of the TIRF medicine must 15d be reduced by one half if a CYP3A4 17d be reduced by one half if a CYP3A4 inhibitor is prescribed in the same inhibitor is prescribed in the same patient patient. -Not asked- l7e I don?t know 1 Question not asked in the 12-month Survey After the initial review and subsequent to QR, the sruvey was updated and r?e-submitted to the FDA. The FDA provided feedback and the following revisions were made (see Appendix A and Appendix B) to the sruvey and protocol, as appropriate, to incorporate these requests: 0 Revise the statement on page 11 of the proposed survey protocol of ?Participants will be informed that prescribers from these states are not eligible to participate and physicians who practice in these states will not receive compensation for their participation.? to ?Participants will be informed that prescribers from these states are eligible to participate, but they will not receive compensation for their participation.? This change was made in the protocol and the survey invitation letter. 0 Base the study analysis for representativeness of prescribers on at least prescribers' medical specialty, medical degree, and geography. Representativeness of prescribers on their medical specialtv, medical degree, and geography, the comparison of medical specialty and medical degree were not calculated because this data was not available for analvsis.lnclude in analyses all eligible surveys that are completed. 0 Include in analyses all eligible surveys that are completed. This information was incorporated in the 12-month report; it will also be incorporated in all subsequent analyses Appendix includes a copy of the Top-Line Findings Report: Findings Report: Qualitative Research to Evaluate the Prescriber? and Pharmacist 12-month REMS Assessment Surveys for TIRF Medicines. 3.2 Survey Sample This sruvey was conducted among a random sample of prescribers who were em'olled in the TIRF REMS Access Program as of 15 August 2013. A target sample of 300 prescribers who 355 Prescriber KAB Assessment Report Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 15 of 67 were enrolled in the TIRF REMS Access Program was planned for the survey. The size of the sample was determined based on both practical and statistical considerations. 3.2.1 Eligibility Subject recruitment was from a random sample of prescribers who were enrolled in the TIRF REMS Access Program. Respondents or their immediate family members who had ever worked for any of the TRIG companies, RelayHealth, McKesson Specialty Care Solutions, United BioSource Corporation (UBC), or the FDA were not eligible to participate. Respondents who participated in the first wave of the TIRF survey (12-month TIRF REMS Access Program Assessment) were not eligible to participate. 3.2.2 Recruitment Subject recruitment was performed via a letter sent through the United States Postal Service (USPS), and via email (Section 5.1.1 for more detail). The required number of completed surveys was not achieved within approximately 10 days after the first mailing; thus a second and a third mailing were sent to non-respondents from the original sample to maximize participation. Following the third mailing, the prescriber survey sample had not reached the target; therefore, a new random sample was selected and invitations were mailed through the USPS or e-mailed. Prescribers were given the option of taking the survey by telephone via the Survey Coordinating Center or online via a secure website. All participating prescribers were offered an honorarium of $125 for a completed survey. The survey was estimated to take approximately 20 minutes to complete. 3.3 Questions and Statements on Key Risk Messages The questions and statements comprising the knowledge survey were constructed to test the prescribers’ understanding of the key risk messages of the REMS. The questions were to be answered either by selecting options from multiple-choice lists that include statements of the specific key risk messages or by choosing “Yes” or “True,” “No” or “False,” or “I Don’t Know” regarding statements about TIRF medicines. For statements or questions that use “True” or “Yes” vs. “False” or “No” response options, the desired response for key risk messages is generally “True” or “Yes” indicating knowledge of, or behavior in accordance with, the objectives of the REMS. However, some questions were formatted to have the respondent disagree with the statement as written by providing response options of “False” or “No” to avoid having the same affirmative answer for all desired responses. REMS statements, corresponding questions, and desired responses covering the key risk messages are identified below and can be found in the complete survey questionnaire (Appendix A). FDA_1356 Prescriber KAB Assessment Report Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies 3.3.1 Page 16 of 67 Key Risk Message 1 Key Risk Message 1 referred to the prescriber’s knowledge of the specific contraindications for TIRF medicines in opioid non-tolerant patients. Questions in bold face type were added as key risk message questions based on FDA Feedback. Key Risk Message 1: TIRF medicines are contraindicated in opioid non-tolerant patients. Question No. Question Desired response 5 Please select “True,” “False,” or “I don’t know” for each of the following. According to the labeling for TIRF medicines, patients with cancer who are considered opioid-tolerant are those: 5a Who are taking around-the-clock opioid therapy for underlying persistent cancer pain for one week or longer True 5b Who are not currently taking opioid therapy, but have taken opioid therapy before False 5c Who have no known contraindications to the drug fentanyl, but are not currently taking around-theclock opioid therapy False 7 Please answer “True,” “False,” or “I don’t know” for each statement based on the labeling for TIRF medicines. 7a TIRF medicines are contraindicated in opioid non-tolerant patients because life-threatening respiratory depression could occur at any dose. True 7b Death has occurred in opioid non-tolerant patients treated with some fentanyl products. True 7c TIRF medicines may be used to treat opioid non-tolerant patients. False 7d Prescribers starting a patient on a TIRF medicine must begin with titration from the lowest dose available for that specific product, even if the patient has previously taken another TIRF medicine. True FDA_1357 Prescriber KAB Assessment Report Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies 3.3.2 Page 17 of 67 Key Risk Message 2 Key Risk Message 2 referred to the prescriber’s knowledge of the indications for prescribing TIRF medicines for the management of breakthrough pain in opioid-tolerant adult cancer patients. Questions in bold face type were added as key risk message questions based on FDA Feedback. This key risk message includes both a behavior question (Question 9) and a knowledge question (Question 13). Key Risk Message 2: TIRF medicines are only indicated for the management of breakthrough pain in adult cancer patients 18 years of age and older (16 years of age and older for Actiq® brand and generic equivalents) who are already receiving and who are tolerant to around-theclock opioid therapy for their underlying persistent cancer pain. Question No. Question Desired response 9 In your practice, for which of the following indications do you prescribe TIRF medicines to opioid tolerant patients? Please answer “Yes,” “No,” or “I don’t know” for each option. 9a Acute or postoperative pain No 9b Headache or migraine pain No 9c Dental pain No 9d Breakthrough pain from cancer Yes 9e Chronic non-cancer pain No 13 The patients described are experiencing breakthrough pain. According to the labeling, a TIRF medicine is not appropriate for one of them. Which patient should not receive a TIRF medicine? Please select one option. 3.3.3 13b. Adult female with localized breast cancer; just completed a mastectomy and reconstructive surgery; persistent cancer pain managed with 30 mg oral morphine daily for the past 6 weeks. Key Risk Message 3 Key Risk Message 3 referred to the prescriber’s knowledge of the risk factors and signs and symptoms of opioid abuse in patients who take TIRF medicines. FDA_1358 Prescriber KAB Assessment Report Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 18 of 67 Key Risk Message 3: TIRF medicines contain fentanyl, an opioid agonist and a Schedule IIcontrolled substance, with abuse liability similar to other opioid analgesics. Question No. Question Desired response 7 Please answer “True,” “False,” or “I don’t know” for each statement based on the labeling for TIRF medicines. 7e It is important to monitor for signs of abuse and addiction in patients who take TIRF medicines. 8 Which of the following are risk factors for opioid abuse? Please answer “Yes,” “No,” or “I don’t know” for each option. 8a A personal history of psychiatric illness Yes 8b A personal history of past or current alcohol or drug abuse, or a family history of illicit drug use or alcohol abuse Yes 10 Please answer “True,” “False,” or “I don’t know” for each statement based on the labeling for TIRF medicines. 10a TIRF medicines can be abused in a manner similar to other opioid agonists. 3.3.4 True True Key Risk Message 4 Key Risk Message 4 referred to the prescriber’s knowledge of the interchangeability of TIRF medicines based on route of administration, pharmacokinetic absorption, and dosage. Questions in bold face type were added as key risk message questions based on FDA Feedback. Key Risk Message 4: TIRF medicines are not interchangeable with each other, regardless of route of administration. Question No. 10 10b 10c Question Desired response Please answer “True,” “False,” or “I don’t know” for each statement based on the labeling for TIRF medicines. TIRF medicines are interchangeable with each other regardless of route of administration. The conversion of one TIRF medicine for another TIRF medicine may result in a fatal overdose because of differences in the pharmacokinetics of fentanyl absorption. False True FDA_1359 Prescriber KAB Assessment Report Transmucosal Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 19 of 67 Key Risk Message 4: TIRF medicines are not interchangeable with each other, regardless of route of administration. Question Question Desired response No. 10d Dosimg 0t? TIRF medicmes IS not equivalent 011 True a 11nc10g1am-to-nncrog1am ba51s. A patient is already taking a TIRF medicine 14b. The prescriber must not but wants to change their medicine. His/her convert to another TIRF medicine doctor decides to prescribe a different TIRF on a microgram-per-microgram l4 medicine (that is not a bioequivalent generic basis because these medicines have version of a branded product) in its place. di??erent absorption properties and According to the labeling. 110w should the this could result in a fentanyl prescriber proceed? Please select one option. overdose. 3.4 Additional Questions The survey also contained questions (Question lZa-f) about the requirements of the TIRF REMS Access Program and the use of the TIRF educational materials in their practice. The following questions about behaviors were asked after the key risk message questions: Question No. Question How ?'equently do you perform the following activities when dispensing TIRF 12 medicines? Please answer ?Always.? ?Only with the ?rst prescription.? ?Sometimes.? ?Never.? or don?t know." 12a Ask patients (or their caregivers) about the presence of children in the home 12b Instruct patients (or their caregivers) not to share TIRF medicines with anyone else 12c Counsel patients (or their caregivers) that accidental exposure to TIRF medicines by a child may be fatal 12d Instruct patients (or their caregivers) to keep TIRF medicines out of the reach of children to prevent accidental exposm?e 129 Instruct patients (or their caregivers) about proper disposal of any mnlsed or partially used TIRF medicines 12f Give patients (or their caregivers) the Medication Guide for their TIRF medicine 360 Prescriber KAB Assessment Report Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies 4. STATISTICAL METHODS 4.1 Study Population 4.1.1 Primary Analysis Population Page 20 of 67 The primary population for analysis was all eligible prescribers who completed the survey. Eligible prescribers were defined as those respondents who answered Yes to Question 1 (agree to take part in survey), and Question 3 (enrolled in the TIRF REMS Access program), and No to Question 2 (participated in past survey) and Question 4 (worked for a TRIG company, UBC, RelayHealth, McKesson Specialty Care Solutions, or FDA). A completed survey was a survey from an eligible prescriber in which all non-eligibility questions were answered as appropriate. Note that some questions may not be answered because of skip logic in the survey questionnaire. 4.1.2 Sub-populations of Interest The following sub-group analyses were conducted if the sub-group included at least 20 respondents. Sub-group analysis 1: Reading Medication Guide or Full Prescribing Information (Questions 20, 21, 22, and 23): • S-1a - Respondents who received and read the Full Prescribing Information for the TIRF medicine that they prescribe, or who received and read the Medication Guide. • S-1b - Respondents who did not receive or did not read the Full Prescribing Information for the TIRF medication that they prescribe (answered “No” or “I don’t know” to Question 21) and did not receive or did not read the Medication Guide for the TIRF medicine that they prescribe (answered “No” or “I don’t know” to Question 23). Sub-group analysis 2: Medical degree of respondents (Question 32): • S-2a - MD • S-2b - DO • S-2c - Nurse Practitioner • S-2d - Physician Assistant Sub-group analysis 3: Time to complete survey - Internet: • S-3a - <10 min • S-3b - 10 to <20 min • S-3c - ≥ 20 min FDA_1361 Prescriber KAB Assessment Report Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 21 of 67 Sub-group analysis 4: Time to complete survey - Telephone: • S-4a - <10 min • S-4b - 10 to <20 min • S-4c - ≥ 20 min Sub-group analysis 5: Modality to complete survey: • S-5a - Internet • S-5b – Telephone Sub-group analysis 6: Time practicing medicine (Question 33): • S-6a - Less than 3 years • S-6b - 3 to 5 years • S-6c - 6 to 15 years • S-6d - More than 15 years Sub-group analysis 7: Number of times per months prescribing TIRF medicines within the last 6 months (Question 29): • S-7a - None • S-7b - 1-2 times a month • S-7c - 3 - 5 times a month • S-7d - More than 5 times a month Sub-group analyses will be performed for Tables 6.1 and 6.2, 7.1, 7.2, 8.1, 8.2, 9.1, 9.2. 4.1.2.1 Primary Analyses Primary analyses were performed for all key risk messages, evaluating the number and percentage of correct responses for each individual question/item defined by the key risk message. The correct response to each question/item was identified in the body of the risk message table (Section 3.3). 4.1.2.2 Secondary Analyses Secondary analyses evaluated the number and percentages of correct responses and the average number of correct answers within the risk message to assess demonstrated understanding of the comprehensive key risk message. A correct response rate of 65% or FDA_1362 Prescriber KAB Assessment Report Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 22 of 67 greater was considered to represent adequate understanding of each concept or key risk message. 4.1.3 Prescriber Report of Adverse Event, Product Complaint, or Medical Information Request during Survey A prescriber may have reported a product complaint, or an adverse event experienced by their patients either while taking the online survey in the free text field or while in conversation with the Survey Coordinating Center. If the event was mentioned to a Survey Coordinating Center Associate, the Associate documented the safety event and the respondent’s contact information, if provided. The prescriber was also informed that a representative from the appropriate TIRF medicine manufacturer may contact them to obtain additional information about the adverse event or product complaint. Surveys completed on the Internet were monitored for any comments recorded in the free text field. Information on all reports (Internet or Telephone) that constituted an adverse event or product complaint was forwarded to the appropriate TIRF medicine manufacturer for processing within 1 business day of awareness of the event as outlined in the Adverse Event/Product Complaint Project Specific Procedure (AE/PC PSP). 5. RESULTS Results of the prescriber responses to questions in the KAB survey are summarized in this section, and a full set of responses can be found in Appendix B. 5.1 Survey Participants 5.1.1 Survey Participant Administration Results A total of 5,108 prescribers were sent letters inviting them to participate in this survey (Table 1). An additional 11,986 reminder letters were sent. Some prescribers may have received more than 1 reminder letter. In all, 425 prescribers who expressed interest in the survey were screened for eligibility. The number of respondents found eligible for participating in the survey was 302, all of whom completed the survey. Of the 302 eligible complete respondents, 289 (95.7%) completed the survey online, and 13 (4.3%) completed it by telephone (Table 3). There were no duplicate surveys. Based on the TRIG Sponsors interpretation of state laws regarding prescriber reimbursement, respondents from Massachusetts (MA), Vermont (VT), and Minnesota (MN) were eligible to participate in the survey; however, they were not eligible to receive the $125 honorarium. Letters were sent to prescribers in these states, and 2 respondents from Massachusetts chose to participate despite receiving no honorarium. FDA_1363 Prescriber KAB Assessment Report Transmucosal Irmnediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page_23 of 67 Table 1. Survey Participant Administration Results Screened Prescribers N=425l Summary Statistic All Respondents Number of invitations issued to prescribers 5108 Number of reminder letters issued to prescribers 11986 Number of prescribers screened for participation 425 Number of prescribers eligible for participation 302 71 . 11 Method of Sluvey Completion Nlunber of surveys completed by telephone 13 4.32 Nlunber of surveys completed by intemet 289 95.72 1 The denominator for the percentage of eligible prescribers is the munber of screened prescribers (N =425). 2 The denominator for percentages completed by telephone or Internet is the number of eligible prescribers As shown in Table 2, a total of 425 prescribers agreed to participate in this smvey and of those 302 prescribers reported that they were em?olled in the TIRF REMS Access program; 49 prescribers were ineligible because they reported that they were not em'olled in the program or they did not know whether they were em?olled. Seventeen respondents were ineligible because they had previously taken part in the smyey about TIRF medicines and 49 (1 respondents did not know if they had participated; therefore, they were considered ineligible. Five respondents were ineligible for the smvey because they, or an immediate family member, had worked for UBC or a TRIG company in the past, or did not know whether they, or an immediate family member, had worked for a TRIG company, UBC, RelayHealth, McKesson Specialty Care Solutions, or the FDA in the past, and 1 prescriber preferred not to answer and thus was considered ineligible. 364 Prescriber KAB Assessment Repo? Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page_24 of 67 Table 2. Survey Participant Screening Results Screened Prescribers Question Question 1: Do you agree to participate in this survey? Yes 423 99.5 302 100.0 No1 2 0.5 Question 2: Have you ever taken part in this survey about TIRF medicines before? TIRF medicines include AbstralO, Actiq", Fentora", Lazanda?, Onsolis?, Subsyso, and generic versions of any of these brands. Yes1 17 4.0 No 357 84.0 302 100.0 I don?t know1 49 11.5 Question not asked2 2 0.5 Question 3: Are you enrolled in the TIRF REMS Access program? Yes 308 72.5 302 100.0 No1 24 5.6 I don?t know1 25 5.9 Question not asked2 68 16.0 Question 4: Have you or any of your immediate family members ever worked for any of the following companies or agencies? Please select all that apply.3 Anesta LLC.1 0 0.0 Archimedes Phanna US. Inc.1 0 0.0 Cephalon. Inc. (a wholly-owned subsidiaiy 1 02 of Teva Phannaceutical Industries. Ltd.)1 Endo Phaimaceuticals. Inc.1 0 0.0 Galena Biophanna1 0 0.0 Insys Therapeutic s1 0 0.0 Mallinckrodt1 0 0.0 McKesson Specialty Care Solutions1 0 0.0 Meda Phaimaceuticalsl 0 0.0 Mylan Inc.1 1 0.2 365 Prescriber KAB Assessment Report Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industiv Group (TRIG) of Companies Page_25 of 67 Table 2. Survey Participant Screening Results Screened Prescribers Hug-1:522:23 [1):th Question Par Phalmaceutical. Inc.1 0 0.0 ProStrakan. Inc.1 0 0.0 RelayHealthl 0 0.0 Teva Pharmaceuticals. Ltd.1 2 0.5 United BioSource Corporation1 0 0.0 FDA1 0 0.0 None of these apply4 302 71.1 302 100.0 I don?t know1 1 0.2 Prefer not to answer1 1 0.2 Question not asked2 117 27.5 1 Ineligible to participate in the survey. 2 Question not asked due to previous question elimination. 3 More than 1 response can be selected. so percentages may not sum to 100%. 4 Ineligible if selected in addition to another response. Those taking the suivey online took a mean of 17.0 i 9.75 minutes to complete, while those taking it by telephone took a mean of 27.0 i 3.16 minutes. Most (11:214; 70.9%) online participants completed the smvey within 20 minutes. while all telephone participants (11:75; 24.8%) took 20 minutes or more (Table 3). Table 3. Time to Complete Survey for Completers Only (Minutes) Time to Complete Survey Summary Statistic Telephone Internet Total1 13 289 302 Mean (Standard Deviation) 27.0 (3.16) 17.0 (9.75) 17.5 (9.77) Minimum 21 5 5 Median 26.3 15.0 15.2 Maximum 34 109 109 366 Prescriber KAB Assessment Report Transmucosal Irmnediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page_26 of 67 Table 3. Time to Complete Survey for Completers Only (Minutes) Time to Complete Survey Summary Statistic Telephone Internet Totall Category 5 <10 Minutes 0 47 47 10 <15 Minutes 0 97 97 15 <20 Minutes 0 70 70 20 <25 Minutes 3 36 39 25 <30 Minutes 9 22 31 30 Minutes or More 1 17 18 1 Number of eligible prescribers completing the survey (See Table 1). 5.1.2 Demographic Characteristics of Prescribers who Completed the Survey The demographic characteristics of eligible prescribers who completed the sruvey are presented in Table 4. The survey included 27.5% respondents from the Northeast, 15.2% from the Midwest, 33.1% from the South, and 23.5% from the West region of the United States (US). The proportion of eligible completed prescribers within each geographic region was similar to the overall proportion of prescribers em?olled in the TIRF REMS Access Program as of 19 October 2013 in each geographic region (Table 4). There were no respondents from Puerto Rico, Northern Mariana Islands, US Virgin Islands, American Samoa, and Guam identi?ed as ?Other? in Table 4. The most common healthcare degree was an MD and the most medical specialties were pain management and oncology Of respondents who were medical doctors, 117 of the respondents had practiced medicine for more than 15 years. 367 Prescriber KAB Assessment Report Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page_27 of 67 Table 4 Demographic Characteristics of Eligible Prescribers Eligible Completed Prescribers Question N=302l Question 31: What is your gender? Male 197 65.2 Female 103 34.1 Prefer not to answer 2 07 Question 32: What is your medical degree? MD 182 60.3 DO 22 7.3 Nlu?se Practitioner 66 21.9 Physician?s Assistant 30 99 Prefer not to answer 2 07 Question 33: In total, how many years have you been practicing medicine, since completing your post?graduate education? Less than 3 years 28 9.3 3-5 years 49 16.2 6-10 years 55 18.2 11-15 years 51 16.9 More than 15 years 117 38.7 Prefer not to answer 2 0.7 Question 35: What is your medical specialty? Oncology 69 22.8 Primary Care 30 9.9 Pain Management 148 49.0 Other (please specify)2 53 17.5 368 Prescriber KAB Assessment Report Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page_28 of 67 Table 4 Demographic Characteristics of Eligible Prescribers Eligible Completed Prescribers Question N=302l Question 34: In which state or US Territory do you practice?3 Eligible and Complete Enrolled in TIRF REMS Respondents ccess Program as of Geographic Region3 l90ct2013 Northeast 83 27.5 2063 22.8 Midwest 46 15.2 1534 17.0 South 100 33.1 3010 33.3 West 71 23.5 2432 26.9 Other 0 0.0 3 0.0 Prefer not to answer 2 0.7 1 Niunber of eligible prescribers completing the survey (See Table 1). 2 Other medical specialties are presented in Appendix B. Listing 3. 3 According to the 2001 Geographic Area Regions set by the US Census Bureau. Geography Division. Northeast includes CT. MA. ME. NH. NJ. NY. PA. RI. and VT. Midwest includes IA. IL. IN. KS. MI. MN. MO. ND. NE. OH. SD. and WI. South includes AL. AR. DC. DE. FL. GA. KY. LA. MD. MS. NC. OK. SC. TN. TX. VA. and WV. West includes AKUT. WA. and WY. Other includes Puerto Rico. Northern Mariana Islands. US Virgin Islands. American Samoa. and Guam. Verbatim responses of prescribers who described their medical specialty as ?other? (see Table 4) are listed in Appendix B, Listing 2. 5.1.3 Prescribing Habits of Eligible Prescribers Related to TIRF Products Over the 6 months preceding the Stuyey, 173 of the prescribers recalled prescribing TIRF medicines 1 to 2 times a month. The most frequently prescribed TIRF product was Actiq or its generic equivalent (74.2% of prescribers), followed by Fentora by 58.5% of prescribers Table 5. 369 Prescriber KAB Assessment Report Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page_29 of 67 Table 5. Prescribing Habits of Respondents Completing the Survey Eligible Completed Prescribers Question N=302l Question 29: On average, how many times per month have you prescribed the TIRF medicines within the last 6 months? None 54 17.9 1-2 times per month 173 57_ 3 3-5 times per month 44 14.6 More than 5 times per month 18 6.0 I don?t remember 13 43 Question 30: Please select the TIRF medicines that you have prescribed within the last 6 months (select all that apply): 2 Abstral? 10 4.0 Actiq? 01' generic Actiq 184 74.2 Fentora? 145 58.5 Lazanda? 16 6.5 Onsolis? 4 1.6 Subsys? 56 22.6 (answered None to Question 29) 54 1 Number of eligible prescribers completing the survey (See Table 2 Percentages are calculated based on the sample presented with this question because of skip logic in the survey. Not applicable 5.1.4 TIRF Medicines Educational Materials Prescribers were asked about their access to educational materials for TIRF medicines, speci?cally the Prescribing Information, the Medication Guide, and the Patient- Prescriber Agreement Form (PPAF) (Table 6). Ahnost all prescribers reported they had received or had access to the F1111 Prescribing Information and the Medication Guide (282; 93.4%; 273; 90.4% respectively). Of those with access to these materials, 86.2% and 90.1% indicated that they had read the Full Prescribing Information and the Medication Guide, respectively. Additionally, most prescribers reported reviewing the PPAF with each patient or their caregiver signing the PPAF and having the patient/caregiver Sign the PPAF and giving a copy of the PPAF to the patient 370 Prescriber KAB Assessment Repo? Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 30 of 67 Table 6. Responses to Questions About the TIRF Medicines Educational Materials and the TIRF Patient-Prescriber-Agreement Form Question Eligible Completed Prescribers N=302l Question 20: Did you receive or do you have access to the Full Prescribing Information for the TIRF medicine that you prescribe? Yes 282 93.4 No 6 2.0 I don?t know 14 4.6 Question 21: Did you read the Full Prescribing Information for the TIRF medicine that you prescribe?2 Yes 243 86.2 No 33 11.7 I don?t know 6 2.1 (answered No or I don?t 20 know to Question 20) Question 22: Did you receive or do you have access to the Medication Guide for the TIRF medicine that you prescribe? Yes 273 90.4 No 8 2.6 I don?t know 21 7.0 Question 23: Did you read the Medication Guide for the TIRF medicine that you prescribe?2 Yes 246 90.1 No 24 8.8 I don?t know 3 1.1 (answered No 01? I don?t 29 know to Question 22) Question 24: Did you or do you have any questions about the information in the Full Prescribing Information or Medication Guide? Yes3 37 12.3 No 243 80.5 I don?t know 22 7.3 371 Prescriber KAB Assessment Rep01t Transmucosal Iimnediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 31 of 67 Table 6. Responses to Questions About the TIRF Medicines Educational Materials and the TIRF Patient?Prescriber-Agreement Form Question 26: Do you review the Patient?Prescriber Agreement Form with each of your patients for whom you prescribe TIRF medicines or their caregiver? Yes 262 86.8 No 25 8.3 I don?t know 15 5.0 Question 27: Do you and the patient or their caregiver sign the Patient-Prescriber Agreement Form for TIRF medicines after you have reviewed it with him/her?2 Yes 242 92.4 No 12 4.6 I don?t know 8 3.1 (answered No or I don?t 40 know to Question 26) Question 28: Do you give a copy of the Patient?Prescriber Agreement Form for TIRF medicines to the patient or their caregiver? Yes 243 80.5 No 34 11.3 I don?t know 25 8.3 Niunber of eligible prescribers completing the survey (See Table 1). 2 Percentages are calculated based on the sample presented with this question and this may not re?ect the entire sample because of skip logic in the survey. 3 Verbatim texts for questions about the information in the Full Prescribing Infomiation are presented in Appendix B. Listing 1. There were 37 respondents who typed a response into the free text ?eld for Question 24 (Did you or do you have any questions about the information in the Full Prescribing Information or Medication Guide?) The verbatim responses are listed in Appendix B. Listing 1). 5.2 KAB Survey Objectives 5.2.1 Key Risk Message Results The focus of this section of the document is on the ?ndings for the total eligible respondent population who completed the smvey. A srumnaiy of results by sub-group are described in a separate section of the document, Section 5.2.3. 372 Prescriber KAB Assessment Report Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 32 of 67 5.2.1.1 Key Risk Message 1 Key Risk Message 1: TIRF Medicines Are ontraindicated in Opioid Non-Tolerant Patients. Analysis of responses to components of Question 5 for Key Risk Message 1 showed that a high percentage of prescribers understand that TIRF medicines are contraindicated in opioid non-tolerant patients because life-threatening respiratory depression could occur (n=265; 87.7%) and that death has occurred in opioid non-tolerant patients treated with some fentanyl products (n=283; Most prescribers were aware patients just starting a TIRF medicine must begin with titration from the lowest available dose for that product (11:244; 80.8%) and that TIRF medicines may not be used to treat opioid non-tolerant patients (n=242; (Table 7). Overall, evidence of Imderstanding of the comprehensive key risk message is ?u?ther supported by the average munber of correct responses identi?ed as 6.0 out of 7. Table 7. Responses Linked to Key Risk Message 1: TIRF Medicines Are Contraindicated in Opioid Non-Tolerant Patients Eligible Completed Prescribers N=302l Question (95% Question 5: Please select ?True,? ?False,? or don?t know? for each of the following. According to the labeling for TIRF medicines, patients with cancer who are considered opioid? tolerant are those: 5a: Who are taking around?the?clock opioid therapy for underlying persistent cancer pain for one week or longer5 90.4 True2 273 (86.5. 93.5) False 24 7.9 I don?t know 5 1.7 5b: Who are not currently taking opioid therapy, but have taken opioid therapy before True 28 9.3 88.1 F1 2 a 56 266 (83.9. 91.5) I don?t know 8 2.6 373 Prescriber KAB Assessment Report Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 33 of 67 Table 7. Responses Linked to Key Risk Message 1: TIRF Medicines Are Contraindicated in Opioid Non-Tolerant Patients Eligible Completed Prescribers N=302l Question (95% 5c: Who have no known contraindications to the drug fentanyl, but are not currently taking around?the?clock opioid therapy True 39 12.9 82.1 False2 248 (77.3. 86.3) I don?t know 15 5.0 Question 7: Please answer ?True,? ?False,? or don?t know? for each statement based on the labeling for TIRF medicines. 7a: TIRF medicines are contraindicated in opioid non?tolerant patients because life?threatening respiratory depression could occur at any dose. Tmez 265 (83.279712) False 32 10.6 I don?t know 5 1.7 7b: Death has occurred in opioid non-tolerant patients treated with some fentanyl products. me 283 (90.932762) False 3 1.0 I don?t know 16 5.3 7c: TIRF medicines may be used to treat opioid non?tolerant patients. Tnle 43 14.2 Falsez 242 (75:92:45) I don?t know 17 5.6 374 Prescriber KAB Assessment Report Transmucosal Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 34 of 67 Table 7. Responses Linked to Key Risk Message 1: TIRF Medicines Are Contraindicated in Opioid Non-Tolerant Patients Eligible Completed Prescribers N=302l Question 7d: Prescribers starting a patient on a TIRF medicine must begin with titration from the lowest dose available for that speci?c product, even if the patient has previously taken another TIRF medicine. Tmez 244 (75:92:35.1) False 52 17.2 I don?t know 6 2.0 Secondary Analysis: Demonstrated Understanding 0 correct responses 1 0.3 1 correct response 2 0.7 2 correct responses 1 0.3 3 correct responses 7 2.3 4 correct responses 23 7.6 5 correct responses 41 13.6 6 correct responses 90 29.8 7 correct responses 137 45.4 Average munber of correct responses 4 6.0 (5.8. 7.0) I Number of eligible prescribers completing the sru'vey (See Table 1). 2 Indicates the correct response(s) to each question or item within a question. 3 All con?dence intervals are exact binomial 95% con?dence intervals. One-sided 95 con?dence interval using the normal approximation to the Poisson distribution. 5 Question 5a was included in the protocol as follows: Who are taking around-the-clock opioid therapy for underlying persistent chronic pain for one week or longer. The word ?chronic? was replaced with ?cancer? and presented to the prescribers in the survey accurately. 5.2.1.2 Key Risk Message 2 Key Risk Message 2: TIRF Medicines Are Only Indicated for the Management of Breakthrough Pain in Adult Cancer Patients 18 Years of Age and Older (I 6 Years of Age and Older for Actiq Brand and Generic Equivalents) Who Are Ah?eady Receiving and Who Are Tolerant to Arormd-The-C lock Opioid Therapy for Their Underlying Persistent Cancer Pain. 375 Prescriber KAB Assessment Report Transmucosal Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 35 of 67 Responses to components of Question 9 for Key Risk Message 2 indicate that a high percentage of respondents prescribe TIRF medicines for the approved indication of treatment of breakthrough cancer pain in opioid-tolerant patients (n=279; 92.4%) and not for patients with acute or postoperative pain headache or migraine pain or dental pain (Table 8). Question 13 presented respondents with descriptions of 4 patients experiencing breakthrough pain and asked them to select the case that should not receive a TIRF medicine. The con'ect response was given by 199 prescribers. Because Question 9 is related to the behavior of the prescribers. the secondary analysis showing demonstration of lmderstanding could not be performed. Table 8. Responses Linked to Key Risk Message 2: TIRF Medicines Are Only Indicated for the Management of Breakthrough Pain in Adult Cancer Patients 18 Years of Age and Older (16 Years of Age and Older for Actiq? Brand and Generic Equivalents) Who Are Already Receiving and Who Are Tolerant to Around-The-Clock Opioid Therapy for Their Underlying Persistent Cancer Pain Eligible Completed Prescribers N=302l (95% Question Question 9: In your practice, for which of the following indications do you prescribe TIRF medicines to opioid tolerant patients? Please answer ?Yes,? or don?t know? for each option. 9a: Acute or postoperative pain Yes 17 5.6 4 93.0 No 281 (89.6. 95.6) I don?t know 4 1.3 9b: Headache or migraine pain Yes 20 6.6 4 92.4 No 279 (88.8. 95.1) I don?t know 3 1.0 9c: Dental pain Yes 5 1.7 4 96.7 No 292 (94.0. 98.4) I don?t know 5 1.7 376 Prescriber KAB Assessment Report Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Table 8. Page 36 of 67 Responses Linked to Key Risk Message 2: TIRF Medicines Are Only Indicated for the Management of Breakthrough Pain in Adult Cancer Patients 18 Years of Age and Older (16 Years of Age and Older for Actiq? Brand and Generic Equivalents) Who Are Already Receiving and Who Are Tolerant to Around-The-Clock Opioid Therapy for Their Underlying Persistent Cancer Pain Eligible Completed Prescribers N=302l Question 11 (95% on3 9d: Breakthrough pain from cancer 4 92.4 Yes 279 (88.8. 95.1) No 22 7.3 I don?t know 1 0.3 9e: Chronic non-cancer pain Yes 119 39.4 4 58.9 No 178 (53.2. 64.5) I don?t know 5 1.7 Question 13: The patients described are experiencing breakthrough pain. According to the labeling, a TIRF medicine is not appropriate for one of them. Which patient should not receive a TIRF medicine? Please select one option. 13a: Adult male with advanced 11mg cancer: underlying persistent cancer pain managed with 25 mcg/hour transdermal fentanyl patches for the past two months. 36 11.9 13b: Adult female with localized breast cancer: just completed a mastectomy and reconstructive surgery: persistent cancer pain managed with 30 mg oral morphine daily for the past 6 weeks.2 199 65.9 13c: Adult male patient with advanced prostate cancer who. over the last 2 weeks. has been prescribed 100 mg oral morphine daily for pain due to bone metastasis. 12 4.0 377 Prescriber KAB Assessment Report Transmucosal Irmnediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 37 of 67 Table 8. Responses Linked to Key Risk Message 2: TIRF Medicines Are Only Indicated for the Management of Breakthrough Pain in Adult Cancer Patients 18 Years of Age and Older (16 Years of Age and Older for Actiq? Brand and Generic Equivalents) Who Are Already Receiving and Who Are Tolerant to Around-The-Clock Opioid Therapy for Their Underlying Persistent Cancer Pain Eligible Completed Prescribers N=302l Question 11 (95% 13d: Adult female with advanced sarcoma 28 9.3 who has been taking a daily dose of 12 mg oral hydromorphone for the last 3 weeks. 13c: I don?t know 27 8.9 1 Number of eligible prescribers completing the sru'vey (See Table 1). 2 Indicates the correct response(s) to each question or item within a question. 3 All con?dence intervals are exact binomial 95% con?dence intervals. 4Indicates the desired behavior(s) to each question or item within the question. 5.2.1.3 Key Risk Message 3 Key Risk Message 3: TIRF Medicines Contain Fentanyl, an Opioid Agonist, and a Schedule II Controlled Substance, With Abuse Liability Similar to Other Opioid Analgesics. Responses to components of Questions 7, 8, and 10 for Key Risk Message 3 showed that a high percentage of prescribers were aware that it is important to monitor for signs of abuse and addiction in patients who take TIRF medicines a personal history of illness is a risk factor for opioid abuse a personal history of past or current alcohol or ding abuse or family history of drug and alcohol abuse is a risk factor for opioid abuse and that TIRF medicines can be abused in a manner similar to other opioid agonists Overall, evidence of rmderstanding of the comprehensive key risk message is fmther supported by the average nmnber of correct responses identi?ed as 3.8 out of 4 (Table 9). 378 Prescriber KAB Assessment Report Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 38 of 67 Table 9. Responses Linked to Key Risk Message 3: TIRF Medicines Contain Fentanyl, an Opioid Agonist, and a Schedule II Controlled Substance, With Abuse Liability Similar to Other Opioid Analgesics. Eligible Completed Prescribers N=302l uestion (95% Question 7: Please answer ?True,? ?False,? or don?t know? for each statement about TIRF medicines. 7e: It is important to monitor for signs of abuse and addiction in patients who take TIRF medicines. 99.0 2 Tm 299 (97.1. 99.8) False 2 0.7 I don?t know 1 0.3 Question 8: Which of the following are risk factors for opioid abuse? Please answer ?Yes,? or don?t know? for each option. 8a: A personal history of illness 82.8 2 5 Yes 2 0 (78.0. 86.9) No 31 10.3 I don?t know 21 7.0 8b: A personal history of past or current alcohol or drug abuse, or a family history of illicit drug use or alcohol abuse 2 99.0 Yes 299 (97.1. 99.8) No 2 0.7 I don?t know 1 0.3 Question 10: Please answer ?True,? ?False,? or don?t know? for each statement about TIRF medicines. 10a: TIRF medicines can be abused in a manner similar to other opioid agonists. 2 96.4 Tme 291 (93.6. 98.2) False 9 3.0 I don?t know 2 0.7 379 Prescriber KAB Assessment Report Transmucosal Irmnediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 39 of 67 Table 9. Responses Linked to Key Risk Message 3: TIRF Medicines Contain Fentanyl, an Opioid Agonist, and a Schedule II Controlled Substance, With Abuse Liability Similar to Other Opioid Analgesics. Eligible Completed Prescribers Question 3 (95% CI) Secondary Analysis: Demonstrated Understanding 0 correct responses 0 0.0 1 correct response 0 0.0 2 correct responses 8 2.6 3 correct responses 53 17.5 4 correct responses 241 79.8 Average number of correct responses 4 3.8 (3.6. 4.0) 1 Number of eligible prescribers completing the survey (See Table 1). 2 Indicates the correct response(s) to each question or item within a question. 3 All con?dence intervals are exact binomial 95% con?dence intervals. 4 One-sided 95 con?dence interval using the normal approximation to the Poisson distribution. 5.2.1.4 Key Risk Message 4 Key Risk Message 4: TIRF Medicines Are Not Interchangeable With Each Other, Regardless of Route of Administration. Responses to components of Questions 10 and 14 for Key Risk Message 4 showed that 279 prescribers rmderstood that TIRF medicines are not interchangeable with each other regardless of the route of administration, that the conversion of one TIRF medicine to another may result in a fatal overdose (n=286; and that dosing of different TIRF medicines is not equivalent on a microgram-to-microgram basis (n=274; Question 14 dealt with the process the prescribers must adopt in converting a patient ??om one TIRF medicine to another. In response, 225 prescribers correctly responded that conversion must not be done on a microgram?to-microgram basis (Table 10). Overall, evidence of rmderstanding of the comprehensive key risk message is ?uther supported by the average number of correct responses identi?ed as 3.5 out of 4. 380 Prescriber KAB Assessment Report Transmucosal Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 40 of 67 Table 10. Responses Linked to Key Risk Message 4: TIRF Medicines Are Not Interchangeable With Each Other, Regardless of Route of Administration. Eligible Completed Prescribers N=302l Question (95% CI) Question 10: Please answer ?True,? ?False,? or don?t know? for each statement about TIRF medicines. 10b: TIRF medicines are interchangeable with each other regardless of route of administration. True 16 5.3 False? 279 92.4 (88.8. 95.1) I don?t know 7 2.3 10c: The conversion of one TIRF medicine for another TIRF medicine may result in a fatal overdose because of differences in the pharmacokinetics of fentanyl absorption. 94.7 Truez?3 286 (91.5. 96.9) False 7 2.3 I don?t know 9 3.0 10d: Dosing of TIRF medicines is not equivalent on a microgram?to-microgram basis. 90.7 23 me 274 (86.9. 93.8) False 16 5.3 I don?t know 12 4.0 14: A patient is already taking a TIRF medicine but wants to change their medicine. His/her doctor decides to prescribe a different TIRF medicine (that is not a bioequivalent generic version of a branded product) in its place. According to the labeling, how should the prescriber proceed? Please select one option. 14a: The prescriber can safely convert to the equivalent dosage of the new TIRF medicine as 6 2.0 it has the same effect as other TIRF medicines. 14b: The prescriber not convert to another TIRF medicine on a micrograrn-per-micrograrn basis because these medicines have different 225 74.5 (69.2. 79.3) absorption properties and this could result in a fentanyl overdose.2 381 Prescriber KAB Assessment Report Transmucosal Irmnediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 41 of 67 Table 10. Responses Linked to Key Risk Message 4: TIRF Medicines Are Not Interchangeable With Each Other, Regardless of Route of Administration. Eligible Completed Prescribers Question 11 (95% CI) 14c: Convert from the other TIRF medicine to 2 8 3 the new TIRF medicine at half of the dose. 14d: The prescriber should base the starting dose of the newly prescribed TIRF medicine 011 34 11 3 the dose of the opioid medicine used for their underlying persistent cancer pain. Me: I don?t know. 12 4.0 Secondary Analysis: Demonstrated Understanding 0 correct responses 1 0.3 1 correct response 3 1.0 2 correct responses 28 9.3 3 correct responses 75 24.8 4 correct responses 195 64.6 Average number of correct responses4 3.5 (3.3. 4.0) 1 Number of eligible prescribers completing the survey (See Table 1). 2 Indicates the correct response(s) to each question or item within a question. 3 All con?dence intervals are exact binomial 95% con?dence intervals. 4 One-sided 95 con?dence interval using the normal approximation to the Poisson distribution. 5.2.2 Other Survey Questions 5.2.2.1 Additional Questions about TIRF Medicines Safety Table 11 srmimarizes the prescribers? responses to questions about the safety of TIRF medicines; 21 of these questions were included within key risk message questions (Section 5.2.1) and 17 were additional questions beyond those associated with the key risk messages. Although, Table 11 presents the results of all 38 questions, this section highlights results of responses from the 17 additional questions. Over half of the (n=l83; 60.6%) prescribers surveyed correctly identi?ed that a cancer patient should not be started on a TIRF medicines and an arormd?the-clock opioid at the same time, while 105 prescribers responded that this is acceptable; 196 of prescribers correctly indicated that a cancer patient who has been on an around-the-clock 382 Prescriber KAB Assessment Report Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 42 of 67 opioid for one day should not start taking a TIRF medicine for breakthrough pain; and 160 (53.0%) responded that patients should not continue to take TIRF medicines if they stop taking their around-the-clock opioid medicine. This concept was a key risk message in the patient survey and also resulted in a low score. Prescribers are educated on this concept in the educational program and in the PPAF. Prescribers low understanding of this concept is likely have affected the level of understanding in the patient/caregivers. A majority of prescribers correctly identified the description of opioid-tolerant patients by the listed opioid preparations and corresponding doses of 8 mg oral hydromorphone/day (68.5%), 60 mg oral morphine/day (89.1%), 30 mg/day oral oxycodone (76.2%), 25 mcg transdermal fentanyl/hour (80.8%), 25 mg/day oral oxymorphone (69.9%), or an equianalgesic dose of another oral opioid (65.9%). Most of prescribers (n=254; 84.1%) correctly indicated that for a patient starting titration with a TIRF medicine, an appropriate dose is the lowest available dose, unless the Full Prescribing Information provides specific guidance (84.1%%). When presented with the scenario of a patient who has started on the lowest dose of a TIRF medicine, and, after 30 minutes, the breakthrough pain has not been sufficiently relieved, 205 (67.9%) prescribers correctly responded that guidance regarding additional doses should be based on the productspecific Medication Guide because the recommendations are not the same for all TIRF medicines. Question 17 as outlined in Table 11, demonstrates that the majority (225, 74.5%) of prescribers have a high level of understanding pertaining to the safe use of a TIRF medicine with a CYP3A4 inhibitor and the need for monitoring the dosage for their patient. Further, this data reflects that the prescribers clearly understand the need to carefully monitor the patient for opioid toxicity to avoid any potential cause for fatal respiratory depression. Of the 302 respondents who completed the survey, 199 (65.9%) correctly stated that a patient who had a mastectomy and reconstructive surgery for localized breast cancer with persistent cancer pain managed with 30 mg/day oral morphine for 6 weeks should not receive TIRF medicines because the patient does not meet the definition of opioid tolerant. Furthermore, the majority (225, 74.5%) of prescribers correctly indicated that the prescriber must not convert a patient to another TIRF medicine on a microgram-per-microgram basis because these medicines have different absorption properties and this could result in a fentanyl overdose. Nearly all prescribers surveyed (n=298; 98.7%) understood that TIRF medicines contain fentanyl in an amount that could be fatal for children of all ages, for individuals for whom they were not prescribed, and for those who are not opioid tolerant. Two hundred and seventy-eight (92.1%) prescribers were aware that patients must be informed that TIRF medicines should not be used for acute or postoperative pain, pain from injuries, headache/migraine, or any other short-term pain. One hundred and seventy-five (57.9%) prescribers understood that patients should be instructed not to continue their TIRF medicines if they stop taking their around-the-clock opioid medicine; 299 (99.0%) agreed that patients must be instructed not to share their TIRF medicine with anyone else, even if FDA_1383 Prescriber KAB Assessment Report Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industiv Group (TRIG) of Companies that person has the same and 160 indicated that if patients stop taking their aromid-the-clock opioid pain medicine, they must stop taking their TIRF medicine. Page 43 of 67 Table 11. Responses to Additional Questions About the Safe Use of TIRF Medicines Eligible Completed Prescribers Question N=302l Question 5: Please answer ?True,? ?False,? or don?t know? for each of the following. According to the labeling, patients considered opioid-tolerant are those: 5a: Who are taking regular opioid therapy for underlying persistent cancer pain for one week or longer.? Tine2 273 90.4 False 24 7.9 I don?t know 5 1.7 5b: Who are not currently taking opioid therapy, but have taken opioid therapy before. Tine 28 9.3 False2 266 88.1 I don?t know 8 2.6 5c: Who have no known contraindications to the drug fentanyl, but are not currently taking around-the?clock opioid therapy 1'1th 39 12.9 False2 248 82.1 I don?t know 15 5.0 Question 6: Please answer ?True,? ?False,? or don?t know? for each statement based on the labeling for TIRF medicines. 6a: A cancer patient can be started on a TIRF medicine and an around-the?clock opioid at the same time. Tine 105 34.8 False2 183 60.6 I don?t know 14 4.6 384 Prescriber KAB Assessment Report Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 44 of 67 Table 11. Responses to Additional Questions About the Safe Use of TIRF Medicines Eligible Completed Prescribers Question N=302l 6b: A cancer patient who has been on an around?the?clock opioid for 1 day can start taking a TIRF medicine for breakthrough pain. True 86 28.5 False2 196 64.9 I don?t know 20 6.6 Question 7: Please answer ?True,? ?False,? or don?t know? for each statement based on the labeling for TIRF medicines. 7a: TIRF medicines are contraindicated in opioid non?tolerant patients because life- threatening respiratory depression could occur at any dose. Tme2 265 87.7 False 32 10.6 I don?t know 5 1.7 7b: Death has occurred in opioid non-tolerant patients treated with some fentanyl products. Tme2 283 93.7 False 3 1.0 I don?t know 16 5.3 7c: TIRF medicines may be used to treat opioid non?tolerant patients. False2 242 80.1 True 43 14.2 I don?t know 17 5.6 7d: Prescribers starting a patient on a TIRF medicine must begin with titration from the lowest dose available for that speci?c product, even if the patient has previously taken another TIRF medicine. True2 244 80.8 False 52 17.2 I don?t know 6 2.0 385 Prescriber KAB Assessment Report Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 45 of 67 Table 11. Responses to Additional Questions About the Safe Use of TIRF Medicines Eligible Completed Prescribers Question N=302l 7e: It is important to monitor for signs of abuse and addiction in patients who take TIRF medicines. Tme2 299 99.0 False 2 0.7 I don?t know 1 0.3 Question 8: Which of the following are risk factors for opioid abuse? Please answer ?Yes,? or don?t know? for each option. 8a: A personal history of illness Yes2 250 82.8 No 31 10.3 I don?t know 21 7.0 SD: A personal history of past or current alcohol or drug abuse, or a family history of illicit drug use or alcohol abuse Yes2 299 99.0 No 2 0.7 I don?t know 1 0.3 8c: A family history of asthma Yes 12 4.0 No2 271 89.7 I don?t know 19 6.3 Question 9: In your practice, for which of the following indications do you prescribe TIRF medicines to opioid tolerant patients? Please answer ?Yes,? or don?t know? for each option. 9a: Acute or postoperative pain Yes 17 5.6 No4 281 93.0 I don?t know 4 1.3 386 Prescriber KAB Assessment Report Transmucosal Release Fentanyl (TIRF) TIRF REMS Industw Group (TRIG) of Companies Page 46 of 67 Table 11. Responses to Additional Questions About the Safe Use of TIRF Medicines Eligible Completed Prescribers Question N=302l 9b: Headache or migraine pain Yes 20 6.6 No4 279 92.4 I don?t know 3 1-0 9c: Dental pain Yes 5 1.7 No4 292 96.7 I don?t know 5 1.7 9d: Breakthrough pain from cancer Yes4 279 92.4 No 22 7.3 I don?t know 1 0.3 9e: Chronic non?cancer pain Yes 119 39.4 No4 178 58.9 I don?t know 5 1.7 Question 10: Please answer ?True,? ?False,? or don?t know? for each statement based on the labeling for TIRF medicines. 10a: TIRF medicines can be abused in a manner similar to other opioid agonists. Tme2 291 96.4 False 9 3.0 I don?t know 2 0.7 10b: TIRF medicines are interchangeable with each other regardless of route of administration. Tme 16 5.3 False2 279 92.4 I don?t know 7 2.3 387 Prescriber KAB Assessment Rep01t Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 47 of 67 Table 11. Responses to Additional Questions About the Safe Use of TIRF Medicines Eligible Completed Prescribers Question N=302l 10c: The conversion of one TIRF medicine for another TIRF medicine may result in a fatal overdose because of differences in the pharmacokinetics of fentanyl absorption. Tme2 286 94.7 False 7 2.3 I don?t know 9 3.0 10d: Dosing of TIRF medicines is not equivalent on a mic rogram-to-microgram basis. True2 274 90.7 False 16 5.3 I don?t know 12 4.0 Question 11: Please select ?True,? ?False,? or don?t know? for each of the following. According to the labeling for TIRF medicines, patients considered opioid-tolerant are those who are taking, for one week or longer, at least: 11a: 8 mg oral hydromorphone/day Tme2 207 68.5 False 64 21.2 I don?t know 31 10.3 11b: 60 mg oral morphine/day. Tme2 269 89.1 False 16 5.3 I don?t know 17 5.6 11c: 30 mg oral oxycodone/day Tme2 230 76.2 False 47 15.6 I don?t know 25 8.3 388 Prescriber KAB Assessment Report Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 48 of 67 Table 11. Responses to Additional Questions About the Safe Use of TIRF Medicines Eligible Completed Prescribers Question N=302l 11d: 25 transdermal fentanyl/hour Tme2 244 80.8 False 34 11.3 I don?t know 24 7.9 He: 25 mg oral oxymorphone/day Tme2 211 69.9 False 39 12.9 I don?t know 52 17.2 11f: An equianalgesic dose of another oral opioid Tme2 199 65.9 False 68 22.5 I don?t know 35 11.6 Question 13: The patients described are experiencing breakthrough pain. According to the labeling, a TIRF medicine is not appropriate for one of them. Which patient should not receive a TIRF medicine? Please select one option. Adult female with localized breast cancer: just completed a mastectomy and reconstructive surgery: persistent cancer pain managed with 30 111g oral morphine daily for the past 6 weeks.2 199 65.9 Adult male with advanced 11mg cancer: underlying persistent cancer pain managed with 25 mcg/hour transdennal fentanyl patches for the past two months. 36 11.9 Adult male patient with advanced prostate cancer who. over the last 2 weeks. has been prescn'bed 100 mg oral 11101phine daily for pain due to bone metastasis 12 4.0 Adult female with advanced sarcoma who has been taking a daily dose of 12 mg oral hydromorphone for the last 3 weeks 28 9.3 I don?t know 27 8.9 389 Prescriber KAB Assessment Report Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 49 of 67 Table 11. Responses to Additional Questions About the Safe Use of TIRF Medicines Eligible Completed Prescribers Question N=302l Question 14: A patient is already taking a TIRF medicine but wants to change their medicine. His/her doctor decides to prescribe a different TIRF medicine (that is not a bioequivalent generic version of a branded product) in its place. According to the labeling, how should the prescriber proceed? Please select one option. 14a. The prescriber can safely convert to the equivalent dosage of the new TIRF medicine as it has the effect as other TIRF medicines. 2.0 14b. The prescriber must not convert to another TIRF medicine on a microgram-per-microgram basis because these medicines have different absorption properties and this could result in a fentanyl overdose.2 225 14c. Convert ?om the other TIRF medicine to the new TIRF medicine at half of the dose. 25 8.3 14d. The prescriber should base the starting dose of the newly prescribed TIRF medicine 011 the dose of the opioid medicine used for their underlying persistent cancer pain. 34 11.3 14e. I don?t know. 12 4.0 Question 15: A patient is starting titration with a TIRF medicine. What dose must they start with? Please select one option. The lowest available dose. rurless individual product Full 254 84.1 Prescribing Information provides product-speci?c guidance.2 An appropriate dose based on the dose of the opioid 37 123 medicine used for rurderlying persistent cancer pain. The dose that the prescriber believes is appropriate based 011 8 2,6 their clinical experience. The median available dose. 1 0.3 I don?t know. 2 0.7 390 Prescriber KAB Assessment Report Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 50 of 67 Table 11. Responses to Additional Questions About the Safe Use of TIRF Medicines Question Eligible Completed Prescribers N=302l Question 16: A prescriber has started titrating a patient with the lowest dose of a TIRF medicine. However, after 30 minutes the breakthrough pain has not been suf?ciently relieved. What should they advise the patient to do? Please pick the best option of the scenarios described. 16a. Take another (identical) dose of the TIRF medicine 73 24.2 16b. Take a dose of an altemative rescue medicine. 16 53 16c. Provide guidance based 011 the product-specific 205 67.9 Medication Guide because the instructions are not the same for all TIRF medicines. 2 16d. Double the dose and take immediately. 3 1.0 16e. I don?t know. 5 1.7 Question 17: A patient is taking a TIRF medicine and the doctor would like to prescribe a CYP3A4 inhibitor. Please pick the best option of the scenarios described. 17a: The patient can?t be prescribed because using it at the same time as a TIRF medicine could be fatal. 11 3.6 17b: Use of a TIRF medicine with a CYP3A4 inhibitor may require dosage adjustment: carefully monitor the patient for opioid toxicity. otherwise such use may cause potentially fatal respiratory depression.2 225 74.5 17c: There is no possible drug interaction between CYP3A4 inhibitors and TIRF medicines. 1.0 17d: The dose of the TIRF medicine must be reduced by one-half if a CYP3A4 inhibitor is prescribed in the same patient. 13 4.3 17e: I don?t know. 50 16.6 391 Prescriber KAB Assessment Report Transmucosal Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 51 of 67 Table 11. Responses to Additional Questions About the Safe Use of TIRF Medicines Eligible Completed Prescribers Question N=302l Question 18: Before initiating treatment with a TIRF medicine, prescribers must review the Medication Guide with the patient. Please select ?True,? ?False,? or don?t know? for each of the following counseling statements. 18a: TIRF medicines contain fentanyl in an amount that could be fatal to children of all ages, in individuals for whom they were not prescribed, and in those who are not opioid tolerant. True2 298 98.7 False 1 0.3 I don?t know 3 1.0 18b: Inform patients that TIRF medicines must not be used for acute or postoperative pain, pain from injuries, headache/migraine, or any other short-term pain. Tme2 278 92.1 False 16 5.3 I don?t know 8 2.6 18c: Instruct patients that, if they stop taking their around?the?clock opioid medicine, they can continue to take their TIRF medicine. Tme 95 31.5 False2 175 57.9 I don?t know 32 10.6 18d: Instruct patients never to share their TIRF medicine with anyone else, even if that person has the same True2 299 99.0 False 3 1.0 I don?t know 0 0.0 392 Prescriber KAB Assessment Rep01t Transmucosal Iimnediate Release Fentanyl (TIRF) TIRF REMS Industn7 Group (TRIG) of Companies Page 52 of 67 Table 11. Responses to Additional Questions About the Safe Use of TIRF Medicines Eligible Completed Prescribers Question N=302l Question 19: Can patients continue to take their TIRF medicine if they stop taking their around-the-clock opioid medicine? Yes 105 34.8 No2 160 53.0 I don?t know. 37 12.3 1 Number of eligible prescribers completing the survey (See Table 1). 2 Indicates the correct response(s) to each question or item within a question. 3 Question 5a was included in the protocol as follows: Who are taking around-the-clock opioid therapy for underlying persistent chronic pain for one week or longer. The word ?cancer? was replaced with chronic and presented to the prescribers in the survey accurately. The question as presented in the survey has been updated for reporting purposes. 4Indicates the desired behavior(s) to each question or item within a question. 5.2.2.2 Prescriber Activities When Prescribing TIRF Medicines Prescribers were asked about speci?c activities perf01med when prescribing TIRF medicines (Table 12). More than one-half of prescribers indicated they always ask patients (or their caregivers) about the presence of children in the home. Prescribers take care to instluct patients (or their caregivers) not to share TIRF medicines (n=239; When asked about counseling patients/caregivers that accidental exposure to TIRF medicines by a child might be fatal, 197 prescribers selected ?always?, 63 responded ?only with fn'st prescription?, and 31 answered ?sometimes?. In response to the question about instructing patients/caregivers to keep TIRF medicines out of the reach of children, 220 selected ?always,? 46 selected ?only with the ?rst prescription,? and 28 selected ?sometimes.? With regard to instructing patients/caregivers about proper disposal of any Imused or partially used TIRF medicines, 187 answered ?always,? 62 answered ?only with the ?st prescription,? and 37 responded ?sometimes.? Less than one-half of prescribers always give patients/caregivers the Medication Guide for their TIRF medicine. and 35.8% give their patients/caregivers the Medication Guide for their TIRF medicine only with the ?st prescription. 393 Prescriber KAB Assessment Report Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industn7 Group (TRIG) of Companies Page 53 of 67 Table 12. Responses to All Questions About Activities When Prescribing TIRF Medicines Question Eligible Completed Prescrihers N=302l Question 12: How frequently do you perform the following activities when prescribing TIRF medicines? Please answer ?Always,? ?Only with the first prescription,? ?Sometimes,? ?Never,? or don?t know.? 12a: Ask patients (or their caregivers) about the presence of children in the home. Always 170 56.3 Only with the ?st prescription 70 23.2 Sometimes 48 15.9 Never 11 3.6 I don?t know 3 1.0 12b: Instruct patients (or their caregivers) not to share TIRF medicines with anyone else. Always 239 79.1 Only with the ?rst prescription 37 12.3 Sometimes 19 6.3 Never 5 1.7 I don?t know 2 0.7 12c: Counsel patients (or their caregivers) that accidental exposure to TIRF medicines by a child may be fatal. Always 197 65.2 Only with the ?st prescription 63 20.9 Sometimes 3 1 10.3 Never 8 2.6 I don?t know 3 1.0 394 Prescriber KAB Assessment Report Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industn7 Group (TRIG) of Companies Page 54 of 67 Table 12. Responses to All Questions About Activities When Prescribing TIRF Medicines Eligible Completed Prescribers Question N=302l 12d: Instruct patients (or their caregivers) to keep TIRF medicines out of the reach of children to prevent accidental exposure. Always 220 72.8 Only with the fn?st prescription 46 15.2 Sometimes 28 9.3 Never 5 1.7 I don?t know 3 1.0 12e: Instruct patients (or their caregivers) about proper disposal of any unused or partially used TIRF medicines. Always 187 61.9 Only with the ?st prescription 62 20.5 Sometimes 37 12.3 Never 12 4.0 I don?t know 4 1.3 12f: Give patients (or their caregivers) the Medication Guide for their TIRF medicine. Always 142 47.0 Only with the fn?st prescription 108 35.8 Sometimes 26 8.6 Never 20 6.6 I don?t know 6 2.0 1 Ntunber of eligible prescribers completing the sru'vey (See Table 1). 5.2.3 Analyses of Sub-populations To assess prescriber understanding of key risk messages. sub-group analyses as described in Section 4.1.2 were conducted. The full set of sub-group analysis tables is provided in Appendix B. With only 13 respondents who completed the telephone smvey, sub-group analysis based on time to complete smvey using the telephone modality was not carried out. Of the 13 respondents who completed the survey via telephone. the correct response rate when asked to identify patients with cancer who are considered opioid-tolerant was 53.8% by 395 Prescriber KAB Assessment Report Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 55 of 67 selecting the “False” response to Question 5b: “Who are not currently taking opioid therapy, but have taken opioid therapy before” compared with the correct response rate of 89.6% for those who used the Internet. Of the 13 phone respondents, 7 (53.8%) telephone respondents correctly selected the “False” response for Question 5c: “Who have no known contraindications to the drug fentanyl, but are not currently taking around-the-clock opioid therapy” (Key Risk Message 1) compared with 83.4% in the sub-group that used the Internet (Appendix B, Table 6.1.5). Of the 35 prescribers who had not read the Medication Guide or Full Prescribing Information, 24 (68.6%) were aware that TIRF medicines may not be used in opioid nontolerant patients (Question 7c; Key Risk Message 1) compared with 218 (81.6%) prescribers who read the Medication Guide or PI (Appendix B, Table 6.1.1). 65.7% (n=23) of 35 respondents who had not read the Medication Guide or the Full Prescribing Information correctly identified “a personal history of psychiatric illness” as a risk factor for opioid abuse (Question 8a, Key Risk Message 1) compared with 85.0% among those who had read the Medication Guide or PI (Appendix B, Table 8.1.1). Respondents who completed the survey in less than 10 minutes had a low correct response rate of 57.4% when asked about prescribing an alternate TIRF medicine that is not a bioequivalent generic version of the branded product (Question 14, Key Risk Message 4) compared with the more than 75% correct response rate among those who took longer to complete the survey (Appendix B, Table 9.1.3). 5.3 Spontaneous Comments or Medical Information Requests Verbatim comments, questions, and requests for medical information are listed in Appendix B, Listing 3. • • • • • • • 5.4 Two statements related to lack of clarity regarding definition of opioid-tolerant; Three questions related to requests for more information on drug interactions; Seven statements dealt with the need for better understanding of dosage and dose titration guidelines; 4 requests concerned guidelines for conversion; There were 3 requests for adverse event information; Two requests had to do with equianalgesic data; One was a request or update medical information; and One request was for a copy of the Medication Guide. (Appendix B, Listing 2). Summary of Correct Responses for Key Risk Messages The 4 key risk messages included in the survey included 22 components detailing these key risk messages. Respondents demonstrated a high level of understanding of the 4 key risk messages, as there was a correct response rate of greater than 70% for 20 components of the key risk message questions. Question 13 that asked prescribers to identify from a drop-down list of case descriptions of patients for whom TIRF medicine is not appropriate had a correct response rate of 65.9%. Twelve of the 22 components elicited correct response rates in FDA_1396 Prescriber KAB Assessment Report Transmucosal Irmnediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 56 of 67 excess of 90% (Table 13). A tabulated srumnary of the results of the primary analyses of correct responses to questions rmder each key risk message is shown below (Table 13). Directed by the FDA, Question 9 (In your practice, for which of the following indications do you prescribe TIRF medicines to opioid tolerant patients?), which is a behavior assessment question, was included in Key Risk Message 2. Given this question documents behaviors, there is no correct answer but there are desired responses, which according to the protocol was the selection of the ?No? responses for the options ?acute or postoperative pain, headache or migraine pain, dental pain, and chronic non-cancer pain? and the ?Yes? response for the option ?breakthrough pain from cancer? (Table 13). Accordingly, the number of responses and percentages shown against each option of Question 9 in Table 13 represent the numbers of respondents and percentages of respondents reporting the desired behavior for each option. Table 13. Summary of Correct Responses for Key Risk Messages Correct Key Risk Message Question Question Responses Key Risk Message 1: TIRF Medicines 5 Patients with cancer who are considered Are Contraindicated in Opioid Non- opioid-tolerant are those: Tolerant Patients Who are taking arormd-the- clock opioid therapy for 5a lurderlying persistent chronic 273 90.4 pain for one week or longer (Correct Response True) Who are not currently taking opioid therapy. but have taken 5 . . . oprord therapy before (Correct 266 88 1 Response False) Who have no known contraindications to the drug 5c feutanyl. but are not currently 248 82.1 taking arormd-the-clock opioid therapy (Correct Response False) 397 Prescriber KAB Assessment Report Transmucosal Iimnediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Table 13. Summary of Correct Responses for Key Risk Messages Page 57 of 67 Key Risk Message Question Question Correct Responses Key Risk Message 1 (cont?d) 7a TIRF medicines are contraindicated in opioid non- tolerant patients because life- threatening respiratory depression could occur at any dose (Correct Response True) 265 87.7 7b Death has occurred in opioid non-tolerant patients treated with some fentanyl products (Correct Response True) 283 93.7 7c TIRF medicines may be used to treat opioid non-tolerant patients (Correct Response False) 242 80.1 7d Prescribers starting a patient on a TIRF medicine must begin with titration from the lowest dose available for that speci?c product. even if the patient has previously taken another TIRF medicine (Correct Response True) 244 80.8 Key Risk Message 2: TIRF Medicines Are Only Indicated for the Management of Breakthrough Pain in Adult Cancer Patients 18 Years of Age and Older (16 Years of Age and Older for Actiq? Brand and Generic Equivalents) Who Are Already Receiving and W110 Are Tolerant to Around-"Ilie-C lock Opioid Therapy for Their Underlying Persistent Cancer Pain In your practice, for which of the following indications do you prescribe TIRF medicines to opioid tolerant patients? 9a Acute or postoperative pain (Desired Behavior No) 281 93.0 9b Headache or migraine pain (Desired Behavior No) 279 92.4 9c Dental pain (Desired Behavior No) 292 96.7 398 Prescriber KAB Assessment Rep01t Transmueosal Iimnediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 58 of 67 Table 13. Summary of Correct Responses for Key Risk Messages Correct Key Risk Message Question Question Responses Key Risk Message 2 (cont (1) 9d pam from cancer 279 92.4 (Deszred Behavior Yes) Chronic non-cancer pain 96 (Desired Behavior No) 178 58'9 The patients described are experiencing breakthrough pain. According to the labeling. 13 a TIRF medicine is not appropriate for one of them. Which patient should not receive a TIRF medicine? Adult female with localized breast cancer; just completed a mastectomy and reconstructive surgery: persistent cancer pain managed with 30 mg oral morphine daily for the past 6 weeks (Correct Response) 199 65.9 399 Prescriber KAB Assessment Report Transmucosal Iimnediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Table 13. Summary of Correct Responses for Key Risk Messages Page 59 of 67 Key Risk Message Question Question Correct Responses Key Risk Message 3: TIRF Medicines Contain Fentanyl. an Opioid Agonist and a Schedule II Controlled Substance. With Abuse Liability Similar to Other Opioid Analgesics 7e It is important to monitor for signs of abuse and addiction in patients who take TIRF medicines (Correct Response True) 299 99.0 Which of the following are risk factors for opioid abuse? 8a A personal history of illness (Correct Response Yes) 250 82.8 8b A personal history of past or current alcohol or abuse. or a family history of illicit drug use or alcohol abuse (Correct Response Yes) 299 99.0 10a TIRF medicines can be abused in a manner similar to other opioid agonists (Correct Response True) 291 96.4 Key Risk Message 4: TIRF Medicines Are Not Interchangeable With Each Other. Regardless of Route of Administration 10b TIRF medicines are interchangeable with each other regardless of route of administration (Correct Response False) 279 92.4 10c The conversion of one TIRF medicine for another TIRF medicine may result in a fatal overdose because of differences in the pharmacokinetics of fentanyl absorption (Correct Response True) 286 94.7 400 Prescriber KAB Assessment Report Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industrv Group (TRIG) of Companies Page 60 of 67 Table 13. Summary of Correct Responses for Key Risk Messages Correct Key Risk Message Question Question Responses Key Risk Message 4 (cont?d) Dosing of TIRF medicines is 10d not equivalent on a microgram- 274 90.7 to-microgram basrs (Correct Response True) A patient is already taking a TIRF medicine but wants to change their medicine. His/her doctor decides to prescribe a different TIRF l4 medicine (that is not a bioequivalent generic version of a branded product) in its place. According to the labeling, how should the prescriber proceed? The prescriber must not convert to another TIRF medicine on a microgram-per-microgram basis 14b because these medicines have 225 74.5 different absorption properties and this could result in a fentanyl overdose (Correct Response). 6. DISCUSSION, CONCLUSIONS, AND RECOMNIENDATIONS The prescriber KAB survey included responses from 302 TIRF medicine prescribers invited from a random sample of all prescribers enrolled in the REMS. The specific goals of the prescriber KAB survey was to assess prescribers? understanding of the risks associated with TIRF medicine use, the selection of appropriate patients for treatment with TIRF medicines, preventing inappropriate conversion between TIRF medicines, and ensuring safe use of TIRF medicines while preventing exposure to children and others for whom TIRF medicines were not prescribed. Following the 12 March 2013 FDA feedback on the 12-month TIRF REMS Access Program Assessment Report, the survey questionnaire was modified as described in Section 3.1. Based on the FDA recommendations, the key risk message questions listed in Table 14 were reworded and/or added to key risk messages for the 24-month KAB survey. (Questions 5b, 9c, and 13b that were not part of any key risk message in the 12-month survey were added to key risk messages in the 24-month survey.) 401 Prescriber KAB Assessment Report Transmucosal Irmnediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 61 of 67 As demonstrated in Table 14 there were no signi?cant differences in correct response rates for most questions in each of the key risk messages between the 12-month and 24-month assessments. The 2 questions that elicited noticeably higher rates of correct responses in the 24-month Slu'vey were added as key risk message questions for the 24?month sruvey. These Questions (5a and 5c) related to the concept of opioid-tolerant patients. Although Question 9, identi?ed as a behavior question, was included as a key risk message following the FDA recommendation, the desired response to the item 9e lurder Question 9 did not show improvement in the present sruvey over the 12-month sruvey (Table 14). The inclusion of Questions 5a, and 5c as key risk messages and the re-wording (Section 3.1.1) helped improve the measurement of prescriber understanding. As for the other questions listed in Table 14, the correct response rates were similar for both 12-month and 24-month surveys. Table 14 Correct Response Rates in the 24?month KAB Survey Compared with the 12-month KAB Survey in Key Risk Message Questions Modi?ed Between the Two Versions lZ?Month 24-Month lZ?Month 24?Month Survey Survey Survey Survey Questions as Presented in the 24-Month Correct Correct Question Question Survey Response Response Number Number Rate Rate Please answer ?True." ?False.? or don?t know? for each of the following. According labeling. patients consrdered oprord-tolerant are those: Who are taking regular opioid therapy for underlying persistent cancer pain for one week or - a - a longer 7.9 90.4 (Correct Response True) Who are not crurently taking opioid therapy. but 5b 5b have taken opioid therapy before 88.7 88.1 (Correct Response False) Who are not crurently taking opioid therapy. but with no known intolerance or hypersensitivity to Sc 5c 15.6 82.1 the drug fentanyl (Correct Response False) 402 Prescriber KAB Assessment Report Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 62 of 67 Table 14 Correct Response Rates in the 24-month KAB Survey Compared with the 12-month KAB Survey in Key Risk Message Questions Modi?ed Between the Two Versions lZ?Month 24?Month lZ-Month 24-Month Survey Survey Survey Survey Questions as Presented in the 24-Month Correct Correct Question Question Survey Response Response Number Number Rate Rate For which of the following indications do you 8 9 prescriber TIRF medicines to opioid tolerant patients? Please answer ?Yes." No.? or don?t know? for each option Chronic non-cancer pain 8e 9e 54.3 58.9 (Desired Behavior No) The patients described are experiencing breakthrough pain. According to the labeling. a 11 13 TIRF medicine is not appropriate for one of them. Which patient should not receive a TIRF medicine? Please select one option. Adult female with localized breast cancer: just completed a mastectomy and reconstructive 1 1b 13b sm'geiy: persistent cancer pain managed with 30 54.3 65.9 mg oral morphine daily for the past 6 weeks. (Correct Response No) A patient is ah?eady taking a TIRF medicine but wants to change their medicine. His/her doctor decides to prescribe a different TIRF medicine 12 14 (that is not a bioequivalent generic version of a branded product) in its place. According to the labeling. 110w should the prescriber proceed? Please select one option. 403 Prescriber KAB Assessment Report Transmucosal Irmnediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 63 of 67 Table 14 Correct Response Rates in the 24-month KAB Survey Compared with the lZ-month KAB Survey in Key Risk Message Questions Modi?ed Between the Two Versions lZ?Month 24?Month lZ-Month 24-Month Survey Survey Survey Survey Questions as Presented in the 24?Month Correct Correct Question Question Survey Response Response Number Number Rate Rate The prescriber must not convert to another TIRF medicine 011 a microgram-per?microgram basis because these medicines have different 12b 14b 75.5 74.5 absorption properties and this could result in a fentanyl overdose (Correct Response) The concept that a patient must discontinue a TIRF medicine when they stop taking their arormd-the-clock opioid, while not a key risk message for the prescribers, received a low correct response rate. Prescribers are educated on this concept in the educational program and in the PPAF. Prescribers low imderstanding of this concept is likely to have affected the level of imderstanding of respondents in the patient smvey. The TRIG is exploring options to increase awareness of this important safety message. The overall higher level of imderstanding of the remaining items/ questions throughout the 4 key risk messages indicates that prescribers are knowledgeable about the safe of TIRF medicines. The consistent high level of prescribers tmderstanding of key risk messages between the 12-month and 24-month sruveys indicates that the prescriber education program is meeting the goals of the TIRF REMS with the tools cmrently in place. 404 Prescriber KAB Assessment Report Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Appendix A Page 64 of 67 Prescriber Survey Protocol FDA_1405 PROTOCOL TITLE: Quantitative Testing of Prescriber Knowledge, Attitudes, and Behavior about Transmucosal Immediate Release Fentanyl (TIRF) Products Safety and Use Information SPONSOR: TIRF REMS Industry Group (TRIG) Archimedes Pharma US Inc. Cephalon, Inc. (a wholly-owned subsidiary of Teva Pharmaceutical Industries, Ltd.) Galena Biopharma Insys Therapeutics Mallinckrodt Meda Pharmaceuticals Mylan, Inc. Par Pharmaceutical, Inc. VERSION: 5.0 DATE: 10 SEP 2013 APPROVED: FINAL FDA_1406 TIRF REMS Industry Group (TRIG) Transmucosal Immediate Release Fentanyl (TIRF) Products Prescriber KAB Survey Protocol TABLE OF CONTENTS Version 5.0 10 Sep 2013 PAGE TABLE OF CONTENTS ......................................................................................... 2 1. LIST OF ABBREVIATIONS .................................................................................. 3 2. BACKGROUND ..................................................................................................... 4 3. OBJECTIVES OF THE EVALUATION SURVEY ............................................... 5 4. METHODS .............................................................................................................. 5 4.1 4.1.1 4.1.2 4.1.3 Survey Design .......................................................................................................... 5 Qualitative Research on the Survey ......................................................................... 6 Questions on REMS Goals ...................................................................................... 6 Additional Questions................................................................................................ 9 4.2 4.2.1 Participant Recruitment.......................................................................................... 10 Measures to Minimize Bias in the Sample............................................................. 10 5. 5.1.1 5.1.2 5.1.3 STUDY POPULATION ........................................................................................ 10 Sample Size ............................................................................................................ 10 Inclusion Criteria.................................................................................................... 11 Exclusion Criteria .................................................................................................. 11 6. SURVEY PROCESS ............................................................................................. 12 6.1 6.1.1 6.1.2 Screening and Survey Administration ................................................................... 12 Telephone ............................................................................................................... 12 Internet ................................................................................................................... 12 6.2 Measures to Minimize Bias in the Survey Process ................................................ 12 7. 7.1.1 7.1.2 ANALYSIS ............................................................................................................ 13 Description of Primary Analyses ........................................................................... 13 Description of Secondary Analyses ....................................................................... 14 8. SAFETY EVENT REPORTING ........................................................................... 14 9. PRIVACY PROTECTION AND CONFIDENTIALITY...................................... 14 LIST OF APPENDICES Appendix A Prescriber Questionnaire...........................................................................16 Appendix B Prescriber Invitation Letter ....................................................................... 37 Appendix C Qualitative Research Report ..................................................................... 38 2 of 38 FDA_1407 TIRF REMS Industry Group (TRIG) Transmucosal Immediate Release Fentanyl (TIRF) Products Prescriber KAB Survey Protocol 1. Version 5.0 10 Sep 2013 LIST OF ABBREVIATIONS CATI CI EDC ETASU FDA HIPAA ISI KAB PI REMS SE/PSP TIRF TIRF REMS TRIG UBC US Computer-Assisted Telephone Interviewing Confidence Interval Electronic Data Capture Elements to Assure Safe Use Food and Drug Administration Health Insurance Portability and Accountability Act Important Safety Information Knowledge, Attitudes and Behavior Prescribing Information Risk Evaluation and Mitigation Strategy Safety Event Project Specific Procedure Transmucosal Immediate Release Fentanyl TIRF REMS Access Program TIRF REMS Industry Group United BioSource Corporation United States 3 of 38 FDA_1408 TIRF REMS Industry Group (TRIG) Transmucosal Immediate Release Fentanyl (TIRF) Products Prescriber KAB Survey Protocol 2. Version 5.0 10 Sep 2013 BACKGROUND Transmucosal Immediate Release Fentanyl (TIRF) medicines include the class of immediaterelease opioid analgesics that are indicated only for the management of breakthrough pain in cancer patients 18 years of age or older (16 or older for Actiq® and equivalent generics) who are already receiving and already tolerant to opioid therapy for their underlying persistent cancer pain. The TIRF medicines include Abstral®, Actiq®, Fentora®, Lazanda®, Onsolis®, Subsys®, and generic versions of any of these brands. The TIRF REMS Industry Group (TRIG) includes Archimedes Pharma US Inc.; Cephalon, Inc. (a wholly-owned subsidiary of Teva Pharmaceutical Industries, Ltd.); Endo Pharmaceuticals Inc.; Galena Biopharma; Insys Therapeutics; Mallinckrodt; Meda Pharmaceuticals; Mylan, Inc.; and Par Pharmaceutical, Inc. The Food and Drug Administration (FDA) has determined that a class-wide Risk Evaluation and Mitigation Strategy (REMS) is required to mitigate the risk of misuse, abuse, addiction, overdose, and serious complications due to medication errors with the use of TIRF medicines. The TIRF REMS Access Program (hereafter referred to as TIRF REMS) was approved by the FDA on December 28, 2011. The TIRF REMS consists of a Medication Guide, Elements to Assure Safe Use (ETASU), an Implementation System, and a timetable for submission of assessments of the REMS. The goals of the TIRF REMS are to mitigate the risk of misuse, abuse, addiction, overdose and serious complications due to medication errors by the following: 1. Prescribing and dispensing TIRF medicines only to appropriate patients, which includes use only in opioid-tolerant patients. 2. Preventing inappropriate conversion between TIRF medicines. 3. Preventing accidental exposure to children and others for whom it was not prescribed. 4. Educating prescribers, pharmacists, and patients on the potential for misuse, abuse, addiction, and overdose of TIRF medicines. An important component of the TIRF REMS assessment is the conduct of quantitative evaluation surveys to assess prescribers’ understanding and knowledge of the safe use and appropriate prescribing of TIRF medicines as described in the TIRF REMS educational materials, enrollment form, and Prescribing Information (PI) of each product. This protocol will describe the administration of the surveys that will be conducted among prescribers who are enrolled in the TIRF REMS Access Program. Data from the surveys, together with other REMS evaluation metrics, will be used to determine whether changes need to be made to the REMS processes or educational materials to make them more effective in achieving the goals of the REMS. 4 of 38 FDA_1409 TIRF REMS Industry Group (TRIG) Transmucosal Immediate Release Fentanyl (TIRF) Products Prescriber KAB Survey Protocol Version 5.0 10 Sep 2013 The surveys will be implemented so that data will be available for inclusion in the REMS Assessment Reports that will be submitted to the FDA at 12 months after approval of the TIRF REMS and annually thereafter. 3. OBJECTIVES OF THE EVALUATION SURVEY The evaluation survey will use a questionnaire to document the level of knowledge and assess the attitudes and behavior of prescribers around the following key information and risk messages communicated through the REMS: 1. TIRF medicines are contraindicated in opioid non-tolerant patients. 2. TIRF medicines are only indicated for the management of breakthrough pain in adult cancer patients 18 years of age and older (16 or older for Actiq® and equivalent generics) who are already receiving and who are tolerant to around-the-clock opioid therapy for their underlying persistent cancer pain. 3. TIRF medicines contain fentanyl, an opioid agonist and a Schedule II-controlled substance, with abuse liability similar to other opioid analgesics. 4. TIRF medicines are not interchangeable with each other, regardless of route of administration. 5. Patients and their caregivers must be instructed that TIRF medicines contain a medicine in an amount that can be fatal in children, in individuals for whom it is not prescribed, and in those who are not opioid tolerant. The survey will also collect data on behaviors, such as receipt and use of educational materials and compliance with REMS requirements. 4. METHODS The survey was designed in collaboration between the TRIG and United BioSource Corporation (UBC) and will be administered by UBC. 4.1 Survey Design This survey will be conducted among a sample of prescribers who are enrolled in the TIRF REMS Access Program. Respondents who participate in the first wave of the TIRF survey will not be eligible to participate in subsequent survey waves. The survey will be administered using the following modalities:  Self-administered, online through a secure website 5 of 38 FDA_1410 TIRF REMS Industry Group (TRIG) Transmucosal Immediate Release Fentanyl (TIRF) Products Prescriber KAB Survey Protocol  Version 5.0 10 Sep 2013 Telephone surveys facilitated by a trained interviewer from the Survey Coordinating Center using a computer-assisted telephone interviewing (CATI) program The survey will begin with screening questions to confirm respondent eligibility to participate in the survey. Completion of the entire survey is expected to take approximately 20 minutes. The survey included in Appendix A is written to reflect wording for both methods of survey administration: Internet-based and telephone. All respondents who complete the survey and who provide their contact information will be mailed a $125 honorarium for their time. 4.1.1 Qualitative Research on the Survey The FDA provided feedback to the TRIG on the KAB survey results for prescribers included in the 12-month REMS Assessment results. The FDA requested that the TRIG investigate the causes for low correct response rates to specific questions in the survey by conducting research to determine the reasons for the poor performance on these questions, and to assess proposed revised wording to select questions. Qualitative research was performed with 7 prescribers who were recruited from the list of prescribers who completed surveys for the 12-month TIRF REMS Assessment and met the definition of “low performer,” i.e., provided an incorrect response on 3 to 7 of the 10 targeted responses/questions from the 12-month TIRF REMS Assessment. Among the prescribers interviewed, the need to provide a “frame-of-reference” for responding was frequent feedback. In addition, some of the findings suggest potential knowledge gap with respect to:    Definition of opioid tolerance; How to convert patients from one TIRF medicine to another TIRF medicine; and Content pertaining to CYP3A4 inhibitors. The findings from this research have been incorporated into the survey in Appendix A. The qualitative research report can be found in Appendix C. 4.1.2 Questions on REMS Goals The Knowledge, Attitudes and Behaviors (KAB) questionnaire is made up of multiple-choice, close-ended statements or questions (the majority of which use true/false or yes/no dichotomous response options), and one open-ended question. These will evaluate current knowledge, attitudes, and behavior regarding the key risk messages noted in Section 3. Questions will be presented in several formats:  Statements or questions asking the respondent to indicate whether a statement or question is true or false, or if they do not know the answer (there is a similar set of statements and questions that use “yes” or “no” as potential response options); 6 of 38 FDA_1411 TIRF REMS Industry Group (TRIG) Transmucosal Immediate Release Fentanyl (TIRF) Products Prescriber KAB Survey Protocol Version 5.0 10 Sep 2013  Statements or questions asking the respondent to choose from a defined list of possible statements or answers; and  One question allowing for the respondent to list questions about the products or comments. Questionnaires will be analyzed to determine prescriber understanding of each key risk message. For statements or questions that use “true” or “yes” vs. “false” or “no” response options, the desired response for key risk messages is generally “true” or “yes” indicating knowledge of, or behavior in accordance with, the objectives of the REMS. However, some questions are formatted to have the respondent disagree with the statement as written by providing response options of “false” or “no” to avoid having the same affirmative answer for all desired responses. REMS statements, corresponding questions, and desired responses covering the key risk messages are identified below and can be found in the complete survey questionnaire (Appendix A). Key Risk Message 1: TIRF medicines are contraindicated in opioid non-tolerant patients. Question No. 5 5a 5b 5c 7 7a 7b 7c 7d Question Desired response Please select “True,” “False,” or “I don’t know” for each of the following. According to the labeling for TIRF medicines, patients with cancer who are considered opioid-tolerant are those: Who are taking around-the-clock opioid therapy for TRUE underlying persistent chronic pain for one week or longer Who are not currently taking opioid therapy, but have FALSE taken opioid therapy before Who have no known contraindications to the drug fentanyl, but are not currently taking around-the-clock FALSE opioid therapy Please answer “True,” “False,” or “I don’t know” for each statement based on the labeling for TIRF medicines. TIRF medicines are contraindicated in opioid non-tolerant patients because life-threatening respiratory depression TRUE could occur at any dose. Death has occurred in opioid non-tolerant patients treated TRUE with some fentanyl products. TIRF medicines may be used to treat opioid non-tolerant FALSE patients. Prescribers starting a patient on a TIRF medicine must begin with titration from the lowest dose available for that TRUE specific product, even if the patient has previously taken another TIRF medicine. 7 of 38 FDA_1412 TIRF REMS Industry Group (TRIG) Transmucosal Immediate Release Fentanyl (TIRF) Products Prescriber KAB Survey Protocol Version 5.0 10 Sep 2013 Key Risk Message 2: TIRF medicines are only indicated for the management of breakthrough pain in adult cancer patients 18 years of age and older (16 years of age and older for Actiq® brand and generic equivalents) who are already receiving and who are tolerant to around-the-clock opioid therapy for their underlying persistent cancer pain. Question No. 9 9a 9b 9c 9d 9e 13 Question Desired response In your practice, for which of the following indications do you prescribe TIRF medicines to opioid tolerant patients? Please answer “Yes,” “No,” or “I don’t know” for each option. Acute or postoperative pain NO Headache or migraine pain NO Dental pain NO Breakthrough pain from cancer YES Chronic non-cancer pain NO 13b. Adult female with localized breast cancer; just completed a The patients described are experiencing breakthrough pain. mastectomy and According to the labeling, a TIRF medicine is not appropriate for reconstructive one of them. Which patient should not receive a TIRF medicine? surgery; persistent Please select one option. cancer pain managed with 30 mg oral morphine daily for the past 6 weeks. Key Risk Message 3: TIRF medicines contain fentanyl, an opioid agonist and a Schedule II-controlled substance, with abuse liability similar to other opioid analgesics. Question No. 7 7e 8 8a 8b 10 10a Question Desired response Please answer “True,” “False,” or “I don’t know” for each statement based on the labeling for TIRF medicines. It is important to monitor for signs of abuse and addiction in TRUE patients who take TIRF medicines. Which of the following are risk factors for opioid abuse? Please answer “Yes,” “No,” or “I don’t know” for each option. A personal history of psychiatric illness YES A personal history of past or current alcohol or drug abuse, or a YES family history of illicit drug use or alcohol abuse Please answer “True,” “False,” or “I don’t know” for each statement based on the labeling for TIRF medicines. TIRF medicines can be abused in a manner similar to other TRUE opioid agonists. 8 of 38 FDA_1413 TIRF REMS Industry Group (TRIG) Transmucosal Immediate Release Fentanyl (TIRF) Products Prescriber KAB Survey Protocol Version 5.0 10 Sep 2013 Key Risk Message 4: TIRF medicines are not interchangeable with each other, regardless of route of administration. Question No. 10 10b 10c 10d 14 4.1.3 Question Desired response Please answer “True,” “False,” or “I don’t know” for each statement based on the labeling for TIRF medicines. TIRF medicines are interchangeable with each other regardless FALSE of route of administration. The conversion of one TIRF medicine for another TIRF medicine may result in a fatal overdose because of differences in TRUE the pharmacokinetics of fentanyl absorption. Dosing of TIRF medicines is not equivalent on a microgram-toTRUE microgram basis. 14b. The prescriber must not convert to another TIRF medicine on a A patient is already taking a TIRF medicine but wants to change microgram-pertheir medicine. His/her doctor decides to prescribe a different microgram basis TIRF medicine (that is not a bioequivalent generic version of a because these branded product) in its place. According to the labeling, how medicines have should the prescriber proceed? Please select one option. different absorption properties and this could result in a fentanyl overdose. Additional Questions The survey includes questions about the requirements of the TIRF REMS Access Program and receipt and understanding of the TIRF educational materials and the Patient-Prescriber Agreement Form. The following question about behaviors will be asked after the key risk message questions: Question 12: How frequently do you perform the following activities when prescribing TIRF medicines? Please answer “Always,” “Only with the first prescription,” “Sometimes,” “Never,” or “I don’t know.” Ask patients (or their caregivers) about the presence of children in the home Instruct patients (or their caregivers) not to share TIRF medicines with anyone else Counsel patients (or their caregivers) that accidental exposure to TIRF medicines by a child may be fatal Instruct patients (or their caregivers) to keep TIRF medicines out of the reach of children to prevent accidental exposure Instruct patients (or their caregivers) about proper disposal of any unused or partially used TIRF medicines Give patients (or their caregivers) the Medication Guide for their TIRF medicine Demographic information will be collected at the end of the survey. 9 of 38 FDA_1414 TIRF REMS Industry Group (TRIG) Transmucosal Immediate Release Fentanyl (TIRF) Products Prescriber KAB Survey Protocol 4.2 Version 5.0 10 Sep 2013 Participant Recruitment A random sample of prescribers who are enrolled in the TIRF REMS Access Program will be invited to participate via an invitation letter. The text of the sample written invitation to prescribers can be found in Appendix B. If the required number of completed surveys is not achieved within the expected timeframe of approximately one to two weeks after the first mailing, reminder letters will be sent to non-respondents from the original sample with subsequent fax, e-mail, or United States (US) Mail follow-up to maximize participation. The distribution within the mailing to the second sample will be adjusted in accordance with the allocation in the original sample. If these efforts do not result in the required number of surveys within two to three weeks, then a new sample of prescribers will be randomly selected. All respondents who complete the survey and who provide their contact information will be mailed a $125 honorarium to thank them for their participation. Prescribers who practice in Vermont, Massachusetts, or Minnesota and complete the survey will not receive compensation. Participants will be informed that prescribers from these states are eligible to participate, but they will not receive compensation for their participation. The mailing will also include a Thank You Letter, a copy of the Important Safety Information (ISI), and a copy of the correct answers to key risk message questions. 4.2.1 Measures to Minimize Bias in the Sample The sample of prescribers who are invited to participate will be a random sample of all enrolled prescribers. The sample of participating prescribers will be self-selected since respondents will voluntarily respond to the invitation to participate; however, the survey recruitment strategies are intended to recruit a heterogeneous sample of prescribers for participation. Prescribers will be offered online or telephone options for completing the survey. Multiple modalities for survey data collection allow for wider survey access to a more heterogeneous population. Respondents will be provided a unique code during the recruitment process and will be asked to provide the unique code to gain access to the online survey or when calling the Survey Coordinating Center. The code will be deactivated after use to minimize the possibility for fraud. 5. STUDY POPULATION 5.1.1 Sample Size A sample of 300 healthcare providers who are enrolled in the TIRF REMS Access Program is proposed for each survey wave. The size of the sample was determined based on both practical and statistical considerations. There is no target comprehension rate specified a priori. A sample of 300 completed surveys will allow estimation of the comprehension rate for each risk message with a moderately high degree of precision. The table below shows the 10 of 38 FDA_1415 TIRF REMS Industry Group (TRIG) Transmucosal Immediate Release Fentanyl (TIRF) Products Prescriber KAB Survey Protocol Version 5.0 10 Sep 2013 precision of the estimates for level of understanding using two-sided 95% confidence intervals (CIs) obtained with the sample size of 300 completed surveys. The noted CIs are used to indicate that for any survey-estimated rate of understanding, the true population rate of understanding is at least as high as the lower limit of the 95% CI and may be as high as the upper limit of the 95% CI. Table 5.1: Precision of Estimated Rates of Understanding with a Sample Size of 300 Estimated Rate of Understanding 5% 10% 15% 20% 25% 30% 35% 40% 45% 50% 55% 60% 65% 70% 75% 80% 85% 90% 95% 5.1.2 Estimated Confidence Interval 2.8% 6.8% 11.2% 15.6% 20.2% 24.9% 29.6% 34.4% 39.3% 44.2% 49.2% 54.2% 59.3% 64.5% 69.7% 75.0% 80.4% 86.0% 91.9% 8.1% 14.0% 19.6% 25.0% 30.3% 35.5% 40.7% 45.8% 50.8% 55.8% 60.7% 65.6% 70.4% 75.1% 79.8% 84.4% 88.8% 93.2% 97.2% Inclusion Criteria All prescribers who are enrolled in the TIRF REMS Access Program are eligible to participate in this survey, with the exceptions noted below. 5.1.3 Exclusion Criteria The following respondents are not eligible to participate in the surveys:  Prescribers who have previously participated in the TIRF REMS KAB survey  Prescribers or their immediate family members who have ever worked for ever worked for Anesta LLC, Archimedes Pharma US Inc.; Cephalon, Inc. (a wholly-owned subsidiary of Teva Pharmaceutical Industries, Ltd); Endo Pharmaceuticals Inc.; Galena Biopharma; Insys Therapeutics; Mallinckrodt; Meda Pharmaceuticals; Mylan, Inc.; Par Pharmaceutical, Inc.; ProStrakan Inc.; Teva Pharmaceuticals, Ltd.; UBC; McKesson Specialty Care Solutions; RelayHealth; or the FDA. 11 of 38 FDA_1416 TIRF REMS Industry Group (TRIG) Transmucosal Immediate Release Fentanyl (TIRF) Products Prescriber KAB Survey Protocol 6. Version 5.0 10 Sep 2013 SURVEY PROCESS The survey will begin with screening questions to confirm respondent eligibility to participate in the survey. Completion of the entire survey is expected to take approximately 20 minutes. 6.1 Screening and Survey Administration The questionnaire will begin with a screening module with questions to confirm prescriber eligibility. Depending on the answers to the screening questions, survey participation could either be terminated or continued. If ineligible, the respondent is immediately notified with a “thank you” message that survey participation has ended. If eligible, the respondent is allowed to continue survey participation. The data entry system used for both methods of survey administration has been validated and is secure for receiving and storing survey data. The system is 21 CFR Part 11 and Health Insurance Portability and Accountability Act (HIPAA) compliant. Prescriber-identifying information will be stored separately from survey data. 6.1.1 Telephone A trained interviewer from the Survey Coordinating Center will conduct the telephone interviews using a CATI program. The screening and main elements of the questionnaire will be administered sequentially during the same telephone call. Telephone interviewing allows participation of prescribers who do not have Internet access. It will also be convenient for prescribers to participate since they can call in and be interviewed at their convenience during the specified time period when the Survey Coordinating Center is available. 6.1.2 Internet An Internet-based survey system will also be used for conducting the KAB surveys. If the prescriber selects to participate in the survey online, he/she will be directed to a secured website to complete screening questions. An Internet survey will be convenient for respondents to participate since they can complete the questionnaire at any time. 6.2 Measures to Minimize Bias in the Survey Process A number of controls will be in place to ensure the survey is conducted in a controlled and professional manner and to minimize bias. For example, a unique code will be given to each survey participant and the code will be inactivated after use to minimize fraud. Telephone interviewers are highly trained and use a standardized script to administer interviews. All questions will be programmed to ensure that questions are asked in the appropriate sequence. Skip patterns will be clearly indicated. Respondents cannot go back to a question once the question has been answered and cannot skip ahead. All questions must be answered in order to complete the survey. Response options presented in a list will be randomized to 12 of 38 FDA_1417 TIRF REMS Industry Group (TRIG) Transmucosal Immediate Release Fentanyl (TIRF) Products Prescriber KAB Survey Protocol Version 5.0 10 Sep 2013 minimize positional bias. Programming will be reviewed by quality control and simulated users (User Acceptance Testing) prior to implementing the survey. 7. ANALYSIS Information obtained from the survey will be reported as descriptive statistics for the survey administration, study population, and the survey questions. The data from the sample population will be reported using frequency distributions of responses to all questions. The following will be reported as part of this analysis:  The number of invitations issued to prescribers  The number of reminder letters  The number of respondents screened for participation  The number of respondents eligible for participation  The number of respondents eligible for participation who complete the survey  Representativeness of prescribers based on geography  Description of survey participants, including:  Gender  Medical degree of respondent: MD, DO, NP, PA  Medical specialty  Years of professional experience  How many times per month TIRF medicines prescribed in the last 6 months  Geographic region of practice Additional descriptive statistics may be reported as appropriate. 7.1.1 Analysis Population The analysis population will be based on eligible prescribers who completed all questions presented to them in the survey (“completers”). 13 of 38 FDA_1418 TIRF REMS Industry Group (TRIG) Transmucosal Immediate Release Fentanyl (TIRF) Products Prescriber KAB Survey Protocol 7.1.2 Version 5.0 10 Sep 2013 Description of Primary Analyses Primary analyses are done for all key risk messages using data from all completers. The primary analysis for a key risk message evaluates the rate for each correct response to each individual question/item defined by the key risk message. The specific correct response to each question/item is identified in the body of the risk message table. 7.1.3 Description of Secondary Analyses Secondary analyses are done only for those key risk messages that contain multiple questions/items using data from all completers. The secondary analysis entails a frequency distribution of the number of respondents who got 0, 1, etc. correct responses across the total number of items for the given key risk message. 8. SAFETY EVENT REPORTING The term ‘Safety Event’ is defined as any information reported by a survey respondent that meets the criteria of an adverse event or product complaint. While it is not the intention of the survey to solicit the report of information that meets the criteria of a Safety Event, it is possible that a respondent may spontaneously report information that meets this criteria in free text fields of the survey (Internet-based administration) or while in conversation with the Survey Coordinating Center (telephone-based administration). The Internet-based questionnaires will be monitored for any comments recorded in the free text fields. If an event is mentioned to a Survey Coordinating Center Associate, the Associate will document the safety event and the respondent’s contact information. Respondents will also be informed that a representative from the appropriate TIRF medicine manufacturer may contact them if there are questions about the survey. Information on all reports (Internet or telephone) that may constitute an adverse event or other safety event will be forwarded to the appropriate TIRF medicine manufacturer as described in the Safety Event Project Specific Procedure (SE/PSP). Additional detail regarding processes for adverse event reporting will be specified in the SE/PSP. 9. PRIVACY PROTECTION AND CONFIDENTIALITY All data collected during the survey will be held confidential. The electronic data capture (EDC) system used for data collection encrypts all identifiable information, and respondent identifiers are stored separately from the survey responses. Respondent names and addresses are collected in order to mail the $125 honorarium, a Thank You Letter, the correct responses to key risk messages, and the ISI after the survey is completed. Respondent contact information is also requested when necessary to comply with a federal or state law or regulation, including without limitation, reporting payments made to physicians under the federal physician payment sunshine provisions in addition to instances where a safety event is reported and a TIRF medicine manufacturer must obtain follow-up information (see Section 8 above). 14 of 38 FDA_1419 TIRF REMS Industry Group (TRIG) Transmucosal Immediate Release Fentanyl (TIRF) Products Prescriber KAB Survey Protocol Version 5.0 10 Sep 2013 Respondents will be informed when they access the survey that they may be contacted if there are any questions about their survey responses. Respondents will be informed that their answers to the survey questions will not affect their ability to prescribe TIRF medicines. 15 of 38 FDA_1420 TIRF REMS Industry Group (TRIG) Transmucosal Immediate Release Fentanyl (TIRF) Products Prescriber KAB Survey Protocol Appendix A Version 5.0 10 Sep 2013 Prescriber Questionnaire Survey Legend  [PROGRAMMER] is used to indicate directions to the programmer and is set in bold, red, uppercase letters between square brackets.  (INTERVIEWER) is used to indicate directions to the telephone interviewer and is set in bold, blue, text between parentheses. This text appears when content is to be administered by telephone only (for example, spontaneous adverse event reporting).  [ONLINE] indicates a question is worded specifically for administering the survey online. [PHONE] indicates a question is worded specifically to be read by a telephone interviewer and differs from the online text.  [BEGIN ONLINE/PHONE SURVEY CONTENT] and [END SURVEY CONTENT] are used to indicate to the programmer the type of survey administration and the beginning and end of the survey or sections within the survey content, for example, [BEGIN ADVERSE EVENT/PRODUCT COMPLAINT] and [END ADVERSE EVENT/PRODUCT COMPLAINT].  [TERMINATE] is displayed next to responses that should cause the survey to end. The following termination language will be programmed into the survey or read by the interviewer unless different language is specified with the question. Thank you very much for your time today. Based on your answer, you are not eligible to take this survey. We appreciate your interest in the survey.  [RANDOMIZE LIST] is inserted before questions to indicate to the programmer that the responses should be randomized. Responses such as “I don’t know,” “Prefer not to answer” or “None of the above” will always appear at the end of the randomized responses.  [GO TO Qx] (skip logic) is inserted after a response to indicate to the programmer that the survey should skip to the indicated question (for example, [GO TO Q17] skips to question 17). If no skip logic is indicated the survey continues to the next question in the sequence.  [MULTILINE INPUT] indicates to the programmer that multiple lines should be provided for data entry (for example, two address lines or a free-text response). 16 of 38 FDA_1421 TIRF REMS Industry Group (TRIG) Transmucosal Immediate Release Fentanyl (TIRF) Products Prescriber KAB Survey Protocol Version 5.0 10 Sep 2013 Survey Legend  [DROP-DOWN LIST INPUT WITH STATES TABLE] indicates to the programmer that the response should be a drop-down list containing the states and US territories in the table below. Alabama Georgia Massachusetts New York Tennessee Alaska Guam Michigan North Carolina Texas American Samoa Hawaii Minnesota North Dakota Arizona Idaho Mississippi Illinois Missouri Indiana Montana Northern Mariana Islands US Virgin Islands Iowa Nebraska Kansas Nevada Kentucky New Hampshire Louisiana New Jersey Maine New Mexico Arkansas California Colorado Connecticut Delaware District of Columbia Florida Maryland Ohio Oklahoma Oregon Pennsylvania Puerto Rico Rhode Island Utah Vermont Virginia Washington West Virginia Wisconsin Wyoming South Carolina South Dakota  The following is used to categorize survey populations into standard geographic regions but it is not displayed in the survey. Geographic Distribution (based on address) 1: Northeast, Midwest, South, and West regions Northeast Region  New England Division - ME, NH, VT, MA, RI, CT  Middle Atlantic Division - NY, NJ, PA Midwest Region  East North Central Division - OH, IN, IL, MI, WI  West North Central Division - MN, IA, MO, ND, SD, NE, KS South Region  South Atlantic Division - DE, MD, DC, VA, WV, NC, SC, GA, FL  East South Central Division - KY, TN, AL, MS  West South Central Division - AR, LA, OK, TX 17 of 38 FDA_1422 TIRF REMS Industry Group (TRIG) Transmucosal Immediate Release Fentanyl (TIRF) Products Prescriber KAB Survey Protocol Version 5.0 10 Sep 2013 Survey Legend West  Mountain Division - MT, ID, WY, CO, NM, AZ, UT, NV  Pacific Division WA, OR, CA, AK, HI  The following US territories are categorized as Other: Puerto Rico, Northern Mariana Islands, US Virgin Islands, American Samoa, and Guam. 1 U.S. Census Bureau, last revised Friday, 27-Jul-2001 12:59:43 EDT. [BEGIN SURVEY CONTENT] [ONLINE PREAMBLE 1] Before you begin, we would like to share some important information about this survey. The manufacturers of Transmucosal Immediate Release Fentanyl (TIRF) medicines are conducting this survey, as required by the FDA, to assess prescribers’ understanding of the safe use and prescribing of these medicines. These medicines are known as rapid onset opioids and referred to in this survey as “TIRF medicines.” The TIRF medicines include Abstral®, Actiq®, Fentora®, Lazanda®, Onsolis®, Subsys®, and generic versions of any of these brands. The manufacturers of these medicines include Archimedes Pharma US Inc.; Cephalon, Inc. (a wholly-owned subsidiary of Teva Pharmaceutical Industries, Ltd.); Endo Pharmaceuticals Inc.; Galena Biopharma; Insys Therapeutics; Mallinckrodt; Meda Pharmaceuticals; Mylan, Inc.; and Par Pharmaceutical, Inc. The survey will take approximately 20 minutes. There are no known risks to you in taking this survey. You may refuse to take part or withdraw at any time. Your answers to the questions or your decision to take part in the survey will not affect your ability to prescribe TIRF medicines. How We Use Your Information Your answers to the survey questions will be combined with answers given by other healthcare professionals taking the survey. All answers will be put together and reported in anonymous form to the manufacturers of TIRF medicines. Your name will not be used in any report. If you are eligible to take the survey, complete all the questions, and provide your contact information, you will receive a $125 honorarium for your time and participation. This compensation represents the fair value for your services in connection with completion of the survey. The amount of the compensation was not determined in any manner that takes into account the volume or value of any referrals or business otherwise generated by you. Your name and address will be used to send you the honorarium after you complete the survey. Your personal information will also be used if we have questions about your survey or if we are required to use your information to comply with a federal or state law or regulation, including without limitation, reporting payments made to physicians under the federal 18 of 38 FDA_1423 TIRF REMS Industry Group (TRIG) Transmucosal Immediate Release Fentanyl (TIRF) Products Prescriber KAB Survey Protocol Version 5.0 10 Sep 2013 physician payment sunshine provisions. Physicians who practice in Vermont, Massachusetts, or Minnesota should be aware that they will not be permitted to receive payment for survey completion and may elect not to complete the survey. Providing a telephone number is optional. Your telephone number will be used only if there are any questions about your survey responses. How We Protect Your Privacy We respect that the privacy of your personal information is important to you. You will not be contacted for marketing purposes based on your personal information or your answers to the survey. Neither the manufacturers of TIRF medicines nor their contractors will sell, transfer, or rent your information. Your answers will be kept strictly confidential. Your personal information will not be used in a manner inconsistent with this document. Your privacy will be protected; however, research survey records may be inspected by the FDA. Your choice to allow manufacturers of TIRF medicines to use your information is entirely voluntary but necessary to take part in this survey. How to Learn More about This Survey If you have questions about the survey, or problems with the survey, please contact the Survey Coordinating Center at 1-877-379-3297. Be sure to write down this telephone number; it will not be displayed again. Taking the Survey Once you have answered a question and moved on, you cannot go back and change your answers. Thank you for your participation in this survey. [END ONLINE PREAMBLE 1] 19 of 38 FDA_1424 TIRF REMS Industry Group (TRIG) Transmucosal Immediate Release Fentanyl (TIRF) Products Prescriber KAB Survey Protocol Version 5.0 10 Sep 2013 [PHONE PREAMBLE 1] Before you begin, we would like to share some important information about this survey. The manufacturers of Transmucosal Immediate Release Fentanyl (TIRF) medicines are conducting this survey, as required by the FDA, to assess prescribers’ understanding of the safe use and prescribing of these medicines. These medicines are known as rapid onset opioids and referred to in this survey as “TIRF medicines.” (INTERVIEWER: Say “TIRF” then spell out T-IR-F) The TIRF medicines include Abstral®, Actiq®, Fentora®, Lazanda®, Onsolis®, Subsys®, and generic versions of any of these brands. The manufacturers of these medicines include Archimedes Pharma US Inc.; Cephalon, Inc. (a wholly-owned subsidiary of Teva Pharmaceutical Industries, Ltd.); Endo Pharmaceuticals Inc.; Galena Biopharma; Insys Therapeutics; Mallinckrodt; Meda Pharmaceuticals; Mylan, Inc; and Par Pharmaceutical, Inc. The survey will take approximately 20 minutes. There are no known risks to you in taking this survey. You may refuse to take part or withdraw at any time. Your answers to the questions or your decision to take part in the survey will not affect your ability to prescribe TIRF medicines. Now I would like to read some information about how your contact information will be used. Your answers to the survey questions will be combined with answers given by other healthcare professionals taking the survey. All answers will be put together and reported in anonymous form to the manufacturers of TIRF medicines. Your name will not be used in any report. If you are eligible to take the survey, complete all the questions, and provide your contact information, you will receive a $125 honorarium for your time and participation. This compensation represents the fair value for your services in connection with completion of the survey. The amount of the compensation was not determined in any manner that takes into account the volume or value of any referrals or business otherwise generated by you. Your name and address will be used to send you the honorarium after you complete the survey. Your personal information will also be used if we have questions about your survey or if we are required to use your information to comply with a federal or state law or regulation, including without limitation, reporting payments made to physicians under the federal physician payment sunshine provisions. Physicians who practice in Vermont, Massachusetts, or Minnesota should be aware that they will not be permitted to receive payment for survey completion and may elect not to complete the survey. Providing a telephone number is optional. Your telephone number will be used only if there are any questions about your survey responses. Now I would like to tell you some information about how we protect your privacy. We respect that the privacy of your personal information is important to you. You will not be contacted for marketing purposes based on your personal information or your answers to the survey. Neither the manufacturers of TIRF medicines nor their contractors will sell, transfer, or rent your information. Your answers will be kept strictly confidential. Your personal 20 of 38 FDA_1425 TIRF REMS Industry Group (TRIG) Transmucosal Immediate Release Fentanyl (TIRF) Products Prescriber KAB Survey Protocol Version 5.0 10 Sep 2013 information will not be used in a manner inconsistent with this document. Your privacy will be protected; however, research survey records may be inspected by the FDA. Your choice to allow manufacturers of TIRF medicines to use your information is entirely voluntary but necessary to take part in this survey. Now I will tell you how you can learn more about this survey. Please have a pen or pencil ready to write down a telephone number you can call should you have any questions about the survey. If you have questions about the survey, please ask me at any time. If you have questions at a later time, please contact the Survey Coordinating Center at 1-877-379-3297. Please feel free to ask me to repeat any questions or statements as we go through the survey. Once you have answered a question and moved on, you cannot go back and change your answers. Thank you for your participation in this survey. [END PHONE PREAMBLE 1] 21 of 38 FDA_1426 TIRF REMS Industry Group (TRIG) Transmucosal Immediate Release Fentanyl (TIRF) Products Prescriber KAB Survey Protocol Version 5.0 10 Sep 2013 [BEGIN INCLUSION/EXCLUSION QUESTIONS] 1. Your agreement to participate in this survey confirms mutual understanding in connection with completion of the survey and the fair market value of the payment to be rendered in connection with those services. Do you agree to participate in this survey? 2. 3. 4. ○ Yes ○ No [TERMINATE] Have you ever taken part in this survey about TIRF medicines before? TIRF medicines include Abstral®, Actiq®, Fentora®, Lazanda®, Onsolis®, Subsys®, and generic versions of any of these brands. ○ Yes [ONLY TERMINATE AFTER WAVE 1] ○ No ○ I don’t know [ONLY TERMINATE AFTER WAVE 1] Are you enrolled in the TIRF REMS Access program? ○ Yes ○ No [TERMINATE] ○ I don’t know [TERMINATE] Have you or any of your immediate family members ever worked for any of the following companies or agencies? Please select all that apply. □ □ Anesta LLC [TERMINATE] □ Cephalon, Inc. (a wholly-owned subsidiary of Teva Pharmaceutical Industries, Ltd.) [TERMINATE] □ Endo Pharmaceuticals Inc. [TERMINATE] □ Galena Biopharma [TERMINATE] Archimedes Pharma US Inc. [TERMINATE] 22 of 38 FDA_1427 TIRF REMS Industry Group (TRIG) Transmucosal Immediate Release Fentanyl (TIRF) Products Prescriber KAB Survey Protocol □ Insys Therapeutics [TERMINATE] □ Mallinckrodt [TERMINATE] □ McKesson Specialty Care Solutions [TERMINATE] □ Meda Pharmaceuticals [TERMINATE] □ Mylan, Inc. [TERMINATE] □ Par Pharmaceutical, Inc. [TERMINATE] □ ProStrakan, Inc. [TERMINATE] □ RelayHealth [TERMINATE] □ Teva Pharmaceuticals, Ltd. [TERMINATE] □ United BioSource Corporation [TERMINATE] □ FDA [TERMINATE] □ None of these apply [IF SELECTED IN ADDITION TO OTHER RESPONSES, TERMINATE] □ I don’t know [TERMINATE] □ Prefer not to answer [TERMINATE] Version 5.0 10 Sep 2013 [END INCLUSION/EXCLUSION QUESTIONS] 23 of 38 FDA_1428 TIRF REMS Industry Group (TRIG) Transmucosal Immediate Release Fentanyl (TIRF) Products Prescriber KAB Survey Protocol 5. Version 5.0 10 Sep 2013 Please select “True,” “False,” or “I don’t know” for each of the following. According to the labeling for TIRF medicines, patients with cancer who are considered opioid-tolerant are those: [RANDOMIZE LIST] Who are taking around-the-clock opioid therapy for underlying persistent chronic pain for one week or longer 5b. Who are not currently taking opioid therapy, but have taken opioid therapy before 5c. Who have no known contraindications to the drug fentanyl, but are not currently taking around-the-clock opioid therapy 5a. 6. True False I don’t know ○ ○ ○ ○ ○ ○ ○ ○ ○ Please answer “True,” “False,” or “I don’t know” for each statement based on the labeling for TIRF medicines. [RANDOMIZE LIST] A cancer patient can be started on a TIRF medicine and an around-the-clock opioid at the same time. 6b. A cancer patient who has been on an around-the-clock opioid for 1 day can start taking a TIRF medicine for breakthrough pain. 6a. 24 of 38 True False I don’t know ○ ○ ○ ○ ○ ○ FDA_1429 TIRF REMS Industry Group (TRIG) Transmucosal Immediate Release Fentanyl (TIRF) Products Prescriber KAB Survey Protocol 7. Please answer “True,” “False,” or “I don’t know” for each statement based on the labeling for TIRF medicines. [RANDOMIZE LIST] TIRF medicines are contraindicated in opioid nontolerant patients because life-threatening respiratory depression could occur at any dose. 7b. Death has occurred in opioid non-tolerant patients treated with some fentanyl products. 7c. TIRF medicines may be used to treat opioid non-tolerant patients. 7d. Prescribers starting a patient on a TIRF medicine must begin with titration from the lowest dose available for that specific product, even if the patient has previously taken another TIRF medicine. 7e. It is important to monitor for signs of abuse and addiction in patients who take TIRF medicines. 7a. 8. 8c. True False I don’t know ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ Which of the following are risk factors for opioid abuse? Please answer “Yes,” “No,” or “I don’t know” for each option. [RANDOMIZE LIST] 8a. 8b. Version 5.0 10 Sep 2013 A personal history of psychiatric illness A personal history of past or current alcohol or drug abuse, or a family history of illicit drug use or alcohol abuse A family history of asthma 25 of 38 Yes No I don’t know ○ ○ ○ ○ ○ ○ ○ ○ ○ FDA_1430 TIRF REMS Industry Group (TRIG) Transmucosal Immediate Release Fentanyl (TIRF) Products Prescriber KAB Survey Protocol 9. Version 5.0 10 Sep 2013 In your practice, for which of the following indications do you prescribe TIRF medicines to opioid tolerant patients? Please answer “Yes,” “No,” or “I don’t know” for each option. [RANDOMIZE LIST] Yes No I don’t know ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ 9a. 9b. 9c. 9d. 9e. Acute or postoperative pain Headache or migraine pain Dental pain Breakthrough pain from cancer Chronic non-cancer pain 10. Please answer “True,” “False,” or “I don’t know” for each statement based on the labeling for TIRF medicines. [RANDOMIZE LIST] True False I don’t know ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ 10a. TIRF medicines can be abused in a manner similar to other opioid agonists. 10b. TIRF medicines are interchangeable with each other regardless of route of administration. 10c. The conversion of one TIRF medicine for another TIRF medicine may result in a fatal overdose because of differences in the pharmacokinetics of fentanyl absorption. 10d. Dosing of TIRF medicines is not equivalent on a microgramto-microgram basis. 11. Please select “True,” “False,” or “I don’t know” for each of the following. According to the labeling for TIRF medicines, patients considered opioid-tolerant are those who are taking, for one week or longer, at least: [RANDOMIZE LIST] 11a. 11b. 11c. 11d. 11e. 11f. 8 mg oral hydromorphone/day 60 mg oral morphine/day 30 mg oral oxycodone/day 25 mcg transdermal fentanyl/hour 25 mg oral oxymorphone/day An equianalgesic dose of another oral opioid 26 of 38 True False I don’t know ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ FDA_1431 TIRF REMS Industry Group (TRIG) Transmucosal Immediate Release Fentanyl (TIRF) Products Prescriber KAB Survey Protocol 12. Version 5.0 10 Sep 2013 How frequently do you perform the following activities when prescribing TIRF medicines? Please answer “Always,” “Only with the first prescription,” “Sometimes,” “Never,” or “I don’t know.” [RANDOMIZE LIST] 12a. Ask patients (or their caregivers) about the presence of children in the home 12b. Instruct patients (or their caregivers) not to share TIRF medicines with anyone else 12c. Counsel patients (or their caregivers) that accidental exposure to TIRF medicines by a child may be fatal 12d. Instruct patients (or their caregivers) to keep TIRF medicines out of the reach of children to prevent accidental exposure 12e. Instruct patients (or their caregivers) about proper disposal of any unused or partially used TIRF medicines 12f. Give patients (or their caregivers) the Medication Guide for their TIRF medicine Always Only with the first prescription ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ 27 of 38 Sometimes Never I don’t know FDA_1432 TIRF REMS Industry Group (TRIG) Transmucosal Immediate Release Fentanyl (TIRF) Products Prescriber KAB Survey Protocol 13. Version 5.0 10 Sep 2013 The patients described are experiencing breakthrough pain. According to the labeling, a TIRF medicine is not appropriate for one of them. Which patient should not receive a TIRF medicine? Please select one option. [RANDOMIZE LIST] 13a. ○ Adult male with advanced lung cancer; underlying persistent cancer pain managed with 25 mcg/hour transdermal fentanyl patches for the past two months. Adult female with localized breast cancer; just completed a mastectomy and reconstructive surgery; persistent cancer pain managed with 30 mg oral morphine daily for the past 6 weeks. Adult male patient with advanced prostate cancer who, over the last 2 weeks, has been prescribed 100 mg oral morphine daily for pain due to bone metastasis. Adult female with advanced sarcoma who has been taking a daily dose of 12 mg oral hydromorphone for the last 3 weeks. I don’t know 13b. ○ 13c. ○ 13d. ○ 13e. ○ 14. A patient is already taking a TIRF medicine but wants to change their medicine. His/her doctor decides to prescribe a different TIRF medicine (that is not a bioequivalent generic version of a branded product) in its place. According to the labeling, how should the prescriber proceed? Please select one option. [RANDOMIZE LIST] 14a. 14b. 14c. 14d. 14e. ○ ○ ○ ○ ○ The prescriber can safely convert to the equivalent dosage of the new TIRF medicine as it has the same effect as other TIRF medicines. The prescriber must not convert to another TIRF medicine on a microgram-permicrogram basis because these medicines have different absorption properties and this could result in a fentanyl overdose. Convert from the other TIRF medicine to the new TIRF medicine at half of the dose. The prescriber should base the starting dose of the newly-prescribed TIRF medicine on the dose of the opioid medicine used for their underlying persistent cancer pain. I don’t know 28 of 38 FDA_1433 TIRF REMS Industry Group (TRIG) Transmucosal Immediate Release Fentanyl (TIRF) Products Prescriber KAB Survey Protocol 15. Version 5.0 10 Sep 2013 A patient is starting titration with a TIRF medicine. What dose must they start with? Please select one option. [RANDOMIZE LIST] 15a. ○ 15b. ○ 15c. ○ 15d. 15e. 16. ○ ○ A prescriber has started titrating a patient with the lowest dose of a TIRF medicine. However, after 30 minutes the breakthrough pain has not been sufficiently relieved. What should they advise the patient to do? Please pick the best option of the scenarios described. [RANDOMIZE LIST] 16a. 16b. 16c. ○ ○ 16d. 16e. ○ ○ 17. 17a. 17b. 17c. 17d. An appropriate dose based on the dose of the opioid medicine used for underlying persistent cancer pain. The dose that the prescriber believes is appropriate based on their clinical experience. The lowest available dose, unless individual product Full Prescribing Information provides product-specific guidance. The median available dose. I don’t know ○ Take another (identical) dose of the TIRF medicine immediately. Take a dose of an alternative rescue medicine. Provide guidance based on the product-specific Medication Guide because the instructions are not the same for all TIRF medicines. Double the dose and take immediately. I don’t know A patient is taking a TIRF medicine and the doctor would like to prescribe erythromycin, a CYP3A4 inhibitor. Please pick the best option of the scenarios described. [RANDOMIZE LIST] ○ ○ ○ ○ 17e. ○ The patient can’t be prescribed erythromycin, because using it at the same time as a TIRF medicine could be fatal. Use of a TIRF medicine with a CYP3A4 inhibitor may require a dosage adjustment; carefully monitor the patient for opioid toxicity, otherwise such use may cause potentially fatal respiratory depression. There is no possible drug interaction between CYP3A4 inhibitors and TIRF medicines. The dose of the TIRF medicine must be reduced by one half if a CYP3A4 inhibitor is prescribed in the same patient. I don’t know 29 of 38 FDA_1434 TIRF REMS Industry Group (TRIG) Transmucosal Immediate Release Fentanyl (TIRF) Products Prescriber KAB Survey Protocol 18. Before initiating treatment with a TIRF medicine, prescribers must review the Medication Guide with the patient. Please select “True,” “False,” or “I don’t know” for each of the following counseling statements. [RANDOMIZE LIST] 18a. TIRF medicines contain fentanyl in an amount that could be fatal to children of all ages, in individuals for whom they were not prescribed, and in those who are not opioid tolerant. 18b. Inform patients that TIRF medicines must not be used for acute or postoperative pain, pain from injuries, headache/migraine, or any other short-term pain. 18c. Instruct patients that, if they stop taking their aroundthe-clock opioid medicine, they can continue to take their TIRF medicine. 18d. Instruct patients to never share their TIRF medicine with anyone else, even if that person has the same symptoms. 19. Version 5.0 10 Sep 2013 True False I don’t know ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ Can patients continue to take their TIRF medicine if they stop taking their around-theclock opioid medicine? ○ Yes ○ No ○ I don’t know [PREAMBLE 2] The next set of questions is about the educational materials for TIRF medicines and the TIRF Patient-Prescriber Agreement. As a reminder, the TIRF medicines include Abstral®, Actiq®, Fentora®, Lazanda®, Onsolis®, Subsys® and generic versions of any of these brands. 20. Did you receive or do you have access to the Full Prescribing Information for the TIRF medicine(s) that you prescribe? ○ Yes ○ No [GO TO Q22] ○ I don’t know [GO TO Q22] 30 of 38 FDA_1435 TIRF REMS Industry Group (TRIG) Transmucosal Immediate Release Fentanyl (TIRF) Products Prescriber KAB Survey Protocol 21. 22. 23. 24. 25. Version 5.0 10 Sep 2013 Did you read the Full Prescribing Information for the TIRF medicine(s) that you prescribe? ○ Yes ○ No ○ I don’t know Did you receive or do you have access to the Medication Guide for the TIRF medicine(s) that you prescribe? ○ Yes ○ No [GO TO Q24] ○ I don’t know [GO TO Q24] Did you read the Medication Guide for the TIRF medicine(s) that you prescribe? ○ Yes ○ No ○ I don’t know Did you or do you have any questions about the information in the Full Prescribing Information or Medication Guide? ○ Yes ○ No [GO TO Q26] ○ I don’t know [GO TO Q260] What are your questions? [MULTILINE INPUT] 31 of 38 FDA_1436 TIRF REMS Industry Group (TRIG) Transmucosal Immediate Release Fentanyl (TIRF) Products Prescriber KAB Survey Protocol 26. 27. 28. Version 5.0 10 Sep 2013 Do you review the Patient-Prescriber Agreement Form with each of your patients for whom you prescribe TIRF medicines or their caregiver? ○ Yes ○ No [GO TO Q28] ○ I don’t know [GO TO Q28] Do you and the patient or their caregiver sign the Patient-Prescriber Agreement Form for TIRF medicines after you have reviewed it with him/her? ○ Yes ○ No ○ I don’t know Do you give a copy of the Patient-Prescriber Agreement Form for TIRF medicines to the patient or their caregiver? ○ Yes ○ No ○ I don’t know [DEMOGRAPHICS PREAMBLE] There are just a few more questions to help us combine your answers with other answers we have received. 29. On average, how many times per month have you prescribed the TIRF medicines within the last 6 months? ○ None [GO TO DEMOGRAPHICS PREAMBLE 2] ○ 1 – 2 times per month ○ 3 – 5 times per month ○ More than 5 times per month ○ I don’t remember 32 of 38 FDA_1437 TIRF REMS Industry Group (TRIG) Transmucosal Immediate Release Fentanyl (TIRF) Products Prescriber KAB Survey Protocol 30. Version 5.0 10 Sep 2013 Please select the TIRF medicines that you have prescribed within the last 6 months (select all that apply): □ Abstral® □ Actiq® or generic Actiq® □ Fentora® □ Lazanda® □ Onsolis® □ Subsys® [DEMOGRAPHICS PREAMBLE 2] These last few questions are for demographic purposes. 31. 32. What is your gender? ○ Male ○ Female ○ Prefer not to answer What is your medical degree? ○ MD ○ DO ○ Nurse Practitioner ○ Physician Assistant ○ Prefer not to answer 33 of 38 FDA_1438 TIRF REMS Industry Group (TRIG) Transmucosal Immediate Release Fentanyl (TIRF) Products Prescriber KAB Survey Protocol 33. 34. Version 5.0 10 Sep 2013 In total, how many years have you been practicing medicine, since completing your education? ○ Less than 3 years ○ 3 – 5 years ○ 6 – 10 years ○ 11 – 15 years ○ More than 15 years ○ Prefer not to answer In which state do you practice? [DROP-DOWN LIST INPUT WITH STATES TABLE WITH “Prefer not to answer” at END] 35. What is your medical specialty? ○ Oncology ○ Primary care ○ Pain management ○ Other (please specify): _____________________ ○ No designated specialty [PHONE ONLY: BEGIN ADVERSE EVENT/PRODUCT COMPLAINT] (INTERVIEWER: Please record if respondent spontaneously reported an adverse event or product complaint during the course of this interview.) ○ Yes ○ No [GO TO CLOSING 1] Enter Safety Adverse Event Verbatim [MULTILINE INPUT] 34 of 38 FDA_1439 TIRF REMS Industry Group (TRIG) Transmucosal Immediate Release Fentanyl (TIRF) Products Prescriber KAB Survey Protocol Version 5.0 10 Sep 2013 (INTERVIEWER: Indicate to the respondent that someone may call back to ask more questions about the adverse event or product complaint that was reported.) [END ADVERSE EVENT/PRODUCT COMPLAINT] [CLOSING 1] We would like to send you a $125 honorarium within the next few weeks to thank you for your time, but we need your name and address to do so. If you do not provide your name and address you will not receive the honorarium for your time and participation in the survey. As a reminder, physicians who practice in Vermont, Massachusetts, or Minnesota should be aware that they will not be permitted to receive payment for survey completion. Do you agree to give us your name and mailing address so we can send you the honorarium? ○ Yes ○ No [SKIP TO CLOSING 2] FIRST NAME: _______________________________________________ LAST NAME: _______________________________________________ ADDRESS: [MULTILINE INPUT] CITY: _____________________________________ STATE: [DROP-DOWN LIST INPUT WITH STATES TABLE] ZIP: ___________ [CLOSING 2] We would also like to ask for your telephone number. Providing your telephone number is optional and it will be used to contact you only if there are questions about your survey responses. 36. ○ ○ Do you want to provide your telephone number? Yes No [SKIP TO CLOSING 3] Telephone: ________________________________ 35 of 38 FDA_1440 TIRF REMS Industry Group (TRIG) Transmucosal Immediate Release Fentanyl (TIRF) Products Prescriber KAB Survey Protocol Version 5.0 10 Sep 2013 [END CLOSING 2] [CLOSING 3] That ends the survey. Thank you again for your help. [END OF SURVEY CONTENT] 36 of 38 FDA_1441 TIRF REMS Industry Group (TRIG) Transmucosal Immediate Release Fentanyl (TIRF) Products Prescriber KAB Survey Protocol Appendix B Version 5.0 10 Sep 2013 Prescriber Invitation Letter [CURR_DATE] [PRESCRIBER NAME] [STREET_ADDR] [CITY], [STATE] [ZIP] Dear [PRESCRIBER NAME]: You were selected to receive this letter because you have enrolled in the TIRF REMS Access Program. We are contacting you to invite you to participate in a survey being conducted by the manufacturers of Transmucosal Immediate Release Fentanyl (TIRF) medicines, as required by the Food and Drug Administration (FDA). The purpose of the survey is to assess prescribers’ understanding of the safe and appropriate use of these medicines. The TIRF medicines include Abstral®, Actiq®, Fentora®, Lazanda®, Onsolis®, Subsys™, and generic versions of any of these brands. The manufacturers of TIRF medicines (collectively referred to as the “TIRF REMS Industry Group”) include Archimedes Pharma US Inc.; Cephalon, Inc. (a wholly-owned subsidiary of Teva Pharmaceutical Industries, Ltd.); Endo Pharmaceuticals Inc.; Galena Biopharma; Insys Therapeutics; Mallinckrodt; Meda Pharmaceuticals; Mylan, Inc., and Par Pharmaceutical, Inc. These manufacturers are looking for 300 prescribers to complete the survey. Eligible prescribers who complete the survey will be sent a $125 honorarium to thank them for their time. The survey will take 15-20 minutes. Your answers will be kept strictly confidential and will be combined with the answers from other prescribers who take this survey. Your name will not be used in the report of this survey and your contact information will only be used to send you a $125 honorarium for the time you took to complete the survey and if required to comply with a federal or state law or regulation, including without limitation, reporting payments made to physicians under the federal physician payment sunshine provisions. Prescribers who practice in Vermont, Massachusetts, or Minnesota should be aware that they will not be permitted to receive payment for survey completion and may elect not to complete the survey. You are under no obligation to participate in this survey. If you are interested in participating, go to www.XXXXXXXXXX.com anytime or call 1-877-379-3297, 8AM to 8PM Eastern Time Monday through Friday. You will be asked to give this unique code prior to starting the survey: [CODE_ID]. Please have this letter with you at the time you take the survey. Thank you in advance for your help with this important effort. Sincerely, TIRF REMS Industry Group * We recommend that you take the survey on a desktop or laptop computer. Taking the survey on mobile devices, such as smart phones, tablets, and e-notebooks, is not supported. 37 of 38 FDA_1442 TIRF REMS Industry Group (TRIG) Transmucosal Immediate Release Fentanyl (TIRF) Products Prescriber KAB Survey Protocol Appendix C Version 5.0 10 Sep 2013 Qualitative Research Report 38 of 38 FDA_1443 Prescriber KAB Assessment Report Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Appendix B Page 65 of 67 Prescriber Survey Listings and Sub-group Analysis Tables FDA_1444 Listing 1 VERBATIM RESPONSES TO QUESTION 24 (Questions about the information in the Full Prescribing Information or Medication Guide) Verbatim Response Answered incorrectly -- meant to select 'no questions' dose titration. any speci?c guiediliness How can I get a copy of the medication guide so I can better educate my patients? HOW TO CONVERSION. How to dose these medications when converting from other opiate short acting 1x? I asked the pharmacist at the time of prescribing. I had questions regarding dosing. but they were answered by another physician in the of?ce. I have received guides in the past and have access at my of?ce where I am not at this time. I have asked the representatives questions in the past that I do not presently remember. I do not have any questions at this moment but answered in that I have had questions in the past. I have used these products for years. I DID have questions when I began initially using these products. I cannot recall particular questions right now. It has been a long time since I prescribed the TIRF (Lazanda). so I would need to review both guides prior to prescribing it again. Once I have done so. I would not have any other questions. More safety issues. and conversion issue questions na 110116 110116 SOffy 110116 NOT ENOUGH INFO RE TITRATION OF DOSING opiods in with subsys safe and effective doses without causing respiratory depression. side effects that can occur other than respiratory depression Please send me all the information and update about these rneds Questions were answered by drug rep from Fentora. Question was regarding 3rd dose after taking 2nd dose 30 mins a?er dose was ineffective. Side effects on nteeth caries speci?cs of opioid interaction Subsys titration kit instructions and what is in the titration kit the defnrition of opioid tolerant patient is confusing. Client: TRIG Project: TIRF Wave 2 Report Run Date and Time: 11/18/2013 11:29:00 AM Page 1 of 2 445 Verbatim Response the source or data behind the information related to whether the different brand are equianalgesic or not they were answered by the rep. What are the available studies to demonstrate equitable dosing between the many TIRF medications? what are the interactions with other meds in the cyp450 system? What are the percentages of Cyp3A4 polymorphisms or any other polymorphism which are currently being investigated involving what dose of morphine is required to be considered opioid tolerant? Have questions about the conversion ratio among the medications what is the optimal way to use Fentora where do I this info Will there be indictations for other diagnoses? would like conversion chart 110116 110116 110116 110116 Client: TRIG Project: TIRF Wave 2 Report Run Date and Time: 11/18/2013 11:29:00 AM Page 2 of 2 446 Listing 2 VERBATIM RESPONSES TO QUESTION 35 (OTHER MEDICAL SPECIALTY) Verbatim Response hospice Family Practice neurology Physical Medicine and Rehab NP hospitalist Hospice Palliative Med Orthopedics Hospice Palliative Care palliative care Family Practice Pain Mg1nt& Addiction general surgery Pulmonary/C CM Palliative Medicine PM&R/Addictionology Internal medicine Rehab Pain Rhemnatology supportive oncology wom1d care Family Practice/Primary Care Primary care and addictionolgy Anesthesia Pain Hospice Palliative Medicine rehabilitation medicine hospice and palliative Client: TRIG Project: TIRF Wave 2 Report Run Date and Time: 11/13/2013 2:22:00 PM Page 1 of 2 447 Verbatim Response Oncology Phamlacy RADIATION ONCOLOGY oncology Client: TRIG Project: TIRF Wave 2 Report Run Date and Time: 11/13/2013 2:22:00 PM Page 2 of 2 448 Listing 3 VERBATIM RESPONSES TO REPORTED ADVERSE EVENTS, PRODUCT COMPLAINTS OR REQUESTS FOR MEDICAL INFORMATION Verbatim Response Answered incorrectly -- meant to select 'no questions' dose titration. any speci?c guiediliness How can I get a copy of the medication guide so I can better educate my patients? HOW TO CONVERSION. How to dose these medications when converting from other opiate short acting 1x? I asked the pharmacist at the time of prescribing. I had questions regarding dosing. but they were answered by another physician in the of?ce. I have received guides in the past and have access at my of?ce where I am not at this time. I have asked the representatives questions in the past that I do not presently remember. I do not have any questions at this moment but answered in that I have had questions in the past. I have used these products for years. I DID have questions when I began initially using these products. I cannot recall particular questions right now. It has been a long time since I prescribed the TIRF (Lazanda). so I would need to review both guides prior to prescribing it again. Once I have done so. I would not have any other questions. More safety issues. and conversion issue questions na 110116 110116 SOffy 110116 NOT ENOUGH INFO RE TITRATION OF DOSING opiods in conjrurction with subsys safe and effective doses without causing respiratory depression. side effects that can occur other than respiratory depression Please send me all the information and update about these meds Questions were answered by drug rep from Fentora. Question was regarding 3rd dose after taking 2nd dose 30 mins a?er dose was ineffective. Side effects on nteeth caries speci?cs of opioid interaction Subsys titration kit instructions and what is in the titration kit the de?nition of opioid tolerant patient is confusing. Client: TRIG Project: TIRF Wave 2 Report Run Date and Time: 11/18/2013 11:30:00 AM Page 1 of 2 449 Verbatim Response the source or data behind the information related to whether the different brand are equianalgesic or not they were answered by the rep. What are the available studies to demonstrate equitable dosing between the many TIRF medications? what are the interactions with other meds in the cyp450 system? What are the percentages of Cyp3A4 polymorphisms or any other polymorphism which are currently being investigated involving what dose of morphine is required to be considered opioid tolerant? Have questions about the conversion ratio among the medications what is the optimal way to use Fentora where do I this info Will there be indictations for other diagnoses? would like conversion chart 110116 110116 110116 110116 Client: TRIG Project: TIRF Wave 2 Report Run Date and Time: 11/18/2013 11:30:00 AM Page 2 of 2 450 TABLE 1.1 SURVEY ADNIINISTRATION STATISTICS Question The number of invitations issued to . .. 5108 p1 escr 1bers The number of reminder letters . .- . 11,986 ma1led to p1esc11bels The nlunber of respondents screened 42 for participation The number of respondents eligible for 302 participation The number of respondents eligible for participation who completed the 302 71.1 smvey By Telephone 13 3.1 By Internet 289 68.0 This is the denominator for the percentages in this table Client: TRIG Project: TIRF Wave 2 Report Run Date and Time: 11/14/2013 10:56:00 AM Page 1 of 451 TABLE 1.2 TIME TO COMPLETE SURVEY (COMPLETERS ONLY) Time to Complete Survey Summary Statistic Telephone Internet Total 1 3 289 302 Mean (SD) 27.0 (3.16) 17.0 (9.75) 17.5 (9.77) Minimmn 2 5 5 Median 26.3 15.0 15.2 Maximum 34 109 109 Category Telephone Internet Total 5 to <10 Minutes 0 47 47 10 to <15 Minutes 0 97 97 15 to <20 Minutes 0 70 70 20 to <25 Minutes 3 36 39 25 to <30 Minutes 9 22 31 30 Minutes 01? More 1 17 18 Client: TRIG Project: TIRF Wave 2 Report Run Date and Time: 11/13/2013 1:19:00 PM Page 1 of 452 TABLE 1.3 SURVEY PARTICIPANT SCREENING RESULTS All Respondents and Complete . :42 5 espondents Question Question 1: Do you agree to participate in this survey? Yes 423 99.5 302 100.0 No ?1 2 0.5 Question 2: Have you ever taken part in this survey about TIRF medicines before? TIRF medicines include Abstral?, Actiq?, Fentora?, Lazanda?, Onsolis?, Subsys?, and generic versions of any of these brands. Yes ?1 17 4.0 No 357 84.0 302 100.0 I don't know ?1 49 11.5 Question not asked 2 0.5 Question 3: Are you enrolled in the TIRF REMS Access program? Yes ?1 308 72.5 302 100.0 No 24 5.6 I don't knowm 25 5.9 Question not asked 68 16.0 Client: TRIG Project: TIRF Wave 2 Report Run Date and Time: 11/14/2013 11:29:00 AM Page 1 of 2 453 All Res ondents Eligible and Complete N=p425 Respondents Question Question 4: Have you or any of your immediate family members ever worked for any of the following companies or agencies? Please select all that apply. ?31 Anesta LLC ?1 0 0.0 Archimedes Phanna US Inc.[? 0 0.0 ephalon. Inc. (a wholly-owned 1 0.2 subsidiary of Teva Phannaceutical Industries. Ltd.)m Endo Pharmaceuticals Inc. 0 0.0 Galena Biophanna 0 0.0 Insys Therapeutics 0 0.0 Mallinckrodtm 0 0.0 McKesson Specialty Care 0 0.0 Solutions Meda Pharmaceuticals 0 0.0 Mylan. Incm 1 0.2 Par Pha1maceutical. Inc.? 0 0.0 ProStrakan. 111cm 0 0.0 RelayHealth 0 0.0 Teva Phannaceuticals. 2 0.5 United BioSource Corporation 0 0.0 FDA ?1 0 0.0 None of these apply [41 302 71.1 302 100.0 I don?t know 1 0.2 Prefer not to answer 1 0.2 Question not asked 1 17 27.5 Ineligible to participate in the survey. Question not asked due to a previous question elimination. More than one response can be selected. so percentages may not sum to 100%. Ineligible if selected in addition to another response. Client: TRIG Project: TIRF Wave 2 Report Run Date and Time: 11/14/2013 11:29:00 AM Page 2 of 2 454 TABLE 2 DESCRIPTION OF ELIGIBLE AND COMPLETE RESPONDENTS Question Eligible and Complete Respondents Question 29: On average, how many times per month have you prescribed the TIRF medicines within the last 6 months? None 54 17.9 1 2 times per month 173 57.3 3 5 times per month 44 14.6 More than 5 times per month 18 6.0 I don?t remember 13 4.3 Question 30: Please select the TIRF medicines that you have prescribed within the last 6 months: (select all that apply) Abstral? 10 4.0 Actiq? or generic Actiq? 184 74.2 Fentora? 145 58.5 Lazanda? 16 6.5 Onsolis? 4 1.6 Subsys? 56 22.6 (answered None to Question 29) 54 Question 31: What is your gender? Male 197 65.2 Female 103 34.1 Prefer not to answer 2 0.7 Question 32: What is your medical degree? MD 182 60.3 DO 22 7.3 Niu?se Practitioner 66 21.9 Physician Assistant 30 9.9 Prefer not to answer 2 0.7 Client: TRIG Project: TIRF Wave 2 Report Run Date and Time: 11/14/2013 11:34:00 AM Page 1 of 2 455 Eligible and Complete Respondents Question Question 33: In total, how many years have you been practicing medicine, since completing your education? (MDs and DOs, only) Less than 3 years 28 9.3 3 - 5 years 49 16.2 6 - 10 years 55 18.2 11 - 15 years 51 16.9 More than 15 years 117 38.7 Prefer not to answer 2 0.7 Question 35: What is your medical specialty? Oncology 69 22.8 Primary care 30 9.9 Pain management 148 49.0 Other (please specify) 53 17.5 ?1 This question is presented only to the sub-group of prescribers who answered or ?Prefer not to answer? in Question 32. Percentages are based 011 the number of prescribers to whom this question was presented. Other medical specialties are presented in Listing 3. Client: TRIG Project: TIRF Wave 2 Report Run Date and Time: 11/14/2013 11:34:00 AM Page 2 of 2 456 TABLE 2.1 GEOGRAPHIC DISTRIBUTION (BASED ON QUESTION 31 IN WHICH STATE OR US TERRITORY DO YOU PRACTICE) Geographic Region Eligible and Complete Respondents 190ct2013 Northeast 83 27.5 2063 22.8 Midwest 46 15.2 1534 17.0 South 100 33.1 3010 33.3 West 71 23.5 2432 26.9 Other 0 0.0 3 0.0 Prefer not to answer 2 0. 7 0 0.0 ?1 US. Census Bm?eau. last revised Friday. 27-Jul-2001 12:59:43 EDT. Geography Division. Northeast includes CT. MA. ME. NH. NJ. NY. PA. RI. and VT. Midwest includes IA. IL. IN. KS. MI. MN. MO. ND. NE. OH. SD. and WI. South includes AL. AR. DC. DE. FL. GA. KY. LA. MD. MS. NC. OK. SC. TN. TX. VA. and WV. West includes AK. AZ. CA. CO. HI. ID. MT. NM. NV. OR. UT. WA. and WY. The following US territories are categorized as Other: Puerto Rico. Northern Mariana Islands. US Virgin Islands. American Samoa. and Guam. Client: TRIG Project: Report Run Date and Time: 11/13/2013 12:03:00 PM Page 1 of 457 TABLE 3 MEDICINES RESPONSES TO THE QUESTIONS ABOUT THE SAFE USE OF TIRF Question Eligible and Complete Respondents opioid-tolerant are those: Question 5: Please select ?True,? ?False,? or don?t know? for each of the following. According to the labeling for TIRF medicines, patients with cancer who are considered one week or longer 5a: Who are taking around-the-clock opioid therapy for underlying persistent chronic pain for True ?1 273 90.4 False 24 7.9 I don't know 5 1.7 5b: Who are not currently taking opioid therapy, but have taken opioid therapy before False ?1 266 88.1 Tme 28 9.3 I don't know 8 2.6 around-the-clock opioid therapy 5c: Who have no known contraindications to the drug fentanyl, but are not currently taking False ?1 248 82.1 True 39 12.9 I don't know 15 5.0 on the labeling for TIRF medicines. Question 6: Please answer ?True,? ?False,? or don?t know? for each statement based 6a: A cancer patient can be started on a TIRF medicine and an around-the-clock opioid at the same time. False ?1 183 60.6 True 105 34.8 I don't know 14 4.6 Client: TRIG Project: TIRF Wave 2 Report Run Date and Time: 11/14/2013 12:03:00 PM Page 1 of 9 458 Question Eligible and Complete Respondents 6b: A cancer patient who has been on an around?the?clock opioid for 1 day can start taking a TIRF medicine for breakthrough pain. False ?1 196 64.9 True 86 28.5 I don't know 20 6.6 Question 7: Please answer ?True,? ?False,? or don?t know? for each statement based on the labeling for TIRF medicines. 7a: TIRF medicines are contraindicated in opioid non?tolerant patients because life?threatening respiratory depression could occur at any dose. True ?1 265 87.7 False 32 10.6 I don't know 5 1.7 7b: Death has occurred in opioid non-tolerant patients treated with some fentanyl products. True ?1 283 93.7 False 3 1.0 I don't know 16 5.3 7c: TIRF medicines may be used in treat opioid non-tolerant patients. False ?1 242 80.1 True 43 14.2 I don't know 17 5.6 7d: Prescribers starting a patient on a TIRF medicine must begin with titration from the lowest dose available for that speci?c product, even if the patient has previously taken another TIRF medicine. True ?1 244 80.8 False 52 17.2 I don't know 6 2.0 Client: TRIG Project: TIRF WaveZ Report Run Date and Time: 11/14/2013 12:03:00 PM Page 2 of 9 459 Eligible and Complete Respondents Question 7e: It is important to monitor for signs of abuse and addiction in patients who take TIRF medicines. True ?1 299 99.0 False 2 0.7 I don't know 1 0.3 Question 8: Which of the following are risk factors for opioid abuse? Please answer ?Yes,? or don?t know? for each option. 8a: A personal history of illness Yes ?1 250 82.8 No 31 10.3 I don't know 21 7.0 8b: A personal history of past or current alcohol or drug abuse, or a family history of illicit drug use or alcohol abuse Yes ?1 299 99.0 No 2 0.7 I don't know 1 0.3 8c: A family history of asthma N0 ?1 271 89.7 Yes 12 4.0 I don't know 19 6.3 Question 9: In your practice, for which of the following indications do you prescribe TIRF medicines to opioid tolerant patients? Please answer ?Yes,? or don?t know? for each option. 9a: Acute or postoperative pain No ?1 281 93.0 Yes 17 5.6 I don't know 4 1.3 Client: TRIG Project: TIRF Wave 2 Report Run Date and Time: 11/14/2013 12:03:00 PM Page 3 of 9 460 Eligible and Complete Question 9b: Headache or migraine pain No ?1 279 92.4 Yes 20 6.6 I don't know 3 1.0 9c: Dental pain No ?1 292 96.7 Yes 5 1.7 I don't know 5 1.7 9d: Breakthrough pain from cancer Yes ?1 279 92.4 No 22 7.3 I don't know 1 0.3 9e: Chronic non?cancer pain No ?1 178 58.9 Yes 119 39.4 I don't know 5 1.7 Question 10: Please answer ?True,? ?False,? or don?t know? for each statement based on the labeling for TIRF medicines. 10a: TIRF medicines can be abused in a manner similar to other opioid agonists. True ?1 291 96.4 False 9 3 .0 I don't know 2 0.7 10b: TIRF medicines are interchangeable with each other regardless of route of administration. False ?1 279 92.4 True 16 5.3 I don't know 7 2.3 Client: TRIG Project: TIRF WaveZ Report Run Date and Time: 11/14/2013 12:03:00 PM Page 4 of 9 461 Question Eligible and Complete Respondents 10c: The conversion of one TIRF medicine for another TIRF medicine may result in a fatal overdose because of differences in the pharmacokinetics of fentanyl absorption. True ?1 286 94.7 False 7 2.3 I don't know 9 3.0 10d: Dosing of TIRF medicines is not equivalent on a microgram?to?microgram basis. True ?1 274 90.7 False 16 5.3 I don't know 12 4.0 Quesiton 11: Please select ?True,? ?False,? or don?t know? for each of the following. According to the labeling for TIRF medicines, patients considered opioid-tolerant are those who are taking, for one week or longer, at least: 11a: 8 mg oral hydromorphone/day True ?1 207 68.5 False 64 21.2 I don't know 31 10.3 11b: 60 mg oral morphine/day True ?1 269 89.1 False 16 5.3 I don't know 17 5.6 11c: 30 mg oral oxycodone/day True ?1 230 76.2 False 47 15.6 I don't know 25 8.3 11d: 25 transdermal fentanyl/hour True ?1 244 80.8 False 34 11.3 I don't know 24 7.9 Client: TRIG Project: TIRF Wave 2 Report Run Date and Time: 11/14/2013 12:03:00 PM Page 5 of 9 462 Eligible and Complete Question 1161:1233?? lle: 25 mg oral oxymorphone/day True ?1 211 69.9 False 39 12.9 I don't know 52 17.2 11f: An equianalgesic dose of another oral opioid True ?1 199 65.9 False 68 22.5 I don't know 35 11.6 Question 13: The patients described are experiencing breakthrough pain. According to the labeling, a TIRF medicine is not appropriate for one of them. Which patient should not receive a TIRF medicine? Please select one option. Adult female with localized breast cancer: just completed a mastectomy and sm?geiy: persistent cancer pain managed with 30 mg oral morphine daily for the past 6 weeks. 199 65.9 Adult female with advanced sarcoma who has been taking a daily dose of 12 mg oral hydrommphone for the last 3 weeks. 36 11.9 Adult male patient with advanced prostate cancer who. over the last 2 weeks. has been prescribed 100 mg oral mOIphine daily for pain due to bone metastasis. 12 4.0 Adult male with advanced 11mg cancer: 1mderlying persistent cancer pain managed with 25 meg/hour transdermal fentanyl patches for the past two months. 28 9.3 I don?t know 27 8.9 Client: TRIG Project: TIRF Wave 2 Report Run Date and Time: 11/14/2013 12:03:00 PM Page 6 of 9 463 Question Eligible and Complete Respondents Question 14: A patient is already taking a TIRF medicine but wants to change their medicine. His/her doctor decides to prescribe a different TIRF medicine (that is not a bioequivalent generic version of a branded product) in its place. According to the labeling, how should the prescriber proceed? Please select one option. The prescriber must not convert to another TIRF medicine 011 a microgram-per-microgram basis because these medicines have different absorption properties and this could result in a fentanyl overdose. 225 74.5 The prescriber can safely convert to the equivalent dosage of the new TIRF medicine as it has the same effect as other TIRF medicines. 2.0 Convert from the other TIRF medicine to the new TIRF medicine at half of the dose. 8.3 The prescriber should base the starting dose of the newly-prescribed TIRF medicine 011 the dose of the opioid medicine used for their ruiderlying persistent cancer pain. 34 11.3 I don?t know 12 4.0 Question 15: A patient is starting titration with a TIRF medicine. What dose must they start with? Please select one option. The lowest available dose. unless individual product Full Prescribing 254 84.1 Information provides product-speci?c guidance. An appropriate dose based 011 the dose of the opioid medicine used 37 12.3 for rmderlying persistent cancer pain. The dose that the prescriber believes is appropriate based on their 8 2.6 clinical experience. The median available dose. 1 0.3 I don?t know 2 0.7 Client: TRIG Project: TIRF Wave 2 Report Run Date and Time: 11/14/2013 12:03:00 PM Page 7 of 9 464 Question Eligible and Complete Respondents Question 16: A prescriber has started titrating a patient with the lowest dose of a TIRF medicine. However, alter 30 minutes the breakthrough pain has not been suf?ciently relieved. What should they advise the patient to do? Please pick the best option of the scenarios described. Provide guidance based 011 the product-speci?c Medication Guide 205 67.9 because the instructions are not the same for all TIRF medicines. Take another (identical) dose of the TIRF medicine immediately. 73 24.2 Take a dose of an alternative rescue medicine. 16 5.3 Double the dose and take immediately. 3 1.0 I don?t know 5 1.7 Question 17: A patient is taking a TIRF medicine and the doctor would like to prescribe a CYP3A4 inhibitor. Please pick the best option of the scenarios described. Use of a TIRF medicine with a CYP3A4 inhibitor may require a 225 74.5 dosage adjustment; carefully monitor the patient for opioid toxicity. otheiwise such use may cause potentially fatal respiratory depression. The patient can?t be prescribed because using it at the 11 3.6 same time as a TIRF medicine could be fatal. There is no possible drug interaction between CYP3A4 inhibitors 3 1.0 and TIRF medicines. The dose of the TIRF medicine must be reduced by one half if a 13 4.3 YP3A4 inhibitor is prescribed in the same patient. I don?t know 50 16.6 Question 18: Before initiating treatment with a TIRF medicine, prescribers must review the Medication Guide with the patient. Please select ?True,? ?False,? or don?t know? for each of the following counseling statements. 18a: TIRF medicines contain fentanyl in an amount that could be fatal to children of all ages, in individuals for whom they were not prescribed, and in those who are not opioid tolerant. True ?1 298 98.7 False 1 0.3 I don't know 3 1.0 Client: TRIG Project: TIRF Wave 2 Report Run Date and Time: 11/14/2013 12:03:00 PM Page 8 of 9 465 Question Eligible and Complete Respondents 18b: Inform patients that TIRF medicines must not be used for acute or postoperative pain, pain from injuries, headache/migraine, or any other short-term pain. True ?1 278 92.1 False 16 5.3 I don't know 8 2.6 18c: Instruct patients that, if they stop taking their around ?the?clock opioid medicine, they can continue to take their TIRF medicine. False ?1 175 57.9 True 95 31.5 I don't know 32 10.6 18d: Instruct patients to never share their TIRF medicine with anyone else, even if that person has the same True ?1 299 99.0 False 3 1.0 I don't know 0 0.0 Question 19: Can patients continue to take their TIRF medicine if they stop taking their around- the?clock opioid medicine? Yes ?1 105 34.8 No 160 53.0 I don't know 37 12.3 Correct response Client: TRIG Project: TIRF Wave 2 Report Run Date and Time: 11/14/2013 12:03:00 PM Page 9 of 9 466 TABLE 4 RESPONSES TO QUESTIONS ABOUT THE TIRF EDUCATIONAL MATERIALS AND THE TIRF PATIENT-PRESCRIBER AGREEMENT FORM Question Eligible and Complete Respondents medicine(s) that you prescribe? Question 20: Did you receive or do you have access to the Full Prescribing Information for the TIRF Yes 282 93 .4 No 6 2.0 I don't know 14 4.6 Question 21: Did you read the Full Prescribing Information for the TIRF medicine(s) that you prescribe?m Yes 243 86.2 No 33 11.7 I don't know 6 2.1 (answered No or I don?t know to Question 20) 20 medicine(s) that you prescribe? Question 22: Did you receive or do you have access to the Medication Guide for the TIRF Yes 273 90.4 No 8 2.6 I don't know 21 7.0 Question 23: Did you read the Medication Guide for the TIRF medicine(s) that you prescribe? Yes 246 90.1 No 24 8.8 I don't know 3 1.1 (answered No or I don?t know to Question 22) 29 Information or Medication Guide? Question 24: Did you or do you have any questions about the information in the Full Prescribing Yesm 37 12.3 No 243 80.5 I don't know 22 7.3 Client: TRIG Project: TIRF Wave 2 Report Run Date and Time: 11/13/2013 11:05:00 AM Page 1 of 2 467 Question Eligible and Complete Respondents Question 26: Do you review the Patient?Prescriber Agreement Form with each of your patients for whom you prescribe TIRF medicines or their caregiver? Yes 262 86.8 No 25 8.3 I don't know 15 5.0 Question 27: Do you and the patient or their caregiver sign the Patient-Prescriber Agreement Form for TIRF medicines after you have reviewed it with him/her? Yes 242 92.4 No 12 4.6 I don't know 8 3.1 (answered No or I don ?t know to Question 26) 4O Question 28: Do you give a copy of the Patient?Prescriber Agreement Form for TIRF medicines to the patient or their caregiver? Yes 243 80.5 No 34 11.3 I don't know 25 8.3 Verbatim texts for questions about the information in the Full Prescribing Information are presented in Listing 1. Percentages are calculated based on the sample presented with this question because of skip logic in the survey. Client: TRIG Project: TIRF Wave 2 Report Run Date and Time: 11/13/2013 11:05:00 AM Page 2 of 2 468 TABLE 5 PRESCRIBING TIRF MEDICINES RESPONSES TO QUESTIONS ABOUT ACTIVITIES WHEN Question Prescribers Question 12: How frequently do you perform the following activities when prescribing TIRF medicines? Please answer ?Always,? ?Only with the ?rst prescription,? ?Sometimes,? ?Never,? or don?t know.? 12a: Ask patients (or their caregivers) about the presence of children in the home Always 170 56.3 Only with the ?rst prescription 70 23.2 Sometimes 48 15.9 Never 11 3 .6 I don't know 3 1.0 12b: Instruct patients (or their caregivers) not 0 share TIRF medicines with anyone else Always 239 79.1 Only with the ?rst prescription 37 12.3 Sometimes 19 6.3 Never 5 1.7 I don't know 2 0.7 12c: Counsel patients (or their caregivers) that accidental exposure to TIRF medicines by a child may be fatal Always 197 65.2 Only with the ?rst prescription 63 20.9 Sometimes 31 10.3 Never 8 2.6 I don't know 3 1.0 Client: TRIG Project: TIRF Wave2 Report Run Date and Time: 11/13/2013 11:07:00 AM Page 1 of 2 469 Question Prescribers 12d: Instruct patients (or their caregivers) to keep TIRF medicines out of the reach of children to prevent accidental exposure Always 220 72.8 Only with the ?rst prescription 46 15.2 Sometimes 28 9.3 Never 5 1.7 I don't know 3 1.0 12e: Instruct patients (or their caregivers) about proper disposal of any unused or partially used TIRF medicines Always 187 61.9 Only with the ?rst prescription 62 20.5 Sometimes 37 12.3 Never 12 4.0 I don't know 4 1.3 12f: Give patients (or their caregivers) the Medication Guide for their TIRF medicine Always 142 47.0 Only with the ?rst prescription 108 35.8 Sometimes 26 8.6 Never 20 6.6 I don't know 6 2.0 Client: TRIG Project: TIRF Wave2 Report Run Date and Time: 11/13/2013 11:07:00 AM Page 2 of 2 470 TABLE 6.1 PRIMARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #1 KEY RISK MESSAGE 1: TIRF MEDICINES ARE CONTRAINDICATED IN OPIOID NON-TOLERANT PATIENTS. Question Eligible and Complete Respondents (95% c1) ?21 Question 5: Please select ?True,? ?False,? or don?t know? for each of the following. According to the labeling for TIRF medicines, patients with cancer who are considered opioid-tolerant are those: 5a: Who are taking around?tbe?clock opioid therapy for underlying persistent chronic pain for one week or longer 90.4 mm 273 (86.5. 93.5) False 24 7.9 I don't know 5 1.7 5b: Who are not currently taking opioid therapy, but have taken opioid therapy before 88.1 False 266 (83.9. 91.5) True 28 9.3 I don't know 8 2.6 5c: Who have no known contraindications to the drug fentanyl, but are not currently taking around?the-clock opioid therapy 82.1 False 248 (77.3. 86.3) True 39 12.9 I don't know 15 5.0 Client: TRIG Project: TIRF Wave 2 Report Run Date and Time: 11/14/2013 12:06:00 PM Page 1 of 2 471 Eligible and Complete Respondents Question (95% CI) '21 Question 7: Please answer ?True,? ?False,? or don?t know? for each statement based on the labeling for TIRF medicines. 7a: TIRF medicines are contraindicated in opioid non-tolerant patients because life-threatening respiraton? depression could occur at any dose. 87.7 True 265 (83591.2) False 32 10.6 I don't know 5 1.7 7b: Death has occurred in opioid non-tolerant patients treated with some fentanyl products. True 283 (909339762) False 3 1.0 I don't know 16 5.3 7c: TIRF medicines may be used in opioid non-tolerant patients. False 242 (75829845) Due 43 14.2 I don't know 17 5 .6 7d: Prescribers starting a patient on a TIRF medicine must begin with titration from the lowest dose available for that specific product, even if the patient has previously taken another TIRF medicine. 80.8 True 244 (75.9. 85.1) False 52 17.2 I don't know 6 2.0 Correct response mAll con?dence intervals are exact binomial 95% con?dence intervals. Client: TRIG Project: TIRF Wave 2 Report Run Date and Time: 11/14/2013 12:06:00 PM Page 2 of 2 472 TABLE 6.1.1 PRIMARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #1 KEY RISK MESSAGE l: TIRF MEDICINES ARE CONTRAINDICATED IN OPIOID NON-TOLERANT PATIENTS. SUB-GROUP ANALYSIS 1: READING MEDICATION GUIDE OR FULL PRESCRIBING INFORMATION (QUESTIONS 20, 21, 22 AND 23): S-la - Respondents who received and read the Full Prescribing Information for the TIRF medicine that they prescribe, or who received and read the Medication Guide. 0 S-lb - Respondents who did not receive or did not read the Full Prescribing Information for the TIRF medication that they prescribe (answered ?No? or don?t know? to Question 21) and did not receive or did not read the Medication Guide for the TIRF medicine that they prescribe (answered ?No? or don?t know? to Question 23). 1a S-lb Read Medication Guide or Did not read Medication ti Prescribing Info ues on 267 (95% Cl) (95% CI) Question 5: Please select ?True,? ?False,? or don?t know? for each of the following. According to the labeling for TIRF medicines, patients with cancer who are considered opioid-tolerant are those: 5a: Who are taking around?the?clock opioid therapy for underlying persistent chronic pain for one week or longer True 243 (86.94342) 30 (69%?9752) False 22 8.2 2 5.7 I don't know 2 0.7 3 8.6 5b: Who are not currently taking opioid therapy, but have taken opioid therapy before False 238 (84.859126) 28 (63.819316) True 25 9.4 3 8.6 I don't know 4 1.5 4 11.4 Client: TRIG Project: TIRF Wave 2 Report Run Date and Time: 11/14/2013 12:03:00 PM Page 1 of 3 Question S?lb S?la . . Read Medication Guide or not read Medication - - Guide or Prescribing Info . . Prescribing Info (95% CI) (95% CI) 5c: Who have no known contraindications to the drug fentanyl, but are not currently taking around-the-clock opioid therapy 83.5 71.4 False 223 (78.5. 87.8) 25 (53.7. 85.4) True 35 13.1 4 11.4 I don't know 9 3.4 6 17.1 Question 7: Please answer ?True,? ?False,? or don?t know? for each statement based on the labeling for TIRF medicines. 7a: TIRF medicines are contraindicated in opioid non-tolerant patients because life-threatening respiraton depression could occur at any dose. 88.8 80.0 True 237 (84.3. 92.3) 28 (63.1. 91.6) False 26 9.7 6 17.1 I don't know 4 1.5 1 2.9 7b: Death has occurred in opioid non-tolerant patients treated wi th some fentanyl products. Tme 252 (90.998368) 31 (73.28.9668) False 3 1.1 0 0.0 I don't know 12 4.5 4 11.4 7c: TIRF medicines may be used in opioid non-tolerant patients. False 111 218 (76.28661) 24 (50.38831) True 38 14.2 5 14.3 I don't know 11 4.1 6 17.1 Client: TRIG Project: TIRF WaveZ Report Run Date and Time: 11/14/2013 12:03:00 PM Page 2 of 3 474 Question S?la S?lb Read Medication Guide or not read Medication - - Guide or Prescribing Info . Prescribing Info (95% CI) (95% CI) 7d: Prescribers starting a patient on a TIRF medicine must begin with titration from the lowest dose available for that speci?c product, even if the patient has previously taken another TIRF medicine. 81.6 74.3 True 218 (76.5. 86.1) 26 (56.7. 87.5) False 45 16.9 7 20.0 I don't know 4 1.5 2 5.7 Correct response Client: TRIG Project: TIRF Wave2 Report Run Date and Time: 11/14/2013 12:03:00 PM Page 3 of 3 475 TABLE 6.1.2 PRIMARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #1 KEY RISK MESSAGE l: TIRF MEDICINES ARE CONTRAINDICATED IN OPIOID NON-TOLERANT PATIENTS. SUB-GROUP ANALYSIS 2: MEDICAL DEGREE OF RESPONDENTS (QUESTION 32): S-2a - MD S-2b DO S-2c Nurse Practitioner S-2d - Physician Assistant Question S?2a S?2b S?2c S?2d MD D0 Nurse Practitioner Physician Assistant (95% CI) (95% CI) (95% CI) (95% CI) Question 5: Please select ?True,? ?False,? or don?t know? for each of the following. According to the labeling for TIRF medicines, patients with cancer who are considered opioid-tolerant are those: 5a: Who are taking around-the-clock opioid therapy for underlying persistent chronic pain for one week or longer 87.9 95.5 95.5 90.0 True ?1 160 (82.3. 21 (77.2. 63 (87.3. 27 (73.5. 92.3) 99.9) 99.1) 97.9) False 19 10don't know 6.7 Client: TRIG Project: TIRF Wave2 Report Run Date and Time: 11/14/2013 12:03:00 PM Page 1 of 4 476 S-2a S-2b S-2c S-2d MD D0 Nurse Practitioner Physician Assistant (95% CI) (95% CI) (95% CI) (95% CI) 5b: Who are not currently taking opioid therapy, but have taken opioid therapy before 86.8 86.4 90.9 90.0 False ?1 158 (81.0. 19 (65.1. 60 (81.3. 27 (73.5. 91.4) 97.1) 96.6) 97.9) True 17 9.3 3 13.6 6 9.1 2 6.7 I don't know 7 3.8 0 0.0 0 0.0 3.3 5c: Who have no known contraindications to the drug fentanyl, but are not currently taking around?the?clock opioid therapy 80.2 81.8 87.9 80.0 False ?1 146 (73.7. 18 (59.7. 58 (77.5. 24 (61.4. 85.7) 94.8) 94.6) 92.3) True 28 15.4 3 13.6 6.1 4 13.3 I don't know 8 4.4 4.5 4 6.1 2 6.7 Client: TRIG Project: Report Run Date and Time: 11/14/2013 12:03:00 PM Page 2 of 4 477 S?2a S?2b S?2c S-2d Ml) D0 Nurse Practitioner Physician Assistant (95% CI) (95% CI) (95% CI) (95% CI) TIRF medicines. Question 7: Please answer ?True,? ?False,? or don?t know? for each statement based on the labeling for 7a: TIRF medicines are contraindicated in opioid non?tolerant patients because life?threatening respiratory depression could occur at any dose. 87.9 90.9 80.3 100.0 True ?1 160 (82.3. 20 (70.8. 53 (68.7. 30 (88.4. 92.3) 98.9) 89.1) 100.0) False 19 10.4 2 9.1 11 16.7 0 0.0 I don't know 0.0 7b: Death has occurred in opioid non?tolerant patients treated with some fentanyl products. 95.1 95.5 89.4 93.3 True ?1 173 (90.8. 21 (77.2. 59 (79.4. 28 (77.9. 97.7) 99.9) 95.6) 99.2) False don't know 7 3.8 0 0.0 7 10.6 2 6.7 Client: TRIG Project: TIRF Wave2 Report Run Date and Time: 11/14/2013 12:03:00 PM Page 3 of 4 478 S-2a S?2b S?2c S-2d MD D0 Nurse Practitioner Physician Assistant (95% CI) (95% CI) (95% CI) (95% CI) 7c: TIRF medicines may be used in opioid non?tolerant patients. 80.2 90.9 74.2 83.3 False ?1 146 (73.7. 20 (70.8. 49 (62.0. 25 (65.3. 85.7) 98.9) 84.2) 94.4) True 27 14.8 2 9.1 11 16.7 3 10.0 I don't know 6.7 7d: Prescribers starting a patient on a TIRF medicine must begin with titration from the lowest dose available for that speci?c product, even if the patient has previously taken another TIRF medicine. 81.9 63.6 81.8 83.3 True ?1 149 (75.5. 14 (40.7. 54 (70.4. 25 (65.3. 87.2) 82.8) 90.2) 94.4) False 28 15.4 8 36.4 11 16.7 5 16.7 I don't know 0.0 Correct response Client: TRIG Project: TIRF Wave2 Report Run Date and Time: 11/14/2013 12:03:00 PM Page 4 of 4 479 TABLE 6.1.3 PRIMARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #1 KEY RISK MESSAGE l: TIRF MEDICINES ARE CONTRAINDICATED IN OPIOID NON-TOLERANT PATIENTS. SUB-GROUP ANALYSIS 3: TIME TO COMPLETE SURVEY INTERNET: S-3a - <10 min 0 S-3b 10 to <20 min 0 S-3c 20 min S-3a S?3b S?3c <10 min 10 to <20 min 220 min Question N=l67 (95% CI) (95% CI) (95% CI) Question 5: Please select ?True,? ?False,? or don?t know? for each of the following. According to the labeling for TIRF medicines, patients with cancer who are considered opioid-tolerant are those: 5a: Who are taking around?the?clock opioid therapy for underlying persistent chronic pain for one week or longer 80.9 92.8 90.7 True ?1 38 (66.7. 155 (87.8. 68 (81.7. 90.9) 96.2) 96.2) False 7 14.9 11 6.6 6 8.0 I don't know 2 4.3 0.6 1.3 5b: Who are not currently taking opioid therapy, but have taken opioid therapy before 85.1 89.2 93.3 False ?1 40 (71.7. 149 (83.5. 70 (85.1. 93.8) 93.5) 97.8) True don't know 5 10.6 3 1.8 0 0.0 5c: Who have no known contraindications to the drug fentanyl, but are not currently taking around?the-clock opioid therapy 80.9 83.2 85.3 False ?1 38 (66.7. 139 (76.7. 64 (75.3. 90.9) 88.6) 92.4) True 5 10.6 20 12.0 9 12.0 I don't know 4 8.5 8 4.8 2 2.7 Client: TRIG Project: TIRF Wave 2 Report Run Date and Time: 11/14/2013 12:03:00 PM Page 1 of 2 480 Question S-3a s30 S?3c <10 min 10 to <20 min 220 min N=l67 (95% CI) (95% CI) (95% CI) Question 7: Please answer ?True,? ?False,? or don?t know? for each statement based on the labeling for TIRF medicines. 7a: TIRF medicines are contraindicated in opioid non-tolerant patients because life-threatening respiraton' depression could occur at any dose. 83.0 86.8 93.3 True ?1 39 (69.2. 145 (80.7. 70 (85.1. 92.4) 91.6) 97.8) False 7 14.9 18 10.8 5 6.7 I don't know 1 2.1 4 2.4 0 0.0 7b: Death has occurred in opioid non?tolerant patients treated with some fentanyl products. 93.6 94.0 92.0 True ?1 44 (82.5. 157 (89.3. 69 (83.4. 98.7) 97.1) 97.0) False 1 2.1 0.6 1.3 I don't know 2 4.3 9 5.4 5 6.7 7c: TIRF medicines may be used in opioid non-tolerant patients. 76.6 80.2 84.0 False ?1 36 (62.0. 134 (73.4. 63 (73.7. 87.7) 86.0) 91.4) True 9 19.1 22 13.2 10 13.3 I don't know 2 4.3 11 6.6 2 2.7 7d: Prescribers starting a patient on a TIRF medicine must begin with titration from the lowest dose available for that speci?c product, even if the patient has previously taken another TIRF medicine. 85.1 77.8 82.7 True ?1 40 (71.7. 130 (70.8. 62 (72.2. 93.8) 83.9) 90.4) False 7 14.9 31 18.6 13 17.3 I don't know 0 0.0 6 3.6 0 0.0 Conect response Client: TRIG Project: TIRF Wave2 Report Run Date and Time: 11/14/2013 12:03:00 PM Page 2 of 2 481 TABLE 6.1.5 PRIMARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #1 KEY RISK MESSAGE l: TIRF MEDICINES ARE CONTRAINDICATED IN OPIOID NON-TOLERANT PATIENTS. SUB-GROUP ANALYSIS 5: MODALITY TO COMPLETE SURVEY: S-5a - Internet 0 - Telephone Question S?5b Internet Telephone (95% CI) (95% CI) opioid-tolerant are those: Question 5: Please select ?True,? ?False,? or don?t know? for each of the following. According to the labeling for TIRF medicines, patients with cancer who are considered week or longer 5a: Who are taking around?the?clock opioid therapy for underlying persistent chronic pain for one me 261 (86.93335) 12 (64%?5398) False 24 8.3 0 0.0 I don't know 4 1.4 1 7.7 5b: Who are not currently taking opioid therapy, but have taken opioid therapy before False 259 (8528629) 7 Tme 22 7.6 6 46.2 I don't know 8 2.8 0 0.0 around-the-clock opioid therapy 5c: Who have no known contraindications to the drug fentanyl, but are not currently taking 83.4 53.8 False 241 (78.6. 87.5) 7 (25.1. 80.8) True 34 11.8 5 38.5 I don't know 14 4.8 1 7.7 Client: TRIG Project: TIRF WaveZ Report Run Date and Time: 11/14/2013 12:03:00 PM Page 1 of 2 482 Question Internet Telephone (95% CI) (95% CI) Question 7: Please answer ?True,? ?False,? or don?t know? for each statement based on the labeling for TIRF medicines. 7a: TIRF medicines are contraindicated in opioid non?tolerant patients because life?threatening respiratoly depression could occur at any dose. 87.9 84.6 me 254 (83.6. 91.4) 11 (54.6. 98.1) False 30 10.4 2 15.4 I don't know 5 1.7 0 0.0 7b: Death has occurred in opioid non-tolerant patients treated with some fentanyl products. 93.4 100.0 True 270 (89.9. 96.0) 13 (75.3. 100.0) False 3 1.0 0 0.0 I don't know 16 5.5 0 0.0 7c: TIRF medicines may be used in opioid non?tolerant patients. 80.6 69.2 False 233 (75.6. 85.0) 9 (38.6. 90.9) True 41 14.2 2 15.4 I don't know 15 5.2 2 15.4 7d: Prescribers starting a patient on a TIRF medicine must begin with titration from the lowest dose available for that speci?c product, even if the patient has previously taken another TIRF medicine. 80.3 92.3 True 232 (75.2. 84.7) 12 (64.0. 99.8) False 51 17.6 1 7.7 I don't know 6 2.1 0 0.0 Conect response Client: TRIG Project: TIRF Wave2 Report Run Date and Time: 11/14/2013 12:03:00 PM Page 2 of 2 483 TABLE 6.1.6 PRIMARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #1 KEY RISK MESSAGE l: TIRF MEDICINES ARE CONTRAINDICATED IN OPIOID NON-TOLERANT PATIENTS. SUB-GROUP ANALYSIS 6: TIME PRACTICING MEDICINE (QUESTION 33): S-6a - Less than 3 years S-6b - 3 to 5 years S-6c - 6 to 15 years S-6d - More than 15 years Question S?6a S?6b S?6c S-6d Less than 3 years 3 to 5 years 6 to 15 years More than 15 years N=ll7 (95% CI) (95% CI) (95% CI) (95% CI) Question 5: Please select ?True,? ?False,? or don?t know? for each of the following. According to the labeling for TIRF medicines, patients with cancer who are considered opioid-tolerant are those: 5a: Who are taking around-the-clock opioid therapy for underlying persistent chronic pain for one week or longer 92.9 81.6 91.5 92.3 Tme 26 (76.5. 99.1) 40 (68.0. 91.2) 97 (84.5. 96.0) 108 (85.9. 96.4) False 1 3.6 7 14.3 8 7.5 8 6.8 I don?t know 1 3.6 2 4.1 0.9 1 0.9 Client: TRIG Project: TIRF Wave2 Report Run Date and Time: 11/14/2013 12:04:00 PM Page 1 of 3 484 S?6a S?6b S?6c S-6d Less than 3 years 3 to 5 years 6 to 15 years More than 15 years (95% CI) (95% CI) (95% CI) (95% CI) 5b: Who are not currently taking opioid therapy, but have taken opioid therapy before 89.3 87.8 84.9 90.6 False 25 (71.8. 97.7) 43 (75.2. 95.4) 90 (76.6. 91.1) 106 (83.8. 95.2) True 2 7.1 5 10.2 11 10.4 10 8.5 I don't know 0.9 5c: Who have no known contraindications to the drug fentanyl, but are not currently taking around-the-clock opioid therapy 85.7 87.8 78.3 82.1 False 24 (67.3. 96.0) 43 (75.2. 95.4) 83 (69.2. 85.7) 96 (73.9. 88.5) True 2 7.1 3 6.1 15 14.2 19 16.2 I don't know 1.7 Question 7: Please answer ?True,? ?False,? or don?t know? for each statement based on the labeling for TIRF medicines. 7a: TIRF medicines are contraindicated in opioid non-tolerant patients because life?threatening respiratory depression could occur at any dose. 85.7 83.7 85.8 91.5 True 24 (67.3. 96.0) 41 (70.3. 92.7) 91 (77.7. 91.9) 107 (84.8. 95.8) False 4 14.3 8 16.3 12 11.3 8 6.8 1 don't know 1.7 Client: TRIG Project: TIRF Wave2 Report Run Date and Time: 11/14/2013 12:04:00 PM Page 2 of 3 485 S?6a S?6b S?6c S-6d Less than 3 years 3 to 5 years 6 to 15 years More than 15 years (95% CI) (95% CI) (95% CI) (95% CI) 7b: Death has occurred in opioid non-tolerant patients treated with some fentanyl products. 89.3 91.8 93.4 95.7 True 25 (71.8. 97.7) 45 (80.4. 97.7) 99 (86.9. 97.3) ?2 (90.3. 98.6) False don't know 3 10.7 3 6.1 5 4.7 5 4.3 7c: TIRF medicines may be used in opioid non-tolerant patients. 75.0 75.5 76.4 86.3 False 21 (551.893) 37 (61.1. 86.7) 81 (67.2. 84.1) 101 (78.7. 92.0) True 5 17.9 9 18.4 16 15.1 13 11.1 I don't know 2.6 7d: Prescribers starting a patient on a TIRF medicine must begin with titration from the lowest dose available for that speci?c product, even if the patient has previously taken another TIRF medicine. 75.0 77.6 86.8 77.8 True 21 (55.1. 89.3) 38 (63.4. 88.2) 92 (78.8. 92.6) 91 (69.2. 84.9) False 7 25.0 11 22.4 11 10.4 23 19.7 I don't know 2.6 Correct response Client: TRIG Project: TIRF Wave 2 Report Run Date and Time: 11/14/2013 12:04:00 PM Page 3 of 3 486 TABLE 6.1.7 PRIMARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #1 KEY RISK MESSAGE l: TIRF MEDICINES ARE CONTRAINDICATED IN OPIOID NON-TOLERANT PATIENTS. SUB-GROUP ANALYSIS 7: NUMBER OF TIMES PER MONTHS PRESCRIBING TIRF MEDICINES WITHIN THE LAST 6 MONTHS (QUESTION 29): S-7a - None S-7b - 1-2 times a month S-7c - 3 - 5 times a month S-7d - More than 5 times a month Question S?7d S?7a S?7b S?7c . None 1-2 times a month 3 - 5 times a month More a (95% CI) (95% CI) (95% CI) (95% CI) Question 5: Please select ?True,? ?False,? or don?t know? for each of the following. According to the labeling for TIRF medicines, patients with cancer who are considered opioid-tolerant are those: 5a: Who are taking around-the-clock opioid therapy for underl?ng persistent chronic pain for one week or longer 96.3 93.1 81.8 77.8 True 52 (87.3. 99.5) 161 (88.2. 96.4) 36 (67.3. 91.8) 14 (52.4. 93.6) False 1 1.9 11 6.4 7 15.9 3 16.7 I don't know 5.6 Client: TRIG Project: TIRF Wave2 Report Run Date and Time: 11/14/2013 12:06:00 PM Page 1 of 3 487 S?7d S?7a S?7c More than 5 times a None 1-2 times a month 3 - 5 times a month month Question (95% CI) (95% CI) (95% CI) (95% CI) 5b: Who are not currently taking opioid therapy, but have taken opioid therapy before 81.5 91.9 84.1 88.9 False 44 (68.6. 90.7) 159 (86.8. 95.5) 37 (69.9. 93.4) 16 (65.3. 98.6) True 7 13.0 11 6.4 6 13.6 2 11.1 I don't know 0.0 5c: Who have no known contraindications to the drug fentanyl, but are not currently taking around?the?clock opioid therapy 81.5 85.0 72.7 88.9 False 44 (68.6. 90.7) 147 (78.8. 89.9) 32 (57.2. 85.0) 16 (653.986) True 6 11.1 18 10.4 9 20.5 2 11.1 I don't know 0.0 Question 7: Please answer ?True,? ?False,? or don?t know? for each statement based on the labeling for TIRF medicines. 7a: TIRF medicines are contraindicated in opioid non?tolerant patients because life?threatening respiratory depression could occur at any dose. 87.0 87.9 93.2 83.3 True 47 (75.1. 94.6) 152 (82.0. 92.3) 41 (81.3. 98.6) 15 (58.6. 96.4) False 6 11.1 17 9.8 3 6.8 3 16.7 I don't know 0.0 Client: TRIG Project: TIRF Wave2 Report Run Date and Time: 11/14/2013 12:06:00 PM Page 2 of 3 488 S?7d S?7a S?7c More than 5 times a None l-2 times a month 3 - 5 times a month month Question (95% CI) (95% CI) (95% CI) (95% CI) 7b: Death has occurred in opioid non-tolerant patients treated with some fentanyl products. 96.3 94.2 90.9 94.4 True 52 (87.3. 99.5) 163 (89.6. 97.2) 40 (78.3. 97.5) 17 (72.7. 99.9) False don't know 0.0 7c: TIRF medicines may be used in opioid non?tolerant patients. 77.8 83.2 84.1 72.2 False 42 (64.4. 88.0) 144 (76.8. 88.5) 37 (69.9. 93.4) 13 (46.5. 90.3) True 7 13.0 20 11.6 7 15.9 2 11.1 I don't know 16.7 7d: Prescribers starting a patient on a TIRF medicine must begin with titration from the lowest dose available for that speci?c product, even if the patient has previously taken another TIRF medicine. 77.8 82.7 86.4 61.1 True 42 (64.4. 88.0) 143 (76.2. 88.0) 38 (72.6. 94.8) 11 (35.7. 82.7) False 10 18.5 26 15.0 6 13.6 7 38.9 I don't know 0.0 Correct response Client: TRIG Project: TIRF Wave2 Report Run Date and Time: 11/14/2013 12:06:00 PM Page 3 of 3 489 TABLE 6.2 SECONDARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #1 KEY RISK MESSAGE l: TIRF MEDICINES ARE CONTRAINDICATED IN OPIOID NON-TOLERANT PATIENTS. Eligible and Complete Respondents Demonstrated Understanding 0 correct responses 1 0.3 1 correct response 2 0.7 2 correct responses 1 0.3 3 correct responses 7 2.3 4 correct responses 23 7.6 5 correct responses 41 13.6 6 correct responses 90 29.8 7 correct responses 137 45.4 Average number of correct responses 6.0 (5.8. 7.0) ll] One-sided 95 con?dence interval using the normal approximation to the Poisson distribution. Client: TRIG Project: TIRF Wave 2 Report Run Date and Time: 11/11/2013 3:19:00 PM Page 1 of 490 TABLE 6.2.1 SECONDARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #1 KEY RISK MESSAGE l: TIRF MEDICINES ARE CONTRAINDICATED IN OPIOID NON-TOLERANT PATIENTS. SUB-GROUP ANALYSIS 1: READING MEDICATION GUIDE OR FULL PRESCRIBING INFORMATION (QUESTIONS 20, 21, 22 AND 23): S-la - Respondents who received and read the Full Prescribing Information for the TIRF medicine that they prescribe, or who received and read the Medication Guide. 0 S-lb - Respondents who did not receive or did not read the Full Prescribing Information for the TIRF medication that they prescribe (answered ?No? or don?t know? to Question 21) and did not receive or did not read the Medication Guide for the TIRF medicine that they prescribe (answered ?No? or don?t know? to Question 23). S-la S-lb Read Medication Guide Did not read Medication or Guide or Demonstrated Understandmg Prescribing Info Prescribing Info 0 correct responses 0 0.0 1 2.9 1 correct response 1 0.4 1 2.9 2 correct responses 1 0.4 0 0.0 3 correct responses 4 1.5 3 8.6 4 correct responses 20 7.5 3 8.6 5 correct responses 36 13.5 5 14.3 6 correct responses 81 30.3 9 25.7 7 correct responses 124 46.4 13 37.1 Average number of correct responses 6.1 (5.9. 7.0) 5.5 (4.8. 7.0) One-sided 95 con?dence interval using the nomral approximation to the Poisson distribution. Client: TRIG Project: TIRF Wave2 Report Run Date and Time: 11/13/2013 1:25:00 PM Page 1 of 491 TABLE 6.2.2 SECONDARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #1 KEY RISK MESSAGE l: TIRF MEDICINES ARE CONTRAINDICATED IN OPIOID NON-TOLERANT PATIENTS. SUB-GROUP ANALYSIS 2: MEDICAL DEGREE OF RESPONDENTS (QUESTION 32): S-2a - MD 0 8-21) - D0 0 S-2c Nurse Practitioner S-2d - Physician Assistant S-2a S-2b S-2c S-2d MD DO Nurse Practitioner Physician Assistant Demonstrated Understanding 0 correct responses correct response correct responses correct responses correct responses 12 6.6 2 9.1 7 10.6 2 6.7 5 correct responses 26 14.3 3 13.6 8 12.1 4 13.3 6 correct responses 52 28.6 9 40.9 19 28.8 10 33.3 7 correct responses 83 45.6 8 36.4 30 45.5 14 46.7 Average number of correct responses 6.0 (5.7. 7.0) 6.0 (5.2. 7.0) 6.0 (5.5. 7.0) 6.2 (5.5. 7.0) One-sided 95 con?dence interval using the normal approximation to the Poisson distribution. Client: TRIG Project: TIRF Wave 2 Report Run Date and Time: 11/13/2013 1:25:00 PM Page 1 of 492 TABLE 6.2.3 SECONDARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #1 KEY RISK MESSAGE l: TIRF MEDICINES ARE CONTRAINDICATED IN OPIOID NON-TOLERANT PATIENTS. SUB-GROUP ANALYSIS 3: TIME TO COMPLETE SURVEY INTERNET: 0 8-33 - <10 min 0 S-3b 10 to <20 min 0 S-3c 20 min S-3a S?3b S-min Demonstrated Understanding N=l67 0 correct responses correct response correct responses correct responses correct responses 1 2.1 19 11.4 3 4.0 5 correct responses 8 17.0 20 12.0 8 10.7 6 correct responses 16 34.0 44 26.3 26 34.7 7 correct responses 18 38.3 80 47.9 36 48.0 Average number of correct responses 5.9 (5.3. 7.0) ?1 6.0 (5.7. 7.0) 6.2 (5.7. 7.0) One-sided 95 con?dence interval using the normal approximation to the Poisson distribution. Client: TRIG Project: TIRF Wave 2 Report Run Date and Time: 11/13/2013 1:26:00 PM Page 1 of 493 TABLE 6.2.5 SECONDARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #1 KEY RISK MESSAGE l: TIRF MEDICINES ARE CONTRAINDICATED IN OPIOID NON-TOLERANT PATIENTS. SUB-GROUP ANALYSIS 5: MODALITY TO COMPLETE SURVEY: S-5a Internet 0 - Telephone Internet Telephone Demonstrated Understanding 0 correct responses 1 0.3 0 0.0 1 correct response 1 0.3 1 7.7 2 correct responses 1 0.3 0 0.0 3 correct responses 7 2.4 0 0.0 4 correct responses 23 8.0 0 0.0 5 correct responses 36 12.5 5 38.5 6 correct responses 86 29.8 4 30.8 7 correct responses 134 46.4 3 23.1 Average number of correct responses 6.1 (5.8. 7.0) 5.5 (4.4. 7.0) [ll One-sided 95 con?dence interval using the normal approximation to the Poisson distribution. Client: TRIG Project: TIRF Wave2 Report Run Date and Time: 11/13/2013 1:27:00 PM Page 1 of 494 TABLE 6.2.6 SECONDARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #1 KEY RISK MESSAGE l: TIRF MEDICINES ARE CONTRAINDICATED IN OPIOID NON-TOLERANT PATIENTS. SUB-GROUP ANALYSIS 6: TINIE PRACTICING MEDICINE (QUESTION 33): S-6a - Less than 3 years S-6b - 3 to 5 years S-6c - 6 to 15 years S-6d - More than 15 years S-6a S-6b S-6c S-6d Less than 3 years 3 to 5 years 6 to 15 years More than 15 years Demonstrated Understanding N=l 17 0 correct responses correct response correct responses correct responses correct responses 5 17correct responses 1 3.6 10 20.4 18 17.0 12 10.3 6 correct responses 9 32.1 17 34.7 26 24.5 38 32.5 7 correct responses 12 42.9 17 34.7 50 47.2 56 47.9 Average number of correct responses 5.9 (5.2. 5.9 (5.3. 6.0 (5.6. 6.2 (5.8. One-sided 95 con?dence interval using the normal approximation to the Poisson distribution. Client: TRIG Project: TIRF Wave 2 Report Run Date and Time: 11/13/2013 1:28:00 PM Page 1 of 495 TABLE 6.2.7 SECONDARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #1 KEY RISK MESSAGE l: TIRF MEDICINES ARE CONTRAINDICATED IN OPIOID NON-TOLERANT PATIENTS. SUB-GROUP ANALYSIS 7: NUMBER OF TIMES PER MONTHS PRESCRIBING TIRF MEDICINES WITHIN THE LAST 6 MONTHS (QUESTION 29): S-7a - None S-7b - 1-2 times a month S-7c - 3 - 5 times a month S-7d - More than 5 times a month S-7a S-7b S-7c S-7d None 1-2 times a month 3 - 5 times a month More than 5 times a Demonstrated Understanding month 0 correct responses correct response 11.1 2 correct responses correct responses correct responses 6 11.1 10 5.8 5 11.4 0 0.0 5 correct responses 8 14.8 21 12.1 4 9.1 3 16.7 6 correct responses 13 24.1 55 31.8 15 34.1 6 33.3 7 correct responses 25 46.3 84 48.6 18 40.9 7 38.9 Average number of correct responses 6.0 (5.4. 7.0) 6.2 (5.9. 7.0) 5.9 (5.3. 7.0) 5.7 (4.7. 7.0) One-sided 95 con?dence interval using the normal approximation to the Poisson distribution. Client: TRIG Project: TIRF Wave 2 Report Run Date and Time: 11/13/2013 1:28:00 PM Page 1 of 496 TABLE 7.1 PRIMARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #2 KEY RISK MESSAGE 2: TIRF MEDICINES ARE ONLY INDICATED FOR THE MANAGEMENT OF BREAKTHROUGH PAIN IN ADULT CANCER PATIENTS 18 YEARS OF AGE AND OLDER (16 YEARS OF AGE AND OLDER FOR BRAND AND GENERIC EQUIVALENTS) WHO ARE ALREADY RECEIVING AND WHO ARE TOLERAN TO AROUND- THE-CLOCK OPIOID THERAPY FOR THEIR UNDERLYING PERSISTENT CANCER PAIN. Eligible and Complete Respondents Question (95% CI) Question 9: In your practice, for which of the following indications do you prescribe TIRF medicines to opioid tolerant patients? Please answer ?Yes,? or don?t know? for each option. 9a: Acute or postoperative pain 93.0 N0 281 (89.6. 95.6) Yes 17 5.6 I don't know 4 1.3 9b: Headache or migraine pain 92.4 No 279 (88.8. 95.1) Yes 20 6.6 I don't know 3 1.0 9c: Dental pain 96.7 N0 292 (94.0. 98.4) Yes 5 1.7 I don't know 5 1.7 Client: TRIG Project: TIRF Wave 2 Report Run Date and Time: 11/11/2013 4:33:00 PM Page 1 of 2 497 Eligible and Complete Respondents Question (95% CI) 9d: Breakthrough pain from cancer 92.4 Yes 279 (88.8. 95.1) No 22 7.3 I don't know 1 0.3 9e: Chronic non?cancer pain 58.9 N0 178 (53.2. 64.5) Yes 119 39.4 I don't know 5 1.7 Question 13: The patients described are experiencing breakthrough pain. According to the labeling, a TIRF medicine is not appropriate for one of them. Which patient should not receive a TIRF medicine? Please select one option. Adult female with localized breast cancer: just completed a mastectomy and reconstructive surgery: persistent cancer pain managed with 30 111g oral morphine daily for the past 6 weeks. 199 65.9 (60.2. 71.2) Adult female with advanced sarcoma who has been taking a daily dose of 12 mg oral hydromorphone for the last 3 weeks. 36 11.9 Adult male patient with advanced prostate cancer who. over the last 2 weeks. has been prescribed 100 mg oral 11101phine daily for pain due to bone metastasis. 12 4.0 Adult male with advanced lung cancer; 1mderlying persistent cancer pain managed with 25 111cg/1101u?transde1mal fentanyl patches for the past two months. 28 9.3 I don?t know 27 8.9 Correct response All con?dence intervals are exact binomial 95% con?dence intervals. Client: TRIG Project: Report Run Date and Time: 11/11/2013 4:33:00 PM Page 2 of 2 498 TABLE 7.1.1 PRIMARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #2 KEY RISK MESSAGE l: TIRF MEDICINES ARE CONTRAINDICATED IN OPIOID NON-TOLERANT PATIENTS. SUB-GROUP ANALYSIS 1: READING MEDICATION GUIDE OR FULL PRESCRIBING INFORMATION (QUESTIONS 20, 21, 22 AND 23): S-la - Respondents who received and read the Full Prescribing Information for the TIRF medicine that they prescribe, or who received and read the Medication Guide. 0 S-lb - Respondents who did not receive or did not read the Full Prescribing Information for the TIRF medication that they prescribe (answered ?No? or don?t know? to Question 21) and did not receive or did not read the Medication Guide for the TIRF medicine that they prescribe (answered ?No? or don?t know? to Question 23). Question S?la 54!) Read Medication Guide or not read Medication Guide Prescribing Info or Prescribing Info (95% CI) (95% c1) each option. Question 9: In your practice, for which of the following indications do you prescribe TIRF medicines to opioid tolerant patients? Please answer ?Yes,? or don?t know? for 9a: Acute or postoperative pain NO 248 (89.95.9957) 33 (80.959393don't know 4 1.5 0 0.0 9b: Headache or migraine pain NO 246 (88.95.9151) 33 (80.982393don't know 3 1.1 0 0.0 Client: TRIG Project: TIRF WaveZ Report Run Date and Time: 11/12/2013 3:29:00 PM Page 1 of 3 499 S?lb S?la . . . . Read Medication Guide or not read 1v?1;d1catlon Gulde Prescribin Info . . Question Info (95% CI) (95% CI) 9c: Dental pain 96.6 97.1 No 258 (93.7. 98.4) 34 (85.1. 99.don't know 4 1.5 1 2.9 9d: Breakthrough pain from cancer 92.9 88.6 Yes 248 (89.1. 95.7) 31 (73.3. 96.8) No 18 6.7 11.4 I don't know 1 0.4 0.0 9e: Chronic non?cancer pain 59.2 57.1 No 158 (53.0. 65.1) 20 (39.4. 73.7) Yes 105 39.3 14 40.0 I don't know 4 1.5 1 2.9 Client: TRIG Project: TIRF Wave2 Report Run Date and Time: 11/12/2013 3:29:00 PM Page 2 of 3 500 Question S?la Read Medication Guide or S?lb Did not read Medication Guide . . 01' Info Prescribing Info Question 13: The patients described are experiencing breakthrough pain. According to the labeling, a TIRF medicine is not appropriate for one of them. Which patient should not receive a TIRF medicine? Please select one option. Adult female with localized breast cancer: just completed a mastectomy and surgery: persistent cancer pain managed with 30 mg oral mo1phine daily for the past 6 weeks. 178 66.7 (60.7. 72.3) 60.0 21 (42.1. 76.1) Adult female with advanced sarcoma who has been taking a daily dose of 12 mg oral hydromorphone for the last 3 weeks. 31 11.6 5 14.3 Adult male patient with advanced prostate cancer who. over the last 2 weeks. has been prescribed 100 mg oral morphine daily for pain due to bone metastasis. 12 Adult male with advanced 11mg cancer: Imderlying persistent cancer pain managed with 25 111cg/hourtransdermal fentanyl patches for the past two months. 25 9.4 I don?t know 21 7.9 6 17.1 Correct response Client: TRIG Project: TIRF Wave 2 Report Run Date and Time: 11/12/2013 3:29:00 PM Page 3 of 3 501 TABLE 7.1.2 PRIMARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #2 KEY RISK MESSAGE l: TIRF MEDICINES ARE CONTRAINDICATED IN OPIOID NON-TOLERANT PATIENTS. SUB-GROUP ANALYSIS 2: MEDICAL DEGREE OF RESPONDENTS (QUESTION 32): S-2a - NIT) D0 0 S-2c Nurse Practitioner S-2d - Physician Assistant Question S?2a S?2b S?2c S?2d MD D0 Nurse Practitioner Physician Assistant (95% CI) (95% CI) (95% CI) (95% CI) Question 9: In your practice, for which of the following indications do you prescribe TIRF medicines to opioid tolerant patients? Please answer ?Yes,? or don?t know? for each option. 9a: Acute or postoperative pain 100.0 92.9 95.5 89.4 No 169 (88.1. 96.1) 21 (77.2. 99.9) 59 (79.4. 95.6) 30 (88'4? 100.don't know 0.0 Client: TRIG Project: TIRF Wave2 Report Run Date and Time: 11/12/2013 2:01:00 PM Page 1 of 502 S?2a S-2b S-2c S-2d NH) DO Nurse Practitioner Physician Assistant Question (953: CI) CI) (9500/? C1) 9b: Headache or migraine pain NO 164 (849899140) 21 (77.925399) 64 (89.95396) 28 (77.993392don't know 0.0 9c: Dental pain NO 175 (92.92.5384) 21 (77.925399) 64 (89.957396) 30 (1233:. 100.don't know 0.0 9d: Breakthrough pain from cancer Yes 168 (8725357) 21 (77.925399) 60 (81.299966) 28 (77.95.9392don't know 1 0.5 0.0 0 0.0 0.0 Client: TRIG Project: TIRF Wave 2 Report Run Date and Time: 11/12/2013 2:01:00 PM Page 2 of 4 503 S?2a S-2b S?2c S?2d NH) DO Nurse Practitioner Physician Assistant (95% CI) (95% CI) (95% CI) (95% CI) 9e: Chronic non-cancer pain 59.9 59.1 53.0 66.7 N0 109 (52.4. 67.1) 13 (36.4. 79.3) 35 (40.3. 65.4) 20 (47.2. 82.7) Yes 70 38.5 9 40.9 30 45.5 9 30.0 I don't know 3.3 Question 13: The patients described are experiencing breakthrough pain. According to the labeling, a TIRF medicine is not appropriate for one of them. Which patient should not receive a TIRF medicine? Please select one option. Adult female with localized breast cancer: just completed a mastectomy and reconstructive sm'ger'y; persistent cancer pain managed with 30 mg oral morphine daily for the past 6 weeks. 123 67.6 (60.3. 74.3) 12 4. (32.2. 75.6) 43 65.2 (52.4. 76.5) 21 70.0 (50.6. 85.3) Adult female with advanced sarcoma who has been taking a daily dose of 12 mg oral hydromorphone for the last 3 weeks. 19 10.4 18.2 10.6 16.7 Client: TRIG Project: TIRF Wave 2 Report Run Date and Time: 11/12/2013 2:01:00 PM Page 3 of 504 Question S?2a MD S?2b DO S?2c Nurse Practitioner S?2d Physician Assistant (95% CI) (95% CI) (95% CI) (95% CI) Adult male patient with advanced prostate cancer who. over the last 2 weeks. has been prescribed 100 mg oral morphine daily for pain due to bone metastasis. 10 5.5 0.0 1.5 3.3 Adult male with advanced 11mg cancer: underlying persistent cancer pain managed with 25 111cg/h01u' transdennal fentanyl patches for the past two months. 16 8.8 9.1 9.1 10.0 I don?t know 14 7.7 18.2 13.6 0.0 Correct response Client: TRIG Project: TIRF WaveZ Report Run Date and Time: 11/12/2013 2:01:00 PM Page 4 of 4 505 TABLE 7.1.3 PRIMARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #2 KEY RISK MESSAGE l: TIRF MEDICINES ARE CONTRAINDICATED IN OPIOID NON-TOLERANT PATIENTS. SUB-GROUP ANALYSIS 3: TIME TO COMPLETE SURVEY - INTERNET: S-3a - <10 min 0 S-3b 10 to <20 min 0 S-3c 20 min S?3a S?3b S?min Question (95% CI) (95% CI) (95% CI) Question 9: In your practice, for which of the following indications do you prescribe TIRF medicines to opioid tolerant patients? Please answer ?Yes,? or don?t know? for each option. 9a: Acute or postoperative pain 95.7 92.2 93.3 No ?1 45 (85.5. 154 (87.1. 70 (85.1. 99.5) 95.8) 97.don't know 1 2.1 2 1.2 1 1.3 9b: Headache or migraine pain 93.6 92.8 89.3 No ?1 44 (82.5. 155 (87.8. 67 (80.1. 98.7) 96.2) 95.don't know 0 0.0 2 1.2 1 1.3 9c: Dental pain 93.6 97.0 97.3 No ?1 44 (82.5. 162 (93.2. 73 (90.7. 98.7) 99.0) 99.don't know 2 4.3 3 1.8 0 0.0 Client: TRIG Project: TIRF Wave2 Report Run Date and Time: 11/12/2013 2:10:00 PM Page 1 3 506 S-3a S-3b S?min Question (95% CI) (95% CI) (95% CD 9d: Breakthrough pain from cancer 95.7 95.8 81.3 Yes ?1 45 (85.5. 160 (91.6. 61 (70.7. 99.5) 98.3) 89.18.7 I don't know 0 0.0 1 0.6 0 0.0 9e: Chronic non-cancer pain 66.0 55.1 60.0 No ?1 31 (50.7. 92 (47.2. 45 (48.0. 79.1) 62.8) 71.1) Yes 15 31.9 72 43.1 29 38.7 I don't know 1 2.1 3 1.8 1 1.3 Client: TRIG Project: Report Run Date and Time: 11/12/2013 2:10:00 PM Page 2 of 3 507 Question S-3a <10 min S?3b 10 to <20 min S-3c 20 min (95% CI) (95% CI) (95% CI) Question 13: The patients described are experiencing breakthrough pain. According to the labeling, a TIRF medicine is not appropriate for one of them. Which patient should not receive a TIRF medicine? Please select one option. Adult female with localized breast cancer; just completed a mastectomy and reconstructive surgery: persistent cancer pain managed with 30 mg oral morphine daily for the past 6 weeks. 1 22 46.8 (32.1. 61.9) 120 71.9 (64.4. 78.5) 68.0 (56.2. 78.3) Adult female with advanced sarcoma who has been taking a daily dose of 12 mg oral hydromorphone for the last 3 weeks. 17.0 9.0 11 14.7 Adult male patient with advanced prostate cancer who. over the last 2 weeks. has been prescribed 100 mg oral morphine daily for pain due to bone metastasis. 6.4 4.2 0.0 Adult male with advanced 11mg cancer: imderlying persistent cancer pain managed with 25 meg/horn transdennal fentanyl patches for the past two months. 12.8 13 7.8 9.3 I don?t know 17.0 12 7.2 8.0 Correct response Client: TRIG Project: Report Run Date and Time: 11/12/2013 2:10:00 PM Page 3 3 508 TABLE 7.1.5 PRIMARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #2 KEY RISK MESSAGE l: TIRF MEDICINES ARE CONTRAINDICATED IN OPIOID NON-TOLERANT PATIENTS. SUB-GROUP ANALYSIS 5: MODALITY TO COMPLETE SURVEY: S-5a - Internet 0 - Telephone Internet Telephone (95% CI) (95% CI) Question 9: In your practice, for which of the following indications do you prescribe TIRF medicines to opioid tolerant patients? Please answer ?Yes,? or don?t know? for each option. 9a: Acute or postoperative pain 93.1 92.3 No 269 (89.5. 95.7) 12 (64.0. 99.don't know 4 1.4 0 0.0 9b: Headache or migraine pain 92.0 100.0 N0 266 (88.3. 94.9) 13 (75.3. 100.0) Yes 20 6.9 0.0 I don't know 3 1.0 0 0.0 9c: Dental pain 96.5 100.0 N0 279 (93.7. 98.3) 13 (75.3. 100.0) Yes 5 1.7 0.0 I don't know 5 1.7 0.0 Client: TRIG Project: TIRF WaveZ Report Run Date and Time: 11/12/2013 2:18:00 PM Page 1 of 3 509 S?5a Internet Telephone (95% CI) (95% CI) 9d: Breakthrough pain from cancer 92.0 100.0 Yes 266 (88.3. 94.9) 13 (75.3. 100.don't know 1 0.3 0 0.0 9e: Chronic non?cancer pain 58.1 76.9 No 168 (52.2. 63.9) 10 (46.2. 95.0) Yes 116 40.1 3 23.1 I don't know 5 1.7 0 0.0 Client: TRIG Project: TIRF Wave 2 Report Run Date and Time: 11/12/2013 2:18:00 PM Page 2 of 3 Question Internet Telephone N=l3 (95% CI) (95% CI) Question 13: The patients described are experiencing breakthrough pain. According to the labeling, a TIRF medicine is not appropriate for one of them. Which patient should not receive a TIRF medicine? Please select one option. Adult female with localized breast cancer: just completed a mastectomy and reconstiuctive surgery: persistent cancer pain managed with 30 mg oral 11101phine daily for the past 6 weeks. 193 66.8 (61.0. 72.2) 46.2 (19.2. 74.9) Adult female with advanced sarcoma who has been taking a daily dose of 12 111g oral hydromorphone for the last 3 weeks. 34 11.8 Adult male patient with advanced prostate cancer who. over the last 2 weeks. has been prescribed 100 mg oral morphine daily for pain due to bone metastasis. 10 Adult male with advanced 11mg cancer: imderlying persistent cancer pain managed with 25 meg/hom? transdennal fentanyl patches for the past two months. 26 9.0 I don?t know 26 9.0 7.7 Correct response Client: TRIG Project: Report Run Date and Time: 11/12/2013 2:18:00 PM Page 3 of 3 1 TABLE 7.1.6 PRIMARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #2 KEY RISK MESSAGE l: TIRF MEDICINES ARE CONTRAINDICATED IN OPIOID NON-TOLERANT PATIENTS. SUB-GROUP ANALYSIS 6: TIME PRACTICING MEDICINE (QUESTION 33): S-6a - Less than 3 years S-6b - 3 to 5 years S-6c - 6 to 15 years S-6d - More than 15 years Question S?6a S-6b S?6c S?6d Less than 3 years 3 to 5 years 6 to 15 years More than 15 years N=ll7 (95% CI) (95% CI) (95% CI) (95% CI) Question 9: In your practice, for which of the following indications do you prescribe TIRF medicines to opioid tolerant patients? Please answer ?Yes,? or don?t know? for each option. 9a: Acute or postoperative pain 96.4 87.8 93.4 94.0 N0 27 (81.7. 99.9) 43 (75.2. 95.4) 99 (86.9. 97.3) 110 (88.1. 97.6) Yes 0 0.0 5 10.2 5 4.7 7 6.0 I don't know 0.0 Client: TRIG Project: TIRF Wave2 Report Run Date and Time: 11/12/2013 2:25:00 PM Page 1 of 4 S?6a S?6b S?6c S-6d Less than 3 years 3 to 5 years 6 to 15 years More than 15 years Question N=l 17 (95% CI) (95% CI) (95% CI) (95% CI) 9b: Headache or migraine pain 96.4 93.9 92.5 90.6 N0 27 (81.7. 99.9) 46 (83.1. 98.7) 98 (85.7. 96.7) 106 (83.8. 95.don't know 0.0 9c: Dental pain 96.4 98.0 95.3 97.4 N0 27 (81.7. 99.9) 48 (89.1. 99.9) 101 (89.3. 98.5) ?4 (92.7. 99.don't know 0.0 9d: Breakthrough pain from cancer 96.4 91.8 91.5 92.3 YES 27 (81.7. 99.9) 45 (80.4. 97.7) 97 (84.5. 96.0) 108 (85.9. 96.don't know 0.0 Client: TRIG Project: TIRF Wave2 Report Run Date and Time: 11/12/2013 2:25:00 PM Page 2 S?6a S-6b S?6c S-6d Less than 3 years 3 to 5 years 6 to 15 years More than 15 years Question N=l 17 (95% CI) (95% CI) (95% CI) (95% CI) 9e: Chronic non-cancer pain 71.4 63.3 64.2 48.7 NO 20 (51.3. 86.8) 31 (48.3. 76.6) 68 (54.3. 73.2) 57 (39.4. 58.1) Yes 7 25.0 17 34.7 35 33.0 60 51.3 I don't know 0.0 Question 13: The patients described are experiencing breakthrough pain. According to the labeling, a TIRF medicine is not appropriate for one of them. Which patient should not receive a TIRF medicine? Please select one option. Adult female with localized breast cancer: just completed a mastectomy and 75.0 67.3 594 69.2 Slug?; 21 (55.1. 89.3) 33 (52.5. 80.1) 63 (49.5. 68.9) 81 (60.0. 77.4) Slstent cancel paln managed with 30 mg oral morphine daily for the past 6 weeks. Adult female with advanced sarcoma who has been taking a daily dose of 1 3.6 5 10.2 16 15.1 13 11.1 12 mg oral hydromorphone for the last 3 weeks. Client: TRIG Project: TIRF Wave 2 Report Run Date and Time: 11/12/2013 2:25:00 PM Page 3 of 4 51 4 Question S?6a Less than 3 years S-6b 3 to 5 years S?6c 6 to 15 years S?6d More than 15 years N=ll7 (95% CI) (95% CI) (95% CI) (95% CI) Adult male patient with advanced prostate cancer who. over the last 2 weeks. has been prescribed 100 mg oral morphine daily for pain due to bone metastasis. 7.1 2.0 5.7 2.6 Adult male with advanced lung cancer; underlying persistent cancer pain managed with 25 111cg/h01u? transdermal fentanyl patches for the past two months. 3.6 6.1 12 11.3 12 10.3 I don?t know 10.7 14.3 8.5 6.8 Correct response Client: TRIG Project: TIRF Wave2 Report Run Date and Time: 11/12/2013 2:25:00 PM Page 4 of TABLE 7.1.7 PRIMARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #2 KEY RISK MESSAGE l: TIRF MEDICINES ARE CONTRAINDICATED IN OPIOID NON-TOLERANT PATIENTS. SUB-GROUP ANALYSIS 7: NUMBER OF TIMES PER MONTHS PRESCRIBING TIRF MEDICINES WITHIN THE LAST 6 MONTHS (QUESTION 29): S-7a - None S-7b - 1-2 times a month S-7c - 3 - 5 times a month S-7d - More than 5 times a month S?7d S?7a S?7b S?7c . None 1-2 times a month 3 - 5 times a month More trifhumes a Question (95% CD (95% CI) (95% CI) (95% c1) Question 9: In your practice, for which of the following indications do you prescribe TIRF medicines to opioid tolerant patients? Please answer ?Yes,? or don?t know? for each option. 9a: Acute or postoperative pain 92.6 94.8 86.4 94.4 NO 50 (82.1. 97.9) 164 (90.4. 97.6) 38 (72.6. 94.8) 17 (72.7. 99.13.6 1 5.6 I don't know 0.0 Client: TRIG Project: TIRF Wave2 Report Run Date and Time: 11/14/2013 4:15:00 PM Page 1 of 4 8?73. S-7c More uni?Z: times a None 1?2 times a month 3 - 5 times a month month (95% CI) (95% CI) (95% CI) (95% CI) 9b: Headache or migraine pain 94.4 93.1 86.4 88.9 No 51 (84.6. 98.8) 161 (88.2. 96.4) 38 (72.6. 94.8) 16 (65.3. 98.13.6 2 11.1 I don't know 0.0 9c: Dental pain 96.3 97.7 95.5 94.4 No 52 (87.3. 99.5) 169 (94.2. 99.4) 42 (84 5.99.4) 17 (72.7. 99.don't know 0.0 9d: Breakthrough pain from cancer 83.3 93.1 97.7 94.4 Yes 45 (70.7. 92.1) 161 (88.2. 96.4) 43 (88.0. 99.9) 17 (72.7. 99.9) No 8 14don't know 1 1.9 0 0.0 0 0.0 0.0 Client: TRIG Project: TIRF Wave 2 Report Run Date and Time: 11/14/2013 4:15:00 PM Page 2 S?7d S?7a S?7b S?7c . None 1?2 times a month 3 - 5 times a month More a Question N=l73 (95% CI) (95% CI) (95% CI) (95% CI) 9e: Chronic non-cancer pain 77.8 59.0 50.0 38.9 N0 42 (64.4. 88.0) 102 (51.2. 66.4) 22 (34.6. 65.4) 7 (17.3. 64.3) Yes 10 18.5 69 39.9 22 50.0 11 61.1 I don't know 0.0 Question 13: The patients described are experiencing breakthrough pain. According to the labeling, a TIRF medicine is not appropriate for one of them. Which patient should not receive a TIRF medicine? Please select one option. Adult female with localized breast cancer: just completed a mastectomy and reconstructive sru?ger?y: persistent cancer pain managed with 30 mg oral morphine daily for the past 6 weeks. 39 72.2 (58.4. 83.5) 112 64.7 (57.1. 71.8) 26 59.1 (43.2. 73.7) 16 88.9 (65.3. 98.6) Adult female with advanced sarcoma who has been taking a daily dose of 12 111g oral hydromorphone for the last 3 weeks. 9.3 23 13.3 13.6 5.6 Client: TRIG Project: TIRF WaveZ Report Run Date and Time: 11/14/2013 4:15:00 PM Page 3 of Question S?7a None S?7b 1?2 times a month N=l73 S-7c 3 5 times a month S?7d More than 5 times a month (95% CI) (95% CI) (95% CI) (95% CI) Adult male patient with advanced prostate cancer who. over the last 2 weeks. has been prescribed 100 mg oral morphine daily for pain due to bone metastasis. Adult male with advanced lung cancer; underlying persistent cancer pain managed with 25 111cg/h01u? transdermal fentanyl patches for the past two months. 16 9.2 7 15.9 I don?t know 16 9.2 Correct response Client: TRIG Project: TIRF WaveZ Report Run Date and Time: 11/14/2013 4:15:00 PM Page 4 of 4 TABLE 7.2 SECONDARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #2 KEY RISK MESSAGE 2: TIRF MEDICINES ARE ONLY INDICATED FOR THE MANAGEMENT OF BREAKTHROUGH PAIN IN ADULT CANCER PATIENTS 18 YEARS OF AGE AND OLDER (16 YEARS OF AGE AND OLDER FOR BRAND AND GENERIC EQUIVALENTS) WHO ARE ALREADY RECEIVING AND WHO ARE TOLERANT TO AROUND- THE-CLOCK OPIOID THERAPY FOR THEIR UNDERLYING PERSISTENT CANCER PAIN. Prescribers Demonstrated Understanding 0 correct responses 0 0.0 1 correct response 4 1.3 2 correct responses 5 1.7 3 correct responses 22 7.3 4 correct responses 46 15.2 5 correct responses 106 35.1 6 correct responses 119 39.4 Average number of correct responses 5.0 (4.8. 6.0) One-sided 95 con?dence interval using the normal approximation to the Poisson distribution Client: TRIG Project: TIRF Wave 2 Report Run Date and Time: 11/13/2013 11:23:00 AM Page 1 of 520 TABLE 7.2.1 SECONDARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #2 KEY RISK MESSAGE l: TIRF MEDICINES ARE CONTRAINDICATED IN OPIOID NON-TOLERANT PATIENTS. SUB-GROUP ANALYSIS 1: READING MEDICATION GUIDE OR FULL PRESCRIBING INFORNIATION (QUESTIONS 20, 21, 22 AND 23): S-la - Respondents who received and read the Full Prescribing Information for the TIRF medicine that they prescribe, or who received and read the Medication Guide. 0 S-lb - Respondents who did not receive or did not read the Full Prescribing Information for the TIRF medication that they prescribe (answered ?No? or don?t know? to Question 21) and did not receive or did not read the Medication Guide for the TIRF medicine that they prescribe (answered ?No? or don?t know? to Question 23). S-la S-lb Read Medication Guide Did not read Medication . or Guide or Demonstrated Understanding Prescribing Info Prescribing Info 0 correct responses 0 0.0 0 0.0 1 correct response 4 1.5 0 0.0 2 correct responses 4 1.5 1 2.9 3 correct responses 19 7.1 3 8.6 4 correct responses 41 15.4 5 14.3 5 correct responses 91 34.1 15 42.9 6 correct responses 108 40.4 11 31.4 Average number of correct responses 5.0 (4.8. 6.0) 4.9 (4.3. [110ne-sided 95 con?dence interval using the normal approximation to the Poisson distribution. Client: TRIG Project: TIRF Wave2 Report Run Date and Time: 11/13/2013 1:29:00 PM Page 1 of 521 TABLE 7.2.2 SECONDARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #2 KEY RISK MESSAGE 1: TIRF MEDICINES ARE CONTRAINDICATED IN OPIOID NON-TOLERAN PATIENTS. SUB-GROUP ANALYSIS 2: MEDICAL DEGREE OF RESPONDENTS (QUESTION 32): S-2a - MI) 0 DO 0 S-2c Nurse Practitioner S-2d - Physician Assistant S-2a S-2b S-2c S-2d NID DO Nurse Practitioner Physician Assistant Demonstrated Understanding 0 correct responses correct response correct responses correct responses 11 6.0 4.5 7 10.6 3 10.0 4 correct responses 27 14.8 6 27.3 9 13.6 3 10.0 5 correct responses 65 35.7 8 36.4 24 36.4 8 26.7 6 correct responses 72 39.6 7 31.8 24 36.4 16 53.3 Average number of correct responses 5.0 (4.7. 5.0 (4.2. 4.9 (4.5. 6.0) 5.2 (4.5. 6.0) [ll One-sided 95 con?dence interval using the normal approximation to the Poisson distribution. Client: TRIG Project: TIRF Wave2 Report Run Date and Time: 11/13/2013 1:29:00 PM Page 1 of 522 TABLE 7.2.3 SECONDARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #2 KEY RISK MESSAGE 1: TIRF MEDICINES ARE CONTRAINDICATED IN OPIOID NON-TOLERANT PATIENTS. SUB-GROUP ANALYSIS 3: TIME TO COMPLETE SURVEY INTERNET: S-3a - <10 min 0 S-3b 10 to <20 min 0 S-3c 20 min S-3a S-3b S-min Demonstrated Understanding 0 correct responses 0 0.0 0.0 0 0.0 1 correct response correct responses correct responses 4 8.5 10 6.0 8 10.7 4 correct responses 8 17.0 23 13.8 13 17.3 5 correct responses 14 29.8 65 38.9 20 26.7 6 correct responses 19 40.4 65 38.9 31 41.3 Average number of correct responses 4.9 (4.4. 6.0) 5.0 (4.8. 6.0) 4.9 (4.5. 6.0) "1 One-sided 95 con?dence interval using the normal approximation to the Poisson distribution. Client: TRIG Project: TIRF Wave 2 Report Run Date and Time: 11/13/2013 1:30:00 PM Page 1 of 523 TABLE 7.2.5 SECONDARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #2 KEY RISK MESSAGE l: TIRF MEDICINES ARE CONTRAINDICATED IN OPIOID NON-TOLERANT PATIENTS. SUB-GROUP ANALYSIS 5: MODALITY TO COMPLETE SURVEY: S-5a Internet 0 - Telephone S-5b Internet Telephone Demonstrated Understanding 0 correct responses 0 0.0 0 0.0 1 correct response 4 1.4 0 0.0 2 correct responses 5 1.7 0 0.0 3 correct responses 22 7.6 0 0.0 4 correct responses 44 15.2 2 15.4 5 correct responses 99 34.3 7 53.8 6 correct responses 115 39.8 4 30.8 Average number of correct responses 5.0 (4.8. 6.0) 5.2 (4.1. 6.0) One-sided 95 con?dence interval using the normal approximation to the Poisson distribution. Client: TRIG Project: Report Run Date and Time: 11/13/2013 1:30:00 PM Page 1 of 524 TABLE 7.2.6 SECONDARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #2 KEY RISK MESSAGE 1: TIRF MEDICINES ARE CONTRAINDICATED IN OPIOID NON-TOLERANT PATIENTS. SUB-GROUP ANALYSIS 6: TIIWE PRACTICING MEDICINE (QUESTION 33): S-6a - Less than 3 years S-6b - 3 to 5 years S-6c - 6 to 15 years S-6d - More than 15 years S-6a S-6b S-6c S-6d Less than 3 years 3 to 5 years 6 to 15 years More than 15 years Demonstrated Understanding N=l 17 0 correct responses correct response correct responses correct responses 1 3.6 10.2 6 5.7 10 8.5 4 correct responses 2 7.1 7 14.3 15 14.2 22 18.8 5 correct responses 12 42.9 15 30.6 40 37.7 38 32.5 6 correct responses 13 46.4 21 42.9 40 37.7 44 37.6 Average number of correct responses 5.3 (4.6. 6.0) 5.0 (4.5. 6.0) "1 5.0 (4.6. 6.0) 4.9 (4.6. 6.0) ?1 ll] One-sided 95 con?dence interval using the normal approximation to the Poisson distribution. Client: TRIG Project: TIRF WaveZ Report Run Date and Time: 11/13/2013 1:31:00 PM Page 1 of 525 TABLE 7.2.7 SECONDARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #2 KEY RISK MESSAGE 1: TIRF MEDICINES ARE CONTRAINDICATED IN OPIOID NON-TOLERAN PATIENTS. SUB-GROUP ANALYSIS 7: NUMBER OF TIMES PER MONTHS PRESCRIBING TIRF MEDICINES WITHIN THE LAST 6 MONTHS (QUESTION 29): 0 8-73 - None 0 S-7b - 1-2 times a month 0 S-7c - 3 - 5 times a month 0 S-7d - More than 5 times a month S-7a S-7b S-7c S-7d None 1-2 times a month 3 - 5 times a month More than 5 times a Demonstrated Understanding month 0 correct responses correct response correct responses correct responses 6 11correct responses 2 3.7 31 17.9 7 15.9 2 11.1 5 correct responses 14 25.9 58 33.5 18 40.9 11 61.1 6 correct responses 30 55.6 69 39.9 13 29.5 4 22.2 Average number of correct responses 5.2 (4.7. 6.0) 5.0 (4.7. 6.0) "1 4.8 (4.2. 6.0) "1 5.0 (4.1. 6.0) "1 One-sided 95 con?dence interval using the normal approximation to the Poisson distribution. Client: TRIG Project: TIRF Wave 2 Report Run Date and Time: 11/13/2013 1:32:00 PM Page 1 of 526 TABLE 8.1 PRIMARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #3 KEY RISK MESSAGE 3: TIRF MEDICINES CONTAIN FENTANYL, AN OPIOID AGONIST AND A SCHEDULE II CONTROLLED SUBSTANCE, WITH ABUSE LIABILITY SIMILAR TO OTHER OPIOID ANALGESICS. Eligible and Complete Respondents Question (95% CI) "1 on the labeling for TIRF medicines. Question 7: Please answer ?True,? ?False,? or don?t know? for each statement based 7e: It is important to monitor for signs of abuse and addiction in patients who take TIRF medicines. 99.0 Tm 299 (97.1. 99.8) False 2 0. 7 I don't know 1 0.3 Question 8: Which of the following are risk factors for opioid abuse? Please answer ?Yes,? or don?t know? for each option. 8a: A personal history of illness 82.8 Yes 250 (78.0. 86.9) No 31 10.3 I don't know 21 7.0 use or alcohol abuse 8b: A personal history of past or current alcohol or drug abuse, or a family history of illicit drug 99.0 [11 Yes 299 (97.1. 99.8) No 2 0.7 I don't know 1 0.3 Client: TRIG Project: TIRF Wave 2 Report Run Date and Time: 11/15/2013 12:30:00 PM Page 1 of 2 527 Question Eligible and Complete Respondents (95% CI) "1 Question 10: Please answer ?True,? ?False,? or don?t know? for each statement based on the labeling for TIRF medicines. 10a: TIRF medicines can be abused in a manner similar to other opioid agonists. 96.4 True 291 (93.6. 98.2) False 9 3.0 I don't know 2 0.7 COITCCI A11 con?dence intelvals are exact binomial 95% con?dence intelvals. Client: TRIG Project: TIRF Wave 2 Report Run Date and Time: 11/15/2013 12:30:00 PM Page 2 of 2 528 TABLE 8.1.1 PRIMARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #3 KEY RISK MESSAGE l: TIRF MEDICINES ARE CONTRAINDICATED IN OPIOID NON-TOLERANT PATIENTS. SUB-GROUP ANALYSIS 1: READING MEDICATION GUIDE OR FULL PRESCRIBING INFORMATION (QUESTIONS 20, 21, 22 AND 23): S-la - Respondents who received and read the Full Prescribing Information for the TIRF medicine that they prescribe, or who received and read the Medication Guide. 0 S-lb - Respondents who did not receive or did not read the Full Prescribing Information for the TIRF medication that they prescribe (answered ?No? or don?t know? to Question 21) and did not receive or did not read the Medication Guide for the TIRF medicine that they prescribe (answered ?No? or don?t know? to Question 23). S?la 54" Read Medication Guide or D'd Mt g?gxid'catwn Prescribing Info . Question Prescribing Info (95% CI) (95% CI) Question 7: Please answer ?True,? ?False,? or don?t know? for each statement based on the labeling for TIRF medicines. 7e: It is important to monitor for signs of abuse and addiction in patients who take TIRF medicines. 98.9 100.0 True 264 (96.8. 99.8) 35 (90.0. 100.0) False 2 0.7 0 0.0 I don't know 1 0.4 0 0.0 Question 8: Which of the following are risk factors for opioid abuse? Please answer ?Yes,? or don?t know? for each option. 8a: A personal history of illness 85.0 65.7 Yes 227 (80.2. 89.1) 23 (47.8. 80.9) No 24 9.0 7 20.0 I don't know 16 6.0 5 14.3 Client: TRIG Project: TIRF Wave 2 Report Run Date and Time: 11/12/2013 3:28:00 PM Page 1 of 2 529 Question S?lb S?la . . Read Medication Guide or not read Medication - - Guide or Info . Prescribing Info (95% CI) (95% CI) 8b: A personal history of past or current alcohol or drug abuse, or a family history of illicit drug use or alcohol abuse 98.9 100.0 Yes 264 (96.8. 99.8) 35 (90.0. 100.don't know 1 0.4 0 0.0 Question 10: Please answer ?True,? ?False,? or don?t know? for each statement based on the labeling for TIRF medicines. 10a: TIRF medicines can be abused in a manner similar to other opioid agonists. 96.6 94.3 True 258 (93.7. 98.4) 33 (808.993) False 9 3.4 0 0.0 I don't know 0 0.0 2 5.7 Correct response Client: TRIG Project: TIRF Wave2 Report Run Date and Time: 11/12/2013 3:28:00 PM Page 2 of 2 530 TABLE 8.1.2 PRIMARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #3 KEY RISK MESSAGE 1: TIRF MEDICINES ARE CONTRAINDICATED IN OPIOID NON-TOLERANT PATIENTS. SUB-GROUP ANALYSIS 2: MEDICAL DEGREE OF RESPONDENTS (QUESTION 32): S-2a - MD S-2b DO 0 S-2c Nurse Practitioner S-2d - Physician Assistant Question S-2a S-2b S-ZC S-2d MD D0 Nurse Practitioner Physician Assistant (95% CI) (95% CI) (95% CI) (95% CI) Question 7: Please answer ?True,? ?False,? or don?t know? for each statement based on the labeling for TIRF medicines. 7e: It is important to monitor for signs of abuse and addiction in patients who take TIRF medicines. 99.5 100.0 95.5 96.7 True ?1 181 (97.0. 21 66 (94.6. 29 100.0) (77.2. 99.9) 100.0) (82.8. 99.9) False don't know 3.3 Client: TRIG Project: TIRF Wave2 Report Run Date and Time: 11/12/2013 3:33:00 PM Page 1 of 3 531 S?2a S?2b S?2c S?2d MD DO Nurse Practitioner Physician Assistant Question (953CI) (953CI) (953CI) Question 8: Which of the following are risk factors for opioid abuse? Please answer ?Yes,? or don?t know? for each option. 8a: A personal history of illness Yes 153 (77.3%91) 16 (49.25393) 52 (673-8879) 27 (73.29329) No 16 8.8 5 22.7 9 13.6 1 3.3 I don't know personal history of past or current alcohol or drug abuse, or a family history of illicit drug use or alcohol abuse 99.5 100.0 {33135 21 66 33:don't know 0.0 Client: TRIG Project: TIRF Wave 2 Report Run Date and Time: 11/12/2013 3:33:00 PM Page 2 of 3 532 Question S?2a S?2b S-2c S?2d MD DO Nurse Practitioner Physician Assistant (95% CI) (95% CI) (95% CI) (95% CI) Question 10: Please answer ?True,? ?False,? or don?t know? for each statement based on the labeling for TIRF medicines. 10a: TIRF medicines can be abused in a manner similar to other opioid agonists. 100.0 96.2 97.0 93.3 True 175 (92.2. 98.4) 22 (84'6? 64 (89.5. 99.6) 28 (77.9. 99.2) 100.0) False don't know 0.0 Correct response Client: TRIG Project: TIRF Wave2 Report Run Date and Time: 11/12/2013 3:33:00 PM Page 3 of 3 533 TABLE 8.1.3 PRIMARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #3 KEY RISK MESSAGE l: TIRF MEDICINES ARE CONTRAINDICATED IN OPIOID NON-TOLERANT PATIENTS. SUB-GROUP ANALYSIS 3: TIME TO COMPLETE SURVEY - INTERNET: S-3a - <10 min 0 S-3b 10 to <20 min 0 S-3c 20 min S-3a S?3b S?min Question N=l67 (95% CI) (95% CI) (95% CI) Question 7: Please answer ?True,? ?False,? or don?t know? for each statement based on the labeling for TIRF medicines. 7e: It is important to monitor for signs of abuse and addiction in patients who take TIRF medicines. 95.7 99.4 100.0 True ?1 45 (85.5. 166 (96.7. 75 (95.2. 99.5) 100.0) 100.0) False 1 2.1 0.6 0 0.0 I don't know 1 2.1 0 0.0 0 0.0 Question 8: Which of the following are risk factors for opioid abuse? Please answer ?Yes,? or don?t know? for each option. 8a: A personal history of illness 80.9 85.0 78.7 Yes ?1 38 (66.7. 142 (78.7. 59 (67.7. 90.9) 90.1) 87.12.0 Idon't know 5 10.6 9 5.4 7 9.3 Client: TRIG Project: TIRF Wave2 Report Run Date and Time: 11/12/2013 3:40:00 PM Page 1 2 534 Question S-3a S-3b S?min (95% CI) (95% CI) (95% CI) 8b: A personal history of past or current alcohol or drug abuse, or a family history of illicit drug use or alcohol abuse 100.0 98.2 100.0 Yes ?1 47 (92.5. 164 (94.8. 75 (95.2. 100.0) 99.6) 100.don't know 0 0.0 0.6 0 0.0 Question 10: Please answer ?True,? ?False,? or don?t know? for each statement based on the labeling for TIRF medicines. 10a: TIRF medicines can be abused in a manner similar to other opioid agonists. 97.9 96.4 94.7 True ?1 46 (88.7. 161 (92.3. 71 (86.9. 99.9) 98.7) 98.5) False don't know 0 0.0 0.6 1.3 Correct response Client: TRIG Project: TIRF Wave2 Report Run Date and Time: 11/12/2013 3:40:00 PM Page 2 of 2 535 TABLE 8.1.5 PRIMARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #3 KEY RISK MESSAGE l: TIRF MEDICINES ARE CONTRAINDICATED IN OPIOID NON-TOLERANT PATIENTS. SUB-GROUP ANALYSIS 5: MODALITY TO COMPLETE SURVEY: S-5a - Internet 0 S-5b - Telephone Internet Telephone ?Vo (95% CI) (95% CI) Question 7: Please answer ?True,? ?False,? or don?t know? for each statement based on the labeling for TIRF medicines. 7e: It is important to monitor for signs of abuse and addiction in patients who take TIRF medicines. 99.0 100.0 True 286 (970.998) 13 (75.3. 100.0) False 2 0.7 0 0.0 I don't know 1 0.3 0 0.0 Question 8: Which of the following are risk factors for opioid abuse? Please answer ?Yes,? or don?t know? for each option. 8a: A personal history of illness 82.7 84.6 Yes 239 (77.8. 86.9) 11 (54.6. 98.1) No 29 10.0 2 15.4 I don't know 21 7.3 0 0.0 use or alcohol abuse 8b: A personal histony of past or current alcohol or drug abuse, or a family history of illicit drug 99.0 100.0 Yes 286 (97.0. 99.8) 13 (75.3. 100.don't know 1 0.3 0 0.0 Client: TRIG Project: TIRF WaveZ Report Run Date and Time: 11/12/2013 3:44:00 PM Page 1 536 Question Internet Telephone N=l3 (95% CI) (95% CI) Question 10: Please answer ?True,? ?False,? or don?t know? for each statement based on the labeling for TIRF medicines. 10a: TIRF medicines can be abused in a manner similar to other opioid agonists. 96.2 100.0 True 278 (93.3. 98.1) 13 (75.3. 100.0) False 9 3.1 0 0.0 I don't know 2 0.7 0 0.0 Correct response Client: TRIG Project: TIRF WaveZ Report Run Date and Time: 11/12/2013 3:44:00 PM Page 2 of 2 537 TABLE 8.1.6 PRIMARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #3 KEY RISK MESSAGE l: TIRF MEDICINES ARE CONTRAINDICATED IN OPIOID NON-TOLERANT PATIENTS. SUB-GROUP ANALYSIS 6: TIME PRACTICING MEDICINE (QUESTION 33): S-6a - Less than 3 years S-6b - 3 to 5 years S-6c - 6 to 15 years S-6d - More than 15 years Question sub S?c S?6d Less than 3 years 3 to 5 years 6 to 15 years More than 15 years N=ll7 (95% CI) (95% CI) (95% CI) (95% CI) Question 7: Please answer ?True,? ?False,? or don?t know? for each statement based on the labeling for TIRF medicines. 7e: It is important to monitor for signs of abuse and addiction in patients who take TIRF medicines. 100.0 100.0 95.9 99.1 True ?1 28 (87.7. 47 105 117 (96.9. 1000) (86.0. 99.5) (94.9. 100.0) 1000) False 0.0 Idon't know 0.0 Client: TRIG Project: TIRF Wave2 Report Run Date and Time: 11/12/2013 3:59:00 PM Page 1 2 538 S?6a S?6b S?6c S?6d Less than 3 years 3 to 5 years 6 to 15 years More than 15 years Question N=ll7 CI) (95?02 CI) CI) Question 8: Which of the following are risk factors for opioid abuse? Please answer ?Yes,? or don?t know? for each option. 8a: A personal history of illness Yes 111 22 (59.039617) 40 (68.30612) 88 98 (75.883399) No 2 7.1 6 12.2 11 10.4 12 10.3 I don't know 4 14personal history of past or current alcohol or drug abuse, or a family history of illicit drug use or alcohol abuse Yes 111 27 (81.959199) 48 (89.?399) 106 (9622800) ?6 (95.2.91 (1100don't know 0.0 Question 10: Please answer ?True,? ?False,? or don?t know? for each statement based on the labeling for TIRF medicines. 10a: TIRF medicines can be abused in a manner similar to other opioid agonists. 96.4 100.0 98.1 93.2 True 27 (81.7. 99.9) 49 (92.7. 100.0) 104 (93.4. 99.8) 109 (87.0. 97.0) False 6.0 Idon't know 0.9 Correct response Client: TRIG Project: TIRF Wave2 Report Run Date and Time: 11/12/2013 3:59:00 PM Page 2 of 2 539 TABLE 8.1.7 PRIMARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #3 KEY RISK MESSAGE l: TIRF MEDICINES ARE CONTRAINDICATED IN OPIOID NON-TOLERANT PATIENTS. SUB-GROUP ANALYSIS 7: NUMBER OF TIMES PER MONTHS PRESCRIBING TIRF MEDICINES WITHIN THE LAST 6 MONTHS (QUESTION 29): S-7a - None S-7b - 1-2 times a month S-7c - 3 - 5 times a month S-7d - More than 5 times a month S?7d S?7a S?7b S?7c . None 1-2 times a month 3 - 5 times a month More tgt?lfht?mes a Question N=l73 ?Vo (95% (95% CI) (95% CI) (95% c1) Question 7: Please answer ?True,? ?False,? or don?t know? for each statement based on the labeling for TIRF medicines. 7e: It is important to monitor for signs of abuse and addiction in patients who take TIRF medicines. 98.1 99.4 100.0 100.0 Tnle ?1 53 (90.1. 172 (96.8. 44 (92.0. 18 (81.5. 100.0) 100.0) 100.0) 100.0) False don?t know 0.0 Client: TRIG Project: TIRF Wave2 Report Run Date and Time: 11/12/2013 4:03:00 PM Page 1 of 3 540 S?7d S?7a S?7b S?7c . None 1?2 times a month 3 - 5 times a month More a Question (95% CI) (95% CI) (95% CI) (95% CI) Question 8: Which of the following are risk factors for opioid abuse? Please answer ?Yes,? or don?t know? for each option. 8a: A personal history of illness 79.6 83.2 88.6 83.3 Yes 43 (66.5. 89.4) 144 (76.8. 88.5) 39 (75.4. 96.2) 15 (58.6. 96.4) No 4 7.4 19 11.0 3 6.8 3 16.7 I don't know 7 13personal history of pastor current alcohol or drug abuse, or a family history of illicit drug use or alcohol abuse 94 4 100.0 100.0 100173 (97.9. 44 (92.0. 18 (81.5. 100.0) 100.0) 100.don't know 0.0 Client: TRIG Project: TIRF Wave2 Report Run Date and Time: 11/12/2013 4:03:00 PM Page 2 of 3 541 Question S?7a S?7b S?7c S?7d None 1?2 times a month 3 - 5 times a month More gingham? a N=l73 (95% CI) (95% CI) (95% CI) (95% Cl) Question 10: Please answer ?True,? ?False,? or don?t know? for each statement based on the labeling for medicines. 10a: TIRF medicines can be abused in a manner similar to other opioid agonists. 100.0 92.6 97.1 95.5 True 50 (82.1. 97.9) 168 (93.4. 99.1) 42 (84.5. 99.4) 18 (815? 100.0) False don't know 0.0 Correct response Client: TRIG Project: TIRF Wave2 Report Run Date and Time: 11/12/2013 4:03:00 PM Page 3 of 3 542 TABLE 8.2 SECONDARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #3 KEY RISK MESSAGE 3: TIRF MEDICINES CONTAIN FENTANYL, AN OPIOID AGONIST AND A SCHEDULE II CONTROLLED SUBSTANCE, WITH ABUSE LIABILITY SINIILAR TO OTHER OPIOID ANALGESICS. Eligible and Complete Respondents Demonstrated Understanding 0 correct responses 0 0.0 1 correct response 0 0.0 2 correct responses 8 2.6 3 correct responses 53 17.5 4 correct responses 241 79.8 Average number of correct responses 3.8 (3.6. 4.0) ?1 One-sided 95 con?dence interval using the normal approximation to the Poisson distribution Client: TRIG Project: TIRF Wave 2 Report Run Date and Time: 11/12/2013 4:06:00 PM Page 1 of 543 TABLE 8.2.1 SECONDARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #3 KEY RISK MESSAGE l: TIRF MEDICINES ARE CONTRAINDICATED IN OPIOID NON-TOLERANT PATIENTS. SUB-GROUP ANALYSIS 1: READING MEDICATION GUIDE OR FULL PRESCRIBING INFORMATION (QUESTIONS 20, 21, 22 AND 23): S-la - Respondents who received and read the Full Prescribing Information for the TIRF medicine that they prescribe, or who received and read the Medication Guide. 0 S-lb - Respondents who did not receive or did not read the Full Prescribing Information for the TIRF medication that they prescribe (answered ?No? or don?t know? to Question 21) and did not receive or did not read the Medication Guide for the TIRF medicine that they prescribe (answered ?No? or don?t know? to Question 23). S-la 541? Read Medication Guide or Did not read Medication Prescribing Info Guide or Demonstrated Understanding Prescribing Info 0 correct responses 0 0.0 0 0.0 1 correct response 0 0.0 0 0.0 2 correct responses 7 2.6 1 2.9 3 correct responses 41 15.4 12 34.3 4 correct responses 219 82.0 22 62.9 Average number of correct responses 3.8 (3.6. 4.0) 3.6 (3.0. 4.0) [ll One-sided 95 con?dence interval using the approximation to the Poisson distribution. Client: TRIG Project: TIRF Wave 2 Report Run Date and Time: 11/12/2013 3:30:00 PM Page 1 of 544 TABLE 8.2.2 SECONDARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #3 KEY RISK MESSAGE l: TIRF MEDICINES ARE CONTRAINDICATED IN OPIOID NON-TOLERANT PATIENTS. SUB-GROUP ANALYSIS 2: MEDICAL DEGREE OF RESPONDENTS (QUESTION 32): S-2a - MD DO S-2c Nurse Practitioner - Physician Assistant S-2a S-2b S-2c S-2d MD DO Nurse Practitioner Physician Assistant Demonstrated Understanding 0 correct responses correct response correct responses 10.0 3 correct responses 34 18.7 27.3 12 18.2 1 3.3 4 correct responses 146 80.2 15 68.2 52 78.8 26 86.7 Average number of correct responses 3.8 (3.6. 4.0) ?1 3.6 (3.0. 4.0) ?1 3.8 (3.4. 4.0) 3.8 (3.2. 4.0) ?1 One-sided 95 con?dence interval using the normal approximation to the Poisson distribution. Client: TRIG Project: TIRF WaveZ Report Run Date and Time: 11/13/2013 1:34:00 PM Page 1 of 545 TABLE 8.2.3 SECONDARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #3 KEY RISK MESSAGE l: TIRF MEDICINES ARE CONTRAINDICATED IN OPIOID NON-TOLERANT PATIENTS. SUB-GROUP ANALYSIS 3: TINIE TO COMPLETE SURVEY - INTERNET: S-3a - <10 min 0 S-3b 10 to <20 min 0 S-3c 20 min S-3a S-3b S-min Demonstrated Understanding N=l67 0 correct responses 0 0.0 0.0 0 0.0 1 correct response correct responses correct responses 8 17.0 27 16.2 16 21.3 4 correct responses 37 78.7 136 81.4 57 76.0 Average number of correct responses 3.7 (3.3. 4.0) 3.8 (3.5. 4.0) 3.7 (3.4. 4.0) ?1 One-sided 95 con?dence interval using the normal approximation to the Poisson distribution. Client: TRIG Project: TIRF WaveZ Report Run Date and Time: 11/13/2013 1:35:00 PM Page 1 of 546 TABLE 8.2.5 SECONDARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #3 KEY RISK MESSAGE l: TIRF MEDICINES ARE CONTRAINDICATED IN OPIOID NON-TOLERANT PATIENTS. SUB-GROUP ANALYSIS 5: MODALITY TO COMPLETE SURVEY: Internet 0 - Telephone S-5b Internet Telephone Demonstrated Understanding N=l3 0 correct responses 0 0.0 0 0.0 1 correct response 0 0.0 0 0.0 2 correct responses 8 2.8 0 0.0 3 correct responses 51 17.6 2 15.4 4 correct responses 230 79.6 11 84.6 Average number of correct responses 3.8 (3.6. 4.0) 3.8 (3.0. 4.0) ?1 One-sided 95 con?dence interval using the normal approximation to the Poisson distribution. Client: TRIG Project: TIRF Wave2 Report Run Date and Time: 11/13/2013 1:35:00 PM Page 1 of 547 TABLE 8.2.6 SECONDARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #3 KEY RISK MESSAGE l: TIRF MEDICINES ARE CONTRAINDICATED IN OPIOID NON-TOLERANT PATIENTS. SUB-GROUP ANALYSIS 6: TINIE PRACTICING MEDICINE (QUESTION 33): S-6a - Less than 3 years S-6b - 3 to 5 years S-6c - 6 to 15 years S-6d - More than 15 years S-6a S-6b S-6c S-6d Less than 3 years 3 to 5 years 6 to 15 years More than 15 years Demonstrated Understanding N=l 17 0 correct responses con?ect response correct responses correct responses 6 21.4 8 16.3 17 16.0 22 18.8 4 correct responses 21 75.0 39 79.6 87 82.1 92 78.6 Average number of correct responses 3.7 (3.1. 4.0) 3.8 (3.3. 4.0) "1 3.8 (3.5. 4.0) 3.8 (3.5. 4.0) ?1 One-sided 95 con?dence interval using the nomial approximation to the Poisson distribution. Client: TRIG Project: TIRF WaveZ Report Run Date and Time: 11/13/2013 1:36:00 PM Page 1 of 548 TABLE 8.2.7 SECONDARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #3 KEY RISK MESSAGE l: TIRF MEDICINES ARE CONTRAINDICATED IN OPIOID NON-TOLERANT PATIENTS. SUB-GROUP ANALYSIS 7: NUMBER OF TIMES PER MONTHS PRESCRIBING TIRF MEDICINES WITHIN THE LAST 6 MONTHS (QUESTION 29): S-7a - None S-7b - 1-2 times a month S-7c - 3 - 5 times a month S-7d - More than 5 times a month S-7a S-7b S-7c S-7d None 1-2 times a month 3 - 5 times a month More than 5 times a Demonstrated Understanding month N=l8 0 correct responses correct response correct responses correct responses 11 20.4 31 17.9 5 11.4 3 16.7 4 correct responses 39 72.2 140 80.9 38 86.4 15 83.3 Average number of correct responses 3.6 (3.2. 4.0) ?1 3.8 (3.6. 4.0) ?1 3.8 (3.4. 4.0) 3.8 (3.1. 4.0) ?1 One-sided 95 con?dence interval using the normal approximation to the Poisson distribution. Client: TRIG Project: TIRF Wave2 Report Run Date and Time: 11/13/2013 1:37:00 PM Page 1 of 549 TABLE 9.1 PRIMARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #4 KEY RISK MESSAGE 4: TIRF MEDICINES ARE NOT INTERCHANGEABLE WITH EACH OTHER, REGARDLESS OF ROUTE OF ADMINISTRATION. Eligible and Complete Respondents Question (95% CI) '21 Question 10: Please answer ?True,? ?False,? or don?t know? for each statement based on the labeling for TIRF medicines. 10b: TIRF medicines are interchangeable with each other regardless of route of administration. 92.4 False 279 (88.8. 951) True 16 5.3 I don't know 7 2.3 10c: The conversion of one TIRF medicine for another TIRF medicine may result in a fatal overdose because of differences in the pharmacokinetics of fentanyl absorption. True 286 (91.95.9769) False 7 2.3 I don't know 9 3.0 10d: Dosing of TIRF medicines is not equivalent on a microgram-to-microgram basis. we 274 (869999738) False 16 5.3 I don't know 12 4.0 Client: TRIG Project: TIRF Wave 2 Report Run Date and Time: 11/12/2013 4:27:00 PM Page 1 of 2 550 Question Eligible and Complete Respondents (95% CI) ?1 Question 14: A patient is already taking a TIRF medicine but wants to change their medicine. His/her doctor decides to prescribe a different TIRF medicine (that is not a bioequivalent generic version of a branded product) in its place. According to the labeling, how should the prescriber proceed? Please select one option. The prescriber must not convert to another TIRF medicine on a microgram-per-microgram basis because these medicines have different absorption 225 (69 242:9 3) properties and this could result in a fentanyl overdose. ?1 The prescriber can safely convert to the equivalent dosage of the new TIRF medicine as it has the same 6 2.0 effect as other TIRF medicines. Convert ??om the other TIRF medicine to the new 2 8 3 TIRF medicine at half of the dose. The prescriber should base the starting dose of the newly-prescribed TIRF medicine on the dose 11.3 0p101d medicrne used for their per srstent cancer pain. I don?t know 12 4.0 COHCCI All con?dence intervals are exact binomial 95% confidence intervals. Client: TRIG Project: TIRF Wave 2 Report Run Date and Time: 11/12/2013 4:27:00 PM Page 2 of 2 551 TABLE 9.1.1 PRIMARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #4 RISK MESSAGE 4: TIRF MEDICINES ARE NOT INTERCHANGEABLE WITH EACH OTHER, REGARDLESS OF ROUTE OF ADMINISTRATION. SUB-GROUP ANALYSIS 1: READING MEDICATION GUIDE OR FULL PRESCRIBING INFORMATION (QUESTIONS 20, 21, 22 AND 23): S-la - Respondents who received and read the Full Prescribing Information for the TIRF medicine that they prescribe, or who received and read the Medication Guide. 0 S-lb - Respondents who did not receive or did not read the Full Prescribing Information for the TIRF medication that they prescribe (answered ?No? or don?t know? to Question 21) and did not receive or did not read the Medication Guide for the TIRF medicine that they prescribe (answered ?No? or don?t know? to Question 23). Question 84 a S-lb Read Medication Guide or Did not read Medication Guide Prescribing Info or Prescribing Info (yo (95% CI) (95% CI) Question 10: Please answer ?True,? ?False,? or don?t know? for each statement based on the labeling for TIRF medicines. 10b: TIRF medicines are interchangeable with each other regardless of route of administration. 92.1 94.3 False 246 (88.2. 95.1) 33 (80.8. 99.3) True 16 6.0 0.0 I don't know 5 1.9 2 5.7 10c: The conversion of one TIRF medicine for another TIRF medicine may result in a fatal overdose because of differences in the pharmacokinetics of fentanyl absorption. 95.1 91.4 me 254 (91.8. 97.4) 32 (76.9. 98.2) False 7 2.6 0 0.0 I don't know 6 2.2 3 8.6 Client: TRIG Project: TIRF Wave2 Report Run Date and Time: 11/18/2013 11:05:00 AM Page 1 of 2 552 S?lb S?la . . . . Read Medication Guide or not read Riemcatlon Gmde Prescribin Info . . Question Info (95% CI) (95% CI) 10d: Dosing of TIRF medicines is not equivalent on a microgram?to-microgram basis. 91.8 82.9 me 245 (87.8. 94.8) 29 (66.4. 93.4) False 13 4.9 3 8.6 I don't know 9 3.4 3 8.6 Question 14: A patient is already taking a TIRF medicine but wants to change their medicine. His/her doctor decides to prescribe a different TIRF medicine (that is not a bioequivalent generic version of a branded product) in its place. According to the labeling, how should the prescriber proceed? Please select one option. The prescriber must not convert to another TIRF medicine 011 a microgra111-per-microgra111 basis because these medicines have different absorption properties and this could result in a fentanyl overdose. 197 73.8 (68.1. 79.0) 28 80.0 (63.1. 91.6) The prescriber can safely convert to the equivalent dosage of the new TIRF medicine as it has the same effect as other TIRF medicines. 2.2 0.0 Convert from the other TIRF medicine to the new TIRF medicine at half of the dose. 23 8.6 The prescriber should base the starting dose of the newly- prescribed TIRF medicine on the dose of the opioid medicine used for their lmderlying persistent cancer pain. 29 10.9 14.3 I don?t know 12 0.0 Correct response Client: TRIG Project: TIRF Wave2 Report Run Date and Time: 11/18/2013 11:05:00 AM Page 2 of 2 553 TABLE 9.1.2 PRIMARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #4 RISK MESSAGE 4: TIRF MEDICINES ARE NOT INTERCHANGEABLE WITH EACH OTHER, REGARDLESS OF ROUTE OF ADMINISTRATION. SUB-GROUP ANALYSIS 2: MEDICAL DEGREE OF RESPONDENTS (QUESTION 32): S-2a - NH) S-2b DO S-2c Nurse Practitioner S-2d - Physician Assistant Question S-2a S-2b S-2c S-2d MD D0 Nurse Practitioner Physician Assistant (95% CI) (95% CI) (95% CI) (95% CI) Question 10: Please answer ?True,? ?False,? or don?t know? for each statement based on the labeling for TIRF medicines. 10b: TIRF medicines are interchangeable with each other regardless of route of administration. 91.8 90.9 92.4 96.7 False 167 (86.8. 95.3) 20 (70.8. 98.9) 61 (83.2. 97.5) 29 (82.8. 99.9) True don't know 0.0 Client: TRIG Project: TIRF Wave2 Report Run Date and Time: 11/18/2013 11:11:00 AM Page 1 of 4 554 S?2a S?2b S?2c S?2d MD DO Nurse Practitioner Physician Assistant (95% CI) (95% CI) (95% CI) (95% CI) 10c: The conversion of one TIRF medicine for another TIRF medicine may result in a fatal overdose because of differences in the pharmacokinetics of fentanyl absorption. True 175 (92.95.0284) 20 (709899989) 61 (8333-375) 28 (77.993392) False don't know 5 2.7 0 0.0 3 4.5 3.3 10d: Dosing of TIRF medicines is not equivalent on a microgram?to-microgram basis. True 169 (88.95.9961) 20 (70.299989) 55 (72.81393 1.4) 28 (77.993392) False 8 4.4 1 4.5 7 10.6 0 0.0 I don't know 6.7 Client: TRIG Project: TIRF Wave2 Report Run Date and Time: 11/18/2013 11:11:00 AM Page 2 of 4 555 Question S?2a S?2b S?2c S-2d MD DO Nurse Practitioner Physician Assistant (95% CI) (95% CI) (95% CI) (95% CI) Question 14: A patient is already taking a TIRF medicine but wants to change their medicine. His/her doctor decides to prescribe a different TIRF medicine (that is not a bioequivalent generic version of a branded product) in its place. According to the labeling, how should the prescriber proceed? Please select one option. The prescn'ber must not convert to another TIRF medicine on a microgram- per-microgram basis because these medicines have different properties and this could result in a fentanyl overdose. 133 73.1 (66.0. 79.4) 14 63.6 (40.7. 82.8) 78.8 (67.0. 87.9) 83.3 (65.3. 94.4) The prescriber can safely convert to the equivalent dosage of the new TIRF medicine as it has the same effect as other TIRF medicines. 2.2 4.5 0.0 3.3 Convert ?'om the other TIRF medicine to the new TIRF medicine at half of the dose. 21 11.5 9.1 1.5 3.3 Client: TRIG Project: TIRF Wave2 Report Run Date and Time: 11/18/2013 11:11:00 AM Page 3 of 4 556 S?2a S?2b S?2c S?2d Ml) DO Nurse Practitioner Physician Assistant Question (95% CI) (95% CI) (95% CI) (95% CI) The prescriber should base the staiting dose of the newly-prescn'bed TIRF medicine on the dose of the 20 11.0 4.5 10 15.2 2 6.7 opioid medicine used for their 1u1de1?lying persistent cancer pain. Idon?t know 4 2.2 18.2 3 4.5 3.3 Correct response Client: TRIG Project: TIRF WaveZ Report Run Date and Time: 11/18/2013 11:11:00 AM Page 4 of 4 557 TABLE 9.1.3 PRIMARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #4 RISK MESSAGE 4: TIRF MEDICINES ARE NOT INTERCHANGEABLE WITH EACH OTHER, REGARDLESS OF ROUTE OF ADMINISTRATION SUB-GROUP ANALYSIS 3: TIME TO COMPLETE SURVEY INTERNET: S-3a - <10 min 0 S-3b 10 to <20 min 0 S-3c 20 min Question S-3a S-3b S?min (95% CI) (95% CI) (95% CI) Question 10: Please answer ?True,? ?False,? or don?t know? for each statement based on the labeling for TIRF medicines. 10b: TIRF medicines are interchangeable with each other regardless of route of administration. 93.6 93.4 89.3 False ?1 44 (82.5. 156 (88.5. 67 (80.1. 98.7) 96.7) 95.3) True don't know 1 2.1 3 1.8 3 4.0 10c: The conversion of one TIRF medicine for another TIRF medicine may result in a fatal overdose because of differences in the pharmacokinetics of fentanyl absorption. 95.7 94.0 97.3 True ?1 45 (85.5. 157 (89.3. 73 (90.7. 99.5) 97.1) 99.7) False don't know 0 0.0 5 3.0 2 2.7 10d: Dosing of TIRF medicines is not equivalent on a microgram-to-microgram basis. 91.5 92.2 89.3 True ?1 43 (79.6. 154 (87.1. 67 (80.1. 97.6) 95.8) 95.3) False don't know 2 4.3 8 4.8 1 1.3 Client: TRIG Project: TIRF Wave2 Report Run Date and Time: 11/18/2013 11:06:00 AM Page 1 2 558 Question S-3a S-3b S-min (95% CI) (95% CI) (95% CI) Question 14: A patient is already taking a TIRF medicine but wants to change their medicine. His/her doctor decides to prescribe a different TIRF medicine (that is not a bioequivalent generic version of a branded product) in its place. According to the labeling, how should the prescriber proceed? Please select one option. The prescriber must not convert to another TIRF medicine 011 a microgram-per- microgram basis because these medicines have different properties and this could result in a fentanyl overdose. 27 57.4 (42.2. 71.7) 129 77.2 (70.1. 83.4) 78.7 (67.7. 87.3) The prescn'ber can safely convert to the equivalent dosage of the new TIRF medicine as it has the same effect as other TIRF medicines. 0.0 1.8 2.7 Convert from the other TIRF medicine to the new TIRF medicine at half of the dose. 10.6 13 7.8 8.0 The prescriber should base the starting dose of the newly-prescribed TIRF medicine on the dose of the opioid medicine used for their underlying persistent cancer pain. 13 27.7 14 8.4 8.0 I don?t know 4.3 4.8 2.7 Correct response Client: TRIG Project: Report Run Date and Time: 11/18/2013 11:06:00 AM Page 2 2 559 TABLE 9.1.5 PRIMARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #4 RISK MESSAGE 4: TIRF MEDICINES ARE NOT INTERCHANGEABLE WITH EACH OTHER, REGARDLESS OF ROUTE OF ADMINISTRATION SUB-GROUP ANALYSIS 5: MODALITY TO COMPLETE SURVEY: - Internet S-5b - Telephone Internet Telephone (95% CI) (95% CI) Question 10: Please answer ?True,? ?False,? or don?t know? for each statement based on the labeling for TIRF medicines. 10b: TIRF medicines are interchangeable with each other regardless of route of administration. 92.4 92.3 False 267 (88.7. 95.2) 12 (64.0. 99.8) True 15 5.2 1 7.7 I don't know 7 2.4 0 0.0 10c: The conversion of one TIRF medicine for another TIRF medicine may result in a fatal overdose because of differences in the pharmacokinetics of fentanyl absorption. True 275 11 (54.21.1068. 1) False 7 2.4 0 0.0 I don't know 7 2.4 2 15.4 10d: Dosing of TIRF medicines is not equivalent on a microgram?to-microgram basis. True 264 (87.29343) 10 (46.75.9950) False 14 4.8 2 15.4 I don't know 11 3.8 1 7.7 Client: TRIG Project: TIRF Wave 2 Report Run Date and Time: 11/18/2013 11:06:00 AM Page 1 of 2 560 S-5a S-5b Internet Telephone (95% CI) (95% CI) Question 14: A patient is already taking a medicine but wants to change their medicine. His/her doctor decides to prescribe a different TIRF medicine (that is not a bioequivalent generic version of a branded product) in its place. According to the labeling, how should the prescriber proceed? Please select one option. The prescriber must not convert to another TIRF medicine 011 a microgram-per-micro gram basis because these medicines have 215 (69 34:9 3) 10 (46 726995 0) different absorption properties and this could result in a fentanyl overdose. The prescriber can safely convert to the equivalent dosage of the new TIRF medicine 7.7 same effect as other TIRF medicines. Convert ?'om the other TIRF medicine to the new TIRF 24 8.3 1 7.7 medicine at half of the dose. The prescriber should base the starting dose of the newly- prescribed TIRF medicine 011 the dose of the opioid medicine used 33 11'4 1 7'7 for their imderlying persistent cancer pain. I don?t know 12 4.2 0 0.0 Correct response Client: TRIG Project: TIRF Wave 2 Report Run Date and Time: 11/18/2013 11:06:00 AM Page 2 of 2 561 TABLE 9.1.6 PRIMARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #4 RISK MESSAGE 4: TIRF MEDICINES ARE NOT INTERCHANGEABLE WITH EACH OTHER, REGARDLESS OF ROUTE OF ADMINISTRATION. SUB-GROUP ANALYSIS 6: TINIE PRACTICING MEDICINE (QUESTION 33): S-6a - Less than 3 years S-6b - 3 to 5 years S-6c - 6 to 15 years S-6d - More than 15 years Question S-6a S-6b S-6c S-6d Less than 3 years 3 to 5 years 6 to 15 years More than 15 years (95% CI) (95% CI) (95% CI) (95% CI) Question 10: Please answer ?True,? ?False,? or don?t know? for each statement based on the labeling for TIRF medicines. 10b: TIRF medicines are interchangeable with each other regardless of route of administration. 92.9 95.9 92.5 90.6 False 26 (76.5. 99.1) 47 (86.0. 99.5) 98 (85.7. 96.7) 106 (83.8. 95.2) True don't know 2.6 Client: TRIG Project: TIRF Wave2 Report Run Date and Time: 11/18/2013 11:16:00 AM Page 1 4 562 Question S-6a S?6b S?6c S?6d Less than 3 years 3 to 5 years 6 to 15 years More than 15 years N=ll7 (95% CI) (95% CI) (95% CI) (95% CI) 10c: The conversion of one TIRF medicine for another TIRF medicine may result in a fatal overdose because of differences in the pharmacokinetics of fentanyl absorption. True 7'8 (13-79 43 (758279854) 102 (90.95.9290) 1? (239.924.1998. 1) 100.0) False don't know 2.6 10d: Dosing of TIRF medicines is not equivalent on a microgram-to-microgram basis. True 25 (71.85377) 39 100 (88.95379) 108 (85.95364) False 0 0.0 7 14.3 4 3.8 5 4.3 I don't know 10.7 3 6.1 1.9 4 3.4 Client: TRIG Project: TIRF WaveZ Report Run Date and Time: 11/18/2013 11:16:00 AM Page 2 of 4 563 Question S-6a S?6b S?6c S?6d Less than 3 years 3 to 5 years 6 to 15 years More than 15 years N=ll7 (95% CI) (95% CI) (95% CI) (95% CI) Question 14: A patient is already taking a TIRF medicine but wants to change their medicine. His/her doctor decides to prescribe a different TIRF medicine (that is not a bioeqnivalent generic version of a branded product) in its place. According to the labeling, how should the prescriber proceed? Please select one option. The prescriber must not convert to another TIRF medicine on a microgram- per?microgram basis because these medicines have different absorption properties and this could result in a fentanyl overdose. 71.4 20 (51.3. 86.8) 36 73.5 (58.9. 85.1) 71.7 76 (62.1. 80.0) 91 77.8 (69.2. 84.9) The prescriber can safely convert to the equivalent dosage of the new TIRF medicine as it has the same effect as other TIRF medicines. 4.1 2.6 Convert from the other TIRF medicine to the new TIRF medicine at half of the dose. 2.0 10 9.4 13 Client: TRIG Project: TIRF WaveZ Report Run Date and Time: 11/18/2013 11:16:00 AM Page 3 of 4 564 S?6a S?6b Less than 3 years 3 to 5 years 6 to 15 years More than 15 years (95% CI) (95% CI) (95% CI) (95% CI) The prescriber should base the starting dose of the newly-prescn'bed TIRF medicine on the dose of 5 17.9 16.3 15 14.2 6 5.1 the opioid medicine used for their tmderlying persistent cancer pain. I don?t know 2 7.1 4.1 4 3.8 4 3.4 Correct response Client: TRIG Project: TIRF Wave2 Report Run Date and Time: 11/18/2013 11:16:00 AM Page 4 of 4 565 TABLE 9.1.7 PRIMARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #4 RISK MESSAGE 4: TIRF MEDICINES ARE NOT INTERCHANGEABLE WITH EACH OTHER, REGARDLESS OF ROUTE OF ADMINISTRATION. SUB-GROUP ANALYSIS 7: NUMBER OF TIMES PER MONTHS PRESCRIBING TIRF MEDICINES WITHIN THE LAST 6 MONTHS (QUESTION 29): S-7a - None S-7b - 1-2 times a month S-7c - 3 - 5 times a month S-7d - More than 5 times a month Question 8?71, S-7c More than?; times a None 1?2 times a month 3 - 5 times a month month N=l73 (95% CI) (95% CI) (95% CI) (95% CI) Question 10: Please answer ?True,? ?False,? or don?t know? for each statement based on the labeling for TIRF medicines. 10b: TIRF medicines are interchangeable with each other regardless of route of administration. 98.1 90.8 90.9 94.4 False 53 (90'1? 157 (85.4. 94.6) 40 (78.3. 97.5) 17 (72.7. 99.9) 100.0) True don't know 0 0.0 6 3.5 0 0.0 5.6 Client: TRIG Project: TIRF Wave2 Report Run Date and Time: 11/18/2013 11:16:00 AM Page 1 of 4 566 Question S?7d S?7a S?7b S?7c . None 1-2 times a month 3 - 5 times a month More trafhtimes a N=l73 (95% Cl) (95% CI) (95% CI) (95% CI) 10c: The conversion of one TIRF medicine for another TIRF medicine may result in a fatal overdose because of differences in the pharmacokinetics of fentanyl absorption. True 50 (82.95.9679) 165 (91.915380) 42 (84.25394) 16 (65.22.4386) False don't know 11.1 10d: Dosing of TIRF medicines is not equivalent on a microgram-to-microgram basis. True 45 162 (88.939668) 41 (81.23.9286) 16 (65.239986) False 11.1 I don't know 0.0 Client: TRIG Project: TIRF Wave2 Report Run Date and Time: 11/18/2013 11:16:00 AM Page 2 of 4 567 Question S?7a S?7b S?7c S?7d None 1-2 times a month 3 - 5 times a month More 22:; fhtimes a N=l73 (95% Cl) (95% CI) (95% CI) (95% CI) Question 14: A patient is already taking a TIRF medicine but wants to change their medicine. His/her doctor decides to prescribe a different TIRF medicine (that is not a bioequivalent generic version of a branded product) in its place. According to the labeling, how should the prescriber proceed? Please select one option. The prescn'ber must not convert to another TIRF medicine on a microgram- per-microgram basis because these medicines have different properties and this could result in a fentanyl overdose. 43 79.6 (66.5. 89.4) 128 74.0 (66.8. 80.4) 33 75.0 (59.7. 86.8) 83.3 (58.6. 96.4) The prescn'ber can safely convert to the equivalent dosage of the new TIRF medicine as it has the same effect as other TIRF medicines. 3.7 1.2 2.3 Convert from the other TIRF medicine to the new TIRF medicine at half of the dose. l3 9.1 0.0 Client: TRIG Project: TIRF Wave2 Report Run Date and Time: 11/18/2013 11:16:00 AM Page 3 of 4 568 The prescriber should base the starting dose of the newly-prescribed TIRF medicine on the dose of the opioid medicine used for their underlying persistent cancer pain. 5.6 22 12.7 11.4 11.1 I don?t know 5.6 4.6 2.3 0.0 Correct response Client: TRIG Project: 2 Report Run Date and Time: 11/18/2013 11:16:00 AM Page 4 of 569 TABLE 9.2 SECONDARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #4 KEY RISK MESSAGE 4: TIRF MEDICINES ARE NOT INTERCHANGEABLE WITH EACH OTHER, REGARDLESS OF ROUTE OF ADMINISTRATION. Eligible and Complete Respondents Demonstrated Understanding 0 correct responses 1 0.3 1 correct response 3 1.0 2 correct responses 28 9.3 3 correct responses 75 24.8 4 correct responses 195 64.6 Average number of correct responses 3.5 (3.3. 4.0) ll] One-sided 95 con?dence interval using the normal approximation to the Poisson distribution Client: TRIG Project: TIRF Wave 2 Report Run Date and Time: 11/11/2013 3:56:00 PM Page 1 of 570 TABLE 9.2.1 SECONDARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #4 KEY RISK MESSAGE 1: TIRF MEDICINES ARE CONTRAINDICATED IN OPIOID NON-TOLERANT PATIENTS. SUB-GROUP ANALYSIS 1: READING MEDICATION GUIDE OR FULL PRESCRIBING INFORMATION (QUESTIONS 20, 21, 22 AND 23): S-la - Respondents who received and read the Full Prescribing Information for the TIRF medicine that they prescribe, or who received and read the Medication Guide. 0 S-lb - Respondents who did not receive or did not read the Full Prescribing Information for the TIRF medication that they prescribe (answered ?No? or don?t know? to Question 21) and did not receive or did not read the Medication Guide for the TIRF medicine that they prescribe (answered ?No? or don?t know? to Question 23). S-la S-lb Read Medication Guide Did not read Medication or Guide or Demonstrated Understanding Prescribing Info Prescribing Info 0 correct responses 1 0.4 0 0.0 1 correct response 2 0.7 1 2.9 2 correct responses 25 9.4 3 8.6 3 correct responses 66 24.7 9 25.7 4 correct responses 173 64.8 22 62.9 Average number of correct responses 3.5 (3.3. 4.0) 3.5 (3.0. 4.0) [ll One-sided 95 con?dence interval using the normal approximation to the Poisson distribution. Client: TRIG Project: TIRF Wave2 Report Run Date and Time: 11/13/2013 1:37:00 PM Page 1 of 571 TABLE 9.2.2 SECONDARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #4 KEY RISK MESSAGE l: TIRF MEDICINES ARE CONTRAINDICATED IN OPIOID NON-TOLERANT PATIENTS. SUB-GROUP ANALYSIS 2: MEDICAL DEGREE OF RESPONDENTS (QUESTION 32): S-S-2c Nurse Practitioner S-2d - Physician Assistant S-2a S-2b S-2c S-2d MD DO Nurse Practitioner Physician Assistant Demonstrated Understanding 0 correct responses correct response correct responses 15 8.2 4 18.2 6 9.1 3 10.0 3 correct responses 45 24.7 6 27.3 19 28.8 4 13.3 4 correct responses 119 65.4 12 54.5 40 60.6 23 76.7 Average number of correct responses 3.5 (3.3. 4.0) 3.4 (2.7. 3.5 (3.1. 4.0) 3.7 (3.1. 4.0) One-sided 95 con?dence interval using the normal approximation to the Poisson distribution. Client: TRIG Project: TIRF Wave 2 Report Run Date and Time: 11/13/2013 1:38:00 PM Page 1 of 572 TABLE 9.2.3 SECONDARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #4 KEY RISK MESSAGE l: TIRF MEDICINES ARE CONTRAINDICATED IN OPIOID NON-TOLERANT PATIENTS. SUB-GROUP ANALYSIS 3: TINIE TO COMPLETE SURVEY - INTERNET: 0 8-33 - <10 min 0 S-3b 10 to <20 min 0 S-3c 20 min S-3a S-3b S-min Demonstrated Understanding 0 correct responses correct response correct responses 7 14.9 12 7.2 8 10.7 3 correct responses 15 31.9 41 24.6 18 24.0 4 correct responses 25 53.2 112 67.1 49 65.3 Average number of correct responses 3.4 (2.9. 4.0) 3.6 (3.3. 4.0) 3.5 (3.2. 4.0) ?1 One-sided 95 con?dence interval using the normal approximation to the Poisson distribution. Client: TRIG Project: TIRF Wave 2 Report Run Date and Time: 11/13/2013 1:38:00 PM Page 1 of 573 TABLE 9.2.5 SECONDARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #4 KEY RISK MESSAGE l: TIRF MEDICINES ARE CONTRAINDICATED IN OPIOID NON-TOLERANT PATIENTS. SUB-GROUP ANALYSIS 5: MODALITY TO COMPLETE SURVEY: S-5a Internet 0 - Telephone S-5a S-5b Internet Telephone Demonstrated Understanding 0 correct responses 1 0.3 0 0.0 1 correct response 1 0.3 2 15.4 2 correct responses 27 9.3 1 7.7 3 correct responses 74 25.6 1 7.7 4 correct responses 186 64.4 9 69.2 Average number of correct responses 3.5 (3.4. 4.0) 3.3 (2.5. 4.0) One-sided 95 con?dence interval using the normal approximation to the Poisson distribution. Client: TRIG Project: TIRF Wave 2 Report Run Date and Time: 11/13/2013 1:39:00 PM Page 1 of 574 TABLE 9.2.6 SECONDARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #4 KEY RISK MESSAGE l: TIRF MEDICINES ARE CONTRAINDICATED IN OPIOID NON-TOLERANT PATIENTS. SUB-GROUP ANALYSIS 6: TINIE PRACTICING MEDICINE (QUESTION 33): S-6a - Less than 3 years S-6b - 3 to 5 years S-6c - 6 to 15 years S-6d - More than 15 years S-6a S-6b S-6c S-6d Less than 3 years 3 to 5 years 6 to 15 years More than 15 years Demonstrated Understanding N=l 17 0 correct responses con?ect response correct responses 1 3.6 6 12.2 11 10.4 10 8.5 3 correct responses 11 39.3 10 20.4 26 24.5 28 23.9 4 correct responses 16 57.1 30 61.2 69 65.1 78 66.7 Average number of correct responses 3.5 (3.0. 4.0) 3.4 (2.9. 4.0) "1 3.5 (3.2. 3.6 (3.3. 4.0) ?1 One-sided 95 con?dence interval using the nomial approximation to the Poisson distribution. Client: TRIG Project: TIRF WaveZ Report Run Date and Time: 11/13/2013 1:40:00 PM Page 1 of 575 TABLE 9.2.7 SECONDARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #4 KEY RISK MESSAGE l: TIRF MEDICINES ARE CONTRAINDICATED IN OPIOID NON-TOLERANT PATIENTS. SUB-GROUP ANALYSIS 7: NUMBER OF TIMES PER MONTHS PRESCRIBING TIRF MEDICINES WITHIN THE LAST 6 MONTHS (QUESTION 29): S-7a - None S-7b - 1-2 times a month S-7c - 3 - 5 times a month S-7d - More than 5 times a month S-7a S-7b S-7c S-7d None 1-2 times a month 3 - 5 times a month More than 5 times :1 Demonstrated Understanding month 0 correct responses correct response 11.1 2 correct responses 6 11.1 14 8.1 5 11.4 1 5.6 3 correct responses 10 18.5 48 27.7 10 22.7 0 0.0 4 correct responses 37 68.5 110 63.6 29 65.9 15 83.3 Average number of correct responses 3.5 (3.1. 4.0) ?1 3.5 (3.3. 4.0) 3.5 (3.1. 4.0) 3.6 (2.8. 4.0) One-sided 95 con?dence interval using the normal approximation to the Poisson distribution. Client: TRIG Project: TIRF Wave 2 Report Run Date and Time: 11/13/2013 1:40:00 PM Page 1 of 576 Prescriber KAB Assessment Report Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Appendix C Page 66 of 67 Findings Report: Qualitative Research to Evaluate the Prescriber and Pharmacist 12-month REMS Assessment Surveys for TIRF Medicines FDA_1577 Findings Report: Qualitative Research to Evaluate the Prescriber and Pharmacist 12-month REMS Assessment Surveys for Transmucosal Immediate Release Fentanyl (TIRF) Medicines UBC Contacts: 920 Harvest Drive Suite 200 Blue Bell, PA 19422 www.unitedbiosource.com Megan Leone-Perkins, PhD, Research Lead Blythe Vito, Senior Manager 215-390-1385 16 December 2013 Version 3.0 FDA_1578 TABLE OF CONTENTS TABLE OF CONTENTS ....................................................................................................................................... 2 1 INTRODUCTION ........................................................................................................................................ 3 2 RESEARCH OBJECTIVES .......................................................................................................................... 3 3 RESEARCH DESIGN ................................................................................................................................. 4 3.1 Overview .................................................................................................................................... 4 3.2 Eligibility Criteria......................................................................................................................... 5 3.3 Recruitment................................................................................................................................ 5 3.4 Participant Demographics .......................................................................................................... 6 4 INTERVIEW DESIGN .................................................................................................................................. 6 4.1 Prior to the Interview Session .................................................................................................... 6 4.2 During the Interview ................................................................................................................... 7 5 RESEARCH FINDINGS ............................................................................................................................... 8 5.1 Prescribers ................................................................................................................................. 8 5.1.1 Frame of Reference (Questions 8, new 7, NEW 19) .............................................................. 8 5.1.2 Definition of Opioid Tolerance (Questions 5, 11) ................................................................. 10 5.1.3 Risks Associated with TIRF Medicine Conversion (Question 12) ........................................ 13 5.1.4 Risks associated with CYP3A4 Inhibitor (Question 15) ....................................................... 14 5.2 Pharmacists ............................................................................................................................. 15 5.2.1 Frame of Reference (Questions 5, 8, NEW 7) ..................................................................... 15 5.3 Conclusion ............................................................................................................................... 19 6 APPENDIX A: SURVEY QUESTIONS USED IN QUALITATIVE RESEARCH .................................................... 20 TIRF Medicines Prescriber/Pharmacist Qualitative Research Final Report 2 FDA_1579 1 INTRODUCTION The Food and Drug Administration (FDA) has approved a shared risk evaluation and mitigation strategy (REMS) for the class of transmucosal immediate-release fentanyl (TIRF) products. The products in the TIRF REMS Program include ABSTRAL® (fentanyl) sublingual tablets CII, ACTIQ® (fentanyl citrate) oral transmucosal lozenge CII, FENTORA® (fentanyl buccal tablet) CII, LAZANDA® (fentanyl) nasal spray CII, and ONSOLIS® (fentanyl buccal soluble film) CII, SUBSYS® (fentanyl) sublingual spray CII, as well as generic forms of the aforementioned products. The FDA provided feedback to the TIRF REMS Industry Group (TRIG) on the Knowledge, Attitude, and Behavior survey results for prescribers and pharmacists included in the 12-month REMS Assessment results. The FDA requested that the TRIG investigate the causes for low correct response rates to specific questions in the survey by conducting research to determine the reasons for the poor performance on these questions. The research undertaken included review of the questions identified by the FDA that had low correct response rates, as well as two new questions approved by the TRIG. This document describes how this research was conducted, including a description of research participants, and major findings used to inform KAB survey revisions. 2 RESEARCH OBJECTIVES The purpose of this qualitative research was to investigate the causes for low correct response rates to specific prescriber and pharmacist questions used in the survey administered as part of the TIRF REMS Access Program 12-month REMS Assessment. Additionally, this research was conducted to assess proposed revised wording to select questions, as well as to assess comprehension of two additional questions. The questions reviewed during the qualitative research interviews included the following (see Appendix A for full question sets. Readers should note that the survey content that is displayed in blue font represents proposed revised wording.):   Prescribers reviewed: o 10 items from the Prescriber 12-month REMS Assessment Survey Questions: 5a, 5c, 8e, 11b, 12c, 12d, 15a-d o New questions 7 and 19 Pharmacists reviewed: o 7 items from the Pharmacist 12-month REMS Assessment Survey Questions: 5a, 5c, 8 (a-e); o New question 7 TIRF Medicines Prescriber/Pharmacist Qualitative Research Final Report 3 FDA_1580 The objectives of this research were to:  Evaluate clarity and comprehension of questions and answer options used in the 12month assessment;  Identify terms, questions or topics for clarification or revision based on any areas of confusion with or misunderstanding for current wording;  Determine how participants understand specific questions and why those questions are answered a particular way;  Determine how certain questions might be understood differently and answered more accurately if further clarified;  Evaluate alternative language for these questions. 3 RESEARCH DESIGN 3.1 OVERVIEW (b) (4) TIRF Medicines Prescriber/Pharmacist Qualitative Research Final Report 4 FDA_1581 3.2 ELIGIBILITY CRITERIA (b) (4) 3.3 RECRUITMENT (b) (4) TIRF Medicines Prescriber/Pharmacist Qualitative Research Final Report 5 FDA_1582 3.4 PARTICIPANT DEMOGRAPHICS (b) (4) 4 INTERVIEW DESIGN (b) (4) TIRF Medicines Prescriber/Pharmacist Qualitative Research Final Report 6 FDA_1583 584 TIRF Medicines Prescriber/Pharmacist Qualitative Research Final Report 5 RESEARCH FINDINGS (b) (4) TIRF Medicines Prescriber/Pharmacist Qualitative Research Final Report 8 FDA_1585 586 TIRF Medicines Prescriber/Pharmacist Qualitative Research Final Report 587 TIRF Medicines Prescriber/Pharmacist Qualitative Research Final Report 10 588 TIRF Medicines Prescriber/Pharmacist Qualitative Research Final Report 11 589 TIRF Medicines Prescriber/Pharmacist Qualitative Research Final Report 12 590 TIRF Medicines Prescriber/Pharmacist Qualitative Research Final Report 13 591 TIRF Medicines Prescriber/Pharmacist Qualitative Research Final Report 14 592 TIRF Medicines Prescriber/Pharmacist Qualitative Research Final Report 15 593 TIRF Medicines Prescriber/Pharmacist Qualitative Research Final Report 16 594 TIRF Medicines Prescriber/Pharmacist Qualitative Research Final Report 17 595 TIRF Medicines Prescriber/Pharmacist Qualitative Research Final Report 18 5.3 CONCLUSION (b) (4) TIRF Medicines Prescriber/Pharmacist Qualitative Research Final Report 19 FDA_1596 6 APPENDIX A: SURVEY QUESTIONS USED IN QUALITATIVE RESEARCH The following survey questions were studied during the qualitative research interviews. A hard copy was sent to each participant as appropriate by stakeholder and returned to the research facility after the interviews were completed. Readers should note that survey content displayed in blue font represents alternative survey questions/responses developed for this research. APPENDIX A: Survey Questions Used in Qualitative Research FDA_1597 20 TIRF Medicines Prescriber Survey The Moderator will review the enclosed questions with you during the interview. Please do not fill in the answer choices. This document is only meant to guide your discussion with the Moderator. APPENDIX A: Survey Questions Used in Qualitative Research FDA_1598 21 599 APPENDIX A: Survey Questions Used in Qualitative Research 600 APPENDIX A: Survey Questions Used in Qualitative Research 601 APPENDIX A: Survey Questions Used in Qualitative Research 602 APPENDIX A: Survey Questions Used in Qualitative Research 603 APPENDIX A: Survey Questions Used in Qualitative Research 604 APPENDIX A: Survey Questions Used in Qualitative Research 605 APPENDIX A: Survey Questions Used in Qualitative Research TIRF Medicines Pharmacist Survey The Moderator will review the enclosed questions with you during the interview. Please do not fill in the answer choices. This document is only meant to guide your discussion with the Moderator. APPENDIX A: Survey Questions Used in Qualitative Research FDA_1606 29 607 APPENDIX A: Survey Questions Used in Qualitative Research 608 APPENDIX A: Survey Questions Used in Qualitative Research 609 APPENDIX A: Survey Questions Used in Qualitative Research Prescriber KAB Assessment Report Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Appendix D Page 67 of 67 Prescriber Survey Protocol Track Change Document: Comparison of 12-month Survey to 24-month Survey FDA_1610 PROTOCOL TITLE: Quantitative Testing of Prescriber Knowledge, Attitudes, and Behavior about Transmucosal Immediate Release Fentanyl (TIRF) Products Safety and Use Information SPONSOR: TIRF REMS Industry Group (TRIG) Archimedes Pharma US Inc. Cephalon, Inc. (a wholly-owned subsidiary of Teva Pharmaceutical Industries, Ltd.) Endo Pharmaceuticals Inc. Galena Biopharma Insys Therapeutics Mallinckrodt, the Pharmaceuticals Business of Covidien Meda Pharmaceuticals Mylan, Inc. Par Pharmaceutical, Inc. VERSION: 54.0 DATE: 10 SEP23 May 2013 APPROVED: FINAL FDA_1611 TIRF REMS Industry Group (TRIG) Transmucosal Immediate Release Fentanyl (TIRF) Products Prescriber KAB Survey Protocol TABLE OF CONTENTS Version 54 0 10 Sep23 May 2013 PAGE TABLE OF CONTENTS ......................................................................................... 2 1. LIST OF ABBREVIATIONS .................................................................................. 3 2. BACKGROUND ..................................................................................................... 4 3. OBJECTIVES OF THE EVALUATION SURVEY ............................................... 5 4. METHODS .............................................................................................................. 5 4.1 4.1.1 4.1.2 4.1.3 Survey Design .......................................................................................................... 5 Qualitative Research on the Survey ......................................................................... 6 Questions on REMS Goals ...................................................................................... 6 Additional Questions.............................................................................................. 10 4.2 4.2.1 Participant Recruitment.......................................................................................... 10 Measures to Minimize Bias in the Sample............................................................. 11 5. 5.1.1 5.1.2 5.1.3 STUDY POPULATION ........................................................................................ 11 Sample Size ............................................................................................................ 11 Inclusion Criteria.................................................................................................... 12 Exclusion Criteria .................................................................................................. 12 6. SURVEY PROCESS ............................................................................................. 12 6.1 6.1.1 6.1.2 Screening and Survey Administration ................................................................... 13 Telephone ............................................................................................................... 13 Internet ................................................................................................................... 13 6.2 Measures to Minimize Bias in the Survey Process ................................................ 13 7. 7.1.1 7.1.2 ANALYSIS ............................................................................................................ 14 Description of Primary Analyses ........................................................................... 14 Description of Secondary Analyses ................................................................... 1514 8. SAFETY EVENT REPORTING ........................................................................... 15 9. PRIVACY PROTECTION AND CONFIDENTIALITY...................................... 15 LIST OF APPENDICES Appendix A Prescriber Questionnaire........................................................................... 16 Appendix B Prescriber Invitation Letter ................................................................... 3634 Appendix C Qualitative Research Report ................................................................. 3735 2 of 37 FDA_1612 TIRF REMS Industry Group (TRIG) Transmucosal Immediate Release Fentanyl (TIRF) Products Prescriber KAB Survey Protocol 1. Version 54 0 10 Sep23 May 2013 LIST OF ABBREVIATIONS CATI CI EDC ETASU FDA HIPAA ISI KAB PI REMS SE/PSP TIRF TIRF REMS TRIG UBC US Computer-Assisted Telephone Interviewing Confidence Interval Electronic Data Capture Elements to Assure Safe Use Food and Drug Administration Health Insurance Portability and Accountability Act Important Safety Information Knowledge, Attitudes and Behavior Prescribing Information Risk Evaluation and Mitigation Strategy Safety Event Project Specific Procedure Transmucosal Immediate Release Fentanyl TIRF REMS Access Program TIRF REMS Industry Group United BioSource Corporation United States 3 of 37 FDA_1613 TIRF REMS Industry Group (TRIG) Transmucosal Immediate Release Fentanyl (TIRF) Products Prescriber KAB Survey Protocol 2. Version 54 0 10 Sep23 May 2013 BACKGROUND Transmucosal Immediate Release Fentanyl (TIRF) medicines include the class of immediaterelease opioid analgesics that are indicated only for the management of breakthrough pain in cancer patients 18 years of age or older (16 or older for Actiq® and equivalent generics) who are already receiving and already tolerant to opioid therapy for their underlying persistent cancer pain. The TIRF medicines include Abstral®, Actiq®, Fentora®, Lazanda®, Onsolis®, Subsys®, and generic versions of any of these brands. The TIRF REMS Industry Group (TRIG) includes Archimedes Pharma US Inc.; Cephalon, Inc. (a wholly-owned subsidiary of Teva Pharmaceutical Industries, Ltd.); Endo Pharmaceuticals Inc.; Galena Biopharma; Insys Therapeutics; Mallinckrodt, the Pharmaceuticals Business of Covidien; Meda Pharmaceuticals; Mylan, Inc.; and Par Pharmaceutical, Inc. The Food and Drug Administration (FDA) has determined that a class-wide Risk Evaluation and Mitigation Strategy (REMS) is required to mitigate the risk of misuse, abuse, addiction, overdose, and serious complications due to medication errors with the use of TIRF medicines. The TIRF REMS Access Program (hereafter referred to as TIRF REMS) was approved by the FDA on December 28, 2011. The TIRF REMS consists of a Medication Guide, Elements to Assure Safe Use (ETASU), an Implementation System, and a timetable for submission of assessments of the REMS. The goals of the TIRF REMS are to mitigate the risk of misuse, abuse, addiction, overdose and serious complications due to medication errors by the following: 1. Prescribing and dispensing TIRF medicines only to appropriate patients, which includes use only in opioid-tolerant patients. 2. Preventing inappropriate conversion between TIRF medicines. 3. Preventing accidental exposure to children and others for whom it was not prescribed. 4. Educating prescribers, pharmacists, and patients on the potential for misuse, abuse, addiction, and overdose of TIRF medicines. An important component of the TIRF REMS assessment is the conduct of quantitative evaluation surveys to assess prescribers’ understanding and knowledge of the safe use and appropriate prescribing of TIRF medicines as described in the TIRF REMS educational materials, enrollment form, and Prescribing Information (PI) of each product. This protocol will describe the administration of the surveys that will be conducted among prescribers who are enrolled in the TIRF REMS Access Program. Data from the surveys, together with other REMS evaluation metrics, will be used to determine whether changes need to be made to the REMS processes or educational materials to make them more effective in achieving the goals of the REMS. 4 of 37 FDA_1614 TIRF REMS Industry Group (TRIG) Transmucosal Immediate Release Fentanyl (TIRF) Products Prescriber KAB Survey Protocol Version 54 0 10 Sep23 May 2013 The surveys will be implemented so that data will be available for inclusion in the REMS Assessment Reports that will be submitted to the FDA at 12 months after approval of the TIRF REMS and annually thereafter. 3. OBJECTIVES OF THE EVALUATION SURVEY The evaluation survey will use a questionnaire to document the level of knowledge and assess the attitudes and behavior of prescribers around the following key information and risk messages communicated through the REMS: 1. TIRF medicines are contraindicated in opioid non-tolerant patients. 2. TIRF medicines are only indicated for the management of breakthrough pain in adult cancer patients 18 years of age and older (16 or older for Actiq® and equivalent generics) who are already receiving and who are tolerant to around-the-clock opioid therapy for their underlying persistent cancer pain. 3. TIRF medicines contain fentanyl, an opioid agonist and a Schedule II-controlled substance, with abuse liability similar to other opioid analgesics. 4. TIRF medicines are not interchangeable with each other, regardless of route of administration. 5. Patients and their caregivers must be instructed that TIRF medicines contain a medicine in an amount that can be fatal in children, in individuals for whom it is not prescribed, and in those who are not opioid tolerant. The survey will also collect data on behaviors, such as receipt and use of educational materials and compliance with REMS requirements. 4. METHODS The survey was designed in collaboration between the TRIG and United BioSource Corporation (UBC) and will be administered by UBC. 4.1 Survey Design This survey will be conducted among a sample of prescribers who are enrolled in the TIRF REMS Access Program. Respondents who participate in the first wave of the TIRF survey will not be eligible to participate in subsequent survey waves. The survey will be administered using the following modalities:  Self-administered, online through a secure website 5 of 37 FDA_1615 TIRF REMS Industry Group (TRIG) Transmucosal Immediate Release Fentanyl (TIRF) Products Prescriber KAB Survey Protocol  Version 54 0 10 Sep23 May 2013 Telephone surveys facilitated by a trained interviewer from the Survey Coordinating Center using a computer-assisted telephone interviewing (CATI) program The survey will begin with screening questions to confirm respondent eligibility to participate in the survey. Completion of the entire survey is expected to take approximately 20 minutes. The survey included in Appendix A is written to reflect wording for both methods of survey administration: Internet-based and telephone. All respondents who complete the survey and who provide their contact information will be mailed a $125 honorarium for their time. 4.1.1 Qualitative Research on the Survey The FDA provided feedback to the TRIG on the KAB survey results for prescribers included in the 12-month REMS Assessment results. The FDA requested that the TRIG investigate the causes for low correct response rates to specific questions in the survey by conducting research to determine the reasons for the poor performance on these questions, and to assess proposed revised wording to select questions. Qualitative research was performed with 7 prescribers who were recruited from the list of prescribers who completed surveys for the 12-month TIRF REMS Assessment and met the definition of “low performer,” i.e., provided an incorrect response on 3 to 7 of the 10 targeted responses/questions from the 12-month TIRF REMS Assessment. Among the prescribers interviewed, the need to provide a “frame-of-reference” for responding was frequent feedback. In addition, some of the findings suggest potential knowledge gap with respect to:    Definition of opioid tolerance; How to convert patients from one TIRF medicine to another TIRF medicine; and Content pertaining to CYP3A4 inhibitors. The findings from this research have been incorporated into the survey in Appendix A. The qualitative research report can be found in Appendix C. 4.1.2 Questions on REMS Goals The Knowledge, Attitudes and Behaviors (KAB) questionnaire is made up of multiple-choice, close-ended statements or questions (the majority of which use true/false or yes/no dichotomous response options), and one open-ended question. These will evaluate current knowledge, attitudes, and behavior regarding the key risk messages noted in Section 3. Questions will be presented in several formats:  Statements or questions asking the respondent to indicate whether a statement or question is true or false, or if they do not know the answer (there is a similar set of statements and questions that use “yes” or “no” as potential response options); 6 of 37 FDA_1616 TIRF REMS Industry Group (TRIG) Transmucosal Immediate Release Fentanyl (TIRF) Products Prescriber KAB Survey Protocol Version 54 0 10 Sep23 May 2013  Statements or questions asking the respondent to choose from a defined list of possible statements or answers; and  One question allowing for the respondent to list questions about the products or comments. Questionnaires will be analyzed to determine prescriber understanding of each key risk message. For statements or questions that use “true” or “yes” vs. “false” or “no” response options, the desired response for key risk messages is generally “true” or “yes” indicating knowledge of, or behavior in accordance with, the objectives of the REMS. However, some questions are formatted to have the respondent disagree with the statement as written by providing response options of “false” or “no” to avoid having the same affirmative answer for all desired responses. REMS statements, corresponding questions, and desired responses covering the key risk messages are identified below and can be found in the complete survey questionnaire (Appendix A). Key Risk Message 1: TIRF medicines are contraindicated in opioid non-tolerant patients. Question No. 5 5a 5b 5c 7 7a 7b 7c Question Desired response Please select “True,” “False,” or “I don’t know” for each of the following.According to the labeling for TIRF medicines, patients with cancer who are considered opioid-tolerant are those: Who are taking around-the-clock opioid therapy for underlying persistent chronic pain for one week or TRUE longer Who are not currently taking opioid therapy, but FALSE have taken opioid therapy before Who have no known contraindications to the drug fentanyl, but are not currently taking around-theFALSE clock opioid therapy Please answer “True,” “False,” or “I don’t know” for each statement based on the labeling for TIRF medicines. TIRF medicines are contraindicated in opioid nontolerant patients because life-threatening respiratory TRUE depression could occur at any dose. Death has occurred in opioid non-tolerant patients TRUE treated with some fentanyl products. TIRF medicines may be used to treat opioid nonFALSE tolerant patients. 7 of 37 FDA_1617 TIRF REMS Industry Group (TRIG) Transmucosal Immediate Release Fentanyl (TIRF) Products Prescriber KAB Survey Protocol 7d Prescribers starting a patient on a TIRF medicine must begin with titration from the lowest dose available for that specific product, even if the patient has previously taken another TIRF medicine. Version 54 0 10 Sep23 May 2013 TRUE Key Risk Message 2: TIRF medicines are only indicated for the management of breakthrough pain in adult cancer patients 18 years of age and older (16 years of age and older for Actiq® brand and generic equivalents) who are already receiving and who are tolerant to around-theclock opioid therapy for their underlying persistent cancer pain. Question Question Desired response No. In your practice, for which of the following indications do you prescribe TIRF 9 medicines to opioid tolerant patients? Please answer “Yes,” “No,” or “I don’t know” for each option. Acute or postoperative pain NO 9a Headache or migraine pain NO 9b Dental pain NO 9c Breakthrough pain from cancer YES 9d Chronic non-cancer pain NO 9e 13b. Adult female with localized breast cancer; just completed a The patients described are experiencing breakthrough pain. mastectomy and According to the labeling, a TIRF medicine is not reconstructive 13 appropriate for one of them. Which patient should not surgery; persistent receive a TIRF medicine? Please select one option. cancer pain managed with 30 mg oral morphine daily for the past 6 weeks. 8 of 37 FDA_1618 TIRF REMS Industry Group (TRIG) Transmucosal Immediate Release Fentanyl (TIRF) Products Prescriber KAB Survey Protocol Version 54 0 10 Sep23 May 2013 Key Risk Message 3: TIRF medicines contain fentanyl, an opioid agonist and a Schedule IIcontrolled substance, with abuse liability similar to other opioid analgesics. Question No. 7 7e 8 8a 8b 10 10a Question Desired response Please answer “True,” “False,” or “I don’t know” for each statement based on the labeling for TIRF medicines. It is important to monitor for signs of abuse and addiction in patients who take TIRF TRUE medicines. Which of the following are risk factors for opioid abuse? Please answer “Yes,” “No,” or “I don’t know” for each option. A personal history of psychiatric illness YES A personal history of past or current alcohol or drug abuse, or a family history of YES illicit drug use or alcohol abuse Please answer “True,” “False,” or “I don’t know” for each statement based on the labeling for TIRF medicines. TIRF medicines can be abused in a manner TRUE similar to other opioid agonists. Key Risk Message 4: TIRF medicines are not interchangeable with each other, regardless of route of administration. Question No. 10 10b 10c 10d 14 Question Desired response Please answer “True,” “False,” or “I don’t know” for each statement based on the labeling for TIRF medicines. TIRF medicines are interchangeable with each other regardless of route of administration. FALSE The conversion of one TIRF medicine for another TIRF medicine may result in a fatal overdose because of differences in the pharmacokinetics of fentanyl absorption. Dosing of TIRF medicines is not equivalent on a microgram-to-microgram basis. A patient is already taking a TIRF medicine but wants to change their medicine. His/her doctor decides to prescribe a different TIRF medicine (that is not a bioequivalent generic version of a branded product) in its place. According to the labeling, how should the prescriber proceed? Please select one option. TRUE TRUE 14b. The prescriber must not convert to another TIRF medicine on a microgram-permicrogram basis because these medicines 9 of 37 FDA_1619 TIRF REMS Industry Group (TRIG) Transmucosal Immediate Release Fentanyl (TIRF) Products Prescriber KAB Survey Protocol Version 54 0 10 Sep23 May 2013 have different absorption properties and this could result in a fentanyl overdose. 4.1.3 Additional Questions The survey includes questions about the requirements of the TIRF REMS Access Program and receipt and understanding of the TIRF educational materials and the Patient-Prescriber Agreement Form. The following question about behaviors will be asked after the key risk message questions: Question 12: How frequently do you perform the following activities when prescribing TIRF medicines? Please answer “Always,” “Only with the first prescription,” “Sometimes,” “Never,” or “I don’t know.” Ask patients (or their caregivers) about the presence of children in the home Instruct patients (or their caregivers) not to share TIRF medicines with anyone else Counsel patients (or their caregivers) that accidental exposure to TIRF medicines by a child may be fatal Instruct patients (or their caregivers) to keep TIRF medicines out of the reach of children to prevent accidental exposure Instruct patients (or their caregivers) about proper disposal of any unused or partially used TIRF medicines Give patients (or their caregivers) the Medication Guide for their TIRF medicine Demographic information will be collected at the end of the survey. 4.2 Participant Recruitment A random sample of prescribers who are enrolled in the TIRF REMS Access Program will be invited to participate via an invitation letter. The text of the sample written invitation to prescribers can be found in Appendix B. If the required number of completed surveys is not achieved within the expected timeframe of approximately one to two weeks after the first mailing, reminder letters will be sent to non-respondents from the original sample with subsequent fax, e-mail, or United States (US) Mail follow-up to maximize participation. The distribution within the mailing to the second sample will be adjusted in accordance with the allocation in the original sample. If these efforts do not result in the required number of surveys within two to three weeks, then a new sample of prescribers will be randomly selected. 10 of 37 FDA_1620 TIRF REMS Industry Group (TRIG) Transmucosal Immediate Release Fentanyl (TIRF) Products Prescriber KAB Survey Protocol Version 54 0 10 Sep23 May 2013 All respondents who complete the survey and who provide their contact information will be mailed a $125 honorarium to thank them for their participation. Prescribers who practice in Vermont, Massachusetts, or Minnesota and complete the survey will not receive compensation. Participants will be informed that prescribers from these states are not eligible to participate, but they and physicians who practice in these states will not receive compensation for their participation. The mailing will also include a Thank You Letter, a copy of the Important Safety Information (ISI), and a copy of the correct answers to key risk message questions. 4.2.1 Measures to Minimize Bias in the Sample The sample of prescribers who are invited to participate will be a random sample of all enrolled prescribers. The sample of participating prescribers will be self-selected since respondents will voluntarily respond to the invitation to participate; however, the survey recruitment strategies are intended to recruit a heterogeneous sample of prescribers for participation. Prescribers will be offered online or telephone options for completing the survey. Multiple modalities for survey data collection allow for wider survey access to a more heterogeneous population. Respondents will be provided a unique code during the recruitment process and will be asked to provide the unique code to gain access to the online survey or when calling the Survey Coordinating Center. The code will be deactivated after use to minimize the possibility for fraud. 5. STUDY POPULATION 5.1.1 Sample Size A sample of 300 healthcare providers who are enrolled in the TIRF REMS Access Program is proposed for each survey wave. The size of the sample was determined based on both practical and statistical considerations. There is no target comprehension rate specified a priori. A sample of 300 completed surveys will allow estimation of the comprehension rate for each risk message with a moderately high degree of precision. The table below shows the precision of the estimates for level of understanding using two-sided 95% confidence intervals (CIs) obtained with the sample size of 300 completed surveys. The noted CIs are used to indicate that for any survey-estimated rate of understanding, the true population rate of understanding is at least as high as the lower limit of the 95% CI and may be as high as the upper limit of the 95% CI. 11 of 37 FDA_1621 TIRF REMS Industry Group (TRIG) Transmucosal Immediate Release Fentanyl (TIRF) Products Prescriber KAB Survey Protocol Version 54 0 10 Sep23 May 2013 Table 5.1: Precision of Estimated Rates of Understanding with a Sample Size of 300 Estimated Rate of Understanding 5% 10% 15% 20% 25% 30% 35% 40% 45% 50% 55% 60% 65% 70% 75% 80% 85% 90% 95% 5.1.2 Estimated Confidence Interval 2.8% 6.8% 11.2% 15.6% 20.2% 24.9% 29.6% 34.4% 39.3% 44.2% 49.2% 54.2% 59.3% 64.5% 69.7% 75.0% 80.4% 86.0% 91.9% 8.1% 14.0% 19.6% 25.0% 30.3% 35.5% 40.7% 45.8% 50.8% 55.8% 60.7% 65.6% 70.4% 75.1% 79.8% 84.4% 88.8% 93.2% 97.2% Inclusion Criteria All prescribers who are enrolled in the TIRF REMS Access Program are eligible to participate in this survey, with the exceptions noted below. 5.1.3 Exclusion Criteria The following respondents are not eligible to participate in the surveys: 6.  Prescribers who have previously participated in the TIRF REMS KAB survey  Prescribers or their immediate family members who have ever worked for ever worked for Anesta LLC, Archimedes Pharma US Inc.; Cephalon, Inc. (a wholly-owned subsidiary of Teva Pharmaceutical Industries, Ltd); Endo Pharmaceuticals Inc.; Galena Biopharma; Insys Therapeutics; Mallinckrodt, the Pharmaceuticals Business of Covidien; Meda Pharmaceuticals; Mylan, Inc.; Par Pharmaceutical, Inc.; ProStrakan Inc.; Teva Pharmaceuticals, Ltd.; UBC; McKesson Specialty Care Solutions; RelayHealth; or the FDA. SURVEY PROCESS The survey will begin with screening questions to confirm respondent eligibility to participate in the survey. Completion of the entire survey is expected to take approximately 20 minutes. 12 of 37 FDA_1622 TIRF REMS Industry Group (TRIG) Transmucosal Immediate Release Fentanyl (TIRF) Products Prescriber KAB Survey Protocol 6.1 Version 54 0 10 Sep23 May 2013 Screening and Survey Administration The questionnaire will begin with a screening module with questions to confirm prescriber eligibility. Depending on the answers to the screening questions, survey participation could either be terminated or continued. If ineligible, the respondent is immediately notified with a “thank you” message that survey participation has ended. If eligible, the respondent is allowed to continue survey participation. The data entry system used for both methods of survey administration has been validated and is secure for receiving and storing survey data. The system is 21 CFR Part 11 and Health Insurance Portability and Accountability Act (HIPAA) compliant. Prescriber-identifying information will be stored separately from survey data. 6.1.1 Telephone A trained interviewer from the Survey Coordinating Center will conduct the telephone interviews using a CATI program. The screening and main elements of the questionnaire will be administered sequentially during the same telephone call. Telephone interviewing allows participation of prescribers who do not have Internet access. It will also be convenient for prescribers to participate since they can call in and be interviewed at their convenience during the specified time period when the Survey Coordinating Center is available. 6.1.2 Internet An Internet-based survey system will also be used for conducting the KAB surveys. If the prescriber selects to participate in the survey online, he/she will be directed to a secured website to complete screening questions. An Internet survey will be convenient for respondents to participate since they can complete the questionnaire at any time. 6.2 Measures to Minimize Bias in the Survey Process A number of controls will be in place to ensure the survey is conducted in a controlled and professional manner and to minimize bias. For example, a unique code will be given to each survey participant and the code will be inactivated after use to minimize fraud. Telephone interviewers are highly trained and use a standardized script to administer interviews. All questions will be programmed to ensure that questions are asked in the appropriate sequence. Skip patterns will be clearly indicated. Respondents cannot go back to a question once the question has been answered and cannot skip ahead. All questions must be answered in order to complete the survey. Response options presented in a list will be randomized to minimize positional bias. Programming will be reviewed by quality control and simulated users (User Acceptance Testing) prior to implementing the survey. 13 of 37 FDA_1623 TIRF REMS Industry Group (TRIG) Transmucosal Immediate Release Fentanyl (TIRF) Products Prescriber KAB Survey Protocol 7. Version 54 0 10 Sep23 May 2013 ANALYSIS Information obtained from the survey will be reported as descriptive statistics for the survey administration, study population, and the survey questions. The data from the sample population will be reported using frequency distributions of responses to all questions. The following will be reported as part of this analysis:  The number of invitations issued to prescribers  The number of reminder letters  The number of respondents screened for participation  The number of respondents eligible for participation  The number of respondents eligible for participation who complete the survey  Representativeness of prescribers based on geography  Description of survey participants, including:  Gender  Medical degree of respondent: MD, DO, NP, PA  Medical specialty  Years of professional experience  How many times per month TIRF medicines prescribed in the last 6 months  Geographic region of practice Additional descriptive statistics may be reported as appropriate. 7.1.1 Analysis Population The analysis population will be based on eligible prescribers who completed all questions presented to them in the survey (“completers”). 7.1.17.1.2 Description of Primary Analyses Primary analyses are done for all key risk messages using data from all completers. The primary analysis for a key risk message evaluates the rate for each correct response to each individual question/item defined by the key risk message. The specific correct response to each question/item is identified in the body of the risk message table. 14 of 37 FDA_1624 TIRF REMS Industry Group (TRIG) Transmucosal Immediate Release Fentanyl (TIRF) Products Prescriber KAB Survey Protocol Version 54 0 10 Sep23 May 2013 7.1.27.1.3 Description of Secondary Analyses Secondary analyses are done only for those key risk messages that contain multiple questions/items using data from all completers.. The secondary analysis entails a frequency distribution of the number of respondents who got 0, 1, etc. correct responses across the total number of items for the given key risk message. 8. SAFETY EVENT REPORTING The term ‘Safety Event’ is defined as any information reported by a survey respondent that meets the criteria of an adverse event or product complaint. While it is not the intention of the survey to solicit the report of information that meets the criteria of a Safety Event, it is possible that a respondent may spontaneously report information that meets this criteria in free text fields of the survey (Internet-based administration) or while in conversation with the Survey Coordinating Center (telephone-based administration). The Internet-based questionnaires will be monitored for any comments recorded in the free text fields. If an event is mentioned to a Survey Coordinating Center Associate, the Associate will document the safety event and the respondent’s contact information. Respondents will also be informed that a representative from the appropriate TIRF medicine manufacturer may contact them if there are questions about the survey. Information on all reports (Internet or telephone) that may constitute an adverse event or other safety event will be forwarded to the appropriate TIRF medicine manufacturer as described in the Safety Event Project Specific Procedure (SE/PSP). Additional detail regarding processes for adverse event reporting will be specified in the SE/PSP. 9. PRIVACY PROTECTION AND CONFIDENTIALITY All data collected during the survey will be held confidential. The electronic data capture (EDC) system used for data collection encrypts all identifiable information, and respondent identifiers are stored separately from the survey responses. Respondent names and addresses are collected in order to mail the $125 honorarium, a Thank You Letter, the correct responses to key risk messages, and the ISI after the survey is completed. Respondent contact information is also requested when necessary to comply with a federal or state law or regulation, including without limitation, reporting payments made to physicians under the federal physician payment sunshine provisions in addition to instances where a safety event is reported and a TIRF medicine manufacturer must obtain follow-up information (see Section 8 above). Respondents will be informed when they access the survey that they may be contacted if there are any questions about their survey responses. Respondents will be informed that their answers to the survey questions will not affect their ability to prescribe TIRF medicines. 15 of 37 FDA_1625 TIRF REMS Industry Group (TRIG) Transmucosal Immediate Release Fentanyl (TIRF) Products Prescriber KAB Survey Protocol Appendix A Version 54 0 10 Sep23 May 2013 Prescriber Questionnaire Survey Legend  [PROGRAMMER] is used to indicate directions to the programmer and is set in bold, red, uppercase letters between square brackets.  (INTERVIEWER) is used to indicate directions to the telephone interviewer and is set in bold, blue, text between parentheses. This text appears when content is to be administered by telephone only (for example, spontaneous adverse event reporting).  [ONLINE] indicates a question is worded specifically for administering the survey online. [PHONE] indicates a question is worded specifically to be read by a telephone interviewer and differs from the online text.  [BEGIN ONLINE/PHONE SURVEY CONTENT] and [END SURVEY CONTENT] are used to indicate to the programmer the type of survey administration and the beginning and end of the survey or sections within the survey content, for example, [BEGIN ADVERSE EVENT/PRODUCT COMPLAINT] and [END ADVERSE EVENT/PRODUCT COMPLAINT].  [TERMINATE] is displayed next to responses that should cause the survey to end. The following termination language will be programmed into the survey or read by the interviewer unless different language is specified with the question. Thank you very much for your time today. Based on your answer, you are not eligible to take this survey. We appreciate your interest in the survey.  [RANDOMIZE LIST] is inserted before questions to indicate to the programmer that the responses should be randomized. Responses such as “I don’t know,” “Prefer not to answer” or “None of the above” will always appear at the end of the randomized responses.  [GO TO Qx] (skip logic) is inserted after a response to indicate to the programmer that the survey should skip to the indicated question (for example, [GO TO Q17] skips to question 17). If no skip logic is indicated the survey continues to the next question in the sequence.  [MULTILINE INPUT] indicates to the programmer that multiple lines should be provided for data entry (for example, two address lines or a free-text response). 16 of 37 FDA_1626 TIRF REMS Industry Group (TRIG) Transmucosal Immediate Release Fentanyl (TIRF) Products Prescriber KAB Survey Protocol Version 54 0 10 Sep23 May 2013 Survey Legend  [DROP-DOWN LIST INPUT WITH STATES TABLE] indicates to the programmer that the response should be a drop-down list containing the states and US territories in the table below. Alabama Georgia Massachusetts New York Tennessee Alaska Guam Michigan North Carolina Texas American Samoa Hawaii Minnesota North Dakota Arizona Idaho Mississippi Illinois Missouri Indiana Montana Northern Mariana Islands US Virgin Islands Iowa Nebraska Kansas Nevada Kentucky New Hampshire Louisiana New Jersey Maine New Mexico Arkansas California Colorado Connecticut Delaware District of Columbia Florida Maryland Ohio Oklahoma Oregon Pennsylvania Puerto Rico Rhode Island Utah Vermont Virginia Washington West Virginia Wisconsin Wyoming South Carolina South Dakota  The following is used to categorize survey populations into standard geographic regions but it is not displayed in the survey. Geographic Distribution (based on address) 1: Northeast, Midwest, South, and West regions Northeast Region  New England Division - ME, NH, VT, MA, RI, CT  Middle Atlantic Division - NY, NJ, PA Midwest Region  East North Central Division - OH, IN, IL, MI, WI  West North Central Division - MN, IA, MO, ND, SD, NE, KS South Region  South Atlantic Division - DE, MD, DC, VA, WV, NC, SC, GA, FL  East South Central Division - KY, TN, AL, MS  West South Central Division - AR, LA, OK, TX 17 of 37 FDA_1627 Vasion240 Immdiate Relwel-?entanyl (TIRE Products Prescr?aaKAB 2013 Survey Legend West Mountain Division - MTPaci?c Division WA, OR, CA, AK, HI 0 The following US territories are categorized as Other: Puerto Rico, Northern Mariana Islands. US Virgin Islands. American Samoa. and Guam. 1US. Census Bureau, last revised Friday, 27-Jul-2001 12:59:43 EDT. WSURVEY PREANIBLE 1 Before you begin. we would like to share some important information about this survey. The manufacturers of Transmucosal Inmlediate Release Fentanyl (TIRF) medicines are conducting this survey: as required by the FDA. to assess prescribers? understanding of the safe use and prescribing of these medicines. These medicines are known as rapid onset opioids and referred to in this survey as medicines.? The TIRF medicines include Abstral?. Actiq?. Fentora?= Lazanda?= Onsolis?= Subsys?= and generic versions of any of these brands. The manufacturers of these medicines include Archimedes Phanna US Inc.; Cephalon= Inc. (a wholly-owned subsidiary of Teva Pharmaceutical Industries. Ltd): Endo Pharmaceuticals Inc.: Galena Biopharma: Insys Therapeutics: Mallinckrodt: Meda Pharmaceuticals: Mylan. Inc.; and Par Pharmaceutical. Inc. The survey will take approximately 20 minutes. There are no known risks to you in taking this survey. You may refuse to take part or withdraw at any time. Your answers to the questions or your decision to take part in the sm'vey will not affect your ability to prescribe TIRF medicines. ?ow We Use Your Information] eon-nut mm please note on this as: title Your answers to the sm'vey questions will be combined with answers given by other healthcare professionals taking the survey. All answers will be put together and reported in 3? anonymous form to the manufacturers of TIRF medicines. Your name will not be used in any report. If you are eligible to take the survey. complete all the questions. and provide your contact information. you will receive a $125 honorarium for your time and participation. This compensation represents the fair value for your services in cormection with completion of the survey. The am01mt of the compensation was not determined in any manner that takes into account the volume or value of any referrals or business otherwise generated by you. Your name and address will be used to send you the honorarium after you complete the smvey. Your personal information will also be used if we have questions about your survey or if we are required to use your information to comply with a federal or state law or regulation. including without limitation. reporting payments made to physicians under the federal l8 of37 628 TIRFREMSInrhsu'menp (TRIG) Version240 Immdim vacyProtocol W208 physician pa?nent sunshine provisions. Physicians who practice in Vermont, Massachusetts, or Minnesota should be aware that they will not be permitted to receive paganent for survey completion and may elect not to complete the survey. Providing a telephone number is optional. Your telephone number will be used only if there are any questions about your survey responses. How We Protect Your Privacy] Comment please not: an an; as: title . . . cfdnepaeanble Boldedtulisnotahypahnk' contacted for marketng pugposes based on your personal mformatron or your answers to the survey. Neither the manufacturers of TIRF medicines nor their contractors will sell: transfera information will not be used in a mamrer inconsistent with this document. Your privacy will be protected; howevera research survey records may be inspected by the FDA. Your choice necessag to take part in this survey. [?ow to Learn More about This SurveyI mum]: pleasenote?mrhis mam mhpumdmlimua title . . cream-me oordinatin Center at 1-877-379-3297. Be sure to write down this tele hone number' it will not be displayed again. [1 aking the Survevl Olnlnu'lt [24m]: FDA: please me am this mdedimd mm is Fueled onlim as a 61b landing of?le following tat to my: readability Once you have answered a question and moved on. you carmot 20 back and change your 0:ka answers. Thank you for your participation in this survey. ONLINE PREANIBLE 1 l9 of37 629 TIRF REMS Industry Group (TRIG) Transmucosal Immediate Release Fentanyl (TIRF) Products Prescriber KAB Survey Protocol Version 54 0 10 Sep23 May 2013 [PHONE PREAMBLE 1] Before you begin, we would like to share some important information about this survey. The manufacturers of Transmucosal Immediate Release Fentanyl (TIRF) medicines are conducting this survey, as required by the FDA, to assess prescribers’ understanding of the safe use and prescribing of these medicines. These medicines are known as rapid onset opioids and referred to in this survey as “TIRF medicines.” (INTERVIEWER: Say “TIRF” then spell out T-IR-F) The TIRF medicines include Abstral®, Actiq®, Fentora®, Lazanda®, Onsolis®, Subsys®, and generic versions of any of these brands. The manufacturers of these medicines include Archimedes Pharma US Inc.; Cephalon, Inc. (a wholly-owned subsidiary of Teva Pharmaceutical Industries, Ltd.); Endo Pharmaceuticals Inc.; Galena Biopharma; Insys Therapeutics; Mallinckrodt; (a Pharmaceuticals Business of Covidien); Meda Pharmaceuticals; Mylan, Inc; and Par Pharmaceutical, Inc. The survey will take approximately 20 minutes. There are no known risks to you in taking this survey. You may refuse to take part or withdraw at any time. Your answers to the questions or your decision to take part in the survey will not affect your ability to prescribe TIRF medicines. [ONLINE ONLY]How We Use Your Information [PHONE ONLY] Now I would like to read some information about how your contact information will be used. Your answers to the survey questions will be combined with answers given by other healthcare professionals taking the survey. All answers will be put together and reported in anonymous form to the manufacturers of TIRF medicines. Your name will not be used in any report. If you are eligible to take the survey, complete all the questions, and provide your contact information, you will receive a $125 honorarium for your time and participation. This compensation represents the fair value for your services in connection with completion of the survey. The amount of the compensation was not determined in any manner that takes into account the volume or value of any referrals or business otherwise generated by you. Your name and address will be used to send you the honorarium after you complete the survey. Your personal information will also be used if we have questions about your survey or if we are required to use your information to comply with a federal or state law or regulation, including without limitation, reporting payments made to physicians under the federal physician payment sunshine provisions. Physicians who practice in Vermont, Massachusetts, or Minnesota should be aware that they will not be permitted to receive payment for survey completion and may elect not to complete the survey. Providing a telephone number is optional. Your telephone number will be used only if there are any questions about your survey responses. [ONLINE ONLY] How We Protect Your Privacy 20 of 37 FDA_1630 TIRF REMS Industry Group (TRIG) Transmucosal Immediate Release Fentanyl (TIRF) Products Prescriber KAB Survey Protocol Version 54 0 10 Sep23 May 2013 [PHONE ONLY] Now I would like to tell you some information about how we protect your privacy. We respect that the privacy of your personal information is important to you. You will not be contacted for marketing purposes based on your personal information or your answers to the survey. Neither the manufacturers of TIRF medicines nor their contractors will sell, transfer, or rent your information. Your answers will be kept strictly confidential. Your personal information will not be used in a manner inconsistent with this document. Your privacy will be protected; however, research survey records may be inspected by the FDA. Your choice to allow manufacturers of TIRF medicines to use your information is entirely voluntary but necessary to take part in this survey. We respect that the privacy of your personal information is important to you. You will not be contacted for marketing purposes based on your personal information or your answers to the survey. Neither the manufacturers of TIRF medicines nor their contractors will sell, transfer, or rent your information. Your answers will be kept strictly confidential. Your personal information will not be used in a manner inconsistent with this document. Your privacy will be protected; however, research survey records may be inspected by the FDA. Your choice to allow manufacturers of TIRF medicines to use your information is entirely voluntary but necessary to take part in this survey. [ONLINE ONLY] How to Learn More about This Survey [ONLINE ONLY] If you have questions about the survey, or problems with the survey, please contact the Survey Coordinating Center at 1 877 379 3297. Be sure to write down this telephone number; it will not be displayed again. [PHONE ONLY] Now I will tell you how you can learn more about this survey. Please have a pen or pencil ready to write down a telephone number you can call should you have any questions about the survey. If you have questions about the survey, please ask me at any time. If you have questions at a later time, please contact the Survey Coordinating Center at 1-877379-3297. Please feel free to ask me to repeat any questions or statements as we go through the survey. Once you have answered a question and moved on, you cannot go back and change your answers. Thank you for your participation in this survey. [ONLINE ONLY] Taking the Survey [ONLINE ONLY] Once you have answered a question and moved on, you cannot go back and change your answers. [ONLINE ONLY] Thank you for your participation in this survey. [END PHONE PREAMBLE 1] [BEGIN INCLUSION/EXCLUSION QUESTIONS] 21 of 37 FDA_1631 TIRF REMS Industry Group (TRIG) Transmucosal Immediate Release Fentanyl (TIRF) Products Prescriber KAB Survey Protocol 1. Version 54 0 10 Sep23 May 2013 Your agreement to participate in this survey confirms mutual understanding in connection with completion of the survey and the fair market value of the payment to be rendered in connection with those services. Do you agree to participate in this survey? 2. 3. 4. ○ Yes ○ No [TERMINATE] Have you ever taken part in this survey about TIRF medicines before? TIRF medicines include Abstral®, Actiq®, Fentora®, Lazanda®, Onsolis®, Subsys®, and generic versions of any of these brands. ○ Yes [ONLY TERMINATE AFTER WAVE 1] ○ No ○ I don’t know [ONLY TERMINATE AFTER WAVE 1] Are you enrolled in the TIRF REMS Access program? ○ Yes ○ No [TERMINATE] ○ I don’t know [TERMINATE] Have you or any of your immediate family members ever worked for any of the following companies or agencies? Please select all that apply. □ Anesta LLC [TERMINATE] □ Archimedes Pharma US Inc. [TERMINATE] □ Cephalon, Inc. (a wholly-owned subsidiary of Teva Pharmaceutical Industries, Ltd.) [TERMINATE] □ Endo Pharmaceuticals Inc. [TERMINATE] □ Galena Biopharma [TERMINATE] □ Insys Therapeutics [TERMINATE] 22 of 37 FDA_1632 TIRF REMS Industry Group (TRIG) Transmucosal Immediate Release Fentanyl (TIRF) Products Prescriber KAB Survey Protocol Version 54 0 10 Sep23 May 2013 □ Mallinckrodt, the Pharmaceuticals Business of Covidien [TERMINATE] □ McKesson Specialty Care Solutions [TERMINATE] □ Meda Pharmaceuticals [TERMINATE] □ Mylan, Inc. [TERMINATE] □ Par Pharmaceutical, Inc. [TERMINATE] □ ProStrakan, Inc. [TERMINATE] □ RelayHealth [TERMINATE] □ Teva Pharmaceuticals, Ltd. [TERMINATE] □ United BioSource Corporation [TERMINATE] □ FDA [TERMINATE] □ None of these apply [IF SELECTED IN ADDITION TO OTHER RESPONSES, TERMINATE] □ I don’t know [TERMINATE] □ Prefer not to answer [TERMINATE] [END INCLUSION/EXCLUSION QUESTIONS] 23 of 37 FDA_1633 TIRF REMS Industry Group (TRIG) Transmucosal Immediate Release Fentanyl (TIRF) Products Prescriber KAB Survey Protocol 5. Version 54 0 10 Sep23 May 2013 Please select “True,” “False,” or “I don’t know” for each of the following. According to the labeling for TIRF medicines, patients with cancer who are considered opioid-tolerant are those: [RANDOMIZE LIST] Who are taking around-the-clock opioid therapy for underlying persistent chronic pain for one week or longer 5b. Who are not currently taking opioid therapy, but have taken opioid therapy before 5c. Who have no known contraindications to the drug fentanyl, but are not currently taking around-the-clock opioid therapy 5a. 6. True False I don’t know ○ ○ ○ ○ ○ ○ ○ ○ ○ Please answer “True,” “False,” or “I don’t know” for each statement based on the labeling for TIRF medicines. [RANDOMIZE LIST] A cancer patient can be started on a TIRF medicine and an around-the-clock opioid at the same time. 6b. A cancer patient who has been on an around-the-clock opioid for 1 day can start taking a TIRF medicine for breakthrough pain. 6a. True False I don’t know ○ ○ ○ ○ ○ ○ 24 of 37 FDA_1634 TIRF REMS Industry Group (TRIG) Transmucosal Immediate Release Fentanyl (TIRF) Products Prescriber KAB Survey Protocol 7. Please answer “True,” “False,” or “I don’t know” for each statement based on the labeling for TIRF medicines. [RANDOMIZE LIST] TIRF medicines are contraindicated in opioid nontolerant patients because life-threatening respiratory depression could occur at any dose. 7b. Death has occurred in opioid non-tolerant patients treated with some fentanyl products. 7c. TIRF medicines may be used to treat opioid non-tolerant patients. 7d. Prescribers starting a patient on a TIRF medicine must begin with titration from the lowest dose available for that specific product, even if the patient has previously taken another TIRF medicine. 7e. It is important to monitor for signs of abuse and addiction in patients who take TIRF medicines. 7a. 8. 8c. 9. A personal history of psychiatric illness A personal history of past or current alcohol or drug abuse, or a family history of illicit drug use or alcohol abuse A family history of asthma False I don’t know ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ Yes No I don’t know ○ ○ ○ ○ ○ ○ ○ ○ ○ In your practice, for which of the following indications do you prescribe TIRF medicines to opioid tolerant patients? Please answer “Yes,” “No,” or “I don’t know” for each option. [RANDOMIZE LIST] 9a. 9b. 9c. True Which of the following are risk factors for opioid abuse? Please answer “Yes,” “No,” or “I don’t know” for each option. [RANDOMIZE LIST] 8a. 8b. Version 54 0 10 Sep23 May 2013 Acute or postoperative pain Headache or migraine pain Dental pain Yes No I don’t know ○ ○ ○ ○ ○ ○ ○ ○ ○ 25 of 37 FDA_1635 TIRF REMS Industry Group (TRIG) Transmucosal Immediate Release Fentanyl (TIRF) Products Prescriber KAB Survey Protocol Version 54 0 10 Sep23 May 2013 9d. 9e. Breakthrough pain from cancer Chronic non-cancer pain 10. Please answer “True,” “False,” or “I don’t know” for each statement based on the labeling for TIRF medicines. ○ ○ [RANDOMIZE LIST] 10a. TIRF medicines can be abused in a manner similar to other opioid agonists. 10b. TIRF medicines are interchangeable with each other regardless of route of administration. 10c. The conversion of one TIRF medicine for another TIRF medicine may result in a fatal overdose because of differences in the pharmacokinetics of fentanyl absorption. 10d. Dosing of TIRF medicines is not equivalent on a microgram-to-microgram basis. 11. ○ ○ ○ ○ True False I don’t know ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ Please select “True,” “False,” or “I don’t know” for each of the following. According to the labeling for TIRF medicines, patients considered opioid-tolerant are those who are taking, for one week or longer, at least: [RANDOMIZE LIST] True False I don’t know ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ 11a. 11b. 11c. 11d. 11e. 11f. 8 mg oral hydromorphone/day 60 mg oral morphine/day 30 mg oral oxycodone/day 25 mcg transdermal fentanyl/hour 25 mg oral oxymorphone/day An equianalgesic dose of another oral opioid 12. How frequently do you perform the following activities when prescribing TIRF medicines? Please answer “Always,” “Only with the first prescription,” “Sometimes,” “Never,” or “I don’t know.” [RANDOMIZE LIST] Always Only with Sometimes the first prescription Never I don’t know 26 of 37 FDA_1636 TIRF REMS Industry Group (TRIG) Transmucosal Immediate Release Fentanyl (TIRF) Products Prescriber KAB Survey Protocol 12a. Ask patients (or their caregivers) about the presence of children in the home 12b. Instruct patients (or their caregivers) not to share TIRF medicines with anyone else 12c. Counsel patients (or their caregivers) that accidental exposure to TIRF medicines by a child may be fatal 12d. Instruct patients (or their caregivers) to keep TIRF medicines out of the reach of children to prevent accidental exposure 12e. Instruct patients (or their caregivers) about proper disposal of any unused or partially used TIRF medicines 12f. Give patients (or their caregivers) the Medication Guide for their TIRF medicine 13. Version 54 0 10 Sep23 May 2013 ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ The patients described are experiencing breakthrough pain. According to the labeling, a TIRF medicine is not appropriate for one of them. Which patient should not receive a TIRF medicine? Please select one option. [RANDOMIZE LIST] 13a. ○ 13b. ○ 13c. ○ 13d. ○ 13e. ○ 14. Adult male with advanced lung cancer; underlying persistent cancer pain managed with 25 mcg/hour transdermal fentanyl patches for the past two months. Adult female with localized breast cancer; just completed a mastectomy and reconstructive surgery; persistent cancer pain managed with 30 mg oral morphine daily for the past 6 weeks. Adult male patient with advanced prostate cancer who, over the last 2 weeks, has been prescribed 100 mg oral morphine daily for pain due to bone metastasis. Adult female with advanced sarcoma who has been taking a daily dose of 12 mg oral hydromorphone for the last 3 weeks. I don’t know A patient is already taking a TIRF medicine but wants to change their medicine. His/her doctor decides to prescribe a different TIRF medicine (that is not a 27 of 37 FDA_1637 TIRF REMS Industry Group (TRIG) Transmucosal Immediate Release Fentanyl (TIRF) Products Prescriber KAB Survey Protocol Version 54 0 10 Sep23 May 2013 bioequivalent generic version of a branded product) in its place. According to the labeling, how should the prescriber proceed? Please select one option. [RANDOMIZE LIST] 14a. 14b. 14c. 14d. 14e. 15. ○ ○ ○ ○ ○ The prescriber can safely convert to the equivalent dosage of the new TIRF medicine as it has the same effect as other TIRF medicines. The prescriber must not convert to another TIRF medicine on a microgram-permicrogram basis because these medicines have different absorption properties and this could result in a fentanyl overdose. Convert from the other TIRF medicine to the new TIRF medicine at half of the dose. The prescriber should base the starting dose of the newly-prescribed TIRF medicine on the dose of the opioid medicine used for their underlying persistent cancer pain. I don’t know A patient is starting titration with a TIRF medicine. What dose must they start with? Please select one option. [RANDOMIZE LIST] 15a. 15b. 15c. 15d. 15e. 16. ○ ○ ○ ○ ○ An appropriate dose based on the dose of the opioid medicine used for underlying persistent cancer pain. The dose that the prescriber believes is appropriate based on their clinical experience. The lowest available dose, unless individual product Full Prescribing Information provides product-specific guidance. The median available dose. I don’t know A prescriber has started titrating a patient with the lowest dose of a TIRF medicine. However, after 30 minutes the breakthrough pain has not been sufficiently relieved. What should they advise the patient to do? Please pick the best option of the scenarios described. [RANDOMIZE LIST] 16a. 16b. 16c. ○ ○ 16d. 16e. ○ ○ ○ Take another (identical) dose of the TIRF medicine immediately. Take a dose of an alternative rescue medicine. Provide guidance based on the product-specific Medication Guide because the instructions are not the same for all TIRF medicines. Double the dose and take immediately. I don’t know 28 of 37 FDA_1638 TIRF REMS Industry Group (TRIG) Transmucosal Immediate Release Fentanyl (TIRF) Products Prescriber KAB Survey Protocol 17. 17a. 17b. 17c. 17d. A patient is taking a TIRF medicine and the doctor would like to prescribe erythromycin, a CYP3A4 inhibitor. Please pick the best option of the scenarios described. [RANDOMIZE LIST] ○ ○ ○ ○ 17e. ○ 18. Version 54 0 10 Sep23 May 2013 The patient can’t be prescribed erythromycin, because using it at the same time as a TIRF medicine could be fatal. Use of a TIRF medicine with a CYP3A4 inhibitor may require a dosage adjustment; carefully monitor the patient for opioid toxicity, otherwise such use may cause potentially fatal respiratory depression. There is no possible drug interaction between CYP3A4 inhibitors and TIRF medicines. The dose of the TIRF medicine must be reduced by one half if a CYP3A4 inhibitor is prescribed in the same patient. I don’t know Before initiating treatment with a TIRF medicine, prescribers must review the Medication Guide with the patient. Please select “True,” “False,” or “I don’t know” for each of the following counseling statements. [RANDOMIZE LIST] 18a. TIRF medicines contain fentanyl in an amount that could be fatal to children of all ages, in individuals for whom they were not prescribed, and in those who are not opioid tolerant. 18b. Inform patients that TIRF medicines must not be used for acute or postoperative pain, pain from injuries, headache/migraine, or any other short-term pain. 18c. Instruct patients that, if they stop taking their aroundthe-clock opioid medicine, they can continue to take their TIRF medicine. 18d. Instruct patients to never share their TIRF medicine with anyone else, even if that person has the same symptoms. True False I don’t know ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ 29 of 37 FDA_1639 TIRF REMS Industry Group (TRIG) Transmucosal Immediate Release Fentanyl (TIRF) Products Prescriber KAB Survey Protocol 19. Version 54 0 10 Sep23 May 2013 Can patients continue to take their TIRF medicine if they stop taking their around-theclock opioid medicine? ○ Yes ○ No ○ I don’t know [PREAMBLE 2] The next set of questions is about the educational materials for TIRF medicines and the TIRF Patient-Prescriber Agreement. As a reminder, the TIRF medicines include Abstral®, Actiq®, Fentora®, Lazanda®, Onsolis®, Subsys® and generic versions of any of these brands. 20. 21. 22. Did you receive or do you have access to the Full Prescribing Information for the TIRF medicine(s) that you prescribe? ○ Yes ○ No [GO TO Q22] ○ I don’t know [GO TO Q22] Did you read the Full Prescribing Information for the TIRF medicine(s) that you prescribe? ○ Yes ○ No ○ I don’t know Did you receive or do you have access to the Medication Guide for the TIRF medicine(s) that you prescribe? ○ Yes ○ No [GO TO Q24] ○ I don’t know [GO TO Q24] 30 of 37 FDA_1640 TIRF REMS Industry Group (TRIG) Transmucosal Immediate Release Fentanyl (TIRF) Products Prescriber KAB Survey Protocol 23. 24. Version 54 0 10 Sep23 May 2013 Did you read the Medication Guide for the TIRF medicine(s) that you prescribe? ○ Yes ○ No ○ I don’t know Did you or do you have any questions about the information in the Full Prescribing Information or Medication Guide? ○ Yes ○ No [GO TO Q26]Q26] ○ I don’t know [GO TO Q26Q26026] 25. What are your questions? [MULTILINE INPUT] 26. Do you review the Patient-Prescriber Agreement Form with each of your patients for whom you prescribe TIRF medicines or their caregiver? 27. ○ Yes ○ No [GO TO Q28] ○ I don’t know [GO TO Q28] Do you and the patient or their caregiver sign the Patient-Prescriber Agreement Form for TIRF medicines after you have reviewed it with him/her? ○ Yes ○ No ○ I don’t know 31 of 37 FDA_1641 TIRF REMS Industry Group (TRIG) Transmucosal Immediate Release Fentanyl (TIRF) Products Prescriber KAB Survey Protocol 28. Version 54 0 10 Sep23 May 2013 Do you give a copy of the Patient-Prescriber Agreement Form for TIRF medicines to the patient or their caregiver? ○ Yes ○ No ○ I don’t know [DEMOGRAPHICS PREAMBLE] There are just a few more questions to help us combine your answers with other answers we have received. 29. 30. On average, how many times per month have you prescribed the TIRF medicines within the last 6 months? ○ None [GO TO DEMOGRAPHICS PREAMBLE 2] ○ 1 – 2 times per month ○ 3 – 5 times per month ○ More than 5 times per month ○ I don’t remember Please select the TIRF medicines that you have prescribed within the last 6 months (select all that apply): □ □ Abstral® □ Fentora® or generic Fentora® □ Lazanda® □ Onsolis® □ Subsys® Actiq® or generic Actiq® [DEMOGRAPHICS PREAMBLE 2] These last few questions are for demographic purposes. 32 of 37 FDA_1642 TIRF REMS Industry Group (TRIG) Transmucosal Immediate Release Fentanyl (TIRF) Products Prescriber KAB Survey Protocol 31. 32. 33. 34. Version 54 0 10 Sep23 May 2013 What is your gender? ○ Male ○ Female ○ Prefer not to answer What is your medical degree? ○ MD ○ DO ○ Nurse Practitioner [Go to Q34] ○ Physician Assistant [Go to Q34] ○ Prefer not to answer In total, how many years have you been practicing medicine, since completing your education? ○ Less than 3 years ○ 3 – 5 years ○ 6 – 10 years ○ 11 – 15 years ○ More than 15 years ○ Prefer not to answer In which state do you practice? [DROP-DOWN LIST INPUT WITH STATES TABLE WITH “Prefer not to answer” at END] 33 of 37 FDA_1643 TIRF REMS Industry Group (TRIG) Transmucosal Immediate Release Fentanyl (TIRF) Products Prescriber KAB Survey Protocol 35. Version 54 0 10 Sep23 May 2013 What is your medical specialty? ○ Oncology ○ Primary care ○ Pain management ○ Other (please specify): _____________________ ○ No designated specialty [PHONE ONLY: BEGIN ADVERSE EVENT/PRODUCT COMPLAINT] (INTERVIEWER: Please record if respondent spontaneously reported an adverse event or product complaint during the course of this interview.) ○ Yes ○ No [GO TO CLOSING 1] Enter Safety Adverse Event Verbatim [MULTILINE INPUT] (INTERVIEWER: Indicate to the respondent that someone may call back to ask more questions about the adverse event or product complaint that was reported.) [END ADVERSE EVENT/PRODUCT COMPLAINT] [CLOSING 1] We would like to send you a $125 honorarium within the next few weeks to thank you for your time, but we need your name and address to do so. If you do not provide your name and address you will not receive the honorarium for your time and participation in the survey. As a reminder, physicians who practice in Vermont, Massachusetts, or Minnesota should be aware that they will not be permitted to receive payment for survey completion. Do you agree to give us your name and mailing address so we can send you the honorarium? ○ Yes ○ No [SKIP TO CLOSING 2] 34 of 37 FDA_1644 TIRF REMS Industry Group (TRIG) Transmucosal Immediate Release Fentanyl (TIRF) Products Prescriber KAB Survey Protocol Version 54 0 10 Sep23 May 2013 FIRST NAME: _______________________________________________ LAST NAME: _______________________________________________ ADDRESS: [MULTILINE INPUT] CITY: _____________________________________ STATE: [DROP-DOWN LIST INPUT WITH STATES TABLE] ZIP: ___________ [CLOSING 2] We would also like to ask for your telephone number. Providing your telephone number is optional and it will be used to contact you only if there are questions about your survey responses. 36. ○ ○ Do you want to provide your telephone number? Yes No [SKIP TO CLOSING 3] Telephone: ________________________________ [END CLOSING 2] [CLOSING 3] That ends the survey. Thank you again for your help. [END OF SURVEY CONTENT] 35 of 37 FDA_1645 TIRF REMS Industry Group (TRIG) Transmucosal Immediate Release Fentanyl (TIRF) Products Prescriber KAB Survey Protocol Appendix B Version 54 0 10 Sep23 May 2013 Prescriber Invitation Letter [CURR_DATE] [PRESCRIBER NAME] [STREET_ADDR] [CITY], [STATE] [ZIP] Dear [PRESCRIBER NAME]: You were selected to receive this letter because you have enrolled in the TIRF REMS Access Program. We are contacting you to invite you to participate in a survey being conducted by the manufacturers of Transmucosal Immediate Release Fentanyl (TIRF) medicines, as required by the Food and Drug Administration (FDA). The purpose of the survey is to assess prescribers’ understanding of the safe and appropriate use of these medicines. The TIRF medicines include Abstral®, Actiq®, Fentora®, Lazanda®, Onsolis®, Subsys™, and generic versions of any of these brands. The manufacturers of TIRF medicines (collectively referred to as the “TIRF REMS Industry Group”) include Archimedes Pharma US Inc.; Cephalon, Inc. (a wholly-owned subsidiary of Teva Pharmaceutical Industries, Ltd.); Endo Pharmaceuticals Inc.; Galena Biopharma; Insys Therapeutics; Mallinckrodt, the Pharmaceuticals Business of Covidien; Meda Pharmaceuticals; Mylan, Inc., and Par Pharmaceutical, Inc. These manufacturers are looking for 300 prescribers to complete the survey. Eligible prescribers who complete the survey will be sent a $125 honorarium to thank them for their time. The survey will take 15-20 minutes. Your answers will be kept strictly confidential and will be combined with the answers from other prescribers who take this survey. Your name will not be used in the report of this survey and your contact information will only be used to send you a $125 honorarium for the time you took to complete the survey and if required to comply with a federal or state law or regulation, including without limitation, reporting payments made to physicians under the federal physician payment sunshine provisions. Prescribers who practice in Vermont, Massachusetts, or Minnesota should be aware that they will not be permitted to receive payment for survey completion and may elect not to complete the survey. You are under no obligation to participate in this survey. If you are interested in participating, go to www.XXXXXXXXXX.com anytime or call 1-877-379-3297, 8AM to 8PM Eastern Time Monday through Friday. You will be asked to give this unique code prior to starting the survey: [CODE_ID]. Please have this letter with you at the time you take the survey. Thank you in advance for your help with this important effort. Sincerely, TIRF REMS Industry Group * We recommend that you take the survey on a desktop or laptop computer. Taking the survey on mobile devices, such as smart phones, tablets, and e-notebooks, is not supported. 36 of 37 FDA_1646 TIRF REMS Industry Group (TRIG) Transmucosal Immediate Release Fentanyl (TIRF) Products Prescriber KAB Survey Protocol Appendix C Version 54 0 10 Sep23 May 2013 Qualitative Research Report 37 of 37 FDA_1647 Accenture LLP 1160 West Swedesford Road Berwyn, PA 19312 wvvw.accenture.com August 20, 2014 Food and Drug Administration Center for Drug Evaluation and Research Central Document Room Drug Master File Staff 5901-B Ammendale Road Beltsville, MD 20705?1266 Re: DMF 027320 Holder: McKesson Specialty Health (McKesson) DMF Subject: Transmucosal Immediate Release Fentanyl (TIRF) Access Program Re: REMS Shared Program DMF Type: DMF Submission Information: DMF Annual Report REMS Submission Identi?er: Not Applicable Sequence Number: 0011 Dear Drug Master File Staff: This Type DMF contains the Risk Evaluation and Mitigation Strategy (REMS) for Transmucosal Immediate Release Fentanyl for the Shared System REMS program. Reference is made to the above DMF, which was initially submitted on August 20, 2013. Enclosed, please ?nd the DMF Annual Report (Reporting Period: August 21, 2013 August 20, 2014). The Annual Report includes an administrative information page, a summary of the amendments that have been submitted since the original DMF, and a list of authorized persons to incorporate by reference. McKesson states that information provided in this Master File is current and assures that the material furnished will meet the speci?cations described herein. McKesson also con?rms that the Holder obligations are observed. We request that all information in this ?le be treated as con?dential commercial information to the Food and Drug Administration pursuant to 21 C.F.R. ?20.61, and that no information from this ?le be provided to any unauthorized persons without written consent. If you have any questions or concerns, please do not hesitate to contact Jann Kochel, US. Agent for McKesson, at 610-407-1738 or alternatively via email at jann.a.kochel@accenture.com. Sincerely, .. . arm A. Koc US. Agent Accenture, LP Attachments: Table of Contents for the submission Electronic Submission Speci?cations 648 DMF #027320; Sequence 0011 Shared System REMS Table of Contents Page 1 of 1 ANNUAL REPORT Reporting Period: August 21, 2013 – August 20, 2014 Module Section Description 1.2 Cover Letter Cover Letter w/ Attachments 1.11.3 – Efficacy Information Amendment Annual Report - Summary of Changes 1.4.3 – List of Authorized Persons to Incorporate by Reference List of Authorized Persons FDA_1649 Electronic Submission Specifications This submission is compliant with FDA's Guideline for Industry: Providing Regulatory Submissions in Electronic Format - Human Pharmaceutical Product Applications and Related Submissions Using the eCTD Specifications (June 2008). All files were checked and verified to be free of viruses prior to transmission through the electronic submission gateway. This eCTD has been generated by Accenture, LLP (formerly Octagon Research Solutions Inc.), who has filed an acceptable eCTD pilot with the Center (Pilot Number 900777). Anti-Virus Program Program Version Virus Definition Date Submiss ion Size Symantec Endpoint Protection Edition 11.0.5002.333 08/11/2014 rev. 3 Approx. 1 MB The IT point of contact for this submission is: Name Phone Number Email Address Matt Francis 1-610-407-1854 Matthew.p.francis@accenture.com FDA_1650 ADMINISTRATIVE INFORMATION Holder’s Name: McKesson Specialty Health Holder’s Address: 4343 N. Scottsdale Road Suite 150 Scottsdale, AZ 85251 Holder’s Contact Person: Laura Baloun Contact’s Address: 4343 N. Scottsdale Road Suite 150 Scottsdale, AZ 85251 Contact’s Phone: 480-663-4009 Contact’s Fax: 480-663-4973 Contact’s Email address: laura.baloun@mckesson.com Statement of Commitment: Attached, please find a signed statement of commitment. The statement certifies that the DMF is current and that McKesson will comply with the statements made in it. Agent’s Name: Accenture, LLP Agent’s Address: 1160 West Swedesford Road Berwyn, PA 19312 Agent’s Contact Person: Jann A. Kochel Contact’s Address 1160 West Swedesford Road Berwyn, PA 19312 Contact’s Phone: 610-407-1738 Contact’s Fax: 610-407-8433 Contact’s E-mail address: jann.a.kochel@accenture.com FDA_1651 DMF #027320; Sequence 0011 Shared System REMS 3. 1.4 References Page 1 of 1 List of Authorized Persons to Incorporate by Reference (Annual Report - Reporting Period: August 21, 2013 – August 20, 2014) The following is a complete list of persons authorized to incorporate information in the DMF by reference: x x x x x x x x Cephalon, Inc. – August 28, 2013 Depomed, Inc. – August 28, 2013 Galena BioPharma, Inc. – August 28, 2013 Insys Therapeutics, Inc. – August 28, 2013 Mallinckrodt – August 28, 2013 Meda Pharmaceuticals, Inc. – August 28, 2013 Mylan – August 28, 2013 Par Pharmaceutical, Inc. – August 28, 2013 Please note that the list is unchanged since the original submission. FDA_1652 DMF #027320; Sequence 0011 Shared System REMS Annual Report – August 20, 2014 Page 1 of 1 ANNUAL REPORT - SUMMARY OF CHANGES Reporting Period: August 21, 2013 – August 20, 2014 Date / Sequence Description September 04, 2013 / 0001 Response to Administrative Filing Issue September 09, 2013 / 0002 REMS Modification 1 September 12, 2013 / 0003 Assessment 1 at 6 Months September 16, 2013 / 0004 REMS Modification 2 - Draft September 18, 2013 / 0005 Assessment 2 at 12 Months September 23, 2013 / 0006 REMS Modification 2 – Final December 27, 2013 / 0007 Assessment 3 at 24 Months March 31, 2014 / 0008 Assessment Methodology – RADARS System Report May 20, 2014 / 0009 REMS Modification 3 – Draft May 30, 2014 / 0010 Response to FDA Request for Information, dated May 16, 2014 For further details regarding the above amendments, please see the REMS History (Sequence 0010). FDA_1653 Accenture LLP 1160 West Swedesford Road Berwyn, PA 19312 December 26, 2014 Food and Drug Administration Center for Drug Evaluation and Research Central Document Room Drug Master File Staff 5901-B Ammendale Road Beltsville, MD 20705?1266 Re: DMF 027320 Holder: McKesson Specialty Health (McKesson) DMF Subject: Transmucosal Immediate Release Fentanyl (TIRF) Access Program Re: REMS Shared Program DMF Type: DMF Submission Information: Clinical/Clinical Information REMS Submission Identi?er: Assessment Sequence Number: 0014 Dear Drug Master File Staff: This Type DMF contains the Risk Evaluation and Mitigation Strategy (REMS) for Transmucosal Immediate Release Fentanyl for the Shared System REMS program. Included in this submission, please ?nd the REMS Assessment 4 at 3 years. McKesson states that information provided in this Master File is current and assures that the material furnished will meet the speci?cations described herein. McKesson also con?rms that the Holder obligations are observed. We request that all information in this ?le be treated as confidential commercial information to the Food and Drug Administration pursuant to 21 C.F.R. ?20.6l, and that no information from this file be provided to any unauthorized persons without written consent. Ifyou have any questions or concerns, please do not hesitate to contact Jann Kochel, US. Agent for McKesson, at 610?407- ]738 or alternatively via email atjann.a.kochel@accenture.com. Sincerely, Ja A. Kochel, US. Agent ccenture, LLP Attachments: Table of Contents for the submission Electronic Submission Specifications 654 DMF #027320; Sequence 0014 Shared System REMS Table of Contents Page 1 of 1 Assessment – 3 Years Module Section Description 1.2 Cover Letter Cover Letter w/ Attachments Administrative Information Page 1.16 – Risk Management Plans REMS History REMS Assessment – 3 Years FDA_1655 Electronic Submission Specifications This submission is compliant with FDA's Guideline for Industry: Providing Regulatory Submissions in Electronic Format - Human Pharmaceutical Product Applications and Related Submissions Using the eCTD Specifications (June 2008). All files were checked and verified to be free of viruses prior to transmission through the electronic submission gateway. This eCTD has been generated by Accenture, LLP (formerly Octagon Research Solutions Inc.), who has filed an acceptable eCTD pilot with the Center (Pilot Number 900777). Anti-Virus Program Program Version Virus Definition Date Submission Size Symantec Endpoint Protection Edition 11.0.5002.333 12/22/2014 rev. 1 Approx. 6 MB The IT point of contact for this submission is: Name Phone Number Email Address Matt Francis 1-610-407-1854 Matthew.p.francis@accenture.com FDA_1656 ADMINISTRATIVE INFORMATION Holder’s Name: McKesson Specialty Health Holder’s Address: 4343 N. Scottsdale Road Suite 150 Scottsdale, AZ 85251 Holder’s Contact Person: Laura Baloun Contact’s Address: 4343 N. Scottsdale Road Suite 150 Scottsdale, AZ 85251 Contact’s Phone: 480-663-4009 Contact’s Fax: 480-663-4973 Contact’s Email address: laura.baloun@mckesson.com Statement of Commitment: Attached, please find a signed statement of commitment. The statement certifies that the DMF is current and that McKesson will comply with the statements made in it. Agent’s Name: Accenture, LLP Agent’s Address: 1160 West Swedesford Road Berwyn, PA 19312 Agent’s Contact Person: Jann A. Kochel Contact’s Address 1160 West Swedesford Road Berwyn, PA 19312 Contact’s Phone: 610-407-1738 Contact’s Fax: 610-407-8433 Contact’s E-mail address: jann.a.kochel@accenture.com FDA_1657 DMF #027320; Sequence 0014 Shared System REMS Modification Date Approved Documents Affected No. 1 June 5, 2012 x REMS x Prescriber Program Overview x Education Program x Prescriber Enrollment Form x Patient Provider Agreement Form x Patient and Caregiver Overview x Dear Healthcare Provider Letter x Outpatient Pharmacy Overview x Chain Pharmacy Overview x Inpatient Pharmacy Overview x Outpatient Pharmacy Enrollment Form x Chain Pharmacy Enrollment Form x Inpatient Pharmacy Enrollment form x Outpatient Pharmacy Letter x Inpatient Pharmacy Letter x Dear Distributor Letter x Distributor Enrollment Form x Supporting Document N/A N/A Assessment Report 1 at 6 months – due 06/28/2012 REMS History Page 1 of 7 Overview of Modification Sequence 0002: Edits to Patient-Prescriber Agreement Form, the addition of the Closed System Pharmacy Enrollment Form*, the addition of the newly approved TIRF product, Subsys (fentanyl sublingual spray) and minor editorial changes. *The Closed System Pharmacy Enrollment Form was not formally submitted through the Gateway but was submitted via email on May 18, 2012 and included in the June 5, 2012 FDA approval letter. Sequence 0003: Assessment report covering 12/28/2011 to 04/27/2012 FDA_1658 DMF #027320; Sequence 0014 Shared System REMS Modification Date Approved Documents Affected No. 2 November 7, Draft Documents submitted on or before 2013 09/28/2012 x Chain Pharmacy Enrollment Form x Outpatient Pharmacy Enrollment Form x Closed System Pharmacy Overview x Education Program x Frequently Asked Questions (FAQ) x Outpatient Pharmacy Letter x REMS x Supporting Document N/A N/A Assessment Report 2 at 1 year – due 12/28/2012 2 November 7, Amendment to 2013 09/28/2012 supplement: x Chain Outpatient Pharmacy Enrollment Form x Independent Outpatient Pharmacy Enrollment Form x Closed System Outpatient Pharmacy Enrollment Form x Inpatient Pharmacy Enrollment Form x Distributor Enrollment Form x Prescriber Enrollment Form REMS History Page 2 of 7 Overview of Modification Sequence 0004: Modification proposed to: x Incorporate closed system pharmacies into the TIRF REMS Access Program x Correct minor inconsistencies between the FDA provided versions and the current PDF versions of REMS materials Sequence 0005: Assessment report covering 04/28/2012 to 10/28/2012 Sequence 0006: Modification proposed to: x Revised terminology, processes, and definitions for outpatient pharmacies x Revised attestations for physicians and patients to address concerns regarding patient access x Revised Program Overview and Frequently Asked Questions to improve clarity and content x Updated REMS materials to reflect the completion of the transition phase for the FDA_1659 DMF #027320; Sequence 0014 Shared System REMS Modification Date Approved Documents Affected No. x Patient Provider Agreement Form x Chain Outpatient Pharmacy Overview x Independent Outpatient Pharmacy Overview x Closed System Outpatient Pharmacy Overview x Inpatient Pharmacy Overview x Patient and Caregiver Overview x Prescriber Overview x Education Program x Knowledge Assessment x Frequently Asked Questions (FAQ) x Dear Outpatient Pharmacy Letter x Dear Inpatient Pharmacy Letter x Dear Healthcare Provide Letter x Dear Distributor Letter x REMS x Supporting Document x Website Landing Page N/A N/A Assessment Report 3 at 2 years – due 12/28/2013 REMS History Page 3 of 7 Overview of Modification TIRF REMS Access Program Sequence 0007: Assessment report covering 10/29/2012 to 10/28/2013 FDA_1660 DMF #027320; Sequence 0014 Shared System REMS REMS History Page 4 of 7 Modification Date Approved Documents Affected No. N/A N/A Safety Surveillance Report #1 – due 03/31/2014 3 Approval Pending x x x x x x x x x x x x x x x REMS Prescriber Program Overview Education Program Prescriber Enrollment Form Patient and Caregiver Overview Independent Outpatient Pharmacy Overview Chain Outpatient Pharmacy Overview Closed System Outpatient Pharmacy Overview Inpatient Pharmacy Overview Independent Outpatient Pharmacy Enrollment Form Chain Outpatient Pharmacy Enrollment Form Closed System Outpatient Pharmacy Enrollment Form Inpatient Pharmacy Enrollment form Distributor Enrollment Form FAQ Overview of Modification Sequence 0008: Safety surveillance data covering Q4 2012 to Q3 2013 Sequence 0009: Modification proposed to: x Updated REMS materials to eliminate product specific information which does not impact the safe use of TIRF products x Updated REMS materials to reference the currently approved TIRF products list on the FDA Approved REMS website x Updated REMS materials to remove reference to deactivating patients shown to have multiple prescribers in an overlapping timeframe x Incorporated revised assessment metrics into the Supporting Document x Revised Education Program to emphasize and strengthen appropriate conversion and patient counseling information x Updated REMS and Supporting Document to clarify deactivation of a patient PPAF as opposed to the patient record x Updated pharmacy overview documents and FDA_1661 DMF #027320; Sequence 0014 Shared System REMS REMS History Page 5 of 7 Modification Date Approved Documents Affected No. x Supporting Document x Website Prototype N/A N/A N/A N/A 3 Approval Pending Cash Claim Information Request Response – due 05/30/2014 DMF Annual Report – due 08/20/2014 x REMS x Prescriber Program Overview x Education Program x Knowledge Assessment x Prescriber Enrollment Form x Patient and Caregiver Overview x Independent Outpatient Pharmacy Overview x Chain Outpatient Pharmacy Overview x Closed System Outpatient Pharmacy Overview x Inpatient Pharmacy Overview x Independent Outpatient Pharmacy Overview of Modification x FAQ to call out cash claim requirement x Updated TIRF REMS Access website to incorporate items above and link respective Full Prescribing Information and Medication Guides to DailyMed Sequence 0010: Response to 5/16/2014 FDA Cash Claim Information Request Sequence 0011: DMF Annual Report Sequence 0012: Modification proposed to: x Updated REMS materials to eliminate product specific information which does not impact the safe use of TIRF products x Updated REMS materials to reference the TIRF Products webpage on the TIRF REMS Access website x Updated REMS materials to remove reference to deactivating patients shown to have multiple prescribers in an overlapping timeframe x Incorporated revised assessment metrics into the Supporting Document x Revised Education Program to emphasize and strengthen FDA_1662 DMF #027320; Sequence 0014 Shared System REMS REMS History Page 6 of 7 Modification Date Approved Documents Affected No. Enrollment Form x Chain Outpatient Pharmacy Enrollment Form x Closed System Outpatient Pharmacy Enrollment Form x Inpatient Pharmacy Enrollment form x Distributor Enrollment Form x FAQ x Supporting Document x Website Prototype 3 Approval Pending Unchanged from Sequence 0012, plus: x Dear Healthcare Provider Letter x Dear Outpatient Pharmacy Letter x Dear Inpatient Pharmacy Letter x Dear Distributor Letter Overview of Modification appropriate conversion and patient counseling information x Updated REMS and Supporting Document to clarify deactivation of a patient PPAF as opposed to the patient record x Updated pharmacy overview documents and FAQ to call out cash claim requirement x Updated TIRF REMS Access website to incorporate items above and link respective Full Prescribing Information and Medication Guides to DailyMed x Updated Education Program and Knowledge Assessment to incorporate approved labeling supplement Sequence 0013: Unchanged from Sequence 0012, plus: x Dear Healthcare Provider Letter x Dear Outpatient Pharmacy Letter x Dear Inpatient Pharmacy Letter x Dear Distributor Letter FDA_1663 DMF #027320; Sequence 0014 Shared System REMS Modification Date Approved Documents Affected No. N/A N/A Assessment Report 4 at 3 years – due 12/28/2014 REMS History Page 7 of 7 Overview of Modification Sequence 0014: Assessment report covering 10/29/2013 to 10/28/2014 FDA_1664 Title: Transmucosal Immediate-Release Fentanyl (TIRF) Risk Evaluation and Mitigation Strategy (REMS) Access Program 36-month Assessment Report Reporting Timeframe: 29 OCT 2013 to 28 OCT 2014 Document Number: Final V1.0 Product Name: Transmucosal Immediate-Release Fentanyl Sponsor: TIRF REMS Industry Group (TRIG) of Companies: Cephalon, Inc. (a wholly-owned subsidiary of Teva Pharmaceutical Industries, Ltd.) Depomed, Inc. Galena Biopharma, Inc. Insys Therapeutics Inc. Mallinckrodt Pharmaceuticals Meda Pharmaceuticals, Inc. Mylan, Inc. Par Pharmaceutical, Inc. Confidentiality Statement The information contained herein is confidential and the proprietary property of the TRIG of Companies and its affiliates, and any unauthorized use or disclosure of such information without the prior written authorization of the TRIG is expressly prohibited. FDA_1665 TABLE OF CONTENTS Pg LIST OF TABLES ................................................................................................................... 5 LIST OF ABBREVIATIONS ................................................................................................. 7 EXECUTIVE SUMMARY ..................................................................................................... 9 1 BACKGROUND ........................................................................................................ 15 2 REMS GOALS ........................................................................................................... 16 3 SUPPORTING INFORMATION ON PROPOSED REMS ELEMENTS ........... 16 3.1 Additional Elements ................................................................................................ 17 3.1.1 Medication Guide ............................................................................................ 17 3.1.2 Letters to Healthcare Professionals .................................................................. 17 3.2 Elements To Assure Safe Use ................................................................................. 17 3.2.1 3.3 Prescription Verification .................................................................................. 18 Implementation System........................................................................................... 19 3.3.1 Wholesaler/Distribution Enrollment and Fulfillment ...................................... 20 3.3.2 The TIRF REMS Access Program Compliance [Metric 22] ........................... 20 3.3.3 TIRF REMS Access Program Call Center ...................................................... 20 4 REMS ASSESSMENT PLAN METHODS ............................................................. 20 4.1 Data Sources for REMS Assessments .................................................................... 21 4.1.1 The TIRF REMS Access Program and Product Utilization Statistics ............. 21 4.1.2 Dispensing Activity for Enrolled Pharmacies.................................................. 22 4.1.3 Program Infrastructure and Performance ......................................................... 22 4.1.4 TIRF REMS Access Program Non-Compliance Plan ..................................... 23 4.1.4.1 Non-Compliance Monitoring ....................................................................... 24 4.1.4.2 Corrective Action Measures ........................................................................ 25 4.1.5 Safety Surveillance .......................................................................................... 27 4.1.6 Periodic Surveys of Patients, Prescribers, and Pharmacies ............................. 28 5 RESULTS ................................................................................................................... 29 5.1 REMS Program Utilization ..................................................................................... 29 5.1.1 Patient Enrollment [Metric 1 and 2] ................................................................ 29 5.1.2 Prescriber Enrollment and Inactivations [Metric 3, 4, 5]................................. 29 FDA_1666 5.1.3 Pharmacy Enrollment, Inactivation, and Education [Metric 6, 7, 8] ............... 33 5.1.4 Wholesaler/Distributor Enrollment [Metric 9 and 10]..................................... 39 5.1.5 Dispensing Activity [Metric 11, 12, 13,] ......................................................... 40 5.1.6 Barriers or Delays in Patient Access [Metric 14 and 15]................................. 49 5.2 Program Infrastructure and Performance [Metrics 16, 17, 18, 19] ......................... 54 5.2.1 Backup System for Prescription Validation [Metric 16] ................................. 54 5.2.2 System Interruptions/Errors and Corrective Actions [Metric 17, 19] ............. 54 5.2.3 REMS Call Center [Metric 18] ........................................................................ 57 6 TIRF REMS ACCESS PROGRAM NON-COMPLIANCE.................................. 58 6.1 Audits ...................................................................................................................... 58 6.1.1 Closed System Pharmacy Audits [Metric 20].................................................. 58 6.2 Inpatient Hospital Pharmacy Audits [Metric 21] .................................................... 64 6.3 Stakeholder Non-Compliance [Metric 23, 24, 25, 26, 27, 28] ................................ 64 7 SAFETY SURVEILLANCE ..................................................................................... 93 7.1 Adverse Event Reporting [Metric 29] ..................................................................... 93 7.2 TRIG Sponsor Adverse Event Data of Interest [Metric 30] ................................... 93 7.3 Number of Adverse Events of Special Interest ....................................................... 93 7.4 TIRF Product Surveillance Data [Metric 31] ........................................................ 121 7.4.1 Background .................................................................................................... 121 7.4.2 Poison Center Program .................................................................................. 122 7.4.3 Treatment Center (TC) Program .................................................................... 122 7.4.4 College Survey Program ................................................................................ 123 7.4.5 Impaired Healthcare Workers Program ......................................................... 123 7.4.6 Results ............................................................................................................ 123 7.4.7 Population Rates ............................................................................................ 123 7.4.8 Prescription Rates .......................................................................................... 124 7.4.9 Pediatric Exposures........................................................................................ 125 7.4.10 Comparison of Cases from Reporting Period 1 to Reporting Period 2 ......... 126 8 PERIODIC SURVEYS OF STAKEHOLDERS ................................................... 127 8.1 Key Risk Messages .............................................................................................. 127 8.2 Patient KAB Survey ............................................................................................ 128 FDA_1667 8.2.1 Background and Survey Statistics ................................................................. 128 8.2.2 Patient Survey Results ................................................................................... 128 8.3 Pharmacy KAB Survey ...................................................................................... 129 8.3.1 Background and Survey Statistics ................................................................. 129 8.3.2 Pharmacy Survey Results .............................................................................. 129 8.4 Prescriber KAB Survey ...................................................................................... 130 8.4.1 Background and Survey Statistics ................................................................. 130 8.4.2 Prescriber Survey Results .............................................................................. 130 8.5 Overall Conclusion for KAB Results: ............................................................... 131 9 FDA COMMUNICATIONS ................................................................................... 131 10 POST-APPROVAL STUDIES AND CLINICAL TRIALS ................................. 132 11 OVERALL CONCLUSIONS ................................................................................. 132 12 APPENDICES .......................................................................................................... 135 12.1 Safety Surveillance Aggregate Line Listing Preferred Terms .............................. 136 12.2 RADARS® System Program Report ..................................................................... 136 12.3 RADARS® System Program Report Protocol ...................................................... 136 12.4 Periodic Stakeholder Surveys ............................................................................... 136 12.4.1 Patient KAB Survey....................................................................................... 137 12.4.2 Pharmacy KAB Survey .................................................................................. 138 12.4.3 Prescriber KAB Survey ................................................................................. 139 FDA_1668 LIST OF TABLES Table 1 TIRF Medicines ............................................................................................................15 Table 2 Assessment Report Periods ...........................................................................................16 Table 3 Non-Compliance Activity Monitoring ..........................................................................24 Table 4 Corrective Action Guideline .........................................................................................26 Table 5 Patient Enrollment.........................................................................................................29 Table 6 Prescriber Enrollment....................................................................................................30 Table 7 Prescriber Inactivations .................................................................................................30 Table 8 Prescribers Pending Enrollment ....................................................................................32 Table 9 Pharmacy Enrollment ....................................................................................................33 Table 10 Pharmacy Inactivations .................................................................................................35 Table 11 Pharmacies Pending Enrollment ..................................................................................38 Table 12 Distributor Enrollment ..................................................................................................39 Table 13 Distributor Inactivations................................................................................................39 Table 14 Prescriptions from Outpatient Pharmacies That Did Not Encounter Any REMSRelated Rejections Prior to Being Authorized for Dispensing .....................................41 Table 15 Prescriptions from Outpatient Pharmacies That Encountered at Least One REMSRelated Rejection Prior to Being Authorized for Dispensing .......................................43 Table 16 Time to Authorization for a Prescription that Experienced at Least One Initial REMS-Related Rejection ..............................................................................................47 Table 17 Number of Prescription Authorizations per Closed System Pharmacy ........................48 Table 18 Prescriptions Dispensed During the First 10 Days after Passive Patient Enrollment ...51 Table 19 Prescriptions Dispensed Beyond the First 10 Days after Passive Patient Enrollment Without a PPAF ............................................................................................................53 Table 20 Current Assessment Period Contact Reasons ...............................................................57 Table 21 Non-Compliance Activity Reports by Stakeholder in the Current Reporting Period: 29 October 2013 to 28 October 2014 ............................................................................65 Table 22 Non-Compliance Reports in the Current Reporting Period: 29 October 2013 to 28 October 2014 .................................................................................................................67 Table 23 Number of Cases of Adverse Events of Special Interest ..............................................94 Table 24 Rate of Adverse Events by Total Prescriptions and Total Patients...............................94 Table 25 Cases of Addiction Received from TRIG Sponsors during the Reporting Period: 29 October 2013 - 28 August 2014 ....................................................................................95 FDA_1669 Table 26 Cases of Overdose Received from TRIG Sponsors during the Reporting Period: 29 October 2013 - 28 August 2014 ....................................................................................97 Table 27 Cases of Death Received from TRIG Sponsors during the Reporting Period: 29 October 2013 - 28 August 2014 ..................................................................................100 Table 28 Cases of Pediatric Exposures Received from TRIG Sponsors during the Reporting Period: 29 October 2013 - 28 August 2014 ................................................................120 Table 29 RADARS® System: Data Sources and Specific Events.............................................121 Table 30 RADARS® System Poison Center Program: Reported Exposures by Age Group and Period ...................................................................................................................126 Table 31 Comparison of TIRF Exposure Data from First RADARS Report to the Incremental Data In the Current Reporting Period: Reports of Abuse by Source of Data .............................................................................................................................126 Table 32 Comparison of Poison Center Program Data from First RADARS Report to the Incremental Data in the Current Reporting Period .....................................................127 FDA_1670 LIST OF ABBREVIATIONS AAPCC American Association of Poison Control Center ANDA Abbreviated New Drug Application BTP Breakthrough Pain CS College Survey CAP Corrective Action Plan CSR Call Center Service Representative DoD Department of Defense ETASU Elements to Assure Safe Use FDA Food and Drug Administration HCP ID IR KAB MedDRA Healthcare Provider Identification Immediate Release Knowledge, Attitude, and Behavior Medical Dictionary for Drug Regulatory Activities NC Non-Compliant NCPDP NCRT NDA NDC NPI OTP PMS PPAF PT RADARS® National Council for Prescription Drug Program Non-Compliance Review Team New Drug Application National Drug Code National Provider Identifier Opioid Treatment Program Pharmacy Management System Patient-Prescriber Agreement Form Preferred Terms Researched Abuse, Diversion and Addiction-Related Surveillance Root Cause Analysis Risk Evaluation and Mitigation Strategy Checks conducted by the TIRF REMS Access program to confirm that all safety requirements were met RCA REMS REMS edits FDA_1671 SKIP SOP TC Survey of Key Informants’ Patients Standard Operating Procedure Treatment Center TIRF Transmucosal Immediate-Release Fentanyl TIRF Medicines Transmucosal Immediate-Release Fentanyl product(s) TIRF REMS Access REMS program for TIRF medicines TIRF Sponsors The group of sponsors that are submitting this REMS TRIG TIRF REMS Industry Group UBC United BioSource Corporation US VA United States Veteran’s Association FDA_1672 EXECUTIVE SUMMARY The Transmucosal Immediate-Release Fentanyl (TIRF) Risk Evaluation and Mitigation Strategy (REMS) Access Program was approved by the Food and Drug Administration (FDA) on 28 December 2011 for ABSTRAL®, ACTIQ®, FENTORA®, LAZANDA®, ONSOLIS®, SUBSYS® and generic versions of these TIRF medicines. The TIRF REMS Access Program was successfully launched on 12 March 2012, approximately 11 weeks after REMS approval. The shared system REMS includes a Medication Guide; Elements to Assure Safe Use (ETASU) of prescriber and pharmacy certification, and dispensing to outpatients with evidence of safe use conditions; an Implementation System, and a Timetable for Submission of Assessments. The initial 6-month REMS Assessment Report was submitted on 28 June 2012, the 12-month assessment was submitted on 29 December 2012 and the 24-month assessment was submitted on 29 December 2013. This fourth REMS Assessment Report (36 months) covers the timeframe 29 October 2013 to 28 October 2014. As per agreement with FDA, safety surveillance analyses necessitated slightly different time periods as noted in the relevant sections within the report. As of 12 March 2014 the TIRF REMS Access Program has been fully implemented for 2 years. A major focus during this reporting period was re-enrollment of all stakeholders in the program. As part of re-enrollment, stakeholders were re-educated in order to ensure understanding about the safe use and risks of TIRF medicines. For prescribers and pharmacists this included completing a review of the educational materials and successfully completing the Knowledge Assessment and Enrollment Form. Patient-Prescriber Agreement Forms (PPAFs) also expire every 2 years. This requires prescribers to re-counsel their patients about safe use and risks. Both attest to their understanding of the safe use and risks by signing a new PPAF. Extensive efforts are made using multiple modalities to reach all stakeholders whose enrollment status or PPAF is nearing expiration. Re-enrollment activities continue ensuring appropriate access to TIRF medicines. Prescriber Enrollment At the end of this reporting period, a total of 12,749 prescribers are enrolled in the TIRF REMS Access Program. A total 2,027 were newly enrolled prescribers. During the reporting period, a total of 4,731 prescribers were inactivated, with 4,658 (98.5%) due to expiration of their enrollment at some time during the reporting period. A total of 3,089 prescribers successfully re-enrolled during the reporting period. A few prescribers were inactivated because they opted out of the program or were deceased. During this reporting period, a total of 71 prescribers attempted enrollment but were still pending 3 to 6 months after initiating the enrollment process and a total of 265 prescribers were pending enrollment for longer than 6 months since initiating the enrollment process. The most common reasons for pending enrollment were: no attestation, training not complete, and knowledge assessment failure on the first attempt. Pharmacy Enrollment FDA_1673 At the end of this reporting period, a total of 37,775 pharmacies are enrolled in the TIRF REMS Access Program. A total of 1,585 pharmacies were newly enrolled in the TIRF REMS Access Program. Of the 1,585 newly enrolled pharmacies, 788 were chain pharmacy stores, 588 were independent outpatient pharmacies, 182 were inpatient pharmacies, and 23 were closed system pharmacy locations. During the reporting period, a total of 5,040 pharmacies were inactivated, with 4,802 due to expiration of their enrollment at some time during the period. A total of 50 pharmacies attempted enrollment but were still pending 3 to 6 months after initiating the enrollment process and a total of 229 pharmacies were pending enrollment for longer than 6 months since initiating the enrollment process. The most common reasons for pending enrollment were pending test transaction verification, no attestation and training not complete. Distributors Enrollment During the reporting period 1 newly enrolled distributor and 21 distributors that re-enrolled in this reporting period. There were 10 distributors inactivated during the reporting period due to expiration of enrollment; 2 of these distributors had re-enrolled by the end of the reporting period. Patients During the current reporting period, 9,744 patients had an enrolled status in the TIRF REMS Access Program. Because patients are passively enrolled with their first prescription, they are not required to re-enroll at any point. Instead, prescribers must renew a patient’s PPAF every 2 years. By the design of the program, a patient enrollment status will never change to inactivated. Dispensing Activity A total of 159,560 prescriptions were presented for dispensing in the current reporting period including 158,612 prescriptions from non-closed system pharmacies and 948 prescriptions from closed system pharmacies. Of the total prescriptions presented for dispensing, 90.9% were approved for dispensing without encountering any REMS-related rejections. Of the total 159,560 prescriptions presented for dispensing, 3,738 prescriptions encountered at least one REMS-related rejection due to failure to meet REMS requirements for the prescriber and/or patient and/or pharmacy prior to being authorized for dispensing. The remaining 10,738 prescriptions presented for dispensing encountered at least one REMS-related rejection and were never authorized for dispensing. A single prescription may have been submitted and rejected multiple times. The average time for an initially rejected prescription to become authorized was 4.9 days. The number of prescriptions dispensed outside the established PPAF requirements was nearly eliminated as a result of the corrective actions implemented in the previous reporting period. As reported in the 24-month assessment report the TIRF REMS Access Program finalized the required system enhancements on 15 July 2013 to modify the patient matching in order to prevent patients from receiving more than 3 prescriptions without a PPAF and patients from receiving more than 3 prescriptions within the first 10 days without a PPAF. FDA_1674 Non-Compliance and Audits During the current reporting period, 145 instances of stakeholder non-compliance with the TIRF REMS Access program were reviewed and investigated. This included 120 prescriber reports, 1 wholesaler/distributor report, 17 non-closed system pharmacy reports and 7 closed system pharmacy reports. Five of these closed system pharmacy non-compliance reports were identified during the audits of the 7 enrolled closed system pharmacy entities. Each affected entity was issued a notice through the Non-Compliance Review Team (NCRT) and as a result all investigations have been closed. Details of these cases and actions taken are included in Section 6.1.1 and description of these audits is included in Section 6.1.1. Audits of 7 closed system pharmacy entities were conducted during this reporting period. Five closed system entities were found to be non-compliant with the TIRF REMS Access Program requirements. These pharmacies were re-educated and issued a notice through the NCRT. All cases have been closed. As per the TRIG’s agreement with FDA, inpatient pharmacy hospital audits have not yet been conducted. The TRIG is developing a process to accomplish inpatient pharmacy audits. Therefore, inpatient pharmacy audit data will be included in the 48-month assessment report. Safety Surveillance Data In previous assessment reports, safety surveillance data for TIRF products were presented as an FDA AERS analysis and an analysis of American Association of Poison Control Center (AAPCC) data. Based on FDA feedback, safety surveillance data for this 36-month assessment report and future assessment reports consist of data from the Researched Abuse, Diversion and Addiction-Related Surveillance (RADARS®) System and aggregate adverse event data from all TRIG sponsors. Spontaneous adverse event data including events of addiction, overdose, death and pediatric exposures, were provided by each sponsor and aggregated into one comprehensive line listing. Comparisons of trends within and between these data sources since the introduction of the TIRF REMS Access Program were not possible for this report, given the change in reporting sources for the events of interest. Future REMS Assessment Reports will evaluate trends across reporting periods. RADARS® System Data The initial RADARS® System Report, submitted to FDA in March 2014, included data from 3rd quarter 2012 through 3rd quarter 2013. The RADARS® System Report included within this 36month assessment report includes data from 3rd quarter 2012 through 2nd quarter 2014, an additional 3 quarters of data. (b) (4) FDA_1675 Aggregate Spontaneous Adverse Event Data A total of 367 unique case reports were identi?ed as meeting the criteria for inclusion in the analysis based on case preferred terms and review of the case narrative information. Of the 367 cases, the highest proportion of reports had an outcome of death, and many reports had no cause of death provided. There were 4 reports of addiction, and 2 pediatric exposures. There were no reported overdoses to an identi?ed TIRF product. (Of note, 23 overdose cases from law enforcement are included indicating exposures to purportedly non-pharmaceutical fentanyl.) From the root cause analysis, no reports of inappropriate conversions between TIRF products were identi?ed. Additionally, none of the narratives indicated accidental, unintentional exposures, or non-opioid tolerance. Additional details are included in Section 7.2. Knowledge, Attitudes, and Behavior (KABZ Surveys TRIG determined that a desired threshold of 65% or greater would be considered to represent adequate understanding of each concept or key risk message. The same criterion was applied to the 36-month KAB surveys. The purpose of establishing this threshold was to assist TRIG in tracking and monitoring the level of understanding of key risk messages across each wave to determine if the goals of the REMS are being met and if any modi?cation to the REMS is required. Patient Survey Results 676 In this 36-month survey, all but one of the questions included as part of the key risk messages had a correct response rate of >69%. There was only one question within a key risk message that had a component with an understanding rate below the threshold of 65% which identified the need to stop taking a TIRF medicine if the around-the-clock opioid pain medicine is discontinued. This concept also scored low for prescribers (61.0%) for this reporting period. One question about the safe use of TIRF medicines, not included as a key risk message, had a component regarding use of a TIRF medicine to treat long-lasting painful conditions not caused by cancer had an understanding rate of 25.3%. This concept also scored low for pharmacists (43.7%). These components were the only components scoring consistently low across all three waves of the patient/caregiver KAB survey. The consistently high level of patient understanding of key risk messages in the 24-month and 36-month surveys indicates that the patient education materials is meeting the goals of the TIRF REMS. Pharmacist Survey Results In the pharmacist survey all but one of the questions/components included as part of the key risk messages had a correct response rate of >70%. There was only one question within a key risk message regarding TIRF medicines labeled indications that had a component with an understanding rate below the threshold of 65%, concerning chronic non-cancer pain. This component also had a low correct response rate in the previous survey waves. It should be noted that pharmacist knowledge of uses for which TIRF medicines are not indicated is not a goal of the TIRF REMS. This concept also scored low for patients/caregivers in this reporting period. In addition, there were two questions/components addressing the safe use of TIRF medicines that had a component with an understanding rate below 65%: a cancer patient should not be started on a TIRF medicine and an around-the-clock opioid at the same time (63.3%), and that patients are considered opioid-tolerant if taking an equianalgesic dose of another oral opioid one week or longer. These concepts also scored low for prescribers during this reporting period. The consistently high level of pharmacist understanding of key risk messages in the 24-month and 36-month surveys indicates that the Education Program for Prescribers and Pharmacists is meeting the goals of the TIRF REMS. Changes will be implemented into the 48-month Pharmacist KAB survey based on FDA feedback received on the 24-month assessment report. Prescriber Survey Results In the prescriber survey, of the 21 components of the 4 key risk messages, only 1 component had a response rate less than the threshold of 65%. This component concerned the behavior of prescribing TIRF medicines to opioid tolerant patients with chronic non-cancer pain. The response from prescribers regarding the correct response that TIRF medicines are not prescribed for non-cancer pain has been consistently low for all 3 surveys. While included as part of a key risk message based on FDA request, this question gauges prescriber behavior rather than knowledge. Based on FDA feedback an additional question will be added to the 48-month survey asking prescribers why they feel this is an appropriate use of a TIRF medicine. In addition, there were four questions about the safe use of TIRF medicines that had a component with an understanding rate below the threshold of 65%. Knowledge that a cancer FDA_1677 patient should not be started on a TIRF medicine and an around-the-clock opioid at the same time was 63.3%. This concept also scored low for pharmacists during this reporting period. The desired response of “false” to the behavior question of instructing patients that, if they stop taking their around -the-clock opioid medicine, they can continue to take their TIRF medicine was selected by 61.0% of prescribers. This concept also scored low in the patient/caregiver KAB survey for this reporting period. Similarly, knowledge that patients should not continue to take their TIRF medicine if they stop taking their around-the-clock opioid medicine had a correct response rate of 59.7%. Again, this concept scored low in the patients/caregiver KAB survey. Knowledge that patients are considered opioid-tolerant if taking an equianalgesic dose of another oral opioid one week or longer was selected by 59.0%. For this reporting period, pharmacists also had a similar response for this concept (59.0%). The consistently high level of prescriber understanding of key risk messages in the 24-month and 36-month surveys indicates that the Education Program for Prescribers and Pharmacists is meeting the goals of the TIRF REMS. Changes will be implemented into the 48-month Prescriber KAB survey based on FDA feedback already received from the 24-month TIRF REMS assessment report. Based on the data provided in this report the TRIG concludes that the REMS is meeting its established goals. The improvement in knowledge demonstrated by pharmacists and prescribers and the continued high level of awareness of most key risk messages by patients provides evidence that the current tools are effectively communicating the important safety messages to key stakeholders. Based on our analysis of the data for this 36-month assessment, the TRIG is recommending no REMS modifications at this time. FDA_1678 1 BACKGROUND Opioids remain the mainstay of treatment of moderate to severe pain, but their safe use requires careful consideration of proper patient selection and treatment characteristics in order to mitigate any inherent health risks. Opioids are formulated as both extended-release and immediate-release products. Extendedrelease or long acting opioid products are designed to provide extended analgesic activity to control persistent pain. TIRF medicines and short-acting opioid products have a rapid onset and short duration of action and are designed for the treatment of acute episodes of pain that ‘break through’ the chronic pain control (breakthrough pain, (BTP). All the TIRF medicines are short-acting fentanyl products. As with all high-potency opioid analgesics, there are significant potential risks associated with the use and misuse of TIRF medicines, including acute respiratory depression which may lead to death. With appropriate clinical use in opioid-tolerant patients these risks have been shown to be low. However, instances of diversion, overdose and prescribing to opioid-non-tolerant patients have led to serious and, on occasion, fatal, adverse events demonstrating that shortacting fentanyl products can pose a health risk if not used appropriately. The FDA has determined that a REMS is required to mitigate the risk of misuse, abuse, addiction, overdose, and serious complications due to medication errors with the use of TIRF medicines. The group of Sponsors that are submitting this 36-month REMS include (Cephalon, Inc. [a wholly-owned subsidiary of Teva Pharmaceutical Industries, Ltd.], Depomed, Inc., Galena Biopharma, Inc., Insys Therapeutics Inc., Mallinckrodt Pharmaceuticals, Meda Pharmaceuticals, Mylan, Inc. and Par Pharmaceutical, Inc.) are hereafter referred to as the TIRF Sponsors. The TIRF REMS Access Program is administered by McKesson Specialty Health and RelayHealth. This report is prepared by United BioSource Corporation (UBC). The TIRF medicines that are the subject of this TIRF REMS are shown in Table 1 below. Table 1 TIRF Medicines Product Name (active ingredient)/formulation NDA 022510, ABSTRAL (fentanyl) sublingual tablets NDA 020747, ACTIQ (fentanyl citrate) oral transmucosal lozenge and its authorized generic NDA 021947, FENTORA (fentanyl buccal tablet) NDA 022569, LAZANDA (fentanyl) nasal spray NDA 022266, ONSOLIS (fentanyl), buccal soluble film NDA 202788, SUBSYS (fentanyl sublingual spray) ANDA 077312, fentanyl citrate oral transmucosal lozenge ANDA 078907, fentanyl citrate oral transmucosal lozenge FDA_1679 The TIRF REMS Access Program addresses the current requirements set forth by the FDA and provided to TIRF Sponsors. The program will be monitored over time and modified when and where appropriate. The initial REMS was approved on 28 December 2011 and went live on 12 March 2012. The FDA required an initial report 6 months and 12 months after REMS approval and annually thereafter (Table 2). Reporting periods for each assessment report are described below. To allow for enough time to prepare the report for FDA submission, data cut-off is 60 days prior to the submission date. Table 2 Assessment Report Periods Assessment Report Reporting Period Submission Date 6-Month 28 December 2011 - 27 April 2012 28 June 2012 12-Month 28 April 2012 - 28 October 2012 28 December 2012 24-Month 29 October 2012 - 28 October 2013 28 December 2013 36-Month 29 October 2013 – 28 October 2014 28 December 2014 2 REMS GOALS The goals of the TIRF REMS Access Program are to mitigate the risks of misuse, abuse, addiction, overdose and serious complications due to medication errors by: 1. Prescribing and dispensing TIRF medicines only to appropriate patients, which includes use only in opioid-tolerant patients. 2. Preventing inappropriate conversion between TIRF medicines. 3. Preventing accidental exposure to children and others for whom it was not prescribed. 4. Educating prescribers, pharmacists, and patients on the potential for misuse, abuse, addiction, and overdose of TIRF medicines. 3 SUPPORTING INFORMATION ON PROPOSED REMS ELEMENTS The TIRF Sponsors are executing the TIRF REMS Access Program to ensure the appropriate use of TIRF medicines and proper patient selection. All stakeholders subject to the TIRF REMS Access Program including patients, prescribers, pharmacies and distributors must be enrolled in the TIRF REMS Access Program, educated on the requirements of the program and required to document that they understand and will abide by the ETASU. Program materials are provided on the TIRF medicines in addition to product-specific materials. The Education Program and Knowledge Assessment components of the program contain both TIRF medicine class and product-specific components. All program tools, including enrollment FDA_1680 forms, PPAFs, stakeholder letters, and overview documents containing program information specific to the TIRF REMS Access Program, are available through www.TIRFREMSACCESS.com. The program procedures are monitored for adherence and the TIRF Sponsors will continue to conduct ongoing and retrospective analyses as necessary to comply with all mandates and to maximize the safe use of the TIRF medicines. 3.1 Additional Elements 3.1.1 Medication Guide The product-specific TIRF Medication Guide should be dispensed with each TIRF medicine prescription. Every TIRF medicine has a unique Medication Guide. 3.1.2 Letters to Healthcare Professionals A Communication Plan for the TIRF REMS was not required. However, TIRF Sponsors sent materials to targeted stakeholders to support implementation of the TIRF REMS Access Program at the time of program launch. These communications included Dear Healthcare Provider (HCP) and Dear Pharmacy letters, and informed prescribers and authorized pharmacists on the risks associated with the use of TIRF medicines, the procedures and requirements of the TIRF REMS Access Program and means of reporting adverse events. 3.2 Elements To Assure Safe Use Because of the significant potential health risks associated with prescribing TIRF medicines to opioid non-tolerant patients, it is important that prescribers are aware of the procedures for appropriate patient selection and appropriate dosing and titration. This is achieved by each prescriber’s enrollment through a review of the TIRF REMS Access Education Program including the TIRF medicine’s Full Prescribing Information, successful completion of the Knowledge Assessment, and completion of the enrollment form. TIRF medicines are only available through the TIRF REMS Access Program to reduce the risks of inappropriate patient selection and ensure appropriate dosing and administration of TIRF medicines. To ensure that TIRF medicines are only dispensed to appropriate patients, pharmacies that dispense TIRF medicines must be enrolled into the TIRF REMS Access Program. There are different enrollment requirements for outpatient pharmacies (e.g., retail, mail order, institutional outpatient pharmacies that dispense for outpatient use) and inpatient pharmacies (e.g., hospitals that dispense for inpatient use only). For Long-Term Care and Hospice patients whose prescriptions were obtained through an outpatient pharmacy setting, the pharmacy, patient, and prescriber must be enrolled in the TIRF REMS Access Program. Outpatient pharmacy enrollment requires an authorized pharmacist at the pharmacy to review the TIRF REMS Access Education Program, successfully complete the Knowledge Assessment and submit a completed and signed TIRF REMS Access Program enrollment form. The authorized pharmacist ensures that their Pharmacy Management System (PMS) is able to support communication with the TIRF REMS Access Program using established telecommunication standards. This requires submitting standardized validation test transactions FDA_1681 to validate the system enhancements. The authorized pharmacist is also responsible for educating all pharmacy staff, who participate in dispensing TIRF medicines, on the risks associated with TIRF medicines and the requirements of the TIRF REMS Access Program. For chain pharmacies, an authorized chain pharmacy representative completes the enrollment process on behalf of all individual store locations associated with that chain. The authorized chain pharmacy representative acknowledges that training has been provided to all pharmacy staff involved in the dispensing of TIRF medicines. Once the TIRF REMS Access Education Program and Knowledge Assessment have been completed, the authorized chain pharmacy representative, on behalf of the chain, is required to acknowledge their understanding of the appropriate use of TIRF medicines and agree to adhere to the TIRF REMS Access Program requirements by submitting a completed and signed enrollment form. For inpatient pharmacy enrollment, the authorized pharmacist is required to review the TIRF REMS Access Education Program, successfully complete the Knowledge Assessment, and submit a completed and signed enrollment form on behalf of the pharmacy. The authorized inpatient pharmacist is required to acknowledge that they understand that outpatient pharmacies within their facility must be enrolled separately. Implementation of the TIRF REMS Access Program for closed system outpatient pharmacies launched on 30 June 2012. Closed system outpatient pharmacies are integrated healthcare systems that dispense for outpatient use but their pharmacy management systems are unable to support the process of electronically transmitting the validation and claim information. To enroll in the TIRF REMS Access Program, the authorized pharmacist must review the TIRF REMS Access Education Program, successfully complete the Knowledge Assessment, and submit a completed and signed enrollment form on behalf of the pharmacy. A list of closed system pharmacies that have been trained must be provided to the TIRF REMS Access Program. Patients are passively enrolled in the TIRF REMS Access Program when their first prescription is processed by a pharmacy. A completed PPAF should be sent to the TIRF REMS Access Program by the prescriber within 10 working days from the processing date of the patient’s first prescription for a TIRF medicine. A maximum of 3 prescriptions are allowed within 10 working days from the date that the patient had their first prescription filled. No further prescriptions are to be dispensed after the 10 working day window until a completed PPAF is received. A patient’s HCP can submit a copy of the PPAF to the TIRF REMS Access Program via the Web site, fax, or United States (US) mail. 3.2.1 Prescription Verification Following initial patient enrollment upon processing of a patient’s first TIRF medicine prescription, pharmacies verify for all subsequent prescriptions that both the prescriber and patient are enrolled in the TIRF REMS Access Program and that all REMS requirements are met prior to dispensing. Prescription verification is not required for inpatient use of TIRF medicines. Specific reasons why a prescription would not meet a REMS edit are described in Table 16. FDA_1682 Non-Closed System Pharmacies Prescription verification occurs through a model that uses a pharmacy billing claim and engages a switch provider in the validation process. Upon receipt of a prescription for a TIRF medicine at an enrolled pharmacy, the prescription details are entered into their PMS and a transaction is sent to the TIRF REMS Access Program via a switch provider. If the patient is not enrolled and this is their first prescription, the TIRF REMS Access Program uses the transaction data to automatically transfer patient details into the TIRF REMS Access database for passive enrollment. For all subsequent prescriptions, the REMS database is then interrogated, via the switch provider, to validate the REMS edits (i.e., confirm that all TIRF REMS Access Program requirements are met). In the case where a prescription passes all REMS edits, a billing request is then sent to the payer by the switch provider. Once the payer authorizes payment, the switch provider then authorizes the pharmacy to dispense the TIRF medicine as with a normal prescription, returning an authorization number which is captured by the TIRF REMS Access Program. If the prescription does not pass all REMS edits (e.g., one of the stakeholders was not enrolled), the TIRF REMS Access Program rejects the claim prior to the claim being forwarded to the payer and the pharmacy receives a rejection notice from the switch provider. This automated feedback indicates the reason for rejection, instructs the pharmacist not to dispense the TIRF medicine, and notifies the pharmacist to contact the TIRF REMS Access Program Call Center for further information. Closed System Outpatient Pharmacies Upon receipt of a prescription for a TIRF medicine at an enrolled closed system outpatient pharmacy, a pharmacy staff member will contact the TIRF REMS Access Program via phone or fax to provide prescription details for verification. The TIRF REMS Access Program then validates the enrollment status for the patient, prescriber and pharmacy. If the patient is not enrolled, the TIRF REMS Access Program will use this transaction information to automatically transfer patient details into the TIRF REMS Access database for passive enrollment. If all three stakeholders are enrolled (i.e., passes all REMS edits), the closed system outpatient pharmacy is given an authorization number which is captured by the TIRF REMS Access Program. If the prescription does not pass all REMS edits (e.g., one of the stakeholders is not enrolled), the TIRF REMS Access Program will not provide an authorization number and the closed system outpatient pharmacy will receive a rejection notice. This feedback will be provided to the closed system outpatient pharmacy via phone or fax and will include the reason for rejection, information on how the rejection may be resolved and instructions to not dispense the TIRF prescription until resolution is reached. 3.3 Implementation System The Implementation System and its components are described in the following sections. FDA_1683 3.3.1 Wholesaler/Distribution Enrollment and Fulfillment Wholesalers/distributors who distribute TIRF medicines must be enrolled in the TIRF REMS Access Program before they are allowed to distribute TIRF medicines. For the purpose of the TIRF REMS Access Program, the term distributor refers to wholesaler, distributor, and/or chain pharmacy distributor. TIRF medicine distributors received a Dear Distributor Letter describing the TIRF REMS Access Program and the requirements to purchase TIRF medicines from TIRF Sponsors and sell TIRF medicines to pharmacies upon FDA approval of the program. To enroll, the distributor’s authorized representative must review the distributor program materials, complete and sign the Distributor Enrollment Form and fax it to the TIRF REMS Access Program. TIRF Sponsors have processes in place to prevent shipping TIRF medicines to any distributor who has not completed and signed the enrollment form. 3.3.2 The TIRF REMS Access Program Compliance [Metric 22] The TIRF REMS Access Program NCRT was created by the TRIG on 19 October 2012 and is tasked with reviewing reports of suspected non-compliance with the TIRF REMS Access Program requirements. The NCRT is composed of membership from all TRIG sponsors. There are currently 25 individuals across the 8 sponsors; the functional areas or specialties represented by the members include Regulatory, Medical Affairs, REMS Specialist, Legal, Quality and Drug Safety. TIRF Sponsors monitor prescriber, pharmacy, and wholesaler/distributor activities for compliance with TIRF REMS Access Program requirements. Corrective actions (e.g., reeducation, additional monitoring, process revision, stakeholder inactivation) are instituted by the TIRF Sponsors as appropriate if non-compliance is confirmed. The Non-Compliance Plan is described in Section 4.1.4 (Metric 22) and results of non-compliance investigations are included in Section 6 of this report. 3.3.3 TIRF REMS Access Program Call Center The TIRF REMS Access Program includes a Call Center component. The Call Center is staffed by qualified and trained specialists, who provide TIRF REMS Access Program support to patients, prescribers, pharmacies, and distributors. 4 REMS ASSESSMENT PLAN METHODS The aim of the TIRF REMS Access Program’s evaluation is to assess the effectiveness of the mitigation strategies in meeting the goals of the TIRF REMS Access Program to ensure safe use, proper prescribing, and appropriate distribution of TIRF medicines. Findings from these evaluations are used to identify ways to improve the processes, as needed. Based on communications between TRIG and the FDA, a revised assessment plan was provided by FDA within the 24-Month Assessment Report Acknowledgement Letter. Due to timing of the revised assessment plan the following metrics are not included in this assessment report, but will be reported in the 48-Month Assessment Report: FDA_1684 Metric Number* Metric 21. Report the results of yearly audits of at least 5 randomly selected inpatient hospital pharmacies to assess the performance of the system(s) developed to assure REMS compliance starting in the 48Month Assessment Report. Provide the number of units of use of TIRFs ordered per inpatient hospital pharmacy audited per 12 month period. These reports are to include: • Verification of training for all pharmacists dispensing TIRF products • Verification that processes such as order sets/protocols are in place to assure compliance with the REMS program • Describe any corrective actions taken for any non-compliance items identified above during the audit, as well as preventative measures that were developed as a result of uncovering these non-compliance events *As indicated in the Revised Assessment Plan within the 24-Month REMS Assessment Acknowledgement Letter and the revised Supporting Document submitted 10 December 2014. 4.1 Data Sources for REMS Assessments Data were collected from the following main sources as described in detail below: a) TIRF REMS Access Program utilization statistics (Section 4.1.1), b) dispensing activity for enrolled pharmacies (Section 4.1.2), c) program infrastructure and performance, d) TIRF REMS Access non-compliance plan, e) safety surveillance, f) periodic surveys of patients, HCPs, and pharmacies. All programmed source tables and figures, as well as source data are on file at UBC and available upon request. The individual metrics for each main data source are provided below with a direct link to the results sections of the report. 4.1.1 The TIRF REMS Access Program and Product Utilization Statistics For the assessment of enrollment, utilization, and discontinuation statistics for prescribers, pharmacies, patients, and distributors, the following metrics were tabulated for the current reporting period and cumulatively. Metric Number* Metric a. Patient Enrollment 1. Number of unique patients enrolled 2. Number of patients inactivated b. Prescriber Enrollment 3. Number of prescribers enrolled 4. Number of prescribers that attempted enrollment but whose enrollment is pending for >3 months and >6 months along with the specific reasons why their enrollment is pending 5. Number of prescribers inactivated c. Pharmacy Enrollment FDA_1685 Metric Number* Metric 6 Number of pharmacies enrolled by type (inpatient, chain, independent, closed system; provide identity of closed system entities) 7. Number of pharmacies that attempted enrollment but whose enrollment is pending >3 months and >6 months along with the specific reasons why their enrollment is pending (stratified by type) 8. Number of pharmacies inactivated by type (inpatient, chain, independent, closed system) d. Distributor Enrollment 9. Number of distributors enrolled 10. Number of distributors inactivated *As indicated in the Revised Assessment Plan within the 24-Month REMS Assessment Acknowledgement Letter from FDA and the revised REMS Supporting Document submitted 10 December 2014. 4.1.2 Dispensing Activity for Enrolled Pharmacies For the assessment of dispensing activity the following metrics were tabulated and stratified by pharmacy type for the current reporting period and cumulatively. Metric Number* Metric 11. Number of prescriptions/transactions authorized; for closed systems, provide the number of prescription/transactions per closed system entity 12. Number of prescriptions/transactions denied/rejected and the reasons for denial/rejection. Include the number of prescriptions/transactions rejected for safety issues (provide description of safety issues and any interventions or corrective actions taken) 13. The mean and median amount of time it takes for a prescription that experienced at least one initial REMS-related rejection to be authorized 14. Number of patients with more than three prescriptions dispensed during the first ten days after patient passive enrollment without a PPAF 15. Number of prescriptions dispensed after ten days without a PPAF in place *As indicated in the Revised Assessment Plan within the 24-Month REMS Assessment Acknowledgement Letter from FDA and the revised REMS Supporting Document submitted 10 December 2014. 4.1.3 Program Infrastructure and Performance The following metrics on program infrastructure performance were collected and summarized for the current reporting period. Metric Number* Metric 16. Number of times a backup system was used to validate a prescription, with reason(s) for each instance (for example, pharmacy level problem, switch problem, or REMS database problem) FDA_1686 Metric Number* Metric clearly defined and described 17. Number of times unintended system interruptions occurred for each reporting period. Describe the number of stakeholders affected, how the issue was resolved, and steps put into place to minimize the impact of future interruptions 18. Call center report with • Overall number of contacts 19. • Summary of frequently asked questions • Summary of REMS-related problems reported Description of corrective actions taken to address program/system problems *As indicated in the Revised Assessment Plan within the 24-Month REMS Assessment Acknowledgement Letter from FDA and the revised REMS Supporting Document submitted 10 December 2014. 4.1.4 TIRF REMS Access Program Non-Compliance Plan The TIRF sponsors provide the following data regarding non-compliance in each assessment report (per reporting period). Metric Number* Metric 20. Report the results of yearly audits of at least 3 randomly selected closed pharmacy systems to assess the performance of the system(s) developed to assure REMS compliance. These reports are to include: • Verification of training for all pharmacists dispensing TIRF products 22. 23. • Numbers of prescription authorizations per closed system • Reconciliation of data describing TIRF product prescriptions received by the closed system pharmacy with TIRF product dispensed to patients with a valid enrollment in the TIRF REMS Access program. Data to include the 12 month period preceding the audit date. Include details on how the reconciliation is conducted (e.g., electronic versus manual process). • Describe any corrective actions taken for any non-compliance identified during the audit and corrective actions taken to address non-compliance Description of number, specialties, and affiliations of the personnel that constitute the NonCompliance Review Team (NCRT) as well as: • Description of how the NCRT defines a non-compliance event • Description of how non-compliance information is collected and tracked • Criteria and processes the Team uses to make decisions • Summary of decisions the Team has made during the reporting period • How the Team determines when the compliance plan should be modified Describe each non-compliance event and the corrective action measure taken, as well as the FDA_1687 Metric Number* Metric outcome of the corrective action 24. Number of TIRF prescriptions dispensed that were written by non-enrolled prescribers and include steps taken to prevent future occurrences 25. Number of prescriptions dispensed by non-enrolled pharmacies and include steps taken to prevent future occurrences 26. Number of times a TIRF prescription was dispensed because a pharmacy (closed or open system) was able to bypass REMS edits and if any such events occurred, describe how these events were identified 27. Number of times a TIRF was prescribed to an opioid non-tolerant individual. Include what was done to minimize such instances; if any such events occurred, describe how these events were identified 28. Number of instances of inappropriate conversions between TIRF products, as well as any outcome of such an event. If any such events occurred, describe how these events were identified *As indicated in the Revised Assessment Plan within the 24-Month REMS Assessment Acknowledgement Letter and the revised Supporting Document submitted 10 December 2014. 4.1.4.1 Non-Compliance Monitoring The TIRF REMS Access Program is in place to ensure the safe and appropriate use of TIRF medications. The goal of the Non-Compliance Plan is to help TRIG identify and investigate deviations from and non-compliance (NC) with TIRF REMS requirements in order to ensure patient safety and continuously improve the program. A confirmed NC event is one for which the information collected through investigation of the potential NC event clearly indicates that a program deviation has occurred and/or evidence of the program goals not being met through stakeholder actions is identified. The TIRF REMS Access Program routinely monitors stakeholder activity to identify potential incidents of NC events with program requirements. The TIRF REMS Access Program investigates all reports of suspected NC. Routine monitoring of stakeholder activity includes, but is not limited to, the types identified in Table 3. Non-compliance information is collected through standard program reports, spontaneous reports identified via the program’s Call Center, vendor/sponsor reported events, outreach to relevant stakeholders to validate data/information and solicit further information, and investigation of the TIRF REMS Access database. The data are tracked through a NC case that is opened on the stakeholder record in the TIRF REMS Access database. Table 3 indicates each defined NC activity and the method of monitoring. Table 3 Non-Compliance Activity Monitoring Stakeholder Scenario # Pharmacy 1 Non-Compliance Activity Submission of a claim that did not go through the REMS edits. A TIRF medicine was FDA_1688 dispensed without verifying through the TIRF pharmacy management system that the prescriber is enrolled and active, and that the patient is enrolled or has not been inactivated in the program. 2 Dispensing activity for enrolled outpatient pharmacies during reporting period not matching distributor shipment data for that pharmacy. 3 Pharmacy is dispensing TIRF medicine while suspended or deactivated from the TIRF REMS Access program. 4 [Placeholder for additional scenario if needed] 5 Authorized Inpatient Pharmacy does not comply with the requirements of the TIRF REMS Access program. 6 Inpatient Pharmacy dispenses for outpatient use 7 Submission of inappropriately altered claim to meet TIRF REMS system requirements (e.g. changing prescriber) Closed System Pharmacy 1 Dispensing prescriptions outside of the closed system authorization process. Wholesaler/ Distributor 1 Wholesaler/Distributor is suspended or deactivated from the TIRF REMS Access program and is purchasing or distributing TIRF medicines. 2 Wholesaler/Distributor fills an order for TIRF medicines for a non-enrolled stakeholder. 1 Prescriber is prescribing TIRF medicines while suspended or deactivated from the TIRF REMS Access program. 2 Prescriber failure to have a complete PPAF on file in a timely manner (5 or more patients enrolled by the prescriber without a complete PPAF on file, with each patient having greater than 10 working days lapse from initial enrollment date). Patient 1 The Patient receives prescriptions for TIRF medicines from multiple prescribers within an overlapping time frame that is suggestive of misuse, abuse, or addiction All Stakeholders 1 ENROLLMENT MONITORING ONLY: Monitor stakeholders who are not enrolled in TIRF and are associated with non-compliance cases. Prescriber If a NC event is confirmed, additional investigation is conducted to determine the scope, impact, and root cause of the event. Stakeholders are notified of the investigation via a formal letter from the TIRF REMS Access Program (see section 4.1.4.2. below) and may also be requested to develop a Corrective Action Plan (CAP). All CAPs are reviewed and approved by the NCRT. The NCRT will determine if the NC Protocol should be modified as the program evolves. Any changes to the plan proposed by the NCRT will be voted upon by the TRIG. 4.1.4.2 Corrective Action Measures Decisions are made through the NCRT based on the severity of the action as well as the information collected during the investigation. Stakeholders that fail to comply with one or more elements of the TIRF REMS Access Program will be subject to corrective action. FDA_1689 Appropriate corrective actions are determined by the TIRF REMS Access Program according to the severity of the event as defined below: • Minor - An unintended (e.g., first-time) event. The corrective action typically involves a written notice to the stakeholder and re-education of the program requirements to prevent re-occurrences of the event. • Moderate – Multiple occurrences of the same event or a series of distinct, unintended events. • Serious - Continued events after retraining has occurred. This level of offense may result in a suspension from the program and possible deactivation. Affected stakeholders are provided written notification of all confirmed NC events. Corrective actions for confirmed events may include a Notice, Warning, Suspension, or Deactivation letter (See Table 4). If deemed necessary, temporary suspension of a prescriber, pharmacist or distributor from the TIRF REMS Access Program may be warranted, prohibiting them from prescribing, dispensing or distributing TIRF medicines for a certain period of time. The most severe consequence of a NC event is deactivation, resulting in the stakeholder not being able to receive/prescribe/dispense/distribute TIRF medicines and is applicable to all stakeholders including patients. Formal notifications of non-compliance are sent by the TIRF REMS Access Program to the applicable prescriber, pharmacy, and/or distributor whereas notices for patient non-compliance events are sent to their prescriber. Copies of notices sent to an individual chain outpatient pharmacy store or closed system pharmacy store are also sent to the chain outpatient or closed system pharmacy’s headquarters. Table 4 Event Classification Notices Corrective Action Guideline Description • • • • Patient notices will be sent to a patient's prescriber Minor violations that demonstrate a misunderstanding of the program requirements Notices are intended to re-educate stakeholders 2 Notices in 60 days = Review by Non-Compliance Review Team to determine if escalation to Warning is warranted • 2 Warnings in 60 days = Review by Non-Compliance Review Team to determine if escalation to Suspension is warranted >1 Warning in >60 days = Case-by-Case review for Suspension Warnings • FDA_1690 Event Classification Description • • • Suspension • • • • Deactivation • • • Temporary suspension from the program A suspended pharmacy or distributor may keep existing TIRF inventory but may not purchase or acquire additional TIRF medicines Pharmacies may not dispense TIRF medicines from existing inventory and distributors may not sell/distribute TIRF medicines during suspension If the pharmacy or distributor is part of a larger entity that entity will be notified of the suspension 1 Warning or 2 Notices while Suspended = Review by Non-Compliance Review Team to determine if escalation to Deactivation is warranted 2 Suspensions Within a 12-Month Period = Review by Non-Compliance Review Team to determine if a Deactivation is warranted Deactivation may result from multiple failures to comply with the program elements and/or a non-compliance event for which there is no feasible corrective action Bars stakeholder from providing TIRF medicines for their patients Pharmacies and distributors must return all existing TIRF medicine Patient deactivation will be sent to a patient's prescriber. Patients may only be reinstated into the program by a request from their prescriber 4.1.5 Safety Surveillance The following safety surveillance data were collected. Reporting periods for each type of data were modified based on timing of availability of data. Metric Number* Metric 29. TIRF Sponsors will process adverse event reports related to their specific products and report to the FDA according to current regulations outlined in 21 CFR 314.80 and the sponsor’s respective Standard Operating Procedures 30. TIRF Sponsors will produce one comprehensive report that presents spontaneous adverse event data from all sponsors of the TIRF REMS Access program, as well as data from other databases (characteristics of which are described below). This report will focus on four categories of adverse events of interest: addiction, overdose, death, and pediatric exposures. This report should include the following: • Line listings under each category of adverse events of interest as listed above • Line listings should provide at a minimum the following information: o Identifying case number o Age and Gender of the patient o Date of the event as well as of the report o The Preferred Terms o Indication of TIRF use o Duration of TIRF therapy FDA_1691 Metric Number* Metric • 31. o Concomitant medications o Event Outcome Other metrics of interest include: o Number of event reports in each event category of interest o Counts of adverse events related to inappropriate conversions between TIRF products o Counts of adverse events related to accidental and unintentional exposures o Counts of adverse events that are associated with use of TIRF medicines in nonopioid tolerant patients • Duplicate cases are identified and eliminated • Case reports with adverse events in multiple categories will be listed in each category of interest, and will be noted as such • For each adverse event category, an overall summary analysis of the cases will be provided addressing the root cause(s) of the events • Rate of each adverse event of interest will be calculated using two distinct denominators: the number of prescriptions for TIRF products and the number of patients receiving a TIRF product throughout the reporting interval. Trends and changes in the rates of these events will be compared year-to-year Surveillance data focusing on events of addiction, overdose, death, and pediatric cases should also be drawn from the databases that are listed below. Conclusions regarding these data should be included in and inform the overall conclusions in the summary report referred to in Metric 30 directly above: • Non-medical use of prescription drugs • Surveys conducted at substance abuse treatment programs • College surveys • Poison control center data • Impaired health care workers • Drug-related hospital emergency department visits • Drug-related deaths • Other databases as relevant *As indicated in the Revised Assessment Plan within the 24-Month REMS Assessment Acknowledgement Letter and the revised Supporting Document submitted 10 December 2014. 4.1.6 Periodic Surveys of Patients, Prescribers, and Pharmacies Prescribers’, pharmacists’, and patients’ understanding regarding the appropriate use of TIRF medicines and TIRF REMS Access Program requirements are evaluated through KAB surveys. The surveys are administered to selected prescribers, pharmacies, and patients. FDA_1692 5 RESULTS 5.1 REMS Program Utilization Described in this section are the total numbers of all enrolled stakeholders (prescribers, patients, pharmacies, and distributors), as well as stakeholder inactivations, dispensing activities, and barriers or delays in patient access. 5.1.1 Patient Enrollment [Metric 1 and 2] During the current reporting period, there were 9,744 newly enrolled patients (Table 5). Because patients are passively enrolled with their first prescription there is no patient reenrollment, but prescribers are required to renew PPAFs with patients every 2 years. By the design of the program, a patient enrollment status will never change to inactivated. Table 5 Patient Enrollment Parameter Total Number of Enrolled Patients Current Reporting Period 29OCT2013 to 28OCT2014 Number of Newly Enrolled Patients N (%) Cumulativea,b 28DEC2011 to 28OCT2014 Total Number of Enrolled Patients N (%) 9,744a 29,222b,c a An enrolled patient is a patient who has received at least one prescription for a TIRF prescription. b Includes patients that transitioned into the TIRF REMS Access Program from other individual REMS programs. c Cumulative patients from the end of prior period may differ from last period’s report due to reconciliation of duplicate patients. 5.1.2 Prescriber Enrollment and Inactivations [Metric 3, 4, 5] Cumulatively there have been 12,749 prescribers who have successfully completed enrollment in the program. At the end of this reporting period there are 7,992 prescribers who are currently enrolled. This includes 2,027 newly enrolled prescribers, 3,089 prescribers who re-enrolled and 2,876 who remain active from a previous period (Table 6). Table 7 shows those prescribers who have been inactivated. FDA_1693 Table 6 Prescriber Enrollment Current Reporting Perioda 29OCT2013 to 28OCT2014 N (%) Parameter Number of Prescribers with Enrollment Activity In This Reporting Period Number of Newly Enrolled Prescribers Number of Re-Enrolled Prescribers 5,116 2,027 (39.6%) 3,089 (60.4%) Number of Prescribers Who Remain Enrolled from Previous Reporting Periods 2,876 Total Number of Prescribers Enrolled as of the End of This Reporting Period 7,992 Cumulative Number of Prescribers Ever Enrolledb,c 12,749 a Percentages are based on the total number (N) of enrolled prescribers b Cumulative is defined as sum of all reporting periods. c Number includes prescribers who transitioned into the TIRF REMS Access Program A total of 4,731 prescribers were inactivated at some point during the current reporting period, and the majority of these (4,658; 98.5%) were due to expiration of enrollment. It should be noted that a prescriber is required to enroll every 2 years within the TIRF REMS Access Program. Of those 4,658 prescribers whose enrollment expired at some point during the current reporting period, 3,390 (72.8%) of these prescribers’ statuses remained expired at the end of the reporting period (Table 7). In total, there were 4,760 prescribers who remained inactivated at the end of the reporting period. Table 7 Prescriber Inactivations Parameter Number of Prescribers Who Became Inactivated During this Reporting Period Reason(s) For Inactivationb Deceased Program Opt-Out Non Compliantc Current Reporting Perioda 29OCT2013 to 28OCT2014 N (%) 4,731 2 (<0.1%) 61 (1.3%) 4 (0.1%) FDA_1694 Parameter Suspended Enrollment Expiredd Enrollment remained expired at end of period Current Reporting Perioda 29OCT2013 to 28OCT2014 N (%) 7 (0.1%) 4,658 (98.5%) 3,390 (72.8%) Number of Prescribers Inactivated in This Time Period who Remain Inactivated as of the End of this Reporting Period 3,452 Number of Prescribers Who Were Inactivated in a Previous Reporting Period and Remain Inactive as of the End of This Reporting Period 1,308 Total Number of Prescribers Inactivated as of the End of this Reporting Period 4,760 Cumulative Number of Prescribers Who Have Ever Been Inactivatede 6,635 a Prescribers whose status is ’inactive’ at least once during the reporting period. b Percentages are based on the total number (N) of inactivated prescribers. A prescriber may have more than one reason for inactivation. c Prescribers may be included as both “non-compliant” and “suspended” since before becoming inactivated for non-compliance, prescribers go through a suspension period. d Prescribers whose status is ‘Inactive-Expired’ at any time during the reporting period. e Cumulative is defined as sum of all reporting periods. During the current reporting period, there were 71 prescribers who attempted enrollment but whose enrollment was pending 3 to 6 months later. A total of 265 prescribers were pending enrollment for more than 6 months. Prescribers may have attempted enrollment and become pending in another reporting period. For prescribers pending enrollment for 3 to 6 months, the most frequent reasons were no attestation (81.7%), training not complete (63.4%), and knowledge assessment failure on the first attempt (16.9%). For prescribers pending enrollment for more than 6 months, the most frequent reasons were similar and included no attestation (74.3%), training not complete (72.8%), and knowledge assessment failure on the first attempt (10.2%). The number of prescribers that attempted enrollment but are still pending enrollment for 3 to 6 months or more than 6 months, and the reasons for pending enrollment are shown in Table 8. FDA_1695 Table 8 Prescribers Pending Enrollment Parameter Prescribers Who Attempted Enrollment but are Still Pending Enrollmentc Current Reporting Perioda 29OCT2013 to 28OCT2014 Prescribers Pending Prescribers Pending Enrollment Enrollment ≥3 – 6 Monthsb >6 Monthsb 71 265 Reasons for Pending Enrollment Assessment Failure - Sixth Attempt Invalid DEA Invalid NPI Knowledge Assessment Failure - Fifth Attempt Knowledge Assessment Failure - First Attempt Knowledge Assessment Failure - Third Attempt Missing Address – City Missing Address – State Missing Address – Street Missing Address – Zip Missing DEA Number Missing Email Missing Fax Number Missing NPI Number Missing Phone Number Missing Physician Signature Date Missing Preferred Method of Contact Missing Signature Missing Site Name Missing State License Number No Attestation Pending Enrollment Intake Provided DEA does not have Correct Schedule for this Drug Training Access Suspended Training Not Complete 1 (1.4%) 8 (11.3%) 1 (1.4%) 0 12 (16.9%) 2 (2.8%) 0 0 0 0 0 1 (1.4%) 0 4 (5.6%) 0 3 (4.2%) 0 3 (4.2%) 0 3 (4.2%) 58 (81.7%) 1 (1.4%) 5 (7%) 0 11 (4.2%) 12 (4.5%) 1 (0.4%) 27 (10.2%) 4 (1.5%) 3 (1.1%) 3 (1.1%) 3 (1.1%) 3 (1.1%) 6 (2.3%) 7 (2.6%) 2 (0.8%) 9 (3.4%) 3 (1.1%) 17 (6.4%) 2 (0.8%) 17 (6.4%) 3 (1.1%) 7 (2.6%) 197 (74.3%) 15 (5.7%) 18 (6.8%) 1 (1.4%) 45 (63.4%) 0 193 (72.8%) a Reflects the total number of prescribers pending enrollment in the current reporting period. Prescribers may have attempted enrollment and become pending in another reporting period. b Percentages are based on the total number (N) of prescribers attempting enrollment. Percentages may not add to 100% because a single prescriber may be pending enrollment for more than one reason c Prescribers may be pending enrollment for more than one reason. FDA_1696 5.1.3 Pharmacy Enrollment, Inactivation, and Education [Metric 6, 7, 8] There were a total of 16,102 pharmacies newly enrolled or re-enrolled in this reporting period. Of the 1,585 (9.8%) pharmacies that newly enrolled in the TIRF REMS Access Program, 788 were chain pharmacy stores (subset of 4 chain pharmacy headquarters), 588 were independent outpatient pharmacies, 182 were inpatient pharmacies, and 23 were closed system pharmacy locations. The 23 closed system pharmacies are represented by 7 closed system entities (See Section 5.1.5.). A total of 14,517 (90.2%) pharmacies re-enrolled; 11,138 were chain pharmacy stores (under 48 chain pharmacy headquarters), 2,638 were independent outpatient pharmacies, 472 were inpatient pharmacies, and 215 were closed system pharmacy locations (Table 9). Table 9 Pharmacy Enrollment Parameter Total Number of Pharmacies with Enrollment Activity in this Reporting Period Current Reporting Perioda,b 29OCT2013 to 28OCT2014 Non-Closed System Closed System Total Pharmacies Pharmacies Pharmacies N (%) N (%) N (%) 15,858 244 16,102 Total Number of Newly Enrolled Pharmacies Inpatient Pharmacies Chain Pharmacy Headquarters Chain Pharmacy Stores Independent Outpatient Pharmacies Closed System Headquarters Closed System Pharmacies 1,562 (9.8%) 23 (9.4%) 1,585 (9.8%) 182 (11.7%) N/A 182 (11.5%) Total Number of Re-Enrolled Pharmacies Inpatient Pharmacies Chain Pharmacy Headquarters Chain Pharmacy Stores Independent Outpatient Pharmacies Closed System Headquarters Closed System Pharmacies Number of Pharmacies that Remain Enrolled from a Previous Reporting Period 4 (0.3%) N/A 4 (0.3%) 788 (50.4%) N/A 788 (49.7%) 588 (37.6%) N/A 588 (37.1%) N/A 0 0 N/A 23 (100.0%) 23 (1.5%) 14,296 (90.2%) 221 (90.6%) 14,517 (90.2%) 472 (3.3%) N/A 472 (3.3%) 48 (0.3%) N/A 48 (0.3%) 11,138 (77.9%) N/A 11,138 (76.7%) 2,638 (18.5%) N/A 2,638 (18.2%) N/A 6 (2.7%) 6 (<0.1%) N/A 215 (97.3%) 215 (1.5%) 21,671 2 21,673 FDA_1697 Parameter Inpatient Pharmacies Chain Pharmacy Headquarters Chain Pharmacy Stores Independent Outpatient Pharmacies Closed System Headquarters Closed System Pharmacies Total Number of Pharmacies Enrolled as of the End of this Reporting Period Inpatient Pharmacies Chain Pharmacy Headquarters Chain Pharmacy Stores Independent Outpatient Pharmacies Closed System Headquarters Closed System Pharmacies Cumulative Number of Pharmacies Ever Enrolled Inpatient Pharmacies Chain Pharmacy Headquarters Chain Pharmacy Stores Independent Outpatient Pharmacies Closed System Headquarters Closed System Pharmacies Current Reporting Perioda,b 29OCT2013 to 28OCT2014 Non-Closed System Closed System Total Pharmacies Pharmacies Pharmacies N (%) N (%) N (%) 196 (0.9%) N/A 196 (0.9%) 26 (0.1%) N/A 26 (0.1%) 20,357 (93.9%) N/A 20,357 (93.9%) 1,092 (5.0%) N/A 1,092 (5.0%) N/A 1 (50.0%) 1 (<0.1%) N/A 1 (50.0%) 1 (<0.1%) 37,529 246 37,775 850 (2.3%) N/A 850 (2.3%) 78 (0.2%) N/A 78 (0.2%) 32,283 (86.0%) N/A 32,283 (85.5%) 4,318 (11.5%) N/A 4,318 (11.4%) N/A 7 (2.8%) 7 (<0.1%) N/A 239 (97.2%) 239 (0.6%) 41,303 358 41,661 1,083 (2.6%) N/A 1,083 (2.6%) 90 (0.2%) N/A 90 (0.2%) 34,477 (83.5%) N/A 34,477 (82.8%) 5,653 (13.7%) N/A 5,653 (13.6%) N/A 7 (2.0%) 7 (<0.1%) N/A 351 (98.0%) 351 (0.8%) a Percentages are based on the total number (N) of pharmacies with enrollment activity in this reporting period for the reporting period. b Pharmacies that are enrolled within this reporting period and were still enrolled at the end of the reporting period. c Cumulative number of pharmacies from the end of prior period may differ from last period's report due to reconciliation of duplicate records. As shown in Table 10, there were 5,040 total pharmacies inactivated at least once during the current reporting period including 4,873 non-closed system pharmacies and 167 closed system pharmacies. The non-closed system pharmacies included 2,928 (60.1%) chain pharmacy stores (subset of 18 chain pharmacy headquarters), 1,609 (33.0%) independent outpatient pharmacies, and 318 (6.5%) inpatient pharmacies. FDA_1698 The reason for most pharmacy inactivations was enrollment expired, which was 88.9% of the inactivated chain pharmacy headquarters and at least 93.3% among inactivated pharmacies in the remaining pharmacy categories. Table 10 Pharmacy Inactivations Parameter Current Reporting Perioda 29OCT2013 to 28OCT2014 Non-Closed Closed System System Total Pharmacies Pharmacies Pharmacies N (%) N (%) N (%) 4,873 167 5,040 318 (6.5%) 18 (0.4%) 2,928 (60.1%) 1,609 (33.0%) N/A N/A N/A N/A N/A 167 (100.0%) 318 (6.3%) 18 (0.4%) 2,928 (58.1%) 1,609 (31.9%) 167 (3.3%) Reason(s) for Inpatient Pharmacy Inactivationb Program Opt-Out Enrollment Expiredc Enrollment remained expired at end of period 6 (1.9%) 312 (98.1%) 215 (68.9%) N/A N/A N/A 6 (1.9%) 312 (98.1%) 215 (68.9%) Reason(s) for Chain Pharmacy Headquarters Inactivationd Program Opt-Out Enrollment Expiredc Enrollment remained expired at end of period 2 (11.1%) 16 (88.9%) 9 (56.3%) N/A N/A N/A 2 (11.1%) 16 (88.9%) 9 (56.3%) Number of Pharmacies that Became Inactivated During this Reporting Period Inpatient Pharmacies Chain Pharmacy Headquarters Chain Pharmacy Stores Independent Outpatient Pharmacies Closed System Pharmacies FDA_1699 Current Reporting Perioda 29OCT2013 to 28OCT2014 Non-Closed Closed System System Total Pharmacies Pharmacies Pharmacies N (%) N (%) N (%) Parameter Reason(s) for Chain Pharmacy Store Inactivationd Program Opt-Out Enrollment Expiredc Enrollment remained expired at end of period 195 (6.7%) 2,733 (93.3%) 1,470 (53.8%) N/A N/A N/A 195 (6.7%) 2,733 (93.3%) 1,470 (53.8%) Reason(s) for Independent Outpatient Pharmacy Inactivatione Program Opt-Out Enrollment Expiredc Enrollment remained expired at end of period 35 (2.2%) 1,574 (97.8%) 1,107 (70.3%) N/A N/A N/A 35 (2.2%) 1,574 (97.8%) 1,107 (70.3%) Reason(s) For Closed System Pharmacy Inactivationf Enrollment Expiredc Enrollment remained expired at end of period N/A N/A 167 (100.0%) 112 (67.1%) 167 (100.0%) 112 (67.1%) 3,021 112 3,133 220 (7.3%) 11 (0.4%) 1,649 (54.6%) 1,141 (37.8%) N/A N/A N/A N/A N/A 112 (100.0%) 220 (7.0%) 11 (0.4%) 1,649 (52.6%) 1,141 (36.4%) 112 (3.6%) 3,774 112 3,886 233 (6.2%) 12 (0.3%) 2,194 (58.1%) 1,335 (35.4%) N/A N/A N/A N/A N/A 112 (100.0%) 233 (6.0%) 12 (0.3%) 2,194 (56.5%) 1,335 (34.4%) 112 (2.9%) 7,371 167 7,538 341 (4.6%) N/A 341 (4.5%) Numbers of Pharmacies Inactivated in This Time Period that Remain Inactivated as of the End of this Reporting Period Inpatient Pharmacies Chain Pharmacy Headquarters Chain Pharmacy Stores Independent Outpatient Pharmacies Closed System Pharmacies Total Number of Pharmacies Inactivated as of the End of This Reporting Period Inpatient Pharmacies Chain Pharmacy Headquarters Chain Pharmacy Stores Independent Outpatient Pharmacies Closed System Pharmacies Cumulative Number of Pharmacies Ever Inactivatedg Inpatient Pharmacies FDA_1700 Parameter Chain Pharmacy Headquarters Chain Pharmacy Stores Independent Outpatient Pharmacies Closed System Pharmacies Current Reporting Perioda 29OCT2013 to 28OCT2014 Non-Closed Closed System System Total Pharmacies Pharmacies Pharmacies N (%) N (%) N (%) 20 (0.3%) N/A 20 (0.3%) 5,091 (69.1%) N/A 5,091 (67.5%) 1,919 (26.0%) N/A 1,919 (25.5%) N/A 167 (100.0%) 167 (2.2%) a Pharmacies with ’inactive’ status at least once during the reporting period. b Percentages are based on the total number (N) of inactivated inpatient pharmacies. An inpatient pharmacy may have more than one reason for inactivation. c Pharmacies whose status is ‘Inactive-Expired’ at any time during the enrollment period. d Percentages are based on the total number (N) of inactivated chain pharmacy headquarters or chain pharmacy stores. A chain pharmacy headquarters or chain pharmacy store may have more than one reason for inactivation. e Percentages are based on the total number (N) of inactivated independent outpatient pharmacy stores. An independent outpatient pharmacy store may have more than one reason for inactivation. f Percentages are based on the total number (N) of inactivated closed system pharmacies. A closed system pharmacy may have more than one reason for inactivation. g Cumulative is sum of all reporting period totals. During the current reporting period, there were 50 pharmacies that attempted enrollment but enrollment was pending 3 to 6 months later. As of the end of the reporting period, there were a total of 229 pharmacies pending enrollment for 6 months or longer. Pharmacies may have attempted enrollment and become pending in another reporting period. For pharmacies pending enrollment for 3 to 6 months, the most frequent reasons were pending test transaction verification (56.0%), no attestation (42.0%), and training not complete (36.0%). For pharmacies pending enrollment for 6 months or longer, the most frequent reasons were similar and included pending test transaction verification (52.4%), no attestation (45.4%), and training not complete (34.9%). The number of pharmacies that attempted enrollment but are still pending enrollment for 3 to 6 months or longer than 6 months, and the reasons for pending enrollment are shown in Table 11. FDA_1701 Table 11 Pharmacies Pending Enrollment Current Reporting Perioda 29OCT2013 to 28OCT2014 Pharmacies Pending Enrollment ≥3 - 6Monthsb Parameter Non-Closed System Pharmacies N (%) Pharmacies Pending Enrollment: >6 Monthsb Closed System Total Non-Closed System Closed System Total Pharmacies Pharmacies Pharmacies Pharmacies Pharmacies N (%) N (%) N (%) N (%) N (%) 50 0 50 229 0 229 Invalid DEA 0 0 0 4 (1.7%) 0 4 (1.7%) Invalid NCPDP 0 0 0 3 (1.3%) 0 3 (1.3%) Invalid NPI 0 0 0 2 (0.9%) 0 2 (0.9%) Knowledge Assessment Failure - First Attempt 1 (2.0%) 0 1 (2.0%) 7 (3.1%) 0 7 (3.1%) Knowledge Assessment Failure - Third Attempt 0 0 0 2 (0.9%) 0 2 (0.9%) Missing Address – City 0 0 0 1 (0.4%) 0 1 (0.4%) Missing Address – State 0 0 0 1 (0.4%) 0 1 (0.4%) Missing Address – Street 0 0 0 1 (0.4%) 0 1 (0.4%) Missing Pharmacist Signature Date 0 0 0 3 (1.3%) 0 3 (1.3%) Missing Signature 0 0 0 3 (1.3%) 0 3 (1.3%) 21 (42.0%) 0 21 (42.0%) 104 (45.4%) 0 104 (45.4%) 3 (6.0%) 0 3 (6.0%) 1 (0.4%) 0 1 (0.4%) Pending Test Transaction Verification 28 (56.0%) 0 28 (56.0%) 120 (52.4%) 0 120 (52.4%) Training Not Complete 18 (36.0%) 0 18 (36.0%) 80 (34.9%) 0 80 (34.9%) Pharmacies that Attempted Enrollment but are Still Pending Enrollmentc Reasons for Pending Enrollment No Attestation Pending Enrollment Intake a Reflects the total number of pharmacies pending enrollment in the current reporting period. Pharmacies may have attempted enrollment and became pending in another reporting period. b Percentages are based on the total number (N) of pharmacies attempting enrollment. Percentages may not add up to 100% because a single pharmacy may be pending enrollment for more than one reason. c Pharmacies may be pending enrollment for more than one reason. FDA_1702 5.1.4 Wholesaler/Distributor Enrollment [Metric 9 and 10] During the current reporting period, 1 (4.5%) wholesaler/distributor newly enrolled in the REMS program and 22 (95.5%) re-enrolled (Table 12). There were 10 wholesalers/distributors inactivated during the current reporting period because the enrollment expired and 8 had not re-enrolled by the end of the reporting period (Table 13). Table 12 Distributor Enrollment Current Reporting Perioda 29OCT2013 to 28OCT2014 Parameter N (%) Number of Distributors with Enrollment Activity in This Reporting Period Number of Newly Enrolled Distributors Number of Re-Enrolled Distributors 22 1 (4.5%) 21 (95.5%) Number of Distributors that Remain Enrolled from Previous Reporting Periods 13 Total Number of Distributors Enrolled as of the End of the Reporting Period 35 Cumulative Number of Distributors Ever Enrolledc 45 a Percentages are based on the total number (N) for the relevant Distributors for the period. b Includes Distributors that transitioned into the TIRF REMS Access Program from other individual REMS programs. c Cumulative Distributors from the end of prior period may differ from last period’s report due to reconciliation of duplicate Distributors. Table 13 Distributor Inactivations Current Reporting Perioda 29OCT2013 to 28OCT2014 Parameter Number of Distributors that Became Inactivated in This Reporting Period N (%) 10 Reason(s) for Distributor Inactivation FDA_1703 Current Reporting Perioda 29OCT2013 to 28OCT2014 Parameter Enrollment Expired N (%) c Enrollment remained expired at end of period 10 (100.0%) 8 (80.0%) Number of Distributors that Remain Inactivated From Previous Reporting Periods 2 Total Number of Distributors Inactivated as of the End of the Reporting Period 10 Cumulative Number of Distributors Ever Inactivatedc 14 a Distributors with ‘inactive’ status at least once during the reporting period. b Distributors whose status is ‘Inactive-Expired’ at any time during the enrollment period. c Cumulative is sum of all reporting period totals. 5.1.5 Dispensing Activity [Metric 11, 12, 13,] A total of 159,560 prescriptions were adjudicated for safety by the TIRF REMS Access Program in the current reporting period including 158,612 prescriptions from non-closed system pharmacies and 948 from closed system pharmacies (Table 14). Of the total prescriptions, 90.9% were subsequently approved for dispensing without encountering any REMS-related rejections (i.e., were authorized for dispensing by insurance or cash bin). FDA_1704 Table 14 Prescriptions from Outpatient Pharmacies That Did Not Encounter Any REMS-Related Rejections Prior to Being Authorized for Dispensing Current Reporting Perioda,b 29OCT2013 to 28OCT2014 Parameter Number of Unique Prescriptions Presented for Dispensing Non-Closed System Pharmacies N (%) 158,612 Total Number of Unique Prescriptions That 144,364 (91.0%) Did Not Encounter Any REMS-Related Rejections Prior to Being Authorized for Dispensing Independent Pharmacies 104,019 (65.6%) Chain Pharmacies 40,345 (25.4%) Closed System Pharmacies N/A Cumulativea,b,c 28DEC2011 to 28OCT2014 Closed System Pharmacies N (%) All Pharmacies (Non-Closed and Closed) N (%) Non-Closed System Pharmacies N (%) Closed System Pharmacies N (%) All Pharmacies (Non-Closed and Closed) N (%) 948 159,560 407,228 2,580 409,808 720 (75.9%) 145,084 (90.9%) 356,302 (87.5%) 2,018 (78.2%) 358,320 (87.4%) N/A N/A 720 (75.9%) 104,019 (65.2%) 223,352 (54.8%) 40,345 (25.3%) 132,950 (32.6%) 720 (0.5%) N/A N/A N/A 2,018 (78.2%) 223,352 (54.5%) 132,950 (32.4%) 2,018 (0.5%) a Prescriptions successfully adjudicated for safety (i.e., successful REMS edit).and authorized for dispensing by insurance or cash bin (bin number). b Percentages are based on the total number (N) of unique prescriptions that never encountered a REMS-related rejection for the reporting period. c Includes authorizations from all pharmacies that were enrolled in the TIRF REMS Access Program at any time from inception of the program. FDA_1705 Of the 159,560 unique prescriptions presented for dispensing during the current reporting period, 3,738 prescriptions encountered at least one REMS-related rejection prior to being authorized for dispensing from outpatient pharmacies. There were a total of 10,738 prescriptions that encountered at least one REMS-related rejection and were never authorized for dispensing. Percentages for all rejection reasons may not equal 100% as a prescription may be rejected for multiple reasons. The most frequent rejection reasons for independent pharmacies (n=2,811) were PPAF incomplete (33.7%), PPAF terminated (23.1%), zip code missing (21.3%), and PPAF expired (19.8%). The most frequent rejection reasons for chain pharmacies (n=917) were PPAF terminated (42.4%), PPAF expired (37.8%), PPAF incomplete (23.2%), and Prescriber Identification (ID) not registered (17.8%). The most frequent rejection reasons for closed system pharmacies (n=10) were PPAF terminated (50.0%), PPAF incomplete (50.0%), and PPAF expired (30.0%). Upon receiving an inbound call from a pharmacy provider, the TIRF REMS Access Program Call Center Service Representative (CSR) works to resolve the rejected transaction and to provide instructions on the corrective action needed to successfully process the transaction. Corrective action includes outreach and education to remedy rejected transaction processing. Table 15 presents the results for the prescriptions that encountered at least one REMS-related rejection prior to being authorized for dispensing from outpatient pharmacies. FDA_1706 Table 15 Authorized for Dispensing Prescriptions from Outpatient Pharmacies That Encountered at Least One REMS-Related Rejection Prior to Being Current Reporting Perioda?b 290CT2013 to 280CT2014 . umulatlvea 28DEC2011 to 280CT2014 All All Non-Closed Pharmacies Non-Closed Pharmacies System Closed System (Non?Closed and System Closed System (Non?Closed Pharmacies Pharmacies Closed) Pharmacies Pharmacies and Closed) Parameter Number of Unique Prescriptions Presented for 158.612 948 159.560 407.228 2.580 409.808 Dispensing Total Number of Unique Prescriptions that 3.728 10 3.738 16.978 57 17.035 encountered At Least One Initial REMS?Related Rejection Prior to being Authorized for Dispensing Independent Pharmacies 2.811 2.811 12.311 12.311 Chain Pharmacies 917 917 4.667 4.667 Closed System Pharmacies 10 10 57 57 Independent Pharmacies Reason(s) for Rejectiond Zip Code Missing 598 6.253 PPAF Incomplete 948 3.366 Prescriber last name did not match registered 273 1.691 Prescriber ID not registered 295 1.413 PPAF terminated 650 772 PPAF Expired 557 562 Prescriber is terminated 96 203 Last Name and DOB Missing 44 194 707 Current Reporting Period? . umulatlvea 290CT2013 to 280CT2014 28DEC2011 to 280CT2014 All All Non-Closed Pharmacies Non?Closed Pharmacies System Closed System (Non-Closed and System Closed System (Non-Closed Pharmacies Pharmacies Closed) Pharmacies Pharmacies and Closed) Parameter Pharmacy terminated 19 108 Prescriber not submitted 33 99 First Name Missing 22 61 First Name. Last Name. and Zip Code 1 24 Missing Prescriber Terminated and Last Name 9 21 Mismatch DOB Missing 3 18 Zip Code and Last Name 0 13 First Name and Last Name Missing 0 9 DOB and Zip Code Missing 1 8 Last Name Missing 0 2 Database Failure - System Unavailable due to 0 1 mamtenance First Name. Last Name and DOB Missing 0 1 First Name. Last Name. Zip Code. and DOB 0 1 Missing Multi-Match - two or more patient match on 1 1 same criteria Chain Pharmacies Reason(s) for Rejectiond PPAF Incomplete 213 2.102 Prescriber II) not registered 163 970 708 Current Reporting Period? . a,b,c umulatlve 29OCT2013 to 280CT2014 28DEC2011 to 280CT2014 All All Non?Closed Pharmacies Non?Closed Pharmacies System Closed System (Non-Closed and System Closed System (Non-Closed Pharmacies Pharmacies Closed) Pharmacies Pharmacies and Closed) Parameter Zip Code Missing 32 820 PPAF terminated 389 466 Prescriber last name did not match registered 55 377 PPAF Expired 347 349 Prescriber is terminated 36 74 First Name Missing 3 47 Last Name and DOB Missing 7 32 Pharmacy terminated 6 20 Prescriber ID not submitted 2 17 First Name and Last Name Missing 7 DOB Missing 0 6 First Name. Last Name. and Zip Code 0 6 Missing Multi-Match - two or more patient match on 0 3 same criteria Prescriber Tenninated and Last Name 2 3 Mismatch First Name. Last Name and DOB Missing 0 2 First Name. Last Name. Zip Code. and DOB 0 2 Missing Pharmacy not Registered 0 2 DOB and Zip Code Missing 0 1 Database Failure - System unavailable due to 0 1 system maintenance 709 36-month REMS Assessment Report Transmucosal Iimnediate-Release Fentanyl (TIRF) TIRF REMS Industiy Group (TRIG) of Companies. Page 46 of 139 Current Reporting Perioda?b 290CT2013 to 280CT2014 28DEC2011 to 280CT2014 All All Non?Closed Pharmacies Non?Closed Pharmacies System Closed System (N on-Closed and System Closed System (Non-Closed Pharmacies Pharmacies Closed) Pharmacies Pharmacies and Closed) Parameter First Name and DOB Missing 0 1 Re-register 0 1 Closed System Pharmacies Reason(s) for Rejectiond Zip Code Missing 0 33 PPAF Incomplete 5 10 Prescriber ID not registered 0 9 PPAF tenninated 5 6 Prescriber last name did not match registered 0 6 PPAF Expired 3 3 Prescription successfully adjudicated for safety successful REMS edit).and authorized for dispensing by insurance or cash bin (bin number). Percentages are based on the total number (N) of munber of unique prescriptions that encountered at least one initial REMS-related rejection prior to being authorized for dispensing for the reporting period. Includes authorizations from pharmacies that transitioned into the TIRF REMS Access Program from other individual REMS programs. . . . Prescriptions can be rejected for more than one reason. For all pharmacies, the mean time to authorization for a prescription that experienced at least one initial REMS-related rejection was 4.9 days (Table 16). For closed system pharmacies it took a mean of 10 days compared with chain pharmacy stores and independent outpatient pharmacies that took a mean of 5.1 days and 4.8 days, respectively. The increase in the mean time to authorization between all pharmacies and closed system pharmacies was primarily due to one closed system pharmacy outlier which took 61 days to ?ll ?'om the original reject date. The claim had been rejected for a patient not having a completed PPAF on ?le. Table 16 Time to Authorization for a Prescription that Experienced at Least One Initial REMS-Related Rejection Current Reporting Period Cumulative 29OCT2013 to 280CT2014 28DEC2011 to 280CT2014 Total Mean Time For Prescription to be 4.903 3.327 Authorizeda (Days)b Inpatient Pharmacies -- -- Chain Pharmacy Stores 5.098 4.027 Independent Outpatient Pharmacies 4.820 3.048 Closed System Pharmacies 10.044 6.291 Total Median Time For Prescription to be 1.055 0.157 Authorizeda (Days) Inpatient Pharmacies -- -- Chain Pharmacy Stores 1.727 0.998 Independent Outpatient Pharmacies 0.984 0.063 Closed System Pharmacies 2.475 1.124 Prescriptions included were resolved in the current reporting period. Prescriptions may have been initially rejected in a prew'ous reporting period. Time to authorization for a prescription that experienced at least one initial REMS-related rejection excludes prescriptions processed through the inpatient pharmacy process. As described in Section 5.1.3., a total of 239 closed system pharmacy locations are currently em'olled in the TIRF REMS Access Program. These 239 pharmacy locations are represented by 7 closed system entities em'olled in the TIRF REMS Access Program. These entities include: (m4) 0 National Institutes of Health Clinical Center Pharmacy 0 US. Department of Veterans Affairs (4) 71 1 • DLA Troop Support • (b) (4) During the current reporting period, a total of 730 prescription authorizations were provided through these closed system pharmacy locations and 2,075 were authorized over the cumulative period (Table 17). Table 17 Number of Prescription Authorizations per Closed System Pharmacy Total Number of Closed System Pharmacy Prescription Authorizations (b) (4) Current Reporting Period 29OCT2013 to 28OCT2014 Cumulative 28DEC2011 to 28OCT2014 730 2,075 (b) (4) FDA_1712 (b) (4) Current Reporting Period 29OCT2 Cumulative (b) (4) 5.1.6 Barriers or Delays in Patient Access [Metric 14 and 15] Prescriptions Dispensed Within First 10 Days after Patient Enrollment Across all pharmacies, a total of 9,980 prescriptions were dispensed to 7,983 patients within the first 10 days after patient enrollment (Table 18). The majority of patients (7,956) were dispensed prescriptions by non-closed system pharmacies (9,946 prescriptions). Of the 3,289 patients who received prescriptions without a PPAF, the majority of patients (86.9%) received only 1 fill without a PPAF. A total of 4 patients received more than 3 prescriptions within 10 days without a PPAF on file. All 4 patients had their prescriptions filled through non-closed system pharmacies. It was observed that 4 patients potentially received more than 3 fills within the 10 day period without a PPAF on file. The data indicates these are isolated incidents that happened over 3 days and at 2 separate independent outpatient pharmacies. Both pharmacies have been contacted and the pharmacists verbally confirmed that each patient did not receive greater than 3 prescriptions in the 10 day period. One of the four patients now has a PPAF on file. The TIRF REMS Access Call Center continues to make outbound calls in an attempt to FDA_1713 obtain PPAFs for the 3 remaining patients. The root cause of this report will continue to be investigated and the outcome of this research will be reported in the 48-month assessment report. FDA_1714 Table 18 Prescriptions Dispensed During the First 10 Days after Passive Patient Enrollment Cumulativea,b 28DEC2011 to 28OCT2014 Current Reporting Period 29OCT2013 to 28OCT2014 Non-Closed System Pharmacies N (%) Closed System Pharmacies N (%) Combined Pharmaciesd N (%) Total Pharmacies N (%) Non-Closed System Pharmacies N (%) Closed System Pharmacies N (%) Combined Pharmaciesd N (%) Total Pharmacies N (%) Number of prescriptions dispensed during the first 10 days after patient enrollment 9,946 31 3 9,980 29,355 200 11 29,566 Number of patients dispensed a prescription during the first 10 days after enrollment 7,956 26 1 7,983 24,580 164 5 24,749 1 Fill 3,832 (48.2%) 5 (19.2%) 0 48 (29.3%) 1 (20.0%) 9,709 (39.2%) 2 Fills 902 (11.3%) 1 (3.8%) 0 903 (11.3%) 1,830 (7.4%) 8 (4.9%) 0 1,838 (7.4%) 3 Fills 136 (1.7%) 0 0 136 (1.7%) 268 (1.1%) 1 (0.6%) 0 269 (1.1%) 22 (0.3%) 0 0 22 (0.3%) 61 (0.2%) 2 (1.2%) 0 63 (0.3%) 1 Fill 2,843 (35.7%) 17 (65.4%) 0 1 (20.0%) 12,066 (48.8%) 2 Fills 323 (4.1%) 2 (7.7%) 0 325 (4.1%) 1,144 (4.7%) 5 (3.0%) 3 (60.0%) 1,152 (4.7%) 3 Fills 98 (1.2%) 1 (3.8%) 1 (100.0%) 100 (1.3%) 215 (0.9%) 4 (2.4%) 1 (20.0%) 220 (0.9%) >3 Fills 4 (0.1%) 0 0 4 (0.1%) 9 (<0.1%) 0 0 9 (<0.1%) Parameter With PPAFb >3 Fills Without PPAF 3,837 (48.1%) 9,660 (39.3%) b,c 2,860 (35.8%) 11,969 (48.7%) 96 (58.5%) a Cumulative data from the end of prior period may differ from the last period’s report due to reconciliation of duplicate stakeholders. Percentages are based on the total number of patients for the period. Sum of percentages may be greater than 100 due to patients receiving prescriptions with and without a PPAF during the grace period. c A patient may receive up to 3 fills in the first 10 days after enrollment without a PPAF. b d Patients who have filled a prescription at both a closed system pharmacy and a non-closed system pharmacy. FDA_1715 Prescriptions Dispensed Beyond 10 Days after Patient Enrollment The TIRF REMS Access Program requires that each patient have a Patient-Prescriber Agreement Form (PPAF) submitted to the TIRF REMS Access Program by their prescriber within 10 days of their passive enrollment in order to continue to receive a TIRF medicine. Table 19 below shows the number of prescriptions dispensed beyond the first 10 days without a PPAF on file. From the inception of the TIRF REMS through the current reporting period, 751 prescriptions have been dispensed beyond the first 10 days without a PPAF; 6 prescriptions were in the current reporting period. These 6 prescription fills were all associated with the same patient. Patient records are created by the processing of a patient’s first paid TIRF prescription (i.e., passive patient enrollment), or by the receipt of a PPAF. As a result of the passive patient enrollment process, the TIRF REMS Access Program has two systematic methods utilized to handle patient duplicates. First, the TIRF REMS Access Program systemically identifies and rectifies duplicate records utilizing patient matching logic consisting of key patient identifiers (i.e., Date of Birth, First Name, Last Name, and Zip Code). This occurs as part of the normal course of business when passive patient enrollments and PPAFs are processed; therefore duplicate patient records are not created. Second, the TIRF REMS Access Program systematically identifies potential patient duplicates, which generates a daily report to the TIRF REMS Access Program Call Center to ultimately determine if the record is a valid duplicate. Valid duplicates identified by the TIRF REMS Access Program Call Center are merged into one patient record. The data for the single patient receiving 6 prescriptions were merged into a single patient record upon confirmation of the correct birth date from the pharmacist. FDA_1716 Table 19 Prescriptions Dispensed Beyond the First 10 Days after Passive Patient Enrollment Without a PPAF Cumulativea,b 28DEC2011 to 28OCT2014 Current Reporting Period 29OCT2013 to 28OCT2014 Parameter Fills beyond the first 10 days Without PPAF Filled at NonClosed System Filled at Closed System Filled at Combined Filled at NonClosed Filled at All System Filled at Closed System Filled at Combined Filled at All Pharmacies Pharmacies Pharmaciesb Pharmacies Pharmacies Pharmacies Pharmaciesb Pharmacies N (%) N (%) N (%) N (%) N (%) N (%) N (%) N (%) 6 0 0 6 716 32 3 751 a Cumulative data from the end of prior period may differ from the last period's report due to reconciliation of duplicate stakeholders. b A patient who has filled a prescription at both a closed system pharmacy and a non-closed system pharmacy. FDA_1717 5.2 Program Infrastructure and Performance [Metrics 16, 17, 18, 19] 5.2.1 Backup System for Prescription Validation [Metric 16] During this reporting period there were no instances in which a backup system was used to validate a prescription due to pharmacy level problems, switch problems, or REMS database problems. 5.2.2 System Interruptions/Errors and Corrective Actions [Metric 17, 19] A brief summary of issues identified as system errors and their corrective actions is presented below. Additional system errors that met the definition of non-compliance are presented in Section 6. System Error #4: REMS Website Unavailable Description On 28 October 2013 at 6:48 a.m., the TIRF REMS Access Program was notified by a stakeholder that the REMS website was not available due to the homepage being inaccessible. Upon identification of the issue the website and database logs were immediately reviewed. It was determined that an external user took the home page temporarily offline and that the incident was isolated to the public-facing REMS website; no exposure or unauthorized access to the application or database occurred. Root Cause Intrusion of the public facing REMS website by an external user Correction The REMS website was restored to its original state on 28 October 2013 at 7:53 a.m. and additional scans of the REMS website were conducted to identify and fix any further vulnerability. Resolution Implementation of an annual REMS website scan (or after any major system functionality or software upgrade release) to identify any intrusion activity and adjustment of the website monitoring to alert the program to any identified intrusion activity. System Error #5: TIRF re-enrollment records not merging with main record Description On 06 March 2014, the TIRF REMS Access Program identified an independent outpatient pharmacy that was inadvertently deactivated after re-enrollment due to a merging issue between enrollment and re-enrollment records. When a re-enrollment is initiated, a temporary reenrollment record for that stakeholder is created within the application in order to track whether all required tasks are completed for the re-enrollment. Once all tasks associated with reenrollment are completed, the temporary re-enrollment record merges into the main record and updates any data that were entered during re-enrollment. FDA_1718 The independent outpatient pharmacy had re-enrolled 6 days before their enrollment was expired; however, the temporary re-enrollment record did not successfully merge with the pharmacy’s main enrollment record causing the pharmacy’s enrollment to expire. After further investigation it was found that an unexpected error had occurred due to the timing of the re-enrollment correspondence confirmation with the re-enrollment process. Due to a delay in sending the re-enrollment correspondence confirmation, the re-enrollment record merging process did not complete. Root Cause System coding error Correction The independent outpatient pharmacy was re-activated on 14 March 2014 and on 12 June 2014 the TIRF REMS Access Program confirmed that no claims were impacted. Resolution Implementation of a process to monitor system logs to immediately identify any similar occurrences and an update to system coding to prevent the overlap of the record merge process and the timing of the re-enrollment correspondence confirmation process were both completed on 06 June 2014. System Error #6: Knowledge Assessment Failure Correspondence Displaying Incorrect Text for Question 11 Description On 04 March 2014, the TIRF REMS Access Program identified that the correspondence being sent to stakeholders who fail the Knowledge Assessment included the incorrect question and answer options for question 11. The question/answer had been updated in a TIRF production release on 28 February 2014 in support of Modification 2. The Incomplete Knowledge Assessment correspondence was not updated to align with the revised question/answer. Root Cause Insufficient testing of correspondence related to the Knowledge Assessment when update(s) to questions/answers occurred Correction The Incomplete Knowledge Assessment correspondence was updated to display the correct question and answer for question #11 on 05 March 2014. A total of 28 stakeholders were impacted and all were contacted. A total of 27 of the 28 stakeholders successfully completed reenrollment. Resolution Re-training on the process to test Knowledge Assessment correspondence when any changes are made to questions/answers. FDA_1719 System Error # 8: Direct Connection to Payers Description On 05 April 2012, the TIRF REMS Access Program identified three pharmacy switch vendors that had a direct connection to payers which meant that claims from certain pharmacies could be processed and paid without processing through the REMS edits. Three pharmacy switch vendors were affected. Root Cause Inadequate communication to switch vendors to eliminate direct connections to payers Correction As of 12 July 2012, all switch vendors identified as having direct connection to payers agreed to remove all direct connections to ensure claims are processed through the REMS edits. Resolution The REMS Vendor Communication Instruction and related correspondence for switch vendors was updated to include the following statement (or similar statement): “The switch vendors will ensure that their vendors and data aggregators do not send REMS transactions directly to payers; all REMS transactions are to be sent through the appropriate switch to ensure that all transactions are processed through the REMS Program.” The REMS Vendor Communication Instruction was published on 22 July 2014. System Error # 21: Network Incident Impacting TIRF REMS Description On 22 July 2013, the TIRF REMS Access Program identified a network incident that impacted the REMS database. Two network connectivity losses caused 72 timeouts in REMS transactions which resulted in REMS rejections being received at the pharmacy. Additionally, some stakeholder REMS records failed to import into the REMS database. Root Cause Insufficient internal processes for network change management requests Correction An investigation into the 72 timeouts was immediately performed. It was found that through the 72 timeouts, 17 claims were impacted. For each of these claims the pharmacy received a REMS rejection. The pharmacies were notified of the problem and claims were re-submitted. The final status of these claims included: • 3 claims were reversed • 5 claims were rejected based on REMS edits FDA_1720 • 9 claims were paid The stakeholder records that failed to import into the REMS database were resubmitted and imported successfully. Resolution The network guidelines were updated to prevent this occurrence in the future. A network alert was installed to ensure timely identification of any similar issues. Additionally a process was established for internal communication after implementation of any network change to include the estimated timeline for changes. System Error #25: TIRF REMS Transaction Bypassed REMS Edit Description On 22 July 2014, the TIRF REMS Access Program identified a transaction that came from a pharmacy switch vendor on 21 July 2014 and included a TIRF REMS National Drug Code (NDC) number but was not submitted to the REMS database for adjudication. The transaction routed directly to the third party insurance without passing through REMS edits. The switch vendor software had a coding error which caused the comparison to fail (i.e., the switch did not recognize it as a TIRF product). Root Cause No switch vendor audit to verify REMS compliance Correction On 27 July 2014 the transaction was reversed and successfully reprocessed. The pharmacy received REMS authorization as all stakeholders were enrolled in the REMS. Resolution The REMS Switch Vendor Communication Work Instruction was updated to include an email communication instructing switch vendors to conduct their own post-implementation audit of transactions to ensure adherence to the REMS program requirements. 5.2.3 REMS Call Center [Metric 18] Table 22 below shows reasons for contacting the REMS Call Center by frequency (%). For presentation in the report, this table includes at least 80% of the total cumulative frequency. The most frequent reasons classified under the call reason were pharmacy: enrollment status inquiry (15.4%), PPAF status inquiry (13.8%), and pharmacy claim rejection (13.8%). The call reasons listed below in Table 22 represent 81.8% of calls to the Call Center for the current reporting period. Table 20 Current Assessment Period Contact Reasons Reason Count Percenta Enrollment Status Inquiry 5,366 15.4% PPAF Inquiry 4,816 13.8% FDA_1721 Reason Count Percenta Pharmacy: Pharmacy Claim Rejection 4,801 13.8% PPAF Follow Up 2,767 7.9% Enrollment Follow Up 2,575 7.4% Web Portal Logon Assistance 2,427 7.0% Enrollment Form 1,696 4.9% Other/Miscellaneous 1,557 4.5% General Program Questions 1,525 4.4% 939 2.7% Website Inquiry a The total percentage presented in the table account for 81.8% of all reasons for contacting the Call Center. There are no REMS related problems received by the REMS Call Center to report for the 36-month assessment report. 6 TIRF REMS ACCESS PROGRAM NON-COMPLIANCE 6.1 Audits As part of non-compliance monitoring, TIRF REMS Access Program pharmacies may be subject to periodic data requests and/or audits. Such activities may occur for suspected noncompliance with program requirements based on program monitoring activities. 6.1.1 Closed System Pharmacy Audits [Metric 20] The REMS Assessment Plan includes the following components for closed system pharmacy audits: (1) Verification of training for all pharmacists dispensing TIRF products (2) Numbers of prescription authorizations per closed system (3) Reconciliation of data describing TIRF product prescriptions received by the closed system pharmacy with TIRF product dispensed to patients with a valid enrollment in the TIRF REMS Access Program. The first component is accomplished through the enrollment process for closed system pharmacies. In order to become enrolled the authorized representatives must attest that all pharmacies dispensing TIRF products will be trained on the TIRF REMS Access Program requirements. The second component is done through the closed system pharmacy prescription authorization process. Closed system pharmacists are required to validate the enrollment status of the prescriber and patient prior to dispensing a TIRF product by calling or faxing the prescription details to the TIRF REMS Access Program. The TIRF REMS Access Program maintains records of prescription details and the associated REMS authorization. Table 19 provides information on all prescription authorizations by closed system pharmacy. FDA_1722 36-month REMS Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies. Page 59 of 139 The third and final component includes reconciliation between the closed system pharmacy’s dispensing data and the TIRF REMS Access Program’s REMS authorizations. To conduct this reconciliation, the TIRF REMS Access Program requests dispensing records from the closed system pharmacies and compares the dispensing records to REMS authorization data from the TIRF REMS Access Program. After confirmation that the closed system pharmacy agrees to participate in the reconciliation, a formal written request for data was issued upon request to the authorized representative detailing the data to be provided and the deadline for submission. Specific data requested include: • RX number for each prescription dispensed • DEA number or NPI number of the facility that dispensed each prescription • DEA number or NPI number of the prescriber that issued each prescription • Date and time of each prescription transaction • TIRF REMS Authorization code obtained for each prescription dispensed Due to the structure of some closed system pharmacy networks, the headquarters may be unable to provide data for all pharmacy locations as no central data repository is in existence; each pharmacy location maintains their own data. In these cases a random sample of pharmacy locations was selected by the TIRF REMS Access Program for participation. Findings from each investigation are reviewed with the NCRT and actions were taken in accordance with the Non-Compliance Protocol. Of the 7 audits conducted during this reporting period, 5 closed system pharmacies were found to be non-compliant with the TIRF REMS Access Program requirements. Based on the identification of non-compliance, a non-compliance case was opened for each of these 5 closed system pharmacies. Below are the details of these investigations. Closed System Pharmacy Non-Compliance Case 1: ID#167 (Case #13554751) Request for Data Based on an FDA inquiry on the reason for low utilization (based on REMS authorizations issued) and outreach that was initiated with the Department of Defense (DoD) in May 2013 to request dispensing records. Investigation Dispensing records were provided on 06 January 2014. The dispensing records contained data from program launch through September 2013 and included 282 instances where a TIRF product had been dispensed (both closed system and inpatient sites). The dispensing records provided were compared to authorization data from the TIRF REMS Access Program and data discrepancies were found; however, due to the different identifiers used in both data sources, a full compare could not be completed. FDA_1723 The dispensing records provided were compared to authorization data from the TIRF REMS Access Program and data discrepancies were found; however, due to the different identifiers used in both data sources, a full compare could not be completed. On 28 February 2014, a meeting was held with the DoD Corporate Headquarters’ Authorized Representative to discuss the data discrepancies and next steps of the non-compliance investigation. The Authorized Representative stated that because of the transient nature of their pharmacy staff it is difficult to keep training current. The Authorized Representative agreed to assist in the investigation into the data discrepancies and agreed to provide additional dispensing records for NCRT review by 14 March 2014. The TIRF REMS Access Program also provided the DoD with closed system claim data for their research. The DoD was unable to meet the 14 March 2014 deadline and the additional dispensing records were provided on 17 April 2014. On 08 July 2014, an additional teleconference was held to discuss the data provided and next steps in the non-compliance investigation. The DoD Authorized Representative agreed to provide additional identifiers to the original dispensing data and exclude inpatient dispenses to attempt to tie the two data sources together. The deadline for the additional data was 08 August 2014. The requested dispensing records were provided on 31 July 2014. Findings On 31 July 2014, during a progress update teleconference, the DoD Authorized Representative confirmed that there were 330 instances where TIRF medicines were dispensed without a TIRF REMS authorization. Outcome On 13 August 2014, the NCRT requested that the DoD provide a written summary of the procedures established within the pharmacy locations to ensure on-going compliance, including: • Obtaining signed closed system enrollment forms from all dispensing locations to ensure there is a point of contact within each site to hold accountable • Meeting with the TIRF REMS Access non-compliance team monthly to reconcile data • Re-education at sites provided by the authorized representative, as well as re-education provided by the TIRF REMS Access non-compliance team A written summary was provided by the DoD Authorized Representative on 24 August 2014. A formal Notice for Non-Compliance was issued to the DoD on 09 September 2014. As of the end of the reporting period, no additional non-compliance cases for the DoD have been identified. Closed System Pharmacy Non-Compliance Case 2: ID#206 (Case #20099580) Request for Data FDA_1724 (b) (4) On 21 February 2014, during outreach to to request feedback on the closed system pharmacy process for TIRF REMS Access Program, the Authorized Representative agreed to submit data associated with all instances where TIRF medicines were dispensed. A (b) (4) formal request for data correspondence was issued to on 08 April 2014, with a response requested by 08 May 2014. Investigation Dispensing records were received on 12 May 2014. The data represented their 5 enrolled pharmacies and included 499 instances where a TIRF product was dispensed via the closed system process. The dispensing records provided were compared to authorization data from the TIRF REMS Access Program. Findings A total of 42 instances were identified where a REMS authorization was not received prior to dispensing a TIRF product. Outcome A formal Notice for Non-Compliance, including a list of non-compliant events, was issued to the Authorized Representative. As of the end of the reporting period, no additional non-compliance cases for have been identified. (b) (4) Closed System Pharmacy Non-Compliance Case 3: ID#210 (Case #20312891) Request for Data On 27 February 2014, during outreach to the Veteran’s Administration (VA) to request feedback on the closed system pharmacy process for TIRF REMS Access Program, the Authorized Representative agreed to submit data associated with all instances where TIRF medicines were dispensed. Since each VA site stores their own dispensing records (there is no central data storage), the Authorized Representative requested that the TIRF REMS Access Program select a sample of sites to provide dispensing records. A formal request for data correspondence was issued to the VA on 08 April 2014, with a response requested by 08 May 2014. Investigation Dispensing records were received on 12 May 2014. The data represented 3 pharmacy locations and included 43 instances where a TIRF product was dispensed via the closed system process. The dispensing records provided were compared to authorization data from the TIRF REMS Access Program. Findings A total of 43 instances were identified where a REMS authorization was not received prior to dispensing a TIRF product. FDA_1725 On 18 June 2014, the NCRT requested dispensing records for additional pharmacy locations. On 19 June 2014, the TIRF REMS Access Program provided a selection of 15 pharmacy locations (which represented 10% of the VA enrolled pharmacy locations) to provide dispensing records. The VA was asked to provide the requested data by 31 August 2014. Dispensing records were received on 15 September 2014. Only two of the 15 pharmacy locations dispense TIRF medicines. The dispensing records provided were compared to authorization data from the TIRF REMS Access Program. Of the total 39 instances where drug was dispensed via the closed system process, 17 did not have REMS authorization prior to dispensing drug. Outcome A formal Notice for Non-Compliance was issued to the VA on 02 October 2014, with a request that the VA provide any preventative steps to be put in place to ensure ongoing compliance with their closed system dispensing locations. Closed System Pharmacy Non-Compliance Case 4: ID 256 (Case # 21606341) Request for Data (b) (4) A formal request for data correspondence was issued to on 11 April 2014, with a response requested by 11 May 2014. On 13 May 2014, the Authorized Representative requested as extension to 20 June 2014 as the request needed to be reviewed by the legal and compliance department and patient information would need to be redacted from the data. On 13 June 2014, the Authorized Representative advised that the request for data was approved by the legal and compliance department. An extension until 31 July 2014 was requested because the data would need to be pulled manually since the pharmacy was undergoing a transition to a new system. On 28 July 2014 the Authorized Representative requested an additional extension to 02 September 2014 as a new automated system was being used by the pharmacy and compiling the data would take another month. Investigation Dispensing records were received on 17 September 2014. The data represented 2 pharmacy locations and included 205 instances where a TIRF product was dispensed via the closed system process. The dispensing records provided were compared to the authorization data from the TIRF REMS Access Program. Findings Of the total 205 instances where a TIRF product was dispensed, 76 instances were identified where a REMS authorization was not received prior to dispensing a TIRF product. Outcome (b) (4) On 30 September 2014, the TIRF REMS Access Program inquired whether still needed to dispense under the closed system process or if they now have the ability to enroll as FDA_1726 an independent outpatient pharmacy and process prescriptions electronically to communicate with the TIRF REMS Access system to obtain a REMS authorization prior to dispensing. The (b) (4) Authorized Representative advised that the pharmacy plans to enroll both locations as independent outpatient pharmacies as soon as a successful merge to the new automated system capable of electronic claims processing is complete. To ensure ongoing compliance for their pharmacy locations, the pharmacy plans to re-train all pharmacy staff within the next two months. On 08 October 2014, a formal Notice for Non-Compliance was issued to the Authorized Representative. As of the end of the reporting period, no additional non-compliance cases for have been identified. (b) (4) Closed System Pharmacy Non-Compliance Case 5: ID 215 (Case # 20351073) Request for Data (b) (4) On 25 February 2014, during outreach to to request feedback on the closed system pharmacy process for TIRF REMS Access, the Authorized Representative agreed to participate in a data reconciliation to determine the pharmacy’s compliance with the TIRF (b) (4) REMS Access Program. The Authorized Representative advised that does not have a central system or process that allows pulling of REMS authorization data from all individual locations. Each site would need to individually provide the data. The Authorized Representative proposed that the TIRF REMS Access Program provide REMS authorization data for randomly (b) (4) (b) (4) selected sites and provide the information to and would reconcile their own (b) (4) pharmacy’s data to identify any non-compliance. This process has been used by to conduct audits for other REMS programs. (b) (4) A formal request for data correspondence was issued to on 23 April 2014, with a response requested by 23 May 2014. On 20 May 2014, the Authorized Representative requested (b) (4) an extension to 30 June 2014 as was currently focused on re-enrollment for their closed system locations. Investigation Dispensing records were received on 03 June 2014. The data represented 3 pharmacy locations and included 148 instances where a TIRF product was dispensed via the closed system process. The dispensing records provided were compared to the authorization data from the TIRF REMS Access Program. Findings Of the total 148 instances where a TIRF product was dispensed, 5 instances were identified where a REMS authorization was not received prior to dispensing a TIRF product. Outcome On 03 July 2014, a formal Notice for Non-Compliance was issued to the Authorized Representative. FDA_1727 6.2 Inpatient Hospital Pharmacy Audits [Metric 21] As per the TRIG’s agreement with FDA as documented in an email on 22 September 2014, inpatient pharmacy hospital audits have not yet been conducted. The TRIG is developing a process to accomplish inpatient pharmacy audits. Therefore, inpatient pharmacy audit data will be included in the 48-month assessment report. 6.3 Stakeholder Non-Compliance [Metric 23, 24, 25, 26, 27, 28] During the current reporting period, instances of potential stakeholder non-compliance with the TIRF REMS Access program were reviewed and investigated. A summary of the noncompliance activity is presented in Table 21. FDA_1728 36-month REMS Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies. Table 21 Stakeholder Non-Closed System Pharmacy Page 65 of 139 Non-Compliance Activity Reports by Stakeholder in the Current Reporting Period: 29 October 2013 to 28 October 2014 Non-Compliant Reason (categorized as reported by the stakeholder) No. of events No. of stakeholders Not aware of requirement to process cash claims 6 No. w/1 report: 6 Received reject but dispensed drug 3 No. w/1 report: 3 Dispensed drug without obtaining an authorization 2 No. w/1 report: 2 Not aware of cash claim and received reject but dispensed drug 1 No. w/1 report: 1 No reason provided* 2 No. w/1 report: 2 Inpatient Pharmacy dispenses for outpatient use Dispensed drug without obtaining an authorization 1 No. w/1 report: 1 Submission of inappropriately altered claim to meet TIRF REMS system requirements (e.g. changing prescriber) Altered prescription details for a REMS authorization 1 No. w/1 report: 1 No reason provideda 1 No. w/1 report: 1 Non-Compliance Activity Submission of a claim that did not go through the REMS edits. A TIRF medicine was dispensed without verifying through the TIRF pharmacy management system that the prescriber is enrolled and active, and that the patient is enrolled or has not been inactivated in the program. Total Non-Closed System Pharmacy Cases Wholesaler/ Distributor Wholesaler/Distributor fills an order for TIRF medicines for a non-enrolled stakeholder. No reason provided a Total Wholesaler/Distributor Reports Prescriber Prescriber failure to have a complete PPAF on file in a timely manner (5 or more patients enrolled by the prescriber without a complete PPAF on file, with each patient having greater than 10 working days lapse from initial enrollment date). 17 1 No. w/1 report: 1 1 Not aware of PPAF requirement 25 No. w/1 report: 25 Completed PPAF with patient but failed to send PPAF to TIRF REMS 19 No. w/1 report: 19 Aware of PPAF requirements but failed to complete PPAF 15 No. w/1 report: 15 No reason provideda 61 No. w/1 report: 53 No. w/2 report: 4 FDA_1729 36-month REMS Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies. Total Prescriber Reports Closed System Pharmacy Dispensing prescriptions outside of the closed system authorization process. Dispensed drug without obtaining an authorization Total Closed System Pharmacy Reports Total Number of Reports During This Reporting Period a Stakeholder did not respond despite multiple outreach attempts. b These 7 reports affected 5 closed system entities. Page 66 of 139 120 7 No. w/1 report: 7b 7 145 During the reporting period, there are 4 instances in which a pharmacy dispensed drug from a prescription written by a non-enrolled prescriber. The TIRF REMS Access Program reached out to the non-enrolled prescribers to assist with enrollment. Of those 4 instances, two of the prescribers ultimately completed enrollment and two communicated that they do not intend to enroll. In all 4 instances, the pharmacy that dispensed drug from a prescription written by a non-enrolled prescriber received re-education on program requirements and was issued a notice for non-compliance. No additional compliance cases for these pharmacies have been identified as of the end of the reporting period. The TIRF REMS Access Program identified 4 unique non-enrolled DoD closed-system pharmacy locations that dispensed a TIRF product without REMS authorization in 16 instances. All 4 sites received drug from the same distributor. The distributor received reeducation on program requirements and was issued a notice for non-compliance for distributing TIRF medicines to a non-enrolled pharmacy. In addition, the DoD was re-educated on the closed system pharmacy process to validate the prescription with the TIRF REMS Access Program and receive an authorization code prior to dispensing to patients. There were no instances in which a TIRF was prescribed to an opioid non-tolerant individual reported during this reporting period. Additionally, there were no instances of inappropriate conversions between TIRF products reported during this reporting period. The following tables (Table 22) list resolved NC cases and potential NC events that remained pending as of the end of the reporting interval. FDA_1730 Table 22 Report No.1 20 Non-Compliance Reports in the Current Reporting Period: 29 October 2013 to 28 October 2014 Report Description ID#1211 (Case #15788194) [24-Month Assessment Report Non-Compliance] On 09 September 2013, a prescriber was contacted to request PPAFs for 5 patients who did not have one on file at least 10 days after enrollment. The prescriber provided PPAFs for 2 of the patients, but stated that 3 of the patients in question were not from his/her practice. Report Status Closed Mitigating Action On 10 September 2013, the TIRF REMS Access Program contacted the independent pharmacy associated with the REMS authorized prescriptions for additional information. The pharmacy was unwilling to provide any information on these 3 patients and disconnected the call. All transactions from the pharmacy were reviewed by the NCRT. Seven claims involving 6 patients (including the 3 patients noted above) were identified where the patient’s name was reversed (first name entered as last name, last name entered as first name) after the pharmacy received a rejection from the TIRF REMS Access Program for the reason “no PPAF on file." The pharmacist in charge was contacted on 04 October 2013 and the pharmacist in charge explained that these claims were from electronic prescriptions and processed with the information as it was provided (i.e., names were switched on original prescription). Based on this evidence, the pharmacy was issued a formal Warning for NonCompliance letter. Additionally, the pharmacy was required to provide a CAP that was approved by the NCRT on 06 November 2013 stating that all pharmacy staff members have been trained on the program and have been educated on the importance of inputting correct patient data prior to transmitting pharmacy claims. Additionally all TIRF REMS claims will be checked and verified by a pharmacist. [36-Month Assessment Report Update] The NCRT monitored this pharmacy from 06 November 2013 to 03 February 2014 to ensure that REMS requirements were followed by the pharmacy and that no claims were altered. As of 03 February 2014 the pharmacy submitted all claims in accordance with program requirements and there were no claims found with suspected non-compliance. This non-compliance case was closed FDA_1731 Report No.1 Report Description Report Status Mitigating Action on 03 February 2014 after no further non-compliance cases were observed. Since closing the non-compliance case, no additional non-compliance cases for this pharmacy have been identified. 21 ID# 1271 (Case# 12481943 & 15791475) [24-Month Assessment Report Non-Compliance] Prescriber was issued a first formal Notice for NonCompliance on 12 March 2013 for not submitting PPAFs. On 17 September 2013, the prescriber was again identified for not submitting PPAFs for an additional 11 patients who were at least 10 days past enrollment. The TIRF REMS Access Program made 3 attempts to contact the prescriber, but was advised by the prescriber’s office staff that the prescriber “refused to come to the phone regarding PPAF calls from TIRF REMS Access Program.” By 21 October 2013, only 1 of the 11 outstanding PPAFs were received, and 3 additional patients were identified who did not have a PPAF on file at least 10 days after enrollment. The prescriber submitted none of the outstanding 13 PPAFs. Additionally, seven new patients had been enrolled without a PPAF on file outside of the 10-day window. Bringing the prescribers’ total to 20 patients enrolled without a PPAF. A warning letter requesting a corrective action was issued to the prescriber 05 November 2013. Closed The TIRF REMS Access Program re-educated the prescriber on 03 October 2014. The prescriber advised that he thought his previous non-compliance cases were associated to his previous practice location. The prescriber was reeducated that non-compliance is associated with the prescriber directly, not the practice location. The prescriber stated that he now understands and will work with his office staff to ensure all PPAFs are submitted in the future. The prescriber submitted 4 of the 6 outstanding PPAFs. A second Warning Letter for non-compliance was submitted to the prescriber requiring that a CAP be submitted by 10 November 2014. The prescriber submitted the CAP the same day. The prescriber stated that he would make sure that each patient signs a form prior to leaving the office. The CAP was approved by the NCRT on 22 October 2014. Since closing this non-compliance case, no additional non-compliance cases for this prescriber have been identified. [36-Month Assessment Report Update] FDA_1732 Report No.1 Report Description Report Status Mitigating Action The prescriber failed to submit the corrective action by the deadline of 26 November 2013 and upon contacting the prescriber for a status update, the TIRF REMS Access Program was notified that the prescriber was no longer with the practice. The NCRT reviewed the case details and decided to proceed with suspending the stakeholder if a corrective action was not received by 09 January 2014. The prescriber’s former office was verbally provided this tentative date for suspension so alternate arrangements could be made for any patients continuing therapy. On 13 December 2013, the prescriber was successfully contacted at his new office. He stated that he did not receive the Warning Letter prior to leaving his previous practice. The prescriber was reeducated on the TIRF REMS Access Program requirements and he advised that he would work to submit the corrective action by the deadline of 09 January 2014. The prescriber failed to submit the corrective action and was suspended on 09 January 2014. The prescriber was notified to submit a corrective action by 24 January 2014 in order to be reinstated in the TIRF REMS Access Program. A CAP was received on 14 January 2014 stating that the prescriber will ensure that PPAFs are submitted the same day as when the prescription is written or at FDA_1733 Report No.1 Report Description Report Status Mitigating Action least within the 10 day grace period. To date, the prescriber has submitted PPAFs for 9 of the 20 initially identified patients. Since the prescriber has changed practices, he will be unable to submit PPAFs for the other 11 patients. The prescribers’ suspension was removed on 15 January 2014. Since the suspension has been lifted, the prescriber has enrolled 5 new patients in the TIRF REMS Access Program. PPAFs were received in a timely manner for 3 of the patients. The PPAFs for the remaining 2 patients were received after the end of this reporting period. On 18 September 2014 the prescriber was again identified as not submitting PPAFs for 6 new patients. ID#1292 (Case # 12482115 & 16243002) [24-Month Assessment Report Non-Compliance] Prescriber was issued a first formal Notice for NonCompliance on 8 March 2013 for not submitting PPAFs. [36-Month Assessment Report Update] On 21 October 2013, the prescriber was again identified as not submitting PPAFs for 5 new patients who were at least 10 days past enrollment. Closed The prescriber was contacted on 22 October 2013 and re-educated on the TIRF REMS Access Program requirements. The prescriber stated that he was aware of the TIRF REMS requirements and requested to be sent a list of patients who required PPAFs as he did not have time to discuss. After receiving the list of patients, the prescriber submitted 1 of the 5 PPAFs. On 05 November 2013, the prescriber was contacted by the TIRF REMS Access Program to discuss the outstanding PPAFs. The prescriber advised that he obtains a PPAF with each new patient for whom he prescribes a TIRF prescription and that there may be an issue with his administrative staff submitting the PPAFs. The prescriber stated he would investigate the PPAF submission process with his office staff and contact the Non-Compliance Team once the issue was identified and resolved. The prescriber contacted the TIRF REMS Access Program on 12 November FDA_1734 Report No.1 Report Description Report Status Mitigating Action 2013 to inform the Non-Compliance Team that there was an issue with his office staff submitting the PPAFs in a timely manner. The prescriber submitted the remaining 4 outstanding PPAFs. On 22 November 2013 a second formal Notice for Non-Compliance was issued to the prescriber since this was a repeat offense of enrolling >5 patients without a PPAF by the prescriber. Since closing the non-compliance case, no additional non-compliance cases for this prescriber have been identified. ID#1422 (Case# 12655619,16480983 & 18358046) [24-Month Assessment Report Non-Compliance] Prescriber was issued a first formal Notice for NonCompliance on 26 February 2013 for not submitting PPAFs. [36-Month Assessment Report Update] On 06 November 2013, the pharmacy was again identified as not following the REMS requirements when a prescriber called to discuss a patient who was having difficulties obtaining their prescription. When the TIRF REMS Access Program advised the prescriber that the patients’ PPAF had expired due to 180 days of no activity, the office staff stated that the patient was on monthly therapy. The pharmacy was contacted on 08 November 2013, and the authorized pharmacist confirmed that product was dispensed to the patient without REMS authorization in August, September, and October. All claims were cash claims. The pharmacy authorized designee was reeducated on the TIRF REMS Access Program The TIRF REMS Access Program confirmed that based on claim data the pharmacy received a rejection when trying to process a prescription written by Dr. S on 28 February 2014. The authorized representative for the pharmacy was contacted on 05 March 2014 and advised that he had a prescription for that patient from an enrolled prescriber (Dr. I) not Dr. S. A copy of the prescription was requested. On 06 March 2014, Dr. I was contacted to understand his relationship with the patient. The prescriber stated that he wrote 1 prescription for the patient on (b) (6) upon discharge from the hospital. Dr. I stated that the pharmacy had contacted him requesting that he submit a prescription dated 06 February 2014 as the prescription received for the patient via fax from the prescriber’s office was not legible. The prescriber advised the pharmacy that he had not written a prescription for the patient in February. Dr. I expressed his concern on this activity and indicated he would be submitting a detailed account of his interaction with the pharmacy in writing. When the prescriber contacted the patient, the patient’s mother confirmed that the prescription that was written for the patient by Dr. I at discharge in January was mailed to the pharmacy not faxed. The TIRF REMS Access Program received a copy of the prescription from the FDA_1735 Report No.1 Report Description requirements. On 15 November 2013, a second formal Notice for Non-Compliance letter was issued to the pharmacy. The pharmacy proactively provided a CAP on 22 November 2013 which stated that all pharmacy staff had received reinforcement training on the REMS requirement to receive a REMS authorization prior to dispensing TIRF medicines regardless of the method of payment. All re-trained staff was required to sign an acknowledgement that they understood the training. On 04 March 2014, a patient’s mother called the TIRF REMS Access Program to report that the patient had been hospitalized. During this conversation, she stated that the patient’s pharmacy contacted her on 28 February 2014 to notify her that the patients’ doctor was not enrolled (Dr. S), but the pharmacy had dispensed drug for the patient. Report Status Mitigating Action pharmacy on 06 March 2014. The prescription was written by Dr. I and dated 06 February 2014. The TIRF REMS Access Program reviewed retrospective suspected non-compliance events for the pharmacy. Previous non-compliance cases had been open and investigated, but after no suspicious activity was detected the cases were closed. During investigation of these cases the pharmacy communicated that the issues were due to data error issues. On 10 March 2014, the TIRF REMS Access Program received a copy of the prescription from Dr. S that was written for the patient and dated 06 February 2014. A contact to Dr. I was attempted on 11 March 2014 to obtain the status of his detailed account of his interaction with the pharmacy in writing. The office staff communicated that Dr. I was out of the office on an emergency but he had drafted a letter that he plans to submit to the TIRF REMS Access Program. (b) (6) On 13 March 2014, the prescription written by Dr. I on upon the patient’s discharge from the hospital was compared to the prescription received by the pharmacy that was dated 06 February 2014. The February prescription had void indications while the January prescription was presented clean. The pharmacy confirmed that the January prescription was received via FedEx which is why it was clean while the February prescription was provided via fax. As of 10 April 2014, the written account of the situation from either prescriber had not been received by the TIRF REMS Access Program. The pharmacy authorized representative was contacted and a formalized correspondence was sent to the pharmacy via fax on 10 April 2014 by the NCRT requesting additional information, CAP, and a written account of the incident be provided by 01 May 2014. On 25 April 2014, a written response and CAP was received from the pharmacy that detailed steps to eliminate manual errors made amongst the FDA_1736 Report No.1 Report Description Report Status Mitigating Action pharmacy staff. To prevent the issue in the future, the pharmacy stated they had added a dedicated pharmacist and licensed pharmacy technician to review and evaluate each TIRF REMS prescription that comes into the pharmacy and confirm the status of the patient, the certification of the doctor in the program and to make patients aware of proper protocol and procedure in regard to the TIRF REMS Access Program requirements. Additionally, a new pharmacy operating system would be installed to assist in accountability and tracing of all prescriptions. On 05 May 2014, the NCRT requested additional data from the pharmacy to ensure that the steps detailed in the CAP would address the non-compliance issues at the pharmacy. An addendum to the CAP was received from the pharmacy on 06 May 2014 which outlined the specific details for each instance where a data entry error occurred resulting in a non-compliance event. On 27 May 2014 the non-compliance case was closed and a Warning Letter was issued to the pharmacy acknowledging the receipt of the CAP and subsequent addendum. Since closing the non-compliance case, no additional non-compliance cases for this pharmacy have been identified. ID#1472 (Case #12482016, 14089163, & 15934584) [24-Month Assessment Report Non-Compliance] Prescriber was issued a formal Notice of NonCompliance on 09 April 2013 and a second formal Notice for Non-compliance on 27 August 2013 for not submitting PPAFs. [36-Month Assessment Report Update] On 29 September 2013, the prescriber was again identified for not submitting PPAFs for an additional Closed The TIRF REMS Access Program attempted to contact the prescriber 4 times from 30 September 2013 through 21 October 2013 for re-education on REMS requirements. The prescriber was unable to be reached. A list of patients missing PPAFs was provided via fax to the office staff at their request. The office staff additionally requested that all communication go through a specific office contact. On 07 November 2013, the TIRF REMS Access Program was notified that the prescriber was no longer affiliated with the practice. The office staff stated that no forwarding information for the prescriber was available. On 10 December 2013, additional outreach confirmed that the prescriber was FDA_1737 Report No.1 Report Description 5 patients who were at least 10 days past enrollment. Report Status Mitigating Action still affiliated with the practice. The office staff communicated that they had confused two prescribers in the practice, both of which are under investigation for non-compliance. The office staff stated that all communication needed to go through the specific office contact and requested that they receive no additional contact via phone for PPAFs; all PPAF requests must be provided via fax. The TIRF REMS Access Program re-faxed the list of patients with missing PPAFs to the prescriber’s office. An additional 13 patients without a PPAF on file were identified, for a total of 18 patients without a PPAF on file. On 17 December 2013, a Warning Letter was sent to the prescriber requiring a Corrective Action Plan to be submitted by 07 January 2014. On 20 December 2013, a Corrective Action Plan was received stating that the prescriber was compliant with program requirements and all PPAFs are submitted online. Copies of the confirmations for online submissions of PPAFs were provided for 15 of the 18 total patients. All confirmations provided were from mid-December after initiation of the non-compliance outreach. An additional 15 patients were identified on 08 January 2014 as not having a PPAF on file at least 10 days past enrollment, for a total of 18 outstanding PPAFs. On 09 January 2014, the Corrective Action Plan was denied by the NCRT since the plan submitted as it did not specify what the prescriber would do to ensure ongoing compliance with REMS requirements. The prescriber’s office was contacted and advised that the outstanding 18 PPAFs and a new Corrective Action Plan need to be submitted. A new version of the Corrective Action Plan was received on 10 January 2014, but it was signed by an office staff member. The TIRF REMS Access Program contacted the prescriber’s office on 13 January 2014 to inform the office that the prescriber must sign the plan. A prescriber signed Corrective Action Plan was received on 14 January 2014, stating that PPAFs will be done the same day or within 10 days of a prescription being issued. All 18 outstanding PPAFs were submitted. The Corrective Action Plan was approved by the NCRT on 15 January 2014. Since closing the non-compliance case, no additional non-compliance cases FDA_1738 Report No.1 Report Description Report Status Mitigating Action for this prescriber have been identified. 2 ID#152 (Case # 12482070 & 16449458) [24-Month Assessment Report Non-Compliance] Prescriber was issued a formal Notice for NonCompliance letter on 12 June 2013 for not submitting PPAFs. [36-Month Assessment Report Update] On 05 November 2013, the prescriber was again identified as not submitting PPAFs for 5 new patients who were at least 10 days past enrollment. Closed The TIRF REMS Access Program attempted to contact the prescriber 4 times from 05 November 2013 to 15 November 2013 and was only able to speak with office staff. Staff advised that the person previously responsible for TIRF REMS Access Program requirements (non-HCP staff member) was no longer at the practice. A request for contact correspondence was issued to the prescriber on 19 November 2013. The prescriber failed to contact the TIRF REMS Access Program for re-education by the 10 December 2013 deadline. The prescriber submitted 4 of the 5 outstanding PPAFs between 05 November 2013 and 07 December 2013. The remaining PPAF was for a patient that was identified as not continuing therapy. On 20 December 2013, a second formal Notice for Non-Compliance letter was issued to the prescriber since this was a repeat offense of enrolling >5 patients without a PPAF by the prescriber. As of the end of the reporting period, the remaining 1 PPAF had not been submitted. Since closing the non-compliance case, no additional non-compliance cases for this prescriber have been identified. ID#1622 (Case # 12481270 & 17070007) [24-Month Assessment Report Non-Compliance] Prescriber was issued a formal Notice for NonCompliance letter on 08 April 2013. [36-Month Assessment Report Update] On 20 December 2013, the prescriber was again identified during routine compliance monitoring as not submitting PPAFs for an additional 5 patients who were at least 10 days past enrollment. Closed On 06 January 2014, the TIRF REMS Access Program attempted to contact the prescriber for re-education on the REMS requirements. The prescriber was unavailable for re-education. The office staff requested a list of patients with missing PPAFs and the list was faxed to the office by the TIRF REMS Access Program. On 14 January 2014, during an outbound call the office staff advised that all patients on the list of missing PPAFs were one-time only prescriptions and they were attempting to get these patients to come back into the office to complete PPAFs but to date had been unsuccessful. The TIRF REMS Access Program reiterated that the prescriber needed to be re-educated directly to which the office staff advised that the prescriber would not be available as the prescriber’s Schedule II DEA license was suspended by the Texas Medical Board on 11 December 2013 and is currently under review and awaiting final outcome. FDA_1739 Report No.1 Report Description Report Status Mitigating Action On 15 January 2014, the prescriber was suspended in the TIRF REMS Access Program pending additional information from the Texas Medical Board regarding the status of the prescribers’ DEA license. On 17 January 2014, verbal and written confirmation was received from the Texas Medical Board and the prescriber was deactivated in the TIRF REMS Access Program. A Notice of Deactivation was sent to the prescriber on 20 January 2014 notifying the prescriber that he had been deactivated in the program, and that he could re-enroll in the TIRF REMS Access Program upon reinstatement of his DEA license. The 5 outstanding PPAFs from this non-compliance offense were not received as these patients were not continuing therapy. ID#1641 (Case # 12481214, 14089142, 16966461 & 19073509) [24-Month Assessment Report Non-Compliance] Prescriber was issued a first formal Notice for NonCompliance letter on 07 March 2013 and a second Notice for Non-Compliance letter on 11 July 2013 for not submitting PPAFs. [36-Month Assessment Report Update] On 13 December 2013, the prescriber was identified as not submitting PPAFs for 11 new patients. The TIRF REMS Access Program attempted to contact the prescriber on 16 December 2013 for reeducation on the REMS requirements. A message was left for the prescriber and the office staff was reeducated on the PPAF requirements. On 19 December 2013, the office staff requested a list of patients with missing PPAFs and the list was provided by the TIRF REMS Access Program via fax. On 23 December 2013, the TIRF REMS Access Closed The prescriber was contacted and re-educated on the REMS requirements on 17 April 2014. The prescriber advised that he was now on the pain board for a specific TIRF product and cannot be found non-compliant with program guidelines any longer. The TIRF REMS Access Program explained to the prescriber that the program is mandated by the FDA and no stakeholders are exempt from program requirements. The prescriber stated that the TIRF REMS Access Program should consider patient volume when assessing what is deemed as non-compliance. As of the 22 April 2014, the prescriber submitted 7 of the 9 PPAFs. On 24 April 2014, the NCRT approved suspension of the prescriber, pending successful outreach to the prescriber to inform him of the potential patient access issues. The prescriber was suspended and notified of the suspension on 29 April 2014. The prescriber submitted a Corrective Action Plan stating that the issue within the office was due to frequent turnover in staff and poor training for new staff. As a solution, the office will appoint someone in addition to the prescriber to oversee implementation of the TIRF REMS requirements. The prescriber also provided his personal cell phone number so that the TIRF REMS Access Program can contact him directly for any PPAF issues. The Corrective Action Plan was approved by the NCRT and prescriber’s suspension was lifted on 30 April 2014. To ensure compliance with timely FDA_1740 Report No.1 Report Description Program attempted to contact the prescriber for reeducation on the REMS requirements. A message was left for the prescriber. An additional 6 patients were identified without a PPAF at least 10 days past enrollment on 30 December 2013 for a total of 17 patients without a PPAF at least 10 days past enrollment. The physician was again unavailable when contacted. The prescriber submitted 8 of the 17 outstanding PPAFs. As of 20 January 2014, the prescriber had not contacted the TIRF REMS Access Program for reeducation. A Warning for Non-Compliance with a request for a Corrective Action Plan was issued to the prescriber on 24 January 2014. The deadline for the Corrective Action Plan was 14 February 2014. The prescriber submitted 5 of the 8 outstanding PPAFs. On 06 February 2014, an additional 16 patients were identified without a PPAF at least 10 days past enrollment. The TIRF REMS Access Program attempted to contact the prescriber on 07 February 2014. The office staff was re-educated on PPAF requirements and a message was left for the prescriber reminding him of the 14 February 2014 deadline for the Corrective Action Plan. The TIRF REMS Access Program attempted to contact the prescriber on 11 February 2014 and spoke with the prescribers PA. The prescriber’s PA was reeducated on PPAF requirements, and advised of the deadline for the Corrective Action Plan and the need to speak to the prescriber regarding the 19 patients for whom PPAFs had not been submitted. The prescriber’s PA requested that all documents be re- Report Status Mitigating Action PPAF submission the TIRF REMS Access Program conducted daily PPAF monitoring for the prescriber from 01 May 2014 through 27 June 2014. During this time no patients were identified as not having a PPAF on file at least 10 days past enrollment. The prescriber submitted all of the 9 outstanding PPAFs. Since closing the non-compliance case, no additional non-compliance cases for this prescriber have been identified. FDA_1741 Report No.1 Report Description Report Status Mitigating Action faxed to the office so she could review them with the prescriber. All requested documents were faxed to the office and the prescriber contacted the program on 11 February 2014 and was re-educated. The prescriber was unable to explain why PPAFs had not been received for the 19 patients as he provides one for each patient via fax. The prescriber’s Corrective Action Plan was received on 17 February 2014. On 18 February 2014, the prescriber submitted 14 of the 19 PPAFs and stated that he would work with his office staff to submit the remaining 5 PPAFs. The Corrective Action Plan was approved by the NCRT on 20 February 2014. All 5 outstanding PPAFs were submitted. On 03 April 2014, the prescriber was again identified as not submitting PPAFs for 9 new patients. ID#1651 (Case # 12481066, 14088956, 16966742 & 19221013) [24-Month Assessment Report Non-Compliance] Prescriber was issued a first formal Notice for NonCompliance Letter on 14 March 2013 and a second formal Notice for Non-Compliance on 12 August 2013 for not submitting PPAFs. [36-Month Assessment Report Update] On 13 December 2013, the prescriber was identified as not submitting PPAFs for 10 new patients. The TIRF REMS Access Program attempted to contact the prescriber on 18 December 2013. A message was left for the prescriber and the office staff was re-educated on PPAF requirements. On 07 January 2014, a non-HCP from the prescriber’s office The TIRF REMS Access Program attempted to contact the prescriber multiple times between 10 April 2014 and 30 April 2014. A list of patients missing PPAFs was faxed to the prescriber’s office as requested on 16 April 2014. On 18 April 2014, the TIRF REMS Access Program verified that all 6 PPAFs were submitted via the website, but after the non-compliance case had been initiated. Additional outreach attempts were made from 21 April 2014 to 30 April 2014 to re-educate the prescriber on TIRF REMS Access Program requirements. On 12 May 2014, the TIRF REMS Access Program became aware that the prescriber had been arraigned in federal court on 06 May 2014 on charges of healthcare fraud and distribution of controlled substances. The prescriber was released on a bond that states he cannot prescribe controlled substances. On 14 May 2014, the prescriber contacted the TIRF REMS Access Program with a request to opt out of the program. The request was submitted in writing on the prescriber’s letterhead. The prescriber was deactivated in the program. FDA_1742 Report No.1 Report Description Report Status Mitigating Action contacted the program requesting a list of patients missing PPAFs. A list was faxed by the TIRF REMS Access Program to the office. On 08 January 2014 a request for contact correspondence was issued to the prescriber since there had been multiple unsuccessful attempts to reach the prescriber for re-education. The prescriber failed to contact the TIRF REMS Access Program for re-education by the 22 January 2014 deadline. A Warning for Non-Compliance with a request for a Corrective Action Plan was issued to the prescriber on 29 January 2014. The prescriber failed to submit a Corrective Action Plan by the deadline of 19 February 2014. The TIRF REMS Access Program contacted the prescriber on 20 February 2014, and the prescriber requested an extension to his deadline agreeing to submit a Corrective Action Plan by 25 February 2014. The Corrective Action Plan was received on 25 February 2014 and approved by the NCRT on 26 February 2014. All 10 outstanding PPAFs were submitted. On 10 April 2014, the prescriber was again identified as not submitting PPAFs for 6 new patients. The prescriber has not contacted the program since 14 May 2014. The TIRF REMS Access Program will require NCRT approval if the prescriber attempts to enrolls in the program again. ID#166(Case #17402306) (b) (4) On 06 November 2013, was identified as dispensing a TIRF product for an outpatient without receiving REMS authorization. The pharmacy had initially been enrolled as an inpatient pharmacy, but also dispenses for outpatient use. The pharmacy attempted to enroll as an outpatient pharmacy but was unable to finalize their outpatient enrollment since they were unable to run The TIRF REMS Access Program re-educated the pharmacy on the closed system authorization process and requirements on 08 November 2013. On 12 December 2013, the pharmacy confirmed that the product had been ordered under the inpatient pharmacy enrollment. Dispensing records for all TIRF (b) (4) medicines dispensed through were requested by the TIRF REMS Access Program. On 17 January 2014, the requested dispensing records were received. The TIRF REMS Access Program compared the dispensing records to the REMS FDA_1743 Report No.1 Report Description Report Status test transactions. To accommodate a patient who was currently waiting for a TIRF medication, the pharmacy had enrolled on 05 September 2013 as a closed system pharmacy, but the TIRF medication was dispensed on 03 September 2013, prior to this enrollment date. Mitigating Action authorization data. The TIRF REMS Access Program confirmed that the only instance of non-compliance occurred on 03 September 2014 when the pharmacy dispensed for outpatient use prior to their closed system enrollment. On 07 February 2014, a formal Notice for Non-compliance was issued to the pharmacy. Since closing the non-compliance case, no additional non-compliance cases for this pharmacy have been identified. ID#1692 (Case #12481169 & 17657140) [24-Month Assessment Report Non-Compliance] Prescriber was issued a formal Notice for NonCompliance letter on 31 March 2013 for not submitting PPAFs. [36-Month Assessment Report Update] On 03 February 2014, the prescriber was again identified as not submitting PPAFs for 9 new patients since re-education on 31 March 2013. Closed On 12 February 2014, the prescriber was contacted and re-educated on the TIRF REMS Access Program requirements. The prescriber stated that he does complete a PPAF for each new patient and that there may be an issue with his office staff as there has been turnover since the last non-compliance investigation. The prescriber advised that he takes the program very seriously and will address the matter with his staff. On 17 February 2014, the prescriber’s office called to request a list of patients that were missing PPAFs. The list was faxed to the office. The prescriber submitted all 9 outstanding PPAFs. On 24 February 2014 a second formal Notice for Non-Compliance was issued to the prescriber since this was a repeat offense of enrolling >5 patients without a PPAF by the prescriber. The prescriber submitted 0 of the remaining 4 PPAFs had not been submitted. Since closing the non-compliance case, no additional non-compliance cases for this prescriber have been identified. ID#1772 (Case #13861166 & 18732022) [24-Month Assessment Report Non-Compliance] Prescriber was issued a formal Notice for NonCompliance on 13 August 2013 for not submitting PPAFs. [36-Month Assessment Report Update] Closed The TIRF REMS Access Program attempted to contact the prescriber on 20 March 2014 and spoke with the office staff. A list of patients missing PPAFs was provided verbally. A message was left for the prescriber to contact the TIRF REMS Access Program for re-education. On 07 April 2014, a request for contact correspondence was sent to the prescriber after multiple unsuccessful outreach attempts between 25 March 2014 and 07 April 2014. On 07 April 2014, the prescriber contacted the TIRF REMS Access program FDA_1744 Report No.1 Report Description Report Status On 20 March 2014, the prescriber was identified as not submitting PPAFs for 6 new patients since reeducation occurred on 13 August 2013. ID#1792 (Case #12482456, 18919365 & 20277540) [24-Month Assessment Report Non-Compliance] Prescriber was issued a first formal Notice for NonCompliance on 18 March 2013 for not submitting PPAFs. [36-Month Assessment Report Update] On 27 March 2014 the prescriber was identified as not submitting PPAFs for 16 patients. The TIRF REMS Access Program attempted to contact the prescriber on 02 April 2014 and spoke with the office staff. A list of patients missing PPAFs was faxed to the office per their request. A message was left for the prescriber during this contact and again on 04 April 2014. The prescriber submitted all 16 PPAFs. On 11 April 2014 a second formal Notice for NonCompliance was issued to the prescriber since this was a repeat offense of enrolling >5 patients without a PPAF by the prescriber. On 16 June 2014 the prescriber was again identified as not submitting PPAFs for 6 new patients who were at least 10 days past enrollment. The TIRF REMS Access Program attempted to Mitigating Action and was re-educated on the program requirements. He advised that he assumed his office staff was submitting the PPAFs. On 09 April 2014, a second formal Notice for Non-Compliance was issued to the prescriber since this was a repeat offense of enrolling >5 patients without a PPAF by the prescriber. The prescriber submitted all 6 outstanding PPAFs. Since closing the non-compliance case, no additional non-compliance cases for this prescriber have been identified. Closed The TIRF REMS Access Program re-educated the prescriber on 10 November 2014. The prescriber stated that he has been completing PPAFs and he is not sure why his office staff has not been submitting them. The prescriber submitted none of the 6 outstanding PPAFs. A second Warning for Non-Compliance was issued to the prescriber 13 November 2014 requiring that the prescriber submit a CAP by 04 December 2014. The prescriber submitted a CAP on 01 December 2014 stating that he has met with all of his current staff members to ensure that they understand the importance of the TIRF REMS Program and thoroughly understand the protocol for the completion and submission of PPAFs. Additionally, the prescriber has made several changes within his office, including having TIRF REMS forms readily available to be signed in every patient room and personally reviewing his schedule daily to confirm that every patient who was prescribed a TIRF medicine has been REMS enrolled. The CAP was approved by the NCRT on 03 December 2014 and this non-compliance case was closed. Since closing the non-compliance case, no additional non-compliance cases for this prescriber have been identified. FDA_1745 Report No.1 Report Description Report Status Mitigating Action contact the prescriber multiple times between 18 June 2014 and 27 June 2014. On 30 June 2014 a request for contact correspondence was issued to the prescriber as all outreach attempts had been unsuccessful. The prescriber was re-educated on the TIRF REMS Access Program requirements during an inbound call on 01 July 2014. The prescriber stated that he does complete PPAFs with each patient and relies on his office staff at multiple locations to submit the PPAFs to the program. The prescriber advised that he understands that it is his responsibility to submit a PPAF for each new patient prior to their first prescription. The prescriber submitted 5 of the 6 outstanding PPAFs. The last outstanding PPAF will not be submitted as it was for a patient identified as not continuing therapy. On 11 July 2014 the prescriber was issued a Warning with a request for a Corrective Action Plan. A Corrective Action Plan was received on 14 July 2014 and was denied by the NCRT as it did not align with the re-education that it was the prescriber’s responsibility to submit PPAFs for each patient. The prescriber was advised that a revised Corrective Action Plan was required. On 24 July 2014 a revised Corrective Action Plan was provided by the prescriber stating that moving forward the prescriber would have a folder in each exam room and he would ensure the patient signs while he was with them. The prescriber also stated that he would take personal responsibility to make sure patients are educated and PPAFs are signed. The Corrective Action Plan was approved by the NCRT FDA_1746 Report No.1 Report Description Report Status Mitigating Action and this non-compliance case was closed. On 10 November 2014 the prescriber was again identified as not submitting PPAFs for 6 new patients. ID#180 (Case #17656072, 19221002 & 19890126) On 31 January 2014 the prescriber was identified as not submitting PPAFs for 6 patients. On 03 February 2014, the prescriber’s office staff was re-educated on PPAF requirements. A list of patients missing PPAFs was faxed to the office at the request of the office staff. A request for contact correspondence was issued to the prescriber after multiple unsuccessful outreach attempts between 06 February 2014 and 14 February 2014. The prescriber failed to contact the TIRF REMS Access Program for re-education by the deadline of 10 March 2014. On 12 March 2014, a formal Notice for NonCompliance was issued to the prescriber. All of the 6 PPAFs were submitted. On 10 April 2014, the prescriber was again identified as not submitting PPAFs for 10 patients. The TIRF REMS Access Program contacted the prescriber on 10 April 2014 and provided re-education on the requirements of the program. The prescriber advised that he was not aware that his office staff was not completing the PPAFs and that he was not aware that a Notice of Non-Compliance was issued previously as he was out of the country at the time. The prescriber acknowledged that he understood it was his responsibility to complete and sign a PPAF with each new patient before writing the patient’s first Closed The TIRF REMS Access Program attempted to contact the prescriber on 05 June 2014. The office staff advised that none of the 5 patients were the prescriber’s patients. Copies of all 5 prescriptions were obtained from the pharmacy on 12 June 2014. All prescriptions were written by the prescriber. The prescriber was contacted on 19 June 2014 and re-educated on the TIRF REMS Access Program requirements. He confirmed that the patients were his patients and stated that he was not aware that it was his responsibility to submit PPAFs. The prescriber submitted all 5 PPAFs. On 11 July 2014 the prescriber was issued a Warning letter requiring a Corrective Action Plan be submitted. On 31 July 2014 a Corrective Action Plan (version 1) was received. The NCRT denied the plan as it did not address how the prescriber would complete PPAFs for outpatient dispensing in a hospital setting. The prescriber was advised that a revised Corrective Action Plan was required. On 11 August 2014 a revised Corrective Action Plan (version 2) was received. The plan again did not address what was requested after the denial of the first version of the Corrective Action Plan. The TIRF REMS Access Program attempted to contact the prescriber multiple times to discuss that a revised Corrective Action Plan was required. On 22 August 2014 a revised Corrective Action Plan (version 3) was received before the TIRF REMS Access Program could successfully contact the prescriber to discuss. The NCRT again denied the plan. A written request for a revised Corrective Action Plan was submitted to the prescriber on 29 August 2014. On 23 September 2014, an updated Corrective Action Plan (version 4) was received by the TIRF REMS Access Program. This revised plan was reviewed FDA_1747 Report No.1 Report Description Report Status prescription for a TIRF medicine. None of the outstanding 10 PPAFs were submitted and an additional patient without a PPAF on file was identified, making a total of 11 outstanding PPAFs. The prescriber submitted 8 of the 11 PPAFs. The other 3 outstanding PPAFs would not be submitted as the patient was identified as not continuing therapy. On 18 April 2014 a second formal Notice for NonCompliance was issued to the prescriber since this was a repeat offense of enrolling >5 patients without a PPAF by the prescriber. On 19 May 2014, the prescriber was identified as not submitting PPAFs for 5 new patients who were at least 10 days past enrollment. ID#1872 (Case #15425572 & 18641073) [24-Month Assessment Report Non-Compliance] Prescriber was issued a first formal Notice for NonCompliance on 24 September 2013 for not submitting PPAFs. [36-Month Assessment Report Update] On 17 March 2014, the prescriber was identified for not submitting PPAFs for 9 new patients who were at least 10 days past enrollment. The TIRF REMS Access Program attempted to contact the prescriber on 19 March 2014. The office staff was re-educated and a list of patients missing PPAFs was faxed to the office. A message was left for the prescriber. On 15 April 2014 a request for contact correspondence was sent to the prescriber after multiple unsuccessful contact attempts between 26 Mitigating Action and approved by the NCRT on 24 September 2014. Since closing the non-compliance case, no additional non-compliance cases for this prescriber have been identified. Closed The TIRF REMS Access Program re-educated the prescriber on 10 November 2014. The prescriber stated that he has been completing the PPAFs and is not sure why his office staff has not been submitting them, but he is going to investigate the issue immediately. The prescriber submitted none of the 9 outstanding PPAFs. The prescriber was issued a second Warning for Non-Compliance on 13 November 2014 requiring that a CAP be submitted by 04 December 2014. The prescriber submitted a CAP on 18 November 2014 stating that the office had technical issues with the website causing PPAFs to not be submitted in a timely manner. The prescriber advised that moving forward they will submit PPAFs via fax and keep paper files to ensure tracking of completion of enrollment. The prescriber submitted 8 of the 9 outstanding PPAFs. The prescriber is unable to submit the last outstanding PPAF as the patient was identified as not continuing therapy. On 20 November 2014, the TIRF REMS Access Program contacted the prescriber to get clarification on what difficulties the prescriber had accessing the website. An addendum to the CAP was received on 21 November 2014 clarifying that the website had worked fine initially but then they started FDA_1748 Report No.1 Report Description Report Status March 2014 and 14 April 2014. The prescriber failed to contact the team for re-education by the deadline of 06 May 2014. A call from the prescriber’s office staff regarding PPAF requirement questions was received on 09 May 2014. The TIRF REMS Access Program re-educated the office staff and the prescriber during the call. The prescriber stated that he now understood that it is his responsibility to ensure that each new patient has a PPAF on file. The prescriber submitted 7 of the 9 outstanding PPAFs. The other 2 outstanding PPAFs would not be submitted as the patients were identified as not continuing therapy. A second formal Notice for Non-Compliance was issued to the prescriber on 19 May 2014 since this was a repeat offense of enrolling >5 patients without a PPAF by the prescriber. On 06 November 2014 the prescriber was again identified as not submitting PPAFs for 9 new patients. ID#1882 (Case #13861174 & 18918829) [24-Month Assessment Report Non-Compliance] Prescriber was issued a first formal Notice for NonCompliance on 20 September 2013 for not submitting PPAFs. [36-Month Assessment Report Update] On 27 March 2014 the prescriber was identified as not submitting PPAFs for 6 new patients who were at least 10 days past enrollment. The TIRF REMS Access Program attempted to contact the prescriber multiple times between 31 Mitigating Action having technical issues with the website. The CAP and addendum were approved by the NCRT on 03 December 2014 and this non-compliance case was closed. Since closing the non-compliance case, no additional non-compliance cases for this prescriber have been identified. Closed The TIRF REMS Access Program re-educated the prescriber on 18 November 2014. The prescriber stated that the reason he has not submitted PPAFs is due to user error in completing the attestation electronic signature on the TIRF REMS website. The prescriber was reminded that the office will receive a confirmation from the website when a PPAF is submitted correctly and also provided directions for how to successfully complete and submit the PPAF with the electronic signature. Since closing the non-compliance case, no additional non-compliance cases for this prescriber have been identified. FDA_1749 Report No.1 Report Description Report Status Mitigating Action March 2014 and 24 April 2014. A request for contact correspondence was issued to the prescriber on 24 April 2014. On 20 April 2014, the prescriber’s office staff contacted the TIRF REMS Access Program to obtain a list of patients missing PPAFs. The office staff was re-educated on the TIRF REMS Access Program requirements and was verbally provided a list of patients missing PPAFs. On 12 May 2014 the prescriber was re-educated on the TIRF REMS Access Program requirements during an outbound call. The prescriber stated that PPAFs are submitted via fax and was not aware that PPAFs could be submitted online. The prescriber was provided his login information and provided a tutorial on how to submit PPAFs online. The prescriber submitted 5 of the 6 outstanding PPAFs. The last outstanding PPAF would not be submitted as the patient was identified as not continuing therapy. On 20 May 2014 a second formal Notice for NonCompliance was issued to the prescriber since this was a repeat offense of enrolling >5 patients without a PPAF by the prescriber. On 06 November 2014 the prescriber was again identified as not submitting PPAFs for 6 new patients. ID#1952 (Case #12925513 & 19073027) [24-Month Assessment Report Non-Compliance] Prescriber was issued a first formal Notice for NonCompliance on 17 May 2013 for not submitting PPAFs. Closed The TIRF REMS Access Program attempted to contact the prescriber on 03 April 2013 for re-education. A message was left for the prescriber and the office staff was re-educated. A list of the patients missing PPAFs was requested and was faxed to the office. A request for contact correspondence was issued to the prescriber on 24 April 2014 after multiple unsuccessful contact attempts between 11 April 2014 and FDA_1750 Report No.1 Report Description Report Status 24 April 2014. The prescriber failed to contact the TIRF REMS Access Program for re-education by the deadline of 15 May 2014. An additional 3 patients without PPAFs were identified for a total of 11 outstanding PPAFs. On 21 May 2014 a Warning Letter was issued to the prescriber, requiring that a Corrective Action Plan be submitted by 11 June 2014. A Corrective Action Plan was received on 11 June 2014. The Corrective Action Plan was denied by the NCRT as the plan did not address why the non-compliance event occurred. Additional unsuccessful contacts were made in an attempt to reeducate the prescriber and to request a revised Corrective Action Plan. The prescriber submitted 1 of the outstanding PPAFs and during an outreach attempt, the office staff communicated that the remaining 10 outstanding PPAFs would not be submitted, as the patients were not continuing therapy. A copy of the Corrective Action Plan template was faxed at the request of the office staff. On 26 June 2014, the NCRT decided to suspend the prescriber until a revised CAP was received. The TIRF REMS Access Program contacted the prescriber’s office to communicate the suspension. The office staff stated that they would ensure a revised Corrective Action Plan is submitted immediately. A revised Corrective Action Plan was received on 27 June 2014. The NCRT required additional information before approval of the Corrective Action Plan. The prescriber submitted a supplement to the Corrective Action Plan and the plan was approved on 30 June 2014. The prescriber’s suspension was removed and he was monitored until 01 August 2014. The non-compliance case was closed after no additional non-compliance cases were identified during this time period. Since closing the non-compliance case, no additional non-compliance cases for this prescriber have been identified. [36-Month Assessment Report Update] On 03 April 2014 the prescriber was identified as not submitting PPAFs for 8 new patients who were at least 10 days past enrollment. ID#2042 (Case #12922697 & 19357451) [24-Month Assessment Report Non-Compliance] Prescriber was issued a first formal Notice for NonCompliance on 14 June 2013 for not submitting Mitigating Action Closed The TIRF REMS Access Program attempted to contact the prescriber multiple times between 21 April 2014 and 07 May 2014. A request for contact correspondence was sent to the prescriber on 07 May 2014. The prescriber failed to contact the team for re-education by the deadline of 28 May 2014. A Warning letter was submitted to the prescriber on 05 June 2014, requiring FDA_1751 Report No.1 Report Description Report Status PPAFs. [36-Month Assessment Report Update] On 17 April 2014, the prescriber was identified as not submitting PPAFs for 5 new patients who were at least 10 days past enrollment. Mitigating Action that the prescriber submit a Corrective Action Plan by 26 June 2014. A Corrective Action Plan was received on 24 June 2014 stating that the patients with missing PPAFs were not continuing therapy and that moving forward forms would be completed online with each prescription. The plan was approved by the NCRT on 26 June 2014. The prescriber was monitored from 26 June 2014 to 26 July 2014 and the non-compliance case was closed after no further non-compliance cases were identified during this time period. Since closing the non-compliance case, no additional non-compliance cases for this prescriber have been identified. ID#2142 (Case #12925438 & 20277916) 2013 [24-Month Assessment Report Non-Compliance] Prescriber was issued a first formal Notice for NonCompliance on 07 May 2013 for not submitting PPAFs. [36-Month Assessment Report Update] On 16 June 2014 the prescriber was identified as not submitting PPAFs for 5 new patients who were at least 10 days past enrollment. Closed The TIRF REMS Access Program re-educated the prescriber on 20 June 2014. The prescriber stated that his office staff should be sending PPAFs after they are completed. He stated that he would have a meeting with his staff to reeducate on proper submission of PPAFs. The prescriber submitted 1 of the 5 outstanding PPAFs. The remaining 4 PPAFs would not be submitted as the patients were identified as not continuing therapy. On 26 June 2014 a second formal Notice for Non-Compliance was issued to the prescriber since this was a repeat offense of enrolling >5 patients without a PPAF by the prescriber. Since closing the non-compliance case, no additional non-compliance cases for this prescriber have been identified. ID#2172 (Case #12482378 & 20214979) [24-Month Assessment Report Non-Compliance] Prescriber was issued a first formal Notice for NonCompliance on 13 March 2013 for not submitting PPAFs. [36-Month Assessment Report Update] On 11 June 2014, the prescriber was identified as not submitting PPAFs for 5 new patients who were at least 10 days past enrollment. Closed The TIRF REMS Access Program re-educated the prescriber on 17 June 2014. The prescriber stated that he had not submitted the PPAFs as he did not know that he had to submit PPAFs for patients that he would only be seeing one time. The prescriber submitted 4 of the 5 outstanding PPAFs. The last PPAF would not be submitted as the patient was identified as not continuing therapy. A second formal Notice for Non-Compliance was issued to the prescriber on 26 June 2014 since this was a repeat offense of enrolling >5 patients without a PPAF by the prescriber. Since closing the non-compliance case, no additional non-compliance cases for this prescriber have been identified. FDA_1752 Report No.1 Report Description Report Status Mitigating Action ID#2412 (Case #12903118 & 20954331) [24-Month Assessment Report Non-Compliance] Prescriber was issued a first formal Notice for NonCompliance on 17 April 2013 for not submitting PPAFs. [36-Month Assessment Report Update] On 08 August 2014, the prescriber was identified as not submitting PPAFs for 5 new patients who were at least 10 days past enrollment. Closed The TIRF REMS Access Program re-educated the prescriber on 18 August 2014. The prescriber advised that he had not submitted PPAFs as he changed his EMR system and some of the patient data has not converted over. The prescriber stated that his system is now improved and he will be more mindful in the future. The prescriber submitted 4 of the 5 PPAFs. The last outstanding PPAF would not be submitted as the patient was identified as not continuing therapy. A second formal Notice for Non-Compliance was issued to the prescriber on 28 August 2014 since this was a repeat offense of enrolling >5 patients without a PPAF by the prescriber. Since closing the non-compliance case, no additional non-compliance cases for this prescriber have been identified. ID#243 (Case #19074028 & 20954272) On 03 April 2014 the prescriber was identified as not submitting PPAFs for 5 patients. The TIRF REMS Access Program attempted to contact the prescriber multiple times between 04 April 2014 and 09 May 2014. A request for contact was issued to the prescriber after multiple unsuccessful contact attempts. The prescriber failed to contact the program for re-education by the deadline of 30 May 2014. A formal Notice of Non-Compliance was issued to the prescriber on 06 June 2014. None of the 5 outstanding PPAFs were submitted as all patients were identified as not continuing therapy. On 08 August 2014 the prescriber was again identified as not submitting PPAFs for 7 new patients who were at least 10 days past enrollment. Closed The TIRF REMS Access Program re-educated the prescriber on 27 August 2014. The prescriber stated that her office staff had been submitting completed PPAFs to the pharmacy instead of the TIRF REMS Access Program. She advised that they have corrected the issue and that all PPAFs should be submitted correctly moving forward. The prescriber submitted all 7 outstanding PPAFs. On 04 September 2014 a second formal Notice for Non-Compliance was issued to the prescriber since this was a repeat offense of enrolling >5 patients without a PPAF by the prescriber. Since closing the non-compliance case, no additional non-compliance cases for this prescriber have been identified. ID#2492 (Case #13861249 & 20761198) [24-Month Assessment Report Non-Compliance] Closed The TIRF REMS Access Program attempted to contact the prescriber multiple times between 31 July 2014 and 11 August 2014. A request for contact correspondence was issued to the prescriber after all attempts for contact were FDA_1753 Report No.1 Report Description Report Status Prescriber was issued a first formal Notice for NonCompliance on 13 August 2013 for not submitting PPAFs. [36-Month Assessment Report Update] On 24 July 2014, the prescriber was identified for not submitting PPAFs for 8 new patients who were at least 10 days past enrollment. Mitigating Action unsuccessful. The prescriber failed to contact the program for re-education by the deadline of 09 August 2014. The prescriber submitted 1 of the 8 outstanding PPAFs. The remaining 7 PPAFs will not be submitted as the patients were identified as not continuing therapy. The prescriber was re-educated during an inbound call on 18 September 2014. The prescriber stated that the reason he did not submit PPAFs was because he was working at 3 different offices. The prescriber stated that he now works at one location and understands that it is his responsibility to submit a PPAF for each new patient prior to their first prescription. A second formal Notice for Non-Compliance was issued to the prescriber on 25 September 2014 since this was a repeat offense of enrolling >5 patients without a PPAF by the prescriber. Since closing the non-compliance case, no additional non-compliance cases for this prescriber have been identified. ID#2502 (Case #12903203 & 21174276) [24-Month Assessment Report Non-Compliance] Prescriber was issued a first formal Notice for NonCompliance on 25 April 2013 for not submitting PPAFs. [36-Month Assessment Report Update] On 21 August 2014, the prescriber was identified for not submitting PPAFs for 5 new patients who were at least 10 days past enrollment. Closed The TIRF REMS Access Program re-educated the prescriber on the program requirements on 09 September 2014. The prescriber stated that the reason he did not submit the PPAFs is because he only saw these patients one time. He stated that he now understands that a PPAF is required for each new patient prior to their first prescription regardless of the length of therapy. The prescriber submitted all of the 5 outstanding PPAFs. A second formal Notice for Non-Compliance was issued to the prescriber on 19 September 2014 since this was a repeat offense of enrolling >5 patients without a PPAF by the prescriber. Since closing the non-compliance case, no additional non-compliance cases for this prescriber have been identified. ID#2642 (Case #13861305 & 21103182) [24-Month Assessment Report Non-Compliance] Prescriber was issued a first formal Notice for NonCompliance on 12 August 2013 for not submitting PPAFs. Closed The TIRF REMS Access Program attempted to contact the prescriber for reeducation multiple times between 20 August 2014 and 08 September 2014. A request for contact was issued to the prescriber after all attempts were unsuccessful. The prescriber failed to contact the program for re-education by the deadline of 02 October 2014. The prescriber did not submit any of the outstanding PPAFs as all 6 patients were identified as not continuing therapy. FDA_1754 Report No.1 Report Description Report Status Mitigating Action [36-Month Assessment Report Update] On 18 August 2014, the prescriber was identified for not submitting PPAFs for 6 new patients who were at least 10 days past enrollment. A second formal Notice for Non-Compliance was issued to the prescriber on 09 October 2014 since this was a repeat offense of enrolling >5 patients without a PPAF by the prescriber. Since closing the non-compliance case, no additional non-compliance cases for this prescriber have been identified. ID#2672 (Case #15425426 & 21322228) [24-Month Assessment Report Non-Compliance] Prescriber was issued a first formal Notice for NonCompliance on 11 October 2013 for not submitting PPAFs. [36-Month Assessment Report Update] On 02 September 2014, the prescriber was identified as not submitting PPAFs for 6 new patients. The TIRF REMS Access Program attempted to contact the prescriber multiple times between 02 September 2014 and 15 September 2014. A request for contact correspondence was issued to the prescriber on 18 September 2014 after all attempts to contact were unsuccessful. The prescriber failed to contact the TIRF REMS Access Program for re-education by the deadline of 09 October 2014. The prescriber submitted 2 of the 6 outstanding PPAFs. The remaining 4 PPAFs would not be submitted as those patients were identified as not continuing therapy. A second formal Notice for Non-Compliance was issued to the prescriber on 16 October 2014 since this was a repeat offense of enrolling >5 patients without a PPAF by the prescriber. Since closing the non-compliance case, no additional non-compliance cases for this prescriber have been identified. ID#270 (Case #19220984 & 21275629) On 10 April 2014, the prescriber was identified as not submitting PPAFs for 5 patients. The TIRF REMS Access Program attempted to contact the prescriber multiple times between 11 April 2014 and 28 April 2014. A request for contact was issued on 29 April 2014 after all attempts for contact we unsuccessful. The prescriber failed to contact the program for reeducation by the deadline of 20 May 2014. A formal Notice for Non-Compliance was issued to the The TIRF REMS Access Program attempted to contact the prescriber multiple times between 28 August 2014 and 11 September 2014. A request for contact correspondence was issued to the prescriber after all contact attempts were unsuccessful. The prescriber failed to contact the TIRF REMS Access Program for re-education by the deadline of 07 October 2014. The prescriber submitted none of the 5 outstanding PPAFs as the patients were identified as not continuing therapy. On 17 October 2014 a second formal Notice for Non-Compliance was issued to the prescriber since this was a repeat offense of enrolling >5 patients without a PPAF by the prescriber. FDA_1755 Report No.1 Report Description prescriber on 29 May 2014. The prescriber submitted none of the outstanding PPAFs as all patients were identified as not continuing therapy. Report Status Mitigating Action Since closing the non-compliance case, no additional non-compliance cases for this prescriber have been identified. On 28 August 2014, the prescriber was again identified as not submitting PPAFs for 5 new patients. 1 2 Case was included in the Non-Compliance Activity Reports by Stakeholder Table and as a non-compliance narrative in the 24-Month Report. Case was included in the Non-Compliance Activity Reports by Stakeholder Table in the 24-Month Report. FDA_1756 7 7.1 SAFETY SURVEILLANCE Adverse Event Reporting [Metric 29] TIRF Sponsors process adverse event reports related to their specific products and report to the FDA according to current regulations outlined in 21 CFR 314.80 and the sponsor’s respective Standard Operating Procedures (SOPs). 7.2 TRIG Sponsor Adverse Event Data of Interest [Metric 30] During discussions between the FDA and the TRIG, the FDA requested an aggregate root cause analysis (RCA) be conducted of all spontaneous adverse event reports of addiction, death, overdose, and pediatric exposure from the TIRF Sponsors. Based on this request the TRIG Sponsor companies used a third party, UBC, to conduct this analysis. The sponsors identified the appropriate Medical Dictionary for Drug Regulatory Activities (MedDRA) codes to provide data including narratives or MedWatch forms which UBC summarized based on the FDA’s request (see Appendix 12.1). Reports were reviewed and duplicates consolidated. Originally case reports were selected based on the specified Preferred Terms (PTs); upon UBC’s review of the narrative information some case reports did not meet the specified criteria and were excluded from the analysis. Additionally, literature reports and reports from Poison Centers were excluded. Metrics of interest included: the number of event reports in each event category of interest (addiction, death, overdose, pediatric exposures); counts of adverse events related to inappropriate conversions between TIRF products; counts of adverse events related to accidental and unintentional exposures; and counts of adverse events that are associated with use of TIRF medicines in non-opioid tolerant patients. As per the agreement with FDA, the reporting period for this analysis was 29 October 2013 to 28 August 2014 to allow sufficient time to complete this analysis. There were 367 unique case reports that met the specified criteria. After a review of the 367 MedWatch Forms or narratives, no reports of inappropriate conversions between TIRF products were noted. None of the narratives indicated accidental or unintentional exposures, or non-opioid tolerance. 7.3 Number of Adverse Events of Special Interest The total number of cases of interest are presented in Table 23 below. Of the 367 cases, 362 (98.6%) had an outcome of death, 4 (1%) were reports of addiction, and 2 (0.5%) were pediatric exposures. There were no reported overdoses. Only one case was included in more than one category: one pediatric exposure had an outcome of death. FDA_1757 Table 23 Number of Cases of Adverse Events of Special Interest AEs of Interest Number of Reports Percentage? Total Nlunber of ABS of Interest 367 Addiction 4 1 . 1% Death 362 98.6% Overdose 0 0 Pediatric Exposure 2 0.5% aCases may have more than one adverse event of interest. Table 24 shows the reporting rates for each of the adverse events of special interest using two different denominators. The ?rst denominator is the munber of prescriptions for TIRF products in the time period. Rates are expressed per 100,000 prescriptions. The second is the munber of patients known to be exposed to TRF products dlu?ing the period of interest: 29 October 2013 to 28 August 2014. Rates are expressed per 100,000 exposed population. Table 24 Rate of Adverse Events by Total Prescriptions and Total Patients Number of Adverse Rate of Adverse Events by Rate of Adverse Events by Events Prescriptions' Number of Patients? 94,464) 14,772) Addiction 4 4.23 27.07 Death 362 383.21 2450.58 Overdose 0 - - Pediatric Exposure 2 2.1 1 13.53 aRates are expressed per 100.000 prescriptions. bRates are expressed per 100.000 exposed population. Fom? cases were classi?ed as cases of addiction. While all form were reported dining this reporting period, one case report described events occuning in 2012. Of the foru? cases, one was considered medically signi?cant and was hospitalized; 1 had an outcome of ?not recovered? at the time of the cut off (28 August 2014); 1 had an outcome of ?resolved?; and outcome was lniknown. Table 25 provides details of these four cases. 758 Table 25 Cases of Addiction Received from TRIG Sponsors during the Reporting Period: 29 October 2013 - 28 August 2014 Patient Date UBC TIRF Concomitant Event ID Age Gender Event Report Preferred Term(s) Indication(s) Duration Medications Co?Suspect Product(s) Outcome 1271 71 Male 2014 13MAY2014 Drug dependence. Drug Cancer pain Unknown None reported None reported Medically tolerance. Drug Signi?cant. withdrawal Hospitalized Inappropriate schedule of drug administration 1285 64 Female 01JAN2014 27MAY2014 Abdominal distension. Chronic pain.spinal Unknown Thyroid. Klonopin None reported Not Adverse reaction. Recovered" Anxiety. Bedridden. Not Resolved Cardiac discomfort. Device defective. Device issue. Drug dependence. Fear. General physical health deterioration. Muscular weakness. Abdominal distension. Anger. Anxiety. Detoxi?cation. Feeling abnormal. Pain. Spinal disorder. Weight increased 759 Patient Date UBC TIRF Concomitant Event ID Age Gender Event Report Preferred Term(s) Indication(s) Duration Medications Co?Suspect Product(s) Outcome 1329 72 Male 2012 ZSJUN 2014 Haernorrhage Pain Unknown Morphine. Trarnadex. None reported Recovering" intracranial. Headache. Marijuana Resolving Incorrect dosage administered. Musculoskeletal discomfort. Weight decreased 1360 54 Male 14IUL2014 14IUL2014 Drug \?thdrawal Back pain. neck pain 2 Years None reported None reported Unknown Intentional drug misuse. Off label use The overdose table below represents a group of MedWatch forms generated as the result of one reporter notifying one sponsor of 23 cases of overdose and diversion. In early November 2013, The National Association of Drug Diversion Investigators (N ADDI) contacted a TIRF sponsor company indicating over twenty overdoses occurred in one cormty over a 5 day period. NADDI reported there had been 2 deaths and one person was in critical condition. In some cases Nar?can (naloxone hydrochloride injection) was used in the ?eld to save lives. Two arrests had been made and over one ormce of fentanyl was seized. In the days following this initial report, NADDI contacted the sponsor again to provide an update on the total number of cases and the suspect fentanyl seized. They reported a total of 23 overdoses, three which resulted in death. The fentanyl seized was off? white and somewhat chunky in consistency similar to powder cocaine. Upon investigation, NADDI noted that they do not feel this was a drug diversion as there were high quantities and no recent fentanyl thefts had been reported. The substance was sold in sandwich bags as 1-1.5 ounces as heroin but when tested was found to be fentanyl. NADDI stated they felt this fentanyl was made in a lab in the southwest US or across the border. While these cases do not meet the requirements for reporting within this REMS assessment, the sponsor has chosen to include these cases as the initial report could not rule out fentanyl as the substance in question. These reports are not included in the cormts of cases of adverse events of interest or in the prescription and population rates because it is clear that a TIRF product was not involved. 760 Table 26 Cases of Overdose Received from TRIG Sponsors during the Reporting Period: 29 October 2013 - 28 August 2014 Patient Date UBC TIRF Concomitant Event ID Age Gender Event Report Preferred Term(s) Indication(s) Duration Medications Co?Suspect Product(s) Outcome 1038 UNK Male 01NOV2013 20NOV2013 Drug diversion. Unknown Unknown None reported None reported Death Overdose 1039 UNK Unknown 0 1NOV2013 20NOV2013 Drug diversion. Unknown 2 Years None reported None reported Death Overdose 1040 UNK Unknown 0 1NOV20 1 3 20NOV20 3 Brain death. Drug Unknown Unknown None reported None reported Death diversion. Overdose 104 1 UNK Unknown 0 1NOV20 1 3 20NOV20 3 Drug diversion. Unknown Unknown None reported None reported Unknown Overdose 1042 UNK Unknown 01NOV2013 20NOV2013 Drug diversion. Unknown Unknown None reported None reported Unknown Overdose 1043 UNK Unknown 01NOV2013 20NOV2013 Drug diversion. Unknown Unknown None reported None reported Unknown Overdose 1044 UNK Unknown 01NOV2013 20NOV2013 Drug diversion. Unknown Unknown None reported None reported Unknown Overdose 1045 UNK Unknown 01NOV2013 20NOV2013 Drug diversion. Unknown Unknown None reported None reported Unknown Overdose 1046 UNK Unknown 01NOV2013 20NOV2013 Drug diversion. Unknown Unknown None reported None reported Unknown Overdose 1047 UNK Unknown 01NOV2013 20NOV2013 Drug diversion. Unknown Unknown None reported None reported Unknown Overdose 1048 UNK Unknown 01NOV2013 20NOV2013 Drug diversion. Unknown Unknown None reported None reported Unknown Overdose 1049 UNK Unknown 01NOV2013 20NOV2013 Drug diversion. Unknown Unknown None reported None reported Unknown Overdose 1050 UNK Unknown 01NOV2013 20NOV2013 Drug diversion. Unknown Unknown None reported None reported Unknown Overdose 1051 UNK Unknown 01NOV2013 20NOV2013 Drug diversion. Unknown Unknown None reported None reported Unknown Overdose 761 Patient Date UBC TIRF Concomitant Event ID Age Gender Event Report Preferred Term(s) Indication(s) Duration Medications Co?Suspect Product(s) Outcome 1052 UNK Unknown 01NOV2013 20NOV2013 Drug diversion. Unknown Unknown None reported None reported Unknown Overdose 1053 UNK Unknown 01NOV2013 20NOV2013 Drug diversion. Unknown Unknown None reported None reported Unknown Overdose 1054 UNK Unknown 01NOV2013 20NOV2013 Drug diversion. Unknown Unknown None reported None reported Unknown Overdose 1055 UNK Unknown 01NOV2013 20NOV2013 Drug diversion. Unknown Unknown None reported None reported Unknown Overdose 1056 UNK Unknown 01NOV2013 20NOV2013 Drug diversion. Unknown Unknown None reported None reported Unknown Overdose 1057 UNK Unknown 01NOV2013 20NOV2013 Drug diversion. Unknown Unknown None reported None reported Unknown Overdose 1058 UNK Unknown 01NOV2013 20NOV2013 Drug diversion. Unknown Unknown None reported None reported Unknown Overdose 1059 UNK Unknown 01NOV2013 20NOV2013 Drug diversion. Unknown Unknown None reported None reported Unknown Overdose 1060 UNK Unknown 01NOV2013 20NOV2013 Drug diversion. Unknown Unknown None reported None reported Unknown Overdose 762 The data provided by the six TRIG sponsors showed 362 cases with an outcome of death (Table 27). Of those, 223 (62%) had a preferred term of death with no cause of death indicated, 83 (23%) cases had a preferred term of a malignancy (cancer, carcinoma, myeloma, metastatic, lymphoma, glioblastoma, leukemia, neoplasm). There was one case with the term “mass” reported as the preferred term. Respiratory failure and respiratory depression appear as preferred terms for five cases. Six (2%) cases have a preferred term of cardiac death, cardiac arrest or myocardial infarction. One case (0.3%) of death was a result of suicide. The reporter indicated that the patient committed suicide due to pain after stopping fentanyl. Forty seven of the 362 reported deaths were identified through the TIRF REMS Access Programs PPAF renewal process. That is, during the outreach to the prescribers’ offices to request a PPAF renewal, the program learned of 47 patient deaths. FDA_1763 Table 27 Cases of Death Received from TRIG Sponsors during the Reporting Period: 29 October 20 13 - 28 August 2014 Patient Date UBC TIRF Concomitant Event ID Age Gender Event Report Preferred Term(s) Indication(s) Duration Medications Co?Suspect Product(s) Outcome 100 1 67 Female 0 290C T20 13 Death. Adverse event Pain Unknown None reported None reported Death 1002 50 Male 0 1 JAN 20 1 3 290C T20 13 Death. Adverse event Unknown Unknown None reported None reported Death 1003 66 Male 29IUN2013 29OCT2013 Death Cancer pain 2013 -06-12 - Oxycodone None reported Death 20 1 3 -O6-29 1004 62 Female Unknown 290C T20 13 Death Unknown Unknown None reported None reported Death 1005 41 Female 2013 29OCT2013 Disease progression Unknown Unknown None reported None reported Death 1006 78 Male 2013 29OCT2013 Death Unknown Unknown None reported None reported Death 1007 5 7 Female 07OCT2013 300C T20 13 Death Unknown Unknown None reported None reported Death 1008 UNK Female Unknown 300C T20 13 Death Cancer pain 2013 -06-12 - None reported None reported Death UNK 1009 UNK Male Unknown 300C T20 13 Death Cancer pain 2013 -06-12 - None reported None reported Death UNK 1010 UNK Female Unknown 300C T20 13 Death Cancer pain 2013 -O6- 1 2 - None reported None reported Death UNK 101 UNK Male Unknown 300C T20 13 Death Cancer pain 2013 -06- 2 - None reported None reported Death UNK 1012 UNK Male Unknown 300C T20 13 Death Cancer pain 2013 -06-12 - None reported None reported Death UNK 1013 UNK Female Unknown 300C T20 13 Death Cancer pain 2013 -06-12 - None reported None reported Death UNK 10 14 48 Female Unknown 300C T20 13 Death Unknown Unknown None reported Fentanyl Citrate Death 10 1 5 52 Male Unknown 0 1NOV20 3 Neoplasm malignant. Unknown Unknown None reported None reported Death Treatment noncompliance 10 16 69 Female Unknown 01NOV2013 Disease progression. Unknown 2 Years None reported None reported Death Treatment noncompliance 10 7 54 Male Unknown 0 1NOV20 3 Neoplasm malignant Unknown Unknown None reported None reported Death 1018 73 Female 2013 01NOV2013 Disease progression Unknown Unknown None reported None reported Death 10 19 64 Male Unknown 04NOV20 3 Death Unknown Unknown None reported Fentanyl itrate Death 1020 62 Male Unknown 14NOV20 3 Death Unknown Unknown None reported None reported Death 764 Patient Date UBC Concomitant Event ID Age Gender Event Report Preferred Term(s) Indication(s) Duration Medications Co?Suspect Product(s) Outcome 102 1 78 Female 0 1 AN 20 1 3 14NOV2013 Cardiac arrest. Unknown Unknown None reported Fentanyl Patch. Death Conduction disorder. Hydromorphone Lethargy. Respiratory arrest. Respiratory depression. Sornnolence 1025 59 Female 0 1 JAN 20 1 3 14NOV2013 Acidosis. Blood Unknown Unknown None reported Fentanyl Patch Death creatinine increased. Cardiac arrest. Coma. Hypotension. Hypothermia. Renal failure. Respiratory depression 103 1 5 1 Female Unknown 18NOV2013 Death Unknown Unknown None reported None reported Death 1032 64 Male Unknown 18NOV2013 Death Unknown Unknown None reported None reported Death 1033 50 Female Unknown 18NOV2013 Death Unknown Unknown None reported None reported Death 1034 60 Male 18NOV2013 Death. Drug prescribing Unknown Unknown None reported None reported Death error 103 5 UNK Male Unknown 1 8NOV2013 Death Unknown Unknown None reported None reported Death 1036 64 Female 10NOV201 3 19NOV2013 Death Unknown Unknown None reported None reported Death 103 7 5 3 Female 2 5MAR201 2 19NOV2013 Death Rectal cancer Unknown Adderall. Dilaudid. None reported Death Lorazepam. Oxycontin. Wellbutrin. Zana?ex 1061 65 Female 01] AN 20 3 22NOV2013 Drug me?ectiV'e. Breakthrough cancer Unknown Oxycontin. Oxy IR. None reported Death Cardiac arrest. Death. pain Duragesic. Methadone. Malignant neoplasm Vicodin progression. Myocardial infarction. Pain. Systemic lupus erythematosus 1062 35 Male Unknown 26NOV2013 Death. Treatment Unknown Unknown None reported None reported Death noncompliance 1063 41 Female 05NOV2013. 03DEC2013 Death. Adverse event. Breakthrough cancer Unknown Fentanyl. Roxanol None reported Death 010CT2013 Hospitalisation pain 1064 69 Male Unknown 06DEC2013 Neoplasm malignant Cancer pain Unknown None reported None reported Death 1065 UNK Unknown 2013 09DEC2013 Death Unknown Unknown None reported None reported Death 765 Patient Date UBC Concomitant Event ID Age Gender Event Report Preferred Term(s) Indication(s) Duration Medications Co?Suspect Product(s) Outcome 1066 75 Male Unknown 12DEC2013 Death Unknown Unknown None reported None reported Death 1067 40 Male 3 OOCTZO 3 . 2DEC 20 13 Death. Unresponsive to Unknown Unknown None reported None reported Death 010CT2013 stimuli 1068 63 Male 0 AN 20 3 13DEC2013 Death Unknown Unknown None reported None reported Death 1069 5 5 Female Unknown 1 9DEC 20 13 Disease progression. Unknown Unknown None reported None reported Death Treatment noncompliance 1070 58 Female Unknown 27DEC2013 Death Unknown Unknown None reported None reported Death 107 1 76 Male Unknown 3 20 13 Adverse event. Disease Unknown Unknown None reported None reported Death progression. Plasma cell myeloma 1072 50 Male Unknown 31DEC2013 Disease progression. Unknown Unknown None reported None reported Death Glioblastoma. Hospice care 10 73 4 7 Female Unknown 3 1 DEC 20 13 Adverse event. Unknown Unknown None reported None reported Death Metastases to peritoneum 1074 5 6 Female Unknown 3 1 DEC 20 13 Colon cancer Unknown 1 8 Days None reported None reported Death metastatic. Hospice care 1075 44 Male Unknown 3 1 DEC 20 13 Glioblastoma. Hospice Unknown Unknown None reported None reported Death care 1076 72 Female Unknown 3 1 DEC 20 13 Hospice care. Unknown Unknown None reported None reported Death 1077 47 Male Unknown 3 1 DEC 20 13 Brain neoplasm Unknown Unknown None reported None reported Death Hospice care 1078 63 Male Unknown 3 1 DEC 20 13 Aspergillus infection Unknown Unknown None reported None reported Death 1079 5 8 Male 05APR2012 02] AN 20 14 Anal cancer. Adverse Breakthrough cancer Unknown None reported None reported Death event pain 1080 52 Male 3 02J AN 20 14 Adverse event. Breakthrough cancer Unknown None reported None reported Death Neoplasm malignant. pain Drug me?ectiV'e 108 70 Male Unknown 02J AN 20 14 Disease progression Unknown Unknown None reported None reported Death 1082 45 Male Unknown 03J AN 20 14 Death Unknown 1 Months None reported None reported Death 766 Patient Date UBC Concomitant Event ID Age Gender Event Report Preferred Term(s) Indication(s) Duration Medications Co?Suspect Product(s) Outcome 1083 67 Female 20DEC201 3 . 03J AN 20 14 Death. Sepsis. Lung Unknown Unknown None reported None reported Death 17DEC2013 neoplasm malignant 1086 41 Male 03Cardiac arrest. Death Cancer 2013 -04-23 - Dilaudid None reported Death UNK 1087 47 Female 13NOV201 3. 22J AN 20 14 Death. Central nervous Metastatic pain- Unknown Ms ontin. None reported Death 1 system lesion. Hepatic neoplasma related pain Hydrocodone. 1 1 SEP20 13 . encephalopathy. Lorazepam. Lomotil. ISEP2013 . Hepatic failure. Malaise Remeron 1 1 SEP20 1 3 1088 6 1 Female 02Encephalopathy. Breakthrough cancer Unknown Oxycontin. Oxycodone. None reported Death Respiratory failure pain Lorazepam. Levothyroxine. Vitamin D3. Flonase. Triamcinolone 1089 53 Male Unknown 24JAN2014 Death Cancer pain Unknown None reported None reported Death 1090 49 Female Unknown 28JAN2014 Death Breakthrough cancer Unknown Fentanyl None reported Death pain 1092 59 Male Unknown 03FEB2014 Death Unknown Unknown None reported None reported Death 1093 UNK Female MAR20 12 06FEB2014 Disease progression Unknown Unknown None reported None reported Death 1094 54 Female Unknown 14FEB2014 Death Unknown Unknown None reported None reported Death 1095 69 Female Unknown 1 7FEB2014 Death Unknown Unknown None reported None reported Death 1096 5 7 Female 28FEB20 13 7FEB2014 Death Unknown Unknown None reported None reported Death 1097 78 Female Unknown 1 8FEB2014 Death Lung cancer Unknown Hydromorphone. None reported Death lonidine. Baclofen. Bupivacaine. Dilaudid. Methadone 1098 77 Female 0 AN 20 3 1 8F EB20 1 4 Death Unknown Unknown None reported None reported Death 1099 54 Female Unknown 2OFEB2014 Breast cancer. Lung Unknown Unknown None reported None reported Death carcinoma cell type unspeci?ed stage IV 1 100 5 1 Female Unknown 20F EB20 1 4 Death Unknown Unknown None reported None reported Death 1101 49 Male 28APR2012 20F EB2014 Death Unknown Unknown None reported None reported Death 1102 77 Male Unknown 20F EB2014 Death Unknown Unknown None reported None reported Death 1 103 70 Male 1 2OFEB2014 Death Cancer pain Unknown None reported Fentanyl Citrate Death 767 Patient Date UBC Concomitant Event ID Age Gender Event Report Preferred Term(s) Indication(s) Duration Medications Co?Suspect Product(s) Outcome 1 104 79 Female Unknown 20FEB2014 Death Unknown Unknown None reported Fentanyl Citrate Death 1 105 54 Female Unknown 2 Death Unknown Unknown None reported None reported Death 1 106 69 Male Unknown 24FEB2014 Renal cancer Pain Unknown None reported None reported Death 1 108 59 Female Unknown 24FEB2014 Death Unknown Unknown None reported None reported Death 1 109 UNK Female Unknown 24FEB2014 Death Pain management Unknown None reported None reported Death 1110 UNK Female Unknown 25FEB2014 Death Unknown Unknown None reported opaxone Death 1 1 1 1 UNK Male Unknown 26FEB2014 Death Unknown Unknown None reported None reported Death 1 1 12 59 Male Unknown 26FEB2014 Death Unknown Unknown None reported None reported Death 1 1 13 5 3 Female 1 8APR2012 26FEB2014 Death Metastatic neoplasm Unknown None reported Fentanyl Citrate Death 1 1 14 69 Female 09AUG2013 27FEB2014 Hospice care. Death Unknown Unknown lonazepam. Senna-S. None reported Death Fentanyl. Fluoxetine. Ibuprofen? Megace. Metoprolol. Olanzapine. Warfarin 1 1 15 57 Female Unknown 27FEB2014 Breast cancer metastatic Unknown 2 Years Tylenol. Albuterol. None reported Death Anastrozole. etirizine. lonazepam. Senna S. Hydroxyzine. Humalog. Lactulose. Lidodernl. Milk of Magnesia. Naproxen. Oxycodone. Oxycontin. Miralax 1 1 16 48 Female Unknown 2 7FEB2014 Death Unknown Unknown None reported None reported Death 1 1 17 60 Female Unknown 28FEB2014 Lung cancer metastatic Unknown Unknown None reported None reported Death 1 1 18 66 Female Unknown 28F EB20 1 4 Death Unknown Unknown None reported None reported Death 1 1 19 60 Male Unknown 28F EB2014 Colon cancer stage IV Breakthrough cancer Unknown None reported None reported Death pain 1 120 5 7 Female 16APR2012 28FEB2014 Death Unknown Unknown None reported None reported Death 1 12 60 Female 22MAY20 12 28FEB2014 Death Unknown Unknown None reported Fentanyl Citrate Death 1 122 74 Female 24JUL20 1 2 2 8FEB20 14 Death Unknown Unknown None reported Fentanyl itrate Death 768 Patient Date UBC Concomitant Event ID Age Gender Event Report Preferred Term(s) Indication(s) Duration Medications Co?Suspect Product(s) Outcome 1123 45 Female 18NOV2013. O4MAR2014 Fernur fracture. Mass. Metastatic lesion pain Unknown Oxycontin. None reported Death 09AUGZOI3 Fracture. Bone cancer. Robaxin. Dilaudid. Breast cancer Lasix. metastatic. Fall. hemotherapeutics Hospitalisation. NOS. Lisionopril. Osteoarthritis Oxycodone 1124 62 Female Unknown O4MAR2014 Death Unknown Unknown None reported None reported Death 1125 79 Female Unknown O4MAR2014 Death Unknown Unknown None reported None reported Death 1126 UNK Female Unknown O4MAR2014 Disease progression. Cancer pain 2014-02-26 - None reported None reported Death Pancreatic carcinoma UNK metastatic 1 127 5 8 Female 02DEC2013 O4MAR20 14 Metastatic neoplasm Cancer pain Unknown None reported None reported Death 1128 52 Female Unknown 05MAR2014 Death Unknown Unknown None reported None reported Death 1129 UNK Male Unknown 05MAR2014 Death Unknown 2014-02-26 - None reported None reported Death UNK 1130 UNK Unknown Unknown 05MAR2014 Death Unknown Unknown None reported None reported Death 1 13 1 79 Female 2013 05MAR2014 Death Unknown Unknown None reported Fentanyl Citrate Death 1 133 UNK Female 01JAN2012 O6MAR2014 Death. Feeling Unknown Unknown None reported None reported Death abnormal. Unresponsive to stimuli 1134 69 Female Unknown O6MAR2014 Neoplasm malignant Breakthrough pain Unknown Roxicodone None reported Death 1 13 5 5 8 Female Unknown 06MAR2014 Death Unknown Unknown None reported None reported Death 1136 UNK Female Unknown 06MAR2014 Death Unknown Unknown None reported None reported Death 1 137 UNK Female Unknown 06MAR2014 Death Unknown Unknown None reported None reported Death 1 13 8 39 Female 1 1NOV2012 06MAR2014 Death Unknown Unknown None reported Fentanyl Citrate Death 1139 53 Male Unknown 07MAR2014 Death Unknown Unknown None reported None reported Death 1140 83 Male Unknown 10MAR2014 Death Unknown Unknown None reported None reported Death 1141 66 Male Unknown 10MAR2014 Death Unknown Unknown None reported None reported Death 1142 68 Female Unknown 10MAR2014 Disease recurrence Unknown Unknown None reported None reported Death 1143 64 Male Unknown 1 1MAR2014 Death Unknown Unknown None reported None reported Death 1144 75 Male Unknown 1 1MAR2014 Neoplasm malignant Unknown Unknown None reported None reported Death 769 Patient Date UBC Concomitant Event ID Age Gender Event Report Preferred Term(s) Indication(s) Duration Medications Co?Suspect Product(s) Outcome 1145 31 Male Unknown 11MAR2014 Crohn's disease. Off Chronic and severe Unknown Stargesic None reported Death label use crolm's disease of small and large intest 1146 60 Male Unknown 11MAR2014 Death Colon cancer pain Unknown Oxycontin None reported Death 1 147 48 Female 19MAY20 12 12MAR20 14 Death Unknown Unknown None reported None reported Death 1 148 48 Female Unknown 12MAR2014 Death Unknown Unknown None reported None reported Death 1 149 UNK Female Unknown 13MAR2014 Death Pain Unknown None reported None reported Death 1 1 50 59 Male JUL20 12 13MAR2014 Death Unknown Unknown None reported Fentanyl Citrate Death 1 1 52 75 Male 0 7MAR2014 Death Unknown Unknown None reported None reported Death 1 1 53 48 Male 04IUN 20 13 7MAR2014 Neoplasm Progression Unknown Unknown None reported None reported Death 1 15 5 5 3 Female 21MAR2013 17MAR2014 Neoplasm Progression Cancer pain Unknown None reported None reported Death 1 156 54 Female 20DEC2013 17MAR2014 Death Unknown 1 3 - None reported None reported Death UNK 58 66 Male 05MAY20 12 17MAR2014 Death Unknown Unknown None reported None reported Death 1159 UNK Female Unknown 17MAR2014 Drug Ineffective/Death Breakthrough cancer Unknown None reported None reported Unknowna pain 1 160 62 Male 1 SSEP2013 17MAR2014 Death Unknown Unknown None reported None reported Death 1 161 64 Female AUG201 2 1 7MAR20 14 Neoplasm Progression Cancer pain Unknown None reported None reported Death 1 162 UNK Female Unknown 17MAR2014 Death Unknown Unknown None reported None reported Death 1 163 42 Male Unknown 18MAR2014 Glioblastoma Unknown Unknown None reported None reported Death rrlultifonne 1 164 65 Female Unknown 18MAR2014 Death Unknown Unknown None reported None reported Death 1165 UNK Male Unknown 18MAR2014 Death Prostate cancer 2014-02-26 - None reported None reported Death UNK 1 166 UNK Female Unknown 18MAR2014 Death Cancer pain 2014-02-26 - None reported None reported Death UNK 1 167 60 Female SEP20 13 19MAR2014 Death Unknown Unknown None reported Fentanyl Citrate Death 1168 59 Female 18MAR2014. 20MAR2014 Chronic obstructive Metastatic lung cancer Unknown None reported None reported Death 1 5MAR2014 pulmonary disease. Hypotension. Sepsis. Pnerunonia. Acute respiratory failure 1 169 8 1 Male 0 AN 20 1 3 20MAR2014 Death Unknown Unknown None reported None reported Death 770 Patient Date UBC Concomitant Event ID Age Gender Event Report Preferred Term(s) Indication(s) Duration Medications Co?Suspect Product(s) Outcome 1170 UNK Female Unknown 20MAR2014 Neoplasm malignant Unknown 2014-02-26 - None reported None reported Death UNK 1171 UNK Male Unknown 20MAR2014 Death. Drug effect Breakthrough cancer 2014-02-26 - Morphine None reported Death decreased pain UNK 172 39 Female Unknown 21MAR2014 Malaise Breakthrough cancer Unknown None reported None reported Death pam 1173 75 Female Unknown 21MAR2014 Lung cancer metastatic Breakthrough pain 1 Years None reported Percocet Death 1175b 0.7 Unknown Unknown 24MAR2014 Death. Off label use Unknown Unknown None reported None reported Death 1 1 76 5 5 Male 1 20 2 24MAR20 14 Death Unknown 1 Weeks None reported None reported Death 1 1 77 68 Male 27APR2012 24MAR20 14 Death Unknown Unknown None reported None reported Death 1 178 UNK Female Unknown 25MAR2014 Death Unknown Unknown None reported None reported Death 1179 59 Female Unknown 25MAR2014 Renal cancer Unknown Unknown None reported None reported Death 1 180 5 1 Male Unknown 25MAR2014 Death Unknown Unknown None reported Fentanyl Citrate Death 1 182 61 Male Unknown 27MAR2014 Death Unknown Unknown None reported None reported Death 1 183 46 Male 0 1 AN 20 3 27MAR20 14 Myocardial infarction Unknown Unknown None reported None reported Death 1 185 5 3 Female Unknown 27MAR2014 Death Unknown Unknown None reported None reported Death 1 186 59 Male Unknown 27MAR2014 Death Unknown Unknown None reported None reported Death 1 187 UNK Male Unknown 27MAR2014 Death Unknown Unknown None reported Fentanyl Citrate Death 1 188 43 Female Unknown 27MAR2014 Death Unknown Unknown None reported Fentanyl Citrate Death 1 189 59 Male Unknown 27MAR2014 Death Unknown Unknown None reported Fentanyl Citrate Death 1 190 63 Female Unknown 27MAR2014 Death Unknown Unknown None reported Fentanyl Citrate Death 1191 UNK Female Unknown 28MAR2014 Disease progression Unknown Unknown None reported None reported Death 1 192 UNK Female Unknown 28MAR2014 Death Unknown Unknown None reported None reported Death 1 193 54 Male 06JAN2014. 3 Neoplasm malignant. Breakthrough cancer Unknown Gabapentin. Dilaudid None reported Death 0 2012. Pain. Herpes zoster. pain 0 1NOV201 2. Polyneuropathy. 01NOV2012. Cholecystitis 1APR20 1 2 1 194 UNK Female Unknown 31MAR2014 Death Unknown Unknown None reported None reported Death 1195 62 Unknown Unknown 0 1APR2014 Endometrial cancer Breakthrough cancer Unknown None reported None reported Death metastatic pam 1 196 UNK Unknown Unknown O3APR2014 Death Unknown Unknown None reported None reported Death 771 Patient Date UBC Concomitant Event ID Age Gender Event Report Preferred Term(s) Indication(s) Duration Medications Co?Suspect Product(s) Outcome 1197 UNK Unknown Unknown 07APR2014 Death Pain due to cancer 2 Years None reported None reported Death 1 198 61 Male Unknown 07APR2014 Death Unknown Unknown None reported None reported Death 1 199 63 Male Unknown 07APR2014 Death Unknown Unknown None reported None reported Death 1200 60 Male Unknown 07APR2014 Death Unknown Unknown None reported None reported Death 1201 47 Male Unknown 07APR2014 Colon cancer Unknown Unknown None reported None reported Death 1202 34 Female Unknown 07APR2014 Ocular cancer Unknown Unknown None reported None reported Death metastatic. Ocular neoplasm 1203 54 Male 30APR2012 07APR2014 Colon Cancer. Death Unknown Unknown None reported Fentanyl Citrate Death 1204 46 Female Unknown 07APR2014 Death Unknown Unknown None reported Fentanyl Citrate Death 1205 60 Male Unknown 07APR2014 In?uenza. Death. Breakthrough pain Unknown Advair. Aluminum Fentanyl Citrate. Death Renal Failure Acute. Hydroxide-Magnesium lonazepam. Atelectasis. Pneumonia Hydroxide- Dexarnethasone. Pseudomonal. Simethicone. benadryl. Polyethylene Glycol Decubitus Ulcer. Bisacodyl. Daliresp. 3350 Neuralgia. Respiratory Ensure Plus. Failure. Myalgia. ?uconazole. Anxiety. Diarrhea. Hydrocortisone. Abdominal Pain Ipratropitun?'AlbutemL Iron-B12 -Vitamins. Ketoconazole. Levo?oxacin. Levothyroxine. Loratadine. Methadone. Mucinex. Nexilun. Oxycodone. Silver Sulfadiazine. Singulair. Xanax. Xylocaine. Zomig 1206 72 Female Unknown 07APR2014 Death Unknown Unknown None reported Fentanyl Citrate Death 1208 65 Male Unknown 08APR2014 Death Unknown Unknown None reported Fentanyl Citrate Death 1209 73 Female Unknown 08APR2014 Death Unknown Unknown None reported Fentanyl Citrate Death 12 10 3 1 Male 0APR2014 Death Unknown Unknown None reported None reported Death 121 1 54 Female Unknown 10APR2014 Disease progression Unknown Unknown None reported None reported Death 1212 46 Female Unknown 1 1APR2014 Death Unknown Unknown None reported None reported Death 772 Patient Date UBC Concomitant Event ID Age Gender Event Report Preferred Term(s) Indication(s) Duration Medications Co?Suspect Product(s) Outcome 12 13 UNK Female Unknown 1 1APR2014 Death Unknown 20 12-08-1 - None reported None reported Death UNK 1214 70 Male 2013 11APR2014 Death Unknown Unknown None reported Fentanyl Citrate Death 12 5 46 Female Unknown 14APR2014 Death Unknown Unknown None reported None reported Death 1216 71 Female Unknown 14APR2014 Death Unknown Unknown None reported Fentanyl Citrate Death 12 1 7 UNK Female Unknown 1 5APR2014 Drug ine?ective. Unknown 20 12-07-3 - None reported None reported Death Neoplasm progression 2012-08-14 12 1 8 45 Female Unknown 1 5APR20 4 Death Unknown Unknown None reported None reported Death 12 19 6 1 Female Unknown 1 6APR2014 Death Unknown Unknown None reported None reported Death 1220 54 Male 06JUL2012 17APR2014 Death Unknown Unknown None reported None reported Death 122 5 1 Female 0 1APR20 3 7APR2014 Death Unknown Unknown None reported None reported Death 1222 75 Female Unknown 1 7APR2014 Endometrial cancer Breakthrough cancer Unknown Dilaudid. Fentanyl None reported Death metastatic pain 1223 71 Male Unknown 17APR2014 Breast cancer metastatic Unknown Unknown None reported None reported Death 1224 UNK Female Unknown 1 7APR2014 Death Unknown 2012-07-3 - None reported None reported Death UNK 1225 5 8 Female Unknown 1 7APR2014 Disease progression Cancer pain Unknown None reported None reported Death 1226 5 7 Female Unknown 1 8APR20 1 4 Death Unknown Unknown None reported None reported Death 1227 66 Male Unknown 1 8APR2014 Death Cancer pain Unknown None reported None reported Death 1228 49 Female Unknown 2 1APR2014 Adenomatous polyposis Unknown Unknown None reported None reported Death coli 1229 UNK Female Unknown 2 1APR20 4 Death Unknown Unknown None reported None reported Death 1230 48 Female Unknown 22APR2014 Death Unknown Unknown None reported None reported Death 123 5 1 Male IOIUL2012 22APR2014 Death Indication not speci?ed Unknown None reported None reported Death 1232 UNK Male Unknown 22APR2014 Disease progression Breakthrough pain 2012-05 - Hydrocodone. None reported Death UNK Lorazepam. Nucynta. Zofran 1233 62 Male Unknown 22APR2014 Death Unknown Unknown None reported Fentanyl Citrate Death 1234 2 8 Male Unknown 2 3APR2014 Sepsis. Disease Cancer pain Unknown None reported None reported Death progressron 773 Patient Date UBC Concomitant Event ID Age Gender Event Report Preferred Term(s) Indication(s) Duration Medications Co?Suspect Product(s) Outcome 123 5 70 Female Unknown 24APR20 1 4 Cardiac amyloidosis Unknown Unknown Dexamethazon. None reported Death Levothyroxine. Nexium. Potassium. Calcium. arafate 1236 92 Female Unknown 24APR2014 Death Unknown Unknown None reported Fentanyl Citrate Death 123 7 73 Male Unknown 25APR2014 Death Unknown Unknown None reported None reported Death 123 8 64 Male 20 1 3 2 5APR2014 Death Unknown Unknown None reported None reported Death 1239 39 Female Unknown 27APR2014 Death. Malaise Unknown Unknown None reported None reported Death 1240 52 Male Unknown 28APR2014 Death Unknown Unknown None reported None reported Death 1241 59 Male Unknown 29APR2014 Tracheal cancer Pain from malignant Unknown None reported None reported Death neoplasm 1242 80 Female 25NOV20 3 29APR2014 Death Breakthrough cancer 1 1:"2013- Fentanyl Patch. None reported Death pain UNK Oxycodone. Hydrocodone/Acetamin ophen 1243 83 Female MAY20 1 2 29APR2014 Death Unknown Unknown None reported None reported Death 1244 UNK Male Unknown 30APR2014 Death Unknown 2012-05 - None reported None reported Death UNK 1245 49 Male Unknown 01MAY2014 Death Unknown Unknown None reported None reported Death 1246 76 Male 3 0 14 Death Unknown Unknown None reported None reported Death 1247 40 Female 07JUN2012 01MAY2014 Neoplasm Progression Pain Lortab None reported Death UNK (HydrocodonefAcetami nophen). Fentanyl Patch. Compazine (Prochlorperazine). Xanax (Alprasolam). Wellbutrin (Bupropion). Omeprazole 1248 79 Male Unknown 0 14 Death Unknown Unknown None reported Fentanyl Citrate Death 1249 52 Male 16MAR2012 02MAY2014 Neoplasm Progression Pain with lung cancer Unknown None reported None reported Death 774 Patient Date UBC Concomitant Event ID Age Gender Event Report Preferred Term(s) Indication(s) Duration Medications Co?Suspect Product(s) Outcome 1250 UNK Male Unknown 02MAY2014 Neoplasm progression Breakthrough cancer 2013-12-12 - Aspirin. lonazepam. None reported Death pain UNK ymbalta. Durabac. Lopressor. Lyrica. Oxycodone. Plaquenil. Spiriva. Zana?ex 1251 77 Female 3 1MAY2012 05MAY2014 Death Unknown Unknown None reported None reported Death 1252 65 Male 03 SEP2012 06MAY2014 Death Unknown 2013 -12-12 - None reported None reported Death UNK 1253 UNK Male Unknown 07MAY2014 Application site Cancer pain 2013-12-12 - None reported None reported Death irritation. Neoplasm UNK progression 1254 47 Male Unknown 07MAY2014 Pancreatic carcinoma Cancer pain Unknown None reported None reported Death metastatic 1255 UNK Male Unknown 07MAY2014 Death Unknown Unknown None reported None reported Death 1256 65 Male Unknown 08MAY2014 Death Unknown Unknown None reported None reported Death 125 7 6 1 Male Unknown 08MAY20 14 Death Unknown Unknown None reported Fentanyl Citrate Death 1258 38 Female Unknown 09MAY2014 Death Unknown Unknown None reported None reported Death 1259 54 Female 04FEB2013 09MAY2014 Mass. Death Chronic low back pain Unknown Phenergan. $01113. None reported Death Restoril. Fiorinal. Avinza. Xanax 1260 47 Female Unknown 09MAY2014 Death Unknown Unknown None reported None reported Death 1261 UNK Unknown Unknown 09MAY2014 Death Unknown Unknown None reported None reported Death 1262 46 Female O6APR201 3 O9MAY20 14 Death Unknown Unknown None reported None reported Death 1263 UNK Female Unknown 09MAY2014 Neoplasm progression Cancer pain 2013 -12-12 - Ms-Contin. Percoset None reported Death UNK 1264 UNK Male Unknown 09MAY2014 Renal failure Chronic pain 2013-12-12 - None reported None reported Death UNK 1266 UNK Female Unknown 12MAY20 14 Death Unknown 20 3 -04 - None reported None reported Death UNK 1267 5 7 Female Unknown 12MAY20 14 Death Unknown Unknown None reported Fentanyl Citrate Death 1268 62 Female Unknown 13MAY2014 Death Unknown Unknown None reported None reported Death 1269 73 Female Unknown 13MAY2014 Lung cancer metastatic Severe pain from Unknown None reported None reported Death metastatic lung cancer 775 Patient Date UBC Concomitant Event ID Age Gender Event Report Preferred Term(s) Indication(s) Duration Medications Co?Suspect Product(s) Outcome 1270 UNK Female Unknown Death Pancreatic cancer 2012-06-29 - None reported None reported Death UNK 1272 UNK Female Unknown 13MAY2014 Endometrial cancer Cancer pain Unknown None reported None reported Death metastatic. Ovarian cancer metastatic 1273 64 Male 20 12 3MAY20 14 Death Unknown Unknown None reported None reported Death 1274 UNK Female Unknown 14MAY2014 Disease progression. Pain due to cancer Unknown None reported None reported Death Systemic lupus erythematosus 1275 44 Male Unknown 14MAY2014 Death Colon cancer pain Unknown None reported None reported Death 1276 77 Female Unknown 15MAY2014 Death Malignant neoplasm Unknown None reported None reported Death metastatic to bone 1277 52 Female 20] AN 20 1 4 16MAY2014 Metastatic neoplasm Cancer pain Unknown Methadone. Various None reported Death Other Medications 1278 65 Female Unknown 16MAY2014 Death Unknown Unknown None reported None reported Death 1279 UNK Male Unknown 16MAY2014 Myocardial infarction Unknown Unknown None reported None reported Death 1280 31 Unknown Unknown 16MAY2014 Death Unknown Unknown None reported None reported Death 1281 UNK Male Unknown 19MAY2014 Death Cancer pain 2014-04-2 - Morphine. Percocet None reported Death UNK 1282 UNK Male Unknown 22MAY2014 Neoplasm progression Unknown 2014-04-21 - None reported None reported Death UNK 1284 50 Female Unknown 23MAY2014 Death Unknown Unknown None reported Fentanyl Citrate Death 1286 39 Male Unknown 27MAY2014 Death Unknown Unknown None reported Fentanyl Citrate Death 1287 62 Female Unknown 28MAY2014 Death Unknown Unknown None reported None reported Death 1288 55 Female Unknown 29MAY2014 Death Unknown 5 Months None reported None reported Death 1289 UNK Unknown Unknown 29MAY2014 Death Unknown Unknown None reported None reported Death 1290 67 Female Unknown 29MAY2014 Death Unknown 5 Months None reported None reported Death 1291 UNK Unknown Unknown 30MAY2014 Death Unknown Unknown None reported None reported Death 1292 UNK Male Unknown 30MAY2014 Neoplasm malignant Cancer pain Unknown None reported None reported Death 1293 54 Female 27MAY2014. 30MAY2014 Breast cancer Unknown Unknown None reported None reported Death 23MAY2014 metastatic. 1294 62 Male 16JUL2013 30MAY2014 Neoplasm malignant Unknown Unknown None reported None reported Death 1296 47 Female Unknown O2JUN 2014 Neoplasm malignant Unknown Unknown None reported None reported Death 776 Patient Date UBC Concomitant Event ID Age Gender Event Report Preferred Term(s) Indication(s) Duration Medications Co?Suspect Product(s) Outcome 1297 54 Female Unknown 02IUN 2014 Death Unknown Unknown None reported Fentanyl Citrate Death 1298 23 Female Unknown 03IUN 2014 Aicardi's Off Drug use for Unknown None reported None reported Death label use unapproved indication.aicardi 1299 73 Female 03JUN 2014 Death Unknown Unknown None reported None reported Death 1300 62 Female Unknown 03JUN 2014 Breast cancer metastatic Pain related to Unknown None reported None reported Death metastatic breast cancer 130 1 29 Female 01MAY20 l4 03IUN2014 Death. Hospice care Breakthrough cancer Unknown Lyrica. Norco. None reported Death pain Hydrocodone. Gabapentin. Morphine. Metoclopramide. Prilosec 1302 UNK Unknown Unknown 03 JUN 2014 Death Unknown 2013-04 - None reported None reported Death UNK 1303 UNK Female Unknown 03JUN 2014 Dysarthria. Death. Drug Cancer pain. pain Unknown Valium. Klor-Con. Prednisone. Death ineffective. Memory ymbalta. Percocet. Hydrornorphone. impairment. Periorbital Duragesic Oxycontin oedema 1304 5 1 Male Unknown 06JUN2014 Death Pain Unknown Voltaren Gel. None reported Death Duragesic. Msir 1305 62 Female Unknown O6IUN 2014 Prostate cancer Breakthrough pain Unknown Fentanyl Patch None reported Death metastatic 1306 42 Male Unknown 06JUN 2014 Death Unknown Unknown None reported None reported Death 1308 UNK Male Unknown 09JUN 2014 Death Unknown Unknown None reported None reported Death 1 3 09 UNK Female Unknown 1 1 JUN 20 14 Death Unknown Unknown None reported None reported Death 13 1 1 5 1 Female Unknown 1 2014 Death Unknown Unknown None reported None reported Death 1312 58 Female Unknown 11IUN 2014 Death Unknown Unknown None reported Fentanyl Citrate Death 1 3 1 3 4 8 Female Unknown 1 2IUN 20 14 Death Unknown Unknown None reported None reported Death 1 3 l4 UNK Unknown Unknown 1 21UN20 14 Condition aggravated Cancer pain Unknown None reported None reported Death 1 3 5 72 Female um 20 14 3JUN2014 Death Unknown Unknown None reported None reported Death l3 l6 UNK Male 2012 13JUN2014 Death Unknown UNK - 2012 None reported None reported Death 13 1 7 40 Female 20.TUL201 3 6JUN2014 Condition aggravated Cancer pain Unknown None reported None reported Death 777 Patient Date UBC Concomitant Event ID Age Gender Event Report Preferred Term(s) Indication(s) Duration Medications Co?Suspect Product(s) Outcome 13 18 22 Male Unknown 1 7IUN2014 Occupational Exposure Unknown Unknown None reported Fentanyl Citrate Death to Product. Circulatory Collapse. Death 1319 61 Female 290C T2013 18IUN 2014 Disease progression Breakthrough pain Unknown None reported None reported Death 1 320 76 Male Unknown 1 8JUN2014 Colon Cancer. Death Unknown Unknown None reported Fentanyl Citrate Death 1 32 UNK Female Unknown 1 9JUN2014 Death Unknown Unknown None reported None reported Death 1322 UNK Male Unknown 19JUN2014 Cardiac death. label Pain 2012-08-16 - None reported None reported Death use UNK 1323 6 1 Male Unknown 24JUN2014 Lung neoplasm Pain Unknown None reported None reported Death malignant 1324 UNK Female Unknown 24IUN 2014 Disease progression Unknown Unknown None reported None reported Death 1325 UNK Female Unknown 24IUN 2014 Death Unknown Unknown None reported None reported Death 1326 UNK Male Unknown 24JUN 2014 Death Unknown Unknown None reported None reported Death 1327 UNK Female Unknown 24JUN 2014 Neoplasm progression Cancer pain Unknown None reported None reported Death 1 3 28 UNK Female Unknown 24JUN 20 14 Death. Off Label Use Preoperative care Unknown None reported Fentanyl Citrate Death 13 30 UNK Male Unknown 2 5JUN2014 Death Unknown Unknown None reported None reported Death 1331 61 Male Unknown 25JUN 2014 Death Unknown Unknown None reported Fentanyl Citrate Death 1333 51 Female Unknown 27IUN 2014 Death Unknown Unknown None reported None reported Death 1334 64 Female Unknown 27IUN 2014 Death Unknown Unknown None reported None reported Death 1335 UNK Male Unknown 27IUN 2014 Death Unknown Unknown None reported None reported Death 1336 67 Male Unknown 3OJUN 2014 Cardiac disorder Unknown Unknown None reported None reported Death 1 3 3 7 5 8 Female Unknown 3 OJUN 20 14 Acute rnyeloid Breakthrough cancer Unknown None reported None reported Death leukaemia. pain Hospitalisation. 13 3 8 5 1 Female 0 1AUG2012 3 OIUN2014 Colon cancer recurrent Breakthrough cancer Unknown Fentanyl. Roxanol. None reported Death pain Ativan. Lovenox. Potassitun 13 39 5 6 Male Unknown 3 OJUN2014 Death Unknown Unknown None reported None reported Death 1340 UNK Female Unknown 3OJUN 2014 Death Breast cancer 2013-06-25 - Hydromorphone. None reported Death UNK Methadone 778 Patient Date UBC Concomitant Event ID Age Gender Event Report Preferred Term(s) Indication(s) Duration Medications Co?Suspect Product(s) Outcome 1341 UNK Male Unknown 3OIUN 2014 Neoplasm progression Unknown 2014-02-26 - None reported None reported Death UNK 1342 UNK Female Unknown 30JUN 2014 Death Unknown Unknown None reported Fentanyl Citrate Death 1343 64 Female Unknown 01.TUL2014 Pancreatic carcinoma Unknown 2 Years None reported None reported Death metastatic 1344 88 Female Unknown 0 JUL2014 Death Unknown Unknown None reported None reported Death 1345 UNK Female Unknown 0 JUL2014 Neoplasm progression Breakthrough cancer None reported None reported Death pain UNK 1346 27 Male Unknown 03IUL2014 Complications of Unknown Unknown None reported None reported Death transplant surgery 1347 5 5 Male Unknown 03 JUL2014 Metastasis. Small cell Unknown Unknown None reported None reported Death lung cancer 1348 UNK Male Unknown 03 .TUL2014 Death Unknown 20 1 3 - 1 0-01 - None reported None reported Death UNK 1349 UNK Female Unknown 07JUL2014 Rectal cancer metastatic Unknown Unknown None reported None reported Death 13 5 1 63 Female 0 201 l. 08JUL2014 Pain. Renal cell Pain control Unknown None reported None reported Death 13IUL2009 carcinoma 1 3 52 UNK Male Unknown 08IUL20 14 Death Unknown Unknown None reported None reported Death 1353 UNK Male Unknown 08IUL2014 Death Unknown Unknown None reported None reported Death 1 3 54 62 Male Unknown 09 IUL20 14 Death Unknown Unknown None reported None reported Death 1355 60 Female 051UL2014 Death Unknown Unknown None reported None reported Death 13 56 UNK Female Unknown 1 JUL2014 Neoplasm progression Unknown 20 13 -04-23 - None reported None reported Death UNK 1357 UNK Female Unknown 11IUL2014 Neoplasm progression Unknown 2013-04-23 - None reported None reported Death UNK 1358 43 Male Unknown Pancreatic carcinoma Unknown Unknown None reported None reported Death metastatic 1 3 59 5 5 Male Unknown 14.TUL20 l4 Pancreatic carcinoma Unknown Unknown None reported None reported Death metastatic 1361 65 Female Unknown Death Unknown Unknown None reported None reported Death 1362 58 Female Unknown Death Liver metastasis.portal Unknown Oxycodone. Duragesic None reported Death 779 Patient Date UBC Concomitant Event ID Age Gender Event Report Preferred Term(s) Indication(s) Duration Medications Co?Suspect Product(s) Outcome 1363 75 Male 1 SJUL2O 14 Death Unknown 2013 -04-23 - None reported None reported Death UNK 1364 UNK Male Unknown 16IUL2014 Death Unknown Unknown None reported None reported Death 1365 73 Male Unknown 2 1 IUL20 14 Death Unknown Unknown None reported None reported Death 1 3 66 UNK Male Unknown 2 1 JUL2O 14 Death Unknown Unknown None reported Fentanyl itrate Death 1367 73 Female Unknown 22JUL2014 Death Unknown Unknown None reported None reported Death 1368 68 Female Unknown 22JUL2014 Death Unknown Unknown None reported None reported Death 1369 UNK Male Unknown 22JUL2014 Death Unknown 2014-06 - None reported None reported Death UNK 1370 UNK Male Unknown 22IUL2014 Death Unknown Unknown None reported Fentanyl Citrate Death 13 72 6 1 Female Unknown 23 IUL2014 Breast cancer metastatic Unknown Unknown None reported None reported Death 1373 UNK Male Unknown 2SJUL2014 Death Unknown Unknown None reported Fentanyl Citrate Death 1374 UNK Unknown 01AUG2012 2SJUL2014 Death Unknown Unknown None reported None reported Death 13 75 71 Male 27IUN2014 2SJUL2014 Sepsis/Total organ Chronic neuropathic (1 None reported None reported Death failure pain day) 1376 UNK Female Unknown 28JUL2014 Death Unknown Unknown None reported None reported Death 1 3 77 5 5 Female Unknown 29JUL20 14 Breast cancer metastatic Unknown Unknown None reported None reported Death 1 3 78 66 Female Unknown 29IUL20 14 Death Unknown Unknown None reported None reported Death 1379 UNK Female Unknown 30IUL2014 Death Unknown Unknown None reported Fentanyl Citrate Death 13 80 73 Female 12JAN2013 3 14 Death Unknown 2014-04-21 - None reported None reported Death UNK 3 8 UNK Male Unknown 3 JUL2O 14 Death Unknown 20 14-04-2 - None reported None reported Death UNK 1382 UNK Female Unknown 31IUL2014 Death Unknown Unknown None reported None reported Death 1 3 83 8 6 Male Unknown 04AUG20 14 Cardiac disorder. Lumbar pain Unknown Lidodemr Patch. Ms None reported Death Coronary artery bypass. ontin. Sancuso. Death. Myocardial Voltaren Gel infarction. OE label use. Prostate cancer 13 84 UNK Male Unknown 04AUGZO 14 Death Breakthrough pain 20 12-08-1 1 - None reported None reported Death UNK 1385 71 Female Unknown 05AUG2014 Disease progression Unknown Unknown None reported None reported Death 1386 50 Female Unknown 05AUG2014 Metastatic neoplasm Unknown Unknown None reported None reported Death 780 Patient Date UBC Concomitant Event ID Age Gender Event Report Preferred Term(s) Indication(s) Duration Medications Co?Suspect Product(s) Outcome 1387 46 Female Unknown 05AUG2014 Death Unknown Unknown None reported None reported Death 1389 UNK Female Unknown 06AUG2014 Death Unknown Unknown None reported None reported Death 1390 UNK Male Unknown 07AUG2014 Neoplasm malignant Unknown Unknown None reported None reported Death 1 39 1 72 Male 26JUN 20 1 3 1 1AUG2014 Death Unknown Unknown None reported None reported Death 1392 UNK Male Unknown 11AU02014 Death Unknown Unknown None reported None reported Death 1393 UNK Male Unknown 11AU02014 Death Unknown Unknown None reported None reported Death 1394 59 Male Unknown 12AU02014 Gastrointestinal Cancer pain Unknown Duragesic. Ativan. None reported Death carcinoma. Liver Zo?ran. Fentanyl disorder 1395 7 1 Female Unknown 12AUGZO 14 Death Unknown Unknown None reported None reported Death 1396 76 Female Unknown 12AU02014 Lung neoplasm Cancer pain Unknown None reported None reported Death malignant 1397 UNK Female Unknown 14AUG2014 Death Unknown Unknown None reported None reported Death 1398 45 Female Unknown 14AUG2014 Death Unknown Unknown None reported None reported Death 1399 UNK Female Unknown 14AUG2014 Death Unknown Unknown None reported None reported Death 1400 UNK Female Unknown 14AUG2014 Death Unknown Unknown None reported None reported Death 140 1 50 Female 23NOV201 3 14AUG2014 Death Unknown Unknown None reported Fentanyl Citrate Death 1402 UNK Male Unknown 15AU02014 Death Unknown Unknown None reported None reported Death 1403 54 Female 27NOV2013 1 SAUGZO 14 Breast Cancer. Death Cancer pain Unknown None reported Fentanyl Citrate Death 1404 42 Male 3 0DEC2013 19AUGZO 14 Death Unknown Unknown None reported None reported Death 1405 UNK Female Unknown 19AUG2014 Death Unknown 2 Years None reported None reported Death 1406 5 6 Female 0 10CT2012 19AUG2014 Death Unknown Unknown None reported Fentanyl Citrate Death 1407 UNK Male Unknown 20AUG2014 Death Unknown Unknown None reported None reported Death 1408 29 Male 14DEC2012 20AUG2014 Testis cancer Cancer pain Unknown None reported None reported Death 1409 40 Female Unknown 21AUG2014 Death Unknown Unknown None reported None reported Death 1410 73 Female 3 10CT2012 2 1AUG2014 Death Unknown Unknown None reported None reported Death 1411 UNK Female Unknown 21AUG2014 Breast cancer metastatic Unknown Unknown None reported None reported Death 1412 68 Male Unknown 22AU02014 Renal cancer metastatic Unknown Unknown None reported None reported Death 1413 UNK Male Unknown 22AU02014 Completed suicide. Unknown Unknown None reported None reported Death Pain 1414 UNK Female Unknown 25AUG2014 Sarcoma metastatic Unknown Unknown None reported None reported Death 781 Patient Date UBC Concomitant Event ID Age Gender Event Report Preferred Term(s) Indication(s) Duration Medications Co?Suspect Product(s) Outcome 141 5 UNK Female Unknown 2 SAUGZO 14 Death Unknown Unknown None reported None reported Death 1416 UNK Female Unknown 25AUGZOI4 Death Unknown Unknown None reported Fentanyl Citrate Death 141 7 49 Female Unknown 27AUGZO 14 Death Unknown Unknown None reported None reported Death 141 8 UNK Male Unknown 27AUGZO 14 Death Unknown 20 14-06 - None reported None reported Death UNK The source data for this patient did not include an event outcome of death. Death is noted in the preferred term for this case. Patient 1175 is also described in the table for pediatric exposures (Table 28). 782 There were two pediatric cases reported during this reporting period (Table 28). One case had an outcome of death and one case had an outcome of unknown at the time of this report. There was a report of an 8 month old who was exposed to fentanyl and died. The reporter, an attorney, reported the death was related to the fentanyl use; however, this was not medically confirmed at the time of this assessment report. The second pediatric case, with an outcome of unknown, was a 12-year-old female who was prescribed oral transmucosal fentanyl citrate for an unknown indication. The preferred term for this case was drug administered to patient of inappropriate age. No further details were obtained despite extensive follow-up attempts. FDA_1783 Table 28 Cases of Pediatric Exposures Received from TRIG Sponsors during the Reporting Period: 29 October 2013 - 28 August 2014 Patient Date UBC TIRF Concomitant Co?Suspect Event ID Age Gender Event Report Preferred Term(s) Indication(s) Duration Medications Product(s) Outcome 1175a 0.7 Unknown Unknown 24MAR2014 Death. Off label use Unknown Unknown None reported None reported Death 1181 12 Female Unknown 26MAR2014 Drug Administered Unknown Unknown None reported Fentanyl Citrate Unknown To Patient Of Inappropriate Age Patient 1175 is also described in the table for cases of death (Table 27). 784 7.4 TIRF Product Surveillance Data [Metric 31] 7.4.1 Background Surveillance data focusing on events of abuse, misuse, and death were evaluated using data from the RADARS® System for the time period 3rd quarter 2012 through 2nd quarter 2014. Data from five programs that gather data from unique populations along the spectrum of drug abuse were used to monitor for the non-medical use (abuse and misuse) of TIRF products. Drug diversion data are sparse for TIRF products and are therefore not included in this report. The data sources and the specific events evaluated in each are shown in Table 29 below. Table 29 Data Source 1. Poison Center Treatment Center Surveys 2. Opioid Treatment Programs 3. Key Informants Survey 4.. College Survey 5. Impaired Healthcare Workers Program RADARS® System: Data Sources and Specific Events Abuse a Intentional Misuse Unintentional Therapeutic Errors Unintended General Exposures Emergency Department Visits & Hospitalizations Deaths      Major Medical Outcomes and Deathse  b b c d a Abuse defined as exposure resulting from intentional improper or incorrect use of a substance where the victim was likely attempting to gain a high euphoric effect or some other psychotropic effect b Abuse defined as a respondent endorsing the use of a product to get high in the past 30 days c Abuse defined as endorsement of a non-medical use of a drug in the past 90 days d All reported cases are considered abuse e This column includes the events included in the column titled “deaths” as well as major medical outcomes that did not lead to death Trends over time for the TIRF products were compared to three comparator groups that are not directly impacted by the TIRF REMS to determine how the trend in TIRF rates compares to the secular trend in other opioids. The comparators used in this report were: • Schedule II IR opioids • Schedule II opioids • Schedule II opioids excluding methadone FDA_1785 The schedule II opioids comparator group was updated for this report to include sufentanil as it was recently released on the market. Additionally, schedule II opioids were analyzed with and without methadone as methadone prescriptions exclude dispensing in opioid treatment centers and therefore prescriptions are undercounted. Data from IMS Health are used to estimate total prescriptions dispensed and total dosing units dispensed at the 3-digit ZIP-code level for all TIRF REMS opioids and comparator groups. Totals of prescriptions and dosing units in the three digit zip codes covered by the RADARS® System Programs were computed and used as the denominators when calculating product availability rates. IMS data does not capture methadone dispensed through opioid treatment programs, thus the count of methadone prescriptions is an undercount. Rates of abuse, misuse, overdose, addiction and death were calculated using the 2010 US decennial census estimated from the three-digit zip codes covered in the RADARS® System Programs as the denominator. Additional details can be found in the RADARS® System Report Protocol (Appendix 12.3). 7.4.2 Poison Center Program The RADARS® System Poison Center Program obtains data from individuals within the general population and from healthcare providers who are seeking advice regarding potential toxic exposures, including exposures to prescription opioids and stimulants. The objectives of the Poison Center Program are to detect product-specific prescription drug abuse and misuse in near real-time and to identify geographic sites with disproportionately high rates of abuse and misuse. Poison center data collected through the System provide an estimate of change in intentional abuse for these drugs. The Poison Center Program gathers data from 48 regional US Poison Centers covering 46 states, including urban, suburban and rural regions (over 90% of the US population). In total, poison centers receive over 2.3 million exposure calls per year. Investigators at each participating poison center collect data using a nationally standardized electronic health record. The Poison Center Program provides heightened sensitivity and quick response time, which may help detect emerging prescription drug abuse and misuse problems. 7.4.3 Treatment Center (TC) Program The Treatment Center Programs are comprised of both the Opioid Treatment Program (OTP) and the Survey of Key Informants’ Patients (SKIP) Program. Data for this reporting period (collected in 2nd quarter 2014) from the OTP involved 61 methadone maintenance treatment programs in 34 states. The objectives of the OTP are to estimate 1-month prevalence and the injection rate of prescription and illicit opioid and non-opioid drugs among patients admitted to opioid treatment programs. In addition, the OTP seeks to determine the patient’s drug of choice and the source of the primary drug. Patients enrolling in the participating OTPs are voluntarily recruited for the study and complete a self-administered anonymous questionnaire within the first week of admission. OTPs in rural and urban areas of the United States have been recruited as study sites. Data collected in this reporting period (2nd quarter 2014) from the SKIP involved 106 substance abuse treatment programs covering 46 states. These primarily private treatment centers include representation from urban, suburban and rural centers. Each newly admitted patient with a diagnosis of prescription opioid analgesic abuse or dependence is offered the opportunity to complete a standardized self-administered questionnaire that solicits information on specific FDA_1786 prescription drugs abused in the past 30 days. The objectives of SKIP are to monitor the incidence of abuse/misuse of many different prescribed opioids, to determine the characteristics of the abuse/misuse patterns, and to develop intervention strategies. The OTP and SKIP programs complement each other by addressing different socioeconomic demographics involved in prescription drug abuse. Both programs use a common base questionnaire so that data can be combined. 7.4.4 College Survey Program The College Survey program is an online questionnaire that collects data from self-identified students attending a 2- or 4-year college, university or technical school at least part-time during the specified sampling period. Data on non-medical use (abuse/misuse) of specific prescription drugs are collected at the completion of the fall and spring academic semesters/quarters and at the end of the summer. The objectives of the College Survey Program are to estimate the scope of non-medical prescription drug use among US college students, determine the drug source and determine the route of drug administration among these students. A target of 2000 surveys is completed three times per year with enrollment stratified into the four US Census-regions to ensure nationwide distribution of respondents. A nationwide panel company is utilized to identify and target ideal responders. Students are sent an invitation to participate in the study and they receive credits upon completion of the survey. The survey inquires about the nonmedical use of prescription drugs by capturing product specific endorsements. 7.4.5 Impaired Healthcare Workers Program The Impaired Health Care Worker Program is a subset of three contributing programs. Data on impaired healthcare works are aggregated by combining data from these three sources into one data set: • Reports from several regulatory agencies, including medical boards, pharmacy boards, dental boards and nursing boards are obtained and summarized. These agencies specialize in the detection, treatment and sanctioning of impaired health workers who are involved in the diversion of prescription pharmaceuticals. • Poison Center case notes are reviewed and cases which indicate the individual involved in the exposure is a health care worker are flagged. • Respondents in the Treatment Center Programs self-identify as health care workers on the questionnaire. 7.4.6 Results Summary results of the analyses of the four data sources are presented below. The full report from the RADARS® System Program is included as Appendix 12.2. 7.4.7 Population Rates (b) (4) FDA_1787 7.4.8 Prescription Rates 788 7.4.9 Pediatric Exposures 789 7.4.10 Comparison of Cases from Reporting Period 1 to Reporting Period 2 790 8 PERIODIC SURVEYS 0F STAKEHOLDERS Surveys were conducted to assess patients?/caregivers?, pharmacists?, and prescribers? KAB regarding the safe use of TIRF medicines as described in the educational materials for all stakeholders, enrollment form (pharmacists and prescribers only), Full Prescribing Information (pharmacists and prescribers only) and medication guides (prescribers and patients) for each product, and the PPAF (prescribers and patients only). The survey protocols describe the administration of the individual surveys that were conducted among patients who are treated with TIRF medicines or their caregivers, prescribers, and pharmacists; the survey KAB reports include summarization of all data collected during the survey (see Appendix 12.4.1, 12.4.2, and 12.4.3, respectively, for the patient, pharmacist, and prescriber KAB reports which include the protocol and survey). Data ?om the surveys, together with other REMS evaluation metrics, will be used to determine whether changes need to be made to the REMS processes or educational materials to make them more e?ec?ve in achieving the goals of the REMS. 8.1 Key Risk Messages The questions and statements within the KAB surveys for patients/caregivers, pharmacists, and prescribers were constructed to test the stakeholders? understanding of the key risk messages of the REMS. The TRIG established a desired threshold of 65%. A correct response rate of 65% or greater was considered to represent adequate understanding of each concept or key risk message. The purpose of this threshold was to assist TRIG in tracking and monitoring the data for each key risk message across each wave ultimately providing direction in determining which area(s) 791 would require improvement to ensure the patient/caregiver, pharmacist, and prescriber KAB surveys were meeting the goals of the REMS. 8.2 Patient KAB Survey 8.2.1 Background and Survey Statistics The specific goals of the TIRF medicines patient/caregiver KAB survey were to evaluate the level of knowledge and assess the attitudes and behavior of patients/caregivers regarding TIRF medicines. The focus of the survey included the potential for life-threatening breathing problems that can lead to death, the need for patients to take TIRF medicines if they are opioid-tolerant and strictly follow the directions of the HCP, the caution that patients should not switch from a TIRF medicine to another medicine that contains fentanyl without talking to an HCP, the requirements that patients should not give TIRF medicines to anyone else even if they have the same symptoms, and that TIRF medicines should be stored in a safe place away from children and properly disposed of. The survey also included questions about whether patients received, read, and understood the product-specific Medication Guide and the PPAF. For the patient KAB survey, invitations (and reminders) were sent to all known patients/caregivers who had filled a prescription within the 4 months prior to survey launch. From among those who responded to the invitation, 229 patients/caregivers completed the survey (there were only 4 caregivers who participated in the survey). Although the survey had a target of 300 completed responders, the pool of 1343 patients/caregivers who were mailed the invitation was small. The response of 229 completed surveys from this limited pool is within the expected response rate to mailed invitations (17.1%; 229/1343).The target 300 eligible completed surveys was not achieved, a sample of 229 completed surveys is adequate to draw conclusions regarding patient understanding of safe use of TIRF medicines. 8.2.2 Patient Survey Results In this 36-month survey, all but one of the questions included as part of the key risk messages had a correct response rate of >69%. There was only one question within a key risk message (Question 12 in Key Risk Message 3) that had a component with an understanding rate below the desired threshold of 65% (Component 12b: If a patient stops taking around-the-clock opioid pain medicine, they must also stop taking the TIRF medicine; correct response ‘True’; correct response rate 36.7%). This concept also scored low for prescribers (61.0%) for this reporting period. In addition, there was one question included as part of the additional questions about the safe use of TIRF medicines and not included as a key risk message (Question 10; For which of the following conditions should you use a TIRF medicine?) that had a component with an understanding rate below the desired threshold of 65% (Component 10e; Long-lasting painful conditions not caused by cancer; correct response ‘No’, correct response rate 25.3%). This component also had a low correct response rate in the previous survey waves. Although the questions are worded differently for the 36-month survey period, this concept also scored low for pharmacists (43.7%). These components were the only low scoring components in all three waves of the patient/caregiver KAB survey. FDA_1792 Question 32 (Did the doctor or someone in the doctor’s office explain the Patient-Prescriber Agreement Form to you?) shows an increased response (77.7%) compared to the previous two waves which supports that the healthcare professionals are discussing with their patients the safe use and risks of TIRF medicines. The consistently high level of patient understanding of key risk messages in the 24-month and 36-month surveys indicates that the REMS goals are being met with the tools currently in place. The higher level of understanding in patients who read most or all of the medication guide demonstrates effective communication of the key risk messages, which may also be reinforced by prescribers and pharmacists. For complete data and results see Appendix 12.4.1. 8.3 Pharmacy KAB Survey 8.3.1 Background and Survey Statistics The specific goals of the TIRF medicines pharmacist KAB survey were to assess pharmacist understanding of the risks associated with TIRF medicine use, the specific indications for treatment with TIRF medicines, and that TIRF medicines are contraindicated in opioid nontolerant patients. The survey also included questions about the pharmacists’ access to educational materials for TIRF medicines. For the pharmacist KAB survey, invitations (and reminders) were sent to a random sample of pharmacies enrolled in the TIRF REMS Access Program. From among those who responded to the invitation, 300 pharmacists completed the survey; thus the program goal was achieved within the specific time period. 8.3.2 Pharmacy Survey Results In this 36-month survey, all but one of the questions/components included as part of the key risk messages had a correct response rate of >70%. There was only one question within a key risk message (Question 9 [Per the approved labeling for TIRF medicines, for which of the following indications can TIRF medicines be prescribed to opioid tolerant patients?] in Key Risk Message 2) that had a component with an understanding rate below the desired threshold of 65% (Component 9e: Chronic non-cancer pain; correct response “No”; correct response rate 43.7%). This component also had a low correct response rate in the previous survey waves. For the other 4 components of Question 9, the desired responses were greater than 86% in the 36-month survey. It should be noted that pharmacist knowledge of uses for which TIRF medicines are not indicated is not a goal of the TIRF REMS. This concept also scored low patients/caregivers (25.3%; presented as Long-lasting painful conditions not caused by cancer). In addition, there were two questions included as part of the additional questions about the safe use of TIRF medicines (and not included as part of a key risk message) that had a component with an understanding rate below 65%. The correct response rate for Component 6a which addresses knowledge that a cancer patient should not be started on a TIRF medicine and an around-the-clock opioid at the same time was 63.3%. This concept also scored low for prescribers (60.0%) during this reporting period. The correct response for component 11f that addresses the knowledge that patients are considered opioid-tolerant if taking an equianalgesic dose of another oral opioid one week or longer was 59.0%. These concepts also scored low for prescribers (59.0%) during this reporting period. FDA_1793 The consistently high level of pharmacist understanding of key risk messages in the 24-month and 36-month surveys indicates that the Education Program for Prescribers and Pharmacists is meeting the goals of the TIRF REMS. Changes will be implemented into the 48-month Pharmacist KAB survey based on FDA feedback received on the 24-month assessment report. For complete data and results see Appendix 12.4.2. 8.4 Prescriber KAB Survey 8.4.1 Background and Survey Statistics The specific goals of the TIRF medicines prescriber KAB survey were to assess prescribers’ understanding of the risks associated with TIRF medicine use, the selection of appropriate patients for treatment with TIRF medicines, preventing inappropriate conversion between TIRF medicines, and ensuring safe use of TIRF medicines while preventing exposure to children and others for whom TIRF medicines were not prescribed. For the prescriber KAB survey invitations (and reminders) were sent to a random sample of prescribers enrolled in the TIRF REMS Access Program. From among those who responded to the invitation, 300 prescribers completed the survey; thus, the program goal was achieved within the specific period. 8.4.2 Prescriber Survey Results In the 36-month prescriber KAB survey, of the 21 components of the 4 key risk messages, only 1 component had a response rate less than the desired threshold of 65%. As a measure of prescribers’ behavior, 62.0% (n=186) of respondents gave the desired response “No” to Question 9 (In your practice, for which of the following indications do you prescribe TIRF medicines to opioid tolerant patients? Component 9e: Chronic non-cancer pain). The response from prescribers regarding the desired response that TIRF medicines are not prescribed for non-cancer pain has been consistently low for all 3 surveys (Wave 1: 54.3%; Wave 2: 58.9%; Wave 3: 62.0%). Based on FDA feedback an additional question will be added to the 48-month survey asking prescribers why they feel this is an appropriate use of a TIRF medicine. For the other 4 components of Question 9, the desired responses were greater than 87% in the 36-month survey. In addition, there were four questions included as part of the additional questions about the safe use of TIRF medicines (and not included as part of a key risk message) that had a component with an understanding rate below the desired threshold of 65%. The correct response rate for component 6a which addresses knowledge that a cancer patient should not be started on a TIRF medicine and an around-the-clock opioid at the same time was 63.3%. This concept also scored low for pharmacists. The desired response of ‘False” for component 18c (Instruct patients that, if they stop taking their around -the-clock opioid medicine, they can continue to take their TIRF medicine) that assessed prescriber behavior was selected by 61.0% of prescribers. This concept also scored low in the patient/caregiver KAB survey for this reporting period. Similarly, Question 19, which addresses the knowledge that patients should not continue to take their TIRF medicine if they stop taking their around-the-clock opioid medicine had a correct response rate of 59.7%. This concept also scored low in the patients/caregiver KAB survey for this reporting period. In response to Question 11 component 11f, that addresses the knowledge that patients are considered opioid-tolerant if taking an equianalgesic dose of another oral opioid one week or FDA_1794 longer, was selected by 59.0% (177) of prescribers. For this reporting period, pharmacists also had a similar low rate of correct response for this concept (59.0%). The consistently high level of prescriber understanding of key risk messages in the 24-month and 36-month surveys indicates that the Education Program for Prescribers and Pharmacists is meeting the goals of the TIRF REMS. Changes will be implemented into the 48-month Prescriber KAB survey based on FDA feedback received on the 24-month TIRF REMS assessment report. For complete data and results see Appendix 12.4.3. 8.5 Overall Conclusion for KAB Results: The TRIG will evaluate the concepts that have scored low among stakeholders to determine if any action is warranted. The TRIG will continue to work with the FDA to refine, on a continual basis, the steps to mitigate risks associated with TIRF medicines. 9 FDA COMMUNICATIONS During this reporting period REMS Modification 2 was approved and implemented. Modification 2 for the TIRF REMS consisted of the following: • Incorporate closed system pharmacies into the TIRF REMS Access Program • Correct minor inconsistencies between the FDA provided versions and the current PDF versions of REMS materials Submission of REMS Modification 3 was completed on 10 December 2014. Modification 3 for the TIRF REMS consisted of the following: • Updated REMS materials to eliminate product specific information which does not impact the safe use of TIRF products • Updated REMS materials to reference the TIRF Products webpage on the TIRF REMS Access website • Updated REMS materials to remove reference to deactivating patients shown to have multiple prescribers in an overlapping timeframe • Incorporated revised assessment metrics into the Supporting Document • Revised Education Program to emphasize and strengthen appropriate conversion and patient counseling information • Updated REMS and Supporting Document to clarify deactivation of a patient PPAF as opposed to the patient record • Updated pharmacy overview documents and FAQ to call out cash claim requirement • Updated TIRF REMS Access website to incorporate items above and link respective Full Prescribing Information and Medication Guides to DailyMed • Updated Education Program and Knowledge Assessment to incorporate approved labeling supplement FDA_1795 TRIG is currently awaiting feedback from FDA on REMS Modification 3 which includes the revised Assessment Plan aligning to the Agency’s 21 August 2014 REMS Acknowledgement/ REMS Assessment Plan Revision communication to the TRIG and individual TIRF products application holders. Although Modification 3 is not approved, this assessment report has addressed the metrics aligning with the revised assessment plan provided in the REMS Assessment Acknowledgement/REMS Assessment Plan Revision and presented in Modification 3. 10 POST-APPROVAL STUDIES AND CLINICAL TRIALS FDA should refer to the most recent periodic safety report from each TIRF sponsor for updated information on post-approval studies and/or clinical trials. 11 OVERALL CONCLUSIONS The TIRF REMS Access Program was approved on 28 December 2011 and successfully launched on 12 March 2012, approximately 11 weeks after approval. This 36-month assessment report covers the timeframe between 29 October 2013 and 28 October 2014. A major focus during this reporting period was re-enrollment of all stakeholders in the program. As part of re-enrollment, stakeholders were re-educated in order to ensure understanding about the safe use and risks of TIRF medicines. Extensive efforts are made using multiple modalities to reach all stakeholders whose enrollment status or PPAF is nearing expiration. Re-enrollment activities continue ensuring appropriate access to TIRF medicines. REMS enrollment continues to increase, with 2,027 new prescribers, 1,585 new pharmacies, and 1 new distributor enrolled in this reporting period. A total of 159,560 prescriptions were presented for dispensing during this reporting period, and 145,084 (90.9%) prescriptions did not encounter any REMS-related rejection prior to being authorized. These data indicate that the program does not present a significant barrier to accessing these important medications while continuing to meet the safety goals of the REMS. The number of prescriptions dispensed outside the established PPAF requirements was nearly eliminated as a result of the corrective actions implemented during this reporting period to significantly reduce this occurrence. The TIRF REMS Access Program continues to monitor the electronic systems and stakeholder reports for issues and, where appropriate, corrective actions or system improvements are instituted. During the current reporting period, 145 instances of stakeholder non-compliance with the TIRF REMS Access program were reviewed and investigated. This included 120 prescriber reports, 1 wholesaler/distributor report, 17 non-closed system pharmacy reports and 7 closed system pharmacy reports. Five of these closed system pharmacy non-compliance reports were identified during the audits of the 7 enrolled closed system pharmacy entities. Each affected entity was issued a notice through the NCRT and as a result all investigations have been closed. As per the TRIG’s agreement with FDA, inpatient pharmacy hospital audits have not yet been conducted. The TRIG is developing a process to accomplish inpatient pharmacy audits. Therefore, inpatient pharmacy audit data will be included in the 48-month assessment report. FDA_1796 The REMS goal of educating prescribers and pharmacists on the potential for misuse, abuse, addiction, and overdose is being documented through the completion of the Knowledge Assessment, which is required for enrollment. Effectiveness of the educational program is evaluated through the pharmacy and prescriber KAB surveys that are performed prior to each assessment report. Results of the 36-month surveys indicate a high level of understanding of safe use of TIRF medicines by pharmacists and prescribers. Key risk messages that are important for these stakeholders to understand include the fact that TIRF medicines are contraindicated in opioid non-tolerant patients, are only indicated for the management of breakthrough pain in adult cancer patients, contain fentanyl with abuse liability similar to other opioid analgesics, and are not interchangeable with each other on a mcg-to-mcg basis regardless of route of administration. Due to the high level of understanding of these concepts by pharmacists and prescribers, no modifications to the educational program or Knowledge Assessment are recommended at this time. Patient education is completed through HCP counseling and completion of a PPAF. The patient KAB survey results indicate that the patient-oriented educational materials including the PPAF and Medication Guide for each product are effective tools at communicating safe use messages to patients, including the importance of not sharing TIRF medicines, taking TIRF medicines as prescribed, and properly disposing unused TIRF medicines. One identified area of potential improvement is patient understanding of the need to stop taking TIRF medicines if around-theclock opioid therapy is stopped. The proposed Modification 3 includes updates to the education program to reinforce the importance of this information being shared with patients by pharmacists and prescribers. Data collected through the RADARS® System showed that there were few event counts for TIRF products for all the Poison Center outcome variables: intentional abuse, intentional misuse, unintentional therapeutic errors, unintentional general exposures, emergency room visits or hospitalizations and major outcomes or death. Population rates for the Poison Center, Treatment Center and College Survey outcome variables tended to be lower than rates for Schedule II IR opioids, Schedule II opioids and Schedule II opioids excluding methadone. Prescription rates for the TIRF REMS products and Poison Center outcomes differed only occasionally from the comparator opioid groups. However, in the Treatment Center and College Survey, populations that are likely to have more experienced users, prescription rates for TIRF products tended to be higher than those for comparator opioids. The analysis of spontaneous reports of adverse events of interest aggregated data from TRIG sponsors with currently marketed products. There were 367 unique case reports that met the specified criteria for addiction, overdose, death, and pediatric exposures. After a review of the associated MedWatch Forms or narratives for root cause analysis, no reports of inappropriate conversions between TIRF products were noted. Additionally, none of the narratives indicated accidental, unintentional exposures or use by non-opioid tolerant patients. There were only two cases of pediatric exposure; neither provided sufficient detail to perform a root cause analysis. Data from the safety surveillance of adverse events of interest as well as RADARS® System data are consistent in showing low numbers of abuse, overdose and pediatric exposures cases associated with TIRF medicines. The primary RADARS® System data sources, with the exception of Poison Center data, are solicited via survey (Treatment Programs and College FDA_1797 Surveys) and describe patterns of abuse or misuse. Trends comparing RADARS® System data with the 3 selected comparator groups showed no substantial differences; solicited reports from the two survey populations were somewhat higher than the comparator groups, but showed a decline in rates over the time period. Poison Control and adverse event reports from sponsors are spontaneously reported. The Poison Center data show a small number of reported deaths, whereas 98.6% of the spontaneous reports with the specified adverse events of interest had an outcome of death. In the case of Poison Center data, cases are generally identified in the course of the reporter asking for assistance regarding an exposure; an outcome of death may be obtained during follow-up by the Poison Center. The predominance of death reports in the data provided by the TIRF medicines manufacturers was not unexpected, given that patients who are treated with TIRF medicines for the labeled indication are generally very ill from their underlying condition. There were few deaths with events describing outcomes specifically associated with respiratory or cardiac failure. Based on the data provided in this TIRF REMS Access Program Assessment Report the TRIG concludes that the REMS is meeting its established goals. The consistent high level of knowledge demonstrated by pharmacists, prescribers and patients provides evidence that the current tools are effectively communicating the important safety messages to key stakeholders. Based on our analysis of the data for this 36-month assessment, the TRIG is recommending no further REMS modifications beyond Modification 3 which is pending approval at this time. FDA_1798 12 APPENDICES 799 12.1 Safety Surveillance Aggregate Line Listing Preferred Terms 12.2 RADARS® System Program Report 12.3 RADARS® System Program Report Protocol 12.4 Periodic Stakeholder Surveys FDA_1800 12.1 Case Criteria: 0 Only US cases 0 No AAPCC or literature search cases 0 In addition to performing searches on the below preferred terms, sponsors will search for: All cases with an outcome of death 0 Cases related to patients aged 0 through 18 Safety Surveillance Aggregate Line Listing Preferred Terms 0 Cases to be included in the reporting period date range will be based on MedWatch Form field ?Date Received by Manufacturer? (G4) Preferred Terms for FDA Requested Cases of Addiction, Death, Overdose and Pediatric Exposure Primary SOC High Level Group High Level Term Preferred Term erdose Injury, and procedural Medication errors Overdoses Accidental overdose complications Injury, and procedural Medication errors Overdoses Intentional overdose complications Injury, pOisomng and procedural Medication errors Overdoses Overdose complications Injury, paisoning and procedural Medication errors Overdoses Prescribed overdose complications ath General disorders and administration Fatal outcomes Death and sudden death Accidental death Site conditions General disorders and administration Fatal outcomes Death and sudden death Brain death Site conditions General Disorders and adimnistration Fatal outcomes Death and sudden death Cardiac death Site conditions General disorders and administration Fatal outcomes Death and sudden death Death Site conditions General disorders and administrations Fatal outcomes Death and sudden death Death neonatal Site conditions General disorders and. administration Fatal outcomes Death and sudden death Sudden cardiac death Site conditions General Disorders and administration Fatal outcomes Death and sudden death Sudden death Site conditions General disorders and adirunistration Fatal outcomes Death and sudden death Agonal death struggle Site conditions General disorders and adirunistration General system disorders General Signs and Apparent death Site conditions NEC NEC Cardiac disorders Cardiac Ventricular and cardiac arrest Cardio?respiratory arrest Cardiac disorders Cardiac Ventricular and cardiac arrest Cardiac arrest Respiratory, thoracic and mediastinal disorders Respiratory disorders NEC Breathing abnormalities Respiratory arrest Pregnancy, puerperium and perinatal conditions Abortions and stillbirth Stillbirth and foetal death Foetal death isuse disorders I disorders NEC I Substance-related disorders I Intentional drug misuse buse 801 Primary SOC High Level Group High Level Term Preferred Term disorders disorders NEC Substance-related disorders Drug abuse appropriate Injury. pOisormig and procedural Medication errors Maladministrations Drug administered at complications inappropriate Site Injury. porsormig and procedural Medication errors Mala dminis tra tions Inappropriate schedule of drug complications administration edication Error Injury. pOisormig and procedural Medication errors Maladministrations Incorrect dosage administered comphcations In'i . oisonin and rocedural . . . . . Ina ro riate schedule of dru Ky .g . Medication errors Maladministrations pp . . . comphcations administration ccidental In'i . oisonin and rocedural . . Accidental ex osures to . try .g . Medication errors Acc1dental exposure to product complications product Injury. p01sormig and procedural Medication errors Acc1dental exposures to Acc1dental exposure to product complications product by child In'i . oisonin and rocedural . . . uy Medication errors Overdoses Acc1dental overdose complications Injury. poisoning and procedural Chemical injury and Poisoning and toxicity Accidental poisoning complications poisoning . . . . Failure of child resistant General disorders and administration . . . . . . . . . Product quality issues Product packaging issue mechamsm for pharmaceutical Site conditions product ependence disorders disorders NEC Substance-related disorders Dependence disorders disorders NEC Substance-related disorders Drug dependence disorders disorders NEC Substance-related disorders Drug dependence. antepartum disorders disorders NEC Substance-related disorders Drug dependence. postpartum disorders disorders NEC Substance-related disorders Polysubstance dependence Text?String Search Terms for Narratives Addiction Multiple ding overdose Son Nephew Overdose Expired Daughter Aunt Drug dependence Passed away Grandmother Uncle Death Infant Grandfather Mom Pediatric exposure Child Sister Pop Died Mother Brother Dad Fatal Father Niece 802 12.2 RADARS© System Program Report RADARS® System Report Transmucosal Immediate Release Fentanyl (TIRF) Risk Evaluation and Mitigation Strategy (REMS): Surveillance Monitoring For Cephalon, Inc. (a wholly-owned subsidiary of Teva Pharmaceutical Industries, Ltd.) Depomed, Inc. Galena Biopharma, Inc. Insys Therapeutics Inc. Mallinckrodt Pharmaceuticals Meda Pharmaceuticals, Inc. Mylan, Inc. Par Pharmaceutical, Inc. December 16, 2014 Confidential This report contains information that may be confidential, proprietary and/or exempt from disclosure under applicable law. Any dissemination, distribution or copying of this document is strictly prohibited without our prior written consent, which may be withheld for any reason solely at our discretion. CONFIDENTIAL RADARS® System Report Page 1 of 94 FOLLOWING THIS PAGE, FDA_1804 TO FDA_1896 WITHHELD IN FULL AS B(4)/CCI FDA_1803 12.3 RADARS© System Program Report Protocol Transmucosal Immediate Release Fentanyl (TIRF) Risk Evaluation and Mitigation Strategy (REMS): Surveillance Monitoring Protocol For Cephalon, Inc. (a wholly-owned subsidiary of Teva Pharmaceutical Industries, Ltd.) Depomed, Inc. Galena Biopharma, Inc. Insys Therapeutics Inc. Mallinckrodt Pharmaceuticals Meda Pharmaceuticals, Inc. Mylan, Inc. Par Pharmaceutical, Inc. Dec 15, 2014 Confidential This protocol contains information that may be confidential and/or proprietary. Any dissemination, distribution or copying of this document is strictly prohibited without our prior written consent, which may be withheld for any reason solely at our discretion. CONFIDENTIAL Page 1 of 17 FOLLOWING THIS PAGE, FDA_1898 TO FDA_1908 WITHHELD IN FULL AS B(4)/CCI FDA_1897 7. Appendices 909 7.2 Shell Tables Table x.x.x The System Poison Center Program Intentional Abuse Rates over Time by Drug Group Third Quarter 2012 through Third Quarter 2013 Intercept Slope Percent Quarterly p-value Rate Rate Ratio p-value for Change difference for Drug Group (95% Cl) p-value (95% CI) difference (95% Cl) p-value (95% CI) difference Population Adjusted Rate TIRF Products Schedule II IR Opioids Schedule II Opioids Schedule II Opioids Excluding Methadone Prescription Adjusted Rate TIRF Products Schedule II IR Opioids Schedule II Opioids Schedule II Opioids Excluding Methadone Table x.x.x The System Treatment Center Programs Past 90 Day Endorsement of Non-Medical Use Over Time by Drug Group Third Quarter 2012 through Third Quarter 2013 Intercept Slope Percent Quarterly p-value Rate Rate Ratio p-value for Change difference for Drug Group (95% Cl) p-value (95% Cl) difference (95% Cl) p-value (95% Cl) difference Population Adjusted Rate TIRF Products x.xm Schedule II IR Opioids Schedule II Opioids xaoom x.xxnt Schedule II Opioids Excluding x.)000( x.)000( x.)000( Methadone Prescription Adjusted Rate TIRF Products Schedule II IR Opioids xaoom x.xxnt Schedule II Opioids x.)000( x.)000( x.)000( Schedule II Opioids Excluding x.)000( x.X)o0( x.)000( Methadone 1 Table x.x.x The System College Survey Program Past 90 Day Mentions Over Time by Drug Group Third Quarter 2012 through Third Quarter 2013 Intercept Slope Percent Quarterly p-value Rate Rate Ratio p-value for Change difference for Drug Group (95% Cl) p-value (95% Cl) difference (95% Cl) p-value (95% Cl) difference Population Adjusted Rate TIRF Products x.xm Schedule II IR Opioids Schedule II Opioids x.xxnr Schedule II Opioids Excluding x.)000( x.)000( x.)000( Methadone Prescription Adjusted Rate TIRF Products Schedule II IR Opioids x.xxnr Schedule II Opioids x.)000( x.)000( x.)000( Schedule II Opioids Excluding x.)000( x.X)o0( x.)000( Methadone Table x.x.x The System Impaired Healthcare Worker Program Cases Over Time by Drug Group Third Quarter 2012 through Third Quarter 2013 Intercept Slope Percent Quarterly p-value Rate Rate Ratio p-value for Change difference for Drug Group (95% Cl) p-value (95% Cl) difference (95% Cl) p-value (95% Cl) difference Population Adjusted Rate TIRF Products x.xm Schedule II IR Opioids Schedule II Opioids x.xxnr Schedule II Opioids Excluding x.)000( x.)000( x.)000( Methadone Prescription Adjusted Rate TIRF Products Schedule II IR Opioids x.xxnr Schedule II Opioids x.)000( x.)000( x.)000( Schedule II Opioids Excluding x.)000( x.X)o0( x.)000( Methadone 12.4.1 Patient KAB Survey Patient KAB Assessment Report Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Title: Page 1 of 52 Transmucosal Immediate Release Fentanyl (TIRF) REMS Assessment Quantitative Testing of Patient Knowledge, Attitudes, and Behavior (KAB) about TIRF Products’ Safety and Use Information Document Number Wave 3, 36-month REMS Assessment; Version 1.0 Survey Time Period 18 August 2014 to 22 October 2014 Product Name: Transmucosal Immediate Release Fentanyl Sponsor: TIRF REMS Industry Group (TRIG) of Companies: Cephalon, Inc. (a wholly-owned subsidiary of Teva Pharmaceutical Industries, Ltd.) Depomed, Inc Galena Biopharma, Inc. Insys Therapeutics Mallinckrodt Pharmaceuticals Meda Pharmaceuticals Mylan, Inc. Par Pharmaceutical, Inc. Date: 19 December 2014 Confidentiality Statement The information contained herein is confidential and the proprietary property of the TRIG of Companies and its affiliates, and any unauthorized use or disclosure of such information without the prior written authorization of the TRIG is expressly prohibited. FDA_1915 Patient KAB Assessment Report Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies TABLE OF CONTENTS Page 2 of 52 PAGE TABLE OF CONTENTS......................................................................................................... 2  LIST OF TABLES ................................................................................................................... 3  LIST OF APPENDICES .......................................................................................................... 4  LIST OF ABBREVIATIONS .................................................................................................. 5  1.  PATIENT SURVEY BACKGROUND ............................................................. 6  2.  PATIENT SURVEY OBJECTIVES .................................................................. 7  3.  SURVEY METHODOLOGY ............................................................................ 7  3.1  Survey Sample.................................................................................................... 7  3.1.1  Eligibility ............................................................................................................ 8  3.1.2  Recruitment ........................................................................................................ 8  3.1.2.1  Direct Letter Program......................................................................................... 8  3.2  Questions and Statements on Key Risk Messages ............................................. 8  3.2.1  Key Risk Message 1 ........................................................................................... 9  3.2.2  Key Risk Message 2 ........................................................................................... 9  3.2.3  Key Risk Message 3 ......................................................................................... 10  3.2.4  Key Risk Message 4 ......................................................................................... 10  3.2.5  Key Risk Message 5 ......................................................................................... 10  3.2.6  Key Risk Message 6 ......................................................................................... 11  4.  Statistical Methods ........................................................................................... 11  4.1  Study Population .............................................................................................. 11  4.1.1  Primary Analysis Population ............................................................................ 11  4.1.2  Sub-groups of Interest ...................................................................................... 11  4.1.2.1  Primary Analyses ............................................................................................. 13  4.1.2.2  Secondary Analyses ......................................................................................... 13  4.1.3  Patient Report of an Adverse Event, Product Complaint, or Medical Information Request during the Survey ........................................................... 13  5.  RESULTS......................................................................................................... 13  5.1  Survey Participants ........................................................................................... 13  5.1.1  Survey Participant Administration Results ...................................................... 13  FDA_1916 Patient KAB Assessment Report Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 3 of 52 5.1.2  Patient/Caregiver Demographics...................................................................... 19  5.1.3  TIRF Medicines Education Materials .............................................................. 22  5.1.4  Patient-Prescriber Agreement Form ................................................................. 27  5.2  KAB Survey Objectives ................................................................................... 29  5.2.1  Key Risk Message Results ............................................................................... 29  5.2.1.1  Key Risk Message 1 ......................................................................................... 29  5.2.1.2  Key Risk Message 2 ......................................................................................... 29  5.2.1.3  Key Risk Message 3 ......................................................................................... 31  5.2.1.4  Key Risk Message 4 ......................................................................................... 33  5.2.1.5  Key Risk Message 5 ......................................................................................... 34  5.2.1.6  Key Risk Message 6 ......................................................................................... 35  5.2.2  Other Survey Questions ................................................................................... 38  5.2.2.1  Additional Questions about TIRF Medicines Safety ....................................... 38  5.2.3  Sub-group Analysis of Responses to Key Risk Messages ............................... 40  5.2.3.1  Reading the Medication Guide (Sub-group S-1).............................................. 40  5.2.3.2  All other Sub-group Analyses .......................................................................... 42  5.3  Spontaneous Reporting of Adverse Events, Product Complaints, or Medical Information Requests ......................................................................... 43  5.4  Summary of Correct Responses for Key Risk Messages ................................. 43  6.  FDA FEEDBACK ............................................................................................ 47  7.  DISCUSSION, AND CONCLUSIONS ........................................................... 47  LIST OF TABLES Table 1.  Survey Participant Administration Results .................................................... 15  Table 2.  Survey Participant Screening Results ............................................................ 16  Table 3.  Time to Complete Survey for Completers (Minutes) .................................... 19  Table 4.  Demographic Characteristics of Eligible Patients/Caregivers ....................... 20  Table 5.  Responses to Questions About TIRF Medication Guides ............................. 23  Table 6.  Responses to Questions About the Patient-Prescriber Agreement Form ............................................................................................................... 28  FDA_1917 Patient KAB Assessment Report Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 4 of 52 Table 7.  Key Risk Message 1: TIRF Medicines Can Cause Life-Threatening Breathing Problems That Can Lead to Death ................................................ 29  Table 8.  Key Risk Message 2: Patients Should Not Take TIRF Medicines If They Are Not Opioid Tolerant ....................................................................... 30  Table 9.  Key Risk Message 3: TIRF Medicines Should Be Taken Exactly As Prescribed By The Healthcare Provider ......................................................... 32  Table 10.  Risk Message 4: Patients Should Not Switch From a TIRF Medicine to Another Medicine That Contains Fentanyl Without Talking to a Healthcare Provider ....................................................................................... 34  Table 11.  Key Risk Message 5: Patients Should Not Give TIRF Medicines to Anyone Else Even if They Have the Same Symptoms .................................. 35  Table 12.  Key Risk Message 6: TIRF Medicines Should be Stored in a Safe Place Away From Children and Properly Disposed ...................................... 36  Table 13.  Responses to Additional Questions about the Safe Use of TIRF Medicines ....................................................................................................... 38  Table 14.  Correct Responses and Response Rates to Key Risk Message Questions Based on Extent of Reading of Medication Guide ....................... 41  Table 15.  Summary of Correct Responses for Key Risk Messages............................... 44  Table 16.  Correct/Desired Response Rate of Low Scoring Questions across the Three Patient/Caregiver KAB Survey Waves................................................ 48  LIST OF APPENDICES Appendix A  Patient Survey Protocol.................................................................................. 50  Appendix B  Patient Survey Listings and Sub-group Analyses Tables .............................. 51  Appendix C  Patient Survey Protocol Track Change Document: Comparison of 24month Survey to 36-month Survey ................................................................ 52  FDA_1918 Patient KAB Assessment Report Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 5 of 52 LIST OF ABBREVIATIONS AE/PC PSP Adverse Event/Product Complaint Project Specific Procedure CI Confidence Interval ETASU Elements to Assure Safe Use FDA Food and Drug Administration HCP Healthcare Professional KAB Knowledge, Attitudes and Behavior NA Not Applicable PPAF Patient-Prescriber Agreement Form PBM Pharmacy Benefits Manager REMS Risk Evaluation and Mitigation Strategy SCC Survey Coordinating Center SD Standard Deviation TIRF Transmucosal Immediate Release Fentanyl TIRF Medicines Transmucosal Immediate Release Fentanyl products TIRF REMS Access Program REMS Program for TIRF medicines TRIG TIRF REMS Industry Group UBC United BioSource Corporation US United States USPS United States Postal Service FDA_1919 Patient KAB Assessment Report Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies 1. Page 6 of 52 PATIENT SURVEY BACKGROUND Transmucosal Immediate Release Fentanyl (TIRF) medicines are a class of immediaterelease opioid analgesics that are indicated only for the management of breakthrough pain in cancer patients 18 years of age or older (16 or older for Actiq® [fentanyl citrate oral transmucosal lozenge] and equivalent generics) who are already receiving and already tolerant to opioid therapy for their underlying persistent cancer pain. The TIRF medicines include Abstral®, Actiq®, Fentora®, Lazanda®, Onsolis®, Subsys®, and generic versions of any of these brands. The TIRF Risk Evaluation and Mitigation Strategy (REMS) Industry Group (TRIG) includes Cephalon, Inc. (a wholly-owned subsidiary of Teva Pharmaceutical Industries, Ltd.), Depomed, Inc., Galena Biopharma, Inc., Insys Therapeutics, Mallinckrodt Pharmaceuticals, Meda Pharmaceuticals, Mylan, Inc., and Par Pharmaceutical, Inc. The Food and Drug Administration (FDA) has determined that a shared system REMS is required to mitigate the risk of misuse, abuse, addiction, overdose, and serious complications due to medication errors with the use of TIRF medicines. The TIRF REMS Access Program (hereafter referred to as TIRF REMS) was approved by the FDA on 28 December 2011. The TIRF REMS consists of a Medication Guide, Elements to Assure Safe Use (ETASU), an Implementation System, and a Timetable for Submission of Assessments of the REMS. The goals of the TIRF REMS are to mitigate the risk of misuse, abuse, addiction, overdose, and serious complications due to medication errors by the following: 1. Prescribing and dispensing TIRF medicines only to appropriate patients, which includes use only in opioid-tolerant patients. 2. Preventing inappropriate conversion between TIRF medicines. 3. Preventing accidental exposure to children and others for whom it was not prescribed. 4. Educating prescribers, pharmacists, and patients on the potential for misuse, abuse, addiction, and overdose of TIRF medicines. An important component of the TIRF REMS assessment is the conduct of quantitative evaluation surveys to assess patients’/caregivers’ knowledge, attitudes, and behavior (KAB) regarding the safe use of TIRF medicines as described in the educational materials. Administration of the surveys conducted among patients/caregivers who are enrolled in the TIRF REMS Access Program is described in the protocol (See Appendix A). Note: Protocol and Survey question revisions from the 24-month assessment report are identified in the track change version found in Appendix C. Data from the surveys, together with other REMS evaluation metrics, will be used to determine whether changes need to be made to the REMS processes or educational materials to make them more effective in achieving the goals of the REMS. FDA_1920 Patient KAB Assessment Report Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 7 of 52 This report describes the results from the patient surveys conducted for the 36-month TIRF REMS Access Program Assessment. The 36-month KAB survey launched on 18 August 2014 and closed on 22 October 2014. 2. PATIENT SURVEY OBJECTIVES The evaluation survey uses a questionnaire to document the level of knowledge and assess the attitudes and behavior of patients regarding the following key information and risk messages communicated through the REMS: 1. TIRF medicines can cause life-threatening breathing problems that can lead to death. 2. Patients should not take TIRF medicines if they are not opioid tolerant. 3. TIRF medicines should be taken exactly as prescribed by the healthcare provider. 4. Patients should not switch from a TIRF medicine to another medicine that contains fentanyl without talking to a healthcare provider. 5. Patients should not give TIRF medicines to anyone else even if they have the same symptoms. 6. TIRF medicines should be stored in a safe place away from children and properly disposed. The survey also includes questions about whether patients received, read, and understood the product-specific Medication Guide and Patient-Prescriber Agreement Form (PPAF). 3. SURVEY METHODOLOGY This section summarizes the survey design and the questions that were constructed to test patient understanding of the key risk messages of the REMS. Full details of the survey design are in the protocol, provided in Appendix A. 3.1 Survey Sample This survey was conducted among patients who had a prescription filled for a TIRF medicine within the 120 days prior to the survey launch date. A sample of 300 patients treated with TIRF medicines was targeted for this third KAB survey conducted from 18 August 2014 to 22 October 2014. The size of the sample was determined on both practical and statistical considerations. The survey was written to reflect wording for both methods of survey administration: Internet-based and telephone. FDA_1921 Patient KAB Assessment Report Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies 3.1.1 Page 8 of 52 Eligibility Eligibility criteria included patients, 18 years of age or older, and caregivers, 18 years of age or older, who cared for patients who were unable to take the survey for themselves. Respondents who (or respondents whose immediate family members) had ever worked for any of the TRIG companies, McKesson Specialty Care Solutions, RelayHealth, United BioSource Corporation (UBC), or the FDA were not eligible to participate in this survey. Respondents who participated in previous waves of the survey (12-month TIRF REMS Access Program Assessment or the 24-month TIRF REMS Access Program Assessment) were not eligible to participate. 3.1.2 Recruitment Patients were recruited via a direct letter program. Patients’ invitation letters (Appendix A) informed patients that participants who completed the survey and who provided their contact information would be mailed a $50 gift card to thank them for their participation. The thank you letter included the correct answers to key risk message questions, and a copy of the product-specific Medication Guide. Patients were recruited through a national pharmacy network partner and a Pharmacy Benefits Manager (PBM). All patients who filled one or more prescriptions during the 120 days prior to 18 August 2014 were invited to participate. 3.1.2.1 Direct Letter Program Patients were recruited via a letter of invitation sent through the United States Postal Service (USPS). The required number of completed surveys was not achieved within approximately 10 days after the first mailing; therefore, subsequent mailings were sent to non-respondents from the original sample to maximize participation. 3.2 Questions and Statements on Key Risk Messages The questions and statements comprising the knowledge survey were constructed to test the patients’ understanding of the key risk messages of the REMS. The questions were to be answered either by selecting options from multiple-choice lists that include statements of the specific key risk messages or by choosing “Yes” or “True,” “No” or “False,” or “I don’t know” regarding statements about TIRF medicines. For statements or questions that had “True” or “Yes” vs. “False” or “No” response options, the desired response for key risk messages was generally “True” or “Yes” indicating knowledge of, or behavior in accordance with, the objectives of the REMS. However, some questions were formatted to have the respondent disagree with the statement as written by providing response options of “False” or “No” to avoid having the same affirmative answer for all desired responses. REMS statements, corresponding questions, and desired responses covering the key risk messages are identified below and can be found in the complete survey questionnaire (Appendix A). FDA_1922 Patient KAB Assessment Report Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies 3.2.1 Page 9 of 52 Key Risk Message 1 Key Risk Message 1 refers to the patient’s/caregiver’s knowledge that TIRF medicines can cause life-threatening breathing problems. Key Risk Message 1: TIRF medicines can cause life-threatening breathing problems that can lead to death. Question No. Question Desired response 13 Please answer True, False, or I don’t know for each statement about the TIRF medicine that was most recently prescribed for you. 13d TIRF medicines can cause life-threatening breathing problems that can lead to death. 3.2.2 True Key Risk Message 2 Key Risk Message 2 refers to the patient’s/caregiver’s awareness that TIRF medicines should be taken only by opioid-tolerant adult patients. Key Risk Message 2: Patients should not take TIRF medicines if they are not opioid tolerant. Question No. Question Desired response Please answer True, False, or I don’t know for the following statement: 11 12 TIRF medicines should only be taken by patients who are opioid tolerant. True Please answer True, False, or I don’t know for each of the following statements. 12a Opioid tolerant means that a patient is already taking other opioid pain medicines around the clock and their body is used to these medicines. 13 Please answer True, False, or I don’t know for each statement about the TIRF medicine that was most recently prescribed for you. 13b It is OK for patients to take TIRF medicines for headache pain. True False FDA_1923 Patient KAB Assessment Report Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies 3.2.3 Page 10 of 52 Key Risk Message 3 Key Risk Message 3 refers to the patient’s/caregiver’s knowledge that TIRF medicines should be taken exactly as prescribed by the healthcare provider. Key Risk Message 3: TIRF medicines should be taken exactly as prescribed by the healthcare provider. Question No. Question Desired response Please answer True, False, or I don’t know for each of the following statements. 12 12b 13/17 13c 17b 3.2.4 If a patient stops taking around-the-clock opioid pain medicine, they must also stop taking the TIRF medicine. True Please answer True, False, or I don’t know for each statement about the TIRF medicine that was most recently prescribed for you. TIRF medicines should be taken exactly as prescribed by the doctor. It is OK to take TIRF medicines for short-term pain that will go away in a few days. True False Key Risk Message 4 Key Risk Message 4 refers to the patient’s knowledge of the interchangeability of TIRF medicines. Key Risk Message 4: Patients should not switch from a TIRF medicine to another medicine that contains fentanyl without talking to a healthcare provider. Question No. Question Desired response Please answer True, False, or I don’t know for each of the following statements. 12 It is safe to switch to another medicine that contains fentanyl without talking to a healthcare provider first. 12c False 3.2.5 Key Risk Message 5 Key Risk Message 5 refers to the patient’s/caregiver’s awareness that TIRF medicines should not be given to anyone else even if they have the same symptoms. Key Risk Message 5: Patients should not give TIRF medicines to anyone else even if they have the same symptoms. Question No. Question Desired response Please answer True, False, or I don’t know for each of the following statements. 12 A patient may give TIRF medicines to another person if they have the same symptoms as the patient. 12d False Please answer True, False, or I don’t know for each statement about the TIRF medicine that was most recently prescribed for you. 17 Selling or giving away TIRF medicines is against the law. 17a True FDA_1924 Patient KAB Assessment Report Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies 3.2.6 Page 11 of 52 Key Risk Message 6 Key Risk Message 6 refers to the patient’s/caregiver’s knowledge that TIRF medicines should be stored in a safe place away from children and properly disposed. Key Risk Message 6: TIRF medicines should be stored in a safe place away from children and properly disposed. Question No. Question Desired response Please answer True, False, or I don’t know for each statement about the TIRF medicine that was most recently prescribed for you. 13/17 TIRF medicines should be stored in a safe place out of the reach of children. 13a True TIRF medicines must be disposed of as described in the specific product’s Medication Guide. 17c True A TIRF medicine can cause an overdose and death in any child who takes it. 17e True What should you do if an adult who has not been prescribed a Get emergency TIRF medicine takes a TIRF medicine? (Please select one.) 14 help right away. 4. STATISTICAL METHODS 4.1 Study Population 4.1.1 Primary Analysis Population The primary population for analysis was all eligible patients who completed the survey. Eligible patients were defined as those respondents who answered Yes to Question 1 (agree to take part in survey), Yes to Question 2 (filled a prescription for a TIRF medicine in the last 4 months) or Yes to Question 3 (Caregiver for someone who had filled a prescription for a TIRF medicine in the last 4 months), No to Question 5 (participated in past survey), selected an age group ≥18 years of age for Question 6 (patient and caregiver), and No to Question 8 (worked for a TRIG company, UBC, or FDA). A completed survey was a survey in which all questions as appropriate were answered. Some questions may not have been answered by respondents due to skip logic in the survey questionnaire. 4.1.2 Sub-groups of Interest The following sub-group analyses of responses to key risk messages were conducted when the sub-group included at least 20 respondents. Sub-group analysis 1: Reading Medication Guide (Question 18, Question 23, and Question 24): • S-1a - Respondents who got the Medication Guide and read at least most of it • S-1b - Respondents who did not get a Medication Guide or answered, “I don’t know” or who got a Medication Guide and read only some of it or answered, “I don’t know.” FDA_1925 Patient KAB Assessment Report Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 12 of 52 Sub-group analysis 2: Understanding of Medication Guide (Question 25): • S-2a - Respondents who understood all of it or most of it • S-2b - Respondents who understood some of it • S-2c - Respondents who answered None or “I don’t know” • S-2d - Respondents who answered, “I don’t know” to receipt or reading of the Medication Guide. Sub-group analysis 3: Time to complete survey - Internet: • S-3a - <10 min • S-3b - 10 to<20 min • S-3c - ≥20 min Sub-group analysis 4: Time to complete survey - Telephone: • S-4a - <10 min • S-4b - 10 to <20 min • S-4c - ≥20 min Sub-group analysis 5: Modality to complete survey: • S-5a - Internet • S-5b – Telephone Sub-group analysis 6: Highest level of education (Question 37): • S-6a – Less than, Some, or High school graduate/GED or prefer not to answer • S-6b - Some college or associate’s degree • S-6c - Bachelor’s degree or Master’s degree • S-6d - Professional or Doctoral degree Sub-group analysis 7: Age group of respondent (Question 6): • S-7a – 18 to 39 • S-7b – 40 to 49 • S-7c – 50 to 59 • S-7d – 60 or older Results of sub-group analyses performed are provided in Appendix B, Tables 6.1, 7.1, 7.2, 8.1, 8.2, 9.1, 10.1, 10.2, 11.1, and 11.2. Answers from caregivers and answers from patients were combined for the sub-group analysis. FDA_1926 Patient KAB Assessment Report Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies 4.1.2.1 Page 13 of 52 Primary Analyses Primary analyses were done for all key risk messages. The primary analysis for a key risk message evaluated the number and percentage of each correct response for each individual question/item defined by the key risk message. The correct response to each question/item is included in the body of the risk message table (Section 3.3). 4.1.2.2 Secondary Analyses Secondary analyses evaluated the number and percentages of correct responses and the average of correct responses within the risk message overall to assess understanding of the comprehensive key risk message. A correct response rate of 65% or greater was considered to represent adequate understanding of each concept or key risk message. 4.1.3 Patient Report of an Adverse Event, Product Complaint, or Medical Information Request during the Survey A patient or caregiver may have reported an adverse event or product complaint while taking the online survey in the free text field of the Internet-based survey. Patients or caregivers who opted for the telephone-based survey may have reported an adverse event or a product complaint while in conversation with the Survey Coordinating Center (SCC). If an event was mentioned to the SCC Associate, the Associate documented the adverse event or product complaint, the verbatim response, and the respondent’s contact information, if provided. The respondent was informed that a representative from the appropriate TIRF medicine sponsor might contact them to obtain additional information about the adverse event or product complaint. Internet surveys were monitored for any comments recorded in the free text field. Information on all reports (Internet or telephone) that constituted an adverse event or product complaint was forwarded to the appropriate TIRF medicine sponsor for processing within one business day of awareness of the event as outlined in the Adverse Event/Product Complaint Project Specific Procedure (AE/PC PSP). 5. RESULTS Results of the patient responses to questions in the KAB survey are summarized in this section, and a full set of responses can be found in Appendix B. 5.1 Survey Participants 5.1.1 Survey Participant Administration Results Patients were recruited through a national pharmacy chain network partner and a PBM. Prior to mailing out invitation letters, all patients who previously completed the survey were removed. In addition, patients common to both lists were only sent one invitation letter. Based on the number of prescriptions filled during the 120 days prior to survey implementation (18 August 2014), the national pharmacy chain network partner identified 993 possible participants and the PBM identified 350 possible participants among patients and caregivers. All of these possible participants were sent a survey invitation letter. A total of 1,986 reminder letters were sent to non-responders (some potential participants received FDA_1927 Patient KAB Assessment Report Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 14 of 52 more than one reminder letter). Of the 1343 possible participants, 272 respondents accessed the survey and were screened for eligibility; 229 of the 272 (84.2%) respondents met eligibility criteria and completed the survey (Table 1). Of the 229 respondents, 78 (34.1%) completed the survey by telephone, and 151 (65.9%) completed it on the Internet. Although, the survey had a target of 300 eligible completed responders, the initial population of 1,343 possible participants was small. The response of 229 completed surveys is a participation rate of 17.1% (229/1343). Although, the target of 300 eligible completed surveys was not achieved, a sample of 229 completed surveys is adequate to draw conclusions regarding patient understanding of safe use of TIRF medicines. See Table A below. Table A: Precision of Estimated Rates with a Sample Size of 229 (2-sided 95% Confidence Interval)   Estimated Rate of Understanding 50.5% 55.0% 60.0% 65.0% 70.0% 75.0% 80.0% 85.0% 90.0% 95.0% 100.0% Estimated Confidence Interval 43.13% 47.89% 53.16% 58.06% 63.48% 68.52% 74.13% 79.39% 85.31% 91.03% 98.40% 56.44% 61.16% 66.23% 70.81% 75.74% 80.17% 84.90% 89.12% 93.53% 97.26% 100.0%              FDA_1928 Patient KAB Assessment Report Transmucosal Release Fentanyl (TIRF) TIRF REMS Industrv Group (TRIG) of Companies Page 15 of 52 Table 1. Survey Participant Administration Results Screened Patients/Caregivers N=272l All Respondents Summary Statistic Number of invitations issued to patients/caregivers 1343 Number of reminder letters issued to patients/caregivers 1986 Number of patients/caregivers screened for 1 participation 272 Number of patients/caregivers eligible for participation 229 2 84.2 Number of eligible respondents completing the survey 229 100.0 Method of Survey Completion Nrunber of sruveys completed by telephone 78 34.13 Nrunber of sruveys completed by internet 151 65,93 1 The denominator for the percentages of eligible patients/caregivers is the munber of screened patients/caregivers 2 The denominator for percentages of eligible patients/caregivers completing the survey is the rumrber of eligible patients. 3 The denominator for percentages completed by telephone or Internet is the number of eligible patients/caregivers who completed the survey Of the 272 respondents (Table 1), the screening procedru'e identi?ed 229 eligible participants (including 225 patients and 4 caregivers) all of whom completed the survey (Table 2). Due to the small nrunber of caregivers participating in the sruvey, the majority of results are reported for patients and caregivers combined. As shown in Table 2, a total of 272 patients/caregivers agreed to participate in this sruvey. Dru?ing the screening process it was determined 43 respondents were not eligible to participate in the survey because they either indicated that they had not ?lled a prescription for a TIRF medicine within the last 4 months either for themselves or as a the caregiver of a patient, that they had participated in or did not know whether they participated in a survey about TIRF medicines before, or that they or an family member had worked for a TRIG company, the FDA, or UBC . 929 Patient KAB Assessment Report Transmucosal Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 16 of 52 Thus. there were 229 eligible participants (including fom? caregivers), all of whom completed the smvey (Table 2). Table 2. Survey Participant Screening Results Eligible and Complete Screened Patients/Caregivers Respondents Question Question 1: Do you agree to participate in this survey? Yes 272 100.0 229 100.0 No1 0 0.0 generic versions of any of these brands. Question 2: Within the last 4 months, have you ?lled a prescription for yourself for a transmucosal immediate release fentanyl medicine (known as medicines?)? TIRF medicines include Abstral?, Actiq?, Fentora?, Lazanda?, 0nsolis?, Subsys?, and the Yes 262 96.3 225 98don?t know 1 0.4 0 0.0 Question not asked2 0 0.0 Question 3: Are you a caregiver for someone who has ?lled a prescription for a TIRF medicine Within the last 4 months? As a reminder, TIRF medicines include Abstral?, Actiq?, Fentora?, Lazanda?, 0nsolis?, Subsys?, and the generic versions of any of these brandsdon?t know1 1 0.4 Question not asked 2 262 96.3 Question 5: Have you ever taken part in a survey about a TIRF medicine before? Yesl 20 7.4 No 233 85.7 229 100.0 I don?t know1 13 4.8 Question not asked 2 6 2.2 930 Patient KAB Assessment Repo? Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 17 of 52 Table 2. Survey Participant Screening Results Eligible and Complete Question Pa?esggsiedgivers Question 6: Which of the following groups best describes your age? Under 181 1.7 30?39 26 9.6 26 11.4 40?49 65 23.9 65 28.4 50?59 91 33.5 88 38.4 60?69 38 14.0 38 16.6 70 or older 8 2.9 8 3.5 Prefer not to answer1 1 0.4 Question not asked 2 39 14.3 Question 7: Which of the following groups best describes the patient?s age? (Caregivers, only) Under older 0 0.0 0 0.0 Prefer not to answer 0 0.0 Question not asked2 268 98.5 931 Patient KAB Assessment Repo? Transmucosal Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 18 of 52 Table 2. Survey Participant Screening Results Eligible and Complete Screened Patients/Caregivers Respondents Question Question 8: Have you or any of your immediate family members ever worked for any of the following companies or agencies? Please select all that apply.3 Anesta LLC.1 0 0.0 Cephalon. Inc. (a wholly-owned 0 0.0 subsidiary of Teva Phaimaceutical Industries. Ltd.) 1 Depomed. Inc.1 0 0.0 Galena Biophanna1 0 0.0 Insys Therapeutics1 0 0.0 Mallinckrodt Phannaceuticalsl 1 0.4 McKesson Specialty Care Solutions1 0 0.0 Meda Phannaceuticalsl 0 0.0 Mylan. Inc.1 0 0.0 Par Pharmaceutical. Inc.1 0 0.0 RelayHealth1 0 0.0 Teva Phannaceuticals. Ltd.1 0 0.0 United BioSom?ce Cmporation1 0 0.0 FDA1 1 0.4 No4 229 84.2 229 100.0 I don?t know1 1 0.4 Ineligible to participate in the survey. 2 Question not asked due to previous question elimination. 3 More than one response can be selected. so percentages may not 5111]) to 100%. 4 Ineligible if selected in addition to another response. Of the 229 patient/caregivers, 78 completed the sm'vey by telephone, and 151 completed it 011 the Intemet (Table 3). Those taking the smvey online took an average of 13.1 minutes to complete it. while those taking it by telephone took an average of 20.8 minutes. 932 Patient KAB Assessment Report Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 19 of 52 Table 3. Time to Complete Survey for Completers (Minutes) Time to Complete Survey for Completers (Minutes) Summary Statistic Telephone Internet Total1 78 151 229 Mean (i SD) 20.8 (6.20) 13.1 (5.61) 15.7 (6.87) Minimum 13 5 5 Median 18.9 11.7 15.0 Maxinnun 50 41 50 Category 0 <5 Minutes 0 1 1 5 <10 Minutes 0 49 49 10 <15 Minutes 6 60 66 15 <20 Minutes 41 21 62 20 <25 Minutes 15 17 32 25 <30 Minutes 10 1 11 30 Minutes or More 6 2 8 Niunber of eligible respondents completing the sun'ey (Table 1). SD Standard Deviation 5.1.2 Patient/Caregiver Demographics The demographic characteristics of respondents who completed the smvey are shown in Table 4. The largest number of respondents (n=153; 66.8%) were in the 40? 59 years age group, the majority of respondents (n=136, 59.4%) were females, and 187 respondents had at least some college or an Associate?s degree or higher education. Most prescriptions ?lled in the 4 months preceding the survey included 112 for Actiq? (including generic versions), 59 for Subsys, and 55 for Fentora?. Most participants (n=83; 36.2%) were from the South, followed by the Northeast (n=55; West (n=5 1; and Midwest (n=40; 17.5%) regions of the United States (US) (Table 4). 933 Patient KAB Assessment Repo? Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page_20 of 52 Table 4. Demographic Characteristics of Eligible Patients/Caregivers Patients Caregivers Patients Caregivers Questlon N=229l Question 4: For which TIRF medicines have you ?lled a prescription in the last 4 months. Please select all that apply. 2 Abstral 6 2.7 0 0.0 6 2.6 Actiq. including generic versions 110 48-9 2 50-0 112 48-9 of Actiq Fentora 54 24.0 1 25.0 55 24.0 Onsolis 0 0.0 0 0.0 0 0.0 Subsys 57 25.3 2 50.0 59 25.8 Other 8 3.6 0 0.0 8 3.5 Question 6: Which of the following groups best describes your age1.7 30?39 26 11.6 0 0.0 26 11.4 40 ?49 61 27.1 4 100.0 65 28.4 50 59 88 39.1 0 0.0 88 38.4 60 ?69 38 16.9 0 0.0 38 16.6 70 or older 8 3.6 0 0.0 8 3.5 Question 36: What is your gender? Male 90 40.0 2 50.0 92 40.2 Female 134 59.6 2 50.0 136 59.4 Prefer not to answer 1 0.4 0 0.0 1 0.4 934 Patient KAB Assessment Repo? Transmucosal Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page_21 of 52 Table 4. Demographic Characteristics of Eligible Patients/Caregivers Patients Caregivers Patients Question (3:232:58 Question 37: What is the highest level of education you have completed? Less than high school 0 0.0 0 0.0 0 0.0 Some high school 5 2.2 0 0.0 5 2.2 High School graduate/GED 36 16.0 1 25.0 37 16.2 Some college/Associates degree 102 45.3 0 0.0 102 44.5 Bachelor?s degree 47 20.9 2 50.0 49 21.4 Master?s degree 22 9.8 0 0.0 22 9.6 Professional or Doctoral degree 13 5.8 1 25.0 14 6.1 Prefer not to answer 0 0.0 0 0.0 0 0.0 Question 38: What is the main language you speak at home? (Please select only one) English 224 99.6 4 100.0 228 99.6 French 0 0.0 0 0.0 0 0.0 Spanish 1 0.4 0 0.0 1 0.4 Portuguese 0 0.0 0 0.0 0 0.0 Italian 0 0.0 0 0.0 0 0.0 German 0 0.0 0 0.0 0 0.0 Chinese 0 0.0 0 0.0 0 0.0 Japanese 0 0.0 0 0.0 0 0.0 Korean 0 0.0 0 0.0 0 0.0 Other 0 0.0 0 0.0 0 0.0 Prefer not to answer 0 0.0 0 0.0 0 0.0 Question 39: Are you Hispanic or Latino? Yes 7 3.1 1 25.0 8 3.5 No 216 96.0 3 75.0 219 95.6 Prefer not to answer 2 0.9 0 0.0 2 0.9 935 Patient KAB Assessment Report Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 22 of 52 Table 4. Demographic Characteristics of Eligible Patients/Caregivers Patients Caregivers Question N=229l Question 40: For informational purposes only, indicate which of the following US. census categories best describes your race? American Indian or Alaska Native 3 1.3 0 0.0 3 1.3 Asian (on'gins of Far EastSoutheast Asia or the Indian subcontinent) Black or African American 9 4.0 0 0.0 9 3.9 Native Hawaiian or Other Paci?c 0 0.0 0 0.0 0 0,0 Islander White 198 88.0 3 75.0 201 87.8 Two or more races 6 2.7 0 0.0 6 2.6 Other 3 1.3 1 25.0 4 1.7 Prefer not to answer 6 2.7 0 0.0 6 2.6 Geographic Distribution (based on Question 41 State or US Territory)2 Northeast 54 24.0 1 25.0 55 24.0 Midwest 39 17.3 1 25.0 40 17.5 South 81 36.0 2 50.0 83 36.2 West 51 22.7 0 0.0 51 22.3 Other 0 0.0 0 0.0 0 0.0 Prefer not to answer Number of eligible respondents completing the survey (See Table 1). 2 More than one response can be selected. so percentages may not to 100%. 3 US. Census Bureau. last revised Friday. 27-Jul-2001 12:59:43 EDT.. Geography Division. Northeast includes CT. MA. ME. NH. NJ. NY. PA. RI. and VT. Midwest includes IA. IL. IN. KS. MI. MN. MO. ND. NE. OH. SD. and WI. South includes AL. AR. DC. DE. FL. GA. KY. LA. MD. MS. NC. OK. SC. TN. TX. VA. and WV. West includes AK. AZ. CA. 0 HI. ID. MT. NM. NV. OR. UT. WA. and WY. The following US territories are categorized as Other: Puerto Rico. Northern Mariana Islands. US Virgin Islands. American Samoa. and Guam. 5.1.3 TIRF Medicines Education Materials Respondents were asked about their awareness of educational materials for TIRF medicines, speci?cally the Medication Guide (Table 5). and the Patient-Prescriber Agreement Form 936 Patient KAB Assessment Repo? Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page_23 of 52 (Table 6). Of the 229 respondents, 217 reported they had received the Medication Guide for the TIRF medicine prescribed to them. Of these, 122 respondents reported receiving the Medication Guide from their doctor or doctor?s of?ce with 102 of the respondents receiving it at the ?rst appointment with the prescribing doctor; and 193 respondents received it from their pharmacy with 172 of the respondents stating they received the Medication Guide each time a prescription was ?lled. Most respondents who received the Medication Guide indicated they read the Medication Guide (n=209; of these, 193 respondents read all or most of it, and 184 respondents indicated lmderstanding all or most of the Medication Guide. There were 130 respondents who indicated someone offered to explain the medication guide to them; of these, 91 respondents indicated the doctor or someone in the doctor?s of?ce offered to explain the Medication Guide and 102 respondents indicated their pharmacist offered to explain the Medication Guide. Table 5. Responses to Questions About TIRF Medication Guides Patients Caregivers Patients Caregivers Question N=229l Question 18: Have you ever received a Medication Guide for the TIRF medicine that was prescribed for you? Yes 213 94.7 4 100.0 217 94don?t know 3 1.3 0 0.0 3 1.3 Question 19: Did you receive the Medication Guide from the doctor who prescribed the TIRF medicine or someone in the doctor?s of?ce?2 Yes 122 57.3 0 0.0 122 56.2 No 74 34.7 4 100.0 78 35.9 I don?t know 17 8.0 0 0.0 17 7.8 (answered No or I 12 0 12 don?t know to Question 18) Question 20: When was the Medication Guide given to you? Please select all that apply.? 3 At the ?rst appointment 102 83.6 0 0.0 102 83.6 with the doctor who prescribed the TIRF medicine At the last appointment 24 19_7 0 0.0 24 19.7 with the doctor who prescribed the TIRF medicine 937 Patient KAB Assessment Repo? Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page_24 of 52 Table 5. Responses to Questions About TIRF Medication Guides Patients Caregivers Patients Caregivers Question N=229l I don?t remember 17 13.9 0.0 17 13.9 (answered No or I 103 4 107 don?t know to Question 18 or No or I don?t know to Question 19) Question 21: Did you receive the Medication Guide for the TIRF medicine from the pharmacy?2 Yes 189 88.7 4 100.0 193 88don?t know 10 4.7 0 0.0 10 4.6 (answered No or I 12 0 12 don?t know to Question 18) Question 22: How frequently do you receive a Medication Guide for the TIRF medicine at the pharmacy? 2 Only with the ?st ?lled 7 3_7 0 0,0 7 3.6 prescription Each time a prescription is 168 88.9 4 100.0 172 89.1 ?lled Other4 don?t know 8 4.2 0 0.0 8 4.1 (answered No or I 36 0 36 don?t know to Question 18 or No or I don?t know to Question 21) Question 23: Did you read the Medication Guide? 2 Yes 207 97.2 2 50.0 209 96.3 No 5 2.3 2 50.0 7 3.2 I don?t know 1 0.5 0 0.0 1 0.5 938 Patient KAB Assessment Report Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page_25 of 52 Table 5. Responses to Questions About TIRF Medication Guides Patients Caregivers ?23321: Question N=229l (answered No or I 12 12 don?t know to Question 18) Question 24: How much did you read? 2 All of it 123 59.4 2 100.0 125 59.8 Most of it 68 32.9 0 0.0 68 32.5 Some don?t know 0 0.0 0 0.0 0 0.0 (answered No or I 18 2 20 don?t know to Question 18 or No or I don?t know to Question 23) Question 25: How much of the Medication Guide did you understand?2 All of it 102 49.3 0 0.0 102 48.8 Most of it 80 38.6 2 100.0 82 39.2 Some of it 25 12.1 0 0.0 25 12.0 None don?t know 0 0.0 0 0.0 0 0.0 (answered No or I 18 2 20 don?t know to Question 18 or No or I don?t know to Question 23) Question 26: Did someone offer to explain the Medication Guide to you?2 Yes 128 60.1 2 50.0 130 59.9 No 74 34.7 1 25.0 75 34.6 I don?t know 11 5.2 1 25.0 12 5.5 (answered No or I 12 0 12 don?t know to Question 18) 939 Patient KAB Assessment Repo? Transmucosal Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page_26 of 52 Table 5. Responses to Questions About TIRF Medication Guides Patients Caregivers Patients Caregivers Question N=229l Question 27: Who offered to explain the Medication Guide to you? Please select all that apply 2?3 The doctor or another 90 703 1 50.0 91 70.0 healthcare professional in the doctor?s of?ce The pharmacist where the 100 78.1 2 1000 102 78.5 TIRF medicine prescription was ?lled Someone else (specify the 10 7_3 0 0,0 10 7_7 type of person but not his/her name)5 (answered No or I 97 2 99 don?t know to Question 18 or No or I don?t know to Question 26) Question 28: Did you accept the offer to have the Medication Guide explained to you?2 Yes 73 57.0 1 50.0 74 56.9 No 53 41.4 1 50.0 54 41.5 I don?t know 2 1.6 0 0.0 2 1.5 (answered No or I 97 2 99 don?t know to Question 18 or No or I don?t know to Question 26) Question 29: How much of the explanation did you understand? 2 All of it 48 65.8 1 100.0 49 66.2 Most of it 23 31.5 0 0.0 23 31.1 Some 2.7 None don?t know 0 0.0 0 0.0 0 0.0 940 Patient KAB Assessment Report Transmucosal Iimnediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page_27 of 52 Table 5. Responses to Questions About TIRF Medication Guides Patients Caregivers Patients Caregivers Question N=229l (answered No 01' I 152 3 155 don?t know to Question 18 or No or I don?t know to Question 26 or No or I don?t know to Question 28) Questiop 30: Did you or do you have any questions about the information in the Medication Guide? Yes6 196 92.0 4 100.0 200 92.2 I don?t know 2 0.9 0 0.0 2 0.9 (answered No or I 12 0 12 don?t know to Question 18) 1 Number of eligible respondents completing the survey (See Table 1). 2 Percentages are calculated based on the sample presented with this question because of skip logic in the s1u'vey. 3 More than one response can be selected. so percentages may not sum to 100%. 4 Verbatim text for ?other? for 110w frequently the Medication Guide is received from the pharmacy (Question 22) are presented in Listing 1. 5 Verbatim text for other persons offering to explain the Medication Guide (Question 27) are presented in Listing 7 6 Questions about the information in the Medication Guide (Question 30) are presented in Listing 3. NA Not Applicable The responses to Questions 22, 27 and 30 are listed in Listing 1, Listing 2, and Listing 3, respectively. 5.1.4 Patient-Prescriber Agreement Form After respondents were asked the questions regarding the key risk messages, they were asked if they had received, read, and 1mderstood the PPAF. A total of 178 respondents indicated that someone at the doctor?s of?ce had explained the PPAF to them, and of these, 140 respondents understood all of it and 33 1mderstood most of it. The PPAF was signed by 179 respondents of these, 137 responders reported receiving a copy of the signed PPAF (Table 6). 941 Patient KAB Assessment Report Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page_28 of 52 Table 6. Responses to Questions About the Patient-Prescriber Agreement Form Patients Caregivers Patients Caregivers Question N=229l Question 32: Did the doctor or someone in the doctor?s of?ce explain the Patient-Prescriber Agreement Form to you? Yes 176 78.2 2 50.0 178 77.7 No 27 12.0 1 25.0 28 12.2 I don?t know 22 9.8 1 25.0 23 10.0 Question 33: How much of the explanation did you understand?2 All of it 139 79.0 1 50.0 140 78.7 Most of it 32 18.2 1 50.0 33 18.5 Some 1.7 None ofit don?t know 2 1.1 0 0.0 2 1.1 (answered know to Question 32) Question 34: Did you sign a Patient-Prescriber Agreement Form? Yes 176 78.2 3 75.0 179 78.2 No 17 7.6 1 25.0 18 7.9 I don?t know 32 14.2 0 0.0 32 14.0 Question 35: Did the doctor or someone in the doctor?s of?ce give you a copy of the signed Patient?Prescriber Agreement Form?2 Yes 134 76.1 3 100.0 137 76.5 No 22 12.5 0 0.0 22 12.3 I don?t know 20 11.4 0 0.0 20 11.2 (answered know to Question 34) 1 Number of eligible respondents completing the survey (See Table 2 Percentages are calculated based on the sample presented with this question because of skip logic in the sm'vey. NA Not Applicable 942 Patient KAB Assessment Report Transmucosal Irmnediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page_29 of 52 5.2 KAB Survey Objectives 5.2.1 Key Risk Message Results The focus of this section of the document is on the ?ndings for the total respondent population (patients plus caregivers). 5.2.1.1 Key Risk Message 1 Key Risk Message 1 refers to the patient?s/caregiver?s knowledge that TIRF medicines can cause life-threatening breathing problems that can lead to death. Analysis of responses to Question 13d for Key Risk Message 1 showed that 209 of the 229 eligible respondents were aware of the risk of life-threatening breathing problems with TIRF medicines (Table 7). Table 7. Key Risk Message 1: TIRF Medicines Can Cause Life-Threatening Breathing Problems That Can Lead to Death Patients Caregivers Patients Caregivers N=229l Question 11 (95% (95% (95% Question 13: Please answer True, False, or I don?t know for each statement about the TIRF medicine that was most recently prescribed for you the patient. 13d: TIRF medicines can cause life-threatening breathing problems that can lead to death. 100.0 91.1 91.3 True2 205 4 (39.8. 209 (86.6. 94.5) 100.0) (86.8. 94.6) False don?t know Nrunber of eligible respondents completing the survey (See Table 1). 2 Indicates the correct response(s) to each question or component within a question. 3 All con?dence intervals are exact binomial 95% con?dence intervals. 5.2.1.2 Key Risk Message 2 Key Risk Message 2 refers to the patient?s/caregiver?s knowledge that they should not take TIRF Medicines if they are not opioid tolerant. Three questions defmed this key risk message (Table 8). In response to the statement in Question 11 that TIRF medicines should only be taken by patients who are opioid tolerant, 195 respondents gave the correct (True) response. 943 Patient KAB Assessment Report Transmucosal Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 30 of 52 The majority of respondents (n=187; 81.7%) also understood that opioid tolerant means that a patient is already taking other opioid pain medicines ar01md-the-clock and their body is used to these medicines (Question 12a). In response to Component 13b, 159 knew that it is not okay for patients to-take TIRF medicines for headache pain, while 54 respondents selected the don?t know? option. Of the 159 respondents who correctly answered Component 13b (?It is OK for patients to take IRF medicines for headache pain), 141 respondents had read most of the Medication Guide and 18 respondents had read some or none of it (see Table 14). Overall, evidence of understanding of the comprehensive key risk message is fluther supported by the average number of correct responses identi?ed as 2.4 (one-sided 95% con?dence interval 2.2, 3.0) out of a possible 3 (Table 8). Table 8. Key Risk Message 2: Patients Should Not Take TIRF Medicines If They Are Not Opioid Tolerant Patients Caregivers Patients Caregivers N=229l Question (95% CD3 (95% c1)" (95% CD3 Question 11: Please answer True, False, or I don?t know for the following statement: TIRF medicines should only be taken by patients who are opioid tolerant. 100.0 84.9 85.2 Tme2 191 4 (39.100.0) (799 89 False don?t know 28 12.4 0 0.0 28 12.2 Question 12: Please answer True, False, or I don?t know for the following statements: 12a: Opioid tolerant means that a patient is already taking other opioid pain medicines around the clock and their body is used to these medicines. 100.0 81.3 81.7 Tme2 183 4 (39.8. 187 (75.6. 86.2) 100.0) (76.0. 86.5) False don?t know 23 10.2 0 0.0 23 10.0 944 Patient KAB Assessment Report Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 31 of 52 Table 8. Key Risk Message 2: Patients Should Not Take TIRF Medicines If They Are Not Opioid Tolerant Patients Caregivers Patients Caregivers N=229l Question (95% (95% CD3 (95% Question 13: Please answer True, False, or I don?t know for each statement about the TIRF medicine that was most recently prescribed for you. 13b: It is OK for patients to take TIRF medicines for headache pain. True 16 7.1 0 0.0 16 7.0 False: 157 (63235.7) 2 (6.8.0922) 159 (63:72.3) I don?t know 52 23.1 2 50.0 54 23.6 Secondary Analyses: Demonstrated Understanding 0 correct responses correct response correct responses 72 32.0 2 50.0 74 32.3 3 c01rect responses 122 54.2 2 50.0 124 54.1 Average number of 2.4 2.5 2.4 correct responses (2.2. 3.0)4 (1.2. 3.0)4 (2.2. 3.0) 4 1 Number of eligible respondents completing the survey (See Table 1). 2 Indicates the correct response(s) to each question or component within a question. 3 All con?dence intervals are exact binomial 95% con?dence intervals. 4 One-sided 95 con?dence interval using the normal approximation to the Poisson distribution. 5.2.1.3 Key Risk Message 3 Key Risk Message 3 refers to the patient?s/caregiver?s knowledge that TIRF medicines should be taken exactly as prescribed by the healthcare provider. Three questions defme this key risk message (Table 9). In response to Question 12b, 84 respondents rmderstood that if a patient stops taking arormd-the-clock opioid pain medicine, they must also stop taking the TIRF medicine while 58 answered incorrectly and 87 selected the don?t know? option. Of the 84 respondents who gave the correct response, 79 read most of the Medication Guide while 5 read some or none of the Medication Guide. Of the 58 respondents who answered this question incorrectly, 46 had read most of the Medication Guide and of the 87 respondents who selected the don?t know? response, 68 had read most of the Medication Guide (see Table 14). 945 Patient KAB Assessment Repo? Transmucosal Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 32 of 52 Responding to Component 13c, 227 respondents understood that TIRF medicines should be taken exactly as prescribed by the doctor, and 190 knew that is not all right to take TIRF medicines for short-tenn pain that will go away in a few days (Component 17b). Overall, evidence of luiderstanding of the comprehensive key risk message is further supported by the average number of correct responses identi?ed as 2.2 (one-sided 95% CI 2.0, 3.0) out of a possible 3 (Table 9). Table 9. Key Risk Message 3: TIRF Medicines Should Be Taken Exactly As Prescribed By The Healthcare Provider Patients Caregivers Patients Caregivers N=229l Question 11 (95% (95% (95% Question 12: Please answer True, False, or I don?t know for each of the following statements. 12b: If a patient stops taking around?the?clock opioid pain medicine, they must also stop taking the TIRF medicine. 36.7 True2 83 (3036633 6) 1 (0 35;; 6) 84 (30.43-3) False 57 25.3 1 25.0 58 25.3 I don?t know 85 37.8 2 50.0 87 38.0 Question 13: Please answer True, False, or I don?t know for each statement about the TIRF medicine that was most recently prescribed for you. 13c: TIRF medicines should be taken exactly as prescribed by the doctor. 99 1 100.0 99.1 rme? 223 4 (39.8. 227 (96.9. (96?8? 999) 100.0) 99.9) False don?t know 0 0.0 0 0.0 0 0.0 Question 17: Please answer True, False, or I don?t know for each statement about the TIRF medicine that was most recently prescribed for you the patient. 17b: It is OK to take TIRF medicines for short-term pain that will go away in a few days. True 100.0 83.0 False2 186 (771 '87 4) 4 (39.8. 190 (77.5. 100.0) 87.6) 946 Patient KAB Assessment Report Transmucosal Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 33 of 52 Table 9. Key Risk Message 3: TIRF Medicines Should Be Taken Exactly As Prescribed By The Healthcare Provider Patients Caregivers Patients Caregivers N=229l Question 11 (95% (95% (95% CD3 I don?t know 27 12.0 0 0.0 27 11.8 Secondary Analysis: Demonstrated Understanding 0 correct responses 0 0.0 0 0.0 0.0 1 correct response 30 13.3 0 0.0 30 13.1 2 correct responses 123 54.7 3 75.0 126 55.0 3 correct responses 72 32.0 1 25.0 73 31.9 Average munber of 2.2 2.3 2.2 correct responses (2.0. 3.0)4 (1.0. 3.0)4 (2.0. 3.0)4 1 Nrunber of eligible respondents completing the survey (See Table 1Indicates the correct response(s) to each question or component Within a question. 3 All con?dence intervals are exact binomial 95% con?dence intervals. 4 One-sided 95 con?dence interval using the normal approximation to the Poisson distribution. 5.2.1.4 Key Risk Message 4 Key Risk Message 4 refers to the patient?s/caregiver?s knowledge that they must not switch from a TIRF medicine to another medicine that contains fentanyl without talking to a healthcare provider (Table 10). Of the 229 respondents, 222 rmderstood that it is not safe to switch to another medicine that contains fentanyl without talking to a healthcare provider fn?st. 947 Patient KAB Assessment Report Transmucosal Iimnediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 34 of 52 Table 10. Risk Message 4: Patients Should Not Switch From a TIRF Medicine to Another Medicine That Contains Fentanyl Without Talking to a Healthcare Provider Patients Caregivers Patients Caregivers N=229l Question (95% (95% (95% Question 12: Please answer True, False, or I don?t know for each of the following statements. 12c: It is safe to switch to another medicine that contains fentanyl without talking to a healthcare provider first True 2 0.9 0 0.0 2 0.9 100.0 96.9 96.9 False2 218 4 (39.8. 222 (93.7. 98.7) 100.0) (93.8. 98.8) I don?t know Nlunber of eligible respondents completing the survey (See Table 7 . . . . . Indicates the correct response(s) to each question or component a question. 3 . . . . All con?dence mtervals are exact bmormal 95% con?dence mtervals. 5.2.1.5 Key Risk Message 5 Key Risk Message 5 refers to patient?s/caregiver?s knowledge that TIRF medicines should not be given to anyone else even if they have the same (Table 11). For Component 12d, 227 respondents understood that a patient may not give TIRF medicines to another person if they have the same as the patient, and 227 respondents lmderstood that selling or giving away TIRF medicines is against the law (Component 17a). Overall, evidence of Imderstanding of the comprehensive key risk message is ?uther supported by the average number of correct responses identi?ed as 2.0 (one-sided 95% CI 1.8. 2.0) out of a possible 2 (Table 11). 948 Patient KAB Assessment Report Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 35 of 52 Table 11. Key Risk Message 5: Patients Should Not Give TIRF Medicines to Anyone Else Even if They Have the Same Patients Caregivers 25mm.? aregivers . 1 Question (95% (95% (95% CD3 Question 12: Please answer True, False, or I don?t know for each of the following statements. 12d: A patient may give TIRF medicines to another person if they have the same as the patient. True 1 0.4 0 0.0 1 0.4 99.1 100.0 99.1 1 2 a 56 223 (96.8. 99.9) 4 (39.8. 100.0) 227 (96.9. 99.9) I don?t know 1 0.4 0 0.0 1 0.4 Question 17: Please answer True, False, or I don?t know for each statement about the TIRF medicine that was most recently prescribed for you. 17a: Selling or giving away TIRF medicines is against the law. Tmez 223 (96.939199) 4 (39.22800) 227 (96.939199) False don?t know 1 0.4 0 0.0 1 0.4 Secondary Analysis: Demonstrated Understanding 0 correct responses correct response correct responses 221 98.2 4 100.0 225 98.3 Average number of 2.0 (1.8. 2.0 (0.8. 2.0 (1.8. correct responses 2.0) 4 2.0) 4 2.0) 4 1 Nrunber of eligible respondents completing the survey (See Table 1Indicates the correct response(s) to each question or component Within a question. 3 . . . . All con?dence mten'als are exact binomial 95% con?dence intervals. One-Sided 95 con?dence interval the nomral approxrrnation to the Porsson distribution. 5.2.1.6 Key Risk Message 6 Key Risk Message 6 refers to the patient?s/caregiver?s knowledge that TIRF medicines should be stored in a safe place away from children and properly disposed (Table 12). 949 Patient KAB Assessment Repo? Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 36 of 52 Component 13a elicited the correct (True) response from 227 respondents who were knowledgeable that TIRF medicines should be stored in a safe place out of the reach of children. In addition, 215 respondents imderstood that TIRF medicines must be disposed of as described in the speci?c product?s Medication Guide (Component 17c). Also, most respondents (n=207; 90.4%) 1mderstood that a TIRF medicine can cause an overdose and death in any child who takes it (Component 17e); and that they should get emergency help right way (n=202; 88.2%) if an adult who has not been prescribed a TIRF medicine takes a TIRF medicine (Question 14) Overall, evidence of understanding of the comprehensive key risk message is fluther supported by the average number of correct responses identi?ed as 3.7 (one-sided 95% I 3.5, 4.0) out of a possible 4 (Table 12). Table 12. Key Risk Message 6: TIRF Medicines Should be Stored in a Safe Place Away From Children and Properly Disposed Patients Caregivers Patients Caregivers N=229l Question 11 (95% (95% (95% Question 13: Please answer True, False, or I don?t know for each statement about the TIRF medicine that was most recently prescribed for you. 13a: TIRF medicines should be stored in a safe place out of the reach of children. Truez 223 99.1 4 100.0 227 99.1 (96.8. 99.9) (39.8. 100.0) (96.9. 99.9) False don?t know 1 0.4 0 0.0 0.4 Question 17: Please answer True, False, or I don?t know for each statement about the TIRF medicine that was most recently prescribed for you. 17c: TIRF medicines must be disposed of as described in the speci?c product?s Medication Guide. ??62 21 1 (89.98? 986.6) 4 215 (902)? 996.6) False don?t know 14 6.2 0.0 14 6.1 17e: A TIRF medicine can cause an overdose and death in any child who takes it. ??62 203 (85.299238) 4 207 (85.989339) False don?t know 20 8.9 0 0.0 20 8.7 950 Patient KAB Assessment Repo? Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 37 of 52 Table 12. Key Risk Message 6: TIRF Medicines Should be Stored in a Safe Place Away From Children and Properly Disposed Patients Caregivers Patients Caregivers N=229l Question 11 (95% (95% (95% Question 14: What should you do if an adult who has not been prescribed a TIRF medicine takes a TIRF medicine? (Please select one.) Get emergency help 1 9 8 88.0 4 100.0 202 88.2 right away2 (83.0. 91.9) (39.8. 100.0) (83.3. 92.1) Do nothing hom?and see the person 15 OK I don't know 20 8.9 0 0.0 20 8.7 Secondary Analyses: Demonstrated Understandin 0 c01rect responses conect response correct responses correct responses 41 18.2 0 0.0 41 17.9 4 correct responses 173 76.9 4 100.0 177 77.3 . 3.7 (3.5. 4.0(2.4. 3.7 Average ntunber of 4.0)4 4.0) 4 (35? correct responses 4 1 of eligible respondents completing the survey (See Table 1). 2 Indicates the correct response(s) to each question or component within a question. 3 All con?dence intervals are exact binomial 95% con?dence intervals. 4 One-sided 95 con?dence interval using the normal approximation to the Poisson distribution. 951 Patient KAB Assessment Report Transmucosal Iimnediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 38 of 52 5.2.2 Other Survey Questions 5.2.2.1 Additional Questions about TIRF Medicines Safety Table 13 summarizes the patient/caregiver responses to additional questions about the safe use of TIRF medicines beyond those associated with the key risk messages. The results generally indicate that respondents were aware of most of the precautions needed to ensm?e safe use of TIRF medicines. See Section 5.2.1 for all key risk message question results. The majority of respondents (200; 87.3%) indicated a Health Care Professional (HC P) from the doctor?s of?ce discussed the risks and possible side effects of the prescribed TIRF medicine while 23 respondents indicated these were not discussed and 6 respondents did not recall having this conversation. Most respondents imderstood that TIRF medicines should not be used for headache or migraine pain (179; dental pain (200; and pain after surgery (161; Only 58 respondents indicated they were aware that TIRF medicines are not indicated for long-lasting painful conditions not caused by cancer, however, 151 of the 229 respondents knew that TIRF medicines should be used for breakthrough pain from cancer. Most respondents (214; 93.4%) indicated that someone in the doctor?s office explained how to use the prescribed TIRF medicines and 185 respondents indicated someone in the doctor?s of?ce advised them on the proper storage of the prescribed TIRF medicines. The majority (162; 70.7%) were also aware that TIRF medicines are only available through the TIRF REMS Access Program. Table 13. Responses to Additional Questions about the Safe Use of TIRF Medicines Patients Caregivers Patients &1 Caregivers Question N4 Question 9: Did the doctor, nurse, or other healthcare professional in the doctor?s of?ce ever talk to you about the risks and possible side effects of the TIRF medicine that was most recently prescribed for you? medicines include Abstral?, Actiq?, Fentora?, Lazanda?, Onsolis?, Subsys?, and the generic versions of these brands. Yes 197 87.6 3 75.0 200 87.3 No 22 9.8 1 25.0 23 10.0 I don't know 6 2.7 0 0.0 6 2.6 952 Patient KAB Assessment Repo? Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 39 of 52 Table 13. Responses to Additional Questions about the Safe Use of TIRF Medicines Patients Caregivers Patients &1 Caregivers Question 10: For which of the following conditions should you use a TIRF medicine? 10a: Headache or migraine pain Yes 25 11.1 0 0.0 25 10.9 No2 175 77.8 4 100.0 179 78.2 I don't know 25 11.1 0 0.0 25 10.9 10b: Breakthrough pain from cancer Yes2 148 65.8 3 75.0 151 65.9 No 70 31.1 1 25.0 71 31.0 I don?t know 7 3.1 0 0.0 7 3.1 10c: Dental pain Yes 3 1.3 0 0.0 3 1.3 No2 197 87.6 3 75.0 200 87.3 I don't know 25 11.1 1 25.0 26 11.4 10d: Pain after surgery Yes 43 19.1 1 25.0 44 19.2 No2 159 70.7 2 50.0 161 70.3 I don't know 23 10.2 1 25.0 24 10.5 10e: Long?lasting painful conditions not caused by cancer Yes 147 65.3 3 75.0 150 65.5 No 2 58 25.8 0 0.0 58 25.3 I don't know 20 8.9 1 25.0 21 9.2 Question 15: Did the doctor, nurse, or other healthcare professional in the doctor?s of?ce ever tell you how to use the TIRF medicine that was most recently prescribed for? Yes 210 93.3 4 100.0 214 93don?t know 2 0.9 0 0.0 2 0.9 953 Patient KAB Assessment Report Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 40 of 52 Table 13. Responses to Additional Questions about the Safe Use of TIRF Medicines Patients Caregivers Patients &1 Caregivers Question 16: Did the doctor, nurse, or other healthcare professional in the doctor?s of?ce ever tell you how to store or keep the TIRF medicine that was most recently prescribed for you? Yes 183 81.3 2 50.0 185 80.8 No 36 16.0 2 50.0 38 16.6 I don't know 6 2.7 0 0.0 6 2.6 Question 17: Please answer True, False, or I don?t know for each statement about the TIRF medicine that was most recently prescribed for you. 17d: TIRF medicines are only available to patients through a special program (called the TIRF REMS Access program). True2 159 70.7 3 75.0 162 70.7 False don't know 57 25.3 1 25.0 58 25.3 1 N1unber of eligible respondents completing the survey (See Table 1Indicates the correct response(s) to each question or component Within a question. 5.2.3 Sub-group Analysis of Responses to Key Risk Messages To ?uther assess patient/caregiver understanding of key risk messages, sub-group analyses as described in Section 4.1.2 were conducted. 5.2.3.1 Reading the Medication Guide (Sub-group S-l) Table 14 correct response rates for the 6 key risk messages by respondents who got the Medication Guide and read at least most of it (sub-group S-la) and by respondents who did not get a Medication Guide or answered don?t know,? or who got a Medication Guide and read only some of it or answered don?t know? (sub-group S- 1b). Respondents who read all or most of the Medication Guide had a higher correct response rate than those who read some or none of the Medication Guide, or did not know, with the exception of two questions where correct response rate was 99% and 100% for sub-group S-la and sub-group Sl-b, respectively. The largest difference in correct reponse rate between the sub-groups was seen in Key Risk Message 2 (Patients Should Not Take TIRF Medicines If They Are Not Opioid Tolerant) and Key Risk Message 3 (TIRF Medicines Should Be Taken Exactly As Prescribed By The Healthcare Provider). 954 Patient KAB Assessment Report Transmucosal Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 41 of 52 Overall, the results indicate that respondents who read all or most of the Medication Guide were better informed regarding the safe use of TIRF medicines. Therefore, the Medication Guide is an effective tool to help patients lmderstand the key risk messages based on the goals of the TIRF REMS. Table 14. Correct Responses and Response Rates to Key Risk Message Questions Based on Extent of Reading of Medication Guide Correct Response Rates Read Most of the $123232? Message Question Medication Guide Medication Guide N?l93 6 13d: TIRF medicines can cause life- 1 threatenin breathin roblems that can lead 180 93'3 29 80'6 (88.8. 96.4) (64.0. 91.8) to death 11: TIRF medicines should only be taken by 170 88.1 2 69.4 patients who are opioid tolerant (82.7. 92.3) (51.9. 83.7) 12a: Opioid tolerant means that a patient is 2 ah?eady taking other opioid pain medicines 163 84.5 24 66.7 aromid-the-clock and their body is used to (78.6. 89.3) (49.0. 81.4) these medicines 13b: It is OK for patients to take TIRF 141 73.1 18 50.0 medicines for headache pain (66.2. 79.2) (32.9. 67.1) 12b: If a patient stops taking aromid-the- . . . . . 40.9 13.9 clock op101d pam medlcme. they must also stop taking the TIRF medicine 3 13c: TIRF medicines should be taken exactly 193 100.0 34 94.4 as prescribed by the doctor (98.1. 100.0) (81.3. 99.3) 17b: It is OK to take TIRF medicines for short-term ain that will 0 awa in a few 168 87'0 22 61'] (81.5. 91.4) (43.5. 76.9) days 12c: It is safe to switch to another medicine 97 4 94 4 4 that contains fentanyl without talking to a 188 34 . . (94.1. 99.2) (81.3. 99.3) healthcare p10v1der ?rst 955 Patient KAB Assessment Report Transmucosal Iimnediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 42 of 52 Table 14. Correct Responses and Response Rates to Key Risk Message Questions Based on Extent of Reading of Medication Guide Correct Response Rates 1135:; Read Most of the lezzifzgif Message Question Medication Guide Medication Guide 6 12d: A patient may give TIRF medicines to another erson if the have the same 191 99'0 36 1000 .y (96.3. 99.9) (90.3. 100.0) 5 as the patient 17a: Selling or giving away TIRF medicines 192 99.5 3 5 97.2 is against the law (97.1. 100.0) (85.5. 99.9) 13a: TIRF medicines should be stored in a 191 99.0 36 100.0 safe place out of the reach of children (96.3. 99.9) (90.3. 100.0) 17c: TIRF medicines must be disposed of as described in the speci?c product?s 185 95'9 30 83'3 Medication Guide (92.0. 98.2) (67.2. 93.6) 6 l7e: A TIRF medicine can cause an overdose 17 6 91.2 31 86.1 and death in any child who takes it (86.3. 94.8) (70.5. 95.3) 14: What should you do if an adult who has not been prescribed a TIRF medicine takes a 173 89.6 29 80.6 TIRF medicine? (84.4. 93.6) (64.0. 91.8) Get emergency help right away 5.2.3.2 All other Sub-group Analyses For sub-group analysis 2 (Understanding the Medication Guide) respondents who indicated they lmderstood all or most of the Medication Guide had a higher correct response rate for Key Risk Message 2 (Patients Should Not Take TIRF Medicines If They Are Not Opioid Tolerant) and Key Risk Message 3 (TIRF Medicines Should Be Taken Exactly As Prescribed By The Healthcare Provider) compared with those who indicated they understood some of the Medication Guide, indicated ?none?/?I don?t know? or did not get or read the Medication Guide. 956 Patient KAB Assessment Report Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 43 of 52 For sub-group analysis 5 (Modality to Complete the Survey), respondents who took the survey via Internet had a higher correct response rate for Key Risk Message 2 and components of Key Risk Message 3. For sub-group analysis 6 (Highest Level of Education) respondents who had a high school degree or less tended to have a lower correct response rate for Key Risk Message Question 2, and a component of Key Risk Message 3. For all other sub-group analyses no sub-group-related trends were evident. The full set of sub-group analysis tables is provided in Appendix B. 5.3 Spontaneous Reporting of Adverse Events, Product Complaints, or Medical Information Requests Among all survey respondents (N=229; Table 1), there were 38 reports of a potential adverse event, product complaint, and/or medical information request associated with the use of TIRF medicines made during a telephone interview or while activating a gift card. (Appendix B, Listing 4). Respondents who completed the survey online had the option to write in any questions they had in the free-text field. Of the 15 reports made in the free text field of the online survey, 11 were requests for medical information related to adverse events, withdrawal, drug administration, and dosage. The remaining 4 responses were comments that their questions had been answered by the HCP or they had no questions (Appendix B, Listing 3). 5.4 Summary of Correct Responses for Key Risk Messages The six key risk messages included in the survey included 14 components detailing these key risk messages. A tabulated summary of correct responses for each component is presented in Table 15. Of the 14 components,12 components had a response rate > 80%. The correct response rate for Component 13b (It is OK for patients to take TIRF medicines for headache pain) was 69.4% and for Component 12b (If a patient stops taking around-the-clock opioid pain medicine, they must also stop taking the TIRF medicine) was 36.7% which fell below the desired level of understanding of 65% (Table 15). FDA_1957 Patient KAB Assessment Report Transmucosal Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 44 of 52 Table 15. Summary of Correct Responses for Key Risk Messages Key Risk Message Question Question Correct Responses (95% CI) Key Risk Message 1: TIRF medicines can cause life-threatening breathing problems 13. Please answer True. False. or I don?t know for each statement about the TIRF medicine that was most recently prescribed for you. that can lead to death. 13d TIRF medicines can cause life-threatening breathing 209 91.3 problems that can lead to death. (Correct Response (86.8. 94.6) ?True Key Risk Message 2: Patients should not Please answer True. False. or I don?t know for the following statement: :akeTItRF medicines If they are Mt op101d 11 TIRF medicines should only be taken by patients 195 85.2 0 eian who are opioid tolerant. (Correct Response ?True?) (79.9. 89.5) 12a Opioid tolerant means that a patient is already taking other opioid pain medicines around the clock and 187 81.7 their body is used to these medicines. (Correct (76.0. 86.5) Response rue 13. Please answer True. False. or I don?t know for each statement about the TIRF medicine that was most recently prescribed for you. 13b It is OK for patients to take TIRF medicines for 159 69.4 headache pain. (Correct Response ?False?) (63.0. 75.3) Key Risk Message 3: TIRF medicines 12. Please answer Tiue. False. or I don?t know for each of the following statements. 3:01? ll :1 taken exachv as prescribed by 12b If a patient stops taking aromid-the-clock opioid pain ea cal p1 ov1 e1 medicine. they must also stop taking the TIRF medicine. (Correct Response rue 84 36'7 (30.4. 43.3) 958 Patient KAB Assessment Report Transmucosal Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Table 15. Summary of Correct Responses for Key Risk Messages Page 45 of 52 Key Risk Message Question Question Correct Responses (95% CI) 13/17 Please answer True. False. or I don?t know for each statement about the TIRF medicine that was most recently prescribed for you. 13c TIRF medicines should be taken exactly as 227 99.1 prescribed by the doctor. (Correct Response rue (96.9. 99.9) 17b It is OK to take TIRF medicines for short-teim pain . . 83.0 that Will go away in a few days. (Correct Response 190 (77.5. 87.6) False Key Risk Message 4: Patients should not 12 Please answer True. False. or I don?t know for each switch from a TIRF medicine to another of the following statements. medicine that contains fentanyl Without 12c It is safe to switch to another medicine that contains talking to a healthcare prov1der. . . . 96.9 fentanyl Without talkmg to a healthcare prov1der ?rst. 222 a (93.8. 98.8) (Correct Response False Key Risk Message 5: Patients should not 12 Please answer True. False. or I don?t know for each give TIRF medicines to anyone else even if of the following statements. they have the same 12d A patient may give TIRF medicines to another person 99 1 if they have the same as the patient. 227 (96.9. 99.9) (Correct Ressponse False 17. Please answer True. False. or I don?t know for each statement about the TIRF medicine that was most recently prescribed for you. 17a Selling or giving away TIRF medicines is against the 227 99.1 law. (Correct Response ?True (96.9. 99.9) 959 Patient KAB Assessment Report Transmucosal Iimnediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 46 of 52 Table 15. Summary of Correct Responses for Key Risk Messages Key Risk Message Question Question Correct Responses (95% CI) Key Risk Message 6: TIRF medicines should be stored in a safe place away from children and properly disposed. 13/17. Please answer True. False. or I don?t know for each statement about the TIRF medicine that was most recently prescribed for you. 13a TIRF medicines should be stored in a safe place out 227 99.1 of the reach of Children. (Correct Response ?True (96.9. 99.9) 17c TIRF medicines must be disposed of as described in 93 9 the speci?c product?s Medication Guide. (Correct 215 .. (90.0. 96.6) Response True l7e A TIRF medicine can cause an overdose and death in 207 90.4 any child who takes it. (Correct Response rue (85.8. 93.9) 14 What should you do if an adult who has not been prescribed a TIRF medicine takes a TIRF medicine? 202 88.2 (Please select one.) (Correct Response: Get (83.3. 92.1) emergencv help right away.) 960 Patient KAB Assessment Report Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies 6. Page 47 of 52 FDA FEEDBACK There was no FDA feedback provided on the 24-month assessment of the TIRF REMS. 7. DISCUSSION, AND CONCLUSIONS Discussion For the patient KAB survey, invitations (and reminders) were sent to all known patients/caregivers who had filled a prescription within the 4 months prior to survey launch. From among those who responded to the invitation, 229 patients/caregivers completed the survey (there were only 4 caregivers who participated in the survey). Although, the survey had a target of 300 completed responders, the pool of 1343 patients/caregivers, who were mailed the invitation, was small. The response of 229 completed surveys from this limited pool is within the expected response rate to mailed invitations (17.1%; 229/1343). The specific goals of the TIRF medicines patient/caregiver KAB survey were to evaluate the level of knowledge and assess the attitudes and behavior of patients/caregivers regarding TIRF medicines. The focus of the survey included the potential for life-threatening breathing problems that can lead to death, the need for patients to take TIRF medicines if they are opioid-tolerant and strictly follow the directions of the HCP, the caution that patients should not switch from a TIRF medicine to another medicine that contains fentanyl without talking to an HCP, the requirements that patients should not give TIRF medicines to anyone else even if they have the same symptoms, and that TIRF medicines should be stored in a safe place away from children and properly disposed of. The survey also included questions about whether patients received, read, and understood the product-specific Medication Guide and the PPAF. In this 36-month survey, all but one of the questions included as part of the key risk messages had a correct response rate of >69%. There was only one question within a key risk message (Question 12 in Key Risk Message 3) that had a component with an understanding rate below the desired threshold of 65% (Component 12b: If a patient stops taking around-the-clock opioid pain medicine, they must also stop taking the TIRF medicine; correct response ‘True’; correct response rate 36.7%). This concept also scored low in the prescriber KAB survey for this reporting period. In addition, there was one question included as part of the additional questions about the safe use of TIRF medicines and not included as a key risk message (Question 10; For which of the following conditions should you use a TIRF medicine?) that had a component with an understanding rate below the desired threshold of 65% (Component 10e; Long-lasting painful conditions not caused by cancer; desired response ‘No’, response rate 25.3%). For the other 4 components of Question 10, the desired responses were greater than 65% in the 36-month survey. Although the questions are worded differently for the 36-month survey period, this concept also scored low for pharmacists (43.7%). These components were the only low scoring components in all three waves of the patient/caregiver KAB survey. FDA_1961 Patient KAB Assessment Report Tr?ansmucosal Immediate Release Fentanyl (TIRF) TIRF REMS hrdustry Group (TRIG) of Companies Page 48 of 52 Question 32 (Did the doctor or someone in the doctor?s office explain the Patient-Prescriber Agreement Form to you?) (Table 6) shows an increased response compared to the previous two waves which supports that the healthcare professionals are discussing with their patients the safe use and risks of TIRF medicines. A comparison of the three waves is shown in Table 16. Table 16. Correct/Desired Response Rate of Low Scoring Questions across the Three Patient/Caregiver KAB Survey Waves. 36-Month Survey Correct/Desired Response Rate 36- 12-Month 24-Month Month Questions as Survey Survey Survey Presented in the 36- Correct/Desired Correct/Desired Question Month Survey Response Rate Response Rate Number Please answer ?True,? ?False,? or don?t know? for each of the following statements. 12 If a patient stops taking around-the-clock opioid pain medicine, they 12b must also stop taking 42.7 34.1 36.7 the TIRF medicine. (Correct Response True) For which of the following conditions should you use a TIRF medicine? 101 Long-lasting painful 1 conditions not caused lOe by cancer 24.5 21.9 25.3 (Desired Response No) I This was part of Question 9 (9e) in 12-month Patient/ aregiver KAB survey. Question 9 was worded as follows for the 12-morrth KAB survey: For which of the following conditions should I use a TIRF medicine? Response option for 9e whas ?chronic non-cancer pain". 962 Patient KAB Assessment Report Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 49 of 52 Conclusions The consistently high level of patient understanding of key risk messages in the 24-month and 36-month surveys indicates that the REMS goals are being met with the tools currently in place. The higher level of understanding in patients who read most or all of the medication guide demonstrates effective communication of the key risk messages, which may also be reinforced by prescribers and pharmacists. The TRIG will evaluate the concepts that have scored low among stakeholders to determine if any action is warranted. The TRIG will continue to work with the FDA to refine, on a continual basis, the steps to mitigate risks associated with TIRF medicines. FDA_1963 Patient KAB Assessment Report Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Appendix A Page 50 of 52 Patient Survey Protocol FDA_1964 PROTOCOL TITLE: Quantitative Testing of Patient/Caregiver Knowledge, Attitudes, and Behavior about Transmucosal Immediate Release Fentanyl (TIRF) Products Safety and Use Information SPONSOR: TIRF REMS Industry Group (TRIG) Cephalon, Inc. (a wholly-owned subsidiary of Teva Pharmaceutical Industries, Ltd.) Depomed, Inc. Galena Biopharma, Inc. Insys Therapeutics Mallinckrodt Pharmaceuticals Meda Pharmaceuticals Mylan, Inc. Par Pharmaceutical, Inc. VERSION: 7.0 DATE: 18MAY2014 APPROVED: Final FDA_1965 TABLE OF CONTENTS PAGE TABLE OF CONTENTS ......................................................................................... 2 1. LIST OF ABBREVIATIONS .................................................................................. 3 2. BACKGROUND ..................................................................................................... 4 3. OBJECTIVES OF THE EVALUATION SURVEY ............................................... 5 4. METHODS .............................................................................................................. 5 4.1 Qualitative Research on the Survey ......................................................................... 5 4.2 4.2.1 4.2.2 Survey Design .......................................................................................................... 5 Questions and Statements on REMS Goals ............................................................. 6 Additional Questions................................................................................................ 9 4.3 4.3.1 Subject Recruitment ................................................................................................. 9 Measures to Minimize Bias in the Sample............................................................. 10 5. 5.1.1 5.1.2 5.1.3 STUDY POPULATION ........................................................................................ 11 Sample Size ............................................................................................................ 11 Inclusion Criteria.................................................................................................... 11 Exclusion Criteria .................................................................................................. 12 6. SURVEY PROCESS ............................................................................................. 12 6.1 6.1.1 6.1.2 Screening and Survey Administration ................................................................... 12 Telephone ............................................................................................................... 12 Internet ................................................................................................................... 12 6.2 Measures to Minimize Bias in the Survey Process ................................................ 13 7. ANALYSIS ............................................................................................................ 13 8. SAFETY EVENT REPORTING ........................................................................... 14 9. PRIVACY PROTECTION AND CONFIDENTIALITY...................................... 14 LIST OF APPENDICES APPENDIX A Screening and Main Questionnaire........................................................... 16 APPENDIX B SAMPLE Patient Letter of Invitation ....................................................... 41 FDA_1966 1. LIST OF ABBREVIATIONS CATI CI EDC ETASU FDA HIPAA IRB KAB PBM PPAF REMS SE PSP TIRF TIRF REMS TRIG UBC US Computer-Assisted Telephone Interviewing Confidence Interval Electronic Data Capture Elements to Assure Safe Use Food and Drug Administration Health Insurance Portability and Accountability Act Institutional Review Board Knowledge, Attitudes and Behavior Pharmacy Benefits Management Patient-Prescriber Agreement Form Risk Evaluation and Mitigation Strategy Safety Event Project Specific Procedure Transmucosal Immediate Release Fentanyl TIRF REMS Access Program TIRF REMS Industry Group United BioSource Corporation United States FDA_1967 2. BACKGROUND Transmucosal Immediate Release Fentanyl (TIRF) medicines include the class of immediaterelease opioid analgesics, which are indicated only for the management of breakthrough pain in cancer patients 18 years of age or older (16 or older for Actiq® and equivalent generics) who are already receiving and tolerant to opioid therapy for their underlying persistent cancer pain. The TIRF medicines include Abstral®, Actiq®, Fentora®, Lazanda®, Onsolis®, Subsys®, and generic versions of any of these brands. The TIRF REMS Industry Group (TRIG) includes Cephalon, Inc. (a wholly-owned subsidiary of Teva Pharmaceutical Industries, Ltd.); Depomed, Inc.; Galena Biopharma, Inc.; Insys Therapeutics; Mallinckrodt Pharmaceuticals; Meda Pharmaceuticals; Mylan, Inc.; and Par Pharmaceutical, Inc. The Food and Drug Administration (FDA) has determined that a class-wide Risk Evaluation and Mitigation Strategy (REMS) is required to mitigate the risks of misuse, abuse, addiction, overdose and serious complications due to medication errors with the use of TIRF medicines. The TIRF REMS Access Program (hereafter referred to as TIRF REMS) was approved by the FDA on December 28, 2011. The TIRF REMS consists of a Medication Guide, Elements to Assure Safe Use (ETASU), an Implementation System, and a Timetable for Submission of Assessments of the REMS. The goals of the TIRF REMS are to mitigate the risk of misuse, abuse, addiction, overdose, and serious complications due to medication errors by: 1. Prescribing and dispensing TIRF medicines only to appropriate patients, which includes use only in opioid-tolerant patients 2. Preventing inappropriate conversion between TIRF medicines 3. Preventing accidental exposure to children and others for whom it was not prescribed 4. Educating prescribers, pharmacists, and patients on the potential for misuse, abuse, addiction, and overdose of TIRF medicines An important component of the TIRF REMS assessment is the conduct of quantitative evaluation surveys to assess patients’ and caregivers’ knowledge, attitudes, and behavior (KAB) regarding the safe use of TIRF medicines as described in the product-specific Medication Guide. This protocol will describe the administration of the surveys that will be conducted among patients who are treated with TIRF medicines, or their caregivers. Data from the surveys, together with other REMS evaluation metrics, will be used to determine whether changes need to be made to the REMS processes and/or educational materials to make them more effective in achieving the goals of the REMS. The surveys will be implemented so that data will be available for inclusion in the REMS Assessment Reports that will be submitted to the FDA at 12 months after approval of the TIRF REMS and annually thereafter. FDA_1968 3. OBJECTIVES OF THE EVALUATION SURVEY The evaluation survey will use a questionnaire to document the level of knowledge and assess the attitudes and behavior of patients around the following key information and risk messages communicated through the REMS: 1) TIRF medicines can cause life-threatening breathing problems that can lead to death. 2) Patients should not take TIRF medicines if they are not opioid tolerant. 3) TIRF medicines should be taken exactly as prescribed by the healthcare provider. 4) Patients should not switch from a TIRF medicine to another medicine that contains fentanyl without talking to a healthcare provider. 5) Patients should not give TIRF medicines to anyone else even if they have the same symptoms. 6) TIRF medicines should be stored in a safe place away from children and properly disposed. The survey will also include questions about whether patients received, read, and understood the product-specific Medication Guide and Patient-Prescriber Agreement Form (PPAF). 4. METHODS The survey was designed in collaboration between the TRIG and United BioSource Corporation (UBC), and will be administered by UBC. 4.1 Qualitative Research on the Survey Qualitative research to test patient comprehension was performed on the patient survey in 2012. Findings were incorporated into the survey prior to implementation of Wave 1. 4.2 Survey Design This survey will be conducted among a sample of patients or their caregivers who have filled a prescription for a TIRF medicine within the past 4 months prior to survey launch. Respondents who have participated in a previous wave of the TIRF REMS KAB survey will not be eligible to participate in subsequent survey waves. The survey will be administered using the following modalities: • Self-administered, online through a secure website FDA_1969 • Telephone surveys facilitated by a trained interviewer from the Survey Coordinating Center using a computer-assisted telephone interviewing (CATI) program The survey will begin with screening questions to confirm respondent eligibility to participate in the survey. Completion of the entire survey is expected to take approximately 20 minutes. The survey included in Appendix B is written to reflect wording for both methods of survey administration: Internet-based and telephone administration. 4.2.1 Questions and Statements on REMS Goals The questionnaire is made up of multiple-choice, closed-ended statements or questions (the majority of which use true/false or yes/no dichotomous response options), and open-ended questions. These will evaluate current knowledge, attitudes, and behavior regarding the key risk messages noted in Section 3. The survey is written to follow principles of health literacy and readability. Questionnaire items will be presented in several formats: • Statements or questions asking the respondent to indicate whether the statement or question is true or false, or if they do not know the answer (there is a similar set of statements and questions that use “yes,” “no,” or “I don’t know” as potential response options); • Statements or questions asking the respondent to choose from a defined list of possible statements or answers; and • Questions allowing for the respondent to provide information about when, where and from whom they obtained a Medication Guide, as well as to list questions they have about information in the Medication Guides. Questionnaires will be analyzed to determine patient understanding of each key risk message. For statements or questions that use “true” or “yes” vs. “false” or “no” response options, the desired response for the key risk messages is generally “true” or “yes” indicating knowledge of, or behavior in accordance with, the objectives of the REMS. However, some questions are formatted to have the respondent disagree with the statement as written by providing response options of “false” or “no” to avoid having the same affirmative answer for all desired responses. REMS statements, corresponding questions, and desired responses covering the key risk messages are identified below and can be found in the complete survey questionnaire (Appendix A). For better readability, the patient questions, only, are presented in the key risk messages tables. Caregiver questions are presented in Appendix A. FDA_1970 Key Risk Message 1: TIRF medicines can cause life-threatening breathing problems that can lead to death. Question No. Question Desired response 13 Please answer True, False, or I don’t know for each statement about the TIRF medicine that was most recently prescribed for you. 13d TIRF medicines can cause life-threatening breathing problems that can lead to death. TRUE Key Risk Message 2: Patients should not take TIRF medicines if they are not opioid tolerant. Question No. Question Desired response Please answer True, False, or I don’t know for the following statement: 11 12 12a 13 13b TIRF medicines should only be taken by patients TRUE who are opioid tolerant. Please answer True, False, or I don’t know for each of the following statements. Opioid tolerant means that a patient is already taking other opioid pain medicines around-theTRUE clock and their body is used to these medicines. Please answer True, False, or I don’t know for each statement about the TIRF medicine that was most recently prescribed for you. It is OK for patients to take TIRF medicines for FALSE headache pain. FDA_1971 Key Risk Message 3: TIRF medicines should be taken exactly as prescribed by the healthcare provider. Question No. Question Desired response 12 Please answer True, False, or I don’t know for each of the following statements. 12b If a patient stops taking around-the-clock opioid pain medicine, they must also stop taking the TIRF medicine. 13/17 13c 17b TRUE Please answer True, False, or I don’t know for each statement about the TIRF medicine that was most recently prescribed for you. TIRF medicines should be taken exactly as TRUE prescribed by the doctor. It is OK to take TIRF medicines for short-term FALSE pain that will go away in a few days. Key Risk Message 4: Patients should not switch from a TIRF medicine to another medicine that contains fentanyl without talking to a healthcare provider. Question No. 12 12c Question Desired response Please answer True, False, or I don’t know for each of the following statements. It is safe to switch to another medicine that contains fentanyl without talking to a healthcare FALSE provider first. FDA_1972 Key Risk Message 5: Patients should not give TIRF medicines to anyone else even if they have the same symptoms. Question Question No. 12 12d 17 17a Desired response Please answer True, False, or I don’t know for each of the following statements. A patient may give TIRF medicines to another person if they have the same symptoms as the FALSE patient. Please answer True, False, or I don’t know for each statement about the TIRF medicine that was most recently prescribed for you. Selling or giving away TIRF medicines is against TRUE the law. Key Risk Message 6: TIRF medicines should be stored in a safe place away from children and properly disposed. Question Question No. 13/17 13a 17c 17e 14 4.2.2 Desired response Please answer True, False, or I don’t know for each statement about the TIRF medicine that was most recently prescribed for you. TIRF medicines should be stored in a safe TRUE place out of the reach of children. TIRF medicines must be disposed of as described in the specific product’s TRUE Medication Guide. A TIRF medicine can cause an overdose TRUE and death in any child who takes it. What should you do if an adult who has not Get emergency help right been prescribed a TIRF medicine takes a away. TIRF medicine? (Please select one.) Additional Questions Questions about the requirements of the TIRF REMS, and receipt and understanding of the Medication Guides and PPAF will be asked after the key risk message questions, and will be followed by the collection of demographic information at the completion of the survey. 4.3 Subject Recruitment Patients will be recruited through a direct letter program. Patients will be invited through a network of national pharmacies and/or a pharmacy benefits management (PBM) partner, FDA_1973 which will provide a broad demographic coverage and include patients in 49 states. Leveraging one or more of these partners, a list will be created of patients who have filled a prescription for a TIRF medicine within 4 months prior to survey launch (first prescriptions and refills). Patients in this list will be invited to participate in the survey through an invitation letter (Appendix B) mailed directly to the patients on the pharmacy or PBM’s letterhead at the corporate level via the United States (US) Postal Service. The invitation will indicate that participants will receive a $50 gift card for completing the survey. Each invitation will also include a unique code and directions for accessing the survey either via the Internet or by telephone through an interviewer at the Survey Coordinating Center. The unique code will be used to identify the manufacturer of the most recent TIRF prescription that the patient filled. A sample of patients who have filled a prescription for a TIRF medicine within the 4 months prior to survey launch will be chosen from the pharmacy partner’s and/or PBM’s database. This sampling approach will be used to create several batches of survey invitations. The overall number of unique patients and the duration of the survey period will dictate the size and number of invitation batches. If the required number of completed surveys is not achieved within a reasonable time frame, a second mailing will be sent to non-respondents from the original batch mailing and initial invitations will be sent to patients in the second batch. If the required number of completed surveys is still not achieved within a reasonable time frame, reminder letters will be sent to the patients in the second batch and initial invitations will be sent to the third batch of patients. If these efforts do not result in the required number of surveys within a reasonable time frame, then a new sample of patients may be selected if available. The intervals for sending reminder invitations to non-responders and for selecting a new sample will be condensed as necessary based on the actual rate of survey accrual relative to the proximity of the target survey close date. All respondents who complete the survey and who provide their contact information will be mailed a $50 gift card to thank them for their participation. The mailing will include a thank you letter, a copy of the product-specific Medication Guide, and a copy of the correct answers to the key risk message questions. 4.3.1 Measures to Minimize Bias in the Sample The sample of participating patients will be self-selected since respondents will voluntarily respond to the invitation to participate; however, the survey recruitment strategies are intended to recruit a heterogeneous sample of patients for participation. Respondents will be offered online or telephone options for completing the survey. Multiple modalities for survey data collection allow for wider survey access to a more heterogeneous population. Respondents will be provided a unique code during the recruitment process and will be asked to provide the unique code to gain access to the online survey or when calling the Survey FDA_1974 Coordinating Center. The code will be deactivated after use to minimize the possibility for fraud. 5. STUDY POPULATION 5.1.1 Sample Size A sample of 300 patients treated with TIRF medicines is proposed for the survey wave. The size of the sample was determined based on both practical and statistical considerations. There is no target comprehension rate specified a priori. A sample of 300 completed surveys will allow estimation of the comprehension rate for each key risk message with a moderately high degree of precision. The table below shows the precision of the estimates for level of understanding using two-sided 95% confidence intervals (CIs) obtained with the sample size of 300 completed surveys. The noted CIs are used to indicate that for any survey-estimated rate of understanding, the true population rate of understanding is at least as high as the lower limit of the 95% CI and may be as high as the upper limit of the 95% CI. Table 5.1: Precision of Estimated Rates of Understanding with a Sample Size of 300 Estimated Rate of Understanding 5% 10% 15% 20% 25% 30% 35% 40% 45% 50% 55% 60% 65% 70% 75% 80% 85% 90% 95% 5.1.2 Estimated Confidence Interval 2.8% 8.1% 6.8% 14.0% 11.2% 19.6% 15.6% 25.0% 20.2% 30.3% 24.9% 35.5% 29.6% 40.7% 34.4% 45.8% 39.3% 50.8% 44.2% 55.8% 49.2% 60.7% 54.2% 65.6% 59.3% 70.4% 64.5% 75.1% 69.7% 79.8% 75.0% 84.4% 80.4% 88.8% 86.0% 93.2% 91.9% 97.2% Inclusion Criteria The following respondents are eligible to participate in the survey: • Patients who are 18 years of age or older who have filled a prescription for at least one of the TIRF medicines within 4 months prior to survey launch FDA_1975 • 5.1.3 Caregivers 18 years of age or older who care for patients who have filled a TIRF medicine prescription within the past 4 months prior to survey launch and are unable to take the survey for themselves Exclusion Criteria The following respondents are not eligible to participate in the surveys: • Patients who have previously participated in the TIRF REMS KAB survey (this exclusion applies to the second and subsequent waves only) • Patients or their immediate family members who have ever worked for Anesta LLC, Cephalon, Inc. (a wholly-owned subsidiary of Teva Pharmaceutical Industries, Ltd.); Depomed, Inc.; Galena Biopharma; Insys Therapeutics; Mallinckrodt Pharmaceuticals; Meda Pharmaceuticals; Mylan, Inc.; Par Pharmaceutical, Inc.; Teva Pharmaceuticals, Ltd.; UBC; McKesson Specialty Care Solutions; RelayHealth; or the FDA. 6. SURVEY PROCESS 6.1 Screening and Survey Administration The questionnaire will begin with a screening module with questions to confirm patient eligibility. The entire survey is expected to take approximately 20 minutes to complete. Depending on the answers to the screening questions, survey participation could either be terminated or continued. If ineligible, respondents are immediately notified with a thank you message that survey participation has ended. If eligible, respondents are allowed to continue survey participation. The electronic data capture (EDC) system that is used for both methods of survey administration has been validated and is secure for receiving and storing survey data. The system is 21 CFR Part 11 and Health Insurance Portability and Accountability Act (HIPAA) compliant. Patient-identifying information will be stored separately from survey data. 6.1.1 Telephone The telephone survey is facilitated by a trained interviewer from the Survey Coordinating Center using a CATI program. The respondent will be required to provide a unique code to access the survey. Working from a CATI script, the interviewer will read questions or statements to the respondent and enter the responses into the EDC system. Screening and main elements of the questionnaire will be administered sequentially during the same telephone call. Telephone interviewing allows participation of respondents who do not have Internet access, or prefer to complete the survey in this manner. 6.1.2 Internet An Internet-based survey system will also be used for conducting the KAB surveys. If respondents select to participate in the survey online, they will be directed to a secured FDA_1976 website and instructed to enter a unique code to access the survey. An Internet survey will be convenient for respondents to participate since they can complete the questionnaire at any convenient time and location during the specified survey time period. 6.2 Measures to Minimize Bias in the Survey Process A number of controls will be in place to ensure the survey is conducted in a controlled and professional manner and to minimize bias. For example, a unique code will be given to each survey participant and the code will be inactivated after use to minimize fraud. Telephone interviewers are highly trained and use a standardized script to administer the survey. All questions will be programmed to ensure that questions are asked in the appropriate sequence. Skip patterns will be clearly indicated. Respondents cannot go back to a question once the question has been answered and cannot skip ahead. All questions must be answered in order to complete the survey. Response options presented in a list will be randomized to minimize positional bias. Programming will be reviewed by quality control and simulated users (User Acceptance Testing) prior to implementing the survey. 7. ANALYSIS Information obtained from the survey will be reported as descriptive statistics for the survey administration, study population, and the survey questions. Any free text fields will be grouped into applicable categories. Verbatim text from open-ended questions will be displayed when appropriate. The following will be reported as part of this analysis: • The number of invitations issued • The number of reminder letters • The number of respondents screened for participation • The number of respondents eligible for participation • The number of respondents who completed all questions presented to them • Description of survey participants, including: − Type of respondent (patient/caregiver) − Age (patient/caregiver) − Gender (respondent) − Educational level (respondent) − Main language spoken at home (respondent) FDA_1977 • − Ethnicity (respondent) − Race (respondent) − Geographic region (respondent) Data from all respondents who completed all questions presented to them in the survey (“completers”) will be analyzed, including: − Frequency distribution of responses to each key risk message question. − Percent of completers selecting desired response to each question relating to each key risk message and 95% CI. Measurement of understanding will be computed for each question of the key risk message individually. A secondary analysis will be conducted to determine the number of completers who answered all items correctly for the key risk message. Behavior questions will be summarized on a question-by-question basis and are not included in the analysis by key risk message. Additional analyses may be performed as needed. 8. SAFETY EVENT REPORTING The survey will be conducted via the Internet and by telephone. It is possible that a respondent may report an adverse event or other safety event experienced while taking TIRF medicines either in free text fields of the survey or while in conversation with the Survey Coordinating Center. If an event is mentioned to a Survey Coordinating Center Associate, the Associate will document the safety event and the respondent’s contact information. The respondent will also be informed that a representative from the appropriate TIRF medicine manufacturer may contact him/her if there are questions about the survey. The Internet-based questionnaires will be monitored for any comments recorded in free text fields. Information on all comments that may constitute an adverse event or other safety event will be forwarded to the appropriate TIRF medicine manufacturer as described in the Safety Event Project Specific Procedure (SE PSP). Additional detail regarding processes for adverse event reporting will be specified in the SE PSP. 9. PRIVACY PROTECTION AND CONFIDENTIALITY All data collected during the survey will be held confidential. The EDC system used for data collection encrypts all identifiable information and respondent identifiers are stored separately from the survey responses. FDA_1978 Respondent names and addresses are collected in order to mail a $50 gift card, a Thank You Letter, a product-specific Medication Guide, and correct survey responses to key risk message questions after the survey is completed. Respondent contact information is also requested in the event a safety event is reported and a TIRF medicine manufacturer must obtain follow-up information. A respondent may be contacted only if clarification or follow-up is needed regarding a possible safety event that was mentioned to the interviewer or recorded in free text fields of the online survey. Respondents will be informed when they access the survey that they may be contacted if there are any questions about their survey responses. Respondents will be informed that their answers to the survey questions will not affect their ability to receive TIRF medicines. This protocol and survey will be reviewed and approved by a central Institutional Review Board (IRB) before administration of the survey. FDA_1979 APPENDIX A Screening and Main Questionnaire Survey Legend • [PROGRAMMER] is used to indicate directions to the programmer and is set in bold, red, uppercase letters between square brackets. [PATIENT] indicates text applicable to a patient when it differs from survey text for caregivers, parents and legal guardians. [PARENT/CAREGIVER/LEGAL GUARDIAN] indicates text applicable to parents, caregivers, and legal guardians when it differs from survey text for patients. • (INTERVIEWER) is used to indicate directions to the telephone interviewer and is set in bold, blue, text between parentheses. This text appears when content is to be administered by tlelphone only (for example, spontaneous adverse event reporting). • [ONLINE] indicates a question is worded specifically for administering the survey online. [PHONE] indicates a question is worded specifically to be read by a telephone interviewer and differs from the online text. • [BEGIN ONLINE/PHONE SURVEY CONTENT] and [END SURVEY CONTENT] are used to indicate to the programmer the type of survey administration and the beginning and end of the survey or sections within the survey content, for example, [BEGIN ADVERSE EVENT/PRODUCT COMPLAINT] and [END ADVERSE EVENT/PRODUCT COMPLAINT]. • [TERMINATE] is displayed next to responses that should cause the survey to end. The following termination language will be programmed into the survey or read by the interviewer unless different language is specified with the question. Thank you very much for your time today. Based on your answer, you are not eligible to take this survey. We appreciate your interest in the survey. • [RANDOMIZE LIST] is inserted before questions to indicate to the programmer that the responses should be randomized. Responses such as “I don’t know,” “Prefer not to answer” or “None of the above” will always appear at the end of the randomized responses. • [GO TO Ax] (Skip logic) is inserted after a response to indicate to the programmer that the survey should skip to the indicated question (for example, [GO TO Q17] skips to question 17). If no skip logic is indicated the survey continues to the next question in the sequence. FDA_1980 Survey Legend • [FREE TEXT] indicates to the programmer that one line should be provided for data entry. • [MULTILINE INPUT] indicates to the programmer that multiple lines should be provided for data entry (for example, two address lines). • [DROP-DOWN LIST INPUT WITH STATES TABLE] indicates to the programmer that the response should be a drop-down list containing the states in the table below. Alabama Georgia Massachusetts New York Tennessee Alaska Guam Michigan North Carolina Texas American Samoa Hawaii Minnesota North Dakota Idaho Mississippi Arizona Illinois Missouri Arkansas Indiana Montana Northern Mariana Islands US Virgin Islands California Iowa Nebraska Colorado Kansas Nevada Connecticut Kentucky New Hampshire Delaware Louisiana New Jersey District of Columbia Maine New Mexico Florida Maryland Utah Vermont Ohio Virginia Oklahoma Washington Oregon West Virginia Pennsylvania Wisconsin Puerto Rico Wyoming Rhode Island South Carolina South Dakota • The following is used to categorize survey populations into standard geographic regions but it is not displayed in the survey. Geographic Distribution (based on address) 1: Northeast, Midwest, South, and West regions Northeast Region − New England Division - ME, NH, VT, MA, RI, CT − Middle Atlantic Division - NY, NJ, PA Midwest Region − East North Central Division - OH, IN, IL, MI, WI − West North Central Division - MN, IA, MO, ND, SD, NE, KS South Region − South Atlantic Division - DE, MD, DC, VA, WV, NC, SC, GA, FL − East South Central Division - KY, TN, AL, MS FDA_1981 Survey Legend − West South Central Division - AR, LA, OK, TX West − Mountain Division - MT, ID, WY, CO, NM, AZ, UT, NV − Pacific Division WA, OR, CA, AK, HI • The following US territories are categorized as Other: Puerto Rico, Northern Mariana Islands, US Virgin Islands, American Samoa, and Guam. 1 U.S. Census Bureau, last revised Friday, 27-Jul-2001 12:59:43 EDT. FDA_1982 [BEGIN SURVEY CONTENT] [ONLINE PREAMBLE 1] Before you begin, we would like to share some important information about this survey. The survey is being conducted by the makers of Abstral®, Actiq®, Fentora®, Lazanda®, Onsolis®, Subsys® and the generic versions of any of these brands. These are Transmucosal Immediate Release Fentanyl medicines, also known as rapid onset opioids (and sometimes called “fast acting fentanyls”) or TIRF medicines. The information collected will help the makers of TIRF medicines know if patients and their caregivers understand important information about taking these medicines. The survey will take about 20 minutes. There are no known risks to you in taking this survey. You may refuse to take part or withdraw at any time without penalty or loss of benefits to which you are otherwise entitled. Your answers to the questions or your decision to take part in the survey will not affect your ability to receive or take TIRF medicines. How We Use Your Information Your answers to the survey questions will be combined with answers given by other people taking the survey. All answers will be put together and reported in anonymous form to manufacturers of TIRF medicines. Your name will not be used in any report. If you are eligible to take the survey, complete all the questions, and provide your contact information, you will receive a $50 gift card for your time. Your name and address will be used only to send you the gift card, a Thank You Letter, a product-specific Medication Guide, and a copy of the correct answers to key risk message questions, after you complete the survey. Providing a telephone number is optional. Your telephone number will be used only if there are any questions about your answers. How We Protect Your Privacy We respect that the privacy of your personal information is important to you. You will not be contacted for marketing purposes based on your personal information or your answers to the survey. Neither the manufacturers of TIRF medicines nor their contractors will sell, transfer, or rent your information. Your answers will be kept strictly confidential. Your privacy will be protected; however, research survey records may be inspected by the FDA (Food and Drug (b) (4) Administration) and a company called ., which is the Institutional Review Board (IRB) that looks out for the interest of survey participants. Your choice to allow the manufacturers of TIRF medicines to use your information is entirely voluntary, but necessary to take part in this survey. FDA_1983 If you have questions about your rights as a research participant or related concerns, you may (b) (4) contact the IRB at . Be sure to write down this telephone number; it will not be displayed again. How to Learn More About This Survey If you have questions about the survey, or have any problems with the survey, please contact the Survey Coordinating Center at 1-877-379-3297. The information in this survey should not take the place of talking with your doctor or health care professional. If you have any questions about your condition or treatment or that of the person you care for, or if you would like more information about TIRF medicines, talk to your doctor, pharmacist, or other health care professional. Once you have answered a question and moved on, you cannot go back and change your answers. Thank you for your participation in this survey. [END ONLINE PREAMBLE 1] FDA_1984 [PHONE PREAMBLE 1] Before you begin, we would like to share some important information about this survey. The survey is being conducted by the makers of Abstral®, Actiq®, Fentora®, Lazanda®, Onsolis®, Subsys® and the generic versions of any of these brands. These are Transmucosal Immediate Release Fentanyl medicines, also known as rapid onset opioids (INTERVIEWER: Please pause briefly) (and sometimes called “fast acting fentanyls”) or TIRF medicines. (INTERVIEWER: Pronounce “TIRF,” then spell out T-I-R-F). The information collected will help the makers of TIRF medicines know if patients and their caregivers understand important information about taking these medicines. The survey will take about 20 minutes. There are no known risks to you in taking this survey. You may refuse to take part or withdraw at any time without penalty or loss of benefits to which you are otherwise entitled. Your answers to the questions or your decision to take part in the survey will not affect your ability to receive or take TIRF medicines. Now I would like to tell you about how your contact information will be used. Your answers to the survey questions will be combined with answers given by other people taking the survey. All answers will be put together and reported in anonymous form to manufacturers of TIRF medicines. Your name will not be used in any report. If you are eligible to take the survey, complete all the questions, and provide your contact information, you will receive a $50 gift card for your time. Your name and address will be used only to send you the gift card, a Thank You Letter, a product-specific Medication Guide, and a copy of the correct answers to key risk message questions, after you complete the survey. Providing a telephone number is optional. Your telephone number will be used only if there are any questions about your answers. Now I would like to tell you about how we protect your privacy. We respect that the privacy of your personal information is important to you. You will not be contacted for marketing purposes based on your personal information or your answers to the survey. Neither the manufacturers of TIRF medicines nor their contractors will sell, transfer, or rent your information. Your answers will be kept strictly confidential. Your privacy will be protected; however, research survey records may be inspected by the FDA (Food and Drug (b) (4) Administration) and a company called ., which is the Institutional Review Board (IRB) that looks out for the interest of survey participants. Your choice to allow the manufacturers of TIRF medicines to use your information is entirely voluntary, but necessary to take part in this survey. If you have questions about your rights as a research participant or related concerns, you may (b) (4) contact the IRB at FDA_1985 The information in this survey should not take the place of talking with your doctor or health care professional. If you have any questions about your condition or treatment or that of the person you care for, or if you would like more information about TIRF medicines, talk to your doctor, pharmacist, or other health care professional. Please feel free to ask me to repeat any questions or statements as we go through the survey. Once you have answered a question and moved on, you cannot go back and change your answers. Thank you for your participation in this survey. [END PHONE PREAMBLE 1] FDA_1986 1. 2. 3. Do you agree to take part in this survey? ○ Yes ○ No [TERMINATE] Within the last 4 months, have you filled a prescription for yourself for a transmucosal immediate release fentanyl medicine (known as “TIRF medicines”)? TIRF medicines include Abstral®, Actiq®, Fentora®, Lazanda®, Onsolis®, Subsys®, and the generic versions of any of these brands. ○ Yes [GO TO Q4] ○ No ○ I don’t know Are you a caregiver for someone who has filled a prescription for a TIRF medicine within the last 4 months? TIRF medicines include Abstral®, Actiq®, Fentora®, Lazanda®, Onsolis®, Subsys® and the generic versions of any of these brands. ○ Yes ○ No [TERMINATE] ○ I don’t know [TERMINATE] FDA_1987 4. 5. [PATIENT] For which TIRF medicines have you filled a prescription in the last 4 months? Please select all that apply. [CAREGIVER] For which TIRF medicines has the person you care for filled a prescription in the last 4 months? Please select all that apply. □ Abstral □ Actiq, including generic versions of Actiq □ Fentora □ Lazanda □ Onsolis □ Subsys □ Other □ I don’t know [CLEAR ALL OTHER SELECTIONS] Have you ever taken part in a survey about a TIRF medicine before? ○ Yes [TERMINATE] ○ No ○ I don’t know [TERMINATE] FDA_1988 6. 7. Which of the following groups best describes your age? ○ Under 18 [TERMINATE] ○ 18 – 29 ○ 30 – 39 ○ 40 – 49 ○ 50 – 59 ○ 60 – 69 ○ 70 or older ○ Prefer not to answer [TERMINATE] [CAREGIVER ONLY] Which of the following groups best describes the patient’s age? ○ Under 16 ○ 16 – 29 ○ 30 – 39 ○ 40 – 49 ○ 50 – 59 ○ 60 – 69 ○ 70 or older ○ Prefer not to answer [TERMINATE] FDA_1989 8. Have you or any of your immediate family members ever worked for any of the following companies or agencies? Please select all that apply. □ Anesta LLC [TERMINATE] □ Cephalon, Inc. (a wholly-owned subsidiary of Teva Pharmaceutical Industries, Ltd.) [TERMINATE] □ □ Depomed, Inc. [TERMINATE] □ □ Insys Therapeutics [TERMINATE] Galena Biopharma, Inc. [TERMINATE] Mallinckrodt Pharmaceuticals [TERMINATE] □ McKesson Specialty Care Solutions [TERMINATE] □ Meda Pharmaceuticals [TERMINATE] □ Mylan, Inc. [TERMINATE] □ Par Pharmaceutical, Inc. [TERMINATE] □ RelayHealth[TERMINATE] □ Teva Pharmaceuticals, Ltd. [TERMINATE] □ United BioSource Corporation [TERMINATE] □ FDA (Food and Drug Administration) [TERMINATE] □ □ No [IF SELECTED IN ADDITION TO OTHER RESPONSES, TERMINATE] I don’t know [TERMINATE] [PREAMBLE 2] [PATIENT]Please answer the following questions based on information about the TIRF medicine that was most recently prescribed for you. TIRF medicines include Abstral®, Actiq®, Fentora®, Lazanda®, Onsolis®, Subsys®, and the generic versions of these brands. Please think of the information that you read or that was provided to you by a doctor, nurse, or other healthcare professional. If you don’t know the answers to any of the following questions please respond “I don’t know” instead of guessing the correct responses. FDA_1990 [CAREGIVER]Please answer the following questions based on information about the TIRF medicine that was most recently prescribed for the patient. TIRF medicines include Abstral®, Actiq®, Fentora®, Lazanda®, Onsolis®, Subsys®, and the generic versions of these brands. Please think of the information that you read or that was provided to you or to the patient by a doctor, nurse, or other healthcare professional. If you don’t know the answers to any of the following questions please respond “I don’t know” instead of guessing the correct responses. 9. [PATIENT] Did the doctor, nurse, or other healthcare professional in the doctor’s office ever talk to you about the risks and possible side effects of the TIRF medicine that was most recently prescribed for you? TIRF medicines include Abstral®, Actiq®, Fentora®, Lazanda®, Onsolis®, Subsys®, and the generic versions of these brands. [CAREGIVER] Did the doctor, nurse, or other healthcare professional in the doctor’s office ever talk to you about the risks and possible side effects of the TIRF medicine that was most recently prescribed to the patient? TIRF medicines include Abstral®, Actiq®, Fentora®, Lazanda®, Onsolis®, Subsys®, and the generic versions of these brands. 10. ○ Yes ○ No ○ I don’t know [PATIENT] For which of the following conditions should you use a TIRF medicine? [CAREGIVER] For which of the following conditions should the person you take care of use a TIRF medicine? Yes No I don’t [RANDOMIZE LIST] know 10a. Headache or migraine pain ○ ○ ○ 10b. Breakthrough pain from cancer ○ ○ ○ 10c. Dental pain ○ ○ ○ 10d. Pain after surgery ○ ○ ○ 10e. Long-lasting painful conditions not caused by cancer ○ ○ ○ 11. Please answer True, False, or I don’t know for the following statement: FDA_1991 TIRF medicines should only be taken by patients who are opioid tolerant. 12. ○ True ○ False ○ I don’t know Please answer True, False, or I don’t know for each of the following statements. True False I don’t [RANDOMIZE LIST] know 12a. Opioid tolerant means that a patient is already taking other opioid pain medicines around-the-clock and their body is used to these medicines. ○ ○ ○ 12b. If a patient stops taking around-the-clock opioid pain medicine, they must also stop taking the TIRF medicine. ○ ○ ○ 12c. It is safe to switch to another medicine that contains fentanyl without talking to a healthcare provider first. ○ ○ ○ 12d. A patient may give TIRF medicines to another person if they have the same symptoms as the patient. ○ ○ ○ FDA_1992 13. [PATIENT] Please answer True, False, or I don’t know for each statement about the TIRF medicine that was most recently prescribed for you. [CAREGIVER] Please answer True, False, or I don’t know for each statement about the TIRF medicine that was most recently prescribed for the patient. I don’t [RANDOMIZE LIST] True False know 13a. TIRF medicines should be stored in a safe place out of the reach of children. ○ ○ ○ 13b. It is OK for patients to take TIRF medicines for headache pain. ○ ○ ○ 13c. TIRF medicines should be taken exactly as prescribed by the doctor. ○ ○ ○ 13d. TIRF medicines can cause life-threatening breathing problems that can lead to death. ○ ○ ○ 14. What should you do if an adult who has not been prescribed a TIRF medicine takes a TIRF medicine? (Please select one.) [RANDOMIZE LIST] ○ Wait an hour and see if the person is OK. ○ Get emergency help right away. ○ Do nothing. ○ I don’t know. FDA_1993 15. [PATIENT] Did the doctor, nurse, or other healthcare professional in the doctor’s office ever tell you how to use the TIRF medicine that was most recently prescribed for you? [CAREGIVER] Did the doctor, nurse, or other healthcare professional in the doctor’s office ever tell you how to use the TIRF medicine that was most recently prescribed for the patient? 16. ○ Yes ○ No ○ I don’t know [PATIENT] Did the doctor, nurse, or other healthcare professional in the doctor’s office ever tell you how to store or keep the TIRF medicine that was most recently prescribed for you? [CAREGIVER] Did the doctor, nurse, or other healthcare professional in the doctor’s office ever tell you how to store or keep the TIRF medicine that was most recently prescribed for the patient? ○ Yes ○ No ○ I don’t know FDA_1994 17. [PATIENT] Please answer True, False, or I don’t know for each statement about the TIRF medicine that was most recently prescribed for you. [CAREGIVER] Please answer True, False, or I don’t know for each statement about the TIRF medicine that was most recently prescribed for the patient. [RANDOMIZE LIST] True False I don’t know 17a. Selling or giving away TIRF medicines is against the law. ○ ○ ○ 17b. It is OK to take TIRF medicines for short-term pain that will go away in a few days. ○ ○ ○ 17c. TIRF medicines must be disposed of as described in the specific product’s Medication Guide. ○ ○ ○ 17d. TIRF medicines are only available to patients through a pharmacy enrolled in a special program (called the TIRF REMS Access Program). ○ ○ ○ 17e. A TIRF medicine can cause an overdose and death in any child who takes it. ○ ○ ○ [PREAMBLE 3] [PATIENT] The next set of questions is about the Medication Guide for the TIRF medicine that was most recently prescribed for you. [CAREGIVER] The next set of questions is about the Medication Guide for the TIRF medicine that was most recently prescribed for the patient. [BOTH] A Medication Guide is a paper handout that contains important information about the risks associated with the use of a TIRF medicine and how to use it safely. Medication Guides always include the title “Medication Guide” followed by the name of the medicine and its pronunciation. The Medication Guide usually has a section titled “What is the most important information I should know?” The Medication Guide is in a question-and-answer format and may be given to you by your pharmacist, doctor, or other healthcare professional. FDA_1995 18. [PATIENT] Have you ever received a Medication Guide for the TIRF medicine that was prescribed for you? [CAREGIVER] Have you or the patient ever received a Medication Guide for the TIRF medicine that was prescribed for the patient? 19. ○ Yes ○ No [GO TO PREAMBLE 4] ○ I don’t know [GO TO PREAMBLE 4] [PATIENT] Did you receive the Medication Guide from the doctor who prescribed the TIRF medicine or someone in the doctor’s office? [CAREGIVER] Did you or the patient receive the Medication Guide from the doctor who prescribed the TIRF medicine or someone in the doctor’s office? 20. ○ Yes ○ No [GO TO Q21] ○ I don’t know [GO TO Q21] [PATIENT] When was the Medication Guide given to you? Please select all that apply. [CAREGIVER] When was the Medication Guide given to you or the patient? Please select all that apply. □ At the first appointment with the doctor who prescribed the TIRF medicine □ At the last appointment with the doctor who prescribed the TIRF medicine □ I don’t remember [CLEAR ALL OTHER SELECTIONS] FDA_1996 21. [PATIENT] Did you receive the Medication Guide for the TIRF medicine from the pharmacy? [CAREGIVER] Did you or the patient receive the Medication Guide for the TIRF medicine from the pharmacy? 22. ○ Yes ○ No [GO TO Q23] ○ I don’t know [GO TO Q23] [PATIENT] How frequently do you receive a Medication Guide for the TIRF medicine at the pharmacy? [CAREGIVER] How frequently do you or the patient receive a Medication Guide for the TIRF medicine at the pharmacy? 23. 24. ○ Only with the first filled prescription ○ Each time a prescription is filled ○ Other (please specify): _____________________________ ○ I don’t know Did you read the Medication Guide? ○ Yes ○ No [GO TO Q26] ○ I don’t know [GO TO Q26] How much did you read? ○ All of it ○ Most of it ○ Some of it ○ I don’t know FDA_1997 25. 26. 27. How much of the Medication Guide did you understand? ○ All of it ○ Most of it ○ Some of it ○ None of it ○ I don’t know Did someone offer to explain the Medication Guide to you? ○ Yes ○ No [GO TO Q30] ○ I don’t know [GO TO Q30] Who offered to explain the Medication Guide to you? Please select all that apply. □ The doctor or another healthcare professional in the doctor’s office □ The pharmacist where the TIRF medicine prescription was filled □ Someone else (specify the type of person but not his/her name) [FREE TEXT] 28. Did you accept the offer to have the Medication Guide explained to you? ○ Yes ○ No [GO TO Q30] ○ I don’t know [GO TO Q30] FDA_1998 29. 30. 31. How much of the explanation did you understand? ○ All of it ○ Most of it ○ Some of it ○ None of it ○ I don’t know Did you or do you have any questions about the information in the Medication Guide? ○ Yes ○ No [GO TO PREAMBLE 4] ○ I don’t know [GO TO PREAMBLE 4] What are your questions? [MULTILINE INPUT] [PREAMBLE 4] The next set of questions is about the Patient-Prescriber Agreement Form for TIRF medicines. As a reminder, TIRF medicines include Abstral®, Actiq®, Fentora®, Lazanda®, Onsolis®, Subsys®, and the generic versions of any of these brands. The Patient-Prescriber Agreement is a form that is signed by the doctor and the patient or their caregiver. This form may also be referred to as the Prescriber-Patient Agreement. [END PREAMBLE 4] 32. Did the doctor or someone in the doctor’s office explain the Patient-Prescriber Agreement Form to you? ○ Yes ○ No [GO TO Q34] ○ I don’t know [GO TO Q34] FDA_1999 33. 34. How much of the explanation did you understand? ○ All of it ○ Most of it ○ Some of it ○ None of it ○ I don’t know [PATIENT] Did you sign a Patient-Prescriber Agreement Form? [CAREGIVER] Did you or the person you are caring for sign a Patient-Prescriber Agreement Form? 35. ○ Yes ○ No [GO TO DEMOGRAPHICS PREAMBLE] ○ I don’t know [GO TO DEMOGRAPHICS PREAMBLE] Did the doctor or someone in the doctor’s office give you a copy of the signed Patient-Prescriber Agreement Form? ○ Yes ○ No ○ I don’t know [DEMOGRAPHICS PREAMBLE] There are just a few more questions to help us combine your answers with other answers we have received. 36. What is your gender? ○ Male ○ Female ○ Prefer not to answer FDA_2000 37. 38. What is the highest level of education you have completed? ○ Less than high school ○ Some high school ○ High school graduate/GED ○ Some college/Associate’s degree ○ Bachelor’s degree ○ Master’s degree ○ Professional or Doctoral degree ○ Prefer not to answer What is the main language you speak at home? ○ English ○ French ○ Spanish ○ Portuguese ○ Italian ○ German ○ Chinese ○ Japanese ○ Korean ○ Other ○ Prefer not to answer FDA_2001 39. 40. 41. Are you Hispanic or Latino? ○ Yes ○ No ○ Prefer not to answer For informational purposes only, which of the following U.S. census categories best describes your race? ○ American Indian or Alaska Native ○ Asian (origins of Far East, Southeast Asia or the Indian subcontinent) ○ Black or African American ○ Native Hawaiian or Other Pacific Islander ○ White ○ Two or more races ○ Other ○ Prefer not to answer In which state do you live? [DROP-DOWN LIST INPUT WITH STATES TABLE WITH “Prefer not to answer” AT END] FDA_2002 [PHONE ONLY: ADVERSE EVENT/PRODUCT COMPLAINT] (INTERVIEWER: Please record if respondent spontaneously reported an adverse event or product complaint during the course of this interview.) ○ Yes ○ No [GO TO CLOSING 1] Enter Safety Adverse Event Verbatim [MULTILINE INPUT] (INTERVIEWER: Indicate to the respondent that someone may call back to ask more questions about the adverse event or product complaint that was reported.) [END ADVERSE EVENT/PRODUCT COMPLAINT] [CLOSING 1] You are eligible to receive a $50 gift card for your time completing the survey. In order to receive the gift card, we need to collect your name and address so that we can mail it to you. If you do not provide your name and address you will not receive the gift card for your time taking the survey. Do you agree to give us your name and mailing address so we can send your payment? ○ Yes ○ No [SKIP TO CLOSING 2] FIRST NAME: [FREE TEXT] LAST NAME: [FREE TEXT] ADDRESS: [MULTILINE INPUT] CITY: [FREE TEXT] STATE: [DROP-DOWN LIST INPUT WITH STATES TABLE] ZIP: [5 NUMERIC CHARACTERS ONLY] FDA_2003 [CLOSING 2] We would also like to ask for your telephone number. Providing your telephone number is optional and it will be used to contact you only if there are questions about your survey responses. Do you want to provide your telephone number? ○ Yes ○ No [SKIP TO CLOSING 3] Telephone: [10-DIGIT NUMERIC CHARACTERS] [END CLOSING 2] [CLOSING 3] This is the end of the survey. If you have questions about the survey, please contact the Survey Coordinating Center at 1-877-379-3297. Thank you again for your help. [END OF SURVEY CONTENT] FDA_2004 APPENDIX B SAMPLE Patient Letter of Invitation [PAT_FIRST_NAME] [PAT_LAST_NAME [CURR_DATE] [PAT_STREET_ADDR] [PAT_CITY], [PAT_STATE] [PAT_ZIP] Dear [PAT_FULL_NAME]: Thank you for choosing [pharmacy partner or PBM name] for your prescription needs. The purpose of this letter is to inform you about a voluntary research survey being conducted by [COMPANY], the maker of [BRAND_GENERIC]. The survey is part of an FDA requirement to find out if patients and/or their caregivers understand important safety information about [BRAND] and other medicines like it. The first 300 people who complete this 20-minute survey and provide their contact information will receive a $50 [pharmacy partner or PBM name] gift card from [COMPANY] to thank them for their time. You may be eligible to take part if you have taken [BRAND] and are 18 years of age or older. If you are unable to take the survey yourself, a caregiver who is 18 or older may be eligible to take the survey for you. The survey asks questions about the type of information you received about [BRAND] and where you get your medical information. If you are interested in participating and to find out if you are eligible: • • Go to www.TIRFREMSsurvey.com any time or Call 877-379-3297, 8 a.m. to 8 p.m. Eastern Time, Monday through Friday Please have this letter with you at the time you take the survey. You will be asked to provide this code prior to starting the survey: [CODE_ID]. *It is recommended that you take the survey on a desktop or laptop computer. Taking the survey on mobile devices, such as smart phones, tablets, and e-notebooks, is not supported. (over, please) FDA_2005 You are not required to take part in this survey. If you choose to take part, please be assured that your contact information and your individual responses will be kept strictly confidential. You will not be asked to identify yourself to participate in the survey. However, if you wish to receive the $50 gift card from [COMPANY], you must provide your name and contact information for delivery. Your answers to the survey questions will be combined with answers given by others, and your name will not be used in any written report or publication. Neither taking the survey nor your answers to the questions will affect your ability to receive or take [BRAND]. Sincerely, [Pharmacy partner or PBM name] [COMPANY] funded the cost of the gift card, the cost of mailing this letter and paid a fee to [pharmacy partner or PBM name]. The research study is not being conducted by [pharmacy partner or PBM name]. No information that can identify you, your medication, or your health condition will be provided by [pharmacy partner or PBM name] to [COMPANY]. This letter provides information about a drug prescribed by your doctor and is not a recommendation by [pharmacy partner or PBM name] to use a particular drug for your condition. Call [pharmacy partner or PBM name] toll free at xxx-xxx-xxxx if you do not wish to continue receiving mailings about [BRAND] from [pharmacy partner or PBM name]. FDA_2006 Patient KAB Assessment Report Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Appendix B Page 51 of 52 Patient Survey Listings and Sub-group Analyses Tables FDA_2007 TABLE 6.1.1 PRIMARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #1 IN ELIGIBLE AND COMPLETE RESPONDENTS KEY RISK MESSAGE 1: TIRF MEDICINES CAN CAUSE LIFE-THREATENING BREATHING PROBLEMS THAT CAN LEAD TO DEATH. SUB-GROUP ANALYSIS 1: READING MEDICATION GUIDE (QUESTION 18, QUESTION 23, AND QUESTION 24): S-la - Respondents who received the Medication Guide and read at least most of it. S-lb - Respondents who did not receive a Medication Guide or answered don?t know? or who received a Medication Guide and read only some of it or answered don?t know.? S?lb 31a . Read some or none of Read most of Med Guide Med Guide Question (95% CI) (95% CI) Question 13: Please answer True, False, or I don?t know for each statement about the TIRF medicine that was most recently prescribed for you. 13d: TIRF medicines can cause life-threatening breathing problems that can lead to death. 93.3 80.6 True 180 (88.8. 96.4) 29 (64.0. 91.8) False 1 0.5 0 0.0 I don?t know 12 6.2 7 19.4 Correct response Note: All con?dence intervals are exact binomial 95% con?dence intervals. Client: TRIG Project: TIRF Wave3 Report Run Date and Time: 10/30/2014 2:15 PM Page 1 of TABLE 7.1.1 PRIMARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #2 IN ELIGIBLE AND COMPLETE RESPONDENTS KEY RISK MESSAGE 2: PATIENTS SHOULD NOT TAKE TIRF MEDICINES IF THEY ARE NOT OPIOID TOLERANT. SUB-GROUP ANALYSIS 1: READING MEDICATION GUIDE (QUESTION 18, QUESTION 23, AND QUESTION 24): S-la - Respondents who received the Medication Guide and read at least most of it. S-lb - Respondents who did not receive a Medication Guide or answered don?t know? or who received a Medication Guide and read only some of it or answered don?t know.? la S?lb . Read some or none of Read most of Med Guide Med Guide Question (95% CI) (95% CI) Question 11: Please answer True, False, or I don?t know for the following statement: TIRF medicines should only be taken by patients who are opioid tolerant. 88.1 69.4 True 170 (82.7. 92.3) 25 (51.9. 83.7) False 5 2.6 1 2.8 I don't know 18 9.3 10 27.8 Question 12: Please answer True, False, or I don?t know for each of the following statements. 12a: Opioid tolerant means that a patient is already taking other opioid pain medicines around- the-clock and their body is used to these medicines. 84.5 66.7 me 163 (78.6. 89.3) 24 (49.0. 81.4) False 14 7.3 5 13.9 I don't know 16 8.3 7 19.4 Client: TRIG Project: TIRF Wave3 Report Run Date and Time: 10/31/2014 1:45 PM Page 1 of 2 13b: It is OK for patients to take medicines for headache pain. 73.1 50.0 False 141 (66.2, 79.2) 18 (32.9, 67.1) True 12 6.2 4 1.1 I don't know 40 20.7 14 38.9 Correct response Note: All con?dence intervals are exact binomial 95% con?dence intervals. Client: TRIG Project: TIRF Wave 3 Report Run Date and Time: 10/31/2014 1:45 PM Page 2 of 2 0 TABLE 7.2.1 SECONDARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #2 IN ELIGIBLE AND COMPLETE RESPONDENTS KEY RISK MESSAGE 2: PATIENTS SHOULD NOT TAKE TIRF MEDICINES IF THEY ARE NOT OPIOID TOLERANT. SUB-GROUP ANALYSIS 1: READING MEDICATION GUIDE (QUESTION 18, QUESTION 23, AND QUESTION 24): S-la - Respondents who received the Medication Guide and read at least most of it. S-lb - Respondents who did not receive a Medication Guide or answered don?t know? or who received a Medication Guide and read only some of it or answered don?t know.? S-la 54" Read most of Med Guide Read some or none of Demonstrated Understanding Med Guide 0 correct responses 5 2.6 5 13.9 1 correct response 15 7.8 6 16.7 2 correct responses 60 31.1 14 38.9 3 correct responses 113 58.5 11 30.6 Average number of correct responses 2.5 (2.3. 3.0) 1.9 (1.5. 3.0) One-sided 95 con?dence interval using the normal approximation to the Poisson distribution. Client: TRIG Project: TIRF Wave 3 Report Run Date and Time: 10/30/2014 2:18 PM Page 1 of 1 TABLE 8.1.1 PRIMARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #3 IN ELIGIBLE AND COMPLETE RESPONDENTS RISK MESSAGE 3: TIRF NIEDICINES SHOULD BE TAKEN EXACTLY AS PRESCRIBED BY THE HEALTHCARE PROVIDER. SUB-GROUP ANALYSIS 1: READING MEDICATION GUIDE (QUESTION 18, QUESTION 23, AND QUESTION 24): S-la - Respondents who received the Medication Guide and read at least most of it. S-lb - Respondents who did not receive a Medication Guide or answered don?t know? or who received a Medication Guide and read only some of it or answered don?t know.? S?la S?lb Read most of Med Guide Readgf?g?ggm 0f Question N=l93 Question 12: Please answer True, False, or I don?t know for each of the following statements. 12b: If a patient stops taking around?the?clock opioid pain medicine, they must also stop taking the TIRF medicine. 40.9 13.9 True 79 (33.9. 48.2) 5 (4.7. 29.5) False 46 23.8 12 33.3 I don't know 68 35.2 19 52.8 Question 13: Please answer True, False, or I don?t know for each statement about the TIRF medicine that was most recently prescribed for you. 13c: TIRF medicines should be taken exactly as prescribed by the doctor. 100.0 94.4 Tm" 193 (98.1. 100.0) 34 (81.3. 99.3) False 0 0.0 2 5.6 I don't know 0 0.0 0 0.0 Client: TRIG Project: TIRF Wave3 Report Run Date and Time: 10/30/2014 2:19 PM Page 1 of 2 2 Question S-lb S-la Read some or none of Read most of Med Guide . N-l93 Med Guide (95% CI) (95% CI) Question 17: Please answer True, False, or I don?t know for each statement about the TIRF medicine that was most recently prescribed for you. 17b: It is OK to take TIRF medicines for short-term pain that will go away in a few days. 87.0 61.1 False 168 (81.5. 91.4) 22 (43.5. 76.9) True 10 5.2 2 5.6 I don?t know 15 7.8 12 33.3 Correct response Note: All con?dence intervals are exact binomial 95% con?dence intervals. Client: TRIG Project: TIRF Wave3 Report Run Date and Time: 10/30/2014 2:19 PM Page 2 of 2 3 TABLE 8.2.1 SECONDARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #3 IN ELIGIBLE AND COMPLETE RESPONDENTS KEY RISK MESSAGE 3: TIRF MEDICINES SHOULD BE TAKEN EXACTLY AS PRESCRIBED BY THE HEALTHCARE PROVIDER. SUB-GROUP ANALYSIS 1: READING MEDICATION GUIDE (QUESTION 18, QUESTION 23, AND QUESTION 24): S-la - Respondents who received the Medication Guide and read at least most of it. S-lb - Respondents who did not receive a Medication Guide or answered don?t know? or who received a Medication Guide and read only some of it or answered don?t know.? S-la 541? Read most of Med Guide Read some or none of Demonstrated Understanding Med Guide 0 correct responses 0 0.0 0 0.0 1 conect response 16 8.3 14 38.9 2 correct responses 107 55.4 19 52.8 3 correct responses 70 36.3 3 8.3 Average number of correct responses 2.3 (2.1. 3.0) 1.7 (1.3. 3.0) One-sided 95 con?dence interval using the normal approximation to the Poisson distribution. Client: TRIG Project: TIRF Wave3 Report Run Date and Time: 10/30/2014 2:20 PM Page 1 of 4 TABLE 9.1.1 PRIMARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #4 IN ELIGIBLE AND COMPLETE RESPONDENTS RISK MESSAGE 4: PATIENTS SHOULD NOT SWITCH FROM A TIRF MEDICINE TO ANOTHER MEDICINE THAT CONTAINS FENTANYL WITHOUT TALKING TO A HEALTHCARE PROVIDER. SUB-GROUP ANALYSIS 1: READING MEDICATION GUIDE (QUESTION 18, QUESTION 23, AND QUESTION 24): S-la - Respondents who received the Medication Guide and read at least most of it. S-lb - Respondents who did not receive a Medication Guide or answered don?t know? or who received a Medication Guide and read only some of it or answered don?t know.? S?la S-lb Read most of Med Guide Read??giggigzne of Question N=l93 Question 12: Please answer True, False, or I don?t know for each of the following statements. 12c: It is safe to switch to another medicine that contains fentanyl without talking to a healthcare provider ?rst. 97.4 94.4 False 188 (94.1. 99.2) 34 (81.3. 99.3) True 2 1.0 0 0.0 I don't know 3 1.6 2 5.6 Correct response Note: All con?dence intervals are exact binomial 95% con?dence intervals. Client: TRIG Project: TIRF Wave3 Report Run Date and Time: 10/30/2014 2:20 PM Page 1 of 5 TABLE 10.1.1 PRIMARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #5 IN ELIGIBLE AND COMPLETE RESPONDENTS KEY RISK MESSAGE 5: PATIENTS SHOULD NOT GIVE TIRF MEDICINES TO ANYONE ELSE EVEN IF THEY HAVE THE SAME SUB-GROUP ANALYSIS 1: READING MEDICATION GUIDE (QUESTION 18, QUESTION 23, AND QUESTION 24): S-la - Respondents who received the Medication Guide and read at least most of it. S-lb - Respondents who did not receive a Medication Guide or answered don?t know? or who received a Medication Guide and read only some of it or answered don?t know.? S-la S-lb Read most of Med Guide ?$133323: ne of Question N=l93 Question 12: Please answer True, False, or I don?t know for each of the following statements. 12d: A patient may give TIRF medicines to another person if they have the same as the patient. 99.0 100.0 False 191 (96.3. 99.9) 36 (90.3. 100.0) True 1 0.5 0 0.0 I don?t know 1 0.5 0 0.0 Question 17: Please answer True, False, or I don?t know for each statement about the TIRF medicine that was most recently prescribed for you. 17a: Selling or giving away TIRF medicines is against the law. 99.5 97.2 True 192 (97.1. 100.0) 35 (85.5. 99.9) False 1 0.5 0 0.0 I don?t know 0 0.0 1 2.8 Correct response Note: All con?dence intervals are exact binomial 95% con?dence intervals. Client: TRIG Project: TIRF Wave3 Report Run Date and Time: 10/30/2014 2:21 PM Page 1 of 6 TABLE 10.2.1 IN ELIGIBLE AND COMPLETE RESPONDENTS KEY RISK MESSAGE 5: PATIENTS SHOULD NOT GIVE TIRF MEDICINES TO ANYONE ELSE EVEN IF THEY HAVE THE SAME SECONDARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #5 SUB-GROUP ANALYSIS 1: READING MEDICATION GUIDE (QUESTION 18, QUESTION 23, AND QUESTION 24): S-la - Respondents who received the Medication Guide and read at least most of it. S-lb - Respondents who did not receive a Medication Guide or answered don?t know? or who received a Medication Guide and read only some of it or answered don?t know.? S-la S-lb Read most of Med Guide Read some or none of Demonstrated Understanding Med Guide 0 correct responses 0 0.0 0 0.0 1 conect response 3 1.6 1 2.8 2 correct responses 190 98.4 35 97.2 Average number of correct responses 2.0 (1.8. 2.0) 2.0 (1.6. 2.0) One-sided 95 con?dence interval using the normal approximation to the Poisson distribution. Client: TRIG Project: TIRF Wave 3 Report Run Date and Time: 10/30/2014 2:22 PM Page 1 of 7 TABLE 11.1.1 PRIMARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #6 IN ELIGIBLE AND COMPLETE RESPONDENTS KEY RISK MESSAGE 6: TIRF MEDICINES SHOULD BE STORED IN A SAFE PLACE AWAY FROM CHILDREN AND PROPERLY DISPOSED. SUB-GROUP ANALYSIS 1: READING MEDICATION GUIDE (QUESTION 18, QUESTION 23, AND QUESTION 24): S-la - Respondents who received the Medication Guide and read at least most of it. S-lb - Respondents who did not receive a Medication Guide or answered don?t know? or who received a Medication Guide and read only some of it or answered don?t know.? la S?lb . Read some or none of Read most of Med Guide Med Guide Question (95% CI) (95% CI) Question 13: Please answer True, False, or I don?t know for each statement about the TIRF medicine that was most recently prescribed for you. 13a: TIRF medicines should be stored in a safe place out of the reach of children. 99.0 100.0 Tm" 191 (96.3. 99.9) 36 (90.3. 100.0) False 0.5 0 0.0 I don't know 1 0.5 0 0.0 Question 17: Please answer True, False, or I don?t know for each statement about the TIRF medicine that was most recently prescribed for you. 17c: TIRF medicines must be disposed of as described in the speci?c product?s Medication Guide. 95.9 83.3 Tm" 185 (92.0. 98.2) 30 (67.2. 93.6) False 0 0.0 0 0.0 I don't know 8 4.1 6 16.7 Client: TRIG Project: TIRF Wave3 Report Run Date and Time: 10/30/2014 2:23 PM Page 1 of 2 8 S-lb S-la Read some or none of Read most of Med Guide . Med Guide Question (95% CI) (95% CI) l7e: A TIRF medicine can cause an overdose and death in any child who takes it. 91.2 86.1 True 176 (86.3. 94.8) 31 (70.5. 95.3) False 1 0.5 1 2.8 I don't know 16 8.3 4 11.1 Question 14: What should you do if an adult who has not been prescribed a TIRF medicine takes a TIRF medicine? (Please select one.) . 89.6 80.6 . Get emergency help ught away. 173 (84.4. 93.6) 29 (64.0. 91.8) Do nothing. 0 0.0 0 0.0 Walt an hour and see If the person don't know. 15 7.8 5 13.9 Correct response Note: All con?dence intervals are exact binomial 95% con?dence intervals. Client: TRIG Project: TIRF Wave3 Report Run Date and Time: 10/30/2014 2:23 PM Page 2 of 2 9 TABLE 11.2.1 SECONDARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #6 IN ELIGIBLE AND COMPLETE RESPONDENTS KEY RISK MESSAGE 6: TIRF MEDICINES SHOULD BE STORED IN A SAFE PLACE AWAY FROM CHILDREN AND PROPERLY DISPOSED. SUB-GROUP ANALYSIS 1: READING MEDICATION GUIDE (QUESTION 18, QUESTION 23, AND QUESTION 24): S-la - Respondents who received the Medication Guide and read at least most of it. S-lb - Respondents who did not receive a Medication Guide or answered don?t know? or who received a Medication Guide and read only some of it or answered don?t know.? S-la S-lb Read most of Med Guide Read some or none of Demonstrated Understanding Med Guide 0 correct responses 0 0.0 0 0.0 1 conect response 1 0.5 1 2.8 2 correct responses 5 2.6 4 11.1 3 correct responses 34 17.6 7 19.4 4 correct responses 153 79.3 24 66.7 Average number of correct responses 3.8 (3.5. 4.0) 3.5 (3.0. 4.0) One-sided 95% con?dence interval using the normal approximation to the Poisson distribution. Client: TRIG Project: TIRF Wave 3 Report Run Date and Time: 10/30/2014 2:24 PM Page 1 of TABLE 6.1.2 PRIMARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #1 IN ELIGIBLE AND COMPLETE RESPONDENTS KEY RISK MESSAGE 1: TIRF MEDICINES CAN CAUSE LIFE-THREATENING BREATHING PROBLEMS THAT CAN LEAD TO DEATH. SUB-GROUP ANALYSIS 2: UNDERSTANDING OF MEDICATION GUIDE (QUESTION 18, 23, AND 25) • S-2a - Respondents who understood all of it or most of it • S-2b – Respondents who understood some of it • S-2c – Respondents who answered None or “I don’t know” • S-2d - Respondents who answered “I don’t know” to receipt or reading of the Medication Guide. Client: TRIG Project: TIRF Wave 3 Report Run Date and Time: 11/3/2014 9:20 AM Page   1 of 2 FDA_2021 13d: TIRF medicines can cause life?threatening breathing problems that can lead to death. 92.4 88.0 85.0 True 170 (87,6, 95.8) 22 (68.8, 97.5) 0 17 (62.1, 96.8) False 0don't know 13 7.1 3 12.0 0 - 3 15.0 Correct response Note: All con?dence intervals are exact binomial 95% con?dence intervals. Client: TRIG Project: TIRF Wave 3 Report Run Date and Time: 11/3/2014 9:20 AM Page 2 of 2 TABLE 7.1.2 PRIMARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #2 IN ELIGIBLE AND COMPLETE RESPONDENTS KEY RISK MESSAGE 2: PATIENTS SHOULD NOT TAKE TIRF MEDICINES IF THEY ARE NOT OPIOID TOLERANT. SUB-GROUP ANALYSIS 2: UNDERSTANDING OF MEDICATION GUIDE (QUESTION 18, 23, AND 25) S-2a - Respondents who understood all of it or most of it S-2b Respondents who understood some of it S-2c - Respondents who answered None or don?t know? 0 S-2d - Respondents who answered don?t know? to receipt or reading of the Medication Guide. S-2a Understood All S?2b S?2c Did not Get or Understood Some None/I don?t know Read Medication or Most . (95% CI) (95% CI) (95% CI) (95% CI) Question 11: Please answer True, False, or I don?t know for the following statement: TIRF medicines should only be taken by patients who are opioid tolerant. 89.1 68.0 70.0 True ?1 164 (83.7. 17 (46.5. 0 - 14 (45.7. 93.2) 85.1) 88.1) False 2 1.1 3 12.0 0 - 5.0 I don?t know 18 9.8 5 20.0 0 - 5 25.0 Client: TRIG Project: TIRF Wave3 Report Run Date and Time: 11/3/2014 9:22 AM Page 1 of 2 Question S-2d S-2a S?2b S?2c Did not Get or Understood Understood Some None/I don?t know Read Medication or Most . Guide (95% CI) (95% CI) (95% CI) (95% CI) Question 12: Please answer True, False, or I don?t know for each of the following statements. 12a: Opioid tolerant means that a patient is already taking other opioid pain medicines around-the-clock and their body is used to these medicines. 84.8 64.0 75.0 True ?1 156 (78.8. 16 (42.5. 0 - 15 (50.9. 89.6) 82.0) 91.3) False 13 7.1 3 12.0 0 3 15.0 I don't know 15 8.2 6 24.0 0 - 2 10.0 Question 13: Please answer True, False, or I don?t know for each statement about the TIRF medicine that was most recently prescribed for you. 13b: It is OK for patients to take TIRF medicines for headache pain. 72.8 60.0 50.0 False ?1 134 (65.8. 15 (38.7. 0 - 10 (27.2. 79.1) 78.9) 72.8) True 10.0 I don't know 36 19.6 10 40.0 0 8 40.0 Correct response Note: All con?dence intervals are exact binomial 95% con?dence intervals. Client: TRIG Project: TIRF Wave3 Report Run Date and Time: 11/3/2014 9:22 AM Page 2 of 2 TABLE 7.2.2 SECONDARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #2 IN ELIGIBLE AND COMPLETE RESPONDENTS KEY RISK MESSAGE 2: PATIENTS SHOULD NOT TAKE TIRF MEDICINES IF THEY ARE NOT OPIOID TOLERANT. SUB-GROUP ANALYSIS 2: UNDERSTANDING OF MEDICATION GUIDE (QUESTION 18, 23, AND 25) S-2a - Respondents who understood all of it or most of it S-2b Respondents who understood some of it S-2c - Respondents who answered None or don?t know? 0 S-2d - Respondents who answered don?t know? to receipt or reading of the Medication Guide. S-2a S-2d Understood All S-2b S-2c Did not Get or Understood Some None/I don?t know Read Medication Demonstrated Understanding or Guide 0 correct responses 15.0 1 correct response 13 7.1 6 24.0 0 - 2 10.0 2 correct responses 57 31.0 9 36.0 0 - 8 40.0 3 correct responses 109 59.2 8 32.0 0 - 7 35.0 Average number of correct responses 2.5 (2.3. 1.9 (1.5. - 2.0 (1.4. 3.0) ?1 3.0) ?1 3.0) ?1 One-sided 95 con?dence interval using the normal approximation to the Poisson distribution. Client: TRIG Project: TIRF Wave 3 Report Run Date and Time: 11/3/2014 11:00 AM Page 1 of TABLE 8.1.2 PRIMARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #3 IN ELIGIBLE AND COMPLETE RESPONDENTS RISK MESSAGE 3: TIRF MEDICINES SHOULD BE TAKEN EXACTLY AS PRESCRIBED BY THE HEALTHCARE PROVIDER. SUB-GROUP ANALYSIS 2: UNDERSTANDING OF MEDICATION GUIDE (QUESTION 18, 23, AND 25) S-2a - Respondents who understood all of it or most of it S-2b Respondents who understood some of it S-2c Respondents who answered None or don?t know? 0 S-2d - Respondents who answered don?t know? to receipt or reading of the Medication Guide. S-2a S-2d Understood All S?2b S-2c Did not Get or Understood Some None/I don?t know Read Medication or Most . (95% CI) (95% CI) (95% CI) (95% CI) Question 12: Please answer True, False, or I don?t know for each of the following statements. 12b: If a patient stops taking around?the?clock opioid pain medicine, they must also stop taking the TIRF medicine. 40.2 28.0 15.0 True 74 (33.1. 47.7) 7 (12.1. 49.4) 0 3 (3.2. 37.9) False 48 26.1 3 12.0 0 - 7 35.0 I don't know 62 33.7 15 60.0 0 - 10 50.0 Question 13: Please answer True, False, or I don?t know for each statement about the TIRF medicine that was most recently prescribed for you. Client: TRIG Project: TIRF Wave3 Report Run Date and Time: 11/3/2014 9:23 AM Page 1 of 2 S-2d S-2a S?2b S-2c Did not Get or Understood Understood Some None/I don?t know Read Medication or Most . Question Guide (95% CI) (95% CI) (95% CI) (95% CI) 13c: TIRF medicines should be taken exactly as prescribed by the doctor. 100.0 100.0 90.0 True ?1 184 (98.0. 25 0 - 18 100.0) (86.3. 100.0) (68.3. 98.8) False 10.0 I don't know 0 0.0 0 0.0 - 0 0.0 Question 17: Please answer True, False, or I don?t know for each statement about the TIRF medicine that was most recently prescribed for you. 17b: It is OK to take TIRF medicines for short-term pain that will go away in a few days. 85.9 76.0 65.0 - False 158 (80.0. 90.6) 19 (54.9. 90.6) 0 13 (40.8. 84.6) True 10.0 I don't know 16 8.7 6 24.0 0 - 5 25.0 Correct response Note: All con?dence intervals are exact binomial 95% con?dence intervals. Client: TRIG Project: TIRF Wave3 Report Run Date and Time: 11/3/2014 9:23 AM Page 2 of 2 TABLE 8.2.2 SECONDARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #3 IN ELIGIBLE AND COMPLETE RESPONDENTS KEY RISK MESSAGE 3: TIRF MEDICINES SHOULD BE TAKEN EXACTLY AS PRESCRIBED BY THE HEALTHCARE PROVIDER. SUB-GROUP ANALYSIS 2: UNDERSTANDING OF MEDICATION GUIDE (QUESTION 18, 23, AND 25) S-2a - Respondents who understood all of it or most of it S-2b Respondents who understood some of it S-2c - Respondents who answered None or don?t know? 0 - Respondents who answered don?t know? to receipt or reading of the Medication Guide. S-2a S-2d Understood All S-2b S-2c Did not Get or Understood Some None/I don?t know Read Medication Demonstrated Understanding or Guide 0 correct responses correct response 17 9.2 6 24.0 0 - 7 35.0 2 correct responses 102 55.4 12 48.0 0 - 12 60.0 3 correct responses 65 3 5.3 7 28.0 0 - 1 5.0 Average number of correct responses 2.3 (2.1. 2.0 (1.6. - 1.7 (1.2. 3.0) ?1 3.0) ?1 3.0) ?1 One-sided 95 con?dence interval using the normal approximation to the Poisson distribution. Client: TRIG Project: TIRF Wave3 Report Run Date and Time: 11/3/2014 9:24 AM Page 1 of TABLE 9.1.2 PRIMARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #4 IN ELIGIBLE AND COMPLETE RESPONDENTS RISK MESSAGE 4: PATIENTS SHOULD NOT SWITCH FROM A TIRF MEDICINE TO ANOTHER MEDICINE THAT CONTAINS FENTANYL WITHOUT TALKING TO A HEALTHCARE PROVIDER. SUB-GROUP ANALYSIS 2: UNDERSTANDING OF MEDICATION GUIDE (QUESTION 18, 23, AND 25) • S-2a - Respondents who understood all of it or most of it • S-2b – Respondents who understood some of it • S-2c – Respondents who answered None or “I don’t know” • S-2d - Respondents who answered “I don’t know” to receipt or reading of the Medication Guide. Client: TRIG Project: TIRF Wave 3 Report Run Date and Time: 11/3/2014 9:25 AM Page   1 of 2 FDA_2029 2a S-2d Understood All S?2b S-2c Did not Get or Understood Some None/I don?t know Read Medication ?r N-25 N-0 'd Question - Ill (95% CI) (95% CI) (95% CI) (95% CI) Question 12: Please answer True, False, or I don?t know for each of the following statements. 12c: It is safe to switch to another medicine that contains fentanyl without talking to a healthcare provider ?rst. 96.7 100.0 95.0 False 178 (93.0. 98.8) 25 (86.3. 100.0) 0 19 (75.1. 99.9) True 1don?t know 4 2.2 0 0.0 - 1 5.0 Correct response Note: All con?dence intervals are exact binomial 95% con?dence intervals. Client: TRIG Project: TIRF Wave3 Report Run Date and Time: 11/3/2014 9:25 AM Page 2 of TABLE 10.1.2 KEY RISK MESSAGE 5: PATIENTS SHOULD NOT GIVE TIRF MEDICINES TO ANYONE ELSE EVEN IF THEY HAVE THE SAME SUB-GROUP ANALYSIS 2: UNDERSTANDING OF MEDICATION GUIDE (QUESTION 18, 23, AND 25) S-2a - Respondents who understood all of it or most of it S-2b Respondents who understood some of it S-2c Respondents who answered None or don?t know? S-2d - Respondents who answered don?t know? to receipt or reading of the Medication Guide. PRIMARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #5 IN ELIGIBLE AND COMPLETE RESPONDENTS Underss'tzgd S-2b S?2c Did not Get or Question 01: Undergrz): Some None/I 12:1? know Read af?liation CI) CI) (950? CI) CI) Question 12: Please answer True, False, or I don?t know for each of the following statements. 12d: A patient may give TIRF medicines to another person if they have the same as the patient. 100.0 False 182 (96.939999) 25 (86.13%800) 0 20 {33:35 True don't know 0.0 Client: TRIG Project: TIRF Wave3 Report Run Date and Time: 11/3/2014 9:28 AM Page 1 of 2 Question 17: Please answer True, False, or I don?t know for each statement about the TIRF medicine that was most recently prescribed for you. 17a: Selling or giving away TIRF medicines is against the law. 100.0 96.0 95.0 True ?1 184 (98.0. 24 19 100.0) (79.6. 99.9) (75.1. 99.9) False don't know 0 0.0 0.0 1 Correct response Note: All con?dence intervals are exact binomial 95% con?dence intervals. Client: TRIG Project: TIRF Wave3 Report Run Date and Time: 11/3/2014 9:28 AM Page 2 of 2 TABLE 10.2.2 IN ELIGIBLE AND COMPLETE RESPONDENTS KEY RISK MESSAGE 5: PATIENTS SHOULD NOT GIVE TIRF MEDICINES TO ANYONE ELSE EVEN IF THEY HAVE THE SAME SUB-GROUP ANALYSIS 2: UNDERSTANDING OF MEDICATION GUIDE (QUESTION 18, 23, AND 25) S-2a - Respondents who understood all of it or most of it S-2b Respondents who understood some of it S-2c Respondents who answered None or don?t know? 0 S-2d - Respondents who answered don?t know? to receipt or reading of the Medication Guide. SECONDARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #5 S-2d Undefs-tzoahd All 5'2? 1:223? or Understood Some None/I don?t know d' . Demonstrated Understanding or 0? lcatlon Guide 0 correct responses correct response correct responses 182 98.9 24 96.0 0 - 19 95.0 Average number of correct responses 2.0 (1.8. 2.0 (1.5. - 2.0 (1.4. One-sided 95 con?dence interval using the normal approximation to the Poisson distribution. Client: TRIG Project: TIRF Wave 3 Report Run Date and Time: 11/3/2014 9:33 AM Page 1 of TABLE 11.1.2 PRIMARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #6 IN ELIGIBLE AND COMPLETE RESPONDENTS KEY RISK MESSAGE 6: TIRF MEDICINES SHOULD BE STORED IN A SAFE PLACE AWAY FROM CHILDREN AND PROPERLY DISPOSED. SUB-GROUP ANALYSIS 2: UNDERSTANDING OF MEDICATION GUIDE (QUESTION 18, 23, AND 25) • S-2a - Respondents who understood all of it or most of it • S-2b – Respondents who understood some of it • S-2c – Respondents who answered None or “I don’t know” • S-2d - Respondents who answered “I don’t know” to receipt or reading of the Medication Guide. Client: TRIG Project: TIRF Wave 3 Report Run Date and Time: 11/3/2014 9:31 AM Page   1 of 3 FDA_2034 Question S-2a S-2d Understood All 84" S-ZC Did not (fet or or Most Understood Some None/I don?t know Read Medlcation Guide (95% CI) (95% CI) (95% CI) (95% CI) Question 13: Please answer True, False, or I don?t know for each statement about the TIRF medicine that was most recently prescribed for you. 13a: TIRF medicines should be stored in a safe place out of the reach of children. 98 9 100.0 100.0 True ?1 182 (961 '99 9) 25 (86.3. 0 - 20 (83.2. 100.0) 100.0) False don't know 0.0 Question 17: Please answer True, False, or I don?t know for each statement about the TIRF medicine that was most recently prescribed for you. 17c: TIRF medicines must be disposed of as described in the speci?c product?s Medication Guide. 96.2 88.0 80.0 - True 177 (92.3. 98.5) 22 (68.8. 97.5) 0 16 (56.3. 94.3) False don't know 7 3.8 3 12.0 0 - 4 20.0 Client: TRIG Project: TIRF Wave3 Report Run Date and Time: 11/3/2014 9:31 AM Page 2 of 3 S-2d S-2a S?2b S?2c Did not Get or Understood Understood Some None/I don?t know Read Medication or Most . (95% CI) (95% CI) (95% CI) (95% CI) 17e: A TIRF medicine can cause an overdose and death in any child who takes it. 91.3 80.0 95.0 - True 168 (86.3. 94.9) 20 (59.3. 93.2) 0 19 (75.1. 99.9) False don't know 14 7.6 5 20.0 0 - 5.0 Question 14: What should you do if an adult who has not been prescribed a TIRF medicine takes a TIRF medicine? (Please select one.) Get emergency help right 88.6 88.0 85.0 away. ?1 163 (83.1. 92.8) 22 (68.8. 97.5) 0 17 (62.1. 96.8) Do nothing0.0 Walt an hour and see don?t know10.0 Correct response Note: All con?dence intervals are exact binomial 95% con?dence intervals. Client: TRIG Project: TIRF Wave 3 Report Run Date and Time: 11/3/2014 9:31 AM Page 3 of 3 TABLE 11.2.2 IN ELIGIBLE AND COMPLETE RESPONDENTS KEY RISK MESSAGE 6: TIRF MEDICINES SHOULD BE STORED IN A SAFE PLACE AWAY FROM CHILDREN AND PROPERLY DISPOSED. SUB-GROUP ANALYSIS 2: UNDERSTANDING OF MEDICATION GUIDE (QUESTION 18, 23, AND 25) S-2a - Respondents who understood all of it or most of it S-2b Respondents who understood some of it S-2c - Respondents who answered None or don?t know? 0 S-2d - Respondents who answered don?t know? to receipt or reading of the Medication Guide. SECONDARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #6 S-2a S-2d Understood All S-2b S-2c Did not Get or Understood Some None/I don?t know Read Medication Demonstrated Understanding or Guide 0 correct responses correct response correct responses correct responses 29 15.8 9 36.0 0 - 3 15.0 4 correct responses 147 79.9 15 60.0 0 - 15 75.0 Average number of correct responses 3.8 (3.5. 3.6 (2.9. - 3.6 (2.9. 4.0) ?1 4.0) ?1 4.0) [11 One-sided 95% con?dence interval using the nonnal approximation to the Poisson distribution. Client: TRIG Project: TIRF Wave3 Report Run Date and Time: 11/3/2014 9:32 AM Page 1 of TABLE 6.1.3 PRIMARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #1 IN ELIGIBLE AND COMPLETE RESPONDENTS KEY RISK MESSAGE 1: TIRF MEDICINES CAN CAUSE LIFE-THREATENING BREATHING PROBLEMS THAT CAN LEAD TO DEATH. SUB-GROUP ANALYSIS 3: TIME TO COMPLETE SURVEY - INTERNET: S-3a - <10 min 0 S-S-3c - 20 min Question S-3a S?3b S-min (95% CI) (95% CI) (95% CI) Question 13: Please answer True, False, or I don?t know for each statement about the TIRF medicine that was most recently prescribed for you. 13d: TIRF medicines can cause life-threatening breathing problems that can lead to death. 88.0 92.6 100.0 True ?1 44 (75.7. 75 (84.6. 20 (83.2. 95.5) 97.2) 100.0) False don?t know 6 12.0 6 7.4 0 0.0 Correct response Note: All con?dence intervals are exact binomial 95% con?dence intervals. Client: TRIG Project: TIRF Wave3 Report Run Date and Time: 10/31/2014 1:48 PM Page 1 of TABLE 7.1.3 PRIMARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #2 IN ELIGIBLE AND COMPLETE RESPONDENTS KEY RISK MESSAGE 2: PATIENTS SHOULD NOT TAKE TIRF MEDICINES IF THEY ARE NOT OPIOID TOLERANT. SUB-GROUP ANALYSIS 3: TIME TO COMPLETE SURVEY - INTERNET: S-3a - <10 min 0 S-S-3c - 20 min S-3a S?3b S-3c <10 min 10 to <20 min 220 min (95% CI) (95% CI) (95% CI) Question 11: Please answer True, False, or I don?t know for the following statement: TIRF medicines should only be taken by patients who are opioid tolerant. 84.0 91.4 90.0 True ?1 42 (70.9. 74 (83.0. 18 (68.3. 92.8) 96.5) 98.8) False don't know 7 14.0 5 6.2 2 10.0 Question 12: Please answer True, False, or I don?t know for each of the following statements. 12a: Opioid tolerant means that a patient is already taking other opioid pain medicines around- the-clock and their body is used to these medicines. 80.0 87.7 80.0 True ?1 40 (66.3. 71 (78.5. 16 (56.3. 90.0) 93.9) 94.3) False 7 14.0 4 4.9 2 10.0 I don't know 3 6.0 6 7.4 2 10.0 Client: TRIG Project: TIRF Wave3 Report Run Date and Time: 11/3/2014 1:04 PM Page 1 of 2 Question S?3a S?3b S-3c <10 min 10 to <20 min 220 min N=8l (95% CI) (95% CI) (95% CI) Question 13: Please answer True, False, or I don?t know for each statement about the TIRF medicine that was most recently prescribed for you. 13b: It is OK for patients to take TIRF medicines for headache pain. 68.0 71.6 85.0 False ?1 34 (53.3. 58 (60.5. 17 (62.1. 80.5) 81.1) 96.8) True don't know 12 24.0 17 21.0 3 15.0 Correct response Note: All con?dence intervals are exact binomial 95% con?dence intervals. Client: TRIG Project: TIRF Wave3 Report Run Date and Time: 11/3/2014 1:04 PM Page 2 of 2 TABLE 7.2.3 SECONDARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #2 IN ELIGIBLE AND COMPLETE RESPONDENTS KEY RISK MESSAGE 2: PATIENTS SHOULD NOT TAKE TIRF MEDICINES IF THEY ARE NOT OPIOID TOLERANT. SUB-GROUP ANALYSIS 3: TIME TO COMPLETE SURVEY - INTERNET: S-3a - <10 min 0 S-S-3c - 220 min S-3a S-3b S-min Demonstrated Understanding N=8l 0 correct responses correct response 4 8.0 6 7.4 3 15.0 2 correct responses 20 40.0 19 23.5 3 15.0 3 correct responses 24 48.0 53 65.4 14 70.0 Average number of correct responses 2.3 (2.0. 2.5 (2.2. 2.6 (2.0. 30> ?1 3.0) ?1 3.0) ?1 [?011e-sided 95 con?dence interval using the normal approximation to the Poisson distribution. Client: TRIG Project: TIRF Wave 3 Report Run Date and Time: 10/31/2014 1:57 PM Page 1 of TABLE 8.1.3 PRIMARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #3 IN ELIGIBLE AND COMPLETE RESPONDENTS RISK MESSAGE 3: TIRF NIEDICINES SHOULD BE TAKEN EXACTLY AS PRESCRIBED BY THE HEALTHCARE PROVIDER. SUB-GROUP ANALYSIS 3: TIME TO COMPLETE SURVEY - INTERNET: S-3a - <10 min 0 S-S-3c - 220 min Question S-3a S?3b S-3c <10 min 10 to <20 min 220 min N=8l (95% CI) (95% CI) (95% CI) Question 12: Please answer True, False, or I don?t know for each of the following statements. 12b: If a patient stops taking around-the-clock opioid pain medicine, they must also stop taking the TIRF medicine. 46.0 40.7 50.0 True ?1 23 (31.8. 33 (29.9. 10 (27.2. 60.7) 52.2) 72.8) False 11 22.0 21 25.9 4 20.0 1 don't know 16 32.0 27 33.3 6 30.0 Question 13: Please answer True, False, or I don?t know for each statement about the TIRF medicine that was most recently prescribed for you. 13c: TIRF medicines should be taken exactly as prescribed by the doctor. 100.0 98.8 100.0 Tnle ?1 50 (92.9. 80 (93.3. 20 (83.2. 100.0) 100.0) 100.0) False don?t know 0 0.0 0 0.0 0 0.0 Client: TRIG Project: TIRF Wave3 Report Run Date and Time: 10/31/2014 1:58 PM Page 1 of 2 Question S?3a S?3b S-3c <10 min 10 to <20 min 220 min N=8l (95% CI) (95% CI) (95% CI) Question 17: Please answer True, False, or I don?t know for each statement about the TIRF medicine that was most recently prescribed for you. 17b: It is OK to take TIRF medicines for short-term pain that will go away in a few days. 82.0 85.2 95.0 False ?1 41 (68.6. 69 (75.6. 19 (75.1. 91.4) 92.1) 999) True don't know 6 12.0 7 8.6 0 0.0 Correct response Note: All con?dence intervals are exact binomial 95% con?dence intervals. Client: TRIG Project: TIRF Wave3 Report Run Date and Time: 10/31/2014 1:58 PM Page 2 of 2 TABLE 8.2.3 SECONDARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #3 IN ELIGIBLE AND COMPLETE RESPONDENTS KEY RISK MESSAGE 3: TIRF MEDICINES SHOULD BE TAKEN EXACTLY AS PRESCRIBED BY THE HEALTHCARE PROVIDER. SUB-GROUP ANALYSIS 3: TIME TO COMPLETE SURVEY - INTERNET: S-3a - <10 min 0 S-3b - 10 to<20 min 0 S-3c - 220 min S-3a S-3b S-3c <10 min 10 to <20 min 220 min Demonstrated Understanding N=8l 0 correct responses correct response 7 14.0 9 11.1 0 0.0 2 correct responses 22 44.0 43 53.1 11 55.0 3 correct responses 21 42.0 29 35.8 9 45.0 Average number of correct responses 2.3 (1.9. 2.2 (2.0. 2.5 (1.9. 3.0) ?1 3.0) ?1 3.0) ?1 [?011e-sided 95 con?dence interval using the normal approximation to the Poisson distribution. Client: TRIG Project: TIRF Wave 3 Report Run Date and Time: 10/31/2014 1:59 PM Page 1 of TABLE 9.1.3 PRIMARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #4 IN ELIGIBLE AND COMPLETE RESPONDENTS RISK MESSAGE 4: PATIENTS SHOULD NOT SWITCH FROM A TIRF MEDICINE TO ANOTHER MEDICINE THAT CONTAINS FENTANYL WITHOUT TALKING TO A HEALTHCARE PROVIDER. SUB-GROUP ANALYSIS 3: TIME TO COMPLETE SURVEY - INTERNET: S-3a - <10 min 0 S-3b - 10 to<20 min 0 S-3c - 220 min S?3a S?3b S?3c <10 min 10 to <20 min 220 min Question N=8l (95% CI) (95% CI) (95% CI) IQuestion 12: Please answer True, False, or I don?t know for each of the following statements. 12c: It is safe to switch to another medicine that contains fentanyl without talking to a healthcare provider ?rst. 100.0 95 1 100.0 False ?1 50 (92.9. 77 20 (83.2. 100.0) (87'8? 986) 100.don't know 0 0.0 2 2.5 0 0.0 Conect response Note: All con?dence intervals are exact binomial 95% con?dence intervals. Client: TRIG Project: TIRF Wave3 Report Run Date and Time: 11/3/2014 9:09 AM Page 1 of 1 TABLE 10.1.3 PRIMARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #5 IN ELIGIBLE AND COMPLETE RESPONDENTS KEY RISK MESSAGE 5: PATIENTS SHOULD NOT GIVE TIRF MEDICINES TO ANYONE ELSE EVEN IF THEY HAVE THE SAME SUB-GROUP ANALYSIS 3: TIME TO COMPLETE SURVEY - INTERNET: S-3a - <10 min 0 S-3b - 10 to<20 min 0 S-3c - 220 min S?3a S?3b S-3c <10 min 10 to <20 min 220 min Question N=8l (95% CI) (95% CI) (95% CI) Question 12: Please answer True, False, or I don?t know for each of the following statements. 12d: A patient may give TIRF medicines to another person if they have the same as the patient. 98.0 100.0 100.0 False ?1 49 (89.4. 81 (95.5. 20 (83.2. 99.9) 100.0) 100.0) True don?t know 0 0.0 0 0.0 0 0.0 Question 17: Please answer True, False, or I don?t know for each statement about the TIRF medicine that was most recently prescribed for you. 17a: Selling or giVing away TIRF medicines is against the law. 100.0 98.8 100.0 True ?1 50 (92.9. 80 (93.3. 20 (83.2. 100.0) 100.0) 100.0) False don't know 0 0.0 0 0.0 0 0.0 Correct response Note: All con?dence intervals are exact binomial 95% con?dence intervals. Client: TRIG Project: TIRF Wave3 Report Run Date and Time: 10/31/2014 2:01 PM Page 1 of TABLE 10.2.3 SECONDARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #5 IN ELIGIBLE AND COMPLETE RESPONDENTS KEY RISK MESSAGE 5: PATIENTS SHOULD NOT GIVE TIRF MEDICINES TO ANYONE ELSE EVEN IF THEY HAVE THE SAME SUB-GROUP ANALYSIS 3: TIME TO COMPLETE SURVEY - INTERNET: S-3a - <10 min 0 S-3b - 10 to<20 min 0 S-3c - 220 min S-3a S-3b S-3c <10 min 10 to <20 min 220 min Demonstrated Understanding N=8l 0 correct responses correct response correct responses 49 98.0 80 98.8 20 100.0 Average nlunber of correct responses 2.0 (1.7. 2.0 (1.7. 2.0 (1.5. 2.0) ?1 2.0) ?1 2.0) ?1 ll] One-sided 95 con?dence interval using the normal approximation to the Poisson distribution. Client: TRIG Project: TIRF Wave 3 Report Run Date and Time: 10/31/2014 2:02 PM Page 1 of TABLE 11.1.3 PRIMARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #6 IN ELIGIBLE AND COMPLETE RESPONDENTS KEY RISK MESSAGE 6: TIRF MEDICINES SHOULD BE STORED IN A SAFE PLACE AWAY FROM CHILDREN AND PROPERLY DISPOSED. SUB-GROUP ANALYSIS 3: TIME TO COMPLETE SURVEY - INTERNET: S-3a - <10 min 0 S-3b - 10 to<20 min 0 S-3c - 220 min S-3a S?3b S-3c <10 min 10 to <20 min 220 min (95% CI) (95% CI) (95% CI) Question 13: Please answer True, False, or I don?t know for each statement about the TIRF medicine that was most recently prescribed for you. 13a: TIRF medicines should be stored in a safe place out of the reach of children. 96.0 100.0 100.0 Tme ?1 48 (86.3. 81 (95.5. 20 (83.2. 99.5) 100.0) 100.0) False don?t know 1 2.0 0 0.0 0 0.0 Question 17: Please answer True, False, or I don?t know for each statement about the TIRF medicine that was most recently prescribed for you. 17c: TIRF medicines must be disposed of as described in the speci?c product?s Medication Guide. 92.0 96.3 95.0 True ?1 46 (80.8. 78 (89.6. 19 (75.1. 97.8) 99.2) 99.9) False don?t know 4 8.0 3 3.7 5.0 Client: TRIG Project: TIRF Wave3 Report Run Date and Time: 10/31/2014 2:04 PM Page 1 of 2 S?3a S?3b S-3c <10 min 10 to <20 min 220 min Question N=8l (95% CI) (95% CI) (95% CI) 17e: A TIRF medicine can cause an overdose and death in any child who takes it. 92.0 92.6 85.0 True ?1 46 (80.8. 75 (84.6. 17 (62.1. 97.8) 97.2) 96.8) False 1 2.0 1.2 0 0.0 I don't know 3 6.0 5 6.2 3 15.0 Question 14: What should you do if an adult who has not been prescribed a TIRF medicine takes a TIRF medicine? (Please select one.) Get emergency help 88'0 91?4 95'0 . 44 (75.7. 74 (83.0. 19 (75.1. ?g1? 95.5) 96.5) 99.9) Do nothing. 0 0.0 0 0.0 0 0.0 Wait an hour and see if the person don't know. 4 8.0 4 4.9 1 5.0 Correct response Note: All con?dence intervals are exact binomial 95% con?dence intervals. Client: TRIG Project: TIRF Wave3 Report Run Date and Time: 10/31/2014 2:04 PM Page 2 of 2 TABLE 11.2.3 SECONDARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #6 IN ELIGIBLE AND COMPLETE RESPONDENTS KEY RISK MESSAGE 6: TIRF MEDICINES SHOULD BE STORED IN A SAFE PLACE AWAY FROM CHILDREN AND PROPERLY DISPOSED. SUB-GROUP ANALYSIS 3: TIME TO COMPLETE SURVEY - INTERNET: S-3a - <10 min 0 S-3b - 10 to<20 min 0 S-3c - 220 min S-3a S-3b S-3c <10 min 10 to <20 min 220 min Demonstrated Understanding N=8l 0 correct responses correct response correct responses correct responses 11 22.0 7 8.6 3 15.0 4 correct responses 37 74.0 70 86.4 16 80.0 Average munber of correct responses 3.7 (3.2. 3.8 (3.4. 3.8 (3.0. 4-0) ?1 4.0) ?1 4.0) ?1 One-sided 95% con?dence interval using the nonnal approximation to the Poisson distribution. Client: TRIG Project: TIRF Wave 3 Report Run Date and Time: 10/31/2014 2:05 PM Page 1 of TABLE 6.1.4 PRIMARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #1 IN ELIGIBLE AND COMPLETE RESPONDENTS KEY RISK MESSAGE 1: TIRF MEDICINES CAN CAUSE LIFE-THREATENING BREATHING PROBLEMS THAT CAN LEAD TO DEATH. SUB-GROUP ANALYSIS 4: TIME TO COMPLETE SURVEY - TELEPHONE: S-4a - <10 min 0 S-S-4c - 220 min S-4a S?4b S?4c <10 min 10 to <20 min 220 min Question N=3l (95% CI) (95% CI) (95% CI) Question 13: Please answer True, False, or I don?t know for each statement about the TIRF medicine that was most recently prescribed for you. 13d: TIRF medicines can cause life?threatening breathing problems that can lead to death. 87.2 93.5 True ?1 0 - 41 (74.3. 29 (78.6. 95.2) 99.2) False - 0 0.0 1 3.2 I don't know 0 - 6 12.8 1 3.2 Correct response Note: All con?dence intervals are exact binomial 95% con?dence intervals. Client: TRIG Project: TIRF Wave3 Report Run Date and Time: 10/31/2014 2:06 PM Page 1 of TABLE 7.1.4 PRIMARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #2 IN ELIGIBLE AND COMPLETE RESPONDENTS KEY RISK MESSAGE 2: PATIENTS SHOULD NOT TAKE TIRF MEDICINES IF THEY ARE NOT OPIOID TOLERANT. SUB-GROUP ANALYSIS 4: TIME TO COMPLETE SURVEY - TELEPHONE: S-4a - <10 min 0 S-S-4c - 220 min S?<20 min 220 min (95% CI) (95% CI) (95% CI) Question 11: Please answer True, False, or I don?t know for the following statement: TIRF medicines should only be taken by patients who are opioid tolerant. 83.0 71.0 True ?1 0 - 39 (69.2. 22 (52.0. 92.4) 85.8) False don't know 0 - 7 14.9 7 22.6 Question 12: Please answer True, False, or I don?t know for each of the following statements. 12a: Opioid tolerant means that a patient is already taking other opioid pain medicines around- the-clock and their body is used to these medicines. 74.5 80.6 True ?1 0 - 35 (59.7. 25 (62.5. 86.1) 92.5) False 0 - 6 12.8 0 0.0 I don't know 0 - 6 12.8 6 19.4 Client: TRIG Project: TIRF Wave3 Report Run Date and Time: 11/3/2014 1:04 PM Page 1 of 2 Question S?4a S?4b 5-46 <10 min 10 to <20 min 220 min (95% CI) (95% CI) (95% CI) Question 13: Please answer True, False, or I don?t know for each statement about the TIRF medicine that was most recently prescribed for you. 13b: It is OK for patients to take TIRF medicines for headache pain. 68.1 58.1 False ?1 0 - 32 (52.9. 18 (39.1. 80.9) 75.5) True 0 - 2 4.3 4 12.9 I don't know 0 - 13 27.7 29.0 Correct response Note: All con?dence intervals are exact binomial 95% con?dence intervals. Client: TRIG Project: TIRF Wave3 Report Run Date and Time: 11/3/2014 1:04 PM Page 2 of 2 TABLE 7.2.4 SECONDARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #2 IN ELIGIBLE AND COMPLETE RESPONDENTS KEY RISK MESSAGE 2: PATIENTS SHOULD NOT TAKE TIRF MEDICINES IF THEY ARE NOT OPIOID TOLERANT. SUB-GROUP ANALYSIS 4: TIME TO COMPLETE SURVEY - TELEPHONE: S-4a - <10 min 0 S-S-4c - 220 min S-4a S-4b S-4c <10 min 10 to <20 min 220 min Demonstrated Understanding N=3l 0 correct responses correct response 0 - 5 10.6 3 9.7 2 correct responses 0 - 16 34.0 16 51.6 3 correct responses 0 - 23 48.9 10 32.3 Average number of correct responses - 2.3 (1.9. 2.1 (1.7. 3.0) ?1 3.0) ?1 One-sided 95 con?dence interval using the normal approximation to the Poisson distribution. Client: TRIG Project: TIRF Wave 3 Report Run Date and Time: 10/31/2014 2:10 PM Page 1 of TABLE 8.1.4 PRIMARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #3 IN ELIGIBLE AND COMPLETE RESPONDENTS RISK MESSAGE 3: TIRF NIEDICINES SHOULD BE TAKEN EXACTLY AS PRESCRIBED BY THE HEALTHCARE PROVIDER. SUB-GROUP ANALYSIS 4: TIME TO COMPLETE SURVEY - TELEPHONE: S-4a - <10 min 0 S-S-4c - 220 min Question S?<20 min 220 min (95% CI) (95% CI) (95% CI) Question 12: Please answer True, False, or I don?t know for each of the following statements. 12b: If a patient stops taking around?the-clock opioid pain medicine, they must also stop taking the TIRF medicine. 32.3 17.0 Tnle ?1 0 - 8 10 (16.7. (7.6. 30.8) 51.4) False 0 - 11 23.4 11 35.5 I don't know 0 - 28 59.6 10 32.3 Question 13: Please answer True, False, or I don?t know for each statement about the TIRF medicine that was most recently prescribed for you. 13c: TIRF medicines should be taken exactly as prescribed by the doctor. 100.0 96.8 True ?1 0 - 47 (92.5. 30 (83.3. 100.0) 99.9) False 0 - 0 0.0 3.2 I don't know 0 - 0 0.0 0 0.0 Client: TRIG Project: TIRF Wave3 Report Run Date and Time: 10/31/2014 2:13 PM Page 1 of 2 Question S?4a S?4b 5-46 <10 min 10 to <20 min 220 min (95% CI) (95% CI) (95% CI) Question 17: Please answer True, False, or I don?t know for each statement about the TIRF medicine that was most recently prescribed for you. 17b: It is OK to take TIRF medicines for short-term pain that will go away in a few days. 76.6 80.6 False ?1 0 - 36 (62.0. 25 (62.5. 87.7) 925) True don't know 0 - 9 19.1 5 16.1 Correct response Note: All con?dence intervals are exact binomial 95% con?dence intervals. Client: TRIG Project: TIRF Wave3 Report Run Date and Time: 10/31/2014 2:13 PM Page 2 of 2 TABLE 8.2.4 SECONDARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #3 IN ELIGIBLE AND COMPLETE RESPONDENTS KEY RISK MESSAGE 3: TIRF MEDICINES SHOULD BE TAKEN EXACTLY AS PRESCRIBED BY THE HEALTHCARE PROVIDER. SUB-GROUP ANALYSIS 4: TIME TO COMPLETE SURVEY - TELEPHONE: S-4a - <10 min 0 S-S-4c - 220 min S-4a S-4b S-4c <10 min 10 to <20 min 220 min Demonstrated Understanding 0 correct responses correct response 0 - 11 23.4 3 9.7 2 correct responses 0 - 28 59.6 22 71.0 3 correct responses 0 - 8 17.0 6 19.4 Average number of correct responses - 1.9 (1.6. 2.1 (1.7. 3.0) [11 3.0) [11 One-sided 95 con?dence interval using the normal approximation to the Poisson distribution. Client: TRIG Project: TIRF Wave 3 Report Run Date and Time: 10/31/2014 2:12 PM Page 1 of TABLE 9.1.4 PRIMARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #4 IN ELIGIBLE AND COMPLETE RESPONDENTS RISK MESSAGE 4: PATIENTS SHOULD NOT SWITCH FROM A TIRF MEDICINE TO ANOTHER MEDICINE THAT CONTAINS FENTANYL WITHOUT TALKING TO A HEALTHCARE PROVIDER. SUB-GROUP ANALYSIS 4: TIME TO COMPLETE SURVEY - TELEPHONE: S-4a - <10 min 0 S-S-4c - 220 min S-4a S-4b 84c <10 min 10 to <20 min 220 min Question (95% CI) (95% CI) (95% CI) Question 12: Please answer True, False, or I don?t know for each of the following statements. 12c: It is safe to switch to another medicine that contains fentanyl without talking to a healthcare provider ?rst. 100.0 90.3 False ?1 0 - 47 (92.5. 28 (74.2. 100.0) 98.0) True don't know 0 - 0 0.0 3 9.7 Correct response Note: All con?dence intervals are exact binomial 95% con?dence intervals. Client: TRIG Project: TIRF Wave3 Report Run Date and Time: 10/31/2014 2:13 PM Page 1 of TABLE 10.1.4 PRIMARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #5 IN ELIGIBLE AND COMPLETE RESPONDENTS KEY RISK MESSAGE 5: PATIENTS SHOULD NOT GIVE TIRF MEDICINES TO ANYONE ELSE EVEN IF THEY HAVE THE SAME SUB-GROUP ANALYSIS 4: TIME TO COMPLETE SURVEY - TELEPHONE: S-4a - <10 min 0 S-S-4c - 220 min Question S-4a S-4b S4c <10 min 10 to <20 min 220 min (95% CI) (95% CI) (95% CI) Question 12: Please answer True, False, or I don?t know for each of the following statements. 12d: A patient may give TIRF medicines to another person if they have the same as the patient. 97.9 100.0 False ?1 0 - 46 (88.7. 31 (88.8. 99.9) 100.0) True don?t know 0 - 2.1 0 0.0 Question 17: Please answer True, False, or I don?t know for each statement about the TIRF medicine that was most recently prescribed for you. 17a: Selling or giving away TIRF medicines is against the law. 100.0 96.8 True ?1 0 - 47 (92.5. 30 (83.3. 100.0) 99.9) False don't know 0 - 0 0.0 3.2 Correct response Note: All con?dence intervals are exact binomial 95% con?dence intervals. Client: TRIG Project: TIRF Wave3 Report Run Date and Time: 10/31/2014 2:21 PM Page 1 TABLE 10.2.4 SECONDARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #5 IN ELIGIBLE AND COMPLETE RESPONDENTS KEY RISK MESSAGE 5: PATIENTS SHOULD NOT GIVE TIRF MEDICINES TO ANYONE ELSE EVEN IF THEY HAVE THE SAME SUB-GROUP ANALYSIS 4: TIME TO COMPLETE SURVEY - TELEPHONE: S-4a - <10 min 0 S-S-4c - 220 min S-4a S-4b S-4c <10 min 10 to <20 min 220 min Demonstrated Understanding 0 correct responses correct response 0 - 2.1 3.2 2 correct responses 0 - 46 97.9 30 96.8 Average number of correct responses - 2.0 (1.6. 2.0 (1.6. 2.0) ?1 2.0) ?1 One-sided 95 con?dence interval using the normal approximation to the Poisson distribution. Client: TRIG Project: TIRF Wave 3 Report Run Date and Time: 10/31/2014 2:23 PM Page 1 of TABLE 11.1.4 PRIMARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #6 IN ELIGIBLE AND COMPLETE RESPONDENTS KEY RISK MESSAGE 6: TIRF MEDICINES SHOULD BE STORED IN A SAFE PLACE AWAY FROM CHILDREN AND PROPERLY DISPOSED. SUB-GROUP ANALYSIS 4: TIME TO COMPLETE SURVEY - TELEPHONE: S-4a - <10 min 0 S-S-4c - 220 min S?<20 min 220 min (95% CI) (95% CI) (95% CI) Question 13: Please answer True, False, or I don?t know for each statement about the TIRF medicine that was most recently prescribed for you. 13a: TIRF medicines should be stored in a safe place out of the reach of children. 100.0 100.0 True ?1 0 - 47 (92.5. 31 (88.8. 100.0) 100.0) False don't know 0 - 0 0.0 0 0.0 Question 17: Please answer True, False, or I don?t know for each statement about the TIRF medicine that was most recently prescribed for you. 17c: TIRF medicines must be disposed of as described in the speci?c product?s Medication Guide. 89.4 96.8 True ?1 0 - 42 (76.9. 30 (83.3. 96.5) 99.9) False don't know 0 - 5 10.6 1 3.2 Client: TRIG Project: TIRF Wave3 Report Run Date and Time: 10/31/2014 2:25 PM Page 1 of 2 S?4a S?4b 5-46 <10 min 10 to <20 min 220 min Question (95% CI) (95% CI) (95% CI) 17e: A TIRF medicine can cause an overdose and death in any child who takes it. 93.6 80.6 True ?1 0 - 44 (82.5. 25 (62.5. 98.7) 92.5) False don't know 0 - 3 6.4 6 19.4 Question 14: What should you do if an adult who has not been prescribed a TIRF medicine takes a TIRF medicine? (Please select one.) Get emergency help 83 ?0 83 '9 away. 924) 945) Do nothing. 0 - 0 0.0 0 0.0 Wait an hour and see if the person is OK. 0 2'1 3'2 I don't know. 0 - 7 14.9 4 12.9 Correct response Note: All con?dence intervals are exact binomial 95% con?dence intervals. Client: TRIG Project: TIRF Wave3 Report Run Date and Time: 10/31/2014 2:25 PM Page 2 of 2 TABLE 11.2.4 SECONDARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #6 IN ELIGIBLE AND COMPLETE RESPONDENTS KEY RISK MESSAGE 6: TIRF MEDICINES SHOULD BE STORED IN A SAFE PLACE AWAY FROM CHILDREN AND PROPERLY DISPOSED. SUB-GROUP ANALYSIS 4: TIME TO COMPLETE SURVEY - TELEPHONE: S-4a - <10 min 0 S-S-4c - 220 min S-4a S-4b S-4c <10 min 10 to <20 min 220 min Demonstrated Understanding 0 correct responses correct response correct responses correct responses 0 - 12 25.5 8 25.8 4 correct responses 0 - 33 70.2 21 67.7 Average number of correct responses - 3.7 (3.2. 3.6 (3.1. 4.0) ?1 4.0) ?1 One-sided 95% con?dence interval using the normal approximation to the Poisson distribution. Client: TRIG Project: TIRF Wave 3 Report Run Date and Time: 10/31/2014 2:26 PM Page 1 of TABLE 6.1.5 PRIMARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #1 IN ELIGIBLE AND COMPLETE RESPONDENTS KEY RISK MESSAGE 1: TIRF MEDICINES CAN CAUSE LIFE-THREATENING BREATHING PROBLEMS THAT CAN LEAD TO DEATH. SUB-GROUP ANALYSIS 5: MODALITY TO COMPLETE SURVEY: S-5a - Internet 0 S-5b - Telephone Question Internet Telephone (95% CI) (95% CI) Question 13: Please answer True, False, or I don?t know for each statement about the TIRF medicine that was most recently prescribed for you. 13d: TIRF medicines can cause life?threatening breathing problems that can lead to death. 92.1 89.7 True 139 (86.5. 95.8) 70 (80.8. 95.5) False 0 0.0 1 1.3 I don't know 12 7.9 7 9.0 Correct response Note: All con?dence intervals are exact binomial 95% con?dence intervals. Client: TRIG Project: TIRF Wave3 Report Run Date and Time: 11/3/2014 11:50 AM Page 1 of TABLE 7.1.5 PRIMARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #2 IN ELIGIBLE AND COMPLETE RESPONDENTS KEY RISK MESSAGE 2: PATIENTS SHOULD NOT TAKE TIRF MEDICINES IF THEY ARE NOT OPIOID TOLERANT. SUB-GROUP ANALYSIS 5: MODALITY TO COMPLETE SURVEY: - Internet 0 S-5b - Telephone Question S?5b Internet Telephone (95% CI) (95% CI) Question 11: Please answer True, False, or I don?t know for the following statement: TIRF medicines should only be taken by patients who are opioid tolerant. 88.7 78.2 me 134 (82.6. 93.3) 61 (67.4. 86.8) False 3 2.0 3 3.8 Idon't know 14 9.3 14 17.9 Question 12: Please answer True, False, or I don?t know for each of the following statements. 12a: Opioid tolerant means that a patient is already taking other opioid pain medicines around-the- clock and their body is used to these medicines. 84.1 76.9 True 127 (77.3. 89.5) 60 (66.0. 85.7) False 13 8.6 6 7.7 I don't know 11 7.3 12 15.4 Client: TRIG Project: TIRF Wave3 Report Run Date and Time: 11/3/2014 1:05 PM Page 1 of 2 Question S-5b Internet Telephone (95% CI) (95% CI) Question 13: Please answer True, False, or I don?t know for each statement about the TIRF medicine that was most recently prescribed for you. 13b: It is OK for patients to take TIRF medicines for headache pain. 72.2 64.1 False 109 (64.3. 79.2) 50 (52.4. 74.7) True 10 6.6 6 7.7 I don't know 32 21.2 22 28.2 Correct response Note: All con?dence intervals are exact binomial 95% con?dence intervals. Client: TRIG Project: TIRF Wave3 Report Run Date and Time: 11/3/2014 1:05 PM Page 2 of 2 TABLE 7.2.5 SECONDARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #2 IN ELIGIBLE AND COMPLETE RESPONDENTS KEY RISK MESSAGE 2: PATIENTS SHOULD NOT TAKE TIRF MEDICINES IF THEY ARE NOT OPIOID TOLERANT. SUB-GROUP ANALYSIS 5: MODALITY TO COMPLETE SURVEY: S-5a - Internet 0 S-5b - Telephone S-5b Demonstrated Understanding 11:21.21? 0 correct responses 5 3.3 5 6.4 1 conect response 13 8.6 8 10.3 2 c01rect responses 42 27.8 32 41.0 3 correct responses 91 60.3 33 42.3 Average number of correct responses 2.5 (2.2. 3.0) 2.2 (1.9. 3.0) One-sided 95 con?dence interval using the normal approximation to the Poisson distribution. Client: TRIG Project: TIRF Wave3 Report Run Date and Time: 11/3/2014 11:58 AM Page 1 of TABLE 8.1.5 PRIMARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #3 IN ELIGIBLE AND COMPLETE RESPONDENTS RISK MESSAGE 3: TIRF NIEDICINES SHOULD BE TAKEN EXACTLY AS PRESCRIBED BY THE HEALTHCARE PROVIDER. SUB-GROUP ANALYSIS 5: MODALITY TO COMPLETE SURVEY: - Internet 0 S-5b - Telephone Question S?5a S-5b Internet Telephone (95% CI) (95% CI) Question 12: Please answer True, False, or I don?t know for each of the following statements. 12b: If a patient stops taking around?the-clock opioid pain medicine, they must also stop taking the TIRF medicine. 43.7 23.1 111 True 66 (35.7. 52.0) 18 (14.3. 34.0) False 36 23.8 22 28.2 I don't know 49 32.5 38 48.7 Question 13: Please answer True, False, or I don?t know for each statement about the TIRF medicine that was most recently prescribed for you. 13c: TIRF medicines should be taken exactly as prescribed by the doctor. 99.3 98.7 True 150 (96.4. 100.0) 77 (93.1. 100.0) False 1 0.7 1 1.3 I don't know 0 0.0 0 0.0 Client: TRIG Project: TIRF Wave3 Report Run Date and Time: 11/3/2014 12:00 PM Page 1 of 2 Question S-5a Internet Telephone (95% CI) (95% CI) Question 17: Please answer True, False, or I don?t know for each statement about the TIRF medicine that was most recently prescribed for you. 17b: It is OK to take TIRF medicines for short-term pain that will go away in a few days. 85.4 78.2 False 129 (78.8. 90.6) 61 (67.4. 86.8) True 9 6.0 3 3.8 I don't know 13 8.6 14 17.9 Correct response Note: All con?dence intervals are exact binomial 95% con?dence intervals. Client: TRIG Project: TIRF Wave3 Report Run Date and Time: 11/3/2014 12:00 PM Page 2 of 2 TABLE 8.2.5 SECONDARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #3 IN ELIGIBLE AND COMPLETE RESPONDENTS KEY RISK MESSAGE 3: TIRF MEDICINES SHOULD BE TAKEN EXACTLY AS PRESCRIBED BY THE HEALTHCARE PROVIDER. SUB-GROUP ANALYSIS 5: MODALITY TO COMPLETE SURVEY: S-5a - Internet 0 S-5b - Telephone S-5a Demonstrated Understanding 1:123? 0 correct responses 0 0.0 0 0.0 1 conect response 16 10.6 14 17.9 2 conect responses 76 50.3 50 64.1 3 correct responses 59 39.1 14 17.9 Average number of correct responses 2.3 (2.1. 3.0) 2.0 (1.7. 3.0) One-sided 95 con?dence interval using the normal approximation to the Poisson distribution. Client: TRIG Project: TIRF Wave3 Report Run Date and Time: 11/3/2014 12:01 PM Page 1 of TABLE 9.1.5 PRIMARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #4 IN ELIGIBLE AND COMPLETE RESPONDENTS RISK MESSAGE 4: PATIENTS SHOULD NOT SWITCH FROM A TIRF MEDICINE TO ANOTHER MEDICINE THAT CONTAINS FENTANYL WITHOUT TALKING TO A HEALTHCARE PROVIDER. SUB-GROUP ANALYSIS 5: MODALITY TO COMPLETE SURVEY: - Internet 0 - Telephone S?5b Internet Telephone Question (95% CI) (95% CI) Question 12: Please answer True, False, or I don?t know for each of the following statements. 12c: It is safe to switch to another medicine that contains fentanyl without talking to a healthcare provider ?rst. 97.4 96.2 False 147 (93.4. 99.3) 75 (89.2. 99.2) True 2 1.3 0 0.0 I don't know 2 1.3 3 3.8 Correct response Note: All con?dence intervals are exact binomial 95% con?dence intervals. Client: TRIG Project: TIRF Wave3 Report Run Date and Time: 11/3/2014 12:03 PM Page 1 of 1 TABLE 10.1.5 PRIMARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #5 IN ELIGIBLE AND COMPLETE RESPONDENTS KEY RISK MESSAGE 5: PATIENTS SHOULD NOT GIVE TIRF MEDICINES TO ANYONE ELSE EVEN IF THEY HAVE THE SAME SUB-GROUP ANALYSIS 5: MODALITY TO COMPLETE SURVEY: - Internet - Telephone Question S?5a $51) Internet Telephone (95% CI) (95% CI) Question 12: Please answer True, False, or I don?t know for each of the following statements. 12d: A patient may give TIRF medicines to another person if they have the same as the patient. [11 99.3 98.7 False 150 (96.4. 100.0) 77 (93.1. 100.0) True 1 0.7 0 0.0 I don?t know 0 0.0 1.3 Question 17: Please answer True, False, or I don?t know for each statement about the TIRF medicine that was most recently prescribed for you. 17a: Selling or giving away TIRF medicines is against the law. 99.3 98.7 True 150 (96.4. 100.0) 77 (93.1. 100.0) False 1 0.7 0 0.0 I don?t know 0 0.0 1.3 Correct response Note: All con?dence intervals are exact binomial 95% con?dence intervals. Client: TRIG Project: TIRF Wave3 Report Run Date and Time: 11/3/2014 12:04 PM Page 1 ofl TABLE 10.2.5 SECONDARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #5 IN ELIGIBLE AND COMPLETE RESPONDENTS KEY RISK MESSAGE 5: PATIENTS SHOULD NOT GIVE TIRF MEDICINES TO ANYONE ELSE EVEN IF THEY HAVE THE SAME SUB-GROUP ANALYSIS 5: MODALITY TO COMPLETE SURVEY: S-5a - Internet 0 S-5b - Telephone S-5a Demonstrated Understanding 1113:1151: T113233 ne 0 correct responses 0 0.0 0 0.0 1 correct response 2 1.3 2 2.6 2 correct responses 149 98.7 76 97.4 Average number of con?ect responses 2.0 (1.8. 2.0) 2.0 (1.7. 2.0) One-sided 95 con?dence interval using the normal approximation to the Poisson distribution. Client: TRIG Project: TIRF Wave 3 Report Run Date and Time: 11/3/2014 12:05 PM Page 1 of TABLE 11.1.5 PRIMARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #6 IN ELIGIBLE AND COMPLETE RESPONDENTS KEY RISK MESSAGE 6: TIRF MEDICINES SHOULD BE STORED IN A SAFE PLACE AWAY FROM CHILDREN AND PROPERLY DISPOSED. SUB-GROUP ANALYSIS 5: MODALITY TO COMPLETE SURVEY: - Internet 0 - Telephone S?5b Internet Telephone Question (95% CI) (95% CI) Question 13: Please answer True, False, or I don?t know for each statement about the TIRF medicine that was most recently prescribed for you. 13a: TIRF medicines should be stored in a safe place out of the reach of children. 98.7 100.0 True 149 (95.3. 99.8) 78 (95.4. 100.0) False 1 0.7 0 0.0 I don't know 1 0.7 0 0.0 Question 17: Please answer True, False, or I don?t know for each statement about the TIRF medicine that was most recently prescribed for you. 17c: TIRF medicines must be disposed of as described in the speci?c product?s Medication Guide. 94.7 92.3 True 143 (89.8. 97.7) 72 (84.0. 97.1) False 0 0.0 0 0.0 I don't know 8 5.3 6 7.7 17e: A TIRF medicine can cause an overdose and death in any child who takes it. 91.4 88.5 True 138 (85.7. 95.3) 69 (79.2. 94.6) False 2 1.3 0 0.0 I don't know 11 7.3 9 11.5 Client: TRIG Project: TIRF Wave3 Report Run Date and Time: 11/3/2014 12:06 PM Page 1 of 2 Get emergency help right away. 137 90.7 65 83.3 (84.9, 94.8) (73.2, 90.8) Do nothing. 0 0.0 0 0.0 Waitanhour and see ifthe 5 3 3 2 2 6 person is OK. I don't know. 9 6.0 11 14.1 Correct response Note: All con?dence intervals are exact binomial 95% con?dence intervals. Client: TRIG Project: TIRF Wave 3 Report Run Date and Time: 11/3/2014 12:06 PM Page 2 of 2 TABLE 11.2.5 SECONDARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #6 IN ELIGIBLE AND COMPLETE RESPONDENTS KEY RISK MESSAGE 6: TIRF MEDICINES SHOULD BE STORED IN A SAFE PLACE AWAY FROM CHILDREN AND PROPERLY DISPOSED. SUB-GROUP ANALYSIS 5: MODALITY TO COMPLETE SURVEY: S-5a - Internet 0 S-5b - Telephone S-5a Demonstrated Understanding 1121:1151: 0 correct responses 0 0.0 0 0.0 conect response 2 1.3 0 0.0 2 conect responses 5 3.3 4 5.1 3 correct responses 21 13.9 20 25.6 4 correct responses 123 81.5 54 69.2 Average number of correct responses 3.8 (3.5. 4.0) 3.6 (3.3. 4.0) One-sided 95% con?dence interval using the nonnal approximation to the Poisson distribution. Client: TRIG Project: TIRF Wave 3 Report Run Date and Time: 11/3/2014 12:07 PM Page 1 of TABLE 6.1.6 PRIMARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #1 IN ELIGIBLE AND COMPLETE RESPONDENTS KEY RISK MESSAGE l: TIRF MEDICINES CAN CAUSE LIFE-THREATENING BREATHING PROBLEMS THAT CAN LEAD TO DEATH. SUB-GROUP ANALYSIS 6: HIGHEST LEVEL OF EDUCATION (QUESTION 37): S-6a Less than, Some, or High school graduate/GED or prefer not to answer 0 S-6b - Some college or associate?s degree 0 S-6c - Bachelor?s degree or Master?s degree 0 S-6d - Professional or Doctoral degree S?6a S?6b S?6c S?6d High School Some college Bachelor or Master Doctoral degree Question N=l4 (95% CI) (95% CI) (95% CI) (95% CI) Question 13: Please answer True, False, or I don?t know for each statement about the TIRF medicine that was most recently prescribed for you. 13d: TIRF medicines can cause life-threatening breathing problems that can lead to death. 85.7 90.2 97.2 85.7 True 36 (71.5. 94.6) 92 (82.7. 95.2) 69 (90.2. 99.7) 12 (57.2. 98.2) False don?t know 6 14.3 9 8.8 2 2.8 2 14.3 Correct response Note: All con?dence intervals are exact binomial 95% con?dence intervals. Client: TRIG Project: TIRF Wave3 Report Run Date and Time: 11/3/2014 12:10 PM Page 1 of TABLE 7.1.6 PRIMARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #2 IN ELIGIBLE AND COMPLETE RESPONDENTS KEY RISK MESSAGE 2: PATIENTS SHOULD NOT TAKE TIRF MEDICINES IF THEY ARE NOT OPIOID TOLERANT. SUB-GROUP ANALYSIS 6: HIGHEST LEVEL OF EDUCATION (QUESTION 37): S-6a Less than, Some, or High school graduate/GED or prefer not to answer 0 S-6b - Some college or associate?s degree 0 S-6c - Bachelor?s degree or Master?s degree 0 S-6d - Professional or Doctoral degree S?6a S?6b S-6c S?6d High School Some college Bachelor or Master Doctoral degree Question N=7l N=l4 (95% CI) (95% CI) (95% CI) (95% CI) Question 11: Please answer True, False, or I don?t know for the following statement: TIRF medicines should only be taken by patients who are opioid tolerant. 69.0 88.2 90.1 85.7 True 29 (52.9. 82.4) 90 (80.4. 93.8) 64 (80.7. 95.9) 12 (57.2. 98.2) False don't know 10 23.8 10 9.8 6 8.5 2 14.3 Client: TRIG Project: TIRF Wave3 Report Run Date and Time: 11/3/2014 1:05 PM Page 1 of Question S-6a S-6b S-6c S-6d High School Some college Bachelor or Master Doctoral degree N=7l N=l4 (95% CI) (95% CI) (95% CI) (95% CI) Question 12: Please answer True, False, or I don?t know for each of the following statements. 12a: Opioid tolerant means that a patient is already taking other opioid pain medicines around?the?clock and their body is used to these medicines. 76.2 84.3 84.5 64.3 True 32 (60.5. 87.9) 86 (75.8. 90.8) 60 (74.0. 92.0) 9 (35.1. 87.2) False 11don't know 5 11.9 7 6.9 7 9.9 4 28.6 Question 13: Please answer True, False, or I don?t know for each statement about the TIRF medicine that was most recently prescribed for you. 13b: It is OK for patients to take TIRF medicines for headache pain. 57.1 67.6 77.5 78.6 False 24 (41.0. 72.3) 69 (57.7. 76.6) 55 (66.0. 86.5) 11 (49.2. 95.3) True don't know 15 35.7 25 24.5 12 16.9 2 14.3 Correct response Note: All con?dence intervals are exact binomial 95% con?dence intervals. Client: TRIG Project: TIRF Wave3 Report Run Date and Time: 11/3/2014 1:05 PM Page 2 TABLE 7.2.6 SECONDARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #2 IN ELIGIBLE AND COMPLETE RESPONDENTS KEY RISK MESSAGE 2: PATIENTS SHOULD NOT TAKE TIRF MEDICINES IF THEY ARE NOT OPIOID TOLERANT. SUB-GROUP ANALYSIS 6: HIGHEST LEVEL OF EDUCATION (QUESTION 37): S-6a Less than, Some, or High school graduate/GED or prefer not to answer 0 S-6b - Some college or associate?s degree 0 S-6c - Bachelor?s degree or Master?s degree 0 S-6d - Professional or Doctoral degree S-6a S-6b S-6c S-6d High School Some college Bachelor or Master Doctoral degree Demonstrated Understanding 0 correct responses correct response 7 16.7 7.8 4 5.6 2 14.3 2 correct responses 18 42.9 33 32.4 20 28.2 3 21.4 3 correct responses 14 33.3 57 55.9 45 63.4 8 57.1 Average number of correct responses 2.0 (1.7. 2.4 (2.1. 2.5 (2.2. 2.3 (1.6. 3.0) ?1 3.0) ?1 3.0) ?1 3.0) ?1 One-sided 95 con?dence interval using the normal approximation to the Poisson distribution. Client: TRIG Project: TIRF Wave 3 Report Run Date and Time: 11/3/2014 12:12 PM Page 1 of TABLE 8.1.6 PRIMARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #3 IN ELIGIBLE AND COMPLETE RESPONDENTS RISK MESSAGE 3: TIRF NIEDICINES SHOULD BE TAKEN EXACTLY AS PRESCRIBED BY THE HEALTHCARE PROVIDER SUB-GROUP ANALYSIS 6: HIGHEST LEVEL OF EDUCATION (QUESTION 37): S-6a Less than, Some, or High school graduate/GED or prefer not to answer 0 S-6b - Some college or associate?s degree 0 S-6c - Bachelor?s degree or Master?s degree 0 S-6d - Professional or Doctoral degree S?6a S?6b S?6c S-6d High School Some college Bachelor or Master Doctoral degree Question N=7l N=l4 (95% CI) (95% CI) (95% CI) (95% CI) Question 12: Please answer True, False, or I don?t know for each of the following statements. 12b: If a patient stops taking around?the?clock opioid pain medicine, they must also stop taking the TIRF medicine. 19.0 40.2 42.3 35.7 True 8 (8.6. 34.1) 41 (30.6. 50.4) 30 (30.6. 54.6) 5 (12.8. 64.9) False 12 28.6 21 20.6 21 29.6 4 28.6 Idon't know 22 52.4 40 39.2 20 28.2 5 35.7 Client: TRIG Project: TIRF Wave3 Report Run Date and Time: 11/3/2014 12:15 PM Page 1 of 2 Question S-6a S-6b S-6c S-6d High School Some college Bachelor or Master Doctoral degree N=7l (95% CI) (95% CI) (95% CI) (95% CI) Question 13: Please answer True, False, or I don?t know for each statement about the TIRF medicine that was most recently prescribed for you. 13c: TIRF medicines should be taken exactly as prescribed by the doctor. 100.0 100.0 99.0 98.6 True ?1 42 (91.6. 101 70 14 (76.8. 100.0) (94.7. 100.0) (92.4. 100.0) 100.0) False don't know 0 0.0 0 0.0 0 0.0 0.0 Question 17: Please answer True, False, or I don?t know for each statement about the TIRF medicine that was most recently prescribed for you. 17b: It is OK to take TIRF medicines for short-term pain that will go away in a few days. 83.3 78.4 88.7 85.7 False 35 (68.6. 93.0) 80 (69.2. 86.0) 63 (79.0. 95.0) 12 (57.2. 98.2) True don?t know 6 14.3 12 11.8 7 9.9 2 14.3 Correct response Note: All con?dence intervals are exact binomial 95% con?dence intervals. Client: TRIG Project: TIRF Wave3 Report Run Date and Time: 11/3/2014 12:15 PM Page 2 TABLE 8.2.6 SECONDARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #3 IN ELIGIBLE AND COMPLETE RESPONDENTS KEY RISK MESSAGE 3: TIRF MEDICINES SHOULD BE TAKEN EXACTLY AS PRESCRIBED BY THE HEALTHCARE PROVIDER. SUB-GROUP ANALYSIS 6: HIGHEST LEVEL OF EDUCATION (QUESTION 37): S-6a Less than, Some, or High school graduate/GED or prefer not to answer 0 S-6b - Some college or associate?s degree 0 S-6c - Bachelor?s degree or Master?s degree 0 S-6d - Professional or Doctoral degree S-6a S-6b S-6c S-6d High School Some college Bachelor or Doctoral degree Demonstrated Understanding Master N=7l 0 correct responses correct response 6 14.3 15 14.7 7 9.9 2 14.3 2 correct responses 29 69.0 54 52.9 36 50.7 7 50.0 3 correct responses 7 16.7 33 32.4 28 39.4 5 35.7 Average number of correct responses 2.0 (1.7. 2.2 (1.9. 2.3 (2.0. 2.2 (1.6. 3.0) ?1 3.0) ?1 3.0) ?1 3.0) ?1 One-sided 95 con?dence interval using the normal approximation to the Poisson distribution. Client: TRIG Project: TIRF Wave 3 Report Run Date and Time: 11/3/2014 12:16 PM Page 1 of TABLE 9.1.6 PRIMARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #4 IN ELIGIBLE AND COMPLETE RESPONDENTS RISK MESSAGE 4: PATIENTS SHOULD NOT SWITCH FROM A TIRF MEDICINE TO ANOTHER MEDICINE THAT CONTAINS FENTANY WITHOUT TALKING TO A HEALTHCARE PROVIDER. SUB-GROUP ANALYSIS 6: HIGHEST LEVEL OF EDUCATION (QUESTION 37): S-6a Less than, Some, or High school graduate/GED or prefer not to answer 0 S-6b - Some college or associate?s degree 0 S-6c - Bachelor?s degree or Master?s degree 0 S-6d - Professional or Doctoral degree S?6a S?6b S?6c S-6d High School Some college Bachelor or Master Doctoral degree Question (95% CI) (95% CI) (95% CI) (95% CI) Question 12: Please answer True, False, or I don?t know for each of the following statements. 12c: It is safe to switch to another medicine that contains fentanyl without talking to a healthcare provider ?rst. 97.6 97.1 97.2 92.9 False 41 (87.4. 99.9) 99 (91.6. 99.4) 69 (90.2. 99.7) 13 (66.1. 99.8) True don't know 1 2.4 2 2.0 1 1.4 7.1 Correct response Note: All con?dence intervals are exact binomial 95% con?dence intervals. Client: TRIG Project: TIRF Wave3 Report Run Date and Time: 11/3/2014 12:17 PM Page 1 of TABLE 10.1.6 ELIGIBLE AND COMPLETE RESPONDENTS KEY RISK MESSAGE 5: PATIENTS SHOULD NOT GIVE TIRF MEDICINES TO ANYONE ELSE EVEN IF THEY S-6a Less than, Some, or High school graduate/GED or prefer not to answer 0 S-6b - Some college or associate?s degree 0 S-6c - Bachelor?s degree or Master?s degree 0 S-6d - Professional or Doctoral degree HAVE THE SAME SUB-GROUP ANALYSIS 6: HIGHEST LEVEL OF EDUCATION (QUESTION 37): PRIMARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #5 IN S?6a S?6b S-6c S?6d High School Some college Bachelor or Master Doctoral degree Question N=7l N=l4 (95% CI) (95% CI) (95% Cl) (95% CI) Question 12: Please answer True, False, or I don?t know for each of the following statements. 12d: A patient may give TIRF medicines to another person if they have the same as the patient. 100.0 99.0 98.6 100.0 False ?1 42 (91.6. 101 (94.7. 70 (92.4. 14 (76.8. 100.0) 100.0) 100.0) 100.don't know 0.0 Client: TRIG Project: TIRF Wave3 Report Run Date and Time: 11/3/2014 12:22 PM Page 1 of 2 Question S-6a S-6b S-6c S-6d High School Some college Bachelor or Master Doctoral degree (95% CI) (95% CI) (95% CI) (95% CI) prescribed for you. Question 17: Please answer True, False, or I don?t know for each statement about the TIRF medicine that was most recently 17a: Selling or giving away TIRF medicines is against the law. 100.0 99.0 98.6 100.0 True ?1 42 (91.6. 101 (94.7. 70 (92.4. 14 (76.8. 100.0) 100.0) 100.0) 100.0) False don't know 0.0 Correct response Note: All con?dence intervals are exact binomial 95% con?dence intervals. Client: TRIG Project: TIRF Wave3 Report Run Date and Time: 11/3/2014 12:22 PM Page 2 of TABLE 10.2.6 IN ELIGIBLE AND COMPLETE RESPONDENTS KEY RISK MESSAGE 5: PATIENTS SHOULD NOT GIVE TIRF MEDICINES TO ANYONE ELSE EVEN IF THEY HAVE THE SAME SUB-GROUP ANALYSIS 6: HIGHEST LEVEL OF EDUCATION (QUESTION 37): S-6a Less than, Some, or High school graduate/GED or prefer not to answer 0 S-6b - Some college or associate?s degree 0 S-6c - Bachelor?s degree or Master?s degree 0 S-6d - Professional or Doctoral degree SECONDARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #5 S-6a S-6b S-6c S-6d High School Some college Bachelor or Master Doctoral degree Demonstrated Understanding 0 correct responses conect response correct responses 42 100.0 100 98.0 69 97.2 14 100.0 Average number of correct responses 2.0 (1.6. 2.0 (1.8. 2.0 (1.7. 2.0 (1.4. 2.0) ?1 2.0) ?1 2.0) ?1 2.0) ?1 One-sided 95 con?dence interval using the normal approximation to the Poisson distribution. Client: TRIG Project: TIRF Wave 3 Report Run Date and Time: 11/3/2014 12:18 PM Page 1 of TABLE 11.1.6 ELIGIBLE AND COMPLETE RESPONDENTS KEY RISK MESSAGE 6: TIRF MEDICINES SHOULD BE STORED IN A SAFE PLACE AWAY FROM CHILDREN AND PROPERLY DISPOSED. SUB-GROUP ANALYSIS 6: HIGHEST LEVEL OF EDUCATION (QUESTION 37): S-6a Less than, Some, or High school graduate/GED or prefer not to answer 0 S-6b - Some college or associate?s degree 0 S-6c - Bachelor?s degree or Master?s degree 0 S-6d - Professional or Doctoral degree PRIMARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #6 IN Question S-6a S?6b S-6c S?6d High School Some college Bachelor or Master Doctoral degree N=7l N=l4 (95% CI) (95% CI) (95% CI) (95% CI) Question 13: Please answer True, False, or I don?t know for each statement about the TIRF medicine that was most recently prescribed for you. 13a: TIRF medicines should be stored in a safe place out of the reach of children. 97 6 99.0 100.0 100.0 True ?1 41 (87 4 '99 9) 101 (94.7. 71 (94.9. 14 (76.8. 100.0) 100.0) 100.0) False don?t know 0.0 Client: TRIG Project: TIRF Wave3 Report Run Date and Time: 11/3/2014 12:22 PM Page 1 of 3 Question S-6a S-6b S-6c S-6d High School Some college Bachelor or Master Doctoral degree N=7l N=l4 (95% CI) (95% CI) (95% CI) (95% CI) Question 17: Please answer True, False, or I don?t know for each statement about the TIRF medicine that was most recently prescribed for you. 17c: TIRF medicines must be disposed of as described in the speci?c product?s Medication Guide. True 38 (77319373) 96 (87.839178) 68 (88.95.9891) 13 (66.959993) False don't know 7.1 l7e: A TIRF medicine can cause an overdose and death in any child who takes it. True 36 (71.259746) 93 (839939259) 65 (82.2368) 13 (66.95.9998) False don?t know 6 14.3 9 8.8 4 5.6 1 7.1 Client: TRIG Project: TIRF Wave3 Report Run Date and Time: 11/3/2014 12:22 PM Page 2 of 3 S-6a S-6b S-6c S-6d High School Some college Bachelor or Master Doctoral degree Question N=7l N=l4 (95% CI) (95% CI) (95% CI) (95% CI) Question 14: What should you do if an adult who has not been prescribed a TIRF medicine takes a TIRF medicine? (Please select one.) Get emergency help right 38 90.5 91 89.2 63 88.7 10 71.4 away. (77.4. 97.3) (81.5. 94.5) (79.0. 95.0) (41.9. 91.6) Do nothing0.0 Wait an hour and see person 15 OK. I don't know28.6 Correct response Note: All con?dence intervals are exact binomial 95% con?dence intervals. Client: TRIG Project: TIRF Wave3 Report Run Date and Time: 11/3/2014 12:22 PM Page 3 of 3 TABLE 11.2.6 SECONDARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #6 IN ELIGIBLE AND COMPLETE RESPONDENTS KEY RISK MESSAGE 6: TIRF MEDICINES SHOULD BE STORED IN A SAFE PLACE AWAY FROM CHILDREN AND PROPERLY DISPOSED. SUB-GROUP ANALYSIS 6: HIGHEST LEVEL OF EDUCATION (QUESTION 37): S-6a Less than, Some, or High school graduate/GED or prefer not to answer 0 S-6b - Some college or associate?s degree 0 S-6c - Bachelor?s degree or Master?s degree 0 S-6d - Professional or Doctoral degree S-6a S-6b S-6c S-6d High School Some college Bachelor or Master Doctoral degree Demonstrated Understanding N=l4 0 correct responses correct response correct responses 14.3 3 correct responses 12 28.6 16 15.7 11 15.5 2 14.3 4 correct responses 29 69.0 81 79.4 57 80.3 10 71.4 Average number of correct responses 3.6 (3.2. 3.7 (3.4. 3.8 (3.4. 3.6 (2.7. 40> ?1 4.0) ?1 4.0) 4.0) One-sided 95% con?dence interval using the normal approximation to the Poisson distribution. Client: TRIG Project: TIRF Wave 3 Report Run Date and Time: 11/3/2014 12:21 PM Page 1 of TABLE 6.1.7 PRIMARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #1 IN ELIGIBLE AND COMPLETE RESPONDENTS KEY RISK MESSAGE l: TIRF MEDICINES CAN CAUSE LIFE-THREATENING BREATHING PROBLEMS THAT CAN LEAD TO DEATH. SUB-GROUP ANALYSIS 7: AGE GROUP OF RESPONDENT (QUESTION 6): S-7a 18 to 39 S-7b 40 to 49 S-7c 50 to 59 S-7d 60 or older Question S?7a S?7b S?7c S?older (95% CI) (95% CI) (95% CI) (95% Cl) prescribed for you. Question 13: Please answer True, False, or I don?t know for each statement about the TIRF medicine that was most recently 13d: TIRF medicines can cause life-threatening breathing problems that can lead to death. 86.7 95.4 89.8 91.3 True 26 (69.3. 96.2) 62 (87.1. 99.0) 79 (81.5. 95.2) 42 (79.2. 97.6) False don't know 4 13.3 3 4.6 9 10.2 3 6.5 Correct response Note: All con?dence intervals are exact binomial 95% con?dence intervals. Client: TRIG Project: TIRF Wave3 Report Run Date and Time: 11/3/2014 12:36 PM Page 1 of TABLE 7.1.7 PRIMARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #2 IN ELIGIBLE AND COMPLETE RESPONDENTS KEY RISK MESSAGE 2: PATIENTS SHOULD NOT TAKE TIRF MEDICINES IF THEY ARE NOT OPIOID TOLERANT. SUB-GROUP ANALYSIS 7: AGE GROUP OF RESPONDENT (QUESTION 6): 0 S-7a 18 to 39 S-7b 40 to 49 0 S-7c 50 to 59 S-7d 60 or older S?7a S?7b S?7c S?older Question =46 (95% CI) (95% CI) (95% CI) (95% CI) Question 11: Please answer True, False, or I don?t know for the following statement: TIRF medicines should only be taken by patients who are opioid tolerant. 86.7 87.7 85.2 80.4 True 26 (693.962) 57 (77.2. 94.5) 75 (76.1. 91.9) 37 (66.1. 90.6) False 0.0 3 4.6 2 2.3 2.2 Idon't know 4 13.3 5 7.7 11 12.5 8 17.4 Client: TRIG Project: TIRF Wave3 Report Run Date and Time: 11/3/2014 1:08 PM Page 1 of Question S-7a S-7b S-7c S-older (95% CI) (95% CI) (95% CI) (95% CI) Question 12: Please answer True, False, or I don?t know for each of the following statements. 12a: Opioid tolerant means that a patient is already taking other opioid pain medicines around?the?clock and their body is used to these medicines. 80.0 89.2 79.5 76.1 True 24 (61.4. 92.3) 58 (79.1. 95.6) 70 (69.6. 87.4) 35 (61.2. 87.4) False 13.0 I don't know 5 16.7 3 4.6 10 11.4 5 10.9 prescribed for you. Question 13: Please answer True, False, or I don?t know for each statement about the TIRF medicine that was most recently 13b: It is OK for patients to take TIRF medicines for headache pain. 66.7 70.8 69.3 69.6 False 20 (47.2. 82.7) 46 (58.2. 81.4) 61 (58.6. 78.7) 32 (54.2. 82.3) True 3 10don't know 7 23.3 15 23.1 20 22.7 12 26.1 Correct response Note: All con?dence intervals are exact binomial 95% con?dence intervals. Client: TRIG Project: TIRF Wave3 Report Run Date and Time: 11/3/2014 1:08 PM Page 2 of TABLE 7.2.7 SECONDARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #2 IN ELIGIBLE AND COMPLETE RESPONDENTS KEY RISK MESSAGE 2: PATIENTS SHOULD NOT TAKE TIRF MEDICINES IF THEY ARE NOT OPIOID TOLERANT. SUB-GROUP ANALYSIS 7: AGE GROUP OF RESPONDENT (QUESTION 6): S-7a 18 to 39 S-7b 40 to 49 0 S-7c 50 to 59 S-7d 60 or older S-7a S-7b S-7c S-older Demonstrated Understanding 0 correct responses correct response 3 10.0 5 7.7 7 8.0 6 13.0 2 correct responses 8 26.7 21 32.3 29 33.0 16 34.8 3 correct responses 17 56.7 38 58.5 47 53.4 22 47.8 Average number of correct responses 2.3 (1.9. 2.5 (2.2. 2.3 (2.1. 2.3 (1.9. 3.0) ?1 3.0) ?1 3.0) ?1 3.0) ?1 One-sided 95 con?dence inten?al using the normal approximation to the Poisson distribution. Client: TRIG Project: TIRF Wave 3 Report Run Date and Time: 11/3/2014 12:50 PM Page 1 of TABLE 8.1.7 PRIMARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #3 IN ELIGIBLE AND COMPLETE RESPONDENTS RISK MESSAGE 3: TIRF NIEDICINES SHOULD BE TAKEN EXACTLY AS PRESCRIBED BY THE HEALTHCARE PROVIDER. SUB-GROUP ANALYSIS 7: AGE GROUP OF RESPONDENT (QUESTION 6): S-7a 18 to 39 S-7b 40 to 49 S-7c 50 to 59 S-7d 60 or older S?7a S?7b S?7c S?older Question (95% CI) (95% CI) (95% CI) (95% CI) Question 12: Please answer True, False, or I don?t know for each of the following statements. 12b: If a patient stops taking around?the?clock opioid pain medicine, they must also stop taking the TIRF medicine. 33.3 38.5 36.4 37.0 True 10 (17.3. 52.8) 25 (26.7. 51.4) 32 (26.4. 47.3) 17 (23.2. 52.5) False 6 20.0 15 23.1 21 23.9 16 34.8 I don't know 14 46.7 25 38.5 35 39.8 13 28.3 Client: TRIG Project: TIRF Wave3 Report Run Date and Time: 11/3/2014 12:54 PM Page 1 of Question S-7a S-7b S-7c S-older (95% CI) (95% CI) (95% CI) (95% CI) prescribed for you. Question 13: Please answer True, False, or I don?t know for each statement about the TIRF medicine that was most recently 13c: TIRF medicines should be taken exactly as prescribed by the doctor. 100.0 100.0 98.5 98.9 True ?1 30 (88.4. 64 87 46 (92.3. 100.0) (91.7. 100.0) (93.8. 100.0) 1000) False don't know 0.0 prescribed for you. Question 17: Please answer True, False, or I don?t know for each statement about the TIRF medicine that was most recently 17b: It is OK to take TIRF medicines for short?term pain that will go away in a few days. 70.0 89.2 81.8 84.8 False 21 (50.6. 85.3) 58 (79.1. 95.6) 72 (72.2. 89.2) 39 (71.1. 93.7) True don't know 8 26.7 5 7.7 8 9.1 6 13.0 Correct response Note: All con?dence intervals are exact binomial 95% con?dence intervals. Client: TRIG Project: TIRF Wave3 Report Run Date and Time: 11/3/2014 12:54 PM Page 2 of TABLE 8.2.7 SECONDARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #3 IN ELIGIBLE AND COMPLETE RESPONDENTS KEY RISK MESSAGE 3: TIRF MEDICINES SHOULD BE TAKEN EXACTLY AS PRESCRIBED BY THE HEALTHCARE PROVIDER. SUB-GROUP ANALYSIS 7: AGE GROUP OF RESPONDENT (QUESTION 6): 0 S-7a 18 to 39 S-7b 40 to 49 0 S-7c 50 to 59 S-7d 60 or older S-7a S-7b S-7c S-older Demonstrated Understanding 0 correct responses correct response 26.7 7 10.8 10 11.4 5 10.9 2 correct responses 13 43.3 34 52.3 53 60.2 26 56.5 3 correct responses 9 30.0 24 36.9 25 28.4 15 32.6 Average number of correct responses 2.0 (1.6. 2.3 (2.0. 2.2 (1.9. 2.2 (1.9. 3.0) ?1 3.0) ?1 3.0) ?1 3.0) ?1 One-sided 95 con?dence inten?al using the normal approximation to the Poisson distribution. Client: TRIG Project: TIRF Wave3 Report Run Date and Time: 11/3/2014 12:58 PM Page 1 of TABLE 9.1.7 PRIMARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #4 IN ELIGIBLE AND COMPLETE RESPONDENTS RISK MESSAGE 4: PATIENTS SHOULD NOT SWITCH FROM A TIRF MEDICINE TO ANOTHER MEDICINE THAT CONTAINS FENTANY WITHOUT TALKING TO A HEALTHCARE PROVIDER. SUB-GROUP ANALYSIS 7: AGE GROUP OF RESPONDENT (QUESTION 6): S-7a 18 to 39 S-7b 40 to 49 S-7c 50 to 59 S-7d 60 or older S?7a S?7b S?7c S?older Question (95% CI) (95% CI) (95% CI) (95% CI) Question 12: Please answer True, False, or I don?t know for each of the following statements. 12c: It is safe to switch to another medicine that contains fentanyl without talking to a healthcare provider ?rst. 100.0 98.5 96.6 93.5 False ?1 30 (88.4. 64 (91.7. 85 43 100.0) 100.0) (90.4. 99.3) (82.1. 98.6) True don't know 4.3 Correct response Note: All con?dence intervals are exact binomial 95% con?dence intervals. Client: TRIG Project: TIRF Wave3 Report Run Date and Time: 11/3/2014 1:09 PM Page 1 of TABLE 10.1.7 ELIGIBLE AND COMPLETE RESPONDENTS PRIMARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #5 IN KEY RISK MESSAGE 5: PATIENTS SHOULD NOT GIVE TIRF MEDICINES TO ANYONE ELSE EVEN IF THEY HAVE THE SAME SUB-GROUP ANALYSIS 7: AGE GROUP OF RESPONDENT (QUESTION 6): 0 S-7a 18 to 39 S-7b 40 to 49 0 S-7c 50 to 59 S-7d 60 or older S?7a S?7b S?7c S?older Question =88 (95% CI) (95% CI) (95% CI) (95% CI) Question 12: Please answer True, False, or I don?t know for each of the following statements. 12d: A patient may give TIRF medicines to another person if they have the same as the patient. 100.0 98.5 100.0 97 8 False ?1 30 (88.4. 64 (91.7. 88 (95.9. 45 (88 '99 9) 100.0) 100.0) 100.0) True don't know 2.2 Client: TRIG Project: TIRF Wave3 Report Run Date and Time: 11/3/2014 1:09 PM Page 1 of 2 00 Question S-7a S-7b S-7c S-older (95% CI) (95% CI) (95% CI) (95% CI) Question 17: Please answer True, False, or I don?t know for each statement about the TIRF medicine that was most recently prescribed for you. 17a: Selling or giving away TIRF medicines is against the law. 100.0 98.5 98.9 100.0 True ?1 30 (88.4. 64 (91.7. 87 (93.8. 46 (92.3. 100.0) 100.0) 100.0) 100.0) False don't know 0.0 Correct response Note: All con?dence intervals are exact binomial 95% con?dence intervals. Client: TRIG Project: TIRF Wave3 Report Run Date and Time: 11/3/2014 1:09 PM Page 2 of TABLE 10.2.7 SECONDARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #5 IN ELIGIBLE AND COMPLETE RESPONDENTS KEY RISK MESSAGE 5: PATIENTS SHOULD NOT GIVE TIRF MEDICINES TO ANYONE ELSE EVEN IF THEY HAVE THE SAME SUB-GROUP ANALYSIS 7: AGE GROUP OF RESPONDENT (QUESTION 6): 0 S-7a 18 to 39 S-7b 40 to 49 0 S-7c 50 to 59 S-7d 60 or older 8-7 a S-7b S-7c S-older Demonstrated Understanding 0 correct responses correct response correct responses 30 100.0 63 96.9 87 98.9 45 97.8 Average number of correct responses 2.0 (1.6. 2.0 (1.7. 2.0 (1.7. 2.0 (1.6. 2.0) ?1 2.0) ?1 2.0) ?1 2.0) ?1 One-sided 95 con?dence interval using the normal approximation to the Poisson distribution. Client: TRIG Project: TIRF Wave 3 Report Run Date and Time: 11/3/2014 1:02 PM Page 1 of 02 TABLE 11.1.7 PRIMARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #6 IN ELIGIBLE AND COMPLETE RESPONDENTS KEY RISK MESSAGE 6: TIRF MEDICINES SHOULD BE STORED IN A SAFE PLACE AWAY FROM CHILDREN AND PROPERLY DISPOSED. SUB-GROUP ANALYSIS 7: AGE GROUP OF RESPONDENT (QUESTION 6): 8-73 18 to 39 S-7b 40 to 49 S-7c 50 to 59 S-7d 60 or older Question S?7a S?7b S?7c S?older (95% CI) (95% Cl) (95% CI) (95% CI) Question 13: Please answer True, False, or I don?t know for each statement about the TIRF medicine that was most recently prescribed for you. 13a: TIRF medicines should be stored in a safe place out of the reach of children. 100.0 100.0 98.5 98.9 True ?1 30 (88.4. 64 87 46 (92.3. 1000) (91.7. 100.0) (93.8. 100.0) 100.0) False don't know 0.0 Client: TRIG Project: TIRF Wave3 Report Run Date and Time: 11/3/2014 1:10 PM Page 1 of 3 03 Question S-7a S-7b S-7c S-older (95% CI) (95% CI) (95% CI) (95% CI) Question 17: Please answer True, False, or I don?t know for each statement about the TIRF medicine that was most recently prescribed for you. 17c: TIRF medicines must be disposed of as described in the speci?c product?s Medication Guide. True 29 (82.959799) 58 (79.83.9256) 84 (88.985387) 44 (85.95.9795) False don't know 1 3.3 7 10.8 4 4.5 2 4.3 l7e: A TIRF medicine can cause an overdose and death in any child who takes it. Tme 28 (719939392) 62 (87.95.9190) 77 (78.877336) 40 (73:35.1) False don't know 2 6.7 3 4.6 9 10.2 6 13.0 Client: TRIG Project: TIRF Wave3 Report Run Date and Time: 11/3/2014 1:10 PM Page 2 of 3 04 S-7a S-7b S-7c S-older (95% CI) (95% CI) (95% CI) (95% CI) Question 14: What should you do if an adult who has not been prescribed a TIRF medicine takes a TIRF medicine? (Please select one.) Get emergency help right 27 90.0 57 87.7 79 89.8 39 84.8 away. (73.5. 97.9) (77.2. 94.5) (81.5. 95.2) (71.1. 93.7) Do nothing0.0 Walt an hour and see person 15 OK. I don't know10.9 Correct response Note: All con?dence intervals are exact binomial 95% con?dence intervals. Client: TRIG Project: TIRF Wave 3 Report Run Date and Time: 11/3/2014 1:10 PM Page 3 of 3 05 TABLE 11.2.7 SECONDARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #6 IN ELIGIBLE AND COMPLETE RESPONDENTS KEY RISK MESSAGE 6: TIRF MEDICINES SHOULD BE STORED IN A SAFE PLACE AWAY FROM CHILDREN AND PROPERLY DISPOSED. SUB-GROUP ANALYSIS 7: AGE GROUP OF RESPONDENT (QUESTION 6): 0 S-7a 18 to 39 S-7b 40 to 49 0 S-7c 50 to 59 S-7d 60 or older S-7a S-7b S-7c S-older Demonstrated Understanding 0 correct responses correct response correct responses 0 0.0 1.5 3 3.4 5 10.9 3 correct responses 3 10.0 14 21.5 19 21.6 5 10.9 4 correct responses 26 86.7 49 75.4 66 75.0 36 78.3 Average number of correct responses 3.8 (3.2. 3.7 (3.3. 3.7 (3.4. 3.7 (3.2. 4.0) ?1 4.0) ?1 4.0) ?1 4.0) ?1 One-sided 95% con?dence interval using the normal approximation to the Poisson distribution. Client: TRIG Project: TIRF Wave3 Report Run Date and Time: 11/3/2014 1:08 PM Page 1 of 06 Listing 1 VERBATIM RESPONSES TO QUESTION 22 (How frequently do you receive a Medication Guide for the TIRF medicine at the pharmacy?) Verbatim Response every other time 6? (4) pharmacy Every couple months with every new box only had gotten once There is a Medication Guide in each box of Fentora I receive Client: TRIG Project: TIRF Wave3 Report Run Date and Time: 11/5/2014 11:07 AM Page 1 of 1 07 Listing 2 VERBATIM RESPONSES TO QUESTION 27 (Other person offering explanation of the Medication Guide) Verbatim Response Representative for the study Epocrates PDA app for handling medication interactions home Nurse Phannacy Tech Phannacy Tech ?lling my script spouse The PA (4) Pharmacy Technician Client: TRIG Project: TIRF Wave3 Report Run Date and Time: 11/5/2014 11:08 AM Page 1 of 1 08 Listing 3 VERBATIM RESPONSES TO QUESTION 30 (Questions about the information in the Medication Guide) Verbatim Response about the kit I should get also got questions answered in past as I called 1-800 asked to help understand them but can't remember now as I have been on this medication for like 13+ Don't . Effects of long temr use and recognizing withdrawal How do I if my pharmacy is registered? They directed me to the web page and the phone munber to call for any questions. How taking the medication affects your bladder? I to the doc once that I swallowed the drug (according to the instruction in the guide). and he said I should never do that b/c then I wouldn't get any bene?t from the swallowed drug. so my questions are (l)how can I accelerate the dissolution of the drug and (2)why does the guide say to swallow it if (presumably) stomach acids wipe it out? i was told it is ok to take long term? I would have appreciated it if at the outset someone had explained to me how dif?cult it is to stop taking opiod therapy before I made the decision to go onto such therapy. (4) It was than four years ago: I do not remember. Pharmacist answered the 1 or 2 questions I had. Proper disposal of lurfmished medication The important information was not in the literature The question (which has been answered) was related to the dosage. When you put the transdemral patch on how long does it take before it starts to work? 24 hours or immediately? Where can I get the container for the empty lollipops? WHY SO Client: TRIG Project: TIRF Wave3 Report Run Date and Time: 11/5/2014 11:15 AM Page 1 of 09 Listing 4 REPORTED ADVERSE EVENTS, PRODUCT COMPLAINTS, or Requests for Medical Information Verbatim Response "Been having troubles with my bladder since I started taking it." "hard time moving ar01md" get depressed and I can't sleep at night". have pain management for my pain", "just came home from hospital, for steroid shots. due to tears in my arms". "I'm not well", "I'm in severe pain. it's a little dif?cult today", have a lump they found in my breast", and in my stomach, I'm waiting for that to come back". "because they found liunps all in my body all over me", "it started when I called just had sharp pain in my aim. it's killing me" have headaches". had an allergic reaction to Subsys". had breathing problems and seizures with that reaction before". have cluster migraines". have had a neck injury". wish they would have included the important stuff in the literature about dry mouth and messing with your enamel. I found out from my Dentist" Client: TRIG Project: TIRF Wave3 Report Run Date and Time: 11/5/2014 12:19 PM Page 1 of 4 10 Verbatim Response "nausea". 501b weight loss with in 3 weeks. Not eaten in 3 days with vomiting and diarrhea last week. Chronic Pancreatitis. Took a shot for diarrhea and it made sick. 25AUG2014 4:59 PM ?You know something. I had a lot of trouble this month Merck/Medco was the cause of it. Even though my doctor made a human error merck did get the proper information in time enough to send them out. In we are only allowed a 30 day supply. I had to wear 1 patch instead of 2 for like 10 days. Not a single pharmacist explained it to me all they kept saying was do you want brand or generic. I told them just as the doctor has written it. They ?nally got it straight and I never received it until. lurtil like the 12th.? was sick for 2 weeks; I haven?t eaten in 3 days. I?ve lost 50 pounds in 3 weeks because I haven?t been able to eat and I don?t know if it?s because of the patches but they must work. I did not overuse the lozenges I only use what the doctor tells me? ?Par pharmaceutical sends me the overlays for the patches because they don?t stay on my skin? still get close to rimning out but it wasn?t actually until this last month that decrease to 1 instead of 2? ?Yes what?s happened is I?ve lost so much weight. all my teeth fell out after radiation? ?This past month I asked the pharmacist at Merck/Medco what should I do that I was out of medicine. and I had to go down to 1 patch and if that was ok or not ok. and they never answered? ?It was his hmnan error. he forgot to put the micrograms on there. it was remedied immediately but they didn?t ?ll it correctly? ?It wouldn?t stay on my skin; I used duct tape for a while til I fmally got Par Pharmaceuticals to send me an overlay? have severe diarrhea and throwing 11p last month it was both at the same time? ?My diarrhea comes in spurts of maybe several times a month then it clears up and I?m ok? could take a shot for the diarrhea but it made me really ill the last time? "That?s why I take it" (Long-lasting painful conditions not caused by cancer) Question 11 "True you have to have heavy duty migraine pain like I have" have got nerve damage that leads to migraine type pain" "I?ve got a bad memory the doctor says it isn?t Alzheimer?s but I believe it is." Client: TRIG Project: TIRF Wave3 Report Run Date and Time: 11/5/2014 12:19 PM Page 2 of 4 1 1 Verbatim Response "Where can I get the container for the empty lollipops? do the whole thing at once I pass out. It's just to much medicine and it makes me fall asleep not pass out. It makes me drowsy and fall asleep. I have a lot of health problems." "you mean pain from my shingles" this was in reference to him answering page 11 ?No. I?m not using it for that even though I was told it could be used it for that? Q10 (Breakthrough pain from cancer) ?technically it?s no. but I?ve been using it for migraines. Because none of the other medicines work. and I have a rare migraine disease." "For me. yes. but teclmically. no." "Because when I have a migraine. I end up having strokes." Chronic Back injuries Q10 I have chronic back and cancer I asked the Dr about the side effects and he didn?t know about them. He doesn?t know what my side effects should be. I?ve been on pain meds for a long time and what he is telling me it is supposed to be doing. it isn?t doing. It isn?t lasting long. have true pain.? I get tired all the time. I have a problem getting this medication because Medicare says hysil psycosis isn't cancer even though I am 011 Chemo for it and it's very painful and nothing else works for me. I have psoriatic arthritis and hysil which hysil is very rare and there isn't a lot of studies 011 it but it's just like cancer. I have a cold I have tumor pain in my head I'm not feeling well. I'm on chemo and some days I have good days others not so. I'm sick: I'm temiinally ill. I have PSD and Fibromyalgia: I had my knees replaced - it's eating away at my legs and bladder. it's like cancer- I have seizures to. I've been in the hospital so long" "Prescribed for back pain" Keeps falling off the sticks. Breaks apart off the stick they don't work properly and the cost is ridiculous when they don't work. She said it only works 45 minutes and then the pain is back. This product is so expensive if I didn't have health insurance I could never afford it. I have never seen a prescription be so costly. about the kit I should get also got questions answered in past as I called 1-800 asked to help rmderstand them but can't remember now as I have been on this medication for like 13+ Effects of long term use and recognizing withdrawal Client: TRIG Project: TIRF Wave3 Report Run Date and Time: 11/5/2014 12:19 PM Page 3 of 4 12 Verbatim Response How taking the medication affects your bladder? I mentioned to the doc once that I swallowed the drug (according to the instruction in the guide). and he said I should never do that b/c then I wouldn't get any bene?t ?om the swallowed drug. so my questions are (l)how can I accelerate the dissolution of the drug and (2)why does the guide say to swallow it if (presumably) stomach acids wipe it out? i was told it is ok to take long term? I would have appreciated it if at the outset someone had explained to me how dif?cult it is to stop taking opiod therapy before I made the decision to go onto such therapy. Proper disposal of un?nished medication The important information was not in the literature When you put the transdeimal patch on 110w long does it take before it starts to work? 24 hours or irmnediately? Where can I get the container for the empty lollipops? WHY SO I have a heart monitor and I have severe cramping in my left leg it's only happened a couple of times I think I am going to go see me heart Dr. just to be safe "History of migraines. and its not the migraines its problems with my neck that causes pain in my head." "Just changed the medicine because I didn't like it. Their to sweet. they had the original one that tasted like chalk and then they switched to the new ones that taste like sugar. New medication doesn't seem to work like old medicine. It dissolves to fast to much sugar. think it dissolves to fast because it dissolves in 5 minutes. Doesn't last but 5 minutes." I can?t swallow. so these medications are a god send to me. I wanted to make you aware that I recently changed from Actiq back to Fentora because the Actiq was messing up my teeth. I had oral cancer and issues with my mouth. The Actiq was causing pain in my mouth?. ?It caused a lot of accelerated damage to my teeth so I had to stop taking it?. ?Where I had to place it, it bums and was hinting my mouth". ?It got to the point where I could barely even keep them in my mouth because of the pain? Client: TRIG Project: TIRF Wave3 Report Run Date and Time: 11/5/2014 12:19 PM Page 4 of 4 13 Patient KAB Assessment Report Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Appendix C Page 52 of 52 Patient Survey Protocol Track Change Document: Comparison of 24month Survey to 36-month Survey FDA_2114 PROTOCOL TITLE: SPONSOR: VERSION: DATE: APPROVED Quantitative Testing of Patient/Caregiver Knowledge, Attitudes, and Behavior about Transmucosal Immediate Release Fentanyl (TIRF) Products Safety and Use Information TIRF REMS Industry Group (TRIG) ,Cephalon, Inc. (a wholly-owned subsidiary Deleted: Archimedes Phi-Ina US Inc. 11 of Teva Pharmaceutical Industries, Ltd.) Denomed Inc, Galena Biopharmaa? Insys Therapeutics Mallinckrodt Pharmaceuticals Meda Pharmaceuticals Mylan, Inc. Par Pharmaceutical, Inc. 70 _l Final Deleted: Endo Pharmaceuticals Deleted: Deleted: 6 Deleted: 10 Sep 2013 Deleted: FINAL 15 TABLE OF CONTENTS PAGE TABLE OF CONTENTS ......................................................................................... 2 1. LIST OF ABBREVIATIONS .................................................................................. 3 2. BACKGROUND ..................................................................................................... 4 3. OBJECTIVES OF THE EVALUATION SURVEY ............................................... 5 4. METHODS .............................................................................................................. 5 4.1 Qualitative Research on the Survey ......................................................................... 5 4.2 4.2.1 4.2.2 Survey Design .......................................................................................................... 5 Questions and Statements on REMS Goals ............................................................. 6 Additional Questions................................................................................................ 9 4.3 4.3.1 Subject Recruitment ................................................................................................. 9 Measures to Minimize Bias in the Sample............................................................. 10 5. 5.1.1 5.1.2 5.1.3 STUDY POPULATION ........................................................................................ 11 Sample Size ............................................................................................................ 11 Inclusion Criteria.................................................................................................... 11 Exclusion Criteria .................................................................................................. 12 6. SURVEY PROCESS ............................................................................................. 12 6.1 6.1.1 6.1.2 Screening and Survey Administration ................................................................... 12 Telephone ............................................................................................................... 12 Internet ................................................................................................................... 12 6.2 Measures to Minimize Bias in the Survey Process ................................................ 13 7. ANALYSIS ............................................................................................................ 13 8. SAFETY EVENT REPORTING ........................................................................... 14 9. PRIVACY PROTECTION AND CONFIDENTIALITY...................................... 14 LIST OF APPENDICES APPENDIX A Screening and Main Questionnaire...........................................................16 APPENDIX B SAMPLE Patient Letter of Invitation .......................................................41 FDA_2116 1. LIST OF ABBREVIATIONS CATI Computer-Assisted Telephone Interviewing CI Con?dence Interval EDC Electronic Data Capture ETASU Elements to Assure Safe Use FDA Food and Drug Administration HIPAA Health Insurance Portability and Accountability Act IRB Institutional Review Board KAB Knowledge. Attitudes and Behavior PBM Pharmacy Bene?ts Management PPAF Patient-Prescriber Agreement Form REMS Risk Evaluation and Mitigation Strategy SE Safety Event Project Speci?c Procedure Deleted: TIRF Transmucosal Inmiediate Release Fentanyl TIRF REMS TIRF REMS Access Program TRIG TIRF REMS Industry Group UBC United BioSource Corporation US United States 17 2. BACKGROUND Transmucosal Immediate Release Fentanyl (TIRF) medicines include the class of immediate- release opioid analgesics. which are indicated only for the management of breakthrough pain in cancer patients 18 years of age or older (16 or older for Actiq? and equivalent generics) Formatted: Superscript who are already receiving and tolerant to ioid therapy for their underlging persistent cancer Deleted: already pain. The TIRF medicines include Abstral . Actiqg. FentoraP. Lazandq . OnsolisAE. SubsysA . Matted: Superscript and generic versions of any of these brands. The TIRF REMS Industry Group (TRIG) Matted: Smetscn'pt includes ,Cephalon. Inc. (a wholly-owned subsidiary of Teva Pharmaceutical Industries. Ltd): Dep01ned_Inc.: Galena Biopharma. Inc.; Insys Therapeutics: Mallinckrodt Pharmaceuticals; Meda Pharmaceuticals: Mylan. Inc.: and Par Pharmaceutical. Inc. Formatted: Stperscr'pt Formatted: Slperscr?pt Formatted: Stperscr'pt The Food and Drug Administration (FDA) has determined that a class-wide Risk Evaluation matte?: Mr? and Mitigation Strategy (REMS) is required to mitigate the risks of misuse. abuse. addiction, W9M1WS "mm Us overdose and serious complications due to medication errors with the use of TM medicines. Deleted: Endo Plume-mils The TIRF REMS Access Program (herea?er referred to as TIRF REMS) was approved by the Deleted: FDA on December 28. 2011. The TIRF REMS consists of a Medication Guide. Elements to Assure Safe Use (ETASU). an Implementation System. and a Timetabl for Submissior of Assessment of the REMS. The Deleted: timetable goals of the TIRF REMS are to mitigate the risk of misuse. abuse. addiction. overdose; and serious complications due to medication errors by: Deleted: submission Deleted: am 1. Prescribing and dispensing TIRF medicines only to appropriate patients, which includes use only in opioid-tolerant patients 2. Preventing inappropriate conversion between TIRF medicines 3. Preventing accidental exposure to children and others for whom it was not prescribed 4. Educating prescribers. pharmacists. and patients on the potential for misuse. abuse. addiction, and overdose of TIRF medicines An important component of the TIRF REMS assessment is the conduct of quantitative evaluation surveys to assess patients? and caregivers? knowledge. attitudes. and behavior (KAB) regarding the safe use of TIRF medicines'as described in the product-speci?c Deleted: Medication Guide. This protocol will describe the administration of the surveys that will be conducted among patients who are treated with TIRF medicines. or their caregivers. Data ?om the surveys. together with other REMS evaluation metrics. will be used to determine whether changes need to be made to the REMS processes and/or educational materials to make them more e?ective in achieving the goals of the REMS. The surveys will be implemented so that data will be available for inclusion in the REMS Assessment Reports that will be submitted to the FDA at 12 months after approval of the TIRF REMS and annually therea?er. 1 8 3. OBJECTIVES OF THE EVALUATION SURVEY The evaluation survey will use a questionnaire to document the level of knowledge and assess the attitudes and behavior of patients around the following key information and risk messages communicated through the REMS: l) TIRF medicines can cause life-threatening breathing problems that can lead to death. 2) Patients should not take TIRF medicines if they are not opioid tolerant. 3) TIRF medicines should be taken exactly as prescribed by the healthcare provider. 4) Patients should not switch from a TIRF medicine to another medicine that contains fentanyl without talking to a healthcare provider. 5) Patients should not give TIRF medicines to anyone else even if they have the same 6) TIRF medicines should be stored in a safe place away from children and properly disposed. The survey will also include questions about whether patients received. read. and lmderstood the product-speci?c Medication Guide and Patient-Prescriber Agreement Form (PPAF). 4. METHODS The survey was designed in collaboration between the TRIG and United BioSource Corporation (UBC). and will be administered by UBC. 4.1 Qualitative Research on the Survey Qualitative research to test patient comprehension was performed on the patient survey in 201-2. Findings were incorporated into the survey prior to implementation of Wave 1. 4.2 Survey Design This survey will be conducted among a sample of patients or their caregivers who have ?lled a prescription for a TIRF medicine within the past 4 months prior to survey launch Deleted: mum caregivers Respondents who have participated in a previous wave of the TIRF REMS KAB survey will not be eligible to participate in subsequent survey waves. The survey will be administered using the following modalities: Self-administered. online through a secure website 19 0 Telephone surveys facilitated by a trained interviewer from the Survey Coordinating Center using a computer-assisted telephone interviewing (CATI) program The survey will begin with screening questions to con?rm respondent eligibility to participate in the survey. Completion of the entire survey is expected to take approximately 20 minutes. The survey included in Appendix is written to re?ect wording for both methods of smvey administration: Internet-based and telephone administration. 4.2.1 Questions and Statements on REMS Goals The questionnaire gmade up of multiple-choice. closed-ended statements or questions (the Deleted: KAB items of?! majority of which use true/false or yes/no dichotomous response options). and open-ended Deleted: are questions. These will evaluate current knowledge. attitudes. and behavior regarding the key risk messages noted in Section 3. The survey is written to follow principles of health literacy and readability. Questionnaire items will be presented in several formats: Statements or questions asking the respondent to indicate whether tl_re,statement or Belem: I question is true or false. or if they do not know the answer (there is a similar set of statements and questions that use ?yes.? or don?t know? as potential response options): 0 Statements or questions asking the respondent to choose from a de?ned list of possible statements or answers: and 0 Questions allowing for the respondent to provide information about when. Where and from whom they obtained a Medication Guide. as well as to list questions they have about information in the Medication Guides. Questionnaires will be analyzed to determine patient understanding of each key risk message. For statements or questions that use ?true? or ?yes? vs. ?false? or ?no? response options. the desired response for the key risk messages is generally ?true? or ?yes" indicating knowledge of. or behavior in accordance with. the objectives of the REMS. However. some questions are formatted to have the respondent disagree with the statement as written by providing response options of ?false? or ?no? to avoid having the same af?rmative answer for all desired responses. REMS statements. corresponding questions. and desired responses covering the key risk messages are identi?ed below and can be found in the complete survey questionnaire (Appendix A). For better readability. the patient questions. only. are presented in the key risk messages tables. Caregiver questions are presented in Appendix A. 20 Key Risk Message 1: TIRF medicines can cause life-threatening breathing problems that can lead to death. Question No. Question Desired response 13 Please answer True, False, or I don’t know for each statement about the TIRF medicine that was most recently prescribed for you. 13d TIRF medicines can cause life-threatening breathing problems that can lead to death. TRUE Key Risk Message 2: Patients should not take TIRF medicines if they are not opioid tolerant. Question No. Question Desired response Please answer True, False, or I don’t know for the following statement: 11 12 12a 13 13b TIRF medicines should only be taken by patients TRUE who are opioid tolerant. Please answer True, False, or I don’t know for each of the following statements. Opioid tolerant means that a patient is already taking other opioid pain medicines around-theTRUE clock and their body is used to these medicines. Please answer True, False, or I don’t know for each statement about the TIRF medicine that was most recently prescribed for you. It is OK for patients to take TIRF medicines for FALSE headache pain. FDA_2121 Key Risk Message 3: TIRF medicines should be taken exactly as prescribed by the healthcare provider. Question No. Question Desired response 12 Please answer True, False, or I don’t know for each of the following statements. 12b If a patient stops taking around-the-clock opioid pain medicine, they must also stop taking the TIRF medicine. 13/17 13c 17b TRUE Please answer True, False, or I don’t know for each statement about the TIRF medicine that was most recently prescribed for you. TIRF medicines should be taken exactly as TRUE prescribed by the doctor. It is OK to take TIRF medicines for short-term FALSE pain that will go away in a few days. Key Risk Message 4: Patients should not switch from a TIRF medicine to another medicine that contains fentanyl without talking to a healthcare provider. Question No. 12 12c Question Desired response Please answer True, False, or I don’t know for each of the following statements. It is safe to switch to another medicine that contains fentanyl without talking to a healthcare FALSE provider first. FDA_2122 Kev Risk Message 5: Patients should not give TIRF medicines to anyone else even if they have the same Question Question Desired response No. 12 Please answer True. False. or I don?t know for each of the following statements. A patient may give TIRF medicines to another 12d person if they have the same as the FALSE patient. 17 Please answer True. False. or I don?t know for each statement about the TIRF medicine that was most recently prescribed for you. 17a 3:111:11: Ior gm mg aw ay TIRF medicmes is against TRUE Key Risk Message 6: TIRF medicines should be stored in a safe place away from children and properly disposed. Question Question Desired response No. 13/17 Please answer True. False. or I don?t know for each statement about the TIRF medicine that was most recently prescribed for you. TIRF medicines should be stored in a safe 13a place out of the reach of children. TRUE TIRF medicines must be disposed of as 17c described in the speci?c product?s TRUE Medication Guide. A TIRF medicine can cause an overdose 17? and death in any child who takes it. TRUE What should you do if an adult who has not been prescribed a TIRF medicine takes a TIRF medicine? (Please select one.) Get emergency help right /:Deleted: 13 4.2.2 Additional Questions Questions about the requirements of the TIRF REMS. and receipt and understanding of the Medication Guides and PPAF will be asked a?er the key risk message questions. and will be followed by the collection of demographic information at the completion of the survey. 4.3 Subject Recruitment Patients will be recruited through a direct letter program. Patients will be invited through a network of national pharmacies and? a pharmacy bene?ts management (PBM) partner. which will provide abroad demographic coverage and include patients in 49 states. Leveraging one or more of these partners, a list will be created of patients who have ?lled a prescription for a TIRF medicine within 4 months prior to survey launch (?rst prescriptions and re?lls). Patients in this list will be invited to participate in the survey through an invitation letter (Appendix B) mailed directly to the patients on the pharmacy or letterhead at the corporate level via the United States (US) Postal Service. Deleted: each have I ,The invitation will indicate that participants will receive a $50 gift card for completing the survey. Each invitation will also include a unique code and directions for accessing the survey either via the Internet or by telephone through an interviewer at the Survey Coordinating Center. The unique code will be used to identify the manufacturer of the most recent TIRF prescription that the patient ?lled. Asample of patients who have ?lled a prescription for a TIRF medicine within the 4 months prior to survey launch will be chosen from the pharmacy partner?s and/or database. This sampling approach will be used to create several batches of survey invitations. The face-iv: anyconparsation?orthissuppon? Deleted: participate inthe mdidne becoutactedfordiispmpose Iflpracribu in?mmtionpackrt including bemailedtotheprescriber Prescriberswillnot overall number of 1mique patients and the duration of the survey period will dictate the size and number of invitation batches. If the required number of completed surveys is not achieved Deleted: random Deleted: PBM within a reasonable time frame. a second mailing will be sent to non-respondents from the original batch mailing and initial invitations will be sent to patients in the second batch. If the required number of completed surveys is still not achieved within a reasonable time ?ame. reminder letters will be sent to the patients in the second batch and initial invitations will be sent to the third batch of patients. If these efforts do not result in the required number of surveys within a reasonable time ?ame. then a new sample of patients may be selected i_f available. The intervals for sending reminder invitations to non-responders and for selecting a new sample will be condensed as necessary based on the actual rate of survey accrual relative to the proximity of the target survey close date. All respondents who complete the survey and who provide their contact information will be mailed a $50 gift card to thank them for their participation. The mailing will include a thank you letter. a copy of the product-speci?c Medication Guide. and a copy of the correct answers to the key risk message questions. 4.3.1 Measures to Minimize Bias in the Sample The sample of participating patients will be self-selected since respondents will voluntarily respond to the invitation to participate; however. the survey recruitment strategies are intended to recruit a heterogeneous sample of patients for participation. Respondents will be offered online or telephone options for completing the survey. Multiple modalities for sru'vey data collection allow for wider survey access to a more heterogeneous population. Respondents will be provided a unique code during the recruitment process and will be asked to provide the unique code to gain access to the online survey or when calling the Survey Deleted: random 1 24 Coordinating Center. The code will be deactivated after use to minimize the possibility for fraud. 5. STUDY POPULATION 5.1.1 Sample Size A sample of 300 patients treated with TIRF medicines is proposed for the survey wave. The size of the sample was determined based on both practical and statistical considerations. There is no target comprehension rate specified a priori. A sample of 300 completed surveys will allow estimation of the comprehension rate for each key risk message with a moderately high degree of precision. The table below shows the precision of the estimates for level of understanding using two-sided 95% confidence intervals (CIs) obtained with the sample size of 300 completed surveys. The noted CIs are used to indicate that for any survey-estimated rate of understanding, the true population rate of understanding is at least as high as the lower limit of the 95% CI and may be as high as the upper limit of the 95% CI. Table 5.1: Precision of Estimated Rates of Understanding with a Sample Size of 300 Estimated Rate of Understanding 5% 10% 15% 20% 25% 30% 35% 40% 45% 50% 55% 60% 65% 70% 75% 80% 85% 90% 95% 5.1.2 Estimated Confidence Interval 2.8% 8.1% 6.8% 14.0% 11.2% 19.6% 15.6% 25.0% 20.2% 30.3% 24.9% 35.5% 29.6% 40.7% 34.4% 45.8% 39.3% 50.8% 44.2% 55.8% 49.2% 60.7% 54.2% 65.6% 59.3% 70.4% 64.5% 75.1% 69.7% 79.8% 75.0% 84.4% 80.4% 88.8% 86.0% 93.2% 91.9% 97.2% Inclusion Criteria The following respondents are eligible to participate in the survey: • Patients who are 18 years of age or older who have filled a prescription for at least one of the TIRF medicines within 4 months prior to survey launch FDA_2125 Caregivers 18 years of age or older who care for patients who have ?lled a TIRF medicine prescription within the past 4 months prior to survey launch and are unable to take the survey for themselves 5.1.3 Exclusion Criteria The following respondents are not eligible to participate in the surveys: 0 Patients who have previously participated in the TIRF REMS KAB survey (this exclusion applies to the second and subsequent waves only) 0 Patients or their immediate family members who have ever worked for Anesta LLC. 'Cephalon. Inc. (a wholly-owned subsidiary of Teva Pharmaceutical Industries. Ltd.); Deleted: Archimedes Pharma US Inc; De omed Inc.; Galena Bio harma: Ins Thera eutics: Mallinckrodt Phannaceuticals: Deleted: EndoPhamncelm'cals Meda Phannaceuticals; Mylan. Inc.; Par Pharmaceutical, Pharmaceuticals. Deleted; ProStnkanInc; Ltd.; UBC: McKesson Specialty Care Solutions: RelayHealth; or the FDA. 6. SURVEY PROCESS 6.1 Screening and Survey Administration The questionnaire will begin with a screening module with questions to con?rm patient eligibility. The entire survey is expected to take approximately 20 minutes to complete. Depending on the answers to the screening questions. survey participation could either be terminated or continued. If ineligible. respondents are immediately noti?ed with a thank you message that survey participation has ended. If eligible. respondents are allowed to continue survey participation. The electronic data capture (EDC) system that is used for both methods of survey administration has been validated and is secure for receiving and storing survey data. The system is 21 CFR Part 11 and Health Insurance Portability and Accountability Act (HIPAA) compliant. Patient-identifying information will be stored separately ?om survey data. 6.1.1 Telephone The telephone survey is facilitated by a trained interviewer from the Survey Coordinating Center using a CATI program. The respondent will be required to provide a unique code to access the survey. Working from a CATI script. the interviewer will read questions or statements to the respondent and enter the responses into the EDC system. Screening and main elements of the questionnaire will be administered sequentially during the same telephone call. Telephone interviewing allows participation of respondents who do not have Internet access. or prefer to complete the survey in this manner. 6.1.2 Internet An Internet-based survey system will also be used for conducting the KAB surveys. If respondents select to participate in the survey online. they will be directed to a secured 26 website and instructed to enter a unique code to access the survey. An Internet survey will be convenient for respondents to participate since they can complete the questionnaire at any convenient time and location during the speci?ed survey time period. 6.2 Measures to Minimize Bias in the Survey Process A number of controls will be in place to ensure the survey is conducted in a controlled and professional manner and to minimize bias. For example. a unique code will be given to each survey participant and the code will be inactivated a?er use to minimize fraud. Telephone interviewers are highly trained and use a standardized script to administer the survey Deleted: interviews All questions will be programmed to ensure that questions are asked in the appropriate sequence. Skip patterns will be clearly indicated. Respondents cannot go back to a question once the question has been answered and cannot skip ahead. All questions must be answered in order to complete the survey. Response options presented in a list will be randomized to minimize positional bias. Programming will be reviewed by quality control and simulated users (User Acceptance Testing) prior to implementing the survey. 7. ANALYSIS Information obtained from the survey will be reported as descriptive statistics for the survey administration. study population. and the survey questions. Any free text ?elds will be grouped into applicable categories. Verbatim text from open-ended questions will be displayed when appropriate. The following will be reported as part of this analysis: 0 The number of invitations issued 0 The number of reminder letters 0 The number of respondents screened for participation 0 The number of respondents eligible for participation 0 The number of respondents who completed all questions presented to them 0 Description of survey participants. including: Type of respondent (patient/caregiver) Age (patient/caregiver) Gender (respondent) Educational level (respondent) Main language spoken at home (respondent) 27 - Ethnicity (respondent) Race (respondent) Geographic region (respondent) 0 Data from all respondents who completed all questions presented to them in the survey (?completers") will be analyzed. including: Frequency distribution of responses to each key risk message question. Percent of completers selecting desired response to each question relating to each key risk message and 95% CI. Measurement of understanding will be computed for each question of the key risk message individually. A secondary analysis will be conducted to determine the number of completers who answered all items correctly for the key risk message. Behavior questions will be summarized on a question-by-question basis and are not included in the analysis by key risk message. Additional analyses may be performed as needed. 8. SAFETY EVENT REPORTING The survey will be conducted via the Internet and by telephone. It is possible that a respondent may report an adverse event or other safety event experienced while taking TIRE medicines either in free text ?elds of the survey or while in conversation with the Survey Coordinating Center. If an event is mentioned to a Survey Coordinating Center Associate. the Associate will document the safety event and the respondent?s contact information. The respondent will also be informed that a representative from the appropriate TIRF medicine manufacturer may contact him/her if there are questions about the survey. The Internet-based questionnaires will be monitored for any comments recorded in ?ee text ?elds. Information on all comments that may constitute an adverse event or other safety event will be forwarded to the appropriate TIRF medicine manufacturer as described in the Safety Event Project Speci?c Procedure (SE PSP). Additional detail regarding processes for adverse event reporting will be speci?ed in the Deleted: SE /(oeaetea:/ 9. PRIVACY PROTECTION AND CONFIDENTIALITY All data collected during the survey will be held con?dential. The EDC system used for data collection all identi?able information and respondent identi?ers are stored separately from the survey responses. 28 Respondent names and addresses are collected in order to mail a $50 gift card, a Thank You Letter, a product-specific Medication Guide, and correct survey responses to key risk message questions after the survey is completed. Respondent contact information is also requested in the event a safety event is reported and a TIRF medicine manufacturer must obtain follow-up information. A respondent may be contacted only if clarification or follow-up is needed regarding a possible safety event that was mentioned to the interviewer or recorded in free text fields of the online survey. Respondents will be informed when they access the survey that they may be contacted if there are any questions about their survey responses. Respondents will be informed that their answers to the survey questions will not affect their ability to receive TIRF medicines. This protocol and survey will be reviewed and approved by a central Institutional Review Board (IRB) before administration of the survey. FDA_2129 APPENDIX A Screening and Main Questionnaire Survey Legend • [PROGRAMMER] is used to indicate directions to the programmer and is set in bold, red, uppercase letters between square brackets. [PATIENT] indicates text applicable to a patient when it differs from survey text for caregivers, parents and legal guardians. [PARENT/CAREGIVER/LEGAL GUARDIAN] indicates text applicable to parents, caregivers, and legal guardians when it differs from survey text for patients. • (INTERVIEWER) is used to indicate directions to the telephone interviewer and is set in bold, blue, text between parentheses. This text appears when content is to be administered by tlelphone only (for example, spontaneous adverse event reporting). • [ONLINE] indicates a question is worded specifically for administering the survey online. [PHONE] indicates a question is worded specifically to be read by a telephone interviewer and differs from the online text. • [BEGIN ONLINE/PHONE SURVEY CONTENT] and [END SURVEY CONTENT] are used to indicate to the programmer the type of survey administration and the beginning and end of the survey or sections within the survey content, for example, [BEGIN ADVERSE EVENT/PRODUCT COMPLAINT] and [END ADVERSE EVENT/PRODUCT COMPLAINT]. • [TERMINATE] is displayed next to responses that should cause the survey to end. The following termination language will be programmed into the survey or read by the interviewer unless different language is specified with the question. Thank you very much for your time today. Based on your answer, you are not eligible to take this survey. We appreciate your interest in the survey. • [RANDOMIZE LIST] is inserted before questions to indicate to the programmer that the responses should be randomized. Responses such as “I don’t know,” “Prefer not to answer” or “None of the above” will always appear at the end of the randomized responses. • [GO TO Ax] (Skip logic) is inserted after a response to indicate to the programmer that the survey should skip to the indicated question (for example, [GO TO Q17] skips to question 17). If no skip logic is indicated the survey continues to the next question in the sequence. FDA_2130 Survey Legend indicates to the programmer that one line should be provided for data entr y. indicates to the programmer that multiple lines should be provided for data entry (for example. two address lines). Deleted: or a ?ee-text response) LIST STATES indicates to the programmer that the response should be a drop-down list containing the states in the table below. Alabama Georgia Massachusetts New York Alaska Guam Michigan North Carolina American Hawaii Minnesota North Dakota Samoa Idaho Mississippi Northern Arizona Illinois Missouri Mariana Arkansas Indiana Montana Islands California Iowa Nebraska Ohro Colorado Kansas Nevada Oklahoma Connecticut Kentucky New Hampshire Oregon Delaware Louisiana New Jersey District Of Maine New Mexico Puerto ch0 Columbia Rhode Island Maryland Florida South Carolina South Dakota West Virginia The following is used to categorize survey populations into standard geographic regions but it is not displayed in the survey. Geographic Distribution (based on address) 1: Northeast. Midwest. South. and West regions Northeast Region New England Division - ME. NH. VT. MA. RI. CT Middle Atlantic Division - NY. NJ. PA Midwest Region East North Central Division - OH. IN. IL. MI. WI West North Central Division - MNSouth Region South Atlantic Division - DE. IVIDEast South Central Division - KY. TN, AL. MS 31 Survey Legend − West South Central Division - AR, LA, OK, TX West − Mountain Division - MT, ID, WY, CO, NM, AZ, UT, NV − Pacific Division WA, OR, CA, AK, HI • The following US territories are categorized as Other: Puerto Rico, Northern Mariana Islands, US Virgin Islands, American Samoa, and Guam. 1 U.S. Census Bureau, last revised Friday, 27-Jul-2001 12:59:43 EDT. FDA_2132 SURVEY PREANIBLE 1] Before you begin. we would like to share some important information about this survey. The survey is being conducted by the makers of AbstralP. Actiq?. FentoraP. LazandaP. OnsolisP. Formatted: Superscript Subsys? and the generic versions of any of these brands. These are lransmucosal meediate Formatted: Superscript gelease gentanyl medicines. also known as rapid onset opioids (and sometimes called ?fast Matted: acting fentanyls?) or TIRF medicines. Matted: Superscript The information collected will help the makers of TIRF medicines know if patients and their Formatted: caregivers understand important information about taking these medicines. The survey will Formatted: Superscript take about 20 minutes. There are no known risks to you in taking this survey. You may refuse to take part or withdraw at any time without penalty or loss of bene?ts to which you are otherwise entitled. Your answers to the questions or your decision to take part in the survey will not affect your ability to receive or take TIRF medicines. How \Ve Use Your Information Your answers to the survey questions will be combined with answers given by other people taking the survey. All answers will be put together and reported in anonymous form to manufacturers of TIRF medicines. Your name will not be used in any report. If you are eligible to take the survey. complete all the questions. and provide your contact information. you will receive a $50 gi? card for your time. Your name and address will be used only to send you the gift card. a Thank You Letter. a product-speci?c Medication Guide. and a copy of the correct answers to key risk message questions. a?er you complete the survey. Providing a telephone number is optional. Your telephone number will be used only if there are any questions about your answers. How \Ve Protect Your Privacy We respect that the privacy of your personal information is important to you. You will not be contacted for marketing purposes based on your personal information or your answers to the survey. Neither the manufacturers of IRF medicines nor their contractors will sell. transfer. or rent your information. Your answers will be kept strictly confidential. Your privacy will be protected; however. research survey records may be inspected by the FDA (Food and Drug Administration) and a company called which is the Institutional Review Board (IRB) that looks out for the interest of participants Your /[Deleted=) choice to allow the manufacturers of TIRF medicines to use your information is entirely voluntary. but necessary to take part in this survey. ?ow to Learn More About This Survey /[Moved (insertion) 33 If you have guestions about the survey. or have any groblems with the survey: please contact . - - - - 7 Moved down Onoeyouhxveansweredl A . . . . change your answers 1 If you have questlons about your as a research part1c1pant or related concerns. you may contact the IRB at Be sure to write down this telephone number; it will not be displayed again. Moved up How to Learn More About This Sum 11 problem with t1: survey, please contact the Survey Coordinating Caner at 1-877-379-3297 1 The information in this survey should not take the place of talking with your doctor or health care professional. If you have any questions about your condition or treatment or that of the person you care for. or if you would like more information about TIRF medicines, talk to your doctor. pharmacist, or other health care professional. Once you have answered a Question and moved oni you cannot go back and change your /[Moved (insertion) Thank you for your participation in this survey. ONLINE PREALVIBLE l] 34 1] Before you begin. we would like to share some important information about this survey. The survey is being conducted by the makers of Abstralf?. Actqu. Fentoraf. Lazandzf, Onsolisf?. /[Formatued: Superscript Subsys;Q and the generic versions of any of these brands. These are Transmucosal Immediate Formatted: Superscript Release Fentanyl medicines. also known as rapid onset opioids (INTERVIEVVER: Please Matted; Superscript pause brie?y) (and sometimes called ?fast acting fentanyls?) or TIRF medicines. Matted: (INTERVIEWER: Pronounce then spell out Matted: Simmt Formatted: Stperscr?pt The information collected will help the makers of TIRF medicines know if patients and their caregivers understand important information about taking these medicines. The survey will take about 20 minutes. There are no known risks to you in taking this survey. You may refuse to take part or withdraw at any time without penalty or loss of bene?ts to which you are otherwise entitled. Your answers to the questions or your decision to take part in the survey will not affect your ability to receive or take TIRF medicines. Now I would like to tell you about how your contact information will be used. Your answers to the survey questions will be combined with answers given by other people taking the survey. All answers will be put together and reported in anonymous form to manufacturers of TIRF medicines. Your name will not be used in any report. If you are eligible to take the sm'vey. complete all the questions. and provide your contact information. you will receive a $50 gi? card for your time. Your name and address will be used only to send you the gift card. a Thank You Letter. a product-speci?c Medication Guide. and a copy of the correct answers to key risk message questions. after you complete the survey. Providing a telephone number is optional. Your telephone number will be used only if there are any questions about your answers. Now I would like to tell you about how we protect your privacy. We respect that the privacy of your personal information is important to you. You will not be contacted for marketing purposes based on your personal information or your answers to the survey. Neither the manufacturers of TIRF medicines nor their contractors will sell. transfer. or rent your information. Your answers will be kept strictly confidential. Your privacy will be protected: however. research survey records may be inspected by the FDA (Food and Drug Administration) and a company called mm" which is the I Institutional Review Board (IRB) that looks out for the interest of survey palticipants_Your Deleted: choice to allow the manufacturers of TIRF medicines to use your information is entirely voluntary. but necessary to take part in this survey. Moved down Please feel ?ee to askme to repeat any questions or statemnts aswe go through I A the 51m 1 youcannot 35 If you have questions about your rights as a research participant or related concerns. you may contact the at The information in this survey should not take the place of talking with your doctor or health care professional. If you have any questions about your condition or treatment or that of the person you care for. or if you would like more information about TIRF medicines, talk to your doctor. pharmacist. or other health care professional. glease feel free to ask me to repeat any Questions or statements as we go through the survey. /l Moved (insertion) Once you have answered a question and moved oni you cannot go back and change your answers. Thank you for your participation in this survey. PHONE PREAIVIBLE l] 36 Do you agree to take part in this survey? 0 Yes 0 No Within the last 4 months, have you ?lled a prescription for yourself for a transmucosal immediate release fentanyl medicine (known as medicines?)? TIRF medicines include Abstralf?. Actiq?. FentoraP, Lazandao, OnsolisP, and the generic /[Formatted: English Supersaipt versions of any of these brands. Formatted: English Superscript l? . . 0 Yes TO Formatted En9'5h (U 5) Formatted: English (U.S.), Superscript No Formatted: Englidi Superscript Formatted: English (U.S.), Superscript I don?t know Are you a caregiver for someone who has ?lled a prescription for a TIRF medicine within the last 4 months? medicines include Abstralo, Actiqo, Fentorqg. Deleted: As aramnder' LazandaAQ, Onsolis? SubsysA and the generic versions of any of these brands. Formatted; English Superscript 0 Yes Formatted: English Superscript Formatted: Englidi Superscript No Formatted: English Superscript Formatted: English Superscript Idon?tknow mm 819% (U 5) Su .pt 37 For which TIRF medicines have you ?lled a prescription in the last 4 months? Please select all that apply. 4' For which TIRF medicines has the person you care for ?lled a prescription in the last 4 months? Please select all that apply. Abstral El Actiq. including generic versions of Actiq El Fentora El Lazanda El Onsolis El Subsys Other I don?t know ALL OTHER Deleted: 5. Have you ever taken part in a survey about a TIRF medicine before? 0 Yes No 0 I don?t know 38 6. 7. Which of the following groups best describes your age? ○ Under 18 [TERMINATE] ○ 18 – 29 ○ 30 – 39 ○ 40 – 49 ○ 50 – 59 ○ 60 – 69 ○ 70 or older ○ Prefer not to answer [TERMINATE] [CAREGIVER ONLY] Which of the following groups best describes the patient’s age? ○ Under 16 ○ 16 – 29 ○ 30 – 39 ○ 40 – 49 ○ 50 – 59 ○ 60 – 69 ○ 70 or older ○ Prefer not to answer [TERMINATE] FDA_2139 8. Have you or any of your immediate family members ever worked for any of the following companies or agencies? Please select all that apply. QM El Anesta LLC Cephalon. Inc. (a wholly-owned subsidiary of Teva Pharmaceutical Industries, [369?: ll Ltd.) Depomed_Inc. Galena Biopharmalii Insys Therapeutics Mallinckrodt McKesson Specialty Care Solutions Meda Pharmaceuticals Mylan. Inc. Par Pharmaceutical. Inc. ge'etw 11 Teva Pharmaceuticals, Ltd. United BioSource Corporation FDA (Food and Drug Administration) No SELECTED IN ADDITION TO OTHER RESPONSES, I don?t know 2] answer the following questions based on information about the TIRF medicine that was most recently prescribed for you. TIRF medicines include Abstra 0. Acti Q, FentoraQ, LazandaP, OnsolisAO, and the generic versions of these brands. Please think Formatted: Stperscr'pt Formatted: Stperscr?pt of the information that you read or that was provided to you by a doctor, nurse, or other healthcare professional. Ifyou don?t know the answers to any of the following questions please respond don?t know? instead of guessing the correct responses. Formatted: Stperscr'pt Formatted: Stperscr?pt Formatted: Stperscr'pt Formatted: Stperscr?pt 1 40 answer the following questions based on information about the TIRF medicine that was most recently prescribed for the patient. TIRF medicines include Abstralo, Formatted: Superscript Actiqf. FentoraP, Lazandaf?, Onsolisf. and the generic versions of these brands. Formatted: Superscript Please think of the information that you read or that was provided to you or to the patient by a Matted: Wrint doctor. nurse. or other healthcare professional. Ifyou don?t know the answers to any of the Matted: Wt followmg questions please respond don?t know? instead of guessmg the correct responses. atted: . Formatted: Stperscr'pt 9 Did the doctor. nurse. or other healthcare professional in the doctor?s o?ice ever talk to you about the risks and possible side effects of the TIRF medicine that was most recently prescribed for you? TIRF medicines include AbstralP. Actqu, /[Formatted: Superscript FentoraQ, LazandaP. Onsolng. and the generic versions of these brands. Formatted: Superscript Formatted: Stperscr'pt Did the doctor, nurse, or other healthcare professional in the doctor?s 3mm 5 ript of?ce ever talk to you about the risks and possible side effects of the TIRF medicine awed. that was most recently prescribed to the patient? TIRF medicines include Abstra I: Actiqo, FentoraP, LazandaP, OnsolisP, and the generic versions of these a I I Formatted: Stperscr'pt brands. Formatted: Stperscr'pt 0 Yes Formatted: Stperscr'pt Formatted: Stpersa'pt NO Formatted: Stperscr?pt Form tted: I don?t know a 10. For which of the following conditions should you use a TIRF medicine? /[De'ete? I For which of the following conditions should the person you take care /l ?den? of use a TIRF medicine? 9 Yes I d?n know 10a. Headache or migraine pain 0 0 10b. Breakthrough pain from cancer 0 0 10c. Dental pain 0 0 0 10d. Pain after surgery 0 0 10e. Long-lasting painful conditions not caused by cancer 0 11. Please answer True, False, or I don?t know for the following statement: 41 TIRF medicines should only be taken by patients who are opioid tolerant. 12. ○ True ○ False ○ I don’t know Please answer True, False, or I don’t know for each of the following statements. True False I don’t [RANDOMIZE LIST] know 12a. Opioid tolerant means that a patient is already taking other opioid pain medicines around-the-clock and their body is used to these medicines. ○ ○ ○ 12b. If a patient stops taking around-the-clock opioid pain medicine, they must also stop taking the TIRF medicine. ○ ○ ○ 12c. It is safe to switch to another medicine that contains fentanyl without talking to a healthcare provider first. ○ ○ ○ 12d. A patient may give TIRF medicines to another person if they have the same symptoms as the patient. ○ ○ ○ FDA_2142 13. [PATIENT] Please answer True, False, or I don’t know for each statement about the TIRF medicine that was most recently prescribed for you. [CAREGIVER] Please answer True, False, or I don’t know for each statement about the TIRF medicine that was most recently prescribed for the patient. I don’t [RANDOMIZE LIST] True False know 13a. TIRF medicines should be stored in a safe place out of the reach of children. ○ ○ ○ 13b. It is OK for patients to take TIRF medicines for headache pain. ○ ○ ○ 13c. TIRF medicines should be taken exactly as prescribed by the doctor. ○ ○ ○ 13d. TIRF medicines can cause life-threatening breathing problems that can lead to death. ○ ○ ○ 14. What should you do if an adult who has not been prescribed a TIRF medicine takes a TIRF medicine? (Please select one.) [RANDOMIZE LIST] ○ Wait an hour and see if the person is OK. ○ Get emergency help right away. ○ Do nothing. ○ I don’t know. FDA_2143 15. [PATIENT] Did the doctor, nurse, or other healthcare professional in the doctor’s office ever tell you how to use the TIRF medicine that was most recently prescribed for you? [CAREGIVER] Did the doctor, nurse, or other healthcare professional in the doctor’s office ever tell you how to use the TIRF medicine that was most recently prescribed for the patient? 16. ○ Yes ○ No ○ I don’t know [PATIENT] Did the doctor, nurse, or other healthcare professional in the doctor’s office ever tell you how to store or keep the TIRF medicine that was most recently prescribed for you? [CAREGIVER] Did the doctor, nurse, or other healthcare professional in the doctor’s office ever tell you how to store or keep the TIRF medicine that was most recently prescribed for the patient? ○ Yes ○ No ○ I don’t know FDA_2144 17. 173. 17b. 17c. 17d. l7e. Please answer True. False. or I don?t know for each statement about the TIRF medicine that was most recently prescribed for you. Please answer True. False, or I don?t know for each statement about the TIRF medicine that was most recently prescribed for the patient. law. will go away in a few days. speci?c product?s Medication Guide. REMS Access Program). True False I don?t know Selling or giving away medicines is against the It is OK to take TIRF medicines for short-term pain that TIRF medicines must be disposed of as described in the TIRF medicines are only available to patients through a pharmacy enrolled in a special program (called the TIRF 0 0 /[Deleted: program A TIRF medicine can cause an overdose and death in 0 any child who takes it. 3] The next set of questions is about the Medication Guide for the TIRF medicine that was most recently prescribed for you. The next set of questions is about the Medication Guide for the medicine that was most recently prescribed for the patient. A Medication Guide is a paper handout that contains important information about the risks associated with the use of a TIRF medicine and how to use it safely. Medication Guides always include the title ?Medication Guide? followed by the name of the medicine and its pronunciation. The Medication Guide usually has a section titled ?What is the most important information I should know?? The Medication Guide is in a question-and-answer format and may be given to you by your pharmacist, doctor. or other healthcare professional. Deleted: or /[Deleted: PREAMBLE 3111 1 45 I8. 19. 20. Have you ever received a Medication Guide for the TIRF medicine that was prescribed for you? Have you or the patient ever received a Medication Guide for the TIRF medicine that was prescribed for the patient? 0 Yes 0 No TO PREAMBLE 4] 0 I don?t know TO PREANIBLE 4] Did you receive the Medication Guide from the doctor who prescribed the TIRF medicine or someone in the doctor?s of?ce? Did you or the patient receive the Medication Guide from the doctor who prescribed the TIRF medicine or someone in the doctor?s of?cedon?t know TO When was the Medication Guide given to you? Please select all that apply. When was the Medication Guide given to you or the patient? Please select all that apply. At the ?rst appointment with the doctor who prescribed the TIRF medicine Q, At the last appointment with the doctor who prescribed the TIRF medicine EL I don?t remember ALL OTHER 1 46 21. [PATIENT] Did you receive the Medication Guide for the TIRF medicine from the pharmacy? [CAREGIVER] Did you or the patient receive the Medication Guide for the TIRF medicine from the pharmacy? 22. ○ Yes ○ No [GO TO Q23] ○ I don’t know [GO TO Q23] [PATIENT] How frequently do you receive a Medication Guide for the TIRF medicine at the pharmacy? [CAREGIVER] How frequently do you or the patient receive a Medication Guide for the TIRF medicine at the pharmacy? 23. 24. ○ Only with the first filled prescription ○ Each time a prescription is filled ○ Other (please specify): _____________________________ ○ I don’t know Did you read the Medication Guide? ○ Yes ○ No [GO TO Q26] ○ I don’t know [GO TO Q26] How much did you read? ○ All of it ○ Most of it ○ Some of it ○ I don’t know FDA_2147 25. How much of the Medication Guide did you understand? 0 All of it 0 Most of it 0 Some of it 0 None of it 0 I don?t know 26. Did someone offer to explain the Medication Guide to youdon?t know TO 27. Who offered to explain the Medication Guide to you? Please select all that apply_ wet?: (saw Deleted: The doctor or another healthcare professional in the doctor?s o?ice The pharmacist where the TIRF medicine prescription was ?lled El Someone else (specify the type of person but not his/her name) TEXTL /[De'eted= 28. Did you accept the offer to have the Medication Guide explained to youdon?t know TO 1 48 29. How much of the explanation did you understand? 0 All of it 0 Most of it 0 Some of it 0 None of it I don?t know 30. Did you or do you have any questions about the information in the Medication Guide? 0 Yes 0 No TO PREANIBLE 4] 0 I don?t know TO PREANIBLE 4] 31. What are your questions? 4] The next set of questions is about the Patient-Prescriber Agreement Form for TIRF medicines. As a reminder, TIRF medicines include Abstralo. Actqu. FentoraP. LazandaP, OnsolisP. Formatted: Superscript and the generic versions of any of these brands. The Patient-Prescriber Agreement is Formatted: Superscript a form that is signed by the doctor and the patient or their caregiver. This form may also be Matted; referred to as the Prescriber-Patient Agreement. Formatted: Stlperscript Formatted: Stperscr'pt PREAMBLE 4] Formatted: Stperscr'pt 32. Did the doctor or someone in the doctor?s o?'ice explain the Patient-Prescriber Agreement Form to youdon?t know TO 1 49 33. 34. How much of the explanation did you understand? ○ All of it ○ Most of it ○ Some of it ○ None of it ○ I don’t know [PATIENT] Did you sign a Patient-Prescriber Agreement Form? [CAREGIVER] Did you or the person you are caring for sign a Patient-Prescriber Agreement Form? 35. ○ Yes ○ No [GO TO DEMOGRAPHICS PREAMBLE] ○ I don’t know [GO TO DEMOGRAPHICS PREAMBLE] Did the doctor or someone in the doctor’s office give you a copy of the signed Patient-Prescriber Agreement Form? ○ Yes ○ No ○ I don’t know [DEMOGRAPHICS PREAMBLE] There are just a few more questions to help us combine your answers with other answers we have received. 36. What is your gender? ○ Male ○ Female ○ Prefer not to answer FDA_2150 37. 38. What is the highest level of education you have completed? 0 0 What is the main language you speak at home?, 0 0 Less than high school Some high school High school graduate/GED Some college/Associate?s degree Bachelor?s degree Master?s degree Professional or Doctoral degree Prefer not to answer English French Spanish Portuguese Italian German Chinese Japanese Korean Other Prefer not to answer 51 39. Are you Hispanic or Latino? 0 0 Yes No Prefer not to answer 40. For informational purposes only. which of the following U.S. census categories best describes your race?' 0 American Indian or Alaska Native Asian (origins of Far East. Southeast Asia or the Indian subcontinent) Black or African American Native Hawaiian or Other Paci?c Islander White Two or more races Other Prefer not to answer 41. In which state do you live? LIST INPUT WITH STATES TABLE WITH ?Prefer not to answer? AT 52 ONLY: ADVERSE (INTERVIEWER: Please record if respondent spontaneously reported an adverse event or product complaint during the course of this interview.) 0 Yes 0 No TO CLOSING 1] Enter Safety Adverse Event Verbatim (INTERVIEWER: Indicate to the respondent that someone may callback to ask more questions about the adverse event or product complaint that was reported.) ADVERSE 1] you are eligible to receive a $50 gift card for your time completing the survey. In order Formatted: Font: Bold to receive the gift card, we need to collect your name and address so that we can mail it to you. If you do not provide your name and address you will not receive the gift card for your time taking the survey. Do you agree to give us your name and mailing address so we can send your payment? numbering 0 Yes 0 No TO CLOSING 2] FIRST NAME: TEXTL Deleted: LAST NAME: TEXTL Deleted: ADDRESS: I CITY: TEXTL Deleted: STATE: LIST INPUT WITH STATES I ZIP: l5 NUMERIC CHARACTERS ONLYL Formatted: Font color: Red 53 2] NV would also like to ask for your telephone number. Providing your telephone number Formatted: Font: Bold is optional and it will be used to contact you only if there are questions about your survey responses. . Deleted ,Do you want to prov1de your telephone number? Formatted Une spadng smgle, No bullets or 0 Yes numbenng No T0 CLOSING 3] Telephone: NUMERIC Fm? ?1 Deleted: CLOSING 2 3] This is the end of the survey. Ifyou have questions about the survey, please contact the Survey Coordinating Center at 1-87 7 -3 79-3297 . Thank you again for your help. OF SURVEY 54 APPENDIX B SAMPLE Patient Letter of Invitation [PAT_FIRST_NAME] [PAT_LAST_NAME [CURR_DATE] [PAT_STREET_ADDR] [PAT_CITY], [PAT_STATE] [PAT_ZIP] Dear [PAT_FULL_NAME]: Thank you for choosing [pharmacy partner or PBM name] for your prescription needs. The purpose of this letter is to inform you about a voluntary research survey being conducted by [COMPANY], the maker of [BRAND_GENERIC]. The survey is part of an FDA requirement to find out if patients and/or their caregivers understand important safety information about [BRAND] and other medicines like it. The first 300 people who complete this 20-minute survey and provide their contact information will receive a $50 [pharmacy partner or PBM name] gift card from [COMPANY] to thank them for their time. You may be eligible to take part if you have taken [BRAND] and are 18 years of age or older. If you are unable to take the survey yourself, a caregiver who is 18 or older may be eligible to take the survey for you. The survey asks questions about the type of information you received about [BRAND] and where you get your medical information. If you are interested in participating and to find out if you are eligible: • • Go to www.TIRFREMSsurvey.com any time or Call 877-379-3297, 8 a.m. to 8 p.m. Eastern Time, Monday through Friday Please have this letter with you at the time you take the survey. You will be asked to provide this code prior to starting the survey: [CODE_ID]. *It is recommended that you take the survey on a desktop or laptop computer. Taking the survey on mobile devices, such as smart phones, tablets, and e-notebooks, is not supported. (over, please) FDA_2155 You are not required to take part in this survey. If you choose to take part, please be assured that your contact information and your individual responses will be kept strictly confidential. You will not be asked to identify yourself to participate in the survey. However, if you wish to receive the $50 gift card from [COMPANY], you must provide your name and contact information for delivery. Your answers to the survey questions will be combined with answers given by others, and your name will not be used in any written report or publication. Neither taking the survey nor your answers to the questions will affect your ability to receive or take [BRAND]. Sincerely, [Pharmacy partner or PBM name] [COMPANY] funded the cost of the gift card, the cost of mailing this letter and paid a fee to [pharmacy partner or PBM name]. The research study is not being conducted by [pharmacy partner or PBM name]. No information that can identify you, your medication, or your health condition will be provided by [pharmacy partner or PBM name] to [COMPANY]. This letter provides information about a drug prescribed by your doctor and is not a recommendation by [pharmacy partner or PBM name] to use a particular drug for your condition. Call [pharmacy partner or PBM name] toll free at xxx-xxx-xxxx if you do not wish to continue receiving mailings about [BRAND] from [pharmacy partner or PBM name]. FDA_2156 12.4.2 Pharmacy KAB Survey 57 Pharmacy KAB Assessment Report Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Title: Page 1 of 50 Transmucosal Immediate Release Fentanyl (TIRF) REMS Assessment Quantitative Testing of Pharmacist Knowledge, Attitudes, and Behavior (KAB) about TIRF Products’ Safety and Use Information Document Number Wave 3, 36-month REMS Assessment; Version 1.0 Survey Time Period 18 August 2014 – 22 October 2014 Product Name: Transmucosal Immediate Release Fentanyl Sponsor: TIRF REMS Industry Group (TRIG) of Companies: Cephalon, Inc. (a wholly-owned subsidiary of Teva Pharmaceutical Industries, Ltd.) Depomed, Inc. Galena Biopharma, Inc. Insys Therapeutics Mallinckrodt Pharmaceuticals Meda Pharmaceuticals Mylan, Inc. Par Pharmaceutical, Inc. Date: 19 December 2014 Confidentiality Statement The information contained herein is confidential and the proprietary property of the TRIG of Companies and its affiliates, and any unauthorized use or disclosure of such information without the prior written authorization of the TRIG is expressly prohibited. FDA_2158 Pharmacy KAB Assessment Report Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies TABLE OF CONTENTS Page 2 of 50 PAGE TABLE OF CONTENTS......................................................................................................... 2  LIST OF TABLES ................................................................................................................... 3  LIST OF APPENDICES .......................................................................................................... 4  LIST OF ABBREVIATIONS .................................................................................................. 5  1.  PHARMACIST SURVEY BACKGROUND .................................................... 6  2.  PHARMACIST SURVEY OBJECTIVES......................................................... 7  3.  SURVEY METHODOLOGY ............................................................................ 7  3.1  Survey Sample.................................................................................................... 7  3.1.1  Eligibility ............................................................................................................ 8  3.1.2  Recruitment ........................................................................................................ 8  3.2  Questions and Statements on Key Risk Messages ............................................. 8  3.2.1  Key Risk Message 1 ........................................................................................... 9  3.2.2  Key Risk Message 2 ........................................................................................... 9  3.2.3  Key Risk Message 3 ......................................................................................... 10  3.2.4  Key Risk Message 4 ......................................................................................... 11  3.3  Additional Questions ........................................................................................ 11  4.  STATISTICAL METHODS ............................................................................ 12  4.1  Study Population .............................................................................................. 12  4.1.1  Primary Analysis Population ............................................................................ 12  4.1.2  Sub-groups of Interest ...................................................................................... 12  4.1.2.1  Primary Analyses ............................................................................................. 13  4.1.2.2  Secondary Analyses ......................................................................................... 13  4.1.3  Pharmacist Report of an Adverse Event, Product Complaint, or Medical Information Request during the Survey ............................................. 13  5.  RESULTS......................................................................................................... 14  5.1  Survey Participants ........................................................................................... 14  5.1.1  Survey Participant Administration Results ...................................................... 14  5.1.2  Pharmacist Demographic and TIRF Product Dispensing Characteristics .................................................................................................. 18  FDA_2159 Pharmacy KAB Assessment Report Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 3 of 50 5.1.3  TIRF Medicines Educational Materials ........................................................... 21  5.2  KAB Survey Objectives ................................................................................... 22  5.2.1  Key Risk Message Results ............................................................................... 22  5.2.1.1  Key Risk Message 1 ......................................................................................... 22  5.2.1.2  Key Risk Message 2 ......................................................................................... 25  5.2.1.3  Key Risk Message 3 ......................................................................................... 27  5.2.1.4  Key Risk Message 4 ......................................................................................... 29  5.2.2  Other Survey Questions ................................................................................... 31  5.2.2.1  Additional Questions about TIRF Medicines Safety ....................................... 31  5.2.2.2  Pharmacist Activities When Dispensing TIRF Medicines ............................... 34  5.2.3  Sub-group Analysis of Responses to Key Risk Messages ............................... 38  5.3  Spontaneous Reporting of Adverse Events, Product Complaints, or Medical Information Requests ......................................................................... 38  5.4  Summary of Correct Responses for Key Risk Messages ................................. 39  6.  FDA FEEDBACK ............................................................................................ 44  7.  DISCUSSION AND CONCLUSIONS ............................................................ 44  LIST OF TABLES Table 1.  Survey Participant Administration Results .................................................... 14  Table 2.  Survey Participant Screening Results ............................................................ 16  Table 3.  Time to Complete Survey for Completers (Minutes) .................................... 17  Table 4.  Demographic Characteristics of Eligible Pharmacists ................................... 19  Table 5.  Characteristics of Respondents Completing the Survey ................................ 20  Table 6.  Responses to Questions About TIRF Medicines Educational Materials ........................................................................................................ 21  Table 7.  Responses Linked to Key Risk Message 1: TIRF Medicines Are Contraindicated in Opioid Non-Tolerant Patients ......................................... 23  Table 8.  Responses Linked to Key Risk Message 2: TIRF Medicines Are Only Indicated for the Management of Breakthrough Pain in Adult Cancer Patients 18 Years of Age and Older (16 Years of Age and Older for Actiq® Brand and Generic Equivalents) Who Are Already Receiving and Who Are Tolerant to Around-The-Clock Opioid Therapy for Their Underlying Persistent Cancer Pain ................................... 26  FDA_2160 Pharmacy KAB Assessment Report Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 4 of 50 Table 9.  Responses Linked to Key Risk Message 3: TIRF Medicines Contain Fentanyl, an Opioid Agonist and a Schedule II Controlled Substance, With Abuse Liability Similar to Other Opioid Analgesics. ........................... 28  Table 10.  Responses Linked to Key Risk Message 4: TIRF Medicines Are Not Interchangeable with Each Other, Regardless of Route of Administration. .............................................................................................. 30  Table 11.  Responses to Additional Questions about the Safe Use of TIRF Medicines ....................................................................................................... 31  Table 12.  Responses to Additional Questions about the Safe Use of TIRF Medicines: Question asked of Inpatient Pharmacists, Only ......................... 34  Table 13.  Responses to Questions about Activities When Dispensing TIRF Medicines ....................................................................................................... 35  Table 14.  Responses to All Questions about Activities When Dispensing TIRF Medicines: Asked of Inpatient Pharmacies Only.......................................... 37  Table 15.  Responses to All Questions about Activities When Dispensing TIRF Medicines: Outpatient Pharmacists Only...................................................... 37  Table 16.  Responses to All Questions about Activities When Dispensing TIRF Medicines: Closed System Pharmacy Outpatient Pharmacists Only ............ 38  Table 17.  Summary of Correct Responses for Key Risk Messages............................... 40  Table 18.  Correct/Desired Response Rate of Low Scoring Questions Across the Three Pharmacist KAB Survey Waves. ......................................................... 45  LIST OF APPENDICES Appendix A Pharmacy Survey Protocol ............................................................................. 48  Appendix B Pharmacy Survey Listings and Sub-group Analysis Tables .......................... 49  Appendix C Pharmacy Survey Protocol Track Change Document: Comparison of 24-month Survey to 36-month Survey........................................................... 50  FDA_2161 Pharmacist KAB Assessment Report Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 5 of 50 LIST OF ABBREVIATIONS AE/PC PSP Adverse Event/Product Complaint Project Specific Procedure CSP Closed System Pharmacy ETASU Elements to Assure Safe Use FDA Food and Drug Administration KAB Knowledge, Attitudes, and Behavior NA Not Applicable REMS Risk Evaluation and Mitigation Strategy SD Standard Deviation SCC Survey Coordinating Center TIRF Transmucosal Immediate Release Fentanyl TIRF medicines Transmucosal Immediate Release Fentanyl products TIRF REMS Access Program REMS Program for TIRF medicines TRIG TIRF REMS Industry Group UBC United BioSource Corporation US United States USPS United States Postal Service FDA_2162 Pharmacist KAB Assessment Report Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies 1. Page 6 of 50 PHARMACIST SURVEY BACKGROUND Transmucosal Immediate Release Fentanyl (TIRF) medicines are a class of immediaterelease opioid analgesics that are indicated only for the management of breakthrough pain in cancer patients 18 years of age or older (16 or older for Actiq® [fentanyl citrate oral transmucosal lozenge] and equivalent generics) who are receiving and already tolerant to opioid therapy for their underlying persistent cancer pain. The TIRF medicines include Abstral®, Actiq®, Fentora®, Lazanda®, Onsolis®, Subsys®, and their generic equivalents. The TIRF Risk Evaluation and Mitigation Strategy (REMS) Industry Group (TRIG) includes Cephalon, Inc. (a wholly-owned subsidiary of Teva Pharmaceutical Industries, Ltd.), Depomed, Inc., Galena Biopharma, Inc., Insys Therapeutics, Mallinckrodt Pharmaceuticals, Meda Pharmaceuticals, Mylan, Inc., and Par Pharmaceutical, Inc. The Food and Drug Administration (FDA) has determined that a shared system REMS is required to mitigate the risk of misuse, abuse, addiction, overdose, and serious complications due to medication errors with the use of TIRF medicines. The TIRF REMS Access Program (hereafter referred to as TIRF REMS) was approved by the FDA on 28 December 2011. The TIRF REMS consists of a Medication Guide, Elements to Assure Safe Use (ETASU), an Implementation System, and a Timetable for Submission of Assessments of the REMS. The goals of the TIRF REMS are to mitigate the risk of misuse, abuse, addiction, overdose, and serious complications due to medication errors by the following: 1. Prescribing and dispensing TIRF medicines only to appropriate patients, which includes use only in opioid-tolerant patients. 2. Preventing inappropriate conversion between TIRF medicines. 3. Preventing accidental exposure to children and others for whom it was not prescribed. 4. Educating prescribers, pharmacists, and patients on the potential for misuse, abuse, addiction, and overdose of TIRF medicines. An important component of the TIRF REMS assessment is the conduct of quantitative evaluation surveys to assess pharmacists’ understanding and knowledge of the safe use and appropriate prescribing of TIRF medicines as described in the TIRF REMS educational materials, enrollment form, and Prescribing Information of each product. Administration of the surveys conducted among pharmacies enrolled in the TIRF REMS Access Program is described in the protocol (See Appendix A). Note: Protocol and Survey question revisions from the 24-month assessment report are identified in the track change version found in Appendix C. Data from the surveys, together with other REMS evaluation metrics, will be used to determine whether changes need to be made to the REMS processes or educational materials to make them more effective in achieving the goals of the REMS. FDA_2163 Pharmacist KAB Assessment Report Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 7 of 50 This report describes the results from the pharmacists survey conducted for the 36-month TIRF REMS Access Program Assessment. The 36-month Knowledge, Attitudes, and Behavior (KAB) survey launched on 18 August 2014 and closed on 22 October 2014. 2. PHARMACIST SURVEY OBJECTIVES The evaluation survey uses a questionnaire to document the level of knowledge and assess the attitudes and behavior of pharmacists regarding the following key information and risk messages communicated through the REMS: 1. TIRF medicines are contraindicated in opioid non-tolerant patients. 2. TIRF medicines are only indicated for the management of breakthrough pain in adult cancer patients 18 years of age and older (16 or older for Actiq® and equivalent generics) who are already receiving and who are tolerant to around-the-clock opioid therapy for their underlying persistent cancer pain. 3. TIRF medicines contain fentanyl, an opioid agonist and a Schedule II controlled substance, with abuse liability similar to other opioid analgesics. 4. TIRF medicines are not interchangeable with each other, regardless of route of administration. 5. Patients and their caregivers must be instructed that TIRF medicines contain a medicine in an amount that can be fatal in children, in individuals for whom it is not prescribed, and in those who are not opioid tolerant. The survey also collects data on behaviors, such as receipt and use of educational materials and compliance with REMS requirements. 3. SURVEY METHODOLOGY This section summarizes the survey design and the questions that were designed to test pharmacist understanding of the key risk messages of the REMS. Full details of the survey design are in the protocol, which can be found in Appendix A. 3.1 Survey Sample This survey was conducted among a random sample of pharmacists who were enrolled in the TIRF REMS Access Program as of 05 August 2014. A target sample of 300 pharmacists who dispense TIRF products and were known to have received the REMS educational materials were surveyed in this third KAB survey conducted from 18 August 2014 to 22 October 2014. The size of the sample was determined on both practical and statistical considerations. The survey was written to reflect wording for both methods of survey administration: Internet-based and telephone. FDA_2164 Pharmacist KAB Assessment Report Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies 3.1.1 Page 8 of 50 Eligibility Subjects were recruited from a random sample of pharmacists from pharmacies that were enrolled in the TIRF REMS Access Program. Any pharmacist who worked at an enrolled pharmacy was eligible to participate. Respondents or respondents with immediate family members who had ever worked for any of the TRIG companies, McKesson Specialty Care Solutions, RelayHealth, United BioSource Corporation (UBC), or the FDA were not eligible to participate. Respondents who participated in the previous waves of the survey (12-month TIRF REMS Access Program Assessment or the 24-month TIRF REMS Access Program Assessment) were not eligible to participate. 3.1.2 Recruitment Subjects were recruited via invitation letter sent through the United States Postal Service (USPS) or via fax (see Section 5.1.1 for more detail). The required number of completed surveys was not achieved within approximately 10 days after the first mailing; thus additional mailings were distributed to non-respondents from the original sample to maximize participation. Each letter of invitation included a unique code needed to complete the survey. There were three categories of pharmacies which were sampled: Closed System Pharmacy (CSP), Inpatient Pharmacy, and Outpatient Pharmacy. Each type of pharmacy was provided with a unique access code since some questions in the survey were specific to only one type of pharmacy. The code was deactivated after the respondent had initiated the survey (whether or not the survey was completed). Pharmacists were given the option of taking the survey by telephone via the Survey Coordinating Center (SCC) or online via a secure website. All participating pharmacists were offered an honorarium of $50 for a completed survey. The survey was estimated to take approximately 20 minutes to complete. 3.2 Questions and Statements on Key Risk Messages The questions and statements comprising the knowledge survey were constructed to test the pharmacists’ understanding of the key risk messages of the REMS. The questions were to be answered either by selecting options from multiple-choice lists that include statements of the specific key risk messages or by choosing “Yes” or “True,” “No” or “False,” or “I Don’t Know” regarding statements about TIRF medicines. For statements or questions that had “True” or “Yes” vs. “False” or “No” response options, the desired response for key risk messages was generally “True” or “Yes” indicating knowledge of, or behavior in accordance with, the objectives of the REMS. However, some questions were formatted to have the respondent disagree with the statement as written by providing response options of “False” or “No” to avoid having the same affirmative answer for all desired responses. FDA_2165 Pharmacist KAB Assessment Report Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 9 of 50 REMS statements, corresponding questions, and desired responses covering the key risk messages are identified below and can be found in the complete survey questionnaire (Appendix A). 3.2.1 Key Risk Message 1 Key Risk Message 1 referred to the pharmacist’s knowledge of the specific contraindications for TIRF medicines in opioid non-tolerant patients. Key Risk Message 1: TIRF medicines are contraindicated in opioid non-tolerant patients. Question No. 5 5a 5b 5c 7 7a 7b 7c 7d 3.2.2 Question Desired response Please select True, False, or I don’t know for each of the following. According to the labeling for TIRF medicines, patients with cancer who are considered opioid-tolerant are those: Who are taking around-the-clock opioid therapy for underlying True persistent cancer pain for one week or longer Who are not currently taking opioid therapy, but have taken opioid False therapy before Who have no known contraindications to the drug fentanyl, but are not False currently taking around-the-clock opioid therapy Please answer True, False, or I don’t know for each statement based on the labeling for TIRF medicines. TIRF medicines are contraindicated in opioid non-tolerant patients because life-threatening respiratory depression could occur at any True dose. Death has occurred in opioid non-tolerant patients treated with some True fentanyl products. TIRF medicines may be used in opioid non-tolerant patients. False Prescribers starting a patient on a TIRF medicine must begin with titration from the lowest dose available for that specific product, even True if the patient has previously taken another TIRF medicine. Key Risk Message 2 Key Risk Message 2 referred to the pharmacist’s knowledge of the indications for prescribing TIRF medicines for the management of breakthrough pain in opioid-tolerant adult cancer patients. FDA_2166 Pharmacist KAB Assessment Report Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 10 of 50 Key Risk Message 2: TIRF medicines are only indicated for the management of breakthrough pain in adult cancer patients 18 years of age and older (16 years of age and older for Actiq® brand and generic equivalents) who are already receiving and who are tolerant to around-theclock opioid therapy for their underlying persistent cancer pain. Question No. Question Desired response 9 Per the approved labeling for TIRF medicines, for which of the following indications can TIRF medicines be prescribed to opioid tolerant patients? Please answer Yes, No, or I don’t know for each option. 9a Acute or postoperative pain No 9b Headache or migraine pain No 9c Dental pain No 9d Breakthrough pain from cancer Yes 9e Chronic non-cancer pain No 3.2.3 Key Risk Message 3 Key Risk Message 3 referred to the pharmacist’s knowledge of the risk factors and signs and symptoms of opioid abuse in patients who take TIRF medicines. Key Risk Message 3: TIRF medicines contain fentanyl, an opioid agonist and a Schedule II controlled substance, with abuse liability similar to other opioid analgesics. Question No. Question Desired response 7 Please answer True, False, or I don’t know for each statement about TIRF medicines. 7e It is important to monitor for signs of abuse and addiction in patients who take TIRF medicines. 8 Which of the following are risk factors for opioid abuse? Please answer Yes, No, or I don’t know for each option. 8a A personal history of psychiatric illness Yes 8b A personal history of past or current alcohol or drug abuse, or a family history of illicit drug use or alcohol abuse Yes 10 Please answer True, False, or I don’t know for each statement about TIRF medicines. 10a TIRF medicines can be abused in a manner similar to other opioid agonists. True True FDA_2167 Pharmacist KAB Assessment Report Transmucosal Irmnediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 11 of 50 3.2.4 Key Risk Message 4 Key Risk Message 4 referred to the pharmacist?s knowledge of the interchangeability of TIRF medicines based on route of administration, pharmacokinetic absorption, and dosage. Key Risk Message 4: TIRF medicines are not interchangeable with each other, regardless of route of administration. Question Question Desired No. response 10 Please answer True. False. or I don?t know for each statement about TIRF medicines. TIRF medicines are interchangeable with each other regardless of 10b route of administration. False The conversion of one TIRF medicine for another TIRF medicine 10c may result in a fatal overdose because of differences in the True phannacokinetics of fentanyl absorption. Dosing of TIRF medicines is not equivalent on a microgram-to- 10d . . microgram basrs. True 3.3 Additional Questions The survey also contained questions (Question lZa-t) about the requirements of the TIRF REMS Access Program and receipt and tmderstanding of the TIRF educational materials. The following questions about behaviors were asked after the key risk message questions: Qulfls?tion Question 12 How frequently do you perform the following activities when dispensing TIRF medicines? 12a Ask patients (or their caregivers) about the presence of children in the home 12b Instruct patients (or their caregivers) not to share TIRF medicines with anyone else Cormsel patients (or their caregivers) that accidental exposru?e to TIRF medicines by a 12c . child may be fatal Instruct patients (or their caregivers) to keep TIRF medicines out of the reach of 12d . . children to prevent accrdental exposure Instruct patients (or their caregivers) about proper disposal of any Imused or partially 12e . . used TIRF medicmes 12f Give patients (or their caregivers) the Medication Guide for their TIRF medicine 68 Pharmacist KAB Assessment Report Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies 4. STATISTICAL METHODS 4.1 Study Population 4.1.1 Primary Analysis Population Page 12 of 50 The primary population for analysis was all eligible pharmacists who completed the survey. Eligible pharmacists were defined as those respondents who answered Yes to Question 1 (agree to take part in survey), and to Question 3 (work at a pharmacy that is enrolled in the TIRF REMs Access Program), and No to Question 2 (participated in past survey) and Question 4 (worked for a TRIG company, UBC, or FDA). A completed survey was a survey in which all non-eligibility questions as appropriate were answered. Some questions may not have been answered because of skip logic in the survey questionnaire. 4.1.2 Sub-groups of Interest The following sub-group analyses of responses to key risk messages were conducted when the sub-group included at least 20 respondents. Of note, sub-group analysis 3 was not done since only 13 pharmacists completed the survey via telephone. Sub-group analysis 1: Reading Medication Guide or Full Prescribing Information (Questions 18, 19, 20 and 21): • S-1a - Respondents who read the Full Prescribing Information (Question 19) and Medication Guide for the TIRF medicine that they dispense (Question 21). • S-1b - Respondents who responded No or I don’t know to getting and reading the Full Prescribing Information and to getting and reading the Medication Guide for the TIRF medicine that they dispense. Sub-group analysis 2: Time to complete survey - Internet: • S-2a - <10 min • S-2b - 10 to <20 min • S-2c - ≥20 min Sub-group analysis 3: Time to complete survey: Telephone • S-2a - <10 min • S-2b - 10 to <20 min • S-2c - ≥20 min Sub-group analysis 4: Modality to complete survey: • S-4a - Internet • S-4b – Telephone FDA_2169 Pharmacist KAB Assessment Report Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 13 of 50 Sub-group analysis 5: Time practicing as a pharmacist (Question 28): • S-5a - Less than 3 years • S-5b - 3 to 5 years • S-5c - 6 to 15 years • S-5d - More than 15 years Sub-group analysis 6: Number of times per month dispensed TIRF medicines within the last 6 months (Question 25): • S-6a - None • S-6b - 1 - 2 times per month • S-6c - 3 - 5 times per month • S-6d - More than 5 times per month Results of sub-group analyses performed are provided in Appendix B. 4.1.2.1 Primary Analyses Primary analyses were done for all key risk messages. The primary analysis for a key risk message evaluated the number and percentage of correct responses for each individual question/component defined by the key risk message. The correct response to each question/component was identified in the body of the risk message table (Section 3.3). 4.1.2.2 Secondary Analyses Secondary analyses evaluated the number and percentages of correct responses and the average number of correct responses within the risk message overall to assess understanding of the comprehensive key risk message. A correct response rate of 65% or greater was considered to represent adequate understanding of each concept or key risk message. 4.1.3 Pharmacist Report of an Adverse Event, Product Complaint, or Medical Information Request during the Survey A pharmacist may have reported an adverse event or other event experienced by a patient while taking a TIRF product either in free text fields while taking the online survey or while in conversation with the SCC Associate. If an event was mentioned to the SCC Associate, the Associate documented the event or complaint, the verbatim response, and the pharmacist’s contact information, if provided. The pharmacist was also informed that a representative from the appropriate TIRF medicine sponsor may contact them to obtain additional information about the event. The Internet surveys were monitored for any comments recorded in the free text field. Information on all reports (Internet or telephone) that constituted an adverse event or other event was forwarded to the appropriate TIRF medicine sponsor for processing within 1 business day of awareness of the event as outlined in the Adverse Event/Product Complaint Project Specific Procedure (AE/PC PSP). FDA_2170 Pharmacist KAB Assessment Report Transmucosal Irmnediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 14 of 50 5. RESULTS Results of the pharmacist responses to questions in the KAB sruvey are srunrnarized in this section and a full set of responses can be formd in Appendix B. 5.1 Survey Participants 5.1.1 Survey Participant Administration Results A total of 4,022 pharmacists were invited to participate in this sruvey (Table 1). Of those invited to participate, 2625 were outpatient pharmacists, 1,056 were inpatient pharmacists, and 341 were pharmacists practicing in SPs. An additional 9,051 reminder letters were sent in six separate mailings. Most pharmacists may have received more than 1 reminder letter. There were no duplicate surveys. Note: Once the target number of 300 completed sruveys was achieved the sruvey was closed. From the total of 404 respondents who agreed to participate in the sruvey, 300 pharmacists met eligibility criteria and completed the sruvey. Of these 300 pharmacists, 287 completed the sruvey online, and 13 completed it by telephone. Of the 300 pharmacists who completed the sruvey, 1 was a SP pharmacist, 15 were inpatient pharmacists, and 284 were outpatient pharmacists (see Table 14, Table 15, and Table 16). Table 1. Survey Participant Administration Results Screened Pharmacists N=404l All Respondents Summary Statistic Number of invitations issued to phanrracists 4022 Number of reminder letters issued to pharmacists 9051 Number of pharmacists screened for participation 4041 Number of pharmacists eligible for participation 3002 74.3 Number of screened pharmacists eligible for participation who answered all questions presented to 300 100.00 them Pharmacist KAB Assessment Report Transmucosal Irmnediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 15 of 50 Table 1. Survey Participant Administration Results Screened Pharmacists N=404l All Respondents Summary Statistic Method of Survey Completion Nlunber of sruveys completed by telephone 13 4,33 Nmnber of sruveys completed by Internet 287 9 5.73 1 The denominator for the percentage of eligible phannacists is the number of screened phamracists 2 The denominator for percentages of eligible pharmacists completing the survey is the munber of eligible pharmacists 3 The denominator for percentages completed by telephone or Internet is the munber of eligible pharmacists who completed the survey. As shown in Table 2, a total of 404 pharmacists agreed to participate in this survey. Dining the screening process it was determined 104 respondents were not eligible to participate in the sruvey because they either indicated they had participated in or did not know whether they participated in a smvey about TIRF medicines before, worked in pharmacies that were not em?olled or they did not know whether their pharmacy was em?olled in the TIRF indicated they, or an immediate family member, had worked for a TRIG company, UBC, or FDA in the past or the respondent did not know if they or an family member had worked for a TRIG company, UBC, or FDA in the past. . Thus, there were 300 eligible participants, all of whom completed the survey (Table 2). 72 Phannacist KAB Assessment Report Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industlv Group (TRIG) of Companies Page 16 of 50 Table 2. Survey Participant Screening Results Screened Pharmacists Question Question 1: Do you agree to participate in this survey? Yes 404 100.0 300 100.0 No1 0 0.0 versions of any of these brands Question 2: Have you ever taken part in this survey about TIRF medicines before? TIRF medicines include Abstralo, Actqu, FentoraO, Lazanda?, OnsolisO, Subsyso and generic Yesl 18 4.5 No 336 83.2 300 100.0 I don?t know1 50 12.4 Question not asked2 0 0.0 Question 3: Do you work in a pharmacy that is enrolled in the TIRF REMS Access Program? Yes 306 75.7 300 100.0 No1 8 2.0 I don?t know1 22 5.4 Question not asked2 68 16.8 Question 4: Have you or any of your immediate family members ever worked for any of the following companies or agencies? Please select all that apply.3 Anesta LLC.1 1 0.2 Cephalon. Inc. (a wholly-owned subsidiary of Teva 1 0.2 Phanuaceutical Industn'es. Ltd.)l Depomed. Inc. 1 0.2 Galena Biophanna1 0.2 Insys Therapeutics1 1 0.2 Phalmaceuticals1 0.2 McKesson Specialty Care 1 0.2 Solutionsl Meda Pharmaceuticals1 1 0.2 Mylan Inc.1 1 0.2 Par Phannaceutical. Inc.1 1 0.2 RelayHealth1 0.2 73 Phannacist KAB Assessment Repon Transmucosal Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 17 of 50 Table 2. Survey Participant Screening Results Screened Pharmacists Question Teva Pharmaceuticals. Ltd.1 2 0.5 United BioSource Coqaoration1 1 0.2 FDA1 1 0.2 None of these apply4 301 74.5 300 100.0 I don?t know1 4 1.0 Prefer not to answer1 0 0.0 Question not asked2 98 24.3 1 Ineligible to participate in the surveyQuest1on not asked due to prevrous question elimination. 3 More than one response can be selected. so percentages may not sum to 100%. 4 Ineligible if selected in addition to another response. Phannacists taking the sruvey online took an average of 13.5 minutes to complete it, while those taking it by telephone took an average of 18.6 minutes (Table 3). Table 3. Time to Complete Survey for Completers (Minutes) Summary Statistic Telephone Internet Total1 13 287 300 Mean (i SD) 18.6 (3.94) 13.5 (7.33) 13.8 (7.29) Minimum 14 4 4 Median 18.0 11.5 11.9 Maximum 28 60 60 Category 0 <5 Minutes 0 4 4 5 <10 Minutes 0 106 106 10 <15 Minutes 1 94 95 15 <20 Minutes 8 40 48 20 <25 Minutes 3 21 24 25 <30 Minutes 1 10 11 30 Minutes or More 0 12 12 1 Number of eligible pharmacists completing the sun'ey (See Table 1). SD Standard Deviation 74 Pharmacist KAB Assessment Report Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies 5.1.2 Page 18 of 50 Pharmacist Demographic and TIRF Product Dispensing Characteristics The demographic characteristics of pharmacists who completed the survey are shown in Table 4, and their experience with prescribing TIRF medicines is summarized in Table 5. The majority of pharmacists who completed the survey were male (186, 62.0%), and out of 300 eligible pharmacists, 202 (67.3%) had been a practicing pharmacist for 11 or more years. Respondents from the South, Northeast, and Midwest reflected 37.7%, 27.7%, and 20.3% of total respondents, respectively, while respondents from the Western region of the United States (US) composed 14.3% of total respondents. There were no respondents from Puerto Rico, Northern Mariana Islands, US Virgin Islands, American Samoa, and Guam identified as “Other” in Table 4 below. Most pharmacists (230, 76.7%) functioned as the pharmacist-in-charge for the TIRF REMS Access Program where they worked. Note: FDA feedback received in August 2014 recommended that in future pharmacist surveys to consider including a higher percentage of non-supervisory dispensing pharmacists; this will be addressed in the 48-month Pharmacist KAB report. The majority of pharmacists (213, 71.0%) had dispensed a TIRF medicine zero to 2 times per month within the past 6 months. The most frequently dispensed TIRF medicine within the 6 months prior to taking the survey was Actiq® or generic Actiq® (127/168 pharmacists, 75.6%). Note: Two pharmacists indicated that they dispensed Onsolis® during the 6 months prior to taking the survey. However, Onsolis® was not available to any pharmacy at that time. Onsolis® was last available in May 2011. FDA_2175 Pharmacist KAB Assessment Report Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 19 of 50 Table 4. Demographic Characteristics of Eligible Pharmacists Eligible Completed Pharmacists Question N=300l Question 27: What is your gender? Male 186 62.0 Female 108 36.0 Prefer not to answer 6 2.0 Question 28: In total, how many years have you been a practicing pharmacist? Less than 3 years 16 5.3 3-5 years 28 9.3 6-10 years 50 16.7 11-15 years 52 17.3 More than 15 years 150 50.0 Prefer not to answer 4 13 Question 29: In which state do you practice?2 Northeast 83 27.7 Midwest 61 20.3 South 1 13 3 7.7 West 43 14.3 Other 0 0.0 Prefer not to answer 0 0.0 1 Number of eligible pharmacists completing the sun'ey (See Table 1). 2 US. Census Blu?eau. last revised Friday. 27-Jul-2001 12:59:43 EDT. Geography Division. Northeast includes CT. MA. ME. NH. NJ. NY. PA. RI. and VT. Midwest includes IA. IL. IN. KS. MI. MN. MO. ND. NE. OH. SD. and W1. South includes AL. AR. DC. DE. FL. GA. KY. LA. MD. MS. NC. OK. SC. TN. TX. VA. and WV. West includes AK. AZ. CA. O. I-H. ID. MT. NM. NV. OR. UT. WA. and WY. The following US territories are categorized as Other: Puerto Rico. Northern Mariana Islands. US Virgin Islands. American Samoa. and Guam. 76 Pharmacist KAB Assessment Repon Transmucosal Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Table 5. Characteristics of Respondents Completing the Survey Page_20 of 50 Eligible Completed Pharmacists Question N=3ool Question 24: Are you the Pharmacist in Charge for the TIRF REMS Access Program where you work? Yes 230 76.7 No 68 22.7 I don?t know 2 0.7 Question 25: On average, how many times per month have you dispensed TIRF medicines within the last 6 months None 132 44.0 1-2 times per month 81 27.0 3-5 times per month 36 12.0 More than 5 times per month 31 10.3 I don?t remember 20 6.7 Question 26: Please select the TIRF medicine(s) that you have dispensed within the last 6 months (select all that Abstral? 16 9.5 Actiq? or genen'c Actiq? 127 75.6 Fentora? 85 50.6 Lazanda? 10 6.0 Onsolis? 2 1.2 Subsys? 43 25.6 (answered None to 132 Question 25) 1Number of eligible pharmacists completing the sun'ey (See Table 1). 2 Percentages are calculated based on the sample presented with this question because of skip logic in the sm'vey. 3 More than one response can be selected. so percentages may not sum to 100%. Not applicable. 77 Pharmacist KAB Assessment Report Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page_21 of 50 5.1.3 TIRF Medicines Educational Materials Pharmacists were asked about their access to educational materials for TIRF medicines, speci?cally the Full Prescribing Information and the Medication Guide (Table 6). Almost all pharmacists reported they had received or had access to the Full Prescribing Information and the Medication Guide (294, 98.0%: and 292, 97.3%, respectively). Of those with access to these materials, 79.9% and 88.0%, respectively, indicated that they had read the Full Prescribing Information and the Medication Guide. Table 6. Responses to Questions About TIRF Medicines Educational Materials Eligible Completed Pharmacists Question N=300l Question 18: Did you receive or do you have access to the Full Prescribing Information for the TIRF medicine(s) that you dispense? Yes 294 98.0 No 3 1.0 I don?t know 3 1.0 Question 19: Did you read the Full Prescribing Information for the TIRF medicine(s) that you dispense?2 Yes 235 79.9 No 49 16.7 I don?t know 10 3.4 (answered No or I don ?t 6 know to Question 18) Question 20: Did you receive or do you have access to the Medication Guide for the TIRF medicine(s) that you dispense? Yes 292 97.3 No 2 0.7 I don?t know 6 2.0 Question 21: Did you read the Medication Guide for the TIRF medicine(s) that you dispense?2 Yes 257 88.0 No 29 9.9 I don?t know 6 2_1 (answered No or I don?t 8 know to Question 20) 78 Pharmacist KAB Assessment Report Transmucosal Irmnediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 22 of 50 Table 6. Responses to Questions About TIRF Medicines Educational Materials Eligible Completed Pharmacists Question Question 22: Did you or do you have any questions about the information in the Full Prescribing Information or Medication Guide? Yes3 22 7.3 No 265 88.3 I don?t know 13 4.3 1 Nrunber of eligible pharmacists completing the survey (See Table 1). 2 Percentages are calculated based on the sample presented with this question because of skip logic in the survey. 3 Verbatim text for questions about the information in the Full Prescribing Information or the Medication Guide are presented in Appendix B. Listing 1. Not Applicable 5.2 KAB Survey Objectives 5.2.1 Key Risk Message Results The focus of this section of the doc1unent is on the ?ndings for the total eligible respondent population that completed the smvey. A summary of results by sub-group is provided in a separate section of the document, Section 5.2.3. 5.2.1.1 Key Risk Message 1 Key Risk Message 1 refers to the pharmacist?s knowledge of the speci?c contraindications for TIRF medicines. Analysis of responses to components of Question 5 for Key Risk Message 1 showed that a high percentage of pharmacists knew that patients with cancer who are considered opioid- tolerant are those who are taking arormd-the-clock opioid therapy for cancer pain for one week or longer (281, and are those who are crurently taking opioid therapy (261, Somewhat less understood was cancer patients with no known contraindications to the drug fentanyl, but who are not taking arormd-the-clock opioid therapy, are not considered opioid tolerant (236, however, the correct response rate did increase from the previous s1uvey wave correct response rate of 76.0%. Analysis of responses to components of Question 7 for Key Risk Message 1 showed that a high percentage of pharmacists knew that TIRF medicines are contraindicated in opioid non- tolerant patients (272, 90.7%) and that death has occ1ured in opioid non-tolerant patients treated with some fentanyl products (281, Similarly, 237 pharmacists were aware that dose titration for patients starting a TIRF medicine must begin with the lowest available dose for that product, and that TIRF medicines may not be used to treat opioid non- tolerant patients (251, (Table 7). Overall, evidence of understanding of this key risk 79 Pharmacist KAB Assessment Report Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industn7 Group (TRIG) of Companies Page_23 of 50 information is fluther supported by the average number of correct responses identi?ed as 6.1 out of a possible 7. Table 7. Responses Linked to Key Risk Message 1: TIRF Medicines Are Contraindicated in Opioid Non-Tolerant Patients Eligible Completed Pharmacists N=300l uestion (95% Question 5: Please select True, False, or I don?t know for each of the following. According to the labeling for TIRF medicines, patients with cancer who are considered opioid? tolerant are those: 5a: Who are taking around-the-clock opioid therapy for underlying persistent cancer pain for one week or longer 2 93.7 Tlue 281 (90.3. 96.1) False 11 3.7 I don?t know 8 2_7 5b: Who are not currently taking opioid therapy, but have taken opioid therapy before True 29 9.7 2 87.0 False 261 (82.7. 90.6) I don?t know 10 3.3 5c: Who have no known contraindications to the drug fentanyl, but are not currently taking around?the?clock opioid therapy True 44 14.7 2 78.7 False 236 (73.6. 83.2) I don?t know 20 6.7 80 Pharmacist KAB Assessment Repon Transmucosal Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page_24 of 50 Table 7. Responses Linked to Key Risk Message 1: TIRF Medicines Are Contraindicated in Opioid Non-Tolerant Patients Eligible Completed Pharmacists . Question (95% Question 7: Please answer True, False, or I don?t know for each statement based on the labeling for TIRF medicines. 7a: TIRF medicines are contraindicated in opioid non?tolerant patients because life?threatening respiratory depression could occur at any dose. 2 90.7 Tme 272 (86.8. 93.7) False 19 6.3 I don?t know 9 3.0 7b: Death has occurred in opioid non-tolerant patients treated with some fentanyl products. 2 93.7 Tnle 281 (90.3. 96.1) False 4 1.3 I don?t know 15 5-0 7c: TIRF medicines may be used in opioid non?tolerant patients. Tme 39 13.0 2 83.7 False 251 (79.0. 87.7) I don?t know 10 3.3 7d: Prescribers starting a patient on a TIRF medicine must begin with titration from the lowest dose available for that speci?c product, even if the patient has previously taken another TIRF medicine. 2 79.0 Tme 237 (73.9. 83.5) False 50 16.7 I don?t know 13 4-3 Pharmacist KAB Assessment Report Transmucosal Irmnediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page_25 of 50 Table 7. Responses Linked to Key Risk Message 1: TIRF Medicines Are Contraindicated in Opioid Non?Tolerant Patients Eligible Completed Pharmacists Question 3 (95% CI) Secondary Analysis: Demonstrated Understanding 0 correct responses 0 0.0 1 correct response 2 0.7 2 correct responses 9 3.0 3 correct responses 5 1.7 4 correct responses 15 5.0 5 correct responses 40 13.3 6 correct responses 79 26.3 7 correct responses 150 50.0 Average number of correct responses 6.1 (5.8. 7.0)4 1 Number of eligible pharmacists completing the srurey (See Table 1). 2 Indicates the correct response(s) to each question or component within a question. 3 All con?dence intervals are exact binomial 95% con?dence intervals. 4 One-sided 95 con?dence interval using the nomral approximation to the Poisson distribution. 5.2.1.2 Key Risk Message 2 Key Risk Message 2 refers to the pharmacist?s knowledge of the approved indications for prescribing TIRF medicines to opioid tolerant patients. Responses to components of Question 9 (Per the approved labeling for medicines, for which of the following indications can medicines be prescribed to opioid tolerant patients? Please answer Yes, No, or I don ?t know for each option.) for Key Risk Message 2 indicates that 275 pharmacists were aware that TIRF medicines are indicated for opioid-tolerant patients with breakthrough pain from cancer and not for patients with acute or postoperative pain headache or migraine pain or dental pain (Table 8). For Component 9e (Chronic non-cancerpain), only 43.7% of pharmacists correctly responded that TIRF medicines should not be prescribed for chronic non-cancer pain. Further discussion is provided in Section 5.4. Overall, evidence of lmderstanding of this key risk information is fruther supported by the average number of correct responses identi?ed as 4.1 out of a possible 5. 82 Phannacist KAB Assessment Repon Transmucosal Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Table 8. Page_26 of 50 Responses Linked to Key Risk Message 2: TIRF Medicines Are Only Indicated for the Management of Breakthrough Pain in Adult Cancer Patients 18 Years of Age and Older (16 Years of Age and Older for Actiq? Brand and Generic Equivalents) Who Are Already Receiving and Who Are Tolerant to Around-The-Clock Opioid Therapy for Their Underlying Persistent Cancer Pain Question Eligible Completed Pharmacists N=300l (95% Question 9: Per the approved labeling for TIRF medicines, for which of the following indications can TIRF medicines be prescribed to opioid tolerant patients? Please answer Yes, No, or I don?t know for each option. 9a: Acute or postoperative pain Yes 33 11.0 2 86.7 No 260 (82.3. 90.3) I don?t know 7 2.3 9b: Headache or migraine pain Yes 9 3.0 2 90.7 No 272 (86.8. 93.7) I don?t know 19 6.3 9c: Dental pain Yes 5 1.7 2 97.0 No 291 (94.4. 98.6) I don?t know 4 1.3 9d: Breakthrough pain from cancer 2 91.7 Yes 275 (87.9. 94.5) No 23 7.7 I don?t know 2 0.7 83 Pharmacist KAB Assessment Report Transmucosal Irmnediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page_27 of 50 Table 8. Responses Linked to Key Risk Message 2: TIRF Medicines Are Only Indicated for the Management of Breakthrough Pain in Adult Cancer Patients 18 Years of Age and Older (16 Years of Age and Older for Actiq? Brand and Generic Equivalents) Who Are Already Receiving and Who Are Tolerant to Around-The-Clock Opioid Therapy for Their Underlying Persistent Cancer Pain Eligible Completed Pharmacists N=300l Question 11 (95% CD3 9e: Chronic non-cancer pain Yes 146 48.7 2 43.7 No 13 1 (38.0. 49.5) I don?t know 23 7.7 Secondary Analysis: Demonstrated Understanding 0 correct responses 1 0.3 1 correct response 7 2.3 2 correct responses 8 2.7 3 correct responses 41 13.7 4 correct responses 132 44.0 5 correct responses 111 37.0 Average number of correct responses 4.1 (3.9. 5.0) 4 1 Number of eligible pharmacists completing the survey (See Table 1). 2 Indicates the correct response(s) to each question or component within a question. 3 All con?dence intervals are exact binomial 95% con?dence intervals. 4 One-sided 95 con?dence interval using the nomral approximation to the Poisson distribution. 5.2.1.3 Key Risk Message 3 Key Risk Message 3 refers to the pharmacist?s knowledge of the risk factors and signs and of opioid abuse in patients who take TIRF medicines. Responses to components of Questions 7, 8, and 10 for Key Risk Message 3 showed that 288 pharmacists were aware that it is important to monitor for signs of abuse and addiction in patients who take TIRF medicines; a personal history of past or current alcohol or drug abuse or family history of drug and alcohol abuse is a risk factor for opioid abuse (298, and TIRF medicines can be abused in a manner similar to other opioid agonists 84 Pharmacist KAB Assessment Report Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page_28 of 50 (283, Somewhat less was that a personal history of ilhiess is a risk factor for opioid abuse (213, (Table 9). Overall, evidence of 1mderstanding of this key risk inf01mation is further supported by the average number of con'ect responses identi?ed as 3.6 out of a possible 4. Table 9. Responses Linked to Key Risk Message 3: TIRF Medicines Contain Fentanyl, an Opioid Agonist and a Schedule II Controlled Substance, With Abuse Liability Similar to Other Opioid Analgesics. Eligible Completed Pharmacists N=300l Question (95% Question 7: Please answer True, False, or I don?t know for each statement based on the labeling for TIRF medicines. 7e: It is important to monitor for signs of abuse and addiction in patients who take TIRF medicines. 96.0 True2 288 (93.1. 97.9) False 7 2.3 I don?t know 5 1.7 Question 8: Which of the following are risk factors for opioid abuse? Please answer Yes, No, or I don?t know for each option. 8a: A personal history of illness 2 71.0 Yes 213 (65.5. 76.1) No 46 15.3 I don?t know 41 13.7 SD: A personal history of past or current alcohol or drug abuse, or a family history of illicit drug use or alcohol abuse 2 99.3 Yes 298 (97.6. 99.9) No 0 0.0 I don?t know 2 0.7 85 Pharmacist KAB Assessment Report Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page_29 of 50 Table 9. Responses Linked to Key Risk Message 3: TIRF Medicines Contain Fentanyl, an Opioid Agonist and a Schedule II Controlled Substance, With Abuse Liability Similar to Other Opioid Analgesics. Eligible Completed Pharmacists . N=3ool Question (95% Question 10: Please answer True, False, or I don?t know for each statement about TIRF medicines. 10a: TIRF medicines can be abused in a manner similar to other opioid agonists. 2 94.3 True 283 (91.1. 96.7) False 12 4.0 I don?t know 5 1.7 Secondary Analysis: Demonstrated Understanding 0 correct responses 1 0.3 1 correct response 1 0.3 2 correct responses 12 4.0 3 correct responses 87 29.0 4 correct responses 199 66.3 Average number of correct responses 3.6 (3.4. 4.0) 4 1 Number of eligible pharmacists completing the survey (See Table 1). 2 Indicates the correct response(s) to each question or component Within a question. 3 All con?dence intervals are exact binomial 95% con?dence intervals. 4 One-sided 95 con?dence interval using the normal approximation to the Poisson distribution. 5.2.1.4 Key Risk Message 4 Key Risk Message 4 refers to the pharmacist?s knowledge that TIRF medicines are not interchangeable regardless of the route of administration. Responses to components of Question 10 c, and d) for Key Risk Message 4 showed that 280 pharmacists rmderstood TIRF medicines are not interchangeable with each other regardless of the route of administration; 279 pharmacists understood the conversion of one TIRF medicine to another may result in a fatal overdose; and 270 pharmacists rmderstood dosing of TIRF medicines is not equivalent on a microgram?to-microgram basis (Table 10). Overall. evidence of rmderstanding of this key risk information is fruther supported by the average number of correct responses identi?ed as 2.8 out of a possible 3. 86 Pharmacist KAB Assessment Report Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 30 of 50 Table 10. Responses Linked to Key Risk Message 4: TIRF Medicines Are Not Interchangeable with Each Other, Regardless of Route of Administration. Eligible Completed Pharmacists Question 11 (95% Question 10: Please answer True, False, or I don?t know for each statement based on the labeling for TIRF medicines. 10b: TIRF medicines are interchangeable with each other regardless of route of administration. True 13 4.3 2 93 .3 False 280 (89.9. 95.9) I don?t know 7 2.3 10c: The conversion of one TIRF medicine for another TIRF medicine may result in a fatal overdose because of differences in the pharmacokinetics of fentanyl absorption. True2 279 93 '0 (89.5. 95.6) False 13 4.3 I don?t know 8 2.7 10d: Dosing of TIRF medicines is not equivalent on a microgram-to-microgram basis. True2 270 90.0 (86.0. 93.2) False 20 6.7 I don?t know 10 3.3 Secondary Analysis: Demonstrated Understanding 0 correct responses 3 1.0 1 correct response 9 3.0 2 c01rect responses 44 14.7 3 correct responses 244 81.3 Average number of correct responses 2.8 (2.6. 3 .0)4 1 Number of eligible pharmacists completing the survey (See Table 2 Indicates the correct response(s) to each question or component Within a question. 3 All con?dence intervals are exact binomial 95% con?dence intervals. 4 One-sided 95 con?dence interval using the normal approximation to the Poisson distribution. 87 Pharmacist KAB Assessment Report Transmucosal Irmnediate Release Fentanyl (TIRF) TIRF REMS Industn7 Group (TRIG) of Companies Page 31 of 50 5.2.2 Other Survey Questions 5.2.2.1 Additional Questions about TIRF Medicines Safety Table 11 summarizes the pharmacists? responses to additional questions about the safe use of TIRF medicines beyond those associated with the key risk messages. Responses to these additional questions generally confnmed the pharmacists? Imderstanding of the safety issues and the risks associated with taking TIRF medicines. Question 6 (see Table 11) assists in determining the pharmacist rmderstanding of arormd-the- clock usage, and 63.3% of pharmacists correctly indicated that a cancer patient should not be started on a TIRF medicine and an around-the-clock opioid at the same time, and 74.0% rmderstood a cancer patient who had been on an ar?ound-the-clock opioid for one day should not start taking a TIRF medicine for breakthrough pain. For Question 11, greater than 70% of pharmacists correctly identi?ed an opioid drug/dose regimen that, when taken by the patient, identi?es patients as opioid tolerant according to the labeling for TIRF medicines. However, fewer understood that an equianalgesic dose of another oral opioid could also meet the de?nition of opioid tolerant (correct response 59.0%; Table 11). For Question 13, pharmacists correctly indicated that TIRF medicines may not be sold, loaned, or transferred to another pharmacy pharmacy staff who dispense TIRF medicines must be educated on the requirements of the TIRF REMS Access Program and that TIRF medicines with the same route of administration cannot be substituted with each other Thirteen inpatient pharmacists correctly indicated that it is not OK to dispense TIRF medicines from the inpatient pharmacy inventory to an outpatient for home use (Table 12). Table 11. Responses to Additional Questions about the Safe Use of TIRF Medicines Eligible Completed Pharmacists Question N=300l Question 6: Please answer True, False, or I don?t know for each statement based on the labeling for TIRF medicines. 6a: A cancer patient can be started on a TIRF medicine and an around?the?clock opioid at the same time. True 85 28.3 False2 190 63 .3 I don?t know 25 8.3 88 Pharmacist KAB Assessment Repon Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 32 of 50 Table 11. Responses to Additional Questions about the Safe Use of TIRF Medicines Eligible Completed Pharmacists Question N=300l 6b: A cancer patient who has been on an around-the?clock opioid for 1 day can start taking a TIRF medicine for breakthrough pain. True 57 19.0 False2 222 74.0 I don?t know 21 7-0 Question 8: Which of the following are risk factors for opioid abuse? Please answer Yes, No, or I don?t know for each option. 8c: A family history of asthma Yes 25 8.3 No2 260 86.7 I don't know 15 5.0 Question 11: Please select True, False, or I don?t know for each of the following. According to the labeling for TIRF medicines, patients considered opioid-tolerant are those who are taking, for one week or longer, at least: 11a: 8 mg oral hydromorphone/day True2 229 76.3 False 31 10.3 I don?t know 40 13.3 11b: 60 mg oral morphine/day True2 254 84. 7 False 15 5 .0 I don?t know 31 10.3 11c: 30 mg oral oxycodone/day True 2 220 73.3 False 38 12.7 I don?t know 42 14.0 89 Pharmacist KAB Assessment Repon Transmucosal Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 33 of 50 Table 11. Responses to Additional Questions about the Safe Use of TIRF Medicines Eligible Completed Pharmacists Question N=300l 11d: 25 transdermal fentanyl/hour Tmez 223 74.3 False 31 10.3 I don?t know 46 15.3 lle: 25 mg oral oxymorphone/day True2 213 71.0 False 26 8.7 I don?t know 61 20.3 11f: An equianalgesic dose of another oral opioid Tmez 177 59.0 False 57 19.0 I don?t know 66 22.0 Question 13: Please answer True, False, or I don?t know for each statement about TIRF medicines. 13a: TIRF medicines may be sold, loaned, or transferred to another pharmacy. True 11 3.7 False2 276 92.0 I don?t know 13 4.3 13b: All pharmacy staff that dispenses TIRF medicines must be educated on the requirements of the TIRF REMS Access Program. Tme2 284 94.7 False 10 3.3 I don?t know 6 2.0 90 Pharmacist KAB Assessment Report Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 34 of 50 Table 11. Responses to Additional Questions about the Safe Use of TIRF Medicines Eligible Completed Pharmacists Question N=300l 13c: TIRF medicines with the same route of administration can be substituted with each other if the pharmacy is out of stock for one product. True 2 0.7 False2 293 97.7 I don?t know 5 1.7 1 Number of eligible pharmacists completing the sru'vey (See Table 1). 2Indicates the correct response(s) to each question or component within a question. Table 12. Responses to Additional Questions about the Safe Use of TIRF Medicines: Question asked of Inpatient Pharmacists, Only Eligible Completed Pharmacists Question N=300l Question 17: Please answer True, False, or I don?t know for the following statement about TIRF medicines. (Inpatient pharmacists, only) It is OK to dispense TIRF medicines from the inpatient pharmacy inventory to an outpatient for use at home.3 True 2 13.3 False2 13 86. 7 I don?t know 0 0.0 1 Question asked of inpatient pharmacists only. 2 Indicates the correct response(s) to each question or component within a question. 3 This question is presented only to a sub-group of pharmacists. Percentages are based on the nrunber of phamracists to whom this question was presented. 5.2.2.2 Pharmacist Activities When Dispensing TIRF Medicines Pharmacists were asked about speci?c activities performed when dispensing TIRF medicines (Table 13). Of the 300 eligible pharmacists, 174 responded they always ask their patients (or a patient?s caregiver) about the presence of children in the home; 22.7% responded that they ask only with the f'nst prescription. Additionally, 74.7% responded they always instruct Pharmacist KAB Assessment Report Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 35 of 50 patients (or their caregivers) not to share TIRF medicines, 72.0% responded they always cormsel patients (or their caregivers) that accidental exposm'e to TIRF medicines by a child may be fatal, 74.7% responded they always instruct patients (or their caregivers) to keep TIRF medicines out of reach of children, 67.7% responded they always instruct patients (or their caregivers) about proper disposal of any Imused or partially used TIRF medicines, and 89.3% responded they always give patients (or their caregivers) the Medication Guide for TIRF medicine. Table 13. Responses to Questions about Activities When Dispensing TIRF Medicines Question Eligible Completed Pharmacists Question 12: How frequently do you perform the following activities when dispensing TIRF medicines? Please answer Always, Only with the ?rst prescription, Sometimes, Never, or I don?t know. 12a: Ask patients (or their caregivers) about the presence of children in the home. Always 174 58.0 Only with the ?rst prescription 68 22.7 Sometimes 33 1 1.0 Never 14 4.7 I don?t know 11 3.7 12b: Instruct patients (or their caregivers) not to share TIRF medicines wi th anyone else. Always 224 74.7 Only with the fn?st prescription 45 15.0 Sometimes I 7 5.7 Never 6 2.0 I don?t know 8 2.7 12c: Counsel patients (or their caregivers) that accidental exposure to TIRF medicines by a child may be fatal. Always 216 72.0 Only with the ?rst prescription 53 17.7 Sometimes 16 5.3 Never 6 2.0 I don?t know 9 3.0 92 Pharmacist KAB Assessment Report Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 36 of 50 Table 13. Responses to Questions about Activities When Dispensing TIRF Medicines Eligible Completed Pharmacists Question N=300l to prevent accidental exposure. 12d: Instruct patients (or their caregivers) to keep TIRF medicines out of the reach of children Always 224 74.7 Only with the fu?st prescription 48 16.0 Sometimes I 7 5.7 Never 3 1.0 I don?t know 8 2.7 used TIRF medicines. 12e: Instruct patients (or their caregivers) about proper disposal of any unused or partially Always 203 67.7 Only with the ?rst prescription 63 21.0 Sometimes 23 7.7 Never 3 1.0 I don?t know 8 2.7 12f: Give patients (or their caregivers) the Medication Guide for their TIRF medicine. Always 268 89.3 Only with the ?st prescription 20 6.7 Sometimes 3 1 .0 Never 1 0.3 I don?t know 8 2.7 1 Number of eligible pharmacists completing the survey (See Table 1). Speci?c pharmacy types (inpatient, outpatient, and SP pharmacies) were each asked a single different question regarding pharmacy systems and processes. Question 14 was presented only to pharmacy respondents from inpatient pharmacies (N =1 5) as identi?ed through the access code entered by the respondent (Table 14). Of the 15 respondents, 7 reported their pharmacy has processes to ensure compliance with the TIRF REMS Access Program requirements. 93 Pharmacist KAB Assessment Repon Transmucosal Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 37 of 50 Table 14. Responses to All Questions about Activities When Dispensing TIRF Medicines: Asked of Inpatient Pharmacies Only Eligible Completed Inpatient Pharmacists Question N=15l Question 14: Does the inpatient pharmacy where you work have an established system, order sets, protocols and/or other measures to help ensure appropriate patient selection and compliance with the requirements of the TIRF REMS Access Program? [Inpatient pharmacists onlydon't know 3 20.0 1 Number of eligible inpatient pharmacists completing the survey. 2 This question is presented only to a sub-group of phamracists. Percentages are based on the munber of inpatient phannacists to whom this question was presented. Question 15 was presented only to phaimacy respondents from outpatient pharmacies (n=284) as identi?ed through the access code entered by the respondent. This sub-population did not include respondents from SPs (Table 15). Of the 284 respondents, 254 reported their pharmacy processes prescriptions for TIRF medicines though their pharmacy management system. Table 15. Responses to All Questions about Activities When Dispensing TIRF Medicines: Outpatient Pharmacists Only Eligible Completed Outpatient . Pharmacists Question 41 Question 15: Does the outpatient or retail pharmacy where you work process all TIRF medicine prescriptions, regardless of method of payment, through the pharmacy management system? [Outpatient pharmacists only]2 Yes 254 89.4 No 6 2.1 I don't know 24 8.5 Nlunber of eligible outpatient pharmacists completing the Siu'vey. 2 This question is presented only to a sub-group of pharmacists. Percentages are based on the munber of outpatient phannacists to Whom this question was presented. 94 Pharmacist KAB Assessment Report Transmucosal Irmnediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 38 of 50 Question 16 was presented only to pharmacy respondents from SPs (N as identi?ed through the access code entered by the respondent (Table 16). The single respondent indicated his/her pharmacy processes all prescriptions for TIRF medicines though the TIRF REMS Access Call Center. Table 16. Responses to All Questions about Activities When Dispensing TIRF Medicines: Closed System Pharmacy Outpatient Pharmacists Only Eligible Completed CSP Pharmacists Question N=ll Question 16: Does the pharmacy where you work process all TIRF medicine prescriptions, regardless of method of payment, through the TIRF REMS Access Call Center? Outpatient pharmacists only]2 Yes 1 100.0 No 0 0.0 I don't know 0 0.0 1 Nrunber of eligible SP outpatient pharmacists completing the survey. 2 This question is presented only to a sub-group of pharmacists. Percentages are based on the number of CSP pharmacists to whom this question was presented. 5.2.3 Sub-group Analysis of Responses to Key Risk Messages To ?uther assess pharmacist 1mderstanding of key risk messages, sub-group analyses as described in Section 4.1.2 were conducted. Sub-group analysis of time to complete the survey for telephone respondents was not done since there were less than 20 respondents in this sub-group (telephone respondents; n=13). For the remaining sub-group analyses that were performed, results are similar to the results in the primary analysis population, and no trends are evident, with the exception of a lower correct response rate for those who took the survey by telephone for most questions in Key Risk Message 1 and for Key Risk Message 4, Question 10 d. The full set of sub-group analysis tables is provided in Appendix B. 5.3 Spontaneous Reporting of Adverse Events, Product Complaints, or Medical Information Requests Among all srnvey respondents Table 1), there were no adverse events or product complaints reported. In the Internet sruvey, respondents had the option to write in any questions they had when asked ?W7mt are your questions?? Respondents who took the telephone sruvey could have spontaneously asked a question. This resulted in 19 individual responses by various completers, of which 8 were requests for medical information and 11 were indications that the ??ee text ?eld was not applicable or they had no questions (Appendix B, Listing 1). 95 Pharmacist KAB Assessment Report Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies 5.4 Page 39 of 50 Summary of Correct Responses for Key Risk Messages The four key risk messages included 19 components detailing these key risk messages. A tabulated summary of correct response rates for each component is presented below (Table 17). The correct response rate was greater than or equal to 90% for 11 of the key risk message components, between 70% and 90% for 7 components, and was 43.7% for a single component (Question 9: Per the approved labeling for TIRF medicines, for which of the following indications can TIRF medicines be prescribed to opioid tolerant patients? Component 9E: Chronic non-cancer pain; Correct response “No”) which is below the desired level of understanding of 65%. FDA_2196 Pharmacist KAB Assessment Report Transmucosal Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 40 of 50 Table 17. Summary of Correct Responses for Key Risk Messages Key Risk Message Question Question Correct Responses (95% CI) Key Risk Message 1: TIRF Medicines Are Contraindicated in Opioid Non-Tolerant Patients 5. Please select True, False, or I don?t know for each of the following. According to the labeling for TIRF medicines, patients with cancer who are considered opioid-tolerant are those: Sa Who are taking around-the-clock opioid therapy for 281 93.7 underlying persistent cancer pain for one week or (903. 96.1) longer (Correct Response rue 5b Who are not currently taking opioid therapy. but 261 87.0 have taken opioid therapy before (Correct Response (82.7. 90.6) ?False 5c Who have no known contraindications to the drug 236 78.7 fentanyl. but are not cmrently taking arormd-the- (73.6. 83.2) Clock opioid therapy (Correct Response ?False 7. Please answer True, False, or I don?t know for each statement based on the labeling for TIRF medicines. 7a TIRF medicines are contraindicated in opioid non- 272 90.7 tolerant patients because life-tln?eatening respiratory (86.8. 9 37) depression could occur at any dose (Correct Response rue 7b Death has occmred in opioid non-tolerant patients 281 93.7 treated with some fentanyl products (Correct (903. 96.1) Response rue 7c TIRF medicines may be used to treat opioid 11011- 251 83.7 tolerant patients (Correct Response ?False?) (79.0. 87.7) 97 Pharmacist KAB Assessment Report Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Table 17. Summary of Correct Responses for Key Risk Messages Page 41 of 50 Key Risk Message Key Risk Message 1: TIRF Medicines Are Contraindicated in Opioid Non-Tolerant Patients (continued) Question Question Correct Responses (95% CI) 7d Prescribers starting a patient on a TIRF medicine 237 79.0 must begin with titration from the lowest dose (739. 83.5) available for that speci?c product. even if the patient has previously taken another TIRF medicine (Correct Response rue Key Risk Message 2: TIRF Medicines are only Indicated for the Management of Breakthrough Pain in Adult Cancer Patients 18 Years of Age and Older (16 Years of Age and Older for Actiq? Brand and Generic Equivalents) who are already Receiving and who are Tolerant to Around-the?Clock Opioid Therapy for their Underlying Persistent Cancer Pain 9. Per the approved labeling for TIRF medicines, for which of the following indications can TIRF medicines be prescribed to opioid tolerant patients? Please answer Yes, No, or I don?t know for each option. 9a Acute or postoperative pain 260 86.7 (Correct Response ?No (82.3. 903) 9b Headache or migraine pain 272 90.7 (Correct Response ?No (86. 8. 9 3_7) 9c Dental pain 291 97.0 (Correct Response ?No (94_4_ 98.6) 9d Breakthrough pain from cancer 275 91.7 (Correct Response ?Yes (87.9. 94_ 5) 9e Chronic non-cancer pain 131 43.7 (Correct Response ?No (38.0. 495) 98 Pharmacist KAB Assessment Report Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 42 of 50 Table 17. Summary of Correct Responses for Key Risk Messages Key Risk Message Question Question Correct Responses (95% CI) Key Risk Message 3: TIRF Medicines 7. Please answer True, False, or I don?t know for each statement based on the labeling for Contain Fentanyl, an Opioid Agonist and TIRF medicines. a Schedule II Controlled Substance, with Abuse Liability Similar to other Opioid Analgesics 7e It is important to monitor for signs of abuse and 288 96.0 addiction in patients who take TIRF medicines (93_1_ 979) (Correct Response True) 8. Which of the following are risk factors for opioid abuse? Please answer Yes, No, or I don?t know for each option. 8a A personal history of illness (Correct 213 71.0 Response ?Yes (65.5. 76.1) 8b A personal history of past or eiurent alcohol or diug 298 99.3 abuse. or a family history of illicit drug use or (97.6. 99.9) alcohol abuse (Correct Response es 10. Please answer True, False, or I don?t know for each statement about TIRF medicines. 10a TIRF medicines can be abused in a manner similar 283 94.3 to other opioid agonists (Correct Response rue (91.1. 96.7) 99 Pharmacist KAB Assessment Report Transmucosal Iimnediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Table 17. Summary of Correct Responses for Key Risk Messages Page 43 of 50 Key Risk Message Question Question Correct Responses (95% CI) Key Risk Message 4: TIRF Medicines are 10b TIRF medicines are interchangeable with each other 280 93.3 not Interchangeable with each other, regardless of route of administration (Correct (89.9. 959) Regardless of Route of Administration Response ?False 10c The conversion of one TIRF medicine for another 279 93.0 TIRF medicine may result in a fatal overdose (89.5. 95.6) because of differences in the pharmacokinetics of fentanyl absorption (Correct Response rue 10d Dosing of TIRF medicines is not equivalent on a 270 90.0 uncrogram-to-microgram basis (Correct Response (86.0. 9 3_ 2) rue Pharmacist KAB Assessment Report Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies 6. Page 44 of 50 FDA FEEDBACK FDA provided the following feedback on the 24-month assessment of the TIRF REMS, received in August 2014. This feedback was received too late to incorporate changes into the 36-month Pharmacist KAB survey but changes based on FDA feedback will be incorporated into the 48-month Pharmacist KAB survey. 7. • In the pharmacist survey, 81% of those surveyed functioned as the pharmacist in charge for their operations. In future pharmacist surveys, consider ensuring that a higher percentage of non-supervisory dispensing pharmacists are included. • Given that pharmacists often have the opportunity to see all of the prescriptions that a patient is taking, include a question in the pharmacist survey regarding the CYP3A4 interactions with TIRFs. • Also include a question in the pharmacist survey regarding their understanding that patients are to stop taking their TIRF when they stop taking their around-the-clock opioid. DISCUSSION AND CONCLUSIONS Discussion For the pharmacist KAB survey invitations (and reminders) were sent to a random sample of pharmacies enrolled in the TIRF REMS Access Program. From among those who responded to the invitation, 300 pharmacists completed the survey; thus the program sample size was achieved within the specific time period. The specific goals of the TIRF medicines pharmacist KAB survey were to assess pharmacist understanding of the risks associated with TIRF medicine use, the specific indications for treatment with TIRF medicines, and that TIRF medicines are contraindicated in opioid nontolerant patients. They survey also included questions about the pharmacists’ access to educational materials for TIRF medicines. In this 36-month survey, all but one of the questions/components included as part of the key risk messages had a correct response rate of >70%. There was only one question within a key risk message (Question 9 [Per the approved labeling for TIRF medicines, for which of the following indications can TIRF medicines be prescribed to opioid tolerant patients?] in Key Risk Message 2) that had a component with an understanding rate below the desired threshold of 65% (Component 9e: Chronic non-cancer pain; correct response “No”; correct response rate 43.7%). For the other 4 components of Question 9, the desired responses were greater than 86% in the 36-month survey. It should be noted that pharmacist knowledge of uses for which TIRF medicines are not indicated is not a goal of the TIRF REMS. This concept also scored low patients/caregivers (25.3%; presented as Long-lasting painful conditions not caused by cancer). FDA_2201 Pharmacist KAB Assessment Report Transmucosal Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 45 of 50 In addition, there were two questions included as part of the additional questions about the safe use of TIRF medicines (and not included as part of a key risk message) that had a component with an rmderstanding rate below 65% (See Table 18). The correct response for Component 6a which addresses knowledge that a cancer patient should not be started 011 a TIRF medicine and an around-the-clock opioid at the same time was 63.3%. This concept also scored low for prescribers during this reporting period. The correct response for component 11f that addresses the knowledge that patients are considered opioid-tolerant if taking an equianalgesic dose of another oral opioid one week or longer, was 59.0%. This concept also scored low for prescribers during this reporting period. As also shown in Table 18, the correct response rate was consistently low for Components 6a and 11f between the 24-month and 36-month Pharmacist KAB sruveys and for Component 9e across all three sruveys (the 12-month, the 24-month and the 36-month Pharmacist KAB surveys). Table 18. Correct/Desired Response Rate of Low Scoring Questions Across the Three Pharmacist KAB Survey Waves. 36? lZ-Month 24?Month 36?Month Month Survey Survey Survey Survey 1n Correct/Desired Correct/Desired Correct/Desired Question Response Rate Response Rate Response Rate Number Please answer ?True,? ?False,? or don?t know? 62 for each statement based on the labeling for TIRF medicines. A cancer patient can be started on a TIRF medicine and an 6a2 aroruid-the-clock opioid at the Not asked 65.3 63.3 same time. (Desired Response False) Per the approved labeling for TIRF medicines, for which of the following 91 indications can TIRF medicines be prescribed to opioid tolerant patients? Please answer Yes, No, or I don?t know for each option Pharmacist KAB Assessment Report Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 46 of 50 Table 18. Correct/Desired Response Rate of Low Scoring Questions Across the Three Pharmacist KAB Survey Waves. 36- lZ-Month 24-Month 36?Month Month . . Survey Survey Survey Survey Qt?zgg?sn?egzg? 1n Correct/Desired Correct/Desired Correct/Desired Question Response Rate Response Rate Response Rate Number 1 Chronic non-cancer pain 2 9e 29.8 47.0 43.7 (Desired Response No) Please select ?True,? ?False,? or don?t know? for each of the following. 112 According to the labeling for TIRF medicines, patients considered opioid-tolerant are those who are taking, for one week or longer, at least: An equianalgesic dose of 1 1f 2 another oral opioid Not asked 59,0 590 (Desired Response True) I This was part of Question 8 (8e) in 12-month Pharmacist KAB surrey. Question 8 was worded as follows for the 12-month KAB sruvey: For which of the following indications can TIRF medicines be prescribed to opioid tolerant patients? Please answer ?Yes.? or don?t know" for each option. 2 Not asked as a key risk message. Although responses for components in Table 18 are below the desired threshold of 65%, the responses for other components within the same questions or for similar concepts are high. Although the majority of the respondents scored less than the desired threshold of 65% in Component 6a, 74.0% of the respondents understood a cancer patient who had been on an around-the-clock opioid for one day should not start taking a TIRF medicine for breakthrough pain (Component 6b). In addition, the majority of the respondents indicated patients with cancer who are considered opioid tolerant are those who are taking arormd-the-clock opioid therapy for tmderlying persistent cancer pain for one week or longer (Component 5a, Key Risk Message 1). For Question 11, which also addresses opioid tolerance by asking the respondent to identify speci?c medications and doses that if taken by a patient for one week or longer would identify the patient as opioid tolerant, most of the respondents identi?ed a response for all components, except component 11f (equimmlgesic dose of another oral opioid) having a lower response rate Pharmacist KAB Assessment Report Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 47 of 50 Conclusions The consistently high level of pharmacist understanding of key risk messages in the 24month and 36-month surveys indicates that the Education Program for Prescribers and Pharmacists is meeting the goals of the TIRF REMS. The TRIG will evaluate the concepts that have scored low among stakeholders to determine if any action is warranted. As stated above, changes will be implemented into the 48-month Pharmacist KAB survey based on FDA feedback received on the 24-month assessment report. The TRIG will continue to work with the FDA to refine, on a continual basis, the steps to mitigate risks associated with TIRF medicines. FDA_2204 Pharmacist KAB Assessment Report Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Appendix A Page 48 of 50 Pharmacy Survey Protocol FDA_2205 PROTOCOL TITLE: Quantitative Testing of Pharmacist Knowledge, Attitudes, and Behavior about Transmucosal Immediate Release Fentanyl (TIRF) Products Safety and Use Information SPONSOR: TIRF REMS Industry Group (TRIG) Cephalon, Inc. (a wholly-owned subsidiary of Teva Pharmaceutical Industries, Ltd.) Depomed, Inc. Galena Biopharma, Inc. Insys Therapeutics Mallinckrodt Pharmaceuticals Meda Pharmaceuticals Mylan, Inc. Par Pharmaceutical, Inc. VERSION: 6.0 DATE: 18MAY2014 APPROVED: Final FDA_2206 TABLE OF CONTENTS PAGE TABLE OF CONTENTS ......................................................................................... 2 1. LIST OF ABBREVIATIONS .................................................................................. 3 2. BACKGROUND ..................................................................................................... 4 3. OBJECTIVES OF THE EVALUATION SURVEY ............................................... 5 4. METHODS .............................................................................................................. 5 4.1 4.1.1 4.1.2 4.1.3 Survey Design .......................................................................................................... 5 Qualitative Research on the Survey ......................................................................... 6 Questions and Statements on REMS Goals ............................................................. 6 Additional Questions................................................................................................ 9 4.2 4.2.1 Participant Recruitment.......................................................................................... 10 Measures to Minimize Bias in the Sample............................................................. 10 5. 5.1.1 5.1.2 5.1.3 STUDY POPULATION ........................................................................................ 10 Sample Size ............................................................................................................ 10 Inclusion Criteria.................................................................................................... 11 Exclusion Criteria .................................................................................................. 11 6. SURVEY PROCESS ............................................................................................. 12 6.1 6.1.1 6.1.2 Screening and Survey Administration ................................................................... 12 Telephone ............................................................................................................... 12 Internet ................................................................................................................... 12 6.2 Measures to Minimize Bias in the Survey Process ................................................ 12 7. 7.1.1 7.1.1.1 7.1.1.2 ANALYSIS ............................................................................................................ 13 Analysis Population ............................................................................................... 13 Description of Primary Analyses ........................................................................... 13 Description of Secondary Analyses ....................................................................... 14 8. SAFETY EVENT REPORTING ........................................................................... 14 9. PRIVACY PROTECTION AND CONFIDENTIALITY...................................... 14 LIST OF APPENDICES Appendix A Pharmacist Questionnaire ......................................................................... 15 Appendix B SAMPLE Pharmacist Invitation Letter..................................................... 33 FDA_2207 1. LIST OF ABBREVIATIONS CATI CSP CI EDC ETASU FDA HIPAA ISI KAB PI REMS SE PSP TIRF TIRF REMS TRIG UBC US Computer-Assisted Telephone Interviewing Closed System Pharmacy Confidence Interval Electronic Data Capture Elements to Assure Safe Use Food and Drug Administration Health Insurance Portability and Accountability Act Important Safety Information Knowledge, Attitudes and Behavior Prescribing Information Risk Evaluation and Mitigation Strategy Safety Event Project Specific Procedure Transmucosal Immediate Release Fentanyl TIRF REMS Access Program TIRF REMS Industry Group United BioSource Corporation United States FDA_2208 2. BACKGROUND Transmucosal Immediate Release Fentanyl (TIRF) medicines include the class of immediaterelease opioid analgesics that are indicated only for the management of breakthrough pain in cancer patients 18 years of age or older (16 or older for Actiq® and equivalent generics) who are already receiving and tolerant to opioid therapy for their underlying persistent cancer pain. The TIRF medicines include Abstral®, Actiq®, Fentora®, Lazanda®, Onsolis®, Subsys®, and generic versions of any of these brands. The TIRF REMS Industry Group (TRIG) includes Cephalon, Inc. (a wholly-owned subsidiary of Teva Pharmaceutical Industries, Ltd.); Depomed, Inc.; Galena Biopharma, Inc.; Insys Therapeutics; Meda Pharmaceuticals; Mallinckrodt Pharmaceuticals; Mylan, Inc.; and Par Pharmaceutical, Inc. The Food and Drug Administration (FDA) has determined that a class-wide Risk Evaluation and Mitigation Strategy (REMS) is required to mitigate the risk of misuse, abuse, addiction, overdose, and serious complications due to medication errors with the use of TIRF medicines. The TIRF REMS Access Program (hereafter referred to as TIRF REMS) was approved by the FDA on December 28, 2011. The TIRF REMS consists of a Medication Guide, Elements to Assure Safe Use (ETASU), an Implementation System, and a Timetable for Submission of Assessments of the REMS. The goals of the TIRF REMS are to mitigate the risk of misuse, abuse, addiction, overdose, and serious complications due to medication errors by: 1. Prescribing and dispensing TIRF medicines only to appropriate patients, which includes use only in opioid-tolerant patients 2. Preventing inappropriate conversion between TIRF medicines 3. Preventing accidental exposure to children and others for whom it was not prescribed 4. Educating prescribers, pharmacists, and patients on the potential for misuse, abuse, addiction, and overdose of TIRF medicines An important component of the TIRF REMS is the conduct of quantitative evaluation surveys to assess pharmacists’ understanding and knowledge of the safe use and appropriate prescribing of TIRF medicines as described in the TIRF REMS educational materials, enrollment form, and Prescribing Information (PI). This protocol will describe the administration of the surveys that will be conducted among pharmacists who are enrolled in the TIRF REMS Access Program. Data from the surveys, together with other REMS evaluation metrics, will be used to determine whether changes need to be made to the REMS processes or educational materials to make them more effective in achieving the goals of the REMS. FDA_2209 The surveys will be implemented so that data will be available for inclusion in the REMS Assessment Reports that will be submitted to the FDA at 12 months after approval of the TIRF REMS and annually thereafter. 3. OBJECTIVES OF THE EVALUATION SURVEY The evaluation survey will use a questionnaire to document the level of knowledge and assess the attitudes and behavior of pharmacists around the following key information and risk messages communicated through REMS: 1. TIRF medicines are contraindicated in opioid non-tolerant patients. 2. TIRF medicines are only indicated for the management of breakthrough pain in adult cancer patients 18 years of age and older (16 or older for Actiq® and equivalent generics) who are already receiving and who are tolerant to around-the-clock opioid therapy for their underlying persistent cancer pain. 3. TIRF medicines contain fentanyl, an opioid agonist and a Schedule II controlled substance, with abuse liability similar to other opioid analgesics. 4. TIRF medicines are not interchangeable with each other, regardless of route of administration. 5. Patients and their caregivers must be instructed that TIRF medicines contain a medicine in an amount that can be fatal in children, in individuals for whom it is not prescribed, and in those who are not opioid tolerant. The survey will also collect data on behaviors, such as receipt and use of educational materials and compliance with REMS requirements. 4. METHODS The survey was designed in collaboration between the TRIG and United BioSource Corporation (UBC), and will be administered by UBC. 4.1 Survey Design This survey will be conducted among a sample of pharmacists who are enrolled in the TIRF REMS Access Program. Respondents who have participated in a previous wave of the TIRF survey will not be eligible to participate in subsequent survey waves. The survey will be administered using the following modalities: • Self-administered via the Internet through a secure website FDA_2210 • Telephone surveys facilitated by a trained interviewer from the Survey Coordinating Center using a computer-assisted telephone interviewing (CATI) program The survey will begin with screening questions to confirm respondent eligibility to participate in the survey. Completion of the entire survey is expected to take up to 20 minutes. The survey included in Appendix A is written to reflect wording for both methods of survey administration: Internet-based and telephone. All respondents who complete the survey and who provide their contact information will be mailed a $50 honorarium for their time. 4.1.1 Qualitative Research on the Survey The FDA provided feedback to the TRIG on the Knowledge, Attitude, and Behavior (KAB) survey results for pharmacists included in the 12-month REMS Assessment results. The FDA requested that the TRIG investigate the causes for low correct response rates to specific questions in the survey by conducting research to determine the reasons for the poor performance on these questions and to assess proposed revised wording to select questions. Qualitative research was performed in 2013 prior to Wave 2 of the survey. Findings were incorporated into the survey and results from the revised survey were included in the 24month REMS Assessment Report, 4.1.2 Questions and Statements on REMS Goals The KAB questionnaire is made up of multiple-choice, close-ended statements or questions (the majority of which use true/false or yes/no dichotomous response options), and one openended question. These will evaluate current knowledge, attitudes, and behavior regarding the key risk messages noted in Section 3. Questions will be presented in several formats: • Statements or questions asking the respondent to indicate whether a statement or question is true or false, or if they do not know the answer (there is a similar set of statements and questions that use “yes” or “no” as potential response options); • Statements or questions asking the respondent to choose from a defined list of possible statements or answers; and • One question allowing for the respondent to list questions or comments. Questionnaires will be analyzed to determine pharmacist understanding of each key risk message. For statements or questions that use “true” or “yes” vs. “false” or “no” response options, the desired response for the key risk messages is generally “true” or “yes” indicating knowledge of, or behavior in accordance with, the objectives of the REMS. However, some questions are FDA_2211 formatted to have the respondent disagree with the statement as written by providing response options of “false” or “no” to avoid having the same affirmative answer for all desired responses. REMS statements, corresponding questions, and desired responses covering the key risk messages are identified below and can be found in the complete survey questionnaire (Appendix A). Key Risk Message 1: TIRF medicines are contraindicated in opioid non-tolerant patients. Question No. 5 5a 5b 5c 7 7a 7b 7c 7d Question Desired response Please select True, False, or I don’t know for each of the following. According to the labeling for TIRF medicines, patients with cancer who are considered opioid-tolerant are those: Who are taking around-the-clock opioid therapy for underlying, persistent cancer pain for one week or TRUE longer Who are not currently taking opioid therapy, but FALSE have taken opioid therapy before Who have no known contraindications to the drug fentanyl, but are not currently taking around-theFALSE clock opioid therapy Please answer True, False, or I don’t know for each statement based on the labeling for TIRF medicines. TIRF medicines are contraindicated in opioid nontolerant patients because life-threatening respiratory TRUE depression could occur at any dose. Death has occurred in opioid non-tolerant patients TRUE treated with some fentanyl products. TIRF medicines may be used in opioid non-tolerant FALSE patients. Prescribers starting a patient on a TIRF medicine must begin with titration from the lowest dose TRUE available for that specific product, even if the patient has previously taken another TIRF medicine. FDA_2212 Key Risk Message 2: TIRF medicines are only indicated for the management of breakthrough pain in adult cancer patients 18 years of age and older (16 years of age and older for Actiq® brand and generic equivalents) who are already receiving and who are tolerant to around-theclock opioid therapy for their underlying persistent cancer pain. Question No. 9 9a 9b 9c 9d 9e Question Desired response Per the approved labeling for TIRF medicines, for which of the following indications can TIRF medicines be prescribed to opioid tolerant patients? Please answer Yes, No, or I don’t know for each option. Acute or postoperative pain NO Headache or migraine pain NO Dental pain NO Breakthrough pain from cancer YES Chronic non-cancer pain NO Key Risk Message 3: TIRF medicines contain fentanyl, an opioid agonist and a Schedule II controlled substance with abuse liability similar to other opioid analgesics. Question No. 7 7e 8 8a 8b 10 10a Question Desired response Please answer True, False, or I don’t know for each statement based on the labeling for TIRF medicines. It is important to monitor for signs of abuse and addiction in patients who take TIRF TRUE medicines. Which of the following are risk factors for opioid abuse? Please answer Yes, No, or I don’t know for each option. A personal history of psychiatric illness YES A personal history of past or current alcohol or drug abuse, or a family history of YES illicit drug use or alcohol abuse Please answer True, False, or I don’t know for each statement based on the labeling for TIRF medicines. TIRF medicines can be abused in a manner TRUE similar to other opioid agonists. FDA_2213 Key Risk Message 4: TIRF medicines are not interchangeable with each other, regardless of route of administration. Question No. 10 10b 10c 10d 4.1.3 Question Desired response Please answer True, False, or I don’t know for each statement based on the labeling for TIRF medicines. TIRF medicines are interchangeable with each other regardless of route of FALSE administration. The conversion of one TIRF medicine for another TIRF medicine may result in a fatal TRUE overdose because of differences in the pharmacokinetics of fentanyl absorption. Dosing of TIRF medicines is not equivalent TRUE on a microgram-to-microgram basis. Additional Questions The survey includes questions about the requirements of the TIRF REMS Access Program, receipt and understanding of the TIRF educational materials, and behaviors. The following question about behaviors will be asked after the key risk message questions. Question 12: How frequently do you perform the following activities when dispensing TIRF medicines? Please answer Always, Only with the first prescription, Sometimes, Never, or I don’t know. Ask patients (or their caregivers) about the presence of children in the home Instruct patients (or their caregivers) not to share TIRF medicines with anyone else Counsel patients (or their caregivers) that accidental exposure to TIRF medicines by a child may be fatal Instruct patients (or their caregivers) to keep TIRF medicines out of the reach of children to prevent accidental exposure Instruct patients (or their caregivers) about proper disposal of any unused or partially used TIRF medicines Give patients (or their caregivers) the Medication Guide for their TIRF medicine Demographic information will be collected at the end of the survey. FDA_2214 4.2 Participant Recruitment A random sample of “pharmacists in charge” from pharmacies that are enrolled in the TIRF REMS Access Program will be invited to participate via an invitation letter. Any pharmacist who works at an enrolled pharmacy may participate. The text of the sample written invitation to pharmacists can be found in Appendix B. If the required number of completed surveys is not achieved within the expected timeframe of approximately one to two weeks after the first mailing, reminder letters will be sent to nonresponders from the original sample with subsequent fax, e-mail, or United States (US) Mail follow-up to maximize participation. The distribution within the mailing to the second sample will be adjusted in accordance with the allocation in the original sample. If these efforts do not result in the required number of surveys within two to three weeks, then a new sample of pharmacists will be randomly selected. The unique code provided in the invitation letter will be linked to the type of pharmacy (inpatient, outpatient, or Closed System Pharmacy [CSP]) in which the pharmacist works, based on the information provided as part of the TIRF REMS Access Program enrollment. All respondents who complete the survey and who provide their contact information will be mailed a $50 honorarium to thank them for their participation. The mailing will include a Thank You Letter, a copy of the Important Safety Information (ISI), and a copy of the correct answers to key risk message questions. 4.2.1 Measures to Minimize Bias in the Sample The sample of participating pharmacists will be self-selected since respondents will voluntarily respond to the invitation to participate; however, the survey recruitment strategies are intended to recruit a heterogeneous sample of pharmacies (e.g., chain and independent store) for participation. Pharmacists will be offered Internet-based or telephone options for completing the survey. Multiple modalities for survey data collection allow for wider survey access to a more heterogeneous population. Respondents will be provided a unique code during the recruitment process and will be asked to provide the unique code to gain access to the Internet-based survey or when calling the Survey Coordinating Center. The code will be deactivated after use to minimize the possibility for fraud. 5. STUDY POPULATION 5.1.1 Sample Size A sample of 300 pharmacists who are enrolled in the TIRF REMS Access Program is proposed for each survey wave. The size of the sample was determined based on both practical and statistical considerations. There is no target comprehension rate specified a priori. A sample of 300 completed surveys will allow estimation of the comprehension rate FDA_2215 for each risk message with a moderately high degree of precision. The table below shows the precision of the estimates for level of understanding using two-sided 95% confidence intervals (CIs) obtained with the sample size of 300 completed surveys. The noted CIs are used to indicate that for any survey-estimated rate of understanding, the true population rate of understanding is at least as high as the lower limit of the 95% CI and may be as high as the upper limit of the 95% CI. Table 5.1: Precision of Estimated Rates of Understanding with a Sample Size of 300 Estimated Rate of Understanding 5% 10% 15% 20% 25% 30% 35% 40% 45% 50% 55% 60% 65% 70% 75% 80% 85% 90% 95% 5.1.2 Estimated Confidence Interval 2.8% 6.8% 11.2% 15.6% 20.2% 24.9% 29.6% 34.4% 39.3% 44.2% 49.2% 54.2% 59.3% 64.5% 69.7% 75.0% 80.4% 86.0% 91.9% 8.1% 14.0% 19.6% 25.0% 30.3% 35.5% 40.7% 45.8% 50.8% 55.8% 60.7% 65.6% 70.4% 75.1% 79.8% 84.4% 88.8% 93.2% 97.2% Inclusion Criteria Pharmacists who work at pharmacies that are enrolled in the TIRF REMS Access Program are eligible to participate in this survey, with the exceptions noted below. 5.1.3 Exclusion Criteria The following respondents are not eligible to participate in the surveys: • Pharmacists who have previously participated in the TIRF REMS KAB survey. • Pharmacists or their immediate family members who have ever worked for Anesta LLC; Cephalon, Inc. (a wholly-owned subsidiary of Teva Pharmaceutical Industries, Ltd.); Depomed, Inc.; Galena Biopharma, Inc.; Insys Therapeutics; Mallinckrodt Pharmaceuticals; Meda Pharmaceuticals; Mylan, Inc.; Par Pharmaceutical, Inc.; Teva Pharmaceuticals, Ltd.; UBC; McKesson Specialty Care Solutions; RelayHealth; or the FDA. FDA_2216 6. SURVEY PROCESS The survey will begin with screening questions to confirm respondent eligibility to participate in the survey. Completion of the entire survey is expected to take approximately 20 minutes. 6.1 Screening and Survey Administration The questionnaire will begin with a screening module with questions to confirm pharmacist eligibility. Depending on the answers to the screening questions, survey participation could either be terminated or continued. If ineligible, the respondent is immediately notified with a “thank you” message that survey participation has ended. If eligible, the respondent is allowed to continue survey participation. The data entry system used for both methods of survey administration has been validated and is secure for receiving and storing survey data. An Internet-based data repository will be used to store survey data and other relevant program information. The system is 21 CFR Part 11 and Health Insurance Portability and Accountability Act (HIPAA) compliant. Pharmacistidentifying information will be stored separately from survey data. 6.1.1 Telephone A trained interviewer from the Survey Coordinating Center will conduct the telephone interviews using a CATI program. The screening and main elements of the questionnaire will be administered sequentially during the same telephone call. Telephone interviewing allows participation of pharmacists who do not have Internet access or prefer taking the survey over the telephone. It will also be convenient for pharmacists to participate since they can call in and be interviewed at their convenience during the specified time period when the Survey Coordinating Center is available. 6.1.2 Internet An Internet-based survey system will also be used for conducting the KAB surveys. If the pharmacist selects to participate in the survey via the Internet, he/she will be directed to a secured website where he/she will be instructed to complete screening questions. An Internetbased survey will be convenient for respondents to participate since they can complete the questionnaire at any convenient time and location during the specified time period when the Survey Coordinating Center is available. 6.2 Measures to Minimize Bias in the Survey Process A number of controls will be in place to ensure the survey is conducted in a controlled and professional manner and to minimize bias. For example, a unique code will be given to each survey participant and the code will be inactivated after use to minimize fraud. Telephone interviewers are highly trained and use a standardized script to administer the survey. All questions will be programmed to ensure that questions are asked in the appropriate sequence. Skip patterns will be clearly indicated. Respondents cannot go back to a question FDA_2217 once the question has been answered and cannot skip ahead. All questions must be answered in order to complete the survey. Response options presented in a list will be randomized to minimize positional bias. Programming will be reviewed by quality control and simulated users (User Acceptance Testing) prior to implementing the survey. 7. ANALYSIS Information obtained from the survey will be reported as descriptive statistics for the survey administration, study population, and the survey questions. The data from the sample population will be reported using frequency distributions of responses to all questions. The following will be reported as part of this analysis: • The number of invitations issued to pharmacists • The number of reminder letters issued to pharmacists • The number of respondents screened for participation • The number of respondents eligible for participation • The number of respondents eligible for participation who answered all questions presented to them • Representativeness of pharmacists based on geography • Description of survey participants, including: o Gender o Years of professional experience o How many times per month TIRF medicines dispensed in the last 6 months Additional descriptive statistics may be reported as appropriate. 7.1.1 Analysis Population The analysis population will be based on eligible pharmacists who completed all questions presented to them in the survey (“completers”). 7.1.1.1 Description of Primary Analyses Primary analyses are done for all key risk messages using data from all completers. The primary analysis for a key risk message evaluates the rate for each correct response to each individual question/item defined by the key risk message. The specific correct response to each question/item is identified in the body of the risk message table. FDA_2218 7.1.1.2 Description of Secondary Analyses Secondary analyses are done only for those key risk messages that contain multiple questions/items using data from all completers. The secondary analysis entails a frequency distribution of the number of completers who got 0, 1, etc. correct responses across the total number of items for the given key risk message. 8. SAFETY EVENT REPORTING The term ‘Safety Event’ is defined as any information reported by a survey respondent that meets the criteria of an adverse event or product complaint. While it is not the intention of the survey to solicit the report of information that meets the criteria of a Safety Event, it is possible that a respondent may spontaneously report information that meets this criteria in free text fields of the survey (Internet-based administration) or while in conversation with the Survey Coordinating Center (telephone-based administration). The Internet-based questionnaires will be monitored for any comments recorded in the free text fields. If an event is mentioned to a Survey Coordinating Center Associate, the Associate will document the safety event and the respondent’s contact information. Respondents will also be informed that a representative from the appropriate TIRF medicine manufacturer may contact them if they have questions about the survey. Information on all reports (Internet or telephone) that may constitute an adverse event or other safety event will be forwarded to the appropriate TIRF medicine manufacturer as described in the Safety Event Project Specific Procedure (SE PSP). Additional detail regarding processes for adverse event reporting will be specified in the SE PSP. 9. PRIVACY PROTECTION AND CONFIDENTIALITY All data collected during the survey will be held confidential. The electronic data capture (EDC) system used for data collection encrypts all identifiable information, and respondent identifiers are stored separately from the survey responses. Respondent names and addresses are collected in order to mail the $50 honorarium, a Thank You Letter, correct survey responses to key risk message questions, and the ISI after the survey is completed. Respondent contact information is also needed in the event that a safety event is reported and a TIRF medicine manufacturer must obtain follow-up information (see Section 8 above). Respondents will be informed when they access the survey that they may be contacted if there are any questions about their survey responses. Respondents will be informed that their answers to the survey questions will not affect their ability to dispense TIRF medicines. FDA_2219 Appendix A Pharmacist Questionnaire Survey Legend • [PROGRAMMER] is used to indicate directions to the programmer and is set in bold, red, uppercase letters between square brackets. • (INTERVIEWER) is used to indicate directions to the telephone interviewer and is set in bold, blue, text between parentheses. This text appears when content is to be administered by telephone only (for example, spontaneous adverse event reporting). • [ONLINE] indicates a question is worded specifically for administering the survey online. [PHONE] indicates a question is worded specifically to be read by a telephone interviewer and differs from the online text. • [BEGIN ONLINE/PHONE SURVEY CONTENT] and [END SURVEY CONTENT] are used to indicate to the programmer the type of survey administration and the beginning and end of the survey or sections within the survey content, for example, [BEGIN ADVERSE EVENT/PRODUCT COMPLAINT] and [END ADVERSE EVENT/PRODUCT COMPLAINT]. • [TERMINATE] is displayed next to responses that should cause the survey to end. The following termination language will be programmed into the survey or read by the interviewer unless different language is specified with the question. Thank you very much for your time today. Based on your answer, you are not eligible to take this survey. We appreciate your interest in the survey. • [RANDOMIZE LIST] is inserted before questions to indicate to the programmer that the responses should be randomized. Responses such as “I don’t know,” “Prefer not to answer” or “None of the above” will always appear at the end of the randomized responses. • [GO TO Qx] (skip logic) is inserted after a response to indicate to the programmer that the survey should skip to the indicated question (for example, [GO TO Q17] skips to question 17). If no skip logic is indicated the survey continues to the next question in the sequence. • [FREE TEXT] indicates to the programmer that one line should be provided for data entry. • [MULTILINE INPUT] indicates to the programmer that multiple lines should be FDA_2220 Survey Legend provided for data entry (for example, two address lines). • [DROP-DOWN LIST INPUT WITH STATES TABLE] indicates to the programmer that the response should be a drop-down list containing the states in the table below. Alabama Georgia Massachusetts New York Tennessee Alaska Guam Michigan North Carolina Texas American Samoa Hawaii Minnesota North Dakota Idaho Mississippi Arizona Illinois Missouri Arkansas Indiana Montana Northern Mariana Islands US Virgin Islands California Iowa Nebraska Colorado Kansas Nevada Connecticut Kentucky New Hampshire Delaware Louisiana New Jersey District of Columbia Maine New Mexico Maryland Florida Utah Vermont Ohio Virginia Oklahoma Washington Oregon West Virginia Pennsylvania Wisconsin Puerto Rico Wyoming Rhode Island South Carolina South Dakota The following is used to categorize survey populations into standard geographic regions but it is not displayed in the survey. Geographic Distribution (based on address) 1: Northeast, Midwest, South, and West regions Northeast Region − − New England Division - ME, NH, VT, MA, RI, CT Middle Atlantic Division - NY, NJ, PA Midwest Region − − East North Central Division - OH, IN, IL, MI, WI West North Central Division - MN, IA, MO, ND, SD, NE, KS South Region − − South Atlantic Division - DE, MD, DC, VA, WV, NC, SC, GA, FL East South Central Division - KY, TN, AL, MS West South Central Division - AR, LA, OK, TX West FDA_2221 Survey Legend − − Mountain Division - MT, ID, WY, CO, NM, AZ, UT, NV Pacific Division WA, OR, CA, AK, HI The following US territories are categorized as Other: Puerto Rico, Northern Mariana Islands, US Virgin Islands, American Samoa, and Guam. 1 U.S. Census Bureau, last revised Friday, 27-Jul-2001 12:59:43 EDT. FDA_2222 [BEGIN SURVEY CONTENT] [ONLINE PREAMBLE 1] Before you begin, we would like to share some important information about this survey. The manufacturers of Transmucosal Immediate Release Fentanyl (TIRF) medicines are conducting this survey, as required by the FDA, to assess pharmacists’ understanding of the safe use and dispensing of these medicines. These medicines are known as rapid onset opioids and referred to in this survey as “TIRF medicines.” The TIRF medicines include Abstral®, Actiq®, Fentora®, Lazanda®, Onsolis®, Subsys®, and generic versions of any of these brands. The manufacturers of these medicines include Cephalon, Inc. (a wholly-owned subsidiary of Teva Pharmaceutical Industries, Ltd.); Depomed, Inc.; Galena Biopharma, Inc.; Insys Therapeutics; Mallinckrodt Pharmaceuticals; Meda Pharmaceuticals; Mylan, Inc.; and Par Pharmaceutical, Inc. The survey will take 15-20 minutes. There are no known risks to you in taking this survey. You may refuse to take part or withdraw at any time. Your answers to the questions or your decision to take part in the survey will not affect your ability to dispense TIRF medicines. How We Use Your Information Your answers to the survey questions will be combined with answers given by other pharmacists taking the survey. All answers will be put together and reported in anonymous form to the manufacturers of TIRF medicines. Your name will not be used in any report. If you are eligible to take the survey, complete all the questions, and provide your contact information, you will receive a $50 honorarium for your time and participation. Your name and address will be used to send you the honorarium after you complete the survey. Your personal information will also be used if we have questions about your survey or if we are required to use your information to comply with a federal or state law or regulation. Providing a telephone number is optional. Your telephone number will be used only if there are any questions about your survey responses. How We Protect Your Privacy We respect that the privacy of your personal information is important to you. You will not be contacted for marketing purposes based on your personal information or your answers to the survey. Neither the manufacturers of TIRF medicines nor their contractors will sell, transfer, or rent your information. Your answers will be kept strictly confidential. Your privacy will be protected; however, research survey records may be inspected by the FDA. Your choice to allow manufacturers of TIRF medicines to use your information is entirely voluntary but necessary to take part in this survey. How to Learn More about This Survey FDA_2223 If you have questions about the survey, or problems with the survey, please contact the Survey Coordinating Center at 1-877-379-3297. Be sure to write down this telephone number; it will not be displayed again. Taking the Survey Once you have answered a question and moved on, you cannot go back and change your answers. Thank you for your participation in this survey. [END ONLINE PREAMBLE 1] FDA_2224 [PHONE PREAMBLE 1] Before you begin, we would like to share some important information about this survey. The manufacturers of Transmucosal Immediate Release Fentanyl (TIRF) medicines are conducting this survey, as required by the FDA, to assess pharmacists’ understanding of the safe use and dispensing of these medicines. These medicines are known as rapid onset opioids and referred to in this survey as “TIRF medicines.” (INTERVIEWER: Say “TIRF” then spell out T-IR-F) The TIRF medicines include Abstral®, Actiq®, Fentora®, Lazanda®, Onsolis®, Subsys®, and generic versions of any of these brands. The manufacturers of these medicines include Cephalon, Inc. (a wholly-owned subsidiary of Teva Pharmaceutical Industries, Ltd.); Depomed, Inc.; Galena Biopharma, Inc.; Insys Therapeutics; Mallinckrodt Pharmaceuticals; Meda Pharmaceuticals; Mylan, Inc.; and Par Pharmaceutical, Inc. The survey will take 15-20 minutes. There are no known risks to you in taking this survey. You may refuse to take part or withdraw at any time. Your answers to the questions or your decision to take part in the survey will not affect your ability to dispense TIRF medicines. Now I would like to read some information about how your contact information will be used. Your answers to the survey questions will be combined with answers given by other pharmacists taking the survey. All answers will be put together and reported in anonymous form to the manufacturers of TIRF medicines. Your name will not be used in any report. If you are eligible to take the survey, complete all the questions, and provide your contact information, you will receive a $50 honorarium for your time and participation. Your name and address will be used to send you the honorarium after you complete the survey. Your personal information will also be used if we have questions about your survey or if we are required to use your information to comply with a federal or state law or regulation. Providing a telephone number is optional. Your telephone number will be used only if there are any questions about your survey responses. Now I would like to tell you some information about how we protect your privacy. We respect that the privacy of your personal information is important to you. You will not be contacted for marketing purposes based on your personal information or your answers to the survey. Neither the manufacturers of TIRF medicines nor their contractors will sell, transfer, or rent your information. Your answers will be kept strictly confidential. Your privacy will be protected; however, research survey records may be inspected by the FDA. Your choice to allow manufacturers of TIRF medicines to use your information is entirely voluntary but necessary to take part in this survey. Now I will tell you how you can learn more about this survey. Please have a pen or pencil ready to write down a telephone number you can call should you have any questions about the survey. If you have questions about the survey, please ask me at any time. If you have questions at a later time, please contact the Survey Coordinating Center at 1-877-379-3297. FDA_2225 Please feel free to ask me to repeat any questions or statements as we go through the survey. Once you have answered a question and moved on, you cannot go back and change your answers. Thank you for your participation in this survey. [END PHONE PREAMBLE 1] FDA_2226 [BEGIN INCLUSION/EXCLUSION QUESTIONS] 1. Your agreement to participate in this survey confirms mutual understanding in connection with completion of the survey and the fair market value of the payment to be rendered in connection with those services. Do you agree to participate in this survey? 2. 3. 4. ○ Yes ○ No [TERMINATE] Have you ever taken part in this survey about TIRF medicines before? TIRF medicines include Abstral®, Actiq®, Fentora®, Lazanda®, Onsolis®, Subsys®, and generic versions of any of these brands. ○ Yes [TERMINATE] ○ No ○ I don’t know [TERMINATE] Do you work in a pharmacy that is enrolled in the TIRF REMS Access Program? ○ Yes ○ No [TERMINATE] ○ I don’t know [TERMINATE] Have you or any of your immediate family members ever worked for any of the following companies or agencies? Please select all that apply. □ □ Anesta LLC [TERMINATE] Cephalon, Inc. (a wholly-owned subsidiary of Teva Pharmaceutical Industries, Ltd.) [TERMINATE] □ Depomed, Inc. [TERMINATE] □ Galena Biopharma, Inc. [TERMINATE] □ Insys Therapeutics [TERMINATE] FDA_2227 □ Mallinckrodt Pharmaceuticals [TERMINATE] □ McKesson Specialty Care Solutions [TERMINATE] □ Meda Pharmaceuticals [TERMINATE] □ Mylan, Inc. [TERMINATE] □ Par Pharmaceutical, Inc. [TERMINATE] □ RelayHealth [TERMINATE] □ Teva Pharmaceuticals, Ltd. [TERMINATE] □ United BioSource Corporation [TERMINATE] □ FDA [TERMINATE] □ None of these apply [IF SELECTED IN ADDITION TO OTHER RESPONSES, TERMINATE] □ I don’t know [TERMINATE] □ Prefer not to answer [TERMINATE] [END INCLUSION/EXCLUSION QUESTIONS] 5. Please select True, False, or I don’t know for each of the following. According to the labeling for TIRF medicines, patients with cancer who are considered opioid-tolerant are those: [RANDOMIZE LIST] Who are taking around-the-clock opioid therapy for underlying, persistent cancer pain for one week or longer Who are not currently taking opioid therapy, but have 5b. taken opioid therapy before Who have no known contraindications to the drug 5c. fentanyl, but are not currently taking around-the-clock opioid therapy 5a. 6. True False I don’t know ○ ○ ○ ○ ○ ○ ○ ○ ○ Please answer True, False, or I don’t know for each statement based on the labeling for FDA_2228 TIRF medicines. [RANDOMIZE LIST] 6a. A cancer patient can be started on a TIRF medicine and an around-the-clock opioid at the same time. 6b. A cancer patient who has been on an around-the-clock opioid for 1 day can start taking a TIRF medicine for breakthrough pain. 7. True False I don’t know ○ ○ ○ ○ ○ ○ Please answer True, False, or I don’t know for each statement based on the labeling for TIRF medicines. [RANDOMIZE LIST] 7a. TIRF medicines are contraindicated in opioid nontolerant patients because life-threatening respiratory depression could occur at any dose. 7b. Death has occurred in opioid non-tolerant patients treated with some fentanyl products. 7c. TIRF medicines may be used in opioid non-tolerant patients. 7d. Prescribers starting a patient on a TIRF medicine must begin with titration from the lowest dose available for that specific product, even if the patient has previously taken another TIRF medicine. 7e. It is important to monitor for signs of abuse and addiction in patients who take TIRF medicines. True False I don’t know ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ FDA_2229 8. Which of the following are risk factors for opioid abuse? Please answer Yes, No, or I don’t know for each option. [RANDOMIZE LIST] 8a. 8b. 8c. 9. Yes No I don’t know ○ ○ ○ ○ ○ ○ ○ ○ ○ A personal history of psychiatric illness A personal history of past or current alcohol or drug abuse, or a family history of illicit drug use or alcohol abuse A family history of asthma Per the approved labeling for TIRF medicines, for which of the following indications can TIRF medicines be prescribed to opioid tolerant patients? Please answer Yes, No, or I don’t know for each option. [RANDOMIZE LIST] Yes No I don’t know ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ 9a. 9b. 9c. 9d. 9e. Acute or postoperative pain Headache or migraine pain Dental pain Breakthrough pain from cancer Chronic non-cancer pain 10. Please answer True, False, or I don’t know for each statement based on the labeling for TIRF medicines. [RANDOMIZE LIST] 10a. TIRF medicines can be abused in a manner similar to other opioid agonists. 10b. TIRF medicines are interchangeable with each other regardless of route of administration. 10c. The conversion of one TIRF medicine for another TIRF medicine may result in a fatal overdose because of differences in the pharmacokinetics of fentanyl absorption. 10d. Dosing of TIRF medicines is not equivalent on a microgram-to-microgram basis. True False I don’t know ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ FDA_2230 11. Please select True, False, or I don’t know for each of the following. According to the labeling for TIRF medicines, patients considered opioid-tolerant are those who are taking, for one week or longer, at least: [RANDOMIZE LIST] 11a. 11b. 11c. 11d. 11e. 11f. 8 mg oral hydromorphone/day 60 mg oral morphine/day 30 mg oral oxycodone/day 25 mcg transdermal fentanyl/hour 25 mg oral oxymorphone/day An equianalgesic dose of another oral opioid True False I don’t know ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ 12. How frequently do you perform the following activities when dispensing TIRF medicines? Please answer Always, Only with the first prescription, Sometimes, Never, or I don’t know. [RANDOMIZE LIST] 12a Ask patients (or their caregivers) about the presence of children in the home 12b Instruct patients (or their caregivers) not to share TIRF medicines with anyone else 12c Counsel patients (or their caregivers) that accidental exposure to TIRF medicines by a child may be fatal 12d Instruct patients (or their caregivers) to keep TIRF medicines out of the reach of children to prevent accidental exposure 12e Instruct patients (or their caregivers) about proper disposal of any unused or partially used TIRF medicines 12f. Give patients (or their caregivers) the Medication Guide for their TIRF medicine Always Only with the first prescription ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ Sometimes Never I don’t know FDA_2231 13. Please answer True, False, or I don’t know for each statement about TIRF medicines. [RANDOMIZE LIST] 13a. TIRF medicines may be sold, loaned, or transferred to another pharmacy. 13b. All pharmacy staff that dispenses TIRF medicines must be educated on the requirements of the TIRF REMS Access Program. 13c. TIRF medicines with the same route of administration can be substituted with each other if the pharmacy is out of stock for one product. 14. 15. True False I don’t know ○ ○ ○ ○ ○ ○ ○ ○ ○ [INPATIENT PHARMACIST] Does the inpatient pharmacy where you work have an established system, order sets, protocols and/or other measures to help ensure appropriate patient selection and compliance with the requirements of the TIRF REMS Access Program? ○ Yes ○ No ○ I don’t know [OUTPATIENT PHARMACIST] Does the outpatient or retail pharmacy where you work process all TIRF medicine prescriptions, regardless of method of payment, through the pharmacy management system? ○ Yes ○ No ○ I don’t know FDA_2232 16. 17. [CSP OUTPATIENT PHARMACIST] Does the pharmacy where you work process all TIRF medicine prescriptions, regardless of method of payment, through the TIRF REMS Access Call Center? ○ Yes ○ No ○ I don’t know [INPATIENT PHARMACIST] Please answer True, False, or I don’t know for the following statement about TIRF medicines. It is OK to dispense TIRF medicines from the inpatient pharmacy inventory to an outpatient for use at home. True False I don’t know ○ ○ ○ [PREAMBLE 3] The next set of questions is about the educational materials for TIRF medicines. As a reminder, the TIRF medicines include Abstral®, Actiq®, Fentora®, Lazanda®, Onsolis®, Subsys®, and generic versions of any of these brands. 18. 19. Did you receive or do you have access to the Full Prescribing Information for the TIRF medicine(s) that you dispense? ○ Yes ○ No [GO TO Q20] ○ I don’t know [GO TO Q20] Did you read the Full Prescribing Information for the TIRF medicine(s) that you dispense? ○ Yes ○ No ○ I don’t know FDA_2233 20. 21. 22. 23. Did you receive or do you have access to the Medication Guide for the TIRF medicine(s) that you dispense? ○ Yes ○ No [GO TO Q22] ○ I don’t know [GO TO Q22] Did you read the Medication Guide for the TIRF medicine(s) that you dispense? ○ Yes ○ No ○ I don’t know Did you or do you have any questions about the information in the Full Prescribing Information or Medication Guide? ○ Yes ○ No [GO TO DEMOGRAPHICS PREAMBLE ] ○ I don’t know [GO TO DEMOGRAPHICS PREAMBLE] What are your questions? [MULTILINE INPUT] [DEMOGRAPHICS PREAMBLE] There are just a few more questions to help us combine your answers with other answers we have received. 24. Are you the Pharmacist in Charge for the TIRF REMS Access Program where you work? ○ Yes ○ No ○ I don’t know FDA_2234 25. 26. On average, how many times per month have you dispensed TIRF medicine within the last 6 months? ○ None [Go to DEMOGRAPHICS PREAMBLE 2] ○ 1 – 2 times per month ○ 3 – 5 times per month ○ More than 5 times per month ○ I don’t remember Please select the TIRF medicine(s) that you have dispensed within the last 6 months. Please select all that apply. □ Abstral® □ Actiq® or generic Actiq® □ Fentora® □ Lazanda® □ Onsolis® □ Subsys® [DEMOGRAPHICS PREAMBLE 2] These last few questions are for demographic purposes. 27. What is your gender? ○ Male ○ Female ○ Prefer not to answer FDA_2235 28. 29. In total, how many years have you been a practicing pharmacist? ○ Less than 3 years ○ 3 – 5 years ○ 6 – 10 years ○ 11 – 15 years ○ More than 15 years ○ Prefer not to answer In which state do you practice? [DROP-DOWN LIST INPUT WITH STATES TABLE WITH “Prefer not to answer” AT END] [PHONE ONLY: BEGIN ADVERSE EVENT/PRODUCT COMPLAINT] (INTERVIEWER: Please record if respondent spontaneously reported an adverse event or product complaint during the course of this interview.) ○ Yes ○ No [GO TO CLOSING 1] Enter Safety Adverse Event Verbatim [MULTILINE INPUT] (INTERVIEWER: Indicate to the respondent that someone may call back to ask more questions about the adverse event or product complaint that was reported.) [END ADVERSE EVENT/PRODUCT COMPLAINT] [CLOSING 1] We would like to send you a $50 honorarium within the next few weeks to thank you for your time, but we need your name and address to do so. If you do not provide your name and address you will not receive the honorarium for your time and participation in the survey. FDA_2236 Do you agree to give us your name and mailing address so we can send you the honorarium? ○ Yes ○ No [SKIP TO CLOSING 2] FIRST NAME: [FREE TEXT] LAST NAME: [FREE TEXT] ADDRESS: [MULTILINE INPUT] CITY: [FREE TEXT] STATE: [DROP-DOWN LIST INPUT WITH STATES TABLE] ZIP: [5 NUMERIC CHARACTERS ONLY] [CLOSING 2] We would also like to ask for your telephone number. Providing your telephone number is optional and it will be used to contact you only if there are questions about your survey responses. Do you want to provide your telephone number? ○ Yes ○ No [SKIP TO CLOSING 3] Telephone: [MUST BE 10-DIGIT NUMERIC CHARACTERS] [END CLOSING 2] [CLOSING 3] That ends the survey. Thank you again for your help. [END OF SURVEY CONTENT] FDA_2237 Appendix B SAMPLE Pharmacist Invitation Letter [CURR_DATE] [PHARMACY_NAME] [PHARMACY _STREET_ADDR] [PHARMACY_CITY], [PHARMACY _STATE] [PHARMACY _ZIP] [PHARMACY_FAX_NUMBER] Dear [PHARMACIST_IN CHARGE] Your Pharmacy was selected to receive this letter, because of enrollment in the TIRF REMS Access Program. We are contacting you to inform you about a survey being conducted by the manufacturers of Transmucosal Immediate Release Fentanyl (TIRF) medicines, as required by the Food and Drug Administration (FDA). The purpose of the survey is to assess pharmacists’ understanding of the safe and appropriate use of these medicines. The TIRF medicines include Abstral®, Actiq®, Fentora®, Lazanda®, Onsolis®, Subsys®, and generic versions of any of these brands. The manufacturers of TIRF medicines include Cephalon, Inc. (a wholly-owned subsidiary of Teva Pharmaceutical Industries, Ltd.); Depomed, Inc.; Galena Biopharma, Inc.; Insys Therapeutics; Meda Pharmaceuticals; Mallinckrodt Pharmaceuticals; Mylan, Inc.; and Par Pharmaceutical, Inc. (collectively referred to as the “TIRF REMS Industry Group”). These manufacturers are looking for 300 pharmacists to complete the survey. Eligible pharmacists who complete the survey will be sent a $50 honorarium to thank them for their time. The survey will take 15-20 minutes. Your answers will be kept strictly confidential and will be combined with the answers from other pharmacists who take this survey. Your name will not be used in the report of this survey and your contact information, if provided, will only be used to send you a $50 honorarium for your time to complete the survey. You are under no obligation to participate in this survey. Only one pharmacist from each enrolled pharmacy can participate. If you are interested in participating and to find out if you are eligible: • • Go to www.TIRFREMSsurvey.com any time or Call 1-877-379-3297, 8 a.m. to 8 p.m. Eastern Time, Monday through Friday Please have this letter with you at the time you take the survey. You will be asked to provide this code prior to starting the survey: [CODE_ID]. *We recommend that you take the survey on a desktop or laptop computer. Taking the survey on mobile devices, such as smart phones, tablets, and e-notebooks, is not supported. Neither taking the survey nor your answers to the questions will affect your ability to dispense any of the TIRF medicines identified above. FDA_2238 Sincerely, The TIRF REMS Survey Team 1?877?379?3297 survey.com Pharmacist KAB Assessment Report Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Appendix B Page 49 of 50 Pharmacy Survey Listings and Sub-group Analysis Tables FDA_2240 TABLE 6.1.1 PRIMARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #1 KEY RISK MESSAGE l: TIRF MEDICINES ARE CONTRAINDICATED IN OPIOID NON-TOLERANT PATIENTS. Sub-group analysis 1: Reading Medication Guide or Full Prescribing Information (Questions 18, 19, 20 and 21): S-la-Respondents who read the Full Prescribing Information (Question 19) and Medication Guide for the TIRF medicine that they dispense (Question 21). S-lb-Respondents who responded ?No? or don?t know? to getting and reading the Full Prescribing Information and to getting and reading the Medication Guide for the TIRF medicine that they dispense. S?la S-lb Read Medication Guide or Did Mt read Medication . . Guide and Full Prescribing ti Full Prescribing Info Info ues on 274 6 0/0 0/0 (95% CI) (95% CI) Question 5: Please select True, False, or I don?t know for each of the following. According to the labeling for TIRF medicines, patients with cancer who are considered opioid-tolerant are those: Sa: Who are taking around?the-clock opioid therapy for underlying, persistent cancer pain for one week or longer 93.8 92.3 True 257 (90.3. 96.3) 24 (74.9. 99.1) False 10 3.6 1 3.8 I don't know 7 2.6 1 3.8 5b: Who are not currently taking opioid therapy, but have taken opioid therapy before 87.2 84.6 False 239 (82.7. 90.9) 22 (65.1. 95.6) True 26 9.5 3 11.5 I don't know 9 3.3 1 3.8 Client: TRIG Project: TIRF Wave3 Report Run Date and Time: 10/14/2014 3:31 PM Page 1 of 3 Question S-lb S?la . . . Read Medication Guide or Did Mt read Medication . . Guide and Full Prescribing Full Info m" (95% CI) (95% CI) 5c: Who have no known contraindications to the drug fentanyl, but are not currently taking around- the?clock opioid therapy 78.5 80.8 False 215 (73.1. 83.2) 21 (60.6. 93.4) True 41 15.0 3 11.5 I don't know 18 6.6 2 7.7 Question 7: Please answer True, False, or I don?t know for each statement based on the labeling for TIRF medicines. 7a: TIRF medicines are contraindicated in opioid non?tolerant patients because life?threatening respiratory depression could occur at any dose. me 248 (86.399537) 24 (74.95391) False 18 6.6 1 3.8 I don't know 8 2.9 1 3.8 7b: Death has occurred in opioid non?tolerant patients treated with some fentanyl products. True 257 (90.23.3363) 24 (74.99391) False 4 1.5 0 0.0 I don't know 13 4.7 2 7.7 7c: TIRF medicines may be used in opioid non-tolerant patients. False 229 (78.85.8678) 22 (65.83.9656) Tine 35 12.8 4 15.4 I don't know 10 3.6 0 0.0 Client: TRIG Project: TIRF Wave3 Report Run Date and Time: 10/14/2014 3:31 PM Page 2 of 3 7d: Prescribers starting a patient on a TIRF medicine must begin with titration from the lowest dose available for that speci?c product, even if the patient has previously taken another TIRF medicine. True 218 (742-8642) 19 (522-8184) False 45 16.4 19.2 I don't know 11 4.0 2 7.7 Correct Response Note: All con?dence intervals are exact binomial 95% con?dence intervals. Client: TRIG Project: TIRF Wave 3 Report Run Date and Time: 10/14/2014 3:31 PM Page 3 of 3 TABLE 6.2.1 SECONDARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #1 KEY RISK TIRF MEDICINES ARE CONTRAINDICATED IN OPIOID NON-TOLERANT PATIENTS. Sub-group analysis 1: Reading Medication Guide or Full Prescribing Information (Questions 18, 19, 20 and 21): S-la-Respondents who read the Full Prescribing Information (Question 19) and Medication Guide for the TIRF medicine that they dispense (Question 21). S-lb-Respondents who responded ?No? or don?t know? to getting and reading the Full Prescribing Information and to getting and reading the Medication Guide for the TIRF medicine that they dispense. la S-lb Read Medication Guide or Did not read Medication . . Guide and Full Prescribing Demonstrated Full Prescribing Info Info Understanding 0 correct responses 0 0.0 0 0.0 1 correct response 1 0.4 1 3.8 2 correct responses 9 3.3 0 0.0 3 correct responses 4 1.5 1 3.8 4 correct responses 14 5.1 1 3.8 5 correct responses 38 13.9 2 7.7 6 correct responses 70 25.5 9 34.6 7 correct responses 138 50.4 12 46.2 Average number 0f com? 6.1 (5.8. 7.0) ?1 6.0 (5 .2. 7.0) ?1 responses One-sided 95 con?dence interval using the normal approximation to the Poisson distribution Client: TRIG Project: TIRF Wave3 Report Run Date and Time: 10/14/2014 9:18 AM Page 1 of TABLE 7.1.1 PRIMARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #2 KEY RISK MESSAGE 2: TIRF MEDICINES ARE ONLY INDICATED FOR THE MANAGEMENT OF BREAKTHROUGH PAIN IN ADULT CANCER PATIENTS 18 YEARS OF AGE AND OLDER (16 YEARS OF AGE AND OLDER FOR BRAND AND GENERIC EQUIVALENTS) WHO ARE ALREADY RECEIVING AND WHO ARE TOLERANT TO AROUND- THE-CLOCK OPIOID THERAPY FOR THEIR UNDERLYING PERSISTENT CANCER PAIN. Sub-group analysis 1: Reading Medication Guide or Full Prescribing Information (Questions 18, 19, 20 and 21): S-la-Respondents who read the Full Prescribing Information (Question 19) and Medication Guide for the TIRF medicine that they dispense (Question 21). S-lb-Respondents who responded ?No? or don?t know? to getting and reading the Full Prescribing Information and to getting and reading the Medication Guide for the TIRF medicine that they dispense. Question S-la S-lb Read Medication Guide or Did not read Medication . . Gulde and Full Prescribing Full Info Info (95% CI) (95% CI) Question 9: Per the approved labeling for TIRF medicines, for which of the following indications can TIRF medicines be prescribed to opioid tolerant patients? Please answer Yes, No, or I don?t know for each option. 9a: Acute or postoperative pain 86.1 92.3 N0 236 (81.5. 90.0) 24 (74.9. 99.1) Yes 33 12.0 0 0.0 I don't know 5 1.8 7.7 Client: TRIG Project: TIRF Wave3 Report Run Date and Time: 10/14/2014 3:30 PM Page 1 of 2 S-lb Reaamwifaiivcm Question Full Info Info (95% CI) (95% CI) 9b: Headache or migraine pain 249 (86989-9940) 23 (69.85316don't know 16 5.8 3 11.5 9c: Dental pain N0 266 (9433-9187) 25 (8035-9299don't know 3 1.1 1 3.8 9d: Breakthrough pain from cancer 251 (87.97i 954.6) 24 (74.95391don't know 1 0.4 1 3.8 9e: Chronic non?cancer pain N0 122 Bag-550.6) 9 (17.32.5657) Yes 132 48.2 14 53.8 I don't know 20 7.3 3 11.5 Correct Response Note: All con?dence intervals are exact binomial 95% con?dence intervals. Client: TRIG Project: TIRF Wave3 Report Run Date and Time: 10/14/2014 3:30 PM Page 2 of 2 TABLE 7.2.1 SECONDARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #2 KEY RISK MESSAGE 2: TIRF MEDICINES ARE ONLY INDICATED FOR THE MANAGEMENT OF BREAKTHROUGH PAIN IN ADULT CANCER PATIENTS 18 YEARS OF AGE AND OLDER (16 YEARS OF AGE AND OLDER FOR BRAND AND GENERIC EQUIVALENTS) WHO ARE ALREADY RECEIVING AND WHO ARE TOLERANT TO AROUND- THE-CLOCK OPIOID THERAPY FOR THEIR UNDERLYING PERSISTENT CANCER PAIN. Sub-group analysis 1: Reading Medication Guide or Full Prescribing Information (Questions 18, 19, 20 and 21): S-la-Respondents who read the Full Prescribing Information (Question 19) and Medication Guide for the TIRF medicine that they dispense (Question 21). S-lb-Respondents who responded ?No? or don?t know? to getting and reading the Full Prescribing Information and to getting and reading the Medication Guide for the TIRF medicine that they dispense. S-la Did not Read Medication Guide or . . . Demonstrated Full Prescribing Info Guide and Understanding 0 correct responses 1 0.4 0.0 1 correct response 6 2.2 1 3.8 2 correct responses 8 2.9 0 0.0 3 correct responses 38 13.9 3 11.5 4 correct responses 117 42.7 15 57.7 5 correct responses 104 3 8.0 7 26.9 ?zgg?eegumber 0f com? 4.1 (3.9. 5.0) ?1 4.0 (3.4. 5.0) ?1 [ll One-sided 95 con?dence interval using the normal approximation to the Poisson distribution Client: TRIG Project: TIRF Wave3 Report Run Date and Time: 10/14/2014 9:25 AM Page 1 of TABLE 8.1.1 PRIMARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #3 KEY RISK MESSAGE 3: TIRF MEDICINES CONTAIN FENTANYL, AN OPIOID AGONIST AND A SCHEDULE II-CONTROLLED SUBSTANCE, WITH ABUSE LIABILITY SIMILAR TO OTHER OPIOID ANALGESICS. Sub-group analysis 1: Reading Medication Guide or Full Prescribing Information (Questions 18, 19, 20 and 21): S-la-Respondents who read the Full Prescribing Information (Question 19) and Medication Guide for the TIRF medicine that they dispense (Question 21). S-lb-Respondents who responded ?No? or don?t know? to getting and reading the Full Prescribing Information and to getting and reading the Medication Guide for the TIRF medicine that they dispense. S?la S'lb Read Medication Guide or Did not read Medication . . Guide and Full Prescribing ti Full Info Info ues on 274 6 (95% CI) (95% CI) Question 7: Please answer True, False, or I don?t know for each statement based on the labeling for TIRF medicines. 7e: It is important to monitor for signs of abuse and addiction in patients who take TIRF medicines. 96.0 96.2 Tm" 26" (92.9. 98.0) 25 (80.4. 99.9) False 6 2.2 1 3.8 I don't know 5 1.8 0 0.0 Question 8: Which of the following are risk factors for opioid abuse? Please answer Yes, No, or I don?t know for each option. 8a: A personal history of illness 71.5 65.4 Yes 196 (65.8. 76.8) 17 (44.3. 82.8) No 44 16.1 2 7.7 I don't know 34 12.4 7 26.9 Client: TRIG Project: TIRF Wave3 Report Run Date and Time: 10/28/2014 10:17 AM Page 1 of 2 S-lb Question S-la . . . Read Medication Guide or Did not read Medication . . Guide and Full Prescribing Full Info m" (95% CI) (95% CI) 8b: A personal history of past or current alcohol or drug abuse, or a family history of illicit drug use or alcohol abuse 99.3 100.0 Yes 272 (97.4. 99.9) 26 (86.8. 100.don't know 2 0.7 0 0.0 Question 10: Please answer True, False, or I don?t know for each statement based on the labeling for TIRF medicines. 10a: TIRF medicines can be abused in a manner similar to other opioid agonists. 94.2 96.2 True 258 (90.7. 96.6) 25 (80.4. 99.9) False 11 4.0 1 3.8 I don't know 5 1.8 0 0.0 Correct Response Note: All con?dence intervals are exact binomial 95% con?dence intervals. Client: TRIG Project: TIRF Wave3 Report Run Date and Time: 10/28/2014 10:17 AM Page 2 of 2 TABLE 8.2.1 SECONDARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #3 KEY RISK MESSAGE 3: TIRF MEDICINES CONTAIN FENTANYL, AN OPIOID AGONIST AND A SCHEDULE II-CONTROLLED SUBSTANCE, WITH ABUSE LIABILITY SIMILAR TO OTHER OPIOID ANALGESICS. Sub-group analysis 1: Reading Medication Guide or Full Prescribing Information (Questions 18, 19, 20 and 21): S-la-Respondents who read the Full Prescribing Information (Question 19) and Medication Guide for the TIRF medicine that they dispense (Question 21). S-lb-Respondents who responded ?No? or don?t know? to getting and reading the Full Prescribing Information and to getting and reading the Medication Guide for the TIRF medicine that they dispense. 1a S-lb Read Medication Guide or Did not read Medicatlon . . Guide and Full Prescribing Demonstrated Full Prescribing Info Info Understanding 0 correct responses 1 0.4 0 0.0 1 correct response 1 0.4 0 0.0 2 correct responses 11 4.0 1 3.8 3 correct responses 78 28.5 9 34.6 4 correct responses 183 66.8 16 61.5 Average number 0f ?one? 3.6 (3.4. 4.0) ?1 3.6 (3.0. 4.0) ?1 responses One-sided 95 con?dence interval using the normal approximation to the Poisson distribution Client: TRIG Project: TIRF Wave3 Report Run Date and Time: 10/28/2014 10:17 AM Page 1 of TABLE 9.1.1 PRIMARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #4 KEY RISK MESSAGE 4: TIRF MEDICINES ARE NOT INTERCHANGEABLE WITH EACH OTHER, REGARDLESS OF ROUTE OF ADMINISTRATION. Sub-group analysis 1: Reading Medication Guide or Full Prescribing Information (Questions 18, 19, 20 and 21): S-la-Respondents who read the Full Prescribing Information (Question 19) and Medication Guide for the TIRF medicine that they dispense (Question 21). S-lb-Respondents who responded ?No? or don?t know? to getting and reading the Full Prescribing Information and to getting and reading the Medication Guide for the TIRF medicine that they dispense. S-la S?lb Read Medication Guide or Did Mt read Medlcatlon . . Guide and Full Prescribmg Full Prescribing Info In to ues on 274 6 (95% CI) (95% CI) Question 10: Please answer True, False, or I don?t know for each statement based on the labeling for TIRF medicines. 10b: TIRF medicines are interchangeable with each other regardless of route of administration. 93.4 92.3 False 256 (89.8. 96.1) 24 (74.9. 99.1) True 12 4.4 1 3.8 I don?t know 6 2.2 1 3.8 10c: The conversion of one TIRF medicine for another TIRF medicine may result in a fatal overdose because of differences in the pharmacokinetics of fentanyl absorption. 93.1 92.3 True 255 (89.4. 95.8) 24 (74.9. 99.1) False 12 4.4 1 3.8 I don't know 7 2.6 1 3.8 Client: TRIG Project: TIRF Wave3 Report Run Date and Time: 10/14/2014 3:31 PM Page 1 of 2 10d: Dosing of TIRF medicines is not equivalent on a microgram?to-microgram basis. 89.4 96.2 True 245 (85.2, 92.8) 25 (80.4, 99.9) False 20 7.3 0 0.0 I don't know 9 3.3 3.8 Correct Response Note: All con?dence intervals are exact binomial 95% con?dence intervals. Client: TRIG Project: TIRF Wave 3 Report Run Date and Time: 10/14/2014 3:31 PM Page 2 of 2 TABLE 9.2.1 SECONDARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #4 KEY RISK MESSAGE 4: TIRF MEDICINES ARE NOT INTERCHANGEABLE WITH EACH OTHER, REGARDLESS OF ROUTE OF ADMINISTRATION. Sub-group analysis 1: Reading Medication Guide or Full Prescribing Information (Questions 18, 19, 20 and 21): S-la-Respondents who read the Full Prescribing Information (Question 19) and Medication Guide for the TIRF medicine that they dispense (Question 21). S-lb-Respondents who responded ?No? or don?t know? to getting and reading the Full Prescribing Information and to getting and reading the Medication Guide for the TIRF medicine that they dispense. S-lb S-la . . . Read Medication Guide or Did not read Medication . . Guide and Full Prescribing Demonstrated Full Prescribing Info Info Understanding 0 correct responses 3 1.1 0 0.0 1 correct response 8 2.9 1 3.8 2 correct responses 41 15.0 3 11.5 3 correct responses 222 81.0 22 84.6 Average number 0f 2.8 (2.6. 3.0) ?1 2.8 (2.3. 3 .0) ?1 responses One-sided 95 con?dence interval using the normal approximation to the Poisson distribution Client: TRIG Project: TIRF Wave3 Report Run Date and Time: 10/14/2014 9:34 AM Page 1 of TABLE 6.1.2 PRIMARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #1 KEY RISK MESSAGE 1: TIRF MEDICINES ARE CONTRAINDICATED IN OPIOID NON-TOLERANT PATIENTS. SUB-GROUP ANALYSIS 2: TIME TO COMPLETE SURVEY INTERNET: S-S-2c - 20 min S-2a S-2b S-min Question (95% CI) (95% CI) (95% CI) Question 5: Please select True, False, or I don?t know for each of the following. According to the labeling for TIRF medicines, patients with cancer who are considered opioid-tolerant are those: 5a: Who are taking around-the-clock opioid therapy for underlying, persistent cancer pain for one week or longer 94.5 96.3 97.7 True ?1 104 (88.5. 129 (91.5. 42 (87.7. 98.0) 98.8) 99.9) False don't know 1 0.9 2 1.5 2.3 5b: Who are not currently taking opioid therapy, but have taken opioid therapy before 89.1 89.6 86.0 False ?1 98 (81.7. 120 (83.1. 37 (72.1. 94.2) 94.2) 94.7) True don't know 3 2.7 2 1.5 2 4.7 Client: TRIG Project: TIRF Wave3 Report Run Date and Time: 10/14/2014 3:32 PM Page 1 of 3 Question S?2a S?2b S-min N=ll0 N=l34 (95% CI) (95% CI) (95% CI) 5c: Who have no known contraindications to the drug fentanyl, but are not currently taking around-the-clock opioid therapy 79.1 79.1 90.7 False ?1 87 (70.3. 106 (71.2. 39 (77.9. 86.3) 85.6) 97.4) True 18 16.4 20 14.9 2 4.7 I don't know 5 4.5 8 6.0 2 4.7 Question 7: Please answer True, False, or I don?t know for each statement based on the labeling for TIRF medicines. 7a: TIRF medicines are contraindicated in opioid non-tolerant patients because life-threatening respiratory depression could occur at any dose. 89.1 89.6 97.7 True ?1 98 (81.7. 120 (83.1. 42 (87.7. 94.2) 94.2) 99.9) False don't know 4 3.6 3 2.2 1 2.3 7b: Death has occurred in opioid non-tolerant patients treated with some fentanyl products. 92.7 94.8 97.7 True ?1 102 (86.2. 127 (89.5. 42 (87.7. 96.8) 97.9) 99.9) False don't know 5 4.5 7 5.2 1 2.3 7c: TIRF medicines may be used in opioid non-tolerant patients. 83.6 81.3 100.0 False ?1 92 (75.4. 109 (73.7. 43 (91.8. 90.0) 87.5) 100.0) True 12 10.9 22 16.4 0 0.0 I don't know 6 5.5 3 2.2 0 0.0 Client: TRIG Project: TIRF Wave3 Report Run Date and Time: 10/14/2014 3:32 PM Page 2 Question S?2a S?2b S-min N=l34 (95% CI) (95% CI) (95% CI) 7d: Prescribers starting a patient on a TIRF medicine must begin with titration from the lowest dose available for that specific product, even if the patient has previously taken another TIRF medicine. 80.0 74.6 86.0 True ?1 88 (71.3. 100 (66.4. 37 (72.1. 87.0) 81.7) 94.7) False 14 12.7 29 21.6 6 14.0 I don't know 8 7.3 5 3.7 0 0.0 Correct Response Note: All con?dence intervals are exact binomial 95% con?dence intervals. Client: TRIG Project: TIRF Wave3 Report Run Date and Time: 10/14/2014 3:32 PM Page 3 of 3 TABLE 6.2.2 SECONDARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #1 KEY RISK MESSAGEI: TIRF MEDICINES ARE CONTRAINDICATED IN OPIOID NON-TOLERANT PATIENTS. SUB-GROUP ANALYSIS 2: TINIE TO COMPLETE SURVEY INTERNET: S-2a - <10 min 0 S-2b 10 to <20 min 0 S-2c - 20 min S-2a S-2b S-min Demonstrafed Understandmg 0 correct responses correct response correct responses 4 3.6 2 1.5 0.0 3 correct responses correct responses correct responses 13 11.8 21 15.7 3 7.0 6 correct responses 33 30.0 33 24.6 10 23.3 7 correct responses 54 49.1 66 49.3 29 67.4 Average number of 6.1 (5.7. 6.1 (5.7. 6.6 (5.9. correct responses 7.0) 7.0) 7.0) ll] One-sided 95 con?dence interval using the normal approximation to the Poisson distribution Client: TRIG Project: TIRF Wave3 Report Run Date and Time: 10/14/2014 10:05 AM Page 1 of TABLE 7.1.2 PRIMARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #2 KEY RISK MESSAGE 2: TIRF MEDICINES ARE ONLY INDICATED FOR THE MANAGEMENT OF BREAKTHROUGH PAIN IN ADULT CANCER PATIENTS 18 YEARS OF AGE AND OLDER (16 YEARS OF AGE AND OLDER FOR BRAND AND GENERIC EQUIVALENTS) WHO ARE ALREADY RECEIVING AND WHO ARE TOLERANT TO AROUND- THE-CLOCK OPIOID THERAPY FOR THEIR UNDERLYING PERSISTENT CANCER PAIN. SUB-GROUP ANALYSIS 2: TINIE TO COMPLETE SURVEY INTERNET: S-2a - <10 min 0 S-2b 10 to <20 min 0 S-2c 20 min Question S-2a S-2b S?min (95% CI) (95% CI) (95% CI) Question 9: Per the approved labeling for TIRF medicines, for which of the following indications can TIRF medicines be prescribed to opioid tolerant patients? Please answer Yes, No, or I don?t know for each option. 9a: Acute or postoperative pain 82.7 89.6 90.7 No ?1 91 (74.3. 120 (83.1. 39 (77.9. 89.3) 94.2) 97.4) Yes 17 15.5 11 8.2 2 4.7 I don't know 2 1.8 3 2.2 2 4.7 9b: Headache or migraine pain 90.9 88.1 97.7 No ?1 100 (83.9. 118 (81.3. 42 (87.7. 95.6) 93.0) 99.don't know 6 5.5 11 8.2 2.3 Client: TRIG Project: TIRF Wave3 Report Run Date and Time: 10/14/2014 3:32 PM Page 1 of 2 S?2a S?2b S-min Question N=l34 (95% CI) (95% CI) (95% CI) 9c: Dental pain 96.4 98.5 97.7 No ?1 106 (91.0. 132 (94.7. 42 (87.7. 99.0) 99.8) 99.don't know 1 0.9 1 0.7 1 2.3 9d: Breakthrough pain from cancer 90.9 91.0 95.3 Yes ?1 100 (83.9. 122 (84.9. 41 (84.2. 95.6) 95.3) 99.don't know 1 0.9 1 0.7 0 0.0 9e: Chronic non-cancer pain 33.6 48.5 51.2 No ?1 37 (24.9. 65 (39.8. 22 (35.5. 43.3) 57.3) 66.7) Yes 61 55.5 61 45.5 19 44.2 I don't know 12 10.9 8 6.0 2 4.7 Correct Response Note: All con?dence intervals are exact binomial 95% con?dence intervals. Client: TRIG Project: TIRF Wave3 Report Run Date and Time: 10/14/2014 3:32 PM Page 2 of 2 TABLE 7.2.2 SECONDARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #2 KEY RISK MESSAGE 2: TIRF MEDICINES ARE ONLY INDICATED FOR THE MANAGEMENT OF BREAKTHROUGH PAIN IN ADULT CANCER PATIENTS 18 YEARS OF AGE AND OLDER (16 YEARS OF AGE AND OLDER FOR BRAND AND GENERIC EQUIVALENTS) WHO ARE ALREADY RECEIVING AND WHO ARE TOLERANT TO AROUND- THE-CLOCK OPIOID THERAPY FOR THEIR UNDERLYING PERSISTENT CANCER PAIN. SUB-GROUP ANALYSIS 2: TIME TO COMPLETE SURVEY INTERNET: 0 8-23 - <10 min 0 S-2b 10 to <20 min 0 S-2c - 20 min S-2a S-2b S-min D?m?nstraf?d N=l34 Understandmg 0 correct responses correct response correct responses correct responses 16 14.5 20 14.9 4 9.3 4 correct responses 58 52.7 50 37.3 17 39.5 5 correct responses 29 26.4 57 42.5 21 48.8 Average nlunber of 3.9 (3.6. 4.2 (3.9. 4.3 (3.8. correct responses 5.0) 5.0) 5.0) [ll One-sided 95 con?dence interval using the normal approximation to the Poisson distribution Client: TRIG Project: TIRF Wave3 Report Run Date and Time: 10/14/2014 10:11 AM Page 1 of TABLE 8.1.2 PRIMARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #3 KEY RISK MESSAGE 3: TIRF MEDICINES CONTAIN FENTANYL, AN OPIOID AGONIST AND A SCHEDULE II-CONTROLLED SUBSTANCE, WITH ABUSE LIABILITY SIMILAR TO OTHER OPIOID ANALGESICS. SUB-GROUP ANALYSIS 2: TIME TO COMPLETE SURVEY INTERNETS-2c 20 min Question S?2a S?2b S?min N=l34 (95% CI) (95% CI) (95% CI) Question 7: Please answer True, False, or I don?t know for each statement based on the labeling for TIRF medicines. 7e: It is important to monitor for signs of abuse and addiction in patients who take TIRF medicines. 94.5 96.3 97.7 True ?1 104 (88.5. 129 (91.5. 42 (87.7. 98.0) 98.8) 99.9) False don't know 3 2.7 2 1.5 0 0.0 Question 8: Which of the following are risk factors for opioid abuse? Please answer Yes, No, or I don?t know for each option. 8a: A personal history of illness 73.6 65.7 81.4 Yes ?1 81 (64.4. 88 (57.0. 35 (66.6. 81.6) 73.7) 91.6) No 16 14.5 24 17.9 3 7.0 I don't know 13 11.8 22 16.4 5 11.6 Client: TRIG Project: TIRF Wave3 Report Run Date and Time: 10/28/2014 10:18 AM Page 1 of 2 Question S?2a S?2b S-min N=ll0 N=l34 (95% CI) (95% CI) (95% CI) 8b: A personal history of past or current alcohol or drug abuse, or a family history of illicit drug use or alcohol abuse 99.1 99.3 100.0 Yes ?1 109 (95.0. 133 (95.9. 43 (91.8. 100.0) 100.0) 100.don't know 1 0.9 0.7 0 0.0 Question 10: Please answer True, False, or I don?t know for each statement based on the labeling for TIRF medicines. 10a: TIRF medicines can be abused in a manner similar to other opioid agonists. 95.5 94.0 93.0 True ?1 105 (89.7. 126 (88.6. 40 (80.9. 98.5) 97.4) 98.5) False don't know 1 0.9 3 2.2 0 0.0 Correct Response Note: All con?dence intervals are exact binomial 95% con?dence intervals. Client: TRIG Project: TIRF Wave3 Report Run Date and Time: 10/28/2014 10:18 AM Page 2 of 2 TABLE 8.2.2 SECONDARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #3 KEY RISK MESSAGE 3: TIRF MEDICINES CONTAIN FENTANYL, AN OPIOID AGONIST AND A SCHEDULE II-CONTROLLED SUBSTANCE, WITH ABUSE LIABILITY SIMILAR TO OTHER OPIOID ANALGESICS. SUB-GROUP ANALYSIS 2: TIME TO COMPLETE SURVEY INTERNET: S-2a - <10 min 0 S-2b 10 to <20 min 0 S-2c 20 min S-2a S-2b S-min D?m?nstraf?d N=l34 Understandmg 0 correct responses correct response correct responses correct responses 31 28.2 43 32.1 8 18.6 4 correct responses 75 68.2 83 61.9 33 76.7 Average number of 3.6 (3.3. 3.6 (3.3. 3.7 (3.2. correct responses 4.0) 4.0) 4.0) ?1 One-sided 95 con?dence interval using the normal approximation to the Poisson distribution Client: TRIG Project: TIRF Wave3 Report Run Date and Time: 10/28/2014 10:18 AM Page 1 of TABLE 9.1.2 PRIMARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #4 KEY RISK MESSAGE 4: TIRF MEDICINES ARE NOT INTERCHANGEABLE WITH EACH OTHER, REGARDLESS OF ROUTE OF ADMINISTRATION. SUB-GROUP ANALYSIS 2: TIME TO COMPLETE SURVEY INTERNET: - <10 min 0 S-2b 10 to <20 min 0 S-2c - 20 min S-2a S?2b S-min (95% CI) (95% CI) (95% CI) Question 10: Please answer True, False, or I don?t know for each statement based on the labeling for TIRF medicines. 10b: TIRF medicines are interchangeable with each other regardless of route of administration. 92.7 93.3 97.7 False ?1 102 (86.2. 125 (87.6. 42 (87.7. 96.8) 96.9) 99.9) True 4 3.6 7 5.2 2.3 I don't know 4 3.6 2 1.5 0 0.0 10c: The conversion of one TIRF medicine for another TIRF medicine may result in a fatal overdose because of differences in the pharmacokinetics of fentanyl absorption. 91.8 92.5 97.7 True ?1 101 (85.0. 124 (86.7. 42 (87.7. 96.2) 96.4) 99.9) False don't know 3 2.7 4 3.0 0 0.0 Client: TRIG Project: TIRF Wave3 Report Run Date and Time: 10/14/2014 3:32 PM Page 1 of 2 S?2a S?2b S-min Question N=l34 (95% CI) (95% CI) (95% CI) 10d: Dosing of TIRF medicines is not equivalent on a microgram-to-microgram basis. 88.2 91.8 95.3 True ?1 97 (80.6. 123 (85.8. 41 (84.2. 93.6) 95.8) 99.4) False don't know 3 2.7 6 4.5 0 0.0 Correct Response Note: All con?dence intervals are exact binomial 95% con?dence intervals. Client: TRIG Project: TIRF Wave3 Report Run Date and Time: 10/14/2014 3:32 PM Page 2 of 2 TABLE 9.2.2 SECONDARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #4 KEY RISK MESSAGE 4: TIRF MEDICINES ARE NOT INTERCHANGEABLE WITH EACH OTHER, REGARDLESS OF ROUTE OF ADMINISTRATION. SUB-GROUP ANALYSIS 2: TO COMPLETE SURVEY INTERNET: - <10 min 0 S-2b 10 to <20 min 0 S-2c - 20 min S-2a S-2b S-min Demonstrated N=l34 Understandmg 0 correct responses correct response correct responses 20 18.2 17 12.7 4 9.3 3 correct responses 86 78.2 111 82.8 39 90.7 Average nlunber of 2.7 (2.5. 2.8 (2.5. 2.9 (2.5. correct responses 3.0) 3.0) 3.0) ll] One-sided 95 con?dence interval using the normal approximation to the Poisson distribution Client: TRIG Project: TIRF Wave3 Report Run Date and Time: 10/14/2014 10:18 AM Page 1 of TABLE 6.1.3 PRIMARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #1 KEY RISK MESSAGE 1: TIRF MEDICINES ARE CONTRAINDICATED IN OPIOID NON-TOLERANT PATIENTS. SUB-GROUP ANALYSIS 3: TIME TO COMPLETE SURVEY TELEPHONE: S-3a - <10 min 0 S-3b 10 to <20 min 0 S-3c - 20 min S-3a S?3b S-min (95% CI) (95% CI) (95% CI) Question 5: Please select True, False, or I don?t know for each of the following. According to the labeling for TIRF medicines, patients with cancer who are considered opioid-tolerant are those: 5a: Who are taking around?the?clock opioid therapy for underlying, persistent cancer pain for one week or longer 33.3 75.0 True 0 3 (7.5. 70.1) 3 (915$ False 0 - 2 22.2 1 25.0 I don't know 0 - 4 44.4 0 0.0 5b: Who are not currently taking opioid therapy, but have taken opioid therapy before 44.4 50.0 False ?1 0 - 4 (7183-87) 2 (6.8. 93.2) True 0 - 2 22.2 2 50.0 I don't know 0 - 3 33.3 0 0.0 Client: TRIG Project: TIRF Wave3 Report Run Date and Time: 10/15/2014 4:24 PM Page 1 of 3 Question S-3a $-30 S-min (95% CI) (95% CI) (95% CI) 5c: Who have no known contraindications to the drug fentanyl, but are not currently taking around-the?clock opioid therapy 33.3 25.0 False 0 3 (7.5. 70.1) 1 (0.6. 80.6) True 0 3 33.3 1 25.0 I don't know 0 - 3 33.3 2 50.0 Question 7: Please answer True, False, or I don?t know for each statement based on the labeling for TIRF medicines. 7a: TIRF medicines are contraindicated in opioid non-tolerant patients because life-threatening respiratory depression could occur at any dose. 88.9 100.0 True ?1 0 - 8 (51.8. 4 (39.8. 99.7) 100.0) False don't know 0 - 1 11.1 0 0.0 7b: Death has occurred in opioid no n?tolerant patients treated with some fentanyl products. 88.9 5 . True 0 8 2 (6.8.0922) False 0 - 0 0.0 1 25.0 I don't know 0 - 1 11.1 1 25.0 7c: TIRF medicines may be used in opioid non?tolerant patients. 55.6 5 . False 5 2 (6.8.0922) True 0 - 3 33.3 2 50.0 I don't know 0 - 1 11.1 0 0.0 Client: TRIG Project: TIRF Wave3 Report Run Date and Time: 10/15/2014 4:24 PM Page 2 of 3 Question S-3a S-3b S-min (95% CI) (95% CI) (95% CI) 7d: Prescribers starting a patient on a TIRF medicine must begin with titration from the lowest dose available for that speci?c product, even if the patient has previously taken another TIRF medicine. 88.9 100.0 True 0 - 8 (51.8. 4 (39.8. 99.7) 100.0) False don't know 0 - 0 0.0 0 0.0 Correct Response Note: All con?dence intervals are exact binomial 95% con?dence intervals. Client: TRIG Project: TIRF Wave3 Report Run Date and Time: 10/15/2014 4:24 PM Page 3 of 3 TABLE 6.2.3 SECONDARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #1 KEY RISK MESSAGEI: TIRF MEDICINES ARE CONTRAINDICATED IN OPIOID NON-TOLERANT PATIENTS. SUB-GROUP ANALYSIS 3: TINIE TO COMPLETE SURVEY TELEPHONE: S-3a - <10 min 0 S-3b 10 to <20 min 0 S-3c - 20 min S-3a S-3b S-3c Demonstrated 70%) identified a desired response for all components; however, component 11f (equianalgesic dose of another oral opioid) having a low response of 59.0%. Conclusions The consistently high level of prescriber understanding of key risk messages in the 24-month and 36-month surveys indicates that the Education Program for Prescribers and Pharmacists is meeting the goals of the TIRF REMS. The TRIG will evaluate the concepts that have scored low among stakeholders to determine if any action is warranted. As stated above, changes will be implemented into the 48-month Prescriber KAB survey based on FDA feedback received on the 24-month TIRF REMS assessment report. The TRIG will continue to work with the FDA to refine, on a continual basis, the steps to mitigate risks associated with TIRF medicines. FDA_2413 Prescriber KAB Assessment Report Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Appendix A Page 52 of 54 Prescriber Survey Protocol FDA_2414 PROTOCOL TITLE: Quantitative Testing of Prescriber Knowledge, Attitudes, and Behavior about Transmucosal Immediate Release Fentanyl (TIRF) Products Safety and Use Information SPONSOR: TIRF REMS Industry Group (TRIG) Cephalon, Inc. (a wholly-owned subsidiary of Teva Pharmaceutical Industries, Ltd.) Depomed, Inc. Galena Biopharma, Inc. Insys Therapeutics Mallinckrodt Pharmaceuticals Meda Pharmaceuticals Mylan, Inc. Par Pharmaceutical, Inc. VERSION: 7.0 DATE: 25JUL2014 APPROVED: Final FDA_2415 TABLE OF CONTENTS PAGE TABLE OF CONTENTS ......................................................................................... 2 1. LIST OF ABBREVIATIONS .................................................................................. 3 2. BACKGROUND ..................................................................................................... 4 3. OBJECTIVES OF THE EVALUATION SURVEY ............................................... 5 4. METHODS .............................................................................................................. 5 4.1 4.1.1 4.1.2 4.1.3 Survey Design .......................................................................................................... 5 Qualitative Research on the Survey ......................................................................... 6 Questions on REMS Goals ...................................................................................... 6 Additional Questions................................................................................................ 9 4.2 4.2.1 Participant Recruitment............................................................................................ 9 Measures to Minimize Bias in the Sample............................................................. 10 5. 5.1.1 5.1.2 5.1.3 STUDY POPULATION ........................................................................................ 10 Sample Size ............................................................................................................ 10 Inclusion Criteria.................................................................................................... 11 Exclusion Criteria .................................................................................................. 11 6. SURVEY PROCESS ............................................................................................. 11 6.1 6.1.1 6.1.2 Screening and Survey Administration ................................................................... 11 Telephone ............................................................................................................... 12 Internet ................................................................................................................... 12 6.2 Measures to Minimize Bias in the Survey Process ................................................ 12 7. 7.1.1 7.1.2 7.1.3 ANALYSIS ............................................................................................................ 12 Analysis Population ............................................................................................... 13 Description of Primary Analyses ........................................................................... 13 Description of Secondary Analyses ....................................................................... 13 8. SAFETY EVENT REPORTING ........................................................................... 14 9. PRIVACY PROTECTION AND CONFIDENTIALITY...................................... 14 LIST OF APPENDICES Appendix A Prescriber Questionnaire........................................................................... 15 Appendix B SAMPLE Prescriber Invitation Letter ...................................................... 37 FDA_2416 1. LIST OF ABBREVIATIONS CATI CI EDC ETASU FDA HIPAA ISI KAB PI REMS SE PSP TIRF TIRF REMS TRIG UBC US Computer-Assisted Telephone Interviewing Confidence Interval Electronic Data Capture Elements to Assure Safe Use Food and Drug Administration Health Insurance Portability and Accountability Act Important Safety Information Knowledge, Attitudes and Behavior Prescribing Information Risk Evaluation and Mitigation Strategy Safety Event Project Specific Procedure Transmucosal Immediate Release Fentanyl TIRF REMS Access Program TIRF REMS Industry Group United BioSource Corporation United States FDA_2417 2. BACKGROUND Transmucosal Immediate Release Fentanyl (TIRF) medicines include the class of immediaterelease opioid analgesics that are indicated only for the management of breakthrough pain in cancer patients 18 years of age or older (16 or older for Actiq® and equivalent generics) who are already receiving and tolerant to opioid therapy for their underlying persistent cancer pain. The TIRF medicines include Abstral®, Actiq®, Fentora®, Lazanda®, Onsolis®, Subsys®, and generic versions of any of these brands. The TIRF REMS Industry Group (TRIG) includes Cephalon, Inc. (a wholly-owned subsidiary of Teva Pharmaceutical Industries, Ltd.); Depomed, Inc.; Galena Biopharma, Inc.; Insys Therapeutics; Mallinckrodt Pharmaceuticals; Meda Pharmaceuticals; Mylan, Inc.; and Par Pharmaceutical, Inc. The Food and Drug Administration (FDA) has determined that a class-wide Risk Evaluation and Mitigation Strategy (REMS) is required to mitigate the risk of misuse, abuse, addiction, overdose, and serious complications due to medication errors with the use of TIRF medicines. The TIRF REMS Access Program (hereafter referred to as TIRF REMS) was approved by the FDA on December 28, 2011. The TIRF REMS consists of a Medication Guide, Elements to Assure Safe Use (ETASU), an Implementation System, and a Timetable for Submission of Assessments of the REMS. The goals of the TIRF REMS are to mitigate the risk of misuse, abuse, addiction, overdose, and serious complications due to medication errors by the following: 1. Prescribing and dispensing TIRF medicines only to appropriate patients, which includes use only in opioid-tolerant patients. 2. Preventing inappropriate conversion between TIRF medicines. 3. Preventing accidental exposure to children and others for whom it was not prescribed. 4. Educating prescribers, pharmacists, and patients on the potential for misuse, abuse, addiction, and overdose of TIRF medicines. An important component of the TIRF REMS assessment is the conduct of quantitative evaluation surveys to assess prescribers’ understanding and knowledge of the safe use and appropriate prescribing of TIRF medicines as described in the TIRF REMS educational materials, enrollment form, and Prescribing Information (PI) of each product. This protocol will describe the administration of the surveys that will be conducted among prescribers who are enrolled in the TIRF REMS Access Program. Data from the surveys, together with other REMS evaluation metrics, will be used to determine whether changes need to be made to the REMS processes or educational materials to make them more effective in achieving the goals of the REMS. FDA_2418 The surveys will be implemented so that data will be available for inclusion in the REMS Assessment Reports that will be submitted to the FDA at 12 months after approval of the TIRF REMS and annually thereafter. 3. OBJECTIVES OF THE EVALUATION SURVEY The evaluation survey will use a questionnaire to document the level of knowledge and assess the attitudes and behavior of prescribers around the following key information and risk messages communicated through the REMS: 1. TIRF medicines are contraindicated in opioid non-tolerant patients. 2. TIRF medicines are only indicated for the management of breakthrough pain in adult cancer patients 18 years of age and older (16 or older for Actiq® and equivalent generics) who are already receiving and who are tolerant to around-the-clock opioid therapy for their underlying persistent cancer pain. 3. TIRF medicines contain fentanyl, an opioid agonist and a Schedule II-controlled substance, with abuse liability similar to other opioid analgesics. 4. TIRF medicines are not interchangeable with each other, regardless of route of administration. 5. Patients and their caregivers must be instructed that TIRF medicines contain a medicine in an amount that can be fatal in children, in individuals for whom it is not prescribed, and in those who are not opioid tolerant. The survey will also collect data on behaviors, such as receipt and use of educational materials and compliance with REMS requirements. 4. METHODS The survey was designed in collaboration between the TRIG and United BioSource Corporation (UBC) and will be administered by UBC. 4.1 Survey Design This survey will be conducted among a sample of prescribers who are enrolled in the TIRF REMS Access Program. Respondents who participate in the previous wave of the TIRF survey will not be eligible to participate in subsequent survey waves. The survey will be administered using the following modalities: • Self-administered, online through a secure website FDA_2419 • Telephone surveys facilitated by a trained interviewer from the Survey Coordinating Center using a computer-assisted telephone interviewing (CATI) program The survey will begin with screening questions to confirm respondent eligibility to participate in the survey. Completion of the entire survey is expected to take approximately 20 minutes. The survey included in Appendix A is written to reflect wording for both methods of survey administration: Internet-based and telephone. All respondents who complete the survey and who provide their contact information will be mailed a $125 honorarium for their time. 4.1.1 Qualitative Research on the Survey The FDA provided feedback to the TRIG on the Knowledge, Attitudes and Behaviors (KAB) survey results for prescribers included in the 12-month REMS Assessment results. The FDA requested that the TRIG investigate the causes for low correct response rates to specific questions in the survey by conducting research to determine the reasons for the poor performance on these questions, and to assess proposed revised wording to select questions. Qualitative research was performed in 2013 prior to Wave 2 of the survey. Findings were incorporated into the survey and results from the revised survey were included in the 24month REMS Assessment Report, 4.1.2 Questions on REMS Goals The KAB questionnaire is made up of multiple-choice, close-ended statements or questions (the majority of which use true/false or yes/no dichotomous response options), and one openended question. These will evaluate current knowledge, attitudes, and behavior regarding the key risk messages noted in Section 3. Questions will be presented in several formats: • Statements or questions asking the respondent to indicate whether a statement or question is true or false, or if they do not know the answer (there is a similar set of statements and questions that use “yes” or “no” as potential response options); • Statements or questions asking the respondent to choose from a defined list of possible statements or answers; and • One question allowing for the respondent to list questions about the products or comments. Questionnaires will be analyzed to determine prescriber understanding of each key risk message. For statements or questions that use “true” or “yes” vs. “false” or “no” response options, the desired response for key risk messages is generally “true” or “yes” indicating knowledge of, FDA_2420 or behavior in accordance with, the objectives of the REMS. However, some questions are formatted to have the respondent disagree with the statement as written by providing response options of “false” or “no” to avoid having the same affirmative answer for all desired responses. REMS statements, corresponding questions, and desired responses covering the key risk messages are identified below and can be found in the complete survey questionnaire (Appendix A). Key Risk Message 1: TIRF medicines are contraindicated in opioid non-tolerant patients. Question No. 5 5a 5b 5c 7 7a 7b 7c 7d Question Desired response Please select True, False, or I don’t know for each of the following. According to the labeling for TIRF medicines, patients with cancer who are considered opioid-tolerant are those: Who are taking around-the-clock opioid therapy for TRUE underlying, persistent cancer pain for one week or longer Who are not currently taking opioid therapy, but have FALSE taken opioid therapy before Who have no known contraindications to the drug fentanyl, but are not currently taking around-the-clock FALSE opioid therapy Please answer True, False, or I don’t know for each statement based on the labeling for TIRF medicines. TIRF medicines are contraindicated in opioid non-tolerant patients because life-threatening respiratory depression TRUE could occur at any dose. Death has occurred in opioid non-tolerant patients treated TRUE with some fentanyl products. TIRF medicines may be used to treat opioid non-tolerant FALSE patients. Prescribers starting a patient on a TIRF medicine must begin with titration from the lowest dose available for that TRUE specific product, even if the patient has previously taken another TIRF medicine. Key Risk Message 2: TIRF medicines are only indicated for the management of breakthrough pain in adult cancer patients 18 years of age and older (16 years of age and older for Actiq® brand and generic equivalents) who are already receiving and who are tolerant to around-the-clock opioid therapy for their underlying, persistent cancer pain. Question No. 9 9a Question Desired response In your practice, for which of the following indications do you prescribe TIRF medicines to opioid tolerant patients? Please answer Yes, No, or I don’t know for each option. Acute or postoperative pain NO FDA_2421 9b 9c 9d 9e Headache or migraine pain Dental pain Breakthrough pain from cancer Chronic non-cancer pain 13 The patients described are experiencing breakthrough pain. According to the labeling, a TIRF medicine is not appropriate for one of them. Which patient should not receive a TIRF medicine? Please select one option. NO NO YES NO 13b. Adult female with localized breast cancer; just completed a mastectomy and reconstructive surgery; persistent cancer pain managed with 30 mg oral morphine daily for the past 6 weeks. Key Risk Message 3: TIRF medicines contain fentanyl, an opioid agonist and a Schedule II-controlled substance, with abuse liability similar to other opioid analgesics. Question No. 7 7e 8 8a 8b 10 10a Question Desired response Please answer True, False, or I don’t know for each statement based on the labeling for TIRF medicines. It is important to monitor for signs of abuse and addiction in TRUE patients who take TIRF medicines. Which of the following are risk factors for opioid abuse? Please answer Yes, No, or I don’t know for each option. A personal history of psychiatric illness YES A personal history of past or current alcohol or drug abuse, or a YES family history of illicit drug use or alcohol abuse Please answer True, False, or I don’t know for each statement based on the labeling for TIRF medicines. TIRF medicines can be abused in a manner similar to other TRUE opioid agonists. Key Risk Message 4: TIRF medicines are not interchangeable with each other, regardless of route of administration. Question No. 10 10b 10c Question Desired response Please answer True, False, or I don’t know for each statement based on the labeling for TIRF medicines. TIRF medicines are interchangeable with each other regardless FALSE of route of administration. The conversion of one TIRF medicine for another TIRF TRUE medicine may result in a fatal overdose because of differences in FDA_2422 10d 14 4.1.3 the pharmacokinetics of fentanyl absorption. Dosing of TIRF medicines is not equivalent on a microgram-tomicrogram basis. A patient is already taking a TIRF medicine but wants to change their medicine. His/her doctor decides to prescribe a different TIRF medicine (that is not a bioequivalent generic version of a branded product) in its place. According to the labeling, how should the prescriber proceed? Please select one option. TRUE 14b. The prescriber must not convert to another TIRF medicine on a microgram-permicrogram basis because these medicines have different absorption properties and this could result in a fentanyl overdose. Additional Questions The survey includes questions about the requirements of the TIRF REMS Access Program and receipt and understanding of the TIRF educational materials and the Patient-Prescriber Agreement Form. The following question about behaviors will be asked after the key risk message questions: Question 12: How frequently do you perform the following activities when prescribing TIRF medicines? Please answer Always, Only with the first prescription, Sometimes, Never, or I don’t know. Ask patients (or their caregivers) about the presence of children in the home Instruct patients (or their caregivers) not to share TIRF medicines with anyone else Counsel patients (or their caregivers) that accidental exposure to TIRF medicines by a child may be fatal Instruct patients (or their caregivers) to keep TIRF medicines out of the reach of children to prevent accidental exposure Instruct patients (or their caregivers) about proper disposal of any unused or partially used TIRF medicines Give patients (or their caregivers) the Medication Guide for their TIRF medicine Demographic information will be collected at the end of the survey. 4.2 Participant Recruitment A random sample of prescribers who are enrolled in the TIRF REMS Access Program will be invited to participate via an invitation letter. The text of the sample written invitation to prescribers can be found in Appendix B. If the required number of completed surveys is not achieved within the expected timeframe of approximately one to two weeks after the first mailing, reminder letters will be sent to non-responders from the original sample with subsequent fax, e-mail, or United States (US) Mail follow-up to maximize participation. The distribution within the mailing to the second sample will be adjusted in accordance with the allocation in the original sample. If these efforts do not result in the required number of FDA_2423 surveys within two to three weeks, then a new sample of prescribers will be randomly selected. All respondents who complete the survey and who provide their contact information will be mailed a $125 honorarium to thank them for their participation. Prescribers who practice in Vermont, Massachusetts, or Minnesota and complete the survey will not receive compensation. Participants will be informed that prescribers from these states are eligible to participate, but they will not receive compensation for their participation. The mailing will also include a Thank You Letter, a copy of the Important Safety Information (ISI), and a copy of the correct answers to key risk message questions. 4.2.1 Measures to Minimize Bias in the Sample The sample of prescribers who are invited to participate will be a random sample of all enrolled prescribers. The sample of participating prescribers will be self-selected since respondents will voluntarily respond to the invitation to participate; however, the survey recruitment strategies are intended to recruit a heterogeneous sample of prescribers for participation. Prescribers will be offered online or telephone options for completing the survey. Multiple modalities for survey data collection allow for wider survey access to a more heterogeneous population. Respondents will be provided a unique code during the recruitment process and will be asked to provide the unique code to gain access to the online survey or when calling the Survey Coordinating Center. The code will be deactivated after use to minimize the possibility for fraud. 5. STUDY POPULATION 5.1.1 Sample Size A sample of 300 healthcare providers who are enrolled in the TIRF REMS Access Program is proposed for each survey wave. The size of the sample was determined based on both practical and statistical considerations. There is no target comprehension rate specified a priori. A sample of 300 completed surveys will allow estimation of the comprehension rate for each risk message with a moderately high degree of precision. The table below shows the precision of the estimates for level of understanding using two-sided 95% confidence intervals (CIs) obtained with the sample size of 300 completed surveys. The noted CIs are used to indicate that for any survey-estimated rate of understanding, the true population rate of understanding is at least as high as the lower limit of the 95% CI and may be as high as the upper limit of the 95% CI. Table 5.1: Precision of Estimated Rates of Understanding with a Sample Size of 300 Estimated Rate of Understanding Estimated Confidence Interval FDA_2424 5% 10% 15% 20% 25% 30% 35% 40% 45% 50% 55% 60% 65% 70% 75% 80% 85% 90% 95% 5.1.2 2.8% 6.8% 11.2% 15.6% 20.2% 24.9% 29.6% 34.4% 39.3% 44.2% 49.2% 54.2% 59.3% 64.5% 69.7% 75.0% 80.4% 86.0% 91.9% 8.1% 14.0% 19.6% 25.0% 30.3% 35.5% 40.7% 45.8% 50.8% 55.8% 60.7% 65.6% 70.4% 75.1% 79.8% 84.4% 88.8% 93.2% 97.2% Inclusion Criteria All prescribers who are enrolled in the TIRF REMS Access Program are eligible to participate in this survey, with the exceptions noted below. 5.1.3 Exclusion Criteria The following respondents are not eligible to participate in the surveys: 6. • Prescribers who have previously participated in the TIRF REMS KAB survey • Prescribers or their immediate family members who have ever worked for ever worked for Anesta LLC; Cephalon, Inc. (a wholly-owned subsidiary of Teva Pharmaceutical Industries, Ltd); Depomed, Inc.; Galena Biopharma, Inc.; Insys Therapeutics; Mallinckrodt Pharmaceuticals; Meda Pharmaceuticals; Mylan, Inc.; Par Pharmaceutical, Inc.; Teva Pharmaceuticals, Ltd.; UBC; McKesson Specialty Care Solutions; RelayHealth; or the FDA. SURVEY PROCESS The survey will begin with screening questions to confirm respondent eligibility to participate in the survey. Completion of the entire survey is expected to take approximately 20 minutes. 6.1 Screening and Survey Administration The questionnaire will begin with a screening module with questions to confirm prescriber eligibility. Depending on the answers to the screening questions, survey participation could either be terminated or continued. If ineligible, the respondent is immediately notified with a FDA_2425 “thank you” message that survey participation has ended. If eligible, the respondent is allowed to continue survey participation. The data entry system used for both methods of survey administration has been validated and is secure for receiving and storing survey data. The system is 21 CFR Part 11 and Health Insurance Portability and Accountability Act (HIPAA) compliant. Prescriber-identifying information will be stored separately from survey data. 6.1.1 Telephone A trained interviewer from the Survey Coordinating Center will conduct the telephone interviews using a CATI program. The screening and main elements of the questionnaire will be administered sequentially during the same telephone call. Telephone interviewing allows participation of prescribers who do not have Internet access. It will also be convenient for prescribers to participate since they can call in and be interviewed at their convenience during the specified time period when the Survey Coordinating Center is available. 6.1.2 Internet An Internet-based survey system will also be used for conducting the KAB surveys. If the prescriber selects to participate in the survey online, he/she will be directed to a secured website to complete screening questions. An Internet survey will be convenient for respondents to participate since they can complete the questionnaire at any time. 6.2 Measures to Minimize Bias in the Survey Process A number of controls will be in place to ensure the survey is conducted in a controlled and professional manner and to minimize bias. For example, a unique code will be given to each survey participant and the code will be inactivated after use to minimize fraud. Telephone interviewers are highly trained and use a standardized script to administer the survey. All questions will be programmed to ensure that questions are asked in the appropriate sequence. Skip patterns will be clearly indicated. Respondents cannot go back to a question once the question has been answered and cannot skip ahead. All questions must be answered in order to complete the survey. Response options presented in a list will be randomized to minimize positional bias. Programming will be reviewed by quality control and simulated users (User Acceptance Testing) prior to implementing the survey. 7. ANALYSIS Information obtained from the survey will be reported as descriptive statistics for the survey administration, study population, and the survey questions. The data from the sample population will be reported using frequency distributions of responses to all questions. The following will be reported as part of this analysis: FDA_2426 • The number of invitations issued to prescribers • The number of reminder letters • The number of respondents screened for participation • The number of respondents eligible for participation • The number of respondents eligible for participation who complete the survey • Representativeness of prescribers based on geography • Description of survey participants, including: − Gender − Medical degree of respondent: MD, DO, NP, PA − Medical specialty − Years of professional experience − How many times per month TIRF medicines prescribed in the last 6 months − Geographic region of practice Additional descriptive statistics may be reported as appropriate. 7.1.1 Analysis Population The analysis population will be based on eligible prescribers who completed all questions presented to them in the survey (“completers”). 7.1.2 Description of Primary Analyses Primary analyses are done for all key risk messages using data from all completers. The primary analysis for a key risk message evaluates the rate for each correct response to each individual question/item defined by the key risk message. The specific correct response to each question/item is identified in the body of the risk message table. 7.1.3 Description of Secondary Analyses Secondary analyses are done only for those key risk messages that contain multiple questions/items using data from all completers. The secondary analysis entails a frequency distribution of the number of respondents who got 0, 1, etc. correct responses across the total number of items for the given key risk message. FDA_2427 8. SAFETY EVENT REPORTING The term ‘Safety Event’ is defined as any information reported by a survey respondent that meets the criteria of an adverse event or product complaint. While it is not the intention of the survey to solicit the report of information that meets the criteria of a Safety Event, it is possible that a respondent may spontaneously report information that meets this criteria in free text fields of the survey (Internet-based administration) or while in conversation with the Survey Coordinating Center (telephone-based administration). The Internet-based questionnaires will be monitored for any comments recorded in the free text fields. If an event is mentioned to a Survey Coordinating Center Associate, the Associate will document the safety event and the respondent’s contact information. Respondents will also be informed that a representative from the appropriate TIRF medicine manufacturer may contact them if there are questions about the survey. Information on all reports (Internet or telephone) that may constitute an adverse event or other safety event will be forwarded to the appropriate TIRF medicine manufacturer as described in the Safety Event Project Specific Procedure (SE PSP). Additional detail regarding processes for adverse event reporting will be specified in the SE PSP. 9. PRIVACY PROTECTION AND CONFIDENTIALITY All data collected during the survey will be held confidential. The electronic data capture (EDC) system used for data collection encrypts all identifiable information, and respondent identifiers are stored separately from the survey responses. Respondent names and addresses are collected in order to mail the $125 honorarium, a Thank You Letter, the correct responses to key risk messages, and the ISI after the survey is completed. Respondent contact information is also requested when necessary to comply with a federal or state law or regulation, including without limitation, reporting payments made to physicians under the federal physician payment sunshine provisions in addition to instances where a safety event is reported and a TIRF medicine manufacturer must obtain follow-up information (see Section 8 above). Respondents will be informed when they access the survey that they may be contacted if there are any questions about their survey responses. Respondents will be informed that their answers to the survey questions will not affect their ability to prescribe TIRF medicines. FDA_2428 Appendix A Prescriber Questionnaire Survey Legend • [PROGRAMMER] is used to indicate directions to the programmer and is set in bold, red, uppercase letters between square brackets. • (INTERVIEWER) is used to indicate directions to the telephone interviewer and is set in bold, blue, text between parentheses. This text appears when content is to be administered by telephone only (for example, spontaneous adverse event reporting). • [ONLINE] indicates a question is worded specifically for administering the survey online. [PHONE] indicates a question is worded specifically to be read by a telephone interviewer and differs from the online text. • [BEGIN ONLINE/PHONE SURVEY CONTENT] and [END SURVEY CONTENT] are used to indicate to the programmer the type of survey administration and the beginning and end of the survey or sections within the survey content, for example, [BEGIN ADVERSE EVENT/PRODUCT COMPLAINT] and [END ADVERSE EVENT/PRODUCT COMPLAINT]. • [TERMINATE] is displayed next to responses that should cause the survey to end. The following termination language will be programmed into the survey or read by the interviewer unless different language is specified with the question. Thank you very much for your time today. Based on your answer, you are not eligible to take this survey. We appreciate your interest in the survey. • [RANDOMIZE LIST] is inserted before questions to indicate to the programmer that the responses should be randomized. Responses such as “I don’t know,” “Prefer not to answer” or “None of the above” will always appear at the end of the randomized responses. • [GO TO Qx] (skip logic) is inserted after a response to indicate to the programmer that the survey should skip to the indicated question (for example, [GO TO Q17] skips to question 17). If no skip logic is indicated the survey continues to the next question in the sequence. • [FREE TEXT] indicates to the programmer that one line should be provided for data entry. • [MULTILINE INPUT] indicates to the programmer that multiple lines should be provided for data entry (for example, two address lines). FDA_2429 Survey Legend • [DROP-DOWN LIST INPUT WITH STATES TABLE] indicates to the programmer that the response should be a drop-down list containing the states and US territories in the table below. Alabama Georgia Massachusetts New York Tennessee Alaska Guam Michigan North Carolina Texas American Samoa Hawaii Minnesota North Dakota Idaho Mississippi Arizona Illinois Missouri Arkansas Indiana Montana Northern Mariana Islands US Virgin Islands California Iowa Nebraska Colorado Kansas Nevada Connecticut Kentucky New Hampshire Delaware Louisiana New Jersey District of Columbia Maine New Mexico Florida Maryland Utah Vermont Ohio Virginia Oklahoma Washington Oregon West Virginia Pennsylvania Wisconsin Puerto Rico Wyoming Rhode Island South Carolina South Dakota • The following is used to categorize survey populations into standard geographic regions but it is not displayed in the survey. Geographic Distribution (based on address) 1: Northeast, Midwest, South, and West regions Northeast Region − New England Division - ME, NH, VT, MA, RI, CT − Middle Atlantic Division - NY, NJ, PA Midwest Region − East North Central Division - OH, IN, IL, MI, WI − West North Central Division - MN, IA, MO, ND, SD, NE, KS South Region − South Atlantic Division - DE, MD, DC, VA, WV, NC, SC, GA, FL − East South Central Division - KY, TN, AL, MS − West South Central Division - AR, LA, OK, TX FDA_2430 Survey Legend West − Mountain Division - MT, ID, WY, CO, NM, AZ, UT, NV − Pacific Division WA, OR, CA, AK, HI • The following US territories are categorized as Other: Puerto Rico, Northern Mariana Islands, US Virgin Islands, American Samoa, and Guam. 1 U.S. Census Bureau, last revised Friday, 27-Jul-2001 12:59:43 EDT. FDA_2431 [BEGIN SURVEY CONTENT] [ONLINE PREAMBLE 1] Before you begin, we would like to share some important information about this survey. The manufacturers of Transmucosal Immediate Release Fentanyl (TIRF) medicines are conducting this survey, as required by the FDA, to assess prescribers’ understanding of the safe use and prescribing of these medicines. These medicines are known as rapid onset opioids and referred to in this survey as “TIRF medicines.” The TIRF medicines include Abstral®, Actiq®, Fentora®, Lazanda®, Onsolis®, Subsys®, and generic versions of any of these brands. The manufacturers of these medicines include Cephalon, Inc. (a wholly-owned subsidiary of Teva Pharmaceutical Industries, Ltd.); Depomed, Inc.; Galena Biopharma, Inc.; Insys Therapeutics; Mallinckrodt Pharmaceuticals; Meda Pharmaceuticals; Mylan, Inc.; and Par Pharmaceutical, Inc. The survey will take approximately 20 minutes. There are no known risks to you in taking this survey. You may refuse to take part or withdraw at any time. Your answers to the questions or your decision to take part in the survey will not affect your ability to prescribe TIRF medicines. How We Use Your Information Your answers to the survey questions will be combined with answers given by other healthcare professionals taking the survey. All answers will be put together and reported in anonymous form to the manufacturers of TIRF medicines. Your name will not be used in any report. If you are eligible to take the survey, complete all the questions, and provide your contact information, you will receive a $125 honorarium for your time and participation. This compensation represents the fair value for your services in connection with completion of the survey. The amount of the compensation was not determined in any manner that takes into account the volume or value of any referrals or business otherwise generated by you. Your name and address will be used to send you the honorarium after you complete the survey. Your personal information will also be used if we have questions about your survey or if we are required to use your information to comply with a federal or state law or regulation, including without limitation, reporting payments made to physicians under the federal physician payment sunshine provisions. Physicians who practice in Vermont, Massachusetts, or Minnesota should be aware that they will not be permitted to receive payment for survey completion and may elect not to complete the survey. Providing a telephone number is optional. Your telephone number will be used only if there are any questions about your survey responses. How We Protect Your Privacy We respect that the privacy of your personal information is important to you. You will not be contacted for marketing purposes based on your personal information or your answers to the survey. Neither the manufacturers of TIRF medicines nor their contractors will sell, transfer, or rent your information. Your answers will be kept strictly confidential. Your personal FDA_2432 information will not be used in a manner inconsistent with this document. Your privacy will be protected; however, research survey records may be inspected by the FDA. Your choice to allow manufacturers of TIRF medicines to use your information is entirely voluntary but necessary to take part in this survey. How to Learn More about This Survey If you have questions about the survey, or problems with the survey, please contact the Survey Coordinating Center at 1-877-379-3297. Be sure to write down this telephone number; it will not be displayed again. Taking the Survey Once you have answered a question and moved on, you cannot go back and change your answers. Thank you for your participation in this survey. [END ONLINE PREAMBLE 1] FDA_2433 [PHONE PREAMBLE 1] Before you begin, we would like to share some important information about this survey. The manufacturers of Transmucosal Immediate Release Fentanyl (TIRF) medicines are conducting this survey, as required by the FDA, to assess prescribers’ understanding of the safe use and prescribing of these medicines. These medicines are known as rapid onset opioids and referred to in this survey as “TIRF medicines.” (INTERVIEWER: Say “TIRF” then spell out T-IR-F) The TIRF medicines include Abstral®, Actiq®, Fentora®, Lazanda®, Onsolis®, Subsys®, and generic versions of any of these brands. The manufacturers of these medicines include Cephalon, Inc. (a wholly-owned subsidiary of Teva Pharmaceutical Industries, Ltd.);Depomed, Inc.; Galena Biopharma, Inc.; Insys Therapeutics; Mallinckrodt Pharmaceuticals; Meda Pharmaceuticals; Mylan, Inc; and Par Pharmaceutical, Inc. The survey will take approximately 20 minutes. There are no known risks to you in taking this survey. You may refuse to take part or withdraw at any time. Your answers to the questions or your decision to take part in the survey will not affect your ability to prescribe TIRF medicines. Now I would like to read some information about how your contact information will be used. Your answers to the survey questions will be combined with answers given by other healthcare professionals taking the survey. All answers will be put together and reported in anonymous form to the manufacturers of TIRF medicines. Your name will not be used in any report. If you are eligible to take the survey, complete all the questions, and provide your contact information, you will receive a $125 honorarium for your time and participation. This compensation represents the fair value for your services in connection with completion of the survey. The amount of the compensation was not determined in any manner that takes into account the volume or value of any referrals or business otherwise generated by you. Your name and address will be used to send you the honorarium after you complete the survey. Your personal information will also be used if we have questions about your survey or if we are required to use your information to comply with a federal or state law or regulation, including without limitation, reporting payments made to physicians under the federal physician payment sunshine provisions. Physicians who practice in Vermont, Massachusetts, or Minnesota should be aware that they will not be permitted to receive payment for survey completion and may elect not to complete the survey. Providing a telephone number is optional. Your telephone number will be used only if there are any questions about your survey responses. Now I would like to tell you some information about how we protect your privacy. We respect that the privacy of your personal information is important to you. You will not be contacted for marketing purposes based on your personal information or your answers to the survey. Neither the manufacturers of TIRF medicines nor their contractors will sell, transfer, or rent your information. Your answers will be kept strictly confidential. Your personal FDA_2434 information will not be used in a manner inconsistent with this document. Your privacy will be protected; however, research survey records may be inspected by the FDA. Your choice to allow manufacturers of TIRF medicines to use your information is entirely voluntary but necessary to take part in this survey. Now I will tell you how you can learn more about this survey. Please have a pen or pencil ready to write down a telephone number you can call if you have any questions about the survey. If you have questions about the survey, please ask me at any time. If you have questions at a later time, please contact the Survey Coordinating Center at 1-877-379-3297. Please feel free to ask me to repeat any questions or statements as we go through the survey. Once you have answered a question and moved on, we cannot go back and change your answers. Thank you for your participation in this survey. [END PHONE PREAMBLE 1] FDA_2435 [BEGIN INCLUSION/EXCLUSION QUESTIONS] 1. Your agreement to participate in this survey confirms mutual understanding in connection with completion of the survey and the fair market value of the payment to be rendered in connection with those services. Do you agree to participate in this survey? 2. 3. 4. ○ Yes ○ No [TERMINATE] Have you ever taken part in this survey about TIRF medicines before? TIRF medicines include Abstral®, Actiq®, Fentora®, Lazanda®, Onsolis®, Subsys®, and generic versions of any of these brands. ○ Yes [TERMINATE] ○ No ○ I don’t know [TERMINATE] Are you enrolled in the TIRF REMS Access Program? ○ Yes ○ No [TERMINATE] ○ I don’t know [TERMINATE] Have you or any of your immediate family members ever worked for any of the following companies or agencies? Please select all that apply. □ Anesta LLC [TERMINATE] □ Cephalon, Inc. (a wholly-owned subsidiary of Teva Pharmaceutical Industries, Ltd.) [TERMINATE] □ Depomed, Inc. [TERMINATE] □ Galena Biopharma, Inc. [TERMINATE] □ Insys Therapeutics [TERMINATE] FDA_2436 □ Mallinckrodt Pharmaceuticals [TERMINATE] □ McKesson Specialty Care Solutions [TERMINATE] □ Meda Pharmaceuticals [TERMINATE] □ Mylan, Inc. [TERMINATE] □ Par Pharmaceutical, Inc. [TERMINATE] □ RelayHealth [TERMINATE] □ Teva Pharmaceuticals, Ltd. [TERMINATE] □ United BioSource Corporation [TERMINATE] □ FDA [TERMINATE] □ None of these apply [IF SELECTED IN ADDITION TO OTHER RESPONSES, TERMINATE] □ I don’t know [TERMINATE] □ Prefer not to answer [TERMINATE] [END INCLUSION/EXCLUSION QUESTIONS] FDA_2437 5. Please select True, False, or I don’t know for each of the following. According to the labeling for TIRF medicines, patients with cancer who are considered opioid-tolerant are those: [RANDOMIZE LIST] Who are taking around-the-clock opioid therapy for underlying, persistent cancer pain for one week or longer 5b. Who are not currently taking opioid therapy, but have taken opioid therapy before 5c. Who have no known contraindications to the drug fentanyl, but are not currently taking around-the-clock opioid therapy 5a. 6. False I don’t know ○ ○ ○ ○ ○ ○ ○ ○ ○ Please answer True, False, or I don’t know for each statement based on the labeling for TIRF medicines. [RANDOMIZE LIST] A cancer patient can be started on a TIRF medicine and an around-the-clock opioid at the same time. 6b. A cancer patient who has been on an around-the-clock opioid for 1 day can start taking a TIRF medicine for breakthrough pain. 6a. True True False I don’t know ○ ○ ○ ○ ○ ○ FDA_2438 7. Please answer True, False, or I don’t know for each statement based on the labeling for TIRF medicines. [RANDOMIZE LIST] TIRF medicines are contraindicated in opioid nontolerant patients because life-threatening respiratory depression could occur at any dose. 7b. Death has occurred in opioid non-tolerant patients treated with some fentanyl products. 7c. TIRF medicines may be used to treat opioid non-tolerant patients. 7d. Prescribers starting a patient on a TIRF medicine must begin with titration from the lowest dose available for that specific product, even if the patient has previously taken another TIRF medicine. 7e. It is important to monitor for signs of abuse and addiction in patients who take TIRF medicines. True False I don’t know ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ 7a. 8. Which of the following are risk factors for opioid abuse? Please answer Yes, No, or I don’t know for each option. [RANDOMIZE LIST] 8a. 8b. 8c. A personal history of psychiatric illness A personal history of past or current alcohol or drug abuse, or a family history of illicit drug use or alcohol abuse A family history of asthma Yes No I don’t know ○ ○ ○ ○ ○ ○ ○ ○ ○ FDA_2439 9. In your practice, for which of the following indications do you prescribe TIRF medicines to opioid tolerant patients? Please answer Yes, No, or I don’t know for each option. [RANDOMIZE LIST] Yes No I don’t know ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ 9a. 9b. 9c. 9d. 9e. Acute or postoperative pain Headache or migraine pain Dental pain Breakthrough pain from cancer Chronic non-cancer pain 10. Please answer True, False, or I don’t know for each statement based on the labeling for TIRF medicines. [RANDOMIZE LIST] True False I don’t know ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ 10a. TIRF medicines can be abused in a manner similar to other opioid agonists. 10b. TIRF medicines are interchangeable with each other regardless of route of administration. 10c. The conversion of one TIRF medicine for another TIRF medicine may result in a fatal overdose because of differences in the pharmacokinetics of fentanyl absorption. 10d. Dosing of TIRF medicines is not equivalent on a microgramto-microgram basis. 11. Please select True, False, or I don’t know for each of the following. According to the labeling for TIRF medicines, patients considered opioid-tolerant are those who are taking, for one week or longer, at least: [RANDOMIZE LIST] 11a. 11b. 11c. 11d. 11e. 11f. 8 mg oral hydromorphone/day 60 mg oral morphine/day 30 mg oral oxycodone/day 25 mcg transdermal fentanyl/hour 25 mg oral oxymorphone/day An equianalgesic dose of another oral opioid True False I don’t know ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ FDA_2440 12. How frequently do you perform the following activities when prescribing TIRF medicines? Please answer Always, Only with the first prescription, Sometimes, Never, or I don’t know. [RANDOMIZE LIST] 12a. Ask patients (or their caregivers) about the presence of children in the home 12b. Instruct patients (or their caregivers) not to share TIRF medicines with anyone else 12c. Counsel patients (or their caregivers) that accidental exposure to TIRF medicines by a child may be fatal 12d. Instruct patients (or their caregivers) to keep TIRF medicines out of the reach of children to prevent accidental exposure 12e. Instruct patients (or their caregivers) about proper disposal of any unused or partially used TIRF medicines 12f. Give patients (or their caregivers) the Medication Guide for their TIRF medicine Always Only with the first prescription ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ Sometimes Never I don’t know FDA_2441 13. The patients described are experiencing breakthrough pain. According to the labeling, a TIRF medicine is not appropriate for one of them. Which patient should not receive a TIRF medicine? [RANDOMIZE LIST] 13a. ○ Adult male with advanced lung cancer; underlying persistent cancer pain managed with 25 mcg/hour transdermal fentanyl patches for the past two months. Adult female with localized breast cancer; just completed a mastectomy and reconstructive surgery; persistent cancer pain managed with 30 mg oral morphine daily for the past 6 weeks. Adult male patient with advanced prostate cancer who, over the last 2 weeks, has been prescribed 100 mg oral morphine daily for pain due to bone metastasis. Adult female with advanced sarcoma who has been taking a daily dose of 12 mg oral hydromorphone for the last 3 weeks. I don’t know 13b. ○ 13c. ○ 13d. ○ 13e. ○ 14. A patient is already taking a TIRF medicine but wants to change their medicine. His/her doctor decides to prescribe a different TIRF medicine (that is not a bioequivalent generic version of a branded product) in its place. According to the labeling, how should the prescriber proceed? Please select one option. [RANDOMIZE LIST] 14a. 14b. 14c. 14d. 14e. ○ ○ ○ ○ ○ The prescriber can safely convert to the equivalent dosage of the new TIRF medicine as it has the same effect as other TIRF medicines. The prescriber must not convert to another TIRF medicine on a microgram-permicrogram basis because these medicines have different absorption properties and this could result in a fentanyl overdose. Convert from the other TIRF medicine to the new TIRF medicine at half of the dose. The prescriber should base the starting dose of the newly-prescribed TIRF medicine on the dose of the opioid medicine used for their underlying persistent cancer pain. I don’t know. FDA_2442 15. A patient is starting titration with a TIRF medicine. What dose must they start with? Please select one option. [RANDOMIZE LIST] 15a. ○ 15b. ○ 15c. ○ 15d. 15e. ○ ○ 16. A prescriber has started titrating a patient with the lowest dose of a TIRF medicine. However, after 30 minutes the breakthrough pain has not been sufficiently relieved. What should they advise the patient to do? Please pick the best option of the scenarios described. [RANDOMIZE LIST] 16a. 16b. 16c. ○ ○ 16d. 16e. ○ ○ 17. 17a. 17b. An appropriate dose based on the dose of the opioid medicine used for underlying persistent cancer pain. The dose that the prescriber believes is appropriate based on their clinical experience. The lowest available dose, unless individual product Full Prescribing Information provides product-specific guidance. The median available dose. I don’t know. ○ Take another (identical) dose of the TIRF medicine immediately. Take a dose of an alternative rescue medicine. Provide guidance based on the product-specific Medication Guide because the instructions are not the same for all TIRF medicines. Double the dose and take immediately. I don’t know. A patient is taking a TIRF medicine and the doctor would like to prescribe erythromycin, a CYP3A4 inhibitor. Please pick the best option of the scenarios described. [RANDOMIZE LIST] ○ ○ 17c. ○ 17d. ○ 17e. ○ The patient can’t be prescribed erythromycin, because using it at the same time as a TIRF medicine could be fatal. Use of a TIRF medicine with a CYP3A4 inhibitor may require a dosage adjustment; carefully monitor the patient for opioid toxicity, otherwise such use may cause potentially fatal respiratory depression. There is no possible drug interaction between CYP3A4 inhibitors and TIRF medicines. The dose of the TIRF medicine must be reduced by one half if a CYP3A4 inhibitor is prescribed in the same patient. I don’t know. FDA_2443 18. Before initiating treatment with a TIRF medicine, prescribers must review the Medication Guide with the patient. Please select True, False, or I don’t know for each of the following counseling statements. [RANDOMIZE LIST] TIRF medicines contain fentanyl in an amount that could be fatal to children of all ages, in individuals for whom they were not prescribed, and in those who are not opioid tolerant. 18b. Inform patients that TIRF medicines must not be used for acute or postoperative pain, pain from injuries, headache/migraine, or any other short-term pain. True False I don’t know ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ 18a. Instruct patients that, if they stop taking their aroundthe-clock opioid medicine, they can continue to take their TIRF medicine. 18d. Instruct patients to never share their TIRF medicine with anyone else, even if that person has the same symptoms. 18c. 19. Can patients continue to take their TIRF medicine if they stop taking their around-theclock opioid medicine? ○ Yes ○ No ○ I don’t know [PREAMBLE 2] The next set of questions is about the educational materials for TIRF medicines and the TIRF Patient-Prescriber Agreement. As a reminder, the TIRF medicines include Abstral®, Actiq®, Fentora®, Lazanda®, Onsolis®, Subsys® and generic versions of any of these brands. 20. Did you receive or do you have access to the Full Prescribing Information for the TIRF medicine(s) that you prescribe? ○ Yes ○ No [GO TO Q22] ○ I don’t know [GO TO Q22] FDA_2444 21. 22. 23. 24. 25. Did you read the Full Prescribing Information for the TIRF medicine(s) that you prescribe? ○ Yes ○ No ○ I don’t know Did you receive or do you have access to the Medication Guide for the TIRF medicine(s) that you prescribe? ○ Yes ○ No [GO TO Q24] ○ I don’t know [GO TO Q24] Did you read the Medication Guide for the TIRF medicine(s) that you prescribe? ○ Yes ○ No ○ I don’t know Did you or do you have any questions about the information in the Full Prescribing Information or Medication Guide? ○ Yes ○ No [GO TO Q26] ○ I don’t know [GO TO Q26] What are your questions? [MULTILINE INPUT] FDA_2445 26. 27. 28. Do you review the Patient-Prescriber Agreement Form with each of your patients for whom you prescribe TIRF medicines or their caregiver? ○ Yes ○ No [GO TO Q28] ○ I don’t know [GO TO Q28] Do you and the patient or their caregiver sign the Patient-Prescriber Agreement Form for TIRF medicines after you have reviewed it with him/her? ○ Yes ○ No ○ I don’t know Do you give a copy of the Patient-Prescriber Agreement Form for TIRF medicines to the patient or their caregiver? ○ Yes ○ No ○ I don’t know [DEMOGRAPHICS PREAMBLE 1] There are just a few more questions to help us combine your answers with other answers we have received. 29. On average, how many times per month have you prescribed the TIRF medicines within the last 6 months? ○ None [GO TO DEMOGRAPHICS PREAMBLE 2] ○ 1 – 2 times per month ○ 3 – 5 times per month ○ More than 5 times per month ○ I don’t remember FDA_2446 30. Please select the TIRF medicines that you have prescribed within the last 6 months. Please select all that apply. □ Abstral® □ Actiq® or generic Actiq® □ Fentora® □ Lazanda® □ Onsolis® □ Subsys® [DEMOGRAPHICS PREAMBLE 2] These last few questions are for demographic purposes. 31. 32. What is your gender? ○ Male ○ Female ○ Prefer not to answer What is your medical degree? ○ MD ○ DO ○ Nurse Practitioner ○ Physician Assistant ○ Prefer not to answer FDA_2447 33. 34. In total, how many years have you been practicing medicine, since completing your education? ○ Less than 3 years ○ 3 – 5 years ○ 6 – 10 years ○ 11 – 15 years ○ More than 15 years ○ Prefer not to answer In which state do you practice? [DROP-DOWN LIST INPUT WITH STATES TABLE WITH “Prefer not to answer” at END] 35. What is your medical specialty? ○ Oncology ○ Primary care ○ Pain management ○ Other (please specify): [FREE TEXT] ○ No designated specialty [PHONE ONLY: BEGIN ADVERSE EVENT/PRODUCT COMPLAINT] (INTERVIEWER: Please record if respondent spontaneously reported an adverse event or product complaint during the course of this interview.) ○ Yes ○ No [GO TO CLOSING 1] Enter Safety Adverse Event Verbatim [MULTILINE INPUT] FDA_2448 (INTERVIEWER: Indicate to the respondent that someone may call back to ask more questions about the adverse event or product complaint that was reported.) [END ADVERSE EVENT/PRODUCT COMPLAINT] [CLOSING 1] We would like to send you a $125 honorarium within the next few weeks to thank you for your time, but we need your name and address to do so. If you do not provide your name and address you will not receive the honorarium for your time and participation in the survey. As a reminder, physicians who practice in Vermont, Massachusetts, or Minnesota should be aware that they will not be permitted to receive payment for survey completion. Do you agree to give us your name and mailing address so we can send you the honorarium? ○ Yes ○ No [SKIP TO CLOSING 2] FIRST NAME: [FREE TEXT] LAST NAME: [FREE TEXT] ADDRESS: [MULTILINE INPUT] CITY: [FREE TEXT] STATE: [DROP-DOWN LIST INPUT WITH STATES TABLE] ZIP: [5 NUMERIC CHARACTERS ONLY] [CLOSING 2] We would also like to ask for your telephone number. Providing your telephone number is optional and it will be used to contact you only if there are questions about your survey responses. Do you want to provide your telephone number? ○ Yes ○ No [SKIP TO CLOSING 3] FDA_2449 Telephone: [MUST BE 10-DIGIT NUMERIC CHARACTERS] [END CLOSING 2] [CLOSING 3] That ends the survey. Thank you again for your help. [END OF SURVEY CONTENT] FDA_2450 Appendix B SAMPLE Prescriber Invitation Letter [CURR_DATE] [PRESCRIBER NAME] [STREET_ADDR] [CITY], [STATE] [ZIP] Dear [PRESCRIBER NAME]: You were selected to receive this letter because you have enrolled in the TIRF REMS Access Program. We are contacting you to invite you to participate in a survey being conducted by the manufacturers of Transmucosal Immediate Release Fentanyl (TIRF) medicines, as required by the Food and Drug Administration (FDA). The purpose of the survey is to assess prescribers’ understanding of the safe and appropriate use of these medicines. The TIRF medicines include Abstral®, Actiq®, Fentora®, Lazanda®, Onsolis®, Subsys®, and generic versions of any of these brands. The manufacturers of TIRF medicines (collectively referred to as the “TIRF REMS Industry Group”) include Cephalon, Inc. (a wholly-owned subsidiary of Teva Pharmaceutical Industries, Ltd.); Depomed, Inc.; Galena Biopharma, Inc.; Insys Therapeutics; Mallinckrodt Pharmaceuticals; Meda Pharmaceuticals; Mylan, Inc., and Par Pharmaceutical, Inc. These manufacturers are looking for 300 prescribers to complete the survey. Eligible prescribers who complete the survey will be sent a $125 honorarium to thank them for their time. The survey will take 15-20 minutes. Your answers will be kept strictly confidential and will be combined with the answers from other prescribers who take this survey. Your name will not be used in the report of this survey and your contact information will only be used to send you a $125 honorarium for the time you took to complete the survey and if required to comply with a federal or state law or regulation, including without limitation, reporting payments made to physicians under the federal physician payment sunshine provisions. Prescribers who practice in Vermont, Massachusetts, or Minnesota should be aware that they will not be permitted to receive payment for survey completion and may elect not to complete the survey. You are under no obligation to participate in this survey. If you are interested in participating, go to www.XXXXXXXXXX.com anytime or call 1-877-379-3297, 8AM to 8PM Eastern Time Monday through Friday. You will be asked to give this unique code prior to starting the survey: [CODE_ID]. * We recommend that you take the survey on a desktop or laptop computer. Taking the survey on mobile devices, such as smart phones, tablets, and e-notebooks, is not supported. Please have this letter with you at the time you take the survey. Thank you in advance for your help with this important effort. Sincerely, The TIRF REMS Survey Team FDA_2451 1?877?379?3297 survey.com Prescriber KAB Assessment Report Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Appendix B Page 53 of 54 Prescriber Survey Listings and Sub-group Analysis Tables FDA_2453 TABLE 6.1.1 PRIMARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #1 KEY RISK MESSAGE 1: TIRF MEDICINES ARE CONTRAINDICATED IN OPIOID NON-TOLERANT PATIENTS. SUB-GROUP ANALYSIS 1: READING MEDICATION GUIDE OR FULL PRESCRIBING INFORMATION (QUESTIONS 20, 21, 22, AND 23): S-la - Respondents who received and read the Full Prescribing Information for the TIRF medicine that they prescribe, or who received and read the Medication Guide. S-lb - Respondents who did not receive or did not read the Full Prescribing Information for the TIRF medication that they prescribe (answered ?No? or don?t know? to Question 21) and did not receive or did not read the Medication Guide for the TIRF medicine that they prescribe (answered ?No? or don?t know? to Question 23). Question S?la S-lb Read Medication Guide or Did not read Medication Guide Prescribing Info or Prescribing Info (95% CI) (95% CI) Question 5: Please select True, False, or I don?t know for each of the following. According to the labeling for TIRF medicines, patients with cancer who are considered opioid-tolerant are those: 5a: Who are taking around-the-clock opioid therapy for underlying, persistent cancer pain for one week or longer 90.3 87.9 Tm" 241 (86.1. 93.5) 29 (71.8. 96.6) False 19 7.1 3 9.1 I don't know 7 2.6 1 3.0 5b: Who are not currently taking opioid therapy, but have taken opioid therapy before 87.6 81.8 False 234 (83.1. 91.3) 27 (64.5. 93.0) True 19 7.1 5 15.2 I don't know 14 5.2 1 3.0 Client: TRIG Project: TIRF Wave3 Report Run Date and Time: 10/20/2014 1:45 PM Page 1 of 3 S-la S-lb Read Medication Guide or Did not read Medication Guide . Prescribing Info or Prescribing Info Question (95% CI) (95% CI) 5c: Who have no known contraindications to the drug fentanyl, but are not currently taking around- the-clock opioid therapy 86.5 84.8 False 231 (81.8. 90.4) 28 (68.1. 94.9) True 26 9.7 2 6.1 I don't know 10 3.7 3 9.1 Question 7: Please answer True, False, or I don?t know for each statement based on the labeling for TIRF medicines. 7a: TIRF medicines are contraindicated in opioid non-tolerant patients because life?threatening respiratory depression could occur at any dose. True 233 (82.877310) 27 (64.29830) False 27 10.1 5 15.2 I don?t know 7 2.6 1 3.0 7b: Death has occurred in opioid non-tolerant patients treated with some fentanyl products. True 259 (94.927387) 28 (6885-9849) False 0.4 1 3.0 I don't know 7 2.6 4 12.1 7c: TIRF medicines may be used to treat opioid non-tolerant patients. False 223 (78.52578) 23 (51.63844) True 38 14.2 8 24.2 I don't know 6 2.2 2 6.1 Client: TRIG Project: TIRF Wave3 Report Run Date and Time: 10/20/2014 1:45 PM Page 2 of 3 Question S-la Read Medication Guide or Did not read Medication Guide S-lb Prescribing Info or Prescribing Info (95% CI) (95% CI) 7d: Prescribers starting a patient on a TIRF medicine must begin with titration from the lowest dose available for that speci?c product, even if the patient has previously taken another TIRF medicine. 86.1 66.7 True 230 (81.4. 90.1) 22 (48.2. 82.0) False 31 11.6 11 33.3 I don't know 6 2.2 0 0.0 Correct Response Note: All con?dence intervals are exact binomial 95% con?dence intervals. Client: TRIG Project: TIRF Wave3 Report Run Date and Time: 10/20/2014 1:45 PM Page 3 of 3 TABLE 6.2.1 SECONDARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #1 KEY RISK TIRF MEDICINES ARE CONTRAINDICATED IN OPIOID NON-TOLERANT PATIENTS. SUB-GROUP ANALYSIS 1: READING MEDICATION GUIDE OR FULL PRESCRIBING INFORMATION (QUESTIONS 20, 21, 22, AND 23): S-la - Respondents who received and read the Full Prescribing Information for the TIRF medicine that they prescribe, or who received and read the Medication Guide. 0 S-lb - Respondents who did not receive or did not read the Full Prescribing Information for the TIRF medication that they prescribe (answered ?No? or don?t know? to Question 21) and did not receive or did not read the Medication Guide for the TIRF medicine that they prescribe (answered ?No? or don?t know? to Question 23). S-la S-lb Read Medication Guide or Did not read Medication Demonstrated Prescribing Info Guide or Understanding Prescribing Info 0 correct responses 0 0.0 0 0.0 1 correct response 1 0.4 0 0.0 2 correct responses 3 1.1 1 3.0 3 correct responses 6 2.2 2 6.1 4 correct responses 11 4.1 4 12.1 5 correct responses 35 13.1 4 12.1 6 correct responses 70 26.2 14 42.4 7 correct responses 141 52.8 8 24.2 Average number 0f cone? 6.2 (5.9. 7.0) ?1 5.6 (4.9. 7.0) ?1 responses One-sided 95 con?dence interval using the normal approximation to the Poisson distribution Client: TRIG Project: TIRF Wave3 Report Run Date and Time: 10/15/2014 1:34 PM Page 1 of TABLE 7.1.1 PRIMARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #2 KEY RISK MESSAGE 2: TIRF MEDICINES ARE ONLY INDICATED FOR THE MANAGEMENT OF BREAKTHROUGH PAIN IN ADULT CANCER PATIENTS 18 YEARS OF AGE AND OLDER (16 YEARS OF AGE AND OLDER FOR BRAND AND GENERIC EQUIVALENTS) WHO ARE ALREADY RECEIVING AND WHO ARE TOLERANT TO AROUND- THE-CLOCK OPIOID THERAPY FOR THEIR UNDERLYING PERSISTENT CANCER PAIN. SUB-GROUP ANALYSIS 1: READING MEDICATION GUIDE OR FULL PRESCRIBING INFORMATION (QUESTIONS 20, 21, 22, AND 23): S-la - Respondents who received and read the Full Prescribing Information for the TIRF medicine that they prescribe, or who received and read the Medication Guide. 0 S-lb - Respondents who did not receive or did not read the Full Prescribing Information for the TIRF medication that they prescribe (answered ?No? or don?t know? to Question 21) and did not receive or did not read the Medication Guide for the TIRF medicine that they prescribe (answered ?No? or don?t know? to Question 23). Question S?la S-lb Read Medication Guide or Did not read Medication Guide Prescribing Info or Prescribing Info (95% CI) (95% CI) Question 9: In your practice, for which of the following indications do you prescribe TIRF medicines to opioid tolerant patients? Please answer Yes, No, or I don?t know for each option. 9a: Acute or postoperative pain 88.8 75.8 No 237 (84.3. 92.3) 25 (57.7. 88.9) Yes 29 10.9 8 24.2 I don't know 1 0.4 0 0.0 Client: TRIG Project: TIRF Wave3 Report Run Date and Time: 10/28/2014 Page 1 of 3 S-la S-lb Read Medication Guide or Did not read Medication Guide . Prescribing Info or Prescribing Info Question (95% CI) (95% CI) 9b: Headache or migraine pain 89.9 87.9 No 240 (85.6. 93.2) 29 (71.8. 96.6) Yes 27 10.1 4 12.1 I don't know 0 0.0 0 0.0 9c: Dental pain 97.4 97.0 No 260 (94.7. 98.9) 32 (84.2. 99.don't know 0 0.0 0 0.0 9d: Breakthrough pain from cancer 95.9 97.0 Yes 256 (92.7. 97.9) 32 (84.2. 99.don't know 0 0.0 0 0.0 9e: Chronic non?cancer pain 62.5 57.6 N0 167 (56.4. 68.4) 19 (39.2. 74.5) Yes 98 36.7 14 42.4 I don?t know 2 0.7 0 0.0 Client: TRIG Project: TIRF Wave3 Report Run Date and Time: 10/28/2014 Page 2 of 3 S-la S-lb Read Medication Guide or Did not read Medication Guide . Prescribing Info or Prescribing Info Question (95% CI) (95% CI) Question 13: The patients described are experiencing breakthrough pain. According to the labeling, a TIRF medicine is not appropriate for one of them. Which patient should not receive a TIRF medicine? Please select one option. Adult female with localized breast cancer: just completed a mastectomy and surgery: persistent cancer pain 176 59 695:1 6 23 5 69'7 managed with 30 mg oral 1'3? 84'4) morphine daily for the past 6 weeks. Adult female with advanced sarcoma who has been taking a daily dose of 12 mg oral 28 10.5 2 6.1 hydromorphone for the last 3 weeks. Adult male patient with advanced prostate cancer who. over the last 2 weeks. has been prescribed 100 17 6.4 2 6.1 mg oral mOIphine daily for pain due to bone metastasis. Adult male with advanced lung cancer: lmderlying persistent cancer pain managed with 25 19 7.1 3 9.1 mcg/horu? transdennal fentanyl patches for the past two months. Idon?t know 27 10.1 3 9.1 Correct Response Note: All con?dence intervals are exact binomial 95% con?dence intervals. Client: TRIG Project: TIRF Wave3 Report Run Date and Time: 10/28/2014 9:19 AM Page 3 of 3 TABLE 7.2.1 SECONDARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #2 KEY RISK MESSAGE 2: TIRF MEDICINES ARE ONLY INDICATED FOR THE MANAGEMENT OF BREAKTHROUGH PAIN IN ADULT CANCER PATIENTS 18 YEARS OF AGE AND OLDER (16 YEARS OF AGE AND OLDER FOR BRAND AND GENERIC EQUIVALENTS) WHO ARE ALREADY RECEIVING AND WHO ARE TOLERANT TO AROUND- THE-CLOCK OPIOID THERAPY FOR THEIR UNDERLYING PERSISTENT CANCER PAIN. SUB-GROUP ANALYSIS 1: READING MEDICATION GUIDE OR FULL PRESCRIBING INFORMATION (QUESTIONS 20, 21, 22, AND 23): S-la - Respondents who received and read the Full Prescribing Information for the TIRF medicine that they prescribe, or who received and read the Medication Guide. 0 S-lb - Respondents who did not receive or did not read the Full Prescribing Information for the TIRF medication that they prescribe (answered ?No? or don?t know? to Question 21) and did not receive or did not read the Medication Guide for the TIRF medicine that they prescribe (answered ?No? or don?t know? to Question 23). 1a S-lb Read Medication Guide or Did not grad! Medication Demonstrated Prescribing Info .e or Understanding 67 Prescribing Info 0 correct responses 0 0.0 0 0.0 1 correct response 3 1.1 0 0.0 2 correct responses 3 1.1 1 3.0 3 correct responses 18 6.7 2 6.1 4 correct responses 41 15.4 7 21.2 5 correct responses 103 38.6 14 42.4 6 correct responses 99 37.1 9 27.3 Average number ofcorrect 5-0 (4.8. 6.0) 4.8 (4.1 6.0) responses One-sided 95 con?dence interval using the normal approximation to the Poisson distribution Client: TRIG Project: TIRF Wave3 Report Run Date and Time: 10/15/2014 1:50 PM Page 1 of TABLE 8.1.1 PRIMARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #3 KEY RISK MESSAGE 3: TIRF MEDICINES CONTAIN FENTANYL, AN OPIOID AGONIST AND A SCHEDULE II-CONTROLLED SUBSTANCE, WITH ABUSE LIABILITY SIMILAR TO OTHER OPIOID ANALGESICS. SUB-GROUP ANALYSIS 1: READING MEDICATION GUIDE OR FULL PRESCRIBING INFORNIATION (QUESTIONS 20, 21, 22, AND 23): S-la - Respondents who received and read the Full Prescribing Information for the TIRF medicine that they prescribe, or who received and read the Medication Guide. 0 S-lb - Respondents who did not receive or did not read the Full Prescribing Information for the TIRF medication that they prescribe (answered ?No? or don?t know? to Question 21) and did not receive or did not read the Medication Guide for the TIRF medicine that they prescribe (answered ?No? or don?t know? to Question 23). Question S-la S-lb Read Medication Guide or Did not read Medication Guide Prescribing Info or Prescribing Info (95% CI) (95% CI) Question 7: Please answer True, False, or I don?t know for each statement based on the labeling for TIRF medicines. 7e: It is important to monitor for signs of abuse and addiction in patients who take TIRF medicines. 99.6 100.0 True 266 (97.9. 100.0) 33 (89.4. 100.0) False 1 0.4 0 0.0 I don't know 0 0.0 0 0.0 Client: TRIG Project: TIRF Wave3 Report Run Date and Time: 10/28/2014 9:13 AM Page 1 of 2 Question S-la S-lb Read Medication Guide or Did not read Medication Guide Prescribing Info or Prescribing Info (95% CI) (95% CI) Question 8: Which of the following are risk factors for opioid abuse? Please answer Yes, No, or I don?t know for each option. 8a: A personal history of illness 85.4 72.7 Yes 228 (80.6. 89.4) 24 (54.5. 86.7) No 17 6.4 6 18.2 I don?t know 22 8.2 3 9.1 8b: A personal history of past or current alcohol or drug abuse, or a family history of illicit drug use or alcohol abuse 99.6 100.0 Yes 266 (97.9. 100.0) 33 (89.4. 100.don't know 0 0.0 0.0 Question 10: Please answer True, False, or I don?t know for each statement based on the labeling for TIRF medicines. 10a: TIRF medicines can be abused in a manner similar to other opioid agonists. 97.8 93.9 me 261 (95.2. 99.2) 31 (79.8. 99.3) False 6 2.2 1 3.0 I don't know 0 0.0 1 3.0 Correct Response Note: All con?dence intervals are exact binomial 95% con?dence intervals. Client: TRIG Project: TIRF Wave3 Report Run Date and Time: 10/28/2014 9:13 AM Page 2 of 2 TABLE 8.2.1 SECONDARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #3 KEY RISK MESSAGE 3: TIRF MEDICINES CONTAIN FENTANYL, AN OPIOID AGONIST AND A SCHEDULE II-CONTROLLED SUBSTANCE, WITH ABUSE LIABILITY SIMILAR TO OTHER OPIOID ANALGESICS. SUB-GROUP ANALYSIS 1: READING MEDICATION GUIDE OR FULL PRESCRIBING INFORNIATION (QUESTIONS 20, 21, 22, AND 23): S-la - Respondents who received and read the Full Prescribing Information for the TIRF medicine that they prescribe, or who received and read the Medication Guide. 0 S-lb - Respondents who did not receive or did not read the Full Prescribing Information for the TIRF medication that they prescribe (answered ?No? or don?t know? to Question 21) and did not receive or did not read the Medication Guide for the TIRF medicine that they prescribe (answered ?No? or don?t know? to Question 23). S-la S-lb Read Medication Guide or Did not read Medication Prescribing Info Guide or Demonstrated Understanding Prescribing Info 0 correct responses 0 0.0 0 0.0 1 correct response 0 0.0 0 0.0 2 correct responses 4 1.5 1 3.0 3 correct responses 39 14.6 9 27.3 4 correct responses 224 83.9 23 69.7 Average number 0f ?one? 3.8 (3 .6. 4.0) ?1 3.7(3. 1. 4.0) ?1 responses One-sided 95 con?dence interval using the normal approximation to the Poisson distribution Client: TRIG Project: TIRF Wave3 Report Run Date and Time: 10/28/2014 9:13 AM Page 1 of TABLE 9.1.1 PRIMARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #4 KEY RISK MESSAGE 4: TIRF MEDICINES ARE NOT INTERCHANGEABLE WITH EACH OTHER, REGARDLESS OF ROUTE OF ADMINISTRATION. SUB-GROUP ANALYSIS 1: READING MEDICATION GUIDE OR FULL PRESCRIBING INFORMATION (QUESTIONS 20, 21, 22, AND 23): S-la - Respondents who received and read the Full Prescribing Information for the TIRF medicine that they prescribe, or who received and read the Medication Guide. 0 S-lb - Respondents who did not receive or did not read the Full Prescribing Information for the TIRF medication that they prescribe (answered ?No? or don?t know? to Question 21) and did not receive or did not read the Medication Guide for the TIRF medicine that they prescribe (answered ?No? or don?t know? to Question 23). Question S?la S?lb Read Medication Guide or Did not read Medication Guide Prescribing Info or Prescribing Info (95% CI) (95% CI) Question 10: Please answer True, False, or I don?t know for each statement based on the labeling for TIRF medicines. 10b: TIRF medicines are interchangeable with each other regardless of route of administration. 93.6 87.9 False 250 (90.0. 96.2) 29 (71.8. 96.6) True 12 4.5 3 9.1 I don't know 5 1.9 1 3.0 10c: The conversion of one TIRF medicine for another TIRF medicine may result in a fatal overdose because of differences in the pharmacokinetics of fentanyl absorption. 96.6 97.0 True 258 (93.7. 98.4) 32 (84.2. 99.9) False 5 1.9 1 3.0 I don't know 4 1.5 0 0.0 Client: TRIG Project: TIRF Wave3 Report Run Date and Time: 10/15/2014 1:58 PM Page 1 of 2 S?la S?lb Read Medication Guide or Did not read Medication Guide Prescribing Info or Prescribing Info Question (95% CI) (95% CI) 10d: Dosing of TIRF medicines is not equivalent on a microgram?to-microgram basis. 92.1 78.8 True 246 (88.2. 95.1) 26 (61.1. 91.0) False 13 4.9 5 15.2 I don't know 8 3.0 2 6.1 Question 14: A patient is already taking a TIRF medicine but wants to change their medicine. His/her doctor decides to prescribe a different TIRF medicine (that is not a bioequivalent generic version of a branded product) in its place. According to the labeling, how should the prescriber proceed? Please select one option. The prescn'ber must not convert to another TIRF medicine 011 a microgra111-per-microgram basis because these medicines have different properties and this could result in a fentanyl overdose. 202 75.7 (70.1. 80.7) 63.6 21 (45.1. 79.6) Convert ??om the other TIRF medicine to the new TIRF medicine at half of the dose. 24 9.0 The prescn'ber can safely convert to the equivalent dosage of the new TIRF medicine as it has the same effect as other TIRF medicines. 0.4 The prescriber should base the starting dose of the newly- prescribed TIRF medicine 011 the dose of the opioid medicine used for their lmderlying persistent cancer pain. 26 9.7 6 18.2 I don?t know. 14 Correct Response Note: All con?dence intervals are exact binomial 95% con?dence intervals. Client: TRIG Project: TIRF Wave3 Report Run Date and Time: 10/15/2014 1:58 PM Page 2 of 2 TABLE 9.2.1 SECONDARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #4 KEY RISK MESSAGE 4: TIRF MEDICINES ARE NOT INTERCHANGEABLE WITH EACH OTHER, REGARDLESS OF ROUTE OF ADMINISTRATION. SUB-GROUP ANALYSIS 1: READING MEDICATION GUIDE OR FULL PRESCRIBING INFORMATION (QUESTIONS 20, 21, 22, AND 23): S-la - Respondents who received and read the Full Prescribing Information for the TIRF medicine that they prescribe, or who received and read the Medication Guide. 0 S-lb - Respondents who did not receive or did not read the Full Prescribing Information for the TIRF medication that they prescribe (answered ?No? or don?t know? to Question 21) and did not receive or did not read the Medication Guide for the TIRF medicine that they prescribe (answered ?No? or don?t know? to Question 23). S-la S-lb Read Medication Guide or Did not read Medication Demonstrated Prescribing Info Guide or 0 correct responses 2 0.7 0 0.0 1 correct response 5 1.9 2 6.1 2 correct responses 14 5.2 4 12.1 3 correct responses 61 22.8 10 30.3 4 correct responses 185 69.3 17 51.5 Average number of correct 3.6 (3.4. 4.0) 3.3 (2.8. 4.0) responses One-sided 95 con?dence interval using the normal approximation to the Poisson distribution Client: TRIG Project: TIRF Wave3 Report Run Date and Time: 10/15/2014 2:00 PM Page 1 of TABLE 6.1.2 PRIMARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #1 KEY RISK MESSAGE 1: TIRF MEDICINES ARE CONTRAINDICATED IN OPIOID NON-TOLERAN PATIENTS. SUB-GROUP ANALYSIS 2: MEDICAL DEGREE OF RESPONDENTS (QUESTION 32): S?2a - MD S-2b - DO S-2c - Nurse Practitioner S-2d - Physician Assistant S?2a S?2b S?2c S?2d MD DO Nurse Practitioner Physician Assistant Question (95% CI) (95% CI) (95% CI) (95% CI) Question 5: Please select True, False, or I don?t know for each of the following. According to the labeling for TIRF medicines, patients with cancer who are considered opioid-tolerant are those: 5a: Who are taking around?the?clock opioid therapy for underlying, persistent cancer pain for one week or longer 89.2 87.0 94.3 91.7 True 166 (83.9. 93.3) 20 (66.4. 97.2) 50 (84.3. 98.8) 33 (77.5. 98.2) False don?t know 0.0 Client: TRIG Project: TIRF Wave 3 Report Run Date and Time: 10/20/2014 1:47 PM Page 1 of3 S-2a S-2b S-2c S-2d MD DO Nurse Practitioner Physician Assistant Question (95% CI) (95% CI) (95% CI) (95% CI) 5b: Who are not currently taking opioid therapy, but have taken opioid therapy before 84.9 87.0 88.7 94.4 False 158 (79.0. 89.8) 20 (66.4. 97.2) 47 (77.0. 95.7) 34 (81.3. 99.3) True don?t know 5.6 5c: Who have no known contraindications to the drug fentanyl, but are not currently taking around-the-clock opioid therapy 86.6 78.3 88.7 88.9 False 161 (80.8. 91.1) 18 (56.3. 92.5) 47 (77.0. 95.7) 32 (73.9. 96.9) True 18 9.7 5 21.7 2 3.8 3 8.3 I don't know 2.8 Question 7: Please answer True, False, or I don?t know for each statement based on the labeling for TIRF medicines. 7a: TIRF medicines are contraindicated in opioid non-tolerant patients because life?threatening respiratory depression could occur at any dose. 86.6 91.3 90.6 77.8 True 161 (808.911) 21 (72.0. 98.9) 48 (79.3. 96.9) 28 (60.8. 89.9) False 20 10.8 2 8.7 3 5.7 7 19.4 I don?t know 2.8 Client: TRIG Project: TIRF Wave3 Report Run Date and Time: 10/20/2014 1:47 PM Page 2 of 3 S-2a S-2b S-2c S-2d MD D0 Nurse Practitioner Physician Assistant Question (95% CI) (95% CI) (95% CI) (95% CI) 7b: Death has occurred in opioid non?tolerant patients treated with some fentanyl products. 97.3 95.7 88.7 97.2 True 181 (93.8. 99.1) 22 (781.999) 47 (77.0. 95.7) 35 (855.999) False don?t know 2.8 7c: TIRF medicines may be used to treat opioid non-tolerant patients. 83.3 82.6 81.1 77.8 False 155 (77.2. 88.4) 19 (61.2. 95.0) 43 (68.0. 90.6) 28 (60.8. 89.9) True 29 15.6 3 13.0 6 11.3 8 22.2 I don't know 0.0 7d: Prescribers starting a patient on a TIRF medicine must begin with titration from the lowest dose available for that speci?c product, even if the patient has previously taken another TIRF medicine. 82.8 78.3 86.8 88.9 True 154 (76.6. 87.9) 18 (56.3. 92.5) 46 (74.7. 94.5) 32 (73.9. 96.9) False 28 15.1 5 21.7 7 13.2 2 5.6 Idon't know 5.6 Correct Response Note: All con?dence intervals are exact binomial 95% con?dence intervals. Client: TRIG Project: TIRF Wave3 Report Run Date and Time: 10/20/2014 1:47 PM Page 3 TABLE 6.2.2 SECONDARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #1 KEY RISK MESSAGEI: TIRF MEDICINES ARE CONTRAINDICATED IN OPIOID NON-TOLERANT PATIENTS. SUB-GROUP ANALYSIS 2: MEDICAL DEGREE OF RESPONDENTS (QUESTION 32): S-S-2c - Nurse Practitioner S-2d - Physician Assistant S-2a S-2b S-2c S-2d NID DO Nurse Practitioner Physician Assistant Demonstrated Understanding 0 correct responses correct response correct responses correct responses correct responses c01rect responses 23 12.4 4 17.4 5 9.4 6 16.7 6 correct responses 51 27.4 4 17.4 17 32.1 11 30.6 7 correct responses 93 50.0 12 52.2 27 50.9 17 47.2 Average number of correct responses 6.710351%. One-sided 95 con?dence inten?al using the normal approximation to the Poisson distribution Client: TRIG Project: TIRF Wave3 Report Run Date and Time: 10/16/2014 12:50 PM Page 1 of TABLE 7.1.2 PRIMARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #2 KEY RISK MESSAGE 2: TIRF MEDICINES ARE ONLY INDICATED FOR THE MANAGEMENT OF BREAKTHROUGH PAIN IN ADULT CANCER PATIENTS 18 YEARS OF AGE AND OLDER (16 YEARS OF AGE AND OLDER FOR BRAND AND GENERIC EQUIVALENTS) WHO ARE ALREADY RECEIVING AND WHO ARE TOLERANT TO AROUND-THE-CLOCK OPIOID THERAPY FOR THEIR UNDERLYING PERSISTENT CANCER PAIN. SUB-GROUP ANALYSIS 2: MEDICAL DEGREE OF RESPONDENTS (QUESTION 32): S-2a - MD S-2b - DO S-2c - Nurse Practitioner S-2d - Physician Assistant S?2a S?2b S?2c S?2d MD D0 Nurse Practitioner Physician Assistant Question (95% CI) (95% CI) (95% CI) (95% CI) Question 9: In your practice, for which of the following indications do you prescribe TIRF medicines to opioid tolerant patients? Please answer Yes, No, or I don?t know for each option. 9a: Acute or postoperative pain 87.1 87.0 88.7 86.1 N0 162 (81.4. 91.6) 20 (66.4. 97.2) 47 (77.0. 95.7) 31 (70.5. 95.3) Yes 24 12.9 3 13.0 6 11.3 4 11.1 Idon't know 0 0.0 0 0.0 0 0.0 2.8 Client: TRIG Project: TIRF Wave3 Report Run Date and Time: 10/28/2014 9:18 AM Page 1 of4 S-2a S-2b S-2c S-2d MI) D0 Nurse Practitioner Physician Assistant Question (95% CI) (95% CI) (95% CI) (95% CI) 9b: Headache or migraine pain 87.1 87.0 96.2 97.2 N0 162 (81.4. 91.6) 20 (66.4. 97.2) 51 (87.0. 99.5) 35 (85.5. 99.9) Yes 24 12.9 3 13.0 2 3.8 2.8 I don't know 0.0 9c: Dental pain 95 7 100.0 100.0 100(85.2. 53 (93.3. 36 (90.3. 100.0) 100.0) 100.don't know 0.0 9d: Breakthrough pain from cancer 98.1 95.7 91.3 97.2 Yes 178 (917.981) 21 (72.0. 98.9) 52 (899? 35 (85.5. 99.9) 100.don't know 0.0 9e: Chronic non-cancer pain Client: TRIG Project: TIRF Wave3 Report Run Date and Time: 10/28/2014 9:18 AM Page 2 of 4 S-2a S-2b S-2c S-2d MI) D0 Nurse Practitioner Physician Assistant Question (95% CI) (95% CI) (95% CI) (95% CI) 61.8 52.2 66.0 63.9 No 115 (54.4. 68.8) 12 (30.6. 73.2) 35 (51.7. 78.5) 23 (46.2. 79.2) Yes 69 37.1 11 47.8 18 34.0 13 36.1 I don?t know 2 1.1 0 0.0 0.0 0.0 Question 13: The patients described are experiencing breakthrough pain. According to the labeling, a TIRF medicine is not appropriate for one of them. Which patient should not receive a TIRF medicine? Please select one option. Adult female with localized breast cancer: just completed a mastectomy and reconstructive sru?gel?y: persistent cancer pain managed with 30 mg oral morphine daily for the past 6 weeks. 129 69.4 (62.2. 75.9) 13 56.5 (34.5. 76.8) 35 66.0 (51.7. 78.5) 21 58.3 (40.8. 74.5) Adult female with advanced sarcoma who has been taking a daily dose of 12 111g oral hydromorphone for the last 3 weeks. 13 7.0 17.4 13.2 13.9 Client: TRIG Project: TIRF Wave3 Report Run Date and Time: 10/28/2014 9:18 AM Page 3 of 4 Question S-2a MD S-2b DO S-2c Nurse Practitioner S?2d Physician Assistant (95% CI) (95% CI) (95% CI) (95% CI) Adult male patient with advanced prostate cancer who. over the last 2 weeks. has been prescribed 100 mg oral morphine daily for pain due to bone metastasis. 13 7.0 0.0 8.3 Adult male with advanced lung cancer: underlying persistent cancer pain managed with 25 mcg/horn' transdermal fentanyl patches for the past two months. 11 4.3 9.4 13.9 I don?t know 20 10.8 21.7 Correct Response Note: All con?dence intervals are exact binomial 95% con?dence intervals. Client: TRIG Project: TIRF Wave3 Report Run Date and Time: 10/28/2014 9:18 ANI Page 4 of 4 TABLE 7.2.2 SECONDARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #2 KEY RISK MESSAGE 2: TIRF MEDICINES ARE ONLY INDICATED FOR THE MANAGEMENT OF BREAKTHROUGH PAIN IN ADULT CANCER PATIENTS 18 YEARS OF AGE AND OLDER (16 YEARS OF AGE AND OLDER FOR BRAND AND GENERIC EQUIVALENTS) WHO ARE ALREADY RECEIVING AND WHO ARE TOLERANT TO AROUND-THE-CLOCK OPIOID THERAPY FOR THEIR UNDERLYING PERSISTENT CANCER PAIN. SUB-GROUP ANALYSIS 2: MEDICAL DEGREE 0F RESPONDENTS (QUESTION 32): S-2a - NH) 0 S?2b - DO 0 S-2c - Nurse Practitioner S-2d - Physician Assistant S-2a S-2b S-2c S-2d MD DO Nurse Practitioner Physician Assistant Demonstrated Understanding 0 c01rect responses conect response correct responses conect responses 12 6.5 3 13.0 2 3.8 2 5.6 4 c01rect responses 29 15.6 4 17.4 8 15.1 7 19.4 5 couect responses 71 38.2 8 34.8 23 43.4 15 41.7 6 correct responses 68 36.6 7 30Client: TRIG Project: TIRF Wave 3 Report Run Date and Time: 10/16/2014 12:59 PM Page 1 of 2 Average number of correct responses 5.0 (4.7, 4.7 (4.0, 5.2 (4.6, 5.0 (4.4, 6mm 6mm 6mm 6mm [ll One-sided 95 con?dence interval using the normal approximation to the Poisson distribution Client: TRIG Project: TIRF Wave 3 Report Run Date and Time: 10/16/2014 12:59 PM Page 2 of 2 TABLE 8.1.2 PRIMARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #3 KEY RISK MESSAGE 3: TIRF MEDICINES CONTAIN FENTANY L, AN OPIOID AGONIST AND A SCHEDULE CONTROLLED SUBSTANCE, WITH ABUSE LIABILITY SIMILAR TO OTHER OPIOID ANALGESICS. SUB-GROUP ANALYSIS 2: MEDICAL DEGREE OF RESPONDENTS (QUESTION 32): S-2a - MD - DO S-2c - Nurse Practitioner - Physician Assistant Question S?2a S-2b S?2c MI) D0 Nurse Practitioner Physician Assistant (95% CI) (95% CI) (95% CI) (95% CI) Question 7: Please answer True, False, or I don?t know for each statement based on the labeling for TIRF medicines. 7e: It is important to monitor for signs of abuse and addiction in patients who take TIRF medicines. 99.5 100.0 100.0 100.0 True [11 185 (97.0. 23 (85.2. 53 (93.3. 36 (90.3. 100.0) 100.0) 100.0) 100.0) False don't know 0.0 Client: TRIG Project: TIRF Wave3 Report Run Date and Time: 10/28/2014 9:13 AM Page 1 of3 Question S-2a S-2b S-2c S-2d MI) D0 Nurse Practitioner Physician Assistant (95% CI) (95% CI) (95% CI) (95% CI) Question 8: Which of the following are risk factors for opioid abuse? Please answer Yes, No, or I don?t know for each option. 8a: A personal history of illness 88.2 69.6 77.4 80.6 Yes 164 (82.6. 92.4) 16 (47.1. 86.8) 41 (63.8. 87.7) 29 (64.0. 91.8) No 12 6.5 4 17.4 4 7.5 3 8.3 Idon't know 10 5.4 3 13.0 8 15.1 4 11.1 8b: A personal histmy of past or current alcohol or drug abuse, or a family history of illicit drug use or alcohol abuse 100.0 95 7 100.0 100.0 Yes ?1 186 (98.(93.3. 36 (90.3. 100.0) 100.0) 100.don't know 0.0 Question 10: Please answer True, False, or I don?t know for each statement based on the labeling for TIRF medicines. 10a: TIRF medicines can be abused in a manner similar to other opioid agonists. 100.0 100.0 96.8 96.2 Tnle ?1 180 23 (85.2. 51 36 (90.3. (93.1. 98.8) 1000) (87.0. 99.5) 1000) False don't know 0.0 Client: TRIG Project: TIRF Wave3 Report Run Date and Time: 10/28/2014 9:13 AM Page 2 of3 [1] Correct Response Note: All confidence intervals are exact binomial 95% confidence intervals. Client: TRIG Project: TIRF Wave 3 Report Run Date and Time: 10/28/2014 9:13 AM Page   3 of 3 FDA_2480 TABLE 8.2.2 SECONDARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #3 KEY RISK MESSAGE 3: TIRF MEDICINES CONTAIN FENTANY L, AN OPIOID AGONIST AND A SCHEDULE CONTROLLED SUBSTANCE, WITH ABUSE LIABILITY SIMILAR TO OTHER OPIOID ANALGESICS. SUB-GROUP ANALYSIS 2: MEDICAL DEGREE OF RESPONDENTS (QUESTION 32): S-2a - MD 0 S-2b - DO 0 S-2c - Nurse Practitioner S-2d - Physician Assistant S-2a S-2b MJ) DO Nurse Practitioner Physician Assistant Demonstrated Understanding 0 correct responses correct response correct responses correct responses 25 13.4 6 26.1 10 18.9 7 19.4 4 correct responses 159 85.5 16 69.6 41 77.4 29 80.6 Average number of correct responses 3.8 (3.6. 3.7 (3.0. 3.7 (3.3 3.8 (3.3. 40> ?1 4.0) ?1 4.0) 4.0) ?1 ll] One-sided 95 con?dence interval using the normal approximation to the Poisson distribution Client: TRIG Project: TIRF Wave 3 Report Run Date and Time: 10/28/2014 9:12 AM Page 1 of TABLE 9.1.2 PRIMARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #4 KEY RISK MESSAGE 4: TIRF MEDICINES ARE NOT INTERCHANGEABLE WITH EACH OTHER, REGARDLESS OF ROUTE OF ADMINISTRATION. SUB-GROUP ANALYSIS 2: MEDICAL DEGREE OF RESPONDENTS (QUESTION 32): S-S-2c - Nurse Practitioner S-2d - Physician Assistant Question S?2a S?2b S-2c S?2d MD D0 Nurse Practitioner Physician Assistant (95% CI) (95% CI) (95% CI) (95% CI) Question 10: Please answer True, False, or I don?t know for each statement based on the labeling for TIRF medicines. 10b: TIRF medicines are interchangeable with each other regardless of route of administration. 111 90.9 95.7 96.2 97.2 False 169 (85.8. 94.6) 22 (78.1. 99.9) 51 (87.0. 99.5) 35 (85.5. 99.9) True don?t know 0.0 Client: TRIG Project: TIRF Wave3 Report Run Date and Time: 10/16/2014 2:11 PM Page 1 of 4 Question S-2a S-2b S-2c S-2d MD D0 Nurse Practitioner Physician Assistant (95% CI) (95% CI) (95% CI) (95% CI) 10c: The conversion of one TIRF medicine for another TIRF medicine may result in a fatal overdose because of differences in the pharmacokinetics of fentanyl absorption. 100.0 100.0 True 179 (92.35.9285) 23 $323) 50 (84.?38.8) 36 33%) False don't know 0.0 10d: Dosing of TIRF medicines is not equivalent on a microgram-to-microgram basis. True 167 (84.229837) 23 Egg 47 (7733-9757) 34 (81.24.1393) 100.0) False don't know 2.8 Client: TRIG Project: TIRF Wave3 Report Run Date and Time: 10/16/2014 2:11 PM Page 2 of4 Question S-2a S-2b S-2c S-2d MD D0 Nurse Practitioner Physician Assistant (95% CI) (95% CI) (95% CI) (95% CI) Question 14: A patient is already taking a TIRF medicine but wants to change their medicine. His/her doctor decides to prescribe a different TIRF medicine (that is not a bioeqnivalent generic version of a branded product) in its place. According to the labeling, how should the prescriber proceed? Please select one option. The prescriber must not convert to another TIRF medicine on a microgram- per-Inicrogram basis because these medicines have different absorption properties and this could result in a fentanyl overdose. 137 73.7 (66.7. 79.8) 17 73.9 (51.6. 89.8) 40 75.5 (61.7. 86.2) 28 77.8 (60.8. 89.9) Convert from the other TIRF medicine to the new TIRF medicine at half of the dose. 16 8.6 17.4 9.4 0.0 The prescriber can safely convert to the equivalent dosage of the new TIRF medicine as it has the same effect as other TIRF medicines. 1.1 0.0 0.0 2.8 Client: TRIG Project: TIRF Wave3 Report Run Date and Time: 10/16/2014 2:11 PM Page 3 of 4 S-2a S-2b S-2c S-2d MD D0 Nurse Practitioner Physician Assistant Question (95% CI) (95% CI) (95% CI) (95% CI) The prescriber should base the starting dose of the newly-prescribed TIRF medicine on the dose of 21 11.3 4.3 5 9.4 5 13.9 the opioid medicine used for their underlying persistent cancer pain. I don?t know5.6 Con?ect Response Note: All con?dence intervals are exact binomial 95% con?dence intervals. Client: TRIG Project: TIRF Wave3 Report Run Date and Time: 10/16/2014 2:11 PM Page 4 of4 TABLE 9.2.2 SECONDARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #4 KEY RISK MESSAGE 4: TIRF MEDICINES ARE NOT INTERCHANGEABLE WITH EACH OTHER, REGARDLESS OF ROUTE OF ADMINISTRATION. SUB-GROUP ANALYSIS 2: MEDICAL DEGREE OF RESPONDENTS (QUESTION 32): S-2a - MD 0 S-2b - DO 0 S-2c - Nurse Practitioner S-2d - Physician Assistant S-2a S-2b S-2c S-2d NID DO Nurse Practitioner Physician Assistant Demonstrated Understanding 0 correct responses correct response correct responses correct responses 44 23.7 7 30.4 14 26.4 6 16.7 4 correct responses 122 65.6 16 69.6 35 66.0 28 77.8 Average number of correct responses 3.5 (3.3. 3.7 (3.0. 3.5 (3.1. 3.7 (3.2. 4-0) ?1 4.0) ?1 4.0) 4.0) ?1 One-sided 95 con?dence interval using the normal approximation to the Poisson distribution Client: TRIG Project: TIRF Wave 3 Report Run Date and Time: 10/16/2014 2:12 PM Page 1 of TABLE 6.1.3 PRIMARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #1 KEY RISK MESSAGE 1: TIRF MEDICINES ARE CONTRAINDICATED IN OPIOID S-3a - <10 min 0 S-3b 10 to <20 min 0 S-3c - 20 min NON-TOLERANT PATIENTS. SUB-GROUP ANALYSIS 3: TIME TO COMPLETE SURVEY INTERNET: Question S?3a S-3b S-min (95% CI) (95% CI) (95% CI) Question 5: Please select True, False, or I don?t know for each of the following. According to the labeling for TIRF medicines, patients with cancer who are considered opioid-tolerant are those: 5a: Who are taking around?the?clock opioid therapy for underlying, persistent cancer pain for one week or longer 84.0 91.9 93.2 True ?1 42 (70.9. 159 (86.8. 55 (83.5. 92.8) 95.5) 98.1) False 8 16.0 8 4.6 4 6.8 I don't know 0 0.0 6 3.5 0 0.0 5b: Who are not currently taking opioid therapy, but have taken opioid therapy before 90.0 87.9 89.8 False ?1 45 (78.2. 152 (82.0. 53 (79.2. 96.7) 92.3) 96.2) True don't know 1 2.0 10 5.8 4 6.8 Client: TRIG Project: TIRF Wave3 Report Run Date and Time: 10/20/2014 1:47 PM Page 1 of 3 Question S-3a $.30 S-min (95% CI) (95% CI) (95% CI) 5c: Who have no known contraindications to the drug fentanyl, but are not currently taking around? the-clock opioid therapy 90.0 89.0 84.7 False ?1 45 (78.2. 154 (83.4. 50 (73.0. 96.7) 93.3) 92.8) True 4 8.0 9 5.2 8 13.6 I don't know 1 2.0 10 5.8 1 1.7 Question 7: Please answer True, False, or I don?t know for each statement based on the labeling for TIRF medicines. 7a: TIRF medicines are contraindicated in opioid non-tolerant patients because life?threatening respiratory depression could occur at any dose. 80.0 87.9 86.4 True ?1 40 (66.3. 152 (82.0. 51 (75.0. 90.0) 92.3) 94.0) False 7 14.0 16 9.2 8 13.6 I don't know 3 6.0 5 2.9 0 0.0 7b: Death has occurred in opioid non-tolerant patients treated with some fentanyl products. 96.0 96.5 91.5 True ?1 48 (86.3. 167 (92.6. 54 (81.3. 99.5) 98.7) 97.2) False don't know 2 4.0 6 3.5 3 5.1 7c: TIRF medicines may be used to treat opioid non?tolerant patients. 82.0 81.5 81.4 False ?1 41 (68.6. 141 (74.9. 48 (69.1. 91.4) 87.0) 90.3) True 8 16.0 26 15.0 10 16.9 I don't know 1 2.0 6 3.5 1 1.7 Client: TRIG Project: TIRF Wave3 Report Run Date and Time: 1:47 PM Page 2 of 3 10/20/2014 Question S-3a S-3b S-min (95% CI) (95% CI) (95% CI) 7d: Prescribers starting a patient on a TIRF medicine must begin with titration from the lowest dose available for that speci?c product, even if the patient has previously taken another TIRF medicine. 82.0 86.1 79.7 True ?1 41 (68.6. 149 (80.1. 47 (67.2. 91.4) 90.9) 89.0) False 8 16.0 20 11.6 11 18.6 I don't know 1 2.0 4 2.3 1.7 Correct Response Note: All con?dence intervals are exact binomial 95% con?dence intervals. Client: TRIG Project: TIRF Wave3 Report Run Date and Time: 10/20/2014 1:47 PM Page 3 of 3 TABLE 6.2.3 SECONDARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #1 KEY RISK TIRF MEDICINES ARE CONTRAINDICATED IN OPIOID NON-TOLERANT PATIENTS. SUB-GROUP ANALYSIS 3: TIME TO COMPLETE SURVEY INTERNET: S?3a - <10 min 0 S-3b 10 to <20 min 0 S-3c 20 min S-3a S-3b S-min Demonstrated Understanding 0 correct responses correct response 0 0.0 0.6 0 0.0 2 correct responses 0 0.0 3 1.7 1.7 3 correct responses 3 6.0 0.6 2 3.4 4 correct responses correct responses 8 16.0 22 12.7 7 11.9 6 correct responses 14 28.0 47 27.2 19 32.2 7 correct responses 23 46.0 92 53.2 27 45.8 Average number of correct responses 6.0 (5.5. 6.2 (5.9. 6.1 (5.5. 7.0) 7.0) 7-0) ?1 One-sided 95 con?dence interval using the normal approximation to the Poisson distribution Client: TRIG Project: TIRF Wave 3 Report Run Date and Time: 10/16/2014 2:23 PM Page 1 of TABLE 7.1.3 PRIMARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #2 KEY RISK MESSAGE 2: TIRF MEDICINES ARE ONLY INDICATED FOR THE MANAGEMENT OF BREAKTHROUGH PAIN IN ADULT CANCER PATIENTS 18 YEARS OF AGE AND OLDER (16 YEARS OF AGE AND OLDER FOR BRAND AND GENERIC EQUIVALENTS) WHO ARE ALREADY RECEIVING AND WHO ARE TOLERANT TO AROUND- THE-CLOCK OPIOID THERAPY FOR THEIR UNDERLYING PERSISTENT CANCER PAIN. SUB-GROUP ANALYSIS 3: TIME TO COMPLETE SURVEY INTERNET: S-3a - <10 min 0 S-3b 10 to <20 min 0 S-3c 20 min S-3a s31) S?min (95% CI) (95% 0) (95% CI) Question 9: In your practice, for which of the following indications do you prescribe TIRF medicines to opioid tolerant patients? Please answer Yes, No, or I don?t know for each option. 9a: Acute or postoperative pain 92.0 87.3 83.1 No ?1 46 (80.8. 151 (81.4. 49 (71.0. 97.8) 91.9) 91.6) Yes 4 8.0 21 12.1 10 16.9 I don't know 0 0.0 1 0.6 0 0.0 9b: Headache or migraine pain 88.0 89.0 93.2 No ?1 44 (75.7. 154 (83.4. 55 (83.5. 95.5) 93.3) 98.1) Yes 6 12.0 19 11.0 4 6.8 I don't know 0 0.0 0 0.0 0 0.0 Client: TRIG Project: TIRF Wave3 Report Run Date and Time: 10/28/2014 9:18 AM Page 1 of 3 S?3a S?3b S-min Question N=l73 (95% CI) (95% CI) (95% CI) 91?: Dental pain 98.0 97.7 98.3 No ?1 49 (89.4. 169 (94.2. 58 (90.9. 99.9) 99.4) 100.don't know 0 0.0 0 0.0 0 0.0 9d: Breakthrough pain from cancer 96.0 96.5 93.2 Yes ?1 48 (86.3. 167 (92.6. 55 (83.5. 99.5) 98.7) 98.don't know 0 0.0 0 0.0 0 0.0 9e: Chronic non-cancer pain 70.0 61.8 61.0 No ?1 35 (55.4. 107 (54.2. 36 (47.4. 82.1) 69.1) 73.5) Yes 14 28.0 65 37.6 23 39.0 I don't know 1 2.0 1 0.6 0 0.0 Client: TRIG Project: TIRF Wave3 Report Run Date and Time: 10/28/2014 Page 2 Question S?3a S?3b S-min N=l73 (95% CI) (95% CI) (95% CI) Question 13: The patients described are experiencing breakthrough pain. According to the labeling, a TIRF medicine is not appropriate for one of them. Which patient should not receive a TIRF medicine? Please select one option. Adult female with localized breast cancer: just completed a mastectomy and srn'geiy; persistent cancer pain managed with 30 111g oral 11101phine daily for the past 6 weeks. 26 52.0 (37.4. 66.3) 116 67.1 (59.5. 74.0) 76.3 (63.4. 86.4) Adult female with advanced sarcoma who has been taking a daily dose of 12 mg oral hydromorphone for the last 3 weeks. 12.0 17 9.8 Adult male patient with advanced prostate cancer who. over the last 2 weeks. has been prescribed 100 mg oral morphine daily for pain due to bone metastasis. 14.0 4.0 6.8 Adult male with advanced 11ng cancer; underlying persistent cancer pain managed with 25 meg/how transdermal fentanyl patches for the past two months. 8.0 8.7 3.4 I don?t know 14.0 18 10.4 Correct Response Note: All con?dence intervals are exact binomial 95% con?dence intervals. Client: TRIG Project: TIRF Wave3 Report Run Date and Time: 10/28/2014 Page 3 of 3 TABLE 7.2.3 SECONDARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #2 KEY RISK MESSAGE 2: TIRF MEDICINES ARE ONLY INDICATED FOR THE MANAGEMENT OF BREAKTHROUGH PAIN IN ADULT CANCER PATIENTS 18 YEARS OF AGE AND OLDER (16 YEARS OF AGE AND OLDER FOR BRAND AND GENERIC EQUIVALENTS) WHO ARE ALREADY RECEIVING AND WHO ARE TOLERANT TO AROUND-THE-CLOCK OPIOII) THERAPY FOR THEIR UNDERLYING PERSISTENT CANCER PAIN. SUB-GROUP ANALYSIS 3: TINIE TO COMPLETE SURVEY INTERNET: S-3a - <10 min 0 S-3b 10 to <20 min 0 S-3c 20 min S-3a S-3b S-min Demonstrated =50 0 correct responses correct response correct responses correct responses correct responses 7 14.0 28 16.2 10 16.9 5 correct responses 21 42.0 67 38.7 20 33.9 6 correct responses 17 34.0 63 36.4 24 40.7 Client: TRIG Project: TIRF Wave 3 Report Run Date and Time: 10/20/2014 10:06 AM Page 1 of 2 Average number of correct responses 5.0 (4.4, 5.0 (4.7, 5.1 (4.6, 60m 6mm amm [ll One-sided 95 con?dence interval using the normal approximation to the Poisson distribution Client: TRIG Project: TIRF Wave 3 Report Run Date and Time: 10/20/2014 10:06 AM Page 2 of 2 TABLE 8.1.3 PRIMARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #3 KEY RISK MESSAGE 3: TIRF MEDICINES CONTAIN FENTANYL, AN OPIOID S-3a - <10 min AGONIST AND A SCHEDULE II-CONTROLLED SUBSTANCE, WITH ABUSE LIABILITY SIMILAR TO OTHER OPIOID ANALGESICS. SUB-GROUP ANALYSIS 3: TIME TO COMPLETE SURVEY INTERNET: S-3b 10 to <20 min 0 S-3c 20 min S?3a S?3b S?min Question N=l73 (95% CI) (95% CI) (95% CI) Question 7: Please answer True, False, or I don?t know for each statement based on the labeling for TIRF medicines. 7e: It is important to monitor for signs of abuse and addiction in patients who take TIRF medicines. 98 0 100.0 100.0 True ?1 49 (89 4 '99 9) 173 (97.9. 59 (93.9. 100.0) 100.0) False don't know 0 0.0 0 0.0 0 0.0 Question 8: Which of the following are risk factors for opioid abuse? Please answer Yes, No, or I don?t know for each option. 8a: A personal history of illness 84.0 87.9 79.7 Yes 42 (70.9. 92.8) 152 (82.0. 92.3) 47 (67.2. 89.10.2 I don't know 5 10.0 10 5.8 6 10.2 Client: TRIG Project: TIRF Wave3 Report Run Date and Time: 10/28/2014 9:12 AM Page 1 of 2 Question S?3a S?3b S-3c <10min 10to<20min 220mm (95% CI) (95% CI) (95% CI) 8b: A personal history of past or current alcohol or drug abuse, or a family history of illicit drug use or alcohol abuse 100.0 100.0 100.0 Yes ?1 50 (92.9. 173 (97.9. 59 (93.9. 100.0) 100.0) 100.don't know 0 0.0 0.0 0 0.0 Question 10: Please answer True, False, or I don?t know for each statement based on the labeling for TIRF medicines. 10a: TIRF medicines can be abused in a manner similar to other opioid agonists. 94.0 98.8 94.9 True 47 (83.5. 98.7) 171 (95.9. 99.9) 56 (85.9. 98.9) False don't know 0 0.0 0.0 1 1.7 Correct Response Note: All con?dence intervals are exact binomial 95% con?dence intervals. Client: TRIG Project: TIRF Wave3 Report Run Date and Time: 10/28/2014 9:12 AM Page 2 of 2 TABLE 8.2.3 SECONDARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #3 KEY RISK MESSAGE 3: TIRF MEDICINES CONTAIN FENTANY L, AN OPIOID AGONIST AND A SCHEDULE CONTROLLED SUBSTANCE, WITH ABUSE LIABILITY SIMILAR TO OTHER OPIOID ANALGESICS. SUB-GROUP ANALYSIS 3: TIME TO COMPLETE SURVEY INTERNET: S-3a - <10 min 0 S-3b 10 to <20 min 0 S-3c - 20 min S-3a S-3b S-min Demonstrated Understanding N=l73 0 correct responses correct response correct responses correct responses 8 16.0 21 12.1 13 22.0 4 correct responses 40 80.0 151 87.3 45 76.3 Average number of correct responses 3.8 (3.3. 3.9 (3.6. 3.7 (3.3. 40> 4.0) ?1 4.0) ?1 One-sided 95 con?dence interval using the nomral approximation to the Poisson distribution Client: TRIG Project: TIRF Wave 3 Report Run Date and Time: 10/28/2014 9:12 AM Page 1 of TABLE 9.1.3 PRIMARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #4 KEY RISK MESSAGE 4: TIRF MEDICINES ARE NOT INTERCHANGEABLE WITH EACH OTHER, REGARDLESS OF ROUTE OF ADMINISTRATION. SUB-GROUP ANALYSIS 3: TIME TO COMPLETE SURVEY INTERNET: S-3a - <10 min 0 S-3b 10 to <20 min 0 S-3c - 20 min S-3a S-3b S-min Question N=l73 (95% CI) (95% CI) (95% CI) Question 10: Please answer True, False, or I don?t know for each statement based on the labeling for TIRF medicines. 10b: TIRF medicines are interchangeable with each other regardless of route of administration. 92.0 93.6 91.5 False ?1 46 (80.8. 162 (88.9. 54 (81.3. 97.8) 96.8) 97.2) True don't know 1 2.0 2 1.2 2 3.4 10c: The conversion of one TIRF medicine for another TIRF medicine may result in a fatal overdose because of differences in the pharmacokinetics of fentanyl absorption. 94.0 98.3 94.9 True ?1 47 (83.5. 170 (95.0. 56 (85.9. 98.7) 99.6) 98.9) False 2 4.0 0.6 3 5.1 I don't know 1 2.0 2 1.2 0 0.0 Client: TRIG Project: TIRF Wave3 Report Run Date and Time: 10/16/2014 2:39 PM Page 1 of 3 S-3a S-3b S-min (95% CI) (95% CI) (95% CI) 10d: Dosing of TIRF medicines is not equivalent on a microgram?to-microgram basis. 86.0 89.6 96.6 True ?1 43 (73.3. 155 (84.1. 57 (88.3. 94.2) 93.7) 99.6) False 5 10.0 11 6.4 1 1.7 I don't know 2 4.0 7 4.0 1.7 Question 14: A patient is already taking a TIRF medicine but wants to change their medicine. His/her doctor decides to prescribe a different TIRF medicine (that is not a bioequivalent generic version of a branded product) in its place. According to the labeling, how should the prescriber proceed? Please select one option. The prescriber must not convert to another TIRF medicine 011 a microgram-per- microgram basis because these 34 medicines have different properties and this could result in a fentanyl overdose. ?1 68.0 (53.3. 80.5) 131 75.7 (68.6. 81.9) 48 81.4 (69.1. 90.3) Convert from the other TIRF medicine to the new TIRF medicine at half of the dose. 14 8.1 8.5 The prescriber can safely convert to the equivalent dosage of the new TIRF medicine 0 as it has the same effect as other TIRF medicines. 0.0 1.2 0.0 Client: TRIG Project: TIRF Wave3 Report Run Date and Time: 10/16/2014 2:39 PM Page 2 of 3 S-3a S-3b S-min (95% CI) (95% CI) (95% CI) The prescn'ber should base the starting dose of the newly-prescribed meme?? 12 24.0 14 8.1 8.5 dose of the op101d medicine used for their lmderlying persistent cancer pain. I don?t know. 2 4.0 12 6.9 1.7 Correct Response Note: All con?dence intervals are exact binomial 95% con?dence intervals. Client: TRIG Project: TIRF Wave3 Report Run Date and Time: 10/16/2014 2:39 PM Page 3 of 3 TABLE 9.2.3 SECONDARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #4 KEY RISK MESSAGE 4: TIRF MEDICINES ARE NOT INTERCHANGEABLE WITH EACH OTHER, REGARDLESS OF ROUTE OF ADMINISTRATION. SUB-GROUP ANALYSIS 3: TIIWE TO COMPLETE SURVEY INTERNET: S-3a - <10 min 0 S-3b 10 to <20 min 0 S-3c 20 min S-min Demonstrated Understanding 0 correct responses correct response correct responses correct responses 13 26.0 38 22.0 14 23.7 4 correct responses 30 60.0 119 68.8 43 72.9 Average number of correct responses 3.4 (3.0. 3.6 (3.3. 3.6 (3.2. 4.0) 4.0) ?1 4.0) [11 One-sided 95 con?dence interval using the normal approximation to the Poisson distribution Client: TRIG Project: TIRF Wave 3 Report Run Date and Time: 10/16/2014 2:40 PM Page 1 of TABLE 6.1.4 PRIMARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #1 KEY RISK MESSAGE 1: TIRF MEDICINES ARE CONTRAINDICATED IN OPIOID NON-TOLERANT PATIENTS. SUB-GROUP ANALYSIS 4: TIME TO COMPLETE SURVEY TELEPHONE: S-4a - <10 min 0 S-4b 10 to <20 min 0 S-4c 20 min Question S-4a S-4b S-min (95% CI) (95% CI) (95% CI) Question 5: Please select True, False, or I don?t know for each of the following. According to the labeling for TIRF medicines, patients with cancer who are considered opioid-tolerant are those: 5a: Who are taking around?the?clock opioid therapy for underlying, persistent cancer pain for one week or longer 100.0 73.3 True ?1 0 3 (29.2. 11 (44.9. 100.0) 92.2) False 0 0 0.0 2 13.3 I don't know 0 0 0.0 2 13.3 5b: Who are not currently taking opioid therapy, but have taken opioid therapy before 33.3 66'7 False 0 (0.8. 90.6) 10 ($88.24) True 0 2 66.7 5 33.3 I don't know 0 0 0.0 0 0.0 Client: TRIG Project: TIRF Wave3 Report Run Date and Time: 10/20/2014 1:48 PM Page 1 of 3 Question S-4a S-min (95% CI) (95% CI) (95% CI) 5c: Who have no known contraindications to the drug fentanyl, but are not currently taking around-the?clock opioid therapy 60.0 33.3 False ?1 0 1 9 (32.3. (0.8. 90.6) 83.7) True 0 2 66.7 5 33.3 I don't know 0 0 0.0 6.7 Question 7: Please answer True, False, or I don?t know for each statement based on the labeling for TIRF medicines. 7a: TIRF medicines are contraindicated in opioid non-tolerant patients because life?threatening respiratory depression could occur at any dose. 100.0 93.3 True ?1 0 3 (29.2. 14 (68.1. 100.0) 99.8) False 0 0 0.0 6.7 I don't know 0 0 0.0 0 0.0 7b: Death has occurred in opioid non-tolerant patients treated with some fentanyl products. 100.0 100.0 True ?1 0 3 (29.2. 15 (78.2. 100.0) 100.0) False 0 0 0.0 0 0.0 I don't know 0 0 0.0 0 0.0 7c: TIRF medicines may be used to treat opioid non?tolerant patients. 100.0 33.3 False ?1 0 1 15 (78.2. (0.8. 90.6) 1000) True 0 2 66.7 0 0.0 I don't know 0 0 0.0 0 0.0 Client: TRIG Project: TIRF Wave3 Report Run Date and Time: 10/20/2014 1:48 PM Page 2 of 3 Question S-4a S-min (95% CI) (95% CI) (95% CI) 7d: Prescribers starting a patient on a TIRF medicine must begin with titration from the lowest dose available for that speci?c product, even if the patient has previously taken another TIRF medicine. 93.3 33.3 True ?1 0 1 14 68.1. (0.8. 90.6) (99.8) False 0 2 66.7 1 6.7 I don't know 0 0 0.0 0 0.0 Correct Response Note: All con?dence intervals are exact binomial 95% con?dence intervals. Client: TRIG Project: TIRF Wave3 Report Run Date and Time: 10/20/2014 1:48 PM Page 3 of 3 TABLE 6.2.4 SECONDARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #1 KEY RISK MESSAGEI: TIRF MEDICINES ARE CONTRAINDICATED IN OPIOID NON-TOLERANT PATIENTS. SUB-GROUP ANALYSIS 4: TIME TO COMPLETE SURVEY TELEPHONE: 0 8?43 - <10 min 0 S-4b 10 to <20 min 0 S-4c 20 min S-4a S-4b S-min Demonstrated Understanding 0 correct responses correct response correct responses correct responses 0 - 1 33.3 1 6.7 4 correct responses 0 - 1 33.3 2 13.3 5 correct responses 0 - 0 0.0 2 13.3 6 correct responses 0 - 1 33.3 3 20.0 7 correct responses 0 - 0 0.0 7 46.7 Average number of correct responses - 4.3 (2.4. 5.9 (4.8. 7.0) ?1 7.0) ?1 One-sided 95 con?dence interval using the normal approximation to the Poisson distribution Client: TRIG Project: TIRF Wave 3 Report Run Date and Time: 10/16/2014 2:57 PM Page 1 of TABLE 7.1.4 PRIMARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #2 KEY RISK MESSAGE 2: TIRF MEDICINES ARE ONLY INDICATED FOR THE MANAGEMENT OF BREAKTHROUGH PAIN IN ADULT CANCER PATIENTS 18 YEARS OF AGE AND OLDER (16 YEARS OF AGE AND OLDER FOR BRAND AND GENERIC EQUIVALENTS) WHO ARE ALREADY RECEIVING AND WHO ARE TOLERANT TO AROUND- THE-CLOCK OPIOID THERAPY FOR THEIR UNDERLYING PERSISTENT CANCER PAIN. SUB-GROUP ANALYSIS 4: TINIE TO COMPLETE SURVEY TELEPHONE: S-4a - <10 min 0 S-4b 10 to <20 min 0 S-4c 20 min Question S-4a S-4b S?min (95% CI) (95% CI) (95% CI) each option. Question 9: In your practice, for which of the following indications do you prescribe TIRF medicines to opioid tolerant patients? Please answer Yes, No, or I don?t know for 9a: Acute or postoperative pain 100.0 N0 0 1 (0.5.3936) 15 $33) Yes 0 2 66.7 0 0.0 I don't know 0 0 0.0 0 0.0 9b: Headache or migraine pain 93.3 N0 0 2 (9.269792) 14 (9698; Yes 0 1 33.3 1 6.7 I don't know 0 0 0.0 0 0.0 Client: TRIG Project: TIRF Wave3 Report Run Date and Time: 10/28/2014 Page 1 of 3 S?4a S?4b 8-min Question (95?02 CI) CI) (95?02 CI) 9c: Dental pain 66.7 93'3 N0 0 2 (9.4. 99.2) 14 ($55 Yes 0 1 33.3 1 6.7 I don't know 0 0 0.0 0 0.0 9d: Breakthrough pain from cancer 100.0 100.0 Yes ?1 0 3 (29.2. 15 (78.2. 100.0) 100.don't know 0 0 0.0 0 0.0 9e: Chronic non?cancer pain 46.7 0 1 (0.3.3936) 7 Yes 0 2 66.7 8 53.3 I don't know 0 0 0.0 0 0.0 Client: TRIG Project: TIRF Wave3 Report Run Date and Time: 10/28/2014 Page 2 of 3 Question S?4a <10 min S?4b 10 to <20 min 220mm S-4c (95% CI) (95% CI) (95% CI) Question 13: The patients described are experiencing breakthrough pain. According to the labeling, a TIRF medicine is not appropriate for one of them. Which patient should not receive a TIRF medicine? Please select one option. Adult female with localized breast cancer: just completed a mastectomy and reconstructive Slu?gely; persistent cancer pain managed with 30 111g oral mOIphine dain for the past 6 weeks. I 1 33.3 (0.8. 90.6) 11 73.3 (44.9. 92.2) Adult female with advanced sarcoma who has been taking a daily dose of 12 mg oral hydromorphone for the last 3 weeks. 33.3 6.7 Adult male patient with advanced prostate cancer who. over the last 2 weeks. has been prescribed 100 111g oral morphine daily for pain due to bone metastasis. 33.3 0.0 Adult male with advanced lung cancer: rmderlying persistent cancer pain managed with 25 mcg/horu' transdermal fentanyl patches for the past two months. 0.0 6.7 I don?t know 0.0 13.3 Correct Response Note: All con?dence intervals are exact binomial 95% con?dence intervals. Client: TRIG Project: TIRF Wave3 Report Run Date and Time: 10/28/2014 Page 3 of 3 TABLE 7.2.4 SECONDARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #2 KEY RISK MESSAGE 2: TIRF MEDICINES ARE ONLY INDICATED FOR THE MANAGEMENT OF BREAKTHROUGH PAIN IN ADULT CANCER PATIENTS 18 YEARS OF AGE AND OLDER (16 YEARS OF AGE AND OLDER FOR BRAND AND GENERIC EQUIVALENTS) WHO ARE ALREADY RECEIVING AND WHO ARE TOLERANT TO AROUND-THE-CLOCK OPIOID THERAPY FOR THEIR UNDERLYING PERSISTENT CANCER PAIN. SUB-GROUP ANALYSIS 4: TINIE TO COMPLETE SURVEY - TELEPHONE: S-4a - <10 min 0 S-4b 10 to <20 min 0 S-4c 20 min S-4a S-4b S-min Demonstrated Understanding 0 correct responses correct response correct responses 0 - 1 33.3 0 0.0 3 correct responses 0 - 1 33.3 0 0.0 4 correct responses 0 - 0 0.0 3 20.0 5 correct responses 0 - 1 33.3 8 53.3 6 correct responses 0 - 0.0 4 26.7 Client: TRIG Project: TIRF Wave 3 Report Run Date and Time: 10/16/2014 2:56 PM Page 1 of 2 0 Average number of correct responses - 3.3 (1.6, 5.1 (4.1, 6.0) 6.0) [ll One-sided 95 con?dence interval using the normal approximation to the Poisson distribution Client: TRIG Project: TIRF Wave 3 Report Run Date and Time: 10/16/2014 2:56 PM Page 2 of 2 1 TABLE 8.1.4 PRIMARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #3 KEY RISK MESSAGE 3: TIRF MEDICINES CONTAIN FENTANYL, AN OPIOID AGONIST AND A SCHEDULE II-CONTROLLED SUBSTANCE, WITH ABUSE LIABILITY SIMILAR TO OTHER OPIOID ANALGESICS. SUB-GROUP ANALYSIS 4: TIME TO COMPLETE SURVEY TELEPHONE: S-4a - <10 min 0 S-4b 10 to <20 min 0 S-4c 20 min Question S?4a 84b s41min (95% CI) (95% CI) (95% CI) Question 7: Please answer True, False, or I don?t know for each statement based on the labeling for TIRF medicines. 7e: It is important to monitor for signs of abuse and addiction in patients who take TIRF medicines. 100.0 100.0 True ?1 0 3 (29.2. 15 (78.2. 100.0) 100.0) False 0 0 0.0 0 0.0 I don't know 0 0 0.0 0 0.0 Question 8: Which of the following are risk factors for opioid abuse? Please answer Yes, No, or I don?t know for each option. 8a: A personal history of illness 73(44.9. 92.2) No 0 1 33.3 2 13.3 I don?t know 0 2 66.7 2 13.3 8b: A personal history of past or current alcohol or drug abuse, or a family history of illicit drug use or alcohol abuse Client: TRIG Project: TIRF Wave3 Report Run Date and Time: 10/28/2014 Page 1 of 2 2 S?4a 84b S-min Question (95% CI) (95% CI) (95% CI) 100.0 93.3 Yes ?1 0 3 (29.2. 14 (68.1. 100.0) 99.don't know 0 0 0.0 0 Question 10: Please answer True, False, or I don?t know for each statement based on the labeling for TIRF medicines. 10a: TIRF medicines can be abused in a manner similar to other opioid agonists. 100.0 100.0 True ?1 0 3 (29.2. 15 (78.2. 100.0) 100.0) False 0 0 0.0 0 I don't know 0 0 0.0 0 Correct Response Note: All con?dence intervals are exact binomial 95% con?dence intervals. Client: TRIG Project: TIRF Wave3 Report Run Date and Time: 10/28/2014 Page 2 of 2 3 TABLE 8.2.4 SECONDARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #3 KEY RISK MESSAGE 3: TIRF MEDICINES CONTAIN FENTANY L, AN OPIOID AGONIST AND A SCHEDULE CONTROLLED SUBSTANCE, WITH ABUSE LIABILITY SIMILAR TO OTHER OPIOID ANALGESICS. SUB-GROUP ANALYSIS 4: TIME TO COMPLETE SURVEY TELEPHONE: S-4a - <10 min 0 S-4b 10 to <20 min 0 S-4c - 20 min S-4a S-4b S-min Demonstrated Understanding 0 correct responses correct response correct responses correct responses 0 - 3 100.0 3 20.0 4 correct responses Average number of correct responses - 3.0 (1.4. 3.7 (2.9. 4.0) ?1 4.0) ?1 One-sided 95 con?dence interval using the normal approximation to the Poisson distribution Client: TRIG Project: TIRF Wave 3 Report Run Date and Time: 10/28/2014 9:11 AM Page 1 of 1 4 TABLE 9.1.4 PRIMARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #4 KEY RISK MESSAGE 4: TIRF MEDICINES ARE NOT INTERCHANGEABLE WITH EACH OTHER, REGARDLESS OF ROUTE OF ADMINISTRATION. SUB-GROUP ANALYSIS 4: TIME TO COMPLETE SURVEY TELEPHONE: S-4a - <10 min 0 S-4b 10 to <20 min 0 S-4c 20 min Question S-min (95% CI) (95% CI) (95% CI) Question 10: Please answer True, False, or I don?t know for each statement based on the labeling for TIRF medicines. 10b: TIRF medicines are interchangeable with each other regardless of route of administration. 100.0 93.3 False ?1 0 3 (29.2. 14 (68.1. 100.0) 99.8) True 0 0 0.0 0 0.0 I don?t know 0 0 0.0 6.7 10c: The conversion of one TIRF medicine for another TIRF medicine may result in a fatal overdose because of differences in the pharmacokinetics of fentanyl absorption. 100.0 93.3 True ?1 0 3 (29.2. 14 (68.1. 100.0) 99.8) False 0 0 0.0 0 0.0 I don't know 0 0 0.0 6.7 Client: TRIG Project: TIRF Wave3 Report Run Date and Time: 10/17/2014 1:31 PM Page 1 of 3 5 84a S?4b 5-min Question (95% CI) (95% CI) (95% CI) 10d: Dosing of TIRF medicines is not equivalent on a microgram-to-microgram basis. 100.0 93.3 True ?1 0 3 (29.2. 14 (68.1. 100.0) 99.8) False 0 0 0.0 1 6.7 I don't know 0 0 0.0 0 0.0 Question 14: A patient is already taking a TIRF medicine but wants to change their medicine. His/her doctor decides to prescribe a different TIRF medicine (that is not a bioequivalent generic version of a branded product) in its place. According to the labeling, how should the prescriber proceed? Please select one option. The prescriber must not convert to another TIRF medicine on a microgram?per- microgram basis because these 0 medicines have different properties and this could result in a fentanyl overdose. 66.7 (9.4. 99.2) 53.3 (26.6. 78.7) Convert from the other TIRF medicine to the new TIRF medicine at half of the dose. 33.3 26.7 The prescriber can safely convert to the equivalent dosage of the new TIRF medicine 0 as it has the same effect as other TIRF medicines. 0.0 6.7 Client: TRIG Project: TIRF Wave3 Report Run Date and Time: 10/17/2014 1:31 PM Page 2 of 3 6 S?4a S?4b 5-min Question (95% CI) (95% CI) (95% CI) The prescriber should base the starting dose of the newly-prescribed TIRF medicine 011 the dose of the opioid 0 0'0 6'7 medicine used for their underlying persistent cancer pain. I don?t know. 0 0.0 6.7 Correct Response Note: All con?dence intervals are exact binomial 95% con?dence intervals. Client: TRIG Project: TIRF Wave3 Report Run Date and Time: 10/17/2014 1:31 PM Page 3 of 3 7 TABLE 9.2.4 SECONDARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #4 KEY RISK MESSAGE 4: TIRF MEDICINES ARE NOT INTERCHANGEABLE WITH EACH OTHER, REGARDLESS OF ROUTE OF ADMINISTRATION. SUB-GROUP ANALYSIS 4: TIME TO COMPLETE SURVEY TELEPHONE: S-4a - <10 min 0 S-4b 10 to <20 min 0 S-4c 20 min S?4a S-4b S-min Demonstrated Understanding 0 correct responses correct response correct responses correct responses 0 - 1 33.3 5 33.3 4 correct responses 0 - 2 66.7 8 53.3 Average number of correct responses - 3.7 (1.8. 3.3 (2.6. 4.0) ?1 4.0) ?1 One-sided 95 con?dence interval using the normal approximation to the Poisson distribution Client: TRIG Project: TIRF Wave 3 Report Run Date and Time: 10/16/2014 2:56 PM Page 1 of 1 8 TABLE 6.1.5 PRIMARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #1 KEY RISK MESSAGE 1: TIRF MEDICINES ARE CONTRAINDICATED IN OPIOID NON-TOLERANT PATIENTS. SUB-GROUP ANALYSIS 5: MODALITY TO COMPLETE SURVEY: S-5a - Internet 0 - Telephone Question S?5a S?5b Internet Telephone (95% CI) (95% CI) Question 5: Please select True, False, or I don?t know for each of the following. According to the labeling for TIRF medicines, patients with cancer who are considered opioid-tolerant are those: 5a: Who are taking around?the?clock opioid therapy for underlying, persistent cancer pain for one week or longer True 256 (869899839) 14 (52.17.9836) False 20 7.1 2 11.1 I don't know 6 2.1 2 11.1 5b: Who are not currently taking opioid therapy, but have taken opioid therapy before False 250 (84330721) 11 (35.67%.8127) True 17 6.0 7 38.9 I don't know 15 5.3 0 0.0 5c: Who have no known contraindications to the drug fentanyl, but are not currently taking around?the?clock opioid therapy 88.3 55.6 False 249 (84.0. 91.8) 10 (30.8. 78.5) True 21 7.4 7 38.9 I don't know 12 4.3 1 5.6 Client: TRIG Project: TIRF Wave3 Report Run Date and Time: 10/20/2014 1:48 PM Page 1 of 2 9 Question Internet Telephone (95% CI) (95% Cl) labeling for TIRF medicines. Question 7: Please answer True, False, or I don?t know for each statement based on the 7a: TIRF medicines are contraindicated in opioid non?tolerant patients because life?threatening respiratory depression could occur at any dose. 86.2 94.4 True 243 (81.6. 90.0) 17 (72.7. 99.9) False 31 11.0 1 5.6 I don't know 8 2.8 0 0.0 7b: Death has occurred in opioid non?tolerant patients treated with some fentanyl products. 95.4 100.0 me 269 (92.2. 97.5) 18 (81.5. 100.0) False 2 0.7 0 0.0 I don?t know 11 3.9 0 0.0 7c: TIRF medicines may be used to treat opioid non?tolerant patients. 81.6 88.9 False 230 (76.5. 85.9) 16 (65.3. 98.6) True 44 15.6 2 11.1 I don't know 8 2.8 0 0.0 7d: Prescribers starting a patient on a TIRF medicine must begin with titration from the lowest dose available for that speci?c product, even if the patient has previously taken another TIRF medicine. 84.0 83.3 True 237 (79.2. 88.1) 15 (58.6. 96.4) False 39 13.8 3 16.7 I don't know 6 2.1 0 0.0 Correct Response Note: All con?dence intervals are exact binomial 95% con?dence intervals. Client: TRIG Project: TIRF Wave3 Report Run Date and Time: 10/20/2014 1:48 PM Page 2 of 2 TABLE 6.2.5 SECONDARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #1 KEY RISK MESSAGEI: TIRF MEDICINES ARE CONTRAINDICATED IN OPIOID NON-TOLERANT PATIENTS. SUB-GROUP ANALYSIS 5: MODALITY TO COMPLETE SURVEY: S-5a - Internet 0 S-5b - Telephone Internet Telephone Demonstrated Understanding 0 correct responses 0 0.0 0 0.0 1 correct response 1 0.4 0 0.0 2 correct responses 4 1.4 0 0.0 3 correct responses 2.1 2 11.1 4 correct responses 12 4.3 3 16.7 5 correct responses 37 13.1 2 11.1 6 correct responses 80 28.4 4 22.2 7 correct responses 142 50.4 7 38.9 Average number of correct responses 6.1 (5.9. 5.6 (4.7. 7.0) ?1 7.0) ?1 One-sided 95 con?dence interval using the normal approximation to the Poisson distribution Client: TRIG Project: TIRF Wave3 Report Run Date and Time: 10/16/2014 3:03 PM Page 1 of 1 TABLE 7.1.5 PRIMARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #2 KEY RISK MESSAGE 2: TIRF MEDICINES ARE ONLY INDICATED FOR THE MANAGEMENT OF BREAKTHROUGH PAIN IN ADULT CANCER PATIENTS 18 YEARS OF AGE AND OLDER (16 YEARS OF AGE AND OLDER FOR BRAND AND GENERIC EQUIVALENTS) WHO ARE ALREADY RECEIVING AND WHO ARE TOLERANT TO AROUND- THE-CLOCK OPIOID THERAPY FOR THEIR UNDERLYING PERSISTENT CANCER PAIN. SUB-GROUP ANALYSIS 5: MODALITY TO COMPLETE SURVEY: S-5a - Internet 0 S-5b - Telephone Question S-5a S?5b Internet Telephone (95% CI) (95% CI) Question 9: In your practice, for which of the following indications do you prescribe TIRF medicines to opioid tolerant patients? Please answer Yes, No, or I don?t know for each option. 9a: Acute or postoperative pain 87.2 88.9 N0 246 (82.8. 90.9) 16 (65.3. 98.6) Yes 35 12.4 2 11.1 I don't know 1 0.4 0 0.0 9b: Headache or migraine pain 89.7 88.9 N0 253 (85.6. 93.0) 16 (65.3. 98.6) Yes 29 10.3 2 11.1 I don't know 0 0.0 0 0.0 Client: TRIG Project: TIRF Wave3 Report Run Date and Time: 10/28/2014 9:17 AM Page 1 of 3 Internet Telephone (95% CI) (95% CI) 9c: Dental pain 97.9 88.9 No 276 (95.4. 99.2) 16 (65.3. 98.6) Yes 6 2.1 2 11.1 I don't know 0 0.0 0 0.0 9d: Breakthrough pain from cancer 95.7 100.0 270 (92.7. 97.8) 18 (81.5. 100.don't know 0 0.0 0 0.0 9e: Chronic non?cancer pain 63.1 44.4 N0 178 (57.2. 68.8) 8 (21.5. 69.2) Yes 102 36.2 10 55.6 I don't know 2 0.7 0 0.0 Client: TRIG Project: TIRF Wave3 Report Run Date and Time: 10/28/2014 9:17 AM Page 2 of 3 Internet Telephone (95% CI) (95% CI) Question 13: The patients described are experiencing breakthrough pain. According to the labeling, a TIRF medicine is not appropriate for one of them. Which patient should not receive a TIRF medicine? Please select one option. Adult female with localized breast cancer: just completed a mastectomy and reconstructive surgery; persistent cancer pain 187 (60 (26.31 8) 12 (41 6 7) managed with 30 mg oral morphine daily for the past 6 weeks. Adult female with advanced sarcoma who has been taking a daily dose of 12 111g oral 28 9.9 2 11.1 hydromorphone for the last 3 weeks. Adult male patient with advanced prostate cancer who. over the last 2 weeks. has been prescribed 100 18 6.4 1 5.6 mg oral morphine daily for pain due to bone metastasis. Adult male with advanced lung cancer: rurderlying persistent cancer pain managed with 25 21 7.4 1 5.6 mcg/horu' transdermal fentanyl patches for the past two months. Idon?t know 28 9.9 2 11.1 Correct Response Note: All con?dence intervals are exact binomial 95% con?dence intervals. Client: TRIG Project: TIRF Wave3 Report Run Date and Time: 10/28/2014 9:17 AM Page 3 of 3 TABLE 7.2.5 SECONDARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #2 KEY RISK MESSAGE 2: TIRF MEDICINES ARE ONLY INDICATED FOR THE MANAGEMENT OF BREAKTHROUGH PAIN IN ADULT CANCER PATIENTS 18 YEARS OF AGE AND OLDER (16 YEARS OF AGE AND OLDER FOR BRAND AND GENERIC EQUIVALENTS) WHO ARE ALREADY RECEIVING AND WHO ARE TOLERANT TO AROUND- THE-CLOCK OPIOID THERAPY FOR THEIR UNDERLYING PERSISTENT CANCER PAIN. SUB-GROUP ANALYSIS 5: MODALITY TO COMPLETE SURVEY: S-5a - Internet 0 - Telephone S-5a S-5b Internet Telephone Demonstrated Understanding 0 correct responses 0 0.0 0 0.0 1 correct response 3 1.1 0 0.0 2 correct responses 3 1.1 1 5.6 3 correct responses 19 6.7 1 5.6 4 correct responses 45 16.0 3 16.7 5 correct responses 108 38.3 9 50.0 6 correct responses 104 36.9 4 22.2 Average number of correct responses 450%]? [ll One-sided 95 con?dence interval using the normal approximation to the Poisson distribution Client: TRIG Project: TIRF Wave3 Report Run Date and Time: 10/16/2014 3:05 PM Page 1 of TABLE 8.1.5 PRIMARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #3 KEY RISK MESSAGE 3: TIRF MEDICINES CONTAIN FENTANYL, AN OPIOID AGONIST AND A SCHEDULE II-CONTROLLED SUBSTANCE, WITH ABUSE LIABILITY SIMILAR TO OTHER OPIOID ANALGESICS. SUB-GROUP ANALYSIS 5: MODALITY TO COMPLETE SURVEY: - Internet 0 - Telephone Question Internet Telephone ?Vo (95% CI) (95% CI) labeling for TIRF medicines. Question 7: Please answer True, False, or I don?t know for each statement based on the 7e: It is important to monitor for signs of abuse and addiction in patients who take TIRF medicines. 99.6 100.0 True 281 (98.0. 100.0) 18 (81.5. 100.0) False 1 0.4 0.0 I don't know don?t know for each option. Question 8: Which of the following are risk factors for opioid abuse? Please answer Yes, 8a: A personal history of illness 85.5 61.1 Yes 241 (80.8. 89.4) 11 (35.7. 82.7) No 20 7.1 16.7 I don?t know 21 7.4 4 22.2 Client: TRIG Project: TIRF Wave3 Report Run Date and Time: 10/28/2014 9:10 AM Page 1 of 2 Question S-5b Internet Telephone (95% CI) (95% CI) 8b: A personal history of past or current alcohol or drug abuse, or a family history of illicit drug use or alcohol abuse 100.0 94.4 Yes 282 (98.7. 100.0) 17 (72.7. 99.don't know 0 0.0 0 0.0 Question 10: Please answer True, False, or I don?t know for each statement based on the labeling for TIRF medicines. 10a: TIRF medicines can be abused in a manner similar to other opioid agonists. 97.2 100.0 me 274 (94.5. 98.8) 18 (81.5. 100.0) False 7 2.5 0.0 I don't know 1 0.4 0.0 Correct Response Note: All con?dence intervals are exact binomial 95% con?dence intervals. Client: TRIG Project: TIRF Wave3 Report Run Date and Time: 10/28/2014 Page 2 of 2 TABLE 8.2.5 SECONDARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #3 KEY RISK MESSAGE 3: TIRF MEDICINES CONTAIN FENTANYL, AN OPIOID AGONIST AND A SCHEDULE II-CONTROLLED SUBSTANCE, WITH ABUSE LIABILITY SIMILAR TO OTHER OPIOID ANALGESICS. SUB-GROUP ANALYSIS 5: MODALITY TO COMPLETE SURVEY: - Internet 0 - Telephone S-5a Internet Telephone Demonstrated Understanding 0 correct responses 0 0.0 0.0 1 correct response 0 0.0 0.0 2 correct responses 4 1.4 1 5.6 3 correct responses 42 14.9 6 33.3 4 correct responses 236 83.7 11 61.1 Average number of correct responses 3.8 (3.6. 3.6 (2.8. 4.0) ?1 4.0) ?1 One-sided 95 con?dence interval using the normal approximation to the Poisson distribution Client: TRIG Project: TIRF Wave3 Report Run Date and Time: 10/28/2014 9:10 AM Page 1 of TABLE 9.1.5 PRIMARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #4 KEY RISK MESSAGE 4: TIRF MEDICINES ARE NOT INTERCHANGEABLE WITH EACH OTHER, REGARDLESS OF ROUTE OF ADMINISTRATION. SUB-GROUP ANALYSIS 5: MODALITY TO COMPLETE SURVEY: - Internet - Telephone Question 35b Internet Telephone (95% CI) (95% CI) Question 10: Please answer True, False, or I don?t know for each statement based on the labeling for TIRF medicines. 10b: TIRF medicines are interchangeable with each other regardless of route of administration. 92.9 94.4 False 262 (89.3. 95.6) 17 (72.7. 99.9) True 15 5.3 0 0.0 I don't know 5 1.8 1 5.6 10c: The conversion of one TIRF medicine for another TIRF medicine may result in a fatal overdose because of differences in the pharmacokinetics of fentanyl absorption. True 273 (94250885) 17 (72.?919.9) False 6 2.1 0 0.0 I don't know 3 1.1 1 5.6 10d: Dosing of TIRF medicines is not equivalent on a microgram-to-microgram basis. True 255 (8623336) 17 (72.93.9199) False 17 6.0 1 5.6 I don't know 10 3.5 0 0.0 Client: TRIG Project: TIRF Wave3 Report Run Date and Time: 10/16/2014 3:13 PM Page 1 of 2 Question Internet Telephone (95% CI) (95% CI) select one option. Question 14: A patient is already taking a TIRF medicine but wants to change their medicine. His/her doctor decides to prescribe a different TIRF medicine (that is not a bioeqnivalent generic version of a branded product) in its place. According to the labeling, how should the prescriber proceed? Please The prescriber must not convert to another TIRF medicine 011 a microgra111-per-microgram basis because these medicines have different properties and this could result in a fentanyl overdose. 213 75.5 (70.1. 80.4) 10 55.6 (30.8. 78.5) Convert ?'om the other TIRF medicine to the new TIRF medicine at half of the dose. 21 7.4 27.8 The prescriber can safely convert to the equivalent dosage of the new TIRF medicine as it has the same effect as other TIRF medicines. 0.7 The prescriber should base the starting dose of the newly- prescribed TIRF medicine 011 the dose of the opioid medicine used for their tmderlying persistent cancer pain. 31 11.0 I don?t know. Correct Response Note: All con?dence intervals are exact binomial 95% con?dence intervals. Client: TRIG Project: TIRF Wave3 Report Run Date and Time: 10/16/2014 3:13 PM Page 2 of 2 TABLE 9.2.5 SECONDARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #4 KEY RISK MESSAGE 4: TIRF MEDICINES ARE NOT INTERCHANGEABLE WITH EACH OTHER, REGARDLESS OF ROUTE OF ADMINISTRATION. SUB-GROUP ANALYSIS 5: MODALITY TO COMPLETE SURVEY: - Internet 0 - Telephone Internet Telephone Demonstrated Understanding 0 correct responses 2 0.7 0 0.0 1 correct response 6 2.1 5.6 2 correct responses 17 6.0 5.6 3 correct responses 65 23.0 6 33.3 4 correct responses 192 68.1 10 55.6 Average nlunber of con'ect responses 3.6 (3.4. 3.4 (2.7. 4.0) ?1 4.0) ?1 One-sided 95 con?dence interval using the normal approximation to the Poisson distribution Client: TRIG Project: TIRF Wave3 Report Run Date and Time: 10/16/2014 3:15 PM Page 1 of 1 TABLE 6.1.6 PRIMARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #1 KEY RISK MESSAGE l: TIRF MEDICINES ARE CONTRAINDICATED IN OPIOID NON-TOLERAN PATIENTS. SUB-GROUP ANALYSIS 6: TIME PRACTICING MEDICINE (QUESTION 33): S-6a - Less than 3 years 0 S-6b - 3 to 5 years 0 S-6c - 6 to 15 years 0 S-6d - More than 15 years S?6a S?6b S?6c S?6d Less than 3 years 3 to 5 years 6 to 15 years More than 15 years Question (95% CI) (95% CI) (95% CI) (95% CI) Question 5: Please select True, False, or I don?t know for each of the following. According to the labeling for TIRF medicines, patients with cancer who are considered opioid-tolerant are those: 5a: Who are taking around?the?clock opioid therapy for underlying, persistent cancer pain for one week or longer 83.3 88.6 90.0 91.9 True ?1 25 (65.3. 31 (73.3. 99 (82.8. 113 (85.6. 94.4) 96.8) 94.9) 96.0) False 5 16.7 4 11.4 7 6.4 6 4.9 I don't know 3.3 Client: TRIG Project: TIRF Wave 3 Report Run Date and Time: 10/20/2014 1:48 PM Page 1 of 4 S-6a S-6b S-6c S-6d Less than 3 years 3 to 5 years 6 to 15 years More than 15 years Question (95% CI) (95% CI) (95% CI) (95% CI) 5b: Who are not currently taking opioid therapy, but have taken opioid therapy before 93.3 82.9 83.6 89.4 False ?1 28 (77.9. 29 (66.4. 92 (75.4. 110 (82.6. 99.2) 93.4) 90.0) 94.3) True 2 6.7 1 2.9 12 10.9 9 7.3 I don't know 0 0.0 5 14.3 6 5.5 4 3.3 5c: Who have no known contraindications to the drug fentanyl, but are not currently taking around?the?clock opioid therapy 76.7 94.3 82.7 89.4 False ?1 23 (57.7. 33 (80.8. 91 (74.3. 110 (82.6. 90.1) 99.3) 89.3) 94.3) True 5 16.7 2 5.7 11 10.0 10 8.1 I don't know 2.4 Client: TRIG Project: TIRF Wave3 Report Run Date and Time: 10/20/2014 1:48 PM Page 2 of4 S-6a S-6b S-6c S-6d Less than 3 years 3 to 5 years 6 to 15 years More than 15 years (95% CI) (95% CI) (95% CI) (95% CI) Question 7: Please answer True, False, or I don?t know for each statement based on the labeling for TIRF medicines. 7a: TIRF medicines are contraindicated in opioid non?tolerant patients because life?threatening respiratory depression could occur at any dose. 90.0 82.9 85.5 87.8 True ?1 27 (73.5. 29 (66.4. 94 (77.5. 108 (80.7. 97.9) 93.4) 91.5) 93.0) False 2 6.7 4 11.4 12 10.9 14 11.4 I don't know 1 3.3 2 5.7 4 3.6 0.8 7b: Death has occurred in opioid non?tolerant patients treated with some fentanyl products. 96.7 94.3 93.6 97.6 True ?1 29 (82.8. 33 (80.8. 103 (87.3. 120 (93.0. 99.9) 99.3) 97.4) 99.5) False don't know 1 3.3 2 5.7 7 6.4 0.8 Client: TRIG Project: TIRF Wave 3 Report Run Date and Time: 10/20/2014 1:48 PM Page 3 of 4 S-6a S-6b S-6c S-6d Less than 3 years 3 to 5 years 6 to 15 years More than 15 years Question (95% CI) (95% CI) (95% CI) (95% CI) 7c: TIRF medicines may be used to treat opioid non?tolerant patients. 83.3 88.6 80.0 81.3 False ?1 25 (65.3. 31 (73.3. 88 (71.3. 100 (73.3. 94.4) 96.8) 87.0) 87.8) True 4 13.3 3 8.6 18 16.4 21 17.1 I don't know 1 3.3 2.9 4 3.6 2 1.6 7d: Prescribers starting a patient on a TIRF medicine must begin with titration from the lowest dose available for that speci?c product, even if the patient has previously taken another TIRF medicine. 83.3 80.0 88.2 81.3 True ?1 25 (65.3. 28 (63.1. 97 (80.6. 100 (73.3. 94.4) 91.6) 93.6) 87.8) False 5 16.7 4 11.4 13 11.8 20 16.3 I don't know 2.4 Correct Response Note: All con?dence intervals are exact binomial 95% con?dence intervals. Client: TRIG Project: TIRF Wave3 Report Run Date and Time: 10/20/2014 1:48 PM Page 4 of 4 TABLE 6.2.6 SECONDARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #1 KEY RISK MESSAGEI: TIRF MEDICINES ARE CONTRAINDICATED IN OPIOID NON-TOLERANT PATIENTS. SUB-GROUP ANALYSIS 6: TIME PRACTICING MEDICINE (QUESTION 33): S-6a - Less than 3 years 0 S-6b - 3 to 5 years 0 S-6c - 6 to 15 years 0 S-6d - More than 15 years S-6a S-6b S-6c S-6d Less than 3 years 3 to 5 years 6 to 15 years More than 15 Demonstrated Understanding years 0 correct responses correct response correct responses correct responses correct responses correct responses 5 16.7 4 11.4 14 12.7 16 13.0 6 correct responses 11 36.7 14 40.0 28 25.5 31 25.2 7 correct responses 12 40.0 15 42.9 54 49.1 66 53.7 Average number of correct responses 20035.17. 220351213. Client: TRIG Project: TIRF Wave 3 Report Run Date and Time: 10/16/2014 3:22 PM Page 1 of 2 [1] One-sided 95 % confidence interval using the normal approximation to the Poisson distribution Client: TRIG Project: TIRF Wave 3 Report Run Date and Time: 10/16/2014 3:22 PM Page   2 of 2 FDA_2537 TABLE 7.1.6 PRIMARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #2 KEY RISK MESSAGE 2: TIRF MEDICINES ARE ONLY INDICATED FOR THE MANAGEMENT OF BREAKTHROUGH PAIN IN ADULT CANCER PATIENTS 18 YEARS OF AGE AND OLDER (16 YEARS OF AGE AND OLDER FOR BRAND AND GENERIC EQUIVALENTS) WHO ARE ALREADY RECEIVING AND WHO ARE TOLERANT TO AROUND-THE-CLOCK OPIOID THERAPY FOR THEIR UNDERLYING PERSISTENT CANCER PAIN. SUB-GROUP ANALYSIS 6: TIME PRACTICING MEDICINE (QUESTION 33): S-6a - Less than 3 years 0 S-6b - 3 to 5 years 0 S-6c - 6 to 15 years 0 S-6d - More than 15 years S?6a S?6b S?6c S?6d Less than 3 years 3 to 5 years 6 to 15 years More than 15 years Question (95% CI) (95% CI) (95% CI) (95% CI) Question 9: In your practice, for which of the following indications do you prescribe TIRF medicines to opioid tolerant patients? Please answer Yes, No, or I don?t know for each option. 9a: Acute or postoperative pain 96.7 88.6 84.5 87.0 N0 29 (82.8. 99.9) 31 (73.3. 96.8) 93 (76.4. 90.7) 107 (79.7. 92.4) Yes 1 3.3 4 11.4 16 14.5 16 13.0 I don't know 0 0.0 0.0 1 0.9 0 0.0 Client: TRIG Project: TIRF Wave3 Report Run Date and Time: 10/28/2014 9:16 AM Page 1 of 4 S-6a S-6b S-6c S-6d Less than 3 years 3 to 5 years 6 to 15 years More than 15 years Question (95% CI) (95% CI) (95% CI) (95% CI) 9b: Headache or migraine pain 90.0 88.6 91.8 87.8 No 27 (73.5. 97.9) 31 (73.3. 96.8) 101 (85.0. 96.2) 108 (80.7. 93.0) Yes 3 10.0 4 11.4 9 8.2 15 12.2 I don't know 0.0 9c: Dental pain 100.0 97.1 98.2 95.9 N0 30 (88'4? 34 (85.1. 99.9) 108 (93.6. 99.8) 118 (90.8. 98.7) 100.don?t know 0.0 9d: Breakthrough pain from cancer 96.7 91.4 98.2 95.1 Yes 29 (82.8. 99.9) 32 (76.9. 98.2) 108 (93.6. 99.8) 117 (89.7. 98.don't know 0.0 Client: TRIG Project: TIRF Wave3 Report Run Date and Time: 10/28/2014 9:16 AM Page 2 S-6a S-6b S-6c S-6d Less than 3 years 3 to 5 years 6 to 15 years More than 15 years Question (95% CI) (95% CI) (95% CI) (95% CI) 9e: Chronic non?cancer pain 73.3 57.1 71.8 51.2 No 22 (54.1. 87.7) 20 (39.4. 73.7) 79 (62.4. 80.0) 63 (42.0. 60.3) Yes 8 26.7 14 40.0 30 27.3 60 48.8 I don't know 0.0 Question 13: The patients described are experiencing breakthrough pain. According to the labeling, a TIRF medicine is not appropriate for one of them. Which patient should not receive a TIRF medicine? Please select one option. Adult female with localized breast cancer: just completed a masmtomy and 63.3 71.4 60.0 70.7 S?P?gelyl 19 (43.9. 80.1) 25 (53.7. 85.4) 66 (50.2. 69.2) 87 (61.9. 78.6) pe151stentcance1 pam managed with 30 mg oral m01phine daily for the past 6 weeks. Adult female with advanced sarcoma who has been taking a daily dose of 4 13.3 4 11.4 15 13.6 7 5.7 12 111g oral 11yd1?om01phone for the last 3 weeks. Client: TRIG Project: TIRF Wave 3 Report Run Date and Time: 10/28/2014 9:16 AM Page 3 of 4 Question S-6a Less than 3 years S-6b 3 to 5 years S-6c 6 to 15 years S-6d More than 15 years (95% CI) (95% CI) (95% CI) (95% CI) Adult male patient with advanced prostate cancer who. over the last 2 weeks. has been prescribed 100 mg oral morphine daily for pain due to bone metastasis. 6.7 6.4 Adult male with advanced 11mg cancer; underlying persistent cancer pain managed with 25 mcg/hom' transdennal fentanyl patches for the past two months. 13.3 2.9 12 10.9 4.1 I don?t know 3.3 8.6 10 9.1 l6 13.0 Correct Response Note: All con?dence intervals are exact binomial 95% con?dence intervals. Client: TRIG Project: TIRF Wave3 Report Run Date and Time: 10/28/2014 9:16 ANI Page 4 of 4 TABLE 7.2.6 SECONDARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #2 KEY RISK MESSAGE 2: TIRF MEDICINES ARE ONLY INDICATED FOR THE MANAGEMENT OF BREAKTHROUGH PAIN IN ADULT CANCER PATIENTS 18 YEARS OF AGE AND OLDER (16 YEARS OF AGE AND OLDER FOR BRAND AND GENERIC EQUIVALENTS) WHO ARE ALREADY RECEIVING AND WHO ARE TOLERANT TO AROUND-THE-CLOCK OPIOII) THERAPY FOR THEIR UNDERLYING PERSISTENT CANCER PAIN. SUB-GROUP ANALYSIS 6: TIME PRACTICING MEDICINE (QUESTION 33): S-6a - Less than 3 years 0 S-6b - 3 to 5 years 0 S-6c - 6 to 15 years 0 S-6d - More than 15 years S-6a S-6b S-6c S-6d Less than 3 years 3 to 5 years 6 to 15 years More than 15 Demonstrated Understanding years 0 correct responses correct response correct responses correct responses correct responses 5 16.7 5 14.3 20 18.2 18 14.6 5 correct responses 11 36.7 13 37.1 38 34.5 55 44.7 Client: TRIG Project: TIRF Wave3 Report Run Date and Time: 10/16/2014 3:27 PM Page 1 of 2 6 correct responses 13 43.3 13 37.1 44 40.0 36 29.3 Average number of correct responses 5.2 (4.5, 4.9 (4.3, 5.0 (4.7, 4.9 (4.6, 6.0) 6.0) 6.0) ?1 6.0) ?1 [ll One-sided 95 con?dence interval using the normal approximation to the Poisson distribution Client: TRIG Project: TIRF Wave 3 Report Run Date and Time: 10/16/2014 3:27 PM Page 2 of 2 TABLE 8.1.6 PRIMARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #3 KEY RISK MESSAGE 3: TIRF MEDICINES CONTAIN FENTANY L, AN OPIOID AGONIST AND A SCHEDULE CONTROLLED SUBSTANCE, WITH ABUSE LIABILITY SIMILAR TO OTHER OPIOID ANALGESICS. SUB-GROUP ANALYSIS 6: TIME PRACTICING MEDICINE (QUESTION 33): S-6a - Less than 3 years S-6b - 3 to 5 years S-6c - 6 to 15 years S-6d - More than 15 years Question S?6a S?6b S?6c S?6d Less than 3 years 3 to 5 years 6 to 15 years More than 15 years (95% CI) (95% CI) (95% CI) (95% CI) Question 7: Please answer True, False, or I don?t know for each statement based on the labeling for TIRF medicines. 7e: It is important to monitor for signs of abuse and addiction in patients who take TIRF medicines. 100.0 100.0 100.0 99.2 True ?1 30 (88.4. 35 (90.0. 110 (96.7. 122 (95.6. 100.0) 100.0) 100.0) 100.0) False don't know 0.0 Client: TRIG Project: TIRF Wave3 Report Run Date and Time: 10/28/2014 9:09 AM Page 1 of3 S-6a S-6b S-6c S-6d Less than 3 years 3 to 5 years 6 to 15 years More than 15 years (95% CI) (95% CI) (95% CI) (95% CI) Question 8: Which of the following are risk factors for opioid abuse? Please answer Yes, No, or I don?t know for each option. 8a: A personal history of illness 90.0 80.0 82.7 84.6 Yes 27 (73.5. 97.9) 28 (63.1. 91.6) 91 (74.3. 89.3) 104 (76.9. 90.don't know 1 3.3 4 11personal history of past or current alcohol or drug abuse, or a family history of illicit drug use or alcohol abuse 100.0 100.0 99.1 100.0 Yes ?1 30 (88.4. 35 (90.0. 109 (95.0. 123 (97.0. 100.0) 100.0) 100.0) 100.don't know 0.0 Client: TRIG Project: TIRF Wave 3 Report Run Date and Time: 10/28/2014 9:09 AM Page 2 of 3 Question S-6a S-6b S-6c S-6d Less than 3 years 3 to 5 years 6 to 15 years More than 15 years (95% CI) (95% CI) (95% CI) (95% CI) Question 10: Please answer True, False, or I don?t know for each statement based on the labeling for TIRF medicines. 10a: TIRF medicines can be abused in a manner similar to other opioid agonists. 100.0 96.7 95.5 98.4 True 29 (82.8. 99.9) 35 (900? 105 (89.7. 98.5) 121 (94.2. 99.8) 100.0) False don't know 0.0 Correct Response Note: All con?dence intervals are exact binomial 95% con?dence intervals. Client: TRIG Project: TIRF Wave3 Report Run Date and Time: 10/28/2014 9:09 AM Page 3 TABLE 8.2.6 SECONDARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #3 KEY RISK MESSAGE 3: TIRF MEDICINES CONTAIN FENTANY L, AN OPIOID AGONIST AND A SCHEDULE CONTROLLED SUBSTANCE, WITH ABUSE LIABILITY SIMILAR TO OTHER OPIOID ANALGESICS. SUB-GROUP ANALYSIS 6: TIME PRACTICING MEDICINE (QUESTION 33): S-6a - Less than 3 years 0 S-6b - 3 to 5 years 0 S-6c - 6 to 15 years 0 S-6d - More than 15 years S-6a S-6b S-6c S-6d Less than 3 years 3 to 5 years 6 to 15 years More than 15 years Demonstrated Understanding 0 correct responses correct response correct responses correct responses 4 13.3 7 20.0 17 15.5 20 16.3 4 correct responses 26 86.7 28 80.0 89 80.9 102 82.9 Average number of correct responses 3.9 (3.3. 3.8 (3.3. 3.8 (3.5. 3.8 (3.5. 4-0) ?1 4.0) ?1 4.0) 4.0) ?1 One-sided 95 con?dence interval using the normal approximation to the Poisson distribution Client: TRIG Project: TIRF Wave 3 Report Run Date and Time: 10/28/2014 9:09 AM Page 1 of TABLE 9.1.6 PRIMARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #4 KEY RISK MESSAGE 4: TIRF MEDICINES ARE NOT INTERCHANGEABLE WITH EACH OTHER, REGARDLESS OF ROUTE OF ADMINISTRATION. SUB-GROUP ANALYSIS 6: TIME PRACTICING MEDICINE (QUESTION 33): S-6a - Less than 3 years 0 S-6b - 3 to 5 years 0 S-6c - 6 to 15 years 0 S-6d - More than 15 years Question S?6a S?6b S?c S?6d Less than 3 years 3 to 5 years 6 to 15 years More than 15 years (95% CI) (95% CI) (95% CI) (95% CI) Question 10: Please answer True, False, or I don?t know for each statement based on the labeling for TIRF medicines. 10b: TIRF medicines are interchangeable with each other regardless of route of administration. 111 96.7 94.3 90.0 94.3 False 29 (82.8. 99.9) 33 (80.8. 99.3) 99 (82.8. 94.9) ?6 (88.6. 97.7) True don?t know 1.6 Client: TRIG Project: TIRF Wave3 Report Run Date and Time: 10/16/2014 3:34 PM Page 1 of 4 Question S-6a S-6b S-6c S-6d Less than 3 years 3 to 5 years 6 to 15 years More than 15 years (95% CI) (95% CI) (95% CI) (95% CI) 10c: The conversion of one TIRF medicine for another TIRF medicine may result in a fatal overdose because of differences in the pharmacokinetics of fentanyl absorption. True 29 (82.95.9799) 33 (80.93.1393) 107 (92.927594) ?9 (91.959791) False don?t know 1 3.3 1 2.9 0.0 2 1.6 10d: Dosing of TIRF medicines is not equivalent on a microgram-to-microgram basis. True 26 30 101 (852: .9862) 113 36.0) False don't know 1.6 Client: TRIG Project: TIRF Wave3 Report Run Date and Time: 10/16/2014 3:34 PM Page 2 of 4 Question S-6a S-6b S-6c S-6d Less than 3 years 3 to 5 years 6 to 15 years More than 15 years (95% CI) (95% CI) (95% CI) (95% CI) Question 14: A patient is already taking a TIRF medicine but wants to change their medicine. His/her doctor decides to prescribe a different TIRF medicine (that is not a bioequivalent generic version of a branded product) in its place. According to the labeling, how should the prescriber proceed? Please select one option. The prescriber must not convert to another TIRF medicine on a microgram- per-microgram basis because these medicines have different properties and this could result in a fentanyl overdose. 23 76.7 (57.7. 90.1) 29 82.9 (66.4. 93.4) 80 72.7 (63.4. 80.8) 89 72.4 (63.6. 80.0) Convert from the other TIRF medicine to the new TIRF medicine at half of the dose. 3.3 2.9 7.3 16 13.0 The prescriber can safely convert to the equivalent dosage of the new TIRF medicine as it has the same effect as other TIRF medicines. 0.0 0.0 0.9 1.6 Client: TRIG Project: TIRF Wave3 Report Run Date and Time: 10/16/2014 3:34 PM Page 3 of 4 S-6a S-6b S-6c Less than 3 years 3 to 5 years 6 to 15 years More than 15 years (95% CI) (95% CI) (95% CI) (95% CI) The prescriber should base the starting dose of the newly-prescribed TIRF medicine on the dose of the 3 10.0 3 8.6 15 13.6 11 8.9 opioid medicine used for their underlying persistent cancer pain. I don?t know. 3 10.0 2 5.7 6 5.5 5 4.1 Correct Response Note: All con?dence intervals are exact binomial 95% con?dence intervals. Client: TRIG Project: TIRF Wave3 Report Run Date and Time: 10/16/2014 3:34 PM Page 4 of4 TABLE 9.2.6 SECONDARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #4 KEY RISK MESSAGE 4: TIRF MEDICINES ARE NOT INTERCHANGEABLE WITH EACH OTHER, REGARDLESS OF ROUTE OF ADMINISTRATION. SUB-GROUP ANALYSIS 6: TIME PRACTICING MEDICINE (QUESTION 33): S-6a - Less than 3 years 0 S-6b - 3 to 5 years 0 S-6c - 6 to 15 years 0 S-6d - More than 15 years S-6a S-6b S-6c S-6d Less than 3 years 3 to 5 years 6 to 15 years More than 15 years Demonstrated Understanding 0 correct responses correct response correct responses 4 13correct responses 5 16.7 5 14.3 34 30.9 27 22.0 4 correct responses 21 70.0 26 74.3 68 61.8 85 69.1 Average number of correct responses 3.6 (3.0. 3.6 (3.0. 3.5 (3.2. 3.6 (3.3. 4.0) ?1 4.0) ?1 4.0) ?1 4.0) ?1 One-sided 95 con?dence interval using the normal approximation to the Poisson distribution Client: TRIG Project: TIRF Wave3 Report Run Date and Time: 10/16/2014 3:35 PM Page 1 of TABLE 6.1.7 PRIMARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #1 KEY RISK MESSAGE l: TIRF MEDICINES ARE CONTRAINDICATED IN OPIOID NON-TOLERANT PATIENTS. SUB-GROUP ANALYSIS 7: NUMBER OF TIMES PER MONTHS PRESCRIBING TIRF MEDICINES WITHIN THE LAST 6 MONTHS (QUESTION 29): S-7a - None S-7b - 1 - 2 times a month S-7c - 3 - 5 times a month S-7d - More than 5 times a month S-7d S-7a S-7b S-7c . None 1? 2 times per month 3? 5 times per month More per Question (95% CI) (95% CI) (95% CI) (95% CI) Question 5: Please select True, False, or I don?t know for each of the following. According to the labeling for TIRF medicines, patients with cancer who are considered opioid-tolerant are those: 5a: Who are taking around?the?clock opioid therapy for underlying, persistent cancer pain for one week or longer 92.2 90.9 88.9 80.8 True 59 (82.7. 97.4) 140 (85.2. 94.9) 40 (75.9. 96.3) 21 (60.6. 93.4) False 15.4 I don't know 3.8 Client: TRIG Project: TIRF Wave3 Report Run Date and Time: 10/20/2014 1:49 PM Page 1 of 3 S-7d S-7a S-7b S-7c . None 1? 2 times per month 3? 5 times per month More per Question (95% CI) (95% CI) (95% CI) (95% CI) 5b: Who are not currently taking opioid therapy, but have taken opioid therapy before 82.8 88.3 86.7 88.5 False 53 (71.3. 91.1) 136 (82.2. 92.9) 39 (73.2. 94.9) 23 (69.8. 97.6) Tune 11.5 I don't know 0.0 5c: Who have no known contraindications to the drug fentanyl, but are not currently taking around?the?clock opioid therapy 84.4 87.0 84.4 88.5 False 54 (73.1. 92.2) 134 (80.7. 91.9) 38 (70.5. 93.5) 23 (69.8. 97.6) True 5 7.8 14 9.1 6 13.3 3 11.5 I don't know 0.0 Question 7: Please answer True, False, or I don?t know for each statement based on the labeling for TIRF medicines. 7a: TIRF medicines are contraindicated in opioid non?tolerant patients because life?threatening respiratory depression could occur at any dose. 82.8 89.0 82.2 88.5 True 53 (71.3. 91.1) 137 (82.9. 93.4) 37 (67.9. 92.0) 23 (69.8. 97.6) False 8 12.5 14 9.1 7 15.6 3 11.5 Idon't know 0.0 Client: TRIG Project: TIRF Wave3 Report Run Date and Time: 10/20/2014 1:49 PM Page 2 of 3 S-7d S-7a S-7b S-7c . None 1? 2 times per month 3? 5 times per month More maxim? per Question (95% CI) (95% CI) (95% CI) (95% CI) 7b: Death has occurred in opioid non-tolerant patients treated with some fentanyl products. 95.3 96.1 95.6 100.0 True 61 (86.9. 99.0) 148 (91.7. 98.6) 43 (84.9. 99.5) 26 (86.8. 100.0) False don?t know 3 4.7 4 2.6 2 4.4 0.0 7c: TIRF medicines may be used to treat opioid non-tolerant patients. 79.7 81.2 82.2 88.5 False 51 (67.8. 88.7) 125 (74.1. 87.0) 37 (67.9. 92.0) 23 (69.8. 97.6) True 10 15.6 26 16.9 8 17.8 2 7.7 I don't know 3.8 7d: Prescribers starting a patient on a TIRF medicine must begin with titration from the lowest dose available for that specific product, even if the patient has previously taken another TIRF medicine. 85.9 83.8 86.7 76.9 True 55 (75.0. 93.4) 129 (77.0. 89.2) 39 (73.2. 94.9) 20 (56.4. 91.0) False 6 9.4 22 14.3 6 13.3 6 23.1 I don't know 0.0 Correct Response Note: All con?dence intervals are exact binomial 95% con?dence intervals. Client: TRIG Project: TIRF Wave3 Report Run Date and Time: 10/20/2014 1:49 PM Page 3 of 3 TABLE 6.2.7 SECONDARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #1 KEY RISK MESSAGEI: TIRF MEDICINES ARE CONTRAINDICATED IN OPIOID NON-TOLERANT PATIENTS. SUB-GROUP ANALYSIS 7: NUMBER OF TIMES PER MONTHS PRESCRIBING TIRF MEDICINES WITHIN THE LAST 6 MONTHS (QUESTION 29): 0 8-73 - None 0 S-7b - 1 - 2 times a month 0 S-7c - 3 - 5 times a month 0 S-7d - More than 5 times a month S-7a S-7b S-7c S-7d None 1-2 times a month 3 - 5 times a month More than 5 Demonstrated Understanding times a month 0 correct responses correct response correct responses correct responses correct responses correct responses 7 10.9 23 14.9 7 15.6 1 3.8 6 correct responses 15 23.4 47 30.5 10 22.2 11 42.3 7 correct responses 33 51.6 74 48.1 23 51.1 11 42.3 Client: TRIG Project: TIRF Wave3 Report Run Date and Time: 10/16/2014 3:38 PM Page 1 of 2 Average number of correct responses 6.0 (5.5, 6.2 (5.8, 6.1 (5.5, 6.1 (5.3, 7.0) 7.0) ?1 7.0) ?1 7.0) ?1 '11 One-sided 9s con?dence interval using the normal approximation to the Poisson distribution Client: TRIG Project: TIRF Wave 3 Report Run Date and Time: 10/16/2014 3:38 PM Page 2 of 2 TABLE 7.1.7 PRIMARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #2 KEY RISK MESSAGE 2: TIRF MEDICINES ARE ONLY INDICATED FOR THE MANAGEMENT OF BREAKTHROUGH PAIN IN ADULT CANCER PATIENTS 18 YEARS OF AGE AND OLDER (16 YEARS OF AGE AND OLDER FOR ACTIQ® BRAND AND GENERIC EQUIVALENTS) WHO ARE ALREADY RECEIVING AND WHO ARE TOLERANT TO AROUND-THE-CLOCK OPIOID THERAPY FOR THEIR UNDERLYING PERSISTENT CANCER PAIN. SUB-GROUP ANALYSIS 7: NUMBER OF TIMES PER MONTHS PRESCRIBING TIRF MEDICINES WITHIN THE LAST 6 MONTHS (QUESTION 29): • S-7a - None • S-7b - 1 - 2 times a month • S-7c - 3 - 5 times a month • S-7d - More than 5 times a month Client: TRIG Project: TIRF Wave 3 Report Run Date and Time: 10/28/2014 9:15 AM Page   1 of 5 FDA_2558 Question S-7d S-7a S-7b SJC More than 5 None 1?2 times a month 3 5 times a month times a month (95% CI) (95% CI) (95% CI) (95% CI) Question 9: In your practice, for which of the following indications do you prescribe TIRF medicines to opioid tolerant patients? Please answer Yes, No, or I don?t know for each option. 9a: Acute or postoperative pain NO 56 (76.27344) 132 (79.255.970.23) 42 (81.973386) 22 (65:11:56) Yes 8 12.5 21 13.6 3 6.7 4 15.4 I don't know 0.0 9b: Headache or migraine pain NO 63 134 (80.23319) 41 (78.981 917.5) 23 (69.83376) 100.0) Yes 1 1.6 20 13.0 4 8.9 3 11.5 I don?t know 0 0.0 0 0.0 0.0 0 0.0 Client: TRIG Project: TIRF Wave3 Report Run Date and Time: 10/28/2014 9:15 AM Page 2 of S-7a . S-7b . 8-76 Morse-Zhlan 5 None 1-2 times a month 3 5 times a month times a month Question CI) CI) CI) CI) 9c: Dental pain N0 64 32;? 149 (92359889) 44 (889279899) 25 (80259299) 100.don't know 0.0 9d: Breakthrough pain from cancer YES 62 (89:?9996) 149 (92.95.9889) 44 (8833-9899) 24 (74.99%.391don?t know 0.0 9e: Chronic non?cancer pain NO 52 (69239.9) 95 (5326794) 22 10 (20.322.15.894) Yes 12 18.8 58 37.7 23 51.1 16 61.5 I don't know 0.0 Client: TRIG Project: TIRF Wave3 Report Run Date and Time: 10/28/2014 9:15 AM Page 3 Question S-7d S-7a S-7b S-7c More than 5 None 1-2 times a month 3 5 times a month times a month (95% CI) (95% CI) (95% CI) (95% CI) Question 13: The patients described are experiencing breakthrough pain. According to the labeling, a TIRF medicine is not appropriate for one of them. Which patient should not receive a TIRF medicine? Please select one option. Adult female with localized breast cancer: just completed a mastectomy and reconstructive surgery: persistent cancer pain managed with 30 mg oral morphine daily for the past 6 weeks. 29 45.3 (32.8. 58.3) 105 68.2 (60.2. 75.4) 37 82.2 (67.9. 92.0) 21 80.8 (60.6. 93.4) Adult female with advanced sarcoma who has been taking a daily dose of 12 mg oral hydromorphone for the last 3 weeks. 14.1 16 10.4 4.4 7.7 Client: TRIG Project: TIRF Wave3 Report Run Date and Time: 10/28/2014 9:15 AM Page 4 of 5 S-7a S-7c Morse Zlilan 5 None 1?2 times a month 3 5 times a month times a month (95% Cl) (95% Cl) (95% CI) (95% CI) Adult male patient with advanced prostate cancer who. over the last 2 weeks. has been 9 14.1 6 3.9 6.7 3.8 prescribed 100 mg oral morphine daily for pain due to bone metastasis. Adult male with advanced 11mg cancer: underlying persistent cancer pain managed with 25 7 10.9 13 8.4 2.2 0 0.0 mcg/hom? transdennal fentanyl patches for the past two months. I don?t know 10 15.6 14 9.1 4.4 2 7.7 Con?ect Response Note: All con?dence intervals are exact binomial 95% con?dence intervals. Client: TRIG Project: TIRF Wave3 Report Run Date and Time: 10/28/2014 9:15 AM Page 5 of 5 TABLE 7.2.7 SECONDARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #2 KEY RISK MESSAGE 2: TIRF MEDICINES ARE ONLY INDICATED FOR THE MANAGEMENT OF BREAKTHROUGH PAIN IN ADULT CANCER PATIENTS 18 YEARS OF AGE AND OLDER (16 YEARS OF AGE AND OLDER FOR BRAND AND GENERIC EQUIVALENTS) WHO ARE ALREADY RECEIVING AND WHO ARE TOLERANT TO AROUND-THE-CLOCK OPIOII) THERAPY FOR THEIR UNDERLYING PERSISTENT CANCER PAIN. SUB-GROUP ANALYSIS 7: NUMBER OF TIMES PER MONTHS PRESCRIBING TIRF MEDICINES WITHIN THE LAST 6 MONTHS (QUESTION 29): 8-73 - None S-7b - - 2 times a month S-7c - 3 - 5 times a month S-7d - More than 5 times a month S-7a S-7b S-7c S-7d None 1-2 times a month 3 - 5 times a month More than 5 Demonstrated Understanding times a month 0 correct responses correct response correct responses correct responses 11.5 4 correct responses 14 21.9 20 13.0 9 20.0 4 15.4 Client: TRIG Project: TIRF Wave3 Report Run Date and Time: 10/16/2014 3:42 PM Page 1 of2 5 correct responses 27 42.2 53 34.4 19 42.2 14 53.8 6 correct responses 22 34.4 61 39.6 16 35.6 5 19.2 Average number of correct responses 5.1 (4.6, 5.0 (4.7, 5.1 (4.6, 4.8 (4.1, 6.0) ?1 6.0) 6.0) ?1 6.0) ?1 One-sided 95 con?dence interval using the normal approximation to the Poisson distribution Client: TRIG Project: TIRF Wave 3 Report Run Date and Time: 10/16/2014 3:42 PM Page 2 of 2 TABLE 8.1.7 PRIMARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #3 KEY RISK MESSAGE 3: TIRF MEDICINES CONTAIN FENTANY L, AN OPIOID AGONIST AND A SCHEDULE II- CONTROLLED SUBSTANCE, WITH ABUSE LIABILITY SIMILAR TO OTHER OPIOID ANALGESICS. SUB-GROUP ANALYSIS 7: NUMBER OF TIMES PER MONTHS PRESCRIBING TIRF MEDICINES WITHIN THE LAST 6 MONTHS (QUESTION 29): S-7a - None 0 S-7b - 1 - 2 times a month 0 S-7c - 3 - 5 times a month 0 S-7d - More than 5 times a month Question S-7a S'7b S-7c 5 None 1?2 times a month 3 5 times a month times a month (95% CI) (95% CI) (95% CI) (95% CI) Question 7: Please answer True, False, or I don?t know for each statement based on the labeling for TIRF medicines. 7e: It is important to monitor for signs of abuse and addiction in patients who take TIRF medicines. 98.4 100.0 100.0 100.0 True ?1 63 (91.6. 154 (97.6. 45 (92.1. 26 (86.8. 100.0) 100.0) 100.0) 100.0) False don't know 0.0 Client: TRIG Project: TIRF Wave3 Report Run Date and Time: 10/28/2014 9:09 AM Page 1 of 3 S-7d S-7a S-7b S-7c More than 5 None 1?2 times a month 3 5 times a month times a month Question (95% CI) (95% CI) (95% CI) (95% CI) Question 8: Which of the following are risk factors for opioid abuse? Please answer Yes, No, or I don?t know for each option. 8a: A personal history of illness 78.1 87.7 82.2 73.1 Yes 50 (66.0. 87.5) 135 (81.4. 92.4) 37 (67.9. 92.0) 19 (52.2. 88.11.5 I don?t know 8 12.5 9 5.8 4 8.9 4 15.4 8b: A personal history of past or current alcohol or drug abuse, or a family history of illicit drug use or alcohol abuse 100.0 100.0 100.0 96 2 Yes ?1 64 (94.4. 154 (97.6. 45 (92.1. 25 (80 4 '99 9) 100.0) 100.0) 100.don't know 0.0 Client: TRIG Project: TIRF Wave3 Report Run Date and Time: 10/28/2014 9:09 AM Page 2 of 3 Question S-7d S-7a S-7b S-7c More than 5 None 1?2 times a month 3 5 times a month times a month (95% CI) (95% CI) (95% CI) (95% CI) Question 10: Please answer True, False, or I don?t know for each statement based on the labeling for TIRF medicines. 10a: TIRF medicines can be abused in a manner similar to other opioid agonists. 100.0 93.8 98.1 97.8 True 60 (84.8. 98.3) 151 (94.4. 99.6) 44 (88.2. 99.9) 26 (86'8? 100.0) False don't know 1 1.6 0.0 0 0.0 0 0.0 Correct Response Note: All con?dence intervals are exact binomial 95% con?dence intervals. Client: TRIG Project: TIRF Wave3 Report Run Date and Time: 10/28/2014 9:09 AM Page 3 TABLE 8.2.7 SECONDARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #3 KEY RISK MESSAGE 3: TIRF MEDICINES CONTAIN FENTANY L, AN OPIOID AGONIST AND A SCHEDULE CONTROLLED SUBSTANCE, WITH ABUSE LIABILITY SIMILAR TO OTHER OPIOID ANALGESICS. SUB-GROUP ANALYSIS 7: NUMBER OF TIMES PER MONTHS PRESCRIBING TIRF MEDICINES WITHIN THE LAST 6 MONTHS (QUESTION 29): S-7a - None 0 S-7b - 1 - 2 times a month 0 S-7c - 3 - 5 times a month 0 S-7d - More than 5 times a month S-7a S-7b S-7c S-7d None 1-2 times a month 3 - 5 times a month More than 5 Demonstrated Understanding N: times a month 0 correct responses correct response correct responses correct responses 13 20.3 20 13.0 9 20.0 6 23.1 4 correct responses 48 75.0 133 86.4 36 80.0 19 73.1 Average number of correct responses 3.7 (3.3. 3.9 (3.6. 3.8 (3.3. 3.7 (3.1. 40> ?1 4.0) ?1 4.0) 4.0) ?1 One-sided 95 con?dence interval using the normal approximation to the Poisson distribution Client: TRIG Project: TIRF Wave 3 Report Run Date and Time: 10/28/2014 9:08 AM Page 1 of TABLE 9.1.7 PRIMARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #4 KEY RISK MESSAGE 4: TIRF MEDICINES ARE NOT INTERCHANGEABLE WITH EACH OTHER, REGARDLESS OF ROUTE OF ADMINISTRATION. SUB-GROUP ANALYSIS 7: NUMBER OF TIMES PER MONTHS PRESCRIBING TIRF MEDICINES WITHIN THE LAST 6 MONTHS (QUESTION 29): S-7a - None 0 S-7b - 1 - 2 times a month 0 S-7c - 3 - 5 times a month 0 S-7d - More than 5 times a month Question S?7d S-7a S-7b 5-76 None 1?2 times a month 3 5 times a month $222235; (95% CI) (95% CI) (95% CI) (95% CI) Question 10: Please answer True, False, or I don?t know for each statement based on the labeling for TIRF medicines. 10b: TIRF medicines are interchangeable with each other regardless of route of administration. 92.2 92.2 93.3 96.2 False 59 (82.7. 97.4) 142 (86.8. 95.9) 42 (81.7. 98.6) 25 (80.4. 99.9) True don't know 0.0 Client: TRIG Project: TIRF Wave3 Report Run Date and Time: 10/16/2014 3:48 PM Page 1 of 4 Question S-7d S-7a S-7b S-7c More than 5 None 1?2 times a month 3 5 times a month times a month (95% CI) (95% CI) (95% CI) (95% CI) 10c: The conversion of one TIRF medicine for another TIRF medicine may result in a fatal overdose because of differences in the pharmacokinetics of fentanyl absorption. True 59 (82.97%9274) 150 (93:39.3) 44 (833.927.9899) 26 (1:69: 100.0) False don?t know 0.0 10d: Dosing of TIRF medicines is not equivalent on a microgram?to-microgram basis. True 56 (76887544) 139 (8423344) 42 (8 1 273938.15) 26 - False don't know 0.0 Client: TRIG Project: TIRF Wave3 Report Run Date and Time: 10/16/2014 3:48 PM Page 2 of 4 Question S-7d S-7a S-7b S-7c More than 5 None 1?2 times a month 3 5 times a month times a month (95% CI) (95% CI) (95% CI) (95% CI) Question 14: A patient is already taking a TIRF medicine but wants to change their medicine. His/her doctor decides to prescribe a different TIRF medicine (that is not a bioeqnivalent generic version of a branded product) in its place. According to the labeling, how should the prescriber proceed? Please select one option. The prescriber must not convert to another TIRF medicine on a microgram- per-microgram basis because these medicines have different absorption properties and this could result in a fentanyl overdose. 47 73.4 (60.9. 83.7) 117 76.0 (68.4. 82.5) 32 71.1 .7. 83.6) 'Ji 18 69.2 (48.2. 85.7) Convert from the other TIRF medicine to the new TIRF medicine at half of the dose. 9.4 11 7.1 The prescriber can safely convert to the equivalent dosage of the new TIRF medicine as it has the same effect as other TIRF medicines. 1.6 0.6 0.0 3.8 Client: TRIG Project: TIRF Wave3 Report Run Date and Time: 10/16/2014 3:48 PM Page 3 of 4 The prescriber should base the starting dose of the newly-prescribed TIRF medicine on the dose of 6 9.4 17 the opioid medicine used for their underlying persistent cancer pain. 11.0 13.3 7.7 I don?t know. 4 6.3 8 5.2 4.4 3.8 Correct Response Note: All con?dence intervals are exact binomial 95% con?dence intervals. Client: TRIG Project: TIRF Wave 3 Report Run Date and Time: 10/16/2014 3:48 PM Page 4 of 4 TABLE 9.2.7 SECONDARY ANALYSIS OF RESPONSES TO QUESTIONS LINKED TO KEY RISK MESSAGE #4 KEY RISK MESSAGE 4: TIRF MEDICINES ARE NOT INTERCHANGEABLE WITH EACH OTHER, REGARDLESS OF ROUTE OF ADMINISTRATION. SUB-GROUP ANALYSIS 7: NUMBER OF TIMES PER MONTHS PRESCRIBING TIRF MEDICINES WITHIN THE LAST 6 MONTHS (QUESTION 29): 0 8-73 - None 0 S-7b - 1 - 2 times a month 0 S-7c - 3 - 5 times a month 0 S-7d - More than 5 times a month S-7a S-7b S-7c S-7d None 1-2 times a month 3 - 5 times a More than 5 0 correct responses correct response correct responses correct responses 17 26.6 30 19.5 13 28.9 7 26.9 4 correct responses 41 64.1 107 69.5 29 64.4 18 69.2 Average number of correct responses 3.5 (3.1. 3.6 (3.3. 3.6 (3.1. 3.7 (3.0. 40) 4.0) 4.0) 4.0) One-sided 95 con?dence interval using the normal approximation to the Poisson distribution Client: TRIG Project: TIRF Wave 3 Report Run Date and Time: 10/16/2014 3:50 PM Page 1 of Listing 1 VERBATIM RESPONSES TO QUESTION 24 (Questions about the information in the full prescribing information or medication guide) Verbatim Response answered last question incorrectly: should have been no Any guides regarding conversion to alternative TIRF agents is helpful as that is felt to be the most risky time with this med. use. are there online guides to prescribing Can patients stop taking their aromid the clock opioid medications and still continue TIRF products? Can you continue TRIF meds after stopping long actin meds? Despite not being 'approved for migraine and acute pain.? I have patients whom I inherited 011 these medications (for migraine). They work well and I have continued them. As for acute pain. Oral fentanyl has been given in a hospital setting in the recovery room. Why is this not approved? DOES interfere? 61101 110116 Generally question about cross titration between medications and how to do it more accurately. How to monitor intake through qualitative UDS if patient taking rarley I asked my rep I do not prescribe these medications 011 a regular basis and I do not intend to prescribe them regularly. i typed yes. 011 accident I would like a copy emailed or mailed to have readily available to review. Is there any upcoming information on conversion ratios of different fentanyl products? It was a while ago and I do not recall. I do rememeber that my question at that time was answered in regards to the subscribing of the medication. mainly concerning dosing. titration. and conversions need close monitoring of these patients any new studies no questions No questions. 110116 none currently None now none right now Client: TRIG Project: TIRF Wave3 Report Run Date and Time: 10/31/2014 9:00 AM Page 1 of 2 Verbatim Response 110116 . Not exactly clear about medication interaction with the 3A4 pathway One type better indicated for certain conditions compared to the others? Proper starting dose. dose escalation questions question about whether fentora could be placed sublingual (answer 110) since patient had bad dental abscesses that made mucosal placement dif?cult The genomic contribution to the problems to Fentanyl and its detoxi?cation pro?les as well as its phannacokinetics is rarely discussed in the past when was that information known? They were answered by the pharmacology representative visiting of?ce. they were answered by the rep and pointed out in the medication guide use of TIRF medicine in noncancerous chronic pain patients? W110 decided which guidelines would be used? Why do I have to ?ll out a form each time. Client: TRIG Project: TIRF Wave3 Report Run Date and Time: 10/31/2014 9:00 AM Page 2 of 2 Listing 2 VERBATIM RESPONSES TO QUESTION 35 (OTHER MEDICAL SPECIALTY) Verbatim Response PMR of?ce orthopedics Hospice and Palliative Medicine Nelu?ology FIBROMYALGIA Anesthesia palliative care hospice Hematology Anesthesiology Family Practice. Addiction Palliative Medicine nephrology Family practice- pain management gynecologic oncology physical medicine physical medicine and rehab. rehab/physiatry/pain oncology and palliative care Transplant Stu?geiy Hospital Medicine Palliative /Hospice Palliative Medicine Neiu?osurgery oncologic emergencies Pediatric Hematology/Oncology Client: TRIG Project: TIRF Wave3 Report Run Date and Time: 10/31/2014 9:03 AM Page 1 of 2 Verbatim Response Intemal Medicine/Hospice Physiatiy pain and addiction medicine with osteopathic inaniplative medicine Pediatric Palliative Care Geriatlics palliative care and hospice Physical Medicine and Rehab geiiatn'cs Hospice Palliative Care hospice and palliative care HPM Client: TRIG Project: TIRF Wave3 Report Run Date and Time: 10/31/2014 9:03 AM Page 2 of 2 Listing 3 VERBATIM RESPONSES TO REPORTED ADVERSE EVENTS, PRODUCT COMPLAINTS OR REQUESTS FOR MEDICAL INFORMATION Verbatim Response I don't prescribe Actiq. Actiq causes cavities. I had one patient need dental work. Any guides regarding conversion to altemative TIRF agents is helpful as that is felt to be the most risky time with this med. use. are there online guides to prescribing Can patients stop taking their aromld the clock opioid medications and still continue TIRF products? Can you continue TRIF meds after stopping long actin meds? Despite not being 'approved for migraine and acute pain.? I have patients whom I inherited 011 these medications (for migraine). They work well and I have continued them. As for acute pain. Oral fentanyl has been given in a hospital setting in the recovery room. Why is this not approved? DOES interfere? Generally question about cross titration between medications and 110w to do it more accurately. How to monitor intake through qualitative UDS if patient taking rarley I would like a copy emailed or mailed to have readily available to review. Is there any upcoming information on conversion ratios of different fentanyl products? mainly conceming dosing. titration. and conversions Not exactly clear about medication interaction with the 3A4 pathway One type better indicated for certain conditions compared to the others? Proper starting dose. dose escalation questions question about whether fentora could be placed sublingual (answer 110) since patient had bad dental abscesses that made mucosal placement dif?cult The genomic contribution to the problems to Fentanyl and its detoxi?cation pro?les as well as its phannacokinetics is rarely discussed in the past when was that information known? use of TIRF medicine in noncancerous chronic pain patients? W110 decided which guidelines would be used? Why do I have to ?ll out a form each time. Client: TRIG Project: TIRF Wave3 Report Run Date and Time: 10/31/2014 9:05 AM Page 1 of Prescriber KAB Assessment Report Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Appendix C Page 54 of 54 Prescriber Survey Protocol Track Change Document: Comparison of 24-month Survey to 36-month Survey FDA_2579 PROTOCOL TITLE: SPONSOR: VERSION: DATE: APPROVED Quantitative Testing of Prescriber Knowledge, Attitudes, and Behavior about Transmucosal Immediate Release Fentanyl (TIRF) Products Safety and Use Information TIRF REMS Industry Group (TRIG) ,Cephalon, Inc. (a wholly-owned subsidiary Deleted: Archimedes Pharnn vs Inc. 11 of Teva Pharmaceutical Industries, Ltd.) DepomedI Iuc. Galena Biopharma? Insys Therapeutics Mallinckrodt Pharmaceuticals Meda Pharmaceuticals Mylan, Inc. Par Pharmaceutical, Inc. 70 25JUL2014. Final Deleted: Deleted: 10 SEP 2013 Deleted: FINAL TABLE OF CONTENTS PAGE TABLE OF CONTENTS ......................................................................................... 2 1. LIST OF ABBREVIATIONS .................................................................................. 3 2. BACKGROUND ..................................................................................................... 4 3. OBJECTIVES OF THE EVALUATION SURVEY ............................................... 5 4. METHODS .............................................................................................................. 5 4.1 4.1.1 4.1.2 4.1.3 Survey Design .......................................................................................................... 5 Qualitative Research on the Survey ......................................................................... 6 Questions on REMS Goals ...................................................................................... 6 Additional Questions................................................................................................ 9 4.2 4.2.1 Participant Recruitment............................................................................................ 9 Measures to Minimize Bias in the Sample............................................................. 10 5. 5.1.1 5.1.2 5.1.3 STUDY POPULATION ........................................................................................ 10 Sample Size ............................................................................................................ 10 Inclusion Criteria.................................................................................................... 11 Exclusion Criteria .................................................................................................. 11 6. SURVEY PROCESS ............................................................................................. 11 6.1 6.1.1 6.1.2 Screening and Survey Administration ................................................................... 11 Telephone ............................................................................................................... 12 Internet ................................................................................................................... 12 6.2 Measures to Minimize Bias in the Survey Process ................................................ 12 7. 7.1.1 7.1.2 7.1.3 ANALYSIS ............................................................................................................ 12 Analysis Population ............................................................................................... 13 Description of Primary Analyses ........................................................................... 13 Description of Secondary Analyses ....................................................................... 13 8. SAFETY EVENT REPORTING ........................................................................... 14 9. PRIVACY PROTECTION AND CONFIDENTIALITY...................................... 14 LIST OF APPENDICES Appendix A Prescriber Questionnaire...........................................................................15 Appendix B SAMPLE Prescriber Invitation Letter ......................................................37 FDA_2581 1. LIST OF ABBREVIATIONS CATI Computer-Assisted Telephone Interviewing CI Con?dence Interval EDC Electronic Data Capture ETASU Elements to Assure Safe Use FDA Food and Drug Administration HIPAA Health Insurance Portability and Accountability Act ISI Important Safety Information KAB Knowledge. Attitudes and Behavior PI Prescribing Information REMS Risk Evaluation and Mitigation Strategy SE Safety Event Project Speci?c Procedure Deleted: TIRF Transmucosal Inmlediate Release Fentanyl TIRF REMS TIRF REMS Access Program TRIG TIRF REMS Industry Group UBC United BioSource Corporation US United States 2. BACKGROUND Transmucosal Immediate Release Fentanyl (TIRF) medicines include the class of immediate- release opioid analgesics that are indicated only for the management of breakthrough pain in cancer patients 18 years of age or older (16 or older for Actqu and equivalent generics) who Formatted: Superscript are already receiving and tolerant to opioid therapy for their underlying persistent cancer pain. Deleted: already The TIRF medicines include Abstralg. Actiqw. FentoraP. Lazanda?w. Onsolis?w. and A Matted: Superscript generic versions of any of these brands. The TIRF REMS Industry Group (TRIG) includes Matted. Superscript 'Cephalon. Inc. (a wholly-owned subsidiary of Teva Pharmaceutical Industries, Ltd.): Formatted: Wript Depomed. Inc.: Galena Biopharma. Inc.;Insys Therapeutics: Mallinckrodt Pharmaceuticals: mm ?pt Meda Pharmaceuticals: Mylan. Inc.: and Par Pharmaceutical, Inc. . Formatted: The Food and Drug Administration (FDA) has determined that a class-wide Risk Evaluation mm?: mm? and Mitigation Strategy (REMS) is required to mitigate the risk of misuse. abuse. addiction. De'eted1md? US overdose. and serious complications due to medication errors with the use of TIRF medicines. Deleted: Endo Phamoeu?cals The REMS Access Program (herea?er referred to as TIRF REMS) was approved by the Deleted: FDA on December 28. 2011. The TIRF REMS consists of a Medication Guide. Elements to Assure Safe Use (ETASU). an Implementation System. and a Tinretabl for Submissior of Assessment of the REMS. The Deleted: timetable goals of the TIRF REMS are to mitigate the risk of misuse. abuse. addiction. overdose; and serious complications due to medication errors by the following: Deleted: submission Deleted: mam 1. Prescribing and dispensing TIRF medicines only to appropriate patients, which includes use only in opioid-tolerant patients. 2. Preventing inappropriate conversion between TIRF medicines. 3. Preventing accidental exposure to children and others for whom it was not prescribed. 4. Educating prescribers. pharmacists. and patients on the potential for misuse. abuse. addiction. and overdose of TIRF medicines. An important component of the TIRF REMS assessment is the conduct of quantitative evaluation surveys to assess prescribers? understanding and knowledge of the safe use and appropriate prescribing of TIRF medicines as described in the TIRF REMS educational materials. enrollment form. and Prescribing Information (PI) of each product. This protocol will describe the administration of the surveys that will be conducted among prescribers who are enrolled in the TIRF REMS Access Program. Data from the surveys. together with other REMS evaluation metrics. will be used to determine whether changes need to be made to the REMS processes or educational materials to make them more effective in achieving the goals of the REMS. The surveys will be implemented so that data will be available for inclusion in the REMS Assessment Reports that will be submitted to the FDA at 12 months after approval of the TIRF REMS and annually thereafter. 3. OBJECTIVES OF THE EVALUATION SURVEY The evaluation survey will use a questionnaire to document the level of knowledge and assess the attitudes and behavior of prescribers around the following key information and risk messages communicated through the REMS: 1. TIRF medicines are contraindicated in opioid non-tolerant patients. 2. TIRF medicines are only indicated for the management of breakthrough pain in adult cancer patients 18 years of age and older (16 or older for Actiq? and equivalent Formatted: Superscript generics) who are already receiving and who are tolerant to around-the-clock opioid therapy for their underlying persistent cancer pain. 3. TIRF medicines contain fentanyl. an opioid agonist and a Schedule II-controlled substance. with abuse liability similar to other opioid analgesics. 4. TIRF medicines are not interchangeable with each other. regardless of route of administration. 5. Patients and their caregivers must be instructed that TIRF medicines contain a medicine in an am01mt that can be fatal in children. in individuals for whom it is not prescribed. and in those who are not opioid tolerant. The survey will also collect data on behaviors. such as receipt and use of educational materials and compliance with REMS requirements. 4. METHODS The survey was designed in collaboration between the RIG and United BioSource Corporation (UBC) and will be administered by UBC. 4.1 Survey Design This survey will be conducted among a sample of prescribers who are enrolled in the TIRF REMS Access Program. Respondents who participate in the previouswave of the TIRF Deleted: ?rst survey will not be eligible to participate in subsequent survey waves. The survey will be administered using the following modalities: Self-administered. online through a secure website 0 Telephone surveys facilitated by a trained interviewer from the Survey Coordinating Center using a computer-assisted telephone interviewing (CATI) program The survey will begin with screening questions to con?rm respondent eligibility to participate in the survey. Completion of the entire survey is expected to take approximately 20 minutes. The survey included in Appendix A is written to re?ect wording for both methods of survey administration: Intemet-based and telephone. All respondents who complete the survey and who provide their contact information will be mailed a $125 honorarium for their time. 4.1.1 Qualitative Research on the Survey The FDA provided feedback to the TRIG on the Knowledge. Attitudes and Behaviors Deleted: KAB survey results for prescribers included in the 12-month REMS Assessment results. The FDA requested that the TRIG investigate the causes for low correct response rates to speci?c questions in the survey by conducting research to determine the reasons for the poor performance on these questions. and to assess proposed revised wording to select questions. incorporated into the sun' ey and results ?orn the re\ ised sun ev ere included 111 the 24- month REMS Assessment Report. 4.1.2 ,Questions on REMS Goals 7 Deleted: Qualitative research was perfon'md with TheKAB'questionnaire is made up of multiple-choice. close-ended statements or questions who comm my: form . . . . . (the majority of use true/false or yes/no dichotomous response options). and one open- myihpmided ?1th ended question. These will evaluate current knowledge. attitudes. and behavior regarding the on 3 1? 7 of?! 10 targeted MSG/questions from . . . the 12-month TIRF Rm Assm 11 key risk messages noted in Section 3. Among a, prescribe-s mm the med ,0 provide a ??lrm-of-reference? for responding was ?eqnentfeetback haddi?onsmneofthe?nding suggest potential knowledg gap with respect to? of opioid toleranoe? - - Statements or questions askmg the respondent to mdrcate whether a statement or [cm I m? question rs true or false. or if they do not know the answer (there is a set of <#>Coutent pertaining" toCYP3A4inhibitors1] cs 9* u. as The 511m ?om this research MW bear statements and questions that use yes or no as potential response options). in: ted mun yin A The qualitative research report can be found in Appendix Questions will be presented in several formats: Statements or questions asking the respondent to choose from a de?ned list of possible . statements or answers: and Deleted: Knowledge, Attitudes mdBehaviom Deleted: 0 One question allowing for the respondent to list questions about the products or comments. Questionnaires will be analyzed to determine prescriber understanding of each key risk message. For statements or questions that use ?true? or ?yes? vs. ?false" or ?no" response options. the desired response for key risk messages is generally ?true" or ?yes" indicating knowledge of. or behavior in accordance with. the objectives of the REMS. However. some questions are formatted to have the respondent disagree with the statement as written by providing response options of ?false? or ?no? to avoid having the same af?rmative answer for all desired responses . REMS statements. corresponding questions. and desired responses covering the key risk messages are identi?ed below and can be found in the complete survey questionnaire (Appendix A). Kev Risk Message 1: TIRF medicines are contraindicated in opioid non-tolerant patients. Qulsitron Question Desired response Please select,Truejalse_ or} don?t know, for each of the fo lowing. According to the Deleted: 5 labeling for TIRF medicines. patients with cancer who are considered opioid-tolerant are Deleted: .. those: . . Deleted: Who are taking around-the-clock oprord therapy for 53 TRUE Deleted: underlying; canceg pain for one week or longer 5b Who are not currently taking opioid therapy. but have FALSE De'eted? taken opioid therapy before Deleted: chronic Who have no known contraindications to the drug 5e fentanyl. but are not currently taking around-the-clock FALSE opioid therapy 7 Please answerIruejalse. or} don?t know, for each statement based on the labeling for Deleted: TIRF medicines. Deleted: .. TIRF medicines are contraindicated in opioid non-tolerant Del . . . . . . eted. 7a patlents because life-threatemng respuatory depressron TRUE . could occur at any dose. Deleted' Death has occurred in opioid non-tolerant patients treated Deleted: 7b . TRUE some fentanyl products. 7c TIRF medicines may be used to treat opioid non-tolerant FALSE patients. Prescribers starting a patient on a TIRF medicine must 7d begin with titration from the lowest dose available for that TRUE speci?c product. even if the patient has previously taken another TIRF medicine. Key Risk Message 2: TIRF medicines are only indicated for the management of breakthrough pain in I adult cancer patients 18 years of age and older (16 years of age and older for Actiqko brand and generic equivalents) who are already receiving and who are tolerant to around-the-clock opioid therapy for their underlying; persistent cancer pain. Formatted: Superscript Deleted Qulflinon Question Desired response Deleted 9 In your practice. for which of the following indications do you prescribe IIRP medicines Deleted to opioid tolerant patients? Please or,I don?t know, for each option. 1% Deleted 9a Acute or postoperative pain N0 Deleted 9b Headache or migraine pain NO 9c Dental pain N0 9d Breakthrough pain from cancer YES 9e Chronic non-cancer pain NO 13b. Adult female with localized breast cancer: just The patients described are experiencing breakthrough pain. completed mastectomy and Accordmg to the labeling. a TIRF medicme is not appropriate for . 13 reconstructive one of them. Which patient should not receive a TIRF medicine? Please select one option. surgery: persistent cancer pain managed with 30 mg oral morphine daily for the past 6 weeks. Kev Risk Message 3: TIRF medicines contain fentanyl. an opioid agonist and a Schedule II-controlled substance. with abuse liability similar to other opioid analgesics. Qulelitlon Question Desired response 7 Please or} don?t knovs; for each statement based on the labeling for Deleted: TIRF medicines. Deleted: .. It is important to monitor for signs of abuse and addiction in . . . Del ted: 7e patients who take TIRF medicmes. TRUE Ie ed? 8 Which of the following are risk factors for opioid abuse? Please De et don?t know; for each option. Deleted: 83 A personal history of illness YES Deleted: 8b A personal history of past or current alcohol or drug abuse. or a YES Deleted: family history of illicit drug use or alcohol abuse Deleted: 10 Please answer?'ruej'alse, or,I don?t know, for each statement based on the labeling for Deleted: .. TIRF medicmes. Deleted- 10a TIRF medicmes can be abused in a manner smnlar to other TRUE Deleted: opioid agonists. Deleted: Kev Risk Message 4: TIRF medicines are not interchangeable with each other. regardless of route of Deleted: Deleted: Deleted: Deleted: Deleted: administration. Qulflihon Question Desired response 10 Please answerIruejalse. or} don?t know, for each statement based on the labeling for TIRF medicines. 10b TIRF medicmes are interchangeable With each other regardless FALSE of route of administration. 10? The conversron of one TIRF medicine for another TIRF TRUE medicine may result in a fatal overdose because of differences in MM Deleted: Deleted: Deleted: waww the pharmacokinetics of fentanyl absorption. Dosing of TIRF medicines is not equivalent on a microgram-to- 10d . . TRUE imcro gram ba515. 14b. The prescriber must not convert to another TIRF A patient is already taking a TIRF medicine but wants to change gigs-1:111:13? ar- their medicine. His/her doctor decides to prescribe a different . gr 56 . l4 TIRF medicine (that is not a bioequivalent generic version of a microgr am asis . . . . because these branded product) in its place. Accordmg to the labeling. how . . . medicmes have . 0 . should the prescriber proceed. Please select one option. different absorption properties and this could result in a fentanyl overdose. 4.1.3 Additional Questions The survey includes questions about the requirements of the TIRF REMS Access Program and receipt and understanding of the TIRF educational materials and the Patient-Prescriber Agreement Form. The following question about behaviors will be asked after the key risk message questions: Question 12: How frequently do you perform the following activities when prescribing TIRF medicines? Please answerAlways?nly with the ?rst prescriptionMSometimesaNever, or} don?t Deleted: know, Deleted: Ask patients (or their caregivers) about the presence of children in the home Deleted: Instruct patients (or their caregivers) not to share TIRF medicines with anyone else Deleted: Counsel patients (or their caregivers) that accidental exposure to TIRF medicines by a child may be Deleted- fatal Instruct patients (or their caregivers) to keep TIRF medicines out of the reach of children to prevent De'eted: accidental exposure Deleted: Instruct patients (or their caregivers) about proper disposal of any unused or partially used TIRF medicines Give patients (or their caregivers) the Medication Guide for their TIRF medicine Demographic information will be collected at the end of the survey. 4.2 Participant Recruitment A random sample of prescribers who are enrolled in the TIRF REMS Access Program will be invited to participate via an invitation letter. The text of the sample written invitation to prescribers can be found in Appendix B. If the required number of completed Sluveys is not achieved within the expected time?ame of approximately one to two weeks after the ?rst mailing. reminder letters will be sent to non-responders from the original sample with /[Deleted: respondents subsequent fax. e-mail. or United States (US) Mail follow-up to maximize participation. The distribution within the mailing to the second sample will be adjusted in accordance with the allocation in the original sample. If these efforts do not result in the required number of surveys within two to three weeks, then a new sample of prescribers will be randomly selected. All respondents who complete the survey and who provide their contact information will be mailed a $125 honorarium to thank them for their participation. Prescribers who practice in Vermont, Massachusetts, or Minnesota and complete the survey will not receive compensation. Participants will be informed that prescribers from these states are eligible to participate, but they will not receive compensation for their participation. The mailing will also include a Thank You Letter, a copy of the Important Safety Information (ISI), and a copy of the correct answers to key risk message questions. 4.2.1 Measures to Minimize Bias in the Sample The sample of prescribers who are invited to participate will be a random sample of all enrolled prescribers. The sample of participating prescribers will be self-selected since respondents will voluntarily respond to the invitation to participate; however, the survey recruitment strategies are intended to recruit a heterogeneous sample of prescribers for participation. Prescribers will be offered online or telephone options for completing the survey. Multiple modalities for survey data collection allow for wider survey access to a more heterogeneous population. Respondents will be provided a unique code during the recruitment process and will be asked to provide the unique code to gain access to the online survey or when calling the Survey Coordinating Center. The code will be deactivated after use to minimize the possibility for fraud. 5. STUDY POPULATION 5.1.1 Sample Size A sample of 300 healthcare providers who are enrolled in the TIRF REMS Access Program is proposed for each survey wave. The size of the sample was determined based on both practical and statistical considerations. There is no target comprehension rate specified a priori. A sample of 300 completed surveys will allow estimation of the comprehension rate for each risk message with a moderately high degree of precision. The table below shows the precision of the estimates for level of understanding using two-sided 95% confidence intervals (CIs) obtained with the sample size of 300 completed surveys. The noted CIs are used to indicate that for any survey-estimated rate of understanding, the true population rate of understanding is at least as high as the lower limit of the 95% CI and may be as high as the upper limit of the 95% CI. Table 5.1: Precision of Estimated Rates of Understanding with a Sample Size of 300 Estimated Rate of Understanding Estimated Confidence Interval FDA_2589 5% 2.8% 8.1% 10% 6.8% 14.0% 15% 11.2% 19.6% 20% 15.6% 25.0% 25% 20.2% 30.3% 30% 24.9% 35.5% 35% 29.6% 40.7% 40% 34.4% 45.8% 45% 39.3% 50.8% 50% 44.2% 55.8% 55% 49.2% 60.7% 60% 54.2% 65.6% 65% 59.3% 70.4% 70% 64.5% 75.1% 75% 69.7% 79.8% 80% 75.0% 84.4% 85% 80.4% 88.8% 90% 86.0% 93.2% 95% 91.9% 97.2% 5.1.2 Inclusion Criteria All prescribers who are enrolled in the TIRE REMS Access Program are eligible to participate in this survey. with the exceptions noted below. 5.1.3 Exclusion Criteria The following respondents are not eligible to participate in the surveys: Prescribers who have previously participated in the TIRF REMS KAB survey 0 Prescribers or their immediate family members who have ever worked for ever worked for Anesta LLC;Cephalon. Inc. (a wholly-owned subsidiary of _Teva Pharmaceutical Deleted: ,AxchimedesPhanm US Inc; Industries. Ltd); De omed Inc.; Galena Biopharma. Inc.? Insys Therapeutics: Deleted: EndoPharmaceuticals Mallinckrodt Pharmaceuticals: Meda Pharmaceuticals: Mylan. Inc.: Par Deleted? Phannaceutical. Inc.;Teva Pharmaceuticals. Ltd.; UBC: McKesson Specialty Care A Dem?: Solutions: RelayHealth: or the FDA. 6. SURVEY PROCESS The survey will begin with screening questions to con?rm respondent eligibility to participate in the survey. Completion of the entire survey is expected to take approximately 20 minutes. 6.1 Screening and Survey Administration The questionnaire will begin with a screening module with questions to con?rm prescriber eligibility. Depending on the answers to the screening questions. survey participation could either be terminated or continued. If ineligible. the respondent is immediately noti?ed with a ?thank you? message that survey participation has ended. If eligible. the respondent is allowed to continue survey participation. The data entry system used for both methods of survey administration has been validated and is secure for receiving and storing survey data. The system is 21 CFR Part 11 and Health Insurance Portability and Accountability Act (HIPAA) compliant. Prescriber-identifying information will be stored separately from survey data. 6.1.1 Telephone A trained interviewer from the Survey Coordinating Center Will conduct the telephone interviews using a CATI program. The screening and main elements of the questionnaire will be administered sequentially during the same telephone call. Telephone interviewing allows participation of prescribers who do not have Internet access. It will also be convenient for prescribers to participate since they can call in and be interviewed at their convenience during the speci?ed time period when the Survey Coordinating Center is available. 6.1.2 Internet An Intemet-based survey system will also be used for conducting the KAB surveys. If the prescriber selects to participate in the survey online. he/she will be directed to a secured website to complete screening questions. An Internet survey will be convenient for respondents to participate since they can complete the questionnaire at any time. 6.2 Measures to Minimize Bias in the Survey Process A number of controls will be in place to ensure the survey is conducted in a controlled and professional manner and to minimize bias. For example. a unique code will be given to each survey participant and the code will be inactivated a?er use to minimize fraud. Telephone interviewers are highly trained and use a standardized script to administer the survey, Deleted: interviews All questions will be programmed to ensure that questions are asked in the appropriate sequence. Skip patterns will be clearly indicated. Respondents cannot go back to a question once the question has been answered and cannot skip ahead. All questions must be answered in order to complete the survey. Response options presented in a list will be randomized to minimize positional bias. Programming will be reviewed by quality control and simulated users (User Acceptance Testing) prior to implementing the survey. 7. ANALYSIS Information obtained from the survey will be reported as descriptive statistics for the survey administration. study population. and the survey questions. The data from the sample population will be reported using frequency distributions of responses to all questions. The following will be reported as part of this analysis: • The number of invitations issued to prescribers • The number of reminder letters • The number of respondents screened for participation • The number of respondents eligible for participation • The number of respondents eligible for participation who complete the survey • Representativeness of prescribers based on geography • Description of survey participants, including: − Gender − Medical degree of respondent: MD, DO, NP, PA − Medical specialty − Years of professional experience − How many times per month TIRF medicines prescribed in the last 6 months − Geographic region of practice Additional descriptive statistics may be reported as appropriate. 7.1.1 Analysis Population The analysis population will be based on eligible prescribers who completed all questions presented to them in the survey (“completers”). 7.1.2 Description of Primary Analyses Primary analyses are done for all key risk messages using data from all completers. The primary analysis for a key risk message evaluates the rate for each correct response to each individual question/item defined by the key risk message. The specific correct response to each question/item is identified in the body of the risk message table. 7.1.3 Description of Secondary Analyses Secondary analyses are done only for those key risk messages that contain multiple questions/items using data from all completers. The secondary analysis entails a frequency distribution of the number of respondents who got 0, 1, etc. correct responses across the total number of items for the given key risk message. FDA_2592 8. SAFETY EVENT REPORTING The term ?Safety Event? is de?ned as any information reported by a survey respondent that meets the criteria of an adverse event or product complaint. While it is not the intention of the survey to solicit the report of information that meets the criteria of a Safety Event. it is possible that a respondent may spontaneously report information that meets this criteria in free text ?elds of the survey (Intemet-based administration) or while in conversation with the Survey Coordinating Center (telephone-based administration). The Intemet-based questionnaires will be monitored for any comments recorded in the free text ?elds. If an event is mentioned to a Survey Coordinating Center Associate. the Associate will document the safety event and the respondent?s contact information. Respondents will also be informed that a representative ?om the appropriate TIRF medicine manufacturer may contact them if there are questions about the survey. Information on all reports (Internet or telephone) that may constitute an adverse event or other safety event will be forwarded to the appropriate TIRF medicine manufacturer as described in the Safety Event Project Speci?c Procedure Deleted: Additional detail regarding processes for adverse event reporting will be speci?ed in the SE Deleted: 9. PRIVACY PROTECTION AND CONFIDENTIALITY All data collected during the survey will be held con?dential. The electronic data capture (EDC) system used for data collection all identi?able information. and respondent identi?ers are stored separately from the survey responses. Respondent names and addresses are collected in order to mail the $125 honorarium. a Thank You Letter. the correct responses to key risk messages. and the 181 after the survey is completed. Respondent contact information is also requested when necessary to comply with a federal or state law or regulation. including without limitation. reporting payments made to physicians under the federal physician payment sunshine provisions in addition to instances where a safety event is reported and a TIRF medicine manufacturer must obtain follow-up information (see Section 8 above). Respondents will be informed when they access the survey that they may be contacted if there are any questions about their survey responses. Respondents will be informed that their answers to the survey questions will not affect their ability to prescribe TIRF medicines. Appendix A Prescriber Questionnaire Survey Legend is used to indicate directions to the programmer and is set in bold. red. uppercase letters between square brackets. (INTERVIEVVER) is used to indicate directions to the telephone interviewer and is set in bold. blue. text between parentheses. This text appears when content is to be administered by telephone only (for example. spontaneous adverse event reporting). 0 indicates a question is worded speci?cally for administering the survey online. indicates a question is worded speci?cally to be read by a telephone interviewer and differs from the online text. 0 SURVEY and SURVEY are used to indicate to the programmer the type of survey administration and the beginning and end of the survey or sections within the survey content. for example. GIN ADVERSE and ADVERSE is displayed next to responses that should cause the survey to end. The following termination language will be programmed into the survey or read by the interviewer unless different language is speci?ed with the question. hank you very much for your time today. Based on your answer, you are not eligible to take this survey. We appreciate your interest in the survey. 0 is inserted before questions to indicate to the programmer that the responses should be randomized. Responses such as don?t know." ?Prefer not to answer" or ?None of the above" will always appear at the end of the randomized responses. 0 TO Qx] (skip logic) is inserted after a response to indicate to the programmer that the survey should skip to the indicated question (for example. TO skips to question 17). Ifno skip logic is indicated the survey continues to the next question in the sequence. 0 indicates to the programmer that one line should be provided for data indicates to the programmer that multiple lines should be provided for data entry (for example. two address lines). Deleted: or a Mm) Survey Legend • [DROP-DOWN LIST INPUT WITH STATES TABLE] indicates to the programmer that the response should be a drop-down list containing the states and US territories in the table below. Alabama Georgia Massachusetts New York Tennessee Alaska Guam Michigan North Carolina Texas American Samoa Hawaii Minnesota North Dakota Idaho Mississippi US Virgin Islands Arizona Illinois Missouri Arkansas Indiana Montana Northern Mariana Islands California Colorado Connecticut Delaware District of Columbia Florida Iowa Kansas Kentucky Louisiana Maine Maryland Nebraska Nevada New Hampshire New Jersey New Mexico Utah Vermont Ohio Virginia Oklahoma Washington Oregon West Virginia Pennsylvania Wisconsin Puerto Rico Wyoming Rhode Island South Carolina South Dakota • The following is used to categorize survey populations into standard geographic regions but it is not displayed in the survey. Geographic Distribution (based on address) 1: Northeast, Midwest, South, and West regions Northeast Region − New England Division - ME, NH, VT, MA, RI, CT − Middle Atlantic Division - NY, NJ, PA Midwest Region − East North Central Division - OH, IN, IL, MI, WI − West North Central Division - MN, IA, MO, ND, SD, NE, KS South Region − South Atlantic Division - DE, MD, DC, VA, WV, NC, SC, GA, FL − East South Central Division - KY, TN, AL, MS − West South Central Division - AR, LA, OK, TX FDA_2595 Survey Legend West − Mountain Division - MT, ID, WY, CO, NM, AZ, UT, NV − Pacific Division WA, OR, CA, AK, HI • The following US territories are categorized as Other: Puerto Rico, Northern Mariana Islands, US Virgin Islands, American Samoa, and Guam. 1 U.S. Census Bureau, last revised Friday, 27-Jul-2001 12:59:43 EDT. FDA_2596 SURVEY PREANIBLE 1] Before you begin. we would like to share some important information about this survey. The manufacturers of Transmucosal Immediate Release Fentanyl (TIRF) medicines are conducting this survey. as required by the FDA. to assess prescribers? understanding of the safe use and prescribing of these medicines. These medicines are known as rapid onset opioids and referred to in this survey as medicines.? The TIRF medicines include Abstralf?. Actiq?. Formatted: Superscript FentoraQ. LazandaP. Onsolisf?. Subsys?g. and generic versions of any of these brands. The Formatted: Superscript manufacturers of these medicines include'Cephalon. Inc. (a wholly-owned subsidiary of Teva Mama; WWI Pharmaceutical Industries. Ltd.): Depomed_Inc.: Galena Biopharma. Inc:l Insys Therapeutics; Matted: Wript Mallinckrodt Pharmaceuticals: Meda Pharmaceuticals: Mylan. Inc.: and Par Pharmaceutical. . Formatted: Stperscr'pt Inc. The survey Will take approxrmately 20 minutes. Formatted: Stperscr'pt There are no known risks to you in taking this survey. You may refuse to take part or Deleted: US In?; withdraw at any time. Your answers to the questions or your decision to take part in the De'eted? Em? ?mm? survey will not affect your ability to prescribe TIRF medicines. How \Ve Use Your Information Your answers to the survey questions will be combined with answers given by other healthcare professionals taking the survey. All answers will be put together and reported in anonymous form to the manufacturers of TIRF medicines. Your name will not be used in any report. If you are eligible to take the survey. complete all the questions. and provide your contact information, you will receive a $125 honorarium for your time and participation. This compensation represents the fair value for your services in connection with completion of the survey. The amount of the compensation was not determined in any manner that takes into account the volume or value of any referrals or business otherwise generated by you. Your name and address will be used to send you the honorarium after you complete the survey. Your personal information will also be used if we have questions about your survey or if we are required to use your information to comply with a federal or state law or regulation. including without limitation. reporting payments made to physicians under the federal physician payment s1mshine provisions. Physicians who practice in Vermont. Massachusetts. or Minnesota should be aware that they will not be permitted to receive payment for survey completion and may elect not to complete the survey. Providing a telephone number is optional. Your telephone number will be used only if there are any questions about your survey responses. How \Ve Protect Your Privacy We respect that the privacy of your personal information is important to you. You will not be contacted for marketing purposes based on your personal information or your answers to the survey. Neither the manufacturers of TIRF medicines nor their contractors will sell. transfer. or rent your information. Your answers will be kept strictly con?dential. Your personal information will not be used in a manner inconsistent with this document. Your privacy will be protected; however, research survey records may be inspected by the FDA. Your choice to allow manufacturers of TIRF medicines to use your information is entirely voluntary but necessary to take part in this survey. How to Learn More about This Survey If you have questions about the survey, or problems with the survey, please contact the Survey Coordinating Center at 1-877-379-3297. Be sure to write down this telephone number; it will not be displayed again. Taking the Survey Once you have answered a question and moved on, you cannot go back and change your answers. Thank you for your participation in this survey. [END ONLINE PREAMBLE 1] FDA_2598 1] Before you begin. we would like to share some important information about this survey. The manufacturers of Transmucosal Immediate Release Fentanyl medicines are conducting this survey. as required by the FDA. to assess prescribers? understanding of the safe use and prescribing of these medicines. These medicines are known as rapid onset opioids and referred to in this survey as medicines.? (INTERVIEVVER: Say then spell out The TIRE medicines include AbstralP. Actiqo. FentoraP. Lazanda?. OnsolisP. Formatted: Superscript and generic versions of any of these brands. The manufacturers of these medicines include Formatted: Superscript ,Cephalon. Inc. (a wholly-owned subsidiary of Teva Pharmaceutical Industries. Matted: Writ omed Inc.: Galena Bio harma. Inc.? In Thera eutics; Mallinckrodt Matted. Superscript Pharmaceuticals: Meda Pharmaceuticals: Mylan. Inc: and Par Pharmaceutical. Inc. The survey Matted: will take approximately 20 minutes. mm ?pt Deleted:AmhimedsPhannaUSInc; There are no known risks to you in taking this survey. You may refuse to take part or withdraw at any time. Your answers to the questions or your decision to take part in the mmw?m?ls survey will not affect your ability to prescribe TIRF medicines. Deleted: Now I would like to read some information about how your contact information will be used. Your answers to the survey questions will be combined with answers given by other healthcare professionals taking the survey. All answers will be put together and reported in anonymous form to the manufacturers of TIRF medicines. Your name will not be used in any report. If you are eligible to take the survey. complete all the questions. and provide your contact information. you will receive a $125 honorarium for your time and participation. This compensation represents the fair value for your services in connection with completion of the survey. The amormt of the compensation was not determined in any manner that takes into account the volume or value of any referrals or business otherwise generated by you. Your name and address will be used to send you the honorarium after you complete the survey. Your personal information will also be used if we have questions about your survey or if we are required to use your information to comply with a federal or state law or regulation. including without limitation. reporting payments made to physicians under the federal physician payment sunshine provisions. Physicians who practice in Vermont. Massachusetts. or Minnesota should be aware that they will not be permitted to receive payment for survey completion and may elect not to complete the survey. Providing a telephone number is optional. Your telephone number will be used only if there are any questions about your survey responses. Now I would like to tell you some information about how we protect your privacy. We respect that the privacy of your personal information is important to you. You will not be contacted for marketing purposes based on your personal information or your answers to the survey. Neither the manufacturers of TIRF medicines nor their contractors will sell. transfer. or rent your information. Your answers will be kept strictly con?dential. Your personal information will not be used in a manner inconsistent with this document. Your privacy will be protected: however. research survey records may be inspected by the FDA. Your choice to allow manufacturers of TIRF medicines to use your information is entirely voluntary but necessary to take part in this survey. Now I will tell you how you can learn more about this survey. Please have a pen or pencil ready to write down a telephone number you can call i_?you have any questions about the Deleted: should survey. If you have questions about the survey. please ask me at any time. If you have questions at a later time. please contact the Survey Coordinating Center at 1-877-3 79-3297. Please feel free to ask me to repeat any questions or statements as we go through the survey. Once you have answered a question and moved on. ?cannot go back and change your Deleted: you answers. Thank you for your participation in this survey. PHONE PREAIVIBLE l] INC LUSION QUE Your agreement to participate in this survey con?rms mutual understanding in connection with completion of the survey and the fair market value of the payment to be rendered in connection with those services. Do you agree to participate in this survey? 0 Yes 0 N0 2 Have you ever taken part in this survey about TIRF medicines before? TIRF I medicines include Abstralf, Actiq?, FentoraP, LazandaP, OnsolisP, and generic versions of any of these brands. I 0 Yes LTERMINATFJ 0 No I I don?t know LTERMINATEJ 3. Are you enrolled in the TIRF REMS Access Program? Formatted: Stpersa'pt Formatted: Stperscr'pt Formatted: Stpersa'pt Formatted: Stpersa?pt Formatted: Stpersa'pt Formatted: Stperscr'pt Deleted: ONLY Deleted: AFTER WAVE 1 Deleted: ONLY KM Deleted: WAVE 0 Yes 0 No I don?t know 4. Have you or any of your immediate family members ever worked for any of the following companies or agencies? Please select all that apply. Anesta LLC El Cephalon, Inc. (a wholly-owned subsidiary of Teva Pharmaceutical Industries, Ltd.) Deleted: 110m Deleted: 11 Deleted: Endo Phannaoeuticals Whip A Galena Biopharma. Inc. Insys Therapeutics Formatted: Font: 13 pt, Englidi (U.S.) Mallinckrodt Pharmaceuticals McKesson Specialty Care Solutions Meda Pharmaceuticals Mylan. Inc. Par Pharmaceutical, Inc. RelayHealth Deleted: Teva Pharmaceuticals, Ltd. United BioSource Corporation FDA El None of these apply SELECTED IN ADDITION TO OTHER RESPONSES, I don?t know Prefer not to answer 5a. 5b. 5c. 63. 6b. Deleted: Please selectiruejalse, orJ don?t know for each of the following. Deleted: According to the labeling for TIRF medicines, patients with cancer who are considered Deleted: oprord-tolerant are those: Deleted: .. True False I don?t De'eted= know Who are taking around-the-clock opioid therapy for underlying; persistent cancer. pain for one week or longer 0 Deleted: chronic Who are not currently taking opioid therapy. but have taken opioid therapy before 0 0 Who have no known contraindications to the drug fentanyl. but are not currently taking around-the-clock opioid therapy Please answerIruejalse, orJ don?t know, for each statement based on the labeling for Deleted: TIRF medicines. Deleted: .. Deleted: True False I don?t Deleted: .. know Deleted: A cancer patient can be started on a TIRF medicine and an around-the-clock opioid at the same time. 0 A cancer patient who has been on an around-the?clock opioid for 1 day can start taking a TIRF medicine for breakthrough pain. 7a. 7b. 7c. 7d. 7e. 8a. 8b. 8c. Please answerJruejalse. or} don?t know, for each statement based on the labeling for Deleted: .. TIRF medicines. ?ne'eted: Deleted: True False I don?t Deleted: .. know Deleted: TIRF medicines are contraindicated in opioid non- tolerant patients because life-threatening respiratory depression could occur at any dose. Death has occurred in opioid non-tolerant patients treated with some fentanyl products. 0 TIRF medicines may be used to treat opioid non-tolerant patients. 0 Prescribers starting a patient on a TIRF medicine must begin with titration from the lowest dose available for that speci?c product. even if the patient has previously 0 0 taken another TIRF medicine. It is important to monitor for signs of abuse and addiction in patients who take TIRF medicines. Deleted: don?t know for each option. De'eted? Deleted: Yes Deleted: .. Deleted: A personal history of illness 0 A personal history of past or current alcohol or drug abuse. or a family history of illicit drug use or alcohol 0 abuse A family history of asthma 9a. 9b. 9c. 9d. 9e. 10. 10a. 10b. 10c. 10d. 11. 11a. 11b. 11c. 11d. lle. 11f. In your practice. for which of the following indications do you prescribe TIRF medicines to opioid tolerant patients? Please answer'YesHNo. or} don?t know, for each Deleted: option. Deleted; Del ted: Yes No I don?t know Deleted: Deleted: Acute or postoperative pain 0 Headache or migraine pain 0 0 Dental pain 0 Breakthrough pain from cancer 0 0 Chronic non-cancer pain 0 Please answeriruejalse. orJ don?t know for each statement based on the labeling for Deleted: .. TIRF medicines. Deleted: Deleted: True False I don?t Deleted: .. know Deleted: TIRF medicines can be abused in a manner similar to other opioid agonists. TIRF medicines are interchangeable with each other 0 regardless of route of administration. The conversion of one TIRF medicine for another TIRF medicine may result in a fatal overdose because of differences in the pharmacokinetics of fentanyl absorption. Dosing of TIRF medicines is not equivalent on a microgram- to-microgram basis. Please selectJrueJalse, or} don?t know for each of the following. According to the /[Deleted: .. labeling for TIRF medicines. patients considered opioid-tolerant are those who are ?elem: taking, for one week or longer. at least: Deleted: Deleted: True False I don?t Deleted: know 8 mg oral hydromorphone/day 60 mg oral morphine/day 30 mg oral oxycodone/day 25 transdermal fentanyl/hour 25 mg oral oxymorphone/day 0 An equianalgesic dose of another oral opioid 12. 12a. 12b. 12c. 12d. 12e. 12f. How frequently do you perform the following activities when prescribing TIRF medicines? Please answerAlwayshOnly with the ?rst prescription}ometimes?ever. or/[ Deleted: I don?t know; Deleted: Deleted: Always Only with Sometimes Never I don?t the first know prescription Deleted: Deleted: Deleted: Ask patients (or their caregivers) about the presence 0 0 Deleted: of children in the home Instruct patients (or their caregivers) not to share TIRF medicines with anyone else Counsel patients (or their caregivers) that accidental exposure to TIRF medicines by a child may be fatal Instruct patients (or their caregivers) to keep TIRF medicines out of the reach of 0 children to prevent accidental exposure Instruct patients (or their caregivers) about proper disposal of any unused or partially used TIRF medicines Give patients (or their caregivers) the Medication Guide for their TIRF medicine 13. 13a. 13b. 13c. 13d. l3e. 14. 14a. 14b. 14c. 14d. Me. The patients described are experiencing breakthrough pain. According to the labeling. a TIRF medicine is not appropriate for one of them. Which patient should not receive a TIRF medicine? Deleted: Please select one option 0 Adult male with advanced 11mg cancer: lmderlying persistent cancer pain managed with 25 meg/hour transdermal fentanyl patches for the past two months. 0 Adult female with localized breast cancer; just completed a mastectomy and reconstructive surgery: persistent cancer pain managed with 30 mg oral morphine daily for the past 6 weeks. 0 Adult male patient with advanced prostate cancer who. over the last 2 weeks. has been prescribed 100 mg oral morphine daily for pain due to bone metastasis. 0 Adult female with advanced sarcoma who has been taking a daily dose of 12 mg oral hydromorphone for the last 3 weeks. 0 I don?t know A patient is already taking a TIRF medicine but wants to change their medicine. His/her doctor decides to prescribe a different TIRF medicine (that is not a bioequivalent generic version of a branded product) in its place. According to the labeling. how should the prescriber proceed? Please select one option. The prescriber can safely convert to the equivalent dosage of the new TIRF medicine as it has the same effect as other TIRF medicines. The prescriber must not convert to another TIRF medicine on a microgram-per- 0 microgram basis because these medicines have different absorption properties and this could result in a fentanyl overdose. Convert from the other TIRF medicine to the new TIRF medicine at half of the dose. The prescriber should base the starting dose of the newly-prescribed TIRF 0 medicine on the dose of the opioid medicine used for their underlying persistent cancer pain. 0 I don?t know; 15. A patient is starting titration with a TIRF medicine. What dose must they start with? Please select one option. [RANDOMIZE LIST] 15a. ○ 15b. ○ 15c. ○ 15d. 15e. ○ ○ 16. A prescriber has started titrating a patient with the lowest dose of a TIRF medicine. However, after 30 minutes the breakthrough pain has not been sufficiently relieved. What should they advise the patient to do? Please pick the best option of the scenarios described. [RANDOMIZE LIST] 16a. 16b. 16c. ○ ○ 16d. 16e. ○ ○ 17. 17a. 17b. An appropriate dose based on the dose of the opioid medicine used for underlying persistent cancer pain. The dose that the prescriber believes is appropriate based on their clinical experience. The lowest available dose, unless individual product Full Prescribing Information provides product-specific guidance. The median available dose. I don’t know. ○ Take another (identical) dose of the TIRF medicine immediately. Take a dose of an alternative rescue medicine. Provide guidance based on the product-specific Medication Guide because the instructions are not the same for all TIRF medicines. Double the dose and take immediately. I don’t know. A patient is taking a TIRF medicine and the doctor would like to prescribe erythromycin, a CYP3A4 inhibitor. Please pick the best option of the scenarios described. [RANDOMIZE LIST] ○ ○ 17c. ○ 17d. ○ 17e. ○ The patient can’t be prescribed erythromycin, because using it at the same time as a TIRF medicine could be fatal. Use of a TIRF medicine with a CYP3A4 inhibitor may require a dosage adjustment; carefully monitor the patient for opioid toxicity, otherwise such use may cause potentially fatal respiratory depression. There is no possible drug interaction between CYP3A4 inhibitors and TIRF medicines. The dose of the TIRF medicine must be reduced by one half if a CYP3A4 inhibitor is prescribed in the same patient. I don’t know. FDA_2608 Before initiating treatment with a TIRF medicine, prescribers must review the 18. Medication Guide with the patient. Please selectIrueJalse, or,I don?t know for each Deleted: of the following counseling statements. Deleted: True False I don?t Dehmd? know Deleted: 18a. TIRF medicines contain fentanyl in an amount that Deleted: could be fatal to children of all ages. in individuals for whom they were not prescribed, and in those who are not opioid tolerant. 18b. Inform patients that TIRF medicines must not be used for acute or postoperative pain. pain ?om injuries, headache/migraine. or any other short-term pain. 18c. Instruct patients that. if they stop taking their around- the-clock opioid medicine. they can continue to take 0 0 their TIRF medicine. 18d. Instruct patients to never share their TIRF medicine with anyone else. even if that person has the same 19. Can patients continue to take their TIRF medicine if they stop taking their around-the- clock opioid medicinedon?t know 2] The next set of questions is about the educational materials for TIRF medicines and the TIRF Patient-Prescriber Agreement. As a reminder. the TIRF medicines include AbstralP, Actqu. Formatted: Superscript FentoraQ. LazandaP. OnsolisP. and generic versions of any of these brands. Formatted: Superscript Formatted: Superscript 20. Did you receive or do you have access to the Full Prescribing Information for the Formatted: Superscript TIRF medicine(s) that you prescribe? Formatted: Superscript 0 Yes Formatted: Superscript No TO 0 I don?t know TO 21. Did you read the Full Prescribing Information for the TIRF medicine(s) that you prescribedon?t know 22. Did you receive or do you have access to the Medication Guide for the TIRF medicine(s) that you prescribedon?t know TO 23. Did you read the Medication Guide for the medicine(s) that you prescribedon?t know 24. Did you or do you have any questions about the information in the Full Prescribing Information or Medication Guidedon?t know TO /[De eted= 0] 25. What are your questions? 0 26. 27. 28. Do you review the Patient-Prescriber Agreement Form with each of your patients for whom you prescribe TIRF medicines or their caregiver? ○ Yes ○ No [GO TO Q28] ○ I don’t know [GO TO Q28] Do you and the patient or their caregiver sign the Patient-Prescriber Agreement Form for TIRF medicines after you have reviewed it with him/her? ○ Yes ○ No ○ I don’t know Do you give a copy of the Patient-Prescriber Agreement Form for TIRF medicines to the patient or their caregiver? ○ Yes ○ No ○ I don’t know [DEMOGRAPHICS PREAMBLE 1] There are just a few more questions to help us combine your answers with other answers we have received. 29. On average, how many times per month have you prescribed the TIRF medicines within the last 6 months? ○ None [GO TO DEMOGRAPHICS PREAMBLE 2] ○ 1 – 2 times per month ○ 3 – 5 times per month ○ More than 5 times per month ○ I don’t remember FDA_2611 30. Please select the TIRF medicines that you have prescribed within the last 6 months; Please .select all that apply, Abstral? Actqu or generic ActiqO Font: Engish (U.S.), Font: Engish (U.S.), Superscr'pt Font: Engish (U.S.), Supersath Font: Engish (U.S.), Supersa'pt Font: Engish (U.S.), Superscr'pt Font: Engish (U.S.), Supel'sa'pt Fentora? Lazanda?O Onsolis:a Subsygo Font: Engish (U.S.), Supersa?pt PREAIVIBLE 2] These last few questions are for demographic purposes. 31. What is your gender? 0 Male 0 Female 0 Prefer not to answer 32. What is your medical degree? 0 MD 0 D0 0 Nurse Practitioner 0 Physician Assistant 0 Prefer not to answer 2 33. In total. how many years have you been practicing medicine, since completing your education? 0 Less than 3 years 0 3 5 years 0 6 10 years 0 ll 15 years 0 More than 15 years 0 Prefer not to answer 34. In which state do you practice? LIST INPUT WITH STATES TABLE WITH ?Prefer not to answer? at 35. What is your medical specialty? 0 Oncology Primary care Pain management Other (please specify): TEXTL No designated specialty ONLY: BEGIN ADVERSE (INTERVIEVVER: Please record if respondent spontaneously reported an adverse event or product complaint during the course of this interview.) 0 Yes 0 No TO CLOSING 1] Enter Safety Adverse Event Verbatim 3 (INTERVIEWER: Indicate to the respondent that someone may call back to ask more questions about the adverse event or product complaint that was reported.) ADVERSE 1] )Ve would like to send you a $125 honorarium within the next few weeks to thank you Formatted: Font: Bold for your time, but we need your name and address to do so. If you do not provide your name and address you will not receive the honorarium for your time and participation in the survey. As a reminder, physicians who practice in Vermont, Massachusetts, or Minnesota should be aware that they will not be permitted to receive payment for survey completion. Do you agree to give us your name and mailing address so we can send you the honorarium? 0 Yes 0 No T0 CLOSING 2] FRST NAME: /[Deleted: LAST NAME: TEXTL Formatted: Deleted: ADDRESS: CITY: TEXTL /[Deleted: STATE: LIST INPUT STATES ZIP: [5 NUIVIERIC CHARACTERS ONLYL Formatted: Font color: Red 2] \Ve would also like to ask for your telephone number. Providing your telephone number is optional and it will be used to contact you only if there are questions about your survey responses. 'Do you want to provide your telephone number? Deleted: 0 Yes Formatted: No bullets or numbering N0 TO CLOSING 3] 4 I ted: Telephone: BE NUNIERIC CHARACTERSL Dee CLOSING 2] 3] That ends the survey. Thank you again for your help. OF SURVEY 5 Appendix SAMPLE Prescriber Invitation Letter Dear You were selected to receive this letter because you have enrolled in the TIRF REMS Access Program. We are contacting you to invite you to participate in a survey being conducted by the manufacturers of Transmucosal Immediate Release Fentanyl (TIRE) medicines. as required by the Food and Drug Administration (FDA). The purpose of the survey is to assess prescribers? understandin of the safe and appropriate use of these medicines. The TIRF medicines include Abstra 0. 0. Lazandao. Onsolisf. and generic versions of any of these brands. Formatted: Stperscr'pt Formatted: Stperscr'pt Formatted: Stperscr'pt Deleted: Formatted: Stperscr'pt Formatted: Stperscr'pt Deleted: Archimedes Pharma US Inc Deleted: Endo Phanmceuu?cals The manufacturers of TIRF medicines (collectively referred to as the REMS Industry Group?) include ,Cephalon. Inc. (a wholly-owned subsidiary of Teva Pharmaceutical Industries. Ltd.); Depomed. Inc.: Galena Biopharma. Ines. Insys Therapeutics: Mallinckrodt Pharmaceuticals: Meda Pharmaceuticals: Mylan. Inc.. and Par Pharmaceutical. Inc. These manufacturers are looking for 300 prescribers to complete the survey. Eligible prescribers who complete the survey will be sent a $125 honorarium to thank them for their time. The survey will take 15-20 minutes. Deleted: Your answers will be kept strictly con?dential and will be combined with the answers from other prescribers who take this survey. Your name will not be used in the report of this survey and your contact infomlation will only be used to send you a $125 honorarium for the time you took to complete the survey and if required to comply with a federal or state law or regulation. including without limitation. reporting payments made to physicians under the federal physician payment sunshine provisions. Prescribers who practice in Vermont. Massachusetts. or Minnesota should be aware that they will not be permitted to receive payment for survey completion and may elect not to complete the survey. You are under no obligation to participate in this survey. Ifyou are interested in participating. go to anytime or call 1-877-379-3297, 8AM to 8PM Eastern Time Monday through Friday. You will be asked to give this unique code prior to starting the survey: lease have this letter with 011 at the time 011 take the sm've . Thank ou in advance for our hel Moved (insertion) . . ii Moved (insertion) We recommend that you take the survey on a desktop or laptop computer. Taking the survey on Deleted: TIRF REMS Industry mobile devices. such as smart phones. tablets. and e-notebooks. is not supported. Moved up Pleasehave this letterwithyonat thetimeywtakethestmy 'I?hankyouinadvance . Deleted ?Page Break Appendix Qualitative Research Report?I 6 A The TIRF REMS Survey Team 1-877-3 79-3297 wuwIIRFREMSsun'eycom Moved up mm Fonnatted: Font: 14 pt, Bold Formatted: Space Afbet: 0 pt, Une spacing: single 7 Accenture LLP 1160 West Swedesford Road Berwyn, PA 19312 August 20, 2015 Food and Drug Administration Center for Drug Evaluation and Research Central Document Room Drug Master File Staff 590l?B Ammendale Road Beltsville, MD 20705-1266 Re: DMF 027320 Holder: McKesson Specialty Health (McKesson) DMF Subject: Transmucosal Immediate Release Fentanyl (T IRF) Access Program Re: REMS Shared Program DMF Type: DMF Submission Information: DMF Annual Report REMS Submission Identi?er: Not Applicable Sequence Number: 0017 Dear Drug Master File Staff: This Type DMF contains the Risk Evaluation and Mitigation Strategy (REMS) for Transmucosal Immediate Release Fentanyl for the Shared System REMS program. Reference is made to the above DMF, which was initially submitted on August 20, 2013. Enclosed, please ?nd the DMF Annual Report (Reporting Period: August 21, 2014 August 20, 20 5). The Annual Report includes an administrative information page, a summary of the amendments that have been submitted during this reporting period, and a list of authorized persons to incorporate by reference. McKesson states that information provided in this Master File is current and assures that the material furnished will meet the speci?cations described herein. McKesson also con?rms that the Holder obligations are observed. We request that all information in this ?le be treated as con?dential commercial information to the Food and Drug Administration pursuant to 21 CPR. ?20.61, and that no information from this ?le be provided to any unauthorized persons Without written consent. If you have any questions or concerns, please do not hesitate to contact Jann Kochel, US. Agent for McKesson, at 610?407-1738 or alternatively via email at jann.a.kochel@accenture.com. Sincerely, angels/Q Jann A. Kochel, US. Agent Accenture, LLP Attachments: Table of Contents for the submission Electronic Submission Speci?cations 8 DMF #027320; Sequence 0017 Shared System REMS Table of Contents Page 1 of 1 ANNUAL REPORT Reporting Period: August 21, 2014 – August 20, 2015 Module Section Description 1.2 Cover Letter Cover Letter w/ Attachments 1.11.3 – Efficacy Information Amendment Annual Report - Summary of Changes 1.4.3 – List of Authorized Persons to Incorporate by Reference List of Authorized Persons FDA_2619 Electronic Submission Specifications This submission is compliant with FDA's Guideline for Industry: Providing Regulatory Submissions in Electronic Format - Human Pharmaceutical Product Applications and Related Submissions Using the eCTD Specifications (June 2008). All files were checked and verified to be free of viruses prior to transmission through the electronic submission gateway. This eCTD has been generated by Accenture, LLP (formerly Octagon Research Solutions Inc.), who has filed an acceptable eCTD pilot with the Center (Pilot Number 900777). Anti-Virus Program Program Version Virus Definition Date Submission Size Symantec Endpoint Protection Edition 11.0.5002.333 8/16/2015 rev. 21 Approx. 1 MB The IT point of contact for this submission is: Name Phone Number Email Address Matt Francis 1-610-407-1854 Matthew.p.francis@accenture.com FDA_2620 ADMINISTRATIVE INFORMATION Holder’s Name: McKesson Specialty Health Holder’s Address: 4343 N. Scottsdale Road Suite 150 Scottsdale, AZ 85251 Holder’s Contact Person: Laura Baloun Contact’s Address: 4343 N. Scottsdale Road Suite 150 Scottsdale, AZ 85251 Contact’s Phone: 480-663-4009 Contact’s Fax: 480-663-4973 Contact’s Email address: laura.baloun@mckesson.com Statement of Commitment: Attached, please find a signed statement of commitment. The statement certifies that the DMF is current and that McKesson will comply with the statements made in it. Agent’s Name: Accenture, LLP Agent’s Address: 1160 West Swedesford Road Berwyn, PA 19312 Agent’s Contact Person: Jann A. Kochel Contact’s Address 1160 West Swedesford Road Berwyn, PA 19312 Contact’s Phone: 610-407-1738 Contact’s Fax: 610-407-8433 Contact’s E-mail address: jann.a.kochel@accenture.com FDA_2621 DMF #027320; Sequence 0017 Shared System REMS 3. 1.4 References Page 1 of 1 List of Authorized Persons to Incorporate by Reference (Annual Report - Reporting Period: August 21, 2014 – August 20, 2015) The following is a complete list of persons authorized to incorporate information in the DMF by reference: x x x x x x x x x Actavis Laboratories Inc. – June 17, 2015 BioDelivery Sciences International, Inc. – March 20, 2015 Cephalon, Inc. – August 28, 2013 Depomed, Inc. – August 28, 2013 Galena BioPharma, Inc. – August 28, 2013 Insys Therapeutics, Inc. – August 28, 2013 Mallinckrodt – August 28, 2013 Mylan – August 28, 2013 Par Pharmaceutical, Inc. – August 28, 2013 Please note that during the reporting period, McKesson submitted letters of authorization for Actavis Laboratories Inc. and BioDelivery Sciences International, Inc., and withdrew authorization for Meda Pharmaceuticals, Inc. FDA_2622 DMF #027320; Sequence 0017 Shared System REMS Annual Report – August 20, 2015 Page 1 of 1 ANNUAL REPORT - SUMMARY OF CHANGES Reporting Period: August 21, 2014 – August 20, 2015 Date / Sequence Description November 25, 2014 / 0012 REMS Modification 3 - Draft December 10, 2014 / 0013 REMS Modification 3 - Final December 26, 2014 / 0014 Assessment 4 at 3 Years March 20, 2015 / 0015 Letter of Authorization for BioDelivery Sciences International, Inc. Letter of Withdrawal for Meda Pharmaceuticals, Inc. June 17, 2015 / 0016 Letter of Authorization for Actavis Laboratories Inc. For further details regarding the above REMS amendments, please see the REMS History (Sequence 0014). FDA_2623 Accenture LLP 1160 West Swedesford Road Berwyn, PA 19312 December 28, 2015 Food and Drug Administration Center for Drug Evaluation and Research Central Document Room Drug Master File Staff 5901?8 Ammenclale Road Beltsville, MD 20705?1266 Re: DMF 027320 Holder: McKesson Specialty Health (McKesson) DMF Subject: Transmucosal Immediate Release Fentanyl (TIRE) Access Program Re: REMS Shared Program DMF Type: DMF Submission Information: Clinical/Clinical Information REMS Submission Identi?er: Assessment Sequence Number: 0019 Dear Drug Master File Staff: This Type DMF contains the Risk Evaluation and Mitigation Strategy (REMS) for Transmucosal Immediate Release Fentanyl for the Shared System REMS program. Included in this submission, please ?nd the REMS Assessment 5 at 4 years. McKesson states that information provided in this Master File is current and assures that the material furnished will meet the Speci?cations described herein. McKesson also con?rms that the Holder obligations are observed. We request that all information in this file be treated as con?dential commercial information to the Food and Drug Administration pursuant to 2i C.F.R. ?20.6l, and that no information from this ?le be provided to any unauthorized persons without written consent. If you have any questions or concerns, please do not hesitate to contact Jann Kochel, US. Agent for McKesson, at 610407? 1738 or alternatively via email Sincerely, arm A. Kochel= US. Agent Accenture, LLP Attachments: Table of Contents for the submission Electronic Submission Specifications DMF #027320; Sequence 0019 Shared System REMS Table of Contents Page 1 of 1 Assessment – 4 Years Module Section Description 1.2 Cover Letter Cover Letter w/ Attachments Administrative Information Page 1.16 – Risk Management Plans REMS History REMS Assessment – 4 Years FDA_2625 Electronic Submission Specifications This submission is compliant with FDA's Guidelines for Industry and current eCTD specifications. All files were checked and verified to be free of viruses prior to transmission through the electronic submission gateway. Anti-Virus Program Program Version Virus Definition Date Submission Size Symantec Endpoint Protection Edition 11.0.5002.333 12/21/2015 rev. 2 Approx. 15 MB The IT point of contact for this submission is: Name Phone Number Email Address Matt Francis 1-610-407-1854 Matthew.p.francis@accenture.com FDA_2626 ADMINISTRATIVE INFORMATION Holder’s Name: McKesson Specialty Health Holder’s Address: 4343 N. Scottsdale Road Suite 150 Scottsdale, AZ 85251 Holder’s Contact Person: Laura Baloun Contact’s Address: 4343 N. Scottsdale Road Suite 150 Scottsdale, AZ 85251 Contact’s Phone: 480-663-4009 Contact’s Fax: 480-663-4973 Contact’s Email address: laura.baloun@mckesson.com Statement of Commitment: Attached, please find a signed statement of commitment. The statement certifies that the DMF is current and that McKesson will comply with the statements made in it. Agent’s Name: Accenture, LLP Agent’s Address: 1160 West Swedesford Road Berwyn, PA 19312 Agent’s Contact Person: Jann A. Kochel Contact’s Address 1160 West Swedesford Road Berwyn, PA 19312 Contact’s Phone: 610-407-1738 Contact’s Fax: 610-407-8433 Contact’s E-mail address: jann.a.kochel@accenture.com FDA_2627 DMF #027320; Sequence 0019 Shared System REMS Modification Date Approved Documents Affected No. 1 June 5, 2012 x REMS x Prescriber Program Overview x Education Program x Prescriber Enrollment Form x Patient Provider Agreement Form x Patient and Caregiver Overview x Dear Healthcare Provider Letter x Outpatient Pharmacy Overview x Chain Pharmacy Overview x Inpatient Pharmacy Overview x Outpatient Pharmacy Enrollment Form x Chain Pharmacy Enrollment Form x Inpatient Pharmacy Enrollment form x Outpatient Pharmacy Letter x Inpatient Pharmacy Letter x Dear Distributor Letter x Distributor Enrollment Form x Supporting Document N/A N/A Assessment Report 1 at 6 months – due 06/28/2012 REMS History Page 1 of 7 Overview of Modification Sequence 0002: Edits to Patient-Prescriber Agreement Form, the addition of the Closed System Pharmacy Enrollment Form*, the addition of the newly approved TIRF product, Subsys (fentanyl sublingual spray) and minor editorial changes. *The Closed System Pharmacy Enrollment Form was not formally submitted through the Gateway but was submitted via email on May 18, 2012 and included in the June 5, 2012 FDA approval letter. Sequence 0003: Assessment report covering 12/28/2011 to 04/27/2012 FDA_2628 DMF #027320; Sequence 0019 Shared System REMS Modification Date Approved Documents Affected No. 2 November 7, Draft Documents 2013 submitted on or before 09/28/2012 x Chain Pharmacy Enrollment Form x Outpatient Pharmacy Enrollment Form x Closed System Pharmacy Overview x Education Program x Frequently Asked Questions (FAQ) x Outpatient Pharmacy Letter x REMS x Supporting Document N/A N/A Assessment Report 2 at 1 year – due 12/28/2012 2 November 7, Amendment to 09/28/2012 2013 supplement: x Chain Outpatient Pharmacy Enrollment Form x Independent Outpatient Pharmacy Enrollment Form x Closed System Outpatient Pharmacy Enrollment Form x Inpatient Pharmacy Enrollment Form x Distributor Enrollment Form x Prescriber Enrollment Form REMS History Page 2 of 7 Overview of Modification Sequence 0004: Modification proposed to: x Incorporate closed system pharmacies into the TIRF REMS Access Program x Correct minor inconsistencies between the FDA provided versions and the current PDF versions of REMS materials Sequence 0005: Assessment report covering 04/28/2012 to 10/28/2012 Sequence 0006: Modification proposed to: x Revised terminology, processes, and definitions for outpatient pharmacies x Revised attestations for physicians and patients to address concerns regarding patient access x Revised Program Overview and Frequently Asked Questions to improve clarity and content x Updated REMS materials to reflect the completion of the transition phase for the FDA_2629 DMF #027320; Sequence 0019 Shared System REMS Modification Date Approved Documents Affected No. x Patient Provider Agreement Form x Chain Outpatient Pharmacy Overview x Independent Outpatient Pharmacy Overview x Closed System Outpatient Pharmacy Overview x Inpatient Pharmacy Overview x Patient and Caregiver Overview x Prescriber Overview x Education Program x Knowledge Assessment x Frequently Asked Questions (FAQ) x Dear Outpatient Pharmacy Letter x Dear Inpatient Pharmacy Letter x Dear Healthcare Provide Letter x Dear Distributor Letter x REMS x Supporting Document x Website Landing Page N/A N/A Assessment Report 3 at 2 years – due 12/28/2013 REMS History Page 3 of 7 Overview of Modification TIRF REMS Access Program Sequence 0007: Assessment report covering 10/29/2012 to 10/28/2013 FDA_2630 DMF #027320; Sequence 0019 Shared System REMS REMS History Page 4 of 7 Modification Date Approved Documents Affected No. N/A N/A Safety Surveillance Report #1 – due 03/31/2014 3 December 24, 2014 x x x x x x x x x x x x x x x REMS Prescriber Program Overview Education Program Prescriber Enrollment Form Patient and Caregiver Overview Independent Outpatient Pharmacy Overview Chain Outpatient Pharmacy Overview Closed System Outpatient Pharmacy Overview Inpatient Pharmacy Overview Independent Outpatient Pharmacy Enrollment Form Chain Outpatient Pharmacy Enrollment Form Closed System Outpatient Pharmacy Enrollment Form Inpatient Pharmacy Enrollment form Distributor Enrollment Form FAQ Overview of Modification Sequence 0008: Safety surveillance data covering Q4 2012 to Q3 2013 Sequence 0009: Modification proposed to: x Updated REMS materials to eliminate product specific information which does not impact the safe use of TIRF products x Updated REMS materials to reference the currently approved TIRF products list on the FDA Approved REMS website x Updated REMS materials to remove reference to deactivating patients shown to have multiple prescribers in an overlapping timeframe x Incorporated revised assessment metrics into the Supporting Document x Revised Education Program to emphasize and strengthen appropriate conversion and patient counseling information x Updated REMS and Supporting Document to clarify deactivation of a patient PPAF as opposed to the patient record x Updated pharmacy overview documents and FDA_2631 DMF #027320; Sequence 0019 Shared System REMS REMS History Page 5 of 7 Modification Date Approved Documents Affected No. x Supporting Document x Website Prototype N/A N/A N/A N/A 3 December 24, 2014 Cash Claim Information Request Response – due 05/30/2014 DMF Annual Report – due 08/20/2014 x REMS x Prescriber Program Overview x Education Program x Knowledge Assessment x Prescriber Enrollment Form x Patient and Caregiver Overview x Independent Outpatient Pharmacy Overview x Chain Outpatient Pharmacy Overview x Closed System Outpatient Pharmacy Overview x Inpatient Pharmacy Overview x Independent Outpatient Pharmacy Overview of Modification x FAQ to call out cash claim requirement x Updated TIRF REMS Access website to incorporate items above and link respective Full Prescribing Information and Medication Guides to DailyMed Sequence 0010: Response to 5/16/2014 FDA Cash Claim Information Request Sequence 0011: DMF Annual Report Sequence 0012: Modification proposed to: x Updated REMS materials to eliminate product specific information which does not impact the safe use of TIRF products x Updated REMS materials to reference the TIRF Products webpage on the TIRF REMS Access website x Updated REMS materials to remove reference to deactivating patients shown to have multiple prescribers in an overlapping timeframe x Incorporated revised assessment metrics into the Supporting Document x Revised Education Program to emphasize and strengthen FDA_2632 DMF #027320; Sequence 0019 Shared System REMS REMS History Page 6 of 7 Modification Date Approved Documents Affected No. Enrollment Form x Chain Outpatient Pharmacy Enrollment Form x Closed System Outpatient Pharmacy Enrollment Form x Inpatient Pharmacy Enrollment form x Distributor Enrollment Form x FAQ x Supporting Document x Website Prototype 3 December 24, 2014 N/A N/A Unchanged from Sequence 0012, plus: x Dear Healthcare Provider Letter x Dear Outpatient Pharmacy Letter x Dear Inpatient Pharmacy Letter x Dear Distributor Letter Assessment Report 4 at 3 years – due 12/28/2014 Overview of Modification appropriate conversion and patient counseling information x Updated REMS and Supporting Document to clarify deactivation of a patient PPAF as opposed to the patient record x Updated pharmacy overview documents and FAQ to call out cash claim requirement x Updated TIRF REMS Access website to incorporate items above and link respective Full Prescribing Information and Medication Guides to DailyMed x Updated Education Program and Knowledge Assessment to incorporate approved labeling supplement Sequence 0013: Unchanged from Sequence 0012, plus: x Dear Healthcare Provider Letter x Dear Outpatient Pharmacy Letter x Dear Inpatient Pharmacy Letter x Dear Distributor Letter Sequence 00014: Assessment report covering 10/29/2013 to 10/28/2014 FDA_2633 DMF #027320; Sequence 0019 Shared System REMS REMS History Page 7 of 7 Modification Date Approved Documents Affected No. N/A N/A BioDelivery Sciences International – Letter of Authorization Overview of Modification Sequence 0015: BioDelivery Sciences International – Letter of Authorization N/A N/A Actavis Laboratories Inc. – Letter of Authorization Sequence 0016: Actavis Laboratories Inc. – Letter of Authorization N/A N/A DMF Annual Report – due 08/20/2015 Sequence 0017: DMF Annual Report N/A N/A 36-Month Assessment – Consolidated Information Requests N/A N/A Assessment Report 5 at 4 years – due 12/28/2015 Sequence 0018: Response to FDA 36Month Assessment Information Requests Sequence 00019: Assessment report covering 10/29/2014 to 10/28/2015 FDA_2634 48-month REMS Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 1 of 112 Title: Transmucosal Immediate-Release Fentanyl (TIRF) Risk Evaluation and Mitigation Strategy (REMS) Access Program 48-month Assessment Report Reporting Timeframe: 29 OCT 2014 to 28 OCT 2015 Document Number: FINAL v 1.0 Product Name: Transmucosal Immediate-Release Fentanyl Sponsor: TIRF REMS Industry Group (TRIG) of Companies: Actavis Laboratories FL, Inc. BioDelivery Sciences International, Inc. Cephalon, Inc. (a wholly-owned subsidiary of Teva Pharmaceutical Industries, Ltd.) Depomed, Inc. Galena Biopharma, Inc. Insys Therapeutics Inc. Mallinckrodt Pharmaceuticals Mylan, Inc. Par Pharmaceutical, Inc. Confidentiality Statement The information contained herein is confidential and the proprietary property of the TRIG of Companies and its affiliates, and any unauthorized use or disclosure of such information without the prior written authorization of the TRIG is expressly prohibited. FDA_2635 48-month REMS Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 2 of 112 TABLE OF CONTENTS Pg LIST OF TABLES ................................................................................................................... 5 LIST OF ABBREVIATIONS ................................................................................................. 7 OVERVIEW ............................................................................................................................. 9 1 BACKGROUND ........................................................................................................ 15 2 REMS GOALS ........................................................................................................... 16 3 SUPPORTING INFORMATION ON PROPOSED REMS ELEMENTS ........... 16 3.1 Additional Elements ................................................................................................ 17 3.1.1 Medication Guide ............................................................................................ 17 3.1.2 Letters to Healthcare Professionals.................................................................. 17 3.2 Elements to Assure Safe Use .................................................................................. 17 3.2.1 3.3 Prescription Verification .................................................................................. 19 Implementation System........................................................................................... 20 3.3.1 Wholesaler/Distribution Enrollment and Fulfillment ...................................... 20 3.3.2 The TIRF REMS Access Program Compliance [Metric 22] ........................... 20 3.3.3 TIRF REMS Access Program Call Center ...................................................... 20 4 REMS ASSESSMENT PLAN METHODS ............................................................. 21 4.1 Data Sources for REMS Assessments .................................................................... 22 4.1.1 The TIRF REMS Access Program and Product Utilization Statistics ............. 22 4.1.2 Dispensing Activity for Enrolled Pharmacies ................................................. 23 4.1.3 Program Infrastructure and Performance ......................................................... 24 4.1.4 TIRF REMS Access Program Non-Compliance Plan ..................................... 24 4.1.4.1 Non-Compliance Monitoring ....................................................................... 25 4.1.5 Safety Surveillance .......................................................................................... 26 4.1.6 Periodic Surveys of Patients, Prescribers, and Pharmacies ............................. 27 5 RESULTS ................................................................................................................... 28 5.1 REMS Program Utilization ..................................................................................... 28 5.1.1 Patient Enrollment [Metric 1 and 2] ................................................................ 28 5.1.2 Prescriber Enrollment and Inactivations [Metric 3, 4, 5] ................................ 28 5.1.3 Pharmacy Enrollment, Inactivation, and Education [Metric 6, 7, 8] ............... 31 FDA_2636 48-month REMS Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 3 of 112 5.1.4 Wholesaler/Distributor Enrollment [Metric 9 and 10] .................................... 38 5.1.5 Dispensing Activity [Metric 11, 12, 13,] ......................................................... 39 5.1.6 Barriers or Delays in Patient Access [Metric 14 and 15] ................................ 54 5.2 Program Infrastructure and Performance [Metrics 16, 17, 18, 19] ......................... 59 5.2.1 Backup System for Prescription Validation [Metric 16] ................................. 59 5.2.2 System Interruptions/Errors and Corrective Actions [Metric 17, 19] ............. 59 5.2.3 REMS Call Center [Metric 18] ........................................................................ 60 6 TIRF REMS ACCESS PROGRAM NON-COMPLIANCE ................................. 60 6.1 Stakeholder Non-Compliance [Metric 23, 24, 25, 26, 27, 28] ................................ 61 6.2 Audits ...................................................................................................................... 71 6.2.1 Closed System Pharmacy Audits [Metric 20].................................................. 71 6.2.2 Inpatient Hospital Pharmacy Audits [Metric 21] ............................................. 75 7 SAFETY SURVEILLANCE ..................................................................................... 76 7.1 Adverse Event Reporting [Metric 29] ..................................................................... 76 7.2 TRIG Sponsor Adverse Event Data of Interest [Metric 30] ................................... 76 7.3 Number of Adverse Events of Special Interest ....................................................... 77 7.4 TIRF Product Surveillance Data [Metric 31] .......................................................... 87 7.4.1 Background ...................................................................................................... 87 7.4.2 RADARS Results ............................................................................................ 88 8 PERIODIC SURVEYS OF STAKEHOLDERS ..................................................... 95 8.1 Key Risk Messages ................................................................................................. 95 8.2 Patient KAB Survey ................................................................................................ 95 8.3 Pharmacy KAB Survey ........................................................................................... 96 8.4 Prescriber KAB Survey ........................................................................................... 97 8.5 Overall Conclusion for KAB Results...................................................................... 98 9 FDA COMMUNICATIONS ..................................................................................... 98 10 POST-APPROVAL STUDIES AND CLINICAL TRIALS ................................... 98 11 DISCUSSION ............................................................................................................. 99 12 APPENDICES .......................................................................................................... 102 12.1 Non-Compliance Protocol..................................................................................... 103 12.2 Safety Surveillance Aggregate Line Listing Preferred Terms .............................. 104 FDA_2637 48-month REMS Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 4 of 112 12.3 Safety Surveillance Aggregate Line Listing of Deaths ......................................... 105 12.4 RMPDC Responses to FDA Requests .................................................................. 106 12.5 RADARS System Program Report Protocol ........................................................ 107 12.6 RADARS System Program Report ....................................................................... 108 12.7 Periodic Stakeholder Surveys ............................................................................... 109 12.7.1 Patient KAB Survey....................................................................................... 110 12.7.2 Pharmacy KAB Survey .................................................................................. 111 12.7.3 Prescriber KAB Survey ................................................................................. 112 FDA_2638 48-month REMS Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 5 of 112 LIST OF TABLES Table 1 TIRF Medicines ............................................................................................................15 Table 2 Assessment Report Periods ...........................................................................................16 Table 3 36-Month FDA Assessment Report FDA Acknowledgement Letter Requests ............21 Table 4 Patient Enrollment.........................................................................................................28 Table 5 Prescriber Enrollment ...................................................................................................29 Table 6 Prescriber Inactivations .................................................................................................30 Table 7 Prescribers Pending Enrollment ....................................................................................31 Table 8 Pharmacy Enrollment ....................................................................................................32 Table 9 Pharmacy Inactivations .................................................................................................34 Table 10 Pharmacies Pending Enrollment ..................................................................................37 Table 11 Distributor Enrollment ..................................................................................................38 Table 12 Distributor Inactivations................................................................................................39 Table 13 Prescriptions from Outpatient Pharmacies That Did Not Encounter Any REMSRelated Rejections Prior to Being Authorized for Dispensing .....................................40 Table 14 Reasons for Prescriptions Not Meeting REMS Edit Requirements ..............................41 Table 15 Prescriptions from Outpatient Pharmacies That Encountered at Least One REMSRelated Rejection Prior to Being Authorized for Dispensing .......................................43 Table 16 Prescriptions That Encountered at Least One REMS-Related Rejection and Never Authorized for Dispensing from Outpatient Pharmacies ..............................................47 Table 17 Time to Authorization for a Prescription that Experienced at Least One Initial REMS-Related Rejection ..............................................................................................51 Table 18 Number of Prescription Authorizations per Closed System Pharmacy ........................52 Table 19 Prescriptions Dispensed During the First 10 Days after Passive Patient Enrollment ...56 Table 20 Prescriptions Dispensed Beyond the First 10 Days after Passive Patient Enrollment Without a PPAF ............................................................................................................58 Table 21 Current Assessment Period Contact Reasons ...............................................................60 Table 22 Non-Compliance Activity Reports by Stakeholder in the Current Reporting Period: 29 October 2014 to 28 October 2015 ............................................................................62 Table 23 Non-Compliance Reports in the Current Reporting Period: 29 October 2014 to 28 October 2015 .................................................................................................................65 Table 24 Closed System Pharmacy Audits ..................................................................................72 Table 25 Number of Cases of Adverse Events of Special Interest ..............................................78 FDA_2639 48-month REMS Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 6 of 112 Table 26  Rate of Adverse Events by Total Prescriptions ............................................................78  Table 27  Rate of Adverse Events by Total Patients .....................................................................79  Table 28  Cases of Addiction Received from TRIG Sponsors during the Reporting Period: 29 August 2014 - 28 August 2015 .....................................................................................80  Table 29  Cases of Overdose Received from TRIG Sponsors during the Reporting Period: 29 August 2014 - 28 August 2015 .....................................................................................83  Table 30  Cases of Pediatric Exposures Received from TRIG Sponsors during the Reporting Period: 29 August 2014 - 28 August 2015 ....................................................................86  Table 31  RADARS System: Data Sources and Specific Events.................................................87  Table 32  Summary of RADARS Findings by Program, Outcome, and Denominator ................91  FDA_2640 48-month REMS Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 7 of 112 LIST OF ABBREVIATIONS AAPCC American Association of Poison Control Center ANDA Abbreviated New Drug Application AP Authorized Pharmacist BTP Breakthrough Pain CS College Survey CAP Corrective Action Plan CFR Code of Federal Regulations CSR Call Center Service Representative DMF Drug Master File DoD Department of Defense ETASU Elements to Assure Safe Use FDA Food and Drug Administration HCP ID IR KAB LTC MedDRA Healthcare Provider Identification Immediate Release Knowledge, Attitude, and Behavior Long-Term Care Medical Dictionary for Drug Regulatory Activities MLU Military Logistics Unit NCPDP NCRT NDA NDC NPI OTP PMS PPAF PT RADARS© National Council for Prescription Drug Program Non-Compliance Review Team New Drug Application National Drug Code National Provider Identifier Opioid Treatment Program Pharmacy Management System Patient-Prescriber Agreement Form Preferred Terms Researched Abuse, Diversion and Addiction-Related Surveillance FDA_2641 48-month REMS Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies REMS REMS edits Page 8 of 112 SKIP SOP TC Risk Evaluation and Mitigation Strategy Checks conducted by the TIRF REMS Access Program to confirm that all safety requirements were met Survey of Key Informants’ Patients Standard Operating Procedure Treatment Center TIRF Transmucosal Immediate-Release Fentanyl TIRF Medicines Transmucosal Immediate-Release Fentanyl product(s) TIRF REMS Access REMS program for TIRF medicines TIRF Sponsors The group of sponsors that are submitting this REMS TRIG TIRF REMS Industry Group UBC United BioSource Corporation US VA United States Veteran’s Association FDA_2642 48-month REMS Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 9 of 112 OVERVIEW The Transmucosal Immediate-Release Fentanyl (TIRF) Risk Evaluation and Mitigation Strategy (REMS) Access program was approved by the Food and Drug Administration (FDA) on 28 December 2011 for ABSTRAL®, ACTIQ®, FENTORA®, LAZANDA®, ONSOLIS®, SUBSYS® and generic versions of these TIRF medicines. The TIRF REMS Access program was successfully launched on 12 March 2012, approximately 11 weeks after REMS approval. The shared system REMS includes a Medication Guide; Elements to Assure Safe Use (ETASU) of prescriber and pharmacy certification, and dispensing to outpatients with evidence of safe use conditions; an Implementation System, and a Timetable for Submission of Assessments. In the last 3 years, the TIRF REMS Access program assessment reports were submitted according to the following schedule: Assessment Report Reporting Period Submission Date 6-Month 28 December 2011 - 27 April 2012 28 June 2012 12-Month 28 April 2012 - 28 October 2012 28 December 2012 24-Month 29 October 2012 - 28 October 2013 28 December 2013 36-Month 29 October 2013 – 28 October 2014 28 December 2014 This fifth REMS assessment report (48 months) covers the timeframe from October 2014 to 28 October 2015. As per agreement with FDA, safety surveillance analyses necessitated slightly different time periods as noted in the relevant sections within the report. As of 12 March 2015, the TIRF REMS Access program has been fully implemented for 3 years. Prescriber Enrollment At the end of this reporting period, 9,096 prescribers were enrolled in the TIRF REMS Access program. A total of 2,340 were newly enrolled in the TIRF REMS Access program and 1,822 prescribers successfully re-enrolled during the reporting period. A total of 2,095 prescribers were inactivated, with 2,071 (98.9%) due to expiration of their enrollment at some time during the reporting period. A few prescribers were inactivated because they opted out of the program or were deceased. Based on historical review of the prescription activity by the subsequently inactivated prescribers, access to TIRF medicines appears unimpeded. During this reporting period, 53 prescribers attempted enrollment but were still pending 3 to 6 months after initiating the enrollment process and 309 prescribers were pending enrollment for longer than 6 months since initiating the enrollment process. The most common reasons for pending enrollment were: no attestation, training not complete, and knowledge assessment failure on the first attempt. FDA_2643 48-month REMS Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 10 of 112 Pharmacy Enrollment At the end of this reporting period, 43,216 pharmacies were enrolled (had activity in this reporting period or remained enrolled from the previous reporting period) in the TIRF REMS Access program. A total of 5,892 pharmacies were newly enrolled in the TIRF REMS Access program during this reporting period. Of the newly enrolled dispensing pharmacies (e.g., excluding pharmacy headquarters), 5,286 were chain pharmacy stores, 510 were independent outpatient pharmacies, 87 were inpatient pharmacies, and 7 were closed system pharmacy locations. During this reporting period, a total of 4,920 pharmacies were inactivated, with 4,810 inactivations due to expiration of their enrollment. Based on review of the inactivated pharmacies historical dispensing volume, access to TIRF medicines appears unimpeded. A total of 44 pharmacies attempted enrollment but were still pending 3 to 6 months after initiating the process and a total of 198 pharmacies were pending enrollment for longer than 6 months. The most common reasons for pending enrollment were pending test transaction verification, no attestation, and training not complete. Distributors Enrollment During the reporting period, there were 3 newly enrolled distributors and 13 distributors that reenrolled. There were 3 distributors inactivated during the reporting period due to enrollment expiration; 1 of these distributors had re-enrolled by the end of the reporting period. Although there were 2 distributors who remained inactivated at the end of the reporting period, access to TIRF medicines is unimpeded because both locations were acquired by other entities. Patients As of the end of the reporting period 37,930 patients have been enrolled, of these 8,740 were newly enrolled in the TIRF REMS Access program during this reporting period. Because patients are passively enrolled with their first prescription, they are not required to re-enroll at any point. Instead, prescribers must renew a patient’s Patient-Prescriber Agreement Form (PPAF) every 2 years. By the design of the program, a patient’s enrollment status will never change to inactivated. Dispensing Activity A total of 152,686 prescriptions were submitted to the TIRF REMS Access program for approval in the current reporting period, including 152,228 prescriptions from non-closed system pharmacies and 458 prescriptions from closed system pharmacies. Of the total prescriptions submitted for approval, 143,763 (94.2%) were approved for dispensing without encountering any REMS-related rejections. A total of 8,923 prescriptions encountered at least one REMS-related rejection due to failure to meet REMS requirements for the prescriber and/or patient and/or pharmacy. Of these, 1,735 prescriptions were ultimately authorized for dispensing and the remaining 7,188 prescriptions were never authorized for dispensing. A single prescription may have been submitted and rejected multiple times. The average time for a prescription that had at least one REMS-related rejection to become authorized was 6.7 days (median 1.3 days). FDA_2644 48-month REMS Assessment Report Transmucosal Irmnediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 11 of 112 Non-Compliance Dm?ing the crurent reporting period, 101 con?rmed instances of stakeholder non-compliance with the TIRF REMS Access program requirements were reviewed and investigated. This included 89 prescriber reports and 12 non-closed system pharmacy reports. There were no wholesaler/distributor? or closed system pharmacy reports. A description of these cases including 94 activity reports and 7 narratives are included in Section 6, Table 22 and Table 23, respectively. Closed System Pltarmacv and Inpatient Pltarmacv Audits Audits of 6 closed system pharmacy entities were conducted during this reporting period. Two closed system entities (#361 and #376) were formd to be non-compliant with the TIRF REMS Access program requirements. These pharmacies were re-educated and issued a notice of non- compliance by the Non-Compliance Review Team (N RT). Both non-compliance cases have since been closed. A description of the audits and details of these cases and actions taken are provided in Section 6.2.1. Since submission of the 36-Month FDA Assessment Report, the TIRF REMS Industry Group (TRIG) developed and implemented an inpatient pharmacy questionnaire to conduct the required inpatient pharmacy audits. Audits of 6 inpatient pharmacies were conducted dru'ing this reporting period and no non-compliance was identi?ed for any inpatient pharmacy. A description of the audit questionnaire and a of the audit fmdings are included in Section 6.2.2. Safetv Surveillance Data Safety surveillance data for this 48-month assessment report consists of data from the Researched Abuse, Diversion and Addiction-Related Sluveillance System and aggregate adverse event data from all TRIG sponsors. RADARS System Data Data from 5 RADARS System Programs that gather data from 1mique populations along the spectrum of drug abuse were used to monitor for the non-medical use (abuse and misuse) of TIRF products. Based on FDA request, the data included in this report compare event rates for a time period prior to full implementation of the TIRF REMS and a time period after REMS implementation. a? (4) 48-month REMS Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 12 of 112 A description of these data is included in Section 7.4 of this report, and the complete methods and results are included in the RADARS System Report in Appendix 12.6. Aggregate Spontaneous Adverse Event Data of Interest Spontaneous adverse event data of interest including events of addiction, overdose, death and pediatric exposures were provided by each sponsor and aggregated into one comprehensive line listing. A total of 312 unique case reports were identified as meeting the criteria for inclusion in the analysis based on case preferred terms and review of the case narrative information. Of the 312 cases, the highest proportion of reports had an outcome of death (291, 93.3%), and many reports had no cause of death provided. There were 12 (3.8%) reports of addiction, and 4 (1.3%) pediatric exposures. There were 6 (1.9%) reported overdoses to an identified TIRF product. After a review of the associated MedWatch Forms or narratives for root cause analysis, no reports of inappropriate conversions between TIRF products were noted. Additionally, none of the narratives indicated unintentional exposures or use by non-opioid tolerant patients. There was one report of accidental exposure with an outcome of recovered/resolved during the reporting period. There were 4 reports of pediatric exposure. In 3 of the 4 reports, the medication was intentionally prescribed to the pediatric patient. The fourth report had insufficient information to determine if the pediatric patient took the TIRF medicine. When comparing the current reporting period (29 August 2014-28 August 2015) rate of adverse events by prescription to results in the 36-month report (29 August 2013-28 August 2014), the number of cases per 100,000 prescriptions increased for addiction (10.7 vs. 4.2), overdose (5.3 vs. 0), and pediatric exposure (3.6 vs. 2.1). Conversely, the number of cases of death per 100,000 prescriptions decreased in the current reporting period compared with the 36-month report period (258.6 vs. 383.2). When comparing the current reporting period (29 August 2014-28 August 2015) rate of adverse events by patient to results in the 36-month report (29 August 2013-28 August 2014), the number of cases per 100,000 patients increased for addiction (75.4 vs. 27.1), overdose (37.7 vs. 0), and pediatric exposure (25.1 vs. 13.5). Conversely, the number of cases of death per 100,000 patients decreased in the current reporting period compared with the 36-month report period (1827.7 vs. 2450.6). Additional details are included in Section 7.2. Knowledge, Attitudes, and Behavior (KAB) Surveys TRIG determined that a desired threshold of 65% or greater would be considered to represent adequate understanding of each concept or key risk message for the 48-month KAB surveys. The purpose of establishing this threshold was to assist TRIG in tracking and monitoring the level of understanding of key risk messages across each wave to determine if the goals of the REMS are being met and if any modification to the REMS is required. Patient Survey Results In the 48-month patient survey, 13 of the 19 components of the 6 key risk messages had a response rate >80%, and 3 components had a correct response rate between 67.7% and 74.8%. FDA_2646 48-month REMS Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 13 of 112 The remaining 3 components within key risk messages 2 and 3 had a correct response rate which fell below the desired threshold of 65%. Patients scored consistently low on 2 of 19 components across all survey waves which included 1) TIRF medicines should not be taken for long-lasting pain not from cancer, like arthritis joint pain (43.9% correct), and 2) a patient must stop taking their TIRF medicine if they stop taking their around-the-clock opioid pain medicine (39.4% correct). In addition, revising one question (TIRF medicines should only be taken by patients who are opioid tolerant) to be specific to ‘cancer’ patients, resulted in a large decrease in the correct response rate from the previous survey (85.2% to 43.5%), which may indicate that some respondents were receiving TIRF medicine for a non-cancer associated indications. The consistently high level of patient understanding of key risk messages in this 48-month survey indicates that the goals of the TIRF REMS are being met with existing tools. In general, there is an overall trend across all patient/caregiver KAB surveys conducted (12-month, 24month, 36-month, and 48-month surveys) toward maintenance or improvement in patient/caregiver knowledge and understanding of the key risk messages. Pharmacist Survey Results In the 48-month pharmacist survey, 20 of the 29 components of the 4 key risk messages had a response rate >80%, and 7 components had a response rate between 65.1% to 78.7%. Two components within the key risk messages had a correct response rate below the desired threshold of 65% (Component 6c and Component 9e). The correct response rate for Component 6c (A patient must stop taking their TIRF medicine if they stop taking their around-the-clock opioid pain medicine) was 41.9%. This component was added to the 48-month survey based on feedback provided by FDA in the 24-month and the 36-month FDA REMS Acknowledgement Letter. Correct response rate for Component 9e (Chronic non-cancer pain is not an indication for which TIRF medicines can be prescribed) was 50.8% for this 48-month survey. Component 9e has had a low correct response rate across all pharmacist KAB surveys conducted (12-month, 24-month, 36-month, and 48-month surveys). The survey score for Component 9e may indicate that some respondents are dispensing TIRF medicines for non-cancer associated indications. The consistently high level of pharmacists’ understanding of key risk messages in the latest (48month) survey indicates that the Education Program for Pharmacists is meeting the goals of the TIRF REMS. In general, there is an overall trend across all pharmacist KAB surveys conducted (12-month, 24-month, 36-month, and 48-month surveys) toward increasing improvement in pharmacist knowledge and understanding of the key risk messages. Prescriber Survey Results In the 48-month prescriber survey, 21 of the 31 components of the 4 key risk messages had a correct response rate >80% and 9 components had a correct response rate between 67.7% and 78.7%. For Component 9e, 201 prescribers (64.8%) indicated they do not prescribe TIRF medicines for chronic non-cancer pain. The 34.2% of prescribers who stated they do prescribe TIRF medicines for chronic non-cancer pain were presented with 2 additional questions as FDA_2647 48-month REMS Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 14 of 112 requested by the FDA; the type of chronic pain conditions they prescribe a TIRF medicine to treat, and the reasons for selecting a TIRF medicine to treat these conditions. Based on prescriber responses, and the high percentage of respondents who indicated they received and read the REMS educational materials, the responses may reflect behavior more than knowledge. That is, prescribers are aware of the labeled indication but choose to prescribe off-label for certain patients. The consistently high level of prescriber understanding of key risk messages in the latest (48month) survey indicates that the Education Program for Prescribers is meeting the goals of the TIRF REMS. In general, there is an overall trend across all prescriber KAB surveys conducted (12-month, 24-month, 36-month, and 48-month surveys) toward increasing improvement in prescriber knowledge and understanding of the key risk messages. FDA_2648 48-month REMS Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies 1 Page 15 of 112 BACKGROUND Opioids remain the mainstay of treatment of moderate to severe pain, but their safe use requires careful consideration of proper patient selection and treatment characteristics in order to mitigate any inherent health risks. Opioids are formulated as both extended-release and immediate-release (IR) products. Extended- release or long acting opioid products are designed to provide extended analgesic activity to control persistent pain. TIRF medicines and short-acting opioid products have a rapid onset and short duration of action and are designed for the treatment of acute episodes of pain that ‘break through’ chronic pain control (breakthrough pain, BTP). All the TIRF medicines are short-acting fentanyl products. As with all high-potency opioid analgesics, there are significant potential risks associated with use and misuse of TIRF medicines, including acute respiratory depression which may lead to death. With appropriate clinical use in opioid-tolerant patients these risks have been shown to be low. However, instances of diversion, overdose and prescribing to opioid-non-tolerant patients have led to serious and, on occasion, fatal adverse events demonstrating that shortacting fentanyl products can pose a significant health risk if not used appropriately. The FDA has determined that a REMS is required to mitigate the risk of misuse, abuse, addiction, overdose, and serious complications due to medication errors with the use of TIRF medicines. The group of Sponsors who are submitting this 48-month REMS (Actavis Laboratories FL, Inc., BioDelivery Sciences International, Inc., Cephalon, Inc. [a wholly-owned subsidiary of Teva Pharmaceutical Industries, Ltd.], Depomed, Inc., Galena Biopharma, Inc., Insys Therapeutics Inc., Mallinckrodt Pharmaceuticals, Mylan, Inc. and Par Pharmaceutical, Inc.) are herein referred to as TIRF Sponsors. Two companies joined the TRIG during the reporting period: Actavis Laboratories FL, Inc. joined on 06 February 2015 and BDSI replaced Meda Pharmaceuticals on 11 March 2015. The TIRF REMS Access program is administered by McKesson Specialty Health and RelayHealth. This report has been prepared by United BioSource Corporation (UBC). The TIRF medicines subject to the TIRF REMS are itemized in Table 1 below. Table 1 TIRF Medicines Product Name (active ingredient)/formulation NDA 22510, ABSTRAL (fentanyl) sublingual tablets NDA 20747, ACTIQ (fentanyl citrate) oral transmucosal lozenge and its authorized generic NDA 21947, FENTORA (fentanyl buccal tablet) NDA 22569, LAZANDA (fentanyl) nasal spray NDA 22266, ONSOLIS (fentanyl), buccal soluble film NDA 202788, SUBSYS (fentanyl sublingual spray) ANDA 77312, fentanyl citrate oral transmucosal lozenge ANDA 78907, fentanyl citrate oral transmucosal lozenge FDA_2649 48-month REMS Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 16 of 112 The TIRF REMS Access program addresses the current requirements set forth by the FDA and provided to TIRF Sponsors. The program will be monitored over time and modified when and where appropriate. The initial REMS was approved on 28 December 2011 and went live on 12 March 2012. The FDA required 6-month and 12-month reports during the first year after approval, and then annually thereafter (Table 2). Reporting periods for each assessment report are described below. Data cut-off is 60 days prior to the submission date. Due to availability of data and the time needed to generate/analyze the data, safety surveillance reporting utilizes a modified data cutoff. The RADARS System reporting includes data from 3rd quarter 2012 through 2nd quarter 2015 and the aggregate spontaneous adverse event data of interest includes data from 29 August 2014 through 28 August 2015. Table 2 Assessment Report Periods Assessment Report Reporting Period Submission Date 6-Month 28 December 2011 – 27 April 2012 28 June 2012 12-Month 28 April 2012 – 28 October 2012 28 December 2012 24-Month 29 October 2012 – 28 October 2013 28 December 2013 36-Month 29 October 2013 – 28 October 2014 28 December 2014 48-Month 29 October 2014 – 28 October 2015 28 December 2015 2 REMS GOALS The goals of the TIRF REMS Access program are to mitigate the risks of misuse, abuse, addiction, overdose and serious complications due to medication errors by: 1. Prescribing and dispensing TIRF medicines only to appropriate patients, which includes use only in opioid-tolerant patients. 2. Preventing inappropriate conversion between TIRF medicines. 3. Preventing accidental exposure to children and others for whom it was not prescribed. 4. Educating prescribers, pharmacists, and patients on the potential for misuse, abuse, addiction, and overdose of TIRF medicines. 3 SUPPORTING INFORMATION ON PROPOSED REMS ELEMENTS The TIRF Sponsors are executing the TIRF REMS Access program to ensure the appropriate use of TIRF medicines and proper patient selection. All stakeholders subject to the TIRF REMS Access program, including patients, prescribers, pharmacies and distributors, must be enrolled FDA_2650 48-month REMS Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 17 of 112 in the TIRF REMS Access program, educated on the requirements of the program and required to document that they understand and will abide by the ETASU. Program materials are provided on the TIRF medicines in addition to product-specific materials. The Education Program and Knowledge Assessment components of the program contain both TIRF medicine class and product-specific components. All program tools, including enrollment forms, PPAFs, stakeholder letters, and overview documents containing program information specific to the TIRF REMS Access program, are available at www.TIRFREMSACCESS.com. The program procedures are monitored for adherence and the TIRF Sponsors will continue to conduct ongoing and retrospective analyses as necessary to comply with all mandates and to maximize the safe use of the TIRF medicines. 3.1 Additional Elements 3.1.1 Medication Guide The product-specific TIRF Medication Guide should be dispensed with each TIRF medicine prescription. Every TIRF medicine has a unique Medication Guide. 3.1.2 Letters to Healthcare Professionals A Communication Plan for the TIRF REMS was not required. However, TIRF Sponsors sent materials to targeted stakeholders to support implementation of the TIRF REMS Access program at the time of program launch. These communications included Dear Healthcare Provider (HCP) and Dear Pharmacy letters, and informed prescribers and authorized pharmacists on the risks associated with the use of TIRF medicines, the procedures and requirements of the TIRF REMS Access program and means to report adverse events. 3.2 Elements to Assure Safe Use Because of the significant potential health risks associated with prescribing TIRF medicines to opioid non-tolerant patients, it is important that prescribers are aware of the procedures for appropriate patient selection and appropriate dosing and titration. This is achieved by each prescriber’s enrollment through a review of the TIRF REMS Access Education program including the TIRF medicine’s Full Prescribing Information, successful completion of the Knowledge Assessment, and completion of the prescriber enrollment form. TIRF medicines are only available through the TIRF REMS Access program to reduce the risks of inappropriate patient selection and ensure appropriate dosing and administration of TIRF medicines. To ensure that TIRF medicines are only dispensed to appropriate patients, pharmacies that dispense TIRF medicines must be enrolled in the TIRF REMS Access program. There are different enrollment requirements for outpatient pharmacies (e.g., retail, mail order, institutional outpatient pharmacies that dispense for outpatient use) and inpatient pharmacies (e.g., hospitals that dispense for inpatient use only). For Long-Term Care (LTC) and Hospice patients whose prescriptions were obtained through an outpatient pharmacy setting, the pharmacy, patient, and prescriber must be enrolled in the TIRF REMS Access program. FDA_2651 48-month REMS Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 18 of 112 Outpatient pharmacy enrollment requires an authorized pharmacist at the pharmacy to review the TIRF REMS Access Education program, successfully complete the Knowledge Assessment and submit a completed and signed TIRF REMS Access program enrollment form. The authorized pharmacist ensures that their Pharmacy Management System (PMS) is able to support communication with the TIRF REMS Access program using established telecommunication standards. This requires submitting standardized test transactions to validate the system enhancements. The authorized pharmacist is responsible for educating all pharmacy staff who participate in dispensing TIRF medicines on the risks associated with TIRF medicines and the requirements of the TIRF REMS Access program. For chain pharmacies, an authorized chain pharmacy representative completes the enrollment process on behalf of all individual store locations associated with that chain. The authorized chain pharmacy representative acknowledges that training has been provided to all pharmacy staff involved in the dispensing of TIRF medicines. Once the TIRF REMS Access Education program and Knowledge Assessment have been completed, the authorized chain pharmacy representative, on behalf of the chain, is required to acknowledge their understanding of the appropriate use of TIRF medicines and agree to adhere to the TIRF REMS Access program requirements by submitting a completed and signed enrollment form. For inpatient pharmacy enrollment, the authorized pharmacist is required to review the TIRF REMS Access Education program, successfully complete the Knowledge Assessment, and submit a completed and signed enrollment form on behalf of the pharmacy. The authorized inpatient pharmacist is required to acknowledge that they understand that outpatient pharmacies within their facility must be enrolled separately. Implementation of the TIRF REMS Access program for closed system outpatient pharmacies launched on 30 June 2012. Closed system outpatient pharmacies are integrated healthcare systems that dispense for outpatient use but their PMS is unable to support the process of electronically transmitting the validation and claim information. To enroll in the TIRF REMS Access program, the authorized pharmacist must review the TIRF REMS Access Education program, successfully complete the Knowledge Assessment, and submit a completed and signed enrollment form on behalf of the pharmacy. A list of closed system pharmacy locations that have been trained must be provided to the TIRF REMS Access program. Patients are passively enrolled in the TIRF REMS Access program when their first prescription is processed by a pharmacy. A completed PPAF should be sent to the TIRF REMS Access program by the prescriber within 10 working days from the processing date of the patient’s first prescription for a TIRF medicine. A maximum of 3 prescriptions are allowed within 10 working days from the date that the patient has their first prescription filled. No further prescriptions are to be dispensed after the 10 working day window until a completed PPAF is received. A patient’s HCP can submit a copy of the PPAF to the TIRF REMS Access program via the Web site, fax, or United States (US) mail. FDA_2652 48-month REMS Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies 3.2.1 Page 19 of 112 Prescription Verification Following initial patient enrollment, upon processing of a patient’s first TIRF medicine prescription, pharmacies verify for all subsequent prescriptions that both the prescriber and patient are enrolled in the TIRF REMS Access program and that all REMS requirements are met prior to dispensing. Prescription verification is not required for inpatient use of TIRF medicines. Non-Closed System Pharmacies Prescription verification occurs through a model that uses a pharmacy billing claim and engages a switch provider in the validation process. Upon receipt of a prescription for a TIRF medicine at an enrolled pharmacy, the prescription details are entered into their PMS and a transaction is sent to the TIRF REMS Access program via a switch provider. If the patient is not enrolled and this is their first prescription, the TIRF REMS Access program uses the transaction data to automatically transfer patient details into the TIRF REMS Access program database for passive enrollment. For all subsequent prescriptions, the REMS database is then interrogated, via the switch provider, to validate the REMS edits (i.e., confirm that all TIRF REMS Access program requirements are met). In the case where a prescription passes all REMS edits, a billing request is then sent to the payer by the switch provider. Once the payer authorizes payment, the switch provider then authorizes the pharmacy to dispense the TIRF medicine as with a normal prescription, returning an authorization number which is captured by the TIRF REMS Access program. Specific reasons why a prescription would not meet a REMS edit are described in Table 17. If the prescription does not pass all REMS edits (e.g., one of the stakeholders was not enrolled), the TIRF REMS Access program rejects the claim prior to the claim being forwarded to the payer and the pharmacy receives a rejection notice from the switch provider. This automated feedback indicates the reason for rejection, instructs the pharmacist not to dispense the TIRF medicine, and notifies the pharmacist to contact the TIRF REMS Access program Call Center for further information. Closed System Outpatient Pharmacies Upon receipt of a prescription for a TIRF medicine at an enrolled closed system outpatient pharmacy, a pharmacy staff member will contact the TIRF REMS Access program via phone or fax to provide prescription details for verification. The TIRF REMS Access program then validates the enrollment status for the patient, prescriber and pharmacy. If the patient is not enrolled, the TIRF REMS Access program will use this transaction information to automatically transfer patient details into the TIRF REMS Access database for passive enrollment. If all three stakeholders are enrolled (i.e., passes all REMS edits), the closed system outpatient pharmacy is given an authorization number which is captured by the TIRF REMS Access program. If the prescription does not pass all REMS edits (e.g., one of the stakeholders is not enrolled), the TIRF REMS Access program will not provide an authorization number and the closed system FDA_2653 48-month REMS Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 20 of 112 outpatient pharmacy will receive a rejection notice. This feedback is provided to the closed system outpatient pharmacy via phone or fax and includes the reason for rejection, information on how the rejection may be resolved and instructions to not dispense the TIRF prescription until resolution is reached. 3.3 Implementation System The Implementation System and its components are described in the following sections. 3.3.1 Wholesaler/Distribution Enrollment and Fulfillment Wholesalers/distributors who distribute TIRF medicines must be enrolled in the TIRF REMS Access program before they are allowed to distribute TIRF medicines. For the purpose of the TIRF REMS Access program, the term distributor refers to a wholesaler, distributor, and/or chain pharmacy distributor. TIRF medicine distributors received a Dear Distributor Letter describing the TIRF REMS Access program and the requirements to purchase TIRF medicines from TIRF Sponsors and sell TIRF medicines to pharmacies upon FDA approval of the program. To enroll, the distributor’s authorized representative must review the distributor program materials, complete and sign the Distributor Enrollment Form and fax it to the TIRF REMS Access program. TIRF Sponsors have processes in place to prevent shipping TIRF medicines to any distributor who has not completed and signed the enrollment form. 3.3.2 The TIRF REMS Access Program Compliance [Metric 22] The TIRF REMS Access program NCRT was created by the TRIG on 19 October 2012 and is tasked with reviewing reports of suspected non-compliance with the TIRF REMS Access program requirements. The NCRT is composed of membership from all TRIG sponsors. There are currently 24 individuals across the 9 sponsors; the functional areas or specialties represented by the members include Regulatory, Medical Affairs, REMS Specialist, Legal, Quality and Drug Safety. TIRF Sponsors monitor prescriber, pharmacy, and wholesaler/distributor activities for compliance with TIRF REMS Access program requirements. Corrective actions (e.g., reeducation, additional monitoring, process revision, and stakeholder inactivation) are instituted by the TIRF Sponsors as appropriate if non-compliance is confirmed. The Non-Compliance Plan is described in Section 4.1.4 (Metric 22) and results of non-compliance investigations are included in Section 6 of this report. The full Non-Compliance Protocol is included in Appendix 12.1. 3.3.3 TIRF REMS Access Program Call Center The TIRF REMS Access program maintains a Call Center component. The Call Center is staffed by qualified and trained specialists, who provide TIRF REMS Access program support to patients, prescribers, pharmacies, and distributors. FDA_2654 48-month REMS Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies 4 Page 21 of 112 REMS ASSESSMENT PLAN METHODS The aim of the TIRF REMS Access program’s evaluation is to assess the effectiveness of the mitigation strategies in meeting the goals of the TIRF REMS Access program to ensure safe use, proper prescribing, and appropriate distribution of TIRF medicines. Findings from these evaluations are used to identify ways to improve the processes, as needed. The 36-Month FDA assessment report Acknowledgement Letter included multiple new requests to be incorporated into the 48-Month FDA assessment report. Due to timing of this correspondence, requested items #2 and #3 (Table 3) are not included in this assessment report. As communicated to FDA on 08 September 2015, these items will be reported in the 48-Month Supplemental Report estimated to be submitted to FDA on 04 May 2016. In reference to request #4, TRIG has provided information in Section 5.1.2 to address the potential patient-access issues of health professionals and pharmacies who did not re-enroll in the TIRF REMS Access program. Based on review of their historical prescription activity, only 8.6% of prescribers had recent prescription activity and chose not to re-enroll. These prescribers account for less than 6.0% of the cumulative number of prescribers who have ever been inactivated and these prescribers had an average of no more than 4 prescriptions total over the course of the reporting period. At present 1,144 pharmacies remained inactivated at the end of this reporting period with 64% never having had any TIRF prescription activity since their initial enrollment in the TIRF REMS Access program. Based on this analysis, there is no barrier to patient access and further outreach is unwarranted. Table 3 Request Number* 2. 3. 36-Month FDA Assessment Report FDA Acknowledgement Letter Requests FDA Request In order to assess the TIRF REMS goal of prescribing and dispensing TIRF products only to appropriate patients, which includes use only in opioid-tolerant patients, conduct the following analysis: Identify a health care database that includes an adequate number of TIRF product users. Within that database, by year, provide the number of total unique patients dispensed an initial prescription for a TIRF product in the outpatient setting. Determine what proportion of those total unique patients received a prescription for an opioid analgesic product prior to the prescription for the TIRF product. Provide these data separately for patients receiving an opioid analgesic within the 7days prior and within the 30-days prior to the initial TIRF prescription. Before embarking on this analysis, provide to FDA your choice of database and the estimated number of TIRF users in the database so that we can determine if the number is adequate. We are not able to establish whether the TIRF REMS is achieving the goal of preventing inappropriate conversion between TIRF medicines. In order to better understand how many people are at risk for inappropriate conversion between TIRF medicines, we need a better idea of how long patients stay on one TIRF and whether they shift between TIRF products or just stop them completely. Conduct a persistency analysis based on the data available on the prescriptions processed through the switch system used by retail pharmacies. This analysis should demonstrate the number of patients starting on a TIRF and follow them over weeks and months to summarize their treatment course and change in therapy. The TIRF products can be grouped together, and the specific drug does FDA_2655 48-month REMS Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Request Number* Page 22 of 112 FDA Request not need to be disclosed. Following the discontinuation of the TIRF, the persistency analysis should also depict what treatment option the patient uses next. This will be either full discontinuation or switching to another TIRF product. There may be gaps in between prescriptions; propose what duration of gap will be considered to mean that the patient has remained on treatment with a TIRF and provide a rationale for selection of that gap length. Conduct outreach to a representative sample of those health professionals and pharmacies that did not re-enroll in the TIRF REMS Access program so as to ascertain their reasons and report the results in your next assessment report. We are concerned about potential patient access issues. 4. *Numbering is aligned with the numbering of the FDA requests communicated in the 36-Month FDA assessment report Acknowledgement Letter. 4.1 Data Sources for REMS Assessments Data were collected from the following main sources as described in detail below: a) TIRF REMS Access program utilization statistics (Section 4.1.1), b) dispensing activity for enrolled pharmacies (Section 4.1.2), c) program infrastructure and performance, d) TIRF REMS Access non-compliance plan, e) safety surveillance, and f) periodic surveys of patients, HCPs, and pharmacies. All programmed source tables and figures, as well as source data are on file at UBC and available upon request. The individual metrics for each main data source are provided below with a direct link to the results sections of the report. Note: Every metric number shown in the following tables is used to identify the respective metric in the headers and text of the results (see Section 5). 4.1.1 The TIRF REMS Access Program and Product Utilization Statistics For the assessment of enrollment, utilization, and discontinuation statistics for prescribers, pharmacies, patients, and distributors, the following metrics were tabulated for the current reporting period and cumulatively. Metric Number* Metric a. Patient Enrollment 1. Number of unique patients enrolled 2. Number of patients inactivated b. Prescriber Enrollment 3. Number of prescribers enrolled 4. Number of prescribers that attempted enrollment but whose enrollment is pending for >3 months and >6 months along with the specific reasons why their enrollment is pending 5. Number of prescribers inactivated FDA_2656 48-month REMS Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Metric Number* Metric c. Pharmacy Enrollment Page 23 of 112 6 Number of pharmacies enrolled by type (inpatient, chain, independent, closed system; provide identity of closed system entities) 7. Number of pharmacies that attempted enrollment but whose enrollment is pending >3 months and >6 months along with the specific reasons why their enrollment is pending (stratified by type) 8. Number of pharmacies inactivated by type (inpatient, chain, independent, closed system) d. Distributor Enrollment 9. Number of distributors enrolled 10. Number of distributors inactivated *Numbering corresponds with the current TIRF REMS Access program Supporting Document (approved on 24 December 2014). 4.1.2 Dispensing Activity for Enrolled Pharmacies For the assessment of dispensing activity the following metrics were tabulated and stratified by pharmacy type for the current reporting period and cumulatively. Metric Number* Metric 11. Number of prescriptions/transactions authorized; for closed systems, provide the number of prescription/transactions per closed system entity 12. Number of prescriptions/transactions denied/rejected and the reasons for denial/rejection. Include the number of prescriptions/transactions rejected for safety issues (provide description of safety issues and any interventions or corrective actions taken) 13. The mean and median amount of time it takes for a prescription that experienced at least one initial REMS-related rejection to be authorized 14. Number of patients with more than three prescriptions dispensed during the first ten days after patient passive enrollment without a PPAF 15. Number of prescriptions dispensed after ten days without a PPAF in place *Numbering corresponds with the current TIRF REMS Access program Supporting Document (approved on 24 December 2014). FDA_2657 48-month REMS Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies 4.1.3 Page 24 of 112 Program Infrastructure and Performance The following metrics on program infrastructure performance were collected and summarized for the current reporting period. Metric Number* Metric 16. Number of times a backup system was used to validate a prescription, with reason(s) for each instance (for example, pharmacy level problem, switch problem, or REMS database problem) clearly defined and described 17. Number of times unintended system interruptions occurred for each reporting period. Describe the number of stakeholders affected, how the issue was resolved, and steps put into place to minimize the impact of future interruptions 18. Call center report with • Overall number of contacts 19. • Summary of frequently asked questions • Summary of REMS-related problems reported Description of corrective actions taken to address program/system problems *Numbering corresponds with the current TIRF REMS Access program Supporting Document (approved on 24 December 2014). 4.1.4 TIRF REMS Access Program Non-Compliance Plan The TIRF sponsors provide the following data regarding non-compliance in each assessment report (per reporting period). Metric Number* Metric 20. Report the results of yearly audits of at least 3 randomly selected closed pharmacy systems to assess the performance of the system(s) developed to assure REMS compliance. These reports are to include: • Verification of training for all pharmacists dispensing TIRF products • Numbers of prescription authorizations per closed system • Reconciliation of data describing TIRF product prescriptions received by the closed system pharmacy with TIRF product dispensed to patients with a valid enrollment in the TIRF REMS Access program. Data to include the 12-month period preceding the audit date. Include details on how the reconciliation is conducted (e.g., electronic versus manual process). • Describe any corrective actions taken for any non-compliance identified during the audit and corrective actions taken to address non-compliance FDA_2658 48-month REMS Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 25 of 112 Metric Number* Metric 21. Report the results of yearly audits of at least 5 randomly selected inpatient hospital pharmacies to assess the performance of the system(s) developed to assure REMS compliance starting in the 48Month assessment report. Provide the number of units of use of TIRFs ordered per inpatient hospital pharmacy audited per 12 month period. These reports are to include: • Verification of training for all pharmacists dispensing TIRF products 22. • Verification that processes such as order sets/protocols are in place to assure compliance with the REMS program • Describe any corrective actions taken for any non-compliance identified during the audit, as well as preventative measures that were developed as a result of uncovering these noncompliance events Description of number, specialties, and affiliations of the personnel that constitute the NonCompliance Review Team (NCRT) as well as: • Description of how the NCRT defines a non-compliance event • Description of how non-compliance information is collected and tracked • Criteria and processes the Team uses to make decisions • Summary of decisions the Team has made during the reporting period • How the Team determines when the compliance plan should be modified 23. Describe each non-compliance event and the corrective action measure taken, as well as the outcome of the corrective action 24. Number of TIRF prescriptions dispensed that were written by non-enrolled prescribers and include steps taken to prevent future occurrences 25. Number of prescriptions dispensed by non-enrolled pharmacies and include steps taken to prevent future occurrences 26. Number of times a TIRF prescription was dispensed because a pharmacy (closed or open system) was able to bypass REMS edits and if any such events occurred, describe how these events were identified 27. Number of times a TIRF was prescribed to an opioid non-tolerant individual. Include what was done to minimize such instances; if any such events occurred, describe how these events were identified 28. Number of instances of inappropriate conversions between TIRF products, as well as any outcome of such an event. If any such events occurred, describe how these events were identified *Numbering corresponds with the current TIRF REMS Access program Supporting Document (approved on 24 December 2014). 4.1.4.1 Non-Compliance Monitoring The goal of the Non-Compliance Plan is to help TRIG identify and investigate deviations from and non-compliance with TIRF REMS requirements to ensure patient safety and continuously improve the program. A confirmed non-compliance event is one for which the information collected through investigation of the potential non-compliance event clearly indicates that a FDA_2659 48-month REMS Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 26 of 112 program deviation has occurred and/or evidence of the program goals not being met through stakeholder actions is identified. The TIRF REMS Access program routinely monitors stakeholder activity to identify potential incidents of non-compliance events with program requirements and investigates all reports of suspected non-compliance. Non-compliance information is collected through standard program reports, spontaneous reports identified via the program’s Call Center, vendor/sponsor reported events, outreach to relevant stakeholders to validate data/information and solicit further information, and investigation of the TIRF REMS Access database. The data are tracked through a non-compliance case that is opened on the stakeholder record in the TIRF REMS Access database. If a non-compliance event is confirmed, additional investigation is conducted to determine the scope, impact, and root cause of the event. Stakeholders are notified of the investigation via a formal letter from the TIRF REMS Access program and may also be requested to develop a Corrective Action Plan (CAP). All CAPs are reviewed and approved by the NCRT. The NCRT will determine if the Non-Compliance Protocol should be modified as the program evolves. Any changes to the plan proposed by the NCRT will be voted upon by the TRIG. As requested by FDA in the 36-Month FDA Assessment Report Acknowledgement Letter, the full Non-Compliance Protocol is included in Appendix 12.1. 4.1.5 Safety Surveillance The following safety surveillance data were collected. Reporting periods for each type of data were modified based on timing of availability of data. Metric Number* Metric 29. TIRF Sponsors will process adverse event reports related to their specific products and report to the FDA according to current regulations outlined in 21 Code of Federal Regulations (CFR) 314.80 and the sponsor’s respective Standard Operating Procedures 30. TIRF Sponsors will produce one comprehensive report that presents spontaneous adverse event data from all sponsors of the TIRF REMS Access program, as well as data from other databases (characteristics of which are described below). This report will focus on four categories of adverse events of interest: addiction, overdose, death, and pediatric exposures. This report should include the following: • Line listings under each category of adverse events of interest as listed above • Line listings should provide at a minimum the following information: o Identifying case number o Age and Gender of the patient o Date of the event as well as of the report o The Preferred Terms o Indication of TIRF use o Duration of TIRF therapy o Concomitant medications FDA_2660 48-month REMS Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Metric Number* Metric o • 31. Page 27 of 112 Event Outcome Other metrics of interest include: o Number of event reports in each event category of interest o Counts of adverse events related to inappropriate conversions between TIRF products o Counts of adverse events related to accidental and unintentional exposures o Counts of adverse events that are associated with use of TIRF medicines in nonopioid tolerant patients • Duplicate cases are identified and eliminated • Case reports with adverse events in multiple categories will be listed in each category of interest, and will be noted as such • For each adverse event category, an overall summary analysis of the cases will be provided addressing the root cause(s) of the events • Rate of each adverse event of interest will be calculated using two distinct denominators: the number of prescriptions for TIRF products and the number of patients receiving a TIRF product throughout the reporting interval. Trends and changes in the rates of these events will be compared year-to-year Surveillance data focusing on events of addiction, overdose, death, and pediatric cases should also be drawn from the databases that are listed below. Conclusions regarding these data should be included in and inform the overall conclusions in the summary report referred to in Metric 30 directly above: • Non-medical use of prescription drugs • Surveys conducted at substance abuse treatment programs • College surveys • Poison control center data • Impaired health care workers • Drug-related hospital emergency department visits • Drug-related deaths • Other databases as relevant *Numbering corresponds with the current TIRF REMS Access program Supporting Document (approved on 24 December 2014). 4.1.6 Periodic Surveys of Patients, Prescribers, and Pharmacies Prescribers’, pharmacists’, and patients’ understanding regarding the appropriate use of TIRF medicines and TIRF REMS Access program requirements are evaluated through Knowledge, Attitude, and Behavior (KAB) surveys. The surveys are administered to selected prescribers, pharmacies, and patients. FDA_2661 48-month REMS Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies 5 Page 28 of 112 RESULTS 5.1 REMS Program Utilization Described in this section are the total numbers of all enrolled stakeholders (prescribers, patients, pharmacies, and distributors), as well as stakeholder inactivations, dispensing activities, and barriers or delays in patient access. 5.1.1 Patient Enrollment [Metric 1 and 2] During the current reporting period, there were 8,740 newly enrolled patients (Table 4). Because patients are passively enrolled with their first prescription there is no patient reenrollment, but prescribers are required to renew PPAFs with patients every 2 years. By design, a patient’s enrollment status will never change to inactivated. Table 4 Patient Enrollment Parameter Current Reporting Period 29OCT2014 to 28OCT2015 Number of Newly Enrolled Patients N (%) Cumulativea,b 28DEC2011 to 28OCT2015 Total Number of Enrolled Patients N (%) 8,740a 37,930b,c Total Number of Enrolled Patients a An enrolled patient is a patient who has received at least one prescription for a TIRF prescription. b Includes patients that transitioned into the TIRF REMS Access program from other individual REMS programs. c Cumulative patients from the end of prior period may differ from last period’s report due to reconciliation of duplicate patients. 5.1.2 Prescriber Enrollment and Inactivations [Metric 3, 4, 5] Cumulatively there have been 15,100 prescribers who have successfully completed enrollment in the program. At the end of this reporting period there are 9,096 prescribers who are currently enrolled. This includes 2,340 newly enrolled prescribers, 1,822 prescribers who re-enrolled and 4,934 who remain active from a previous period (Table 5). Table 6 shows those prescribers who have been inactivated. FDA_2662 48-month REMS Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Table 5 Page 29 of 112 Prescriber Enrollment Parameter Number of Prescribers with Enrollment Activity In This Reporting Period Number of Newly Enrolled Prescribers Number of Re-Enrolled Prescribers Current Reporting Perioda 29OCT2014 to 28OCT2015 N (%) 4,162 2,340 (56.2%) 1,822 (43.8%) Number of Prescribers Who Remain Enrolled from Previous Reporting Periods 4,934 Total Number of Prescribers Enrolled as of the End of This Reporting Period 9,096 15,100 Cumulative Number of Prescribers Ever Enrolledb,c a Percentages are based on the total number (N) of enrolled prescribers b Cumulative is defined as sum of all reporting periods. c Number includes prescribers who transitioned into the TIRF REMS Access program A total of 2,095 prescribers were inactivated at some point during the current reporting period, and the majority of these (2,071, 98.9%) were due to expiration of enrollment. It should be noted that a prescriber is required to enroll every 2 years within the TIRF REMS Access program. Of those 2,071 prescribers whose enrollment expired at some point during the current reporting period, 1,650 (79.7%) remained expired at the end of the reporting period (Table 6). In total, there were 6,007 prescribers who remained inactivated at the end of the reporting period. Of the total 6,007 prescribers inactivated as of the end of this reporting period, 8.6% (n=516) are those prescribers who had recent prescription activity and chose to not re-enroll. These prescribers account for less than 6.0% (516/8,730) of the cumulative number of prescribers who have ever been inactivated and these prescribers had an average of no more than 4 prescriptions total over the course of the reporting period. FDA_2663 48-month REMS Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Table 6 Page 30 of 112 Prescriber Inactivations Parameter Number of Prescribers Who Became Inactivated During this Reporting Period Reason(s) For Inactivationb Deceased Program Opt-Out Non Compliantc Suspended Enrollment Expiredd Enrollment remained expired at end of period Current Reporting Perioda 29OCT2014 to 28OCT2015 N (%) 2,095 6 (0.3%) 13 (0.6%) 2 (0.1%) 4 (0.2%) 2,071 (98.9%) 1,650 (79.7%) Number of Prescribers Inactivated in This Time Period who Remain Inactivated as of the End of this Reporting Period 1,671 Number of Prescribers Who Were Inactivated in a Previous Reporting Period and Remain Inactive as of the End of This Reporting Period 4,336 Total Number of Prescribers Inactivated as of the End of this Reporting Period 6,007 8,730 Cumulative Number of Prescribers Who Have Ever Been Inactivatede a Prescribers whose status is ’inactive’ at least once during the reporting period. b Percentages are based on the total number (N) of inactivated prescribers. A prescriber may have more than one reason for inactivation. c Prescribers may be included as both “non-compliant” and “suspended” since before becoming inactivated for non-compliance, prescribers go through a suspension period. d Prescribers whose status is ‘Inactive-Expired’ at any time during the reporting period. e Cumulative is defined as sum of all reporting periods. During the current reporting period, there were 53 prescribers who attempted enrollment but whose enrollment was pending 3 to 6 months later. A total of 309 prescribers were pending enrollment for more than 6 months within the current reporting period. Prescribers may have attempted enrollment and become pending in another reporting period. For prescribers pending enrollment for 3 to 6 months, the most frequent reasons were no attestation (77.4%), training not complete (52.8%), and knowledge assessment failure on the first attempt (15.1%). For prescribers pending enrollment for more than 6 months, the most frequent reasons were similar and included no attestation (73.1%), training not complete (59.5%), and knowledge assessment failure on the first attempt (16.5%). FDA_2664 48-month REMS Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 31 of 112 The number of prescribers that attempted enrollment but are still pending enrollment for 3 to 6 months or more than 6 months, and the reasons for pending enrollment are shown in Table 7. Table 7 Prescribers Pending Enrollment Current Reporting Perioda 29OCT2014 to 28OCT2015 Prescribers Pending Prescribers Pending Enrollment Enrollment Parameter ≥3 – 6 Monthsb >6 Monthsb 53 309 Prescribers Who Attempted Enrollment but are Still Pending Enrollmentc Reasons for Pending Enrollment Assessment Failure - Sixth Attempt 0 1 (0.3%) Invalid DEA 4 (7.5%) 24 (7.8%) Invalid NPI 2 (3.8%) 14 (4.5%) Knowledge Assessment Failure - First Attempt 8 (15.1%) 51 (16.5%) Knowledge Assessment Failure - Second Attempt 1 (1.9%) 6 (1.9%) Knowledge Assessment Failure - Third Attempt 1 (1.9%) 7 (2.3%) Missing DEA Number 1 (1.9%) 11 (3.6%) Missing Email 1 (1.9%) 2 (0.6%) Missing NPI Number 1 (1.9%) 8 (2.6%) Missing Physician Signature Date 0 13 (4.2%) Missing Signature 0 13 (4.2%) Missing State License Number 1 (1.9%) 7 (2.3%) No Attestation 41 (77.4%) 226 (73.1%) Pending Enrollment Intake 2 (3.8%) 9 (2.9%) Provided DEA does not have Correct Schedule for this Drug 5 (9.4%) 36 (11.7%) Training Access Suspended 0 1 (0.3%) Training Not Complete 28 (52.8%) 184 (59.5%) a Reflects the total number of prescribers pending enrollment in the current reporting period. Prescribers may have attempted enrollment and become pending in another reporting period. b Percentages are based on the total number (N) of prescribers attempting enrollment. Percentages may not add to 100% because a single prescriber may be pending enrollment for more than one reason. c Prescribers may be pending enrollment for more than one reason. 5.1.3 Pharmacy Enrollment, Inactivation, and Education [Metric 6, 7, 8] There were a total of 28,617 pharmacies newly enrolled or re-enrolled in this reporting period. Of the 5,892 (20.6%) pharmacies that newly enrolled in the TIRF REMS Access program, 5,286 were chain pharmacy stores, 510 were independent outpatient pharmacies, 87 were inpatient pharmacies, and 7 were closed system pharmacy locations. The 7 closed system pharmacies are represented by 7 closed system entities (See Section 5.1.5). A total of 22,725 FDA_2665 48-month REMS Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 32 of 112 (79.4%) pharmacies re-enrolled; 21,550 were chain pharmacy stores, 992 were independent outpatient pharmacies, 143 were inpatient pharmacies, and 2 were closed system pharmacy locations (Table 8). Table 8 Pharmacy Enrollment Parameter Total Number of Pharmacies with Enrollment Activity in this Reporting Period Current Reporting Perioda,b 29OCT2014 to 28OCT2015 Non-Closed System Closed System Total Pharmacies Pharmacies Pharmacies N (%) N (%) N (%) 28,607 10 28,617 Total Number of Newly Enrolled Pharmacies Inpatient Pharmacies Chain Pharmacy Headquartersc Chain Pharmacy Stores Independent Outpatient Pharmacies Closed System Headquartersc Closed System Pharmacies 5,885 (20.6%) 7 (70.0%) 5,892 (20.6%) 87 (1.5%) 2 (<0.1%) 5,286 (89.8%) 510 (8.7%) N/A N/A N/A N/A N/A N/A 0 7 (100.0%) 87 (1.5%) 2 (<0.1%) 5,286 (89.7%) 510 (8.7%) 0 (<0.1%) 7 (0.1%) Total Number of Re-Enrolled Pharmacies Inpatient Pharmacies Chain Pharmacy Headquartersc Chain Pharmacy Stores Independent Outpatient Pharmacies Closed System Headquartersc Closed System Pharmacies 22,722 (79.4%) 3 (30.0%) 22,725 (79.4%) 143 (0.6%) 37 (0.2%) 21,550 (94.8%) 992 (4.4%) N/A N/A N/A N/A N/A N/A 1 (33.3%) 2 (66.7%) 143 (0.6%) 37 (0.2%) 21,550 (94.8%) 992 (4.4%) 1 (<0.1%) 2 (<0.1%) 14,361 238 14,599 638 (4.4%) 42 (0.3%) 10,618 (73.9%) 3,063 (21.3%) N/A N/A N/A N/A N/A N/A 5 (2.1%) 233 (97.9%) 638 (4.4%) 42 (0.3%) 10,618 (72.7%) 3,063 (21.0%) 5 (<0.1%) 233 (1.6%) Number of Pharmacies that Remain Enrolled from a Previous Reporting Period Inpatient Pharmacies Chain Pharmacy Headquartersc Chain Pharmacy Stores Independent Outpatient Pharmacies Closed System Headquartersc Closed System Pharmacies FDA_2666 48-month REMS Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 33 of 112 Current Reporting Perioda,b 29OCT2014 to 28OCT2015 Non-Closed System Closed System Total Pharmacies Pharmacies Pharmacies Parameter N (%) N (%) N (%) 42,968 248 43,216 Total Number of Pharmacies Enrolled as of the End of this Reporting Period Inpatient Pharmacies 868 (2.0%) N/A 868 (2.0%) Chain Pharmacy Headquartersc 81 (0.2%) N/A 81 (0.2%) Chain Pharmacy Stores 37,454 (87.2%) N/A 37,454 (86.7%) Independent Outpatient Pharmacies 4,565 (10.6%) N/A 4,565 (10.6%) Closed System Headquartersc N/A 6 (2.4%) 6 (<0.1%) Closed System Pharmacies N/A 242 (97.6%) 242 (0.6%) Cumulative Number of Pharmacies Ever Enrolledd,e Inpatient Pharmacies Chain Pharmacy Headquartersc Chain Pharmacy Stores Independent Outpatient Pharmaciesc Closed System Headquarters Closed System Pharmacies 47,348 359 47,707 1,168 (2.5%) 92 (0.2%) 39,929 (84.3%) 6,159 (13.0%) N/A N/A N/A N/A N/A N/A 7 (1.9%) 352 (98.1%) 1,168 (2.4%) 92 (0.2%) 39,929 (83.7%) 6,159 (12.9%) 7 (<0.1%) 352 (0.7%) a Percentages are based on the total number (N) of pharmacies with enrollment activity in this reporting period. Pharmacies that are enrolled within this reporting period and were still enrolled at the end of the reporting period. c The number of Chain Pharmacy Headquarters and Closed System Headquarters may not be associated with the number of Chain Pharmacy Stores and Closed System Pharmacies, respectively. Chain Pharmacy Stores or Closed System Pharmacies may be associated with a Headquarter enrolled in a previous reporting period. d Cumulative number of pharmacies from the end of prior period may differ from last period's report due to reconciliation of duplicate records. e One pharmacy is counted as both a Chain Pharmacy Headquarter and a Closed System Headquarter as they transitioned their pharmacy type during this reporting period due to obtaining the ability to electronically adjudicate claims. b As shown in Table 9, there were 4,920 total pharmacies inactivated at least once during the current reporting period including 4,919 non-closed system pharmacies and 1 closed system pharmacy. The non-closed system pharmacies included 4,382 (89.1%) chain pharmacy stores, 422 (8.6%) independent outpatient pharmacies, and 112 (2.3%) inpatient pharmacies. The reason for most pharmacy inactivations was expired enrollment, which was 33.3% of the inactivated chain pharmacy headquarters and at least 85.7% among inactivated pharmacies in the remaining pharmacy categories. At present, 1,144 pharmacies remained inactivated at the end of this reporting period with 64% never having had any TIRF prescription activity since their initial enrollment in the TIRF REMS Access program. Based on this analysis, there is no barrier to patient access and further outreach is unwarranted. FDA_2667 48-month REMS Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Table 9 Page 34 of 112 Pharmacy Inactivations Current Reporting Perioda 29OCT2014 to 28OCT2015 Non-Closed System Pharmacies N (%) Closed System Pharmacies N (%) Total Pharmacies N (%) 4,919 1 4,920 112 (2.3%) 3 (0.1%) 4,382 (89.1%) 422 (8.6%) N/A N/A N/A N/A N/A 1 (100.0%) 112 (2.3%) 3 (0.1%) 4,382 (89.1%) 422 (8.6%) 1 (0.0%) Reason(s) for Inpatient Pharmacy Inactivationb Program Opt-Out Enrollment Expiredc Enrollment remained expired at end of period 16 (14.3%) 96 (85.7%) 68 (70.8%) N/A N/A N/A 16 (14.3%) 96 (85.7%) 68 (70.8%) Reason(s) for Chain Pharmacy Headquarters Inactivationd Program Opt-Out Enrollment Expiredc Enrollment remained expired at end of period 2 (66.7%) 1 (33.3%) 0 N/A N/A N/A 2 (66.7%) 1 (33.3%) 0 Reason(s) for Chain Pharmacy Store Inactivationd Program Opt-Out Enrollment Expiredc Enrollment remained expired at end of period 87 (2.0%) 4,295 (98.0%) 645 (15.0%) N/A N/A N/A 87 (2.0%) 4,295 (98.0%) 645 (15.0%) Reason(s) for Independent Outpatient Pharmacy Inactivatione Program Opt-Out Enrollment Expiredc Enrollment remained expired at end of period 5 (1.2%) 417 (98.8%) 326 (78.2%) N/A N/A N/A 5 (1.2%) 417 (98.8%) 326 (78.2%) N/A 1 (100.0%) 1 (100.0%) Parameter Number of Pharmacies that Became Inactivated During this Reporting Period Inpatient Pharmacies Chain Pharmacy Headquarters Chain Pharmacy Stores Independent Outpatient Pharmacies Closed System Pharmacies Reason(s) For Closed System Pharmacy Inactivationf Enrollment Expiredc FDA_2668 48-month REMS Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 35 of 112 Current Reporting Perioda 29OCT2014 to 28OCT2015 Parameter Enrollment remained expired at end of period Numbers of Pharmacies Inactivated in This Time Period that Remain Inactivated as of the End of this Reporting Period Inpatient Pharmacies Chain Pharmacy Headquarters Chain Pharmacy Stores Independent Outpatient Pharmacies Closed System Pharmacies Total Number of Pharmacies Inactivated as of the End of This Reporting Period Inpatient Pharmacies Chain Pharmacy Headquarters Chain Pharmacy Stores Independent Outpatient Pharmacies Closed System Pharmacies Non-Closed System Pharmacies N (%) N/A Closed System Pharmacies N (%) Total Pharmacies N (%) 1 (100.0%) 1 (100.0%) 1,145 1 1,146 84 (7.3%) 2 (0.2%) 728 (63.6%) 331 (28.9%) N/A N/A N/A N/A N/A 1 (100.0%) 84 (7.3%) 2 (0.2%) 728 (63.5%) 331 (28.9%) 1 (0.1%) 4,381 111 4,492 300 (6.8%) 12 (0.3%) 2,475 (56.5%) 1,594 (36.4%) N/A N/A N/A N/A N/A 111 (100.0%) 300 (6.7%) 12 (0.3%) 2,475 (55.1%) 1,594 (35.5%) 111 (2.5%) 12,289 168 12,457 Cumulative Number of Pharmacies Ever Inactivatedg Inpatient Pharmacies 453 (3.7%) N/A 453 (3.6%) Chain Pharmacy Headquarters 23 (0.2%) N/A 23 (0.2%) Chain Pharmacy Stores 9,476 (77.1%) N/A 9,476 (76.1%) Independent Outpatient Pharmacies 2,337 (19.0%) N/A 2,337 (18.8%) Closed System Pharmacies N/A 168 (100.0%) 168 (1.3%) a Pharmacies with ’inactive’ status at least once during the reporting period. b Percentages are based on the total number (N) of inactivated inpatient pharmacies. An inpatient pharmacy may have more than one reason for inactivation. c Pharmacies whose status is ‘Inactive-Expired’ at any time during the enrollment period. d Percentages are based on the total number (N) of inactivated chain pharmacy headquarters or chain pharmacy stores. A chain pharmacy headquarters or chain pharmacy store may have more than one reason for inactivation. e Percentages are based on the total number (N) of inactivated independent outpatient pharmacy stores. An independent outpatient pharmacy store may have more than one reason for inactivation. f Percentages are based on the total number (N) of inactivated closed system pharmacies. A closed system pharmacy may have more than one reason for inactivation. g Cumulative is sum of all reporting period totals. FDA_2669 48-month REMS Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 36 of 112 During the current reporting period, there were 44 pharmacies that attempted enrollment but enrollment was pending 3 to 6 months later. As of the end of the reporting period, there were a total of 198 pharmacies pending enrollment for 6 months or longer. Pharmacies may have attempted enrollment and become pending in another reporting period. For pharmacies pending enrollment for 3 to 6 months, the most frequent reasons were pending test transaction verification (63.6%), no attestation (34.1%), and training not complete (22.7%). For pharmacies pending enrollment for 6 months or longer, the most frequent reasons were similar and included pending test transaction verification (52.0%), no attestation (44.9%), and training not complete (35.9%). The number of pharmacies that attempted enrollment but are still pending enrollment for 3 to 6 months or longer than 6 months, and the reasons for pending enrollment are shown in Table 10. FDA_2670 48-month REMS Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Table 10 Page 37 of 112 Pharmacies Pending Enrollment Current Reporting Perioda 29OCT2014 to 28OCT2015 Pharmacies Pending Enrollment ≥3 - 6Monthsb Parameter Pharmacies that Attempted Enrollment but are Still Pending Enrollmentc Non-Closed System Pharmacies N (%) 44 Pharmacies Pending Enrollment: >6 Monthsb Closed System Total Non-Closed System Closed System Total Pharmacies Pharmacies Pharmacies Pharmacies Pharmacies N (%) N (%) N (%) N (%) N (%) 0 44 198 0 198 Reasons for Pending Enrollment Invalid DEA 2 (4.5%) 0 2 (4.5%) 6 (3.0%) 0 6 (3.0%) Invalid NCPDP 1 (2.3%) 0 1 (2.3%) 4 (2.0%) 0 4 (2.0%) Invalid NPI 1 (2.3%) 0 1 (2.3%) 3 (1.5%) 0 3 (1.5%) Knowledge Assessment Failure - First Attempt 1 (2.3%) 0 1 (2.3%) 6 (3.0%) 0 6 (3.0%) Knowledge Assessment Failure - Third Attempt 1 (2.3%) 0 1 (2.3%) 1 (0.5%) 0 1 (0.5%) Missing DEA Number 0 0 0 1 (0.5%) 0 1 (0.5%) No Attestation 15 (34.1%) 0 15 (34.1%) 89 (44.9%) 0 89 (44.9%) Pending Enrollment Intake 1 (2.3%) 0 1 (2.3%) 6 (3.0%) 0 6 (3.0%) Pending Test Transaction Verification 28 (63.6%) 0 28 (63.6%) 103 (52.0%) 0 103 (52.0%) Switch Provider Contract Not Signed 0 0 0 1 (0.5%) 0 1 (0.5%) Training Not Complete 10 (22.7%) 0 10 (22.7%) 71 (35.9%) 0 71 (35.9%) a Reflects the total number of pharmacies pending enrollment in the current reporting period. Pharmacies may have attempted enrollment and became pending in another reporting period. b Percentages are based on the total number (N) of pharmacies attempting enrollment. Percentages may not add up to 100% because a single pharmacy may be pending enrollment for more than one reason. c Pharmacies may be pending enrollment for more than one reason. FDA_2671 48-month REMS Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies 5.1.4 Page 38 of 112 Wholesaler/Distributor Enrollment [Metric 9 and 10] During the current reporting period, 3 (18.8%) wholesalers/distributors newly enrolled in the REMS program and 13 (81.3%) re-enrolled (Table 11). There were 3 wholesalers/distributors inactivated during the current reporting period due to enrollment expiration and 2 had not re-enrolled by the end of the reporting period (Table 12). Both distributors who remained inactivated at the end of the reporting period were acquired by other entities. Table 11 Distributor Enrollment Current Reporting Perioda 29OCT2014 to 28OCT2015 Parameter Number of Distributors with Enrollment Activity in This Reporting Period N (%) 16 Number of Newly Enrolled Distributors 3 (18.8%) Number of Re-Enrolled Distributors 13 (81.3%) Number of Distributors that Remain Enrolled from Previous Reporting Periods 21 Total Number of Distributors Enrolled as of the End of the Reporting Period 37 48 Cumulative Number of Distributors Ever Enrolledc a Percentages are based on the total number (N) for the relevant Distributors for the period. b Includes Distributors that transitioned into the TIRF REMS Access program from other individual REMS programs. c Cumulative Distributors from the end of prior period may differ from last period’s report due to reconciliation of duplicate Distributors. FDA_2672 48-month REMS Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 39 of 112 Table 12 Distributor Inactivations Current Reporting Perioda 29OCT2014 to 28OCT2015 Parameter Number of Distributors that Became Inactivated in This Reporting Period N (%) 3 Reason(s) for Distributor Inactivation Enrollment Expiredb Enrollment remained expired at end of period 3 (100.0%) 2 (66.7%) Number of Distributors that Remain Inactivated From Previous Reporting Periods 9 Total Number of Distributors Inactivated as of the End of the Reporting Period 11 Cumulative Number of Distributors Ever Inactivatedc,d 17 a Percentages are based on the total number (N) for the relevant inactivated Distributors for the period. Distributors with ‘inactive’ status at least once during the reporting period. c Distributors whose status is ‘Inactive-Expired’ at any time during the enrollment period. d Cumulative is sum of all reporting period totals. b 5.1.5 Dispensing Activity [Metric 11, 12, 13,] A total of 152,686 prescriptions were adjudicated for safety by the TIRF REMS Access program in the current reporting period including 152,228 prescriptions from non-closed system pharmacies and 458 from closed system pharmacies (Table 13). Of the total prescriptions, 94.2% were subsequently approved for dispensing without encountering any REMS-related rejections (i.e., were authorized for dispensing by insurance or cash bin). FDA_2673 48-month REMS Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 40 of 112 Table 13 Prescriptions from Outpatient Pharmacies That Did Not Encounter Any REMS-Related Rejections Prior to Being Authorized for Dispensing Current Reporting Perioda,b 29OCT2014 to 28OCT2015 Parameter Number of Unique Prescriptions Submitted for Authorization Non-Closed System Pharmacies N (%) 152,228 Cumulativea,b,c 28DEC2011 to 28OCT2015 Closed System Pharmacies N (%) All Pharmacies (Non-Closed and Closed) N (%) Non-Closed System Pharmacies N (%) Closed System Pharmacies N (%) All Pharmacies (Non-Closed and Closed) N (%) 458 152,686 558,038 3,037 561,075 Total Number of Unique Prescriptions That 143,365 (94.2%) 398 (86.9%) 143,763 (94.2%) 498,591 (89.3%) 2,415 (79.5%) 501,006 (89.3%) Did Not Encounter Any REMS-Related Rejections Prior to Being Authorized for Dispensing Independent Pharmacies 107,430 (70.6%) N/A 107,430 (70.4%) 329,849 (59.1%) N/A 329,849 (58.8%) Chain Pharmacies 35,935 (23.6%) N/A 35,935 (23.5%) 168,742 (30.2%) N/A 168,742 (30.1%) Closed System Pharmacies N/A 398 (86.9%) 398 (0.3%) N/A 2,415 (79.5%) 2,415 (0.4%) a Prescriptions successfully adjudicated for safety (i.e., successful REMS edit) and authorized for dispensing by insurance or cash bin (bin number). b Percentages are based on the total number (N) of unique prescriptions that never encountered a REMS-related rejection for the reporting period. c Includes authorizations from all pharmacies that were enrolled in the TIRF REMS Access program at any time from inception of the program. FDA_2674 48-month REMS Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 41 of 112 When a prescription is presented it must meet the REMS edit requirements before it may be authorized for dispensing, or it is rejected. The reasons why a prescription will not meet a REMS edit requirement are included in Table 14. If a prescription is rejected, the pharmacy must contact the TIRF REMS Access program to rectify the rejected transaction. Upon receiving an inbound call from a pharmacy provider, the TIRF REMS Access program Call Center Service Representative (CSR) works to resolve the rejected transaction and to provide instructions on the corrective action needed to successfully process the transaction. Corrective action includes outreach and education to remedy rejected transaction processing. Of the 152,686 unique prescriptions submitted for approval during the current reporting period, 1,735 prescriptions encountered at least one REMS-related rejection prior to being authorized for dispensing from outpatient pharmacies (Table 15). There were a total of 7,188 prescriptions that encountered at least one REMS-related rejection and were never authorized for dispensing (Table 16). Table 14 Reasons for Prescriptions Not Meeting REMS Edit Requirements Reason Description Prescriber ID Not Enrolled/Not Found Found the prescriber last name but not the NPI, DEA or State License Number or both prescriber last name and ID are not found PPAF Incomplete Patient’s PPAF is in an complete status; the PPAF is missing information Patient Zip Code Missing Patient’s zip code was not submitted on the transaction Prescriber Last Name Did Not Match Name Registered Prescriber last name on the transaction did not match the prescriber last name associated with the Prescriber ID Pharmacy Not Enrolled Pharmacy is not enrolled; the pharmacy has not completed the enrollment or re-enrollment process Prescriber ID not registered Found the prescriber last name but the NPI, DEA or State License Number does not match prescriber. PPAF expired Patient’s PPAF expired. (i.e. no prescription activity for 6 months) PPAF terminated Patient’s PPAF terminated (2 year expiration) Prescriber is terminated Prescriber enrollment terminated. Pharmacy terminated Pharmacy enrollment terminated Table 15 presents the results for the prescriptions that encountered at least one REMS-related rejection prior to being authorized for dispensing from outpatient pharmacies. The most frequent rejection reasons for independent pharmacies (n=1,254) were zip code missing (25.3%), PPAF incomplete (24.0%), Prescriber ID not registered (17.4%), Prescriber last name did not match register (12.8%), PPAF expired (9.4%), and PPAF terminated (9.1%). FDA_2675 48-month REMS Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 42 of 112 The most frequent rejection reasons for chain pharmacies (n=481) were Prescriber last name did not match registered (27.0%), Prescriber ID not registered (24.5%), PPAF incomplete (16.2%), PPAF terminated (11.0%), PPAF expired (9.4%), zip code missing (8.3%), and Prescriber is terminated (8.1%). No prescriptions from closed system pharmacies encountered a REMS-related rejection prior to being authorized for dispensing in the current reporting period. Table 16 presents the results for the prescriptions that encountered at least one REMS-related rejection and were never authorized for dispensing from outpatient pharmacies. As stated previously, of the 152,686 unique prescriptions submitted for approval during the current reporting period there were a total of 7,188 prescriptions that encountered at least one REMSrelated rejection and were never authorized for dispensing. The most frequent rejection reasons for independent pharmacies (n=3,959) were Prescriber ID not registered (38.7%), zip code missing (26.1%), Prescriber last name did not match registered (12.8%), Prescriber is terminated (12.0%). The most frequent rejection reasons for chain pharmacies (n=3,169) were Prescriber ID not registered (53.4%), Prescriber last name did not match registered (21.5%), Prescriber is terminated (10.5%), and zip code missing (8.2%). The most frequent rejection reasons for closed system pharmacies (n=60) were Prescriber ID not registered (41.7%), Pharmacy terminated (21.7%), Prescriber last name did not match registered (16.7%), and Prescriber is terminated (13.3%). FDA_2676 48-month REMS Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 43 of 112 Table 15 Prescriptions from Outpatient Pharmacies That Encountered at Least One REMS-Related Rejection Prior to Being Authorized for Dispensing Current Reporting Perioda,b 29OCT2014 to 28OCT2015 Parameter Number of Unique Prescriptions Submitted for Authorization Total Number of Unique Prescriptions that encountered At Least One Initial REMS-Related Rejection Prior to being Authorized for Dispensing Independent Pharmacies Chain Pharmacies Closed System Pharmacies Independent Pharmacies Reason(s) for Rejectiond Zip Code Missing PPAF Incomplete Prescriber last name did not match registered PrescriberID not registered PPAF terminated PPAF Expired Prescriber is terminated Last Name and DOB Missing PrescriberID not submitted Non-Closed System Pharmacies N (%) All Pharmacies Closed System (Non-Closed and Pharmacies Closed) N (%) N (%) Cumulativea,b,c 28DEC2011 to 28OCT2015 Non-Closed System Pharmacies N (%) Closed System Pharmacies N (%) All Pharmacies (Non-Closed and Closed) N (%) 152,228 458 152,686 558,038 3,037 561,075 1,735 (1.1%) 0 1,735 (1.1%) 18,576 (3.3%) 57 (1.9%) 18,633 (3.3%) 1,254 (0.8%) 481 (0.3%) N/A N/A N/A 0 1,254 (0.8%) 481 (0.3%) 0 13,432 (2.4%) 5,144 (0.9%) N/A N/A N/A 57 (1.9%) 13,432 (2.4%) 5,144 (0.9%) 57 (<0.1%) 317 (25.3%) 301 (24.0%) 161 (12.8%) 218 (17.4%) 114 (9.1%) 118 (9.4%) 77 (6.1%) 14 (1.1%) 29 (2.3%) N/A N/A N/A N/A N/A N/A N/A N/A N/A 6,475 (48.2%) 3,648 (27.2%) 1,839 (13.7%) 1,621 (12.1%) 885 (6.6%) 680 (5.1%) 280 (2.1%) 208 (1.5%) 128 (1.0%) N/A N/A N/A N/A N/A N/A N/A N/A N/A FDA_2677 48-month REMS Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 44 of 112 Current Reporting Perioda,b 29OCT2014 to 28OCT2015 Parameter Pharmacy terminated First Name Missing Prescriber Terminated and Last Name Mismatch DOB Missing First Name, Last Name, and Zip Code Missing Zip Code and Last Name First Name and Last Name Missing DOB and Zip Code Missing Last Name Missing Database Failure - System Unavailable due to maintenance First Name, Last Name and DOB Missing First Name, Last Name, Zip Code, and DOB Missing Multi-Match - two or more patient match on same criteria Chain Pharmacy Stores Reason(s) for Rejectiond PPAF Incomplete PrescriberID not registered Zip Code Missing PPAF terminated Prescriber last name did not match registered Non-Closed System Pharmacies N (%) 8 (0.6%) 7 (0.6%) 6 (0.5%) 6 (0.5%) 0 0 1 (0.1%) 1 (0.1%) 0 0 All Pharmacies Closed System (Non-Closed and Pharmacies Closed) N (%) N (%) N/A N/A N/A N/A N/A N/A N/A N/A N/A N/A Cumulativea,b,c 28DEC2011 to 28OCT2015 Non-Closed System Pharmacies N (%) 116 (0.9%) 68 (0.5%) 27 (0.2%) 24 (0.2%) 24 (0.2%) 13 (0.1%) 10 (0.1%) 9 (0.1%) 2 (<0.1%) 1 (<0.1%) Closed System Pharmacies N (%) N/A N/A N/A N/A N/A N/A N/A N/A N/A N/A 0 0 N/A N/A 1 (<0.1%) 1 (<0.1%) N/A N/A 0 N/A 1 (<0.1%) N/A 78 (16.2%) 118 (24.5%) 40 (8.3%) 53 (11.0%) 130 (27.0%) N/A N/A N/A N/A N/A 2,180 (42.4%) 1,087 (21.1%) 860 (16.7%) 517 (10.1%) 506 (9.8%) N/A N/A N/A N/A N/A All Pharmacies (Non-Closed and Closed) N (%) FDA_2678 48-month REMS Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 45 of 112 Current Reporting Perioda,b 29OCT2014 to 28OCT2015 Parameter PPAF Expired Prescriber is terminated First Name Missing Last Name and DOB Missing Pharmacy terminated PrescriberID not submitted First Name and Last Name Missing DOB Missing First Name, Last Name, and Zip Code Missing Multi-Match - two or more patient match on same criteria Prescriber Terminated and Last Name Mismatch First Name, Last Name and DOB Missing First Name, Last Name, Zip Code, and DOB Missing Pharmacy not Registered DOB and Zip Code Missing Database Failure - System unavailable due to system maintenance First Name and DOB Missing Last Name Missing Re-register Non-Closed System Pharmacies N (%) 45 (9.4%) 39 (8.1%) 9 (1.9%) 8 (1.7%) 6 (1.2%) 2 (0.4%) 0 0 0 0 All Pharmacies Closed System (Non-Closed and Pharmacies Closed) N (%) N (%) N/A N/A N/A N/A N/A N/A N/A N/A N/A N/A Cumulativea,b,c 28DEC2011 to 28OCT2015 Non-Closed System Pharmacies N (%) 394 (7.7%) 113 (2.2%) 56 (1.1%) 40 (0.8%) 26 (0.5%) 19 (0.4%) 7 (0.1%) 6 (0.1%) 6 (0.1%) 3 (0.1%) Closed System Pharmacies N (%) N/A N/A N/A N/A N/A N/A N/A N/A N/A N/A 0 0 0 N/A N/A N/A 3 (0.1%) 2 (<0.1%) 2 (<0.1%) N/A N/A N/A 0 0 0 N/A N/A N/A 2 (<0.1%) 1 (<0.1%) 1 (<0.1%) N/A N/A N/A 0 1 (0.2%) 0 N/A N/A N/A 1 (<0.1%) 1 (<0.1%) 1 (<0.1%) N/A N/A N/A All Pharmacies (Non-Closed and Closed) N (%) FDA_2679 48-month REMS Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 46 of 112 Current Reporting Perioda,b 29OCT2014 to 28OCT2015 Non-Closed System Pharmacies N (%) All Pharmacies Closed System (Non-Closed and Pharmacies Closed) N (%) N (%) Cumulativea,b,c 28DEC2011 to 28OCT2015 Non-Closed System Pharmacies N (%) Closed System Pharmacies N (%) All Pharmacies (Non-Closed and Closed) N (%) Parameter Closed System Pharmacies Reason(s) for Rejectiond Zip Code Missing N/A 0 N/A 33 (57.9%) PPAF Incomplete N/A 0 N/A 10 (17.5%) PrescriberID not registered N/A 0 N/A 9 (15.8%) PPAF terminated N/A 0 N/A 6 (10.5%) Prescriber last name did not match registered N/A 0 N/A 6 (10.5%) PPAF Expired N/A 0 N/A 3 (5.3%) a Prescription successfully adjudicated for safety (i.e., successful REMS edit).and authorized for dispensing by insurance or cash bin (bin number). b Percentages are based on the total number (N) of number of unique prescriptions that encountered at least one initial REMS-related rejection prior to being authorized for dispensing for the reporting period. c Includes authorizations from pharmacies that transitioned into the TIRF REMS Access program from other individual REMS programs. d Prescriptions can be rejected for more than one reason. FDA_2680 48-month REMS Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 47 of 112 Table 16 Prescriptions That Encountered at Least One REMS-Related Rejection and Never Authorized for Dispensing from Outpatient Pharmacies Current Reporting Perioda,b 29OCT2014 to 28OCT2015 Parameter Number of Unique Prescriptions Submitted for Authorization Total Number of Unique Prescriptions that encountered At Least One Initial REMS-Related Rejection and Never Authorized for Dispensing Independent Pharmacies Chain Pharmacies Closed System Pharmacies Independent Pharmacies Reason(s) for Rejectiond PrescriberID not registered Prescriber last name did not match registered Zip Code Missing PPAF Incomplete Prescriber is terminated Pharmacy terminated PPAF terminated PrescriberID not submitted PPAF Expired Non-Closed System Pharmacies N (%) All Pharmacies Closed System (Non-Closed and Pharmacies Closed) N (%) N (%) Cumulativea,b,c 28DEC2011 to 28OCT2015 Non-Closed System Pharmacies N (%) Closed System Pharmacies N (%) All Pharmacies (Non-Closed and Closed) N (%) 152,228 458 152,686 558,038 3,037 561,075 7,128 (4.7%) 60 (13.1%) 7,188 (4.7%) 40,871 (7.3%) 565 (18.6%) 41,436 (7.4%) 3,959 (2.6%) 3,169 (2.1%) N/A N/A N/A 60 (13.1%) 3,959 (2.6%) 3,169 (2.1%) 60 (<0.1%) 20,117 (3.6%) 20,754 (3.7%) N/A N/A N/A 565 (18.6%) 20,117 (3.6%) 20,754 (3.7%) 565 (0.1%) 1,533 (38.7%) 753 (19.0%) 1,032 (26.1%) 137 (3.5%) 476 (12.0%) 104 (2.6%) 68 (1.7%) 100 (2.5%) 44 (1.1%) N/A N/A N/A N/A N/A N/A N/A N/A N/A 9,632 (47.9%) 3,891 (19.3%) 2,357 (11.7%) 2,087 (10.4%) 1,691 (8.4%) 665 (3.3%) 412 (2.0%) 410 (2.0%) 250 (1.2%) N/A N/A N/A N/A N/A N/A N/A N/A N/A FDA_2681 48-month REMS Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 48 of 112 Current Reporting Perioda,b 29OCT2014 to 28OCT2015 Parameter Last Name and DOB Missing Prescriber Terminated and Last Name Mismatch First Name Missing Multi-Match - two or more patient match on same criteria First Name, Last Name, and Zip Code Missing DOB Missing First Name and Last Name Missing First Name, Last Name, Zip Code, and DOB Missing Last Name Missing Zip Code and Last Name Chain Pharmacies Reason(s) for Rejectiond PrescriberID not registered Prescriber last name did not match registered PPAF Incomplete Prescriber is terminated Pharmacy terminated PPAF terminated Zip Code Missing PrescriberID not submitted PPAF Expired Non-Closed System Pharmacies N (%) 44 (1.1%) 28 (0.7%) 17 (0.4%) 3 (0.1%) All Pharmacies Closed System (Non-Closed and Pharmacies Closed) N (%) N (%) N/A N/A N/A N/A Cumulativea,b,c 28DEC2011 to 28OCT2015 Non-Closed System Pharmacies N (%) 101 (0.5%) 95 (0.5%) 46 (0.2%) 8 (<0.1%) Closed System Pharmacies N (%) N/A N/A N/A N/A 4 (0.1%) 2 (0.1%) 3 (0.1%) 0 N/A N/A N/A N/A 7 (<0.1%) 3 (<0.1%) 3 (<0.1%) 2 (<0.1%) N/A N/A N/A N/A 0 0 N/A N/A 1 (<0.1%) 1 (<0.1%) N/A N/A 1,691 (53.4%) 682 (21.5%) 77 (2.4%) 332 (10.5%) 70 (2.2%) 61 (1.9%) 260 (8.2%) 34 (1.1%) 36 (1.1%) N/A N/A N/A N/A N/A N/A N/A N/A N/A 13,578 (65.4%) 2,463 (11.9%) 2,245 (10.8%) 1,434 (6.9%) 409 (2.0%) 379 (1.8%) 371 (1.8%) 240 (1.2%) 230 (1.1%) N/A N/A N/A N/A N/A N/A N/A N/A N/A All Pharmacies (Non-Closed and Closed) N (%) FDA_2682 48-month REMS Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 49 of 112 Current Reporting Perioda,b 29OCT2014 to 28OCT2015 Parameter Last Name and DOB Missing First Name Missing Prescriber Terminated and Last Name Mismatch Multi-Match - two or more patient match on same criteria First Name and Last Name Missing Pharmacy not Registered Last Name Missing DOB and Zip Code Missing Database Failure - System unavailable due to system maintenance Closed System Pharmacies Reason(s) for Rejectiond PrescriberID not registered Prescriber last name did not match registered PPAF Incomplete Pharmacy terminated Prescriber is terminated Zip Code Missing PPAF terminated PPAF Expired Multi-Match - two or more patient match on same criteria Non-Closed System Pharmacies N (%) 59 (1.9%) 31 (1.0%) 14 (0.4%) 0 All Pharmacies Closed System (Non-Closed and Pharmacies Closed) N (%) N (%) N/A N/A N/A N/A Cumulativea,b,c 28DEC2011 to 28OCT2015 Non-Closed System Pharmacies N (%) 67 (0.3%) 61 (0.3%) 28 (0.1%) 11 (0.1%) Closed System Pharmacies N (%) N/A N/A N/A N/A 0 0 4 (0.1%) 0 0 N/A N/A N/A N/A N/A 10 (<0.1%) 10 (<0.1%) 4 (<0.1%) 1 (<0.1%) 1 (<0.1%) N/A N/A N/A N/A N/A N/A N/A N/A N/A N/A N/A N/A N/A N/A 25 (41.7%) 10 (16.7%) 2 (3.3%) 13 (21.7%) 8 (13.3%) 1 (1.7%) 1 (1.7%) 1 (1.7%) 0 N/A N/A N/A N/A N/A N/A N/A N/A N/A 307 (54.3%) 103 (18.2%) 55 (9.7%) 41 (7.3%) 34 (6.0%) 28 (5.0%) 4 (0.7%) 2 (0.4%) 1 (0.2%) All Pharmacies (Non-Closed and Closed) N (%) FDA_2683 48-month REMS Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 50 of 112 Current Reporting Perioda,b 29OCT2014 to 28OCT2015 Cumulativea,b,c 28DEC2011 to 28OCT2015 All All Non-Closed Non-Closed Pharmacies Pharmacies System Closed System (Non-Closed and System Closed System (Non-Closed Pharmacies Pharmacies Closed) Pharmacies Pharmacies and Closed) Parameter N (%) N (%) N (%) N (%) N (%) N (%) Prescriber Terminated and Last Name Mismatch N/A 0 N/A 1 (0.2%) PrescriberID not submitted N/A 0 N/A 1 (0.2%) a Prescription successfully adjudicated for safety (i.e., successful REMS edit).and authorized for dispensing by insurance or cash bin (bin number). b Percentages are based on the total number (N) of number of unique prescriptions that encountered at least one initial REMS-related rejection prior to being authorized for dispensing for the reporting period. c Includes authorizations from pharmacies that transitioned into the TIRF REMS Access program from other individual REMS programs. d Prescriptions can be rejected for more than one reason. FDA_2684 48-month REMS Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 51 of 112 In the 36-Month FDA Assessment Report Acknowledgement Letter, the FDA remarked that there was a notable increase in mean and median prescription processing times during the 36month reporting period versus the previous reporting period. The FDA requested that TRIG investigate and identify the causes of these increasing delays in prescription processing and report the results in the 48-month assessment report. For all pharmacies, the mean time to authorization for a prescription that experienced at least one initial REMS-related rejection was 6.7 days while the median time was 1.3 days (Table 17). For chain pharmacy stores it took a mean of 7.8 days (median 2.2 days) compared with independent outpatient pharmacies that took a mean of 6.3 days (median 1.0 day). There were no inpatient or closed system pharmacies with data to report in the current reporting period as no REMS-related rejections were received by these pharmacies. The increase in the mean time to authorization between chain and independent pharmacies may be primarily due to the relatively low number of prescriptions with at least one initial REMS-related rejection (n=1,735 [1.1%]). For comparison, in the 36-month report the number of prescriptions with at least one initial REMS-related rejection was 3,738 (2.3% of total prescriptions). Table 17 Time to Authorization for a Prescription that Experienced at Least One Initial REMSRelated Rejection Total Mean Time For Prescription to be Authorizeda (Days)b Inpatient Pharmacies Chain Pharmacy Stores Independent Outpatient Pharmacies Closed System Pharmacies Current Reporting Period 29OCT2014 to 28OCT2015 Cumulative 28DEC2011 to 28OCT2015 6.683 3.647 -7.805 6.253 -- -4.382 3.354 6.291 1.320 0.213 Total Median Time For Prescription to be Authorizeda (Days) Inpatient Pharmacies --Chain Pharmacy Stores 2.171 1.036 Independent Outpatient Pharmacies 1.031 0.089 Closed System Pharmacies -1.124 a Prescriptions included were resolved in the current reporting period. Prescriptions may have been initially rejected in a previous reporting period. b Time to authorization for a prescription that experienced at least one initial REMS-related rejection excludes prescriptions processed through the inpatient pharmacy process. FDA_2685 48-month REMS Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 52 of 112 As described in Section 5.1.3., a total of 7 closed-system pharmacy entities were enrolled in the TIRF REMS Access program during this reporting period. These entities include: • (b) (4) • • • • • • National Institutes of Health Clinical Center Pharmacy U.S. Department of Veterans Affairs (b) (4) DLA Troop Support (b) (4) During the current reporting period, a total of 398 prescription authorizations were provided through these closed system pharmacy locations (Table 18). During this reporting period on (b) (4) 18 May 2015, transitioned from being a closed-system pharmacy to a non-closed system pharmacy due to the pharmacy obtaining the ability to electronically adjudicate claims. Therefore, the prescription authorizations described (b) (4) in Table 18 for only represent prescriptions processed prior to this transition. Table 18 Number of Prescription Authorizations per Closed System Pharmacy Current Reporting Period 29OCT2014 to 28OCT2015 Cumulative 28DEC2011 to 28OCT2015 398 2,472 Total Number of Closed System Pharmacy Prescription Authorizations (b) (4) (b) (4) FDA_2686 48-month REMS Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 53 of 112 Current Reporting Period 29OCT2014 to 28OCT2015 Cumulative 28DEC2011 to 28OCT2015 (b) (4) (b) (4) FDA_2687 48-month REMS Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 54 of 112 Current Reporting Period 29OCT2014 to 28OCT2015 Cumulative 28DEC2011 to 28OCT2015 (b) (4) a During this reporting period on 18 May 2015, (b) (4) closed system pharmacy to a non-closed system pharmacy. changed from a In the 36-Month FDA Assessment Report Acknowledgement Letter, the FDA requested that the closed-system pharmacies authorization process be re-evaluated as to whether a novel authorization process was warranted or technically feasible and report the conclusions in the 48month assessment report. The TRIG has determined that the current prescription authorization volume for closed-system pharmacies is less than 1% of all TIRF prescriptions and due to the absence of complaints with the current process, no changes are warranted at this time. The TRIG will continue to monitor and assess the need for an alternate solution as appropriate. 5.1.6 Barriers or Delays in Patient Access [Metric 14 and 15] Prescriptions Dispensed Within First 10 Days after Patient Enrollment Across all pharmacies, a total of 8,101 prescriptions were dispensed to 6,715 patients within the first 10 days after patient enrollment (Table 19). The majority of patients (n=6,702) were dispensed prescriptions by non-closed system pharmacies (8,087 prescriptions). Of the 2,059 patients who received prescriptions without a PPAF, the majority of patients (30.7%) received only 1 fill without a PPAF. A total of 8 patients received 3 prescriptions within 10 days without a PPAF on file. All 8 patients had their prescriptions filled through non-closed system pharmacies. During this reporting period, it was observed that 1 patient potentially received more than 3 fills within the 10-day period without a PPAF on file from a non-closed system pharmacy. 48-Month Assessment Report Update In the 36-month assessment report, it was reported that 4 patients received more than 3 prescriptions within 10 days without a PPAF on file. All 4 patients had their prescriptions filled through non-closed system pharmacies. Upon review of all 4 patients’ prescription FDA_2688 48-month REMS Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 55 of 112 instances and detail, it was verified that none of the 4 patients received more than 3 prescriptions within 10 days without a PPAF on file. For Patients 1 through 3, the same independent outpatient pharmacy submitted duplicate prescriptions that did not count towards the 10-day period and also submitted reversal prescriptions for these claims. Since the prescription status did not change, it first appeared that the patients received multiple prescriptions when in fact they had not. It was confirmed that the 3 patients received only 3 unique prescriptions each within the 10 day period. For Patient 4, a different independent outpatient pharmacy submitted 4 prescriptions. Three prescriptions were batched billed from the pharmacy’s pharmacy management system simultaneously, causing the prescriptions to pass through the REMS edits sub-seconds apart. Since a patient record was not found, the patient was passively enrolled in the TIRF REMS Access program 3 times. A fourth prescription was submitted and subsequently reversed. Ultimately, it was confirmed that the patient received only 3 unique prescriptions within the 10-day period. The data indicate these are isolated incidents that happened over 3 days and at 2 separate independent outpatient pharmacies. Both pharmacies were contacted and the pharmacists verbally confirmed that each patient did not receive greater than 3 prescriptions in the 10-day period. The pharmacists were re-educated on the TIRF REMS Access program prescription process. PPAFs were appropriately submitted for all 4 patients. FDA_2689 48-month REMS Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 56 of 112 Table 19 Prescriptions Dispensed During the First 10 Days after Passive Patient Enrollment Cumulativea,b 28DEC2011 to 28OCT2015 Current Reporting Period 29OCT2014 to 28OCT2015 Non-Closed System Pharmacies N (%) Closed System Pharmacies N (%) Combined Pharmaciesd N (%) Total Pharmacies N (%) Non-Closed System Pharmacies N (%) Closed System Pharmacies N (%) Combined Pharmaciesd N (%) Total Pharmacies N (%) Number of prescriptions dispensed during the first 10 days after patient enrollment 8,087 14 0 8,101 37,444 211 11 37,666 Number of patients dispensed a prescription during the first 10 days after enrollment 6,702 13 0 6,715 31,249 174 5 31,428 1 Fill 3,704 (55.3%) 5 (38.5%) 0 1 (20.0%) 13,427 (42.7%) 2 Fills 770 (11.5%) 1 (7.7%) 0 771 (11.5%) 2,606 (8.3%) 9 (5.2%) 0 2,615 (8.3%) 3 Fills 104 (1.6%) 0 0 104 (1.5%) 380 (1.2%) 1 (0.6%) 0 381 (1.2%) 18 (0.3%) 0 0 18 (0.3%) 80 (0.3%) 2 (1.1%) 0 82 (0.3%) 1 Fill 2,052 (30.6%) 7 (53.8%) 0 1 (20.0%) 14,072 (44.8%) 2 Fills 188 (2.8%) 0 0 188 (2.8%) 1,333 (4.3%) 5 (2.9%) 3 (60.0%) 1,341 (4.3%) 3 Fills 8 (0.1%) 0 0 8 (0.1%) 223 (0.7%) 4 (2.3%) 1 (20.0%) 228 (0.7%) >3 Fills 1 (<0.1%) 0 0 1 (<0.1%) 10 (<0.1%) 0 0 10 (<0.1%) Parameter With PPAFb >3 Fills Without PPAF 3,709 (55.2%) 13,373 (42.8%) 53 (30.5%) b,c 2,059 (30.7%) 13,971 (44.7%) 100 (57.5%) a Cumulative data from the end of prior period may differ from the last period’s report due to reconciliation of duplicate stakeholders. Percentages are based on the total number of patients for the period. Sum of percentages may be greater than 100 due to patients receiving prescriptions with and without a PPAF during the grace period. c A patient may receive up to 3 fills in the first 10 days after enrollment without a PPAF. d Patients who have filled a prescription at both a closed system pharmacy and a non-closed system pharmacy. b FDA_2690 48-month REMS Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 57 of 112 Prescriptions Dispensed Beyond 10 Days after Patient Enrollment The TIRF REMS Access program requires that each patient have a PPAF submitted to the TIRF REMS Access program by their prescriber within 10 days of their passive enrollment in order to continue to receive a TIRF medicine. Table 20 below shows the number of prescriptions dispensed beyond the first 10 days without a PPAF on file. From the inception of the TIRF REMS through the current reporting period, 759 prescriptions have been dispensed beyond the first 10 days without a PPAF; only 1 prescription was reported in the current reporting period. TRIG is currently researching the root cause for this 1 prescription that was dispensed beyond 10 days after patient enrollment, and the findings will be reported in the 60-month report. FDA_2691 48-month REMS Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 58 of 112 Table 20 Prescriptions Dispensed Beyond the First 10 Days after Passive Patient Enrollment Without a PPAF Cumulativea,b 28DEC2011 to 28OCT2015 Current Reporting Period 29OCT2014 to 28OCT2015 Filled at NonFilled at Closed Closed System System Pharmacies Pharmacies Parameter Fills beyond the first 10 days Without PPAF a b Filled at Combined Pharmaciesb Filled at NonFilled at Closed Closed Filled at All System System Pharmacies Pharmacies Pharmacies Filled at Combined Pharmaciesb Filled at All Pharmacies N (%) N (%) N (%) N (%) N (%) N (%) N (%) N (%) 1 0 0 1 724 32 3 759 Cumulative data from the end of prior period may differ from the last period's report due to reconciliation of duplicate stakeholders. A patient who has filled a prescription at both a closed system pharmacy and a non-closed system pharmacy. FDA_2692 48-month REMS Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies 5.2 Program Infrastructure and Performance [Metrics 16, 17, 18, 19] 5.2.1 Backup System for Prescription Validation [Metric 16] Page 59 of 112 During this reporting period there were no instances in which a backup system was used to validate a prescription due to pharmacy level problems, switch problems, or REMS database problems. 5.2.2 System Interruptions/Errors and Corrective Actions [Metric 17, 19] There were no unintended system interruptions during this reporting period [Metric 17]. There was one report of unintended system interruptions that occurred in this reporting period [Metric 19]. A brief summary of this issue identified as a system error/problem and the corrective action is presented below. System Error and Corrective Action #1 (#23): Description On 15 November 2013, 16 patients were identified who had a PPAF expired that received prescriptions outside the grace period requirements. The grace period requirement states that a patient can receive a maximum of 3 prescriptions within 10-day duration after PPAF expiration. The grace period begins once the patient receives their first prescription after the PPAF has expired. Root Cause Inadequate communication of pending action defined during TRIG-vendor meeting on 16 November 2011. Containment On 17 March 2015, system updates were completed to allow for multiple PPAF expirations per patient to initiate the grace period rather than rejecting claims received after the second and subsequent PPAF expirations. Correction The REMS program Change Management Process document needed to clearly identify and track program change inputs and requestors was completed on 15 September 2012. The Product Change Request Procedure SOP-OP-005 was published, and monitoring since that time showed no missed actions/inputs to prompt offering change. No additional violations of the REMS requirements have been reported to date since the problem was identified. Resolution Prior to completion of the system updates, on 10 January 2014, all 16 patients, originally reported with expired PPAFs, were confirmed to have a current PPAF on file. FDA_2693 48-month REMS Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies 5.2.3 Page 60 of 112 REMS Call Center [Metric 18] Table 21 below shows reasons for contacting the REMS Call Center by frequency (%). For presentation in the report, this table includes at least 80% of the total cumulative frequency. The most frequent reasons classified under the call reason were pharmacy claim rejection (18.9%), enrollment status inquiry (15.7%), PPAF status inquiry (10.3%), and Web portal logon assistance (8.3%). The call reasons listed below in Table 21 represent 80.6% of calls to the Call Center for the current reporting period. Table 21 Current Assessment Period Contact Reasons Reason Count Percenta Pharmacy: Pharmacy Claim Rejection 3,300 18.9% Enrollment Status Inquiry 2,746 15.7% PPAF Inquiry 1,796 10.3% Web Portal Logon Assistance 1,448 8.3% Identifier Issues 948 5.4% Other/Miscellaneous 909 5.2% Enrollment Form 890 5.1% General Program Questions 872 5.0% Relay Health Transfer – Tier 2 Support 663 3.8% Potential Adverse Event 501 2.9% a The total percentage presented in the table account for 80.6% of all reasons for contacting the Call Center. There were no REMS- related barriers reported to the REMS Call Center to report during this reporting period. 6 TIRF REMS ACCESS PROGRAM NON-COMPLIANCE In the 36-month FDA Report Assessment Acknowledgement Letter, FDA requested that the criteria as to how compliance decisions are made by the NCRT be included with the 48-month assessment report, along with the Non-Compliance Protocol (Appendix 12.1). FDA also commented that the presentation of non-compliance data in the 36-month assessment report was disorganized. Events found in one non-compliance section of the report sounded similar to events reported in other areas, and thus it was unclear whether these different sources were referring to distinct events or were describing the same event. In addition, while the noncompliance activity table indicated seven instances where closed system pharmacies dispensed drugs without obtaining authorization, the audit conducted by the TRIG reported 513 such incidents. The FDA requested that this section be organized and harmonized with these various components into one clear presentation that was comprehensive and eliminates duplication. FDA_2694 48-month REMS Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 61 of 112 Given this feedback, the non-compliance section was reorganized and clarifying text has been added throughout Section 6, to allow for clean interpretation of the data and events that took place during this reporting period. Non-compliance is reported via four methods within this assessment report. 1. Stakeholder Non-Compliance Table: Non-compliance cases that have been identified during this reporting period by any stakeholder are counted in the table in Section 6.1, Table 22. 2. Stakeholder Non-Compliance Narratives: Stakeholders who are associated with instances of non-compliance resulting from an NCRT “Warning” or any assessment monitoring are described via non-compliance narrative in Section 6.1, Table 23. 3. CSP Audit Results: Non-compliance cases identified through the CSP audits are described via audit summary in Section 6.2.1. 4. Inpatient Hospital Pharmacy Audit Results: Non-compliance cases identified through the inpatient audits would be described via audit summary in Section 6.2.2; however, no non-compliance was identified through these audits and therefore no audit summaries have been included. These four methods of reporting non-compliance are additive in nature. Non-compliance cases discussed within the audit sections or the non-compliance narratives are not counted within the non-compliance table. Prescribers or pharmacies represented in the table are not described in the audit sections or the non-compliance narrative table. 6.1 Stakeholder Non-Compliance [Metric 23, 24, 25, 26, 27, 28] Each unique stakeholder non-compliance case is investigated and non-compliance activity is generally reported two ways during a reporting period, either as a confirmed non-compliance activity report as in Table 22 or it is described in a narrative as in Table 23. If single noncompliance cases are reported over time and appear, for example, in Table 22 for two consecutive assessment reports, the Stakeholder’s third offense will warrant a CAP and then all offenses are reported in a narrative only, and not in Table 22. Any confirmed non-compliance event that results in an NCRT “Warning” or is a result of any assessment monitoring (includes closed system monitoring and inpatient pharmacy audits) will be reported in a narrative as in Table 23 [Metric 23]. During the current reporting period, instances of potential stakeholder non-compliance with the TIRF REMS Access program were reviewed and investigated. A summary of the noncompliance activity is presented in Table 22. FDA_2695 48-month REMS Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 62 of 112 Table 22 Non-Compliance Activity Reports by Stakeholder in the Current Reporting Period: 29 October 2014 to 28 October 2015 Stakeholdera Non-Compliance Activity Non-Closed System Pharmacy Submission of a claim that did not go through the REMS edits. A TIRF medicine was dispensed without verifying through the TIRF PMS that the prescriber is enrolled and active, and that the patient is enrolled or has not been inactivated in the program. Submission of inappropriately altered claim to meet TIRF REMS system requirements (e.g. changing prescriber) Prescriber Prescriber failure to have a complete PPAF on file in a timely manner (5 or more patients enrolled by the prescriber without a complete PPAF on file, with each patient having greater than 10 working days lapse from initial enrollment date). Non-Compliant Reason (categorized as reported by the stakeholder) No. of events No. of stakeholders Not aware of requirement to process cash claims 7 No. w/1 report: 7 Received reject but dispensed drug 3 No. w/1 report: 3 Dispensed drug without obtaining an authorization 1 No. w/1 report: 1 Altered prescription details for a REMS authorization 1 No. w/1 report: 1 Total Non-Closed System Pharmacy Cases 12 Not aware of PPAF requirementb 18 No. w/1 report: 18 Completed PPAF with patient but failed to send PPAF to TIRF REMS 34 No. w/1 report: 34 Aware of PPAF requirements but failed to complete PPAFb 9 No. w/1 report: 9 No reason provided 21 No. w/1 report: 21 Total Prescriber Reports 82 Total Number of Reports 94 During This Reporting Period a There were no non-compliance cases for Wholesaler/Distributors or Closed-System Pharmacies. b One Prescriber had two non-compliance events in two non-compliance categories. During the reporting period, there were a total of 3 instances where TIRF prescriptions were dispensed by a non-closed system pharmacy (Table 22) that were written by non-enrolled prescribers after receiving a rejection from the TIRF REMS Access program [Metric 24]. 1. On 23 October 2014, a pharmacy contacted the TIRF REMS Access program to troubleshoot a reject received due to a prescriber not being enrolled in the program. During the interaction with the TIRF REMS Access program, the pharmacy confirmed that drug was dispensed to the patient, despite receiving a reject. On 24 October 2014, the TIRF REMS Access non-compliance team contacted the pharmacy’s authorized FDA_2696 48-month REMS Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 63 of 112 representative and re-education was provided. The pharmacist confirmed that they understood that TIRF REMS drugs could not be dispensed without first obtaining a REMS authorization. On 11 November 2014, the TIRF REMS Access program issued a notice of non-compliance to the pharmacy. The TIRF REMS Access program made multiple attempts to reach the prescriber to assist with enrollment, but the prescriber did not respond. 2. On 14 April 2015, a pharmacy contacted the TIRF REMS Access program to inquire about assisting a prescriber with enrollment. During the interaction with the TIRF REMS Access program, the pharmacy confirmed that drug was dispensed to the patient on two separate occasions. The pharmacy advised that when they received a reject for the prescriber who wrote the prescription, the processed the prescription using an alternate enrolled prescriber from the same practice. On 20 April 2015, the TIRF REMS Access non-compliance team contacted the pharmacy’s authorized representative and reeducation was provided. The pharmacist advised they dispensed drug so that the patient would not be without treatment. The pharmacist confirmed that they understood that TIRF REMS drugs could not be dispensed without first obtaining a REMS authorization. On 24 April 2015, the TIRF REMS Access program issued a notice of non-compliance to the pharmacy. The TIRF REMS Access program contacted the prescriber to assist with enrollment, and on 14 April 2015 the prescriber successfully enrolled in the TIRF REMS Access program. 3. On 07 July 2015, a pharmacy contacted the TIRF REMS Access program to troubleshoot a reject received due to a prescriber not being enrolled in the program. During the interaction with the TIRF REMS Access program, the pharmacy confirmed that drug was dispensed to the patient, despite receiving a reject. On 13 July 2015, the TIRF REMS Access non-compliance team contacted the pharmacy’s authorized representative and re-education was provided. The pharmacist advised they dispensed drug so that the patient would not be without treatment. The pharmacist confirmed that they understood that TIRF REMS drugs could not be dispensed without first obtaining a REMS authorization. On 21 July 2015, the TIRF REMS Access program issued a notice of non-compliance to the pharmacy. The TIRF REMS Access program contacted the prescriber to assist with enrollment, and on 17 July 2015 the prescriber advised he did not have time to enroll in a REMS program and stated he understood that he would be unable to prescriber TIRF medicines until enrollment was completed. No additional compliance cases for these pharmacies have been identified as of the end of the reporting period. There were no instances in which a prescription was dispensed by a non-enrolled pharmacy [Metric 25]. As shown in Table 22, there were 12 instances in which a TIRF prescription was dispensed because a pharmacy (closed or open system) was able to bypass REMS edits [Metric 26]. FDA_2697 48-month REMS Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 64 of 112 No reports of TIRF medicines being prescribed to an opioid non-tolerant individual [Metric 27] or cases of inappropriate conversions between TIRF products [Metric 28] were received by sponsor companies during this reporting period. Table 23 summarizes in narrative form all resolved non-compliance cases (n=6) and potential non-compliance events that remain pending as of the end of the reporting interval (n=1). FDA_2698 48-month REMS Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 65 of 112 Table 23 Non-Compliance Reports in the Current Reporting Period: 29 October 2014 to 28 October 2015 Report Description (N=7) Report Status ID# 283 (Case # 13861174, 18918829 & 22270353) Closed [24-Month Assessment Report Non-Compliance] Prescriber was issued a first formal Notice for NonCompliance on 20 September 2013 for not submitting PPAFs for 5 patients. [36-Month Assessment Report Non-Compliance] Prescriber was issued a second Notice for NonCompliance on 20 May 2014 for not submitting PPAFs for 6 patients. On 10 November 2014 the prescriber was again identified as not submitting PPAFs for 6 patients. Mitigating Action The TIRF REMS Access program re-educated the prescriber on 18 November 2014. The prescriber stated that the reason he has not submitted PPAFs is due to user error in completing the attestation electronic signature on the TIRF REMS website. The prescriber was reminded that the office will receive a confirmation from the website when a PPAF is submitted correctly and also provided directions on how to successfully complete and submit the PPAFs with the electronic signature. [48-Month Assessment Report Update] The prescriber was issued a Warning for Non-Compliance on 05 December 2014 requiring that a CAP be submitted by 30 December 2014. The prescriber submitted a CAP on 29 December 2014. The CAP was not approved as it did not align with the reeducation provided to the prescriber; rather, the prescriber requested that the faxes and website be checked for the missing PPAFs. The prescriber stated that the forms were faxed because the prescriber had no success submitting forms on the website. A revised CAP was requested and received on 16 January 2015. Again, the CAP was not approved as it did not align with the re-education provided to the prescriber. The corrective action stated that the prescriber understood the guidelines/policies for prescribing TIRF medicines. A revised CAP was again requested and received on 17 February 2015. The corrective action stated that the prescriber and his staff were trained on how to submit PPAFs via fax and the website. This CAP was approved by the NCRT on 19 February 2015. Since closing the non-compliance case, no additional non-compliance cases for this prescriber have been identified. FDA_2699 48-month REMS Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Report Description (N=7) Report Status ID# 294 (Case # 20214924 & 22596663) Closed On 11 June 2014 the prescriber was identified as not submitting PPAFs for 5 patients. The TIRF REMS Access program attempted to contact the prescriber multiple times between 12 June 2014 and 16 July 2014. A request for contact was issued to the prescriber after multiple unsuccessful contact attempts. The prescriber failed to contact the program for re-education by the deadline of 18 July 2014. A formal Notice of Non-Compliance was issued to the prescriber on 18 July 2014. None of the outstanding 5 PPAFs were submitted as all patients were identified as not continuing therapy. Page 66 of 112 Mitigating Action The TIRF REMS Access program attempted to contact the prescriber multiple times between 04 December 2014 and 30 December 2014. A request for contact was issued to the prescriber after multiple unsuccessful contact attempts. The prescriber failed to contact the program for re-education by the deadline of 21 January 2015. After no response to additional attempts to contact, a Warning letter was issued to the prescriber on 05 February 2015 requiring that a CAP is submitted by 26 February 2015. A CAP was received on 20 February 2015 stating that patients are seen at different locations and the signed PPAFs were misplaced. The prescriber stated that starting immediately PPAFs will be completed online. The NCRT approved the CAP on 11 February 2015. Since closing the non-compliance case, no additional non-compliance cases for this prescriber have been identified. On 04 December 2014 the prescriber was again identified as not submitting PPAFs for 7 new patients who were at least 10 days past enrollment. ID# 305 (Case # 12481943, 15791475, 21540583 & 23454251) [24-Month Assessment Report Non-Compliance] Prescriber was issued a first formal Notice for NonCompliance on 12 March 2013 for not submitting PPAFs for 13 patients and a Warning letter requiring a CAP on 05 November 2013 for not submitting PPAFs for 11 patients. [36-Month Assessment Report Non-Compliance] The prescriber failed to submit a CAP by the deadline of 26 November 2013. To prevent patient access issues, the prescriber was granted an extension until 09 January 2014 by the NCRT as the prescriber was Closed The prescriber was contacted and re-educated on 17 February 2015. The prescriber stated that the patient count for the outstanding PPAFs is a small percentage of his patient population and he did not understand why this was considered non-compliance. The TIRF REMS Access program reminded the prescriber that he is responsible to submit PPAFs for every new patient prior to their first prescription. Due to the number and severity of offenses, the prescriber was suspended from the TIRF REMS Access program on 26 February 2015 and required to submit a new CAP within 10 business days. A CAP was received the same day. The NCRT did not approve the CAP as there were too limited of details provided to ensure the prescriber understands the requirements and will comply. A revised CAP was received on 02 March 2015 and approved by the NCRT on 03 March 2015. The noncompliance case was closed and the TIRF REMS Access program FDA_2700 48-month REMS Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Report Description (N=7) Report Status in the process of transitioning office practices. The prescriber failed to submit a CAP by the extended deadline and was suspended from the TIRF REMS Access program. A CAP was received on 14 January 2014 stating that the prescriber will ensure that PPAFs are submitted the same day as when the prescription is written or at least within the 10 day grace period. The CAP was approved by the NCRT on 15 January 2014 and the prescriber’s suspension from the TIRF REMS Access program was removed. Page 67 of 112 Mitigating Action monitored the prescriber’s adherence to PPAF activities for 30 days. In addition to monitoring, the CEO/Head of Practice at this prescriber’s location was contacted and informed of the trend in non-compliance associated to this prescriber. PPAFs for all new patients were received within the grace period. Since closing the non-compliance case, no additional non-compliance cases for this prescriber have been identified. On 18 September 2014 the prescriber was again identified as not submitting PPAFs for 6 patients. The prescriber was issued a second Warning Letter on 20 October 2014 requiring a CAP be submitted by 10 November 2014. A CAP was received the same day and approved by the NCRT on 22 October 2014. [48-Month Assessment Report Non-Compliance] On 05 February 2015, the prescriber was again identified as not submitting PPAFs for 9 patients. ID# 314 (Case # 13861166, 18732022 & 23904486) [24-Month Assessment Report Non-Compliance] Prescriber was issued a formal Notice for NonCompliance on 13 August 2013 for not submitting PPAFs for 5 patients. [36-Month Assessment Report Non-Compliance] Prescriber was issued a second formal Notice for Non-Compliance on 09 April 2014 for not submitting PPAFs for 6 patients. Closed The prescriber was contacted and re-educated on 12 March 2015. The prescriber stated that he understands that it is his responsibility to ensure that PPAFs are submitted for each new patient prior to their first prescription. A first Warning letter was issued on 24 March 2015 requiring a CAP be submitted by 21 April 2015. A CAP was received on 08 April 2015. The NCRT did not approve the CAP as it did not address why the non-compliance occurred and the corrective action moving forward. A revised CAP was received on 23 April 2015. The NCRT did not approve the CAP as the prescriber needed to take responsibility for submitting PPAFs and not rely on his office staff to complete the PPAFs. A revised CAP was received on 06 May 2015 stating that the prescriber would personally fill out the PPAFs for new patients. This FDA_2701 48-month REMS Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Report Description (N=7) Report Status Page 68 of 112 Mitigating Action [48-Month Assessment Report Non-Compliance] CAP was approved by the NCRT. On 03 March 2015, the prescriber was again identified as not submitting PPAFs for 5 patients. Since closing the non-compliance case, no additional non-compliance cases for this prescriber have been identified. ID#357 (Case 12925438, 20277916, 25221416 #) [24-Month Assessment Report Non-Compliance] Prescriber was issued a formal Notice for NonCompliance on 07 May 2013 for not submitting PPAFs for 6 patients. [36-Month Assessment Report Non-Compliance] Prescriber was issued a second formal Notice for Non-Compliance on 26 June 2014 for not submitting PPAFs for 5 patients. [48-Month Assessment Report Update] On 04 June 2015 the prescriber was identified as not submitting PPAFs for 5 new patients who were at least 10 days past enrollment. Closed The prescriber was contacted by the TIRF REMS Access program and was re-educated on 08 July 2015. The prescriber stated that the reason for missing PPAFs was due to his busy practice location and his staff's difficulty in keeping up with paperwork. The prescriber confirmed he understood that it is his responsibility to ensure that PPAF's are completed and submitted. The prescriber submitted 4 of the 5 PPAFs. The last outstanding PPAF will not be submitted as it was for a patient identified as not continuing therapy. On 16 July 2015 the NCRT issued a first Warning letter with a request for a CAP by 06 August 2015. A CAP was received from the prescriber on 20 July 2015. After 2 attempts at prescriber outreach, on 27 July 2015, the prescriber’s office staff was advised that due to lack of information provided in the CAP, it was not approved and should be revised and resubmitted. The prescriber provided a revised CAP with additional information on 04 August 2015. The prescriber stated that PPAF pads had been placed inside of every patient room and forms had been added to the front desk. Additionally, one senior staff member was placed in charge of faxing all forms to ensure that every form sent to the TIRF REMS Access program receives a fax confirmation. Forms would be sent once in the morning and once at the end of the day to ensure that they are all submitted to the TIRF REMS Access program. The NCRT approved the CAP on 12 August 2015 and this non-compliance case was closed. Since closing the non-compliance case, no additional non-compliance cases for this prescriber have been identified. FDA_2702 48-month REMS Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Report Description (N=7) Report Status ID#359 (Case # 20687552, 22901956, 25616311) Closed On 18 July 2014, the prescriber was identified as not submitting PPAFs for 6 patients. On 18 July 2014 the prescriber was re-educated on the TIRF REMS Access program requirements. The prescriber stated that office staff handled completion of PPAFs and the reason the PPAFs had not been submitted was due to a change in his office locations. The prescriber confirmed he now understood that submission of PPAFs was his responsibility. On 24 July 2014, a formal Notice for Non-Compliance was issued to the prescriber. The prescriber submitted 5 of the 6 PPAFs. The last outstanding PPAF will not be submitted as it was for a patient identified as not continuing therapy. On 26 December 2014, the prescriber was again identified as not submitting PPAFs for 5 patients. On 21 January 2015, a request for contact correspondence was sent to the prescriber after multiple unsuccessful contact attempts between 02 January and 21 January 2015. The prescriber failed to contact the team for re-education by the deadline of 11 February 2015. A second formal Notice for Non-Compliance was issued to the prescriber on 20 February 2015. The prescriber submitted 3 of the 5 PPAFs. The last 2 outstanding PPAFs will not be submitted as they were for patients identified as not continuing therapy. Page 69 of 112 Mitigating Action The TIRF REMS Access program re-educated the prescriber on 13 July 2015. The prescriber stated that his fax machine had not been working and most of his staff had changed since his last non-compliant event. The prescriber confirmed that he understood that it is his responsibility to complete and submit PPAFs for all patients. The prescriber submitted 1 of the 5 PPAFs. The last 4 outstanding PPAFs will not be submitted as they were for patients identified as not continuing therapy. A first Warning letter was issued on 27 July 2015 requiring a CAP by 17 August 2015. A CAP was received from the prescriber on 05 August 2015; however, it was unsigned by the prescriber. The prescriber stated that they had set up their electronic medical records to issue a message alert in a patient’s file when any of the practitioners prescribed a TIRF medicine. When the medical assistant received a TIRF REMS prescription from the doctor to be input into the patient’s electronic chart, the message would alert the staff to complete the PPAF during the patient’s visit and send to the TIRF REMS Access program by end of business the same day. All staff had been educated on the policy change, effective 05 August 2015. The NCRT approved the CAP on 12 August 2015 pending prescriber signature. On 18 August 2015, a signed CAP was received from the prescriber and this non-compliance case was closed. Since closing the non-compliance case, no additional non-compliance cases for this prescriber have been identified. On 02 July 2015, the prescriber was again identified as not submitting PPAFs for 5 patients who were at least 10 days past enrollment. FDA_2703 48-month REMS Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Report Description (N=7) ID#380 (Case # 25444573, 26320577) On 22 June 2015, the prescriber was identified as not submitting PPAFs for 6 patients. On 06 July 2015, a request for contact correspondence was sent to the prescriber after multiple unsuccessful contact attempts between 22 June and 04 July 2015. The TIRF REMS Access program made an additional 6 outreach attempts following the issuance of the request for contact correspondence. On 03 August 2015 a formal Notice for Non-Compliance was issued to the prescriber, and the prescriber was re-educated. The 6 outstanding PPAFs will not be submitted as they were for patients identified as not continuing therapy. Report Status Open Page 70 of 112 Mitigating Action On 18 September 2015, a request for contact correspondence was sent with a Prescriber Overview after multiple unsuccessful outreach attempts between 26 August and 11 September 2015. The prescriber failed to contact the TIRF REMS Access program for re-education by the deadline of 10 October 2015. The 6 outstanding PPAFs will not be submitted as they were for patients identified as not continuing therapy. A first Warning letter was issued on 26 October 2015 with a request for a CAP. On 02 November 2015, a CAP was received from the prescriber; however, on 12 November 2015, the NCRT did not approve the plan as it did not align with the re-education received by the prescriber. The NCRT is following up with the prescriber to obtain a valid CAP. On 03 August 2015, the prescriber was again identified as not submitting PPAFs for 6 patients. FDA_2704 48-month REMS Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies 6.2 Page 71 of 112 Audits As part of non-compliance monitoring, TIRF REMS Access program pharmacies may be subject to periodic data requests and/or audits. Such activities may occur for suspected non-compliance with program requirements based on program monitoring activities. 6.2.1 Closed System Pharmacy Audits [Metric 20] The REMS Assessment Plan includes the following components for closed system pharmacy audits: (1) Verification of training for all pharmacists dispensing TIRF products (2) Numbers of prescription authorizations per closed system (3) Reconciliation of data describing TIRF product prescriptions received by the closed system pharmacy with TIRF product dispensed to patients with a valid enrollment in the TIRF REMS Access program. The first component of the closed system pharmacy audit requirement is accomplished through the enrollment process for closed system pharmacies. To become enrolled the authorized representatives must attest that all pharmacies dispensing TIRF products will be trained on the TIRF REMS Access program requirements. The second component is done through the closed system pharmacy prescription authorization process. Closed system pharmacists are required to validate the enrollment status of the prescriber and patient prior to dispensing a TIRF product by calling or faxing the prescription details to the TIRF REMS Access program. The TIRF REMS Access program maintains records of prescription details and the associated REMS authorization. Table 18 provides information on all prescription authorizations by closed system pharmacy. The third and final component includes reconciliation between the closed system pharmacy’s dispensing data and the TIRF REMS Access program’s REMS authorizations. To conduct this reconciliation, the TIRF REMS Access program requests dispensing records from the closed system pharmacies and compares the dispensing records to REMS authorization data from the TIRF REMS Access program. After confirmation that the closed system pharmacy agrees to participate in the reconciliation, a formal written request for data is issued upon request to the authorized representative detailing the data to be provided and the deadline for submission. Specific data requested include: • RX number for each prescription dispensed • DEA number or NPI number of the facility that dispensed each prescription • DEA number or NPI number of the prescriber that issued each prescription • Date and time of each prescription transaction • TIRF REMS Authorization code obtained for each prescription dispensed • Due to the structure of some closed system pharmacy networks, the headquarters may be unable to provide data for all pharmacy locations as no central data repository is in existence; each pharmacy location maintains their own data. In these cases a random FDA_2705 48-month REMS Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 72 of 112 sample of pharmacy locations was selected by the TIRF REMS Access program for participation. • Findings from each investigation are reviewed with the NCRT and actions were taken in accordance with the Non-Compliance Protocol. The CSP assessment metric required auditing of at least 3 randomly selected CSPs. The TRIG proactively included all closed-system pharmacies in the audit with a request to provide dispensing records from 01 April 2014 through 30 April 2015. As a result, there were 6 audits conducted during this 48-month monitoring reporting period and 2 closed system pharmacies (ID #361 and #376) were found to be non-compliant with the TIRF REMS Access program requirements. Based on the identification of non-compliance, a non-compliance case was opened for each of these 2 closed system pharmacies. Below are the details of these 6 closed-system pharmacy audits. Table 24 summarizes the reconciliation of the dispensing data from each closed system pharmacy and the authorizations received from the TIRF REMS Access program during the course of the 6 audits. Table 24 Closed System Pharmacy Audits Audit ID Number Date Closed System Monitoring Request for Data Sent Date Dispensing Records Received1 Total Dispenses/Total Dispenses Not Authorized by the REMS 1 (ID#361) 09 June 2015 18 June 2015 76/53 Y 27/15 Y 239/0 N 0/0 N 48/0 N 2 2 (ID#376) 21 May 2015 11 August 3 (ID#CS1) 21 March 2015 22 June 2015 4 (ID#CS2) 26 May 2015 08 June 2015 5 (ID#CS4) 22 May 2015 01 July 2015 3 NonCompliance Identified? 6 (ID#CS6) 21 May 2015 19 June 2015 9/0 N 1 The date range for dispensing records received was 01 April 2014 through 30 April 2015. 2 Additional data was requested after the initial receipt of dispensing records. This follow-up data were received on 30 September 2015. 3 Pharmacy provided confirmation that no TIRF medicines were dispensed during the reporting period (01 April 2014-30 April 2015). Additional details on the 2 closed pharmacy audits that identified non-compliance are identified below. Closed System Pharmacy Audit 1: ID#361 (Case #25478537) Request for Data On 19 May 2015, the TIRF REMS Access program conducted outreach to request feedback on the closed system pharmacy process, and spoke with the Authorized Pharmacist (AP). The AP advised that all of the pharmacies were required to follow the TIRF REMS Access program guidelines; however, they do not have any requirements on how they document the authorization FDA_2706 48-month REMS Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 73 of 112 numbers. The AP stated that every Pharmacist In Charge of an individual pharmacy has been trained on the program requirements. The AP requested the prescription authorization data from the TIRF REMS Access program so that he can match it to his pharmacy’s data. On 09 June 2015 dispensing data for Department of Defense (DoD) locations were sent to the AP via email. A formal closed system monitoring request for data was sent via email, with a response requested by 19 June 2015. Investigation Dispensing records were provided on 18 June 2015, and the TIRF REMS Access program began to reconcile the data. The dispensing records contained data from July 2014 through May 2015 and included 78 instances where a TIRF product had been dispensed during the monitoring period. The dispensing records provided were compared to authorization data from the TIRF REMS Access program and data discrepancies were found and showed that in 55 of the 78 occurrences drug was dispensed without obtaining an authorization. The TIRF REMS Access program conducted outreach to confirm that the DoD had provided 100% of their dispensing data, among all of their dispensing locations, to complete reconciliation. On 08 July 2015, the AP confirmed that the pharmacy had provided 100% of their dispensing data, including military logistics unit (MLU) locations. The team continued to reconcile information received, ensuring that MLU locations were excluded from the data.* Findings On 17 July 2015, after excluding MLU locations, reconciliation of the data showed 76 instances of dispensing TIRF medicines during this monitoring period. In 53 of the 76 instances TIRF medicines were dispensed without obtaining an authorization. Outcome A formal Notice for Non-Compliance was issued on 23 July 2015. Re-education concluded on 09 September 2015 both verbally and via e-mail contact. On 06 November 2015, the CAP was received from the AP. The AP stated that he conducted education and training at 8 separate DoD locations (49 dispensing transactions) and 1 non-enrolled pharmacy (1 transaction) and provided copies of the Closed System Pharmacy Overview. The AP had contacted the Chiefs of Pharmacy and Medical Logistics and instructed to use documentation in the patient’s Electronic Health Record instead of the Pharmacy Dispensing Profile. The procurement channels were blocked for 3 outpatient pharmacy locations representing the remaining 3 dispensing transactions. The plan was reviewed and approved by NCRT on 11 November 2015. As of the end of the reporting period, no additional non-compliance cases for the DoD have been identified. *FDA issued a REMS communication to each of the TIRF Sponsors on 29 June 2012 stating that it had determined that TIRF medicines can continue to be distributed to DoD MLU locations without enrolling them in the REMS. FDA_2707 48-month REMS Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 74 of 112 Closed System Pharmacy Audit 2: ID#376 (Case #26141978) Request for Data On 21 May 2015, during a call with the Veteran’s Administration (VA) to request feedback on the closed system pharmacy process, the VA Authorized Representative stated they do not have a process to record the TIRF approval number. Each individual pharmacy is responsible for training their staff and each site had been provided the TIRF REMS Access program Guidelines. A formal request for data correspondence was issued to the VA on 21 May 2015, with a response requested by 21 June 2015. Investigation In the request for data of 27 February 2014, the VA Authorized Representative had advised that each VA site stores their own dispensing records (there is no central data storage) and they requested that the TIRF REMS Access program select a sample of sites to provide dispensing records. Therefore, on 04 June 2015, the TIRF REMS Access program provided 10 randomly selected and enrolled VA closed-system dispensing locations (accounting for 10% of the enrolled population for VA) to the VA for reconciliation. After many attempts to seek status of the data request, the dispensing data were received by the team by 11 August 2015 and reconciled by the TIRF REMS Access program. The closed system pharmacy dispensing data showed that only 1 of the 10 locations had dispensing activity during the reporting period. The single location dispensed 13 instances of TIRF medications without authorization. On 18 August 2015, the NCRT recommended selecting a larger population of enrolled VA locations to request additional dispensing data. On 20 August 2015, they further requested that the VA provide updated dispensing data for the 5 locations determined to have non-compliance activity during the 36-month assessment to determine if these sites continue to dispense without authorizations. Findings By 30 September 2015, data had been received from VA and reconciled by the TIRF REMS Access program. The closed system pharmacy dispensing data supported that 3 of the 5 additional locations had dispensing activity during the monitoring period. The 3 locations dispensed a total of 27 instances of TIRF medication. Two of the 3 locations each had 1 instance of dispensing without an authorization. The NCRT recommended issuing a second notice of noncompliance. Outcome A formal Notice for Non-Compliance was issued to the headquarters on 09 October 2015 and the notice was distributed to the pharmacy locations on 29 October 2015. Re-education occurred both verbally and via e-mail on the same date. In response to the Non-Compliance Letter of 29 October 2015, 3 sites responded with a Corrective Action plan in November 2015 (2 sites by 12 November 2015 and 1 site by 16 November 2015). FDA_2708 48-month REMS Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 75 of 112 For 1 site, the event occurred because there was no SOP for documenting the authorization number. An SOP was developed and implemented to ensure that all requirements of the TIRF REMS Access program are implemented. The SOP was in place since May 2015. Compliance with the SOP has been self-audited and self-auditing will continue in the future. At Site 2, the event occurred because on 03 November 2014, a fentanyl lozenge prescription was dispensed because pharmacy staff involved was unaware of the REMS program. On 04 December 2014, new order for drug was issued; however, at the time, pharmacy staff who were aware of the REMS contacted the provider. As a result of intervention, the medical order for the fentanyl lozenge was discontinued and a new order for morphine 10mg/5mL was issued. In short, the provider decided to switch to another drug instead of enrolling in the REMS program. A number of corrective actions were put into place: the pharmacy staff involved was counseled by the supervisor. A sign was placed in the vault, indicating that TIRF medicines cannot be dispensed without verifying that the physician and the patient are enrolled in the REMS program and have the proper authorization from the TIRF REMS Access program. A mail message with specific instructions regarding the TIRF REMS Access program was sent to Pharmacy Staff. The TIRF REMS Access program internet address was included in the orderable item as follows (FDA REMS program. Verify before prescribing/dispensing. www.TIRFREMSAccess.com). The corrective actions have been in place since 29 October 2015, no additional events have occurred to assess if these actions were effective, and no further actions are pending implementation. At Site 3: the event occurred because there was a change in staffing and management in January 2013. There was limited dispensing of the TIRF medicines and change in personnel, so the current staff had forgotten or were not aware of the requirements to obtain authorization prior to dispensing. A CAP was developed to educate pharmacy staff that included education requirements for all staff to complete the TIRF REMS Access Education program; a copy of their certificate of completion is to be added to their competency folder; the TIRF medicines will be marked on the shelf to remind staff to acquire the dispensing authorization number prior to filling; a pharmacy service SOP was written to include steps needed when processing and filling a TIRF medicines prescription; a review of the TIRF REMS Access program will be added to an annual competency review; and a bi-annual review will be completed to confirm compliance. The CAP has been in place since July 2015. Non-compliance prevention that is currently in place includes following the CAP, completion of the bi-annual internal audit, and annual review of the SOP. All CAPs were approved on 14 December 2015. It should be noted that in the 36-month report, there were 39 instances where drug was dispensed via the closed system process of which 17 did not have REMS authorization prior to dispensing. There was a marked improvement in compliance this reporting period. As of the end of the reporting period, no additional non-compliance cases for the VA have been identified. 6.2.2 Inpatient Hospital Pharmacy Audits [Metric 21] Since submission of the 36-Month FDA Assessment Report, the TRIG developed an inpatient pharmacy questionnaire to conduct the required inpatient pharmacy audits. FDA_2709 48-month REMS Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 76 of 112 The audit questionnaire invitation was faxed to Authorized Inpatient Pharmacists of pharmacies enrolled in the TIRF REMS Access program requesting their participation. Once the AP agreed to participate, they received the audit questionnaire to complete, which included 2 qualifying questions to determine eligibility to participate in the audit: 1. Is your pharmacy a hospital pharmacy? Yes/No 2. In the previous 12 months, has your hospital pharmacy dispensed TIRF medicine? Yes/No If the answer was no to either of the qualifying questions, the pharmacy did not qualify for the audit. If they answered yes to both qualifying questions, they were asked to finalize the Audit Questionnaire by completing the following 3 questions: 1. Provide the number of units dispensed within . (See National Drug Code [NDC] list for a current listing of TIRF NDCs) ________units of use of TIRFs dispensed to patients. 2. Did all pharmacists who dispensed TIRF medicines complete training on the TIRF REMS Access program prior to dispensing these products? Yes/No 3. Do you have procedures in place such as order sets/protocols to assure compliance with the TIRF REMS program requirements? Yes/No. If yes, are you willing to provide examples of an order set or protocol? All completed questionnaires were to be returned to the TIRF REMS Access program via fax or phone by the date specified on the audit invitation. A total of 24 enrolled inpatient locations were solicited for participation in the audit. Four of the 24 pharmacies did not respond to the audit initiation and 2 pharmacies decided not to participate. The remaining 18 pharmacy locations agreed to participate and completed the qualifying questions associated with the audit questionnaire. Of the 18 pharmacies, 12 pharmacies answered no to at least one of the qualifying questions and were either not a hospital inpatient pharmacy facility or had not dispensed TIRFs in the previous 12 months. The remaining 6 qualified to participate in the audit, and proceeded with answering the 3 remaining audit questions. Based on responses to the 3 audit questions, the 6 audited inpatient hospital pharmacies were evaluated compliant with the TIRF REMS Access program requirements. Therefore, the 6 audits were closed and no non-compliance cases were opened. 7 7.1 SAFETY SURVEILLANCE Adverse Event Reporting [Metric 29] TIRF Sponsors process adverse event reports related to their specific products and report to the FDA according to current regulations outlined in 21 CFR 314.80 and the sponsor’s respective Standard Operating Procedures (SOPs). 7.2 TRIG Sponsor Adverse Event Data of Interest [Metric 30] Based on the current Assessment Plan, TRIG has conducted an aggregate root cause analysis of all spontaneous adverse event reports of addiction, death, overdose, and pediatric exposure from FDA_2710 48-month REMS Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 77 of 112 the TIRF Sponsors. Based on this requirement the TRIG Sponsor companies used a third party, UBC, to conduct this analysis. The sponsors identified the appropriate Medical Dictionary for Drug Regulatory Activities (MedDRA) codes to provide data including narratives or MedWatch forms which UBC summarized based on the FDA’s request (see Appendix 12.2). Reports were reviewed and duplicates consolidated, when possible. Originally case reports were selected based on the specified Preferred Terms (PTs); upon UBC’s review of the narrative information, some case reports did not meet the specified criteria and were excluded from the analysis. Additionally, literature reports and reports from Poison Centers were excluded. Metrics of interest included: the number of event reports in each event category of interest (addiction, death, overdose, pediatric exposures); counts of adverse events related to inappropriate conversions between TIRF products; counts of adverse events related to accidental and unintentional exposures; and counts of adverse events that are associated with use of TIRF medicines in non-opioid tolerant patients. In the 36-Month FDA Assessment Report Acknowledgement Letter, the FDA stated that none of the TRIG spontaneous adverse events included a root cause analysis as specified in the Assessment Plan and requested that a root cause analysis of adverse events be reported to the TRIG Sponsors in the 48-month assessment report. The analysis has been added and data tables now report the potential causality for each case if sufficient information was available to make a determination. If there was insufficient information available and the potential causality could not be determined, this was noted in the table. The reporting period used for this analysis was 29 August 2014 to 28 August 2015 to allow sufficient time to complete this analysis. There were 312 unique case reports that met the specified criteria. After a review of the 312 MedWatch Forms or narratives, no reports of inappropriate conversions between TIRF products were noted. None of the narratives indicated unintentional exposures, or non-opioid tolerance. There was one report of accidental exposure during the reporting period where a female was accidentally exposed to a TIRF medication by her neighbor who was prescribed a TIRF medicine for cancer pain. 7.3 Number of Adverse Events of Special Interest The total number of cases of interest reported during this reporting period is presented in Table 25 below. Of the 312 cases, 291 (93.3%) had an outcome of death, 12 (3.8%) were reports of addiction, 6 (1.9%) were reports of overdose, and 4 (1.3%) were pediatric exposures. FDA_2711 48-month REMS Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 78 of 112 Table 25 Number of Cases of Adverse Events of Special Interest AEs of Interest Number of Reports Total Number of AEs of Interest a Percentagea 312 Addiction 12 3.8% Death 291 93.3% Overdose 6 1.9% Pediatric Exposure 4 1.3% Cases may have more than one adverse event of interest. Table 26 shows the current reporting period rates for each of the adverse events of special interest per 100,000 prescriptions. The rates per 100,000 prescriptions included for 29 August 2013-28 August 2014 is provided as a reference for the rates provided in the 36-Month FDA Assessment Report. Table 26 Rate of Adverse Events by Total Prescriptions Current Reporting Period (29AUG2014-28AUG2015) Reported During Previous Reporting Period (29AUG2013-28AUG2014) Number of Adverse Events Adverse Event Rates per 100,000 Prescriptions (N=112,522) Number of Adverse Events Adverse Event Rates per 100,000 Prescriptions (N=94,464) Addiction 12 10.66 4 4.23 Death 291 258.62 362 383.21 Overdose 6 5.33 0 0 Pediatric Exposure 4 3.55 2 2.12 Adverse Events of Interest Table 27 shows the current reporting period rates for each of the adverse events of special interest per 100,000 population. The rates per 100,000 patients included for 29 August 201328 August 2014 is provided as a reference for the rates provided in the 36-Month FDA Assessment Report. FDA_2712 48-month REMS Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Table 27 Page 79 of 112 Rate of Adverse Events by Total Patients Current Reporting Period (29AUG2014-28AUG2015) Reported During Previous Reporting Period (29AUG2013-28AUG2014) Number of Adverse Events Adverse Event Rates per 100,000 Patients (N=15,922) Number of Adverse Events Adverse Event Rates per 100,000 Patients (N=14,772) Addiction 12 75.37 4 27.08 Death 291 1827.66 362 2450.58 Overdose 6 37.68 0 0 Pediatric Exposure 4 25.12 2 13.54 Adverse Events of Interest Twelve (12) cases were classified as cases of addiction. Of the 12 cases, 3 had an outcome of “not recovered/not resolved” at the time of the cut off (28 August 2015); 1 had an outcome of “resolved”; and 7 had an outcome of “unknown.” One patient experienced multiple events with different event outcomes of ongoing, recovered/resolved, and unknown (case outcome listed as ongoing). Table 28 provides details of these 12 cases. None of the 12 cases provided sufficient detail to perform a root cause analysis. FDA_2713 48-month REMS Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 80 of 112 Table 28 Cases of Addiction Received from TRIG Sponsors during the Reporting Period: 29 August 2014 - 28 August 2015 Patient Date UBC ID Age Gender Event 1495 48 Female 24SEP2014, Unknown 1512 UNK Male 1544 UNK 1545 Report Preferred Term(s) Indication(s) TIRF Duration Concomitant Medications Co-Suspect Product(s) Event Outcome Potential Causality1 26SEP2014 Drug withdrawal syndrome, Off label use Off label use, pain Unknown None reported None reported Recovered/ Insufficient Resolved Information Unknown 14OCT2014 Drug dependence Unknown Unknown None reported None reported Unknown Possibly related Female Unknown 21NOV2014 Drug abuse Unknown UNK None reported None reported Unknown Possibly related UNK Male Unknown 21NOV2014 Drug abuse Unknown UNK None reported None reported Unknown Insufficient information 1603 60 Female Gabapentin, Vancomycin, Phenergan, Evista Fentanyl Transdermal System Ongoing Related 1665 59 Female 07APR2015, 11MAY2015 Off label use, Arthralgia, Neck pain, back 2015-04-07 - Valium Unknown, Drug ineffective, Drug pain UNK Unknown, withdrawal syndrome, Gait Unknown, disturbance, Unknown, Musculoskeletal pain Unknown, Unknown Morphine Not Possibly Recovered/ related Not Resolved 1666 UNK Female DEC2014, 26FEB2015 Staphylococcal infection, 18DEC2014, Drug withdrawal DEC2014, syndrome, Suicidal NOV2014, ideation, Retching, Unknown, Constipation, Dependence, Unknown, Drug effect decreased, Unknown, Hyposmia, Incorrect drug Unknown, administration duration, Unknown, Intentional product use Unknown, issue, Nausea Unknown NOV2014, Unknown, Unknown, Unknown 12MAY2015 Weight decreased, Drug effect incomplete, Drug withdrawal syndrome, Product quality issue Surgery, Unknown gastrointestinal disorder, surgery, gastrointestinal disorder, osteoporosis Cancer pain, breakthrough cancer pain 2014 - UNK Hydromorphone None reported Unknown Possibly related FDA_2714 48-month REMS Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Patient Page 81 of 112 Date UBC ID Age Gender Event 1713 68 Female Unknown 05AUG2015 Drug dependence, Pain from cancer Unknown Intentional product misuse radiation treatments Oxycontin None reported Not Not related Recovered/ Not Resolved 1738 UNK Male OCT2014, OCT2014, Unknown 30OCT2014 Constipation, Intentional Arthritis drug misuse, Off label use Unknown None reported Oxycodone Not Possibly Recovered/ related Not Resolved 1774 UNK Male Unknown 10MAR2015 Drug dependence, Drug ineffective, Loss of consciousness, Off label use, Product quality issue 2013-10 UNK None reported Fentanyl Patches Unknown Possibly related 1802 UNK Female DEC2013, Unknown 21MAY2015 Drug dependence, Off label Pain use 2013-12 UNK Celexa, Fentanyl None reported Patch Unknown Possibly related 1827 UNK Male Unknown 25AUG2015 Depression, Drug dependence, Drug withdrawal syndrome, Therapy cessation Unknown None reported Unknown Possibly related Report Preferred Term(s) Indication(s) Chronic back pain Unknown TIRF Duration Concomitant Medications Co-Suspect Product(s) None reported Event Outcome Potential Causality1 1 Potential causality was reported if sufficient information was available to make a determination. If there was insufficient information available and the potential causality cannot be determined, this was noted in the table. UNK = Unknown FDA_2715 48-month REMS Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 82 of 112 As a result of this review, 291 reports of death were noted. Sixteen of these 291 reported deaths were identified through the TIRF REMS Access program’s PPAF renewal/follow-up process. A total of 172 reports of death without any other adverse event were reported. Of these 172 cases, 166 cases did not include enough information (e.g., indication for use, patient medical history, dates of use of the TIRF medication, and/or concomitant medications) to allow for an assessment of causality. In 6 cases, the cause of death was reported as related to an underlying cancer, and in 1 case, follow up information revealed that the patient was prescribed a TIRF medication, but never took the medication. Of the 119 death case reports, 78 reports were due to neoplasm progression where death was attributed to cancer and 14 reports with an outcome of death were attributed to an underlying medical condition; two reports with death as an outcome were reported as disease progression both involving patients with cancer; one was due to an apparent suicide. However, the report also noted that patient had a medical history that included Stage IV esophageal cancer. There was one report of an accidental death involving a patient taking a TIRF medicine for pain who died in a house fire, and one report of drug toxicity that was accidental after TIRF medicine ingestion and anesthesia. There were 7 cases with death as an outcome and off-label use as the Preferred Term but none were considered related to a TIRF product (6 reported an unknown cause and 1 reported a “natural” cause). There was one overdose that resulted in death involving a patient’s daughter using the patient’s TIRF product and oral opioids. The last 14 reports of death included 4 reports of heart attack, cardiac arrest, or a heart disorder, 1 report of heart failure, 3 reports where a patient had a diagnosis of metastatic cancer and the death was not related to a TIRF medication, 1 death due to COPD, 1 death due to hepatic failure, 1 death due to septic shock due to cholecystitis. Three deaths were due to unknown causes. A full line listing of deaths is presented in Appendix 12.3. There were 6 overdose cases reported during this reporting period (Table 29). One case had an outcome of death with causality reported as possibly related. This case also appears in the death listing (Appendix 12.3). The remaining 5 cases included: 1 case with an unknown outcome, 2 cases with an outcome of recovered/resolved at the time of this report and 2 cases with an outcome of not recovered/not resolved. Five of the 6 cases did not provide sufficient detail to perform a root cause analysis. The final case with an outcome of death had a causality assessment of possibly related and was referenced above. FDA_2716 48-month REMS Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 83 of 112 Table 29 Cases of Overdose Received from TRIG Sponsors during the Reporting Period: 29 August 2014 - 28 August 2015 Patient Date UBC ID Age Gender Event Report Preferred Term(s) Indication(s) 1533 38 Female 05NOV2014, OCT2014, 2014, 2014, 2014, 2014 10NOV2014 Streptococcal infection, Sepsis, Drug tolerance, Overdose, Product quality issue, Underdose Addison's disease, off label use, fibromyalgia, osteoporosis 1540 UNK Male Unknown 19NOV2014 Accidental overdose, Pain relief after Apparent death, Dental cervical surgeries implantation, Dental prosthesis user, Intentional product use issue, Mechanical ventilation, Tooth loss 1600 UNK Unknown 01OCT2014, 01OCT2014, 01OCT2014 24FEB2015 Breakthrough pain, Overdose, Respiratory depression 1625 56 Female 23MAR2015 Overdose, Abdominal Complex regional pain upper, Diarrhoea, pain syndrome, off Drug withdrawal label use syndrome, Rhinorrhoea, Vomiting, Yawning, Drug dispensing error 22MAR2015, MAR2015, MAR2015, MAR2015, MAR2015, MAR2015, MAR2015, FEB2015 Cancer pain TIRF Duration Concomitant Medications Co-Suspect Product(s) Event Outcome 2014-03 – UNK None reported None reported Not Recovered/ Not Resolved, Related Unknown None reported None reported Not Recovered/ Not Resolved Possibly related Unknown None reported None reported Recovered/ Resolved Possibly related 2015-03-22 Amitiza, Armour None reported Recovered/ - 2015-03- Thyroid, Estradiol Resolved 21 Testosterone, Fentanyl, Healthy Hair Skin and Nails B Complex/ Biotin, Lisinopril, Omeprazole, Potassium Chlor-Er, Progesterone, Vitamin D Cap D2 Ergo Calcifier Potential Causality1 Related FDA_2717 48-month REMS Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Patient Page 84 of 112 Date UBC ID Age Gender Event Report Indication(s) TIRF Duration Concomitant Medications Co-Suspect Product(s) 1668 UNK Female Unknown 13MAY2015 Overdose Cancer pain Unknown None reported Fentanyl Patch Unknown Insufficient information 17952 UNK Female Unknown 07MAY2015 Overdose Unknown Unknown None reported None reported Death Possibly related Preferred Term(s) Event Outcome Potential Causality1 1 Potential causality was reported if sufficient information was available to make a determination. If there was insufficient information available and the potential causality cannot be determined, this was noted in the table. 2 Patient 1795 is also described in the table for death found in Appendix 12.3. UNK = unknown. FDA_2718 48-month REMS Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 85 of 112 There were 4 pediatric cases reported during this reporting period (Table 30). No case had an outcome of death and 3 cases had an outcome of unknown at the time of this report. In 3 of the 4 reports, the medication was intentionally prescribed to the pediatric patient. The fourth report had insufficient information to determine if the pediatric patient took the TIRF medicine. No further details were obtained despite extensive follow-up attempts. FDA_2719 48-month REMS Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 86 of 112 Table 30 Cases of Pediatric Exposures Received from TRIG Sponsors during the Reporting Period: 29 August 2014 - 28 August 2015 Patient Date CoSuspect Event Product(s) Outcome Potential Causality1 None reported None reported Unknown Insufficient information Unknown None reported None reported Unknown Pediatric exposure resulting from offlabel prescribing Drug administered to Chronic patient of inappropriate pancreatitis age, Product use issue Unknown Dilaudid, Percocet, Clonazepam None reported Unknown Pediatric exposure resulting from offlabel prescribing Drug administered to Unknown patient of inappropriate age 2014-03 UNK None reported None reported Not Recovered/ Pediatric exposure Not Resolved resulting from offlabel prescribing UBC ID Age Gender Event 1474 15 Female Unknown 29AUG2014 Drug administered to Unknown patient of inappropriate age Unknown 1478 15 Female Unknown 03SEP2014 Drug administered to Unknown patient of inappropriate age 1553 9 Male Unknown 12DEC2014 1586 UNK Male Unknown 30JAN2015 Report Preferred Term(s) TIRF Indication(s) Duration Concomitant Medications 1 Potential causality was reported if sufficient information was available to make a determination. If there was insufficient information available and the potential causality cannot be determined, this was noted in the table. UNK = unknown. FDA_2720 48-month REMS Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 87 of 112 7.4 TIRF Product Surveillance Data [Metric 31] 7.4.1 Background Surveillance data focusing on events of abuse, misuse, and death were evaluated using data from the RADARS System for the time period July 2010 to June 2015. Based on FDA request, the data included in this report compare event rates for a time period prior to full implementation of the TIRF REMS and a time period after REMS implementation. Additional updates to the RADARS System data analysis were made based on FDA feedback provided in the 36-Month FDA assessment report Acknowledgement Letter. Specific responses to each FDA request can be found in Appendix 12.4. Data from five programs that gather data from unique populations along the spectrum of drug abuse were used to monitor for the non-medical use (abuse and misuse) of TIRF products. The data sources and the specific events evaluated in each are shown in Table 31 below. Table 31 RADARS System: Data Sources and Specific Events Data Source 1. Poison Center Program Treatment Center Programs 2. Opioid Treatment Programs 3. Key Informants Survey 4. College Survey Abuse a Intentional Misuse Unintentional Therapeutic Errors Unintended General Exposures Emergency Department Visits & Hospitalizations Deaths      Major Medical Outcomes and Deathse  b b c d 5. Impaired Health Care Workers Program a Abuse defined as exposure resulting from intentional improper or incorrect use of a substance where the victim was likely attempting to gain a high euphoric effect or some other psychotropic effect b Abuse defined as a respondent endorsing the use of a product to get high in the past 30 days c Abuse defined as endorsement of a non-medical use of a drug in the past 90 days d All reported cases are considered abuse; data may include a small fraction of drug diversion information. e This column includes the events included in the column titled “deaths” as well as major medical outcomes that did not lead to death FDA_2721 48-month REMS Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 88 of 112 Trends over time for the TIRF products were compared to 3 comparator groups that are not directly impacted by the TIRF REMS to determine how the trend in TIRF rates compares to the secular trend in other opioids. The comparators used in this report were: • Schedule II IR opioids • Schedule II opioids • Schedule II opioids excluding methadone Recently, IR hydrocodone was changed from a Schedule III opioid to a Schedule II opioid. As IR hydrocodone was not included in the group of Schedule II opioids in previous reports and was not a Schedule II drug for the entire study period, data were analyzed two ways. The primary analyses were conducted without IR hydrocodone in the Schedule II IR opioid group. Sensitivity analyses were then conducted as if IR hydrocodone was a Schedule II IR opioid for all quarters. Data from IMS Health are used to estimate total prescriptions dispensed and total dosing units dispensed at the 3-digit ZIP-code level for all TIRF REMS opioids and comparator groups. Totals of prescriptions and dosing units in the three digit zip codes covered by the RADARS System Programs were computed and used as the denominators when calculating product availability rates. IMS data does not capture methadone dispensed through opioid treatment programs (OTPs), thus the count of methadone prescriptions is an undercount. Prescription rates will be scaled per 10,000 prescriptions and dosing rates will be scaled per 100,000. Rates of abuse, misuse, overdose, unintentional therapeutic errors, unintentional general exposures, emergency department visits/hospitalizations, deaths, and major medical outcomes were calculated using the 2010 US decennial census estimated from the three-digit zip codes covered in the RADARS System Programs as the denominator. Population rates will be scaled per 100,000 population. Additional details regarding the data sources and specific events can be found in the RADARS System Report Protocol (Appendix 12.5). 7.4.2 RADARS Results This RADARS System Report summary presents the results of an analyses of the effectiveness of the TIRF REMS drawn from 5 data sources (i.e., Poison Center Program, Treatment Center Programs combined [includes OTP survey and SKIP], College Survey, and Impaired Healthcare Workers Program). The full report from the RADARS System Program is included as Appendix 12.6. (b) (4) FDA_2722 48-month REMS Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 89 of 112 (b) (4) FDA_2723 48-month REMS Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 90 of 112 48-month REMS Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 91 of 112 Table 32 Summary of RADARS Findings by Program, Outcome, and Denominator Percentage change Program Poison Center Program Outcome Intentional abuse exposure Denominator Population Prescriptions dispensed Dosage units dispensed Intentional misuse exposure Population Prescriptions dispensed Dosage units dispensed Unintentional therapeutic error Population Drug group Interaction (b) (4) TIRF Products Schedule II IR Opioids Schedule II Opioids Schedule II Opioids Excluding Methadone TIRF Products Schedule II IR Opioids Schedule II Opioids Schedule II Opioids Excluding Methadone TIRF Products Schedule II IR Opioids Schedule II Opioids Schedule II Opioids Excluding Methadone TIRF Products Schedule II IR Opioids Schedule II Opioids Schedule II Opioids Excluding Methadone TIRF Products Schedule II IR Opioids Schedule II Opioids Schedule II Opioids Excluding Methadone TIRF Products Schedule II IR Opioids Schedule II Opioids Schedule II Opioids Excluding Methadone TIRF Products Schedule II IR Opioids Schedule II Opioids FDA_2725 48-month REMS Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Program Outcome Denominator Prescriptions dispensed Dosage units dispensed Unintentional general exposure Population Prescriptions dispensed Dosage units dispensed Emergency Population department visits/hospitalization exposure Prescriptions dispensed Page 92 of 112 Drug group Schedule II Opioids Excluding Methadone TIRF Products Schedule II IR Opioids Schedule II Opioids Schedule II Opioids Excluding Methadone TIRF Products Schedule II IR Opioids Schedule II Opioids Schedule II Opioids Excluding Methadone TIRF Products Schedule II IR Opioids Schedule II Opioids Schedule II Opioids Excluding Methadone TIRF Products Schedule II IR Opioids Schedule II Opioids Schedule II Opioids Excluding Methadone TIRF Products Schedule II IR Opioids Schedule II Opioids Schedule II Opioids Excluding Methadone TIRF Products Schedule II IR Opioids Schedule II Opioids Schedule II Opioids Excluding Methadone TIRF Products Schedule II IR Opioids Schedule II Opioids (b) (4) Percentage change (95% CI) Interaction p-value FDA_2726 48-month REMS Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Program Outcome Denominator Dosage units dispensed Major medical outcomes and death exposure Population Prescriptions dispensed Dosage units dispensed Treatment Center Past 30 day use to Programs get high Combined Population Prescriptions dispensed Dosage units dispensed Page 93 of 112 Drug group Schedule II Opioids Excluding Methadone TIRF Products Schedule II IR Opioids Schedule II Opioids Schedule II Opioids Excluding Methadone TIRF Products Schedule II IR Opioids Schedule II Opioids Schedule II Opioids Excluding Methadone TIRF Products Schedule II IR Opioids Schedule II Opioids Schedule II Opioids Excluding Methadone TIRF Products Schedule II IR Opioids Schedule II Opioids Schedule II Opioids Excluding Methadone TIRF Products Schedule II IR Opioids Schedule II Opioids Schedule II Opioids Excluding Methadone TIRF Products Schedule II IR Opioids Schedule II Opioids Schedule II Opioids Excluding Methadone TIRF Products Schedule II IR Opioids Schedule II Opioids (b) (4) Percentage change (95% CI) Interaction p-value FDA_2727 48-month REMS Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Program College Survey Program Outcome Past 3 month nonmedical use Denominator Population Prescriptions dispensed Dosage units dispensed Impaired Health Care Worker Program Abuse Population Page 94 of 112 Drug group Schedule II Opioids Excluding Methadone TIRF Products (b) (4) Percentage change (95% CI) Interaction p-value Schedule II IR Opioids Schedule II Opioids Schedule II Opioids Excluding Methadone TIRF Products Schedule II IR Opioids Schedule II Opioids Schedule II Opioids Excluding Methadone TIRF Products Schedule II IR Opioids Schedule II Opioids Schedule II Opioids Excluding Methadone TIRF Products Schedule II IR Opioids Schedule II Opioids Schedule II Opioids Excluding Methadone Prescriptions dispensed TIRF Products Schedule II IR Opioids Schedule II Opioids Schedule II Opioids Excluding Methadone Dosage units dispensed TIRF Products Schedule II IR Opioids Schedule II Opioids Schedule II Opioids Excluding Methadone FDA_2728 48-month REMS Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies 8 Page 95 of 112 PERIODIC SURVEYS OF STAKEHOLDERS Surveys were conducted to assess patients’/caregivers’, pharmacists’, and prescribers’ KAB regarding the safe use of TIRF medicines as described in the educational materials for all stakeholders, enrollment form (pharmacists and prescribers only), Full Prescribing Information (pharmacists and prescribers only) and medication guides (prescribers and patients) for each product, and the PPAF (prescribers and patients only). The survey protocols describe the administration of the individual surveys that were conducted among patients who are treated with TIRF medicines or their caregivers, prescribers, and pharmacists; the survey KAB reports include summarization of all data collected during the survey (see Appendix 12.7.1, 12.7.2, and 12.7.3, respectively, for the patient, pharmacist, and prescriber KAB reports which include the protocol and survey). Data from the surveys, together with other REMS evaluation metrics, will be used to determine whether changes need to be made to the REMS processes or educational materials to make them more effective in achieving the goals of the REMS. 8.1 Key Risk Messages The questions and statements within the KAB surveys for patients/caregivers, pharmacists, and prescribers were constructed to test the stakeholders’ understanding of the key risk messages of the REMS. The TRIG established a desired threshold of 65%. A correct response rate of 65% or greater was considered to represent adequate understanding of each concept or key risk message. The purpose of this threshold was to assist TRIG in tracking and monitoring the data for each key risk message across each wave ultimately providing direction in determining which area(s) would require improvement to ensure the patient/caregiver, pharmacist, and prescriber KAB surveys were meeting the goals of the REMS. 8.2 Patient KAB Survey The patient survey launched on 24 July 2015 and closed on 03 September 2015. Feedback from FDA was provided in the 36-month Assessment Report Acknowledgement Letter and where applicable these changes were implemented in the 48-month survey. Changes included removing ‘Onsolis’ as a response option throughout the survey because it is no longer available, moving specified existing survey questions under key risk messages, and including an analysis of demographics of the patient survey respondents compared to the demographics of patients receiving a TIRF product. The specific goals of the TIRF medicines patient/caregiver KAB survey were to evaluate the level of knowledge and assess the attitudes and behavior of patients/caregivers regarding TIRF medicines. The focus of the survey included the following: 1) TIRF medicines can cause lifethreatening breathing problems that can lead to death, patients should take TIRF medicines only if they are opioid-tolerant, and patients should strictly follow the directions of the HCP, 2) patients should not switch from a TIRF medicine to another medicine that contains fentanyl without talking to an HCP, 3) patients should not give TIRF medicines to anyone else even if they have the same symptoms, and 4) TIRF medicines should be stored in a safe place away from children and properly disposed. The survey also included questions about whether patients received, read, and understood the product-specific Medication Guide and the PPAF. FDA_2729 48-month REMS Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 96 of 112 Invitations (and reminders) were sent to all known patients/caregivers who had filled a prescription within the 4 months (120 days) prior to survey launch. From the total of 432 patients/caregivers who accessed the survey, 314 (72.7%) respondents met eligibility criteria, and of those who met eligibility criteria, 310 (98.7%) completed the survey, exceeding the target of 300 completed surveys. The geographic distribution of survey respondents was similar to the general population of TIRF users (comparison requested by FDA). In general, there is an overall trend across all patient/caregiver KAB surveys conducted (12month, 24-month, 36-month, and 48-month surveys) toward maintenance or improvement in patient/caregiver knowledge and understanding of the key risk messages. Of the 19 components included as part of the 6 key risk messages, 13 components had a response rate >80%, and 3 components had a correct response rate between 67.7% and 74.8%. The remaining 3 components within key risk messages 2 and 3 had a correct response rate which fell below the desired threshold of 65%. Patients scored consistently low on two of 19 components across all survey waves which included 1) TIRF medicines should not be taken for long-lasting pain not from cancer, like arthritis joint pain (43.9% correct) and 2) a patient must stop taking their TIRF medicine if they stop taking their around-the-clock opioid pain medicine (39.4% correct). In addition, revising one question (TIRF medicines should only be taken by patients who are opioid tolerant) to be specific to ‘cancer’ patients, resulted in a large decrease in the correct response rate from the previous survey (85.2% to 43.5%), which may indicate that some respondents were receiving TIRF medicine for a non-cancer associated indications. For complete data and results see Appendix 12.7.1. 8.3 Pharmacy KAB Survey The pharmacy survey launched on 31 August 2015 and closed on 16 September 2015. Feedback from FDA was provided in the 24-month and 36-month Assessment Report Acknowledgement Letters and where applicable these changes were implemented in the 48-month survey. Changes included steps to include a higher percentage of non-supervisory dispensing pharmacists participate in the survey, adding questions addressing CYP3A4 interactions with TIRF medicines and that patients are to stop taking their TIRF when they stop taking their around-the-clock opioid, removing ‘Onsolis’ as a response option throughout the survey because it is no longer available, and moving specified existing survey questions under key risk messages. The specific goals of the TIRF medicines pharmacist KAB survey were to assess pharmacist understanding of the risks associated with TIRF medicine use, the specific indications for treatment with TIRF medicines, and that TIRF medicines are contraindicated in opioid nontolerant patients. The survey also included questions about whether pharmacists received, read, understood, and used the product-specific educational materials, and included questions about compliance with the REMS requirements. Invitations (and reminders) were sent to a random sample of pharmacies enrolled in the TIRF REMS Access program as of 30 June 2015, and were distributed to pharmacists who dispense TIRF products and were known to have received the REMS educational materials. From the total of 607 pharmacists who accessed the survey, 334 (55.0%) pharmacists met eligibility criteria, and of those who met eligibility criteria, 301 (90.1%) completed the survey, exceeding the target of 300 completed surveys. FDA_2730 48-month REMS Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 97 of 112 In general, there is an overall trend across all pharmacist KAB surveys conducted (12-month, 24month, 36-month, and 48-month surveys) toward increasing improvement in pharmacist knowledge and understanding of the key risk messages. Of the 29 components included as part of the 4 key risk messages, 20 components of the key risk messages had a response rate >80%, and 7 components had a response rate between 65.1% to 78.7%. Two components within the key risk messages had a correct response rate below the desired threshold of 65% (Component 6c and Component 9e). The correct response rate for Component 6c (A patient must stop taking their TIRF medicine if they stop taking their around-the-clock opioid pain medicine) was 41.9%. This component was added to the 48-month survey based on feedback provided by FDA in the 24-month and the 36-month FDA REMS Acknowledgement Letter. Correct response rate for Component 9e (Chronic non-cancer pain is not an indication for which TIRF medicines can be prescribed) was 50.8% for this 48-month survey. Component 9e has had a low correct response rate across all pharmacist KAB surveys conducted (12-month, 24-month, 36-month, and 48month surveys). The survey score for Component 9e may indicate that some respondents are dispensing TIRF medicines for non-cancer associated indications. For complete data and results see Appendix 12.7.2. 8.4 Prescriber KAB Survey The prescriber survey launched on 31 August 2015 and closed on 16 October 2015. Feedback from FDA was provided in the 24-month and 36-month Assessment Report Acknowledgement Letter and where applicable these changes were implemented in the 48-month survey. Changes included adding questions on whether the respondent works in a closed system, and for respondents who stated they prescribe TIRF medicines for chronic non-cancer pain addressing why they feel that this is an appropriate use of TIRF medicines, removing ‘Onsolis’ as a response option throughout the survey because it is no longer available, moving specified existing survey questions under key risk messages, removing Question 19 (Can patients continue to take their TIRF medicine if they stop taking their around-the-clock opioid medicine?), and including an analysis of demographics of the prescriber survey respondents compared to the demographics of the general population of TIRF prescribers. The specific goals of the TIRF medicines prescriber KAB survey were to assess prescribers’ understanding of the risks associated with TIRF medicine use, the selection of appropriate patients for treatment with TIRF medicines, preventing inappropriate conversion between TIRF medicines, and ensuring safe use of TIRF medicines while preventing exposure to children and others for whom TIRF medicines were not prescribed. The survey also included questions about whether prescribers received, read, understood, and used the product-specific educational materials, and included questions about compliance with the REMS requirements. Invitations (and reminders) were sent to a random sample of prescribers who prescribed TIRF products, were known to have received the REMS educational materials, and who were enrolled in the TIRF REMS Access program as of 30 June 2015. From the total of 587 respondents who accessed the survey, 350 (59.6%) respondents met eligibility criteria, and of those who met eligibility criteria, 310 (88.6%) completed the survey, exceeding the target of 300 completed surveys. The geographic distribution of survey respondents was similar to the overall population of prescribers who prescribe TIRF medicines (comparison requested by FDA). FDA_2731 48-month REMS Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 98 of 112 In general, there is an overall trend across all prescriber KAB surveys conducted (12-month, 24month, 36-month, and 48-month surveys) toward increasing improvement in prescriber knowledge and understanding of the key risk messages. Of the 31 components included as part of the 4 key risk messages, 21 components of the key risk messages had a correct response rate >80% and 9 components had a correct response rate between 67.7% and 78.7%. For Component 9e, 201 prescribers (64.8%) indicated they do not prescribe TIRF medicines for chronic noncancer pain. The 34.2% of prescribers who stated they do prescribe TIRF medicines for chronic non-cancer pain were presented with 2 additional questions as requested by the FDA; the type of chronic pain conditions they prescribe a TIRF medicine to treat, and the reasons for selecting a TIRF medicine to treat these conditions. Based on prescriber responses, and the high percentage of respondents who indicated they received and read the REMS educational materials, the responses may reflect behavior more than knowledge. That is, prescribers are aware of the labeled indication but choose to prescribe off-label for certain patients. For complete data and results see Appendix 12.7.3. 8.5 Overall Conclusion for KAB Results The consistently high level of stakeholder understanding of key risk messages in the 48-month surveys indicates that the goals of the TIRF REMS are being met with existing tools. The TRIG will evaluate the concepts that have scored low among stakeholders to determine if any action is warranted. The TRIG will continue to work with the FDA to refine, on a continual basis, the steps to mitigate risks associated with TIRF medicines. 9 FDA COMMUNICATIONS REMS Modification 3 was approved by FDA on 24 December 2014. All metrics included in the revised and approved assessment plan have been incorporated into this 48-Month FDA Assessment Report. Post-submission of the 36-Month FDA Assessment Report, TRIG responded to 4 information requests and provided a response to the 36-Month FDA Assessment Report Acknowledgement Letter. Per agreement with FDA a consolidated Drug Master File (DMF) submission was made on 12 October 2015, to include all correspondence related to the 36-Month FDA Assessment Report. Within the Acknowledgement Letter FDA made 3 requests that, based on timing for receipt of the communication, could not be included in this assessment report. As acknowledged by FDA on 13 November 2015, the TRIG plans to submit a Supplemental Report with 2 of these requests with an estimated submission date of 04 May 2016. As discussed in Section 4, the remaining request for outreach to prescribers and pharmacies that did not re-enroll is unwarranted as no barrier to patient access has been observed. 10 POST-APPROVAL STUDIES AND CLINICAL TRIALS FDA should refer to the most recent periodic safety report from each TIRF sponsor for updated information on post-approval studies and/or clinical trials. FDA_2732 48-month REMS Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies 11 Page 99 of 112 DISCUSSION The TIRF REMS Access program was approved on 28 December 2011 and successfully launched on 12 March 2012, approximately 11 weeks after approval. This 48-month assessment report covers the timeframe between 29 October 2014 and 28 October 2015. REMS enrollment continues to increase, with 2,340 new prescribers (Section 5.1.2), 5,892 new pharmacies (Section 5.1.3), and 3 new distributor(s) (Section 5.1.4) enrolled in this reporting period. A total of 152,686 prescriptions were submitted for approval during this reporting period, and 143,763 (94.2%) prescriptions encountered no REMS-related rejections prior to being authorized (Section 5.1.5). These data plus the ongoing stakeholder re-enrollment activity indicate that the program does not present a significant barrier to accessing these important medications while continuing to meet the safety goals of the REMS. Prescription dispensing outside the established PPAF requirements was nearly eliminated as a result of the corrective actions implemented during the previous reporting period to significantly reduce this occurrence (Section 5.1.6). In this 48-month report there was only one prescription for one patient dispensed beyond 10 days after patient enrollment compared with 6 prescriptions for one patient in the 36-month report. The TIRF REMS Access program continues to monitor the electronic systems and stakeholder reports for issues and, where appropriate, corrective actions or system improvements are instituted. During the current reporting period, 101 confirmed instances of stakeholder non-compliance with the TIRF REMS Access program were reviewed and investigated. This included 89 prescriber reports and 12 non-closed system pharmacy reports (a total of 94 cases presented in Table 22 and 7 narratives included in Table 23). Of the cases presented by non-compliance scenario (Table 22), a decrease was seen in the number of confirmed instances of noncompliance between the 36-Month Assessment Report and this reporting period for inpatient pharmacy dispenses for outpatient use (1 vs. 0 reports), submission of a claim that did not go through REMS edits (14 vs. 12 reports), dispensing prescriptions outside of the closed system authorization process (7 vs. 0), and prescriber failure to have a complete PPAF on file in a timely manner (120 vs. 82 reports). There were no wholesaler/distributor or closed system pharmacy reports during this reporting period (Section 6.1) as opposed to one report during the last reporting period. Audits of 6 closed system pharmacy entities were conducted during this reporting period. Two closed system entities were found to be non-compliant with the TIRF REMS Access program requirements. These pharmacies were re-educated, issued a notice through the NCRT and submitted a CAP which was approved by the NCRT. All cases have been closed (Section 6.2). A decrease was seen in the number of instances where a REMS authorization was not received prior to dispensing a TIRF product between the 36-Month Assessment Report and the current reporting period (513 vs. 68 instances). Since submission of the 36-Month FDA Assessment Report, the TRIG developed and implemented an inpatient pharmacy questionnaire to conduct the required inpatient pharmacy audits. Audits of 6 inpatient pharmacies were conducted during this reporting period and no noncompliance was identified for any inpatient pharmacy. FDA_2733 48-month REMS Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 100 of 112 (b) (4) The analysis of spontaneous reports of adverse events of interest used aggregated data from TRIG sponsors with currently marketed products. There were 312 unique case reports that met the specified criteria for addiction (n=12), overdose (n=6), death (n=291), and pediatric exposures (n=4). After a review of the associated MedWatch Forms or narratives for root cause analysis, no reports of inappropriate conversions between TIRF products were noted. Additionally, only one of the narratives indicated accidental, unintentional exposures and there were no cases of use by non-opioid tolerant patients. There was one report of accidental exposure with an outcome of recovered/resolved during the reporting period. There were 4 reports of pediatric exposure (Section 7). In 3 of the 4 reports, the medication was intentionally prescribed to the pediatric patient. The fourth report had insufficient information to determine if the pediatric patient took the TIRF medicine. The REMS goal of educating prescribers and pharmacists on the potential for misuse, abuse, addiction, and overdose is being documented through the completion of the Knowledge Assessment, which is required for enrollment. Effectiveness of the educational program is evaluated through the pharmacy and prescriber KAB surveys that are performed prior to each assessment report. Results of the 48-month surveys indicate a high level of understanding of safe use of TIRF medicines by pharmacists and prescribers. Key risk messages that are important for these stakeholders to understand include the fact that TIRF medicines are contraindicated in opioid non-tolerant patients, are only indicated for the management of breakthrough pain in adult cancer patients, contain fentanyl with abuse liability similar to other opioid analgesics, and are not interchangeable with each other on a mcg-to-mcg basis regardless of route of administration. Two exceptions where pharmacists scored low included understanding that a patient must stop taking their TIRF medicine if they stop taking their around-the-clock opioid pain medicine (41.9% correct), and that TIRF medicines are not indicated for chronic non-cancer pain (50.8% correct), which may indicate that some respondents are dispensing TIRF medicines for noncancer-associated indications. For prescribers, 34.2% stated they do prescribe TIRF medicines for chronic non-cancer pain. Based on prescriber responses of the type of chronic pain conditions for which they prescribe and the reasons for selecting a TIRF medicine to treat these conditions, coupled with the high percentage of respondents who indicated they received and read the REMS educational materials, the responses may reflect behavior more than knowledge. That is, prescribers are aware of the labeled indication but choose to prescribe off-label for certain patients. In general, there is an overall trend across all pharmacist and prescriber KAB surveys conducted (12-month, 24-month, 36-month, and 48-month surveys) toward increasing improvement in pharmacist and prescriber knowledge and understanding of the key risk messages. Due to the high level of understanding of these concepts by pharmacists and prescribers, no modifications to FDA_2734 48-month REMS Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 101 of 112 the educational program or Knowledge Assessment are recommended at this time (Sections 8.3 and 8.4, respectively). Patient education is completed through HCP counseling and completion of a PPAF. The patient KAB survey results indicate that the patient-oriented educational materials including the PPAF and Medication Guide for each product are effective tools at communicating safe use messages to patients, including the importance of not sharing TIRF medicines, taking TIRF medicines as prescribed, and properly disposing unused TIRF medicines. In general, there is an overall trend over time (12-month, 24-month, 36-month, and 48-month surveys) toward maintenance or improvement in patient knowledge and understanding of the key risk messages. Patients scored consistently low on 2 of 19 components: 1) that TIRF medicines should not be taken for longlasting pain not from cancer (43.9% correct), like arthritis joint pain, and 2) that a patient must stop taking their TIRF medicine if they stop taking their around-the-clock opioid pain medicine (39.4%). In addition, revising Question 11 (TIRF medicines should only be taken by patients who are opioid tolerant) to be specific to ‘cancer’ patients, resulted in a large decrease in correct response rate from the previous survey (85.2% to 43.5%) , which may indicate that some respondents were receiving TIRF medicine for non-cancer associated indications. The consistently high level of patient understanding of key risk messages in the latest (48-month) survey indicates that the goals of the TIRF REMS are being met with existing tools. Due to the high level of understanding of these concepts by pharmacists and prescribers, no modifications to the educational program or Knowledge Assessment are recommended at this time (Section 8.2). CONCLUSION Based on the data provided in this TIRF REMS Access program assessment report (program and product utilization statistics, dispensing activity, program infrastructure and performance, noncompliance reporting, safety surveillance data and KAB surveys) the TRIG concludes that the REMS is meeting its established goals. Based on our analysis of the data for this 48-month assessment, the TRIG is recommending no REMS modifications at this time. FDA_2735 48-month REMS Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies 12 Page 102 of 112 APPENDICES FDA_2736 48-month REMS Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies 12.1 Page 103 of 112 Non-Compliance Protocol FDA_2737 TIRF REMS ACCESS PROGRAM NON-COMPLIANCE PROTOCOL Version 7.0 October 26, 2015 Revision History Version # Date Author Description of Changes 1.0 February, 2012 (b) (6) Initial Release 2.0 October 10, 2012 (b) (6) • • • • • 3.0 November 2, 2012 (b) (6) • • 3.1 March 15, 2013 (b) (6) • • • • • Added Revision History Removed ‘Draft-Review Required’ Watermark Added Sub-Sections to Section 5 (previously a separate document) o Added 5.1 – Index of Scenarios o Added 5.2 – Severity Reference o Added 5.3 – Corrective Action Reference o Added 5.4 – Monitoring Frequency Reference Updated Scenario Numbering in Section 5.1 Revised Notices Measurement to clarify 2 Notices in 60 days = 1 Warning Revised Section 5.3, Reference – Corrective Actions to include review of multiple non-compliance events for a stakeholder to see if moving to the next level is warranted Correct title of Section 5.4, Reference – Monitoring Frequency Guidelines Corrected misspellings throughout document Revised Section 2 – Removed reference that process flow will be revised upon agreement of Protocol Revised Section 2 - Non-Compliance Process Flow Removed reference that NonCompliance letters need to be developed from Section 4 Revised Section 5.1 – Non-Compliance Scenarios o Revised the monitoring tool in Pharmacy Scenario 2 and Wholesaler/Distributor Scenario 1 o Revised Pharmacy Scenario 3 FDA_2739 Version # Date Author Description of Changes • to be specific to suspended and deactivated stakeholders o Revised language in Pharmacy Scenarios 4, 5 & 6 for clarify o Added a new Pharmacy Scenario for altered claims o Revised Wholesaler/Distributor Scenario 1 to be specific to suspended and deactivated stakeholders o Revised language in Wholesaler/Distributor Scenario 2 for clarity o Revised Prescriber Scenario 1 to be specific to suspended and deactivated stakeholders o Revised language in Prescriber Scenario 2 for clarity o Re-defined ‘timely manner’ in Prescriber Scenario 2 o Revised language in Closed System Pharmacy Scenario 1for clarify o Added a Patient non-compliant scenario o Added an enrollment monitoring scenario for all stakeholders Revised Section 5.4 – Reference – Monitoring Frequency Guidelines o Clarified new report requests will be handled via the Change Management Process o Changed ‘Sponsor Data’ to ‘Sponsor Reporting’ o Changed frequency of Sponsor Reporting from quarterly to every Non-Compliance Review Team Meeting and as needed o Changed frequency of Escalation Log from daily to every Quality Management Workstream meeting and as needed FDA_2740 Version Author Description of Changes 3.2 5/21/13 0 Revised Section 5.1 Non-Compliance Scenarios 0 Removed Pharmacy Scenario 4 4.0 5/24/13 Accepted all changes from versions 3Added Section 6 Non-Compliance Assessment Reporting 5.0 8/8/13 0 Accepted all changes from version 4.1 Corrected page nrunbers 5.0 8/15/13 0? 0 Approved by TRIG Via vote during the 8/15/13 Program Status Call Meeting 5.1 12/ 17/13 0 Revised Section 5.1 Non-Compliance Scenarios 0 Revised Prescriber Scenario 2 de?nition for ?complete PPAF on ?le in a timely manner? 0 Revised Section 5.3 Reference Corrective Action 0 Change ?amrually? to ?within 12 months? 6.0 12/19/13 0 Accepted all changes from version 5.1 6.0 12/23/13 a? 0 Approved via TRIG e-mail vote 6.1 12/5/13 We) 0 Revised Section 5.1 Non-Compliance Scenarios Added Pharmacy Scenario 4: Pharmacy no longer has a valid DEA. Added Prescriber Scenario 3: Prescriber no longer has a valid. schedule DEA. Added Prescriber Scenario 4: Prescribed TIRF medicines to an opioid non-tolerant individual. 0 Added Prescriber Scenario 5: Inappropriate conversions between TIRF products 0 Revised Section 5.2 Severity Inclusion of language for repeat offenders when deternrined amorurt of is reached without any suspected non-compliance Version Date Author Description of Changes activity 0 Revised Section 5.3 Conective Action 0 Inclusion of language for repeat offenders when determined of time is reached without any suspected non- compliance activity 0 Grammatical corrections 7.0 10/26/15 (6) 0 Accepted all changes from version 6.1 TABLE OF CONTENTS 1. Background ........................................................................................................................... 7 2. Goals and Objectives ............................................................................................................ 8 3. Non-Compliance Review Teams and Responsibility............................................................ 8 4. Corrective Actions for Instances of Non-Compliance ........................................................ 12 5. Evaluation Process .............................................................................................................. 14 5.1. Index of Non-Compliance Scenarios .................................................................................. 14 5.2. Reference – Severity ........................................................................................................... 16 5.3. Reference – Corrective Action ............................................................................................ 17 5.4. Reference – Monitoring Frequency Guidelines .................................................................. 18 6. Non-Compliance Assessment Reporting ............................................................................ 19 FDA_2743 1. Background Opioids remain the mainstay of treatment of moderate to severe pain, especially for opioidtolerant patients experiencing cancer breakthrough pain (BTP). Transmucosal immediate release fentanyl (TIRF) medicines are short-acting opioid products that have a rapid onset and relatively short duration of action and are designed for the treatment of episodes of BTP in opioid-tolerant patients with chronic cancer pain . On December 28, 2011, the Food and Drug Administration (FDA) approved a single, shared Risk Evaluation and Mitigation Strategy (REMS) for TIRF products. The shared system strategy, called the TIRF REMS Access program, will be used by all sponsors of TIRF products and is designed to ensure access to important medications for appropriate patients. The TIRF REMS Access program is in place to mitigate the risk of misuse, abuse, addiction, overdose, and serious complications due to medication errors by: a. Prescribing and dispensing TIRF medicines only to appropriate patients, which includes use only in opioid-tolerant patients. b. Preventing inappropriate conversion between fentanyl products. c. Preventing accidental exposure to children and others for whom it was not prescribed. d. Educating prescribers, pharmacists, and patients on the potential for misuse, abuse, addiction, and overdose of TIRF medicines. Compliance with the TIRF REMS Access program (“program”) is necessary in accordance with the appropriate use of TIRF products and proper patient selection. The TIRF REMS Access program includes a continuous evaluation process of compliance to the program. Any deviation from program procedures is evidence of non-compliance and may result in corrective measures, such as a notice, warning, suspension or program deactivation. FDA_2744 2. Goals and Objectives The goal of the non-compliance protocol is to ensure that a system is in place to identify and investigate stakeholder non-compliance with the TIRF REMS Access program by monitoring possible program deviations detected through program reporting and spontaneous events identified by the program. Suspected non-compliance is defined as an instance when it is believed that a stakeholder is not following a program requirement. Suspected non-compliance scenarios may be detected through standard program reports, spontaneous reports identified via the program’s call center or vendor/sponsor reported events. A suspected non-compliant event is deemed compliant in the event the information presented on a stakeholder scenario does not clearly identify or support that a program deviation has occurred and/or no evidence of the program goals not being met are present. A confirmed non-compliant event is when the information present clearly indicates that a program deviation has occurred and/or evidence of the program goals not being met through stakeholder actions is identified. Confirmation of a non-compliant stakeholder act will typically occur after further investigation has been completed and supportive data has been reviewed and presented to the TIRF REMS Access Non-Compliance Review Team. The objectives of this non-compliance protocol are to: • • • • • • • Describe the purpose and activities of the non-compliance Review Team Describe the purpose and activities of the non-compliance Working Group Describe the process to identify program non-compliance Outline an index of possible scenarios of non-compliance Identify data sources to review for suspected non-compliant events Describe suggested actions taken once non-compliance is confirmed Describe the process to monitor program deviations and occurrences of non-compliance 3. Non-Compliance Review Teams and Responsibility A TIRF REMS Access Non-Compliance Review Team (“Review Team”) will be created composed of membership from the TRIG Sponsors. The Review Team will be responsible for review, escalation, and decision-making of all non-compliance cases, and corrective measures are applied when necessary. The responsibilities of the Review Team may not be delegated or transferred to other parties without prior consent of the TRIG sponsors. If the need arises, the Review Team shall have the authority to consult external advisors, experts, or consultants, in order to effectively assess and process cases of program non-compliance. If it is determined that a program modification may be warranted due to cases of non-compliance, the Review Team may need to consult with the FDA_2745 FDA for their review and approval of any changes impacting the REMS submission. Any proposed program modifications must be approved by the TRIG prior to implementation. The Review Team will meet regularly to discuss all issues of non-compliance and/or program modifications, at a frequency interval defined by the TRIG sponsors. The Review Team will consist of members with expertise from various specialties, which may include: 1. Regulatory Affairs 2. REMS specialist 3. Project Management 4. Legal 5. Quality Assurance 6. Commercial 7. Drug Safety and IT Working practices will be developed to describe when the TRIG sponsors would participate in Review Team discussion in connection with potential or actual major deviations from the REMs program. A Non-Compliance Working Group (”Working Group”) will be created from program staff and will be responsible for collecting data and preparing reports for the Review Team, in compliance with Privacy Health Information (PHI) regulations. The Working Group will consist of program agents who have been working with and/or trained on the TRIG non-compliance protocol, as well as have background necessary to evaluate data and make objective decisions on instances of non-compliance, based on the data available. The functions of the Working Group will be to: 1. Review reports, call center logs or audit report data to identify potential incidences of non-compliance 2. Conduct further investigation as needed to clarify the potential incident and identify root cause of deviation 3. Evaluate compliance with the TIRF REMS program stakeholder business rules 4. Respond to identified events of non-compliance in accordance with the established business rules. Propose solutions and actions for confirmed non-compliance events that are not addresses by such business rules. 5. Prepare reports for review and approval by the Review Team Detailed business rules will outline the process, timeline and corrective action plan for each instance of suspected or confirmed program non-compliance identified by the Working Group. FDA_2746 Stakeholders identified as having suspected or confirmed non-compliant events may be contacted by the Working Group via letters, phone calls or fax to resolve issues related to the identified program deviation all in accordance with such business rules. The Working Group will provide the Review Team with reports in advance of their regularly scheduled meetings and will be available to address any questions or clarifications on the content of the report. The Working Group will provide a summary of the suspected or confirmed noncompliant events that they identified during the review period. Once the Review Team receives the report, their responsibility will be to: • • • • Attend all regularly scheduled Review Team meetings to review, assess and make decisions on any non-compliance issues needing attention including any issue that the Working Group could not handle because it was beyond the scope of the business rules used by the Working Group. Identify if an audit of a stakeholder is required Determine if any report or communication should be made to the FDA outside of regular TIRF REMS assessment reports. Determine if changes to the business rules and/or this protocol need to be made, and make such changes. The following process flow outlines the suggested interactions between the Working Group, the Review Team and the program stakeholders as necessary monitor, review and act upon suggested corrective actions for non-compliant scenarios identified. FDA_2747 TIRF REMS Access Program: Non-compliance Review Process chonpim . 1: 3 mm mm!" ?g I I ll sent Suspense? Identification and Investigation Process of Non-Compliant Events Identi?cation Process Call center staff in the TIRF REMS Program or TRIG sponsor companies will refer cases of potential non-compliance to the Working Group. Investigation Process If an instance of potential non-compliance is identi?ed, ?irther investigation will be conducted. This may include: Review case details to determine if evidence of non-compliance exists Make attempt(s) to contact relevant stakeholder to validate data/information and solicit further information 0 Conduct further investigation of TRF REMS Program databases For instances of potential non-compliance that are not described in Section 5, a suggested course of action will be presented to the Review Team. The Working Group will consult with the Review Team if proprietary or commercially sensitive information arises that would not ordinarily be shared among TRIG representatives. 4. Corrective Actions for Instances of Non-Compliance Corrective actions resulting from non-compliance will be determined according to the severity of the action. The stakeholders in this non-compliance protocol include prescribers, patients, distributors, and pharmacies. The primary elements for corrective action include; notices, warnings, suspension, and deactivation based on the requirements of the TIRF REMS Access program. If a prescriber, pharmacy or distributor is suspended or deactivated, information will be made available through the program to assist unaffected stakeholders in finding alternative access to product. Each non-compliant event will be categorized based on the level of severity of the event. The event classifications are as follows: Minor An unintended (e.g., first-time) event. The corrective action will typically result in a written notice being sent to the stakeholder and re-education of the program requirements to prevent any re-occurrences of the event. Moderate A repeated event or a series of different [or distinct], unintended events. An investigation will be conducted by program staff to identify the root cause of the event. Program staff will also work with the stakeholder to create and implement a corrective plan of action. Once implemented, the stakeholder will be monitored for compliance with the plan of action, and provided with a written warning for their files. Serious An event that results in serious or significant injury or potential risk to a patient irrespective of the number of previous non-compliance occurrences, or continued non-compliant events after retraining has occurred. This level of offense will result in a suspension from the program and possible deactivation. Deactivated prescribers will not be able to participate in the TIRF REMS Access program for any existing or future patients, effectively barring their ability to provide TIRF medicines as a therapy for their patients. A deactivated stakeholder may request reinstatement in the TIRF REMS Access program. Requests for reinstatement must be in writing and contain sufficient details of corrective actions taken to prevent any future incidents of non-compliance with elements of the program. Requests for reinstatement will be evaluated by the Review Team and the team will make the final determination on reinstatement. Detailed business rules will outline the process, timeline and corrective action plan for each level of program non-compliance. FDA_2749 The Review Groups will determine whether a suspended pharmacy or distributor will be permitted to keep an inventory of TIRF medicines already acquired prior to suspension. Pharmacies may not dispense TIRF medicines from such existing inventory during the suspension and distributors may not sell and/or distribute TIRF medicines. If a suspended outpatient pharmacy or distributor is part of a larger entity, the parent entity will be notified of the noncompliant activity and resultant suspension. Deactivated pharmacies and distributors will be required to return all existing TIRF medicine inventory. Patient notices that result from violations of program elements will be sent to a patient’s prescriber. FDA_2750 5. Evaluation Process 5.1. Index of Non-Compliance Scenarios Stakeholder Pharmacy Scenario # 1 2 3 Non-Compliance Activity Submission of a claim that did not go through the REMS edits. A TIRF medicine was dispensed without verifying through the TIRF pharmacy management system that the prescriber is enrolled and active, and that the patient is enrolled or has not been inactivated in the program. Dispensing activity for enrolled outpatient pharmacies during reporting period not matching distributor shipment data for that pharmacy. Pharmacy is dispensing TIRF medicine while suspended or deactivated from the TIRF REMS Access program. 4 Pharmacy no longer has a valid DEA 5 Authorized Inpatient Pharmacy does not comply with the requirements of the TIRF REMS Access program. 6 Inpatient Pharmacy dispenses for outpatient use 7 Wholesaler/ Distributor 1 Submission of inappropriately altered claim to meet TIRF REMS system requirements (e.g. changing prescriber) Wholesaler/Distributor is suspended or deactivated from the TIRF REMS Access program and is purchasing or distributing TIRF medicines. 2 Wholesaler/Distributor fills an order for TIRF medicines for a non enrolled stakeholder. Prescriber 1 2 Prescriber is prescribing TIRF medicines while suspended or deactivated from the TIRF REMS Access program. Prescriber failure to have a complete PPAF on file in a timely manner (5 or more patients enrolled by the prescriber without a complete PPAF on file, with each patient having greater than 10 working days lapse from intial enrollment date). 3 Prescriber no longer has a valid, schedule II DEA. 4 Prescribed TIRF medicines to an opioid non-tolerant individual. 5 Inappropriate conversions between TIRF products. Monitoring Tool Audit or Spontaneous event reported Audit or Sponsor reported Audit or Spontaneous event reported Audit or Spontaneous event reported Audit or Spontaneous event reported Audit or Spontaneous event reported Audit or Spontaneous event reported Sponsor reported Audit or Spontaneous event reported Audit or Spontaneous event reported Program Report Audit or Spontaneous event reported Audit or Spontaneous event reported Audit or Spontaneous event reported FDA_2751 Closed System Pharmacy Patient 1 All Stakeholders 1 1 Dispensing prescriptions outside of the closed system authorization process. The Patient receives prescriptions for TIRF medicines from multiple prescribers within an overlapping time frame that is suggestive of misuse, abuse, or addiction ENROLLMENT MONITORING ONLY: Monitor stakeholders who are not enrolled in TIRF and are associated with non-compliance cases. Program Report Audit or Spontaneous event reported Program Reports FDA_2752 5.2. Reference – Severity Severity Guideline Level of Severity Minor Moderate Serious Definition First identification of a non-compliant event or since 24 months from the closure of a previous case. >1 non-compliance issue, without a warning on file >1 non-compliance issue with a warning on file or an event that results in serious or significant injury or potential risk to a patient irrespective of the number of previous noncompliance occurrences FDA_2753 5.3. Reference – Corrective Action Corrective Action Guideline Action Notices Warnings Suspension Deactivation Measure Patient notices will be sent to a patient's prescriber Minor violations that demonstrate a misunderstanding of the program requirements Notices are intended to re-educate stakeholders 2 Notices in 60 days = Review by Non-Compliance Review Team to determine if a Warning is warranted Previous case resulted in a notice due to unsuccessful outreach attempts and unable to successfully outreach for current case. 2 Warnings in 60 days = Review by Non-Compliance Review Team to determine if a Suspension is warranted >1 Warning and/or suspension in >60 days = Case-byCase review for Suspension Temporary deactivation from the program A suspended pharmacy or distributor may keep existing TIRF inventory but may not purchase or acquire additional TIRF medicines Pharmacies may not dispense TIRF medicines from existing inventory and distributors may not sell/distribute TIRF medicines during suspension If the pharmacy or distributor is part of a larger entity that entity will be notified of the suspension 1 Warning or 2 Notices while Suspended = Review by Non-Compliance Review Team to determine if a Deactivation is warranted 2 Suspensions within 12 months = Review by NonCompliance Review Team to determine if a Deactivation is warranted Deactivations may result in multiple failures to comply with the program elements and/or non-compliance where there is no feasible corrective action Bars stakeholder to provide TIRF medicines as a therapy for their patients Pharmacies and distributors must return all existing TIRF medicine Patient deactivation will be sent to a patient's prescriber. Patients may only be reinstated into the program by a request from their prescriber FDA_2754 5.4. Reference – Monitoring Frequency Guidelines Monitoring Frequency Guideline Report Category Existing Reports Report Does Not Exist Sponsor Reported KAB Surveys Escalation Log Frequency Bi-Monthly Cost/Timeline TBD - Report request will be handled via the Change Management Process During every Non-Compliance Review Team Meeting and as needed 12 and 24 months from the date of the REMS approval and as needed thereafter During every Quality Management Workstream meeting and as needed FDA_2755 6. Non-Compliance Assessment Reporting Confirmed non-compliance events will be provided to the Companies’ 3rd party vendor for inclusion in FDA assessment reports. FDA_2756 48-month REMS Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies 12.2 Page 104 of 112 Safety Surveillance Aggregate Line Listing Preferred Terms FDA_2757 48-month REMS Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies I. Case Criteria: Only US cases No American Association of Poison Control Center (AAPCC) or literature search cases In addition to performing searches on the below preferred terms, sponsors will search for: o All cases with an outcome of death o Cases related to patients aged 0 through 18 Cases to be included in the reporting period date range will be based on MedWatch Form field “Date Received by Manufacturer” (G4) • • • • II. Case Identification a. Addiction Line Listing Cases of addiction will be identified through the following Preferred Terms. Sponsors are responsible for reviewing all cases pulled by these Preferred Terms and determining whether each is deemed as a case of addiction by their company. Only cases identified by a Sponsor’s company as cases of addiction should be provided to UBC. Preferred Terms for FDA Requested Cases of Addiction Primary SOC High Level Group High Level Term Preferred Term Psychiatric disorders Psychiatric disorders NEC Substance-related disorders Intentional drug misuse Psychiatric disorders NEC Substance-related disorders Drug abuse Medication errors Maladministrations Drug administered at inappropriate site Misuse Abuse Psychiatric disorders Inappropriate Injury, poisoning and procedural complications Page 1 of 7 FDA_2758 48-month REMS Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Preferred Terms for FDA Requested Cases of Addiction Primary SOC High Level Group High Level Term Preferred Term Injury, poisoning and procedural complications Medication errors Maladministrations Inappropriate schedule of drug administration Injury, poisoning and procedural complications Medication errors Maladministrations Incorrect dose administered Injury, poisoning and procedural complications Medication errors Maladministrations Incorrect dosage administered Injury, poisoning and procedural complications Medication errors Maladministrations Inappropriate schedule of drug administration Medication errors Accidental exposures to product Accidental exposure to product Psychiatric disorders Psychiatric disorders NEC Substance-related disorders Dependence Psychiatric disorders Psychiatric disorders NEC Substance-related disorders Drug dependence Psychiatric disorders Psychiatric disorders NEC Substance-related disorders Drug dependence, antepartum Psychiatric disorders Psychiatric disorders NEC Substance-related disorders Drug dependence, postpartum Psychiatric disorders Psychiatric disorders NEC Substance-related disorders Polysubstance dependence Medication Error Accidental Injury, poisoning and procedural complications Dependence Page 2 of 7 FDA_2759 48-month REMS Assessment Rep01t Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies b. Overdose Line Listing Cases of overdose will be identi?ed though the following Preferred Teims. Preferred Terms for FDA Requested Cases of Overdose . Preferred Term Primary SOC High Level Group High Level Term Overdose Ii' . . . Accidental overdose ?my p01sonmg an ioce 111a Medication eirors Overdoses complications Injiuy, poisoning and procedural Medication eirors Overdoses Intentional overdose complications Ii . . . . iJiuy,p01sonmg an ioce Medication eirors Overdoses Oveidose complications Injiuy, poisoning and rocediu'al Medication eirors Overdoses Prescribed overdose complications Ii? d?d'l Ch'l" .. .. . .. iJiuy,p01sonmg an ioce em?? mlmy an P01sonmg and tox1c1ty Acc1dentalp01sonmg complications pOisonmg Page 3 of7 48-month REMS Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies c. Death Line Listing Cases of death will be identified through the following Preferred Terms or a reported outcome of death. Preferred Terms for FDA Requested Cases of Death Primary SOC High Level Group High Level Term Preferred Term General disorders and administration site conditions Fatal outcomes Death and sudden death Accidental death General disorders and administration site conditions Fatal outcomes Death and sudden death Brain death General Disorders and administration site conditions Fatal outcomes Death and sudden death Cardiac death General disorders and administration site conditions Fatal outcomes Death and sudden death Death General disorders and administrations site conditions Fatal outcomes Death and sudden death Death neonatal General disorders and administration site conditions Fatal outcomes Death and sudden death Sudden cardiac death General Disorders and administration site conditions Fatal outcomes Death and sudden death Sudden death General disorders and administration site conditions Fatal outcomes Death and sudden death Agonal death struggle Death Page 4 of 7 FDA_2761 48-month REMS Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Preferred Terms for FDA Requested Cases of Death Primary SOC High Level Group High Level Term Preferred Term General disorders and administration site conditions General system disorders NEC General signs and symptoms NEC Apparent death General disorders and administration site conditions Therapeutic and nontherapeutic effects (excl toxicity) Therapeutic and nontherapeutic responses Drug ineffective/death Cardiac disorders Cardiac arrhythmias Ventricular arrhythmias and cardiac arrest Cardio-respiratory arrest Cardiac disorders Cardiac arrhythmias Ventricular arrhythmias and cardiac arrest Cardiac arrest Respiratory, thoracic and mediastinal disorders Respiratory disorders NEC Breathing abnormalities Respiratory arrest Pregnancy, puerperium and perinatal conditions Abortions and stillbirth Stillbirth and foetal death Foetal death Page 5 of 7 FDA_2762 48-month REMS Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies d. Pediatric Exposure Line Listing Cases of pediatric exposure will be identified through the following Preferred Terms or any case involving patients 0-18 years of age. Preferred Terms for FDA Requested Cases of Pediatric Exposure Primary SOC High Level Group High Level Term Preferred Term Injury, poisoning and procedural complications Medication errors Accidental exposures to product Accidental exposure to product by child Injury, poisoning and procedural complications Product use issues Product use issues NEC Drug administered to patient of inappropriate age General disorders and administration site conditions Product quality issues Product packaging issue Failure of child resistant mechanism for pharmaceutical product Accidental Page 6 of 7 FDA_2763 48-month REMS Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies e. Case Identification for Any Table Through Text-string Searches In addition to the agreed upon Preferred Terms, Sponsors will also provide cases based on text-string searches using the below terms. Sponsors will inform UBC if cases are provided that are not aligned with the approved Preferred Terms, but were identified through a text-string search. Text-string Search Terms for Narratives Addiction Multiple drug overdose Son Nephew Overdose Expired Daughter Aunt Drug dependence Passed away Grandmother Uncle Death Infant Grandfather Mom Pediatric exposure Child Sister Pop Died Mother Brother Dad Fatal Father Niece Inappropriate Conversion Inappropriate Accidental Intentional Non-opioid Tolerant Page 7 of 7 FDA_2764 48-month REMS Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies 12.3 Page 105 of 112 Safety Surveillance Aggregate Line Listing of Deaths FDA_2765 48-month REMS Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies. Cases of Death Received from TRIG Sponsors during the Reporting Period: 29 August 2014 - 28 August 2015 UBC ID Patient Age Patient Gender Event Date Report Date Preferred Term(s) TIRF Duration 1472 19 Male 01JAN2012 29AUG2014 Death Unknown Unknown None reported None reported Death Insufficient information 1473 UNK Male Unknown 29AUG2014 Death Cancer pain Unknown None reported None reported Death Insufficient information 1475 UNK Male 12AUG2014 01SEP2014 Death Breakthrough Unknown pain None reported None reported Death Not related 1477 UNK Female Unknown 02SEP2014 Death Unknown Unknown None reported None reported Death Insufficient information 1480 61 Male 08SEP2014 10SEP2014 Death Unknown Unknown None reported None reported Death Not related 1482 66 Female 10SEP2014 16SEP2014 Death Pain Unknown None reported None reported Death Not related 1483 54 Male 29MAR2013 16SEP2014 Death Unknown Unknown None reported None reported Death Insufficient information 1484 71 Male 12SEP2014 17SEP2014 Death Breakthrough 2014-06 pain UNK None reported None reported Death Insufficient information 1485 UNK Female Unknown 23SEP2014 Death Unknown Unknown None reported None reported Death Not related 1486 55 Unknown Unknown 23SEP2014 Death Unknown Unknown None reported None reported Death Not related 1487 83 Female Unknown 23SEP2014 Death, Hospice care Severe pain related to malignancy Unknown None reported None reported Death Not related 1488 49 Female 06JUN2014 23SEP2014 Death Unknown Unknown None reported None reported Death Insufficient information 1489 57 Female 01MAY2014 23SEP2014 Death Unknown Unknown None reported None reported Death Insufficient information 1490 UNK Female Unknown 24SEP2014 Death Unknown Unknown None reported None reported Death Not related 1491 UNK Male Unknown 25SEP2014 Death Unknown Unknown None reported None reported Death Not related 1492 64 Female Unknown 25SEP2014 Ovarian cancer metastatic Cancer pain Unknown None reported None reported Death Not related 1493 51 Female Unknown 26SEP2014 Death Unknown Unknown None reported None reported Death Not related 1494 50 Female 2014 26SEP2014 Disease progression Breakthrough Unknown pain None reported None reported Death Not related Indication(s) Concomitant Medications Co-Suspect Product(s) Event Outcome Potential Causality1 Page 1 of 23 FDA_2766 48-month REMS Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Bold text indicates FDA requests/comments. Italicized text represents the response to each item. 1. A more detailed data analysis section that presents the statistical methods used, how calculations were performed, and the assumptions made, at the level of detail as provided in your April 2, 2015, response to the March 19, 2015, FDA Information Request. In addition, include a pre-post REMS means analyses and trend analyses (e.g. segmented regression analyses), statistically comparing event rates for a timeperiod immediately prior to full implementation of the TIRF REMS with an equivalent period of time after REMS implementation. As requested, a more detailed analysis section was added to the protocol. The detailed analysis section includes the additional requested means and trend analyses. FDA also requested that an equal number of quarter of data be included pre and post TIRF REMS. However this will not be possible for all programs. For example, there are now 12 quarters of data available post-REMS but as only 11 quarters of pre-TIRF REMS data are available for college survey. Please note that it is not a requirement of the model that an equal number of quarters are included pre and post TIRF REMS, but rather that there are enough quarters to model a trend in both the pre and post TIRF REMS period. To standardize and still represent an adequate period of time pre-TIRF REMS for trending we suggest including 8 quarters of data. 2. Present the data at the dosage unit level as well as population and URDD levels. We presented population, prescription, and dosing unit rates in the last report and will continue to provide these same rates for future reports. We did not include URDD rates as this scale is not necessarily additive. For example if a subject had both Actiq® and Fentora® prescribed in the same quarter, the de-identified aggregate data we receive from IMS would count this person twice instead of once thus failing to preserve uniqueness of subjects across drugs. Number of prescription and number of dosage units are additive. 3. The RADARS treatment center data (Opioid Treatment Program and Survey of Key Informants Patients) programs are confounded by the fact that the number of treatment centers participating in each quarter fluctuates (although the overall numbers are generally increasing). In subsequent submissions, limit the presentation of treatment center data to centers that have contributed data in all of the time-periods assessed. In addition, provide the various versions of the survey instruments/pill cards in use throughout the time-periods assessed with dates provided indicating when each instrument was in use. Based on analysis through 2Q15, limiting the data to only those treatment centers with respondents since 3Q09 will change the coverage region from roughly 349 treatment center sites to only 24 treatment center sites. Instead, we suggest presenting both the data for all centers, in addition to those 24 treatment centers, in order to judge the sensitivity of the result to the increasing number of treatment centers included in the two programs over time. Page 1 of 1 FDA_2767 48-month REMS Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies. UBC ID Patient Age Patient Gender Event Date Report Date Preferred Term(s) TIRF Duration 1496 UNK Male Unknown 26SEP2014 Death Unknown Unknown None reported None reported Death Insufficient information 1498 61 Male 30MAY2014 29SEP2014 Neoplasm progression Breakthrough Unknown pain None reported None reported Death Not related 1501 UNK Female Unknown 03OCT2014 Death Unknown 10 Years None reported None reported Death Not related 1502 52 Female Unknown 03OCT2014 Death Unknown Unknown None reported None reported Death Not related 1503 72 Male Unknown 03OCT2014 Metastasis, Bladder cancer Unknown Unknown None reported None reported Death Not related 1505 UNK Male Unknown 08OCT2014 Death Unknown Unknown None reported None reported Death Insufficient information 1506 UNK Male Unknown 10OCT2014 Death Unknown 2014-06 UNK None reported None reported Death Insufficient information 1507 UNK Female Unknown 13OCT2014 Death Unknown Unknown None reported None reported Death Not related 1508 UNK Male Unknown 13OCT2014 Death Unknown Unknown None reported None reported Death Not related 1509 41 Female 07OCT2014 13OCT2014 Neoplasm progression Breakthrough 2014-10-02 - Advil, Ativan, cancer pain UNK Carafate, Dexamethasone, Emend, Lactulose, Marinol, Norco, Ondansetron, Oxycodone, Sancuso, Senokot, Temazepam, Warfarin, Fentanyl Patch None reported Death Not related 1510 UNK Female Unknown 13OCT2014 Death Unknown Unknown None reported None reported Death Insufficient information 1511 55 Male 01JUN2014 14OCT2014 Death Unknown Unknown None reported None reported Death Not related 1513 UNK Male 2014 14OCT2014 Death Breakthrough 2014-07-18 - None reported pain UNK None reported Death Not related 1514 UNK Female Unknown 14OCT2014 Death Unknown Unknown None reported None reported Death Insufficient information 1515 UNK Unknown Unknown 15OCT2014 Death Unknown Unknown None reported None reported Death Not related Indication(s) Concomitant Medications Co-Suspect Product(s) Event Outcome Potential Causality1 Page 2 of 23 FDA_2768 48-month REMS Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies. UBC ID Patient Age Patient Gender Event Date Report Date Preferred Term(s) TIRF Duration 1517 59 Male Unknown 16OCT2014 Death Unknown Unknown None reported None reported Death Not related 1518 60 Male Unknown 17OCT2014 Death Unknown Unknown None reported None reported Death Insufficient information 1520 68 Male Unknown 22OCT2014 Death, Product use issue Scoliosis, chronic pain Unknown None reported None reported Death Not related 1521 UNK Male Unknown 23OCT2014 Death Unknown Unknown None reported None reported Death Insufficient information 1522 69 Male 23OCT2014 23OCT2014 Death Unknown Unknown None reported None reported Death Not related 1523 UNK Female Unknown 23OCT2014 Death Unknown Unknown None reported None reported Death Insufficient information 1524 79 Male Unknown 23OCT2014 Prostate cancer Cancer pain Unknown None reported None reported Death Not related 1525 69 Male 24OCT2014 28OCT2014 Neoplasm progression Cancer pain Unknown Morphine None reported Death Not related 1526 UNK Female Unknown 29OCT2014 Death Unknown Unknown None reported None reported Death Not related 1527 66 Male 21OCT2014, Unknown 30OCT2014 Completed Low back suicide, Off label pain use Unknown Methadone None reported Death Insufficient information 1528 61 Female 22OCT2014 31OCT2014 Neoplasm progression Lung cancer 2014-09 UNK Dexamethasone, Gilotrif, Percocet, Fentanyl Patch None reported Death Not related 1529 69 Male 01JAN2014 03NOV2014 Death Unknown Unknown None reported None reported Death Not related 1530 78 Female 29MAR2014, 29MAR2014, 29MAR2014, 29MAR2014, 29MAR2014, 24MAR2014, 24MAR2014, Unknown 04NOV2014 Death, Unknown Gastrointestinal sounds abnormal, Lung infection, Traumatic lung injury, Urine output decreased, Atrial fibrillation, Respiratory failure, Somnolence Unknown None reported None reported Death Not related Indication(s) Concomitant Medications Co-Suspect Product(s) Event Outcome Potential Causality1 Page 3 of 23 FDA_2769 48-month REMS Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies. UBC ID Patient Age Patient Gender Event Date Report Date Preferred Term(s) TIRF Duration 1531 52 Male 02MAY2013 05NOV2014 Neoplasm progression Cancer pain 2012-12-27 - Afinitor, Albuterol, None reported UNK Amlodipine, Ativan, Celexa, Dilaudid, Exalgo ER, Phenergan, Relistor, Sennokot S Death Not related 1532 UNK Male Unknown 07NOV2014 Death Unknown Unknown None reported None reported Death Insufficient information 1535 UNK Male Unknown 10NOV2014 Death Unknown Unknown None reported None reported Death Insufficient information 1536 UNK Female Unknown 11NOV2014 Death Unknown Unknown None reported None reported Death Insufficient information 1537 28 Male Unknown 14NOV2014 Death Unknown Unknown None reported None reported Death Not related 1538 61 Female 01FEB2013 14NOV2014 Death Unknown Unknown None reported None reported Death Insufficient information 1539 60 Male Unknown 19NOV2014 Death Pain Unknown None reported None reported Death Not related Indication(s) Concomitant Medications Co-Suspect Product(s) Event Outcome Potential Causality1 1541 64 Male Unknown 20NOV2014 Death Unknown Unknown None reported None reported Death Not related 1542 UNK Female 2013 20NOV2014 Death Unknown Unknown None reported None reported Death Insufficient information 1543 UNK Female Unknown 20NOV2014 Death Unknown Unknown None reported None reported Death Insufficient information 1546 UNK Female Unknown 21NOV2014 Death Unknown Unknown None reported None reported Death Insufficient information 1548 71 Female 27APR2014 26NOV2014 Neoplasm progression Unknown Unknown None reported None reported Death Not related 1549 UNK Female Unknown 26NOV2014 Death Unknown Unknown None reported None reported Death Insufficient information 1550 UNK Male Unknown 26NOV2014 Death Unknown Unknown None reported None reported Death Insufficient information 1551 UNK Male Unknown 01DEC2014 Death Unknown Unknown None reported None reported Death Insufficient information 1552 UNK Female Unknown 08DEC2014 Death Unknown Unknown None reported None reported Death Insufficient information Page 4 of 23 FDA_2770 48-month REMS Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies. UBC ID Patient Age Patient Gender Event Date Report Date Preferred Term(s) TIRF Duration 1554 52 Female Unknown 15DEC2014 Death Unknown Unknown None reported None reported Death Not related 1555 UNK Female Unknown 18DEC2014 Death Unknown Unknown None reported None reported Death Not related 1556 UNK Female Unknown 19DEC2014 Disease progression Cancer pain Unknown None reported None reported Death Not related 1558 70 Female 23APR2013 23DEC2014 Neoplasm progression Breakthrough 2013-01-22 - Carboplatin, None reported cancer pain UNK Complex B-100, Darbepoetin, Gemcitabine, Lisinopril, MsContin, Oxycodone Hydrochloride, Paclitaxel, Potassium Chloride, Senna Plus, Vitamin D2 Death Not related 1560 UNK Male Unknown 29DEC2014 Death Unknown Unknown None reported None reported Death Insufficient information 1561 58 Female Unknown 29DEC2014 Death Unknown Unknown None reported None reported Death Insufficient information 1562 66 Female 31DEC2012 29DEC2014 Death Unknown Unknown None reported None reported Death Insufficient information 1563 72 Male 25DEC2014 05JAN2015 Neoplasm progression Breakthrough 2014-12-24 - Haldol, Morphine cancer pain UNK Concentrate, Oxycodone, Phenobarbital, Fentanyl Patch None reported Death Not related 1564 UNK Male Unknown 07JAN2015 Death Unknown 2014-03 UNK None reported None reported Death Insufficient information 1565 UNK Male Unknown 08JAN2015 Death Unknown Unknown None reported None reported Death Insufficient information 1566 67 Male 12JAN2015, 30NOV2014 12JAN2015 Death, Pneumonia Pain Unknown Duragesic None reported Death Not related 1567 65 Male 30NOV2014, 01FEB2013, Unknown 12JAN2015 Pneumonia, Lung Pain cancer metastatic, Death Unknown None reported None reported Death Not related Indication(s) Concomitant Medications Co-Suspect Product(s) Event Outcome Potential Causality1 Page 5 of 23 FDA_2771 48-month REMS Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies. UBC ID Patient Age Patient Gender Event Date Report Date Preferred Term(s) TIRF Duration 1570 63 Male Unknown 13JAN2015 Death Unknown Unknown None reported None reported Death Not related 1571 44 Female Unknown 13JAN2015 Breast cancer metastatic Cancer pain Unknown None reported None reported Death Not related 1572 UNK Female Unknown 14JAN2015 Death Breakthrough Unknown cancer pain None reported None reported Death Insufficient information 1573 UNK Female Unknown 14JAN2015 Death Unknown Unknown None reported None reported Death Insufficient information 1574 46 Male 15JAN2015 15JAN2015 Death Unknown Unknown None reported None reported Death Insufficient information 1575 84 Male 31MAR2014 16JAN2015 Death Unknown Unknown None reported None reported Death Insufficient information 1576 UNK Female Unknown 20JAN2015 Death Unknown Unknown None reported None reported Death Insufficient information 1577 56 Male 11JAN2015 20JAN2015 Death Breakthrough Unknown cancer pain Fentanyl, None reported Meropenem, Insulin Death Not related 1579 49 Female Unknown 20JAN2015 Death Unknown Unknown None reported None reported Death Not related 1580 67 Male JAN2013 22JAN2015 Cholecystitis, Unknown Septic shock, Death, Intentional product misuse, Hypotension, Ischaemic hepatitis, Rhabdomyolysis, Disseminated intravascular coagulation, Hepatic necrosis Unknown None reported APAP, Drug, Ethanol Death Not related 1581 83 Female Unknown 23JAN2015 Death Unknown Unknown None reported None reported Death Insufficient information 1582 UNK Male Unknown 27JAN2015 Death Unknown Unknown None reported None reported Death Not related 1583 UNK Male Unknown 27JAN2015 Death Unknown Unknown None reported None reported Death Not related 1584 UNK Female Unknown 27JAN2015 Uterine cancer Unknown Unknown None reported None reported Death Not related Indication(s) Concomitant Medications Co-Suspect Product(s) Event Outcome Potential Causality1 Page 6 of 23 FDA_2772 48-month REMS Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies. UBC ID Patient Age Patient Gender Event Date Report Date Preferred Term(s) TIRF Duration 1585 UNK Male Unknown 29JAN2015 Death Unknown Unknown None reported None reported Death Insufficient information 1587 50 Female Unknown 30JAN2015 Breast cancer metastatic Cancer pain, pain Unknown None reported Morphine Death Sulfate, Fentanyl Transdermal System Not related 1588 47 Male Unknown 02FEB2015 Death Unknown Unknown None reported None reported Death Not related 1589 UNK Male Unknown 02FEB2015 Death Unknown Unknown None reported None reported Death Insufficient information 1590 74 Female 01JAN2013 05FEB2015 Death Cancer pain Unknown None reported None reported Death Not related 1591 33 Male OCT2013 06FEB2015 Death Unknown Unknown None reported None reported Death Insufficient information 1592 UNK Female DEC2014 09FEB2015 Death, Therapy cessation Unknown Unknown None reported None reported Death Insufficient information 1593 UNK Male Unknown 11FEB2015 Death Unknown Unknown None reported None reported Death Not related 1595 UNK Male Unknown 16FEB2015 Death Unknown Unknown None reported None reported Death Insufficient information 1596 32 Female Unknown 17FEB2015 Death Unknown Unknown None reported None reported Death Not related 1597 UNK Male Unknown 18FEB2015 Neoplasm progression Breakthrough Unknown cancer pain Oxycodone, Oxycontin None reported Death Not related 1598 UNK Male Unknown 19FEB2015 Death Unknown Unknown None reported None reported Death Not related 1599 UNK Female Unknown 23FEB2015 Death Unknown Unknown None reported None reported Death Insufficient information 1601 59 Male Unknown 24FEB2015 Death Unknown Unknown None reported None reported Death Insufficient information 1602 UNK Male Unknown 24FEB2015 Death Unknown 2014-03 UNK None reported None reported Death Insufficient information 1605 UNK Female Unknown 27FEB2015 Death Unknown Unknown None reported None reported Death Insufficient information 1606 UNK Male Unknown 27FEB2015 Death Unknown Unknown None reported None reported Death Insufficient information Indication(s) Concomitant Medications Co-Suspect Product(s) Event Outcome Potential Causality1 Page 7 of 23 FDA_2773 48-month REMS Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies. UBC ID Patient Age Patient Gender Event Date Report Date Preferred Term(s) 1607 UNK Male Unknown 27FEB2015 Death 1610 32 Female 01AUG2007 12MAR2015 1611 UNK Female Unknown 1612 UNK Male 1613 88 1615 1616 TIRF Duration Indication(s) Unknown Concomitant Medications Co-Suspect Product(s) Event Outcome Potential Causality1 Unknown None reported None reported Death Insufficient information Accidental death Pain Unknown Oxycontin, Dilaudid, None reported Duragesic, Ambien, Klonopin, Seroquel Death Not related 12MAR2015 Death Unknown Unknown None reported None reported Death Insufficient information Unknown 12MAR2015 Death Unknown Unknown None reported None reported Death Insufficient information Female Unknown 13MAR2015 Death Cancer pain Unknown None reported None reported Death Insufficient information UNK Male Unknown 17MAR2015 Death Unknown Unknown None reported None reported Death Not related UNK Female Unknown 17MAR2015 Death Unknown Unknown None reported None reported Death Insufficient information 1617 51 Male Unknown 17MAR2015 Malignant neoplasm progression Unknown Unknown None reported None reported Death Not related 1618 60 Female Unknown 18MAR2015 Death Unknown Unknown None reported None reported Death Not related 1620 51 Male 15MAY2013 19MAR2015 Death Breakthrough 29 Days cancer pain None reported None reported Death Insufficient information 1621 UNK Male Unknown 19MAR2015 Death Unknown Unknown None reported None reported Death Insufficient information 1622 UNK Male Unknown 19MAR2015 Death Unknown Unknown None reported None reported Death Insufficient information 1623 UNK Male 2013 20MAR2015 Colon cancer, Death Breakthrough Unknown pain None reported None reported Death Not related 1624 45 Female 01JAN2013 23MAR2015 Death Unknown Unknown None reported None reported Death Not related 1626 UNK Female Unknown 24MAR2015 Death Unknown Unknown None reported None reported Death Insufficient information 1627 UNK Female Unknown 24MAR2015 Death Unknown Unknown None reported None reported Death Insufficient information 1628 UNK Female Unknown 25MAR2015 Death Unknown Unknown None reported None reported Death Not related Page 8 of 23 FDA_2774 48-month REMS Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies. UBC ID Patient Age Patient Gender Event Date Report Date Preferred Term(s) 1629 59 Female Unknown 26MAR2015 Death Unknown 1630 UNK Female Unknown 27MAR2015 Death 1631 UNK Female Unknown 27MAR2015 1632 UNK Female Unknown 1633 UNK Female Unknown 1634 UNK Female 1635 UNK 1636 TIRF Duration Indication(s) Unknown Concomitant Medications Co-Suspect Product(s) Event Outcome Potential Causality1 None reported None reported Death Insufficient information Breakthrough 21 Days cancer pain None reported None reported Death Not related Death Unknown Unknown None reported None reported Death Insufficient information 31MAR2015 Death Unknown Unknown None reported None reported Death Not related 01APR2015 Death Unknown Unknown None reported None reported Death Insufficient information Unknown 01APR2015 Death Unknown Unknown None reported None reported Death Insufficient information Male Unknown 01APR2015 Neoplasm progression Unknown Unknown None reported None reported Death Not related UNK Female Unknown 02APR2015 Death Unknown Unknown None reported None reported Death Insufficient information 1637 45 Female 01JAN2013 03APR2015 Death Unknown Unknown None reported None reported Death Insufficient information 1638 76 Female Unknown 06APR2015 Death Unknown Unknown None reported None reported Death Insufficient information 1639 UNK Female Unknown 07APR2015 Death Unknown Unknown None reported None reported Death Insufficient information 1640 47 Female Unknown 08APR2015 Death Unknown Unknown None reported None reported Death Insufficient information 1641 60 Male Unknown 09APR2015 Death Unknown Unknown None reported None reported Death Not related 1645 51 Female Unknown 21APR2015 Death Unknown Unknown None reported None reported Death Not related 1646 UNK Female Unknown 22APR2015 Death Unknown Unknown None reported None reported Death Not related 1647 58 Male 20NOV2013 24APR2015 Death Unknown Unknown None reported None reported Death Insufficient information 1648 41 Male Unknown 27APR2015 Death Unknown Unknown None reported None reported Death Not related 1649 32 Female 25APR2015 27APR2015 Neoplasm progression Breakthrough 2015-04-18 - Dilaudid, Fentanyl cancer pain UNK Patch None reported Death Not related Page 9 of 23 FDA_2775 48-month REMS Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies. UBC ID Patient Age Patient Gender Event Date Report Date Preferred Term(s) TIRF Duration 1650 UNK Unknown Unknown 27APR2015 Death Unknown Unknown None reported None reported Death Insufficient information 1651 UNK Male Unknown 30APR2015 Death Unknown Unknown None reported None reported Death Not related 1652 UNK Male Unknown 30APR2015 Death Unknown Unknown None reported None reported Death Not related 1653 UNK Female Unknown 30APR2015 Neoplasm progression Cancer pain 2013-06 UNK Arimidex, Herceptin None reported Death Not related 1654 UNK Female Unknown 04MAY2015 Death Unknown Unknown None reported None reported Death Not related 1655 UNK Female Unknown 04MAY2015 Neoplasm progression Unknown Unknown None reported None reported Death Not related 1656 UNK Female Unknown 06MAY2015 Death Cancer Unknown None reported None reported Death Not related 1657 UNK Female Unknown 06MAY2015 Malnutrition, Neoplasm progression Breakthrough 2014-09-26 - Amox-Tr-K Clv, None reported cancer pain 2015-01-02 Abraxane, Advair Diskus, Cyproheptadine, Digoxin, Dronabinol, Gemzar, HydrocodoneAcetaminophen, Lisinopril, Lomotil, Marinol, Megace, Neulasta, Spiriva with Handihaler Death Not related Indication(s) Concomitant Medications Co-Suspect Product(s) Event Outcome Potential Causality1 Page 10 of 23 FDA_2776 48-month REMS Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies. UBC ID Patient Age Patient Gender Event Date Report Date Preferred Term(s) TIRF Duration 1658 UNK Male Unknown 06MAY2015 Malnutrition, Neoplasm progression Breakthrough 2014-07-16 - Allopurinol, None reported cancer pain UNK Dexilant, Exforge, Gabapentin, Hydrocodone/Ibupro fen, Levothyroxine, Lidocaine, Lomotil, Magnesium, Megestrol, Metoclopramide, Metoprolol Succinate ER, Ondansetron, Potassium Chloride, Stivarga, Temazepam, Tramadol, Trilipix, Vitamin B-12, Duragesic Death Not related 1659 UNK Female Unknown 07MAY2015 Death Unknown Unknown None reported None reported Death Not related 1660 UNK Male Unknown 08MAY2015 Death Unknown Unknown None reported None reported Death Insufficient information 1661 UNK Female Unknown 08MAY2015 Death Unknown Unknown None reported None reported Death Insufficient information 1662 UNK Male Unknown 11MAY2015 Death Unknown Unknown None reported None reported Death Not related 1663 UNK Unknown Unknown 11MAY2015 Death Unknown Unknown None reported None reported Death Not related 1664 53 Male Unknown 11MAY2015 Death Unknown Unknown None reported None reported Death Not related 1667 UNK Male Unknown 13MAY2015 Death Unknown Unknown None reported None reported Death Not related 1669 UNK Female Unknown 13MAY2015 Death Unknown Unknown None reported None reported Death Insufficient information 1670 78 Male 15MAY2015 14MAY2015 Neoplasm progression Pain 2015-04-23 - None reported UNK None reported Death Not related 1671 UNK Male Unknown 19MAY2015 Death Colon cancer Unknown metastatic None reported None reported Death Insufficient information 1672 47 Female Unknown 19MAY2015 Breast cancer metastatic Cancer pain None reported None reported Death Not related Indication(s) Unknown Concomitant Medications Co-Suspect Product(s) Event Outcome Potential Causality1 Page 11 of 23 FDA_2777 48-month REMS Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies. UBC ID Patient Age Patient Gender Event Date Report Date Preferred Term(s) TIRF Duration 1673 54 Female Unknown 20MAY2015 Death Unknown Unknown None reported None reported Death Not related 1674 UNK Male Unknown 21MAY2015 Death Unknown Unknown None reported None reported Death Insufficient information 1675 UNK Male Unknown 27MAY2015 Death Unknown Unknown None reported None reported Death Not related 1676 UNK Female Unknown 28MAY2015 Death Unknown Unknown None reported None reported Death Insufficient information 1677 61 Female Unknown 29MAY2015 Death Unknown Unknown None reported None reported Death Not related 1678 UNK Female Unknown 02JUN2015 Death Unknown Unknown None reported None reported Death Insufficient information 1679 71 Female Unknown 02JUN2015 Death Unknown Unknown None reported None reported Death Insufficient information 1680 66 Male Unknown 08JUN2015 Death Breakthrough Unknown cancer pain None reported None reported Death Not related 1681 UNK Male Unknown 08JUN2015 Death Unknown 2015-03-22 - None reported UNK None reported Death Insufficient information 1682 43 Male Unknown 15JUN2015 Death Breakthrough Unknown cancer pain Methadone, Oxycodone None reported Death Insufficient information 1683 52 Female Unknown 15JUN2015 Death Breakthrough Unknown cancer pain Methadone, Oxycodone None reported Death Insufficient information 1684 UNK Female Unknown 16JUN2015 Neoplasm progression Breakthrough Unknown cancer pain None reported None reported Death Not related Indication(s) Concomitant Medications Co-Suspect Product(s) Event Outcome Potential Causality1 Page 12 of 23 FDA_2778 48-month REMS Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies. UBC ID Patient Age Patient Gender Event Date Report Date Preferred Term(s) TIRF Duration 1686 67 Female 26JAN2015 16JUN2015 Neoplasm progression Pain Unknown Caltrate 600/ None reported Vitamin D, Carafate, Compazine, Diphenhydramine HCL, Docusate Calcium, Flaxseed Oil, Ibuprofen, Levothyroxine Sodium, Nexium, Oxycodone HCL, Pancrealipase, Potassium Gluconate, Prednisone, Pristiq, Promethazine HCL, Robaxin, Tamoxifen Citrate, Vitamin B12, Vitamin D, Zofran, Fentanyl Patch Death Not related 1687 74 Male 24MAR2015 16JUN2015 Neoplasm progression Cancer pain 2015-02-10 - Amlodipine None reported UNK Besylate, Calcitriol, Dexamethasone, Finasteride, Folic Acid, Marinol, Methadone HCL, Metoclopramide HCL, Miralax, Nexium, Ondansetron HCL, Oxycodone HCL, Senna Plus Death Not related Indication(s) Concomitant Medications Co-Suspect Product(s) Event Outcome Potential Causality1 Page 13 of 23 FDA_2779 48-month REMS Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies. UBC ID Patient Age Patient Gender Event Date Report Date Preferred Term(s) TIRF Duration 1688 85 Female 12APR2015 16JUN2015 Neoplasm progression Pain, cancer pain 2015-03-20 - Amlodipine None reported UNK Besylate, Atenolol, Crestor, Dexamethasone, Folic Acid, Lasix, Methadone HCL, Mugard, Oxycodone HCL, Vitamin B-12, Xanax Death Not related 1689 UNK Male Unknown 16JUN2015 Death Unknown Unknown None reported None reported Death Insufficient information 1690 69 Female 08AUG2013 18JUN2015 Death Unknown 2015-03-22 - None reported UNK None reported Death Insufficient information 1691 82 Male 12JUN2015, Unknown, Unknown 18JUN2015 Death, Dementia, Breakthrough 2014-08-12 - None reported Malaise cancer pain UNK None reported Death Not related 1692 UNK Male Unknown 19JUN2015 Death Unknown Unknown None reported None reported Death Not related 1693 UNK Female Unknown 22JUN2015 Death Unknown Unknown None reported None reported Death Not related 1694 85 Female 01NOV2013 29JUN2015 Neoplasm progression Breakthrough Unknown cancer pain None reported None reported Death Not related 1695 UNK Female Unknown 07JUL2015 Death Unknown Unknown None reported None reported Death Insufficient information 1696 47 Male 25NOV2013 08JUL2015 Death Unknown Unknown None reported None reported Death Insufficient information 1697 57 Male 16DEC2013 09JUL2015 Death Unknown Unknown None reported None reported Death Insufficient information 1698 24 Female 2015 13JUL2015 Death Unknown Unknown None reported None reported Death Not related 1699 81 Male 04MAY2015, Unknown, Unknown 16JUL2015 Cardiac failure, Drug effect incomplete, Off label use Thalamic pain Unknown Carvedilol, Fentanyl None reported Patch Death Not related 1700 UNK Male Unknown 21JUL2015 Neoplasm progression Unknown None reported Death Not related Indication(s) Unknown Concomitant Medications Co-Suspect Product(s) None reported Event Outcome Potential Causality1 Page 14 of 23 FDA_2780 48-month REMS Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies. UBC ID Patient Age Patient Gender Event Date Report Date Preferred Term(s) TIRF Duration 1701 UNK Male Unknown 21JUL2015 Neoplasm progression Unknown Unknown None reported None reported Death Not related 1702 54 Male 14SEP2013 21JUL2015 Death Unknown Unknown None reported None reported Death Insufficient information 1703 36 Male 15JUN2015 22JUL2015 Neoplasm progression Breakthrough Unknown cancer pain None reported None reported Death Not related 1705 51 Female 04AUG2013 23JUL2015 Death Unknown Unknown None reported None reported Death Insufficient information 1706 UNK Female Unknown 24JUL2015 Death Unknown Unknown None reported None reported Death Insufficient information 1707 47 Female 06MAR2014 27JUL2015 Neoplasm progression Unknown Unknown None reported None reported Death Not related 1708 UNK Male Unknown 27JUL2015 Terminal state Pain Unknown None reported None reported Death Not related 1709 UNK Female Unknown 27JUL2015 Death Cancer pain Unknown Oxycontin None reported Death Insufficient information 1710 64 Female 23DEC2013 28JUL2015 Neoplasm progression Unknown Unknown None reported None reported Death Not related 1711 57 Male 06APR2014 29JUL2015 Neoplasm progression Pain 2013-08-28 - None reported UNK None reported Death Not related 1712 UNK Male Unknown 04AUG2015 Death Unknown Unknown None reported None reported Death Insufficient information 1714 57 Female Unknown 05AUG2015 Death Unknown Unknown None reported None reported Death Not related 1715 48 Male Unknown 10AUG2015 Death Unknown Unknown None reported None reported Death Not related 1716 58 Male Unknown 11AUG2015 Hepatic failure Breakthrough Unknown pain None reported None reported Death Insufficient information 1717 UNK Female Unknown 13AUG2015 Death Unknown 2015-03-22 - None reported UNK None reported Death Insufficient information 1718 87 Male 11JAN2014 20AUG2015 Death Breakthrough 2013-09-11 - None reported cancer pain UNK None reported Death Not related 1719 UNK Male Unknown 24AUG2015 Death Unknown Unknown None reported None reported Death Not related 1721 UNK Male MAY2015 24AUG2015 Death, Hospice care Unknown Unknown None reported None reported Death Insufficient information Indication(s) Concomitant Medications Co-Suspect Product(s) Event Outcome Potential Causality1 Page 15 of 23 FDA_2781 48-month REMS Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies. UBC ID Patient Age Patient Gender Event Date Report Date Preferred Term(s) 1722 UNK Female Unknown 25AUG2015 Neoplasm Unknown malignant, Death 1724 50 Male 18SEP2013 27AUG2015 1725 UNK Female Unknown 1729 UNK Unknown 1730 UNK 1731 TIRF Duration Indication(s) Concomitant Medications Co-Suspect Product(s) Event Outcome Potential Causality1 Unknown None reported None reported Death Insufficient information Metastatic neoplasm Breakthrough Unknown pain None reported None reported Death Insufficient information 27AUG2015 Death Unknown Unknown None reported None reported Death Insufficient information Unknown 29AUG2014 Death Unknown Unknown None reported None reported Death insufficient information Male Unknown 03SEP2014 Disease progression Breakthrough Unknown cancer pain None reported None reported Death not related 56 Female 20AUG2014 10SEP2014 Disease progression Breakthrough Unknown cancer pain None reported None reported Death not related 1732 UNK Male Unknown 16SEP2014 Death Metastatic bone pain 2014-08-20 - Cymbalta, None reported UNK Etravirine, Gabapentin, Lipitor, Ms-Contin, Periostat, Ritonavir, Trazodone, Truvada Death not related 1734 45 Female 04OCT2014 06OCT2014 Neoplasm progression Unknown Unknown None reported None reported Death not related 1735 63 Female 05OCT2014 06OCT2014 Neoplasm progression Unknown 2014-09-17 - None reported UNK None reported Death Not related 1736 UNK Male Unknown 10OCT2014 Myocardial infarction, Neoplasm progression Breakthrough 2014-10 cancer pain, UNK pain Declomycin, Dexamethasone, Diflucan, Doc-QLace, Docusate, Fentanyl Patch None reported Death not related 1737 UNK Unknown Unknown 27OCT2014 Death Unknown Unknown None reported None reported Death Insufficient information 1739 UNK Unknown Unknown 31OCT2014 Death Breakthrough 2014-10 cancer pain UNK None reported None reported Death Insufficient information 1740 UNK Female Unknown 04NOV2014 Neoplasm progression Cancer pain None reported None reported Death not related 2014 - UNK Page 16 of 23 FDA_2782 48-month REMS Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies. UBC ID Patient Age Patient Gender Event Date Report Date Preferred Term(s) 1742 38 Male 05NOV2014, Unknown 10NOV2014 Death, Off label use Pain 1743 UNK Unknown Unknown 20NOV2014 Neoplasm progression 1744 86 Female 28APR2014 25NOV2014 1745 UNK Female Unknown 1747 48 Male 1748 UNK 1749 TIRF Duration Indication(s) 2013-11 UNK Concomitant Medications Morphine, Oxycodone Co-Suspect Product(s) Event Outcome Potential Causality1 None reported Death Insufficient information Breakthrough 2014-03-04 - None reported cancer pain UNK None reported Death not related Death Breakthrough 2014-02-06 - None reported cancer pain UNK None reported Death Insufficient information 25NOV2014 Neoplasm progression Cancer pain 2014-09-29 - None reported UNK None reported Death Not related 25NOV2014 25NOV2014 Neoplasm progression Breakthrough 2014-11-07 - None reported cancer pain UNK None reported Death Not related Unknown Unknown 26NOV2014 Death Unknown Unknown None reported Death Insufficient information 57 Male 14NOV2014 26NOV2014 Neoplasm progression Cancer pain 2014-11-03 - Oxycodone, None reported UNK Oxycodone/Acetami nophen, Valium Death Not related 1750 67 Female 28NOV2014 01DEC2014 Death Breakthrough 2014-09-29 - None reported cancer pain 2014-11-28 None reported Death Not related 1751 76 Female 18FEB2014, 23DEC2013 02DEC2014 Disease Chronic progression, Off pancreatitis label use None reported Death Not related None reported 2013-12-23 - None reported 2014-01-23 Page 17 of 23 FDA_2783 48-month REMS Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies. UBC ID Patient Age Patient Gender Event Date Report Date Preferred Term(s) TIRF Duration 1752 UNK Female Unknown 05DEC2014 Death, Off label use Chronic pain 2014-05-09 - Dilaudid, None reported UNK Furosemide, Glumetza, Imodium, Insulin, Kadian, Lyrica, Morphine Sulfate, Nitroglycerin, Orencia, Phenergan, Potassium, Pravastatin, Prednisone, Protonix, Singulair, Spironolactone, Synthroid, Vitamin B3, Xanax, Xarelto, Zebeta Death Not related 1753 UNK Male Unknown 13DEC2014 Neoplasm progression Breakthrough Unknown cancer pain None reported Death Not related 1754 UNK Unknown Unknown 17DEC2014 Neoplasm progression Cancer pain 2014-11-13 - None reported 2014-12-08 None reported Death Not related 1755 58 Female 22DEC2014 22DEC2014 Neoplasm progression Cancer pain Unknown None reported None reported Death Not related 1757 UNK Unknown Unknown 12JAN2015 Death Breakthrough Unknown cancer pain None reported None reported Death Insufficient information 1758 UNK Unknown Unknown 12JAN2015 Neoplasm progression Breakthrough Unknown cancer pain None reported None reported Death Not related 1759 55 Male 13JAN2015, Unknown 13JAN2015 Death, Off label use Chronic pain Unknown None reported None reported Death Insufficient information 1760 UNK Female Unknown 16JAN2015 Neoplasm progression Breakthrough 2014-08-18 - None reported cancer pain UNK None reported Death Not related Indication(s) Concomitant Medications Dilaudid, Flonase, Marinol, Promethazine, Senokot-S, Viagra Co-Suspect Product(s) Event Outcome Potential Causality1 Page 18 of 23 FDA_2784 48-month REMS Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies. UBC ID Patient Age Patient Gender Event Date Report Date Preferred Term(s) TIRF Duration 1762 47 Male 17JAN2015, Unknown 19JAN2015 Myocardial infarction, Off label use Chronic pain 2014-11-19 - Clindamycin None reported UNK Hydrochloride, Cymbalta, Flexeril, Lyrica, Medrol, Norco, Oxycodone, Silvadene, Ultram, Duragesic Death Not related 1763 UNK Unknown Unknown 19JAN2015 Death, Off label use Post 2014-04-28 - None reported laminectomy UNK syndrome, coccydynia, fibromyalgia, chronic pain None reported Death Insufficient information 1764 UNK Unknown Unknown 21JAN2015 Death Breakthrough Unknown cancer pain None reported Death Not related 1765 61 Female 18JAN2015, Unknown 23JAN2015 Chronic Breakthrough 2014-10-13 obstructive pain, pain UNK pulmonary disease, Off label use Adavir Disku Aer, None reported Ambien, Ativan, Azor, Brovana, Celebrex, Compazine, Cymbalta, Daliresp, Geodon, Hemocyte, Lamictal, Lopid, Oxycodone, Oxygen, Pravastatin, Prednisone, Provigil, Roxanol, Singulair, Sodium Chloride, Soma, Spiriva, Tylenol, Vitamin D, Xanax, Zofran, Duragesic Death Not related 1766 UNK Male Unknown 27JAN2015 Neoplasm progression Breakthrough Unknown cancer pain None reported None reported Death Not related 1767 UNK Male Unknown 02FEB2015 Neoplasm progression Unknown None reported None reported Death Not related Indication(s) Unknown Concomitant Medications None reported Co-Suspect Product(s) Event Outcome Potential Causality1 Page 19 of 23 FDA_2785 48-month REMS Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies. UBC ID Patient Age Patient Gender Event Date Report Date Preferred Term(s) TIRF Duration 1768 UNK Female Unknown 06FEB2015 Neoplasm progression Cancer pain 2014-08-18 - None reported UNK None reported Death Not related 1769 UNK Unknown Unknown 10FEB2015 Neoplasm progression Breakthrough 2014-02-11 - None reported cancer pain UNK None reported Death Not related 1770 73 Male 07FEB2015 24FEB2015 Myocardial infarction Breakthrough Unknown cancer pain None reported Death Insufficient information 1771 49 Male 25FEB2015, 25FEB2015 26FEB2015 Death, Neoplasm Breakthrough 2015-02-05 - Lantus, Metformin, None reported progression cancer pain UNK Omeprazole, Trilipix, Zestoretic Death Not related 1772 71 Male 28JAN2015 27FEB2015 Neoplasm progression Cancer pain None reported Death not related 1773 UNK Female Unknown 05MAR2015 Neoplasm progression Breakthrough Unknown cancer pain None reported None reported Death not related 1775 UNK Female Unknown 23MAR2015 Neoplasm progression Cancer pain Unknown None reported None reported Death not related 1776 UNK Female Unknown 27MAR2015 Neoplasm progression Breakthrough Unknown cancer pain None reported None reported Death not related 1777 67 Female 20MAR2015 27MAR2015 Neoplasm progression Chronic pain 2015-02-24 - Calcium UNK None reported Death not related 1779 UNK Unknown Unknown 09APR2015 Death Unknown Unknown None reported None reported Death insufficient information 1780 UNK Male Unknown 09APR2015 Neoplasm progression Cancer pain Unknown None reported None reported Death not related 1781 52 Female 02MAR2015 14APR2015 Death Breakthrough 2015-01-08 - None reported cancer pain UNK None reported Death not related 1782 70 Female 15APR2015 16APR2015 Neoplasm progression Cancer pain None reported None reported Death not related 1783 UNK Male Unknown 20APR2015 Death, Off label use Chronic pain 2015-04-01 - None reported 2015-04-08 None reported Death not related 1784 UNK Female Unknown 20APR2015 Death, Off label use Chronic pain 2015-02-25 - None reported 2015-04-09 None reported Death not related Indication(s) Concomitant Medications None reported 2015-01-27 - None reported UNK Unknown Co-Suspect Product(s) Event Outcome Potential Causality1 Page 20 of 23 FDA_2786 48-month REMS Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies. UBC ID Patient Age Patient Gender Event Date Report Date Preferred Term(s) TIRF Duration 1785 UNK Female Unknown 24APR2015 Off label use, Respiratory disorder, Sedation, Toxicity to various agents Degenerative Unknown disc disease None reported Exalgo Death Possibly related 1786 UNK Female Unknown 27APR2015 Neoplasm progression Breakthrough Unknown cancer pain None reported None reported Death not related 1787 UNK Male Unknown 28APR2015 Neoplasm progression Cancer pain Unknown None reported None reported Death not related 1788 UNK Male Unknown 28APR2015 Hallucination, Neoplasm progression Breakthrough 2015-01 cancer pain UNK None reported None reported Death not related 1789 UNK Male Unknown 01MAY2015 Neoplasm progression Breakthrough 2014-08 cancer pain UNK None reported None reported Death not related 1790 UNK Female 2015 01MAY2015 Neoplasm progression Breakthrough 2015-04-17 - None reported cancer pain UNK None reported Death not related 1791 UNK Male Unknown 01MAY2015 Neoplasm progression Breakthrough 2015-04-17 - None reported cancer pain UNK None reported Death not related 1792 UNK Male Unknown 01MAY2015 Neoplasm progression Breakthrough 2015-02-13 - None reported cancer pain UNK None reported Death not related 1793 UNK Female Unknown 04MAY2015 Neoplasm progression Breakthrough 2015-04-28 - None reported cancer pain UNK None reported Death not related 1794 UNK Unknown Unknown 06MAY2015 Death Unknown Unknown None reported None reported Death insufficient information 17952 UNK Female Unknown 07MAY2015 Overdose Unknown Unknown None reported None reported Death Possibly related 1796 56 Female 07APR2015 11MAY2015 Neoplasm progression Breakthrough 2015-01-14 - Bupi, Clonidine, cancer pain UNK Dilaudid None reported Death not related 1798 58 Female 08MAY2015 11MAY2015 Neoplasm progression Unknown None reported Death not related 1799 UNK Female Unknown 13MAY2015 Neoplasm progression Breakthrough Unknown cancer pain None reported Death not related Indication(s) Concomitant Medications 2015-03-24 - None reported 2015-05-06 None reported Co-Suspect Product(s) Event Outcome Potential Causality1 Page 21 of 23 FDA_2787 48-month REMS Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies. UBC ID Patient Age Patient Gender Event Date Report Date Preferred Term(s) TIRF Duration 1801 UNK Unknown Unknown 19MAY2015 Death, Off label use Breakthrough Unknown pain None reported None reported Death insufficient information 1803 UNK Male Unknown 21MAY2015 Death Unknown None reported None reported Death insufficient information 1804 UNK Male Unknown 22MAY2015 Neoplasm progression Breakthrough 2015-03-09 - Amitiza, Aspirin, None reported cancer pain UNK Calcium, Diazepam, Finasteride, Furosemide, Lyrica, Megace, Metoprolol, Potassium, Protonix, Sucralfate, Duragesic Death not related 1805 UNK Unknown Unknown 01JUN2015 Death Unknown Unknown None reported None reported Death insufficient information 1806 UNK Unknown Unknown 01JUN2015 Death Unknown Unknown None reported None reported Death insufficient information 1807 UNK Female Unknown 02JUN2015 Death Unknown Unknown None reported None reported Death insufficient information 1810 UNK Male Unknown 15JUN2015 Death Unknown Unknown None reported None reported Death insufficient information 1811 61 Male 26MAY2015 16JUN2015 Neoplasm progression Colon cancer, Unknown carcinoma of liver, lung cancer None reported None reported Death not related 1812 UNK Male Unknown 16JUN2015 Death Breakthrough 2015-05-11 - None reported cancer pain 2015-05-18 None reported Death not related 1813 56 Male 13JUN2015 18JUN2015 Death Unknown 2015-05-27 - None reported UNK None reported Death not related 1816 63 Female 16JUN2015, Unknown 25JUN2015 Neoplasm progression, Pneumonia Breakthrough 2015-03-25 - None reported cancer pain 2015-06-08 None reported Death not related Indication(s) Unknown Concomitant Medications Co-Suspect Product(s) Event Outcome Potential Causality1 Page 22 of 23 FDA_2788 48-month REMS Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies. UBC ID Patient Age Patient Gender Event Date Report Date Preferred Term(s) TIRF Duration 1817 65 Female 28MAY2015 29JUN2015 Neoplasm progression 1818 62 Male 29JUN2015, 29JUN2015, Unknown, Unknown 01JUL2015 Cardiac arrest, Breakthrough Unknown Myocardial cancer pain infarction, Chest pain, Haemoptysis 1820 68 Male 14JUL2015 14JUL2015 Neoplasm progression Breakthrough 2015-07-07 - None reported cancer pain UNK 1821 68 Female 11JUL2015 28JUL2015 Neoplasm progression 1822 UNK Female Unknown 03AUG2015 1824 UNK Male Unknown 1826 53 Female 1828 UNK 1829 1830 Indication(s) Concomitant Medications Co-Suspect Product(s) Breakthrough 2015-05-04 - Atenolol, Ativan, None reported cancer pain UNK Diovan, Levothyroxine, Lexapro, Omeprazole, Zofran Event Outcome Potential Causality1 Death not related Death not related None reported Death not related Breakthrough 2015-06-08 - None reported cancer pain UNK None reported Death not related Death Cancer pain None reported Death not related 10AUG2015 Neoplasm progression Breakthrough 2015-05 cancer pain UNK None reported None reported Death not related 22AUG2015 25AUG2015 Neoplasm progression Breakthrough 2014-12 cancer pain 2015-08 None reported None reported Death not related Female 25AUG2015 28AUG2015 Neoplasm progression Unknown 2015-07-02 - None reported UNK None reported Death not related UNK Male Unknown 24JUL2015 Cardiac disorder Breakthrough Unknown cancer pain Horizant, Oxycontin None reported Death not related UNK Male Unknown 27JUL2015 Hepatic failure Cimex, Klonopin, None reported Losartan Hctz, Mobic, Omeprazole, Spiriva Inhaler, Tessalon, Ventolin Inhaler, Fentanyl Patch 2015-04-27 - None reported UNK Breakthrough Unknown None reported None reported Death not related cancer pain 1 Potential causality was reported if sufficient information was available to make a determination. If there was insufficient information available and the potential causality cannot be determined, this was noted in the table. 2 Patient 1795 is also described in the table for overdose (Table 29 of the Assessment Report). Unk = unknown. Page 23 of 23 FDA_2789 48-month REMS Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies 12.4 Page 106 of 112 RMPDC Responses to FDA Requests FDA_2790 48-month REMS Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Bold text indicates FDA requests/comments. Italicized text represents the response to each item. 1. A more detailed data analysis section that presents the statistical methods used, how calculations were performed, and the assumptions made, at the level of detail as provided in your April 2, 2015, response to the March 19, 2015, FDA Information Request. In addition, include a pre-post REMS means analyses and trend analyses (e.g. segmented regression analyses), statistically comparing event rates for a timeperiod immediately prior to full implementation of the TIRF REMS with an equivalent period of time after REMS implementation. As requested, a more detailed analysis section was added to the protocol. The detailed analysis section includes the additional requested means and trend analyses. FDA also requested that an equal number of quarter of data be included pre and post TIRF REMS. However this will not be possible for all programs. For example, there are now 12 quarters of data available post-REMS but as only 11 quarters of pre-TIRF REMS data are available for college survey. Please note that it is not a requirement of the model that an equal number of quarters are included pre and post TIRF REMS, but rather that there are enough quarters to model a trend in both the pre and post TIRF REMS period. To standardize and still represent an adequate period of time pre-TIRF REMS for trending we suggest including 8 quarters of data. 2. Present the data at the dosage unit level as well as population and URDD levels. We presented population, prescription, and dosing unit rates in the last report and will continue to provide these same rates for future reports. We did not include URDD rates as this scale is not necessarily additive. For example if a subject had both Actiq® and Fentora® prescribed in the same quarter, the de-identified aggregate data we receive from IMS would count this person twice instead of once thus failing to preserve uniqueness of subjects across drugs. Number of prescription and number of dosage units are additive. 3. The RADARS treatment center data (Opioid Treatment Program and Survey of Key Informants Patients) programs are confounded by the fact that the number of treatment centers participating in each quarter fluctuates (although the overall numbers are generally increasing). In subsequent submissions, limit the presentation of treatment center data to centers that have contributed data in all of the time-periods assessed. In addition, provide the various versions of the survey instruments/pill cards in use throughout the time-periods assessed with dates provided indicating when each instrument was in use. Based on analysis through 2Q15, limiting the data to only those treatment centers with respondents since 3Q09 will change the coverage region from roughly 349 treatment center sites to only 24 treatment center sites. Instead, we suggest presenting both the data for all centers, in addition to those 24 treatment centers, in order to judge the sensitivity of the result to the increasing number of treatment centers included in the two programs over time. Page 1 of 1 FDA_2791 48-month REMS Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies 12.5 Page 107 of 112 RADARS System Program Report Protocol FDA_2792 Transmucosal Immediate Release Fentanyl (TIRF) Risk Evaluation and Mitigation Strategy (REMS): Surveillance Monitoring Protocol For Actavis Laboratories FL, Inc. BioDelivery Sciences International, Inc. Cephalon, Inc. (a wholly-owned subsidiary of Teva Pharmaceutical Industries, Ltd.) Depomed, Inc. Galena Biopharma, Inc. Insys Therapeutics Inc. Mallinckrodt Pharmaceuticals Mylan, Inc. Par Pharmaceutical, Inc. October 1, 2015 Confidential This protocol contains information that may be confidential and/or proprietary. Any dissemination, distribution or copying of this document is strictly prohibited without our prior written consent, which may be withheld for any reason solely at our discretion. FOLLOWING THIS PAGE, FDA_2794 TO FDA_2805 WITHHELD IN FULL AS B(4)/CCI FDA_2793 7. Appendices 7.1 Shell Tables Table x.x.x The RADARS® System xxx Program xxxx Pre Post Comparison Means Model From July 2010 to Current Pre-TIRM REMS Mean Post-TIRF REMS Mean Drug group (10Q3 to 12Q2) (12Q3 to current) Rate Ratio(95% CI) p-value for % change p-value for interaction Population Adjusted Rate per 100,000 population TIRF Products xxx (xxx-xxx) xxx (xxx-xxx) xxx (xxx-xxx) xxxx xxxx Schedule II IR Opioids xxx (xxx-xxx) xxx (xxx-xxx) xxx (xxx-xxx) xxxx xxxx Schedule II Opioids xxx (xxx-xxx) xxx (xxx-xxx) xxx (xxx-xxx) xxxx xxxx Schedule II Opioids Excluding Methadone xxx (xxx-xxx) xxx (xxx-xxx) xxx (xxx-xxx) xxxx xxxx Prescription Adjusted Rate per 10,000 prescriptions TIRF Products xxx (xxx-xxx) xxx (xxx-xxx) xxx (xxx-xxx) xxxx xxxx Schedule II IR Opioids xxx (xxx-xxx) xxx (xxx-xxx) xxx (xxx-xxx) xxxx xxxx Schedule II Opioids xxx (xxx-xxx) xxx (xxx-xxx) xxx (xxx-xxx) xxxx xxxx Schedule II Opioids Excluding Methadone xxx (xxx-xxx) xxx (xxx-xxx) xxx (xxx-xxx) xxxx xxxx Dose Unit Adjusted Rate per 100,000 TIRF Products xxx (xxx-xxx) xxx (xxx-xxx) xxx (xxx-xxx) xxxx xxxx Schedule II IR Opioids xxx (xxx-xxx) xxx (xxx-xxx) xxx (xxx-xxx) xxxx xxxx Schedule II Opioids xxx (xxx-xxx) xxx (xxx-xxx) xxx (xxx-xxx) xxxx xxxx Schedule II Opioids Excluding Methadone xxx (xxx-xxx) xxx (xxx-xxx) xxx (xxx-xxx) xxxx xxxx FDA_2807 Table x.x.x The RADARS® System xxx Program xxx Trend Model From July 2010 to Current Intercept Drug Group Pre Post % change (95% CI) Slope p-value for difference p-value for interaction Pre Post % change (95% CI) p-value for difference p-value for interaction Population TIRF Products x.xxx x.xxx xx.xx%(xx.xx%,xx.xx%) x.xxx x.xxx x.xxx x.xxx xx.xx%(xx.xx%,xx.xx%) x.xxx x.xxx Schedule II IR Opioids x.xxx x.xxx xx.xx%(xx.xx%,xx.xx%) x.xxx x.xxx x.xxx x.xxx xx.xx%(xx.xx%,xx.xx%) x.xxx x.xxx Schedule II Opioids x.xxx x.xxx xx.xx%(xx.xx%,xx.xx%) x.xxx x.xxx x.xxx x.xxx xx.xx%(xx.xx%,xx.xx%) x.xxx x.xxx Schedule II Opioids Excluding Methadone x.xxx x.xxx xx.xx%(xx.xx%,xx.xx%) x.xxx x.xxx x.xxx x.xxx xx.xx%(xx.xx%,xx.xx%) x.xxx x.xxx Prescription Adjusted Rate TIRF Products x.xxx x.xxx xx.xx%(xx.xx%,xx.xx%) x.xxx x.xxx x.xxx x.xxx xx.xx%(xx.xx%,xx.xx%) x.xxx x.xxx Schedule II IR Opioids x.xxx x.xxx xx.xx%(xx.xx%,xx.xx%) x.xxx x.xxx x.xxx x.xxx xx.xx%(xx.xx%,xx.xx%) x.xxx x.xxx Schedule II Opioids x.xxx x.xxx xx.xx%(xx.xx%,xx.xx%) x.xxx x.xxx x.xxx x.xxx xx.xx%(xx.xx%,xx.xx%) x.xxx x.xxx Schedule II Opioids Excluding Methadone x.xxx x.xxx xx.xx%(xx.xx%,xx.xx%) x.xxx x.xxx x.xxx x.xxx xx.xx%(xx.xx%,xx.xx%) x.xxx x.xxx Dose Unit Adjusted Rate TIRF Products x.xxx x.xxx xx.xx%(xx.xx%,xx.xx%) x.xxx x.xxx x.xxx x.xxx xx.xx%(xx.xx%,xx.xx%) x.xxx x.xxx Schedule II IR Opioids x.xxx x.xxx xx.xx%(xx.xx%,xx.xx%) x.xxx x.xxx x.xxx x.xxx xx.xx%(xx.xx%,xx.xx%) x.xxx x.xxx Schedule II Opioids x.xxx x.xxx xx.xx%(xx.xx%,xx.xx%) x.xxx x.xxx x.xxx x.xxx xx.xx%(xx.xx%,xx.xx%) x.xxx x.xxx Schedule II Opioids Excluding Methadone x.xxx x.xxx xx.xx%(xx.xx%,xx.xx%) xx.xx%(xx.xx%,xx.xx%) x.xxx x.xxx FDA_2808 Table x.x.x Cumulative Mention Rates per 100,000 Population, 10,000 Prescriptions and 100,000 Dose Units 2012Q3-XXXXQX Total Cumulative Rates Pre TIRF REMS Post TIRF REMS July 2010-June 2012 July 2012-current Poison Center Abuse Cases/Mentions x/x x/x Population Rate per 100,000 x.xxxx x.xxxx Prescription Rate per 10,000 x.xxxx x.xxxx Dose Unit Rate per 100,000 x.xxxx x.xxxx Treatment Center Surveys Cases/Mentions x/x x/x Population Rate per 100,000 x.xxxx x.xxxx Prescription Rate per 10,000 x.xxxx x.xxxx Dose Unit Rate per 100,000 x.xxxx x.xxxx Opioid Treatment Program Cases/Mentions x/x x/x Population Rate per 100,000 x.xxxx x.xxxx Prescription Rate per 10,000 x.xxxx x.xxxx Dose Unit Rate per 100,000 x.xxxx x.xxxx Survey of Key Informant Cases/Mentions x/x x/x Population Rate per 100,000 x.xxxx x.xxxx Prescription Rate per 10,000 x.xxxx x.xxxx Dose Unit Rate per 100,000 x.xxxx x.xxxx College Survey Cases/Mentions x/x x/x Population Rate per 100,000 x.xxxx x.xxxx Prescription Rate per 10,000 x.xxxx x.xxxx Dose Unit Rate per 100,000 x.xxxx x.xxxx Impaired Healthcare Worker Program Cases x/x x/x Population Rate per 100,000 x.xxxx x.xxxx Prescription Rate per 10,000 x.xxxx x.xxxx Dose Unit Rate per 100,000 x.xxx x.xxx FDA_2809 Table x.x.x The RADARS System Poison Center Program Reported Deaths by Age Group and Period 2012Q3-XXXXQX Age Group Pre TIRF REMS Post TIRF REMS July 2010-June 2012 July 2012- current 0-5 years 3 (3) 1 (1) 6-12 years 0 (0) 0 (0) 13-19 years 1 (1) 3 (3) Mentions (Cases) Table x.x.x The RADARS System Poison Center Program Reported Deaths by Age, Medical Outcome and Period 2012Q3-XXXXQ2 Time Period 2010Q32013Q3 2013Q42014Q2 Case Year Number Quarter Age Group 72917219 20123 <=5 years 72969297 73034925 1975719 8239739 58064 1219402 1787732 20123 20124 20123 20142 Exposure Reason Unintentional General <=5 years Unintentional General <=5 years Unintentional General 13-19 years Intentional Abuse <=5 years Unintentional Therapeutic Error 20141 13-19 years 20142 13-19 years 20142 13-19 years Intentional Misuse Intentional Abuse Intentional Abuse Medical Outcome No effect Minor effect Minor effect Moderate effect Not followed, minimal clinical effects possible Major effect Moderate effect Not followed, minimal clinical effects possible FDA_2810 Time Period XXXXQXXXXXQX XXXXQXXXXXQX Case Number Year Quarter Age Group Exposure Reason Medical Outcome FDA_2811 48-month REMS Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies 12.6 Page 108 of 112 RADARS System Program Report FDA_2812 RADARS® SYSTEM REPORT Transmucosal Immediate Release Fentanyl (TIRF) Risk Evaluation and Mitigation Strategy (REMS): Surveillance Monitoring December 6, 2015 CONFIDENTIAL Page 1 of 375 FOLLOWING THIS PAGE, FDA_2814 TO FDA_3187 WITHHELD IN FULL AS B(4)/CCI FDA_2813 48-month REMS Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies 12.7 Page 109 of 112 Periodic Stakeholder Surveys FDA_3188 48-month REMS Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 110 of 112 12.7.1 Patient KAB Survey FDA_3189 Patient KAB Assessment Report Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Title: Page 1 of 54 Transmucosal Immediate Release Fentanyl (TIRF) REMS Assessment Quantitative Testing of Patient Knowledge, Attitudes, and Behavior (KAB) about TIRF Products’ Safety and Use Information Document Number: Wave 4, 48-month REMS Assessment Version 1.0 Survey Time Period: 24 July 2015 to 03 September 2015 Product Name: Transmucosal Immediate Release Fentanyl Sponsor: TIRF REMS Industry Group (TRIG) of Companies: Actavis Laboratories FL, Inc. BioDelivery Sciences International, Inc. (BDSI) Cephalon, Inc. (a wholly-owned subsidiary of Teva Pharmaceutical Industries, Ltd.) Depomed, Inc. Galena Biopharma, Inc. Insys Therapeutics, Inc. Mallinckrodt Pharmaceuticals Mylan, Inc. Par Pharmaceutical, Inc. Date: 15 December 2015 Confidentiality Statement The information contained herein is confidential and the proprietary property of the TRIG of Companies and its affiliates, and any unauthorized use or disclosure of such information without the prior written authorization of the TRIG is expressly prohibited. FDA_3190 Patient KAB Assessment Report Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies TABLE OF CONTENTS Page 2 of 54 PAGE TABLE OF CONTENTS......................................................................................................... 2 LIST OF TABLES ................................................................................................................... 3 LIST OF APPENDICES .......................................................................................................... 4 LIST OF ABBREVIATIONS .................................................................................................. 5 1. PATIENT SURVEY BACKGROUND ............................................................. 7 1.1 Changes to the KAB Survey for Patients/Caregivers Based on FDA Feedback............................................................................................................. 8 2. PATIENT SURVEY OBJECTIVES .................................................................. 9 3. SURVEY METHODOLOGY ............................................................................ 9 3.1 Survey Sample.................................................................................................... 9 3.1.1 Eligibility ............................................................................................................ 9 3.1.2 Recruitment ...................................................................................................... 10 3.2 Questions and Statements on Key Risk Messages ........................................... 10 3.2.1 Key Risk Message 1 ......................................................................................... 11 3.2.2 Key Risk Message 2 ......................................................................................... 11 3.2.3 Key Risk Message 3 ......................................................................................... 12 3.2.4 Key Risk Message 4 ......................................................................................... 12 3.2.5 Key Risk Message 5 ......................................................................................... 13 3.2.6 Key Risk Message 6 ......................................................................................... 13 4. Statistical Methods ........................................................................................... 13 4.1 Study Population .............................................................................................. 13 4.1.1 Primary Analysis Population ............................................................................ 13 4.2 Primary Analyses ............................................................................................. 14 4.3 Secondary Analyses ......................................................................................... 14 4.4 Patient Report of a Potential Adverse Event, Product Complaint, or Medical Information Request during the Survey ............................................. 14 5. RESULTS......................................................................................................... 15 5.1 Survey Participants ........................................................................................... 15 5.1.1 Survey Participant Administration Results ...................................................... 15 FDA_3191 Patient KAB Assessment Report Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 3 of 54 5.1.2 Patient/Caregiver Demographics...................................................................... 20 5.1.2.1 Comparison of Survey Respondents to the General Population of TIRF Users ................................................................................................................. 24 5.1.3 TIRF Medicines Education Materials .............................................................. 25 5.1.4 Patient-Prescriber Agreement Form ................................................................. 29 5.2 Key Risk Messages .......................................................................................... 30 5.2.1 Key Risk Message 1 ......................................................................................... 30 5.2.2 Key Risk Message 2 ......................................................................................... 31 5.2.3 Key Risk Message 3 ......................................................................................... 34 5.2.4 Key Risk Message 4 ......................................................................................... 38 5.2.5 Key Risk Message 5 ......................................................................................... 40 5.2.6 Key Risk Message 6 ......................................................................................... 41 5.2.7 Other Survey Questions ................................................................................... 44 5.2.7.1 Additional Questions about TIRF Medicines Safety ....................................... 44 5.3 Spontaneous Reporting of Adverse Events, Product Complaints, or Medical Information Requests ......................................................................... 46 6. DISCUSSION AND CONCLUSIONS ............................................................ 46 LIST OF TABLES Table 1. Survey Participant Administration Results .................................................... 15 Table 2. Survey Participant Screening Results ............................................................ 16 Table 3. Time to Complete Survey for Completers Only ............................................ 20 Table 4. Description and Representativeness of Eligible Patients/Caregivers ............ 21 Table 5. Comparison of Survey Respondents to General Population of TIRF Users .............................................................................................................. 24 Table 6. Responses to Questions About TIRF Medication Guide ............................... 26 Table 7. Responses to Questions About the Patient-Prescriber Agreement Form....... 29 Table 8. Key Risk Message 1: TIRF Medicines Can Cause Life-Threatening Breathing Problems That Can Lead to Death ................................................ 31 Table 9. Key Risk Message 2: Patients Should Not Take TIRF Medicines if They Are Not Opioid Tolerant ................................................................................ 32 FDA_3192 Patient KAB Assessment Report Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 4 of 54 Table 10. Trends in Correct Response Rates by Modality for Completing the Survey (Internet versus Telephone) ............................................................... 33 Table 11. Trends in Correct Response Rates by Highest Level of Education ............... 34 Table 12. Key Risk Message 3: TIRF Medicines Should be Taken Exactly as Prescribed by the Healthcare Provider ........................................................... 35 Table 13. Trends in Correct Response Rates by Highest Level of Education ............... 38 Table 14. Risk Message 4: Patients Should Not Switch From a TIRF Medicine to Another Medicine That Contains Fentanyl Without Talking to a Healthcare Provider ....................................................................................... 39 Table 15. Trends in Correct Response Rates by Highest Level of Education ............... 40 Table 16. Key Risk Message 5: Patients Should Not Give TIRF Medicines to Anyone Else Even if They Have the Same Symptoms .................................. 41 Table 17. Key Risk Message 6: TIRF Medicines Should be Stored in a Safe Place Away From Children and Properly Disposed ................................................ 42 Table 18. Trends in Correct Response Rates by Highest Level of Education ............... 44 Table 19. Responses to Additional Questions about the Safe Use of TIRF Medicines ....................................................................................................... 45 Table 20. Correct Response Rate Over Time ................................................................ 48 LIST OF APPENDICES Appendix A Patient Survey Protocol Track Change Document: Comparison of 36month Survey to 48-month Survey ................................................................ 53 Appendix B Patient Survey Listings and Stratified Analyses Tables ................................ 54 FDA_3193 Patient KAB Assessment Report Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 5 of 54 LIST OF ABBREVIATIONS AE/PC PSP Adverse Event/Product Complaint Project Specific Procedure BDSI BioDelivery Sciences International CI Confidence Interval ETASU Elements to Assure Safe Use FDA Food and Drug Administration HCP Healthcare Professional KAB Knowledge, Attitudes and Behavior N/A Not Applicable PPAF Patient-Prescriber Agreement Form PBM Pharmacy Benefits Manager REMS Risk Evaluation and Mitigation Strategy SCC Survey Coordinating Center SD Standard Deviation TIRF Transmucosal Immediate Release Fentanyl TIRF Medicines Transmucosal Immediate Release Fentanyl products TIRF REMS Access Program REMS Program for TIRF medicines TRIG TIRF REMS Industry Group UBC United BioSource Corporation US United States USPS United States Postal Service FDA_3194 Patient KAB Assessment Report Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 6 of 54 Executive Summary The 48-month Knowledge, Attitudes, and Behavior (KAB) survey for patients receiving Transmucosal Immediate Release Fentanyl (TIRF) medicines or their caregivers was conducted as part of the 48-Month TIRF Risk Evaluation and Mitigation Strategy (REMS) Access Program Assessment. The survey launched on 24 July 2015 and closed on 03 September 2015. Food and Drug Administration (FDA) feedback was provided in the 36-month Assessment Report Acknowledgement Letter and where applicable these changes were implemented in the 48month survey. Changes included removing ‘Onsolis’ as a response option throughout the survey because it is no longer available, moving specified existing survey questions under key risk messages, and including an analysis of demographics of the patient survey respondents compared to the demographics of patients receiving a TIRF product. The specific goals of the TIRF medicines patient/caregiver KAB survey were to evaluate the level of knowledge and assess the attitudes and behavior of patients/caregivers regarding TIRF medicines. The focus of the survey included the following: 1) TIRF medicines can cause lifethreatening breathing problems that can lead to death, patients should take TIRF medicines only if they are opioid-tolerant, and patients should strictly follow the directions of the Healthcare Professional (HCP), 2) patients should not switch from a TIRF medicine to another medicine that contains fentanyl without talking to an HCP, 3) patients should not give TIRF medicines to anyone else even if they have the same symptoms, and 4) TIRF medicines should be stored in a safe place away from children and properly disposed. The survey also included questions about whether patients received, read, and understood the product-specific Medication Guide and the Patient-Prescriber Agreement Form (PPAF). Invitations (and reminders) were sent to all known patients/caregivers who had filled a prescription within the 4 months (120 days) prior to survey launch. From the total of 432 patients/caregivers who accessed the survey, 314 (72.7%) respondents met eligibility criteria, and of those who met eligibility criteria, 310 (98.7%) completed the survey, exceeding the target of 300 completed surveys. The geographic distribution of survey respondents was similar to the general population of TIRF users (comparison requested by FDA). In general, there is an overall trend across all patient/caregiver KAB surveys conducted (12month, 24-month, 36-month, and 48-month surveys) toward maintenance or improvement in patient/caregiver knowledge and understanding of the key risk messages. Of the 19 components included as part of key risk messages, 13 components had a response rate >80%, and 3 components had a correct response rate between 67.7% and 74.8% . The remaining 3 components within key risk messages 2 and 3 had a correct response rate which fell below the desired threshold of 65%. Patients scored consistently low on two of 19 components across all survey waves which included 1) TIRF medicines should not be taken for long-lasting pain not from cancer, like arthritis joint pain and 2) a patient must stop taking their TIRF medicine if they stop taking their around-the-clock opioid pain medicine. In addition, revising one question (TIRF medicines should only be taken by patients who are opioid tolerant) to be specific to ‘cancer’ patients, resulted in a large decrease in the correct response rate, which may indicate that some respondents were receiving TIRF medicine for a non-cancer associated indications. FDA_3195 Patient KAB Assessment Report Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 7 of 54 The consistently high level of patient understanding of key risk messages in this 48-month survey indicates that the goals of the TIRF REMS Access Program are being met with existing tools. The TIRF REMS Industry Group (TRIG) will evaluate the concepts that have scored low among stakeholders to determine if any action is warranted. The TRIG will continue to work with the FDA to refine, on a continual basis, the steps to mitigate risks associated with TIRF medicines. 1. PATIENT SURVEY BACKGROUND Transmucosal Immediate Release Fentanyl (TIRF) medicines are a class of immediate-release opioid analgesics indicated for the management of breakthrough pain in cancer patients 18 years of age or older (16 or older for Actiq® [fentanyl citrate oral transmucosal lozenge] and equivalent generics) who are receiving and already tolerant to opioid therapy for their underlying persistent cancer pain. The FDA has determined that a shared system REMS is required to mitigate the risk of misuse, abuse, addiction, overdose, and serious complications due to medication errors with the use of TIRF medicines. The TIRF REMS Access Program was approved by the FDA on 28 December 2011. This report describes the results from the patient surveys conducted for the 48-Month TIRF REMS Access Program Assessment, and reflects the reporting period of 29 October 2014 to 28 October 2015. The 48-month KAB survey launched on 24 July 2015 and closed on 03 September 2015. The TIRF medicines include Abstral®, Actiq®, Fentora®, Lazanda®, Subsys®, and their generic equivalents. The TRIG includes Actavis Laboratories FL, Inc.; BioDelivery Sciences International, Inc. (BDSI); Cephalon, Inc. (a wholly-owned subsidiary of Teva Pharmaceutical Industries, Ltd.); Depomed, Inc.; Galena Biopharma, Inc.; Insys Therapeutics, Inc.; Mallinckrodt Pharmaceuticals; Mylan, Inc.; and Par Pharmaceutical, Inc. Two companies joined the TRIG during the reporting period: Actavis Laboratories FL, Inc. joined on 6 February 2015 and BDSI replaced Meda Pharmaceuticals on 11 March 2015. The TIRF REMS Access Program consists of a Medication Guide, Elements to Assure Safe Use (ETASU), an Implementation System, and a Timetable for Submission of Assessments of the REMS. The goals of the TIRF REMS Access Program are to mitigate the risk of misuse, abuse, addiction, overdose, and serious complications due to medication errors by the following: 1. Prescribing and dispensing TIRF medicines only to appropriate patients, which includes use only in opioid-tolerant patients. 2. Preventing inappropriate conversion between TIRF medicines. 3. Preventing accidental exposure to children and others for whom it was not prescribed. 4. Educating prescribers, pharmacists, and patients on the potential for misuse, abuse, addiction, and overdose of TIRF medicines. FDA_3196 Patient KAB Assessment Report Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 8 of 54 An important component of the TIRF REMS Access Program Assessment is the conduct of quantitative evaluation surveys to assess patients’/caregivers’ understanding and knowledge of the safe use of TIRF medicines as described in the TIRF REMS Access Program educational materials. Administration of the surveys conducted among patients/caregivers enrolled in the TIRF REMS Access Program is described in the protocol (See Appendix A). Note: Protocol and Survey question revisions from the 36-month assessment report are identified as tracked changes. Data from the surveys, together with other REMS evaluation metrics, will be used to determine whether changes need to be made to the REMS processes or educational materials to make them more effective in achieving the goals of the REMS. 1.1 Changes to the KAB Survey for Patients/Caregivers Based on FDA Feedback FDA Feedback was received on the KAB survey for patients/caregivers in the 36-month Assessment Report Acknowledgement Letter received by the TRIG sponsors on 04 August 2015. FDA requested the following be implemented in the 48-month survey and analysis: • • • • Remove Onsolis as a response option throughout the survey as it is no longer available Move an existing survey question (Question 10a-e) into Key Risk Message 3 Move Question 13b from Key Risk Message 2 to Key Risk Message 3 Include an analysis of demographics of the patient survey respondents compared to the demographics of patients receiving a TIRF product The patient/caregiver KAB Survey invitations were distributed upon survey launch on 24 July 2015. Although the FDA feedback was received on 04 August 2015 after the launch of the survey, the removal of “Onsolis” as a response option was successfully completed during the survey data collection period with no impact to patients/caregivers taking the survey or the survey results presented in this report. In addition to this survey change, the FDA requests related to the allocation of questions to key risk messages for analysis were successfully implemented and are included in this report. The remaining FDA request was to provide an analysis of how the demographics of the patient survey respondents compare to the demographics of actual TIRF patients. Due to timing of the request and the time required to obtain these data, this information was unable to be included in the 48-Month FDA Assessment Report. As communicated to FDA on 09 September 2015, the TRIG plans to submit a Supplemental Report to FDA to include items that were unable to be included in this assessment report based on the timing of the 36-Month FDA Assessment Report Acknowledgement Letter. A comparison of geographic data between survey respondents and the general population of TIRF patients are included in this report; the full demographic comparison will be included in the Supplemental Report estimated to be delivered on May 4, 2016. FDA_3197 Patient KAB Assessment Report Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies 2. Page 9 of 54 PATIENT SURVEY OBJECTIVES The evaluation survey uses a questionnaire to document the level of knowledge and assess the attitudes and behavior of patients regarding the following key information and risk messages communicated through the REMS: 1. TIRF medicines can cause life-threatening breathing problems that can lead to death. 2. Patients should not take TIRF medicines if they are not opioid tolerant. 3. TIRF medicines should be taken exactly as prescribed by the healthcare provider. 4. Patients should not switch from one TIRF medicine to another medicine that contains fentanyl without talking to a healthcare provider. 5. Patients should not give TIRF medicines to anyone else even if they have the same symptoms. 6. TIRF medicines should be stored in a safe place away from children and properly disposed. This survey also included questions about whether patients received, read, and understood the product-specific Medication Guide and PPAF. 3. SURVEY METHODOLOGY This section summarizes the survey design and the questions developed to test patient understanding of the key risk messages of the REMS. Full details of the survey design are in the protocol, provided in Appendix A. 3.1 Survey Sample A sample of 300 patients treated with TIRF medicines was planned for this fourth KAB survey which was expected to be open from 24 July 2015 to 20 October 2015. This lengthened survey period (in comparison to previous years) was planned in an effort to meet the survey goal, which had not been achieved in some previous waves. The survey sample size was determined based on both practical and statistical considerations. The survey was written to reflect wording for both methods of survey administration: Internet-based and telephone. 3.1.1 Eligibility This survey was conducted on patients identified from the TIRF REMS Access Program database and a Pharmacy Benefits Manager (PBM). All patients 18 years or older who filled one or more prescriptions for at least one of the TIRF medicines during the 120 days prior to 24 July 2015 were eligible to participate; caregivers (age 18 years or older) of eligible patients who were unable to take the survey for themselves were eligible to participate. Respondents or respondents with immediate family members who had ever worked for any of the TRIG companies, McKesson Specialty Care Solutions, RelayHealth, United BioSource Corporation FDA_3198 Patient KAB Assessment Report Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 10 of 54 (UBC), or the FDA were not eligible to participate; nor were any respondents who participated in the previous waves of the survey (the 12-month TIRF REMS Access Program Assessment, the 24-month TIRF REMS Access Program Assessment, or the 36-month TIRF REMS Access Program Assessment). 3.1.2 Recruitment Patients who were passively enrolled in the TIRF REMS Access Program as of 30 June 2015 and had received a TIRF medicine in the previous 4 months (120 days) were invited to participate via an invitation letter sent through the United States Postal Service (USPS) (see Section 5.1.1 for more details). Address verification was required on these data due to the limited data points collected through the PPAF. In order to obtain this additional information a public records database was used and those data combined with the TIRF REMS Access Program data were used to distribute invitations to the patient population. Additional patients were identified for participation through a PBM partner, which provided a broad demographic coverage and included patients in 49 states. Through use of these sources, a list was created of patients who had filled a prescription for a TIRF medicine within 4 months (120 days) prior to survey launch (first prescriptions and refills). Full details are provided in the protocol (Appendix A). The required number of completed surveys was not achieved within approximately 10 days after the first mailing; thus additional mailings were distributed to non-respondents from the original sample to maximize participation. Each letter of invitation included a unique code needed to access the survey. The code was deactivated after the respondent had initiated the survey (whether or not the survey was completed). Patients were given the option of taking the survey by telephone via the Survey Coordinating Center (SCC) or online via a secure website. The survey was estimated to take approximately 20 minutes to complete. All respondents who completed the survey and provided their contact information were mailed a $50 gift card for participating. The mailing included a thank you letter, a copy of the productspecific Medication Guide, and a copy of the correct answers to the key risk message questions. 3.2 Questions and Statements on Key Risk Messages The questions and statements comprising the knowledge survey were constructed to test the patients’/caregivers’ understanding of the key risk messages of the REMS. The questions were to be answered either by selecting options from multiple-choice lists that include statements of the specific key risk messages or by choosing “Yes” or “True,” “No” or “False,” or “I don’t know” regarding statements about TIRF medicines. For statements or questions that had “True” or “Yes” vs. “False” or “No” response options, the desired response for key risk messages was generally “True” or “Yes” indicating knowledge of, or behavior in accordance with, the objectives of the REMS. However, some questions were formatted to have the respondent disagree with the statement as written by providing response options of “False” or “No” to avoid having the same affirmative answer for all desired responses. FDA_3199 Patient KAB Assessment Report Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 11 of 54 REMS statements, corresponding questions, and desired responses covering the key risk messages are identified below and can be found in the complete survey questionnaire (Appendix A). For better readability, only patient questions are presented in the key risk messages tables below. The same questions, with modified wording as appropriate for caregivers, are presented in the survey protocol (Appendix A). 3.2.1 Key Risk Message 1 Key Risk Message 1 refers to the patient’s/caregiver’s knowledge that TIRF medicines can cause life-threatening breathing problems. Key Risk Message 1: TIRF medicines can cause life-threatening breathing problems that can lead to death. Question No. Question Desired response 13 Please answer True, False, or I don’t know for each statement about the TIRF medicine that was most recently prescribed for you. 13d TIRF medicines can cause life-threatening breathing problems that can lead to death. 3.2.2 True Key Risk Message 2 Key Risk Message 2 refers to the patient’s/caregiver’s awareness that TIRF medicines should be taken only by opioid-tolerant adult patients. Key Risk Message 2: Patients should not take TIRF medicines if they are not opioid tolerant. Question No. Question Desired response Please answer True, False, or I don’t know for the following statement: 11 12 12a TIRF medicines should only be taken by patients who are opioid tolerant. True Please answer True, False, or I don’t know for each of the following statements. Opioid tolerant means that a patient is already taking other opioid pain medicines around-the-clock and their body is used to these medicines. True FDA_3200 Patient KAB Assessment Report Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies 3.2.3 Page 12 of 54 Key Risk Message 3 Key Risk Message 3 refers to the patient’s/caregiver’s knowledge that TIRF medicines should be taken exactly as prescribed by the healthcare provider. Key Risk Message 3: TIRF medicines should be taken exactly as prescribed by the healthcare provider. Question No. Question Desired response 10 For which of the following conditions should you use a TIRF medicine? Headache or migraine pain 10a No Breakthrough pain from cancer 10b Yes No Dental pain 10c No Pain after surgery 10d No Long-lasting pain not from cancer, like arthritis joint pain 10e 12 Please answer True, False, or I don’t know for each of the following statements. 12b A patient must stop taking their TIRF medicine if they stop taking their around-the-clock opioid pain medicine. 13/17 13b 13c 17b 3.2.4 True Please answer True, False, or I don’t know for each statement about the TIRF medicine that was most recently prescribed for you. It is OK for patients to take TIRF medicines for headache pain. TIRF medicines should be taken exactly as prescribed by the doctor. It is OK to take TIRF medicines for short-term pain that will go away in a few days. False True False Key Risk Message 4 Key Risk Message 4 refers to the patient’s/caregiver’s knowledge of the interchangeability of TIRF medicines. Key Risk Message 4: Patients should not switch from one TIRF medicine to another medicine that contains fentanyl without talking to a healthcare provider. Question No. Question Desired response Please answer True, False, or I don’t know for each of the following statements. 12 It is safe to switch to another medicine that contains fentanyl without talking to a healthcare provider first. 12c False FDA_3201 Patient KAB Assessment Report Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies 3.2.5 Page 13 of 54 Key Risk Message 5 Key Risk Message 5 refers to the patient’s/caregiver’s awareness that TIRF medicines should not be given to anyone else even if they have the same symptoms. Key Risk Message 5: Patients should never give TIRF medicines to anyone else even if they have the same symptoms. Question No. Question Desired response Please answer True, False, or I don’t know for each of the following statements. 12 A patient may give TIRF medicines to another person if they have the same symptoms as the patient. 12d False Please answer True, False, or I don’t know for each statement about the TIRF medicine that was most recently prescribed for you. 17 Selling or giving away TIRF medicines is against the law. 17a True 3.2.6 Key Risk Message 6 Key Risk Message 6 refers to the patient’s/caregiver’s knowledge that TIRF medicines should be stored in a safe place away from children and properly disposed. Key Risk Message 6: TIRF medicines should be stored in a safe place away from children and properly disposed. Question No. Question Desired response Please answer True, False, or I don’t know for each statement about the TIRF medicine that was most recently prescribed for you. 13/17 TIRF medicines should be stored in a safe place out of the reach of children. 13a True TIRF medicines must be disposed of as described in the specific product’s Medication Guide. 17c True A TIRF medicine can cause an overdose and death in any child who takes it. 17e True What should you do if an adult who has not been prescribed a Get emergency TIRF medicine takes a TIRF medicine? (Please select one.) 14 help right away. 4. STATISTICAL METHODS 4.1 Study Population 4.1.1 Primary Analysis Population The primary population for analysis was all eligible patients/caregivers who completed the survey. Eligible respondents were defined as those respondents who answered Yes to Question 1 (agree to take part in survey), Yes to Question 2 (filled a prescription for a TIRF medicine in the last 4 months) or Yes to Question 3 (caregiver for someone who had filled a prescription for a TIRF medicine in the last 4 months), and No to Question 5 (participated in past survey), and No to Question 8 (worked for a TRIG company, UBC, or FDA). Respondents also must have selected an age group ≥18 years of age for Question 6 (patient and caregiver). A survey was considered “completed” when an eligible patient/caregiver answered all relevant questions. FDA_3202 Patient KAB Assessment Report Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies 4.2 Page 14 of 54 Primary Analyses Primary analyses were performed for all key risk messages. The primary analysis for a key risk message evaluated the number and percentage of correct responses for each individual question/component included in the key risk message. Confidence intervals (95% CI) were calculated using the exact binomial method around the percentage of correct responses. Primary analyses were then stratified by questions/characteristics of interest: 1) Those who indicated they both received the Medication Guide and read most of it versus those who responded No or I don’t know or who received it and read only some of it or answered I don’t know (Questions 18, 23, and 24). 2) Those who indicated they understood all or most of the Medication Guide versus those who understood some of it versus those understood none or did not know if they understood versus those who did not know whether they received or read the Medication Guide (Question 25). 3) Whether the survey was completed via the internet or telephone. 4) Highest level of education (Question 37). 5) Age group of respondent (Question 6). Stratified analyses were conducted only when at least two of the stratified response categories had at least 50 respondents (e.g., for analysis 3 above, at least 50 respondents had to respond they completed the survey via the internet and at least 50 had to respond they completed it by telephone in order for that analysis to be conducted). 4.3 Secondary Analyses As an indicator of the overall level of comprehension of the entire key risk message, descriptive analyses of the number and percentage of responders who answered various proportions of the key risk message components correctly are presented (e.g., the proportion who answered one question in the key risk message correctly, those who answered two questions correctly, those who answered three component questions correctly, etc.). Confidence intervals (95% CI) were calculated for the proportion of respondents who answered all component questions of the key risk message correctly. 4.4 Patient Report of a Potential Adverse Event, Product Complaint, or Medical Information Request during the Survey A patient or caregiver may have reported a potential adverse event or other event experienced by a patient while taking a TIRF product either in free text fields while taking the online survey or while in conversation with the SCC Associate. If an event was mentioned to the SCC Associate, the Associate documented the adverse event or complaint, the verbatim response, and the respondent’s contact information, if provided. The respondent was also informed that a representative from the appropriate TIRF medicine sponsor may contact him/her to obtain additional information about the event. Internet surveys were monitored for any comments recorded in the free text field. Information on all reports (Internet or telephone) that constituted FDA_3203 Patient KAB Assessment Report Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 15 of 54 an adverse event or other event was forwarded to the appropriate TIRF medicine sponsor for processing within 1 business day of awareness of the event as outlined in the Adverse Event/Product Complaint Project Specific Procedure (AE/PC PSP). 5. RESULTS Unless otherwise indicated, data tables contain the question presented to the patients. Analyses were summarized by overall population, and not by type of respondent (patient vs. caregiver) since only 4 caregivers participated in the survey. Results of the patient’s/caregiver’s responses to questions in the KAB survey are summarized in this section; stratified analysis tables and overall listings are provided in Appendix B. 5.1 Survey Participants 5.1.1 Survey Participant Administration Results Survey recruitment was performed using the names obtained through the TIRF REMS Access Program database and a PBM (See Section 3.1 for survey methodology details). Based on the number of prescriptions filled or refilled during the 120 days prior to survey implementation (24 July 2015), the TIRF REMS Access Program database identified 4993 potential participants and the PBM identified 576 potential participants. As shown in Table 1, all 5569 possible participants were sent a survey invitation letter. A total of 447 reminder letters were sent to nonresponders (some potential participants may have received more than one reminder letter). Successful survey recruitment through leveraging data collected by the TIRF REMS Access Program (as described in Section 3.1), resulted in the patient/caregiver KAB survey closing early on 03 September 2015 once 310 surveys were collected. From the total of 432 patients/caregivers who accessed the survey, 314 (72.7%) respondents met eligibility criteria, and of those who met eligibility criteria, 310 (98.7%) completed the survey. Of the 310 respondents who completed the survey, 194 (62.6%) completed the survey online, and 116 (37.4%) completed it by telephone (Table 3). Table 1. Survey Participant Administration Results Summary Statistic N % Number of invitations distributed 5569 Number of invitations returned as undeliverable 148 Number of reminder letters distributed 447 All Respondents 1 432 8.0 Eligible Respondents 2 314 72.7 Completed survey 3 310 98.7 FDA_3204 Patient KAB Assessment Report Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Table 1. Page 16 of 54 Survey Participant Administration Results Summary Statistic Did not complete the survey 3 Respondents not eligible 2, 4 N % 4 1.3 118 27.3 1 Number of respondents who accessed the survey. Percentage is based on the number of invitations distributed excluding the number of invitations returned as undeliverable. 2 Percentage is based on the number of all respondents. 3 Percentages are based on the number of eligible respondents. 4 Number of respondents who did not meet eligibility criteria or did not complete eligibility questions. As shown in Table 2, of the 432 respondents who accessed the survey, 374 patients/caregivers answered at least 1 survey question, and 58 respondents did not answer any of the survey questions and were discontinued. Of the 432 prescribers who started the survey, 373 agreed to participate. During the screening process it was determined 60 of the 374 respondents who answered at least 1 survey question were not eligible to participate in the survey because they either did not agree to participate in the survey (1 respondent), indicated that they had not or did not know whether they filled a prescription for a TIRF medicine within the last 4 months either for themselves or as a the caregiver of a patient (16 respondents), that they had participated in or did not know whether they participated in a survey about TIRF medicines before (41 respondents), or that they or an immediate family member had worked for a TRIG company, the FDA, or UBC (1 respondent). In addition, 1 of the 432 respondents who answered at least 1 survey question discontinued the survey at Question 2. Thus, there were 314 eligible participants (patients/caregivers) (Table 2); 310 respondents (98.7%) completed the survey (Table 1). Table 2. Survey Participant Screening Results Question Patients/Caregivers (N=432) n % Yes 373 86.3 No 1 1 0.2 Discontinued 58 13.4 Question 1: Do you agree to take part in this survey? FDA_3205 Patient KAB Assessment Report Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Table 2. Page 17 of 54 Survey Participant Screening Results Question Patients/Caregivers (N=432) n % Question 2: Within the last 4 months (120 days), have you filled a prescription for yourself for a transmucosal immediate release fentanyl medicine (known as “TIRF medicines“)? TIRF medicines include Abstral®, Actiq®, Fentora®, Lazanda®, Subsys®, and the generic versions of any of these brands. Yes 352 81.5 No 14 3.2 I don't know 6 1.4 Question not asked 2 1 0.2 Discontinued 59 13.7 Question 3: Are you a caregiver for someone who has filled a prescription for a TIRF medicine within the last 4 months (120 days)? TIRF medicines include Abstral®, Actiq®, Fentora®, Lazanda®, Subsys® and the generic versions of any of these brands. Yes 4 0.9 15 3.5 1 0.2 352 81.5 Question not asked 2 1 0.2 Discontinued 59 13.7 No 1 I don't know 1 N/A (Answered "Yes" to Question 2) Question 5: Have you ever taken part in a survey about a TIRF medicine before? Yes 1 29 6.7 315 72.9 12 2.8 Question not asked 2 17 3.9 Discontinued 59 13.7 No I don't know 1 Question 6: Which of the following groups best describes your age? Under 18 1 0 18 - 29 5 1.2 30 - 39 20 4.6 FDA_3206 Patient KAB Assessment Report Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Table 2. Page 18 of 54 Survey Participant Screening Results Question Patients/Caregivers (N=432) n % 40 - 49 66 15.3 50 - 59 132 30.6 60 - 69 76 17.6 16 3.7 70 or older Prefer not to answer 1 0 Question not asked 2 58 13.4 Discontinued 59 13.7 Question 7: Which of the following groups best describes the patient’s age? 3 Under 16 0 16 - 29 0 30 - 39 0 40 - 49 1 50 - 59 0 60 - 69 2 0.5 70 or older 1 0.2 Prefer not to answer 1 0 Question not asked 2 369 85.4 Discontinued 59 13.7 0.2 Question 8: Have you or any of your immediate family members ever worked for any of the following companies or agencies? Please select all that apply. 4 Actavis Laboratories FL, Inc. 1 0 Anesta LLC 1 0 BioDelivery Services International (BDSI) 1 0 Cephalon, Inc. (a wholly-owned subsidiary of Teva Pharmaceutical Industries Ltd.) 1] 1 Depomed, Inc. 1 0 Galena Biopharma, Inc. 1 0 0.2 FDA_3207 Patient KAB Assessment Report Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Table 2. Page 19 of 54 Survey Participant Screening Results Question Patients/Caregivers (N=432) n Insys Therapeutics, Inc. 1 0 Mallinckrodt Pharmaceuticals 1 0 McKesson Specialty Care Solutions 1 0 Mylan, Inc. 1 0 Par Pharmaceutical, Inc. 1 0 RelayHealth 1 0 Teva Pharmaceuticals, Ltd. 1 0 United BioSource Corporation 1 0 FDA (Food and Drug Administration) 1 0 No 5 % 314 72.7 I don't know 1 0 Question not asked 2 58 13.4 Discontinued 59 13.7 1 Ineligible to participate in the survey. Question not asked due to termination response from a previous question or skip pattern. 3 Only caregivers are asked this question. 4 More than one response can be selected, so percentages may not sum to 100%. 5 Ineligible if selected in addition to another response. Note: Respondents who discontinued the survey before completing all eligibility questions without being identified as ineligible in any of the previous questions are counted as discontinued. Once a respondent is counted as discontinued, they will count as discontinued in all subsequent eligibility questions. 2 Those taking the survey online took a mean of 14 minutes to complete it, while those taking it by telephone took a mean of 21 minutes (Table 3). FDA_3208 Patient KAB Assessment Report Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Table 3. Page 20 of 54 Time to Complete Survey for Completers Only Time to Complete Survey for Completers (Minutes) Summary Statistic Telephone Internet Total 1 N 116 194 310 Mean (± SD) 21.69 (9.062) 14.42 (8.677) 17.14 (9.487) Minimum 14.1 4.5 4.5 Median 19.61 12.81 16.47 Maximum 102.3 85.8 102.3 0 – <5 Minutes 0 2 2 5 – <10 Minutes 0 52 52 10 – <15 Minutes 1 81 82 15 – <20 Minutes 68 30 98 20 – <25 Minutes 31 12 43 25 – <30 Minutes 7 9 16 30 Minutes or More 9 8 17 Category 1 Number of eligible respondents completing the survey (Table 1). 5.1.2 Patient/Caregiver Demographics The demographic characteristics of respondents who completed the survey are shown in Table 4. The largest number of patients (128; 41.3%) were 50 – 59 years of age. More than half of the respondents (176; 56.8%) were females, and 247 (79.7%) respondents had at least some college or an Associate’s degree or higher education. Prescriptions for Subsys® (146; 33.8%) and Actiq® including generic versions (127; 29.4%) were filled most frequently in the 4 months preceding the survey. Most participants (117; 37.7%) were from the South, followed by the West (81; 26.1%), Midwest (61; 19.7%) and Northeast (51; 16.5%), regions of the United States (US) (Table 4). Based on FDA feedback, the patient survey was updated to remove Onsolis® as a response option throughout the survey as it is no longer available. Prior to this removal, 2 patients selected Onsolis® as a response for Question 4. These responses were removed from the analysis, and the change was not considered to have affected the overall survey results (See Section 1.1). FDA_3209 Patient KAB Assessment Report Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Table 4. Page 21 of 54 Description and Representativeness of Eligible Patients/Caregivers Eligible/Completed Patients & Caregivers Question (N=310) 1 n % Question 4: For which TIRF medicines have you filled a prescription in the last 4 months (120 days)? Please select all that apply. Abstral 15 3.5 Actiq, including generic versions of Actiq 127 29.4 Fentora 66 15.3 Lazanda 19 4.4 Subsys 146 33.8 Other 15 3.5 1 0.2 17 3.9 59 13.7 I don't know Question not asked Discontinued 2 Respondent's age based on Question 6: Which of the following groups best describes your age? 18 - 29 5 1.6 30 - 39 19 6.1 40 - 49 65 21.0 50 - 59 129 41.6 60 - 69 76 24.5 70 or older 16 5.2 Patient's age based on Question 6/7: Which of the following groups best describes your age/the patient's age? Under 16 0 16 - 29 5 1.6 30 - 39 19 6.1 40 - 49 65 21.0 50 - 59 128 41.3 60 - 69 77 24.8 FDA_3210 Patient KAB Assessment Report Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Table 4. Page 22 of 54 Description and Representativeness of Eligible Patients/Caregivers Eligible/Completed Patients & Caregivers Question (N=310) 1 n % 16 5.2 Male 133 42.9 Female 176 56.8 1 0.3 Less than high school 4 1.3 Some high school 7 2.3 High school graduate/GED 48 15.5 Some college/Associates' degree 123 39.7 Bachelor's degree 71 22.9 Master's degree 38 12.3 Professional or Doctoral degree 15 4.8 Prefer not to answer 4 1.3 English 309 99.7 French 0 Spanish 0 Portuguese 0 Italian 0 German 0 Chinese 0 Japanese 0 70 or older Question 36: What is your gender? Prefer not to answer Question 37: What is the highest level of education you have completed? Question 38: What is the main language you speak at home? FDA_3211 Patient KAB Assessment Report Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Table 4. Page 23 of 54 Description and Representativeness of Eligible Patients/Caregivers Eligible/Completed Patients & Caregivers Question (N=310) 1 n % Korean 0 Other 0 Prefer not to answer 1 0.3 Yes 9 2.9 No 296 95.5 5 1.6 Question 39: Are you Hispanic or Latino? Prefer not to answer Question 40: For informational purposes only, which of the following U.S. census categories best describes your race? American Indian or Alaska Native 3 1.0 Asian (origins of Far East, Southeast Asia or the Indian subcontinent) 2 0.6 Black or African American 15 4.8 Native Hawaiian or Other Pacific Islander 3 1.0 White 265 85.5 Other 4 1.3 Prefer not to answer 11 3.5 7 2.3 Northeast 51 16.5 Midwest 61 19.7 South 117 37.7 Two or more races Geographic Distribution (based on Question 41 - In which state do you live?) 3 FDA_3212 Patient KAB Assessment Report Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Table 4. Page 24 of 54 Description and Representativeness of Eligible Patients/Caregivers Eligible/Completed Patients & Caregivers Question (N=310) 1 n % West 81 26.1 Other 0 Prefer not to answer 0 1 Number of eligible respondents completing the survey (See Table 1). 2 Question not asked due to termination response from a previous question or skip pattern. U.S. Census Bureau, last revised Friday, 27-Jul-2001 12:59:43 EDT., Geography Division. Northeast includes CT, MA, ME, NH, NJ, NY, PA, RI, and VT. Midwest includes IA, IL, IN, KS, MI, MN, MO, ND, NE, OH, SD, and WI. South includes AL, AR, DC, DE, FL, GA, KY, LA, MD, MS, NC, OK, SC, TN, TX, VA, and WV. West includes AK, AZ, CA, CO, HI, ID, MT, NM, NV, OR, UT, WA, and WY. The following US territories are categorized as Other: Puerto Rico, Northern Mariana Islands, US Virgin Islands, American Samoa, and Guam. 3 5.1.2.1 Comparison of Survey Respondents to the General Population of TIRF Users Comparison of the survey respondents to the general population of TIRF users (as requested by the FDA) showed the geographic distribution of respondents to the patient survey was similar to the overall population of TIRF users (Table 5). Table 5. Comparison of Survey Respondents to General Population of TIRF Users Question Eligible/Completed Patients & Caregivers (N=310) n (%) Patients Who Have Taken a TIRF Medicine in the Last 4 Months (120 days) 1 (N=9858) n (%) Geographic Distribution 2 Northeast 51 (16.5) 1811 (18.4) Midwest 61 (19.7) 1305 (13.2) South 117 (37.7) 4021 (40.8) West 81 (26.1) 2706 (27.4) Other 0 0 FDA_3213 Patient KAB Assessment Report Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Table 5. Page 25 of 54 Comparison of Survey Respondents to General Population of TIRF Users Question Eligible/Completed Patients & Caregivers (N=310) n (%) Patients Who Have Taken a TIRF Medicine in the Last 4 Months (120 days) 1 (N=9858) n (%) Prefer not to answer 0 0 Missing 0 15 (0.2) 1 Based on data obtained from the TIRF REMS Access Program database. Based on Patient KAB Survey Question 41; U.S. Census Bureau, last revised Friday, 27-Jul-2001 12:59:43 EDT., Geography Division. Northeast includes CT, MA, ME, NH, NJ, NY, PA, RI, and VT. Midwest includes IA, IL, IN, KS, MI, MN, MO, ND, NE, OH, SD, and WI. South includes AL, AR, DC, DE, FL, GA, KY, LA, MD, MS, NC, OK, SC, TN, TX, VA, and WV. West includes AK, AZ, CA, CO, HI, ID, MT, NM, NV, OR, UT, WA, and WY. Other includes Puerto Rico, Northern Mariana Islands, US Virgin Islands, American Samoa and Guam. Note: Percentages are based on the patients and caregivers with informative data. 2 5.1.3 TIRF Medicines Education Materials Respondents were asked about their awareness of educational materials about TIRF medicines, specifically the Medication Guide (Table 6), and the Patient-Prescriber Agreement Form (Table 7). Of the 310 respondents, 298 (96.1%) reported they had received the Medication Guide for the TIRF medicine prescribed for them. Of these 298 respondents, 174 respondents (58.4%) reported receiving the Medication Guide from their doctor or doctor’s office, with 146 respondents (83.9%) receiving it at the first appointment with the prescribing doctor. Most respondents (250; 83.9%) reported receiving the Medication Guide from their pharmacy with 230 of these respondents (92.0%) stating they received the Medication Guide each time a prescription was filled. Of the 298 respondents who received the Medication Guide, most respondents (287; 96.3%) indicated they read the Medication Guide; of these 287 respondents 273 respondents (95.1%) read all of it or most of it, and 263 respondents (91.6%) indicated understanding all or most of the Medication Guide. Over half of the respondents who received the Medication Guide (171; 57.4%) indicated someone offered to explain the medication guide to them; of these, 123 respondents (71.9%) indicated the doctor or someone in the doctor’s office offered to explain the Medication Guide and 127 respondents (74.3%) indicated their pharmacist offered to explain the Medication Guide. Of the 171 respondents, 119 (69.6%) indicated they accepted the offer to have the Medication Guide explained to them, and of those 119 respondents, 117 (98.3%) indicated they understood all or most of the explanation. A total of 16 (5.4%) respondents FDA_3214 Patient KAB Assessment Report Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 26 of 54 indicated they had questions about the information in the Medication Guide (See Appendix B, Listing 3). Table 6. Responses to Questions About TIRF Medication Guide Eligible/Completed Patients & Caregivers Question (N=310) 1 n % Question 18: Have you ever received a Medication Guide for the TIRF medicine that was prescribed for you? Yes 298 96.1 No 7 2.3 I don't know 5 1.6 Question 19: Did you receive the Medication Guide from the doctor who prescribed the TIRF medicine or someone in the doctor's office? 2 Yes 174 58.4 No 106 35.6 I don't know 18 (6.0) N/A (Answered "No" or "I don't know" to Question 18) 12 Question 20: When was the Medication Guide given to you? Please select all that apply. 2,3 At the first appointment with the doctor who prescribed the TIRF medicine 146 83.9 At the last appointment with the doctor who prescribed the TIRF medicine 23 13.2 I don't remember 24 13.8 N/A (answered "No" or "I don't know" to Question 18 or 19) 136 Question 21: Did you receive the Medication Guide for the TIRF medicine from the pharmacy? 2 Yes 250 83.9 No 33 11.1 I don't know 15 5.0 N/A (Answered "No" or "I don't know" to Question 18) 12 Question 22: How frequently do you receive a Medication Guide for the TIRF medicine at the pharmacy? 2 Only with the first filled prescription Each time a prescription is filled 8 3.2 230 92.0 FDA_3215 Patient KAB Assessment Report Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Table 6. Page 27 of 54 Responses to Questions About TIRF Medication Guide Eligible/Completed Patients & Caregivers Question (N=310) 1 n % Other (please specify):4 3 1.2 I don't know 9 3.6 N/A (Answered "No" or "I don't know" to Question 18 or 21) 60 Question 23: Did you read the Medication Guide? 2 Yes 287 96.3 No 8 2.7 I don't know 3 1.0 N/A (Answered "No" or "I don't know" to Question 18) 12 Question 24: How much did you read? 2 All of it 198 69.0 Most of it 75 26.1 Some of it 13 4.5 I don't know 1 0.3 N/A (Answered "No" or "I don't know" to Question 18 or 23) 23 Question 25: How much of the Medication Guide did you understand? 2 All of it 155 54.0 Most of it 108 37.6 Some of it 23 8.0 None of it 0 I don't know 1 N/A (Answered "No" or "I don't know" to Question 18 or 23) 23 0.3 Question 26: Did someone offer to explain the Medication Guide to you? 2 Yes 171 57.4 No 111 37.2 I don't know 16 5.4 N/A (Answered "No" or "I don't know" to Question 18) 12 FDA_3216 Patient KAB Assessment Report Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Table 6. Page 28 of 54 Responses to Questions About TIRF Medication Guide Eligible/Completed Patients & Caregivers Question (N=310) 1 n % Question 27: Who offered to explain the Medication Guide to you? Please select all that apply. 2 The doctor or another healthcare professional in the doctor's office 123 71.9 The pharmacist where the TIRF medicine prescription was filled 127 74.3 Someone else 5 15 8.8 N/A (Answered "No" or "I don't know" to Question 18 or 26) 139 Question 28: Did you accept the offer to have the Medication Guide explained to you? 2 Yes 119 69.6 No 49 28.7 I don't know 3 1.8 N/A (Answered "No" or "I don't know" to Question 18 or 26) 139 Question 29: How much of the explanation did you understand? 2 All of it 92 77.3 Most of it 25 21.0 Some of it 2 1.7 None of it 0 I don't know 0 N/A (Answered "No" or "I don't know" to Question 18, 26 or 28) 191 Question 30: Did you or do you have any questions about the information in the Medication Guide? 2 Yes 6 16 5.4 No 277 93.0 FDA_3217 Patient KAB Assessment Report Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 29 of 54 Table 6. Responses to Questions About TIRF Medication Guide Eligible/Completed Patients Caregivers Question 1 I don't know 5 1.7 (Answered "No" or don't know" to Question 18) 12 1 Number of eligible respondents completing the survey (See Table 1). 2 Percentages are calculated based on the sample presented with this question because of skip logic in the sm'vey. 3 More than one response can be selected. so percentages may not $11111 to 100%. 4 Verbatim text for ?other? for how frequently the Medication Guide is received from the pharmacy (Question 22) is presented in Appendix B. Listing 1. 5 Verbatim text for other persons offering to explain the Medication Guide (Question 27) is presented in Appendix B. Listing 2. 6 Questions about the information in the Medication Guide (Question 30) are presented in Appendix B. Listing 3. The responses to Questions 22, 27 and 30 are listed in Appendix B. Listing 1, Appendix B, Listing 2, and Appendix B, Listing 3, respectively. 5.1.4 Patient-Prescriber Agreement Form After respondents were asked questions regarding the key risk messages, they were asked if they had received, read, and lmderstood the PPAF. A total of 256 respondents indicated that someone at the doctor?s of?ce had explained the PPAF to them. and of the 256 respondents, 204 respondents understood all of it and 44 understood most of it. The PPAF was signed by 248 respondents of the 248 respondents, 180 responders reported receiving a copy of the signed PPAF (Table 7). Table 7. Responses to Questions About the Patient-Prescriber Agreement Form Eligible/Completed Patients Caregivers Question 1 Question 32: Did the doctor or someone in the doctor?s of?ce explain the Patient-Prescriber Agreement Form to you? Yes 256 82.6 No 27 8.7 I don't know 2 7 8. 7 8 Patient KAB Assessment Report Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Table 7. Page 30 of 54 Responses to Questions About the Patient-Prescriber Agreement Form Question Eligible/Completed Patients & Caregivers (N=310) 1 n % All of it 204 79.7 Most of it 44 17.2 Some of it 4 1.6 None of it 1 0.4 I don't know 3 1.2 N/A (Answered "No" or "I don't know" to Question 32) 54 Question 33: How much of the explanation did you understand? 2 Question 34: Did you sign a Patient-Prescriber Agreement Form? Yes 248 80.0 No 13 4.2 I don't know 49 15.8 Question 35: Did the doctor or someone in the doctor’s office give you a copy of the signed Patient-Prescriber Agreement Form? 2 Yes 180 72.6 No 27 10.9 I don't know 41 16.5 N/A (Answered "No" or "I don't know" to Question 34) 62 1 2 Number of eligible respondents completing the survey (See Table 1). Percentages are calculated based on the sample presented with this question because of skip logic in the survey. 5.2 Key Risk Messages 5.2.1 Key Risk Message 1 Key Risk Message 1 refers to the patient’s/caregiver’s knowledge that TIRF medicines can cause life-threatening breathing problems that can lead to death. Most patients/caregivers (91.9%, (95% CI: 88.3- 94.7) were aware of the risk of life-threatening breathing problems with TIRF medicines (Table 8). FDA_3219 Patient KAB Assessment Report Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 31 of 54 Analyses stratified by whether the Medication Guide was received and read (Received and read: N=273; Did not receive or read: N=37), and if the Medication Guide was read and understood (Understood most or all N=263, Understood some N=23, Did not understand N=1, Did not receive or read N=23) were not performed for any of the key risk messages because they did not meet the criteria of ≥50 respondents within at least two response categories. No trends were evident when the results for Key Risk Message 1 were stratified by modality for completing the survey (internet versus telephone), respondent highest level of education, and by the age group of the respondent (Appendix B). Table 8. Key Risk Message 1: TIRF Medicines Can Cause Life-Threatening Breathing Problems That Can Lead to Death Question Eligible/Completed Patients & Caregivers N=310 1 n % (95% CI) 2 Question 13: Please answer True, False, or I don’t know for each statement about the TIRF medicine that was most recently prescribed for you / the patient. 13d: TIRF medicines can cause life-threatening breathing problems that can lead to death. True 3 285 91.9 (88.3 - 94.7) False 3 1.0 I don’t know 22 7.1 1 Number of eligible respondents completing the survey (See Table 1). 95% exact two-sided confidence intervals are calculated using the Clopper-Pearson method. 3 .Indicates the correct response(s) to each question or component within a question. 2 5.2.2 Key Risk Message 2 Key Risk Message 2 refers to the patient’s/caregiver’s knowledge that the patient should not take TIRF Medicines if they are not opioid tolerant. Two components defined this key risk message (Table 9). Less than half of the respondents understood that TIRF medicines should only be taken by cancer patients who are opioid tolerant (43.5%, 95% CI: 38.0-49.3). This question was reworded from the previous survey to specify the patients as ‘cancer’ patients. FDA_3220 Patient KAB Assessment Report Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 32 of 54 Most respondents (90.3%, 95% CI: 86.5-93.4) correctly indicated that opioid tolerant means that a patient is already taking other opioid pain medicines around-the-clock and their body is used to these medicines. Overall, 41.6% (95% CI: 36.1-47.3) provided correct responses for both components of Key Risk Message 2. Table 9. Key Risk Message 2: Patients Should Not Take TIRF Medicines if They Are Not Opioid Tolerant Question Eligible/Completed Patients & Caregivers (N=310) 1 n % (95% CI) 2 Question 11: Please answer True, False, or I don't know for the following statement: TIRF medicines should only be taken by cancer patients who are opioid tolerant. True 3 135 43.5 (38.0 - 49.3) False 122 39.4 I don't know 53 17.1 Question 12: Please answer True, False, or I don't know for each of the following statements. 12a: Opioid tolerant means that a patient is already taking other opioid pain medicines aroundthe-clock and their body is used to these medicines. True 3 280 90.3 (86.5 - 93.4) False 14 4.5 I don't know 16 5.2 0 correct responses 24 7.7 1 correct response 157 50.6 129 41.6 (36.1 - 47.3) Secondary Analyses: Number of Correct Responses 2 correct responses 1 Number of eligible respondents completing the survey (See Table 1). 95% exact two-sided confidence intervals are calculated using the Clopper-Pearson method.. 3 Indicates the correct response(s) to each question or component within a question. 2 FDA_3221 Patient KAB Assessment Report Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 33 of 54 There was a trend toward a higher correct response rate for Question 11 in respondents that took the survey via the internet (Table 10) and a trend toward a higher correct response rate for Question 11 and Component 12a in respondents with a higher education (Table 11). No trends were evident when the results for Key Risk Message 2 were stratified by by the age group of the respondent (Appendix B). Table 10. Trends in Correct Response Rates by Modality for Completing the Survey (Internet versus Telephone) Stratification Question Modality Internet (N=194) Telephone (N=116) Correct Response Rate Correct Response Rate Question n % ([95% CI) 1 n % (95% CI) 1 Key Risk Message 2 11. TIRF medicines should only be taken by cancer patients who are opioid tolerant. True 1 94 48.5 (41.2 - 55.7) 41 35.3 (26.7 - 44.8) 95% exact two-sided confidence intervals are calculated using the Clopper-Pearson method. FDA_3222 Patient KAB Assessment Report Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Table 11. Page 34 of 54 Trends in Correct Response Rates by Highest Level of Education Stratification Question Highest Level of Education GED or less (N=63) College (N=123) Correct Response Rate Correct Response Rate Question n % (95% CI) 1 n % (95% CI) 1 BA/BS or MS/MA (N=109) Professional or Doctoral Degree (N=15) Correct Response Rate Correct Response Rate n % (95% CI) 1 n % ([95% CI) 1 7 46.7 (21.3 - 73.4) Key Risk Message 2 11. TIRF medicines should only be taken by cancer patients who are opioid tolerant. True 25 39.7 (27.6-52.8) 51 41.5 (32.7-50.7) 52 47.7 (38.1 - 57.5) 12a. Opioid tolerant means that a patient is already taking other opioid pain medicines around-the-clock and their body is used to these medicines. True 1 51 81.0 (69.1-89.8) 112 91.1 (84.6-95.5) 104 95.4 (89.6 - 98.5) 13 86.7 (59.5 - 98.3) 95% exact two-sided confidence intervals are calculated using the Clopper-Pearson method. 5.2.3 Key Risk Message 3 Key Risk Message 3 refers to the patient’s/caregiver’s knowledge that TIRF medicines should be taken exactly as prescribed by the healthcare provider. Nine components define this key risk message (Table 12). For Components 10a-10e, which in previous surveys were not included as part of a key risk message, most respondents understood that TIRF medicines should not be used for headache or migraine pain (80.6%, 95% CI: 75.8-84.9) or dental pain (90.3%, 95% CI: 86.5-93.4). Over half of the respondents understood the TIRF medicines should not be used for pain after surgery (67.7%, 95% CI: 62.2-72.9). Less than half (43.9%, 95% CI: 38.3-49.6) of respondents indicated they were aware that TIRF medicines are not indicated for long-lasting painful conditions not caused by cancer; however, 68.4% (95% CI: 62.9-73.5) knew that TIRF medicines should be used for breakthrough pain from cancer. In response to Component 12b, 122 respondents (39.4%, 95% CI: 33.9-45.0) understood that if a patient stops taking around-the-clock opioid pain medicine, they must also stop taking the TIRF medicine. FDA_3223 Patient KAB Assessment Report Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 35 of 54 For Component 13b, 74.8% of respondents (95% CI: 69.6-79.6) correctly indicated that it is not okay for patients to take TIRF medicines for headache pain, and all respondents (100%, 95% CI: 98.8-100.0) understood that TIRF medicines should be taken exactly as prescribed by the doctor. For Component 17b, 86.1% (95% CI: 81.8 - 89.8) knew that is not okay to take TIRF medicines for short-term pain that will go away in a few days. Overall, 15.8% (95% CI: 11.9-20.4) correctly answered all components of the key risk message; 33.9% missed no more than one component, and 52.2% missed no more than two of the nine components. Table 12. Key Risk Message 3: TIRF Medicines Should be Taken Exactly as Prescribed by the Healthcare Provider Question Eligible/Completed Patients & Caregivers (N=310) 1 n % (95% CI) 2 Question 10: For which of the following conditions should you use a TIRF medicine? 10a: Headache or migraine pain Yes 32 10.3 No 3 250 80.6 (75.8 - 84.9) I don't know 28 9.0 Yes 3 212 68.4 (62.9 - 73.5) No 80 25.8 I don't know 18 5.8 Yes 8 2.6 No 3 280 90.3 (86.5 - 93.4) I don't know 22 7.1 65 21.0 10b: Breakthrough pain from cancer 10c: Dental pain 10d: Pain after surgery Yes FDA_3224 Patient KAB Assessment Report Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Table 12. Page 36 of 54 Key Risk Message 3: TIRF Medicines Should be Taken Exactly as Prescribed by the Healthcare Provider Question Eligible/Completed Patients & Caregivers (N=310) 1 n No 3 I don't know % (95% CI) 2 210 67.7 (62.2 - 72.9) 35 11.3 135 43.5 136 43.9 (38.3 - 49.6) 39 12.6 10e: Long-lasting pain not from cancer, like arthritis joint pain Yes No 3 I don't know Question 12: Please answer True, False, or I don't know for each of the following statements. 12b: A patient must stop taking their TIRF medicine if they stop taking their around-the-clock opioid pain medicine. True 3 122 39.4 (33.9 - 45.0) False 93 30.0 I don't know 95 30.6 Question 13: Please answer True, False, or I don't know for each statement about the TIRF medicine that was most recently prescribed for you. 13b: It is OK for patients to take TIRF medicines for headache pain. True 20 6.5 False 3 232 74.8 (69.6 - 79.6) I don't know 58 18.7 True 3 310 100.0 (98.8-100.0) False 0 I don't know 0 13c: TIRF medicines should be taken exactly as prescribed by the doctor. FDA_3225 Patient KAB Assessment Report Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Table 12. Page 37 of 54 Key Risk Message 3: TIRF Medicines Should be Taken Exactly as Prescribed by the Healthcare Provider Question Eligible/Completed Patients & Caregivers (N=310) 1 % (95% CI) 2 n Question 17: Please answer True, False, or I don't know for each statement about the TIRF medicine that was most recently prescribed for you. 17b: It is OK to take TIRF medicines for short-term pain that will go away in a few days. True 13 4.2 False 3 267 86.1 (81.8 - 89.8) I don't know 30 9.7 Secondary Analysis: Number of Correct Responses 0 correct responses 0 1 correct response 3 1.0 2 correct responses 9 2.9 3 correct responses 12 3.9 4 correct responses 15 4.8 5 correct responses 40 12.9 6 correct responses 69 22.3 7 correct responses 57 18.4 8 correct responses 56 18.1 49 15.8 (11.9-20.4) 9 correct responses 1 Number of eligible respondents completing the survey (See Table 1). 95% exact two-sided confidence intervals are calculated using the Clopper-Pearson method. 3 Indicates the correct response(s) to each question or component within a question. 2 There was a trend toward a higher correct response rate for Components 12b and 13b in respondents with a higher education (Table 13). No trends were evident when the results for Key Risk Message 3 were stratified by modality for completing the survey (internet versus telephone) and by the age group of the respondent (Appendix B). FDA_3226 Patient KAB Assessment Report Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Table 13. Page 38 of 54 Trends in Correct Response Rates by Highest Level of Education Stratification Question Highest Level of Education GED or less (N=63) College (N=123) Correct Response Rate Correct Response Rate Question n % (95% CI) 1 n % (95% CI) 1 BA/BS or MS/MA (N=109) Professional or Doctoral Degree (N=15) Correct Response Rate Correct Response Rate n % (95% CI) 1 n % ([95% CI) 1 Key Risk Message 3 12b: A patient must stop taking their TIRF medicine if they stop taking their around-the-clock opioid pain medicine. True 12 19.0 (10.2-30.9) 48 39.0 (30.4-48.2) 54 49.5 (39.8 - 59.3) 8 53.3 (26.6 - 78.7) 84.4 (76.2-90.6) 9 60.0 (32.3-83.7) 13b: It is OK for patients to take TIRF medicines for headache pain. False 1 43 68.3 (55.3-79.4) 88 71.5 (62.7-79.3) 92 95% exact two-sided confidence intervals are calculated using the Clopper-Pearson method. 5.2.4 Key Risk Message 4 Key Risk Message 4 refers to the patient’s/caregiver’s knowledge that they must not switch from a TIRF medicine to another medicine that contains fentanyl without talking to a healthcare provider (Table 14). Of the 310 respondents, 95.2% (95% CI: 92.1-97.3) understood that it is not safe to switch to another medicine that contains fentanyl without talking to a healthcare provider first. FDA_3227 Patient KAB Assessment Report Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Table 14. Page 39 of 54 Risk Message 4: Patients Should Not Switch From a TIRF Medicine to Another Medicine That Contains Fentanyl Without Talking to a Healthcare Provider Question Eligible/Completed Patients & Caregivers (N=310) 1 n % (95% CI) 2 Question 12: Please answer True, False, or I don't know for each of the following statements. 12c: It is safe to switch to another medicine that contains fentanyl without talking to a healthcare provider first. True 5 1.6 False 3 295 95.2 (92.1 - 97.3) I don't know 10 3.2 1 Number of eligible respondents completing the survey (See Table 1). 95% exact two-sided confidence intervals are calculated using the Clopper-Pearson method. 3 Indicates the correct response(s) to each question or component within a question. 2 There was a trend toward a higher correct response rate for Component 12c in respondents with higher education (Table 15). No trends were evident when the results for Key Risk Message 4 were stratified by modality for completing the survey (internet versus telephone) and by the age group of the respondent (Appendix B). FDA_3228 Patient KAB Assessment Report Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Table 15. Page 40 of 54 Trends in Correct Response Rates by Highest Level of Education Stratification Question Highest Level of Education GED or less (N=63) College (N=123) Correct Response Rate Correct Response Rate Question n % (95% CI) 1 n % (95% CI) 1 BA/BS or MS/MA (N=109) Professional or Doctoral Degree (N=15) Correct Response Rate Correct Response Rate n % (95% CI) 1 n % ([95% CI) 1 Key Risk Message 4 12c: It is safe to switch to another medicine that contains fentanyl without talking to a healthcare provider first. False 1 54 85.7 (74.6-93.3) 119 96.7 (91.9-99.1) 107 98.2 (93.5 - 99.8) 15 100.0 (78.2 - 100.0) 95% exact two-sided confidence intervals are calculated using the Clopper-Pearson method. 5.2.5 Key Risk Message 5 Key Risk Message 5 refers to patient’s/caregiver’s knowledge that TIRF medicines should not be given to anyone else even if they have the same symptoms (Table 16). For Component 12d, 99.4% (95% CI: 97.7 - 99.9) understood that a patient may not give TIRF medicines to another person if they have the same symptoms as the patient, and 98.7% (95% CI: 96.7 - 99.6) understood that selling or giving away TIRF medicines is against the law (Component 17a). Overall, 98.1% (95% CI: 95.8-99.3) correctly answered both components of the key risk message. No trends were evident when the results for Key Risk Message 5 were stratified by modality for completing the survey (internet versus telephone), respondent highest level of education, and by the age group of the respondent (Appendix B). FDA_3229 Patient KAB Assessment Report Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Table 16. Page 41 of 54 Key Risk Message 5: Patients Should Not Give TIRF Medicines to Anyone Else Even if They Have the Same Symptoms Question Eligible/Completed Patients & Caregivers (N=310) 1 n % (95% CI) 2 Question 12: Please answer True, False, or I don't know for each of the following statements. 12d: A patient may give TIRF medicines to another person if they have the same symptoms as the patient. True 0 False[2] I don't know 308 99.4 (97.7 - 99.9) 2 0.6 Question 17: Please answer True, False, or I don't know for each statement about the TIRF medicine that was most recently prescribed for you. 17a: Selling or giving away TIRF medicines is against the law. True[2] 306 98.7 (96.7 - 99.6) False 2 0.6 I don't know 2 0.6 Secondary Analysis: Number of Correct Responses 0 correct responses 0 1 correct response 6 1.9 304 98.1 (95.8-99.3) 2 correct responses 1 Number of eligible respondents completing the survey (See Table 1). All confidence intervals are exact binomial 95% confidence intervals. 3 Indicates the correct response(s) to each question or component within a question. 2 5.2.6 Key Risk Message 6 Key Risk Message 6 refers to the patient’s/caregiver’s knowledge that TIRF medicines should be stored in a safe place away from children and properly disposed (Table 17). Almost all respondents (99.7%, 95% CI: 98.2-100.0) correctly responded that TIRF medicines should be stored in a safe place out of the reach of children (Component 13a). Most respondents FDA_3230 Patient KAB Assessment Report Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 42 of 54 (88.1%, 95% CI: 83.9-91.5) correctly indicated they should get emergency help right away if an adult who has not been prescribed a TIRF medicine takes a TIRF medicine (Question 14), and 96.5% (95% CI: 93.7 - 98.2) understood that TIRF medicines must be disposed of as described in the specific product’s Medication Guide (Component 17c). In addition, 93.2% (95% CI: 89.8 - 95.8) understood that a TIRF medicine can cause an overdose and death in any child who takes it (Component 17e). Overall, 81.3% correctly answered all components of the key risk message. Table 17. Key Risk Message 6: TIRF Medicines Should be Stored in a Safe Place Away From Children and Properly Disposed Question Eligible/Completed Patients & Caregivers (N=310) 1 n % (95% CI) 2 Question 13: Please answer True, False, or I don't know for each statement about the TIRF medicine that was most recently prescribed for you. 13a: TIRF medicines should be stored in a safe place out of the reach of children. True 3 309 99.7 (98.2-100.0) False 1 0.3 I don't know 0 Question 14: What should you do if an adult who has not been prescribed a TIRF medicine takes a TIRF medicine? (Please select one.) Wait an hour and see if the person is OK. 6 1.9 273 88.1 (83.9 - 91.5) Do nothing. 1 0.3 I don't know. 30 9.7 Get emergency help right away. 3 Question 17: Please answer True, False, or I don't know for each statement about the TIRF medicine that was most recently prescribed for you. 17c: TIRF medicines must be disposed of as described in the specific product’s Medication Guide. True 3 299 96.5 (93.7 - 98.2) False 2 0.6 FDA_3231 Patient KAB Assessment Report Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Table 17. Page 43 of 54 Key Risk Message 6: TIRF Medicines Should be Stored in a Safe Place Away From Children and Properly Disposed Question I don't know Eligible/Completed Patients & Caregivers (N=310) 1 n % (95% CI) 2 9 2.9 17e: A TIRF medicine can cause an overdose and death in any child who takes it. True 3 289 93.2 (89.8 - 95.8) False 2 0.6 I don't know 19 6.1 Secondary Analysis: Number of Correct Responses 0 correct responses 0 1 correct response 2 0.6 2 correct responses 8 2.6 3 correct responses 48 15.5 252 81.3 (76.5-85.5) 4 correct responses 1 Number of eligible respondents completing the survey (See Table 1). 95% exact two-sided confidence intervals are calculated using the Clopper-Pearson method. 3 Indicates the correct response(s) to each question or component within a question. 2 There was a trend toward a higher correct response rate for Question 14 in respondents with a higher education (Table 18). No trends were evident when the results for Key Risk Message 4 were stratified by modality for completing the survey (internet versus telephone) and by the age group of the respondent (Appendix B). FDA_3232 Patient KAB Assessment Report Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Table 18. Page 44 of 54 Trends in Correct Response Rates by Highest Level of Education Stratification Question Highest Level of Education GED or less (N=63) College (N=123) Correct Response Rate Correct Response Rate Question n % (95% CI) 1 n % (95% CI) 1 BA/BS or MS/MA (N=109) Professional or Doctoral Degree (N=15) Correct Response Rate Correct Response Rate n % (95% CI) 1 n % ([95% CI) 1 Key Risk Message 6 14. What should you do if an adult who has not been prescribed a TIRF medicine takes a TIRF medicine? (Please select one.) Get emergency help right away 1 52 82.5 (70.9-90.9) 109 88.6 (81.6-93.6) 98 89.9 (82.7 - 94.9) 14 93.3 (68.1 - 99.8) 95% exact two-sided confidence intervals are calculated using the Clopper-Pearson method. 5.2.7 Other Survey Questions 5.2.7.1 Additional Questions about TIRF Medicines Safety Table 19 summarizes the patient/caregiver responses to additional questions about the safe use of TIRF medicines beyond those associated with the key risk messages. The results generally indicate that respondents were educated by a HCP on the precautions to be taken to ensure safe use of TIRF medicines. See Section 5.2 for all key risk message question results. The majority of respondents (83.5%) indicated someone in the doctor’s office discussed the risks and possible side effects of the prescribed TIRF medicine. Most respondents (95.5%) indicated that someone in the doctor’s office explained how to use the prescribed TIRF medicines and 82.3% indicated someone in the doctor’s office advised them on the proper storage of the prescribed TIRF medicines. The majority (76.1%) were also aware that TIRF medicines are only available through the TIRF REMS Access Program. FDA_3233 Patient KAB Assessment Report Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Table 19. Page 45 of 54 Responses to Additional Questions about the Safe Use of TIRF Medicines Question Eligible/Completed Patients & Caregivers (N=310) 1 n % Question 9: Did the doctor, nurse, or other healthcare professional in the doctor’s office ever talk to you about the risks and possible side effects of the TIRF medicine that was most recently prescribed for you? TIRF medicines include Abstral®, Actiq®, Fentora®, Lazanda®, Subsys®, and the generic versions of these brands. Yes 259 83.5 No 36 11.6 I don't know 15 4.8 Question 15: Did the doctor, nurse, or other healthcare professional in the doctor’s office ever tell you how to use the TIRF medicine that was most recently prescribed for you? Yes 296 95.5 No 9 2.9 I don't know 5 1.6 Question 16: Did the doctor, nurse, or other healthcare professional in the doctor’s office ever tell you how to store or keep the TIRF medicine that was most recently prescribed for you? Yes 255 82.3 No 49 15.8 I don't know 6 1.9 Question 17: Please answer True, False, or I don't know for each statement about the TIRF medicine that was most recently prescribed for you. 17d: TIRF medicines are only available to patients through a pharmacy enrolled in a special program (called the TIRF REMS Access Program). True 236 76.1 False 8 2.6 I don't know 66 21.3 1 2 Number of eligible respondents completing the survey (See Table 1). Indicates the correct response(s) to each question or component within a question. FDA_3234 Patient KAB Assessment Report Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies 5.3 Page 46 of 54 Spontaneous Reporting of Adverse Events, Product Complaints, or Medical Information Requests Among all survey respondents (N=310; Table 1), there were 34 reports of a potential adverse event or product complaint associated with the use of TIRF medicines made during a telephone interview or while activating a gift card via telephone (29 reports), or within the survey free text field during the online survey (5 reports). Verbatim statements are provided in Appendix B, Listing 4. 6. DISCUSSION AND CONCLUSIONS Discussion Survey invitations (and reminders) were sent to all known patients/caregivers who had filled a prescription within the 4 months prior to survey launch. From among the 310 who responded to the invitation, 306 patients and 4 caregivers completed the survey. The specific goals of the TIRF medicines patient/caregiver KAB survey were to evaluate the level of knowledge and assess the attitudes and behavior of patients/caregivers regarding TIRF medicines. The focus of the survey included the following: 1) TIRF medicines can cause lifethreatening breathing problems that can lead to death, patients should take TIRF medicines only if they are opioid-tolerant, and patients should strictly follow the directions of the HCP, 2) patients should not switch from a TIRF medicine to another medicine that contains fentanyl without talking to an HCP, 3) patients should not give TIRF medicines to anyone else even if they have the same symptoms, and 4) TIRF medicines should be stored in a safe place away from children and properly disposed. The survey also included questions about whether patients received, read, and understood the product-specific Medication Guide and the PPAF. Comparison of the survey respondents to the general population of TIRF users (as requested by FDA) showed the geographic distribution of respondents to the patient survey was similar to the overall population of TIRF users (Table 5). A full comparison of demographics of the survey respondents to the general population of TIRF users will be included in the Supplemental Report estimated to be delivered on May 4, 2016. Of the 19 components included as part of key risk messages, 13 components had a response rate >80%, and 3 components had a correct response rate between 67.7% and 74.8%. The remaining 3 components within key risk messages 2 and 3 had a correct response rate which fell below the desired threshold of 65%. Question 11 in the 36-month survey was worded: ‘TIRF medicines should only be taken by patients who are opioid tolerant’ and scored 85.2%. Prior to this survey implementation, it was reworded to ‘TIRF medicines should only be taken by cancer patients who are opioid tolerant’ and scored 43.5%. Since a high percentage of respondents understood the definition of ‘opioid tolerant” (Component 12a, 90.3%), the survey score for Question 11 may indicate that some respondents were receiving TIRF medicine for a non-cancer associated indications.. FDA_3235 Patient KAB Assessment Report Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 47 of 54 Correct response rate for Component 10e,TIRF medicines should not be used for long-lasting pain not from cancer, like arthritis joint pain, was 43.9% for this 48-month survey. However, for Components 10a-10d, most respondents understood that TIRF medicines should not be used for headache or migraine pain (80.6%) and dental pain (90.3%); and, over half understood the TIRF medicines should not be used for pain after surgery (67.7%) and should be used for breakthrough pain from cancer (68.4%). Components 10a-10e were not included as part of a key risk message in previous surveys. In addition, correct response rate for Component 12b (a patient must stop taking their TIRF medicine if they stop taking their around-the-clock opioid pain medicine) was 39.4% in this 48-month survey. Two of the components mentioned above with a score below the desired level of understanding of 65% for this survey (Component 10e and 12b) have had a low correct response rate across all patient/caregiver KAB surveys conducted (12-month, 24-month, 36-month, and 48-month surveys); however, response rates are trending toward an increase in understanding of the use of TIRF medicines (see Table 20). As shown in Table 20, there is a clear and consistent indication of improvement (i.e., numeric trend) in knowledge and understanding of the key risk messages. Table 20 includes key risk messages and questions/components within each key risk message as presented in the 48-month survey. It is important to note the question/component numbering, wording, and association with a specific key risk message may have changed across survey waves based on FDA feedback or other decisions made by the TRIG. FDA_3236 Patient KAB Assessment Report Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Table 20. 48-Month Survey Question Number Page 48 of 54 Correct Response Rate Over Time Questions as Presented in the 48-Month Survey 12-Month Survey Correct/Desired Response Rate % (95% CI) 24-Month Survey Correct/Desired Response Rate % (95% CI) 36-Month Survey Correct/Desired Response Rate % (95% CI) 48-Month Survey Correct/Desired Response Rate % (95% CI) Key Risk Message 1: TIRF Medicines Can Cause Life-threatening Breathing Problems That Can Lead to Death 13 Please answer True, False, or I don’t know for each statement about the TIRF medicine that was most recently prescribed for you. 13d TIRF medicines can cause lifethreatening breathing problems that can lead to death. (Correct Response True) 90.1 (85.0, 93.9) 90.1 (86.1, 93.2) 91.3 (86.8, 94.6) 91.9 (88.3 - 94.7) Key Risk Message 2: Patients Should Not Take TIRF Medicines if They Are Not Opioid Tolerant 11/12 11 12a Please answer True, False, or I don’t know for the following statement: TIRF medicines should only be taken by cancer patients who are opioid tolerant (Correct Response True) 2 90.6 (85.6, 94.3) 91.7 (88.0, 94.6) 85.2 (79.9, 89.5) 43.5 (38.0 - 49.3) Opioid tolerant means that a patient is already taking other opioid pain medicines around the clock and their body is used to these medicines. (Correct Response True) 91.7 (86.8, 95.2) 88.4 (84.3, 91.8) 81.7 (76.0, 86.5) 90.3 (86.5 - 93.4) 78.22 80.6 (75.8 - 84.9) Key Risk Message 3: TIRF Medicines Should Be Taken Exactly as Prescribed By the Healthcare Provider 10 For which of the following conditions should you use a TIRF medicine? 10a Headache or migraine pain. (Correct Response No) 72.92 77.52 FDA_3237 Patient KAB Assessment Report Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Table 20. 48-Month Survey Question Number Page 49 of 54 Correct Response Rate Over Time Questions as Presented in the 48-Month Survey 12-Month Survey Correct/Desired Response Rate % (95% CI) 24-Month Survey Correct/Desired Response Rate % (95% CI) 36-Month Survey Correct/Desired Response Rate % (95% CI) 48-Month Survey Correct/Desired Response Rate % (95% CI) 10b Breakthrough pain from cancer. (Correct Response Yes) 69.82 64.22 65.92 68.4 (62.9 - 73.5) 10c Dental pain. (Correct Response No) 89.62 87.42 87.32 90.3 (86.5 - 93.4) 10d Pain after surgery. (Correct Response No) 2 67.72 68.52 70.32 67.7 (62.2 - 72.9) Long-lasting pain not from cancer, like arthritis joint pain (Correct Response No) 2 24.52 21.92 25.32 43.9 (38.3 - 49.6) 36.7 (30.4, 43.3) 39.4 (33.9 - 45.0) 10e 12 Please answer True, False, or I don’t know for each of the following statements. 12b 13/17 A patient must stop taking their TIRF medicine if they stop taking their around-the-clock opioid pain medicine. (Correct Response True) 2 42.7 (35.6, 50.0) 34.1 (28.8, 39.8) Please answer True, False, or I don’t know for each statement about the TIRF medicine that was most recently prescribed for you. 13b It is OK for patients to take TIRF medicines for headache pain. (Correct Response False) 70.8 (63.9, 77.2) 68.2 (62.6, 73.4) 13c TIRF medicines should be taken exactly as prescribed by the doctor. (Correct Response True) 100.0 (98.1, 100.0) 99.7 (98.2, 100.0) 69.4 (63.0, 75.3) 99.1 (96.9, 99.9) 74.8 (69.6 - 79.6) 100.0 (98.8 - 100.0) FDA_3238 Patient KAB Assessment Report Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Table 20. 48-Month Survey Question Number 17b Page 50 of 54 Correct Response Rate Over Time Questions as Presented in the 48-Month Survey It is OK to take TIRF medicines for short-term pain that will go away in a few days. (Correct Response False) 12-Month Survey Correct/Desired Response Rate % (95% CI) 24-Month Survey Correct/Desired Response Rate % (95% CI) 36-Month Survey Correct/Desired Response Rate % (95% CI) 48-Month Survey Correct/Desired Response Rate % (95% CI) 82.3 (76.1, 87.4) 83.4 (78.8, 87.5) 83.0 (77.5, 87.6) 86.1 (81.8 - 89.8) Key Risk Message 4: Patients Should Not Switch From a TIRF Medicine to Another Medicine That Contains Fentanyl Without Talking to a Healthcare Provider 12 Please answer True, False, or I don’t know for each of the following statements. 12c It is safe to switch to another medicine that contains fentanyl without talking to a healthcare provider first. (Correct Response False) 96.9 (93.3, 98.8) 94.4 (91.1, 96.7) 96.9 (93.8, 98.8) 95.2 (92.1 - 97.3) Key Risk Message 5: Patients Should Never Give TIRF Medicines to Anyone Else Even if They Have the Same Symptoms 12 Please answer True, False, or I don’t know for each of the following statements. 12d 17 A patient may give TIRF medicines to another person if they have the same symptoms as the patient. (Correct Response False) 100.0 (98.1, 100.0) 98.0 (95.7, 99.3) 99.1 (96.9, 99.9) 99.4 (97.7 - 99.9) Please answer True, False, or I don’t know for each statement about the TIRF medicine that was most recently prescribed for you. 17a Selling or giving away TIRF medicines is against the law. (Correct Response True) 97.9 (94.8, 99.4) 98.3 (96.2, 99.5) 99.1 (96.9, 99.9) 98.7 (96.7 - 99.6) FDA_3239 Patient KAB Assessment Report Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Table 20. 48-Month Survey Question Number Page 51 of 54 Correct Response Rate Over Time Questions as Presented in the 48-Month Survey 12-Month Survey Correct/Desired Response Rate % (95% CI) 24-Month Survey Correct/Desired Response Rate % (95% CI) 36-Month Survey Correct/Desired Response Rate % (95% CI) 48-Month Survey Correct/Desired Response Rate % (95% CI) Key Risk Message 6: TIRF Medicines Should be Stored in a Safe Place Away From Children and Properly Disposed 13/17 13a 17c 17e 14 1 2 Please answer True, False, or I don’t know for each statement about the TIRF medicine that was most recently prescribed for you. TIRF medicines should be stored in a safe place out of the reach of children. (Correct Response True) 100.0 (98.1, 100.0) 100.0 (98.8, 100.0) 99.1 (96.9, 99.9) 99.7 (98.2 - 100.0) TIRF medicines must be disposed of as described in the specific product’s Medication Guide. (Correct Response True) 95.8 (92.0, 98.2) 94.4 (91.1, 96.7) 93.9 (90.0, 96.6) 96.5 (93.7 - 98.2) 90.6 91.1 90.4 93.2 (85.6, 94.3) (87.3, 94.0) (85.8, 93.9) (89.8 - 95.8) 89.1 (83.8, 93.1) 87.4 (83.1, 90.9) 88.2 (83.3, 92.1) 88.1 (83.9 - 91.5) A TIRF medicine can cause an overdose and death in any child who takes it. (Correct Response True) What should you do if an adult who has not been prescribed a TIRF medicine takes a TIRF medicine? (Please select one.) (Correct Response: Get emergency help right away.) Questions presented have been changed from previous survey waves. 95% confidence interval is not provided since the component was not part of a key risk message during reporting period. FDA_3240 Patient KAB Assessment Report Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 52 of 54 Conclusions In general, there is an overall trend over time toward maintenance or improvement in patient knowledge and understanding of the key risk messages (Table 20). Patients scored consistently low on two of 19 components: that TIRF medicines should not be taken for long-lasting pain not from cancer, like arthritis joint pain, and that a patient must stop taking their TIRF medicine if they stop taking their around-the-clock opioid pain medicine. In addition, revising Question 11 (TIRF medicines should only be taken by patients who are opioid tolerant) to be specific to ‘cancer’ patients, resulted in a large decrease in correct response rate, which may indicate that some respondents were receiving TIRF medicine for a non-cancer associated indications. The consistently high level of patient understanding of key risk messages in the latest (48-month) survey indicates that the goals of the TIRF REMS Access Program are being met with existing tools. The TRIG will evaluate the concepts that have scored low among stakeholders to determine if any action is warranted. The TRIG will continue to work with the FDA to refine, on a continual basis, the steps to mitigate risks associated with TIRF medicines. FDA_3241 Patient KAB Assessment Report Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Appendix A Page 53 of 54 Patient Survey Protocol Track Change Document: Comparison of 36month Survey to 48-month Survey FDA_3242 PROTOCOL TITLE: SPONSOR: VERSION: DATE: APPROVED Quantitative Testing of Patient/Caregiver Knowledge, Attitudes, and Behavior about Transmucosal Immediate Release Fentanyl (TIRF) Products Safety and Use Information TIRF REMS Industry Group (TRIG) Actavis Laboratories FL, Inc. BioDeliverv Sciences International, Inc. (BDSI) (reelaced Mala Pharmaceuticals on .March 11I 20152 Cephalon, Inc. (a wholly?owned subsidiary of Teva Pharmaceutical Industries, Ltd.) Depomed, Inc. Galena Biopharma, Inc. Insys Therapeutics, Inc. Mallinckrodt Pharmaceuticals 1 Mylan, Inc. Par Pharmaceutical, Inc. _04.0 Formatted: Font: Bold, Italic Formatted: Font: Italic Formatted: Space Alter: 0 pt, Line spac?ng: single TABLE OF CONTENTS PAGE TABLE OF CONTENTS ......................................................................................... 2 1. LIST OF ABBREVIATIONS .................................................................................. 3 2. BACKGROUND ..................................................................................................... 4 3. OBJECTIVES OF THE EVALUATION SURVEY ............................................... 5 4. METHODS .............................................................................................................. 5 4.1 Qualitative Research on the Survey ......................................................................... 5 4.2 4.2.1 4.2.2 Survey Design .......................................................................................................... 5 Questions and Statements on REMS Goals ............................................................. 6 Additional Questions.............................................................................................. 11 4.3 4.3.1 Subject Recruitment ............................................................................................... 12 Measures to Minimize Bias in the Sample............................................................. 13 5. 5.1.1 5.1.2 5.1.3 STUDY POPULATION ........................................................................................ 13 Sample Size ............................................................................................................ 13 Inclusion Criteria.................................................................................................... 14 Exclusion Criteria .................................................................................................. 14 6. SURVEY PROCESS ............................................................................................. 15 6.1 6.1.1 6.1.2 Screening and Survey Administration ................................................................... 15 Telephone ............................................................................................................... 15 Internet ................................................................................................................... 15 6.2 Measures to Minimize Bias in the Survey Process ................................................ 15 7. ANALYSIS ............................................................................................................ 16 8. SAFETY EVENT REPORTING ........................................................................... 17 9. PRIVACY PROTECTION AND CONFIDENTIALITY...................................... 17 LIST OF APPENDICES APPENDIX A Screening and Main Questionnaire...........................................................18 APPENDIX B SAMPLE Patient Letter of Invitation .......................................................49 FDA_3244 1. LIST OF ABBREVIATIONS BDSI CATI CI EDC ETASU FDA HIPAA IRB KAB PBM PPAF REMS SE PSP TIRF TIRF REMS TRIG UBC US BioDelivery Sciences International, Inc. Computer-Assisted Telephone Interviewing Confidence Interval Electronic Data Capture Elements to Assure Safe Use Food and Drug Administration Health Insurance Portability and Accountability Act Institutional Review Board Knowledge, Attitudes, and Behavior Pharmacy Benefits Management Patient-Prescriber Agreement Form Risk Evaluation and Mitigation Strategy Safety Event Project Specific Procedure Transmucosal Immediate Release Fentanyl TIRF REMS Access Program TIRF REMS Industry Group United BioSource Corporation United States FDA_3245 2. BACKGROUND Transmucosal Immediate Release Fentanyl (TIRF) medicines include the class of immediaterelease opioid analgesics, which are indicated only for the management of breakthrough pain in cancer patients 18 years of age or older (16 or older for Actiq® and equivalent generics) who are already receiving and tolerant to opioid therapy for their underlying persistent cancer pain. The TIRF medicines include Abstral®, Actiq®, Fentora®, Lazanda®, Onsolis®, Subsys®, and generic versions of any of these brands. The TIRF REMS Industry Group (TRIG) includes Actavis Laboratories FL, Inc.; BioDelivery Sciences International, Inc. (BDSI) (replaced Meda Pharmaceuticals on March 11, 2015); Cephalon, Inc. (a wholly-owned subsidiary of Teva Pharmaceutical Industries, Ltd.); Depomed, Inc.; Galena Biopharma, Inc.; Insys Therapeutics, Inc; Mallinckrodt Pharmaceuticals; Meda Pharmaceuticals; Mylan, Inc.; and Par Pharmaceutical, Inc. The Food and Drug Administration (FDA) has determined that a class-wide Risk Evaluation and Mitigation Strategy (REMS) is required to mitigate the risks of misuse, abuse, addiction, overdose and serious complications due to medication errors with the use of TIRF medicines. The TIRF REMS Access Program (hereafter referred to as TIRF REMS) was approved by the FDA on December 28, 2011. The TIRF REMS consists of a Medication Guide, Elements to Assure Safe Use (ETASU), an Implementation System, and a Timetable for Submission of Assessments of the REMS. The goals of the TIRF REMS are to mitigate the risk of misuse, abuse, addiction, overdose, and serious complications due to medication errors by: 1. Prescribing and dispensing TIRF medicines only to appropriate patients, which includeincludes use only in opioid-tolerant patients 2. Preventing inappropriate conversion between TIRF medicines 3. Preventing accidental exposure to children and others for whom it was not prescribed 4. Educating prescribers, pharmacists, and patients on the potential for misuse, abuse, addiction, and overdose of TIRF medicines An important component of the TIRF REMS assessment is the conduct of quantitative evaluation surveys to assess patients’ and caregivers’ knowledge, attitudes, and behavior (KAB) regarding the safe use of TIRF medicines as described in the product-specific Medication Guide. This protocol will describe the administration of the surveys that will be conducted among patients who are treated with TIRF medicines, or their caregivers. Data from the surveys, together with other REMS evaluation metrics, will be used to determine whether changes need to be made to the REMS processes and/or educational materials to make them more effective in achieving the goals of the REMS. FDA_3246 The surveys will be implemented so that data will be available for inclusion in the REMS Assessment Reports that will be submitted to the FDA at 12 months after approval of the TIRF REMS and annually thereafter. 3. OBJECTIVES OF THE EVALUATION SURVEY The evaluation survey will use a questionnaire to document the level of knowledge and assess the attitudes and behavior of patients around the following key information and risk messages communicated through the REMS: 1) TIRF medicines can cause life-threatening breathing problems that can lead to death. 2) Patients should not take TIRF medicines if they are not opioid tolerant. 3) TIRF medicines should be taken exactly as prescribed by the healthcare provider. 4) Patients should not switch from onea TIRF medicine to another medicine that contains fentanyl without talking to a healthcare provider. 5) Patients should nevernot give TIRF medicines to anyone else even if they have the same symptoms. 6) TIRF medicines should be stored in a safe place away from children and properly disposed. The survey will also include questions about whether patients received, read, and understood the product-specific Medication Guide and Patient-Prescriber Agreement Form (PPAF). 4. METHODS The survey was designed in collaboration between the TRIG and United BioSource Corporation (UBC), and will be administered by UBC. 4.1 Qualitative Research on the Survey Qualitative research to test patient comprehension was performed on the patient survey in 2012. Findings were incorporated into the survey prior to implementation of Wave 1. 4.2 Survey Design This survey will be conducted among a sample of patients or their caregivers who have filled a prescription for a TIRF medicine within the past 4 months (120 days) prior to survey launch. Respondents who have participated in a previous wave of the TIRF REMS KAB Surveysurvey will not be eligible to participate in subsequent survey waves. FDA_3247 The survey will be administered using the following modalities: • Self-administered, online through a secure website • Telephone surveys facilitated by a trained interviewer from the Survey Coordinating Center using a computer-assisted telephone interviewing (CATI) program The survey will begin with screening questions to confirm respondent eligibility to participate in the survey. Completion of the entire survey is expected to take approximately 20 minutes. The survey included in Appendix B is written to reflect wording for both methods of survey administration: Internet-based and telephone administration. 4.2.1 Questions and Statements on REMS Goals The questionnaire is made up of multiple-choice, closed-ended statements or questions (the majority of which use true/false or yes/no dichotomous response options), and open-ended questions. These will evaluate current knowledge, attitudes, and behavior regarding the key risk messages noted in Section 3. The survey is written to follow principles of health literacy and readability. Questionnaire items will be presented in several formats: • Statements or questions asking the respondent to indicate whether the statement or question is true or false, or if they do not know the answer (there is a similar set of statements and questions that use “yes,” “no,” or “I don’t know” as potential response options); • Statements or questions asking the respondent to choose from a defined list of possible statements or answers; and • Questions allowing for the respondent to provide information about when, where and from whom they obtained a Medication Guide, as well as to list questions they have about information in the Medication Guides. Questionnaires will be analyzed to determine patient understanding of each key risk message. For statements or questions that use “true” or “yes” vs. “false” or “no” response options, the desired response for the key risk messages is generally “true” or “yes” indicating knowledge of, or behavior in accordance with, the objectives of the REMS. However, some questions are formatted to have the respondent disagree with the statement as written by providing response options of “false” or “no” to avoid having the same affirmative answer for all desired responses. REMS statements, corresponding questions, and desired responses covering the key risk messages are identified below and can be found in the complete survey questionnaire FDA_3248 (Appendix A). For better readability, the patient questions, only, are presented in the key risk messages tables. Caregiver questions are presented in Appendix A. FDA_3249 Key Risk Message 1: TIRF medicines can cause life-threatening breathing problems that can lead to death. Question No. Question Desired Responseresponse 13 Please answer True, False, or I don’t know for each statement about the TIRF medicine that was most recently prescribed for you. 13d TIRF medicines can cause life-threatening breathing problems that can lead to death. TRUE Key Risk Message 2: Patients should not take TIRF medicines if they are not opioid tolerant. Question No. Question Desired Responseresponse Please answer True, False, or I don’t know for the following statement: 11 12 12a 13 13b TIRF medicines should only be taken by cancer TRUE patients who are opioid tolerant. Please answer True, False, or I don’t know for each of the following statements. Opioid tolerant means that a patient is already taking other opioid pain medicines around-theTRUE clock and their body is used to these medicines. Please answer True, False, or I don’t know for each statement about the TIRF medicine that was most recently prescribed for you. It is OK for patients to take TIRF medicines for FALSE headache pain. FDA_3250 Key Risk Message 3: TIRF medicines should be taken exactly as prescribed by the healthcare provider. Question No. Question Desired Responseresponse 10 For which of the following conditions should you use a TIRF medicine? 10a Headache or migraine pain NO 10b Breakthrough pain from cancer YES 10c Dental pain NO 10d Pain after surgery NO 10e 12 12b 13/17 13c 13b 17b Long-lasting pain not from cancer, like arthritis NO joint pain Please answer True, False, or I don’t know for each of the following statements. AIf a patient must stop taking their TIRF medicine if they stop taking their stops taking around-theTRUE clock opioid pain medicine, they must also stop taking the TIRF medicine. Please answer True, False, or I don’t know for each statement about the TIRF medicine that was most recently prescribed for you. TIRF medicines should be taken exactly as TRUE prescribed by the doctor. It is OK for patients to take TIRF medicines for FALSE headache pain. It is OK to take TIRF medicines for short-term FALSE pain that will go away in a few days. Key Risk Message 4: Patients should not switch from onea TIRF medicine to another medicine that contains fentanyl without talking to a healthcare provider. Question No. 12 12c Question Desired Responseresponse Please answer True, False, or I don’t know for each of the following statements. It is safe to switch to another medicine that contains fentanyl without talking to a healthcare FALSE provider first. FDA_3251 Formatted: English (U.K.) Fonnatted: Space After: 12 pt, Line spacing: At least 14 pt Key Risk Message 5: Patients should nevernot give TIRF medicines to anyone else even if they have the same symptoms. Question Question No. 12 12d 17 17a Desired Responseresponse Please answer True, False, or I don’t know for each of the following statements. A patient may give TIRF medicines to another person if they have the same symptoms as the FALSE patient. Please answer True, False, or I don’t know for each statement about the TIRF medicine that was most recently prescribed for you. Selling or giving away TIRF medicines is against TRUE the law. Key Risk Message 6: TIRF medicines should be stored in a safe place away from children and properly disposed. Question Question No. 13/17 13a 17c 17e 14 4.2.2 Desired Responseresponse Please answer True, False, or I don’t know for each statement about the TIRF medicine that was most recently prescribed for you. TIRF medicines should be stored in a safe TRUE place out of the reach of children. TIRF medicines must be disposed of as described in the specific product’s TRUE Medication Guide. A TIRF medicine can cause an overdose TRUE and death in any child who takes it. What should you do if an adult who has not Get emergency help right been prescribed a TIRF medicine takes a away. TIRF medicine? (Please select one.) Additional Questions Questions about the requirements of the TIRF REMS, and receipt and understanding of the Medication Guides and PPAF will be asked after the key risk message questions, and will be followed by the collection of demographic information at the completion of the survey. FDA_3253 4.3 Subject Recruitment A random sample of patients who are passively enrolled in the TIRF REMS Access Program and have received a TIRF medicine in the previous 4 months (120 days) will be invited to participate via an invitation letter. Address verification is required on these data due to the limited data points collected through the PPAF. In order to obtain this additional information a public records database will be used and those data combined with the TIRF REMS Access Program data will be used to distribute those invitations to the select patient population. Additional patients will be identified for participation throughPatients will be recruited through a direct letter program. Patients will be invited through a network of national pharmacies and/or a pharmacy benefits management (PBM) partner, which will provide a broad demographic coverage and include patients in 49 states. Through useLeveraging one or more of these sourcespartners, a list will be created of patients who have filled a prescription for a TIRF medicine within 4 months (120 days) prior to survey launch (first prescriptions and refills). Patients in this list will be invited to participate in the survey through an invitation letter (Appendix B). The letter will be sent from the Survey Coordinating Center and) mailed directly to the patients on UBC letterhead (for the patients being invited by way of the TIRF REMS Access Program database and the public record database)the pharmacy or the PBM’s letterhead at the corporate level (for those patients being recruited through the PBM). Both invitation letters will be mailed via the United States (US) Postal Service. The invitation will indicate that participants will receive a $50 gift card for completing the survey. Each invitation will also include a unique code and directions for accessing the survey either via the Internet or by telephone through an interviewer at the Survey Coordinating Center. The unique code will be used to identify the manufacturer of the most recent TIRF prescription that the patient filled. A sample of patients who have filled a prescription for a TIRF medicine within the 4 months (120 days) prior to survey launch will be chosen from the TIRF REMS Access Program databasepharmacy partner’s and/or PBM’s database. This sampling approach will be used to create several batches of survey invitations. The overall number of unique patients and the duration of the survey period will dictate the size and number of invitation batches. If the required number of completed surveys is not achieved within a reasonable time frame, a second mailing will be sent to non-respondents from the original batch mailing and initial invitations will be sent to patients in the second batch. If the required number of completed surveys is still not achieved within a reasonable time frame, reminder letters will be sent to the patients in the second batch and initial invitations will be sent to the third batch of patients. If these efforts do not result in the required number of surveys within a reasonable time frame, then a new sample of patients may be selected if available. The intervals for sending reminder invitations to non-responders and for selecting a new sample will be condensed as necessary based on the actual rate of survey accrual relative to the proximity of the target survey close date. All respondents who complete the survey and who provide their contact information will be mailed a $50 gift card to thank them for their participation. The mailing will include a thank FDA_3254 you letter, a copy of the product-specific Medication Guide, and a copy of the correct answers to the key risk message questions. 4.3.1 Measures to Minimize Bias in the Sample The sample of participating patients will be self-selected since respondents will voluntarily respond to the invitation to participate; however, the survey recruitment strategies are intended to recruit a heterogeneous sample of patients for participation. Respondents will be offered online or telephone options for completing the survey. Multiple modalities for survey data collection allow for wider survey access to a more heterogeneous population. Respondents will be provided a unique code during the recruitment process and will be asked to provide the unique code to gain access to the online survey or when calling the Survey Coordinating Center. The code will be deactivated after use to minimize the possibility for fraud. 5. STUDY POPULATION 5.1.1 Sample Size A sample of 300 patients treated with TIRF medicines is proposed for the survey wave. The size of the sample was determined based on both practical and statistical considerations. There is no target comprehension rate specified a priori. A sample of 300 completed surveys will allow estimation of the comprehension rate for each key risk message with a moderately high degree of precision. The table below shows the precision of the estimates for level of understanding using two-sided 95% confidence intervals (CIs) obtained with the sample size of 300 completed surveys. The noted CIs are used to indicate that for any survey-estimated rate of understanding, the true population rate of understanding is at least as high as the lower limit of the 95% CI and may be as high as the upper limit of the 95% CI. FDA_3255 Table 5.1: Precision of Estimated Rates of Understanding with a Sample Size of 300 Estimated Rate of Understanding 5% 10% 15% 20% 25% 30% 35% 40% 45% 50% 55% 60% 65% 70% 75% 80% 85% 90% 95% 5.1.2 Estimated Confidence Interval 2.8% 8.1% 6.8% 14.0% 11.2% 19.6% 15.6% 25.0% 20.2% 30.3% 24.9% 35.5% 29.6% 40.7% 34.4% 45.8% 39.3% 50.8% 44.2% 55.8% 49.2% 60.7% 54.2% 65.6% 59.3% 70.4% 64.5% 75.1% 69.7% 79.8% 75.0% 84.4% 80.4% 88.8% 86.0% 93.2% 91.9% 97.2% Inclusion Criteria The following respondents are eligible to participate in the survey: • Patients who are 18 years of age or older who have filled a prescription for at least one of the TIRF medicines within 4 months (120 days) prior to survey launch • Caregivers 18 years of age or older who care for patients who have filled a TIRF medicine prescription within the past 4 months (120 days) prior to survey launch and are unable to take the survey for themselves 5.1.3 Exclusion Criteria The following respondents are not eligible to participate in the surveys: • Patients who have previously participated in the TIRF REMS KAB survey (this exclusion applies to the second and subsequent waves only) • Patients or their immediate family members who have ever worked for Actavis Laboratories FL, Inc., Anesta LLC, BioDelivery Sciences International, Inc. (BDSI),Anesta LLC, Cephalon, Inc. (a wholly-owned subsidiary of Teva Pharmaceutical Industries, Ltd.); Depomed, Inc.; Galena Biopharma; Insys Therapeutics, Inc.;; Mallinckrodt Pharmaceuticals; Meda Pharmaceuticals; Mylan, Inc.; Par Pharmaceutical, Inc.; Teva Pharmaceuticals, Ltd.; UBC; McKesson Specialty Care Solutions; RelayHealth; or the FDA. FDA_3256 6. SURVEY PROCESS 6.1 Screening and Survey Administration The questionnaire will begin with a screening module with questions to confirm patient eligibility. The entire survey is expected to take approximately 20 minutes to complete. Depending on the answers to the screening questions, survey participation could either be terminated or continued. If ineligible, respondents are immediately notified with a thank you message that survey participation has ended. If eligible, respondents are allowed to continue survey participation. The electronic data capture (EDC) system that is used for both methods of survey administration has been validated and is secure for receiving and storing survey data. The system is 21 CFR Part 11 and Health Insurance Portability and Accountability Act (HIPAA) compliant. Patient-identifying information will be stored separately from survey data. 6.1.1 Telephone The telephone survey is facilitated by a trained interviewer from the Survey Coordinating Center using a CATI program. The respondent will be required to provide a unique code to access the survey. Working from a CATI script, the interviewer will read questions or statements to the respondent and enter the responses into the EDC system. Screening and main elements of the questionnaire will be administered sequentially during the same telephone call. Telephone interviewing allows participation of respondents who do not have Internet access, or prefer to complete the survey in this manner. 6.1.2 Internet An Internet-based survey system will also be used for conducting the KAB surveys. If respondents select to participate in the survey online, they will be directed to a secured website and instructed to enter a unique code to access the survey. An Internet survey will be convenient for respondents to participate since they can complete the questionnaire at any convenient time and location during the specified survey time period. 6.2 Measures to Minimize Bias in the Survey Process A number of controls will be in place to ensure the survey is conducted in a controlled and professional manner and to minimize bias. For example, a unique code will be given to each survey participant and the code will be inactivated after use to minimize fraud. Telephone interviewers are highly trained and use a standardized script to administer the survey. All questions will be programmed to ensure that questions are asked in the appropriate sequence. Skip patterns will be clearly indicated. Respondents cannot go back to a question once the question has been answered and cannot skip ahead. All questions must be answered in order to complete the survey. Response options presented in a list will be randomized to minimize positional bias. Programming will be reviewed by quality control and simulated users (User Acceptance Testing) prior to implementing the survey. FDA_3257 7. ANALYSIS Information obtained from the survey will be reported as descriptive statistics for the survey administration, study population, and the survey questions. Any free text fields will be grouped into applicable categories. Verbatim text from open-ended questions will be displayed when appropriate. The following will be reported as part of this analysis: • The number of invitations issued • The number of reminder letters • The number of respondents screened for participation • The number of respondents eligible for participation • The number of respondents who completed all questions presented to them • Description of survey participants, including: • − Type of respondent (patient/caregiver) − Age (patient/caregiver) − Gender (respondent) − Educational level (respondent) − Main language spoken at home (respondent) − Ethnicity (respondent) − Race (respondent) − Geographic region (respondent) Data from all respondents who completed all questions presented to them in the survey (“completers”) will be analyzed, including: − Frequency distribution of responses to each key risk message question. − Percent of completers selecting desired response to each question relating to each key risk message and 95% CI. FDA_3258 Measurement of understanding will be computed for each question of the key risk message individually. A secondary analysis will be conducted to determine the number of completers who answered all items correctly for the key risk message. Behavior questions will be summarized on a question-by-question basis and are not included in the analysis by key risk message. Additional analyses may be performed as needed. 8. SAFETY EVENT REPORTING The survey will be conducted via the Internet and by telephone. It is possible that a respondent may report an adverse event or other safety event experienced while taking TIRF medicines either in free text fields of the survey or while in conversation with the Survey Coordinating Center. If an event is mentioned to a Survey Coordinating Center Associate, the Associate will document the safety event and the respondent’s contact information. The respondent will also be informed that a representative from the appropriate TIRF medicine manufacturer may contact him/her if there are questions about the survey. The Internet-based questionnaires will be monitored for any comments recorded in free text fields. Information on all comments that may constitute an adverse event or other safety event will be forwarded to the appropriate TIRF medicine manufacturer as described in the Safety Event Project Specific Procedure (SE PSP). Additional detail regarding processes for adverse event reporting will be specified in the SE PSP. 9. PRIVACY PROTECTION AND CONFIDENTIALITY All data collected during the survey will be held confidential. The EDC system used for data collection encrypts all identifiable information and respondent identifiers are stored separately from the survey responses. Respondent names and addresses are collected in order to mail a $50 gift card, a Thank You Letter, a product-specific Medication Guide, and correct survey responses to key risk message questions after the survey is completed. Respondent contact information is also requested in the event a safety event is reported and a TIRF medicine manufacturer must obtain follow-up information. A respondent may be contacted only if clarification or follow-up is needed regarding a possible safety event that was mentioned to the interviewer or recorded in free text fields of the online survey. Respondents will be informed when they access the survey that they may be contacted if there are any questions about their survey responses. Respondents will be informed that their answers to the survey questions will not affect their ability to receive TIRF medicines. This protocol and survey will be reviewed and approved by a central Institutional Review Board (IRB) before administration of the survey. FDA_3259 APPENDIX A Screening and Main Questionnaire Survey Legend Formatted Table is used to indicate directions to the programmer and is set in bold. red. uppercase letters between square brackets. 0 indicates text applicable to a patient when it differs from survey text for caregivers. parents and legal guardians. indicates text applicable to parents. caregivers. and legal guardians when it differs from survey text for patients. (INTERVIEWER) is used to indicate directions to the telephone interviewer and is set in bold. blue. text between parentheses. This text appears when content is to be administered by telephonet-l-el-phene only (for example. spontaneous adverse event reporting). 0 indicates a question is worded speci?cally for administering the survey online. indicates a question is worded specifically to be read by a telephone interviewer and differs from the online text. 0 and SURVEY are used to indicate to the programmer the type of survey administration and the beginning and end of the survey or sections within the survey content. for example. ADVERSE and ADVERSE is displayed next to responses that should cause the survey to end. The following termination language will be programmed into the survey or read by the interviewer unless different language is speci?ed with the question. hank you very much for your time today. Based on your answer, you are not eligible to take this survey. We appreciate your interest in the survey. 0 is inserted before questions to indicate to the programmer that the responses should be randomized. Responses such as don?t know." ?Prefer not to answer? or ?None of the above" will always appear at the end of the randomized responses. 0 TO (Skip logic) is inserted after a response to indicate to the programmer that the survey should skip to the indicated question (for example. TO skips to Survey Legend Formatted Table question 17). Ifno skip logic is indicated the survey continues to the next question in the sequence. 0 Response options for questions that allow multiple responses must be indicated with check boxes (D). At least one option must be selected for the question to be considered answered. 0 If any response option requires text to be collected and does not need another question label. show after the response option. 0 Response options for questions that allow only one response must be indicated with radio buttons (0 If any response option requires text to be collected and does not need another question label. show after the response option. if applicable. 0 indicates to the programmer that one line should be provided for data entgg. indicates to the programmer that multiple lines should be provided for data entry (for example, two address lines). Survey Legend Formatted Table I LIST WITH STATES indicates to the programmer that the response should be a drop-down list containing the states in the table below. Alabama Georgia Alaska Guam American Hawaii 5311103 Idaho Arizona Illinois Arkansas Indiana Calrfomia Iow?a Colorado Kansas Connecticut Kentucky Delaware Louisiana District of Maine Columbia Maryland Florida Massachusetts Michigan Minnesota Mississippi Missouri Montana Nebraska Nevada New Hampshire New Jersey New Mexico New York North Carolina North Dakota Northern Mariana Islands Ohio Oklahoma Oregon Puerto Rico Rhode Island South Carolina South Dakota Tennessee Texas US Virgin Islands Utah Vermont Virginia Washington West Virginia Wisconsin Wyoming The following is used to categorize survey populations into standard geographic regions but it is not displayed in the survey. Geographic Distribution (based on address) 1: Northeast. Midwest. South. and West regions Northeast Region New England Division - ME. NH. MA. RI. CT Middle Atlantic Division - NY. NJ. PA Midwest Region East North Central Division - OH. IN. IL. MI. WI West North Central Division - MNSouth Region South Atlantic Division - DEEast South Central Division - KY. TN. AL. MS West South Central Division - AR. LA. OK. TX \Vest Mountain Division - MTPaci?c Division WA. OR. CA. AK. HI Survey Legend ?rimmed Table I The following US territories are categorized as Other: Puerto Rico. Northern Mariana Islands. US Virgin Islands. American Samoa and Guam. I 1 US. Census Bureau, last revised Friday, 27-Jul-2001 12:59:43 EDT. SURVEY ONLINE PREAIVIBLE l] Before you begin, we would like to share some important information about this survey. The Formatted: Don't adjust space between Latin survey is being conducted by UBC on behalf of the Transmucosal Immediate Release gm my: 3?13"? Space hem Fentanyl (TIRF) Risk aluation and Mitigation Strategy (REMS) Access Program REMS Access Program? or Q'Progamg sponsors of which include the makers of AbstralO? Actiqo, FentoraQ. ,OLazanda .Oasel?i?ss. ?Subsys? and the generic versions of any of these brands. These TIRF Medicines also known as rapid onset opioids (and sometimes called ?fast acting fentanyls? 1. Please note that references to the TIRF REMS Access Program in this introduction include the sponsors of the Program. as well as its retained agents or contractors. including The information collected will help the makers of TIRF Medicinesmedic?ines know if patients and their caregivers understand important information about taking these medicines. The survey will take about 20 minutes. There are no known risks to you in taking this survey. You may refuse to take part or withdraw at any time without penalty or loss of bene?ts to which you are otherwise entitled. Your answers to the questions or your decision to take part in the survey will not affect your ability to receive or take TIRF Medicinesmed-ie-ines. How We Use Your Information The terms of the TIRF REMS Access Program Patient-Prescriber Agreement Form (PPAF) 011 ?le and the Patient Privacy Notice contained therein. provide that the TIRF REMS Access Progam may receive. use: and share your health information. using a lurigue identi?er instead of your name. in order to evaluate the proper use of TIRF Medicines and report to the Food and Drug Administration (FDA) about the effectiveness of the Program. Should you choose to participate in the survey. you agree that any information you provide during the course of the smyey may be used or shared with the TIRF REMS Access Program according to these terms. Your answers to the survey questions will be combined with answers given by other people Formatted: Don?t adjust space between Latin taking the survey. All answers will be collected by UBC. compiledpu-t-teget-her and reported Ex ?Just Space hem in anonymous form to gm TIRF REMS Access Program and the Mined-mines. Your name will not be used in any report. If you are eligible to take the survey. complete all the questions, and provide your contact information, you will receive a $50 gift card for your time. Your name and address will be received only by UBC and will be used only to send you the gi? card, a Thank You Letter. a product-speci?c Medication Guide, and a copy of the correct answers to key risk message questions. a?er you complete the survey. Providing a telephone number is optional. Your telephone number will be used only if there are any questions about your answers. How We Protect Your Privacy Formatted: Don't adjust space between Latin and As?an text, Don't adjust space between We respect that the privacy of your personal information is important to you. You will not be Man text and mmbets contacted for marketing purposes based on your personal information or your answers to the survey. T_he REMS Access Progranmeedieines?ner?their earn-teeters? will 1_iot sell transfer (except in connection with reporting to the or rent your information. WWMYOUI privacy will be protected; however research survey records may be inspected by the FDA (-F-eod?me??Br-ue Manama?and a company called which 18 the Institutional Review Board that looks out for the interest of survey participants. Your choice to allow the REMS Access Progranmie?ieines to use your information is entirely voluntary, but necessary to take part in this survey. Please be assured that our contact information and 0111' individual res onses will be ke strictly con?dential. As noted above. however. information you provide will be combined with infonnation and suwey responses provided by others and shared or reported in anon ous form. artici atin in the sun'e ou acknowled and a ree that such combined anonymous data may be used by the TIRF REMS Access Program and disclosed to the FDA. By participating. you also acknowledge that the FDA and/01? IRB. may inspect the records related to this survey which may include your individual responses. If you have questions about your rights as a research participant or related concerns. you may Fonnatted: Don't adjust space between Latin - - .- - contact the IRB at . Be sure to wr1te down telephone number. 1t Will not Asian. I and nu I be displayed again. How to Learn More About This Survey If you have questions about the survey, or have any problems with the survey. please contact the Survey Coordinating Center at 1-877-3 79-3297. The information in this survey should not take the place of talking with your doctor or health care professional. If you have any questions about your condition or treatment or that of the person you care for. or if you would like more information about TIRF Medic inesmedrieines. talk to your doctor. pharmacist. or other health care professional. Formatted: Default Paragraph Font, Font: Bold Formatted: Default Paragaph Font, Font: Once you have answered a question and moved on. you cannot go back and change your Bold. English (UK) answersk Formatted: English (U.K.) Thank you for your participation in this survey. ONLINE PREAB-IBLE 1] [BEGIN PHONE PREAMBLE 1] Before you begin, we would like to share some important information about this survey. The survey is being conducted by UBC on behalf of the Transmucosal Immediate Release Fentanyl (TIRF) Risk Evaluation and Mitigation Strategy (REMS) Access Program (“TIRF REMS Access Program” or Program) sponsors of which include the makers of Abstral®, Actiq®, Fentora®, Lazanda®, Onsolis®, Subsys® and the generic versions of any of these brands. These TIRF Medicinesare Transmucosal Immediate Release Fentanyl medicines, also known as rapid onset opioids (INTERVIEWER: Please pause briefly) (and sometimes called “fast acting fentanyls”) or TIRF Medicines. Please note that references to the TIRF REMS Access Program in this introduction include the sponsors of the Program, as well as its retained agents or contractors, including UBC medicines. (INTERVIEWER: Pronounce “TIRF,” then spell out T-I-R-F). The information collected will help the makers of TIRF Medicinesmedicines know if patients and their caregivers understand important information about taking these medicines. The survey will take about 20 minutes. There are no known risks to you in taking this survey. You may refuse to take part or withdraw at any time without penalty or loss of benefits to which you are otherwise entitled. Your answers to the questions or your decision to take part in the survey will not affect your ability to receive or take TIRF Medicinesmedicines. Now I would like to tell you about how your contact information will be used. The terms of the TIRF REMS Access Program Patient-Prescriber Agreement Form (PPAF) on file and the Patient Privacy Notice contained therein, provide that the TIRF REMS Access Program may receive, use, and share your health information, using a unique identifier instead of your name, in order to evaluate the proper use of TIRF Medicines and report to the Food and Drug Administration (FDA) about the effectiveness of the Program. Should you choose to participate in the survey, you agree that any information you provide during the course of the survey may be used or shared with the TIRF REMS Access Program according to these terms. Your answers to the survey questions will be combined with answers given by other people taking the survey. All answers will be collected by UBC, compiled,put together and reported in anonymous form to themanufacturers of TIRF REMS Access Program and the FDAmedicines. Your name will not be used in any report. If you are eligible to take the survey, complete all the questions, and provide your contact information, you will receive a $50 gift card for your time. Your name and address will be received only by UBC and will be used only to send you the gift card, a Thank You Letter, a product-specific Medication Guide, and a copy of the correct answers to key risk message questions, after you complete the survey. FDA_3267 Providing a telephone number is optional. Your telephone number will be used only if there are any questions about your answers. Now I would like to tell you about how we protect your privacy. We respect that the privacy of your personal information is important to you. You will not be contacted for marketing purposes based on your personal information or your answers to the survey. The Neither the manufacturers of TIRF REMS Access Programmedicines nor their contractors will not sell, transfer (except in connection with reporting to the FDA),, or rent your information. Your answers will be kept strictly confidential. Your privacy will be protected; however, research survey records may be inspected by the FDA (Food and Drug (b) (4) Administration) and a company called ., which is the Institutional Review Board (IRB) that looks out for the interest of survey participants. Your choice to allow the manufacturers of TIRF REMS Access Programmedicines to use your information is entirely voluntary, but necessary to take part in this survey. Please be assured that your contact information, and your individual responses will be kept strictly confidential. As noted above, however, information you provide will be combined with information and survey responses provided by others and shared or reported in anonymous form. By participating in the survey, you acknowledge and agree that such combined anonymous data may be used by the TIRF REMS Access Program and disclosed to the FDA. By participating, you also acknowledge that the FDA and/or IRB, may inspect the records related to this survey which may include your individual responses. If you have questions about your rights as a research participant or related concerns, you may (b) (4) contact the IRB at The information in this survey should not take the place of talking with your doctor or health care professional. If you have any questions about your condition or treatment or that of the person you care for, or if you would like more information about TIRF Medicinesmedicines, talk to your doctor, pharmacist, or other health care professional. Please feel free to ask me to repeat any questions or statements as we go through the survey. Once you have answered a question and moved on, you cannot go back and change your answers. Thank you for your participation in this survey. [END PHONE PREAMBLE 1] FDA_3268 IN 1. 2. 3. Do you agree to take part in this survey? ○ Yes ○ No [TERMINATE] Within the last 4 months (120 days),, have you filled a prescription for yourself for a transmucosal immediate release fentanyl medicine (known as “TIRF medicines”)? TIRF medicines include Abstral®, Actiq®, Fentora®, Lazanda®, Onsolis®, Subsys®, and the generic versions of any of these brands. ○ Yes [GO TO Q4] ○ No ○ I don’t know Are you a caregiver for someone who has filled a prescription for a TIRF medicine within the last 4 months (120 days)?? TIRF medicines include Abstral®, Actiq®, Fentora®, Lazanda®, Onsolis®, Subsys® and the generic versions of any of these brands. ○ Yes ○ No [TERMINATE] ○ I don’t know [TERMINATE] FDA_3270 4. 5. [PATIENT] For which TIRF medicines have you filled a prescription in the last 4 months (120 days)?? Please select all that apply. [CAREGIVER] For which TIRF medicines has the person you care for filled a prescription in the last 4 months (120 days)?? Please select all that apply. □ Abstral □ Actiq, including generic versions of Actiq □ Fentora □ Lazanda □ Onsolis □ Subsys □ Other □ I don’t know [CLEAR ALL OTHER SELECTIONS] Have you ever taken part in a survey about a TIRF medicine before? ○ Yes [TERMINATE] ○ No ○ I don’t know [TERMINATE] FDA_3271 6. 7. Which of the following groups best describes your age? ○ Under 18 [TERMINATE] ○ 18 – 29 ○ 30 – 39 ○ 40 – 49 ○ 50 – 59 ○ 60 – 69 ○ 70 or older ○ Prefer not to answer [TERMINATE] [CAREGIVER ONLY] Which of the following groups best describes the patient’s age? ○ Under 16 ○ 16 – 29 ○ 30 – 39 ○ 40 – 49 ○ 50 – 59 ○ 60 – 69 ○ 70 or older ○ Prefer not to answer [TERMINATE] FDA_3272 8. Have you or any of your immediate family members ever worked for any of the following companies or agencies? Please select all that apply. □ Actavis Laboratories FL, Inc. [TERMINATE] □ Anesta LLC [TERMINATE] □ BioDelivery Services International (BDSI) [TERMINATE] □ Cephalon, Inc. (a wholly-owned subsidiary of Teva Pharmaceutical Industries, Ltd.) [TERMINATE] □ □ Depomed, Inc. [TERMINATE] □ □ Insys Therapeutics, Inc. [TERMINATE] Galena Biopharma, Inc. [TERMINATE] Mallinckrodt Pharmaceuticals [TERMINATE] □ McKesson Specialty Care Solutions [TERMINATE] □ Meda Pharmaceuticals [TERMINATE] □ Mylan, Inc. [TERMINATE] □ Par Pharmaceutical, Inc. [TERMINATE] □ RelayHealth[TERMINATE] □ Teva Pharmaceuticals, Ltd. [TERMINATE] □ United BioSource Corporation [TERMINATE] □ FDA (Food and Drug Administration) [TERMINATE] □ □ No [IF SELECTED IN ADDITION TO OTHER RESPONSES, TERMINATE] I don’t know [TERMINATE] [END INCLUSION/EXCLUSION QUESTIONS] [BEGIN [PREAMBLE 2 - DISPLAY ON SAME PAGE WITH NEXT QUESTION] FDA_3273 ?Please answer the following questions based on information about Formatted: Font: Bold the TIRF medicine that was most recently prescribed for you. TIRF medicines include Abstralg', Actiqg, Fentora?, Lazandag', and the generic versions of /{Formatted: Font: Bold these brands. Please think of the information that you read or that was provided to you by a doctor, nurse, or other healthcare professional. If you don?t know the answers to any of the following questions please respond don?t know? instead of guessing the correct responses. JEND GIN answer the following questions based on information Formatted: English (U.K.) /{Formatted: Font: Bold about the TIRF medicine that was most recently prescribed for the patient. TIRF medicines include AbstraIQ, Actiqs', Fentora?, Lazandas', and the Formatted: Font: Bold generic versions of these brands. Please think of the information that you read or that was provided to you or to the patient by a doctor, nurse, or other healthcare professional. If you don?t know the answers to any of the following questions please respond don?t know? instead of guessing the correct responses. CARE PREABIBLE 2] Did the doctor. nurse. or other healthcare professional in the doctor?s of?ce ever talk to you about the risks and possible side effects of the IRF medicine that was most recently prescribed for you? TIRF medicines include Abstral?. Actiq?. Fentora?. Lazanda?. and the generic versions of these brands. Did the doctor. nurse. or other healthcare professional in the doctor?s of?ce ever talk to you about the risks and possible side effects of the TIRF medicine that was most recently prescribed to the patient? TIRF medicines include Abstralo. Actiqo. FentoraO. Lazandae. and the generic versions of these brandsdon?t know Formatted: Space After: 0 pt, ljne spac'ng: single 10. 10a. 10b. 10c. 10d. lOe. ll. 12. 12a. 12b. 12c. For which of the following conditions should you use a TIRF medicine? For which of the following conditions should the person you take care of use a TIRF medicine? Yes Headache or migraine pain 0 Breakthrough pain from cancer 0 0 Dental pain 0 0 Pain a?er surgery 0 Long-lasting not ?awed-by 0 cancer. like arthritis joint pain Please answer True. False. or I don?t know for the following statement: TIRF medicines should only be taken by cancer patients who are opioid tolerant. 0 True 0 False I don?t know Please answer True. False. or I don?t know for each of the following statements. ?matted Table True False I don?t . DORIIZE know Opioid tolerant means that a patient is already taking other opioid pain medicines around-the-clock and their 0 0 body is used to these medicines. AI-f?e patient must stop taking their TIRF medicine if they stop taking thei1 steps-takir-rg?around- -the-clock opioid pain medicine?WNW It is safe to switch to another medicine that contains fentanyl without talking to a healthcare provider ?rst. 12d. A patient may give TIRF medicines to another person if they have the same symptoms as the patient. ○ ○ ○ FDA_3276 13. 13a. 13b. 13c. 13d. 14. Please answer True, False, or I don?t know for each statement about the TIRF medicine that was most recently prescribed for you. Please answer True. False. or I don?t know for each statement about the TIRF medicine that was most recently prescribed for the patient. I ?t True False 0" know TIRF medicines should be stored in a safe place out of the reach of children. It is OK for patients to take TIRF medicines for headache pain. 0 TIRF medicines should be taken exactly as prescribed by the doctor. 0 TIRF medicines can cause life-threatening breathing 0 problems that can lead to death. What should you do if an adult who has not been prescribed a TIRF medicine takes a man? Tame TIRF medicine? (Please select one.) ?man?: we?: Lem 0'08 0 Wait an hour and see if the person is OK. 0 Get emergency help right away. 0 Do nothing. 0 I don?t know. 15. [PATIENT] Did the doctor, nurse, or other healthcare professional in the doctor’s office ever tell you how to use the TIRF medicine that was most recently prescribed for you? [CAREGIVER] Did the doctor, nurse, or other healthcare professional in the doctor’s office ever tell you how to use the TIRF medicine that was most recently prescribed for the patient? 16. ○ Yes ○ No ○ I don’t know [PATIENT] Did the doctor, nurse, or other healthcare professional in the doctor’s office ever tell you how to store or keep the TIRF medicine that was most recently prescribed for you? [CAREGIVER] Did the doctor, nurse, or other healthcare professional in the doctor’s office ever tell you how to store or keep the TIRF medicine that was most recently prescribed for the patient? ○ Yes ○ No ○ I don’t know FDA_3278 17. 17a. 17b. 17c. 17d. l7e. Please answer True. False. or I don?t know for each statement about the TIRF medicine that was most recently prescribed for you. Please answer True. False. or I don?t know for each statement about the TIRF medicine that was most recently prescribed for the patient. True False I don?t know Selling or giving away TIRF medicines is against the 0 law. It is OK to take TIRF medicines for short-term pain that 0 will go away in a few days. TIRF medicines must be disposed of as described in the 0 speci?c product?s Medication Guide. TIRF medicines are only available to patients through a pharmacy enrolled in a special program (called the TIRF REMS Access Program). A TIRF medicine can cause an overdose and death in any child who takes it. PREANIBLE 3 DISPLAY ON SANIE PAGE NEXT ?The next set of questions is about the Medication Guide for the Fonnatted: Font: Bold TIRF medicine that was most recently prescribed for you? Formatted: Font: Bold ?The next set of questions is about the Medication Guide for the Formatted: Font: Bold TIRF medicine that was most recently prescribed for the patient. WA Medication Guide is a paper handout that contains important information Formatted: Font: Bold about the risks associated with the use of a TIRF medicine and how to use it safely. Formatted: Font: Bold Medication Guides always include the title ?Medication Guide? followed by the name of Formatted: Font: Bold the medicine?and its pronunciation. The Medication Guide usually has a section titled ?What is the most important information I should know?? The Medication Guide is in a question?and?answer format and may be given to you by your pharmacist, doctor, or other healthcare professional. 3] 18. [PATIENT] Have you ever received a Medication Guide for the TIRF medicine that was prescribed for you? [CAREGIVER] Have you or the patient ever received a Medication Guide for the TIRF medicine that was prescribed for the patient? 19. ○ Yes ○ No [GO TO PREAMBLE 4] ○ I don’t know [GO TO PREAMBLE 4] [PATIENT] Did you receive the Medication Guide from the doctor who prescribed the TIRF medicine or someone in the doctor’s office? [CAREGIVER] Did you or the patient receive the Medication Guide from the doctor who prescribed the TIRF medicine or someone in the doctor’s office? 20. ○ Yes ○ No [GO TO Q21] ○ I don’t know [GO TO Q21] [PATIENT] When was the Medication Guide given to you? Please select all that apply. [CAREGIVER] When was the Medication Guide given to you or the patient? Please select all that apply. □ At the first appointment with the doctor who prescribed the TIRF medicine □ At the last appointment with the doctor who prescribed the TIRF medicine □ I don’t remember [CLEAR ALL OTHER SELECTIONS] FDA_3280 21. Did you receive the Medication Guide for the TIRF medicine from the pharmacy? GIVE Did you or the patient receive the Medication Guide for the TIRF medicine from the pharmacydon?t know TO 22. How frequently do you receive a Medication Guide for the TIRF medicine at the pharmacy? How frequently do you or the patient receive a Medication Guide for the TIRF medicine at the pharmacy? 0 Only with the ?rst ?lled prescription 0 Each time a prescription is ?lled Other (please specify): . Font cob" Red 0 I don?t know 23. Did you read the Medication Guidedon?t know TO 24. How much did you read? 0 All of it 0 Most of it 0 Some of it 0 I don?t know 25. 26. 27. How much of the Medication Guide did you understand? ○ All of it ○ Most of it ○ Some of it ○ None of it ○ I don’t know Did someone offer to explain the Medication Guide to you? ○ Yes ○ No [GO TO Q30] ○ I don’t know [GO TO Q30] Who offered to explain the Medication Guide to you? Please select all that apply. □ The doctor or another healthcare professional in the doctor’s office □ The pharmacist where the TIRF medicine prescription was filled □ Someone else [IF SELECTED, SHOW THE FOLLOWING ON THE SAME PAGE:] Specify(specify the type of person but not his/her name:) [FREE TEXT] 28. Did you accept the offer to have the Medication Guide explained to you? ○ Yes ○ No [GO TO Q30] ○ I don’t know [GO TO Q30] FDA_3282 29. How much of the explanation did you understandyou have any questions about the information in the Medication Guide? 0 A QUESTION 30 DISPLAY Q31 ON SAIVIE 31. What are your questions? PREANIBLE 4 DISPLAY ON PAGE AS NEXT [the next set of questions is about the Patient-Prescriber A reement Form for TIRF medicines. As a reminder, TIRF medicines include Abstral Actiqg, Fentoras, Lazandag', and the generic versions of any of these brands. The Patient-Prescriber Agreement is a form that is signed by the doctor and the patient or their caregiver. This form may also be referred to as the Prescriber-Patient Agreement. PREANIBLE 4L All of it Most of it Some of it None of it I don?t know Yes No TO PREAMBLE 4] I don?t know TO PREAB-IBLE 4] Formatted: Font: Bold, Font color: Red, English (U.K.) Formatted: Font: Bold /{Formatted: Font: Bold Fonnatted: Progranmer Direction 32. 33. 34. Did the doctor or someone in the doctor’s office explain the Patient-Prescriber Agreement Form to you? ○ Yes ○ No [GO TO Q34] ○ I don’t know [GO TO Q34] How much of the explanation did you understand? ○ All of it ○ Most of it ○ Some of it ○ None of it ○ I don’t know [PATIENT] Did you sign a Patient-Prescriber Agreement Form? [CAREGIVER] Did you or the person you are caring for sign a Patient-Prescriber Agreement Form? 35. ○ Yes ○ No [GO TO DEMOGRAPHICS PREAMBLE] ○ I don’t know [GO TO DEMOGRAPHICS PREAMBLE] Did the doctor or someone in the doctor’s office give you a copy of the signed Patient-Prescriber Agreement Form? ○ Yes ○ No ○ I don’t know FDA_3284 PREAIVIBLE DISPLAY ON SANIE PAGE AS NEXT ?There are just a few more questions to help us combine your answers with other answers /{Fonnatted: Font: Bold we have received. 36. What is your gender? 0 Male 0 Female 0 Prefer not to answer 37. What is the highest level of education you have completed? 0 Less than high school 0 Some high school 0 High school graduate/GED 0 Some college/Associate?s degree 0 Bachelor?s degree 0 Master?s degree 0 Professional or Doctoral degree 0 Prefer not to answer 38. What is the main language you speak at home? 0 0 English French Spanish Portuguese Italian German Chinese Japanese Korean Other Prefer not to answer Formatted: Space After: 0 pt, Line spac?ng: single 39. Are you Hispanic or Latino? 0 Yes 0 N0 0 Prefer not to answer 40. 41. For informational purposes only, which of the following U.S. census categories best describes your race? ○ American Indian or Alaska Native ○ Asian (origins of Far East, Southeast Asia or the Indian subcontinent) ○ Black or African American ○ Native Hawaiian or Other Pacific Islander ○ White ○ Two or more races ○ Other ○ Prefer not to answer In which state do you live? [DROP-DOWN LIST INPUT WITH STATES TABLE WITH “Prefer not to answer” AT END] FDA_3288 ADVERSE CONIPLAINT KEEP ON ONE (INTERVIEWER: Please record if respondent spontaneously reported an adverse event or product complaint during the course of this interview.) 0 Yes 0 No TO CLOSING 1] Enter Safety Adverse Event Verbatim (INTERVIEWER: Indicate to the respondent that someone may callback to ask more questions about the adverse event or product complaint that was reported.) ADVERSE 1 KEEP ON ONE You are eligible to receive a $50 gift card for your time completing the survey. In order to receive the gift card, we need to collect your name and address so that we can mail it to you. If you do not provide your name and address you will not receive the gift card for your time taking the survey. Do you agree to give us your name and mailing address so we can send your payment? 0 Yes 0 No TO CLOSING 2] FIRST NAME: LAST NAME: ADDRESS: CITY: STATE: LIST INPUT STATES Formatted: Space After: 12 pt, Keep with next ZIP: BE 5 DIGIT CLOSING 1 2 KEEP ON ONE we would also like to ask for your telephone number. Providing your telephone number is optional and it will be used to contact you only if there are questions about your survey responses. Do you want to provide your telephone number? 0 Yes 0 No TO CLOSING 3] Telephone: BE 10-DIGIT CLOSING 2] CLOSING 3] his is the end of the survey. ?If you have questions about the survey, please contact the Formatted: Font: Bold Survey Coordinating Center at 1-877-379-3297. gThank you again for your help? \[Fonnatted: Font: Bold Formatted: Font: Bold CLOSING 3 Formatted: Font: Notde SURVEY APPENDIX B SAMPLE Patient Letter of Invitation [PAT_FIRST_NAME] [PAT_LAST_NAME [CURR_DATE] [PAT_STREET_ADDR] [PAT_CITY], [PAT_STATE] [PAT_ZIP] Dear [PAT_FULL_NAME]: Thank you for choosing [pharmacy partner or PBM name] for your prescription needs. The purpose of this letter is to inform you about a voluntary research survey being conducted by [COMPANY], the maker of [BRAND_GENERIC]. The survey is part of an FDA requirement to find out if patients and/or their caregivers understand important safety information about [BRAND] and other medicines like it. The first 300 people who complete this 20-minute survey and provide their contact information will receive a $50 [pharmacy partner or PBM name] gift card from [COMPANY] to thank them for their time. You may be eligible to take part if you have taken [BRAND] and are 18 years of age or older. If you are unable to take the survey yourself, a caregiver who is 18 or older may be eligible to take the survey for you. The survey asks questions about the type of information you received about [BRAND] and where you get your medical information. If you are interested in participating and to find out if you are eligible: • • Go to www.TIRFREMSsurvey.com any time or Call 877-379-3297, 8 a.m. to 8 p.m. Eastern Time, Monday through Friday Please have this letter with you at the time you take the survey. You will be asked to provide this code prior to starting the survey: [CODE_ID]. *It is recommended that you take the survey on a desktop or laptop computer. Taking the survey on mobile devices, such as smart phones, tablets, and e-notebooks, is not supported. (over, please) FDA_3291 You are not required to take part in this survey. If you choose to take part, please be assured that your contact information and your individual responses will be kept strictly confidential. You will not be asked to identify yourself to participate in the survey. However, if you wish to receive the $50 gift card from [COMPANY], you must provide your name and contact information for delivery. Your answers to the survey questions will be combined with answers given by others, and your name will not be used in any written report or publication. Neither taking the survey nor your answers to the questions will affect your ability to receive or take [BRAND]. Sincerely, [Pharmacy partner or PBM name] [COMPANY] funded the cost of the gift card, the cost of mailing this letter and paid a fee to [pharmacy partner or PBM name]. The research study is not being conducted by [pharmacy partner or PBM name]. No information that can identify you, your medication, or your health condition will be provided by [pharmacy partner or PBM name] to [COMPANY]. This letter provides information about a drug prescribed by your doctor and is not a recommendation by [pharmacy partner or PBM name] to use a particular drug for your condition. Call [pharmacy partner or PBM name] toll free at xxx-xxx-xxxx if you do not wish to continue receiving mailings about [BRAND] from [pharmacy partner or PBM name]. FDA_3292 Patient KAB Assessment Report Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Appendix B Page 54 of 54 Patient Survey Listings and Stratified Analyses Tables FDA_3293 TRIG Page 1 of TIRF Patient/Caregiver KAB 03DEC2015 Table 1.1: Survey Administration Statistics Parameter, Number of invitations distributed 5569 Number of invitations returned as undeliverable 148 Number of reminder letters distributed 447 All Respondentsm 432 (8.0) Eligible Respondentsm 314 (72.7) Completed surveym 310 (98.7) Did not complete the surveym 4 (1.3) Respondents not eligiblemm 18 (27.3) Nmnber of respondents who accessed the survey. Percentage is based on the number of imitations distributed excluding the number of invitations retm?ned as mldeliverable. Percentage is based on the number of all respondents. 3] Percentages are based on the number of eligible respondents. Number of respondents who did not meet eligibility criteria or did not complete eligibility questions. Data Source: ADPQ Program: TSADMSAS TRIG Page 1 of 3 TIRF Patient/Caregiver KAB 03DEC2015 Table 1.2: Survey Panticipant Eligibility Results All Respondents Patients/Caregivers Question Question 1: Do you agree to take part in this survey? Yes 373 (86.3) Nom 1 (0.2) Discontinued 58 (13.4) Question 2: Within the last 4 months (120 days), have you filled a prescription for yourself for a transmucosal immediate release fentanyl medicine (known as medicines?)? TIRF medicines include Abstral?, Actiq?, Fentora?, Lazanda?, Subsys?, and the generic versions of any of these brands. Yes 352 (81.5) No 14 (3.2) I don't know 6 (1.4) Question not asked 1 (0.2) Discontinued 59 (13.7) Question 3: Are you a caregiver for someone who has ?lled a prescription for a TIRF medicine within the last 4 months (120 days)? TIRF medicines include Abstral?, Actiq?, Fentora?, Lazanda?, Subsys? and the generic versions of any of these brands. Yes 4 (0.9) Now 15 (3.5) I don't known] 1 (0.2) (Answered "Yes" to Question 2) 352 (81.5) Question not asked 1 (0.2) Discontinued 59 (13.7) Question 4: For which TIRF medicines have you filled a prescription in the last 4 months (120 days)? Please select all that apply. Abstral 15 (3.5) Actiq. including generic versions of Actiq 127 (29.4) Fentora 66 (15.3) Lazanda 19 (4.4) Subsys 146 (33.8) Other 15 (3.5) I don't know 1 (0.2) Data Source: ADPQ, ADTQ Program: TRIG Page 2 of 3 TIRF Patient/Caregiver KAB 03DEC2015 Table 1.2: Survey Participant Eligibility Results All Respondents Patients/Caregivers Question Question not asked 17 (3.9) Discontinued 59 (13.7) Question 5: Have you ever taken part in a survey about a TIRF medicine before? Yesm 29 (6.7) No 3 1 5 (72.9) I don't knowm 12 (2.8) Question not asked 17 (3.9) Discontinued 59 (13.7) Question 6: Which of the following groups best describes your age? Under 18?] 0 18 - 29 5 (1-2) 30 - 39 20 (4.6) 40 -49 66 (15.3) 50 - 59 132 (30.6) 60 - 69 76 (17.6) 70 or older 16 (3.7) Prefer not to answerll] 0 Question not asked 58 (13.4) Discontinued 59 (13.7) Question 7: Which of the following groups best describes the patient?s age?[31 Under (0-(0-5) 70 or older 1 (0.2) Prefer not to answerm 0 Data Source: ADPQ, ADTQ Program: TRIG TIRF Patient/Caregiver KAB Table 1.2: Survey Participant Eligibility Results All Respondents Page 3 of 3 03DEC2015 Question Patients/Caregivers Question not asked 369 (85.4) Discontinued 59 (13.7) Question 8: Have you or any of your immediate family members ever worked for any of the following companies or agencies? Please select all that apply. Actavis Laboratories FL. Incl? Anesta BioDelivery Services International ephalon. Inc. (a wholly-ovmed subsidiary of Teva Phannaceutical Industries p?n A Depomed. Inc.[l] Galena Biopharma. Incl? Insys Therapeutics. Inom Mallinckrodt Pharmaceuticalsm McKesson Specialty Care Solutionsm Mylan. Inc.? Par Pharmaceutical. 111cm Teva Pham1aceuticals. United BioSource Corporationm FDA (Food and Drug Administration)m 0 NOW 314 (72.7) I don't known] 0 Question not asked 58 (13.4) Discontinued 59 (13.7) Ineligible to participate in the survey. Question not asked due to termination response from a previous question or skip pattern. 3] Only caregivers are asked this question. Ineligible to participate in the survey if selected in addition to other responses. Note: Respondents who discontinued the survey before completing all eligibility questions Without being identi?ed as ineligible in any of the pren'ous questions are comlted as discontinued. Once a respondent is counted as discontinued. they will count as discontinued in all subsequent eligibility questions. Data Source: ADPQ, ADTQ Program: TRIG Page 1 of 1 TIRF Patient/Caregiver KAB 03DEC2015 Table 1.3: Time to Complete Survey Completed Surveys Telephone Internet Total Summary Statistic (minutes) 1 16 194 310 Mean (SD) 21.69 (9.062) 14.42 (8.677) 17.14 (9.487) Minimum 14. 1 4. 5 4. 5 Median 19.61 12.81 16.47 Maxinnun 102.3 85.8 102.3 Category, 11 0 to <5 Minutes 0 2 2 5 to <10 Minutes 0 52 52 10 to <15 Minutes 1 81 82 15 to <20 Minutes 68 30 98 20 to <25 Minutes 31 12 43 25 to <30 Minutes 7 9 16 30 Minutes or more 9 8 17 Data Source: ADPQ Program: TRIG TIRF Patient/Caregiver KAB Page 1 of 3 03DEC2015 Table 2: Description and Representativeness of Eligible Patients/Caregivers Completed Surveys Patients/Caregivers Question 11 Respondent's age based on Question 6: Which of the following groups best describes your age? 18 - 29 5 (1.6) 30 - 39 19 (6.1) 40 - 49 65 (21.0) 50 - 59 129 (41.6) 60 - 69 76 (24.5) 70 or older 16 (5.2) Patient's age based on Question 6/7: Which of the following groups best describes your age/the patient's age? Under 16 0 16 - 29 5 (1.6) 30 - 39 19 (6.1) 40 - 49 65 (21-0) 50 - 59 128 (41.3) 60 - 69 77 (24.8) 70 or older 16 (5.2) Question 36: What is your gender? Male 133 (42.9) Female 176 (56.8) Prefer not to answer 1 (0.3) Question 37: What is the highest level of education you have completed? Less than high school 4 (1.3) Some high school 7 (2.3) High school graduate/GED 48 (15.5) Some college/Associates' degree 123 (39.7) Bachelor's degree 71 (22.9) Master's degree 38 (12.3) Professional or Doctoral degree 15 (4.8) Prefer not to answer 4 (1.3) Data Source: ADPQ, ADTQ Program: TDESC.SAS TRIG TIRF Patient/Caregiver KAB Page 2 of 3 03DEC2015 Table 2: Description and Representativeness of Eligible Patients/Caregivers Completed Surveys Patients/Caregivers Question 11 Question 38: What is the main language you speak at home? English 309 (99.7) French 0 Spanish 0 Portuguese 0 Italian 0 German 0 Chinese 0 Japanese 0 Korean 0 Other 0 Prefer not to answer 1 (0.3) Question 39: Are you Hispanic or Latino? Yes 9 (2.9) No 296 (95.5) Prefer not to answer 5 (1.6) Question 40: For informational purposes only, which of the following US. census categories best describes your race? American Indian or Alaska Native 3 (1.0) Asian (origins of Far East. Southeast Asia or the Indian subcontinent) 2 (0.6) Black or African American 15 (4.8) Native Hawaiian or Other Paci?c Islander 3 (1.0) White 265 (85.5) Other 4 (1.3) Prefer not to answer 11 (3.5) Two or more races 7 (2.3) Geographic Distribution (based on Question 41 In which state do you Northeast 5 1 (16.5) Midwest 61 (19.7) Data Source: ADPQ, ADTQ Program: TDESC.SAS TRIG TIRF Patient/Caregiver KAB Page 3 of3 03DEC2015 Table 2: Description and Representativeness of Eligible Patients/Caregivers Completed Surveys Patients/Caregivers Question 11 South 117 (37.7) West 81 (26.1) Other 0 Prefer not to answer 0 US Census Bureau. last revised Friday. 27-Jul-2001 12:59:43 EDT.. Geography Diw'sion. Northeast includes CT. MA. ME. NH. NJ. NY. PA. RI. and VT. Midwest includes LA. IL. IN. KS. MI. MN. MO. ND. NE. OH. SD. and WI. South includes AL. AR. DC. DE. FL. GA. KY. LA. MD. MS. NC. OK. SC. TN. TX. VA. and WV. West includes AK. AZ. CA. CO. HI. ID. MT. NM. NV. OR. UT. WA. and WY. Other includes Puerto Rico. Northern Mariana Islands. US Virgin Islands. American Samoa and Guam. Data Source: ADPQ, ADTQ Program: TDESCSAS TRIG Page 1 of TIRF Patient/Caregiver KAB 03DEC2015 Table 2a: Comparison of Survey Respondents to General Population of TIRF Users Patients Who Have Taken a TIRF Eligible/Completed Medicine in the Last Patients Caregivers 4 Months (120 days)[11 Question 11 Geographic Distributional Northeast 51 (16.5) 1811 (18.4) Midwest 61 (19.7) 1305 (13.2) South 117 (37.7) 4021 (40.8) West 81 (26.1) 2706 (27.4) Other 0 0 Prefer not to answer 0 0 Missing 0 15 (0.2) Based on data obtained from the TIRF REMS Access Program database. Based on Patient KAB Survey Question 41: US. Census Bureau. last revised Friday. 27-Jul-2001 12:59:43 EDT.. Geography Dixision. Northeast includes CT. MA ME. NH. NJ. NY. PA. RI. and VT. Midwest includes IA. IL. IN. KS. MI. MN. MO. ND. NE. OH. SD. and WI. South includes AL. AR. DC. DE. FL. GA. KY. LA. Iva. MS. NC. OK. SC. TN. TX. VA. and WV. West includes AK. AZ. CA CO. HI. ID. MT. NM. NV. OR. UT. WA. and WY. Other includes Puerto Rico. Northern Mariana Islands. US Virgin Islands. American Samoa and Guam. Note: Percentages are based on the patients and caregivers with informative data. Data Source: ADPQ, ADTQ, Program: TTIRFPOPSAS TRIG TIRF Patient/Caregiver KAB Page 1 of 4 03DEC2015 Table 3: Responses to All Questions about the Safe Use of TIRF Medicines Completed Surveys Patients/Caregivers Question 11 Question 9: Did the doctor, nurse, or other healthcare professional in the doctor?s of?ce ever talk to you about the risks and possible side effects of the TIRF medicine that was most recently prescribed for you? TIRF medicines include Abstral?, Actiq?, Fentora?, Lazanda?, Subsys?, and the generic versions of these brands. Yes 259 (83.5) No 36 (11.6) I don't know 15 (4.8) Question 10: For which of the following conditions should you use a TIRF medicine? 10a: Headache or migraine pain Yes 32 (10.3) Noll] 250 (80.6) I don't know 28 (9.0) 10b: Breakthrough pain from cancer Yesl? 212 (68.4) No 80 (25.8) I don't know 18 (5.8) 10c: Dental pain Yes 8 (2.6) Now 280 (90.3) I don't know 22 (7.1) 10d: Pain after surgery Yes 65 (21.0) Now 210 (67.7) I don't know 35 (11.3) 10e: Long-lasting pain not from cancer, like arthritis joint pain Yes 135 (43.5) Noll] 136 (43.9) I don't know 39 (12.6) Question 11: Please answer True, False, or I don't know for the following statement: TIRF medicines should only be taken by cancer patients who are opioid tolerant. Data Source: ADPQ, ADTQ Program: TEX.SAS TRIG Page 2 of 4 TIRF Patient/Caregiver KAB 03DEC2015 Table 3: Responses to All Questions about the Safe Use of TIRF Medicines Completed Surveys Patients/Caregivers Question 11 Truem 135 (43.5) False 122 (39.4) I don't know 53 (17.1) Question 12: Please answer True, False, or I don't know for each of the following statements. 12a: Opioid tolerant means that a patient is ah'eady taking other opioid pain medicines around?the?clock and their body is used to these medicines. Truem 280 (90.3) False 14 (4.5) I don't know 16 (5.2) 12b: A patient must stop taking their TIRF medicine if they stop taking their around?the?clock opioid pain medicine. Truem 122 (39.4) False 93 (30.0) I don't know 95 (30.6) 12c: It is safe to switch to another medicine that contains fentanyl without talking to a healthcare provider first. True 5 (1.6) Falsem 295 (95.2) I don't know 10 (3.2) 12d: A patient may give TIRF medicines to another person if they have the same as the patient. True 0 Falsem 308 (99.4) I don't know 2 (0.6) Question 13: Please answer True, False, or I don't know for each statement about the TIRF medicine that was most recently prescribed for you. 13a: TIRF medicines should be stored in a safe place out of the reach of children. Truem 309 (99.7) False 1 (0.3) I don't know 0 13b: It is OK for patients to take TIRF medicines for headache pain. Data Source: ADPQ, ADTQ Program: TEX.SAS TRIG TIRF Patient/Caregiver KAB Page 3 of 4 03DEC2015 Table 3: Responses to All Questions about the Safe Use of TIRF Medicines Completed Surveys Patients/Caregivers Question 11 True 20 (6.5) Falsem 232 (74.8) I don't know 58 (18.7) 13c: TIRF medicines should be taken exactly as prescribed by the doctor. Truem 310 (100.0) False 0 I don't know 0 13d: TIRF medicines can cause life?threatening breathing problems that can lead to death. Truem 285 (91.9) False 3 (1.0) I don't know 22 (7.1) medicine? (Please select one.) Question 14: What should you do if an adult who has not been prescribed a TIRF medicine takes a TIRF Wait an hour and see if the person is OK. 6 (1.9) Get emergency help right away? 273 (88.1) Do nothing. 1 (0.3) I don't know. 30 (9.7) to use the TIRF medicine that was most recently prescribed for you? Question 15: Did the doctor, nurse, or other healthcare professional in the doctor?s of?ce ever tell you how Yes 296 (95.5) No 9 (2.9) I don't know 5 (1.6) to store or keep the TIRF medicine that was most recently prescribed for you? Question 16: Did the doctor, nurse, or other healthcare professional in the doctor?s office ever tell you how Yes 255 (82.3) No 49 (15.8) I don't know 6 (1.9) was most recently prescribed for you. Question 17: Please answer True, False, or I don't know for each statement about the TIRF medicine that 17a: Selling or giving away TIRF medicines is against the law. Data Source: ADPQ, ADTQ Program: TEX.SAS TRIG TIRF Patient/Caregiver KAB Page 4 of 4 03DEC2015 Table 3: Responses to All Questions about the Safe Use of TIRF Medicines Completed Surveys Patients/Caregivers Question 11 Truem 306 (98.7) False 2 (0.6) I don't know 2 (0.6) 17b: It is OK to take TIRF medicines for short?term pain that will go away in a few days. True 13 (4.2) Falsem 267 (86.1) I don't know 30 (9.7) 17c: TIRF medicines must be disposed of as described in the speci?c product?s Medication Guide. 1] Truel 299 (96.5) False 2 (0.6) I don't know 9 (2.9) (called the TIRF REMS Access Program). 17d: TIRF medicines are only available to patients through a pharmacy enrolled in a special program True 236 (76.1) False 8 (2.6) I don't know 66 (21.3) 17e: A TIRF medicine can cause an overdose and death in any child who takes it. Truem 289 (93.2) False 2 (0.6) I don't know 19 (6.1) Correct response. Data Source: ADPQ, ADTQ Program: TEX.SAS TRIG TIRF Patient/Caregiver KAB Page 1 of 3 03DEC2015 Table 4: Responses to Questions about TIRF Educational Materials Completed Surveys Question Patients/Caregivers Question 18: Have you ever received a Medication Guide for the TIRF medicine that was prescribed for you? Yes 298 (96.1) No 7 (2.3) I don't know 5 (1.6) someone in the doctor's office?!? Question 19: Did you receive the Medication Guide from the doctor Who prescribed the TIRF medicine or Yes 174 (58.4) No 106 (35.6) I don't know 18 (6.0) (Answered "No" or don?t know" to Question 18) 12 Question 20: When was the Medication Guide given to you? Please select all that apply.m At the ?rst appointment with the doctor who prescribed the TIRF medicine 146 (83.9) At the last appointment with the doctor who prescribed the TIRF medicine 23 (13.2) I don't remember 24 (13.8) (answered "No" or don 't know" to Question 18 or 19) 136 Question 21: Did you receive the Medication Guide for the TIRF medicine from the pharmacy?m Yes 250 (83.9) No 33 (11.1) I don't know 15 (5.0) (Answered "No" or "1 don?t know" to Question 18) 12 pharmacy?m Question 22: How frequently do you receive a Medication Guide for the TIRF medicine at the Only with the ?rst ?lled prescription 8 (3.2) Each time a prescription is ?lled 230 (92.0) Other (please specify):m 3 (1.2) I don't know 9 (3.6) (Answered "No" or don?t know" to Question 18 or 21) 60 Question 23: Did you read the Medication Guide?m Yes 287 (96.3) Data Source: ADPQ, ADTQ Program: TEDUCSAS TRIG TIRF Patient/Caregiver KAB Page 2 of 3 03DEC2015 Table 4: Responses to Questions about TIRF Educational Materials Completed Surveys Patients/Caregivers Question 11 No 8 (2.7) I don't know 3 (1.0) (Answered "No" or don?t know" to Question 18) 12 Question 24: How much did you read?[11 All ofit 198 (69.0) Most of it 75 (26.1) Some of it 13 (4.5) I don't know 1 (0.3) (Answered "No" or Question 18 or 23) 23 Question 25: How much of the Medication Guide did you understand?m All ofit 155 (54.0) Most of it 108 (37.6) Some of it 23 (8.0) None of it 0 I don't know 1 (0.3) (Answered "No" or "1 don?t know" to Question 18 or 23) 23 Question 26: Did someone offer to explain the Medication Guide to you(37.2) I don't know 16 (5.4) (Answered "No" or don?t know" to Question 18) 12 Question 27: Who offered to explain the Medication Guide to you? Please select all that apply.m The doctor or another healthcare professional in the doctor's of?ce 123 (71.9) The pharmacist where the TIRF medicine prescription was ?lled 127 (74.3) Someone elsep] 15 (8.8) (Answered "No" or don't know" to Question 18 or 26) 139 Question 28: Did you accept the offer to have the Medication Guide explained to Yes 1 19 (69.6) Data Source: ADPQ, ADTQ Program: TEDUCSAS TRIG TIRF Patient/Caregiver KAB Page 3 of 3 03DEC2015 Table 4: Responses to Questions about TIRF Educational Materials Completed Surveys Patients/Caregivers Question 11 No 49 (28.7) I don't know 3 (1.8) (Answered "No" or don?t know" to Question 18 or 26) 139 Question 29: How much of the explanation did you understand?m All ofit 92 (77.3) Most of it 25 (21.0) Some of it 2 (1.7) None of it 0 I don't know 0 (Answered "No" or don?t know" to Question 18, 26 or 28) 191 Question 30: Did you or do you have any questions about the information in the Medication Guide?m Yesw 16 (5.4) No 277 (93.0) I don?t know 5 (1.7) (Answered "No" or don't know" to Question 18) 12 Percentages are calculated based on the sample presented with this question because of skip logic in the survey. Verbatim texts for question 22 (Other frequency of receiw'ng a Medication Guide in the phannacy) are presented in Listing 1. Verbatim texts for question 27 (Other type of person explaining Medication Guide) are presented in Listing 2. Verbatim texts for questions about the Medication Guide are presented in Listing 3. Data Source: ADPQ, ADTQ Program: TEDUCSAS TRIG TIRF Patient/Caregiver KAB Page 1 of 03DEC2015 Table 5: Responses to Questions about the Patient-Prescriber Agreement Form - Completed Surveys Patients/Caregivers (N =3 10) Question 11 Form to you? Question 32: Did the doctor or someone in the doctor?s of?ce explain the Patient-Prescriber Agreement Yes 256 (82.6) No 27 (8.7) I don't know 27 (8.7) Question 33: How much of the explanation did you understand?[11 All of it 204 (79.7) Most ofit 44 (17.2) Some of it 4 (1.6) None of it 1 (0.4) I don't know 3 (1.2) (Armrered "No" or don?t know" to Question 32) 54 Question 34: Did you sign a Patient?Prescriber Agreement Form? Yes 248 (80.0) No 13 (4.2) I don't know 49 (15.8) Patient?Prescriber Agreement Form?m Question 35: Did the doctor or someone in the doctor?s of?ce give you a copy of the signed Yes 180 (72.6) No 2 7 (10. 9) I don't know 41 (16. 5) (Answered "No" or don?t know" to Question 34) 62 Percentages are calculated based 011 the sample presented with this question because of skip logic in the sun'ey. Data Source: ADPQ, ADTQ Program: TPPAFSAS 0 TRIG Page 1 of TIRF Patient/Caregiver KAB 03DEC2015 Table 6.1: Primary Analysis of Responses to Questions Linked to Key Risk Message #1 - Completed Surveys Key Risk Message TIRF medicines can cause life-threatening breathing problems that can lead to death. Patients/Caregivers Question 11 [95% Question 13: Please answer True, False, or I don't know for each statement about the TIRF medicine that was most recently prescribed for you. 13d: TIRF medicines can cause life?threatening breathing problems that can lead to death. Truem 285 (91.9) [88.3 - 94.7] False 3 (1.0) I don't know 22 (7.1) 95% exact two-sided con?dence intervals are calculated using the Clopper-Pearson method. Correct response. Data Source: ADPQ, ADTQ Program: 1 TRIG TIRF Patient/Caregiver KAB Page 1 of 1 03DEC2015 Table 6.1.3: Responses to Questions Linked to Key Risk Message #1 by Modality to Complete Survey Completed Surveys Key Risk Message TIRF medicines can cause life-threatening breathing problems that can lead to death. Modality to Complete Survey Internet Telephone Question 11 [95% 11 [95% Question 13: Please answer True, False, or I don't know for each statement about the TIRF medicine that was most recently prescribed for you. 13d: TIRF medicines can cause life?threatening breathing problems that can lead to death. Truem 177 (91.2) [86.3 - 94.8] 108 (93.1) [86.9 - 97.0] False 3 (1.5) 0 I don't know 14 (7.2) 8 (6.9) 95% exact two-sided con?dence intervals are calculated using the Clopper-Pearson method. Conect response. Data Source: ADPQ, ADTQ Program: TRIG Page 1 of TIRF Patient/Caregiver KAB 03DEC2015 Table 6.1.4: Responses to Questions Linked to Key Risk Message #1 by Highest Level of Education - Completed Suweys Key Risk Message TIRF medicines can cause life-threatening breathing problems that can lead to death. Highest Level of Education Professional or GED or less College or Doctoral Degree Question 11 [95% 11 [95% 11 [95% 11 [95% Question 13: Please answer True, False, or I don't know for each statement about the TIRF medicine that was most recently prescribed for you. 13d: TIRF medicines can cause life-threatening breathing problems that can lead to death. Truem 56 (88.9) [78.4 - 95.4] 113 (91.9) [85.6 - 96.0] 102 (93.6) [87.2 - 97.4] 14 (93.3) [68.1 - 99.8] False 0 1 (0.8) 2 (1.8) 0 I don't know 7 (11.1) 9 (7.3) 5 (4.6) 1 (6.7) 95% exact two-sided con?dence intervals are calculated using the Clopper-Pearson method. Correct response. Note: or less" includes "Less than high school." "Some high school." "High school graduate/GED." or "Prefer not to answer." "College" includes "Some college/Associate's degree." or includes "Bachelor's degree" and "Master's degree." "Professional or Doctoral degree" includes "Professional or Doctoral degree." Data Source: ADPQ, ADTQ Program: 3 TRIG Page 1 of 1 TIRF Patient/Caregiver KAB 03DEC2015 Table 6.1.5: Responses to Questions Linked to Key Risk Message #1 by Age Group of Respondent - Completed Surveys Key Risk Message TIRF medicines can cause life-threatening breathing problems that can lead to death. Age Group of Respondent older Question [95% 11 [95% 11 [95% [95% cum Question 13: Please answer True, False, or I don't know for each statement about the TIRF medicine that was most recently prescribed for you. 13d: TIRF medicines can cause life-threatening breathing problems that can lead to death. Truem 24 (100.0) [85.8 - 100.0] 59 (90.8) [81.0 - 96.5] 118 (91.5) [85.3 - 95.7] 84 (91.3) [83.6 - 96.2] False 0 0 2 (1.6) 1 (1.1) I don't know 0 6 (9.2) 9 (7.0) 7 (7.6) 95% exact two-sided con?dence intervals are calculated using the Clopper-Pearson method. Conect response. Data Source: ADPQ, ADTQ Program: TRIG Page 1 of TIRF Patient/Caregiver KAB 03DEC2015 Table 7.1: Primary Analysis of Responses to Questions Linked to Key Risk Message #2 - Completed Surveys Key Risk Message Patients should not take TIRF medicines if they are not opioid tolerant. Patients/Caregivers Question 11 [95% Question 11: Please answer True, False, or I don't know for the following statement: TIRF medicines should only be taken by cancer patients who are opioid tolerant. Truem 135 (43.5) [38.0 - 49.3] False 122 (39.4) I don't know 53 (17.1) Question 12: Please answer True, False, or I don't know for each of the following statements. 12a: Opioid tolerant means that a patient is ah?eady taking other opioid pain medicines around?the?clock and their body is used to these medicines. Truem 280 (90.3) [86.5 - 93.4] False 14 (4.5) I don't know 16 (5.2) 95% exact two-sided con?dence intervals are calculated using the Clopper-Pearson method. Correct response. Data Source: ADPQ, ADTQ Program: 5 TRIG TIRF Patient/Caregiver KAB Page 1 of 03DEC2015 Table 7.1.3: Responses to Questions Linked to Key Risk Message #2 by Modality to Complete Survey Completed Suweys Key Risk Message Patients should not take TIRF medicines if they are not opioid tolerant. Question Modality to Complete Survey Internet Telephone (N =l94) =116) [95% "1 [95% Question 11: Please answer True, False, or I don't know for the following statement: TIRF medicines should only be taken by cancer patients who are opioid tolerant. Truem 94 (48.5) [41.2 - 55.7] 41 (35.3) [26.7 - 44.8] False 75 (38.7) 47 (40.5) I don't know 25 (12.9) 28 (24.1) Question 12: Please answer True, False, or I don't know for each of the following statements. 12a: Opioid tolerant means that a patient is ah?eady taking other opioid pain medicines around?the?clock and their body is used to these medicines. Truem 179 (92.3) [87.6 - 95.6] 101 (87.1) [79.6 - 92.6] False 8 (4.1) 6 (5.2) I don't know 7 (3.6) 9 (7.8) 95% exact two-sided con?dence intervals are calculated using the Clopper-Pearson method. Correct response. Data Source: ADPQ, ADTQ Program: 6 TRIG TIRF Patient/Caregiver KAB Page 1 of 1 03DEC2015 Table 7.1.4: Responses to Questions Linked to Key Risk Message #2 by Highest Level of Education - Completed Suweys Key Risk Message Patients should not take TIRF medicines if they are not opioid tolerant. Question GED or less [95% Highest Level of Education College [95% cull] or [95% "1 Professional or Doctoral Degree [95% Question 11: Please answer True, False, or I don't know for the following statement: TIRF medicines should only be taken by cancer patients who are opioid tolerant. Truem 25 (39.7) [27.6 - 52.8] 51 (41.5) [32.7 - 50.7] 52 (47.7) [38.1 - 57.5] 7 (46.7) [21.3 - 73.4] False 26 (41.3) 51 (41.5) 39 (35.8) 6 (40.0) Idon't know 12 (19.0) 21 (17.1) 18 (16.5) 2 (13.3) Question 12: Please answer True, False, or I don't know for each of the following statements. 12a: Opioid tolerant means that a patient is ah?eady taking other opioid pain medicines around-the?clock and their body is used to these medicines. Truem 51 (81.0) [69.1 - 89.8] 112 (91.1) [84.6 - 95.5] 104 (95.4) [89.6 - 98.5] 13 (86.7) [59.5 - 98.3] False 4 (6.3) 7 (5.7) 1 (0.9) 2 (13.3) I don't know 8 (12.7) 4 (3.3) 4 (3.7) 0 95% exact two-sided con?dence inten'als are calculated using the Clopper-Pearson method. Correct response. Note: or less" includes "Less than high school." "Some high school." "High school graduate/GED." or "Prefer not to answer." "College" includes "Some college/Associate's degree." or includes "Bachelor's degree" and "Master's degree." "Professional or Doctoral degree" includes "Professional or Doctoral degree." Data Source: ADPQ, ADTQ Program: 7 TRIG Page 1 of TIRF Patient/Caregiver KAB 03DEC2015 Table 7.1.5: Responses to Questions Linked to Key Risk Message #2 by Age Group of Respondent - Completed Surveys Key Risk Message Patients should not take TIRF medicines if they are not opioid tolerant. Age Group of Respondent older Question [95% 11 [95% 11 [95% [95% cum Question 11: Please answer True, False, or I don't know for the following statement: TIRF medicines should only be taken by cancer patients who are opioid tolerant. Truem 14 (58.3) [36.6 - 77.9] 27 (41.5) [29.4 - 54.4] 60 (46.5) [37.7 - 55.5] 34 (37.0) [27.1 - 47.7] False 8 (33.3) 30 (46.2) 47 (36.4) 37 (40.2) Idon't know 2 (8.3) 8 (12.3) 22 (17.1) 21 (22.8) Question 12: Please answer True, False, or I don't know for each of the following statements. 12a: Opioid tolerant means that a patient is ah?eady taking other opioid pain medicines around-the-clock and their body is used to these medicines. Truem 23 (95.8) [78.9 - 99.9] 59 (90.8) [81.0 - 96.5] 120 (93.0) [87.2 - 96.8] 78 (84.8) [75.8 - 91.4] False 1 (4.2) 2 (3.1) 4 (3.1) 7 (7.6) I don't know 0 4 (6.2) 5 (3.9) 7 (7.6) 95% exact two-sided con?dence intervals are calculated using the Clopper-Pearson method. Correct response. Data Source: ADPQ, ADTQ Program: 8 TRIG Page 1 of TIRF Patient/Caregiver KAB 03DEC2015 Table 7.2: Secondary Analysis of Responses to Questions Linked to Key Risk Message #2 - Completed Surveys Key Risk Message Patients should not take TIRF medicines if they are not opioid tolerant. Patients/Caregivers Correct Responses 11 [95% CI]ll] 0 correct responses 24 (7.7) 1 correct response 157 (50.6) 2 correct responses 129 (41.6) [36.1 - 47.3] 95% exact two-sided con?dence intervals are calculated using the lopper-Pearson method. Data Source: ADPQ, ADTQ Program: TRIG TIRF Patient/Caregiver KAB Page 1 of 2 03DEC2015 Table 8.1: Primary Analysis of Responses to Questions Linked to Key Risk Message #3 - Completed Surveys Key Risk Message TIRF medicines should be taken exactly as prescribed by the healthcare provider. Patients/Caregivers Question 11 [95% Question 10: For which of the following conditions should you use a TIRF medicine? 10a: Headache or migraine pain Yes 32 (10.3) Now 250 (80.6) [75.8 - 84.9] I don't know 28 (9.0) 10b: Breakthrough pain from cancer Yesm 212 (68.4) [62.9 - 73.5] No 80 (25.8) I don't know 18 (5.8) 10c: Dental pain Yes 8 (2.6) Non] 280 (90.3) [86.5 - 93.4] I don't know 22 (7.1) 10d: Pain after surgery Yes 65 (21.0) 210 (67.7) [62.2 - 72.9] I don't know 35 (11.3) 10e: Long?lasting pain not from cancer, like arthritis joint pain Yes 135 (43.5) 136 (43.9) [38.3 - 49.6] I don't know 39 (12.6) Question 12: Please answer True, False, or I don't know for each of the following statements. 12b: A patient must stop taking their TIRF medicine if they stop taking their around-the-clock opioid pain medicine. Truem 122 (39.4) [33.9 - 45.0] False 93 (30.0) Data Source: ADPQ, ADTQ Program: TRIG TIRF Patient/Caregiver KAB Page 2 of 2 03DEC2015 Table 8.1: Primary Analysis of Responses to Questions Linked to Key Risk Message #3 - Completed Surveys Key Risk Message TIRF medicines should be taken exactly as prescribed by the healthcare provider. Patients/Caregivers Question 11 [95% I don't know 95 (30.6) was most recently prescribed for you. Question 13: Please answer True, False, or I don't know for each statement about the TIRF medicine that 13b: It is OK for patients to take TIRF medicines for headache pain. True 20 (6.5) Falsem 232 (74.8) [69.6 - 79.6] I don't know 58 (18.7) 13c: TIRF medicines should be taken exactly as prescribed by the doctor. Truem 310 (100.0) [98.8 - 100.0] False I don't know 0 was most recently prescribed for you. Question 17: Please answer True, False, or I don't know for each statement about the TIRF medicine that 17b: It is OK to take TIRF medicines for short-term pain that will go away in a few days. True 13 (4.2) Falsem 267 (86.1) [81.8 - 89.8] I don't know 30 (9.7) 95% exact two-sided con?dence intervals are calculated using the Clopper-Pearson method. Correct response. Data Source: ADPQ, ADTQ Program: TRIG TIRF Patient/Caregiver KAB Page 1 of 2 03DEC2015 Table 8.1.3: Responses to Questions Linked to Key Risk Message #3 by Modality to Complete Survey Completed Surveys Key Risk Message TIRF medicines should be taken exactly as prescribed by the healthcare provider. Modality to Complete Survey Internet Telephone (N =194) Question 11 [95% 11 [95% Question 10: For which of the following conditions should you use a TIRF medicine? 10a: Headache or migraine pain Yes 24 (12.4) 8 (6.9) Non] 155 (79.9) [73.6 - 85.3] 95 (81.9) [73.7 - 88.4] I don't know 15 (7.7) 13 (11.2) 10b: Breakthrough pain from cancer Yesm 140 (72.2) [65.3 - 78.3] 72 (62.1) [52.6 - 70.9] No 49 (25.3) 31 (26.7) I don't know 5 (2.6) 13 (11.2) 10c: Dental pain Yes 4 (2.1) 4 (3.4) Now 177 (91.2) [86.3 - 94.8] 103 (88.8) [81.6 - 93.9] I don't know 13 (6.7) 9 (7.8) 10d: Pain after surgery Yes 36 (18.6) 29 (25.0) Non] 136 (70.1) [63.1 - 76.5] 74 (63.8) [54.4 - 72.5] Idon't know 22 (11.3) 13 (11.2) 10e: Long?lasting pain not from cancer, like arthritis joint pain Yes 76 (39.2) 59 (50.9) New 95 (49.0) [41.7 - 56.2] 41 (35.3) [26.7 - 44.8] I don't know 23 (11.9) 16 (13.8) Question 12: Please answer True, False, or I don't know for each of the following statements. 12b: A patient must stop taking their TIRF medicine if they stop taking their around-the?clock opioid pain medicine. Truem 81 (41.8) [34.7 - 49.0] 41 (35.3) [26.7 - 44.8] Data Source: ADPQ, ADTQ Program: TRIG Page 2 of 2 TIRF Patient/Caregiver KAB 03DEC2015 Table 8.1.3: Responses to Questions Linked to Key Risk Message #3 by Modality to Complete Survey Completed Surveys Key Risk Message TIRF medicines should be taken exactly as prescribed by the healthcare provider. Modality to Complete Survey Internet Telephone Question 11 [95% 11 [95% False 56 (28.9) 37 (31.9) I don't know 57 (29.4) 38 (32.8) Question 13: Please answer True, False, or I don't know for each statement about the TIRF medicine that was most recently prescribed for you. 13b: It is OK for patients to take TIRF medicines for headache pain. True 14 (7.2) 6 (5.2) Falsem 144 (74.2) [67.5 - 80.2] 88 (75.9) [67.0 - 83.3] I don't know 36 (18.6) 22 (19.0) 13c: TIRF medicines should be taken exactly as prescribed by the doctor. Truem 194 (100.0) [98.1 - 100.0] 116 (100.0) [96.9 - 100.0] False 0 I don't know 0 0 Question 17: Please answer True, False, or I don't know for each statement about the TIRF medicine that was most recently prescribed for you. 17b: It is OK to take TIRF medicines for short-term pain that will go away in a few days. True 7 (3.6) 6 (5.2) Falsem 170 (87.6) [82.2 - 91.9] 97 (83.6) [75.6 - 89.8] I don't know 17 (8.8) 13 (11.2) 95% exact two-sided con?dence inten'als are calculated using the Clopper-Pearson method. Correct response. Data Source: ADPQ, ADTQ Program: TRIG TIRF Patient/Caregiver KAB Page 1 of 3 03DEC2015 Table 8.1.4: Responses to Questions Linked to Key Risk Message #3 by Highest Level of Education - Completed Surveys Key Risk Message TIRF medicines should be taken exactly as presclibed by the healthcare provider. Question GED or less [95% Highest Level of Education College [95% or [95% Professional or Doctoral Degree [95% Question 10: For which of the following conditions should you use a TIRF medicine? 10a: Headache or migraine pain Yes 7 (11.1) 14 (11.4) 8 (7.3) 3 (20.0) Now 49 (77.8) [65.5 - 87.3] 97 (78.9) [70.6 - 85.7] 94 (86.2) [78.3 - 92.1] 10 (66.7) [38.4 - 88.2] I don't know 7 (11.1) 12 (9.8) 7 (6.4) 2 (13.3) 10b: Breakthrough pain from cancer Yesm 44 (69.8) [57.0 - 80.8] 76 (61.8) [52.6 - 70.4] 80 (73.4) [64.1 - 81.4] 12 (80.0) [51.9 - 95.7] No 13 (20.6) 40 (32.5) 25 (22.9) 2 (13.3) I don't know 6 (9.5) 7 (5.7) 4 (3.7) 1 (6.7) 10c: Dental pain Yes 1 (1.6) 5 (4.1) 2 (1.8) 0 Non] 58 (92.1) [82.4 - 97.4] 106 (86.2) [78.8 - 91.7] 103 (94.5) [88.4 - 98.0] 13 (86.7) [59.5 - 98.3] I don't know 4 (6.3) 12 (9.8) 4 (3.7) 2 (13.3) 10d: Pain after surgery Yes 15 (23.8) 29 (23.6) 19 (17.4) 2 (13.3) Data Source: ADPQ, ADTQ Program: TRIG TIRF Patient/Caregiver KAB Page 2 of 3 03DEC2015 Table 8.1.4: Responses to Questions Linked to Key Risk Message #3 by Highest Level of Education - Completed Suweys Key Risk Message TIRF medicines should be taken exactly as presclibed by the healthcare provider. Highest Level of Education Professional or GED or less College or Doctoral Degree Question 11 [95% 11 [95% cull] [95% "1 [95% 39 (61.9) [48.8 - 73.9] 80 (65.0) [55.9 - 73.4] 81 (74.3) [65.1 - 82.2] 10 (66.7) [38.4 - 88.2] I don't know 9 (14.3) 14 (11.4) 9 (8.3) 3 (20.0) 10e: Long?lasting pain not from cancer, like arthritis joint pain Yes 28 (44.4) 56 (45.5) 45 (41.3) 6 (40.0) Non] 29 (46.0) [33.4 - 59.1] 48 (39.0) [30.4 - 48.2] 54 (49.5) [39.8 - 59.3] 5 (33.3) [11.8 - 61.6] I don't know 6 (9.5) 19 (15.4) 10 (9.2) 4 (26.7) Question 12: Please answer True, False, or I don't know for each of the following statements. 12b: A patient must stop taking their TIRF medicine if they stop taking their around-the-clock opioid pain medicine. Truem 12 (19.0) [10.2 - 30.9] 48 (39.0) [30.4 - 48.2] 54 (49.5) [39.8 - 59.3] 8 (53.3) [26.6 - 78.7] False 23 (36.5) 43 (35.0) 24 (22.0) 3 (20.0) I don't know 28 (44.4) 32 (26.0) 31 (28.4) 4 (26.7) Question 13: Please answer True, False, or I don't know for each statement about the TIRF medicine that was most recently prescribed for you. 13b: It is OK for patients to take TIRF medicines for headache pain. True 7(11.1) 8 (6.5) 2 (1.8) 3 (20.0) Falsem 43 (68.3) [55.3 - 79.4] 88 (71.5) [62.7 - 79.3] 92 (84.4) [76.2 - 90.6] 9 (60.0) [32.3 - 83.7] Data Source: ADPQ, ADTQ Program: TRIG Page 3 of 3 TIRF Patient/Caregiver KAB 03DEC2015 Table 8.1.4: Responses to Questions Linked to Key Risk Message #3 by Highest Level of Education - Completed Suiyeys Key Risk Message TIRF medicines should be taken exactly as prescribed by the healthcare provider. Highest Level of Education Professional or GED or less College or Doctoral Degree Question 11 [95% 11 [95% cull] [95% 11 [95% I don't know 13 (20.6) 27 (22.0) 15 (13.8) 3 (20.0) 13c: TIRF medicines should be taken exactly as prescribed by the doctor. Tmem 63 (100.0) [94.3 - 100.0] 123 (100.0) [97.0 - 100.0] 109 (100.0) [96.7 - 100.0] 15 (100.0) [78.2 - 100.0] False 0 0 0 0 I don't know 0 0 0 Question 17: Please answer True, False, or I don't know for each statement about the TIRF medicine that was most recently prescribed for you. 17b: It is OK to take TIRF medicines for short-term pain that will go away in a few days. True 3 (4.8) 6 (4.9) 2 (1.8) 2 (13.3) Falsem 52 (82.5) [70.9 - 90.9] 108 (87.8) [80.7 - 93.0] 98 (89.9) [82.7 - 94.9] 9 (60.0) [32.3 - 83.7] Idon't know 8 (12.7) 9 (7.3) 9 (8.3) 4 (26.7) 95% exact two-sided con?dence inten'als are calculated using the Clopper-Pearson method. Correct response. Note: or less" includes "Less than high school." "Some high school." "High school graduate/GED." or "Prefer not to answer." "College" includes "Some college/Associate?s degree." or includes "Bachelor's degree" and "Master's degree." "Professional or Doctoral degree" includes "Professional or Doctoral degree." Data Source: ADPQ, ADTQ Program: TRIG Page 1 of 3 TIRF Patient/Caregiver KAB 03DEC2015 Table 8.1.5: Responses to Questions Linked to Key Risk Message #3 by Age Group of Respondent - Completed Surveys Key Risk Message TIRF medicines should be taken exactly as prescribed by the healthcare provider. Age Group of Respondent older Question [95% 11 [95% 11 [95% 011?? [95% 011?? Question 10: For which of the following conditions should you use a TIRF medicine? 10a: Headache or migraine pain Yes 1 (4.2) 7 (10.8) 17 (13.2) 7 (7.6) Non] 20 (83.3) [62.6 - 95.3] 51 (78.5) [66.5 - 87.7] 101 (78.3) [70.2 - 85.1] 78 (84.8) [75.8 - 91.4] I don't know 3 (12.5) 7 (10.8) 11 (8.5) 7 (7.6) 10b: Breakthrough pain from cancer Yesm 19 (79.2) [57.8 - 92.9] 43 (66.2) [53.4 - 77.4] 93 (72.1) [63.5 - 79.6] 57 (62.0) [51.2 - 71.9] No 4 (16.7) 16 (24.6) 31 (24.0) 29 (31.5) I don't know 1 (4.2) 6 (9.2) 5 (3.9) 6 (6.5) 10c: Dental pain Yes 0 2 (3.1) 4 (3.1) 2 (2.2) 22 (91.7) [73.0 - 99.0] 57 (87.7) [77.2 - 94.5] 118 (91.5) [85.3 - 95.7] 83 (90.2) [82.2 - 95.4] I don't know 2 (8.3) 6 (9.2) 7 (5.4) 7 (7.6) 10d: Pain after surgery Yes 2 (8.3) 19 (29.2) 30 (23.3) 14 (15.2) Non] 20 (83.3) [62.6 - 95.3] 41 (63.1) [50.2 - 74.7] 84 (65.1) [56.2 - 73.3] 65 (70.7) [60.2 - 79.7] Data Source: ADPQ, ADTQ Program: TRIG Page 2 of 3 TIRF Patient/Caregiver KAB 03DEC2015 Table 8.1.5: Responses to Questions Linked to Key Risk Message #3 by Age Group of Respondent - Completed Surveys Key Risk Message TIRF medicines should be taken exactly as prescribed by the healthcare provider. Age Group of Respondent older Question 11 [95% 11 [95% 11 [95% c1191 [95% Idon't know 2 (8.3) 5 (7.7) 15 (11.6) 13 (14.1) 10e: Long?lasting pain not from cancer, like arthritis joint pain Yes 7 (29.2) 27 (41.5) 53 (41.1) 48 (52.2) New 15 (62.5) [40.6 - 81.2] 28 (43.1) [30.8 - 56.0] 55 (42.6) [34.0 - 51.6] 38 (41.3) [31.1 - 52.1] I don't know 2 (8.3) 10 (15.4) 21 (16.3) 6 (6.5) Question 12: Please answer True, False, or I don't know for each of the following statements. 12b: A patient must stop taking their TIRF medicine if they stop taking their around-the-clock opioid pain medicine. Truem 17 (70.8) [48.9 - 87.4] 22 (33.8) [22.6 - 46.6] 54 (41.9) [33.2 - 50.9] 29 (31.5) [22.2 - 42.0] False 4 (16.7) 25 (38.5) 43 (33.3) 21 (22.8) I don't know 3 (12.5) 18 (27.7) 32 (24.8) 42 (45.7) Question 13: Please answer True, False, or I don't know for each statement about the TIRF medicine that was most recently prescribed for you. 13b: It is OK for patients to take TIRF medicines for headache pain. True 0 7 (10.8) 9 (7.0) 4 (4.3) Falsem 19 (79.2) [57.8 - 92.9] 48 (73.8) [61.5 - 84.0] 98 (76.0) [67.7 - 83.1] 67 (72.8) [62.6 - 81.6] Idon't know 5 (20.8) 10 (15.4) 22 (17.1) 21 (22.8) 13c: TIRF medicines should be taken exactly as prescribed by the doctor. Data Source: ADPQ, ADTQ Program: TRIG Page 3 of 3 TIRF Patient/Caregiver KAB 03DEC2015 Table 8.1.5: Responses to Questions Linked to Key Risk Message #3 by Age Group of Respondent - Completed Surveys Key Risk Message TIRF medicines should be taken exactly as prescribed by the healthcare provider. Age Group of Respondent older Question 11 [95% c1111] 11 [95% '11 [95% "1 [95% 011?? Truem 24 (100.0) [85.8 - 100.0] 65 (100.0) [94.5 - 100.0] 129 (100.0) [97.2 - 100.0] 92 (100.0) [96.1 - 100.0] False 0 0 0 I don't know 0 0 0 Question 17: Please answer True, False, or I don't know for each statement about the TIRF medicine that was most recently prescribed for you. 17b: It is OK to take TIRF medicines for short-term pain that will go away in a few days. True 0 3 (4.6) 4 (3.1) 6 (6.5) Falsem 22 (91.7) [73.0 - 99.0] 59 (90.8) [81.0 - 96.5] 113 (87.6) [80.6 - 92.7] 73 (79.3) [69.6 - 87.1] I don't know 2 (8.3) 3 (4.6) 12 (9.3) 13 (14.1) 95% exact two-sided con?dence intervals are calculated using the Clopper-Pearson method. Correct response. Data Source: ADPQ, ADTQ Program: TRIG Page 1 of TIRF Patient/Caregiver KAB 03DEC2015 Table 8.2: Secondary Analysis of Responses to Questions Linked to Key Risk Message #3 - Completed Surveys Key Risk Message TIRF medicines should be taken exactly as prescribed by the healthcare provider. Patients/Caregivers Correct Responses 11 [95% 0 correct responses 0 1 correct response 3 (1.0) 2 correct responses 9 (2.9) 3 correct responses 12 (3.9) 4 correct responses 15 (4.8) 5 correct responses 40 (12.9) 6 correct responses 69 (22.3) 7 correct responses 57 (18.4) 8 correct responses 56 (18.1) 9 correct responses 49 (15.8) [11.9 - 20.4] 95% exact two-sided con?dence intervals are calculated using the Clopper-Pearson method. Data Source: ADPQ, ADTQ Program: TRIG Page 1 of TIRF Patient/Caregiver KAB 03DEC2015 Table 9.1: Primary Analysis of Responses to Questions Linked to Key Risk Message #4 - Completed Surveys Key Risk Message Patients should not switch from one TIRF medicine to another medicine that contains fentanyl without talking to a healthcare provider. Patients/Caregivers Question 11 [95% Question 12: Please answer True, False, or I don't know for each of the following statements. 12c: It is safe to switch to another medicine that contains fentanyl without talking to a healthcare provider first. True 5 (1.6) Falsep] 295 (95.2) [92.1 - 97.3] I don't know 10 (3.2) 95% exact two-sided con?dence intervals are calculated using the Clopper-Pearson method. Correct response. Data Source: ADPQ, ADTQ Program: TRIG TIRF Patient/Caregiver KAB Page 1 of 1 03DEC2015 Table 9.1.3: Responses to Questions Linked to Key Risk Message #4 by Modality to Complete Survey Completed Surveys Key Risk Message Patients should not switch from one TIRF medicine to another medicine that contains fentanyl without talking to a healthcare provider. Question Modality to Complete Survey Internet Telephone [95% 11 [95% Question 12: Please answer True, False, or I don't know for each of the following statements. 12c: It is safe to switch to another medicine that contains fentanyl without talking to a healthcare provider ?rst. True 1 (0.5) 4 (3.4) Falsem 189 (97.4) [94.1 - 99.2] 106 (91.4) [84.7 - 95.8] I don't know 4 (2.1) 6 (5.2) 95% exact two-sided con?dence intervals are calculated using the Clopper-Pearson method. Conect response. Data Source: ADPQ, ADTQ Program: TRIG Page 1 of 1 TIRF Patient/Caregiver KAB 03DEC2015 Table 9.1.4: Responses to Questions Linked to Key Risk Message #4 by Highest Level of Education - Completed Surveys Key Risk Message Patients should not switch from one TIRF medicine to another medicine that contains fentanyl without talking to a healthcare provider. Highest Level of Education Professional or GED or less College or Doctoral Degree Question [95% 11 [95% "1 [95% 11 [95% Cl] "1 Question 12: Please answer True, False, or I don't know for each of the following statements. 12c: It is safe to switch to another medicine that contains fentanyl without talking to a healthcare provider f'n'st. True 4 (6.3) 0 1 (0.9) 0 Falsem 54 (85.7) [74.6 - 93.3] 119 (96.7) [91.9 - 99.1] 107 (98.2) [93.5 - 99.8] 15 (100.0) [78.2 - 100.0] I don't know 5 (7.9) 4 (3.3) 1 (0.9) 0 95% exact two-sided con?dence inten'als are calculated using the Clopper-Pearson method. Correct response. Note: or less" includes "Less than high school." "Some high school." "High school graduate/GED." or "Prefer not to answer." "College" includes "Some college/Associate's degree." or includes "Bachelor's degree" and "Master's degree." "Professional or Doctoral degree" includes "Professional or Doctoral degree." Data Source: ADPQ, ADTQ Program: TRIG Page 1 of 1 TIRF Patient/Caregiver KAB 03DEC2015 Table 9.1.5: Responses to Questions Linked to Key Risk Message #4 by Age Group of Respondent - Completed Surveys Key Risk Message Patients should not switch from one TIRF medicine to another medicine that contains fentanyl without talking to a healthcare provider. Age Group of Respondent older Question 11 [95% 11 [95% "1 0/0) [95% 11 [95% "1 Question 12: Please answer True, False, or I don't know for each of the following statements. 12c: It is safe to switch to another medicine that contains fentanyl without talking to a healthcare provider first. True 0 (1.5) 1 (0.8) 3 (3.3) Falsem 24 (100.0) [85.8 - 100.0] 62 (95.4) [87.1 - 99.0] 126 (97.7) [93.4 - 99.5] 83 (90.2) [82.2 - 95.4] I don't know 0 2 (3.1) 2 (1.6) 6 (6.5) 95% exact two-sided con?dence intervals are calculated using the Clopper-Pearson method. Correct response. Data Source: ADPQ, ADTQ Program: TRIG Page 1 of 1 TIRF Patient/Caregiver KAB 03DEC2015 Table 10.1: Primary Analysis of Responses to Questions Linked to Key Risk Message #5 - Completed Surveys Key Risk Message Patients should never give TIRF medicines to anyone else even if they have the same Patients/Caregivers Question 11 [95% Question 12: Please answer True, False, or I don't know for each of the following statements. 12d: A patient may give TIRF medicines to another person if they have the same as the patient. True 0 Falsem 308 (99.4) [97.7 - 99.9] I don't know 2 (0.6) Question 17: Please answer True, False, or I don't know for each statement about the TIRF medicine that was most recently prescribed for you. 17a: Selling or giving away TIRF medicines is against the law. Truem 306 (98.7) [96.7 - 99.6] False 2 (0.6) I don't know 2 (0.6) 95% exact two-sided con?dence intervals are calculated using the Clopper-Pearson method. Correct response. Data Source: ADPQ, ADTQ Program: TRIG TIRF Patient/Caregiver KAB Page 1 of 1 03DEC2015 Table 10.1.3: Responses to Questions Linked to Key Risk Message #5 by Modality to Complete Survey Completed Suweys Key Risk Message Patients should never give TIRF medicines to anyone else even if they have the same Question Modality to Complete Survey Internet Telephone [95% 11 [95% Question 12: Please answer True, False, or I don't know for each of the following statements. 12d: A patient may give TIRF medicines to another person if they have the same as the patient. True 0 0 Falsem 192 (99.0) [96.3 - 99.9] 116 (100.0) [96.9 - 100.0] I don't know 2 (1.0) 0 Question 17: Please answer True, False, or I don't know for each statement about the TIRF medicine that was most recently prescribed for you. 17a: Selling or giving away TIRF medicines is against the law. Truem 192 (99.0) [96.3 - 99.9] 114 (98.3) [93.9 - 99.8] False 1 (0.5) 1 (0.9) I don't know 1 (0.5) 1 (0.9) 95% exact two-sided con?dence intervals are calculated using the Clopper-Pearson method. Conect response. Data Source: ADPQ, ADTQ Program: TRIG TIRF Patient/Caregiver KAB Page 1 of 1 03DEC2015 Table 10.1.4: Responses to Questions Linked to Key Risk Message #5 by Highest Level of Education - Completed Surveys Key Risk Message Patients should never give TIRF medicines to anyone else even if they have the same Question GED or less [95% Highest Level of Education College [95% cull] or [95% "1 Professional or Doctoral Degree [95% Question 12: Please answer True, False, or I don't know for each of the following statements. 12d: A patient may give TIRF medicines to another person if they have the same as the patient. True 0 0 0 Falsem 62 (98.4) [91.5 - 100.0] 122 (99.2) [95.6 - 100.0] 109 (100.0) [96.7 - 100.0] 15 (100.0) [78.2 - 100.0] I don't know 1 (1.6) (0.8) 0 Question 17: Please answer True, False, or I don't know for each statement about the TIRF medicine that was most recently prescribed for you. 17a: Selling or giving away TIRF medicines is against the law. Truem 62 (98.4) [91.5 - 100.0] 120 (97.6) [93.0 - 99.5] 109 (100.0) [96.7 - 100.0] 15 (100.0) [78.2 - 100.0] False 0 2 (1.6) 0 I don't know 1 (1.6) (0.8) 0 95% exact two-sided con?dence inten'als are calculated using the Clopper-Pearson method. Correct response. Note: or less" includes "Less than high school." "Some high school." "High school graduate/GED." or "Prefer not to answer." "College" includes "Some college/Associate's degree." or includes "Bachelor's degree" and "Master's degree." "Professional or Doctoral degree" includes "Professional or Doctoral degree." Data Source: ADPQ, ADTQ Program: TRIG Page 1 of 1 TIRF Patient/Caregiver KAB 03DEC2015 Table 10.1.5: Responses to Questions Linked to Key Risk Message #5 by Age Group of Respondent - Completed Surveys Key Risk Message Patients should never give TIRF medicines to anyone else even if they have the same Age Group of Respondent older Question [95% 11 [95% 11 [95% [95% cum Question 12: Please answer True, False, or I don't know for each of the following statements. 12d: A patient may give TIRF medicines to another person if they have the same as the patient. True 0 0 0 Falsep] 24 (100.0) [85.8 - 100.0] 64 (98.5) [91.7 - 100.0] 129 (100.0) [97.2 - 100.0] 91 (98.9) [94.1 - 100.0] I don't know 0 (1.5) 1 (1.1) Question 17: Please answer True, False, or I don't know for each statement about the TIRF medicine that was most recently prescribed for you. 17a: Selling or giving away TIRF medicines is against the law. Truem 24 (100.0) [85.8 - 100.0] 64 (98.5) [91.7 - 100.0] 128 (99.2) [95.8 - 100.0] 90 (97.8) [92.4 - 99.7] False 0 1 (1.5) 1 (0.8) I don't know 0 0 0 2 (2.2) 95% exact two-sided con?dence intervals are calculated using the Clopper-Pearson method. Correct response. Data Source: ADPQ, ADTQ Program: TRIG Page 1 of TIRF Patient/Caregiver KAB 03DEC2015 Table 10.2: Secondary Analysis of Responses to Questions Linked to Key Risk Message #5 - Completed Surveys Key Risk Message Patients should never give TIRF medicines to anyone else even if they have the same Patients/Caregivers Correct Responses 11 [95% 0 correct responses 0 1 correct response 6 (1.9) 2 correct responses 304 (98.1) [95.8 - 99.3] 95% exact two-sided con?dence intervals are calculated using the Clopper-Pearson method. Data Source: ADPQ, ADTQ Program: TRIG Page 1 of 1 TIRF Patient/Caregiver KAB 03DEC2015 Table 11.1: Primary Analysis of Responses to Questions Linked to Key Risk Message #6 - Completed Surveys Key Risk Message TIRF medicines should be stored in a safe place away from children and properly disposed. Patients/Caregivers Question 11 [95% Question 13: Please answer True, False, or I don't know for each statement about the TIRF medicine that was most recently prescribed for you. 13a: TIRF medicines should be stored in a safe place out of the reach of children. Truem 309 (99.7) [98.2 - 100.0] False (0.3) I don't know 0 Question 14: What should you do if an adult who has not been prescribed a TIRF medicine takes a TIRF medicine? (Please select one.) Wait an hour and see if the person is OK. 6 (1.9) Get emergency help right awaym 273 (88.1) [83.9 - 91.5] Do nothing. 1 (0.3) I don?t know. 30 (9.7) Question 17: Please answer True, False, or I don't know for each statement about the TIRF medicine that was most recently prescribed for you. 17c: TIRF medicines must be disposed of as described in the speci?c product?s Medication Guide. Truem 299 (96.5) [93.7 - 98.2] False 2 (0.6) I don't know 9 (2.9) l7e: A TIRF medicine can cause an overdose and death in any child who takes it. Truem 289 (93.2) [89.8 - 95.8] False 2 (0.6) I don't know 19 (6.1) 95% exact two-sided con?dence intervals are calculated using the lopper-Pearson method. Correct response. Data Source: ADPQ, ADTQ Program: TRIG TIRF Patient/Caregiver KAB Page 1 of 1 03DEC2015 Table 11.1.3: Responses to Questions Linked to Key Risk Message #6 by Modality to Complete Survey Completed Suweys Key Risk Message TIRF medicines should be stored in a safe place away from children and properly disposed. Question Modality to Complete Survey Internet (N =194) [95% Telephone [95% Question 13: Please answer True, False, or I don't know for each statement about the TIRF medicine that was most recently prescribed for you. 13a: TIRF medicines should be stored in a safe place out of the reach of children. Truem 193 (99.5) [97.2 - 100.0] 116 (100.0) [96.9 - 100.0] False 1 (0.5) 0 I don't know 0 0 Question 14: What should you do if an adult who has not been prescribed a TIRF medicine takes a TIRF medicine? (Please select one.) Wait an hour and see if the person is OK. 6 (3.1) 0 Get emergency help right awaym 173 (89.2) [83.9 - 93.2] 100 (86.2) [78.6 - 91.9] Do nothing. 1 (0.5) 0 I don't know. 14 (7.2) 16 (13.8) Question 17: Please answer True, False, or I don't know for each statement about the TIRF medicine that was most recently prescribed for you. 17c: TIRF medicines must be disposed of as described in the speci?c product?s Medication Guide. Truem 188 (96.9) [93.4 - 98.9] 111 (95.7) [90.2 - 98.6] False 1 (0.5) 1 (0.9) I don't know 5 (2.6) 4 (3.4) 17e: A TIRF medicine can cause an overdose and death in any child who takes it. True 183 (94.3) [90.1 - 97.1] 106 (91.4) [84.7 - 95.8] False 1 (0.5) 1 (0.9) I don't know 10 (5.2) 9 (7.8) 95% exact two-sided con?dence intervals are calculated using the Clopper-Pearson method. Correct response. Data Source: ADPQ, ADTQ Program: TRIG TIRF Patient/Caregiver KAB Page 1 of 2 03DEC2015 Table 11.1.4: Responses to Questions Linked to Key Risk Message #6 by Highest Level of Education - Completed Surveys Key Risk Message TIRF medicines should be stored in a safe place away from children and properly disposed. Question GED or less [95% Highest Level of Education College [95% cull] or (We) [95% "1 Professional or Doctoral Degree [95% Question 13: Please answer True, False, or I don't know for each statement about the TIRF medicine that was most recently prescribed for you. 13a: TIRF medicines should be stored in a safe place out of the reach of children. Truem 63 (100.0) [94.3 - 100.0] 122 (99.2) [95.6 - 100.0] 109 (100.0) [96.7 - 100.0] 15 (100.0) [78.2 - 100.0] False 0 (0.8) 0 0 I don't know 0 0 0 0 Question 14: What should you do if an adult who has not been prescribed a TIRF medicine takes a TIRF medicine? (Please select one.) Wait an hour and see if the person is OK. 1 (1.6) 2 (1.6) 3 (2.8) 0 Get emergency help ?ght awaym 52 (82.5) [70.9 - 90.9] 109 (88.6) [81.6 - 93.6] 98 (89.9) [82.7 - 94.9] 14 (93.3) [68.1 - 99.8] Do nothing. 0 (0.8) 0 0 I don't know. 10 (15.9) 11 (8.9) 8 (7.3) 1 (6.7) Question 17: Please answer True, False, or I don't know for each statement about the TIRF medicine that was most recently prescribed for you. 17c: TIRF medicines must be disposed of as described in the speci?c product?s Medication Guide. Truem 61 (96.8) [89.0 - 99.6] 117 (95.1) [89.7 - 98.2] 107 (98.2) [93.5 - 99.8] 14 (93.3) [68.1 - 99.8] False 1 (1.6) 0 1 (0.9) 0 I don't know 1 (1.6) 6 (4.9) 1 (0.9) 1 (6.7) Data Source: ADPQ, ADTQ Program: TRIG Page 2 of 2 TIRF Patient/Caregiver KAB 03DEC2015 Table 11.1.4: Responses to Questions Linked to Key Risk Message #6 by Highest Level of Education - Completed Surveys Key Risk Message TIRF medicines should be stored in a safe place away from children and properly disposed. Highest Level of Education Professional or GED or less College or Doctoral Degree Question 11 [95% 11 [95% 11 [95% [95% 17e: A TIRF medicine can cause an overdose and death in any child who takes it. Truem 57 (90.5) [80.4 - 96.4] 114 (92.7) [86.6 - 96.6] 105 (96.3) [90.9 - 99.0] 13 (86.7) [59.5 - 98.3] False (1.6) 1 (0.8) 0 0 I don't know 5 (7.9) 8 (6.5) 4 (3.7) 2 (13.3) 95% exact two-sided con?dence intervals are calculated using the CIopper-Pearson method. Correct response. Note: or less" includes "Less than high school." "Some high school." "High school graduate/GED." or "Prefer not to answer." "College" includes "Some college/Associate?s degree." or includes "Bachelor's degree" and "Master's degree." "Professional or Doctoral degree" includes "Professional or Doctoral degree." Data Source: ADPQ, ADTQ Program: TRIG Page 1 of 2 TIRF Patient/Caregiver KAB 03DEC2015 Table 11.1.5: Responses to Questions Linked to Key Risk Message #6 by Age Group of Respondent - Completed Surveys Key Risk Message TIRF medicines should be stored in a safe place away from children and properly disposed. Age Group of Respondent older Question [95% [95% 11 [95% "1 [95% 011?? Question 13: Please answer True, False, or I don't know for each statement about the TIRF medicine that was most recently prescribed for you. 13a: TIRF medicines should be stored in a safe place out of the reach of children. Truem 24 (100.0) [85.8 - 100.0] 64 (98.5) [91.7 - 100.0] 129 (100.0) [97.2 - 100.0] 92 (100.0) [96.1 - 100.0] False 0 (1.5) 0 0 I don't know 0 0 0 0 Question 14: What should you do if an adult who has not been prescribed a TIRF medicine takes a TIRF medicine? (Please select one.) Wait an hour and see if the person is OK. 0 3 (4.6) 1 (0.8) 2 (2.2) Get emergency help ?ght awaym 24 (100.0) [85.8 - 100.0] 58 (89.2) [79.1 - 95.6] 116 (89.9) [83.4 - 94.5] 75 (81.5) [72.1 - 88.9] Do nothing. 0 0 1 (0.8) 0 I don't know. 0 4 (6.2) 11 (8.5) 15 (16.3) Question 17: Please answer True, False, or I don't know for each statement about the TIRF medicine that was most recently prescribed for you. 17c: TIRF medicines must be disposed of as described in the speci?c product?s Medication Guide. Truem 23 (95.8) [78.9 - 99.9] 63 (96.9) [89.3 - 99.6] 127 (98.4) [94.5 - 99.8] 86 (93.5) [86.3 - 97.6] False 0 0 1 (0.8) 1 (1.1) I don't know 1 (4.2) 2 (3.1) 1 (0.8) 5 (5.4) 17e: A TIRF medicine can cause an overdose and death in any child who takes it. Data Source: ADPQ, ADTQ Program: TRIG Page 2 of 2 TIRF Patient/Caregiver KAB 03DEC2015 Table 11.1.5: Responses to Questions Linked to Key Risk Message #6 by Age Group of Respondent - Completed Surveys Key Risk Message TIRF medicines should be stored in a safe place away from children and properly disposed. Age Group of Respondent older Question 11 [95% [95% '11 [95% "1 [95% 011?? Truem 23 (95.8) [78.9 - 99.9] 62 (95.4) [87.1 - 99.0] 121 (93.8) [88.1 - 97.3] 83 (90.2) [82.2 - 95.4] False 0 1 (1.5) 1 (0.8) 0 I don't know 1 (4.2) 2 (3.1) 7 (5.4) 9 (9.8) 95% exact two-sided con?dence intervals are calculated using the Clopper-Pearson method. onect response. Data Source: ADPQ, ADTQ Program: TRIG Page 1 of TIRF Patient/Caregiver KAB 03DEC2015 Table 11.2: Secondary Analysis of Responses to Questions Linked to Key Risk Message #6 - Completed Surveys Key Risk Message TIRF medicines should be stored in a safe place away from children and properly disposed. Patients/Caregivers Correct Responses 11 [95% 0 correct responses 0 1 correct response 2 (0.6) 2 correct responses 8 (2.6) 3 correct responses 48 (15.5) 4 correct responses 252 (81.3) [76.5 - 85.5] 95% exact two-sided con?dence intervals are calculated using the Clopper-Pearson method. Data Source: ADPQ, ADTQ Program: TRIG Page 1 of TIRF Patient/Caregiver KAB 03DEC2015 Listing 1: Listing of Verbatim Responses to Question #22 (How frequently do you receive a Medication Guide for the TIRF medicine at the pharmacy?) - Completed Surveys Verbatim Responses In each box Medication is FedExed to me. One was in each box that contained the spray Data Source: ADPQ Program: LQ.SAS TRIG Page 1 of TIRF Patient/Caregiver KAB 03DEC2015 Listing 2: Listing of Verbatim Responses to Question #27 (Who offered to explain the Medication Guide to you?) Completed Surveys Verbatim Responses Caregiver Drug Rep Lending care representative PA read it to her Pharm. Rep. RELATIVE Rep from company that makes Subsys SPOUSE (AN R.N.) Sale's Rep Sale's Rep Someone ?om the manufacturer The Dr's PA drug rep pharmasuitical representative someone gave a call Data Source: ADPQ Program: LQ.SAS TRIG Page 1 of 2 TIRF Patient/Caregiver KAB 03DEC2015 Listing 3: Listing of Verbatim Responses to Question #31 (Questions about the Medication Guide) Completed Surveys Verbatim Responses 'On the effect on your teeth. Is it sugar that gives it the taste?? 'I've had a problem with it rotting my teeth.? Any statement that I was not 100% clear on. I stated to the Doctor or Pham1acist that am not clear about what that means. I take full control of my Healthcare and do not depend on the Doctor completely. I go to another Doctor for a second opinion and I extensively research the combination of medicines that I take. I will not take oral opioids. In fact I told the Doctor I did not want Subsy and the reason why! A?er my explanation he assured me that the form of delivery is different from the Patch. but the long term use on my body is not different. He stated the delivery of the medication is different. and since you refuse to take anything by mouth for pain Subsy might be a good alternative for you. I relented. and agreed to try it beginning with a 15 day supply. 100 morning and 100 at night. DOESNT GIVE ENOUGH INFO ON SERIOUS SIDE EFFECTS MAKES IT SEEM TO HARMLESS SIDE EFFECTS FOR A STRONG NARCOTIC GIVEN WHENALL OTHER PAIN MLEDS STOP WORKIMG THIS MAKES SEEM ITS GOING DO GREAT THINGS STOP PAIN OTHER MEDS DONT DOESNT WORK WELL IN MANANGING PAININ FACT DOESNT REALLY WORK ALSO ALOT BAD SIDE EFFECTS BLEED THROUGH RECTUM ALSO VOMIT BLOODWORSE CONSTIPATIONCANT GO AT ALL MATTER WHAT TRY TAKE ABLE HAVE BOWEL MOVEMENT LIKE STONES INSIDE YOU TO LARGE PASS CUTS RECTUM CANNOT 0 ON OWN. MIND ALTERING HIGH LOW HAPPY SAD MAD CRazy make others around you scared of your behavior be aromld you. Cannot get grip reality all this negative no positive outcome from it pain level still 10 plus such great cost make pharmeceutocal company rich ourageous no hospitals or pharmacies afford carry nr insurance COMPANIES PAY. MY INSURANCE COMPANY DIDNT REALIZE OR TOLD OF COST DOCTORS NOT ADVISED WHEN GOING FOR EXCEPTION SO PATIENT ABLE TRY IT CAN GET PAIN MANAGENIENT DOCTORS THROWN OFFAS A PROVIDER AND HARD FIND GET GOOD PAIN MANAGEMENT DOCTORS FDAMADE SO HARD FOR REALLYILL PATIENTS GET PAIN MEDS BECAUSE OF ABUSE BY TAKING FOR FUN FDA MUST KNOW OF SIDE EFFECTS REALLY BADMAKE PATIENTS SICKER. HARD DETOX VFROM 6 WEEKS STILL Heing bad bowel worsebeforeta Doctor instructed me to continue to use SUBSYS in spite of his refusal to re?ll my Morphine Sulfate. 15 mg.. due to the fact that I had THC in my UA. (I'd been out-of-state but still not legal in my state.) I was given TWO con?icting instructions. by SUBSYS and it's distributor: to stop taking it and to continue taking it. Really infuriating. First I was on the spray now im on the lollis and I thik they are making me have hallucinations and im ?xing to tell them to stop giving them me. And the sprays work better than the lolli pops. ive been told there is a patch. but I haven't been o?eredit. and its very expensive. theres only one pharmacy in that has it. doesn't have it. and theres only one pharmacy that keeps it its a and no other pharmacys wont order it. and I think that?s important you should be able to ?nd your medicine. the spray was mailed to you. but the lollis you cant get in a 100 mile radius its (ms) the one will get it but no other will get it and they leave it upon you to ?nd the pham1acy.. you put a lollipop in your mouth and the thing sticks out it says to knaw on the end- children think theyre suckers cause of the way they look like dumb-dumbs. I think they need to rethink their the way it looks. Has an addition been added to inform the user that teeth will be damaged and lost with the prolonged use of this product? Data Source: ADPQ Program: LQ.SAS TRIG Page 2 of 2 TIRF Patient/Caregiver KAB 03DEC2015 Listing 3: Listing of Verbatim Responses to Question #31 (Questions about the Medication Guide) Completed Surveys Verbatim Responses How to dispense (use) the lozenge medication If I didn't get relief from the ?rst dose.could I take another dose.& 110w soon a?er the ?rst dose. JUST TALKED OVER BASIC QUESTIONS I HAD ABOUT HOW AND WHEN TO USE IT LIke uh. the dangers of taking the medicine. how often is too much to take it. can I take less of the medicine. can I take more that type of deal. The general safety of taking the negatives and positives of taking the medicine. No current questions. at the time there were just vocabulary clari?cations I needed. One out of every 3 there is no binning sensation. I feel no instant relief of pain. I cant open the package. When to begin taking next strength Why is it only available for cancer patience? Why is the base of the medicine sugar - bad for teeth serious dental problems why is the medicine based with sugar? its being strictly guided for cancer patients- its unfair - my insurance doesn't want to pay for it now. Data Source: ADPQ Program: LQ.SAS TRIG TIRF Patient/Caregiver KAB Page 1 of 4 03DEC2015 Listing 4: Listing of Potential Adverse Events and/or Product Complaints Reported by Modality hallucinations and im ?xing to tell them to stop giving them me. And the sprays work better than the 1011i pops. ive been told there is a patch. but I haven't been offeredit. and its very expensive. theres only one pharmacy in (bus) that has it M's) doesn't have it. and theres only one phamracy that keeps it its a (m6) and no other pharmacys wont order it. and I think that's important you should be able to ?nd your medicine. the spray was mailed to you. but the lollis you cant get in a 100 mile radius its the one (we) will get it but no other a? (6) will get it and they leave it upon you to ?nd the pham1acy.. you put a 1011i pop in your mouth and the thing sticks out it says to knaw on the end- children think theyre suckers cause of the way they look like dumb-dimlbs. I think they need to rethink their the way it looks. Modality of Verbatim Text Report Why is the base of the medicine sugar - its bad for your teeth I?ve had serious dental Telephone problems- why is the medicine based with sugar? I take fentanol because I have ?bromyalgia and I have arthritis I don?t know if it is related Telephone or not but my doctors don?t even know about it yet. I just found out on Tuesday that I?ve had a mass in my uterus. I don?t know if it is cancer or not. 'On the e?ect on your teeth. Is it sugar that gives it the taste?? 'I?ve had a problem with it Telephone rotting my teeth.? ?I?ve had trouble with Actiq. I don?t know if they?re genetic or not? ?I?ve had them come off the stick. and I?ve found that the holder. some are fat and some are skinny.? ?They break up." ?And most important. is the effect on the teeth.? I am really sick. I need to call you back. I am really sick. Going outside makes me really Telephone sick. I use it for breakthrough pain but not for cancer- I have MS. Well I do have joint pain but Telephone that's because of my back pain from surgeries. I am in pain constantly so I don't know how to answer these. I can't see small stuff. It's being strictly guided for cancer patients and its unfair - my insurance doesn?t want to pay for it and I have an attorney to ?ght it- that's wrong. I used subsys for chronic pain until it was too hard to get from the pharmacy. Telephone I would like to have my Fentora back - this Fentanyl isn't working. Telephone I have severe back pain. I take the Actiq for breakthrough pain for my back. I use this for Telephone my back. I use them for breakthough pain ?om these things - pg 11 (arthritis pain question) Telephone And it?s hard to stick on sometimes. It really gives you trouble sometimes. Telephone First I was on the spray now im on the lollis and I thik they are making me have Telephone Data Source: Program: LQAE.SAS TRIG TIRF Patient/Caregiver KAB Page 2 of 4 03DEC2015 Listing 4: Listing of Potential Adverse Events and/or Product Complaints Reported by Modality Verbatim Text Modality of Report 0 I took all these pain medications they had me pooping baby arms not to be gross 0 And waking up somewhere in a ditch 0 After taking a multitude of narcotics I was taking the patches and people were telling me I was falling asleep in my soup and all kinds of crazy stu?l scary situation 0 When I was taking the patched I didn?t have any realization of the potency of it and the fast acting abilities and the ability to shut down my respiratory system in not taken properly 0 My experiences 12 years of taking these medications people may have the same problems I had the broken bones. burns. everything else- damaging my liver and kidneys in the process 0 OxyContin and Morphine and Fentanyl patch they are all potent and very dangerous When taking them they sent me through a loop the fentanyl patch especially in the 100mg form it would do nothing then 4 hours later I?d become a zombie and not know what I was doing for the next 2 days it was scary stuff Telephone The Actiq is slower acting. I had an allergic reaction to Fentora. I itch. breakout and it doesn't help with the pain. It gives me a reaction. I take it for long time pain. Fentora gives me a rash. The second round of fentora I broke out had a rash till bleeding. It hits hard and I have side effects. Telephone When you spray it in your mouth. the Sprayers don't work properly. I end up being short at the end of the month because I get so many duds. It's not just the one product. it seems to be in every strength. When it does pop. sometimes it doesn?t spray. Like there isn?t air in it. It seems like there isn?t anything to trigger it. It looks ?ne. but when you go to hit it there?s nothing there. Telephone One out of every 3 there is no burning sensation. I feel no instant relief of pain. I cant open the package. Telephone I have back problems- I don't use it for cancer it's my spine. Telephone Right now I?m using the Subsys which is not helping me at all. I have a fractured back from osteoporosis. I fractured my foot. a rib. The one you spray under your tonguee?ective. I know I need a stronger dose of it. but my insurance doesn?t cover it. Telephone "That stuff is highly addictive 0k and what they did to me should be criminal. I went through some serious pain and depression and whatever" It was really painful. the withdrawal from fentanyl is one of the worst" I am dependent on opiates I have major pain problems" "they should have provisions to not drop someone cold turkey. believe me it was very pain?Jl and uncomfortable" Telephone I don't know why I've been coughing all day- my breathing has been yucky- the humidity in (ms) is awful. Telephone "It made me sick as a dog." "There are more dangerous side effects than they tell you on the box." "Still six weeks later and I'm still having bad side e?ects." Telephone Patient passed away. Summer 2015. speci?c date unknown. "He stopped taking the medication once he was admitted to Hospice in (We) and they took him off of it." Telephone it gives me dry heaves- I don't take it for recreational purposes. Telephone didn?t take it that long and it made me sick" haven?t taken it in a couple months? Telephone Data Source: Program: LQAE.SAS TRIG TIRF Patient/Caregiver KAB Page 3 of 4 03DEC2015 Listing 4: Listing of Potential Adverse Events and/or Product Complaints Reported by Modality Verbatim Text Modality of Report leg on- Actiq would rot my teeth- He kept me from rolling my wheelchair off the bridge because the pain was so bad- I thought about taking a chainsaw to the rest of my legs the pain was so bad- thats how bad it was. I had surgery on my nose- Telephone I have diarrhea and vomit consistently. Telephone My other medication was tuming me into a zombie. I was taking the patches and all of a sudden boom I?d fall asleep in my soup. I was on that patch for a couple of years and it made me nauseas. I?m good for half of the day then the pain start coming back a little bit. I could function normally prior to that when I?m over doing it. able to obtain normal conversation. my head not bouncing off my shoulders. like a bobble head. You don?t know what kind of hell I went through. This medication was a godsend it?s just expensive. I had a lot of hoops to get through. I?m shooting it and taking it in my toes. I got one elbow. Telephone "As I sit here in pain" Internet Only other one I?ve had when I was diagnosed with my cancer is the like lollipops that were fentanyl that you suck on I didn?t like that. they didn?t do anything for me having dentures they didn?t work so hot" ?I?ve tried all the milligrams of the fentora and the only one that seems works for me is the 400 mg when I take 2 of them every so often? got hepatitis and through a blood transfusion" Telephone DOESNT GIVE ENOUGH INFO ON SERIOUS SIDE EFFECTS MAKES IT SEEM TO HARMLESS SIDE EFFECTS FOR A STRONG NARCOTIC GIVEN WHENALL OTHER PAIN MEDS STOP THIS MAKES SEEM ITS GOING DO GREAT THINGS STOP PAIN OTHER MEDS DONT DOESNT WORK WELL IN MANANGING PAININ FACT DOESNT REALLY WORK ALSO ALOT BAD SIDE EFFECTS BLEED THROUGH RECTUM ALSO VOMIT BLOODWORSE CONSTIPATIONCANT GO AT ALL MATTER WHAT TRY TAKE ABLE HAVE BOWEL MOVEMENT LIKE STONES INSIDE YOU TO LARGE PASS CUTS RECTUM CANNOT 0 ON OWN. MIND ALTERING HIGH LOW HAPPY SAD MAD CRazy make others around you scared of your behavior be around you. Cam10t get grip reality all this negative no positive outcome from it pain level still 10 plus such great cost make pharmeceutocal company rich ourageous no hospitals or pharmacies afford carry nr insurance COIVIPANTES WILING PAY. MY INSURANCE COIVIPANY DIDNT REALIZE OR TOLD OF COST DOCTORS NOT ADVISED WHEN GOING FOR EXCEPTION SO PATIENT ABLE TRY IT CAN GET PAIN MANAGEMENT DOCTORS THROWN OFFAS A PROVIDER AND HARD FIND GET GOOD PAIN MANAGEMENT DOCTORS FDAMADE SO HARD FOR REALLYILL PATIENTS GET PAIN MEDS BECAUSE OF ABUSE BY TAKING FOR FUN FDA MUST KNOW OF SIDE EFFECTS REALLY BADMAKE PATIENTS SICKER. HARD DETOX VFROM 6 WEEKS STILL Hcing bad bowel worsebeforeta Internet Doctor instructed me to continue to use SUBSYS in spite of his refusal to re?ll my Morphine Sulfate. 15 mg.. due to the fact that I had THC in my UA. (I'd been out-of-state but still not legal in my state.) Iwas given TWO con?icting instructions. by SUBSYS and it's distributor: to stop taking it and to continue taking it. Really infuriating. Internet Data Source: Program: LQAE.SAS TRIG TIRF Patient/Caregiver KAB Page 4 of 4 03DEC2015 Listing 4: Listing of Potential Adverse Events and/or Product Complaints Reported by Modality hallucinations on it and thought my husband killed himself so I went to the ward. It's horrible- it made me hallucinate so bad and I thought my husband was dead- and so I went to the ward. It was really bad and now I have to do therapy. I just put our son on the bus and I came into the garage and I saw my husband hanging there. then I heard him in the attic so crawled through the attic and my hands got cut- then I called 911. It made me hallucinate so bad I seen my husband dead. Modality of Verbatim Text Report Husband passed about two weeks ago Internet I?d be doing better if I was feeling better. I just have my pain. the weather has been hot for Internet so many days and my pain acts up. When Ireceived a call from you before about doing a survey I had Labyrinthitis. It's like Telephone being on the worst amusement park ride ever. shaking and tossing you around back and forth. It's like Hell. It was horrible. I just was so far gone it was terriblemade me hallucinate and sent me to the ward. I had really bad Telephone Data Source: Program: LQAE.SAS 48-month REMS Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 111 of 112 12.7.2 Pharmacy KAB Survey FDA_3355 Pharmacy KAB Assessment Report Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Title: Page 1 of 51 Transmucosal Immediate Release Fentanyl (TIRF) REMS Assessment Quantitative Testing of Pharmacist Knowledge, Attitudes, and Behavior (KAB) about TIRF Products’ Safety and Use Information Document Number: Wave 4, 48-month REMS Assessment Version 1.0 Survey Time Period: 31 August 2015 – 16 September 2015 Product Name: Transmucosal Immediate Release Fentanyl Sponsor: TIRF REMS Industry Group (TRIG) of Companies: Actavis Laboratories FL, Inc. BioDelivery Sciences International, Inc. (BDSI) Cephalon, Inc. (a wholly-owned subsidiary of Teva Pharmaceutical Industries, Ltd.) Depomed, Inc. Galena Biopharma, Inc. Insys Therapeutics, Inc. Mallinckrodt Pharmaceuticals Mylan, Inc. Par Pharmaceutical, Inc. Date: 15 December 2015 Confidentiality Statement The information contained herein is confidential and the proprietary property of the TRIG of Companies and its affiliates, and any unauthorized use or disclosure of such information without the prior written authorization of the TRIG is expressly prohibited. FDA_3356 Pharmacy KAB Assessment Report Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies TABLE OF CONTENTS Page 2 of 51 PAGE TABLE OF CONTENTS......................................................................................................... 2 LIST OF TABLES ................................................................................................................... 3 LIST OF APPENDICES .......................................................................................................... 4 LIST OF ABBREVIATIONS .................................................................................................. 5 1. PHARMACIST SURVEY BACKGROUND ......................................................... 7 1.1 Changes to the KAB Survey for Pharmacists Based on FDA Feedback ................ 8 2. PHARMACIST SURVEY OBJECTIVES.............................................................. 9 3. SURVEY METHODOLOGY ................................................................................. 9 3.1 Survey Sample......................................................................................................... 9 3.1.1 Eligibility ............................................................................................................... 10 3.1.2 Recruitment ........................................................................................................... 10 3.2 Questions and Statements on Key Risk Messages ................................................ 10 3.2.1 Key Risk Message 1 .............................................................................................. 11 3.2.2 Key Risk Message 2 .............................................................................................. 12 3.2.3 Key Risk Message 3 .............................................................................................. 13 3.2.4 Key Risk Message 4 .............................................................................................. 13 3.3 Additional Questions ............................................................................................. 14 4. STATISTICAL METHODS ................................................................................. 14 4.1 Study Population ................................................................................................... 14 4.1.1 Primary Analysis Population ................................................................................. 14 4.2 Primary Analyses .................................................................................................. 14 4.3 Secondary Analyses .............................................................................................. 15 4.4 Pharmacist Report of a Potential Adverse Event, Product Complaint, or Medical Information Request during the Survey .................................................. 15 5. RESULTS.............................................................................................................. 15 5.1 Survey Participants ................................................................................................ 16 5.1.1 Survey Participant Administration Results ........................................................... 16 5.1.2 Description of Eligible Pharmacists who Completed the Survey ......................... 20 5.1.3 TIRF Medicines Educational Materials ................................................................ 22 FDA_3357 Pharmacy KAB Assessment Report Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 3 of 51 5.2 Key Risk Messages 23 5.2.1 Key Risk Message 1 23 5.2.2 Key Risk Message 2 28 5.2.3 Key Risk Message 3 31 5.2.4 Key Risk Message 4 33 5.2.5 Other Survey Questions 35 5.2.5.1 Additional Questions about TIRF Medicines Safety 35 5.2.5.2 Pharmacist Activities When Dispensing TIRF Medicines 37 5.3 Spontaneous Reporting of Potential Adverse Events, Product Complaints, or Medical Information Requests 41 6. DISCUSSION AND CONCLUSIONS 41 LIST OF TABLES Table 1. Survey Participant Administration Results 16 Table 2. Survey Participant Screening Results 17 Table 3. Time to Complete Survey for Completers Only 19 Table 4. Description of Eligible Pharmacists 21 Table 5. Responses to Questions About TIRF Medicines Educational Materials 22 Table 6. Responses Linked to Key Risk Message 1: TIRF Medicines Are ontraindicated in Opioid Non-Tolerant Patients 25 Table 7. Responses Linked to Key Risk Message 2: TIRF Medicines Are Only Indicated for the Management of Breakthrough Pain in Adult Cancer Patients 18 Years of Age and Older (16 Years of Age and Older for Actiq? Brand and Generic Equivalents) Who Are Ah'eady Receiving and Who Are Tolerant to Arormd-The-C lock Opioid Therapy for Their Underlying Persistent Cancer Pain 29 Table 8. Responses Linked to Key Risk Message 3: TIRF Medicines Contain Fentanyl, an Opioid Agonist and a Schedule Controlled Substance, With Abuse Liability Similar to Other Opioid Analgesics 32 Table 9. Responses Linked to Key Risk Message 4: TIRF Medicines Are Not Interchangeable with Each Other, Regardless of Route of Administration 34 Table 10. Responses to Additional Questions about the Safe Use of TIRF Medicines 36 Pharmacy KAB Assessment Report Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 4 of 51 Table 11. Responses to Additional Questions about the Safe Use of TIRF Medicines: Question Asked of Inpatient Pharmacists Only 37 Table 12. Responses to Questions about Activities When Dispensing TIRF Medicines 38 Table 13. Responses to All Questions about Activities When Dispensing TIRF Medicines: Asked of Inpatient Pharmacies Only 40 Table 14. Responses to All Questions about Activities When Dispensing TIRF Medicines: Outpatient Pharmacists Only 40 Table 15. Oirect Response Rate Over Time 43 LIST OF APPENDICES Appendix A Pharmacy Sluvey Protocol Track Change Document: Comparison of 36-month Stuvey to 48-month Stuvey 50 Appendix Pharmacy Sluvey Listings and Strati?ed Analyses Tables 51 Pharmacist KAB Assessment Report Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 5 of 51 LIST OF ABBREVIATIONS AE/PC PSP Adverse Event/Product Complaint Project Specific Procedure BDSI BioDelivery Sciences International, Inc. CI Confidence Interval CSP Closed System Pharmacy ETASU Elements to Assure Safe Use FDA Food and Drug Administration ISI Important Safety Information KAB Knowledge, Attitudes, and Behavior N/A Not Applicable REMS Risk Evaluation and Mitigation Strategy SD Standard Deviation SCC Survey Coordinating Center TIRF Transmucosal Immediate Release Fentanyl TIRF medicines Transmucosal Immediate Release Fentanyl products TIRF REMS Access Program REMS Program for TIRF medicines TRIG TIRF REMS Industry Group UBC United BioSource Corporation US United States USPS United States Postal Service FDA_3360 Pharmacist KAB Assessment Report Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 6 of 51 Executive Summary The 48-month Knowledge, Attitudes, and Behavior (KAB) survey for pharmacists who dispense Transmucosal Immediate Release Fentanyl (TIRF) medicines was conducted as part of the 48-Month TIRF Risk Evaluation and Mitigation Strategy (REMS) Access Program Assessment. The survey launched on 31 August 2015 and closed on 16 September 2015. Food and Drug Administration (FDA) feedback was provided in the 24-month and 36-month Assessment Report Acknowledgement Letters and where applicable these changes were implemented in the 48-month survey. Changes included steps to include a higher percentage of non-supervisory dispensing pharmacists participate in the survey, adding questions addressing CYP3A4 interactions with TIRF medicines and that patients are to stop taking their TIRF when they stop taking their around-the-clock opioid, removing ‘Onsolis’ as a response option throughout the survey because it is no longer available, and moving specified existing survey questions under key risk messages. The specific goals of the TIRF medicines pharmacist KAB survey were to assess pharmacist understanding of the risks associated with TIRF medicine use, the specific indications for treatment with TIRF medicines, and that TIRF medicines are contraindicated in opioid nontolerant patients. The survey also included questions about whether pharmacists received, read, understood, and used the product-specific educational materials, and included questions about compliance with the REMS requirements. Invitations (and reminders) were sent to a random sample of pharmacies enrolled in the TIRF REMS Access Program as of 30 June 2015, and were distributed to pharmacists who dispense TIRF products and were known to have received the REMS educational materials. From the total of 607 pharmacists who accessed the survey, 334 (55.0%) pharmacists met eligibility criteria, and of those who met eligibility criteria, 301 (90.1%) completed the survey, exceeding the target of 300 completed surveys. In general, there is an overall trend across all pharmacist KAB surveys conducted (12-month, 24-month, 36-month, and 48-month surveys) toward increasing improvement in pharmacist knowledge and understanding of the key risk messages. Of the 29 components included as part of key risk messages, 20 components of the key risk messages had a response rate >80%, and 7 components had a response rate between 65.1% to 78.7%. Two components within the key risk messages had a correct response rate below the desired threshold of 65% (Component 6c and Component 9e). The correct response rate for Component 6c (A patient must stop taking their TIRF medicine if they stop taking their around-the-clock opioid pain medicine) was 41.9%. This component was added to the 48-month survey based on feedback provided by FDA in the 24-month and the 36-month FDA REMS Acknowledgement Letter. Correct response rate for Component 9e (Chronic non-cancer pain is not an indication for which TIRF medicines can be prescribed) was 50.8% for this 48-month survey. Component 9e has had a low correct response rate across all pharmacist KAB surveys conducted (12month, 24-month, 36-month, and 48-month surveys). The survey score for Component 9e may indicate that some respondents are dispensing TIRF medicines for non-cancer associated indications. FDA_3361 Pharmacist KAB Assessment Report Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 7 of 51 The consistently high level of pharmacists’ understanding of key risk messages in the latest (48-month) survey indicates that the Education Program for Pharmacists is meeting the goals of the TIRF REMS Access Program. The TRIG will evaluate the concepts that have scored low among stakeholders to determine if any action is warranted. The TRIG will continue to work with the FDA to refine, on a continual basis, the steps to mitigate risks associated with TIRF medicines. 1. PHARMACIST SURVEY BACKGROUND Transmucosal Immediate Release Fentanyl (TIRF) medicines are a class of immediaterelease opioid analgesics indicated for the management of breakthrough pain in cancer patients 18 years of age or older (16 or older for Actiq® [fentanyl citrate oral transmucosal lozenge] and equivalent generics) who are receiving and already tolerant to opioid therapy for their underlying persistent cancer pain. The FDA has determined that a shared system REMS is required to mitigate the risk of misuse, abuse, addiction, overdose, and serious complications due to medication errors with the use of TIRF medicines. The TIRF REMS Access Program was approved by the FDA on 28 December 2011. This report describes the results from the pharmacist surveys conducted for the 48-Month TIRF REMS Access Program Assessment, and reflects the reporting period of 29 October 2014 to 28 October 2015. The 48-month KAB survey launched on 31 August 2015 and closed on 16 September 2015. The TIRF medicines include Abstral®, Actiq®, Fentora®, Lazanda®, Subsys®, and their generic equivalents. The TRIG includes Actavis Laboratories FL, Inc.; BioDelivery Sciences International, Inc. (BDSI); Cephalon, Inc. (a wholly-owned subsidiary of Teva Pharmaceutical Industries, Ltd.); Depomed, Inc.; Galena Biopharma, Inc.; Insys Therapeutics, Inc.; Mallinckrodt Pharmaceuticals; Mylan, Inc.; and Par Pharmaceutical, Inc. Two companies joined the TRIG during the reporting period: Actavis Laboratories FL, Inc. joined on 6 February 2015 and BDSI replaced Meda Pharmaceuticals on 11 March 2015. The TIRF REMS Access Program consists of a Medication Guide, Elements to Assure Safe Use (ETASU), an Implementation System, and a Timetable for Submission of Assessments of the REMS. The goals of the TIRF REMS Access Program are to mitigate the risk of misuse, abuse, addiction, overdose, and serious complications due to medication errors by the following: 1. Prescribing and dispensing TIRF medicines only to appropriate patients, which includes use only in opioid-tolerant patients. 2. Preventing inappropriate conversion between TIRF medicines. 3. Preventing accidental exposure to children and others for whom it was not prescribed. 4. Educating prescribers, pharmacists, and patients on the potential for misuse, abuse, addiction, and overdose of TIRF medicines. FDA_3362 Pharmacist KAB Assessment Report Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 8 of 51 An important component of the TIRF REMS Access Program Assessment is the conduct of quantitative evaluation surveys to assess pharmacists’ understanding and knowledge of the safe use and appropriate prescribing of TIRF medicines as described in the TIRF REMS Access Program educational materials, TIRF REMS Access Program Pharmacy Enrollment Form, and Prescribing Information of each product. Administration of the surveys conducted among pharmacies enrolled in the TIRF REMS Access Program is described in the protocol (See Appendix A). Note: Protocol and survey question revisions from the 36-month assessment report are identified as tracked changes. Data from the surveys, together with other TIRF REMS Access Program evaluation metrics, will be used to determine whether changes need to be made to the TIRF REMS Access Program processes or educational materials to make them more effective in achieving the goals of the TIRF REMS Access Program. 1.1 Changes to the KAB Survey for Pharmacists Based on FDA Feedback FDA feedback was received on the KAB survey for pharmacists in the 24-month and the 36month FDA REMS Acknowledgement Letters. The FDA provided the following feedback to the TRIG on the KAB survey for pharmacists based on results included in the 24-month REMS Assessment Report. • Given that pharmacists often have the opportunity to see all of the prescriptions that a patient is taking, include a question in the pharmacist survey regarding the CYP3A4 interactions with TIRFs. Also include a question in the pharmacist survey regarding their understanding that patients are to stop taking their TIRF when they stop taking their around-the-clock opioid. • In the pharmacist survey, 81% of those surveyed functioned as the pharmacist in charge for their operations. In future pharmacist surveys, consider ensuring that a higher percentage of non-supervisory dispensing pharmacists are included. This feedback was provided after the launch of the 36-month KAB survey for pharmacists, thus the changes were incorporated into the 48-month KAB survey for pharmacists and results from the revised survey are included in this 48-month KAB Assessment Report. The FDA provided the following feedback to the TRIG on the KAB survey for pharmacists based on results included in the 36-month REMS Assessment Report: • • • • Remove Onsolis as a response option throughout the survey as it is no longer available Move existing surveys questions (Question 11a-f) into Key Risk Message 1 Move an existing surveys question (Question 6a, 6b) into Key Risk Message 2 Move an existing surveys question (Question 13c-f) into Key Risk Message 4 The 36-month Assessment Report Acknowledgement Letter was received by the TRIG sponsors on 04 August 2015. All requested changes were incorporated into the 48-month KAB survey prior to launch. In an effort to ensure that a higher percentage of nonFDA_3363 Pharmacist KAB Assessment Report Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 9 of 51 supervisory dispensing pharmacists were included for this reporting period, the invitation letter was revised and addressed to “Staff Pharmacist” and disseminated to those pharmacies enrolled in the TIRF REMS Access Program. In previous waves, the invitation letter was addressed to the Pharmacist-in-Charge. In order to incorporate FDA’s feedback in the 48month Pharmacist KAB survey, the survey launch date originally scheduled for the second week of August was delayed until 31 August 2015. 2. PHARMACIST SURVEY OBJECTIVES The evaluation survey uses a questionnaire to document the level of knowledge and assess the attitudes and behavior of pharmacists regarding the following key information and risk messages communicated through the REMS: 1. TIRF medicines are contraindicated in opioid non-tolerant patients. 2. TIRF medicines are indicated for the management of breakthrough pain in adult cancer patients 18 years of age and older (16 or older for Actiq® and equivalent generics) who are already receiving and who are tolerant to around-the-clock opioid therapy for their underlying persistent cancer pain. 3. TIRF medicines contain fentanyl, an opioid agonist and a Schedule II controlled substance, with abuse liability similar to other opioid analgesics. 4. TIRF medicines are not interchangeable with each other, regardless of route of administration. 5. Patients and their caregivers must be instructed that TIRF medicines contain a medicine in an amount that can be fatal in children, in individuals for whom it is not prescribed, and in those who are not opioid tolerant. The survey also collects data on behaviors, such as receipt and use of educational materials and compliance with REMS requirements. 3. SURVEY METHODOLOGY This section summarizes the survey design and the questions developed to test pharmacist understanding of the key risk messages of the REMS. Full details of the survey design are in the protocol, which can be found in Appendix A. 3.1 Survey Sample A sample of 300 pharmacists who dispense TIRF products and were known to have received the REMS educational materials was planned for this fourth KAB survey which was expected to be open from 31 August 2015 to 20 October 2015. The survey sample size was determined based on both practical and statistical considerations. The survey was written to reflect wording for both methods of survey administration: Internet-based and telephone. FDA_3364 Pharmacist KAB Assessment Report Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies 3.1.1 Page 10 of 51 Eligibility Subjects were recruited from a random sample of pharmacies enrolled in the TIRF REMS Access Program as of 30 June 2015. All pharmacists who worked at the enrolled pharmacy were eligible to participate, which could result in multiple completed surveys per pharmacy. Respondents or respondents with immediate family members who had ever worked for any of the TRIG companies, McKesson Specialty Care Solutions, RelayHealth, United BioSource Corporation (UBC), or the FDA were not eligible to participate nor were respondents who participated in the previous waves of the survey (the 12-month TIRF REMS Access Program Assessment, the 24-month TIRF REMS Access Program Assessment, or the 36-month TIRF REMS Access Program Assessment). 3.1.2 Recruitment Subjects were recruited via an invitation letter sent through the United States Postal Service (USPS) or via fax (see Section 5.1.1 for more detail). The required number of completed surveys was not achieved within approximately 10 days after the first mailing; thus additional mailings were distributed to non-respondents from the original sample to maximize participation. Each letter of invitation included a unique code needed to access the survey. Three categories of pharmacies were sampled: Closed System Pharmacy (CSP), Inpatient Pharmacy, and Outpatient Pharmacy. Each pharmacy was provided a unique access code based on their pharmacy type because some questions in the survey were specific to only one type of pharmacy. The code was deactivated after the respondent had initiated the survey (whether or not the survey was completed). Pharmacists were given the option of taking the survey by telephone via the Survey Coordinating Center (SCC) or online via a secure website. The survey was estimated to take approximately 15-20 minutes to complete. All respondents who completed the survey and provided their contact information were mailed a $50 gift card for participating. The mailing also included a copy of the Important Safety Information (ISI) and a copy of the correct answers to the key risk message questions. 3.2 Questions and Statements on Key Risk Messages The questions and statements comprising the knowledge survey were constructed to test the pharmacists’ understanding of the key risk messages of the REMS. The questions were to be answered either by selecting options from multiple-choice lists that include statements of the specific key risk messages or by choosing “Yes” or “True,” “No” or “False,” or “I Don’t Know” regarding statements about TIRF medicines. For statements or questions that had “True” or “Yes” vs. “False” or “No” response options, the desired response for key risk messages was generally “True” or “Yes” indicating knowledge of, or behavior in accordance with, the objectives of the REMS. However, some questions were formatted to have the respondent disagree with the statement as written by FDA_3365 Pharmacist KAB Assessment Report Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 11 of 51 providing response options of “False” or “No” to avoid having the same affirmative answer for all desired responses. REMS statements, corresponding questions, and desired responses covering the key risk messages are identified below and can be found in the survey protocol (Appendix A). 3.2.1 Key Risk Message 1 Key Risk Message 1 refers to the pharmacist’s knowledge of the specific contraindications for TIRF medicines in opioid non-tolerant patients and under what conditions a patient is considered opioid tolerant. Key Risk Message 1: TIRF medicines are contraindicated in opioid non-tolerant patients. Question No. 5 5a 5b 5c 7 7a 7b 7c 7d 11 11a 11b 11c 11d 11e 11f Question Desired response Please select True, False, or I don’t know for each of the following. According to the labeling for TIRF medicines, patients with cancer who are considered opioid-tolerant are those: Who are taking around-the-clock opioid therapy for underlying True persistent cancer pain for one week or longer Who are not currently taking opioid therapy, but have taken opioid False therapy before Who have no known contraindications to the drug fentanyl, but are not False currently taking around-the-clock opioid therapy Please answer True, False, or I don’t know for each statement based on the labeling for TIRF medicines. TIRF medicines are contraindicated in opioid non-tolerant patients because life-threatening respiratory depression could occur at any True dose. Death has occurred in opioid non-tolerant patients treated with some True fentanyl products. TIRF medicines may be used in opioid non-tolerant patients. False Prescribers starting a patient on a TIRF medicine must begin with titration from the lowest dose available for that specific product, even True if the patient has previously taken another TIRF medicine. Please select True, False, or I don’t know for each of the following. According to the labeling for TIRF medicines, patients considered opioid-tolerant are those who are taking, for one week or longer, at least: 8 mg oral hydromorphone/day True 60 mg oral morphine/day True 30 mg oral oxycodone/day True 25 mcg transdermal fentanyl/hour True 25 mg oral oxymorphone/day True An equianalgesic dose of another oral opioid True FDA_3366 Pharmacist KAB Assessment Report Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies 3.2.2 Page 12 of 51 Key Risk Message 2 Key Risk Message 2 refers to the pharmacist’s knowledge of the indications for prescribing TIRF medicines for the management of breakthrough pain in opioid-tolerant adult cancer patients, and the timing of administration of the TIRF medicine in relation to the around-theclock opioid therapy to ensure the patient is considered opioid tolerant. Key Risk Message 2: TIRF medicines are only indicated for the management of breakthrough pain in adult cancer patients 18 years of age and older (16 years of age and older for Actiq® brand and generic equivalents) who are already receiving and who are tolerant to around-theclock opioid therapy for their underlying persistent cancer pain. Question No. 6 6a 6b 6c 9 Desired response Please answer True, False, or I don’t know for each statement based on the labeling for TIRF medicines. According to the product labeling, a cancer patient may start a TIRF False medicine and an around-the-clock opioid at the same time. According to the product labeling, a cancer patient who has been on False an around-the-clock opioid for 1 day may start taking a TIRF medicine for breakthrough pain. A patient must stop taking their TIRF medicine if they stop taking True their around-the-clock opioid pain medicine. Per the approved labeling for TIRF medicines, for which of the following indications can TIRF medicines be prescribed to opioid tolerant patients? Please answer Yes, No, or I don’t know for each option. Question 9a Acute or postoperative pain No 9b Headache or migraine pain No 9c Dental pain No 9d Breakthrough pain from cancer Yes 9e Chronic non-cancer pain No FDA_3367 Pharmacist KAB Assessment Report Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies 3.2.3 Page 13 of 51 Key Risk Message 3 Key Risk Message 3 refers to the pharmacist’s knowledge of the risk factors for opioid abuse and importance in monitoring for signs of abuse in patients who take TIRF medicines. Key Risk Message 3: TIRF medicines contain fentanyl, an opioid agonist and a Schedule II controlled substance, with abuse liability similar to other opioid analgesics. Question No. Question Desired response 7 Please answer True, False, or I don’t know for each statement about TIRF medicines. 7e It is important to monitor for signs of abuse and addiction in patients who take TIRF medicines. 8 Which of the following are risk factors for opioid abuse? Please answer Yes, No, or I don’t know for each option. 8a A personal history of psychiatric illness Yes 8b A personal history of past or current alcohol or drug abuse, or a family history of illicit drug use or alcohol abuse Yes 10 Please answer True, False, or I don’t know for each statement based on the labeling for TIRF medicines. 10a TIRF medicines can be abused in a manner similar to other opioid agonists. 3.2.4 True True Key Risk Message 4 Key Risk Message 4 refers to the pharmacist’s knowledge of the interchangeability of TIRF medicines based on route of administration, pharmacokinetic absorption, and dosage. Key Risk Message 4: TIRF medicines are not interchangeable with each other, regardless of route of administration. Question No. Question Desired response 10 Please answer True, False, or I don’t know for each statement based on the labeling for TIRF medicines. 10b TIRF medicines are interchangeable with each other regardless of route of administration. False 10c The conversion of one TIRF medicine for another TIRF medicine may result in a fatal overdose because of differences in the pharmacokinetics of fentanyl absorption. True 10d 13 13c Dosing of TIRF medicines is not equivalent on a microgram-toTrue microgram basis. Please answer True, False, or I don’t know for each statement about TIRF medicines. TIRF medicines with the same route of administration can be substituted with each other if the pharmacy is out of stock for one False product. FDA_3368 Pharmacist KAB Assessment Report Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies 3.3 Page 14 of 51 Additional Questions The survey also contained questions (Question 12a-f) about the requirements of the TIRF REMS Access Program, receipt and understanding of the TIRF educational materials, and behaviors. The following questions about behaviors were asked after the key risk message questions: Question No. Question 12 How frequently do you perform the following activities when dispensing TIRF medicines? Please answer Always, Only with the first prescription, Sometimes, Never, or I don’t know. 12a Ask patients (or their caregivers) about the presence of children in the home 12b Instruct patients (or their caregivers) not to share TIRF medicines with anyone else 12c Counsel patients (or their caregivers) that accidental exposure to TIRF medicines by a child may be fatal 12d Instruct patients (or their caregivers) to keep TIRF medicines out of the reach of children to prevent accidental exposure 12e Instruct patients (or their caregivers) about proper disposal of any unused or partially used TIRF medicines 12f Give patients (or their caregivers) the Medication Guide for their TIRF medicine 4. STATISTICAL METHODS 4.1 Study Population 4.1.1 Primary Analysis Population The primary population for analysis was all eligible pharmacists who completed the survey. Eligible pharmacists were defined as those respondents who answered Yes to Question 1 (agree to take part in survey), and Yes to Question 3 (work at a pharmacy that is enrolled in the TIRF REMs Access Program), and No to Question 2 (participated in past survey) and No to Question 4 (worked for a TRIG company, UBC, RelayHealth, McKesson Specialty Care Solutions, or FDA). A survey was considered “completed” when an eligible pharmacist answered all relevant questions. 4.2 Primary Analyses Primary analyses were performed for all key risk messages. The primary analysis for a key risk message evaluated the number and percentage of correct responses for each individual question/component included in the key risk message. Confidence intervals (95% CI) were calculated using the exact binomial method around the percentage of correct responses. FDA_3369 Pharmacist KAB Assessment Report Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 15 of 51 Primary analyses were then stratified by questions/characteristics of interest: 1) Those who indicated they both received and read the Medication Guide and Full Prescribing Information versus those who did not and those who responded they did not or did not know whether they had (Questions 18-21). 2) Whether the survey was completed via the internet or telephone 3) Time in pharmacy practice (Question 28). 4) The number of times per month they dispensed TIRF medicines within the last 6 months (Question 25). Stratified analyses were conducted only when at least two of the stratified response categories had at least 50 respondents (e.g., for analysis 2 above, at least 50 pharmacists had to respond they completed the survey via the internet and at least 50 had to respond they completed it by telephone in order for that analysis to be conducted). 4.3 Secondary Analyses As an indicator of the overall level of comprehension of the entire key risk message, descriptive analyses of the number and percentage of responders who answered various proportions of the key risk message components correctly are presented (e.g., the proportion who answered one question in the key risk message correctly, those who answered two questions correctly, those who answered three component questions correctly, etc.). Confidence intervals (95% CI) were calculated for the proportion of respondents who answered all component questions of the key risk message correctly. 4.4 Pharmacist Report of a Potential Adverse Event, Product Complaint, or Medical Information Request during the Survey A pharmacist may have reported a potential adverse event or other event experienced by a patient while taking a TIRF product either in free text fields while taking the online survey or while in conversation with the SCC Associate. If an event was mentioned to the SCC Associate, the Associate documented the event or complaint, the verbatim response, and the pharmacist’s contact information, if provided. The pharmacist was also informed that a representative from the appropriate TIRF medicine sponsor may contact him/her to obtain additional information about the event. The Internet surveys were monitored for any comments recorded in the free text field. Information on all reports (Internet or telephone) that constituted an adverse event or other event was forwarded to the appropriate TIRF medicine sponsor for processing within 1 business day of awareness of the event as outlined in the Adverse Event/Product Complaint Project Specific Procedure (AE/PC PSP). 5. RESULTS Results of the pharmacist’s responses to questions in the KAB survey are summarized in this section; stratified analysis tables and overall listings are provided in Appendix B. FDA_3370 Pharmacist KAB Assessment Report Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies 5.1 Survey Participants 5.1.1 Survey Participant Administration Results Page 16 of 51 In an effort to ensure that a higher percentage of non-supervisory dispensing pharmacists were included for this reporting period, the invitation letter was revised and addressed to “Staff Pharmacist” and disseminated to those pharmacies enrolled in the TIRF REMS Access Program (question added as requested by the FDA). A total of 4906 pharmacists were identified and all were sent letters inviting them to participate in this survey (Table 1). Of those invited to participate, 571 were inpatient pharmacists, 2478 were outpatient pharmacists, and 36 were pharmacists practicing in CSPs (no CSP outpatient pharmacists participated in the survey; see Section 5.2.7). An additional 4593 reminder letters were sent to non-responders (See Section 3.1 for survey methodology details). Most pharmacists received more than 1 reminder letter. The survey was closed once the target number of 300 completed surveys was achieved. As noted in Section 3.1 availability of the survey was expected to extend through 20 October 2015. The survey launch date had been delayed in order to incorporate FDA feedback on the survey received in the 36-Month FDA Assessment Report Acknowledgement Letter. Successful recruitment resulted in the survey closing earlier than expected on 16 September 2015. From the total of 607 pharmacists who accessed the survey, 334 (55.0%) pharmacists met eligibility criteria, and of those who met eligibility criteria, 301 (90.1%) completed the survey. Of these 301 pharmacists, 293 (97.3%) completed the survey online, and 8 (2.7 %) completed it by telephone (Table 3). Table 1. Survey Participant Administration Results Summary Statistic Number of invitations distributed Number of invitations returned as undeliverable N % 4906 45 Number of reminder letters distributed 4593 All Respondents 1 607 12.5 Eligible Respondents 2 334 55.0 Completed survey 3 301 90.1 Did not complete the survey 3 33 9.9 273 45.0 Respondents not eligible 2,4 1 Number of respondents who accessed the survey. Percentage is based on the number of invitations distributed excluding the number of invitations returned as undeliverable. 2 Percentage is based on the number of all respondents. 3 Percentages are based on the number of eligible respondents. 4 Number of respondents who did not meet eligibility criteria or did not complete eligibility questions. FDA_3371 Pharmacist KAB Assessment Report Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 17 of 51 As shown in Table 2, of the 607 pharmacists who accessed the sruvey, a total of 426 pharmacists agreed to participate in this survey. Diu'ing the screening process it was determined 92 respondents were not eligible to participate in the survey because they either did not agree to participate in the survey (1 respondent), indicated they had participated in or did not know whether they participated in a survey about TIRF medicines before (61 respondents), worked in pharmacies that were not em'olled or they did not know whether their pharmacy was em?olled in the TIRF REMS Access Program (27 respondents), or indicated they, or an immediate family member, had worked for a TRIG company, UBC, or FDA in the past or the respondent did not know if they or an immediate family member had worked for a TRIG company, UBC, or FDA in the past (2 respondents). Thus, there were 334 eligible participants; with 301 of these pharmacists completing the s1uyey (Table 2). Table 2. Survey Participant Screening Results Screened Pharmacists Question Question 1: Do you agree to participate in this survey? Yes 426 70.2 No 1 1 0.2 Discontinued 1 80 29.7 Question 2: Have you ever taken part in this survey about TIRF medicines before? TIRF medicines include Abstralo, Actiqo, Fentorao, Lazandao, Subsyso, and generic versions of any of these brandsdon't know 1 52 8.6 Question not asked 2 1 0.2 Discontinued 1 80 29.7 Pharmacist KAB Assessment Report Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Table 2. Page 18 of 51 Survey Participant Screening Results Question Screened Pharmacists (N=607) n (%) n % Question 3: Do you work in a pharmacy that is enrolled in the TIRF REMS Access Program? Yes 338 55.7 No[1] 9 1.5 I don't know 1 18 3.0 Question not asked 2 62 10.2 Discontinued 180 29.7 Question 4: Have you or any of your immediate family members ever worked for any of the following companies or agencies? Please select all that apply. 3 Actavis Laboratories FL, Inc. 1 1 Anesta, LLC[1] 0 BioDelivery Services International, Inc. (BDSI) 1 0 Cephalon, Inc. (a wholly-owned subsidiary of Teva Pharmaceutical Industries, Ltd.) 1 0 Depomed, Inc. 1 0 1 0 Insys Therapeutics, Inc. 1 0 Galena Biopharma, Inc Mallinckrodt Pharmaceuticals 1 McKesson Specialty Care Solutions 1 2 0.2 0.3 0 [1] 1 0.2 Par Pharmaceutical, Inc. 1 2 0.3 RelayHealth 1 0 Teva Pharmaceuticals, Ltd. 1 1 United BioSource Corporation 1 0 FDA 1 0 Mylan, Inc. None of these apply 4 I don't know 1 0.2 334 55.0 2 0.3 FDA_3373 Pharmacist KAB Assessment Report Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Table 2. Page 19 of 51 Survey Participant Screening Results Screened Pharmacists (N=607) n (%) Question n Prefer not to answer 1 % 0 Question not asked 2 89 14.7 Discontinued 180 29.7 1 Ineligible to participate in the survey. Question not asked due to previous termination response. 3 More than one response can be selected, so percentages may not sum to 100%. 4 Ineligible to participate in the survey if selected additionally to another response. Note: Respondents who discontinued the survey before completing all eligibility questions without being identified as ineligible in any of the previous questions are counted as discontinued. Once a respondent is counted as discontinued, they will count as discontinued in all subsequent eligibility questions. 2 Pharmacists taking the survey online took a mean of 15 minutes to complete it, while those taking it by telephone took a mean of 17 minutes (Table 3). Table 3. Time to Complete Survey for Completers Only Time to Complete Survey for Completers (Minutes) Summary Statistic Telephone Internet Total 1 N 8 293 301 Mean (± SD) 17.53 (2.755) 15.19 (8.913) 15.25 (8.812) Minimum 15.3 4.7 4.7 Median 16.27 12.78 12.93 Maximum 21.5 68.4 68.4 0 – <5 Minutes 0 1 1 5 – <10 Minutes 0 97 97 10 – <15 Minutes 0 77 77 15 – <20 Minutes 6 58 64 Category FDA_3374 Pharmacist KAB Assessment Report Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Table 3. Page 20 of 51 Time to Complete Survey for Completers Only Time to Complete Survey for Completers (Minutes) 20 – <25 Minutes 2 34 36 25 – <30 Minutes 0 9 9 30 Minutes or More 0 17 17 1 Number of eligible pharmacists completing the survey (See Table 1). SD = Standard Deviation 5.1.2 Description of Eligible Pharmacists who Completed the Survey The characteristics of pharmacists who completed the survey are shown in Table 4. Most pharmacists (245; 81.4%) functioned as the pharmacist-in-charge for the TIRF REMS Access Program where they work. Despite efforts to ensure that a higher percentage of nonsupervisory dispensing pharmacists were included for this reporting period, only 17.6% of respondents indicated they were not the pharmacist-in-charge. The majority of pharmacists had dispensed a TIRF medicine either not at all (118; 39.2%) or 1 to 2 times per month (112; 37.2%) within the past 6 months. The most frequently dispensed TIRF medicine within the 6 months prior to taking the survey was Actiq® or generic Actiq® (117; 63.9%). The majority of pharmacists who completed the survey were male (192; 63.8%), and out of the 301 eligible pharmacists, 195 (64.8%) had been a practicing pharmacist for 11 or more years. Most participants (119; 39.5%) were from the South, followed by the Northeast (71; 23.6%), Midwest (61; 20.3%) and West (47; 15.6%), regions of the United States (US). There was 1 respondent from Puerto Rico identified as “Other” in Table 4 below. FDA_3375 Pharmacist KAB Assessment Report Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page_21 of 51 Table 4. Description of Eligible Pharmacists ti Eligible/Completed Pharmacists Ques on Question 24: Are you the Pharmacist in Charge for the TIRF REMS Access Program where you work? Yes 245 81.4 No 53 17.6 I don?t know 3 1.0 Question 25: On average, how many times per month have you dispensed TIRF medicines within the last 6 months None 118 39.2 1-2 times per month 112 37.2 3-5 times per month 25 8.3 More than 5 times per month 29 9.6 I don?t remember 17 5.6 Question 26: Please select the TIRF medicine(s) that you have dispensed within the last 6 months (select all that apply): 2?3 Abstral? 12 6.6 Actiq? or generic Actiq? 117 63 .9 Fentora? 63 34.4 Lazanda? 13 7.1 Subsys? 58 3 1.7 (answered None to Question 25) 118 Question 27: What is your gender? Male 192 63 .8 Female 101 33.6 Prefer not to answer 8 2.7 Question 28: In total, how many years have you been a practicing pharmacist? Less than 3 years 17 5.6 3-5 years 33 11.0 6-10 years 51 16.9 11-15 years 36 12.0 More than 15 years 159 52.8 Prefer not to answer 5 1.7 Pharmacist KAB Assessment Report Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Table 4. Page 22 of 51 Description of Eligible Pharmacists Eligible/Completed Pharmacists N=3011 Question n % Geographic Distribution (based on Question 29 - In which state do you practice?)? 4 Northeast 71 23.6 Midwest 61 20.3 South 119 39.5 West 47 15.6 Other 1 0.3 Prefer not to answer 2 0.7 1 Number of eligible pharmacists completing the survey (See Table 1). Percentages are calculated based on the number of respondents to whom the question was presented. 3 More than one response can be selected, so percentages may not sum to 100%. 4 U.S. Census Bureau, last revised Friday, 27-Jul-2001 12:59:43 EDT., Geography Division. Northeast includes CT, MA, ME, NH, NJ, NY, PA, RI, and VT. Midwest includes IA, IL, IN, KS, MI, MN, MO, ND, NE, OH, SD, and WI. South includes AL, AR, DC, DE, FL, GA, KY, LA, MD, MS, NC, OK, SC, TN, TX, VA, and WV. West includes AK, AZ, CA, CO, HI, ID, MT, NM, NV, OR, UT, WA, and WY. Other includes Puerto Rico, Northern Mariana Islands, US Virgin Islands, American Samoa and Guam. 2 5.1.3 TIRF Medicines Educational Materials Pharmacists were asked about their access to educational materials for TIRF medicines, specifically the Full Prescribing Information and the Medication Guide (Table 5). Almost all pharmacists reported they had received or had access to the Full Prescribing Information and the Medication Guide (299; 99.3%; and 300; 99.7%, respectively). Of those with access to these materials, 82.6% and 87.7%, respectively, indicated that they had read the Full Prescribing Information and the Medication Guide. Table 5. Responses to Questions About TIRF Medicines Educational Materials Eligible/Completed Pharmacists N=3011 Question n % Question 18: Did you receive or do you have access to the Full Prescribing Information for the TIRF medicine(s) that you dispense? Yes 299 No 0 I don’t know 2 99.3 0.7 FDA_3377 Pharmacist KAB Assessment Report Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Table 5. Page 23 of 51 Responses to Questions About TIRF Medicines Educational Materials Eligible/Completed Pharmacists N=3011 Question n % Question 19: Did you read the Full Prescribing Information for the TIRF medicine(s) that you dispense? 2 Yes 247 82.6 No 45 15.1 I don’t know 7 2.3 N/A (answered No or I don’t know to Question 18) 2 Question 20: Did you receive or do you have access to the Medication Guide for the TIRF medicine(s) that you dispense? Yes 300 No 0 I don’t know 1 99.7 0.3 Question 21: Did you read the Medication Guide for the TIRF medicine(s) that you dispense? 2 Yes 263 87.7 No 30 10.0 I don’t know 7 2.3 N/A (answered No or I don’t know to Question 20) 1 Question 22: Did you or do you have any questions about the information in the Full Prescribing Information or Medication Guide? Yes 3 5 1.7 No 283 94.0 I don’t know 13 4.3 1 Number of eligible pharmacists completing the survey (See Table 1). Percentages are calculated based on the sample presented with this question because of skip logic in the survey. 3 Verbatim text for questions about the information in the Full Prescribing Information or the Medication Guide is presented in Appendix B, Listing 1. 2 5.2 Key Risk Messages 5.2.1 Key Risk Message 1 Key Risk Message 1 refers to the pharmacist’s knowledge of the specific contraindications for TIRF medicines in opioid non-tolerant patients and under what conditions a patient is considered opioid tolerant. FDA_3378 Pharmacist KAB Assessment Report Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 24 of 51 A high percentage of pharmacists knew that patients with cancer who are considered opioidtolerant are those who are taking around-the-clock opioid therapy for cancer pain for one week or longer (92.7%, 95% CI: 89.1-95.4) and are those who are currently taking opioid therapy (87.4%, 95% CI: 83.1-90.9) (Table 6). In addition, most understood that cancer patients with no known contraindications to the drug fentanyl, but who are not taking aroundthe-clock opioid therapy, are not considered opioid tolerant (82.4%, 95% CI: 77.6-86.5). Ninety-one percent (91.0%, 95% CI: 87.2-94.0) of pharmacists knew that TIRF medicines are contraindicated in opioid non-tolerant patients because life-threatening respiratory depression could occur and that death has occurred in opioid non-tolerant patients treated with some fentanyl products (95.3%, 95%CI: 92.3-97.4). Eighty-five percent (85.4%, 95% CI: 80.9-89.2) were aware that TIRF medicines may not be used to treat opioid non-tolerant patients (85.4%). Similarly, 80.7% (95% CI: 75.8-85.0) of pharmacists were aware that dose titration for patients starting a TIRF medicine must begin with the lowest available dose for that product. The majority of pharmacists were aware of the regimens that defined an opioid-tolerant patient: 8 mg oral hydromorphone/day (78.8%, 95% CI: 73.7-83.2), 60 mg oral morphine/day (89.7%, 95% CI: 85.7-92.9), 30 mg oral oxycodone/day (77.1%, 95%CI: 71.981.7), 25 mcg transdermal fentanyl/hour (77.1%; 95% CI: 71.9-81.7), 25 mg oral oxymorphone/day (73.4%, 95% CI: 68.1-78.3), and an equianalgesic dose of another oral opioid (65.1%, 95% CI: 59.4-70.5). Overall, 29.6% (95% CI: 24.5-35.1) of respondents answered all 13 components of key risk message 1 correctly, 51.5% missed no more than one component and 63.8% missed no more than two. Analyses stratified by whether the Full Prescribing Information and Medication Guide were received and read (Received and read: N=273; Did not receive or read: N=28) and by modality for completing the survey (internet [N=293] versus telephone [N=8]) were not performed for any of the key risk messages because they did not meet the criteria of ≥50 respondents within at least two response categories. Stratification by time in practice or number of times TIRF medicines were dispensed in the last 6 months did not result in any evident trends (Appendix B). FDA_3379 Pharmacist KAB Assessment Report Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Table 6. Page 25 of 51 Responses Linked to Key Risk Message 1: TIRF Medicines Are Contraindicated in Opioid Non-Tolerant Patients Question Eligible/Completed Pharmacists N=301 1 n % (95% CI) 2 Question 5: Please select True, False, or I don’t know for each of the following. According to the labeling for TIRF medicines, patients with cancer who are considered opioidtolerant are those: 5a: Who are taking around-the-clock opioid therapy for underlying persistent cancer pain for one week or longer True 3 279 92.7 (89.1 - 95.4) False 22 7.3 I don’t know 0 5b: Who are not currently taking opioid therapy, but have taken opioid therapy before True 27 9.0 False 3 263 87.4 (83.1 - 90.9) I don’t know 11 3.7 5c: Who have no known contraindications to the drug fentanyl, but are not currently taking around-the-clock opioid therapy True 44 14.6 False 3 248 82.4 (77.6 - 86.5) 9 3.0 I don’t know Question 7: Please answer True, False, or I don’t know for each statement based on the labeling for TIRF medicines. 7a: TIRF medicines are contraindicated in opioid non-tolerant patients because life-threatening respiratory depression could occur at any dose. True 3 274 91.0 (87.2 - 94.0) False 19 6.3 I don’t know 8 2.7 FDA_3380 Pharmacist KAB Assessment Report Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Table 6. Page 26 of 51 Responses Linked to Key Risk Message 1: TIRF Medicines Are Contraindicated in Opioid Non-Tolerant Patients Question Eligible/Completed Pharmacists N=301 1 n % (95% CI) 2 7b: Death has occurred in opioid non-tolerant patients treated with some fentanyl products. True 3 287 95.3 (92.3 - 97.4) False 4 1.3 I don’t know 10 3.3 7c: TIRF medicines may be used in opioid non-tolerant patients. True 35 11.6 False 3 257 85.4 (80.9 - 89.2) 9 3.0 I don’t know 7d: Prescribers starting a patient on a TIRF medicine must begin with titration from the lowest dose available for that specific product, even if the patient has previously taken another TIRF medicine. True 3 243 80.7 (75.8 - 85.0) False 45 15.0 I don’t know 13 4.3 Question 11: Please select True, False, or I don’t know for each of the following. According to the labeling for TIRF medicines, patients considered opioid-tolerant are those who are taking, for one week or longer, at least: 11a: 8 mg oral hydromorphone/day True 3 237 78.7 (73.7 - 83.2) False 30 10.0 I don’t know 34 11.3 270 89.7 (85.7 - 92.9) 11b: 60 mg oral morphine/day. True 3 FDA_3381 Pharmacist KAB Assessment Report Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Table 6. Page 27 of 51 Responses Linked to Key Risk Message 1: TIRF Medicines Are Contraindicated in Opioid Non-Tolerant Patients Question Eligible/Completed Pharmacists N=301 1 n % (95% CI) 2 False 11 3.7 I don’t know 20 6.6 True 3 232 77.1 (71.9 - 81.7) False 41 13.6 I don’t know 28 9.3 True 3 232 77.1 (71.9 - 81.7) False 42 14.0 I don’t know 27 9.0 True 3 221 73.4 (68.1 - 78.3) False 36 12.0 I don’t know 44 14.6 True 3 196 65.1 (59.4 - 70.5) False 49 16.3 I don’t know 56 18.6 11c: 30 mg oral oxycodone/day 11d: 25 mcg transdermal fentanyl/hour 11e: 25 mg oral oxymorphone/day 11f: An equianalgesic dose of another oral opioid Secondary Analysis: Number of Correct Responses 0 correct responses 0 1 correct response 1 0.3 2 correct responses 1 0.3 3 correct responses 2 0.7 4 correct responses 4 1.3 FDA_3382 Pharmacist KAB Assessment Report Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Table 6. Page 28 of 51 Responses Linked to Key Risk Message 1: TIRF Medicines Are Contraindicated in Opioid Non-Tolerant Patients Question Eligible/Completed Pharmacists N=301 1 n % (95% CI) 2 5 correct responses 5 1.7 6 correct responses 9 3.0 7 correct responses 13 4.3 8 correct responses 11 3.7 9 correct responses 30 10.0 10 correct responses 33 11.0 11 correct responses 37 12.3 12 correct responses 66 21.9 89 29.6 (24.5 - 35.1) 13 correct responses 1 Number of eligible pharmacists completing the survey (See Table 1). 95% exact two-sided confidence intervals are calculated using the Clopper-Pearson method. 3 Indicates the correct response(s) to each question or component within a question. 2 5.2.2 Key Risk Message 2 Key Risk Message 2 refers to the pharmacist’s knowledge of the indications for prescribing TIRF medicines for the management of breakthrough pain in opioid-tolerant adult cancer patients, and the timing of administration of the TIRF medicine in relation to the around-theclock opioid therapy to ensure the patient is considered opioid tolerant. Sixty-nine percent (69.1%, 95% CI: 63.5-74.3) of pharmacists correctly indicated that a cancer patient should not be started on a TIRF medicine and an around-the-clock opioid at the same time, and 82.1% (95% CI: 77.2-86.2) correctly indicated that a cancer patient who had been on an around-the-clock opioid for one day should not start taking a TIRF medicine for breakthrough pain (Table 7). Forty-two percent (41.9%; 95% CI: 36.2-47.7) understood that a patient must stop taking their TIRF medicine if they stop taking their around-the-clock opioid pain medicine (question added as requested by the FDA). In addition, 92.0% of pharmacists (95% CI: 88.4-94.8) were aware that TIRF medicines are indicated for opioid-tolerant patients with breakthrough pain from cancer and not for patients with acute or postoperative pain (90.0%, 95% CI: 86.1-93.2), headache or migraine pain (93.0%, 95% CI: 89.5-95.6), or dental pain (98.3%, 95% CI: 96.2-99.5). Fifty-one percent (50.8%, 95% CI: 45.0 - 56.6) correctly responded that TIRF medicines should not be prescribed for chronic non-cancer pain. FDA_3383 Pharmacist KAB Assessment Report Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 29 of 51 Overall, 22.3% (95% CI: 17.7-27.4) correctly answered all components of the key risk message; 45.6% missed no more than one component question, and 70.2% missed no more than two of the eight components. Stratification by time in practice or number of times TIRF medicines were dispensed in the last 6 months did not result in any evident trends (Appendix B). Table 7. Responses Linked to Key Risk Message 2: TIRF Medicines Are Only Indicated for the Management of Breakthrough Pain in Adult Cancer Patients 18 Years of Age and Older (16 Years of Age and Older for Actiq® Brand and Generic Equivalents) Who Are Already Receiving and Who Are Tolerant to Around-The-Clock Opioid Therapy for Their Underlying Persistent Cancer Pain Question Eligible/Completed Pharmacists N=301 1 n % (95% CI) 2 Question 6: Please answer True, False, or I don’t know for each statement based on the labeling for TIRF medicines. 6a: According to the product labeling, a cancer patient may start a TIRF medicine and an around-the-clock opioid at the same time. True 70 23.3 False 3 208 69.1 (63.5 - 74.3) I don’t know 23 7.6 6b: According to the product labeling, a cancer patient who has been on an around-the-clock opioid for 1 day can start taking a TIRF medicine for breakthrough pain. True 37 12.3 False 3 247 82.1 (77.2 - 86.2) I don’t know 17 5.6 6c: A patient must stop taking their TIRF medicine if they stop taking their around-the-clock opioid pain medicine. True 3 126 41.9 (36.2 - 47.7) False 136 45.2 I don’t know 39 13.0 FDA_3384 Pharmacist KAB Assessment Report Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Table 7. Page 30 of 51 Responses Linked to Key Risk Message 2: TIRF Medicines Are Only Indicated for the Management of Breakthrough Pain in Adult Cancer Patients 18 Years of Age and Older (16 Years of Age and Older for Actiq® Brand and Generic Equivalents) Who Are Already Receiving and Who Are Tolerant to Around-The-Clock Opioid Therapy for Their Underlying Persistent Cancer Pain Question Eligible/Completed Pharmacists N=301 1 n % (95% CI) 2 Question 9: Per the approved labeling for TIRF medicines, for which of the following indications can TIRF medicines be prescribed to opioid tolerant patients? Please answer Yes, No, or I don’t know for each option. 9a: Acute or postoperative pain Yes 22 7.3 No 3 271 90.0 (86.1 - 93.2 8 2.7 Yes 12 4.0 No 3 280 93.0 (89.5 - 95.6) 9 3.0 Yes 2 0.7 No 3 296 98.3 (96.2 - 99.5) 3 1.0 Yes 3 277 92.0 (88.4 - 94.8) No 24 8.0 I don’t know 0 I don’t know 9b: Headache or migraine pain I don’t know 9c: Dental pain I don’t know 9d: Breakthrough pain from cancer FDA_3385 Pharmacist KAB Assessment Report Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Table 7. Page 31 of 51 Responses Linked to Key Risk Message 2: TIRF Medicines Are Only Indicated for the Management of Breakthrough Pain in Adult Cancer Patients 18 Years of Age and Older (16 Years of Age and Older for Actiq® Brand and Generic Equivalents) Who Are Already Receiving and Who Are Tolerant to Around-The-Clock Opioid Therapy for Their Underlying Persistent Cancer Pain Question Eligible/Completed Pharmacists N=301 1 n % (95% CI) 2 Yes 131 43.5 No 3 153 50.8 (45.0 - 56.6) I don’t know 17 5.6 9e: Chronic non-cancer pain Secondary Analysis: Number of Correct Responses 0 correct responses 0 1 correct response 2 0.7 2 correct responses 2 0.7 3 correct responses 11 3.7 4 correct responses 26 8.6 5 correct responses 49 16.3 6 correct responses 74 24.6 7 correct responses 70 23.3 67 22.3 (17.7 - 27.4) 8 correct responses 1 Number of eligible pharmacists completing the survey (See Table 1). All confidence intervals are exact binomial 95% confidence intervals. 3 Indicates the correct response(s) to each question or component within a question. 2 5.2.3 Key Risk Message 3 Key Risk Message 3 refers to the pharmacist’s knowledge of the risk factors for opioid abuse and importance in monitoring for signs of abuse in patients who take TIRF medicines. Results in Table 8 show that 97.3% (95% CI: 94.8-98.8) of pharmacists were aware that it is important to monitor for signs of abuse and addiction in patients who take TIRF medicines. In addition, most respondents correctly indicated that a personal history of psychiatric illness is a risk factor for opioid abuse (75.4%, 95% CI: 70.1-80.2), that a personal history of past or FDA_3386 Pharmacist KAB Assessment Report Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 32 of 51 current alcohol or drug abuse or family history of drug or alcohol abuse is a risk factor for opioid abuse 95% I: and that TIRF medicines can be abused in a manner similar to other opioid agonists 95.7%, 95% CI: Overall, 69.1% (95% CI: 63.5-74.3) of pharmacists correctly answered all components of the key risk message, and 98% missed no more than one of the 4 component questions. Strati?cation by time in practice or number of times TIRF medicines were dispensed in the last 6 months did not result in any evident trends (Appendix B). Table 8. Responses Linked to Key Risk Message 3: TIRF Medicines Contain Fentanyl, an Opioid Agonist and a Schedule II Controlled Substance, With Abuse Liability Similar to Other Opioid Analgesics Eligible/Completed Pharmacists 1 Question (95% CI) 2 Question 7: Please answer True, False, or I don?t know for each statement based on the labeling for TIRF medicines. 7e: It is important to monitor for signs of abuse and addiction in patients who take TIRF medicines. True 3 293 97.3 (94.8 - 98.8) False 7 2.3 I don?t know 1 0.3 Question 8: Which of the following are risk factors for opioid abuse? Please answer Yes, No, or I don?t know for each option. 8a: A personal history of illness 227 75.4 3 Yes (70.1 - 80.2) No 43 14.3 I don?t know 31 10.3 8b: A personal history of past or current alcohol or drug abuse, 01' a family history of illicit drug use or alcohol abuse 297 98.7 3 Yes (96.6 - 99.6) No 2 0.7 I don?t know 2 0.7 Pharmacist KAB Assessment Report Transmucosal Irmnediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 33 of 51 Table 8. Responses Linked to Key Risk Message 3: TIRF Medicines Contain Fentanyl, an Opioid Agonist and a Schedule II Controlled Substance, With Abuse Liability Similar to Other Opioid Analgesics Eligible/Completed Pharmacists 1 Question (95% CI) 2 Question 10: Please answer True, False, or I don?t know for each statement about TIRF medicines. 10a: TIRF medicines can be abused in a manner similar to other opioid agonists. True 3 288 95.7 (92.7 - 97.7) False 8 2.7 I don?t know 5 1.7 Secondary Analysis: Number of Correct Responses 0 correct responses 0 1 correct response 0 2 correct responses 6 2'0 3 correct responses 87 28'9 208 69.1 4 correct responses (63.5 - 74.3) 1 Nrunber of eligible pharmacists completing the survey (See Table 1). 2 All con?dence intervals are exact binomial 95% con?dence intervals. 3 Indicates the correct response(s) to each question or component within a question. 5.2.4 Key Risk Message 4 Key Risk Message 4 refers to the pharmacist?s knowledge of the interchangeability of TIRF medicines based on route of administration, pharmacokinetic absorption, and dosage. Ahnost all pharmacists 95% I: 89.9-95.9) rmderstood TIRF medicines are not interchangeable with each other regardless of the route of administration; 92.7% (95% I: 89.1-95.4) rmderstood the conversion of one TIRF medicine to another may result in a fatal overdose; and 92.7% (95% CI: 89.1-95.4) lmderstood that dosing of TIRF medicines is not equivalent on a microgram-to-microgram basis (Table 9). Ahnost all pharmacists 95% I: 96.2-99.5) correctly indicated that TIRF medicines with the same route of administration cannot be substituted with each other if the pharmacy is out of stock. Pharmacist KAB Assessment Report Transmucosal Release Fentanyl (TIRF) TIRF REMS Industiv Group (TRIG) of Companies Page 34 of 51 Overall, 80.7% (95% I: 75.8-85.0) of pharmacists correctly answered all components of the key risk message, 97% missed no more than one of the 4 component questions. Strati?cation by time in practice or number of times TIRF medicines were dispensed in the last 6 months did not result in any evident trends (Appendix B). Table 9. Responses Linked to Key Risk Message 4: TIRF Medicines Are Not Interchangeable with Each Other, Regardless of Route of Administration Eligible/Completed Pharmacists 1 Question (95% CI) 2 Question 10: Please answer True, False, or I don?t know for each statement based on the labeling for TIRF medicines. 10b: TIRF medicines are interchangeable with each other regardless of route of administration. True 14 4.7 281 93.4 Fl 3 a 56 (89.9 95.9) I don?t know 6 2.0 10c: The conversion of one TIRF medicine for another TIRF medicine may result in a fatal overdose because of differences in the pharmacokinetics of fentanyl absorption. True 3 279 92.7 (89.1 - 95.4) False 11 3.7 I don?t know 11 3.7 10d: Dosing of TIRF medicines is not equivalent on a microgram?to-microgram basis. True 3 279 92.7 (89.1 - 95.4) False 14 4.7 I don?t know 8 2.7 Pharmacist KAB Assessment Report Transmucosal Irmnediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 35 of 51 Table 9. Responses Linked to Key Risk Message 4: TIRF Medicines Are Not Interchangeable with Each Other, Regardless of Route of Administration Eligible/Completed Pharmacists 1 Question 11 (95% CI) 2 Question 13: Please answer True, False, or I don?t know for each statement about TIRF medicines. 13c: TIRF medicines with the same route of administration can be substituted with each other if the pharmacy is out of stock for one product. True 3 1.0 False 2 296 98.3% (96.2 - 99.5) I don?t know 2 0.7 Secondary Analysis: Number of Correct Responses 0 correct responses 0 1 correct response 2 0.7 2 correct responses 7 2.3 3 correct responses 49 16.3 243 80.7 4 OITCC (75.8 - 85.0) 1 Nrunber of eligible pharmacists completing the survey (See Table 1). 2 All con?dence intervals are exact binomial 95% con?dence intervals. 3 Indicates the correct response(s) to each question or component within a question. 5.2.5 Other Survey Questions 5 2.5.1. Additional Questions about TIRF Medicines Safety Table 10 srumnar?izes the pharmacists? responses to additional questions about the safe use of TIRF medicines beyond those associated with the key risk messages. Most pharmacists correctly indicated that use of a TIRF medicine with a CYP3A4 inhibitor may require dosage adjustment and monitoring of the patient as potentially fatal respiratory depression could occru'(question added as requested by the FDA) . The majority of pharmacists correctly indicated that a family history of asthma is not a risk factor for opioid abuse In addition. 92.7% of pharmacists correctly indicated that TIRF medicines may not be sold, loaned, or transferred to another pharmacy, and that pharmacy staff who dispense TIRF Pharmacist KAB Assessment Report Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 36 of 51 medicines must be educated on the requirements of the TIRF REMS Access Program (90.7%). Thirteen (86.7%) inpatient pharmacists correctly indicated that it is not OK to dispense TIRF medicines from the inpatient pharmacy inventory to an outpatient for home use (Table 11). Table 10. Responses to Additional Questions about the Safe Use of TIRF Medicines Question Eligible/Completed Pharmacists N=301 1 n % Question 6: Please answer True, False, or I don’t know for each statement based on the labeling for TIRF medicines. 6d: Use of a TIRF medicine with a CYP3A4 inhibitor may require dosage adjustment and monitoring of the patient for opioid toxicity as potentially fatal respiratory depression could occur. True 2 275 91.4 False 8 2.7 I don’t know 18 6.0 Question 8: Which of the following are risk factors for opioid abuse? Please answer Yes, No, or I don’t know for each option. 8c: A family history of asthma Yes 33 11.0 No2 249 82.7 I don't know 19 6.3 Question 13: Please answer True, False, or I don’t know for each statement about TIRF medicines. 13a: TIRF medicines may be sold, loaned, or transferred to another pharmacy. 7 2.3 False 2 279 92.7 I don’t know 15 5.0 True 13b: All pharmacy staff that dispenses TIRF medicines must be educated on the requirements of the TIRF REMS Access Program. 90.7 True2 273 FDA_3391 Pharmacist KAB Assessment Report Transmucosal Iimnediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 37 of 51 Table 10. Responses to Additional Questions about the Safe Use of TIRF Medicines Eligible/Completed Pharmacists Question False 23 7-6 I don?t know 5 1-7 1 Niunber of eligible pharmacists who completed the sru?vey (See Table 1). 2Indicates the correct response(s) to each question or component within a question. Table 11. Responses to Additional Questions about the Safe Use of TIRF Medicines: Question Asked of Inpatient Pharmacists Eligible/Completed Pharmacists Question 1 Question 17: Please answer True, False, or I don?t know for the following statement about TIRF medicines. (Inpatient pharmacists, only) It is OK to dispense TIRF medicines from the inpatient pharmacy inventory to an outpatient for use at home.2 True 0 False 3 13 86.7 I don?t know 2 13-3 N1unber of eligible inpatient pharmacists who completed the Slu'vey 2 This question is presented only to the sub-group of inpatient pharmacists. Percentages are based on this subgroup of N=l 5. 3 Indicates the correct response(s) to each question or component within a question. 5.2.5.2 Pharmacist Activities When Dispensing TIRF Medicines Pharmacists were asked about speci?c activities performed when dispensing TIRF medicines (Table 12). Of the 301 eligible phaimacists who completed the sruvey, 59.8% responded they always ask their patients (or a patient?s caregiver) about the presence of children in the home; 22.3% responded that they ask only with the ?rst prescription. Additionally, 78.1% responded they always instluct patients (or their caregivers) not to share TIRF medicines; 71.8% responded they always counsel patients (or their caregivers) that accidental exposure to TIRF medicines Pharmacist KAB Assessment Report Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 38 of 51 by a child may be fatal, 79.1% responded they always instruct patients (or their caregivers) to keep TIRF medicines out of reach of children, 69.4% responded they always instruct patients (or their caregivers) about proper disposal of any unused or partially used TIRF medicines, and 92.4% responded they always give patients (or their caregivers) the Medication Guide for TIRF medicine. Table 12. Responses to Questions about Activities When Dispensing TIRF Medicines Question Eligible/Completed Pharmacists N=301 1 n % Question 12: How frequently do you perform the following activities when dispensing TIRF medicines? Please answer Always, Only with the first prescription, Sometimes, Never, or I don’t know. 12a: Ask patients (or their caregivers) about the presence of children in the home. Always 180 59.8 Only with the first prescription 67 22.3 Sometimes 36 12.0 Never 9 3.0 I don’t know 9 3.0 12b: Instruct patients (or their caregivers) not to share TIRF medicines with anyone else. Always 235 78.1 Only with the first prescription 42 14.0 Sometimes 14 4.7 Never 6 2.0 I don’t know 4 1.3 12c: Counsel patients (or their caregivers) that accidental exposure to TIRF medicines by a child may be fatal. Always 216 71.8 Only with the first prescription 48 15.9 Sometimes 27 9.0 Never 4 1.3 I don’t know 6 2.0 FDA_3393 Pharmacist KAB Assessment Report Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Table 12. Page 39 of 51 Responses to Questions about Activities When Dispensing TIRF Medicines Question Eligible/Completed Pharmacists N=301 1 n % 12d: Instruct patients (or their caregivers) to keep TIRF medicines out of the reach of children to prevent accidental exposure. Always 238 79.1 Only with the first prescription 39 13.0 Sometimes 16 5.3 Never 4 1.3 I don’t know 4 1.3 12e: Instruct patients (or their caregivers) about proper disposal of any unused or partially used TIRF medicines. Always 209 69.4 Only with the first prescription 66 21.9 Sometimes 20 6.6 Never 3 1.0 I don’t know 3 1.0 12f: Give patients (or their caregivers) the Medication Guide for their TIRF medicine. Always 278 92.4 Only with the first prescription 14 4.7 Sometimes 4 1.3 Never 2 0.7 I don’t know 3 1.0 1 Number of eligible pharmacists completing the survey (See Table 1). Specific pharmacy types (inpatient, outpatient, and CSP pharmacies) were each asked a single, different question regarding pharmacy systems and processes. Question 14 was presented only to respondents from inpatient pharmacies (N=15) as identified through the access code entered by the respondent (Table 13). Of the 15 respondents, 53.3% reported their pharmacy has processes to ensure compliance with the TIRF REMS Access Program requirements. FDA_3394 Pharmacist KAB Assessment Report Transmucosal Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 40 of 51 Table 13. Responses to All Questions about Activities When Dispensing TIRF Medicines: Asked of Inpatient Pharmacies Only Eligible/Completed Inpatient Pharmacists Question Question 14: Does the inpatient pharmacy where you work have an established system, order sets, protocols and/or other measures to help ensure appropriate patient selection and compliance with the requirements of the TIRF REMS Access Program? [Inpatient pharmacists only] 2 Yes 8 53.3 No 7 46.7 I don't know 0 1 Number of eligible inpatient pharmacists who completed the survey. 2 This question is presented only to a sub-group of pharmacists. Percentages are based on the number of inpatient phamracists to whom this question was presented. Question 15 was presented only to pharmacy respondents from outpatient pharmacies (n=286) as identi?ed though the access code entered by the respondent. This sub-population did not include respondents from SPs (Table 14). Of the 286 respondents, 91.6% reported their pharmacy processes prescriptions for TIRF medicines tln?ough their pharmacy management system. Table 14. Responses to All Questions about Activities When Dispensing TIRF Medicines: Outpatient Pharmacists Only Eligible/Completed Outpatient . Pharmacists Question 1 Question 15: Does the outpatient or retail pharmacy where you work process all TIRF medicine prescriptions, regardless of method of payment, through the pharmacy management system? [Outpatient pharmacists only] 2 Yes 262 91.6 No 10 3.5 I don't know 14 4.9 Nrunber of eligible outpatient pharmacists who completed the sruvey. 2 This question is presented only to a sub-group of pharmacists. Percentages are based on the number of outpatient pharmacists to whom this question was presented. Pharmacist KAB Assessment Report Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 41 of 51 Question 16 (Does the pharmacy where you work process all TIRF medicine prescriptions, regardless of method of payment, through the TIRF REMS Access Call Center?) was presented only to pharmacy respondents from CSPs; however, no CSP outpatient pharmacists participated in the survey. 5.3 Spontaneous Reporting of Potential Adverse Events, Product Complaints, or Medical Information Requests Among all survey respondents (N=301, Table 1), there were 3 reports of a potential adverse event or product complaint associated with the use of TIRF medicines made within the survey free text field during the online survey. Verbatim statements are provided in Appendix B, Listing 2. 6. DISCUSSION AND CONCLUSIONS Discussion Survey invitations (and reminders) were sent to a random sample of pharmacies enrolled in the TIRF REMS Access Program. From among those who responded to the invitation, 301 pharmacists completed the survey. Thus, the required sample size was achieved within the planned survey period. The specific goals of the TIRF medicines pharmacist KAB survey were to assess pharmacist understanding of the risks associated with TIRF medicine use, the specific indications for treatment with TIRF medicines, and that TIRF medicines are contraindicated in opioid nontolerant patients. The survey also included questions about the pharmacists’ access to educational materials for TIRF medicines. Despite efforts to ensure that a higher percentage of non-supervisory dispensing pharmacists were included for this reporting period, only 17.6% of respondents indicated they were not the pharmacist-in-charge (question added as requested by FDA). Of the 29 components included as part of key risk messages, 20 components of the key risk messages had a response rate >80%, and 7 components had a response rate between 65.1% to 78.7%. Two components within the key risk messaged had a correct response rate below the desired threshold of 65% (Component 6c and Component 9e). The correct response rate for Component 6c (A patient must stop taking their TIRF medicine if they stop taking their around-the-clock opioid pain medicine) was 41.9%. This component was added to the 48-month survey based on feedback provided by FDA in the 24-month and the 36-month FDA REMS Acknowledgement Letter (See Section 1.1). Correct response rate for Component 9e (Chronic non-cancer pain is not an indication for which TIRF medicines can be prescribed) was 50.8% for this 48-month survey, which fell below the desired level of understanding of 65%. Component 9e has had a low correct response rate across all pharmacist KAB surveys conducted (12-month, 24-month, 36-month, and 48-month surveys). However, the correct response rate is trending up (Table 15). The FDA_3396 Pharmacist KAB Assessment Report Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 42 of 51 survey score for Component 9e may indicate that some respondents are dispensing TIRF medicines for non-cancer associated indications. As shown in Table 15, there is a clear and consistent indication of improvement (i.e., numeric trend) in knowledge and understanding of the key risk messages. Table 15 includes key risk messages and questions/components within each key risk message as presented in the 48-month survey. It is important to note the question/component numbering, wording, and association with a specific key risk message may have changed across survey waves based on FDA feedback or other decisions made by the TRIG. FDA_3397 Pharmacist KAB Assessment Report Transmucosal Iimnediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 43 of 51 Table 15. Correct Response Rate Over Time 48-Month lZ-Month Survey 24-Month Survey 36-Month Survey 48-Month Survey Survey Questions as Presented in Correct/Desired Correct/Desired Correct/Desired Correct/Desired Question the 48-Month Survey Response Response Response Response Number (95% CI) (95% CI) (95% CI) (95% CI) Key Risk Message 1: TIRF Medicines Are Contraindicated in Opioid Non?Tolerant Patients 5 Please select True. False. or I don?t know for each of the following. According to the labeling for TIRF medicines. patients with cancer who are considered opioid-tolerant are those: 1 53 W110 are taking around-the- clogk 1oplord therapytfor 12 62 90 3 93.7 92-7 1111. er persrs en cancer (86.4. 93.4) (90.3. 96.1) (89.1 - 95.4) pam for one week or longer (Conecr Response True) 1 5b W110 are 110tc1ure11tly taking opioid therapy. but have 80 12 80.7 87.0 87,4 taken opioid therapy before (75 7. 85.0) (82.7. 90.6) (83.1 - 90.9) (Correct Response ?False 5c W110 have no known contraindications to the drug fentanyl. but are not currently 1 5 62 76.0 78.7 82.4 taking around-the-clock (70.8. 80.7) (73.6. 83.2) (77.6 - 86.5) opioid therapy Response False) 1 7 Please answer Tnle. False. or I don?t know for each statement based on the labeling for TIRF medicines. 1 7a TIRF medicines are contraindicated in opioid ., depression could occur at any (81.7. 89.8) (81.6. 89.7) (86.8. 93.7) (87.2 - 94.0) dose (Conect Response True) Pharmacist KAB Assessment Report Transmucosal Iimnediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 44 of 51 Table 15. Correct Response Rate Over Time 48-Month lZ-Month Survey 24-Month Survey 36-Month Survey 48-Month Survey Survey Questions as Presented in Correct/Desired Correct/Desired Correct/Desired Correct/Desired Question the 48-Month Survey Response Response Response Response Number (95% CI) (95% CI) (95% CI) (95% CI) 7b Death has occurred in opioid non-tolerant patients treated 92.1 93.7 93 .7 95.3 with some fentanyl products (884. 94,8) (90.3. 96.1) (90.3. 96.1) (92.3 - 97.4) (Conect Response True) 7c TIRF medicines may be used to treat opioid non-tolerant 78.5 82.0 83.7 8 54 patients (Conecr Response (73.4. 83.0) (77.2. 86.2) (79.0. 87.7) (80.9 - 89.2) False) 1 7d Prescribers starting a patient on a TIRF medicine must begin with titration from the lowest dose available for that 78.5 82.7 79.0 80.7 speci?c product. even if the (73,4. 830) (77.9. 86.8) (73.9. 83.5) (75.8 - 85.0) patient has previously taken another TIRF medicine (Cozrect Response True) 11 Please select True. False. or I don?t know for each of the following. According to the labeling for TIRF medicines. patients considered opioid- tolerant are those who are taking. for one week or longer. at least: 8 mg oral 78 7 11a hydromorphone/day (Cozrect 79.02 76.32 (73.7 - 83.2) Response True) 60 mg oral morphine/day A 2 2 89.7 Mb (Correct Response True) 85'0 84'7 (85.7 - 92.9) 30 mg oral oxycodone/day A 2 2 77.1 ?c (Correct Response True) 71'3 73'3 (71.9 - 81.7) 25 inc transdennal 2 2 77.1 11d 72.0 74.3 fentanyl/hour (Cozrect (71-9 81-7) Pharmacist KAB Assessment Report Transmucosal Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 45 of 51 Table 15. Correct Response Rate Over Time 48-Month lZ-Month Survey 24?Month Survey 36-Month Survey 48-Month Survey Survey Questions as Presented in Correct/Desired Correct/Desired Correct/Desired Correct/Desired Question the 48-Month Survey Response Response Response Response Number (95% CI) (95% CI) (95% CI) (95% CI) Response True) 25 mg oral oxymorphone/day A 2 2 73.4 1 1e (Cozrecr Response True) 71'0 71'0 (68.1 - 78.3) An equianalgesic dose of . . A 2 2 65.1 11f another oral op101d (Conect 59.0 59.0 (59.4 70.5) Response True) Key Risk Message 2: TIRF Medicines Are Only Indicated for the Management of Breakthrough Pain in Adult Cancer Patients 18 Years of Age and Older (16 Years of Age and Older for Actiq? Brand and Generic Equivalents) Who Are Already Receiving and Who Are Tolerant to Around?the?Clock Opioid Therapy for Their Underlying Persistent Cancer Pain 6 Please answer True. False. or I don?t know for each statement based on the labeling for TIRF medicine. 6a According to the product labeling. a cancer patient may start a TIRF medicine and an around-the-clock opioid at the same time (Cozrecr Response False) 1 65.3 63.3 69.1 (63.5 - 74.3) 6b According to the product labeling. a cancer patient who has been on an around- the-clock opioid for 1 day may start taking a TIRF medicine for breakthrough pain (Correct Response False) 1 74.7 74.0 82.1 (77.2 - 86.2) Pharmacist KAB Assessment Report Transmucosal Irmnediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 46 of 51 Table 15. Correct Response Rate Over Time 48-Month lZ-Month Survey 24-Month Survey 36-Month Survey 48-Month Survey Survey Questions as Presented in Correct/Desired Correct/Desired Correct/Desired Correct/Desired Question the 48-Month Survey Response Response Response Response Number (95% CI) (95% CI) (95% CI) (95% CI) A patient must stop taking their TIRF medicine if they 41 9 6c stop taking their around-the- . . . . . (36.2 - 47.7) clock op101d pain medicme (Conect Response True) 9 Per the approved labeling for TIRF medicines. for which of the following indications can TIRF medicines be prescribed to opioid tolerant patients? Please answer Yes. No. or I don?t know for each option. 9a Acute or postoperative pain 78.1 84.7 86 7 90 (Calv?echesmnse N0) (73.1. 82.7) (80.1. 88.6) (82.3. 90.3) (86.1 932) 9b Headache or migraine pain 89.1 92.3 90.7 93.0 (Conect Response No) (85,0. 924) (88.7. 95.1) (86.8. 93.7) (89.5 - 95.6) 9c Dental pain 94.7 96.7 97.0 98.3 (Con?ectReSponse N0) (91.5. 96.9) (94.0. 98.4) (94.4. 98.6) (96.2 - 99.5) 9d CBgizghrough pain from 83 .4 89.3 91.7 92.0 Response Yes) (78.8. 87.5) (85.3. 92.6) (87.9. 94.5) (88.4 - 94.8) 9e Chronic non-cancer pain 29 82 47.0 43.7 50.8 (Conect Response No) (41.2. 52.8) (38.0. 49.5) (45.0 - 56.6) Pharmacist KAB Assessment Report Transmucosal Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 47 of 51 Table 15. Correct Response Rate Over Time 48-Month lZ-Month Survey 24?Month Survey 36-Month Survey 48-Month Survey Survey Questions as Presented in Correct/Desired Correct/Desired Correct/Desired Correct/Desired Question the 48-Month Survey Response Response Response Response Number (95% CI) (95% CI) (95% CI) (95% CI) Key Risk Message 3: TIRF Medicines Contain Fentanyl, an Opioid Agonist and a Schedule II Controlled Substance, with Abuse Liability Similar to other Opioid Analgesics 7 Please answer True. False. or I don?t know for each statement based on the labeling for TIRF medicines. 7e It is important to monitor for medicines (Conecr Response (95.3. 99.1) (94.0. 98.4) (93.1. 97.9) (94.8 - 98.8) True) 8 Which of the following are risk factors for opioid abuse? Please answer Yes. No. or I don?t know for each option. 83 11:33:23: 66'6 72'0 71'0 75'4 Response Yes) (60.9. 71.9) (66.6. 77.0) (65.5. 76.1) (70.1 - 80.2) 8b A personal history of past or current alcohol or drug abuse. or a family history of 99.7 99.0 99.3 98.7 illicit drug use or alcohol (982. 1000) (97.1. 99.8) (97.6. 99.9) (96.6 - 99.6) abuse (C017'ecf Response Yes) 10 Please answer True. False. or I don?t know for each statement based on the labeling for TIRF medicines. 1 10a TIRF medicines can be abused in a manner similar to 90.4 94.0 94.3 95.7 other opioid agonists (86.5. 93.5) (90.7. 96.4) (91.1. 96.7) (92.7 - 97.7) (Correct Response True) Key Risk Message 4: TIRF Medicines Are Not Interchangeable with Each Other, Regardless of Route of Administration 10 Please answer True. False. or I don?t know for each statement based on the labeling for TIRF medicines. 1 10b TIRF medicines are 9 50 94,7 9 3_ 3 93.4 Phaimacist KAB Assessment Report Transmucosal Irmnediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Table 15. Correct Response Rate Over Time Page 48 of 51 48-Month Survey Question Number Questions as Presented in the 48-Month Survey lZ-Month Survey Correct/Desired Response (95% CI) 24-Month Survey Correct/Desired Response (95% CI) 36-Month Survey Correct/Desired Response (95% CI) 48-Month Survey Correct/Desired Response (95% CI) interchangeable with each other regardless of route of administration (Correct Response False) (91.9. 97.2) (91.5. 96.9) (89.9. 95.9) (89.9 - 95.9) 10c The conversion of one TIRF medicine for another TIRF medicine may result in a fatal overdose because of differences in the pharmacokinetics of fentanyl absorption (Correct Response True) 92.7 (89.2. 95.4) 92.0 (88.3. 94.8) 93.0 (89.5. 95.6) 92.7 (89.1 - 95.4) 10d Dosing of TIRF medicines is not equivalent on a 111icrogram-to-microgram basis (Correct Response True) 92.4 (88.8. 95.1) 91.3 (87.6. 94.3) 90.0 (86.0. 93.2) 92.7 (89.1 - 95.4) 13 Please answer True. False. or I don?t know for each statement about TIRF medicines. 13c TIRF medicines with the same route of administration can be substituted with each other if the pharmacy is out of stock for one product (Cozrect Response False) 95.72 96.3 97.7 98.3 (96.2 - 99.5) 1 Questions presented have been changed from previous sm'vey waves. 2 95% con?dence interval is not provided since the component was not part of a key risk message during reporting period. Pharmacist KAB Assessment Report Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 49 of 51 Conclusions In general, there is an overall trend over time toward maintaining, or even increasing, pharmacist knowledge and understanding of the key risk messages. The consistently high level of pharmacists’ understanding of key risk messages in the latest (48-month) survey indicates that the Education Program for Pharmacists is meeting the goals of the TIRF REMS Access Program. Two exceptions where pharmacists scored low included understanding that a patient must stop taking their TIRF medicine if they stop taking their around-the-clock opioid pain medicine, and that TIRF medicines are not indicated for chronic non-cancer pain, which may indicate that some respondents are dispensing TIRF medicines for non-cancer associated indications. The TRIG will evaluate the concepts that have scored low among stakeholders to determine if any action is warranted. The TRIG will continue to work with the FDA to refine, on a continual basis, the steps to mitigate risks associated with TIRF medicines. FDA_3404 Pharmacist KAB Assessment Report Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Appendix A Page 50 of 51 Pharmacy Survey Protocol Track Change Document: Comparison of 36-month Survey to 48-month Survey FDA_3405 Style De?nition: Bullet Paragraph: No billets or numbering PROTOCOL TITLE: Quantitative Testing of Pharmacist Knowledge, Attitudes, and Behavior about Transmucosal Immediate Release Fentanyl (TIRF) Products Safety and Use Information SPONSOR: TIRF REMS Industry Group (TRIG) Actavis Laboratories Inc. BioDeliverv Sciences International, Inc. (BDSI) (reylaced on Formatted: Font: Bold, Italic .March 11: 20152 Cephalon, Inc. (a wholly-owned subsidiary of Teva Pharmaceutical Industries, Ltd.) Depomed, Inc. Galena Biopharma, Inc. Insys Therapeutics? Mallinckrodt Pharmaceuticals WW Formatted: Font: Italic Mylan, Inc. Par Pharmaceutical, Inc. VERSION: 26.0 DATE: APPROVED: TABLE OF CONTENTS PAGE TABLE OF CONTENTS ......................................................................................... 2 1. LIST OF ABBREVIATIONS .................................................................................. 3 2. BACKGROUND ..................................................................................................... 4 3. OBJECTIVES OF THE EVALUATION SURVEY ............................................... 5 4. METHODS .............................................................................................................. 5 4.1 4.1.1 4.1.2 4.1.3 Survey Design .......................................................................................................... 5 Qualitative Research on the Survey ......................................................................... 6 Questions and Statements on REMS Goals ............................................................. 6 Additional Questions.............................................................................................. 11 4.2 4.2.1 Participant Recruitment.......................................................................................... 12 Measures to Minimize Bias in the Sample............................................................. 13 5. 5.1.1 5.1.2 5.1.3 STUDY POPULATION ........................................................................................ 13 Sample Size ............................................................................................................ 13 Inclusion Criteria.................................................................................................... 14 Exclusion Criteria .................................................................................................. 14 6. SURVEY PROCESS ............................................................................................. 14 6.1 6.1.1 6.1.2 Screening and Survey Administration ................................................................... 15 Telephone ............................................................................................................... 15 Internet ................................................................................................................... 15 6.2 Measures to Minimize Bias in the Survey Process ................................................ 15 7. 7.1.1 7.1.1.1 7.1.1.2 ANALYSIS ............................................................................................................ 16 Analysis Population ............................................................................................... 16 Description of Primary Analyses ........................................................................... 16 Description of Secondary Analyses ....................................................................... 17 8. SAFETY EVENT REPORTING ........................................................................... 17 9. PRIVACY PROTECTION AND CONFIDENTIALITY...................................... 17 LIST OF APPENDICES Appendix A Pharmacist Questionnaire .........................................................................18 Appendix B SAMPLE Pharmacist Invitation Letter.....................................................38 FDA_3407 1. LIST OF ABBREVIATIONS BDSI CATI CSP CI EDC ETASU FDA HIPAA ISI KAB PI REMS SE PSP TIRF TIRF REMS TRIG UBC US BioDelivery Sciences International, Inc. Computer-Assisted Telephone Interviewing Closed System Pharmacy Confidence Interval Electronic Data Capture Elements to Assure Safe Use Food and Drug Administration Health Insurance Portability and Accountability Act Important Safety Information Knowledge, Attitudes, and Behavior Prescribing Information Risk Evaluation and Mitigation Strategy Safety Event Project Specific Procedure Transmucosal Immediate Release Fentanyl TIRF REMS Access Program TIRF REMS Industry Group United BioSource Corporation United States FDA_3408 2. BACKGROUND Transmucosal Immediate Release Fentanyl (TIRF) medicines include the class of immediaterelease opioid analgesics that are indicated only for the management of breakthrough pain in cancer patients 18 years of age or older (16 or older for Actiq® and equivalent generics) who are already receiving and tolerant to opioid therapy for their underlying persistent cancer pain. The TIRF medicines include Abstral®, Actiq®, Fentora®, Lazanda®, Onsolis®, Subsys®, and generic versions of any of these brands. The TIRF REMS Industry Group (TRIG) includes Actavis Laboratories FL, Inc.; BioDelivery Sciences International, Inc. (BDSI) (replaced Meda Pharmaceuticals on March 11, 2015); Cephalon, Inc. (a wholly-owned subsidiary of Teva Pharmaceutical Industries, Ltd.); Depomed, Inc.; Galena Biopharma, Inc.; Insys Therapeutics, Inc.; ; Meda Pharmaceuticals; Mallinckrodt Pharmaceuticals; Mylan, Inc.; and Par Pharmaceutical, Inc. The Food and Drug Administration (FDA) has determined that a class-wide Risk Evaluation and Mitigation Strategy (REMS) is required to mitigate the risk of misuse, abuse, addiction, overdose, and serious complications due to medication errors with the use of TIRF medicines. The TIRF REMS Access Program (hereafter referred to as TIRF REMS) was approved by the FDA on December 28, 2011. The TIRF REMS consists of a Medication Guide, Elements to Assure Safe Use (ETASU), an Implementation System, and a Timetable for Submission of Assessments of the REMS. The goals of the TIRF REMS are to mitigate the risk of misuse, abuse, addiction, overdose, and serious complications due to medication errors by: 1. Prescribing and dispensing TIRF medicines only to appropriate patients, which includes use only in opioid-tolerant patients 2. Preventing inappropriate conversion between TIRF medicines 3. Preventing accidental exposure to children and others for whom it was not prescribed 4. Educating prescribers, pharmacists, and patients on the potential for misuse, abuse, addiction, and overdose of TIRF medicines An important component of the TIRF REMS is the conduct of quantitative evaluation surveys to assess pharmacists’ understanding and knowledge of the safe use and appropriate prescribing of TIRF medicines as described in the TIRF REMS educational materials, enrollment form, and Prescribing Information (PI). This protocol will describe the administration of the surveys that will be conducted among pharmacists who are enrolled in the TIRF REMS Access Program. Data from the surveys, together with other REMS evaluation metrics, will be used to determine whether changes need to be made to the REMS processes or educational materials to make them more effective in achieving the goals of the REMS. FDA_3409 The surveys will be implemented so that data will be available for inclusion in the REMS Assessment Reports that will be submitted to the FDA at 12 months after approval of the TIRF REMS and annually thereafter. 3. OBJECTIVES OF THE EVALUATION SURVEY The evaluation survey will use a questionnaire to document the level of knowledge and assess the attitudes and behavior of pharmacists around the following key information and risk messages communicated through REMS: 1. TIRF medicines are contraindicated in opioid non-tolerant patients. 2. TIRF medicines are only indicated for the management of breakthrough pain in adult cancer patients 18 years of age and older (16 or older for Actiq® and equivalent generics) who are already receiving and who are tolerant to around-the-clock opioid therapy for their underlying persistent cancer pain. 3. TIRF medicines contain fentanyl, an opioid agonist and a Schedule II controlled substance, with abuse liability similar to other opioid analgesics. 4. TIRF medicines are not interchangeable with each other, regardless of route of administration. 5. Patients and their caregivers must be instructed that TIRF medicines contain a medicine in an amount that can be fatal in children, in individuals for whom it is not prescribed, and in those who are not opioid tolerant. The survey will also collect data on behaviors, such as receipt and use of educational materials and compliance with REMS requirements. 4. METHODS The survey was designed in collaboration between the TRIG and United BioSource Corporation (UBC), and will be administered by UBC. 4.1 Survey Design This survey will be conducted among a sample of pharmacists who are enrolled in the TIRF REMS Access Program. Respondents who have participated in a previous wave of the TIRF survey will not be eligible to participate in subsequent survey waves. The survey will be administered using the following modalities: • Self-administered via the Internet through a secure website FDA_3410 • Telephone surveys facilitated by a trained interviewer from the Survey Coordinating Center using a computer-assisted telephone interviewing (CATI) program The survey will begin with screening questions to confirm respondent eligibility to participate in the survey. Completion of the entire survey is expected to take up to 20 minutes. The survey included in Appendix A is written to reflect wording for both methods of survey administration: Internet-based and telephone. All respondents who complete the survey and who provide their contact information will be mailed a $50 honorarium for their time. 4.1.1 Qualitative Research on the Survey The FDA provided feedback to the TRIG on the Knowledge, AttitudesAttitude, and Behavior (KAB) survey results for pharmacists included in the 12-month REMS Assessment results. The FDA requested that the TRIG investigate the causes for low correct response rates to specific questions in the survey by conducting research to determine the reasons for the poor performance on these questions and to assess proposed revised wording to select questions. Qualitative research was performed in 2013 prior to Wave 2 of the survey. Findings were incorporated into the survey and results from the revised survey were included in the 24month REMS Assessment Report, 4.1.2 Questions and Statements on REMS Goals The KAB questionnaire is made up of multiple-choice, close-ended statements or questions (the majority of which use true/false or yes/no dichotomous response options), and one openended question. These will evaluate current knowledge, attitudes, and behavior regarding the key risk messages noted in Section 3. Questions will be presented in several formats: • Statements or questions asking the respondent to indicate whether a statement or question is true or false, or if they do not know the answer (there is a similar set of statements and questions that use “yes” or “no” as potential response options); • Statements or questions asking the respondent to choose from a defined list of possible statements or answers; and • One question allowing for the respondent to list questions or comments. Questionnaires will be analyzed to determine pharmacist understanding of each key risk message. For statements or questions that use “true” or “yes” vs. “false” or “no” response options, the desired response for the key risk messages is generally “true” or “yes” indicating knowledge of, or behavior in accordance with, the objectives of the REMS. However, some questions are FDA_3411 formatted to have the respondent disagree with the statement as written by providing response options of “false” or “no” to avoid having the same affirmative answer for all desired responses. REMS statements, corresponding questions, and desired responses covering the key risk messages are identified below and can be found in the complete survey questionnaire (Appendix A). Key Risk Message 1: TIRF medicines are contraindicated in opioid non-tolerant patients. Question No. 5 5a 5b 5c 7 7a 7b 7c 7d 11 11a 11b 11c 11d 11e Desired Responseresponse Please select True, False, or I don’t know for each of the following. According to the labeling for TIRF medicines, patients with cancer who are considered opioid-tolerant are those: Who are taking around-the-clock opioid therapy for underlying, persistent cancer pain for one week or TRUE longer Who are not currently taking opioid therapy, but FALSE have taken opioid therapy before Who have no known contraindications to the drug fentanyl, but are not currently taking around-theFALSE clock opioid therapy Please answer True, False, or I don’t know for each statement based on the labeling for TIRF medicines. TIRF medicines are contraindicated in opioid nontolerant patients because life-threatening respiratory TRUE depression could occur at any dose. Death has occurred in opioid non-tolerant patients TRUE treated with some fentanyl products. TIRF medicines may be used in opioid non-tolerant FALSE patients. Prescribers starting a patient on a TIRF medicine must begin with titration from the lowest dose TRUE available for that specific product, even if the patient has previously taken another TIRF medicine. Please select True, False, or I don’t know for each of the following. According to the labeling for TIRF medicines, patients considered opioid-tolerant are those who are taking, for one week or longer, at least: 8 mg oral hydromorphone/day TRUE 60 mg oral morphine/day TRUE 30 mg oral oxycodone/day TRUE 25 mcg transdermal fentanyl/hour TRUE 25 mg oral oxymorphone/day TRUE Question FDA_3412 An equianalgesic dose of another oral opioid TRUE 3 Key Risk Message 2: TIRF medicines are only indicated for the management of breakthrough pain in adult cancer patients 18 years of age and older (16 years of age and older for Actiq? brand and generic equivalents) who are already receiving and who are tolerant to around-the- clock opioid therapy for their underlying persistent cancer pain. Formatted Table Question Formatted Table No. Question Desired Mei-espouse 6 Please answer True. False. or I don?t know for each statement based on the - labeling for TIRF medicines. According to the product labeling. a cancer 6_a patient may start a TIRF medicine and an FALSE around-the-clock opioid at the same time. According to the product labeling. a cancer patient who has been 011 an around-the- clock opioid for 1 day may start taking a TIRF medicine for breakthrough pain. A patient must stop taking their TIRF medicine if they stop taking their around- the-clock opioid pain medicine. Per the approved labeling for TIRF medicines. for which of the following 9 indications can medicines be prescribed to opioid tolerant patients? Please answer Yes. No. or I don?t know for each option. 9a Acute or postoperative pain N0 9b Headache or migraine pain N0 9c Dental pain N0 9d Breakthrough pain from cancer YES 9e Chronic non-cancer pain N0 4 Kev Risk Message 3: TIRF medicines contain fentanyl. an opioid agonist and a Schedule controlled substance with abuse liability similar to other opioid analgesics. Qu;sotion Question Desired RESQODSW 7 Please answer True. False. or I don?t know for each statement based on the labeling for TIRF medicines. It is important to monitor for signs of abuse 7e and addiction in patients who take TIRF TRUE medicines. 8 Which of the following are risk factors for opioid abuse? Please answer Yes. No. or I don?t know for each option. 8a A personal history of illness YES A personal history of past or current 8b alcohol or drug abuse. or a family history of YES illicit drug use or alcohol abuse Please answer True. False. or I don?t know for each statement based on the 10 labeling for TIRF medicines. 10a TIRF medicmes can be abused in a manner TRUE similar to other opioid agonists. Formatted: Space After: 0 pt, line spacing: single 5 Key Risk Message 4: TIRF medicines are not interchangeable with each other, regardless of route of administration. Question No. 10 10b 10c 10d 13 13c 4.1.3 Question Desired Responseresponse Please answer True, False, or I don’t know for each statement based on the labeling for TIRF medicines. TIRF medicines are interchangeable with each other regardless of route of FALSE administration. The conversion of one TIRF medicine for another TIRF medicine may result in a fatal TRUE overdose because of differences in the pharmacokinetics of fentanyl absorption. Dosing of TIRF medicines is not equivalent TRUE on a microgram-to-microgram basis. Please answer True, False, or I don’t know for each statement about TIRF medicines. TIRF medicines with the same route of administration can be substituted with each FALSE other if the pharmacy is out of stock for one product. Additional Questions The survey includes questions about the requirements of the TIRF REMS Access Program, receipt and understanding of the TIRF educational materials, and behaviors. The following question about behaviors will be asked after the key risk message questions. Question 12: How frequently do you perform the following activities when dispensing TIRF medicines? Please answer Always, Only with the first prescription, Sometimes, Never, or I don’t know. Ask patients (or their caregivers) about the presence of children in the home Instruct patients (or their caregivers) not to share TIRF medicines with anyone else Counsel patients (or their caregivers) that accidental exposure to TIRF medicines by a child may be fatal Instruct patients (or their caregivers) to keep TIRF medicines out of the reach of children to prevent accidental exposure Instruct patients (or their caregivers) about proper disposal of any unused or partially used TIRF medicines Give patients (or their caregivers) the Medication Guide for their TIRF medicine FDA_3416 Demographic information will be collected at the end of the survey. 4.2 Participant Recruitment A random sample of ?pharmacists?i?-ehm-oe: from pharmacies that are enrolled in the TIRF REMS Access Program will be invited to participate via an invitation letter to their phalmacy ?WI-pharmacist 1n The text of the sample written invitation to pharmacists can be found in Appendix B. If the required number of completed surveys is not achieved within the expected timeframe of approximately one to two weeks after the ?rst mailing. reminder letters will be sent to non- responders ?'om the original sample with subsequent fax. e-mail. or United States (U S) Mail follow-up to maximize participation. The distribution within the mailing to the second sample will be adjusted in accordance with the allocation in the original sample. If these efforts do not result in the required nmnber of surveys within two to three weeks. then a new sample of pharmacists will be randomly selected. The unique code provided in the invitation letter will be linked to the type of pharmacy (inpatient. outpatient. or Closed System Pharmacy in which the pharmacist works. based on the information provided as part of the TIRF REMS Access Program enrollment. Formatted: Space After: 0 pt, Une spac'ng: single 7 All respondents who complete the survey and who provide their contact information will be mailed a $50 honorarium to thank them for their participation. The mailing will include a Thank You Letter, a copy of the Important Safety Information (ISI), and a copy of the correct answers to key risk message questions. 4.2.1 Measures to Minimize Bias in the Sample The sample of participating pharmacists will be self-selected since respondents will voluntarily respond to the invitation to participate; however, the survey recruitment strategies are intended to recruit a heterogeneous sample of pharmacies (e.g., chain and independent store) for participation. Pharmacists will be offered Internet-based or telephone options for completing the survey. Multiple modalities for survey data collection allow for wider survey access to a more heterogeneous population. Respondents will be provided a unique code during the recruitment process and will be asked to provide the unique code to gain access to the Internet-based survey or when calling the Survey Coordinating Center. The code will be deactivated after use to minimize the possibility for fraud. 5. STUDY POPULATION 5.1.1 Sample Size A sample of 300 pharmacists who are enrolled in the TIRF REMS Access Program is proposed for each survey wave. The size of the sample was determined based on both practical and statistical considerations. There is no target comprehension rate specified a priori. A sample of 300 completed surveys will allow estimation of the comprehension rate for each risk message with a moderately high degree of precision. The table below shows the precision of the estimates for level of understanding using two-sided 95% confidence intervals (CIs) obtained with the sample size of 300 completed surveys. The noted CIs are used to indicate that for any survey-estimated rate of understanding, the true population rate of understanding is at least as high as the lower limit of the 95% CI and may be as high as the upper limit of the 95% CI. FDA_3418 Table 5.1: Precision of Estimated Rates of Understanding with a Sample Size of 300 Estimated Rate of Understanding 5% 10% 15% 20% 25% 30% 35% 40% 45% 50% 55% 60% 65% 70% 75% 80% 85% 90% 95% 5.1.2 Estimated Confidence Interval 2.8% 6.8% 11.2% 15.6% 20.2% 24.9% 29.6% 34.4% 39.3% 44.2% 49.2% 54.2% 59.3% 64.5% 69.7% 75.0% 80.4% 86.0% 91.9% 8.1% 14.0% 19.6% 25.0% 30.3% 35.5% 40.7% 45.8% 50.8% 55.8% 60.7% 65.6% 70.4% 75.1% 79.8% 84.4% 88.8% 93.2% 97.2% Inclusion Criteria Pharmacists who work at pharmacies that are enrolled in the TIRF REMS Access Program are eligible to participate in this survey, with the exceptions noted below. 5.1.3 Exclusion Criteria The following respondents are not eligible to participate in the surveys: 6. • Pharmacists who have previously participated in the TIRF REMS KAB survey. • Pharmacists or their immediate family members who have ever worked for Actavis Laboratories FL, Inc.; Anesta LLC; BioDelivery Sciences International, Inc. (BDSI);Anesta LLC; Cephalon, Inc. (a wholly-owned subsidiary of Teva Pharmaceutical Industries, Ltd.); Depomed, Inc.; Galena Biopharma, Inc.; Insys Therapeutics, Inc.;; Mallinckrodt Pharmaceuticals; Meda Pharmaceuticals; Mylan, Inc.; Par Pharmaceutical, Inc.; Teva Pharmaceuticals, Ltd.; UBC; McKesson Specialty Care Solutions; RelayHealth; or the FDA. SURVEY PROCESS The survey will begin with screening questions to confirm respondent eligibility to participate in the survey. Completion of the entire survey is expected to take approximately 20 minutes. FDA_3419 6.1 Screening and Survey Administration The questionnaire will begin with a screening module with questions to confirm pharmacist eligibility. Depending on the answers to the screening questions, survey participation could either be terminated or continued. If ineligible, the respondent is immediately notified with a “thank you” message that survey participation has ended. If eligible, the respondent is allowed to continue survey participation. The data entry system used for both methods of survey administration has been validated and is secure for receiving and storing survey data. An Internet-based data repository will be used to store survey data and other relevant program information. The system is 21 CFR Part 11 and Health Insurance Portability and Accountability Act (HIPAA) compliant. Pharmacistidentifying information will be stored separately from survey data. 6.1.1 Telephone A trained interviewer from the Survey Coordinating Center will conduct the telephone interviews using a CATI program. The screening and main elements of the questionnaire will be administered sequentially during the same telephone call. Telephone interviewing allows participation of pharmacists who do not have Internet access or prefer taking the survey over the telephone. It will also be convenient for pharmacists to participate since they can call in and be interviewed at their convenience during the specified time period when the Survey Coordinating Center is available. 6.1.2 Internet An Internet-based survey system will also be used for conducting the KAB surveys. If the pharmacist selects to participate in the survey via the Internet, he/she will be directed to a secured website where he/she will be instructed to complete screening questions. An Internetbased survey will be convenient for respondents to participate since they can complete the questionnaire at any convenient time and location during the specified time period when the Survey Coordinating Center is available. 6.2 Measures to Minimize Bias in the Survey Process A number of controls will be in place to ensure the survey is conducted in a controlled and professional manner and to minimize bias. For example, a unique code will be given to each survey participant and the code will be inactivated after use to minimize fraud. Telephone interviewers are highly trained and use a standardized script to administer the survey. All questions will be programmed to ensure that questions are asked in the appropriate sequence. Skip patterns will be clearly indicated. Respondents cannot go back to a question once the question has been answered and cannot skip ahead. All questions must be answered in order to complete the survey. Response options presented in a list will be randomized to minimize positional bias. Programming will be reviewed by quality control and simulated users (User Acceptance Testing) prior to implementing the survey. FDA_3420 7. ANALYSIS Information obtained from the survey will be reported as descriptive statistics for the survey administration, study population, and the survey questions. The data from the sample population will be reported using frequency distributions of responses to all questions. The following will be reported as part of this analysis: • The number of invitations issued to pharmacists • The number of reminder letters issued to pharmacists • The number of respondents screened for participation • The number of respondents eligible for participation • The number of respondents eligible for participation who answered all questions presented to them • Representativeness of pharmacists based on geography • Description of survey participants, including: o Gender o Years of professional experience o How many times per month TIRF medicines dispensed in the last 6 months Additional descriptive statistics may be reported as appropriate. 7.1.1 Analysis Population The analysis population will be based on eligible pharmacists who completed all questions presented to them in the survey (“completers”). 7.1.1.1 Description of Primary Analyses Primary analyses are done for all key risk messages using data from all completers. The primary analysis for a key risk message evaluates the rate for each correct response to each individual question/item defined by the key risk message. The specific correct response to each question/item is identified in the body of the risk message table. FDA_3421 7.1.1.2 Description of Secondary Analyses Secondary analyses are done only for those key risk messages that contain multiple questions/items using data from all completers. The secondary analysis entails a frequency distribution of the number of completers who got 0, 1, etc. correct responses across the total number of items for the given key risk message. 8. SAFETY EVENT REPORTING The term ‘Safety Event’ is defined as any information reported by a survey respondent that meets the criteria of an adverse event or product complaint. While it is not the intention of the survey to solicit the report of information that meets the criteria of a Safety Event, it is possible that a respondent may spontaneously report information that meets this criteria in free text fields of the survey (Internet-based administration) or while in conversation with the Survey Coordinating Center (telephone-based administration). The Internet-based questionnaires will be monitored for any comments recorded in the free text fields. If an event is mentioned to a Survey Coordinating Center Associate, the Associate will document the safety event and the respondent’s contact information. Respondents will also be informed that a representative from the appropriate TIRF medicine manufacturer may contact them if they have questions about the survey. Information on all reports (Internet or telephone) that may constitute an adverse event or other safety event will be forwarded to the appropriate TIRF medicine manufacturer as described in the Safety Event Project Specific Procedure (SE PSP). Additional detail regarding processes for adverse event reporting will be specified in the SE PSP. 9. PRIVACY PROTECTION AND CONFIDENTIALITY All data collected during the survey will be held confidential. The electronic data capture (EDC) system used for data collection encrypts all identifiable information, and respondent identifiers are stored separately from the survey responses. Respondent names and addresses are collected in order to mail the $50 honorarium, a Thank You Letter, correct survey responses to key risk message questions, and the ISI after the survey is completed. Respondent contact information is also needed in the event that a safety event is reported and a TIRF medicine manufacturer must obtain follow-up information (see Section 8 above). Respondents will be informed when they access the survey that they may be contacted if there are any questions about their survey responses. Respondents will be informed that their answers to the survey questions will not affect their ability to dispense TIRF medicines. FDA_3422 Appendix A Pharmacist Questionnaire Survey Legend [PROGRAMMER] is used to indicate directions to the programmer and is set in bold, red, uppercase letters between square brackets. (INTERVIEWER) is used to indicate directions to the telephone interviewer and is set in bold, blue, text between parentheses. This text appears when content is to be administered by telephone only (for example, spontaneous adverse event reporting). [ONLINE] indicates a question is worded specifically for administering the survey online. [PHONE] indicates a question is worded specifically to be read by a telephone interviewer and differs from the online text. [BEGIN ONLINE/PHONE SURVEY CONTENT] and [END SURVEY CONTENT] are used to indicate to the programmer the type of survey administration and the beginning and end of the survey or sections within the survey content, for example, [BEGIN ADVERSE EVENT/PRODUCT COMPLAINT] and [END ADVERSE EVENT/PRODUCT COMPLAINT]. [TERMINATE] is displayed next to responses that should cause the survey to end. The following termination language will be programmed into the survey or read by the interviewer unless different language is specified with the question. Thank you very much for your time today. Based on your answer, you are not eligible to take this survey. We appreciate your interest in the survey. [RANDOMIZE LIST] is inserted before questions to indicate to the programmer that the responses should be randomized. Responses such as “I don’t know,” “Prefer not to answer” or “None of the above” will always appear at the end of the randomized responses. Response options for questions that allow multiple responses must be indicated with check boxes (□). At least one option must be selected for the question to be considered answered. If any response option requires text to be collected and does not need another question label, show [FREE TEXT] after the response option. Response options for questions that allow only one response must be indicated with radio buttons (). If any response option requires text to be collected and does not need another question label, show [FREE TEXT] after the response option, if applicable. [GO TO Qx] (skip logic) is inserted after a response to indicate to the programmer that the FDA_3423 Survey Legend survey should skip to the indicated question (for example, [GO TO Q17] skips to question 17). If no skip logic is indicated the survey continues to the next question in the sequence. [FREE TEXT] indicates to the programmer that one line should be provided for data entry. [MULTILINE INPUT] indicates to the programmer that multiple lines should be provided for data entry (for example, two address lines). [DROP-DOWN LIST INPUT WITH STATES TABLE] indicates to the programmer that the response should be a drop-down list containing the states in the table below. Alabama Georgia Massachusetts New York Alaska Guam Michigan North Carolina Texas American Samoa Hawaii Minnesota North Dakota Idaho Mississippi Arizona Illinois Missouri Arkansas Indiana Montana Northern Mariana Islands US Virgin Islands California Colorado Connecticut Delaware District of Columbia Iowa Kansas Kentucky Louisiana Maine Nebraska Nevada New Hampshire New Jersey New Mexico Maryland Florida Tennessee Utah Vermont Ohio Virginia Oklahoma Washington Oregon West Virginia Pennsylvania Wisconsin Puerto Rico Wyoming Rhode Island South Carolina South Dakota The following is used to categorize survey populations into standard geographic regions but it is not displayed in the survey. Geographic Distribution (based on address) 1: Northeast, Midwest, South, and West regions Northeast Region − − New England Division - ME, NH, VT, MA, RI, CT Middle Atlantic Division - NY, NJ, PA Midwest Region − − East North Central Division - OH, IN, IL, MI, WI West North Central Division - MN, IA, MO, ND, SD, NE, KS FDA_3424 Survey Legend South Region − − South Atlantic Division - DE, MD, DC, VA, WV, NC, SC, GA, FL East South Central Division - KY, TN, AL, MS West South Central Division - AR, LA, OK, TX West − − Mountain Division - MT, ID, WY, CO, NM, AZ, UT, NV Pacific Division WA, OR, CA, AK, HI The following US territories are categorized as Other: Puerto Rico, Northern Mariana Islands, US Virgin Islands, American Samoa, and Guam. 1 U.S. Census Bureau, last revised Friday, 27-Jul-2001 12:59:43 EDT. FDA_3425 [BEGIN SURVEY CONTENT] [BEGIN ONLINE PREAMBLE 1] Before you begin, we would like to share some important information about this survey. The manufacturers of Transmucosal Immediate Release Fentanyl (TIRF) medicines are conducting this survey, as required by the FDA, to assess pharmacists’ understanding of the safe use and dispensing of these medicines. These medicines are known as rapid onset opioids and referred to in this survey as “TIRF medicines.” The TIRF medicines include Abstral®, Actiq®, Fentora®, Lazanda®, Onsolis®, Subsys®, and generic versions of any of these brands. The manufacturers of these medicines include Actavis Laboratories FL, Inc.; BioDelivery Sciences International, Inc. (BDSI); Cephalon, Inc. (a wholly-owned subsidiary of Teva Pharmaceutical Industries, Ltd.); Depomed, Inc.; Galena Biopharma, Inc.; Insys Therapeutics, Inc.;; Mallinckrodt Pharmaceuticals; Meda Pharmaceuticals; Mylan, Inc.; and Par Pharmaceutical, Inc. The survey will take 15-20 minutes. There are no known risks to you in taking this survey. You may refuse to take part or withdraw at any time. Your answers to the questions or your decision to take part in the survey will not affect your ability to dispense TIRF medicines. How We Use Your Information Your answers to the survey questions will be combined with answers given by other pharmacists taking the survey. All answers will be put together and reported in anonymous form to the manufacturers of TIRF medicines. Your name will not be used in any report. If you are eligible to take the survey, complete all the questions, and provide your contact information, you will receive a $50 honorarium for your time and participation. Your name and address will be used to send you the honorarium after you complete the survey. Your personal information will also be used if we have questions about your survey or if we are required to use your information to comply with a federal or state law or regulation. Providing a telephone number is optional. Your telephone number will be used only if there are any questions about your survey responses. How We Protect Your Privacy We respect that the privacy of your personal information is important to you. You will not be contacted for marketing purposes based on your personal information or your answers to the survey. Neither the manufacturers of TIRF medicines nor their contractors will sell, transfer, or rent your information. Your answers will be kept strictly confidential. Your privacy will be protected; however, research survey records may be inspected by the FDA. Your choice to allow manufacturers of TIRF medicines to use your information is entirely voluntary but necessary to take part in this survey. FDA_3426 How to Learn More about This Survey If you have questions about the survey, or problems with the survey, please contact the Survey Coordinating Center at 1-877-379-3297. Be sure to write down this telephone number; it will not be displayed again. Taking the Survey Once you have answered a question and moved on, you cannot go back and change your answers. Thank you for your participation in this survey. [END ONLINE PREAMBLE 1] FDA_3427 [BEGIN PHONE PREAMBLE 1] Before you begin, we would like to share some important information about this survey. The manufacturers of Transmucosal Immediate Release Fentanyl (TIRF) medicines are conducting this survey, as required by the FDA, to assess pharmacists’ understanding of the safe use and dispensing of these medicines. These medicines are known as rapid onset opioids and referred to in this survey as “TIRF medicines.” (INTERVIEWER: Say “TIRF” then spell out T-IR-F) The TIRF medicines include Abstral®, Actiq®, Fentora®, Lazanda®, Onsolis®, Subsys®, and generic versions of any of these brands. The manufacturers of these medicines include Actavis Laboratories FL, Inc.; BioDelivery Sciences International, Inc. (BDSI); Cephalon, Inc. (a wholly-owned subsidiary of Teva Pharmaceutical Industries, Ltd.); Depomed, Inc.; Galena Biopharma, Inc.; Insys Therapeutics, Inc.;; Mallinckrodt Pharmaceuticals; Meda Pharmaceuticals; Mylan, Inc.; and Par Pharmaceutical, Inc. The survey will take 15-20 minutes. There are no known risks to you in taking this survey. You may refuse to take part or withdraw at any time. Your answers to the questions or your decision to take part in the survey will not affect your ability to dispense TIRF medicines. Now I would like to read some information about how your contact information will be used. Your answers to the survey questions will be combined with answers given by other pharmacists taking the survey. All answers will be put together and reported in anonymous form to the manufacturers of TIRF medicines. Your name will not be used in any report. If you are eligible to take the survey, complete all the questions, and provide your contact information, you will receive a $50 honorarium for your time and participation. Your name and address will be used to send you the honorarium after you complete the survey. Your personal information will also be used if we have questions about your survey or if we are required to use your information to comply with a federal or state law or regulation. Providing a telephone number is optional. Your telephone number will be used only if there are any questions about your survey responses. Now I would like to tell you some information about how we protect your privacy. We respect that the privacy of your personal information is important to you. You will not be contacted for marketing purposes based on your personal information or your answers to the survey. Neither the manufacturers of TIRF medicines nor their contractors will sell, transfer, or rent your information. Your answers will be kept strictly confidential. Your privacy will be protected; however, research survey records may be inspected by the FDA. Your choice to allow manufacturers of TIRF medicines to use your information is entirely voluntary but necessary to take part in this survey. Now I will tell you how you can learn more about this survey. Please have a pen or pencil ready to write down a telephone number you can call should you have any questions about the survey. If you have questions about the survey, please ask me at any time. If you have FDA_3428 questions at a later time, please contact the Survey Coordinating Center at 1-877-379-3297. Please feel free to ask me to repeat any questions or statements as we go through the survey. Once you have answered a question and moved on, you cannot go back and change your answers. Thank you for your participation in this survey. [END PHONE PREAMBLE 1] FDA_3429 [BEGIN INCLUSION/EXCLUSION QUESTIONS] 1. Your agreement to participate in this survey confirms mutual understanding in connection with completion of the survey and the fair market value of the payment to be rendered in connection with those services. Do you agree to participate in this survey? 2. 3. 4. ○ Yes ○ No [TERMINATE] Have you ever taken part in this survey about TIRF medicines before? TIRF medicines include Abstral®, Actiq®, Fentora®, Lazanda®, Onsolis®, Subsys®, and generic versions of any of these brands. ○ Yes [TERMINATE] ○ No ○ I don’t know [TERMINATE] Do you work in a pharmacy that is enrolled in the TIRF REMS Access Program? ○ Yes ○ No [TERMINATE] ○ I don’t know [TERMINATE] Have you or any of your immediate family members ever worked for any of the following companies or agencies? Please select all that apply. □ Actavis Laboratories FL, Inc. [TERMINATE] □ Anesta LLC [TERMINATE] □ BioDelivery Sciences International, Inc. (BDSI) [TERMINATE] □ □ Cephalon, Inc. (a wholly-owned subsidiary of Teva Pharmaceutical Industries, Ltd.) [TERMINATE] Depomed, Inc. [TERMINATE] FDA_3430 □ Galena Biopharma, Inc. [TERMINATE] □ Insys Therapeutics, Inc. [TERMINATE] □ Mallinckrodt Pharmaceuticals [TERMINATE] □ McKesson Specialty Care Solutions [TERMINATE] □ Meda Pharmaceuticals [TERMINATE] □ Mylan, Inc. [TERMINATE] □ Par Pharmaceutical, Inc. [TERMINATE] □ RelayHealth [TERMINATE] □ Teva Pharmaceuticals, Ltd. [TERMINATE] □ United BioSource Corporation [TERMINATE] □ FDA [TERMINATE] □ None of these apply [IF SELECTED IN ADDITION TO OTHER RESPONSES, TERMINATE] □ I don’t know [TERMINATE] □ Prefer not to answer [TERMINATE] [END INCLUSION/EXCLUSION QUESTIONS] 5. Please select True, False, or I don’t know for each of the following. According to the labeling for TIRF medicines, patients with cancer who are considered opioid-tolerant are those: [RANDOMIZE LIST] Who are taking around-the-clock opioid therapy for underlying, persistent cancer pain for one week or longer Who are not currently taking opioid therapy, but have 5b. taken opioid therapy before Who have no known contraindications to the drug 5c. fentanyl, but are not currently taking around-the-clock opioid therapy 5a. True False I don’t know ○ ○ ○ ○ ○ ○ ○ ○ ○ FDA_3431 6. Please answer True, False, or I don’t know for each statement based on the labeling for TIRF medicines. [RANDOMIZE LIST] 6a. According to the product labeling, aA cancer patient may startcan be started on a TIRF medicine and an aroundthe-clock opioid at the same time. 6b. According to the product labeling, aA cancer patient who has been on an around-the-clock opioid for 1 day maycan start taking a TIRF medicine for breakthrough pain. 6c. A patient must stop taking their TIRF medicine if they stop taking their around-the-clock opioid pain medicine. 6d. Use of a TIRF medicine with a CYP3A4 inhibitor may require dosage adjustment and monitoring of the patient for opioid toxicity as potentially fatal respiratory depression could occur. 7. True False I don’t know ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ Please answer True, False, or I don’t know for each statement based on the labeling for TIRF medicines. [RANDOMIZE LIST] 7a. TIRF medicines are contraindicated in opioid nontolerant patients because life-threatening respiratory depression could occur at any dose. 7b. Death has occurred in opioid non-tolerant patients treated with some fentanyl products. 7c. TIRF medicines may be used in opioid non-tolerant patients. 7d. Prescribers starting a patient on a TIRF medicine must begin with titration from the lowest dose available for that specific product, even if the patient has previously taken another TIRF medicine. 7e. It is important to monitor for signs of abuse and addiction in patients who take TIRF medicines. True False I don’t know ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ FDA_3432 8. Which of the following are risk factors for opioid abuse? Please answer Yes, No, or I don’t know for each option. [RANDOMIZE LIST] 8a. 8b. 8c. 9. 9e. 10. No I don’t know ○ ○ ○ ○ ○ ○ ○ ○ ○ A personal history of psychiatric illness A personal history of past or current alcohol or drug abuse, or a family history of illicit drug use or alcohol abuse A family history of asthma Per the approved labeling for TIRF medicines, for which of the following indications can TIRF medicines be prescribed to opioid tolerant patients? Please answer Yes, No, or I don’t know for each option. [RANDOMIZE LIST] 9a. 9b. 9c. 9d. Yes Yes No I don’t know ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ Acute or postoperative pain Headache or migraine pain Dental pain Breakthrough pain from cancer Chronic non-cancer pain Please answer True, False, or I don’t know for each statement based on the labeling for TIRF medicines. [RANDOMIZE LIST] 10a. TIRF medicines can be abused in a manner similar to other opioid agonists. 10b. TIRF medicines are interchangeable with each other regardless of route of administration. 10c. The conversion of one TIRF medicine for another TIRF medicine may result in a fatal overdose because of differences in the pharmacokinetics of fentanyl absorption. 10d. Dosing of TIRF medicines is not equivalent on a microgram-to-microgram basis. True False I don’t know ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ FDA_3433 11. Please select True, False, or I don’t know for each of the following. According to the labeling for TIRF medicines, patients considered opioid-tolerant are those who are taking, for one week or longer, at least: [RANDOMIZE LIST] 11a. 11b. 11c. 11d. 11e. 11f. 8 mg oral hydromorphone/day 60 mg oral morphine/day 30 mg oral oxycodone/day 25 mcg transdermal fentanyl/hour 25 mg oral oxymorphone/day An equianalgesic dose of another oral opioid True False I don’t know ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ 12. How frequently do you perform the following activities when dispensing TIRF medicines? Please answer Always, Only with the first prescription, Sometimes, Never, or I don’t know. [RANDOMIZE LIST] 12a Ask patients (or their caregivers) about the presence of children in the home 12b Instruct patients (or their caregivers) not to share TIRF medicines with anyone else 12c Counsel patients (or their caregivers) that accidental exposure to TIRF medicines by a child may be fatal 12d Instruct patients (or their caregivers) to keep TIRF medicines out of the reach of children to prevent accidental exposure 12e Instruct patients (or their caregivers) about proper disposal of any unused or partially used TIRF medicines 12f. Give patients (or their caregivers) the Medication Guide for their TIRF medicine Always Only with the first prescription ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ Sometimes Never I don’t know FDA_3434 13. Please answer True, False, or I don’t know for each statement about TIRF medicines. [RANDOMIZE LIST] 13a. TIRF medicines may be sold, loaned, or transferred to another pharmacy. 13b. All pharmacy staff that dispenses TIRF medicines must be educated on the requirements of the TIRF REMS Access Program. 13c. TIRF medicines with the same route of administration can be substituted with each other if the pharmacy is out of stock for one product. 14. 15. True False I don’t know ○ ○ ○ ○ ○ ○ ○ ○ ○ [INPATIENT PHARMACIST] Does the inpatient pharmacy where you work have an established system, order sets, protocols and/or other measures to help ensure appropriate patient selection and compliance with the requirements of the TIRF REMS Access Program? ○ Yes ○ No ○ I don’t know [OUTPATIENT PHARMACIST] Does the outpatient or retail pharmacy where you work process all TIRF medicine prescriptions, regardless of method of payment, through the pharmacy management system? ○ Yes ○ No ○ I don’t know FDA_3435 16. 17. [CSP OUTPATIENT PHARMACIST] Does the pharmacy where you work process all TIRF medicine prescriptions, regardless of method of payment, through the TIRF REMS Access Call Center? ○ Yes ○ No ○ I don’t know [INPATIENT PHARMACIST] Please answer True, False, or I don’t know for the following statement about TIRF medicines. It is OK to dispense TIRF medicines from the inpatient pharmacy inventory to an outpatient for use at home. True False I don’t know ○ ○ ○ [BEGIN PREAMBLE 3] The next set of questions is about the educational materials for TIRF medicines. As a reminder, the TIRF medicines include Abstral®, Actiq®, Fentora®, Lazanda®, Onsolis®, Subsys®, and generic versions of any of these brands. [END PREAMBLE 3] 18. Did you receive or do you have access to the Full Prescribing Information for the TIRF medicine(s) that you dispense? ○ Yes ○ No [GO TO Q20] ○ I don’t know [GO TO Q20] FDA_3436 19. 20. 21. 22. Did you read the Full Prescribing Information for the TIRF medicine(s) that you dispense? ○ Yes ○ No ○ I don’t know Did you receive or do you have access to the Medication Guide for the TIRF medicine(s) that you dispense? ○ Yes ○ No [GO TO Q22] ○ I don’t know [GO TO Q22] Did you read the Medication Guide for the TIRF medicine(s) that you dispense? ○ Yes ○ No ○ I don’t know Did you or do you have any questions about the information in the Full Prescribing Information or Medication Guide? ○ Yes ○ No [GO TO DEMOGRAPHICS PREAMBLE ] ○ I don’t know [GO TO DEMOGRAPHICS PREAMBLE] [IF QUESTION 22 = YES, DISPLAY ON SAME PAGE] 23. What are your questions? [MULTILINE INPUT] FDA_3437 [BEGIN DEMOGRAPHICS PREAMBLE 1 - DISPLAY ON SAME PAGE WITH NEXT QUESTION] There are just a few more questions to help us combine your answers with other answers we have received. [END DEMOGRAPHICS PREAMBLE 1] 24. 25. 26. Are you the Pharmacist in Charge for the TIRF REMS Access Program where you work? ○ Yes ○ No ○ I don’t know On average, how many times per month have you dispensed TIRF medicine within the last 6 months? ○ None [Go to DEMOGRAPHICS PREAMBLE 2] ○ 1 – 2 times per month ○ 3 – 5 times per month ○ More than 5 times per month ○ I don’t remember Please select the TIRF medicine(s) that you have dispensed within the last 6 months. Please select all that apply. □ Abstral® □ Actiq® or generic Actiq® □ Fentora® □ Lazanda® □ Onsolis® □ Subsys® FDA_3438 [BEGIN DEMOGRAPHICS PREAMBLE 2 - DISPLAY ON SAME PAGE WITH NEXT QUESTION] These last few questions are for demographic purposes. [END DEMOGRAPHICS PREAMBLE 2] 27. What is your gender? ○ Male ○ Female ○ Prefer not to answer FDA_3439 28. 29. In total, how many years have you been a practicing pharmacist? ○ Less than 3 years ○ 3 – 5 years ○ 6 – 10 years ○ 11 – 15 years ○ More than 15 years ○ Prefer not to answer In which state do you practice? [DROP-DOWN LIST INPUT WITH STATES TABLE WITH “Prefer not to answer” AT END] [PHONE -ONLY: BEGIN ADVERSE EVENT/PRODUCT COMPLAINT – KEEP ON ONE PAGE] (INTERVIEWER: Please record if respondent spontaneously reported an adverse event or product complaint during the course of this interview.) ○ Yes ○ No [GO TO CLOSING 1] Enter Safety Adverse Event Verbatim [MULTILINE INPUT] (INTERVIEWER: Indicate to the respondent that someone may call back to ask more questions about the adverse event or product complaint that was reported.) [END ADVERSE EVENT/PRODUCT COMPLAINT] [BEGIN CLOSING 1 – KEEP ON ONE PAGE] We would like to send you a $50 honorarium within the next few weeks to thank you for your time, but we need your name and address to do so. If you do not provide your name and address you will not receive the honorarium for your time and participation in the survey. FDA_3440 Do you agree to give us your name and mailing address so we can send you the honorarium? 0 Yes 0 N0 TO CLOSING 2] FIRST NAME: LAST NAME: ADDRESS: CITY: STATE: LIST INPUT WITH STATES ZIP: BE 5 CLOSING 1 BEGIN 2 KEEP ON ONE \Ve would also like to ask for your telephone number. Providing your telephone number is optional and it will be used to contact you only if there are questions about your survey responses. Do you want to provide your telephone number? 0 Yes No TO CLOSING 3] Telephone: BE CLOSING 2] CLOSING 3] [that ends the survey. Thank you again for your help. Formatted: Font: Bold CLOSING 3 SURVEY Appendix B SAMPLE Pharmacist Invitation Letter [CURR_DATE] [PHARMACY_NAME] [PHARMACY _STREET_ADDR] [PHARMACY_CITY], [PHARMACY _STATE] [PHARMACY _ZIP] [PHARMACY_FAX_NUMBER] Dear [PHARMACIST_IN CHARGE] Your Pharmacy was selected to receive this letter, because of enrollment in the TIRF REMS Access Program. We are contacting you to inform you about a survey being conducted by the manufacturers of Transmucosal Immediate Release Fentanyl (TIRF) medicines, as required by the Food and Drug Administration (FDA). The purpose of the survey is to assess pharmacists’ understanding of the safe and appropriate use of these medicines. The TIRF medicines include Abstral®, Actiq®, Fentora®, Lazanda®, Onsolis®, Subsys®, and generic versions of any of these brands. The manufacturers of TIRF medicines include Actavis Laboratories FL, Inc.; BioDelivery Sciences International, Inc. (BDSI); Cephalon, Inc. (a wholly-owned subsidiary of Teva Pharmaceutical Industries, Ltd.); Depomed, Inc.; Galena Biopharma, Inc.; Insys Therapeutics, Inc.; ; Meda Pharmaceuticals; Mallinckrodt Pharmaceuticals; Mylan, Inc.; and Par Pharmaceutical, Inc. (collectively referred to as the “TIRF REMS Industry Group”). These manufacturers are looking for 300 pharmacists to complete the survey. Eligible pharmacists who complete the survey will be sent a $50 honorarium to thank them for their time. The survey will take 15-20 minutes. Your answers will be kept strictly confidential and will be combined with the answers from other pharmacists who take this survey. Your name will not be used in the report of this survey and your contact information, if provided, will only be used to send you a $50 honorarium for your time to complete the survey. You are under no obligation to participate in this survey. Only one pharmacist from each enrolled pharmacy can participate. If you are interested in participating and to find out if you are eligible: • • Go to www.TIRFREMSsurvey.com any time or Call 1-877-379-3297, 8 a.m. to 8 p.m. Eastern Time, Monday through Friday Please have this letter with you at the time you take the survey. You will be asked to provide this code prior to starting the survey: [CODE_ID]. *We recommend that you take the survey on a desktop or laptop computer. Taking the survey on mobile devices, such as smart phones, tablets, and e-notebooks, is not supported. FDA_3443 Neither taking the survey nor your answers to the questions will affect your ability to dispense any of the TIRF medicines identified above. Sincerely, The TIRF REMS Survey Team 1-877-379-3297 www.TIRFREMSsurvey.com FDA_3444 Pharmacist KAB Assessment Report Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Appendix B Page 51 of 51 Pharmacy Survey Listings and Stratified Analyses Tables FDA_3445 TRIG Page 1 of TIRF Pharmacist KAB 03DEC2015 Table 1.1: Survey Administration Statistics Parameter, Number of invitations distributed 4906 Nlunber of invitations returned as mldeliverable 45 Number of reminder letters distributed 4593 All Respondentsm 607 (12.5) Eligible Respondentsm 334 (55.0) Completed surveym 301 (90.1) Did not complete the surveym 33 (9.9) Respondents not eligiblemm 273 (45.0) Number of respondents who accessed the survey. Percentage is based on the number of invitations distributed excluding the number of invitations returned as undeliverable. Percentage is based on the number of all respondents. 31 Percentages are based on the number of eligible respondents. Number of respondents who did not meet eligibility criteria or did not complete eligibility questions. Data Source: ADPQ Program: TSADMSAS TRIG Page 1 of 2 TIRF Pharmacist KAB 03DEC2015 Table 1.2: Survey Participant Eligibility Results All Respondents Pharmacists Question Question 1: Do you agree to participate in this survey? Yes 426 (70.2) Now 1 (0.2) Discontinued 180 (29.7) Question 2: Have you ever taken part in this survey about TIRF medicines before? TIRF medicines include Abstral?, Actiq?, Fentora?, Lazanda?, Subsys?, and generic versions of any of these brands. Yesm 9 (1.5) No 365 (60.1) I don't know? 52 (8.6) Question not asked 1 (0.2) Discontinued 180 (29.7) Question 3: Do you work in a pharmacy that is enrolled in the TIRF REMS Access Program? Yes 338 (55.7) Now 9 (1.5) I don't known] 18 (3.0) Question not asked 62 (10.2) Discontinued 180 (29.7) companies or agencies? Please select all that apply. Question 4: Have you or any of your immediate family members ever worked for any of the following Actavis Laboratories FL. Inc.[? 1 (0.2) Anesta. 0 BioDelivery Serxices International. Inc. 0 Cephalon. Inc. (a wholly-owned subsidiary of Tex-?a Pharmaceutical Industries. Ltd.)m 0 Depomed. Inc.[? 0 Galena Biophanna. Inc.[1] 0 Insys Therapeutics. Incl? 0 Mallinckrodt 2 (0.3) McKesson Specialty Care Solutionsm 0 Mylan. 111cm 1 (0.2) Data Source: ADPQ, ADTQ Program: TRIG Page 2 of 2 TIRF Pharmacist KAB 03DEC2015 Table 1.2: Survey Participant Eligibility Results - All Respondents Pharmacists Question 11 Par Pharmaceutical. Inc.m 2 (0.3) RelayHealthm 0 Teva Pharmaceuticals. 1 (0.2) United BioSource Corporationm 0 0 None of these 334 (55.0) I don't known] 2 (0.3) Prefer not to answerm 0 Question not asked 89 (14.7) Discontinued 180 (29.7) Ineligible to participate in the survey. Question not asked due to previous termination response. Ineligible to participate in the survey if selected in addition to other responses. Note: Respondents who discontinued the survey before completing all eligibility questions without being identi?ed as ineligible in any of the preVious questions are counted as discontinued. Once a respondent is comited as discontinued. they will count as discontinued in all subsequent eligibility questions. Data Source: ADPQ, ADTQ Program: TRIG Page 1 of 1 TIRF Pharmacist KAB 03DEC2015 Table 1.3: Time to Complete Survey Completed Surveys Telephone Internet Total Summary Statistic (minutes) 8 293 301 Mean (SD) 17.53 (2.755) 15.19 (8.913) 15.25 (8.812) Minimum 15.3 4. 7 4. 7 Median 16.27 12.78 12.93 Maxinnun 21.5 68.4 68.4 Category, 11 0 to <5 Minutes 0 5 to <10 Minutes 0 97 97 10 to <15 Minutes 0 77 77 15 to <20 Minutes 6 58 64 20 to <25 Minutes 2 34 36 25 to <30 Minutes 0 9 9 30 Minutes or more 0 17 17 Data Source: ADPQ Program: TRIG Page 1 of 2 TIRF Pharmacist KAB 03DEC2015 Table 2: Description of Eligible Pharmacists Completed Surveys Pharmacists Question 11 Question 24: Are you the Pharmacist in Charge for the TIRF REMS Access Program where you work? Yes 245 (81.4) No 53 (17.6) I don't know 3 (1.0) Question 25: On average, how many times per month have you dispensed TIRF medicine within the last 6 months? None 118 (39.2) 1 - 2 times per month 112 (37.2) 3 - 5 times per month 25 (8.3) More than 5 times per month 29 (9.6) I don't remember 17 (5.6) Question 26: Please select the TIRF medicine(s) that you have dispensed within the last 6 months. Please select all that apply!" Abstral? 12 (6.6) Actiq? or generic Actiq? 117 (63.9) Fentora? 63 (34.4) Lazanda? 13 (7.1) Subsys? 58 (31.7) (Armrered "None" to Question 25) 118 Question 27: What is your gender? Male 192 (63.8) Female 101 (33.6) Prefer not to answer 8 (2.7) Question 28: In total, how many years have you been a practicing pharmacist? Less than 3 years 17 (5.6) 3 - 5 years 33 (11.0) 6 - 10 years 51 (16.9) 11 - 15 years 36 (12.0) More than 15 years 159 (52.8) Data Source: ADPQ, ADTQ Program: TDESC.SAS TRIG Page 2 of 2 TIRF Pharmacist KAB 03DEC2015 Table 2: Description of Eligible Pharmacists - Completed Surveys Pharmacists Question 11 Prefer not to answer 5 (1.7) Geographic Distribution (based on Question 29 - In which state do you practice?)m Northeast 71 (23.6) Midwest 61 (20.3) South 119 (39.5) West 47 (15.6) Other 1 (0.3) Prefer not to answer 2 (0.7) Percentages are calculated based on the number of respondents to whom the question was presented. US. Census Bureau. last revised Friday. 27-Jul-2001 12:59:43 EDT.. Geography Division. Northeast includes CT. MA. ME. NH. NJ. NY. PA. RI. and VT. Midwest includes IA. IL. IN. KS. MI. MN. MO. ND. NE. OH. SD. and WI. South includes AL. AR. DC. DE. FL. GA. KY. LA. MD. MS. NC. OK. SC. TN. TX. VA. and WV. West includes AK. AZ. CA. CO. HI. ID. MT. NM. NV. 0R. UT. WA. and WY. Other includes Puerto Rico. Northern Mariana Islands. US Virgin Islands. American Samoa and Guam. Data Source: ADPQ, ADTQ Program: TDESC.SAS TRIG TIRF Pharmacist KAB Page 1 of 6 03DEC2015 Table 3: Responses to All Questions about the Safe Use of TIRF Medicines Completed Surveys Question Pharmacists Question 5: Please select True, False, or I don't know for each of the following. According to the labeling for TIRF medicines, patients with cancer who are considered opioid-tolerant are those: 5a: Who are taking around-the-clock opioid therapy for underlying, persistent cancer pain for one week or longer Truem 279 (92.7) False 22 (7.3) I don't know 0 5b: Who are not currently taking opioid therapy, but have taken opioid therapy before True 27 (9.0) Falsem 263 (87.4) I don't know 11 (3.7) 5c: Who have no known contraindications to the drug fentanyl, but are not currently taking around-the-clock opioid therapy True 44 (14.6) Falsem 248 (82.4) I don't know 9 (3.0) medicines. Question 6: Please answer True, False, or I don't know for each statement based on the labeling for TIRF opioid at the same time. 6a: According to the product labeling, a cancer patient may start a IRF medicine and an around-the-clock True 70 (23.3) Falsem 208 (69.1) I don't know 23 (7.6) may start taking a IRF medicine for breakthrough pain. 6b: According to the product labeling, a cancer patient who has been on an around-the-clock opioid for 1 day True 37 (12.3) Falsem 247 (82.1) I don't know 17 (5.6) medicine. 6c: A patient must stop taking their IRF medicine if they stop taking their around-the-clock opioid pain Truem 126 (41.9) Data Source: ADPQ, ADTQ Program: TEX.SAS TRIG TIRF Pharmacist KAB Page 2 of 6 03DEC2015 Table 3: Responses to All Questions about the Safe Use of TIRF Medicines Completed Surveys Pharmacists Question 11 False 136 (45.2) I don't know 39 (13.0) patient for opioid toxicity as potentially fatal respiratory depression could occur. 6d: Use of a IRF medicine with a CYP3A4 inhibitor may require dosage adjustment and monitoring of the True 275 (91.4) False 8 (2.7) I don't know 18 (6.0) medicines. Question 7: Please answer True, False, or I don't know for each statement based on the labeling for TIRF depression could occur at any dose. 7a: IRF medicines are contraindicated in opioid non-tolerant patients because life-threatening respiratory Truem 274 (91.0) False 19 (6.3) I don't know 8 (2.7) 7b: Death has occurred in opioid non-tolerant patients treated with some fentanyl products. Truem 287 (95.3) False 4 (1.3) I don't know 10 (3.3) 7c: IRF medicines may be used in opioid non-tolerant patients. True 3 5 (1 1.6) Falsem 257 (85.4) I don't know 9 (3.0) 7d: Prescribers starting a patient on a IRF medicine must begin with titration from the lowest dose available for that speci?c product, even if the patient has previously taken another IRF medicine. Truem 243 (80.7) False 45 (15.0) I don't know 13 (4.3) 7e: It is important to monitor for signs of abuse and addiction in patients who take TIRF medicines. Truem 293 (97.3) False 7 (2.3) Data Source: ADPQ, ADTQ Program: TEX.SAS TRIG TIRF Pharmacist KAB Page 3 of 6 03DEC2015 Table 3: Responses to All Questions about the Safe Use of TIRF Medicines Completed Surveys Pharmacists Question 11 I don't know 1 (0.3) know for each option. Question 8: Which of the following are risk factors for opioid abuse? Please answer Yes, No, or I don't 8a: A personal history of illness Yesm 227 (75.4) No 43 (14.3) I don't know 31 (10.3) 8b: A personal history of past or current alcohol or drug abuse, or a family history of illicit drug use or alcohol abuse Yesm 297 (98.7) No 2 (0.7) I don't know 2 (0.7) 8c: A family history of asthma Yes 33 (11.0) No 249 (82.7) I don't know 19 (6.3) option. Question 9: Per the approved labeling for medicines, for which of the following indications can TIRF medicines be prescribed to opioid tolerant patients? Please answer Yes, No, or I don't know for each 9a: Acute or postoperative pain Yes 22 (7.3) Non] 271 (90.0) I don't know 8 (2.7) 9b: Headache or migraine pain Yes 12 (4.0) Noll] 280 (93.0) I don't know 9 (3.0) 9c: Dental pain Yes 2 (0-7) Now 296 (98.3) Data Source: ADPQ, ADTQ Program: TEX.SAS TRIG TIRF Pharmacist KAB Page 4 of 6 03DEC2015 Table 3: Responses to All Questions about the Safe Use of TIRF Medicines Completed Surveys Pharmacists Question 11 I don't know 3 (1.0) 9d: Breakthrough pain from cancer Yesm 277 (92.0) No 24 (8.0) I don't know 0 9e: Chronic non-cancer pain Yes 131 (43.5) No'? 153 (50.8) I don't know 17 (5.6) medicines. Question 10: Please answer True, False, or I don't know for each statement based on the labeling for TIRF 100: IRF medicines can be abused in a manner similar to other opioid agonists. 1] Tme' 288 (95.7) False 8 (2.7) I don't know 5 (1.7) 10b: IRF medicines are interchangeable with each other regardless of route of administration. True 14 (4.7) Falsem 281 (93.4) I don't know 6 (2.0) of differences in the pharmacokinetics of fentanyl absorption. 10c: The conversion of one TIRF medicine for another TIRF medicine may result in a fatal overdose because Truem 279 (92.7) False 11 (3.7) I don't know 11 (3.7) 10d: Dosing of TIRF medicines is not equivalent on a microgram-to-microgram basis. Truem 279 (92.7) False 14 (4.7) I don't know 8 (2.7) Data Source: ADPQ, ADTQ Program: TEX.SAS TRIG TIRF Pharmacist KAB Page 5 of 6 03DEC2015 Table 3: Responses to All Questions about the Safe Use of TIRF Medicines Completed Surveys Question Pharmacists at least: Question 11: Please select True, False, or I don't know for each of the following. According to the labeling for TIRF medicines, patients considered opioid-tolerant are those who are taking, for one week or longer, 11a: 8 mg oral lo?dromorphone/day Truem 237 (78.7) False 30 (10.0) I don't know 34 (11.3) 11b: 60 mg oral morphine/day Truem 270 (89.7) False 11 (3.7) I don't know 20 (6.6) 110: 30 mg oral oxymdone/ddv Truem 232 (77.1) False 41 (13.6) I don't know 28 (9.3) 11d: 25 meg lransdermalfentam'l/hour Truem 232 (77.1) False 42 (14.0) I don't know 27 (9.0) He: 25 mg oral oxymotphone/day Truem 221 (73.4) False 36 (12.0) I don't know 44 (14.6) 11f: An equianalgesie dose of another oral opioid Truem 196 (65.1) False 49 (16.3) I don't know 56 (18.6) Question 13: Please answer True, False, or I don't know for each statement about TIRF medicines. 130: IRF medicines may be sold, loaned, or transferred to another pharmaqv. Data Source: ADPQ, ADTQ Program: TEX.SAS TRIG TIRF Pharmacist KAB Page 6 of 6 03DEC2015 Table 3: Responses to All Questions about the Safe Use of TIRF Medicines Completed Surveys Pharmacists Question 11 True 7 (2.3) False 279 (92.7) I don't know 15 (5.0) 13b: All pharmacy staff that dispenses IRF medicines must be educated on the requirements of the IRF REMS Access Program. True 273 (90.7) False 23 (7.6) I don't know 5 (1.7) 13c: IRF medicines with the same route of administration can be substituted with each other if the pharmacy is out of stock for one product. True 3 (1.0) Falsem 296 (98.3) I don't know 2 (0.7) Correct response. Data Source: ADPQ, ADTQ Program: TEX.SAS TRIG TIRF Pharmacist KAB Page 1 of 03DEC2015 Table 4: Responses to Questions about TIRF Educational Materials Completed Surveys Question Pharmacists medicine(s) that you dispense? Question 18: Did you receive or do you have access to the Full Prescribing Information for the TIRF Yes 299 (99.3) No 0 I don't know 2 (0.7) Question 19: Did you read the Full Prescribing Information for the TIRF medicine(s) that you dispense?m Yes 247 (82.6) No 45 (15.1) I don't know 7 (2.3) (Answered "No" or don?t know" to Question 18) 2 you dispense? Question 20: Did you receive or do you have access to the Medication Guide for the TIRF medicine(s) that Yes 300 (99.7) No 0 I don't know 1 (0.3) Question 21: Did you read the Medication Guide for the TIRF medicine(s) that you dispense?m Yes 263 (87.7) No 30 (10.0) I don't know 7 (2.3) (Answered "No" or don?t know" to Question 20) 1 Information or Medication Guide?m Question 22: Did you or do you have any questions about the information in the Full Prescribing Yes 5 (1.7) No 283 (94.0) I don't know 13 (4.3) Percentages are calculated based on the sample presented with this question because of skip logic in the survey. Verbatim texts for question about the Medication Guide are presented in Listing 1. Data Source: ADPQ, ADTQ Program: TEDUCSAS TRIG TIRF Pharmacist KAB Page 1 of 3 03DEC2015 Table 5: Responses to Questions about the Activities when Dispensing TIRF Medicines and Equipments in the Pharmacy Completed Surveys Question Pharmacists Question 12: How frequently do you perform the following activities when dispensing TIRF medicines? Please answer Always, Only with the first prescription, Sometimes, Never, or I don't know. 120: Ask patients (or their caregivers) about the presence of children in the home Always 180 (59.8) Only with the ?rst prescription 67 (22.3) Sometimes 36 (12.0) Never 9 (3-0) I don't know 9 (3.0) 12b: Instruct patients (or their caregivers) not to share IRF medicines with anyone else Always 235 (78.1) Only with the ?rst prescription 42 (14.0) Sometimes 14 (4.7) Never 6 (2.0) I don?t know 4 (1.3) 12c: Counsel patients (or their caregivers) that accidental exposure to IRF medicines by a child may be fatal Always 216 (71.8) Only with the ?rst prescription 48 (15.9) Sometimes 27 (9.0) Never 4 (1.3) I don't know 6 (2.0) accidental exposure 12d: Instruct patients (or their caregivers) to keep TIRF medicines out of the reach of children to prevent Always 238 (79.1) Only with the ?rst prescription 39 (13.0) Sometimes 16 (5.3) Never 4 (1.3) I don't know 4 (1.3) medicines 12e: Instruct patients (or their caregivers) about proper disposal of any unused or partially used IRF Data Source: ADPQ, ADTQ Program: TACT.SAS TRIG TIRF Pharmacist KAB Page 2 of 3 03DEC2015 Table 5: Responses to Questions about the Activities when Dispensing TIRF Medicines and Equipments in the Pharmacy Completed Sun'eys Pharmacists Question 11 Always 209 (69.4) Only with the ?rst prescription 66 (21.9) Sometimes 20 (6.6) Never 3 (1-0) I don't know 3 (1.0) 12f: Give patients (or their caregivers) the Medication Guide for their IRF medicine Always 278 (92.4) Only with the ?rst prescription 14 (4.7) Sometimes 4 (1.3) Never 2 (0-7) I don't know 3 (1.0) Question 14: Does the inpatient pharmacy where you work have an established system, order sets, protocols and/or other measures to help ensure appropriate patient selection and compliance with the requirements of the TIRF REMS Access Program? (Inpatient Pharmacists, only)m Yes 8 (53.3) No 7 (46.7) I don't know 0 Pharmacists, only)m Question 15: Does the outpatient or retail pharmacy where you work process all TIRF medicine prescriptions, regardless of method of payment, through the pharmacy management system? (Outpatient Yes 262 (91.6) No 10 (3.5) I don't know 14 (4.9) Question 16: Does the pharmacy where you work process all TIRF medicine prescriptions, regardless of method of payment, through the TIRF REMS Access Call Center? (CSP Outpatient Pharmacists, only)[ll Yes 0 No 0 I don't know 0 medicines. (Inpatient Pharmacists, only)m Question 17: Please answer True, False, or I don't know for the following statement about TIRF Data Source: ADPQ, ADTQ Program: TACT.SAS TRIG TIRF Pharmacist KAB Page 3 of 3 03DEC2015 Table 5: Responses to Questions about the Activities when Dispensing TIRF Medicines and Equipments in the Pharmacy Completed Suweys Question Pharmacists It is OK to dispense IRF medicines from the inpatient pharmacy inventory to an outpatient for use at home. True 0 False 13 (86.7) I don't know 2 (13.3) Percentages are calculated based on the sample presented with this question. Data Source: ADPQ, ADTQ Program: TACT.SAS TRIG TIRF Pharmacist KAB Page 1 of 3 03DEC2015 Table 6.1: Primary Analysis of Responses to Questions Linked to Key Risk Message #1 - Completed Surveys Key Risk Message TIRF medicines are contraindicated in opioid non-tolerant patients. Question Pharmacists [95% Question 5: Please select True, False, or I don't know for each of the following. According to the labeling for TIRF medicines, patients with cancer who are considered opioid?tolerant are those: 5a: Who are taking around-the-clock opioid therapy for underlying, persistent cancer pain for one week or longer Truem 279 (92.7) [89.1 - 95.4] False 22 (7.3) I don't know 0 5b: Who are not currently taking opioid therapy, but have taken opioid therapy before True 27 (9.0) Falsem 263 (87.4) [83.1 - 90.9] I don't know 11 (3.7) 5c: Who have no known contraindications to the drug fentanyl, but are not currently taking around-the-clock opioid therapy True 44 (14.6) Falsem 248 (82.4) [77.6 - 86.5] I don't know 9 (3.0) medicines. Question 7: Please answer True, False, or I don't know for each statement based on the labeling for TIRF depression could occur at any dose. 7a: medicines are contraindicated in opioid non-tolerant patients because life-threatening respiratory Truem 274 (91.0) [87.2 - 94.0] False 19 (6.3) I don't know 8 (2.7) 7b: Death has occurred in opioid non-tolerant patients treated with some fentanyl products. Truem 287 (95.3) [92.3 - 97.4] False 4 (1.3) I don't know 10 (3.3) 7c: TIRF medicines may be used in opioid non-tolerant patients. Data Source: ADPQ, ADTQ Program: TRIG TIRF Pharmacist KAB Page 2 of 3 03DEC2015 Table 6.1: Primary Analysis of Responses to Questions Linked to Key Risk Message #1 - Completed Surveys Key Risk Message TIRF medicines are contraindicated in opioid non-tolerant patients. Pharmacists Question 11 [95% True 3 5 (1 1.6) Falsem 257 (85.4) [80.9 - 89.2] I don't know 9 (3.0) 7d: Prescribers starting a patient on a TIRF medicine must begin with titration from the lowest dose available for that specific product, even if the patient has previously taken another TIRF medicine. Truep] 243 (80.7) [75.8 - 85.0] False 45 (15.0) I don't know 13 (4.3) at least: Question 11: Please select True, False, or I don't know for each of the following. According to the labeling for TIRF medicines, patients considered opioid-tolerant are those who are taking, for one week or longer, 11a: 8 mg oral [wdromorphone/day Truep] 237 (78.7) [73.7 - 83.2] False 30 (10.0) I don't know 34 (11.3) 11b: 60 mg oral morphine/day 2] Truel 270 (89.7) [85.7 - 92.9] False 11 (3.7) I don't know 20 (6.6) 11c: 30 mg oral oxycodone/ddv 2] Truel 232 (77.1) [71.9 - 81.7] False 41 (13.6) I don't know 28 (9.3) 11d: 25 transdermalfentanrl/hour Truem 232 (77.1) [71.9 - 81.7] False 42 (14.0) I don't know 27 (9.0) Data Source: ADPQ, ADTQ Program: TRIG Page 3 of 3 TIRF Pharmacist KAB 03DEC2015 Table 6.1: Primary Analysis of Responses to Questions Linked to Key Risk Message #1 - Completed Surveys Key Risk Message TIRF medicines are contraindicated in opioid non-tolerant patients. Pharmacists Question 11 [95% 11c: 25 mg oral on?morphone/dqv Truem 221 (73.4) [68.1 - 78.3] False 36 (12.0) I don't know 44 (14.6) 11f: An equianalgesic dose of another oral opioid Truem 196 (65.1) [59.4 - 70.5] False 49 (16.3) I don't know 56 (18.6) 95% exact two-sided con?dence intervals are calculated using the lopper-Pearson method. Correct response. Data Source: ADPQ, ADTQ Program: TRIG Page 1 of 4 TIRF Pharmacist KAB 03DEC2015 Table 6.1.3: Responses to Questions Linked to Key Risk Message #1 by Time Practicing as Pharmacist - Completed Surveys Key Risk Message TIRF medicines are contraindicated in opioid non-tolerant patients. Time Practicing as Pharmacist Less than 3 years 3 to 5 years 6 to 15 years More than 15 years Question 11 [95% [95% '11 [95% "1 [95% 011?? Question 5: Please select True, False, or I don't know for each of the following. According to the labeling for TIRF medicines, patients with cancer who are considered opioid-tolerant are those: 5a: Who are taking around-the-clock opioid therapy for underlying, persistent cancer pain for one week or longer Truem 15 (88.2) [63.6 - 98.5] 31 (93.9) [79.8 - 99.3] 80 (92.0) [84.1 - 96.7] 149 (93.7) [88.7 - 96.9] False 2 (11.8) 2 (6.1) 7 (8.0) 10 (6.3) I don't know 0 0 0 0 5b: Who are not currently taking opioid therapy, but have taken opioid therapy before True 1 (5.9) 4 (12.1) 3 (3.4) 19 (11.9) Falsem 16 (94.1) [71.3 - 99.9] 29 (87.9) [71.8 - 96.6] 79 (90.8) [82.7 - 95.9] 135 (84.9) [78.4 - 90.1] I don't know 0 0 5 (5.7) 5 (3.1) 5c: Who have no known contraindications to the drug fentanyl, but are not currently taking around-the-clock opioid therapy True 0 5 (15.2) 15 (17.2) 24 (15.1) Falsem 17 (100.0) [80.5 - 100.0] 28 (84.8) [68.1 - 94.9] 68 (78.2) [68.0 - 86.3] 131 (82.4) [75.6 - 88.0] I don't know 0 0 4 (4.6) 4 (2.5) Question 7: Please answer True, False, or I don't know for each statement based on the labeling for TIRF medicines. 7a: IRF medicines are contraindicated in opioid non-tolerant patients because life-threatening respiratory depression could occur at any dose. Data Source: ADPQ, ADTQ Program: TRIG TIRF Pharmacist KAB Page 2 of 4 03DEC2015 Table 6.1.3: Responses to Questions Linked to Key Risk Message #1 by Time Practicing as Pharmacist - Completed Surveys Key Risk Message TIRF medicines are contraindicated in opioid non-tolerant patients. Less than 3 years (N=l7) Time Practicing as Pharmacist 3 to 5 years 6 to 15 years More than 15 years Question 11 [95% 11 [95% '11 [95% "1 [95% 011?] Truem 16 (94.1) [71.3 - 99.9] 31 (93.9) [79.8 - 99.3] 78 (89.7) [81.3 - 95.2] 144 (90.6) [84.9 - 94.6] False 0 7 (8.0) 12 (7.5) Idon't know 1 (5.9) 2 (6.1) 2 (2.3) 3 (1.9) 7b: Death has occurred in opioid non-tolerant patients treated with some fentanyl products. Truem 17 (100.0) [80.5 - 100.0] 33 (100.0) [89.4 - 100.0] 84 (96.6) [90.3 - 99.3] 149 (93.7) [88.7 - 96.9] False 0 0 1 (1.1) 3 (1.9) I don't know 0 0 2 (2.3) 7 (4.4) 7c: IRF medicines maybe used in opioid non-tolerant patients. True 0 6 (6.9) 29 (18.2) Falsem 15 (88.2) [63.6 - 98.5] 32 (97.0) [84.2 - 99.9] 81 (93.1) [85.6 - 97.4] 126 (79.2) [72.1 - 85.3] I don't know 2 (11.8) 1 (3.0) 0 4 (2.5) 7d: Prescribers starting a patient on a IRF medicine must begin with titration from the lowest dose available for that specific product, even if the patient has previously taken another TIRF medicine. Truem 14 (82.4) [56.6 - 96.2] 24 (72.7) [54.5 - 86.7] 71 (81.6) [71.9 - 89.1] 130 (81.8) [74.9 - 87.4] False 2 (11.8) 8 (24.2) 14 (16.1) 21 (13.2) I don't know 1 (5.9) 1 (3.0) 2 (2.3) 8 (5.0) Data Source: ADPQ, ADTQ Program: TRIG TIRF Pharmacist KAB Page 3 of 4 03DEC2015 Table 6.1.3: Responses to Questions Linked to Key Risk Message #1 by Time Practicing as Pharmacist - Completed Surveys Key Risk Message TIRF medicines are contraindicated in opioid non-tolerant patients. Question Less than 3 years [95% Time Practicing as Pharmacist 3 to 5 years [95% 6 to 15 years [95% c1191 More than 15 years [95% Question 11: Please select True, False, or I don't know for each of the following. According to the labeling for TIRF medicines, patients considered opioid?tolerant are those who are taking, for one week or longer, at least: 110: 8 mg oral m1dromorphone/day Truem 11 (64.7) [38.3 - 85.8] 26 (78.8) [61.1 - 91.0] 66 (75.9) [65.5 - 84.4] 131 (82.4) [75.6 - 88.0] False 2 (11.8) 1 (3.0) 12 (13.8) 15 (9.4) I don't know 4 (23.5) 6 (18.2) 9 (10.3) 13 (8.2) 11b: 60 mg oral morphine/day Truem 15 (88.2) [63.6 - 98.5] 28 (84.8) [68.1 - 94.9] 77 (88.5) [79.9 - 94.3] 146 (91.8) [86.4 - 95.6] False (5.9) (3.0) 4 (4.6) 5 (3.1) I don't know 1 (5.9) 4 (12.1) 6 (6.9) 8 (5.0) 11c: 30 mg oral oxvcodone/day Truem 12 (70.6) [44.0 - 89.7] 25 (75.8) [57.7 - 88.9] 65 (74.7) [64.3 - 83.4] 126 (79.2) [72.1 - 85.3] False 4 (23.5) 3 (9.1) 14 (16.1) 20 (12.6) I don't know 1 (5.9) 5 (15.2) 8 (9.2) 13 (8.2) 11d: 25 meg transdermalfentanyMtour True 10 (58.8) [32.9 - 81.6] 22 (66.7) [48.2 - 82.0] 72 (82.8) [73.2 - 90.0] 125 (78.6) [71.4 - 84.7] Data Source: ADPQ, ADTQ Program: TRIG TIRF Pharmacist KAB Page 4 of 4 03DEC2015 Table 6.1.3: Responses to Questions Linked to Key Risk Message #1 by Time Practicing as Pharmacist - Completed Surveys Key Risk Message TIRF medicines are contraindicated in opioid non-tolerant patients. Time Practicing as Pharmacist Less than 3 years 3 to 5 years 6 to 15 years More than 15 years Question 11 [95% c1] ?1 [95% 11 [95% c1191 [95% False 5 (29.4) 6 (18.2) 9 (10.3) 22 (13.8) I don't know 2 (11.8) 5 (15.2) 6 (6.9) 12 (7.5) 11c: 25 mg oral on'motphone/dqv Truem 10 (58.8) [32.9 - 81.6] 26 (78.8) [61.1 - 91.0] 57 (65.5) [54.6 - 75.4] 125 (78.6) [71.4 - 84.7] False 4 (23.5) 2 (6.1) 16 (18.4) 14 (8.8) I don't know 3 (17.6) 5 (15.2) 14 (16.1) 20 (12.6) 11f: An equianalgesic dose of (mother oral opioid Truem 10 (58.8) [32.9 - 81.6] 21 (63.6) [45.1 - 79.6] 58 (66.7) [55.7 - 76.4] 105 (66.0) [58.1 - 73.4] False 4 (23.5) 4 (12.1) 19 (21.8) 22 (13.8) I don't know 3 (17.6) 8 (24.2) 10 (11.5) 32 (20.1) 95% exact two-sided con?dence intervals are calculated using the Clopper-Pearson method. Conect response. Data Source: ADPQ, ADTQ Program: TRIG TIRF Pharmacist KAB Page 1 of 5 03DEC2015 Table 6.1.4: Responses to Questions Linked to Key Risk Message #1 by Number of Times Dispensing TIRF Medicines per Month Within the Last 6 Months Completed Surveys Key Risk Message TIRF medicines are contraindicated in opioid non-tolerant patients. Question Number of Times Dispensing TIRF Medicines per Month Within the Last 6 Months None [95% 1 - 2 times per month [95% 3 5 times per month [95% More than 5 times per month [95% I don't remember [95% Question 5: Please select True, False, or I don't know for each of the following. According to the labeling for TIRF medicines, patients with cancer who are considered opioid-tolerant are those: 5a: Who are taking around-the-clock opioid therapy for underlying, persistent cancer pain for one week or longer Truem 110 (93.2) [87.1 - 97.0] 104 (92.9) [86.4 - 96.9] 24 (96.0) [79.6 - 99.9] 26 (89.7) [72.6 - 97.8] 15 (88.2) [63.6 - 98.5] False 8 (6.8) 8 (7.1) 1 (4.0) 3 (10.3) 2 (11.8) I don't know 0 0 0 0 0 5b: Who are not currently taking opioid therapy, but have taken opioid therapy before True 8 (6.8) 11 (9.8) 4 (16.0) 1 (3.4) 3 (17.6) Falsem 106 (89.8) [82.9 - 94.6] 95 (84.8) [76.8 - 90.9] 21 (84.0) [63.9 - 95.5] 27 (93.1) [77.2 - 99.2] 14 (82.4) [56.6 - 96.2] I don't know 4 (3.4) 6 (5.4) 0 1 (3.4) 0 5c: Who have no known contraindications to the drug fentanyl, but are not currently taking around-the-clock opioid therapy True 10 (8.5) 20 (17.9) 7 (28.0) 5 (17.2) 2 (11.8) Falsep] 105 (89.0) [81.9 - 94.0] 88 (78.6) [69.8 - 85.8] 18 (72.0) [50.6 - 87.9] 23 (79.3) [60.3 - 92.0] 14 (82.4) [56.6 - 96.2] I don't know 3 (2.5) 4 (3.6) 0 1 (3.4) 1 (5.9) Question 7: Please answer True, False, or I don't know for each statement based on the labeling for TIRF medicines. Data Source: ADPQ, ADTQ Program: TRIG Page 2 of 5 TIRF Pharmacist KAB 03DEC2015 Table 6.1.4: Responses to Questions Linked to Key Risk Message #1 by Number of Times Dispensing TIRF Medicines per Month Within the Last 6 Months Completed Surveys Key Risk Message TIRF medicines are contraindicated in opioid non-tolerant patients. Number of Times Dispensing TIRF Medicines per Month Within the Last 6 Months 1 - 2 times 3 - 5 times More than 5 times I don't None per month per month per month remember Question [95% [95% [95% Cl] "1 [95% "1 [95% '11 7a: IRF medicines are contraindicated in opioid non-tolerant patients because life-threatening respiratory depression could occur at any dose. Truem 103 (87.3) [79.9 - 92.7] 106 (94.6) [88.7 - 98.0] 21 (84.0) [63.9 - 95.5] 27 (93.1) [77.2 - 99.2] 17 (100.0) [80.5 - 100.0] False 12 (10.2) 2 (1.8) 3 (12.0) 2 (6.9) 0 I don't know 3 (2.5) 4 (3.6) 1 (4.0) 0 0 7b: Death has occurred in opioid non-tolerant patients treated with some fentanyl products. Truem 115 (97.5) [92.7 - 99.5] 105 (93.8) [87.5 - 97.5] 24 (96.0) [79.6 - 99.9] 28 (96.6) [82.2 - 99.9] 15 (88.2) [63.6 - 98.5] False 0 2 (1.8) 0 1 (3.4) 1 (5.9) Idon't know 3 (2.5) 5 (4.5) 1 (4.0) 0 1 (5.9) 7c: IRF medicines may be used in opioid non-tolerant patients. True 18 (15.3) 9 (8.0) 5 (20.0) 2 (6.9) 1 (5.9) Falsem 96 (81.4) [73.1 - 87.9] 100 (89.3) [82.0 - 94.3] 19 (76.0) [54.9 - 90.6] 27 (93.1) [77.2 - 99.2] 15 (88.2) [63.6 - 98.5] I don't know 4 (3.4) 3 (2.7) (4.0) 0 1 (5.9) 7d: Prescribers starting a patient on a IRF medicine must begin with titration from the lowest dose available for that specific product, even if the patient has previously taken another TIRF medicine. Truem 91 93 19 l6(94.l) [71.3-99.9] Data Source: ADPQ, ADTQ Program: TRIG TIRF Pharmacist KAB Page 3 of 5 03DEC2015 Table 6.1.4: Responses to Questions Linked to Key Risk Message #1 by Number of Times Dispensing TIRF Medicines per Month Within the Last 6 Months Completed Surveys Key Risk Message TIRF medicines are contraindicated in opioid non-tolerant patients. Number of Times Dispensing TIRF Medicines per Month Within the Last 6 Months 1 - 2 times 3 5 times More than 5 times I don't None per month per month per month remember Question [95% 11 [95% '11 [95% Cl] "1 [95% Cl]m [95% "1 False 21 (17.8) 14 (12.5) 5 (20.0) 4 (13.8) 1 (5.9) I don't know 6 (5.1) 5 (4.5) 1 (4.0) 1 (3.4) 0 Question 11: Please select True, False, or I don't know for each of the following. According to the labeling for TIRF medicines, patients considered opioid-tolerant are those who are taking, for one week or longer, at least: Ila: 8 mg oral m'dromorphone/day Truem 91 (77.1) [68.5 - 84.3] 87 (77.7) [68.8 - 85.0] 18 (72.0) [50.6 - 87.9] 26 (89.7) [72.6 - 97.8] 15 (88.2) [63.6 - 98.5] False 9 (7.6) 15 (13.4) 3 (12.0) 3 (10.3) 0 Idon't know 18 (15.3) 10 (8.9) 4 (16.0) 0 2 (11.8) 11b: 60 mg oral morphine/day Truem 102 (86.4) [78.9 - 92.0] 103 (92.0) [85.3 - 96.3] 22 (88.0) [68.8 - 97.5] 28 (96.6) [82.2 - 99.9] 15 (88.2) [63.6 - 98.5] False 6 (5.1) 2 (1.8) 1 (4.0) 1 (3.4) 1 (5.9) I don't know 10 (8.5) 7 (6.3) 2 (8.0) 0 1 (5.9) 11c: 30 mg oral oxrcodone/dqv Truem 88 (74.6) [65.7 - 82.1] 87 (77.7) [68.8 - 85.0] 14 (56.0) [34.9 - 75.6] 27 (93.1) [77.2 - 99.2] 16 (94.1) [71.3 - 99.9] False 17 (14.4) 15 (13.4) 6 (24.0) 2 (6.9) 1 (5.9) Data Source: ADPQ, ADTQ Program: TRIG TIRF Pharmacist KAB Page 4 of 5 03DEC2015 Table 6.1.4: Responses to Questions Linked to Key Risk Message #1 by Number of Times Dispensing TIRF Medicines per Month Within the Last 6 Months Completed Surveys Key Risk Message TIRF medicines are contraindicated in opioid non-tolerant patients. Number of Times Dispensing TIRF Medicines per Month Within the Last 6 Months 1 - 2 times 3 - 5 times More than 5 times I don't None per month per month per month remember Question [95% 11 [95% "1 [95% "1 [95% Cl] "1 [95% "1 I don't know 13 (11.0) 10 (8.9) 5 (20.0) 0 0 11d: 25 meg transdermalfentanyl/hour Truem 90 (76.3) [67.6 - 83.6] 87 (77.7) [68.8 - 85.0] 16 (64.0) [42.5 - 82.0] 25 (86.2) [68.3 - 96.1] 14 (82.4) [56.6 - 96.2] False 16 (13.6) 15 (13.4) 5 (20.0) 4 (13.8) 2 (11.8) I don't know 12 (10.2) 10 (8.9) 4 (16.0) 0 (5.9) He: 25 mg oral oxymorphone/dqv Truem 84 (71.2) [62.1 - 79.2] 81 (72.3) [63.1 - 80.4] 16 (64.0) [42.5 - 82.0] 27 (93.1) [77.2 - 99.2] 13 (76.5) [50.1 - 93.2] False 14 (11.9) 19 (17.0) 1 (4.0) 2 (6.9) 0 I don't know 20 (16.9) 12 (10.7) 8 (32.0) 0 4 (23.5) 11f: An equianalgesic dose of (mother oral opioid Truem 76 (64.4) [55.1 - 73.0] 68 (60.7) [51.0 - 69.8] 16 (64.0) [42.5 - 82.0] 22 (75.9) [56.5 - 89.7] 14 (82.4) [56.6 - 96.2] False 18 (15.3) 21 (18.8) 4 (16.0) 5 (17.2) 1 (5.9) I don't know 24 (20.3) 23 (20.5) 5 (20.0) 2 (6.9) 2 (11.8) 95% exact two-sided con?dence intervals are calculated using the Clopper-Pearson method. Conect response. Data Source: ADPQ, ADTQ Program: TRIG TIRF Pharmacist KAB Data Source: ADPQ, ADTQ Page 5 of 5 03DEC2015 Program: TKRMS.SAS FDA_3473 TRIG Page 1 of TIRF Pharmacist KAB 03DEC2015 Table 6.2: Secondary Analysis of Responses to Questions Linked to Key Risk Message #1 - Completed Surveys Key Risk Message TIRF medicines are contraindicated in opioid non-tolerant patients. Pharmacists Correct Responses 11 [95% CI]ll] 0 correct responses 0 1 correct response 1 (0.3) 2 correct responses 1 (0.3) 3 correct responses 2 (0.7) 4 correct responses 4 (1.3) 5 correct responses 5 (1.7) 6 correct responses 9 (3.0) 7 correct responses 13 (4.3) 8 correct responses 11 (3.7) 9 correct responses 30 (10.0) 10 correct responses 33 (11.0) 11 correct responses 37 (12.3) 12 correct responses 66 (21.9) 13 correct responses 89 (29.6) [24.5 - 35.1] 95% exact two-sided con?dence intervals are calculated using the Clopper-Pearson method. Data Source: ADPQ, ADTQ Program: TRIG Page 1 of 2 TIRF Pharmacist KAB 03DEC2015 Table 7.1: Primary Analysis of Responses to Questions Linked to Key Risk Message #2 - Completed Surveys Key Risk Message TIRF medicines are only indicated for the management of breakthrough pain in adult cancer patients 18 years of age and older (16 years of age and older for Actiq? brand and generic equivalents) who are already receiving and who are tolerant to around?the?clock opioid therapy for their underlying persistent cancer pain. Pharmacists Question 11 [95% Question 6: Please answer True, False, or I don't know for each statement based on the labeling for TIRF medicines. 6a: According to the product labeling, a cancer patient may start a IRF medicine and an around-the-clock opioid at the same time. True 70 (23.3) Falsem 208 (69.1) [63.5 - 74.3] I don't know 23 (7.6) 6b: According to the product labeling, a cancer patient who has been on an around-the-clock opioid for 1 day may start taking a IRF medicine for breakthrough pain. True 37 (12.3) Falsem 247 (82.1) [77.2 - 86.2] I don't know 17 (5.6) 6c: A patient must stop taking their IRF medicine ifthey stop taking their around-the-clock opioid pain medicine. Truem 126 (41.9) [36.2 - 47.7] False 136 (45.2) I don't know 39 (13.0) Question 9: Per the approved labeling for TIRF medicines, for which of the following indications can TIRF medicines be prescribed to opioid tolerant patients? Please answer Yes, No, or I don't know for each option. 9a: Acute or postoperative pain Yes 22 (7.3) 271 (90.0) [86.1 - 93.2] I don't know 8 (2.7) 9b: Headache or migraine pain Yes 12 (4.0) Data Source: ADPQ, ADTQ Program: TKRM.SAS TRIG TIRF Pharmacist KAB Page 2 of 2 03DEC2015 Table 7.1: Primary Analysis of Responses to Questions Linked to Key Risk Message #2 - Completed Surveys Key Risk Message TIRF medicines are only indicated for the management of breakthrough pain in adult cancer patients 18 years of age and older (16 years of age and older for Actiq? brand and generic equivalents) who are already receiving and who are tolerant to around?the?clock opioid therapy for their underlying persistent cancer pain. Pharmacists Question 11 [95% 01'? Nov] 280 (93.0) [89.5 - 95.6] I don't know 9 (3.0) 90: Dental pain Yes 2 (0.7) 296 (98.3) [96.2 - 99.5] I don't know 3 (1.0) 9d: Breakthrough pain from cancer Yesm 277 (92.0) [88.4 - 94.8] No 24 (8.0) I don't know 0 9e: Chronic non-cancer pain Yes 131 (43.5) Now 153 (50.8) [45.0 - 56.6] I don't know 17 (5.6) 95% exact two-sided con?dence intervals are calculated using the Clopper-Pearson method. Correct response. Data Source: ADPQ, ADTQ Program: TRIG TIRF Pharmacist KAB Page 1 of 3 03DEC2015 Table 7.1.3: Responses to Questions Linked to Key Risk Message #2 by Time Practicing as Pharmacist - Completed Surveys Key Risk Message TIRF medicines are only indicated for the management of breakthrough pain in adult cancer patients 18 years of age and older (16 years of age and older for Actiq? brand and generic equivalents) who are already receiving and who are tolerant to around-the?clock opioid therapy for their underlying persistent cancer pain. Question Time Practicing as Pharmacist Less than 3 years [95% 3 to 5 years [95% 6 to 15 years [95% "1 More than 15 years [95% Question 6: Please answer True, False, or I don't know for each statement based on the labeling for TIRF medicines. 6a: According to the product labeling, a cancer patient may start a IRF medicine and an around-the-clock opioid at the same time. True 2 (11.8) 4 (12.1) 17 (19.5) 45 (28.3) Falsem 14 (82.4) [56.6 - 96.2] 27 (81.8) [64.5 - 93.0] 64 (73.6) [63.0 - 82.4] 103 (64.8) [56.8 - 72.2] I don't know 1 (5.9) 2 (6.1) 6 (6.9) 11 (6.9) 6b: According to the product labeling, a cancer patient who has been on an around-the-clock opioid for 1 day may start taking a IRF medicine for breakthrough pain. True 2 (11.8) 2 (6.1) 6 (6.9) 27 (17.0) Falsem 13 (76.5) [50.1 - 93.2] 30 (90.9) [75.7 - 98.1] 76 (87.4) [78.5 - 93.5] 125 (78.6) [71.4 - 84.7] I don't know 2 (11.8) 1 (3.0) 5 (5.7) 7 (4.4) 6c: A patient must stop taking their IRF medicine ifthey stop taking their around-the-clock opioid pain medicine. Truem 10 (58.8) [32.9 - 81.6] 17 (51.5) [33.5 - 69.2] 34 (39.1) [28.8 - 50.1] 64 (40.3) [32.6 - 48.3] False 6 (35.3) 7 (21.2) 40 (46.0) 82 (51.6) I don't know 1 (5.9) 9 (27.3) 13 (14.9) 13 (8.2) Data Source: ADPQ, ADTQ Program: TRIG TIRF Pharmacist KAB Page 2 of 3 03DEC2015 Table 7.1.3: Responses to Questions Linked to Key Risk Message #2 by Time Practicing as Pharmacist - Completed Surveys Key Risk Message TIRF medicines are only indicated for the management of breakthrough pain in adult cancer patients 18 years of age and older (16 years of age and older for Actiq? brand and generic equivalents) who are already receiving and who are tolerant to around-the?clock opioid therapy for their underlying persistent cancer pain. Question Time Practicing as Pharmacist Less than 3 years [95% 3 to 5 years [95% "1 6 to 15 years [95% More than 15 years [95% Question 9: Per the approved labeling for TIRF medicines, for which of the following indications can TIRF medicines be prescribed to opioid tolerant patients? Please answer Yes, No, or I don't know for each option. 9a: Acute or postoperative pain Yes 2 (11.8) 1 (3.0) 5 (5.7) 13 (8.2) 15 (88.2) [63.6 - 98.5] 31 (93.9) [79.8 - 99.3] 78 (89.7) [81.3 - 95.2] 143 (89.9) [84.2 - 94.1] I don't know 0 1 (3.0) 4 (4.6) 3 (1.9) 9b: Headache or migraine pain Yes 0 2 (6.1) 2 (2.3) 8 (5.0) Non] 16 (94.1) [71.3 - 99.9] 29 (87.9) [71.8 - 96.6] 83 (95.4) [88.6 - 98.7] 147 (92.5) [87.2 - 96.0] I don't know 1 (5.9) 2 (6.1) 2 (2.3) 4 (2.5) 9c: Dental pain Yes 0 0 2 (1.3) Now 17 (100.0) [80.5 - 100.0] 32 (97.0) [84.2 - 99.9] 86 (98.9) [93.8 - 100.0] 156 (98.1) [94.6 - 99.6] Idon't know 0 (3.0) 1 (1.1) 1 (0.6) 9d: Breakthrough pain from cancer Data Source: ADPQ, ADTQ Program: TRIG TIRF Pharmacist KAB Page 3 of 3 03DEC2015 Table 7.1.3: Responses to Questions Linked to Key Risk Message #2 by Time Practicing as Pharmacist - Completed Surveys Key Risk Message TIRF medicines are only indicated for the management of breakthrough pain in adult cancer patients 18 years of age and older (16 years of age and older for Actiq? brand and generic equivalents) who are already receiving and who are tolerant to around-the?clock opioid therapy for their underlying persistent cancer pain. Time Practicing as Pharmacist Less than 3 years 3 to 5 years 6 to 15 years More than 15 years Question 11 [95% 11 [95% 11 [95% [95% Yesm 15 (88.2) [63.6 - 98.5] 29 (87.9) [71.8 - 96.6] 83 (95.4) [88.6 - 98.7] 145 (91.2) [85.7 - 95.1] No 2 (11.8) 4 (12.1) 4 (4.6) 14 (8.8) I don't know 0 0 0 9e: Chronic non-cancer pain Yes 9 (52.9) 14 (42.4) 31 (35.6) 76 (47.8) Now 8 (47.1) [23.0 - 72.2] 15 (45.5) [28.1 - 63.6] 48 (55.2) [44.1 - 65.9] 78 (49.1) [41.1 - 57.1] I don't know 0 4 (12.1) 8 (9.2) 5 (3.1) 95% exact two-sided con?dence intervals are calculated using the Clopper-Pearson method. Correct response. Data Source: ADPQ, ADTQ Program: TRIG TIRF Pharmacist KAB Page 1 of 3 03DEC2015 Table 7.1.4: Responses to Questions Linked to Key Risk Message #2 by Number of Times Dispensing TIRF Medicines per Month Within the Last 6 Months - Completed Surveys Key Risk Message TIRF medicines are only indicated for the management of breakthrough pain in adult cancer patients 18 years of age and older (16 years of age and older for Actiq? brand and generic equivalents) who are already receiving and who are tolerant to around-the-clock opioid therapy for their underlying persistent cancer pain. Question Number of Times Dispensing TIRF Medicines per Month Within the Last 6 Months None [95% 1 - 2 times per month [95% '11 3 5 times per month [95% More than 5 times per month [95% cum I don't remember (N=l7) [95% CI]'ll Question 6: Please answer True, False, or I don't know for each statement based on the labeling for TIRF medicines. 6a: According to the product labeling, a cancer patient may start a IRF medicine and an around-the-clock opioid at the same time. True 24 (20.3) 23 (20.5) 9 (36.0) 9 (31.0) 5 (29.4) Falsem 82 (69.5) [60.3 - 77.6] 82 (73.2) [64.0 - 81.1] 13 (52.0) [31.3 - 72.2] 19 (65.5) [45.7 - 82.1] 12 (70.6) [44.0 - 89.7] I don't know 12 (10.2) 7 (6.3) 3 (12.0) 1 (3.4) 0 6b: According to the product labeling, a cancer patient who has been on an around-the-clock opioid for 1 day may start taking a IRF medicine for breakthrough pain. True 11 (9.3) 16 (14.3) 3 (12.0) 5 (17.2) 2 (11.8) Falsem 99 (83.9) [76.0 - 90.0] 90 (80.4) [71.8 - 87.3] 21 (84.0) [63.9 - 95.5] 23 (79.3) [60.3 - 92.0] 14 (82.4) [56.6 - 96.2] I don't know 8 (6.8) 6 (5.4) 1 (4.0) (3.4) (5.9) 6c: A patient must stop taking their IRF medicine if they stop taking their around-the-clock opioid pain medicine. Truem 47 (39.8) [30.9 - 49.3] 48 (42.9) [33.5 - 52.6] 8 (32.0) [14.9 - 53.5] 16 (55.2) [35.7 - 73.6] 7 (41.2) [18.4 - 67.1] False 49 (41.5) 52 (46.4) 15 (60.0) 12 (41.4) 8 (47.1) Idon't know 22 (18.6) 12 (10.7) 2 (8.0) 1 (3.4) 2 (11.8) Data Source: ADPQ, ADTQ Program: TRIG Page 2 of 3 TIRF Pharmacist KAB 03DEC2015 Table 7.1.4: Responses to Questions Linked to Key Risk Message #2 by Number of Times Dispensing TIRF Medicines per Month Within the Last 6 Months - Completed Surveys Key Risk Message TIRF medicines are only indicated for the management of breakthrough pain in adult cancer patients 18 years of age and older (16 years of age and older for Actiq? brand and generic equivalents) who are already receiving and who are tolerant to around-the-clock opioid therapy for their underlying persistent cancer pain. Number of Times Dispensing TIRF Medicines per Month Within the Last 6 Months 1 - 2 times 3 5 times More than 5 times I don't None per month per month per month remember Question 11 [95% 11 [95% '11 [95% [95% cum [95% C11'll Question 9: Per the approved labeling for TIRF medicines, for which of the following indications can TIRF medicines be prescribed to opioid tolerant patients? Please answer Yes, No, or I don't know for each option. 9a: Acute or postoperative pain Yes 5 (4.2) 9 (8.0) 3 (12.0) 3 (10.3) 2 (11.8) Non] 111 (94.1) [88.2 - 97.6] 98 (87.5) [79.9 - 93.0] 21 (84.0) [63.9 - 95.5] 26 (89.7) [72.6 - 97.8] 15 (88.2) [63.6 - 98.5] I don't know 2 (1.7) 5 (4.5) 1 (4.0) 0 0 9b: Headache or migraine pain Yes 2 (1.7) 7 (6.3) 1 (4.0) 2 (6.9) 0 Non] 113 (95.8) [90.4 - 98.6] 103 (92.0) [85.3 - 96.3] 22 (88.0) [68.8 - 97.5] 25 (86.2) [68.3 - 96.1] 17 (100.0) [80.5 - 100.0] I don't know 3 (2.5) 2 (1.8) 2 (8.0) 2 (6.9) 0 9c: Dental pain Yes 1 (0.8) (0.9) 0 0 0 Non] 116 (98.3) [94.0 - 99.8] 109 (97.3) [92.4 - 99.4] 25 (100.0) [86.3 - 100.0] 29 (100.0) [88.1 - 100.0] 17 (100.0) [80.5 - 100.0] I don't know 1 (0.8) 2 (1.8) 0 0 0 Data Source: ADPQ, ADTQ Program: TRIG TIRF Pharmacist KAB Page 3 of 3 03DEC2015 Table 7.1.4: Responses to Questions Linked to Key Risk Message #2 by Number of Times Dispensing TIRF Medicines per Month Within the Last 6 Months Completed Surveys Key Risk Message TIRF medicines are only indicated for the management of breakthrough pain in adult cancer patients 18 years of age and older (16 years of age and older for Actiq? brand and generic equivalents) who are already receiving and who are tolerant to around-the-clock opioid therapy for their underlying persistent cancer pain. Question Number of Times Dispensing TIRF Medicines per Month Within the Last 6 Months None [95% 1 - 2 times per month [95% 3 - 5 times per month [95% More than 5 times per month [95% I don't remember (N=l7) [95% 9d: Breakthrough pain from cancer Yesm 108 (91.5) [85.0 - 95.9] 103 (92.0) [85.3 - 96.3] 22 (88.0) [68.8 - 97.5] 27 (93.1) [77.2 - 99.2] 17 (100.0) [80.5 - 100.0] No 10 (8.5) 9 (8.0) 3 (12.0) 2 (6.9) 0 I don't know 0 0 0 0 0 99: Chronic non-cancer pain Yes 50 (42.4) 47 (42.0) 16 (64.0) 12 (41.4) 6 (35.3) Now 58 (49.2) [39.8 - 58.5] 61 (54.5) [44.8 - 63.9] 8 (32.0) [14.9 - 53.5] 16 (55.2) [35.7 - 73.6] 10 (58.8) [32.9 - 81.6] I don't know 10 (8.5) 4 (3.6) 1 (4.0) 1 (3.4) (5.9) 95% exact two-sided con?dence intervals are calculated using the Clopper-Pearson method. Correct response. Data Source: ADPQ, ADTQ Program: TRIG Page 1 of TIRF Pharmacist KAB 03DEC2015 Table 7.2: Secondary Analysis of Responses to Questions Linked to Key Risk Message #2 - Completed Surveys Key Risk Message TIRF medicines are only indicated for the management of breakthrough pain in adult cancer patients 18 years of age and older (16 years of age and older for Actiq? brand and generic equivalents) who are already receiving and who are tolerant to around?the?clock opioid therapy for their underlying persistent cancer pain. Pharmacists Correct Responses 11 [95% 0 correct responses 0 1 correct response 2 (0.7) 2 correct responses 2 (0.7) 3 correct responses 11 (3.7) 4 correct responses 26 (8.6) 5 correct responses 49 (16.3) 6 correct responses 74 (24.6) 7 correct responses 70 (23.3) 8 correct responses 67 (22.3) [17.7 - 27.4] 95% exact two-sided con?dence intervals are calculated using the Clopper-Pearson method. Data Source: ADPQ, ADTQ Program: TRIG TIRF Pharmacist KAB Page 1 of 03DEC2015 Table 8.1: Primary Analysis of Responses to Questions Linked to Key Risk Message #3 - Completed Surveys Key Risk Message TIRF medicines contain fentanyl, an opioid agonist and a Schedule II controlled substance with abuse liability similar to other opioid analgesics. Question Pharmacists [95% medicines. Question 7: Please answer True, False, or I don't know for each statement based on the labeling for TIRF 7e: It is important to monitor for signs of abuse and addiction in patients who take IRF medicines. Truem 293 (97.3) [94.8 - 98.8] False 7 (2.3) I don't know 1 (0.3) know for each option. Question 8: Which of the following are risk factors for opioid abuse? Please answer Yes, No, or I don't 8a: A personal history of illness Yesm 227 (75.4) [70.1 - 80.2] No 43 (14.3) I don't know 31 (10.3) 8b: A personal history of past or current alcohol or drug abuse, or a family history of illicit drug use or alcohol abuse Yesm 297 (98.7) [96.6 - 99.6] No 2 (0.7) I don?t know 2 (0.7) medicines. Question 10: Please answer True, False, or I don't know for each statement based on the labeling for TIRF 10a: TIRF medicines can be abused in a manner similar to other opioid agonists. Truem 288 (95.7) [92.7 - 97.7] False 8 (2.7) I don't know 5 (1.7) 95% exact two-sided con?dence intervals are calculated using the Clopper-Pearson method. Correct response. Data Source: ADPQ, ADTQ Program: TRIG TIRF Pharmacist KAB Page 1 of 2 03DEC2015 Table 8.1.3: Responses to Questions Linked to Key Risk Message #3 by Time Practicing as Pharmacist - Completed Suweys Key Risk Message TIRF medicines contain fentanyl, an opioid agonist and a Schedule II controlled substance with abuse liability similar to other opioid analgesics. Question Less than 3 years [95% Time Practicing as Pharmacist 3 to 5 years [95% "1 6 to 15 years [95% More than 15 years [95% Question 7: Please answer True, False, or I don't know for each statement based on the labeling for TIRF medicines. 7e: It is important to monitor for signs of abuse and addiction in patients who take TIRF medicines. Truem 17 (100.0) [80.5 - 100.0] 33 (100.0) [89.4 - 100.0] 86 (98.9) [93.8 - 100.0] 152 (95.6) [91.1 - 98.2] False 0 0 1 (1.1) 6 (3.8) I don't know 0 0 0 1 (0.6) Question 8: Which of the following are risk factors for opioid abuse? Please answer Yes, No, or I don't know for each option. 8a: A personal history of illness Yesm 16 (94.1) [71.3 - 99.9] 29 (87.9) [71.8 - 96.6] 71 (81.6) [71.9 - 89.1] 108 (67.9) [60.1 - 75.1] No 0 4(12.1) 6 (6.9) 33 (20.8) I don't know 1 (5.9) 0 10 (11.5) 18(11.3) 8b: A personal history of past or current alcohol or drug abuse, or a amily history of illicit drug use or alcohol abuse Yesm 17 (100.0) [80.5 - 100.0] 33 (100.0) [89.4 - 100.0] 86 (98.9) [93.8 - 100.0] 156 (98.1) [94.6 - 99.6] No 0 0 0 2 (1.3) I don't know 0 0 1 (1.1) 1 (0.6) Question 10: Please answer True, False, or I don't know for each statement based on the labeling for TIRF medicines. Data Source: ADPQ, ADTQ Program: TRIG Page 2 of 2 TIRF Pharmacist KAB 03DEC2015 Table 8.1.3: Responses to Questions Linked to Key Risk Message #3 by Time Practicing as Pharmacist - Completed Suweys Key Risk Message TIRF medicines contain fentanyl, an opioid agonist and a Schedule II controlled substance with abuse liability similar to other opioid analgesics. Time Practicing as Pharmacist Less than 3 years 3 to 5 years 6 to 15 years More than 15 years Question [95% 11 [95% "1 [95% 11 [95% "1 100: IRF medicines can be abused in a manner similar to other opioid agonists. Truem 16 (94.1) [71.3 - 99.9] 31 (93.9) [79.8 - 99.3] 83 (95.4) [88.6 - 98.7] 153 (96.2) [92.0 - 98.6] False 0 1 (3.0) 2 (2.3) 5 (3.1) I don't know 1 (5.9) 1 (3.0) 2 (2.3) 1 (0.6) 95% exact two-sided con?dence intervals are calculated using the Clopper-Pearson method. Correct response. Data Source: ADPQ, ADTQ Program: TRIG TIRF Pharmacist KAB Page 1 of 2 03DEC2015 Table 8.1.4: Responses to Questions Linked to Key Risk Message #3 by Number of Times Dispensing TIRF Medicines per Month Within the Last 6 Months Completed Surveys Key Risk Message TIRF medicines contain fentanyl, an opioid agonist and a Schedule II controlled substance with abuse liability similar to other opioid analgesics. Question Number of Times Dispensing TIRF Medicines per Month Within the Last 6 Months None [95% 1 - 2 times per month [95% "1 3 - 5 times per month [95% More than 5 times per month [95% I don't remember (N=l7) [95% 011'" Question 7: Please answer True, False, or I don't know for each statement based on the labeling for TIRF medicines. 7e: It is important to monitor for signs of abuse and addiction in patients who take TIRF medicines. Truem 115 (97.5) [92.7 - 99.5] 107 (95.5) [89.9 - 98.5] 25 (100.0) [86.3 - 100.0] 29 (100.0) [88.1 - 100.0] 17 (100.0) [80.5 - 100.0] False 2 (1.7) 5 (4.5) 0 0 0 I don't know 1 (0.8) 0 0 0 0 Question 8: Which of the following are risk factors for opioid abuse? Please answer Yes, No, or I don't know for each option. 8a: A personal history of illness Yesm 90 (76.3) [67.6 - 83.6] 89 (79.5) [70.8 - 86.5] 17 (68.0) [46.5 - 85.1] 20 (69.0) [49.2 - 84.7] 11 (64.7) [38.3 - 85.8] No 14 (11.9) 14 (12.5) 7 (28.0) 5 (17.2) 3 (17.6) I don't know 14 (11.9) 9 (8.0) 1 (4.0) 4 (13.8) 3 (17.6) 8b: A personal history of past or current alcohol or drug abuse, or a family histonv of illicit drug use or alcohol abuse Yesm 116 (98.3) [94.0 - 99.8] 111 (99.1) [95.1 - 100.0] 25 (100.0) [86.3 - 100.0] 28 (96.6) [82.2 - 99.9] 17 (100.0) [80.5 - 100.0] No 0 1 (0.9) 0 1 (3.4) 0 I don't know 2 (1.7) 0 0 0 0 Data Source: ADPQ, ADTQ Program: TRIG TIRF Pharmacist KAB Page 2 of 2 03DEC2015 Table 8.1.4: Responses to Questions Linked to Key Risk Message #3 by Number of Times Dispensing TIRF Medicines per Month Within the Last 6 Months Completed Surveys Key Risk Message TIRF medicines contain fentanyl, an opioid agonist and a Schedule II controlled substance with abuse liability similar to other opioid analgesics. Question Number of Times Dispensing TIRF Medicines per Month Within the Last 6 Months None [95% 1 - 2 times per month [95% 3 - 5 times per month [95% More than 5 times per month [95% I don't remember (N=l7) [95% 011'" Question 10: Please answer True, False, or I don't know for each statement based on the labeling for TIRF medicines. 100: medicines can be abused in a manner similar to other opioid agonists. Truem 113 (95.8) [90.4 - 98.6] 110 (98.2) [93.7 - 99.8] 22 (88.0) [68.8 - 97.5] 27 (93.1) [77.2 - 99.2] 16 (94.1) [71.3 - 99.9] False 3 (2.5) 2 (1.8) (4.0) 2 (6.9) 0 Idon't know 2 (1.7) 0 2 (8.0) 0 1 (5.9) 95% exact two-sided con?dence intervals are calculated using the Clopper-Pearson method. Correct response. Data Source: ADPQ, ADTQ Program: TRIG Page 1 of TIRF Pharmacist KAB 03DEC2015 Table 8.2: Secondary Analysis of Responses to Questions Linked to Key Risk Message #3 - Completed Surveys Key Risk Message TIRF medicines contain fentanyl, an opioid agonist and a Schedule II controlled substance with abuse liability similar to other opioid analgesics. Pharmacists Correct Responses 11 [95% 0 correct responses 0 1 correct response 0 2 correct responses 6 (2.0) 3 correct responses 87 (28.9) 4 correct responses 208 (69.1) [63.5 - 74.3] 95% exact two-sided con?dence intervals are calculated using the Clopper-Pearson method. Data Source: ADPQ, ADTQ Program: TRIG TIRF Pharmacist KAB Page 1 of 03DEC2015 Table 9.1: Primary Analysis of Responses to Questions Linked to Key Risk Message #4 - Completed Surveys Key Risk Message TIRF medicines are not interchangeable with each other, regardless of route of administration. Question Pharmacists [95% medicines. Question 10: Please answer True, False, or I don't know for each statement based on the labeling for TIRF 10b: IRF medicines are interchangeable with each other regardless of route of administration. True 14 (4.7) Falsep] 281 (93.4) [89.9 - 95.9] I don't know 6 (2.0) of differences in the pharmacokinetics of fentanyl absorption. 10c: The conversion of one IRF medicine for another TIRF medicine may result in a fatal overdose because 2] Truel 279 (92.7) [89.1 - 95.4] False 11 (3.7) I don?t know 11 (3.7) 10d: Dosing of TIRF medicines is not equivalent on a microgram-to-microgram basis. 2] Truel 279 (92.7) [89.1 - 95.4] False 14 (4.7) I don't know 8 (2.7) Question 13: Please answer True, False, or I don't know for each statement about TIRF medicines. is out of stock for one product. 13c: IRF medicines with the same route of administration can be substituted with each other if the pharmacy True 3 (1.0) Falsem 296 (98.3) [96.2 - 99.5] I don't know 2 (0.7) 95% exact two-sided con?dence intervals are calculated using the lopper-Pearson method. Correct response. Data Source: ADPQ, ADTQ Program: TRIG TIRF Pharmacist KAB Page 1 of 2 03DEC2015 Table 9.1.3: Responses to Questions Linked to Key Risk Message #4 by Time Practicing as Pharmacist - Completed Surveys Key Risk Message TIRF medicines are not interchangeable with each other, regardless of route of administration. Question Less than 3 years [95% Time Practicing as Pharmacist 3 to 5 years [95% '11 6 to 15 years [95% "1 More than 15 years [95% 011?? Question 10: Please answer True, False, or I don't know for each statement based on the labeling for TIRF medicines. 10b: IRF medicines are interchangeable with each other regardless of route of administration. True 0 (3.0) 5 (5.7) 8 (5.0) Falsep] 17 (100.0) [80.5 - 100.0] 31 (93.9) [79.8 - 99.3] 80 (92.0) [84.1 - 96.7] 148 (93.1) [88.0 - 96.5] I don't know 0 (3.0) 2 (2.3) 3 (1.9) 10c: The conversion of one TIRF medicine for another TIRF medicine may result in a fatal overdose because of differences in the pharmacokinetics of fentanyl absorption. Truem 15 (88.2) [63.6 - 98.5] 32 (97.0) [84.2 - 99.9] 81 (93.1) [85.6 - 97.4] 146 (91.8) [86.4 - 95.6] False 2 (11.8) 0 2 (2.3) 7 (4.4) I don't know 0 (3.0) 4 (4.6) 6 (3.8) 10d: Dosing of IRF medicines is not equivalent on a microgram-to-microgram basis. Truem 16 (94.1) [71.3 - 99.9] 31 (93.9) [79.8 - 99.3] 82 (94.3) [87.1 - 98.1] 145 (91.2) [85.7 - 95.1] False 0 1 (3.0) 3 (3.4) 10 (6.3) I don't know 1 (5.9) (3.0) 2 (2.3) 4 (2.5) Question 13: Please answer True, False, or I don't know for each statement about TIRF medicines. 13c: IRF medicines with the same route of administration can be substituted with each other if the pharmacy is out of stock for one product. Data Source: ADPQ, ADTQ Program: TRIG TIRF Pharmacist KAB Page 2 of 2 03DEC2015 Table 9.1.3: Responses to Questions Linked to Key Risk Message #4 by Time Practicing as Pharmacist - Completed Surveys Key Risk Message TIRF medicines are not interchangeable with each other, regardless of route of administration. Time Practicing as Pharmacist Less than 3 years 3 to 5 years 6 to 15 years More than 15 years (N=l59) Question 11 [95% [95% '11 [95% "1 [95% 011?? True 0 1 (3.0) 1 (1.1) 1 (0.6) Falsem 17 (100.0) [80.5 - 100.0] 32 (97.0) [84.2 - 99.9] 86 (98.9) [93.8 - 100.0] 156 (98.1) [94.6 - 99.6] I don't know 0 0 0 2 (1.3) 95% exact two-sided con?dence intervals are calculated using the Clopper-Pearson method. onect response. Data Source: ADPQ, ADTQ Program: TRIG Page 1 of 2 TIRF Pharmacist KAB 03DEC2015 Table 9.1.4: Responses to Questions Linked to Key Risk Message #4 by Number of Times Dispensing TIRF Medicines per Month Within the Last 6 Months Completed Surveys Key Risk Message TIRF medicines are not interchangeable with each other, regardless of route of administration. Number of Times Dispensing TIRF Medicines per Month Within the Last 6 Months 1 - 2 times 3 5 times More than 5 times I don't None per month per month per month remember Question [95% 11 [95% '11 [95% Cl] "1 [95% Cl]m [95% "1 Question 10: Please answer True, False, or I don't know for each statement based on the labeling for TIRF medicines. 10b: IRF medicines are interchangeable with each other regardless of route of administration. True 5 (4.2) 4 (3.6) 1 (4.0) 2 (6.9) 2 (11.8) Falsem 110 (93.2) [87.1 - 97.0] 105 (93.8) [87.5 - 97.5] 24 (96.0) [79.6 - 99.9] 27 (93.1) [77.2 - 99.2] 15 (88.2) [63.6 - 98.5] I don't know 3 (2.5) 3 (2.7) 0 0 0 10c: The conversion of one TIRF medicine for another TIRF medicine may result in a fatal overdose because of di?'erences in the pharmacokinetics of fentanyl absorption. Truem 109 (92.4) [86.0 - 96.5] 104 (92.9) [86.4 - 96.9] 25 (100.0) [86.3 - 100.0] 25 (86.2) [68.3 - 96.1] 16 (94.1) [71.3 - 99.9] False 5 (4.2) 3 (2.7) 0 2 (6.9) 1 (5.9) I don't know 4 (3.4) 5 (4.5) 0 2 (6.9) 0 10d: Dosing of IRF medicines is not equivalent on a microgram-to-microgram basis. Truep] 109 (92.4) [86.0 - 96.5] 105 (93.8) [87.5 - 97.5] 21 (84.0) [63.9 - 95.5] 27 (93.1) [77.2 - 99.2] 17 (100.0) [80.5 - 100.0] False 5 (4.2) 5 (4.5) 3 (12.0) 1 (3.4) 0 I don't know 4 (3.4) 2 (1.8) 1 (4.0) 1 (3.4) 0 Question 13: Please answer True, False, or I don't know for each statement about TIRF medicines. Data Source: ADPQ, ADTQ Program: TRIG TIRF Pharmacist KAB Page 2 of 2 03DEC2015 Table 9.1.4: Responses to Questions Linked to Key Risk Message #4 by Number of Times Dispensing TIRF Medicines per Month Within the Last 6 Months - Completed Surveys Key Risk Message TIRF medicines are not interchangeable with each other, regardless of route of administration. Number of Times Dispensing TIRF Medicines per Month Within the Last 6 Months - 2 times 3 5 times More than 5 times I don't None per month per month per month remember (N=ll8) (N=l7) Question 11 [95% "1 [95% "1 [95% Cl] "1 [95% Cl] "1 [95% C1]'ll 13c: IRF medicines with the same route of administration can be substituted with each other if the pharmacy is out of stock for one product. True 2 (1.7) 0 1 (4.0) 0 0 Falsem 116 (98.3) [94.0 - 99.8] 110 (98.2) [93.7 - 99.8] 24 (96.0) [79.6 - 99.9] 29 (100.0) [88.1 - 100.0] 17 (100.0) [80.5 - 100.0] I don't know 0 2 (1.8) 0 0 0 95% exact two-sided con?dence inten'als are calculated using the Clopper-Pearson method. Conect response. Data Source: ADPQ, ADTQ Program: TRIG Page 1 of TIRF Pharmacist KAB 03DEC2015 Table 9.2: Secondary Analysis of Responses to Questions Linked to Key Risk Message #4 - Completed Surveys Key Risk Message TIRF medicines are not interchangeable with each other, regardless of route of administration. Pharmacists Correct Responses 11 [95% 0 correct responses 0 1 correct response 2 (0.7) 2 correct responses 7 (2.3) 3 correct responses 49 (16.3) 4 correct responses 243 (80.7) [75.8 - 85.0] 95% exact two-sided con?dence intervals are calculated using the Clopper-Pearson method. Data Source: ADPQ, ADTQ Program: TRIG Page 1 of TIRF Pharmacist KAB 03DEC2015 Listing 1: Listing of Verbatim Responses to Question #27 (Questions about the Full Prescribing Information or the Medication Guide) Completed Surveys Verbatim Responses EACH DRUG REQUIRES A SOURCE CHECK Exact route of administration - apparently. one of my patients complained that theproduct 'leaked'. I was trying to get info to verify or dispute that claim. I LIKE TO GET PICTURE PRESENTATION ON THIS SO WE CAN HELP CUSTOMER ABOUT THIS DRUG The full prescribing information is confusing for each product. The FDA should consider harmonizing the prescribing information for all medications in this same class The noti?cation system for TIRFs is a little hard to understand. have done test claims but to do an actual claim didn't seem to be addressed. Data Source: ADPQ Program: LQ.SAS TRIG TIRF Pharmacist KAB Page 1 of 03DEC2015 Listing 2: Listing of Potential Adverse Events and/or Product Complaints Reported by Modality harmonizing the prescribing information for all medications in this same class Modality of Verbatim Text Report Exact route of administration - apparently. one of my patients complained that theproduct Internet "leaked". I was trying to get info to verify or dispute that claim. The noti?cation system for TIRFs is a little hard to understand. have done test claims but to Internet do an actual claim didn't seem to be addressed. The ?ill prescribing information is confusing for each product. The FDA should consider Internet Data Source: Program: LQAESAS 48-month REMS Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 112 of 112 12.7.3 Prescriber KAB Survey FDA_3498 Prescriber KAB Assessment Report Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Title: Page 1 of 63 Transmucosal Immediate Release Fentanyl (TIRF) REMS Assessment Quantitative Testing of Prescriber Knowledge, Attitudes, and Behavior (KAB) about TIRF Products’ Safety and Use Information Document Number Wave 4, 48-month REMS Assessment Version 1.0 Survey Time Period 31 August 2015 to 16 October 2015 Product Name: Transmucosal Immediate Release Fentanyl Sponsor: TIRF REMS Industry Group (TRIG) of Companies: Actavis Laboratories FL, Inc. BioDelivery Sciences International, Inc. (BDSI) Cephalon, Inc. (a wholly-owned subsidiary of Teva Pharmaceutical Industries, Ltd.) Depomed, Inc. Galena Biopharma, Inc. Insys Therapeutics, Inc. Mallinckrodt Pharmaceuticals Mylan, Inc. Par Pharmaceutical, Inc. Date: 15 December 2015 Confidentiality Statement The information contained herein is confidential and the proprietary property of the TRIG of Companies and its affiliates, and any unauthorized use or disclosure of such information without the prior written authorization of the TRIG is expressly prohibited. FDA_3499 Prescriber KAB Assessment Report Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies TABLE OF CONTENTS Page 2 of 63 PAGE TABLE OF CONTENTS......................................................................................................... 2 LIST OF IN-TEXT TABLES .................................................................................................. 3 LIST OF APPENDICES .......................................................................................................... 4 LIST OF ABBREVIATIONS .................................................................................................. 5 1. PRESCRIBER SURVEY BACKGROUND .......................................................... 7 1.1 Changes to the KAB Survey for Prescribers Based on FDA Feedback.................. 8 2. PRESCRIBER SURVEY OBJECTIVES ............................................................... 9 3. SURVEY METHODOLOGY............................................................................... 10 3.1 Survey Sample ...................................................................................................... 10 3.1.1 Eligibility .............................................................................................................. 10 3.1.2 Recruitment ........................................................................................................... 10 3.2 Questions and Statements on Key Risk Messages ................................................ 11 3.2.1 Key Risk Message 1 .............................................................................................. 11 3.2.2 Key Risk Message 2 .............................................................................................. 12 3.2.3 Key Risk Message 3 .............................................................................................. 14 3.2.4 Key Risk Message 4 .............................................................................................. 15 3.3 Additional Questions............................................................................................. 15 4. STATISTICAL METHODS ................................................................................. 16 4.1 Study Population ................................................................................................... 16 4.1.1 Primary Analysis Population ................................................................................ 16 4.2 Primary Analysis ................................................................................................... 16 4.3 Secondary Analysis ............................................................................................... 17 4.4 Prescriber Report of a Potential Adverse Event, Product Complaint, or Medical Information Request during the Survey .................................................. 17 5. RESULTS ............................................................................................................. 17 5.1 Survey Participants................................................................................................ 17 5.1.1 Survey Participant Administration Results ........................................................... 17 5.1.2 Description of Eligible Prescribers who Completed the Survey........................... 22 FDA_3500 Prescriber KAB Assessment Report Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 3 of 63 5.1.2.1 Comparison of Survey Respondents to the General Population of Prescribers ............................................................................................................. 24 5.1.3 TIRF Medicines Educational Materials ................................................................ 25 5.2 Key Risk Messages ............................................................................................... 27 5.2.1 Key Risk Message 1 .............................................................................................. 27 5.2.2 Key Risk Message 2 .............................................................................................. 32 5.2.3 Key Risk Message 3 .............................................................................................. 42 5.2.4 Key Risk Message 4 .............................................................................................. 43 5.2.5 Other Survey Questions ........................................................................................ 46 5.2.5.1 Additional Questions about TIRF Medicines Safety ............................................ 46 5.2.5.2 Prescriber Activities When Prescribing TIRF Medicines ..................................... 48 5.3 Spontaneous Reporting of Adverse Events, Product Complaints or Medical Information Requests .............................................................................. 50 6. DISCUSSION AND CONCLUSIONS ................................................................ 51 LIST OF IN-TEXT TABLES Table 1. Survey Participant Administration Results .................................................... 18 Table 2. Survey Participant Screening Results ............................................................ 19 Table 3. Time to Complete Survey for Completers Only ............................................ 21 Table 4. Description of Eligible Prescribers ................................................................ 22 Table 5. Comparison of Survey Respondents to General Population of TIRF Prescribers ...................................................................................................... 25 Table 6. Responses to Questions About the TIRF Medicines Educational Materials and the TIRF Patient-Prescriber-Agreement Form ........................ 26 Table 7. Responses Linked to Key Risk Message 1: TIRF Medicines Are Contraindicated in Opioid Non-Tolerant Patients ......................................... 29 Table 8. Responses Linked to Key Risk Message 2: TIRF Medicines Are Only Indicated for the Management of Breakthrough Pain in Adult Cancer Patients 18 Years of Age and Older (16 Years of Age and Older for Actiq® Brand and Generic Equivalents) Who Are Already Receiving and Who Are Tolerant to Around-The-Clock Opioid Therapy for Their Underlying Persistent Cancer Pain ................................... 33 Table 9. Types of Chronic Pain Conditions Reported - Completed Surveys for Prescribers Who Prescribed TIRF Medicines for Chronic NonCancer Pain .................................................................................................... 37 FDA_3501 Prescriber KAB Assessment Report Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 4 of 63 Table 10. Reasons for Selecting a TIRF Medicine Reported - Completed Surveys for Prescribers Who Prescribed TIRF Medicines for Chronic Non-Cancer Pain .................. 39 Table 11. Key Risk Message 2: Trends in Correct Response Rates by Prescribing Frequency Within Last 6 Months ............................................... 41 Table 12. Responses Linked to Key Risk Message 3: TIRF Medicines Contain Fentanyl, an Opioid Agonist, and a Schedule II Controlled Substance, With Abuse Liability Similar to Other Opioid Analgesics.......... 42 Table 13. Responses Linked to Key Risk Message 4: TIRF Medicines Are Not Interchangeable With Each Other, Regardless of Route of Administration ............................................................................................... 44 Table 14. Responses to Additional Questions About the Safe Use of TIRF Medicines ....................................................................................................... 46 Table 15. Responses to All Questions About Activities When Prescribing TIRF Medicines ....................................................................................................... 49 Table 16. Correct Response Rates Over Time ............................................................... 53 LIST OF APPENDICES Appendix A Prescriber Survey Protocol Track Change Document: Comparison of 36-month Survey to 48-month Survey........................................................... 62 Appendix B Prescriber Survey Listings and Stratified Analyses Tables ........................... 63 FDA_3502 Prescriber KAB Assessment Report Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 5 of 63 LIST OF ABBREVIATIONS AE/PC PSP Adverse Event/Product Complaint Project Specific Procedure BDSI BioDelivery Sciences International, Inc. CI Confidence Interval DoD Department of Defense ETASU Elements to Assure Safe Use FDA Food and Drug Administration ISI Important Safety Information KAB Knowledge, Attitudes, and Behavior N/A Not Applicable NIH National Institutes of Health PPAF Patient-Prescriber Agreement Form REMS Risk Evaluation and Mitigation Strategy SD Standard Deviation SCC Survey Coordinating Center TIRF Transmucosal Immediate Release Fentanyl TIRF medicines Transmucosal Immediate Release Fentanyl product(s) TIRF REMS Access Program REMS Program for TIRF medicines TRIG TIRF REMS Industry Group UBC United BioSource Corporation US United States USPS United States Postal Service VA Department of Veterans Affairs FDA_3503 Prescriber KAB Assessment Report Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 6 of 63 Executive Summary The 48-month Knowledge, Attitudes, and Behavior (KAB) survey for prescribers who prescribe Transmucosal Immediate Release Fentanyl (TIRF) medicines was conducted as part of the 48-Month TIRF Risk Evaluation and Mitigation Strategy (REMS) Access Program Assessment. The survey launched on 31 August 2015 and closed on 16 October 2015. Food and Drug Administration (FDA) feedback was provided in the 24-month and 36month Assessment Report Acknowledgement Letter and where applicable these changes were implemented in the 48-month survey. Changes included adding questions on whether the respondent works in a closed system, and for respondents who stated they prescribe TIRF medicines for chronic non-cancer pain addressing why they feel that this is an appropriate use of TIRF medicines, removing ‘Onsolis’ as a response option throughout the survey because it is no longer available, moving specified existing survey questions under key risk messages, removing Question 19 (Can patients continue to take their TIRF medicine if they stop taking their around-the-clock opioid medicine?), and including an analysis of demographics of the prescriber survey respondents compared to the demographics of the general population of TIRF prescribers. The specific goals of the TIRF medicines prescriber KAB survey were to assess prescribers’ understanding of the risks associated with TIRF medicine use, the selection of appropriate patients for treatment with TIRF medicines, preventing inappropriate conversion between TIRF medicines, and ensuring safe use of TIRF medicines while preventing exposure to children and others for whom TIRF medicines were not prescribed. The survey also included questions about whether prescribers received, read, understood, and used the product-specific educational materials, and included questions about compliance with the REMS requirements. Invitations (and reminders) were sent to a random sample of prescribers who prescriber TIRF products, were known to have received the REMS educational materials, and who were enrolled in the TIRF REMS Access Program as of 30 June 2015. From the total of 587 respondents who accessed the survey, 350 (59.6%) respondents met eligibility criteria, and of those who met eligibility criteria, 310 (88.6%) completed the survey, exceeding the target of 300 completed surveys. The geographic distribution of survey respondents was similar to the overall population of prescribers who prescribe TIRF medicines (comparison requested by FDA). In general, there is an overall trend across all prescriber KAB surveys conducted (12-month, 24-month, 36-month, and 48-month surveys) toward increasing improvement in prescriber knowledge and understanding of the key risk messages. Of the 31 components included as part of key risk messages, 21 components of the key risk messages had a correct response rate >80% and 9 components had a correct response rate between 67.7% and 78.7%. For Component 9e, 201 prescribers (64.8%) indicated they do not prescribe TIRF medicines for chronic non-cancer pain. The 34.2% of prescribers who stated they do prescribe TIRF medicines for chronic non-cancer pain were presented with 2 additional questions as requested by the FDA; the type of chronic pain conditions they prescribe a TIRF medicine to FDA_3504 Prescriber KAB Assessment Report Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 7 of 63 treat, and the reasons for selecting a TIRF medicine to treat these conditions. Based on prescriber responses, and the high percentage of respondents who indicated they received and read the REMS educational materials, the responses may reflect behavior more than knowledge. That is, prescribers are aware of the labeled indication but choose to prescribe off-label for certain patients. The consistently high level of prescriber understanding of key risk messages in the latest (48month) survey indicates that the Education Program for Prescribers is meeting the goals of the TIRF REMS Access Program. The TRIG will evaluate the concepts that have scored low among stakeholders to determine if any action is warranted. The TRIG will continue to work with the FDA to refine, on a continual basis, the steps to mitigate risks associated with TIRF medicines. 1. PRESCRIBER SURVEY BACKGROUND Transmucosal Immediate Release Fentanyl (TIRF) medicines are a class of immediaterelease opioid analgesics indicated for the management of breakthrough pain in cancer patients 18 years of age or older (16 or older for Actiq® [fentanyl citrate oral transmucosal lozenge] and equivalent generics) who are receiving and already tolerant to opioid therapy for their underlying persistent cancer pain. The FDA has determined that a shared system REMS is required to mitigate the risk of misuse, abuse, addiction, overdose, and serious complications due to medication errors with the use of TIRF medicines. The TIRF REMS Access Program was approved by the FDA on 28 December 2011. This report describes the results from the prescriber surveys conducted for the 48-Month TIRF REMS Access Program Assessment, and reflects the reporting period of 29 October 2014 to 28 October 2015. The 48-month Knowledge, Attitudes, and Behavior (KAB) survey launched on 31 August 2015 and closed on 16 October 2015. The TIRF medicines include Abstral®, Actiq®, Fentora®, Lazanda®, Subsys®, and their generic equivalents. The TRIG includes Actavis Laboratories FL, Inc.; BioDelivery Sciences International, Inc. (BDSI); Cephalon, Inc. (a wholly-owned subsidiary of Teva Pharmaceutical Industries, Ltd.); Depomed, Inc.; Galena Biopharma, Inc.; Insys Therapeutics, Inc.; Mallinckrodt Pharmaceuticals; Mylan, Inc.; and Par Pharmaceutical, Inc. Two companies joined the TRIG during the reporting period: Actavis Laboratories FL, Inc. joined on 6 February 2015 and BDSI replaced Meda Pharmaceuticals on 11 March 2015. The TIRF REMS Access Program consists of a Medication Guide, Elements to Assure Safe Use (ETASU), an Implementation System, and a Timetable for Submission of Assessments of the REMS. The goals of the TIRF REMS Access Program are to mitigate the risk of misuse, abuse, addiction, overdose, and serious complications due to medication errors by the following: 1. Prescribing and dispensing TIRF medicines only to appropriate patients, which includes use only in opioid-tolerant patients. FDA_3505 Prescriber KAB Assessment Report Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 8 of 63 2. Preventing inappropriate conversion between TIRF medicines. 3. Preventing accidental exposure to children and others for whom it was not prescribed. 4. Educating prescribers, pharmacists, and patients on the potential for misuse, abuse, addiction, and overdose of TIRF medicines. An important component of the TIRF REMS Access Program Assessment is the conduct of quantitative evaluation surveys to assess prescribers’ understanding and knowledge of the safe use and appropriate prescribing of TIRF medicines as described in the TIRF REMS Access Program educational materials, enrollment form, and Prescribing Information of each product. Administration of the surveys conducted among prescribers who are enrolled in the TIRF REMS Access Program is described in the protocol (See Appendix A). Note: Protocol and survey question revisions from the 36-month assessment report are identified as tracked changes. Data from the surveys, together with other REMS evaluation metrics, will be used to determine whether changes need to be made to the REMS processes or educational materials to make them more effective in achieving the goals of the REMS. 1.1 Changes to the KAB Survey for Prescribers Based on FDA Feedback FDA feedback was received on the KAB survey for prescribers in the 24-month and the 36month FDA REMS Acknowledgement Letters. The FDA provided the following feedback to the TRIG on the KAB survey for prescribers based on results included in the 24-month REMS Assessment Report. • In the prescriber survey, only 59% correctly stated that TIRF should not be used to treat “chronic non-cancer pain.” It is not clear if this represents a knowledge deficit or a disagreement with how these medicines should be used. In the next survey, include a supplemental question directed at those who respond incorrectly to this question to follow-up as to why they feel that this is an appropriate use of TIRFs. • In future surveys of prescribers, report the proportion of prescriber respondents that work in closed systems. This feedback was provided after the launch of the 36-month KAB survey for prescribers, thus the changes were incorporated into the 48-month KAB survey for prescribers and results from the revised survey are included in this 48-month KAB Assessment Report. The FDA provided the following feedback to the TRIG on the KAB survey for prescribers based on results included in the 36-month REMS Assessment Report: • Remove Onsolis as a response option throughout the survey as it is no longer available FDA_3506 Prescriber KAB Assessment Report Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies • • • • • Page 9 of 63 Move existing survey questions (Question 7b, Question 11a-f) into Key Risk Message 1 Move existing survey question (Question 6a, 6b, 18b, 18c) into Key Risk Message 2 Move an existing survey question (Question 10d) into Key Risk Message 4 Remove Question 19 Include an analysis of demographics of the prescriber survey respondents compared to the demographics of the general population of TIRF prescribers The 36-month Assessment Report Acknowledgement Letter was received by the TRIG sponsors on 04 August 2015. All but one of the requested changes were incorporated into the 48-month KAB survey prior to launch. In order to incorporate FDA’s feedback in the 48month Prescriber KAB survey, the survey launch date originally scheduled for the second week of August was delayed until 31 August 2015. The remaining FDA request was to provide an analysis of how the demographics of the prescriber survey respondents compare to the demographics of the general population of TIRF prescribers. Due to timing of the request and the time required to obtain these data, this information was unable to be included in the 48-Month FDA Assessment Report. As communicated to FDA on 09 September 2015, the TRIG plans to submit a Supplemental Report to FDA to include items that were unable to be included in this assessment report based on the timing of the 36-Month FDA Assessment Report Acknowledgement Letter. A comparison of geographic data between survey respondents and the general population of TIRF prescribers are included in this report; the full demographic comparison will be included in the Supplemental Report estimated to be delivered on May 4, 2016. 2. PRESCRIBER SURVEY OBJECTIVES The evaluation survey uses a questionnaire to document the level of knowledge and assess the attitudes and behaviors of prescribers regarding the following key information and risk messages communicated through the REMS: 1. TIRF medicines are contraindicated in opioid non-tolerant patients. 2. TIRF medicines are indicated for the management of breakthrough pain in adult cancer patients 18 years of age and older (16 or older for Actiq® and equivalent generics) who are already receiving and who are tolerant to around-the-clock opioid therapy for their underlying persistent cancer pain. 3. TIRF medicines contain fentanyl, an opioid agonist, and a Schedule II controlled substance, with abuse liability similar to other opioid analgesics. 4. TIRF medicines are not interchangeable with each other, regardless of route of administration. FDA_3507 Prescriber KAB Assessment Report Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 10 of 63 5. Patients and their caregivers must be instructed that TIRF medicines contain a medicine in an amount that can be fatal in children, in individuals for whom it is not prescribed, and in those who are not opioid tolerant. The survey also collects data on behaviors, such as receipt and use of educational materials and compliance with REMS requirements. 3. SURVEY METHODOLOGY This section summarizes the survey design and the questions developed to test prescriber understanding of the key risk messages of the REMS. Full details of the survey design are in the protocol, which can be found in Appendix A. 3.1 Survey Sample A sample of 300 prescribers who prescribe TIRF products and were known to have received the REMS educational materials was planned for this fourth KAB survey which was expected to be open from 31 August 2015 to 20 October 2015. The survey sample size was determined based on both practical and statistical considerations. The survey was written to reflect wording for both methods of survey administration: Internet-based and telephone. 3.1.1 Eligibility Subjects were recruited from a random sample of prescribers who were enrolled in the TIRF REMS Access Program as of 30 June 2015. Respondents or respondents with immediate family members who had ever worked for any of the TRIG companies, RelayHealth, McKesson Specialty Care Solutions, United BioSource Corporation (UBC), or the FDA were not eligible to participate, nor were respondents who participated in the previous waves of the survey (12-month TIRF REMS Access Program Assessment, the 24-month TIRF REMS Access Program Assessment, or the 36-month TIRF REMS Access Program Assessment). 3.1.2 Recruitment Subjects were recruited via an invitation letter via email and through the United States Postal Service (USPS) (Section 5.1.1 for more detail). The required number of completed surveys was not achieved within approximately 10 days after the first mailing; thus, additional invitations were sent via email to non-respondents from the original sample to maximize participation. Each letter of invitation included a unique code needed to access the survey. The code was deactivated after the respondent had initiated the survey (whether or not the survey was completed). Prescribers were given the option of taking the survey by telephone via the Survey Coordinating Center (SCC) or online via a secure website. The survey was estimated to take approximately 20 minutes to complete. FDA_3508 Prescriber KAB Assessment Report Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 11 of 63 All respondents who completed the survey and provided their contact information were mailed a $125 gift card for participating, with the exception of prescribers who practiced in Massachusetts, Minnesota or Vermont (due to state laws prohibiting it). The mailing also included a copy of the Important Safety Information (ISI) and a copy of the correct answers to key risk message questions. 3.2 Questions and Statements on Key Risk Messages The questions and statements comprising the knowledge survey were constructed to test the prescribers’ understanding of the key risk messages of the REMS. The questions were to be answered either by selecting options from multiple-choice lists that include statements of the specific key risk messages or by choosing “Yes” or “True,” “No” or “False,” or “I Don’t Know” regarding statements about TIRF medicines. For statements or questions that use “True” or “Yes” vs. “False” or “No” response options, the desired response for key risk messages is generally “True” or “Yes” indicating knowledge of, or behavior in accordance with, the objectives of the REMS. However, some questions were formatted to have the respondent disagree with the statement as written by providing response options of “False” or “No” to avoid having the same affirmative answer for all desired responses. REMS statements, corresponding questions, and desired responses covering the key risk messages are identified below and can be found in the survey protocol (Appendix A). 3.2.1 Key Risk Message 1 Key Risk Message 1 refers to the prescriber’s knowledge of the specific contraindications for TIRF medicine in opioid non-tolerant patients and under what conditions a patient is considered opioid tolerant. Key Risk Message 1: TIRF medicines are contraindicated in opioid non-tolerant patients. Question No. Question Desired response 5 Please select True, False, or I don’t know for each of the following. According to the labeling for TIRF medicines, patients with cancer who are considered opioid-tolerant are those: 5a Who are taking around-the-clock opioid therapy for underlying persistent cancer pain for one week or longer True 5b Who are not currently taking opioid therapy, but have taken opioid therapy before False 5c Who have no known contraindications to the drug fentanyl, but are not currently taking around-the-clock opioid therapy False 7 Please answer True, False, or I don’t know for each statement based on the labeling for TIRF medicines. FDA_3509 Prescriber KAB Assessment Report Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 12 of 63 Key Risk Message 1: TIRF medicines are contraindicated in opioid non-tolerant patients. Question No. Question Desired response 7a TIRF medicines are contraindicated in opioid non-tolerant patients because life-threatening respiratory depression could occur at any dose. True 7b Death has occurred in opioid non-tolerant patients treated with some fentanyl products. True 7c TIRF medicines may be used to treat opioid non-tolerant patients. False 7d 13 13a 13b 13c 13d 13e 13f 3.2.2 Prescribers starting a patient on a TIRF medicine must begin with titration from the lowest dose available for that specific product, True even if the patient has previously taken another TIRF medicine. Please select True, False, or I don’t know for each of the following. According to the labeling for TIRF medicines, patients considered opioid-tolerant are those who are taking, for one week or longer, at least: 8 mg oral hydromorphone/day True 60 mg oral morphine/day True 30 mg oral oxycodone/day True 25 mcg transdermal fentanyl/hour True 25 mg oral oxymorphone/day True An equianalgesic dose of another oral opioid True Key Risk Message 2 Key Risk Message 2 refers to the prescriber’s knowledge of the indications for prescribing TIRF medicines for the management of breakthrough pain in opioid-tolerant adult cancer patients, and the timing of administration of the TIRF medicine in relation to the around-theclock opioid therapy to ensure the patient is considered opioid tolerant. This key risk message includes a behavior question (Questions 9) and knowledge questions (Questions 6 and 15, and components of Question 20). FDA_3510 Prescriber KAB Assessment Report Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 13 of 63 Key Risk Message 2: TIRF medicines are only indicated for the management of breakthrough pain in adult cancer patients 18 years of age and older (16 years of age and older for Actiq® brand and generic equivalents) who are already receiving and who are tolerant to around-theclock opioid therapy for their underlying persistent cancer pain. Question No. 6 6a 6b Question Desired response Please answer True, False, or I don’t know for each statement based on the labeling for TIRF medicines. According to the product labeling, a cancer patient may start a False TIRF medicine and an around-the-clock opioid at the same time. According to the product labeling, a cancer patient who has False been on an around-the-clock opioid for 1 day may start taking a TIRF medicine for breakthrough pain 9 In your practice, for which of the following indications do you prescribe TIRF medicines to opioid tolerant patients? Please answer Yes, No, or I don’t know for each option. 9a Acute or postoperative pain No 9b Headache or migraine pain No 9c Dental pain No 9d Breakthrough pain from cancer Yes 9e Chronic non-cancer pain No 15 20 20b 20c 15b. Adult female with localized breast cancer; just completed The patients described are experiencing breakthrough pain. a mastectomy and According to the labeling, a TIRF medicine is not appropriate reconstructive for one of them. Which patient should not receive a TIRF surgery; persistent medicine? Please select one option. cancer pain managed with 30 mg oral morphine daily for the past 6 weeks. Before initiating treatment with a TIRF medicine, prescribers must review the Medication Guide with the patient. Please select True, False, or I don’t know for each of the following counseling statements. Inform patients that TIRF medicines must not be used for acute True or postoperative pain, pain from injuries, headache/migraine, or any other short-term pain. Instruct patients that they can continue to take their TIRF False medicine, if they stop taking their around-the-clock opioid medicine. FDA_3511 Prescriber KAB Assessment Report Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies 3.2.3 Page 14 of 63 Key Risk Message 3 Key Risk Message 3 refers to the prescriber’s knowledge of the risk factors for opioid abuse and importance in monitoring for signs of abuse in patients who take TIRF medicines. Key Risk Message 3: TIRF medicines contain fentanyl, an opioid agonist and a Schedule IIcontrolled substance, with abuse liability similar to other opioid analgesics. Question No. Question Desired response 7 Please answer True, False, or I don’t know for each statement based on the labeling for TIRF medicines. 7e It is important to monitor for signs of abuse and addiction in patients who take TIRF medicines. 8 Which of the following are risk factors for opioid abuse? Please answer Yes, No, or I don’t know for each option. 8a A personal history of psychiatric illness Yes 8b A personal history of past or current alcohol or drug abuse, or a family history of illicit drug use or alcohol abuse Yes 12 Please answer True, False, or I don’t know for each statement based on the labeling for TIRF medicines. 12a TIRF medicines can be abused in a manner similar to other opioid agonists. True True FDA_3512 Prescriber KAB Assessment Report Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies 3.2.4 Page 15 of 63 Key Risk Message 4 Key Risk Message 4 refers to the prescriber’s knowledge of the interchangeability of TIRF medicines based on route of administration, pharmacokinetic absorption, and dosage. Key Risk Message 4: TIRF medicines are not interchangeable with each other, regardless of route of administration. Question No. 12 12b Question Desired response Please answer True, False, or I don’t know for each statement based on the labeling for TIRF medicines. TIRF medicines are interchangeable with each other regardless of route of administration. False 12c The conversion of one TIRF medicine for another TIRF medicine may result in a fatal overdose because of differences in the pharmacokinetics of fentanyl absorption. True 12d Dosing of TIRF medicines is not equivalent on a microgram-tomicrogram basis. True A patient is already taking a TIRF medicine but wants to change their medicine. His/her doctor decides to prescribe a different TIRF medicine (that is not a bioequivalent generic version of a branded product) in its place. According to the labeling, how should the prescriber proceed? Please select one option. 16b. The prescriber must not convert to another TIRF medicine on a microgram-permicrogram basis because these medicines have different absorption properties and this could result in a fentanyl overdose. 16 3.3 Additional Questions The survey also contained questions (Question 14a-f) about the requirements of the TIRF REMS Access Program and receipt and understanding of the TIRF educational materials and the Patient-Prescriber Agreement Form. The following questions about behaviors were asked after the key risk message questions. FDA_3513 Prescriber KAB Assessment Report Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 16 of 63 Question No. Question 14 How frequently do you perform the following activities when dispensing TIRF medicines? Please answer Always, Only with the first prescription, Sometimes, Never, or I don’t know.” 14a Ask patients (or their caregivers) about the presence of children in the home 14b Instruct patients (or their caregivers) not to share TIRF medicines with anyone else 14c Counsel patients (or their caregivers) that accidental exposure to TIRF medicines by a child may be fatal 14d Instruct patients (or their caregivers) to keep TIRF medicines out of the reach of children to prevent accidental exposure 14e Instruct patients (or their caregivers) about proper disposal of any unused or partially used TIRF medicines 14f Give patients (or their caregivers) the Medication Guide for their TIRF medicine 4. STATISTICAL METHODS 4.1 Study Population 4.1.1 Primary Analysis Population The primary population for analysis was all eligible prescribers who completed the survey. Eligible prescribers were defined as those respondents who answered Yes to Question 1 (agree to take part in survey) and Yes to Question 3 (enrolled in the TIRF REMS Access Program), and No to Question 2 (participated in past survey) and No to Question 4 (worked for a TRIG company, UBC, RelayHealth, McKesson Specialty Care Solutions, or FDA). A survey was considered “completed” when an eligible prescriber answered all relevant questions. 4.2 Primary Analysis Primary analyses were performed for all key risk messages. The primary analysis for a key risk message evaluated the number and percentage of correct responses for each individual question/component included in the key risk message. Confidence intervals (95% CI) were calculated using the exact binomial method around the percentage of correct responses. Primary analyses were then stratified by questions/characteristics of interest: 1) Those who indicated they both received/had access to and read the Medication Guide and Full Prescribing Information versus those who did not and those who responded they did not or did not know whether they had (Questions 21-24). 2) Medical degree of respondents (Question 33). 3) Whether the survey was completed via the internet or telephone FDA_3514 Prescriber KAB Assessment Report Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 17 of 63 4) Time practicing medicine (Question 34). 5) The number of times per month they prescribed TIRF medicines within the last 6 months (Question 30). 6) Respondents practicing in a Closed Healthcare System (Question 35). Stratified analyses were conducted only when at least two of the stratified response categories had at least 50 respondents (e.g., for analysis 3 above, at least 50 prescribers had to respond they completed the survey via the internet and at least 50 had to respond they completed it by telephone in order for that analysis to be conducted). 4.3 Secondary Analysis As an indicator of the overall level of comprehension of the entire key risk message, descriptive analyses of the number and percentage of responders who answered various proportions of the key risk message components correctly are presented (e.g., the proportion who answered one question in the key risk message correctly, those who answered two questions correctly, those who answered three component questions correctly, etc.). Confidence intervals (95% CI) were calculated for the proportion of respondents who answered all component questions of the key risk message correctly. 4.4 Prescriber Report of a Potential Adverse Event, Product Complaint, or Medical Information Request during the Survey A prescriber may have reported a potential adverse event or other event experienced by a patient while taking a TIRF product either in free text fields while taking the online survey or while in conversation with the SCC Associate. If an event was mentioned to the SCC Associate, the Associate documented the event or complaint, the verbatim response, and the prescriber’s contact information, if provided. The prescriber was also informed that a representative from the appropriate TIRF medicine sponsor might contact him/her to obtain additional information about the event. The Internet surveys were monitored for any comments recorded in the free text field. Information on all reports (Internet or telephone) that constituted an adverse event or other event was forwarded to the appropriate TIRF medicine sponsor for processing within 1 business day of awareness of the event as outlined in the Adverse Event/Product Complaint Project Specific Procedure (AE/PC PSP). 5. RESULTS Results of the prescriber’s responses to questions in the KAB survey are summarized in this section; stratified analysis tables and overall listings are provided in Appendix B. 5.1 Survey Participants 5.1.1 Survey Participant Administration Results A total of 8210 prescribers were sent letters inviting them to participate in this survey (Table 1). An additional 19,215 reminder letters were sent to non-responders (See Section 3.1 for FDA_3515 Prescriber KAB Assessment Report Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 18 of 63 survey methodology details). Most prescribers received more than 1 reminder letter. Once the target number of completed surveys was achieved (a sample of 300 prescribers was planned), the survey was closed. As noted in Section 3.1, the survey was expected to be open through 20 October 2015. The survey launch date had been delayed in order to incorporate FDA feedback on the survey received in the 36-Month FDA Assessment Report Acknowledgement Letter. Successful recruitment resulted in the survey closing earlier than expected on 16 October 2015. From the total of 587 respondents who accessed the survey, 350 prescribers (59.6%) met eligibility criteria, and of those who met eligibility criteria, 310 (88.6%) completed the survey. One respondent completed the survey twice. Only the responses from the first survey were included. Of these 310 prescribers, 303 (97.7%) completed the survey online, and 7 (2.3%) completed it by telephone (Table 3). Based on the TRIG Sponsors interpretation of state laws regarding prescriber reimbursement, respondents from Massachusetts, Vermont, and Minnesota were eligible to participate in the survey. However, they were not eligible to receive the $125 honorarium. Four respondents from Massachusetts and two respondents from Minnesota participated in the survey. Table 1. Survey Participant Administration Results Summary Statistic N Number of invitations distributed 8210 Number of invitations returned as undeliverable 437 Number of reminder letters distributed % 19,215 587 7.6 Eligible Respondents 2 350 59.6 Completed survey 3 310 88.6 Did not complete the survey 3 40 11.4 237 40.4 All Respondents 1 Respondents not eligible 2,4 1 Number of respondents who accessed the survey. Percentage is based on the number of invitations distributed excluding the number of invitations returned as undeliverable. 2 Percentage is based on the number of all respondents. 3 Percentages are based on the number of eligible respondents. 4 Number of respondents who did not meet eligibility criteria or did not complete eligibility questions. As shown in Table 2, of the 587 prescribers who accessed the survey, 489 prescribers answered at least 1 survey question and 98 respondents did not answer any of the survey FDA_3516 Prescriber KAB Assessment Report Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 19 of 63 questions and were discontinued. Of the 489 prescribers who started the survey, 485 agreed to participate. During the screening process it was determined that 139 of the 489 respondents who answered at least 1 survey question were not eligible to participate in the survey because they either did not agree to participate in the survey (4 respondents), indicated they had participated in or did not know whether they participated in a survey about TIRF medicines before (86 respondents), were not enrolled or did not know whether they were enrolled in the TIRF REMS Access Program (31 respondents), or indicated they, or an immediate family member, had worked for a TRIG company, UBC, or FDA in the past or did not know if they or an immediate family member had worked for a TRIG company, UBC, or FDA in the past (16 respondents). In addition, 2 of the 489 prescribers who answered at least 1 survey question discontinued the survey at Question 3. Thus, there were 350 eligible participants (Table 2), with 310 (88.6%) completing the survey (Table 1). Table 2. Survey Participant Screening Results Screened Prescribers N=587 Question n % Yes 485 82.6 No 1 4 0.7 Discontinued 98 16.7 Question 1: Do you agree to take part in this survey? Question 2: Have you ever taken part in this survey about TIRF medicines before? TIRF medicines include Abstral®, Actiq®, Fentora®, Lazanda®, Subsys®, and generic versions of any of these brands. Yes 1 30 5.1 No 399 68.0 56 9.5 4 0.7 98 16.7 I don’t know 1 Question not asked Discontinued 2 FDA_3517 Prescriber KAB Assessment Report Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Table 2. Page 20 of 63 Survey Participant Screening Results Screened Prescribers N=587 Question n % Question 3: Are you enrolled in the TIRF REMS Access Program? Yes 366 62.4 17 2.9 14 2.4 Question not asked 2 90 15.3 Discontinued 100 17.0 No 1 I don’t know 1 Question 4: Have you or any of your immediate family members ever worked for any of the following companies or agencies? Please select all that apply. 3 Actavis Laboratories FL, Inc 1 1 Anesta LLC 1 0 BioDelivery Services International, Inc. (BDSI) 1 0 Cephalon, Inc. (a wholly-owned subsidiary of Teva Pharmaceutical Industries, Ltd.) 1 3 Depomed, Inc. 1 0 Galena Biopharma, Inc. 1 0 Insys Therapeutics, Inc. 1 5 Mallinckrodt Pharmaceuticals 1 0 McKesson Specialty Care Solutions 1 0 Mylan, Inc. 1 0 Par Pharmaceutical, Inc. 1 0 RelayHealth 1 Teva Pharmaceuticals, Ltd. 2 0 FDA 1 0 I don’t know 1 0.5 0.9 0 1 United BioSource Corporation 1 None of these apply 4 0.2 0.3 350 59.6 3 0.5 FDA_3518 Prescriber KAB Assessment Report Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Table 2. Page 21 of 63 Survey Participant Screening Results Screened Prescribers N=587 Question n % Prefer not to answer 1 3 0.5 Question not asked 1 121 20.6 Discontinued 100 17.0 1 Ineligible to participate in the survey. Question not asked due to previous question termination. 3 More than one response can be selected, so percentages may not sum to 100%. 4 Ineligible to participate in the survey if selected additionally to another response. Note: Respondents who discontinued the survey before completing all eligibility questions without being identified as ineligible in any of the previous questions are counted as discontinued. Once a respondent is counted as discontinued, they will count as discontinued in all subsequent eligibility questions. 2 Prescribers taking the survey online took a mean of 16 minutes to complete it, while those taking it by telephone took a mean of 25 minutes (Table 3). Table 3. Time to Complete Survey for Completers Only Time to Complete Survey (Minutes) Summary Statistic Telephone Internet Total 1 N 7 303 310 Mean (± SD) 25.37 (4.816) 16.33 (7.797) 16.54 (7.853) Minimum 20.1 4.0 4.0 Median 25.05 15.00 15.10 Maximum 35.3 60.4 60.4 0 to <5 Minutes 0 1 1 5 – <10 Minutes 0 59 59 10 – <15 Minutes 0 91 91 15 – <20 Minutes 0 85 85 Category FDA_3519 Prescriber KAB Assessment Report Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Table 3. Page 22 of 63 Time to Complete Survey for Completers Only Time to Complete Survey (Minutes) 1 Summary Statistic Telephone Internet Total 1 20 – <25 Minutes 3 37 40 25 – <30 Minutes 3 12 15 30 Minutes or More 1 18 19 Number of eligible prescribers completing the survey (See Table 1). 5.1.2 Description of Eligible Prescribers who Completed the Survey The demographic characteristics of prescribers who completed the survey are shown in Table 4. The majority of respondents are male (61.9%) and most respondents (95.5%) did not practice within a closed healthcare system (question added as requested by the FDA). Most respondents had prescribed a TIRF medicine either not at all (24.8%) or 1-2 times per month (49.7%) within the 6 months preceding the survey, and of the TIRF medicines prescribed within the last 6 months, Actiq® or generic Actiq® was most frequently prescribed (58.8%). The most common healthcare degree among respondents was MD (57.4%), and the most common medical specialty was pain management (48.7%). Most prescribers had practiced medicine for 6 years or longer (73.9%). The survey included 31.3% of respondents from the South, 30.6% from the West, 22.6% from the Northeast, and 14.8% from the Midwest region of the United States (US). There was 1 respondent from Puerto Rico identified as “Other” in Table 4. Table 4. Description of Eligible Prescribers Question Eligible/Completed Prescribers N=310 1 n % Question 30: On average, how many times per month have you prescribed the TIRF medicines within the last 6 months? None 77 24.8 1 – 2 times per month 154 49.7 3 – 5 times per month 49 15.8 More than 5 times per month 17 5.5 I don’t remember 13 4.2 FDA_3520 Prescriber KAB Assessment Report Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Table 4. Page 23 of 63 Description of Eligible Prescribers Question Eligible/Completed Prescribers N=310 1 n % Question 31: Please select the TIRF medicines that you have prescribed within the last 6 months. Please select all that apply. 2 Abstral® 26 11.2 Actiq ® or generic Actiq® 137 58.8 94 40.3 22 9.4 105 45.1 Fentora ® Lazanda Subsys ® ® N/A (answered None to Question 30) 77 Question 32: What is your gender? Male 192 61.9 Female 116 37.4 2 0.6 MD 178 57.4 DO 26 8.4 Nurse Practitioner 68 21.9 Physician Assistant 35 11.3 Prefer not to answer 3 1.0 Prefer not to answer Question 33: What is your medical degree? Question 34: In total, how many years have you been practicing medicine, since completing your post-graduate education? Less than 3 years 41 13.2 3-5 years 38 12.3 6-10 years 71 22.9 11-15 years 51 16.5 More than 15 years 107 34.5 Prefer not to answer 2 0.6 FDA_3521 Prescriber KAB Assessment Report Transmucosal Iimnediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 24 of 63 Table 4. Description of Eligible Prescribers Eligible/Completed Prescribers Question ues on I 0 rac cemacos ea cares sem, suc as: 0 ,01' . Qti35Dypti' yt Yes 14 4.5 No 296 95.5 Question 36: In which state or US territory do you practice? 3 Northeast 70 22.6 Midwest 46 14.8 South 97 3 1 .3 West 95 30.6 Other 1 0.3 Prefer not to answer 1 0.3 Question 37: What is your medical specialty? Oncology 65 21.0 Primary Care 28 9.0 Pain Management 151 48.7 Other (please specify) 4 65 21.0 No designated specialty 1 0.3 1Number of eligible prescribers completing the smwey (See Table 1). 2 Percentages are calculated based on the sample presented with this question because of skip logic in the survey. 3 US. Census Bureau. last revised Friday. 27-Jul-2001 12:59:43 EDT.. Geography Division. Northeast includes CT. MA. ME. NH. NJ. NY. PA. RI. and VT. Midwest includes LA. IL. IN. KS. MI. MN. MO. ND. NE. OH. SD. and W1. South includes AL. AR. DC. DE. FL. GA. KY. LA. MD. MS. NC. OK. SC. TN. TX. VA. and WV. West includes AK. AZ. CA. CO HI. ID. MT. NM. NV. OR. UT. WA. and WY. The following US territories are categorized as Other: Puerto Rico. Northern Mariana Islands. US Virgin Islands. American Samoa. and Guam. 4 Verbatim text for question about medical specialty are presented in Appendix B. Listing 4. 5.1.2.1 Comparison of Survey Respondents to the General Population of Prescribers Comparison of the smvey respondents to the general population of TIRF prescribers (as requested by the FDA) showed the geographic distribution of respondents to the prescriber survey was similar to the overall population of prescribers who prescribe TIRF medicines (Table 5). Prescriber KAB Assessment Report Transmueosal Irmnediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page_25 of 63 Table 5. Comparison of Survey Respondents to General Population of TIRF Prescribers Prescribers of TIRF Medicines Eligible/Completed in the Past 6 Prescribers Months 1 Question 11 Geographic Distribution 2 Northeast 70 (22.6) 1854 (21.0) Midwest 46 (14.8) 1532 (17.4) South 97 (31.3) 3047 (34.6) West 95 (30.6) 2374 (26.9) Other 1 (0.3) 5 (0.1) Prefer not to answer 1 (0.3) 0 1 Based on data obtained from the TIRF REMS Access Program database. 2 Based on Prescriber KAB Survey Question 36: US. Census Bureau. last revised Friday. 27-Jul-2001 12:59:43 EDT.. Geography Division. Northeast includes CT. MA. ME. NH. NJ. NY. PA. RI. and VT. Midwest includes IA. IL. IN. KS. MI. MN. MO. ND. NE. OH. SD. and W1. South includes AL. AR. DC. DE. FL. GA. KY. LA. MD. MS. NC. OK. SC. TN. TX. VA. and WV. West includes AK. AZ. CA. CO. HI. II). MT. NM. NV. OR. UT. WA. and WY. Other includes Puerto Rico. Northern Mariana Islands. US Virgin Islands. American Samoa and Guam. Note: Percentages are based on the prescribers with infonnative data. 5.1.3 TIRF Medicines Educational Materials Prescribers were asked about their access to educational materials for TIRF medicines, speci?cally the F1111 Prescribing Information, the Medication Guide, and the Patient- Prescriber Agreement Form (PPAF) (Table 6). Ahnost all prescribers reported they had received or had access to the F1111 Prescribing Information and the Medication Guide Of those with access to these materials, 83.2% indicated that they had read the Full Prescribing Information and 93.1% indicated that they had read the Medication Guide. Additionally, most prescribers reported reviewing the PPAF with each patient or their caregiver and of those, 93.0% indicated they and the patient/caregiver sign the PPAF and 87.1% indicated that they give a copy of the PPAF to the patient or the patient?s caregiver. Prescr?iber KAB Assessment Report Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Table 6. and the TIRF Patient-Prescriber-Agreement Form Page 26 of 63 Responses to Questions About the TIRF Medicines Educational Materials Question Eligible/Completed Prescribers 1 Question 21: Did you receive or do you have access to the Full Prescribing Information for the TIRF medicine(s) that you prescribe? Yes 286 92.3 No 9 2.9 I don't know 15 4.8 Question 22: Did you read the Full Prescribing Information for the TIRF medicine(s) that you prescribe? 2 Yes 238 83.2 No 41 14.3 I don't know 7 2.4 (answered No or I don?t know to Question 21) 24 Question 23: Did you receive or do you have access to the Medication Guide for the TIRF medicine(s) that you prescribe? Yes 276 89.0 No 10 3 .2 I don?t know 24 7.7 Question 24: Did you read the Medication Guide for the TIRF medicine(s) that you prescribe? 2 Yes 257 93.1 No 14 5.1 I don't know 5 1.8 (answered No or I don?t know to Question 23) 34 Question 25: Did you or do you have any questions about the information in the Full Prescribing Information or Medication Guide? Yes 3 12 3.9 No 272 87.7 I don't know 26 8.4 Prescriber KAB Assessment Report Transmucosal Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Table 6. and the TIRF Patient-Prescriber-Agreement Form Page 27 of 63 Responses to Questions About the TIRF Medicines Educational Materials Question Eligible/Completed Prescribers 1 Question 27: Do you review the Patient-Prescriber Agreement Form with each of your patients for whom you prescribe TIRF medicines or their caregiver? Yes 286 92.3 No 17 5.5 I don't know 7 2.3 Question 28: Do you and the patient or their caregiver sign the Patient?Prescriber Agreement Form for TIRF medicines after you have reviewed it with him/her? 2 Yes 266 93.0 No 9 3.1 I don't know 11 3.8 (answered No or I don ?t know to Question 27) 24 Question 29: Do you give a copy of the Patient?Prescriber Agreement Form for TIRF medicines to the patient or their caregiver? 2 Yes 249 87.1 No 21 7.3 I don't know 16 (5.6) 5.6 (answered No or I don ?t know to Question 27) 24 1Number of eligible prescribers completing the Sln'vey (See Table 1) 2 Percentages are calculated based on the sample presented with this question because of skip logic in the survey. 3 Verbatim text for questions about the information in the Full Prescribing Information or Medication Guide is presented in Appendix B. Listing 3. 5.2 Key Risk Messages 5.2.1 Key Risk Message 1 Key Risk Message 1 refers to the prescriber?s knowledge of the speci?c contraindications for TIRF medicine in opioid non-tolerant patients and lmder what conditions a patient is considered opioid tolerant. Most prescribers knew that patients with cancer who are considered opioid-tolerant are those who are taking around-the-clock opioid therapy for cancer pain for one week or longer Prescriber KAB Assessment Report Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 28 of 63 (95.2%, 95% CI: 92.1-97.3) and are those who are currently taking opioid therapy (93.9%, 95% CI: 90.6-96.3) (Table 7). In addition, most understood that cancer patients with no known contraindications to the drug fentanyl, but who are not taking around-the-clock opioid therapy, are not considered opioid tolerant (86.8%, 95% CI: 82.5-90.3). Ninety percent (90.3%, 95% CI: 86.5-93.4) of prescribers knew that TIRF medicines are contraindicated in opioid non-tolerant patients because life-threatening respiratory depression could occur and that death has occurred in opioid non-tolerant patients treated with some fentanyl products (96.1%, 95% CI: 93.3-98.0). Eighty-five percent (84.8%, 95% CI: 80.488.6) were aware that TIRF medicines may not be used to treat opioid non-tolerant patients. Similarly, 85.5% (95% CI: 81.1-89.2) of prescribers were aware that dose titration for patients starting a TIRF medicine must begin with the lowest available dose for that product. The majority of prescribers were aware of the regimens that defined an opioid-tolerant patient: 8 mg oral hydromorphone/day (72.9%, 95% CI: 67.6-77.8), 60 mg oral morphine/day (94.5%, 95% CI:91.4-96.8), 30 mg oral oxycodone/day (78.7%, 95% CI: 73.783.1), 25 mcg transdermal fentanyl/hour (85.5%; 95% CI: 81.1-89.2), 25 mg oral oxymorphone/day (72.3%, 95% CI: 66.9-77.2), and an equianalgesic dose of another oral opioid (67.7%, 95% CI: 62.2-72.9). Overall, 30.3% (95% CI: 25.3-35.8) of respondents answered all 13 components of key risk message 1 correctly, 52.6% missed no more than one component and 67.8% missed no more than two. Analyses stratified by whether the Full Prescribing Information and Medication Guide were received and read (Received and read: N=273; Did not receive or read: N=37), by modality for completing the survey (internet [N=303] versus telephone [N=7]) and whether the prescribers practiced in a closed healthcare system (Yes: N=14; No: N=296) were not performed for any of the key risk messages because they did not meet the criteria of ≥50 respondents within at least two response categories. No trends were evident when the results for key risk message 1 were stratified by the healthcare degree of respondents, time practicing medicine, or number of times TIRF medicines were prescribed in the past 6 months (Appendix B). FDA_3526 Prescriber KAB Assessment Report Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Table 7. Page 29 of 63 Responses Linked to Key Risk Message 1: TIRF Medicines Are Contraindicated in Opioid Non-Tolerant Patients Question Eligible/Completed Prescribers N=3101 n % (95% CI) 2 Question 5: Please select True, False, or I don’t know for each of the following. According to the labeling for TIRF medicines, patients with cancer who are considered opioid-tolerant are those: 5a: Who are taking around-the-clock opioid therapy for underlying persistent cancer pain for one week or longer True 3 295 95.2 (92.1 - 97.3) False 14 4.5 I don’t know 1 0.3 5b: Who are not currently taking opioid therapy, but have taken opioid therapy before True 15 4.8 False 3 291 93.9 (90.6 - 96.3) 4 1.3 I don’t know 5c: Who have no known contraindications to the drug fentanyl, but are not currently taking around-the-clock opioid therapy True 33 10.6 False 3 269 86.8 (82.5 - 90.3) 8 2.6 I don’t know Question 7: Please answer True, False, or I don’t know for each statement based on the labeling for TIRF medicines. 7a: TIRF medicines are contraindicated in opioid non-tolerant patients because life-threatening respiratory depression could occur at any dose. True 3 280 90.3 (86.5 - 93.4) False 23 7.4 I don’t know 7 2.3 7b: Death has occurred in opioid non-tolerant patients treated with some fentanyl products. True 3 298 96.1 FDA_3527 Prescriber KAB Assessment Report Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Table 7. Page 30 of 63 Responses Linked to Key Risk Message 1: TIRF Medicines Are Contraindicated in Opioid Non-Tolerant Patients Question Eligible/Completed Prescribers N=3101 n % (95% CI) 2 (93.3 - 98.0) False 2 0.6 I don’t know 10 3.2 7c: TIRF medicines may be used to treat opioid non-tolerant patients. True 38 12.3 False 3 263 84.8 (80.4 - 88.6) 9 2.9 I don’t know 7d: Prescribers starting a patient on a TIRF medicine must begin with titration from the lowest dose available for that specific product, even if the patient has previously taken another TIRF medicine. True 3 265 85.5 (81.1 - 89.2) False 40 12.9 I don’t know 5 1.6 Question 13: Please select True, False, or I don’t know for each of the following. According to the labeling for TIRF medicines, patients considered opioid-tolerant are those who are taking, for one week or longer, at least: 13a: 8 mg oral hydromorphone/day True 3 226 72.9 (67.6 - 77.8) False 57 18.4 I don’t know 27 8.7 True 3 293 94.5 (91.4 - 96.8) False 11 3.5 I don’t know 6 1.9 13b: 60 mg oral morphine/day. FDA_3528 Prescriber KAB Assessment Report Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Table 7. Page 31 of 63 Responses Linked to Key Risk Message 1: TIRF Medicines Are Contraindicated in Opioid Non-Tolerant Patients Question Eligible/Completed Prescribers N=3101 n % (95% CI) 2 True 3 244 78.7 (73.7 - 83.1) False 46 14.8 I don’t know 20 6.5 True 3 265 85.5 (81.1 - 89.2) False 27 8.7 I don’t know 18 5.8 True 3 224 72.3 (66.9 - 77.2) False 33 10.6 I don’t know 53 17.1 True 3 210 67.7 (62.2 - 72.9) False 55 17.7 I don’t know 45 14.5 13c: 30 mg oral oxycodone/day 13d: 25 mcg transdermal fentanyl/hour 13e: 25 mg oral oxymorphone/day 13f: An equianalgesic dose of another oral opioid Secondary Analysis: Number of Correct Responses 0 correct responses 0 1 correct response 0 2 correct responses 1 0.3 3 correct responses 1 0.3 4 correct responses 1 0.3 FDA_3529 Prescriber KAB Assessment Report Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Table 7. Page 32 of 63 Responses Linked to Key Risk Message 1: TIRF Medicines Are Contraindicated in Opioid Non-Tolerant Patients Question Eligible/Completed Prescribers N=3101 n % (95% CI) 2 5 correct responses 0 6 correct responses 7 2.3 7 correct responses 10 3.2 8 correct responses 21 6.8 9 correct responses 23 7.4 10 correct responses 36 11.6 11 correct responses 47 15.2 12 correct responses 69 22.3 94 30.3 (25.3 - 35.8) 13 correct responses 1 Number of eligible prescribers completing the survey (See Table 1). 95% exact two-sided confidence intervals are calculated using the Clopper-Pearson method. 3 Indicates the correct response(s) to each question or component within a question. 2 5.2.2 Key Risk Message 2 Key Risk Message 2 refers to the prescriber’s knowledge of the indications for prescribing TIRF medicines for the management of breakthrough pain in opioid-tolerant adult cancer patients, and the timing of administration of the TIRF medicine in relation to the around-theclock opioid therapy to ensure the patient is considered opioid tolerant. Sixty-nine percent (69.0%, 95% CI: 63.6-74.1) of prescribers correctly indicated that a cancer patient should not be started on a TIRF medicine and an around-the-clock opioid at the same time, and 72.9% (95% CI: 67.6-77.8) correctly indicated that a cancer patient who had been on an around-the-clock opioid for one day should not start taking a TIRF medicine for breakthrough pain (Table 8). In addition, 92.9% of prescribers (95% CI: 89.5-95.5) were aware that TIRF medicines are indicated for opioid-tolerant patients with breakthrough pain from cancer and not for patients with acute or postoperative pain (90.3%, 95% CI: 86.5-93.4), headache or migraine pain (94.8%, 95% CI: 91.8-97.0), or dental pain (98.4%, 95% CI: 96.3-99.5). Sixty-five percent (64.8%, 95% CI: 59.2-70.2) correctly responded that TIRF medicines should not be prescribed for chronic non-cancer pain. The 34.2% of prescribers who stated they do FDA_3530 Prescriber KAB Assessment Report Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 33 of 63 prescribe TIRF medicines for chronic non-cancer pain were presented with 2 additional questions as requested by FDA. Question 10 addressed the type of chronic pain conditions they prescribe a TIRF medicine to treat (Table 9). The most frequently reported conditions were back pain (32.1%), cancer pain (22.6%), neuropathic pain (21.7%), post-operative pain (18.9%), and chronic pain (17.9%). Question 11 addressed the reasons for selecting a TIRF medicine to treat these conditions (Table 10). The most frequently reported reasons were efficacy (35.8%), that they are fast acting (34.0%), and that other types of medications have failed (28.3%). Verbatim responses for Questions 10 and 11 can be found in Listing 1.1 and Listing 2.1, respectively (Appendix B). Most prescribers (73.2%, 95% CI: 67.9-78.1) correctly indicated that a TIRF medicine should not be prescribed to an adult female with localized breast cancer who just completed a mastectomy and reconstructive surgery and who has persistent cancer pain managed with 30 mg oral morphine daily for the past 6 weeks (Table 8). A high percentage of prescribers (93.9%, 95% CI: 90.6-96.3) were aware that patients must be informed that TIRF medicines should not be used for acute or postoperative pain, pain from injuries, headache/migraine, or any other short-term pain; and most (72.9%, 95% CI: 67.6-77.8) correctly indicated that patients should be instructed that if they stop taking their around-the-clock opioid medicine, they cannot continue to take their TIRF medicine. Overall, 26.5% (95% CI: 21.6-31.7) correctly answered all components of the key risk message, 53.0% missed no more than one component question, and 71.4% missed no more than two of the 10 component questions. Table 8. Responses Linked to Key Risk Message 2: TIRF Medicines Are Only Indicated for the Management of Breakthrough Pain in Adult Cancer Patients 18 Years of Age and Older (16 Years of Age and Older for Actiq® Brand and Generic Equivalents) Who Are Already Receiving and Who Are Tolerant to Around-The-Clock Opioid Therapy for Their Underlying Persistent Cancer Pain Question Eligible/Completed Prescribers N=310 1 n % (95% CI) 2 Question 6: Please answer True, False, or I don’t know for each statement based on the labeling for TIRF medicines. 6a: According to the product labeling, a cancer patient may start a TIRF medicine and an around-the-clock opioid at the same time. True 75 24.2 False 3 214 69.0 (63.6 - 74.1) I don’t know 21 6.8 FDA_3531 Prescriber KAB Assessment Report Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Table 8. Page 34 of 63 Responses Linked to Key Risk Message 2: TIRF Medicines Are Only Indicated for the Management of Breakthrough Pain in Adult Cancer Patients 18 Years of Age and Older (16 Years of Age and Older for Actiq® Brand and Generic Equivalents) Who Are Already Receiving and Who Are Tolerant to Around-The-Clock Opioid Therapy for Their Underlying Persistent Cancer Pain Question Eligible/Completed Prescribers N=310 1 n % (95% CI) 2 6b: According to the product labeling, a cancer patient who has been on an around-the-clock opioid for 1 day may start taking a TIRF medicine for breakthrough pain. True 62 20.0 False 3 226 72.9 (67.6 - 77.8) I don’t know 22 7.1 Question 9: In your practice, for which of the following indications do you prescribe TIRF medicines to opioid tolerant patients? Please answer Yes, No, or I don’t know for each option. 9a: Acute or postoperative pain Yes 28 9.0 No 3 280 90.3 (86.5 - 93.4) 2 0.6 Yes 16 5.2 No 3 294 94.8 (91.8 - 97.0) I don’t know 9b: Headache or migraine pain I don’t know 0 9c: Dental pain Yes 5 1.6 No 3 305 98.4 (96.3 - 99.5) I don’t know 0 9d: Breakthrough pain from cancer Yes 3 288 92.9 (89.5 - 95.5) FDA_3532 Prescriber KAB Assessment Report Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Table 8. Page 35 of 63 Responses Linked to Key Risk Message 2: TIRF Medicines Are Only Indicated for the Management of Breakthrough Pain in Adult Cancer Patients 18 Years of Age and Older (16 Years of Age and Older for Actiq® Brand and Generic Equivalents) Who Are Already Receiving and Who Are Tolerant to Around-The-Clock Opioid Therapy for Their Underlying Persistent Cancer Pain Question Eligible/Completed Prescribers N=310 1 n % (95% CI) 2 No 22 7.1 I don’t know 0 9e: Chronic non-cancer pain Yes 106 34.2 No 3 201 64.8 (59.2 - 70.2) 3 (1.0) I don’t know Question 15: The patients described are experiencing breakthrough pain. According to the labeling, a TIRF medicine is not appropriate for one of them. Which patient should not receive a TIRF medicine? Please select one option. 15a: Adult male with advanced lung cancer; underlying persistent cancer pain managed with 25 mcg/hour transdermal fentanyl patches for the past two months. 26 8.4 15b: Adult female with localized breast cancer; just completed a mastectomy and reconstructive surgery; persistent cancer pain managed with 30 mg oral morphine daily for the past 6 weeks. 3 227 73.2 (67.9 - 78.1) 15c: Adult male patient with advanced prostate cancer who, over the last 2 weeks, has been prescribed 100 mg oral morphine daily for pain due to bone metastasis. 18 5.8 15d: Adult female with advanced sarcoma who has been taking a daily dose of 12 mg oral hydromorphone for the last 3 weeks. 19 6.1 15e: I don’t know 20 6.5 FDA_3533 Prescriber KAB Assessment Report Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Table 8. Page 36 of 63 Responses Linked to Key Risk Message 2: TIRF Medicines Are Only Indicated for the Management of Breakthrough Pain in Adult Cancer Patients 18 Years of Age and Older (16 Years of Age and Older for Actiq® Brand and Generic Equivalents) Who Are Already Receiving and Who Are Tolerant to Around-The-Clock Opioid Therapy for Their Underlying Persistent Cancer Pain Question Eligible/Completed Prescribers N=310 1 n % (95% CI) 2 Question 20: Before initiating treatment with a TIRF medicine, prescribers must review the Medication Guide with the patient. Please select True, False, or I don’t know for each of the following counseling statements. 20b: Inform patients that TIRF medicines must not be used for acute or postoperative pain, pain from injuries, headache/migraine, or any other short-term pain. True 3 291 93.9 (90.6 - 96.3) False 12 3.9 I don’t know 7 2.3 20c: Instruct patients that they can continue to take their TIRF medicine, if they stop taking their around-the-clock opioid medicine. True 64 20.6 False 3 226 72.9 (67.6 - 77.8) I don’t know 20 6.5 Secondary Analysis: Number of Correct Responses 0 correct response 0 1 correct response 0 2 correct responses 1 0.3 3 correct responses 3 1.0 4 correct responses 5 1.6 5 correct responses 12 3.9 6 correct responses 29 9.4 7 correct responses 39 12.6 8 correct responses 57 18.4 FDA_3534 Prescriber KAB Assessment Report Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Table 8. Page 37 of 63 Responses Linked to Key Risk Message 2: TIRF Medicines Are Only Indicated for the Management of Breakthrough Pain in Adult Cancer Patients 18 Years of Age and Older (16 Years of Age and Older for Actiq® Brand and Generic Equivalents) Who Are Already Receiving and Who Are Tolerant to Around-The-Clock Opioid Therapy for Their Underlying Persistent Cancer Pain Eligible/Completed Prescribers N=310 1 Question n % (95% CI) 2 9 correct responses 82 26.5 10 correct responses 82 26.5 (21.6 - 31.7) 1 Number of eligible prescribers completing the survey (See Table 1) 95% exact two-sided confidence intervals are calculated using the Clopper-Pearson method. 3 Indicates the correct response(s) to each question or component within a question. 2 Table 9. Types of Chronic Pain Conditions Reported - Completed Surveys for Prescribers Who Prescribed TIRF Medicines for Chronic NonCancer Pain Question Prescribers (N=106) 1 n (%) n % Question 10: For what type(s) of chronic pain conditions do you prescribe a TIRF medicine to opioid tolerant patients? Total Number of Responses 2 214 Back Pain 34 32.1 Cancer Pain 24 22.6 Neuropathic Pain 23 21.7 Post-operative Pain 20 18.9 Chronic Pain 19 17.9 Joint Pain 11 10.4 Reflex Sympathetic Dystrophy 10 9.4 Complex Regional Pain Syndrome 8 7.5 Spinal Pain 8 7.5 FDA_3535 Prescriber KAB Assessment Report Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Table 9. Page 38 of 63 Types of Chronic Pain Conditions Reported - Completed Surveys for Prescribers Who Prescribed TIRF Medicines for Chronic NonCancer Pain Question Prescribers (N=106) 1 n (%) n % Neck Pain 5 4.7 Abdominal Pain 4 3.8 Musculoskeletal Pain 4 3.8 Sickle Cell 4 3.8 Gastrointestinal Pain 3 2.8 Migraines 3 2.8 Palliative Care 3 2.8 Pancreatitis 3 2.8 Spinal Stenosis 3 2.8 Breakthrough Pain 2 1.9 Oral Pain 2 1.9 Wound Pain 2 1.9 Allergic to Morphine and Dilaudid 1 0.9 Chronic Wounds 1 0.9 Intestinal Absorption Problems 1 0.9 Ischemic Peripheral Vascular Disease 1 0.9 Multiple Sclerosis 1 0.9 Neuropathy 1 0.9 Radiculopathy 1 0.9 Somatic Pain 1 0.9 FDA_3536 Prescriber KAB Assessment Report Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Table 9. Page 39 of 63 Types of Chronic Pain Conditions Reported - Completed Surveys for Prescribers Who Prescribed TIRF Medicines for Chronic NonCancer Pain Question Prescribers (N=106) 1 n (%) n % Trauma Pain 1 0.9 Wound Care 1 0.9 Other[3] 9 8.5 1 Number and percentages are based on the subset of completed surveys where prescribers responded "Yes" to prescribing TIRF medicines for chronic non-cancer pain (Question 9e: In your practice, for which of the following indications do you prescribe TIRF medicines to opioid tolerant patients? Chronic Non-Cancer Pain"Yes") and were subsequently presented Question 10 and Question 11. 2 Total number of responses may exceed the number of prescribers and percentages may not equal 100% as multiple responses were provided by some prescribers. 3 Other includes responses that were not categorized or responses that did not include a medical condition (see Appendix B Listing 1.1). Table 10. Reasons for Selecting a TIRF Medicine Reported - Completed Surveys for Prescribers Who Prescribed TIRF Medicines for Chronic NonCancer Pain Question Prescribers (N=106) 1 n % Question 11: Why do you select a TIRF medicine to treat these chronic pain conditions in patients who are opioid tolerant? Total Number of Responses 2 169 Efficacy 38 35.8 Fast Acting 36 34.0 Other Types of Medications have Failed 30 28.3 Breakthrough Pain 15 14.2 Ease of Use 5 4.7 Preferred Route of Administration 5 4.7 Abuse/Diversion Deterrence 4 3.8 FDA_3537 Prescriber KAB Assessment Report Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Table 10. Page 40 of 63 Reasons for Selecting a TIRF Medicine Reported - Completed Surveys for Prescribers Who Prescribed TIRF Medicines for Chronic NonCancer Pain Question Prescribers (N=106) 1 n % Long Duration of Action 4 3.8 Opioid Rotation 3 2.8 Potency 3 2.8 Quality of Life 3 2.8 Insurance 2 1.9 Pain Management 2 1.9 Compliance 1 0.9 Consistent Control 1 0.9 Less Toxicities Compared to Other Opioids 1 0.9 Patient Cannot Tolerate Other Options 1 0.9 Practice Preference 1 0.9 Preferred route of Administration 1 0.9 Prescribed by Another Physician before Becoming a Patient 1 0.9 Severe Pain 1 0.9 Other 3 11 10.4 1 Number and percentages are based on the subset of completed surveys where prescribers responded "Yes" to prescribing TIRF medicines for chronic non-cancer pain (Question 9e: In your practice, for which of the following indications do you prescribe TIRF medicines to opioid tolerant patients? Chronic Non-Cancer Pain"Yes") and were subsequently presented Question 10 and Question 11. 2 Total number of responses may exceed the number of prescribers and percentages may not equal 100% as multiple responses were provided by some prescribers. 3 Other includes responses that were not categorized or responses that did not include a medical condition (see Appendix B Listing 2.1). Stratification by number of times TIRF medicines were dispensed in the last 6 months resulted in one numeric trend (not statistically significant; Table 11). The more frequently TIRF medicines were prescribed within the past 6 months, the more likely prescribers were to prescribe them for dental pain. No other trends were observed (Appendix B). FDA_3538 Prescriber KAB Assessment Report Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Table 11. Page 41 of 63 Key Risk Message 2: Trends in Correct Response Rates by Prescribing Frequency Within Last 6 Months Stratification Question Number of Times Prescribing TIRF Medicines per Month Within the Last 6 Months None (N=77) 1 - 2 times per month (N=154) 3 - 5 times per month (N=49) More than 5 times per month (N=17) I don't remember (N=13) Correct Response Rate Correct Response Rate Correct Response Rate Correct Response Rate Correct Response Rate Question n % (95% CI) 1 n % (95% CI) 1 n % (95% CI) 1 n % (95% CI) 1 n % (95% CI) 1 Key Risk Message 2 9. In your practice, for which of the following indications do you prescribe TIRF medicines to opioid tolerant patients? Please answer Yes, No, or I don't know for each option. 9c. Dental pain No 1 77 100.0 (95.3-100.0) 153 99.4 (96.4-100.0) 47 95.9 (86.0 - 99.5) 15 88.2 (63.6 - 98.5) 13 100.0 (75.3-100.0) 95% exact two-sided confidence intervals are calculated using the Clopper-Pearson method. FDA_3539 Prescriber KAB Assessment Report Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies 5.2.3 Page 42 of 63 Key Risk Message 3 Key Risk Message 3 refers to the prescriber’s knowledge of the risk factors for opioid abuse and importance of monitoring for signs of abuse in patients who take TIRF medicines. Results in Table 12 show that 98.7% (95% CI: 96.7-99.6) of prescribers were aware that it is important to monitor for signs of abuse and addiction in patients who take TIRF medicines. In addition, most respondents correctly indicated that a personal history of psychiatric illness is a risk factor for opioid abuse (84.5%, 95% CI: 80.0-88.4), that a personal history of past or current alcohol or drug abuse or family history of drug or alcohol abuse is a risk factor for opioid abuse (98.7%, 95% CI: 96.7-99.6); and that TIRF medicines can be abused in a manner similar to other opioid agonists (94.2%, 95% CI: 91.0-96.5). Overall, 79.0% (95% CI: 74.1-83.4) of prescribers correctly answered all components of the key risk message, and 97.7% missed no more than one of the 4 component questions. Stratification by degree, time in practice or number of times TIRF medicines were dispensed in the last 6 months did not result in any evident trends (Appendix B). Table 12. Responses Linked to Key Risk Message 3: TIRF Medicines Contain Fentanyl, an Opioid Agonist, and a Schedule II Controlled Substance, With Abuse Liability Similar to Other Opioid Analgesics Question Eligible/Completed Prescribers N= 310 1 n % (95% CI) 2 Question 7: Please answer True, False, or I don’t know for each statement about TIRF medicines. 7e: It is important to monitor for signs of abuse and addiction in patients who take TIRF medicines. True 3 306 98.7 (96.7 - 99.6) False 2 0.6 I don’t know 2 0.6 Question 8: Which of the following are risk factors for opioid abuse? Please answer Yes, No, or I don’t know for each option. 8a: A personal history of psychiatric illness Yes 3 262 84.5 (80.0 - 88.4) No 28 9.0 I don’t know 20 6.5 FDA_3540 Prescriber KAB Assessment Report Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Table 12. Page 43 of 63 Responses Linked to Key Risk Message 3: TIRF Medicines Contain Fentanyl, an Opioid Agonist, and a Schedule II Controlled Substance, With Abuse Liability Similar to Other Opioid Analgesics Question Eligible/Completed Prescribers N= 310 1 n % (95% CI) 2 8b: A personal history of past or current alcohol or drug abuse, or a family history of illicit drug use or alcohol abuse 306 98.7 (96.7 - 99.6) No 4 1.3 I don’t know 0 Yes 3 Question 12: Please answer True, False, or I don’t know for each statement based on the labeling for TIRF medicines. 12a: TIRF medicines can be abused in a manner similar to other opioid agonists. True 3 292 94.2 (91.0 - 96.5) False 12 3.9 I don’t know 6 1.9 Secondary Analysis: Number of Correct Responses 0 correct responses 1 1 correct response 0 2 correct responses 6 1.9 3 correct responses 58 18.7 245 79.0 (74.1 - 83.4) 4 correct responses 0.3 1 Number of eligible prescribers completing the survey (See Table 1) All confidence intervals are exact binomial 95% confidence intervals. 3 Indicates the correct response(s) to each question or component within a question. 2 5.2.4 Key Risk Message 4 Key Risk Message 4 refers to the prescriber’s knowledge of the interchangeability of TIRF medicines based on route of administration, pharmacokinetic absorption, and dosage. Almost all prescribers (92.6%; 95% CI: 89.1-95.2) understood TIRF medicines are not interchangeable with each other regardless of the route of administration; 95.5% (95% CI: FDA_3541 Prescriber KAB Assessment Report Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 44 of 63 92.5-97.5) understood the conversion of one TIRF medicine to another may result in a fatal overdose; and 90.0% (95% CI: 86.1-93.1) understood that dosing of TIRF medicines is not equivalent on a microgram-to-microgram basis (Table 13). The majority of prescribers (77.4%, 95% CI: 72.4-82.0) correctly indicated that, when a patient wants to change his/her TIRF medicine, the prescriber must not convert to another TIRF medicine on a microgramper-microgram basis because these medicines have different absorption properties and this could result in a fentanyl overdose. Overall, 67.7% (95% CI: 62.2-72.9) of prescribers correctly answered all components of the key risk message, 92.2% missed no more than one of the 4 component questions. Stratification by degree, time in practice or number of times TIRF medicines were dispensed in the last 6 months did not result in any evident trends (Appendix B). Table 13. Responses Linked to Key Risk Message 4: TIRF Medicines Are Not Interchangeable With Each Other, Regardless of Route of Administration Question Eligible/Completed Prescribers N=310 1 n % (95% CI) 2 Question 12: Please answer True, False, or I don’t know for each statement about TIRF medicines. 12b: TIRF medicines are interchangeable with each other regardless of route of administration. True 13 4.2 False 3 287 92.6 (89.1 - 95.2) I don’t know 10 3.2 12c: The conversion of one TIRF medicine for another TIRF medicine may result in a fatal overdose because of differences in the pharmacokinetics of fentanyl absorption. True 3 296 95.5 (92.5 - 97.5) False 6 1.9 I don’t know 8 2.6 12d: Dosing of TIRF medicines is not equivalent on a microgram-to-microgram basis. True 3 279 90.0 (86.1 - 93.1) False 21 6.8 I don’t know 10 3.2 FDA_3542 Prescriber KAB Assessment Report Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Table 13. Page 45 of 63 Responses Linked to Key Risk Message 4: TIRF Medicines Are Not Interchangeable With Each Other, Regardless of Route of Administration Question Eligible/Completed Prescribers N=310 1 n % (95% CI) 2 16: A patient is already taking a TIRF medicine but wants to change their medicine. His/her doctor decides to prescribe a different TIRF medicine (that is not a bioequivalent generic version of a branded product) in its place. According to the labeling, how should the prescriber proceed? Please select one option. 16a: The prescriber can safely convert to the equivalent dosage of the new TIRF medicine as it has the same effect as other TIRF medicines. 3 1.0 16b: The prescriber must not convert to another TIRF medicine on a microgram-per-microgram basis because these medicines have different absorption properties and this could result in a fentanyl overdose. 3 240 77.4 (72.4 - 82.0) 16c: Convert from the other TIRF medicine to the new TIRF medicine at half of the dose. 22 7.1 16d: The prescriber should base the starting dose of the newly-prescribed TIRF medicine on the dose of the opioid medicine used for their underlying persistent cancer pain. 33 10.6 16e: I don’t know 12 3.9 Secondary Analysis: Number of Correct Responses 0 correct responses 3 1.0 1 correct response 8 2.6 2 correct responses 13 4.2 3 correct responses 76 24.5 210 67.7 (62.2 - 72.9) 4 correct responses 1 Number of eligible prescribers completing the survey (See Table 1). 95% exact two-sided confidence intervals are calculated using the Clopper-Pearson method. 3 Indicates the correct response(s) to each question or component within a question. 2 FDA_3543 Prescriber KAB Assessment Report Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies 5.2.5 Other Survey Questions 5.2.5.1 Additional Questions about TIRF Medicines Safety Page 46 of 63 Table 14 summarizes the prescribers’ responses to additional questions about the safe use of TIRF medicines beyond those associated with the key risk messages. A high percentage of prescribers (90.6%) correctly indicated a family history of asthma is not a risk factor for opioid abuse. Most prescribers (86.1%) correctly indicated that for a patient starting a TIRF medicine, an appropriate dose is the lowest available dose, unless the Full Prescribing Information provides specific guidance. When presented with the scenario of a patient who has started on the lowest dose of a TIRF medicine, and for whom the breakthrough pain has not been sufficiently relieved after 30 minutes, 68.7% prescribers correctly responded that they should follow the guidance based on the product-specific Medication Guide because the recommendations are not the same for all TIRF medicines. The majority of prescribers (75.8%) correctly indicated use of a TIRF medicine with a CYP3A4 inhibitor may require a dose adjustment, and that the patient needs to be monitored for opioid toxicity to minimize the risk of fatal respiratory depression. Nearly all prescribers surveyed (99.4%) understood that TIRF medicines contain fentanyl in an amount that could be fatal for children of all ages, for individuals for whom they were not prescribed, and for those who are not opioid tolerant. In addition, 99.7% understood that patients must be instructed not to share their TIRF medicine with anyone else, even if that person has the same symptoms. Table 14. Responses to Additional Questions About the Safe Use of TIRF Medicines Question Eligible/Completed Prescribers N=310 1 n % Question 8: Which of the following are risk factors for opioid abuse? Please answer Yes, No, or I don’t know for each option. 8c: A family history of asthma Yes 12 3.9 No 2 281 90.6 I don’t know 17 5.5 FDA_3544 Prescriber KAB Assessment Report Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Table 14. Page 47 of 63 Responses to Additional Questions About the Safe Use of TIRF Medicines Question Eligible/Completed Prescribers N=310 1 n % Question 17: A patient is starting titration with a TIRF medicine. What dose must they start with? Please select one option. 17a. An appropriate dose based on the dose of the opioid medicine used for underlying persistent cancer pain. 35 11.3 17b. The dose that the prescriber believes is appropriate based on their clinical experience. 3 1.0 267 86.1 17d. The median available dose. 2 0.6 17e. I don’t know. 3 1.0 17c. The lowest available dose, unless individual product Full Prescribing Information provides product-specific guidance. 2 Question 18: A prescriber has started titrating a patient with the lowest dose of a TIRF medicine. However, after 30 minutes the breakthrough pain has not been sufficiently relieved. What should they advise the patient to do? Please pick the best option of the scenarios described. 18a. Take another (identical) dose of the TIRF medicine immediately. 78 25.2 18b. Take a dose of an alternative rescue medicine. 13 4.2 18c. Provide guidance based on the product-specific Medication Guide because the instructions are not the same for all TIRF medicines. 2 213 68.7 18d. Double the dose and take immediately. 5 1.6 18e. I don’t know. 1 0.3 Question 19: A patient is taking a TIRF medicine and the doctor would like to prescribe erythromycin, a CYP3A4 inhibitor. Please pick the best option of the scenarios described. 19a: The patient can’t be prescribed erythromycin, because using it at the same time as a TIRF medicine could be fatal. 14 4.5 19b: Use of a TIRF medicine with a CYP3A4 inhibitor may require dosage adjustment; carefully monitor the patient for opioid toxicity, otherwise such use may cause potentially fatal respiratory depression. 2 235 75.8 19c: There is no possible drug interaction between CYP3A4 inhibitors and TIRF medicines. 6 1.9 19d: The dose of the TIRF medicine must be reduced by one-half if a CYP3A4 inhibitor is prescribed in the same patient. 10 3.2 FDA_3545 Prescriber KAB Assessment Report Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Table 14. Page 48 of 63 Responses to Additional Questions About the Safe Use of TIRF Medicines Question 19e: I don’t know. Eligible/Completed Prescribers N=310 1 n % 45 14.5 Question 20: Before initiating treatment with a TIRF medicine, prescribers must review the Medication Guide with the patient. Please select True, False, or I don’t know for each of the following counseling statements. 20a: TIRF medicines contain fentanyl in an amount that could be fatal to children of all ages, in individuals for whom they were not prescribed, and in those who are not opioid tolerant. True 2 308 99.4 False 1 0.3 I don’t know 1 0.3 20d: Instruct patients never to share their TIRF medicine with anyone else, even if that person has the same symptoms. True 2 309 False 0 I don’t know 1 1 2 99.7 0.3 Number of eligible prescribers completing the survey (See Table 1). Indicates the correct response(s) to each question or component within a question. 5.2.5.2 Prescriber Activities When Prescribing TIRF Medicines Prescribers were asked about specific activities performed when prescribing TIRF medicines (Table 15). More than half of prescribers indicated they always ask patients (or their caregivers) about the presence of children in the home (57.4%), always instruct patients (or their caregivers) not to share TIRF medicines with anyone else (80.3%), always counsel patients (or their caregivers) that accidental exposure by a child may be fatal (65.5%), always instruct patients (or their caregivers) to keep TIRF medicines out of the reach of children (71.0%), and always instruct patients (or their caregivers) about proper disposal of TIRF medicines (61.3%). In addition, 45.2% indicated they always give patients (or their caregivers) the Medication Guide for their TIRF medicine, whereas 39.7% indicated they give it only with the first prescription. FDA_3546 Prescriber KAB Assessment Report Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Table 15. Page 49 of 63 Responses to All Questions About Activities When Prescribing TIRF Medicines Question Eligible/Completed Prescribers N=310 1 n % Question 14: How frequently do you perform the following activities when prescribing TIRF medicines? Please answer Always, Only with the first prescription, Sometimes, Never, or I don’t know. 14a: Ask patients (or their caregivers) about the presence of children in the home. Always 178 57.4 Only with the first prescription 75 24.2 Sometimes 42 13.5 Never 11 3.5 I don’t know 4 1.3 14b: Instruct patients (or their caregivers) not to share TIRF medicines with anyone else. Always 249 80.3 Only with the first prescription 43 13.9 Sometimes 13 4.2 Never 3 1.0 I don’t know 2 0.6 14c: Counsel patients (or their caregivers) that accidental exposure to TIRF medicines by a child may be fatal. Always 203 65.5 Only with the first prescription 66 21.3 Sometimes 27 8.7 Never 11 3.5 I don’t know 3 1.0 FDA_3547 Prescriber KAB Assessment Report Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Table 15. Page 50 of 63 Responses to All Questions About Activities When Prescribing TIRF Medicines Question Eligible/Completed Prescribers N=310 1 n % 14d: Instruct patients (or their caregivers) to keep TIRF medicines out of the reach of children to prevent accidental exposure. Always 220 71.0 Only with the first prescription 61 19.7 Sometimes 19 6.1 Never 7 2.3 I don’t know 3 1.0 14e: Instruct patients (or their caregivers) about proper disposal of any unused or partially used TIRF medicines. Always 190 61.3 Only with the first prescription 74 23.9 Sometimes 37 11.9 Never 6 1.9 I don’t know 3 1.0 14f: Give patients (or their caregivers) the Medication Guide for their TIRF medicine. Always 140 45.2 Only with the first prescription 123 39.7 Sometimes 23 7.4 Never 21 6.8 I don’t know 3 1.0 1 Number of eligible prescribers completing the survey (See Table 1). 5.3 Spontaneous Reporting of Adverse Events, Product Complaints or Medical Information Requests Among all survey respondents (N=310, Table 1), there were 86 reports of a potential adverse event or product complaint associated with the use of TIRF medicines made within the survey free text field during the online survey, and 4 reports made during the telephone survey. Verbatim statements are provided in Appendix B, Listing 5. FDA_3548 Prescriber KAB Assessment Report Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies 6. Page 51 of 63 DISCUSSION AND CONCLUSIONS Discussion Survey invitations (and reminders) were sent to a random sample of prescribers enrolled in the TIRF REMS Access Program. From among those who responded to the invitation, 310 prescribers completed the survey. Thus, the required sample size was achieved within the planned survey period. The specific goals of the TIRF medicines prescriber KAB survey were to assess prescribers’ understanding of the risks associated with TIRF medicine use, the selection of appropriate patients for treatment with TIRF medicines, preventing inappropriate conversion between TIRF medicines, and ensuring safe use of TIRF medicines while preventing exposure to children and others for whom TIRF medicines were not prescribed. Comparison of survey respondents to the general population of TIRF prescribers (as requested by FDA) showed the geographic distribution of respondents to the prescriber survey was similar to the overall population of prescribers who prescribe TIRF medicines Table 5). A full comparison of demographics of the survey respondents to the general population of TIRF prescribers will be included in the Supplemental Report estimated to be delivered on May 4, 2016. Of the 31 components included as part of key risk messages, 21 components of the key risk messages had a correct response rate >80% and 9 components had a correct response rate between 67.7% and 78.7%. For Component 9e, 201 prescribers (64.8%) indicated they do not prescribe TIRF medicines for chronic non-cancer pain. A total of 106 prescribers (34.2%) indicated they do prescribe TIRF medicines for chronic non-cancer pain. The 106 prescribers who indicated they do prescribe TIRF medicines for chronic non-cancer pain were presented with 2 additional questions as requested by the FDA. Question 10 addressed the type of chronic pain conditions they prescribe a TIRF medicine to treat (see Table 9). The most frequently reported conditions were back pain (32.1%), cancer pain (22.6%), neuropathic pain (21.7%), post-operative pain (18.9%), and chronic pain (17.9%). Question 11 addressed the reasons for selecting a TIRF medicine to treat these conditions (see Table 10). The most frequently reported reasons were efficacy (35.8%), that they are fast acting (34.0%), and that other types of medications have failed (28.3%). Given these reasons, and the high percentage of respondents who indicated they received and read the REMS educational materials, the responses to Questions 10 and 11 may reflect behavior more than knowledge. That is, prescribers are aware of the labeled indication but choose to prescribe off-label for certain patients. Component 9e in this survey has had a low correct response rate across all prescriber KAB surveys conducted (12-month, 24-month, 36-month, and 48-month surveys). However, the correct response rate is trending up (Table 16). There is a clear and consistent indication of improvement (i.e., numeric trend) in knowledge and understanding of the key risk messages. Table 16 includes key risk messages and FDA_3549 Prescriber KAB Assessment Report Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 52 of 63 questions/components within each key risk message as presented in the 48-month survey. It is important to note the question/component numbering, wording, and association with a specific key risk message may have changed across survey waves based on FDA feedback or other decisions made by the TRIG. FDA_3550 Prescriber KAB Assessment Report Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Table 16. 48-Month Survey Question Number Page 53 of 63 Correct Response Rates Over Time Questions as Presented in the 48-Month Survey 12-Month Survey Correct/Desired Response % (95% CI) 24-Month Survey Correct/Desired Response % (95% CI) 36-Month Survey Correct/Desired Response % (95% CI) 48-Month Survey Correct/Desired Response % (95% CI) Key Risk Message 1: TIRF Medicines Are Contraindicated in Opioid Non-Tolerant Patients 5 Please select True, False, or I don’t know for each of the following. According to the labeling for TIRF medicines, patients with cancer who are considered opioid-tolerant are those: 1 5a Who are taking around-theclock opioid therapy for underlying persistent cancer pain for one week or longer (Correct Response True) 1 7.9 5b Who are not currently taking opioid therapy, but have taken opioid therapy before (Correct Response False) 88.72 5c Who have no known contraindications to the drug fentanyl, but are not currently taking around-theclock opioid therapy (Correct Response False) 1 15.62 7 7a 2 90.4 90.0 (86.5, 93.5) (86.0, 93.2) 88.1 87.0 (83.9, 91.5) (82.7, 90.6) 82.1 86.3 (77.3, 86.3) (81.9, 90.0) 95.2 (92.1 - 97.3) 93.9 (90.6 - 96.3) 86.8 (82.5 - 90.3) Please answer True, False, or I don’t know for each statement based on the labeling for TIRF medicines. 1 TIRF medicines are contraindicated in opioid non-tolerant patients because life-threatening respiratory depression could occur at any dose (Correct Response True) 87.4 (83.1, 90.9) 87.7 86.7 (83.5, 91.2) (82.3, 90.3) 90.3 (86.5 - 93.4) FDA_3551 Prescriber KAB Assessment Report Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Table 16. Page 54 of 63 Correct Response Rates Over Time Questions as Presented in the 48-Month Survey 12-Month Survey Correct/Desired Response % (95% CI) 24-Month Survey Correct/Desired Response % (95% CI) 36-Month Survey Correct/Desired Response % (95% CI) 48-Month Survey Correct/Desired Response % (95% CI) 7b Death has occurred in opioid non-tolerant patients treated with some fentanyl products (Correct Response True) 95.7 95.7 (92.8, 97.7) 93.7 95.7 (90.3, 96.2) (92.7, 97.7) 96.1 (93.3 - 98.0) 7c TIRF medicines may be used to treat opioid nontolerant patients (Correct Response False) 82.5 82.5 (77.7, 86.6) 80.1 82.0 (75.2, 84.5) (77.2, 86.2) 7d Prescribers starting a patient on a TIRF medicine must begin with titration from the lowest dose available for that specific product, even if the patient has previously taken another TIRF medicine (Correct Response True) 83.1 83.1 (78.4, 87.2) 80.8 84.0 (75.9, 85.1) (79.4, 88.0) 13 Please select True, False, or I don’t know for each of the following. According to the labeling for TIRF medicines, patients considered opioidtolerant are those who are taking, for one week or longer, at least: 13a 8 mg oral hydromorphone/day (Correct Response True) N/A 68.5 13b 60 mg oral morphine/day (Correct Response True) N/A 89.12 92.32 94.5 (91.4 - 96.8) 13c 30 mg oral oxycodone/day (Correct Response True) N/A 76.22 78.02 78.7 (73.7 - 83.1) 48-Month Survey Question Number 2 70.3 2 84.8 (80.4 - 88.6) 85.5 (81.1 - 89.2) 72.9 (67.6 - 77.8) FDA_3552 Prescriber KAB Assessment Report Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Table 16. 48-Month Survey Question Number Page 55 of 63 Correct Response Rates Over Time Questions as Presented in the 48-Month Survey 12-Month Survey Correct/Desired Response % (95% CI) 24-Month Survey Correct/Desired Response % (95% CI) 36-Month Survey Correct/Desired Response % (95% CI) 48-Month Survey Correct/Desired Response % (95% CI) 13d 25 mcg transdermal fentanyl/hour (Correct Response True) N/A 80.82 83.72 85.5 (81.1 - 89.2) 13e 25 mg oral oxymorphone/day (Correct Response True) N/A 69.92 74.72 72.3 (66.9 - 77.2) 13f An equianalgesic dose of another oral opioid (Correct Response True) N/A 65.92 59.02 67.7 (62.2 - 72.9) Key Risk Message 2: TIRF Medicines Are Only Indicated for the Management of Breakthrough Pain in Adult Cancer Patients 18 Years of Age and Older (16 Years of Age and Older for Actiq® Brand and Generic Equivalents) Who Are Already Receiving and Who Are Tolerant to Around-theClock Opioid Therapy for Their Underlying Persistent Cancer Pain 6 Please answer True, False, or I don’t know for each statement based on the labeling for TIRF medicines. 6a According to the product labeling, a cancer patient may start a TIRF medicine and an around-the-clock opioid at the same time (Correct Response False) 1 N/A 60.62 60.02 69.0 (63.6 - 74.1) 6b According to the product labeling, a cancer patient who has been on an aroundthe-clock opioid for 1 day may start taking a TIRF medicine for breakthrough pain (Correct Response False) 1 N/A 64.92 70.32 72.9 (67.6 - 77.8) FDA_3553 Prescriber KAB Assessment Report Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Table 16. 48-Month Survey Question Number Page 56 of 63 Correct Response Rates Over Time Questions as Presented in the 48-Month Survey 12-Month Survey Correct/Desired Response % (95% CI) 24-Month Survey Correct/Desired Response % (95% CI) 36-Month Survey Correct/Desired Response % (95% CI) 48-Month Survey Correct/Desired Response % (95% CI) 9 In your practice, for which of the following indications do you prescribe TIRF medicines to opioid tolerant patients? Please answer Yes, No, or I don’t know for each option. 1 9a Acute or postoperative pain (Desired Behavior response No) 86.4 (82.0, 90.1) 9b Headache or migraine pain (Desired Behavior response No) 86.8 86.8 (82.4, 90.4) 9c Dental pain (Desired Behavior response No) 96.0 (93.2, 97.9) 9d Breakthrough pain from cancer (Desired Behavior response Yes) 95.4 (92.3, 97.4) 9e Chronic non-cancer pain (Desired Behavior Response: No) 15 The patients described are experiencing breakthrough pain. According to the labeling, a TIRF medicine is not appropriate for one of them. Which patient should not receive a TIRF medicine? 1 54.32 93.0 87.3 (89.6, 95.6) (83.0, 90.9) 92.4 89.7 (88.8, 95.1) (85.7, 92.9) 96.7 97.3 (94.0, 98.4) (94.8, 98.8) 92.4 96.0 (88.8, 95.1) (93.1, 97.9) 58.9 62.0 (53.2, 64.5) (56.2, 67.5) 90.3 (86.5 - 93.4) 94.8 (91.8 - 97.0) 98.4 (96.3 - 99.5) 92.9 (89.5 - 95.5) 64.8 (59.2 - 70.2) FDA_3554 Prescriber KAB Assessment Report Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Table 16. Page 57 of 63 Correct Response Rates Over Time Questions as Presented in the 48-Month Survey 12-Month Survey Correct/Desired Response % (95% CI) 15b Adult female with localized breast cancer; just completed a mastectomy and reconstructive surgery; persistent cancer pain managed with 30 mg oral morphine daily for the past 6 weeks (Correct Response) 54.32 20 Before initiating treatment with a TIRF medicine, prescribers must review the Medication Guide with the patient. Please select True, False, or I don’t know for each of the following counseling statements. 20b Inform patients that TIRF medicines must not be used for acute or postoperative pain, pain from injuries, headache/migraine, or any other short-term pain (Correct Response True) 91.72 92.12 90.72 20c Instruct patients that they can continue to take their TIRF medicine, if they stop taking their around-theclock opioid medicine (Correct Response False) 1 68.52 2 2 48-Month Survey Question Number 24-Month Survey Correct/Desired Response % (95% CI) 65.9 57.9 2 36-Month Survey Correct/Desired Response % (95% CI) 48-Month Survey Correct/Desired Response % (95% CI) 66.3 73.2 (67.9 - 78.1) (60.7, 71.7) 61.0 93.9 (90.6 - 96.3) 72.9 (67.6 - 77.8) FDA_3555 Prescriber KAB Assessment Report Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Table 16. 48-Month Survey Question Number Page 58 of 63 Correct Response Rates Over Time Questions as Presented in the 48-Month Survey 12-Month Survey Correct/Desired Response % (95% CI) 24-Month Survey Correct/Desired Response % (95% CI) 36-Month Survey Correct/Desired Response % (95% CI) 48-Month Survey Correct/Desired Response % (95% CI) Key Risk Message 3: TIRF Medicines Contain Fentanyl, an Opioid Agonist and a Schedule II Controlled Substance, with Abuse Liability Similar to other Opioid Analgesics 7 Please answer True, False, or I don’t know for each statement based on the labeling for TIRF medicines. 1 7e It is important to monitor for signs of abuse and addiction in patients who take TIRF medicines (Correct Response True) 8 Which of the following are risk factors for opioid abuse? Please answer Yes, No, or I don’t know for each option. 8a A personal history of psychiatric illness (Correct Response Yes) 82.5 (77.7, 86.6) 8b A personal history of past or current alcohol or drug abuse, or a family history of illicit drug use or alcohol abuse (Correct Response Yes) 99.3 (97.6, 99.9) 12 Please answer True, False, or I don’t know for each statement based on the labeling for TIRF medicines. 1 12a TIRF medicines can be abused in a manner similar to other opioid agonists (Correct Response True) 99.7 (98.2, 100.0) 97.7 (95.3, 99.1) 99.0 (97.1, 99.8) 82.8 (78.0, 86.9) 99.0 (97.1, 99.8) 96.4 (93.6, 98.2) 99.7 (98.2, 100.0) 98.7 (96.7 - 99.6) 84.0 (79.4, 88.0) 84.5 (80.0 - 88.4) 99.7 (98.2, 100.0) 98.7 (96.7 - 99.6) 97.3 (94.8, 98.8) 94.2 (91.0 - 96.5) FDA_3556 Prescriber KAB Assessment Report Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Table 16. 48-Month Survey Question Number Page 59 of 63 Correct Response Rates Over Time Questions as Presented in the 48-Month Survey 12-Month Survey Correct/Desired Response % (95% CI) 24-Month Survey Correct/Desired Response % (95% CI) 36-Month Survey Correct/Desired Response % (95% CI) 48-Month Survey Correct/Desired Response % (95% CI) Key Risk Message 4: TIRF Medicines Are Not Interchangeable with Each Other, Regardless of Route of Administration 12 Please answer True, False, or I don’t know for each statement based on the labeling for TIRF medicines. 1 12b TIRF medicines are interchangeable with each other regardless of route of administration (Correct Response False) 95.7 (92.8, 97.7) 12c The conversion of one TIRF medicine for another TIRF medicine may result in a fatal overdose because of differences in the pharmacokinetics of fentanyl absorption (Correct Response True) 94.7 (91.5, 96.9) 12d Dosing of TIRF medicines is not equivalent on a microgram-to-microgram basis (Correct Response True) 90.4 (86.5, 93.5) 92.4 (88.8, 95.1) 94.7 (91.5, 96.9) 90.7 (86.9, 93.8) 93.0 (89.5, 95.6) 92.6 (89.1 - 95.2) 96.7 (94.0, 98.4) 95.5 (92.5 - 97.5) 90.7 (86.8, 93.7) 90.0 (86.1 - 93.1) FDA_3557 Prescriber KAB Assessment Report Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Table 16. 48-Month Survey Question Number 1 2 Page 60 of 63 Correct Response Rates Over Time Questions as Presented in the 48-Month Survey 12-Month Survey Correct/Desired Response % (95% CI) 24-Month Survey Correct/Desired Response % (95% CI) 36-Month Survey Correct/Desired Response % (95% CI) 48-Month Survey Correct/Desired Response % (95% CI) 16 A patient is already taking a TIRF medicine but wants to change their medicine. His/her doctor decides to prescribe a different TIRF medicine (that is not a bioequivalent generic version of a branded product) in its place. According to the labeling, how should the prescriber proceed? 1 16b The prescriber must not convert to another TIRF medicine on a microgramper-microgram basis because these medicines have different absorption properties and this could result in a fentanyl overdose (Correct Response). 1 75.52 74.5 (69.2, 79.3) 74.3 (69.0, 79.2) 77.4 (72.4 - 82.0) Questions presented have been changed from previous survey waves. 95% confidence interval is not provided since the component was not part of a key risk message during reporting period. FDA_3558 Prescriber KAB Assessment Report Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 61 of 63 Conclusions In general, there is an overall trend over time toward increasing improvement in prescriber knowledge and understanding of the key risk messages (Table 16). The consistently high level of prescriber understanding of key risk messages in the latest (48-month) survey indicates that the Education Program for Prescribers is meeting the goals of the TIRF REMS Access Program. Based on prescriber responses, and the high percentage of respondents who indicated they received and read the TIRF REMS Access Program educational materials, the responses may reflect behavior more than knowledge. For the single component that addresses indications for which a TIRF medicine is prescribed, responses may reflect prescriber behavior. That is, prescribers are aware of the labeled indication but choose to prescribe off-label for certain patients. The TRIG will continue to work with the FDA to refine, on a continual basis, the steps to mitigate risks associated with TIRF medicines. FDA_3559 Prescriber KAB Assessment Report Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Appendix A Page 62 of 63 Prescriber Survey Protocol Track Change Document: Comparison of 36-month Survey to 48-month Survey FDA_3560 PROTOCOL TITLE: SPONSOR: VERSION: DATE: APPROVED Quantitative Testing of Prescriber Knowledge, Attitudes, and Behavior about Transmucosal Immediate Release Fentanyl (TIRF) Products Safety and Use Information TIRF REMS Industry Group (TRIG) Actavis Laboratories Inc. BioDeliverv Sciences International: Inc. Style De?nition: Bullet Paragraph: Bulleted Level: 1 Aligned at: 0' Inth at: 0.25" 1 (BDSI) (rglaced on A Formatted: Font: Not Bold, Not Italic March 11, 2015 Cephalon, Inc. (a wholly-owned subsidiary of Teva Pharmaceutical Industries, Ltd.) Depomed, Inc. Galena Biopharma, Inc. Insys Therapeutics, Inc. Mallinckrodt Pharmaceuticals WW Mylan, Inc. Par Pharmaceutical, Inc. 1_01.0 Formatted: Font: Not Italic TABLE OF CONTENTS PAGE TABLE OF CONTENTS 2 1. LIST OF ABBREVIATIONS 3 2. BACKGROUND 4 3. OBJECTIVES OF THE EVALUATION SURVEY 5 4. METHODS 5 4.1 Survey Design 5 4.1.1 Qualitative Research on the Survey 6 4.1.2 Questions on REMS Goals 6 4. 1.3 Additional Questions 12 4.2 Participant Recruitment 12 4.2.1 Measures to Minimize Bias in the Sample l3 5. STUDY POPULATION 13 5.1.1 Sample Size 13 5.1.2 Inclusion Criteria 14 5.1.3 Exclusion Criteria l4 6. SURVEY PROCESS 14 6.1 Screening and Survey Administration 15 6. 1.1 Telephone 15 6. 1.2 Internet 15 6.2 Measures to Minimize Bias in the Survey Process 15 7. ANALYSIS 16 7.1.1 Analysis Population 16 7.1.2 Description of Primary Analyses 16 7.1.3 Description of Secondary Analyses 17 8. SAFETY EVENT REPORTING l7 9. PRIVACY PROTECTION AND CONFIDENTIALITY 17 LIST OF APPENDICES Appendix A Prescriber Questionnaire 18 Appendix SAMPLE Prescriber Invitation Letter 44 ?\[Formatted: Bottom: 0.88' 1. LIST OF ABBREVIATIONS BDSI CATI CI EDC ETASU FDA HIPAA ISI KAB PI REMS SE PSP TIRF TIRF REMS TRIG UBC US BioDelivery Sciences International, Inc. Computer-Assisted Telephone Interviewing Confidence Interval Electronic Data Capture Elements to Assure Safe Use Food and Drug Administration Health Insurance Portability and Accountability Act Important Safety Information Knowledge, Attitudes, and Behavior Prescribing Information Risk Evaluation and Mitigation Strategy Safety Event Project Specific Procedure Transmucosal Immediate Release Fentanyl TIRF REMS Access Program TIRF REMS Industry Group United BioSource Corporation United States FDA_3563 2. BACKGROUND Transmucosal Immediate Release Fentanyl (TIRF) medicines include the class of immediaterelease opioid analgesics that are indicated only for the management of breakthrough pain in cancer patients 18 years of age or older (16 or older for Actiq® and equivalent generics) who are already receiving and tolerant to opioid therapy for their underlying persistent cancer pain. The TIRF medicines include Abstral®, Actiq®, Fentora®, Lazanda®, Onsolis®, Subsys®, and generic versions of any of these brands. The TIRF REMS Industry Group (TRIG) includes Actavis Laboratories FL, Inc.; BioDelivery Sciences International, Inc. (BDSI) (replaced Meda Pharmaceuticals on March 11, 2015); Cephalon, Inc. (a wholly-owned subsidiary of Teva Pharmaceutical Industries, Ltd.); Depomed, Inc.; Galena Biopharma, Inc.; Insys Therapeutics, Inc.;; Mallinckrodt Pharmaceuticals; Meda Pharmaceuticals; Mylan, Inc.; and Par Pharmaceutical, Inc. The Food and Drug Administration (FDA) has determined that a class-wide Risk Evaluation and Mitigation Strategy (REMS) is required to mitigate the risk of misuse, abuse, addiction, overdose, and serious complications due to medication errors with the use of TIRF medicines. The TIRF REMS Access Program (hereafter referred to as TIRF REMS) was approved by the FDA on December 28, 2011. The TIRF REMS consists of a Medication Guide, Elements to Assure Safe Use (ETASU), an Implementation System, and a Timetable for Submission of Assessments of the REMS. The goals of the TIRF REMS are to mitigate the risk of misuse, abuse, addiction, overdose, and serious complications due to medication errors by the following: 1. Prescribing and dispensing TIRF medicines only to appropriate patients, which includes use only in opioid-tolerant patients. 2. Preventing inappropriate conversion between TIRF medicines. 3. Preventing accidental exposure to children and others for whom it was not prescribed. 4. Educating prescribers, pharmacists, and patients on the potential for misuse, abuse, addiction, and overdose of TIRF medicines. An important component of the TIRF REMS assessment is the conduct of quantitative evaluation surveys to assess prescribers’ understanding and knowledge of the safe use and appropriate prescribing of TIRF medicines as described in the TIRF REMS educational materials, enrollment form, and Prescribing Information (PI) of each product. This protocol will describe the administration of the surveys that will be conducted among prescribers who are enrolled in the TIRF REMS Access Program. Data from the surveys, together with other REMS evaluation metrics, will be used to determine whether changes need to be made to the REMS processes or educational materials to make them more effective in achieving the goals of the REMS. FDA_3564 The surveys will be implemented so that data will be available for inclusion in the REMS Assessment Reports that will be submitted to the FDA at 12 months after approval of the TIRF REMS and annually thereafter. 3. OBJECTIVES OF THE EVALUATION SURVEY The evaluation survey will use a questionnaire to document the level of knowledge and assess the attitudes and behavior of prescribers around the following key information and risk messages communicated through the REMS: 1. TIRF medicines are contraindicated in opioid non-tolerant patients. 2. TIRF medicines are only indicated for the management of breakthrough pain in adult cancer patients 18 years of age and older (16 or older for Actiq® and equivalent generics) who are already receiving and who are tolerant to around-the-clock opioid therapy for their underlying persistent cancer pain. 3. TIRF medicines contain fentanyl, an opioid agonist and a Schedule II-controlled substance, with abuse liability similar to other opioid analgesics. 4. TIRF medicines are not interchangeable with each other, regardless of route of administration. 5. Patients and their caregivers must be instructed that TIRF medicines contain a medicine in an amount that can be fatal in children, in individuals for whom it is not prescribed, and in those who are not opioid tolerant. The survey will also collect data on behaviors, such as receipt and use of educational materials and compliance with REMS requirements. 4. METHODS The survey was designed in collaboration between the TRIG and United BioSource Corporation (UBC) and will be administered by UBC. 4.1 Survey Design This survey will be conducted among a sample of prescribers who are enrolled in the TIRF REMS Access Program. Respondents who participate in the previous wave of the TIRF survey will not be eligible to participate in subsequent survey waves. The survey will be administered using the following modalities: • Self-administered, online through a secure website FDA_3565 • Telephone surveys facilitated by a trained interviewer from the Survey Coordinating Center using a computer-assisted telephone interviewing (CATI) program The survey will begin with screening questions to confirm respondent eligibility to participate in the survey. Completion of the entire survey is expected to take approximately 20 minutes. The survey included in Appendix A is written to reflect wording for both methods of survey administration: Internet-based and telephone. All respondents who complete the survey and who provide their contact information will be mailed a $125 honorarium for their time. 4.1.1 Qualitative Research on the Survey The FDA provided feedback to the TRIG on the Knowledge, Attitudes, and Behaviors (KAB) survey results for prescribers included in the 12-month REMS Assessment results. The FDA requested that the TRIG investigate the causes for low correct response rates to specific questions in the survey by conducting research to determine the reasons for the poor performance on these questions, and to assess proposed revised wording to select questions. Qualitative research was performed in 2013 prior to Wave 2 of the survey. Findings were incorporated into the survey and results from the revised survey were included in the 24month REMS Assessment Report, 4.1.2 Questions on REMS Goals The KAB questionnaire is made up of multiple-choice, close-ended statements or questions (the majority of which use true/false or yes/no dichotomous response options), and one openended question. These will evaluate current knowledge, attitudes, and behavior regarding the key risk messages noted in Section 3. Questions will be presented in several formats: • Statements or questions asking the respondent to indicate whether a statement or question is true or false, or if they do not know the answer (there is a similar set of statements and questions that use “yes” or “no” as potential response options); • Statements or questions asking the respondent to choose from a defined list of possible statements or answers; and • One question allowing for the respondent to list questions about the products or comments. Questionnaires will be analyzed to determine prescriber understanding of each key risk message. For statements or questions that use “true” or “yes” vs. “false” or “no” response options, the desired response for key risk messages is generally “true” or “yes” indicating knowledge of, or behavior in accordance with, the objectives of the REMS. However, some questions are FDA_3566 formatted to have the respondent disagree with the statement as written by providing response options of ?false? or ?no? to avoid having the same af?rmative answer for all desired responses. REMS statements. corresponding questions. and desired responses covering the key risk messages are identi?ed below and can be found in the complete survey questionnaire (Appendix A). Key Risk Message 1: TIRF medicines are contraindicated in opioid non-tolerant patients. Formatted: Font: 12 pt AQuestion . Correct AnswerDc-sir-ed Formatted: Font: 12 pt No. response; Formatted: Font: 12 pt Please select True. False. or I don?t know for each of the following. According to 5 the labeling for TIRF medicines. patients with cancer who are considered opioid- Formatted: Font: 12 pt tolerant are those: Who are taking around-the-clock opioid therapy for 5a underlying. persistent cancer pain for one week or TRUE Formatted: Font: 12 pt longer 5b :N'ho are not currently takinkgcopiOid therapy. but FALSE med: Font: 12 pt uavc [11:1 UCLUIC Who have no known contraindications to the drug 5c fentanyl. but are not currently taking around-the- FALSE Formatted: Font: 12 pt clock opioid therapy Please answer True. False. or I don?t know for each statement based on the .7 Formatted: Font: 12 pt ?A?sni'm raucuus 1m]. mcuryuico. TIRF medicines are contraindicated in opioid non- 7a tolerant patients because life-threatening respiratory TRUE Formatted: Font: 12 pt A depression could occur at any dose. Death has occurred in opioid non-tolerant patients .71) TRUE Formatted: Fontucaicu Wlul DULIIC icurauyl 7e TIRF medicmes may be used to treat opioid non- FALSE med: Font: 12 pt ??-tolerarrt patients. Prescribers starting a patient on a TIRF medicine 7d must begin With titration from the lowest dose TRUE New Font. it A 12 Ft PlUUllLl. CVCH ll. [11: paucul has previously taken another TIRF medicine. Please select True. False. or I don?t know for each of the following. According Formatted: Space After: 0 pt, ljne spacing: to the labeling for TIRF medicinesI patients considered opioid-tolerant are angle those who are takin . for one week or lon er. at least: . . Formatted Table Formatted: Font: 12 pt Formatted Table Formatted: Centered 13am 8 mg oral hydromoghone/daw. Formatted: Font: 12 pt, Not Bold \[Formatted: Font: 12 pt ha Key Risk Message 2: TIRF medicines are only indicated for the management of breakthrough pain in adult cancer patients 18 years of age and older (16 years of age and older for Actiq? brand and generic equivalents) who are already receiving and who are tolerant to around-the- clock opioid therapy for their underl?ng, persistent cancer pain. Formatted: Font: 12 pt SW Question Desired response 9 Please answer True False. or I don?t know for each statement based on the labeling for TIRF medicines. According to the product labeling. a cancer patient may FALSE start a TIRF medicine and an arormd-the-clock opioid at the same time. According to the product labeling. a cancer patient who has FALSE been on an aromid-the-clock opioid for 1 day may start taking a TIRF medicine for breakthrough pain 9 In your practice. for which of the following indications do you prescribe TIRF Formatted: Font: 12 pt medicines to opioid tolerant patients? Please answer Yes. No. or I don?t know for each option. pa Acute or postoperative pain N0 Formatted: Font: 12 pt pb Headache or migraine pain N0 Formatted: Font: 12 pt 2e Dental pain NO Formatted: Font: 12 pt 9d Breakthrough pain from cancer YES Formatted: Font; 12 pt 9e Chronic non-cancer pain N0 Matted: Font: 12 pt inab- Adult ?If Formatted: Font: 12 pt female with localized breast cancer: just The patients described are experiencing breakthrough pain. completed a According to the labeling. a TIRF medicine is not mastectomy and . . . W16 Wt reconstructive Formatted: Font: 12 pt receive a TIRF medicine? Please select one option. surgery: cancer pain managed with 30 mg oral morphine daily for the past 6 weeks. 20 Before initiating treatment with a TIRF medicine, prescribers must review the Medicatiop Guide with the patient. Please select True. Fa_lse. or I don?t know for each of the following c01mselin2 statements. Infonn patients that TIRF medicines must not be used for acute or postoperative pain: pain from injuries, headache/migraine. or any other short-tenn pain. TRUE patients that they can continue to take their TIRF medicinea if they stop taking their around-the-clock opioid medicine. FALSE Formatted: Space After: 0 pt, Line spac?ng: single Eel: Risk Message 3: TIRF medicines contain fentanyl. an opioid agonist and a Schedule II- Fonnatted: Font: 12 pt controlled substance. with abuse liability similar to other opioid analgesics. . Correct Question A Formatted: Font: 12 pt No question Amara-mul? Formatted: Font: 12 pt Please answer True. False. or I don?t know for each statement based on the A7 CA.- Tm?c' MAA:n:nnl-I matted: 12 It IGUVIIJJE In? Luvulyuuro. It is im ortant to monitor for si of abuse and addiction ?7e . p? Tn?, Jig? TRUE Formatted: Font: 12 pt Lu paucula WLIU tan: 1m]. mcuuduco. Which of the following are risk factors for opioid abuse? Please answer Yes. No. M- I ?wk ?tum. Formatted: Font: 12 pt 1 MUW LUI vayu vyuvu. Asa A personal history of illness YES Formatted: Font: 12 pt A personal history of past or current alcohol or drug abuseYES Fonnatted: Font: 12 pt history of illicit drug use or alcohol abuse Please answer True. False. or I don?t know for each statement based on the 12-141 mun? c? Tm, Formatted: Font: 12 pt 11 atted- m. 12 It TIRF medicines can be abused in a manner similar to other 123% WW3 TRUE Fonnatted: Font: 12 pt Formatted: Line spadng: single Key Risk Message 4: TIRF medicines are not interchangeable with each other. regardless of Formatted: 12 pt route of administration. Question A . . Formatted: 12 pt question?W ho. Please answer True. False. or I don?t know for each statement based on the labeling 240? .. Formatted: 2 12 Lu]. 1. 1m TIRF med'cines are interchan eable w'th each other with ?mi; 1 FALSE Formatted: 12 pt ILEGIUILBO U1 U1 The conversion of one TIRF medicine for another TIRF mug medicine may result in a fatal overdose because of TRUE Formatted: 12 pt differences in the pharmacokinetics of fentanyl absorption. Dosin of TIRF medicines is not uivalent on a 12?1? .2 mg.? 1. - TRUE /{Formatted: 12 pt Udblb. @4451 The Formatted: 12 pt prescriber must not convert to another A patient is already taking a TIRF medicine but wants to TIRF medicine on a change their medicine. His/her doctor decides to prescribe a microgram-per- different TIRF medicine that is not a bioe uivalent eneric micro basis 1?6-14 :n ?n ?gm ?m gra Formatted: 12 pt 01? An A wyauau uu. a? ?pnminn AAnAin \ulDlUu VI. (1 lell?l) In 113 Flabb. LIKE labeling. how should the prescriber proceed? Please select one option. medicines have different absorption properties and this could result in a fentanyl overdose. a Formatted: Une spadng: single Formatted: Font: Bold 4.1.3 Additional Questions The survey includes questions about the requirements of the TIRF REMS Access Program and receipt and understanding of the TIRF educational materials and the Patient-Prescriber Agreement Form. The following question about behaviors will be asked a?er the key risk message questions: Question How frequently do you perform the following activities when prescribing TIRF medicines? Please answer Always, Only with the first prescription, Sometimes, Never, or I don?t know. Ask patients (or their caregivers) about the presence of children in the home Instruct patients (or their caregivers) not to share TIRF medicines with anyone else Counsel patients (or their caregivers) that accidental exposure to TIRF medicines by a child may be fatal Instruct patients (or their caregivers) to keep TIRF medicines out of the reach of children to prevent accidental exposure Instruct patients (or their caregivers) about proper disposal of any unused or partially used TIRF medicines Give patients (or their caregivers) the Medication Guide for their TIRF medicine Demographic information will be collected at the end of the survey. 4.2 Participant Recruitment A random sample of prescribers who are enrolled in the TIRF REMS Access Program will be Formatted: Left invited to participate via an invitation letter. The text of the sample written invitation to prescribers can be found in Appendix B. If the required number of completed surveys is not achieved within the expected timefrarne of approximately one to two weeks alter the ?rst mailing. reminder letters will be sent to non-responders from the original sample with subsequent fax. e-mail. or United States (US) Mail follow-up to maximize participation. The distribution within the mailing to the second sample will be adjusted in accordance with the allocation in the original sample. If these efforts do not result in the required munber of surveys within two to three weeks. then a new sample of prescribers will be randomly selected. All respondents who complete the survey and who provide their contact information will be mailed a $125 honorarium to thank them for their participation. Prescribers who practice in Vermont. Massachusetts. or Minnesota and complete the survey will not receive compensation. Participants will be informed that prescribers from these states are eligible to participate. but they will not receive compensation for their participation. The mailing will also include a Thank You Letter. a copy of the Important Safety Information (181). and a copy of the correct answers to key risk message questions. 4.2.1 Measures to Minimize Bias in the Sample The sample of prescribers who are invited to participate will be a random sample of all enrolled prescribers. The sample of participating prescribers will be self-selected since respondents will voluntarily respond to the invitation to participate; however, the survey recruitment strategies are intended to recruit a heterogeneous sample of prescribers for participation. Prescribers will be offered online or telephone options for completing the survey. Multiple modalities for survey data collection allow for wider survey access to a more heterogeneous population. Respondents will be provided a unique code during the recruitment process and will be asked to provide the unique code to gain access to the online survey or when calling the Survey Coordinating Center. The code will be deactivated after use to minimize the possibility for fraud. 5. STUDY POPULATION 5.1.1 Sample Size A sample of 300 healthcare providers who are enrolled in the TIRF REMS Access Program is proposed for each survey wave. The size of the sample was determined based on both practical and statistical considerations. There is no target comprehension rate specified a priori. A sample of 300 completed surveys will allow estimation of the comprehension rate for each risk message with a moderately high degree of precision. The table below shows the precision of the estimates for level of understanding using two-sided 95% confidence intervals (CIs) obtained with the sample size of 300 completed surveys. The noted CIs are used to indicate that for any survey-estimated rate of understanding, the true population rate of understanding is at least as high as the lower limit of the 95% CI and may be as high as the upper limit of the 95% CI. FDA_3573 Table 5.1: Precision of Estimated Rates of Understanding with a Sample Size of 300 Estimated Rate of Understanding 5% 10% 15% 20% 25% 30% 35% 40% 45% 50% 55% 60% 65% 70% 75% 80% 85% 90% 95% 5.1.2 Estimated Confidence Interval 2.8% 6.8% 11.2% 15.6% 20.2% 24.9% 29.6% 34.4% 39.3% 44.2% 49.2% 54.2% 59.3% 64.5% 69.7% 75.0% 80.4% 86.0% 91.9% 8.1% 14.0% 19.6% 25.0% 30.3% 35.5% 40.7% 45.8% 50.8% 55.8% 60.7% 65.6% 70.4% 75.1% 79.8% 84.4% 88.8% 93.2% 97.2% Inclusion Criteria All prescribers who are enrolled in the TIRF REMS Access Program are eligible to participate in this survey, with the exceptions noted below. 5.1.3 Exclusion Criteria The following respondents are not eligible to participate in the surveys: 6. • Prescribers who have previously participated in the TIRF REMS KAB survey • Prescribers or their immediate family members who have ever worked for ever worked for Actavis Laboratories FL, Inc.; Anesta LLC; BioDelivery Sciences International, Inc. (BDSI); Cephalon, Inc. (a wholly-owned subsidiary of Teva Pharmaceutical Industries, Ltd); Depomed, Inc.; Galena Biopharma, Inc.; Insys Therapeutics, Inc.;; Mallinckrodt Pharmaceuticals; Meda Pharmaceuticals; Mylan, Inc.; Par Pharmaceutical, Inc.; Teva Pharmaceuticals, Ltd.; UBC; McKesson Specialty Care Solutions; RelayHealth; or the FDA. SURVEY PROCESS The survey will begin with screening questions to confirm respondent eligibility to participate in the survey. Completion of the entire survey is expected to take approximately 20 minutes. FDA_3574 6.1 Screening and Survey Administration The questionnaire will begin with a screening module with questions to confirm prescriber eligibility. Depending on the answers to the screening questions, survey participation could either be terminated or continued. If ineligible, the respondent is immediately notified with a “thank you” message that survey participation has ended. If eligible, the respondent is allowed to continue survey participation. The data entry system used for both methods of survey administration has been validated and is secure for receiving and storing survey data. The system is 21 CFR Part 11 and Health Insurance Portability and Accountability Act (HIPAA) compliant. Prescriber-identifying information will be stored separately from survey data. 6.1.1 Telephone A trained interviewer from the Survey Coordinating Center will conduct the telephone interviews using a CATI program. The screening and main elements of the questionnaire will be administered sequentially during the same telephone call. Telephone interviewing allows participation of prescribers who do not have Internet access. It will also be convenient for prescribers to participate since they can call in and be interviewed at their convenience during the specified time period when the Survey Coordinating Center is available. 6.1.2 Internet An Internet-based survey system will also be used for conducting the KAB surveys. If the prescriber selects to participate in the survey online, he/she will be directed to a secured website to complete screening questions. An Internet survey will be convenient for respondents to participate since they can complete the questionnaire at any time. 6.2 Measures to Minimize Bias in the Survey Process A number of controls will be in place to ensure the survey is conducted in a controlled and professional manner and to minimize bias. For example, a unique code will be given to each survey participant and the code will be inactivated after use to minimize fraud. Telephone interviewers are highly trained and use a standardized script to administer the survey. All questions will be programmed to ensure that questions are asked in the appropriate sequence. Skip patterns will be clearly indicated. Respondents cannot go back to a question once the question has been answered and cannot skip ahead. All questions must be answered in order to complete the survey. Response options presented in a list will be randomized to minimize positional bias. Programming will be reviewed by quality control and simulated users (User Acceptance Testing) prior to implementing the survey. FDA_3575 7. ANALYSIS Information obtained from the survey will be reported as descriptive statistics for the survey administration, study population, and the survey questions. The data from the sample population will be reported using frequency distributions of responses to all questions. The following will be reported as part of this analysis: • The number of invitations issued to prescribers • The number of reminder letters • The number of respondents screened for participation • The number of respondents eligible for participation • The number of respondents eligible for participation who complete the survey • Representativeness of prescribers based on geography • Description of survey participants, including: − Gender − Medical degree of respondent: MD, DO, NP, PA − Medical specialty − Years of professional experience − How many times per month TIRF medicines prescribed in the last 6 months − Geographic region of practice Additional descriptive statistics may be reported as appropriate. 7.1.1 Analysis Population The analysis population will be based on eligible prescribers who completed all questions presented to them in the survey (“completers”). 7.1.2 Description of Primary Analyses Primary analyses are done for all key risk messages using data from all completers. The primary analysis for a key risk message evaluates the rate for each correct response to each individual question/item defined by the key risk message. The specific correct response to each question/item is identified in the body of the risk message table. FDA_3576 7.1.3 Description of Secondary Analyses Secondary analyses are done only for those key risk messages that contain multiple questions/items using data from all completers. The secondary analysis entails a frequency distribution of the number of respondents who got 0, 1, etc. correct responses across the total number of items for the given key risk message. 8. SAFETY EVENT REPORTING The term ‘Safety Event’ is defined as any information reported by a survey respondent that meets the criteria of an adverse event or product complaint. While it is not the intention of the survey to solicit the report of information that meets the criteria of a Safety Event, it is possible that a respondent may spontaneously report information that meets this criteria in free text fields of the survey (Internet-based administration) or while in conversation with the Survey Coordinating Center (telephone-based administration). The Internet-based questionnaires will be monitored for any comments recorded in the free text fields. If an event is mentioned to a Survey Coordinating Center Associate, the Associate will document the safety event and the respondent’s contact information. Respondents will also be informed that a representative from the appropriate TIRF medicine manufacturer may contact them if there are questions about the survey. Information on all reports (Internet or telephone) that may constitute an adverse event or other safety event will be forwarded to the appropriate TIRF medicine manufacturer as described in the Safety Event Project Specific Procedure (SE PSP). Additional detail regarding processes for adverse event reporting will be specified in the SE PSP. 9. PRIVACY PROTECTION AND CONFIDENTIALITY All data collected during the survey will be held confidential. The electronic data capture (EDC) system used for data collection encrypts all identifiable information, and respondent identifiers are stored separately from the survey responses. Respondent names and addresses are collected in order to mail the $125 honorarium, a Thank You Letter, the correct responses to key risk messages, and the ISI after the survey is completed. Respondent contact information is also requested when necessary to comply with a federal or state law or regulation, including without limitation, reporting payments made to physicians under the federal physician payment sunshine provisions in addition to instances where a safety event is reported and a TIRF medicine manufacturer must obtain follow-up information (see Section 8 above). Respondents will be informed when they access the survey that they may be contacted if there are any questions about their survey responses. Respondents will be informed that their answers to the survey questions will not affect their ability to prescribe TIRF medicines. FDA_3577 Appendix A Prescriber Questionnaire Suwey Legend is used to indicate directions to the programmer and is set in bold. red. uppercase letters between square brackets. (INTERVIEVVER) is used to indicate directions to the telephone interviewer and is set in bold. blue. text between parentheses. This text appears when content is to be administered by telephone only (for example. spontaneous adverse event reporting). I indicates a question is worded speci?cally for administering the survey online. 0 indicates a question is worded speci?cally to be read by a telephone interviewer and differs from the online text. 0 SURVEY and SURVEY are used to indicate to the programmer the type of survey administration and the beginning and end of the survey or sections within the survey content. for example. GIN ADVERSE and ADVERSE is displayed next to responses that should cause the survey to end. The following termination language will be programmed into the survey or read by the interviewer unless different language is speci?ed with the question. I Thank you very much for your time today. Based on your answer, you are not eligible Formatted: Indent: Le?: 0.25" to take this survey. We appreciate your interest in the survey. 0 is inserted before questions to indicate to the programmer that the responses should be randomized. Responses such as don?t know." ?Prefer not to answer? or ?None of the above" will always appear at the end of the randomized responses. 0 Response options for questions that allow multiple responses must be indicated with check boxes At least one option must be selected for the question to be considered answered. 0 If any response option requires text to be collected and does not need another question label. show after the response 0 Response options for questions that allow only one response must be indicated with radio Survey Legend buttons (○). • If any response option requires text to be collected and does not need another question label, show [FREE TEXT] after the response option, if applicable. • [FREE TEXT] indicates to the programmer that one line should be provided for data entry. • [MULTILINE INPUT] indicates to the programmer that multiple lines should be provided for data entry (for example, two address lines). • [DROP-DOWN LIST INPUT WITH STATES TABLE] indicates to the programmer that the response should be a drop-down list containing the states and US territories in the table below. Alabama Georgia Massachusetts New York Tennessee Alaska Guam Michigan North Carolina Texas American Samoa Hawaii Minnesota North Dakota Idaho Mississippi Arizona Illinois Missouri Arkansas Indiana Montana Northern Mariana Islands US Virgin Islands California Colorado Connecticut Delaware District of Columbia Florida Iowa Kansas Kentucky Louisiana Maine Maryland Nebraska Nevada New Hampshire New Jersey New Mexico Utah Vermont Ohio Virginia Oklahoma Washington Oregon West Virginia Pennsylvania Wisconsin Puerto Rico Wyoming Rhode Island South Carolina South Dakota • The following is used to categorize survey populations into standard geographic regions but it is not displayed in the survey. Geographic Distribution (based on address) 1: Northeast, Midwest, South, and West regions Northeast Region − New England Division - ME, NH, VT, MA, RI, CT − Middle Atlantic Division - NY, NJ, PA FDA_3579 Survey Legend Midwest Region − East North Central Division - OH, IN, IL, MI, WI − West North Central Division - MN, IA, MO, ND, SD, NE, KS South Region − South Atlantic Division - DE, MD, DC, VA, WV, NC, SC, GA, FL − East South Central Division - KY, TN, AL, MS − West South Central Division - AR, LA, OK, TX West − Mountain Division - MT, ID, WY, CO, NM, AZ, UT, NV − Pacific Division WA, OR, CA, AK, HI • The following US territories are categorized as Other: Puerto Rico, Northern Mariana Islands, US Virgin Islands, American Samoa, and Guam. 1 U.S. Census Bureau, last revised Friday, 27-Jul-2001 12:59:43 EDT. FDA_3580 [BEGIN SURVEY CONTENT] [BEGIN ONLINE PREAMBLE 1] Before you begin, we would like to share some important information about this survey. The manufacturers of Transmucosal Immediate Release Fentanyl (TIRF) medicines are conducting this survey, as required by the FDA, to assess prescribers’ understanding of the safe use and prescribing of these medicines. These medicines are known as rapid onset opioids and referred to in this survey as “TIRF medicines.” The TIRF medicines include Abstral®, Actiq®, Fentora®, Lazanda®, Onsolis®, Subsys®, and generic versions of any of these brands. The manufacturers of these medicines include Actavis Laboratories FL, Inc.; BioDelivery Sciences International, Inc. (BDSI); Cephalon, Inc. (a wholly-owned subsidiary of Teva Pharmaceutical Industries, Ltd.); Depomed, Inc.; Galena Biopharma, Inc.; Insys Therapeutics, Inc.;; Mallinckrodt Pharmaceuticals; Meda Pharmaceuticals; Mylan, Inc.; and Par Pharmaceutical, Inc. The survey will take approximately 20 minutes. There are no known risks to you in taking this survey. You may refuse to take part or withdraw at any time. Your answers to the questions or your decision to take part in the survey will not affect your ability to prescribe TIRF medicines. How We Use Your Information Your answers to the survey questions will be combined with answers given by other healthcare professionals taking the survey. All answers will be put together and reported in anonymous form to the manufacturers of TIRF medicines. Your name will not be used in any report. If you are eligible to take the survey, complete all the questions, and provide your contact information, you will receive a $125 honorarium for your time and participation. This compensation represents the fair value for your services in connection with completion of the survey. The amount of the compensation was not determined in any manner that takes into account the volume or value of any referrals or business otherwise generated by you. Your name and address will be used to send you the honorarium after you complete the survey. Your personal information will also be used if we have questions about your survey or if we are required to use your information to comply with a federal or state law or regulation, including without limitation, reporting payments made to physicians under the federal physician payment sunshine provisions. Physicians who practice in Vermont, Massachusetts, or Minnesota should be aware that they will not be permitted to receive payment for survey completion and may elect not to complete the survey. Providing a telephone number is optional. Your telephone number will be used only if there are any questions about your survey responses. How We Protect Your Privacy We respect that the privacy of your personal information is important to you. You will not be contacted for marketing purposes based on your personal information or your answers to the survey. Neither the manufacturers of TIRF medicines nor their contractors will sell, transfer, or rent your information. Your answers will be kept strictly confidential. Your personal FDA_3581 information will not be used in a manner inconsistent with this document. Your privacy will be protected; however, research survey records may be inspected by the FDA. Your choice to allow manufacturers of TIRF medicines to use your information is entirely voluntary but necessary to take part in this survey. How to Learn More about This Survey If you have questions about the survey, or problems with the survey, please contact the Survey Coordinating Center at 1-877-379-3297. Be sure to write down this telephone number; it will not be displayed again. Taking the Survey Once you have answered a question and moved on, you cannot go back and change your answers. Thank you for your participation in this survey. [END ONLINE PREAMBLE 1] FDA_3582 [BEGIN PHONE PREAMBLE 1] Before you begin, we would like to share some important information about this survey. The manufacturers of Transmucosal Immediate Release Fentanyl (TIRF) medicines are conducting this survey, as required by the FDA, to assess prescribers’ understanding of the safe use and prescribing of these medicines. These medicines are known as rapid onset opioids and referred to in this survey as “TIRF medicines.” (INTERVIEWER: Say “TIRF” then spell out T-IR-F) The TIRF medicines include Abstral®, Actiq®, Fentora®, Lazanda®, Onsolis®, Subsys®, and generic versions of any of these brands. The manufacturers of these medicines include Actavis Laboratories FL, Inc.; BioDelivery Sciences International, Inc. (BDSI); Cephalon, Inc. (a wholly-owned subsidiary of Teva Pharmaceutical Industries, Ltd.); Depomed, Inc.; Galena Biopharma, Inc.; Insys Therapeutics, Inc.;; Mallinckrodt Pharmaceuticals; Meda Pharmaceuticals; Mylan, Inc.;; and Par Pharmaceutical, Inc. The survey will take approximately 20 minutes. There are no known risks to you in taking this survey. You may refuse to take part or withdraw at any time. Your answers to the questions or your decision to take part in the survey will not affect your ability to prescribe TIRF medicines. Now I would like to read some information about how your contact information will be used. Your answers to the survey questions will be combined with answers given by other healthcare professionals taking the survey. All answers will be put together and reported in anonymous form to the manufacturers of TIRF medicines. Your name will not be used in any report. If you are eligible to take the survey, complete all the questions, and provide your contact information, you will receive a $125 honorarium for your time and participation. This compensation represents the fair value for your services in connection with completion of the survey. The amount of the compensation was not determined in any manner that takes into account the volume or value of any referrals or business otherwise generated by you. Your name and address will be used to send you the honorarium after you complete the survey. Your personal information will also be used if we have questions about your survey or if we are required to use your information to comply with a federal or state law or regulation, including without limitation, reporting payments made to physicians under the federal physician payment sunshine provisions. Physicians who practice in Vermont, Massachusetts, or Minnesota should be aware that they will not be permitted to receive payment for survey completion and may elect not to complete the survey. Providing a telephone number is optional. Your telephone number will be used only if there are any questions about your survey responses. Now I would like to tell you some information about how we protect your privacy. We respect that the privacy of your personal information is important to you. You will not be contacted for marketing purposes based on your personal information or your answers to the survey. Neither the manufacturers of TIRF medicines nor their contractors will sell, transfer, or rent your information. Your answers will be kept strictly confidential. Your personal FDA_3583 information will not be used in a manner inconsistent with this document. Your privacy will be protected; however, research survey records may be inspected by the FDA. Your choice to allow manufacturers of TIRF medicines to use your information is entirely voluntary but necessary to take part in this survey. Now I will tell you how you can learn more about this survey. Please have a pen or pencil ready to write down a telephone number you can call if you have any questions about the survey. If you have questions about the survey, please ask me at any time. If you have questions at a later time, please contact the Survey Coordinating Center at 1-877-379-3297. Please feel free to ask me to repeat any questions or statements as we go through the survey. Once you have answered a question and moved on, we cannot go back and change your answers. Thank you for your participation in this survey. [END PHONE PREAMBLE 1] FDA_3584 [BEGIN INCLUSION/EXCLUSION QUESTIONS] 1. Your agreement to participate in this survey confirms mutual understanding in connection with completion of the survey and the fair market value of the payment to be rendered in connection with those services. Do you agree to participate in this survey? 2. 3. 4. ○ Yes ○ No [TERMINATE] Have you ever taken part in this survey about TIRF medicines before? TIRF medicines include Abstral®, Actiq®, Fentora®, Lazanda®, Onsolis®, Subsys®, and generic versions of any of these brands. ○ Yes [TERMINATE] ○ No ○ I don’t know [TERMINATE] Are you enrolled in the TIRF REMS Access Program? ○ Yes ○ No [TERMINATE] ○ I don’t know [TERMINATE] Have you or any of your immediate family members ever worked for any of the following companies or agencies? Please select all that apply. □ Actavis Laboratories FL, Inc. [TERMINATE] □ Anesta LLC [TERMINATE] □ BioDelivery Sciences International, Inc. (BDSI) [TERMINATE] □ Cephalon, Inc. (a wholly-owned subsidiary of Teva Pharmaceutical Industries, Ltd.) [TERMINATE] □ Depomed, Inc. [TERMINATE] FDA_3585 □ Galena Biopharma, Inc. [TERMINATE] □ Insys Therapeutics, Inc. [TERMINATE] □ Mallinckrodt Pharmaceuticals [TERMINATE] □ McKesson Specialty Care Solutions [TERMINATE] □ Meda Pharmaceuticals [TERMINATE] □ Mylan, Inc. [TERMINATE] □ Par Pharmaceutical, Inc. [TERMINATE] □ RelayHealth [TERMINATE] □ Teva Pharmaceuticals, Ltd. [TERMINATE] □ United BioSource Corporation [TERMINATE] □ FDA [TERMINATE] □ None of these apply [IF SELECTED IN ADDITION TO OTHER RESPONSES, TERMINATE] □ I don’t know [TERMINATE] □ Prefer not to answer [TERMINATE] [END INCLUSION/EXCLUSION QUESTIONS] FDA_3586 5a. 5b. 5c. 6a. 6b. Please select True. False. or I don?t know for each of the following. According to the labeling for TIRF medicines. patients with cancer who are considered opioid-tolerant are those: True False I don?t know Who are taking around-the-clock opioid therapy for underlying. persistent cancer pain for one week or longer 0 0 Who are not currently taking opioid therapy. but have taken opioid therapy before 0 0 Who have no known contraindications to the drug fentanyl. but are not currently taking around-the-clock opioid therapy Please answer True. False. or I don?t know for each statement based on the labeling for TIRF medicines. True False I don?t know According to the product labeling. aA-?cancer patient may starteaa?be?started?ega TIRF medicine and an around- 0 the-clock opioid at the same time. According to the product labeling= a?cancer patient who has been on an around-the-clock opioid for 1 day Fonnatted: English Formatted: English Formatted: English Formatted: English mayeag start taking a TIRF medicine for breakthrough 0 pain. 7. Please answer True, False, or I don’t know for each statement based on the labeling for TIRF medicines. [RANDOMIZE LIST] TIRF medicines are contraindicated in opioid nontolerant patients because life-threatening respiratory depression could occur at any dose. 7b. Death has occurred in opioid non-tolerant patients treated with some fentanyl products. 7c. TIRF medicines may be used to treat opioid non-tolerant patients. 7d. Prescribers starting a patient on a TIRF medicine must begin with titration from the lowest dose available for that specific product, even if the patient has previously taken another TIRF medicine. 7e. It is important to monitor for signs of abuse and addiction in patients who take TIRF medicines. True False I don’t know ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ 7a. 8. Which of the following are risk factors for opioid abuse? Please answer Yes, No, or I don’t know for each option. [RANDOMIZE LIST] 8a. 8b. 8c. A personal history of psychiatric illness A personal history of past or current alcohol or drug abuse, or a family history of illicit drug use or alcohol abuse A family history of asthma Yes No I don’t know ○ ○ ○ ○ ○ ○ ○ ○ ○ FDA_3588 9. In your practice. for which of the following indications do you prescribe TIRF medicines to opioid tolerant patients? Please answer Yes. No. or I don?t know for each option. 9a. Acute or postoperative pain 9b. Headache or migraine pain 9c. Dental pain 9d. Breakthrough pain ?om cancer 9e. Chronic non-cancer pain tolerant patients? do you select a TIRF medicine to treat these chronic pain conditions in patients who are opioid tolerant? TIRF medicines. 4-991 TIRF medicines can be abused in a manner similar to other opioid agonists. I TIRF medicines are interchangeable with each other regardless of route of administration. I The conversion of one TIRF medicine for another TIRF medicine may result in a fatal overdose because of di?erences in the pharmacokinetics of fentanyl absorption. Yes No I don?t know 0 Formatted: Left, Indent: Left: 0.06', Space Before: 0 pt, No bullets or numbering Formatted Table iPrue False {-6094 matted?an Formatted: Font: 1 DISPLAY 910 and 911 ON SUBSEQUENT For type(s) of chronic pain conditions do you prescribe a TIRF medicine to opioid Please answer Tme= Falsea or I don?t know for each statement based on the labeling for True False Idon?t know 0 10d. Dosing of TIRF medicines is not equivalent on a microgramto-microgram basis. ○ ○ ○ FDA_3590 Please select True. False. or I don?t know for each of the following. According to the mad Table labeling for TIRF medicines. patients considered opioid-tolerant are those who are taking. for one week or longer. at least: True False I don?t know 4-1-81 8 mg oral hydromorphone/day 0 60 mg oral morphine/day 30 mg oral oxycodone/day 0 4-1-4- 25 transdermal fentanyl/hour 0 44+. 25 mg oral oxymorphone/day An equianalgesic dose of another oral opioid Formatted Table 4?1?1 How frequently do you perform the following activities when prescribing TIRF medicin 5. Please answer Always. Only with the first prescription. Sometimes. Never. or I don?t know. Always Only with Sometimes Never Idon?t know the ?rst prescription 4-3-81 Ask patients (or their caregivers) about the presence 0 of children in the home Eb: Instruct patients (or their caregivers) not to share TIRF medicines with anyone else He: Counsel patients (or their caregivers) that accidental exposure to TIRF medicines by a child may be fatal Instruct patients (or their caregivers) to keep TIRF medicines out of the reach of 0 children to prevent accidental exposure 4?241 Instruct patients (or their caregivers) about proper disposal of any unused or partially used TIRF medicines Give patients (or their caregivers) the Medication Guide for their TIRF medicine The patients described are experiencing breakthrough pain. According to the labeling. A mad Table a TIRF medicine is not appropriate for one of them. Which patient should not receive a TIRF medicine? Please select one option. LIST WITH I KNOW ALWAYS AT THE 4?3971 0 Adult male with advanced 11mg cancer: lmderlying persistent cancer pain managed with 25 mcg/hour transdermal fentanyl patches for the past two months. I 4?34?! 0 Adult female with localized breast cancer; just completed a mastectomy and reconstructive surgery: persistent cancer pain managed with 30 mg oral morphine daily for the past 6 weeks. I 4-we- _1 0 Adult male patient with advanced prostate cancer who. over the last 2 weeks. has been prescribed 100 mg oral morphine daily for pain due to bone metastasis. I +5611 0 Adult female with advanced sarcoma who has been taking a daily dose of 12 mg oral hydromorphone for the last 3 weeks. I 4-3921 0 I don?t know A patient is already taking a TIRF medicine but wants to change their medicine. His/her doctor decides to prescribe a different TIRF medicine (that is not a bioequivalent generic version of a branded product) in its place. According to the labeling. how should the prescriber proceed? Please select one option. LIST I KNOW ALWAYS AT THE I 4?1311 0 The prescriber can safely convert to the equivalent dosage of the new TIRF medicine as it has the same effect as other TIRF medicines. I +4le The prescriber must not convert to another TIRF medicine on a microgram-per- 0 microgram basis because these medicines have different absorption properties and this could result in a fentanyl overdose. I +4tL._l 0 Convert from the other TIRF medicine to the new TIRF medicine at half of the dose. I 4?1411 The prescriber should base the starting dose of the newly-prescribed TIRF 0 medicine on the dose of the opioid medicine used for their underlying persistent cancer pain. I 4-4134 Idon?t know. A patient is starting titration with a TIRF medicine. What dose must they start with? Please select one option. LIST I KNOW ALWAYS AT THE 4?21; I 449-; 0 An appropriate dose based on the dose of the opioid medicine used for underlying persistent cancer pain. I lib-l The dose that the prescriber believes is appropriate based on their clinical experience. I 4?5-9; 0 The lowest available dose. unless individual product Full Prescribing Information provides product-speci?c guidance. 4-5671 The median available dose. I don?t know. 1 A prescriber has started titrating a patient with the lowest dose of a TIRF medicine. However. after 30 minutes the breakthrough pain has not been sufficiently relieved. What should they advise the patient to do? Please pick the best option of the scenarios described. LIST I KNOW ALWAYS AT THE Formatted: Centered +6971 0 Take another (identical) dose of the TIRF medicine immediately. 0 Take a dose of an altemative rescue medicine. lee?l 0 Provide guidance based on the product-speci?c Medication Guide because the instructions are not the same for all TIRF medicines. 4-644 0 Double the dose and take immediately. 0 I don?t know. A patient is taking a TIRF medicine and the doctor would like to prescribe a CYP3A4 inhibitor. Please pick the best option of the scenarios described. LIST I ALWAYS AT THE Formatted: Centered The patient can?t be prescribed because using it at the same time as a TIRF medicine could be fatal. I 4549-. Use of a TIRF medicine with a CYP3A4 inhibitor may require a dosage adjustment: carefully monitor the patient for opioid toxicity. otherwise such use may cause potentially fatal respiratory depression. Fe There is no possible drug interaction between CYP3A4 inhibitors and TIRF medicines. I F6: The dose of the TIRF medicine must be reduced by one half if a CYP3A4 inhibitor is prescribed in the same patient. I 45+: 0 I don?t know. Before initiating treatment with a TIRF medicine, prescribers must review the Medication Guide with the patient. Please select True. False. or I don?t know for each of the following counseling statements. True False I Formatted: Centered know I +89; TIRF medicines contain fentanyl in an amount that could be fatal to children of all ages. in individuals for whom they were not prescribed. and in those who are not opioid tolerant. I +8497: Inform patients that TIRF medicines must not be used for acute or postoperative pain. pain from injuries. headache/migraine. or any other short-term pain. 4-8?2 Instruct patients that they can continue to take their TIRF medicine. if they stop taking their around- the- clock opioid W. +8147: Instruct patients to never share their TIRF medicine with anyone else. even if that person has the same 4% 9 ?es f- 140 /[ronnatted: English (U.K.) BEGIN 2 DISPLAY ON SANIE PAGE AS NEXT AThe next set of questions is about the educational materials for TIRF medicines and the Fonnatted: Font: Bold TIRF Patient-Prescriber Agreement. As a reminder, the TIRF medicines include Abstrals', Actiqs', Fentora?, Lazandas', and generic versions of any of Formatted: Font: Bold these brands. Did you receive or do you have access to the Full Prescribing Information for the medicine(s) that you prescribe? ○ Yes ○ No [GO TO Q23]Q22] ○ I don’t know [GO TO Q23]Q22] 21.22 Did you read the Full Prescribing Information for the TIRF medicine(s) that you prescribe? ○ Yes ○ No ○ I don’t know 22.23 Did you receive or do you have access to the Medication Guide for the TIRF medicine(s) that you prescribe? ○ Yes ○ No [GO TO Q25]Q24] ○ I don’t know [GO TO Q25]Q24] 23.24 Did you read the Medication Guide for the TIRF medicine(s) that you prescribe? ○ Yes ○ No ○ I don’t know 24.25 Did you or do you have any questions about the information in the Full Prescribing Information or Medication Guide? ○ Yes ○ No [GO TO Q27Q26] ○ I don’t know [GO TO Q27Q26] [IF QUESTION 26 = YES, DISPLAY ON SAME PAGE] FDA_3596 What are your questions? Do you review the Patient-Prescriber Agreement Form With each of your patients for whom you prescribe TIRF medicines or their caregiver? 0 Yes 0 No TO DENIOGRAPHICS 11928} I don?t know TO DENIOGRAPHICS PREANIBLE 1 Q2v8-} Formatted: Space After: 0 pt, Une spac?ng: single Do you and the patient or their caregiver sign the Patient-Prescriber Agreement Form for TIRF medicines after you have reviewed it with him/herdon?t know Do you give a copy of the Patient-Prescriber Agreement Form for TIRF medicines to the patient or their caregiverdon?t know PREANIBLE - DISPLAY ON SAME PAGE NEXT AThere are just a few more questions to help us combine your answers with other answers Formatted: Font: de we have received, /[Formatted: Font: Not Bold DENIOGRAPHICS PREAMBLE 1 90?1) On average. how many times per month have you prescribed the TIRF medicines within the last 6 months? 0 None TO 2] 2 times per month 0 3 5 times per month 0 More than 5 times per month 0 I don?t remember 39-3_1 Please select the TIRF medicines that you have prescribed within the last 6 months. Please select all that apply. Abstra1? Actiq? or generic ActiqQ Fentoraa Lazanda? a Ms SubsysO DENIOGRAPHIC PREANIBLE 2 - DISPLAY ON SAME PAGE NEXT [These last few questions are for demographic purposes, Formatted: Font: Bold \[Formattaed: Font: Not Bold IEND DEMOGRAPHICS PREAMBLE 2 3+3_2 What is your gender? 0 Male 0 Female 0 Prefer not to answer What is your medical degree? 0 MD 0 DO 0 Nurse Practitioner 0 Physician Assistant 0 Prefer not to answer Formatted: English In total. how many years have you been practicing medicine, since completing your education? 0 Less than 3 years 0 3 5 years 0 6 10 years 0 ll 15 years 0 More than 15 years 0 Prefer not to answer Do you practice in a closed healthcare system, such as: VA or 0 Yes N2 Formatted: English (U.K.) In which state do you practice? LIST INPUT WITH STATES TABLE WITH ?Prefer not to answer? at What is your medical specialty? 0 Oncology 0 Primary care 0 Pain management 0 Other (please specify): No designated specialty BEGIN ADVERSE ONIPLAINT KEEP ON ONE (INTERVIEWER: Please record if respondent spontaneously reported an adverse event or product complaint during the course of this interview.) 0 Yes ○ No [GO TO CLOSING 1] Enter Safety Adverse Event Verbatim [MULTILINE INPUT] (INTERVIEWER: Indicate to the respondent that someone may call back to ask more questions about the adverse event or product complaint that was reported.) [END ADVERSE EVENT/PRODUCT COMPLAINT] [BEGIN CLOSING 1 – KEEP ON ONE PAGE] We would like to send you a $125 honorarium within the next few weeks to thank you for your time, but we need your name and address to do so. If you do not provide your name and address you will not receive the honorarium for your time and participation in the survey. As a reminder, physicians who practice in Vermont, Massachusetts, or Minnesota should be aware that they will not be permitted to receive payment for survey completion. Do you agree to give us your name and mailing address so we can send you the honorarium? ○ Yes ○ No [GOSKIP TO CLOSING 2] FIRST NAME: [FREE TEXT] LAST NAME: [FREE TEXT] ADDRESS: [MULTILINE INPUT] CITY: [FREE TEXT] STATE: [DROP-DOWN LIST INPUT WITH STATES TABLE] ZIP: [MUST BE 5 NUMERIC CHARACTERS ONLY] [END CLOSING 1] FDA_3602 2 KEEP ON ONE W'e would also like to ask for your telephone number. Providing your telephone number is optional and it will be used to contact you only if there are questions about your survey responses. Do you want to provide your telephone number? 0 Yes No T0 CLOSING 3] Telephone: BE CLOSING 2] CLOSING 3] AThat ends the surveyuThank you again for your help.? Fonnatted: Font: Bold Formatted: Font: Bold CLOSING 3 atted: Font: Edd SURVEY Appendix SAMPLE Prescriber Invitation Letter Fonnatted: Bottom: 0.69' Dear You were selected to receive this letter because you have enrolled in the TIRF REMS Access Program. We are contacting you to invite you to participate in a survey being conducted by the manufacturers of Transmucosal Immediate Release Fentanyl (TIRF) medicines. as required by the Food and Drug Administration (FDA). The purpose of the survey is to assess prescribers? understandin% of the safe and appropriate use of these medicines. The TIRF medicines include Abstralo. Actiq . Fentorao. Lazandao. and generic versions of any of these brands. The manufacturers of TIRF medicines (collectively referred to as the REMS Industry -Group") include Actavis Laboratories FL. Inc.: BioDelivery Sciences International. Inc. Formatted: Font: 12pt Cephalon. Inc. (a wholly-owned subsidiary of Teva Pharmaceutical Industries. Ltd): Depomed. Inc.: Galena Biopharma. Inc.: Insys Therapeutics Inert Mallinckrodt Pharmaceuticals: Merle WMylan. Inc.. and Par Phamraceutical. Inc. These manufacturers are looking for 300 prescribers to complete the survey. Eligible prescribers who complete the survey will be sent a $125 honorarium to thank them for their time. The survey will take 15-20 minutes. Your answers will be kept strictly con?dential and will be combined with the answers from other prescribers who take this survey. Your name will not be used in the report of this survey and your contact information will only be used to send you a $125 honorarium for the time you took to complete the survey and if required to comply with a federal or state law or regulation. including without limitation. reporting payments made to physicians under the federal physician payment sunshine provisions. Prescribers who practice in Vermont. Massachusetts. or Minnesota should be aware that they will not be pemiitted to receive payment for survey completion and may elect not to complete the survey. You are under no obligation to participate in this survey. If you are interested in participating. go to wwa'IRFREMSsun'evmcom anytime or call 1-877-379-3297, 8AM to 8PM Eastern Time Monday through Friday. You will be asked to give this luiique code prior to starting the survey: We recommend that you take the survey on a desktop or laptop computer. Taking the survey on mobile devices. such as smart phones. tablets. and e-notebooks. is not supported. Please have this letter with you at the time you take the survey. Thank you in advance for your help with this important effort. Sincerely. The TIRF REMS Survey Team 1-877-3 79-3297 Formatted: Space After: 12 pt, Line spac?ng: At least 14 pt Prescriber KAB Assessment Report Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Appendix B Page 63 of 63 Prescriber Survey Listings and Stratified Analyses Tables Listing 1.1 and Listing 2.1 includes individual responses to Question 10 (For what type(s) of chronic pain conditions do you prescribe a TIRF medicine to opioid tolerant patients?), and Question 11 (Why do you select a TIRF medicine to treat these chronic pain conditions in patients who are opioid tolerant?), respectively. Aggregate data for Question 10 is provided in Table 9 and aggregate data for Question 11 is provided in Table 10. The verbatim responses are provided unedited as submitted by the prescriber. FDA_3606 TRIG Page 1 of TIRF Prescriber KAB 03DEC2015 Table 1.1: Survey Administration Statistics Parameter, Number of invitations distributed 8210 Nlunber of invitations returned as Imdeliverable 437 Number of reminder letters distributed 19215 All Respondentsm 587 (7.6) Eligible Respondentsm 350 (59.6) Completed surveym 310 (88.6) Did not complete the surveym 40 (11.4) Respondents not eligiblemm 237 (40.4) Number of respondents who accessed the survey. Percentage is based on the number of invitations distributed excluding the number of invitations returned as undeliverable. Percentage is based on the number of all respondents. 31 Percentages are based on the number of eligible respondents. Number of respondents who did not meet eligibility criteria or did not complete eligibility questions. Data Source: ADPQ Program: TSADMSAS TRIG Page 1 of 2 TIRF Prescriber KAB 03DEC2015 Table 1.2: Survey Participant Eligibility Results All Respondents Prescribers Question Question 1: Do you agree to participate in this survey? Yes 485 (82.6) Now 4 (0.7) Discontinued 98 (16.7) Question 2: Have you ever taken part in this survey about TIRF medicines before? TIRF medicines include Abstral?, Actiq?, Fentora?, Lazanda?, Subsys?, and generic versions of any of these brands. Yes?1 30 (5.1) No 399 (68.0) I don't know? 56 (9.5) Question not asked 4 (0.7) Discontinued 98 (16.7) Question 3: Are you enrolled in the TM REMS Access Program? Yes 366 (62.4) Now 17 (2.9) I don't known] 14 (2.4) Question not asked 90 (15.3) Discontinued 100 (17.0) Question 4: Have you or any of your immediate family members ever worked for any of the following companies or agencies? Please select all that apply. Actavis Laboratories FL. Incl? (0.2) Anesta. 0 BioDelivery Serxices International. Inc. 0 Cephalon. Inc. (a wholly-owned subsidiary of Tex-?a Pharmaceutical Industries. Ltd.)m 3 (0.5) Depomed. Inc.[? 0 Galena Biophanna. 111cm 0 Insys Therapeutics. hlc.[1] 5 (0.9) Mallinckrodt 0 McKesson Specialty Care Solutionsm 0 Mylan. Incl? 0 Data Source: ADPQ, ADTQ Program: TRIG Page 2 of 2 TIRF Prescriber KAB 03DEC2015 Table 1.2: Survey Participant Eligibility Results - All Respondents Prescribers Question 11 Par Pharmaceutical. Inem 0 RelayHealthm 0 Teva Pharmaceuticals. 2 (0.3) United BioSource Corporationm 0 0 None of these 350 (59.6) I don't known] 3 (0.5) Prefer not to answerm 3 (0.5) Question not asked 121 (20.6) Discontinued 100 (17.0) Ineligible to participate in the survey. Question not asked due to previous question termination. Ineligible to participate in the survey if selected in addition to another response. Note: Respondents who discontinued the survey before completing all eligibility questions without being identi?ed as ineligible in any of the preVious questions are counted as discontinued. Once a respondent is comited as discontinued. they will count as discontinued in all subsequent eligibility questions. Data Source: ADPQ, ADTQ Program: TRIG Page 1 of TIRF Preseriber KAB 03DEC2015 Table 1.3: Time to Complete Survey Completed Surveys Telephone Internet Total Summary Statistic (minutes) 7 303 3 10 Mean (SD) 25.37 (4.816) 16.33 (7.797) 16.54 (7.853) Minimum 20. 1 4.0 4.0 Median 25.05 15.00 15.10 Maxinnun 35.3 60.4 60.4 Category, 11 0 to <5 Minutes 0 5 to <10 Minutes 0 59 59 10 to <15 Minutes 0 91 91 15 to <20 Minutes 0 85 85 20 to <25 Minutes 3 37 4O 25 to <30 Minutes 3 12 15 30 Minutes or more 1 18 19 Data Source: ADPQ Program: 0 TRIG Page 1 of 2 TIRF Prescriber KAB 03DEC2015 Table 2: Description of Eligible Prescribers Completed Surveys Prescribers Question 11 Question 30: On average, how many times per month have you prescribed the TIRF medicines within the last 6 months? None 77 (24.8) 1 - 2 times per month 154 (49.7) 3 - 5 times per month 49 (15.8) More than 5 times per month 17 (5.5) I don't remember 13 (4.2) Question 31: Please select the TIRF medicines that you have prescribed within the last 6 months. Please select all that apply.m Abstral? 26 (11.2) Actiq? or generic Actiq? 137 (58.8) Fentora? 94 (40.3) Lazanda? 22 (9.4) Subsys? 105 (45.1) (Anm'ered "None" to Question 30) 77 Question 32: What is your gender? Male 192 (61.9) Female 116 (37.4) Prefer not to answer 2 (0.6) Question 33: What is your medical degree? MD 178 (57.4) DO 26 (8.4) Nurse Practitioner 68 (21.9) Physician Assistant 3 5 (11.3) Prefer not to answer 3 (1.0) Question 34: In total, how many years have you been practicing medicine, since completing your education? Less than 3 years 41 (13.2) 3 - 5 years 38 (12.3) 6 - 10 years 71 (22.9) Data Source: ADPQ, ADTQ Program: TDESC.SAS 1 TRIG Page 2 of 2 TIRF Prescriber KAB 03DEC2015 Table 2: Description of Eligible Prescribers Completed Surveys Prescribers Question 11 11 - 15 years 51 (16.5) More than 15 years 107 (34.5) Prefer not to answer 2 (0.6) Question 35: Do you practice in a closed healthcare system, such as: VA, or Yes 14 (4.5) No 296 (95.5) Geographic Distribution (based on Question 36 - In which state do you practice?)m Northeast 70 (22.6) Midwest 46 (14.8) South 97 (31.3) West 95 (30.6) Other 1 (0.3) Prefer not to answer 1 (0.3) Question 37: What is your medical specialty? Oncology 65 (21.0) Primary care 28 (9.0) Pain management 151 (48.7) Other (please 65 (21.0) No designated specialty 1 (0.3) Percentages are calculated based on the sample presented with this question because of skip logic in the survey. US Census Bureau. last revised Friday. 27-Jul-2001 12:59:43 EDT.. Geography Diw'sion. Northeast includes CT. MA. ME. NH. NJ. NY. PA. RI. and VT. Midwest includes LA. IL. IN. KS. MI. MN. MO. ND. NE. OH. SD. and WI. South includes AL. AR. DC. DE. FL. GA. KY. LA. MD. MS. NC. OK. SC. TN. TX. VA. and WV. West includes AK. AZ. CA. CO. HI. ID. MT. NM. NV. OR. UT. WA. and WY. Other includes Puerto Rico. Northern Mariana Islands. US Virgin Islands. American Samoa and Guam. Verbatim texts for question about medical specialty will be presented in Listing 4. Data Source: ADPQ, ADTQ Program: TDESCSAS 2 TRIG TIRF Prescriber KAB Page 1 of 03DEC2015 Table 2a: Comparison of Survey Respondents to General Population of TIRF Prescribers Prescribers of Eligible/Completed TIRF Medicines Prescribers in the Past 6 Months?! Question 11 Geographic Distributional Northeast 70 (22.6) 1854 (21.0) Midwest 46 (14.8) 1532 (17.4) South 97 (31.3) 3047 (34.6) West 95 (30.6) 2374 (26.9) Other 1 (0.3) 5 (0.1) Prefer not to answer 1 (0.3) 0 Based on data obtained from the TIRF REMS Access Program database. Based on Prescriber KAB Survey Question 36: US. Census Bureau. last revised Friday. 27-Jul-2001 12:59:43 EDT.. Geography Diu'sion. Northeast includes CT. MA. ME. NH. NJ. NY. PA. RI. and VT. Midwest includes IA. IL. IN. KS. MI. MN. MO. ND. NE. OH. SD. and WI. South includes ALSC. TN. TX. VA. and WV. West includes AK. AZ. CA CO. HI. ID. MT. NM. NV. OR. UT. WA. and WY. Other includes Puerto Rico. Northern Mariana Islands. US Virgin Islands. American Samoa and Guam. Note: Percentages are based on the prescribers with informative data. Data Source: ADPQ, ADTQ, Program: TTIRFPOPSAS 3 TRIG TIRF Prescriber KAB Page 1 of 8 03DEC2015 Table 3: Responses to All Questions about the Safe Use of TIRF Medicines Completed Surveys Question Prescribers Question 5: Please select True, False, or I don't know for each of the following. According to the labeling for TIRF medicines, patients with cancer who are considered opioid-tolerant are those: 5a: Who are taking around-the-clock opioid therapy for underlying, persistent cancer pain for one week or longer Truem 295 (95.2) False 14 (4.5) I don't know 1 (0.3) 5b: Who are not currently taking opioid therapy, but have taken opioid therapy before True 15 (4.8) Falsem 291 (93.9) I don't know 4 (1.3) 5c: Who have no known contraindications to the drug fentanyl, but are not currently taking around-the-clock opioid therapy True 33 (10.6) Falsem 269 (86.8) I don't know 8 (2.6) medicines. Question 6: Please answer True, False, or I don't know for each statement based on the labeling for TIRF opioid at the same time. 6a: According to the product labeling, a cancer patient may start a IRF medicine and an around-the-clock True 75 (24.2) Falsem 214 (69.0) I don't know 21 (6.8) may start taking a IRF medicine for breakthrough pain. 6b: According to the product labeling, a cancer patient who has been on an around-the-clock opioid for 1 do}: True 62 (20.0) Falsem 226 (72.9) I don't know 22 (7.1) medicines. Question 7: Please answer True, False, or I don't know for each statement based on the labeling for TIRF Data Source: ADPQ, ADTQ Program: TEX.SAS 4 TRIG TIRF Prescriber KAB Page 2 of 8 03DEC2015 Table 3: Responses to All Questions about the Safe Use of TIRF Medicines Completed Surveys Question Prescribers depression could occur at any dose. 7a: IRF medicines are contraindicated in opioid non-tolerant patients because life-threatening respiratory Truem 280 (90.3) False 23 (7.4) I don't know 7 (2.3) 7b: Death has occurred in opioid non-tolerant patients treated with some fentanyl products. Truem 298 (96.1) False 2 (0.6) I don't know 10 (3.2) 7c: IRF medicines may be used in opioid non-tolerant patients. True 38 (12.3) Falsem 263 (84.8) I don't know 9 (2.9) 7d: Prescribers starting a patient on a TIRF medicine must begin with titration from the lowest dose available for that specific product, even if the patient has previously taken another IRF medicine. Truem 265 (85.5) False 40 (12.9) I don't know 5 (1.6) 7e: It is important to monitor for signs of abuse and addiction in patients who take IRF medicines. Truem 306 (98.7) False 2 (0.6) I don't know 2 (0.6) know for each option. Question 8: Which of the following are risk factors for opioid abuse? Please answer Yes, No, or I don't 8a: A personal history of illness Yesm 262 (84.5) No 28 (9.0) I don't know 20 (6.5) abuse 8b: A personal history of past or current alcohol or drug abuse, or a family history of illicit drug use or alcohol Data Source: ADPQ, ADTQ Program: TEX.SAS 5 TRIG TIRF Prescriber KAB Page 3 of 8 03DEC2015 Table 3: Responses to All Questions about the Safe Use of TIRF Medicines Completed Surveys Prescribers Question 11 Yesm 306 (98.7) No 4 (1.3) I don't know 0 8c: A family history of asthma Yes 12 (3.9) No? 281 (90.6) I don't know 17 (5.5) Question 9: In your practice, for which of the following indications do you prescribe TIRF medicines to opioid tolerant patients? Please answer Yes, No, or I don't know for each option. 9a: Acute or postoperative pain Yes 28 (9.0) No?? 280 (90.3) I don't know 2 (0.6) 9b: Headache or migraine pain Yes 16 (5.2) Now 294 (94.8) I don't know 0 9c: Dental pain Yes 5 (1.6) Now 305 (98.4) I don't know 0 9d: Breakthrough pain from cancer Yesm 288 (92.9) No 22 (7.1) I don't know 0 9e: Chronic non-cancer pain Yesm 106 (34.2) Non] 201 (64.8) I don't know 3 (1.0) Data Source: ADPQ, ADTQ Program: TEX.SAS 6 TRIG TIRF Prescriber KAB Page 4 of 8 03DEC2015 Table 3: Responses to All Questions about the Safe Use of TIRF Medicines Completed Surveys Question Prescribers medicines. Question 12: Please answer True, False, or I don't know for each statement based on the labeling for TIRF 12a: TIRF medicines can be abused in a manner similar to other opioid agonists. Truem 292 (94.2) False 12 (3.9) I don't know 6 (1.9) 12b: IRF medicines are interchangeable with each other regardless of route of administration. True 13 (4.2) Falsem 287 (92.6) I don't know 10 (3.2) of differences in the pharmacokinetics of fentanyl absorption. 12c: The conversion of one IRF medicine for another TIRF medicine may result in a fatal overdose because Truem 296 (95.5) False 6 (1.9) I don't know 8 (2.6) 12d: Dosing of IRF medicines is not equivalent on a microgram-to-microgram basis. Truem 279 (90.0) False 21 (6.8) I don't know 10 (3.2) at least: Question 13: Please select True, False, or I don't know for each of the following. According to the labeling for TIRF medicines, patients considered opioid-tolerant are those who are taking, for one week or longer, 13a: 8 mg oral hydromorphone/day Truem 226 (72.9) False 57 (18.4) I don't know 27 (8-7) 13b: 60 mg oral morphine/day Truem 293 (94.5) False 11 (3.5) I don't know 6 (1.9) Data Source: ADPQ, ADTQ Program: TEX.SAS 7 TRIG TIRF Prescriber KAB Page 5 of 8 03DEC2015 Table 3: Responses to All Questions about the Safe Use of TIRF Medicines Completed Surveys Prescribers Question 11 130: 30 mg oral Truem 244 (78.7) False 46 (14.8) I don't know 20 (6.5) 13d: 25 meg tronsdermalfentom'l/hour Truem 265 (85.5) False 27 (8.7) I don't know 18 (5.8) 13e: 25 mg oral oxymorphone/day Truem 224 (72.3) False 33 (10.6) I don't know 53 (17.1) 13f: An equianalgesic dose of another oral opioid Truem 210 (67.7) False 55 (17.7) I don't know 45 (14.5) Question 15: The patients described are experiencing breakthrough pain. According to the labeling, a TIRF medicine is not appropriate for one of them. Which patient should not receive a TIRF medicine? Please select one option. Adult male with advanced lung cancer; underlying persistent cancer pain managed 26 (8.4) with 25 meg/hour transdennal fentanyl patches for the past two months. Adult female with localized breast cancer; just completed a mastectomy and 227 (73.2) reconstructive surgery. persistent cancer pain managed with 30 mg oral morphine daily for the past 6 weeksm Adult male patient with advanced prostate cancer who. over the last 2 weeks. has 18 (5.8) been prescribed 100 mg oral morphine daily for pain due to bone metastasis. Adult female with advanced sarcoma who has been taking a daily dose of 12 mg oral 19 (6.1) hydromorphone for the last 3 weeks. I don't know 20 (6.5) Data Source: ADPQ, ADTQ Program: TEX.SAS 8 TRIG TIRF Prescriber KAB Page 6 of 8 03DEC2015 Table 3: Responses to All Questions about the Safe Use of TIRF Medicines Completed Surveys Question Prescribers one option. Question 16: A patient is already taking a TIRF medicine but wants to change their medicine. His/her doctor decides to prescribe a different TIRF medicine (that is not a bioequivalent generic version of a branded product) in its place. According to the labeling, how should the prescriber proceed? Please select The prescriber can safely convert to the equivalent dosage of the new TIRF 3 (1.0) medicine as it has the same effect as other TIRF medicines. The prescriber must not convert to another TIRF medicine on a 240 (77.4) microgram-per-microgram basis because these medicines have different absorption properties and this could result in a fentanyl overdose!? Convert from the other TIRF medicine to the new TIRF medicine at half of the dose. 22 (7.1) The prescriber should base the starting dose of the newly-prescribed TIRF medicine 33 (10.6) on the dose of the opioid medicine used for their underlying persistent cancer pain. I don't know. 12 (3.9) select one option. Question 17: A patient is starting titration with a TIRF medicine. What dose must they start with? Please An appropriate dose based on the dose of the opioid medicine used for underlying 35 (11.3) persistent cancer pain. The dose that the prescriber believes is appropriate based on their clinical 3 (1.0) experience. The lowest available dose. 1n11ess individual product Full Prescribing Information 267 (86.1) provides product-speci?c guidancem The median available dose. 2 (0.6) I don't know. 3 (1.0) advise the patient to do? Please pick the best option of the scenarios described. Question 18: A prescriber has started titrating a patient with the lowest dose of a TIRF medicine. However, after 30 minutes the breakthrough pain has not been suf?ciently relieved. What should they Take another (identical) dose of the TIRF medicine immediately. 78 (25.2) Take a dose of an alternative rescue medicine. 13 (4.2) Provide guidance based on the product-speci?c Medication Guide because the 213 (68.7) instructions are not the same for all TIRF medicinesm Double the dose and take inmiediately. 5 (1.6) I don't know. 1 (0.3) CYP3A4 inhibitor. Please pick the best option of the scenarios described. Question 19: A patient is taking a TIRF medicine and the doctor would like to prescribe a Data Source: ADPQ, ADTQ Program: TEX.SAS 9 TRIG TIRF Prescriber KAB Page 7 of 8 03DEC2015 Table 3: Responses to All Questions about the Safe Use of TIRF Medicines Completed Surveys Prescribers Question 11 The patient can't be prescribed because using it at the same time as a 14 (4.5) TIRF medicine could be fatal. Use of a TIRF medicine with a CYP3A4 inhibitor may require a dosage adjustment: 235 (75.8) carefully monitor the patient for opioid toxicity. otherwise such use may cause potentially fatal respiratory depression? There is no possible drug interaction between CYP3A4 inhibitors and TIRF 6 (1.9) medicines. The dose of the TIRF medicine must be reduced by one half if a CYP3A4 inhibitor 10 (3.2) is prescribed in the same patient. I don't know. 45 (14.5) statements. Question 20: Before initiating treatment with a TIRF medicine, prescribers must review the Medication Guide with the patient. Please select True, False, or I don't know for each of the following counseling for whom they were not prescribed, and in those who are not opioid tolerant. 20a: IRF medicines contain fentanyl in an amount that could be fatal to children of all ages, in individuals Truem 308 (99.4) False (0.3) I don't know 1 (0.3) headache/migraine, or any other short-term pain. 20b: Inform patients that IRF medicines must not be used for acute or postoperative pain, pain from injuries, Truem 291 (93.9) False 12 (3.9) I don't know 7 (2.3) around-the-clock opioid medicine. 20c: Instruct patients that they can continue to take their TIRF medicine, ifthey stop taking their True 64 (20.6) Falsem 226 (72.9) I don't know 20 (6.5) 20d: Instruct patients to never share their IRF medicine with anyone else, even if that person has the same Truem 309 (99.7) False Data Source: ADPQ, ADTQ Program: TEX.SAS TRIG TIRF Preseriber KAB Page 8 of 8 03DEC2015 Table 3: Responses to All Questions about the Safe Use of TIRF Medicines Completed Surveys Preseribers Question 11 I don't know 1 (0.3) Correct response. Verbatim for the type of chronic non-cancer pain and reason for selecting TIRF medicines to treat chronic non-cancer pain are presented in Listing 1 and Listing 2. Data Source: ADPQ, ADTQ Program: TEX.SAS TRIG TIRF Prescriber KAB Page 1 of 1 03DEC2015 Table 4: Responses to Questions about TIRF Educational Materials Completed Surveys Question Prescribers medicine(s) that you prescribe? Question 21: Did you receive or do you have access to the Full Prescribing Information for the TIRF Yes 286 (92.3) No 9 (2.9) I don't know 15 (4.8) Question 22: Did you read the Full Prescribing Information for the TIRF medicine(s) that you prescribe?? Yes 238 (83.2) No 41 (14.3) I don't know 7 (2.4) (Answered "No" or don?t know" to Question 21) 24 you prescribe? Question 23: Did you receive or do you have access to the Medication Guide for the TIRF medicine(s) that Yes 276 (89.0) No 10 (3.2) I don't know 24 (7.7) Question 24: Did you read the Medication Guide for the TIRF medicine(s) that you prescribe?m Yes 257 (93.1) No 14 (5.1) I don't know 5 (1.8) (Answered "No" or don?t know" to Question 23) 34 Information or Medication Guide? Question 25: Did you or do you have any questions about the information in the Full Prescribing Yesm 12 (3.9) No 272 (87.7) I don't know 26 (8.4) Percentages are calculated based on the sample presented with this question because of skip logic in the sm'vey. Verbatim texts for question about the Medication Guide are presented in Listing 3. Data Source: ADPQ, ADTQ Program: TEDUCSAS TRIG TIRF Prescriber KAB Page 1 of 03DEC2015 Table 5: Responses to Questions about the Patient-Prescriber Agreement Form - Completed Surveys Prescribers (N =3 10) Question 11 you prescribe TIRF medicines or their caregiver? Question 27: Do you review the Patient-Prescriber Agreement Form with each of your patients for whom Yes 286 (92.3) No 17 (5.5) I don't know 7 (2.3) Question 28: Do you and the patient or their caregiver si TIRF medicines after you have reviewed it with him/her? the Patient-Prescriber Agreement Form for Yes 266 (93.0) No 9 (3.1) I don't know 11 (3.8) (Armrered "No" or don?t know" to Question 27) 24 patient or their caregiver? Question 29: Do you give a copy of the Patient-Prescriber Agreement Form for TIRF medicines to the Yes 249 (87.1) No 21 (7.3) I don't know 16 (5.6) (Answered "No" or don?t know" to Question 27) 24 Percentages are calculated based on the sample presented with this question because of skip logic in the survey. Data Source: ADPQ, ADTQ Program: TPPAF.SAS TRIG Page 1 of 2 TIRF Prescriber KAB 03DEC2015 Table 6: Responses to Questions about the Activities when Prescribing TIRF Medicines - Completed Surveys Prescribers Question Question 14: How frequently do you perform the following activities when prescribing TIRF medicines? Please answer Always, Only with the ?rst prescription, Sometimes, Never, or I don't know. 14a: Ask patients (or their caregivers) about the presence of children in the home Always 178 (57.4) Only with the ?rst prescription 75 (24.2) Sometimes 42 (13.5) Never 11 (3.5) I don't know 4 (1.3) 14b: Instruct patients (or their caregivers) not to share IRF medicines with anyone else Always 249 (80.3) Only with the ?rst prescription 43 (13.9) Sometimes 13 (4.2) Never 3 (1.0) I don?t know 2 (0.6) 14c: Counsel patients (or their caregivers) that accidental exposure to IRF medicines by a child may be fatal Always 203 (65.5) Only with the ?rst prescription 66 (21.3) Sometimes 27 (8.7) Never 11 (3.5) I don't know 3 (1.0) accidental exposure 14d: Instruct patients (or their caregivers) to keep TIRF medicines out of the reach of children to prevent Always 220 (71.0) Only with the ?rst prescription 61 (19.7) Sometimes 19 (6. 1) Never 7 (2.3) I don't know 3 (1.0) medicines 14e: Instruct patients (or their caregivers) about proper disposal of any unused or partially used IRF Data Source: ADPQ, ADTQ Program: TACT.SAS TRIG Page 2 of 2 TIRF Prescriber KAB 03DEC2015 Table 6: Responses to Questions about the Activities when Prescribing TIRF Medicines - Completed Surveys Prescribers Question Always 190 (61.3) Only with the ?rst prescription 74 (23.9) Sometimes 37 (11.9) Never 6 (1-9) I don't know 3 (1.0) 14f: Give patients (or their caregivers) the Medication Guide for their IRF medicine Always 140 (45.2) Only with the ?rst prescription 123 (39.7) Sometimes 23 (7.4) Never 21 (6.8) I don't know 3 (1.0) Data Source: ADPQ, ADTQ Program: TACT.SAS TRIG TIRF Prescriber KAB Page 1 of 3 03DEC2015 Table 7.1: Primary Analysis of Responses to Questions Linked to Key Risk Message #1 - Completed Surveys Key Risk Message TIRF medicines are contraindicated in opioid non-tolerant patients. Question Prescribers [95% Question 5: Please select True, False, or I don't know for each of the following. According to the labeling for TIRF medicines, patients with cancer who are considered opioid?tolerant are those: 5a: Who are taking around-the-clock opioid therapy for underlying, persistent cancer pain for one week or longer Truem 295 (95.2) [92.1 - 97.3] False 14 (4.5) I don't know 1 (0.3) 5b: Who are not currently taking opioid therapy, but have taken opioid therapy before True 15 (4.8) Falsem 291 (93.9) [90.6 - 96.3] I don't know 4 (1.3) 5c: Who have no known contraindications to the drug fentanyl, but are not currently taking around-the-clock opioid therapy True 33 (10.6) Falsem 269 (86.8) [82.5 - 90.3] I don't know 8 (2.6) medicines. Question 7: Please answer True, False, or I don't know for each statement based on the labeling for TIRF depression could occur at any dose. 7a: medicines are contraindicated in opioid non-tolerant patients because life-threatening respiratory Truem 280 (90.3) [86.5 - 93.4] False 23 (7.4) I don't know 7 (2.3) 7b: Death has occurred in opioid non-tolerant patients treated with some fentanyl products. Truem 298 (96.1) [93.3 - 98.0] False 2 (0.6) I don't know 10 (3.2) 7c: TIRF medicines may be used in opioid non-tolerant patients. Data Source: ADPQ, ADTQ Program: TRIG TIRF Prescriber KAB Page 2 of 3 03DEC2015 Table 7.1: Primary Analysis of Responses to Questions Linked to Key Risk Message #1 - Completed Surveys Key Risk Message TIRF medicines are contraindicated in opioid non-tolerant patients. Prescribers 10) Question 11 [95% True 3 8 (12.3) Falsem 263 (84.8) [80.4 - 88.6] I don't know 9 (2.9) 7d: Prescribers starting a patient on a TIRF medicine must begin with titration from the lowest dose available for that specific product, even if the patient has previously taken another TIRF medicine. Truep] 265 (85.5) [81.1 - 89.2] False 40 (12.9) I don't know 5 (1.6) at least: Question 13: Please select True, False, or I don't know for each of the following. According to the labeling for TIRF medicines, patients considered opioid-tolerant are those who are taking, for one week or longer, 13a: 8 mg oral hydromorphone/day Truep] 226 (72.9) [67.6 - 77.8] False 57 (18.4) I don't know 27 (8.7) 13b: 60 mg oral morphine/day 2] Truel 293 (94.5) [91.4 - 96.8] False 11 (3.5) I don't know 6 (1.9) 13c: 30 mg oral oxycodone/day 2] Tme? 244 (78.7) [73.7 - 83.1] False 46 (14.8) I don't know 20 (6.5) 13d: 25 transdermalfentanrl/hour 2] Truel 265 (85.5) [81.1 - 89.2] False 27 (8.7) I don't know 18 (5.8) Data Source: ADPQ, ADTQ Program: TRIG Page 3 of 3 TIRF Prescriber KAB 03DEC2015 Table 7.1: Primary Analysis of Responses to Questions Linked to Key Risk Message #1 - Completed Surveys Key Risk Message TIRF medicines are contraindicated in opioid non-tolerant patients. Prescribers Question 11 [95% 13c: 25 mg oral on?morphone/dqv Truem 224 (72.3) [66.9 - 77.2] False 33 (10.6) I don't know 53 (17. 1) 13f: An equianalgesic dose of another oral opioid Truem 210 (67.7) [62.2 - 72.9] False 55 (17.7) I don't know 45 (14.5) 95% exact two-sided con?dence intervals are calculated using the lopper-Pearson method. Correct response. Data Source: ADPQ, ADTQ Program: TRIG TIRF Prescriber KAB Page 1 of 4 03DEC2015 Table 7.1.2: Responses to Questions Linked to Key Risk Message #1 by Medical Degree of Respondents - Completed Surveys Key Risk Message TIRF medicines are contraindicated in opioid non-tolerant patients. Question M1) [95% cull] Medical Degree of Respondents D0 [95% "1 Nurse Practitioner [95% Physician Assistant [95% Question 5: Please select True, False, or I don't know for each of the following. According to the labeling for TIRF medicines, patients with cancer who are considered opioid-tolerant are those: 5a: Who are taking around-the-clock opioid therapy for underlying, persistent cancer pain for one week or longer Truem 170 (95.5) [91.3 - 98.0] 26 (100.0) [86.8 - 100.0] 63 (92.6) [83.7 - 97.6] 33 (94.3) [80.8 - 99.3] False 8 (4.5) 0 4 (5.9) 2 (5.7) I don't know 0 0 1 (1.5) 0 5b: Who are not currently taking opioid therapy, but have taken opioid therapy before True 10 (5.6) 1 (3.8) 4 (5.9) 0 Falsem 165 (92.7) [87.8 - 96.1] 25 (96.2) [80.4 - 99.9] 63 (92.6) [83.7 - 97.6] 35 (100.0) [90.0 - 100.0] I don't know 3 (1.7) 0 1 (1.5) 0 5c: Who have no known contraindications to the drug fentanyl, but are not currently taking around-the-clock opioid therapy True 17 (9.6) 4 (15.4) 10 (14.7) 2 (5.7) Falsem 156 (87.6) [81.9 - 92.1] 21 (80.8) [60.6 - 93.4] 57 (83.8) [72.9 - 91.6] 32 (91.4) [76.9 - 98.2] Idon't know 5 (2.8) 1 (3.8) 1 (1.5) 1 (2.9) Question 7: Please answer True, False, or I don't know for each statement based on the labeling for TIRF medicines. 7a: IRF medicines are contraindicated in opioid non-tolerant patients because life-threatening respiratory depression could occur at any dose. Data Source: ADPQ, ADTQ Program: TRIG TIRF Prescriber KAB Page 2 of 4 03DEC2015 Table 7.1.2: Responses to Questions Linked to Key Risk Message #1 by Medical Degree of Respondents - Completed Surveys Key Risk Message TIRF medicines are contraindicated in opioid non-tolerant patients. Medical Degree of Respondents MD DO Nurse Practitioner Physician Assistant (N=l78) Question 11 [95% [95% 11 [95% 11 [95% C1191 Truem 162 (91.0) [85.8 - 94.8] 24 (92.3) [74.9 - 99.1] 59 (86.8) [76.4 - 93.8] 33 (94.3) [80.8 - 99.3] False 13 (7.3) 2 (7.7) 7 (10.3) 1 (2.9) Idon't know 3 (1.7) 0 2 (2.9) 1 (2.9) 7b: Death has occurred in opioid non-tolerant patients treated with some fentanyl products. Truem 173 (97.2) [93.6 - 99.1] 24 (92.3) [74.9 - 99.1] 66 (97.1) [89.8 - 99.6] 33 (94.3) [80.8 - 99.3] False 2 (1.1) 0 0 0 I don't know 3 (1.7) 2 (7.7) 2 (2.9) 2 (5.7) 7c: IRF medicines maybe used in opioid non-tolerant patients. True 23 (12.9) 3 (11.5) 8 (11.8) 3 (8.6) Falsem 150 (84.3) [78.1 - 89.3] 22 (84.6) [65.1 - 95.6] 57 (83.8) [72.9 - 91.6] 32 (91.4) [76.9 - 98.2] Idon't know 5 (2.8) 1 (3.8) 3 (4.4) 0 7d: Prescribers starting a patient on a IRF medicine must begin with titration from the lowest dose available for that specific product, even if the patient has previously taken another TIRF medicine. Truem 152 (85.4) [79.3 - 90.2] 24 (92.3) [74.9 - 99.1] 56 (82.4) [71.2 - 90.5] 31 (88.6) [73.3 - 96.8] False 23 (12.9) 2 (7.7) 10 (14.7) 4 (11.4) I don't know 3 1.7) 0 2 (2.9) Data Source: ADPQ, ADTQ Program: TRIG TIRF Prescriber KAB Page 3 of 4 03DEC2015 Table 7.1.2: Responses to Questions Linked to Key Risk Message #1 by Medical Degree of Respondents - Completed Surveys Key Risk Message TIRF medicines are contraindicated in opioid non-tolerant patients. Question MD [95% Medical Degree of Respondents no [95% "1 Nurse Practitioner [95% Physician Assistant [95% Question 13: Please select True, False, or I don't know for each of the following. According to the labeling for TIRF medicines, patients considered opioid?tolerant are those who are taking, for one week or longer, at least: 13a: 8 mg oral hrdromorphone/day Truem 135 (75.8) [68.9 - 81.9] 18 (69.2) [48.2 - 85.7] 43 (63.2) [50.7 - 74.6] 27 (77.1) [59.9 - 89.6] False 26 (14.6) 7 (26.9) 20 (29.4) 4 (11.4) I don't know 17 (9.6) 1 (3.8) 5 (7.4) 4 (11.4) 13b: 60 mg oral morphine/day Truem 165 (92.7) [87.8 - 96.1] 25 (96.2) [80.4 - 99.9] 65 (95.6) [87.6 - 99.1] 35 (100.0) [90.0 - 100.0] False 8 (4.5) 1 (3.8) 2 (2.9) 0 I don't know 5 (2.8) 0 1 (1.5) 0 13c: 30 mg oral on'codone/day Truem 143 (80.3) [73.7 - 85.9] 22 (84.6) [65.1 - 95.6] 47 (69.1) [56.7 - 79.8] 29 (82.9) [66.4 - 93.4] False 23 (12.9) 4 (15.4) 14 (20.6) 5 (14.3) I don't know 12 (6.7) 0 7 (10.3) 1 (2.9) 13d: 25 meg transdermalfentanyMtour True 153 (86.0) [80.0 - 90.7] 22 (84.6) [65.1 - 95.6] 54 (79.4) [67.9 - 88.3] 33 (94.3) [80.8 - 99.3] Data Source: ADPQ, ADTQ Program: TRIG TIRF Prescriber KAB Page 4 of 4 03DEC2015 Table 7.1.2: Responses to Questions Linked to Key Risk Message #1 by Medical Degree of Respondents - Completed Surveys Key Risk Message TIRF medicines are contraindicated in opioid non-tolerant patients. Medical Degree of Respondents MD DO Nurse Practitioner Physician Assistant Question 11 [95% 11 [95% "1 [95% 11 [95% False 14 (7.9) 3 (11.5) 9 (13.2) 1 (2.9) Idon't know 11 (6.2) 1 (3.8) 5 (7.4) 1 (2.9) 13e: 25 mg oral oxymotphone/dqv Truem 127 (71.3) [64.1 - 77.9] 16 (61.5) [40.6 - 79.8] 47 (69.1) [56.7 - 79.8] 31 (88.6) [73.3 - 96.8] False 17 (9.6) 6 (23.1) 8 (11.8) 2 (5.7) I don't know 34 (19.1) 4 (15.4) 13 (19.1) 2 (5.7) 13f: An equianalgesic dose of (mother oral opioid Truem 126 (70.8) [63.5 - 77.3] 18 (69.2) [48.2 - 85.7] 43 (63.2) [50.7 - 74.6] 21 (60.0) [42.1 - 76.1] False 27 (15.2) 4 (15.4) 15 (22.1) 9 (25.7) Idon't know 25 (14.0) 4 (15.4) 10 (14.7) 5 (14.3) 95% exact two-sided con?dence intervals are calculated using the Clopper-Pearson method. Conect response. Data Source: ADPQ, ADTQ Program: TRIG TIRF Prescriber KAB Page 1 of 4 03DEC2015 Table 7.1.4: Responses to Questions Linked to Key Risk Message #1 by Time Practicing Medicine - Completed Surveys Key Risk Message TIRF medicines are contraindicated in opioid non-tolerant patients. Question Less than 3 years [95% cull] Time Practicing Medicine 3 to 5 years [95% "1 6 to 15 years [95% More than 15 years [95% Question 5: Please select True, False, or I don't know for each of the following. According to the labeling for TIRF medicines, patients with cancer who are considered opioid-tolerant are those: 5a: Who are taking around-the-clock opioid therapy for underlying, persistent cancer pain for one week or longer Truem 37 (90.2) [76.9 - 97.3] 36 (94.7) [82.3 - 99.4] 117 (95.9) [90.7 - 98.7] 103 (96.3) [90.7 - 99.0] False 3 (7.3) 2 (5.3) 5 (4.1) 4 (3.7) I don't know 1 (2.4) 0 0 5b: Who are not currently taking opioid therapy, but have taken opioid therapy before True 0 0 6 (4.9) 9 (8.4) Falsem 41 (100.0) [91.4 - 100.0] 38 (100.0) [90.7 - 100.0] 113 (92.6) [86.5 - 96.6] 97 (90.7) [83.5 - 95.4] I don't know 0 0 3 (2.5) 1 (0.9) 5c: Who have no known contraindications to the drug fentanyl, but are not currently taking around-the-clock opioid therapy True 2 (4.9) 4 (10.5) 11 (9.0) 15 (14.0) Falsem 39 (95.1) [83.5 - 99.4] 32 (84.2) [68.7 - 94.0] 109 (89.3) [82.5 - 94.2] 88 (82.2) [73.7 - 89.0] I don't know 0 2 (5.3) 2 (1.6) 4 (3.7) Question 7: Please answer True, False, or I don't know for each statement based on the labeling for TIRF medicines. 7a: IRF medicines are contraindicated in opioid non-tolerant patients because life-threatening respiratory depression could occur at any dose. Data Source: ADPQ, ADTQ Program: TRIG TIRF Prescriber KAB Page 2 of 4 03DEC2015 Table 7.1.4: Responses to Questions Linked to Key Risk Message #1 by Time Practicing Medicine - Completed Surveys Key Risk Message TIRF medicines are contraindicated in opioid non-tolerant patients. Less than 3 years Time Practicing Medicine 3 to 5 years 6 to 15 years More than 15 years Question 11 [95% 11 [95% "1 [95% 11 [95% C1191 Truem 36 (87.8) [73.8 - 95.9] 34 (89.5) [75.2 - 97.1] 109 (89.3) [82.5 - 94.2] 100 (93.5) [87.0 - 97.3] False 4 (9.8) 2 (5.3) 11 (9.0) 5 (4.7) Idon't know 1 (2.4) 2 (5.3) 2 (1.6) 2 (1.9) 7b: Death has occurred in opioid non-tolerant patients treated with some fentanyl products. Truem 40 (97.6) [87.1 - 99.9] 35 (92.1) [78.6 - 98.3] 117 (95.9) [90.7 - 98.7] 104 (97.2) [92.0 - 99.4] False 0 0 1 (0.8) 1 (0.9) I don't know 1 (2.4) 3 (7.9) 4 (3.3) 2 (1.9) 7c: IRF medicines maybe used in opioid non-tolerant patients. True 5 (12.2) 4 (10.5) 17 (13.9) 11 (10.3) Falsem 36 (87.8) [73.8 - 95.9] 32 (84.2) [68.7 - 94.0] 100 (82.0) [74.0 - 88.3] 94 (87.9) [80.1 - 93.4] I don't know 0 2 (5.3) 5 (4.1) 2 (1.9) 7d: Prescribers starting a patient on a IRF medicine must begin with titration from the lowest dose available for that specific product, even if the patient has previously taken another TIRF medicine. Truem 34 (82.9) [67.9 - 92.8] 31 (81.6) [65.7 - 92.3] 105 (86.1) [78.6 - 91.7] 93 (86.9) [79.0 - 92.7] False 5 (12.2) 6 (15.8) 15 (12.3) 14 (13.1) I don't know 2 (4.9) 1 (2.6) 2 (1.6) Data Source: ADPQ, ADTQ Program: TRIG TIRF Prescriber KAB Page 3 of 4 03DEC2015 Table 7.1.4: Responses to Questions Linked to Key Risk Message #1 by Time Practicing Medicine - Completed Surveys Key Risk Message TIRF medicines are contraindicated in opioid non-tolerant patients. Question Less than 3 years [95% Time Practicing Medicine 3 to 5 years [95% "1 6 to 15 years [95% More than 15 years [95% Question 13: Please select True, False, or I don't know for each of the following. According to the labeling for TIRF medicines, patients considered opioid?tolerant are those who are taking, for one week or longer, at least: 13a: 8 mg oral hydromorphone/day Truem 27 (65.9) [49.4 - 79.9] 30 (78.9) [62.7 - 90.4] 84 (68.9) [59.8 - 76.9] 84 (78.5) [69.5 - 85.9] False 8 (19.5) 6 (15.8) 29 (23.8) 13 (12.1) I don't know 6 (14.6) 2 (5.3) 9 (7.4) 10 (9.3) 13b: 60 mg oral morphine/day Truem 37 (90.2) [76.9 - 97.3] 37 (97.4) [86.2 - 99.9] 117 (95.9) [90.7 - 98.7] 100 (93.5) [87.0 - 97.3] False 2 (4.9) 0 4 (3.3) 5 (4.7) I don't know 2 (4.9) 1 (2.6) 1 (0.8) 2 (1.9) 13c: 30 mg oral oxvcodone/day Truem 29 (70.7) [54.5 - 83.9] 31 (81.6) [65.7 - 92.3] 95 (77.9) [69.5 - 84.9] 88 (82.2) [73.7 - 89.0] False 8 (19.5) 5 (13.2) 21 (17.2) 11 (10.3) I don't know 4 (9.8) 2 (5.3) 6 (4.9) 8 (7.5) 13d: 25 meg transdermalfentanyMtour True 34 (82.9) [67.9 - 92.8] 32 (84.2) [68.7 - 94.0] 103 (84.4) [76.8 - 90.4] 94 (87.9) [80.1 - 93.4] Data Source: ADPQ, ADTQ Program: TRIG TIRF Prescriber KAB Page 4 of 4 03DEC2015 Table 7.1.4: Responses to Questions Linked to Key Risk Message #1 by Time Practicing Medicine - Completed Surveys Key Risk Message TIRF medicines are contraindicated in opioid non-tolerant patients. Time Practicing Medicine Less than 3 years 3 to 5 years 6 to 15 years More than 15 years Question 11 [95% 11 [95% "1 [95% 11 [95% False 2 (4.9) 5 (13.2) 12 (9.8) 8 (7.5) I don't know 5 (12.2) 1 (2.6) 7 (5.7) 5 (4.7) 13e: 25 mg oral oxymotphone/dqv Tmem 31 (75.6) [59.7 - 87.6] 28 (73.7) [56.9 - 86.6] 89 (73.0) [64.2 - 80.6] 75 (70.1) [60.5 - 78.6] False 0 4 (10.5) 16 (13.1) 12 (11.2) I don't know 10 (24.4) 6 (15.8) 17 (13.9) 20 (18.7) 13f: An equianalgesic dose of (mother oral opioid Truem 26 (63.4) [46.9 - 77.9] 27 (71.1) [54.1 - 84.6] 82 (67.2) [58.1 - 75.4] 74 (69.2) [59.5 - 77.7] False 9 (22.0) 5 (13.2) 22 (18.0) 18 (16.8) Idon't know 6 (14.6) 6 (15.8) 18 (14.8) 15 (14.0) 95% exact two-sided con?dence intervals are calculated using the Clopper-Pearson method. Conect response. Data Source: ADPQ, ADTQ Program: TRIG Page 1 of 5 TIRF Prescriber KAB 03DEC2015 Table 7.1.5: Responses to Questions Linked to Key Risk Message #1 by Number of Times Prescribing TIRF Medicines per Month Within the Last 6 Months - Completed vaeys Key Risk Message TIRF medicines are contraindicated in opioid non-tolerant patients. Number of Times Prescribing TIRF Medicines per Month Within the Last 6 Months 1 - 2 times 3 5 times More than 5 times I don't None per month per month per month remember Question 11 [95% 11 [95% '11 [95% Cl] "1 [95% Cl]m [95% "1 Question 5: Please select True, False, or I don't know for each of the following. According to the labeling for TIRF medicines, patients with cancer who are considered opioid-tolerant are those: 5a: Who are taking around-the-clock opioid therapy for underlying, persistent cancer pain for one week or longer Truem 76 (98.7) [93.0 - 100.0] 144 (93.5) [88.4 - 96.8] 46 (93.9) [83.1 - 98.7] 16 (94.1) [71.3 - 99.9] 13 (100.0) [75.3 - 100.0] False (1.3) 9 (5.8) 3 (6.1) 1 (5.9) 0 I don't know 0 (0.6) 0 0 0 5b: Who are not currently taking opioid therapy, but have taken opioid therapy before True 3 (3.9) 7 (4.5) 2 (4.1) 3 (17.6) 0 Falsem 73 (94.8) [87.2 - 98.6] 145 (94.2) [89.2 - 97.3] 46 (93.9) [83.1 - 98.7] 14 (82.4) [56.6 - 96.2] 13 (100.0) [75.3 - 100.0] Idon't know 1 (1.3) 2 (1.3) (2.0) 0 0 5c: Who have no known contraindications to the drug fentanyl, but are not currently taking around-the-clock opioid therapy True 8 (10.4) 13 (8.4) 6 (12.2) 4 (23.5) 2 (15.4) Falsep] 67 (87.0) [77.4 - 93.6] 136 (88.3) [82.2 - 92.9] 43 (87.8) [75.2 - 95.4] 13 (76.5) [50.1 - 93.2] 10 (76.9) [46.2 - 95.0] I don't know 2 (2.6) 5 (3.2) 0 0 1 (7.7) Question 7: Please answer True, False, or I don't know for each statement based on the labeling for TIRF medicines. Data Source: ADPQ, ADTQ Program: TRIG TIRF Prescriber KAB Page 2 of 5 03DEC2015 Table 7.1.5: Responses to Questions Linked to Key Risk Message #1 by Number of Times Prescribing TIRF Medicines per Month Within the Last 6 Months - Completed Sm'veys Key Risk Message TIRF medicines are contraindicated in opioid non-tolerant patients. Question Number of Times Prescribing TIRF Medicines per Month Within the Last 6 Months None [95% 1 - 2 times per month [95% 3 - 5 times per month [95% Cl] "1 More than 5 times per month [95% cum I don't remember [95% 7a: IRF medicines are contraindicated in opioid non-tolerant patients because life-threatening respiratory depression could occur at any dose. Truem 65 (84.4) [74.4 - 91.7] 141 (91.6) [86.0 - 95.4] 46 (93.9) [83.1 - 98.7] 16 (94.1) [71.3 - 99.9] 12 (92.3) [64.0 - 99.8] False 10 (13.0) 9 (5.8) 2 (4.1) 1 (5.9) (7.7) I don't know 2 (2.6) 4 (2.6) 1 (2.0) 0 0 7b: Death has occurred in opioid non-tolerant patients treated with some fentanyl products. Truem 76 (98.7) [93.0 - 100.0] 147 (95.5) [90.9 - 98.2] 47 (95.9) [86.0 - 99.5] 16 (94.1) [71.3 - 99.9] 12 (92.3) [64.0 - 99.8] False 0 0 1 (2.0) 1 (5.9) 0 Idon't know 1 (1.3) 7 (4.5) 1 (2.0) 0 1 (7.7) 7c: IRF medicines may be used in opioid non-tolerant patients. True 11 (14.3) 19 (12.3) 4 (8.2) 3 (17.6) 1 (7.7) Falsem 64 (83.1) [72.9 - 90.7] 130 (84.4) [77.7 - 89.8] 44 (89.8) [77.8 - 96.6] 13 (76.5) [50.1 - 93.2] 12 (92.3) [64.0 - 99.8] Idon't know 2 (2.6) 5 (3.2) (2.0) 1 (5.9) 0 7d: Prescribers starting a patient on a IRF medicine must begin with titration from the lowest dose available for that specific product, even if the patient has previously taken another TIRF medicine. Truem 68 (88.3) [79.0 - 94.5] 132 (85.7) [79.2 - 90.8] 40 (81.6) [68.0 - 91.2] 16 (94.1) [71.3 - 99.9] 9 (69.2) [38.6 - 90.9] Data Source: ADPQ, ADTQ Program: TRIG TIRF Prescriber KAB Page 3 of 5 03DEC2015 Table 7.1.5: Responses to Questions Linked to Key Risk Message #1 by Number of Times Prescribing TIRF Medicines per Month Within the Last 6 Months - Completed vaeys Key Risk Message TIRF medicines are contraindicated in opioid non-tolerant patients. Number of Times Prescribing TIRF Medicines per Month Within the Last 6 Months 1 - 2 times 3 5 times More than 5 times I don't None per month per month per month remember Question [95% 11 [95% '11 [95% Cl] "1 [95% Cl]m [95% "1 False 9 (11.7) 18 (11.7) 9 (18.4) 1 (5.9) 3 (23.1) I don't know 0 4 (2.6) 0 0 1 (7.7) Question 13: Please select True, False, or I don't know for each of the following. According to the labeling for TIRF medicines, patients considered opioid-tolerant are those who are taking, for one week or longer, at least: 13a: 8 mg oral m'dromorphone/day 4 (23.5) Truem 54 (70.1) [58.6 - 80.0] 109 (70.8) [62.9 - 77.8] 38 (77.6) [63.4 - 88.2] 14 (82.4) [56.6 - 96.2] 11 (84.6) [54.6 - 98.1] False 14 (18.2) 31 (20.1) 7 (14.3) 3 (17.6) 2 (15.4) I don't know 9 (11.7) 14 (9.1) 4 (8.2) 0 0 13b: 60 mg oral morphine/day Truem 70 (90.9) [82.2 - 96.3] 145 (94.2) [89.2 - 97.3] 49 (100.0) [92.7 - 100.0] 17 (100.0) [80.5 - 100.0] 12 (92.3) [64.0 - 99.8] False 3 (3.9) 7 (4.5) 0 0 1 (7.7) I don't know 4 (5.2) 2 (1.3) 0 0 0 13c: 30 mg oral on?codone/dqr Truem 58 (75.3) [64.2 - 84.4] 120 (77.9) [70.5 - 84.2] 44 (89.8) [77.8 - 96.6] 13 (76.5) [50.1 - 93.2] 9 (69.2) [38.6 - 90.9] False 11 (14.3) 24 (15.6) 4 (8.2) 3 (23.1) Data Source: ADPQ, ADTQ Program: TRIG TIRF Prescriber KAB Page 4 of 5 03DEC2015 Table 7.1.5: Responses to Questions Linked to Key Risk Message #1 by Number of Times Prescribing TIRF Medicines per Month Within the Last 6 Months - Completed vaeys Key Risk Message TIRF medicines are contraindicated in opioid non-tolerant patients. Number of Times Prescribing TIRF Medicines per Month Within the Last 6 Months 1 - 2 times 3 - 5 times More than 5 times I don't None per month per month per month remember Question 11 [95% [95% "1 [95% Cl] "1 [95% Cl] "1 [95% "1 I don't know 8 (10.4) 10 (6.5) 1 (2.0) 0 (7.7) 13d: 25 meg transdermalfentanyl/hour Truem 65 (84.4) [74.4 - 91.7] 135 (87.7) [81.4 - 92.4] 41 (83.7) [70.3 - 92.7] 14 (82.4) [56.6 - 96.2] 10 (76.9) [46.2 - 95.0] False 4 (5.2) 11 (7.1) 6 (12.2) 3 (17.6) 3 (23.1) I don't know 8 (10.4) 8 (5.2) 2 (4.1) 0 0 13e: 25 mg oral on'morphone/dqv Truep] 49 (63.6) [51.9 - 74.3] 109 (70.8) [62.9 - 77.8] 41 (83.7) [70.3 - 92.7] 14 (82.4) [56.6 - 96.2] 11 (84.6) [54.6 - 98.1] False 6 (7.8) 20 (13.0) 4 (8.2) 3 (17.6) 0 Idon't know 22 (28.6) 25 (16.2) 4 (8.2) 0 2 (15.4) 13f: An equianolgesic dose of another oral opioid Truem 51 (66.2) [54.6 - 76.6] 107 (69.5) [61.6 - 76.6] 30 (61.2) [46.2 - 74.8] 13 (76.5) [50.1 - 93.2] 9 (69.2) [38.6 - 90.9] False 12 (15.6) 28 (18.2) 12 (24.5) 1 (5.9) 2 (15.4) I don't know 14 (18.2) 19 (12.3) 7 (14.3) 3 (17.6) 2 (15.4) 95% exact two-sided con?dence intervals are calculated using the Clopper-Pearson method. Conect response. Data Source: ADPQ, ADTQ Program: TRIG TIRF Prescriber KAB Page 5 of 5 03DEC2015 Data Source: ADPQ, ADTQ Program: TKRMS.SAS FDA_3641 TRIG Page 1 of TIRF Prescriber KAB 03DEC2015 Table 7.2: Secondary Analysis of Responses to Questions Linked to Key Risk Message #1 - Completed Surveys Key Risk Message TIRF medicines are contraindicated in opioid non-tolerant patients. Prescribers Correct Responses 11 [95% CI]ll] 0 correct responses 0 1 correct response 0 2 correct responses 1 (0.3) 3 correct responses 1 (0.3) 4 correct responses 1 (0.3) 5 correct responses 0 6 correct responses 7 (2.3) 7 correct responses 10 (3.2) 8 correct responses 21 (6.8) 9 correct responses 23 (7.4) 10 correct responses 36 (11.6) 11 correct responses 47 (15.2) 12 correct responses 69 (22.3) 13 correct responses 94 (30.3) [25.3 - 35.8] 95% exact two-sided con?dence intervals are calculated using the Clopper-Pearson method. Data Source: ADPQ, ADTQ Program: TRIG TIRF Prescriber KAB Page 1 of 3 03DEC2015 Table 8.1: Primary Analysis of Responses to Questions Linked to Key Risk Message #2 - Completed Surveys Key Risk Message TIRF medicines are only indicated for the management of breakthrough pain in adult cancer patients 18 years of age and older (16 years of age and older for Actiq? brand and generic equivalents) who are already receiving and who are tolerant to around?the?clock opioid therapy for their underlying, persistent cancer pain. Question Prescribers [95% medicines. Question 6: Please answer True, False, or I don't know for each statement based on the labeling for TIRF opioid at the same time. 6a: According to the product labeling, a cancer patient may start a IRF medicine and an around-the-clock True 75 (24.2) Falsem 214 (69.0) [63.6 - 74.1] I don't know 21 (6.8) may start taking a IRF medicine for breakthrough pain. 6b: According to the product labeling, a cancer patient who has been on an around-the-clock opioid for 1 day True 62 (20.0) Falsem 226 (72.9) [67.6 - 77.8] I don't know 22 (7.1) opioid tolerant patients? Please answer Yes, No, or I don't know for each option. Question 9: In your practice, for which of the following indications do you prescribe TIRF medicines to 9a: Acute or postoperative pain Yes 28 (9.0) 280 (90.3) [86.5 - 93.4] I don't know 2 (0.6) 9b: Headache or migraine pain Yes 16 (5.2) Now 294 (94.8) [91.8 - 97.0] I don't know 0 9c: Dental pain Yes 5 (1.6) Nov] 305 (98.4) [96.3 - 99.5] I don't know 0 Data Source: ADPQ, ADTQ Program: TRIG Page 2 of 3 TIRF Prescriber KAB 03DEC2015 Table 8.1: Primary Analysis of Responses to Questions Linked to Key Risk Message #2 - Completed Surveys Key Risk Message TIRF medicines are only indicated for the management of breakthrough pain in adult cancer patients 18 years of age and older (16 years of age and older for Actiq? brand and generic equivalents) who are already receiving and who are tolerant to around?the?clock opioid therapy for their underlying, persistent cancer pain. Prescribers Question 11 [95% 01'? 9d: Breakthrough pain from cancer Yesm 288 (92.9) [89.5 - 95.5] No 22 (7.1) I don't know 0 9e: Chronic non-cancer pain Yes 106 (34.2) 201 (64.8) [59.2 - 70.2] I don't know 3 (1.0) Question 15: The patients described are experiencing breakthrough pain. According to the labeling, a TIRF medicine is not appropriate for one of them. Which patient should not receive a TIRF medicine? Please select one option. Adult male with advanced 11mg cancer: underlying persistent cancer pain managed 26 (8.4) with 25 meg/hour transdermal fentanyl patches for the past two months. Adult female with localized breast cancer; just completed a mastectomy and 227 (73.2) [67.9 - 78.1] reconstructive surgery. persistent cancer pain managed with 30 mg oral morphine daily for the past 6 weeksm Adult male patient with advanced prostate cancer who. over the last 2 weeks. has 18 (5.8) been prescribed 100 mg oral morphine daily for pain due to bone metastasis. Adult female with advanced sarcoma who has been taking a daily dose of 12 mg oral 19 (6.1) hydromorphone for the last 3 weeks. I don't know 20 (6.5) Question 20: Before initiating treatment with a TIRF medicine, prescribers must review the Medication Guide with the patient. Please select True, False, or I don't know for each of the following counseling statements. 20b: Inform patients that TIRF medicines must not be used for acute or postoperative pain, pain from injuries, headache/migraine, or any other short-term pain. Truem 291 (93.9) [90.6 - 96.3] False 12 (3.9) Data Source: ADPQ, ADTQ Program: TRIG Page 3 of 3 TIRF Prescriber KAB 03DEC2015 Table 8.1: Primary Analysis of Responses to Questions Linked to Key Risk Message #2 - Completed Surveys Key Risk Message TIRF medicines are only indicated for the management of breakthrough pain in adult cancer patients 18 years of age and older (16 years of age and older for Actiq? brand and generic equivalents) who are already receiving and who are tolerant to around?the?clock opioid therapy for their underlying, persistent cancer pain. Prescribers Question 11 [95% 01'? I don't know 7 (2.3) 20c: Instruct patients that they can continue to take their TIRF medicine, if they stop taking their around-the-clock opioid medicine. True 64 (20.6) Falsem 226 (72.9) [67.6 - 77.8] I don't know 20 (6.5) 95% exact two-sided con?dence intervals are calculated using the lopper-Pearson method. Correct response. Data Source: ADPQ, ADTQ Program: TRIG TIRF Prescriber KAB Page 1 of 5 03DEC2015 Table 8.1.2: Responses to Questions Linked to Key Risk Message #2 by Medical Degree of Respondents - Completed Surveys Key Risk Message TIRF medicines are only indicated for the management of breakthrough pain in adult cancer patients 18 years of age and older (16 years of age and older for Actiq? brand and generic equivalents) who are already receiving and who are tolerant to around-the?clock opioid therapy for their underlying, persistent cancer pain. Medical Degree of Respondents Question NID (N=l78) [95% cum D0 [95% "1 Nurse Practitioner [95% Physician Assistant [95% Question 6: Please answer True, False, or I don't know for each statement based on the labeling for TIRF medicines. 6a: According to the product labeling, a cancer patient may start a IRF medicine and an around-the-clock opioid at the same time. True 45 (25.3) 8 (30.8) 14 (20.6) 7 (20.0) Falsem 122 (68.5) [61.2 - 75.3] 18 (69.2) [48.2 - 85.7] 47 (69.1) [56.7 - 79.8] 26 (74.3) [56.7 - 87.5] I don't know 11 (6.2) 0 7 (10.3) 2 (5.7) 6b: According to the product labeling, a cancer patient who has been on an around-the-clock opioid for 1 day may start taking a IRF medicine for breakthrough pain. True 37 (20.8) 9 (34.6) 11 (16.2) 4 (11.4) Falsem 130 (73.0) [65.9 - 79.4] 16 (61.5) [40.6 - 79.8] 50 (73.5) [61.4 - 83.5] 28 (80.0) [63.1 - 91.6] I don't know 11 (6.2) 1 (3.8) 7 (10.3) 3 (8.6) Question 9: In your practice, for which of the following indications do you prescribe TIRF medicines to opioid tolerant patients? Please answer Yes, No, or I don't know for each option. 9a: Acute or postoperative pain Yes 21 (11.8) 1 (3.8) 5 (7.4) 1 (2.9) Non] 157 (88.2) [82.5 - 92.5] 25 (96.2) [80.4 - 99.9] 61 (89.7) [79.9 - 95.8] 34 (97.1) [85.1 - 99.9] Data Source: ADPQ, ADTQ Program: TRIG TIRF Prescriber KAB Page 2 of 5 03DEC2015 Table 8.1.2: Responses to Questions Linked to Key Risk Message #2 by Medical Degree of Respondents - Completed Surveys Key Risk Message TIRF medicines are only indicated for the management of breakthrough pain in adult cancer patients 18 years of age and older (16 years of age and older for Actiq? brand and generic equivalents) who are already receiving and who are tolerant to around-the?clock opioid therapy for their underlying, persistent cancer pain. Medical Degree of Respondents MD D0 Nurse Practitioner Physician Assistant Question 11 [95% cum [95% 11 [95% [95% I don't know 0 0 2 (2.9) 0 9b: Headache or migraine pain Yes 11 (6.2) 1 (3.8) 2 (2.9) 2 (5.7) 167 (93.8) [89.2 - 96.9] 25 (96.2) [80.4 - 99.9] 66 (97.1) [89.8 - 99.6] 33 (94.3) [80.8 - 99.3] I don't know 0 0 0 0 9c: Dental pain Yes 5 (2.8) 0 0 0 Non] 173 (97.2) [93.6 - 99.1] 26 (100.0) [86.8 - 100.0] 68 (100.0) [94.7 - 100.0] 35 (100.0) [90.0 - 100.0] I don't know 0 0 0 9d: Breakthrough pain from cancer Yesm 167 (93.8) [89.2 - 96.9] 24 (92.3) [74.9 - 99.1] 63 (92.6) [83.7 - 97.6] 31 (88.6) [73.3 - 96.8] No 11 (6.2) 2 (7.7) 5 (7.4) 4 (11.4) I don't know 0 0 0 0 9e: Chronic non-cancer pain Yes 57 (32.0) 13 (50.0) 19 (27.9) 17 (48.6) Data Source: ADPQ, ADTQ Program: TRIG TIRF Prescriber KAB Page 3 of 5 03DEC2015 Table 8.1.2: Responses to Questions Linked to Key Risk Message #2 by Medical Degree of Respondents - Completed Surveys Key Risk Message TIRF medicines are only indicated for the management of breakthrough pain in adult cancer patients 18 years of age and older (16 years of age and older for Actiq? brand and generic equivalents) who are already receiving and who are tolerant to around-the?clock opioid therapy for their underlying, persistent cancer pain. Medical Degree of Respondents Ml) D0 Nurse Practitioner Physician Assistant (N=l78) Question 11 [95% cum [95% "1 [95% [95% "1 121 (68.0) [60.6 - 74.8] 13 (50.0) [29.9 - 70.1] 47 (69.1) [56.7 - 79.8] 17 (48.6) [31.4 - 66.0] I don't know 0 0 2 (2.9) 1 (2.9) Question 15: The patients described are experiencing breakthrough pain. According to the labeling, a TIRF medicine is not appropriate for one of them. Which patient should not receive a TIRF medicine? Please select one option. Adult male with advanced 11mg cancer: underlying persistent cancer pain managed with 25 111cg/hour transdermal fentanyl patches for the past two months. 17 (9.6) 2 (7.7) 5 (7.4) 1 (2.9) Adult female with localized breast cancer: just completed a mastectomy and reconstructive surgery: persistent cancer pain managed with 30 mg oral morphine daily for the past 6 weeksm 126 (70.8) [63.5 - 77.3] 19 (73.1) [52.2 - 88.4] 52 (76.5) [64.6 - 85.9] 28 (80.0) [63.1 - 91.6] Data Source: ADPQ, ADTQ Program: TRIG TIRF Prescriber KAB Page 4 of 5 03DEC2015 Table 8.1.2: Responses to Questions Linked to Key Risk Message #2 by Medical Degree of Respondents - Completed Surveys Key Risk Message TIRF medicines are only indicated for the management of breakthrough pain in adult cancer patients 18 years of age and older (16 years of age and older for Actiq? brand and generic equivalents) who are already receiving and who are tolerant to around-the?clock opioid therapy for their underlying, persistent cancer pain. Medical Degree of Respondents Ml) DO Nurse Practitioner Physician Assistant Question 11 [95% cum [95% 11 [95% 11 [95% "1 Adult male patient with 12 (6.7) 2 (7.7) 4 (5.9) 0 advanced prostate cancer who. over the last 2 weeks. has been prescribed 100 mg oral morphine daily for pain due to bone metastasis. Adult female with advanced 8 (4.5) 2 (7.7) 6 (8.8) 3 (8.6) sarcoma who has been taking a daily dose of 12 mg oral hydromorphone for the last 3 weeks. Idon't know 15 (8.4) 1 (3.8) 1 (1.5) 3 (8.6) Question 20: Before initiating treatment with a TIRF medicine, prescribers must review the Medication Guide with the patient. Please select True, False, or I don't know for each of the following counseling statements. 20b: Inform patients that IRF medicines must not be used for acute or postoperative pain, pain from injuries, headache/migraine, or any other short-term pain. Truem 166 (93.3) [88.5 - 96.5] 26 (100.0) [86.8 - 100.0] 62 (91.2) [81.8 - 96.7] 34 (97.1) [85.1 - 99.9] False 10 (5.6) 0 1 (1.5) 1 (2.9) Data Source: ADPQ, ADTQ Program: TRIG TIRF Prescriber KAB Page 5 of5 03DEC2015 Table 8.1.2: Responses to Questions Linked to Key Risk Message #2 by Medical Degree of Respondents - Completed Surveys Key Risk Message TIRF medicines are only indicated for the management of breakthrough pain in adult cancer patients 18 years of age and older (16 years of age and older for Actiq? brand and generic equivalents) who are already receiving and who are tolerant to around-the?clock opioid therapy for their underlying, persistent cancer pain. Medical Degree of Respondents Ml) D0 Nurse Practitioner Physician Assistant Question 11 [95% cum [95% 11 [95% [95% "1 I don't know 2 1.1) 0 5 (7.4) 20c: Instruct patients that they can continue to take their IRF medicine, ifthey stop taking their around-the-clock opioid medicine. True 39 (21.9) 8 (30.8) 14 (20.6) 3 (8.6) Falsem 129 (72.5) [65.3 - 78.9] 17 (65.4) [44.3 - 82.8] 49 (72.1) [59.9 - 82.3] 29 (82.9) [66.4 - 93.4] I don't know 10 (5.6) 1 (3.8) 5 (7.4) 3 (8.6) 95% exact two-sided con?dence intervals are calculated using the Clopper-Pearson method. Correct response. Data Source: ADPQ, ADTQ Program: TRIG TIRF Prescriber KAB Page 1 of 5 03DEC2015 Table 8.1.4: Responses to Questions Linked to Key Risk Message #2 by Time Practicing Medicine - Completed Surveys Key Risk Message TIRF medicines are only indicated for the management of breakthrough pain in adult cancer patients 18 years of age and older (16 years of age and older for Actiq? brand and generic equivalents) who are already receiving and who are tolerant to around-the?clock opioid therapy for their underlying, persistent cancer pain. Time Practicing Medicine Question Less than 3 years [95% cum 3 to 5 years [95% "1 6 to 15 years [95% More than 15 years [95% Question 6: Please answer True, False, or I don't know for each statement based on the labeling for TIRF medicines. 6a: According to the product labeling, a cancer patient may start a IRF medicine and an around-the-clock opioid at the same time. True 8 (19.5) 8 (21.1) 35 (28.7) 24 (22.4) Falsem 30 (73.2) [57.1 - 85.8] 28 (73.7) [56.9 - 86.6] 79 (64.8) [55.6 - 73.2] 75 (70.1) [60.5 - 78.6] I don't know 3 (7.3) 2 (5.3) 8 (6.6) 8 (7.5) 6b: According to the product labeling, a cancer patient who has been on an around-the-clock opioid for 1 day may start taking a IRF medicine for breakthrough pain. True 5 (12.2) 4 (10.5) 30 (24.6) 23 (21.5) Falsem 32 (78.0) [62.4 - 89.4] 30 (78.9) [62.7 - 90.4] 85 (69.7) [60.7 - 77.7] 77 (72.0) [62.5 - 80.2] I don't know 4 (9.8) 4 (10.5) 7 (5.7) 7 (6.5) Question 9: In your practice, for which of the following indications do you prescribe TIRF medicines to opioid tolerant patients? Please answer Yes, No, or I don't know for each option. 9a: Acute or postoperative pain Yes 4 (9.8) 1 (2.6) 14 (11.5) 9 (8.4) Non] 37 (90.2) [76.9 - 97.3] 37 (97.4) [86.2 - 99.9] 107 (87.7) [80.5 - 93.0] 97 (90.7) [83.5 - 95.4] Data Source: ADPQ, ADTQ Program: TRIG TIRF Prescriber KAB Page 2 of 5 03DEC2015 Table 8.1.4: Responses to Questions Linked to Key Risk Message #2 by Time Practicing Medicine - Completed Surveys Key Risk Message TIRF medicines are only indicated for the management of breakthrough pain in adult cancer patients 18 years of age and older (16 years of age and older for Actiq? brand and generic equivalents) who are already receiving and who are tolerant to around-the?clock opioid therapy for their underlying, persistent cancer pain. Time Practicing Medicine Less than 3 years 3 to 5 years 6 to 15 years More than 15 years Question 11 [95% cum [95% 11 [95% [95% I don't know 0 0 1 (0.8) 1 (0.9) 9b: Headache or migraine pain Yes 1 (2.4) 3 (7.9) 5 (4.1) 7 (6.5) 40 (97.6) [87.1 - 99.9] 35 (92.1) [78.6 - 98.3] 117 (95.9) [90.7 - 98.7] 100 (93.5) [87.0 - 97.3] I don't know 0 0 0 0 9c: Dental pain Yes 0 0 2 (1.6) 3 (2.8) Non] 41 (100.0) [91.4 - 100.0] 38 (100.0) [90.7 - 100.0] 120 (98.4) [94.2 - 99.8] 104 (97.2) [92.0 - 99.4] I don't know 0 0 0 9d: Breakthrough pain from cancer Yesm 36 (87.8) [73.8 - 95.9] 38 (100.0) [90.7 - 100.0] 114 (93.4) [87.5 - 97.1] 98 (91.6) [84.6 - 96.1] No 5 (12.2) 0 8 (6.6) 9 (8.4) I don't know 0 0 0 9e: Chronic non-cancer pain Yes 8 (19.5) 11 (28.9) 41 (33.6) 45 (42.1) Data Source: ADPQ, ADTQ Program: TRIG TIRF Prescriber KAB Page 3 of 5 03DEC2015 Table 8.1.4: Responses to Questions Linked to Key Risk Message #2 by Time Practicing Medicine - Completed Surveys Key Risk Message TIRF medicines are only indicated for the management of breakthrough pain in adult cancer patients 18 years of age and older (16 years of age and older for Actiq? brand and generic equivalents) who are already receiving and who are tolerant to around-the?clock opioid therapy for their underlying, persistent cancer pain. Time Practicing Medicine Less than 3 years 3 to 5 years 6 to 15 years More than 15 years Question 11 [95% cum [95% "1 [95% [95% "1 31 (75.6) [59.7 - 87.6] 27 (71.1) [54.1 - 84.6] 81 (66.4) [57.3 - 74.7] 61 (57.0) [47.1 - 66.5] I don't know 2 (4.9) 0 0 1 (0.9) Question 15: The patients described are experiencing breakthrough pain. According to the labeling, a TIRF medicine is not appropriate for one of them. Which patient should not receive a TIRF medicine? Please select one option. Adult male with advanced 11mg cancer: imderlying persistent cancer pain managed with 25 mcg/hour transdermal fentanyl patches for the past two months. 2 (4.9) 4 (10.5) 11 (9.0) 9 (8.4) Adult female with localized breast cancer: just completed a mastectomy and reconstructive surgery: persistent cancer pain managed with 30 111g oral morphine daily for the past 6 weeksm 35 (85.4) [70.8 - 94.4] 27 (71.1) [54.1 - 84.6] 90 (73.8) [65.0 - 81.3] 73 (68.2) [58.5 - 76.9] Data Source: ADPQ, ADTQ Program: TRIG TIRF Prescriber KAB Page 4 of 5 03DEC2015 Table 8.1.4: Responses to Questions Linked to Key Risk Message #2 by Time Practicing Medicine - Completed Surveys Key Risk Message TIRF medicines are only indicated for the management of breakthrough pain in adult cancer patients 18 years of age and older (16 years of age and older for Actiq? brand and generic equivalents) who are already receiving and who are tolerant to around-the?clock opioid therapy for their underlying, persistent cancer pain. Time Practicing Medicine Less than 3 years 3 to 5 years 6 to 15 years More than 15 years Question 11 [95% cum [95% 11 [95% 11 [95% "1 Adult male patient with 0 3 (7.9) 10 (8.2) 5 (4.7) advanced prostate cancer who. over the last 2 weeks. has been prescribed 100 mg oral morphine daily for pain due to bone metastasis. Adult female with advanced 3 (7.3) 2 (5.3) 7 (5.7) 7 (6.5) sarcoma who has been taking a daily dose of 12 mg oral hydromorphone for the last 3 weeks. Idon't know 1 (2.4) 2 (5.3) 4 (3.3) 13 (12.1) Question 20: Before initiating treatment with a TIRF medicine, prescribers must review the Medication Guide with the patient. Please select True, False, or I don't know for each of the following counseling statements. 20b: Inform patients that IRF medicines must not be used for acute or postoperative pain, pain from injuries, headache/migraine, or any other short-term pain. Truem 37 (90.2) [76.9 - 97.3] 36 (94.7) [82.3 - 99.4] 115 (94.3) [88.5 - 97.7] 101 (94.4) [88.2 - 97.9] False 3 (7.3) 1 (2.6) 3 (2.5) 5 (4.7) Data Source: ADPQ, ADTQ Program: TRIG TIRF Prescriber KAB Page 5 of5 03DEC2015 Table 8.1.4: Responses to Questions Linked to Key Risk Message #2 by Time Practicing Medicine - Completed Surveys Key Risk Message TIRF medicines are only indicated for the management of breakthrough pain in adult cancer patients 18 years of age and older (16 years of age and older for Actiq? brand and generic equivalents) who are already receiving and who are tolerant to around-the?clock opioid therapy for their underlying, persistent cancer pain. Time Practicing Medicine Less than 3 years 3 to 5 years 6 to 15 years More than 15 years Question 11 [95% cum [95% 11 [95% cull] [95% "1 Idon't know 1 (2.4) 1 (2.6) 4 (3.3) 1 (0.9) 20c: Instruct patients that they can continue to take their IRF medicine, ifthey stop taking their around-the-clock opioid medicine. True 9 (22.0) 9 (23.7) 26 (21.3) 20 (18.7) Falsem 30 (73.2) [57.1 - 85.8] 27 (71.1) [54.1 - 84.6] 87 (71.3) [62.4 - 79.1] 80 (74.8) [65.4 - 82.7] I don't know 2 (4.9) 2 (5.3) 9 (7.4) 7 (6.5) 95% exact two-sided con?dence intervals are calculated using the Clopper-Pearson method. Conect response. Data Source: ADPQ, ADTQ Program: TRIG Page 1 of 6 TIRF Prescriber KAB 03DEC2015 Table 8.1.5: Responses to Questions Linked to Key Risk Message #2 by Number of Times Prescribing TIRF Medicines per Month Within the Last 6 Months - Completed Sulyeys Key Risk Message TIRF medicines are only indicated for the management of breakthrough pain in adult cancer patients 18 years of age and older (16 years of age and older for Actiq? brand and generic equivalents) who are already receiving and who are tolerant to around-the?clock opioid therapy for their underlying, persistent cancer pain. Number of Times Prescribing TIRF Medicines per Month Within the Last 6 Months 1 2 times 3 5 times More than 5 times I don't None per month per month per month remember (N=l3) Question [95% 11 [95% '11 [95% 11 [95% 11 [95% Question 6: Please answer True, False, or I don't know for each statement based on the labeling for TIRF medicines. 6a: According to the product labeling, a cancer patient may start a IRF medicine and an around-the-clock opioid at the same time. True 11 (14.3) 43 (27.9) 11 (22.4) 7 (41.2) 3 (23.1) Falsem 59 (76.6) [65.6 - 85.5] 101 (65.6) [57.5 - 73.0] 36 (73.5) [58.9 - 85.1] 10 (58.8) [32.9 - 81.6] 8 (61.5) [31.6 - 86.1] I don't know 7 (9.1) 10 (6.5) 2 (4.1) 0 2 (15.4) 6b: According to the product labeling, a cancer patient who has been on an around-the-clock opioid for 1 day may start taking a IRF medicine for breakthrough pain. Tme 11 (14.3) 29 (18.8) 11 (22.4) 5 (29.4) 6 (46.2) Falsem 61 (79.2) [68.5 - 87.6] 112 (72.7) [65.0 - 79.6] 36 (73.5) [58.9 - 85.1] 12 (70.6) [44.0 - 89.7] 5 (38.5) [13.9 - 68.4] I don't know 5 (6.5) 13 (8.4) 2 (4.1) 0 2 (15.4) Question 9: In your practice, for which of the following indications do you prescribe TIRF medicines to opioid tolerant patients? Please answer Yes, No, or I don't know for each option. 9a: Acute or postoperative pain Yes 5 (6.5) 12 (7.8) 8 (16.3) 2 (11.8) 1 (7.7) Data Source: ADPQ, ADTQ Program: TRIG TIRF Prescriber KAB Page 2 of 6 03DEC2015 Table 8.1.5: Responses to Questions Linked to Key Risk Message #2 by Number of Times Prescribing TIRF Medicines per Month Within the Last 6 Months - Completed vaeys Key Risk Message TIRF medicines are only indicated for the management of breakthrough pain in adult cancer patients 18 years of age and older (16 years of age and older for Actiq? brand and generic equivalents) who are already receiving and who are tolerant to around-the-clock opioid therapy for their underlying, persistent cancer pain. Number of Times Prescribing TIRF Medicines per Month Within the Last 6 Months 1 - 2 times 3 - 5 times More than 5 times I don't None per month per month per month remember (N=l3) Question 11 [95% 011?] [95% 11 [95% 11 [95% cull] [95% 72 (93.5) [85.5 - 97.9] 141 (91.6) [86.0 - 95.4] 40 (81.6) [68.0 - 91.2] 15 (88.2) [63.6 - 98.5] 12 (92.3) [64.0 - 99.8] I don't know 0 1 (0.6) 1 (2.0) 0 0 9b: Headache or migraine pain Yes 0 8 (5.2) 6 (12.2) 2 (11.8) 0 Non] 77 (100.0) [95.3 - 100.0] 146 (94.8) [90.0 - 97.7] 43 (87.8) [75.2 - 95.4] 15 (88.2) [63.6 - 98.5] 13 (100.0) [75.3 - 100.0] I don't know 0 0 0 0 0 9c: Dental pain Yes 0 1 (0.6) 2 (4.1) 2 (11.8) 0 77 (100.0) [95.3 - 100.0] 153 (99.4) [96.4 - 100.0] 47 (95.9) [86.0 - 99.5] 15 (88.2) [63.6 - 98.5] 13 (100.0) [75.3 - 100.0] I don't know 0 0 0 0 0 9d: Breakthrough pain from cancer Yesm 68 (88.3) [79.0 - 94.5] 144 (93.5) [88.4 - 96.8] 47 (95.9) [86.0 - 99.5] 16 (94.1) [71.3 - 99.9] 13 (100.0) [75.3 -100.0] No 9 (11.7) 10 (6.5) 2 (4.1) 1 (5.9) 0 Data Source: ADPQ, ADTQ Program: TRIG Page 3 of 6 TIRF Prescriber KAB 03DEC2015 Table 8.1.5: Responses to Questions Linked to Key Risk Message #2 by Number of Times Prescribing TIRF Medicines per Month Within the Last 6 Months - Completed Sulyeys Key Risk Message TIRF medicines are only indicated for the management of breakthrough pain in adult cancer patients 18 years of age and older (16 years of age and older for Actiq? brand and generic equivalents) who are already receiving and who are tolerant to around-the?clock opioid therapy for their underlying, persistent cancer pain. Number of Times Prescribing TIRF Medicines per Month Within the Last 6 Months 1 2 times 3 5 times More than 5 times I don't None per month per month per month remember (N=l3) Question [95% 11 [95% '11 [95% 11 [95% 11 [95% I don't know 0 0 0 0 0 9e: Chronic non-cancer pain Yes 13 (16.9) 53 (34.4) 27 (55.1) 10 (58.8) 3 (23.1) New 64 (83.1) [72.9 - 90.7] 99 (64.3) [56.2 - 71.8] 22 (44.9) [30.7 - 59.8] 7 (41.2) [18.4 - 67.1] 9 (69.2) [38.6 - 90.9] I don't know 0 2 (1.3) 0 0 (7.7) Question 15: The patients described are experiencing breakthrough pain. According to the labeling, a TIRF medicine is not appropriate for one of them. Which patient should not receive a TIRF medicine? Please select one option. Adult male with advanced 4 (5.2) 16 (10.4) 3 (6.1) 2 (11.8) 1 (7.7) lung cancer: underlying persistent cancer pain managed with 25 111cg/110ur transdermal fentanyl patches for the past two months. Data Source: ADPQ, ADTQ Program: TRIG TIRF Prescriber KAB Page 4 of 6 03DEC2015 Table 8.1.5: Responses to Questions Linked to Key Risk Message #2 by Number of Times Prescribing TIRF Medicines per Month Within the Last 6 Months - Completed vaeys Key Risk Message TIRF medicines are only indicated for the management of breakthrough pain in adult cancer patients 18 years of age and older (16 years of age and older for Actiq? brand and generic equivalents) who are already receiving and who are tolerant to around-the-clock opioid therapy for their underlying, persistent cancer pain. Number of Times Prescribing TIRF Medicines per Month Within the Last 6 Months localized breast cancer: just completed a mastectomy and reconstructive surgery: persistent cancer pain managed with 30 mg oral morphine daily for the past 6 weeksm 1 - 2 times 3 - 5 times More than 5 times I don't None per month per month per month remember (N=l3) Question 11 [95% 011?] [95% [95% 11 [95% cull] [95% Adult female with 60 (77.9) [67.0 - 86.6] 107 (69.5) [61.6 - 76.6] 40 (81.6) [68.0 - 91.2] 11 (64.7) [38.3 - 85.8] 9 (69.2) [38.6 - 90.9] Adult male patient with advanced prostate cancer who. over the last 2 weeks. has been prescribed 100 mg oral morphine daily for pain due to bone metastasis. 2 (2.6) 7 (4.5) 4 (8.2) 3 (17.6) 2 (15.4) Data Source: ADPQ, ADTQ Program: TRIG Page 5 of 6 TIRF Prescriber KAB 03DEC2015 Table 8.1.5: Responses to Questions Linked to Key Risk Message #2 by Number of Times Prescribing TIRF Medicines per Month Within the Last 6 Months - Completed Smyeys Key Risk Message TIRF medicines are only indicated for the management of breakthrough pain in adult cancer patients 18 years of age and older (16 years of age and older for Actiq? brand and generic equivalents) who are already receiving and who are tolerant to around-the?clock opioid therapy for their underlying, persistent cancer pain. Number of Times Prescribing TIRF Medicines per Month Within the Last 6 Months 1 - 2 times 3 - 5 times More than 5 times I don't None per month per month per month remember Question 11 [95% 11 [95% [95% 11 [95% 11 [95% Adult female with 6 (7.8) 11 (7.1) 2 (4.1) 0 0 advanced sarcoma who has been taking a daily dose of 12 mg oral hydromorphone for the last 3 weeks. Idon't know 5 (6.5) 13 (8.4) 0 1 (5.9) 1 (7.7) Question 20: Before initiating treatment with a TIRF medicine, prescribers must review the Medication Guide with the patient. Please select True, False, or I don't know for each of the following counseling statements. 20b: Inform patients that IRF medicines must not be used for acute or postoperative pain, pain from injuries, headache/migraine, or any other short-term pain. Truem 70 (90.9) [82.2 - 96.3] 145 (94.2) [89.2 - 97.3] 48 (98.0) [89.1 - 99.9] 17 (100.0) [80.5 - 100.0] 11 (84.6) [54.6 - 98.1] False 5 (6.5) 5 (3.2) (2.0) 0 (7.7) I don't know 2 (2.6) 4 (2.6) 0 0 1 (7.7) 20c: Instruct patients that they can continue to take their IRF medicine, if they stop taking their around-the-clock opioid medicine. True 15 (19.5) 28 (18.2) 13 (26.5) 4 (23.5) 4 (30.8) Data Source: ADPQ, ADTQ Program: TRIG Page 6 of 6 TIRF Prescriber KAB 03DEC2015 Table 8.1.5: Responses to Questions Linked to Key Risk Message #2 by Number of Times Prescribing TIRF Medicines per Month Within the Last 6 Months - Completed Smyeys Key Risk Message TIRF medicines are only indicated for the management of breakthrough pain in adult cancer patients 18 years of age and older (16 years of age and older for Actiq? brand and generic equivalents) who are already receiving and who are tolerant to around-the?clock opioid therapy for their underlying, persistent cancer pain. Number of Times Prescribing TIRF Medicines per Month Within the Last 6 Months 1 - 2 times 3 - 5 times More than 5 times I don't None per month per month per month remember (N=l3) Question 11 [95% 11 [95% [95% 11 [95% 11 [95% Falsem 52 (67.5) [55.9 - 77.8] 121 (78.6) [71.2 - 84.8] 31 (63.3) [48.3 - 76.6] 13 (76.5) [50.1 - 93.2] 9 (69.2) [38.6 - 90.9] I don't know 10 (13.0) 5 (3.2) 5 (10.2) 0 0 95% exact two-sided con?dence intervals are calculated using the Clopper-Pearson method. onect response. Data Source: ADPQ, ADTQ Program: TRIG Page 1 of TIRF Prescriber KAB 03DEC2015 Table 8.2: Secondary Analysis of Responses to Questions Linked to Key Risk Message #2 - Completed Surveys Key Risk Message TIRF medicines are only indicated for the management of breakthrough pain in adult cancer patients 18 years of age and older (16 years of age and older for Actiq? brand and generic equivalents) who are already receiving and who are tolerant to around?the?clock opioid therapy for their underlying, persistent cancer pain. Prescribe-rs Correct Responses 11 [95% 0 correct responses 0 1 correct response 0 2 correct responses 1 (0.3) 3 correct responses 3 (1.0) 4 correct responses 5 (1.6) 5 correct responses 12 (3.9) 6 correct responses 29 (9.4) 7 correct responses 39 (12.6) 8 correct responses 57 (18.4) 9 correct responses 82 (26.5) 10 correct responses 82 (26.5) [21.6 - 31.7] 95% exact two-sided con?dence intervals are calculated using the Clopper-Pearson method. Data Source: ADPQ, ADTQ Program: TRIG TIRF Prescriber KAB Page 1 of 03DEC2015 Table 9.1: Primary Analysis of Responses to Questions Linked to Key Risk Message #3 - Completed Surveys Key Risk Message TIRF medicines contain fentanyl, an opioid agonist and a Schedule II controlled substance, with abuse liability similar to other opioid analgesics. Question Prescribers [95% medicines. Question 7: Please answer True, False, or I don't know for each statement based on the labeling for TIRF 7e: It is important to monitor for signs of abuse and addiction in patients who take IRF medicines. Truem 306 (98.7) [96.7 - 99.6] False 2 (0.6) I don't know 2 (0.6) know for each option. Question 8: Which of the following are risk factors for opioid abuse? Please answer Yes, No, or I don't 8a: A personal history of illness Yesm 262 (84.5) [80.0 - 88.4] No 28 (9.0) I don't know 20 (6.5) 8b: A personal history of past or current alcohol or drug abuse, or a family history of illicit drug use or alcohol abuse Yesm 306 (98.7) [96.7 - 99.6] No 4 (1.3) I don?t know 0 medicines. Question 12: Please answer True, False, or I don't know for each statement based on the labeling for TIRF 12a: TIRF medicines can be abused in a manner similar to other opioid agonists. Truem 292 (94.2) [91.0 - 96.5] False 12 (3.9) I don't know 6 (1.9) 95% exact two-sided con?dence intervals are calculated using the Clopper-Pearson method. Correct response. Data Source: ADPQ, ADTQ Program: TRIG TIRF Prescriber KAB Page 1 of 2 03DEC2015 Table 9.1.2: Responses to Questions Linked to Key Risk Message #3 by Medical Degree of Respondents - Completed Surveys Key Risk Message TIRF medicines contain fentanyl, an opioid agonist and a Schedule II controlled substance, with abuse liability similar to other opioid analgesics. Question NID (N=l78) [95% ?1 Medical Degree of Respondents D0 [95% "1 Nurse Practitioner [95% Physician Assistant [95% Question 7: Please answer True, False, or I don't know for each statement based on the labeling for TIRF medicines. 7e: It is important to monitor for signs of abuse and addiction in patients who take TIRF medicines. Truem 176 (98.9) [96.0 - 99.9] 26 (100.0) [86.8 - 100.0] 66 (97.1) [89.8 - 99.6] 35 (100.0) [90.0 - 100.0] False (0.6) 0 1 (1.5) I don't know 1 (0.6) 0 1 (1.5) Question 8: Which of the following are risk factors for opioid abuse? Please answer Yes, No, or I don't know for each option. 8a: A personal history of illness Yesm 149 (83.7) [77.4 - 88.8] 22 (84.6) [65.1 - 95.6] 57 (83.8) [72.9 - 91.6] 32 (91.4) [76.9 - 98.2] No 17 (9.6) 3 (11.5) 6 (8.8) 2 (5.7) I don't know 12 (6.7) 1 (3.8) 5 (7.4) 1 (2.9) 8b: A personal history of past or current alcohol or drug abuse, or a family history of illicit drug use or alcohol abuse Yesm 176 (98.9) [96.0 - 99.9] 26 (100.0) [86.8 - 100.0] 66 (97.1) [89.8 - 99.6] 35 (100.0) [90.0 - 100.0] No 2 (1.1) 0 2 (2.9) I don't know 0 0 Question 12: Please answer True, False, or I don't know for each statement based on the labeling for TIRF medicines. Data Source: ADPQ, ADTQ Program: TRIG TIRF Prescriber KAB Page 2 of 2 03DEC2015 Table 9.1.2: Responses to Questions Linked to Key Risk Message #3 by Medical Degree of Respondents - Completed Surveys Key Risk Message TIRF medicines contain fentanyl, an opioid agonist and a Schedule II controlled substance, with abuse liability similar to other opioid analgesics. Question NID (N=l78) [95% ?1 Medical Degree of Respondents D0 [95% "1 Nurse Practitioner [95% Physician Assistant [95% 120: TIRF medicines can be abused in a manner similar to other opioid agonists. Truem 166 (93.3) [88.5 - 96.5] 26 (100.0) [86.8 - 100.0] 62 (91.2) [81.8 - 96.7] 35 (100.0) [90.0 - 100.0] False 8 (4.5) 0 4 (5.9) 0 I don't know 4 (2.2) 0 2 (2.9) 0 95% exact two-sided con?dence intervals are calculated using the Clopper-Pearson method. Correct response. Data Source: ADPQ, ADTQ Program: TRIG TIRF Prescriber KAB Page 1 of 2 03DEC2015 Table 9.1.4: Responses to Questions Linked to Key Risk Message #3 by Time Practicing Medicine - Completed Surveys Key Risk Message TIRF medicines contain fentanyl, an opioid agonist and a Schedule II controlled substance, with abuse liability similar to other opioid analgesics. Question Less than 3 years [95% ?1 Time Practicing Medicine 3 to 5 years [95% "1 6 to 15 years [95% More than 15 years [95% Question 7: Please answer True, False, or I don't know for each statement based on the labeling for TIRF medicines. 7e: It is important to monitor for signs of abuse and addiction in patients who take TIRF medicines. Truem 41 (100.0) [91.4 - 100.0] 37 (97.4) [86.2 - 99.9] 121 (99.2) [95.5 - 100.0] 105 (98.1) [93.4 - 99.8] False 0 0 1 (0.8) 1 (0.9) I don't know 0 1 (2.6) 0 1 (0.9) Question 8: Which of the following are risk factors for opioid abuse? Please answer Yes, No, or I don't know for each option. 8a: A personal history of illness Yesm 35 (85.4) [70.8 - 94.4] 34 (89.5) [75.2 - 97.1] 104 (85.2) [77.7 - 91.0] 87 (81.3) [72.6 - 88.2] No 4 (9.8) 4 (10.5) 9 (7.4) 11 (10.3) I don't know 2 (4.9) 0 9 (7.4) 9 (8.4) 8b: A personal history of past or current alcohol or drug abuse, or a family history of illicit drug use or alcohol abuse Yesm 40 (97.6) [87.1 - 99.9] 38 (100.0) [90.7 - 100.0] 120 (98.4) [94.2 - 99.8] 106 (99.1) [94.9 - 100.0] No 1 (2.4) 0 2 (1.6) 1 (0.9) I don't know 0 0 Question 12: Please answer True, False, or I don't know for each statement based on the labeling for TIRF medicines. Data Source: ADPQ, ADTQ Program: TRIG TIRF Prescriber KAB Page 2 of 2 03DEC2015 Table 9.1.4: Responses to Questions Linked to Key Risk Message #3 by Time Practicing Medicine - Completed Surveys Key Risk Message TIRF medicines contain fentanyl, an opioid agonist and a Schedule II controlled substance, with abuse liability similar to other opioid analgesics. Less than 3 years Time Practicing Medicine 3 to 5 years 6 to 15 years More than 15 years Question [95% [95% "1 [95% [95% 120: IRF medicines can be abused in a manner similar to other opioid agonists. Truem 38 (92.7) [80.1 - 98.5] 34 (89.5) [75.2 - 97.1] 115 (94.3) [88.5 - 97.7] 103 (96.3) [90.7 - 99.0] False 2 (4.9) 2 (5.3) 5 (4.1) 3 (2.8) I don't know 1 (2.4) 2 (5.3) 2 (1.6) 1 (0.9) 95% exact two-sided con?dence intervals are calculated using the Clopper-Pearson method. Correct response. Data Source: ADPQ, ADTQ Program: TRIG TIRF Prescriber KAB Page 1 of 2 03DEC2015 Table 9.1.5: Responses to Questions Linked to Key Risk Message #3 by Number of Times Prescribing TIRF Medicines per Month Within the Last 6 Months - Completed vaeys Key Risk Message TIRF medicines contain fentanyl, an opioid agonist and a Schedule II controlled substance, with abuse liability similar to other opioid analgesics. Question Number of Times Prescribing TIRF Medicines per Month Within the Last 6 Months None (N =77) [95% 1 - 2 times per month [95% "1 3 - 5 times per month [95% More than 5 times per month [95% I don't remember (N=l3) [95% 011'" Question 7: Please answer True, False, or I don't know for each statement based on the labeling for TIRF medicines. 7e: It is important to monitor for signs of abuse and addiction in patients who take TIRF medicines. Truem 76 (98.7) [93.0 -100.0] 152 (98.7) [95.4 - 99.8] 48 (98.0) [89.1 - 99.9] 17 (100.0) [80.5 - 100.0] 13 (100.0) [75.3 - 100.0] False 0 1 (0.6) (2.0) 0 0 I don't know 1 (1.3) 1 (0.6) 0 0 0 Question 8: Which of the following are risk factors for opioid abuse? Please answer Yes, No, or I don't know for each option. 8a: A personal history of illness Yesm 67 (87.0) [77.4 - 93.6] 130 (84.4) [77.7 - 89.8] 39 (79.6) [65.7 - 89.8] 16 (94.1) [71.3 - 99.9] 10 (76.9) [46.2 - 95.0] No 5 (6.5) 16 (10.4) 5 (10.2) 1 (5.9) 1 (7.7) I don't know 5 (6.5) 8 (5.2) 5 (10.2) 0 2 (15.4) 8b: A personal history of past or current alcohol or drug abuse, or a family histonv of illicit drug use or alcohol abuse Yesm 77 (100.0) [95.3 - 100.0] 153 (99.4) [96.4 - 100.0] 47 (95.9) [86.0 - 99.5] 17 (100.0) [80.5 - 100.0] 12 (92.3) [64.0 - 99.8] No 0 (0.6) 2 (4.1) 0 (7.7) I don't know 0 0 0 0 0 Data Source: ADPQ, ADTQ Program: TRIG TIRF Prescriber KAB Page 2 of 2 03DEC2015 Table 9.1.5: Responses to Questions Linked to Key Risk Message #3 by Number of Times Prescribing TIRF Medicines per Month Within the Last 6 Months - Completed vaeys Key Risk Message TIRF medicines contain fentanyl, an opioid agonist and a Schedule II controlled substance, with abuse liability similar to other opioid analgesics. Question Number of Times Prescribing TIRF Medicines per Month Within the Last 6 Months None (N =77) [95% 1 - 2 times per month [95% 3 - 5 times per month [95% More than 5 times per month [95% I don't remember (N=l3) [95% 011'" Question 12: Please answer True, False, or I don't know for each statement based on the labeling for TIRF medicines. 120: medicines can be abused in a manner similar to other opioid agonists. Truem 72 (93.5) [85.5 - 97.9] 145 (94.2) [89.2 - 97.3] 47 (95.9) [86.0 - 99.5] 17 (100.0) [80.5 - 100.0] 11 (84.6) [54.6 - 98.1] False 3 (3.9) 7 (4.5) (2.0) 0 1 (7.7) Idon't know 2 (2.6) 2 (1.3) (2.0) 0 1 (7.7) 95% exact two-sided con?dence intervals are calculated using the Clopper-Pearson method. Correct response. Data Source: ADPQ, ADTQ Program: TRIG Page 1 of TIRF Prescriber KAB 03DEC2015 Table 9.2: Secondary Analysis of Responses to Questions Linked to Key Risk Message #3 - Completed Surveys Key Risk Message TIRF medicines contain fentanyl, an opioid agonist and a Schedule II controlled substance, with abuse liability similar to other opioid analgesics. Prescribers Correct Responses 11 [95% 0 correct responses 1 (0.3) 1 correct response 0 2 correct responses 6 (1.9) 3 correct responses 58 (18.7) 4 correct responses 245 (79.0) [74.1 - 83.4] 95% exact two-sided con?dence intervals are calculated using the Clopper-Pearson method. Data Source: ADPQ, ADTQ Program: TRIG Page 1 of 2 TIRF Prescriber KAB 03DEC2015 Table 10.1: Primary Analysis of Responses to Questions Linked to Key Risk Message #4 - Completed Surveys Key Risk Message TIRF medicines are not interchangeable with each other, regardless of route of administration. Prescribers Question 11 [95% Question 12: Please answer True, False, or I don't know for each statement based on the labeling for TIRF medicines. 12b: IRF medicines are interchangeable with each other regardless of route of administration. True 13 (4.2) Falsep] 287 (92.6) [89.1 - 95.2] I don't know 10 (3.2) 12c: The conversion of one IRF medicine for another TIRF medicine may result in a fatal overdose because of differences in the pharmacokinetics of fentanyl absorption. Truem 296 (95.5) [92.5 - 97.5] False 6 (1.9) I don?t know 8 (2.6) 12d: Dosing of TIRF medicines is not equivalent on a microgram-to-microgram basis. Truem 279 (90.0) [86.1 - 93.1] False 21 (6.8) I don't know 10 (3.2) Question 16: A patient is already taking a TIRF medicine but wants to change their medicine. His/her doctor decides to prescribe a different TIRF medicine (that is not a bioequivalent generic version of a branded product) in its place. According to the labeling, how should the prescriber proceed? Please select one option. The prescriber can safely convert to the equivalent dosage of the new TIRF 3 (1.0) medicine as it has the same effect as other TIRF medicines. The prescriber must not convert to another TIRF medicine on a 240 (77.4) [72.4 - 82.0] microgram-per-microgram basis because these medicines have different absorption properties and this could result in a fentanyl overdosem Convert from the other TIRF medicine to the new TIRF medicine at half of the dose. 22 (7.1) The prescriber should base the starting dose of the newly-prescribed TIRF medicine 33 (10.6) on the dose of the opioid medicine used for their underlying persistent cancer pain. Data Source: ADPQ, ADTQ Program: TRIG Page 2 of 2 TIRF Prescriber KAB 03DEC2015 Table 10.1: Primary Analysis of Responses to Questions Linked to Key Risk Message #4 - Completed Surveys Key Risk Message TIRF medicines are not interchangeable with each other, regardless of route of administration. Prescribers Question 11 [95% I don't know. 12 (3.9) 95% exact two-sided con?dence intervals are calculated using the lopper-Pearson method. Correct response. Data Source: ADPQ, ADTQ Program: TRIG TIRF Prescriber KAB Page 1 of 3 03DEC2015 Table 10.1.2: Responses to Questions Linked to Key Risk Message #4 by Medical Degree of Respondents - Completed Surveys Key Risk Message TIRF medicines are not interchangeable with each other, regardless of route of administration. Question M1) [95% cull] Medical Degree of Respondents D0 [95% Nurse Practitioner [95% Physician Assistant [95% Question 12: Please answer True, False, or I don't know for each statement based on the labeling for TIRF medicines. 12b: IRF medicines are interchangeable with each other regardless of route of administration. True 11 (6.2) 0 1 (1.5) 1 (2.9) Falsep] 162 (91.0) [85.8 - 94.8] 25 (96.2) [80.4 - 99.9] 64 (94.1) [85.6 - 98.4] 33 (94.3) [80.8 - 99.3] I don't know 5 (2.8) 1 (3.8) 3 (4.4) 1 (2.9) 12c: The conversion of one TIRF medicine for another TIRF medicine may result in a fatal overdose because of differences in the pharmacokinetics of fentanyl absorption. Truem 169 (94.9) [90.6 - 97.7] 25 (96.2) [80.4 - 99.9] 66 (97.1) [89.8 - 99.6] 33 (94.3) [80.8 - 99.3] False 4 (2.2) 1 (3.8) 1 (1.5) I don't know 5 (2.8) 0 (1.5) 2 (5.7) 12d: Dosing of IRF medicines is not equivalent on a microgram-to-microgram basis. Truem 165 (92.7) [87.8 - 96.1] 23 (88.5) [69.8 - 97.6] 60 (88.2) [78.1 - 94.8] 28 (80.0) [63.1 - 91.6] False 9 (5.1) 2 (7.7) 5 (7.4) 5 (14.3) I don't know 4 (2.2) 1 (3.8) 3 (4.4) 2 (5.7) Question 16: A patient is already taking a TIRF medicine but wants to change their medicine. His/her doctor decides to prescribe a different TIRF medicine (that is not a bioequivalent generic version of a branded product) in its place. According to the labeling, how should the prescriber proceed? Please select one option. Data Source: ADPQ, ADTQ Program: TRIG TIRF Prescriber KAB Page 2 of 3 03DEC2015 Table 10.1.2: Responses to Questions Linked to Key Risk Message #4 by Medical Degree of Respondents - Completed Surveys Key Risk Message TIRF medicines are not interchangeable with each other, regardless of route of administration. Medical Degree of Respondents MD DO Nurse Practitioner Physician Assistant Question 11 [95% 11 [95% "1 [95% 11 [95% The prescriber can safely 1 (0.6) 1 (3.8) 0 1 (2.9) convert to the equivalent dosage of the new TIRF medicine as it has the same effect as other TIRF medicines. The prescriber must not convert to another TIRF medicine on a 111icrogram-per-1nicrogram basis because these medicines have different absorption properties and this could result in a fentanyl overdosem 137 (77.0) [70.1 - 82.9] 21 (80.8) [60.6 - 93.4] 52 (76.5) [64.6 - 85.9] 27 (77.1) [59.9 - 89.6] Convert from the other TIRF medicine to the new TIRF medicine at half of the dose. 12 (6.7) 7 (10.3) 3 (8.6) Data Source: ADPQ, ADTQ Program: TRIG TIRF Prescriber KAB Page 3 of 3 03DEC2015 Table 10.1.2: Responses to Questions Linked to Key Risk Message #4 by Medical Degree of Respondents - Completed Surveys Key Risk Message TIRF medicines are not interchangeable with each other, regardless of route of administration. Medical Degree of Respondents MD DO Nurse Practitioner Physician Assistant Question 11 [95% 11 [95% "1 [95% 11 [95% The prescriber should base 20 (11.2) 4 (15.4) 6 (8.8) 3 (8.6) the starting dose of the newly-prescribed TIRF medicine on the dose of the opioid medicine used for their underlying persistent cancer pain. I don't know. 8 (4.5) 0 3 (4.4) 1 (2.9) 95% exact two-sided con?dence intervals are calculated using the Clopper-Pearson method. Correct response. Data Source: ADPQ, ADTQ Program: TRIG TIRF Prescriber KAB Page 1 of 3 03DEC2015 Table 10.1.4: Responses to Questions Linked to Key Risk Message #4 by Time Practicing Medicine - Completed Suweys Key Risk Message TIRF medicines are not interchangeable with each other, regardless of route of administration. Question Less than 3 years [95% cull] Time Practicing Medicine 3 to 5 years [95% 6 to 15 years [95% More than 15 years [95% Question 12: Please answer True, False, or I don't know for each statement based on the labeling for TIRF medicines. 12b: IRF medicines are interchangeable with each other regardless of route of administration. True 1 (2.4) 0 7 (5.7) 5 (4.7) Falsep] 38 (92.7) [80.1 - 98.5] 38 (100.0) [90.7 - 100.0] 108 (88.5) [81.5 - 93.6] 101 (94.4) [88.2 - 97.9] I don't know 2 (4.9) 0 7 (5.7) 1 (0.9) 12c: The conversion of one TIRF medicine for another TIRF medicine may result in a fatal overdose because of differences in the pharmacokinetics of fentanyl absorption. Truem 39 (95.1) [83.5 - 99.4] 36 (94.7) [82.3 - 99.4] 115 (94.3) [88.5 - 97.7] 104 (97.2) [92.0 - 99.4] False 2 (4.9) 0 2 (1.6) 2 (1.9) I don't know 0 2 (5.3) 5 (4.1) 1 (0.9) 12d: Dosing of IRF medicines is not equivalent on a microgram-to-microgram basis. Truem 36 (87.8) [73.8 - 95.9] 35 (92.1) [78.6 - 98.3] 110 (90.2) [83.4 - 94.8] 96 (89.7) [82.3 - 94.8] False 3 (7.3) 3 (7.9) 8 (6.6) 7 (6.5) I don't know 2 (4.9) 0 4 (3.3) 4 (3.7) Question 16: A patient is already taking a TIRF medicine but wants to change their medicine. His/her doctor decides to prescribe a different TIRF medicine (that is not a bioequivalent generic version of a branded product) in its place. According to the labeling, how should the prescriber proceed? Please select one option. Data Source: ADPQ, ADTQ Program: TRIG TIRF Prescriber KAB Page 2 of 3 03DEC2015 Table 10.1.4: Responses to Questions Linked to Key Risk Message #4 by Time Practicing Medicine - Completed Surveys Key Risk Message TIRF medicines are not interchangeable with each other, regardless of route of administration. Time Practicing Medicine Less than 3 years 3 to 5 years 6 to 15 years More than 15 years Question 11 [95% 11 [95% "1 [95% 11 [95% The prescriber can safely 1 (2.4) 0 0 2 (1.9) convert to the equivalent dosage of the new TIRF medicine as it has the same effect as other TIRF medicines. The prescriber must not convert to another TIRF medicine on a 111icrogram-per-microgram basis because these medicines have different absorption properties and this could result in a fentanyl overdosem 33 (80.5) [65.1 - 91.2] 29 (76.3) [59.8 - 88.6] 97 (79.5) [71.3 - 86.3] 79 (73.8) [64.4 - 81.9] Convert from the other TIRF medicine to the new TIRF medicine at half of the dose. 2 (5.3) 9 (7.4) 11 (10.3) Data Source: ADPQ, ADTQ Program: TRIG TIRF Prescriber KAB Page 3 of 3 03DEC2015 Table 10.1.4: Responses to Questions Linked to Key Risk Message #4 by Time Practicing Medicine - Completed Surveys Key Risk Message TIRF medicines are not interchangeable with each other, regardless of route of administration. Time Practicing Medicine Less than 3 years 3 to 5 years 6 to 15 years More than 15 years Question 11 [95% 11 [95% "1 [95% 11 [95% The prescriber should base 6 (14.6) 6 (15.8) 13 (10.7) 8 (7.5) the starting dose of the newly-prescribed TIRF medicine on the dose of the opioid medicine used for their underlying persistent cancer pain. I don't know. 1 (2.4) (2.6) 3 (2.5) 7 (6.5) 95% exact two-sided con?dence intervals are calculated using the Clopper-Pearson method. Correct response. Data Source: ADPQ, ADTQ Program: TRIG Page 1 of 3 TIRF Prescriber KAB 03DEC2015 Table 10.1.5: Responses to Questions Linked to Key Risk Message #4 by Number of Times Prescribing TIRF Medicines per Month Within the Last 6 Months - Completed vaeys Key Risk Message TIRF medicines are not interchangeable with each other, regardless of route of administration. Number of Times Prescribing TIRF Medicines per Month Within the Last 6 Months 1 - 2 times 3 5 times More than 5 times I don't None per month per month per month remember Question [95% 11 [95% '11 [95% 11 [95% Cl]m [95% "1 Question 12: Please answer True, False, or I don't know for each statement based on the labeling for TIRF medicines. 12b: IRF medicines are interchangeable with each other regardless of route of administration. True 1 (1.3) 6 (3.9) 2 (4.1) 3 (17.6) 1 (7.7) Falsem 76 (98.7) [93.0 - 100.0] 140 (90.9) [85.2 - 94.9] 46 (93.9) [83.1 - 98.7] 13 (76.5) [50.1 - 93.2] 12 (92.3) [64.0 - 99.8] I don't know 0 8 (5.2) 1 (2.0) 1 (5.9) 0 12c: The conversion of one TIRF medicine for another TIRF medicine may result in a fatal overdose because of di?'erences in the pharmacokinetics of fentanyl absorption. Truem 75 (97.4) [90.9 - 99.7] 147 (95.5) [90.9 - 98.2] 46 (93.9) [83.1 - 98.7] 16 (94.1) [71.3 - 99.9] 12 (92.3) [64.0 - 99.8] False 1 (1.3) 3 (1.9) (2.0) 0 1 (7.7) Idon't know 1 (1.3) 4 (2.6) 2 (4.1) 1 (5.9) 0 12d: Dosing of IRF medicines is not equivalent on a microgram-to-microgram basis. Truep] 69 (89.6) [80.6 - 95.4] 139 (90.3) [84.4 - 94.4] 45 (91.8) [80.4 - 97.7] 14 (82.4) [56.6 - 96.2] 12 (92.3) [64.0 - 99.8] False 7 (9.1) 7 (4.5) 4 (8.2) 2 (11.8) 1 (7.7) I don't know 1 (1.3) 8 (5.2) 0 1 (5.9) 0 Data Source: ADPQ, ADTQ Program: TRIG TIRF Prescriber KAB Page 2 of 3 03DEC2015 Table 10.1.5: Responses to Questions Linked to Key Risk Message #4 by Number of Times Prescribing TIRF Medicines per Month Within the Last 6 Months - Completed vaeys Key Risk Message TIRF medicines are not interchangeable with each other, regardless of route of administration. Number of Times Prescribing TIRF Medicines per Month Within the Last 6 Months 1 - 2 times 3 5 times More than 5 times I don't None per month per month per month remember (N=l3) Question 11 [95% "1 [95% "1 [95% Cl] "1 [95% Cl] "1 [95% C1]'ll Please select one option. Question 16: A patient is already taking a TIRF medicine but wants to change their medicine. His/her doctor decides to prescribe a different TIRF medicine (that is not a bioequivalent generic version of a branded product) in its place. According to the labeling, how should the prescriber proceed? The prescriber can safely convert to the equivalent dosage of the new TIRF medicine as it has the same effect as other TIRF medicines. 2 (1.3) 0 0 1 (7.7) The prescriber must not convert to another TIRF medicine on a microgram-per-microgra 111 basis because these medicines have different absorption properties and this could result in a fentanyi overdosem Data Source: ADPQ, ADTQ Program: TRIG Page 3 of 3 TIRF Prescriber KAB 03DEC2015 Table 10.1.5: Responses to Questions Linked to Key Risk Message #4 by Number of Times Prescribing TIRF Medicines per Month Within the Last 6 Months - Completed Suweys Key Risk Message TIRF medicines are not interchangeable with each other, regardless of route of administration. Number of Times Prescribing TIRF Medicines per Month Within the Last 6 Months 1 - 2 times 3 - 5 times More than 5 times I don't None per month per month per month remember Question [95% [95% "1 [95% Cl] "1 [95% Cl] "1 [95% "1 Convert ?om the other 2 (2.6) 11 (7.1) 3 (6.1) 4 (23.5) 2 (15.4) TIRF medicine to the new TIRF medicine at half of the dose. The prescriber should 8 (10.4) 17 (11.0) 4 (8.2) 1 (5.9) 3 (23.1) base the starting dose of the newly-prescribed TIRF medicine on the dose of the opioid medicine used for their underlying persistent cancer pain. I don't know. 4 (5.2) 4 (2.6) 0 2 (11.8) 2 (15.4) 95% exact two-sided con?dence intervals are calculated using the Clopper-Pearson method. Correct response. Data Source: ADPQ, ADTQ Program: TRIG Page 1 of TIRF Prescriber KAB 03DEC2015 Table 10.2: Secondary Analysis of Responses to Questions Linked to Key Risk Message #4 - Completed Surveys Key Risk Message TIRF medicines are not interchangeable with each other, regardless of route of administration. Prescribers Correct Responses 11 [95% 0 correct responses 3 (1.0) 1 correct response 8 (2.6) 2 correct responses 13 (4.2) 3 correct responses 76 (24.5) 4 correct responses 210 (67.7) [62.2 - 72.9] 95% exact two-sided con?dence intervals are calculated using the Clopper-Pearson method. Data Source: ADPQ, ADTQ Program: TRIG TIRF Prescriber KAB Page 1 of2 10DEC2015 Table 11: Types of Chronic Pain Conditions Reported - Completed Surveys for Prescribers Who Prescribed TIRF Medicines for Chronic Non?Cancer Pain Question Prescribers tolerant patients? Question 10: For What type(s) of chronic pain conditions do you prescribe a TIRF medicine to opioid 2] Total Ntunber of Responses[ 214 Back Pain 34 (32.1) Cancer Pain 24 (22.6) Neuropathic Pain 23 (21.7) Post-Operative Pain 20 (18.9) Chronic Pain 19 (17.9) Joint Pain 11 (10.4) Re?ex Sympathetic 10 (9.4) Complex Regional Pain 8 (7.5) Spinal Pain 8 (7.5) Neck Pain 5 (4.7) Abdominal Pain 4 (3.8) Muscoskeletal Pain 4 (3.8) Sickle Cell 4 (3.8) Gastrointestinal Pain 3 (2.8) Migraines 3 (2.8) Palliative Care 3 (2.8) Pancreatitis 3 (2.8) Spinal Stenosis 3 (2.8) Breakthrough Pain 2 (1.9) Oral Pain 2 (1.9) Wound Pain 2 (1.9) Allergic to morphine and dilaudid (0.9) Chronic wounds 1 (0.9) Intestinal absorption problems 1 (0.9) Ischemic Peripheral Vascular Disease 1 (0.9) Data Source: ADPQ, _Qll Program: TC ATQ. SAS TRIG TIRF Prescriber KAB Page 2 of2 Table 11: Types of Chronic Pain Conditions Reported - Completed Surveys for Prescribers Who Prescribed TIRF Medicines for Chronic Non?Cancer Pain Prescribers Question 11 Multiple Sclerosis (0.9) Neuropathy (0.9) Radiculopathy (0.9) Somatic pain 1 (0.9) Trauma Pain 1 (0.9) Wound Care 1 (0.9) Otherm 9 (8.5) Number and percentages are based on the subset of completed surveys where prescribers responded "Yes" to prescribing TIRF medicines for chronic non-cancer pain (Question 9e: In your practice, for which oft/1e following indications do you prescribe TIRF medicines to opioid tolerant patients? Chronic Non-Cancer Pain? "Yes and were subsequently presented Question 10 and Question 11. Total number of responses may exceed the nmnber of prescribers and percentages may not equal 100% as multiple responses were provided by some prescribers. Other includes responses that were not categorized or responses that did not include a medical condition. Data Source: ADPQ, _Qll Program: TC ATQ. SAS TRIG TIRF Prescriber KAB Page 1 of2 10DEC2015 Table 12: Reasons for Selecting a TIRF Medicine Repo?ed - Completed Surveys for Prescribers Who Prescribed TIRF Medicines for Chronic Non-Cancer Pain Question Prescribers opioid tolerant? Question 11: Why do you select a TIRF medicine to treat these chronic pain conditions in patients who are 2] Total Number of Responses[ 169 Ef?cacy 38 (35.8) Fast Acting 36 (34.0) Other Types of Medications have Failed 30 (28.3) Breakthrough Pain 15 (14.2) Ease of Use 5 (4.7) Preferred Route of Administration 5 (4.7) Abuse/Diversion Deterrence 4 (3.8) Long Duration of Action 4 (3.8) Opioid Rotation 3 (2.8) Potency 3 (2.8) Quality of Life 3 (2.8) Insurance 2 (1.9) Pain Management 2 (1.9) Compliance 1 (0.9) Consistent Control 1 (0.9) Less Toxicities Compared to Other Opioids (0.9) Patient Cannot Tolerate Other Options 1 (0.9) Practice Preference (0.9) Preferred route of administration 1 (0.9) Prescribed by another physician before becoming a patient 1 (0.9) Severe Pain 1 (0.9) Data Source: ADPQ, _Qll Program: TC ATQ. SAS TRIG TIRF Prescriber KAB Page 2 of2 Table 12: Reasons for Selecting a TIRF Medicine Reported - Completed Surveys for Prescribers Who Prescribed TIRF Medicines for Chronic Non?Cancer Pain Prescribers Question 11 Otherm 11 (10.4) Number and percentages are based on the subset of completed surveys where prescribers responded "Yes" to prescribing TIRF medicines for chronic non-cancer pain (Question 9e: In your practice, for which of the following indications do you prescribe medicines to opioid tolerant patients? Chronic Non-Cancer Pain- "Yes and were subsequently presented Question 10 and Question 11. Total number of responses may exceed the number of prescribers and percentages may not equal 100% as multiple responses were provided by some prescribers. Other includes responses that were not categorized or responses that did not include a medical condition. Data Source: ADPQ, _Qll Program: TC ATQ. SAS TRIG TIRF Prescriber KAB Page 1 of5 Listing 1.1: Listing of Verbatim Responses to Question #10 (For what type(s) of chronic pain conditions do you prescribe a TIRF medicine to opioid tolerant patients?) Completed Surveys Survey Form II) Verbatim Responses 0004-000763 l) Malignancy related 2) Peripheral neuropathy 0004-001022 100 0004-001315 Arthritis. Refractory or Chronic Neuropathy/Neuralgia responsive to opiates. Degenerative Disc Disease. Chronic wounds or complications. Dental complications or Mucositis. and Metastatic Disease 0004-001213 Arthritis. migraines. neuropathic pain 0004-001225 Back pain. neuropathy 0004-001305 Besides cancer pain. Ihave used TIRF meds for avascular necrosis with joint destruction when regular opioids were required. 0004-001 178 Breakthrough pain in cancer patients. Chronic neuropathic pain and failed back surgery due to nerve damage/irritation in patients that cannot swallow due to other GI/craniofacial medical conditions. 0004-001 197 Burning mouth short gut 0004-000850 CANCER. COMPRESSION FRACTURES 0004-001299 CHRONIC PAIN 0004-001215 CHRONIC SPINAL RELATED PAIN 0004-000773 RPS. severe nonresponsive to other treatment back or neck pain 0004-000578 Cancer pain 0004-000454 Cancer patients 0004-001 102 Cancer related pain only 0004-000886 Cancer related. sickle cell. muscoskeletal. neurologic. 0004-001050 Cancer. spine diseases. severe rheumatologic disease 0004-000852 Chronic back pain Chronic pain secondary to ischemic PVD/non-healing leg wounds 0004-001079 Chronic pain from cancer 0004-001 182 Chronic pain 0004-001075 Chronic pain taking long acting med who need breakthrougn med 0004-000558 Chronic pain when there are severe discrete episodes of debilitating breakthrough pain 0004-001 161 Chronic pain where an oral medication cannot be tolerated. 0004-00 1084 Chronic post surgical (abdominal. lmnbar. orthopedic) pain refractory to other narcotics. Advanced chronic pancreatitis pain. 0004-001239 Chronic regional pain advanced degenerative joint disease: medullary sponge kidney. Data Source: ADPQ Program: LQCAT.SAS TRIG TIRF Prescriber KAB Page 2 of5 Listing 1.1: Listing of Verbatim Responses to Question #10 (For what type(s) of chronic pain conditions do you prescribe a TIRF medicine to opioid tolerant patients?) Completed Surveys Survey Form II) Verbatim Responses 0004-001 176 Chronic sacral pain. chronic back pain that surgery has not helped and patient can't get any relief during BM 0004-001 130 Complex Regional Pain 0004-000383 Complex regional pain Cancer patients. 0004-001290 FAILED BACK . NON OPERATIVE CERVICAL OR LUMBAR DISC DISEASE 0004-000495 Failed Back General chronic pain Severe neck pain Complex Regional pain Any Peripheral Neuropathy 0004-00063 7 Failed Back Postlaminectomy RSD 0004-001 131 Failed Surgical Peripheral Neuropathy 0004-001096 Failed back surgery pain. CRPS 0004-001077 Failed back Chronic low back and neck pain. RSD 0004-000391 Failed back chronic pelvic pain with dyspareunia: 0004-001073 I only have one pt with signi?cant back pain and an extensive operative history-otherwise it is only used for cancer 0004-000851 Intractable back pain in patients with high opioid tolerance 0004-001 105 Life limiting ilhlesses such as COPD. CHF. etc. Those that are progressive. irreversible and terminal. As a palliative care physician I utilize TIRF medicine to manage negative of conditions that have a chronic pain(as well as component. I do not treat 'chronic pain' patients but all conditions I do see have or have the potential to have a pain component. 0004-001 177 MIgraines 0004-001237 PATIENTS WHO HAVE TRIED ALL OTHER INTERVENTIONAL MEDICATIONS 0004-001 149 Patient who need round the clock medicaiton w/o frequent dosing. 0004-001 151 Patients with chronic wounds prior to womld care 0004-001 180 Post thalamic stroke pain 0004-001056 Post-lami 0004-000822 Post-laminectomy Pain Complex Regional Pain 0004-000926 Postlaminectomy severe neuropathy: chronic severe trauma patients-paraplegic.etc. 0004-00 1044 Primarily Cancer Pain 0004-001071 Profound end-stage RA Data Source: ADPQ Program: LQCAT.SAS TRIG Page 3 of 5 TIRF Prescriber KAB Listing 1.1: Listing of Verbatim Responses to Question #10 (For what type(s) of chronic pain conditions do you prescribe a TIRF medicine to opioid tolerant patients?) Completed Surveys Survey Form II) Verbatim Responses 0004-000765 RSD 0004-001 157 RSD 0004-001194 Refractory Neuropathic severe episodic pain 0004-001080 SPINAL STENOSIS. ARTHRITIS. FIBRO 0004-001141 Severe Musculoskeletal and Neuropathic-type pain conditions. 0004-000667 Severe joint pains secondary to avascular necrosis. joint replacements. or severe arthritic conditions. 0004-000799 Severe. unremitting. rapid onset neuropathic pain not controlled by long and other short-acting opioids. and which are luiresponsive to non-opioid medications. a cause is known. and for which other surgical/ injection treatment options have failed. 0004-001304 Spine related. radiculopathy. neuropathy 0004-001 170 TRIGEMINAL NEURALGIA 0004-001027 Uncontrolled with traditional short acting opioids due to speed of onset 0004-000920 We have a patient with chronic abdominal pain. chronic pain after ovarian cancer and a patient with uncontrollable pain after back surgery 0004-000787 abdominal pain due to chrons 0004-001214 back pain 0004-000896 cancer 0004-001206 cancer associated pain. chronic arthritis 0004-001106 cancer pain mainly 0004-000628 cancer pain. chronic pain back. spondylosis. ect) not amenable to other opioid regimens 0004-000833 cancer pain. spinal cord injury pain. nerve pain. muscularskeletal pain 0004-000432 cancer. RSD. some types of neuropathic pain 0004-000444 cancer.chr0nic back pain. migraine 0004-000485 ch. pancreatitis 0004-000433 chronic back pain 0004-000480 chronic back pain. chronic joint pain 0004-001279 chronic cancer related pain 0004-001257 chronic intractable head/facial pain after MVA with facial implants. 0004-000767 chronic low back pains Data Source: ADPQ Program: LQCAT.SAS TRIG TIRF Prescriber KAB Page 4 of 5 10DEC2015 Listing 1.1: Listing of Verbatim Responses to Question #10 (For what twe(s) of chronic pain conditions do you prescribe a TIRF medicine to opioid tolerant patients?) Completed Surveys Survey Form II) Verbatim Responses 0004-00 1 162 chronic neuropathic pain 0004-001 128 chronic pain due to injury. 0a. lumbar 0004-000761 chronic pain that is treatment related and not controlled by other means of medication. 0004-001 168 chronic uncontrolled pain. especially abdominal pain and spine pain conditions 0004-000514 chronic with acute exacerbations 0004-000498 chrons dz post chemo neuropathy post neuropathy 0004-00 1053 end stage life limiting disease in patients who are on hospice. such as advanced arthritis. end stage neurologic disease 0004-001 1 12 failed back 0004-001 199 intolerant to oral opioids due to intestinal absorption problems. cancer pain 0004-000396 low back pain 0004-000923 low back. post lami resistant RSD. Other chronic pain conditions 0004-00 1094 lower back pain. neck pain. rsd. ms rheumatoid arthritis 0004-000477 multiple sclerosis neuropathic pain. diabetic polyneuropathy. cervical/hunbar stenosis. failed neck/back cancer pain (multiple types) 0004-000448 neuropathic pain 0004-000417 non-responsive neuralgia's. crippling CRPS 0004-000473 pancreatitis abdominal pain severe failed back 0004-00 1078 patients who have allergies to dilaudid and morphine and patients on opiates for dressing changes/wound care. 0004-000402 post laminectomy 0004-000759 post laminectomy chronic radiculopathy. spondylolisthesis. foraminal stenosis. 0004-00 1072 post laminectomy severe spinal stenosis. severe total body pain 0004-00 1200 primarily chronic spinal or musculoskeletal pain - may or may not be related to their underlying cancer diagnosis 0004-000569 rare patients for whom conventional IR meds are nle?ective 0004-001292 scoliosis. neuropathic leg pain 0004-001 145 sever chronic Pain from sever arthritis or back surgery if they are opioid tolerant 0004-00 1068 severe cases of RSD that are not responsive to DRG blocks. and around the clock opiod therapy Data Source: ADPQ Program: LQCAT.SAS TRIG TIRF Prescriber KAB Page 5 of 5 10DEC2015 Listing 1.1: Listing of Verbatim Responses to Question #10 (For what type(s) of chronic pain conditions do you prescribe a TIRF medicine to opioid tolerant patients?) Completed Surveys Survey Form Verbatim Responses 0004-00043 5 sickle cell patients. chronic regional pain 0004-000916 sickle cell. abdominal pain 0004-001089 somatic or neuropathic both work 0004-001081 spinal myelopathic pain sickle cell crisis 0004-001308 spinal stenosis. severe joint 0A. chronic pain s/p multi trauma 0004-000555 trigeminal neuralgia 0004-001098 unspeci?ed chronic pain uncontrolled by all other means Note: Question 10 is only asked if Question 9e is answered "Yes". Data Source: ADPQ Program: LQCAT.SAS TRIG Page 1 of TIRF Prescriber KAB Listing 1.2: Listing of Verbatim Responses to Question #10 (For what type(s) of chronic pain conditions do you prescribe a TIRF medicine to opioid tolerant patients?) Incomplete Suweys Survey Form Verbatim Responses 0004-001063 CRPS 0004-001228 Cancer. Neuropathic pain. Chronic intractable pain 0004-001016 Chronic abdominal pain related to multiple surgeries. surgical complications or complex GI issues 0004-001259 Failed back surgery. Lumbar radiculopathy 0004-000361 LBP SC anemia 0004-001003 Usually use fentanyl patch for chronic back or neck pain due to failed surgery. 0004-001258 breakthough pain that is fast acting to allow for transfers from bed to wheelchair on a PRN basis 0004-000324 chronic low back pain 0004-000428 sickle cell anemia 0004-001217 spinal related pain. joint pain. Note: Question 10 is only asked if Question 9e is answered "Yes". Data Source: ADPQ Program: LQCAT.SAS TRIG TIRF Prescriber KAB Page 1 of5 10DEC2015 Listing 2.1: Listing of Verbatim Responses to Question #11 (Why do you select a TIRF medicine to treat these chronic pain conditions in patients who are opioid tolerant?) Completed Surveys Survey Form I1) Verbatim Responses 0004-001237 ABUSE DETERRENT 0004-00 1 194 All else has failed and need the acute onset 0004-000852 Aromld the clock therapy is more advantageous for chronic pain than ?equent dosing of short acting opioids. Less risk of patient abusing patch vs access to multiple pills. 0004-001299 BREAKTHROUGH 0004-001213 Because a non opioid will not work. 0004-001 182 Because nothing else is working. 0004-000667 Because patient?s pain is not controlled with long-acting and short-acting opiates. 0004-00 1075 Because they still work a bit 0004-001 151 Because they work quickly and are very effective 0004-001 199 Better control of pain/functionality usually in cancer patients that have tried other opioids unsucessfully 0004-001315 Breakthrough pain. easier application. patients with Nausea/Vomiting. or di?iculty with P0 routes of medication 0004-001 197 Cant take oral or orals not potent enough 0004-000765 Consistent round the clock pain control 0004-001 105 Ease of use. ef?cacy in most patients. ability to titrate rapidly and safely. 0004-000578 Easy administration and rapid onset 0004-00 1096 Ef?cacy. compliance 0004-001257 Failed all other breakthrough meds previously 0004-000851 Failed multiple other breakthrough opiate analgesics.modalities of pain relief 0004-000391 Failed other opioid agents and still have pain scores greater than 7/ 10.TIRF medicine allows them to function. 0004-00 1068 Failure of the the conventional medications and procedures to proxide relief 0004-001 141 Fast onset of action. Catches BTP episode as quickly as possible allowing greater chance of bringing under control. 0004-001 130 Fastest relief in acute breakthrough pain 0004-000822 For episodes of acute exacerbation from activity. 0004-001 168 For immediate control of sudden acute pain ?ares and to better control the peaks of pain 0004-000761 I do so rarely in patients with non tolerable pain not managed by other means Data Source: ADPQ Program: LQCAT.SAS TRIG TIRF Prescriber KAB Page 2 of5 10DEC2015 Listing 2.1: Listing of Verbatim Responses to Question #11 (Why do you select a TIRF medicine to treat these chronic pain conditions in patients who are opioid tolerant?) Completed Surveys Survey Form I1) Verbatim Responses 0004-00 1098 I only have one patient treated with a TIRF medication and he was previously on the medication before coming to my clinic. He has a complicated history and it is the only medication that controls his chronic pain 0004-00 107 1 I prefer to minimize the number of opioid molecules used in any pain regiment. I only prescribe TIRF product to that are already on fentanyl at least 100mcg/hr 0004-00 1 102 I use this product when we are looking for management of acute. pain ?ares in cancer related pain for patients who are opioid tolerant. I use it there current BTD are not covering severe pain crisis and goal is to keep pt out of the ER setting 0004-00 1050 If needed for adequate pain control 0004-000558 If the pain comes on quickly. These medications bring the quickest relief 0004-000773 It allows fast effective relief for severe episodes of BTP 0004-001 180 It has been effective and the patient entered my care from another provider who had initiated TIRF treatment 0004-001 131 It has proxided them bene?cial control of breakthrough pain when needed. 0004-000759 It helps to minimize the possibility of pill abuse and also helps those who do not want to have pills in their home due to fear of theft 0004-001215 LONG DURATION OF ACTION 0004-000799 Last resort 0004-000886 Less toxicities compared to oral morphine or oxycodone. Better pain relief compared to other short acting pain medications. 0004-001 149 Long acting forms and the fact that I can use a patch and avoid taking frequent doses orally. 0004-001 170 Many non TIRF medications were tried ?rst with little success in pain control and functional stability 0004-000763 Need for rapid onset analgesia with short duration. 0004-00 1077 Nothing has worked that well. Opioid rotation 0004-001308 Only if other meds have failed or opiate genotype suggests abnormal metabolism 0004-001 161 Oral medication is not an option. 0004-001225 Other meds haven't worked 0004-00 1073 Pt did not respond to other opioid therapies including intrathecal pump placement 0004-00 1304 Quick Onset for breakthrough or activity induced pain 0004-00 1079 Quick acting for breakthrough pain 0004-00 1 162 Rapid onset of action Data Source: ADPQ Program: LQCAT.SAS TRIG Page 3 of 5 TIRF Prescriber KAB 10DEC2015 Listing 2.1: Listing of Verbatim Responses to Question #11 (Why do you select a TIRF medicine to treat these chronic pain conditions in patients who are opioid tolerant?) Completed Surveys Survey Form II) Verbatim Responses 0004-001290 TO AVOID MULTIPLE OPIOID MEDICATION 0004-000850 TO GIVE IMMEDIATE BREAK THROUGH PAIN RELIEF 0004-000495 The reason being I have lots of patients by the time they have been referred to me they have tried lots of other of medicines. and none seem to be working. Second reason is if they are already on the patch and that seems to be working. but they still need something for breakthrough pain this will be a good complimentary. 0004-000402 They are already on a long acting opioid. typically fentanyl. and need a fast acting breakthrough agent 0004-001176 They have a sudden pain with BM and the TIRF medication can help in only a few minutes as apposed to 30 - 45 min The have severe pain with BM's and they need the help as soon as they feel that they are going to have a BM 0004-000637 They have failed other opiate meds 0004-000920 They have tried and failed every other break through pain medication and the pain could not be controlled any other way. 0004-000383 To improve function and quality of life. 0004-001305 Tolerating opioids and clearly bene?tting up to a certain dose. 0004-001080 USE THEM AS PART OF OPIOID ROTATION 0004-001214 Well ef?cacy 0004-001044 When short acting and fast onset is necessary. Patients wanting a clear sensorium as much as possible. 0004-000896 addresses pain well. titratable. covered by insurance 0004-001239 augment pain management. 0004-000396 camlot tolerate fentanyl patches 0004-001084 dor pain that is refractory to higher doses of conventional narcotics. 0004-000555 due to severe pain 0004-001027 due to ultra fast time of onset 0004-000444 effectiveness 0004-000916 ef?cacy 0004-000454 ef?cacy lack of other options 0004-000448 ef?cacy of fentanyl product 0004-000628 fast acting relief. Also they must fail other IR med such as norco and percocet. 0004-001094 fast acting. and potent Data Source: ADPQ Program: LQCAT.SAS TRIG TIRF Prescriber KAB Page 4 of 5 10DEC2015 Listing 2.1: Listing of Verbatim Responses to Question #11 (Why do you select a TIRF medicine to treat these chronic pain conditions in patients who are opioid tolerant?) Completed Surveys Survey Form II) Verbatim Responses 0004-001 177 fast acting. failed other medications 0004-001072 fast onset. reliable medication 0004-001022 good 0004-001056 good response to pain relief 0004-000432 immediate onset of relief. History of opioid tolerance and bene?t of opioid rotation 0004-000480 in order to provide immediate release of the medication with a short duration of start of effect 0004-000433 it works and lasts them a little longer. 0004-001 1 12 its effectiveness 0004-00043 5 last resort and works quickly 0004-001200 need for fast acting medication or an intolerance of other available agents 0004-000477 need for more potent effect to cover their persistent pain 0004-001 106 need for ultra-fast acting pain relief 0004-001081 neuropathic pain with acute exacerbation is often refractory to slower onset rescue medicines sickle cell crisis pain can be abrupt and re?actory to slower acting agents 0004-000787 no other medications help quick enough for the episodic pain 0004-001053 non functioning GI tractor to avoid high pill burden. or in cases of possible med diversion. or in cases where patient and care giver cannot follow a schedule of oral meds. 0004-000417 only use if patient has sudden onset short-lasting debilitating pain 0004-001078 onset of action 0004-001 128 pain relief 0004-001279 provides better pain relief 0004-000767 pt has been on chronic opioid therapy with diminishing effects 0004-000485 pt was on before he saw us. no longer of tirf med 2/2 lack of insurance coverage for med. 0004-000473 quick on set of relief and good relief is given when used (patient speci?c. of course) 0004-001 157 quick onset 0004-000514 quick onset. e??ective 0004-001206 quick onset. e??ective pain relief. ease of administration and absorption especially in cancer patients with decreased GI absorption or nausea/vomiting from chemo. ability for patient to quickly titrate to optimal dose Data Source: ADPQ Program: LQCAT.SAS TRIG Page 5 of 5 TIRF Prescriber KAB 10DEC2015 Listing 2.1: Listing of Verbatim Responses to Question #11 (Why do you select a TIRF medicine to treat these chronic pain conditions in patients who are opioid tolerant?) Completed Surveys Survey Form Verbatim Responses 0004-001178 rapid onset and offset which is ideal for true breakthrough or daily ?ares 0004-000569 see prev answer 0004-001292 sseverity 0004-000498 they have positive therapuetic bene?t and have failed other conservative measures. 0004-001145 to help in breakthrough pain addition to long pain meds 0004-000833 to try to decrease baseline pain in order to decrease more short acting medication usage 0004-001089 we need to use the best drug available to control the pain 0004-000926 when they have failed other meds. to prevent visits to ER and to improve quality of life for the patient 0004-000923 works Note: Question 11 is only asked if Question 9e is answered "Yes". Data Source: ADPQ Program: LQCAT.SAS TRIG Page 1 of TIRF Prescriber KAB Listing 2.2: Listing of Verbatim Responses to Question #11 (Why do you select a TIRF medicine to treat these chronic pain conditions in patients who are opioid tolerant?) Incomplete Surveys Survey Form II) Verbatim Responses 0004-001003 Fentanyl patch is harder to abuse also is good in elderly patients who may have kidney issues. 0004-001228 For breakthrough pain 0004-001259 Most are rotated when other pain meds are ineffective 0004-001258 Other immediate release medications have been prescribed in the past and have not worked. Due to my patinets unique disease process and QOL this worked best for her pain. 0004-001063 Patients have tried and failed at other meds before I see them 0004-001016 Usually at the recommendation of the palliative care team or allergies 0004-001217 if a pt is not obtaining adequate relief and function is decreased with up to 4 IR medications/ day 0004-000428 patient preference 0004-000361 poor renal function. poor liver function intolerance of others medication with prominent side effect inability to swallow etc 0004-000324 poor response Note: Question 11 is only asked if Question 9e is answered "Yes". Data Source: ADPQ Program: LQCAT.SAS TRIG Page 1 of TIRF Preseriber KAB 03DEC2015 Listing 3: Listing of Verbatim Responses to Question #26 (Questions about the Medication Guide) Completed Surveys Verbatim Responses Although not applicable to my patient. I would need to refer to the guide re initiating TIRF to any patient already on opiods Best time period and setting to do initial titration. Home vs. in-of?ce initial up-titration to ?nd effective dose. Can they use it without a long acting narcotic? All of my patients are on a long acting narcotic. Guidance on prescribing on individual by supervising physician. How do I prescribe them? I cannot remember I work in inpatient oncology. We have been taught by our pharmacy that the use of certain TIRF medications. speci?cally actiq. is acceptable for inpatient procedure pain control (such as bone marrow aspiration and biopsy) although this seems to be in con?ict with the product labeling which speci?cally contraindicates use for acute operative pain. What relevant info is contained Where do I obtain this information? metabolism with liver enzymes safe measures to prevent accidental overdose. where is guideline available? Data Source: ADPQ Program: LQ.SAS TRIG Page 1 of 3 TIRF Preseriber KAB 03DEC2015 Listing 4: Listing of Verbatim Responses to Question #37 (What is your medical specialty?) Completed Surveys Verbatim Responses Anesthesia Family Family practice Gastroenterology HIV and Family Medicine Hospice and Palliative Care Hospice and Palliative Med Hospice and Palliative Medicine Hospice and Palliative Medicine Hospice and Palliative Medicine/Pain Management Internal Medicine Internal Medicine Interventional Radiology Interventional Radiology Neurology Neurology Neurology Neurology Neurosurgery Oncology Palliative Care Pain and palliative care and rehabilitation Palliative Palliative Palliative Care Palliative Care Palliative Care Data Source: ADPQ Program: LQ.SAS TRIG Page 2 of 3 TIRF Preseriber KAB 03DEC2015 Listing 4: Listing of Verbatim Responses to Question #37 (What is your medical specialty?) Completed Surveys Verbatim Responses Palliative Care Palliative Care Palliative Care Palliative Care Palliative Medicine Palliative Medicine Palliative Medicine Palliative Medicine Palliative Medicine Palliative Medicine Palliative Medicine Palliative Medicine Palliative Medicine Palliative Medicine and Palliative Oncology Palliative care Palliative care Physical Medicine Rehabilitation Physical Medicine Rehabilitation Physical medicine and rehabilitation Radiation Oncology Radiation Oncology anesthesia hospice and palliative medicine hospice/pal] med ortho surgery palliative care palliative care palliative care palliative care Data Source: ADPQ Program: LQ.SAS TRIG Page 3 of 3 TIRF Prescriber KAB 03DEC2015 Listing 4: Listing of Verbatim Responses to Question #37 (What is your medical specialty?) Completed Surveys Verbatim Responses palliative care palliative medicine palliative medicine palliative medicine palliative medicine radiation oncology Data Source: ADPQ Program: LQ.SAS TRIG TIRF Preseriber KAB Page 1 of 4 03DEC2015 Listing 5: Listing of Potential Adverse Events and/or Product Complaints Reported by Modality Modality of Verbatim Text Report Chronic Low Back Pain Internet poor renal function. poor liver function intolerance of others medication with prominent Internet side effect inability to swallow etc Complex regional pain Cancer patients. Internet Failed back chronic pelvic pain with dyspareunia: Internet low back pain Internet post laminectomy Internet non-responsive neuralgia's. crippling CRPS Internet sickle cell anemia Internet cancer. RSD. some types of neuropathic pain Internet chronic back pain Telephone sickle cell patients. chronic regional pain Internet cancer.chronic back pain. migraine Internet neuropathic pain Telephone pancreatitis abdominal pain severe failed back Internet multiple sclerosis neuropathic pain. diabetic polyneuropathy. cervical/lumbar stenosis. Internet failed neck/back cancer pain (multiple types) chronic back pain. chronic joint pain Internet ch. Pancreatitis Internet Failed Back General chronic pain Severe neck pain Complex Regional Telephone pain Any Peripheral Neuropathy chrons dz post chemo neuropathy post neuropathy Internet cancer pain. chronic pain back. spondylosis. ect) not amenable to other Internet opioid regimens Failed Back Postlaminectomy RSD Internet Severe joint pains secondary to avascular necrosis. joint replacements. or severe arthritic Internet conditions. post laminectomy chronic radiculopathy. spondylolisthesis. foraminal stenosis. Internet RSD Internet chronic low back pains Internet Data Source: Program: LQAE.SAS TRIG TIRF Prescriber KAB Page 2 of 4 03DEC2015 Listing 5: Listing of Potential Adverse Events and/or Product Complaints Reported by Modality changes/wound care. Modality of Verbatim Text Report CRPS. severe nonresponsive to other treatment back or neck pain Internet abdominal pain due to chrons Internet Severe. unremitting. rapid onset neuropathic pain not controlled by long and other Internet short-acting opioids. and which are unresponsive to non-opioid medications. a cause is known. and for which other surgical/ injection treatment options have failed. Post-laminectomy Pain Complex Regional Pain For episodes of Internet acute exacerbation from activity. cancer pain. spinal cord injury pain. nerve pain. muscularskeletal pain Internet CANCER. COMPRESSION FRACTURES Internet Intractable back pain in patients with high opioid tolerance Internet Chronic back pain Chronic pain secondary to ischemic PVD/non-healing leg wounds Internet sickle cell. abdominal pain Internet We have a patient with chronic abdominal pain. chronic pain after ovarian cancer and a Internet patient with uncontrollable pain after back surgery. Can they use it without a long acting narcotic? All of my patients are on a long acting narcotic. low back. post lami resistant RSD. Other chronic pain conditions Internet where is guideline available? Internet Postlaminectomy severe neuropathy: chronic severe trauma Internet patients-paraplegic.etc. Chronic abdominal pain related to multiple surgeries. surgical complications or complex GI Internet issues Cancer. spine diseases. severe rhelunatologic disease Internet non functioning GI tractor to avoid high pill burden. or in cases of possible med diversion. Internet or in cases where patient and care giver cannot follow a schedule of oral meds. severe cases of RSD that are not responsive to DRG blocks. and around the clock opiod Internet therapy Profound end-stage RA Internet post laminectomy severe spinal stenosis. severe total body pain Internet I only have one pt with signi?cant back pain and an extensive operative history-otherwise it Internet is only used for cancer Failed back Chronic low back and neck pain. RSD Internet patients who have allergies to dilaudid and morphine and patients on opiates for dressing Internet Data Source: Program: LQAE.SAS TRIG TIRF Prescriber KAB Page 3 of 4 03DEC2015 Listing 5: Listing of Potential Adverse Events and/or Product Complaints Reported by Modality Modality of Verbatim Text Report SPINAL STENOSIS. ARTHRITIS. FIBRO Internet spinal myelopathic pain sickle cell crisis neuropathic pain with acute exacerbation is often Internet refractory to slower onset rescue medicines sickle cell crisis pain can be abrupt and refractory to slower acting agents Chronic post surgical (abdominal. hunbar. orthopedic) pain re?actory to other narcotics. Internet Advanced chronic pancreatitis pain. dor pain that is refractory to higher doses of conventional narcotics. lower back pain. neck pain. rsd. ms rheumatoid arthritis Internet Failed back surgery pain. CRPS Internet unspeci?ed chronic pain uncontrolled by all other means Internet Life limiting ilhlesses such as COPD. CHF. etc. Those that are progressive. irreversible and Internet terminal. As a palliative care physician I utilize TIRF medicine to manage negative of conditions that have a chronic pain(as well as component. I do not treat "chronic pain" patients but all conditions I do see have or have the potential to have a pain component. failed back Internet chronic pain due to injury. oa. lumbar Internet Complex Regional Pain Internet Failed Surgical Peripheral Neuropathy Telephone Prescriber reported use of TIRF product for Severe Musculoskeletal and Neuropathic-type Internet pain conditions. - Question 10 sever chronic Pain from sever arthritis or back surgery if they are opioid tolerant Internet Chronic sacral pain. chronic back pain that surgery has not helped and patient can't get any Internet relief during BM Migraines Internet Breakthrough pain in cancer patients. Chronic neuropathic pain and failed back surgery Internet due to nerve damage/irritation in patients that cannot swallow due to other GI/craniofacial medical conditions. Post thalamic stroke pain Internet TRIGEMINAL NEURALGIA Internet chronic uncontrolled pain. especially abdominal pain and spine pain conditions Internet chronic neuropathic pain Internet RSD Internet Data Source: Program: LQAE.SAS TRIG TIRF Prescriber KAB Page 4 of 4 03DEC2015 Listing 5: Listing of Potential Adverse Events and/or Product Complaints Reported by Modality routes of medication. Arthritis. Refractory or Chronic Neuropathy/Neuralgia responsive to opiates. Degenerative Disc Disease. Chronic wounds or complications. Dental complications or Mucositis. and Metastatic Disease Modality of Verbatim Text Report Patients with chronic wounds prior to wound care Internet intolerant to oral opioids due to intestinal absorption problems. cancer pain. Internet CHRONIC SPINAL RELATED PAIN Internet Burning mouth short gut Internet cancer associated pain. chronic arthritis Internet spinal related pain. joint pain. Internet Prescriber reported use of TIRF product for Refractory Neuropathic severe episodic pain. Internet Prescriber reported use of TIRF product for primarily chronic spinal or musculoskeletal Internet pain - may or may not be related to their underlying cancer diagnosis. Prescriber reported use of TIRF product for Arthritis. migraines. neuropathic pain. Internet Prescriber reported use of TIRF product for back pain. Internet Where do I obtain this infomlation? Internet I work in inpatient oncology. We have been taught by our pharmacy that the use of certain Internet TIRF medications. speci?cally actiq. is acceptable for inpatient procedure pain control (such as bone marrow aspiration and biopsy) although this seems to be in con?ict with the product labeling which speci?cally contraindicates use for acute operative pain. Chronic regional pain advanced degenerative joint disease: medullary sponge Internet kidney. Back pain. Neuropathy Internet chronic intractable head/facial pain after MVA with facial implants. Internet Failed back surgery. Lumbar radiculopathy Internet FAILED BACK . NON OPERATIVE CERVICAL OR LUMBAR DISC Internet DISEASE scoliosis. neuropathic leg pain Internet Spine related. radiculopathy. neuropathy Internet Besides cancer pain. I have used TIRF meds for avascular necrosis with joint destruction Internet when regular opioids were required spinal stenosis. severe joint OA. chronic pain s/p multi trauma Internet Breakthrough pain. easier application. patients with Nausea/Vomiting. or di?iculty with P0 Internet Data Source: Program: LQAE.SAS Accenture LLP 1160 West Swedesford Road Berwyn, PA 19312 May 4, 2016 Food and Drug Administration Center for Drug Evaluation and Research Central Document Room Drug Master File Staff Ammendale Road Beltsville, MD 20705?1266 . Re: DIVIF 027320 Holder: McKesson Specialty Health (McKesson) Subject: Transmucosal Immediate Release Fentanyl (TIRF) Access Program Re: REMS Shared Program DMF Type: DNIF Submission Information: Clinical/Clinical Information REMS Submission Identi?er: Not Applicable Sequence Number: 0023 Dear Drug Master File Staff: This Type DMF contains the Risk Evaluation and Mitigation Strategy (REMS) for Transmucosal Immediate Release Fentanyl for the Shared System REMS program. McKesson hereby provides the Drug Master File Staff 48-Month REMS Supplemental Assessment Report for Transmucosal Immediate-Release Fentanyl (TIRE), version 1, dated April 25, 2016. - .8. Agent Senior Regulatory Project Manager, Regulatory Affairs Accenture, LLP 6 1 0407-1 732 610?407?8483 (Fax) gina.melazzo@accenture.com 4 Attachments: Table of Contents for the submission Electronic Submission Speci?cations DMF #027320; Sequence 0023 Shared System REMS Table of Contents Page 1 of 1 Supplemental Report to the 48-Month Assessment Module Section Description 1.2 Cover Letter Cover Letter 1.16 – Risk Management Plans REMS History Supplemental Report to the 48-Month Assessment TIRF REMS Supplemental Assessment Protocol and Analysis Plan TIRF REMS– Supplemental Assessment Study Report TIRF Persistency Analysis Protocol TIRF Persistency Analysis Final Report Supplemental File 1: TIRF Product NDC Codes Supplemental File 2: NDC Codes for Opioid Analgesics FDA_3708 Electronic Submission Specifications This submission is compliant with FDA's Guidelines for Industry and current eCTD specifications. All files were checked and verified to be free of viruses prior to transmission through the electronic submission gateway. Anti-Virus Program Program Version Virus Definition Date Submission Size Symantec Endpoint Protection Edition 12.1.5337.5000 05/02/2016 rev. 11 Approx. 4.4 MB The IT point of contact for this submission is: Name Phone Number Email Address Matt Francis 1-610-407-1854 Matthew.p.francis@accenture.com FDA_3709 TIRF REMS Access Program Assessment Supplemental file 1: TIRF product NDC codes Product ABSTRAL 03/2011 GNB ABSTRAL 03/2011 GNB ABSTRAL 03/2011 GNB ABSTRAL 03/2011 GNB ABSTRAL 03/2011 GNB ABSTRAL 03/2011 GNB ABSTRAL 03/2011 GNB ABSTRAL 03/2011 GNB ABSTRAL 03/2011 GNB ABSTRAL 03/2011 GNB ABSTRAL 03/2011 GNB ABSTRAL 03/2011 GNB ABSTRAL 03/2011 GNB ABSTRAL 03/2011 GNB ABSTRAL 03/2011 GNB ABSTRAL 03/2011 GNB ABSTRAL 03/2011 GNB ABSTRAL 03/2011 GNB ACTIQ 04/1999 TVN ACTIQ 04/1999 TVN ACTIQ 04/1999 TVN ACTIQ 04/1999 TVN ACTIQ 04/1999 TVN ACTIQ 04/1999 TVN FENTANYL CIT 04/1998 FENTANYL CIT 04/1998 FENTANYL CIT 04/1998 FENTANYL CIT 04/1998 FENTANYL CIT 04/1998 FENTANYL CIT 04/1998 FENTANYL CIT 09/2006 FENTANYL CIT 09/2006 FENTANYL CIT 09/2006 FENTANYL CIT 09/2006 FENTANYL CIT 09/2006 FENTANYL CIT 09/2006 FENTANYL CIT 09/2006 FENTANYL CIT 09/2006 FENTANYL CIT 09/2006 FENTANYL CIT 09/2006 FENTANYL CIT 09/2006 FENTANYL CIT 09/2006 FENTANYL CIT 10/2011 FENTANYL CIT 10/2011 FENTANYL CIT 10/2011 FENTANYL CIT 10/2011 FENTANYL CIT 10/2011 FENTANYL CIT 10/2011 FENTORA 10/2006 TVN FENTORA 10/2006 TVN FENTORA 10/2006 TVN FENTORA 10/2006 TVN FENTORA 10/2006 TVN FENTORA 10/2006 TVN LAZANDA 10/2011 DP7 LAZANDA 10/2011 DP7 SUBSYS 03/2012 INY SUBSYS 03/2012 INY SUBSYS 03/2012 INY SUBSYS 03/2012 INY SUBSYS 03/2012 INY SUBSYS 03/2012 INY SUBSYS 03/2012 INY SUBSYS 03/2012 INY SUBSYS 03/2012 INY SUBSYS 03/2012 INY SUBSYS 03/2012 INY SUBSYS 03/2012 INY SUBSYS 03/2012 INY MKR MKR MKR MKR MKR MKR TEV TEV TEV TEV TEV TEV TEV TEV TEV TEV TEV TEV P.H P.H P.H P.H P.H P.H NDC 42747022104 42747022132 42747022204 42747022232 42747022304 42747022332 42747022404 42747022432 42747022632 42747022804 42747022832 57881033132 57881033232 57881033332 57881033404 57881033432 57881033632 57881033832 63459050230 63459050430 63459050630 63459050830 63459051230 63459051630 00406920230 00406920430 00406920630 00406920830 00406921230 00406921630 55253007001 55253007030 55253007101 55253007130 55253007201 55253007230 55253007301 55253007330 55253007401 55253007430 55253007501 55253007530 49884045955 49884046055 49884046155 49884046255 49884046355 49884046455 63459054128 63459054228 63459054328 63459054428 63459054628 63459054828 13913000901 13913001001 20482000110 20482000130 20482000210 20482000230 20482000410 20482000430 20482000610 20482000630 20482000810 20482000830 20482001201 20482001215 20482001615 TAB SL 100MCG 4 TAB SL 100MCG 32 TAB SL 200MCG 4 TAB SL 200MCG 32 TAB SL 300MCG 4 TAB SL 300MCG 32 TAB SL 400MCG 4 TAB SL 400MCG 32 TAB SL 600MCG 32 TAB SL 800MCG 4 TAB SL 800MCG 32 TAB SL 100MCG 32 TAB SL 200MCG 32 TAB SL 300MCG 32 TAB SL 400MCG 4 TAB SL 400MCG 32 TAB SL 600MCG 32 TAB SL 800MCG 32 LOZ 200MCG 30 LOZ 400MCG 30 LOZ 600MCG 30 LOZ 800MCG 30 LOZ 1200MCG 30 LOZ 1600MCG 30 LOZ 200MCG 30UD LOZ 400MCG 30UD LOZ 600MCG 30UD LOZ 800MCG 30UD LOZ 1200MCG 30UD LOZ 1600MCG 30UD LOZ 200MCG 1 LOZ 200MCG 10X3 BLISTER (30) LOZ 400MCG 1 LOZ 400MCG 10X3 BLISTER (30) LOZ 600MCG 1 LOZ 600MCG 10X3 BLISTER (30) LOZ 800MCG 1 LOZ 800MCG 10X3 BLISTER (30) LOZ 1200MCG 1 LOZ 1200MCG 10X3 BLISTER (30) LOZ 1600MCG 1 0075-01 LOZ 1600MCG 10X3 BLISTER (30) LOZ 200MCG 30 LOZ 400MCG 30 LOZ 600MCG 30 LOZ 800MCG 30 LOZ 1200MCG 30 LOZ 1600MCG 30 TAB BUCCAL 100MCG 28 TAB BUCCAL 200MCG 28 TAB BUCCAL 300MCG 28 TAB BUCCAL 400MCG 28 TAB BUCCAL 600MCG 28 TAB BUCCAL 800MCG 28 NASAL SPRAY 100MCG 1 NASAL SPRAY 400MCG 1 PUMP SPRAY 100MCG 10 PUMP SPRAY 100MCG 30 PUMP SPRAY 200MCG 10 PUMP SPRAY 200MCG 30 PUMP SPRAY 400MCG 10 PUMP SPRAY 400MCG 30 PUMP SPRAY 600MCG 10 PUMP SPRAY 600MCG 30 PUMP SPRAY 800MCG 10 PUMP SPRAY 800MCG 30 PUMP SPRAY 1200MCG 1UD PUMP SPRAY 1200MCG 30 PUMP SPRAY 1600MCG 30 Manufacturer GALENA BIOPHARMA GALENA BIOPHARMA GALENA BIOPHARMA GALENA BIOPHARMA GALENA BIOPHARMA GALENA BIOPHARMA GALENA BIOPHARMA GALENA BIOPHARMA GALENA BIOPHARMA GALENA BIOPHARMA GALENA BIOPHARMA GALENA BIOPHARMA GALENA BIOPHARMA GALENA BIOPHARMA GALENA BIOPHARMA GALENA BIOPHARMA GALENA BIOPHARMA GALENA BIOPHARMA TEVA CNS TEVA CNS TEVA CNS TEVA CNS TEVA CNS TEVA CNS MALLINCKRODT MALLINCKRODT MALLINCKRODT MALLINCKRODT MALLINCKRODT MALLINCKRODT TEVA PHARMACEUTICA TEVA PHARMACEUTICA TEVA PHARMACEUTICA TEVA PHARMACEUTICA TEVA PHARMACEUTICA TEVA PHARMACEUTICA TEVA PHARMACEUTICA TEVA PHARMACEUTICA TEVA PHARMACEUTICA TEVA PHARMACEUTICA TEVA PHARMACEUTICA TEVA PHARMACEUTICA PAR PHARM PAR PHARM PAR PHARM PAR PHARM PAR PHARM PAR PHARM TEVA CNS TEVA CNS TEVA CNS TEVA CNS TEVA CNS TEVA CNS DEPOMED INC DEPOMED INC INSYS THERAPEUTICS INSYS THERAPEUTICS INSYS THERAPEUTICS INSYS THERAPEUTICS INSYS THERAPEUTICS INSYS THERAPEUTICS INSYS THERAPEUTICS INSYS THERAPEUTICS INSYS THERAPEUTICS INSYS THERAPEUTICS INSYS THERAPEUTICS INSYS THERAPEUTICS INSYS THERAPEUTICS FDA_3710 48-Month REMS Supplemental Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 1 of 26 Title: Transmucosal Immediate-Release Fentanyl (TIRF) Risk Evaluation and Mitigation Strategy (REMS) Access Program 48-Month Supplemental Assessment Report Report Date 25 APR 2016 Reporting Timeframe: 29 OCT 2014 to 28 OCT 2015 Document Number: FINAL v 1.0 Product Name: Transmucosal Immediate-Release Fentanyl Sponsor: TIRF REMS Industry Group (TRIG) of Companies: Actavis Laboratories FL, Inc. BioDelivery Sciences International, Inc. Cephalon, Inc. (a wholly-owned subsidiary of Teva Pharmaceutical Industries, Ltd.) Depomed, Inc. Insys Therapeutics Inc. Mallinckrodt Pharmaceuticals Mylan, Inc. Par Pharmaceutical, Inc. Sentynl Therapeutics, Inc. Confidentiality Statement The information contained herein is confidential and the proprietary property of the TRIG of Companies and its affiliates, and any unauthorized use or disclosure of such information without the prior written authorization of the TRIG is expressly prohibited. FDA_3711 48-Month REMS Supplemental Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 2 of 26 TABLE OF CONTENTS Pg LIST OF TABLES ................................................................................................................... 3 LIST OF ABBREVIATIONS ................................................................................................. 4 1 OVERVIEW ................................................................................................................. 5 2 RESULTS ..................................................................................................................... 8 2.1 IMS Study of TIRF Use in Appropriate Patients ...................................................... 8 2.1.1 FDA Correspondence......................................................................................... 8 2.1.2 Objectives .......................................................................................................... 9 2.1.3 Eligibility Criteria .............................................................................................. 9 2.1.4 Results ................................................................................................................ 9 2.2 Persistency Analysis ............................................................................................... 10 2.2.1 Objectives ........................................................................................................ 10 2.2.2 Eligibility Criteria ............................................................................................ 11 2.2.3 Results .............................................................................................................. 11 2.3 Knowledge, Attitude, and Behavior Surveys Data Comparison ............................. 12 2.3.1 Prescriber Report ............................................................................................. 12 2.3.2 Patient Report................................................................................................... 15 3 DISCUSSION ............................................................................................................. 19 4 APPENDICES ............................................................................................................ 22 4.1 IMS Study Protocol ................................................................................................. 23 4.2 IMS Study Report ................................................................................................... 24 4.3 Persistency Analysis Protocol ................................................................................. 25 4.4 Persistency Analysis Report.................................................................................... 26 FDA_3712 48-Month REMS Supplemental Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 3 of 26 LIST OF TABLES Table 1  TIRF Medicines ..............................................................................................................5  Table 2  36-Month FDA Assessment Report: FDA Acknowledgement Letter Requests ............6  Table 3  Number of TIRF Users Included in the IMS Study ........................................................8  Table 4  Comparison of Survey Respondents to General Population of Prescribers ..................13  Table 5  Comparison of Survey Respondents to General Population of TIRF Users .................16  FDA_3713 48-Month REMS Supplemental Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 4 of 26 LIST OF ABBREVIATIONS FDA Food and Drug Administration IR KAB LRx LTC NDA NPA REMS TIRF Immediate Release Knowledge, Attitude, and Behavior IMS Longitudinal Prescription Database Long-term care New Drug Application National Prescription Audit Risk Evaluation and Mitigation Strategy Transmucosal Immediate-Release Fentanyl TIRF Medicines Transmucosal Immediate-Release Fentanyl product(s) TIRF REMS Access REMS program for TIRF medicines TIRF Sponsors The group of sponsors that are submitting this REMS TRIG TIRF REMS Industry Group UBC United BioSource Corporation US United States FDA_3714 48-Month REMS Supplemental Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies 1 Page 5 of 26 OVERVIEW The Food and Drug Administration (FDA) has determined that a Risk Evaluation and Mitigation Strategy (REMS) is required to mitigate the risk of misuse, abuse, addiction, overdose, and serious complications due to medication errors with the use of Transmucosal Immediate-Release Fentanyl (TIRF) medicines. The TIRF REMS Access program was approved by the FDA on 28 December 2011 for ABSTRAL®, ACTIQ®, FENTORA®, LAZANDA®, ONSOLIS®, SUBSYS® and generic versions of these TIRF medicines. The TIRF REMS Access program was successfully launched on 12 March 2012, approximately 11 weeks after REMS approval. This report completes the response to FDA’s 36-Month FDA Acknowledgement Letter, initially received on 04 August 2015, requesting additional analyses of the REMS data. The group of Sponsors who are submitting this 48-Month REMS Assessment Report Supplemental Report (Actavis Laboratories FL, Inc., BioDelivery Sciences International, Inc., Cephalon, Inc. [a wholly-owned subsidiary of Teva Pharmaceutical Industries, Ltd.], Depomed, Inc., Insys Therapeutics Inc., Mallinckrodt Pharmaceuticals, Mylan, Inc., Par Pharmaceutical, Inc., and Sentynl Therapeutics, Inc.) are herein referred to as TIRF Sponsors. One company joined the TRIG since the finalization of the 48-Month FDA Assessment Report submitted in December 2015: Sentynl Therapeutics replaced Galena Biopharma, Inc. on 09 January 2016. The TIRF REMS Access program is administered by McKesson Specialty Health and RelayHealth. This report has been prepared by United BioSource Corporation (UBC). The TIRF medicines subject to the TIRF REMS are itemized in Table 1 below. Table 1 TIRF Medicines Product Name (active ingredient)/formulation NDA 22510, ABSTRAL (fentanyl) sublingual tablets NDA 20747, ACTIQ (fentanyl citrate) oral transmucosal lozenge and its authorized generic NDA 21947, FENTORA (fentanyl) buccal tablet NDA 22569, LAZANDA (fentanyl) nasal spray NDA 22266, ONSOLIS (fentanyl) buccal soluble film NDA 202788, SUBSYS (fentanyl) sublingual spray ANDA 77312, fentanyl citrate oral transmucosal lozenge ANDA 78907, fentanyl citrate oral transmucosal lozenge The FDA’s communication included multiple new requests to be incorporated into the 48-Month REMS Assessment Report. Due to the timing of the FDA’s correspondence, requested items #2 and #3 (Table 2) were not included in the 48-Month REMS Assessment Report. As communicated to the FDA on 08 September 2015, these items are reported in this 48-Month REMS Supplemental Report to be submitted to the FDA on or before 04 May 2016. In addition to items #2 and #3, the FDA’s feedback requested additional analyses for the patient and prescriber Knowledge, Attitude, and Behavior (KAB) surveys. The prescriber survey was to include an analysis of demographics of the prescriber survey respondents compared to the FDA_3715 48-Month REMS Supplemental Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 6 of 26 demographics of the general population of TIRF prescribers. The patient survey was to include an analysis of demographics of the patient survey respondents compared to the demographics of patients receiving a TIRF product. Analyses in this Supplemental Report cover the same time period as the 48-Month FDA Assessment Report submitted in December 2015. Table 2 36-Month FDA Assessment Report: FDA Acknowledgement Letter Requests Request Number* FDA Request 2. IMS Study To assess the TIRF REMS goal of prescribing and dispensing TIRF products only to appropriate patients, which includes use only in opioid-tolerant patients, conduct the following analysis: 1. 2. 3. Identify a health care database that includes an adequate number of TIRF product users. Within that database, by year, provide the number of total unique patients dispensed an initial prescription for a TIRF product in the outpatient setting. Determine what proportion of those total unique patients received a prescription for an opioid analgesic product prior to the prescription for the TIRF product. Provide these data separately for patients receiving an opioid analgesic within the 7-days prior and within the 30-days prior to the initial TIRF prescription. Before embarking on this analysis, provide to FDA your choice of database and the estimated number of TIRF users in the database so that we can determine if the number is adequate. 3. Persistency Analysis We are not able to establish whether the TIRF REMS is achieving the goal of preventing inappropriate conversion between TIRF medicines. To better understand how many people are at risk for inappropriate conversion between TIRF medicines, we need a better idea of how long patients stay on one TIRF and whether they shift between TIRF products or just stop them completely. • Conduct a persistency analysis based on the data available on the prescriptions processed through the switch system used by retail pharmacies. o This analysis should demonstrate the number of patients starting on a TIRF and follow them over weeks and months to summarize their treatment course and change in therapy. o The TIRF products can be grouped together, and the specific drug does not need to be disclosed. • Following the discontinuation of the TIRF, the persistency analysis should also depict what treatment option the patient uses next. This will be either full discontinuation or switching to another TIRF product. • There may be gaps in between prescriptions; propose what duration of gap will be considered to mean that the patient has remained on treatment with a TIRF and provide a rationale for selection of that gap length. FDA_3716 48-Month REMS Supplemental Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Request Number* 12. Page 7 of 26 FDA Request KAB Data Comparison Additional comments and recommended revisions to the stakeholder surveys that should be implemented in subsequent surveys follow below: a. Patient survey: (i.) In subsequent Assessment Reports, provide an analysis of how the demographics of the patient survey respondents compare to the demographics of actual TIRF patients. c. Prescriber survey: (i.) In subsequent Assessment Reports, provide an analysis of how the demographics of the prescriber survey respondents compare to the demographics of actual TIRF prescribers. *Numbering is aligned with the numbering of the FDA requests communicated in the 36-Month FDA’s Assessment Report Acknowledgement Letter. Responses for the remaining requests in number 4-12 were included in the 48-Month FDA Assessment Report submitted in December 2015. Item 1 included general FDA feedback on the overall assessment report and required no response. FDA_3717 48-Month REMS Supplemental Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies 2 Page 8 of 26 RESULTS 2.1 IMS Study of TIRF Use in Appropriate Patients In response to the request from the FDA, a statistical analysis was performed to assess the TIRF REMS Access program goal of prescribing and dispensing TIRF products only to appropriate patients, which includes use only in opioid-tolerant patients. This study used data from the IMS Longitudinal Prescription database (LRx), which contains electronic dispensed records of anonymized prescription claims collected from United States (US) retail, long-term care (LTC), and specialty and mail order pharmacies (outpatient only; prescription medications delivered during inpatient stays are not available). The results of that analysis are summarized below. Patients who filled a TIRF product prescription were identified between 12 March 2012 and 28 October 2015 (the index period). To ascertain previous opioid prescriptions, data were collected from 11 February 2012 to 28 October 2015 (the study period). The IMS Study Protocol is presented in Appendix 4.1. The complete IMS Study Report, including detailed methodology (Section 5), is presented in Appendix 4.2. 2.1.1 FDA Correspondence The FDA requested that TRIG provide the choice of database and the estimated number of TIRF users in the database so that the FDA could determine if the number was adequate prior to embarking on the analysis. The TRIG provided estimated raw counts of TIRF users to FDA on 08 September 2015. On 13 November 2015, FDA confirmed that use of IMS data was acceptable, provided that IMS could adequately respond to the noted inconsistency in the number of TIRF users. (b) (4) FDA_3718 48-Month REMS Supplemental Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 9 of 26 (b) (4) 2.1.2 Objectives The specific objectives outlined by the FDA were: • To document by year the number of total unique patients dispensed an initial prescription for a TIRF product in the outpatient setting. • To determine what proportion of those total unique patients received a prescription for an opioid analgesic product prior to the prescription for the TIRF product. • To provide data separately for patients receiving an opioid analgesic within the 7 days prior and within the 30 days prior to the initial TIRF prescription. 2.1.3 Eligibility Criteria (b) (4) 2.1.4 Results (b) (4) FDA_3719 48-Month REMS Supplemental Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 10 of 26 (b) (4) 2.2 Persistency Analysis (b) (4) 2.2.1 Objectives The specific objectives outlined by the FDA were:  To demonstrate the number of patients starting on a TIRF medicine and follow them over weeks and months to summarize their treatment course and change in therapy.  To depict what treatment option the patient used next following the discontinuation of one TIRF product, as applicable. Note: This analysis used only pharmacy switch data related to the TIRF REMS Access program; therefore, no other data concerning non TIRF REMS products were included in the analysis.  To propose what duration of gap will be considered to mean that the patient has remained on treatment with a TIRF medicine and provide a rationale for selection of that gap length. FDA_3720 48-Month REMS Supplemental Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies 2.2.2 Page 11 of 26 Eligibility Criteria (b) (4) 2.2.3 Results (b) (4) FDA_3721 48-Month REMS Supplemental Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 12 of 26 2.3 Knowledge, Attitude, and Behavior Surveys Data Comparison Prescribers?, pharmacists?, and patients? understanding regarding the appropriate use of TIRF medicines and TIRF REMS Access program requirements are evaluated through KAB surveys. These surveys are administered to selected prescribers, pharmacies, and patients. FDA requested additional analyses to compare the demographics of prescribers and patients who completed the survey to the general population of prescribers and patients, respectively. Data obtained from IMS Health were used to ful?ll this request. It was assumed that these IMS data cover the majority of healthcare providers prescribing and patients receiving TIRF medicines in the outpatient setting. Results of these additional analyses for the prescriber and patient survey data are discussed in Sections 2.3.1 and 2.3.2. 48-Month REMS Supplemental Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 13 of 26 (b) (4) FDA_3723 48-Month REMS Supplemental Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 14 of 26 (b) (4) FDA_3724 48-Month REMS Supplemental Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 15 of 26 (b) (4) FDA_3725 48-Month REMS Supplemental Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 16 of 26 (b) (4) FDA_3726 48-Month REMS Supplemental Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 17 of 26 (b) (4) FDA_3727 48-Month REMS Supplemental Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 18 of 26 (b) (4) FDA_3728 48-Month REMS Supplemental Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 19 of 26 3 DISCUSSION As part of the evaluation of the TIRF REMS Access program, the FDA requested further statistical analyses to assess if the appropriate patients were being prescribed and dispensed TIRF medicines and to assess patients? persistence on TIRF medicines. In addition, analyses were performed to compare the demographics of prescribers and patients who completed the 2015 KAB surveys to the general population of prescribers and patients, respectively. The TRIG worked with IMS to conduct a study to determine whether patients receiving a TRF rescri tion met the ioid tolerance criteria as dictated the TIRF REMS Access rogram. . A rsistenc anal is was conducted to assess atients? rsistence on TIRF medicines. For the rescriber KAB anal 48-Month REMS Supplemental Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group of Companies Page 20 of 26 CONCLUSION This TIRF REMS Access program Supplemental Report (IMS Study, Persistency Analysis, and additional KAB analysis) further characterized TIRF medicine prescription data, patients? persistence while on TIRF medicines, and stakeholder demo . hic data in res nse to the ru est. 48-Month REMS Supplemental Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 21 of 26 The TRIG concludes that the results presented in this TIRF REMS Access program Supplemental Report accurately represent what is occurring overall in the TIRF REMS Access program and what has been previously reported in the annual assessment reports. FDA_3731 48-Month REMS Supplemental Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies 4 Page 22 of 26 APPENDICES FDA_3732 48-Month REMS Supplemental Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies 4.1 Page 23 of 26 IMS Study Protocol FDA_3733 48-Month REMS Supplemental Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies 4.2 Page 24 of 26 IMS Study Report FDA_3734 48-Month REMS Supplemental Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies 4.3 Page 25 of 26 Persistency Analysis Protocol FDA_3735 48-Month REMS Supplemental Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies 4.4 Page 26 of 26 Persistency Analysis Report FDA_3736 TIRF REMS Persistence Analysis Version 1.0 Design Analysis Plan 19FEB2016 Title: Transmucosal Immediate-Release Fentanyl (TIRF) Persistency Analysis Protocol Document Number: Final Version 1.0 Product Name: Transmucosal Immediate-Release Fentanyl Sponsor: TIRF REMS Industry Group (TRIG) of Companies: Actavis Laboratories FL, Inc. BioDelivery Sciences International, Inc. ephalon, Inc. (a wholly-owned subsidiary of Teva Pharmaceutical Industries, Ltd.) Depomed, Inc. Insys Therapeutics Inc. Mallinckr?odt Pharmaceuticals Mylan, Inc. Par Pharmaceutical, Inc. Therapeutics, Inc. FOLLOWING THIS PAGE, TO WITHHELD IN FULL AS Controlled Document opyrighto United BioSource Corporation All Rights Reserved TIRF REMS Access Program Assessment STUDY REPORT April 22, 2016 PREPARED FOR TIRF REMS TRIG c/o Rachel Bonfanti United BioSource Corporation PREPARED BY IMS Health Epidemiology and Drug Safety Real World Evidence Solutions The infonnation in this document is confidential and proprietaiy and may not be disclosed to another party unless disclosm?e is required by law or regulation. FOLLOWING THIS PAGE, TO WITHHELD IN FULL AS IMS Con?dential and proprietary 2016 IMS Health Incorporated and its af?liates. All rights reserved. Trademarks are registered in the United States and in various other countries. TIRF MS ASSESS PR 3T0 30L AND ANALYSIS PLAN 2-25-2016 PREPARED FOR PRE BY TIRF RE VIS TRIG IMS ealth c/o Rachel Bonfanti Real 'orld Evidence Solutions United Biosource Cor noration Epide iiology and 'rug Safety FOLLOWING THIS PAGE, TO WITHHELD IN FULL AS It hm TIRF REMS Persistency Analysis Final Report Title: Transmucosal Immediate-Release Fentanyl (TIRF) Persistency Analysis Final Report Document Number: Final Version 1.0 Product Name: Transmucosal Immediate-Release Fentanyl Sponsors: TIRF REMS Industry Group (TRIG): Version 1.0 18 April 2016 Actavis Laboratories FL, Inc. BioDelivery Sciences International, Inc. Cephalon, Inc. (a wholly-owned subsidiary of Teva Pharmaceutical Industries, Ltd.) Depomed, Inc. Insys Therapeutics Inc. Mallinckrodt Pharmaceuticals Mylan, Inc. Par Pharmaceutical, Inc. Sentynl Therapeutics, Inc. Controlled Document Copyright© United BioSource Corporation All Rights Reserved FOLLOWING THIS PAGE, FDA_3916 TO FDA_3954 WITHHELD IN FULL AS B(4)/CCI FDA_3915 DMF #027320; Sequence 0023 Shared System REMS Modification Date No. Approved 1 June 5, 2012 REMS History Page 1 of 8 Documents Affected Overview of Modification x x Sequence 0002: Edits to Patient-Prescriber Agreement Form, the addition of the Closed System Pharmacy Enrollment Form*, the addition of the newly approved TIRF product, Subsys (fentanyl sublingual spray) and minor editorial changes. x x x x x x x x x x x x x x x x REMS Prescriber Program Overview Education Program Prescriber Enrollment Form Patient Provider Agreement Form Patient and Caregiver Overview Dear Healthcare Provider Letter Outpatient Pharmacy Overview Chain Pharmacy Overview Inpatient Pharmacy Overview Outpatient Pharmacy Enrollment Form Chain Pharmacy Enrollment Form Inpatient Pharmacy Enrollment form Outpatient Pharmacy Letter Inpatient Pharmacy Letter Dear Distributor Letter Distributor Enrollment Form Supporting Document *The Closed System Pharmacy Enrollment Form was not formally submitted through the Gateway but was submitted via email on May 18, 2012 and included in the June 5, 2012 FDA approval letter. FDA_3955 DMF #027320; Sequence 0023 Shared System REMS Modification Date No. Approved N/A N/A 2 November 7, 2013 N/A N/A 2 November 7, 2013 REMS History Page 2 of 8 Documents Affected Overview of Modification Assessment Report 1 at 6 months – due 06/28/2012 Sequence 0003: Assessment report covering 12/28/2011 to 04/27/2012 Draft Documents submitted on or before 09/28/2012 x Chain Pharmacy Enrollment Form x Outpatient Pharmacy Enrollment Form x Closed System Pharmacy Overview x Education Program x Frequently Asked Questions (FAQ) x Outpatient Pharmacy Letter x REMS x Supporting Document Assessment Report 2 at 1 year – due 12/28/2012 Amendment to 09/28/2012 supplement: x Chain Outpatient Pharmacy Enrollment Form x Independent Outpatient Pharmacy Enrollment Form x Closed System Outpatient Pharmacy Enrollment Form Sequence 0004: Modification proposed to: x Incorporate closed system pharmacies into the TIRF REMS Access Program x Correct minor inconsistencies between the FDA provided versions and the current PDF versions of REMS materials Sequence 0005: Assessment report covering 04/28/2012 to 10/28/2012 Sequence 0006: Modification proposed to: x Revised terminology, processes, and definitions for outpatient pharmacies x Revised attestations for physicians and patients to address concerns regarding patient access x Revised Program Overview and Frequently Asked Questions to improve clarity and content FDA_3956 DMF #027320; Sequence 0023 Shared System REMS Modification Date No. Approved REMS History Page 3 of 8 Documents Affected Overview of Modification x x x x x x x x x x x x x x x x x x Inpatient Pharmacy Enrollment Form Distributor Enrollment Form Prescriber Enrollment Form Patient Provider Agreement Form Chain Outpatient Pharmacy Overview Independent Outpatient Pharmacy Overview Closed System Outpatient Pharmacy Overview Inpatient Pharmacy Overview Patient and Caregiver Overview Prescriber Overview Education Program Knowledge Assessment Frequently Asked Questions (FAQ) Dear Outpatient Pharmacy Letter Dear Inpatient Pharmacy Letter Dear Healthcare Provide Letter Dear Distributor Letter Updated REMS materials to reflect the completion of the transition phase for the TIRF REMS Access Program FDA_3957 DMF #027320; Sequence 0023 Shared System REMS Modification Date No. Approved REMS History Page 4 of 8 Documents Affected Overview of Modification x x N/A N/A N/A N/A 3 December 24, 2014 REMS Supporting Document x Website Landing Page Assessment Report 3 at 2 years – due 12/28/2013 Safety Surveillance Report #1 – due 03/31/2014 x x x x x x x x x x REMS Prescriber Program Overview Education Program Prescriber Enrollment Form Patient and Caregiver Overview Independent Outpatient Pharmacy Overview Chain Outpatient Pharmacy Overview Closed System Outpatient Pharmacy Overview Inpatient Pharmacy Overview Independent Outpatient Pharmacy Enrollment Form Sequence 0007: Assessment report covering 10/29/2012 to 10/28/2013 Sequence 0008: Safety surveillance data covering Q4 2012 to Q3 2013 Sequence 0009: Modification proposed to: x Updated REMS materials to eliminate product specific information which does not impact the safe use of TIRF products x Updated REMS materials to reference the currently approved TIRF products list on the FDA Approved REMS website x Updated REMS materials to remove reference to deactivating patients shown to have multiple prescribers in an overlapping timeframe x Incorporated revised assessment metrics into the Supporting Document x Revised Education Program to emphasize and strengthen FDA_3958 DMF #027320; Sequence 0023 Shared System REMS Modification Date No. Approved REMS History Page 5 of 8 Documents Affected x x x x x x x N/A N/A N/A N/A 3 December 24, 2014 Chain Outpatient Pharmacy Enrollment Form Closed System Outpatient Pharmacy Enrollment Form Inpatient Pharmacy Enrollment form Distributor Enrollment Form FAQ Supporting Document Website Prototype Cash Claim Information Request Response – due 05/30/2014 DMF Annual Report – due 08/20/2014 x REMS x Prescriber Program Overview x Education Program x Knowledge Assessment x Prescriber Enrollment Form x Patient and Caregiver Overview Overview of Modification x x appropriate conversion and patient counseling information Updated REMS and Supporting Document to clarify deactivation of a patient PPAF as opposed to the patient record Updated pharmacy overview documents and x FAQ to call out cash claim requirement x Updated TIRF REMS Access website to incorporate items above and link respective Full Prescribing Information and Medication Guides to DailyMed Sequence 0010: Response to 5/16/2014 FDA Cash Claim Information Request Sequence 0011: DMF Annual Report Sequence 0012: Modification proposed to: x Updated REMS materials to eliminate product specific information which does not impact the safe use of TIRF products x Updated REMS materials to reference the TIRF Products webpage on the TIRF REMS Access website FDA_3959 DMF #027320; Sequence 0023 Shared System REMS Modification Date No. Approved REMS History Page 6 of 8 Documents Affected Overview of Modification x x x x x x x x x x x x x Independent Outpatient Pharmacy Overview Chain Outpatient Pharmacy Overview Closed System Outpatient Pharmacy Overview Inpatient Pharmacy Overview Independent Outpatient Pharmacy Enrollment Form Chain Outpatient Pharmacy Enrollment Form Closed System Outpatient Pharmacy Enrollment Form Inpatient Pharmacy Enrollment form Distributor Enrollment Form FAQ Supporting Document Website Prototype x x x x x x Updated REMS materials to remove reference to deactivating patients shown to have multiple prescribers in an overlapping timeframe Incorporated revised assessment metrics into the Supporting Document Revised Education Program to emphasize and strengthen appropriate conversion and patient counseling information Updated REMS and Supporting Document to clarify deactivation of a patient PPAF as opposed to the patient record Updated pharmacy overview documents and FAQ to call out cash claim requirement Updated TIRF REMS Access website to incorporate items above and link respective Full Prescribing Information and Medication Guides to DailyMed Updated Education Program and Knowledge Assessment to incorporate approved labeling supplement FDA_3960 DMF #027320; Sequence 0023 Shared System REMS Modification Date No. Approved 3 December 24, 2014 REMS History Page 7 of 8 Documents Affected Overview of Modification Unchanged from Sequence 0012, plus: x Dear Healthcare Provider Letter x Dear Outpatient Pharmacy Letter x Dear Inpatient Pharmacy Letter x Dear Distributor Letter Sequence 0013: Unchanged from Sequence 0012, plus: x Dear Healthcare Provider Letter x Dear Outpatient Pharmacy Letter x Dear Inpatient Pharmacy Letter x Dear Distributor Letter N/A N/A Assessment Report 4 at 3 years – due 12/28/2014 Sequence 00014: Assessment report covering 10/29/2013 to 10/28/2014 N/A N/A BioDelivery Sciences International – Letter of Authorization Sequence 0015: BioDelivery Sciences International – Letter of Authorization N/A N/A Actavis Laboratories Inc. – Letter of Authorization Sequence 0016: Actavis Laboratories Inc. – Letter of Authorization N/A N/A DMF Annual Report – due 08/20/2015 Sequence 0017: DMF Annual Report N/A N/A 36-Month Assessment – Consolidated Information Requests N/A N/A Assessment Report 5 at 4 years – due 12/28/2015 N/A N/A N/A N/A Sentnyl Therapeutics, Inc. – Letter of Authorization Withdraw Authorization for Galena BioPharma, Inc. Sequence 0018: Response to FDA 36Month Assessment Information Requests Sequence 00019: Assessment report covering 10/29/2014 to 10/28/2015 Sequence 00020: Sentnyl Therapeutics, Inc. – Letter of Authorization Sequence 00021: Letter of Authorization/Withdrawn Letter of Authorization FDA_3961 DMF #027320; Sequence 0023 Shared System REMS Modification Date No. Approved N/A N/A N/A N/A REMS History Page 8 of 8 Documents Affected Overview of Modification Administrative Change; Change in US Agent 48-Month REMS Supplemental Assessment Report Sequence 00022: Administrative Change; Change in US Agent Sequence 00023: 48-Month REMS Supplemental Assessment Report FDA_3962 Accenture LLP 1160 West Swedesford Road Berwyn, PA 19312 August 18, 2016 Food and Drug Administration Center for Drug Evaluation and Research Central Document Room Drug Master File Staff Ammendale Road Beltsville, MD 20705?1266 Re: DMF 027320 . Holder: McKesson Specialty Health (McKesson) DMF Subject: Transmucosal Immediate Release entanyl (TIRF) Access Program Re: REMS Shared Program DMF Type: DMF Submission Information: DMF Annual Report REMS Submission Identi?er: Not Applicable Sequence Number: 0024 Dear Drug Master File Staff: This Type DMF contains the Risk Evaluation and Mitigation Strategy (REMS) for Transmucosal Immediate Release Fentanyl for the Shared System REMS program. Reference is made to the above DMF, which was initially submitted on August 20, 2013. Enclosed, please ?nd the DMF Annual Report (Reporting Period: August 21, 2015 August 20, 2016). The Annual Report includes an administrative information page, a summary of the amendments that have been submitted during this reporting period, and a list of authorized persons to incorporate by reference. McKesson states that information provided in this Master File is current and assures that the material furnished will meet the speci?cations described herein. McKesson also con?rms that the Holder obligations are observed. We request that all information in this ?le be treated as con?dential commercial information by the Food and Drug Administration pursuant to 21 C.F.R. ?20.6l, and that no information from this ?le be provided to any unauthorized persons without the express written consent of the DMF holder. If you have any questions or concerns, please do not hesitate to contact Gina Melazzo, US. Agent for McKesson, at 610?407-1732 or alternatively via email at gina.melazzo@accenture.com. Sincerely, Gina Melazzo, Senior Regulatory Affairs Project Manager US. Agent Accenture, LLP Attachments: Table of Contents for the submission. Electronic Submission Specifications DMF #027320; Sequence 0024 Shared System REMS Table of Contents Page 1 of 1 ANNUAL REPORT Reporting Period: August 21, 2015 – August 20, 2016 Module Section Description 1.2 Cover Letter Cover Letter w/ Attachments 1.11.3 – Efficacy Information Amendment Annual Report - Summary of Changes 1.4.3 – List of Authorized Persons to Incorporate by Reference List of Authorized Persons FDA_3964 Electronic Submission Specifications This submission is compliant with FDA's Guidelines for Industry and current eCTD specifications. All files were checked and verified to be free of viruses prior to transmission through the electronic submission gateway. Anti-Virus Program Program Version Virus Definition Date Submission Size Symantec Endpoint Protection Edition 12.1.5337.5000 08/03/2016 rev. 1 Approx. 405 KB The IT point of contact for this submission is: Name Phone Number Email Address Matt Francis 1-610-407-1854 Matthew.p.francis@accenture.com FDA_3965 ADMINISTRATIVE INFORMATION Holder’s Name: McKesson Specialty Health (McKesson) Holder’s Address: 4343 N. Scottsdale Road Suite 150 Scottsdale, AZ 85251 Holder’s Contact Person: Laura Baloun Contact’s Address: 4343 N. Scottsdale Road Suite 150 Scottsdale, AZ 85251 Contact’s Phone: 480-663-4009 Contact’s Fax: 480-663-4973 Contact’s Email address: laura.baloun@mckesson.com Statement of Commitment: Attached, please find a signed statement of commitment. The statement certifies that the DMF is current and that McKesson will comply with the statements made in it. Agent’s Name: Accenture, LLP Agent’s Address: 1160 West Swedesford Road Berwyn, PA 19312 Agent’s Contact Person: Gina Melazzo Contact’s Address 1160 West Swedesford Road Berwyn, PA 19312 Contact’s Phone: 610-407-1732 Contact’s Fax: 610-407-8433 Contact’s E-mail address: gina.melazzo@accenture.com FDA_3966 DMF #027320; Sequence 0024 Shared System REMS 3. 1.4 References Page 1 of 1 List of Authorized Persons to Incorporate by Reference (Annual Report - Reporting Period: August 21, 2015 – August 20, 2016) The following is a complete list of persons authorized to incorporate information in the DMF by reference: x x x x x x x x x Actavis Laboratories Inc. – June 17, 2015 BioDelivery Sciences International, Inc. – March 20, 2015 Cephalon, Inc. – August 28, 2013 Depomed, Inc. – August 28, 2013 Insys Therapeutics, Inc. – August 28, 2013 Mallinckrodt – August 28, 2013 Mylan – August 28, 2013 Par Pharmaceutical, Inc. – August 28, 2013 Sentynl Therapeutics Inc. – January 15, 2016 Please note that during the reporting period, McKesson submitted a letter of authorization for Sentynl Therapeutics Inc. and withdrew authorization for Galena BioPharma, Inc. FDA_3967 DMF #027320; Sequence 0024 Shared System REMS Annual Report – August 18, 2016 Page 1 of 1 ANNUAL REPORT - SUMMARY OF CHANGES Reporting Period: August 21, 2015 – August 20, 2016 Date / Sequence Description October 12, 2015 / 0018 Response to FDA Information Request – 36-Month Assessment Report December 28, 2015 / 0019 Assessment 5 at 4 Years January 15, 2016 / 0020 Letter of Authorization for Sentynl Therapeutics, Inc. January 15, 2016 / 0021 Letter of Withdrawal for Galena BioPharma, Inc. April 15, 2016 / 0022 Change in Agent May 4, 2016 / 0023 48-Month Supplemental Assessment Report For further details regarding the above REMS amendments, please see the REMS History (Sequence 0023). FDA_3968 January 30, 2017 Food and Drug Administration Center for Drug Evaluation and Research Central Document Room Drug Master File Staff 5901 -B Ammendale Road Beltsville, MD 20705?1266 Re: DMF 027320 Holder: McKesson Specialty Health (McKesson) DMF Subject: Transmucosal Immediate Release Fentanyl (TIRF) Access Program Re: REMS Shared Program DNIF Type: DMF Submission Information: Clinical/Clinical Information REMS Submission Identi?er: Correspondence Sequence Number: 0026 Dear Drug Master File Staff: This Type DMF contains the Risk Evaluation and Mitigation Strategy (REMS) for Immediate Release Fentanyl for the Shared System REMS program. Please find the consolidated response document to the multiple FDA information requests regarding the TIRF REMS Access Program 48?Month FDA Assessment Report located in Module 1.6 of this submission. Please see Page 1 of the consolidated response document for a summary of the FDA requests and correspondences. In addition, the Transmucosal REMS Industry Group (TRIG) would like to con?rm receipt of the FDA Information Request as a follow?up to the 48-month Acknowledgement Letter. The request is currently in process and the TRIG acknowledges that each individual sponsor will be submitting a separate supplemental correspOndence through their individual application to FDA prior to March 30, 2017. McKesson states that information provided in this Master File is current and assures that the material furnished will meet the speci?cations described herein. McKesson also confn'ms that the Holder obligations are observed. We request that all information in this ?le be treated as con?dential commercial information to the Food and Drug Administration pursuant to 21 CPR. ?20.6l, and that no information from this ?le be provided to any unauthorized persons without written consent. If you have any questions or concerns, please do not hesitate to contact Debra Hackett, US. Agent for McKesson, at 610-407?1729 or alternatively Via email at debra.hackett@accenture.com. CONFIDENTIAL DMF 027320; Sequence 0026 Shared System REMS Sincerely, Debra Hackett, US. Agent Accenture, LLP Attachments: Table of Contents for the submission Electronic Submission Speci?cations CONFIDENTIAL DMF #027320; Sequence 0026 Shared System REMS Table of Contents Page 1 of 1 REMS CORRESPONDENCE Module Section Description 1.2 Cover Letter Cover Letter w/ Attachments 1.16 – Risk Management Plans REMS History TIRF REMS Access Program 48-Month FDA Assessment Report Consolidated Information Request DMF Submission FDA_3971 Electronic Submission Specifications This submission is compliant with FDA's Guidelines for Industry and current eCTD specifications. All files were checked and verified to be free of viruses prior to transmission through the electronic submission gateway. Anti-Virus Program Program Version Virus Definition Date Submission Size Symantec Endpoint Protection Edition 12.1.5337.5000 01/26/2017 rev. 8 Approx. 3.9 MB The IT point of contact for this submission is: Name Phone Number Email Address Matt Francis 1-610-407-1854 Matthew.p.francis@accenture.com FDA_3972 ADMINISTRATIVE INFORMATION Holder’s Name: McKesson Specialty Health (McKesson) Holder’s Address: 4343 N. Scottsdale Road Suite 150 Scottsdale, AZ 85251 Holder’s Contact Person: Laura Baloun Contact’s Address: 4343 N. Scottsdale Road Suite 150 Scottsdale, AZ 85251 Contact’s Phone: 480-663-4009 Contact’s Fax: 480-663-4973 Contact’s Email address: laura.baloun@mckesson.com Statement of Commitment: Attached, please find a signed statement of commitment. The statement certifies that the DMF 027320 is current and that McKesson will comply with the statements made in it. Agent’s Name: Accenture, LLP Agent’s Address: 1160 West Swedesford Road, Building One Berwyn, PA 19312 Agent’s Contact Person: Debra Hackett, Senior Regulatory Project Manager, Regulatory Affairs Contact’s Address 1160 West Swedesford Road, Building One Berwyn, PA 19312 Contact’s Phone: 610-407-1729 Contact’s Fax: 610-407-8433 Contact’s E-mail address: debra.hackett@accenture.com FDA_3973 DMF #027320; Sequence 0026 Shared System REMS Modification Date No. Approved 1 June 5, 2012 REMS History Page 1 of 8 Documents Affected Overview of Modification x x Sequence 0002: Edits to Patient-Prescriber Agreement Form, the addition of the Closed System Pharmacy Enrollment Form*, the addition of the newly approved TIRF product, Subsys (fentanyl sublingual spray) and minor editorial changes. x x x x x x x x x x x x x x x x REMS Prescriber Program Overview Education Program Prescriber Enrollment Form Patient Provider Agreement Form Patient and Caregiver Overview Dear Healthcare Provider Letter Outpatient Pharmacy Overview Chain Pharmacy Overview Inpatient Pharmacy Overview Outpatient Pharmacy Enrollment Form Chain Pharmacy Enrollment Form Inpatient Pharmacy Enrollment form Outpatient Pharmacy Letter Inpatient Pharmacy Letter Dear Distributor Letter Distributor Enrollment Form Supporting Document *The Closed System Pharmacy Enrollment Form was not formally submitted through the Gateway but was submitted via email on May 18, 2012 and included in the June 5, 2012 FDA approval letter. FDA_3974 DMF #027320; Sequence 0026 Shared System REMS Modification Date No. Approved N/A N/A 2 November 7, 2013 N/A N/A 2 November 7, 2013 REMS History Page 2 of 8 Documents Affected Overview of Modification Assessment Report 1 at 6 months – due 06/28/2012 Sequence 0003: Assessment report covering 12/28/2011 to 04/27/2012 Draft Documents submitted on or before 09/28/2012 x Chain Pharmacy Enrollment Form x Outpatient Pharmacy Enrollment Form x Closed System Pharmacy Overview x Education Program x Frequently Asked Questions (FAQ) x Outpatient Pharmacy Letter x REMS x Supporting Document Assessment Report 2 at 1 year – due 12/28/2012 Amendment to 09/28/2012 supplement: x Chain Outpatient Pharmacy Enrollment Form x Independent Outpatient Pharmacy Enrollment Form x Closed System Outpatient Pharmacy Enrollment Form x Inpatient Sequence 0004: Modification proposed to: x Incorporate closed system pharmacies into the TIRF REMS Access Program x Correct minor inconsistencies between the FDA provided versions and the current PDF versions of REMS materials Sequence 0005: Assessment Report covering 04/28/2012 to 10/28/2012 Sequence 0006: Modification proposed to: x Revised terminology, processes, and definitions for outpatient pharmacies x Revised attestations for physicians and patients to address concerns regarding patient access x Revised Program Overview and Frequently Asked Questions to improve clarity and content FDA_3975 DMF #027320; Sequence 0026 Shared System REMS Modification Date No. Approved REMS History Page 3 of 8 Documents Affected x x x x x x x x x x x x x x x x x Pharmacy Enrollment Form Distributor Enrollment Form Prescriber Enrollment Form Patient Provider Agreement Form Chain Outpatient Pharmacy Overview Independent Outpatient Pharmacy Overview Closed System Outpatient Pharmacy Overview Inpatient Pharmacy Overview Patient and Caregiver Overview Prescriber Overview Education Program Knowledge Assessment Frequently Asked Questions (FAQ) Dear Outpatient Pharmacy Letter Dear Inpatient Pharmacy Letter Dear Healthcare Provide Letter Dear Distributor Letter REMS Overview of Modification x Updated REMS materials to reflect the completion of the transition phase for the TIRF REMS Access Program FDA_3976 DMF #027320; Sequence 0026 Shared System REMS Modification Date No. Approved REMS History Page 4 of 8 Documents Affected Overview of Modification x N/A N/A N/A N/A 3 December 24, 2014 Supporting Document x Website Landing Page Assessment Report 3 at 2 years – due 12/28/2013 Safety Surveillance Report #1 – due 03/31/2014 x x x x x x x x x x x REMS Prescriber Program Overview Education Program Prescriber Enrollment Form Patient and Caregiver Overview Independent Outpatient Pharmacy Overview Chain Outpatient Pharmacy Overview Closed System Outpatient Pharmacy Overview Inpatient Pharmacy Overview Independent Outpatient Pharmacy Enrollment Form Chain Outpatient Sequence 0007: Assessment Report covering 10/29/2012 to 10/28/2013 Sequence 0008: Safety surveillance data covering Q4 2012 to Q3 2013 Sequence 0009: Modification proposed to: x Updated REMS materials to eliminate product specific information which does not impact the safe use of TIRF products x Updated REMS materials to reference the currently approved TIRF products list on the FDA Approved REMS website x Updated REMS materials to remove reference to deactivating patients shown to have multiple prescribers in an overlapping timeframe x Incorporated revised assessment metrics into the Supporting Document x Revised Education Program to emphasize and strengthen appropriate conversion FDA_3977 DMF #027320; Sequence 0026 Shared System REMS Modification Date No. Approved REMS History Page 5 of 8 Documents Affected x x x x x x N/A N/A N/A N/A 3 December 24, 2014 Pharmacy Enrollment Form Closed System Outpatient Pharmacy Enrollment Form Inpatient Pharmacy Enrollment form Distributor Enrollment Form FAQ Supporting Document Website Prototype Cash Claim Information Request Response – due 05/30/2014 DMF Annual Report – due 08/20/2014 x REMS x Prescriber Program Overview x Education Program x Knowledge Assessment x Prescriber Enrollment Form x Patient and Caregiver Overview x Independent Outpatient Overview of Modification x x and patient counseling information Updated REMS and Supporting Document to clarify deactivation of a patient PPAF as opposed to the patient record Updated pharmacy overview documents and x FAQ to call out cash claim requirement x Updated TIRF REMS Access website to incorporate items above and link respective Full Prescribing Information and Medication Guides to DailyMed Sequence 0010: Response to 5/16/2014 FDA Cash Claim Information Request Sequence 0011: DMF Annual Report Sequence 0012: Modification proposed to: x Updated REMS materials to eliminate product specific information which does not impact the safe use of TIRF products x Updated REMS materials to reference the TIRF Products webpage on the TIRF REMS Access website x Updated REMS FDA_3978 DMF #027320; Sequence 0026 Shared System REMS Modification Date No. Approved REMS History Page 6 of 8 Documents Affected x x x x x x x x x x x Pharmacy Overview Chain Outpatient Pharmacy Overview Closed System Outpatient Pharmacy Overview Inpatient Pharmacy Overview Independent Outpatient Pharmacy Enrollment Form Chain Outpatient Pharmacy Enrollment Form Closed System Outpatient Pharmacy Enrollment Form Inpatient Pharmacy Enrollment form Distributor Enrollment Form FAQ Supporting Document Website Prototype Overview of Modification x x x x x x materials to remove reference to deactivating patients shown to have multiple prescribers in an overlapping timeframe Incorporated revised assessment metrics into the Supporting Document Revised Education Program to emphasize and strengthen appropriate conversion and patient counseling information Updated REMS and Supporting Document to clarify deactivation of a patient PPAF as opposed to the patient record Updated pharmacy overview documents and FAQ to call out cash claim requirement Updated TIRF REMS Access website to incorporate items above and link respective Full Prescribing Information and Medication Guides to DailyMed Updated Education Program and Knowledge Assessment to incorporate approved labeling supplement FDA_3979 DMF #027320; Sequence 0026 Shared System REMS Modification Date No. Approved 3 December 24, 2014 REMS History Page 7 of 8 Documents Affected Overview of Modification Unchanged from Sequence 0012, plus: x Dear Healthcare Provider Letter x Dear Outpatient Pharmacy Letter x Dear Inpatient Pharmacy Letter x Dear Distributor Letter Sequence 0013: Unchanged from Sequence 0012, plus: x Dear Healthcare Provider Letter x Dear Outpatient Pharmacy Letter x Dear Inpatient Pharmacy Letter x Dear Distributor Letter N/A N/A Assessment Report 4 at 3 years – due 12/28/2014 Sequence 00014: Assessment Report covering 10/29/2013 to 10/28/2014 N/A N/A BioDelivery Sciences International – Letter of Authorization Sequence 0015: BioDelivery Sciences International – Letter of Authorization N/A N/A Actavis Laboratories Inc. – Letter of Authorization Sequence 0016: Actavis Laboratories Inc. – Letter of Authorization N/A N/A DMF Annual Report – due 08/20/2015 Sequence 0017: DMF Annual Report N/A N/A 36-Month Assessment – Consolidated Information Requests N/A N/A Assessment Report 5 at 4 years – due 12/28/2015 N/A N/A N/A N/A Sentnyl Therapeutics, Inc. – Letter of Authorization Withdraw Authorization for Galena BioPharma, Inc. Sequence 0018: Response to FDA 36Month Assessment Information Requests Sequence 00019: Assessment Report covering 10/29/2014 to 10/28/2015 Sequence 00020: Sentnyl Therapeutics, Inc. – Letter of Authorization Sequence 00021: Letter of Authorization/Withdrawn Letter of Authorization FDA_3980 DMF #027320; Sequence 0026 Shared System REMS Modification Date No. Approved N/A N/A REMS History Page 8 of 8 Documents Affected Overview of Modification Administrative Change; Change in US Agent 48-Month REMS Supplemental Assessment Report Sequence 00022: Administrative Change; Change in US Agent Sequence 00023: 48-Month REMS Supplemental Assessment Report Sequence 0024: DMF Annual Report N/A N/A N/A N/A DMF Annual Report – due 08/20/2016 N/A N/A NA N/A Administrative Change; Change in US Agent Assessment Report 6 at 5 years – due 12/28/2016 N/A N/A 48-Month FDA Assessment Report Consolidated Information Requests Sequence 00025: Administrative Change; Change in US Agent Sequence 0027: Assessment Report covering 10/29/2015 to 10/28/2016 Sequence 0026: TIRG REMS Access Program 48-Month FDA Assessment Report Consolidated Responses to FDA Information Requests FDA_3981 TIRF REMS Access Program 48-Month FDA Assessment Report Consolidated Information Request DMF Submission   In follow-up to FDA’s review of the TIRF REMS Access Program 48-Month FDA Assessment Report, multiple information requests were issued to the TRIG. As previously agreed to by FDA on 25FEB2015, a response to each information request is provided via email with a consolidated information request being submitted to FDA once the Assessment Report Acknowledgement Letter is received. The complete list of 48-Month FDA Assessment Report information requests and date of each response are shown in the table below. Each individual response is attached. Information Request 1 17MAY2016 2 18JUL2016 3 21JUL2016 N/A 29JUL2016 48-Month Acknowledgement Letter 07DEC2016 and 18JAN2017 Received 19JAN2017 v2.0 Final Summary of Request/Correspondence  Explanation of the calculations for opioid tolerant and non-opioid tolerant in Tables 3b and 6b (IMS Study titled “TIRF REMS Access Program Assessment Study Report (dated April 22, 2016) included in the Supplemental Report submission)  Clarification of how the N of 9,283 was derived in Table 3b (Persistency Analysis titled “TIRF REMS Persistency Analysis Final Report” included in the Supplemental Report submission)  Confirmation of the timeline for the 2016 Knowledge, Attitude, and Behavior (KAB) surveys of prescribers, pharmacists, and patients  Confirmation of what FDA requested changes could and could not be incorporated into the KAB survey results slated for submission by 28DEC2016  Request for FDA to confirm whether all requests should be incorporated into the Assessment Report delaying the submission date until on or before 17FEB2017  TRIG and FDA agreed to submit the 60-Month FDA Assessment Report on or before 28DEC2016, but delay submission of the KAB survey results until on or before 17FEB2017 to allow for all requested changes to be incorporated into the surveys  TRIG and FDA agreed to a teleconference on 03MAR2017 at 2 PM EST to discuss opportunities for obtaining additional data on accidental exposure in children, as well as to discuss and explore new approaches to assessing this REMS with the goal of gathering useful information to better understand the impact of the REMS and to improve the program going forward. Response Provided to FDA 27MAY2016 20JUL2016 28JUL2016 01AUG2016 12DEC2016 and 19JAN2017 FDA_3982   TIRF REMS Access Program 48-Month FDA Assessment Report FDA Information Request 1 Response FDA_3983 Response to 17MAY2016 FDA Questions on 48-Month Supplemental Report The bold text below represents the FDA requests included in the correspondence dated 17MAY2016. The TRIG’s response is shown below each request. 1. FDA Comment: In your “TIRF REMS Access Program Assessment Study Report” (dated April 22, 2016), provide detailed descriptions as to how the percentages for Opioid-Tolerant and Non-Opioid-Tolerant were calculated in Tables 3b and 6b. TRIG Response: Patients were defined as opioid tolerant if they had an opioid analgesic product prescription fill with at least 7 continuous days of sufficient daily dose immediately preceding the TIRF prescription date. Prior prescriptions of opioid analgesic products were identified as ≥ 1 prescription fill for opioid analgesics within 30 days. To account for combinations of products, sufficient daily dose was calculated by summing the daily dose for each prescription fill. Additional details on definitions and calculations can be found in Section F. Drug Exposures of the TIRF REMS Access Program Assessment (dated April 22, 2016). The percentage of opioid tolerant patients was calculated using the number of opioid tolerant patients divided by the total number of patients who received an initial TIRF prescription (Table 3b: 12,406/25,322= 49.0%). Patients shown as non-opioid tolerant were those who received a TIRF prescription, but had not met the criteria for opioid tolerance (e.g., no previous opioid prescription or insufficient dose/days’ supply within the defined time window). The percentage for opioid non-tolerant patients was calculated using the number of non-opioid tolerant patients divided by the number of patients who received an initial TIRF prescription (Table 3b: 12,916/25,322= 51.0%). The same calculation logic for both opioid tolerant patients and non-opioid tolerant patients was used in the sensitivity analysis shown in Table 6b. 27MAY2016    Page 1 of 4  FDA_3984 Response to 17MAY2016 FDA Questions on n 48-Month Supplementtal Report (b) (4) 27MAY2016    Page 2 of 4  P FDA_3985 Response to 17MAY2016 FDA Questions on 48-Month Supplemental Report (b) (4) 2. 27MAY2016    Page 3 of 4  FDA_3986 Response to 17MAY2016 FDA Questions on n 48-Month Supplementtal Report (b) (4) 27MAY2016    Page 4 of 4  P FDA_3987 TIRF REMS Access Program 48-Month FDA Assessment Report FDA Information Request 2 Response FDA_3988 Response to 18JUL2016 FDA Questions on 48-Month Assessment Report   The bold text below represents the FDA requests included in the correspondence dated 18JUL2016. The TRIG’s response is shown below each request. 1. FDA Comment: Have the surveys for the next assessment started yet? TRIG Response: The 2016 Knowledge, Attitude and Behavior (KAB) surveys for prescribers, pharmacists and patients have not yet launched; however, the Electronic Data Capture (EDC) system is in its formal validation stage. 2. If not, when is the planned start date for these surveys? TRIG Response: In order to meet the survey completer goals for each survey and submit the finalized reports per the current Timetable for Submission of Assessments, the launch date for the surveys is anticipated to be on or before 05AUG2016. At this time all protocols have been finalized, the patient materials have been IRB approved and the EDC system used is in its formal validation stage. 3. The DRISK group has some comments on the surveys they would like to have incorporated in the next assessment. TRIG Response: TRIG is open to incorporating these changes. If the changes are minimal, they may be able to be incorporated into the 60-Month FDA Assessment Report for submission in December. Extensive changes or those that necessitate IRB re-review and approval may require a Supplemental Report, a negotiated delay in report submission beyond the 28DEC2016 submission due date, or incorporation into the 2017 KAB Surveys. 20JUL2016    Page 1 of 1  FDA_3989 TIRF REMS Access Program 48-Month FDA Assessment Report FDA Information Request 3 Response FDA_3990 Response to 21JUL2016 FDA Questions on 48-Month Assessment Report   The bold text below represents the FDA requests included in the correspondence dated 21JUL2016. The TRIG’s response is shown below each request. 1. FDA Communication: The FDA would like to provide the following comments to the TRIG regarding the TIRF patient, prescriber, and pharmacist surveys. Additional comments on the full 48-month TIRF REMS assessment will be provided in a separate communication. We do not intend to review updates to your survey methodology based on these recommendations prior to the next assessment. Please provide any updated methodology with your next assessment submission. In addition, within the next 7 days and before starting the survey, let us know if the recommended changes are able to be incorporated or if IRB re-review is needed. If IRB re-review is required, provide a timeline of how much additional time is needed. TRIG Response: The TRIG has carefully reviewed the 21JUL2016 FDA correspondence and has determined that there are some changes that can be readily accommodated and others which will require more substantial changes to the EDC system. In order to reach the survey completer goal and submit the 60-Month FDA Assessment Report as required on or before 28DEC2016, TRIG can incorporate the 5 requests shown in Table 1. These changes are updates to existing questions or small protocol updates. While these updates would delay launch of the survey past the original milestone of 05AUG2016, the TRIG anticipates still being able to meet the survey completer goals and a timely report submission on or before 28DEC2016. The time to incorporate the remaining 11 requests (Table 2) related to adding survey questions and changing inclusion criteria for pharmacists and prescribers would put in jeopardy the TRIG’s ability to meet survey completer goals and submit the report on or before 28DEC2016. The TRIG has identified two possible options for handling the requested changes. The TRIG requests that FDA provide their preference on the below approach options by close of business (COB) Eastern Standard Time (EST) 04AUG2016. The TRIG believes that by incorporating all changes provided in the 21JUL2016 FDA correspondence prior to launch of the 2016 surveys and delaying submission of the 60Month FDA Assessment Report by 45 days (target submission on or before 17FEB2017), it would provide the most comprehensive and timely response to the Agency’s request; therefore, TRIG recommends this approach. Alternatively, the TRIG could incorporate only the items listed below in Table 1 and provide them in the 60-Month FDA Assessment Report to be submitted on or before 28DEC2016. The remaining requests outlined in the 21JUL2016 correspondence (Table 2) would be incorporated into the 2017 KAB Surveys. 28JUL2016    Page 1 of 6  FDA_3991 Response to 21JUL2016 FDA Questions on 48-Month Assessment Report Table 1. FDA Re uests that Can Be Incor orated for 28DEC2016 Submission Stakeholder Patient FDA Feedback* B. Under Key Risk Message 2: Revised question medicines should only be taken by cancer patients who are opioid tolerant?. Return to the original question used in the previous surveys. medicines should only be taken by patients who are opioid tolerant.? TRIG Response Question 11 will be updated to remove reference to ?cancer? Changes to the patient protocol and survey require IRB review prior to launch (approximately 5 days) Change requires re-validation of the EDC system (approximately 4-6 weeks). [The Electronic Data Capture (EDC) system used in the TRIG KAB Surveys is a regulatory compliant/Part ll compliant system. Application changes after validation begins include regression analysis, regulatory assessment, documentation of requirements, coding, code review and unit testing, and formal validation to ensure the changes are implemented as expected, and there is no unforeseen impact to the survey functionality] Patient D. FDA recommends revisions to the questions that ask patients about prescriber activities to allow pharmacists as a potential source of infomiation. Revise question that begin with: Did the doctor, nurse, or other healthcare professional in the doctor's o?ice to: Did doctor, nurse, or other healthcare professional 0 talk to you about the risks and possible side effects of the TIRF medicine that was most recently prescribed for you? 0 tell you how to use the TIRF medicine that was most recently prescribed for you? 0 tell you how to store or keep the TIRF medicine that was most recently prescribed for you? Questions 9. 15. and 16 will be updated to change ?the? to Changes to the patient protocol and survey require IRB review prior to launch (approximately 5 days) Changes require re-validation of the EDC system (approximately 4-6 weeks). [See Table 1. Patient Item bolded item for validation explanation] Pharmacist A. There were no closed system pharmacy (CSP) sm'vey respondents. In addition. the FDA asked the sponsor to recruit more non-supervisory pharmacists. The sponsor reported that despite recruitment efforts. only 18% reported that they were not the pharmacist in charge. FDA the sponsor to continue efforts to recruit closed system pharmacy sm'vey respondents and recruit more non-supervisory pharmacists as survey respondents. TRIG will attempt to recruit more CSP and non- supervisory phamlacist survey respondents 28JUL2016 Page 2 of 6 Response to 21JUL2016 FDA Questions on 48-Month Assessment Report Stakeholder FDA Feedback" Pharmacist F. Provide a description of how pharmacies that dispense TIRF medicines compare to the pharmacies represented by survey respondents. If possible. provide what percentage of orders are from outpatient vs. inpatient vs. closed system pharmacies. In addition for the survey respondents. provide additional information about if multiple regions represented. how many pharmacists were from the same pharmacies. and how many pharmacies were represented in the survey. TRIG Response TRIG will update the analysis as requested Prescriber C. Revise the question: For which indications do you prescribe TIRF medicines to opioid tolerant patients. This assmnes prescribers are only using TIRF medicines for opioid tolerant patients which may not be the case. Example Revision: Per the approved labeling for TIRF medicines, for which of the following indications can medicines be prescribed? to opioid tolerant patients? TRIG will revise Question 9 to remove reference to opioid tolerant patients Change requires re-validation of the EDC system (approximately 4-6 weeks). [See Table 1. Patient Item bolded item for validation explanation] Referenced lettering corresponds with the 21JUL2016 FDA correspondence. 28JUL2016 Page 3 of 6 Response to 21JUL2016 FDA Questions on 48-Month Assessment Report Table 2. FDA Re nests That Cannot be Incor orated for 28DEC2016 Submission Stakeholder FDA Feedback* TRIG Response Patient A. Add question: A side effect of TIRF medicines is the chance of abuse Changes to the patient protocol and survey require or addiction. IRB review prior to launch (approximately 5 days) Change requires EDC to be modi?ed to add a question In addition to. but prior to validation. application development lifecycle processes must be followed for these changes. The 21.TUL2016 FDA correspondence was received after the application development process was complete for all 3 TRIG Surveys. Patient C. Add questions iuider Key Risk Message 5. Example questions: Changes to the patient protocol and survey require 0 TIRF medicines can be misused by people who abuse IRB review prior to launch (approximately 5 days) prescription medicines or street drugs. 0 Keep the TIRF medicine in a safe place to prevent it from being Changes require EDC to be modified to add stolen. questions In addition to. but prior to validation. application development lifecycle processes must be followed for these changes. The ZIJUL2016 FDA correspondence was received after the application development process was complete for all 3 TRIG Surveys. Patient E. The questions in the patient sru'vey about healthcare professional or Changes to the patient protocol and survey require prescriber activities do not correspond to the questions included in IRB review prior to launch (approximately 5 days) the prescriber and phamiacist survey. FDA recommends alignment of these questions. In the patient survey. include additional Changes require EDC to be modi?ed to add questions about the following: questions 0 Did a doctor. nurse. or other healthcare professional ever ask you about the presence of children in the home. In addition to. but prior to validation. application 0 Did a doctor. nurse. or other healthcare professional ever tell development lifecycle Processes must be followed you not to share the TIRF medicines with anyone else. for these changes. The ZUUL2016 FDA 0 Did a doctor. nurse. or other healthcare professional ever correspondence was received after the application counsel you that accidental exposure to TIRF medicines by a development process was complete for all 3 TRIG child may be fatal Surveys. 0 Did a doctor. nurse. or other healthcare professional ever tell you to keep TIRF medicines out of reach of children to prevent 28JUL2016 Page 4 of 6 Response to 21JUL2016 FDA Questions on 48-Month Assessment Report Stakeholder FDA Feedback* accidental exposure. 0 Did a doctor. nurse. or other healthcare professional ever tell you about proper disposal of any unused or partially used TIRF TRIG Response medicines. Pharmacist B. Thirty-nine percent of respondents had not dispensed TIRF Requires changes to recruitment process and medicines within the last six months. FDA recommends limiting materials the survey to pharmacists who have dispensed TIRF medicines in the past six months. Pharmacist C. The questions in the pharmacist survey about pharmacists? reported Changes require EDC to be modi?ed to add activities do not correspond to the questions included in the patient questions survey. FDA recommends alignment of these questions In the pharmacist survey. include additional questions about the following: In addition to. but prior to validation. application 0 How frequently do you perform the following activities when development lifecycle processes must be followed dispensing TIRF medicines? for these changes. The 21.TUL2016 FDA 0 Talk to the patient about the risks and possible side effects of correspondence was received after the application the TIRF medicine that was most recently prescribed? development process was complete for all 3 TRIG 0 Instruct the patient on how to use the TIRF medicine that was Surveys. most recently prescribed? 0 Instruct the patient on 110w to store or keep the TIRF medicine that was most recently prescribed? Pharmacist D. Add question from patient survey to pharmacist smvey to Key Risk Change requires EDC to be modi?ed to add a Message 1: medicines should only be taken by cancer patients question who are opioid tolerant. (T In addition to. but prior to validation. application development lifecycle processes must be followed for these changes. The 21JUL2016 FDA correspondence was received after the application development process was complete for all 3 TRIG Surveys. Pharmacist E. Add a question to assess pharmacists? awareness of the REMS risk Changes require EDC to be modi?ed to add for (misuse. abuse. addiction. overdose. medication questions errors). Example question: Which of the following risks are associated with the use of ransmucosal immediate release fentanvl In addition to. but prior to validation. application (TIRF) medicines? [Add foils]: development lifecycle processes must be followed 0 Misuse for these changes. The 21JUL2016 FDA 0 Abuse correspondence was received after the application 0 Addiction development process was complete for all 3 TRIG Surveys. 28JUL2016 Page 5 of 6 Response to 21JUL2016 FDA Questions on 48-Month Assessment Report Stakeholder FDA Feedback* 0 Overdose TRIG Response for TIRF medicines (misuse. abuse. addiction. overdose). Example question: Which of the following risks are associated with the use of Transmucosal immediate release fentanyl medicines? [Add foils]: 0 Misuse 0 Abuse 0 Addiction 0 Overdose Prescriber A. Twenty-one percent of respondents stated that they had not Requires changes to recruitment process and prescribed a TIRF medicine within the last six months. FDA materials limiting survey respondents to prescribers who have prescribed TIRF medicines in the past 6 months. Prescriber B. Add question from patient sru'vey to prescriber sruvey to Key Risk Change requires EDC to be modi?ed to add a Message 1: TIRF medicines should only be taken by cancer patients question who are opioid tolerant. In addition to. but prior to validation. application development lifecycle processes must be followed for these changes. The 21JUL2016 FDA correspondence was received after the application development process was complete for all 3 TRIG Surveys. Prescriber D. The questions in the prescriber sru'vey about prescriber reported Changes require EDC to be modi?ed to add activities do not correspond to the questions included in the patient questions survey. FDA recommends alignment of these questions. In the prescriber sru'vey. include additional questions about the following: In addition to. but prior to validation. application 0 How ?'equentlr do you peifonn the following activities when development lifecycle processes must be followed prescribing TIRF medicines? for these changes. The ZIJULZOI6 FDA 0 Talk to the patient about the risks and possible side effects correspondence was received after the application of the TIRF medicine that was most recently prescribed? development process was complete for all 3 TRIG Instruct the patient on 110w to use the TIRF medicine that Surveys. was most recently prescribed? Instruct the patient on how to store or keep the TIRF medicine that was most recently prescribed? Prescriber E. Add a question to assess prescriber?s awareness of the REMS risks Changes require EDC to be modi?ed to add questions In addition to. but prior to validation. application development lifecycle processes must be followed for these changes. The 21JUL2016 FDA correspondence was received after the application development process was complete for all 3 TRIG Surveys. Referenced lettering corresponds with the ZIJULZOI6 FDA correspondence. 28JUL2016 Page 6 of 6 TIRF REMS Access Program 48-Month FDA Assessment Report FDA & TRIG Correspondence (29JUL2016-01AUG2016) FDA_3997 Dinesh Anugu From: Sent: To: Cc: Subject: Brown, Wendy Monday, August 01, 2016 12:47 PM Dinesh Anugu Bulkley, Amanda; Sremba, Siressa (Siressa.Sremba@McKesson.com) RE: Submission Proposal INFORMATION REQUEST #3: 48-month, TIRF REMS Assessment Hi Dinesh, I have forwarded the response provided to our DRISK Assessment team and will get back to you if there are additional comments or questions. Thanks, WENDY WENDY B. BROWN, PHARMD, BCACP   Safety Regulatory PM   FDA/OMPT/CDER/OSE/PMS   10903 New Hampshire Ave   WO22 RM4484   Silver Spring, MD 20993   Office:  240‐402‐9140   BB: 240‐731‐8615   Email:  wendy.brown@fda.hhs.gov  THIS MESSAGE IS INTENDED ONLY FOR THE USE OF THE PARTY TO WHOM IT IS ADDRESSED AND MAY CONTAIN INFORMATION THAT IS PREDECISIONAL, PRIVILEGED, CONFIDENTIAL, AND PROTECTED FROM DISCLOSURE UNDER LAW. If you are not the named addressee, or if this message has been addressed to you in error, you are directed not to read, disclose, reproduce, disseminate, or otherwise use this transmission. If you have received this document in error, please immediately notify me by email or telephone.  From: Dinesh Anugu [mailto:danugu@insysrx.com] Sent: Monday, August 01, 2016 3:02 PM To: Brown, Wendy Cc: Bulkley, Amanda; Sremba, Siressa (Siressa.Sremba@McKesson.com) Subject: RE: Submission Proposal INFORMATION REQUEST #3: 48-month, TIRF REMS Assessment   Dear Wendy,    In response to the Agency’s options provided below for the 48‐month TIRF REMS Assessment, TRIG agrees with FDA’s  approach of submission of all items in the assessment plan except the surveys on the December due date, and  submission of the surveys February 17th.    Please let me know if you have any further questions.    Thank you,  Dinesh      Dinesh Reddy Anugu, MS, RAC  Regulatory Affairs Associate  1 FDA_3998   1333 South Spectrum Blvd, Suite 100., Chandler, AZ 85286  P: (480) 500‐3193  F: (602) 910‐2627  danugu@insysrx.com*  www.insysrx.com          From: Brown, Wendy [mailto:Wendy.Brown@fda.hhs.gov]   Sent: Friday, July 29, 2016 5:33 AM  To: Dinesh Anugu   Cc: Bulkley, Amanda ; Sremba, Siressa (Siressa.Sremba@McKesson.com)    Subject: Submission Proposal   INFORMATION REQUEST #3: 48‐month, TIRF REMS Assessment    Hi Dinesh, In response to your proposal, provided on 7/28, via email, the Agency would like the TRIG to consider the following option(s) for submission of the 48-month, TIRF REMS Assessment: 1. Submission of all items in the assessment plan except the surveys on the December due date. 2. Submission of the surveys February 17th This essentially splits the submission, however, we have done this in the past for other assessments. In the case of the TIRF REMS, there is so much data included in the report outside of the surveys that we’d really prefer to begin working on those sections of the assessment in late December/early January. Additionally, there is one correction to a survey comment provided in the 7/21 IR via email:  Original Comment: Add question from patient survey to prescriber and pharmacist survey to Key Risk Message 1: TIRF medicines should only be taken by cancer patients who are opioid tolerant. (T/F/DK)  Additional Comment: Please ensure that the added question is the proposed revised question: TIRF medicines should only be taken by cancer patients who are opioid-tolerant. (T/F/DK) Please provide response by COB, Thursday, August 4. Thanks, WENDY WENDY B. BROWN, PHARMD, BCACP   Safety Regulatory PM   FDA/OMPT/CDER/OSE/PMS   10903 New Hampshire Ave   WO22 RM4484   Silver Spring, MD 20993   Office:  240‐402‐9140   BB: 240‐731‐8615   Email:  wendy.brown@fda.hhs.gov  THIS MESSAGE IS INTENDED ONLY FOR THE USE OF THE PARTY TO WHOM IT IS ADDRESSED AND MAY CONTAIN INFORMATION THAT IS PREDECISIONAL, PRIVILEGED, CONFIDENTIAL, AND PROTECTED FROM DISCLOSURE UNDER LAW. If you are not the named addressee, or if this message has been addressed to you in error, you are directed not to read, disclose, reproduce, disseminate, or otherwise use this transmission. If you have received this document in error, please immediately notify me by email or telephone.  2 FDA_3999 From: Brown, Wendy Sent: Thursday, July 28, 2016 5:07 PM To: 'Dinesh Anugu' Cc: Bulkley, Amanda; Sremba, Siressa (Siressa.Sremba@McKesson.com) Subject: RE: INFORMATION REQUEST #3: 48-month, TIRF REMS Assessment   Hi Dinesh, I have forwarded this information to our DRISK Assessment team for review and will provide their response, as requested, by COB, Thursday, AUGUST 4. Thanks, WENDY WENDY B. BROWN, PHARMD, BCACP   Safety Regulatory PM   FDA/OMPT/CDER/OSE/PMS   10903 New Hampshire Ave   WO22 RM4484   Silver Spring, MD 20993   Office:  240‐402‐9140   BB: 240‐731‐8615   Email:  wendy.brown@fda.hhs.gov  THIS MESSAGE IS INTENDED ONLY FOR THE USE OF THE PARTY TO WHOM IT IS ADDRESSED AND MAY CONTAIN INFORMATION THAT IS PREDECISIONAL, PRIVILEGED, CONFIDENTIAL, AND PROTECTED FROM DISCLOSURE UNDER LAW. If you are not the named addressee, or if this message has been addressed to you in error, you are directed not to read, disclose, reproduce, disseminate, or otherwise use this transmission. If you have received this document in error, please immediately notify me by email or telephone.  From: Dinesh Anugu [mailto:danugu@insysrx.com] Sent: Thursday, July 28, 2016 4:49 PM To: Brown, Wendy Cc: Bulkley, Amanda; Sremba, Siressa (Siressa.Sremba@McKesson.com) Subject: RE: INFORMATION REQUEST #3: 48-month, TIRF REMS Assessment   Dear Wendy,    Please find attached the TRIG’s response for the below Information request# 3.     Also, TRIG is requesting for response on FDA’s preference on the TRIG’s approach (Please see attached document) by  close of business (COB) Eastern Standard Time (EST) 04AUG2016.    Let me know if you have any further questions.    Thank you,  Dinesh         Dinesh Reddy Anugu, MS, RAC  Regulatory Affairs Associate  3 FDA_4000   1333 South Spectrum Blvd, Suite 100., Chandler, AZ 85286  P: (480) 500‐3193  F: (602) 910‐2627  danugu@insysrx.com*  www.insysrx.com            From: Brown, Wendy [mailto:Wendy.Brown@fda.hhs.gov]   Sent: Thursday, July 21, 2016 7:22 AM  To: Dinesh Anugu   Cc: Bulkley, Amanda ; Sremba, Siressa (Siressa.Sremba@McKesson.com)    Subject: INFORMATION REQUEST #3: 48‐month, TIRF REMS Assessment    Hi Dinesh, The FDA would like to provide the following comments to the TRIG regarding the TIRF patient, prescriber, and pharmacist surveys. Additional comments on the full 48-month TIRF REMS assessment will be provided in a separate communication. We do not intend to review updates to your survey methodology based on these recommendations prior to the next assessment. Please provide any updated methodology with your next assessment submission. In addition, within the next 7 days and before starting the survey, let us know if the recommended changes are able to be incorporated or if IRB re-review is needed. If IRB re-review is required, provide a timeline of how much additional time is needed. TIRF REMS Survey Comments 1. Patient Survey Comments A. Add question: A side effect of TIRF medicines is the chance of abuse or addiction. B. Under Key Risk Message 2: Revised question “TIRF medicines should only be taken by cancer patients who are opioid tolerant”. Return to the original question used in the previous surveys, “TIRF medicines should only be taken by patients who are opioid tolerant.” C. Add questions under Key Risk Message 5. Example questions: TIRF medicines can be misused by people who abuse prescription medicines or street drugs.  Keep the TIRF medicine in a safe place to prevent it from being stolen.  D. FDA recommends revisions to the questions that ask patients about prescriber activities to allow pharmacists as a potential source of information. Revise question that begin with: Did the doctor, nurse, or other healthcare professional in the doctor's office ever.... to: Did a doctor, nurse, or other healthcare professional ever....  talk to you about the risks and possible side effects of the TIRF medicine that was most recently prescribed for you? tell you how to use the TIRF medicine that was most recently prescribed for you?   tell you how to store or keep the TIRF medicine that was most recently prescribed for you? E. The questions in the patient survey about healthcare professional or prescriber activities do not correspond to the questions included in the prescriber and pharmacist survey. FDA recommends alignment of these questions. In the patient survey, include additional questions about the following: Did a doctor, nurse, or other healthcare professional ever ask you about the presence of children in the  home. 4 FDA_4001     2. Did a doctor, nurse, or other healthcare anyone else. Did a doctor, nurse, or other healthcare medicines by a child may be fatal Did a doctor, nurse, or other healthcare children to prevent accidental exposure. Did a doctor, nurse, or other healthcare partially used TIRF medicines. professional ever tell you not to share the TIRF medicines with professional ever counsel you that accidental exposure to TIRF professional ever tell you to keep TIRF medicines out of reach of professional ever tell you about proper disposal of any unused or Pharmacist Survey Comments A. There were no closed system pharmacy (CSP) survey respondents. In addition, the FDA asked the sponsor to recruit more non-supervisory pharmacists. The sponsor reported that despite recruitment efforts, only 18% reported that they were not the pharmacist in charge. FDA recommends the sponsor to continue efforts to recruit closed system pharmacy survey respondents and recruit more non-supervisory pharmacists as survey respondents. B. Thirty-nine percent (39%) of respondents had not dispensed TIRF medicines within the last six months. FDA recommends limiting the survey to pharmacists who have dispensed TIRF medicines in the past six months. C. The questions in the pharmacist survey about pharmacists’ reported activities do not correspond to the questions included in the patient survey. FDA recommends alignment of these questions In the pharmacist survey, include additional questions about the following:  o How frequently do you perform the following activities when dispensing TIRF medicines?   Talk to the patient about the risks and possible side effects of the TIRF medicine that was most recently prescribed?  Instruct the patient on how to use the TIRF medicine that was most recently prescribed?  Instruct the patient on how to store or keep the TIRF medicine that was most recently prescribed? D. Add question from patient survey to pharmacist survey to Key Risk Message 1: TIRF medicines should only be taken by cancer patients who are opioid tolerant. (T/F/DK) E. Add a question to assess pharmacists’ awareness of the REMS risk for TIRFs (misuse, abuse, addiction, overdose, medication errors). Example question: Which of the following risks are associated with the use of Transmucosal immediate release fentanyl (TIRF) medicines? [Add foils]:  Misuse (T/F/DK)  Abuse (T/F/DK)  Addiction (T/F/DK)  Overdose (T/F/DK) F. Provide a description of how pharmacies that dispense TIRF medicines compare to the pharmacies represented by survey respondents. If possible, provide what percentage of orders are from outpatient vs. inpatient vs. closed system pharmacies. In addition for the survey respondents, provide additional information about if multiple regions represented, how many pharmacists were from the same pharmacies, and how many pharmacies were represented in the survey. 3. Prescriber Survey Comments A. Twenty-one percent (25%) of respondents stated that they had not prescribed a TIRF medicine within the last six months. FDA recommends limiting survey respondents to prescribers who have prescribed TIRF medicines in the past 6 months. B. Add question from patient survey to prescriber survey to Key Risk Message 1: TIRF medicines should only be taken by cancer patients who are opioid tolerant. (T/F/DK) 5 FDA_4002 C. Revise the question: For which indications do you prescribe TIRF medicines to opioid tolerant patients. This assumes prescribers are only using TIRF medicines for opioid tolerant patients which may not be the case. Example Revision: Per the approved labeling for TIRF medicines, for which of the following indications can TIRF medicines be prescribed? to opioid tolerant patients? D. The questions in the prescriber survey about prescriber reported activities do not correspond to the questions included in the patient survey. FDA recommends alignment of these questions. In the prescriber survey, include additional questions about the following:  o How frequently do you perform the following activities when prescribing TIRF medicines?   Talk to the patient about the risks and possible side effects of the TIRF medicine that was most recently prescribed?  Instruct the patient on how to use the TIRF medicine that was most recently prescribed?  Instruct the patient on how to store or keep the TIRF medicine that was most recently prescribed? E. Add a question to assess prescriber’s awareness of the REMS risks for TIRF medicines (misuse, abuse, addiction, overdose). Example question: Which of the following risks are associated with the use of Transmucosal immediate release fentanyl (TIRF) medicines? [Add foils]:  Misuse (T/F/DK)  Abuse (T/F/DK)  Addiction (T/F/DK)  Overdose (T/F/DK) Please contact us if there are any questions about the above recommendations. Thanks, WENDY WENDY B. BROWN, PHARMD, BCACP   Safety Regulatory PM   FDA/OMPT/CDER/OSE/PMS   10903 New Hampshire Ave   WO22 RM4484   Silver Spring, MD 20993   Office:  240‐402‐9140   BB: 240‐731‐8615   Email:  wendy.brown@fda.hhs.gov  THIS MESSAGE IS INTENDED ONLY FOR THE USE OF THE PARTY TO WHOM IT IS ADDRESSED AND MAY CONTAIN INFORMATION THAT IS PREDECISIONAL, PRIVILEGED, CONFIDENTIAL, AND PROTECTED FROM DISCLOSURE UNDER LAW. If you are not the named addressee, or if this message has been addressed to you in error, you are directed not to read, disclose, reproduce, disseminate, or otherwise use this transmission. If you have received this document in error, please immediately notify me by email or telephone.  From: Brown, Wendy Sent: Wednesday, July 20, 2016 12:18 PM To: 'Dinesh Anugu' Cc: Bulkley, Amanda; Sremba, Siressa (Siressa.Sremba@McKesson.com) Subject: RE: INFORMATION REQUEST #2: 48-month, TIRF REMS Assessment   Hi Dinesh, I appreciate you providing your response so quickly. I have forwarded this information to the team and will get back to you with any additional questions, if received. Thanks, WENDY 6 FDA_4003 WENDY B. BROWN, PHARMD, BCACP   Safety Regulatory PM   FDA/OMPT/CDER/OSE/PMS   10903 New Hampshire Ave   WO22 RM4484   Silver Spring, MD 20993   Office:  240‐402‐9140   BB: 240‐731‐8615   Email:  wendy.brown@fda.hhs.gov  THIS MESSAGE IS INTENDED ONLY FOR THE USE OF THE PARTY TO WHOM IT IS ADDRESSED AND MAY CONTAIN INFORMATION THAT IS PREDECISIONAL, PRIVILEGED, CONFIDENTIAL, AND PROTECTED FROM DISCLOSURE UNDER LAW. If you are not the named addressee, or if this message has been addressed to you in error, you are directed not to read, disclose, reproduce, disseminate, or otherwise use this transmission. If you have received this document in error, please immediately notify me by email or telephone.  From: Dinesh Anugu [mailto:danugu@insysrx.com] Sent: Wednesday, July 20, 2016 11:03 AM To: Brown, Wendy Cc: Bulkley, Amanda; Sremba, Siressa (Siressa.Sremba@McKesson.com) Subject: RE: INFORMATION REQUEST #2: 48-month, TIRF REMS Assessment   Dear Wendy,    Please find attached the TRIG response for the below Information request. Let me know if you have any further  questions.    Thank you,  Dinesh Anugu      Dinesh Reddy Anugu, MS, RAC  Regulatory Affairs Associate  m m m m V   1333 South Spectrum Blvd, Suite 100., Chandler, AZ 85286  P: (480) 500‐3193  F: (602) 910‐2627  danugu@insysrx.com*  www.insysrx.com              From: Brown, Wendy [mailto:Wendy.Brown@fda.hhs.gov]   Sent: Monday, July 18, 2016 12:02 PM  To: Dinesh Anugu   Cc: Bulkley, Amanda   Subject: INFORMATION REQUEST #2: 48‐month, TIRF REMS Assessment    Hi Dinesh, Our team is requesting response to the following questions, by COB, Wednesday, July 20:  Have the surveys for the next assessment started yet? 7 FDA_4004  If not, when is the planned start date for these surveys? The DRISK group has some comments on the surveys they would like to have incorporated in the next assessment. Please let me know if you have questions. Thanks, WENDY WENDY B. BROWN, PHARMD, BCACP   Safety Regulatory PM   FDA/OMPT/CDER/OSE/PMS   10903 New Hampshire Ave   WO22 RM4484   Silver Spring, MD 20993   Office:  240‐402‐9140   BB: 240‐731‐8615   Email:  wendy.brown@fda.hhs.gov  THIS MESSAGE IS INTENDED ONLY FOR THE USE OF THE PARTY TO WHOM IT IS ADDRESSED AND MAY CONTAIN INFORMATION THAT IS PREDECISIONAL, PRIVILEGED, CONFIDENTIAL, AND PROTECTED FROM DISCLOSURE UNDER LAW. If you are not the named addressee, or if this message has been addressed to you in error, you are directed not to read, disclose, reproduce, disseminate, or otherwise use this transmission. If you have received this document in error, please immediately notify me by email or telephone.    CONFIDENTIAL--PLEASE READ This electronic message, including its attachments, is CONFIDENTIAL and contains PROPRIETARY information. Any review, re-transmission, dissemination or other use of, or taking of any action in reliance upon this information by persons or entities other than the intended recipient is prohibited. If you have received this message in error, please immediately notify the sender by reply e-mail and permanently delete this message and its attachments, along with any copies thereof. Thank you. CONFIDENTIAL--PLEASE READ This electronic message, including its attachments, is CONFIDENTIAL and contains PROPRIETARY information. Any review, re-transmission, dissemination or other use of, or taking of any action in reliance upon this information by persons or entities other than the intended recipient is prohibited. If you have received this message in error, please immediately notify the sender by reply e-mail and permanently delete this message and its attachments, along with any copies thereof. Thank you. CONFIDENTIAL--PLEASE READ This electronic message, including its attachments, is CONFIDENTIAL and contains PROPRIETARY information. Any review, re-transmission, dissemination or other use of, or taking of any action in reliance upon this information by persons or entities other than the intended recipient is prohibited. If you have received this message in error, please immediately notify the sender by reply e-mail and permanently delete this message and its attachments, along with any copies thereof. Thank you. 8 FDA_4005 TIRF REMS Access Program 48-Month FDA Assessment Report FDA Acknowledgement Letter Correspondence FDA_4006 Dinesh Anugu From: Brown, Wendy Sent: Thursday, January 19, 2017 8:59 AM To: Dinesh Anugu Cc: Bulkley, Amanda (amanda.bulkley@mckessoncom) Subject: RE: T?Con RESCHEDULE: Receipt of the 48?Month FDA Acknowledgement Letter?TRIG Hi Dinesh, I appreciate you con?rming that this date and time will work for your group. I will solidify this on our calendars and await receipt of your WebEx and call-in information, as appropriate. Thanks so much, WENDY Wendy B. Brown, PharmD, BCACP Safety Regulatory Project Manager Project Management Staff Office of Surveillance and Epidemiology Center for Drug Evaluation and Research US. Food and Drug Administration Tel: 240-402-9140 BB: 240-731-8615 wendy.brown@fda.hhs.gov I Inn-.- THIS MESSAGE IS INTENDED ONLY FOR THE USE OF THE PARTY TO WHOM IT IS ADDRESSED AND MAY CONTAIN INFORMATION THAT IS PREDECISIONAL, PRIVILEGED, CONFIDENTIAL, AND PROTECTED FROM DISCLOSURE UNDER LAW. If you are not the named addressee, or if this message has been addressed to you in error, you are directed not to read, disclose, reproduce, disseminate, or otherwise use this transmission. If you have received this document in error, please immediately notify me by email or telephone. From: Dinesh Anugu Sent: Thursday, January 19, 2017 10:01 AM To: Brown, Wendy Cc: Bulkley, Amanda Subject: RE: T-Con RESCHEDULE: Receipt of the 48-Month FDA Acknowledgement Letter-TRIG Good Morning Wendy, have confirmed with the TRIG and FRIDAY, MARCH 3 2:00 PM EST will work for the meeting with FDA. Thank you, Dinesh Dinesh Reddy Anugu, MS, RAC Regulatory Affairs Associate insvs THERAPEUIICS. INC 1333 South Spectrum Blvd, Suite 100., Chandler, AZ 85286 P: (480) 500-3193 F: (602) 910-2627 danu ins srx.com* From: Brown, Wendy Sent: Wednesday, January 18, 2017 7:56 AM To: Dinesh Anugu Cc: Bulkley, Amanda (amanda.bulkley@mckesson.com) Subject: T-Con RESCHEDULE: Receipt of the 48-Month FDA Acknowledgement Letter-TRIG Importance: High Hi Dinesh, We?ve had some scheduling changes on our side and the FEB 22 date time will no longer work. Please let me know if your group would be available for FRIDAY, MARCH 3 2:00 PM EST. Thanks, WENDY Wendy B. Brown, PharmD, BCACP Safety Regulatory Project Manager Project Management Staff Office of Surveillance and Epidemiology Center for Drug Evaluation and Research US. Food and Drug Administration Tel: 240402-9140 BB: 240-731-8615 wendy.brown@fda.hhs.qov THIS MESSAGE IS INTENDED ONLY FOR THE USE OF THE PARTY TO WHOM IT IS ADDRESSED AND MAY CONTAIN INFORMATION THAT IS PREDECISIONAL, PRIVILEGED, CONFIDENTIAL, AND PROTECTED FROM DISCLOSURE UNDER LAW. If you are not the named addressee, or if this message has been addressed to you in error, you are directed not to read, disclose, reproduce, disseminate, or otherwise use this transmission. If you have received this document in error, please immediately notify me by email or telephone. From: Dinesh Anugu Sent: Monday, December 12, 2016 10:21 AM To: Brown, Wendy Cc: Bulkley, Amanda Subject: RE: Receipt of the 48-Month FDA Acknowledgement Letter-TRIG Dear Wendy, I would like to con?rm Wednesday, February 22, 2017 3:00 PM EST for the meeting with FDA. Please let me know if you have any questions. Thank you, Dinesh Dinesh Reddy Anugu, MS, RAC Regulatory Affairs Associate Therapeutics, Inc. 1333 South Spectrum Blvd, Suite 100., Chandler, AZ 85286 P: (480) 500-3193 F: (602) 910-2627 From: Brown, Wendy Sent: Wednesday, December 07, 2016 6:30 AM To: Dinesh Anugu Cc: Bulkley, Amanda (amanda.bulklev@mckesson.com) Subject: RE: Receipt of the 48-Month FDA Acknowledgement Letter-TRIG Hi Dinesh, I appreciate you following up regarding the request for a meeting. Please let me know which of the dates times below will work for your group: 0 Friday, February 17, 2017 12:30 PM EST 0 Wednesday, February 22, 2017 3:00 PM EST Thanks, WENDY Wendy B. Brown, PharmD, BCACP Safety Regulatory Project Manager Project Management Staff Office of Surveillance and Epidemiology Center for Drug Evaluation and Research U.S. Food and Drug Administration Tel: 240402?9140 BB: 240-731-8615 wendy.brown@fda.hhs.gov nun?a THIS MESSAGE IS INTENDED ONLY FOR THE USE OF THE PARTY TO WHOM IT IS ADDRESSED AND MAY CONTAIN INFORMATION THAT IS PREDECISIONAL, PRIVILEGED, CONFIDENTIAL, AND PROTECTED FROM DISCLOSURE UNDER LAW. If you are not the named addressee, or if this message has been addressed to you in error, you are directed not to read, disclose, reproduce, disseminate, or otherwise use this transmission. If you have received this document in error, please immediately notify me by email or telephone. 3 From: Dinesh Anugu [mailto:danugu@insysrx.com] Sent: Friday, December 02, 2016 3:06 PM To: Brown, Wendy Cc: Bulkley, Amanda (amanda.bulkley@mckesson.com) Subject: Receipt of the 48-Month FDA Acknowledgement Letter-TRIG   Dear Wendy,    The TRIG confirms receipt of the 48‐Month FDA Acknowledgement Letter.  Based on the feedback provided, we are  currently working to provide requested data with the February 17, 2017 submission of the 60‐month REMS Assessment  survey results.  The TRIG acknowledges that FDA has requested a meeting to discuss opportunities for obtaining  additional data on accidental exposure in children, as well as to discuss and explore new approaches to assessing this  REMS with the goal of gathering useful information to better understand the impact of the REMS and to improve the  program going forward.  The TRIG would like to propose that the meeting occur in February, 2017.      Please let me know if you have any questions.    Have a nice weekend!    Thank you,  Dinesh      Dinesh Reddy Anugu, MS, RAC  Regulatory Affairs Associate  Insys Therapeutics, Inc.  1333 South Spectrum Blvd, Suite 100., Chandler, AZ 85286  P: (480) 500‐3193  F: (602) 910‐2627  danugu@insysrx.com*  www.insysrx.com    CONFIDENTIAL--PLEASE READ This electronic message, including its attachments, is CONFIDENTIAL and contains PROPRIETARY information. Any review, re-transmission, dissemination or other use of, or taking of any action in reliance upon this information by persons or entities other than the intended recipient is prohibited. If you have received this message in error, please immediately notify the sender by reply e-mail and permanently delete this message and its attachments, along with any copies thereof. Thank you. CONFIDENTIAL--PLEASE READ This electronic message, including its attachments, is CONFIDENTIAL and contains PROPRIETARY information. Any review, re-transmission, dissemination or other use of, or taking of any action in reliance upon this information by persons or entities other than the intended recipient is prohibited. If you have received this message in error, please immediately notify the sender by reply e-mail and permanently delete this message and its attachments, along with any copies thereof. Thank you. 4 FDA_4010 Accenture LLP 1160 West Swedesford Road Berwyn, PA 19312 December 28, 2016 Food and Drug Administration Center for Drug Evaluation and Research Central Document Room Drug Master File Staff 590 -B Ammendale Road Beltsville, MD 20705-1266 Re: DMF 027320 Holder: McKesson Specialty Health (McKesson) DNIF Subject: Transmucosal Immediate Release Fentanyl (TIRF) Access Program Re: REMS Shared Program DNIF Type: DMF Submission Information: Clinical/Clinical Information REMS Submission Identi?er: Assessment Sequence Number: 0027 Dear Drug Master File Staff: This Type DMF contains the Risk Evaluation and Mitigation Strategy (REMS) for Transmucosal Immediate Release Fentanyl for the Shared System REMS program. McKesson herewith provides the REMS Assessment 6 at 5 years. McKessOn states that the information provided in this Master File is current and assure that the material furnished will meet the speci?cations described herein. McKesson also con?rms that the Holder obligations are observed- We request that all information in this file be treated as con?dential commercial information by the Food and Drug Administration pursuant to 21 OER- ?20.61, and that no information from this file be provided to any unauthorized persons Without the express written consent of the DMF holder. If you have any questions or concerns, please do not hesitate to contact Debra Hackett, US. Agent for McKesson, at 610?407?1 729 or alternatively via email at debra.hackettf?accentureeom. Thank you. Sincerely, in 2? I 3 Debra Hackett, Senior Regulatory Project Manager, Regulatory Affairs US. Agent, Accenture, LLP Attachments: Table of Contents for'the submission Electronic Submission Speci?cations CONFIDENTIAL 1 DMF #027320 - Sequence 0027 Shared System REMS Table of Contents Page 1 of 1 Assessment – 5 years Module Section Description 1.2 Cover Letter Cover Letter w/ Attachments 1.16 – Risk Management Plans REMS History REMS Assessment – 5 years FDA_4012 Electronic Submission Specifications This submission is compliant with FDA's Guidelines for Industry and current eCTD specifications. All files were checked and verified to be free of viruses prior to transmission through the electronic submission gateway. Anti-Virus Program Program Version Virus Definition Date Submission Size Symantec Endpoint Protection Edition 12.1.5337.5000 12/20/2016 rev. 20 Approx. 9.6 MB The IT point of contact for this submission is: Name Phone Number Email Address Matt Francis 1-610-407-1854 Matthew.p.francis@accenture.com FOLLOWING THIS PAGE, FDA_4014 TO FDA_4682 WITHHELD IN FULL AS B(4)/CCI AND B(5)/DELIBERATIVE PROCESS- PENDING MATTER FDA_4013 February 17, 2017 Food and Drug Administration Center for Drug Evaluation and Research Central Document Room Drug Master File Staff 5901 -B Ammendale Road Beltsville, MD 20705?1266 Re: DMF 027320 Holder: McKesson Specialty Health (McKesson) Subject: Transmucosal Immediate Release Fentanyl (T IRF Access Program Re: REMS Shared Program DMF Type: DMF Submission Information: Clinical/Clinical Information REMS Submission Identi?er: Not Applicable Sequence Number: 0028 Dear Drug Master File Staff: This Type DMF contains the Risk Evaluation and Mitigation Strategy (REMS) for Transmucosal Immediate Release entanyl for the Shared System REMS program. Please find the ?60-Month FDA REMS Supplemental Assessment Report (10 February 2017)? that completes the 60-Month FDA REMS Assessment Report submission and addresses some of the FDA requested items included in the 48-Month FDA Assessment Report Acknowledgement Letter. This supplemental assessment report is located in Module 1.16 of this submission. McKesson states that information provided in this Master File is current and assures that the material furnished will meet the speci?cations described herein. McKesson also confirms that the Holder obligations are observed. We request that all information in this ?le be treated as confidential commercial information to the Food and Drug Administration pursuant to 21 OF .R. ?20.61, and that no information from this file be provided to any unauthorized persons without written consent. If you have any questions or concerns regarding this submission, please do not hesitate to contact Debra Hackett, US. Agent for McKesson, at 610?407-1729 or alternatively via email at debra.hackett@accenture.com. Sincerely, gebra Halckett, Agent Accenture, LLP Attachments: Table of Contents for the submission Electronic Submission Specifications DMF #027320; Sequence 0028 Shared System REMS Table of Contents Page 1 of 1 REMS CORRESPONDENCE Module Section Description 1.2 Cover Letter Cover Letter w/ Attachments 1.16 – Risk Management Plans REMS History TIRF REMS Access Program 60-Month FDA REMS Supplemental Assessment Report FDA_4684 Electronic Submission Specifications This submission is compliant with FDA's Guidelines for Industry and current eCTD specifications. All files were checked and verified to be free of viruses prior to transmission through the electronic submission gateway. Anti-Virus Program Program Version Virus Definition Date Submission Size Symantec Endpoint Protection Edition 12.1.5337.5000 02/15/2017 rev. 18 Approx. 4.3 MB The IT point of contact for this submission is: Name Phone Number Email Address Matt Francis 1-610-407-1854 Matthew.p.francis@accenture.com FOLLOWING THIS PAGE, FDA_4686 TO FDA_5363 WITHHELD IN FULL AS B(4)/CCI AND B(5)/DELIBERATIVE PROCESS - PENDING MATTER FDA_4685 DEPARTMENT OF HEALTH & HUMAN SERVICES Public Health Service Food and Drug Administration Rockville, MD 20857 IND 72,411 Insys Therapeutics, Inc. 10220 S. 51st Street Suite 2 Phoenix, AZ 85044 Attention: Kelly D. Tate Director, Regulatory Affairs Dear Mr. Tate: Please refer to your Investigational New Drug Application (IND) submitted under section 505(i) of the Federal Food, Drug, and Cosmetic Act for your fentanyl sublingual spray product. We also refer to the Type B, End-of-Phase 2 (EOP2) meeting between representatives of your firm and FDA on December 17, 2007. The purpose of the meeting was to provide you with feedback on the questions in your October 19, 2007 meeting package, which were specifically related to your preparations for undertaking Phase 3 studies with your product. The official minutes of that meeting are enclosed. You are responsible for notifying us of any significant differences in understanding regarding the meeting outcomes. If you have any questions, call me at 301-796-1191. Sincerely, {See appended electronic signature page} Kimberly Compton, R.Ph. Regulatory Project Manager Division of Anesthesia, Analgesia and Rheumatology Products Office of Drug Evaluation II Center for Drug Evaluation and Research Enclosure FDA_5364 IND 72,411 EOP2 Meeting Minutes Page 2 INDUSTRY MEETING RESPONSES Meeting Date: December 17, 2007 Time: 1:00 PM EST Location: White Oak Conference Room 1315 Application: IND 72,411 Regulatory Status: Active IND Products: Fentanyl Sublingual Spray Proposed Indication: The management of breakthrough cancer pain in patients with malignancies who are already receiving and who are tolerant to opioid therapy for their imderlying cancer. Sponsor: Insys Therapeutics, Inc. Type of Meeting: Type B- End-of-Phase 2 (EOP2) Meeting Chair: Sharon Hertz, M.D., Deputy Director Division of Anesthesia, Analgesia and Rherunatology Products (DAARP) Minutes Recorder: Kimberly Compton, Project Manager, DAARP Industry Representatives Title Kelly Tate, M.A., M.B.A., R.A.C. Director, Regulatory Affairs, Insys Therapeutics, Inc. Ellen Feigal, MD. Chief Medical Of?cer, Insys Therapeutics, Inc. Ramesh Acharya, Chief Scienti?c Of?cer, Insys Therapeutics, Inc. (4) 4 Consultant, (4) (4) Consultant. FDA Title Bob Rappaport, MD. Director, DAARP Yasmin houdhry, MD. Medical Of?cer, DAARP Mary Pumcker, MD, Medical Team Leader, DAARP Elizabeth Bolan, Pharmacology/Toxicology Reviewer, DAARP Dan Mellon, Supervisory Pharmacologist, DAARP Kate Meaker, M.S. Statistical Reviewer, Division of Biometrics II (DBII) David Lee, Clinical Pharmacology Reviewer, Of?ce of Clinical Pharmacology (OCP) Prasad Peri, Pharmaceutical Assessment Lead (PAL), Division of PreMarketing Assessment 1, Of?ce of New Drug Quality Assessment (ONDQA) Janice Weiner, J.D., M.P.H. Regulatory ormsel, Of?ce Of Regulatory Policy Richard Abate, M.S. Safety Evaluator, Of?ce of Surveillance and Epidemiology (OSE) Michael Klein, Director (Acting), Controlled Substances Staff (C SS) Silvia Calderon, Team Leader, SS Kim Compton Regulatory Project Manager, DAARP Meeting Objective: The prupose of the meeting was to provide the sponsor with feedback on questions from their October 19, 2007, meeting package, which were speci?cally related to the sponsor?s preparations for undertaking Phase 3 studies with this product. IND 72,411 EOP2 Meeting Minutes Page 3 Background: On December 14, 2007 (prior to the December 17, 2007 meeting) the Agency forwarded to the firm the comments and responses to the questions posed by the sponsor in their October 19, 2007, meeting package. The sponsor requested further discussion Questions 2 a and c, as well as portions of the Additional Regulatory Comments and CSS Comments were discussed at the meeting. Presented below are the Agency comments related to the sponsor’s background material and responses to questions in the background meeting package. The sponsor’s questions are listed in italics, with Agency responses and comments in bold. Discussion that took place at the meeting follows in normal text. Meeting: Chemistry Questions Question 4 Does the Agency concur that the drug delivery device for Fentanyl SL Spray is an oral delivery system and our proposed controls and testing of in process materials and finished products are adequate to demonstrate quality, strength, identity, purity and safety of products for filing an NDA under 505(b)(2)? FDA Response 1. We concur that drug delivery device can be deemed an oral delivery system. 2. We recommend consideration of the relevant portions of various CMC guidance documents ICH Q3A(R) and ICH Q3B(R), Container Closure Guidance, and Nasal Spray Guidance (links provided below) that may contribute to control of the drug product. 3. Your proposed quality control strategy and attributes for the drug product listed in the specifications are a reasonable starting point, but please consider the following additional comments: a. All impurities in the drug substance and drug product should comply with ICH Q3A(R) (http://www.fda.gov/cder/guidance/4164fnl.htm) and ICH Q3B(R) guidance (http://www.fda.gov/cder/guidance/7385fnl.htm). Impurities that are deemed structural alerts need special consideration and should not exceed an exposure limit of NMT 1.5 mcg/day (see also, Nonclinical Comments). Acceptance criteria should be data-driven and will be evaluated during the NDA review. b. Due to the content of your drug product, you need to provide data addressing leachables in the drug product. Toxicological assessments will be necessary for the leachables. (b) (4) FDA_5366 IND 72,411 EOP2 Meeting Minutes Page 4 c. Provide a DMF for the spray pump and all other device components. Alternately, provide this CMC information in the NDA. d. Refer to the Agency’s Guidance for Industry Container Closure Systems for Packaging Human Drugs and Biologics CHEMISTRY, MANUFACTURING, AND CONTROLS DOCUMENTATION (http://www.fda.gov/cder/guidance/1714fnl.htm). e. In your NDA, provide justification for not testing the oral delivery system for all attributes as per the Agency’s Nasal Spray guidance (http://www.fda.gov/cder/guidance/4234fnl.htm) e.g., weight loss (stability), droplet size distribution (including span) and percentage of droplets less than 10 microns, particulate matter, net content, leachables (stability), viscosity, and spray pattern. f. Define your drug product. For example, clarify how the device (vial and pump) will be assembled, provide appropriate patient instructions, and clarify if the vial and pump are co-packaged and/or foil pouched. g. Stability studies should be performed on the assembled device including the above parameters (mentioned in 3e above) unless justified. h. Provide the details (including validation) of the methods for the determination of the delivered dose, particularly respirable fraction and droplet size distribution. Discussion There was no further discussion of this issue. Chemistry Comments 1. Include a well-documented Pharmaceutical Development Report as per the ICH-Q8 guideline and highlight how critical quality attributes and critical process parameters are identified and controlled. 2. At the beginning of the CMC section of your application, include a table of all facilities. Include specifically what the function of each facility is, the contact name and address, the CFN number, and the complete name and address of the facility. 3. Ensure that all of the above facilities are ready for inspection by the day the application is submitted, and include a statement confirming this in your NDA cover letter. FDA_5367 IND 72,411 EOPZ Meeting Minutes Page 5 4. Provide tabular summaries of your stability data, organized by test parameter and separated by manufacturing site, batch, storage condition and container closure system. Provide graphical summaries of any trending stability data, organized by test parameter, including mean and individual data. Nonclinical Comments 1. You will need to provide complete characterization of leachables and extractables from the drug delivery system for the NDA. For the NDA submission, any impurity or degradation product that exceeds ICH thresholds should be adequately qualified for the NDA submission Adequate quali?cation should include: a. Minimal genetic toxicology screen (two in vitro genetic toxicology studies, one point mutation assay and one chromosome aberration assay) with the isolated impurity, tested up to the limit dose for the assay. b. Repeat dose toxicology of appropriate duration to support the proposed indication. The fentanyl drug substance may contain residual intermediates and/or impurities that contain structural alerts for mutagenicity such as: A speci?cation of NMT mcg/day should be set for genotoxic or potentially genotoxic residual intermediates/impurities. The Division recommends that you consult with your DMF holder to decrease the limit of these impurities. Adequate safety qualification for any potential genotoxic impurities should be provided with the NDA submission and should include: (0) (4) a. Minimal genetic toxicology screen (two in vitro genetic toxicology studies (point mutation assay and chromosomal aberration assay) with the isolated impurity, tested up to the limit dose for the assay. b. Repeat dose toxicology of appropriate duration to support the proposed indication. c. Should this quali?cation produce positive or equivocal results, the impurity speci?cation should be set at NMT (?Mmcg/day, or otherwise justified. Justi?cation may require an assessment for carcinogenic potential in either a standard 2-year rodent bioassay or in an appropriate transgenic mouse model. IND 72,411 EOP2 Meeting Minutes Page 6 Clinical Pharmacology Question Question 1 Does the FDA concur that the human pharmacokinetic studies completed with Fentanyl SL Spray (absolute bioavailability, relative bioavailability compared to Actiq, ascending dose PK, and the effects of oral cavity pH and temperature on absorption rate and relative bioavailability) suffice as the pharmacokinetics package to support the submission of a 505(b)(2) application? FDA Response Yes Discussion There was no further discussion of this issue. Statistical Questions Question 2a Insys proposes, as the main analysis method for the primary efficacy measure and related endpoints, using a repeated measures linear mixed model, and treating data at time points after the use of supplemental (“rescue”) medication as missing. Additionally we will perform sensitivity analyses, including those using imputation, to assess how conclusions about treatment effect depend on the handling of data after use of supplemental medication. Since we understand, in some instances, that the agency has adopted the baseline observation carried forward (BOCF) approach for such data, we will use BOCF to impute pain intensity at time points after the use of supplemental medication, and analyze the withinsubject treatment summary using the Wilcoxon signed rank test. Does the agency agree with this statistical approach? FDA Response The Division’s concern regarding missing data has primarily been in the setting of parallel group, chronic pain trials. In such trials, patients receive treatment for 12 weeks. Patients may experience some reduction in pain intensity, however, they drop out of the study because of intolerable side effects. The Division has advocated using missing data strategies that assign a bad score to patients experiencing unfavorable outcomes. You propose a crossover study design where patients assess pain intensity for 30 minutes following each treatment administration. The missing data concern is not the same as in the setting of parallel group chronic pain trials. In general, a linear mixed model is an acceptable approach for analyzing the data. Your model will include fixed effects for treatment and time. The benefit of including an effect for time is unclear. Including terms for sequence and/or period may be more beneficial. Additional comments will be provided once the protocol and statistical analysis plan have been submitted. FDA_5369 IND 72,411 EOP2 Meeting Minutes Page 7 Sponsor Reply (provided prior to Industry Meeting) Insys noted FDA’s comment that the “benefit of including an effect for time is unclear.” Insys would like to clarify how the time effect is needed to identify the 30minute time point of our main efficacy endpoint, As noted on p. 29 of the briefing document, the primary efficacy endpoint, i.e., the summed Page 7 IND 72,411 Insys Therapeutics Inc. EOPII Meeting Minutes Fentanyl Sublingual Spray pain intensity differences at 30 minutes [SPID(30)], is defined mathematically as a linear combination of pain intensity (PI) at time points up and including 30 minutes. Specifically: SPID(30) = 30*PI(0) – 5*PI(5) – 5*PI(10) – 5*PI(15) – 15*PI(30). However, rather than pre-calculating SPID(30) before statistical analysis, which might require imputation for missing data, we have chosen to implement the mathematical definition within the modeling and to allow the modeling to handle missing data automatically in the normal course of model fitting, without external imputation rules. To see how this might work, consider an implementation of the mixed model using SAS, with PI as dependent variable and with the treatment (TRT) and time (TIME) factors as fixed effects. Suppose the levels of TRT are coded as 0 = Placebo and 1 = Fentanyl SL Spray, and the levels of TIME as 0, 5, 10, 15, 30, 45 and 60 (minutes). Given the model parameters and SPID as a function of PI, a statement in SAS to assess the treatment effect with respect to SPID(30) is: Contrast "Trt effect SPID(30)" TRT*TIME -30 5 5 5 15 0 0 30 -5 -5 -5 -15 0 0; Insys noted the comment that “including terms for sequence and/or period may be beneficial.” In the current analysis plan, the period effect is considered random, nested within subject. As a sensitivity analysis we will model period as a fixed effect, crossed with the subject effect. Also, there are 29 sequences, i.e., 29 different orderings of 3 placebo and 7 Fentanyl SL Spray treatments to which a subject may be randomized; we will examine the sequence effect descriptively. Insys noted the comment that “additional comments will be provided once the protocol and statistical analysis plan have been submitted.” Insys submitted the statistical analysis plan at the agency’s request on December 5. If any questions or comments remain after our teleconference on December 17, Insys will look forward to hearing and discussing them. Discussion Ms. Meaker noted that the Agency’s comment was related to the fact that linear models are often employed for longer study timepoints, so the Division was not sure these were the appropriate models to utilize. However, from the draft statistical analysis plan (SAP) the firm shared by email, she understands that the Agency will see both this analysis and the ANCOVA for the SPID (30) endpoint. FDA_5370 1ND 72,411 EOP2 Meeting Minutes Page 8 This is acceptable with the understanding that the Agency is interested ?rst in the AN OVA model results. Ms. Meaker stated that it is acceptable for the sponsor to conduct mixed-model imputation as a sensitivity analysis, noting that any discrepancies will need to be discussed in the study report. The sponsor stated that they will amend their SAP based on the comments received and of?cially submit it to the IND. Question 2b In addition to citing the primary e?icacy endpoint result, if it is statistically signi?cant, Insys proposes to describe the time course of the treatment effect over the 60-minute breakthrough pain episode by graphing the entarryl SL Spray and placebo Pain Intensity Di?erence (PID) responses along with p-values at the di?erent assessment times. Does the agency agree that if there are p-values 0. 05 the graph may be included in the package insert? FDA Response A graph may be included in the label if it is deemed clinically meaningful and relevant during the course of the review. Discussion There was no fmther discussion of this issue. Question 2c Provided that the statistical test of the primary endpoint is signi?cant at level 0. 05, Insys proposes to statistically test as secondary endpoints Total Pain Relief 0T PAR) at 30 minutes and subject?s Global Evaluation of Study Medication at 30 minutes. Each endpoint will be tested at the 0.05 level. Does the agency agree with this approach? (4) FDA Response Total pain relief at 30 minutes and subject?s Global Evaluation of Study Medication may each be tested at the 0.05 level provided an appropriate statistical strategy for controlling the type I error is pre-specified. Only clinically relevant information (assessed with appropriate statistical methods) will be included in the label. Sponsor Replv (provided prior to Industry Meeting) Insys noted the comments that the secondary endpoints may be tested at the 0.05 level ?provided an appropriate statistical strategy for controlling the type I error is pre-speci?ed. One approach, consistent with the agency?s comment, is to pre- speci?r one of the endpoints to be tested at the 0.05 level, with the other endpoint to be tested at the 0.05 level only if the ?rst is statistically sigrr?carrt. We are also IND 72,411 EOP2 Meeting Minutes Page 9 considering an approach where both endpoints may be tested without prespecifying an order of testing. To control the overall false positive rate in this case, we propose to adjust the p-values from the two statistical tests using Hochberg’s method (Hochberg, Y. (1988), “A Sharper Bonferroni Procedure for Multiple Significance Testing,” Biometrika, 75, 800 - 803.) Does the agency concur that Hochberg’s method is an appropriate statistical strategy for controlling the type I error? Discussion Ms. Meaker stated that the Hochberg method was appropriate. The sponsor stated that they had not yet decided how to address multiplicity. Ms. Meaker stated that it would be most important to pre-specify the plan to control for overall Type I error. Statistical Comments In Section 6, you request “concurrence on the statistical analysis plan for the Phase 3 pivotal trial.” However, the meeting package does not include the protocol or statistical analysis plan for study INS-05-001. Statistical comments will be provided once the protocol and statistical analysis plan have been submitted. Clinical Questions Question 3a Does the Agency concur that a 300 patient database of Fentanyl SL Spray, at doses ranging from 100 mcg to 1600 mcg, 150 of whom are patients who completed a three month safety trial, meets the requirements for the Agency’s proposed safety database? FDA Response Assuming there are no unanticipated safety signals during the Phase 3 clinical trial or subsequently during the development program, a database of 300 patients is reasonable. This number should be comprised entirely of patients and not include normal subjects who have received the investigational product during pharmacokinetic studies. Out of this total number of patients, 150 should have been treated for a minimum of 3 months with investigational product that is reasonably representative of the proposed to-be-marketed doses. Discussion There was no further discussion of this issue. FDA_5372 IND 72,411 EOPZ Meeting Minutes Page 10 Question 3b From a clinical standpoint, does the Agency agree that the combination of completed studies along with the proposed studies undeiwav constitute a filable 505 (2) FDA Response A decision regarding the ?lability of your application will be based upon the application that is submitted and will include factors beyond the nominal clinical development program. The results from a combination of completed and proposed clinical studies appear at this time to be reasonable to form the basis of a determination of product efficacy and safety. We remind you of your commitment to complete both a drug interaction study and a study conducted in patients with stomatitis. Also see Additional Regulatory Comments below for further information on this topic. Discussion There was no fmther discussion of this issue. Question 30 (4) Does the FDA agree with this request? FDA Response (4) If the indication under study occurs in the pediatric population, the Pediatric Research Equity Act (PREA) requires you to study this product in pediatric patients. We note that pursuant to the Food and Drug Administration Amendments Act of 2007 a Pediatric Review Committee will be consulted on all pediatric plans and assessments prior to approval of an application or supplement for which a pediatric assessment is required as well as requests for deferral and waiver of pediatric studies. Therefore, the Division?s comments on this issue should be considered preliminary. Discussion There was no ?uther discussion of this issue. IND 72,411 EOP2 Meeting Minutes Page 11 Additional Regulatory Comments A 505(b)(2) application would be an acceptable approach at this time based on the information provided. The Division recommends that sponsors considering the submission of an application through the 505(b)(2) pathway consult the Agency’s regulations at 21 CFR 314.54, and the October 1999 Draft Guidance for Industry “Applications Covered by Section 505(b)(2)” available at http://www.fda.gov/cder/guidance/index.htm. In addition, FDA has explained the background and applicability of section 505(b)(2) in its October 14, 2003, response to a number of citizen petitions challenging the Agency’s interpretation of this statutory provision (see Dockets 2001P-0323, 2002P-0447, and 2003P-0408 (available at http://www.fda.gov/ohrms/dockets/dailys/03/oct03/102303/02p-0447-pdn0001vol1.pdf)). If you intend to submit a 505(b)(2) application that relies for approval on FDA’s finding of safety and/or effectiveness for one or more listed drugs, you must establish that such reliance is scientifically appropriate, and must submit data necessary to support any aspects of the proposed drug product that represent modifications to the listed drug(s). You should establish a “bridge” (e.g., via comparative bioavailability data) between your proposed drug product and each listed drug upon which you propose to rely to demonstrate that such reliance is scientifically justified. If you intend to rely on literature or other studies for which you have no right of reference but that are necessary for approval, you also must establish that reliance on the studies described in the literature is scientifically appropriate. Sponsor Reply (provided prior to Industry Meeting) Insys noted the FDA comment, “We remind you of your commitment to complete both a drug interaction study and a study conducted in patients with stomatitis.” In the pre-IND meeting minutes from August 25, 2005, FDA commented that Insys should test the delivery system under clinical conditions that may potentially alter the absorption of the product, i.e., stomatitis or drug/drug interactions with other coincident oral medications. Insys did conduct pH and temperature testing in normal volunteers, and there was no impact on the pharmacokinetic profile of Fentanyl SL Spray. Insys is planning to examine the relationship between concomitant medications and adverse events, particularly serious adverse events, in the Phase III safety database. Insys is not planning additional drug-drug interaction studies (specifically, no pharmacokinetic studies are planned) with oral co-incident medications. Does the agency agree with this approach? Insys will be studying this drug delivery system in a minimum of 20 patients with mild, moderate, or severe stomatitis. Insys will identify criteria for mild, moderate, and severe stomatitis, and evaluate safety in terms of local toxicity and systemic events. Insys is not planning a separate pharmacokinetic study in patients with stomatitis. Does the agency agree with this approach? FDA_5374 IND 72,411 EOP2 Meeting Minutes Page 12 In the additional regulatory comments section, FDA refers to establishing a ?bridge via comparative bioavailability data) between your proposed drug product and each listed drug upon which you propose to rely to demonstrate that such reliance is scientz?callyjusti?ed. Insys has performed comparative bioavailability studies of entanyl SL Spray and Actiq; FDA has replied that these studies are su?icient for ?ling an NBA as part of the 5 05b2 strategy. The results of our study with Actiq were consistent with previously published data, and matches data in the public database. The results 0 our stu with entan 1 revealed a bioavailabili Does the agency agree with is approac Discussion Dr. Lee stated that the Agency would need data on systemic blood levels of the product from 8-10 patients with mild stomatitis/mucositis in order to assess if membrane changes would lead to any changes in systemic absorption of the drug. Dr. Rappaport emphasized that this information would be required of the ?rm for this application. Dr. Lee stated that this data did not need to be collected in a separate PK study, but could be a subpopulation of a clinical study. He stated that the ?rm should collect blood samples to obtain Cm, Tm concentration and characterize the elimination phase of the product. Ms. Weiner stated that if the onsor was lannin IND 72,411 EOP2 Meeting Minutes Page 13 Office of Surveillance and Epidemiology (OSE) Comments 1. RISK MINIMIZATION ACTION PLAN— a. A complete review of the full risk management program (also referred to as Risk Minimization Action Plan or RiskMAP*) after the NDA is submitted will be necessary to determine whether the proposed program is acceptable, since additional information regarding risks and safe product use may emerge during ongoing clinical study. You should initiate a dialogue with the Agency regarding your RiskMAP development including a general discussion about the anticipated classrelated risks such as abuse, diversion, overdose in patients, and accidental pediatric exposures. i. Submit your complete RiskMAP with the original NDA submission. Remember to submit all planned materials identified within the RiskMAP that will be necessary to implement your proposal (e.g., training materials, surveys, etc.) ii. We refer you to the following Guidance documents (available on the Agency’s website as listed below) for the most recent publicly available information on CDER’s views on RiskMAPs: − Premarketing Risk Assessment: http://www.fda.gov/cder/guidance/6357fnl.htm − Development and Use of Risk Minimization Action Plans: http://www.fda.gov/cder/guidance/6358fnl.htm> − Good Pharmacovigilance Practices and Pharmacoepidemiologic Assessment: http://www.fda.gov/cder/guidance/6359OCC.htm * We note that Title IX, Subtitle A of the Food and Drug Administration Amendments Act of 2007 (FDAAA) takes effect on March 25, 2008. The comments provided here with respect to RiskMAPs will be considered in the context of a Risk Evaluation and Mitigation Strategy (REMS) after that date. Information regarding submission of a proposed REMS will be forthcoming. b. Submit any information on product medication errors or device failures from the premarketing clinical experience with the NDA application. 2. PROPRIETARY NAME— a. It appears that the proprietary name you plan for this product is “Fentanyl SL Spray.” DMETS (a Division of CDER’s OSE that reviews FDA_5376 1ND 72,411 EOPZ Meeting Minutes Page 14 C. proprietary names) has determined that this proprietary name is unacceptable because it may lead to medication errors. One concern is that ?Fentanyl may not clearly distinguish this product from the established names of other oral fentanyl products Actiq, entora). Additionally, the use of the modifier in the proprietary name is unacceptable for several reasons: ii. The letters are the common medical abbreviation for sublingual and could be confused solely as the route of administration rather than the modi?er for the name resulting in another oral fentanyl product being administered sublingually. In addition, postmarketing surveillance shows that the SL modifier is prone to error and has been misinterpreted as and Lastly, DMETS does not support the use of error-prone abbreviations in drug names or labeling because it contradicts the goals set forth for the Agency by healthcare practitioners and external medication safety organizations. In October 2005, FDA participated in a meeting sponsored by the National Coordinating Council for Medication Error Reporting and Prevention (NCC MERP) entitled ?Drug Name Suffixes and Medication Errors: Exploring the Relationship and Minimizing the Risk? and practicing health care practitioners at this meeting requested that FDA stop approving drug name modifiers that are ambiguous and error prone. Also, in June 2006, FDA launched a campaign in partnership with the Institute for Safe Medication Practices (ISMP) to warn health care providers and consumers not to use error-prone abbreviations.1 To support this effort, DMETS recommends that these dangerous abbreviations not be utilized in labeling. Therefore, reconsider the use of the proprietary name ?Fentanyl SL Spray? and propose an alternate name that uniquely identifies this product in the marketplace and avoids the use of error-prone abbreviations. 3. INDICATION FOR (4) However, this terminology is not consistent with other marketed fentanyl products IND 72,411 EOP2 Meeting Minutes Page 15 Actiq, Fentora) which use the term “opioid-tolerant.” Utilize the “opioid tolerant” terminology throughout your labeling materials. b. Clarify if you intend to implement any measures to prevent off label use. 4. DOSING— a. Your Fentanyl SL Spray and Actiq do not appear to be bioequivalent. Therefore, the Agency is concerned that the Fentanyl SL Spray and Fentora are also not bioequivalent, though this information was not presented in the materials reviewed. b. The fact that there may not be bioequivalence between the proposed Fentanyl SL Spray and the currently commercially available fentanyl products will increase the complexity of prescribing the oral fentanyl products and is a likely source of dosing error. 5. OVERDOSAGE— (b) (4) is not appropriate given that the product is predominantly SL absorbed. 6. PACKAGING— a. Submit the proposed device and all associated packaging (including the foil over wrap and study kit box), your plan of how to distinguish the different strengths of the product, your proprietary name and all associated labels and labeling as soon as possible as they are necessary for our review. b. All warnings on the packaging should be consistent with the currently marketed Fentora brand of fentanyl. 7. DEVICE— a. The Agency is concerned that, to a child, the device may resemble a toy. Clarify what child-resistance mechanisms will be utilized to prevent accidental exposure in children. b. Clarify what feedback the patient will receive from the device to let them know the dose has been delivered. c. Clarify if the product's overfill will be accessible after delivery (either as a partial second dose or through tampering with the device). FDA_5378 IND 72,411 EOP2 Meeting Minutes Page 16 d. Clarify if it will be evident from the device that the dose has already been administered. e. Clarify how the different dosage strength will be differentiated. f. Clarify how this device will differ in appearance from a nasal inhaler. g. Clarify if the device can be taken apart. h. Clarify if usability studies have been completed for this device. If so, the Agency would be interested in reviewing the results. i. Clarify what you will recommend as the proper disposal method for the used device. j. Clarify if you have collected information on device failures in previous studies. Going forward with Phase 3 studies, the Agency recommends a prospective collection of device failures and patient complaints about the device. 8. ADMINISTRATION— a. Clarify the effect if the dose of this product is delivered to parts of the mouth other than underneath the tongue. b. As some cancer patients may be bed-bound and not able to sit upright, clarify if the orientation of the device might affect the delivery of the dose. Discussion There was no further discussion of this issue. Controlled Substance Staff (CSS) Comments 1. As a Schedule II drug under the CSA, all Schedule II regulations and procedures regarding manufacture, distribution, dispensing, storage, recordkeeping, and disposal of study drug should be in place and strictly followed. 2. We are particularly concerned about the 30% of nominal dose of fentanyl that remains in the device following use. Describe how you will prevent diversion or abuse of the remaining active pharmaceutical product. 3. Preliminary PK review suggests that this product has enhanced bioavailability compared to currently available transmucosal fentanyl products as well as an increased Cmax and decreased Tmax when compared to the reference listed drug (RLD.) These same characteristics may influence the safety and the abuse and diversion potential of this product compared to other currently approved FDA_5379 1ND 72,411 EOP2 Meeting Minutes Page 17 formulations of fentanyl. You will need to address how abuse and diversion of this product can be limited, and develop appropriate plans for the disposal of the used product device. The safety concerns that have been identified with the use of other transmucosal fentanyl products will need to be addressed in this product?s RMP. Submit descriptions of all reports and details, including narratives, of all incidents of abuse, misuse, overuse, or overdose (intentional or unintentional), or drug that is lost, stolen, missing or unaccounted for in all clinical studies. Provide narratives and case report forms for patients that drop out from studies where they were discontinued for reasons that might be coded as ?protocol violation?, ?lack of ef?cacy?, ?lost to follow up?, ?non-compliance to study medication or procedures? or for ?other.? Sponsor Replv (provided prior to Industry Meeting) The Controlled Substance Sta? commented that the company should ?provide narratives and case report forms for patients that drop out from studies where they were discontinued for reasons that might be coded as protocol violation, lack of e?icacv, lost to follow up, noncompliance to studv medication or procedures or for other. Insvs notes that this would cover most of the non-safety reasons for early withdrawal. Would the FDA identifv the speci?c issues or concerns they would like to ensure are included in the narratives? Discussion of SS omments Dr. Calderon stated that the Agency has concern about the incidence of diversion or any loss of product by theft, or other types of abuse of the product and wants these terms to be captured in the narratives. The Agency wants to get an idea of how the product behaves and, therefore, is requesting that the fum gather and submit all available information. Dr. Calderon agreed that a discussion of withdrawn patients in the narrative would be acceptable. (0) (4) Dr. Rappaport strongly encom?aged the sponsor to develop a plan to address the issue of child-resistance of lmits removed from the child-resistant blister, but not yet utilized. This plan should be included in the overall for the product. The sponsor indicated that they would develop such a plan and would contact SS for assistance with it. All communication to the Agency should be through the Division project manager. Dr. Rappaport pointed out that at the next milestone meeting for this product, the sponsor should have a very close to fmal developed. The sponsor inquired about a meeting to discuss the and Dr. Rappaport stated that due to 0m limited resoru?ces, the firm should submit their draft along with questions they have on it and the Agency will respond as soon as possible, but could not provide a tirneframe for that response. He advised them to submit this material well in advance of the pre-NDA meeting. Dr. Rappaport stated that the ?rm should focus mainly on the content of the 1ND 72,411 EOP2 Meeting Minutes Page 18 four basic areas of the which potent opioids need to address: labeling, educational efforts for surveillance for problems (especially those with accidental use or misuse), and intervention when signals do arise. Closing Discussion Regarding the Phase 3 protocol INS-05-001 entitled Randomized, Double-Blind, Placebo- Controlled Multi-C enter Study to Evaluate the Safety and Ef?cacy of Fentanyl Sublingual Spray for the Treatment of Breakthrough Cancer Pain,? Dr. Pruucker? stated that substitution of the term ?opioid-treated? in place of ?opioid-tolerant? in the inclusion criteria of this trial was not acceptable. She stated that the ?rm should revert to the previous inclusion criteria language of ?opioid-tolerant.? The sponsor agreed to make this change. Dr. Pruucker also stated that ?fentanyl na'r've? was an inconsistent and confusing term when used to describe eligibility criteria because it seemed to apply only to use of oral transmucosal fentanyl products and not to transdermal products. She requested that the sponsor clarify this in the protocol. The sponsor stated that they would clarify the term to ?short-acting, commercially- available fentanyl.? Dr. Peri stated that all stability studies should be performed on the fmal drug product. The ?rm stated this is what they were doing. The sponsor srunmarized their rmderstanding of the meeting as follows (includes action items) 1. The sponsor understands that the Agency will require fluther analyses if any discrepancies are seen in the ?rst sensitivity analysis. 2. The description of the periods and sequences proposed seem acceptable to the Agency at this point. 3. The sponsor will amend their statistical analysis plan (SAP) based on the comments received and submit it to the IND. 4. The sponsor understands that the Hochberg method is an appropriate strategy and that the plan to control for overall Type I error must be prespeci?ed. 5. The sponsor rmderstands that the proposed pH and temperature are acceptable and that they do not need a separate study of concomitant medications. To address the stomatitis issue, the sponsor should examine the systemic blood levels in 8-10 patients with mild stomatitis. This can be accomplished as part of a clinical trial. (4) 6. IND 72,411 EOP2 Meeting Minutes Page 19 7. The sponsor understands that the Agency wants information on possible abuse, diversion, etc. captured and reported. This information should be reported in the narrative discussions. FDA_5382 Linked Applications ----------------------------IND 72411 Sponsor Name ----------------------INSYS THERAPEUTICS INC Drug Name ---------------------------------------------------------FENTANYL SUBLINGUAL SPRAY --------------------------------------------------------------------------------------------------------This is a representation of an electronic record that was signed electronically and this page is the manifestation of the electronic signature. --------------------------------------------------------------------------------------------------------/s/ ---------------------------------------------------KIMBERLY A COMPTON 02/05/2008 FDA_5383 DEPARTMENT OF HEALTH & HUMAN SERVICES Public Health Service Food and Drug Administration Silver Spring, MD 20993 IND 072411 MEETING MINUTES Insys Therapeutics, Inc. c/o The Weinberg Group Inc. 1220 Nineteenth St, NW Suite 300 Washington, DC 20036 Attention: Lauren H. Wind, M.P.H. Dear Ms. Wind: Please refer to your Investigational New Drug Application (IND) submitted under section 505(i) of the Federal Food Drug and Cosmetic Act for fentanyl sublingual spray. We also refer to the meeting between representatives of Insys and the FDA on August 17, 2010. The purpose of the meeting was to discuss Insys’s preparations for submission of an NDA for this product. A copy of the official minutes of the meeting is attached for your information. Please notify us of any significant differences in understanding regarding the meeting outcomes. If you have any questions, call me at 301-796-1191. Sincerely, {See appended electronic signature page} Kimberly Compton, R.Ph. Senior Regulatory Project Manager Division of Anesthesia and Analgesia Products Office of Drug Evaluation II Center for Drug Evaluation and Research Enclosure FDA_5384 1ND 072411 Page 2 INDUSTRY MEETING Meeting Date: August 17, 2010 Time: 1:30 PM EST Location: White Oak Conference Room 1315 Application: IND 072411 Regulatory Status: Active IND Investigational Product: fentanyl sublingual spray Proposed Indication: management of breakthrough pain in patients with cancer, 18 years of age and older, who are already receiving and who are tolerant to opioid therapy for their rmderlying persistent cancer pain Sponsor: Insys Therapeutics, Inc. Type of Meeting: Type B, PNDA Meeting Chair: Robert Shibuya, M.D., Clinical Team Leader Division of Anesthesia and Analgesia Products (DAAP) Minutes Recorder: Kimberly Compton, Senior Regulatory Project Manager, DAAP Industry Representatives Title John N. Kapoor, Chief Executive Of?cer, Insys Therapeutics, Inc. Michael L. Babich President Chief Operating Of?cer, Insys Therapeutics, Inc. Lany Dillaha, MD. Chief Medical Of?cer, Insys Therapeutics, Inc. Venkat R. Goskonda, Senior Director, Pharmaceutical Development, Insys Therapeutics, Inc. Ashok J. havan, Director of Pharmaceutical Operations, Insys Therapeutics, Inc. Joel I. Falk Executive Vice President, The Weinberg Group Inc. Nicholas M. Fleischer, Vice President, The Weinberg Group Inc. Laru'en H. Wind, M.P.H. Consultant, The Weinberg Group Inc. Teresa I. Hemy, Consultant to The Weinberg Group Inc. Willene Brondum Senior Manager of Regulatory Affairs, Insys Therapeutics, Inc. Neha Parikh Director of Clinical Operations, Insys Therapeutics, Inc. FDA Title Bob A. Rappaport, MD. Director, DAAP Sharon Hertz, MD. Deputy Director, DAAP Luke Yip, MD. Medical Of?cer, DAAP Robert Shibuya, MD. Medical Team Leader, DAAP Elizabeth Bolan, Pharmacology/Toxicology Reviewer, DAAP Dan Mellon, Supervisory Pharmacologist, DAAP Danae hristodoulou, MC Lead, Of?ce of New Drug Quality Assessment (ONDQA) Prasad Peri, Acting Chief, Branch 11, Division of PreMarketing Assessment 1, ONDQA Srikanth Nallani, Clinical Pharmacology Reviewer, Of?ce of Clinical Pharmacology (OC P) Dionne Price, Statistics Team Leader, Division of Biometrics 11 Kate Meaker, M.S. Statistical Reviewer, Division of Biometrics II Kim Compton Senior Regulatory Project Manager, DAAP Kristina Toliver, PharmD. Team Leader, Division of Medication Error Prevention and Analysis (DMEPA), Of?ce of Surveillance and Epidemiology (OSE) Gita Toyserkani, PharmD. Team Leader, Division of Risk Management (DRISK), OSE Stephen Sim, M.D. Reviewer, DRISK, OSE IND 072411 Page 3 Agnes Plante, B.S.N. Jovita Randall Thompson, Ph.D. Mike Klein, R.Ph., Ph.D. Consumer Safety Officer, Office of Compliance Reviewer, Controlled Substance Staff (CSS) Director, CSS Background: On August 12, 2010, (prior to the August 17 meeting) the Agency forwarded to the firm the Agency’s comments and responses to the questions posed by the sponsor in their July 8, 2010, meeting package. The firm indicated they would like to discuss Chemistry Questions 1, 3, 5, and 8, DMEPA Comments, Clinical Questions 4, and 5, and REMS Questions 1 and 2. Presented below are the Agency’s comments and responses to questions in the background meeting package. The sponsor’s questions are listed in italics, with Agency responses and comments in bold. Discussion that took place at the meeting is captured in normal text following the question to which it pertains. Meeting: The sponsor opened the meeting by stating that their company has one focus—the delivery of drugs through spray technology. Chemistry Questions Question 1 Insys proposes to establish controls for the fentanyl drug substance based on standards recommended by the API manufacturer. Are the proposed tests and specifications for the drug substance adequate? FDA Response (b) No, the proposed drug substance specifications are not adequate. The impurity (4) contains a structural alert for mutagenicity and must therefore either (b) (4) be reduced to reflect NMT total daily intake or be adequately qualified for safety. We remind you that drug substance specifications will be assessed during the NDA review as per ICH Q3A(R2) and the FDA draft Guidance: Genotoxic and Carcinogenic Impurities in Drug Substances and Products: Recommended Approaches. Discussion The sponsor stated that they have spoken to their API supplier, and they are comfortable with the (b) (4) (b) (4) specification and so will commit to it. The Division stated that the limit was suitable provided that it was based on the maximum daily dose. The sponsor stated that they will (b) (4) (b) (4) (b) ensure that the impurity ( will be reduced to and will be NMT (4) mcg/day based on the maximum daily dose. FDA_5386 1ND 072411 Page 4 Question 2 Insys proposes to establish controls for the drug product as appropriate for an oral, sublingual dosage form. Are the proposed tests and specifications for the drug product (release and stabilitv) adequate? FDA Response The proposed drug product specifications appear reasonable. We remind you that drug product speci?cations will be assessed during the NDA review as per ICH and the FDA draft Guidance: Genotoxic and arcinogem'c Impurities in Drug Substances and Products: Recommended Approaches. Discussion There was no further discussion on this point. Question 3a Insys intends to propose a shelf-life of 3 years for the drug product, based on long-term stabilitv data. Do the drug product stabilitv batch plan and testing protocol using a approach support the proposed expirv dating? FDA Response With respect to your stability plan, the proposed number of primary stability batches in Table 16, and extent of data to be submitted in the NDA is acceptable. However, the proposed stability protocol in Tables 17 and 18 is unclear and limited with respect to frequency of testing critical spray performance attributes, and is not acceptable. You must demonstrate that critical product quality attributes, spray actuation content, spray content uniformity, droplet size distribution, and spray pattern are consistent and robust at all time points and orientations (mm is not advisable. Discussion The sponsor referred to the handout they shared with the attendees at the meeting (a copy is appended at the end of this docrunent following page 49.) The Division stated that since the product is a solution, is not an issue. In addition, the Division now understands that the product does not require priming, but noted that the sponsor will still need to demonstrate that the product dose delivery is consistent. The Agency is interested in trends in stability data, even if they are small, and large gaps in stability data are not acceptable based on IC standards for testing intervals. The Division stated that the sponsor should provide all relevant development data for review in their NDA at the time of submission. With respect to collecting data at different orientations, the sponsor stated (mm The Division requested that the sponsor provide data to support this claim. The sponsor stated that they could conduct some mm to better support the stability data. 1ND 072411 Page 5 The Division inquired if the NDA would contain 9, 12, and 18-month stability data and the sponsor stated that three batches are still aging and they plan to provide 12 and 18-month data. In order to see any trends, the Division requested data on all aspects of device performance and stability per IC at the speci?ed time points. for the spray characteristics will require further internal discussion. The Division agreed to provide a de?nitive position on this issue as a Post-Meeting Note. (4) *Post?Meeting Note? (4) . rs not acceptable. Testing for all attributes, at minimum for the lowest and highest must be employed as per ICH recommendations for testing intervals, for your NDA batches. You may propose a ?reduced testing? stability protocol, post-approval, after a complete assessment of the critical attributes of your product on stability, with suf?cient supporting stability data in your NDA submission. Be advised, that insuf?cient stability data at the time of NDA submission, may put ?ling of your NDA at risk. The Division observed that the sponsor?s stability program appears extremely complicated. (mm but the Agency still needs to see testing results at the time of NDA submission for review. If the sponsor establishes that the proposed stability program is robust, then they may develop a protocol similar to what they are proposing for their more routine testing; however, IC does not state that one may skip time points in primary stability protocols. The sponsor observed that IC does provide for a reduced design option. The Division stated that in taking such an approach, the sponsor 111115 a risk that there may not be enough data to ?le/evaluate and provide a robust shelf-life for the product in the NDA. Question 3b Insys intends to propose a shelf-life of 3 years for the drug product, based on long-term stability data. Is the proposed format for stability data tables acceptable? FDA Response See response to Question 3a. We remind you that expiration dating will be assessed during the NDA review, as per ICH based on available real-time stability data and statistical analysis evaluation, as applicable. Discussion The Division stated that the stability table formats in Appendix 2 of the briefmg document are acceptable. 1ND 072411 Page 6 Question 4 The NDA will include data on extractables and leachables from the drug product addition, information will be provided by the spray device manufacturer to support the safety of components. Does the Division find that extractables and leachables from the have been adequately characterized? 4 (4) FDA Response Your approach to characterize extractables/leachables, include extractables information from the (m4) and a safety assessment of (mo components in the NDA, appears reasonable. We remind you that the adequacy of your studies to characterize extractables/leachables, will be assessed during the NDA review, based on available data. Discussion There was no ?uther discussion on this point. Question 5 The NDA will include data on drug product spray delivery after long-term storage during stability testing. In addition, Insys will submit data on spray delivery as a function of device orientation. Is the study of spray delivery as a function of device orientation adequate to demonstrate device functionality for bed-bound patients? FDA Response See response to Question 3a. Your proposed stability protocol is insufficient with respect to testing spray delivery with device orientations. You must demonstrate that dose (spray) delivery, spray content uniformity, and spray pattern are consistent and robust in different orientations at all time points. Discussion The sponsor inquired whether the infonnation provided on page 50 of the background package addressed the Agency?s concerns regarding bed-bound patients. The Division stated that the sponsor will need to evaluate spray characteristics at all different device orientations. The sponsor?s proposal is acceptable as long as the study is completed in accordance with the guidance for nasal sprays. Question 6 In anticipation of corrnnercial supplv requirements, the spray device manufacturer will . There are no changes in (mm design from the employed for fabrication of clinical spray device parts. To qualify the commercial spray devices, Insys will manufacture process validation batches using spray devices assembled from parts fabricated with Does the Division agree with the proposed scale-up plan? (4) (4) IND 072411 Page 7 FDA Response Yes, we agree. Discussion There was no further discussion on this point. Question 7 Insys has developed a packaging/labeling scheme for the drug product incorporating color coding for dose differentiation, child resistant/senior accessible blister packaging and secondary package unit counts consistent with expected patient requirements. Does the Division find the proposed packaging/labeling approach suitable for this single-use sublingual spray? FDA Response The proposed packaging/labeling approach appears suitable for the single-use sublingual spray. The adequacy of the proposed packaging/labeling scheme will be assessed during the NDA review. Clarify what you mean by color coding. Color “coding” generally refers to the use of color across product lines so that similar product strengths, active ingredients, or some other overlapping product characteristic utilize the same colors on labels and labeling (e.g. all oral transmucosal fentanyl (OTF) products using the same colors for corresponding strengths). If this type of color coding is what you are referring to we do not recommend the use of the same colors for the same strengths across OTF product lines. However, if you are referring to color differentiation (i.e., the use of color to differentiate the product strengths within your fentanyl sublingual spray product line), the use of color can be an effective means for differentiating product strengths. A full review and evaluation of the labels, with color coding, will be done at the time of the NDA review. Additionally, we note in section 7.2.6.9 of your briefing package, you state that each individual unit-dose system label will contain “at minimum, Product Name, Dose, Lot Number, Date of Expiry.” We recommend you also include the product strength on the label. Discussion There was no further discussion on this point. Division of Medication Error Prevention and Analysis (DMEPA) Comments 1. If you have not already done so, a Failure Mode and Effects Analysis should be conducted to identify any failures that may be associated with this dosing device (e.g., wrong route of administration). 2. Additionally, label comprehension studies should be conducted on any instructions for use. FDA_5390 IND 072411 Page 8 3. Clarify if it will be evident from the device that the dose has already been administered. Discussion The sponsor stated that they plan to complete a full FMEA as well as a labeling comprehension study, and to include information in the Medication Guide on how it will be evident that a dose has ah?eady been administered. Question 8 The NBA will include data on residual in the deliverv device post-dosing. Are the data to be provided adequate to characterize the disposition of residual drug? FDA Response Your proposed disposal plan is not acceptable. You have not discussed priming requirements for your product. Priming will impact the amount of residual drug at the end of use. Based on the gross estimate of your residual product, the residual drug amount(s) is unacceptable. Therefore, you must scienti?cally justify the lowest possible residual to assure performance of your drug product, and describe any modifications to the device material(s) and shape(s) of components, and drug load to minimize residual. Since this is a spray drug product and residual is inevitable, you must propose additional measures, use of a chemical or physical trap to eliminate residual, collection of used devices, and any other means of preventing the potential for abuse and misuse of your drug product. In addition, you must consider the environmental impact of the number of devices to be discarded and propose measures for collection and possible recycling of your devices. We remind you that any possible modifications to your device must be implemented before commercialization, and adequately bridged by CMC data on device performance characteristics. Discussion The sponsor stated that each device is designed to have only one actuation. It does not need to be primed and cannot be ?red again once actuated. The device has a (m4) residual volume after actuation (4) The Division stated that (mm This does not sormd like a practical approach because it is just not likely to be completed on a regular basis. If the sponsor decides to propose such a step, they will need to provide data to show that it will actually man in the home-use situation. The sponsor stated that (m4) IND 072411 Page 9 Question 9 Insys has developed a method for drug product disposal by patients after dosing or for unused product, to address concerns about potential accidental exposure, tampering or diversion. Does the Division find the proposed disposal approaches suitable? FDA Response As discussed above, your proposals for residual drug and device disposition are not acceptable. See response to Question 8. Discussion There was no further discussion on this point. Additional Chemistry Comments 1. Clarify if priming studies have been performed, and if not, provide data to assess the delivered dose in your NDA submission. 2. Provide a list of all manufacturing facilities, in alphabetical order, a statement about their cGMP status, and whether they are ready for inspections at the time of your NDA submission. For all manufacturing sites, provide a contact name with telephone and facsimile number at the site. Clearly specify the responsibilities of each facility, and which sites are intended to be primary or alternate sites. Note that facilities with unacceptable cGMP compliance may risk approvability of the NDA. 3. Provide letters of authorization to allow our review of all supporting master files for the NDA (e.g., drug substance and device manufacturer(s)). Discussion There was no further discussion on this point. Nonclinical Questions Question 1 In the Nonclinical Overview section of the NDA, Insys intends to summarize the nonclinical information presented in the labeling and summary basis of approval documents for Actiq, Fentora® and Onsolis®. Insys will supplement this review with any new nonclinical literature on fentanyl published since the approval of Onsolis (July 16, 2009). Additionally, Insys will include information supporting the safety of drug product impurities and extractables and leachables from the dosing device. Insys will include tabular summaries of the impurity and extractable/leachable safety data and relevant new information present in the published literature if sufficient information is available. Does the Agency concur with this approach? FDA Response Yes, we agree. Your approach sounds acceptable. However, you must identify the product(s) that you intend to reference via the 505(b)(2) regulatory pathway. You cannot FDA_5392 IND 072411 Page 10 rely on the Agency’s Summary Basis of Approval to support the safety of a drug product but you may rely on the Agency’s previous findings of safety and efficacy as represented by the referenced drug product label. Discussion There was no further discussion on this point. Additional Nonclinical Comments 1. Include a detailed discussion of the nonclinical information in the published literature and specifically address how the information within the published domain impacts the safety assessment of your drug product. This discussion should be included in Module 2 of the submission. Include copies of all referenced citations in the NDA submission in Module 4. Journal articles that are not in English must be translated into English. 2. We recommend that sponsors considering the submission of an application through the 505(b)(2) pathway consult the Agency’s regulations at 21 CFR 314.54, and the October 1999 Draft Guidance for Industry Applications Covered by Section 505(b)(2) available at http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm In addition, FDA has explained the background and applicability of section 505(b)(2) in its October 14, 2003, response to a number of citizen petitions challenging the Agency’s interpretation of this statutory provision (see Dockets 2001P-0323, 2002P-0447, and 2003P-0408 (available at http://www.fda.gov/ohrms/dockets/dailys/03/oct03/102303/02p-0447-pdn0001vol1.pdf). If you intend to submit a 505(b)(2) application that relies for approval on FDA’s finding of safety and/or effectiveness for one or more listed drugs, you must establish that such reliance is scientifically appropriate, and must submit data necessary to support any aspects of the proposed drug product that represent modifications to the listed drug(s). You should establish a “bridge” (e.g., via comparative bioavailability data) between your proposed drug product and each listed drug upon which you propose to rely to demonstrate that such reliance is scientifically justified. If you intend to rely on literature or other studies for which you have no right of reference but that are necessary for approval, you also must establish that reliance on the studies described in the literature is scientifically appropriate. 3. The nonclinical information in your proposed drug product label must include relevant exposure margins with adequate justification for how these margins were obtained. If you intend to rely upon the Agency’s previous finding of safety for an approved product, the exposure margins provided in the referenced label must be updated to reflect exposures from your product. If the referenced studies employ a different route of administration or lack adequate information to allow scientifically justified extrapolation to your product, you may need to conduct additional pharmacokinetic studies in animals in order to adequately bridge your product to the referenced product label. 4. New excipients in your drug must be adequately qualified for safety. Studies must be submitted to the IND in accordance as per the following guidance document, Guidance for FDA_5393 IND 072411 Page 11 Industry: Nonclinical Studies for Safety Evaluation of Pharmaceutical Excipients (May 2005) which is available on the CDER web page at the following http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm As noted in the document cited above, “the phrase new excipients means any ingredients that are intentionally added to therapeutic and diagnostic products but which: (1) we believe are not intended to exert therapeutic effects at the intended dosage (although they may act to improve product delivery, e.g., enhancing absorption or controlling release of the drug substance); and (2) are not fully qualified by existing safety data with respect to the currently proposed level of exposure, duration of exposure, or route of administration.” (emphasis added). 5. Any impurity or degradation product that exceeds ICH thresholds must be adequately qualified for safety as described in ICHQ3A(R2) and ICHQ3B(R2) guidances at the time of NDA submission. Adequate qualification would include: – Minimal genetic toxicology screen (two in vitro genetic toxicology studies; e.g., one point mutation assay and one chromosome aberration assay) with the isolated impurity, tested up to the limit dose for the assay. – Repeat dose toxicology of appropriate duration to support the proposed indication. 6. Genotoxic, carcinogenic or impurities that contain a structural alert for genotoxicity must be either reduced to NMT 1.5 mcg/day in the drug substance and drug product or adequate safety qualification must be provided. For an impurity with a structural alert for mutagenicity, adequate safety qualification requires a negative in vitro bacterial reverse mutation assay (Ames assay) ideally with the isolated impurity, tested up to the appropriate top concentration of the assay as outlined in ICHS2A guidance document titled “Guidance on Specific Aspects of Regulatory Gentoxicity Tests for Pharmaceuticals.” Should the Ames assay produce positive or equivocal results, the impurity specification must be set at NMT 1.5 mcg/day, or otherwise justified. Justification for a positive or equivocal Ames assay may require an assessment for carcinogenic potential in either a standard 2-year rodent bioassay or in an appropriate transgenic mouse model. 7. In Module 2 of your NDA (2.6.6.8 Toxicology Written Summary/Other Toxicity), you must include a table listing the drug substance and drug product impurity specifications, the maximum daily exposure to these impurities based on the maximum daily dose of the product, and how these levels compare to ICHQ3A and Q3B qualification thresholds along with a determination if the impurity contains a structural alert for mutagenicity. Any proposed specification that exceeds the qualification threshold should be adequately justified for safety from a toxicological perspective. 8. The NDA submission must contain complete and definitive safety information on potential leachables and extractables from the drug container closure system and/or drug product formulation as outlined in the FDA Guidance for Industry titled “Container Closure Systems for Packaging Human Drugs and Biologics.” The evaluation of extractables and leachables FDA_5394 IND 072411 Page 12 from the drug container closure system or from a transdermal patch product must include specific assessments for residual monomers, solvents, polymerizers, etc.. Based on identified leachables provide a toxicological evaluation to determine the safe level of exposure via the label-specified route of administration. The approach for toxicological evaluation of the safety of leachables must be based on good scientific principles and take into account the specific container closure system or patch, drug product formulation, dosage form, route of administration, and dose regimen (chronic or short-term dosing). As many residual monomers are known genotoxic agents, your safety assessment must take into account the potential that these impurities may either be known or suspected highly reactive and/or genotoxic compounds. The safety assessment should be specifically discussed in module 2.6.6.8 (Toxicology Written Summary/Other Toxicity) of the NDA submission. For additional guidance on extractables and leachables testing, consult the FDA Guidance documents Container Closure Systems for Packaging Human Drugs and Biologics and Nasal Spray and Inhalation Solution, Suspension, and Spray Drug Products – Chemistry, Manufacturing, and Controls Documentation. Additional methodology and considerations have also been described in the PQRI leachables/extractables recommendations to the FDA, which can be found at http://www.pqri.org/pdfs/LE Recommendations to FDA 09-29-06.pdf. 9. Failure to submit adequate impurity qualification, justification for the safety of new excipient use, or an extractable leachable safety assessment, may result in a Refusal-to-File or other adverse action. Discussion There was no further discussion on these points. Clinical Questions Question 1 No specific studies in patients with either renal or hepatic insufficiency have been conducted. It is the Sponsor’s intention to use the same language used in the Actiq® label regarding these patients. Thus, the recommended language for this section would read as follows: (b) (4) Does the Agency agree? FDA Response You are not required to conduct specific studies in patients with renal or hepatic insufficiency with your product. However, we recommend that you conduct a literature search and propose new language if any new information is available at the time of your NDA submission. If no new PK information is available and if there is no new thinking on FDA_5395 1ND 072411 Page 13 the part of the Agency with respect to this class labeling type language, the same language present in the reference drug would be suf?cient. Discussion There was no further discussion on this point. Question 2 Because data on the e?icacy of entanyl SL Spray derive from only one clinical study (INS-05-001), (hm) . Does the Agency agree with this approach? FDA Response Your proposal is not acceptable. You will need to provide an integrated summary of effectiveness (ISE). Refer to the Guidance for Industry- Integrated Summary of Effectiveness, available at ces/UCM079803.pdf for the content of the ISE other than study data. Discussion There was no ?uther discussion on this point. Question 3 The objective of the Integrated Summary of Safety (ISS) is to assess the safety of entanyl SL Spray in opioid-treated subjects with breakthrough cancer pain. The safety parameters to be evaluated include adverse events (AEs), vital signs, clinical laboratory tests, and electrocardiogram (ECG) results. Data from the four clinical pharmacology studies will be presented in the ISS as stand-alone in-text tables, along with the existing summaries from their respective clinical reports. Data from the two Phase 3 studies will be combined to present safety data in cancer subjects, on multiple doses of entanyl SL Spray, and over an extended period of time. The Statistical Analysis Plan (SAP) for the 155, included in this briefing document in Appendix 1, describes the combined analysis of INS-05-001 and INS-06-007. Insys believes that this SAP will provide the clinical data needed to adequately characterize the safety of entanyl SL Spray. Does the Agency concur? FDA Response Your proposed organization of the [88 appears acceptable. We expect the 188 to be a full integration of the trial results and any other information you are relying on for approval of the application. This integration should address how all the pieces together make up the application. You are expected to complete an integrated analysis which addresses how your product is linked to any item(s) you are referencing, how your product is relevant to any other information on which you are relying, and how you believe this represents a complete application package for your product. 1ND 072411 Page 14 Module 2 is intended to be a brief overview or summary and is limited in the amount of content. The 188 is intended to be located in Module 5.3.5.3. You continue to refer to ?opioid-treated? patients. That term is open to interpretation. This product is appropriate for opioid-tolerant patients as de?ned in labeling for similar oral transmucosal fentanyl products. Discussion There was no ?uther discussion on this point. Question 4 The entanyl SL Spray clinical development program, as discussed at the End-of-Phase-2 meeting, consists of three pharmacokinetic studies in healthy volunteers, one pharmacokinetic study in patients with or without mucositis, an e?icacy and safety study in 130 patients, and a 3-month safety study in 2150 patients (Refer to Section 5). Insys believes that these studies will be su?icient to form the basis of a determination of product safety and e?icacy. Does the Agency concur? FDA Response Barring any unanticipated safety signals and presuming the results of your INS-05-001 trial are con?rmed, we agree. With respect to the pharmacokinetic (PK) study in patients with or without mucositis, we recommend that you include cancer patients with oral mucositis of grades 1, 2, 3, and 4. Alternatively, you may study cancer patients with grade 4 oral mucositis, and if there is no change in the PK in this group, patients with lower grade mucositis need not be studied. Discussion The Division stated that studies of the product in grade 4 mucositis patients are not feasible. Also, the product may be used in patients beyond only mild grade mucositis. Therefore, the sponsor should summarize the results of their studies to date and submit them for review. The Division will determine if additional study in this area is needed. If no effect is seen, the sponsor?s studies thus far may be suf?cient, but if an effect is seen in mild mucositis patients, then more study will be needed. The sponsor agreed so submit an executive smnmary of their mucositis data. Question 5 Given that all primary and secondary endpoints were achieved during the Insys placebo-controlled clinical e?icacy study (INS-05-001) and particularly, (m4) Does the Agency agree that such information, if supported by the clinical data, is suitable for inclusion in the label? IND 072411 Page 15 FDA Response For the primary ef?cacy endpoint, a graphical representation of the data may be included in the label. (mm For secondary ef?cacy endpoints, only clinically relevant information (assessed with appropriate outcome measures and analyzed with appropriate statistical methods) will be included in the label. Discussion The sponsor stated that (W4) REMS Questions Question 1 Given the ?uid nature REMS for immediate-release opioids, when will the Agency be able to provide more guidance on this issue? FDA Response This product, as well as all transmucosal immediate-release fentanyl products, will require a Risk Evaluation and Mitigation Strategy (REMS). A standardized type of REMS for these products is currently under Agency development and review; this information will be provided to you as soon as it is available. In the meantime, note that, at a minimum, your REMS will consist of the following elements: Medication Guide, Elements to Assure Safe Use, Implementation System and Timetable for Submission of Assessments. Your REMS must also address proper disposal of residual fentanyl product in the device, prescribing to opioid-tolerant patients only, appropriate dosing of these fentanyl products, and surveillance for misuse and abuse. You must submit a complete REMS at the time of initial NDA submission. Submit your REMS and REMS Supporting Document with your initial NDA submission as well as all planned materials identified within the proposed REMS that will be necessary to implement your proposal. Education should emphasize the safety messages important for safe use of the product. Product marketing materials generally are not appropriate to educate about product risks. IND 072411 Page 16 Discussion The Division stated that the Agency is currently evaluating how an appropriate REMS for this class of product will look and plans to share this with all companies involved in development of products in this class; however, there is no specific timeline. It is possible this may still be unresolved at the time the sponsor submits their NDA. The Division stated that the sponsor may contact other companies that have products in this class and are working on REMS programs to see if they are willing to work together on a REMS. The Agency stated that a single system to include all products in the class is optimal, but each sponsor may need to first establish their own system as we move toward a shared REMS in the future. If there is any update on what the Agency feels is an appropriate classwide REMS by the time the minutes of the meeting are issued, it will be included as a Post-Meeting Note. ***Post-Meeting Note— The Agency is facilitating a meeting to discuss REMS for the class of transmucosal, immediate-release fentanyl (TIRF) products on Oct 28, 2010. Insys has been invited. The Division emphasized that the sponsor may find that working together with other companies toward a shared REMS may leverage firms that are not as willing to work on a shared REMS. The sponsor stated that, rather than working with other companies for a shared system, they commit to the ETASU and Medication Guides already in place for other products in this class. Question 2 Is the Agency considering a single, shared REMS program for immediate-release opioids? FDA Response We strongly recommend that you work with the other manufacturers of transmucosal immediate-release fentanyl products. In order to minimize the burden on the healthcare system and its various stakeholders, we recognize the importance of having one shared REMS system for all of these products, not just a REMS for an innovator and its generics. Discussion The Division stated that, while the Agency will continue to keep the sponsor updated on REMS requirements for this class of drugs, there have been situations where requirements have changed near the end of a review cycle delaying an action. If the NDA meets the minimum REMS requirements, it will certainly be fileable, but the Division is not certain how the class REMS will be implemented. The Division cannot guarantee that this application would not be caught in a period of change that would impact the Division’s ability to approve the product and/or the sponsor’s ability to market their product if approved. The Division is aware that, in particular, smaller companies seem receptive to working together to further this classswide REMS. The Division does not want any risk to the patient, their family, or pets, which may occur if they are exposed to any product remaining in used or unused devices. The sponsor will need to address this in their REMS. In addition, the Division does not want the patient or family members taking the device apart and risking exposure. This is especially concerning if the exposed individual is a non-opioid-tolerant caregiver. FDA_5399 1ND 072411 Page 17 The abuse issue is separate but still needs to be addressed as well. The sponsor stated (mm The Division suggested the sponsor focus on those aspects The Division stated that the sponsor will also need to address the issue of multiple bottles being in the home at the same time, as this lends itself to theft, while the residual product (m4) is a potential for accidental exposure. The Division suggested the sponsor consider employing a secondary packaging to keep track of what has been used and what remains. In addition, education of patients about proper storage is an essential element of the REMS. Any data the sponsor has to demonstrate that patients understand and will take steps to ensure proper storage will be helpful. The sponsor stated that they do have child-resistant blister packaging as part of their secondary packaging. The Division stated that it is important to include in the NDA all work that has been done to demonstrate how dif?cult it is to recovery any residual from the device. Such data helps support any statements in that area. Discussions of attempts people have made to abuse the product are typically part of any Advisory Committees on this topic, so the sponsor will need to know about them and be able to address them in their REMS. The sponsor should also be able to explain what will be done with rmused units, since the product is used only as needed. The Controlled Substance Staff (C SS) requested that data to support the sponsor?s belief that in the class be submitted, as well as a proposal for proper storage of the product in the home. They directed the sponsor to formulate a proposal supported with data and submit it with the NDA. The sponsor stated that they will The Agency instructed the sponsor to submit data to support that with their NDA, along with placebo-?lled, fmal versions of the device. The Division recommended that the ?rm consider secondary storage locations and issues, e. if the patient has several devices out at once in different locations, as well as data on what happens if the product is sprayed into other ori?ces (such as the nose) by accident. The Agency requested that the sponsor submit to the NDA any medication error data from the clinical trials as well. The sponsor agreed. The Division stated that, at this time, formulation-speci?c disposal will be needed for the REMS because the products are different from one another and there is no single disposal method that can be applied to all. The sponsor does not need to explore every single method to reclaim the residual, but those that someone who is somewhat motivated might employ should be considered. There are experts in this ?eld who could provide fru?ther input if needed. SS stated that they would be willing to review any proposals on this aspect of the product if the sponsor submits them. Their standard review time is approximately 30 days. (4) (4) The Division stated that it is worth exploring The sponsor stated, however, IND 072411 Page 18 (4) Note-- An abuse potential study with your product, is not recommended. The abuse potential and safety of fentanyl is well known. Fentanyl is 80 to 100 times more potent then morphine. We have safety concerns with assessing this product in an abuse potential study. An abuse potential study measures the liking/euphoric effect of a drug and typically involves the administration of the drug at higher doses than the drug?s therapeutic recommended doses. Also, the subject population in these studies, although experienced recreational users, are typically not tolerant to the respiratory depressant effects of the drug. At the meeting, you referred to the product as an In your Pre-Meeting package there is reference to (July 8, 2010 Meeting Brie?ng Package, page 44). Any claims made on (m4) or any claims made on the relative safety of your product compared to any current marketed fentanyl product would need to be supported with replicated data. In addition, we are particularly concerned about the possible use of the drug-device in commission of criminal acts because of the ease and rapidity of administering the drug either in a victim?s mouth, or by inhalation, or in a drink. Fentanyl does not have an insigni?cant oral bioavailability. The victim could be rapidly overcome and, depending on the dose. This could result in serious morbidity or mortality. You need to address this concern and how such possible abuse or misuse of the product can be prevented. You need to monitor drug use and accountability among subjects and monitor abuse- related adverse events in all future clinical studies with Fentanyl SL Spray. These data should be presented in tabular format in the NDA, when submitted. Provide information on the expected number of dosage units of Fentanyl SL Spray that will be used per day for breakthrough pain. As with other transmucosal fentanyl products, in considering the patient population (opioid-tolerant patients), you do not propose a dose titration schedule for Fentanyl SL Spray, though as described, patients receive blister packs of 12 to 28 spray devices at one time when ?lling a prescription and are instructed to employ one dose, 1 or 2 spray devices as needed to attenuate breakthrough pain. Division of Scienti?c Investigations (DSI) Comments Comments I to concern submission of data to the NDA that will be used for site selection and site inspection including information about potential use of electronic data capture of subject pain assessments for the primary endpoint. The Division of Scienti?c Investigations is piloting a ?risk based site model? computer program, and the fourth item as well as the document, ?Summary Level Clinical Site Data for Data Integrity Review and Inspection Planning in NDA and BLA Submissions? relate to this pilot. IND 072411 Page 19 I. Request for general study related information as well as specific Clinical Investigator (CI) information to be used in site selection: A. Please include the following information in a tabular format for the clinical trial: 1. Site number 2. Primary investigator 3. Location: City State, Country, including contact information (phone, fax, email) B. Please include the following information in a tabular format by site for the clinical trial: 1. Number of subjects screened at each site by site 2. Number of subjects treated at each site by site 3. Number of subjects treated who prematurely discontinued at each site by site C. Please include the following information in a tabular format for the clinical trial: 1. Name, address and contact information of all Contract Research Organizations (CROs) used in the conduct of the clinical trials 2. The location (actual physical site where documents are maintained and would be available for inspection) for all source data generated by the CROs with respect to their roles and responsibilities in conduct of respective studies 3. The location (actual physical site where documents are maintained and would be available for inspection) of sponsor/monitor files (e.g. monitoring master files, drug accountability files, SAE files, etc.) D. Sample blank case report form II. Request for Individual Patient Data Listings to be used for inspections: For the trial INS-05-001 entitled “A Randomized, Double-Blind, Placebo-Controlled Multi-Center Study to Evaluate the Safety and Efficacy of Fentanyl Sublingual Spray (Fentanyl SL Spray) for the Treatment of Breakthrough Cancer Pain,” please submit site-specific individual subject data (“line”) listings from the datasets: A. Line listings for each site listing the subject number screened and reason for subjects who did not meet eligibility requirements B. Line listings by site and subject, of treatment assignment and treatment administered. For this study, the listing for the treatment assignment refers to the 7 doses of active and 3 doses FDA_5402 IND 072411 Page 20 of placebo test article that were distributed to each subject during the double-blind period C. Line listings by site and subject, of drop-outs and discontinued subjects with date and reason D. Line listings by site of evaluable subjects/ non-evaluable subjects and reason not evaluable E. Line listings by site and subject, of AEs, SAEs, deaths and dates F. Line listings by site and subject, of protocol violations and/or deviations reported in the NDA, description of the deviation/violation G. Line listings by site and subject, of the primary endpoint efficacy parameter, Summed Pain Intensity Difference at 30 minutes (SPID30) and all of the pain values that were used to calculate this value (i.e. pain values from 0 to 30 minutes) H. Line listings by site and subject, of the endpoint efficacy parameter, Summed Pain Intensity Difference at 60 minutes (SPID60) and all of the pain values from after 30 minutes up to and including 60 minutes that were used to calculate this value I. Line listings by site and by subject, of concomitant medications III. Additional request if electronic data capture of subject pain assessments (ediary) was used: A. Information concerning the electronic diary including instructions for use provided to subjects and investigators during the trial (Please include a description of support services available to subjects and investigators during the trial.) B. Document the nature of the data generated by the electronic diary and describe the procedures used by the clinical investigator to collect and review the electronic diary C. During the clinical trial, did sites retain the data in paper form or have access electronically? If electronic access, please describe D. Data captured on the eCRFs and the eDiaries were provided to the CI on CD(s) at the close of the study (Please state who provided the CD(s) and the contents of the CD(s).) E. Concerning the software: a. Who designed and developed the software? b. Could it be modified, or has it been modified? If so, by whom? c. Has the software been validated? Who validated the software? d. What was the process used to validate the software? How was the validation process documented? FDA_5403 IND 072411 Page 21 e. Were error logs maintained (for errors in software and systems) and do they identify corrections made? f. If data could be modified, how would the sponsor be aware of any changes? F. Concerning Data Flow: a. Who was authorized to access the system and enter data or change data? b. Is there an audit trail to record changes to subject entries, including who, when, and why the change was made? c. Are there edit checks and data logic checks for acceptable ranges of values? d. How are the data transmitted from the subject to the sponsor or CRO? G. Concerning Computerized System Security: a. How was system access managed, e.g., access privileges, authorization/deauthorization procedures, physical access controls? Are there records describing the names of authorized personnel, their titles, and a description of their access privileges? b. What methods were used to access computerized systems, e.g., identification code/password combinations, tokens, biometric signatures, electronic signatures, digital signatures? c. How were the data secured in case of disasters, e.g., power failure? Are there contingency plans and backup files? d. Were there controls in place to prevent, detect, and mitigate effects of computer viruses on study data and software? e. Were controls in place to prevent data from being altered, browsed, queried, or reported via external software applications that do not enter through the protective system software? f. When and how was data accessible to the clinical investigator? H. Were there written procedures for software validation, data collection, and computerized system security? I. To facilitate our understanding of how data were transmitted from the eDiary and prepared for submission to the Agency, please provide a flow diagram that tracks the course of data generated by the subject through submission in the NDA. Please also include a diagram that tracks the course of the data to the clinical investigator for archiving at the end of the trial. The diagram should identify who was responsible for each step in the FDA_5404 1ND 072411 Page 22 process and should also specify points in data?ow where an audit trail exists. IV. Request for Site Level Data for the risk based model D81 is piloting a risk based model for site selection. Electronic submission of site level datasets will facilitate the timely selection of appropriate clinical sites for FDA inspection as part of the application and/or supplement review process. Please refer to the attached document, ?Summary Level Clinical Site Data for Data Integrity Review and Inspection Planning in NDA and BLA Submissions? for further information. We request that you provide datasets, as outlined, for the study submitted in your application. Discussion There was no further discussion on this point. Overall General Comment Attachment 2 contains general comments on the content and format of an NDA submission and a Quality Assessment Tool. The sponsor summarized their understanding of the meeting as follows {includes action itemsThe sponsor lmderstands that the impm?ity limit for (m4) of NMT acceptable as long as the limit is based on the maximum daily dose and will be NMT based on the maximum daily dose. mc g/ day 2. The sponsor clari?ed that the device does not need priming, and rurderstands that they need to demonstrate that the device delivers a consistent spray over time, as well as ?ll in any missing gaps on the stability continuum. 3. The sponsor understands that it is important to evaluate dose delivery over time. 4. The sponsor understands that an abbreviated stability protocol may be acceptable, but only after fully establishing the stability protocol for NDA primary stability batches. The sponsor understands that they may follow this approach, but that it is at their own risk. 5. The issue of (?W?stability data at certain testing intervals being acceptable is to be addressed in a Post-Meeting Note (see page 5 of this document.) 6. The sponsor understands that demonstration of ?mctionality in bed-bormd patients is acceptable as long as they follow the guidance for nasal sprays. 7. The sponsor commits to conduct a FMEA and include that with the NDA. Data from this analysis may be useful for the Medication Guide. 8. The sponsor understands that the application will be ?led if the minimum REMS requirements are addressed but that this is an area that remains Imder development within the Agency. IND 072411 Page 23 9. The sponsor understands that the Agency recommends they reach out to other firms with products in this class and consider working on REMS development cooperatively. 10. The sponsor understands there is a guidance on submission of proprietary names. FDA_5406 IND 072411 Page 24 Attachment 1 _______________________________________________________________________ Summary Level Clinical Site Data for Data Integrity Review and Inspection Planning in NDA and BLA Submissions FOLLOWING THIS PAGE, FDA_5408 TO FDA_5432 WITHHELD IN FULL AS B(4)/CCI FDA_5407 Fentanyl Sublingual Spray Pre-N DA Meeting August 17, 2010 insvs THERAPEUTICS. INC. FDA 5433 il'lS?r?S THERAPEUTICS. INC. CMC Question 3a Clarification of Primary Stability Protocol Design Fentanyl Sublingual Spray 1 Meeting 8/17/10 FDA 5434 THERAPEUTICS. INC. Fentanyl Sublingual Spray Composition . Fentanyl Sublingual Spray Meeting 8/17/10 insvs THERAPEUTICS. INC. Fentanyl Sublingual Spray Rationale for -Design of Primary Fentany! Sublingual Spray 3 Meeting 8/17/10 insvs THERAPEUTICS, Overview of Fentanyl Sublingual Spray Stability Protocol Design a Fentanyl Sublingual Spray Meeting - 8/17/10 insvs Fentanyl Sublingual Spray NDA Stability Program Spray Actuation Content, Spray Content Uniformity, Droplet Size Distribution, Spray Pattern Fentanyl Subiinguai Spray Meeting 8/17/10 i?S?u?S THERAPEUTICS. INC. Illustrative Stability Data Spray Actuation Content an _Il- an. In 1.. 0.. Fentanyl Sublingual Spray 5 Meeting 8/17/10 insvs Illustrative Stability Data Spray Actuation Content 1 2 4 6 8m um_ Fentanyl Sublingual Spray 7 Pre-N DA Meeting? 8/17/10 FDA 5440 --------------------------------------------------------------------------------------------------------This is a representation of an electronic record that was signed electronically and this page is the manifestation of the electronic signature. --------------------------------------------------------------------------------------------------------/s/ ---------------------------------------------------KIMBERLY A COMPTON 10/18/2010 Reference ID: 2851691 FDA_5441 DEPARTMENT OF HEALTH AND HUMAN SERVICES Food and Drug Administration Silver Spring MD 20993 NDA 202788 FILING COMMUNICATION Insys Therapeutics, Inc. (c/o) The Weinberg Group, Inc. 1129 Twentieth Street, NW Suite 600 Washington, DC 20036 Attention: Lauren H. Wind, MPH Senior Consultant The Weinberg Group, Inc. Dear Ms. Wind: Please refer to your New Drug Application (NDA) dated and received March 4, 2011, submitted pursuant to section 505(b)(2) of the Federal Food, Drug, and Cosmetic Act, for fentanyl sublingual spray. We also refer to your submissions dated March 14, and April 5, 15, 21, and 29, 2011. We have completed our filing review and have determined that your application is sufficiently complete to permit a substantive review. Therefore, in accordance with 21 CFR 314.101(a), this application is considered filed 60 days after the date we received your application. The review classification for this application is Standard. Therefore, the user fee goal date is January 4, 2012. We are reviewing your application according to the processes described in the Guidance for Review Staff and Industry: Good Review Management Principles and Practices for PDUFA Products. Therefore, we have established internal review timelines as described in the guidance, which includes the timeframes for FDA internal milestone meetings (e.g., filing, planning, midcycle, team and wrap-up meetings). Please be aware that the timelines described in the guidance are flexible and subject to change based on workload and other potential review issues (e.g., submission of amendments). We will inform you of any necessary information requests or status updates following the milestone meetings or at other times, as needed, during the process. If major deficiencies are not identified during the review, we plan to communicate proposed labeling and, if necessary, any postmarketing commitment requests by December 16, 2011. At this time, we are notifying you that, we have not identified any potential review issues. Please note that our filing review is only a preliminary evaluation of the application and is not indicative of deficiencies that may be identified during our review. Reference ID: 2945323 FDA_5442 NDA 202788 Page 2 We also request that you submit the following information: (b) (4) 1. Provide results from exhaustive extraction studies of the activated HDPE bottle after addition of the maximum amount of drug product. These studies should include extraction with organic and inorganic solvents using ethanol, methanol, isopropanol, acetone, ethyl acetate, as well as water, at various time points (e.g., 1, 3, 6, and 12 hours), at room temperature and after heating and agitation. Provide similar studies under neutral, acidic and basic pH conditions at various time points. 2. Provide a photostability study for the drug product as per ICH Q1B. 3. To enhance patient comprehension, revise your proposed Medication Guide to target a 6th to 8th grade reading ease with a Flesch reading ease score of at least 60%. Your currently proposed Medication Guide has a grade level of 10.2 and a Flesch reading ease score of 50.2%. Refer to the currently approved Abstral Medication Guide as a template for your Medication Guide. 4. Provide the following items to your Risk Evaluation and Mitigation Strategy (REMS): a. Dear Prescriber Letter; b. Dear Inpatient Pharmacist Letter; c. Dear Outpatient Pharmacist Letter; d. REMS Overview – Prescriber; e. REMS Overview – Outpatient pharmacy; f. REMS Overview – Inpatient pharmacy; g. REMS Overview – Patient/Caregiver; and h. Distributor enrollment form. 5. To evaluate the abuse potential of your product, submit: a. an analysis of abuse-related adverse events (AEs). This analysis should include all Phase 1, 2 and 3 clinical studies. For each clinical study, AEs should be categorized by dose and presented in tabular format; b. a pooled analysis of abuse-related AEs. The pooled analysis should contain all abuse-related AEs, collapsed across studies, and categorized by dose; c. information and data related to abuse, misuse, diversion and overdose. Specifically, submit descriptions of all reports and details, including narratives, of Reference ID: 2945323 FDA_5443 NDA 202788 Page 3 an incident of abuse, overuse, or overdose (intentional or unintentional), or drug that is lost, stolen, missing or unaccounted for in all clinical studies; and d. narratives and case report forms for patients that drop out from studies where they were enrolled for reasons that might be coded as "protocol violation," "lack of efficacy," "lost to follow up," "non-compliance to study medication or procedures," and "other." 6. Also, we note that in study INS-09-011, Subject #804 with Grade 2 mucositis has a Cmax value of fentanyl of 1.81 ng/mL and AUClast value of 15.7844 ng/mL.hr. These values are significantly greater than those in patients without mucositis and with Grade 1 mucositis. This information may be included in the product label and used to provide a warning for patients with mucositis. Please respond only to the above requests for information. While we anticipate that any response submitted in a timely manner will be reviewed during this review cycle, such review decisions will be made on a case-by-case basis at the time of receipt of the submission. REQUIRED PEDIATRIC ASSESSMENTS Under the Pediatric Research Equity Act (PREA) (21 U.S.C. 355c), all applications for new active ingredients, new indications, new dosage forms, new dosing regimens, or new routes of administration are required to contain an assessment of the safety and effectiveness of the product for the claimed indication(s) in pediatric patients unless this requirement is waived, deferred, or inapplicable. We acknowledge receipt of your request for a full waiver of pediatric studies for this application. Once we have reviewed your request, we will notify you if the full waiver request is denied and a pediatric drug development plan is required. If you have any questions, call Kathleen Davies, Senior Regulatory Project Manager, at (301) 796-2205. Sincerely, {See appended electronic signature page} Bob A. Rappaport, M.D. Director Division of Anesthesia, Analgesia, and Addiction Products Office of Drug Evaluation II Center for Drug Evaluation and Research Reference ID: 2945323 FDA_5444 --------------------------------------------------------------------------------------------------------This is a representation of an electronic record that was signed electronically and this page is the manifestation of the electronic signature. --------------------------------------------------------------------------------------------------------/s/ ---------------------------------------------------BOB A RAPPAPORT 05/11/2011 Reference ID: 2945323 FDA_5445 From: To: Cc: Subject: Date: Attachments: Importance: Compton, Kimberly "Lauren Wind" Stradley, Sara FW: TIRF REMS "Gold standard" for Insys Thursday, December 22, 2011 4:11:31 PM chain-pharm-enrollment-form.doc chain-pharm-overview.doc distributor-enrollment-form.doc distributor-letter.doc education-program.ppt faq.doc hcp-letter.doc inpatient-pharm-enrollment-form.doc inpatient-pharm-letter.doc inpatient-pharm-overview.doc knowledge-assessment.doc outpatient-pharm-enrollment-form.doc outpatient-pharm-letter.doc outpatient-pharm-overview.doc patient-and-caregiver-overview.doc ppaf.doc prescriber-enrollment-form.doc prescriber-overview.doc rems.doc supp-doc-word.doc website.pdf 111130 TIRF REMS Submission Instructions.docx High Hi Lauren, Attached are the "Gold Standard" TIRF REMS documents, including the Supporting Document and the Web Prototype for Insys to submit to their Subsys NDA ASAP.  Please let them know of the following: 1.  We  have edited the documents to include Subsys in the REMS materials; however, they should review everything thoroughly as we were not able to update the TIRF Education Program and the Web Prototype to include Subsys.  They should update these documents.  Furthermore, the Outpatient Pharmacy Enrollment form and the Chain Pharmacy Enrollment form need to be verified to ensure that the NDC numbers for Subsys are included in the "contract agreement" section of the forms, as applicable. 2. There were typos in some of the REMS materials that were communicated to the TRIG this morning (12/22) and are reflected in the attached documents as track changes.  For reference, the list of typos are also provided below.  Please note, the corrections to the REMS Supporting document were not included in our correspondence this morning. 3.'Attachment 1' is replaced with the existing Attachment 1 in the "Overview for Patient and Caregivers", as the additional information in the 'healthcare provider version' is not necessary. 4. Attached are the submission instructions. _______________________________________________________________ Following are list of Typos: 1.      Education Program for Prescribers and Pharmacists -- Page 7                 First bullet - "... in adult patients with cancer 18 years of ..." [delete the second "with cancer"] 2.      Knowledge Assessment -- Page 1 - Question 2 - Answer B                 "and reconstructive" rather than "andreconstructive" 3.      Dear Healthcare Provider Letter Reference ID: 3064652 FDA_5446         a. Page 5 - Adverse Reactions, last two words - "... TIRF medicine." rather than "... TIRF medicines."         b. Page 6 - Second paragraph, second sentence - "Medication Guides will ..." rather than "Medication guides will ..." 4.      Prescriber Overview - Page 1, first paragraph, fourth line - ")" rather than "))" 5.      REMS Supporting Document         a.      Page 19 - second paragraph, last word - "enrollment" rather than "enrolment"         b.      Page 20 - last word - "medicine" rather than "medicines"         c.      Page 25 - last sentence - "shown" rather than "show"                 d.      Page 26 - "TIRF NDA Sponsors" rather than "TIRF Sponsors"         e.      Page 28                 i.      Figure 7 - "opioid" is misspelled twice                 ii.     Item 7 - "Assessment" rather than "Assessments"         f.      Page 29 - Item 12 - "Assessment" rather than "Assessments" B. The Timetable for Submission of Assessments within the REMS document has been updated to read "TIRF NDA Sponsor" rather than "TIRF Sponsors." C.  Based on the 12/21 T-con, 'Attachment 1' will be replaced with the the existing Attachment 1 in the "Overview for Patient and Caregivers", as the additional information in the 'healthcare provider version' (e.g. NDC numbers) is not necessary.  However, this will not affect the inclusion of  NDC numbers in Pharmacy Chain Enrollment form and the Outpatient Pharmacy Enrollment form; no changes will be made to these forms.   D. We have identified the following typos in the Web Prototype document.  The Web Prototype document does not need to be updated at this time. The TRIG should ensure that these corrections are made before the actual website is launched. a.      Page 3 - Education Program, last line - "LOGGED" or "LOGGED IN" rather than "LOGED"         b.      Page 4 - Chain Pharmacy Enrollment Process                 "CHAIN PHARMACY ENROLLMENT CONFIRMATION" rather than "CHAIN ENROLLMENT CONFIRMATION"         c.      Page 5                 i.      MY ACCOUNT - INPATIENT PHARMACY                         "INPATIENT PHARMACY LOOKUP RESULTS" rather than "INPATIENT PHARMACY LOOKUP RESULT"                 ii.     MY ACCOUNT - OUTPATIENT PHARMACY                         A).     "OUTPATIENT PHARMACY LOOKUP" rather than "PHARMACY LOOKUP"                         B).     "OUTPATIENT PHARMACY LOOKUP RESULTS" rather than "PHARMACY LOOKUP RESULTS" Reference ID: 3064652 FDA_5447         d.      Page 7                 i.      Adverse Reactions, last sentence - "… to each TIRF medicine." rather than "… to each TIRF medicines."                 ii.     Medication Guide, last paragraph, second sentence - "Medication Guides …" rather than "Medication guides …"         e.      Page 9                 i.      Paragraph which begins "When dispensing, …" - Penultimate sentence - "… each time they begin …" rather than                         "… each they begin …"                 ii.     Adverse Reactions, last sentence - "… for each TIRF medicine." rather than "… for each TIRF medicines."                 ii.     Medication Guide, last paragraph, second sentence - "Medication Guides …" rather than "Medication guides …"         f.      Page 10 - Penultimate sentence - "Important Safety Information (ISI) is included …"  [add "(ISI"]         g.      Page 18                 i.      First paragraph, last sentence - "the Providers" rather than ""the Providers"                 ii.     NDC numbers, fifth line - "55253-0072-30" and "55253-0073-30" rather than "555230072-30" and "55523-0073-30"                         iii.    Paragraph which begins "Pharmacy acknowledges …", last sentence - "reserve" rather than "reserves"         h.      Page 52 - Boxed text - "TIRF medicines for" rather than "TIRF medinces for"         i.      Page 53 - Boxed text - "headquarters" rather than "headquaters"         j.      Page 62                 i.      First bullet, first sentence - "agonist" rather than "against"                 ii.     Fourth bullet - "opioids" rather than "opioid"         k.      Page 64 - Second bullet - "dangerous increase" rather than "dangerous increases"         l.      Page 68 - Lazanda, third column - "cancer breakthrough pain episode" rather than "breakthrough pain cancer episode"         m.      Page 70 - Tell the patient, sixth bullet - "medicine" rather than "medicne"         n.      Page 73, first line - "Logged" or "Logged in" rather than "Loged"         o.      Page 86 - The answers to the Knowledge Assessment are not correct as seen on this page are they supposed to be?         p.      Page 93                 i.      First line - "medicines" rather than "medicinces"                 ii.     Item 1 - "each TIRF medicine prescribed" rather than "each TIRF medicines prescribed" Reference ID: 3064652 FDA_5448         q.      Page 111                 i.      NDC numbers, fifth line - "55253-0072-30" and "55253-0073-30" rather than "555230072-30" and "55523-0073-30"                         ii.     Paragraph which begins "Pharmacy acknowledges …", last sentence - "reserve" rather than "reserves"         r.      Page 122                 i.      NDC numbers, fifth line - "55253-0072-30" and "55253-0073-30" rather than "555230072-30" and "55523-0073-30"                         ii.     Paragraph which begins "Pharmacy acknowledges …", last sentence - "reserve" rather than "reserves"         s.      Page 127 - The answers to the Knowledge Assessment are not correct as seen on this page - are they supposed to be?         t.      Page 132                 i.      Item 3 - "I intend to prescribe" rather than "I intend to prescribed"                 ii.     Last sentence - "state" rather than "states"         u.      Page 173 - NDC numbers, Anesta - "55253-0072-30" and "55253-0073-30" rather than "55523-0072-30" and "55523-0073-30" Please let me know if you have any questions. Thanks, Kim Kimberly Compton, R.Ph. Senior Regulatory Project Manager Division of Anesthesia, Analgesia, and Addiction  Products 301-796-1191 Please consider the environment before printing this e-mail.  If you decide to print, please make double-sided copies. FOLLOWING THIS PAGE, FDA_5450 TO FDA_5807 WITHHELD IN FULL AS B(4)/CCI (PROPOSED/DRAFT REMS WEB MATERIALS) Reference ID: 3064652 FDA_5449 --------------------------------------------------------------------------------------------------------This is a representation of an electronic record that was signed electronically and this page is the manifestation of the electronic signature. --------------------------------------------------------------------------------------------------------/s/ ---------------------------------------------------SARA E STRADLEY 12/28/2011 Reference ID: 3064652 FDA_5808 Department of Health and Human Services Food and Drug Administration Center for Drug Evaluation and Research Office of Surveillance and Epidemiology Date: December 29, 2011 To: Bob Rappaport, M.D., Director Division of Anesthesia and Analgesia Products (DAAP) Through: Claudia Karwoski, Pharm.D., Director Division of Risk Management (DRISK) From: Scientific Lead, Doris Auth, Pharm.D., Risk Management Analyst DRISK Review Team Megan Moncur, M.S., Team Leader Gita A. Toyserkani, Pharm.D., MBA, Senior Risk Management Analyst Subject: Drug Name (Established Name): Final Risk Evaluation and Mitigation Strategy (REMS) review for Subsys (Fentanyl) sublingual spray Subsys, fentanyl citrate sublingual spray Dosage and Route: Sublingual spray 100mcg, 200mcg, 400mcg, 600mcg, and 800mcg Therapeutic Class: Opioid Application Type/Number: NDA 202-788 Applicant: Insys Therapeutics, Inc Effective Date: 12/29/20111 Reference ID: 3065316 FDA_5809 1. INTRODUCTION The purpose of this review is to evaluate the proposed Risk Evaluation and Mitigation Strategy (REMS) for Subsys (Fentanyl) sublingual spray. 1.1 Product Overview Subsys is a formulation of fentanyl, a potent opioid analgesic, for administration as a spray via the sublingual route, and a member of a group of Schedule II controlled substances that the Agency has collectively termed transmucosal immediate release fentanyl (TIRF) products. Actiq, Fentora, Onsolis, Abstral, and Lazanda are approved TIRF medicines indicated for the management of breakthrough pain in patients with cancer, 18 years of age and older, who are already receiving and who are tolerant to opioid therapy for their underlying persistent cancer pain. These formulations deliver fentanyl rapidly via the oral mucosa in a variety of dosage forms. Drug delivery in this manner eliminates first pass metabolism that occurs with oral formulations and results in increased bioavailability. Subsys is the first of the transmucosal products to be delivered as a spray for sublingual administration. The time to maximum concentration for Subsys varies with dosage, ranging from 0.67 hours for the 600mcg dose to 1.25 hours for the 100 and 200mcg doses. The proposed indication for Subsys the same as for the approved TIRF medicines. The rate and maximum plasma concentrations vary considerably between the available TIRF medicines, as well as Subsys, therefore, they are not interchangeable. Lifethreatening respiratory depression may occur at any dose in the following situations: in patients who are not opioid tolerant, if accidentally consumed by a child or for anyone for whom they were not prescribed, or if used for the treatment of acute or postoperative pain. It is because of these risks that a REMS is required for the transmucosal immediaterelease fentanyl products. 1.2 Regulatory and Review History for Subsys and the TIRF REMS Subsys has been part of ongoing and interrelated discussions within the Agency that included the review teams for other TIRF products, and often involved Senior Management. Following receipt of the Subsys NDA, Insys Therapeutics, Inc became a member of the TIRF REMS Industry Working Group (TRIG) and began collaborating with the group to align the Single-Shared System (SSS). Following are highlights of key regulatory actions and communications regarding the REMS for Subsys as well as the TIRF REMS Single Shared System: 17 August 2010: Pre-NDA meeting, fentanyl sublingual spray (FSS), (IND 72-411, meeting minutes memo dated 10/18/10, Author: Compton, K) Insys was instructed to submit a REMS for FSS with their original NDA submission which must include a Medication Guide, Elements to Assure Safe Use, an Implementation System, and a Timetable for Assessments. The development of a Single Shared REMS for all manufacturers of TIRF products was discussed and Insys was encouraged to work with other manufacturers towards this goal. 28 October 2010: Meeting with all TIRF medicine sponsors (innovator and generic), to inform them that, in order to minimize the burden on healthcare providers and patients, a Effective Date: 12/29/20112 Reference ID: 3065316 FDA_5810 single-shared REMS should be implemented for the TIRF medicines (Meeting Minutes: memo dated 01/03/2011; Author: Adeolu, Abolade A). 12 November 2010: REMS Notification letters were issued to all of the sponsors of the pending and approved TIRF products. The letters described the elements of the TIRF single-shared REMS that could be standardized and implemented for each TIRF product individualy, and ultimately across all TIRF medicines collectively, as a single-shared REMS. 04 March 2011: Subsys (NDA 202788; Seq No. 000) submitted. The original submission included a proposed REMS similar to the approved individual REMS for Abstral. 09 December 2011: Submission of the TIRF REMS SSS to the NDAs for Actiq, Fentora, Onsolis, Abstral, Lazanda, and to the ANDA for Fentanyl Citrate Oral Transmucosal Lozenge. 28 December 2011: Approval of the TIRF REMS Single Shared System for the above TIRF medicines.  28 December 2011: Submission of SUBSYS REMS (NDA 202-788, Sequence 028). 2. MATERIALS REVIEWED 2.1 Data and Information Sources reviewed Subsys Proposed REMS, submitted on December 28, 2011 Subsys Prescribing Information, original submitted on 3/4/11, revision December 28, 2011 2.2 Data and Information Sources referenced DRISK Final REMS Review for the TIRF Products, Reviewer Toyserkani GA, dated December 27, 2011. 3. RESULTS OF REVIEW OF PROPOSED SUBSYS RISK EVALUATION AND MITIGATION STRATEGY Insys submitted the proposed REMS for Subsys which is identical to the approved TIRF REMS SSS with the following exceptions:  The Subys product name was added to the following documents: o All Letters (Dear Healthcare Provider, Inpatient and Outpatient Pharmacy, and Distributor) o Patient Prescriber Agreement o REMS Supporting Document  Attachment 1 of the REMS (approved TIRF products) was also updated to include Subsys and is appended to the following documents: o All Overviews (Prescriber, Outpatient and Inpatient Pharmacy, Patient and Caregiver, Wholesaler) Effective Date: 12/29/20113 Reference ID: 3065316 FDA_5811 All Enrollment forms (Prescriber, Outpatient, Chain, and Inpatient Pharmacy, and Wholesaler/Distributor) 0 Product speci?c information on Subsys was added to the Educational Program. Please refer to the December 27, 2011 Final REMS Review which describes the REMS document and REMS appended materials and provides concmrence with the single-shared REMS for the TIRF medicines.1 4. DISCUSSION AND RECOMMENDATIONS The DRISK Review Team ?nds the proposed REMS for SUBSYS, as submitted December 28, 2011 (and appended to this review) to be acceptable, and recommends approval. Following approval of Subsys, each sponsor of an approved TIRF product in the will submit a proposed REMS modi?cation which will be updated to include Subsys. 1 Toyserkani G. Final REMS Review for Transmucosal Immediate-Release Fentanyl (TIRF) Products (NDAS 22-510. 20-747. 21-947. 22-569. 21-947. and 22-266). dated December 27. 2011. Effective Date: 12/29/201 14 FOLLOWING THIS PAGE, TO WITHHELD IN FULL AS FDA 5812 Reference 3065316 REMS WEB MATERIALS) --------------------------------------------------------------------------------------------------------This is a representation of an electronic record that was signed electronically and this page is the manifestation of the electronic signature. --------------------------------------------------------------------------------------------------------/s/ ---------------------------------------------------DORIS A AUTH 12/29/2011 CLAUDIA B KARWOSKI 12/30/2011 concur Reference ID: 3065316 FDA_5922 Risk Evaluation and Mitigation Strategy (REMS) Memorandum U.S. FOOD AND DRUG ADMINISTRATION CENTER FOR DRUG EVALUATION AND RESEARCH Office of Drug Evaluation II Division of Anesthesia, Analgesia, and Addiction Products NDA/BLA #s: PRODUCTS: APPLICANT: FROM: 202788 Subsys (fentanyl sublingual spray) Insys, Inc. Bob A. Rappaport, M.D., Director, Division of Anesthesia, Analgesia, and Addiction Products DATE: January 2, 2011 Section 505-1 of the Federal Food, Drug, and Cosmetic Act (FDCA) authorizes FDA to require the submission of a risk evaluation and mitigation strategy (REMS) if FDA determines that such a strategy is necessary to ensure that the benefits of the drug outweigh the risks (section 505-1(a)). Section 505-1(a)(1) provides the following factors: (A) (B) (C) (D) (E) (F) The estimated size of the population likely to use the drug involved; The seriousness of the disease or condition that is to be treated with the drug; The expected benefit of the drug with respect to such disease or condition; The expected or actual duration of treatment with the drug; The seriousness of any known or potential adverse events that may be related to the drug and the background incidence of such events in the population likely to use the drug; Whether the drug is a new molecular entity (NME). After consultations between the Office of New Drugs and the Office of Surveillance and Epidemiology, we have determined that a REMS that includes elements to assure safe use is necessary for fentanyl sublingual spray to ensure that the benefits of the drug outweigh the risks of misuse, abuse, addiction, overdose, and serious complications due to medication errors. In reaching this determination we considered the following: A. The estimated number of patients in the United States with breakthrough cancer pain is between 1 to 2 million. This estimate is based upon the number of patients with cancer in the US (American Cancer Society), the proportion of cancer patients with moderate to severe pain1, and the proportion of cancer patients with breakthrough pain2. 1 Marieke HJ, van den Beuken-van Everdingen MHJ, deRijke JM, Kessels SG, Schouten HC, van Kleef M, Patijn. High prevalence of pain in patients with cancer in a large population-based study in The Netherlands. Pain 2007;132:312-320. Reference ID: 3065862 FDA_5923 B. The patients for this product are cancer patients with pain that cannot be adequately controlled using around-the-clock oral or transdermal opioids alone. Many of these patients have multiple concurrent complications of their underlying disease and therapy. C. The expected benefit of the drug to patients is that the delivery system is different from the existing oral transmucosal fentanyl products. This product is the first of these products to be formulated as a sublingual spray. D. The expected duration of treatment with the drug will be from days for the sickest patients who are preterminal, to months for patients with less tumor burden and longer prognoses for survival. E. The most serious of the known adverse events that are related to the use of fentanyl-containing products include death, respiratory depression, and CNS depression which occur primarily if the product is not used properly. In addition to the aforementioned risks, fentanyl sublingual spray, as other fentanyl-containing products, can have a potential to increase intracranial pressure and induce bradyarrythmias. F. Fentanyl sublingual spray is not a new molecular entity In accordance with section 505-1 of FDCA and under 21 CFR 208, FDA has determined that a Medication Guide is required for Subsys (fentanyl sublingual spray). FDA has determined that Subsys (fentanyl sublingual spray) poses a serious and significant public health concern requiring the distribution of a Medication Guide. The Medication Guide is necessary for patients’ safe and effective use of Subsys (fentanyl sublingual spray). FDA has determined that Subsys (fentanyl sublingual spray) is a product for which patient labeling could help prevent serious adverse effects and that has serious risks relative to benefits of which patients should be made aware because information concerning the risks could affect patients’ decisions to use, or continue to use Subsys (fentanyl sublingual spray). The elements of the REMS will be a Medication Guide, elements to assure safe use including prescribers training, pharmacies certification, and dispensing Subsys (fentanyl sublingual spray) to patients with evidence or other documentation of safe use conditions, an implementation system, and a timetable for submission of assessments of the REMS. Bob A. Rappaport, M.D. Director, Division of Anesthesia, Analgesia, and Addiction Products 2 Portenoy RK, Payne D, Jacobsen P. Breakthrough pain: characteristics and impact in patients with cancer pain. Pain 1999;81:129-134. Reference ID: 3065862 FDA_5924 This is a representation of an electronic record that was signed electronically and this page is the manifestation of the electronic signature. ls/ SARA STRADLEY 01/02/2012 BOB A RAPPAPORT 01/03/2012 FOLLOWING THIS PAGE, TO WITHHELD IN FULL AS REMS WEB MATERIALS) Reference ID: 3065862 February 8, 2012 Bob Rappaport, M.D. Director Division of Anesthesia, Analgesia and Addiction Products Food and Drug Administration Central Document Room 5901-B Ammendale Road Beltsville, MD 20705-1266 Re: NDA 202788: SUBSYS (Fentanyl Sublingual Spray) for the management of breakthrough cancer pain Sequence No. 0033: Amendment to the Approved REMS Dear Dr. Rappaport: Reference is made to Insys Therapeutics, Inc.’s New Drug Application 202788 for SUBSYS (Fentanyl Sublingual Spray) approved on January 4, 2012. Reference is also made to Kim Compton’s email to Susan Franks of the TIRF REMS Industry Working Group dated February 1, 2012, which contained instructions regarding the language to use in this cover letter, as well as Kim Compton’s email on December 22, 2011 regarding Risk Evaluation and Mitigation Strategy (REMS) documentation. The SUBSYS REMS was approved on January 4, 2012 as part of the single, shared REMS system developed for the transmucosal immediate-release fentanyl (TIRF) class of products. The REMS system has not been implemented yet and at this time, no data are available to generate an assessment report. This submission contains the following aggregate files: • REMS and Materials • Supporting Document This submission also contains the following individual files: • REMS • Prescriber Overview • Education Program • Knowledge Assessment • Prescriber Enrollment Form • PPAF • Patient and Caregiver Overview • FAQ • Website • HCP Letter • Outpatient Pharmacy Overview • Chain Pharmacy Overview • Inpatient Pharmacy Overview FDA_6136 • • • • • • • • Outpatient Pharmacy Enrollment Form Chain Pharmacy Enrollment Form Inpatient Pharmacy Enrollment Form Outpatient Pharmacy Letter Inpatient Pharmacy Letter Distributor Letter Distributor Enrollment Form Supporting Document_Word Should you have any questions or require additional information, please contact me by phone at +1 202.730.4101, facsimile at 202.833.7057, or email at lauren.wind@weinberggroup.com. Very truly yours, Lauren H. Wind, MPH Senior Consultant The Weinberg Group Inc. LHW/lw FDA_6137 Electronic Submission Specifications This submission is compliant with FDA's Guideline for Industry: Providing Regulatory Submissions in Electronic Format - Human Pharmaceutical Product Applications and Related Submissions Using the eCTD Specifications (June 2008). All files were checked and verified to be free of viruses prior to transmission through the electronic submission gateway. Anti-Virus Program Program Version Virus Definition Date Submission Size Symantec Endpoint Protection 11.0.5002.333 2/8/2012 rev. 4 Approx. 26 MB The IT point of contact for this submission is: Name Phone Number Email Address Lauren Wind 202-730-4101 Lauren.Wind@weinberggroup.com FDA_6138 MEMORANDUM DEPARTMENT OF HEALTH AND HUMAN SERVICES PUBLIC HEALTH SERVICE FOOD AND DRUG ADMINISTRATION CENTER FOR DRUG EVALUATION AND RESEARCH DATE: June 1, 2012 TO: Division of Anesthesia, Analgesia, and Addiction Products; Office of Generic Drugs FROM: Division of Risk Management; Office of Regulatory Policy SUBJECT: Documentation of sponsor agreement for TIRF REMS modification #1 APPLICATION/DRUG: NDA 020747 NDA 021947 NDA 022266 NDA 022510 NDA 022569 NDA 202788 ANDA 077312 ANDA 078907 Actiq (fentanyl citrate) oral transmucosl lozenge and its authorized generic Fentora (fentanyl buccal tablets) Onsolis (fentanyl buccal soluble film) Abstral (fentanyl) sublingual tablets Lazanda (fentanyl) nasal spray Subsys (fentanyl) sublingual spray Fentanyl Citrate Oral Transmucosal Lozenge Fentanyl Citrate Oral Transmucosal Lozenge This memo serves as documentation of agreement between OSE/DRISK and the sponsors of the TIRF REMS Access program for the first modification of the single, shared system TIRF REMS. The proposed REMS modification supplemental application was received in February 2012 for each of the above applications. The modified REMS and its appended materials approved for this modification supplement have additional changes to those proposed in the February submission. The attached documentation includes email correspondence and track changed documents indicating that FDA and the TRIG agreed on the modified REMS. The rationale for this memo of documentation is due to the time constraints of the above sponsors submitting the current modified REMS to their individual files as amendments to their supplemental applications, which could take up to two weeks. The modified REMS contains a closed system pharmacy enrollment form that must be approved in order to complete enrollment of the closed system pharmacies, formally termed integrated health care systems. Our enforcement discretion letter to the TIRF sponsors, dated March 20, 2012, says “after June 30, 2012, all Integrated Health Care Systems are enrolled in the TIRF REMS Access Program”. Reference ID: 3139338 FDA_6140 In addition to this memo, cross-reference the DRISK review dated June 1, 2012 authored by Megan Moncur. Attached Documentation Table of Contents: 1. Memorandum from TIRF REMS Industry Working Group (TRIG) 2. Email to TRIG dated May 15, 2012 proposing changes to REMS a. Clean REMS document- May 15, 2012 b. Tracked REMS document- May 15, 2012 c. Clean Patient-Prescriber Agreement Form- May 15, 2012 d. Tracked Patient-Prescriber Agreement Form- May 15, 2012 e. Clean Closed System Pharmacy Enrollment Form- May 15, 2012 f. Tracked Closed System Pharmacy Enrollment Form- May 15, 2012 3. Email from TRIG dated May 30, 2012 accepting tracked proposals and proposing new tracked changes a. Tracked REMS document- May 30, 2012 b. Tracked Patient-Prescriber Agreement Form- May 30, 2012 c. Tracked Closed System Pharmacy Enrollment Form- May 30, 2012 4. Email to TRIG dated May 31, 2012 stating DRISK agreement with the additional revisions proposed by the TRIG on May 30th Reference ID: 3139338 page 4 page 5 page 6 page 22 page 38 page 41 page 44 page 47 page 50 page 51 page 67 page 70 page 73 FDA_6141 il'lS'r'S May 31,2012 Bob Rappaport, M.D., Director Division of Anesthesia, Analgesia and Addiction Products Food and Drug Administration Central Document Room 5901-B Ammendale Road Beltsville, MD 20705-1266 Re: Transmucosal Immediate Release entanyl (T IRF) REMS - Modification 1 (Original Submissions dated February 2012) Dear Dr. Rappaport: In connection with the Amendment to the Approved REMS submitted by the individual companies which compose the TIRF REMS Industry Working Group (TRIG) in early February 2012, reference is made to the telephone communication dated May 25, 2012 between FDA, Nancy Dickinson and Megan Moncur, and myself on behalf of the TIRF REMS Industry Working Group (TRIG) in which the feedback was requested for the following documents previously provided by Darrell Jenkins in his email to Christine Kampf of the TRIG dated May 15, 2012: REMS 0 Closed System Pharmacy Enrollment Form PPAF Further reference is made to the e-mail response containing the feedback on the REMS documents submitted by myself on behalf of the TRIG on May 30, 2012 and subsequent email dated May 31, 2012 from Mark Liberatore of FDA indicating the Agency?s acceptance of the proposed modi?cations to the abovementioned documents. The TRIG (see list below) unanimously agrees with the ?nal versions of the documents forwarded to Mr. Libcratore on May 31 and respectfully requests approval for TIRF REMS Modi?cation 1. Sincerely, WWI law/Ln Willene M. Brondum Senior Manager, Regulatory Affairs cc: Archimedes Pharma, Cephalon Teva Pharmaceuticals, Covidien, Endo Pharmaceuticals, Insys Therapeutics, Inc., Meda Pharmaceuticals, Par Pharmaceutical Inc., ProStrakan, Sandoz Inc. 1077C Soul: sure 3' F'Itncl'x. 850411 ?lune! 607.910.26l7 for: FDA 6142 Reference ID: 3139338 From: To: Subject: Date: Attachments: Jenkins Darrell Comptonl Kimberly; Sullivan MatdieW' Auth DoriS' Uberatore Mark' Everett Kristen' Dickinson, Nang Clark; LemleyI Carrie; Moncurl MQan; Miller Kristen' Jenkins Darrell' Won Katherine' Racoosin Judith A FW: Documents for TRIG Tuesday, May 15, 2012 6:45:15 PM 120515 fda clean rem.doc.docx 120515 fda redline rem.doc? 120515 fda redline tjent- escriber- reement-form. 120515 fda clean 120515 +fda clean Closed S?tem Pharrn? Enrollment Form.docx 120515 +fda redline Closed 5 tem Pharm Enrollment Form. fyi From: Jenkins, Darrell Sent: Tuesday, May 15, 2012 6:41 PM To: '01an Kampf'; 'Ottinger, James' Cc: Jenkins, Darrell; Liberatore, Mark Subject: Documents for TRIG Please review the attached documents and let us know as soon as you can whether you have any questions, comments, and/or revisions. Once these documents are agreed upon, we can approve the REMS Modi?cation (including the closed system enrollment form). Redline and clean versions of the following documents are attached (note: the base documents for the redline versions are noted in the document): 1. REMS document 2. 3. Closed system enrollment form Thanks. Darrell. FOLLOWING THIS PAGE, TO WITHHELD IN FULL AS REMS WEB MATERIALS) Reference ID: 3139338 43 From: Willene Brondum To: Liberatore Mark' Jenkins Darrell' BradlgyI Sean Cc: DickinsonI Nang Clark Subject: TRIG Submlluon re: 5/15 forms Date: Wednesday, May 30, 2012 11:18:33 AM Attachments: 120515 REMS TRIG Feedback Redline.docx 120515 Closed S?em Pharmg Enrollment Form - TRIG Feedback - Redline.docx 120515 a?ent?geecn?ber?Qreement?form TRIG Feedback Redline.docx Importance: High Mr. Liberatore, On the TRIG, attached please ?nd the TRIG redline versions of the following documents FDA previously updated on May 15 to include closed system pharmacies: 0 REMS 0 Closed System Pharmacy Enrolhnent Form 0 PPAF The TRIG apologizes for the delay in returning these documents. Please do not hesitate to contact me if there are any other adjustments needed to these documents. If the documents are satisfactory as redlined, please advise and I will return the memo requested by Nancy Dickinson and Megan Moncur in our telephone conversation last Friday, May 25. Thanks very much! Willy Brondum Senior Manager, Regulatory Affairs ?1595 YMERAPEUHCS. INC 10220 South 51St Street, Suite 2, Phoenix, AZ 85044 P: (602) 910-2617 Ext. 9022 F: (602)910-2627 C: (602) 750-8039 This email and any ?les transmitted with it are con?dential and intended solely for the use of the individual or entity to whom they are addressed. If you have received this email in error please notify the system manager. This message may contain con?dential information and is intended only for the individual named. If you are not the named addressee you should not disseminate, distribute or copy this e-mail. Please notify the sender immediately by e-mail if you have received this e-mail by mistake and delete this e-mail from your system. If you are not the intended recipient you are noti?ed that disclosing, copying, distributing or taking any action in reliance on the contents of this information is strictly prohibited. FOLLOWING THIS PAGE, T0 WITHHELD IN FULL AS REMS 33 Reference ID: 3139338 WFR ATFRI AI 3? From: To: Cc: Subject: Date: Liberatore, Mark "Willene Brondum" Dickinson, Nancy Clark; Moncur, Megan; Jenkins, Darrell; Bradley, Sean RE: TRIG Submission re: 5/15 forms Thursday, May 31, 2012 9:54:47 AM Hi Willy,   The team has looked at the emailed documents from the TRIG, and agree with the proposals. Would you please send us a memo with all of the sponsors listed which states that the sponsors also agree?   Please contact me via email with any questions.   Thank You, -Mark From: Willene Brondum [mailto:wbrondum@insysrx.com] Sent: Wednesday, May 30, 2012 11:18 AM To: Liberatore, Mark; Jenkins, Darrell; Bradley, Sean Cc: Dickinson, Nancy Clark Subject: TRIG Submission re: 5/15 forms Importance: High Mr. Liberatore,   On the TRIG, attached please find the TRIG redline versions of the following documents FDA previously updated on May 15 to include closed system pharmacies:   ·          REMS ·          Closed System Pharmacy Enrollment Form ·          PPAF The TRIG apologizes for the delay in returning these documents.  Please do not hesitate to contact me if there are any other adjustments needed to these documents.  If the documents are satisfactory as redlined, please advise and I will return the memo requested by Nancy Dickinson and Megan Moncur in our telephone conversation last Friday, May 25.   Thanks very much!   Willy Brondum Senior Manager, Regulatory Affairs 10220 South 51st Street, Suite 2, Phoenix, AZ 85044 P: (602) 910-2617 Ext. 9022  *  F: (602) 910-2627  *  C: (602) 750-8039 wbrondum@insysrx.com *  www.insysrx.com     Reference ID: 3139338 FDA_6211 This email and any files transmitted with it are confidential and intended solely for the use of the individual or entity to whom they are addressed. If you have received this email in error please notify the system manager. This message may contain confidential information and is intended only for the individual named. If you are not the named addressee you should not disseminate, distribute or copy this e-mail. Please notify the sender immediately by e-mail if you have received this e-mail by mistake and delete this e-mail from your system. If you are not the intended recipient you are notified that disclosing, copying, distributing or taking any action in reliance on the contents of this information is strictly prohibited. Reference ID: 3139338 FDA_6212 --------------------------------------------------------------------------------------------------------This is a representation of an electronic record that was signed electronically and this page is the manifestation of the electronic signature. --------------------------------------------------------------------------------------------------------/s/ ---------------------------------------------------MEGAN M MONCUR 06/01/2012 concur Reference ID: 3139338 FDA_6213 Department of Health and Human Services Public Health Service Food and Drug Administration Center for Drug Evaluation and Research Office of Surveillance and Epidemiology Office of Medication Error Prevention and Risk Management Risk Evaluation and Mitigation Strategy (REMS) Modification Review Date: June 01, 2012 Reviewer(s): Division of Risk Management (DRISK) Megan Moncur, M.S. Senior Risk Management Gita A. Toyserkani, Pharm.D., MBA, Senior Risk Management Analyst Doris Auth, Pharm.D., Risk Management Analyst Team Leader: Megan Moncur, M.S. DRISK Division Director Claudia Manzo, Pharm.D. DRISK Drug Name(s): See table below Therapeutic Class: Opioid Agonist: Transmucosal Immediate-Release Fentanyl (TIRF) Products Drug Name Dosage and Route Sublingual tablet Oral transmucosal lozenge Buccal tablet Application Type/Number NDA 22-510 Supplement Number S-005 Applicant/ Sponsor Prostrakan, Inc. TSI # Abstral (fentanyl) Actiq NDA 20-747 S-034 Cephalon, Inc. (fentanyl citrate) Fentora NDA 21-947 S-015 Cephalon, Inc. 290 (fentanyl citrate) Lazanda Nasal spray NDA 22-569 S-007 Archimedes (fentanyl) Pharma US Inc. Onsolis Buccal NDA 22-266 S-009 Meda (fentanyl) soluble film Pharmaceuticals Subsys Sublingual NDA 202-788 S-003 Insys Therapy (fentanyl) spray *** This document contains proprietary and confidential information that should not be released to the public. ** Reference ID: 3139386 FDA_6214 1 INTRODUCTION The purpose of this review is to document the Office of Surveillance and Epidemiology (OSE), Division of Risk Management’s (DRISK) acceptance of the proposed Risk Evaluation and Mitigation Strategy (REMS) Modification for the Transmucosal Immediate-Release Fentanyl (TIRF) Single-Shared REMS. This is the first modification that has been proposed for the TIRF REMS. 1.1 BACKGROUND TIRF medicines are short-acting fentanyl products indicated for the management of breakthrough pain in adults with cancer who are routinely taking other opioid pain medicines around-the-clock for pain. The approved TIRF medicines include: Abstral (fentanyl) sublingual tablet, Actiq (fentanyl citrate) oral transmucosal lozenge Fentora (fentanyl citrate) buccal tablet, Lazanda (fentanyl) nasal spray, Onsolis (fentanyl) buccal soluble film, Subsys (fentanyl) sublingual spray, and Approved generic equivalents of these products 1.2 REGULATORY AND OTHER RELEVANT HISTORY A single-shared REMS program, the TIRF REMS Access Program, was approved on December 28, 2011. Subsequently, an enforcement discretion letter was issued 1 that detailed conditions and timelines that were to be met during transition to the full operation of the TIRF REMS, including deadlines for launch of the system (March 12, 2012), for implementation of a solution to allow closed system pharmacies 2 to participate in the TIRF REMS (April 30, 2012), and for enrolling closed system pharmacies in the TIRF REMS (June 30, 2012). 1 There have been two enforcement discretion letters issued for the TIRF REMS. The first letter was issued on January 31, 2012, but was superseded. The second letter was approved in DARRTS on March 20, 2012, but, inadvertently, not provided to TIRF sponsors until May 11, 2012. 2 For the purpose of the TIRF REMS, a closed system pharmacy is defined as an outpatient pharmacy that uses a pharmacy management system that does not support the process of electronically transmitting the validation and claim information currently required by the TIRF REMS Access program. For example, some pharmacies that are part of integrated healthcare delivery systems may qualify as closed system pharmacies. Reference ID: 3139386 FDA_6215 At the time of the TIRF REMS approval, an NDA for the TIRF product Subsys was under review. On January 4, 2012, Subsys received agency approval; FDA notified the TIRF sponsors that they would be required to submit a REMS Modification to include the newly approved product. The TIRF sponsors proposed additional, editorial revisions to include in the REMS modification. Consequently, a REMS Modification was also required to be submitted for Subsys. The REMS Modifications were received in February 2012 3. On February 29, 2012, DAAAP notified DRISK that new packaging configurations for Subsys were under review, and therefore, new NDC numbers would need to be included in the relevant TIRF materials. During a teleconference on March 16, 2012, FDA notified the TIRF sponsors of the need to revise the NDC numbers, and informed them of other required editorial changes (e.g. including the correct version of Attachment 1). The TIRF sponsors provided verbal approval for FDA to incorporate these minor changes on their behalf, thus precluding the need for another submission. On March 12, 2012, the single-shared system was launched. Shortly thereafter, multiple offices across the agency were contacted by external stakeholders with concerns and questions about the TIRF REMS. Many of the concerns raised referenced operational issues, which the TIRF sponsors were able to effectively manage and address within the context of the approved REMS. However, to address a concern that was raised about the privacy language in the Patient-Provider Agreement Form (PPAF) 4, FDA determined that changes to the REMS would be required. To expedite approval of these changes, they were incorporated in the February 2012 REMS modification that was already under review. On April 12, 2012, the TIRF sponsors submitted (via e-mail) a proposed closed system pharmacy enrollment form. To ensure that enrollment of closed system pharmacies could be completed prior to the June 30th deadline, as specified in the enforcement discretion letter, FDA revised the REMS document to incorporate information about the closed system pharmacy solution and the new enrollment form. FDA informed the TIRF sponsors that the closed system revisions, and the revisions to the PPAF would be added to the REMS modification already under review; redline versions of the revised documents were e-mailed to the sponsors on May 15, 2012. The TIRF sponsors documented their acceptance of all revisisions proposed by FDA in a memo that they e-mailed to OSE Project Manager, Mark Liberatore, on May 31, 2012 (see Memorandum to File, dated June 01, 2012). All revisions are discussed further in Section 3. 3 The REMS Modifications were submitted to each TIRF sponsor’s NDA between February 08 and 13, 2012 4 The stakeholder, who was both a physician and pain patient, expressed concern that language in the PPAF was asking people to relinquish their rights to their protected health information (PHI) in order to have access to TIRF medications. Reference ID: 3139386 FDA_6216 2 MATERIALS REVIEWED 2.1 DATA AND INFORMATION SOURCES The following materials were reviewed: • • NDA submissions: Drug Name Application Type & Number Supplement Number FDA Received Date Abstral NDA 22-510 S-005 February 13, 2012 Actiq NDA 20-747 S-034 February 08, 2012 Fentora NDA 21-947 S-015 February 09, 2012 Lazanda NDA 22-569 S-007 February 10, 2012 Onsolis NDA 22-266 S-009 February 10, 2012 Subsys NDA 202-788 S-003 February 08, 2012 Submission(s) sent via e-mail to the OSE Project Management staff o April 12, 2012; e-mail to Darrell Jenkins (closed system enrollment form) o May 30, 2012; e-mail to Mark Liberatore (additional revisions proposed by TIRF sponsors) The following materials were referenced: • 2.2 May 31, 2012; e-mail to Mark Liberatore (Memo from TIRF sponsors) ANALYSIS TECHNIQUES The REMS modification was reviewed for conformance with Title IX, Subtitle A, Section 901 of the Food Drug Administration Amendments Act of 2007 (FDAAA), and to ensure that only FDA-required changes were made. Reference ID: 3139386 FDA_6217 3 RESULTS OF REMS MODIFICATION REVIEW An overview of the documents that have been revised under this REMS Modification is included in the table below. For additional details, refer to Appendix 1 for redline versions of all revised documents. Document Name Overview of revision(s) REMS document > Added revised PPAF attestation > Added information about closed system pharmacies, and the related enrollment form > Removed the word ‘proposed’ from the coversheet Attachment 1 > Added Subsys to the list of products PPAF > Revised attestation and privacy language to address stakeholder concerns Closed System Pharmacy Enrollment Form > New form Pharmacy Enrollment Forms (Outpatient and Chain) > NDC#s for Subsys were added and subsequently revised Education Program > Updated product-specific information to include Subsys Letters (Outpatient Pharmacy, Inpatient Pharmacy, and Distributor) >Subsys added to the list of products mentioned in the letters 4 > Replaced submitted version of Attachment 1 (which includes extraneous information) with version that only lists the names of the TIRF products DISCUSSION & CONCLUSION In conclusion, the revisions proposed in the TIRF REMS modification (submitted by individual TIRF sponsors between February 8 through 13, 2012), and described in Section 3 above, are acceptable. 5 RECOMMENDATIONS DRISK recommends approval of the TIRF REMS modification submitted in February 2012, and appended to this review (see Appendix 2). Reference ID: 3139386 FDA_6218 APPENDIX 1 Redline Versions of Revised Documents FOLLOWING THIS PAGE, TO WITHHELD IN FDA 6219 Reference ID: 3139386 FULL AS REMS WEB MATERIALS) --------------------------------------------------------------------------------------------------------This is a representation of an electronic record that was signed electronically and this page is the manifestation of the electronic signature. --------------------------------------------------------------------------------------------------------/s/ ---------------------------------------------------MEGAN M MONCUR 06/04/2012 ROBERT B SHIBUYA 06/04/2012 I concur (signing for Claudia Manzo). Reference ID: 3139386 FDA_6394 September 25, 2012 Bob Rappaport, M.D. Director Division of Anesthesia, Analgesia and Addiction Products Food and Drug Administration Central Document Room 5901-B Ammendale Road Beltsville, MD 20705-1266 Re: NDA 202788: SUBSYS™ (fentanyl sublingual spray) for the management of breakthrough cancer pain Sequence No. 0041: TIRF REMS Modification #2 Dear Dr. Rappaport: Reference is made to Insys Therapeutics, Inc.’s New Drug Application 202788 for SUBSYS (fentanyl sublingual spray) approved on January 4, 2012. Reference is also made to Mark Liberatore’s e-mail dated June 28, 2012 in which he provided an overview of the additional changes needed to incorporate closed system pharmacies into the TIRF REMS Access Program for pre-submission review by Wednesday, July 25, 2012. The following files were transmitted to Mark Liberatore via email on July 24, 2012, but FDA requested that this information be formally submitted to the NDA. In response to this request, the following revised files are provided in this sequence: • Chain Pharmacy Enrollment Form • Closed System Pharmacy Overview • Education Program • FAQ • Outpatient Pharmacy Enrollment Form • Outpatient Pharmacy Letter • REMS (Please note: There is one difference from the previous submission made in July. In Section III a reference “ANDA” Sponsors was added.) • TIRF Supporting Document Should you have any questions or require additional information, please contact me by phone at +1 202.730.4101, facsimile at 202.833.7057, or email at lauren.wind@weinberggroup.com. Very truly yours, Lauren H. Wind, MPH Senior Consultant The Weinberg Group Inc. LHW/lw FDA_6395 Electronic Submission Specifications This submission is compliant with FDA's Guideline for Industry: Providing Regulatory Submissions in Electronic Format - Human Pharmaceutical Product Applications and Related Submissions Using the eCTD Specifications (June 2008). All files were checked and verified to be free of viruses prior to transmission through the electronic submission gateway. Anti-Virus Program Program Version Virus Definition Date Submission Size Symantec Endpoint Protection 11.0.5002.333 9/23/2012 rev. 8 Approx. 1.5 MB The IT point of contact for this submission is: Name Phone Number Email Address Lauren Wind 202-730-4101 Lauren.Wind@weinberggroup.com FDA_6396 Department of Health and Human Services Public Health Service Food and Drug Administration Center for Drug Evaluation and Research Of?ce of Surveillance and Epidemiology Of?ce of Medication Error Prevention and Risk Management Interim Comments on Risk Evaluation and Mitigation Strategy (REMS) Set 1 Date: Reviewers: Team Leader: February 1, 2013 Division of Risk Management Division Director: Claudia Manzo, Pharm.D. Drug Name(s): See Table below Therapeutic Class: Opioid Agonist Dosage and Route: Transmucosal Immediate-Release Fentanyl (TIRF) Kimberly Lehrfeld, Phann.D., Risk Management Analyst Division of Risk Management Reema Mehta, Phann.D., M.P.H. Division of Risk Management Drug Dosage and Application Supplement Applicant/ TSI Name Route Type/Number Number Sponsor Abstral Sublingual NDA 22-510 S-007 Prostrakan, Inc. 290 (fentanyl) tablet Actiq Oral NDA 20-747 S-O37 ephalon, Inc. 290 (fentanyl transmucosal citrate) lozenge Fentora Buccal tablet NDA 21-947 8-01 7 ephalon, Inc. 290 (fentanyl citrate) Lazanda Nasal spray NDA 22-569 S-OOS Archimedes 290 (fentanyl) Phanna US Inc. Onsolis Buccal soluble NDA 22-266 S-012 Meda 290 (fentanyl) ?lm Pharmaceuticals Subsys Sublingual NDA 202-788 S-004 Insys Therapy 290 (fentanyl) spray This document contains proprietary and con?dential information that should not be released to the public. Reference ID: 3254767 CONTENTS 1 INTRODUCTION ....................................................................................................... 1 1.1 Background .......................................................................................................... 1 1.2 Regulatory History: .............................................................................................. 2 2 MATERIALS REVIEWED ........................................................................................ 3 3 SUMMARY OF APPLICANT’S PROPOSED REMS MODIFICATION ................ 3 3.1 REMS Document and REMS Appended Materials ............................................. 3 3.2 REMS Supporting Document: ............................................................................. 8 4 ADDITIONAL MODIFICATIONS PROPOSED BY THE AGENCY ..................... 8 4.1 REMS document .................................................................................................. 8 4.2 REMS Appended Materials ............................................................................... 10 4.3 REMS Supporting Document............................................................................. 14 5 RECOMMENDATIONS FOR THE REVIEW DIVISION ...................................... 14 6 COMMENTS FOR THE APPLICANT .................................................................... 15 6.1 REMS Document (see Attachment 1 for redlined REMS document): .............. 15 6.2 REMS Appended material ................................................................................. 16 6.3 REMS Supporting Document............................................................................. 21 6.4 General Comments ............................................................................................. 21 ATTACHMENTS: ............................................................................................................ 22 Reference ID: 3254767 FDA_6398 1 INTRODUCTION This is an interim review of the proposed modification of the Transmucosal Immediate Release Fentanyl (TIRF) Risk Evaluation and Mitigation Strategy (REMS) submitted by the Transmucosal REMS Industry Group sponsors (TRIG) between September 24 – 28, 2012 (See Section 2, Table 1) 1.1 BACKGROUND TIRF medicines are short-acting fentanyl products indicated for the management of breakthrough pain in adults with cancer who are routinely taking other opioid pain medicines around-the-clock for pain. The approved TIRF medicines include: • Abstral (fentanyl) sublingual tablet, • Actiq (fentanyl citrate) oral transmucosal lozenge • Fentora (fentanyl citrate) buccal tablet, • Lazanda (fentanyl) nasal spray, • Onsolis (fentanyl) buccal soluble film, • Subsys (fentanyl) sublingual spray, and • Approved generic equivalents of these products The TIRF medicines are approved under a single shared system REMS that has the following goals: The goals of the TIRF REMS Access program are to mitigate the risk of misuse, abuse, addiction, overdose and serious complications due to medication errors by: 1. Prescribing and dispensing TIRF medicines only to appropriate patients, which includes use only in opioid-tolerant patients. 2. Preventing inappropriate conversion between TIRF medicines. 3. Preventing accidental exposure to children and others for whom it was not prescribed. 4. Educating prescribers, pharmacists, and patients on the potential for misuse, abuse, addiction, and overdose of TIRF medicines. The elements included in the program are Medication Guides for each individual TIRF medicine and the following Elements to Assure Safe Use (ETASU): Reference ID: 3254767 • Healthcare providers who prescribe TIRF medicines for outpatient use are specially certified • TIRF medicines will only be dispensed by pharmacies that are specially certified FDA_6399 • TIRF medicines will only be dispensed for outpatient use with evidence or other documentation of safe-use conditions. The timetable for submission of TIRF REMS Access Program assessments is at 6 and 12 months from the date of the initial REMS approval, and annually thereafter. 1.2 REGULATORY HISTORY: A single shared REMS program, the TIRF REMS Access Program, was approved on December 28, 2011. On June 30, 2012, the TIRF REMS was modified for the following reasons: • Modification of the REMS document to allow participation of Closed System Pharmacies and inclusion of a closed system enrollment form. • Addition of information about Subsys (fentanyl sublingual spray), whose REMS was newly approved on January 4, 2012, to pharmacy enrollment forms, DHCP letters, the education program, and Attachment 1 of the REMS. On June 28, 2012, FDA requested a modification to the TIRF REMS to incorporate information about the closed system pharmacies into the appended REMS materials. The TRIG was sent the following request via email: I. Create the following document: 1. TIRF REMS Program Overview for Closed System Pharmacies II. Modify the following documents: 1. REMS Document Minor modification on page 11 to add the new Overview to the list 2. FAQ Add the following or a similar question: What if our pharmacy's management system cannot communicate with the TIRF REMS Access program (e.g. does not electronically transmit claims information)? You will need to contact the TIRF REMS Access program at 1-866-822-1483 to see if you qualify to enroll as a "closed system pharmacy". 3. Website Please provide feedback and/or a proposal as to what closed system pharmacy information and/or which documents will be posted on the TIRF REMS Website (we note your e-mail to Kimberly Compton on 6/22/2012 that stated that the enrollment form will not be posted, given that a pharmacy needs to be validated as being a closed system pharmacy prior to their enrollment). For example, closed-system pharmacies that are seeking to enroll in the TIRF REMS should understand that Reference ID: 3254767 FDA_6400 there is a mechanism for them to participate in the REMS; however, it also needs to be clear this mechanism is not an option for pharmacies that can process through their pharmacy management system. 4. Supporting Document 2 • Update to include information and a section on 'Closed System Pharmacies' • Update your REMS Assessment Plan and TIRF REMS Access Non-Compliance Plan MATERIALS REVIEWED Table 1: NDA submissions Drug Name Application Type & Number Abstral® NDA 22-510 ® Actiq NDA 20-747 Fentora® NDA 21-947 ® Lazanda NDA 22-569 Onsolis® NDA 22-266 ® Subsys NDA 202-788 FDA Received Date September 28, 2012 September 26, 2012 September 26, 2012 September 28, 2012 September 26, 2012 September 25, 2012 Supplement Number 0 3 1 5 12 4 REMS documents included in these submissions: 3 • TIRF REMS document • TIRF REMS Supporting document • TIRF REMS Closed System Pharmacy Overview • TIRF REMS Patient-Prescriber Agreement Form (PPAF) • TIRF REMS Frequently Asked Questions (FAQs) SUMMARY OF APPLICANT’S PROPOSED REMS MODIFICATION 3.1 3.1.1 REMS DOCUMENT AND REMS APPENDED MATERIALS Closed System Pharmacy Overview Document As requested by FDA, a reference to the Closed System Pharmacy Overview document was added to page 11. Additionally, a Closed System Pharmacy Overview document was added as an appended REMS material, which contains a similar format as the other overview documents contained within the program. Reviewer Comment: Upon review, it was determined the Closed System Pharmacy Overview document could benefit from revisions to improve clarity and flow. As a result, the document was revised (see Attachment 11). Additionally, the Agency has Reference ID: 3254767 FDA_6401 included a request for the TRIG to implement similar changes to the overview documents for the other stakeholders, as applicable. 3.1.2 Patient Prescriber Agreement Form (PPAF) 1. Removal of patient phone number as a mandatory field necessary for patient enrollment On August 30, 2012, the TRIG provided the Agency with the following request via email: Some TIRF sponsors have received complaints from physicians indicating that the current requirement for the patient’s phone number to be populated on the PPAF is affecting their practice of medicine. Because the patient phone number is not used by McKesson for anything specific at this point, the TRIG proposes removing it as a requirement for PPAF completion. As this is a minor change, McKesson is able to make the change to the system so that the phone number is not a required field and when the full REMS is ultimately filed to the DMF, the actual form will then be changed to delete the space for inputting the patient’s phone number. Reviewer Comment: On September 20, 2012, an email was sent to the TRIG acknowledging the TRIG’s intention to stop requiring a patient phone number in order to enroll patients. The form will be revised as part of this modification. 2. Changes in attestations in PPAF: In September 2012, the TRIG notified FDA they have received several complaints from TIRF-enrolled physicians that the attestation language in the PPAF regarding the requirement that a patient “is currently using around the clock opioid medication” and “is opioid tolerant” in order to be deemed eligible to use a TRIF medicine is restricting prescriber’s use of medical judgment in the care of their patients. As of November 29, TRIG reported the following: • 4 prescribers have altered the PPAF to indicate their intention to prescribe to non-opioid tolerant patient and as a result these patients have not been allowed to enroll in the TIRF REMS Access Program or receive TIRF medicine. • Reference ID: 3254767 2 prescribers have written letters about cancer patient that had been on TIRF products without any around-the-clock opioids for at least 7 years, prior to the TIRF REMS implementation, and now do not have access to this medicine. FDA_6402 • TRIG has received informal feedback from other prescribers that indicate these concerns may be more widespread. Reviewer Comment: DAAAP has also received informal feedback from physicians expressing the same sentiments that have been communicated by physicians to the TRIG sponsors. The TIRF REMS Implementation Team recommends the following revision to the PPAF to address the concern regarding patient access while maintaining the integrity of the program and protecting the safety of patients: Prescriber Attestations: 1. My patient is currently using around the clock opioid medication and has been for at least one (1) week. I understand that TIRF medicines are indicated only for the management of breakthrough pain in patients with cancer, who are already receiving, and who are tolerant to, around-the-clock opioid therapy for their underlying persistent pain. 2. I understand that TIRF medicines are contraindicated for use in opioid non-tolerant patients, and know that fatal overdose can occur at any dose. 3. My patient is opioid tolerant. I understand that pPatients considered opioid-tolerant are those who are regularly taking at least: 60 mg oral morphine/day; 25 micrograms transdermal fentanyl/hour; 30 mg oral oxycodone/day; 8 mg oral hydromorphone/day; 25 mg oral oxymorphone/day; or an equianalgesic dose of another opioid for one week or longer. Patient Attestations: Removal of the following attestation: I understand that before I can take any TIRF medicine, I must be regularly using another opioid pain medicine, around the clock, for my constant pain. Maintenance of this revised attestation: I understand that if I stop taking my another opioid pain medicine that I have been taking regularly, around-the-clock, opioid pain medicine for my constant pain, then I must also stop taking my TIRF medicine. The TIRF REMS Access Program still provides a consistent message and important restrictions that will adequately mitigate the risk of misuse, abuse, addiction, overdose and serious complications due to medication errors. These revisions will decrease the impact of the REMS on the practice of medicine and allow patients who were appropriately treated prior to the implementation of the TIRF REMS Access Program to continue to receive TIRF medicines. Additionally, as a result of these revisions to the PPAF, the TIRF REMS document was edited to reflect the revised attestations. Reference ID: 3254767 FDA_6403 3.1.3 Prescriber Enrollment Form On July 20, 2012, the TRIG requested feedback from the FDA regarding the necessity of closed-system prescribers to enroll in the TIRF REMS Access program. The TRIG had that approximately 30-35 providers at the National Institutes of Health (NIH) were unable to register in the TIRF REMS because the prescribers at their institution do not have a DEA number, which is required to enroll in the TIRF REMS Access program. Some government closed system healthcare systems do not require prescribers to have an individual DEA number (i.e. NIH and Department of Defense). Reviewer Comment: On July 30, 2012, FDA provided a response via email stating that all prescribers that are prescribing TIRF medications for outpatient use must enroll in the TIRF REMS Access program. A teleconference was scheduled for August 9, 2012, to discuss these issues. The purpose of the teleconference was to discuss how the DEA number is currently used by the TRIG, and if the closed system prescribers have another unique identifier which can be used in the same way as the DEA number. TRIG indicated that the DEA number is used for three purposes. • to validate that the identity of the prescriber, • to validate that a prescriber is eligible to prescribe schedule CII drugs, and • to provide real time information to the pharmacy during the claims adjudication process that a prescriber is enrolled in the TIRF REMS Access program. TRIG acknowledged that, since closed systems do not adjudicate claims, the National Provider Identifier (NPI) number could potentially be used in lieu of the DEA number for validation of these prescribers. An NPI number is unique to an individual prescriber, available online, and easy and free to obtain Furthermore, the TRIG proposed a three step solution to address the problem. • Enrollment: closed system prescribers can by-pass the need to populate the DEA field when enrolling by using a faxed form instead of the website. Therefore, the prescriber would only be required to provide their respective NPI number. • Prescription verification via the call center: TRIG could modify the fields required for prescription verification to only include the NPI number for the prescriber when closed system pharmacies call the call center • Validation of no individual DEA number: TRIG may require documentation from the closed systems that states their prescribers are not required to have individual DEA numbers in order to prescriber CII medications. On September 27, 2012, the TRIG informed FDA via email that the TRIG approved the first 2 options above on September 18, 2012. On October 15, 2012, TRIG informed FDA the enrollment solution should be in place by November 15, 2012. The solutions proposed by the TRIG are acceptable by the FDA. Reference ID: 3254767 FDA_6404 3.1.4 TIRF REMS Frequently Asked Questions (FAQ) document As requested by FDA, the following language was added: “What if our pharmacy’s management system cannot communicate with the TIRF REMS Access program (e.g. does not electronically transmit claims information)? You will need to contact the TIRF REMS Access program at 1-866-822-1483 to see if you qualify to enroll as a “closed system pharmacy.” 3.1.5 Website Prototype In response to the Agency’s request for feedback and/or proposal for what closed system pharmacy information/documents should be posted on the TIRF REMS Website, the TRIG proposes: 1. On Page 165 “Resources for Pharmacies”, the addition of a link to the Closed System Pharmacy Overview 2. On Page 167 “About the TIRF REMS Access Program”, the inclusion of a new paragraph to educate closed-system pharmacies seeking to enroll in the TIRF REMS: “Closed System Pharmacies (e.g. integrated healthcare systems that dispense for outpatient use with pharmacy management systems unable to support the process of electronically transmitting the validation and claim information required) will not be eligible to purchase or dispense TIRF medicines unless an authorized pharmacist has reviewed the TIRF REMS Access Education Program and successfully completed the Knowledge Assessment and enrollment form. Enrolled pharmacies can only dispense prescriptions for TIRF medicines if the TIRF REMS Access program is contacted and authorization is received prior to the dispensing of a TIRF prescription.” 3. In addition to the requested additions to the Website, the TRIG notified the Agency of its intention to implement the following updates: · Page 18: Update Subsys NDCs on Terms and Conditions · Page 68: Education Slide ‐ Update Subsys and Onsolis Trade Names · Page 92: Spelling correction #6 (labeled) · Page 101: Spelling correction #3 (labeled) · Page 109: Spelling correction #3 (labeled) · Page 110: Update Subsys NDCs on Terms and Conditions · Page 120: Spelling correction #3 (labeled) · Page 121 Update Subsys NDCs on Terms and Conditions · Page 132: Revised Language for PPAF in #12 · Page 133: Remove PPAF Phone Number Requirement · Page 134: Revise Language for PPAF · Page 171: Replace with 'short‐version' of Attachment 1 Reference ID: 3254767 FDA_6405 · · Pages 90/99/107/118: Registration Complete update language to provide appropriate next step Pages 92/101/109/120:Attestationmake the attestation requirement more prominent 3.1.6 Education Program TRIG corrected Onsolis and Subsys product names on page 19, in the table. 3.1.7 Chain Pharmacy and Outpatient Pharmacy Enrollment Forms The TRIG proposed the following edits: 1. Corrected the spelling of “labeled” 2. Capitalized medicine in the name of the document : ‘List of TIRF Medicines Available only through the TIRF REMS Access program’ 3. Added the Par Pharmaceutical NDC numbers 49884-459-55, 49884-46055, 49884-461-55, 49884-462-55, 49884-463-55, and 49884-464-55 to the form’s Terms & Conditions. 3.2 REMS SUPPORTING DOCUMENT: As requested by FDA, the REMS Supporting Document was updated to add a specific section, “Closed System Pharmacies,” as well as to include references and information pertaining to closed system pharmacies in the REMS Assessment Plan and TIRF REMS Access Non-Compliance Plan. 4 ADDITIONAL MODIFICATIONS PROPOSED BY THE AGENCY 4.1 REMS DOCUMENT 1. Clarification of the definition for wholesaler distributors FDA received an inquiry from a third party logistics (3PL) provider regarding their need to enroll in the TIRF REMS program. The 3PL was informed by the TRIG that they needed to enroll in the TIRF REMS as a wholesale distributor. However, the 3PL expressed concern regarding their ability to comply with all of the REMS requirements (e.g., providing an EDI 867 transmission). Therefore, DRISK and Office of Compliance met internally to assess the role of 3PLs in the drug supply chain and to assess the need to revise the TIRF REMS to better clarify the types of wholesaler distributors that must enroll in the program. The following criteria were identified to improve clarity regarding wholesaler distribution enrollment: Reference ID: 3254767 • Allow 3PLs who do not take title to or direct the sale or disposition of TIRFs to participate in the TIRF supply chain without enrolling in the REMS. • Ensure that 3PLs who do take title to or direct the sale or disposition of TIRFs are enrolled in the REMS, and comply with the REMS requirements. FDA_6406 • Maintains the current restricted distribution channel for TIRFs without creating unnecessary barriers. The proposed changes to the Implementation System in the REMS document include the addition of the underlined text below: TIRF Sponsors will ensure that wholesaler distributors who take title to or direct the sale or disposition of TIRF medicines to persons other than a consumer or patient are enrolled in the TIRF REMS Access program and comply with the program requirements for wholesale distributors. 2. Clarification of types of Outpatient pharmacies The current classification and nomenclature for pharmacies described in the approved TIRF REMS document is unclear. The REMS document states “Outpatient Pharmacies”, “Chain Pharmacies” and “Closed System Pharmacies” dispense TIRF medicines for outpatient use. However, the current “Outpatient Pharmacy” category does not include Chain and Closed System pharmacies. Therefore, the current “outpatient pharmacy” category should be renamed “nonchain outpatient pharmacy” to clarify how it is distinct from the other pharmacies which dispense for outpatient use. In addition, the non-chain, chain and closed system pharmacies should be subcategories under the “Outpatient Pharmacies” category, since they all dispense for outpatient use and are required to verify the prescriber and patient are enrolled prior to dispensing TIRF medications. The “Inpatient Pharmacy” category should not be revised. The 3 subcategories of outpatient pharmacies (non-chain, chain and closed system) should be clearly defined in the REMS document since they all have different enrollment procedures. First, there are different enrollment forms for each. In addition, the processes for enrolling additional closed system and chain pharmacy locations are different from each other and from how a unique nonchain pharmacy enrolls. In summary, the TIRF REMS document should be revised to: • • • Reference ID: 3254767 Rename the current “outpatient pharmacy” category “Non-chain Outpatient Pharmacy.” Re-organize by creating an “Outpatient Pharmacy” category with the following subcategories: - non-chain outpatient pharmacy, - chain outpatient pharmacy and - closed system outpatient pharmacy Define the subcategories of Outpatient Pharmacies that have different enrollment forms and processes FDA_6407 The majority of the proposed changes regarding outpatient pharmacies to the TIRF REMS document are in Section II.B.2. and are shown below. In addition, “outpatient pharmacy” was changed to “non-chain outpatient pharmacy” throughout the remainder of the document. See attachment 1 for all changes in the REMS document. 2. TIRF medicines will only be dispensed by pharmacies that are specially certified. a. TIRF Sponsors will ensure that TIRF medicines will only be dispensed by certified pharmacies. To become certified to dispense TIRF medicines, each pharmacy must be enrolled in the TIRF REMS Access program. b. Each pharmacy will be required to designate an authorized pharmacy representative (chain pharmacy and closed system pharmacies) or authorized pharmacist (outpatient non-chain and inpatient pharmacies) to complete enrollment on behalf of the pharmacy(s). c. There are different enrollment requirements for : • outpatient pharmacies (e.g., retail, mail order, institutional outpatient pharmacies that dispense for outpatient use), including chain pharmacies, but excluding closed system pharmacies (see definition below). i. chain pharmacy Retail, mail order or institutional outpatient pharmacies that are part of 10 or more stores with the same ownership ii. non-chain pharmacy Retail, mail order, or institutional outpatient pharmacies that have less than 10 stores owned by a single entity iii. closed system pharmacies pharmacy For the purposes of this REMS, a closed system pharmacy is defined as an outpatient pharmacy that uses a pharmacy management system that does not support the process of electronically transmitting the validation and claim information currently required by the TIRF REMS Access program. For example, some pharmacies that are part of integrated healthcare delivery systems may qualify as closed system pharmacies. • 4.2 Reference ID: 3254767 inpatient pharmacies (e.g., hospitals, in-hospital hospices, and long-term care facilities that dispense for inpatient use) REMS APPENDED MATERIALS FDA_6408 The titles of the following REMS appended materials were revised as a result of the proposed clarifications to the REMS document described in Section 4.1: Previous Title Outpatient Pharmacy Enrollment Form Chain Pharmacy Enrollment Form Closed System Pharmacy Enrollment Form Inpatient Pharmacy Enrollment Form Outpatient Pharmacy Overview Document Chain Pharmacy Overview Document 4.2.1 Proposed New Title Non-Chain Outpatient Pharmacy Enrollment Form Chain Outpatient Pharmacy Enrollment Form Closed System Outpatient Pharmacy Enrollment Form Inpatient Pharmacy Enrollment Form Non-Chain Outpatient Pharmacy Overview Document Chain Outpatient Pharmacy Overview Document Patient Prescriber Agreement Form (PPAF): Revision of Patient Privacy Notice statement on PPAF: Upon review of the PPAF, it was noted that the patient privacy statement below implies the TIRF REMS Access program collects and reports to the FDA safety data including any “side effects” an enrolled patient experiences with a TIRF medication. However, the adverse event data reported for patients receiving TIRF medication is de-identified to protect the patient’s identity. Therefore, in order to accurately reflect an enrolled patient’s health information that is evaluated and reported to the FDA, the following revisions are proposed: I allow the TIRF REMS Access program to receive, use, and share my Health Information, using a unique, encrypted identifier instead of my name, in order to: a. Evaluate and report to the FDA about the proper use of TIRF medicines and the effectiveness of the TIRF REMS Access program. b. Report to the FDA, about side effects from TIRF medicines and the TIRF REMS Access program effectiveness. 4.2.2 Pharmacy and Prescriber Enrollment Forms Addition of a field for Knowledge Assessment Authorization Number Upon review of pharmacy and prescriber enrollment forms, it was noted that the form did not include a field for enrolled healthcare providers to indicate their Knowledge Assessment online training authorization number. The forms also do not provide instruction for submission of the Knowledge Assessment quiz if it was completed on paper. The following forms were revised to allow stakeholders to include this information on enrollment forms: Reference ID: 3254767 FDA_6409 • • • • • Chain Outpatient Pharmacy Enrollment Form Non-Chain Outpatient Pharmacy Enrollment Form Closed System Outpatient Pharmacy Enrollment Form Inpatient Pharmacy Enrollment Form Prescriber Enrollment Form 4.2.3 Dear Healthcare Provider Letters (DHCP) The TIRF REMS document states the DHCP letters should remain on the TIRF REMS Access Website for 1 year after approval on December 27, 2012. Therefore, the links to the DHCP letters can be removed from the website. 4.2.4 Frequently Asked Questions (FAQ) document 1. Revision of FAQ document as a result of the revisions to the REMS document described in Section 4.1. 2. Revision of text to reflect the completion of the transition phase from individual REMS programs to a single shared TIRF REMS program. After September 12, 2012, any pharmacy that has not agreed to the shared terms and conditions must re-enroll. When the TIRF REMS was approved on December 29, 2012, pharmacies which were enrolled in individual TIRF medication REMS programs were automatically transitioned into the single shared system TIRF REMS Access Program. In order to remain in the program and continue dispensing TIRF medicines, outpatient pharmacies had until September 12, 2012 to submit a signed shared terms and conditions document to the TIRF REMS Access Program. After that date, any pharmacy that had not complied would be inactivated and would be required to reenroll in the TIRF REMS Access Program in order to dispense TIRF medications. In order to reflect this, the FAQ document has been revised as follows: “If I have previously enrolled in an individual TIRF REMS do I need to enroll in the shared TIRF REMS Access Program?” All pharmacy enrollment information was transferred from the individual TIRF REMS to the TIRF REMS Access Program on March 12, 2012. If the authorized pharmacist or pharmacy representative logged onto the TIRF REMS Access Program website and agreed to the shared program terms and conditions before September 12, 2012, your pharmacy is able to order and dispense all TIRF medications. If the authorized pharmacist or pharmacy representative has not agreed to the shared terms and conditions, your pharmacy will need to enroll in the TIRF REMS Access Program (see how to enroll below). You will be required to re-enroll in the shared TIRF REMS Access Program two (2) years after your last enrollment in an individual Reference ID: 3254767 FDA_6410 REMS program if you wish to continue dispensing these products. You will be notified by the TIRF REMS Access program in advance of the need to re-enroll. Outpatient Pharmacy Beginning mm/dd/yyyy, your enrollment information will be automatically entered into the new shared TIRF REMS Access program, but you will need to agree to the shared program terms and conditions before you can order and dispense all TIRF medicines. Your enrollment in the shared TIRF REMS Access program allows dispensing of all TIRF medicines that are covered under the TIRF REMS Access program. The website for the shared TIRF REMS Access program can be accessed at www.TIRFREMSaccess.com. Once the program is available, you will have six months to agree to the shared program terms and conditions. Until you agree to the shared program terms and conditions, you will be able to dispense those TIRF medicines with an individual REMS program, in which you were previously enrolled. However, if you do not to agree to the shared program terms and conditions within six months, you will no longer be able to order or dispense any TIRF medicine. You can use your existing secure user ID and password from any one of your individual REMS programs to access the TIRF REMS Access website at www.TIRFREMSaccess.com. The user ID and password you use to initially log on will become your permanent user ID and password for the shared TIRF REMS Access program. Once you have logged in, review your account information and make any necessary updates. You are required to agree to the shared program terms and conditions to complete enrollment for the new shared program. You will be required to re enroll in the shared TIRF REMS two (2) years after your last enrollment in an individual REMS program if you wish to continue dispensing these products. You will be notified by the TIRF REMS Access program in advance of the need to re enroll. Chain Pharmacy Beginning mm/dd/yyyy, your enrollment information will be automatically entered into the new shared TIRF REMS Access program, but you will need to execute a TIRF REMS Access program contract with their switch provider before you can order and dispense all TIRF medicines. Reference ID: 3254767 FDA_6411 Once the program is available, you will have six months to sign the new TIRF REMS Access program contract. Until you sign the new contract, you will be able to dispense those TIRF medicines with an individual REMS program, in which you were previously enrolled. However, if you do not sign the new contract within six months, you will no longer be able to order or dispense any TIRF medicine. You can use your existing secure user ID and password from any one of your individual REMS programs to access the TIRF REMS Access website at www.TIRFREMSaccess.com The user ID and password you use to initially log on will become your permanent user ID and password for the shared TIRF REMS Access program. You will be required to re enroll in the shared TIRF REMS Access program two years after your last enrollment in an individual TIRF REMS if you wish to continue dispensing these products. You will be notified by the TIRF REMS Access program in advance of the need to re enroll. 4.3 REMS SUPPORTING DOCUMENT REMS Assessment Plan changes will be addressed in the current REMS Assessment which was submitted on December 21, 2012. 5 RECOMMENDATIONS FOR THE REVIEW DIVISION We recommend that the following comments on the TRIF REMS Access Program proposal be sent to the TRIG. Please request that the TRIG respond to these comments as soon as possible to facilitate further review for this submission. The comments below are based on DRISK’s preliminary review of the REMS modification proposal for TIRF products. Appended to this review is the REMS modification proposal and the following REMS materials including our track changes (see Attachment 1 – 12). 1. REMS Document 2. Non-Chain Outpatient Pharmacy Enrollment Form 3. Chain Outpatient Pharmacy Enrollment Form 4. Closed System Outpatient Pharmacy Enrollment Form 5. Inpatient Pharmacy Enrollment Form 6. Prescriber Enrollment Form 7. Frequently Asked Questions (FAQ) 8. Non-Chain Outpatient Pharmacy Overview 9. Chain Outpatient Pharmacy Overview Reference ID: 3254767 FDA_6412 10. Closed System Outpatient Pharmacy Overview Document 11. Patient Prescriber Agreement Form 12. TIRF REMS Access Program Education Program 13. Website “Resources for Pharmacists” page 165 14. Website “Registration Identifier Question 2” pages 50-53 The applicant should be reminded that the REMS Supporting Document must be consistent with all changes made to the REMS document. 6 6.1 COMMENTS FOR THE APPLICANT REMS DOCUMENT See Attachment 1 for redlined REMS document 1. Revision of REMS document to reflect the clarification of the types of outpatient pharmacies. The current classification of pharmacies described in the approved TIRF REMS should be revised to improve clarity. The current “outpatient pharmacy” category should be renamed “non-chain outpatient pharmacy” to clarify how it is distinct from the other pharmacies which dispense for outpatient use. In addition, the non-chain, chain and closed system pharmacies should be subcategories under the “Outpatient Pharmacies” category, since they all dispense for outpatient use and are required to verify the prescriber and patient are enrolled prior to dispensing TIRF medications. The “Inpatient Pharmacy” category should not be revised. The 3 subcategories of outpatient pharmacies (non-chain, chain and closed system) should be clearly defined in the REMS document since they all have different enrollment procedures. In summary, the TIRF REMS document should be revised to: • • • Rename the current “outpatient pharmacy” category “Non-chain Outpatient Pharmacy.” Re-organize by creating an “Outpatient Pharmacy” category with the following subcategories: - non-chain outpatient pharmacy, - chain outpatient pharmacy and - closed system outpatient pharmacy Define the enrollment forms and procedures for the subcategories of Outpatient Pharmacies In addition, “outpatient pharmacy” was changed to “non-chain outpatient pharmacy” throughout the remainder of the document. See Attachment 1 for all changes in the REMS document. Reference ID: 3254767 FDA_6413 2. Clarification of the definition for wholesaler distributor FDA received an inquiry from a third party logistics (3PL) provider regarding their need to enroll in the TIRF REMS program. FDA identified the following criteria to improve clarity regarding wholesaler distribution enrollment: • Allow 3PLs who do not take title to or direct the sale or disposition of TIRFs to participate in the TIRF supply chain without enrolling in the REMS. • Ensure that 3PLs who do take title to or direct the sale or disposition of TIRFs are enrolled in the REMS, and comply with the REMS requirements. • Maintains the current restricted distribution channel for TIRFs without creating unnecessary barriers. Therefore, revise the TIRF REMS to include the addition of the underlined text below: II. C. 1. TIRF Sponsors will ensure that wholesaler distributors who take title to or direct the sale or disposition of TIRF medicines to persons other than a consumer or patient are enrolled in the TIRF REMS Access program and comply with the program requirements for wholesale distributors. 3. Revision of Section II.B.1.b.ii.m. : Patient – Prescriber attestations to reflect changes described below in Section 6.2.5 Patient - Prescriber Agreement Form (see Attachment 11 for redlined version of the PPAF). 6.2 REMS APPENDED MATERIAL 6.2.1 TIRF REMS ACCESS Program Enrollment Forms See Attachments 2 - 6 for redlined Enrollment forms 1. Revision of Titles of Enrollment Forms As a result of the above clarification in the REMS document, the titles of the following TIRF REMS Access program enrollment forms must be revised as indicated: Previous Title Outpatient Pharmacy Enrollment Form Chain Pharmacy Enrollment Form Closed System Pharmacy Enrollment Form Reference ID: 3254767 Proposed New Title Non-Chain Outpatient Pharmacy Enrollment Form Chain Outpatient Pharmacy Enrollment Form Closed System Outpatient Pharmacy Enrollment Form FDA_6414 Inpatient Pharmacy Enrollment Form Inpatient Pharmacy Enrollment Form 2. Addition of a field for Knowledge Assessment Authorization Number to Pharmacy and Prescriber Enrollment Forms The forms do not include a field for enrolled healthcare providers to indicate their Knowledge Assessment online training authorization number. The forms also do not provide instructions for submission of the Knowledge Assessment quiz if it was completed on paper. Update the following forms with this information. • • • • • 6.2.2 Non-Chain Outpatient Pharmacy Enrollment Form Chain Outpatient Pharmacy Enrollment Form Closed System Outpatient Pharmacy Enrollment Form Inpatient Pharmacy Enrollment Form Prescriber Enrollment Form TIRF REMS Access program Frequently Asked Questions (FAQ) document See Attachment 7 for redlined FAQ document 1. Revision of FAQ document as a result of the revisions to the REMS document. 2. Revision of text to reflect the completion of the transition phase from individual REMS programs to a single shared TIRF REMS program. After September 12, 2012, any pharmacy that has not agreed to the shared terms and conditions must re-enroll. In order to reflect the new terms of enrollment after September 12, 2012, the following FAQ question has been revised as indicated below: “If I have previously enrolled in an individual TIRF REMS do I need to enroll in the shared TIRF REMS Access Program?” All pharmacy enrollment information was transferred from the individual TIRF REMS to the TIRF REMS Access Program on March 12, 2012. If the authorized pharmacist or pharmacy representative logged onto the TIRF REMS Access Program website and agreed to the shared program terms and conditions before September 12, 2012, your pharmacy is able to order and dispense all TIRF medications. If the authorized pharmacist or pharmacy representative has not agreed to the shared terms and conditions, your pharmacy will need to enroll in the TIRF REMS Access Program (see how to enroll below). You will be required to re-enroll in the shared TIRF REMS Access Program two (2) years after your last enrollment in an individual REMS program if you wish to continue dispensing these Reference ID: 3254767 FDA_6415 products. You will be notified by the TIRF REMS Access program in advance of the need to re-enroll. 6.2.3 Non-Chain and Chain Outpatient Pharmacy Overview See Attachment 8 and 9 for redlined Outpatient Pharmacy Overviews 1. Revision of titles of Overview Documents As a result of the above clarification to the REMS document, the titles of the following TIRF REMS Access program Overview documents must be revised as indicated:. Previous Title Outpatient Pharmacy Overview Document Chain Pharmacy Overview Document Proposed New Title Non-Chain Outpatient Pharmacy Overview Document Chain Outpatient Pharmacy Overview Document 2. Revision of Non-Chain Outpatient Overview text to reflect the revisions in the REMS document to clarify types of outpatient pharmacies. 3. Revision of text to reflect after September 12, 2012 any pharmacy that has not agreed to the shared terms and conditions must re-enroll (see comment above regarding FAQs for details) 4. Revise the Non-Chain and Chain Outpatient Pharmacy Overviews to follow the same format as the revised Closed System Outpatient Pharmacy Overview document (See Attachment 10 for redlined Closed System Outpatient Pharmacy Overview) 6.2.4 Closed System Outpatient Pharmacy Overview See Attachment 10 for redlined Closed System Outpatient Pharmacy Overview Document 1. The submitted Closed System Outpatient Pharmacy Overview has been revised to improve clarity and flow. 2. Revise the Non-Chain and Chain Outpatient Pharmacy Overviews to follow the same format as the revised Closed System Outpatient Pharmacy Overview document 6.2.5 Patient- Prescriber Agreement Form (PPAF) See Attachment 11 for redlined PPAF 1. Revision of Patient Privacy Notice statement on PPAF Reference ID: 3254767 FDA_6416 The patient privacy statement below implies the TIRF REMS Access program collects and reports to the FDA safety data including any “side effects” an enrolled patient experiences with a TIRF medication. However, the reported adverse event data is de-identified to protect the patient’s identity. Therefore, in order to accurately reflect an enrolled patient’s health information that is evaluated and reported to the FDA, the following revisions are proposed: I allow the TIRF REMS Access program to receive, use, and share my Health Information, using a unique, encrypted identifier instead of my name, in order to: a. Evaluate and report to the FDA about the proper use of TIRF medicines and the effectiveness of the TIRF REMS Access program. b. Report to the FDA, about side effects from TIRF medicines and the TIRF REMS Access program effectiveness. 2. Removal of patient phone number as a requirement for patient enrollment Per FDA email sent September 20, 2012 acknowledging the TRIG’s intention to stop requiring a patient phone number in order to enroll patients, the PPAF has been modified to remove the asterisk indicating this is a required field that must be completed for enrollment. 3. Revision of PPAF Attestations In September 2012, the TRIG notified FDA they have received several complaints from TIRF-enrolled physicians that the attestation language in the PPAF regarding the requirement that a patient “is currently using around the clock opioid medication” and “is opioid tolerant” in order to be deemed eligible to use a TRIF medicine is restricting prescriber’s use of medical judgment in the care of their patients. FDA recommends the following revision to the PPAF to address the concern regarding patient access while maintaining the integrity of the program and protecting the safety of patients: Prescriber Attestations: 1. My patient is currently using around the clock opioid medication and has been for at least one (1) week. I understand that TIRF medicines are indicated only for the management of breakthrough pain in patients with cancer, who are already receiving, and who are tolerant to, around-the-clock opioid therapy for their underlying persistent pain. 2. I understand that TIRF medicines are contraindicated for use in opioid non-tolerant patients, and know that fatal overdose can occur at any dose. 3. My patient is opioid tolerant. I understand that pPatients considered opioid-tolerant are those who are regularly taking at least: 60 mg oral morphine/day; 25 micrograms transdermal fentanyl/hour; 30 mg oral Reference ID: 3254767 FDA_6417 oxycodone/day; 8 mg oral hydromorphone/day; 25 mg oral oxymorphone/day; or an equianalgesic dose of another opioid for one week or longer. Patient Attestations: Removal of the following attestation: I understand that before I can take any TIRF medicine, I must be regularly using another opioid pain medicine, around the clock, for my constant pain. Maintenance of this revised attestation: I understand that if I stop taking my another opioid pain medicine that I have been taking regularly, around-the-clock, opioid pain medicine for my constant pain, then I must also stop taking my TIRF medicine. 6.2.6 Education Program See Attachment 12 for redlined Education Program Update Onsolis and Subsys on Slide 2 to align with TRIG’s proposed revisions in the table on Slide 19: Products Covered Under this Program. 6.2.7 Dear Healthcare Provider Letters Remove links to the DHCP letters from the website. The TIRF REMS document states the DHCP letters should remain on the TIRF REMS Access Website for 1 year after approval on December 27, 2012. Therefore, the links to the DHCP letters can be removed from the website. 6.2.8 TIRF REMS Website 1. FDA acknowledges and accepts the TRIG’s intention to implement the following updates to the Website: · Page 18: Update Subsys NDCs on Terms and Conditions · Page 68: Education Slide ‐ Update Subsys and Onsolis Trade Names · Page 92: Spelling correction #6 (labeled) · Page 101: Spelling correction #3 (labeled) · Page 109: Spelling correction #3 (labeled) · Page 110: Update Subsys NDCs on Terms and Conditions · Page 120: Spelling correction #3 (labeled) · Page 121 Update Subsys NDCs on Terms and Conditions · Page 132: Revised Language for PPAF in #12 · Page 133: Remove PPAF Phone Number Requirement · Page 134: Revise Language for PPAF · Page 171: Replace with 'short‐version' of Attachment 1 · Pages 90/99/107/118: Registration Complete update language to provide appropriate next step Reference ID: 3254767 FDA_6418 · Pages 92/101/109/120:Attestationmake the attestation requirement more prominent 2. Revisions to the following pages on the website: • “Resources for Pharmacists” page 165 of Website Protocol (See Attachment 13) - Links DHCP letters removed from page - Outpatient Pharmacy defined as including Non-Chain, Chain and Closed System Pharmacies. - Definition of types of pharmacies added to page • “Registration Identifier Question 2 –Pharmacy Staff” page 50-53 of Website Protocol 3. Update the website to reflect all revisions to the TIRF REMS Access Program materials. 6.3 REMS SUPPORTING DOCUMENT The REMS Supporting Document must be consistent with all changes made to the REMS document. 6.4 GENERAL COMMENTS 1. Submit the form which will be used by Closed System Outpatient Pharmacies to validate prescriptions by completing and faxing to the TIRF REMS Access Program. 2. Submit the script used by TIRF REMS Access program call center staff when validating prescriptions for Closed System Outpatient Pharmacies. 3. What are the call center hours of operation? 4. Is validation of a Closed System Outpatient Pharmacy’s TIRF prescription possible on weekends or on weekdays when the call center is not operational? Have there been any complaints from Closed System Outpatient Pharmacies due to them not being able to dispense TIRF prescriptions when the call center is not operational? 5. Currently Closed System Outpatient Pharmacies can only validate TIRF prescriptions via phone or fax. Are there plans to provide these pharmacies with an online interface for performing the validation? Resubmission Instructions 1. Submit an amendment to the proposed TIRF REMS. 2. Include all of the REMS materials in the submission. For example, the REMS document, all materials that are appended to the REMS document (including the newly requested materials), and the REMS Supporting Document. 3. For any REMS materials that are being revised, provide both a clean and tracked changes version. Reference ID: 3254767 FDA_6419 4. Submit all REMS materials in MS Word format. a. If certain docrunents, such as the REMS website are only in PDF format, they may be submitted as such. However, our preference is that as many materials as possible be provided in MS Word. ATTACHMENTS: 1. REMS Document 2. Non-Chain Outpatient Pharmacy Enrollment Form 3. Chain Outpatient Pharmacy Enrolhnent Form 4. Closed System Outpatient Pharmacy Em?olhnent Form 5. Inpatient Pharmacy Enrolhnent Form 6. Prescriber Enrollment Form 7. Frequently Asked Questions (FAQ) 8. Non-Chain Outpatient Pharmacy Overview 9. Chain Outpatient Pharmacy Overview 10. Closed System Outpatient Pharmacy Overview Document 11. Patient Prescriber Agreement Form 12. TIRF REMS Access Program Education Program 13. Website ?Resoru?ces for Pharmacists? page 165 FOLLOWING THIS PAGE, TO WITHHELD IN FULL AS REMS FDA 5420 Reference ID: 3254767 WEB MATERIALS) --------------------------------------------------------------------------------------------------------This is a representation of an electronic record that was signed electronically and this page is the manifestation of the electronic signature. --------------------------------------------------------------------------------------------------------/s/ ---------------------------------------------------KIMBERLY LEHRFELD 02/01/2013 TIRF REMS Single Shared System Interim Comments 1 REEMA J MEHTA 02/04/2013 Reference ID: 3254767 FDA_6519 FDA Inquiry Received on 16 April 2013 to TIRF REMS Modification 2 1. Provide a rationale for revising the existing text “fatal overdose” to “fatal respiratory depression” as proposed by the TRIG to the Patient Prescriber Agreement Form, Prescriber attestation #2. “2. I understand that TIRF medicines are contraindicated for use in opioid non-tolerant patients, and know that fatal overdose respiratory depression can occur at any dose.” RESPONSE: Fatal respiratory depression is consistent with the label/ boxed warning for all TIRF medicines. 2. The revised definitions for outpatient pharmacies as proposed by the TRIG have been updated to align with industry standards to prevent confusion. Provide a response to the following: 2a. How is the term “generally”, which is included in the definitions for chain outpatient pharmacies and independent outpatient pharmacies, used to determine the appropriate category designation? RESPONSE: There is no industry standard number of stores for chain vs. independent pharmacies. The definitions allow for flexibility of pharmacies to define their pharmacy type for managing the enrollment process in the TIRF REMS Access program. 2b. Chain outpatient pharmacy: How many pharmacies with less than 10 stores under the same ownership has the TRIG enrolled as a chain pharmacy? Describe what criteria was used to enroll these pharmacies as a chain outpatient pharmacy. RESPONSE: There are four (4) chain outpatient pharmacy headquarters with less than 10 substores enrolled in the TIRF REMS Access program. The pharmacies are enrolled as chain outpatient pharmacies due to their request to have a single authorized pharmacy representative responsible for managing enrollment and training for all stores. 2c. Independent outpatient pharmacy: How many pharmacies with more than 10 stores under the same ownership has the TRIG enrolled as an independent pharmacy? Describe what criteria was used to enroll these pharmacies as an independent outpatient pharmacy. RESPONSE: There are three (3) independent outpatient pharmacies with more than 10 stores enrolled in the TIRF REMS Access program. The pharmacies are enrolled as independent outpatient pharmacies due to their request to have an authorized pharmacy representative from each store responsible for managing enrollment and training of each individual store. 3. From the website prototype (pages 124 & 136), it appears both chain outpatient pharmacies and independent outpatient pharmacies can enroll pharmacy locations and maintain a list of multiple stores in their pharmacy profile. Provide a rationale for the following: 3d. Any differences between the lists managed for independent outpatient pharmacies as compared to chain outpatient pharmacies RESPONSE: The difference is the concept of enrollment. The chain outpatient pharmacy headquarters authorized pharmacy representative can add store locations and mark them as trained on the pharmacy dashboard as appropriate. Each independent outpatient pharmacy must individually enroll and complete test transactions at the store level, regardless if the authorized pharmacist is the same across multiple stores. Pg 1 of 9 Reference ID: 3304530 FDA_6520 FDA Inquiry Received on 16 April 2013 to TIRF REMS Modification 2 Chain outpatient pharmacy headquarters manages the training status of each individual store for which they have taken responsibility whereas the authorized pharmacist for the independent outpatient pharmacy has the ability to manage the enrollment process (enrollment form, training, knowledge assessment, test transactions) for other independent pharmacies for which they are the authorized pharmacist. 3e. Why are separate enrollment forms for chain and independent outpatient pharmacies necessary if both entities can enroll multiple pharmacy locations? RESPONSE: The forms identify the pharmacy type for enrollment purposes. They differ in that the chain enrollment form allows enrollment for multiple pharmacy store locations under one chain enrollment. The independent outpatient pharmacy enrollment form only allows one store to be enrolled per form. Both enrollment forms contain the same 14 acknowledgement statements and Terms and Conditions. 4. Provide a summary of the process for stakeholder enrollment (pharmacy, prescriber) via fax. The summary should include a flowchart of the process and a description of each step within the process. Additionally, provide a response to the following: RESPONSE: Refer to prescriber, independent outpatient pharmacy, chain outpatient pharmacy, inpatient pharmacy and closed system outpatient pharmacy fax enrollment flows in the Appendix beginning on page 4. 4f. Have incomplete prescriber enrollments resulted from a prescriber’s ability to sign the enrollment form before completing the Education Program and Knowledge Assessment? If so, how many? RESPONSE: Enrollment is not deemed as complete until all enrollment requirements are met. A total of 567 prescribers submitted a signed TIRF REMS Access enrollment form prior to completing the Knowledge Assessment. 485 (85.5%) of these prescribers are currently enrolled in the TIRF REMS Access program. The TIRF REMS Access database tracks the completion of each step and upon processing, immediately notifies the stakeholder of ALL outstanding requirements (i.e.; missing signature, missing address, knowledge assessment) via the incomplete correspondence letter. 4g. If the knowledge assessment authorization number is not searchable within the TIRF REMS Access database, how is the TRIG able to identify which stakeholders have completed the assessment online after receipt of an enrollment form? RESPONSE: In clarification, although the Knowledge Assessment code is searchable, current TIRF REMS Access Call Center work instructions were created based on best practices and ease of database navigation. Upon receipt of a faxed enrollment form, the TIRF REMS Access Call Center Agent conducts a search of the TIRF REMS Access database to locate the stakeholder record. Fields used to search the TIRF REMS Access database include: name, city, state, zip code, phone number, fax number and stakeholder identifiers (DEA, NPI, state license number, NCPDP, Medicaid ID, chain ID, enrollment ID). Once the stakeholder has been identified in the TIRF REMS database, the Knowledge Assessment code will be visible if the Knowledge Assessment has been completed. Pg 2 of 9 Reference ID: 3304530 FDA_6521 FDA Inquiry Received on 16 April 2013 to TIRF REMS Modification 2 4h. Once the enrollment form is received and a stakeholder is notified of the need to complete the assessment, how does the TRIG track if it is completed? RESPONSE: The TIRF REMS Access database programmatically tracks the lifecycle of the enrollment from submission to completion regardless if the stakeholder completes the Knowledge Assessment via fax or web. The stakeholder is not enrolled until all steps are completed. 4i. The comment provided by the TRIG indicated that “…it is not required for the KA to be completed prior to the receipt of the enrollment form” is contradictory to the first attestation statement on the enrollment form which states “I have reviewed the TIRF REMS Access Education Program, including the Full Prescribing Information for each TIRF medicine, and I have completed the Knowledge Assessment…” Provide further clarification by what was meant by the TRIG’s comment. RESPONSE: To clarify TRIGs comment, stakeholders are not enrolled until all steps of the enrollment process are completed, including the Knowledge Assessment (KA). If the enrollment form is received prior to the KA, it will be processed but the stakeholder enrollment will be incomplete until a complete KA is received. 5. Patient attestation on the Patient Prescriber Agreement Form 5a. The patient attestation on the Patient Prescriber Agreement Form was revised by the TRIG. Provide a rationale for the revision to the attestation statement. RESPONSE: TRIG’s rationale for this proposed change was an attempt to adapt the following language from the TIRF Medication Guides to the language of the PPAF. “Do not use [TIRF] unless you are regularly using another opioid pain medicine around-theclock for your cancer pain and your body is used to these medicines (this means you are opioid tolerant). You can ask your healthcare provider if you are opioid tolerant.” 5b. The Agency proposes the following revisions to Attestation #2 and inclusion of the deleted attestation as attestation #3. “2. I understand that TIRF medicines should only be taken by patients who are regularly using another opioid, around-the-clock, for constant pain. opioid pain medications. I understand that before I can take any TIRF medicine, I must be opioid tolerant. If I am not taking around-the-clock opioid pain medicine, my prescriber and I have discussed the risks of only taking TIRF medicines. whether I am opioid tolerant.“ “3. I understand that if I stop taking another opioid pain medicine that I have been taking regularly , around the clock, for my constant pain, then I must also stop taking my TIRF medicine. I understand that if I stop taking my around-the-clock opioid pain medicine for my constant pain, I must stop taking my TIRF medicine.” RESPONSE: TRIG agrees with the Agency’s recommendation. The PPAF has been updated. A redlined and clean version of the revised PPAF is attached in the FDA Inquiry to Modification 2 Response email sent to the FDA on May 6, 2013. Pg 3 of 9 Reference ID: 3304530 FDA_6522 FDA Inquiry Received on 16 April 2013 to TIRF REMS Modification 2 APPENDIX – TIRF REMS Access Process Flows Pg 4 of 9 Reference ID: 3304530 FDA_6523 FDA Inquiry Received on 16 April 2013 to IMF REMS Modi?cation 2 TIRF REMS Access - Prescriber - Fax Enrollment Process Flow Reference ID: 3304530 FDA Inquiry Received on 16 April 2013 to IMF REMS Modi?cation 2 11RF REMS Access - Chain Outpatient Pharmacy - Fax Enrollment Process Flow Reference ID: 3304530 FDA Inquiry Received on 16 April 2013 to IMF REMS Modi?cation 2 TIRF REMS Access - Independent Outpatient Pharmacy - Fax Enrollment Process Flow Reference ID: 3304530 FDA Inquiry Received on 16 April 2013 to IMF REMS Modi?cation 2 TIRF REMS Access - Inpatient Pharmacy - Fax Enrollment Process Flow Reference ID: 3304530 FDA Inquiry Received on 16 April 2013 to IMF REMS Modi?cation 2 TIRF REMS Access - Closed System Outpatient Pharmacy - Enrollment Process Flow Reference ID: 3304530 --------------------------------------------------------------------------------------------------------This is a representation of an electronic record that was signed electronically and this page is the manifestation of the electronic signature. --------------------------------------------------------------------------------------------------------/s/ ---------------------------------------------------MARK A LIBERATORE 05/07/2013 Reference ID: 3304530 FDA_6529 Department of Health and Human Services Public Health Service Food and Drug Administration Center for Drug Evaluation and Research Of?ce of Surveillance and Epidemiology Of?ce of Medication Error Prevention and Risk Management Interim Comments on Risk Evaluation and Mitigation Strategy (REMS) Set 2 Date: Reviewers: Team Leader: Division Director: July 24, 2013 Drug Name(s): Therapeutic Class: Dosage and Route: Kimberly Lehrfeld, Pharm.D., Risk Management Analyst Division of Risk Management Reema Mehta, Pharm.D., M.P.H. Division of Risk Management Claudia Manzo, Pharm.D. Division of Risk Management See Table below Opioid Agonist Transmucosal Immediate-Release Fentanyl (TIRF) Drug Dosage and Application Supplement Applicant/ TSI Name Route Type/Number Number Sponsor Abstral Sublingual NDA 22-510 8-005 Galena 290 (fentanyl) tablet BioPharma Actiq Oral NDA 20-747 S-034 ephalon, Inc. 290 (fentanyl transmucosal citrate) lozenge Fentora Buccal tablet NDA 21-947 S-015 ephalon, Inc. 290 (fentanyl citrate) Lazanda Nasal spray NDA 22-569 S-OO7 Archimedes 290 (fentanyl) Phanna US Inc. Onsolis Buccal soluble NDA 22-266 S-009 Meda 290 (fentanyl) ?lm Pharmaceuticals Subsys Sublingual NDA 202-788 S-003 Insys Therapy 290 (fentanyl) spray This document contains proprietary and con?dential information that should not be released to the public. Reference ID: 3361509 CONTENTS 1 INTRODUCTION ....................................................................................................... 1 1.1 Background .......................................................................................................... 1 1.2 Regulatory History: .............................................................................................. 2 2 MATERIALS REVIEWED ........................................................................................ 5 3 Other materials informing this review ......................................................................... 5 4 SUMMARY OF APPLICANT’S PROPOSED REMS MODIFICATION ................ 5 4.1 REMS Document and REMS Appended Materials ............................................. 5 4.2 REMS Supporting Document............................................................................. 12 5 RECOMMENDATIONS FOR THE REVIEW DIVISION ...................................... 12 6 COMMENTS FOR THE APPLICANT .................................................................... 13 6.1 REMS Document ............................................................................................... 13 6.2 Patient Prescriber Agreement Form .................................................................. 13 6.3 TIRF REMS Education Program ..................................................................... 14 6.4 TIRF REMS Knowledge Assessment ................................................................ 14 6.5 REMS Supporting Document............................................................................. 14 6.6 General Comments ............................................................................................. 15 ATTACHMENTS: ............................................................................................................ 16 Reference ID: 3361509 FDA_6531 1 INTRODUCTION This is interim review set #2 of the proposed modification of the Transmucosal Immediate Release Fentanyl (TIRF) Risk Evaluation and Mitigation Strategy (REMS) submitted by the Transmucosal REMS Industry Group sponsors (TRIG) via email on March 11, 2013 and May 6, 2013. 1.1 BACKGROUND TIRF medicines are short-acting fentanyl products indicated for the management of breakthrough pain in adults with cancer who are routinely taking other opioid pain medicines around-the-clock for pain. The approved TIRF medicines include: • Abstral (fentanyl) sublingual tablet, • Actiq (fentanyl citrate) oral transmucosal lozenge • Fentora (fentanyl citrate) buccal tablet, • Lazanda (fentanyl) nasal spray, • Onsolis (fentanyl) buccal soluble film, • Subsys (fentanyl) sublingual spray, and • Approved generic equivalents of these products The TIRF medicines are approved under a single shared system REMS that has the following goals: The goals of the TIRF REMS Access program are to mitigate the risk of misuse, abuse, addiction, overdose and serious complications due to medication errors by: 1. Prescribing and dispensing TIRF medicines only to appropriate patients, which includes use only in opioid-tolerant patients. 2. Preventing inappropriate conversion between TIRF medicines. 3. Preventing accidental exposure to children and others for whom it was not prescribed. 4. Educating prescribers, pharmacists, and patients on the potential for misuse, abuse, addiction, and overdose of TIRF medicines. The elements included in the program are Medication Guides for each individual TIRF medicine and the following Elements to Assure Safe Use (ETASU): Reference ID: 3361509 • Healthcare providers who prescribe TIRF medicines for outpatient use are specially certified • TIRF medicines will only be dispensed by pharmacies that are specially certified FDA_6532 • TIRF medicines will only be dispensed for outpatient use with evidence or other documentation of safe-use conditions. The timetable for submission of TIRF REMS Access Program assessments is at 6 and 12 months from the date of the initial REMS approval, and annually thereafter. 1.2 REGULATORY HISTORY: A single shared REMS program, the TIRF REMS Access Program, was approved on December 28, 2011. On June 30, 2012, the TIRF REMS was modified for the following reasons: • Modification of the REMS document to allow participation of Closed System Pharmacies and inclusion of a closed system enrollment form. • Addition of information about Subsys (fentanyl sublingual spray), whose REMS was newly approved on January 4, 2012, to pharmacy enrollment forms, DHCP letters, the education program, and Attachment 1 of the REMS. On June 28, 2012, FDA requested a modification to the TIRF REMS to incorporate information about the closed system pharmacies into the appended REMS materials. The TRIG was sent the following request via email: I. Create the following document: 1. TIRF REMS Program Overview for Closed System Pharmacies II. Modify the following documents: 1. REMS Document Minor modification on page 11 to add the new Overview to the list 2. FAQ Add the following or a similar question: What if our pharmacy's management system cannot communicate with the TIRF REMS Access program (e.g. does not electronically transmit claims information)? You will need to contact the TIRF REMS Access program at 1-866-822-1483 to see if you qualify to enroll as a "closed system pharmacy". 3. Website Please provide feedback and/or a proposal as to what closed system pharmacy information and/or which documents will be posted on the TIRF REMS Website (we note your e-mail to Kimberly Compton on 6/22/2012 that stated that the enrollment form will not be posted, given that a pharmacy needs to be validated as being a closed system pharmacy prior to their enrollment). For example, closed-system pharmacies that are seeking to enroll in the TIRF REMS should understand that Reference ID: 3361509 FDA_6533 there is a mechanism for them to participate in the REMS; however, it also needs to be clear this mechanism is not an option for pharmacies that can process through their pharmacy management system. 4. Supporting Document • Update to include information and a section on 'Closed System Pharmacies' • Update your REMS Assessment Plan and TIRF REMS Access Non-Compliance Plan On February 4, 2013, FDA provided questions for the TRIG and Interim Comments Set #1 (K Lehrfeld REMS Review, February 2, 2013) On March 11, 2013, TRIG emailed FDA their response to FDA questions (Appendix1). In addition to the response to the FDA’s questions, the email included the following documents. Revised REMS materials • REMS Document • REMS Supporting Document (including the TIRF REMS Web Prototype Screen Capture as a separate document) • TIRF REMS Education Program • Knowledge Assessment • Patient Prescriber Agreement Form • Frequently Asked Questions (FAQ) • Enrollment Forms (Independent Outpatient Pharmacy, Chain Outpatient Pharmacy, Closed System Outpatient Pharmacy, Inpatient Pharmacy, Prescriber, Distributor) • OverviewForms (Independent Outpatient Pharmacy, Chain Outpatient Reference ID: 3361509 New REMS Material Summaries of Changes Documents The TIRF REMS Prescription Authorization Request form TIRF REMS Web Prototype Changes document Email contained a summary of global changes to the TIRF REMS materials (see Appendix 2) FDA_6534 Pharmacy, Closed System Outpatient Pharmacy, Inpatient Pharmacy, Patient and Caregiver, Prescriber) On April 16, 2013, FDA emailed an information request (IR) to the TRIG addressing the following issues. 1. Provide a rational for revising the existing text “fatal overdose” to “fatal respiratory depression” as proposed by the TRIG to the Patient Prescriber Agreement Form, prescriber attestation #2. 2. Provide a rational for using the term “generally” in the definitions for chain and independent outpatient pharmacies. 3. Clarification of the website prototype (pages 124 & 136), which appear to show both chain outpatient pharmacies and independent outpatient pharmacies can enroll pharmacy locations and maintain a list of multiple stores in their pharmacy profile. 4. Provide a summary of the process for stakeholder enrollment (pharmacy, prescriber) via fax. Specifically, the Agency asked the TRIG to identify how many prescribers who enrolled via fax did not complete enrollment due to the KA not being included with the enrollment from. 5. The Agency proposed revisions to patient attestation #2 and inclusion of the deleted attestation #3. We requested TRIG provide adequate rational for any proposed revisions if they do not agree with the revised proposal. May 6, 2013, TRIG emailed the response to the IR (Appendix 3) and the following revised documents to the FDA. Revised REMS materials • Patient Prescriber Agreement Form • Independent Outpatient Pharmacy Enrollment Form • Chain Outpatient Pharmacy Enrollment Form • REMS Supporting document (and appended TIRF REMS Web Prototype) Reference ID: 3361509 New REMS Material Summaries of Changes Documents The TIRF REMS Prescription Authorization Request form Email containing a summary of TRIG proposed revisions to the REMS documents (see Appendix 4) TIRF REMS Web Prototype Changes document (see Appendix 5) FDA_6535 2 3 4 MATERIALS REVIEWED • March 11, 2013 submission, via email • May 6, 2013 submission, via email OTHER MATERIALS INFORMING THIS REVIEW • DRISK TIRF REMS Review (K Lehrfeld February 1, 2013) • Fentora DRISK Review (K. Lehrfeld February 21, 2013) SUMMARY OF APPLICANT’S PROPOSED REMS MODIFICATION REMS DOCUMENT AND REMS APPENDED MATERIALS 4.1 4.1.1 REMS document 1. TRIG revised the category for “Non-chain” Outpatient Pharmacies to “Independent” Outpatient Pharmacies in order to align with industry standard pharmacy terminology. The REMS document text and appended REMS material text was revised accordingly. In addition, the titles of the following REMS appended materials were revised. FDA Proposed Title TRIG Proposed New Title Non-Chain Outpatient Pharmacy Independent Outpatient Pharmacy Enrollment Form Enrollment Form Non-Chain Outpatient Pharmacy Independent Outpatient Pharmacy Overview Document Overview Document Reviewer Comment: FDA agrees with this revision. 2. TRIG inserted the word “generally” into the definition of Chain and Independent Outpatient Pharmacies. On April 16, 2013, DRISK asked the TRIG to clarify how Chain and Independent pharmacies are categorized. In response, the TRIG supplied the following information (see Appendix 3, Question 2, for complete response): • There are four (4) chain outpatient pharmacy headquarters with less than 10 substores enrolled in the TIRF REMS Access program. • There are three (3) independent outpatient pharmacies with more than 10 stores enrolled in the TIRF REMS Access program. • The difference (between chain and independent outpatient pharmacies) is the concept of enrollment. The chain outpatient pharmacy headquarters authorized pharmacy representative can add store locations and mark them as trained on the pharmacy dashboard as appropriate. Each independent outpatient pharmacy must Reference ID: 3361509 FDA_6536 individually enroll and complete test transactions at the store level, regardless if the authorized pharmacist is the same across multiple stores. Reviewer Comment: The TRIG is not using the number of pharmacies to determine chain and independent classifications. The classification is determined by the authorized pharmacy representative responsible for enrollment and training of the associated pharmacies. If the authorized pharmacy representative agrees to take responsibility for assuring and documenting the training of all associated pharmacy’s employees, they can enroll as a chain. However, if the pharmacist-in-charge at individual stores will have the responsibility to ensure and document training, each pharmacy will enroll separately as an independent pharmacy. Therefore, FDA proposes the following pharmacy definitions: • Outpatient Pharmacies i. Chain Outpatient Pharmacy: Retail, mail order or institutional outpatient pharmacies having a chain headquarters that is responsible for ensuring enrollment and training of pharmacy staff within all associated outpatient pharmacies. The chain headquarters will enroll multiple locations (i.e.: chains stores) in TIRF REMS Access. ii. Independent Outpatient Pharmacy: Retail, mail order, or institutional outpatient pharmacies having an authorized pharmacy representative that is responsible for ensuring enrollment and training of pharmacy staff within an individual outpatient pharmacy. Each store will individually enroll in TIRF REMS Access as a single pharmacy location. iii. Closed System Outpatient Pharmacy: Institutional or mail order outpatient pharmacies that uses a pharmacy management system that does not support the process of electronically transmitting the validation and claim information. • Inpatient pharmacies (e.g., hospitals, in-hospital hospices, and long-term care facilities that dispense for inpatient use) 3. The following documents were revised to reflect the changes to these definitions: • FAQ document • Independent Outpatient Pharmacy Overview • Chain Outpatient Pharmacy Overview 4. TRIG agreed to remove the DHCP letter from the TIRF REMS Access Program Website. 5. During the clearance of the REMS document, Office of Chief Counsel (OCC) advised revising the following statement in the Implementation System section (II.B.C.3.1) Reference ID: 3361509 FDA_6537 of the REMS document as noted below. Furthermore, they recommended moving the language to the TIRF REMS Supporting document. TIRF Sponsors will ensure that wholesalers/distributors who take title to or direct the sale or disposition of TIRF medicines to persons other than a consumer or patient distribute TIRF medicines are enrolled in the TIRF REMS Access program and comply with the program requirements for wholesale distributors. 4.1.2 Patient Prescriber Agreement Form (PPAF) 1. On March 11, 2013, the TRIG agreed with the revised prescriber attestation #1 - #3 as indicated below: 1. My patient is currently using around the clock opioid medication and has been for at least one (1) week. I understand that TIRF medicines are indicated only for the management of breakthrough pain in patients with cancer, who are already receiving, and who are tolerant to, around-the-clock opioid therapy for their underlying persistent pain. 2. I understand that TIRF medicines are contraindicated for use in opioid non-tolerant patients, and know that fatal overdose can occur at any dose. 3. My patient is opioid tolerant. I understand that pPatients considered opioid-tolerant are those who are regularly taking at least: 60 mg oral morphine/day; 25 micrograms transdermal fentanyl/hour; 30 mg oral oxycodone/day; 8 mg oral hydromorphone/day; 25 mg oral oxymorphone/day; or an equianalgesic dose of another opioid for one week or longer. 2. TRIG proposed changing “overdose” to “fatal respiratory depression” in the prescriber attestation #2 below. 2) I understand that TIRF medicines are contraindicated for use in opioid nontolerant patients, and know that fatal overdose respiratory depression can occur at any dose. The Sponsor provided no explanation for this revision. On April 16, 2013, FDA sent an IR requesting the TRIG’s rationale for the change. On May 6, 2013, TRIG responded that “Fatal respiratory depression is consistent with the label/ boxed warning for all TIRF medicines.” Reviewer Comment: FDA recommends using fatal overdose for the following reasons: • All TIRF products boxed warning contains both terms fatal overdose and fatal respiratory depression. Reference ID: 3361509 FDA_6538 • The REMS goal is to mitigate the risk of overdose, not fatal respiratory depression. Respiratory depression is one symptom of overdose, therefore overdose I sa more appropriate term to use in this attestation. • 3. On March 11, 2013, the TRIG proposed modifying the patient attestation below. 2) I understand that if I stop taking another opioid pain medicine that I have been taking regularly, around the clock, for my constant pain, then I must also stop taking my TIRF medicine. I understand that before I can take any TIRF medicine, I must be opioid tolerant. My prescriber has discussed with me whether I am opioid tolerant. The TRIG provided no explanation for this revision. On April 16, 2013, FDA sent an IR to request the TRIG’s rationale for the change and proposed the following revisions. 2) I understand that TIRF medications should only be taken by patients who are regularly using another opioid, around-the-clock, for constant pain. opioid pain medications. I understand that before I can take any TIRF medicine, I must be opioid tolerant. If I am not taking around-the-clock opioid pain medicine, my prescriber and I have discussed the risks of only taking TIRF medicines. whether I am opioid tolerant. 3) I understand that if I stop taking another opioid pain medicine that I have been taking regularly , around the clock, for my constant pain, then I must also stop taking my TIRF medicine. I understand that if I stop taking my around-theclock opioid pain medicine for my constant pain, I must stop taking my TIRF medicine. On April 16, 2013, TRIG agreed with the above proposal, via email. 4.1.3 Prescriber Enrollment Form Addition of a field for Knowledge Assessment Authorization Number Upon review of pharmacy and prescriber enrollment forms, it was noted that the form did not provide instruction for submission of the Knowledge Assessment quiz if it was completed on paper. In addition, it did not include a field for enrolled healthcare providers to indicate their Knowledge Assessment online training authorization number. On February 4, 2013, FDA proposed revisions to address these 2 issues. On March 11, 2013, TRIG provided feedback that (1) the Knowledge Assessment (KA) authorization number is not a searchable field in the TIRF REMS Access database and website. (2) It is not required for the KA to be completed prior to the receipt of the enrollment form. Rather, stakeholders are notified upon receipt of the enrollment form if the Reference ID: 3361509 FDA_6539 KA is not complete. As a result, adding the training authorization number to the form could result in stakeholder confusion and potential delays in enrollment. In response to the TRIG’s indication that when enrolling via fax, the stakeholder can attest to completing the KA prior to actually completing the KA, FDA requested a summary of the process for stakeholder enrollment via fax. In addition the following clarifications were requested and responses were received May 6, 2013 (see Appendix 3 for full responses): 1. Have incomplete prescriber enrollments results due to a prescriber’s ability to sign the enrollment form before completing the Education Program and Knowledge Assessment? If so, how many? RESPONSE: A total of 567 prescribers submitted a signed TIRF REMS Access enrollment form prior to completing the Knowledge Assessment. 485 (85.5%) of these prescribers are currently enrolled in the TIRF REMS Access program. 2. If the knowledge assessment authorization number is not searchable within the TRIF REMS Access database, how is the TIRF able to identify which stakeholders have completed the assessment online after receipt of an enrollment form? RESPONSE: In clarification, although the Knowledge Assessment code is searchable, current TIRF REMS Access Call Center work instructions were created based on best practices and ease of database navigation. 3. Once the enrollment form is received and a stakeholder is notified of the need to complete the assessment, how does the TRIG track if it is completed? RESPONSE: The TIRF REMS Access database programmatically tracks the lifecycle of the enrollment from submission to completion regardless if the stakeholder completes the Knowledge Assessment via fax or web. The stakeholder is not enrolled until all steps are completed. 4. The comment provided by the TRIG indicated that “…it is not required for the KA to be completed prior to the receipt of the enrollment form” is contradictory to the first attestation statement on the enrollment form which states “I have reviewed the TIRF REMS Access Education Program, including the Full Prescribing Information for each TIRF medicine, and I have completed the Knowledge Assessment…” Provide further clarification by what was meant by the TRIG’s comment. RESPONSE: To clarify TRIGs comment, stakeholders are not enrolled until all steps of the enrollment process are completed, including the Knowledge Assessment (KA). If the enrollment form is received prior to the KA, it will be processed but the stakeholder enrollment will be incomplete until a complete KA is received. Reviewer Comment: Although FDA has concerns about the TRIGs process for processing faxed enrollment, which does not including a search for the Knowledge Assessment Authorization Number, the need for this may be minimized by agreed upon Reference ID: 3361509 FDA_6540 revisions to the stakeholder enrollment forms. These revisions include adding the following statement to the Prescriber and Pharmacy Enrollment forms. To submit this form via fax, please complete all required fields below and fax pages 1, 2, 3, 4 and 5 to 1-866-822-1487. Please note, you must review the TIRF REMS Access Education Program and successfully complete the Knowledge Assessment to complete enrollment. If you have not completed the Knowledge Assessment online, please include it with this enrollment form. You will receive enrollment confirmation via email or fax. FDA will reassess stakeholder enrollment statistic in future TIRF REMS Access Program Assessments in order to determine if the frequency of KA not being submitted with faxed enrollments is decreasing. 4.1.4 TIRF REMS Frequently Asked Questions (FAQ) document TRIG removed all reference to the transition from individual TIRF REMS programs to the shared system TIRF REMS Access Program. Furthermore, they added a section titled “How long is my enrollment effective in the TIRF REMS Access program?” which describes the reenrollment process to the following sections: • • • • outpatient pharmacies inpatient pharmacies prescribers distributor (wholesaler) How long is my enrollment effective in TIRF REMS Access? Your enrollment is effective for two (2) years. You will be required to re-enroll in the TIRF REMS Access program every two (2) years if you wish to continue dispensing these products. You will be notified by the TIRF REMS Access program in advance of the need to re-enroll. Independent outpatient pharmacies and chain outpatient pharmacies may re-enroll online or by fax. Closed system outpatient pharmacies may re-enroll by fax only. For re-enrollment online, go to the “Enrollment Activity” tab on the TIRF REMS Access program website (www.TIRFREMSaccess.com). The “Enrollment Activity” tab allows you to: • • • • Add to, update, or delete your registration information on file. Review the TIRF REMS Access Education Program. Take the TIRF REMS Access Knowledge Assessment. Submit your enrollment form by providing your attestation and signature. For re-enrollment by fax, review the TIRF REMS Access program Education Materials and submit a new TIRF REMS Access Enrollment Form and Reference ID: 3361509 FDA_6541 Knowledge Assessment to the TIRF REMS Access program at 1-866-822-1487. All TIRF REMS Access Education Materials and Enrollment Forms are available and can be downloaded from www.TIRFREMSaccess.com using Adobe Acrobat Reader or by calling the TIRF REMS Access call center at 1-866-822-1483. Reviewer Comment: FDA agrees with these revisions. 4.1.5 Closed System Outpatient Pharmacy Overview 1. TRIG agreed with revisions to improve clarity and flow of stakeholder overview documents that are appended to the TIRF REMS. They revised the overview documents for Prescribers, Inpatient Pharmacies and Independent and Chain Outpatient Pharmacies to follow the same format. Reviewer comment: FDA agrees with these revisions. 2. The closed pharmacy overview document was revised to indicate during prescription verification a DEA number will be required, if applicable, in order to validate a prescription. This was necessary due to a newly instituted process for enrolling a small number of closed system prescribers who do not require an individual DEA number in order to prescriber CII medicines. This process allows enrollment of these closed system prescribers and validation of a prescription written by these prescribers with only an NPI number. However, the affected prescribers can only enroll via fax. Reviewer comment: FDA agrees with these revisions. 3. TRIG provided additional minor edits to the stakeholder overview documents which do not impact the goals of the REMS or operations. Reviewer comment: FDA agrees with these revisions. 4.1.6 Education Program An efficacy supplement (S-005) which includes new recommendations for safely switching from Actiq (fentanyl oral transmucosal lozenge) to Subsys (fentanyl sublingual spray) is currently under review by the Agency. Accordingly, slides 15 and 19 of the TIRF REMS Education Program were revised to reflect this change. 4.1.7 TIRF REMS Knowledge Assessment An efficacy supplement (S-005) which included new recommendations for safely switching from Actiq (fentanyl oral transmucosal lozenge) to Subsys (fentanyl sublingual spray) is currently under review by the Agency. Accordingly, the following question in the TIRF REMS Knowledge Assessment was revised to reflect this change. Question 11: Conversion between specific only two TIRF medicines has been established and is described in the Prescribing Information for which two products? Select one option. Reference ID: 3361509 FDA_6542 A. B. C. D. 4.2 Lazanda to Actiq Actiq to Fentora Abstral to Fentora Actiq to Subsys Fentora to Actiq Both B & C REMS SUPPORTING DOCUMENT 1. As requested by FDA, the REMS Supporting Document was updated to add a specific section, “Closed System Pharmacies”. Reviewer Comment: FDA agrees with this revision. 2. As requested by FDA, the REMS Supporting document REMS Assessment Plan and TIRF REMS Access Non-Compliance Plan was revised to include references and information pertaining to closed system pharmacies. Reviewer Comment: The Second REMS Assessment submitted on December 21, 2012 is currently under review. Therefore, the TRIG’s proposed changes to the REMS Assessment plan and any future changes will be reviewed under separate cover. 3. On March 11, 2103, TRIG submitted the TIRF REMS Prescription Authorization Request Form for closed system outpatient pharmacies at the FDA request. Reviewer Comment: FDA recommends this form be added to the TIRF REMS Supporting document as an appended material. 4. On May 1, 2013, Abstral ownership transitioned from ProStrakan to Galena BioPharma. In order to support this transition, the REMS Supporting document (Table 1 on page 4) was updated to reflect Galena as the new Applicant/Sponsor. 5. TRIG submitted the Website Protocol changes (see Appendix 5) 5 RECOMMENDATIONS FOR THE REVIEW DIVISION We recommend that the following comments on the TRIF REMS Access Program proposal be sent to the TRIG. Please request that the TRIG respond to these comments as soon as possible to facilitate further review for this submission. The comments below are based on DRISK’s preliminary review of the REMS modification proposal for TIRF products. Appended to this review is the REMS modification proposal and the following REMS materials including our track changes (see Attachment 1 – 12). 1. REMS Document 2. Patient Prescriber Agreement Form 3. TIRF REMS Access Program Education Program Reference ID: 3361509 FDA_6543 4. Website “Resources for Pharmacists” page 165 5. Website “Registration Identifier Question 2” pages 50-53 The applicant should be reminded that the REMS Supporting Document must be consistent with all changes made to the REMS document. 6 6.1 COMMENTS FOR THE APPLICANT REMS DOCUMENT (ATTACHMENT 1) 1. Revise the REMS document to reflect the following pharmacy definitions: • Outpatient Pharmacies i. Chain Outpatient Pharmacy: Retail, mail order or institutional outpatient pharmacies having a chain headquarters that is responsible for ensuring enrollment and training of pharmacy staff within all associated outpatient pharmacies. The chain headquarters will enroll multiple locations (i.e.: chains stores) in TIRF REMS Access. ii. Independent Outpatient Pharmacy: Retail, mail order, or institutional outpatient pharmacies having an authorized pharmacy representative that is responsible for ensuring enrollment and training of pharmacy staff within an individual outpatient pharmacy. Each store will individually enroll in TIRF REMS Access as a single pharmacy location. iii. Closed System Outpatient Pharmacy: Institutional or mail order outpatient pharmacies that uses a pharmacy management system that does not support the process of electronically transmitting the validation and claim information. 2. The following documents were revised to reflect the changes to these definitions: • FAQ document (Attachment 2) • Independent Outpatient Pharmacy Overview (Attachment 3) • Chain Outpatient Pharmacy Overview (Attachment 4) 3. Revise the following statement in the REMS document, Implementation System. TIRF Sponsors will ensure that wholesalers/distributors who take title to or direct the sale or disposition of TIRF medicines to persons other than a consumer or patient distribute TIRF medicines are enrolled in the TIRF REMS Access program and comply with the program requirements for wholesale distributors. 6.2 PATIENT PRESCRIBER AGREEMENT FORM (ATTACHMENT 5) Revise the prescriber attestation #2 (see below) to replace “respiratory depression” with “overdose”. FDA recommends this for the following reasons: Reference ID: 3361509 FDA_6544 • • • All TIRF products boxed warning contains both terms fatal overdose and fatal respiratory depression. Respiratory depression is one symptom of overdose, therefore overdose is more appropriate term to use in this attestation. The REMS goal is to mitigate the risk of overdose 2) I understand that TIRF medicines are contraindicated for use in opioid nontolerant patients, and know that fatal overdose respiratory depression can occur at any dose. 6.3 TIRF REMS EDUCATION PROGRAM (ATTACHMENT 6) An efficacy supplement (S-005) which includes new recommendations for safely switching from Actiq (fentanyl oral transmucosal lozenge) to Subsys (fentanyl sublingual spray) is currently under review by the Agency. Accordingly, slides 15 and 19 of the TIRF REMS Education Program were revised to reflect this change. 6.4 TIRF REMS KNOWLEDGE ASSESSMENT ( ATTACHMENT 7) An efficacy supplement (S-005) which includes new recommendations for safely switching from Actiq (fentanyl oral transmucosal lozenge) to Subsys (fentanyl sublingual spray) is currently under review by the Agency. Accordingly, the following question in the TIRF REMS Knowledge Assessment was revised to reflect this change. Question 11: Conversion between specific only two TIRF medicines has been established and is described in the Prescribing Information for which two products? Select one option. A. B. C. D. 6.5 Lazanda to Actiq Actiq to Fentora Abstral to Fentora Actiq to Subsys Fentora to Actiq Both B & C REMS SUPPORTING DOCUMENT (ATTACHMENT 8) 1. Add the TIRF REMS Prescription Authorization Request Form which closed system pharmacies utilize for requesting prescription verification via fax to the TIRF REMS Supporting document as an appended material. 2. The following underlined text was moved from the TIRF REMS document to the TIRF REMS Supporting document. C. IMPLEMENTATION SYSTEM The Implementation System includes the following: a. Wholesaler/Distributor Enrollment and Fulfillment • TIRF Sponsors will ensure that wholesalers/distributors who distribute TIRF medicines are enrolled in the TIRF REMS Access program before they are allowed to distribute TIRF medicines. Reference ID: 3361509 FDA_6545 • For the purpose of the TIRF REMS Access program, the term distributor refers to wholesaler, distributor, and/or chain outpatient pharmacy distributor who take title to or direct sale or disposition of TIRF medicines to persons other than a consumer or patient. 3. The REMS Supporting Document and appended Web Prototype must be consistent with all changes made to the REMS document and REMS appended materials. 6.6 GENERAL COMMENTS Resubmission Instructions 1) 1 PDF file that includes the REMS document + all appended materials* *The materials below should be appended to the REMS document (in the following order): 1. TIRF REMS Access Prescriber Program Overview 2. TIRF REMS Access Education Program 3. Knowledge Assessment 4. Prescriber Enrollment Form 5. Patient-Prescriber Agreement Form 6. TIRF REMS Access Patient and Caregiver Overview 7. Frequently Asked Questions (FAQs) 8. Dear Healthcare Provider Letter 9. TIRF REMS Access Website 10. Independent Outpatient Pharmacy Overview 11. Chain Outpatient Pharmacy Overview 12. Closed System Outpatient Pharmacy Overview 13. Inpatient Pharmacy Overview 14. Independent Outpatient Pharmacy Enrollment Form 15. Chain Outpatient Pharmacy Enrollment Form 16. Closed System Outpatient Pharmacy Enrollment Form 17. Inpatient Pharmacy Enrollment Form 18. Outpatient Pharmacy Letter 19. Inpatient Pharmacy Letter 20. Dear Distributor Letter 21. Distributor Enrollment Form 2) 1 PDF file that includes the REMS Supporting Document 3) Individual Word files for the REMS document, REMS document and appended materials, the REMS Supporting Document. If you have files that were not created in Word, the individual file may be submitted in PDF (e.g. website) Reference ID: 3361509 FDA_6546 4) The only PDF files that are required to be submitted, are those listed in 1) and 2) above. Individual PDF files of the Word files described in 1) are optional. The PDF files should include the final design format of all REMS materials. APPENDICES: 1. Response to FDA questions, received March 11, 2013 2. TRIG email, received March 11, 2013 3. TRIG IR response, received May 6, 2013 4. TRIG email, received May 6, 2013 5. Web Prototype Changes, received May 6, 2013 ATTACHMENTS: 1. REMS Document, redlined 2. FAQ document, redlined 3. Independent Outpatient Pharmacy Overview, redlined 4. Chain Outpatient Pharmacy Overview, redlined 5. Patient Prescriber Agreement Form, redlined 6. TIRF REMS Access Program Education Program, redlined 7. TIRF REMS Access Program Knowledge Assessment, redlined 8. TIRF REMS Supporting document, redlined Reference ID: 3361509 FDA_6547 Appendix 1: Response to FDA questions, received March 11, 2013 Responses to FDA Modification 2 General Comments to TIRF REMS Assess Program 04Mar 2013 1. Submit the form which will be used by Closed System Outpatient Pharmacies to validate prescriptions by completing and faxing to the TIRF REMS Access Program. We have attached to this email the TIRF REMS Access Prescription Authorization Request form used by closed system outpatient pharmacies to validate prescriptions via fax. 2. Submit the script used by TIRF REMS Access program call center staff when validating prescriptions for Closed System Outpatient Pharmacies. The call center agents adhere to a work instruction when validating prescriptions for closed system outpatient pharmacies. The process is outlined below: 1.) REMS agent requests the closed system pharmacy NPI number or DEA number used to register in the TIRF REMS Access program. 2.) REMS agent uses the number provided to search for the pharmacy in the TIRF REMS Access database and confirms they are a closed system outpatient pharmacy. 3.) If confirmed, the REMS agent collects the following information: Dispensing Pharmacy DEA Patient Date of Birth Rx Date of Service Dispensing Pharmacy NPI Patient First Name Rx Number Dispensing Pharmacy Phone # Patient Last Name Rx NDC # Dispensing Pharmacy Fax # Patient Zip Code Days Supply Prescriber DEA or NPI Prescriber Last Name Quantity for Dispense 4.) This information is used to validate the prescription with the TIRF REMS Access program using the same REMS edits and business rules in the claim adjudication process as used for chain outpatient and independent outpatient pharmacies. o If validated, the system will provide the REMS Agent an Authorization Number which is provided to the closed system caller o If not validated, a rejection reason and information regarding how to resolve the rejection is provided to the closed system caller for follow-up or trouble-shooting 3. What are the call center hours of operation? Monday – Friday: 8am - 8pm ET Reference ID: 3361509 FDA_6548 4. Is validation of a Closed System Outpatient Pharmacy’s TIRF prescription possible on weekends or on weekdays when the call center is not operational? No, validation of closed system prescriptions can only be obtained during TIRF REMS Access program call center hours of operation of Monday – Friday, 8am-8pm ET. Have there been any complaints from Closed System Outpatient Pharmacies due to them not being able to dispense TIRF prescriptions when the call center is not operational? No complaints have been received since the implementation of the closed system outpatient pharmacy solution. 5. Currently Closed System Outpatient Pharmacies can only validate TIRF prescriptions via phone or fax. Are there plans to provide these pharmacies with an online interface for performing the validation? The current prescription authorization volume and absence of complaints does not warrant a change to the current process. Therefore we are not pursuing an online solution at this time. We will continue to monitor and assess the need for an alternate solution as appropriate. Reference ID: 3361509 FDA_6549 Appendix 4: TRIG email, May 6, 2013 From: Servello, Diane L [mailto:Diane.Servello@covidien.com] Sent: Monday, May 06, 2013 4:20 PM To: Liberatore, Mark Cc: Willene Brondum (wbrondum@insysrx.com); Jenkins, Darrell Subject: RE: Follow-up: TIRF REMS Modification 2 Hi Mark: This e-mail provides the TRIG’s response to your April 16, 2012 questions concerning TIRF REMS Modification 2. Our responses to your questions are included in the attached PDF file (“FDA Inquiry to REMS Modification 2 on April 16, 2013 – TRIG Response – Final”). We are also submitting revised documents in two zip files (clean and redline versions). These documents have been revised to reflect the following: • • PPAF – revised patient attestations #2 and #3 per TRIG’s response to FDA’s question, 5b. To support Abstral’s transition from ProStrakan to Galena BioPharma which took effect May 1st, the following REMS Modification 2 document were updated o Supporting Document – updated Applicant/Sponsor name for Abstral in Table 1 on page 4 o Chain Outpatient Pharmacy Enrollment Form – added additional Abstral NDC numbers on page 4 o Independent Outpatient Pharmacy Enrollment Form – added additional Abstral NDC numbers on page 3 o Web Prototype - added additional Abstral NDC numbers on pages 89 and 100. Due to size restrictions, I will be sending the zip files containing the revised documents in two separate e-mails immediately after this e-mail. (You will receive a total to three e-mails for this response.) Please let me know if you require any additional information. Best regards, Diane Servello Diane Servello Sr. Director, Regulatory Affairs - API/Specialty Generics/Regulatory Operations Mallinckrodt (a Covidien Company) 675 McDonnell Blvd. Hazelwood, MO 63042 USA Office: 314-654-3320 Mobile: 256-714-3694 Fax: 314-654-6496 e-mail: diane.servello@covidien.com Reference ID: 3361509 FDA_6550 Appendix 2: TRIG email, March 11, 2013 From: Servello, Diane L [mailto:Diane.Servello@covidien.com] Sent: Monday, March 11, 2013 11:01 AM To: Liberatore, Mark Cc: Jenkins, Darrell; wbrondum@insysrx.com Subject: Response to 2/4/2013 email - TIRF REMS Modification 2 Dear Mark: Please find our response enclosed, addressing the Agency’s e-mail dated February 4, 2013 concerning Modification 2 of the TIRF REMS. We have enclosed two zip files. One file contains red-lined versions of each document and the other file contains “clean” versions. The red-lined versions have been annotated to show the revisions made. We have also enclosed a Word document providing responses to the questions in your February 4, 2013 e-mail. Another Word document is enclosed for the Closed System Rx Authorization form. The following “global” changes have been made throughout the documents and are not annotated: • For all occurrences of “FENTORA® (fentanyl citrate) buccal tablet”, the product name was changed to “FENTORA® (fentanyl buccal tablet)” • Changed the location of parenthesis in the Onsolis trade name from 'Onsolis® (fentanyl) buccal soluble film' to 'Onsolis® (fentanyl buccal soluble film)'. • Replaced the ™ symbol after Subsys with ®. • Changed location of parenthesis in Subsys trade name from 'Subsys™ (fentanyl) sublingual spray' to 'Subsys™ (fentanyl sublingual spray). • Add new Subsys NDCs 20482-001-10 20482-002-10 20482-004-10 20482-006-10 20482-008-10 20482-001-01 20482-002-01 20482-004-01 20482-006-01 20482-008-01 Reference ID: 3361509 FDA_6551 • Changed the following Subsys NDCs: Replaced 20482-012-30 with 20482-012-15 Replaced 20482-016-30 with 20482-016-15 • Changed “Non-chain Outpatient Patient Pharmacy” to “Independent Outpatient Pharmacy” to align with industry standard pharmacy terminology. • Changed “Closed-system Pharmacy” to “Closed System Outpatient Pharmacy” • Changed “Chain Pharmacy” to “Chain Outpatient Pharmacy” • Revised definitions for chain, independent and closed system outpatient pharmacies to align with industry standard pharmacy terminology to prevent confusion upon determining pharmacy type when enrolling in TIRF REMS Access. • Removed language only pertinent to transition of individual REMS programs to TIRF REMS. • Language revisions made throughout documents to clarify processes. Please let me know if you have any questions or concerns. Best regards, Diane Diane Servello Sr. Director, Regulatory Affairs - API/Specialty Generics/Regulatory Operations Mallinckrodt (a Covidien Company) 675 McDonnell Blvd. Hazelwood, MO 63042 USA Office: 314-654-3320 Mobile: 314-409-9646 Fax: 314-654-6496 e-mail: diane.servello@covidien.com Reference ID: 3361509 FDA_6552 FDA Inquiry Received on 16 April 2013 to TIRF REMS Modification 2 1. Provide a rationale for revising the existing text “fatal overdose” to “fatal respiratory depression” as proposed by the TRIG to the Patient Prescriber Agreement Form, Prescriber attestation #2. “2. I understand that TIRF medicines are contraindicated for use in opioid non-tolerant patients, and know that fatal overdose respiratory depression can occur at any dose.” RESPONSE: Fatal respiratory depression is consistent with the label/ boxed warning for all TIRF medicines. 2. The revised definitions for outpatient pharmacies as proposed by the TRIG have been updated to align with industry standards to prevent confusion. Provide a response to the following: 2a. How is the term “generally”, which is included in the definitions for chain outpatient pharmacies and independent outpatient pharmacies, used to determine the appropriate category designation? RESPONSE: There is no industry standard number of stores for chain vs. independent pharmacies. The definitions allow for flexibility of pharmacies to define their pharmacy type for managing the enrollment process in the TIRF REMS Access program. 2b. Chain outpatient pharmacy: How many pharmacies with less than 10 stores under the same ownership has the TRIG enrolled as a chain pharmacy? Describe what criteria was used to enroll these pharmacies as a chain outpatient pharmacy. RESPONSE: There are four (4) chain outpatient pharmacy headquarters with less than 10 substores enrolled in the TIRF REMS Access program. The pharmacies are enrolled as chain outpatient pharmacies due to their request to have a single authorized pharmacy representative responsible for managing enrollment and training for all stores. 2c. Independent outpatient pharmacy: How many pharmacies with more than 10 stores under the same ownership has the TRIG enrolled as an independent pharmacy? Describe what criteria was used to enroll these pharmacies as an independent outpatient pharmacy. RESPONSE: There are three (3) independent outpatient pharmacies with more than 10 stores enrolled in the TIRF REMS Access program. The pharmacies are enrolled as independent outpatient pharmacies due to their request to have an authorized pharmacy representative from each store responsible for managing enrollment and training of each individual store. 3. From the website prototype (pages 124 & 136), it appears both chain outpatient pharmacies and independent outpatient pharmacies can enroll pharmacy locations and maintain a list of multiple stores in their pharmacy profile. Provide a rationale for the following: 3d. Any differences between the lists managed for independent outpatient pharmacies as compared to chain outpatient pharmacies RESPONSE: The difference is the concept of enrollment. The chain outpatient pharmacy headquarters authorized pharmacy representative can add store locations and mark them as trained on the pharmacy dashboard as appropriate. Each independent outpatient pharmacy must individually enroll and complete test transactions at the store level, regardless if the authorized pharmacist is the same across multiple stores. Pg 1 of 9 Reference ID: 3361509 FDA_6553 FDA Inquiry Received on 16 April 2013 to TIRF REMS Modification 2 Chain outpatient pharmacy headquarters manages the training status of each individual store for which they have taken responsibility whereas the authorized pharmacist for the independent outpatient pharmacy has the ability to manage the enrollment process (enrollment form, training, knowledge assessment, test transactions) for other independent pharmacies for which they are the authorized pharmacist. 3e. Why are separate enrollment forms for chain and independent outpatient pharmacies necessary if both entities can enroll multiple pharmacy locations? RESPONSE: The forms identify the pharmacy type for enrollment purposes. They differ in that the chain enrollment form allows enrollment for multiple pharmacy store locations under one chain enrollment. The independent outpatient pharmacy enrollment form only allows one store to be enrolled per form. Both enrollment forms contain the same 14 acknowledgement statements and Terms and Conditions. 4. Provide a summary of the process for stakeholder enrollment (pharmacy, prescriber) via fax. The summary should include a flowchart of the process and a description of each step within the process. Additionally, provide a response to the following: RESPONSE: Refer to prescriber, independent outpatient pharmacy, chain outpatient pharmacy, inpatient pharmacy and closed system outpatient pharmacy fax enrollment flows in the Appendix beginning on page 4. 4f. Have incomplete prescriber enrollments resulted from a prescriber’s ability to sign the enrollment form before completing the Education Program and Knowledge Assessment? If so, how many? RESPONSE: Enrollment is not deemed as complete until all enrollment requirements are met. A total of 567 prescribers submitted a signed TIRF REMS Access enrollment form prior to completing the Knowledge Assessment. 485 (85.5%) of these prescribers are currently enrolled in the TIRF REMS Access program. The TIRF REMS Access database tracks the completion of each step and upon processing, immediately notifies the stakeholder of ALL outstanding requirements (i.e.; missing signature, missing address, knowledge assessment) via the incomplete correspondence letter. 4g. If the knowledge assessment authorization number is not searchable within the TIRF REMS Access database, how is the TRIG able to identify which stakeholders have completed the assessment online after receipt of an enrollment form? RESPONSE: In clarification, although the Knowledge Assessment code is searchable, current TIRF REMS Access Call Center work instructions were created based on best practices and ease of database navigation. Upon receipt of a faxed enrollment form, the TIRF REMS Access Call Center Agent conducts a search of the TIRF REMS Access database to locate the stakeholder record. Fields used to search the TIRF REMS Access database include: name, city, state, zip code, phone number, fax number and stakeholder identifiers (DEA, NPI, state license number, NCPDP, Medicaid ID, chain ID, enrollment ID). Once the stakeholder has been identified in the TIRF REMS database, the Knowledge Assessment code will be visible if the Knowledge Assessment has been completed. Pg 2 of 9 Reference ID: 3361509 FDA_6554 FDA Inquiry Received on 16 April 2013 to TIRF REMS Modification 2 4h. Once the enrollment form is received and a stakeholder is notified of the need to complete the assessment, how does the TRIG track if it is completed? RESPONSE: The TIRF REMS Access database programmatically tracks the lifecycle of the enrollment from submission to completion regardless if the stakeholder completes the Knowledge Assessment via fax or web. The stakeholder is not enrolled until all steps are completed. 4i. The comment provided by the TRIG indicated that “…it is not required for the KA to be completed prior to the receipt of the enrollment form” is contradictory to the first attestation statement on the enrollment form which states “I have reviewed the TIRF REMS Access Education Program, including the Full Prescribing Information for each TIRF medicine, and I have completed the Knowledge Assessment…” Provide further clarification by what was meant by the TRIG’s comment. RESPONSE: To clarify TRIGs comment, stakeholders are not enrolled until all steps of the enrollment process are completed, including the Knowledge Assessment (KA). If the enrollment form is received prior to the KA, it will be processed but the stakeholder enrollment will be incomplete until a complete KA is received. 5. Patient attestation on the Patient Prescriber Agreement Form 5a. The patient attestation on the Patient Prescriber Agreement Form was revised by the TRIG. Provide a rationale for the revision to the attestation statement. RESPONSE: TRIG’s rationale for this proposed change was an attempt to adapt the following language from the TIRF Medication Guides to the language of the PPAF. “Do not use [TIRF] unless you are regularly using another opioid pain medicine around-theclock for your cancer pain and your body is used to these medicines (this means you are opioid tolerant). You can ask your healthcare provider if you are opioid tolerant.” 5b. The Agency proposes the following revisions to Attestation #2 and inclusion of the deleted attestation as attestation #3. “2. I understand that TIRF medicines should only be taken by patients who are regularly using another opioid, around-the-clock, for constant pain. opioid pain medications. I understand that before I can take any TIRF medicine, I must be opioid tolerant. If I am not taking around-the-clock opioid pain medicine, my prescriber and I have discussed the risks of only taking TIRF medicines. whether I am opioid tolerant.“ “3. I understand that if I stop taking another opioid pain medicine that I have been taking regularly , around the clock, for my constant pain, then I must also stop taking my TIRF medicine. I understand that if I stop taking my around-the-clock opioid pain medicine for my constant pain, I must stop taking my TIRF medicine.” RESPONSE: TRIG agrees with the Agency’s recommendation. The PPAF has been updated. A redlined and clean version of the revised PPAF is attached in the FDA Inquiry to Modification 2 Response email sent to the FDA on May 6, 2013. Pg 3 of 9 Reference ID: 3361509 FDA_6555 FDA Inquiry Received on 16 April 2013 to TIRF REMS Modification 2 APPENDIX – TIRF REMS Access Process Flows Pg 4 of 9 Reference ID: 3361509 FDA_6556 FDA Inquiry Received on 16 April 2013 to IMF REMS Modi?cation 2 TIRF REMS Access - Prescriber - Fax Enrollment Process Flow Reference ID: 3361 509 FDA Inquiry Received on 16 April 2013 to IMF REMS Modi?cation 2 TIRF REMS Access - Chain Outpatient Pharmacy - Fax Enrollment Process Flow Reference ID: 3361 509 FDA Inquiry Received on 16 April 2013 to IMF REMS Modi?cation 2 TIRF REMS Access - Independent Outpatient Pharmacy - Fax Enrollment Process Flow Reference ID: 3361 509 FDA Inquiry Received on 16 April 2013 to IMF REMS Modi?cation 2 TIRF REMS Access - Inpatient Pharmacy - Fax Enrollment Process Flow Reference ID: 3361 509 FDA Inquiry Received on 16 April 2013 to IMF REMS Modi?cation 2 TIRF REMS Access - Closed System Outpatient Pharmacy - Enrollment Process Flow Reference ID: 3361 509 Au . ndix 5: Web Proto pe Chanes, Ma 6, 2013 Reference ID: 3361 509 I I I Reference ID: 3361 509 Reference ID: 3361 509 ?1 A ?1 co on Reference ID: 3361 509 Reference ID: 3361 509 Reference ID: 3361 509 5 1 6 3 3 II-1 "In 3 1 1 Reference ID: 3361 509 Initial REMS approval: 12/2011 Most recent modi?cation: TRANSMUCOSAL IMMEDIATE RELEASE FENTANYL (TIRF) RISK EVALUATION AND MITIGATION STRATEGY (REMS) FOLLOWING THIS PAGE, TO WITHHELD IN FULL FDA 6570 Reference ID: 3361509 AS REMS WEB MATERIALS) --------------------------------------------------------------------------------------------------------This is a representation of an electronic record that was signed electronically and this page is the manifestation of the electronic signature. --------------------------------------------------------------------------------------------------------/s/ ---------------------------------------------------KIMBERLY LEHRFELD 08/23/2013 CLAUDIA B MANZO 08/23/2013 concur Reference ID: 3361509 FDA_6682 Department of Health and Human Services Food and Drug Administration Center for Drug Evaluation and Research Office of Surveillance and Epidemiology Office of Medication Error Prevention and Risk Management REMS MODIFICATION REVIEW Date: October 31, 2013 Reviewer(s) Kimberly Lehrfeld, Pharm.D., Risk Management Analyst, Division of Risk Management (DRISK) Kate Heinrich-Oswell, MA, Health Communication Analyst, DRISK Team Leader Reema Mehta, Pharm.D., M.P.H., Team Leader, DRISK Division Director: Claudia Manzo, Pharm.D., Director, DRISK Table 1 Drug Names, Dosage Form and Sponsor: Drug Name Abstral (fentanyl) Actiq (fentanyl citrate) Fentora (fentanyl citrate) Lazanda (fentanyl) Onsolis (fentanyl) Subsys (fentanyl) Dosage Form and Route Sublingual tablet Oral transmucosal lozenge Buccal tablet Application Type/Number NDA 22-510 Sponsor NDA 20-747 Galenya BioPharma Cephalon, Inc. NDA 21-947 Cephalon, Inc. Nasal spray NDA 22-569 DepoMed, Inc. Buccal soluble film Sublingual spray NDA 22-266 Meda Pharmaceuticals Insys Therapy NDA 202-788 Therapeutic Opioid Agonist class: Dosage Transmucosal Immediate release Fentanyl (TIRF) forms: OND Review Division: Reference ID: 3399442 Division of Anesthesia, Analgesia and Addiction Products (DAAAP) FDA_6683 Table 2 Drug Name Application FDA Type & Received Number Date Abstral® NDA 22510 NDA 20747 NDA 21947 NDA 22569 NDA 22266 NDA 202788 Actiq® Fentora® Lazanda® Onsolis® Subsys® OSE RCM #: 2012-2313 TSI #: 290 September 28, 2012 September 26, 2012 September 26, 2012 September 28, 2012 September 26, 2012 September 25, 2012 Supplement FDA Number Amendment Received Date 7 October 18, 2013 37 October 17, 2013 17 October 17, 2013 15 October 29, 2013 12 October 16, 2013 10 October 17, 2013 n/a = not applicable Reference ID: 3399442 FDA_6684 1. INTRODUCTION ....................................................................................................... 5 1.1 BACKGROUND.......................................................................................................... 5 1.2 REGULATORY HISTORY ........................................................................................... 6 2.1 Submissions ............................................................................................................... 7 2.2 Other Materials Informing our review ...................................................................... 7 2. RATIONALE FOR PROPOSED REMS MODIFICATIONS.................................... 7 3. PROPOSED REMS MODIFICATIONS .................................................................... 8 4.1 Goals.......................................................................................................................... 8 4.2 REMS Elements ........................................................................................................ 9 4.3 Supporting Document ............................................................................................. 14 4. REMS ASSESSMENT PLAN .................................................................................. 14 5. CONCLUSION ......................................................................................................... 14 6. RECOMMENDATIONS........................................................................................... 15 ATTACHMENTS ............................................................................................................. 15 Reference ID: 3399442 FDA_6685 EXECUTIVE SUMMARY This is a review of the proposed Risk Evaluation and Mitigation Strategy (REMS) modification for the TIRF REMS Single Shared System initially received between September 25 and September 28, 2012 into the individual sponsors applications and amended through one joint submission into the drug master file (DMF) (027320) on September 24, 2013. The REMS for the TIRF products was originally approved on December 28, 2011to address the risk of misuse, abuse, addiction, overdose and serious complications due to medication errors, and a REMS modification was approved on June 30, 2012. The most recently approved REMS consists of a Medication Guide, elements to assure safe use, implementation system, and a timetable for submission of assessments of the REMS. The TIRF SSS REMS Sponsors submitted a proposed modification to the REMS in response to an e-mail from Mark Libertore, OSE Project Manager on June 28, 2012, requesting modifications to incorporate information about the closed system pharmacies into the REMS document and the appended REMS materials. In addition, proposed modification to the TIRF REMS, including appended REMS materials as applicable, consist of the following: • Revised terminology, processes, and definitions for outpatient pharmacies • Revised terminology and definitions for wholesalers/distributors • Revised attestations for physicians and patients to address concerns regarding patient access • Revised Program Overview and Frequently Asked Questions to improve clarity and content • Updated REMS materials to reflect the completion of the transition phase for the TIRF REMS Access Program DRISK finds the proposed modifications to the TIRF REMS to be acceptable. Reference ID: 3399442 FDA_6686 1. INTRODUCTION This is a review of the TIRF REMS Industry Group’s (TRIG) proposed Risk Evaluation and Mitigation Strategy (REMS) modification #2 for all Transmucosal Immediate Release Fentanyl (TIRF) products (see Table 2) initially received between September 25 and September 28, 2012 into the individual sponsors applications and amended through one joint submission into the drug master file (DMF) (027320) on September 24, 2013. 1.1 BACKGROUND TIRF medicines are short-acting fentanyl products indicated for the management of breakthrough pain in adults with cancer who are routinely taking other opioid pain medicines around-the-clock for pain. The approved TIRF medicines include: • Abstral (fentanyl) sublingual tablet, • Actiq (fentanyl citrate) oral transmucosal lozenge, • Fentora (fentanyl citrate) buccal tablet, • Lazanda (fentanyl) nasal spray, • Onsolis (fentanyl) buccal soluble film, • Subsys (fentanyl) sublingual spray, and • Approved generic equivalents of these products As described in DRISKs December 2, 2011 REMS review, FDA determined that all TIRF products were required to have a REMS to ensure that the benefits of the drug outweighed the increased risk(s) of misuse, abuse, addiction, overdose and serious complications due to medication errors. The TIRF REMS was originally approved on December 28, 2011, and a REMS modification was approved on June 30, 2012. The most recently approved TIRF REMS (approved June 30, 2012) consists of a Medication Guide, elements to assure safe use, an implementation system, and a timetable for submission of assessments of the REMS. The TIRF medicines are approved under a single shared system REMS that has the following goal and objectives: The goal of the TIRF REMS Access program is to mitigate the risk of misuse, abuse, addiction, overdose and serious complications due to medication errors by: 1. Prescribing and dispensing TIRF medicines only to appropriate patients, which includes use only in opioid-tolerant patients. 2. Preventing inappropriate conversion between TIRF medicines. Reference ID: 3399442 FDA_6687 3. Preventing accidental exposure to children and others for whom it was not prescribed. 4. Educating prescribers, pharmacists, and patients on the potential for misuse, abuse, addiction, and overdose of TIRF medicines. The elements included in the program are Medication Guides for each individual TIRF medicine and the following Elements to Assure Safe Use (ETASU): • Healthcare providers who prescribe TIRF medicines for outpatient use are specially certified • TIRF medicines will only be dispensed by pharmacies that are specially certified • TIRF medicines will only be dispensed for outpatient use with evidence or other documentation of safe-use conditions. The timetable for submission of TIRF REMS Access Program assessments is at 6 and 12 months from the date of the initial REMS approval, and annually thereafter. 1.2 REGULATORY HISTORY Following is an overview of the regulatory history for the TIRF REMS modification, initially received on July 18, 2012. • 07/18/12: TRIG emailed Modification #2 documents to FDA • 09/25/12 – 9/28/12: TIRF Sponsors submitted Supplements to their individual NDA (see Table 2) • 02/4/13: FDA emailed comments and revised documents to the TRIG. • 03/11/13: TRIG emailed revised materials to FDA. • 04/16/13: FDA emailed Information Request to TRIG. • 5/6/2013: TRIG emailed the response to the April 16, 2013 IR to the FDA which contained revised TIRF REMS materials. • 7/2/2013: FDA comments and revised documents emailed to the TRIG. • 7/10/2013: TRIG emailed clarifying questions about the documents in the July 2, 2013 email. FDA responded the same day and provided correct versions of the Education Program and Knowledge Assessment. • 8/13/2013: FDA emailed comments and final TIRF REMS document, appended materials and the supporting document to the TRIG. • 9/24/2013: TRIG submitted final documents to the DMF for the TIRF REMS Access Program. • 10/16/2013 - 10/29/2013: TRIG sponsors submitted amendments to individual applications which referenced the DMF and the appropriate Medication Guides. Reference ID: 3399442 FDA_6688 2.1 SUBMISSIONS The following submissions were reviewed for the proposed TIRF REMS modification: • Final TIRF REMS Access Program submission to the DMF, September 24, 2013 Drug Name Application Type & Number Supplement Received Date Abstral® NDA 22-510 Actiq® NDA 20-747 Fentora® NDA 21-947 September 28, 2012 September 26, 2012 September 26, 2012 September 28, 2012 September 26, 2012 September 25, 2012 Lazanda® NDA 22-569 Onsolis® NDA 22-266 Subsys® NDA 202-788 Supplement Number (Sequence No.) 7 (61) 37 (21) 17 (23) 15 (79) 12 (107) 10 (41) Letter of Authorization for DMF received date (Sequence No.) September 11, 2013 (96) September 11, 2013 (29) September 11, 2013 (36) September 11, 2013 (100) September 11, 2013 (114) September 11, 2013 (62) Amendment received date (referencing DMF submission) October 18, 2013 October 17, 2013 October 17, 2013 October 29, 2013 October 16, 2013 October 17, 2013 Supplem Formatted: Font: Bold Number (Sequence No.) 7 ( 81) 37 (31) 17 (37) 15 (105) 12 (117) 10 (66) 2.2 OTHER MATERIALS INFORMING OUR REVIEW • DRISK TIRF REMS Review (K. Lehrfeld February 1, 2013) • Fentora DRISK Review(K. Lehrfeld February 21, 2013) • Abstral DRISK Review(K. Lehrfeld July 5, 2013) • Subsys DRISK Review(K. Lehrfeld July 5, 2013) • DRISK TIRF REMS Review (K. Lehrfeld August 22, 2013) 2. RATIONALE FOR PROPOSED REMS MODIFICATIONS On June 5, 2013, FDA approved the TIRF REMS modification #1, which added a reference to closed system pharmacies to the TIRF REMS document and created a Closed System Pharmacy Enrollment Form. However, this modification did not incorporate any closed system information into any other TIRF REMS materials. On June 28, 2012, FDA requested a modification to the TIRF REMS to incorporate information about the closed system pharmacies into the appended REMS materials. The TRIG was sent the following request via email: Reference ID: 3399442 FDA_6689 I. Create the following document: 1. TIRF REMS Program Overview for Closed System Pharmacies II. Modify the following documents: 1. REMS Document Minor modification on page 11 to add the new Overview to the list 2. FAQ Add the following or a similar question: What if our pharmacy's management system cannot communicate with the TIRF REMS Access program (e.g. does not electronically transmit claims information)? You will need to contact the TIRF REMS Access program at 1-866-822-1483 to see if you qualify to enroll as a "closed system pharmacy". 3. Website Please provide feedback and/or a proposal as to what closed system pharmacy information and/or which documents will be posted on the TIRF REMS Website (we note your e-mail to Kimberly Compton on 6/22/2012 that stated that the enrollment form will not be posted, given that a pharmacy needs to be validated as being a closed system pharmacy prior to their enrollment). For example, closed-system pharmacies that are seeking to enroll in the TIRF REMS should understand that there is a mechanism for them to participate in the REMS; however, it also needs to be clear this mechanism is not an option for pharmacies that can process through their pharmacy management system. 4. Supporting Document • • Update to include information and a section on 'Closed System Pharmacies' Update your REMS Assessment Plan and TIRF REMS Access Non-Compliance Plan 3. PROPOSED REMS MODIFICATIONS The proposed modifications to the REMS elements (received September 24, 2013) are described below. 4.1 GOALS The applicant did not propose changes to the goals of the REMS. Reference ID: 3399442 FDA_6690 4.2 REMS ELEMENTS 4.2.1 Medication Guide The Medication Guides for the individual TRIG products are maintained in the individual applications, not in the DMF. The following products' MGs changed during this review cycle and were reviewed under separate cover by the Office of Medical Policy Patient Labeling Team. Subsys: On July 31, 2013, an efficacy supplement (S-005) for Subsys (fentanyl sublingual spray) was approved. The MG was revised to include new recommendations for safely switching from Actiq (fentanyl oral transmucosal lozenge) to Subsys. Abstral: On July 26, 2013, a labeling supplement (S-010) for Abstral (fentanyl sublingual tablets) was approved. The MG was revised to include the change in ownership from ProStrakan to Galena BioPharma. Fentora: On February 21, 2013, efficacy supplement (S-008) for Fentora (fentanyl buccal tablet), which proposed the addition of the sublingual route of administration for Fentora, was approved. The MG was revised to include the new route of administration. Lazanda: Along with the approval of TIRF REMS Modification 2, Lazanda's MG was revised to include the change in ownership from Archimedes Pharma US, Inc. to Depomed, Inc. (S-017) and to revise the shelf-life for the product after first use to 60 days (S-012). 4.2.2 Elements to Assure Safe Use REMS document 1. Clarification of types of Outpatient pharmacies • Outpatient Pharmacies i. Chain Outpatient Pharmacy: Retail, mail order or institutional outpatient pharmacies having a chain headquarters that is responsible for ensuring enrollment and training of pharmacy staff within all associated outpatient pharmacies. The chain headquarters will enroll multiple locations (i.e.: chains stores) in TIRF REMS Access. ii. Independent Outpatient Pharmacy: Retail, mail order, or institutional outpatient pharmacies having an authorized pharmacy representative that is responsible for ensuring enrollment and training of pharmacy staff within an individual outpatient pharmacy. Each store will individually enroll in TIRF REMS Access as a single pharmacy location. iii. Closed System Outpatient Pharmacy: Institutional or mail order outpatient pharmacies that uses a pharmacy management system that does not support the process of electronically transmitting the validation and claim information. Reference ID: 3399442 FDA_6691 • Inpatient pharmacies (e.g., hospitals, in-hospital hospices, and long-term care facilities that dispense for inpatient use) 2. As requested by FDA, a reference to the Closed System Pharmacy Overview document was added to page 11. Additionally, a Closed System Pharmacy Overview document was added as an appended REMS material. REMS Appended Materials The titles of the following REMS appended materials were revised as a result of the proposed clarifications to the REMS document described above. Previous Title Outpatient Pharmacy Enrollment Form Chain Pharmacy Enrollment Form Closed System Pharmacy Enrollment Form Inpatient Pharmacy Enrollment Form Outpatient Pharmacy Overview Document Chain Pharmacy Overview Document Proposed New Title Independent Outpatient Pharmacy Enrollment Form Chain Outpatient Pharmacy Enrollment Form Closed System Outpatient Pharmacy Enrollment Form Inpatient Pharmacy Enrollment Form Independent Outpatient Pharmacy Overview Document Chain Outpatient Pharmacy Overview Document Patient Prescriber Agreement Form 1. Revision to the Patient Privacy Notice statement on the PPAF. I allow the TIRF REMS Access program to receive, use, and share my Health Information, using a unique, encrypted identifier instead of my name, in order to: a. Evaluate and report to the FDA about the proper use of TIRF medicines and the effectiveness of the TIRF REMS Access program. b. Report to the FDA, about side effects from TIRF medicines and the TIRF REMS Access program effectiveness. 2. Revised PPAF to remove the patient phone number as a mandatory field necessary for patient enrollment. 3. Revised prescriber attestations #1 - #3 on the PPAF, as indicated below. 1. My patient is currently using around the clock opioid medication and has been for at least one (1) week. I understand that TIRF medicines are indicated only for the management of breakthrough pain in patients Reference ID: 3399442 FDA_6692 with cancer, who are already receiving, and who are tolerant to, around-the-clock opioid therapy for their underlying persistent pain. 2. I understand that TIRF medicines are contraindicated for use in opioid non-tolerant patients, and know that fatal overdose can occur at any dose. 3. My patient is opioid tolerant. I understand that pPatients considered opioid-tolerant are those who are regularly taking at least: 60 mg oral morphine/day; 25 micrograms transdermal fentanyl/hour; 30 mg oral oxycodone/day; 8 mg oral hydromorphone/day; 25 mg oral oxymorphone/day; or an equianalgesic dose of another opioid for one week or longer. 4. Revised patient attestation #2 on the PPAF, as indicated below. 2) I understand that TIRF medications should only be taken by patients who are regularly using another opioid, around-the-clock, for constant pain. opioid pain medications. I understand that before I can take any TIRF medicine, I must be opioid tolerant. If I am not taking around-the-clock opioid pain medicine, my prescriber and I have discussed the risks of only taking TIRF medicines. whether I am opioid tolerant. Prescriber and Pharmacy Enrollment Forms 1. Enrollment forms modified to state that the Knowledge Assessment should be submitted with the enrollment form. Dear Healthcare Provider Letter TRIG agreed to remove the DHCP letters from the TRIF REMS Access website. Frequently Asked Questions (FAQ) document 1. TRIG removed all reference to the transition from individual TIRF REMS programs to the shared system TIRF REMS Access Program. Furthermore, they added a section titled “How long is my enrollment effective in the TIRF REMS Access program?” which describes the reenrollment process to the following sections: • • • • outpatient pharmacies inpatient pharmacies prescribers distributor (wholesaler) 2. As requested by FDA, the following language was added: Reference ID: 3399442 FDA_6693 “What if our pharmacy’s management system cannot communicate with the TIRF REMS Access program (e.g. does not electronically transmit claims information)? You will need to contact the TIRF REMS Access program at 1-866-822-1483 to see if you qualify to enroll as a “closed system pharmacy.” TIRF REMS Overview documents 1. As requested by the FDA, a Closed System Outpatient Pharmacy Overview document, modeled after existing TIRF REMS overview documents, was created for this modification. This document was revised during the review period to improve clarity and flow. After revisions were agreed upon, TRIG subsequently revised the overview documents for Prescribers, Inpatient Pharmacies and Independent and Chain Outpatient Pharmacies to follow the same format as the Closed System Outpatient Pharmacy Overview. 2. The closed pharmacy overview document was revised to indicate during prescription verification a DEA number will not be required, if applicable, in order to validate a prescription. This was necessary due to a newly instituted process for enrolling a small number of closed system prescribers who do not require an individual DEA number in order to prescriber CII medicines. This process allows enrollment of these closed system prescribers and validation of a prescription written by these prescribers with only an NPI number. However, the affected prescribers can only enroll via fax. 3. TRIG provided additional minor edits to the stakeholder overview documents which do not impact the goals of the REMS or operations. TIRF REMS Education Program On July 31, 2013, an efficacy supplement (S-005) for Subsys (fentanyl sublingual spray) (NDA 202788) which included new recommendations for safely switching from Actiq (fentanyl oral transmucosal lozenge) to Subsys was approved. Accordingly, slides 15 and 19 of the TIRF REMS Education Program were revised to reflect this change. (see K Lehrfeld REMS Review, July 5, 2013) TIRF REMS Knowledge Assessment On July 31, 2013, an efficacy supplement (S-005) for Subsys (fentanyl sublingual spray) (NDA 202788) which included new recommendations for safely switching from Actiq (fentanyl oral transmucosal lozenge) to Subsys was approved. Accordingly, the following question in the TIRF REMS Knowledge Assessment was revised to reflect this change. (see K Lehrfeld REMS Review, July 5, 2013) Question 11: Conversion between specific only two TIRF medicines has been established and is described in the Prescribing Information for which two products? Select one option. Reference ID: 3399442 FDA_6694 A. B. C. D. Lazanda to Actiq Actiq to Fentora Abstral to Fentora Actiq to Subsys Fentora to Actiq Both B & C Global changes to the TIRF REMS appended materials resulting from a non-safety related labeling change to an individual TIRF products NDA: 1. Changes to the following TIRF REMS product names were globally applied to all REMS materials: • “FENTORA® (fentanyl citrate) buccal tablet” was changed to “FENTORA® (fentanyl buccal tablet)” • “Onsolis® (fentanyl) buccal soluble film” was changed to “Onsolis® (fentanyl buccal soluble film)” • Replaced the ™ symbol after Subsys with ®. • “Subsys™ (fentanyl) sublingual spray” was changed to “Subsys® (fentanyl sublingual spray)” 2. Addition of the following TIRF REMS products new NDCs to the Chain and Independent Outpatient Pharmacy enrollment forms Subsys 20482-001-10 20482-002-10 20482-004-10 20482-006-10 20482-008-10 20482-001-01 20482-002-01 20482-004-01 20482-006-01 20482-008-01 Abstral 57881-331-12 57881-331-32 57881-332-12 57881-332-32 57881-333-12 57881-333-32 57881-334-12 57881-334-32 57881-336-32 57881-338-32 Par Pharmaceutical 49884-459-55 49884-460-55 49884-461-55 49884-462-55 49884-463-55 49884-464-55 3. Changes to the following Subsys NDCs: Replaced 20482-012-30 with 20482-012-15 Replaced 20482-016-30 with 20482-016-15 Reference ID: 3399442 FDA_6695 4.2.3 Implementation System The applicant did not propose changes to the implementation system of the REMS. 4.2.4 Timetable for Submission of Assessments The timetable for submission of assessments of the REMS will remain the same as that approved on December 28, 2011. 4.3 SUPPORTING DOCUMENT 1. As requested by FDA, the REMS Supporting Document was updated to add a specific section, “Closed System Pharmacies”. 2. TRIG proposed adding the closed system pharmacies to the assessment plan in the REMS supporting document. However, the second REMS Assessment submitted on December 21, 2012 is currently under review. Therefore, the TRIG’s proposed changes to the REMS Assessment plan and any future changes will be reviewed under separate cover. 3. Clarification of the definition for wholesaler distributors in the REMS supporting document. TIRF Sponsors will ensure that wholesaler distributors who take title to or direct the sale or disposition of TIRF medicines to persons other than a consumer or patient are enrolled in the TIRF REMS Access program and comply with the program requirements for wholesale distributors. 4. The TIRF REMS Prescription Authorization Request Form for closed system outpatient pharmacies was added to the TIRF REMS Supporting Document as an appended material. 5. On May 1, 2013, Abstral ownership transitioned from ProStrakan to Galena BioPharma. In order to support this transition, the REMS Supporting document (Table 1 on page 4) was updated to reflect Galena as the new Applicant/Sponsor. 6. On September 9, 2013, Lazanda ownership transitioned from Archimedes Pharma US, Inc. to Depomed, Inc. The REMS Supporting document (Table 1 on page 4) was updated to reflect Depomed, Inc. as the new Applicant/Sponsor. 3. REMS ASSESSMENT PLAN The Second REMS Assessment submitted on December 21, 2012 is currently under review. Therefore, the TRIG’s proposed changes to the REMS Assessment plan and any future changes will be reviewed under separate cover. 4. CONCLUSION DRISK finds the proposed TIRF REMS modification as received on September 24, 2013 acceptable. The revisions were proposed in response to an email dated June 28, 2012 by Reference ID: 3399442 FDA_6696 the applicant to update TIRF REMS appended materials with Closed System Outpatient Pharmacy information. In addition, the following revisions were discussed and agreed upon during this review cycle. • Revised terminology, processes, and definitions for outpatient pharmacies • Revised terminology and definitions for wholesalers/distributors • Revised attestations for physicians and patients to address concerns regarding patient access • Revised Program Overview and Frequently Asked Questions to improve clarity and content • Updated REMS materials to reflect the completion of the transition phase for the TIRF REMS Access Program The timetable for submission of assessments of the REMS will remain the same as that approved on December 28, 2011. The REMS assessment plan did not change, and will remain the same as that that described in the December 28, 2011 Approval letter. 5. RECOMMENDATIONS The OSE, DRISK recommends approval of the TIRF REMS Modification, received between September 25-28, 2012 (see Table 2) and last amended through one joint submission into the drug master file (DMF) (027320) on September 24, 2013, and appended to this review. ATTACHMENTS Reference ID: 3399442 FDA_6697 --------------------------------------------------------------------------------------------------------This is a representation of an electronic record that was signed electronically and this page is the manifestation of the electronic signature. --------------------------------------------------------------------------------------------------------/s/ ---------------------------------------------------KIMBERLY LEHRFELD 10/31/2013 TIRF SSS REMS Modification 2 Final review. Review is also attached to DMF 27320 on October 31, 2013. CLAUDIA B MANZO 10/31/2013 concur Reference ID: 3399442 FDA_6698 insvs THERAPEUTICS.INC. May 20,2014 Bob Rappaport, M.D., Director Division of Anesthesia, Analgesia and Addiction Products Food and Drug Administration Central Document Room 5901-B Ammendale Road Beltsville, MD 20705-1266 Re: NBA 202788: (Fentanyl Sublingual Spray) for the management of breakthrough cancer pain Sequence No. 0081: Reference to REMS Modi?cation filed to TIRF REMS DMF #027320 Dear Dr. Rappaport: Reference is made to Insys Therapeutics, Inc.?s New Drug Application 202788 for SUBSYS (Fentanyl Sublingual Spray) approved on January 4, 2012. Additional reference is made to the Letter of Authorization (LOA) for DMF #027320 which contains the Single Shared REMS for Transmucosal Immediate Release Fentanyl (TIRF) products submitted to this application on September 1 1, 2013. Per the guidelines in Section 1.5 of the DMF instruction document entitled, ?Process for Utilizing a Type Drug Master File (DMF) for a Shared System Risk Evaluation and Mitigation Strategy (REMS) Shared System REMS Insys hereby notifies FDA of its submission of Modi?cation #3 to the TIRF REMS DMF #027320 in Sequence 0009 on May 20, 2014. The modi?cations are comprised of changes requested by the FDA in an e-mail dated February 5, 2014, and further changes proposed by the TIRF REMS Industry Group on March 24, 2014 which were subsequently authorized by FDA on April 22, 2014. There have been no post approval clinical trials completed or ongoing during this reporting period. Please note that the 24 Month REMS Assessment for the TIRF REMS Access Program was previously submitted on December 27, 2013 in Sequence 0007 to DMF #027320. Should you have questions or require additional information, please contact me by telephone at 602- 910-2617 Ext. 9022, facsimile at 602-910-2627, or e?mail at Sincerely, 11111111161400 Willene M. Brondum Director, Regulatory Affairs 444 South Ellis Street. Chandler. AZ 85224 I phone: 602.910.2617 I fax: 602.910.2627 Electronic Submission Specifications This submission is compliant with FDA's Guideline for Industry: Providing Regulatory Submissions in Electronic Format - Human Pharmaceutical Product Applications and Related Submissions Using the eCTD Specifications (June 2008). All files were checked and verified to be free of viruses prior to transmission through the electronic submission gateway. This eCTD has been generated by Accenture, LLP (formerly Octagon Research Solutions Inc.), who has filed an acceptable eCTD pilot with the Center (Pilot Number 900777). Anti-Virus Program Program Version Virus Definition Date Submission Size Symantec Endpoint Protection Edition 11.0.5002.333 05/17/2014 rev. 1 Approx. 2.85 MB The IT point of contact for this submission is: Name Phone Number Email Address Willene Brondum 602.910.2617 ext. 9022 wbrondum@insysrx.com FDA_6700 Department of Health and Human Services Food and Drug Administration Center for Drug Evaluation and Research Office of Surveillance and Epidemiology Office of Medication Error Prevention and Risk Management REMS MODIFICATION REVIEW Interim Comments #1 Date: October 20, 2014 Reviewer(s) Cathy A. Miller, MPH, BSN, Risk Management Analyst Division of Risk Management (DRISK) Joan Blair, MPH, Health Communication Analyst, DRISK Team Leader Kimberly Lehrfeld, Pharm.D., DRISK Acting Division Director: Reema Mehta, Pharm.D., M.P.H., DRISK Table 1 Drug Names, Dosage Form and Sponsor: Drug Name Abstral (fentanyl) Actiq (fentanyl citrate) Fentora and Authorized Generic (fentanyl citrate) Lazanda (fentanyl) Onsolis (fentanyl) Subsys (fentanyl) Dosage Form and Route Sublingual tablet Oral transmucosal lozenge Buccal tablet NDA Number 022510 Sponsor 020747 Galenya BioPharma Cephalon, Inc. 021947 Cephalon, Inc. Nasal spray 022569 DepoMed, Inc. Buccal soluble film Sublingual spray 022266 Meda Pharmaceuticals Insys Therapy 202788 Therapeutic Opioid Agonist class: Dosage Transmucosal Immediate release Fentanyl (TIRF) forms: Reference ID: 3645823 FDA_6701 Table 2: TIRF REMS Modification #3 DMF 27320 Seq. No. 0009 received May 20, 2014 Drug Name NDA Number Suppl. Submitted Date; Amendment Submitted Date Suppl. Number (Seq. No.) Abstral Actiq 022510 020747 May 21, 2014 May 21, 2014 S-014 (0089) S-041 (0041) Fentora and AG Lazanda Onsolis Subsys 021947 022569 022266 202788 May 21, 2014 May 21, 2014 May 21, 2014 May 20, 2014 S-022 (0048) S-020 (0115) S-014 (0120) S-012 (0081) Abbreviations: Amend.=Amendment; AG=Authorized Generic; DMF=Drug Master File; LOA=Letter of Authorization; Seq. No.=Sequence Number; Suppl.=Supplement; NDA=New Drug Application OND Review Division: Division of Anesthesia, Analgesia and Addiction Products (DAAAP) OSE RCM #: 2014-2057 TSI #: 290 n/a = not applicable Reference ID: 3645823 FDA_6702 1 INTRODUCTION ....................................................................................................... 4 1.1 BACKGROUND .......................................................................................................... 4 1.2 REGULATORY HISTORY ........................................................................................... 5 2 MATERIALS REVIEWED ........................................................................................ 7 2.1 SUBMISSIONS ........................................................................................................... 7 2.2 OTHER MATERIALS INFORMING OUR REVIEW .......................................................... 8 3 PROPOSED REMS MODIFICATION with Rationale .............................................. 8 3.1 REMOVAL OF NDC NUMBERS.................................................................................. 8 3.2 REMOVAL OF REFERENCE TO GENERICS .................................................................. 9 3.3 REMOVAL OF ‘ATTACHMENT 1’ LIST OF TIRF MEDICINES/REPLACE WITH HYPERLINK TO FDA APPROVED REMS WEBSITE .............................................................. 10 3.4 CRITERIA FOR INACTIVATION OF PATIENT-PRESCRIBER AGREEMENT (PPAF) ...... 12 3.5 REVISION OF REMS ASSESSMENT METRICS ......................................................... 13 3.6 REVISIONS TO ENHANCE KNOWLEDGE ABOUT CONVERSION OF TIRF MEDICINES14 3.7 INFORMATION ABOUT THE TIRF REMS CASH CLAIM TRANSACTION PROCESS .... 15 3.8 UPDATE THE TIRF REMS WEB PROTOTYPE /WEBSITE LANDING PAGE ............... 18 4 RECOMMENDATIONS FOR THE REVIEW DIVISION ...................................... 19 5 COMMENTS FOR THE APPLICANT .................................................................... 19 5.1 GENERAL COMMENTS ............................................................................................ 20 5.2 REMS DOCUMENT (ATTACHMENT 1).................................................................... 21 5.3 FREQUENTLY ASKED QUESTIONS (FAQ) (ATTACHMENT 6) .................................. 21 5.4 INDEPENDENT OUTPATIENT PHARM ENROLLMENT FORM (ATTACHMENT 11) ....... 21 5.5 CHAIN OUTPATIENT PHARM ENROLLMENT FORM (ATTACHMENT 12) ................... 21 5.6 SUPPORTING DOCUMENT ....................................................................................... 22 5.7 WEB PAGE PROTOTYPE (ATTACHMENT 17) ........................................................... 22 Reference ID: 3645823 FDA_6703 1 INTRODUCTION This is a review of the proposed risk evaluation and mitigation strategy (REMS) modification for the Transmucosal Immediate-Release Fentanyl (TIRF) REMS Single Shared System (SSS) submitted by the Transmucosal REMS Industry Group (TRIG) between March 12 and May 21, 2014 (see Table 2 on cover page 2 for detailed submission information). 1.1 BACKGROUND TIRF medicines are short-acting fentanyl products indicated for the management of breakthrough pain in adults with cancer who are routinely taking other opioid pain medicines around-the-clock for pain. The approved TIRF medicines include: • Abstral (fentanyl) sublingual tablet • Actiq (fentanyl citrate) oral transmucosal lozenge • Fentora (fentanyl citrate) buccal tablet • Lazanda (fentanyl) nasal spray, • Onsolis (fentanyl) buccal soluble film • Subsys (fentanyl) sublingual spray • Approved generic equivalents of these products The TIRF medicines are approved under a single shared system REMS that has the following goal and objectives: 1. Prescribing and dispensing TIRF medicines only to appropriate patients, which includes use only in opioid-tolerant patients. 2. Preventing inappropriate conversion between TIRF medicines. 3. Preventing accidental exposure to children and others for whom it was not prescribed. 4. Educating prescribers, pharmacists, and patients on the potential for misuse, abuse, addiction, and overdose of TIRF medicines. The elements included in the program are Medication Guides (MG) for each individual TIRF medicine and the following elements to assure safe use (ETASU): Reference ID: 3645823 • Healthcare providers who prescribe TIRF medicines for outpatient use are specially certified • TIRF medicines will only be dispensed by pharmacies that are specially certified FDA_6704 • TIRF medicines will only be dispensed for outpatient use with evidence or other documentation of safe-use conditions. The timetable for submission of TIRF REMS Access Program assessments is at 6 and 12 months from the date of the initial REMS approval, and annually thereafter. 1.2 REGULATORY HISTORY As described in the DRISK December 2011 REMS review 1, FDA determined that all TIRF products were required to have a REMS to ensure that the benefits of the drug outweighed the increased risks of misuse, abuse, addiction, overdose and serious complications due to medication errors. The SSS TIRF REMS program was approved on December 28, 2011, and REMS modifications were approved on June 5, 2012 2 and November 7, 2013 3. The currently approved TIRF REMS consists of a MG, ETASU, an implementation system, and a timetable for submission of assessments of the REMS. The regulatory history associated with this proposed TIRF REMS modification is as follows: On May 20, 2014, the TIRF SSS REMS Sponsors submitted proposed modifications to the REMS for review and consideration to DMF 27320, following communications between the TIRF REMS Industry Group (TRIG) and Vaishali Jarral, Officer of Surveillance and Epidemiology (OSE) Project Manager that were a result of internal discussions about select elements of the TIRF REMS Program 4: • On February 5, 2014, FDA communicated to the TRIG, via email, suggestions for the next TIRF REMS Modification (#3) which had been discussed during previous months with the workgroup. The purpsose of these changes were to minimize administrative redundancy when revisions to individual TIRF products labeling or packaging occur (see Appendix A) : o Removing NDC numbers from TIRF REMS Pharmacy Enrollment Forms o Removing ‘Attachment A’ from the TIRF REMS document and all TIRF appended materials. This request also included a recommendation to add a page to the TIRF REMS Access Program website containing a listing of currently approved TIRF REMS products, Sponsor Names, Contact phone numbers and link to product specific information for each product, as well as the statement “The TRIG attests that the table will only include 1 DRISK Final TIRF REMS Review December 27, 2011 (G. Toyserkani) 2 DRISK TIRF REMS Modification #1 Review DARRTS June 1, 2012 (M. Moncur) 3 DRISK TIRF REMS Modification #2 Review DARRTS October 31, 2013 (K. Lehrfeld) 4 The TIRF Implementation Workgroup is an internal group of FDA staff from the DRISK, the Division of Anesthesia, Analgesia and Addiction Products (DAAAP), the Office of Center Director (OCD), the Office of Compliance (OC) and the Office of Generic Drugs (OGD) who meet biweekly to discuss current issues pertaining to the TIRF REMS Access Program. Reference ID: 3645823 FDA_6705 products listed in the link titled ‘List of approved application numbers and sponsors’ on the FDA Approved REMS website”. o Remove reference to generics for individual products, replacing instead with an asterisk/footnote that the table includes approved generic equivalents of the covered products, in Table 1 of the Education Program. • On February 18, 2014, the TRIG responded to the 2/8/2014 email (See Appendix B) and accepted all requested revisions. In addition, as previously discussed and agreed upon between the Agency and the TRIG during the review of the TIRF REMS 12-Month Assessment report 5 , the TRIG proposed removal of language from the REMS Supporting Document about deactivation of patients shown to have multiple prescribers in an overlapping timeframe due to concerns of non-compliance. The TRIG explained that they have a limited view of data and is unable to confirm or rule out doctor-shopping behavior because it may result in legitimate patient-access issues. • On March 24, 2014 the TRIG sent an email communication that included the previously agreed upon TIRF REMS modifications along with the following additional proposed modifications: o Revised/editted select language in the Patient Counseling section of the Education Program to strengthen certain information about converting from one TIRF medicine to a different TIRF medicine, and emphasizing TIRF medicines are not equivalent to any other fentanyl product, including TIRF medicines, on a microgram-per-microgram basis, except generic equivalents, based on KAB survey results o Revised the Outpatient Pharmacy Overview document and Frequently Asked Questions (FAQs) with added information about the TIRF REMS Cash Claim process, including defining a Cash Claim, and how to correctly process these claims through TIRF REMS Access Program using the REMS Cash BIN 014780. o Revised the TIRF REMS Access Program website per agreed upon TIRF REMS modifications agreed upon and outlined above. o Revised assessment metrics with FDA/TRIG agreed upon metrics 6 • 5 On April 22, 2014, Office of Surveillance and Epidemiology (OSE) sent an email communication to the TRIG that acknowledged receipt of the proposed TIRF REMS Modifications to-date, and provided instructions for formally submitting a REMS Modification. DRISK 12-Month TIRF REMS Assessment Report DARRTS October 16, 2013 (I. Cerny) 6 The TIRF REMS Assessment was evaluated in a separate OSE/DRISK Review DARRTS June 19, 2014 (I. Cerny) and is also part of ongoing negotiations/discussion between the DRISK TIRF REMS Assessment team and the TRIG. Reference ID: 3645823 FDA_6706 2 • On May 16, 2014, an email information request was sent to the TRIG following internal discussions by the TIRF REMS Implementation Work Group that requested clarification from the TRIG on their proposal to add information in the Outpatient Pharmacy Overview document and FAQ about the TIRF REMS Cash Claim process (See Appendix C). • On May 30, 2014, the TRIG responded to the Agency’s May 16, 2014 information request and subsequent proposal to the TIRF REMS modification, which is discussed below in Sections 3 and 4. (See Appendix D) • On May 20, 2014, the TRIG submitted to DMF 27320 Proposed TIRF REMS Modification #3, with proposed modifications to the TIRF REMS as previously discussed. All TIRF REMS Sponsors subsequently submitted prior approval supplement/Proposed REMS Modification letters referencing DMF 27320 between May 20 and May 21, 2014 (see Table 2 on Page 2 for detailed submission information). The proposed modifications as previously discussed above included the following: 1. Revise REMS materials to eliminate product specific information (NDC numbers and reference to generics) which does not impact the safe use of TIRF Products 2. Revise REMS materials to reference the currently approved TIRF products list on the FDA Approved REMS website rather than including throughout the REMS material as ‘Attachment A’ 3. Revise the criteria in the REMS and REMS Supporting Document for triggers for inactivation of patient PPAF, including remove reference to deactivating patients shown to have multiple prescribers in an overlapping timeframe 4. Revise the REMS Supporting Document to include revised assessment metrics into the REMS Supporting Document, reviewed by the DRISK Assessment team under separate cover 7 5. Revise select Education Program material to emphasize and strengthen appropriate conversion and patient counseling information. 6. Revise the pharmacy overview, FAQ documents, and select enrollment forms (independent and outpatient pharmacy enrollment forms), to add information about TIRF REMS Cash Claims in order to better clarify and define the TIRF REMS Cash Claim and required transaction process 7. Revise the TIRF REMS Access website to incorporate items above and link respective Prescribing Information and MG to DailyMed MATERIALS REVIEWED 2.1 SUBMISSIONS The following submissions were reviewed for the proposed TIRF REMS modification: 7 DRISK 18-Month REMS Assessment Report Review dated June 18, 2014. Reviewer: I. Cerny Reference ID: 3645823 FDA_6707 • TIRF REMS Industry Group (TRIG) versus Drug Master File (DMF 27320) Transmucosal Immediate Release Fentanyl (TIRF) Access Program REMS Modification received May 20, 2014 (Seq. No. 009) and to individual applicant holders as per table below • TIRF REMS Industry Group (TRIG) versus Accenture versus McKesson Specialty Health TIRF REMS Correspondence received May 30, 2014 (Seq. No. 010) 2.2 OTHER MATERIALS INFORMING OUR REVIEW 3 • Cerny, I. DRISK Review of third (24 month, October 29, 2012 to October 28, 2013) Risk Evaluation and Mitigation Strategy (REMS) Consolidated Assessment Report for TIRF Agents dated June 19. • Email communications between FDA/OSE and the TRIG, as identified above in Section 1.2 Regulatory History and appended to this review PROPOSED REMS MODIFICATION WITH RATIONALE 3.1 REMOVAL OF NDC NUMBERS The Agency proposed this modification to revise select REMS materials to eliminate product specific information (NDC numbers) and replace with a link on the TIRF REMS Access Program website that references the information for interested stakeholders. The TIRF Implementation Working Group determined that this revision will reduce burden on the Agency and TRIG for modifications to add or remove product NDC numbers. 8 Agreement was made that removal of this information and replacement with a link to this information that the TRIG will attest to keeping up to date will not impact the safe use of the TIRF products and minimizes the need for repeated modifications as the program continues to grow. 9 The impacted REMS materials include: 1. Independent Outpatient Pharmacy Enrollment Form a. Page 3 (deleted) 2. Chain Outpatient Pharmacy Enrollment Form a. Page 5 (deleted) 3. TIRF REMS Website Prototype a. See Section 3.8 below for details Reviewer Comments: DRISK has reviewed the Sponsor’s latest submission May 20, 2014, and we agree with this proposal to create a new document titled “TIRF 8 TIRF Implementation Workgroup meets bi-weekly to discuss ongoing issues surrounding the TIRF REMS program. The workgroup is comprised of selected members from DRISK, DAAAP, Office of Compliance (OC), Office of Generic Drugs (OGD) and Office of Center Director (OCD) 9 TRIG and FDA/OSE email communications dated February 5, 2014 and February 18, 2014 discussing proposed modifications (Section 1.2) Reference ID: 3645823 FDA_6708 Products with NDC Numbers” which will be available as a PDF link on the TIRF REMS Access website Resources for Pharmacies and Resources for Distributors tabs. However, we have additional recommendations. 1. The TRIG proposal included a hyperlink that referred stakeholders to the main www.TIRFREMSaccess.com site with additional directions to navigate through the Resources tabs to reach the appropriate web page that houses the ‘TIRF Products with NDC numbers’ pdf hyperlink. TRIG’s proposed link to the main TIRF REMS Access Page with direction to navigate to specific tabs is not appropriate In an effort to minimize the need to navigate from the main page through multiple pages of the TIRFREMSaccess.com website required to reach the “TIRF Products with NDC numbers” pdf , please hyperlink directly to the pdf (i.e. www.TIRF REMSaccess.com/XXX). 2. The direct hyperlink to the pdf document “TIRF Products with NDC Numbers” pdf webpage should be included on the Independent outpatient pharmacy enrollment form and the Chain outpatient pharmacy enrollment form as indicated in our marked up track changes documents attached to this review. . 3. Submit a mock-up of the “TIRF Products with NDC Numbers” pdf document as part of the TIRF REMS Program Website Prototype. Our full recommendations are provided in Section 5 along with accompanying Attachments that include DRISK comments and track change documents. 3.2 REMOVAL OF REFERENCE TO GENERICS The Agency proposed this modification to revise select REMS materials to eliminate the reference to generics for specific products which does not impact the safe use of TIRF, and replace the reference to generics with (**) in the title of the table (i.e. Products ** Covered Under this Program), and an accompanying footnote stating “This includes approved generic equivalents of these products”. As discussed above in Section 3.1, this revision originated from internal discussions about certain aspects of the TIRF REMS program that prompt repeated administrative process and modifications including the addition of generic drug names to select REMS material. Agreement was made that removal of this information and replacing with the referenced (**) and footnote did not impact the safe use of the TIRF products and minimizes the need for repeated modifications as the program continues to grow. Impacted REMS materials include: 1. Education Program for Prescribers and Pharmacists a. Page 17-19 table b. TIRF REMS Access Program Web Page 45-47 Reviewer Comments: DRISK has reviewed the Sponsor’s latest submission dated May 20, 2014, and we agree with this proposal. Our full recommendations are provided in Section 5 along with accompanying Attachments that include DRISK comments and track change documents. Reference ID: 3645823 FDA_6709 3.3 REMOVAL OF ‘ATTACHMENT 1’ LIST OF TIRF MEDICINES/REPLACE WITH HYPERLINK TO FDA APPROVED REMS WEBSITE The Agency proposed this modification to remove ‘Attachment 1’ list of TIRF medicines in select REMS documents and replacing the list with a hyperlink that redirects the user to FDA Approved Risk Evaluation and Mitigation Strategy (REMS) website. As discussed above in Section 3.1, this revision originated from internal discussions about certain aspects of the TIRF REMS program that prompt repeated administrative process and modifications including the product list (Attachment 1/Table 1) which appears repetitively throughout select REMS material. Agreement was made that removal of this information did not impact the safe use of the TIRF products and minimizes the need for repeated modifications as the program continues to grow. The impacted REMS materials include: 1. TIRF REMS Document a. Page 3/f b. Page 8/c c. Page 9/c d. Page 11/c e. Page 16 III. 2. TIRF REMS Supporting Document a. Page 3-5 b. Page 40-41 3. Overview for Prescribers a. Page 1 b. Page 6 4. Prescriber Enrollment Form a. Page 1 (No. 6 attestation statement) b. Page 4 (deleted) c. TIRF REMS Access Program Web Page 71 5. Overview for Patients and Caregivers a. Page 1 b. Page 3 (deleted) 6. Independent Outpatient Pharmacy Overview a. Page 1 b. Page 7 (deleted) 7. Chain Outpatient Pharmacy Overview a. Page 1 b. Page 7 (deleted) 8. Closed System Outpatient Pharmacy Overview a. Page 1 b. Page 6 (deleted) 9. Independent Outpatient Pharmacy Enrollment Form Reference ID: 3645823 FDA_6710 a. Page 1 b. Page 5 (deleted) c. TIRF REMS Access Program Web Page 88-89 10. Chain Outpatient Pharmacy Enrollment Form a. Page 1 (No. 3 attestation statement) b. Page 6 (deleted) c. TIRF REMS Access Program Web Page 99-100 11. Closed System Outpatient Enrollment Form a. Page 1 (No. 3 attestation statement) b. Page 3 (deleted) 12. Inpatient Pharmacy Enrollment Form a. Page 1 (No. 3 attestation statement) b. Page 3 (deleted) c. TIRF REMS Access Program Web Page 80 13. Distributor Enrollment Form a. Page 1 b. Page 3 (deleted) 14. TIRF Website Prototype and TIRF Website Landing Page a. See Section 3.8 below Reviewer Comments: DRISK has reviewed the Sponsor’s latest submission dated May 20, 2014, and we agree with the removal of Attachment 1 as previously discussed, throughout REMS and REMS appended material, in order to reduce redundancy throughout the material, however we have additional recommendations. We agree that the information included on the FDA Approved REMS website (i.e. pharmaceutical manufacturer, contact information per product and NDA numbers) for TIRF products is beneficial for a select group of industry stakeholders, and therefore, a link to this information ( “List of Application Numbers and Sponsors” at http://www.fda.gov/downloads/Drugs/DrugSafety/PostmarketDrugSafetyInformationforP atientsandProviders/UCM309784.pdf ) should be provided in the REMS supporting document. Since it is relevant only to the Agency and TRIG members, it is appropriate for it to only be located in the REMS Supporting Document. Since this information is less relevant for patients, providers and pharmacists and distributors, it is not necessary for this link to be included in the REMS appended materials. Therefore, we recommend including a link to the new webpage you created and submitted as Page 148 in the draft Website Prototype in the TIRF REMS document and appended materials wherever you have removed a reference to Attachment 1. Furthermore, we recommend revising the table on Page 148 in the draft Website Prototype document as follows: Reference ID: 3645823 FDA_6711 1. The table submitted should have only the column titles filled in. The remainder of the table should be blank. 2. Add the following attestation statement to Page 148 in the draft Website prototype document that reads: The TRIG attests that the table above will only include products listed in the link titled 'List of approved application numbers and sponsors' on the FDA Approved REMS website. Our full recommendations are provided in Section 5 along with accompanying Attachments that include DRISK comments and track change documents. 3.4 CRITERIA FOR INACTIVATION OF PATIENT-PRESCRIBER AGREEMENT FORM (PPAF) The TRIF proposed a modification to revise the criteria for the description of triggers that will inactive a patient’s PPAF, including the removal of the criteria of ‘patients who receive prescriptions for TIRF medicines from multiple prescribers within an overlapping time frame, that is suggestive of misuse, abuse, or addiction’. The modification also proposes the addition of criteria that will trigger inactivation of a patient PPAF. The current TIRF REMS has only one criteria listed which is “the patient has not filled a prescription for more than six (6) months. This revision proposes adding the following: • PPAF has expired • Patient is deceased • Patient chooses to no longer participate in the TIRF REMS Access Program • Substantive changes to the TIRF REMS Access Program The impacted REMS materials include: 1. TIRF REMS Document a. Page 14/e 2. TIRF REMS Supporting Document a. Page 19 Reviewer Comments: The TRIG’s proposed revisions to eliminate the trigger involving patient receipt of prescriptions from multiple prescribers were prompted by discussions during and subsequent to the DRISK review of the TIRF REMS 12-Month Assessment report 10, at which time agreement was reached to eliminate this criteria trigger due data provided by the TRIG that illustrated false positive results for this metric along with the added criteria that trigger inactivation listed above. 11 Given this information, we agree with this proposed revision. The TRIG proposed the addition of the other criteria listed above, which would trigger the inactivation of a patient PPAF. We note that neither the 12-Month nor the 24-Month 10 Cerny, I. TIRF REMS 12-Month REMS Assessment Review dated October 16, 2013. 11 Jarral V. OSE communication to the TRIG including agreed upon triggers for inactivation of patient PPAF dated September 20, 2013. Reference ID: 3645823 FDA_6712 TIRF REMS Assessment Report found any cases of patients being inactivated during the reporting period. 12 However, this reviewer finds it a feasible possibility the current specific criteria for patient inactivation may lack clarity and it is reasonable to propose added language to emphasize this information. And though we agree with the criteria added to include PPAF has expired, Patient is deceased and Patient chooses to no longer participate in the TIRF REMS Access Program, we do not agree with adding the criteria for when Substantive changes to the TIRF REMS Access Program. The TIRF REMS Access Program is a large and complex program with many moving parts. This criteria item is broad and ambiguous which could lead to confusion about what does and what does not constitute “substantive changes”. Therefore, we recommend removing it from the proposed list of criteria. Our recommendations are provided in Section 5 along with accompanying Attachments that include DRISK comments and track change documents. 3.5 REVISION OF REMS ASSESSMENT METRICS This modification proposes revisions to the select TIRF REMS Assessment Plan metrics. The impacted REMS materials include: 1. TIRF REMS Supporting Document a. Pages 29-34 Reviewer Comments: The TRIG’s proposed revisions to the TIRF REMS Assessment plan that were included in the May 20, 2014 submission were based on numerous discussions between the TRIG and the TIRF REMS Assessment reviewer, along with subsequent discussions during bi-weekly TIRF REMS Implementation Workgroup meetings, which occurred between the time of the 24-Month Assessment report submission on December 27, 2013, and the TRIG’s May 20, 2014 submission of the TIRF REMS Modification. We note that the DRISK TIRF REMS 24-Month Assessment review was not finalized at the time of the May 20 TIRF REMS Modification submission, therefore, internal negotiations regarding the TIRF REMS Assessment plan were still underway. Therefore, following the May 20, 2014 TIRF REMS modification submission, and in conjunction with complete of DRISK TIRF REMS 24-Month Assessment Review on June 18, 2014 13, additional modifications to the TIRF REMS Assessment plan were agreed upon and communication to the TRIG in the FDA August 21, 2014 REMS Assessment Acknowledgement/REMS Plan Revision communication to the TRIG. 14 Therefore, those revisions supersede revisions provided by the TRIG in the current TIRF REMS Modification submitted May 20, 2014. Subsequently, as part of our comments to the TRIG for this TIRF REMS Modification review, we request a revision to the TIRF REMS Assessment Plan submitted with this 12 TRIG 12-Month TIRF REMS Assessment Report, submitted December 20, 2012, and TRIG 24-Month TIRF REMS Assessment Report submitted December 27, 2013. 13 Cerny, I. TIRF 24-Month Assessment Report Review dated June 18, 2014. 14 DAAAP REMS Assessment Acknowledgement/REMS Plan Revision for TIRF REMS sent to the TRIG August 21, 2014. Reference ID: 3645823 FDA_6713 proposed REMS modification to align with the August 21, 2014 REMS Assessment Acknowledgement/REMS Plan Revision communication sent by DAAAP. Additionally, we request revisions to the TIRF REMS Supporting Document that reflect updates to the audit plan, as reflect in the revised TIRF REMS Assessment Plan and acknowledged by the TRIG 15 where they cite regarding the addition of 4(b) - yearly audits of 5 inpatient pharmacies “The results of yearly inpatient audits will be included in 48-month report rather than the 36-month since a process does not yet exist in the TIRF REMS Access program for auditing inpatient pharmacies. The TRIG will need time to design a process to accomplish inpatient pharmacy audits; and, as a result, the inpatient pharmacy audit data will not be available in time for reporting in the 36-month assessment. Closedsystem pharmacy audit information will, however, be available and be included in the 36month report.” Our recommendations to include the revised TIRF REMS Assessment plan with additional information on the audit plan in the TIRF REMS Supporting Document are provided in Section 5 along with accompanying Attachments that include DRISK comments and track change documents. 3.6 REVISIONS TO ENHANCE KNOWLEDGE ABOUT CONVERSION OF TIRF MEDICINES The TRIG states that they are proposing this modification to emphasize and strengthen risk messaging about the conversion of TIRF medicines based on prescriber survey and knowledge assessment results that demonstrated low comprehension of this concept. 16 The impacted REMS materials and proposed revisions include: 1. Education Program for Prescribers and Pharmacists a. Page 14 Appropriate Conversion - Bullet 1 ‘bolded font’ as follows: TIRF medicines are not equivalent to any other fentanyl product, including another TIRF medicine, on a microgram-per-microgram basis. The only exception is for substitution of a generic equivalent for a branded TIRF medicine. b. Page 15 Appropriate Conversion – Bullet 2 ‘bolded font’ as follows: Converting from one TIRF medicine to a different TIRF medicine must not be done on a microgram-per-microgram basis and, must be titrated according to the labeled dosing instructions each time a patient begins use of a new TIRF medicine. c. Page 20 Patient Counseling – Tell the Patient: Added statement as follows: Note: Patients have had difficulty comprehending this concept; please emphasize it to your patients 15 TRIG Email communication to OSE Project Manager Vaishali Jarral dated September 4, 2014. 16 TRIG 24-Month REMS Assessment Report for Transmucosal Immediate-Release Fentanyl (TIRF) received December 27, 2013 (Seq. No. 0007) Reference ID: 3645823 FDA_6714 d. TIRF REMS Access Web Pages 43 and 48 as revised above in a-c Reviewer Comments: The TRIG proposes an emphasis on select language in the Education Program based on low comprehension of the concept. The TIRF REMS 24Month Assessment Report Review found that in general, patients knowledge of key messages about key messages about ‘not to switch TIRF medicines without medical input’ were fairly high (88%+). Prescriber had a high level of understanding that TIRF medicines are not interchangeable with the exception of one subset question where prescribers scored less than 80%: prescribers scored 76% to the subset questions (12b) of Question 4 TIRF medicines are interchangeable with each other regardless of route of administration, which read “The prescriber must not convert from the equivalent TIRF medicine dose to another TIRF medicine because they have different absorption properties and this could result in a fentanyl overdose.” However, prescribers scored between 89%-98% on the other subset questions related to interchangeability of TIRF medicines. Similarly, pharmacy KAB survey results indicated a generally acceptable knowledge about interchangeability of TIRF medicines with 95% answering correctly ‘false’ that “TIRF medicines are interchangeable with each other regardless of route of administration” and similar results to related questions about interchangeability. 17 DRISK believes that, although not a crucial deficiency finding of the TIRF REMS Assessment report, it is a reasonable proposal to strengthen select messaging to help enhance provider and patient knowledge and agree with this proposal with comments as indicated in below in Section 5 along with accompanying Attachments that include DRISK comments and track change documents. 3.7 INFORMATION ABOUT THE TIRF REMS CASH CLAIM TRANSACTION PROCESS The TRIG proposed revisions to add information to select TIRF REMS material to enhance understanding about the correct TIRF REMS Cash Claim transaction process. The TRIG states that these revisions are proposed based on several pharmacies acknowledgement that they are unaware of the cash claim processing requirements, and is documented as part of the TIRF REMS 24-Month Assessment Report (Table 29, NonCompliance Activity Reports by Stakeholders). The impacted REMS materials and proposed revisions include: 1. TIRF REMS Access Program Frequently Asked Questions (FAQ) Document a. Page 8 – Added text: Chain and Independent Outpatient Pharmacy CASH Claim FAQs What is the definition of a TIRF REMS CASH Claim? The definition of a TIRF REMS CASH Claim is any claim for a TIRF medicine that is not electronically transmitted to a Third Party Insurance BIN 17 Cerny, I. DRISK Review of third (24 month, October 29, 2012 to October 28, 2013) Risk Evaluation and Mitigation Strategy (REMS) Consolidated Assessment Report for TIRF Agents dated June 19. Reference ID: 3645823 FDA_6715 using the pharmacy management system and established telecommunication standards. This includes claims for patients without prescription coverage or any paper claims submitted to a program for payment. Does a TIRF REMS CASH claim need to be submitted to the TIRF REMS Access Program? Yes, all TIRF prescriptions, including CASH claims and other claims (i.e. workers comp), must be submitted to the TIRF REMS Access program to validate the enrollment status of the prescriber, patient and pharmacy prior to dispensing TIRF medicine to the patient. How do I submit a TIRF REMS CASH claim to the TIRF REMS Access Program? Prior to dispensing TIRF medicines, transmit using the REMS CASH BIN 014780,to submit a CASH claim to the TIRF REMS Access program 2. Independent Outpatient Pharmacy Overview a. Page 5 – Step 2 Confirm prescriber enrollment. Proposed additions indicated below in bold: -Each pharmacy site must confirm that the prescriber and patient are enrolled in the TIRF REMS Access program prior to dispensing each TIRF prescription by submitting a pharmacy billing claim via the chain pharmacy practice management system. This includes third party insurance claims, cash claims and any other claims (i.e.: workers compensation). Submitting a claim for a patient’s first TIRF prescription through the pharmacy management system will automatically enroll that patient in the TIRF REMS Access program. -To allow the TIRF REMS Access program to confirm prescriber and patient enrollment the pharmacy practice management system must populate the following fields in the pharmacy billing claim*: o Patient First Name, o Patient Last Name, o Patient Date of Birth, o Patient ZIP / Postal Zone, o Quantity Dispensed, o Days Supply, o Prescriber ID, o Prescriber Last Name *Use BIN 014780 for all cash and non-third party claims. 3. Chain Outpatient Pharmacy Overview a. Page 5/6 – Step 2 Confirm prescriber enrollment. Proposed additions indicated below in bold: Reference ID: 3645823 FDA_6716 -Each pharmacy site must confirm that the prescriber and patient are enrolled in the TIRF REMS Access program prior to dispensing each TIRF prescription by submitting a pharmacy billing claim via the chain pharmacy practice management system. This includes third party insurance claims, cash claims and any other claims (i.e.: workers compensation). Submitting a claim for a patient’s first TIRF prescription through the pharmacy management system will automatically enroll that patient in the TIRF REMS Access program. -To allow the TIRF REMS Access program to confirm prescriber and patient enrollment the pharmacy practice management system must populate the following fields in the pharmacy billing claim*: o Patient First Name, o Patient Last Name, o Patient Date of Birth, o Patient ZIP / Postal Zone, o Quantity Dispensed, o Days Supply, o Prescriber ID, o Prescriber Last Name *Use BIN 014780 for all cash and non-third party claims. 4. Closed System Outpatient Pharmacy Overview a. Page 4 – Step 2 Confirm prescriber enrollment. Proposed additions indicated below in bold: - Prior to dispensing each TIRF medicine prescription, confirm that the prescriber and patient are enrolled in the TIRF REMS Access program by contacting the TIRF REMS Access program by phone at 1-866-822-1483 or fax at 1-855-474-3062. This includes third party insurance claims, cash claims and any other claims (i.e.: workers compensation). Reviewer Comments: This proposal was submitted in preliminary communications between FDA and the TRIG, as outlined above in Regulatory History, prior to the formal May 20, 2014 submission of TIRF REMS Modification #3. On May 16, 2014, OSE sent an information request to the TRIG asking additional questions surrounding this proposed modification (see Appendix C). In response, the TRIG provided a response (see Appendix D) with additional details about the proposal, citing select results from the TIRF 24-Month REMS Assessment report, indicating non-compliance activities have occurred with cash transactions of TIRF product dispensing including seven (7) cases/pharmacies reporting not being aware of the cash claim process (utilizing the Cash BIN # when processing a TIRF prescription claim). In six out of seven of these cases, the pharmacist received a rejection but still dispensed the TIRF medicine, and in one case, the pharmacist did not submit a claim at all prior to dispensing the TIRF medicine. Based on our original May 16 inquiry, the TIRF reported that there have been an additional six non-compliance cases since the October 29, 2013 reporting period for the 24-Month Reference ID: 3645823 FDA_6717 TIRF REMS Assessment. In all cases, the pharmacists reported not being aware of the requirement to process cash claims through the TIRF REMS Program or were aware of the cash claim procedure but received a rejection, yet dispensed the TIRF medicine anyway. This information prompted internal TIRF REMS Workgroup discussions about this new awareness of an automation flaw for cash claim transactions for the TIRF REMS Program Switch System, used in pharmacies to communicate with the TIRF REMS Program to verify TIRF enrolment information prior to dispensing TIRF medicines. As discussions continue internally, and the challenges to any considerations that might remedy this issue at the individual pharmacy level, the workgroup agrees that added information, as proposed by the TRIG, may help provide education and awareness to pharmacies and pharmacists, about the correct cash claim transaction process. However, the group also believes that the addition of the following attestation to the Independent Outpatient and Chain Outpatient Pharmacy Enrollment Forms, will further enhance the dissemination of this important information: 15. I understand that differences in pharmacy software may affect automation capabilities for adjudicating prescriptions through the TIRF REMS access program without an insurance claim ((i.e. cash claim). If insurance is not used, pharmacy staff must manually enter the REMS Cash BIN #014780 in order for the transaction to be properly adjudicated through the TIRF REMS Program. Our full recommendations are provided in Section 5 along with accompanying Attachments that include DRISK comments and track change documents. 3.8 UPDATE THE TIRF REMS WEB PROTOTYPE DOCUMENT AND WEBSITE LANDING PAGE This modification proposes revisions to the TIRF REMS Access Web Prototype and Website Landing Page, that incorporations all changes outlined above, where identified, along with the following additional revisions (See Appendix E ‘TIRF Website Prototype Changes’ for a complete list of website revisions): 1. Resources for Prescribers Tab – Page 142 Update Page as follows: a. To remove the PDF icons from MG and PI b. New PDF link for ‘Product List for TIRF REMS Access Program’ c. Combining US Prescribing Information and Medication Guide with hyperlink to DailyMed. 2. Resources for Patients Tab – Page 143 Update Page as follows: a. To remove the PDF icons from MG and PI b. New PDF link for ‘Product List for TIRF REMS Access Program’ c. Combining US Prescribing Information and Medication Guide with hyperlink to DailyMed. 3. Resources for Pharmacists Tab – Page 144 Update Page as follows a. To remove the PDF icons from MG and PI b. New PDF link for ‘Product List for TIRF REMS Access Program’ Reference ID: 3645823 FDA_6718 c. New PDF link for ‘NDC Listing for TIRF REMS Access Program’ d. Combining US Prescribing Information and Medication Guide with hyperlink to DailyMed. 4. Resources for Distributors Tab – Page 145 Update Page as follows: a. To remove the PDF icons from MG and PI b. New PDF link for ‘Product List for TIRF REMS Access Program’ c. New PDF link for ‘NDC Listing for TIRF REMS Access Program’ d. Combining US Prescribing Information and Medication Guide with hyperlink to DailyMed. 5. Product List - Page 148 Update Page as follows: a. Update the page to include ‘Product List’ to replace ‘Attachment 1’ Reviewer Comments: DRISK has reviewed the Sponsor’s latest submission dated May 20, 2014, for the proposed revisions to the REMS Web Prototype, including the website landing page, and other proposed modifications to REMS and appended material. We have provided our full recommended revisions in Section 5 along, with accompanying Attachments which includes DRISK comments and track change documents. 4 RECOMMENDATIONS FOR THE REVIEW DIVISION We recommend that the following comments below (Section 5: Comments for the Applicant) on the TIRF REMS Access Program REMS modification proposal be sent to the TRIG. Please request that the TRIG respond to these comments as soon as possible to facilitate further review for this submission. The comments below are based on DRISK’s preliminary review of the REMS modification proposal for TIRF products. Appended to this review is the REMS modification proposal and the REMS materials including comments and track changes (see Attachments 1 – 17). 5 COMMENTS FOR THE APPLICANT We have the following comments, below, in response to your May 20, 2014 proposed TIRF REMS Modification submission, including redlined/track change documents (Attachments 1-17). Where indicated along with any redlined changes, FDA comments with recommendations in comment boxes in the documents or states FDA agrees with the proposed modification. Your amendment submission must include the following documents: 1. Redlined, Word versions of all TIRF REMS materials which were revised during this modification 2. Clean, Word version of all TIRF REMS materials which were revised during this modification Reference ID: 3645823 FDA_6719 3. One PDF of all final, clean TIRF REMS material (i.e. the TIRF REMS document and all TIRF REMS appended materials), except the TIRF REMS Supporting Document 5.1 GENERAL COMMENTS Throughout the REMS document as well as noted throughout all other REMS appended material, FDA notes the TRIG propose to remove the reference to Attachment 1 and replace is with a hyperlink to the FDA Approved REMS website. FDA agrees with the removal of Attachment 1 throughout the TIRF REMS appended material. FDA further agrees that linking to the FDA TIRF REMS list of products (including NDA numbers, manufacturers and contact information) may be helpful in the TIRF REMS Supporting document for TRIG Sponsors and FDA. However, we do not agree that linking to this FDA webpage would be helpful for other stakeholders (prescribers, patients, pharmacies and distributers). Therefore, FDA proposes instead: 1. All former references in REMS documents and REMS appended materials to the list of TIRF products on Attachment 1 should now provide a link to a new web page on the TIRF REMS Access website (Page 148 in the draft REMS Website Prototype) and not link to the following FDA website: http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforP atientsandProviders/ucm111350.htm The following documents are affected: • REMS Document (Attachment 1) • An Overview for Prescribers (Attachment 2) • Education Program for Prescribers and Pharmacists (Attachment 3) • Prescriber Enrollment Form (Attachment 4) • Overview For Patient and Caregiver (Attachment 5) • Frequently Asked Questions (FAQ) (Attachment 6) • Overview For Independent Outpatient Pharmacies (Attachment 7) • Overview For Chain Outpatient Pharmacies (Attachment 8) • Overview For Closed System Outpatient Pharmacies (Attachment 9) • Overview For Inpatient Pharmacies (Attachment 10) • Independent Outpatient Pharmacy Enrollment Form (Attachment 11) • Chain Outpatient Pharmacy Enrollment Form (Attachment 12) • Closed System Outpatient Pharm Enrollment Form (Attachment 13) • Inpatient Pharmacy Enrollment Form (Attachment 14) • Distributor Enrollment Form (Attachment 15) 2. Please also use this web page link (Page 148 in the TIRF REMS Access Website Prototype) whenever you reference the “Product List for TIRF REMS Access Program” or “Products Covered for TIRF REMS Access Program" on each Resource page (tabs) including the Resources for Prescribers tab, Resources for Patients tab, Resources for Pharmacists tab, and Resources for Distributors tab on the TIRF REMS Access website. Reference ID: 3645823 FDA_6720 5.2 REMS DOCUMENT (ATTACHMENT 1) 1. Most recent modification date will need to be updated to reflect approval of this pending TIRF REMS modification 2. Under #3 TIRF medicines will only be dispensed for outpatient use with evidence or other documentation of safe-use conditions (Item e) the TRIG proposes a listing of criteria that will trigger the inactivation of the patient’s PPAF. FDA agrees with all except the last criteria “Substantive changes to the TIRF REMS Access program”. We believe this is too broad and ambiguous and that this could be a source of confusion. Therefore, we request this criteria item be removed. FREQUENTLY ASKED QUESTIONS (FAQ) (ATTACHMENT 6) 5.3 1. FDA agrees with the proposed modifications, as included in the attached redlined document 5.4 INDEPENDENT OUTPATIENT PHARM ENROLLMENT FORM (ATTACHMENT 11) 1. Based on information provided in the TIRF REMS 24-Month Assessment report and subsequent discussions about pharmacy-level non-compliance with the TIRF REMS Cash Claim process, FDA believes that in addition to added information the TRIG proposes in the FAQ about the Cash Claim transaction process, pharmacy knowledge about this process can be further enhanced through an additional attestation statement, and requests that an added attestation (No. 15) be added as follows and as indicated on the attached redlined document: 15. I understand that differences in pharmacy software may affect automation capabilities for adjudicating prescriptions through the TIRF REMS access program without an insurance claim ((i.e. cash claim). If insurance is not used, pharmacy staff must manually enter the REMS Cash BIN #014780 in order for the transaction to be properly adjudicated through the TIRF REMS Program. 2. FDA agrees with your proposal to add a pdf document “NDC listing for TIRF REMS Access Program products” listing TIRF products with NDC numbers. However, in an effort to minimize the need to navigate from the main page through multiple other pages of the TIRFREMSaccess.com site website to reach the “NDC listing for TIRF REMS Access Program” pdf, we recommend hyperlinking directly to the pdf (i.e. www.TIRF REMSaccess.com/XXX). This PDF link should be listed on this form. 5.5 CHAIN OUTPATIENT PHARM ENROLLMENT FORM (ATTACHMENT 12) 1. Based on information provided in the TIRF REMS 24-Month Assessment report and subsequent discussions about pharmacy-level non-compliance with the TIRF REMS Cash Claim process, FDA believes that in addition to added information the TRIG proposes in the FAQ about the Cash Claim transaction process, pharmacy knowledge about this process can be further enhanced through an Reference ID: 3645823 FDA_6721 additional attestation statement, and requests that an added attestation (No. 15) be added as follows and as indicated on the attached redlined document: 15. I understand that differences in pharmacy software may affect automation capabilities for adjudicating prescriptions through the TIRF REMS access program without an insurance claim ((i.e. cash claim). If insurance is not used, pharmacy staff must manually enter the REMS Cash BIN #014780 in order for the transaction to be properly adjudicated through the TIRF REMS Program. 2. FDA agrees with your proposal to add a pdf document “NDC listing for TIRF REMS Access Program products” listing TIRF products with NDC numbers. However, in an effort to minimize the need to navigate from the main page through multiple other pages of the TIRFREMSaccess.com website to reach the “NDC listing for TIRF REMS Access Program” pdf, we recommend hyperlinking directly to the pdf (i.e. www.TIRF REMSaccess.com/XXX). 5.6 SUPPORTING DOCUMENT 1. Page 3: Background: See the recommendations above in Section 5.1, and included in the attached redlined document 2. Page 19: As stated above in Section 5, FDA agrees with all of the reasons to consider inactivation of a patient PPAF except “or substantive program changes”. We believe this is too broad and ambiguous and that this could be a source of confusion. Therefore, we request this criteria item be removed. 3. Page 29: REMS Assessment Plan: The TIRF REMS Assessment Plan (AP) should be revised/updated to align with the Agency’s August 21, 2014 REMS ASSESSMENT ACKNOWLEDGMENT/REMS ASSESSMENT PLAN REVISION communication to the TRIG and individual TIRF products application holders, including information the TRIG provided in your September 4, 2014 email communication to the FDA about yearly audits “Additionally, within the appended revised AP, the FDA included the addition of 4(b) - yearly audits of 5 inpatient pharmacies…The results of yearly inpatient audits will be included in 48-month report rather than the 36-month since a process does not yet exist in the TIRF REMS Access program for auditing inpatient pharmacies. The TRIG will need time to design a process to accomplish inpatient pharmacy audits; and, as a result, the inpatient pharmacy audit data will not be available in time for reporting in the 36-month assessment. Closed-system pharmacy audit information will, however, be available and be included in the 36-month report.” Since this information supersedes the REMS Assessment Plan submitted in the TIRF REMS Modification dated May 20, 2014, please revise accordingly per above. 5.7 WEB PAGE PROTOTYPE (ATTACHMENT 17) 1. Page 9: See the recommendations above in Section 5, and included in the attached redlined document. Additionally, FDA agrees with your proposal to add a pdf Reference ID: 3645823 FDA_6722 document “NDC listing for TIRF REMS Access Program products” listing TIRF products with NDC numbers. However, in an effort to minimize the need to navigate from the main page through multiple other pages of the TIRFREMSaccess.com website to reach the “NDC listing for TIRF REMS Access Program” pdf, we recommend hyperlinking directly to the pdf (i.e. www.TIRF REMSaccess.com/XXX). 2. This pdf link (www.tirfremsaccess.com/XXX) should be included on the following TIRF REMS forms: a. Independent outpatient pharmacy enrollment form b. Chain outpatient pharmacy enrollment form 3. Page 88: Based on information provided in the TIRF REMS 24-Month Assessment report and subsequent discussions about pharmacy-level noncompliance with the TIRF REMS Cash Claim process, please add the following Attestation to reflect and further emphasize the clarifying information in FAQ. add Attestation: 15. I understand that differences in pharmacy software may affect automation capabilities for adjudicating prescriptions through the TIRF REMS access program without an insurance claim (i.e. cash claim). If insurance is not used, pharmacy staff must manually enter the REMS Cash BIN #014780 in order for the transaction to be properly adjudicated through the TIRF REMS Program. 4. Page 99: Based on information provided in the TIRF REMS 24-Month Assessment report and subsequent discussions about pharmacy-level noncompliance with the TIRF REMS Cash Claim process, please add the following Attestation to reflect and further emphasize the clarifying information in FAQ. add Attestation: 15. I understand that differences in pharmacy software may affect automation capabilities for adjudicating prescriptions through the TIRF REMS access program without an insurance claim ((i.e. cash claim). If insurance is not used, pharmacy staff must manually enter the REMS Cash BIN #014780 in order for the transaction to be properly adjudicated through the TIRF REMS Program. 5. Page 144-145: FDA agrees with the TRIG’s proposal to add a pdf document version listing TIRF products with NDC numbers for the TIRF REMS Access Program. However, in an effort to minimize the need to navigate from the main page through multiple other pages of the TIRFREMaccess.com website to reach the “NDC listing for TIRF REMS Access Program” pdf, we recommend hyperlinking directly to the pdf (i.e. www.TIRFREMSaccess.com/XXX). This PDF link should be placed in the following places: a) Resources for Pharmacists tab of the REMS website b) Resources for Distributors tabs of the REMS website Reference ID: 3645823 FDA_6723 c) Independent outpatient pharmacy enrollment form d) Chain outpatient pharmacy enrollment form Please provide a mock-up of the pdf table listing the products and their NDC numbers as an attachment to the REMS Supporting document. This table, when included as an attachment to the REMS Supporting document, should be blank with the following attestation statement included: The TRIG attests that the table above will only include products listed in the link titled 'List of approved application numbers and sponsors' on the FDA Approved REMS website. 6. Page 148: Landing Page Titled “Currently Approved TIRF REMS Products**”. We agree with the format and content of this table. However, in order to prevent REMS modifications when new products are added or removed from the TIRF REMS Access Program, as part of the Webpage prototype document, this table should be blank with the following attestation statement included: The TRIG attests that the table above will only include products listed in the link titled 'List of approved application numbers and sponsors' on the FDA Approved REMS website. On the live TIRF REMS Access Program website, however, the table should be filled in and the attestation statement should NOT be included. Refer to the ER/LA Opioid analgesics as an example here: http://www.er-laopioidrems.com/IwgUI/rems/products.action along with the approved ER/LA REMS (Page 37) http://www.fda.gov/downloads/Drugs/DrugSafety/PostmarketDrugSafetyInformat ionforPatientsandProviders/UCM311290.pdf for reference. ATTACHMENTS: TIRF REMS and TIRF REMS Appended Materials Reference ID: 3645823 FDA_6724 APPENDICES Appendix A: OSE Email to TRIG dated February 5, 2014 From: Jarral, Vaishali [mailto:Vaishali.Jarral@fda.hhs.gov] Sent: Wednesday, February 05, 2014 1:40 PM To: Werre, Karla L Cc: Liberatore, Mark; Jenkins, Darrell Subject: TIRF SSS REMS modification- proposal Hello Karla, Please see the agency’s proposal to TRIG below in regards to TIRF SSS REMS. Kindly acknowledge the receipt of this email and please send us your feedback within 45 days of the receipt of this email. “ FDA would like to begin discussing potential modifications to the TIRF REMS documents. The purpose of this modification (Modification #3) is to eliminate some product specific information in the REMS materials which does not impact the safe use of these products. 4. Remove NDC numbers from the TIRF REMS Pharmacy Enrollment Forms The TRIG agreed to this revision during Modification2 negotiations. The TRIG agreed to provide a reference on the enrollment forms to a new page on the TIRF REMS Access Program website which will have a listing of the current NDC numbers. The list of current NDC numbers will be updated within 72 hours of a TRIG sponsor notifying the vendor of new NDC numbers. 5. Remove Attachment 1 from the TIRF REMS document and appended materials. Instead, the REMS document and appended materials will include a reference to the list of currently approved TIRF products, which is located at on the FDA Approved Risk Evaluation and Mitigation Strategy (REMS) website (http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformati onforPatientsandProviders/ucm111350.htm ). In addition, the list of approved products will be available on the TIRF REMS Access Program website. The TRIG will submit as part of the TIRF REMS Website Protocol a page which will contain a Table listing of the currently approved TIRF REMS products, Sponsor Name, Contact phone number and link to product specific information for each product as well as the following statement: The TRIG attests that the table above will only include products listed in the link titled 'List of approved application numbers and sponsors' on the FDA Approved REMS website Trade Name Company Phone Number Information Links Reference ID: 3645823 FDA_6725 6. Table 1 in the Education Program Remove the reference to generics for individual products and replace with a footnote that all this table includes approved generic equivalents of the covered products. Products** Covered Under this Program: ** This includes approved generic equivalents of these products Thank you, Vaishali Jarral, M.S., M.B.A Safety Regulatory Project Manager Office of Surveillance and Epidemiology Center for Drug Evaluation and Research Food and Drug Administration 10903 New Hampshire Avenue Building 22, Room 4472 Silver Spring, MD 20993 301.796.4248 Reference ID: 3645823 FDA_6726 Appendix B: TRIG February 18 email response to OSE February 8 email communication From: Werre, Karla L [mailto:Karla.Werre@mallinckrodt.com] Sent: Tuesday, February 18, 2014 10:02 AM To: Jarral, Vaishali Cc: Liberatore, Mark; Amanda Bulkley; Laura Baloun; Siressa Sremba; Servello, Diane L; Werre, Karla L Subject: RE: TIRF SSS REMS modification- proposal Dear Vaishali, Please see the TRIG’s responses below in regards to the Modification #3 proposed by the Agency in its e-mail [February 5, 2014] on the TIRF SSS REMS. The e-mail read: “ FDA would like to begin discussing potential modifications to the TIRF REMS documents. The purpose of this modification (Modification #3) is to eliminate some product specific information in the REMS materials which does not impact the safe use of these products. 1. Remove NDC numbers from the TIRF REMS Pharmacy Enrollment Forms The TRIG agreed to this revision during Modification2 negotiations. The TRIG agreed to provide a reference on the enrollment forms to a new page on the TIRF REMS Access Program website which will have a listing of the current NDC numbers. The list of current NDC numbers will be updated within 72 hours of a TRIG sponsor notifying the vendor of new NDC numbers. TRIG RESPONSE to Item #1 : Pursuant to its agreement during the Modification 2 negotiations, the TRIG again affirms its agreement to this proposal except: that it will update the current NDC numbers within 3 working days rather than 3 calendar days/72 hours after a TRIG sponsor notifies the vendor of the new/changes to the NDC numbers. This amount of time is needed to make the necessary modifications to the website. 2. Remove Attachment 1 from the TIRF REMS document and appended materials. Instead, the REMS document and appended materials will include a reference to the list of currently approved TIRF products, which is located at on the FDA Approved Risk Evaluation and Mitigation Strategy (REMS) website (http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPa tientsandProviders/ucm111350.htm). In addition, the list of approved products will be available on the TIRF REMS Access Program website. The TRIG will submit as part of the TIRF REMS Website Protocol a page which will contain a Table listing of the currently Reference ID: 3645823 FDA_6727 approved TIRF REMS products, Sponsor Name, Contact phone number and link to product specific information for each product as well as the following statement: The TRIG attests that the table above will only include products listed in the link titled 'List of approved application numbers and sponsors' on the FDA Approved REMS website Trade Compa Phone Information TRIG RESPONSE to Item #2: The TRIG agrees to remove Attachment 1 from the TIRF REMS document and appended materials (referred to as Attachment A above) and include a reference in the REMS document and its appended materials to the list of currently approved TIRF products which is located on the FDA Approved Risk Evaluation and Mitigation Strategy (REMS) website. As part of this change, the TRIG agrees to: · Ensure that the list of approved products will also be available on the TIRF REMS Access Program website. · The TRIG will submit as part of the TIRF REMS Website Protocol a page which will contain a Table listing the currently approved TIRF REMS products, Sponsor Name, Contact Phone Number and Information Links to product specific information for each product located on each TRIG Sponsors’ company website(s) as well as the following statement: o The TRIG attests that the table above will only include products listed in the link titled 'List of approved application numbers and sponsors' on the FDA Approved REMS website 3. Table 1 in the Education Program Remove the reference to generics for individual products and replace with a footnote that all this table includes approved generic equivalents of the covered products. Products** Covered Under this Program: Reference ID: 3645823 FDA_6728 ** This includes approved generic equivalents of these products TRIG RESPONSE to Item #3 : TRIG agrees to revise the product table in the Education program to remove the reference to generics for individual products and replace with a single footnote, “**This includes approved generic equivalents of these products.” IN ADDITION to the TRIG’s responses to items listed above, the TRIG seeks the FDA’s response on the following items: · The TRIG inquires as to the FDA’s expected timeline for approval of the TRIG’s response to the assessment metrics submitted on January 31, 2014 by e-mail in documents entitled, “ Evaluation of the Metrics Outlined in FDA Document” and “Metrics to be Deleted/Not Included in FDA Document.” Analysis by the TRIG indicates that approval of the metric enhancements and their inclusion in Modification 3 would need to be received by March 31, 2014 in order to allow for system modification/enhancements and testing to facilitate inclusion of the new metrics in the 36-month assessment report. · For Modification 3, the TRIG proposes removal of language from the REMS Supporting Document to deactivate patients shown to have multiple prescribers in an overlapping timeframe due to TRIG’s concern for deactivating patients for noncompliance. TRIG has a limited view of data and is unable to confirm or rule out doctor-shopping because it may result in legitimate patient-access issues, particularly in view of the FDA’s previous communication to TRIG during our teleconference meeting on November 14, 2013 that it should no longer report on doctor-shopping. · TRIG is currently considering several program enhancements and will notify FDA within 45 days should TRIG decide to include them in Modification 3. Reference ID: 3645823 FDA_6729 Kindest regards, Karla Karla Werre, MBA, RAC(US) Manager, Regulatory Affairs Specialty Generics Mallinckrodt Pharmaceuticals Mallinckrodt Inc. Appendix C: From: Jarral, Vaishali [mailto:Vaishali.Jarral@fda.hhs.gov] Sent: Friday, May 16, 2014 7:28 AM To: Werre, Karla L Cc: Liberatore, Mark Subject: TIRF REMS Modification #3 proposals Hello Karla, Reference is made to your April 15, 2014 response to our inquiry about your proposed “TRIG Recommendations for Programs Enhancements” sent March 24, related to the addition of information in TIRF REMS materials related to Cash Claim FAQs. In your response you clarified that per your 24-month assessment report Table 29 (page 72 of 131),7 instances of non-compliance occurred where TIRF medicines were dispensed without verifying stakeholder enrollment through the TIRF REMS pharmacy management system and that the pharmacies involved “were either not aware of the requirement to process cash claims through the TIRM REMS Program or were aware of the cash claim procedure but received a reject, yet dispensed a TIRF product anyway.” Your response also stated that to address “apparent prescription processing knowledge deficit” the proposed Cash Claim FAQ information would be added to emphasize that “all claims, highlighting cash claims specifically, must be submitted to the TIRF REMS Access Program to verify the enrollment status of the stakeholders before dispensing a TIRF medicine to a patient and to clearly provide the proper BIN number for transmission of cash claims data.” Prior to the information you provided, our understanding of the TIRF REMS Switch system transmission process was that the transaction is adjudicated through the switch automatically, whether the transaction was an insurance or cash claim. It appears that this is not the case and that, in fact, the process involves additional manual steps at the pharmacy level to enter the Cash BIN # into the system in order for the transaction to be adjudicated. We are concerned that the switch system is not a failsafe process for adjudication of TIRF REMS safety verifications prior to dispensing the product. We have the following information request (IR) for the TRIG, in response to the information you have provided: Reference ID: 3645823 FDA_6730 1. Provide a proposal to mitigate this failure mode to assure the Switch System cannot be bypassed prior to dispensing of TIRF products. Describe any ways that participating pharmacies’ systems can be modified in order to automatically: a. adjudicate of cash claims and eliminate the required pharmacist manual entry of a BIN # and/or b. prevent the dispensing of a prescription if the cash claim is not transmitted to the TIRF REMS Access program. c. To what extent have certified pharmacies implemented such automated systems? 2. Please explain the method used to identify the 7 cases/7 pharmacies reported in your 24-month REMS assessment. Is the method used to identify these cases comprehensive in identifying all such cases? 3. Since the 24-month REMS assessment, have you identified any additional cases? 4. Provide the root cause analysis of how these cases occurred along with the TRIG’s proposed plan for future detection/identification of cases such as these. 5. In your proposed modified FAQ, you ask pharmacists to transmit TIRF REMS CASH claims to the TIRF REMS Access Program using the REMS CASH BIN 014780. FDA has heard that pharmacies may be using other processes to transmit their TIRF REMS cash claims. Please confirm that these instructions will work in all pharmacies that participate in the REMS, and that they will not interfere with those pharmacies standard REMS operating procedures. Please submit the response to DMF by May 27, 2014. Thank you Appendix D: TRIG May 30 submission response to May 16 OSE information request about the Cash Claim transaction process (eCTD Seq. No. 0010) Information Request Response to 16MAY2014 FDA Correspondence There were 7 instances of non-compliance identified in the 24-month Assessment that were classified as not aware of the requirement to process cash claims through the TIRF REMS Program or were aware of the cash claim procedure but received a reject, yet dispensed a TIRF product anyway. In 6 of the 7 cases, the pharmacists submitted a claim, received a reject, but still dispensed TIRF medicine. Only 1 case involved a pharmacist who did not submit a claim prior to dispensing a TIRF medicine. Reference ID: 3645823 FDA_6731 1. Provide a proposal to mitigate this failure mode to assure the Switch System cannot be bypassed prior to dispensing of TIRF products. Describe any ways that participating pharmacies’ systems can be modified in order to automatically: 1.a. Adjudicate of cash claims and eliminate the required pharmacist manual entry of a BIN #. Pharmacies utilize different pharmacy software and some systems can be configured to automatically adjudicate cash claims while others may not. The REMS Cash BIN was established to allow pharmacies unable to configure their systems to automatically adjudicate cash claims to still participate in the TIRF REMS program and ensure patient access to TIRF medicines in all pharmacies that elect to participate in the program. The TIRF REMS program requires all enrolled pharmacies to enable their pharmacy management system to support communication with the TIRF REMS Access system, using established telecommunication standards. This allows the TIRF REMS program to automatically intercept the claim via NDC level routing and subsequently interrogate the REMS database, via the Switch Provider, to validate the enrollment status of the prescriber, patient and pharmacy. 1.b. Prevent the dispensing of a prescription if the cash claim is not transmitted to the TIRF REMS Access program. When a pharmacy enrolls in the TIRF REMS Access program, the pharmacist attests that a TIRF medicine will not be dispensed without verifying through a pharmacy management system that the prescriber and pharmacy are enrolled and active, and that the patient has not been inactivated from the program; additionally, that all TIRF medicines, regardless of the method of payment, are submitted and processed through the pharmacy management system. If a prescription is not transmitted to the TIRF REMS Access program there is no way to notify the pharmacist they should not dispense. 1.c. To what extent have certified pharmacies implemented such automated systems? The TIRF REMS program cannot determine the extent of pharmacies using automated systems. As stated above, pharmacies utilize different pharmacy software and some systems can be configured to automatically adjudicate cash Reference ID: 3645823 FDA_6732 claims while others may not. The REMS Cash BIN was established to allow pharmacies unable to configure their systems to automatically adjudicate cash claims to still participate in the TIRF REMS program and ensure patient access to TIRF medicines in all pharmacies that elect to participate in the program. 2. Please explain the method used to identify the 7 cases/7 pharmacies reported in your 24- month REMS assessment. Is the method used to identify these cases comprehensive in identifying all such cases? If a prescription is not transmitted to the TIRF REMS Access program there is no way to identify potential non-compliance. All 7 instances were reported by stakeholders, (6 pharmacies and 1 prescriber), via a phone call into the TIRF REMS Access program call center. All call center agents are trained to identify potential non-compliant events and triage them to the Non-Compliance Review Team for further review, investigation, and appropriate corrective action to mitigate future occurrences. 3. Since the 24-month REMS assessment, have you identified any additional cases? Since the 24-month assessment data cut-off, (October 29, 2013), there have been 6 additional non-compliances cases that have been classified as not aware of the requirement to process cash claims through the TIRF REMS Program or were aware of the cash claim procedure but received a reject, yet dispensed a TIRF product anyway. In 4 of the 6 cases, the pharmacist submitted a claim, received a reject, but still dispensed TIRF medicine. Two cases involved a pharmacist who did not submit a claim prior to dispensing a TIRF medicine. 4. Provide the root cause analysis of how these cases occurred along with the TRIG’s proposed plan for future detection/identification of cases such as these. The root cause is the lack of clear messaging around the requirement for cash claim processing in TIRF REMS resources for pharmacists. As a result, the TRIG is proposing to modify TIRF REMS pharmacist resources to emphasize the importance of submitting cash claims to the TIRF REMS Access program. 5. In your proposed modified FAQ, you ask pharmacists to transmit TIRF REMS CASH claims to the TIRF REMS Access Program using the REMS CASH BIN 014780. FDA has heard that pharmacies may be using other processes to transmit their TIRF REMS cash claims. Please confirm that these instructions will work in all pharmacies that participate in the REMS, and that Reference ID: 3645823 FDA_6733 they will not interfere with those pharmacies standard REMS operating procedures. The instructions in our proposed modified FAQs will work in all pharmacies that participate in the REMS. As stated above, the REMS Cash BIN was established to allow pharmacies unable to configure their systems to automatically adjudicate cash claims to still participate in the TIRF REMS program and ensure patient access to TIRF medicines in all pharmacies that elect to participate in the program.. Some pharmacies may use a different BIN for cash claims; however, the program intercepts the claim via NDC number, regardless of the BIN used, and subsequently interrogates the REMS database, via the Switch Provider, to validate the enrollment status of the prescriber, patient and pharmacy. Reference ID: 3645823 FDA_6734 Appendix E: TIRF Website Prototype Changes ?I'IllFWehslaePlouyped-us Reference ID: 3645823 Reference ID: 3645823 Initial REMS approval: 12/2011 Most recent modi?cation: szoul [Comment will be updated to re?ect the ?nal REMS modi?cationappmval date TRANSMUCOSAL IMMEDIATE RELEASE FENTANYL (TIRF) RISK EVALUATION AND MITIGATION STRATEGY (REMS) Formatted: Numbeied Level: 1 Numbering Style: I, II, Start at: 1 Alignment: Right Aligned at: 0" Indent at: 0.25" FOLLOWING THIS PAGE, TO WITHHELD IN FULL AS REMS WEB MATERIALS) Reference ID: 3645823 --------------------------------------------------------------------------------------------------------This is a representation of an electronic record that was signed electronically and this page is the manifestation of the electronic signature. --------------------------------------------------------------------------------------------------------/s/ ---------------------------------------------------CATHY A MILLER 10/20/2014 KIMBERLY LEHRFELD 11/03/2014 Reference ID: 3645823 FDA_6998 Department of Health and Human Services Food and Drug Administration Center for Drug Evaluation and Research Office of Surveillance and Epidemiology Office of Medication Error Prevention and Risk Management REMS MODIFICATION REVIEW Interim Comments #1 Date: November 4, 2014 Reviewer(s) Cathy A. Miller, MPH, BSN, Risk Management Analyst Division of Risk Management (DRISK) Joan Blair, MPH, Health Communication Analyst, DRISK Team Leader Kimberly Lehrfeld, Pharm.D., DRISK Acting Division Director: Reema Mehta, Pharm.D., M.P.H., DRISK Table 1 Drug Names, Dosage Form and Sponsor: Drug Name Abstral (fentanyl) Actiq (fentanyl citrate) Fentora and Authorized Generic (fentanyl citrate) Lazanda (fentanyl) Onsolis (fentanyl) Subsys (fentanyl) Dosage Form and Route Sublingual tablet Oral transmucosal lozenge Buccal tablet NDA Number 022510 Sponsor 020747 Galenya BioPharma Cephalon, Inc. 021947 Cephalon, Inc. Nasal spray 022569 DepoMed, Inc. Buccal soluble film Sublingual spray 022266 Meda Pharmaceuticals Insys Therapy 202788 Therapeutic Opioid Agonist class: Dosage Transmucosal Immediate release Fentanyl (TIRF) forms: Reference ID: 3653728 FDA_6999 Table 2: TIRF REMS Modification #3 DMF 27320 Seq. No. 0009 received May 20, 2014 Drug Name NDA Number Suppl. Submitted Date; Amendment Submitted Date March 12, 2014; amended July 25, 2014 Suppl. Number (Seq. No.) S-013 (0086; 0091) Abstral Actiq 022510 020747 May 21, 2014 May 21, 2014 S-014 (0089) S-041 (0041) Fentora and AG Lazanda Onsolis Subsys 021947 022569 022266 202788 May 21, 2014 May 21, 2014 May 21, 2014 May 20, 2014 S-022 (0048) S-020 (0115) S-014 (0120) S-012 (0081) Abbreviations: Amend.=Amendment; AG=Authorized Generic; DMF=Drug Master File; LOA=Letter of Authorization; Seq. No.=Sequence Number; Suppl.=Supplement; NDA=New Drug Application OND Review Division: Division of Anesthesia, Analgesia and Addiction Products (DAAAP) OSE RCM #: 2014-2057 TSI #: 290 n/a = not applicable Reference ID: 3653728 FDA_7000 1 1.1 1.2 1.3 2 3 4 INTRODUCTION ....................................................................................................... 4 BACKGROUND .......................................................................................................... 4 REGULATORY HISTORY ........................................................................................... 5 MATERIALS INFORMING OUR REVIEW: ................................................................. 5 PROPOSED REMS MODIFICATION WITH RATIONALE ................................... 5 RECOMMENDATIONS FOR THE REVIEW DIVISION ........................................ 6 COMMENTS FOR THE APPLICANT ...................................................................... 7 Reference ID: 3653728 FDA_7001 1 INTRODUCTION This is a review of the proposed Risk Evaluation and Mitigation Strategy (REMS) modification for the Transmucosal Immediate-Release Fentanyl (TIRF) REMS Single Shared System (SSS) submitted by the Transmucosal REMS Industry Group (TRIG) between March 12 and May 21, 2014 (see Table 2 on cover page 2 for detailed submission information). 1.1 BACKGROUND TIRF medicines are short-acting fentanyl products indicated for the management of breakthrough pain in adults with cancer who are routinely taking other opioid pain medicines around-the-clock for pain. The approved TIRF medicines include: • Abstral (fentanyl) sublingual tablet • Actiq (fentanyl citrate) oral transmucosal lozenge • Fentora (fentanyl citrate) buccal tablet • Lazanda (fentanyl) nasal spray, • Onsolis (fentanyl) buccal soluble film • Subsys (fentanyl) sublingual spray • Approved generic equivalents of these products The TIRF medicines are approved under a single shared system REMS that has the following goal and objectives: 1. Prescribing and dispensing TIRF medicines only to appropriate patients, which includes use only in opioid-tolerant patients. 2. Preventing inappropriate conversion between TIRF medicines. 3. Preventing accidental exposure to children and others for whom it was not prescribed. 4. Educating prescribers, pharmacists, and patients on the potential for misuse, abuse, addiction, and overdose of TIRF medicines. The elements included in the program are Medication Guides(MG) for each individual TIRF medicine and the following Elements to Assure Safe Use (ETASU): Reference ID: 3653728 • Healthcare providers who prescribe TIRF medicines for outpatient use are specially certified • TIRF medicines will only be dispensed by pharmacies that are specially certified FDA_7002 • TIRF medicines will only be dispensed for outpatient use with evidence or other documentation of safe-use conditions. The timetable for submission of TIRF REMS Access Program assessments is at 6 and 12 months from the date of the initial REMS approval, and annually thereafter. 1.2 REGULATORY HISTORY • The regulatory history for the proposed TIRF REMS Modification #3 is detailed in the DRISK TIRF REMS Modification Interim Comments review by Cathy Miller dated October 20, 2014. • On March 12, 2014, Galena Biopharma submitted prior approval supplement (S-013) Abstral (fentanyl) sublingual tablets, proposing the conversion from Actiq (fentanyl citrate) transmucosal lozenge, to Abstral, including a proposed TIRF REMS modification. The proposed revision would affect select TIRF REMS material. • On November 4, 2014, DAAAP approved Abstral prior approval supplement (S013) including revised TIRF REMS documents, reviewed by DRISK 1 which subsequently prompting additional modifications to the TIRF REMS, currently under review, thereby requiring an amendment to the current proposed TIRF REMS Modification #3. 1.3 MATERIALS INFORMING OUR REVIEW: 2 • Miller, C. DRISK REMS Modification Review for Abstral (NDA 22510) DARRTS dated July 29, 2014 • Miller, C. DRISK TIRF REMS Modification Interim Comments #1 review of the TIRF REMS dated October 20, 2014. PROPOSED REMS MODIFICATION WITH RATIONALE On November 4, 2014, Abstral (fentanyl) sublingual tablets (NDA 22510) prior approval supplement/REMS Modification (S-013) was approved 2. This supplement approval included language to allow direct conversion from Actiq (fentanyl) oral transmucosal lozenge, which is bioequivalent to Abstral, without re-titration. This supplement also included the DRISK review of the TIRF REMS and subsequently required revisions to select TIRF REMS material as discussed in the DRISK Abstral REMS Modification Review 3. These revisions to TIRF REMS material include the following: 1. Education Program for Prescribers and Pharmacists: 1 DRISK REMS Modification Review for Abstral (NDA 22510) DARRTS July 29, 2014 (C. Miller) 2 DAAAP Prior Approval Labeling Supplement (S-013) for Abstral (fentanyl) sublingual tablets approval letter dated November 4, 2014. 3 Miller, C. DRISK REMS Modification Review for Abstral (fentanyl) sublinqual tablets completed July 29, 2014 Reference ID: 3653728 FDA_7003 a. Slide 15: For patients being converted specifically from Actiq to Fentora, Actiq to Subsys or Actiq to Abstral, you must refer to the Full Prescribing Information for detailed information b. Slide 17 Products covered Under this Program for Abstral TIRF REMS Knowledge Assessment Question 11: Reviewer comments: Based on the approval of this prior approval supplement, these modifications will need to be incorporated in this TIRF REMS Modification and and are provided in our full recommendations to the TRIG in Section 6 along with accompanying Attachments that include DRISK comments and track change documents. 3 RECOMMENDATIONS FOR THE REVIEW DIVISION We recommend that the following comments below (Section 4 Comments for the Applicant) on the TIRF REMS Access Program proposal. Please request that the TRIG respond to these comments as soon as possible to facilitate further review for this submission. The comments below are based on DRISK’s preliminary review of the REMS modification proposal for TIRF products. Appended to this review is the REMS modification proposal and the REMS materials including comments and track changes Reference ID: 3653728 FDA_7004 4 COMMENTS FOR THE APPLICANT We have the following comments, below, as a result of the approval prior approval supplement (S-013) REMS modification for Abstral (NDA 22510) on November 4, 2014. EDUCATION PROGRAM FOR PRESCRIBERS AND PHARMACISTS (ATTACHMENT 3) 1. Slide 15: Dosage and Administration General, Bullet #3 should be revised as indicated in the redlined document, to reflect the addition new conversion of Actiq to Abstral: For patients being converted specifically from Actiq to Fentora, Actiq to Subsys or Actiq to Abstral,you must refer to the Full Prescribing Information for detailed instructions. 2. Slide 17: Revise the Products covered Under this Program for Abstral, as indicated in the redlined document, under the ‘Initial Dose’ column to read “unless the patient is being converted from 600 mcg ACTIQ. Please see Full Prescribing Information”. WEB PAGE PROTOTYPE (ATTACHMENT 17) 1. Page 46: Update the table to reflect updated information on conversion of Actiq to Abstral. Under the ‘Initial Dose’ column to read “unless the patient is being converted from 600 mcg ACTIQ. Please see Full Prescribing Information” 2. Page 62: Knowledge Assessment Question 11: Update to reflect updated information on conversion of Actiq to Abstral. Multiple choice question should be revised as follows: Reference ID: 3653728 FDA_7005 --------------------------------------------------------------------------------------------------------This is a representation of an electronic record that was signed electronically and this page is the manifestation of the electronic signature. --------------------------------------------------------------------------------------------------------/s/ ---------------------------------------------------CATHY A MILLER 11/04/2014 KIMBERLY LEHRFELD 11/05/2014 Reference ID: 3653728 FDA_7006 inS?r'S November 26, 2014 Sharon Hertz, MD Acting Director, Division of Anesthesia and Analgesia Products Of?ce of Drug Evaluation 11 Center for Drug Evaluation and Research Food and Drug Administration 5901-B Ammendale Road Beltsville, MD 20705-1266 Re: DA 202788: (Fentanyl Sublingual Spray) for the management of breakthrough cancer pain Sequence No. 0090: Reference to Amendment to Prior Approval Supplement TRIF REMS Modi?cation #3 Filed to TIRF REMS DMF #027320 Dear Dr. Hertz: Reference is made to Insys Therapeutics, Inc.?s New Drug Application 202788 for SUBSYS (Fentanyl Sublingual Spray) approved on January 4, 2012. Additional reference is made to the Letter of Authorization (LOA) for DMF #027320 which contains the Single Shared REMS for Transmucosal Immediate Release Fentanyl (TIRF) products submitted to this application on September 1 l, 2013. Per the guidelines in Section 1.5 of the DMF instruction document entitled, ?Process for Utilizing a Type Drug Master File (DMF) for a Shared System Risk Evaluation and Mitigation Strategy (REMS) Shared System REMS Insys hereby noti?es FDA of its submission of an amendment to Modification #3 to the TIRF REMS DMF #027320 in sequence 0012 [November 25, 2014} The modifications to the TIRF REMS program included in this submission are comprised of changes requested by the FDA in e-mails dated October November and November 2014 and furthermore, consist of changes proposed and accepted by the TIRF REMS Industry Group and FDA, respectively on November 2014. All updated TIRF REMS documents are submitted as both red-lined and clean versions in MS Word format. In addition, PDF documents of the RSD with Appendices and REMS with Supporting Materials are provided. Please note that unchanged TIRF REMS documents are not being resubmitted, but are referenced in the Reviewer?s Guide and hyperlinked to the current version. All changes to the website prototype are listed in an MS Word document in tabular format within the red-lined versions, while the website prototype itself is being provided as a MS Word ?le with screenprints in the clean versions. Should you have questions or require additional information, please contact me by telephone at 480- 500-3150, facsimile at 602-910-2627, or e-mail at Sincerely, Venkat Goskonda Vice President, Research and Development Regulatory Affairs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insvs December I l, 2014 Sharon Hertz, MD Acting Director, Division of Anesthesia and Analgesia Products Of?ce of Drug Evaluation 11 Center for Drug Evaluation and Research Food and Drug Administration 5901-B Ammendale Road Beltsville, MD 20705-1266 Re: NBA 202788: (Fentanyl Sublingual Spray) for the management of breakthrough cancer pain Sequence No. 0092: Reference to Amendment to Prior Approval Supplement TRIF REMS Modi?cation #3 Filed to TIRF REMS DMF #027320 Dear Dr. Hertz: Reference is made to Therapeutics, lnc.?s New Drug Application 202788 for SUBSYS (Fentanyl Sublingual Spray) approved on January 4, 2012. Additional reference is made to the Letter of Authorization (LOA) for DMF #027320 which contains the Single Shared REMS for Transmucosal Immediate Release Fentanyl (TIRF) products submitted to this application on September 1 l, 2013. Per the guidelines in Section 1.5 of the DMF instruction document entitled, ?Process for Utilizing a Type Drug Master File (DMF) for a Shared System Risk Evaluation and Mitigation Strategy (REMS) Shared System REMS hereby notifies FDA of its submission of an amendment to Modification #3 to the TIRF REMS DMF #027320 in sequence 0013 [December 10, 2014]. Prior amendments to the REMS for Modi?cation #3 were submitted on April 1, 2014, May 21, 2014 and November 25, 2014. (The last REMS Assessment for the TIRF REMS Access Program was submitted on December 27, 2013.). Also, enclosed for the reference is the medication guide for SUBSYS (Fentanyl Sublingual Spray). In conjunction with the correspondence received November 26, 2014 from Vaishali Jarral of your of?ce, provided herein is the complete documentation of the TIRF REMS Access program including the requested ?Dear? letters which were previously omitted. Please note that for the ease of review, this submission (DMF Sequence 0013) contains the updated TIFR REMS documents in both red- lined and clean versions in MS Word format that were previously submitted via Sequence 0012 on November 25, 2014. All documents are referenced in the Reviewer?s Guide and hyperlinked to their current version. All changes to the website prototype are listed in an MS Word document in tabular format within the red-lined versions, while the website prototype itself is being provided as a MS Word file with screenprints in the clean versions. No new changes requiring additional FDA review are proposed at this time. Should you have questions or require additional information, please contact me by telephone at 480- 500-3150, facsimile at 602-910-2627, or e-mail at Sincerely, Stephen Sherman Vice President, Regulatory Affairs 1333 South Spectrum Boulevard. Suite 100, Chandler. AZ 85286 phone: 4805003127 I fax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epartment of Health and Human Services Food and Drug Administration Center for Drug Evaluation and Research Office of Surveillance and Epidemiology Office of Medication Error Prevention and Risk Management REMS MODIFICATION FINAL REVIEW Date: December 16, 2014 Reviewer(s) Cathy A. Miller, MPH, BSN, Risk Management Analyst Division of Risk Management (DRISK) Joan Blair, MPH, Health Communication Analyst, DRISK Team Leader Kimberly Lehrfeld, Pharm.D., DRISK Acting Division Director: Reema Mehta, Pharm.D., M.P.H., DRISK Table 1 Drug Names, Dosage Form and Sponsor: Drug Name Abstral (fentanyl) Actiq (fentanyl citrate) Fentora and Lazanda (fentanyl) Onsolis (fentanyl) Subsys (fentanyl) Fentanyl Citrate Fentanyl Citrate Dosage Form and Route Sublingual tablet Oral transmucosal lozenge Buccal tablet Nasal spray NDA/ANDA Number 022510 Buccal soluble film Sublingual spray Transmucosal Troche/Lozenge Transmucosal Troche/Lozenge Sponsor 020747 Galenya BioPharma Cephalon, Inc. 021947 022569 Cephalon, Inc. DepoMed, Inc. 022266 202788 Meda Pharmaceuticals Insys Therapy 078907 Mallinckrodt 077312 Par Pharm Therapeutic Opioid Agonist class: Transmucosal Immediate release Fentanyl (TIRF) Dosage forms: Reference ID: 3673716 FDA_7011 OND Review Division: Division of Anesthesia, Analgesia and Addiction Products (DAAAP) OSE RCM: TSI #: 2014-2057 290 Table 2: TIRF REMS Modification #3 DMF 27320 Seq. No. 0009 received May 20, 2014; amended November 25, 2014 Seq. No. 012 and December 10, 2014 Seq. No. 013 Drug Name Abstral Actiq Applicant Holder Numbers NDA 022510 NDA 020747 Fentora NDA 021947 Lazanda NDA 022569 Onsolis NDA 022266 Subsys NDA 202788 Fentanyl Citrate Fentanyl Citrate Reference ID: 3673716 ANDA 077312 ANDA 078907 Suppl. Submitted Date; Amendment Submitted Date March 12, 2014; amended July 25, 2014; December 9, 2014 May 21, 2014; amended December 1, 2014 and December 15, 2014 May 21, 2014; amended November 26, 2014 and December 11, 2014 May 21, 2014; amended November 26, 2014 December 11, 2014 May 21, 2014; amended November 26, 2014 and December 11, 2014 May 21, 2014; amended November 26, 2014 and December 11, 2014 May 20, 2014; amended November 26, 2014 and December 11, 2014 May 21, 2014; amended November 26, 2014 and December 11, 2014 May 20, 2014; November 26, 2014 and December 11, 2014 Suppl. Number (Seq. No.) S-013 (0086; 0091 and 0098 S-014 (0089; 0097 and 0099) S-041 (0041; 0045 0046) S-022 (0048; 0056 and 0057) S-020 (0115; 0120 0123 ) S-014 (0120; 0124 and 0125 ) S-012 (0081; 0090 and 0092) S-006 (0021; 0025 and 0026 ) S-012 (0055; 0059 and 0061 FDA_7012 1 INTRODUCTION ....................................................................................................... 4 1.1 BACKGROUND .......................................................................................................... 4 1.2 REGULATORY HISTORY ........................................................................................... 5 2 MATERIALS REVIEWED ........................................................................................ 7 2.1 SUBMISSIONS ........................................................................................................... 7 2.2 OTHER MATERIALS INFORMING OUR REVIEW ......................................................... 8 3 PROPOSED REMS MODIFICATION....................................................................... 8 3.1 REMOVAL OF NDC NUMBERS.................................................................................. 8 3.2 REMOVAL OF REFERENCE TO GENERICS .................................................................. 9 3.3 REMOVAL OF ATTACHMENT 1’ LIST OF TIRF MEDICINES/REPLACE WITH HYPERLINK TO FDA APPROVED REMS WEBSITE ................................................................ 9 3.4 CRITERIA FOR INACTIVATION OF PATIENT-PRESCRIBER AGREEMENT FORM (PPAF) 2 3.5 REVISION OF REMS ASSESSMENT METRICS ........................................................... 2 3.6 REVISIONS TO ENHANCE KNOWLEDGE ABOUT CONVERSION OF TIRF MEDICINES11 3.7 INFORMATION ABOUT THE TIRF REMS CASH CLAIM TRANSACTION PROCESS .... 11 3.8 UPDATE THE TIRF REMS WEB PROTOTYPE DOCUMENT AND WEBSITE LANDING PAGE 11 3.9 ADDITIONAL MODIFICATIONS PROPOSED RELATED TO ABSTRAL (NDA 22510) PRIOR APPROVAL SUPPLEMENT (S-013) ............................................................................ 11 4 CONCLUSION ......................................................................................................... 13 5 RECOMMENDATIONS........................................................................................... 13 ATTACHMENTS ............................................................................................................. 13 Reference ID: 3673716 FDA_7013 1 INTRODUCTION This is a review of the proposed risk evaluation and mitigation strategy (REMS) modification for the Transmucosal Immediate-Release Fentanyl (TIRF) REMS Single Shared System (SSS) originally submitted by the Transmucosal REMS Industry Group (TRIG) between March 12 and May 21, 2014, and amended between November 25-26, 2014, December 10, 2014 and between December 15, 2014. See Table 2 for detailed submission information. 1.1 BACKGROUND TIRF medicines are short-acting fentanyl products indicated for the management of breakthrough pain in adults with cancer who are routinely taking other opioid pain medicines around-the-clock for pain. The approved TIRF medicines include: • Abstral (fentanyl) sublingual tablet • Actiq (fentanyl citrate) oral transmucosal lozenge • Fentora (fentanyl citrate) buccal tablet • Lazanda (fentanyl) nasal spray, • Onsolis (fentanyl) buccal soluble film • Subsys (fentanyl) sublingual spray • Approved generic equivalents of these products The TIRF medicines are approved under a SSS REMS that has the following goal and objectives: 1. Prescribing and dispensing TIRF medicines only to appropriate patients, which includes use only in opioid-tolerant patients. 2. Preventing inappropriate conversion between TIRF medicines. 3. Preventing accidental exposure to children and others for whom it was not prescribed. 4. Educating prescribers, pharmacists, and patients on the potential for misuse, abuse, addiction, and overdose of TIRF medicines. The elements included in the program are Medication Guides (MG) for each individual TIRF medicine and the following elements to assure safe use (ETASU): Reference ID: 3673716 • Healthcare providers who prescribe TIRF medicines for outpatient use are specially certified • TIRF medicines will only be dispensed by pharmacies that are specially certified FDA_7014 • TIRF medicines will only be dispensed for outpatient use with evidence or other documentation of safe-use conditions. The timetable for submission of TIRF REMS Access Program assessments is at 6 and 12 months from the date of the initial REMS approval, and annually thereafter. 1.2 REGULATORY HISTORY • On May 20, 2014, the TRIG submitted a proposed REMS modification to the SSS TIRF REMS. The regulatory history for the proposed TIRF REMS Modification #3 is detailed in the DRISK TIRF REMS Modification Interim Comments review by Cathy Miller dated October 20, 2014. • On March 12, 2014, Galena Biopharma submitted a prior approval supplement (S-013) Abstral (fentanyl) sublingual tablets, proposing the conversion from Actiq (fentanyl citrate) transmucosal lozenge, to Abstral, including a proposed TIRF REMS modification. It was determined that this proposed revision would affect select TIRF REMS material. • On July 29, 2014, DRISK completed the review of Abstral S-013/Proposed REMS Modification. As cited above, these modifications affected the TIRF REMS, and therefore, would be incorporated into the TIRF REMS modification #3 currently under review. • On November 4, 2014, DAAAP approved Abstral S-013 including revised TIRF REMS documents. • On November 5, 2014, Galena BioPharma sent an email notification to all TRIG TIRF product applicant holders, notifying them of S-013 approval for the conversion of Actiq to Abstral. • On November 5, 2014, the TRIG sent an email communication to OSE (project manager Vaishali Jarral) confirming the approval of Abstral S-013 and the requesting three additional business days to make the changes to the TIRF REMS to incorporate Abstral conversion information. The TRIG proposed the following submission timeline: Reference ID: 3673716 Action Item Current Plan: Date of submission allowing TRIG to incorporate Galena’s changes: Submit finalized documents by e-mail to VJ November 12, 2014 November 17, 2014 Submit all documents to DMF November 18, 2014 November 21, 2014 Submit notification of DMF submission to each individual sponsors’ applications November 19, 2014 November 24, 2014 FDA_7015 • On November 6, 2014, OSE (project manager Vaishali Jarral) sent an email communication to the TRIG agreeing to the TRIG’s requested revision to the timeline and requested that the TRIG submit all final TIRF REMS documents via email in advance of the final submission to the DMF to provide DRISK an opportunity to review all documents for accuracy. • On November 7, 2014, the TRIG sent an email communication to OSE/DRISK (project manager Vaishali Jarral) with clarifying questions related to our November 6, 2014 email communication. They requested that our proposed modification to the TIRF REMS Access Program Knowledge Assessment Question 11 be modified slightly so that there were only four multiple choice answer options due to program issues with formatting that requires only four rather than five options to multiple choice questions. Their proposal read: Select one option a) Actiq to Abstral Lazanda to Actiq b) Actiq to Fentora c) Actiq to Subsys d) All of the above Both B&C • • • On November 7, 2014, OSE/DRISK replied to the TRIG’s email and requested clarification on the formatting of the TIRF REMS Access Program Knowledge Assessment Question 11, specifically, whether they inadvertently failed to strike through “Lazanda to Actiq” in option ‘a’ On November 10, 2014, the TRIG replied to OSE/DRISK November 7, 2014 email and indicated that they failed to strike through “Lazanda to Actiq” in option ‘a’. On November 13, 2014, DRISK was notified by Office of Generic Drugs that there were inconsistencies in the dosage titration information contained in the Abstral U.S. Prescribing Information (USPI) Section 2.2, which were also reflected in relevant TIRF REMS materials. 1 • On November 14, DAAAP notified Galena of the inconsistencies identified in the Abstral USPI. • On November 17, 2014, the TRIG emailed OSE the revised TIRF REMS material, as previously agreed upon, which incorporated revisions to all the TIRF REMS materials made as a result of DRISK TIRF REMS Modification Interim comments #1 and #2 reviews (C. Miller). • On November 18, 2014, the Office of Surveillance and Epidemiology (OSE) (project manager Vaishali Jarral) notified the TRIG via email to correct the error contained in the TIRF REMS Access Education Program Products Covered Under 1 Gierhart, Brenda, Office of Generic Drugs, email communication to OSE and DAAAP dated November 13, 2014. Reference ID: 3673716 FDA_7016 this Program table for Abstral in their final TIRF Modification Submission #3 due to be submitted to the DMF on Friday, November 21, 2014. 2 • On November 25, 2014, the TRIG submitted the final TIRF REMS Modification #3 to drug master file (DMF 27320) Seq. No. 0012, incorporating all previously communicated revisions to the TIRF REMS • Between November 25, 2014 and December 1, 2014 , all TIRF applicant holders submitted amendments to their prior approval supplements for the current TIRF REMS modification (See Table 2 for detailed submission information). • On November 26, 2014, DRISK noted that the TRIG submission of the complete TIRF REMS did not include all the appended material and subsequently, the OSE PM requested, via email, that the TRIG resubmit their final TIRF REMS to include all appended material. OSE also requested that the TRIG notify all applicant holders of the need for their resubmission cover letters referencing the DMF and to assure that all of their submissions included the current Medication Guide (MG) or reference to their current MG in the cover letters. • On December 2, 2014, the TRIG notified OSE via email, that their resubmission of the complete TIRF REMS, as directed above, would be submitted to the DMF on December 10, 2014 and applicant holders would subsequently submit their cover letters to their applications referencing the DMF submission on the following date, December 11, 2014. The TRIG confirmed that they would provide directives to the applicant holders to include their most currently approved MG or reference as such in their cover letters. • On December 9, 2014, Galena submitted the requested Abstral correction to the TIRF REMS Education Program Products Covered document in the TIRF REMS, for prior approval supplement (S-013) (Seq. No. 0098) • On December 10, 2014, the TRIG submitted their final TIRF REMS and all appended material (DMF 27320) (Seq. No. 0013) as a “replace for Seq. No. 0012” which reflects the correct and final TIRF REMS for Modification #3. • Between December 11 – December 15, 2014, the TIRF REMS applicant holders submitted their cover letters referencing the December 10, 2014 submission of the final TIRF REMS reflecting Modification #3 to the (DMF 27320), along with reference to their current MGs. (see Table 2 on Page 2 for detailed submission information) MATERIALS REVIEWED 2.1 SUBMISSIONS • Reference ID: 3673716 TIRF REMS Industry Group (TRIG) Drug Master File (DMF 27320) Transmucosal Immediate Release (TIRF) Access Program REMS Modification received May 20, 2014 (Seq. No. 0099) and submitted to individual applicant holders (see table on page 2) FDA_7017 o TIRF REMS Industry Group (TRIG) Drug Master File (DMF 27320) Transmucosal Immediate Release (TIRF) Access Program REMS Modification Amendment received November 25, 2014 (Seq. No. 012) and to individual applicant holders (see table on page 2) o TIRF REMS Industry Group (TRIG) Drug Master File (DMF 27320) Transmucosal Immediate Release (TIRF) Access Program REMS Modification Amendment received December 10, 2014 (Seq. No. 013) and to individual applicant holders (see table on page 2) • Galena’s Abstral Prior Amendment to Approval Supplement (S-013) REMS Modification dated December 9, 2014 (Seq. No. 0098) 2.2 OTHER MATERIALS INFORMING OUR REVIEW • Miller, C. DRISK REMS Modification Review for Abstral (NDA 22510) DARRTS dated July 29, 2014 o Miller, C. DRISK REMS Modification Addendum Review for Abstral (NDA 22510) DARRTS dated December 10, 2014 3 • Miller, C. DRISK TIRF REMS Modification Review #1 of the TIRF REMS dated October 20, 2014. • Division of Anesthesia, Analgesia, and Addiction Products (DAAAP) Prior Approval Labeling Supplement (S-013) for Abstral (fentanyl) sublingual tablets approval letter dated November 4, 2014. • Miller, C. DRISK TIRF REMS Modification Review #2 of TIRF REMS dated November 5, 2014. • All email communications as referenced in Section 1.2 Regulatory History. PROPOSED REMS MODIFICATION The following information below outlines the Proposed TIRF REMS Modification #3. Details and prior regulatory history for these proposed modifications can be found in DRISK Abstral REMS Modification Review (dated July 29, 2014) DRISK TIRF REMS Modification Review#1 (dated October 20, 2014), and DRISK TIRF REMS Modification Review #2 (dated November 5, 2014). 3.1 REMOVAL OF NDC NUMBERS This modification proposes updates of select REMS materials to eliminate product specific information NDC numbers and replace with a link on the TIRF REMS Access Program website that references the information for interested stakeholders. The revision was made to reduce Sponsor and Agency administrative burden for multiple modifications to incorporate this product specific information. Agreement was made that removal of this information did not impact the safe use of the TIRF products and Reference ID: 3673716 FDA_7018 minimizes the need for repeated modifications as the program continues to grow. The impacted REMS materials include: • • • Independent Outpatient Pharmacy Enrollment Form Chain Outpatient Pharmacy Enrollment Form TIRF REMS Website Prototype Reviewer Comments: See REMS Modification #3 Interim Comments 1 review (C. Miller) dated November 4, 2014 for discussion. 3.2 REMOVAL OF REFERENCE TO GENERICS This modification proposes updates of select REMS materials to eliminate reference to generics which does not impact the safe use of TIRF, and replace the reference generics with (**) beside the trade name drug, and an accompanying footnote stating “This includes approved generic equivalents of these products”. The revision was made to reduce Sponsor and Agency administrative burden for originated from internal discussions about certain aspects of the TIRF REMS program that prompt repeated administrative process and multiple modifications to incorporate this product specific information.. Agreement was made that removal of this information and replacing with the referenced (**) and footnote did not impact the safe use of the TIRF products and minimizes the need for repeated modifications as the program continues to grow. Impacted REMS materials include: • Education Program for Prescribers and Pharmacists Reviewer Comments: See REMS Modification #3 Interim Comments 1 review (C. Miller) dated November 4, 2014 for discussion. 3.3 REMOVAL OF ATTACHMENT 1’ LIST OF TIRF MEDICINES/REPLACE WITH HYPERLINK TO FDA APPROVED REMS WEBSITE This modification proposes the removal of ‘Attachment 1’ list of TIRF medicines in select REMS documents while replacing the list with a hyperlink that redirects the user to FDA Approved Risk Evaluation and Mitigation Strategy (REMS) website. As discussed above in Section 3.1, this revision was made to reduce Sponsor and Agency administrative burden for originated from internal discussions about certain aspects of the TIRF REMS program that prompt repeated administrative process and multiple modifications to incorporate this product specific information.. Agreement was made that removal of this information did not impact the safe use of the TIRF products and minimizes the need for repeated modifications as the program continues to grow. The impacted REMS materials include: • TIRF REMS Document • Prescriber Enrollment Form • TIRF REMS Supporting Document • Overview for Patients and Caregivers • Overview for Prescribers • Independent Outpatient Pharmacy Overview Reference ID: 3673716 FDA_7019 • Chain Outpatient Pharmacy Overview • Closed System Outpatient Enrollment Form • Closed System Outpatient Pharmacy Overview • Inpatient Pharmacy Enrollment Form • Independent Outpatient Pharmacy Enrollment Form • Distributor Enrollment Form • • Chain Outpatient Pharmacy Enrollment Form TIRF Website Prototype and TIRF Website Landing Page Reviewer Comments: See REMS Modification #3 Interim Comments 1 review (C. Miller) dated November 4, 2014 for discussion. 3.4 CRITERIA FOR INACTIVATION OF PATIENT-PRESCRIBER AGREEMENT FORM (PPAF) This modification proposes revisions to the criteria for the description of triggers that will inactive a patient’s PPAF, including the removal of the criteria of ‘patients who receive prescriptions for TIRF medicines from multiple prescribers within an overlapping time frame, that is suggestive of misuse, abuse, or addiction’. The modification also proposes the addition of criteria that will trigger inactivation of a patient PPAF. The current TIRF REMS has only one criteria listed which is “the patient has not filled a prescription for more than six (6) months. This revision resulted in the addition of the following 3 criteria: • PPAF has expired • Patient is deceased • Patient chooses to no longer participate in the TIRF REMS Access Program The impacted REMS materials include: • TIRF REMS Document • TIRF REMS Supporting Document Reviewer Comments: See REMS Modification #3 Interim Comments 1 review (C. Miller) dated November 4, 2014 for discussion. 3.5 REVISION OF REMS ASSESSMENT METRICS As a result of the 24-month TIRF REMS Assessment (submitted December 30, 2013), and subsequent DRISK 24-Month TIRF REMS Assessment review (dated June 19, 2014), changes to the TIRF REMS Assessment were communicated to the TRIG in the TIRF REMS Assessment Acknowledgement letter dated August 21, 2014. The REMS Assessment Plan changes are reflected in the TIRF REMS Supporting document submitted as part of this TIRF REMS Modification. Reviewer Comments: The REMS Assessment Plan changes communicated to the TRIG on August 21, 2014 are accurately reflected in the TIRF REMS Supporting Document. See REMS Modification #3 Interim Comments 1 review (C. Miller) dated November 4, 2014 for discussion. Reference ID: 3673716 FDA_7020 3.6 REVISIONS TO ENHANCE KNOWLEDGE ABOUT CONVERSION OF TIRF MEDICINES The TRIG is proposed a modification to emphasize and strengthen risk messaging about the conversion of TIRF medicines based on prescriber survey and knowledge assessment results that demonstrated low comprehension of this concept. The impacted REMS materials and proposed revisions include: • Education Program for Prescribers and Pharmacists • TIRF REMS Access Website Reviewer Comments: See REMS Modification #3 Interim Comments 1 review (C. Miller) dated November 4, 2014 for discussion. 3.7 INFORMATION ABOUT THE TIRF REMS CASH CLAIM TRANSACTION PROCESS This revision, proposed by the TRIG, added information to select TIRF REMS material to enhance understanding about the correct TIRF REMS Cash Claim transaction process. The TRIG states that these revisions are proposed based on several pharmacies’ acknowledgement that they are unaware of the cash claim processing requirements, and is documented as part of the TIRF REMS 24-Month Assessment Report (Table 29, Non-Compliance Activity Reports by Stakeholders). The impacted REMS materials and proposed revisions include: • TIRF REMS Access Program Frequently Asked Questions (FAQ) Document • Independent Outpatient Pharmacy Overview • Chain Outpatient Pharmacy Overview • Closed System Outpatient Pharmacy Overview Reviewer Comments: See REMS Modification #3 Interim Comments 1 review (C. Miller) dated November 4, 2014 for discussion. 3.8 UPDATE THE TIRF REMS WEB PROTOTYPE DOCUMENT AND WEBSITE LANDING PAGE This modification proposes revisions to the TIRF REMS Access Web Prototype and Website Landing Page, that incorporations all changes outlined above, where identified, along with the following additional revisions, along with updates to the Resources for Prescribers, Resources for Patients and Resources for Distributors Tabs to add a link for the appropriate products list, as requested in DRISK TIRF REMS Modification Interim comments1 review. Reviewer Comments: See REMS Modification #3 Interim Comments 1 review (C. Miller) dated November 4, 2014 for discussion. 3.9 ADDITIONAL MODIFICATIONS PROPOSED RELATED TO ABSTRAL (NDA 22510) PRIOR APPROVAL SUPPLEMENT (S-013) The TIRF REMS Access Program Education Program for Prescribers and Pharmacists Reference ID: 3673716 FDA_7021 Galena’s amended PAS/Proposed REMS Modification submission for S-013 (NDA 22510), as discussed above in Section 1.2 Regulatory History, includes the following proposed revision to Section 2.2 of the Abstral PI: 2.2 Conversion from Actiq The initial dose of Abstral is always 100 mcg with the only exception being patients already using Actiq. a. For patients being converted from Actiq, prescribers must use the Initial Dosing Recommendations for Patients on Actiq. See Table 1 for initial dosing recommendations. Patients must be instructed to stop the use of Actiq and dispose of any remaining units. Table 1: Initial Dosing Recommendations for Patients on ACTIQ Current ACTIQ Dose (mcg) Initial Abstral Dose (mcg) 200 100 mcg 400 200 mcg 600 200 mcg 800 200 mcg 1200 200 mcg 1600 400 mcg b. For patients converting from Actiq doses 400 200 mcg and below, initiate titration with 100 mcg Abstral and proceed using multiples of this strength. As a result, the TIRF REMS Access Program Education Program for Prescribers and Pharmacists – Products Covered Under this Program Table (Abstral) was revised as indicated below: Reference ID: 3673716 FDA_7022 Reviewer Comments: DRISK confirmed in consultation with DAAAP via email on November 14, 2014, that the Abstral dose begins to titrate above 100 mcg when a patient is being converted from greater than or equal to 400 mcg of ACTIQ, not 600 mcg. Subsequently, the language contained in the TIRF REMS Access Program for Prescribers and Pharmacists table for Abstral should read: (unless the patient is being converted from ≥ 400 mcg of ACTIQ – please see Full Prescribing Information). 4 CONCLUSION The REMS Modification to the TIRF REMS Access Program is acceptable to the Office of Surveillance and Epidemiology, Division of Risk Management (OSE/DRISK). All revisions as cited above, were incorporated into the attached TIRF REMS document and appended materials. 5 RECOMMENDATIONS OSE/DRISK recommends approval of the TIRF REMS Modification, received on May 20, 2014, last amended through one joint submission into drug master file (DMF) 27320 on November 25, 2014 and amended December 10, 2014 (see Table 2 for detailed submission information for TIRF product applicant holders), and appended to this review. ATTACHMENTS Transmucosal Immediate-Release Fentanyl (TIRF) REMS Reference ID: 3673716 FDA_7023 Initial REMS approval: 12/2011 Most recent modification: TRANSMUCOSAL IMMEDIATE RELEASE FENTANYL (TIRF) RISK EVALUATION AND MITIGATION STRATEGY (REMS) FOLLOWING THIS PAGE, TO WITHHELD IN FULL AS FDA 7024 Reference ID: 3673716 REMS WEB MATERIALS) --------------------------------------------------------------------------------------------------------This is a representation of an electronic record that was signed electronically and this page is the manifestation of the electronic signature. --------------------------------------------------------------------------------------------------------/s/ ---------------------------------------------------CATHY A MILLER 12/16/2014 REEMA J MEHTA 12/16/2014 I concur. Reference ID: 3673716 FDA_7156 insvs THERAPEUTICS, INC. June 12, 2017 Sharon Hertz, MD Director, Division of Anesthesia and Analgesia Products Of?ce of Drug Evaluation 11 Center for Drug Evaluation and Research Food and Drug Administration 5901-B Ammendale Road Beltsville, MD 20705-1266 NEW SUPPLEMENT FOR NDA PRIOR APPROVAL SUPPLEMENT PROPOSED REMS MODIFICATIONS DUE TO SAFETY LABEL CHANGES SUBMITTED IN SUPPLEMENT S-016 RE: NDA 202788: (Fentanyl Sublingual Spray) for the management of breakthrough cancer pain Sequence No. 0128: PRIOR APPROVAL SUPPLEMENT - PROPOSED REMS MODIFICATIONS DUE TO SAFETY LABEL CHANGES (8-018) Dear Dr. Hertz: Reference is made to the Single Shared REMS for Transmucosal Immediate Release entanyl (TIRF) products approved on December 28, 2011, for Insys Development Company, Inc.?s (Fentanyl Sublingual Spray), which is contained in DMF #027320. Additional reference is made to the Letter of Authorization (LOA) for DMF #027320 submitted in Section 1.4.1 of this application on September 11, 2013. Reference is also made to the REMS Modi?cation Noti?cation letter received on April 10, 2017. Per the guidelines in Section 1.5 of the DMF instruction document entitled, ?Process for Utilizing a Type VDrug Master File (DMF) for a Shared System Risk Evaluation and Mitigation Strategy (REMS) Shared System REMS Insys hereby noti?es FDA of submission of the REMS modi?cation, to update the REMS materials with the recent safety label changes as requested by the FDA in the REMS Modi?cation Noti?cation letter, to the DMF #027320 in sequence 0029 on June 09, 2017. As requested by the Agency, the proposed modi?ed REMS and other REMS-related materials were submitted in Microsoft Word format. In addition to the above REMS modi?cation, as proposed in the response to the 60-Month Assessment Report lnforrnation Request 1 by the TRIG, the proposed Dear Healthcare Provider Letter is submitted to the DMF in Sequence 0030 on June 09, 2017. The Dear Healthcare Provider Letter is provided in a separate sequence as a stand-alone submission to clarify it as a one-time (single-use) communication rather than a new document being appended into the REMS itself. 1333 South Spectrum Boulevard. Suite 100, Chandler, AZ 85286 I phone: 480.500.3127 I fax: 602.910.2627 57 Insys Development Company, Inc. 202,788: (fentanyl sublingual spray) SO 128: Prior Approval Supplement Proposed REMS Modi?cations Due to Safety Label Changes (8-018) Page 2 of 2 If you have any questions regarding this submission, please contact me by telephone at (480) 500-3150 or by email at Sincerely, 3% Stephen Sherman Sr. Vice President, Regulatory Affairs 1333 South Spectrum Boulevard. Suite 100. Chandler, AZ 85286 phone: 480.500.3127 fax: 602.910.2627 I 58 Electronic Submission Specifications This submission is compliant with FDA's Guidelines for Industry and current eCTD specifications. All files were checked and verified to be free of viruses prior to transmission through the electronic submission gateway. Anti-Virus Program Program Version Virus Definition Date Submission Size Symantec Endpoint Protection Edition 12.1.5337.5000 06/11/2017 Rev.1 Approx. 3.1 MB The IT point of contact for this submission is: Name Phone Number Email Address Elena Renaud (480) 500-3166 erenaud@insysrx.com FDA_7159 MEMORANDUM DEPARTMENT OF HEALTH AND HUMAN SERVICES PUBLIC HEALTH SERVICE FOOD AND DRUG ADMINISTRATION CENTER FOR DRUG EVALUATION AND RESEARCH OPEN GOAL DATE REMS Modifications Due to Approved or Ordered Safety Labeling Changes DATE: June 12, 2017 FROM: Mark Liberatore, PharmD; Safety RPM, DAAAP DRUG: Subsys (fentanyl) NDA # 202788  REMS Modification Supplement #: S-018  Labeling Supplement # S-016  Date of Labeling Supplement Approval: December 16, 2016 This memo opens the 60 or 180 day goal date for the above referenced REMS modification supplement according the information provided below: 60 Day Goal Date: If FDA considers the REMS modifications to be conforming, enter the date of receipt of the conforming REMS modification supplement or amendment that conforms to the approved or ordered labeling changes in DARRTS. DARRTS will calculate the action goal date. Reference ID: 4114627 FDA_7161 --------------------------------------------------------------------------------------------------------This is a representation of an electronic record that was signed electronically and this page is the manifestation of the electronic signature. --------------------------------------------------------------------------------------------------------/s/ ---------------------------------------------------MARK A LIBERATORE 06/21/2017 Reference ID: 4114627 FDA_7162 Of?ce of Prescription Drug Promotion Internal Consults Pre-decisional Agency Information* Please Note: The following review is for DRISK onlv and should not be used to provide comments to the )onsor. To: Kate Heinrich Oswell, Health Communications Analyst, DRISK From: L. Shene? Toombs, Regulatory Review Officer, OPDP cc: Sam Skariah, Team Leader, OPDP Wendy Brown, SRPM, OSE Selena Ready, Acting Team Leader, DRISK LaShaun Washington-Batts, Risk Management Analyst, DRISK Kate Heinrich Oswell, Health Communications Analyst, DRISK Carole Broadnax, OPDP CDER-OPDP-RPM Michael Wade, OPDP Date: June 27, 2017 Re: MF 027320 Transmucosal Immediate Release Fentanyl (TIRF) Products Comments on draft Risk Evaluation and Mitigation Strategies (REMS) Materials [Submission date: June 9, 2017 (Sequence: 0029, 0030)] Materials Reviewed OPDP has reviewed the following proposed REMS materials for the TIRF Products: 0 Healthcare Provider (HCP) REMS Materials: 0 Dear Healthcare Provider Letter: Safety Update 0 Chain Outpatient Pharmacy Enrollment Form 63 Reference ID: 4117234 o o o o o o o o o o o o o o  Overview for Chain Outpatient Pharmacies Closed System Outpatient Pharmacy Enrollment Form Overview for Closed System Outpatient Pharmacies Wholesaler/Distributor Enrollment Form Education Program for Prescribers and Pharmacists Frequently Asked Questions Independent Outpatient Pharmacy Enrollment Form Overview for Independent Outpatient Pharmacies Inpatient Pharmacy Enrollment Form Overview for Inpatient Pharmacies Knowledge Assessment Patient-Prescriber Agreement Form Prescriber Enrollment Form Overview for Prescribers Direct-to-Consumer (Patient) REMS Materials: o Overview for Patients and Caregivers  Websites o TIRF REMS Access Program: Web Prototype The version of the draft REMS materials used in this review can be found at: \\CDSESUB1\evsprod\MF027320\027320.enx OPDP offers the following comments on these draft REMS materials for the TIRF products. General Comment Please remind the sponsors that REMS materials are not appropriate for use in a promotional manner. OPDP notes the link www.TIRFREMSaccess.com and toll free numbers such as 1866-822-1483. OPDP recommends that these items represent a direct link to only REMS related information and not be promotional in tone. REMS Materials OPDP does not object to including the following materials in the REMS program (please see Specific Comment[s] below):  Reference ID: 4117234 Healthcare Provider (HCP) REMS Materials: o Dear Healthcare Provider Letter: Safety Update o Chain Outpatient Pharmacy Enrollment Form o Overview for Chain Outpatient Pharmacies o Closed System Outpatient Pharmacy Enrollment Form FDA_7164 o o o o o o o o o o o o  Overview for Closed System Outpatient Pharmacies Wholesaler/Distributor Enrollment Form Education Program for Prescribers and Pharmacists Frequently Asked Questions Independent Outpatient Pharmacy Enrollment Form Overview for Independent Outpatient Pharmacies Inpatient Pharmacy Enrollment Form Overview for Inpatient Pharmacies Knowledge Assessment Patient-Prescriber Agreement Form Prescriber Enrollment Form Overview for Prescribers Direct-to-Consumer (Patient) REMS Materials: o Overview for Patients and Caregivers  Websites o TIRF REMS Access Program: Web Prototype Specific Comment[s] OPDP considers the following statement[s] promotional in tone and recommends revising or deleting them from the REMS piece: o Dear Healthcare Provider Letter: Safety Update  Risk o “Life-threatening respiratory depression could occur at any dose in opioid non-tolerant patients. Deaths have occurred in opioid nontolerant patients treated with some TIRF medicines” The inclusion of this risk statement under the presentation of the Indication for these products minimizes the importance of this risk information. Consider revising the letter to include this information under the Contraindications header in a manner consistent with the approved PI. o “Do not use TIRF medicines in opioid non-tolerant patients; death can occur TIRF medicines are contraindicated for acute or post-operative pain management…”(bolded emphasis original) The utilization of bolded font for these risk statements may imply that these risk statements are more important than the remaining risk information presented under the Contraindications header. Consider Reference ID: 4117234 FDA_7165 revising to present the information under this header in a similar text throughout the presentation. In addition, consider utilizing a separate bullet for each contraindication listed, similar to the presentation in the approved PI. o Education Program for Prescribers and Pharmacists  Risk o “TIRF medicines are contraindicated in opioid non-tolerant patients because life-threatening respiratory depression and death could occur at any dose in patients not taking chronic opioids” (page seven) The inclusion of this risk statement under the presentation of the Indication minimizes the importance of this risk information. Consider revising this REMS piece to include this information under the Contraindications header on page nine, in a manner consistent with the approved PI. o TIRF REMS Access Program: Web Prototype  Please apply our comments for the above presentations to similar presentations in the Web Prototype REMS document. We have no additional comments on these proposed REMS materials at this time. Thank you for your consult. Reference ID: 4117234 FDA_7166 --------------------------------------------------------------------------------------------------------This is a representation of an electronic record that was signed electronically and this page is the manifestation of the electronic signature. --------------------------------------------------------------------------------------------------------/s/ ---------------------------------------------------LATOYA S TOOMBS 06/27/2017 Reference ID: 4117234 FDA_7167 Department of Health and Human Services Food and Drug Administration Center for Drug Evaluation and Research Office of Surveillance and Epidemiology Office of Medication Error Prevention and Risk Management REMS MODIFICATION REVIEW Date: July 12, 2017 Reviewer(s): LaShaun Washington-Batts, Pharm.D. Risk Management Analyst Division of Risk Management (DRISK) Kate Oswell, M.A. Health Communication Specialist DRISK Team Leader: Selena Ready, Pharm.D. DRISK Division Director: Cynthia LaCivita, Pharm.D. DRISK Subject: REMS Modification Therapeutic Class: Opioid Analgesic OND Review Division: Division of Anesthetics, Analgesia, and Addiction Products OSE RCM #: 2017-1183 DMF #: 027320 Drug Name, Dosage Form, NDA Number and Sponsor Name: Drug Name Abstral (fentanyl) Actiq (fentanyl citrate) Fentora and Authorized Generic (fentanyl citrate) Lazanda (fentanyl) Onsolis Reference ID: 4123156 Dosage Form and Route Sublingual tablet Oral transmucosal lozenge Buccal tablet NDA Number 022510 020747 Sponsor Galenya BioPharma Cephalon, Inc. 021947 Cephalon, Inc. Nasal spray Buccal soluble 022569 022266 DepoMed, Inc. Meda Pharmaceuticals FDA_7168 (fentanyl) Subsys (fentanyl) film Sublingual spray fentanyl buccal Buccal tablet fentanyl citrate Oral transmucosal lozenge Oral transmucosal lozenge fentanyl citrate Reference ID: 4123156 202788 Insys Therapy ANDA 079075 ANDA 078907 ANDA 077312 Watson Laboratories, Inc. Mallinckrodt, Inc. Par Pharmaceutical, Inc. FDA_7169 TABLE OF CONTENTS 1. 2. 3. 4. 4.1. 4.2. 5. 6. 6.1. 6.2. 6.3. 7. 8. 9. 10. 11. 12. Introduction ....................................................................................................................................................................... 4 Background ........................................................................................................................................................................ 4 Regulatory History .......................................................................................................................................................... 5 Materials Reviewed......................................................................................................................................................... 5 Submissions .................................................................................................................................................................. 5 Other Materials Informing Our Review............................................................................................................... 6 Rationale for the REMS Modification ...................................................................................................................... 6 Review of the proposed REMS Modification......................................................................................................... 6 Medication Guide........................................................................................................................................................ 6 REMS Document ........................................................................................................................................................ 6 Elements to Assure Safe Use .................................................................................................................................. 8 Implementation System ............................................................................................................................................... 11 Timetable for Submission of Assessments ............................................................................................................ 11 REMS Supporting Document .................................................................................................................................... 11 Recommendations for the Review Division ..................................................................................................... 11 Comments for the Sponsor..................................................................................................................................... 11 Attachments ................................................................................................................................................................ 14 Reference ID: 4123156 FDA_7170 1. INTRODUCTION This review by the Division of Risk Management (DRISK) provides an evaluation of the proposed modification of the transmucosal immediate-release fentanyl (TIRF) risk evaluation and mitigation strategy (REMS) Access Program (TIRF REMS) received on June 9, 2017. This REMS modification is required to conform to safety labeling changes (SLC) approved on December 16, 2016 that address the addition of language related to the risks of misuse, abuse, addiction, overdose, death, and neonatal opioid withdrawal syndrome (NOWS), serotonin syndrome with concomitant use of serotonergic drugs, adrenal insufficiency, androgen deficiency, and risks of concomitant use of opioid analgesics with benzodiazepines or other central nervous system depressants to the Prescribing Information. Thus, the primary purpose of this proposed TIRF REMS modification is to incorporate the approved safety labeling changes within the TIRF REMS document and materials. This review is written by the DRISK, in consultation with the Office of Prescription Drug Promotion (OPDP). 2. BACKGROUND TIRF products are used for the management of breakthrough cancer pain in patients already receiving and who are tolerant to around the clock opioid therapy for their underlying persistent cancer pain. The approved TIRF products include: • • • • • • • Abstral (fentanyl) sublingual tablet Actiq (fentanyl citrate) oral transmucosal lozenge Fentora (fentanyl citrate) buccal tablet Lazanda (fentanyl) nasal spray, Onsolis (fentanyl) buccal soluble film Subsys (fentanyl) sublingual spray Approved generic equivalents of these products The TIRF products are approved under a single, shared system REMS and all Sponsors with approved products in the TIRF REMS are members of the TIRF REMS Industry Group (TRIG). The goals of the TIRF REMS are to mitigate the risk of misuse, abuse, addiction, overdose and serious complications due to medication errors by: • • • • Prescribing and dispensing TIRF medicines only to appropriate patients, which includes use only in opioid-tolerant patients. Preventing inappropriate conversion between TIRF medicines. Preventing accidental exposure to children and others for whom it was not prescribed. Educating prescribers, pharmacists, and patients on the potential for misuse, abuse, addiction, and overdose of TIRF medicines. Reference ID: 4123156 FDA_7171 The REMS is comprised of Medication Guides (MG) for each individual TIRF medicine and the following elements to assure safe use (ETASU): • • • Healthcare providers who prescribe TIRF medicines for outpatient use are specially certified TIRF medicines will only be dispensed by pharmacies that are specially certified TIRF medicines will only be dispensed for outpatient use with evidence or other documentation of safe-use conditions. The timetable for submission of TIRF REMS assessments is at 6 and 12 months from the date of the initial REMS approval, and annually thereafter. The TIRF REMS was approved by the Agency on December 28, 2011 and was launched on March 12, 2012. The TIRF REMS was modified June 5, 2012, November 7, 2013 and December 24, 2014. 3. REGULATORY HISTORY March 22, 2016: The Agency issued SLC notification letters to Sponsors of the TIRF product new drug applications (NDAs). The new safety information to be included in the labeling pertains to the risks of misuse, abuse, addiction, overdose, death, and neonatal opioid withdrawal syndrome; serotonin syndrome with concomitant use of serotonergic drugs; adrenal insufficiency; and androgen deficiency. August 31, 2016: The Agency issued SLC notification letters to the Sponsors of the TIRF product NDAs. The new safety information to be included in the labeling pertains to the risks of concomitant use of opioid analgesics with benzodiazepines or other central nervous system depressants. December 16, 2016: The Agency approved the SLCs for all TIRF products. The new safety information included the following: Updating the warning to include misuse, abuse, addiction, overdose, death, and NOWS, Serotonin Syndrome with concomitant use of serotonergic drugs, adrenal insufficiency, androgen deficiency, and risks of concomitant use of opioid analgesics with benzodiazepines or other central nervous system depressants. June 9, 2017: The TRIG point of contact submitted the TIRF Access Program REMS Modification to the Drug Master File (DMF). June 12, 2017: All TRIG sponsors submitted individual cover letters for the TIRF Access Program REMS Modification to their applications, referencing the DMF Submission. 4. MATERIALS REVIEWED 4.1. SUBMISSIONS • DMF # 027320 eCTD Sequence No. 029 TIRF Access Program REMS Modification received on June 9, 2017. These materials are the subject of this review. Submission Date Product Name Application Supplement Number Number June 12, 2017 Abstral (fentanyl) NDA 022510 17 Reference ID: 4123156 FDA_7172 June 12, 2017 June 12, 2017 June 12, 2017 June 12, 2017 June 12, 2017 June 12, 2017 June 12, 207 June 12, 207 Actiq (fentanyl citrate) Fentora and Authorized Generic (fentanyl citrate) Lazanda (fentanyl) Onsolis(fentanyl) Subsys (fentanyl) Fentanyl buccal tablet Fentanyl citrate lozenge Fentanyl citrate lozenge NDA 020747 NDA 021947 47 27 NDA 022569 NDA 022266 NDA 202788 ANDA 079075 ANDA 078907 ANDA 077312 26 19 18 13 16 9 4.2. OTHER MATERIALS INFORMING OUR REVIEW • • • • • Safety label change notification letters for all TIRF products issued on March 22, 2016 Safety label change notification letters for all TIRF products issued on August 31, 2016 Approval letters for all TIRF product prior approval supplement safety labeling changes issued December 16, 2016. Washington-Batts L. DRISK REMS Modification Rationale Review for TIRFs. March 6, 2017 Toombs, L. Shenee’. OPDP REMS Consult Review. June 27, 2017 5. RATIONALE FOR THE REMS MODIFICATION The proposed TIRF REMS modification was in response to the SLC Approval Letter dated December 16, 2016 that included the addition of language related to the risks of misuse, abuse, addiction, overdose, death, and NOWS, serotonin syndrome with concomitant use of serotonergic drugs, adrenal insufficiency, androgen deficiency, and risks of concomitant use of opioid analgesics with benzodiazepines or other central nervous system depressants to the Prescribing Information. This REMS modification is necessary to align the TIRF REMS document and materials with the SLC. 6. REVIEW OF THE PROPOSED REMS MODIFICATION 6.1. MEDICATION GUIDE There were no changes proposed for this element. 6.2. REMS DOCUMENT The TRIG proposed changes to the REMS Document as described below (modifications in red text and underlined). On page 3, Prescriber Enrollment Form, paragraph iic: – I understand that TIRF medicines are indicated only for the management of breakthrough pain in cancer patients, 18 years of age or older (Actiq and its generic equivalents are approved for 16 years of age and older), who are already receiving and who are tolerant to, around-the-clock opioid therapy for their underlying persistent pain. Reference ID: 4123156 FDA_7173 Reviewer Comment: The Agency agrees with this change as it aligns with the prescribing information. On page 3, Prescriber Enrollment Form, paragraph iie: I understand that TIRF medicines are not for use in the management of acute or postoperative pain, including headache/migraine and dental pain, or in the emergency room. Reviewer Comment: The Agency disagrees with this change and proposes the following language: I understand that TIRF medicines must not be used to treat acute or postoperative pain, including headache/migraine and dental pain, or acute pain in the emergency department. On page 3, Prescriber Enrollment Form, paragraph if: Changes to the TIRF REMS Access website URL to be www.tirfremsaccess.com/TirfUI/rems/products.action Reviewer Comment: The Agency agrees with the change to the TIRF REMS Access website, here and throughout the document. On page 4, Patient Prescriber Agreement Form, paragraph 1): I understand that TIRF medicines are indicated only for the management of breakthrough pain in cancer patients, 18 years of age or older (Actiq and its generic equivalents are approved for 16 years of age and older), who are already receiving and who are tolerant to, around-the-clock opioid therapy for their underlying persistent pain. Reviewer Comment: The Agency agrees with this change as it aligns with the prescribing information. On page 4, Patient Prescriber Agreement Form, paragraph 3): I understand that TIRF medicines are not for use in the management of acute or postoperative pain, including headache/migraine and dental pain, or in the emergency room. Reviewer Comment: The Agency agrees with this addition to the attestation for the Patient-Prescriber Agreement Form, but proposes the following language: I understand that TIRF medicines must not be used to treat acute or postoperative pain, including headache/migraine and dental pain, or acute pain in the emergency department. On page 4, Patient Prescriber Agreement Form, paragraph 4): I understand that patients considered opioid-tolerant are those who are regularly taking at least: 60 mg oral morphine/day; 25 micrograms transdermal fentanyl/hour; 30 mg oral oxycodone/day; 8 mg oral hydromorphone/day; 25 mg oral oxymorphone/day; 60 mg oral hydrocodone/day; or an equianalgesic dose of another opioid daily for one week or longer. Reviewer Comment: The Agency agrees with this change, but proposes the following language: Reference ID: 4123156 FDA_7174 I understand that patients considered opioid-tolerant are those who are taking, for one week or longer, at least: 60 mg oral morphine/day; 25 micrograms transdermal fentanyl/hour; 30 mg oral oxycodone/day; 8 mg oral hydromorphone/day; 25 mg oral oxymorphone/day; 60 mg oral hydrocodone/day; or an equianalgesic dose of another opioid daily for one week or longer. On page 5, Patient Prescriber Agreement Form, paragraph 8): I will store my TIRF medicine securely out of reach of children and teenagers because accidental use by a child, or anyone for whom it was not prescribed, is a medical emergency and can cause death. Reviewer Comment: The Agency disagrees with this change, but proposes the following language: I will store my TIRF medicine in a safe place, out of reach of children and teenagers because accidental use by a child, or anyone for whom it was not prescribed, is a medical emergency and can cause death. On page 8, Chain and Independent Outpatient Enrollment Form, paragraph iiid and page 11, Inpatient Pharmacy Enrollment Form, paragraph iid: I understand that TIRF medicines are contraindicated for use in opioid non-tolerant patients; in the management of acute or postoperative pain, including headache/migraine and dental pain, or in the emergency department; acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment; or in known or suspected gastrointestinal obstruction, including paralytic ileus. Reviewer Comment: The Agency disagrees with this change and proposes that the language remain as originally approved to read: “I understand that TIRF medicines are contraindicated for use in opioid non-tolerant patients.” 6.3. ELEMENTS TO ASSURE SAFE USE 6.3.1. REMS MATERIALS The TRIG proposed changes to the REMS Materials to include safety language for the SLCs in the Education Program for Prescribers and Pharmacists. In addition, the TRIG proposed changes to the Patient-Prescriber Agreement Form, Prescriber Enrollment Form, Inpatient Pharmacy Enrollment Form, Independent Outpatient Enrollment Form, Closed Outpatient Enrollment Form, and Chain Outpatient Enrollment Form. Reviewer Comments: The Agency reviewed all changes to the REM Materials and proposes edits as stated below: Patient-Prescriber Agreement Form: Prescriber Acknowledgments: Reference ID: 4123156 FDA_7175 Revise bullet #3 to state: “I understand that TIRF medicines must not be used to treat acute or postoperative pain, including headache/migraine, dental pain, or acute pain in the emergency department.” Revised bullet #4 to state: “I understand that patients considered opioid-tolerant are those who are taking, for one week or longer, at least: 60 mg oral morphine/day; 25 micrograms transdermal fentanyl/hour; 30 mg oral oxycodone/day; 8 mg oral hydromorphone/day; 25 mg oral oxymorphone/day; 60 mg oral hydrocodone/day; or an equianalgesic dose of another opioid daily. Patient Acknowledgments: Revise bullet #8 state: “I will store my TIRF medicine in a safe place, out of reach of children and teenagers because accidental use by a child, or anyone for whom it was not prescribed, is a medical emergency and can cause death. “ Prescriber Enrollment Form: Revise bullet #5 to better reflect the label: “I understand that TIRF medicines must not be used to treat acute or postoperative pain, including headache/migraine, dental pain, or acute pain in the emergency department.” Remove bullet#6: “I understand that TIRF medicines must not be used to treat any contraindicated conditions described in the full Prescribing Information, such as acute or postoperative pain, including headache/migraine.” Inpatient Pharmacy Enrollment Form, Independent Outpatient Enrollment Form, Closed Outpatient Enrollment Form, Chain Outpatient Enrollment Form: Remove added language to bullet # 4. Language should remain unchanged so that bullet reads, “I understand that TIRF medicines are contraindicated for use in opioid non-tolerant patients.” Education Program for Prescribers and Pharmacists: Page 7- The presentation of this information under the Indication minimizes the importance of this risk information. Remove the last bullet: “TIRF medicines are contraindicated in opioid nontolerant patients because life-threatening respiratory depression and death could occur at any dose in patients not taking chronic opioids” Page 8- Revise last sub bullet to read: “OR an equianalgesic dose of another oral opioid daily Page 9- Revise sub-bullet #1 under Contraindications section to better reflect the label: “Acute or postoperative pain including headache/migraine and dental pain, or acute pain in the emergency department.” Page 10- Revise last statement under Contraindication section to read: “Deaths have occurred in opioid non-tolerant patients treated with fentanyl products.” Reference ID: 4123156 FDA_7176 Page 12- Add the following bullet to the subheading “Risk of Misuse, Abuse, Addiction, and Overdose”: “Doctor shopping” (visiting multiple prescribers to obtain additional prescriptions) is common among drug abusers and people suffering from untreated addiction. Page14- Revise subheading to state: “2. Accidental Ingestion or Exposure” to reflect the label. Page 14- Revise bullet #3 under Accidental Ingestion or Exposure” to read: “Instruct patients to take steps to store TIRF medicines in a safe place out of reach of children. Page15- Revise bullet to state: Any accidental ingestion or exposure, especially in children, may result in respiratory depression or death. Talk with your patients about safe and appropriate storage and disposal of TIRF Medicines.” Page15- Revise the second bullet to mirror label under section 7. “Concomitant use of TIRF medicines with CYP3A4 inhibitors (e.g., certain protease inhibitors, ketoconazole, fluconazole, diltiazem, erythromycin, verapamil) may increase plasma concentrations of fentanyl and prolong opioid adverse reactions, which may cause potentially fatal respiratory depression.” Page 18- Include the following information to address neonatal opioid withdrawal syndrome. “Determine Patient-Specific Risk Factors 4. Pregnancy Prolonged use of TIRF medicines during pregnancy can result in neonatal opioid withdrawal syndrome, which may be life-threatening if not recognized and treated, and requires management according to protocols developed by neonatology experts. If opioid use is required for a prolonged period in a pregnant woman, advise the patient of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available. “ Page 22- Revise bullet #4 to read: “If the prescribed dose no longer adequately manages the breakthrough cancer pain for several consecutive episodes, increase the dose as described in the titration section of the prescribing information. Pharmacists: Instruct patients to consult with their prescriber. Page 28- Revise bullet 3# under “Tell the Patient cont.):” to read: “Accidental ingestion or exposure, especially in children, may result in respiratory depression or death. Always store your TIRF medicine in a safe place away from children and teenagers because accidental use by a child, or anyone for whom it was not prescribed, is a medical emergency and can cause death. Use the child safety kit if one is provided with your TIRF medicine. Pages 29/30- The bullets do not flow with the initial subheading, “Tell the Patient:” Remove the redundant phrase “Inform patients that” or “Inform patients and caregivers that” from these bullets. Reference ID: 4123156 FDA_7177 Page 30- Include the bullet: “Prolonged use of TIRF medicines during pregnancy can result in neonatal opioid withdrawal syndrome, which may be life threatening if not recognized and treated.” TIRF REMS Access Website: Apply our comments on the REMS materials to similar presentations in the Web Prototype REMS document. Final website screenshots should also incorporate these changes. 7. IMPLEMENTATION SYSTEM There were no changes proposed for this element. 8. TIMETABLE FOR SUBMISSION OF ASSESSMENTS There were no changes proposed for this element. 9. REMS SUPPORTING DOCUMENT There were minor editorial revisions proposed for the REMS Supporting Document. Reviewer Comment: The Agency agrees with the revisions to the REMS Supporting Document. 10. RECOMMENDATIONS FOR THE REVIEW DIVISION The comments for the sponsor provided below should be sent to the TRIG with a request to resubmit the TIRF REMS document and materials with the requested changes by July 26, 2017. 11. COMMENTS FOR THE SPONSOR The Agency reviewed the modifications proposed for the TIRF REMS Access Program. We provide the following comments below and redlined versions of the REMS Document and Education Program in the attachments. REMS Supporting Document: The Agency agrees with the minor revisions to the REMS Supporting Document. Further, the Sponsor must make changes to any language impacted by the proposed changes in the REMS Document and Materials provided below. REMS Document: See the attached redline version for agency comments and proposed changes. REMS Materials: See the comments provided below and incorporate changes. Patient-Prescriber Agreement Form: Prescriber Acknowledgments: Reference ID: 4123156 FDA_7178 Revise bullet #3 to state: “I understand that TIRF medicines must not be used to treat acute or postoperative pain, including headache/migraine, dental pain, or acute pain in the emergency department.” Revised bullet #4 to state: “I understand that patients considered opioid-tolerant are those who are taking, for one week or longer, at least: 60 mg oral morphine/day; 25 micrograms transdermal fentanyl/hour; 30 mg oral oxycodone/day; 8 mg oral hydromorphone/day; 25 mg oral oxymorphone/day; 60 mg oral hydrocodone/day; or an equianalgesic dose of another opioid daily. Patient Acknowledgments: Revise bullet #8 state: “I will store my TIRF medicine in a safe place, out of reach of children and teenagers because accidental use by a child, or anyone for whom it was not prescribed, is a medical emergency and can cause death. “ Prescriber Enrollment Form: Revise bullet #5 to better reflect the label: “I understand that TIRF medicines must not be used to treat acute or postoperative pain, including headache/migraine, dental pain, or acute pain in the emergency department.” Remove bullet#6: “I understand that TIRF medicines must not be used to treat any contraindicated conditions describer in the full Prescribing Information, such as acute or postoperative pain, including headache/migraine.” Inpatient Pharmacy Enrollment Form, Independent Outpatient Enrollment Form, Closed Outpatient Enrollment Form, Chain Outpatient Enrollment Form: Remove added language to bullet # 4. Language should remain unchanged so that bullet reads, “I understand that TIRF medicines are contraindicated for use in opioid non-tolerant patients.” Education Program for Prescribers and Pharmacists: We have made edits to align the Education Program with the label. See the Education Program for Prescribers and Pharmacists (attached) for suggested track changes. Please note: Page numbers were added to WORD document to help with the review process only. Page 7- The presentation of this information under the Indication minimizes the importance of this risk information. Remove the last bullet: “TIRF medicines are contraindicated in opioid nontolerant patients because life-threatening respiratory depression and death could occur at any dose in patients not taking chronic opioids” Page 8- Revise last sub bullet to read: “OR an equianalgesic dose of another oral opioid daily Page 9- Revise sub-bullet #1 under Contraindications section to better reflect the label: “Acute or postoperative pain including headache/migraine and dental pain, or acute pain in the emergency department.” Reference ID: 4123156 FDA_7179 Page 10- Revise last statement under Contraindication section to read: “Deaths have occurred in opioid non-tolerant patients treated with fentanyl products.” Page 12- Add the following bullet to the subheading “Risk of Misuse, Abuse, Addiction, and Overdose”: “Doctor shopping” (visiting multiple prescribers to obtain additional prescriptions) is common among drug abusers and people suffering from untreated addiction. Page14- Revise subheading to state: “2. Accidental Ingestion or Exposure” to reflect the label. Page 14- Revise bullet #3 under Accidental Ingestion or Exposure” to read: “Instruct patients to take steps to store TIRF medicines in a safe place out of reach of children. Page15- Revise bullet to state: Any accidental ingestion or exposure, especially in children, may result in respiratory depression or death. Talk with your patients about safe and appropriate storage and disposal of TIRF Medicines.” Page15- Revise the second bullet to mirror label under section 7. “Concomitant use of TIRF medicines with CYP3A4 inhibitors (e.g., certain protease inhibitors, ketoconazole, fluconazole, diltiazem, erythromycin, verapamil) may increase plasma concentrations of fentanyl and prolong opioid adverse reactions, which may cause potentially fatal respiratory depression.” Page 18- Include the following information to address neonatal opioid withdrawal syndrome. “Determine Patient-Specific Risk Factors 4. Pregnancy Prolonged use of TIRF medicines during pregnancy can result in neonatal opioid withdrawal syndrome, which may be life-threatening if not recognized and treated, and requires management according to protocols developed by neonatology experts. If opioid use is required for a prolonged period in a pregnant woman, advise the patient of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available. “ Page 22- Revise bullet #4 to read: “If the prescribed dose no longer adequately manages the breakthrough cancer pain for several consecutive episodes, to increase the dose as described in the titration section of the prescribing information. Pharmacists: Instruct patients to consult with their prescriber.” Page 28- Revise bullet 3# under “Tell the Patient cont.):” to read: “Accidental ingestion or exposure, especially in children, may result in respiratory depression or death. Always store your TIRF medicine in a safe place away from children and teenagers because accidental use by a child, or anyone for whom it was not prescribed, is a medical emergency and can cause death. Use the child safety kit if one is provided with your TIRF medicine. Pages 29/30- The bullets do not flow with the initial subheading, “Tell the Patient:” Remove the redundant phrase “Inform patients that” or “Inform patients and caregivers that” from these bullets. Reference ID: 4123156 FDA_7180 Page 30- Include the bullet: “Prolonged use of TIRF medicines during pregnancy can result in neonatal opioid withdrawal syndrome, which may be life threatening if not recognized and treated.” TIRF REMS Access Website: Apply our comments on the REMS materials to similar presentations in the Web Prototype REMS document. Final website screenshots should also incorporate these changes. Submit the following TIRF REMS Access Program materials with proposed changes to your application no later than COB July 26, 2017: 1. Redlined and Clean, Word REMS Supporting Document 2. Redlined and Clean, Word versions of REMS Document and all materials, submitted as separate files 3. Clean, Final PDF versions of the REMS Document and all materials, submitted as separate files 4. A compiled document containing clean, final formatted PDF versions of the REMS Document and materials for posting on the FDA REMS Website 12. ATTACHMENTS 1. Redlined PDF versions with Agency Comments a. REMS Document b. REMS Education Program Reference ID: 4123156 FDA_7181 Initial REMS approval: 12/2011 Most recent modification: TRANSMUCOSAL IMMEDIATE RELEASE FENTANYL (TIRF) RISK EVALUATION AND MITIGATION STRATEGY (REMS) FOLLOWING THIS PAGE, TO WITHHELD IN FULL AS REMS WEB MATERIALS) FDA 7182 Reference ID: 4123156 --------------------------------------------------------------------------------------------------------This is a representation of an electronic record that was signed electronically and this page is the manifestation of the electronic signature. --------------------------------------------------------------------------------------------------------/s/ ---------------------------------------------------SELENA D READY on behalf of LASHAUN WASHINGTON-BATTS 07/11/2017 CYNTHIA L LACIVITA 07/11/2017 Concur Reference ID: 4123156 FDA_7232 insvs August 21, 2017 Sharon Hertz, MD Director, Division of Anesthesia and Analgesia Products Of?ce of Drug Evaluation II Center for Drug Evaluation and Research Food and Drug Administration 5901-B Ammendale Road Beltsville, MD 20705-1266 REMS Final for approved NDA 202788, Supplement S-018 RE: NDA 202788: (Fentanyl Sublingual Spray) for the management of breakthrough cancer pain Sequence No. 0130: PRIOR APPROVAL SUPPLEMENT - REMS Final for approved NDA 202788, Supplement S-018 Dear Dr. Hertz: Reference is made to the Single Shared REMS for Transmucosal Immediate Release Fentanyl (TIRF) products approved on December 28, 2011, for Insys Development Company, Inc.?s (F entanyl Sublingual Spray), which is contained in DMF #027320. Additional reference is made to the Letter of Authorization (LOA) for DMF #027320 submitted in Section 1.4.1 of this application on September 11, 2013. Reference is also made to the REMS Modi?cation Noti?cation letter received on April 10, 2017. Reference is also made to the Information Request E-mail communication received on July 12, 2017, from Safety Regulatory Project Manager Wendy Brown to incorporated agency?s comments on the REMS Materials. Per the guidelines in Section 1.5 of the DMF instruction document entitled, ?Process for Utilizing a Type Drug Master File (DMF) for a Shared System Risk Evaluation and Mitigation Strategy (REMS) Shared System REMS Insys hereby noti?es FDA of submission of the REMS modi?cation, including the ?nal formatted REMS document, materials including website screenshots, and REMS Supporting Document as separate ?les, as well as a compiled document for posting on the FDA REMS website requested by the FDA in the Information request, to the DMF #027320 in sequence 0031 on August 18, 2017. If you have any questions regarding this submission, please contact me by telephone at (480) 500-3150 or by email at Sincerely, Stephen Sherman Sr. Vice President, Regulatory Affairs 1333 South Spectrum Boulevard, Suite 100, Chandler, AZ 85286/ phone: 480.500.3127 fax: 602.910.2627 Electronic Submission Speci?cations This submission is compliant with FDA's Guidelines for Industry and cmrent eC TD speci?cations. All ?les were checked and veri?ed to be free of Viruses prior to transmission through the electronic submission gateway. Anti-Virus Program Symantec Endpoint Protection Edition Program Version 12.1.5337.5000 Virus Definition Date 08/15/2017 Rev.24 Submission Size Approx. 2.69 MB The IT point of contact for this submission is: Name Elena Renaud Phone Number (480) 500-3166 Email Address Department of Health and Human Services Food and Drug Administration Center for Drug Evaluation and Research Office of Surveillance and Epidemiology Office of Medication Error Prevention and Risk Management REMS MODIFICATION REVIEW Date: August 30, 2017 Reviewer(s): LaShaun Washington-Batts, Pharm.D. Risk Management Analyst Division of Risk Management (DRISK) Kate Oswell, M.A. Health Communication Specialist DRISK Team Leader: Selena Ready, Pharm.D. DRISK Division Director: Cynthia LaCivita, Pharm.D. DRISK Subject: REMS Modification Therapeutic Class: Opioid Analgesic OND Review Division: Division of Anesthetics, Analgesia, and Addiction Products OSE RCM #: 2017-1183 DMF #: 027320 Drug Name, Dosage Form, NDA Number and Sponsor Name: Reference ID: 4146711 FDA_7235 Table 1: Products included in the TIRF REMS Access Program Drug Name Dosage Form NDA and Route Number Abstral (fentanyl) Sublingual tablet 022510 Actiq (fentanyl citrate) Oral transmucosal 020747 lozenge Fentora and Authorized Buccal tablet 021947 Generic (fentanyl citrate) Lazanda (fentanyl) Nasal spray 022569 Onsolis Buccal soluble 022266 (fentanyl) film Subsys (fentanyl) Sublingual spray 202788 fentanyl buccal Buccal tablet fentanyl citrate Oral transmucosal lozenge Oral transmucosal lozenge fentanyl citrate Reference ID: 4146711 ANDA 079075 ANDA 078907 ANDA 077312 Sponsor Galenya BioPharma Cephalon, Inc. Cephalon, Inc. DepoMed, Inc. Meda Pharmaceuticals Insys Therapy Watson Laboratories, Inc. Mallinckrodt, Inc. Par Pharmaceutical, Inc. FDA_7236 TABLE OF CONTENTS 1. Introduction ....................................................................................................................................................................... 4 2. Background ........................................................................................................................................................................ 4 3. Regulatory History .......................................................................................................................................................... 5 4. Materials Reviewed......................................................................................................................................................... 7 4.1. Submissions .................................................................................................................................................................. 7 4.2. Other Materials Informing Our Review............................................................................................................... 7 5. Rationale for the REMS Modification ...................................................................................................................... 7 6. Review of the proposed REMS Modification......................................................................................................... 7 6.1. Medication Guide........................................................................................................................................................ 7 6.2. REMS Document ........................................................................................................................................................ 8 6.3. Elements to Assure Safe Use .................................................................................................................................. 8 6.4. Implementation System............................................................................................................................................. 8 6.5. Timetable for Submission of Assessments ......................................................................................................... 8 6.6. REMS Supporting Document ................................................................................................................................. 8 7. Discussion and Conclusion ........................................................................................................................................... 8 8. Recommendation ............................................................................................................................................................. 9 9. Attachments ....................................................................................................................................................................... 9 Reference ID: 4146711 FDA_7237 1. INTRODUCTION This review by the Division of Risk Management (DRISK) provides an evaluation of the amended proposed modification of the transmucosal immediate-release fentanyl (TIRF) risk evaluation and mitigation strategy (REMS) Access Program (TIRF REMS) received on August 29, 2017. This REMS modification is required to conform to safety labeling changes (SLC) approved on December 16, 2016 that address the addition of language related to the risks of misuse, abuse, addiction, overdose, death, and neonatal opioid withdrawal syndrome (NOWS), serotonin syndrome with concomitant use of serotonergic drugs, adrenal insufficiency, androgen deficiency, and risks of concomitant use of opioid analgesics with benzodiazepines or other central nervous system depressants to the Prescribing Information. Thus, the primary purpose of this proposed TIRF REMS modification is to incorporate the approved safety labeling changes within the TIRF REMS document and materials. This review is written by the DRISK in consultation with the Office of Prescription Drug Promotion (OPDP). 2. BACKGROUND TIRF products are used for the management of breakthrough cancer pain in patients already receiving and who are tolerant to around the clock opioid therapy for their underlying persistent cancer pain. The approved TIRF products include:        Abstral (fentanyl) sublingual tablet Actiq (fentanyl citrate) oral transmucosal lozenge Fentora (fentanyl citrate) buccal tablet Lazanda (fentanyl) nasal spray, Onsolis (fentanyl) buccal soluble film Subsys (fentanyl) sublingual spray Approved generic equivalents of these products The TIRF products are approved under a shared system REMS and all Sponsors with approved products in the TIRF REMS are members of the TIRF REMS Industry Group (TRIG). The goals of the TIRF REMS are to mitigate the risk of misuse, abuse, addiction, overdose and serious complications due to medication errors by:     Prescribing and dispensing TIRF medicines only to appropriate patients, which includes use only in opioid-tolerant patients. Preventing inappropriate conversion between TIRF medicines. Preventing accidental exposure to children and others for whom it was not prescribed. Educating prescribers, pharmacists, and patients on the potential for misuse, abuse, addiction, and overdose of TIRF medicines. Reference ID: 4146711 FDA_7238 The REMS is comprised of Medication Guides (MG) for each individual TIRF medicine and the following elements to assure safe use (ETASU):    Healthcare providers who prescribe TIRF medicines for outpatient use are specially certified TIRF medicines will only be dispensed by pharmacies that are specially certified TIRF medicines will only be dispensed for outpatient use with evidence or other documentation of safe-use conditions. The timetable for submission of TIRF REMS assessments is at 6 and 12 months from the date of the initial REMS approval, and annually thereafter. The TIRF REMS was approved by the Agency on December 28, 2011 and was launched on March 12, 2012. The TIRF REMS was modified June 5, 2012, November 7, 2013 and December 24, 2014. 3. REGULATORY HISTORY The following provides the regulatory history for the TIRF REMS relevant to this review. March 22, 2016: The Agency issued SLC notification letters to Sponsors of the TIRF product new drug applications (NDAs). The new safety information to be included in the labeling pertains to the risks of misuse, abuse, addiction, overdose, death, and neonatal opioid withdrawal syndrome; serotonin syndrome with concomitant use of serotonergic drugs; adrenal insufficiency; and androgen deficiency. August 31, 2016: The Agency issued SLC notification letters to the Sponsors of the TIRF product NDAs. The new safety information to be included in the labeling pertains to the risks of concomitant use of opioid analgesics with benzodiazepines or other central nervous system depressants. December 16, 2016: The Agency approved the SLCs for all TIRF products. The new safety information included the following: Updating the warning to include misuse, abuse, addiction, overdose, death, and NOWS, Serotonin Syndrome with concomitant use of serotonergic drugs, adrenal insufficiency, androgen deficiency, and risks of concomitant use of opioid analgesics with benzodiazepines or other central nervous system depressants. June 9, 2017: The TRIG point of contact submitted the TIRF Access Program REMS Modification to the Drug Master File (DMF) 27320. June 12, 2017: All TRIG sponsors submitted individual cover letters for the TIRF Access Program REMS Modification to their applications, referencing the DMF Submission. July 12, 2017: The Agency emailed comments from the DRISK’s review of the June 9, 2017 submission of the proposed REMS modification1, requesting amended REMS materials by July 26, 2017. July 19, 2017: The TRIG proposed an extension to the requested July 26, 2017 submission date of the REMS Modification. After evaluating the FDA comments received on July 12, 2017, additional time was 1 Washington-Batts L. DAAAP. REMS Modification Review TIRFS. Submitted in DAARTS July 12, 2017 Reference ID: 4146711 FDA_7239 required to fully prepare the documents, create the updated website screenshots, accommodate required sponsor review and voting approval of the final submission, and allow for the publishing and sequence processing by our external DMF submission vendor. The TRIG proposed to email the unformatted final version of the REMS, REMS Supporting Document, appended materials, and listing of website changes on July 31, 2017 andsubmit to the DMF the final formatted REMS, REMS Supporting Document, appended materials including updated website screenshotson August 18, 2017. July 26, 2017: The Agency emailed the TRIG the following comments: FDA is willing to accept the TRIG’s proposal. The TRIG will submit (via email to the FDA POC) the redline and clean Word version of the REMS Document, REMS Supporting Document, appended materials, and listing of website changes on July 31, 2017. The Agency will review the emailed documents to determine if they are acceptable. If approved, the TRIG must submit the final formatted REMS document, materials including website screenshots, and REMS Supporting Document as separate files, as well as, a compiled document for posting on the FDA REMS website, to the DMF on August 18, 2017. In addition to the final submission to the DMF, on August 18, 2017, each applicant must also submit to each respective application, a cross-reference submission titled “REMS Final for approved NDA ######, Supplement S-XXX. July 31, 2017: The TRIG emailed the unformatted final versions of the REMS Document, materials, and Supporting Document. August 11, 2017: The Agency emailed the TRIG the following comments: The Agency will not be able to take an action on the modification until we are able to review TRIG’s submission to the DMF planned for August 18, 2017 of the final formatted REMS document, materials including website screenshots, and REMS Supporting Document. August 18, 2017: The TRIG submitted formatted versions of the REMS Document, materials, and Supporting Document. August 22, 2017: The Agency emailed the TRIG the following comments: We reviewed your August 18th submission of final formatted REMS Document, Supporting Document and Materials. We note there is a discrepancy between the emailed documents and the final formatted submission. Specifically, the Dear Healthcare Provider and Pharmacy Letters that you submitted are not the original letters sent via email on July 31, 2017. You must resubmit by 8/29/2017, the final formatted REMS Document, REMS Supporting Document and appended materials with the original letters. However, please modify the original letters to include a boxed statement at the top of each letter to state the letter ceased distribution in March 2012. See the attachment for a redlined version for your reference. August 29, 2017: The TRIG submitted the final formatted versions of the REMS Document, materials, and Supporting Document. These are the subject of this review. Reference ID: 4146711 FDA_7240 4. MATERIALS REVIEWED 4.1. SUBMISSIONS • DMF # 027320 eCTD Sequence No. 029 TIRF Access Program REMS Modification received on June 9, 2017. Submission Date Product Name Application Supplement Number Number June 12, 2017 Abstral (fentanyl) NDA 022510 17 June 12, 2017 Actiq (fentanyl citrate) NDA 020747 47 June 12, 2017 Fentora and Authorized NDA 021947 27 Generic (fentanyl citrate) June 12, 2017 Lazanda (fentanyl) NDA 022569 26 June 12, 2017 Onsolis(fentanyl) NDA 022266 19 June 12, 2017 Subsys (fentanyl) NDA 202788 18 June 12, 2017 Fentanyl buccal tablet ANDA 079075 13 June 12, 2017 Fentanyl citrate lozenge ANDA 078907 16 June 12, 2017 Fentanyl citrate lozenge ANDA 077312 9   Amended -DMF # 027320 eCTD Sequence No. 0031 TIRF Access Program REMS Modification received on August 18, 2017. Amended - DMF # 027320 eCTD Sequence No. 0033 TIRF Access Program REMS Modification received on August 29, 2017. 4.2. OTHER MATERIALS INFORMING OUR REVIEW   TIRF REMS Modification DRISK Interim Review by L.Washington-Batts finalized in DARRTS on July 12, 2017 Email correspondence to the TRIG dated July 12, 2017 and August 22, 2017 5. RATIONALE FOR THE REMS MODIFICATION The proposed TIRF REMS modification is in response to the SLC Approval Letter dated December 16, 2016 that included the addition of language related to the risks of misuse, abuse, addiction, overdose, death, and NOWS, serotonin syndrome with concomitant use of serotonergic drugs, adrenal insufficiency, androgen deficiency, and risks of concomitant use of opioid analgesics with benzodiazepines or other central nervous system depressants to the Prescribing Information. This REMS modification is necessary to align the TIRF REMS document and REMS materials with the SLC approved on December 16, 2016. 6. REVIEW OF THE PROPOSED REMS MODIFICATION 6.1. MEDICATION GUIDE There were no changes proposed for this element. Reference ID: 4146711 FDA_7241 6.2. REMS DOCUMENT The TRIG submitted a revised REMS Document reflecting the Agency's comments emailed on July 12, 2017. Reviewer Comment: The Agency agrees with the proposed REMS Document. 6.3. ELEMENTS TO ASSURE SAFE USE 6.3.1. REMS MATERIALS The TRIG submitted revised REMS Materials and a list of website changes reflecting the Agency's comments emailed on July 12, 2017 and August 22, 2017. Reviewer Comment: The Agency agrees with the proposed REMS Materials and list of website changes. 6.4. IMPLEMENTATION SYSTEM There were no changes proposed for this element. 6.5. TIMETABLE FOR SUBMISSION OF ASSESSMENTS There were no changes proposed for this element. 6.6. REMS SUPPORTING DOCUMENT The TRIG submitted a revised REMS Supporting Document reflecting the Agency's comments emailed on July 12, 2017. Reviewer Comment: The Agency agrees with the proposed REMS Supporting Document. 7. DISCUSSION AND CONCLUSION DRISK reviewed the proposed REMS modification which was necessary to provide the safety information regarding the SLC for the addition of language related to the risks of misuse, abuse, addiction, overdose, death, and NOWS, serotonin syndrome with concomitant use of serotonergic drugs, adrenal insufficiency, androgen deficiency, and risks of concomitant use of opioid analgesics with benzodiazepines or other central nervous system depressants to the Prescribing Information. The REMS modification was received from the TRIG on June 9, 2017 and the final content of the modified materials were received on August 29, 2017. These materials contained the appropriate changes to the REMS as agreed upon by the Agency. Therefore, the proposed modified TIRF REMS, as appended to this review, for all products covered under the TIRF REMS program (Table 1) is acceptable to DRISK. Reference ID: 4146711 FDA_7242 8. RECOMMENDATION DRISK recommends approval of the proposed TIRF REMS modification as appended to this review. 9. ATTACHMENTS 1. REMS Document and Appended Materials Reference ID: 4146711 FDA_7243 Initial REMS approval: 12/2011 Most recent modification: 08/2017 TRANSMUCOSAL IMMEDIATE RELEASE FENTANYL (TIRF) RISK EVALUATION AND MITIGATION STRATEGY (REMS) Reference ID: 4146711 FDA_7244 I. GOALS The goals of the TIRF REMS Access program are to mitigate the risk of misuse, abuse, addiction, overdose and serious complications due to medication errors by: 1. Prescribing and dispensing TIRF medicines only to appropriate patients, which includes use only in opioid-tolerant patients. 2. Preventing inappropriate conversion between TIRF medicines. 3. Preventing accidental exposure to children and others for whom it was not prescribed. 4. Educating prescribers, pharmacists, and patients on the potential for misuse, abuse, addiction, and overdose of TIRF medicines. II. REMS ELEMENTS A. Medication Guide The product-specific TIRF Medication Guide will be dispensed with each TIRF prescription in accordance with 21 CFR 208.24. The Medication Guides for TIRF medicines are part of the TIRF REMS Access program and will be available on the TIRF REMS Access website (www.TIRFREMSaccess.com). B. Elements to Assure Safe Use 1. Healthcare providers who prescribe TIRF medicines for outpatient use are specially certified. a. TIRF sponsors will ensure that healthcare providers who prescribe TIRF medicines for outpatient use are specially certified. b. To become certified to prescribe TIRF medicines, prescribers will be required to enroll in the TIRF REMS Access program. Prescribers must complete the following requirements to be enrolled: i. Review the TIRF REMS Access education materials (TIRF REMS Access Education Program), including the Full Prescribing Information (FPI) for each TIRF medicine, and successfully complete the Knowledge Assessment (Knowledge Assessment). ii. Complete and sign the Prescriber Enrollment Form. In signing the Prescriber Enrollment Form, each prescriber is required to acknowledge the following: Reference ID: 4146711 a) I have reviewed the TIRF REMS Access Education Program, and I have completed the Knowledge Assessment. I understand the responsible use conditions for TIRF medicines and the risks and benefits of chronic opioid therapy. b) I understand that TIRF medicines can be abused and that this risk should be considered when prescribing or dispensing TIRF medicines in situations FDA_7245 where I am concerned about an increased risk of misuse, abuse, or overdose, whether accidental or intentional. Reference ID: 4146711 c) I understand that TIRF medicines are indicated only for the management of breakthrough pain in cancer patients 18 years of age or older (Actiq and its generic equivalents are approved for 16 years of age and older), who are already receiving, and who are tolerant to, around-the-clock opioid therapy for their underlying persistent cancer pain. d) I understand that TIRF medicines are contraindicated for use in opioid nontolerant patients, and know that fatal overdose can occur at any dose. e) I understand that TIRF medicines must not be used to treat acute or postoperative pain, including headache/migraine, dental pain, or acute pain in the emergency department. f) I understand that converting patients from one TIRF medicine to a different TIRF medicine must not be done on a microgram-per-microgram basis. I understand that TIRF medicines are not interchangeable with each other, regardless of route of administration, and that conversion may result in fatal overdose, unless conversion is done in accordance with labeled productspecific conversion recommendations (refer to the list of currently approved TIRF products located on the TIRF REMS Access website at www.TIRFREMSaccess.com/TirfUI/rems/products.action. Note, a branded TIRF medicine and its specific generic product(s) are interchangeable. g) I understand that the initial starting dose for TIRF medicines for all patients is the lowest dose, unless individual product labels provide product-specific conversion recommendations, and I understand that patients must be titrated individually. h) I will provide a Medication Guide for the TIRF medicine that I intend to prescribe to my patient or their caregiver and review it with them. If I convert my patient to a different TIRF medicine, the Medication Guide for the new TIRF medicine will be provided to, and reviewed with, my patient or their caregiver. i) I will complete and sign a TIRF REMS Access Patient-Prescriber Agreement Form with each new patient, before writing the patient’s first prescription for a TIRF medicine, and renew the agreement every two (2) years. j) I will provide a completed, signed copy of the Patient-Prescriber Agreement Form to the patient and retain a copy for my records. I will also provide a completed, signed copy to the TIRF REMS Access program (through the TIRF REMS Access website or by fax) within ten (10) working days. k) At all follow-up visits, I agree to assess the patient for appropriateness of the dose of the TIRF medicine, and for signs of misuse and abuse. l) I understand that TIRF medicines are only available through the TIRF REMS Access program. I understand and agree to comply with the TIRF REMS FDA_7246 Access program requirements for prescribers. m) I understand that I must re-enroll in the TIRF REMS Access program and successfully complete the enrollment requirements every two (2) years. In signing the Patient-Prescriber Agreement Form, the prescriber documents the following: 1) I understand that TIRF medicines are indicated only for the management of breakthrough pain in cancer patients 18 years of age or older (Actiq and its generic equivalents are approved for 16 years of age and older), who are already receiving, and who are tolerant to, around-the-clock opioid therapy for their underlying persistent cancer pain. 2) I understand that TIRF medicines are contraindicated for use in opioid non-tolerant patients, and know that fatal overdose can occur at any dose. 3) I understand that TIRF medicines are not for use in the management of acute or postoperative pain, including headache/migraine, dental pain, or acute pain in the emergency department. 4) I understand that patients considered opioid-tolerant are those who are taking, for one week or longer, at least: 60 mg oral morphine/day; 25 micrograms transdermal fentanyl/hour; 30 mg oral oxycodone/day; 8 mg oral hydromorphone/day; 25 mg oral oxymorphone/day; 60 mg oral hydrocodone/day; or an equianalgesic dose of another opioid daily. 5) I have provided to, and reviewed with, my patient or their caregiver the Medication Guide for the TIRF medicine I intend to prescribe. 6) If I change my patient to a different TIRF medicine, I will provide the Medication Guide for the new TIRF medicine to my patient or my patient’s caregiver, and I will review it with them. 7) I understand that if I change my patient to a different TIRF medicine, the initial dose of that TIRF medicine for all patients is the lowest dose, unless individual product labels provide product-specific conversion recommendations. 8) I have counseled my patient or their caregiver about the risks, benefits, and appropriate use of TIRF medicines including communication of the following safety messages: A. If you stop taking your around-the-clock pain medicine, you must stop taking your TIRF medicine. B. NEVER share your TIRF medicine. C. Giving a TIRF medicine to someone for whom it has not Reference ID: 4146711 FDA_7247 been prescribed can result in a fatal overdose. D. TIRF medicines can be fatal to a child; used and unused dosage units must be safely stored out of the reach of children living in or likely to visit the home and disposed of in accordance with the specific disposal instructions detailed in the product’s Medication Guide. I will ensure that the patient and/or caregiver understand that, in signing the Patient-Prescriber Agreement Form, they document the following: 1) My prescriber has given me a copy of the Medication Guide for the TIRF medicine I have been prescribed, and has reviewed it with me. 2) I understand that TIRF medicines should only be taken by patients who are regularly using another opioid, around-the-clock, for constant pain. If I am not taking around-the-clock opioid pain medicine, my prescriber and I have discussed the risks of only taking TIRF medicines. 3) I understand that if I stop taking another opioid pain medicine that I have been taking regularly, around-the-clock, for my constant pain, then I must also stop taking my TIRF medicine. 4) I understand how I should take this TIRF medicine, including how much I can take, and how often I can take it. If my prescriber prescribes a different TIRF medicine for me, I will ensure I understand how to take the new TIRF medicine. 5) I understand that any TIRF medicine can cause serious side effects, including life-threatening breathing problems which can lead to death, especially if I do not take my TIRF medicine exactly as my prescriber has directed me to take it. 6) I agree to contact my prescriber if my TIRF medicine does not relieve my pain. I will not change the dose of my TIRF medicine myself or take it more often than my prescriber has directed. 7) I agree that I will never give my TIRF medicine to anyone else, even if they have the same symptoms, since it may harm them or even cause death. 8) I will store my TIRF medicine in a safe place, out of reach of children and teenagers because accidental use by a child, or anyone for whom it was not prescribed, is a medical emergency and can cause death. 9) I have been instructed on how to properly dispose of my partially used or unneeded TIRF medicine remaining from my prescription, and will dispose of my TIRF medicine as soon as I no longer need it. 10) I understand that selling or giving away my TIRF medicine is against the law. Reference ID: 4146711 FDA_7248 11) I have asked my prescriber all the questions I have about my TIRF medicine. If I have any additional questions or concerns in the future about my treatment with my TIRF medicine, I will contact my prescriber. 12) I have reviewed the “Patient Privacy Notice for the TIRF REMS Access Program” and I agree to its terms and conditions which allow my healthcare providers to share my health information, as defined in that document, with the makers of TIRF medicines (TIRF Sponsors) and their agents and contractors for the limited purpose of managing the TIRF REMS Access program. c. Prescribers are required to re-enroll every two (2) years. Additionally, prescribers must re-counsel their patients and complete a new Patient-Prescriber Agreement Form every two (2) years. d. TIRF Sponsors will: i. ii. Ensure that prescriber enrollment can successfully be completed via the TIRF REMS Access website, or by mailing or faxing the forms. Ensure that, as part of the enrollment process, the following materials that are part of the TIRF REMS Access program are available to prescribers. These materials are appended: • TIRF REMS Access Prescriber Program Overview • TIRF REMS Access Education Program • Knowledge Assessment • Prescriber Enrollment Form • Patient-Prescriber Agreement Form • TIRF REMS Access Patient and Caregiver Overview • Frequently Asked Questions (FAQs) • TIRF REMS Access Website iii. Ensure that prescribers have successfully completed the Knowledge Assessment, and ensure that enrollment forms are complete before activating a prescriber’s enrollment in the TIRF REMS Access program. iv. Ensure that prescribers are notified when they are successfully enrolled in the TIRF REMS Access program, and therefore, are certified to prescribe TIRF medicines. v. Monitor education and enrollment requirements for prescribers and may inactivate non-compliant prescribers. Upon initial activation, prescribers remain active until inactivation occurs or expiration of the enrollment period. vi. Ensure that prior to the first availability of the TIRF REMS Access program/website, Dear Healthcare Provider Letters will be sent. The target audience for the letters will include pain management specialists (comprised of anesthesiologists, physical medicine and rehabilitation physicians), primary care Reference ID: 4146711 FDA_7249 physicians, oncologists, oncology nurse practitioners who treat breakthrough pain in patients with cancer, and other appropriately licensed healthcare professionals who prescribe TIRF medicines. The letter will include information on the risks associated with the use of TIRF medicines and will explain to healthcare providers that if they wish to treat patients using TIRF medicines, they must enroll in the TIRF REMS Access program. The letters will be available on the TIRF REMS Access website for 1 year from the date of the mailing. The Dear Healthcare Provider Letter is part of the TIRF REMS Access program and is appended. 2. TIRF medicines will only be dispensed by pharmacies that are specially certified. a. TIRF Sponsors will ensure that TIRF medicines will only be dispensed by certified pharmacies. To become certified to dispense TIRF medicines, each pharmacy must be enrolled in the TIRF REMS Access program. b. Each pharmacy will be required to designate an authorized pharmacy representative (chain and closed system outpatient pharmacies) or authorized pharmacist (independent outpatient and inpatient pharmacies) to complete enrollment on behalf of the pharmacy(s). c. For the purposes of this REMS, there are different requirements for : • Outpatient Pharmacies i. Chain Outpatient Pharmacy: Retail, mail order or institutional outpatient pharmacies having a chain headquarters that is responsible for ensuring enrollment and training of the pharmacy staff of all associated outpatient pharmacies. The chain headquarters will enroll multiple locations (i.e., chain stores) in the TIRF REMS Access program. ii. Independent Outpatient Pharmacy: Retail, mail order, or institutional outpatient pharmacies having an authorized pharmacy representative that is responsible for ensuring enrollment and training of the pharmacy staff within an individual outpatient pharmacy. Each store will individually enroll in the TIRF REMS Access program as a single pharmacy location. iii. Closed System Outpatient Pharmacy: Institutional or mail order outpatient pharmacies that use a pharmacy management system that does not support the process of electronically transmitting the validation and claim information currently required by the TIRF REMS Access program. • Inpatient pharmacies (e.g., hospitals, in-hospital hospices, and long-term care facilities that dispense for inpatient use) d. Chain and Independent Outpatient Pharmacy(s): The authorized pharmacist/pharmacy representative must complete the following requirements to enroll their chain or independent outpatient pharmacy: i. Reference ID: 4146711 Review the TIRF REMS Access Education Program (TIRF REMS Access Education Program) and successfully complete the Knowledge Assessment. FDA_7250 ii. Ensure the pharmacy enables its pharmacy management system to support communication with the TIRF REMS Access program system, using established telecommunication standards, and runs the standardized validation test transaction to validate the system enhancements. iii. Complete and sign the Independent Outpatient Pharmacy Enrollment Form or the Chain Outpatient Pharmacy Enrollment Form for groups of associated pharmacies. In signing the Independent Outpatient Pharmacy Enrollment Form or Chain Outpatient Pharmacy Enrollment Form, the authorized pharmacist is required to acknowledge the following: a) I have reviewed the TIRF REMS Access Education Program, and I have completed the Knowledge Assessment. I understand the risks and benefits associated with TIRF medicines and the requirements of the TIRF REMS Access program for pharmacies. b) I will ensure that all pharmacy staff who participate in dispensing TIRF medicines are educated on the risks associated with TIRF medicines and the requirements of the TIRF REMS Access program, as described in the TIRF REMS Access Education Program. This training should be documented and is subject to audit. c) I understand that converting patients from one TIRF medicine to a different TIRF medicine must not be done on a microgram-per-microgram basis. I understand that TIRF medicines are not interchangeable with each other, regardless of route of administration, and that conversion may result in fatal overdose, unless conversion is done in accordance with labeled product-specific conversion recommendations (refer to the list of currently approved TIRF products located on the TIRF REMS Access website at www.TIRFREMSaccess.com/TirfUI/rems/products.action. Note, a branded TIRF medicine and its specific generic product(s) are interchangeable. d) I understand that TIRF medicines are contraindicated for use in opioid nontolerant patients. e) I understand that the initial starting dose of TIRF medicines for all patients is the lowest dose, unless individual product labels provide product-specific conversion recommendations, and I understand that patients must be titrated individually. f) I understand the importance of discussing the risks and benefits of TIRF medicines with patients and their caregivers, and in particular the importance of taking the drug as prescribed, not sharing with others, and proper disposal. g) I understand that the product-specific Medication Guide must be given to the patient or their caregiver each time a TIRF medicine is dispensed. h) I understand that TIRF medicines will not be dispensed without verifying through our pharmacy management system that the prescriber and pharmacy are enrolled and active, and that the patient has not been inactivated in the program. i) Reference ID: 4146711 I understand that ALL TIRF medicine prescriptions, regardless of the method FDA_7251 of payment, must be processed through our pharmacy management system. j) I understand that all dispensing locations must be enrolled in the TIRF REMS Access program to dispense TIRF medicines. k) I understand that TIRF medicines can only be obtained from wholesalers/distributors that are enrolled in the TIRF REMS Access program. l) I understand that our pharmacy will not sell, loan or transfer any TIRF medicine inventory to any other pharmacy, institution, distributor, or prescriber. m) I understand that our pharmacy must re-enroll in the TIRF REMS Access program and successfully complete the enrollment requirements every two (2) years. n) I understand that TIRF medicines are only available through the TIRF REMS Access program. I understand that the pharmacy must comply with the TIRF REMS Access program requirements for outpatient pharmacies. o) I understand that differences in pharmacy software may affect automation capabilities for adjudicating prescriptions through the TIRF REMS Access program without an insurance claim (i.e.: cash claim). If insurance is not used, pharmacy staff must manually enter the REMS Cash BIN #014780 or the designated chain pharmacy cash bin in order for the transaction to be properly adjudicated through the TIRF REMS Access program. Note: The ‘or the designated chain pharmacy cash bin’ language will not be included in the attestation on the Independent Outpatient Pharmacy Enrollment Form e. Closed System Outpatient Pharmacies: The authorized pharmacist/pharmacy representative must complete the following requirements to enroll their closed system outpatient pharmacy: i. Review the TIRF REMS Access Education Program (TIRF REMS Access Education Program) and successfully complete the Knowledge Assessment. ii. Complete and sign the Closed System Outpatient Pharmacy Enrollment Form. In signing the Closed System Outpatient Pharmacy Enrollment Form, the authorized closed system outpatient pharmacy representative is required to acknowledge the following: a) I have reviewed the TIRF REMS Access Education Program, and I have completed the Knowledge Assessment. I understand the risks and benefits associated with TIRF medicines and the requirements of the TIRF REMS Access program for pharmacies. b) I will ensure that all pharmacy staff who participate in dispensing TIRF medicines are educated on the risks associated with TIRF medicines and the requirements of the TIRF REMS Access program, as described in the TIRF REMS Access Education Program. This training should be documented and is subject to audit. Reference ID: 4146711 FDA_7252 c) I understand that converting patients from one TIRF medicine to a different TIRF medicine must not be done on a microgram-per-microgram basis. I understand that TIRF medicines are not interchangeable with each other, regardless of route of administration, and that conversion may result in fatal overdose, unless conversion is done in accordance with labeled product-specific conversion recommendations (refer to the list of currently approved TIRF products located on the TIRF REMS Access website at www.TIRFREMSaccess.com/TirfUI/rems/products.action. Note, a branded TIRF medicine and its specific generic product(s) are interchangeable. d) I understand that TIRF medicines are contraindicated for use in opioid nontolerant patients. e) I understand that the initial starting dose for TIRF medicines for all patients is the lowest dose, unless individual product labels provide product-specific conversion recommendations, and I understand that patients must be titrated individually. f) I understand the importance of discussing the risks and benefits of TIRF medicines with patients and their caregivers, and in particular the importance of taking the drug as prescribed, not sharing with others, and proper disposal. g) I understand that the product-specific Medication Guide must be given to the patient or their caregiver each time a TIRF medicine is dispensed. h) I understand that a TIRF medicine will not be dispensed without obtaining a TIRF REMS Access prescription authorization number issued by the TIRF REMS Access program prior to dispensing the prescription. A TIRF REMS Access prescription authorization number verifies that the prescriber and pharmacy are enrolled and active, and that the patient has not been inactivated from the program. i) I understand that all dispensing locations must be enrolled in the TIRF REMS Access program to dispense TIRF medicines j) I understand that TIRF medicines can only be obtained from wholesalers/distributors that are enrolled in the TIRF REMS Access program. k) I understand that our pharmacy will not sell, loan or transfer any TIRF inventory to any other pharmacy, institution, distributor, or prescriber. l) I understand that our pharmacy must re-enroll in the TIRF REMS Access program every two (2) years. m) I understand that TIRF medicines are only available through the TIRF REMS Access program. I understand that the pharmacy must comply with the TIRF REMS Access program requirements for outpatient closed system pharmacies. f. Inpatient Pharmacies: Reference ID: 4146711 FDA_7253 The authorized pharmacist must complete the following requirements to successfully enroll their inpatient pharmacy: i. Review the TIRF REMS Access Education Program (TIRF REMS Access Education Program) and successfully complete the pharmacy Knowledge Assessment. ii. Complete and sign the Inpatient Pharmacy Enrollment Form. In signing the Inpatient Pharmacy Enrollment Form, the authorized pharmacist is required to acknowledge the following: a) I have reviewed the TIRF REMS Access Education Program, and I have completed the Knowledge Assessment. I understand the benefits and risks associated with TIRF medicines and the requirements of the TIRF REMS Access program for pharmacies. b) I will ensure that our inpatient pharmacists are educated on the risks associated with TIRF medicines and the requirements of the TIRF REMS Access program, as described in the TIRF REMS Access Education Program. c) I understand that converting patients from one TIRF medicine to a different TIRF medicine must not be done on a microgram-per-microgram basis. I understand that TIRF medicines are not interchangeable with each other, regardless of route of administration, and that conversion may result in fatal overdose, unless conversion is done in accordance with labeled product-specific conversion recommendations (refer to the list of currently approved TIRF products located on the TIRF REMS Access website at www.TIRFREMSaccess.com/TirfUI/rems/products.action). Note, a branded TIRF medicine and its specific generic product(s) are interchangeable. d) I understand that TIRF medicines are contraindicated for use in opioid nontolerant patients. e) I understand that the initial starting dose for TIRF medicines for all patients is the lowest dose, unless individual product labels provide product-specific conversion recommendations, and I understand that patients must be titrated individually. f) I understand that pharmacies within or associated with the healthcare facility that dispense to outpatients must be separately enrolled in and comply with the TIRF REMS Access program to dispense TIRF medicines to outpatients, as described in section B.2.d, above. g) I understand that our inpatient pharmacy must not dispense TIRF medicines for outpatient use. h) I understand that a prescriber who wants to discharge a patient with a TIRF medicine prescription, intended to be dispensed by an outpatient pharmacy, will be required to enroll in the TIRF REMS Access program, as described in section B.1 of this REMS. Reference ID: 4146711 FDA_7254 i) I will establish, or oversee the establishment of, a system, order sets, protocols and/or other measures to help ensure appropriate patient selection and compliance with the requirements of the TIRF REMS Access program. j) I understand that our pharmacy will not sell, loan or transfer any TIRF inventory to any other pharmacy, institution, distributor, or prescriber. k) I understand that TIRF medicines can only be obtained from wholesalers/distributors that are enrolled in the TIRF REMS Access program. l) I understand that our pharmacy must re-enroll in the TIRF REMS Access program every two (2) years. m) I understand that TIRF medicines are available only through the TIRF REMS Access program. I understand and agree to comply with the TIRF REMS Access program requirements for inpatient pharmacies. g. Pharmacies (authorized pharmacist) are required to re-enroll every two (2) years. h. TIRF Sponsors will: i. Ensure that pharmacy enrollment can successfully be completed via the TIRF REMS Access website, by mailing or faxing the forms. ii. Ensure that, as part of the enrollment process, the following materials that are part of the TIRF REMS Access program are available to pharmacies. These materials are appended: • The TIRF REMS Access Program Overview (Independent Outpatient Pharmacy, Chain Outpatient Pharmacy, Closed System Outpatient Pharmacy or Inpatient Pharmacy, as applicable) • TIRF REMS Access Education Program • Knowledge Assessment • Pharmacy Enrollment Form (Independent Outpatient, Chain Outpatient, Closed System Outpatient, or Inpatient, as applicable) • Frequently Asked Questions (FAQs) • TIRF REMS Access Website iii. Ensure that all enrollment forms are complete, and that the authorized pharmacist has successfully completed the Knowledge Assessment before activating a pharmacy’s enrollment in the TIRF REMS Access program. iv. For chain and independent outpatient pharmacies only, TIRF Sponsors will also ensure that the configurations to the pharmacy management system have been validated before enrolling a pharmacy in the TIRF REMS Access program. v. For closed system outpatient pharmacies only, TIRF Sponsors will ensure that, prior to authorizing a pharmacy’s enrollment as a closed system outpatient pharmacy, the pharmacy meets the requirements of being deemed a closed system outpatient pharmacy (see II.B.2.c) Reference ID: 4146711 FDA_7255 vi. Ensure that pharmacies are notified when they are successfully enrolled in the TIRF REMS Access program, and therefore, certified to dispense TIRF medicines. vii. Monitor education and enrollment requirements for pharmacies and inactivate noncompliant pharmacies. Upon initial activation of enrollment, pharmacies remain active until a corrective action of inactivation occurs or expiration of the enrollment period. viii. Ensure that prior to first availability of the TIRF REMS Access program/website, Dear Pharmacy Letters will be sent (one for inpatient pharmacies and one for outpatient pharmacies). The target audience for the letter will include outpatient and inpatient pharmacies that dispense Schedule II drugs and may be involved in dispensing TIRF medicines. The letter will include information on the risks associated with the use of TIRF medicines and the requirements of the TIRF REMS Access program. The letter will be available on the TIRF REMS Access website for 1 year from the date of the mailing. The Dear Pharmacy Letters (Outpatient and Inpatient) are part of the TIRF REMS Access program. These materials are appended. 3. TIRF medicines will only be dispensed for outpatient use with evidence or other documentation of safe-use conditions. a. TIRF Sponsors will ensure that TIRF medicines will only be dispensed for outpatient use if there is documentation in the TIRF REMS Access program system that the dispensing pharmacy and prescriber are enrolled and active, and the patient is not inactive in the TIRF REMS Access program. b. Patients are passively enrolled in the TIRF REMS Access program when their first TIRF medicine prescription is processed at the pharmacy. Patients may continue to receive TIRF medicines while passively enrolled, for up to ten working days, as described in section II.C.5. Prescribers and outpatient pharmacies (including closed system outpatient pharmacies) are enrolled, as previously described in sections B.1 and B.2, respectively. c. For chain and independent outpatient pharmacies: Prior to dispensing TIRF medicines, enrolled outpatient pharmacies will electronically verify documentation of the required enrollments by processing the TIRF prescription through their pharmacy management system. i. If the required enrollments are verified, a unique authorization code will be issued to allow processing and dispensing of the prescription to the patient. ii. If one or more of the required enrollments cannot be verified, the TIRF REMS Access program system will reject the prescription (prior to a claim being forwarded to the payer) and the pharmacy will receive a rejection notice. d. For closed system outpatient pharmacies: prior to dispensing TIRF medicines, enrolled closed system outpatient pharmacies will verify documentation of the required enrollments by contacting the TIRF REMS Access program at 1-866-822-1483, or via fax, and providing the required information from the TIRF prescription. i. Reference ID: 4146711 If the required enrollments are verified, the TIRF REMS Access program will provide a unique authorization code to allow processing and dispensing of the prescription to the patient. FDA_7256 ii. If one or more of the required enrollments cannot be verified, a rejection reason, and information regarding how to resolve the rejection, will be provided. e. Following initial activation, patient PPAFs remain active until a trigger for inactivation occurs. Triggers for PPAF inactivation include: i. The patient has not filled a prescription for more than six (6) months. ii. The PPAF has expired. iii. The patient is deceased. iv. The patient chooses to no longer participate in the TIRF REMS Access program. f. If an active patient transfers from an enrolled prescriber to a non-enrolled or inactive prescriber, the TIRF REMS Access program cannot fill the prescription for TIRF medicines until the new prescriber is active in the TIRF REMS Access program. g. A patient may have more than one current prescriber (e.g., pain management specialist, primary care physician) provided that prescriptions for TIRF medicines are not for the same or overlapping period of treatment. h. Documentation and verification of safe-use conditions are not required for prescriptions ordered within an inpatient healthcare setting and given to an inpatient. C. Implementation System 1. TIRF Sponsors will ensure that wholesalers/distributors who distribute TIRF medicines are enrolled in the TIRF REMS Access program and comply with the program requirements for wholesale distributors. 2. The wholesaler/distributor enrollment process is comprised of the following steps that must be completed by the distributor’s authorized representative, prior to receiving TIRF medicine inventory for distribution: a. Review the distributor TIRF REMS Access program materials b. Complete and sign the Distributor Enrollment Form and send it to the TIRF Sponsors (by fax or mail). In signing the Distributor Enrollment Form, each wholesaler/distributor is required to indicate they understand that TIRF medicines are available only through the TIRF REMS Access program and acknowledges that they must comply with the following program requirements: i. The Wholesaler/Distributor will ensure that relevant staff are trained on the TIRF REMS Access program procedures and will follow the requirements of the TIRF REMS Access program. ii. The Wholesaler/Distributor will ensure that TIRF medicines are only distributed to pharmacies whose enrollment has been validated in the TIRF REMS Access program. iii. The Wholesaler/Distributor will provide complete, unblinded and unblocked data (i.e., EDI 867 transmission) to the TIRF REMS Access program including information on shipments to enrolled pharmacies. iv. The Wholesaler/Distributor will cooperate with periodic audits or non-compliance Reference ID: 4146711 FDA_7257 investigations to ensure that TIRF medicines are distributed in accordance with the program requirements. c. TIRF Sponsors will ensure that all forms are complete prior to enrolling a distributor in the TIRF REMS Access program. d. TIRF Sponsors will notify distributors when they are enrolled in the TIRF REMS Access program and, therefore, able to distribute TIRF medicines. e. Upon initial activation, distributors remain active until an action of inactivation occurs, expiration of the enrollment period, or failure to comply with the pharmacy enrollment verification obligations. If a previously active distributor becomes inactive, the distributor may become active again by completing the distributor enrollment process in its entirety. f. Distributors will be re-educated and re-enrolled in the TIRF REMS Access program every two (2) years. g. The following distributor materials are part of the TIRF REMS Access program. These materials are appended: • • • Dear Distributor Letter Distributor Enrollment Form Frequently Asked Questions 3. TIRF Sponsors will maintain a database of all enrolled entities (prescribers, pharmacies, patients, and distributors) and their status (i.e., active or inactive), and will monitor and evaluate implementation of the TIRF REMS Access program requirements. 4. For chain and independent outpatient pharmacies, TIRF Sponsors will develop a TIRF REMS Access program system that uses existing pharmacy management systems that allow for the transmission of TIRF REMS Access information using established telecommunication standards. The TIRF REMS Access program system will incorporate an open framework that allows a variety of distributors, systems vendors, pharmacies, and prescribers to participate, and that is flexible enough to support the expansion or modification of the TIRF REMS Access program requirements, if deemed necessary in the future. 5. For closed system outpatient pharmacies, TIRF Sponsors will develop a system to allow enrollment and verification of safe use conditions through a telephone system and/or fax. TIRF Sponsors will monitor distribution data and prescription data to ensure that only actively enrolled distributors are distributing, actively enrolled pharmacies are dispensing, and actively enrolled prescribers for outpatient use are prescribing TIRF medicines. Additionally, TIRF Sponsors will monitor to ensure that, when dispensing in an outpatient setting, TIRF medicines are only being dispensed to actively enrolled patients of actively enrolled prescribers. Corrective action or inactivation will be instituted by TIRF Sponsors if non-compliance is found. 6. TIRF Sponsors will monitor prescribers’ compliance with the requirement to complete a Patient-Prescriber Agreement Form with each TIRF patient, and to submit it to the TIRF REMS Access program within ten (10) working days. A maximum of three prescriptions are allowed within 10 working days from when the patient has their first prescription filled. No further prescriptions will be dispensed after the 10 working day window until a completed Patient-Prescriber Agreement Form is received. This will be accomplished by reconciling the Patient-Prescriber Agreements submitted to the TIRF REMS Access Reference ID: 4146711 FDA_7258 program with patient enrollment data captured through the pharmacy management system for chain and independent outpatient pharmacies or through the call center for closed system outpatient pharmacies. 7. TIRF Sponsors will monitor and evaluate all enrolled outpatient pharmacies (including closed system outpatient pharmacies), distributors, and the TIRF REMS Access program vendors to validate the necessary system upgrades and ensure the program is implemented as directed. 8. TIRF Sponsors will evaluate enrolled inpatient pharmacies’ compliance with the TIRF REMS Access program requirements through surveys. 9. TIRF Sponsors will maintain a call center to support patients, prescribers, pharmacies, and distributors in interfacing with the TIRF REMS Access program. 10. TIRF Sponsors will ensure that all materials listed in or appended to the TIRF REMS Access program will be available through the TIRF REMS Access program website www.TIRFREMSaccess.com or by calling the TIRF REMS Access call center at 1-866822-1483. 11. TIRF Sponsors will notify pharmacies, prescribers, and distributors of forthcoming enrollment expiration and the need to re-enroll in the TIRF REMS Access program. Notifications for patients will be sent to the patient’s prescriber. 12. If there are substantive changes to the TIRF REMS Access program, TIRF Sponsors will update all affected materials and notify pharmacies, prescribers, and distributors of the changes, as applicable. Notifications for patients will be sent to the patient’s prescriber. Substantive changes to the TIRF REMS Access program are defined as: a. Significant changes to the operation of the TIRF REMS Access program. b. Changes to the Prescribing Information and Medication Guide that affect the riskbenefit profile of TIRF medicines. 13. Based on monitoring and evaluation of the REMS Elements to Assure Safe Use, TIRF Sponsors will take reasonable steps to improve implementation of these elements and to maintain compliance with the TIRF REMS Access program requirements, as applicable. III. TIMETABLE FOR SUBMISSION OF ASSESSMENTS TIRF NDA Sponsors will submit REMS Assessments to the FDA at 6 and 12 months from the date of the initial REMS approval, and annually thereafter. To facilitate inclusion of as much information as possible, while allowing reasonable time to prepare the submission, the reporting interval covered by each assessment should conclude no earlier than 60 days before the submission date for that assessment. TIRF NDA Sponsors will submit each assessment so that it will be received by the FDA on or before the due date. Reference ID: 4146711 FDA_7259 The Transmucosal Immediate Release Fentanyl (TIRF) REMS Access Program An Overview for Prescribers To prescribe TIRF medicines for outpatient use, Prescribers must enroll in the TIRF REMS Access program. What is the TIRF REMS Access Program? The TIRF REMS (Risk Evaluation and Mitigation Strategy) Access program is designed to ensure informed risk-benefit decisions before initiating treatment and, while patients are on treatment to ensure appropriate use of TIRF medicines. TIRF medicines are available only through a restricted distribution program required by the Food and Drug Administration (FDA), because of the risk for misuse, abuse, addiction, overdose, and serious complications due to medication errors. A list of TIRF medicines available through the TIRF REMS Access program is located on the TIRF Products web page at www.TIRFREMSaccess.com/TirfUI/rems/products.action. How does the TIRF REMS Access program work? The TIRF REMS Access program requires pharmacies, prescribers, patients and wholesalers to enroll in the program in order to utilize TIRF medications. The supply of TIRF medicines to pharmacies is controlled by enrolled distributors, who will verify the current enrollment status of the pharmacy prior to shipment of TIRF medicines. Pharmacies are required to verify the prescriber and the patient are enrolled in the TIRF REMS Access program before dispensing any TIRF medication. NOTE: There are different requirements for inpatient prescribers that only prescribe TIRF medicines for inpatient use. For inpatient administration (e.g. hospitals, inhospital hospices, and long-term care facilities that prescribe for inpatient use), of TIRF medicines, patient and prescriber enrollment in the TIRF REMS Access program is not required. Only the inpatient pharmacy and distributors are required to be enrolled to be able to order and dispense TIRF medicines for inpatient use. Inpatient pharmacies may not dispense TIRF medicines for outpatient use. Reference ID: 4146711 FDA_7260 Overview of the TIRF REMS Access Program for Prescribing to Outpatients: Steps for Enrollment and Program Requirements Prescriber Education & Enrollment (Outpatient Use) All enrollment activities can be completed at www.TIRFREMSaccess.com If I have previously enrolled in an individual TIRF REMS program do I need to enroll in the shared TIRF REMS Access Program? All prescriber enrollment information was transferred from the individual TIRF REMS to the TIRF REMS Access program on March 12, 2012. You will be required to re-enroll in the shared TIRF REMS two (2) years after your last enrollment in an individual REMS program if you wish to continue dispensing these products. You will be notified by the TIRF REMS Access program in advance of the need to re-enroll. The following three sections provide detailed information on the Enrollment Process (Section 1), the Patient Program Requirements (Section 2), and the Prescribing Process (Section 3) for outpatient prescribing of TIRF medicines. Section 1: Enrollment Process Summary of Enrollment Process 1. Create an account and complete registration at www.TIRFREMSaccess.com. 2. Complete the TIRF REMS Access Education Program and Knowledge Assessment. 3. Complete and submit a Prescriber Enrollment form. Detailed Enrollment Process Step 1: Create an account www.TIRFREMSaccess.com • and complete registration at Create an account and complete registration at www.TIRFREMSaccess.com. How do I create an account and complete the TIRF REMS Access registration on-line? • Select the ‘Create My Account’ button on the home page • Complete the Create Account Information section • Select ‘No’ if you have not submitted an enrollment form via fax at the ‘Already enrolled via Fax and have an enrollment ID?’ question • Create User ID and Password and select ‘Create My Account’ • Select ‘Prescriber’ as the option to best describe you and select ‘Continue’ Reference ID: 4146711 FDA_7261 • • Complete required fields on the Prescriber Registration page and select ‘Submit’ to continue Complete required fields in the ‘Site Information’ section by adding your site and select ‘Submit’ Step 2: Complete the TIRF REMS Access Education Program and Knowledge Assessment How do I complete the TIRF REMS Access Education Program by fax? • • • Review the TIRF REMS Access Education Program. A printable version of the TIRF REMS Access Education Program is available online at www.TIRFREMSaccess.com or by contacting the TIRF REMS Access call center at 1-866-822-1483. Once you have reviewed the Education Program complete the Knowledge Assessment and submit by fax to 1-866-822-1487. The TIRF REMS Access program will notify you of the status of your Knowledge Assessment via your indicated preferred method of communication (fax or e-mail). How do I complete the TIRF REMS Access Education Program online? • • • • Select the ‘Start the TIRF REMS Access Education Program’ to proceed to the training upon completion of registration Select ‘Go To Knowledge Assessment’, complete the Knowledge Assessment, and select ‘Submit Assessment’ A Knowledge Assessment Confirmation Code will be provided once the assessment is completed successfully Select ‘Complete Enrollment’ to continue Step 3: Complete and submit Prescriber Enrollment • • To finalize enrollment in the TIRF REMS Access program complete Prescriber Enrollment. If you are unable to enroll online, please call the TIRF REMS Access program call center at 1-866-822-1483 for further assistance. How do I complete the TIRF REMS Access Enrollment on-line? • Upon successful completion of the TIRF REMS Access Education Program and Knowledge Assessment, you will be prompted to review the demographic information previously submitted, read the TIRF REMS Access attestation and enter your electronic signature, today’s date, and check the attestation box before clicking ‘Submit’. NOTE: You are required to re-enroll every two (2) years. You will be notified by the TIRF REMS Access program in advance of the need to re-enroll. Reference ID: 4146711 FDA_7262 Section 2: Patient Program Requirements Summary of Patient Program Requirements 1. Identify appropriate patients 2. Counsel patients 3. Complete and submit the TIRF REMS Access Program Patient-Prescriber Agreement Form Detailed Patient Program Requirements Process Step 1: Identify appropriate patients • Identify appropriate patients based on the guidance provided in the TIRF REMS Access Education Program and the product-specific Full Prescribing Information. Full Prescribing Information is available on-line at www.TIRFREMSaccess.com or by contacting the TIRF REMS Access call center at 1-866-822-1483. Step 2: Counsel Patients • Counsel the patient about the benefits and risks of TIRF medicines and together review the appropriate product-specific Medication Guide. A Patient and Caregiver Overview is available online at www.TIRFREMSaccess.com or by contacting the TIRF REMS Access call center at 1-866-822-1483. Step 3: Complete and submit the TIRF REMS Access Patient-Prescriber Agreement Form • Complete the TIRF REMS Access Program Patient-Prescriber Agreement Form, for each new patient, which must be signed by both you and your patient (not required for inpatients). NOTE: A prescriber must be enrolled in the TIRF REMS Access program to submit a Patient-Prescriber Agreement Form for a patient. How do I complete the Agreement Form by fax? • • • • • TIRF REMS Access Patient-Prescriber Obtain a TIRF REMS Access Patient-Prescriber Agreement Form. A printable version of the Patient-Prescriber Agreement Form is available on-line at www.TIRFREMSaccess.com or by contacting the TIRF REMS Access call center at 1-866-822-1483. Review the TIRF REMS Access Patient-Prescriber Agreement Form with your patient. Complete Prescriber required fields. Have the patient or caregiver complete the patient required fields. Submit Patient-Prescriber Agreement Form by fax to 1-866-822-1487. Reference ID: 4146711 FDA_7263 How do I complete the Agreement Form online? • • • • • • • • • • • TIRF REMS Access Patient-Prescriber Log in to the TIRF REMS Access program from the home page by entering in your User ID and Password Select the heading labeled ‘My Account’ Select the ‘PPAF’ link Review the TIRF REMS Access Patient-Prescriber Agreement Form Enter your electronic signature, today’s date, and check the attestation box Enter the required patient information Have the patient enter their electronic signature, today’s date, and check the attestation box o (NOTE: If applicable, a Patient Representative can enter in their information in the required section on behalf of the patient) Print off two copies of the form by selecting the ‘Print’ button Provide one copy to the patient and keep one for your records Select the ‘Submit’ button to submit the PPAF for the patient You can print the confirmation by selecting the ‘Print Confirmation’ button Section 3: Summary of Prescribing Process 1. Write TIRF medicine prescription. 2. Help patient find an enrolled pharmacy. Detailed Prescribing Process Step 1: Write TIRF medicine prescription • Write a prescription for the appropriate TIRF medicine. Step 2: Help patient find an enrolled pharmacy • • Help each patient find pharmacies which are enrolled in the TIRF REMS Access program. A list of enrolled pharmacies can be found on www.TIRFREMSaccess.com, or by calling 1-866-822-1483. Inform patients that they can also find a participating pharmacy by calling the TIRF REMS Access program at 1-866-822-1483. Reporting Adverse Events and Monitoring To report any adverse events including the misuse, abuse, addiction, or overdose of TIRF medication contact: • TIRF REMS Access program at 1-866-822-1483 and/or Reference ID: 4146711 FDA_7264 • FDA MedWatch program by phone at 1-800-FDA-1088 or online at www.fda.gov/medwatch/report.htm If you have any questions, need additional information, or need additional copies of any TIRF REMS Access documents, please visit www.TIRFREMSaccess.com, or call the TIRF REMS Access program at 1866-822-1483. Reference ID: 4146711 FDA_7265 Transmucosal Immediate Release Fentanyl (TIRF) Products Risk Evaluation and Mitigation Strategy (REMS) TIRF REMS Access Program Education Program for Prescribers and Pharmacists Reference ID: 4146711 FDA_7266 Products Covered Under this Program: • Abstral® (fentanyl) sublingual tablets • Actiq® (fentanyl citrate) oral transmucosal lozenge • Fentora® (fentanyl buccal tablet) • Lazanda® (fentanyl) nasal spray • Onsolis® (fentanyl buccal soluble film) • Subsys ® (fentanyl sublingual spray) • Approved generic equivalents of these products are also covered under this program Reference ID: 4146711 FDA_7267 TIRF REMS Access Education Program: • Before you can enroll in the TIRF REMS Access program, you must review the Education Program, successfully complete the Knowledge Assessment, and sign the acknowledgement statements on the enrollment form. • The Education Program and enrollment can be completed online at www.TIRFREMSaccess.com. The enrollment form may also be downloaded from the website on the Resources tab, completed and faxed into the program at 1-866-822-1487. • Renewal of enrollment is required every 2 years. You will receive a reminder to renew your enrollment at the appropriate time. • Prescribers writing prescriptions for inpatient use only do not need to enroll in the TIRF REMS Access program. Reference ID: 4146711 FDA_7268 TIRF REMS Access Program Goals: The goals of the TIRF REMS Access program are to mitigate the risk of misuse, abuse, addiction, overdose, and serious complications due to medication errors by: 1. Prescribing and dispensing TIRF medicines only to appropriate patients, which includes use only in opioid-tolerant patients. 2. Preventing inappropriate conversion between fentanyl products. 3. Preventing accidental exposure to children and others for whom it was not prescribed. 4. Educating prescribers, pharmacists, and patients on the potential for misuse, abuse, addiction, and overdose. Reference ID: 4146711 FDA_7269 TIRF REMS Access Education Program Overview • This Education Program contains key safety information critical for minimizing the risks associated with TIRF medicines. • The program will address: o Appropriate patient selection o Understanding each patient’s risk factors for misuse, abuse, addiction, and overdose o Dosage and administration o Patient counseling o Effective patient management and follow-up Reference ID: 4146711 FDA_7270 TIRF REMS Access Education Program Overview (cont.) • Information on the TIRF REMS Access program requirements and operations is provided in the TIRF REMS Access program overviews for prescribers and pharmacies, which can be accessed at www.TIRFREMSaccess.com. • This Education Program is NOT a substitute for reading the Full Prescribing Information for each TIRF medicine. • Please also review the Full Prescribing Information and familiarize yourself with the contents of the Medication Guide for each product prescribed. Reference ID: 4146711 FDA_7271 Appropriate Patient Selection Indication: • TIRF medicines are indicated only for the management of breakthrough pain in cancer patients 18 years of age and older who are already receiving and who are tolerant to around-the-clock opioid therapy for underlying persistent cancer pain. – The only exception is for Actiq, and its generic equivalents, which are approved for cancer patients 16 years and older. Reference ID: 4146711 FDA_7272 Appropriate Patient Selection (cont.) Definition of Opioid Tolerance: • Patients considered opioid-tolerant are those who are taking, for one week or longer, at least: o 60 mg oral morphine/day o 25 mcg transdermal fentanyl/hour o 30 mg oral oxycodone/day o 8 mg oral hydromorphone/day o 25 mg oral oxymorphone/day o 60 mg oral hydrocodone/day o OR an equianalgesic dose of another oral opioid daily • Patients must remain on around-the-clock opioids when taking a TIRF medicine. Reference ID: 4146711 FDA_7273 Appropriate Patient Selection (cont.) • TIRF medicines are intended to be used only in the care of opioid-tolerant patients with cancer and only by healthcare professionals who are knowledgeable of, and skilled in, the use of Schedule II opioids to treat cancer pain. Contraindications: • TIRF medicines must not be used in opioid non-tolerant patients or in • the management of acute or postoperative pain including headache/migraine, dental pain, or acute pain in the emergency department, • acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment, • known or suspected gastrointestinal obstruction, including paralytic ileus, • known hypersensitivity to fentanyl, or components of the TIRF medicine. Reference ID: 4146711 FDA_7274 Appropriate Patient Selection (cont.) Please see each TIRF medicine’s Full Prescribing Information for a full list of specific situations in which TIRF medicines are not indicated or are contraindicated. Life-threatening respiratory depression could occur at any dose in opioid non-tolerant patients. Deaths have occurred in opioid non-tolerant patients treated with fentanyl products. Reference ID: 4146711 FDA_7275 Determine Patient-Specific Risk Factors 1. Risk of Misuse, Abuse, Addiction, and Overdose • TIRF medicines contain fentanyl, an opioid agonist and Schedule II controlled substance. TIRF medicines contain fentanyl, which has a high potential for abuse similar to other opioids. TIRF medicines can be abused and are subject to misuse, addiction, and criminal diversion. • These risks should be considered when prescribing or dispensing TIRF medicines in situations where the prescriber or pharmacist is concerned about an increased risk of misuse, abuse, addiction, or overdose. • Risk factors for opioid abuse include: o A history of past or current alcohol or drug abuse o A history of psychiatric illness o A family history of illicit drug use or alcohol abuse • Drug seeking tactics include: o emergency calls or visits near the end of office hours o refusal to undergo appropriate examination, testing, or referral o repeated loss of prescriptions o tampering with prescriptions Reference ID: 4146711 FDA_7276 Determine Patient-Specific Risk Factors 1. Risk of Misuse, Abuse, Addiction, and Overdose (cont.) o reluctance to provide prior medical records or contact information for other treating healthcare providers o “doctor shopping” (visiting multiple prescribers to obtain additional prescriptions) is common among drug abusers and people suffering from untreated addiction • Concerns about abuse and addiction should not prevent the proper management of pain. • All patients treated with opioids require careful monitoring for signs of abuse and addiction because use of opioid analgesic products carries the risk of addiction even under appropriate medical use Reference ID: 4146711 FDA_7277 Determine Patient-Specific Risk Factors 1. Risk of Misuse, Abuse, Addiction, and Overdose (cont.) • Measures to help limit abuse of opioid products: o Proper assessment of patients o Safe prescribing practices o Periodic re-evaluation of therapy o Proper dispensing and storage o Keeping detailed records of prescribing information o Keeping a signed TIRF REMS Access Patient-Prescriber Agreement Form o Informing patients/caregivers to protect against theft and misuse of TIRF medicines • TIRF medicines, like other opioids, can be diverted for non-medical use into illicit channels of distribution. Careful record-keeping of prescribing information, including quantity, frequency, and renewal requests as required by state and federal law, is strongly advised. Reference ID: 4146711 FDA_7278 Determine Patient-Specific Risk Factors 2. Accidental Ingestion or Exposure • TIRF medicines contain fentanyl in an amount which can be fatal in: o children, o individuals for whom it is not prescribed, and o those who are not opioid-tolerant • Inform patients that these products have a rapid onset of action. • Instruct patients to take steps to store TIRF medicines in a safe place out of reach of children. • Prescribers and pharmacists must specifically question patients or their caregivers about the presence of children in the home (on a full time or visiting basis) and counsel them regarding the dangers to children from inadvertent exposure. Reference ID: 4146711 FDA_7279 Determine Patient-Specific Risk Factors 2. Accidental Ingestion or Exposure (cont.) • Any accidental ingestion or exposure, especially in children, may result in respiratory depression or death. Talk with your patients about safe and appropriate storage and disposal of TIRF medicines. Reference ID: 4146711 FDA_7280 Determine Patient-Specific Risk Factors 3. Drug Interactions • Fentanyl is metabolized mainly via the human cytochrome P450 (CYP3A4) isoenzyme system; therefore, potential drug interactions may occur when TIRF medicines are given concurrently with agents that affect CPY3A4 activity. • Concomitant use of TIRF medicines with CYP3A4 inhibitors (e.g., certain protease inhibitors, ketoconazole, fluconazole, diltiazem, erythromycin, verapamil) may increaseplasma concentrations of fentanyl and prolong opioid adverse reactions which may cause potentially fatal respiratory depression. • Patients receiving TIRF medicines who begin therapy with, or increase the dose of, CYP3A4 inhibitors are to be carefully monitored for signs of opioid toxicity over an extended period of time. Dosage increases should be done conservatively. • Due to the additive pharmacologic effect, the concomitant use of benzodiazepines or other CNS depressants, including alcohol, increases the risk of respiratory depression, profound sedation, coma, and death. Reference ID: 4146711 FDA_7281 Determine Patient-Specific Risk Factors 3. Drug Interactions (cont.) • The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome. • Monoamine Oxidase Inhibitors (MAOIs) interactions with opioids may manifest as serotonin syndrome. • Mixed Agonist/Antagonist and Partial Agonist Opioid Analgesics may reduce the analgesic effect of TIRF medicines and/or precipitate withdrawal symptoms. • Fentanyl may enhance the neuromuscular blocking action of skeletal muscle relaxants and produce an increased degree of respiratory depression. • Opioids can reduce the efficacy of diuretics by inducing the release of antidiuretic hormone. • The concomitant use of anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. Reference ID: 4146711 FDA_7282 Determine Patient-Specific Risk Factors 4. Pregnancy • Prolonged use of TIRF medicines during pregnancy can result in neonatal opioid withdrawal syndrome, which may be life-threatening if not recognized and treated, and requires management according to protocols developed by neonatology experts. • If opioid use is required for a prolonged period in a pregnant woman, advise the patient of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available. Reference ID: 4146711 FDA_7283 Dosage and Administration General ➢ Patients beginning treatment with a TIRF medicine MUST begin with titration from the lowest dose available for that specific product, even if they have taken another TIRF medicine. Carefully consult the initial dosing instructions in each product’s specific Full Prescribing Information. Appropriate Conversion • TIRF medicines are not interchangeable with each other, regardless of route of administration. Differences exist in the pharmacokinetics of TIRF medicines resulting in clinically important differences in the amount of fentanyl absorbed. • TIRF medicines are not equivalent to any other fentanyl product, including another TIRF medicine, on a microgram-per-microgram basis. The only exception is for substitution of a generic equivalent for a branded TIRF medicine. • Substantial differences exist in the pharmacokinetic profiles of different fentanyl products that result in clinically important differences in the extent of absorption of fentanyl that could result in a fatal overdose. Reference ID: 4146711 FDA_7284 Dosage and Administration General Appropriate Conversion (cont.) • As a result of these differences, the conversion of a TIRF medicine for any other TIRF medicine may result in fatal overdose. • Converting from one TIRF medicine to a different TIRF medicine must not be done on a microgram-per-microgram basis and, must be titrated according to the labeled dosing instructions each time a patient begins use of a new TIRF medicine. • The only exception is for substitutions between a branded TIRF medicine and its generic equivalents. • For patients being converted specifically from Actiq to Fentora, Actiq to Subsys, and Actiq to Abstral, you must refer to the Full Prescribing Information for detailed instructions. Reference ID: 4146711 FDA_7285 Maintenance/Dose Adjustments for all TIRF Medicines • Once a dose that provides adequate analgesia and minimizes adverse reactions is found, that dose should be prescribed for each subsequent episode of breakthrough cancer pain. • Patients must wait at least 2 or 4 hours before treating another episode of breakthrough pain with their TIRF medicines. Please refer to the TIRF medicine’s Full Prescribing Information to determine the time between doses. • Limit the use of TIRF medicines to 4 or fewer doses per day. • If the prescribed dose no longer adequately manages the breakthrough cancer pain for several consecutive episodes, increase the dose as described in the titration section of the prescribing information. • Pharmacists: Instruct patients to consult with their prescriber. • Consider increasing the dose of the around-the-clock opioid medicine used for persistent cancer pain in patients experiencing more than 4 breakthrough cancer pain episodes per day. Reference ID: 4146711 FDA_7286 Products** Covered Under this Program: Dosage and Administration Product Initial Dose Max Dose Per Episode Frequency Titration Abstral? Abstral is always If adequate analgesia is not Patients must wait at If adequate analgesia was not (fentanyl) 100 (unless obtained the patient may use a least 2 hours before obtained with the ?rst 100mgc dose, sublingual the patient is second ABSTRAL dose (after 30 treating another episode continue dose escalation in a tablets being converted minutes) as directed by their of breakthrough pain with stepwise manner over consecutive from 2400 healthcare provider. No more than ABSTRAL. breakthrough episodes until adequate ACTIQ - please two doses of ABSTRAL may be analgesia with tolerable side effects is see Full used to treat an episode of achieved. Prescribing breakthrough pain. Information)_ During titration, patients can be instructed to use multiples of 100 tablets and/or 200 tablets for any single dose. Instruct patients not to use more than 4 tablets at one time. Actiq? (fentanyl Always 200 mcg. If the breakthrough pain episode is Patients must wait at Closely follow patients and change citrate) oral not relieved after 30 minutes, least 4 hours before the dosage level until adequate transmucosal patients may take 1 additional dose treating another analgesia with tolerable side effects is lozenge using the same strength. breakthrough pain achieved with a single unit. episode with ACTIQ. Patients should not take more than 2 doses of ACTIQ per breakthrough pain episode. Note: This table is also available to print for use as a quick reference guide. Please visit for further information and resources. This includes approved generic equivalents of these products. Reference ID: 4146711 Products** Covered Under this Program (cont.): Dosage and Administration Product Initial Dose Max Dose Per Episode Frequency Titration Fentora? FENTORA is If the breakthrough pain episode is For patients being Closely follow patients and change (fentanyl buccal always 100 not relieved after 30 minutes, converted from ACTIQ, the dosage level until adequate tablet) (unless the patient patients may take 1 additional dose prescribers must use the analgesia is achieved with a single is being converted usmg the same strength. Initial Dosmg tablet. Recommendations for from 2600 Patients should not take more than Patients on ACTIQ found During titration, patients can be ACTIQ please 2 doses of FENTORA per in Table 1 of the Full instructed to use multiple tablets (one see breakthrough pain episode. Prescribing Information. on each side of the mouth in the Prescribing The doses of FENTORA upper/lower buccal cavity) until a Information). Patients must wait at least 4 hours in the table are starting maintenance dose is achieved. before treating another doses and not intended to breakthrough pain episode with represent equianalgesic FENTORA. doses to ACTIQ Lazanda? Always100 mcg. Only use LAZANDA once per Limit LAZANDA use to 4 If adequate analgesia was not (fentanyl) nasal cancer breakthrough pain episode; or fewer doses per day. obtained with the ?rst spray i.e. do not redose LAZANDA within 100 dose, continue dose an episode. escalation in a stepwise manner over consecutive breakthrough pain Patients must wait at least 2 hours episodes until adequate analgesia before treating another episode of with tolerable side effects is achieved. breakthrough pain with LAZANDA. Patients should con?rm the dose of LAZANDA that works for them with a second episode of breakthrough pain. Note: This table is also available to print for use as a quick reference guide. Please visit for further information and resources. This includes approved generic equivalents of these products. Reference ID: 4146711 Products** Covered Under this Program (cont.): Dosage and Administration Product Initial Dose Max Dose Per Episode Frequency Titration Onsolis? Always 200 mcg. ONSOLIS should be used only Patients must wait at Titrate using 200 ONSOLIS film (fentanyl buccal once per breakthrough cancer least 2 hours before increments. soluble ?lm) pain episode; i.e. ONSOLIS should treating another not be redosed within an episode. breakthrough pain Instruct patients not to use more than episode with ONSOLIS. 4 ?lms at once. When multiple ?lms are used, films should not be placed on top of each other but may be placed on both sides of the mouth. If adequate pain relief is not achieved after 800 four 200 ONSOLIS ?lms), and the patient has tolerated the 800 dose, treat the next episode by using one 1200 ONSOLIS ?lm. Subsys? SUBSYS is If the breakthrough pain episode is Patients must wait at Closely follow patients and change (fentanyl always 100 not relieved after 30 minutes, least 4 hours before the dosage level until adequate sublingual spray) (unless the patient patients may take 1 additional dose treating another episode analgesia is achieved using a single is being converted using the same strength. of breakthrough pain with dose per episode of breakthrough from 3600 SUBSYS. cancer pain. ACTIQ please Patients should not take more than see Full 2 doses of SUBSYS per episode of Prescribing breakthrough pain. Information. Note: This table is also available to print for use as a quick reference guide. Please visit for further information and resources. This includes approved generic equivalents of these products. Reference ID: 4146711 Patient Counseling ➢ Before initiating treatment with a TIRF medicine, review the productspecific Medication Guide with patients and caregivers, and counsel them on TIRF medicine risks and safe use. ➢ Inform patients of the risk of life-threatening respiratory depression, including information that the risk is greatest when starting the TIRF medicine or when the dosage is increased, and that it can occur even at recommended dosages. • Tell patients exactly how to take the TIRF medicine. Instruct them to take the TIRF medicine strictly as prescribed, with special regard to dosage, dose titration, administration and proper disposal of partially used or unneeded TIRF medicine. Tell the patient: • You must be regularly using another opioid pain medicine, around-the-clock, for your constant pain. • If you stop taking your around-the-clock opioid pain medicine for your constant pain, you must stop taking your TIRF medicine. Reference ID: 4146711 FDA_7290 Patient Counseling Tell the patient (cont.): • Note: Patients have had difficulty comprehending this concept; please emphasize it to your patients. • TIRF medicines can cause serious side effects, including life-threatening breathing problems which can lead to death. You must take TIRF medicines exactly as prescribed. • Contact me or my office if your TIRF medicine does not relieve your pain. Do not change your dose of the TIRF medicine or take the TIRF medicine more often than I have directed. • Accidental ingestion or exposure, especially in children, may result in respiratory depression or death. Always store your TIRF medicine in a safe place away from children and teenagers because accidental use by a child, or anyone for whom it was not prescribed, is a medical emergency and can cause death. Use the child safety kit if one is provided with your TIRF medicine. Reference ID: 4146711 FDA_7291 Patient Counseling Tell the patient (cont.): • Potentially fatal additive effects may occur if the TIRF medicine is used with benzodiazepines or other CNS depressants, including alcohol, and not to use these concomitantly unless supervised by a healthcare provider. • The use of the TIRF medicine, even when taken as recommended, can result in addiction, abuse, and misuse, which can lead to overdose and death. • Opioids could cause a rare but potentially life-threatening condition resulting from concomitant administration of serotonergic drugs. • Avoid taking their TIRF medicine while using any drugs that inhibit monoamine oxidase. • Opioids could cause adrenal insufficiency, a potentially life-threatening condition. • Their TIRF medicine may cause orthostatic hypotension and syncope. Reference ID: 4146711 FDA_7292 Patient Counseling Tell the patient (cont.): • Properly dispose of partially used or unneeded TIRF medicine remaining from a prescription. Refer to the Full Prescribing Information and Medication Guide for each product for specific instructions for disposal. • Prolonged use of TIRF medicines during pregnancy can result in neonatal opioid withdrawal syndrome, which may be life threatening if not recognized and treated. • Never give your TIRF medicine to anyone else, even if they have the same symptoms, because it may harm them or even cause death. • Never sell or give away your TIRF medicine. Doing so is against the law. Reference ID: 4146711 FDA_7293 Effective Patient Management & Follow-up ➢ All patients treated with opioids require careful monitoring. At follow-up visits: • Assess appropriateness of dose, and make any necessary dose adjustments to the TIRF medicine or of their around-the-clock opioid medicine. • Assess for signs of misuse, abuse, or addiction. • Be aware that abuse and addiction are separate and distinct from physical dependence and tolerance. o Abuse of opioids can occur in the absence of addiction, and is characterized by misuse for non-medical purposes, often in combination with other psychoactive substances. o The possibility of physical and/or psychological dependence should be considered when a pattern of inappropriate behavior is observed. Reference ID: 4146711 FDA_7294 Effective Patient Management & Follow-up ➢ All patients treated with opioids require careful monitoring. At follow-up visits (cont.): • TIRF medicines, like other opioids, can be diverted for non-medical use into illicit channels of distribution. Careful record-keeping of prescribing information, including quantity, frequency, and renewal requests as required by state and federal law, is strongly advised. Reference ID: 4146711 FDA_7295 Transmucosal Immediate Release Fentanyl (TIRF) REMS Knowledge Assessment For real-time processing www.TIRFREMSaccess.com. of this Knowledge Assessment, please go to To submit this form via fax, please answer all questions below, fill in the fields at the bottom of the form, and fax all pages to 1-866-822-1487. You will receive enrollment confirmation via email or fax. Question 1 The patients described are all experiencing breakthrough pain, but ONE is not an appropriate patient for a TIRF medicine. Which patient should not receive a TIRF medicine? Select one option A. 12-year-old sarcoma patient, using transdermal fentanyl for her underlying persistent cancer pain. B. Adult female with advanced breast cancer; on 60 mg of oral morphine daily for the past 4 weeks. C. Adult male with advanced lung cancer, his underlying persistent pain is managed with 25 mcg/hour transdermal fentanyl patches for the past 3 months. D. Adult male with multiple myeloma who has bone pain currently managed with 50 mg oral oxymorphone daily for the last 2 weeks. Question 2 The patients described are experiencing breakthrough pain. A TIRF medicine is NOT appropriate for one of them. Which patient should not receive a TIRF medicine? Select one option. A. Adult male with advanced lung cancer; underlying persistent cancer pain managed with 25 mcg/hour transdermal fentanyl patches for the past 2 months. B. Adult female with localized breast cancer; just completed a mastectomy and reconstructive surgery; persistent cancer pain managed with 30 mg oral morphine daily for the past 6 weeks. C. Adult male patient with advanced prostate cancer who, over the last 2 weeks, has been prescribed 100 mg oral morphine daily for pain due to bone metastasis. D. Adult female with advanced sarcoma who has been taking a daily dose of 12 mg oral hydromorphone for the last 3 weeks. DEA Number or Chain ID:________________________ Reference ID: 4146711 FDA_7296 Question 3 Certain factors may increase the risk of abuse and/or diversion of opioid medications. Which of the following is most accurate? Select one option. A. B. C. D. A history of alcohol abuse with the patient or close family members. The patient has a household member with a street drug abuse problem. The patient has a history of prescription drug misuse. All of the above. Question 4 A patient is already taking a TIRF medicine but wants to change their medicine. His/her doctor decides to prescribe a different TIRF medicine (that is not a bioequivalent generic version of a branded product) in its place. How should the prescriber proceed? Select one option. A. The prescriber can safely convert to the equivalent dosage of the new TIRF medicine as it has the same effect as other TIRF medicines. B. The prescriber must not convert from the equivalent TIRF medicine dose to another TIRF medicine because they have different absorption properties and this could result in a fentanyl overdose. C. Convert from the other TIRF medicine to the new TIRF medicine at half of the dose. D. The prescriber should base the starting dose of the newly prescribed TIRF medicine on the dose of the opioid medicine used for their underlying persistent cancer pain. Question 5 A patient is starting titration with a TIRF medicine. What dose must they start with? Select one option. A. An appropriate dose based on the dose of the opioid medicine used for underlying persistent cancer pain. B. The dose that the prescriber believes is appropriate based on their clinical experience. C. The lowest available dose, unless individual product Full Prescribing Information provides product-specific guidance. D. The median available dose. Question 6 A prescriber has started titrating a patient with the lowest dose of a TIRF medicine. However, after 30 minutes, the breakthrough pain has not been sufficiently relieved. What should they advise the patient to do? Select one option. A. Take another (identical) dose of the TIRF medicine immediately. B. Take a dose of an alternative rescue medicine. C. Provide guidance based on the product-specific Medication Guide because the instructions are not the same for all TIRF medicines. D. Double the dose and take immediately. DEA Number or Chain ID:________________________ Reference ID: 4146711 FDA_7297 Question 7 A patient is taking a TIRF medicine and the doctor would like to prescribe erythromycin, a CYP3A4 inhibitor. Which of the following statements is true? Select one option. A. The patient can’t be prescribed erythromycin, because using it at the same time as a TIRF medicine could be fatal. B. Use of a TIRF medicine with a CYP3A4 inhibitor may require dosage adjustment; carefully monitor the patient for opioid toxicity, otherwise such use may cause potentially fatal respiratory depression. C. There is no possible drug interaction between CYP3A4 inhibitors and TIRF medicines. D. The dose of the TIRF medicine must be reduced by one half if a CYP3A4 inhibitor is prescribed in the same patient. Question 8 Before initiating treatment with a TIRF medicine, prescribers must review the Medication Guide with the patient. Which of the following counseling statements is not correct? Select one option. A. TIRF medicines contain fentanyl in an amount that could be fatal to children of all ages, in individuals for whom they were not prescribed, and in those who are not opioid tolerant. B. Inform patients that TIRF medicines must not be used to treat acute or postoperative pain, including headache/migraine, dental pain or acute pain in the emergency department. C. Instruct patients that, if they stop taking their around -the-clock opioid medicine, they can continue to take their TIRF medicine. D. Instruct patients to never share their TIRF medicine with anyone else, even if that person has the same symptoms. Question 9 There is a risk of fatal overdose with inappropriate use of TIRF medicines. Which one of the following answers is most accurate? Select one option. A. B. C. D. TIRF medicines can be fatal if taken by children. TIRF medicines can be fatal if taken by anyone for whom it is not prescribed. TIRF medicines can be fatal if taken by anyone who is not opioid-tolerant. All of the above. Question 10 Which one of the following statements is most accurate regarding the safe storage and disposal of TIRF medicines? Select one option. A. TIRF medicines should be kept in a safe place and out of the reach of children. B. TIRF medicines should be protected from theft. C. Dispose of partially used or unneeded TIRF medicine by following the TIRF medicinespecific procedure specified in the Medication Guide. D. All of the above. Reference ID: 4146711 FDA_7298 DEA Number or Chain ID:________________________ Question 11 Conversion between specific TIRF medicines has been established and is described in the Prescribing Information for which products? Select one option. A. B. C. D. Actiq to Abstral Actiq to Fentora Actiq to Subsys All of the above Prescriber / Authorized Pharmacy Representative ________________________________________ DEA Number _______________________________________________________________________ Chain ID (if applicable) _______________________________________________________________ DEA Number or Chain ID:________________________ Reference ID: 4146711 FDA_7299 The Transmucosal Immediate Release Fentanyl (TIRF) REMS Access Program Prescriber Enrollment Form For real-time processing of enrollment, please go to www.TIRFREMSaccess.com. To submit this form via fax, please complete all required fields below and fax pages 1, 2 and 3 to 1-866-822-1487. Please note, you must review the TIRF REMS Access Education Program and successfully complete the Knowledge Assessment to complete enrollment. If you have not completed the Knowledge Assessment online, please include it with this enrollment form. You will receive enrollment confirmation via email or fax. I understand that TIRF medicines are only available through the TIRF REMS (Risk Evaluation and Mitigation Strategy) Access program and that I must comply with the program requirements. In addition, I acknowledge that: 1. I have reviewed the TIRF REMS Access Education Program, including the Full Prescribing Information for each TIRF medicine, and I have completed the Knowledge Assessment. I understand the responsible use conditions for TIRF medicines and the risks and benefits of chronic opioid therapy. 2. I understand that TIRF medicines can be abused and that this risk should be considered when prescribing or dispensing TIRF medicines in situations where I am concerned about an increased risk of misuse, abuse, or overdose, whether accidental or intentional. 3. I understand that TIRF medicines are indicated only for the management of breakthrough pain in cancer patients 18 years of age or older (Actiq and its generic equivalents are approved for 16 years of age and older), who are already receiving and who are tolerant to, around-the-clock opioid therapy for their underlying persistent cancer pain. 4. I understand that TIRF medicines are contraindicated for use in opioid non-tolerant patients, and know that fatal overdose can occur at any dose. 5. I understand that TIRF medicines must not be used to treat acute or postoperative pain, including headache/migraine, dental pain, or acute pain in the emergency department. 6. I understand that converting patients from one TIRF medicine to a different TIRF medicine must not be done on a microgram-per-microgram basis. I understand that TIRF medicines are not interchangeable with each other, regardless of route of administration, and that conversion may result in fatal overdose, unless conversion is done in accordance with labeled product-specific conversion recommendations (refer to the list of currently approved TIRF products located on the TIRF REMS Access website at www.TIRFREMSaccess.com/TirfUI/rems/products.action. Note, a branded TIRF medicine and its specific generic product(s) are interchangeable. 7. I understand that the initial starting dose for TIRF medicines for all patients is the lowest dose, unless individual product labels provide product-specific conversion recommendations, and I understand that patients must be titrated individually. 8. I will provide a Medication Guide for the TIRF medicine I intend to prescribe to my patient or their caregiver and review it with them. If I convert my patient to a different TIRF medicine, the Medication Guide for the new TIRF medicine will be provided to, and reviewed with my patient or their caregiver. 9. I will complete and sign a TIRF REMS Access Patient-Prescriber Agreement (PPAF) with each new patient, before writing the patient’s first prescription for a TIRF medicine, and renew the agreement every two (2) years. 10. I will provide a completed, signed copy of the Patient-Prescriber Agreement (PPAF) to the patient and retain a copy for my records. I will also provide a completed, signed copy to the TIRF REMS Access program (through the TIRF REMS Access website or by fax) within ten (10) working days. Prescriber Name* (please print): Reference ID: 4146711 FDA_7300 11. At all follow-up visits, I agree to assess the patient for appropriateness of the dose of the TIRF medicine, and for signs of misuse and abuse. 12. I understand that TIRF medicines are only available through the TIRF REMS Access program. I understand and agree to comply with the TIRF REMS Access program requirements for prescribers. 13. I understand that I must re-enroll in the TIRF REMS Access program and successfully complete the enrollment requirements every two (2) years. Prescriber Information: Prescriber Signature* ________________________________________________ First Name* _____________________________ Date* ______________ Last Name* _________________ Credentials ________ State License Number* ___________________________ Site Name* ______________________________ State Issued* ___________________________________ Address* _______________________________ DEA Number* ___________________________________ City* ___________________________________ National Provider Identifier (NPI)* __________________ State* _____________ ZIP* ______________ Phone Number* __________________________ Fax Number* ____________________________ Email* __________________________________ *Required Fields Preferred Method of Communication (please select one):  Fax  Email If you have additional practice sites, state licenses or DEA numbers that you may use when prescribing TIRF medicines, please provide the information requested below. Prescriber Name* (please print):_____________________________ Reference ID: 4146711 FDA_7301 Additional Prescriber Information (All Fields Required) Site Name* ______________________________ State License Number* ___________________________ Address* ________________________________ State Issued* ___________________________________ City* ___________________________________ DEA Number* __________________________________ State* _____________ ZIP* ______________ Phone Number* __________________________ Fax Number* ____________________________ *Required Fields Site Name* ______________________________ State License Number* ___________________________ Address* ________________________________ State Issued* DEA Number* City* ___________________________________ State* _____________ ZIP* ______________ Phone Number* __________________________ Fax Number* ____________________________ *Required Fields Site Name* ______________________________ State License Number* ___________________________ Address* ________________________________ State Issued* DEA Number* City* ___________________________________ State* _____________ ZIP* ______________ Phone Number* __________________________ Fax Number* ____________________________ *Required Fields If you have any questions or require additional information or further copies of any TIRF REMS Access documents, please visit either www.TIRFREMSaccess.com, or call the TIRF REMS Access program at 1-866-822-1483. Prescriber Name* (please print):_____________________________ Reference ID: 4146711 FDA_7302 The Transmucosal Immediate Release Fentanyl (TIRF) REMS Access Program Patient-Prescriber Agreement Form For real-time processing of the Patient Prescriber Agreement Form go to www.TIRFREMSaccess.com. To submit this form via fax, please complete all required fields below and fax all pages to 1-866-8221487. As the prescriber of any TIRF medicine in this TIRF REMS (Risk Evaluation and Mitigation Strategy) Access program, I acknowledge that: 1. I understand that TIRF medicines are indicated only for the management of breakthrough pain in cancer patients 18 years of age and older (Actiq and its generic equivalents are approved for 16 years of age and older), who are already receiving, and who are tolerant to, around-the-clock opioid therapy for their underlying persistent cancer pain. 2. I understand that TIRF medicines are contraindicated for use in opioid non-tolerant patients, and know that fatal overdose can occur at any dose. 3. I understand that TIRF medicines are not for use in the management of acute or postoperative pain, including headache/migraine, dental pain, or acute pain in the emergency department. 4. I understand that patients considered opioid-tolerant are those who are taking, for one week or longer, at least: 60 mg oral morphine/day; 25 micrograms transdermal fentanyl/hour; 30 mg oral oxycodone/day; 8 mg oral hydromorphone/day; 25 mg oral oxymorphone/day; 60 mg oral hydrocodone/day; or an equianalgesic dose of another opioid daily. 5. I have provided to, and reviewed with, my patient or their caregiver the Medication Guide for the TIRF medicine I intend to prescribe. 6. If I change my patient to a different TIRF medicine, I will provide the Medication Guide for the new TIRF medicine to my patient or my patient’s caregiver, and I will review it with them. 7. I understand that if I change my patient to a different TIRF medicine, the initial dose of that TIRF medicine for all patients is the lowest dose, unless individual product labels provide product-specific conversion recommendations. 8. I have counseled my patient or their caregiver about the risks, benefits, and appropriate use of the TIRF medicine including communication of the following safety messages: a. If you stop taking your around-the-clock pain medicine, you must stop taking your TIRF medicine. b. NEVER share your TIRF medicine. c. Giving a TIRF medicine to someone for whom it has not been prescribed can result in a fatal overdose. d. TIRF medicines can be fatal to a child; used and unused dosage units must be safely stored out of the reach of children living in or likely to visit the home and disposed of in accordance with the specific disposal instructions detailed in the product’s Medication Guide. Prescriber (*Required Fields): Prescriber Signature* __________________________ First Name* ___________________________________ DEA Number* _________________________________ Fax* _________________________________________ Date _________________________________________ Last Name*____________________________________ National Provider Identifier (NPI)* _________________ Prescriber Name* (please print):__________________________________ Reference ID: 4146711 FDA_7303 As the patient being prescribed a TIRF medicine, or a legally authorized representative, I acknowledge that: 1. My prescriber has given me a copy of the Medication Guide for the TIRF medicine I have been prescribed, and has reviewed it with me. 2. I understand that TIRF medicines should only be taken by patients who are regularly using another opioid, around-the-clock, for constant pain. If I am not taking around-the-clock opioid pain medicine, my prescriber and I have discussed the risks of only taking TIRF medicines. 3. I understand that if I stop taking my around-the-clock opioid pain medicine for my constant pain, I must stop taking my TIRF medicine. 4. I understand how I should take this TIRF medicine, including how much I can take, and how often I can take it. If my prescriber prescribes a different TIRF medicine for me, I will ensure I understand how to take the new TIRF medicine. 5. I understand that any TIRF medicine can cause serious side effects, including life-threatening breathing problems which can lead to death, especially if I do not take my TIRF medicine exactly as my prescriber has directed me. 6. I agree to contact my prescriber if my TIRF medicine does not relieve my pain. I will not change the dose of my TIRF medicine myself or take it more often than my prescriber has directed. 7. I agree that I will never give my TIRF medicine to anyone else, even if they have the same symptoms, since it may harm them or even cause death. 8. I will store my TIRF medicine in a safe place out of reach of children and teenagers because accidental use by a child, or anyone for whom it was not prescribed, is a medical emergency and can cause death. 9. I have been instructed on how to properly dispose of my partially used or unneeded TIRF medicine remaining from my prescription, and will dispose of my TIRF medicine properly as soon as I no longer need it. 10. I understand that selling or giving away my TIRF medicine is against the law. 11. I have asked my prescriber all the questions I have about my TIRF medicine. If I have any additional questions or concerns in the future about my treatment with my TIRF medicine, I will contact my prescriber. 12. I have reviewed the “Patient Privacy Notice for the TIRF REMS Access Program” below and I agree to its terms and conditions which allow my healthcare providers to share my health information, as defined in this document to the makers of TIRF medicines (TIRF Sponsors) and their agents and contractors for the limited purpose of managing the TIRF REMS Access program. Patient (*Required Fields): Signature* _______________________________________ Date* _________________________________________ First Name* ______________________________________ Last Name*____________________________________ Date of Birth (MM/DD/YYYY)* _______________________ Phone Number _________________________________ State* ________ ZIP* ______________ Patient Representative (if required): Signature* ______________________________ First Name* _____________________________ Relationship to Patient* ___________________ Date* _________________________________________ Last Name*____________________________________ Prescriber Name* (please print):__________________________________ Reference ID: 4146711 FDA_7304 Patient Privacy Notice for the TIRF REMS Access Program For the purpose of the TIRF REMS Access program, my name, address, telephone number and prescription information make up my “Health Information.” My doctors, pharmacists, and healthcare providers may share my Health Information with the TIRF REMS Access program, and contractors that manage the TIRF REMS Access program. My Health Information will be kept in a secure database, and may only be used as stated below. I allow the TIRF REMS Access program to receive, use, and share my Health Information in order to: I. Enroll me in the TIRF REMS Access program and manage my participation (including contacting me) in the TIRF REMS Access program. II. Provide me with educational information about the TIRF REMS Access program. III. Contact my healthcare providers to collect my Health Information for the TIRF REMS Access program. I allow the TIRF REMS Access program to receive, use, and share my Health Information, using a unique, encrypted identifier instead of my name, in order to evaluate the proper use of TIRF medicines and report to the FDA about the effectiveness of the TIRF REMS Access program. I understand that I am not required to sign this written approval. However, if I do not sign, I will not be able to enroll in the TIRF REMS Access program and will not be able to receive TIRF medicines. I understand that I may withdraw this written approval at any time by faxing a signed, written request to the TIRF REMS Access program at 1-866-822-1487. Upon receipt of this written request, the TIRF REMS Access program will notify my healthcare providers about my request. My healthcare providers will no longer be able to share my Health Information with the TIRF REMS Access program once they have received and processed that request. However, withdrawing this written approval will not affect the ability of the TIRF REMS Access program to use and share my Health Information that it has already received to the extent allowed by law. If I withdraw this written approval, I will no longer be able to participate in the TIRF REMS Access program and will no longer be able to receive TIRF medicines. The sponsors of the TIRF REMS Access program agree to protect my information by using and sharing it only for the purposes described. If you have any questions or require additional information or further copies of any TIRF REMS Access documents, please visit either www.TIRFREMSaccess.com, or call the TIRF REMS Access program at 1-866-822-1483. Prescriber Name* (please print):__________________________________ Reference ID: 4146711 FDA_7305 The Transmucosal Immediate Release Fentanyl (TIRF) Risk Evaluation and Mitigation Strategy (REMS) Access Program or TIRF REMS Access Program An Overview for Patients and Caregivers What are TIRF medicines? TIRF medicines are prescription medicines that contain the drug fentanyl. TIRF medicines are used to manage breakthrough pain in adults with cancer who are routinely taking other opioid (narcotic) pain medicines around-the-clock for cancer pain. Please refer to the list of currently approved TIRF products located on the TIRF REMS website at www.TIRFREMSaccess.com/TirfUI/rems/products.action. What is the TIRF REMS Access Program? A REMS, or Risk Evaluation and Mitigation Strategy, is a program to help manage known or potential serious risks of a medicine. Because TIRF medicines have a risk of misuse, abuse, addiction, and overdose, the Food and Drug Administration (FDA) has required that all TIRF medicines only be available through a restricted program called the TIRF REMS Access program. Healthcare professionals who prescribe your TIRF medicine, as well as pharmacies that fill your prescriptions for TIRF medicine, must be enrolled in the program. Why is the TIRF REMS Access Program needed? Your TIRF medicine contains fentanyl, which can cause life threatening breathing problems, which can lead to death. These life threatening breathing problems can occur if you take more TIRF medicine than your healthcare provider tells you to take, or if the TIRF medicine is taken by anyone other than you. The TIRF REMS Access program provides training for prescribers and pharmacists to help them select patients for whom TIRF medicines are appropriate. The TIRF REMS Access program also helps your healthcare provider and pharmacist provide advice and guidance to you on the correct way to use your TIRF medicine, including how to store and dispose of it. How do I participate in the program? You or your caregiver will be required to read and sign the TIRF REMS Access PatientPrescriber Agreement Form to participate in the program. Your healthcare provider will explain the Patient-Prescriber Agreement Form for the TIRF REMS Access program, which you must read and sign before receiving your prescription. Your healthcare provider will ensure that the signed form is submitted to the program. You will be part of the program when your first prescription is filled at a participating pharmacy. Your healthcare provider can identify pharmacies in your area where you can bring your prescription. When you are part of the program, you can start treatment with the TIRF medicine that your healthcare provider has prescribed for you. Reference ID: 4146711 FDA_7306 Overview of Steps for the TIRF REMS Access Program for Patients Step 1 Participating in the Program • • • • • Your healthcare provider will talk with you about the best way to use your TIRF medicine, including the risks and how to store and dispose of it correctly. Your healthcare provider will also review written information about your TIRF medicine with you. This written information is called the Medication Guide. Your healthcare provider will give you a copy of the Medication Guide - read and keep it. Together you and your healthcare provider will complete and sign the TIRF REMS Access Patient-Prescriber Agreement Form. The form gives you important information you need to know and understand before taking a TIRF medicine. You will need to complete a new Patient-Prescriber Agreement Form every two (2) years. You will be notified by your healthcare provider in advance of the need to reenroll. Your healthcare provider will submit a copy to the TIRF REMS Access program. Your healthcare provider will also give you a copy and keep a copy in your medical records. Step 2 Getting a Prescription • • Once you have signed the Patient-Prescriber Agreement Form your healthcare provider will write you a prescription for your TIRF medicine. Your healthcare provider can help you find a participating pharmacy to have your prescription filled, because only pharmacies that are in the TIRF REMS Access program can dispense TIRF medicines. You can also find a participating pharmacy by calling the TIRF REMS Access program at 1-866-822-1483. Step 3 Having your Prescription Filled • • • • The pharmacy will check to make sure that your healthcare provider is enrolled in the TIRF REMS Access program. Only then is the pharmacy allowed to dispense the TIRF medicine to you. You will be automatically enrolled in the TIRF REMS Access program when you receive your first prescription for a TIRF medicine. The pharmacy will remind you how to take, store and dispose of your TIRF medicine correctly. The pharmacy will also give you a copy of the Medication Guide. Read and keep the Medication Guide. Additional Program Information For more information about your TIRF medicine, you can find a copy of the Medication Guide at www.TIRFREMSaccess.com or you can call the TIRF REMS Access program at 1-866-822-1483. Reference ID: 4146711 FDA_7307 TIRF REMS Access Program Frequently Asked Questions (FAQs) I. II. III. IV. V. VI. ALL STAKEHOLDERS FAQs PATIENT FAQs OUTPATIENT PHARMACY FAQs PRESCRIBER FAQs INPATIENT PHARMACY FAQs DISTRIBUTOR (WHOLESALER) FAQs Reference ID: 4146711 FDA_7308 I. ALL STAKEHOLDERS FAQs What is a TIRF Medicine? TIRF medicines are transmucosal immediate release fentanyl prescription medicines used to manage breakthrough pain in adults with cancer who are routinely taking other opioid (narcotic) pain medicines around-the-clock for pain. Click here to see a full list of TIRF medicines. What is a REMS? REMS stands for “Risk Evaluation and Mitigation Strategy.” A Risk Evaluation and Mitigation Strategy (REMS) is a risk management program required by the FDA to ensure that the benefits of a drug outweigh the risks. FDA has determined that a REMS is necessary for all marketed TIRF medicines. What are the goals of the TIRF REMS Access Program? The goals of the TIRF REMS Access program are to mitigate the risk of misuse, abuse, addiction, overdose and serious complications due to medication errors by: 1. Prescribing and dispensing TIRF medicines only to appropriate patients, which includes use only in opioid-tolerant patients. 2. Preventing inappropriate conversion between fentanyl products. 3. Preventing accidental exposure to children and others for whom it was not prescribed. 4. Educating prescribers, pharmacists, and patients on the potential for misuse, abuse, addiction, and overdose. What are the components of the TIRF REMS Access program? Because of the risk for misuse, abuse, addiction, and overdose, TIRF medicines are available only through a restricted program called the TIRF REMS Access program. An overview of the requirements for prescribers, patients, pharmacies, and distributors is included below: • Healthcare providers who prescribe TIRF medicines for outpatient use must review the prescriber educational materials, enroll in the REMS program, and commit to comply with the REMS requirements. • Patients who are prescribed TIRF medicines in an outpatient setting, must understand the risks and benefits of the drug and sign a Patient-Prescriber Agreement Form with their healthcare provider to receive TIRF medicines. These patients will be enrolled by the pharmacy at the time their first prescription is filled. • Outpatient pharmacies that dispense TIRF medicines for outpatient use must enroll in the program, train their pharmacy staff on the REMS requirements, and agree to comply with the REMS requirements. Pharmacy staff can register online to access the Education Program and take the Knowledge Assessment for training purposes. • Inpatient pharmacies that dispense TIRF medicines for inpatient use must enroll in the Program, train their pharmacy staff on the REMS requirements, and agree to comply with the REMS requirements. Pharmacy staff can register online to access the Education Program and take the Knowledge Assessment for training purposes. • Wholesalers and distributors that distribute TIRF medicines must enroll in the program and commit to distributing only to authorized enrolled pharmacies. Reference ID: 4146711 FDA_7309 The educational materials referenced above will be available to prescribers and pharmacies through the TIRF REMS Access program. In an outpatient setting, FDA-approved Medication Guides will be provided to patients by prescribers and pharmacists during counseling about the proper use of TIRF medicines. Inpatient Use Only- Prescribers who prescribe TIRF medicines that will only be used in an inpatient setting (e.g., hospitals, hospices, or long-term care facilities) are not required to enroll in the TIRF REMS Access program. Similarly, patients who receive TIRF medicines in an inpatient setting are not required to enroll in the TIRF REMS Access program. Long term care and hospice patients who obtain their medications from outpatient pharmacies must be enrolled. Why does the TIRF REMS Access program require prescriber enrollment for outpatient prescribing? Prescriber enrollment is required to help ensure that prescribers receive education on the risks and safe use of TIRF medicines, and can demonstrate their understanding of how to mitigate the risks. Additionally, the educational materials will help them understand the requirements of the TIRF REMS Access program. To become enrolled, prescribers must review the TIRF REMS Access Education Program including the Full Prescribing Information and successfully complete the Knowledge Assessment. Are there requirements for prescribers for inpatient use in the TIRF REMS Access program? No. Healthcare providers who prescribe TIRF medicines for inpatient use only are not required to enroll in the TIRF REMS Access program. Why does the TIRF REMS Access program require pharmacy enrollment? Pharmacy enrollment is required to help ensure that pharmacists receive education on the risks and safe use of TIRF medicines. Additionally, the educational materials will help them understand the requirements of the TIRF REMS Access program. Only enrolled pharmacies are eligible to receive shipments of TIRF medicines and/or to dispense prescriptions written by enrolled prescribers for outpatients. A designated authorized pharmacist must review the Education Program and successfully complete the Knowledge Assessment. Only then can the authorized pharmacist complete enrollment on behalf of the pharmacy. The authorized pharmacist will train other staff within the pharmacy in the appropriate dispensing of TIRF medicines according to the TIRF REMS Access program. Prescriptions for outpatient use written by prescribers who are not enrolled in the REMS will not be authorized by the TIRF REMS Access program and TIRF medicines will not be dispensed to an outpatient who is not enrolled. Why does the TIRF REMS Access program require a Patient-Prescriber Agreement Form? The TIRF REMS Access program requires all prescribers to complete and sign a TIRF REMS Access Patient-Prescriber Agreement Form with each new patient, before writing the patient’s first TIRF prescription. The Patient-Prescriber Agreement Form helps to ensure that each patient for whom the TIRF medicine has been prescribed is appropriately counselled on the safe use and storage of the TIRF medicine. The prescriber must keep a copy of the signed Patient- Reference ID: 4146711 FDA_7310 Prescriber Agreement Form in the patient’s chart, give a copy to the patient and submit a copy to the TIRF REMS Access program within 10 working days. A Patient-Prescriber Agreement Form is not required for inpatient use of TIRF medicines. Where do I find a list of local pharmacies that participate in the TIRF REMS Access program? The TIRF REMS Access homepage contains a feature called “Pharmacy Lookup” that is available for prescribers, and distributors, to look up and find enrolled pharmacies. This information can also be obtained by calling the TIRF REMS Access call center at 1-866-822-1483. How can I obtain TIRF REMS Access program materials? All TIRF REMS Access education materials and forms are available and can be downloaded from www.TIRFREMSaccess.com using Adobe Acrobat Reader. Enrollment Forms and the Patient-Prescriber Agreement Forms can be completed online at www.TIRFREMSaccess.com after reviewing the Education Program and successfully completing the Knowledge Assessment. Materials are also available by calling the TIRF REMS Access call center at 1-866-822-1483 for assistance. How do I contact the TIRF REMS Access program? You can contact the TIRF REMS Access program by calling the TIRF REMS Access call center at 1-866-822-1483 or by written correspondence to: TIRF REMS Access, PO Box 29036, Phoenix, AZ 85038 How can I report Adverse Events? Promptly report suspected adverse events associated with the use of a TIRF medicines including misuse, abuse, and overdose directly to the TIRF REMS Access program at 1-866-822-1483. You also may report adverse event information to the FDA MedWatch Reporting System by telephone at (800) FDA-1088 or by mail using Form 3500, available at www.fda.gov/medwatch. Reference ID: 4146711 FDA_7311 II. PATIENT FAQs As a patient, how do I participate with the TIRF REMS Access program? You must sign a Patient-Prescriber Agreement with your prescriber and take your prescription for a TIRF medicine to an ‘enrolled’ pharmacy. The pharmacy will enroll you in the TIRF REMS Access program. Your prescriber will go over important information you need to know before you take the TIRF medicine. Patients in an inpatient setting are not required to participate in the TIRF REMS Access program in order to be prescribed and dispensed TIRF medicines for inpatient use only. However, if your prescriber gives you a prescription for a TIRF medicine to take at home once you leave the inpatient facility, you must sign a Patient-Prescriber Agreement Form with your prescriber to participate in the TIRF REMS Access program. Where do I find a list of local pharmacies that participate in the TIRF REMS Access program? Only pharmacies that are enrolled in the TIRF REMS Access program can dispense TIRF medicines. Your prescriber can help you find a participating pharmacy. You can also get this information by calling the TIRF REMS Access program at 1-866-822-1483. Reference ID: 4146711 FDA_7312 III. OUTPATIENT PHARMACY FAQs What type of Outpatient Pharmacy is my pharmacy?There are 3 types of outpatient pharmacies. They are all required to be enrolled in the TIRF REMS Access program, complete the TIRF REMS Education Program, and verify patient and prescriber enrollment when processing prescriptions. The difference is in how these pharmacies enroll in the program. Independent Outpatient Pharmacy: Retail, mail order or institutional outpatient pharmacies having an authorized pharmacy representative that is responsible for ensuring enrollment and training of the pharmacy staff within an individual outpatient pharmacy. Each store will individually enroll in the TIRF REMS Access program as a single pharmacy location. Chain Outpatient Pharmacy: Retail, mail or institutional outpatient pharmacy having a chain headquarters that is responsible for ensuring enrollment and training of the pharmacy staff of all associated outpatient pharmacies. The chain headquarters will enroll multiple pharmacy locations (i.e.: chain stores) in the TIRF REMS Access program. Closed System Outpatient Pharmacy: Institutional or mail order outpatient pharmacies that uses a pharmacy management system that does not support the process of electronically transmitting the validation and claim information currently required by the TIRF REMS Access program. If you believe you are a closed system outpatient pharmacy, call the TIRF REMS Access program call center at 1-866-822-1483 to discuss enrollment. How does an Independent Outpatient Pharmacy enroll in the TIRF REMS Access program? The authorized pharmacist must review the Education Program, successfully complete the Knowledge Assessment and complete the Independent Outpatient Pharmacy Enrollment Form through the website or complete and fax the signed Enrollment Form and Knowledge Assessment to the TIRF REMS Access program at 1-866-822-1487. The authorized pharmacist must ensure the pharmacy enables their pharmacy management system to support communication with the TIRF REMS Access system, using established telecommunication standards, and run the standardized validation test transactions. Before a pharmacy is able to dispense prescriptions to outpatients, an enrollment form must be received either via the website by faxing or mailing it to the TIRF REMS Access program for each pharmacy requesting enrollment in the program. (See information on chain outpatient pharmacy enrollment below.) How does a Chain Outpatient Pharmacy enroll in the TIRF REMS Access program? An authorized chain outpatient pharmacy representative completes the TIRF REMS Access training, Knowledge Assessment and enrollment on behalf of all the pharmacies within the chain and then documents and manages training of all pharmacy staff by the chains’ internal processes. Pharmacy staff can register online to access the Education Program and take the Knowledge Assessment for training purposes. As part of enrollment, a chain outpatient pharmacy must enable the pharmacy management system to support communication with the TIRF REMS Access system, using established telecommunication standards, and must run the standardized validation test transactions. For further information or to enroll, access the TIRF REMS Access website at Reference ID: 4146711 FDA_7313 www.TIRFREMSaccess.com or call the TIRF REMS Access program call center at 1-866822-1483 for further assistance. How does a Closed System Outpatient Pharmacy enroll in the TIRF REMS Access program? If you believe you are a closed system outpatient pharmacy, call the TIRF REMS Access program call center at 1-866-822-1483 to discuss enrollment. How long is my enrollment effective in TIRF REMS Access? Your enrollment is effective for two (2) years. You will be required to re-enroll in the TIRF REMS Access program every two (2) years if you wish to continue dispensing these products. You will be notified by the TIRF REMS Access program in advance of the need to re-enroll. Independent outpatient pharmacies and chain outpatient pharmacies may re-enroll online or by fax. Closed system outpatient pharmacies may re-enroll by fax only. For re-enrollment online, go to the “Enrollment Activity” tab on the TIRF REMS Access program website (www.TIRFREMSaccess.com). The “Enrollment Activity” tab allows you to: • • • • Add to, update, or delete your registration information on file. Review the TIRF REMS Access Education Program. Take the TIRF REMS Access Knowledge Assessment. Submit your enrollment form by providing your attestation and signature. For re-enrollment by fax, review the TIRF REMS Access program Education Materials and submit a new TIRF REMS Access Enrollment Form and Knowledge Assessment to the TIRF REMS Access program at 1-866-822-1487. All TIRF REMS Access Education Materials and Enrollment Forms are available and can be downloaded from www.TIRFREMSaccess.com using Adobe Acrobat Reader or by calling the TIRF REMS Access call center at 1-866-822-1483. If the patient’s prescription is denied, will the TIRF REMS Access system explain the reason? All TIRF prescriptions (excluding inpatient use), must go through an electronic verification system via the pharmacy management system. When a prescription is denied, an appropriately coded message will be displayed on the pharmacy management system. For assistance, please call the TIRF REMS Access call center at 1-866-822-1483 for any information related to your denial. How does a pharmacy obtain TIRF Medicines from a distributor? Only enrolled distributors are allowed to distribute TIRF medicines to enrolled pharmacies. The TIRF REMS Access program provides frequently updated lists of all pharmacies that are currently enrolled in the program that distributors can use to verify enrollment before distributing TIRF medicines to a pharmacy. Reference ID: 4146711 FDA_7314 Chain and Independent Outpatient Pharmacy CASH Claim FAQs What is the definition of a TIRF REMS CASH Claim? The definition of a TIRF REMS CASH Claim is any claim for a TIRF medicine that is not electronically transmitted to a Third Party Insurance BIN using the pharmacy management system and established telecommunication standards. This includes claims for patients without prescription coverage or any paper claims submitted to a program for payment. Does a TIRF REMS CASH claim need to be submitted to the TIRF REMS Access Program? Yes, all TIRF prescriptions, including CASH claims and other claims (i.e., workers comp), must be submitted to the TIRF REMS Access program to validate the enrollment status of the prescriber, patient and pharmacy prior to dispensing TIRF medicine to the patient. How do I submit a TIRF REMS CASH claim to the TIRF REMS Access Program? Prior to dispensing TIRF medicines, transmit using the REMS CASH BIN 014780,to submit a CASH claim to the TIRF REMS Access program. Reference ID: 4146711 FDA_7315 IV. PRESCRIBER FAQs What is the enrollment process? The prescriber must review the Education Program, successfully complete the Knowledge Assessment and complete an enrollment form through the website at www.TIRFREMSaccess.com, or complete and fax the signed Enrollment Form and Knowledge Assessment to the TIRF REMS Access program at 1-866-822-1487. A prescriber may obtain an enrollment form online from the TIRF REMS Access website (www.TIRFREMSaccess.com) or by calling 1-866-822-1483. The program requires that a signed enrollment form and Knowledge Assessment be received by the TIRF REMS Access program for each prescriber who requests enrollment. Only healthcare providers who will prescribe TIRF medicines for outpatient use are required to be enrolled in the TIRF REMS Access program. How long is my enrollment effective in TIRF REMS Access? Your enrollment is effective for two (2) years. You will be required to re-enroll in the TIRF REMS Access program every two (2) years if you wish to continue dispensing these products. You will be notified by the TIRF REMS Access program in advance of the need to re-enroll. You may re-enroll via your “Enrollment Activity” tab on the TIRF REMS Access program website (www.TIRFREMSaccess.com). The “Enrollment Activity” tab allows you to: • • • • Add to, update, or delete your registration information on file. Review the TIRF REMS Access Education Program. Take the TIRF REMS Access Knowledge Assessment. Submit your enrollment form by providing your attestation and signature. Alternatively, you may also complete re-enrollment via fax by reviewing the TIRF REMS Access program Education Materials and submitting a new TIRF REMS Access Enrollment Form and Knowledge Assessment into the TIRF REMS Access program at 1-866-822-1487. All TIRF REMS Access Education Materials and Enrollment Forms are available and can be downloaded from www.TIRFREMSaccess.com using Adobe Acrobat Reader or by calling the TIRF REMS Access call center at 1-866-822-1483. Where do I find a list of local pharmacies that participate in the TIRF REMS Access program? A list of participating pharmacies can be found on the TIRF REMS Access website (www.TIRFREMSaccess.com) homepage under the link “Pharmacy Lookup”. You may also call 1-866-822-1483. Patients can find a participating pharmacy by calling the TIRF REMS Access program at 1-866-822-1483. Reference ID: 4146711 FDA_7316 Can I write an order for TIRF Medicines for inpatient use? Yes, prescribers can write orders for TIRF medicines for inpatient use without the prescriber or the patient being enrolled in the TIRF REMS Access program. However, the inpatient pharmacy needs to be enrolled in the TIRF REMS Access program to receive and dispense TIRF medicines to inpatients in the healthcare facility. If a prescriber is discharging a patient with a TIRF medicine prescription, intended to be filled by an outpatient pharmacy, then the prescriber must be enrolled in the TIRF REMS Access program and complete a Patient-Prescriber Agreement Form. The prescription for outpatient use can only be filled through an enrolled outpatient pharmacy. Additional information on the TIRF REMS Access Education Program and enrollment can be obtained through the TIRF REMS Access program (www.TIRFREMSaccess.com) or by calling 1-866-822-1483. Reference ID: 4146711 FDA_7317 V. INPATIENT PHARMACY FAQs How do I enroll as an inpatient pharmacy? To enroll, the inpatient pharmacy must designate an authorized pharmacist who will review the required Education Program and successfully complete the Knowledge Assessment for the TIRF REMS Access program. Upon successful completion of the Knowledge Assessment, the authorized pharmacist will complete and sign the Inpatient Pharmacy Enrollment Form through the website (www.TIRFREMSaccess.com). The Knowledge Assessment and Enrollment Form may also be completed, signed, and faxed to the TIRF REMS Access program at 1-866-822-1487. Additional information about the TIRF REMS Access Education Program and enrollment can be obtained through the TIRF REMS Access program (www.TIRFREMSaccess.com) or by calling 1-866-822-1483. How long is my enrollment effective in TIRF REMS Access? Your enrollment is effective for two (2) years. You will be required to re-enroll in the TIRF REMS Access program every two (2) years if you wish to continue dispensing these products. You will be notified by the TIRF REMS Access program in advance of the need to re-enroll. You may re-enroll via your “Enrollment Activity” tab on the TIRF REMS Access program website (www.TIRFREMSaccess.com). The “Enrollment Activity” tab allows you to: • • • • Add to, update, or delete your registration information on file. Review the TIRF REMS Access Education Program. Take the TIRF REMS Access Knowledge Assessment. Submit your enrollment form by providing your attestation and signature. Alternatively, you may also complete re-enrollment via fax by reviewing the TIRF REMS Access program Education Materials and submitting a new TIRF REMS Access Enrollment Form and Knowledge Assessment into the TIRF REMS Access program at 1-866-822-1487. All TIRF REMS Access Education Materials and Enrollment Forms are available and can be downloaded from www.TIRFREMSaccess.com using Adobe Acrobat Reader or by calling the TIRF REMS Access call center at 1-866-822-1483. Can inpatient pharmacies obtain TIRF Medicines in a Healthcare Facility? Yes. However, the inpatient pharmacy within or associated with the healthcare facility must be enrolled in the TIRF REMS Access program before inpatient pharmacies can purchase TIRF medicines. Additional information can be obtained from www.TIRFREMSaccess.com or by calling the TIRF REMS Access call center at 1-866-822-1483. Reference ID: 4146711 FDA_7318 VI. DISTRIBUTOR (WHOLESALER) FAQs Does a distributor have to enroll in the TIRF REMS Access program? Yes, distributors will need to enroll in the TIRF REMS Access program in order to be able to purchase and distribute TIRF medicines. How long is my enrollment effective in TIRF REMS Access? Your enrollment is effective for two (2) years. You will be required to re-enroll in the TIRF REMS Access program every two (2) years if you wish to continue dispensing these products. You will be notified by the TIRF REMS Access program in advance of the need to re-enroll. You can complete re-enrollment via fax by submitting a new TIRF REMS Access Enrollment Form into the TIRF REMS Access program at 1-866-822-1487. TIRF REMS Access Enrollment Forms are available and can be downloaded from www.TIRFREMSaccess.com using Adobe Acrobat Reader or by calling the TIRF REMS Access call center at 1-866-822-1483. What are the TIRF REMS Access program requirements for a distributor? To enroll in the TIRF REMS Access program, a distributor will have to complete and sign the Distributor Enrollment Form. In signing the enrollment form, the distributor is required to indicate that they understand that TIRF medicines are available only through the TIRF REMS Access program and they will comply with the program requirements. How can enrolled distributors access a list of pharmacies that participate in the TIRF REMS Access program? After enrollment, distributors can access the current list of enrolled pharmacies by: • Downloading from a secure FTP site (you will be contacted regarding the TIRF REMS Access secure FTP site once your enrollment is complete). • Utilizing the feature “Pharmacy Look Up” on a password protected section of the TIRF REMS Access website (www.TIRFREMSaccess.com). • Calling the TIRF REMS Access call center at 1-866-822-1483. Reference ID: 4146711 FDA_7319 This letter ceased distribution in November 2013. Subject: Important Drug Warning Announcement of a single shared REMS (Risk Evaluation and Mitigation Strategy) program for all Transmucosal Immediate Release Fentanyl (TIRF) products due to the potential risk of misuse, abuse, addiction, overdose and serious complications due to medication errors The TIRF REMS Access program is a Food and Drug Administration (FDA) required risk management program Dear Healthcare Provider: The purpose of this letter is to make you aware of a change from individual REMS programs to a shared REMS program (the TIRF REMS Access program) and to provide guidance on enrollment into the new shared REMS program beginning mm/dd/yyyy. The individual REMS programs are being converted to the TIRF REMS Access program to reduce the burden on the healthcare providers and the healthcare system of having multiple individual programs. The products covered under this new program include: • • • • • • Abstral® (fentanyl) sublingual tablets Actiq® (fentanyl citrate) oral transmucosal lozenge Fentora® (fentanyl citrate) buccal tablet Lazanda® (fentanyl) nasal spray Onsolis® (fentanyl buccal soluble film) Approved generic equivalents of these products are also covered under this program Prescriber Action: Option 1: If you are already enrolled in at least one individual REMS program • Your enrollment information will be automatically entered into the new shared TIRF REMS Access program. Your enrollment in the shared TIRF REMS Access program allows prescribing of all TIRF medicines that are covered under the TIRF REMS Access program. The website for the shared TIRF REMS Access program can be accessed at www.TIRFREMSaccess.com. • You can use your existing secure user ID and password from any one of your individual REMS programs to access the TIRF REMS Access website at www.TIRFREMSaccess.com and prescribe all TIRF medicines. ▪ The user ID and password you use to initially log on will become your permanent user ID and password for the shared TIRF REMS Access program. • The TIRF REMS Access Education Program is available on the shared TIRF REMS Access website or by calling 1-866-822-1483. We recommend that you review the TIRF REMS Access Education Program for information on all the products that are available under the TIRF REMS Access program. • You will be required to re-enroll in the shared TIRF REMS Access program two (2) years after your last enrollment in an individual REMS program if you wish to continue prescribing these products. You will be notified by the TIRF REMS Access program in advance of the need to re-enroll. • Patients that have already signed a Patient-Prescriber Agreement Form on file will not have to sign another form until their two year enrollment is due. Reference ID: 4146711 FDA_7320 Option 2: If you do not have an existing enrollment in any individual REMS program • Access the TIRF REMS Access program at www.TIRFREMSaccess.com to create an account. • Review the TIRF REMS Access Education Program materials available at www.TIRFREMSaccess.com including the Full Prescribing Information for each product covered in this program, and successfully complete the Knowledge Assessment. • Enroll in the TIRF REMS Access program by completing the Prescriber Enrollment Form and re-enroll every two (2) years. You will be notified by the TIRF REMS Access program in advance of the need to re-enroll. • If you are unable to enroll online, please call the TIRF REMS program call center at 1866-822-1483 for further assistance. The goals of the TIRF REMS Access program are to mitigate the risk of misuse, abuse, addiction, overdose and serious complications due to medication errors by: 1. Prescribing and dispensing TIRF medicines only to appropriate patients, which includes use only in opioid-tolerant patients. 2. Preventing inappropriate conversion between fentanyl products. 3. Preventing accidental exposure to children and others for whom it was not prescribed. 4. Educating prescribers, pharmacists, and patients on the potential for misuse, abuse, addiction, and overdose of TIRF medicines. This new shared program replaces the individual product REMS that were previously available. Any prescribers, pharmacies, patients and distributors enrolled in these programs will be automatically transitioned to the new shared TIRF REMS Access program beginning mm/dd/yyyy. If you have not enrolled in one or more of these individual REMS programs and you intend to prescribe any of these products for outpatient use you must enroll in the TIRF REMS program. For inpatient administration (e.g. hospitals, in-patient hospices, and long-term care facilities that dispense for inpatient use) of these products, patient and prescriber enrollment in the TIRF REMS Access program is not required. TIRF medicines are opioid analgesics indicated only for the management of breakthrough pain in cancer patients 18 years of age and older (16 years of age and older for Actiq® brand and generic equivalents) who are already receiving and who are tolerant to around-the-clock opioid therapy for their underlying persistent cancer pain, unless otherwise indicated in the product label. Patients considered opioid-tolerant are those who are regularly taking at least 60 mg oral morphine/day, or at least 25 micrograms transdermal fentanyl/hour, or at least 30 mg of oral oxycodone/day, or at least 8 mg oral hydromorphone/day, or at least 25 mg oral oxymorphone/day or an equianalgesic dose of another opioid for one week or longer. To help you understand the TIRF REMS Access program the following program materials are available at www.TIRFREMSaccess.com or can be ordered by calling 1-866-822-1483: • Prescriber Program Overview • TIRF REMS Access Education Program • Knowledge Assessment Form • Prescriber Enrollment Form • Frequently Asked Questions You can also access the following patient materials at www.TIRFREMSaccess.com or Reference ID: 4146711 FDA_7321 order them by calling 1-866-822-1483: • An Overview for Patients and Caregivers • Patient-Prescriber Agreement Form • Frequently Asked Questions • Full Prescribing Information and Medication Guides for each TIRF medicine To access the above information and to enroll in the TIRF REMS Access program, visit www.TIRFREMSaccess.com or call 1-866-822-1483 to have enrollment materials sent to you. Reference ID: 4146711 FDA_7322 Selected Important Safety Information IMPORTANCE OF PROPER PATIENT SELECTION, DOSING, and POTENTIAL FOR ABUSE TIRF medicines contain fentanyl, an opioid agonist and a Schedule II controlled substance, with an abuse liability similar to other opioid analgesics. TIRF medicines can be abused in a manner similar to other opioid agonists, legal or illicit. Consider the potential for abuse when prescribing or dispensing TIRF medicines in situations where the physician or pharmacist is concerned about an increased risk of misuse, abuse or diversion. Schedule II opioid substances which include morphine, oxycodone, hydromorphone, oxymorphone, and methadone have the highest potential for abuse and risk of fatal overdose due to respiratory depression. Serious adverse events, including deaths, in patients treated with some oral transmucosal fentanyl medicines have been reported. Deaths occurred as a result of improper patient selection (e.g., use in opioid non-tolerant patients) and/or improper dosing. The substitution of a TIRF medicine for any other fentanyl medicine, including another TIRF medicine, may result in fatal overdose. TIRF medicines are indicated only for the management of breakthrough pain in adult cancer patients 18 years of age and older (16 years of age and older for Actiq® brand and generic equivalents) who are already receiving and who are tolerant to around-the-clock opioid therapy for their underlying persistent cancer pain. Patients considered opioid-tolerant are those who are taking: • at least 60 mg of oral morphine/daily • at least 25 mcg transdermal fentanyl/hour • at least 30 mg of oral oxycodone daily • at least 8 mg oral hydromorphone daily • at least 25 mg oral oxymorphone daily • or an equianalgesic dose of another opioid daily for a week or longer. TIRF medicines are contraindicated in opioid non-tolerant patients and are contraindicated in the management of acute or postoperative pain, including headache/migraine and dental pain, or use in the emergency room. Please see the individual medicine prescribing information for a full list of specific situations in which TIRF medicines are not indicated or are contraindicated. Lifethreatening respiratory depression could occur at any dose in opioid non-tolerant patients. Deaths have occurred in opioid non-tolerant patients treated with some TIRF medicines. When prescribing, do not convert patients on a mcg per mcg basis from another fentanyl medicine to a TIRF medicine, except for substitutions between a branded TIRF medicine and its generic equivalent. Patients beginning treatment with TIRF medicines must begin with titration from the lowest available dose for that specific medicine. Carefully consult the Initial Dosing Instructions in the TIRF medicine-specific Full Prescribing Information. When dispensing, TIRF medicines are not interchangeable with each other, regardless of route of administration. Differences exist in the pharmacokinetics of TIRF medicines resulting in Reference ID: 4146711 FDA_7323 clinically important differences in the amount of fentanyl absorbed that could cause a fatal overdose. Converting patients from one TIRF medicine to a different TIRF medicine must not be done on a microgram-per-microgram basis, and must be titrated according to the labeled dosing instructions each time they begin use of a new TIRF medicine. The only exception is for substitution between a branded TIRF medicine and its specific generic equivalent. Special care must be used when dosing TIRF medicines. Refer to the Full Prescribing Information for the individual TIRF medicine for guidance on the maximum number of doses that can be taken per breakthrough pain episode and the time that patients must wait before treating another episode of breakthrough pain with the TIRF medicine. TIRF medicines are intended to be used only in the care of opioid-tolerant cancer patients and only by healthcare professionals who are knowledgeable of, and skilled in, the use of Schedule II opioids to treat cancer pain. Patients and their caregivers must be instructed that TIRF medicines contain a medicine in an amount which can be fatal in children, in individuals for whom it is not prescribed, and in those who are not opioid-tolerant. All medicines must be kept out of the reach of children. The concomitant use of TIRF medicines with cytochrome P450 3A4 inhibitors may result in an increase in fentanyl plasma concentrations, and may cause potentially fatal respiratory depression. Adverse Reactions The most commonly observed adverse reactions with TIRF medicines include typical opioid adverse reactions, such as nausea, vomiting, constipation, somnolence, dizziness, and headache. Refer to individual medicine prescribing information for all adverse reactions. Expect opioid side effects and manage them accordingly. Please see the individual Full Prescribing Information for each TIRF medicine for all information including boxed warnings, and Medication Guide for important safety information for each TIRF medicine. Adverse Event Reporting Promptly report suspected adverse events including misuse, abuse, addiction and overdoses directly to the TIRF REMS Access program at 1-866-822-1483. You also may report adverse event information to the FDA MedWatch Reporting System by telephone at 1-800-FDA-1088 or by mail using Form 3500, available at www.fda.gov/medwatch. Medication Guide It is important that you discuss the risks of TIRF medicines with your patients and encourage them to read the relevant Medication Guide. The Medication Guide provides important information on the safe and effective use of TIRF medicines and you will need to review the appropriate Medication Guide for the TIRF medicine you prescribe/dispense to your patient. Patients should be counseled on the need to store TIRF medicines safely out of the reach of children and other persons for whom the medicine is not prescribed. Reference ID: 4146711 FDA_7324 Provide your patient with a copy of the appropriate Medication Guide for the TIRF medicine you prescribe. Medication Guides will be provided to you by the manufacturers of individual TIRF medicines. If you require additional Medication Guides you can: • Print copies from the TIRF REMS Access program website at www.TIRFREMSaccess.com. • Contact the TIRF REMS Access program at 1-866-822-1483. Sincerely, TIRF REMS Access Industry Group Reference ID: 4146711 FDA_7325 Attachment 1: List of TIRF Medicines Available Only through the TIRF REMS Access Program ▪ ▪ ▪ ▪ ▪ ▪ ABSTRAL® (fentanyl) sublingual tablets ACTIQ® (fentanyl citrate) oral transmucosal lozenge FENTORA® (fentanyl citrate) buccal tablet LAZANDA® (fentanyl) nasal spray ONSOLIS® (fentanyl buccal soluble film) Approved generic equivalents of these products are also covered under this program. Reference ID: 4146711 FDA_7326 Home Page Important Safety Information (ISI) is included on the bottom of the Home Page. To reduce the space and image distortion, ISI is not shown as part of Home Page in this document. Reference ID: 4146711 FDA_7327 The Transmucosal Immediate Release Fentanyl (TIRF) REMS Access Program An Overview for Independent Outpatient Pharmacies To dispense TIRF medicines, your Independent Outpatient Pharmacy must enroll in the TIRF REMS Access program. What is the TIRF REMS Access Program? The TIRF REMS (Risk Evaluation and Mitigation Strategy) Access program is designed to ensure informed risk-benefit decisions before initiating treatment and, while patients are on treatment, to ensure appropriate use of TIRF medicines. TIRF medicines are available only through a restricted distribution program required by the Food and Drug Administration (FDA), because of the risk for misuse, abuse, addiction, overdose, and serious complications due to medication errors. A list of TIRF medicines available through the TIRF REMS Access program is located on the TIRF Products web page at www.TIRFREMSaccess.com/TirfUI/rems/products.action. How does the TIRF REMS Access program work? The TIRF REMS Access program requires pharmacies, prescribers, patients and wholesalers to enroll in the program in order to utilize TIRF medications. The supply of TIRF medicines to pharmacies is controlled by enrolled distributors, who will verify the current enrollment status of the pharmacy prior to shipment of TIRF medicines. Pharmacies are required to verify the prescriber and the patient are enrolled in the TIRF REMS Access program before dispensing any TIRF medication. Does your pharmacy qualify as an Independent Outpatient Pharmacy? For the purposes of this REMS, an independent outpatient pharmacy is defined as an outpatient pharmacy such as a retail, mail or institutional outpatient pharmacy having an authorized pharmacy representative that is responsible for ensuring enrollment and training of the pharmacy staff within an individual outpatient pharmacy. Each store will individually enroll in TIRF REMS Access as a single pharmacy location. Additionally, to qualify as an independent outpatient pharmacy, your pharmacy must use a pharmacy management system to electronically transmit the required validation and claim information to the TIRF REMS Access program using established telecommunication standards. NOTE: There are different requirements for inpatient pharmacies that only dispense for inpatient use. Please refer to “An Overview for Inpatient Pharmacies” for more information. Options and Requirements for the TIRF REMS Access Program for Independent Outpatient Pharmacies Pharmacy Education, Enrollment & Pharmacy Management Systems All enrollment activities can be completed at www.TIRFREMSaccess.com Reference ID: 4146711 FDA_7328 If I have previously enrolled in an individual TIRF REMS do I need to enroll in the shared TIRF REMS Access Program? All pharmacy enrollment information was transferred from the individual TIRF REMS to the TIRF REMS Access Program on March 12, 2012. If the authorized pharmacist or pharmacy representative logged onto the TIRF REMS Access program website and agreed to the shared program terms and conditions before September 12, 2012, your pharmacy is able to order and dispense all TIRF medications. If the authorized pharmacist or pharmacy representative has not agreed to the shared terms and conditions, your pharmacy will need to enroll in the TIRF REMS Access program (see how to enroll below). You will be required to re-enroll in the shared TIRF REMS two (2) years after your last enrollment in an individual REMS program if you wish to continue dispensing these products. You will be notified by the TIRF REMS Access program in advance of the need to re-enroll. The following two sections provide detailed information on the Enrollment Process (Section 1) and the Dispensing Process (Section 2) for TIRF medicines in an independent outpatient pharmacy. Section 1: Enrollment Process Summary of Enrollment: 1. Select an individual to be your Authorized Independent Outpatient Pharmacy Representative. 2. Create an account and complete registration at www.TIRFREMSaccess.com. 3. Complete the TIRF REMS Access Education Program and Knowledge Assessment. 4. Complete and submit an Independent Outpatient Pharmacy Enrollment form. 5. Enable the pharmacy management system to support communication with the TIRF REMS Access system. 6. Train pharmacy staff. Detailed Enrollment Process Step 1: Select an individual to be your Authorized Chain Representative • Select an authorized pharmacy representative to establish and oversee the TIRF REMS Access program requirements. Step 2: Create an account www.TIRFREMSaccess.com Reference ID: 4146711 and complete registration at FDA_7329 • Create an account at www.TIRFREMSaccess.com registration on behalf of your pharmacy. and then complete How do I create an account and complete the TIRF REMS Access registration on-line? • • • • • • • • Select the Create Account button on the home page Complete the Create Account Information section Select ‘No’ if you have not submitted an enrollment form via fax at the ‘Already enrolled via Fax and have an enrollment ID?’ prompt Create User ID and password and select ‘Create My Account’ Select ‘Pharmacy’ as the option to best describe you and select ‘Continue’ Select ‘Independent Outpatient Authorized Pharmacist’ Review the content in the pop-up box and select ‘Confirm’ to continue Complete required fields on the Independent Outpatient Pharmacy Registration page and select ‘Submit’ to continue Step 3: Complete the TIRF REMS Access Education Program and Knowledge Assessment How do I complete the TIRF REMS Access Education Program by fax? • Review the TIRF REMS Access Education Program. A printable version of the TIRF REMS Access Education Program is available online at www.TIRFREMSaccess.com or by contacting the TIRF REMS Access call center at 1-866-822-1483. • Once you have reviewed the Education Program complete the Knowledge Assessment and submit by fax to 1-866-822-1487. • The TIRF REMS Access program will notify you of the status of your Knowledge Assessment via your indicated preferred method of communication (fax or e-mail). How do I complete the TIRF REMS Access Education Program online? • • • Select the ‘Start the TIRF REMS Access Education Program’ to proceed to the training upon completion of registration Select ‘Go To Knowledge Assessment’, complete the Knowledge Assessment, and select ‘Submit Assessment’ A Knowledge Assessment Confirmation Code will be provided once the assessment is completed successfully Step 4: Complete Enrollment • • and submit Independent Outpatient Pharmacy To finalize enrollment in the TIRF REMS Access program complete Independent Outpatient Pharmacy Enrollment. If you are unable to enroll online, please call the TIRF REMS Access program call center at 1-866-822-1483 for further assistance. Reference ID: 4146711 FDA_7330 How do I complete the TIRF REMS Access Enrollment on-line? • Upon successful completion of the TIRF REMS Access Education Program and Knowledge Assessment, you will be prompted to read the TIRF REMS Access attestation and enter your electronic signature, today’s date, and check the attestation box before clicking ‘Submit’. NOTE: You are required to re-enroll every two (2) years. You will be notified by the TIRF REMS Access program in advance of the need to re-enroll. Step 5: Confirm the Pharmacy Management communication with the TIRF REMS Access system • • System supports Following completion of steps 1-4 above, you will receive instruction on how to submit test transactions to the TIRF REMS Access program. Successful submission of the test transaction confirms the pharmacy management system supports communication with the TIRF REMS Access system. After successful completion of the test transactions you will receive enrollment confirmation. Step 6: Train Pharmacy Staff • • Ensure that all pharmacy staff involved in the processing and dispensing of TIRF medicines have been trained to only dispense TIRF medicines in accordance with the TIRF REMS Access program requirements. o Pharmacy staff can register online to access the Education Program and take the Knowledge Assessment for training purposes. Ensure that this training is documented and retained by the pharmacy. This documentation should include the pharmacist/pharmacy staff member’s name, the date training was completed and the method of training as a minimum. Section 2: Dispensing Process Summary of Dispensing Process 1. Confirm pharmacy staff is trained. 2. Confirm patient and prescriber enrollment in TIRF REMS Access Program. 3. Dispense TIRF medication. 4. Counsel patient and provide medication guide. Detailed Dispensing Process Step 1: Confirm that the Pharmacy staff is trained • Ensure all pharmacy staff involved in the processing and dispensing of TIRF medicines have been trained to specifically dispense TIRF medicines in accordance with the TIRF REMS Access program requirements available at www.TIRFREMSaccess.com. (see Section 1, Step 6: Train Pharmacy Staff). Reference ID: 4146711 FDA_7331 Step 2: Confirm prescriber and patient enrollment • • • Each pharmacy site must confirm that the prescriber and patient are enrolled in the TIRF REMS Access program prior to dispensing each TIRF prescription by submitting a pharmacy billing claim via the chain pharmacy practice management system. This includes third party insurance claims, cash claims and any other claims (i.e.: workers compensation). Submitting a claim for a patient’s first TIRF prescription through the pharmacy management system will automatically enroll that patient in the TIRF REMS Access program. To allow the TIRF REMS Access program to confirm prescriber and patient enrollment the pharmacy practice management system must populate the following fields in the pharmacy billing claim*: o Patient First Name, o Patient Last Name, o Patient Date of Birth, o Patient ZIP / Postal Zone, o Quantity Dispensed, o Days Supply, o Prescriber ID, o Prescriber Last Name *Use BIN 014780 for all cash and non-third party claims. If the prescriber or patient enrollment is not confirmed, or if any other rejection message is received that prevents the prescription from being filled, contact the TIRF REMS Access call center at 1-866-822-1483 for further instruction. Step 3: Dispense TIRF Medication • Receive approval from the TIRF REMS Access program and then prepare, label and dispense the medication. Step 4: Counsel Patient and Provide Medication Guide • • Advise the patient on how to take, store and dispose of TIRF medicine appropriately. Provide a copy of the product specific Medication Guide to the patient with each prescription. Reporting Adverse Events and Monitoring To report any adverse events including the misuse, abuse, addiction, or overdose of TIRF medication contact: • TIRF REMS Access program at 1-866-822-1483 and/or Reference ID: 4146711 FDA_7332 • FDA MedWatch program by phone at 1-800-FDA-1088 or online at www.fda.gov/medwatch/report.htm If you have any questions, need additional information, or need additional copies of any TIRF REMS Access documents, please visit www.TIRFREMSaccess.com, or call the TIRF REMS Access program at 1-866822-1483. Reference ID: 4146711 FDA_7333 The Transmucosal Immediate Release Fentanyl (TIRF) REMS Access Program An Overview for Chain Outpatient Pharmacies To dispense TIRF medicines, your Chain Outpatient Pharmacy must enroll in the TIRF REMS Access program. What is the TIRF REMS Access Program? The TIRF REMS (Risk Evaluation and Mitigation Strategy) Access program is designed to ensure informed risk-benefit decisions before initiating treatment and, while patients are on treatment, to ensure appropriate use of TIRF medicines. TIRF medicines are available only through a restricted distribution program required by the Food and Drug Administration (FDA), because of the risk for misuse, abuse, addiction, overdose, and serious complications due to medication errors. A list of TIRF medicines available through the TIRF REMS Access program is located on the TIRF Products web page at www.TIRFREMSaccess.com/TirfUI/rems/products.action. How does the TIRF REMS Access program work? The TIRF REMS Access program requires pharmacies, prescribers, patients and wholesalers to enroll in the program in order to utilize TIRF medications. The supply of TIRF medicines to pharmacies is controlled by enrolled distributors, who will verify the current enrollment status of the pharmacy prior to shipment of TIRF medicines. Pharmacies are required to verify the prescriber and the patient are enrolled in the TIRF REMS Access program before dispensing any TIRF medication. Does your pharmacy qualify as a Chain Outpatient Pharmacy? For the purposes of this REMS, a chain outpatient pharmacy is defined as an outpatient pharmacy such as a retail, mail order or institutional outpatient pharmacy having a chain headquarters that is responsible for ensuring enrollment and training of the pharmacy staff of all associated outpatient pharmacies. The chain headquarters will enroll multiple pharmacy locations (i.e.: chain stores) in the TIRF REMS Access program. Additionally, to qualify as a chain outpatient pharmacy, your pharmacy must use a pharmacy management system to electronically transmit the required validation and claim information to the TIRF REMS Access program using established telecommunication standards. NOTE: There are different requirements for inpatient pharmacies that only dispense for inpatient use. Please refer to “An Overview for Inpatient Pharmacies” for more information. Reference ID: 4146711 FDA_7334 Overview of the TIRF REMS Access Program for Chain Pharmacies: Steps for Enrollment and Program Requirements Chain Outpatient Pharmacy Management Systems Education, Enrollment & Outpatient Pharmacy All enrollment activities can be completed at www.TIRFREMSaccess.com If I have previously enrolled in an individual TIRF REMS do I need to enroll in the shared TIRF REMS Access Program? All pharmacy enrollment information was transferred from the individual TIRF REMS to the TIRF REMS Access program on March 12, 2012. If the authorized pharmacist or pharmacy representative logged onto the TIRF REMS Access program website, executed a TIRF REMS Access contract with their switch provider to agree to the shared program terms and conditions before September 12, 2012, your pharmacy is able to order and dispense all TIRF medications. If the authorized pharmacist or pharmacy representative has not agreed to the shared terms and conditions, your pharmacy will need to enroll in the TIRF REMS Access program (see how to enroll below). You will be required to re-enroll in the shared TIRF REMS two (2) years after your last enrollment in an individual REMS program if you wish to continue dispensing these products. You will be notified by the TIRF REMS Access program in advance of the need to re-enroll. The following two sections provide detailed information on the Enrollment Process (Section 1) and the Dispensing Processes (Section 2) for TIRF medicines in a chain outpatient pharmacy. Section 1: Enrollment Process Summary of Enrollment Process 1. Execute a TIRF REMS Access contract with your switch provider. 2. Select an individual to be your Authorized Chain Outpatient Pharmacy Representative. 3. Create an account and complete registration at www.TIRFREMSaccess.com 4. Complete the TIRF REMS Access Education Program and Knowledge Assessment. 5. Complete and submit a Chain Outpatient Pharmacy Enrollment form 6. Enable the pharmacy management system to support communication with the TIRF REMS Access system. 7. Train pharmacy staff. Reference ID: 4146711 FDA_7335 Detailed Enrollment Process Step 1: Execute a TIRF REMS Access contract with your switch provider • • Call the TIRF REMS Access program at 1-866-822-1483. The TIRF REMS program will notify your switch provider and advise that a contract must be executed for participation in the program. Your account executive will contact you directly and work with you to establish a contractual agreement. Step 2: Select an individual to be your Authorized Chain Outpatient Pharmacy Representative • Select an authorized chain outpatient pharmacy representative to establish and oversee the TIRF REMS Access program requirements. Step 3: Create an account www.TIRFREMSaccess.com • and complete registration at Create an account at www.TIRFREMSaccess.com and then complete registration at the corporate level on behalf of your individual pharmacies. How do I create an account and complete the TIRF REMS Access registration on-line? • Select the Create Account button on the home page • Complete the Create Account Information section • Select ‘No’ if you have not submitted an enrollment form via fax at the ‘Already enrolled via Fax and have an enrollment ID?’ prompt • Create User ID and password and select ‘Create My Account’ • Select ‘Pharmacy’ as the option to best describe you and select ‘Continue’ • Select ‘Chain Outpatient Pharmacy – Authorized Chain Outpatient Pharmacy Representative’ • Review the content in the pop-up box and select ‘Confirm’ to continue • Complete required fields on the Chain Outpatient Pharmacy Registration page and select ‘Submit’ to continue Step 4: Complete the TIRF REMS Access Education Program and Knowledge Assessment How do I complete the TIRF REMS Access Education Program by fax? • Review the TIRF REMS Access Education Program. A printable version of the TIRF REMS Access Education Program is available online at www.TIRFREMSaccess.com or by contacting the TIRF REMS Access call center at 1-866-822-1483. Reference ID: 4146711 FDA_7336 • • Once you have reviewed the Education Program complete the Knowledge Assessment and submit by fax to 1-866-822-1487. The TIRF REMS Access program will notify you of the status of your Knowledge Assessment via your indicated preferred method of communication (fax or e-mail). How do I complete the TIRF REMS Access Education Program online? • Select the ‘Start the TIRF REMS Access Education Program’ to proceed to the training upon completion of registration • Select ‘Go To Knowledge Assessment’, complete the Knowledge Assessment, and select ‘Submit Assessment’ • A Knowledge Assessment Confirmation Code will be provided once the assessment is completed successfully Step 5: Complete and submit Chain Outpatient Pharmacy Enrollment • • • To finalize enrollment in the TIRF REMS Access program complete Chain Outpatient Pharmacy Enrollment. If you are unable to enroll online, please call the TIRF REMS Access program call center at 1-866-822-1483 for further assistance. How do I complete the TIRF REMS Access Enrollment on-line? Upon successful completion of the TIRF REMS Access Education Program and Knowledge Assessment, you will be prompted to read the TIRF REMS Access attestation and enter your electronic signature, today’s date, and check the attestation box before clicking ‘Submit’. NOTE: You are required to re-enroll every two (2) years. You will be notified by the TIRF REMS Access program in advance of the need to re-enroll. Step 6: Confirm the Pharmacy Management communication with the TIRF REMS Access system • • System supports A chain outpatient pharmacy is required to complete test transactions one time on behalf of all their stores. Following completion of steps 1-5 above, you will receive instruction on how to submit test transactions to the TIRF REMS Access program. Successful submission of the test transaction confirms the pharmacy management system supports communication with the TIRF REMS Access system. After successful completion of the test transactions you will receive enrollment confirmation. Reference ID: 4146711 FDA_7337 Step 7: Train Pharmacy Staff • • • Ensure that all chain outpatient pharmacy staff involved in the processing and dispensing of TIRF medicines have been trained to only dispense TIRF medicines in accordance with the TIRF REMS Access program requirements. o Pharmacy staff can register online to access the Education Program and take the Knowledge Assessment for training purposes. Ensure that this training is documented and retained by the chain outpatient pharmacy in accordance to the chains’ internal processes. This documentation should include the pharmacist/pharmacy staff member’s name, the date training was completed and the method of training, as a minimum. The list of pharmacy sites that have been trained should be updated by the Authorized Chain Outpatient Pharmacy Representative on the Chain Outpatient Pharmacy Dashboard where all chain stores are listed at www.TIRFREMSaccess.com. This list should include the required Pharmacy Information for each pharmacy site. Section 2: Dispensing Process Summary of Dispensing Process 1. Confirm pharmacy staff is trained. 2. Confirm patient and prescriber enrollment in TIRF REMS Access Program. 3. Dispense TIRF medication. 4. Counsel patient and provide medication guide. Detailed Dispensing Process Step 1: Confirm that the Pharmacy staff is trained • Ensure all pharmacy staff involved in the processing and dispensing of TIRF medicines have been trained to specifically dispense TIRF medicines in accordance with the TIRF REMS Access program requirements available at www.TIRFREMSaccess.com. (see Section 1, Step 7: Train pharmacy staff). Step 2: Confirm prescriber and patient enrollment • Each pharmacy site must confirm that the prescriber and patient are enrolled in the TIRF REMS Access program prior to dispensing each TIRF prescription by submitting a pharmacy billing claim via the chain outpatient pharmacy practice management system. This includes third party insurance claims, cash claims and any other claims (i.e.: workers compensation). Submitting a claim for a patient’s first TIRF prescription through the pharmacy management system will automatically enroll that patient in the TIRF REMS Access program. Reference ID: 4146711 FDA_7338 • To allow the TIRF REMS Access program to confirm prescriber and patient enrollment the chain outpatient pharmacy practice management system must populate the following fields in the pharmacy billing claim*: o Patient First Name, o Patient Last Name, o Patient Date of Birth, o Patient ZIP / Postal Zone, o Quantity Dispensed, o Days Supply, o Prescriber ID, o Prescriber Last Name *Use BIN 014780 for all cash and non-third party claims. • If the prescriber or patient enrollment is not confirmed, or if any other rejection message is received that prevents the prescription from being filled, contact the TIRF REMS Access call center at 1-866-822-1483 for further instruction. Step 3: Dispense TIRF Medication • Receive approval from the TIRF REMS Access program and then prepare, label and dispense the medication. Step 4: Counsel Patient and Provide Medication Guide • • Advise the patient on how to take, store and dispose of TIRF medicines appropriately. Provide a copy of the product specific Medication Guide to the patient with each prescription. Reporting Adverse Events and Monitoring To report any adverse events including the misuse, abuse, addiction, or overdose of TIRF medication contact: • • TIRF REMS Access program at 1-866-822-1483 and/or FDA MedWatch program by phone at 1-800-FDA-1088 or online at www.fda.gov/medwatch/report.htm If you have any questions, need additional information, or need additional copies of any TIRF REMS Access documents, please visit www.TIRFREMSaccess.com, or call the TIRF REMS Access program at 1866-822-1483. Reference ID: 4146711 FDA_7339 The Transmucosal Immediate Release Fentanyl (TIRF) REMS Access Program An Overview for Closed System Outpatient Pharmacies To dispense TIRF medicines, your Closed System Outpatient Pharmacy must enroll in the TIRF REMS Access program. What is the TIRF REMS Access program? The TIRF REMS (Risk Evaluation and Mitigation Strategy) Access program is designed to ensure informed risk-benefit decisions before initiating treatment, while patients are on treatment, and to ensure appropriate use of TIRF medicines. TIRF medicines are available only through a required Food and Drug Administration (FDA) restricted distribution program, because of the risk for misuse, abuse, addiction, overdose, and serious complications due to medication errors. A list of TIRF medicines available through the TIRF REMS Access program is located on the TIRF Products web page at www.TIRFREMSaccess.com/TirfUI/rems/products.action. How does the TIRF REMS Access program work? The TIRF REMS Access program requires pharmacies, prescribers, patients and wholesalers to enroll in the program in order to utilize TIRF medications. The supply of TIRF medicines to pharmacies is controlled by enrolled distributors, who will verify the current enrollment status of the pharmacy prior to shipment of TIRF medicines. Pharmacies are required to verify the prescriber and the patient are enrolled in the TIRF REMS Access program before dispensing any TIRF medication. Does your institution qualify as a Closed System Outpatient Pharmacy? For the purposes of this REMS, a closed system outpatient pharmacy is defined as an outpatient pharmacy that uses a pharmacy management system that does not support the process of electronically transmitting the validation and claim information currently required by the TIRF REMS Access program. For example, some pharmacies that are part of integrated healthcare delivery systems may qualify as closed system outpatient pharmacies. NOTE: There are different requirements for outpatient pharmacies that support the process of electronically transmitting claim information, and for inpatient pharmacies that only dispense for inpatient use. Please refer to “An Overview for Chain Outpatient Pharmacies”, “An Overview for Independent Outpatient Pharmacies” or “An Overview for Inpatient Pharmacies” for more information. If you do not qualify as a closed system outpatient pharmacy, please refer to the requirements for the other type of pharmacies. The following two sections provide detailed information on the Enrollment Process (Section 1) and the Dispensing Processes (Section 2) for TIRF medicines in a closed system outpatient pharmacy. Reference ID: 4146711 FDA_7340 Section 1: Enrollment Process Summary of Enrollment Process 1. Confirm that your facility qualifies as a closed system outpatient pharmacy. 2. Select an individual to be your Authorized Closed System Outpatient Pharmacy Representative. 3. Complete the TIRF REMS Access Education Program and Knowledge Assessment. 4. Complete and submit a Closed System Outpatient Pharmacy Enrollment Form. 5. Train pharmacy staff. Detailed Enrollment Process Step 1: Confirm your facility qualifies as a Closed System Outpatient Pharmacy • • Notify the TIRF REMS Access program by phone at 1-866-822-1483 or by email to information@TIRFREMSaccess.com that you are a closed system outpatient pharmacy. When your pharmacy is validated as a closed system outpatient pharmacy, a Closed System Outpatient Pharmacy Enrollment Form will be provided. Step 2: Select an individual to be your Authorized Closed System Outpatient Pharmacy Representative • Select an authorized closed system outpatient pharmacy representative to establish and oversee the TIRF REMS Access program requirements. Step 3: Complete the TIRF REMS Access Education Program • • • • • • • • • Review the TIRF REMS Access Education Program and successfully complete the Knowledge Assessment. The TIRF REMS Access Education Program is available online at the TIRF REMS Access program website www.TIRFREMSaccess.com or by contacting the TIRF REMS Access call center at 1-866-822-1483. If Knowledge Assessment was completed on paper, Fax to 1-855-474-3062 or email the Knowledge Assessment to information@TIRFREMSaccess.com with enrollment form (see Step 4: Complete and submit enrollment form). How do I complete the TIRF REMS Access Education Program online? Select the Create Account button on the home page Complete the Create Account Information section ‘Already enrolled via Fax and have an enrollment ID?’ - Select No Create User ID and password and select the Create my Account button Select ‘Pharmacy’ as the option to best describe you and select ‘Continue’ In response to Question 2, select ‘Pharmacy Staff’ Review the content in the pop-up box and select ‘Confirm’ to continue Reference ID: 4146711 FDA_7341 • • • • • Complete required fields in Pharmacy Staff details Select ‘Other’ from the dropdown list in the Chain Pharmacy name and populate the name of your closed system outpatient pharmacy organization in the ‘Other’ field and submit form Select the ‘Start the TIRF REMS Access Education Program’ to proceed to the training Once you have completed the Education Program, select the ‘Go To Knowledge Assessment’ button and complete A Knowledge Assessment Confirmation Code will be provided once the assessment is completed successfully Step 4: Complete and Submit Enrollment Form • • • Complete and return the Closed System Outpatient Pharmacy Enrollment Form by fax to 1-855-474-3062. The authorized closed system outpatient pharmacy representative will receive an Enrollment Confirmation letter and instructions for enrolling dispensing locations within the closed system outpatient pharmacy by using a standard file template provided by the TIRF REMS Access program. If you did not complete the Education Program online then you need to submit the Knowledge Assessment form with the Enrollment form. Re-enroll every two (2) years. You will be notified by the TIRF REMS Access program in advance of the need to re-enroll. Step 5: Train Pharmacy Staff • • All closed system outpatient pharmacy staff involved in processing and dispensing of TIRF medications must be trained to dispense TIRF medicines in accordance with the TIRF REMS Access Education Program requirements available at www.TIRFREMSaccess.com. Ensure that this training is documented and retained by the closed system outpatient pharmacy. This documentation should include the pharmacist/pharmacy staff member’s name, the date training was completed and the method of training as a minimum. Reference ID: 4146711 FDA_7342 Section 2: Dispensing Process Summary of Dispensing Process 1. 2. 3. 4. Confirm pharmacy staff is trained. Confirm patient and prescriber enrollment in TIRF REMS Access Program. Dispense TIRF medication. Counsel patient and provide medication guide. Detailed Dispensing Process Step 1: Confirm that the Pharmacy staff is trained • Ensure all pharmacy staff involved in the processing and dispensing of TIRF medicines have been trained to specifically dispense TIRF medicines in accordance with the TIRF REMS Access program requirements available at www.TIRFREMSaccess.com. (see Section 1, Step 5: Train pharmacy staff). Step 2: Confirm prescriber and patient enrollment: Prior to dispensing each TIRF medicine prescription, confirm that the prescriber and patient are enrolled in the TIRF REMS Access program by contacting the TIRF REMS Access program by phone at 1-866-822-1483 or fax at 1-855-474-3062. This includes third party insurance claims, cash claims and any other claims (i.e., workers compensation). • To confirm enrollment confirmation by phone: o o Contact the TIRF REMS Access program at 1-866-822-1483 and select option #2. Provide the following required data from the TIRF prescription to obtain an authorization to dispense: Dispensing Pharmacy DEA Dispensing Pharmacy NPI Dispensing Pharmacy Phone # Dispensing Pharmacy Fax # Prescriber DEA or NPI ▪ ▪ • Patient Date of Birth Patient First Name Patient Last Name Patient Zip Code Prescriber Last Name Rx Date of Service Rx Number Rx NDC Days Supply Quantity for Dispense If validated, you will be supplied a prescription authorization number which indicates you can dispense TIRF medicine. If not validated, you will be provided a rejection reason and information regarding how to resolve the rejection. To confirm enrollment confirmation by fax: o Reference ID: 4146711 Populate all of the required fields on the TIRF REMS Access Prescription Authorization Form and fax to 1-855-474-3062. To obtain a TIRF REMS Access Prescription Authorization Form which may be reproduced to use continually, please email information@TIRFREMSaccess.com. FDA_7343 ▪ ▪ If validated, you will be supplied a prescription authorization number via fax within one (1) business day which indicates you can dispense the TIRF medicine. If not validated, you will be provided a rejection reason and information regarding how to resolve the rejection using the phone number provided on the request. Step 3: Dispensing • Receive the prescription authorization number from the TIRF REMS Access program and then prepare, label and dispense the medication. Step 4: Counsel patient and provide Medication Guide • • Counsel the patient on the appropriate use, safe storage, and the proper disposal procedures of TIRF medicines. Provide a copy of the product specific Medication Guide to the patient with each prescription. Reporting Adverse Events and Monitoring To report any adverse events including the misuse, abuse, addiction, or overdose of TIRF medication contact: • • TIRF REMS Access program at 1-866-822-1483 and/or FDA MedWatch program by phone at 1-800-FDA-1088 or online at www.fda.gov/medwatch/report.htm If you have any questions, need additional information, or need additional copies of any TIRF REMS Access documents, please visit www.TIRFREMSaccess.com, or call the TIRF REMS Access program at 1-866822-1483. Reference ID: 4146711 FDA_7344 The Transmucosal Immediate Release Fentanyl (TIRF) REMS Access Program An Overview for Inpatient Pharmacies (e.g. hospitals, in-hospital hospices, and long-term care facilities that dispense for inpatient use). To dispense TIRF medicines, your Inpatient Pharmacy must enroll in the TIRF REMS Access program. What is the TIRF REMS Access Program? The TIRF REMS (Risk Evaluation and Mitigation Strategy) Access program is designed to ensure informed risk-benefit decisions before initiating treatment and, while patients are on treatment, to ensure appropriate use of TIRF medicines. TIRF medicines are available only through a restricted distribution program required by the Food and Drug Administration (FDA), because of the risk for misuse, abuse, addiction, overdose, and serious complications due to medication errors. A list of TIRF medicines available through the TIRF REMS Access program is located on the TIRF Products web page at www.TIRFREMSaccess.com/TirfUI/rems/products.action. How does the TIRF REMS Access program work? The TIRF REMS Access program requires pharmacies, prescribers, patients and wholesalers to enroll in the program in order to utilize TIRF medications. The supply of TIRF medicines to pharmacies is controlled by enrolled distributors, who will verify the current enrollment status of the pharmacy prior to shipment of TIRF medicines. Pharmacies are required to verify the prescriber and the patient are enrolled in the TIRF REMS Access program before dispensing any TIRF medication. Does your pharmacy qualify as an Inpatient Pharmacy? For the purposes of this REMS, an inpatient pharmacy is defined as a pharmacy where the patient’s care is coordinated on-site at a care facility and the pharmacy claims are submitted as a medical benefit. Important Information about Outpatient Pharmacies within the Facility Outpatient pharmacies, within or associated with the healthcare facility, that provide dispensing services to outpatients must be separately enrolled in the TIRF REMS Access program and comply with the TIRF REMS Access program to dispense TIRF medicines to outpatients. Please refer to “An Overview for Outpatient Pharmacies” for more information. Additionally, any prescribers who prescribe TIRF medicines to outpatients must also be enrolled in the TIRF REMS Access program. Overview of the TIRF REMS Access Program for Inpatient Pharmacies: Steps for Enrollment and Program Requirements Inpatient Pharmacy Education and Enrollment All enrollment activities can be completed at www.TIRFREMSaccess.com Reference ID: 4146711 FDA_7345 If I have previously enrolled in an individual TIRF REMS do I need to enroll in the shared TIRF REMS Access Program? All pharmacy enrollment information was transferred from the individual TIRF REMS to the TIRF REMS Access program on March 12, 2012. Your enrollment in the shared TIRF REMS Access program allows dispensing of all TIRF medicines that are covered under the TIRF REMS Access program. The website for the shared TIRF REMS Access program can be accessed at www.TIRFREMSaccess.com. You will be required to re-enroll in the shared TIRF REMS two (2) years after your last enrollment in an individual REMS program if you wish to continue dispensing these products. You will be notified by the TIRF REMS Access program in advance of the need to re-enroll. The following two sections provide detailed information on the Enrollment Process (Section 1) and the Implementation Processes (Section 2) for TIRF medicines in an inpatient pharmacy. Section 1: Enrollment Process Summary of Enrollment 1. Select an individual to be your Authorized Inpatient Pharmacy Representative. 2. Create an account and complete registration at www.TIRFREMSaccess.com. 3. Complete the TIRF REMS Access Education Program and Knowledge Assessment. 4. Complete and submit an Inpatient Pharmacy Enrollment form. 5. Train pharmacy staff. Detailed Enrollment Process Step 1: Select an individual to be your Authorized Chain Representative • Select an authorized pharmacy representative to establish and oversee the TIRF REMS Access program requirements. Step 2: Create an account www.TIRFREMSaccess.com • and complete Create an account at www.TIRFREMSaccess.com registration on behalf of your pharmacy. registration and then at complete How do I create an account and complete the TIRF REMS Access registration on-line? • Select the Create Account button on the home page • Complete the Create Account Information section • Select ‘No’ if you have not submitted an enrollment form via fax at the ‘Already enrolled via Fax and have an enrollment ID?’ prompt. • Create User ID and password and select ‘Create My Account’ Reference ID: 4146711 FDA_7346 • • • • Select ‘Pharmacy’ as the option to best describe you and select ‘Continue’ Select ‘Inpatient Pharmacy – Authorized Pharmacy Representative’ Review the content in the pop-up box and select ‘Confirm’ to continue Complete required fields on the Inpatient Pharmacy Registration page and select ‘Submit’ to continue Step 3: Complete the TIRF REMS Access Education Program and Knowledge Assessment How do I complete the TIRF REMS Access Education Program by fax? • Review the TIRF REMS Access Education Program. A printable version of the TIRF REMS Access Education Program is available online at www.TIRFREMSaccess.com or by contacting the TIRF REMS Access call center at 1-866-822-1483. • Once you have reviewed the Education Program complete the Knowledge Assessment and submit by fax to 1-866-822-1487 • The TIRF REMS Access program will notify you of the status of your Knowledge Assessment via your indicated preferred method of communication (fax or e-mail) How do I complete the TIRF REMS Access Education Program online? • Select the ‘Start the TIRF REMS Access Education Program’ to proceed to the training upon completion of registration • Select ‘Go To Knowledge Assessment’ button and complete upon completion of the Education Program • A Knowledge Assessment Confirmation Code will be provided once the assessment is completed successfully. Step 4: Complete and submit Inpatient Pharmacy Enrollment • • • To finalize enrollment in the TIRF REMS Access program complete Inpatient Pharmacy Enrollment If you are unable to enroll online, please call the TIRF REMS Access program call center at 1-866-822-1483 for further assistance. How do I complete the TIRF REMS Access Enrollment on-line? Upon successful completion of the TIRF REMS Access Education Program and Knowledge Assessment, you will be prompted to read the TIRF REMS Access attestation and enter your electronic signature, today’s date, and check the attestation box before clicking ‘Submit’. NOTE: You are required to re-enroll every two (2) years. You will be notified by the TIRF REMS Access program in advance of the need to re-enroll. Reference ID: 4146711 FDA_7347 Section 2: Implementation Process Summary of Implementation Process 1. Ensure appropriate patient selection and compliance with TIRF REMS Access program requirements 2. Train Pharmacy Staff Detailed Implementation Process Step 1: Ensure appropriate patient selection and compliance with TIRF REMS Access program requirements • • • The authorized inpatient pharmacist must establish or oversee the system, order sets, protocols, and/or other measures to help ensure appropriate patient selection and compliance with the requirements of the TIRF REMS Access program. The authorized inpatient pharmacist must ensure the inpatient pharmacy does not sell, loan or transfer any TIRF medicines to any other pharmacy, institution, distributor, or prescriber. Inpatient pharmacies may not dispense TIRF medicines for outpatient use. Step 2: Train Pharmacy Staff • The authorized inpatient pharmacist must ensure that inpatient pharmacists and other relevant inpatient staff are educated on the risks associated with TIRF medicines and the requirements of the TIRF REMS Access program, as described in the Education Program. o Pharmacy staff can register online to access the Education Program and take the Knowledge Assessment for training purposes. Reporting Adverse Events and Monitoring To report any adverse events including the misuse, abuse, addiction, or overdose of TIRF medication contact: • • TIRF REMS Access program at 1-866-822-1483 and/or FDA MedWatch program by phone at 1-800-FDA-1088 or online at www.fda.gov/medwatch/report.htm If you have any questions, need additional information, or need additional copies of any TIRF REMS Access documents, please visit www.TIRFREMSaccess.com, or call the TIRF REMS Access program at 1-866822-1483. Reference ID: 4146711 FDA_7348 The Transmucosal Immediate Release Fentanyl (TIRF) REMS Access Program Independent Outpatient Pharmacy Enrollment Form For real-time processing of enrollment, please go to www.TIRFREMSaccess.com. To submit this form via fax, please complete all required fields below and fax pages 1, 2, 3 and 4 to 1-866-822-1487. Please note, you must review the TIRF REMS Access Education Program and successfully complete the Knowledge Assessment to complete enrollment. If you have not completed the Knowledge Assessment online, please include it with this enrollment form. You will receive enrollment confirmation via email or fax. I understand that TIRF medicines are only available through the TIRF REMS (Risk Evaluation and Mitigation Strategy) Access program and that I must comply with the program requirements. In addition, as the designated authorized independent outpatient pharmacy representative, I acknowledge that: 1. I have reviewed the TIRF REMS Access Education Program, and I have completed the Knowledge Assessment. I understand the risks and benefits associated with TIRF medicines and the requirements of the TIRF REMS Access program for pharmacies. 2. I will ensure that all pharmacy staff who participate in dispensing TIRF medicines are educated on the risks associated with TIRF medicines and the requirements of the TIRF REMS Access program, as described in the TIRF REMS Access Education Program. This training should be documented and is subject to audit. 3. I understand that converting patients from one TIRF medicine to a different TIRF medicine must not be done on a microgram-per-microgram basis. I understand that TIRF medicines are not interchangeable with each other, regardless of route of administration, and that conversion may result in fatal overdose, unless conversion is done in accordance with labeled product-specific conversion recommendations (refer to the list of currently approved TIRF products located on the TIRF REMS Access website at www.TIRFREMSaccess.com/TirfUI/rems/products.action). Note, a branded TIRF medicine and its specific generic product(s) are interchangeable. 4. I understand that TIRF medicines are contraindicated for use in opioid non-tolerant patients. 5. I understand that the initial starting dose for TIRF medicines for all patients is the lowest dose, unless individual product labels provide product-specific conversion recommendations, and I understand that patients must be titrated individually. 6. I understand the importance of discussing the risks and benefits of TIRF medicines with patients and their caregivers, and in particular the importance of taking the drug as prescribed, not sharing with others, and proper disposal. 7. I understand that the product-specific Medication Guide must be given to the patient or their caregiver each time a TIRF medicine is dispensed. 8. I understand that a TIRF medicine will not be dispensed without verifying through our pharmacy management system that the prescriber and pharmacy are enrolled and active, and that the patient has not been inactivated in the program. 9. I understand that ALL TIRF medicine prescriptions, regardless of the method of payment, must be processed through our pharmacy management system. 10. I understand that all dispensing locations must be enrolled in the TIRF REMS Access program to dispense TIRF medicines. 11. I understand that TIRF medicines can only be obtained from wholesalers/distributors that are enrolled in the TIRF REMS Access program. Pharmacist Name* (please print):__________________________ Reference ID: 4146711 FDA_7349 12. I understand that our pharmacy will not sell, loan or transfer any TIRF medicine inventory to any other pharmacy, institution, distributor, or prescriber. 13. I understand that our pharmacy must re-enroll in the TIRF REMS Access program and successfully complete the enrollment requirements every two (2) years. 14. I understand that TIRF medicines are only available through the REMS program. I understand that the pharmacy must comply with the TIRF REMS Access program requirements for outpatient pharmacies and the terms of the agreement that follow this form. 15. I understand that differences in pharmacy software may affect automation capabilities for adjudicating prescriptions through the TIRF REMS Access program without an insurance claim (i.e.: cash claim). If insurance is not used, pharmacy staff must manually enter the REMS Cash BIN #014780 in order for the transaction to be properly adjudicated through the TIRF REMS Access program. Please note: If you are a chain outpatient pharmacy, please complete the Chain Outpatient Pharmacy Enrollment Form which can be found on www.TIRFREMSaccess.com or call the TIRF REMS Access program at 1-866-822-1483. Authorized Independent Outpatient Pharmacy Representative: Authorized Pharmacist Signature* _____________________________________ Date _____________ First Name* _____________________________ Last Name* ___________________ Title __________ Phone Number* __________________________ Email* ________________________________________ Independent Outpatient Pharmacy Information: Pharmacy Name* _________________________ DEA Number* ____________________________ Address* _______________________________ National Provider Identifier (NPI)* ___________ City* ___________________________________ Medicaid ID _____________________________ State* _____________ ZIP* _______________ State Issued _____________________________ Phone Number* ___________________________ NCPDP Number* _________________________ Fax Number* _____________________________ *Required Fields Preferred Method of Communication (please select one):  Fax  Email After submitting this form, you will receive a fax or email with instructions on how to submit test transaction(s) to the TIRF REMS Access program to ensure that your pharmacy management system has been successfully configured to allow for communication with the TIRF REMS Access program. After successful completion of the test transaction(s) you will receive enrollment confirmation via fax or email. For additional Medicaid IDs that you may use when dispensing TIRF medicines, please complete below: Medicaid ID State Issued Medicaid ID State Issued Medicaid ID State Issued Pharmacist Name* (please print):__________________________ Reference ID: 4146711 FDA_7350 If you have any questions or require additional information or further copies of any TIRF REMS Access documents, please visit either www.TIRFREMSaccess.com, or call the TIRF REMS Access program at 1-866-822-1483. The TIRF REMS Access Program Additional Terms and Conditions Pharmacy (“Pharmacy”) agrees to the following requirements, with respect to the Transmucosal Immediate Release Fentanyl (TIRF) REMS program (the “Program”), sponsored by the Transmucosal REMS Industry Group (hereinafter “TRIG” or “Program Sponsor”) and supported, under the direction of TRIG by McKesson Specialty Arizona Inc and its affiliates including NDCHealth Corporation d/b/a RelayHealth (“RelayHealth”) and McKesson Canada, and any other pharmacy transaction switch system (collectively, ”the Providers”). Pharmacy represents that (i) it shall perform its obligations under these terms and conditions in compliance with all applicable laws and regulations, (ii) Pharmacy’s participation in the Program does not conflict with its obligations under any contracts or other arrangements with any third party, and (iii) Pharmacy is authorized to submit patient information to the Providers for purposes of verifying and tracking each patient’s eligibility to participate in the Program and Pharmacy authorizes Providers and Program Sponsor and their respective designees and agents to use the submitted information for such purposes. Pharmacy agrees to the following Program Requirements: (a) If applicable, enable Pharmacy’s pharmacy practice management system to support the Program, including submission of required data fields and display of Program messages; (b) Respond appropriately to Program messages and alerts in order to comply with Program requirements, including contacting the call center when an exception process occurs; (c) Report all Program Drug dispensing activity for all transmucosal immediate release fentanyl Program Drug NDC #’s. This includes any future drug deemed by FDA to be included in the TIRF REMS Access Program to Providers via submission of all billing and reversal request. Please reference the following link (www.TIRFREMSaccess.com/TirfUI/rems/pdf/NDC listing.pdf) for a detailed list of products (including their NDC numbers) available through the TIRF REMS Access program. This document is available on the Resources tab (for pharmacies and distributors) on the program website at www.TIRFREMSaccess.com. Pharmacy acknowledges that billing request for the Program Drug will not pass to the payer, or cash prescription processor, if the prescriber, pharmacy or patient registration is not verified. Pharmacy authorizes and directs the Providers to de-identify, in accordance with the Health Insurance Portability and Accountability Act of 1996, as amended, its historical and prospective prescriptions claims data submitted to the Providers and/or their affiliates in connection with or related to the Program on behalf of Pharmacy, and to use that de-identified data for purposes of (i) analyzing, identifying, designing and/or enabling a REMS service; (ii) developing communication documentation for such services for both Program Sponsors and Pharmacy; (iii) providing the Program Sponsors with reports and information (including any fees paid, which will be aggregated), for purposes of implementing, maintaining, supporting, monitoring or improving a Program, and (iv) any other purpose required by law. These reports may contain information aggregated by NCPDP number. Further, Pharmacy authorizes Providers to deliver all of the above enumerated data and reports otherwise to be delivered to Program Sponsor to the designee or agent of Program Sponsor. In addition, Pharmacy authorizes Program Sponsor and its contracting Providers, to receive from wholesaler(s) of the Program Drug(s) distribution and purchasing data, including 867 data, with respect to the Program Drug(s). Pharmacy acknowledges that the FDA or Program Sponsor may mandate modification, suspension or termination of a Program. The Providers reserve the right to modify, suspend or terminate any REMS service for any reason, without liability to Switch Systems. Pharmacist Name* (please print):__________________________ Reference ID: 4146711 FDA_7351 EXCEPT FOR PROVIDER’S FRAUD OR INTENTIONAL MISCONDUCT ARISING OUT OF THE SERVICES OR THE PROGRAM, IN NO EVENT WILL THE PROGRAM SPONSOR OR PROVIDER BE LIABLE TO PHARMACY UNDER, IN CONNECTION WITH, OR RELATED TO THE PROGRAM OR THE SERVICES FOR ANY DIRECT, SPECIAL, INCIDENTAL, INDIRECT, OR CONSEQUENTIAL DAMAGES, INCLUDING, BUT NOT LIMITED TO, LOST PROFITS OR LOSS OF GOODWILL, WHETHER BASED ON BREACH OF CONTRACT, WARRANTY, TORT, PRODUCT LIABILITY, OR OTHERWISE, AND WHETHER OR NOT PROVIDERS OR PROGRAM SPONSOR HAS BEEN ADVISED OF THE POSSIBILITY OF SUCH DAMAGE. To the extent any of these terms and conditions conflict with any other written agreement between the parties with respect to the Program, the terms and conditions of such other written agreement shall prevail. Pharmacist Name* (please print):__________________________ Reference ID: 4146711 FDA_7352 The Transmucosal Immediate Release Fentanyl (TIRF) REMS Access Program Chain Outpatient Pharmacy Enrollment Form For real-time processing of enrollment, please go to www.TIRFREMSaccess.com. To submit this form via fax, please complete all required fields below and fax pages 1, 2, 3, 4 and 5 to 1-866-822-1487. Please note, you must review the TIRF REMS Access Education Program and successfully complete the Knowledge Assessment to complete enrollment. If you have not completed the Knowledge Assessment online, please include it with this enrollment form. You will receive enrollment confirmation via email or fax. I understand that TIRF medicines are only available through the TIRF REMS (Risk Evaluation and Mitigation Strategy) Access program and that I must comply with the program requirements. In addition, as the designated authorized chain outpatient pharmacy representative, I acknowledge that: 1. 2. 3. 4. 5. I have reviewed the TIRF REMS Access Education Program, and I have completed the Knowledge Assessment. I understand the risks and benefits associated with TIRF medicines and the requirements of the TIRF REMS Access program for pharmacies. I will ensure that all pharmacy staff who participate in dispensing TIRF medicines are educated on the risks associated with TIRF medicines and the requirements of the TIRF REMS Access program, as described in the Education Program. This training should be documented and is subject to audit. I understand that converting patients from one TIRF medicine to a different TIRF medicine must not be done on a microgram-per-microgram basis. I understand that TIRF medicines are not interchangeable with each other, regardless of route of administration, and that conversion may result in fatal overdose, unless conversion is done in accordance with labeled product-specific conversion recommendations (refer to the list of currently approved TIRF products located on the TIRF REMS Access website at www.TIRFREMSaccess.com/TirfUI/rems/products.action). Note, a branded TIRF medicine and its specific generic product(s) are interchangeable. I understand that TIRF medicines are contraindicated for use in opioid non-tolerant patients. I understand that the initial starting dose for TIRF medicines for all patients is the lowest dose, unless individual product labels provide product-specific conversion recommendations, and I understand that patients must be titrated individually. 6. I understand the importance of discussing the risks and benefits of TIRF medicines with patients and their caregivers, and in particular the importance of taking the drug as prescribed, not sharing with others, and proper disposal. 7. I understand that the product-specific Medication Guide must be given to the patient or their caregiver each time a TIRF medicine is dispensed. 8. I understand that a TIRF medicine will not be dispensed without verifying through our pharmacy management system that the prescriber and pharmacy are enrolled and active, and that the patient has not been inactivated in the program. 9. I understand that ALL TIRF medicine prescriptions, regardless of the method of payment, must be processed through our pharmacy management system. 10. I understand that all dispensing locations must be enrolled in the TIRF REMS Access program to dispense TIRF medicines. 11. I understand that TIRF medicines can only be obtained from wholesalers/distributors that are enrolled in the TIRF REMS Access program. 12. I understand that our pharmacy will not sell, loan or transfer TIRF medicine inventory to any other pharmacy, institution, distributor, or prescriber. Chain ID*:________________________ Reference ID: 4146711 FDA_7353 13. I understand that our pharmacy must re-enroll in the TIRF REMS Access program and successfully complete the enrollment requirements every two (2) years. 14. I understand that TIRF medicines are only available through the REMS program. I understand that the pharmacy must comply with the TIRF REMS Access program requirements for outpatient pharmacies and the terms of the agreement that follow this form. 15. I understand that differences in pharmacy software may affect automation capabilities for adjudicating prescriptions through the TIRF REMS Access program without an insurance claim (i.e.: cash claim). If insurance is not used, pharmacy staff must manually enter the REMS Cash BIN #014780 or the designated chain pharmacy cash bin in order for the transaction to be properly adjudicated through the TIRF REMS Access program. Authorized Chain Outpatient Pharmacy Representative: Authorized Pharmacy Representative Signature* _________________________ Date _____________ First Name* _____________________________ Last Name* ___________________ Title ______ Phone Number* __________________________ Email* ____________________________________ Chain Outpatient Pharmacy Information: Pharmacy Name* _________________________ Chain ID* ________________________________ Address* _______________________________ Phone Number* __________________________ City* ___________________________________ Fax Number* _____________________________ State* _____________ ZIP* _______________ *Required Fields Preferred Method of Communication (please select one):  Fax  Email After submitting this form, you will receive a fax or email with instructions on how to submit test transaction(s) to the TIRF REMS Access program to ensure that your pharmacy management system has been successfully configured to allow for communication with the TIRF REMS Access program. After successful completion of the test transaction(s) you will receive enrollment confirmation via fax or email. Pharmacy sites that have been trained can then be updated to an enrolled status through the Chain Outpatient Pharmacy Dashboard which will list all chain stores at www.TIRFREMSaccess.com Chain ID*:________________________ Reference ID: 4146711 FDA_7354 The following pharmacy information will need to be provided for each trained pharmacy site. Pharmacy Information: Pharmacy Name* _________________________ DEA Number* ____________________________ Address* _______________________________ National Provider Identifier (NPI)* ___________ City* ___________________________________ Medicaid ID _____________________________ State* _____________ ZIP ________________ State Issued _____________________________ Phone Number* ___________________________ NCPDP Number* _________________________ Fax Number* _____________________________ Store Number* ___________________________ *Required Fields Chain ID*: If you have any questions or require additional information or further copies of any TIRF REMS Access documents, please visit either www.TIRFREMSaccess.com, or call the TIRF REMS Access program at 1-866-822-1483. Chain ID*:________________________ Reference ID: 4146711 FDA_7355 The TIRF REMS Access Program Additional Terms and Conditions Pharmacy (“Pharmacy”) agrees to the following requirements, with respect to the Transmucosal Immediate Release Fentanyl (TIRF) REMS program (the “Program”), sponsored by the Transmucosal REMS Industry Group (hereinafter “TRIG” or “Program Sponsor”) and supported, under the direction of TRIG by McKesson Specialty Arizona Inc and its affiliates including NDCHealth Corporation d/b/a RelayHealth (“RelayHealth”) and McKesson Canada, and any other pharmacy transaction switch system (collectively, “the Providers”). Pharmacy represents that (i) it shall perform its obligations under these terms and conditions in compliance with all applicable laws and regulations, (ii) Pharmacy’s participation in the Program does not conflict with its obligations under any contracts or other arrangements with any third party, and (iii) Pharmacy is authorized to submit patient information to the Providers for purposes of verifying and tracking each patient’s eligibility to participate in the Program and Pharmacy authorizes Providers and Program Sponsor and their respective designees and agents to use the submitted information for such purposes. Pharmacy agrees to the following Program Requirements: (a) If applicable, enable Pharmacy’s pharmacy practice management system to support the Program, including submission of required data fields and display of Program messages; (b) Respond appropriately to Program messages and alerts in order to comply with Program requirements, including contacting the call center when an exception process occurs; (c) Report all Program Drug dispensing activity for all transmucosal immediate release fentanyl Program Drug NDC #’s. This includes any future drug deemed by FDA to be included in the TIRF REMS Access Program to Providers via submission of all billing and reversal request. Please reference the following link (www.TIRFREMSaccess.com/TirfUI/rems/pdf/NDC listing.pdf) for a detailed list of products (including their NDC numbers) available through the TIRF REMS Access program. This document is available on the Resources tab (for pharmacies and distributors) on the program website at www.TIRFREMSaccess.com. Pharmacy acknowledges that billing request for the Program Drug will not pass to the payer, or cash prescription processor, if the prescriber, pharmacy or patient registration is not verified. Pharmacy authorizes and directs the Providers to de-identify, in accordance with the Health Insurance Portability and Accountability Act of 1996, as amended, its historical and prospective prescriptions claims data submitted to the Providers and/or their affiliates in connection with or related to the Program on behalf of Pharmacy, and to use that de-identified data for purposes of (i) analyzing, identifying, designing and/or enabling a REMS service; (ii) developing communication documentation for such services for both Program Sponsors and Pharmacy; (iii) providing the Program Sponsors with reports and information (including any fees paid, which will be aggregated), for purposes of implementing, maintaining, supporting, monitoring or improving a Program, and (iv) any other purpose required by law. These reports may contain information aggregated by NCPDP number. Further, Pharmacy authorizes Providers to deliver all of the above enumerated data and reports otherwise to be delivered to Program Sponsor to the designee or agent of Program Sponsor. In addition, Pharmacy authorizes Program Sponsor and its contracting Providers, to receive from wholesaler(s) of the Program Drug(s) distribution and purchasing data, including 867 data, with respect to the Program Drug(s). Pharmacy acknowledges that the FDA or Program Sponsor may mandate modification, suspension or termination of a Program. The Providers reserve the right to modify, suspend or terminate any REMS service for any reason, without liability to Switch Systems. Chain ID*:________________________ Reference ID: 4146711 FDA_7356 EXCEPT FOR PROVIDER’S FRAUD OR INTENTIONAL MISCONDUCT ARISING OUT OF THE SERVICES OR THE PROGRAM, IN NO EVENT WILL THE PROGRAM SPONSOR OR PROVIDER BE LIABLE TO PHARMACY UNDER, IN CONNECTION WITH, OR RELATED TO THE PROGRAM OR THE SERVICES FOR ANY DIRECT, SPECIAL, INCIDENTAL, INDIRECT, OR CONSEQUENTIAL DAMAGES, INCLUDING, BUT NOT LIMITED TO, LOST PROFITS OR LOSS OF GOODWILL, WHETHER BASED ON BREACH OF CONTRACT, WARRANTY, TORT, PRODUCT LIABILITY, OR OTHERWISE, AND WHETHER OR NOT PROVIDERS OR PROGRAM SPONSOR HAS BEEN ADVISED OF THE POSSIBILITY OF SUCH DAMAGE. To the extent any of these terms and conditions conflict with any other written agreement between the parties with respect to the Program, the terms and conditions of such other written agreement shall prevail. Chain ID*:________________________ Reference ID: 4146711 FDA_7357 The Transmucosal Immediate Release Fentanyl (TIRF) REMS Access Program Closed System Outpatient Pharmacy Enrollment Form To enroll in TIRF REMS Access, please complete all required fields below and fax pages 1 and 2 to 1-866-822-1487. You may also scan the completed form and email to: information@TIRFREMSAccess.com. Please note, you must review the TIRF REMS Access Education Program and successfully complete the Knowledge Assessment to complete enrollment. If you have not completed the Knowledge Assessment online, please include it with this enrollment form. You will receive enrollment confirmation via email or fax. I understand that TIRF medicines are only available through the TIRF REMS (Risk Evaluation and Mitigation Strategy) Access program and that I must comply with the program requirements. In addition, as the designated authorized closed system outpatient pharmacy representative, I acknowledge that: 1. 2. 3. 4. 5. I have reviewed the TIRF REMS Access Education Program, and I have completed the Knowledge Assessment. I understand the risks and benefits associated with TIRF medicines and the requirements of the TIRF REMS Access program for pharmacies. I will ensure that all pharmacy staff who participate in dispensing TIRF medicines are educated on the risks associated with TIRF medicines and the requirements of the TIRF REMS Access program, as described in the TIRF REMS Access Education Program. This training should be documented and is subject to audit. I understand that converting patients from one TIRF medicine to a different TIRF medicine must not be done on a microgram-per-microgram basis. I understand that TIRF medicines are not interchangeable with each other, regardless of route of administration, and that conversion may result in fatal overdose, unless conversion is done in accordance with labeled product-specific conversion recommendations (refer to the list of currently approved TIRF products located on the TIRF REMS Access website at www.TIRFREMSaccess.com/TirfUI/rems/products.action). Note, a branded TIRF medicine and its specific generic product(s) are interchangeable. I understand that TIRF medicines are contraindicated for use in opioid non-tolerant patients. I understand that the initial starting dose for TIRF medicines for all patients is the lowest dose, unless individual product labels provide product-specific conversion recommendations, and I understand that patients must be titrated individually. 6. I understand the importance of discussing the risks and benefits of TIRF medicines with patients and their caregivers, and in particular the importance of taking the drug as prescribed, not sharing with others, and proper disposal. 7. I understand that the product-specific Medication Guide must be given to the patient or their caregiver each time a TIRF medicine is dispensed. 8. I understand that a TIRF medicine will not be dispensed without obtaining a TIRF REMS Access prescription authorization number issued by the TIRF REMS Access program prior to dispensing the prescription. A TIRF REMS Access prescription authorization number verifies that the prescriber and pharmacy are enrolled and active, and that the patient has not been inactivated in the program. 9. I understand that all dispensing locations must be enrolled in the TIRF REMS Access program to dispense TIRF medicines. 10. I understand that TIRF medicines can only be obtained from wholesalers/distributors that are enrolled in the TIRF REMS Access program. 11. I understand that our pharmacy will not sell, loan or transfer TIRF medicine inventory to any other pharmacy, institution, distributor, or prescriber. 12. I understand that our pharmacy must re-enroll in the TIRF REMS Access program and successfully complete the enrollment requirements every two (2) years. Closed System Chain ID*: Reference ID: 4146711 FDA_7358 13. I understand that TIRF medicines are only available through the REMS program. I understand that the pharmacy must comply with the TIRF REMS Access program requirements for outpatient closed system pharmacies. Authorized Closed System Outpatient Pharmacy Representative: Authorized Pharmacy Representative Signature* _________________________ Date _____________ First Name* _____________________________ Last Name* ___________________ Title ______ Phone Number* __________________________ Email* ____________________________________ Closed System Outpatient Pharmacy Information: Pharmacy Name* _________________________ Closed System Chain ID* ___________________ Address* _______________________________ Phone Number* __________________________ City* ___________________________________ Fax Number* _____________________________ State* _____________ ZIP* _______________ *Required Fields Preferred Method of Communication (please select one):  Fax  Email After submitting this form, you will receive a fax or email with your enrollment confirmation and instructions on how your pharmacy staff can complete the training process and how your closed system outpatient pharmacy dispensing locations may obtain a TIRF REMS Access Prescription Authorization. If you have any questions or require additional information or further copies of any TIRF REMS Access documents, please visit either www.TIRFREMSaccess.com, or call the TIRF REMS Access program at 1-866-822-1483. Closed System Chain ID*:________________________ Reference ID: 4146711 FDA_7359 The Transmucosal Immediate Release Fentanyl (TIRF) REMS Access Program Inpatient Pharmacy Enrollment Form (e.g. hospitals, in-hospital hospices, and long-term care facilities that dispense for inpatient use) For real-time processing of enrollment, please go to www.TIRFREMSaccess.com. To submit this form via fax, please complete all required fields below and fax pages 1 and 2 to 1-866-822-1487. Please note, you must review the TIRF REMS Access Education Program and successfully complete the Knowledge Assessment to complete enrollment. If you have not completed the Knowledge Assessment online, please include it with this enrollment form. You will receive enrollment confirmation via email or fax. I understand that TIRF medicines are only available through the TIRF REMS (Risk Evaluation and Mitigation Strategy) Access program and that I must comply with the program requirements. In addition, as the designated authorized inpatient pharmacist, I acknowledge that: 1. I have reviewed the TIRF REMS Access Education Program, and I have completed the Knowledge Assessment. I understand the benefits and risks associated with TIRF medicines and the requirements of the TIRF REMS Access program for pharmacies. 2. I will ensure that our inpatient pharmacists are educated on the risks associated with TIRF medicines and the requirements of the TIRF REMS Access program, as described in the TIRF REMS Access Education Program. 3. I understand that converting patients from one TIRF medicine to a different TIRF medicine must not be done on a microgram-per-microgram basis. I understand that TIRF medicines are not interchangeable with each other, regardless of route of administration, and that conversion may result in fatal overdose, unless conversion is done in accordance with labeled product specific conversion recommendations (refer to the list of currently approved TIRF products located on the TIRF REMS Access website at www.TIRFREMSaccess.com/TirfUI/rems/products.action. Note, a branded TIRF medicine and its specific generic product(s) are interchangeable. 4. I understand that TIRF medicines are contraindicated for use in opioid non-tolerant patients. 5. I understand that the initial starting dose for TIRF medicines for all patients is the lowest dose, unless individual product labels provide product-specific conversion recommendations, and I understand that patients must be titrated individually. 6. I understand that pharmacies within or associated with the healthcare facility that dispense to outpatients must be separately enrolled in and comply with the TIRF REMS Access program to dispense TIRF medicines to outpatients. 7. I understand that our inpatient pharmacy must not dispense TIRF medicines for outpatient use. 8. I understand that a prescriber who wants to discharge a patient with a TIRF medicine prescription, intended to be dispensed by an outpatient pharmacy, will be required to enroll in the TIRF REMS Access program. 9. I will establish, or oversee the establishment of, a system, order sets, protocols and/or other measures to help ensure appropriate patient selection and compliance with the requirements of the TIRF REMS Access program. 10. I understand that our pharmacy will not sell, loan or transfer any TIRF medicine inventory to any other pharmacy, institution, distributor, or prescriber. 11. I understand that TIRF medicines can only be obtained from wholesalers/distributors that are enrolled in the TIRF REMS Access program. 12. I understand that our pharmacy must re-enroll in the TIRF REMS Access program every two (2) years. 13. I understand that TIRF medicines are available only through the TIRF REMS Access program. I understand and agree to comply with the TIRF REMS Access program requirements for inpatient pharmacies. Pharmacist Name* (please print): Reference ID: 4146711 FDA_7360 Authorized Inpatient Pharmacist Signature* _______________________________ Date ____________________________________ First Name* ______________________________ Last Name* _______________ Phone Number* __________________________ Email* ___________________________________ Title ________ *Required Fields Inpatient Pharmacy Information Pharmacy Name* _________________________ Address* ________________________________ City* ____________________________________ State* ______________ *Required Fields ZIP* ______________ DEA Number* ____________________________ Pharmacy License Number* ________________ Phone Number* ___________________________ Fax Number* _____________________________ Preferred Method of Communication (please select one):  Fax  Email If you have any questions or require additional information or further copies of any TIRF REMS Access documents, please visit either www.TIRFREMSaccess.com, or call the TIRF REMS Access program at 1-866-822-1483. Pharmacist Name* (please print):__________________________ Reference ID: 4146711 FDA_7361 This letter ceased distribution in November 2013. Subject: Important Drug Warning Announcement of a single shared REMS (Risk Evaluation and Mitigation Strategy) program for all Transmucosal Immediate Release Fentanyl (TIRF) products due to the potential risk of misuse, abuse, addiction, overdose and serious complications due to medication errors The TIRF REMS Access program is a Food and Drug Administration (FDA) required risk management program Dear Outpatient Pharmacy: The purpose of this letter is to make you aware of a change from individual REMS programs to a shared REMS program (the TIRF REMS Access program) and to provide guidance on enrollment into the new shared REMS program beginning mm/dd/yyyy. The individual REMS programs are being converted to the TIRF REMS Access program to reduce the burden on the healthcare providers and the healthcare system of having multiple individual programs. The products covered under this new program include: • • • • • • Abstral® (fentanyl) sublingual tablets Actiq® (fentanyl citrate) oral transmucosal lozenge Fentora® (fentanyl citrate) buccal tablet Lazanda® (fentanyl) nasal spray Onsolis® (fentanyl buccal soluble film) Approved generic equivalents of these products are also covered under this program This new shared program replaces the individual product REMS that were previously available, and any prescribers, pharmacies, patients and distributors enrolled in these programs will be automatically transitioned to the new shared REMS. Outpatient pharmacies from individual product REMS will be automatically transitioned to the new shared REMS, beginning mm/dd/yyyy, but will need to agree to shared program terms and conditions before they can order and dispense all TIRF medicines. If you have not enrolled in one or more of these individual REMS programs and, if any of these products are dispensed for outpatient use in your pharmacy, you must enroll your pharmacy in the shared TIRF REMS Access program. Outpatient Pharmacy Action: Option 1: If you are already enrolled in at least one individual REMS program • Your enrollment information will be automatically entered into the new shared TIRF REMS Access program, but you will need to agree to the shared program terms and conditions before you can order and dispense all TIRF medicines. Your enrollment in the shared TIRF REMS Access program allows dispensing of all TIRF medicines that are covered under the TIRF REMS Access program. The website for the shared TIRF REMS Access program can be accessed at www.TIRFREMSaccess.com. ▪ Once the program is available, you will have six months to agree to the shared program terms and conditions. Until you agree to the shared program terms and conditions, you will be able to dispense those TIRF medicines with an individual REMS program, in which you were previously enrolled. However, if you do not agree to the shared program terms and conditions within six months, you will no longer be able to order or dispense any TIRF medicine. • You can use your existing secure user ID and password from any one of your individual REMS programs to access the TIRF REMS Access website at www.TIRFREMSaccess.com. Reference ID: 4146711 FDA_7362 The user ID and password you use to initially log on will become your permanent user ID and password for the shared TIRF REMS Access program. Once you have logged in, review your account information and make any necessary updates. You are required to agree to the shared program terms and conditions to complete enrollment for the new shared program. You will be required to re-enroll in the shared TIRF REMS two (2) years after your last enrollment in an individual REMS program if you wish to continue dispensing these products. You will be notified by the TIRF REMS Access program in advance of the need to re-enroll. ▪ • • Option 2: If you do not have an existing enrollment in any individual REMS program • Select an authorized pharmacy representative to establish and oversee the TIRF REMS Access program requirements. • Access the TIRF REMS Access program at www.TIRFREMSaccess.com to create an account. • Review the TIRF REMS Access Education Program materials available at www.TIRFREMSaccess.com and successfully complete the Knowledge Assessment. • Enable the pharmacy management system to support communication with the TIRF REMS Access program, using established telecommunication standards, and run the standardized validation test transactions to validate the system enhancements. • Enroll in the TIRF REMS Access program by completing the Outpatient Pharmacy Enrollment Form and re-enroll every two (2) years. You will be notified by the TIRF REMS Access program in advance of the need to re-enroll. • If you are unable to enroll online, please call the TIRF REMS Access program call center at 1-866-822-1483 for further assistance. The goals of the TIRF REMS Access program are to mitigate the risk of misuse, abuse, addiction, overdose and serious complications due to medication errors by: 1. Prescribing and dispensing TIRF medicines only to appropriate patients, which includes use only in opioid-tolerant patients. 2. Preventing inappropriate conversion between fentanyl products. 3. Preventing accidental exposure to children and others for whom it was not prescribed. 4. Educating prescribers, pharmacists, and patients on the potential for misuse, abuse, addiction, and overdose of TIRF medicines TIRF medicines are opioid analgesics indicated only for the management of breakthrough pain in cancer patients 18 years of age and older (16 years of age and older for Actiq® brand and generic equivalents) who are already receiving and who are tolerant to around-the-clock opioid therapy for their underlying persistent pain. Patients considered opioid-tolerant are those who are regularly taking at least 60 mg oral morphine/day, or at least 25 micrograms transdermal fentanyl/hour, or at least 30 mg of oral oxycodone/day, or at least 8 mg oral hydromorphone/day, or at least 25 mg oral oxymorphone/day or an equianalgesic dose of another opioid for one week or longer. To help you understand the TIRF REMS Access program the following program materials are available at www.TIRFREMSaccess.com or can be ordered by calling 1-866-822-1483: • Overview for Outpatient Pharmacies • TIRF REMS Access Education Program • Knowledge Assessment • Frequently Asked Questions Reference ID: 4146711 FDA_7363 • • Outpatient Pharmacy Enrollment Form Full Prescribing Information and Medication Guides for each TIRF medicine Inpatient pharmacies have different REMS requirements. Please see the TIRF REMS Access program - An Overview for Inpatient Pharmacies available at www.TIRFREMSaccess.com. To access the above information and to enroll in the TIRF REMS Access program, visit www.TIRFREMSaccess.com or call 1-866-822-1483 to have enrollment materials sent to you. Reference ID: 4146711 FDA_7364 Selected Important Safety Information IMPORTANCE OF PROPER PATIENT SELECTION, DOSING, and POTENTIAL FOR ABUSE TIRF medicines contain fentanyl, an opioid agonist and a Schedule II controlled substance, with an abuse liability similar to other opioid analgesics. TIRF medicines can be abused in a manner similar to other opioid agonists, legal or illicit. Consider the potential for abuse when prescribing or dispensing TIRF medicines in situations where the physician or pharmacist is concerned about an increased risk of misuse, abuse or diversion. Schedule II opioid substances which include morphine, oxycodone, hydromorphone, oxymorphone, and methadone have the highest potential for abuse and risk of fatal overdose due to respiratory depression. Serious adverse events, including deaths, in patients treated with some oral transmucosal fentanyl medicines have been reported. Deaths occurred as a result of improper patient selection (e.g., use in opioid non-tolerant patients) and/or improper dosing. The substitution of a TIRF medicine for any other fentanyl medicine, including another TIRF medicine, may result in fatal overdose. TIRF medicines are indicated only for the management of breakthrough pain in adult cancer patients 18 years of age and older (16 years of age and older for Actiq® brand and generic equivalents) who are already receiving and who are tolerant to around-the-clock opioid therapy for their underlying persistent cancer pain. Patients considered opioid-tolerant are those who are taking: • at least 60 mg of oral morphine/daily • at least 25 mcg transdermal fentanyl/hour • at least 30 mg of oral oxycodone daily • at least 8 mg oral hydromorphone daily • at least 25 mg oral oxymorphone daily • or an equianalgesic dose of another opioid daily for a week or longer. TIRF medicines are contraindicated in opioid non-tolerant patients and are contraindicated in the management of acute or postoperative pain, including headache/migraine and dental pain, or use in the emergency room. Please see the individual medicine prescribing information for a full list of specific situations in which TIRF medicines are not indicated or are contraindicated. Lifethreatening respiratory depression could occur at any dose in opioid non-tolerant patients. Deaths have occurred in opioid non-tolerant patients treated with some TIRF medicines. When prescribing, do not convert patients on a mcg per mcg basis from another fentanyl medicine to a TIRF medicine, except for substitutions between a branded TIRF medicine and its generic equivalent. Patients beginning treatment with TIRF medicines must begin with titration from the lowest available dose for that specific medicine. Carefully consult the Initial Dosing Instructions in the TIRF medicine-specific Full Prescribing Information. When dispensing, TIRF medicines are not interchangeable with each other, regardless of route of administration. Differences exist in the pharmacokinetics of TIRF medicines resulting in Reference ID: 4146711 FDA_7365 clinically important differences in the amount of fentanyl absorbed that could cause a fatal overdose. Converting patients from one TIRF medicine to a different TIRF medicine must not be done on a microgram-per-microgram basis, and must be titrated according to the labeled dosing instructions each time they begin use of a new TIRF medicine. The only exception is for substitution between a branded TIRF medicine and its specific generic equivalent. Special care must be used when dosing TIRF medicines. Refer to the Full Prescribing Information for the individual TIRF medicine for guidance on the maximum number of doses that can be taken per breakthrough pain episode and the time that patients must wait before treating another episode of breakthrough pain with the TIRF medicine. TIRF medicines are intended to be used only in the care of opioid-tolerant cancer patients and only by healthcare professionals who are knowledgeable of, and skilled in, the use of Schedule II opioids to treat cancer pain. Patients and their caregivers must be instructed that TIRF medicines contain a medicine in an amount which can be fatal in children, in individuals for whom it is not prescribed, and in those who are not opioid-tolerant. All medicines must be kept out of the reach of children. The concomitant use of TIRF medicines with cytochrome P450 3A4 inhibitors may result in an increase in fentanyl plasma concentrations, and may cause potentially fatal respiratory depression. Adverse Reactions The most commonly observed adverse reactions with TIRF medicines include typical opioid adverse reactions, such as nausea, vomiting, constipation, somnolence, dizziness, and headache. Refer to individual medicine prescribing information for all adverse reactions. Expect opioid side effects and manage them accordingly. Please see the individual Full Prescribing Information for each TIRF medicine for all information including boxed warnings, and Medication Guide for important safety information for each TIRF medicine. Adverse Event Reporting Promptly report suspected adverse events including misuse, abuse, addiction and overdoses directly to the TIRF REMS Access program at 1-866-822-1483. You also may report adverse event information to the FDA MedWatch Reporting System by telephone at 1-800-FDA-1088 or by mail using Form 3500, available at www.fda.gov/medwatch. Medication Guide It is important that you discuss the risks of TIRF medicines with your patients and encourage them to read the relevant Medication Guide. The Medication Guide provides important information on the safe and effective use of TIRF medicines and you will need to review the appropriate Medication Guide for the TIRF medicine you prescribe/dispense to your patient. Patients should be counseled on the need to store TIRF medicines safely out of the reach of children and other persons for whom the medicine is not prescribed. Reference ID: 4146711 FDA_7366 Provide your patient with a copy of the appropriate Medication Guide for the TIRF medicine you prescribe. Medication Guides will be provided to you by the manufacturers of individual TIRF medicines. If you require additional Medication Guides you can: • Print copies from the TIRF REMS Access program website at www.TIRFREMSaccess.com. • Contact the TIRF REMS Access program at 1-866-822-1483. Sincerely, TIRF REMS Access Industry Group Reference ID: 4146711 FDA_7367 Attachment 1: List of TIRF Medicines Available Only through the TIRF REMS Access Program ▪ ▪ ▪ ▪ ▪ ▪ ABSTRAL® (fentanyl) sublingual tablets ACTIQ® (fentanyl citrate) oral transmucosal lozenge FENTORA® (fentanyl citrate) buccal tablet LAZANDA® (fentanyl) nasal spray ONSOLIS® (fentanyl buccal soluble film) Approved generic equivalents of these products are also covered under this program. Reference ID: 4146711 FDA_7368 Attachment 2 Standardized validation test transaction required to validate pharmacy system enhancements Participating pharmacies must demonstrate that their pharmacy management system can receive and display program reject codes and messages. The software certification process requires the pharmacy to submit several test transactions via their pharmacy management system. Pharmacies will not be able to successfully process transactions for TIRF medicines through the pharmacy management system until these system changes have been implemented. Test Transaction Flow TEST #1 REQUIRED DATA FIELDS – PHARMACY SUBMITS THE REQUIRED DATA FIELDS: ° Submits a prescription billing request to RelayHealth BIN # 014780, PCN REMS with the following data fields populated; • Patient First Name................................... TIRFREMSTEST • Patient Last Name.................................... Smithers • Date of Birth............................................. 19841105 • Patient ZIP/Postal Zone........................... 07921 • Drug Name............................................... TIRFPRODUCT 100 mcg – NDC # 42747-0221-32 • Quantity Dispensed.................................. 12 • Days Supply............................................. 4 • Prescriber ID............................................. BA1111119 • Prescriber Last Name.............................. REMSTEST • Test #1 Response ° A Successful Expected Response will look like this: ° Transaction Response Status.................. “R” (Rejected) ° Reject Code.............................................. “NN” ° Additional Message Information: *REMS* – This is certification test message # 1 for TIRF REMS. Resubmit this transaction with the following value in the in the Intermediary Authorization ID or Patient ID field – [NNNNNNNNNN] ° Next Step – Proceed to Test #2 ° An Unsuccessful Response will look like this: ° Transaction Response Status.................. “R” (Rejected) ° Reject Code.............................................. “Will vary based upon missing/invalid required field” ° Additional Message Information: Missing/ Invalid [field] ° Next Step – Call your software vendor and provide the vendor the field provided in the reject message, request the vendor to enable the submission of that field in your pharmacy management system. Once, this has been resolved Test 1 needs to be resubmitted. Reference ID: 4146711 FDA_7369 TEST #2 RE-SUBMIT CLAIM WITH OVER-RIDE PROVIDED – PHARMACY RE-SUBMITS CLAIM WITH OVERRIDE PROVIDED FROM TEST #1. ° Receives and reviews the prescription billing request reject code and message for override value ° Inputs the identified code value provided in the reject message: ° Intermediary Authorization ID, or ° Patient ID ° Resubmits the prescription billing request. • Test #2 Response ° A Successful Expected Response will look like this: ° Transaction Response Status.................. “P” (Paid) ° Additional Message Information: *REMS* – This is certification test message # 2 for TIRF REMS. Submit a reversal request for this prescription to complete TIRF REMS certification testing ° Next Step – Proceed to Test #3 ° An Unsuccessful Response will look like this: ° Transaction Response Status.................. “R” (Rejected) ° Reject Code.............................................. “Will vary based upon missing/invalid required field” ° Additional Message Information: Missing/ Invalid [field] ° Next Step – Call your software vendor and request the vendor enable the submission of either the Patient ID or Intermediary Authorization ID field in your pharmacy management system. TEST #3 REVERSE CLAIM- PHARMACY SUBMITS ° Receives and reviews the prescription billing request and message ° Submits the prescription reversal request for the previously approved billing request. • Test #3 Expected Response ° A Successful Expected Response will look like this: ° Transaction Response Status = “A” (Approved) ° Additional Message Information: *REMS* – This is certification test message # 3 for TIRF REMS. TIRF REMS certification testing for NCPDP Telecommunication Standard is complete. ° Next Step – Vendor Verification Test complete. ° An Unsuccessful Response will look like this: ° Transaction Response Status.................. “R” (Rejected) ° Reject Code.............................................. “NN” ° Additional Message Information: “Invalid test transaction sequence” Reference ID: 4146711 FDA_7370 This letter ceased distribution in November 2013. Subject: Important Drug Warning Announcement of a single shared REMS (Risk Evaluation and Mitigation Strategy) program for all Transmucosal Immediate Release Fentanyl (TIRF) products due to the potential risk of misuse, abuse, addiction, overdose and serious complications due to medication errors The TIRF REMS Access program is a Food and Drug Administration (FDA) required risk management program Dear Inpatient Pharmacy: The purpose of this letter is to make you aware of a change from individual REMS programs to a shared REMS program (the TIRF REMS Access program) and to provide guidance on enrollment into the new shared REMS program beginning mm/dd/yyyy. The individual REMS programs are being converted to the TIRF REMS Access program to reduce the burden on the healthcare providers and the healthcare system of having multiple individual programs. The products covered under this new program include: • • • • • • Abstral® (fentanyl) sublingual tablets Actiq® (fentanyl citrate) oral transmucosal lozenge Fentora® (fentanyl citrate) buccal tablet Lazanda® (fentanyl) nasal spray Onsolis® (fentanyl buccal soluble film) Approved generic equivalents of these products are also covered under this program This new shared program replaces the individual product REMS that were previously available. Any prescribers, pharmacies, patients and distributors enrolled in these programs will be automatically transitioned to the new shared TIRF REMS Access program beginning mm/dd/yyyy. If you have not enrolled in one or more of these individual REMS programs, and if any of these products are prescribed and dispensed in your healthcare facility (e.g., hospitals, inhospital hospices, and long-term care facilities that dispense for inpatient use), you must enroll your inpatient pharmacy in the shared TIRF REMS Access program. For inpatient administration of these products, patient and prescriber enrollment in the TIRF REMS Access program is not required. Inpatient Pharmacy Action: Option 1: If you are already enrolled in at least one individual REMS program • Your enrollment information will be automatically entered into the new shared TIRF REMS Access program. Your enrollment in the shared TIRF REMS Access program allows dispensing of all TIRF medicines that are covered under the TIRF REMS Access program. The website for the shared TIRF REMS Access program can be accessed at www.TIRFREMSAccess.com. • You can use your existing secure user ID and password from any one of your individual REMS programs to access the TIRF REMS Access website at www.TIRFREMSaccess.com. ▪ The user ID and password you use to initially log on will become your permanent user ID and password for the shared TIRF REMS Access program. Reference ID: 4146711 FDA_7371 • • The TIRF REMS Education Program is also available on the shared TIRF REMS Access website. Alternatively, you can request this information by calling 1-866-822-1483. You will be required to re-enroll in the shared TIRF REMS two (2) years after your last enrollment in an individual REMS program if you wish to continue dispensing these products. You will be notified by the TIRF REMS Access program in advance of the need to re-enroll. Option 2: If you do not have an existing enrollment in any individual REMS program • Select an authorized pharmacist to establish and oversee the TIRF REMS Access program requirements. • Access the TIRF REMS Access program at www.TIRFREMSaccess.com to create an account. • Review the TIRF REMS Access Education Program materials available at www.TIRFREMSaccess.com and successfully complete the Knowledge Assessment. • Enroll in the TIRF REMS Access program by completing the Inpatient Pharmacy Enrollment Form and re-enroll every two (2) years. You will be notified by the TIRF REMS Access program in advance of the need to re-enroll. • If you are unable to enroll online, please call the TIRF REMS Access program call center at 1-866-822-1483 for further assistance. The goals of the TIRF REMS Access program are to mitigate the risk of misuse, abuse, addiction, overdose and serious complications due to medication errors by: 1. Prescribing and dispensing TIRF medicines only to appropriate patients, which includes use only in opioid-tolerant patients. 2. Preventing inappropriate conversion between fentanyl products. 3. Preventing accidental exposure to children and others for whom it was not prescribed. 4. Educating prescribers, pharmacists, and patients on the potential for misuse, abuse, addiction, and overdose of TIRF medicines. TIRF medicines are opioid analgesics indicated only for the management of breakthrough pain in cancer patients 18 years of age and older (16 years of age and older for Actiq® brand and generic equivalents) who are already receiving and who are tolerant to around-the-clock opioid therapy for their underlying persistent cancer pain, unless otherwise indicated in the product label. Patients considered opioid-tolerant are those who are regularly taking at least 60 mg oral morphine/day, or at least 25 micrograms transdermal fentanyl/hour, or at least 30 mg of oral oxycodone/day, or at least 8 mg oral hydromorphone/day, or at least 25 mg oral oxymorphone/day or an equianalgesic dose of another opioid for one week or longer. To help you understand the TIRF REMS Access program, the following program materials are available at www.TIRFREMSaccess.com or can be ordered by calling 1-866-822-1483: • Overview for Inpatient Pharmacies • TIRF REMS Access Education Program • Knowledge Assessment • Frequently Asked Questions • Inpatient Pharmacy Enrollment Form • Full Prescribing Information and Medication Guides for each TIRF medicine Outpatient pharmacies within the facility providing dispensing services to discharged inpatients or outpatients have different REMS requirements. In order to dispense TIRF medicines to Reference ID: 4146711 FDA_7372 outpatients, a separate enrollment in the TIRF REMS Access program is required (see the TIRF REMS Access program - An Overview for Outpatient Pharmacies available at www.TIRFREMSaccess.com). To access the above information and to enroll in the TIRF REMS Access program, visit www.TIRFREMSaccess.com or call 1-866-822-1483 to have enrollment materials sent to you. Reference ID: 4146711 FDA_7373 Selected Important Safety Information IMPORTANCE OF PROPER PATIENT SELECTION, DOSING, and POTENTIAL FOR ABUSE TIRF medicines contain fentanyl, an opioid agonist and a Schedule II controlled substance, with an abuse liability similar to other opioid analgesics. TIRF medicines can be abused in a manner similar to other opioid agonists, legal or illicit. Consider the potential for abuse when prescribing or dispensing TIRF medicines in situations where the physician or pharmacist is concerned about an increased risk of misuse, abuse or diversion. Schedule II opioid substances which include morphine, oxycodone, hydromorphone, oxymorphone, and methadone have the highest potential for abuse and risk of fatal overdose due to respiratory depression. Serious adverse events, including deaths, in patients treated with some oral transmucosal fentanyl medicines have been reported. Deaths occurred as a result of improper patient selection (e.g., use in opioid non-tolerant patients) and/or improper dosing. The substitution of a TIRF medicine for any other fentanyl medicine, including another TIRF medicine, may result in fatal overdose. TIRF medicines are indicated only for the management of breakthrough pain in adult cancer patients 18 years of age and older (16 years of age and older for Actiq® brand and generic equivalents) who are already receiving and who are tolerant to around-the-clock opioid therapy for their underlying persistent cancer pain. Patients considered opioid-tolerant are those who are taking: • at least 60 mg of oral morphine/daily • at least 25 mcg transdermal fentanyl/hour • at least 30 mg of oral oxycodone daily • at least 8 mg oral hydromorphone daily • at least 25 mg oral oxymorphone daily • or an equianalgesic dose of another opioid daily for a week or longer. TIRF medicines are contraindicated in opioid non-tolerant patients and are contraindicated in the management of acute or postoperative pain, including headache/migraine and dental pain, or use in the emergency room. Please see the individual medicine prescribing information for a full list of specific situations in which TIRF medicines are not indicated or are contraindicated. Lifethreatening respiratory depression could occur at any dose in opioid non-tolerant patients. Deaths have occurred in opioid non-tolerant patients treated with some TIRF medicines. When prescribing, do not convert patients on a mcg per mcg basis from another fentanyl medicine to a TIRF medicine, except for substitutions between a branded TIRF medicine and its generic equivalent. Patients beginning treatment with TIRF medicines must begin with titration from the lowest available dose for that specific medicine. Carefully consult the Initial Dosing Instructions in the TIRF medicine-specific Full Prescribing Information. When dispensing, TIRF medicines are not interchangeable with each other, regardless of route of administration. Differences exist in the pharmacokinetics of TIRF medicines resulting in Reference ID: 4146711 FDA_7374 clinically important differences in the amount of fentanyl absorbed that could cause a fatal overdose. Converting patients from one TIRF medicine to a different TIRF medicine must not be done on a microgram-per-microgram basis, and must be titrated according to the labeled dosing instructions each time they begin use of a new TIRF medicine. The only exception is for substitution between a branded TIRF medicine and its specific generic equivalent. Special care must be used when dosing TIRF medicines. Refer to the Full Prescribing Information for the individual TIRF medicine for guidance on the maximum number of doses that can be taken per breakthrough pain episode and the time that patients must wait before treating another episode of breakthrough pain with the TIRF medicine. TIRF medicines are intended to be used only in the care of opioid-tolerant cancer patients and only by healthcare professionals who are knowledgeable of, and skilled in, the use of Schedule II opioids to treat cancer pain. Patients and their caregivers must be instructed that TIRF medicines contain a medicine in an amount which can be fatal in children, in individuals for whom it is not prescribed, and in those who are not opioid-tolerant. All medicines must be kept out of the reach of children. The concomitant use of TIRF medicines with cytochrome P450 3A4 inhibitors may result in an increase in fentanyl plasma concentrations, and may cause potentially fatal respiratory depression. Adverse Reactions The most commonly observed adverse reactions with TIRF medicines include typical opioid adverse reactions, such as nausea, vomiting, constipation, somnolence, dizziness, and headache. Refer to individual medicine prescribing information for all adverse reactions. Expect opioid side effects and manage them accordingly. Please see the individual Full Prescribing Information for each TIRF medicine for all information including boxed warnings, and Medication Guide for important safety information for each TIRF medicine. Adverse Event Reporting Promptly report suspected adverse events including misuse, abuse, addiction and overdoses directly to the TIRF REMS Access program at 1-866-822-1483. You also may report adverse event information to the FDA MedWatch Reporting System by telephone at 1-800-FDA-1088 or by mail using Form 3500, available at www.fda.gov/medwatch. Medication Guide It is important that you discuss the risks of TIRF medicines with your patients and encourage them to read the relevant Medication Guide. The Medication Guide provides important information on the safe and effective use of TIRF medicines and you will need to review the appropriate Medication Guide for the TIRF medicine you prescribe/dispense to your patient. Patients should Reference ID: 4146711 FDA_7375 be counseled on the need to store TIRF medicines safely out of the reach of children and other persons for whom the medicine is not prescribed. Provide your patient with a copy of the appropriate Medication Guide for the TIRF medicine you prescribe. Medication Guides will be provided to you by the manufacturers of individual TIRF medicines. If you require additional Medication Guides you can: • Print copies from the TIRF REMS Access program website at www.TIRFREMSaccess.com. • Contact the TIRF REMS Access program at 1-866-822-1483. Sincerely, TIRF REMS Access Industry Group Reference ID: 4146711 FDA_7376 Attachment 1: List of TIRF Medicines Available Only through the TIRF REMS Access Program ▪ ▪ ▪ ▪ ▪ ▪ ABSTRAL® (fentanyl) sublingual tablets ACTIQ® (fentanyl citrate) oral transmucosal lozenge FENTORA® (fentanyl citrate) buccal tablet LAZANDA® (fentanyl) nasal spray ONSOLIS® (fentanyl buccal soluble film) Approved generic equivalents of these products are also covered under this program. Reference ID: 4146711 FDA_7377 This letter ceased distribution in November 2013. Subject: Important Drug Warning Announcement of a single shared REMS (Risk Evaluation and Mitigation Strategy) program for all Transmucosal Immediate Release Fentanyl (TIRF) products due to the potential risk of misuse, abuse, addiction, overdose and serious complications due to medication errors The TIRF REMS Access program is a Food and Drug Administration (FDA) required risk management program Dear Wholesaler/Distributor: The purpose of this letter is to make you aware of a change from individual REMS programs to a shared REMS program (the TIRF REMS Access program) and to provide guidance on enrollment into the new shared REMS program beginning mm/dd/yyyy. The individual REMS programs are being converted to the TIRF REMS Access program to reduce the burden on the healthcare providers and the healthcare system of having multiple individual programs. The products covered under this new program include: • • • • • • Abstral® (fentanyl) sublingual tablets Actiq® (fentanyl citrate) oral transmucosal lozenge Fentora® (fentanyl citrate) buccal tablet Lazanda® (fentanyl) nasal spray Onsolis® (fentanyl buccal soluble film) Approved generic equivalents of these products are also covered under this program. This new shared program replaces the individual product REMS that were previously available, and any prescribers, pharmacies, patients and distributors enrolled in these programs will be automatically transitioned to the new shared TIRF REMS Access program. If you have not enrolled in one or more of these individual REMS programs and you wish to purchase these products in order to fulfill orders from enrolled pharmacies, you must enroll in the TIRF REMS Access program. Distributor Action: Option 1: If you are already enrolled in at least one individual REMS program • Beginning mm/dd/yyyy, your enrollment information will be automatically entered into the new shared TIRF REMS Access program. The website for the shared TIRF REMS Access program can be accessed at www.TIRFREMSaccess.com. • You can use your existing secure user ID and password from any one of your individual REMS programs to access the TIRF REMS Access website at www.TIRFREMSaccess.com o The user ID and password you use to initially log on will become your permanent user ID and password for the shared TIRF REMS Access program. • You will be required to re-enroll in the shared TIRF REMS within two years after your last enrollment in an individual REMS if you wish to continue distributing these products. You will be notified by the REMS program in advance of the need to re-enroll. • By enrolling in the shared TIRF REMS Access program a distributor/wholesaler may distribute all of the TIRF medicines. However, the decision to maintain a direct selling relationship with the wholesaler/distributor is at the sole discretion of each individual TIRF manufacturer. Reference ID: 4146711 FDA_7378 Option 2: If you do not have an existing enrollment in any individual REMS program • Review and understand the requirements of the TIRF REMS Access program. • Verify that relevant staff are trained on the TIRF REMS Access program requirements and procedures • Complete the Distributor Enrollment Form. Forms are available at www.TIRFREMSaccess.com or by calling 1-866-822-1483. • By enrolling in the shared TIRF REMS Access program a distributor/wholesaler may distribute all of the TIRF medicines. However, the decision to maintain a direct selling relationship with the wholesaler/distributor is at the sole discretion of each individual TIRF manufacturer. Distributor Responsibilities in the TIRF REMS Access Program: Verification of TIRF REMS Access program Pharmacy Enrollment Prior to Distributing TIRF medicines • Obtain the current list of enrolled pharmacies by: o Downloading (daily) a complete electronic registry of enrolled pharmacies from a secure FTP site (you will be contacted regarding the TIRF REMS Access secure FTP site once your enrollment is complete), or o Receiving (daily) a complete electronic registry, or o Accessing the website (www.TIRFREMSaccess.com) using a user ID and password, or o Calling the TIRF REMS Access program call center at 1-866-822-1483. • Ensure that pharmacies are enrolled in the TIRF REMS Access program before distributing TIRF medicines. • If a pharmacy places an order for a TIRF medicine, but is not listed on the enrolled list for the TIRF REMS Access program, do not distribute TIRF medicines. Provide periodic distribution data • Provide weekly product activity data (i.e. EDI 867 transmission) to the TIRF REMS Access program including complete (unblinded/unblocked) information to validate compliance with the TIRF REMS Access program. Please note that a manufacturer of products included in Attachment 1 cannot ship TIRF medicines to distributors who have not completed and signed the Distributor Enrollment Form. Refer to the ‘List of TIRF Medicines Available only through the TIRF REMS Access program’ in Attachment 1. Adverse Event Reporting Promptly report suspected adverse events including misuse, abuse, addiction and overdoses directly to the TIRF REMS Access program at 1-866-822-1483. You also may report adverse event information to the FDA MedWatch Reporting System by telephone at 1-800-FDA-1088 or by mail using Form 3500, available at www.fda.gov/medwatch. To access the above information and to enroll in the TIRF REMS Access program, visit www.TIRFREMSaccess.com or call 1-866-822-1483 to have enrollment materials sent to you. Sincerely, TIRF REMS Access Industry Group Reference ID: 4146711 FDA_7379 Attachment 1: List of TIRF Medicines Available Only through the TIRF REMS Access Program ▪ ▪ ▪ ▪ ▪ ▪ ABSTRAL® (fentanyl) sublingual tablets ACTIQ® (fentanyl citrate) oral transmucosal lozenge FENTORA® (fentanyl citrate) buccal tablet LAZANDA® (fentanyl) nasal spray ONSOLIS® (fentanyl buccal soluble film) Approved generic equivalents of these products are also covered under this program. Reference ID: 4146711 FDA_7380 The Transmucosal Immediate Release Fentanyl (TIRF) REMS Access Program Wholesaler / Distributor Enrollment Form To enroll in TIRF REMS Access, complete all required fields below and fax pages 1 and 2 to 1-866-822-1487. You will receive enrollment confirmation via email or fax. TIRF medicines are available only through a FDA mandated REMS (Risk Evaluation and Mitigation Strategy), a restricted distribution program, called the TIRF REMS Access program. Under the TIRF REMS Access program, only prescribers, pharmacies, wholesalers / distributors and patients enrolled in the program are able to prescribe, dispense, distribute, purchase or receive TIRF medicines. Refer to the list of currently approved TIRF products located on the TIRF REMS Access website at www.TIRFREMSaccess.com/TirfUI/rems/products.action. Under the TIRF REMS Access program, wholesalers / distributors must verify the current enrollment of a pharmacy in the TIRF REMS Access program prior to distributing a TIRF medicine to that pharmacy. If the pharmacy location is not enrolled, the distributor must not fill any orders for TIRF medicines until enrollment can be confirmed. The current list of enrolled pharmacies may be accessed via: • receipt of a complete pharmacy registry daily in a mutually agreed format, • a daily download from a secure FTP site, • a password protected section of the website (www.TIRFREMSaccess.com), or • by calling 1-866-822-1483. Your company will receive login information (unique secure user ID and password) to access the TIRF REMS Access program website and you will be contacted regarding the secure FTP site once your enrollment is complete. The Wholesaler / Distributor understands that TIRF medicines are only available through the TIRF REMS Access program and acknowledges that they will comply with the following program requirements: 1. The Wholesaler / Distributor will ensure that relevant staff are trained on the TIRF REMS Access program procedures and will follow the requirements of the TIRF REMS Access program. 2. The Wholesaler / Distributor will ensure that TIRF medicines are only distributed to pharmacies whose enrollment has been verified in the TIRF REMS Access program. 3. The Wholesaler / Distributor will provide complete unblinded and unblocked data (i.e. EDI 867 transmission) to the TIRF REMS Access program, including information on shipments to enrolled pharmacies. 4. The Wholesaler / Distributor will cooperate with periodic audits or non-compliance investigations to ensure that TIRF Medicines are distributed in accordance with the program requirements. Authorized Representative Name* (please print):__________________________ Reference ID: 4146711 FDA_7381 Authorized Wholesalerl Distributor Representative: Signature* Date First Name* Last Name* Phone Number* Email* *Required Fields Wholesaler I Distributor Information: Corporate Wholesaler] Distributor Name* Address* City" State* Email* Phone Number* Fax Number* *Required Fields Preferred Method of Communication (please select one): Fax E-mail A If a DEA number is not available at corporate enter for DEA number in the ?eld above and please provide a list of Distribution Centers with their DEA numbers below. Distribution Centers (DC) Information Please populate the information below for each of your Distribution Centers. DC information: DC DEA Address City State Zip Title Contact Contact Fax Email Name Code First Name Last Name Number If you have any questions or require additional information or further copies of any TIRF REMS Access documents, please visit either or call the TIRF REMS Access program at 1-866-822-1483. Authorized Representative Name* (please print): Reference ID: 4146711 --------------------------------------------------------------------------------------------------------This is a representation of an electronic record that was signed electronically and this page is the manifestation of the electronic signature. --------------------------------------------------------------------------------------------------------/s/ ---------------------------------------------------LASHAUN WASHINGTON-BATTS 08/30/2017 JAMIE C WILKINS PARKER on behalf of CYNTHIA L LACIVITA 08/31/2017 Reference ID: 4146711 FDA_7383 mA U.S. FOOD DRUG ADMINISTRATION Memorandum To: Don's Auth, Associate Director Igor Cemy, REMS Assessment Reviewer Division of Risk Management, Of?ce of Surveillance and Epidemiology (OSE) Judith Racoosin, Deputy Director for Safety Sharon Hertz, Division Director Division of Anesthesia, Analgesia, and Addiction Products, Of?ce of New Drugs From: Tamra Meyer, Reviewer, Division of Epidemiology II (DEPI II), Of?ce of Pharmacovigilance and Epidemiology (OPE), OSE Through: Jana McAninch, Senior Medical Epidemiologist, DEPI II, OPE, OSE Judy Sta??a, Associate Director for Public Health Initiatives, OSE Date: September 21, 2017 Subject: DEPI 11 Responses to the Transmucosal Immediate Release Fentanyl (TIRF) Industry Group (TRIG) Responses Dated March 31, 2017 Reference ID: 4156408 Reference ID: 4156408 Reference ID: 4156408 Reference ID: 4156408 Reference ID: 4156408 Reference ID: 4156408 Interoffice Memorandum – (continued) Page 7 of 14 pages APPENDIX A: TABLES Appendix A Table 1: Transmucosal Immediate-release Fentanyl (TIRF) Product Descriptions and Approval Dates Drug Name Dosage Forms NDA/ANDA Applicant Approval Date Abstral Sublingual Tablet NDA 022510 Sentynl Therapeutics, Inc. 1/7/2011 Actiq Oral Transmucosal Lozenge (“lollipop”) NDA 020747 Cephalon, Inc. 11/4/1998 Fentora Buccal Tablet NDA 021947 Cephalon, Inc. 9/25/2006 Lazanda Nasal Spray NDA 022569 DepoMed, Inc. 6/30/2011 Onsolis Buccal Soluble Film NDA 022266 BioDelivery Sciences International, Inc. 7/16/2009 Subsys Sublingual Spray NDA 202788 Insys Therapeutics, Inc. 1/4/2012 fentanyl citrate Oral Transmucosal Lozenge (“lollipop”) ANDA 78907 Mallinckrodt, Inc. 10/30/2009 fentanyl citrate Oral Transmucosal Lozenge (“lollipop”) ANDA 077312 Par Pharmaceuitcal, Inc. 10/30/2009 fentanyl Oral Transmucosal Lozenge ANDA 079075 Watson Laboratories, Inc. 1/7/2011 citrate (“lollipop”) *Table reproduced from Meyer, TE. Review of NEISS-CADES Data on Pediatric Emergency Department Visits Related to Accidental Exposure to Transmucosal Immediate Release Fentanyl. Dated April 14, 2017. DARRTS Reference ID: 4084489. Memo-TRIG Responses_final.docx Reference ID: 4156408 FDA_7390 Reference ID: 4156408 Interoffice Memorandum – (continued) Page 9 of 14 pages APPENDIX B: Letter from the Transmucosal Immediate Release Fentanyl (TIRF) Industry Group (TRIG) to FDA dated 31MAR2017 Memo-TRIG Responses_final.docx Reference ID: 4156408 FDA_7392 31MAR2017 Reference ID: 4156408 31MAR2017 Reference ID: 4156408 ~12de 31MAR2017 Reference ID: 4156408 31MAR2017 Reference ID: 4156408 Put-?dun? 31MAR2017 Reference ID: 4156408 --------------------------------------------------------------------------------------------------------This is a representation of an electronic record that was signed electronically and this page is the manifestation of the electronic signature. --------------------------------------------------------------------------------------------------------/s/ ---------------------------------------------------TAMRA E MEYER 09/21/2017 JANA K MCANINCH 09/21/2017 JUDY A STAFFA 09/21/2017 Reference ID: 4156408 FDA_7398 mA U.S. FOOD DRUG ADMINISTRATION Memorandum To: Doris Auth, Associate Director Igor Cemy, REMS Assessment Reviewer Division of Risk Management, Of?ce of Surveillance and Epidemiology (OSE) Judith Racoosin, Deputy Director for Safety Sharon Hertz, Division Director Division of Anesthesia, Analgesia, and Addiction Products, Of?ce of New Drugs From: Tamra Meyer, Reviewer, Division of Epidemiology II (DEPI II), O?ice of Pharmacovigilance and Epidemiology (OPE), OSE Through: Jana McAninch, Senior Medical Epidemiologist, DEPI II, OPE, OSE Judy Sta??a, Associate Director for Public Health Initiatives, OSE Date: November 15, 2017 Subject: DEPI 11 Responses to the Transmucosal Immediate Release Fentanyl (TIRF) Industry Group (TRIG) Responses Dated October 16, 2017 a.gov Reference ID: 4181825 Inurof?ee Memorandum - (command) Reference ID: 4181825 Inurof?ee Memorandum - (command) Reference ID: 4181825 Inurof?ee Memorandum - (command) Reference ID: 4181825 Inurof?ee Memorandum - (command) Reference ID: 4181825 Inurof?ee Mancunian-(continued) Pagesd?pages Reference ID: 4181825 Interoffice Memorandum – (continued)  Page 7 of 13 pages  APPENDIX A: TABLES Appendix A Table 1: Transmucosal Immediate-release Fentanyl (TIRF) Product Descriptions and Approval Dates Drug Name Dosage Forms NDA/ANDA Applicant Approval Date Abstral Sublingual Tablet NDA 022510 Sentynl Therapeutics, Inc. 1/7/2011 Actiq Oral Transmucosal Lozenge (“lollipop”) NDA 020747 Cephalon, Inc. 11/4/1998 Fentora Buccal Tablet NDA 021947 Cephalon, Inc. 9/25/2006 Lazanda Nasal Spray NDA 022569 DepoMed, Inc. 6/30/2011 Onsolis Buccal Soluble Film NDA 022266 BioDelivery Sciences International, Inc. 7/16/2009 Subsys Sublingual Spray NDA 202788 Insys Therapeutics, Inc. 1/4/2012 fentanyl citrate Oral Transmucosal Lozenge (“lollipop”) ANDA 78907 Mallinckrodt, Inc. 10/30/2009 fentanyl citrate Oral Transmucosal Lozenge (“lollipop”) ANDA 077312 Par Pharmaceuitcal, Inc. 10/30/2009 fentanyl Oral Transmucosal Lozenge ANDA 079075 Watson Laboratories, Inc. 1/7/2011 citrate (“lollipop”) *Table reproduced from Meyer, TE. Review of NEISS-CADES Data on Pediatric Emergency Department Visits Related to Accidental Exposure to Transmucosal Immediate Release Fentanyl. Dated April 14, 2017. DARRTS Reference ID: 4084489. Memo‐TRIG_Responses_16OCT2017_Final.docx  Reference ID: 4181825 FDA_7405 Interoffice Memorandum – (continued)  Page 8 of 13 pages  APPENDIX B: Letter from the Transmucosal Immediate Release Fentanyl (TIRF) Industry Group (TRIG) to FDA dated 16OCT2017 Memo‐TRIG_Responses_16OCT2017_Final.docx  Reference ID: 4181825 FDA_7406 Interd?ce Memorandum - (continued) FDA Tm Follow-q) ?(?12017 v1.0 FINAL Reference ID: 4181825 Interd?ce Memorandum - (continued) mam mm Reference ID: 4181825 Interd?ce Memorandum - (continued) mmumm. Reference ID: 4181825 Interd?ce Memorandum - (continued) new Reference ID: 4181825 Interd?ce Memorandum - (continued) mummy? locum ?lm 1 Reference ID: 4181825 --------------------------------------------------------------------------------------------------------This is a representation of an electronic record that was signed electronically and this page is the manifestation of the electronic signature. --------------------------------------------------------------------------------------------------------/s/ ---------------------------------------------------TAMRA E MEYER 11/15/2017 JANA K MCANINCH 11/15/2017 JUDY A STAFFA 11/15/2017 Reference ID: 4181825 FDA_7412 Department of Health and Human Services Public Health Service Food and Drug Administration Center for Drug Evaluation and Research Office of Surveillance and Epidemiology Office of Medication Error Prevention and Risk Management Review of the sixth (60 month, October 29, 2015 to October 28, 2016) Risk Evaluation and Mitigation Strategy (REMS) Assessment Report for Transmucosal Immediate Release Fentanyl (TIRF) Agents Date: December 4, 2017 Reviewers: Igor Cerny, Pharm.D. REMS Assessment Analyst Division of Risk Management Shelly Harris, Sc.D., M.P.H. Team Leader Division of Risk Management Associate Director: Doris Auth, Pharm.D. Division of Risk Management Division Director: Cynthia LaCivita, Pharm.D. Division of Risk Management Therapeutic Class: Transmucosal Immediate Release Fentanyl (TIRF) OND Review Division: Division of Anesthesia, Analgesia, and Addiction, Products (DAAAP) Drug Master File #: 27320 OSE RCM #: 2016-2999 Submission Dates: December 28, 2016 (Supporting Document #27) June 15, 2017 (Individual NDA/ANDA submissions) October 16, 2017 Reference ID: 4190326 FDA_7413 Reference ID: 4190326 TIRF Products Drug Dosage and A licant Name Route ANDA pp Abstral Sublingual Tablet NDA semyl? 022510 Therapeutlcs, Inc A t' oral 1 NDA 1 1 I1 1q 020747 .ep 1a on, 1c. Lozenge NDA Fent01a Buccal Tablet 02 1 947 ephalon, Inc. Lazanda Nasal Spray NDA DepoMed, Inc. 022569 0 lis Buccal Soluble NDA Blsopehve1y ?30 Fihn 022266 c1ences Internatlona], Inc . NDA Insys 11) 1bln IS . 1 1 lgua lay 202788 Therapeutlcs, Inc Oral fentanyl ANDA Mallinckrodt, Inc cm?ate 78907 Lozenge fentanyl Oral 1 AN DA P1 Par t' citrate 0773 1 2 lannaceu 1ca Lozenge Inc Oral fentanyl AN DA Watson citrate 079075 Laboratories, Inc. Lozenge FOLLOWING THIS PAGE, TO WITHHELD IN FULL AS PROCESS 4 --------------------------------------------------------------------------------------------------------This is a representation of an electronic record that was signed electronically and this page is the manifestation of the electronic signature. --------------------------------------------------------------------------------------------------------/s/ ---------------------------------------------------IGOR CERNY 12/05/2017 REMS Assessment Review DORIS A AUTH 12/05/2017 CYNTHIA L LACIVITA 12/06/2017 Concur Reference ID: 4190326 FDA_7591 March 31., 2014 Food and Drug Administration Center for Drug Evaluation and Research Central Document Room Drug Master File Staff 590143 Ammendale Road Beitsville, MD 207054266 Re: DMF 027320 Holder: McKesson Speciaity Health (McKesson) DMF Subject: Transmucosal Immediate Release Fentanyl (TIRF) Access Program Re: REMS Shared Program DMF Type: DMF Submission Information: Clinical/Clinical Information REMS Submission Identi?er: Assessment Methodology - Other Sequence Number: 0808 Dear Drug Master File Staff: This Type DMF contains the Risk Evaluation and Mitigation Strategy (REMS) for Transmucosal Immediate Release Fentanyl for the Shared System REMS program. Included in this submission, please ?nd the RADARS System Report Transmucosal Immediate Release Fentanyl (TIRF) Risk Evaluation and Mitigation Strategy (REMS): Surveillance Monitoring covering the period of July 1, 2012 through. September 30, 2013. We also wish to inform the Agency that Accenture LLP, US. Agent, has relocated of?ces. The Administrative Information Page has been updated to reflect the new address and phone numbers. McKesson states that information provided in this Master File is current and assures that the material furnished will meet the speci?cations described herein. McKesson also con?rms that the Holder obligations are observed. We request that all information in this file be treated as confidential commercial information to the Food and Drug Administration pursuant to 21 CPR. ?20.6l and that no information from this ?le be provided to any unauthorized persons without written consent. If you have any questions or concerns, please do not hesitate to contact Jann Kochel, US. Agent for McKesson, at 610?407?1738 or alternatively via email at jann.a.kochel@accenture.com. Sincerely, . Jan A. Kochel, US. Agent centure, LLP Attachments: Table of Contents for the submission Electronic Submission Speci?cations DMF #027320; Sequence 0008 Shared System REMS Table of Contents Page 1 of 1 Assessment Methodology - Other Module Section Description 1.2 Cover Letter Cover Letter w/ Attachments Administrative Information Page 1.16 – Risk Management Plans REMS History RADARS System Report – Transmucosal Immediate Release Fentanyl (TIRF) Risk Evaluation and Mitigation Strategy (REMS): Surveillance Monitoring covering the period of July 1, 2012 through September 30, 2013 FDA_7593 Electronic Submission Specifications This submission is compliant with FDA's Guideline for Industry: Providing Regulatory Submissions in Electronic Format - Human Pharmaceutical Product Applications and Related Submissions Using the eCTD Specifications (June 2008). All files were checked and verified to be free of viruses prior to transmission through the electronic submission gateway. This eCTD has been generated by Accenture, LLP (formerly Octagon Research Solutions Inc.), who has filed an acceptable eCTD pilot with the Center (Pilot Number 900777). Anti-Virus Program Program Version Virus Definition Date Submiss ion Size Symantec Endpoint Protection Edition 11.0.5002.333 04/25/2014 rev. 9 Approx. 2 MB The IT point of contact for this submission is: Name Phone Number Email Address Matt Francis 1-610-407-1854 Matthew.p.francis@accenture.com FDA_7594 ADMINISTRATIVE INFORMATION Holder’s Name: McKesson Specialty Health Holder’s Address: 4343 N. Scottsdale Road Suite 150 Scottsdale, AZ 85251 Holder’s Contact Person: Laura Baloun Contact’s Address: 4343 N. Scottsdale Road Suite 150 Scottsdale, AZ 85251 Contact’s Phone: 480-663-4009 Contact’s Fax: 480-663-4973 Contact’s Email address: laura.baloun@mckesson.com Statement of Commitment: Attached, please find a signed statement of commitment. The statement certifies that the DMF is current and that McKesson will comply with the statements made in it. Agent’s Name: Accenture, LLP Agent’s Address: 1160 West Swedesford Road Berwyn, PA 19312 Agent’s Contact Person: Jann A. Kochel Contact’s Address 1160 West Swedesford Road Berwyn, PA 19312 Contact’s Phone: 610-407-1738 Contact’s Fax: 610-407-8433 Contact’s E-mail address: jann.a.kochel@accenture.com FDA_7595 DMF #027320; Sequence 0008 Shared System REMS Modification Date Approved Documents Affected No. 1 June 5, 2012 x REMS x Prescriber Program Overview x Education Program x Prescriber Enrollment Form x Patient Provider Agreement Form x Patient and Caregiver Overview x Dear Healthcare Provider Letter x Outpatient Pharmacy Overview x Chain Pharmacy Overview x Inpatient Pharmacy Overview x Outpatient Pharmacy Enrollment Form x Chain Pharmacy Enrollment Form x Inpatient Pharmacy Enrollment form x Outpatient Pharmacy Letter x Inpatient Pharmacy Letter x Dear Distributor Letter x Distributor Enrollment Form x Supporting Document N/A N/A Assessment Report 1 at 6 months – due 06/28/2012 2 November 7, Draft Documents REMS History Page 1 of 3 Overview of Modification Sequence 0002: Edits to Patient-Prescriber Agreement Form, the addition of the Closed System Pharmacy Enrollment Form*, the addition of the newly approved TIRF product, Subsys (fentanyl sublingual spray) and minor editorial changes. *The Closed System Pharmacy Enrollment Form was not formally submitted through the Gateway but was submitted via email on May 18, 2012 and included in the June 5, 2012 FDA approval letter. Sequence 0003: Assessment report covering 12/28/2011 to 04/27/2012 Sequence 0004: FDA_7596 DMF #027320; Sequence 0008 Shared System REMS 2013 N/A N/A 2 November 7, 2013 REMS History Page 2 of 3 submitted on or before 09/28/2012 x Chain Pharmacy Enrollment Form x Outpatient Pharmacy Enrollment Form x Closed System Pharmacy Overview x Education Program x Frequently Asked Questions (FAQ) x Outpatient Pharmacy Letter x REMS x Supporting Document Assessment Report 2 at 1 year – due 12/28/2012 Amendment to 09/28/2012 supplement: x Chain Outpatient Pharmacy Enrollment Form x Independent Outpatient Pharmacy Enrollment Form x Closed System Outpatient Pharmacy Enrollment Form x Inpatient Pharmacy Enrollment Form x Distributor Enrollment Form x Prescriber Enrollment Form x Patient Provider Agreement Form x Chain Outpatient Modification proposed to: x Incorporate closed system pharmacies into the TIRF REMS Access Program x Correct minor inconsistencies between the FDA provided versions and the current PDF versions of REMS materials Sequence 0005: Assessment report covering 04/28/2012 to 10/28/2012 Sequence 0006: Modification proposed to: x Revised terminology, processes, and definitions for outpatient pharmacies x Revised attestations for physicians and patients to address concerns regarding patient access x Revised Program Overview and Frequently Asked Questions to improve clarity and content x Updated REMS materials to reflect the completion of the transition phase for the TIRF REMS Access Program FDA_7597 DMF #027320; Sequence 0008 Shared System REMS N/A N/A N/A N/A REMS History Page 3 of 3 Pharmacy Overview x Independent Outpatient Pharmacy Overview x Closed System Outpatient Pharmacy Overview x Inpatient Pharmacy Overview x Patient and Caregiver Overview x Prescriber Overview x Education Program x Knowledge Assessment x Frequently Asked Questions (FAQ) x Dear Outpatient Pharmacy Letter x Dear Inpatient Pharmacy Letter x Dear Healthcare Provide Letter x Dear Distributor Letter x REMS x Supporting Document x Website Landing Page Assessment Report 3 at 2 years – due 12/28/2013 Safety Surveillance Report #1 – due 03/31/2014 Sequence 0007: Assessment report covering 10/29/2012 to 10/28/2013 Sequence 0008: Safety surveillance data covering Q4 2012 to Q3 2013 FDA_7598 .3 Y. $7 M. System Report Transmucosal Immediate Release Fentanyl (TIRF) Risk Evaluation and Mitigation Strategy (REMS): Surveillance Monitoring For Cephalon, Inc. (a wholly-owned subsidiary of Teva Pharmaceutical Industries, Ltd.) Depomed, Inc. Galena Biopharma, Inc. Insys Therapeutics Inc. Mallinckrodt Pharmaceuticals Meda Pharmaceuticals, Inc. Mylan, Inc. Par Pharmaceutical, Inc. Con?den?al This report contains information that may be confidential, proprietary and/or exempt from disclosure under applicable law. Any dissemination, distribution or copying of this document is strictly prohibited without our prior written consent, which may be withheld for any reason solely at our discretion. ROCKV MOUNTAIN Br DRUG Level One Care for ALL CONFIDENTIAL I FOLLOWING THIS PAGE, TO WITHHELD IN FULL Page 1 ?f 82 AS Won, Katherine From: Sent: To: Cc: Subject: Won, Katherine Tuesday, August 21, 2012 2:57 PM lauren.wind@weinberggroup.com Sullivan, Matthew; Liberatore, Mark REMS assessment for NDA 202788 Subsys (fentanyl) sublingual spray Hello Ms. Wind, We are reviewing your REMS assessment dated June 25, 2012, for NDA 202788 Subsys. We are initiating a 90-day discussion period with all the sponsors of TIRF products, including Insys Therapeutics, regarding the first TIRF REMS assessment. We will contact you soon to further discuss this issue. Sincerely, Katherine Katherine S. Won PharmD, MBA LCDR, U.S. Public Health Service Safety Regulatory Project Manager Division of Anesthesia, Analgesia and Addiction Products FDA/CDER/OND/ODEII 10903 New Hampshire Ave. Bldg 22 Rm 3173 Silver Spring, MD 20993 Phone: 301-796-7568 Fax: 301-796-9713 Email: Katherine.Won@fda.hhs.gov 1 Reference ID: 3177674 FDA_7681 --------------------------------------------------------------------------------------------------------This is a representation of an electronic record that was signed electronically and this page is the manifestation of the electronic signature. --------------------------------------------------------------------------------------------------------/s/ ---------------------------------------------------KATHERINE S WON 08/21/2012 Reference ID: 3177674 FDA_7682 DOCUMENT INFORMATION PAGE DARRTS COMIVIUNICATION This page is for FDA internal use only. Do NOT send this Lage with the letter. Application I NDA 202788. ME 27320 Communication Type: Communication Group: Communication Name: Communication ID: Drafted by: Clearance Histoly: Finalized: Filename: Use Statement: Notes: Version: DARRTS 06/03/2012 onespondence SEC 90 1 REMS Acknowledge REMS Assessment REMS ASSESSMENT PLAN REVISION (COR-SEC901REMS-10) (COR-SEC901REMS-17) M.Libel?at01?e 7/25/14. 8/6/14. 8/12/14. 8/15/14. 8/20/14 JRacoosin 7/27/14 K. Leln?feld 8/6/14 P. Ja11i/8-12-l4. 8-15-14 SRT 8/14/14 M. Liberatore 8/21/14 END OF DOCUNIENT INFORMATION PAGE The letter begins on the next page. Reference ID: 3614549 DEPARTMENT OF HEALTH AND HUMAN SERVICES Food and Drug Administration Silver Spring MD 20993 NDA 202788 MF 27320 REMS ASSESSMENT ACKNOWLEDGMENT REMS ASSESSMENT PLAN REVISION Insys Therapeutics, Inc. 444 South Ellis Street Chandler, AZ 85224 Attention: Willene M. Brondum Senior Manager, Regulatory Affairs Dear Ms. Brondum: Please refer to your New Drug Application (NDA) submitted under section 505(b) of the Federal Food, Drug, and Cosmetic Act (FDCA) for Subsys (fentanyl) sublingual spray, 100 mcg, 200 mcg, 400 mcg, 600 mcg, 800 mcg, 1200 mcg, and 1600 mcg. We also refer to your December 30, 2013, submission containing the 24-month assessment of the Transmucosal Immediate-Release Fentanyl (TIRF) risk evaluation and mitigation strategy (REMS) as well as the REMS assessment material submitted to Master File (MF) 27320. This REMS uses a single, shared system for the elements to assure safe use and the REMS assessments. After consultation between the Office of Surveillance and Epidemiology and the Office of New Drugs, we found the REMS assessment to be complete with the following comments: 1. In your one-year assessment report, information regarding the number of enrolled pharmacies from government agencies as well as other integrated systems/mail order data was presented. These categories are absent from your 24-month assessment report. In light of the REMS compliance issues experienced by at least two federal closed systems (the VA and DOD), in future assessment reports, report on the number of enrolled pharmacies in federal and other integrated systems. 2. Although the percentage of Patient-Provider Agreement Forms (PPAFs) received in the 10-day window between patient enrollment and receipt by the REMS program improved from the 12-month report figure (46% vs. 37%), continue to employ strategies that will improve the percentage of PPAFs received in the 10-day window. 3. A total of 73 outpatient pharmacies are described as having an “incomplete configuration,” though no reasons are provided as to why these 73 pharmacies remain in Reference ID: 3614549 FDA_7684 NDA 202788 MF 27320 Page 2 this status. In all subsequent assessment reports, provide complete information regarding why certain pharmacies are not able to configure their systems. 4. In future assessment reports, provide the most recent American Association of Poison Control Centers (AAPCC) case narratives. 5. Regarding RADARS data submissions in the future provide: a. information about the protocols used to generate these data b. data from the RADARS Drug Diversion Program c. the numbers of patients identified to have taken TIRFs for all of the programs for which you present data. 6. In your prescriber survey, only 59% correctly stated that TIRF should not be used to treat “chronic non-cancer pain.” It is not clear if this represents a knowledge deficit or a disagreement with how these medicines should be used. In the next survey, include a supplemental question directed at those who respond incorrectly to this question to followup as to why they feel that this is an appropriate use of TIRFs. 7. In future surveys of prescribers, report the proportion of prescriber respondents that work in closed systems. 8. Given that pharmacists often have the opportunity to see all of the prescriptions that a patient is taking, include a question in the pharmacist survey regarding the CYP3A4 interactions with TIRFs. Also include a question in the pharmacist survey regarding their understanding that patients are to stop taking their TIRF when they stop taking their around-the-clock opioid. 9. In the pharmacist survey, 81% of those surveyed functioned as the pharmacist in charge for their operations. In future pharmacist surveys, consider ensuring that a higher percentage of non-supervisory dispensing pharmacists are included. Our January 4, 2012 approval letter described the REMS assessment plan. During the review of the first and second year TIRF REMS assessment reports, changes to some of the metrics in the assessment plan were discussed both internally as well as with the TIRF REMS Industry Group (TRIG). The revisions provided in this letter serve to further tailor the metrics to those that are most informative regarding the operation and effectiveness of the TIRF REMS program. In brief, the revised REMS assessment plan comprises: • • Scaled back reporting of TIRF utilization data that focuses on the stakeholders enrolled, inactivated, and the numbers of stakeholders affected by enrollment delays Refocused dispensing activity data that includes stratification by closed/non-closed systems. Reference ID: 3614549 FDA_7685 NDA 202788 MF 27320 Page 3 • • • A plan to assess non-compliance with the REMS that includes annual audits of randomly selected closed systems and inpatient systems. Safety surveillance that will consist of one comprehensive report that includes spontaneous adverse event data from all of the drugs under the TIRF REMS and that will focus on four categories of adverse events: addiction, overdose, death, and pediatric exposures. Continued use of stakeholder knowledge surveys to help inform whether the goals of the REMS are being met. The complete revised REMS assessment plan is attached (see Appendix). If you have any questions, call Vaishali Jarral, Safety Regulatory Project Manager in the Office of Surveillance and Epidemiology, at (301) 796-4248. Sincerely, {See appended electronic signature page} Judith A. Racoosin, M.D., M.P.H. Deputy Director for Safety Division of Anesthesia, Analgesia, and Addiction Products Office of Drug Evaluation II Center for Drug Evaluation and Research ENCLOSURES: Revised Assessment Plan Reference ID: 3614549 FDA_7686 NDA 202788 MF 27320 Page 4 APPENDIX: REVISED ASSESSMENT PLAN Assessment Plan for TIRF REMS 1. The TIRF REMS Access Program Utilization Statistics (data presented per reporting period and cumulatively) a. Patient Enrollment: i. Number of unique patients enrolled ii. Number of patients inactivated b. Prescriber Enrollment: i. Number of prescribers enrolled ii. Number of prescribers that attempted enrollment but whose enrollment is pending for >3 months and >6 months along with the specific reasons why their enrollment is pending; iii. Number of prescribers inactivated c. Pharmacy Enrollment: i. Number of pharmacies enrolled by type (inpatient, chain, independent, closed system; provide identity of closed system entities); ii. Number of pharmacies that attempted enrollment but whose enrollment is pending for >3 months and >6 months along with the specific reasons why their enrollment is pending (stratified by type); iii. Number of pharmacies inactivated by type (inpatient, chain, independent, closed system); d. Distributor enrollment: i. Number of distributors enrolled ii. Number of distributors inactivated 2. Dispensing activity for enrolled pharmacies - metrics stratified by pharmacy type (open vs. closed system) a. Number of prescriptions/transactions authorized; for closed systems, provide the number of prescription transactions per closed system entity Reference ID: 3614549 FDA_7687 NDA 202788 MF 27320 Page 5 b. Number of prescriptions/transactions denied and reasons for denial. Include the number of prescriptions/transactions rejected for safety issues (provide description of safety issues and any interventions or corrective actions taken) c. Number of prescriptions/transactions rejected for other reasons (e.g., prescriber not enrolled) with a description of these specific other reasons d. Mean and median amount of time it takes for a prescription that experienced at least one initial REMS-related rejection to be authorized e. Number of patients with more than three prescriptions dispensed during the first ten days after patient passive enrollment without a PPAF f. Number of prescriptions dispensed after ten days without a PPAF in place 3. Program Infrastructure and Performance: The following metrics on program infrastructure performance will be collected (per reporting period): a. Number of times a backup system was used to validate a prescription, with reasons for each instance (for example, pharmacy level problem, switch problem, or REMS database problem) clearly defined and described b. Number of times unintended system interruptions occurred for each reporting period. Describe the number of stakeholders affected, how the issue was resolved, and steps put into place to minimize the impact of future interruptions c. Call center report with i. Overall number of contacts ii. Summary of frequently asked questions iii. Summary of REMS-related problems reported d. Description of corrective actions taken to address program/system problems 4. TIRF REMS Access Non-Compliance Plan: The TIRF sponsors should provide the following data regarding non-compliance in each assessment report (per reporting period): a. Report the results of yearly audits of at least 3 randomly selected closed pharmacy systems to assess the performance of the system(s) developed to assure REMS compliance. These reports are to include: i. Verification of training for all pharmacists dispensing TIRF products ii. Numbers of prescription authorizations per closed system iii. Reconciliation of data describing TIRF product received by the closed system pharmacy with TIRF product dispensed to patients with a valid enrollment in the TIRF REMS program. Data to include the 12 month Reference ID: 3614549 FDA_7688 NDA 202788 MF 27320 Page 6 period preceding the audit date. Include details on how the reconciliation is conducted (e.g., electronic vs. manual process). iv. Describe any corrective actions taken for any non-compliance identified during the audit and corrective actions taken to address non-compliance b. Report the results of yearly audits of at least 5 randomly selected inpatient hospital pharmacies to assess the performance of the system(s) developed to assure REMS compliance. Provide the number of units of use of TIRFs ordered per inpatient hospital pharmacy audited per 12 month period These reports are to include: i. Verification of training for all pharmacists dispensing TIRF products ii. Verification that processes such as order sets/protocols are in place to assure compliance with the REMS program iii. Describe any corrective actions taken for any non-compliance with i and ii identified above during the audit, as well as preventative measures that were developed as a result of uncovering these non-compliance events c. Description of number, specialties, and affiliations of the personnel that constitute the Non-Compliance Review Team (NCRT) as well as: i. Description of how the NCRT defines a non-compliance event ii. Description of how non-compliance information is collected and tracked iii. Criteria and processes the Team uses to make decisions iv. Summary of decisions the Team has made during the reporting period v. How the Team determines when the compliance plan should be modified d. Describe each non-compliance event and the corrective action measure taken, as well as the outcome of the corrective action e. Number of TIRF prescriptions dispensed that were written by non-enrolled prescribers and include steps taken to prevent future occurrences f. Number of prescriptions dispensed by non-enrolled pharmacies and include steps taken to prevent future occurrences g. Number of times a TIRF prescription was dispensed because a pharmacy (closed or open system) was able to bypass REMS edits and if any such events occurred, describe how these events were identified h. Number of times a TIRF was prescribed to an opioid non-tolerant individual. Include what was done to minimize such instances; if any such events occurred, describe how these events were identified Reference ID: 3614549 FDA_7689 NDA 202788 MF 27320 Page 7 i. Number of instances of inappropriate conversions between TIRF products, as well as any outcome of such an event. If any such events occurred, describe how these events were identified 5. Safety Surveillance (data collected per reporting period): a. TIRF Sponsors will process adverse event reports related to their specific products and report to the FDA according to current regulations outlined in 21 CFR 314.80 and the sponsor’s respective Standard Operating Procedures b. TIRF Sponsors will produce one comprehensive report that presents spontaneous adverse event data from all sponsors of the TIRF REMS Access Program, as well as data from other databases (characteristics of which are described below). This report will focus on four categories of adverse events of interest: addiction, overdose, death, and pediatric exposures. This report should include the following: i. Line listings under each category of adverse events of interest as listed above ii. Line listings should provide at a minimum the following information (see sample table provided): 1. Identifying case number 2. Age and Gender of the patient 3. Date of the event as well as of the report 4. The Preferred Terms 5. Indication of TIRF use 6. Duration of TIRF therapy 7. Concomitant medications 8. Event Outcome iii. Other metrics of interest include: 1. Number of event reports in each event category of interest 2. Counts of adverse events related to inappropriate conversions between TIRF products 3. Counts of adverse events related to accidental and unintentional exposures 4. Counts of adverse events that are associated with use of TIRF medicines in non‐opioid tolerant patients iv. Duplicate cases are identified and eliminated Reference ID: 3614549 FDA_7690 NDA 202788 MF 27320 Page 8 v. Case reports with adverse events in multiple categories will be listed in each category of interest, and will be noted as such vi. For each adverse event category, an overall summary analysis of the cases will be provided addressing the root cause(s) of the events vii. Rate of each adverse event of interest will be calculated using two distinct denominators: the number of prescriptions for TIRF products and the number of patients receiving a TIRF product throughout the reporting interval. Trends and changes in the rates of these events will be compared year‐to‐year c. Surveillance data focusing on events of addiction, overdose, death, and pediatric cases should also be drawn from the databases that are listed below. Conclusions regarding these data should be included in and inform the overall conclusions in the summary report referred to in Section 5.b. directly above: i. Non-medical use of prescription drugs ii. Surveys conducted at substance abuse treatment programs iii. College surveys iv. Poison control center data v. Impaired health care workers vii. Drug-related hospital emergency department visits viii. Drug-related deaths ix. Other databases as relevant 6. Periodic Surveys of Patients, Healthcare Providers, and Pharmacies: Prescribers’, pharmacists’, and patients’ understanding regarding the appropriate use of TIRF medicines and TIRF REMS Access Program requirements will be evaluated through knowledge, attitude, and behavior (KAB) surveys. The surveys will be administered to randomly selected prescribers, pharmacists, and patients. Surveys will assess understanding of key messages Reference ID: 3614549 FDA_7691 --------------------------------------------------------------------------------------------------------This is a representation of an electronic record that was signed electronically and this page is the manifestation of the electronic signature. --------------------------------------------------------------------------------------------------------/s/ ---------------------------------------------------JUDITH A RACOOSIN 08/21/2014 Reference ID: 3614549 FDA_7692 DOCUMENT INFORMATION PAGE This page is for FDA internal use only. Do NOT send this Lage with the letter. Application Communication Type: Communication Group: Communication Name: Communication ID: Drafted by: Clearance Histmy: Finalized: Filename: Signatory Authority: Use Statement: Notes: Version: 10/28/20 14 END OF DOCUNIENT INFORMATION PAGE Reference ID: 3800801 NDA 202788 MP 27320 on?espondence SEC 90 1 REMS Acknowledge REMS Assessment (COR-SEC901REMS-10) M. Liberatore 5/27/15 DRISK 7/7/15. 7/16/15 J. Racoosin 7/ 16/ 15 K. Compton ani for M. Sulliva11/7-28-15 SRT 7/22/ 15 M. Liberatore 8/3/15 DDS. Division Director. or Deputy. Person who is covering for the signat01y authority can sign 011 their behalf the signattu'e block 011 the letter will not change). The letter begins on the next page. DEPARTMENT OF HEALTH AND HUMAN SERVICES Food and Drug Administration Silver Spring MD 20993 NDA 202788 MF 27320 REMS ASSESSMENT ACKNOWLEDGMENT Insys, Therapeutics, Inc. 1333 South Spectrum Boulevard Suite 100 Chandler, AZ 85286 Attention: Stephen Sherman Vice President, Regulatory Affairs Dear Mr. Sherman: Please refer to your New Drug Application (NDA) submitted under section 505(b) of the Federal Food, Drug, and Cosmetic Act (FDCA) for Subsys (fentanyl) sublingual spray. We also refer to your December 29, 2014, submission containing the 36-month assessment of the Transmucosal Immediate-Release Fentanyl (TIRF) risk evaluation and mitigation strategy (REMS) as well as the REMS assessment material submitted to Master File (MF) 27320. This REMS uses a single, shared system for the elements to assure safe use and the REMS assessments. After consultation between the Office of Surveillance and Epidemiology and the Office of New Drugs, we found the REMS assessment to be complete with the following comments: 1. We are not able to assess whether the REMS is meeting its goals. The absence of spontaneous adverse event reports citing either use of a TIRF in opioid non-tolerant individuals or inappropriate conversions between TIRF products is not informative because spontaneous reporting systems are subject to under-reporting of adverse events. In addition, the accidental pediatric exposure data presented in the Assessment Report are difficult to assess due to unequal assessment periods and small numbers of cases. Lastly, the survey results indicate areas of low awareness of some important safe use messages. 2. In order to assess the TIRF REMS goal of prescribing and dispensing TIRF products only to appropriate patients, which includes use only in opioid-tolerant patients, conduct the following analysis: Identify a health care database that includes an adequate number of TIRF product users. Within that database, by year, provide the number of total unique patients dispensed an initial prescription for a TIRF product in the outpatient setting. Determine what proportion of those total unique patients received a prescription for an opioid analgesic product prior to the prescription for the TIRF product. Provide these data separately for Reference ID: 3800801 FDA_7694 NDA 202788 MF 27320 Page 2 patients receiving an opioid analgesic within the 7-days prior and within the 30-days prior to the initial TIRF prescription. Before embarking on this analysis, provide to FDA your choice of database and the estimated number of TIRF users in the database so that we can determine if the number is adequate. 3. We are not able to establish whether the TIRF REMS is achieving the goal of preventing inappropriate conversion between TIRF medicines. In order to better understand how many people are at risk for inappropriate conversion between TIRF medicines, we need a better idea of how long patients stay on one TIRF and whether they shift between TIRF products or just stop them completely. Conduct a persistency analysis based on the data available on the prescriptions processed through the switch system used by retail pharmacies. This analysis should demonstrate the number of patients starting on a TIRF and follow them over weeks and months to summarize their treatment course and change in therapy. The TIRF products can be grouped together, and the specific drug does not need to be disclosed. Following the discontinuation of the TIRF, the persistency analysis should also depict what treatment option the patient uses next. This will be either full discontinuation or switching to another TIRF product. There may be gaps in between prescriptions; propose what duration of gap will be considered to mean that the patient has remained on treatment with a TIRF and provide a rationale for selection of that gap length. 4. Conduct outreach to a representative sample of those health professionals and pharmacies who did not re-enroll in the TIRF REMS Access Program so as to ascertain their reasons and report the results in your next Assessment Report. We are concerned about potential patient access issues. 5. There has been a notable increase in mean and median prescription processing times during this reporting period versus the previous period. Investigate and identify the causes of these increasing delays in prescription processing and report the results in your next Assessment Report. 6. None of your reported spontaneous adverse events include a root cause analysis as specified in the Assessment Plan. In your subsequent Assessment Reports, include a root cause analysis of adverse events reported to the TRIG Sponsors. 7. The closed system pharmacies continue to struggle with the REMS authorization processes. Re-evaluate whether a novel authorization process is warranted or technically feasible at this time for the closed system pharmacies and report your conclusions with your next Assessment Report. 8. Your presentation of the non-compliance data in the submitted report is disorganized. Various events are described in Assessment Report Section 6.1.1 and in the Report’s Tables 21 and 22. Events found in one of these areas often sound similar to events reported in other areas, and thus it is unclear whether these different sources are referring to distinct events or are describing the same event. In addition, while your Report’s Table 21 indicates seven Reference ID: 3800801 FDA_7695 NDA 202788 MF 27320 Page 3 instances where closed system pharmacies dispensed drugs without obtaining authorization, the audit conducted by the TRIG reports 513 such incidents. Organize and harmonize these various components into one clear presentation that is comprehensive and eliminates duplication. 9. Provide the criteria as to how compliance decisions are made by the NCRT and include your non-compliance protocol with your next Assessment Report. 10. In subsequent Assessment Report submissions of RADARS data, provide the following: a. A more detailed data analysis section that presents the statistical methods used, how calculations were performed, and the assumptions made, at the level of detail as provided in your April 2, 2015, response to the March 19, 2015, FDA Information Request. In addition, include a pre-post REMS means analyses and trend analyses (e.g. segmented regression analyses), statistically comparing event rates for a time-period immediately prior to full implementation of the TIRF REMS with an equivalent period of time after REMS implementation. b. Present the data at the dosage unit level as well as population and URDD levels. c. The RADARS treatment center data (Opioid Treatment Program and Survey of Key Informants Patients) programs are confounded by the fact that the number of treatment centers participating in each quarter fluctuates (although the overall numbers are generally increasing). In subsequent submissions, limit the presentation of treatment center data to centers that have contributed data in all of the time-periods assessed. In addition, provide the various versions of the survey instruments/pill cards in use throughout the time-periods assessed with dates provided indicating when each instrument was in use. 11. We remind you that the following comments related to the stakeholder surveys were provided in the August 21, 2014, letter to the TRIG. These revisions should be implemented in subsequent surveys along with the new survey revisions described in item 12 below. a. In your prescriber survey, only 59% correctly stated that TIRF should not be used to treat “chronic non-cancer pain.” It is not clear if this represents a knowledge deficit or a disagreement with how these medicines should be used. In the next survey, include a supplemental question directed at those who respond incorrectly to this question to follow-up as to why they feel that this is an appropriate use of TIRFs. b. In future surveys of prescribers, report the proportion of prescriber respondents that work in closed systems. c. Given that pharmacists often have the opportunity to see all of the prescriptions that a patient is taking, include a question in the pharmacist survey regarding the Reference ID: 3800801 FDA_7696 NDA 202788 MF 27320 Page 4 CYP3A4 interactions with TIRFs. Also include a question in the pharmacist survey regarding their understanding that patients are to stop taking their TIRF when they stop taking their around-the-clock opioid. d. In the pharmacist survey, 81% of those surveyed functioned as the pharmacist in charge for their operations. In future pharmacist surveys, consider ensuring that a higher percentage of non-supervisory dispensing pharmacists are included. 12. Additional comments and recommended revisions to the stakeholder surveys that should be implemented in subsequent surveys follow below: a. Patient survey i. In subsequent Assessment Reports, provide an analysis of how the demographics of the patient survey respondents compare to the demographics of actual TIRF patients. ii. For Question 4, remove Onsolis as a response option because it is no longer available. iii. Move Question 13b: It is okay for patients to take TIRF medicines for headache pain to Key Risk Message 3: TIRF medicines should be taken exactly as prescribed by the healthcare provider. iv. Add Question 10a-e: For which of the following conditions should you use a TIRF medicine? to Key Risk Message 3: TIRF medicines should be taken exactly as prescribed by the healthcare provider. b. Pharmacist survey i. For Question 26, remove Onsolis as a response option because it is no longer available. ii. Move Question 6a: A cancer patient can be started on a TIRF medicine and an around the clock opioid at the same time and Question 6b: A cancer patient who has been on an around the clock opioid for 1 day can start taking a TIRF medicine for breakthrough pain to Key Risk Message 2: TIRF medicines are only indicated for the management of breakthrough pain in adult cancer patients who are already receiving and who are tolerant to around-the-clock opioid therapy for their underlying persistent cancer pain. iii. Move Question 11a-f: According to the labeling for TIRF medicines, patients considered opioid-tolerant are those who are taking, for one week or longer, at least to Key Risk Message 1: TIRF medicines are contraindicated in opioid non-tolerant patients. iv. Move Question 13c: TIRF medicines with the same route of administration can be substituted with each other if the pharmacy is out of stock for one product to Key Risk Message 4: TIRF medicines are not interchangeable with each other, regardless of route of administration. Reference ID: 3800801 FDA_7697 NDA 202788 MF 27320 Page 5 c. Prescriber survey i. In subsequent Assessment Reports, provide an analysis of how the demographics of the prescriber survey respondents compare to the demographics of actual TIRF prescribers. ii. For Question 30, remove Onsolis as a response option because it is no longer available. iii. Move Question 6a: A cancer patient can be started on a TIRF medicine and an around the clock opioid at the same time and Question 6b: A cancer patient who has been on an around the clock opioid for 1 day can start taking a TIRF medicine for breakthrough pain to Key Risk Message 2: TIRF medicines are only indicated for the management of breakthrough pain in adult cancer patients who are already receiving and who are tolerant to around-the-clock opioid therapy for their underlying persistent cancer pain. iv. Move Question 7b: Death has occurred in opioid non-tolerant patients treated with some fentanyl products to Key Risk Message 1: TIRF medicines are contraindicated in opioid non-tolerant patients. v. Move Question 10d: Dosing of TIRF medicines is not equivalent on a microgram to microgram basis to Key Message 4: TIRF medicines are not interchangeable with each other, regardless of route of administration. vi. Move Question 11a-f: According to the labeling for TIRF medicines, patients considered opioid-tolerant are those who are taking, for one week or longer, at least to Key Risk Message 1: TIRF medicines are contraindicated in opioid non-tolerant patients. vii. Move Question 18b: Inform patients that TIRF medicines must not be used for acute or postoperative pain, pain from injuries, headache/migraine, or any other short-term pain to Key Risk Message 2: TIRF medicines are only indicated for the management of breakthrough pain in adult cancer patients who are already receiving and who are tolerant to around-the-clock opioid therapy for their underlying persistent cancer pain. viii. Move Question 18c: Instruct patients that if they stop taking their around the clock opioid medicine, they can continue to take their TIRF medicine to Key Risk Message 2: TIRF medicines are only indicated for the management of breakthrough pain in adult cancer patients who are already receiving and who are tolerant to around-the-clock opioid therapy for their underlying persistent cancer pain. ix. Remove Question 19: Can patients continue to take their TIRF medicine if they stop taking their around-the-clock opioid medicine? Reference ID: 3800801 FDA_7698 NDA 202788 MF 27320 Page 6 If you have any questions, call Wendy Brown, Safety Regulatory Project Manager in the Office of Surveillance and Epidemiology, at (240) 402-9140. Sincerely, {See appended electronic signature page} Judith A. Racoosin, M.D., M.P.H. Deputy Director for Safety Division of Anesthesia, Analgesia, and Addiction Products Office of Drug Evaluation II Center for Drug Evaluation and Research Reference ID: 3800801 FDA_7699 --------------------------------------------------------------------------------------------------------This is a representation of an electronic record that was signed electronically and this page is the manifestation of the electronic signature. --------------------------------------------------------------------------------------------------------/s/ ---------------------------------------------------JUDITH A RACOOSIN 08/03/2015 Reference ID: 3800801 FDA_7700 DOCUMENT INFORMATION PAGE This page is for FDA internal use only. Do NOT send this Lage with the letter. Application Communication Type: Communication Group: Communication Name: Communication ID: Drafted by: Clearance Histmy: Finalized: Filename: Signatory Authority: L'se Statement: Notes: Version: 08/04/20 1 5 END OF DOCUNIENT INFORMATION PAGE NDA 202788 MP 27320 Correspondence SEC 90 1 REMS Acknowledge REMS Assessment (COR-SEC901REMS-10) M. Liberatore 9/29/16 J. Racoosin 10/27/16. 11/8/16 D.Aut1111/1/16 Sullivan 11-9 M. Liberatore 1 1/10/16 DDS. Division Director. or Deputy. Person who is covering for the signatory authority can Sign 011 their behalf the signatiu?e block 011 the letter will not change). The letter begins on the next page. Reference ID: 4012463 DEPARTMENT OF HEALTH AND HUMAN SERVICES Food and Drug Administration Silver Spring MD 20993 NDA 202788 MF 27320 REMS ASSESSMENT ACKNOWLEDGMENT Insys Development Co. c/o Insys Therapeutics, Inc. 1333 South Spectrum Blvd., Suite 100 Chandler, AZ 85286 Attention: Stephen Sherman Sr. Vice President, Regulatory Affairs Dear Mr. Sherman: Please refer to your New Drug Application (NDA) submitted under section 505(b) of the Federal Food, Drug, and Cosmetic Act (FDCA) for SUBSYS (fentanyl) sublingual spray. We also refer to your December 29, 2015, submission containing your assessment of the Transmucosal Immediate-Release Fentanyl (TIRF) Products risk evaluation and mitigation strategy (REMS). After consultation between the Office of Surveillance and Epidemiology and the Office of New Drugs, we found the REMS assessment to be complete with the following comments: 1. After review of the 48 month (5th overall) REMS assessment report for the Transmucosal Immediate-Release Fentanyl (TIRF) Products REMS, we conclude that it is not possible to determine whether the overarching goal of the REMS - to mitigate the risk of misuse, abuse, addiction, overdose, and serious complications due to medication errors is being met. a. The first objective (prescribing and dispensing TIRF medicines only to appropriate patients, which includes use only in opioid-tolerant patients) is not being achieved. In the TIRF REMS Industry Group’s (TRIG’s) assessment of opioid tolerance, approximately 42% of patients prescribed TIRF products were not opioid tolerant. It is important that the TRIG further investigate this issue. b. Reference ID: 4012463 It is not possible to determine if the second objective (preventing inappropriate conversion between TIRF medicines) is being met. Though no instances of inappropriate conversions were submitted as a spontaneous report, the persistency analysis provided indicates that the number of patients who may be exposed to inappropriate conversion between TIRF medicines may be as high as 17.1-20.5% of patients receiving TIRF medicines. Further assessment of these findings is also warranted. FDA_7702 NDA 202788 MF 27320 Page 2 2. c. It is also not possible to determine if the third objective (preventing accidental exposure to children and others for whom it was not prescribed) is being met. The case reports for this metric remain quite low thus challenging the ability to assess the impact of the REMS on this objective, particularly since the case reports do not provide enough information to conduct a root cause analysis (RCA). d. The fourth objective (educating prescribers, pharmacists, and patients on the potential for misuse, abuse, addiction, and overdose of TIRF medicines) is partially being met. Overall, patients, prescribers, and pharmacists seem to have an adequate understanding of most of the key risk messages related to preventing inappropriate conversion, accidental exposure, and the potential for misuse, abuse, addiction, and overdose of TIRF medicines; however, all groups had a lower awareness of the need to only prescribe and dispense TIRF medicines to appropriate patients. In order to address the deficiencies outlined in 1a, b, c, and d, we have the following comments: a. Regarding the assessment of opioid tolerance submitted in the 48 month assessment, approximately 42% of patients prescribed TIRF products were not opioid tolerant. The TRIG needs to further investigate this concerning finding. A timeline for a plan to further evaluate this finding should be submitted with the February 17, 2017, submission of the 60 month REMS assessment survey results. At a minimum, further evaluation of this finding will include product-specific assessment of opioid tolerance that each member sponsor will submit only to their NDA or ANDA. Additional details regarding this evaluation will be communicated in a separate letter. b. Regarding the persistency analysis submitted by the TRIG, these data indicate that the number of patients who may be exposed to “inappropriate conversion between TIRF medicines” is not insignificant. Thus these TIRF product switches need to be further assessed by the TRIG and a protocol developed to assess the starting doses of the TIRF products that existing TIRF patients switch to in order to ascertain what proportion of these switches are conducted as per products’ labeling. In addition, if the data system used has outcome data, this would be informative as to whether or not any switch marked as “inappropriate” resulted in any adverse sequelae. Limitations of the databases and/or approaches used are to be included in the protocol. Please submit this protocol with the February 17, 2017, submission of the 60 month REMS assessment survey results; if additional time for protocol development is needed, please request an extension. c. We would like to schedule a meeting to discuss opportunities for obtaining additional data on accidental exposure to children and others for whom TIRF products are not prescribed, as well as to discuss possible ways to address the low Reference ID: 4012463 FDA_7703 NDA 202788 MF 27320 Page 3 awareness of the need to prescribe and dispense TIRF medicines to appropriate patients. 3. Additional comments on the 48 month assessment: a. In the FDA’s 36-month REMS Assessment Acknowledgement Letter (date August 3, 2015), the TRIG was asked to “Conduct outreach to a representative sample of those health professionals and pharmacies who did not re-enroll in the TIRF REMS Access Program so as to ascertain their reasons and report the results in your next Assessment Report. We are concerned about potential patient access issues.” In the 48 month assessment report, the TRIG responded that: “Based on…analysis, there is no barrier to patient access and further outreach is unwarranted.” The TRIG states that 516 prescribers (8.6%) chose to not re-enroll and that these prescribers had an average of no more than four prescriptions total over the course of the reporting period. However, the reasons why these prescribers withdrew from the program are unknown as are the reasons why 1,134 prescribers had their enrollment expire this reporting period and remain expired. Additionally, the reasons why 412 pharmacies chose not to re-enroll are not presented. It is therefore important that the TRIG proceed with conducting an “…outreach to a representative sample of those health professionals and pharmacies who did not re-enroll in the TIRF REMS Access Program so as to ascertain their reasons… (w)e are concerned about potential patient access issues.” Submit a timeline for the plan to conduct this outreach in the February 17, 2017, submission of the 60 month REMS assessment survey results. b. There continues to be a steady increase in mean and median prescription processing times during this reporting period versus the previous periods. The TRIG was previously asked to investigate this finding, but did not do so, instead stating that this finding may be due to a lower number of prescriptions with at least one initial REMS-related rejection this reporting (1,735) period as compared to the 36-month report (3,738). These differences cited by the TRIG do not appear to be so large as to account for some sort of number skewing induced by a small sample size. The TRIG needs to investigate and identify the causes of these increasing delays in prescription processing as these are potential indicators of access barriers. c. The TRIG Protocol for Corrective Actions for Instances of Non-Compliance contains few concrete criteria or decision trees as to how to deal with episodes of non-compliance. Thus it is unclear to us what types of non-compliance actions would reliably lead to suspension or deactivation. The TRIG should add Reference ID: 4012463 FDA_7704 NDA 202788 MF 27320 Page 4 increased specificity to the Non-Compliance Review Team (NCRT) protocol as well as to the Supporting Document of the REMS. In addition, it is concerning that the TRIG’s criteria for an incident of an individual prescriber non-compliance with Patient-Prescriber Agreement Form (PPAF) requirements needs to involve at least “5 or more patients enrolled by the prescriber without a complete PPAF on file, with each patient having greater than 10 working days lapse from initial enrollment date.” These criteria would appear to potentially lead to an under-reporting of PPAF non-compliance. The TRIG should explore mechanisms to capture lower levels of non-compliance. d. Regarding the three instances where a non-closed system pharmacy dispensed a TIRF product after a TIRF REMS rejection, all three reports were brought to the attention of the TRIG only after the pharmacy contacted the REMS. The TRIG should develop a more active mechanism by which to identify and prevent such occurrences. e. Although results for both governmental (Veteran’s Health Administration and Department of Defense) and closed-pharmacy systems appear to have improved from the 36-month audit, they continue to be unsatisfactory. The 36-month REMS Assessment Acknowledgement Letter requested that the TRIG “Re-evaluate whether a novel authorization process is warranted or technically feasible at this time for the closed system pharmacies and report your conclusions with your next Assessment Report.” The TRIG has issued the following response: “The TRIG has determined that the current prescription authorization volume for closedsystem pharmacies is less than 1% of all TIRF prescriptions and due to the absence of complaints with the current process, no changes are warranted at this time.” An absence of complaints does not necessarily mean that a closed pharmacy system process is functioning optimally. These audits are likely one of the best sources of information regarding the performance of these closed-system pharmacies in meeting the REMS requirements. If the TRIG does not favor a novel authorization process for all of the closed-system pharmacies solely due to the poor performance of the governmental entities, the TRIG should propose an outreach to these programs to improve compliance. In addition, the TRIG should be sure to include both governmental entities in the 60-month audit so that their performance in the REMS can continue to be monitored. Lastly, the TRIG presents the process times for prescriptions that have experienced at least one REMS-related rejection. However, data on the overall processing time of a prescription that does not meet with any rejections is unclear. Given that one of the pieces of information solicited during the closed-system audits is “Date and time of each prescription transaction,” this is an excellent opportunity for the TRIG to assess prescription processing times for prescriptions that do not experience any REMS-related rejections. The TRIG should add this component to their closed-system audits. Reference ID: 4012463 FDA_7705 NDA 202788 MF 27320 Page 5 4. f. For the Inpatient Pharmacy audits, six inpatient pharmacies either did not respond to the audit request or decided not to participate. In the current inpatient pharmacy enrollment form, the pharmacy only agrees to have their training audited. We are considering revisions to this enrollment form to allow for process audits so as to increase the potential pool of inpatient pharmacies in the audit and will communicate any required modifications during the review of the next REMS assessment. g. The TRIG reports a number of instances where prescribers were either unaware of requirements to submit a PPAF or chose not to do so. It is important that the TRIG investigate mechanisms to reinforce to prescribers the necessity of timely completion of PPAFs. h. For subsequent submissions of Researched Abuse, Diversion and AddictionRelated Surveillance (RADARS) data that contain CII opioid comparators, expand the CII immediate-release opioid category to include oxycodone/acetaminophen, oxycodone/aspirin, and oxycodone/ibuprofen. i. The Agency has increasing concerns about the use of RADARS data to assess some of the outcomes outlined in the TIRF REMS. Given the limitations of RADARS, the Agency believes that additional data sources that can track adverse outcomes of interest associated with the TIRF products are necessary, and the TRIG must study intermediate objectives more closely related to the REMS intervention. The FDA proposes a meeting with the TRIG to discuss and explore new approaches to assessing this REMS with the goal of gathering useful information to better understand the impact of the REMS and to improve the program going forward. We refer to the July 21, 2016, FDA electronic communication in which comments on the patient, prescriber, and pharmacist surveys were conveyed based upon the 48 month REMS assessment results. We acknowledge the subsequent agreement between the Agency and the TRIG that the survey results for the 60 month TIRF REMS assessment will be submitted to the Agency on February 17, 2017. Reference ID: 4012463 FDA_7706 NDA 202788 MF 27320 Page 6 If you have any questions, call Mark Liberatore, PharmD; Safety Regulatory Project Manager, at (301) 796-2221. Sincerely, {See appended electronic signature page} Judith A. Racoosin, MD, MPH Deputy Director of Safety Division of Anesthesia, Analgesia, and Addiction Products Office of Drug Evaluation II Center for Drug Evaluation and Research Reference ID: 4012463 FDA_7707 --------------------------------------------------------------------------------------------------------This is a representation of an electronic record that was signed electronically and this page is the manifestation of the electronic signature. --------------------------------------------------------------------------------------------------------/s/ ---------------------------------------------------JUDITH A RACOOSIN 11/10/2016 Reference ID: 4012463 FDA_7708 DOCUMENT INFORMATION PAGE This page is for FDA internal use only. Do NOT send this Lage with the letter. Application Communication Type: Communication Group: Communication Name: Communication ID: Drafted by: Clearance History: Finalized: Filename: Signatory Authority: L'se Statement: Notes: Version: 08/2 3/20 16 NDA 202788 onespondence Safety REMS Modi?cation Noti?cation OR-SEC 901REMS-06 M. Liberatore 2/ 6/ 1 7. 4/6/17 DRISK 3/6/17 J. Racoosin 3/6/17 M. Sulliva114/ 7 M. Liberatore 4/ 10/1 7 DDS. Division Director. or Deputy. Person who is covering for the signatOIy authority can sign 011 their behalf the signature block on the letter will not change). FDA determines that a modi?cation to an approved REMS is required Please ensm?e all review disciplines. including DRISK. have provided input on the letter END OF DOCUNIENT INFORMATION PAGE The letter begins on the next page. Reference ID: 4082020 DEPARTMENT OF HEALTH AND HUMAN SERVICES Food and Drug Administration Silver Spring MD 20993 NDA 202788 REMS MODIFICATION NOTIFICATION Insys Development Co., Inc. c/o Insys Therapeutics, Inc. 1333 South Spectrum Blvd. Suite # 100 Chandler, AZ 85286 Attention: Stephen Sherman Vice President, Regulatory Affairs Dear Mr. Sherman: Please refer to your New Drug Application (NDA) submitted under section 505(b) of the Federal Food, Drug, and Cosmetic Act (FDCA) for SUBSYS (fentanyl sublingual spray), which is part of a shared system Risk Evaluation and Mitigation Strategy (REMS), the Transmucosal Immediate-Release Fentanyl (TIRF) REMS access program. RISK EVALUATION AND MITIGATION STRATEGY REQUIREMENT The TIRF REMS, of which SUBSYS is a member, was originally approved on December 28, 2011, and the most recent REMS modification was approved on December 24, 2014. The REMS consists of a Medication Guide, elements to assure safe use, an implementation system, and a timetable for submission of assessments of the REMS. We also refer to our letters dated March 22, and August 31, 2016, notifying you, under Section 505(o)(4) of the FDCA, of new safety information that we believe should be included in the labeling for SUBSYS, and the approval of the safety labeling changes on December 16, 2016. Those labeling changes pertained to the risks of misuse, abuse, addiction, overdose, death and neonatal opioid withdrawal syndrome; serotonin syndrome with concomitant use of serotonergic drugs; adrenal insufficiency; androgen deficiency; and profound sedation, respiratory depression, coma, and death associated with the concomitant use of opioid analgesics and benzodiazepines or other central nervous system depressants, including alcohol. In accordance with section 505-1(g)(4)(B) of the FDCA, we have determined that the approved TIRF REMS, of which SUBSYS is a member, must be modified to ensure that the benefits of the drug outweigh its risks. This determination is based on the need to make changes to the the approved REMS consistent with the safety labeling changes approved on December 16, 2016. Reference ID: 4082020 FDA_7710 NDA 202788 Page 2 Your proposed modified REMS must include modifications to the REMS document, appended materials, and REMS supporting document consistent with the safety label changes approved on December 16, 2016. The timetable for submission of assessments of the proposed modified REMS may remain the same as that approved on June 5, 2012. The proposed REMS modification submission should include a new proposed REMS document and appended REMS materials, as appropriate, that show the complete previously approved REMS with all proposed modifications in track changes. In addition, the submission should also include an update to the REMS supporting document that includes a description of all proposed modifications and their potential impact on other REMS elements. Revisions to the REMS supporting document should be submitted with all changes in track changes. Because we have determined that a modified REMS as described above is necessary to ensure the benefits of SUBSYS outweigh the risks, you must submit a proposed REMS modification within 60 days of the date of this letter. The TIRF REMS Implementation Group (TRIG) should submit the proposed modified REMS to DMF 27320. In accordance with 21 CFR §§ 314.97 and 314.70, and as described in FDA’s draft guidance for industry on Risk Evaluation and Mitigation Strategies: Modifications and Revisions (April 2015), REMS modifications due to approved safety labeling changes are considered major changes that require approval prior to distribution; therefore, submit your cross-reference submission as a Prior Approval Supplement (PAS) to your NDA. Because FDA is requiring the REMS modifications in accordance with section 505-1(g)(4)(B), you are not required to submit an adequate rationale to support the proposed modifications, as long as the proposals are consistent with the modifications described in this letter. If the proposed REMS modification supplement includes changes that differ from the modifications described in this letter, an adequate rationale is required for those additional proposed changes in accordance with section 505-1(g)(4)(A). Prominently identify the submission with the following wording in bold capital letters at the top of the first page of the submission: NEW SUPPLEMENT FOR NDA 202788/S-000 PRIOR APPROVAL SUPPLEMENT PROPOSED REMS MODIFICATIONS DUE TO SAFETY LABEL CHANGES SUBMITTED IN SUPPLEMENT XXX Prominently identify subsequent submissions related to the proposed REMS modification with the following wording in bold capital letters at the top of the first page of the submission: Reference ID: 4082020 FDA_7711 NDA 202788 Page 3 NDA 202788/S-000 PROPOSED REMS MODIFICATION-AMENDMENT To facilitate review of your submission, we request that you submit your proposed modified REMS and other REMS-related materials in Microsoft Word format. If certain documents, such as enrollment forms, are only in PDF format, they may be submitted as such, but the preference is to include as many as possible in Word format. SUBMISSION OF REMS DOCUMENT IN SPL FORMAT In addition to submitting the proposed modified REMS as described above, you can also submit the REMS document in Structured Product Labeling (SPL) format. If you intend to submit the REMS document in SPL format, include the SPL file with your proposed REMS modification submission. For more information on submitting REMS in SPL format, please email REMS Website@fda.hhs.gov. If you do not submit electronically, please send 5 copies of your submission. If you have any questions, call Mark Liberatore, PharmD, Safety Regulatory Project Manager, at (301) 796-2221. Sincerely, {See appended electronic signature page} Judith A. Racoosin, MD, MPH Deputy Director for Safety Division of Anesthesia, Analgesia, and Addiction Products Office of Drug Evaluation II Center for Drug Evaluation and Research Reference ID: 4082020 FDA_7712 --------------------------------------------------------------------------------------------------------This is a representation of an electronic record that was signed electronically and this page is the manifestation of the electronic signature. --------------------------------------------------------------------------------------------------------/s/ ---------------------------------------------------JUDITH A RACOOSIN 04/10/2017 Reference ID: 4082020 FDA_7713 Accenture LLP 1160 West Swedesford Road i - - - - wi?flcentlf?cim accen ure December 28, 2016 Food and Drug Administration Center for Drug Evaluation and Research Central Document Room Drug Master File Staff 5901-B Ammendale Road Beltsville, MD 20705-1266 Re: DMF 027320 Holder: McKesson Specialty Health (McKesson) DIVIF Subject: Transmucosal Immediate Release Fentanyl (TIRF) Access Program Re: REMS Shared Program DNIF Type: DMF Submission Information: Clinical/Clinical Information REMS Submission Identi?er: Assessment Sequence Number: 0027 Dear Drug Master File Staff: This Type DMF contains the Risk Evaluation and Mitigation Strategy (REMS) for Transmucosal Immediate Release Fentanyl for the Shared System REMS program. McKesson herewith provides the REMS Assessment 6 at 5 years. McKesson states that the information provided in this Master File is current and assure that the material ?Jrnished will meet the speci?cations described herein. McKesson also con?rms that the Holder obligations are observed. We request that all information in this ?le be treated as con?dential commercial information by the Food and Drug Administration pursuant to 21 C.F.R. ?20.6l, and that no information from this ?le be provided to any unauthorized persons without the express written consent of the DMF holder- If you have any questions or concerns, please do not hesitate to contact Debra Hackett, US. Agent for McKesson, at 610?407-1729 or alternatively via email at debra.hackett@accenture.com. Thank you. Sincerely, Debra Hackett, Senior Regulatory Project Manager, Regulatory Affairs US. Agent, Accenture, LLP Attachments: Table of Contents for the submission Electronic Submission Speci?cations CONFIDENTIAL 1 DMF #027320 - Sequence 0027 Shared System REMS Table of Contents Page 1 of 1 Assessment – 5 years Module Section Description 1.2 Cover Letter Cover Letter w/ Attachments 1.16 – Risk Management Plans REMS History REMS Assessment – 5 years FDA_4012 Electronic Submission Specifications This submission is compliant with FDA's Guidelines for Industry and current eCTD specifications. All files were checked and verified to be free of viruses prior to transmission through the electronic submission gateway. Anti-Virus Program Program Version Virus Definition Date Submission Size Symantec Endpoint Protection Edition 12.1.5337.5000 12/20/2016 rev. 20 Approx. 9.6 MB The IT point of contact for this submission is: Name Phone Number Email Address Matt Francis 1-610-407-1854 Matthew.p.francis@accenture.com FDA_4013 ADMINISTRATIVE INFORMATION Holder’s Name: McKesson Specialty Health (McKesson) Holder’s Address: 4343 N. Scottsdale Road Suite 150 Scottsdale, AZ 85251 Holder’s Contact Person: Laura Baloun Contact’s Address: 4343 N. Scottsdale Road Suite 150 Scottsdale, AZ 85251 Contact’s Phone: 480-663-4009 Contact’s Fax: 480-663-4973 Contact’s Email address: laura.baloun@mckesson.com Statement of Commitment: Attached, please find a signed statement of commitment. The statement certifies that the DMF 027320 is current and that McKesson will comply with the statements made in it. Agent’s Name: Accenture, LLP Agent’s Address: 1160 West Swedesford Road, Building One Berwyn, PA 19312 Agent’s Contact Person: Debra Hackett, Senior Regulatory Project Manager, Regulatory Affairs Contact’s Address 1160 West Swedesford Road, Building One Berwyn, PA 19312 Contact’s Phone: 610-407-1729 Contact’s Fax: 610-407-8433 Contact’s E-mail address: debra.hackett@accenture.com FDA_4014 DMF #027320; Sequence 0027 Shared System REMS Modification Date No. Approved 1 June 5, 2012 REMS History Page 1 of 8 Documents Affected Overview of Modification   Sequence 0002: Edits to Patient-Prescriber Agreement Form, the addition of the Closed System Pharmacy Enrollment Form*, the addition of the newly approved TIRF product, Subsys (fentanyl sublingual spray) and minor editorial changes.                 REMS Prescriber Program Overview Education Program Prescriber Enrollment Form Patient Provider Agreement Form Patient and Caregiver Overview Dear Healthcare Provider Letter Outpatient Pharmacy Overview Chain Pharmacy Overview Inpatient Pharmacy Overview Outpatient Pharmacy Enrollment Form Chain Pharmacy Enrollment Form Inpatient Pharmacy Enrollment form Outpatient Pharmacy Letter Inpatient Pharmacy Letter Dear Distributor Letter Distributor Enrollment Form Supporting Document *The Closed System Pharmacy Enrollment Form was not formally submitted through the Gateway but was submitted via email on May 18, 2012 and included in the June 5, 2012 FDA approval letter. FDA_4015 DMF #027320; Sequence 0027 Shared System REMS Modification Date No. Approved N/A N/A 2 November 7, 2013 N/A N/A 2 November 7, 2013 REMS History Page 2 of 8 Documents Affected Overview of Modification Assessment Report 1 at 6 months – due 06/28/2012 Sequence 0003: Assessment report covering 12/28/2011 to 04/27/2012 Draft Documents submitted on or before 09/28/2012  Chain Pharmacy Enrollment Form  Outpatient Pharmacy Enrollment Form  Closed System Pharmacy Overview  Education Program  Frequently Asked Questions (FAQ)  Outpatient Pharmacy Letter  REMS  Supporting Document Assessment Report 2 at 1 year – due 12/28/2012 Amendment to 09/28/2012 supplement:  Chain Outpatient Pharmacy Enrollment Form  Independent Outpatient Pharmacy Enrollment Form  Closed System Outpatient Pharmacy Enrollment Form  Inpatient Sequence 0004: Modification proposed to:  Incorporate closed system pharmacies into the TIRF REMS Access Program  Correct minor inconsistencies between the FDA provided versions and the current PDF versions of REMS materials Sequence 0005: Assessment Report covering 04/28/2012 to 10/28/2012 Sequence 0006: Modification proposed to:  Revised terminology, processes, and definitions for outpatient pharmacies  Revised attestations for physicians and patients to address concerns regarding patient access  Revised Program Overview and Frequently Asked Questions to improve clarity and content FDA_4016 DMF #027320; Sequence 0027 Shared System REMS Modification Date No. Approved REMS History Page 3 of 8 Documents Affected                  Pharmacy Enrollment Form Distributor Enrollment Form Prescriber Enrollment Form Patient Provider Agreement Form Chain Outpatient Pharmacy Overview Independent Outpatient Pharmacy Overview Closed System Outpatient Pharmacy Overview Inpatient Pharmacy Overview Patient and Caregiver Overview Prescriber Overview Education Program Knowledge Assessment Frequently Asked Questions (FAQ) Dear Outpatient Pharmacy Letter Dear Inpatient Pharmacy Letter Dear Healthcare Provide Letter Dear Distributor Letter REMS Overview of Modification  Updated REMS materials to reflect the completion of the transition phase for the TIRF REMS Access Program FDA_4017 DMF #027320; Sequence 0027 Shared System REMS Modification Date No. Approved REMS History Page 4 of 8 Documents Affected Overview of Modification  N/A N/A N/A N/A 3 December 24, 2014 Supporting Document  Website Landing Page Assessment Report 3 at 2 years – due 12/28/2013 Safety Surveillance Report #1 – due 03/31/2014            REMS Prescriber Program Overview Education Program Prescriber Enrollment Form Patient and Caregiver Overview Independent Outpatient Pharmacy Overview Chain Outpatient Pharmacy Overview Closed System Outpatient Pharmacy Overview Inpatient Pharmacy Overview Independent Outpatient Pharmacy Enrollment Form Chain Outpatient Sequence 0007: Assessment Report covering 10/29/2012 to 10/28/2013 Sequence 0008: Safety surveillance data covering Q4 2012 to Q3 2013 Sequence 0009: Modification proposed to:  Updated REMS materials to eliminate product specific information which does not impact the safe use of TIRF products  Updated REMS materials to reference the currently approved TIRF products list on the FDA Approved REMS website  Updated REMS materials to remove reference to deactivating patients shown to have multiple prescribers in an overlapping timeframe  Incorporated revised assessment metrics into the Supporting Document  Revised Education Program to emphasize and strengthen appropriate conversion FDA_4018 DMF #027320; Sequence 0027 Shared System REMS Modification Date No. Approved REMS History Page 5 of 8 Documents Affected       N/A N/A N/A N/A 3 December 24, 2014 Pharmacy Enrollment Form Closed System Outpatient Pharmacy Enrollment Form Inpatient Pharmacy Enrollment form Distributor Enrollment Form FAQ Supporting Document Website Prototype Cash Claim Information Request Response – due 05/30/2014 DMF Annual Report – due 08/20/2014  REMS  Prescriber Program Overview  Education Program  Knowledge Assessment  Prescriber Enrollment Form  Patient and Caregiver Overview  Independent Outpatient Overview of Modification   and patient counseling information Updated REMS and Supporting Document to clarify deactivation of a patient PPAF as opposed to the patient record Updated pharmacy overview documents and  FAQ to call out cash claim requirement  Updated TIRF REMS Access website to incorporate items above and link respective Full Prescribing Information and Medication Guides to DailyMed Sequence 0010: Response to 5/16/2014 FDA Cash Claim Information Request Sequence 0011: DMF Annual Report Sequence 0012: Modification proposed to:  Updated REMS materials to eliminate product specific information which does not impact the safe use of TIRF products  Updated REMS materials to reference the TIRF Products webpage on the TIRF REMS Access website  Updated REMS FDA_4019 DMF #027320; Sequence 0027 Shared System REMS Modification Date No. Approved REMS History Page 6 of 8 Documents Affected            Pharmacy Overview Chain Outpatient Pharmacy Overview Closed System Outpatient Pharmacy Overview Inpatient Pharmacy Overview Independent Outpatient Pharmacy Enrollment Form Chain Outpatient Pharmacy Enrollment Form Closed System Outpatient Pharmacy Enrollment Form Inpatient Pharmacy Enrollment form Distributor Enrollment Form FAQ Supporting Document Website Prototype Overview of Modification       materials to remove reference to deactivating patients shown to have multiple prescribers in an overlapping timeframe Incorporated revised assessment metrics into the Supporting Document Revised Education Program to emphasize and strengthen appropriate conversion and patient counseling information Updated REMS and Supporting Document to clarify deactivation of a patient PPAF as opposed to the patient record Updated pharmacy overview documents and FAQ to call out cash claim requirement Updated TIRF REMS Access website to incorporate items above and link respective Full Prescribing Information and Medication Guides to DailyMed Updated Education Program and Knowledge Assessment to incorporate approved labeling supplement FDA_4020 DMF #027320; Sequence 0027 Shared System REMS Modification Date No. Approved 3 December 24, 2014 REMS History Page 7 of 8 Documents Affected Overview of Modification Unchanged from Sequence 0012, plus:  Dear Healthcare Provider Letter  Dear Outpatient Pharmacy Letter  Dear Inpatient Pharmacy Letter  Dear Distributor Letter Sequence 0013: Unchanged from Sequence 0012, plus:  Dear Healthcare Provider Letter  Dear Outpatient Pharmacy Letter  Dear Inpatient Pharmacy Letter  Dear Distributor Letter N/A N/A Assessment Report 4 at 3 years – due 12/28/2014 Sequence 00014: Assessment Report covering 10/29/2013 to 10/28/2014 N/A N/A BioDelivery Sciences International – Letter of Authorization Sequence 0015: BioDelivery Sciences International – Letter of Authorization N/A N/A Actavis Laboratories Inc. – Letter of Authorization Sequence 0016: Actavis Laboratories Inc. – Letter of Authorization N/A N/A DMF Annual Report – due 08/20/2015 Sequence 0017: DMF Annual Report N/A N/A 36-Month Assessment – Consolidated Information Requests N/A N/A Assessment Report 5 at 4 years – due 12/28/2015 N/A N/A N/A N/A Sentnyl Therapeutics, Inc. – Letter of Authorization Withdraw Authorization for Galena BioPharma, Inc. Sequence 0018: Response to FDA 36Month Assessment Information Requests Sequence 00019: Assessment Report covering 10/29/2014 to 10/28/2015 Sequence 00020: Sentnyl Therapeutics, Inc. – Letter of Authorization Sequence 00021: Letter of Authorization/Withdrawn Letter of Authorization FDA_4021 DMF #027320; Sequence 0027 Shared System REMS Modification Date No. Approved N/A N/A REMS History Page 8 of 8 Documents Affected Overview of Modification Administrative Change; Change in US Agent 48-Month REMS Supplemental Assessment Report Sequence 00022: Administrative Change; Change in US Agent Sequence 00023: 48-Month REMS Supplemental Assessment Report Sequence 0024: DMF Annual Report N/A N/A N/A N/A DMF Annual Report – due 08/20/2016 N/A Administrative Change; Change in US Agent Assessment Report 6 at 5 years – due 12/28/2016 7N/A NA N/A Sequence 00025: Administrative Change; Change in US Agent Sequence 0027: Assessment Report covering 10/29/2015 to 10/28/2016 FDA_4022 60-Month REMS Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 1 of 112 Title: Transmucosal Immediate-Release Fentanyl (TIRF) Risk Evaluation and Mitigation Strategy (REMS) Access Program 60-Month FDA REMS Assessment Report Reporting Timeframe: 29 OCT 2015 to 28 OCT 2016 Document Number: Final 1.0 Product Name: Transmucosal Immediate-Release Fentanyl Sponsor: TIRF REMS Industry Group (TRIG) of Companies: Actavis Laboratories FL, Inc. BioDelivery Sciences International, Inc. Cephalon, Inc. (a wholly-owned subsidiary of Teva Pharmaceutical Industries, Ltd.) Depomed, Inc. Insys Therapeutics, Inc. Mallinckrodt Pharmaceuticals Mylan, Inc. Par Pharmaceutical, Inc. Sentynl Therapeutics, Inc. Confidentiality Statement The information contained herein is confidential and the proprietary property of the TRIG of Companies and its affiliates, and any unauthorized use or disclosure of such information without the prior written authorization of the TRIG is expressly prohibited. FDA_4023 60-Month REMS Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 2 of 112 TABLE OF CONTENTS Pg LIST OF TABLES ................................................................................................................... 5 LIST OF FIGURES ................................................................................................................. 7 LIST OF ABBREVIATIONS ................................................................................................. 8 OVERVIEW ........................................................................................................................... 10 1 BACKGROUND ........................................................................................................ 15 2 REMS GOALS ........................................................................................................... 17 3 SUPPORTING INFORMATION ON PROPOSED REMS ELEMENTS ........... 17 3.1 Additional Elements ................................................................................................ 18 3.1.1 Medication Guide ..................................................................................... 18 3.1.2 Letters to Healthcare Professionals .......................................................... 18 3.2 Elements to Assure Safe Use .................................................................................. 18 3.2.1 3.3 Prescription Verification........................................................................... 19 Implementation System........................................................................................... 20 3.3.1 Wholesaler/Distribution Enrollment and Fulfillment ............................... 20 3.3.2 The TIRF REMS Access Program Compliance [Metric 22] .................... 21 3.3.3 TIRF REMS Access Program Call Center ............................................... 21 4 REMS ASSESSMENT PLAN METHODS ............................................................. 21 4.1 Data Sources for REMS Assessments .................................................................... 26 4.1.1 The TIRF REMS Access Program and Product Utilization Statistics...... 26 4.1.2 Dispensing Activity for Enrolled Pharmacies .......................................... 27 4.1.3 Program Infrastructure and Performance.................................................. 27 4.1.4 TIRF REMS Access Program Non-Compliance Plan .............................. 28 4.1.4.1 Non-Compliance Monitoring.................................................................... 29 4.1.5 Safety Surveillance ................................................................................... 29 4.1.6 Periodic Surveys of Patients, Prescribers, and Pharmacies ...................... 31 5 RESULTS ................................................................................................................... 31 5.1 REMS Program Utilization ..................................................................................... 31 5.1.1 Patient Enrollment [Metric 1 and 2] ......................................................... 31 5.1.2 Prescriber Enrollment and Inactivations [Metric 3, 4, 5] ......................... 32 FDA_4024 60-Month REMS Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 3 of 112 5.1.3 Pharmacy Enrollment, Inactivation, and Education [Metric 6, 7, 8] ........ 35 5.1.4 Wholesaler/Distributor Enrollment [Metric 9 and 10] ............................. 41 5.1.5 Dispensing Activity [Metric 11, 12, 13] ................................................... 42 5.1.5.1 Prescriptions Authorized [Metric 11] ....................................................... 42 5.1.5.2 Prescriptions Encountering REMS-related Rejections [Metric 12].......... 44 5.1.5.3 Time to Authorization [Metric 13] ........................................................... 54 5.1.5.4 Prescription Authorizations for Closed-system Pharmacy Entities [Metric 11] ................................................................................................ 56 5.1.6 5.2 Barriers or Delays in Patient Access [Metric 14 and 15] ......................... 59 Program Infrastructure and Performance [Metrics 16, 17, 18, 19] ......................... 64 5.2.1 Backup System for Prescription Validation [Metric 16] .......................... 64 5.2.2 System Interruptions/Errors and Corrective Actions [Metric 17, 19] ...... 64 5.2.3 REMS Call Center [Metric 18] ................................................................. 64 6 TIRF REMS ACCESS PROGRAM NON-COMPLIANCE ................................. 65 6.1 Non-Compliance Feedback from the 48-Month FDA Acknowledgement Letter .. 65 6.2 Stakeholder Non-Compliance [Metric 23, 24, 25, 26, 27, 28] ................................ 66 6.3 Audits ...................................................................................................................... 75 6.3.1 6.3.1.1 6.3.2 7 Closed System Pharmacy Audits [Metric 20] .......................................... 75 Closed System Pharmacy Audit Acknowledgement Letter Items ............ 80 Inpatient Hospital Pharmacy Audits [Metric 21]...................................... 81 SAFETY SURVEILLANCE ..................................................................................... 82 7.1 Adverse Event Reporting [Metric 29] ..................................................................... 82 7.2 TRIG Sponsor Adverse Event Data of Interest [Metric 30] ................................... 82 7.3 Number of Adverse Events of Special Interest ....................................................... 83 7.4 TIRF Product Surveillance Data [Metric 31] .......................................................... 96 7.4.1 Background ............................................................................................... 96 7.4.2 RADARS Results ..................................................................................... 97 8 PERIODIC SURVEYS OF STAKEHOLDERS ................................................... 104 9 FDA COMMUNICATIONS ................................................................................... 104 10 POST-APPROVAL STUDIES AND CLINICAL TRIALS ................................. 104 11 DISCUSSION ........................................................................................................... 104 CONCLUSION .................................................................................................................... 106 FDA_4025 60-Month REMS Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies 12 Page 4 of 112 APPENDICES .......................................................................................................... 107 12.1 Non-Compliance Protocol..................................................................................... 108 12.2 Safety Surveillance Aggregate Line Listing Preferred Terms .............................. 109 12.3 Safety Surveillance Aggregate Line Listing of Deaths ......................................... 110 12.4 RADARS System Program Report Protocol ........................................................ 111 12.5 RADARS System Program Report ....................................................................... 112 FDA_4026 60-Month REMS Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 5 of 112 LIST OF TABLES Table 1 TIRF Medicines ............................................................................................................16 Table 2 Assessment Report Periods ...........................................................................................16 Table 3 48-Month FDA Assessment Report Acknowledgement Letter Requests .....................22 Table 4 Patient Enrollment.........................................................................................................32 Table 5 Prescriber Enrollment ...................................................................................................32 Table 6 Prescriber Inactivations .................................................................................................33 Table 7 Prescribers Pending Enrollment ....................................................................................34 Table 8 Pharmacy Enrollment ....................................................................................................35 Table 9 Pharmacy Inactivations .................................................................................................37 Table 10 Pharmacies Pending Enrollment ..................................................................................40 Table 11 Distributor Enrollment ..................................................................................................41 Table 12 Distributor Inactivations................................................................................................42 Table 13 Prescriptions from Outpatient Pharmacies That Did Not Encounter Any REMSRelated Rejections Prior to Being Authorized for Dispensing .....................................43 Table 14 Reasons for Prescriptions Not Meeting REMS Edit Requirements ..............................44 Table 15 Prescriptions from Outpatient Pharmacies That Encountered at Least One REMSRelated Rejection Prior to Being Authorized for Dispensing .......................................46 Table 16 Prescriptions That Encountered at Least One REMS-Related Rejection and Never Authorized for Dispensing from Outpatient Pharmacies ..............................................50 Table 17 Time to Authorization for a Prescription that Experienced at Least One Initial REMS-Related Rejection ..............................................................................................54 Table 18 Distribution of Time to Authorization for a Prescription that Experienced at Least One Initial REMS-Related Rejection by Pharmacy Type and Overall for the Current Reporting Period ..............................................................................................55 Table 19 Number of Prescription Authorizations per Closed System Pharmacy ........................57 Table 20 Prescriptions Dispensed During the First 10 Days after Passive Patient Enrollment ...61 Table 21 Prescriptions Dispensed Beyond the First 10 Days after Passive Patient Enrollment Without a PPAF ............................................................................................................63 Table 22 Current Assessment Period Contact Reasons ...............................................................64 Table 23 Rates of Prescriber 2 Scenario Cases Over Time..........................................................66 Table 24 Non-Compliance Activity Reports by Stakeholder in the Current Reporting Period: 29 October 2015 to 28 October 2016 ............................................................................67 FDA_4027 60-Month REMS Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 6 of 112 Table 25 Non-Compliance Reports in the Current Reporting Period: 29 October 2015 to 28 October 2016 .................................................................................................................70 Table 26 Closed System Pharmacy Audits ..................................................................................76 Table 27 Number of Cases of Adverse Events of Special Interest ..............................................83 Table 28 Rate of Adverse Events by Total Prescriptions ............................................................84 Table 29 Rate of Adverse Events by Total Patients .....................................................................86 Table 30 Cases of Addiction Received from TRIG Sponsors during the Reporting Period: 29 August 2015 - 28 August 2016 .....................................................................................88 Table 31 New Cases of Addiction Received from TRIG Sponsors in 2016 from a Previous Reporting Period ...........................................................................................................90 Table 32 Cases of Overdose Received from TRIG Sponsors during the Reporting Period: 29 August 2015 - 28 August 2016 .....................................................................................92 Table 33 New Cases of Overdose Received from TRIG Sponsors in 2016 from a Previous Reporting Period ...........................................................................................................93 Table 34 Cases of Pediatric Exposures Received from TRIG Sponsors during the Reporting Period: 29 August 2015 - 28 August 2016 ....................................................................95 Table 35 RADARS System: Data Sources and Specific Events.................................................96 Table 36 Summary of RADARS Findings by Program, Outcome, and Denominator ..............100 FDA_4028 60-Month REMS Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 7 of 112 LIST OF FIGURES Figure 1 Distribution of Time to Authorization for a Prescription that Experienced at Least One Initial REMS-Related Rejection for the Current Reporting Period ...................... 56 FDA_4029 60-Month REMS Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 8 of 112 LIST OF ABBREVIATIONS AE Adverse Event ANDA Abbreviated New Drug Application AR Authorized Representative BTP Breakthrough Pain CAP Corrective Action Plan CFR Code of Federal Regulations DEA Drug Enforcement Administration DMF Drug Master File DoD Department of Defense ETASU Elements to Assure Safe Use FDA Food and Drug Administration HCP ID IR KAB LTC MedDRA Healthcare Provider Identification Immediate Release Knowledge, Attitude, and Behavior Long-Term Care Medical Dictionary for Drug Regulatory Activities NCPDP NCRT NDA NDC NPI OTP PMS PPAF PT RADARS® REMS REMS edits National Council for Prescription Drug Program Non-Compliance Review Team New Drug Application National Drug Code National Provider Identifier Opioid Treatment Program Pharmacy Management System Patient-Prescriber Agreement Form Preferred Terms Researched Abuse, Diversion and Addiction-Related Surveillance Risk Evaluation and Mitigation Strategy Checks conducted by the TIRF REMS Access Program to confirm that all safety requirements were met Standard Operating Procedure SOP FDA_4030 60-Month REMS Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies TIRF Transmucosal Immediate-Release Fentanyl TIRF Medicines Transmucosal Immediate-Release Fentanyl product(s) TIRF REMS Access REMS program for TIRF medicines TIRF Sponsors The group of sponsors that are submitting this REMS TRIG TIRF REMS Industry Group UBC United BioSource Corporation US VA United States Veteran’s Association Page 9 of 112 FDA_4031 60-Month REMS Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 10 of 112 OVERVIEW The Transmucosal Immediate-Release Fentanyl (TIRF) Risk Evaluation and Mitigation Strategy (REMS) Access program was approved by the Food and Drug Administration (FDA) on 28 December 2011 for ABSTRAL®, ACTIQ®, FENTORA®, LAZANDA®, ONSOLIS®, SUBSYS® and generic versions of these TIRF medicines. The TIRF REMS Access program was successfully launched on 12 March 2012, approximately 11 weeks after REMS approval. As of 12 March 2016, the TIRF REMS Access program has been fully implemented for 4 years. The shared system REMS includes a Medication Guide; Elements to Assure Safe Use (ETASU) of prescriber and pharmacy certification, and dispensing to outpatients with evidence of safe use conditions; an Implementation System, and a Timetable for Submission of Assessments. In the last 4 years, the TIRF REMS Access program assessment reports were submitted according to the following schedule: Assessment Report Reporting Period Submission Date 6-Month 28 December 2011 - 27 April 2012 28 June 2012 12-Month 28 April 2012 - 28 October 2012 28 December 2012 24-Month 29 October 2012 - 28 October 2013 28 December 2013 36-Month 29 October 2013 – 28 October 2014 28 December 2014 48-Month 29 October 2014 – 28 October 2015 28 December 2015 This sixth REMS assessment report (60-Month) covers the timeframe from 29 October 2015 to 28 October 2016. As per agreement with FDA, safety surveillance analyses have slightly different time periods as noted in the relevant sections within the report. In addition to the annual submission cycle, a Supplemental Report was submitted to FDA in May 2016. This report included responses to multiple new requests communicated in the 36Month FDA Assessment Report Acknowledgement Letter that could not be included in the December 2015 submission based on timing of the feedback. The FDA agreed to this approach on 08 September 2015 and the report was submitted prior to the deadline of 04 May 2016. On 21 July 2016, FDA provided feedback on the patient, prescriber, and pharmacist surveys. After careful review of the requested changes, the TRIG notified FDA that in order to incorporate all changes, an extension for report submission would be required. As proposed by FDA on 29 July 2016 and agreed to by the TRIG on 01 August 2016, the 60-month KAB survey results will be submitted separately from the overall REMS assessment report on or before 17 February 2017. Additional requests included in the 48-Month FDA Assessment Report Acknowledgement Letter will also be included in the 17 February 2017 submission as requested by FDA and detailed in Section 4. FDA_4032 60-Month REMS Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 11 of 112 Prescriber Enrollment At the end of this reporting period, 8,151 prescribers were enrolled in the TIRF REMS Access program. A total of 1,446 were newly enrolled in the TIRF REMS Access program and 2,631 prescribers successfully re-enrolled during the reporting period. A total of 3,635 prescribers became inactivated, with 3,616 (99.5%) due to expiration of their enrollment at some time during the reporting period. A few prescribers were inactivated because they opted out of the program or were deceased. Of these prescribers who became inactivated during the reporting period due to enrollment expiration, 76.4% had enrollment that remained expired at the end of the period with the remaining 23.6% re-enrolled prior to the end of the reporting period. During this reporting period, 54 prescribers attempted enrollment but were still pending 3 to 6 months after initiating the enrollment process and 194 prescribers were pending enrollment for longer than 6 months since initiating the enrollment process. The most common reasons for pending enrollment were: training not complete, no attestation, the provided Drug Enforcement Administration (DEA) number did not have the correct schedule for prescribing TIRF medicines, knowledge assessment failure on the first attempt, and invalid DEA number. Pharmacy Enrollment At the end of this reporting period, 42,665 pharmacies were enrolled (had activity in this reporting period or remained enrolled from the previous reporting period) in the TIRF REMS Access program. A total of 1,537 pharmacies were newly enrolled in the TIRF REMS Access program during this reporting period. Of the newly enrolled dispensing pharmacies (e.g., excluding pharmacy headquarters), 1,026 were chain pharmacy stores, 387 were independent outpatient pharmacies, 114 were inpatient pharmacies, and 8 were closed system pharmacy locations. During this reporting period, a total of 4,723 dispensing (i.e., not chain pharmacy headquarters) pharmacies were inactivated, with 4,488 inactivations due to expiration of their enrollment. Of those dispensing pharmacies inactivated during the reporting period for enrollment expiration, 53.8% (n=2,416) remained expired at the end of the period, and the remaining 46.2% (n=2,072) re-enrolled prior to the end of the reporting period. A total of 39 pharmacies attempted enrollment but were still pending 3 to 6 months after initiating the process and a total of 209 pharmacies were pending enrollment for longer than 6 months. The most common reasons for pending enrollment were no attestation, pending test transaction verification, and training not complete. Distributors Enrollment During the reporting period, there was 1 newly enrolled distributor and 20 distributors that reenrolled. There were 5 distributors inactivated during the reporting period due to enrollment expiration; 2 of these distributors had re-enrolled by the end of the reporting period. Although there were 3 distributors whose enrollment expired during the reporting period and whose enrollment remained expired as of the end of the reporting period, access to TIRF medicines is unimpeded because these locations were acquired by other enrolled entities or were initially enrolled as the wrong stakeholder type. FDA_4033 60-Month REMS Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 12 of 112 Patients As of the end of the reporting period, 42,164 patients have been enrolled cumulatively; of these, 4,255 were newly enrolled in the TIRF REMS Access program during this reporting period. Because patients are passively enrolled with their first prescription, they are not required to reenroll at any point. Instead, prescribers must renew a patient’s Patient-Prescriber Agreement Form (PPAF) every 2 years. By the design of the program, a patient’s enrollment status will never change to inactivated. Dispensing Activity A total of 117,708 prescriptions were submitted to the TIRF REMS Access program for approval in the current reporting period, including 117,335 prescriptions from non-closed system pharmacies and 373 prescriptions from closed system pharmacies. Of the total prescriptions submitted for approval, 105,076 (89.3%) were approved for dispensing without encountering any REMS-related rejections. A total of 2,363 prescriptions encountered at least one REMS-related rejection prior to being authorized due to failure to meet REMS requirements for the prescriber and/or patient and/or pharmacy. An additional 10,269 prescriptions encountered at least one REMS-related rejection and were never authorized for dispensing. A single prescription may have been submitted and rejected multiple times. The average time for a prescription that had at least one REMS-related rejection to become authorized was 6.3 days (median 2.0 days). Non-Compliance During the current reporting period, 62 confirmed instances of stakeholder non-compliance with the TIRF REMS Access program requirements were reviewed and investigated. This included 54 prescriber reports, 7 non-closed system pharmacy reports, and 1 wholesaler/distributor report. There were no spontaneous closed system pharmacy reports. A description of these cases including 58 activity reports and 4 narratives are included in Section 6.2, Table 24 and Table 25, respectively. Closed System Pharmacy and Inpatient Pharmacy Audits Audits of 6 closed system pharmacy entities were conducted during this reporting period. Four closed system entities (ID#CS7, ID#CS9, ID#CS10, and ID#CS12) were found to be noncompliant with the TIRF REMS Access program requirements. These pharmacies were reeducated and issued a Notice for Non-Compliance by the Non-Compliance Review Team (NCRT). All 4 non-compliance cases have since been closed. A description of the audits and details of these cases and actions taken are provided in Section 6.3.1. Audits of 5 inpatient pharmacies were conducted during this reporting period and 1 inpatient pharmacy was identified as non-compliant. A description of the audit questionnaire and a summary of the audit findings is included in Section 6.3.2. FDA_4034 60-Month REMS Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 13 of 112 Safety Surveillance Data Safety surveillance data for this 60-Month FDA REMS Assessment Report consists of data from the Researched Abuse, Diversion and Addiction-Related Surveillance (RADARS®) System and aggregate adverse event (AE) data from all the TRIG sponsors. RADARS System Data Data from 5 RADARS System Programs that gather data from unique populations along the spectrum of drug abuse were used to monitor for the non-medical use (abuse and misuse) of TIRF products. Based on FDA request, the data included in this report compare event rates for a time period prior to full implementation of the TIRF REMS and a time period after REMS implementation. Descriptively, population rates for the TIRF products across all outcome variables were low compared to rates for the 3 Schedule II opioid comparator arms; while prescription adjusted rates for the TIRF products were higher than the rates for the 3 Schedule II opioid comparator arms. Findings were similar in the sensitivity analysis including hydrocodone in the Schedule II opioids group. In the Poison Center Program, there were only 5 intentional abuse mentions of TIRF products in the pre period, leaving little room for a decrease in the post period, and making this comparison under powered. Pre to post decreases were seen for 7 of the 24 outcome-rate combinations examined for TIRF products, yet only 1 was statistically significant (population rates among individuals entering opioid treatment programs). Lack of significance for the mean decreases may be due to lack of power driven by small event counts. A description of these data is included in Section 7.4 of this report, and the complete methods and results are included in the RADARS System Program Report Protocol and the RADARS System Program Report in Appendix 12.4 and Appendix 12.5, respectively. Aggregate Spontaneous Adverse Event Data of Interest Spontaneous AE data of interest including events of addiction, overdose, death, and pediatric exposures were provided by each sponsor and aggregated into one comprehensive line listing. A total of 353 unique case reports were identified as meeting the criteria for inclusion in the analysis based on case preferred terms and review of the case narrative information. Of the 353 cases, the highest proportion of reports had an outcome of death (344, 97.5%), and many reports had no cause of death provided. There were 6 (1.7%) reports of addiction, and 3 (0.8%) pediatric exposures. There were 4 (1.1%) reported overdoses to an identified TIRF product. After a review of the associated MedWatch Forms or narratives for root cause analysis, no reports of inappropriate conversions between TIRF products were noted. Additionally, none of the narratives indicated unintentional exposures or use by non-opioid tolerant patients. There were 3 reports of pediatric exposure. In all 3 of the reports, the medication was intentionally prescribed to the pediatric patient. When comparing the rate of AEs by prescription in the current reporting period (29 August 2015-28 August 2016) with the results in the 48-month report (29 August 201428 August 2015), the number of cases per 100,000 prescriptions decreased, respectively, for FDA_4035 60-Month REMS Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 14 of 112 addiction (6.8 vs. 10.7), overdose (4.5 vs. 5.3), and pediatric exposure (3.4 vs. 3.6). Conversely, the number of cases of death per 100,000 prescriptions increased in the current reporting period compared with the 48-month report period (389.4 vs. 261.3). When comparing the rate of AEs by patient in the current reporting period (29 August 201528 August 2016) with the results in the 48-month report (29 August 2014-28 August 2015), the number of cases per 100,000 patients decreased, respectively, for addiction (54.0 vs. 75.4) and overdose (36.0 vs. 37.7). A rate increase was observed in pediatric exposure (27.0 vs. 25.1) and death (3,097.2 vs. 1,846.5). Additional details are included in Section 7.2. Knowledge, Attitudes, and Behavior (KAB) Surveys As agreed to by FDA and the TRIG, the 60-month KAB survey results will be submitted separately from the overall REMS assessment report on or before 17 February 2017. FDA_4036 60-Month REMS Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies 1 Page 15 of 112 BACKGROUND Opioids remain the mainstay of treatment of moderate to severe pain, but their safe use requires careful consideration of proper patient selection and treatment characteristics in order to mitigate any inherent health risks. Opioids are formulated as both extended-release and immediate-release (IR) products. Extended-release or long acting opioid products are designed to provide extended analgesic activity to control persistent pain. TIRF medicines and short-acting opioid products have a rapid onset and short duration of action and are designed for the treatment of acute episodes of pain that ‘break through’ chronic pain control (breakthrough pain or ‘BTP’). All the TIRF medicines are short-acting fentanyl products. As with all high-potency opioid analgesics, there are significant potential risks associated with use and misuse of TIRF medicines, including acute respiratory depression, which may lead to death. With appropriate clinical use in opioid-tolerant patients these risks have been shown to be low. However, instances of diversion, overdose, and prescribing to opioid non-tolerant patients have led to serious and, on occasion, fatal AEs demonstrating that short-acting fentanyl products can pose a significant health risk if not used appropriately. The FDA has determined that a REMS is required to mitigate the risk of misuse, abuse, addiction, overdose, and serious complications due to medication errors with the use of TIRF medicines. The group of Sponsors who are submitting this 60-Month FDA REMS Assessment Report (Actavis Laboratories FL, Inc., BioDelivery Sciences International, Inc., Cephalon, Inc. [a wholly-owned subsidiary of Teva Pharmaceutical Industries, Ltd.], Depomed, Inc., Insys Therapeutics, Inc., Mallinckrodt Pharmaceuticals, Mylan, Inc., Par Pharmaceutical, Inc., and Sentynl Therapeutics, Inc.) are herein referred to as TIRF Sponsors. One company joined the TRIG during the reporting period: Sentynl Therapeutics, Inc. replaced Galena Biopharma on 09 January 2016. The TIRF REMS Access program is administered by McKesson Specialty Health and RelayHealth. This report has been prepared by United BioSource Corporation (UBC). The TIRF medicines subject to the TIRF REMS are itemized in Table 1 below. FDA_4037 60-Month REMS Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Table 1 Page 16 of 112 TIRF Medicines Product Name (active ingredient)/formulation NDA 22510, ABSTRAL (fentanyl) sublingual tablets NDA 20747, ACTIQ (fentanyl citrate) oral transmucosal lozenge and its authorized generic NDA 21947, FENTORA (fentanyl buccal tablet) NDA 22569, LAZANDA (fentanyl) nasal spray NDA 22266, ONSOLIS (fentanyl), buccal soluble film NDA 202788, SUBSYS (fentanyl sublingual spray) ANDA 77312, fentanyl citrate oral transmucosal lozenge ANDA 78907, fentanyl citrate oral transmucosal lozenge ANDA 79075, fentanyl buccal tablet Abbreviations: ANDA=Abbreviated New Drug Application; NDA=New Drug Application The TIRF REMS Access program addresses the current requirements set forth by the FDA and provided to TIRF Sponsors. The program will be monitored over time and modified when and where appropriate. The initial REMS was approved on 28 December 2011 and went live on 12 March 2012. The FDA required 6-month and 12-month reports during the first year after approval, and then annually thereafter (Table 2). Reporting periods for each assessment report are described below. Data cut-off is 60 days prior to the submission date. Due to availability of data and the time needed to generate/analyze the data, safety surveillance reporting utilizes a modified data cutoff. The RADARS System reporting includes data from 3rd quarter 2012 through 2nd quarter 2016 and the aggregate spontaneous AE data of interest includes data from 29 August 2015 through 28 August 2016. Table 2 Assessment Report Periods Assessment Report Reporting Period Submission Date 6-Month 28 December 2011 – 27 April 2012 28 June 2012 12-Month 28 April 2012 – 28 October 2012 28 December 2012 24-Month 29 October 2012 – 28 October 2013 28 December 2013 36-Month 29 October 2013 – 28 October 2014 28 December 2014 48-Month 29 October 2014 – 28 October 2015 28 December 2015 60-Month 29 October 2015 – 28 October 2016 28 December 2016 In addition to the annual submission cycle, a Supplemental Report was submitted to FDA in May 2016. This report included responses multiple new requests that were communicated in the 36-Month FDA Assessment Report Acknowledgement Letter that could not be included in the FDA_4038 60-Month REMS Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 17 of 112 December 2015 submission based on timing of the feedback. The FDA agreed to this approach on 08 September 2015 and the report was submitted prior to the deadline of 04 May 2016. On 21 July 2016, FDA provided feedback on the patient, prescriber, and pharmacist surveys. After careful review of the requested changes, the TRIG notified FDA that in order to incorporate all changes, an extension for report submission would be required. As proposed by FDA on 29 July 2016 and agreed to by the TRIG on 01 August 2016, the 60-month KAB survey results will be submitted separately from the overall REMS assessment report on or before 17 February 2017. Additional requests included in the 48-Month FDA Assessment Report Acknowledgement Letter will also be included in the 17 February 2017 submission as requested by FDA and detailed in Section 4. 2 REMS GOALS The goals of the TIRF REMS Access program are to mitigate the risks of misuse, abuse, addiction, overdose and serious complications due to medication errors by: 1. Prescribing and dispensing TIRF medicines only to appropriate patients, which includes use only in opioid-tolerant patients. 2. Preventing inappropriate conversion between TIRF medicines. 3. Preventing accidental exposure to children and others for whom it was not prescribed. 4. Educating prescribers, pharmacists, and patients on the potential for misuse, abuse, addiction, and overdose of TIRF medicines. 3 SUPPORTING INFORMATION ON PROPOSED REMS ELEMENTS The TIRF Sponsors are executing the TIRF REMS Access program to ensure the appropriate use of TIRF medicines and proper patient selection. All stakeholders subject to the TIRF REMS Access program, including patients, prescribers, pharmacies and distributors, must be enrolled in the TIRF REMS Access program, educated on the requirements of the program and required to document that they understand and will abide by the ETASU. Program materials are provided on the TIRF medicines in addition to product-specific materials. The Education Program and Knowledge Assessment components of the program contain both TIRF medicine class and product-specific components. All program tools, including enrollment forms, PPAFs, stakeholder letters, and overview documents containing program information specific to the TIRF REMS Access program, are available at www.TIRFREMSACCESS.com. The program procedures are monitored for adherence and the TIRF Sponsors will continue to conduct ongoing and retrospective analyses as necessary to comply with all mandates and to maximize the safe use of the TIRF medicines. FDA_4039 60-Month REMS Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies 3.1 Additional Elements 3.1.1 Medication Guide Page 18 of 112 The product-specific TIRF Medication Guide should be dispensed with each TIRF medicine prescription. Every TIRF medicine has a unique Medication Guide. 3.1.2 Letters to Healthcare Professionals A Communication Plan for the TIRF REMS was not required. However, TIRF Sponsors sent materials to targeted stakeholders to support implementation of the TIRF REMS Access program at the time of program launch. These communications included Dear Healthcare Provider (HCP) and Dear Pharmacy letters, and informed prescribers and authorized pharmacists on the risks associated with the use of TIRF medicines, the procedures and requirements of the TIRF REMS Access program and means to report AEs. 3.2 Elements to Assure Safe Use Because of the significant potential health risks associated with prescribing TIRF medicines to opioid non-tolerant patients, it is important that prescribers are aware of the procedures for appropriate patient selection and appropriate dosing and titration. This is achieved by each prescriber’s enrollment through a review of the TIRF REMS Access Education program including the TIRF medicine’s Full Prescribing Information, successful completion of the Knowledge Assessment, and completion of the Prescriber Enrollment Form. TIRF medicines are only available through the TIRF REMS Access program to reduce the risks of inappropriate patient selection and ensure appropriate dosing and administration of TIRF medicines. To ensure that TIRF medicines are only dispensed to appropriate patients, pharmacies that dispense TIRF medicines must be enrolled in the TIRF REMS Access program. There are different enrollment requirements for outpatient pharmacies (e.g., retail, mail order, institutional outpatient pharmacies that dispense for outpatient use) and inpatient pharmacies (e.g., hospitals that dispense for inpatient use only). For Long-Term Care (LTC) and Hospice patients whose prescriptions were obtained through an outpatient pharmacy setting, the pharmacy, patient, and prescriber must be enrolled in the TIRF REMS Access program. Outpatient pharmacy enrollment requires an authorized pharmacist at the pharmacy to review the TIRF REMS Access Education program, successfully complete the Knowledge Assessment, and submit a completed and signed TIRF REMS Access program enrollment form. The authorized pharmacist ensures that their Pharmacy Management System (PMS) is able to support communication with the TIRF REMS Access program using established telecommunication standards. This requires submitting standardized test transactions to validate the system enhancements. The authorized pharmacist is responsible for educating all pharmacy staff who participate in dispensing TIRF medicines on the risks associated with TIRF medicines and the requirements of the TIRF REMS Access program. For chain pharmacies, an authorized chain pharmacy representative completes the enrollment process on behalf of all individual store locations associated with that chain. The authorized chain pharmacy representative acknowledges that training has been provided to all pharmacy FDA_4040 60-Month REMS Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 19 of 112 staff involved in the dispensing of TIRF medicines. Once the TIRF REMS Access Education program and Knowledge Assessment have been completed, the authorized chain pharmacy representative, on behalf of the chain, is required to acknowledge their understanding of the appropriate use of TIRF medicines and agree to adhere to the TIRF REMS Access program requirements by submitting a completed and signed enrollment form. For inpatient pharmacy enrollment, the authorized pharmacist is required to review the TIRF REMS Access Education program, successfully complete the Knowledge Assessment, and submit a completed and signed enrollment form on behalf of the pharmacy. The authorized inpatient pharmacist is required to acknowledge that they understand that outpatient pharmacies within their facility must be enrolled separately. Implementation of the TIRF REMS Access program for closed system outpatient pharmacies launched on 30 June 2012. Closed system outpatient pharmacies are integrated healthcare systems that dispense for outpatient use but their PMS is unable to support the process of electronically transmitting the validation and claim information. To enroll in the TIRF REMS Access program, the authorized pharmacist must review the TIRF REMS Access Education program, successfully complete the Knowledge Assessment, and submit a completed and signed enrollment form on behalf of the pharmacy. A list of closed system pharmacy locations that have been trained must be provided to the TIRF REMS Access program. Patients are passively enrolled in the TIRF REMS Access program when their first prescription is processed by a pharmacy. A completed PPAF should be sent to the TIRF REMS Access program by the prescriber within 10 working days from the processing date of the patient’s first prescription for a TIRF medicine. A maximum of 3 prescriptions are allowed within 10 working days from the date that the patient has their first prescription filled. No further prescriptions are to be dispensed after the 10-working-day window until a completed PPAF is received. A patient’s HCP can submit a copy of the PPAF to the TIRF REMS Access program via the Web site, fax, or United States (US) mail. 3.2.1 Prescription Verification Following initial patient enrollment, upon processing of a patient’s first TIRF medicine prescription, pharmacies verify for all subsequent prescriptions that both the prescriber and patient are enrolled in the TIRF REMS Access program and that all REMS requirements are met prior to dispensing. Prescription verification is not required for inpatient use of TIRF medicines. Non-Closed System Pharmacies Prescription verification occurs through a model that uses a pharmacy billing claim and engages a switch provider in the validation process. Upon receipt of a prescription for a TIRF medicine at an enrolled pharmacy, the prescription details are entered into their PMS and a transaction is sent to the TIRF REMS Access program via a switch provider. If the patient is not enrolled and this is their first prescription, the TIRF REMS Access program uses the transaction data to automatically transfer patient details into the TIRF REMS Access program database for passive enrollment. FDA_4041 60-Month REMS Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 20 of 112 For all subsequent prescriptions, the REMS database is then interrogated, via the switch provider, to validate the REMS edits (i.e., confirm that all TIRF REMS Access program requirements are met). In the case where a prescription passes all REMS edits, a billing request is then sent to the payer by the switch provider. Once the payer authorizes payment, the switch provider then authorizes the pharmacy to dispense the TIRF medicine as with a normal prescription, returning an authorization number that is captured by the TIRF REMS Access program. Specific reasons why a prescription would not meet a REMS edit are described in Table 14. If the prescription does not pass all REMS edits (e.g., one of the stakeholders was not enrolled), the TIRF REMS Access program rejects the claim prior to the claim being forwarded to the payer and the pharmacy receives a rejection notice from the switch provider. This automated feedback indicates the reason for rejection, instructs the pharmacist not to dispense the TIRF medicine, and notifies the pharmacist to contact the TIRF REMS Access program Call Center for further information. Closed System Outpatient Pharmacies Upon receipt of a prescription for a TIRF medicine at an enrolled closed system outpatient pharmacy, a pharmacy staff member will contact the TIRF REMS Access program via phone or fax to provide prescription details for verification. The TIRF REMS Access program then validates the enrollment status for the patient, prescriber and pharmacy. If the patient is not enrolled, the TIRF REMS Access program will use this transaction information to automatically transfer patient details into the TIRF REMS Access database for passive enrollment. If all three stakeholders are enrolled (i.e., passes all REMS edits), the closed system outpatient pharmacy is given an authorization number which is captured by the TIRF REMS Access program. If the prescription does not pass all REMS edits (e.g., one of the stakeholders is not enrolled), the TIRF REMS Access program will not provide an authorization number and the closed system outpatient pharmacy will receive a rejection notice. This feedback is provided to the closed system outpatient pharmacy via phone or fax and includes the reason for rejection, information on how the rejection may be resolved and instructions to not dispense the TIRF prescription until resolution is reached. 3.3 Implementation System The Implementation System and its components are described in the following sections. 3.3.1 Wholesaler/Distribution Enrollment and Fulfillment Wholesalers/distributors who distribute TIRF medicines must be enrolled in the TIRF REMS Access program before they are allowed to distribute TIRF medicines. For the purpose of the TIRF REMS Access program, the term distributor refers to a wholesaler, distributor, and/or chain pharmacy distributor. TIRF medicine distributors received a Dear Distributor Letter describing the TIRF REMS Access program and the requirements to purchase TIRF medicines from TIRF Sponsors and sell TIRF medicines to pharmacies upon FDA approval of the program. To enroll, the distributor’s authorized representative (AR) must review FDA_4042 60-Month REMS Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 21 of 112 the distributor program materials, complete and sign the Distributor Enrollment Form and fax it to the TIRF REMS Access program. TIRF Sponsors have processes in place to prevent shipping TIRF medicines to any distributor who has not completed and signed the enrollment form. 3.3.2 The TIRF REMS Access Program Compliance [Metric 22] The TIRF REMS Access program NCRT was created by the TRIG on 19 October 2012 and is tasked with reviewing reports of suspected non-compliance with the TIRF REMS Access program requirements. The NCRT is composed of membership from all the TRIG sponsors. There are currently 29 individuals across the 10 sponsors; the functional areas or specialties represented by the members include Regulatory, Medical Affairs, REMS Specialist, Legal, Quality, and Drug Safety. TIRF Sponsors monitor prescriber, pharmacy, and wholesaler/distributor activities for compliance with TIRF REMS Access program requirements. Corrective actions (e.g., reeducation, additional monitoring, process revision, and stakeholder inactivation) are instituted by the TIRF Sponsors if non-compliance is confirmed, as appropriate. The Non-Compliance Plan is described in Section 4.1.4 and results of non-compliance investigations are included in Section 6 of this report. The full Non-Compliance Protocol is included in Appendix 12.1. 3.3.3 TIRF REMS Access Program Call Center The TIRF REMS Access program maintains a Call Center component. The Call Center is staffed by qualified and trained specialists, who provide TIRF REMS Access program support to patients, prescribers, pharmacies, and distributors. 4 REMS ASSESSMENT PLAN METHODS The aim of the TIRF REMS Access program’s evaluation is to assess the effectiveness of the mitigation strategies in meeting the goals of the TIRF REMS Access program to ensure safe use, proper prescribing, and appropriate distribution of TIRF medicines. Findings from these evaluations are used to identify ways to improve the processes, as needed. The 48-Month FDA Assessment Report Acknowledgement Letter included multiple new requests to be incorporated into the 60-Month FDA REMS Assessment Report or the planned 17 February 2017 submission. Table 3 provides the TRIG’s response to each item communicated in the 48-Month FDA Assessment Report Acknowledgment Letter. FDA_4043 60-Month REMS Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Table 3 Request Number* 2a. Page 22 of 112 48-Month FDA Assessment Report Acknowledgement Letter Requests FDA Request Regarding the assessment of opioid tolerance submitted in the 48-Month FDA REMS Assessment Report, approximately 42% of patients prescribed TIRF products were not opioid tolerant. The TRIG needs to further investigate this concerning finding. A timeline for a plan to further evaluate this finding should be submitted with the 17 February 2017, submission of the 60-month REMS assessment survey results. Response Location The timeline for further evaluation of findings from the IMS Study submitted in the Supplemental Report will be included in the 17 February 2017 submission pending timing of the receipt of the separate letter from FDA. At a minimum, further evaluation of this finding will include product-specific assessment of opioid tolerance that each member sponsor will submit only to their NDA or ANDA. Additional details regarding this evaluation will be communicated in a separate letter. 2b. Regarding the persistency analysis submitted by the TRIG, these data indicate that the number of patients who may be exposed to “inappropriate conversion between TIRF medicines” is not insignificant. Thus these TIRF product switches need to be further assessed by the TRIG and a protocol developed to assess the starting doses of the TIRF products that existing TIRF patients switch to in order to ascertain what proportion of these switches are conducted as per products’ labeling. In addition, if the data system used has outcome data, this would be informative as to whether or not any switch marked as “inappropriate” resulted in any adverse sequelae. Limitations of the databases and/or approaches used are to be included in the protocol. Please submit this protocol with the 17 February 2017, submission of the 60-month REMS assessment survey results; if additional time for protocol development is needed, please request an extension. 2c. We would like to schedule a meeting to discuss opportunities for obtaining additional data on accidental exposure to children and others for whom TIRF products are not prescribed, as well as to discuss possible ways to address the low awareness of the need to prescribe and dispense TIRF medicines to appropriate patients. A protocol for phase II of the Persistency Analysis is planned to be included in the 17 February 2017 submission. A teleconference between FDA and the TRIG is scheduled for 22 February 2016 at 3 PM Eastern Standard Time. FDA_4044 60-Month REMS Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Request Number* 3a. FDA Request In the FDA’s 36-Month FDA Assessment Report Acknowledgement Letter (date 03 August 2015), the TRIG was asked to “Conduct outreach to a representative sample of those health professionals and pharmacies who did not re-enroll in the TIRF REMS Access Program so as to ascertain their reasons and report the results in your next Assessment Report. We are concerned about potential patient access issues.” Page 23 of 112 Response Location A timeline for outreach to a representative sample of health professionals and pharmacies who did not re-enroll to ascertain their reasons for not re-enrolling will be provided in the 17 February 2017 submission. In the 48-Month FDA REMS Assessment Report, the TRIG responded that: “Based on…analysis, there is no barrier to patient access and further outreach is unwarranted.” The TRIG states that 516 prescribers (8.6%) chose to not re-enroll and that these prescribers had an average of no more than four prescriptions total over the course of the reporting period. However, the reasons why these prescribers withdrew from the program are unknown as are the reasons why 1,134 prescribers had their enrollment expire this reporting period and remain expired. Additionally, the reasons why 412 pharmacies chose not to reenroll are not presented. It is therefore important that the TRIG proceed with conducting an “…outreach to a representative sample of those health professionals and pharmacies who did not re-enroll in the TIRF REMS Access Program so as to ascertain their reasons… we are concerned about potential patient access issues.” Submit a timeline for the plan to conduct this outreach in the 17 February 2017, submission of the 60-month REMS assessment survey results. 3b. There continues to be a steady increase in mean and median prescription processing times during this reporting period versus the previous periods. The TRIG was previously asked to investigate this finding, but did not do so, instead stating that this finding may be due to a lower number of prescriptions with at least one initial REMS-related rejection this reporting (1,735) period as compared to the 36-month report (3,738). These differences cited by the TRIG do not appear to be so large as to account for some sort of number skewing induced by a small sample size. The TRIG needs to investigate and identify the causes of these increasing delays in prescription processing as these are potential indicators of access barriers. At the current time it is not possible to distinguish between prescriptions that encounter at least one REMS-related rejection that are quickly resolved and those that are not. However, the TRIG has determined that of all the prescriptions that do encounter at least one REMS-related rejection over 80% are resolved within the first 10 days (See Section 5.1.5.3). FDA_4045 60-Month REMS Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Request Number* 3c. FDA Request The TRIG Protocol for Corrective Actions for Instances of NonCompliance contains few concrete criteria or decision trees as to how to deal with episodes of non-compliance. Thus it is unclear to us what types of non-compliance actions would reliably lead to suspension or deactivation. The TRIG should add increased specificity to the NCRT protocol as well as to the Supporting Document of the REMS. In addition, it is concerning that the TRIG’s criteria for an incident of an individual prescriber non-compliance with PatientPrescriber Agreement Form (PPAF) requirements needs to involve at least “5 or more patients enrolled by the prescriber without a complete PPAF on file, with each patient having greater than 10 working days lapse from initial enrollment date.” These criteria would appear to potentially lead to an underreporting of PPAF noncompliance. The TRIG should explore mechanisms to capture lower levels of non-compliance. 3d. Regarding the three instances where a non-closed system pharmacy dispensed a TIRF product after a TIRF REMS rejection, all 3 reports were brought to the attention of the TRIG only after the pharmacy contacted the REMS. The TRIG should develop a more active mechanism by which to identify and prevent such occurrences. 3e. Although results for both governmental (Veteran’s Health Administration and Department of Defense) and closedpharmacy systems appear to have improved from the 36-month audit, they continue to be unsatisfactory. The 36-Month FDA Assessment Report Acknowledgement Letter requested that the TRIG “Re-evaluate whether a novel authorization process is warranted or technically feasible at this time for the closed system pharmacies and report your conclusions with your next Assessment Report.” The TRIG has issued the following response: “The TRIG has determined that the current prescription authorization volume for closed system pharmacies is less than 1% of all TIRF prescriptions and due to the absence of complaints with the current process, no changes are warranted at this time.” An absence of complaints does not necessarily mean that a closed pharmacy system process is functioning optimally. These audits are likely one of the best sources of information regarding the performance of these closed-system pharmacies in meeting the REMS requirements. If the TRIG does not favor a novel authorization process for all of the closed-system pharmacies solely due to the poor performance of the governmental entities, the TRIG should propose an outreach to these programs to improve compliance. In addition, the TRIG should be sure to include both governmental entities in the 60-month audit so that their performance in the REMS can Page 24 of 112 Response Location The TRIG will consider updates to the Non-Compliance Protocol and the Supporting Document to add increased specificity around how non-compliance actions may lead to suspension or deactivation. A response pertaining to the criteria for an incident of individual non-compliance with PPAF requirements is provided in Section 6.1. The TRIG is looking into a more active mechanism to identify and prevent instances where a nonclosed system pharmacy dispenses a TIRF product after a TIRF REMS rejection is received. Response is included in Section 5.1.5.4 and supporting information is also referenced in the CSP audit information in Section 6.3.1 The TRIG is discussing incorporating an assessment of prescription processing times for prescriptions that do not experience any REMS-related rejections. FDA_4046 60-Month REMS Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Request Number* FDA Request Page 25 of 112 Response Location continue to be monitored. Lastly, the TRIG presents the process times for prescriptions that have experienced at least one REMS-related rejection. However, data on the overall processing time of a prescription that does not meet with any rejections is unclear. Given that one of the pieces of information solicited during the closed-system audits is “Date and time of each prescription transaction,” this is an excellent opportunity for the TRIG to assess prescription processing times for prescriptions that do not experience any REMS-related rejections. The TRIG should add this component to their closed-system audits 3f. For the Inpatient Pharmacy audits, 6 inpatient pharmacies either did not respond to the audit request or decided not to participate. In the current inpatient pharmacy enrollment form, the pharmacy only agrees to have their training audited. We are considering revisions to this enrollment form to allow for process audits so as to increase the potential pool of inpatient pharmacies in the audit and will communicate any required modifications during the review of the next REMS assessment. 3g. The TRIG reports a number of instances where prescribers were either unaware of requirements to submit a PPAF or chose not to do so. It is important that the TRIG investigate mechanisms to reinforce to prescribers the necessity of timely completion of PPAFs. 3h. For subsequent submissions of RADARS data that contain CII opioid comparators, expand the CII immediate-release opioid category to include oxycodone/acetaminophen, oxycodone/aspirin, and oxycodone/ibuprofen. 3i. The Agency has increasing concerns about the use of RADARS data to assess some of the outcomes outlined in the TIRF REMS. Given the limitations of RADARS, the Agency believes that additional data sources that can track adverse outcomes of interest associated with the TIRF products are necessary, and the TRIG must study intermediate objectives more closely related to the REMS intervention. The FDA proposes a meeting with the TRIG to discuss and explore new approaches to assessing this REMS with the goal of gathering useful information to better understand the impact of the REMS and to improve the program going forward. The TRIG looks forward to further communication from FDA on this item. The TRIG will further query noncompliant prescribers to determine more specific reasons of why they were not compliant with the REMS requirements. The TRIG will assess these responses to determine appropriate actions. The TRIG confirms that the CII immediate-release opioid category currently includes these products in the analysis. The TRIG plans to discuss this further during the scheduled 22 February 2016 teleconference. *Numbering is aligned with the numbering of the FDA requests communicated in the 48-Month FDA Assessment Report Acknowledgement Letter. FDA_4047 60-Month REMS Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies 4.1 Page 26 of 112 Data Sources for REMS Assessments Data were collected from the following main sources as described in detail below: a) TIRF REMS Access program utilization statistics (Section 4.1.1), b) dispensing activity for enrolled pharmacies (Section 4.1.2), c) program infrastructure and performance, d) TIRF REMS Access non-compliance plan, e) safety surveillance, and f) periodic surveys of patients, HCPs, and pharmacies. All programmed source tables and figures, as well as source data are on file at UBC and available upon request. Note: Every metric number shown in the following tables is used to identify the respective metric in the headers and text of the results. 4.1.1 The TIRF REMS Access Program and Product Utilization Statistics For the assessment of enrollment, utilization, and discontinuation statistics for prescribers, pharmacies, patients, and distributors, the following metrics were tabulated for the current reporting period and cumulatively. Metric Number* Metric a. Patient Enrollment 1. Number of unique patients enrolled 2. Number of patients inactivated b. Prescriber Enrollment 3. Number of prescribers enrolled 4. Number of prescribers that attempted enrollment but whose enrollment is pending for >3 months and >6 months along with the specific reasons why their enrollment is pending 5. Number of prescribers inactivated c. Pharmacy Enrollment 6 Number of pharmacies enrolled by type (inpatient, chain, independent, closed system; provide identity of closed system entities) 7. Number of pharmacies that attempted enrollment but whose enrollment is pending >3 months and >6 months along with the specific reasons why their enrollment is pending (stratified by type) 8. Number of pharmacies inactivated by type (inpatient, chain, independent, closed system) d. 9. Distributor Enrollment Number of distributors enrolled 10. Number of distributors inactivated *Numbering corresponds with the current TIRF REMS Access program Supporting Document (approved on 24 December 2014). FDA_4048 60-Month REMS Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies 4.1.2 Page 27 of 112 Dispensing Activity for Enrolled Pharmacies For the assessment of dispensing activity, the following metrics were tabulated and stratified by pharmacy type for the current reporting period and cumulatively. Metric Number* Metric 11. Number of prescriptions/transactions authorized; for closed systems, provide the number of prescription/transactions per closed system entity 12. Number of prescriptions/transactions denied/rejected and the reasons for denial/rejection. Include the number of prescriptions/transactions rejected for safety issues (provide description of safety issues and any interventions or corrective actions taken) 13. The mean and median amount of time it takes for a prescription that experienced at least one initial REMS-related rejection to be authorized 14. Number of patients with more than three prescriptions dispensed during the first ten days after patient passive enrollment without a PPAF 15. Number of prescriptions dispensed after ten days without a PPAF in place *Numbering corresponds with the current TIRF REMS Access program Supporting Document (approved on 24 December 2014). 4.1.3 Program Infrastructure and Performance The following metrics on program infrastructure performance were collected and summarized for the current reporting period. Metric Number* Metric 16. Number of times a backup system was used to validate a prescription, with reason(s) for each instance (for example, pharmacy level problem, switch problem, or REMS database problem) clearly defined and described 17. Number of times unintended system interruptions occurred for each reporting period. Describe the number of stakeholders affected, how the issue was resolved, and steps put into place to minimize the impact of future interruptions 18. Call center report with • Overall number of contacts • Summary of frequently asked questions • Summary of REMS-related problems reported 19. Description of corrective actions taken to address program/system problems *Numbering corresponds with the current TIRF REMS Access program Supporting Document (approved on 24 December 2014). FDA_4049 60-Month REMS Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies 4.1.4 Page 28 of 112 TIRF REMS Access Program Non-Compliance Plan The TIRF sponsors provide the following data regarding non-compliance in each assessment report (per reporting period). Metric Number* Metric 20. Report the results of yearly audits of at least 3 randomly selected closed pharmacy systems to assess the performance of the system(s) developed to assure REMS compliance. These reports are to include: • Verification of training for all pharmacists dispensing TIRF products 21. 22. • Numbers of prescription authorizations per closed system • Reconciliation of data describing TIRF product prescriptions received by the closed system pharmacy with TIRF product dispensed to patients with a valid enrollment in the TIRF REMS Access program. Data to include the 12-month period preceding the audit date. Include details on how the reconciliation is conducted (e.g., electronic versus manual process). • Describe any corrective actions taken for any non-compliance identified during the audit and corrective actions taken to address non-compliance Report the results of yearly audits of at least 5 randomly selected inpatient hospital pharmacies to assess the performance of the system(s) developed to assure REMS compliance starting in the 48Month FDA REMS Assessment Report. Provide the number of units of use of TIRFs ordered per inpatient hospital pharmacy audited per 12-month period. These reports are to include: • Verification of training for all pharmacists dispensing TIRF products • Verification that processes such as order sets/protocols are in place to assure compliance with the REMS program • Describe any corrective actions taken for any non-compliance identified during the audit, as well as preventative measures that were developed as a result of uncovering these noncompliance events Description of number, specialties, and affiliations of the personnel that constitute the NCRT as well as: • Description of how the NCRT defines a non-compliance event • Description of how non-compliance information is collected and tracked • Criteria and processes the Team uses to make decisions • Summary of decisions the Team has made during the reporting period • How the Team determines when the compliance plan should be modified 23. Describe each non-compliance event and the corrective action measure taken, as well as the outcome of the corrective action 24. Number of TIRF prescriptions dispensed that were written by non-enrolled prescribers and include steps taken to prevent future occurrences 25. Number of prescriptions dispensed by non-enrolled pharmacies and include steps taken to prevent future occurrences FDA_4050 60-Month REMS Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 29 of 112 Metric Number* Metric 26. Number of times a TIRF prescription was dispensed because a pharmacy (closed or open system) was able to bypass REMS edits and if any such events occurred, describe how these events were identified 27. Number of times a TIRF was prescribed to an opioid non-tolerant individual. Include what was done to minimize such instances; if any such events occurred, describe how these events were identified Number of instances of inappropriate conversions between TIRF products, as well as any outcome of such an event. If any such events occurred, describe how these events were identified *Numbering corresponds with the current TIRF REMS Access program Supporting Document (approved on 24 December 2014). 28. 4.1.4.1 Non-Compliance Monitoring The goal of the Non-Compliance Plan is to help the TRIG identify and investigate deviations from and non-compliance with TIRF REMS requirements to ensure patient safety and continuously improve the program. A confirmed non-compliance event is one for which the information collected through investigation of the potential non-compliance event clearly indicates that a program deviation has occurred and/or evidence of the program goals not being met through stakeholder actions is identified. The TIRF REMS Access program routinely monitors stakeholder activity to identify potential incidents of non-compliance events with program requirements and investigates all reports of suspected non-compliance. Non-compliance information is collected through standard program reports, spontaneous reports identified via the program’s Call Center, vendor/sponsor reported events, outreach to relevant stakeholders to validate data/information and solicit further information, and investigation of the TIRF REMS Access database. The data are tracked through a non-compliance case that is opened on the stakeholder record in the TIRF REMS Access database. If a non-compliance event is confirmed, additional investigation is conducted to determine the scope, impact, and root cause of the event. Stakeholders are notified of the investigation via a formal letter from the TIRF REMS Access program and may also be requested to develop a Corrective Action Plan (CAP). All CAPs are reviewed and approved by the NCRT. The NCRT will determine if the Non-Compliance Protocol should be modified as the program evolves. Any changes to the plan proposed by the NCRT will be voted upon by the TRIG. The full Non-Compliance Protocol is included in Appendix 12.1. 4.1.5 Safety Surveillance The following safety surveillance data were collected. Reporting periods for each type of data were modified based on timing of availability of data. FDA_4051 60-Month REMS Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 30 of 112 Metric Number* Metric 29. TIRF Sponsors will process AE reports related to their specific products and report to the FDA according to current regulations outlined in 21 Code of Federal Regulations (CFR) 314.80 and the sponsors’ respective Standard Operating Procedures. 30. TIRF Sponsors will produce one comprehensive report that presents spontaneous AE data from all sponsors of the TIRF REMS Access program, as well as data from other databases (characteristics of which are described below). This report will focus on four categories of AEs of interest: addiction, overdose, death, and pediatric exposures. This report should include the following: • Line listings under each category of AEs of interest as listed above • • Line listings should provide at a minimum the following information: o Identifying case number o Age and Gender of the patient o Date of the event as well as of the report o The Preferred Terms o Indication of TIRF use o Duration of TIRF therapy o Concomitant medications o Event Outcome Other metrics of interest include: o Number of event reports in each event category of interest o Counts of AEs related to inappropriate conversions between TIRF products o Counts of AEs related to accidental and unintentional exposures o Counts of AEs that are associated with use of TIRF medicines in non-opioid tolerant patients • Duplicate cases are identified and eliminated • Case reports with AEs in multiple categories will be listed in each category of interest, and will be noted as such • For each AE category, an overall summary analysis of the cases will be provided addressing the root cause(s) of the events • Rate of each AE of interest will be calculated using two distinct denominators: the number of prescriptions for TIRF products and the number of patients receiving a TIRF product throughout the reporting interval. Trends and changes in the rates of these events will be compared year-to-year FDA_4052 60-Month REMS Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 31 of 112 Metric Number* Metric 31. Surveillance data focusing on events of addiction, overdose, death, and pediatric cases should also be drawn from the databases that are listed below. Conclusions regarding these data should be included in and inform the overall conclusions in the summary report referred to in Metric 30 directly above: • Non-medical use of prescription drugs • Surveys conducted at substance abuse treatment programs • College surveys • Poison control center data • Impaired health care workers • Drug-related hospital emergency department visits • Drug-related deaths • Other databases as relevant *Numbering corresponds with the current TIRF REMS Access program Supporting Document (approved on 24 December 2014). 4.1.6 Periodic Surveys of Patients, Prescribers, and Pharmacies Prescribers’, pharmacists’, and patients’ understanding regarding the appropriate use of TIRF medicines and TIRF REMS Access program requirements are evaluated through Knowledge, Attitude, and Behavior (KAB) surveys. The surveys are administered to selected prescribers, pharmacies, and patients. 5 5.1 RESULTS REMS Program Utilization Described in this section are the total numbers of all enrolled stakeholders (prescribers, patients, pharmacies, and distributors), as well as stakeholder inactivations, dispensing activities, and barriers or delays in patient access. 5.1.1 Patient Enrollment [Metric 1 and 2] During the current reporting period, there were 4,255 newly enrolled patients (Table 4). Because patients are passively enrolled with their first prescription there is no patient reenrollment, but prescribers are required to renew PPAFs with patients every 2 years. By design, a patient’s enrollment status will never change to inactivated. FDA_4053 60-Month REMS Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Table 4 Page 32 of 112 Patient Enrollment Current Reporting Perioda 29OCT2015 to 28OCT2016 Number of Newly Enrolled Patients N Parameter Cumulativea,b,c 28DEC2011 to 28OCT2016 Total Number of Enrolled Patients N 4,255 42,164 Total Number of Enrolled Patients An enrolled patient is a patient who has received at least one prescription for a TIRF medication. b Includes patients that transitioned into the TIRF REMS Access program from other individual REMS programs. c Cumulative is defined as the sum of all reporting periods. Cumulative patients from the end of prior period may differ from last period’s report due to reconciliation of duplicate patients. a 5.1.2 Prescriber Enrollment and Inactivations [Metric 3, 4, 5] Cumulatively there have been 16,549 prescribers who have successfully completed enrollment in the program. At the end of this reporting period there are 8,151 prescribers who are currently enrolled. This includes 1,446 newly enrolled prescribers, 2,631 prescribers who re-enrolled and 4,074 who remain active from a previous period (Table 5). Table 6 shows those prescribers who have been inactivated. Table 5 Prescriber Enrollment Parameter Total Number of Prescribers with Enrollment Activity In This Reporting Period Number of Newly Enrolled Prescribers Number of Re-Enrolled Prescribers Current Reporting Perioda 29OCT2015 to 28OCT2016 N (%) 4,077 1,446 (35.5%) 2,631 (64.5%) Number of Prescribers Who Remain Enrolled from Previous Reporting Periods 4,074 Total Number of Prescribers Enrolled as of the End of This Reporting Period 8,151 16,549 Cumulative Number of Prescribers Ever Enrolledb,c a Percentages are based on the total number (N) of enrolled prescribers. b Cumulative is defined as the sum of all reporting periods. c Number includes prescribers who transitioned into the TIRF REMS Access program from other individual REMS programs. FDA_4054 60-Month REMS Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 33 of 112 A total of 3,635 prescribers were inactivated at some point during the current reporting period, and the majority of these (3,616, 99.5%) were due to expiration of enrollment. It should be noted that a prescriber is required to enroll every 2 years within the TIRF REMS Access program. Of those 3,616 prescribers whose enrollment expired at some point during the current reporting period, 2,763 (76.4%) remained expired at the end of the reporting period (Table 6). In total, there were 8,401 prescribers who remained inactivated at the end of the reporting period. Table 6 Prescriber Inactivations Parameter Number of Prescribers Who Became Inactivated During this Reporting Period Reason(s) For Inactivationb Deceased Program Opt-Out Non Compliantc Suspended Enrollment Expirede Enrollment remained expired at end of period Current Reporting Perioda 29OCT2015 to 28OCT2016 N (%) 3,635 2 (0.1%) 16 (0.4%) 0d 1 (<0.1%) 3,616 (99.5%) 2,763 (76.4%) Number of Prescribers Inactivated in This Time Period who Remain Inactivated as of the End of this Reporting Period 2,781 Number of Prescribers Who Were Inactivated in a Previous Reporting Period and Remain Inactive as of the End of This Reporting Period 5,620 Total Number of Prescribers Inactivated as of the End of this Reporting Period 8,401 12,365 Cumulative Number of Prescribers Who Have Ever Been Inactivatedf a Prescribers whose status is ‘inactive’ at least once during the reporting period. b Percentages are based on the total number (N) of inactivated prescribers. A prescriber may have more than one reason for inactivation. c Prescribers may be included as both “non-compliant” and “suspended” since before becoming inactivated for non-compliance, prescribers go through a suspension period. d No prescriber inactivations occurred during this reporting period due to non-compliance. There was a significant event of non-compliance reported after the reporting period, which is described in narrative ID#445. e Prescribers whose status is ‘Inactive-Expired’ at any time during the reporting period. f Cumulative is defined as the sum of all reporting periods. FDA_4055 60-Month REMS Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 34 of 112 During the current reporting period, there were 54 prescribers who attempted enrollment but whose enrollment was pending 3 to 6 months later. A total of 194 prescribers were pending enrollment for more than 6 months within the current reporting period. Prescribers may have attempted enrollment and became pending in another reporting period. For prescribers pending enrollment for 3 to 6 months, the most frequent reasons were training not complete (83.3%), no attestation (81.5%), provided DEA number does not have correct schedule for this drug (11.1%), invalid DEA number (7.4%), and knowledge assessment failure on the first attempt (7.4%). For prescribers pending enrollment for more than 6 months, the most frequent reasons were similar and included no attestation (74.7%), training not complete (62.4%), knowledge assessment failure on the first attempt (13.9%), and provided DEA does not have correct schedule for this drug (12.4%). The number of prescribers who attempted enrollment but are still pending enrollment for 3 to 6 months or more than 6 months, and the reasons for pending enrollment are shown in Table 7. Table 7 Prescribers Pending Enrollment Current Reporting Perioda 29OCT2015 to 28OCT2016 Prescribers Pending Prescribers Pending Enrollment Enrollment ≥3 – 6 Monthsb >6 Monthsb Parameter N (%) N (%) 54 194 Prescribers Who Attempted Enrollment but are Still Pending Enrollmentc Reasons for Pending Enrollment Invalid DEA Invalid NPI Knowledge Assessment Failure - First Attempt Knowledge Assessment Failure - Second Attempt Knowledge Assessment Failure - Third Attempt Missing DEA Number Missing Email Missing NPI Number Missing Phone Number Missing Physician Signature Date Missing Signature Missing State License Number No Attestation 4 (7.4%) 2 (3.7%) 4 (7.4%) 0 1 (1.9%) 0 0 1 (1.9%) 1 (1.9%) 3 (5.6%) 3 (5.6%) 0 44 (81.5%) 20 (10.3%) 8 (4.1%) 27 (13.9%) 6 (3.1%) 1 (0.5%) 4 (2.1%) 2 (1.0%) 4 (2.1%) 1 (0.5%) 4 (2.1%) 4 (2.1%) 5 (2.6%) 145 (74.7%) FDA_4056 60-Month REMS Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 35 of 112 Current Reporting Perioda 29OCT2015 to 28OCT2016 Prescribers Pending Prescribers Pending Enrollment Enrollment ≥3 – 6 Monthsb >6 Monthsb Parameter N (%) N (%) Pending Enrollment Intake 2 (3.7%) 7 (3.6%) Provided DEA does not have Correct Schedule for this Drug 6 (11.1%) 24 (12.4%) Training Not Complete 45 (83.3%) 121 (62.4%) a Reflects the total number of prescribers pending enrollment in the current reporting period. Prescribers may have attempted enrollment and become pending in another reporting period. b Percentages are based on the total number (N) of prescribers attempting enrollment. Percentages may not add up to 100% because a single prescriber may be pending enrollment for more than one reason. c Prescribers may be pending enrollment for more than one reason. 5.1.3 Pharmacy Enrollment, Inactivation, and Education [Metric 6, 7, 8] There were a total of 26,543 pharmacies newly enrolled or re-enrolled in this reporting period. Of the 1,537 (5.8%) pharmacies that newly enrolled in the TIRF REMS Access program, 1,026 were chain pharmacy stores, 387 were independent outpatient pharmacies, 114 were inpatient pharmacies, and 8 were closed system pharmacy locations. The 8 closed system pharmacies are represented by 6 closed system entities (See Section 5.1.5.4). A total of 25,006 (94.2%) pharmacies re-enrolled: 22,043 were chain pharmacy stores, 2,260 were independent outpatient pharmacies, 439 were inpatient pharmacies, and 214 were closed system pharmacy locations (Table 8). Table 8 Pharmacy Enrollment Parameter Total Number of Pharmacies with Enrollment Activity in this Reporting Periodb Total Number of Newly Enrolled Pharmacies Inpatient Pharmacies Chain Pharmacy Headquartersc Chain Pharmacy Stores Independent Outpatient Pharmacies Closed System Headquartersc Closed System Pharmacies Current Reporting Perioda 29OCT2015 to 28OCT2016 Non-Closed System Closed System Pharmacies Pharmacies N (%) N (%) 26,316 227 Total Pharmacies N (%) 26,543 1,529 (5.8%) 8 (3.5%) 1,537 (5.8%) 114 (7.5%) 2 (0.1%) 1,026 (67.1%) 387 (25.3%) N/A N/A N/A N/A N/A N/A 0 8 (100.0%) 114 (7.4%) 2 (0.1%) 1,026 (66.8%) 387 (25.2%) 0 8 (0.5%) FDA_4057 60-Month REMS Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Parameter Total Number of Re-Enrolled Pharmacies Inpatient Pharmacies Chain Pharmacy Headquartersc Chain Pharmacy Stores Independent Outpatient Pharmacies Closed System Headquartersc Closed System Pharmacies Number of Pharmacies that Remain Enrolled from a Previous Reporting Period Inpatient Pharmacies Chain Pharmacy Headquartersc Chain Pharmacy Stores Independent Outpatient Pharmacies Closed System Headquartersc Closed System Pharmacies Total Number of Pharmacies Enrolled as of the End of this Reporting Period Inpatient Pharmacies Chain Pharmacy Headquartersc Chain Pharmacy Stores Independent Outpatient Pharmacies Closed System Headquartersc Closed System Pharmacies Cumulative Number of Pharmacies Ever Enrolledd Inpatient Pharmacies Chain Pharmacy Headquartersc Chain Pharmacy Stores Page 36 of 112 Current Reporting Perioda 29OCT2015 to 28OCT2016 Non-Closed System Closed System Total Pharmacies Pharmacies Pharmacies N (%) N (%) N (%) 24,787 (94.2%) 219 (96.5%) 25,006 (94.2%) 439 (1.8%) 45 (0.2%) 22,043 (88.9%) 2,260 (9.1%) N/A N/A N/A N/A N/A N/A 5 (2.3%) 214 (97.7%) 439 (1.8%) 45 (0.2%) 22,043 (88.2%) 2,260 (9.0%) 5 (<0.1%) 214 (0.9%) 16,118 5 16,123 207 (1.3%) 31 (0.2%) 14,466 (89.8%) 1,414 (8.8%) N/A N/A N/A N/A N/A N/A 1 (20.0%) 4 (80.0%) 207 (1.3%) 31 (0.2%) 14,466 (89.7%) 1,414 (8.8%) 1 (<0.1%) 4 (<0.1%) 42,433 232 42,665 760 (1.8%) 78 (0.2%) 37,535 (88.5%) 4,060 (9.6%) N/A N/A N/A N/A N/A N/A 6 (2.6%) 226 (97.4%) 760 (1.8%) 78 (0.2%) 37,535 (88.0%) 4,060 (9.5%) 6 (<0.1%) 226 (0.5%) 48,882 372 49,254 1,244 (2.5%) 94 (0.2%) 41,039 (84.0%) N/A N/A N/A 1,244 (2.5%) 94 (0.2%) 41,039 (83.3%) FDA_4058 60-Month REMS Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Parameter Independent Outpatient Pharmaciesc Closed System Headquarters Closed System Pharmacies Page 37 of 112 Current Reporting Perioda 29OCT2015 to 28OCT2016 Non-Closed System Closed System Total Pharmacies Pharmacies Pharmacies N (%) N (%) N (%) 6,505 (13.3%) N/A 6,505 (13.2%) N/A 7 (1.9%) 7 (<0.1%) N/A 365 (98.1%) 365 (0.7%) a Percentages are based on the total number (N) of pharmacies for the reporting period. Pharmacies that are enrolled within this reporting period and were still enrolled at the end of the reporting period. c Chain Pharmacy Stores or Closed System Pharmacy Stores may be associated with a Chain Pharmacy Headquarter or Closed System Headquarter enrolled in a previous reporting period. d Cumulative number of pharmacies from the end of prior period may differ from last period's report due to reconciliation of duplicate records. b As shown in Table 9, there were 4,736 total pharmacies inactivated at least once during the current reporting period including 4,530 non-closed system pharmacies and 206 closed system pharmacy. The non-closed system pharmacies included 3,043 (67.2%) chain pharmacy stores, 1,222 (27.0%) independent outpatient pharmacies, and 252 (5.6%) inpatient pharmacies. The reason for most dispensing pharmacy inactivations was expired enrollment (95.0%, 4,488/4,723). Table 9 Pharmacy Inactivations Parameter Current Reporting Perioda 29OCT2015 to 28OCT2016 Non-Closed System Closed System Total Pharmacies Pharmacies Pharmacies N (%) N (%) N (%) Number of Pharmacies that Became Inactivated During this Reporting Period Inpatient Pharmacies Chain Pharmacy Headquarters Chain Pharmacy Stores Independent Outpatient Pharmacies Closed System Pharmacies 4,530 206 4,736 252 (5.6%) 13 (0.3%) 3,043 (67.2%) 1,222 (27.0%) N/A N/A N/A N/A N/A 206 (100.0%) 252 (5.3%) 13 (0.3%) 3,043 (64.3%) 1,222 (25.8%) 206 (4.3%) Reason(s) for Inpatient Pharmacy Inactivationb Program Opt-Out Enrollment Expiredc Enrollment remained expired at end of period 3 (1.2%) 249 (98.8%) 201 (80.7%) N/A N/A N/A 3 (1.2%) 249 (98.8%) 201 (80.7%) Reason(s) for Chain Pharmacy Headquarters Inactivationd FDA_4059 60-Month REMS Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Parameter Program Opt-Out Enrollment Expiredc Enrollment remained expired at end of period Page 38 of 112 Current Reporting Perioda 29OCT2015 to 28OCT2016 Non-Closed System Closed System Total Pharmacies Pharmacies Pharmacies N (%) N (%) N (%) 1 (7.7%) N/A 1 (7.7%) 12 (92.3%) N/A 12 (92.3%) 4 (33.3%) N/A 4 (33.3%) Reason(s) for Chain Pharmacy Store Inactivationd Program Opt-Out Enrollment Expiredc Enrollment remained expired at end of period 224 (7.4%) 2,819 (92.6%) 1,242 (44.1%) N/A N/A N/A 224 (7.4%) 2,819 (92.6%) 1,242 (44.1%) Reason(s) for Independent Outpatient Pharmacy Inactivatione Program Opt-Out Enrollment Expiredc Enrollment remained expired at end of period 8 (0.7%) 1,214 (99.3%) 934 (76.9%) N/A N/A N/A 8 (0.7%) 1,214 (99.3%) 934 (76.9%) N/A N/A 206 (100.0%) 39 (18.9%) 206 (100.0%) 39 (18.9%) 2,610 39 2,649 204 (7.8%) 5 (0.2%) 1,459 (55.9%) 942 (36.1%) N/A N/A N/A N/A N/A 39 (100.0%) 204 (7.7%) 5 (0.2%) 1,459 (55.1%) 942 (35.6%) 39 (1.5%) 6,444 137 6,581 484 (7.5%) 17 (0.3%) 3,500 (54.3%) 2,443 (37.9%) N/A N/A N/A N/A N/A 137 (100.0%) 484 (7.4%) 17 (0.3%) 3,500 (53.2%) 2,443 (37.1%) 137 (2.1%) 16,763 360 17,123 Reason(s) For Closed System Pharmacy Inactivationf Enrollment Expiredc Enrollment remained expired at end of period Numbers of Pharmacies Inactivated in This Time Period that Remain Inactivated as of the End of this Reporting Period Inpatient Pharmacies Chain Pharmacy Headquarters Chain Pharmacy Stores Independent Outpatient Pharmacies Closed System Pharmacies Total Number of Pharmacies Inactivated as of the End of This Reporting Period Inpatient Pharmacies Chain Pharmacy Headquarters Chain Pharmacy Stores Independent Outpatient Pharmacies Closed System Pharmacies Cumulative Number of Pharmacies Ever Inactivatedg FDA_4060 60-Month REMS Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 39 of 112 Current Reporting Perioda 29OCT2015 to 28OCT2016 Non-Closed System Closed System Total Pharmacies Pharmacies Pharmacies N (%) N (%) Parameter N (%) Inpatient Pharmacies 696 (4.2%) N/A 696 (4.1%) Chain Pharmacy Headquarters 36 (0.2%) N/A 36 (0.2%) Chain Pharmacy Stores 12,514 (74.7%) N/A 12,514 (73.1%) Independent Outpatient Pharmacies 3,517 (21.0%) N/A 3,517 (20.5%) Closed System Pharmacies N/A 360 (100.0%) 360 (2.1%) a Pharmacies with ‘inactive’ status at least once during the reporting period. b Percentages are based on the total number (N) of inactivated inpatient pharmacies. An inpatient pharmacy may have more than one reason for inactivation. c Pharmacies whose status is ‘Inactive-Expired’ at any time during the enrollment period. d Percentages are based on the total number (N) of inactivated chain pharmacy headquarters or chain pharmacy stores. A chain pharmacy headquarters or chain pharmacy store may have more than one reason for inactivation. e Percentages are based on the total number (N) of inactivated independent outpatient pharmacy stores. An independent outpatient pharmacy store may have more than one reason for inactivation. f Percentages are based on the total number (N) of inactivated closed system pharmacies. A closed system pharmacy may have more than one reason for inactivation. g Cumulative is defined as the sum of all reporting periods. During the current reporting period, there were 39 pharmacies that attempted enrollment but enrollment was pending 3 to 6 months later. As of the end of the reporting period, there were a total of 209 pharmacies pending enrollment for 6 months or longer. Pharmacies may have attempted enrollment and become pending in another reporting period. For pharmacies pending enrollment for 3 to 6 months, the most frequent reasons were no attestation (46.2%), pending test transaction verification (46.2%), and training not complete (30.8%). For pharmacies pending enrollment for 6 months or longer, the most frequent reasons were similar and included pending test transaction verification (54.1%), no attestation (40.2%), and training not complete (34.9%). The number of pharmacies that attempted enrollment but are still pending enrollment for 3 to 6 months or longer than 6 months, and the reasons for pending enrollment are shown in Table 10. FDA_4061 60-Month REMS Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Table 10 Page 40 of 112 Pharmacies Pending Enrollment Current Reporting Perioda 29OCT2015 to 28OCT2016 Pharmacies Pending Enrollment ≥3 - 6Monthsb Parameter Pharmacies that Attempted Enrollment but are Still Pending Enrollment Non-Closed System Pharmacies N (%) 39 Pharmacies Pending Enrollment: >6 Monthsb Closed System Total Non-Closed System Closed System Total Pharmacies Pharmacies Pharmacies Pharmacies Pharmacies N (%) N (%) N (%) N (%) N (%) 0 39 209 0 209 Reasons for Pending Enrollment Invalid DEA 1 (2.6%) 0 1 (2.6%) 3 (1.4%) 0 3 (1.4%) Invalid NCPDP 0 0 0 6 (2.9%) 0 6 (2.9%) Invalid NPI 1 (2.6%) 0 1 (2.6%) 3 (1.4%) 0 3 (1.4%) Knowledge Assessment Failure - First Attempt 2 (5.1%) 0 2 (5.1%) 3 (1.4%) 0 3 (1.4%) Knowledge Assessment Failure - Second 1 (2.6%) 0 1 (2.6%) 2 (1.0%) 0 2 (1.0%) Attempt Knowledge Assessment Failure - Third Attempt 1 (2.6%) 0 1 (2.6%) 4 (1.9%) 0 4 (1.9%) Missing Pharmacist Signature Date 0 0 0 2 (1.0%) 0 2 (1.0%) Missing Signature 0 0 0 2 (1.0%) 0 2 (1.0%) No Attestation 18 (46.2%) 0 18 (46.2%) 84 (40.2%) 0 84 (40.2%) Pending Enrollment Intake 0 0 0 10 (4.8%) 0 10 (4.8%) Pending Test Transaction Verification 18 (46.2%) 0 18 (46.2%) 113 (54.1%) 0 113 (54.1%) Training Not Complete 12 (30.8%) 0 12 (30.8%) 73 (34.9%) 0 73 (34.9%) a Reflects the total number of pharmacies pending enrollment in the current reporting period. Pharmacies may have attempted enrollment and became pending in another reporting period. b Percentages are based on the total number (N) of pharmacies attempting enrollment. Percentages may not add up to 100% because a single pharmacy may be pending enrollment for more than one reason. FDA_4062 60-Month REMS Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies 5.1.4 Page 41 of 112 Wholesaler/Distributor Enrollment [Metric 9 and 10] During the current reporting period, 1 (4.8%) wholesaler/distributor was newly enrolled in the REMS program and 20 (95.2%) re-enrolled (Table 11). There were 5 wholesalers/distributors inactivated during the current reporting period due to enrollment expiration and 3 had not re-enrolled by the end of the reporting period (Table 12). The 3 distributors who became inactivated during this reporting period and remained inactivated at the end of the reporting period were acquired by other enrolled entities or were initially enrolled as the wrong stakeholder type. Table 11 Distributor Enrollment Current Reporting Perioda 29OCT2015 to 28OCT2016 Parameter Number of Distributors with Enrollment Activity in This Reporting Period Number of Newly Enrolled Distributors Number of Re-Enrolled Distributors N (%) 21 1 (4.8%) 20 (95.2%) Number of Distributors that Remain Enrolled from Previous Reporting Periods 14 Total Number of Distributors Enrolled as of the End of the Reporting Period 35 49 Cumulative Number of Distributors Ever Enrolledb,c a Percentages are based on the total number (N) for the relevant distributors for the period. b Includes distributors that transitioned into the TIRF REMS Access program from other individual REMS programs. c Cumulative distributors from the end of prior period may differ from last period’s report due to reconciliation of duplicate distributors. FDA_4063 60-Month REMS Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 42 of 112 Table 12 Distributor Inactivations Current Reporting Perioda 29OCT2015 to 28OCT2016 Parameter N (%) Number of Distributors that Became Inactivated in This Reporting Periodb 5 Reason(s) for Distributor Inactivation Enrollment Expiredc Enrollment remained expired at end of period 5 (100.0%) 3 (60.0%) Number of Distributors that Remain Inactivated From Previous Reporting Periods 11 Total Number of Distributors Inactivated as of the End of the Reporting Period 14 Cumulative Number of Distributors Ever Inactivatedd 22 a Percentages are based on the total number (N) for the relevant inactivated distributors for the period. Distributors with ‘inactive’ status at least once during the reporting period. c Distributors whose status is ‘Inactive-Expired’ at any time during the enrollment period. d Cumulative is defined as the sum of all reporting periods. b 5.1.5 Dispensing Activity [Metric 11, 12, 13] 5.1.5.1 Prescriptions Authorized [Metric 11] A total of 117,708 prescriptions were adjudicated for safety by the TIRF REMS Access program in the current reporting period including 117,335 prescriptions from non-closed system pharmacies and 373 from closed system pharmacies (Table 13). Of the total prescriptions, 89.3% were subsequently approved for dispensing without encountering any REMS-related rejections (i.e., were authorized for dispensing by insurance or cash bin). FDA_4064 60-Month REMS Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 43 of 112 Table 13 Prescriptions from Outpatient Pharmacies That Did Not Encounter Any REMS-Related Rejections Prior to Being Authorized for Dispensing Current Reporting Periodb 29OCT2015 to 28OCT2016 Parameter Number of Unique Prescriptions Submitted for Authorization Non-Closed System Pharmacies N (%) 117,335 Cumulativeb,c 28DEC2011 to 28OCT2016 Closed System Pharmacies N (%) All Pharmacies (Non-Closed and Closed) N (%) Non-Closed System Pharmacies N (%) Closed System Pharmacies N (%) All Pharmacies (Non-Closed and Closed) N (%) 373 117,708 675,373 3,408 678,781 Total Number of Unique Prescriptions That 104,748 (89.3%) 328 (87.9%) 105,076 (89.3%) 602,101 (89.2%) 2,741 (80.4%) 604,842 (89.1%) Did Not Encounter Any REMS-Related Rejections Prior to Being Authorized for Dispensinga Independent Pharmacies 67,353 (57.4%) N/A 67,353 (57.2%) 396,356 (58.7%) N/A 396,356 (58.4%) Chain Pharmacy Stores 37,395 (31.9%) N/A 37,395 (31.8%) 205,745 (30.5%) N/A 205,745 (30.3%) Closed System Pharmacies N/A 328 (87.9%) 328 (0.3%) N/A 2,741 (80.4%) 2,741 (0.4%) a Prescriptions successfully adjudicated for safety (i.e., successful REMS edit) and authorized for dispensing by insurance or cash bin (bin number). b Percentages are based on the total number (N) of unique prescriptions that never encountered a REMS-related rejection for the reporting period. c Includes authorizations from all pharmacies that were enrolled in the TIRF REMS Access program at any time from inception of the program. FDA_4065 60-Month REMS Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies 5.1.5.2 Page 44 of 112 Prescriptions Encountering REMS-related Rejections [Metric 12] When a prescription is presented it must meet the REMS edit requirements before it may be authorized for dispensing, or it is rejected. The reasons why a prescription will not meet a REMS edit requirement are included in Table 14. If a prescription is rejected, the pharmacy must contact the TIRF REMS Access program to rectify the rejected transaction. Upon receiving an inbound call from a pharmacy provider, the TIRF REMS Access program Call Center Associate works to resolve the rejected transaction and to provide instructions on the corrective action needed to successfully process the transaction. Corrective action includes outreach and education to remedy rejected transaction processing. Of the 117,708 unique prescriptions submitted for approval during the current reporting period, 2,363 (2.0%) prescriptions encountered at least one REMS-related rejection prior to being authorized for dispensing from outpatient pharmacies (Table 15). There were a total of 10,269 prescriptions that encountered at least one REMS-related rejection and were never authorized for dispensing (Table 16). Table 14 Reasons for Prescriptions Not Meeting REMS Edit Requirements Reason Description Prescriber Identification (ID) Not Enrolled/Not Found Found the prescriber last name but not the NPI, DEA or State License Number or both prescriber last name and ID are not found PPAF Incomplete Patient’s PPAF is in an incomplete status; the PPAF is missing information Patient Zip Code Missing Patient’s zip code was not submitted on the transaction Prescriber Last Name Did Not Match Name Registered Prescriber last name on the transaction did not match the prescriber last name associated with the Prescriber ID Pharmacy Not Enrolled Pharmacy is not enrolled; the pharmacy has not completed the enrollment or re-enrollment process Prescriber ID Not Registered Found the prescriber last name but the NPI, DEA or State License Number does not match prescriber. PPAF Expired Patient’s PPAF expired due to 2 year PPAF expiration PPAF No Activity Patient’s PPAF has expired due to no transaction activity within past 6 months PPAF Terminated Patient’s PPAF terminated due to 2 year PPAF expiration (status was replaced with PPAF Expired effective 17 March 2015) Prescriber Terminated Prescriber enrollment terminated Pharmacy Terminated Pharmacy enrollment terminated Table 15 presents the results for the prescriptions that encountered at least one REMS-related rejection prior to being authorized for dispensing from outpatient pharmacies. The most FDA_4066 60-Month REMS Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 45 of 112 frequent rejection reasons for independent pharmacies (n=1,212) were PPAF expired (34.9%), PPAF incomplete (26.3%), prescriber ID not registered (11.5%), and zip code missing (10.3%). The most frequent rejection reasons for chain pharmacies (n=1,150) were prescriber last name did not match a registered prescriber (37.0%), PPAF expired (22.8%), zip code missing (15.7%), PPAF incomplete (15.5%), and prescriber ID not registered (9.0%). One prescription from a closed system pharmacy encountered a REMS-related rejection prior to being authorized for dispensing in the current reporting period because of PPAF no activity (e.g., no transaction activity within the past 6 months). Table 16 presents the results for the prescriptions that encountered at least one REMS-related rejection and were never authorized for dispensing from outpatient pharmacies. As stated previously, of the 117,708 unique prescriptions submitted for approval during the current reporting period there were a total of 10,269 prescriptions that encountered at least one REMSrelated rejection and were never authorized for dispensing. The most frequent rejection reasons for independent pharmacies (n=3,386) were prescriber ID not registered (32.6%), prescriber is terminated (23.0%), zip code missing (18.6%), and prescriber last name did not match a registered prescriber (12.8%). The most frequent rejection reasons for chain pharmacies (n=6,839) were prescriber last name did not match a registered prescriber (54.3%), zip code missing (20.4%), prescriber ID not registered (19.0%), and prescriber is terminated (8.7%). The most frequent rejection reasons for closed system pharmacies (n=44) were prescriber ID not registered (52.3%), prescriber last name did not match a registered prescriber (18.2%), pharmacy terminated (13.6%), and prescriber is terminated (9.1%). FDA_4067 60-Month REMS Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industiy Group (TRIG) of Companies Page 46 of 112 Table 15 Prescriptions from Outpatient Pharmacies That Encountered at Least One REMS?Related Rejection Prior to Being Authorized for Dispensing Current Reporting Periodb Cumulative'?c 290CT2015 to 28OCT2016 28DEC2011 to 280CT2016 All All Non-Closed Pharmacies Non?Closed Pharmacies System Closed System (Non-Closed and System Closed System (Non-Closed Pharmacies Pharmacies Closed) Pharmacies Pharmacies and Closed) Parameter Number of Unique Prescriptions Submitted for 117.335 373 117.708 675.373 3.408 678.781 Authorization Total Number of Unique Prescriptions that 2.362 1 2.363 21.733 58 21.791 Encountered At Least One Initial REMS-Related Rejection Prior to being Authorized for Dispensinga Independent Pharmacies 1.212 1.212 15.274 15.274 Chain Pharmacy Stores 1.150 1.150 6.459 6.459 Closed System Pharmacies 1 1 58 58 Independent Pharmacies Reason(s) for Rejectiond Zip Code Missing 125 6.689 PPAF Incomplete 319 4.416 Prescriber last name did not match name registered 79 1.925 Prescriber 1D not registered 139 1.768 PPAF Expired 423 1.102 PPAF tenninated 0 884 Prescriber is terminated 64 343 Last Name and DOB Missing 13 (1 . 220 PPAF No Activity 90 173 60-Month REMS Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 47 of 112 Current Reporting Periodb Cumulativeb?c 290CT2015 to 280CT2016 28DEC2011 to 280CT2016 All All Non-Closed Pharmacies Non?Closed Pharmacies System Closed System (Non-Closed and System Closed System (Non-Closed Pharmacies Pharmacies Closed) Pharmacies Pharmacies and Closed) Parameter Prescriber ID not submitted 19 146 Pharmacy terminated 8 123 First Name Missing 6 73 Prescriber Tenninated and Last Name Mismatch 7 33 DOB Missing 0 24 First Name. Last Name. and Zip Code Missing 0 24 Zip Code and Last Name 0 13 First Name and Last Name Missing 0 10 DOB and Zip Code Missing 0 9 Last Name Missing 0 2 Database Failure - System Unavailable due to 0 1 maintenance First Name. Last Name and DOB Missing 0 1 First Name. Last Name. Zip Code. and DOB 0 1 Missing Multi-Match - two or more patient match on same 0 1 criteria Chain Pharmacy Stores Reason(s) for Rejectiond PPAF Incomplete 178 2.492 Prescriber 1D not registered 104 1.190 Zip Code Missing 181 1.043 Prescriber last name did not match registered 425 931 60-Month REMS Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industiy Group (TRIG) of Companies Page 48 of 112 Current Reporting Periodb Cumulative'?c 290CT2015 to 280CT2016 28DEC2011 to 280CT2016 All All Non-Closed Pharmacies Non?Closed Pharmacies System Closed System (Non-Closed and System Closed System (Non-Closed Pharmacies Pharmacies Closed) Pharmacies Pharmacies and Closed) Parameter PPAF Expired 262 656 PPAF terminated 0 518 Prescriber is terminated 51 163 First Name Missing 50 106 PPAF No Activity 68 100 Last Name and DOB Missing 50 90 Phannacy terminated 1 27 Prescriber II) not submitted 1 20 Prescriber Tenninated and Last Name Mismatch 7 10 DOB Missing 1 7 First Name and Last Name Missing 0 7 First Name. Last Name. and Zip Code Missing 0 6 First Name. Last Name and DOB Missing 2 4 First Name. Last Name. Zip Code. and DOB 1 3 Missing Multi-Match - two or more patient match on same 0 3 cnteria First Name and DOB Missing 1 2 Phannacy not Registered 0 2 DOB and Zip Code Missing 0 1 Database Failure - System unavailable due to system 0 1 maintenance Last Name Missing 0 1 Re-register 0 1 60-Month REMS Assessment Report Transmucosal Iimnediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 49 of 112 Current Reporting Period? 290CT2015 to 280CT2016 Cumulativel?c 28DEC2011 to 28OCT2016 All All Non?Closed Pharmacies Non?Closed Pharmacies System Closed System (Non-Closed and System Closed System (Non-Closed Pharmacies Pharmacies Closed) Pharmacies Pharmacies and Closed) Parameter Closed System Pharmacies Reason(s) for Rej ection?l Zip Code Missing 0 33 PPA Incomplete 0 10 Prescriber II) not registered 0 9 PPAF terminated 0 6 Prescriber last name did not match registered 0 6 PPAF Expired 0 3 PPAF No Activity 1 (100.0%) 1 a Prescription successfully adjudicated for safety successful REMS edit) and authorized for dispensing by insurance or cash bin (bin munber). Percentages are based on the total number (N) of number of unique prescriptions that encormtered at least one initial REMS-related rejection prior to being authorized for dispensing for the reporting period. Includes authorizations from pharmacies that transitioned into the TIRF REMS Access program from other individual REMS programs. Prescriptions can be rejected for more than one reason. 60-Month REMS Assessment Report Transmucosal Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 50 of 112 Table 16 Prescriptions That Encountered at Least One REMS-Related Rejection and Never Authorized for Dispensing from Outpatient Pharmacies Current Reporting Perioda Cumulative" 29OCT2015 to 280CT2016 28DEC2011 to 280CT2016 All All Non-Closed Pharmacies Non?Closed Pharmacies System Closed System (Non-Closed and System Closed System (Non-Closed Pharmacies Pharmacies Closed) Pharmacies Pharmacies and Closed) Parameter Number of Unique Prescriptions Submitted for 117.335 373 117.708 675.373 3.408 678.781 Authorization Total Number of Unique Prescriptions that 10.225 44 10.269 51.539 609 52.148 Encountered At Least One Initial REMS- Related Rejection and Never Authorized for Dispensing Independent Pharmacies 3.386 3.3 86 23.849 23.849 Chain Pharmacy Stores 6.839 6.839 27.690 27.690 Closed System Pharmacies 44 44 609 17.9%) 609 Independent Pharmacies Reason(s) for Rejectionb Prescriber ID not registered 1.105 10.770 Prescriber last name did not match registered 432 4.328 Zip Code Missing 631 2.985 Prescriber is terminated 778 2.468 PPAF Incomplete 168 2.459 Pharmacy terminated 167 827 Prescriber ID not submitted 80 490 PPAF terminated 0 413 60-Month REMS Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 51 of 112 Current Reporting Perioda Cumulative" 290CT2015 to 280CT2016 28DEC2011 to 280CT2016 All All Non-Closed Pharmacies Non?Closed Pharmacies System Closed System (Non-Closed and System Closed System (Non-Closed Pharmacies Pharmacies Closed) Pharmacies Pharmacies and Closed) Parameter PPAF Expired 98 346 PPAF No Activity 75 138 Last Name and DOB Missing 19 120 Prescriber Terminated and Last Name Mismatch 13 108 First Name Missing 8 54 First Name. Last Name. and Zip Code Missing 1 8 Multi-Match - two or more patient match on same 0 8 criteria DOB Missing 1 4 First Name and Last Name Missing 1 4 First Name. Last Name. Zip Code. and DOB 0 2 Missing DOB and Zip Code Missing 1 1 Last Name Missing 0 1 Zip Code and Last Name 0 1 Chain Pharmacy Stores Reason(s) for Rejectionb Prescriber ID not registered 1.298 14.870 Prescriber last name did not match registered 3.711 6.163 PPAF Incomplete 139 2.482 Prescriber is terminated 592 2.019 Zip Code Missing 1.393 1.759 Phannacy terminated 148 557 60-Month REMS Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industiy Group (TRIG) of Companies Page 52 of 112 Current Reporting Perioda Cumulative" 29OCT2015 to 280CT2016 28DEC2011 to 28OCT2016 All All Non-Closed Pharmacies Non?Closed Pharmacies System Closed System (Non-Closed and System Closed System (Non-Closed Pharmacies Pharmacies Closed) Pharmacies Pharmacies and Closed) Parameter PPAF terminated 0 378 Last Name and DOB Missing 314 377 PPAF Expired 115 345 First Name Missing 248 308 Prescriber ID not submitted 27 264 Prescriber Tenninated and Last Name Mismatch 48 75 PPAF No Activity 43 72 Multi-Match - two or more patient match on same 1 12 criteria First Name and Last Name Missing 0 10 Pharmacy not Registered 0 10 Last Name Missing 0 4 DOB Missing 1 1 DOB and Zip Code Missing 0 1 Database Failure - System unavailable due to 0 1 system mamtenance First Name. Last Name. Zip Code. and DOB 1 1 Missing Closed System Pharmacies Reason(s) for Rejectionb Prescriber ID not registered 23 330 Prescriber last name did not match registered 8 111 PPAF Incomplete 0 55 60-Month REMS Assessment Report Transmucosal Iimnediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 53 of 112 Current Reporting Perioda Cumulative' 290CT2015 to 280CT2016 28DEC2011 to 280CT2016 All All Non?Closed Pharmacies Non?Closed Pharmacies System Closed System (Non-Closed and System Closed System (Non-Closed Pharmacies Pharmacies Closed) Pharmacies Pharmacies and Closed) Parameter Pharmacy terminated 6 47 Prescriber is terminated 4 38 Zip Code Missing 3 31 PPAF Expired 3 5 PPAF terminated 0 4 Prescriber Terminated and Last Name Mismatch 1 2 Multi-Match - two or more patient match on same 0 1 criteria Prescriber ID not submitted 0 1 a Percentages are based on the total number (N) of number of unique prescriptions for the period. Prescriptions can be rejected for more than one reason. 60-Month REMS Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies 5.1.5.3 Page 54 of 112 Time to Authorization [Metric 13] In the 48-Month FDA Assessment Report Acknowledgement Letter, the FDA remarked that there continues to be a steady increase in mean and median prescription processing times as observed in the 48-month reporting period data versus the previous reporting period. The FDA requested that the TRIG investigate the cause of increasing delays in prescription processing as these are potential indicators of access barriers. As previously described, a total of 2,363 prescriptions (representing 2.0% of all unique prescriptions submitted for authorization during the reporting period) encountered at least one initial REMS-related rejection prior to being authorized for dispensing. For all pharmacies, the mean time to authorization for a prescription that experienced at least one initial REMS-related rejection was 6.3 days while the median time was 2.0 days (Table 17). For chain pharmacy stores, it took a mean of 7.1 days (median 2.8 days) compared with independent outpatient pharmacies that took a mean of 5.5 days (median 1.7 day). For 1 closed system pharmacy prescription, it took 56.9 days. The TRIG has determined that of all the prescriptions that encounter at least one REMS-related rejection over 80% are resolved within the first 10 days (Table 18; Figure 1). Table 17 Time to Authorization for a Prescription that Experienced at Least One Initial REMSRelated Rejection Total Mean Time For Prescription to be Authorizeda (Days)b Inpatient Pharmacies Chain Pharmacy Stores Independent Outpatient Pharmacies Closed System Pharmacies Current Reporting Period 29OCT2015 to 28OCT2016 6.298 Cumulative 28DEC2011 to 28OCT2016 4.020 -7.136 5.460 56.859c -4.934 3.621 7.162 2.028 0.703 Total Median Time For Prescription to be Authorizeda (Days)b Inpatient Pharmacies --Chain Pharmacy Stores 2.798 1.171 Independent Outpatient Pharmacies 1.676 0.148 c Closed System Pharmacies 56.859 1.158 a Prescriptions included were resolved in the current reporting period. Prescriptions may have been initially rejected in a previous reporting period. b Time to authorization for a prescription that experienced at least one initial REMS-related rejection excludes prescriptions processed through the inpatient pharmacy process. c The mean and median data represent the actual time to authorization for 1 closed system pharmacy prescription. FDA_4076 60-Month REMS Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 55 of 112 Table 18 Distribution of Time to Authorization for a Prescription that Experienced at Least One Initial REMS-Related Rejection by Pharmacy Type and Overall for the Current Reporting Period Total Time For Prescription to be Authorizeda (Days)b Chain Pharmacy Stores (N=1,150) Independent Outpatient Pharmacies (N=1) Closed System Pharmacies (N=1,212) All Pharmacy Types (N=2,363) 0 317 (27.6) 0 384 (31.7) 701 (29.7) 1-10 618 (53.7) 0 662 (54.6) 1,280 (54.2) 11-20 116 (10.1) 0 85 (7.0) 201 (8.5) 21-30 45 (3.9) 0 44 (3.6) 89 (3.8) 31-40 28 (2.4) 0 14 (1.2) 42 (1.8) 41-50 7 (0.6) 0 10 (0.8) 17 (0.7) 51-60 5 (0.4) 1 (100.0) 5 (0.4) 11 (0.5) 61-70 3 (0.3) 0 0 3 (0.1) 71-80 2 (0.2) 0 4 (0.3) 6 (0.3) 81-90 4 (0.3) 0 0 4 (0.2) 91-100 1 (0.1) 0 2 (0.2) 3 (0.1) > 100 4 (0.3) 0 2 (0.2) 6 (0.3) a Prescriptions included were resolved in the current reporting period. Prescriptions may have been initially rejected in a previous reporting period. b Time to authorization for a prescription that experienced at least one initial REMS-related rejection excludes prescriptions processed through the inpatient pharmacy process. Time was rounded to full days for categorization where values up to and including 0.5 days are categorized to the lower category. FDA_4077 60-Month REMS Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 56 of 112 Figure 1 Distribution of Time to Authorization for a Prescription that Experienced at Least One Initial REMS-Related Rejection for the Current Reporting Period 662 600? 400- Number of Prescriptions 200- 0 1-10 11-30 21-30 3140 41-50 51-60131 71410 8l-90 91.100 100 Total Time for Prescription Authorizationm (Days)[2] I Clain Phanmcy SIMCS I hdepmdul Phannacies 5.1.5.4 Prescription Authorizations for Closed-system Pharmacy Entities [Metric 11] As described in Section 5.1.3, a total of 6 closed-system pharmacy entities were enrolled in the TIRF REMS Access program during this reporting period. These entities include: . (4) lb) (4) National Institutes of Health Clinical Center Pharmacy 0 US. Department of Veterans Affairs . mu) 0? (41 mm) mm DLA Troop Support (111(4) 0:114) During the current reporting period, a total of 329 prescription authorizations were provided through these closed system pharmacy locations (Table 19). During the last reporting period on 18 May 2015, transitioned from being a closed-system pharmacy to a non-closed system pharmacy due to the pharmacy obtaining the ability to electronically adjudicate claims. Therefore, the prescription authorizations described 60-Month REMS Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 57 of 112 in Table l9 le? are only included in the cumulative count and only represent prescriptions processed prior to this transition. Table 19 Number of Prescription Authorizations per Closed System Pharmacy Current Reporting Period Cumulative 290CT2015 to 28DEC2011 to 280CT2016 280CT2016 Total Number of Closed System Pharmacy Prescription 329 2,799 Authorizations 60-Month REMS Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 58 of 112 Current Reporting Period Cumulative 290CTZOIS to 28DEC2011 to mm the last reporanspe-iod on 18 May changed from a closed system pharmacy to a non-closed syst. cy. 60-Month REMS Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 59 of 112 In the 48-Month FDA Assessment Report Acknowledgement Letter, the FDA requested that the TRIG propose an outreach to CSPs to improve compliance, if the TRIG does not favor a novel authorization process for all of the CSPs solely due to the poor performance of the governmental entities. Additionally, the FDA requested that the TRIG add the assessment of prescription processing times for prescriptions that do not experience any REMS-related rejections. As reported in the 48-Month FDA REMS Assessment Report, the TRIG has determined that the current prescription authorization volume for CSPs is <1% (329/117,708) of all TIRF prescriptions and CSPs only account for <1% (232/42,665) of all pharmacies enrolled as of the end of this reporting period. To date, no complaints have been received from CSPs on the process; however, the TRIG acknowledges that there have been non-compliance events identified through the CSP audits where REMS processes have been bypassed. One challenge in updating the REMS authorization process to include a web-based modality in order to minimize non-compliance events (as described in many of the CSP audit CAPs), is the transient nature of pharmacy staff at these locations. Regardless of adding a modality to the authorization process, there is still turnover at the pharmacy level that leads to education gaps. A novel authorization process would provide another modality to minimize the risk to bypass REMS edits but still would require education on the process. Additionally, through anecdotal information, the TRIG is aware that some CSP locations are unable to access outside websites and may not be able to utilize a novel authorization process. The TRIG will continue to monitor and assess the need for an alternate solution as appropriate. One potential process the TRIG is evaluating is quarterly review of CSP data rather than an annual review in the current audit process. In addition to this potential process change, the TRIG is discussing incorporating an assessment of prescription processing times for prescriptions that do not experience any REMS-related rejections. 5.1.6 Barriers or Delays in Patient Access [Metric 14 and 15] Prescriptions Dispensed Within First 10 Days after Patient Enrollment Across all pharmacies, a total of 3,270 prescriptions were dispensed to 2,828 patients within the first 10 days after patient enrollment (Table 20). The majority of patients (n=2,817) were dispensed prescriptions by non-closed system pharmacies (3,259 prescriptions). A total of 982 patients received prescriptions without a PPAF from any pharmacy type and the majority received only 1 fill without a PPAF. A total of 3 patients received 3 prescriptions within 10 days without a PPAF on file. All 3 patients had their prescriptions filled through non-closed system pharmacies. No patient received more than 3 fills within 10 days without a PPAF on file. FDA_4081 60-Month REMS Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 60 of 112 48-Month FDA REMS Assessment Report Update During the 48-month assessment period, 1 patient was reported as potentially receiving more than 3 fills within the 10-day period after enrollment without a PPAF on file from a non-closed system pharmacy. This occurred when an independent outpatient pharmacy submitted 4 prescriptions. Two prescriptions were batched billed from the pharmacy’s PMS simultaneously, causing the prescriptions to pass through the REMS edits sub-seconds apart. Since a patient record was not found, the patient was passively enrolled in the TIRF REMS Access program twice. Ultimately, it was confirmed that the patient received only 3 unique prescriptions within the 10-day period. FDA_4082 60-Month REMS Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 61 of 112 Table 20 Prescriptions Dispensed During the First 10 Days after Passive Patient Enrollment Parameter Non-Closed System Pharmacies N (%) Current Reporting Period 29OCT2015 to 28OCT2016 Closed System Combined Pharmacies Pharmaciesd N (%) N (%) Total Pharmacies N (%) Non-Closed System Pharmacies N (%) Cumulativea 28DEC2011 to 28OCT2016 Closed System Combined Pharmacies Pharmaciesd N (%) N (%) Total Pharmacies N (%) Number of prescriptions dispensed during the first 10 days after patient enrollment 3,259 11 0 3,270 40,727 222 11 40,960 Number of patients dispensed a prescription during the first 10 days after enrollment 2,817 11 0 2,828 34,061 185 5 34,251 1,597 (56.7%) 246 (8.7%) 38 (1.3%) 6 (0.2%) 4 (36.4%) 0 0 0 0 0 0 0 1 (20.0%) 0 0 0 15,036 (43.9%) 2,881 (8.4%) 424 (1.2%) 88 (0.3%) With PPAFb 1 Fill 2 Fills 3 Fills >3 Fills 1,601 (56.6%) 14,978 (44.0%) 57 (30.8%) 246 (8.7%) 2,872 (8.4%) 9 (4.9%) 38 (1.3%) 423 (1.2%) 1 (0.5%) 6 (0.2%) 86 (0.3%) 2 (1.1%) Without PPAFb,c 1 Fill 922 (32.7%) 7 (63.6%) 0 929 (32.9%) 14,855 (43.6%) 107 (57.8%) 1 (20.0%) 14,963 (43.7%) 2 Fills 50 (1.8%) 0 0 50 (1.8%) 1,384 (4.1%) 5 (2.7%) 3 (60.0%) 1,392 (4.1%) 3 Fills 3 (0.1%) 0 0 3 (0.1%) 225 (0.7%) 4 (2.2%) 1 (20.0%) 230 (0.7%) >3 Fills 0 0 0 0 10 (<0.1%) 0 0 10 (<0.1%) a Cumulative data from the end of prior period may differ from the last period’s report due to reconciliation of duplicate stakeholders. b Percentages are based on the total number of patients for the period. Sum of percentages may be greater than 100% due to patients receiving prescriptions with and without a PPAF during the grace period. c A patient may receive up to 3 fills in the first 10 days after enrollment without a PPAF. d Patients who have filled a prescription at both a closed system pharmacy and a non-closed system pharmacy. FDA_4083 60-Month REMS Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 62 of 112 Prescriptions Dispensed Beyond 10 Days after Patient Enrollment The TIRF REMS Access program requires that each patient have a PPAF submitted to the TIRF REMS Access program by their prescriber within 10 days of their passive enrollment in order to continue to receive a TIRF medicine. Table 21 below shows the number of prescriptions dispensed beyond the first 10 days without a PPAF on file. From the inception of the TIRF REMS through the current reporting period, 786 prescriptions have been dispensed beyond the first 10 days without a PPAF; no prescriptions dispensed beyond 10 days after enrollment without a PPAF were reported in the current reporting period. 48-Month FDA REMS Assessment Report Update During the 48-month assessment period, 1 patient was reported as potentially receiving a fill that was dispensed beyond the 10 days after enrollment without a PPAF on file. This occurred when an independent outpatient pharmacy submitted 2 prescriptions for the same patient with variation in the spelling of the patient’s last name. The variation caused the patient to become passively enrolled in the TIRF REMS Access program twice. A PPAF was received for the patient and processed on 1 of the 2 enrollment files. The enrollment files were identified to be duplicates and merged into one patient file, with a complete PPAF. Ultimately, it was confirmed that all prescriptions received outside of the 10 days after enrollment were received with a PPAF on file for the patient. FDA_4084 60-Month REMS Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 63 of 112 Table 21 Prescriptions Dispensed Beyond the First 10 Days after Passive Patient Enrollment Without a PPAF Cumulativea 28DEC2011 to 28OCT2016 Current Reporting Period 29OCT2015 to 28OCT2016 Filled at NonFilled at Closed Closed System System Pharmacies Pharmacies Filled at Combined Pharmaciesb Filled at NonFilled at Closed Closed Filled at All System System Pharmacies Pharmacies Pharmacies Filled at Combined Pharmaciesb Filled at All Pharmacies Parameter N N N N N N N N Fills beyond the first 10 days Without PPAF 0 0 0 0 751 32 3 786 a b Cumulative data from the end of prior period may differ from the last period's report due to reconciliation of duplicate stakeholders. A patient who has filled a prescription at both a closed system pharmacy and a non-closed system pharmacy. FDA_4085 60-Month REMS Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 64 of 112 5.2 Program Infrastructure and Performance [Metrics 16, 17, 18, 19] 5.2.1 Backup System for Prescription Validation [Metric 16] During this reporting period there were no instances in which a backup system was used to validate a prescription due to pharmacy level problems, switch problems, or REMS database problems. 5.2.2 System Interruptions/Errors and Corrective Actions [Metric 17, 19] There were no unintended system interruptions during this reporting period [Metric 17]. There were no reports of program/system problems that occurred in this reporting period [Metric 19]. 5.2.3 REMS Call Center [Metric 18] A total of 124,796 calls to the TIRF REMS Access program were received during the reporting period. Table 22 below shows reasons for contacting the REMS Call Center by frequency (%). For presentation in the report, this table includes at least 80% of the total cumulative frequency. The most frequent reasons classified under the call reason were enrollment status inquiry (17.1%), pharmacy: pharmacy claim rejection (16.4%), PPAF inquiry (10.4%), and general program questions (6.1%). The call reasons listed below in Table 22 represent 81.9% of calls to the Call Center for the current reporting period. Table 22 Current Assessment Period Contact Reasons Reason Count Percenta Enrollment Status Inquiry 21,285 17.1% Pharmacy: Pharmacy Claim Rejection 20,451 16.4% PPAF Inquiry 12,962 10.4% General Program Questions 7,667 6.1% Enrollment Follow Up 6,812 5.5% Web Portal Logon Assistance 6,757 5.4% Prescriber: Pharmacy Claim Rejection 6,514 5.2% Enrollment Form 5,728 4.6% Other/Miscellaneous 5,259 4.2% PPAF Follow Up 4,569 3.7% Identifier Issues 4,121 3.3% a The total percentage presented in the table account for 81.9% of all reasons for contacting the Call Center. There were no REMS-related barriers reported to the REMS Call Center during this reporting period. FDA_4086 60-Month REMS Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 65 of 112 6 TIRF REMS ACCESS PROGRAM NON-COMPLIANCE Non-compliance is reported via foru' methods within this assessment report. 1. Stakeholder Non-Compliance Table: Non-compliance cases that have been identi?ed dru?ing this reporting period by any stakeholder are cormted in Section 6.1, Table 24. 2. Stakeholder Non-Compliance Narratives: Stakeholders who are associated with instances of non-compliance resulting from an NCRT ?Warning? or any assessment monitoring are described via non-compliance narrative in Section 6.1, Table 25. 3. SP Audit Results: Non-compliance cases identi?ed through the SP audits are described via audit summary in Section 6.3.1. 4. Inpatient Hospital Pharmacy Audit Results: Non-compliance cases identi?ed through the inpatient audits are described via audit summary in Section 6.3.2. These 4 methods of reporting non-compliance are additive in nature. Non-compliance cases discussed within the audit sections or the non-compliance narratives are not comrted within the non-compliance table. Prescribers or pharmacies represented in the table are not described in the audit sections or the non-compliance narrative table. 6.1 Non-Compliance Feedback from the 48-Month FDA Acknowledgement Letter The 48-Month FDA Acknowledgement Letter stated that FDA is concerning that the criteria for an incident of an individual prescriber non-compliance with PPAF requirements needs to involve at least 5 or more patients em?olled by the prescriber without a complete PPAF on ?le (with each patient having greater than 10 working days lapse from the initial enrollment date). The FDA stated that these criteria would appear to potentially lead to an rmder-reporting of PPAF non-compliance and that the TRIG should explore mechanisms to capture lower levels of non-compliance. Scenarios triggering a non-compliance case rmder the Non-compliance Protocol were designed to monitor for non-compliance with REMS requirements, while mitigating burden on prescribers and barriers for patients. Since the initiation of the Non-compliance Protocol, the NC RT has monitored instances where a prescriber has failed to have a complete PPAF on ?le in a timely manner. Upon identi?cation that a prescriber has 5 or more patients em?olled without a complete PPAF on ?le and each patient is 10 working days past the initial em?olhnent date, a non-compliance case is opened for investigation (?Prescriber 2 Scenario? identi?ed in the Non- compliance Protocol). Considerations that were taken into accormt when establishing this non- compliance scenario was the allowance of a patient receiving up to 3 prescriptions within the ?rst 10 days without a PPAF rmder the approved REMS, the anticipated volume of prescribers writing one-time prescriptions for patients, and the anticipated amormt of communication being sent to the prescriber. The TRIG has evaluated the occurrences of this non-compliance scenario over time by calculating rates of these events using the following denominators: prescribers enrolled as of the end of the reporting period, total nrunber of prescriptions submitted for authorization, and the total number of prescriptions that were authorized by the TIRF REMS Access program. The rates of the Prescriber 2 Scenario across all denominators have gradually 60-Month REMS Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 66 of 112 decreased from the 36-month reporting period to the current reporting period. Based on this notable decrease, the TRIG has determined that this established non-compliance mechanism is working. However, the TRIG will continue to explore mechanisms to capture lower instances of non-compliance. Table 23 Rates of Prescriber 2 Scenario Cases Over Time Per 1,000 prescribersa Per 10,000 submitted prescriptions b Per 10,000 authorized prescriptions c 36-Month FDA REMS Assessment Report (N=120 reports) 48-Month FDA REMS Assessment Report (N=82 reports) 60-Month FDA REMS Assessment Report (N=50 reports) 15.02 9.01 6.13 7.52 5.37 4.25 8.06 5.64 4.65 a The prescriber rates were based on reported number of prescribers enrolled as of the end of the reporting period. The denominators used for the 36-Month, 48-Month, and 60-Month REMS Assessment Report calculations were 7,992; 9,096; 8,151. b The submitted prescription rates were based on the total number of prescriptions submitted for authorization. The denominators used for the 36-Month, 48-Month, and 60-Month REMS Assessment Report calculations were 159,560; 152,686; 117,708. c The authorized prescription rates were based on the number of prescriptions that did not encounter any REMSrelated rejections and was dispensed and the prescriptions that encountered at least one REMS-related rejection, but were eventually authorized and dispensed. The denominators used for the 36-Month, 48-Month, and 60Month REMS Assessment Report calculations were 148,822; 145,498; 107,439. 6.2 Stakeholder Non-Compliance [Metric 23, 24, 25, 26, 27, 28] Each unique stakeholder non-compliance case is investigated and non-compliance activity is generally reported 2 ways during a reporting period, either as a confirmed non-compliance activity report as in Table 24 or it is described in a narrative as in Table 25. If single noncompliance cases are reported over time and appear, for example, in Table 24 for 2 consecutive assessment reports, the Stakeholder’s third offense will warrant a CAP and then all offenses are reported in a narrative only, and not in Table 24. Any confirmed non-compliance event that results in an NCRT “Warning” or is a result of any assessment monitoring (includes closed system monitoring and inpatient pharmacy audits) will be reported in a narrative. During the current reporting period, 62 instances of potential stakeholder non-compliance with the TIRF REMS Access program were reviewed and investigated. A summary of the noncompliance activity is presented in Table 24 and Table 25. FDA_4088 60-Month REMS Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 67 of 112 Table 24 Non-Compliance Activity Reports by Stakeholder in the Current Reporting Period: 29 October 2015 to 28 October 2016 a Stakeholder Non-Compliance Activity Non-Closed System Pharmacy Submission of a claim that did not go through the REMS edits. A TIRF medicine was dispensed without verifying through the TIRF PMS that the prescriber is enrolled and active, and that the patient is enrolled or has not been inactivated in the program. Wholesaler/Distributor Prescriber Wholesaler/Distributor fills an order for TIRF medicines for a non-enrolled stakeholder. Prescriber failure to have a complete PPAF on file in a timely manner (5 or more patients enrolled by the prescriber without a complete PPAF on file, with each patient having greater than 10 working days lapse from the initial enrollment date). Non-Compliant Reason (categorized as reported by the stakeholder) No. of events No. of stakeholders Not aware of requirement to process cash claims 3 No. w/1 report: 3 Received reject but dispensed drug 2 No. w/1 report: 2 Dispensed drug without obtaining an authorization 2 No. w/1 report: 2 Total Non-Closed System Pharmacy Cases 7 No reason provided 1 Total Wholesaler/Distributor Cases 1 Not aware of PPAF requirement 9 No. w/1 report: 9 Completed PPAF with patient but failed to send PPAF to TIRF REMS 18 No. w/1 report: 18 Aware of PPAF requirements but failed to complete PPAF 8 No. w/1 report: 8 No reason provided 15 No. w/1 report: 15 Total Prescriber Reports 50 No. w/1 report: 1 Total Number of 58 Reports During This Reporting Period a There were no spontaneous reports of non-compliance from closed-system pharmacies. FDA_4089 60-Month REMS Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 68 of 112 During the reporting period, there was 1 instance where a TIRF prescription was dispensed by a non-closed system pharmacy that was written by non-enrolled prescribers after receiving a rejection from the TIRF REMS Access program [Metric 24] as described below. On 17 February 2016, the closed system authorization process was not followed, resulting in a pharmacy receiving manual authorization to dispense drug from a Call Center Associate when all safe use conditions were not met. The prescriber who wrote the TIRF prescription was not enrolled, therefore the authorization to dispense should not have been provided to the pharmacy. On 17 February 2016, the TIRF REMS Access program contacted the pharmacy to advise drug should not be dispensed. During the interaction the pharmacy confirmed it had already dispensed drug. TIRF REMS Access program contacted the prescriber, who was advised of enrollment requirements and provided assistance to complete enrollment into the program. Re-training on TIRF REMS Access program requirements and work instructions was provided to both the Call Center Associate who authorized the dispense and all other Call Center Associates. There was 1 instance where a prescription was dispensed by a non-enrolled pharmacy [Metric 25] as described below. The TIRF REMS Access program was notified of a distributor that shipped TIRF medicine(s) to a non-enrolled pharmacy when the non-enrolled pharmacy contacted the TIRF REMS Access program regarding a prescription rejection for reason of pharmacy not enrolled. Upon notification of REMS requirements, the non-enrolled pharmacy shipped the TIRF medicine(s) back to the distributor. The AR for the distributor was reeducated on the REMS requirements and stated that the non-compliant shipment was due to a change in a National Drug Code (NDC) number that was not updated in their system. The NCRT issued a first Notice for Non-Compliance on 23 February 2016 requiring submission of a CAP on 15 March 2016. The distributor provided a CAP stating that programming changes would occur to the system to update all product NDCs that require a system flag that they are restrictions on the TIRF REMS Access program. The NCRT approved the CAP on 28 March 2016. As shown in Table 24, there were 7 instances in which a TIRF prescription was dispensed because a pharmacy (closed or open system) was able to bypass REMS edits [Metric 26]. A total of 4 of these 7 instances were due to not using the cash BIN to process a claim. In all 4 of these instances the pharmacy was re-educated and a Notice for Non-Compliance was issued. The remaining 3 instances are described below. 1. The TIRF REMS Access program received a call for assistance with a REMS rejection due to a PPAF not on file on 02 May 2016. After confirming that the PPAF expired on 28 March 2016 and that the patient would need to complete a new PPAF with the prescriber before medication can be dispensed, the pharmacy confirmed the medication was already dispensed the week before. The pharmacy was re-educated on the REMS requirements and a Notice for Non-Compliance was issued. The TIRF REMS Access program has since confirmed that the patient has a new PPAF on file as of 03 May 2016. FDA_4090 60-Month REMS Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 69 of 112 2. The TIRF REMS Access program received a call for assistance with a REMS rejection due to a lapse in prescriber recertification on 18 May 2016. The pharmacy confirmed that medication was already dispensed to the patient even though a rejection was received on 26 April 2016. The prescriber has since completed re-enrollment as of 18 May 2016. The pharmacy was re-educated on the REMS requirements and a Notice for Non-compliance was issued. 3. The TIRF REMS Access program received a call for assistance with a REMS rejection due to a lapse in prescriber recertification on 05 October 2016. The pharmacy confirmed that the medication was dispensed on 05 September 2016. The prescriber has since completed re-enrollment as of 14 September 2016. The pharmacy was re-educated on the REMS requirements and a Notice for Non-Compliance was issued. No reports of TIRF medicines being prescribed to an opioid non-tolerant individual [Metric 27] or cases of inappropriate conversions between TIRF products [Metric 28] were received by sponsor companies during this reporting period. Table 25 summarizes in narrative form all resolved non-compliance cases (n=4); there were no non-compliance event narratives that remain open as of the end of the reporting interval. FDA_4091 60-Month REMS Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 70 of 112 Table 25 Non-Compliance Reports in the Current Reporting Peliod: 29 October 2015 to 28 October 2016 Report Description (N Report Mitigating Action Status (Case 25444573. 26320577) Closed On 18 September 2015. a request for contact correspondence was [48?Month FDA REMS Assessment Report Non? Compliance] On 22 J1me 2015 the prescriber was identi?ed as not submitting PPAFs for 6 patients. On 06 July 2015. a request for contact correspondence was sent to the prescriber after multiple tnrsuccessful contact attempts between 22 J1me and 04 July 2015. The TIRF REMS Access program made an additional 6 outreach attempts following the issuance of the request for contact correspondence. On 03 August 2015 a formal Notice for Non-Compliance was issued to the prescriber. and the prescriber was re-educated. The 6 outstanding PPAFs will not be submitted as they were for patients identi?ed as not continuing therapy. On 03 August 2015 the prescriber was again identi?ed as not submitting PPAFs for 6 patients. sent with a Prescriber Overview after multiple unsuccessful outreach attempts between 26 August 2015 and 11 September 2015. The prescriber failed to contact the TIRF REMS Access program for re- education by the deadline of 10 October 2015. The 6 outstanding PPAFs will not be submitted as they were for patients identi?ed as not continuing therapy. A ?rst Warning letter was issued on 26 October 2015 with a request for a CAP. On 02 November 2015. a CAP was received from the prescriber: however, 011 12 November 2015. the NCRT did not approve the plan as it did not align with the re-education received by the prescriber. [60-Month FDA REMS Assessment Report Update] Multiple tmsuccessful attempts to reach the prescriber for a valid CAP were made from 12 November 2015 to 16 December 2015. Due to non-response. the prescriber was suspended from the TIRF REMS Access program on 16 December 2015 and required to submit a revised CAP by 04 January 2016. A CAP was received on 17 December 2015. The prescriber stated that the of?ce had implemented a second fax line speci?c to PPAF submissions and the prescriber also received an overview on how to use the website to submit PPAFs. The NCRT approved the CAP on 18 December 2015. Since closing the non-compliance case. no additional non- compliance cases for this prescriber have been identi?ed. 60-Month REMS Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Report Description (N=3) ID#413 (Case # 19987682, 22657145, 103199529) Page 71 of 112 Report Status Closed This prescriber has not been described in a noncompliance narrative in previous assessment reports; however, he had non-compliant activity prior to this reporting period. Information pertaining to previous non-compliance outside of this reporting period has been included for reference. On 08 December 2014 the prescriber was identified as not submitting PPAFs for 6 patients. None of the outstanding 6 PPAFs were submitted as all patients were identified as not continuing therapy. A second formal Notice for Non-Compliance was issued to the prescriber on 12 February 2015. This prescriber was previously included in noncompliance narratives presented in the 36-Month FDA The prescriber was contacted and re-educated on 10 February 2016. The prescriber stated that his office is very busy and the PPAFs may have been lost or misplaced. The TIRF REMS Access program educated the prescriber about the website as the prescriber mentioned that he prefers to do things electronically. The prescriber submitted all 6 PPAFs. A Warning letter was issued to the prescriber requiring that a CAP is submitted by 15 March 2016. A CAP was received on 10 March 2016. The NCRT did not approve the CAP as it did not include a preventative action plan to ensure future adherence to PPAF requirements. A revised CAP was received on 23 March 2016, which stated that the prescriber will make sure that a PPAF will be faxed for every patient that receives a prescription and the portal will be checked to confirm documentation is complete. The revised CAP was approved by the NCRT on 14 April 2016. On 27 May 2014 the prescriber was identified as not submitting PPAFs for 5 patients. The prescriber submitted 3 of the 5 PPAFs, as the remaining 2 PPAFs were identified as not continuing therapy. A formal Notice for Non-Compliance was issued to the prescriber on 03 July 2014. On 05 February 2016 the prescriber was identified as not submitting PPAFs for 6 patients who were at least 10 days past enrollment. ID#422 (Case # 12482456, 18919365, 20277540, 22269972 & 131991271) Mitigating Action Since closing the non-compliance case, no additional noncompliance cases for this prescriber have been identified. Closed The TIRF REMS Access program attempted to contact the prescriber multiple times between 17 March 2016 and 07 April 2016 for re-education. A request for contact, along with the Prescriber Overview, was issued to the prescriber after multiple unsuccessful attempts. The prescriber failed to contact the TIRF REMS Access FDA_4093 60-Month REMS Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Report Description (N=3) REMS Assessment Report (ID #179: Case #12482456, 18919365 & 20277540). [24-Month Assessment Report Non-Compliance] Prescriber was issued a first formal Notice for NonCompliance on 18 March 2013 for not submitting PPAFs. [36-Month FDA REMS Assessment Report NonCompliance] Prescriber was issued a second formal Notice for NonCompliance on 11 April 2014 for not submitting PPAFs and then a Warning on 11 July 2014 requiring submission of a CAP after the prescriber was again identified as not submitting PPAFs for patients at least 10 days past enrollment. The prescriber submitted a CAP on 14 July 2014 that was denied by the NCRT as it did not align with the re-education that it was the prescriber’s responsibility to submit PPAFs for each patient. A revised CAP was received on 24 July 2014 which stated that the prescriber would take personal responsibility to make sure patients are educated and PPAFs are signed. The CAP was approved by the NCRT on 07 August 2014. Page 72 of 112 Report Status Mitigating Action program by the 28 April 2016 deadline. Additional attempts to contact the prescriber were made and re-education was performed on 04 May 2016. The prescriber was issued a Warning with request for a CAP to be submitted by 26 May 2016. A CAP was received on 25 May 2016. The CAP was not approved by the NCRT as it was signed by an office nurse, not the prescriber. A revised CAP was received on 03 June 2016. The CAP was not approved by the NCRT as it did not describe a corrective action to be implemented to ensure the non-compliance was not repeated. A third revised CAP was received on 15 June 2016. The CAP stated that staff would be trained on the TIRF REMS Access website to submit PPAFs and handing out prescription information on TIRF medicines with each PPAF. The CAP was approved by the NCRT on 16 June 2016. Since closing the non-compliance case, no additional noncompliance cases for this prescriber have been identified. A second Warning for Non-Compliance was issued to the prescriber on 13 November 2014 requiring submission of a CAP after the prescriber was again identified as not submitting PPAFs for patients at least FDA_4094 60-Month REMS Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Report Description (N=3) Page 73 of 112 Report Status Mitigating Action Closed The TIRF REMS Access program confirmed that the prescriber signed an agreement with the state Board of Medical Examiners on 21 October 2016 stating that the prescriber would no longer accept new patients and would stop writing prescriptions for controlled substances immediately. The prescriber’s DEA would then officially be deactivated on 31 October 2016. 10 days past enrollment. The prescriber submitted a CAP on 01 December 2014 stating that he has met with all of his current staff members to ensure that they understand the importance of the TIRF REMS Program and thoroughly understand the protocol for the completion and submission of PPAFs. Additionally, the prescriber has made several changes within his office, including having TIRF REMS forms readily available to be signed in every patient room and personally reviewing his schedule daily to confirm that every patient who was prescribed a TIRF medicine has been REMS enrolled. The CAP was approved by the NCRT on 03 December 2014. [60-Month FDA REMS Assessment Report NonCompliance] On 17 March 2016 the prescriber was again identified as not submitting PPAFs for 5 patients. ID#445 (Case # 190342508) The TIRF REMS Access program was notified by a sponsor of a prescriber with a DEA set to be deactivated 31 October 2016. The TIRF REMS Access program reviewed prescription transaction data and confirmed that the prescriber had no prescription activity between 21 October 2016 and 31 October 2016. On 01 November 2016, the TIRF REMS Access program confirmed FDA_4095 60-Month REMS Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Report Description (N=3) Page 74 of 112 Report Status Mitigating Action that the prescribers DEA was no longer active. The TIRF REMS Access program notified the prescriber’s office that the prescriber would be deactivated from the TIRF REMS Access program based on no longer having a valid, Schedule II DEA. a No prescriber inactivations occurred during this reporting period due to non-compliance; however, there was a significant event of non-compliance reported after the reporting period ended on 28 October 2016. FDA_4096 60-Month REMS Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies 6.3 Page 75 of 112 Audits As part of non-compliance monitoring, the TIRF REMS Access program pharmacies may be subject to periodic data requests and/or audits. Such activities may occur for suspected noncompliance with program requirements based on program monitoring activities. 6.3.1 Closed System Pharmacy Audits [Metric 20] The REMS Assessment Plan includes the following components for closed system pharmacy audits: (1) Verification of training for all pharmacists dispensing TIRF products (2) Numbers of prescription authorizations per closed system (3) Reconciliation of data describing TIRF product prescriptions received by the closed system pharmacy with TIRF product dispensed to patients with a valid enrollment in the TIRF REMS Access program. The first component of the closed system pharmacy audit requirement is accomplished through the enrollment process for CSPs. To become enrolled the authorized representatives must attest that all pharmacy staff that participate in dispensing TIRF products will be trained on the TIRF REMS Access program requirements. The second component is done through the closed system pharmacy prescription authorization process. Closed system pharmacists are required to validate the enrollment status of the prescriber and patient prior to dispensing a TIRF product by calling or faxing the prescription details to the TIRF REMS Access program. The TIRF REMS Access program maintains records of prescription details and the associated REMS authorization. Table 19 provides information on all prescription authorizations by closed system pharmacy. The third and final component includes reconciliation between the closed system pharmacy’s dispensing data and the TIRF REMS Access program’s REMS authorizations. To conduct this reconciliation, the TIRF REMS Access program requests dispensing records from the CSPs and compares the dispensing records to REMS authorization data from the TIRF REMS Access program. After confirmation that the closed system pharmacy agrees to participate in the reconciliation, a formal written request for data is issued upon request to the AR detailing the data to be provided and the deadline for submission. Specific data requested include: • RX number for each prescription dispensed • DEA number or National Provider Identifier (NPI) number of the facility that dispensed each prescription • DEA number or NPI number of the prescriber that issued each prescription • Date and time of each prescription transaction • TIRF REMS Authorization code obtained for each prescription dispensed • Due to the structure of some closed system pharmacy networks, the headquarters may be unable to provide data for all pharmacy locations as no central data repository is in existence; each pharmacy location maintains their own data. In these cases, a random sample of pharmacy locations is selected by the TIRF REMS Access program for participation. FDA_4097 60-Month REMS Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies • Page 76 of 112 Findings from each investigation are reviewed with the NCRT and actions are taken in accordance with the Non-Compliance Protocol. The CSP assessment metric required auditing of at least 3 randomly selected CSPs. The TRIG proactively included all CSPs in the audit with a request to provide dispensing records from 01 May 2015 through 30 April 2016. As a result, there were 6 audits conducted during this 60month monitoring reporting period and 4 CSPs (ID#CS7, ID#CS9, ID#CS10 and ID#CS12) were found to be non-compliant with the TIRF REMS Access program requirements. Based on the identification of non-compliance, a non-compliance case was opened for each of these 4 CSPs. Below are the details of these 6 closed-system pharmacy audits. Table 26 summarizes the reconciliation of the dispensing data from each CSP and the authorizations received from the TIRF REMS Access program during the course of the 6 audits. Table 26 Closed System Pharmacy Audits Audit ID Number Date Closed System Monitoring Request for Data Sent Date Dispensing Records Received1 Total Dispenses/Total Dispenses Not Authorized by the REMS 1 (ID#CS7) 26 May 2016 08 July 2016 164/1 Y 0/0 N 2 2 (ID#CS8) 26 May 2016 15 June 2016 3 (ID#CS9) 26 May 2016 07 September 2016 4 (ID#CS10) 5 (ID#CS11) 26 May 2016 26 May 2016 02 September 2016 20 June 2016 2 40/7 27/1 0/0 NonCompliance Identified? Y 3 Y N 6 (ID#CS12) 26 May 2016 02 September 2016 99/59 Y 1 The date range for dispensing records received was 01 May 2015 through 30 April 2016. 2 Pharmacy provided confirmation that no TIRF medicines were dispensed during the reporting period (01 April 2014-30 April 2015). 3 Initial data showed that there was one location with three instances of dispensing TIRF medications without an authorization. However, after issuance of a Notice for Non-Compliance, additional information was received from the pharmacy confirming that the one location only had one instance of dispensing TIRF medications without an authorization. Additional details on the 4 CSP audits that identified non-compliance are identified below. Closed System Pharmacy Audit 1: ID#CS7 (Case #177904062) Request for Data On 26 May 2016, the TIRF REMS Access program initiated outreach to request data pertaining to all instances where TIRF medicines were dispensed from the pharmacy for reconciliation purposes to ensure that the manual closed system process is meeting the goals of the REMS. On 02 June 2016, a formal closed system monitoring request for data was sent via fax to the AR, with a response requested by 24 June 2016. FDA_4098 60?Month REMS Assessment Report Transmucosal Irmnediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 77 of 112 Investigation On 24 June 2016, the AR requested an extension until 08 July 2016 to submit the data. Dispensing records were provided on 08 July 2016, and the TIRF REMS Access program began to reconcile the data. The dispensing records contained data ??om 01 May 2015 through 30 April 2016 and included 164 instances where a TIRF product had been dispensed during the monitoring period. The dispensing records provided were compared to authorization data from the TIRF REMS Access program. To complete the reconciliation, additional data were requested from (mm on 22 August 2016. The additional data were provided on 09 September 2016. Findin 8 Data discrepancies were found during reconciliation and showed that in 1 of the 164 occmrences drug was dispensed without obtaining an authorization. Outcome A second formal Notice for Non-Compliance was issued on 21 September 2016 requiring a CAP be submitted by 21 October 2016. A CAP was received on 20 October 2016 stating that the non- compliant instance occrured because the Pharmacy Technician mistakenly took the patient insurance number written on the script as the REMS authorization number. The pharmacy has a process in place where a hard stop prompt displays in the system when a TIRF is to be dispensed notifying the Pharmacy Technician that the TIRF REMS must be called to obtain an authorization number. The authorization number is then documented before dispensing the medication. The Pharmacy Technician and the Pharmacist have been counseled on the error and the REMS requirements and process have been reinforced. The TRIG approved the CAP on 01 December 2016. Closed System Pharmacy Audit 3: (Case #177372348) Request for Data On 26 May 2016, the TIRF REMS Access program initiated outreach to request data pertaining to all instances where TIRF medicines were dispensed from the pharmacy for reconciliation pruposes to ensure that the manual closed system process is meeting the goals of the REMS. A formal request for data correspondence was issued Via email to the Veteran?s Administration WA) on 26 May 2016. Investigation In the request for data in February 2014, the VA AR had advised that each VA site stores their own dispensing records (there is no central data storage) and they requested that the TIRF REMS Access program select a sample of sites to provide dispensing records. Therefore, on 04 August 2016, the TIRF REMS Access program provided 8 randomly selected and enrolled VA closed-system dispensing locations (accormting for 10% of the enrolled population for VA) to the VA for reconciliation. A response with the data was requested by 16 September 2016. The requested dispensing data were received ??om the VA on 07 September 2016 and reconciled with authorization data from the TIRF REMS Access program. The dispensing records contained 60?Month REMS Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 78 of 112 data from 01 May 2015 through 30 April 2016 and included 40 instances where a TIRF product had been dispensed during the monitoring period. Findin The closed system pharmacy dispensing data showed that 1 location had 7 instances of dispensing TIRF medications without authorization. Outcome A third formal Notice for Non-Compliance was issued to the headquarters on 21 September 2016. A CAP was initiated on 26 September 2016 stating that prior to November 2015, the pharmacy staff were unaware of the requirement to obtain authorization prior to dispensing due to changes in personnel and limited dispensing of TIRF REMS products. The pharmacy is now requiring that all pharmacy clinical staff complete the TIRF REMS Access Education Program. Training will be documented and reviewed bi-annually to ensure compliance. Additionally, the system used at the pharmacies was updated to add a reminder for each TIRF NDC that authorization was required for dispensing and a Standard Operation Procedlu?e (SOP) was developed to de?ne the need for prior authorization and the steps to take to acquire prior authorization. This CAP was approved by the NCRT on 03 November 2016, after the TRIG confumed with the pharmacy that all non-compliant dispenses identi?ed in the 2015- 2016 audit data, were prior to the initiation of this CAP. Closed System Pharmacy Audit 4: (Case #177920269) Request for Data On 26 May 2016, the TIRF REMS Access program initiated outreach to request data pertaining to all instances Where TIRF medicines were dispensed from the pharmacy for reconciliation pmposes to ensm?e that the manual closed system process is meeting the goals of the REMS. A formal request for data correspondence was issued to the on 03 June 2016. Investigation In the request for data in February 2014, the (mu) an?) AR had proposed that the TIRF REMS Access program provide REMS authorization data for randomly selected sites and provide the information to would then reconcile their own pharmacy?s data to identify any non-compliance. This process has been used by to conduct audits for other REMS programs. Therefore, on 04 August 2016, the TIRF REMS Access program provided data for 8 randomly selected and enrolled (m4) closed-system dispensing locations (accounting for 20% of the enrolled population for (mm to (m4) (m4) reconciliation. A response with the data was requested by 16 September 2016. (um) (4) for The requested data were received from on 02 September 2016 and reconciled with authorization data from the TIRF REMS Access program. The dispensing records contained data from 01 May 2015 through 30 April 2016 and included 27 instances where a TIRF product had been dispensed during the monitoring period. 00 60?Month REMS Assessment Report Transmucosal Irmnediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 79 of 112 Findin The closed system pharmacy dispensing data showed that 1 location had 3 instances of dispensing TIRF medications without authorization. Outcome A second formal Notice for Non-Compliance for was issued on 21 September 2016 requiring a CAP by 12 October 2016. Upon receipt of the notice, research was conducted by and additional information was provided to the TIRF REMS Access program. The additional data showed that the non-compliant location only had 1 instance of dispensing TIRF medications without authorization from the TIRF REMS Access program. A revised second formal Notice for Non-Compliance was issued on 26 September 2016. A CAP was received on 26 September 2016, stating that the issue that occurred was due to the pharmacy?s transition to a new pharmacy system and that as of 15 December 2016, all licensed pharmacists will be required to review the REMS guidelines and attest they are aware of all processes. Reminders will also be placed near the TIRF medication storage area to remind pharmacists to obtain authorization prior to dispensing. The NC RT approved the CAP on 17 November 2016. Closed System Pharmacy Audit 5: (Case #145003267) Request for Data On 26 May 2016, the TIRF REMS Access program initiated outreach to request data pertaining to all instances where TIRF medicines were dispensed from the pharmacy for reconciliation pmposes to ensure that the manual closed system process is meeting the goals of the REMS. A formal request for data correspondence was issued to the Department of Defense on 27 May 2016. Investigation In the request for data in May 2015, the Representative had proposed that the TIRF REMS Access program provide REMS authorization data from the TIRF REMS Access program so that they could match it to their pharmacy data. Therefore, on 04 August 2016, the TIRF REMS Access program provided data for all sites (accounting for 100% of the enrolled population for the to the for reconciliation. A response with the data was requested by 16 September 2016. The requested data were received from on 02 September 2016 and reconciled with authorization data ?'om the TIRF REMS Access program. The dispensing records contained data from 01 May 2015 through 30 April 2016 and included 99 instances where a TIRF product had been dispensed during the monitoring period. Findin The closed system pharmacy dispensing data showed that 11 locations had 59 instances of dispensing TIRF medications without authorization. Of the 11 locations, 3 locations were not enrolled in the TIRF REMS Access program. 01 60-Month REMS Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 80 of 112 Outcome The TIRF REMS Access program conducted research to determine whether the 3 non-enrolled sites were the same non-enrolled sites found to be non-compliant during the 48-month assessment period. On 03 October 2016 it was confirmed that 1 of the non-enrolled sites found during this reporting period was also a non-enrolled site identified in the 48-month assessment period. The AR was notified and confirmed that the three non-enrolled sites had been reeducated and would not be dispensing TIRF medicines in the future. A third formal Notice for Non-Compliance for was issued on 06 October 2016 requiring a CAP by 12 October 2016. A CAP was received on 18 October 2016 stating the three non-compliant pharmacy locations were not aware of the prescription authorization requirement. All three locations were educated on the REMS requirements and were marked as deactivated locations that will no longer order or dispense TIRF products. Future plans have been made to conduct ongoing quarterly educational sessions to inform the military treatment facility on the REMS requirements until understanding, awareness, and compliance is stable. The NCRT approved the CAP on 17 November 2016. 6.3.1.1 Closed System Pharmacy Audit Acknowledgement Letter Items In the 48-Month FDA Assessment Report Acknowledgement Letter, FDA requested that both CSP entities that were found to be non-compliant in the 48-month assessment reporting period be included in the 60-month CSP audits. All CSPs were included in the audit process, which included both CSPs that were found to be non-compliant in the 48-Month FDA REMS Assessment Report. Additionally, the FDA requested that the TRIG should propose an outreach to CSPs to improve compliance if the TRIG does not favor a novel authorization process for all of the CSPs solely due to the poor performance of the governmental entities. Further, the FDA requested that the TRIG add the assessment of prescription processing times for prescriptions that do not experience any REMS-related rejections. As described in Section 5.1.5.4 in response to FDA’s request of consider a novel approach for prescription authorization at CSP locations, the TRIG does not favor the addition of a web-based process. As discussed in many of the CSP audit CAPs, one challenge related to updating the REMS authorization process at CSPs to be web-based is the transient nature of pharmacy staff at these locations. Regardless of adding a modality to the authorization process, there is still turnover at the pharmacy level that leads to education gaps. A novel authorization process would provide another modality to minimize the risk to bypass REMS edits but still would require education on the process. Additionally, through anecdotal information, the TRIG is aware that some CSP locations are unable to access outside websites and may not be able to utilize a novel authorization process. The TRIG will continue to monitor and assess the need for an alternate solution as appropriate. One potential process the TRIG is evaluating is quarterly review of CSP data rather than an annual review in the current audit process. In addition to this potential process change, the TRIG is discussing incorporating an assessment of prescription processing times for prescriptions that do not experience any REMS-related rejections. FDA_4102 60-Month REMS Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies 6.3.2 Page 81 of 112 Inpatient Hospital Pharmacy Audits [Metric 21] The inpatient hospital pharmacy audit process is conducted through an audit questionnaire invitation that is faxed to authorized inpatient pharmacists of pharmacies enrolled in the TIRF REMS Access program requesting their participation. Once the authorized inpatient pharmacist agreed to participate, they received the audit questionnaire to complete, which included 2 qualifying questions to determine eligibility to participate in the audit: 1. Is your pharmacy a Hospital Pharmacy? Yes/No 2. In the previous 12 months, has your hospital pharmacy dispensed TIRF medicine? Yes/No If the answer was no to either of the qualifying questions, the pharmacy did not qualify for the audit. If they answered yes to both qualifying questions, they were asked to finalize the questionnaire by completing the following 3 questions: 1. Provide the number of units dispensed within . (See NDC list for a current listing of TIRF NDCs) ________units of use of TIRFs dispensed to inpatients. 2. Did all pharmacists who dispensed TIRF medicines complete training on the TIRF REMS Access program prior to dispensing these products? Yes/No 3. Do you have procedures in place such as order sets/protocols to assure compliance with the TIRF REMS program requirements? Yes/No. If yes, are you willing to provide examples of an order set or protocol? All completed questionnaires were to be returned to the TIRF REMS Access program via fax or phone by the date specified on the audit invitation. A total of 12 enrolled inpatient locations were solicited for participation in the audit. Three of the 12 pharmacies did not respond to the audit invitation. The remaining 9 pharmacy locations agreed to participate and completed the qualifying questions associated with the audit questionnaire. Of the 9 pharmacies, 4 pharmacies answered no to at least one of the qualifying questions and were either not a hospital inpatient pharmacy facility or had not dispensed TIRFs in the previous 12 months. The remaining 5 qualified to participate in the audit, and proceeded with answering the 3 remaining audit questions. Based on responses to the 3 audit questions, 4 of the 5 audited inpatient hospital pharmacies were found to be compliant with the TIRF REMS Access program requirements. One audited inpatient hospital pharmacy was found to be non-compliant with the REMS requirements and a non-compliance case was opened. Inpatient Hospital Pharmacy Audit 6: ID#IA6 (Case #138176646) Questionnaire Completion On 12 May 2016, the Audit Invitation and Questionnaire were faxed to the inpatient pharmacy AR. Outreach was conducted on multiple occasions from 17 May 2016 to 31 May 2016 to confirm receipt and timeline for completion of the questionnaire. A completed questionnaire was received on 06 June 2016. FDA_4103 60-Month REMS Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 82 of 112 Findings The inpatient pharmacy reported dispensing 7 units of TIRF medicines in the previous 12 months. The pharmacy indicated that all pharmacists who dispensed TIRF medicines did not complete training on the TIRF REMS Access program prior to dispensing these products. Outcome A Warning was issued to the pharmacy on 15 June 2016, requesting a CAP be submitted by 29 June 2016. A CAP was received on 29 June 2016 stating that the Medical Safety Pharmacist would be sending the link to the education to all pharmacists to ensure all pharmacists complete the training. Additionally, any new pharmacists will be required to complete the training. The Director of Pharmacy will enforce mandated training every 2 years (in alignment with the pharmacy enrollment renewal). The NCRT approved the CAP on 01 July 2016. Based on the identification of non-compliance at this inpatient hospital pharmacy, the TRIG plans invite this same pharmacy for audit activities again in 2017. 7 7.1 SAFETY SURVEILLANCE Adverse Event Reporting [Metric 29] TIRF Sponsors process AE reports related to their specific products and report to the FDA according to current regulations outlined in 21 CFR 314.80 and the sponsor’s respective SOPs. 7.2 TRIG Sponsor Adverse Event Data of Interest [Metric 30] Based on the current Assessment Plan in the REMS Supporting Document, the TRIG has conducted an aggregate root cause analysis of all spontaneous AE reports of addiction, death, overdose, and pediatric exposure from the TIRF Sponsors. Based on this requirement the TRIG Sponsor companies used a third party, UBC, to conduct this analysis. The sponsors identified the appropriate Medical Dictionary for Drug Regulatory Activities (MedDRA) codes to provide data including narratives or MedWatch forms which UBC summarized based on the FDA’s request (see Appendix 12.2). Reports were reviewed and duplicates consolidated, when possible. Originally case reports were selected based on the specified Preferred Terms (PTs); upon UBC’s review of the narrative information, some case reports did not meet the specified criteria and were excluded from the analysis. Additionally, literature reports and reports from Poison Centers were excluded. Metrics of interest included: the number of event reports in each event category of interest (addiction, death, overdose, pediatric exposures); counts of AEs related to inappropriate conversions between TIRF products; counts of AEs related to accidental and unintentional exposures; and counts of AEs that are associated with use of TIRF medicines in non-opioid tolerant patients. In the 36-Month FDA Assessment Report Acknowledgement Letter, the FDA stated that none of the TRIG spontaneous AEs included a root cause analysis as specified in the Assessment Plan and requested that a root cause analysis of AEs be reported in subsequent assessment reports. The analysis has been added and data tables now report the potential causality for each case if sufficient information was available to make a determination. If there was insufficient FDA_4104 60-Month REMS Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 83 of 112 information available and the potential causality could not be determined, it was noted in the table. The reporting period used for this analysis was 29 August 2015 to 28 August 2016. There were 353 unique case reports that met the specified criteria. After a review of the 353 MedWatch Forms or narratives, no reports of inappropriate conversions between TIRF products were noted. None of the narratives indicated unintentional exposures, or non-opioid tolerance. 7.3 Number of Adverse Events of Special Interest The total number of cases of interest reported during this reporting period is presented in Table 27 below. Of the 353 cases, 344 (97.5%) had an outcome of death, 6 (1.7%) were reports of addiction, 4 (1.1%) were reports of overdose, and 3 (0.8%) were pediatric exposures. There was an increase in deaths this reporting period versus the 48-Month FDA REMS Assessment Report (344 vs. 294). However, a decrease in deaths was observed from the 36-Month FDA REMS Assessment Report to the current reporting period. There was a noted decrease in addiction, overdose and pediatric exposure for this reporting period. From the 48-Month FDA REMS Assessment Report to the 60-Month FDA REMS Assessment Report, reports of addiction have decreased from 12 to 6 cases, overdose is down from 6 cases to 4 cases, and pediatric exposures are down from 4 cases to 3 cases. Table 27 Number of Cases of Adverse Events of Special Interest AEs of Interest Total Number of AEs of Interest Addiction Death Overdose a Pediatric Exposure Cases may have more than one AE of interest. Current Reporting Period (29AUG201528AUG2016)Number of Reportsa N (%) 353 6 (1.7) 344 (97.5) 4 (1.1) 3 (0.8) Table 28 shows the current reporting period rates for each of the AEs of special interest per 100,000 prescriptions. During this reporting period, a TRIG sponsor noted cases that met the criteria for this analysis that had not been previously report. A total of 43 cases were identified including 41 death cases, 1 case of addiction (which resulted in death), and 2 cases of overdose. Identification of these cases impacted the rates previously reported. For this reason, the rates of the AEs of interest for the 36-month, 48-month, and 60-month reporting periods have been adjusted as presented in Table 28. FDA_4105 60-Month REMS Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Table 28 Rate of Adverse Events by Total Prescriptions Page 84 of 112 Data Reported in the 48?Month and 36?Montb FDA REMS Assessment Reports Updates to Data Reported in the 48?Month and 36? Montb FDA REMS Assessment Reports Current Reporting Period Previous Reporting Period Previous Reporting Period Previous Reporting Period Previous Reporting Period 29AUG2013-28AUG2014 Revised AE Revised AE AE Rates per AE Rates per AE Rates per Rates per Rates per 100,000 100,000 100,000 Revised 100,000 Revised 100,000 Number of Prescriptions Number Prescriptions Number Prescriptions Number Prescriptions Number Prescriptions AEs of Interest of AEsa of (N =94,464) of of Addiction 6 6.79 12 10.66 4 4.23 12 10.66 5 5.29 Death 344 389.44 291 258.62 362 383.21 294 261.28 400 423.44 Overdose 4 4.53 6 5.33 0 0.00 6 5.33 2 2.12 Pediatric Exposure 3 3.40 4 3.55 2 2.12 4 3.55 2 2.12 Cases may have more than one AE of special interest. 06 60-Month REMS Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 85 of 112 Table 29 shows the current reporting period rates for each of the AEs of special interest per 100,000 population. The rates previously reported for AEs by total patients was also impacted by the additional 43 cases and revised rates have been calculated. FDA_4107 60-Month REMS Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Table 29 Rate of Adverse Events by Total Patients Page 86 of 112 Data Reported in the 48-Month and 36-Month FDA REMS Assessment Reports Updates to Data Reported in the 48-Month and 36- Month FDA REMS Assessment Reports Current Reporting Period 29AUG2015-28AUG2016 Previous Reporting Period Previous Reporting Period Previous Reporting Period 29AUG2014-28AUG2015 Previous Reporting Period 29AUG2013-28AUG2014 Revised AE AE Rates per AE Rates per AE Rates per Rates per Revised AE 100,000 100,000 100,000 Revised 100,000 Revised Rates per Number Patients Number Patients Number Patients Number Patients Number 100,000 Patients AEs of Interest of (N=ll,107) of of (N =14,772) of of (N=l4,772) Addiction 6 54.02 12 75.37 4 27.08 12 75.37 5 33.85 Death 344 3,097.15 291 1.827.66 362 2.450.58 294 1,846.50 400 2,707.83 Overdose 4 36.01 6 37.68 0 0.00 6 37.68 2 13.54 Pediatric Exposure 3 27.01 4 25.12 2 13.54 4 25.12 2 13.54 Cases may have more than one AE of special interest. 08 60-Month REMS Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 87 of 112 Six cases were classified as cases of addiction. Of the 6 cases, 2 cases had an outcome of “not recovered/not resolved” at the time of the cut off (28 August 2016); and 3 cases had an outcome of “unknown; and 1 had an outcome of death. Table 30 provides details of these 6 cases and Table 31 presents the 1 new case of addiction received that falls in a previous reporting period. FDA_4109 60-Month REMS Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 88 of 112 Table 30 Cases of Addiction Received from TRIG Sponsors during the Reporting Period: 29 August 2015 - 28 August 2016 Patient Date UBC ID Age Gender Event 1939 UNK Unknown Unknown 1988b 31 Male Report Preferred Term(s) Indication(s) Lower back leg 08OCT2015 Intentional product misuse, Product use issue pain 10APR2014, 07DEC2015 Accidental overdose, Headaches 10APR2014, Lethargy, Stupor, 10APR2014, Anhedonia, Decreased 28DEC2011, appetite, Feeling 28DEC2011, abnormal, Insomnia, 28DEC2011, Suicidal ideation, Tooth 28DEC2011, abscess, Headache, 28DEC2011, Nausea, Vomiting, 01JAN2011, Anxiety, Depression, 23JAN2008, Neck pain, Skin abrasion, 23JAN2008, Stress, Migraine, Tooth 23JAN2008, impacted, Toothache, 01JAN2008, Fall, Ligament sprain, 01JAN2008, Drug dependence, Major 01JAN2008, depression, Product use 01JAN2008, issue, Toxicity to various 01JAN2008, agents 08AUG2007, 02JUN2007, 02JUN2007, 01JAN2007, 01JAN2007, 01JAN2006, Unknown, Unknown, Unknown TIRF Duration Concomitant Medications Co-Suspect Product(s) Event Outcome Potential Causalitya Unknown None reported None reported Unknown Not Related 2 Years Elavil, Clonidine, Benadryl, Naproxen, Prochlorperazine, Nexium, Prilosec, Klonopin, Pantoprazole Death Possibly Related Percocet, Lorazepam, Oxycodone, Xanax, Endocet FDA_4110 60-Month REMS Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Patient Page 89 of 112 Date UBC ID Age Gender Event 2048 45 Male 03FEB2016, 02FEB2016 Pain, pain Unknown Nabilone 2111 55 Male APR2016, 28MAR2016 Underdose, Device Back pain, failure, Pain, Product use neuralgia 28MAR2016, issue, Intentional product MAR2016, misuse JAN2016, Unknown 2016-01 UNK None Calcium, Glucosamine, reported Multivitamin /07504101/, Oxycodone, Oxycontin, Saw Palmetto /00833501/, Warfarin 2152 59 Male 04JUN2016, 18MAY2016 Drug withdrawal Unknown syndrome, Drug dependence Breakthrough cancer pain 2015-05 UNK Oxycontin 2259 UNK Male Breakthrough cancer pain 2014-08-07 - Amlodipine, None UNK Hydrochloroth reported iazide Unknown Report Preferred Term(s) 04FEB2016 Coma, Inappropriate schedule of drug administration 15AUG2016 Drug dependence, Drug withdrawal syndrome Indication(s) TIRF Duration Concomitant Medications Co-Suspect Product(s) Ativan, Cocaine None reported Event Outcome Unknown Potential Causalitya Possibly Related Not Possibly Recovered/ Related Not Resolved Unknown Possibly Related Not Possibly Recovered/ Related Not Resolved a Potential causality was reported if sufficient information was available to make a determination. If there was insufficient information available and the potential causality cannot be determined, this was noted in the table. b Patient 1988 is also described in the table for overdose and death found in Appendix 12.3. UNK = Unknown FDA_4111 60-Month REMS Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 90 of 112 Table 31 New Cases of Addiction Received from TRIG Sponsors in 2016 from a Previous Reporting Period Patient Date UBC ID Age Gender Event 1889b UNK Male Unknown Report Preferred Term(s) 28JUL2014c Abnormal behaviour, Disorientation, Drug interaction, Hepatic failure, Inappropriate schedule of drug administration Indication(s) Breakthrough cancer pain TIRF Duration Concomitant Medications Co-Suspect Product(s) 2014-05-30 - None reported Nexavar 2014-06-03 Event Outcome Death Potential Causalitya Possibly Related a Potential causality was reported if sufficient information was available to make a determination. If there was insufficient information available and the potential causality cannot be determined, this was noted in the table. b Patient 1889 is also described in the table for death found in Appendix 12.3. c Case initiated in prior reporting period but was not included in previous reports. UNK = unknown. FDA_4112 60-Month REMS Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 91 of 112 As a result of this review, 344 reports of death were noted. In more than 100 of these cases, the patients died in the hospice setting. Of the 344 reports of death, 142 of the deaths noted the indication for product use was related to breakthrough pain/breakthrough cancer pain and/or a cancer diagnosis. Of the 344 reports of death, 218 cases did not include enough information to allow for an assessment of potential causality. A total of 121 death cases were determined to be not related to the TIRF medication. Of the total 344 reports of death, 4 deaths had a causality of possibly related to the TIRF product. There was one death report that was determined to be related to the TIRF medication in which the prescribing physician confirmed inappropriate use in the case narrative. A full line listing of deaths (cases of death received from TRIG Sponsors during the current reporting period and new cases received from TRIG Sponsors in 2016 from previous reporting periods is presented in Appendix 12.3. There were 4 overdose cases reported during this reporting period (Table 32). Three of the 4 cases had an outcome of death, 2 of those had a causality reported as possibly related and 1 death had insufficient information with no potential causality. These 3 cases also appear in the death listings (Appendix 12.3). The 1 remaining case had an unknown outcome and was determined to be possibly related. Table 33 presents the 2 new cases of overdose that were not previously reported. FDA_4113 60-Month REMS Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 92 of 112 Table 32 Cases of Overdose Received from TRIG Sponsors during the Reporting Period: 29 August 2015 - 28 August 2016 Patient UBC ID Age 1988b 31 2198c 2204 Date Gender Male Event 10APR2014, 10APR2014, 10APR2014, 28DEC2011, 28DEC2011, 28DEC2011, 28DEC2011, 28DEC2011, 01JAN2011, 23JAN2008, 23JAN2008, 23JAN2008, 01JAN2008, 01JAN2008, 01JAN2008, 01JAN2008, 01JAN2008, 08AUG2007, 02JUN2007, 02JUN2007, 01JAN2007, 01JAN2007, 01JAN2006, Unknown, Unknown, Unknown UNK Unknown Unknown 46 Female 07JUL2016, Unknown 32 Female 25MAR2016 Report Preferred Term(s) Indication(s) 07DEC2015 Accidental Headaches overdose, Lethargy, Stupor, Anhedonia, Decreased appetite, Feeling abnormal, Insomnia, Suicidal ideation, Tooth abscess, Headache, Nausea, Vomiting, Anxiety, Depression, Neck pain, Skin abrasion, Stress, Migraine, Tooth impacted, Toothache, Fall, Ligament sprain, Drug dependence, Major depression, Product use issue, Toxicity to various agents TIRF Duration 2 Years Concomitant Medications Elavil, Clonidine, Benadryl, Naproxen, Prochlorperazine, Nexium, Prilosec, Klonopin, Pantoprazole Co-Suspect Event Potential Product(s) Outcome Causalitya Percocet, Death Possibly Related Lorazepam, Oxycodone, Xanax, Endocet 05JUL2016 Overdose 07JUL2016 Oral mucosal blistering, Overdose 19JUL2016 Overdose Unknown Unknown None reported None reported Death Insufficient Information Breakthrough 2016-06-28 None reported None reported Unknown Possibly Related cancer pain - UNK 2217d Breakthrough 2016-07-28 None reported None reported Death Possibly Related cancer pain - UNK a Potential causality was reported if sufficient information was available to make a determination. If there was insufficient information available and the potential causality cannot be determined, this was noted in the table. b Patient 1988 is also described in the table for addiction and death found in Appendix 12.3. c Patient 2198 is also described in the death table found in Appendix 12.3. d Patient 2217 is also described in the death table found in Appendix 12.3. UNK = unknown. FDA_4114 60-Month REMS Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 93 of 112 Table 33 New Cases of Overdose Received from TRIG Sponsors in 2016 from a Previous Reporting Period Patient Date UBC ID Age 1858 UNK Male Unknown 07JAN2014b Hospitalisation, Overdose 1884 50 MAY2014, MAY2014, 2014, 17AUG2013, 2013, Unknown, Unknown, Unknown, Unknown, Unknown, Unknown, Unknown, Unknown, Unknown, Unknown, Unknown, Unknown, Unknown, Unknown, Unknown, Unknown, Unknown, Unknown, Unknown, Unknown, Unknown, Unknown, Unknown Neck pain, 2013-08-17 Flexeril, Opana, 20JUN2014b Accidental overdose, Drug Prevacid back pain, pain - UNK dependence, Blood in hip pressure increased, Off label use, Drug withdrawal syndrome, Back pain, Confusional state, Constipation, Decreased appetite, Diplopia, Dizziness, Drug ineffective, Dysphagia, Dysuria, Fall, Fatigue, Hallucination, Increased upper airway secretion, Lethargy, Local swelling, Nausea, Parosmia, Pruritus, Skin lesion, Vertigo, Vision blurred, Visual impairment, Vomiting Gender Event Female Report Preferred Term(s) TIRF Indication(s) Duration Crohn's disease Concomitant Medications 2015-06-08 None reported - UNK Co-Suspect Product(s) Event Outcome Potential Causalitya None reported Unknown Insufficient Information Fetzima, Vistaril Not Recovered/ Not Resolved Possibly Related a Potential causality was reported if sufficient information was available to make a determination. If there was insufficient information available and the potential causality cannot be determined, this was noted in the table. b Case was initiated in prior reporting period but was not included in previous reports. UNK = unknown. FDA_4115 60-Month REMS Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 94 of 112 There were 3 pediatric cases reported during this reporting period (Table 34). No case had an outcome of death. One report was not resolved and 2 cases had an outcome of unknown at the time of this report. In all reports, the medication was intentionally prescribed to the pediatric patient. No further details were obtained despite extensive follow-up attempts. FDA_4116 60-Month REMS Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 95 of 112 Table 34 Cases of Pediatric Exposures Received from TRIG Sponsors during the Reporting Period: 29 August 2015 - 28 August 2016 Patient Date Gender Event 2119 9 Male 01JAN201 04APR2016 0, Unknown, Unknown, Unknown, Unknown Product use issue, Epidermolysis Blood albumin bullosa pain decreased, Drug administered to patient of inappropriate age, Haemoglobin decreased, Malnutrition Unknown Methadone, Neurontin, Morphine None reported Not Recovered/ Pediatric Not Resolved Exposure Resulting From Off-label Prescribing 2181 14 Male Unknown 21JUN2016 Drug administered to Unknown patient of inappropriate age Unknown None reported None reported Unknown Pediatric Exposure Resulting From Off-label Prescribing 2197 14 Female Unknown 01JUL2016 Drug administered to Unknown patient of inappropriate age, Hospitalisation Unknown None reported None reported Unknown Pediatric Exposure Resulting From Off-label Prescribing Preferred Term(s) Concomitant Medications Potential Causalitya Age Report TIRF Indication(s) Duration CoEvent Suspect Product(s) Outcome UBC ID a Potential causality was reported if sufficient information was available to make a determination. If there was insufficient information available and the potential causality cannot be determined, this was noted in the table. UNK = unknown. FDA_4117 60-Month REMS Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 96 of 112 7.4 TIRF Product Surveillance Data [Metric 31] 7.4.1 Background Surveillance data focusing on events of abuse, misuse, and death were evaluated using data from the RADARS System for the time period July 2010 to June 2016. Based on FDA request, the data included in this report compare event rates for a time period prior to full implementation of the TIRF REMS and a time period after REMS implementation. The 48-Month FDA Assessment Report Acknowledgement Letter requested that the CII immediate-release opioid category be expanded to include oxycodone/acetaminophen, oxycodone/aspirin, and oxycodone/ibuprofen. The TRIG confirms that the CII immediate-release opioid category currently includes these products in the analysis. Data from 5 programs that gather data from unique populations along the spectrum of drug abuse were used to monitor for the non-medical use (abuse and misuse) of TIRF products. The data sources and the specific events evaluated in each are shown in Table 35 below. Table 35 RADARS System: Data Sources and Specific Events Data Source 1. Poison Center Program Treatment Center Programs 2. Opioid Treatment Programs 3. Key Informants Survey 4. College Survey Abuse a Intentional Misuse Unintentional Therapeutic Errors Unintended General Exposures Emergency Department Visits & Hospitalizations Deaths      Major Medical Outcomes and Deathse  b b c d 5. Impaired Health Care Workers Program a Abuse defined as exposure resulting from intentional improper or incorrect use of a substance where the victim was likely attempting to gain a high euphoric effect or some other psychotropic effect b Abuse defined as a respondent endorsing the use of a product to get high in the past 30 days c Abuse defined as endorsement of a non-medical use of a drug in the past 90 days d All reported cases are considered abuse; data may include a small fraction of drug diversion information. e This column includes the events included in the column titled “deaths” as well as major medical outcomes that did not lead to death FDA_4118 60-Month REMS Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 97 of 112 Trends over time for the TIRF products were compared to 3 comparator groups that are not directly impacted by the TIRF REMS to determine how the trend in TIRF rates compares to the secular trend in other opioids. The comparators used in this report were: • Schedule II IR opioids • Schedule II opioids • Schedule II opioids excluding methadone On 06 October 2014, IR hydrocodone was changed from a Schedule III opioid to a Schedule II opioid. As IR hydrocodone was not included in the group of Schedule II opioids in previous reports and was not a Schedule II drug for the entire study period, data were analyzed 2 ways. The primary analyses were conducted without IR hydrocodone in the Schedule II IR opioid group. Sensitivity analyses were then conducted as if IR hydrocodone was a Schedule II IR opioid for all quarters. Data from IMS Health are used to estimate total prescriptions dispensed and total dosing units dispensed at the 3-digit ZIP-code level for all TIRF REMS opioids and comparator groups. Totals of prescriptions and dosing units in the 3-digit zip codes covered by the RADARS System Programs were computed and used as the denominators when calculating product availability rates. IMS data does not capture methadone dispensed through opioid treatment programs (OTPs), thus the count of methadone prescriptions is an undercount. Prescription rates will be scaled per 10,000 prescriptions and dosing rates will be scaled per 100,000. Rates of abuse, misuse, overdose, unintentional therapeutic errors, unintentional general exposures, emergency department visits/hospitalizations, deaths, and major medical outcomes were calculated using the 2010 US decennial census estimated from the 3-digit zip codes covered in the RADARS System Programs as the denominator. Population rates will be scaled per 100,000 population. Additional details regarding the data sources and specific events can be found in the RADARS System Report Protocol (Appendix 12.4). 7.4.2 RADARS Results This RADARS System Report summary presents the results of an analyses of the effectiveness of the TIRF REMS drawn from 5 data sources (i.e., Poison Center Program, Treatment Center Programs combined [includes OTP survey and Survey of Key Informants’ Patients {SKIP}], College Survey, and Impaired Healthcare Workers Program). The full report from the RADARS System Program including limitations of the analyses is included as Appendix 12.5. Poisson regression was used to compare changes in rates of abuse, misuse, and serious medical consequences, including deaths, emergency department visits, therapeutic errors and accidental unsupervised ingestions, over time for the TIRF products to changes over time in rates among 3 comparator groups: Schedule II IR opioids, Schedule II opioids and Schedule II opioids excluding methadone. Two different methods of analysis were applied: a comparison of means model and a comparison of trends model. In the first model, separate means were fit to the pre and post TIRF REMS periods. The pre to post changes in the mean outcome rates were then compared across drug groups. For the second model, separate trend lines were fit to the pre and FDA_4119 60-Month REMS Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 98 of 112 post TIRF REMS data. Comparison of the change in intercepts and slopes were made. Time was divided into 2 periods: pre (3Q2010 through 2Q2012) and post (3Q2012 to 2Q2016). The comparison of means model provided a better fit to the data than the comparison of trends and thus is the focus of this summary. For the Poison Center Program outcomes of intentional abuse, intentional misuse, unintentional therapeutic error, unintentional general, emergency department visits or hospitalization and for all 3 rate types (population, prescription and dosing unit rates), no significant pre to post REMS mean changes were noted in conjunction with implementation of the TIRF REMS. Further, when comparing pre to post mean changes for the TIRF REMS opioids to means changes for Schedule II IR opioids, Schedule II opioids and Schedule II opioids excluding methadone, no significant differences were found. For the outcome of major medical outcome or death, significant increases were seen for the pre to post TIRF REMS periods per prescriptions dispensed and dosing units dispensed. These increases differed significantly from the change for Schedule II IR opioids, Schedule II opioids and Schedule II opioids excluding methadone. As in previous reports, only 2 deaths were reported in the Poison Center Program. Due to the infrequency of the death data, the planned statistical models could not be fit (did not converge). The Treatment Center Programs Combined comprises the OTP and the SKIP Program. For the Treatment Center Programs Combined, the mean abuse outcome decreased from the pre to post period for population rates. There were no significant changes in the prescription- or dosing unitadjusted rates. When comparing these mean changes for the TIRF opioids to that observed for Schedule II IR opioids, population rates differed significantly. For prescription dispensed rates, mean pre to post treatment decreases for the TIRF opioid differed from the change for Schedule II opioids and Schedule II opioids excluding methadone. For the College Survey Program, the mean abuse outcome for the TIRF opioids significantly increased from the pre to post period for all 3 rate types: population, prescriptions dispensed and dosing units dispensed. These increases were different than for IR Schedule II opioid, Schedule II opioids, or Schedule II opioid excluding methadone per prescriptions dispensed only. No significant changes were observed in the Impaired Health Care Worker Program. Lastly, for pediatric exposures, there were 9 cases of children (0-5 years) exposed in the pre period compared with 15 cases in the post period (9, 0-5 years; 5, 13-19 years; 1, age missing [19 or younger]). Table 36 summarizes the results from all RADARS System Programs by outcome of interest and denominator. The percentage change in the cumulative rate from the period before the TIRF REMS was implemented to the period after the TIRF REMS was implemented is displayed with 95% confidence intervals. The p-value displayed in the table measures whether the change observed in comparator opioids is different from the change in TIRF products for a given outcome and rate. Descriptively, population rates for the TIRF products across all outcome variables were low compared to rates for the three Schedule II opioid comparator arms; while prescription adjusted rates for the TIRF products were higher than the rates for the three Schedule II opioid comparator arms. Findings were similar in the sensitivity analysis including hydrocodone in the Schedule II opioids group. In the Poison Center Program, there were only 5 intentional abuse FDA_4120 60-Month REMS Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 99 of 112 mentions to TIRF products in the pre period, leaving little room for a decrease in the post period, and making this comparison under powered. Pre to post decreases were seen for 7 of the 24 outcome-rate combinations examined for TIRF products, yet only 1 was statistically significant (population rates among individuals entering opioid treatment programs). Lack of significance for the mean decreases may be due to lack of power driven by small event counts. FDA_4121 60-Month REMS Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 100 of 112 Table 36 Summary of RADARS Findings by Program, Outcome, and Denominator Program Poison Center Program Outcome Intentional abuse exposure Denominator Population Prescriptions dispensed Dosage units dispensed Intentional misuse exposure Population Prescriptions dispensed Dosage units dispensed Unintentional therapeutic error Population Drug group Percentage change (95% CI) (b) (4) Interaction p-value TIRF Products Schedule II IR Opioids Schedule II Opioids Schedule II Opioids Excluding Methadone TIRF Products Schedule II IR Opioids Schedule II Opioids Schedule II Opioids Excluding Methadone TIRF Products Schedule II IR Opioids Schedule II Opioids Schedule II Opioids Excluding Methadone TIRF Products Schedule II IR Opioids Schedule II Opioids Schedule II Opioids Excluding Methadone TIRF Products Schedule II IR Opioids Schedule II Opioids Schedule II Opioids Excluding Methadone TIRF Products Schedule II IR Opioids Schedule II Opioids Schedule II Opioids Excluding Methadone TIRF Products Schedule II IR Opioids Schedule II Opioids FDA_4122 60-Month REMS Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 101 of 112 Percentage change Program Outcome Denominator Prescriptions dispensed Dosage units dispensed Unintentional general exposure Population Prescriptions dispensed Dosage units dispensed Emergency Population department visits/hospitalization exposure Prescriptions dispensed Drug group Schedule II Opioids Excluding Methadone TIRF Products Schedule II IR Opioids Schedule II Opioids Schedule II Opioids Excluding Methadone TIRF Products Schedule II IR Opioids Schedule II Opioids Schedule II Opioids Excluding Methadone TIRF Products Schedule II IR Opioids Schedule II Opioids Schedule II Opioids Excluding Methadone TIRF Products Schedule II IR Opioids Schedule II Opioids Schedule II Opioids Excluding Methadone TIRF Products Schedule II IR Opioids Schedule II Opioids Schedule II Opioids Excluding Methadone TIRF Products Schedule II IR Opioids Schedule II Opioids Schedule II Opioids Excluding Methadone TIRF Products Schedule II IR Opioids Schedule II Opioids Interaction (b) (4) FDA_4123 60-Month REMS Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Program Outcome Denominator Dosage units dispensed Major medical outcomes and death exposure Population Prescriptions dispensed Dosage units dispensed Treatment Center Past month use to Programs get high Combined Population Prescriptions dispensed Dosage units dispensed Page 102 of 112 Drug group Schedule II Opioids Excluding Methadone TIRF Products Schedule II IR Opioids Schedule II Opioids Schedule II Opioids Excluding Methadone TIRF Products Schedule II IR Opioids Schedule II Opioids Schedule II Opioids Excluding Methadone TIRF Products Schedule II IR Opioids Schedule II Opioids Schedule II Opioids Excluding Methadone TIRF Products Schedule II IR Opioids Schedule II Opioids Schedule II Opioids Excluding Methadone TIRF Products Schedule II IR Opioids Schedule II Opioids Schedule II Opioids Excluding Methadone TIRF Products Schedule II IR Opioids Schedule II Opioids Schedule II Opioids Excluding Methadone TIRF Products Schedule II IR Opioids Schedule II Opioids Percentage change (95% CI) (b) (4) Interaction p-value FDA_4124 60-Month REMS Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Program College Survey Program Outcome Past 3-month nonmedical use Denominator Population Prescriptions dispensed Dosage units dispensed Impaired Health Care Worker Program Abuse Population Page 103 of 112 Drug group Schedule II Opioids Excluding Methadone TIRF Products Percentage change (95% CI) (b) (4) Interaction p-value Schedule II IR Opioids Schedule II Opioids Schedule II Opioids Excluding Methadone TIRF Products Schedule II IR Opioids Schedule II Opioids Schedule II Opioids Excluding Methadone TIRF Products Schedule II IR Opioids Schedule II Opioids Schedule II Opioids Excluding Methadone TIRF Products Schedule II IR Opioids Schedule II Opioids Schedule II Opioids Excluding Methadone Prescriptions dispensed TIRF Products Schedule II IR Opioids Schedule II Opioids Schedule II Opioids Excluding Methadone Dosage units dispensed TIRF Products Schedule II IR Opioids Schedule II Opioids Schedule II Opioids Excluding Methadone FDA_4125 60-Month REMS Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies 8 Page 104 of 112 PERIODIC SURVEYS OF STAKEHOLDERS On 21 July 2016, FDA provided feedback on the patient, prescriber, and pharmacist surveys. After careful review of the requested changes, the TRIG notified FDA that in order to incorporate all changes, an extension for report submission would be required. As proposed by FDA on 29 July 2016 and agreed to by the TRIG on 01 August 2016, the 60-month KAB survey results will be submitted separately from the overall REMS assessment report on or before 17 February 2017. In correspondence received from the FDA on 10 November 2016, the FDA acknowledged the agreement between the Agency and the TRIG that the survey results for the 60-Month FDA REMS Assessment Report will be submitted to the Agency on 17 February 2016. 9 FDA COMMUNICATIONS REMS Modification 3 was approved by FDA on 24 December 2014. Since this last REMS modification, the TRIG has responded to FDA information requests and FDA feedback communications and has submitted Letters of Agreement as required for new sponsors to reference the Drug Master File (DMF). Post-submission of the 48-Month FDA REMS Assessment Report and the Supplemental Report, the TRIG responded to information requests and FDA feedback communications. Per agreement with FDA a consolidated DMF submission will be made and will include all correspondence related to the 48-Month FDA REMS Assessment Report. As proposed by FDA on 29 July 2016 and agreed to by the TRIG on 01 August 2016, the 60-month KAB survey results will be submitted separately from the overall REMS assessment report on or before 17 February 2017. Additional requests included in the 48-Month FDA Assessment Report Acknowledgement Letter will also be included in the 17 February 2017 submission as requested by FDA and detailed in Section 4. 10 POST-APPROVAL STUDIES AND CLINICAL TRIALS FDA should refer to the most recent periodic safety report from each TIRF sponsor for updated information on post-approval studies and/or clinical trials. 11 DISCUSSION The TIRF REMS Access program was approved on 28 December 2011 and successfully launched on 12 March 2012, approximately 11 weeks after approval. This 60-Month FDA REMS Assessment Report covers the timeframe between 29 October 2015 and 28 October 2016. REMS enrollment continues to increase, with 1,446 new prescribers (Section 5.1.2), 1,537 new pharmacies (Section 5.1.3), and 1 new distributor (Section 5.1.4) enrolled in this reporting period. The number of prescribers and pharmacies enrolled as of the end of the reporting period has been relatively stable across the 48-month reporting period and the current reporting period. Conversely, newly enrolled patients have decreased by approximately 50% since the 48-Month FDA_4126 60-Month REMS Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 105 of 112 FDA REMS Assessment Report (from 8,740 newly enrolled patients in the 48-month reporting period to 4,255 during this current reporting period). This decrease may be attributed to the fact that the majority of patients with activity during the reporting period are continuing therapy and are not initiating therapy. Anecdotally, this decrease may be related to more prescribing restrictions in managed care setting as well as prescriber and patient awareness of the opioid epidemic making prescribers less likely to prescribe and patients less inclined to seek TIRF medicines. During the reporting period, a total of 117,708 prescriptions were submitted for approval and 105,076 (89.3%) prescriptions encountered no REMS-related rejections prior to being authorized (Section 5.1.5). These data plus the ongoing stakeholder re-enrollment activity indicate that the program does not present a significant barrier to accessing these important medications while continuing to meet the safety goals of the REMS. Prescription dispensing outside the established PPAF requirements was eliminated as a result of the corrective actions implemented during the previous reporting period to significantly reduce this occurrence (Section 5.1.6). In this 60-Month FDA REMS Assessment Report, there were no prescriptions for any patient dispensed beyond 10 days after patient enrollment compared with 1 prescription for 1 patient in the 48-Month FDA REMS Assessment Report, and 6 prescriptions for 1 patient in the 36-Month FDA REMS Assessment Report. The TIRF REMS Access program continues to monitor the electronic systems and stakeholder reports for issues and, where appropriate, corrective actions or system improvements are instituted. During the current reporting period, 62 confirmed instances of stakeholder non-compliance with the TIRF REMS Access program were reviewed and investigated. This included 54 prescriber reports, 7 non-closed system pharmacy reports, and 1 wholesaler/distributer report (a total of 58 cases presented in Table 24 and 4 narratives included in Table 25). Of the cases presented by non-compliance scenario (Table 24), a decrease was seen in the number of confirmed instances of non-compliance between the 36-Month FDA REMS Assessment Report, the 48-Month FDA REMS Assessment Report, and this reporting period, respectively for inpatient pharmacy dispenses for outpatient use (1 vs. 0 vs. 0 reports), submission of a claim that did not go through REMS edits (14 vs. 12 vs. 7 reports), dispensing prescriptions outside of the closed system authorization process (7 vs. 0 vs. 0), and prescriber failure to have a complete PPAF on file in a timely manner (120 vs. 82 vs. 50 reports). There was one wholesaler/distributor report (filled an order for TIRF medicines for a non-enrolled stakeholder) and no closed system pharmacy reports during this reporting period (Section 6.2) compared with no reports for either during the last reporting period. Audits of 6 closed system pharmacy entities were conducted during this reporting period. Four closed system entities were found to be non-compliant with the TIRF REMS Access program requirements. These pharmacies were re-educated, issued a notice through the NCRT and submitted a CAP which was approved by the NCRT. All cases have been closed (Section 6.3). The number of instances where a REMS authorization was not received prior to dispensing a TIRF product was static between the 48-Month FDA REMS Assessment Report and the current reporting period, and both showed a considerable decrease since the 36-Month FDA REMS Assessment Report (68 vs. 68 vs. 513 instances, respectively). FDA_4127 60-Month REMS Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 106 of 112 Audits of 5 inpatient pharmacies were conducted during this reporting period and 1 inpatient pharmacy was found to be noncompliant with a REMS requirement and a non-compliance case was opened. Data collected through the RADARS System showed that population rates for the TIRF products across all outcome variables were low compared to rates for the 3 Schedule II opioid comparator arms; while prescription-adjusted rates for the TIRF products were higher than the rates for the 3 Schedule II opioid comparator arms. In the Poison Center Program, there were only 5 intentional abuse mentions to TIRF products in the pre period, leaving little room for a decrease in the post period, and making this comparison under powered. Pre to post decreases were seen for 7 of the 24 outcome-rate combinations examined, but only 1 reached statistical significance: population rates among individuals entering opioid treatment programs (Section 7.4). The analysis of spontaneous reports of AEs of interest used aggregated data from the TRIG sponsors with currently marketed products. There were 353 unique case reports that met the specified criteria for addiction (n=6), overdose (n=4), death (n=344), and pediatric exposures (n=3). After a review of the associated MedWatch Forms or narratives for root cause analysis, no reports of inappropriate conversions between TIRF products were noted. There were 3 reports of pediatric exposure (Section 7.2). In all 3 reports, the medication was intentionally prescribed to the pediatric patient. On 21 July 2016, FDA provided feedback on the patient, prescriber, and pharmacist surveys. After careful review of the requested changes, the TRIG notified FDA that in order to incorporate all changes, an extension for report submission would be required. As proposed by FDA on 29 July 2016 and agreed to by the TRIG on 01 August 2016, the 60-month KAB survey results will be submitted separately from the overall REMS assessment report on or before 17 February 2017. This submission will also include additional requests included in the 48Month FDA Assessment Report Acknowledgement Letter. CONCLUSION Based on the data available in this TIRF REMS Access program assessment report (program and product utilization statistics, dispensing activity, program infrastructure and performance, noncompliance reporting, and safety surveillance data) the TRIG concludes that there is no indication that the REMS is not meeting its goals. However, the TRIG acknowledges that the data are limited and that FDA has requested further evaluation, as described in the 48-Month FDA Assessment Report Acknowledgement Letter, to determine whether the REMS is meeting its goals. The TRIG looks forward to discussing with FDA additional data to be used to evaluate and improve upon the REMS. FDA_4128 60-Month REMS Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies 12 Page 107 of 112 APPENDICES FDA_4129 60-Month REMS Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies 12.1 Page 108 of 112 Non-Compliance Protocol FDA_4130 TIRF REMS ACCESS PROGRAM NON-COMPLIANCE PROTOCOL Version 7.0 October 26, 2015 Revision History Version # Date Author Description of Changes 1.0 February, 2012 Meagan Sampogna Initial Release 2.0 October 10, 2012 Laura Baloun • • • • • 3.0 November 2, 2012 Laura Baloun • • 3.1 March 15, 2013 Laura Baloun • • • • • Added Revision History Removed ‘Draft-Review Required’ Watermark Added Sub-Sections to Section 5 (previously a separate document) o Added 5.1 – Index of Scenarios o Added 5.2 – Severity Reference o Added 5.3 – Corrective Action Reference o Added 5.4 – Monitoring Frequency Reference Updated Scenario Numbering in Section 5.1 Revised Notices Measurement to clarify 2 Notices in 60 days = 1 Warning Revised Section 5.3, Reference – Corrective Actions to include review of multiple non-compliance events for a stakeholder to see if moving to the next level is warranted Correct title of Section 5.4, Reference – Monitoring Frequency Guidelines Corrected misspellings throughout document Revised Section 2 – Removed reference that process flow will be revised upon agreement of Protocol Revised Section 2 - Non-Compliance Process Flow Removed reference that NonCompliance letters need to be developed from Section 4 Revised Section 5.1 – Non-Compliance Scenarios o Revised the monitoring tool in Pharmacy Scenario 2 and Wholesaler/Distributor Scenario 1 o Revised Pharmacy Scenario 3 Page 2 of 19 FDA_4132 Version # Date Author Description of Changes • to be specific to suspended and deactivated stakeholders o Revised language in Pharmacy Scenarios 4, 5 & 6 for clarify o Added a new Pharmacy Scenario for altered claims o Revised Wholesaler/Distributor Scenario 1 to be specific to suspended and deactivated stakeholders o Revised language in Wholesaler/Distributor Scenario 2 for clarity o Revised Prescriber Scenario 1 to be specific to suspended and deactivated stakeholders o Revised language in Prescriber Scenario 2 for clarity o Re-defined ‘timely manner’ in Prescriber Scenario 2 o Revised language in Closed System Pharmacy Scenario 1for clarify o Added a Patient non-compliant scenario o Added an enrollment monitoring scenario for all stakeholders Revised Section 5.4 – Reference – Monitoring Frequency Guidelines o Clarified new report requests will be handled via the Change Management Process o Changed ‘Sponsor Data’ to ‘Sponsor Reporting’ o Changed frequency of Sponsor Reporting from quarterly to every Non-Compliance Review Team Meeting and as needed o Changed frequency of Escalation Log from daily to every Quality Management Workstream meeting and as needed Page 3 of 19 FDA_4133 Version # Date Author Description of Changes 3.2 5/21/13 Laura Baloun • 4.0 5/24/13 Laura Baloun Accepted all changes from versions 3.1 and 3.2 4.1 8/7/13 Laura Baloun Added Section 6 – Non-Compliance Assessment Reporting 5.0 8/8/13 Laura Baloun • • Accepted all changes from version 4.1 Corrected page numbers 5.0 8/15/13 Laura Baloun • Approved by TRIG via vote during the 8/15/13 Program Status Call Meeting 5.1 12/17/13 Laura Baloun • Revised Section 5.1 – Non-Compliance Scenarios o Revised Prescriber Scenario 2 definition for ‘complete PPAF on file in a timely manner’ Revised Section 5.3 – Reference – Corrective Action o Change ‘annually’ to ‘within 12 months’ • Revised Section 5.1 – Non-Compliance Scenarios o Removed Pharmacy Scenario 4 6.0 12/19/13 Laura Baloun • Accepted all changes from version 5.1 6.0 12/23/13 Laura Baloun • Approved via TRIG e-mail vote 6.1 12/5/13 Amanda Bulkley • Revised Section 5.1 – Non-Compliance Scenarios o Added Pharmacy Scenario 4: Pharmacy no longer has a valid DEA. o Added Prescriber Scenario 3: Prescriber no longer has a valid, schedule II DEA. o Added Prescriber Scenario 4: Prescribed TIRF medicines to an opioid non-tolerant individual. o Added Prescriber Scenario 5: Inappropriate conversions between TIRF products • Revised Section 5.2 – Severity Inclusion of language for repeat offenders when determined amount of time is reached without any suspected non-compliance Page 4 of 19 FDA_4134 Version # Date Author Description of Changes activity • Revised Section 5.3 – Corrective Action o Inclusion of language for repeat offenders when determined amount of time is reached without any suspected noncompliance activity o Grammatical corrections 7.0 10/26/15 Amanda Bulkley • Accepted all changes from version 6.1 Page 5 of 19 FDA_4135 TABLE OF CONTENTS 1. Background ........................................................................................................................... 7 2. Goals and Objectives ............................................................................................................ 8 3. Non-Compliance Review Teams and Responsibility............................................................ 8 4. Corrective Actions for Instances of Non-Compliance ........................................................ 12 5. Evaluation Process .............................................................................................................. 14 5.1. Index of Non-Compliance Scenarios .................................................................................. 14 5.2. Reference – Severity ........................................................................................................... 16 5.3. Reference – Corrective Action ............................................................................................ 17 5.4. Reference – Monitoring Frequency Guidelines .................................................................. 18 6. Non-Compliance Assessment Reporting ............................................................................ 19 Page 6 of 19 FDA_4136 1. Background Opioids remain the mainstay of treatment of moderate to severe pain, especially for opioidtolerant patients experiencing cancer breakthrough pain (BTP). Transmucosal immediate release fentanyl (TIRF) medicines are short-acting opioid products that have a rapid onset and relatively short duration of action and are designed for the treatment of episodes of BTP in opioid-tolerant patients with chronic cancer pain . On December 28, 2011, the Food and Drug Administration (FDA) approved a single, shared Risk Evaluation and Mitigation Strategy (REMS) for TIRF products. The shared system strategy, called the TIRF REMS Access program, will be used by all sponsors of TIRF products and is designed to ensure access to important medications for appropriate patients. The TIRF REMS Access program is in place to mitigate the risk of misuse, abuse, addiction, overdose, and serious complications due to medication errors by: a. Prescribing and dispensing TIRF medicines only to appropriate patients, which includes use only in opioid-tolerant patients. b. Preventing inappropriate conversion between fentanyl products. c. Preventing accidental exposure to children and others for whom it was not prescribed. d. Educating prescribers, pharmacists, and patients on the potential for misuse, abuse, addiction, and overdose of TIRF medicines. Compliance with the TIRF REMS Access program (“program”) is necessary in accordance with the appropriate use of TIRF products and proper patient selection. The TIRF REMS Access program includes a continuous evaluation process of compliance to the program. Any deviation from program procedures is evidence of non-compliance and may result in corrective measures, such as a notice, warning, suspension or program deactivation. Page 7 of 19 FDA_4137 2. Goals and Objectives The goal of the non-compliance protocol is to ensure that a system is in place to identify and investigate stakeholder non-compliance with the TIRF REMS Access program by monitoring possible program deviations detected through program reporting and spontaneous events identified by the program. Suspected non-compliance is defined as an instance when it is believed that a stakeholder is not following a program requirement. Suspected non-compliance scenarios may be detected through standard program reports, spontaneous reports identified via the program’s call center or vendor/sponsor reported events. A suspected non-compliant event is deemed compliant in the event the information presented on a stakeholder scenario does not clearly identify or support that a program deviation has occurred and/or no evidence of the program goals not being met are present. A confirmed non-compliant event is when the information present clearly indicates that a program deviation has occurred and/or evidence of the program goals not being met through stakeholder actions is identified. Confirmation of a non-compliant stakeholder act will typically occur after further investigation has been completed and supportive data has been reviewed and presented to the TIRF REMS Access Non-Compliance Review Team. The objectives of this non-compliance protocol are to: • • • • • • • Describe the purpose and activities of the non-compliance Review Team Describe the purpose and activities of the non-compliance Working Group Describe the process to identify program non-compliance Outline an index of possible scenarios of non-compliance Identify data sources to review for suspected non-compliant events Describe suggested actions taken once non-compliance is confirmed Describe the process to monitor program deviations and occurrences of non-compliance 3. Non-Compliance Review Teams and Responsibility A TIRF REMS Access Non-Compliance Review Team (“Review Team”) will be created composed of membership from the TRIG Sponsors. The Review Team will be responsible for review, escalation, and decision-making of all non-compliance cases, and corrective measures are applied when necessary. The responsibilities of the Review Team may not be delegated or transferred to other parties without prior consent of the TRIG sponsors. If the need arises, the Review Team shall have the authority to consult external advisors, experts, or consultants, in order to effectively assess and process cases of program non-compliance. If it is determined that a program modification may be warranted due to cases of non-compliance, the Review Team may need to consult with the Page 8 of 19 FDA_4138 FDA for their review and approval of any changes impacting the REMS submission. Any proposed program modifications must be approved by the TRIG prior to implementation. The Review Team will meet regularly to discuss all issues of non-compliance and/or program modifications, at a frequency interval defined by the TRIG sponsors. The Review Team will consist of members with expertise from various specialties, which may include: 1. Regulatory Affairs 2. REMS specialist 3. Project Management 4. Legal 5. Quality Assurance 6. Commercial 7. Drug Safety and IT Working practices will be developed to describe when the TRIG sponsors would participate in Review Team discussion in connection with potential or actual major deviations from the REMs program. A Non-Compliance Working Group (”Working Group”) will be created from program staff and will be responsible for collecting data and preparing reports for the Review Team, in compliance with Privacy Health Information (PHI) regulations. The Working Group will consist of program agents who have been working with and/or trained on the TRIG non-compliance protocol, as well as have background necessary to evaluate data and make objective decisions on instances of non-compliance, based on the data available. The functions of the Working Group will be to: 1. Review reports, call center logs or audit report data to identify potential incidences of non-compliance 2. Conduct further investigation as needed to clarify the potential incident and identify root cause of deviation 3. Evaluate compliance with the TIRF REMS program stakeholder business rules 4. Respond to identified events of non-compliance in accordance with the established business rules. Propose solutions and actions for confirmed non-compliance events that are not addresses by such business rules. 5. Prepare reports for review and approval by the Review Team Detailed business rules will outline the process, timeline and corrective action plan for each instance of suspected or confirmed program non-compliance identified by the Working Group. Page 9 of 19 FDA_4139 Stakeholders identified as having suspected or confirmed non-compliant events may be contacted by the Working Group via letters, phone calls or fax to resolve issues related to the identified program deviation all in accordance with such business rules. The Working Group will provide the Review Team with reports in advance of their regularly scheduled meetings and will be available to address any questions or clarifications on the content of the report. The Working Group will provide a summary of the suspected or confirmed noncompliant events that they identified during the review period. Once the Review Team receives the report, their responsibility will be to: • • • • Attend all regularly scheduled Review Team meetings to review, assess and make decisions on any non-compliance issues needing attention including any issue that the Working Group could not handle because it was beyond the scope of the business rules used by the Working Group. Identify if an audit of a stakeholder is required Determine if any report or communication should be made to the FDA outside of regular TIRF REMS assessment reports. Determine if changes to the business rules and/or this protocol need to be made, and make such changes. The following process flow outlines the suggested interactions between the Working Group, the Review Team and the program stakeholders as necessary monitor, review and act upon suggested corrective actions for non-compliant scenarios identified. Page 10 of 19 FDA_4140 TIRF REMS Access Program: Non-compliance Review Process chonpim . 1: 3 mm mm!" ?g I I ll sent Suspense? Identification and Investigation Process of Non-Compliant Events Identi?cation Process Call center staff in the TIRF REMS Program or TRIG sponsor companies will refer cases of potential non-compliance to the Working Group. Investigation Process If an instance of potential non-compliance is identi?ed, ?irther investigation will be conducted. This may include: Review case details to determine if evidence of non-compliance exists Make attempt(s) to contact relevant stakeholder to validate data/information and solicit further information 0 Conduct further investigation of TRF REMS Program databases For instances of potential non-compliance that are not described in Section 5, a suggested course of action will be presented to the Review Team. The Working Group will consult with the Review Team if proprietary or commercially sensitive information arises that would not ordinarily be shared among TRIG representatives. Page 11 of 19 41 4. Corrective Actions for Instances of Non-Compliance Corrective actions resulting from non-compliance will be determined according to the severity of the action. The stakeholders in this non-compliance protocol include prescribers, patients, distributors, and pharmacies. The primary elements for corrective action include; notices, warnings, suspension, and deactivation based on the requirements of the TIRF REMS Access program. If a prescriber, pharmacy or distributor is suspended or deactivated, information will be made available through the program to assist unaffected stakeholders in finding alternative access to product. Each non-compliant event will be categorized based on the level of severity of the event. The event classifications are as follows: Minor An unintended (e.g., first-time) event. The corrective action will typically result in a written notice being sent to the stakeholder and re-education of the program requirements to prevent any re-occurrences of the event. Moderate A repeated event or a series of different [or distinct], unintended events. An investigation will be conducted by program staff to identify the root cause of the event. Program staff will also work with the stakeholder to create and implement a corrective plan of action. Once implemented, the stakeholder will be monitored for compliance with the plan of action, and provided with a written warning for their files. Serious An event that results in serious or significant injury or potential risk to a patient irrespective of the number of previous non-compliance occurrences, or continued non-compliant events after retraining has occurred. This level of offense will result in a suspension from the program and possible deactivation. Deactivated prescribers will not be able to participate in the TIRF REMS Access program for any existing or future patients, effectively barring their ability to provide TIRF medicines as a therapy for their patients. A deactivated stakeholder may request reinstatement in the TIRF REMS Access program. Requests for reinstatement must be in writing and contain sufficient details of corrective actions taken to prevent any future incidents of non-compliance with elements of the program. Requests for reinstatement will be evaluated by the Review Team and the team will make the final determination on reinstatement. Detailed business rules will outline the process, timeline and corrective action plan for each level of program non-compliance. Page 12 of 19 FDA_4142 The Review Groups will determine whether a suspended pharmacy or distributor will be permitted to keep an inventory of TIRF medicines already acquired prior to suspension. Pharmacies may not dispense TIRF medicines from such existing inventory during the suspension and distributors may not sell and/or distribute TIRF medicines. If a suspended outpatient pharmacy or distributor is part of a larger entity, the parent entity will be notified of the noncompliant activity and resultant suspension. Deactivated pharmacies and distributors will be required to return all existing TIRF medicine inventory. Patient notices that result from violations of program elements will be sent to a patient’s prescriber. Page 13 of 19 FDA_4143 5. Evaluation Process 5.1. Index of Non-Compliance Scenarios Stakeholder Pharmacy Scenario # 1 2 3 Non-Compliance Activity Submission of a claim that did not go through the REMS edits. A TIRF medicine was dispensed without verifying through the TIRF pharmacy management system that the prescriber is enrolled and active, and that the patient is enrolled or has not been inactivated in the program. Dispensing activity for enrolled outpatient pharmacies during reporting period not matching distributor shipment data for that pharmacy. Pharmacy is dispensing TIRF medicine while suspended or deactivated from the TIRF REMS Access program. 4 Pharmacy no longer has a valid DEA 5 Authorized Inpatient Pharmacy does not comply with the requirements of the TIRF REMS Access program. 6 Inpatient Pharmacy dispenses for outpatient use 7 Wholesaler/ Distributor 1 Submission of inappropriately altered claim to meet TIRF REMS system requirements (e.g. changing prescriber) Wholesaler/Distributor is suspended or deactivated from the TIRF REMS Access program and is purchasing or distributing TIRF medicines. 2 Wholesaler/Distributor fills an order for TIRF medicines for a non enrolled stakeholder. Prescriber 1 2 Prescriber is prescribing TIRF medicines while suspended or deactivated from the TIRF REMS Access program. Prescriber failure to have a complete PPAF on file in a timely manner (5 or more patients enrolled by the prescriber without a complete PPAF on file, with each patient having greater than 10 working days lapse from intial enrollment date). 3 Prescriber no longer has a valid, schedule II DEA. 4 Prescribed TIRF medicines to an opioid non-tolerant individual. 5 Inappropriate conversions between TIRF products. Monitoring Tool Audit or Spontaneous event reported Audit or Sponsor reported Audit or Spontaneous event reported Audit or Spontaneous event reported Audit or Spontaneous event reported Audit or Spontaneous event reported Audit or Spontaneous event reported Sponsor reported Audit or Spontaneous event reported Audit or Spontaneous event reported Program Report Audit or Spontaneous event reported Audit or Spontaneous event reported Audit or Spontaneous event reported Page 14 of 19 FDA_4144 Closed System Pharmacy Patient 1 All Stakeholders 1 1 Dispensing prescriptions outside of the closed system authorization process. The Patient receives prescriptions for TIRF medicines from multiple prescribers within an overlapping time frame that is suggestive of misuse, abuse, or addiction ENROLLMENT MONITORING ONLY: Monitor stakeholders who are not enrolled in TIRF and are associated with non-compliance cases. Program Report Audit or Spontaneous event reported Program Reports Page 15 of 19 FDA_4145 5.2. Reference – Severity Severity Guideline Level of Severity Minor Moderate Serious Definition First identification of a non-compliant event or since 24 months from the closure of a previous case. >1 non-compliance issue, without a warning on file >1 non-compliance issue with a warning on file or an event that results in serious or significant injury or potential risk to a patient irrespective of the number of previous noncompliance occurrences Page 16 of 19 FDA_4146 5.3. Reference – Corrective Action Corrective Action Guideline Action Notices Warnings Suspension Deactivation Measure Patient notices will be sent to a patient's prescriber Minor violations that demonstrate a misunderstanding of the program requirements Notices are intended to re-educate stakeholders 2 Notices in 60 days = Review by Non-Compliance Review Team to determine if a Warning is warranted Previous case resulted in a notice due to unsuccessful outreach attempts and unable to successfully outreach for current case. 2 Warnings in 60 days = Review by Non-Compliance Review Team to determine if a Suspension is warranted >1 Warning and/or suspension in >60 days = Case-byCase review for Suspension Temporary deactivation from the program A suspended pharmacy or distributor may keep existing TIRF inventory but may not purchase or acquire additional TIRF medicines Pharmacies may not dispense TIRF medicines from existing inventory and distributors may not sell/distribute TIRF medicines during suspension If the pharmacy or distributor is part of a larger entity that entity will be notified of the suspension 1 Warning or 2 Notices while Suspended = Review by Non-Compliance Review Team to determine if a Deactivation is warranted 2 Suspensions within 12 months = Review by NonCompliance Review Team to determine if a Deactivation is warranted Deactivations may result in multiple failures to comply with the program elements and/or non-compliance where there is no feasible corrective action Bars stakeholder to provide TIRF medicines as a therapy for their patients Pharmacies and distributors must return all existing TIRF medicine Patient deactivation will be sent to a patient's prescriber. Patients may only be reinstated into the program by a request from their prescriber Page 17 of 19 FDA_4147 5.4. Reference – Monitoring Frequency Guidelines Monitoring Frequency Guideline Report Category Existing Reports Report Does Not Exist Sponsor Reported KAB Surveys Escalation Log Frequency Bi-Monthly Cost/Timeline TBD - Report request will be handled via the Change Management Process During every Non-Compliance Review Team Meeting and as needed 12 and 24 months from the date of the REMS approval and as needed thereafter During every Quality Management Workstream meeting and as needed Page 18 of 19 FDA_4148 6. Non-Compliance Assessment Reporting Confirmed non-compliance events will be provided to the Companies’ 3rd party vendor for inclusion in FDA assessment reports. Page 19 of 19 FDA_4149 60-Month REMS Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies 12.2 Page 109 of 112 Safety Surveillance Aggregate Line Listing Preferred Terms FDA_4150 60-month REMS Assessment Report Transrnucosal Irmnediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies I. Case Criteria: 0 Only US cases 0 No American Association of Poison Control Center (AAPCC) or literature search cases 0 In addition to performing searches 011 the below preferred terms. sponsors will search for: All cases with an outcome of death 0 Cases related to patients aged 0 through 18 0 Cases to be included in the reporting period date range will be based orr MedWatch Form field ?Date Received by Manufactru'er" (G4) 0 The data cut-off for the safety surveillance aggregate line listing is 28AUG of each year. Therefore. the crurerrt reporting period for the 60- FDA Assessment Report is 29AUG2015 to 28AUG2016 11. Case Identification a. Addiction Line Listing Cases of addiction will be identi?ed though the following Preferred Terms. Sponsors are responsible for reviewing all cases pulled by these Preferred Terms and determining whether each is deemed as a case of addiction by their company. Only cases identi?ed by a Sponsor?s company as cases of addiction should be provided to UBC. Preferred Terms for FDA Requested Cases of Addiction Primary SOC High Level Group High Level Term Preferred Term Notes Misuse Selected because it disorders disorders Substance-related disorders Intentional drug misuse falls under the NEC substance-related disorders Abuse disorders Substance-related disorders Drug abuse Inappropriate Injury. orsonmg and procedural Medication errors Maladministrations adnmristered at mappropnate srte Page 1 of7 51 60-month REMS Assessment Report Transmucosal Iimnediate-Release Feiitaiiyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Preferred Terms for FDA Requested Cases of Addiction . . . Notes Primary SOC High Level Group High Level Term Preferred Term 1111 . oisonin and rocedural . . . . . Ina ro riate schedule of (1111 Juy . Medication errors pp . . . complications Medication Error In'i . oisonin and rocedural . . . . . . . Juy . Medication eirors Maladmmistrations Inconect dose adnmiistered complications In'i . oisonin and rocedural . . . . . . . Jlry . Medication errors Incorrect dosage admmistered complications In'i . oisonin and rocedin?riate schedule of (1111 Juy . Medication errors Maladininistrations pp . . . complications Accidental In'i . oisonin and rocedural . . Accidental ex osm?es to . Dry . Medication eirors . Acc1dental exposm?e to product complications pioduct Dependence disorders disorders NEC Substance-related disorders Dependence disorders disorders NEC Substance-related disorders Diug dependence disorders disorders NBC Substance-related disorders Diug dependence. antepamun disorders disorders NBC Substance-related disorders Diug dependence. postpamnn disorders disorders NEC Substance-related disorders Polysubstance dependence Page 2 of7 52 60-month REMS Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies b. Overdose Line Listing Cases of overdose will be identi?ed tln?ough the following Prefeired Terms. Preferred Terms for FDA Requested Cases of Overdose . . . Notes Primary SOC High Level Group High Level Term Preferred Term Overdose In'i . oisonin and rocedin?al . . Accidental overdose r1 Juy . Medication errors Overdoses . so In . complications Acczdenra/ Section Iii'i . oisonin and rocedural . . . Juy . Medication errors Overdoses Intentional overdose complications In'i . oisonin and rocedural . . . Medication en'ors Overdoses Overdose complications In'i . oisonin and rocedural . . . Jin . Medication eirors Overdoses Prescribed overdose complications In'iu . oisonin and rocedural Chemical min and . . . . . . . "y . . ?y Pmsomng and tox1c1ty Accrdentalpmsonmg complications porsonmg Page 3 of7 53 60-month REMS Assessment Report Transmucosal Iimnediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies c. Death Line Listing Cases of death will be identi?ed through the following Preferred Tenns or a reponed outcome of death. Preferred Terms for FDA Requested Cases of Death Primary SOC High Level Group High Level Term Preferred Term Notes Death General disorders and administration site conditions Fatal outcomes Death and sudden death Accidental death General disorders and administration site conditions Fatal outcomes Death and sudden death Brain death General Disorders and administration site conditions Fatal outcomes Death and sudden death Cardiac death General disorders and administration site conditions Fatal outcomes Death and sudden death Death General disorders and admimstrations site conditions Fatal outcomes Death and sudden death Death neonatal General disorders and administration site conditions Fatal outcomes Death and sudden death Sudden cardiac death General Disorders and . . . . . . Fatal outcomes Death and sudden death Sudden death Site General disorders and . . . . . . Fatal outcomes Death and sudden death Agonal death struggle Site conditions General disorders and General system disorders General signs and A arent death administration site conditions NEC NEC pp . Therapeutic and . General disorders and . Thera eutic and . . nontherapeutic effects Dlug meffective/death administration site conditions (excl toxicity) nontherapeutic responses Cardiac disorders Cardiac Ventricular and cardiac arrest ardio-respiratory arrest Page 4 of7 54 60-month REMS Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Preferred Terms for FDA Requested Cases of Death Primary SOC High Level Group High Level Term Preferred Term Notes Cardiac disorders Cardiac Ventricular a 1rhyt?1m11as and Cardiac arrest caldlac anest Respiratory. thoracic and Respiratory disorders . . . . . . . medias tinal disorders NE Bleathmg abnonnahtles Respu atory anest Pl?egnailcy? ?lawn.? and Abortions and stillbirth Stillbirth and foetal death Foetal death perinatal Page 5 of7 55 60-month REMS Assessment Report Transmucosal Immediate-Release Feiitaiiyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies d. Pediatric Exposure Line Listing Cases of pediatric exposure will be identi?ed tln'ough the following Prefeired Terms or any case involving patients 0-18 years of age. Preferred Terms for FDA Requested Cases of Pediatric Exposure Primary SOC High Level Group High Level Term Preferred Term Notes Accidental Iiijiuy. poisoning and procedural . . Accidental exposm?es to Accidental exposm'e to product . . Medication eiiors . . complications pi oduct by child Illjul?y. poisoning and procedural Diug administered to patient of . . Product use issues Product use issues NEC . . . complications mappiopiiate age . Failure of child resistant General d1501 deis and . . . . . . . . . . . . . . . Pioduct quality issues Pioduct packagnig issue mechanism fOi phannaceutical adnninstiation Site conditions product Page 6 of 7 56 60-month REMS Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies e. Case Identi?cation for Any Table Through Text-string Searches In addition to the agreed upon Preferred Terms. Sponsors will also provide cases based 011 text-string searches using the below teims. Sponsors will infonn UBC if cases are provided that are not aligned with the approved Prefeired Tenns. but were identi?ed through a text-string search. Text-string Search Terms for Narratives Addiction Multiple drug overdose Son Nephew Overdose Expired Daughter Aimt Drug dependence Passed away Grandmother Uncle Death Infant Grandfather Mom Pediatric exposm?e Child Sister Pop Died Mother Brother Dad Fatal Father Niece Inappropiiate Conversion Inappropriate Accidental Intentional Non-opioid Tolerant Page 7 of 7 57 60-Month REMS Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies 12.3 Page 110 of 112 Safety Surveillance Aggregate Line Listing of Deaths FDA_4158 60-Month REMS Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies UBC ID 1911 Patient Age 53 Patient Gender Male 1912 61 Female 1913 UNK Male 1914 UNK Male 1915 UNK Male 1916 51 Female 1917 UNK Female 1918 76 Male Page 1 of 25 Cases of Death Received from TRIG Sponsors During the Reporting Period: 29AUG2015-28AUG2016 Event Report TIRF Concomitant Co-Suspect Date Date Preferred Term(s) Indication(s) Duration Medications Product(s) Unknown 31AUG2015 Death Breakthrough cancer Unknown Oxycontin, None reported pain Sulfamethoxazole, Oxycodone, Valaciclovir, Oxycontin 30AUG2015 31AUG2015 Neoplasm progression Breakthrough cancer 2015-08-29 - None reported None reported pain UNK DEC2013 31AUG2015 Death Unknown 2015-08-29 - None reported None reported UNK Unknown 31AUG2015 NEOPLASM Unknown Unknown None reported None reported MALIGNANT DEATH Unknown 01SEP2015 Lung neoplasm Unknown Unknown None reported None reported malignant Unknown 02SEP2015 Death Breakthrough cancer Unknown Megace, Lovenox, None reported pain Sudafed, Mucinex, Lidocaine Viscous, Ventolin Hfa, Robaxin, Protonix, Omeprazole, Metoclopramide, Promethazine, Percocet, Effexor, Nasonex, Duragesic, Vesicare, Gabapentin, Lidoderm, Soma, Clonazepam Unknown 02SEP2015 Death Unknown Unknown None reported None reported Unknown 11SEP2015 Death Unknown Unknown None reported None reported Event Outcome Death Potential Causalitya Insufficient Information Death Not Related Death Death Insufficient Information Not Related Death Not Related Death Not Related Death Insufficient Information Insufficient Information Death FDA_4159 60-Month REMS Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 2 of 25 Cases of Death Received from TRIG Sponsors During the Reporting Period: 29AUG2015-28AUG2016 Event Report TIRF Concomitant Co-Suspect Date Date Preferred Term(s) Indication(s) Duration Medications Product(s) JUL2015, 11SEP2015 Drug effect decreased, Breakthrough pain, Unknown Lasix, Multaq, Fentanyl 23AUG2015 Cardiac failure radiation associated Nitro Paste Transdermal congestive pain, cardiac failure System congestive, atrial fibrillation, product used for unknown indication Unknown Unknown 14SEP2015 Death Breakthrough cancer Unknown Fentanyl Patch None reported pain Female Unknown 14SEP2015 Death, Hospitalisation Breakthrough cancer Unknown Fentanyl None reported pain Unknown Unknown 14SEP2015 Death Breakthrough cancer Unknown MS Contin None reported pain Female Unknown 14SEP2015 Death Breakthrough cancer Unknown MS Contin None reported pain Female Unknown 14SEP2015 Death Unknown Unknown None reported None reported UBC ID 1919 Patient Age 77 Patient Gender Male 1920 82 1921 UNK 1922 55 1923 35 1924 UNK 1925 62 Female 05DEC2013 1926 UNK Female Unknown 16SEP2015 Death 1927 UNK Female Unknown 17SEP2015 Neoplasm progression 1928 UNK Female Unknown 18SEP2015 Death 1929 UNK Male Unknown 18SEP2015 Death 1930 UNK Male Unknown 1931 UNK Male Unknown 15SEP2015 Neoplasm progression Breakthrough cancer 2016-02-03 - Aloxi, Ambien, pain, abdominal pain UNK Dilaudid, Fentanyl, Lasix, Megace, Ondansetron, Prevacid, Prochlorperazine Unknown Unknown None reported Event Outcome Death Potential Causalitya Not Related Death Not Related Death Insufficient Information Insufficient Information Insufficient Information Insufficient Information Insufficient Information Death Death Death None reported Death None reported Death Dilaudid, Fentanyl None reported Patch None reported None reported Death None reported None reported Death 18SEP2015 Death Breakthrough cancer 2015-09-11 pain, pain UNK Unknown 2016-02-03 UNK Unknown 2016-02-03 UNK Unknown Unknown None reported None reported Death 21SEP2015 Death Unknown None reported None reported Death Unknown Death Insufficient Information Not Related Insufficient Information Insufficient Information Insufficient Information Insufficient Information FDA_4160 60-Month REMS Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 3 of 25 Cases of Death Received from TRIG Sponsors During the Reporting Period: 29AUG2015-28AUG2016 Event Report TIRF Concomitant Co-Suspect Date Date Preferred Term(s) Indication(s) Duration Medications Product(s) 26FEB2014, 21SEP2015 Neoplasm progression, Breakthrough cancer 2016-02-03 - Ciprofloxacin, None reported Unknown, Gastrointestinal pain UNK Dilaudid, Fentanyl Unknown haemorrhage, Jaundice Injection, Flagyl, cholestatic Lasix, Propofol 26OCT2014 21SEP2015 Neoplasm progression Breakthrough cancer 2016-06-28 - None reported None reported pain UNK 05DEC2013 25SEP2015 Death Unknown Unknown None reported None reported UBC ID 1932 Patient Age 50 Patient Gender Male 1933 63 Male 1935 64 Female 1936 65 Male 20SEP2015 28SEP2015 Neoplasm progression 1937 47 Female 24FEB2014 05OCT2015 Death 1938 UNK Male Unknown 1940 UNK Female 1941 UNK Female 1942 83 Female 1943 UNK Unknown 1944 46 Male 1945 73 Female 1946 UNK Female Event Outcome Death Potential Causalitya Not Related Death Not Related Death Insufficient Information Not Related None reported Death None reported Death 07OCT2015 Death Breakthrough cancer 2016-06-28 - Oxycodone pain UNK Unknown 2015-05 None reported UNK Unknown Unknown None reported None reported Death 2014 12OCT2015 Death Unknown None reported Death Unknown 16OCT2015 Death Unknown 2015-12-01 - None reported UNK Unknown None reported None reported Death 06JUN2015, 19OCT2015 Death, Off label use 2015 Pain 2015 - UNK Death NOV2013, 22OCT2015 Feeling abnormal, 24FEB2014, Disease progression, Unknown, Confusional state, Unknown, Mass, Weight Unknown decreased Breakthrough pain Unknown 29DEC2013 Breakthrough pain Unknown Hydrocodone, None reported Morphine, Oxycodone Dilaudid, Folic None reported Acid, Calcium, Lyrica, Dulcolax, Lovenox, Phenergan, Refmal329, Zofran Fentanyl, None reported Oxycodone and Acetaminophen Klonopin, None reported Oxycodone, Oxycontin, Prozac, Topamax None reported None reported 22OCT2015 Disease progression 03FEB2015, 23OCT2015 Death, Haemoptysis, Skin cancer, chronic 02FEB2015, Upper respiratory tract pain Unknown infection 2012 27OCT2015 Death Unknown 2013-10 UNK 2013-10 UNK Insufficient Information Insufficient Information Insufficient Information Insufficient Information Insufficient Information Death Not Related Death Not Related Death Not Related Death Insufficient Information FDA_4161 60-Month REMS Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 4 of 25 Cases of Death Received from TRIG Sponsors During the Reporting Period: 29AUG2015-28AUG2016 Event Report TIRF Concomitant Co-Suspect Date Date Preferred Term(s) Indication(s) Duration Medications Product(s) Unknown 27OCT2015 Death Unknown 2013-10 None reported None reported UNK Unknown 27OCT2015 Death Unknown Unknown None reported None reported UBC ID 1947 Patient Age UNK Patient Gender Female 1948 UNK Female 1949 UNK 1950 75 Male 1951 UNK Unknown Unknown 1952 50 Male 27SEP2015 1953 UNK Female Unknown 1954 UNK Unknown 1955 UNK 1956 Unknown 31MAR2014 27OCT2015 Death Event Outcome Death Death Unknown Unknown None reported None reported Death Breakthrough pain, pain 11 days Death 02NOV2015 Death Unknown Unknown Dilaudid, None reported 5-Fluorouracil, Allegra, Cis-Platinum, Dexamethasone, Fentanyl, Taxotere None reported None reported 04NOV2015 Neoplasm progression None reported Death 04NOV2015 Death Breakthrough cancer 2015-05-20 - None reported pain 2015-09-27 Unknown Unknown None reported None reported Death Unknown 05NOV2015 Death Unknown Unknown None reported None reported Death Female Unknown 05NOV2015 Death Unknown Unknown None reported None reported Death UNK Male Unknown 10NOV2015 Death Unknown None reported Death 1957 72 Female Unknown 10NOV2015 Death Unknown 2015-04-20 - None reported UNK Unknown None reported None reported Death 1958 UNK Male Unknown 11NOV2015 Death Unknown Unknown None reported None reported Death 1959 UNK Male 2015 11NOV2015 Neoplasm progression Cancer pain None reported Death 1960 UNK Male Unknown 12NOV2015 Death Unknown 2015-07-13 - Methadone UNK Unknown None reported None reported Death 1961 UNK Female Unknown 12NOV2015 DEATH Unknown Unknown None reported Death 19OCT2015, 28OCT2015 Fall, Neutropenia Unknown None reported Death Potential Causalitya Insufficient Information Insufficient Information Insufficient Information Not Related Insufficient Information Not Related Insufficient Information Insufficient Information Insufficient Information Insufficient Information Insufficient Information Insufficient Information Not Related Insufficient Information Insufficient Information FDA_4162 60-Month REMS Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 5 of 25 Cases of Death Received from TRIG Sponsors During the Reporting Period: 29AUG2015-28AUG2016 Event Report TIRF Concomitant Co-Suspect Date Date Preferred Term(s) Indication(s) Duration Medications Product(s) Unknown 16NOV2015 Neoplasm progression Breakthrough cancer 2014-12-22 - None reported None reported pain UNK Unknown 16NOV2015 Neoplasm progression Breakthrough cancer 2014-12-09 - None reported None reported pain UNK Unknown 16NOV2015 Neoplasm progression Breakthrough cancer 2015-06-17 - None reported None reported pain UNK Unknown 16NOV2015 Neoplasm progression Breakthrough cancer 2014-12-10 - None reported None reported pain UNK Unknown 16NOV2015 Neoplasm progression Breakthrough cancer 2014-12-12 - None reported None reported pain UNK Unknown 16NOV2015 Neoplasm progression Breakthrough cancer 2014-12-09 - None reported None reported pain UNK Unknown 16NOV2015 Neoplasm progression Breakthrough cancer 2013-12 Methadone None reported pain UNK Unknown 16NOV2015 Death Unknown Unknown None reported None reported UBC ID 1962 Patient Age UNK Patient Gender Female 1963 UNK Female 1964 UNK Male 1965 UNK Male 1966 UNK Male 1967 UNK Male 1968 UNK Male 1969 UNK Female 1970 65 Female 05JUN2014 1971 UNK Male 1972 UNK 1973 1974 1975 None reported Event Outcome Death Potential Causalitya Not Related Death Not Related Death Not Related Death Not Related Death Not Related Death Not Related Death Not Related Death Insufficient Information Insufficient Information Insufficient Information 16NOV2015 DEATH Unknown Unknown None reported Death Unknown 17NOV2015 Metastases to lymph nodes, Neoplasm progression Breakthrough pain Death Male Unknown 17NOV2015 DEATH Unknown 2015-05-05 - Albuterol None reported UNK Sulphate, Fenofibrate, Folic Acid, Gabapentin, Ibuprofen, Lofexidine, Ondansetron, Pantoprazole, Percocet, Temazepam, Tizanidine Unknown None reported None reported UNK Female Unknown 17NOV2015 DEATH Unknown Unknown None reported None reported Death UNK 86 Unknown Male 26JAN2015 Unknown 17NOV2015 Death 18NOV2015 Death Unknown Unknown Unknown Unknown None reported None reported None reported None reported Death Death Death Insufficient Information Insufficient Information Not Related Insufficient Information FDA_4163 60-Month REMS Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 6 of 25 UBC ID 1976 Patient Age 68 Patient Gender Female Cases of Death Received from TRIG Sponsors During the Reporting Period: 29AUG2015-28AUG2016 Event Report TIRF Concomitant Co-Suspect Date Date Preferred Term(s) Indication(s) Duration Medications Product(s) Unknown 18NOV2015 Death Unknown Unknown None reported None reported Event Outcome Death 1977 UNK Female Unknown 19NOV2015 Death Unknown Unknown None reported None reported Death 1978 UNK Male Unknown 19NOV2015 Death None reported None reported Death 1979 UNK Unknown Unknown 23NOV2015 Death Ureteral cancer, renal Unknown cancer Unknown Unknown None reported None reported Death 1980 55 Male Death UNK None reported Death Not Related 1982 69 Female Unknown 24NOV2015 Death 2015-10-30 - None reported 2015-11-23 2015-11-04 - None reported UNK Unknown None reported None reported 1981 Breakthrough cancer pain Breakthrough cancer pain Unknown Insufficient Information Not Related None reported Death 1983 UNK Female Unknown 24NOV2015 Death Unknown None reported None reported Death 1984 65 Male None reported None reported Death 1985 UNK Male None reported None reported Death Not Related 1986 67 Male None reported None reported Death Not Related 1987 UNK Male 2015-04-21 UNK 2015-11-05 2015-11-17 2015-05-18 UNK 2015-03-18 UNK 2015-03-18 UNK Insufficient Information Insufficient Information Not Related Fentanyl Patch, Marinol, Methadone None reported Death Insufficient Information 23NOV2015, 23NOV2015 Death, Hospitalisation 15NOV2015 Unknown Unknown 23NOV2015 Death 17NOV2015 25NOV2015 Death Unknown 03DEC2015 Neoplasm progression 26NOV2015 03DEC2015 Neoplasm progression Unknown 03DEC2015 Death Breakthrough cancer pain Breakthrough cancer pain Breakthrough cancer pain Breakthrough cancer pain Potential Causalitya Insufficient Information Insufficient Information Not Related FDA_4164 60-Month REMS Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 7 of 25 Cases of Death Received from TRIG Sponsors During the Reporting Period: 29AUG2015-28AUG2016 Event Report TIRF Concomitant Co-Suspect Date Date Preferred Term(s) Indication(s) Duration Medications Product(s) 10APR2014, 07DEC2015 Accidental overdose, Headaches 2 Years Elavil, Clonidine, Percocet, 10APR2014, Lethargy, Stupor, Benadryl, Lorazepam, 10APR2014, Anhedonia, Decreased Naproxen, Oxycodone, 28DEC2011, appetite, Feeling Prochlorperazine, Xanax, Endocet 28DEC2011, abnormal, Insomnia, Nexium, Prilosec, 28DEC2011, Suicidal ideation, Tooth Klonopin, 28DEC2011, abscess, Headache, Pantoprazole 28DEC2011, Nausea, Vomiting, 01JAN2011, Anxiety, Depression, 23JAN2008, Neck pain, Skin 23JAN2008, abrasion, Stress, 23JAN2008, Migraine, Tooth 01JAN2008, impacted, Toothache, 01JAN2008, Fall, Ligament sprain, 01JAN2008, Drug dependence, 01JAN2008, Major depression, 01JAN2008, Product use issue, 08AUG2007, Toxicity to various 02JUN2007, agents 02JUN2007, 01JAN2007, 01JAN2007, 01JAN2006, Unknown, Unknown, Unknown Male Unknown 08DEC2015 Neoplasm progression Breakthrough cancer 2015-03-18 - None reported None reported pain UNK Unknown 26JAN2014 08DEC2015 Death Unknown Unknown None reported None reported UBC ID 1988b Patient Age 31 Patient Gender Male 1989 UNK 1990 57 1991 60 Female 1992 UNK 1993 46 Event Outcome Death Potential Causalitya Possibly Related Death Not Related Death Insufficient Information Not Related Breakthrough cancer 2015-11-05 - Dilaudid, Geodon, None reported pain, leukemia UNK Glivec, Hydromorphone Unknown Unknown None reported None reported Death Female 30MAR2016, 09DEC2015 Completed suicide, 05NOV2015, Fatigue, Somnolence 05NOV2015 Unknown 09DEC2015 DEATH Female 07AUG2014 10DEC2015 Death Breakthrough cancer 2013-12-04 - None reported pain UNK Death None reported Death Insufficient Information Insufficient Information FDA_4165 60-Month REMS Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 8 of 25 Cases of Death Received from TRIG Sponsors During the Reporting Period: 29AUG2015-28AUG2016 Event Report TIRF Concomitant Co-Suspect Date Date Preferred Term(s) Indication(s) Duration Medications Product(s) Unknown 17DEC2015 Neoplasm progression Breakthrough cancer 2015-06-18 - Oxycodone, None reported pain UNK Oxycontin, Xarelto 15DEC2015 17DEC2015 Neoplasm progression Breakthrough cancer 2015-08-25 - None reported None reported pain 2015-12-15 Unknown 21DEC2015 Death Unknown Unknown None reported None reported UBC ID 1994 Patient Age UNK Patient Gender Male 1995 62 Male 1996 59 Male 1997 UNK Female Unknown 21DEC2015 Death Unknown 1998 UNK Female Unknown 22DEC2015 Death 1999 UNK Female Unknown 2000 UNK Female 2001 48 2002 Event Outcome Death Potential Causalitya Not Related Death Not Related Death Insufficient Information Insufficient Information Insufficient Information Insufficient Information Insufficient Information Insufficient Information Insufficient Information Insufficient Information Insufficient Information Insufficient Information None reported Death Unknown 2015-06-18 - None reported UNK Unknown None reported None reported Death 22DEC2015 Death Unknown Unknown None reported None reported Death Unknown 22DEC2015 Death Unknown None reported Death Female 26OCT2014 22DEC2015 Death Unknown 2015-06-18 - None reported UNK Unknown None reported None reported Death 58 Male 23DEC2014 23DEC2015 Death Unknown None reported None reported Death 2003 UNK Female Unknown 23DEC2015 Death None reported None reported Death 2004 UNK Male Unknown 28DEC2015 Death None reported None reported Death 2005 81 Female Unknown 29DEC2015 Death, Product use issue Morphine None reported Death 2006 UNK Male OCT2015 29DEC2015 Neoplasm progression Metoprolol None reported Death Not Related 2007 32 Female Death Not Related 2008 UNK Male Ativan, Decadron, None reported Fentanyl Patch, Oxycodone, Prilosec 2015-10-22 - None reported None reported UNK Death Insufficient Information 23NOV2015, 31DEC2015 Death, Headache Unknown Unknown 04JAN2016 Death 2015-06-18 UNK Unknown 2015-08-25 UNK Unknown 2015-08-25 UNK Used prior to dressing Unknown changes to aid in pain relief Breakthrough cancer 2015-05 pain UNK Pain 2015-10-22 UNK Unknown FDA_4166 60-Month REMS Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 9 of 25 Cases of Death Received from TRIG Sponsors During the Reporting Period: 29AUG2015-28AUG2016 Event Report TIRF Concomitant Co-Suspect Date Date Preferred Term(s) Indication(s) Duration Medications Product(s) Unknown 04JAN2016 Death Unknown 2015-10-22 - None reported None reported UNK Unknown 04JAN2016 Death Unknown 2015-10-22 - None reported None reported UNK Unknown 05JAN2016 Death Unknown Unknown None reported None reported UBC ID 2009 Patient Age UNK Patient Gender Male 2010 UNK Female 2011 UNK Male 2012 53 Male 2013 UNK Male 2014 46 Female 07JAN2016 07JAN2016 Death 2015 68 Male 09JAN2016 11JAN2016 Cardiac arrest 2016 62 Male 2017 2018 UNK UNK 2019 UNK 2020 58 Male 12JAN2016 13JAN2016 Neoplasm progression 2021 UNK Unknown Unknown 13JAN2016 Neoplasm progression 07MAR2014, 06JAN2016 Disease progression, 07MAR2014 Metabolic acidosis Unknown 07JAN2016 Death 17DEC2015, 11JAN2016 Drug ineffective, 17DEC2015, Dysstasia, Fall, 17DEC2015, Cerebrovascular Unknown, accident, Tumour Unknown rupture Unknown 23MAR2014 11JAN2016 Death Female Unknown 12JAN2016 DIABETES MELLITUS SYSTEMIC LUPUS ERYTHEMATOSUS PAIN DEATH Male Unknown 13JAN2016 Death Event Outcome Death Death Death Potential Causalitya Insufficient Information Insufficient Information Insufficient Information Not Related Breakthrough cancer 2014-01-12 - Ativan, Fentanyl, pain UNK Marinol Unknown Unknown None reported None reported Death None reported Death Urinary bladder carcinoma 2014-04-28 - Elavil, Keppra, UNK Msir, Oxycontin, Wellbutrin, Clonazepam Breakthrough cancer 2015-12 None reported pain 2016-01-08 Breakthrough cancer 2013-12-04 - Cipro pain UNK None reported Death Insufficient Information Not Related None reported Death Not Related None reported Death Possibly Related Unknown Unknown Unknown Unknown None reported None reported None reported None reported Death Death Not Related Not Related Breakthrough cancer pain Breakthrough cancer pain, lung cancer, metastases to brain Breakthrough cancer pain 2015-09-22 - None reported 2016-01-05 2015-12-14 - None reported UNK None reported Death None reported Death Insufficient Information Not Related 2015-11-30 - None reported 2016-01-13 None reported Death Not Related FDA_4167 60-Month REMS Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies UBC ID 2022 Patient Age 68 Patient Gender Female 2023 61 Female 2024 76 Female 2025 UNK 2026 74 Female 2027 UNK 2028 Page 10 of 25 Cases of Death Received from TRIG Sponsors During the Reporting Period: 29AUG2015-28AUG2016 Event Report TIRF Concomitant Co-Suspect Date Date Preferred Term(s) Indication(s) Duration Medications Product(s) 04JUN2015, 14JAN2016 Dizziness, Death Unknown Unknown Ambien, Zanaflex, None reported Unknown Valium, Morphine Pump Unknown 14JAN2016 Death, Drug ineffective Unknown Unknown None reported None reported 19FEB2013, 19FEB2013, 19FEB2013, Unknown Unknown Unknown Event Outcome Death Potential Causalitya Not Related Death Insufficient Information Insufficient Information 14JAN2016 Nervousness, Pruritus, Unknown Psychomotor hyperactivity, Death Unknown Fentanyl, Effexor None reported Death 15JAN2016 Death Unknown Unknown None reported None reported Death 25AUG2014 15JAN2016 Death Lung disease None reported Death Male Unknown 15JAN2016 Death Unknown 2015-11-30 - Fentanyl UNK Unknown None reported None reported Death UNK Male Unknown 18JAN2016 Death None reported None reported Death 2029 UNK Female Unknown 19JAN2016 Death None reported None reported Death 2030 62 Female 09JUL2014 19JAN2016 Death None reported None reported Death 2031 60 Female 22FEB2014 19JAN2016 Death None reported None reported Death 2032 61 Female 20OCT2015 21JAN2016 Neoplasm progression Fentanyl Patch None reported Death Not Related 2033 71 Female Unknown 22JAN2016 Death Breakthrough cancer 2015-12-18 pain UNK Unknown 2015-12-03 UNK Breakthrough cancer 2014-06-10 pain UNK Breakthrough cancer 2014-01-15 pain UNK Breakthrough pain 2015-09-08 UNK Unknown Unknown Insufficient Information Insufficient Information Insufficient Information Insufficient Information Not Related None reported None reported Death 2034 58 Male Unknown 25JAN2016 Death Unknown Unknown None reported None reported Death 2035 49 Female Unknown 25JAN2016 Death Unknown Unknown None reported None reported Death 2036 27 Male Unknown 25JAN2016 Death Unknown Unknown None reported None reported Death 2037 52 Male Unknown 25JAN2016 Death Unknown Unknown None reported None reported Death Insufficient Information Insufficient Information Insufficient Information Insufficient Information Insufficient Information Insufficient Information Not Related FDA_4168 60-Month REMS Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 11 of 25 Cases of Death Received from TRIG Sponsors During the Reporting Period: 29AUG2015-28AUG2016 Event Report TIRF Concomitant Co-Suspect Date Date Preferred Term(s) Indication(s) Duration Medications Product(s) Unknown 25JAN2016 Neoplasm malignant Cancer pain Unknown None reported None reported Unknown 26JAN2016 Death, Off label use Chronic pain 2015-12-01 - None reported None reported 2016-01-25 Unknown 28JAN2016 Death Unknown Unknown None reported None reported UBC ID 2038 2039 Patient Age UNK UNK Patient Gender Male Male 2040 53 Female 2041 66 Female 30APR2014 2042 UNK Female Unknown 2043 UNK Male 2044 UNK 2045 28JAN2016 Neoplasm progression Event Outcome Death Death Death Potential Causalitya Not Related Insufficient Information Insufficient Information Not Related None reported Death 29JAN2016 Death Breakthrough cancer 2014-03-01 - Fentanyl Patch, pain UNK Lovenox, Metformin, Naturethroid Unknown Unknown None reported None reported Death Unknown 29JAN2016 Death Unknown Unknown None reported None reported Death Male Unknown 29JAN2016 Death Unknown Unknown None reported None reported Death UNK Male Unknown 29JAN2016 Neoplasm progression Bladder cancer None reported Death 2047 67 Male DEC2014 Unknown None reported Death Not Related 2049 82 Male None reported None reported Death 2050 UNK Male 15JAN2016, 10JAN2016 Unknown 03FEB2016 PULMONARY EMBOLISM CARDIAC DISORDER 04FEB2016 Cardiac failure, Vomiting 04FEB2016 Death 2014-07-30 - Oxycontin 2014-11-15 Unknown None reported Insufficient Information Insufficient Information Insufficient Information Not Related None reported None reported Death 2051 UNK Male Unknown None reported None reported Death 2052 UNK Male Unknown None reported None reported Death Possibly Related Insufficient Information Insufficient Information Not Related 2053 UNK Female Death Not Related 68 46 Female Female Dilaudid, Oxycodone None reported None reported None reported 2054 2055 NOV2014, Unknown 25JAN2016 17JAN2016 None reported None reported Death Death Not Related Not Related Breakthrough cancer 2015-12 pain UNK Unknown 2015-12 UNK 04FEB2016 Death Unknown 2015-12 UNK 04FEB2016 Neoplasm progression Cancer pain 2015-12-11 2016-01-27 05FEB2016 Neoplasm progression, Cancer 2015-12 Thinking abnormal UNK 05FEB2016 Pancreatic carcinoma Breakthrough pain Unknown 08FEB2016 Neoplasm progression Breakthrough cancer 2015-12 pain UNK FDA_4169 60-Month REMS Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies UBC ID 2056 Patient Patient Age Gender UNK Unknown Page 12 of 25 Cases of Death Received from TRIG Sponsors During the Reporting Period: 29AUG2015-28AUG2016 Event Report TIRF Concomitant Co-Suspect Date Date Preferred Term(s) Indication(s) Duration Medications Product(s) Unknown 08FEB2016 Death Unknown Unknown None reported None reported 09FEB2016 DEATH OFF LABEL USE 09FEB2016 SICKLE CELL ANAEMIA OFF LABEL USE 10FEB2016 Death Intervertebral disc degeneration Sickle cell anaemia Unknown None reported None reported Death Potential Causalitya Insufficient Information Not Related Unknown None reported None reported Death Not Related Unknown None reported None reported Death Unknown 11FEB2016 Death Cancer None reported None reported Death Female 08FEB2016 12FEB2016 Death Cancer pain None reported None reported Death 63 Female 10APR2015 15FEB2016 Cardiac arrest Unknown None reported None reported Death 2063 UNK Female Unknown 16FEB2016 Death Unknown 2014-05-28 UNK 2014-05-28 UNK 2015-10-23 UNK 2014-02-12 2015-04-10 Unknown None reported None reported Death 2064 UNK Female Unknown 16FEB2016 Death, Off label use Pain None reported Death 2065 UNK Male Unknown 16FEB2016 Death Unknown 2016-02-05 - None reported 2016-02-16 Unknown None reported None reported Death 2066 56 Female Unknown 17FEB2016 Death Unknown Unknown None reported Death Insufficient Information Insufficient Information Insufficient Information Insufficient Information Insufficient Information Insufficient Information Insufficient Information Insufficient Information 2067 57 Male 18FEB2016 Death, Off label use Pain None reported Death Not Related 2068 UNK 18FEB2016 Death Unknown None reported Death Insufficient Information 2057 59 Male 24NOV2004 2058 UNK 2059 54 Female 06DEC2014 2060 UNK Female 2061 49 2062 Unknown 08OCT2010 10FEB2016, Unknown Unknown 11FEB2016 Levaquin, Carboplatin, Paraplatin, Dexamethasone, Taxol, Zofran, Benadryl, Lyrica, Tramadol, Hydromorphone, Lorazepam, Ibuprofen, Oxycodone 2015-11-11 - None reported 2016-02-10 2016-02-05 - None reported UNK Event Outcome Death FDA_4170 60-Month REMS Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 13 of 25 Cases of Death Received from TRIG Sponsors During the Reporting Period: 29AUG2015-28AUG2016 Event Report TIRF Concomitant Co-Suspect Date Date Preferred Term(s) Indication(s) Duration Medications Product(s) Unknown 18FEB2016 Death Unknown 2015-10-23 - None reported None reported UNK Unknown 18FEB2016 Death Unknown 2015-10-23 - None reported None reported UNK Unknown 18FEB2016 Death Unknown 2015-10-23 - None reported None reported UNK Unknown 19FEB2016 Death Unknown 2015-10-23 - None reported None reported UNK Unknown 19FEB2016 Death Cancer 2015-10-23 - None reported None reported UNK Unknown 19FEB2016 Death Unknown Unknown None reported None reported UBC ID 2069 Patient Age UNK Patient Gender Male 2070 UNK Unknown 2071 UNK Unknown 2072 UNK Female 2073 UNK Male 2074 52 Female 2076 UNK Unknown 10SEP2015 22FEB2016 Death Unknown 2077 UNK Male Unknown 23FEB2016 Death Unknown 2078 UNK Unknown Unknown 24FEB2016 Death Unknown 2079 UNK Male Unknown 25FEB2016 Death Unknown 2080 75 2081 UNK 2082 2083 UNK 52 Female Female 2084 UNK Male Unknown 09FEB2016, Unknown Female Unknown 26FEB2016 Neoplasm progression, Unknown Hospitalisation 29FEB2016 Death Unknown Unknown 01MAR2016 Death Unknown, 01MAR2016 Arteriosclerosis, 26APR2015 Myocardial infarction Unknown 02MAR2016 Death 2016-02-01 UNK 2016-06-03 UNK 2016-02-01 UNK 2016-06-03 UNK 2016-02-24 UNK 2016-06-03 UNK Unknown 3114 days Unknown Breakthrough pain, cardiomyopathy, bundle branch block left, pelvic pain, ischaemic heart disease prophylaxis, depression, anaemia, hypertension Chronic pain 2016-02-01 2016-02-29 Event Outcome Death Death Death Death Death Death None reported None reported Death None reported None reported Death None reported None reported Death None reported None reported Death None reported None reported Death None reported None reported Death None reported None reported Coreg, Aspirin, None reported Duragesic, Effexor, Ferrous Sulfate, Lisinopril Death Death None reported Death None reported Potential Causalitya Insufficient Information Insufficient Information Insufficient Information Insufficient Information Not Related Insufficient Information Insufficient Information Insufficient Information Insufficient Information Insufficient Information Not Related Insufficient Information Not Related Not Related Insufficient Information FDA_4171 60-Month REMS Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies UBC ID 2085 Patient Patient Age Gender UNK Unknown Page 14 of 25 Cases of Death Received from TRIG Sponsors During the Reporting Period: 29AUG2015-28AUG2016 Event Report TIRF Concomitant Co-Suspect Date Date Preferred Term(s) Indication(s) Duration Medications Product(s) Unknown 02MAR2016 Death Cancer pain Unknown None reported None reported Event Outcome Death 2086 UNK Male Unknown 03MAR2016 Death Unknown None reported None reported Death 2087 UNK Male Unknown 07MAR2016 Asthenia, Diplegia, Neoplasm progression None reported Death 2089 42 Female None reported Death 2090 UNK Male None reported Death 2091 64 Male 20JUL2015 Breakthrough cancer 2016-02-01 - Levaquin, pain UNK Oxycodone, Suboxone Breakthrough pain 2016-02-01 - None reported UNK Unknown 2016-02-01 - None reported UNK Unknown Unknown None reported None reported Death 2092 51 Male 07MAR2016 11MAR2016 Hepatic failure None reported Death 2093 UNK Male Unknown None reported Death 2094 UNK Female 2015 11MAR2016 DEATH Breakthrough cancer 2014-12-09 - Fentanyl Patch pain, chronic pain UNK Unknown 2014-12-09 - None reported UNK Unknown Unknown None reported None reported Death 2095 63 Female Unknown 14MAR2016 Death Unknown Unknown None reported None reported Death 2096 UNK Female Unknown 14MAR2016 Death Unknown Unknown None reported None reported Death 2097 40 Female 01JAN2015 15MAR2016 Death Unknown Unknown None reported None reported Death 2098 57 Male 04MAR2016 15MAR2016 Death Death 32 Male 26FEB2016, 16MAR2016 Toxicity to various Unknown, agents, Incorrect route Unknown of drug administration, Off label use 2016-02-24 - None reported UNK 2016-02-24 - Belsomra, Keflex, UNK Lopressor, Vitamin D, Vitamin D3 None reported 2099 Breakthrough cancer pain, neoplasm bone Acute back pain, chronic back pain 2100 UNK Male Cancer pain, cancer pain 2016-02-03 - Fentanyl Patch UNK 03MAR2016, 08MAR2016 Intracranial aneurysm, Unknown Off label use Unknown 08MAR2016 Death Unknown 10MAR2016 Death 11MAR2016 Death 16MAR2016 Death Unknown Duragesic, Death Effexor, Klonopin, Marijuana, Morphine, Oxycontin, Xanax None reported Death Potential Causalitya Insufficient Information Insufficient Information Not Related Insufficient Information Insufficient Information Insufficient Information Not Related Insufficient Information Insufficient Information Insufficient Information Insufficient Information Insufficient Information Not Related Related Not Related FDA_4172 60-Month REMS Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 15 of 25 UBC ID 2101 Patient Age UNK Patient Gender Male Cases of Death Received from TRIG Sponsors During the Reporting Period: 29AUG2015-28AUG2016 Event Report TIRF Concomitant Co-Suspect Date Date Preferred Term(s) Indication(s) Duration Medications Product(s) Unknown 17MAR2016 Death Unknown Unknown None reported None reported Event Outcome Death 2102 UNK Female Unknown 2103 69 Male 2104 UNK Female Unknown 2106 UNK Female Unknown 2107 51 Male 2108 UNK Female Unknown 23MAR2016 DEATH 2109 UNK Female Unknown 2110 UNK Female Unknown 2112 60 Male 2010 2113 UNK Male Unknown 2114 54 Female 29MAR2016 29MAR2016 Disease progression 2115 78 Male 2116 UNK Female 29MAR2016, 29MAR2016 Death, Off label use 24FEB2016 Unknown 29MAR2016 Death 18MAR2016 Death None reported Death None reported Death 21MAR2016 Death 2015-05-18 - None reported UNK Breakthrough cancer 2016-02-23 - None reported pain 2016-03-19 Unknown Unknown None reported None reported Death 22MAR2016 Death Unknown Unknown None reported None reported Death 27OCT2015 23MAR2016 Death Unknown None reported Death Unknown 2016-02-23 - None reported UNK Unknown None reported None reported Death 24MAR2016 Death Unknown Unknown None reported None reported Death 24MAR2016 DEATH Unknown Unknown None reported None reported Death 28MAR2016 DEATH ACUTE Back pain KIDNEY INJURY SEPTIC SHOCK PNEUMONIA STAPHYLOCOCCAL CAPLAN'S SYNDROME OFF LABEL USE 29MAR2016 Death Unknown Unknown Duragesic (Orphenadine Citrate, Paracetamol), Temazepam None reported Death Unknown None reported None reported Death Breakthrough cancer 2016-01-15 - None reported pain 2016-03-29 Pain in hip 2016-02-24 - None reported 2016-03-29 Breakthrough cancer 2016-02-05 - None reported pain 2016-03-29 None reported Death None reported Death None reported Death 19MAR2016 19MAR2016 Death Unknown Potential Causalitya Insufficient Information Insufficient Information Insufficient Information Insufficient Information Insufficient Information Insufficient Information Insufficient Information Insufficient Information Insufficient Information Not Related Insufficient Information Not Related Insufficient Information Insufficient Information FDA_4173 60-Month REMS Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 16 of 25 Cases of Death Received from TRIG Sponsors During the Reporting Period: 29AUG2015-28AUG2016 Event Report TIRF Concomitant Co-Suspect Date Date Preferred Term(s) Indication(s) Duration Medications Product(s) Unknown 31MAR2016 Death Breatkthrough cancer 2 Years Albuterol, None reported pain Tessalon Perle, Ativan, Zofran, Adderall, Oxycontin, Phenergan Unknown 31MAR2016 Death Unknown Unknown None reported None reported UBC ID 2117 Patient Age 46 Patient Gender Male Event Outcome Death Potential Causalitya Insufficient Information 2118 UNK Male Death Insufficient Information Insufficient Information Insufficient Information Insufficient Information Insufficient Information Insufficient Information Insufficient Information Insufficient Information Insufficient Information Insufficient Information Not Related 2120 UNK Female Unknown 04APR2016 Death Unknown Unknown None reported None reported Death 2121 UNK Female Unknown 04APR2016 Death Unknown None reported Death 2122 UNK Female Unknown 06APR2016 Death Unknown 2016-02-03 - None reported UNK Unknown None reported None reported Death 2123 52 Male 07APR2016 09APR2016 Death Death UNK Female Unknown 11APR2016 Death None reported Death 2125 UNK Male Unknown 11APR2016 Death 2015-08-21 - None reported 2016-04-07 2016-01-15 - None reported 2016-04-06 Unknown None reported None reported 2124 Breakthrough cancer pain Breakthrough cancer pain Unknown None reported Death 2126 57 Female Unknown 12APR2016 Death Unknown Unknown None reported None reported Death 2127 UNK Male SEP2014 12APR2016 Death None reported Death 2128 UNK Female Unknown 13APR2016 Death Breakthrough cancer 2014-04-09 - None reported pain UNK Unknown Unknown None reported None reported Death 2129 65 Female 07APR2016 14APR2016 Sepsis Death 2130 46 Female 2014 19APR2016 Death Breakthrough cancer 2016-03-17 - Fentanyl, None reported pain UNK Humalog, Imodium, Lantus, Levothyroxine, Oxycodone, Vitamin B12, Vitamin D3 Unknown Unknown None reported None reported Death Insufficient Information FDA_4174 60-Month REMS Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 17 of 25 Cases of Death Received from TRIG Sponsors During the Reporting Period: 29AUG2015-28AUG2016 Event Report TIRF Concomitant Co-Suspect Date Date Preferred Term(s) Indication(s) Duration Medications Product(s) 20APR2016, 20APR2016 Death, Off label use Pain 2015-12-30 - None reported None reported Unknown 2016-04-20 Unknown 25APR2016 Death Unknown Unknown None reported None reported UBC ID 2132 Patient Age 47 Patient Gender Male 2133 70 Male 2134 UNK Female Unknown 2135 UNK Female Unknown 2136 73 Male 2137 UNK Female 2138 44 Female 2139 UNK Female 2140 UNK Male Unknown 2141 40 Female Unknown 2142 32 Female 18SEP2015 2143 UNK Male Unknown 26APR2016 Death Unknown 2015-12-30 - None reported UNK Unknown None reported 27APR2016 HAEMATOLOGICAL Cancer pain MALIGNANCY 27APR2016 28APR2016 Neoplasm progression Breakthrough cancer 2016-04-20 - Ambien, pain UNK Amlodipine, Compazine, Duragesic, Fentanyl, Lisinopril, Nabuton, Oxycodone, Pravachol, Prednisone, Symbicort, Tramadol Unknown 30APR2016 Neoplasm progression Breakthrough cancer 2016-01-20 - Fentanyl Patch, pain, cancer pain UNK Opana Er Unknown 02MAY2016 Death, Product use Pain Unknown Topamax, issue Dexamethasone, Opana, Tizanidine Unknown 02MAY2016 Death Unknown Unknown None reported Event Outcome Death Potential Causalitya Not Related Death None reported Death None reported Death Insufficient Information Insufficient Information Not Related None reported Death Not Related None reported Death Not Related None reported Death Insufficient Information None reported Death Insufficient Information Not Related 02MAY2016 Death, Neoplasm progression 03MAY2016 Death Breakthrough cancer 2015-11-30 - None reported pain UNK Unknown Unknown None reported None reported Death None reported Death 03MAY2016 Death Breakthrough cancer 2015-08 pain UNK Unknown Unknown None reported None reported Death None reported None reported Death 03MAY2016 DEATH Insufficient Information Not Related Insufficient Information FDA_4175 60-Month REMS Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies UBC ID 2145 Patient Patient Age Gender UNK Unknown Page 18 of 25 Cases of Death Received from TRIG Sponsors During the Reporting Period: 29AUG2015-28AUG2016 Event Report TIRF Concomitant Co-Suspect Date Date Preferred Term(s) Indication(s) Duration Medications Product(s) MAY2016 05MAY2016 Death Cancer pain 2015-11-30 - None reported None reported UNK Unknown 06MAY2016 Death Unknown Unknown None reported None reported 2146 UNK Female 2148 66 Male 22APR2016 06MAY2016 Neoplasm progression 2149 2150 40 UNK Female Male 31OCT2014 09MAY2016 DEATH Unknown 10MAY2016 Neoplasm progression 2151 UNK Female MAY2016 13MAY2016 Sarcoma 2153 UNK Male 2015 18MAY2016 DEATH Breakthrough pain, cancer pain Unknown 2154 UNK Male Unknown 20MAY2016 Death Unknown 2155 UNK Female Unknown 20MAY2016 Death Unknown 2156 62 Male 19JUN2014 23MAY2016 Death Unknown 2157 61 Male 10APR2016 26MAY2016 Death 2158 UNK Male Unknown 31MAY2016 Neoplasm progression 2159 UNK Male Unknown 31MAY2016 Death Breakthrough cancer pain Breakthrough cancer pain Unknown 2160 UNK Male Unknown 31MAY2016 Neoplasm progression 2162 51 Male 2163 70 Female 02JUN2016 03JUN2016 Death 2164 UNK Female Unknown 06JUN2016 Death 27MAY2016 03JUN2016 Completed suicide Breakthrough cancer pain Unknown Unknown 2016-03-24 2016-04-22 Unknown 2016-03-24 UNK 2015-10-08 UNK Unknown Morphine, Oxycodone None reported None reported None reported Death Potential Causalitya Insufficient Information Insufficient Information Not Related None reported None reported Death Death Not Related Not Related Oxycodone, Oxycontin None reported None reported Death None reported Death 2015-05 UNK 2015-05 UNK Unknown None reported None reported Death None reported None reported Death None reported None reported Death None reported None reported Death None reported None reported Death Insufficient Information Insufficient Information Insufficient Information Insufficient Information Insufficient Information Insufficient Information Not Related None reported None reported Death None reported None reported Death None reported None reported Death Insufficient Information None reported None reported Death Insufficient Information None reported None reported Death Insufficient Information 2015-09-11 UNK 2016-04-13 2016-05-30 2016-04-13 UNK Unknown 2014-05-28 UNK Malignant neoplasm 2015-11-03 of bronchus and lung 2016-05-27 in situ Low back pain, 2016-05-11 spondylitis, malignant UNK neoplasm of pancreas Unknown Unknown Event Outcome Death Death Insufficient Information Not Related FDA_4176 60-Month REMS Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 19 of 25 Cases of Death Received from TRIG Sponsors During the Reporting Period: 29AUG2015-28AUG2016 Event Report TIRF Concomitant Co-Suspect Date Date Preferred Term(s) Indication(s) Duration Medications Product(s) Unknown 06JUN2016 Death Unknown Unknown None reported None reported UBC ID 2165 Patient Age UNK Patient Gender Female 2166 UNK Unknown 2167 65 Female MAY2016, Unknown 19AUG2015 2168 62 Female 2016 2169 57 Male 2171 57 Female 2172 UNK Male Unknown 2173 UNK Male Unknown 2174 66 Male 2175 UNK Male Unknown 2176 64 Male 2177 UNK 2178 2179 UNK UNK Event Outcome Death 06JUN2016 Death, Off label use Neoplasm malignant Unknown None reported None reported Death 06JUN2016 Neoplasm progression Breakthrough cancer 2015-06-17 - None reported pain UNK Cancer pain Unknown None reported None reported Death 09JUN2016 PNEUMONITIS Potential Causalitya Insufficient Information Insufficient Information Not Related Chemotherapeutic Death s (Unspecified) None reported Death Not Related Death Insufficient Information None reported Death None reported Death Death 14JUN2016 Death Breakthrough cancer 2015-11-30 - Coumadin, None reported pain UNK Marinol, Methadone, Morphine, Norco, Tramadol, Xeloda Bone cancer Unknown None reported None reported Insufficient Information Insufficient Information Not Related 30JUN2014 15JUN2016 Death Unknown Male Unknown 16JUN2016 Death Female Male Unknown Unknown 30MAY2016 10JUN2016 Neoplasm progression 14MAY2016 13JUN2016 Death 13JUN2016 Toxicity to various agents 14JUN2016 Death 18MAR2016 14JUN2016 Neoplasm progression Breakthrough cancer pain Chronic pain, post laminectomy syndrome, lumbar radiculopathy, cervical radiculopathy Unknown Unknown Drug use for unapproved indication 16JUN2016 Anal cancer metastatic Unknown 16JUN2016 DEATH Unknown 2015-06-17 - None reported UNK 2013-08-07 - Dilaudid, Humira, None reported UNK Methadone 2015-11-30 - None reported UNK Unknown None reported Death 2015-11-30 - None reported UNK Unknown None reported None reported Death None reported Death Unknown Unknown None reported None reported Death Death None reported None reported Not Related Insufficient Information Insufficient Information Insufficient Information Not Related Not Related FDA_4177 60-Month REMS Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 20 of 25 UBC ID 2180 Patient Age 64 Patient Gender Male Cases of Death Received from TRIG Sponsors During the Reporting Period: 29AUG2015-28AUG2016 Event Report TIRF Concomitant Co-Suspect Date Date Preferred Term(s) Indication(s) Duration Medications Product(s) Unknown 21JUN2016 Death Unknown Unknown None reported None reported Event Outcome Death 2182 UNK Female Unknown 2183 51 Female 2184 UNK 2185 Potential Causalitya Insufficient Information Insufficient Information Insufficient Information Insufficient Information Insufficient Information 21JUN2016 Death Unknown Unknown None reported None reported Death 22JUN2016 Product use issue, Death 22JUN2016 Death Interstitial cystitis 8 Years Morphine None reported Death Male 01JAN2008, Unknown Unknown Unknown Unknown None reported None reported Death 56 Male 04JUN2016 22JUN2016 Death 2015-11-24 - None reported UNK None reported Death 2186 91 Female 18JUN2016 24JUN2016 Death Death 43 Male 19JUN2016 24JUN2016 Neoplasm progression None reported Death 2189 UNK Male Unknown 27JUN2016 Death 2015-11-24 - None reported UNK 2016-06-18 - None reported UNK Unknown None reported None reported 2188 Malignant neoplasm of bronchus and lung in situ Breakthrough cancer pain Breakthrough cancer pain Unknown None reported Death 2190 89 Female 26JUN2016 27JUN2016 Death None reported None reported Death 2191 80 Female 27JAN2016 27JUN2016 Death None reported None reported Death 2192 UNK Female Unknown 28JUN2016 Death None reported None reported Death 2193 51 Female 27JUN2016 28JUN2016 Neoplasm progression Lorazepam None reported Death Insufficient Information Insufficient Information Insufficient Information Insufficient Information Not Related 2194 68 Female 14JUN2016 28JUN2016 Neoplasm progression Death Not Related 2195 73 Female 29JUN2016 29JUN2016 Neoplasm progression Amlodipine, None reported Doxycycline, Duragesic Patch, Gabapentin, Levothyroxin, Pantoprazole, Sertraline, Spiriva Breakthrough cancer 2016-04-01 - None reported None reported pain 2016-06-29 Death Not Related Breakthrough cancer 2016-02-09 pain 2016-06-26 Unknown 2016-06-03 UNK Unknown 2016-05-09 2016-06-28 Breakthrough cancer 2016-06-20 pain UNK Breakthrough cancer 2016-06-03 pain UNK Insufficient Information Not Related FDA_4178 60-Month REMS Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 21 of 25 Cases of Death Received from TRIG Sponsors During the Reporting Period: 29AUG2015-28AUG2016 Event Report TIRF Concomitant Co-Suspect Date Date Preferred Term(s) Indication(s) Duration Medications Product(s) Unknown 01JUL2016 Death Unknown Unknown None reported None reported Event Outcome Death Unknown Unknown 43 Female 01JUL2016 2200 UNK Female Unknown 2201 59 Female 03JUL2016 2202 UNK Female Unknown 06JUL2016 Death 2203 52 Female 25JAN2015 06JUL2016 Death 2205 57 Male 10JUL2016 11JUL2016 Neoplasm progression 2206 UNK Female 01JUL2016 12JUL2016 Neoplasm progression 2207 65 Female 10JUL2016 12JUL2016 Neoplasm progression 2208 68 Female 10JUN2016 12JUL2016 Death 2209 53 Male 13JUL2016 14JUL2016 Death 2210 UNK Female Unknown 15JUL2016 Death 2211 2212 UNK 53 Female Male 2015 Unknown 2213 48 Female 2215 UNK Female UBC ID 2196 Patient Age UNK Patient Gender Female 2198c UNK 2199 05JUL2016 Overdose Unknown 05JUL2016 Neoplasm progression None reported None reported Death Breakthrough cancer 2016-06-21 pain, breakthrough UNK cancer pain Unknown Unknown Fentanyl Patch, Morphine, Oxycodone None reported None reported Death None reported Death Fentanyl None reported Death None reported None reported Death None reported None reported Death None reported None reported Death Insufficient Information Insufficient Information Not Related None reported None reported Death Not Related None reported None reported Death Not Related Duragesic Patch None reported Death Oxycodone None reported Death Insufficient Information Not Related None reported None reported Death 15JUL2016 Death 18JUL2016 Death Breakthrough cancer 2016-03-24 pain UNK Unknown 2016-03-24 UNK Unknown 2016-03-24 UNK Breakthrough cancer 2016-03-25 pain 2016-07-10 Unknown 2016-06-28 2016-07-01 Breakthrough cancer 2016-03-25 pain 2016-07-10 Breakthrough cancer 2015-11-09 pain UNK Breakthrough cancer 2016-05-23 pain 2016-07-13 Unknown 2016-05-23 UNK Unknown Unknown Unknown Unknown None reported None reported None reported None reported Death Death 19JUN2016 18JUL2016 Death Pain None reported Death Unknown 18JUL2016 Death Unknown 2016-04-04 - None reported 2016-06-19 Unknown None reported None reported Death 06JUL2016 Death 06JUL2016 Neoplasm progression Unknown Potential Causalitya Insufficient Information Insufficient Information Not Related Insufficient Information Not Related Insufficient Information Not Related Insufficient Information Not Related Insufficient Information FDA_4179 60-Month REMS Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 22 of 25 Cases of Death Received from TRIG Sponsors During the Reporting Period: 29AUG2015-28AUG2016 Event Report TIRF Concomitant Co-Suspect Date Date Preferred Term(s) Indication(s) Duration Medications Product(s) 17JUL2016 19JUL2016 Neoplasm progression Breakthrough pain 2016-07-28 - Oxycodone None reported UNK 25MAR2016 19JUL2016 Overdose Breakthrough cancer 2016-07-28 - None reported None reported pain UNK 19JUL2016 19JUL2016 Neoplasm progression Unknown 2016-04-11 - None reported None reported UNK 20JUL2016 20JUL2016 Death Breakthrough cancer 2016-04-22 - None reported None reported pain 2016-07-20 17OCT2014 20JUL2016 Neoplasm progression Cancer pain 2014-08-19 - Fentanyl, None reported UNK Methadone, Oxycodone Unknown 21JUL2016 Death Unknown Unknown None reported None reported UBC ID 2216 Patient Age 55 Patient Gender Male 2217d 32 Female 2218 62 Male 2219 49 Female 2220 58 Male 2221 UNK Male 2222 UNK Male Unknown 21JUL2016 Neoplasm progression 2223 53 Male 21JUL2016 22JUL2016 Neoplasm progression 2224 UNK Male 19APR2016 22JUL2016 Death 2225 52 Female 01MAY2016 22JUL2016 Death 2226 UNK Female Unknown 2227 67 Female 12APR2015 2228 UNK Female Unknown 2229 52 Male 18FEB2015, 01AUG2014 23JUL2016 Chronic obstructive pulmonary disease 25JUL2016 Death 25JUL2016 Neoplasm progression 28JUL2016 Death, Inappropriate schedule of drug administration Breakthrough cancer pain Breakthrough cancer pain Breakthrough cancer pain Breakthrough cancer pain Sprain of septal cartilage of nose Unknown 2016-04-22 UNK 2016-04-11 UNK 2016-04-11 UNK 2016-04-11 UNK 2015-09-28 2016-07-23 2016-04-11 UNK Breakthrough cancer 2016-04-22 pain UNK Cancer pain 6 Months Event Outcome Death Death Death Death Death Death Potential Causalitya Insufficient Information Possibly Related Not Related Insufficient Information Not Related None reported None reported Death Insufficient Information Not Related Fentanyl, Hydrocodone Hydrocodone, Morphine Oxycodone None reported Death Not Related None reported Death None reported Death None reported None reported Death Insufficient Information Insufficient Information Not Related None reported None reported Death Fentanyl Patch, Hydrocodone, Morphine, Oxycodone Fentanyl None reported Death None reported Death Insufficient Information Not Related Insufficient Information FDA_4180 60-Month REMS Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 23 of 25 UBC ID 2230 Patient Age 45 Patient Gender Female 2231 73 Female 2232 62 Male 2233 UNK Male Cases of Death Received from TRIG Sponsors During the Reporting Period: 29AUG2015-28AUG2016 Event Report TIRF Concomitant Co-Suspect Date Date Preferred Term(s) Indication(s) Duration Medications Product(s) 08OCT2015 28JUL2016 Neoplasm progression Complex regional 2015-08-28 - Oxycodone None reported pain syndrome, UNK breakthrough cancer pain 20JUN2016 28JUL2016 Death Breakthrough cancer 2015-08-28 - None reported None reported pain UNK 18JUL2016 28JUL2016 Neoplasm progression Breakthrough cancer 2015-08-28 - Fentanyl, None reported pain UNK Hydrocodone, Morphine Unknown 28JUL2016 Death Unknown Unknown None reported None reported 2234 64 Male 20JUL2016 2235 UNK Male Unknown 02AUG2016 Death 2236 2237 55 UNK Female Female Unknown Unknown 03AUG2016 Death 03AUG2016 Cardiac arrest Malignant neoplasm of pancreas, part unspecified Breakthrough cancer pain Unknown Chronic pain 2238 UNK Male Unknown 04AUG2016 Death 2239 UNK Male Unknown 2240 UNK Female 2241 90 2242 29JUL2016 Neoplasm progression Event Outcome Death Potential Causalitya Not Related Death Not Related Death Not Related Death Insufficient Information Not Related 2016-04-11 - None reported 2016-07-20 None reported Death Hydromorphone None reported Death None reported None reported None reported None reported Death Death Unknown 2016-04-11 UNK Unknown 2012-12-28 UNK Unknown None reported None reported Death 04AUG2016 Death Unknown Unknown None reported None reported Death Unknown 04AUG2016 Death Unknown Unknown None reported None reported Death Female Unknown 04AUG2016 Death Unknown Unknown None reported None reported Death 60 Male 20JUN2016 04AUG2016 Neoplasm progression None reported Death 2243 UNK Male Unknown 05AUG2016 Death None reported Death 2244 UNK Male Unknown 06AUG2016 Death Breakthrough cancer 2016-04-12 - Enoxaparin, pain UNK Fentanyl, Oxycodone Unknown 2016-04-12 - None reported UNK Breakthrough cancer 2016-04-12 - Fentanyl, pain UNK Hydromorphone None reported Death Insufficient Information Not Related Insufficient Information Insufficient Information Insufficient Information Insufficient Information Insufficient Information Not Related Insufficient Information Insufficient Information FDA_4181 60-Month REMS Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 24 of 25 Cases of Death Received from TRIG Sponsors During the Reporting Period: 29AUG2015-28AUG2016 Event Report TIRF Concomitant Co-Suspect Date Date Preferred Term(s) Indication(s) Duration Medications Product(s) Unknown 08AUG2016 Death Neck pain 2016-04-12 - None reported None reported UNK Unknown 08AUG2016 Death Unknown Unknown None reported None reported UBC ID 2246 Patient Age UNK Patient Gender Female 2247 66 Male 2248 78 Male None reported Death None reported Death None reported Death Not Related None reported Death Not Related None reported Death Not Related None reported Death None reported Death Insufficient Information Not Related None reported Death Not Related 12AUG2016 Death 2016-04-12 - None reported UNK Breakthrough cancer 2016-04-12 - Fentanyl, pain UNK Hydromorphone, Oxycodone Breakthrough cancer 2016-04-12 - Fentanyl Patch pain UNK Breakthrough cancer 2014-08-07 - None reported pain UNK Breakthrough cancer 2014-08-07 - Fentanyl pain UNK Unknown 2014-08-07 - None reported UNK Breakthrough cancer 2014-08-07 - Morphine, pain UNK Oxycodone Breakthrough cancer 2014-08-07 - Hydrocodone pain UNK Unknown Unknown None reported Potential Causalitya Insufficient Information Insufficient Information Insufficient Information Not Related 2249 UNK Female Unknown 09AUG2016 Neoplasm progression 2250 UNK Female Unknown 10AUG2016 Neoplasm progression 2251 60 Female 08OCT2014 10AUG2016 Death 2252 37 Female 01JUL2016 2253 UNK Female Unknown 2254 41 Female 02MAY2016 12AUG2016 Necrotising fasciitis 2255 63 Female 17MAY2016 12AUG2016 Neoplasm progression 2256 UNK Female Unknown None reported Death Unknown 15AUG2016 Death Unknown Unknown None reported None reported Death Male Unknown 15AUG2016 Neoplasm progression None reported Death Male Male Unknown 23JUN2016 None reported Hydromorphone None reported None reported Death Death 2263 UNK Male Unknown 17AUG2016 Death 2014-08-07 UNK Unknown 2014-08-07 UNK Unknown Fentanyl UNK 67 Breakthrough cancer pain Unknown Breakthrough cancer pain Unknown Insufficient Information Insufficient Information Not Related 2257 UNK Female 2258 UNK 2260 2262 None reported None reported Death 2264 UNK Male Unknown 17AUG2016 Death Unknown Unknown None reported None reported Death 09AUG2016 09AUG2016 Death 11AUG2016 Neoplasm progression 11AUG2016 Death 15AUG2016 DEATH 16AUG2016 Death Unknown Event Outcome Death Death Not Related Insufficient Information Insufficient Information Insufficient Information FDA_4182 60-Month REMS Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies UBC ID 2265 Patient Age UNK Patient Gender Male 2266 UNK Male 2267 UNK Male 2268 62 Male 2269 76 Male 2270 34 Male 2271 68 Male Cases of Death Received from TRIG Sponsors During the Reporting Period: 29AUG2015-28AUG2016 Event Report TIRF Concomitant Co-Suspect Date Date Preferred Term(s) Indication(s) Duration Medications Product(s) Unknown 17AUG2016 Death Breakthrough cancer 2015-12 Fentanyl None reported pain UNK Unknown 17AUG2016 Neoplasm progression Breakthrough cancer 2015-12 None reported None reported pain UNK Unknown 19AUG2016 Neoplasm progression Breakthrough cancer 2015-12 Fentanyl None reported pain UNK 13AUG2016, 20AUG2016 Hepatic failure, Malignant neoplasm 2015-12-31 - None reported None reported 13AUG2016 Neoplasm progression of head, face, and 2016-08-13 neck 19AUG2016 20AUG2016 Neoplasm progression Malignant neoplasm 2015-12-31 - None reported None reported of head, face, and UNK neck 20AUG2016 22AUG2016 Death Crohn's disease 2015-12 None reported Ambien, UNK Morphine, Oxycodone 15AUG2016 23AUG2016 Death Malignant neoplasm 2016-07-28 - None reported None reported of spinal cord 2016-08-15 APR2016 24AUG2016 Death Breakthrough cancer 2016-07-28 - Hydrocodone, None reported pain UNK Oxycodone 25APR2016 24AUG2016 Death Breakthrough cancer 2013-12-04 - Oxycodone None reported pain UNK Unknown 24AUG2016 Death Unknown 2013-12-04 - None reported None reported UNK 10AUG2016 25AUG2016 Death Breakthrough cancer 2013-12-04 - Fentanyl None reported pain UNK Unknown 25AUG2016 Death Unknown 2013-12-04 - None reported None reported UNK Unknown 26AUG2016 Death Unknown Unknown None reported None reported Page 25 of 25 Event Outcome Death Death Potential Causalitya Insufficient Information Not Related Death Not Related Death Insufficient Information Death Not Related Death Insufficient Information Death Insufficient Information 2272 UNK Male Death Insufficient Information 2273 56 Male Death Insufficient Information 2274 UNK Male Death Insufficient Information 2275 83 Female Death Insufficient Information 2276 UNK Female Death Insufficient Information 2277 31 Male Death Insufficient Information a Potential causality is reported if sufficient information is available to make a determination. If there is insufficient information available and the potential causality cannot be determined, this is noted in the table. b Patient 1988 is also described in the table for addiction and overdose. c Patient 2198 is also described in the table for overdose. d Patient 2217 is also described in the table for overdose. UNK = Unknown FDA_4183 60-Month REMS Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies UBC ID 1856 1857 1859 1860 1861 1862 1863 1864 1865 1866 1867 1868 1869 1870 1871 1872 New Cases of Death Received from TRIG Sponsors in 2016 from a Previous Reporting Periods Patient Patient Event Report TIRF Concomitant Co-Suspect Age Gender Date Date Preferred Term(s) Indication(s) Duration Medications Product(s) b UNK Female Unknown 04DEC2013 Neoplasm progression Breakthrough cancer 2013-02-19 - None reported None reported pain UNK 33 Female 12DEC2013 19DEC2013b Death Breakthrough pain 2015-06-08 - None reported None reported UNK UNK Female Unknown 08JAN2014b Death Breakthrough cancer 2013-06-27 - None reported None reported pain UNK UNK Male Unknown 14JAN2014b Death Unknown 2013-05-14 - None reported None reported UNK UNK Male Unknown 16JAN2014b Death Unknown 2013-10-17 - None reported None reported UNK UNK Female JAN2014 12FEB2014b Neoplasm progression Breakthrough cancer 2013-10-07 - Fentanyl, None reported pain UNK Methadone UNK Male Unknown 12FEB2014b Death Breakthrough pain 2013-02-14 - None reported None reported UNK UNK Female Unknown 19FEB2014b Death Breakthrough pain 2014-01-28 - None reported None reported UNK UNK Female Unknown 19FEB2014b Death Breakthrough cancer 2014-01-07 - None reported None reported pain UNK UNK Male Unknown 21FEB2014b Death Breakthrough cancer 2013-07-09 - None reported None reported pain UNK UNK Female Unknown 28FEB2014b Death Malignant neoplasm 2015-07-02 - None reported None reported of bronchus and lung UNK in situ, cancer pain b UNK Female Unknown 04MAR2014 Death Breakthrough cancer 2013-08-29 - None reported None reported pain UNK UNK Female Unknown 05MAR2014b Death Cancer pain 2013-03-13 - None reported None reported UNK UNK Female Unknown 05MAR2014b Death Breakthrough pain 2013-05 None reported None reported 2014-01-04 UNK Unknown Unknown 06MAR2014b Death Lung cancer, bone 2013-06-28 - None reported None reported cancer, breakthrough UNK cancer pain UNK Male Unknown 13MAR2014b Death Breakthrough cancer 2014-02-06 - None reported None reported pain UNK Page 1 of 4 Event Outcome Death Potential Causalitya Not Related Death Death Insufficient Information Not Related Death Not Related Death Not Related Death Not Related Death Death Insufficient Information Not Related Death Not Related Death Not Related Death Insufficient Information Death Not Related Death Not Related Death Not Related Death Not Related Death Not Related FDA_4184 60-Month REMS Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies UBC ID 1873 Patient Patient Age Gender UNK Unknown Event Date Unknown 1874 UNK Female Unknown 1875 UNK Male Unknown 1876 UNK Male Unknown 1877 UNK Unknown Unknown 1878 UNK Male Unknown 1879 UNK Male Unknown 1880 UNK Unknown Unknown 1881 UNK Male Unknown 1882 UNK Unknown Unknown 1883 UNK Female Unknown 1885 UNK Female Unknown 1886 UNK Female Unknown 1887 UNK Female Unknown 1888 UNK Male Unknown New Cases of Death Received from TRIG Sponsors in 2016 from a Previous Reporting Periods Report TIRF Concomitant Co-Suspect Date Preferred Term(s) Indication(s) Duration Medications Product(s) b 14MAR2014 Death Unknown 2013-03-13 - None reported None reported UNK 17MAR2014b Death, Off label use Lumbar disc 2013-06 None reported None reported degeneration UNK 20MAR2014b Death Unknown 2013-06-28 - None reported None reported UNK 28MAR2014b Neoplasm progression Breakthrough cancer 2013-11-14 - Diazepam, None reported pain, metastatic UNK Oxycontin, carcinoma Prednisone, Synthroid, Vancomycin, Zofran b 02APR2014 Death Unknown 2013-08 None reported None reported UNK 14APR2014b Neoplasm progression Breakthrough cancer 2014-02-19 - None reported None reported pain UNK 06MAY2014b Death, Malaise Unknown 2013-07 None reported None reported UNK 08MAY2014b Death Unknown 2013-05-20 - None reported None reported UNK 13MAY2014b Death Unknown 2012-06-29 - None reported None reported UNK 14MAY2014b Death Breakthrough cancer 2013-05-15 - None reported None reported pain UNK 17JUN2014b Death, Migraine Cancer pain 2014-10-13 - None reported None reported UNK 23JUN2014b Neoplasm progression Cancer pain 2013-08-17 - None reported None reported UNK 01JUL2014b Neoplasm progression Breakthrough cancer 2014-06-05 - Oxycodone None reported pain UNK 08JUL2014b Death Breakthrough cancer 2014-06-11 - None reported None reported pain UNK 09JUL2014b Respiratory distress Breakthrough cancer 2014-06-11 - Ativan, Fentanyl, None reported pain, breakthrough UNK Norco cancer pain Page 2 of 4 Event Outcome Death Death Potential Causalitya Insufficient Information Insufficient Information Insufficient Information Not Related Death Not Related Death Not Related Death Insufficient Information Insufficient Information Insufficient Information Not Related Death Death Death Death Death Death Death Possibly Related Not Related Death Not Related Death Insufficient Information Possibly Related Death FDA_4185 60-Month REMS Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies UBC ID 1889c 1890 1891 1892 1893 1894 1895 1907 1908 1910 New Cases of Death Received from TRIG Sponsors in 2016 from a Previous Reporting Periods Patient Patient Event Report TIRF Concomitant Co-Suspect Age Gender Date Date Preferred Term(s) Indication(s) Duration Medications Product(s) b UNK Male Unknown 28JUL2014 Abnormal behaviour, Breakthrough cancer 2014-05-30 - None reported Nexavar Disorientation, Drug pain 2014-06-03 interaction, Hepatic failure, Inappropriate schedule of drug administration UNK Female Unknown 28JUL2014b Death Unknown 2014-05-30 - None reported None reported UNK UNK Unknown Unknown 28JUL2014b Death Unknown 2014-05-30 - None reported None reported UNK 57 Unknown 10DEC2013 31JUL2014b Death Unknown 2014-05-30 - None reported None reported UNK UNK Male Unknown 12AUG2014b Neoplasm progression Unknown 2014-02-11 - None reported None reported UNK UNK Male Unknown 12AUG2014b Death Breakthrough cancer 2014-06-19 - None reported None reported pain 2014-07-18 UNK Male Unknown 25AUG2014b Death Unknown 2014-06-19 - None reported None reported UNK 58 Male 01JUN2015, 01JUN2015b Drug ineffective, Death Cancer pain, chronic 2014-10 Atorvastatin None reported Unknown pain UNK Calcium, Baby Aspirin, Diazepam, Dronabinol, Fentanyl Patch, Nuvigil, Oxycodone UNK Unknown Unknown 16JUN2015b Death Unknown 2014-06-19 - None reported None reported UNK 72 Male 14NOV2015, 13AUG2015b General physical health Breakthrough cancer 2015-06-15 - Albuterol, Fentanyl Patches 14NOV2015 deterioration, Neoplasm pain, breakthrough UNK Miralax, Mobic, progression cancer pain Morphine, Phenergan, Ranitidine, Senna, Synthroid Page 3 of 4 Event Outcome Death Potential Causalitya Possibly Related Death Death Insufficient Information Insufficient Information Insufficient Information Not Related Death Not Related Death Insufficient Information Insufficient Information Death Death Death Death Death Insufficient Information Not Related FDA_4186 60-Month REMS Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 4 of 4 New Cases of Death Received from TRIG Sponsors in 2016 from a Previous Reporting Periods UBC Patient Patient Event Report TIRF Concomitant Co-Suspect Event Potential ID Age Gender Date Date Preferred Term(s) Indication(s) Duration Medications Product(s) Outcome Causalitya a Potential causality is reported if sufficient information is available to make a determination. If there is insufficient information available and the potential causality cannot be determined, this is noted in the table. b Case initiated in prior reporting period but was not included in previous reports. c Patient 1889 is also described in the table for addiction. UNK = Unknown FDA_4187 60-Month REMS Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies 12.4 Page 111 of 112 RADARS System Program Report Protocol FDA_4188 Transmucosal Immediate Release Fentanyl (TIRF) Risk Evaluation and Mitigation Strategy (REMS): Surveillance Monitoring Protocol For The TIRF REMS Industy Group Actavis Laboratories FL, Inc. BioDelivery Sciences International, Inc. (BDSI) Cephalon, Inc. (a wholly-owned subsidiary of Teva Pharmaceutical Industries, Ltd.) Depomed, Inc. Insys Therapeutics, Inc. Mallinckrodt Pharmaceuticals Mylan Inc. Par Pharmaceutical, Inc. Sentynl Therapeutics, Inc. August 3, 2016 Confidential This protocol contains information that may be confidential and/or proprietary. Any dissemination, distribution or copying of this document is strictly prohibited without our prior written consent, which may be withheld for any reason solely at our discretion. CONFIDENTIAL Page 1 of 21 FOLLOWING THIS PAGE, FDA_4190 TO FDA_4203 WITHHELD IN FULL AS B(4)/CCI FDA_4189 7. Appendices CONFIDENTIAL Page 16 of 21 7.1 Shell Tables Table The RADARS System per Means Model From July 2010 to June 2016 Drug group Time period Rate (95% CI) Pre TIRF REMS x.xxxx (x.xxxx, x.xxxx) Post TIRF REMS x.xxxx (x.xxxx, x.xxxx) Pre TIRF REMS x.xxxx (x.xxxx, x.xxxx) Post TIRF REMS x.xxxx (x.xxxx, x.xxxx) Pre TIRF REMS x.xxxx (x.xxxx, x.xxxx) Post TIRF REMS x.xxxx (x.xxxx, x.xxxx) Pre TIRF REMS x.xxxx (x.xxxx, x.xxxx) Post TIRF REMS x.xxxx (x.xxxx, x.xxxx) Percentage change (95% CI) p-value p-value for interaction xx.xx% (-xx.xx %, xx.xx %) 0.xxx xx.xx% (-xx.xx %, xx.xx %) 0.xxx 0.xxx xx.xx% (-xx.xx %, xx.xx %) 0.xxx 0.xxx xx.xx% (-xx.xx %, xx.xx %) 0.xxx 0.xxx TIRF Products Schedule II IR Opioids Schedule II Opioids Schedule II Opioids Excluding Methadone CONFIDENTIAL Page 17 of 21 FDA_4205 Table The RADARS System per Piecewise Linear Model From July 2010 to June 2016 Drug group Time period Parameter Estimate (95% CI) Percentage change (95% CI) p-value p-value for interaction Intercept x.xxxx (x.xxxx, x.xxxx) Slope x.xxxx (x.xxxx, x.xxxx) Intercept x.xxxx (x.xxxx, x.xxxx) xx.xx% (-xx.xx %, xx.xx %) 0.xxx Slope x.xxxx (x.xxxx, x.xxxx) xx.xx% (-xx.xx %, xx.xx %) 0.xxx Intercept x.xxxx (x.xxxx, x.xxxx) Slope x.xxxx (x.xxxx, x.xxxx) Intercept x.xxxx (x.xxxx, x.xxxx) xx.xx% (-xx.xx %, xx.xx %) 0.xxx 0.xxx Slope x.xxxx (x.xxxx, x.xxxx) xx.xx% (-xx.xx %, xx.xx %) 0.xxx 0.xxx Intercept x.xxxx (x.xxxx, x.xxxx) Slope x.xxxx (x.xxxx, x.xxxx) Intercept x.xxxx (x.xxxx, x.xxxx) xx.xx% (-xx.xx %, xx.xx %) 0.xxx 0.xxx Slope x.xxxx (x.xxxx, x.xxxx) xx.xx% (-xx.xx %, xx.xx %) 0.xxx 0.xxx Intercept x.xxxx (x.xxxx, x.xxxx) Slope x.xxxx (x.xxxx, x.xxxx) Intercept x.xxxx (x.xxxx, x.xxxx) xx.xx% (-xx.xx %, xx.xx %) 0.xxx 0.xxx Slope x.xxxx (x.xxxx, x.xxxx) xx.xx% (-xx.xx %, xx.xx %) 0.xxx 0.xxx Pre TIRF REMS TIRF Products Post TIRF REMS Pre TIRF REMS Schedule II IR Opioids Post TIRF REMS Pre TIRF REMS Schedule II Opioids Post TIRF REMS Pre TIRF REMS Schedule II Opioids Excluding Methadone Post TIRF REMS Table CONFIDENTIAL Page 18 of 21 FDA_4206 The RADARS System Cumulative Mention Rates of per 100,000 Population, 10,000 Prescriptions and 100,000 Dose Units From July 2010 to June 2016 Total Cumulative Rates Pre TIRF REMS July 2010-June 2012 Post TIRF REMS July 2012-June 2016 Poison Center Program Abuse Cases/Mentions Population Rate per 100,000 Prescription Rate per 10,000 Dose Unit Rate per 100,000 Treatment Center Programs Combined Cases/ Endorsements Population Rate per 100,000 Prescription Rate per 10,000 Dose Unit Rate per 100,000 Opioid Treatment Program Cases/ Endorsements Population Rate per 100,000 Prescription Rate per 10,000 Dose Unit Rate per 100,000 x/x x.xxxx x.xxxx x.xxx x/x x.xxxx x.xxxx x.xxx x/x x.xxxx x.xxxx x.xxx x/x x.xxxx x.xxxx x.xxx x/x x.xxxx x.xxxx x.xxx x/x x.xxxx x.xxxx x.xxx Survey of Key Informants’ Patients Program Cases/ Endorsements Population Rate per 100,000 Prescription Rate per 10,000 Dose Unit Rate per 100,000 x/x x.xxxx x.xxxx x.xxxx x/x x.xxxx x.xxxx x.xxxx College Survey Program Cases/ Endorsements Population Rate per 100,000 Prescription Rate per 10,000 Dose Unit Rate per 100,000 Impaired Health Care Worker Program Mentions Population Rate per 100,000 Prescription Rate per 10,000 Dose Unit Rate per 100,000 x/x x.xxxx x.xxxx x.xxxx x/x x.xxxx x.xxxx x.xxxx x/x x.xxxx x.xxxx x.xxxx x/x x.xxxx x.xxxx x.xxxx CONFIDENTIAL Page 19 of 21 FDA_4207 Table The RADARS System Poison Center Program Reported Deaths by Age, Medical Outcome and Period From July 2010 to June 2016 Time Period xxxxx CONFIDENTIAL Case Number xxxx xxxx Year Quarter xxxxQx xxxxQx Age Group xx-xx xx-xx Exposure Reason xxxx xxxx Medical Outcome Death Death Page 20 of 21 FDA_4208 Table The RADARS System Poison Center Program Reported Pediatric Exposures Listing From July 2010 to June 2016 Time Period Case Number Year Quarter CONFIDENTIAL Age Group Exposure Reason Medical Outcome Page 21 of 21 FDA_4209 60-Month REMS Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies 12.5 Page 112 of 112 RADARS System Program Report FDA_4210 RADARS® SYSTEM REPORT Transmucosal Immediate Release Fentanyl (TIRF) Risk Evaluation and Mitigation Strategy (REMS): Surveillance Monitoring December 13, 2016 CONFIDENTIAL Page 1 of 472 FOLLOWING THIS PAGE, FDA_4212 TO FDA_4682 WITHHELD IN FULL AS B(4)/CCI FDA_4211 February 17, 2017 Food and Drug Administration Center for Drug Evaluation and Research Central Document Room Drug Master File Staff 5901 -B Ammendale Road Beltsville, MD 20705?1266 Re: DMF 027320 Holder: McKesson Specialty Health (McKesson) Subject: Transmucosal Immediate Release Fentanyl (T IRF Access Program Re: REMS Shared Program DMF Type: DMF Submission Information: Clinical/Clinical Information REMS Submission Identi?er: Not Applicable Sequence Number: 0028 Dear Drug Master File Staff: This Type DMF contains the Risk Evaluation and Mitigation Strategy (REMS) for Transmucosal Immediate Release entanyl for the Shared System REMS program. Please find the ?60-Month FDA REMS Supplemental Assessment Report (10 February 2017)? that completes the 60-Month FDA REMS Assessment Report submission and addresses some of the FDA requested items included in the 48-Month FDA Assessment Report Acknowledgement Letter. This supplemental assessment report is located in Module 1.16 of this submission. McKesson states that information provided in this Master File is current and assures that the material furnished will meet the speci?cations described herein. McKesson also confirms that the Holder obligations are observed. We request that all information in this ?le be treated as confidential commercial information to the Food and Drug Administration pursuant to 21 OF .R. ?20.61, and that no information from this file be provided to any unauthorized persons without written consent. If you have any questions or concerns regarding this submission, please do not hesitate to contact Debra Hackett, US. Agent for McKesson, at 610?407-1729 or alternatively via email at debra.hackett@accenture.com. Sincerely, gebra Halckett, Agent Accenture, LLP Attachments: Table of Contents for the submission Electronic Submission Specifications DMF #027320; Sequence 0028 Shared System REMS Table of Contents Page 1 of 1 REMS CORRESPONDENCE Module Section Description 1.2 Cover Letter Cover Letter w/ Attachments 1.16 – Risk Management Plans REMS History TIRF REMS Access Program 60-Month FDA REMS Supplemental Assessment Report FDA_4684 Electronic Submission Specifications This submission is compliant with FDA's Guidelines for Industry and current eCTD specifications. All files were checked and verified to be free of viruses prior to transmission through the electronic submission gateway. Anti-Virus Program Program Version Virus Definition Date Submission Size Symantec Endpoint Protection Edition 12.1.5337.5000 02/15/2017 rev. 18 Approx. 4.3 MB The IT point of contact for this submission is: Name Phone Number Email Address Matt Francis 1-610-407-1854 Matthew.p.francis@accenture.com FDA_4685 ADMINISTRATIVE INFORMATION Holder’s Name: McKesson Specialty Health (McKesson) Holder’s Address: 4343 N. Scottsdale Road Suite 150 Scottsdale, AZ 85251 Holder’s Contact Person: Laura Baloun Contact’s Address: 4343 N. Scottsdale Road Suite 150 Scottsdale, AZ 85251 Contact’s Phone: 480-663-4009 Contact’s Fax: 480-663-4973 Contact’s Email address: laura.baloun@mckesson.com Statement of Commitment: Attached, please find a signed statement of commitment. The statement certifies that the DMF 027320 is current and that McKesson will comply with the statements made in it. Agent’s Name: Accenture, LLP Agent’s Address: 1160 West Swedesford Road, Building One Berwyn, PA 19312 Agent’s Contact Person: Debra Hackett, Senior Regulatory Project Manager, Regulatory Affairs Contact’s Address 1160 West Swedesford Road, Building One Berwyn, PA 19312 Contact’s Phone: 610-407-1729 Contact’s Fax: 610-407-8433 Contact’s E-mail address: debra.hackett@accenture.com FDA_4686 DMF #027320; Sequence 0028 Shared System REMS Modification Date No. Approved 1 June 5, 2012 REMS History Page 1 of 8 Documents Affected Overview of Modification   Sequence 0002: Edits to Patient-Prescriber Agreement Form, the addition of the Closed System Pharmacy Enrollment Form*, the addition of the newly approved TIRF product, Subsys (fentanyl sublingual spray) and minor editorial changes.                 REMS Prescriber Program Overview Education Program Prescriber Enrollment Form Patient Provider Agreement Form Patient and Caregiver Overview Dear Healthcare Provider Letter Outpatient Pharmacy Overview Chain Pharmacy Overview Inpatient Pharmacy Overview Outpatient Pharmacy Enrollment Form Chain Pharmacy Enrollment Form Inpatient Pharmacy Enrollment form Outpatient Pharmacy Letter Inpatient Pharmacy Letter Dear Distributor Letter Distributor Enrollment Form Supporting Document *The Closed System Pharmacy Enrollment Form was not formally submitted through the Gateway but was submitted via email on May 18, 2012 and included in the June 5, 2012 FDA approval letter. FDA_4687 DMF #027320; Sequence 0028 Shared System REMS Modification Date No. Approved N/A N/A 2 November 7, 2013 N/A N/A 2 November 7, 2013 REMS History Page 2 of 8 Documents Affected Overview of Modification Assessment Report 1 at 6 months – due 06/28/2012 Sequence 0003: Assessment report covering 12/28/2011 to 04/27/2012 Draft Documents submitted on or before 09/28/2012  Chain Pharmacy Enrollment Form  Outpatient Pharmacy Enrollment Form  Closed System Pharmacy Overview  Education Program  Frequently Asked Questions (FAQ)  Outpatient Pharmacy Letter  REMS  Supporting Document Assessment Report 2 at 1 year – due 12/28/2012 Amendment to 09/28/2012 supplement:  Chain Outpatient Pharmacy Enrollment Form  Independent Outpatient Pharmacy Enrollment Form  Closed System Outpatient Pharmacy Enrollment Form  Inpatient Sequence 0004: Modification proposed to:  Incorporate closed system pharmacies into the TIRF REMS Access Program  Correct minor inconsistencies between the FDA provided versions and the current PDF versions of REMS materials Sequence 0005: Assessment Report covering 04/28/2012 to 10/28/2012 Sequence 0006: Modification proposed to:  Revised terminology, processes, and definitions for outpatient pharmacies  Revised attestations for physicians and patients to address concerns regarding patient access  Revised Program Overview and Frequently Asked Questions to improve clarity and content FDA_4688 DMF #027320; Sequence 0028 Shared System REMS Modification Date No. Approved REMS History Page 3 of 8 Documents Affected                  Pharmacy Enrollment Form Distributor Enrollment Form Prescriber Enrollment Form Patient Provider Agreement Form Chain Outpatient Pharmacy Overview Independent Outpatient Pharmacy Overview Closed System Outpatient Pharmacy Overview Inpatient Pharmacy Overview Patient and Caregiver Overview Prescriber Overview Education Program Knowledge Assessment Frequently Asked Questions (FAQ) Dear Outpatient Pharmacy Letter Dear Inpatient Pharmacy Letter Dear Healthcare Provide Letter Dear Distributor Letter REMS Overview of Modification  Updated REMS materials to reflect the completion of the transition phase for the TIRF REMS Access Program FDA_4689 DMF #027320; Sequence 0028 Shared System REMS Modification Date No. Approved REMS History Page 4 of 8 Documents Affected Overview of Modification  N/A N/A N/A N/A 3 December 24, 2014 Supporting Document  Website Landing Page Assessment Report 3 at 2 years – due 12/28/2013 Safety Surveillance Report #1 – due 03/31/2014            REMS Prescriber Program Overview Education Program Prescriber Enrollment Form Patient and Caregiver Overview Independent Outpatient Pharmacy Overview Chain Outpatient Pharmacy Overview Closed System Outpatient Pharmacy Overview Inpatient Pharmacy Overview Independent Outpatient Pharmacy Enrollment Form Chain Outpatient Sequence 0007: Assessment Report covering 10/29/2012 to 10/28/2013 Sequence 0008: Safety surveillance data covering Q4 2012 to Q3 2013 Sequence 0009: Modification proposed to:  Updated REMS materials to eliminate product specific information which does not impact the safe use of TIRF products  Updated REMS materials to reference the currently approved TIRF products list on the FDA Approved REMS website  Updated REMS materials to remove reference to deactivating patients shown to have multiple prescribers in an overlapping timeframe  Incorporated revised assessment metrics into the Supporting Document  Revised Education Program to emphasize and strengthen appropriate conversion FDA_4690 DMF #027320; Sequence 0028 Shared System REMS Modification Date No. Approved REMS History Page 5 of 8 Documents Affected       N/A N/A N/A N/A 3 December 24, 2014 Pharmacy Enrollment Form Closed System Outpatient Pharmacy Enrollment Form Inpatient Pharmacy Enrollment form Distributor Enrollment Form FAQ Supporting Document Website Prototype Cash Claim Information Request Response – due 05/30/2014 DMF Annual Report – due 08/20/2014  REMS  Prescriber Program Overview  Education Program  Knowledge Assessment  Prescriber Enrollment Form  Patient and Caregiver Overview  Independent Outpatient Overview of Modification   and patient counseling information Updated REMS and Supporting Document to clarify deactivation of a patient PPAF as opposed to the patient record Updated pharmacy overview documents and  FAQ to call out cash claim requirement  Updated TIRF REMS Access website to incorporate items above and link respective Full Prescribing Information and Medication Guides to DailyMed Sequence 0010: Response to 5/16/2014 FDA Cash Claim Information Request Sequence 0011: DMF Annual Report Sequence 0012: Modification proposed to:  Updated REMS materials to eliminate product specific information which does not impact the safe use of TIRF products  Updated REMS materials to reference the TIRF Products webpage on the TIRF REMS Access website  Updated REMS FDA_4691 DMF #027320; Sequence 0028 Shared System REMS Modification Date No. Approved REMS History Page 6 of 8 Documents Affected            Pharmacy Overview Chain Outpatient Pharmacy Overview Closed System Outpatient Pharmacy Overview Inpatient Pharmacy Overview Independent Outpatient Pharmacy Enrollment Form Chain Outpatient Pharmacy Enrollment Form Closed System Outpatient Pharmacy Enrollment Form Inpatient Pharmacy Enrollment form Distributor Enrollment Form FAQ Supporting Document Website Prototype Overview of Modification       materials to remove reference to deactivating patients shown to have multiple prescribers in an overlapping timeframe Incorporated revised assessment metrics into the Supporting Document Revised Education Program to emphasize and strengthen appropriate conversion and patient counseling information Updated REMS and Supporting Document to clarify deactivation of a patient PPAF as opposed to the patient record Updated pharmacy overview documents and FAQ to call out cash claim requirement Updated TIRF REMS Access website to incorporate items above and link respective Full Prescribing Information and Medication Guides to DailyMed Updated Education Program and Knowledge Assessment to incorporate approved labeling supplement FDA_4692 DMF #027320; Sequence 0028 Shared System REMS Modification Date No. Approved 3 December 24, 2014 REMS History Page 7 of 8 Documents Affected Overview of Modification Unchanged from Sequence 0012, plus:  Dear Healthcare Provider Letter  Dear Outpatient Pharmacy Letter  Dear Inpatient Pharmacy Letter  Dear Distributor Letter Sequence 0013: Unchanged from Sequence 0012, plus:  Dear Healthcare Provider Letter  Dear Outpatient Pharmacy Letter  Dear Inpatient Pharmacy Letter  Dear Distributor Letter N/A N/A Assessment Report 4 at 3 years – due 12/28/2014 Sequence 00014: Assessment Report covering 10/29/2013 to 10/28/2014 N/A N/A BioDelivery Sciences International – Letter of Authorization Sequence 0015: BioDelivery Sciences International – Letter of Authorization N/A N/A Actavis Laboratories Inc. – Letter of Authorization Sequence 0016: Actavis Laboratories Inc. – Letter of Authorization N/A N/A DMF Annual Report – due 08/20/2015 Sequence 0017: DMF Annual Report N/A N/A 36-Month Assessment – Consolidated Information Requests N/A N/A Assessment Report 5 at 4 years – due 12/28/2015 N/A N/A N/A N/A Sentnyl Therapeutics, Inc. – Letter of Authorization Withdraw Authorization for Galena BioPharma, Inc. Sequence 0018: Response to FDA 36Month Assessment Information Requests Sequence 00019: Assessment Report covering 10/29/2014 to 10/28/2015 Sequence 00020: Sentnyl Therapeutics, Inc. – Letter of Authorization Sequence 00021: Letter of Authorization/Withdrawn Letter of Authorization FDA_4693 DMF #027320; Sequence 0028 Shared System REMS Modification Date No. Approved N/A N/A REMS History Page 8 of 8 Documents Affected Overview of Modification Administrative Change; Change in US Agent 48-Month REMS Supplemental Assessment Report Sequence 00022: Administrative Change; Change in US Agent Sequence 00023: 48-Month REMS Supplemental Assessment Report Sequence 0024: DMF Annual Report N/A N/A N/A N/A DMF Annual Report – due 08/20/2016 N/A N/A NA N/A Administrative Change; Change in US Agent Assessment Report 6 at 5 years (60-Month) – due 12/28/2016 N/A N/A 48-Month FDA Assessment Report Consolidated Information Requests N/A N/A 60-Month REMS Supplemental Assessment Report (10 February 2017) Sequence 00025: Administrative Change; Change in US Agent Sequence 0027: 60-Month Assessment Report covering 10/29/2015 to 10/28/2016 Sequence 0026: TIRG REMS Access Program 48-Month FDA Assessment Report Consolidated Responses to FDA Information Requests Sequence 00028: 60-Month REMS Supplemental Assessment Report FDA_4694 60-Month FDA REMS Supplemental Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 1 of 19 Title: Transmucosal Immediate-Release Fentanyl (TIRF) Risk Evaluation and Mitigation Strategy (REMS) Access Program 60-Month Supplemental Assessment Report Reporting Timeframe: 29 October 2015 to 28 October 2016 Document Number: FINAL v 1.0 Product Name: Transmucosal Immediate-Release Fentanyl Sponsor: TIRF REMS Industry Group (TRIG) of Companies: Actavis Laboratories FL, Inc. BioDelivery Sciences International, Inc. Cephalon, Inc. (a wholly-owned subsidiary of Teva Pharmaceutical Industries, Ltd.) Depomed, Inc. Insys Therapeutics, Inc. Mallinckrodt Pharmaceuticals Mylan, Inc. Par Pharmaceutical, Inc. Sentynl Therapeutics, Inc. Date 10 February 2017 Confidentiality Statement The information contained herein is confidential and the proprietary property of the TRIG of Companies and its affiliates, and any unauthorized use or disclosure of such information without the prior written authorization of the TRIG is expressly prohibited. FDA_4695 60-Month FDA REMS Supplemental Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 2 of 19 TABLE OF CONTENTS Pg LIST OF TABLES ................................................................................................................... 3 LIST OF ABBREVIATIONS ................................................................................................. 4 1 OVERVIEW ................................................................................................................. 5 2 RESULTS ..................................................................................................................... 9 2.1 Timeline for Outreach to Sample of Health Professionals and Pharmacies to Ascertain Reasons for Not Re-enrolling ................................................................... 9 2.2 Knowledge, Attitude, and Behavior Surveys ............................................................ 9 2.2.1 Patient Report..................................................................................................... 9 2.2.2 Pharmacy Report .............................................................................................. 11 2.2.3 Prescriber Report ............................................................................................. 13 3 DISCUSSION ............................................................................................................. 14 4 APPENDICES ............................................................................................................ 15 4.1 Persistency Analysis Phase II Protocol ................................................................... 16 4.2 Patient KAB Report ................................................................................................ 17 4.3 Pharmacy KAB Report ........................................................................................... 18 4.4 Prescriber KAB Report ........................................................................................... 19 FDA_4696 60-Month FDA REMS Supplemental Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 3 of 19 LIST OF TABLES Table 1 TIRF Medicines ..............................................................................................................5 Table 2 48-Month FDA REMS Assessment Report: the FDA Acknowledgement Letter Requests ..........................................................................................................................6 FDA_4697 60-Month FDA REMS Supplemental Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 4 of 19 LIST OF ABBREVIATIONS ANDA Abbreviated New Drug Application CI Confidence Interval FDA Food and Drug Administration HCP Healthcare Provider KAB NDA PPAF REMS TIRF Knowledge, Attitude, and Behavior New Drug Application Patient-Prescriber Agreement Form Risk Evaluation and Mitigation Strategy Transmucosal Immediate-Release Fentanyl TIRF Medicines Transmucosal Immediate-Release Fentanyl products TIRF REMS Access program REMS program for TIRF medicines TIRF Sponsors The group of sponsors that are submitting this REMS TRIG TIRF REMS Industry Group FDA_4698 60-Month FDA REMS Supplemental Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies 1 Page 5 of 19 OVERVIEW The Food and Drug Administration (FDA) has determined that a Risk Evaluation and Mitigation Strategy (REMS) is required to mitigate the risk of misuse, abuse, addiction, overdose, and serious complications due to medication errors with the use of Transmucosal Immediate-Release Fentanyl (TIRF) medicines. The TIRF REMS Access program was approved by the FDA on 28 December 2011 for ABSTRAL®, ACTIQ®, FENTORA®, LAZANDA®, ONSOLIS®, SUBSYS® and their generic equivalents, if applicable. The TIRF REMS Access program was successfully launched on 12 March 2012, approximately 11 weeks after the REMS approval. This report completes the 60-Month FDA REMS Assessment Report submission and addresses some of the FDA requested items included in the 48-Month FDA Assessment Report Acknowledgement Letter. The TIRF REMS Industry Group (TRIG) of sponsors who are submitting this 60-Month FDA REMS Supplemental Assessment Report (Actavis Laboratories FL, Inc., BioDelivery Sciences International, Inc., Cephalon, Inc. [a wholly-owned subsidiary of Teva Pharmaceutical Industries, Ltd.], Depomed, Inc., Insys Therapeutics Inc., Mallinckrodt Pharmaceuticals, Mylan, Inc., Par Pharmaceutical, Inc., and Sentynl Therapeutics, Inc.) are herein referred to as TIRF Sponsors. The TIRF REMS Access program is administered by McKesson Specialty Health and RelayHealth. This report has been prepared by United BioSource Corporation. The TIRF medicines subject to the TIRF REMS are itemized in Table 1 below. Table 1 TIRF Medicines Product Name (active ingredient)/formulation NDA 22510, ABSTRAL (fentanyl) sublingual tablets NDA 20747, ACTIQ (fentanyl citrate) oral transmucosal lozenge and its authorized generic NDA 21947, FENTORA (fentanyl buccal tablet) NDA 22569, LAZANDA (fentanyl) nasal spray NDA 22266, ONSOLIS (fentanyl) buccal soluble film NDA 202788, SUBSYS (fentanyl) sublingual spray ANDA 77312, fentanyl citrate oral transmucosal lozenge ANDA 78907, fentanyl citrate oral transmucosal lozenge ANDA 79075, fentanyl buccal tablet Abbreviations: ANDA=Abbreviated New Drug Application; NDA=New Drug Application On 21 July 2016, the FDA provided feedback on the patient/caregiver, prescriber, and pharmacist surveys. After careful review of the requested changes, the TRIG notified the FDA that in order to incorporate all changes, an extension for report submission would be required. As proposed by the FDA on 29 July 2016 and agreed to by the TRIG on 01 August 2016, the 60-month knowledge, attitude, and behavior (KAB) survey results will be submitted separately from the overall REMS assessment report on or before 17 February 2017. The KAB survey FDA_4699 60-Month FDA REMS Supplemental Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 6 of 19 results presented in this supplemental report cover the same time period as the 60-Month FDA REMS Assessment Report submitted in December 2016. In addition to the KAB survey results, this supplemental report also addresses items included in the 48-Month FDA Assessment Report Acknowledgement Letter received in November 2016 per the FDA request. These additional requests are summarized in Table 2. Item #2a requested a timeline to further evaluate the findings of the IMS Health Study submitted in the 48-Month FDA Supplemental Assessment Report. However, to evaluate this request a separate letter from the FDA providing additional details of this evaluation is needed. As TRIG Sponsors started receiving this letter on 23 January 2017, this request is not included in this submission. The remaining items from the 48-Month FDA Assessment Report Acknowledgement Letter (#3d, #3e, and #3g) are currently being discussed by the TRIG and no additional response is available at this time. Table 2 48-Month FDA REMS Assessment Report: the FDA Acknowledgement Letter Requests Request Number* FDA Request 2a. Regarding the assessment of opioid tolerance submitted in the 48-Month FDA REMS Assessment Report, approximately 42% of patients prescribed TIRF products were not opioid tolerant. The TRIG needs to further investigate this concerning finding. A timeline for a plan to further evaluate this finding should be submitted with the 17 February 2017, submission of the 60-month REMS assessment survey results. At a minimum, further evaluation of this finding will include product-specific assessments of opioid tolerance that each member sponsor will submit only to their NDA or ANDA. Additional details regarding this evaluation will be communicated in a separate letter. 2b. Regarding the persistency analysis submitted by the TRIG, these data indicate that the number of patients who may be exposed to “inappropriate conversion between TIRF medicines” is not insignificant. Thus these TIRF product switches need to be further assessed by the TRIG and a protocol developed to assess the starting doses of the TIRF products that existing TIRF patients switch to in order to ascertain what proportion of these switches are conducted as per products’ labeling. In addition, if the data system used has outcome data, this would be informative as to whether or not any switch marked as “inappropriate” resulted in any adverse sequelae. Limitations of the databases and/or approaches used are to be included in the protocol. Please submit this protocol with the 17 February 2017, submission of the 60-month REMS assessment survey results; if additional time for protocol development is needed, please request an extension. Response Location The timeline for further evaluation of findings from the IMS Study submitted in the 48-Month FDA REMS Supplemental Assessment Report is not included in this submission, as TRIG sponsors just started receiving the second letter from the FDA on 23 January 2017. The evaluation requested by the FDA is currently in progress. A protocol for phase II of the Persistency Analysis is included in this submission in Appendix 4.1. FDA_4700 60-Month FDA REMS Supplemental Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Request Number* 3a. FDA Request In the FDA’s 36-Month FDA Assessment Report Acknowledgement Letter (date 03 August 2015), the TRIG was asked to “Conduct outreach to a representative sample of those health professionals and pharmacies who did not re-enroll in the TIRF REMS Access Program so as to ascertain their reasons and report the results in your next Assessment Report. We are concerned about potential patient access issues.” Page 7 of 19 Response Location A timeline for outreach to a representative sample of health professionals and pharmacies who did not re-enroll to ascertain their reasons for not re-enrolling is included in this submission (see Section 2.1). In the 48-Month FDA REMS Assessment Report, the TRIG responded that: “Based on…analysis, there is no barrier to patient access and further outreach is unwarranted.” The TRIG states that 516 prescribers (8.6%) chose to not re-enroll and that these prescribers had an average of no more than 4 prescriptions total over the course of the reporting period. However, the reasons why these prescribers withdrew from the program are unknown as are the reasons why 1,134 prescribers had their enrollment expire this reporting period and remain expired. Additionally, the reasons why 412 pharmacies chose not to reenroll are not presented. It is therefore important that the TRIG proceed with conducting an “…outreach to a representative sample of those health professionals and pharmacies who did not re-enroll in the TIRF REMS Access Program so as to ascertain their reasons… we are concerned about potential patient access issues.” Submit a timeline for the plan to conduct this outreach in the 17 February 2017, submission of the 60-month REMS assessment survey results. 3d. Regarding the 3 instances where a non-closed system pharmacy dispensed a TIRF product after a TIRF REMS rejection, all 3 reports were brought to the attention of the TRIG only after the pharmacy contacted the REMS. The TRIG should develop a more active mechanism by which to identify and prevent such occurrences. The TRIG is looking into a more active mechanism to identify and prevent instances where a nonclosed system pharmacy dispenses a TIRF product after a TIRF REMS rejection is received. 3e. Although results for both governmental (Veteran’s Health Administration and Department of Defense) and closedpharmacy systems appear to have improved from the 36-month audit, they continue to be unsatisfactory. The 36-Month FDA Assessment Report Acknowledgement Letter requested that the TRIG “Re-evaluate whether a novel authorization process is warranted or technically feasible at this time for the closed system pharmacies and report your conclusions with your next Assessment Report.” The TRIG has issued the following response: “The TRIG has determined that the current prescription authorization volume for closed system pharmacies is less than 1% of all TIRF prescriptions and due to the absence of complaints with the current process, no changes are warranted at this time.” An absence of complaints does not necessarily mean that a closed pharmacy system process is functioning optimally. The TRIG is discussing incorporating an assessment of prescription processing times for prescriptions that do not experience any REMS-related rejections. FDA_4701 60-Month FDA REMS Supplemental Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Request Number* FDA Request Page 8 of 19 Response Location These audits are likely one of the best sources of information regarding the performance of these closed-system pharmacies in meeting the REMS requirements. If the TRIG does not favor a novel authorization process for all of the closed-system pharmacies solely due to the poor performance of the governmental entities, the TRIG should propose an outreach to these programs to improve compliance. In addition, the TRIG should be sure to include both governmental entities in the 60-month audit so that their performance in the REMS can continue to be monitored. Lastly, the TRIG presents the process times for prescriptions that have experienced at least one REMS-related rejection. However, data on the overall processing time of a prescription that does not meet with any rejections is unclear. Given that one of the pieces of information solicited during the closed-system audits is “Date and time of each prescription transaction,” this is an excellent opportunity for the TRIG to assess prescription processing times for prescriptions that do not experience any REMS-related rejections. The TRIG should add this component to their closed-system audits 3g. The TRIG reports a number of instances where prescribers were either unaware of requirements to submit a PPAF or chose not to do so. It is important that the TRIG investigate mechanisms to reinforce to prescribers the necessity of timely completion of PPAFs. The TRIG will further query noncompliant prescribers to determine more specific reasons of why they were not compliant with the REMS requirements. The TRIG will assess these responses to determine appropriate actions. Abbreviations: ANDA=Abbreviated New Drug Application; FDA=Food and Drug Administration; PPAF=PatientPrescriber Agreement From; REMS=Risk Evaluation and Mitigation Strategy; TIRF=Transmucosal Immediate Release Fentanyl; TRIG=TIRF REMS Industry Group *Numbering is aligned with the numbering of the FDA requests communicated in the 48-Month FDA’s Assessment Report Acknowledgement Letter. FDA_4702 60-Month FDA REMS Supplemental Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies 2 Page 9 of 19 RESULTS 2.1 Timeline for Outreach to Sample of Health Professionals and Pharmacies to Ascertain Reasons for Not Re-enrolling In response to the request from the FDA, a timeline has been developed to perform outreach to a representative sample of those health professional and pharmacies that did not re-enroll in the TIRF REMS Access program to ascertain their reasons for not re-enrolling. The TRIG has initiated activities to collect these data and results will be included in the 72-Month FDA REMS Assessment Report. 2.2 Knowledge, Attitude, and Behavior Surveys Surveys were conducted to assess patients’/caregivers’, pharmacists’, and prescribers’ KAB regarding the safe use of TIRF medicines as described in the educational materials for all stakeholders including the enrollment form (pharmacists and prescribers only), Full Prescribing Information (pharmacists and prescribers only), medication guides (prescribers and patients) for each product, and the Patient-Prescriber Agreement Form (PPAF; prescribers and patients only). The survey protocols describe the administration of the individual surveys that were conducted among patients who are treated with TIRF medicines or their caregivers, prescribers, and pharmacists. The KAB survey reports include summarization of all data collected during the survey (see Appendix 4.2, Appendix 4.3, and Appendix 4.4, respectively, for the patient, pharmacist, and prescriber KAB reports which include the protocol and survey). Data from the surveys, together with other REMS evaluation metrics, will be used to determine whether changes need to be made to the REMS processes or educational materials to make them more effective in achieving the goals of the REMS. The questions and statements within the KAB surveys for patients/caregivers, pharmacists, and prescribers were constructed to test the stakeholders’ understanding of the key risk messages of the REMS. The TRIG established a desired threshold of 65%. A correct response rate of 65% or greater was considered to represent adequate understanding of each concept or key risk message. The purpose of this threshold was to assist TRIG in tracking and monitoring the data for each key risk message across each wave ultimately providing direction in determining which area(s) would require improvement to ensure the patient/caregiver, pharmacist, and prescriber KAB surveys were meeting the goals of the REMS. A summary of the patient/caregiver, pharmacy, and prescriber survey data are discussed in Sections 2.2.1, 2.2.2, and, 2.2.3 respectively. 2.2.1 Patient Report The specific goals of the TIRF medicines patient/caregiver KAB survey were to evaluate the level of knowledge and assess the attitudes and behavior of patients/caregivers regarding TIRF medicines. The focus of the survey included the following: 1) TIRF medicines can cause lifethreatening breathing problems that can lead to death, patients should take TIRF medicines only if they are opioid-tolerant, and patients should strictly follow the directions of the healthcare provider (HCP), 2) patients should not switch from a TIRF medicine to another medicine that contains fentanyl without talking to a HCP, 3) patients should not give TIRF medicines to anyone else even if they have the same symptoms, and 4) TIRF medicines should be stored in a FDA_4703 60-Month FDA REMS Supplemental Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 10 of 19 safe place away from children and properly disposed. The survey also included questions about whether patients received, read, and understood the product-specific Medication Guide and the PPAF. The patient survey launched on 26 September 2016 and closed on 21 November 2016. Patients who were passively enrolled in the TIRF REMS Access program and had received a TIRF medicine in the previous 4 months (120 days) were invited to participate. From the total of 394 patients/caregivers who accessed the survey, 321 (81.5%) respondents met eligibility criteria, and of those who met eligibility criteria, 310 (96.6%) completed the survey, exceeding the target of 300 completed surveys. Changes to the 60-month KAB survey for patients/caregivers based on the FDA feedback included the addition of 6 survey questions and the revision of 4 survey questions. The change to Question 11 (TIRF medicines should only be taken by patients who are opioid tolerant), and the addition of Question 18 Items 18a through 18c (Please answer True, False, or I don’t know for each statement about the TIRF medicine that was most recently prescribed for you) are discussed with the key risk message results below. For questions not included as part of key risk messages, new Questions 37 through 41 showed most respondents indicated someone in the doctor’s office told them not to share the TIRF medicines with anyone else, counseled them that accidental exposure to TIRF medicines by a child may be fatal, told them to keep TIRF medicines out of reach of children to prevent accidental exposure, and told them about proper disposal of any unused or partially used TIRF medicines; and over half indicated someone in the doctor’s office asked them about the presence of children in their home. In addition, Questions 9, 15, and 16 that ask patients about prescriber activities and were revised to allow pharmacists as a potential source of information, showed most respondents indicated someone in the doctor’s office discussed the risks and possible side effects of the prescribed TIRF medicine, that someone in the doctor’s office explained how to use the prescribed TIRF medicines, and someone in the doctor’s office advised them on the proper storage of the prescribed TIRF medicines. The overall knowledge score of 84.8 (95% confidence interval [CI]: 83.5 86.0) for the survey indicates most respondents demonstrated understanding of the key risk messages. The average knowledge score for each of the key risk messages was greater than 88 for 5 of the 6 key risk messages and was 70.3 for Key Risk Message 3 (TIRF medicines should be taken exactly as prescribed by the healthcare provider). The lower average knowledge score for Key Risk Message 3 reflected the 3 items (described below) with correct response rates <65%. Of the 22 questions/items included as part of key risk messages, 16 items had a correct response rate >80%, and 3 items had a correct response rate between 65% and 80%. The remaining 3 items within Key Risk Message 3 had a correct response rate that fell below the desired level of understanding of 65%. These 3 items included 2 items from Question 10: For which of the following conditions should you use a TIRF medicine? Correct response rate for Item 10d (Pain after surgery [correct response: No]) was 64.2%, and correct response rate for Item 10e (Longlasting pain not from cancer, like arthritis joint pain [correct response: No]) was 39.0%. In addition, the correct response rate for Item 12b (a patient must stop taking their TIRF medicine if they stop taking their around-the-clock opioid pain medicine) was 39.7%. These items also had a low correct response rate across all patient/caregiver KAB surveys conducted (annual waves from the 12-month through the 60-month survey). FDA_4704 60-Month FDA REMS Supplemental Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 11 of 19 When comparing correct response rates from the 12-month KAB survey through the 60-month KAB survey, knowledge and understanding of the key risk messages has generally remained stable over time, including the items mentioned above that fell below the desired level of understanding of 65% for this wave and have had lower correct response rates for all survey waves. Question 11 had a notably improved correct response rate (nearly 90%) once the question was revised back to the original 36-month survey question for this survey. In addition, over 92% of respondents correctly responded that a side effect of TIRF medicines is the chance of abuse or addiction, that TIRF medicines can be misused by people who abuse medicines or street drugs, and TIRF medicines should be kept in a safe place (new Question 18). For complete data and results, see Appendix 4.2. In general, knowledge and understanding of the key risk messages has remained stable over time (Appendix 4.2, Table 21). Patients scored consistently low on 3 of 22 items: that TIRF medicines should not be taken for pain after surgery; that TIRF medicines should not be taken for longlasting pain not from cancer, like arthritis joint pain; and that a patient must stop taking their TIRF medicine if they stop taking their around-the-clock opioid pain medicine. Overall, this 60-month survey shows a high level (greater than or equal to 65% for all but 3 items) of patient understanding of key risk messages based on the REMS goals. The TRIG acknowledges that there is room for improvement around patient knowledge related to conditions for use of a TIRF medicine and stopping a TIRF medicine when stopping their around-the-clock opioid pain medicine. 2.2.2 Pharmacy Report The specific goals of the TIRF medicines pharmacist KAB survey were to assess pharmacist understanding of the risks associated with TIRF medicine use, the specific indications for treatment with TIRF medicines, and that TIRF medicines are contraindicated in opioid non-tolerant patients. The survey also included questions about whether pharmacists received, read, understood, and used the product-specific educational materials, and included questions about compliance with the REMS requirements. The pharmacy survey launched on 26 September 2016 and closed on 13 December 2016. Subjects to complete the pharmacist survey were recruited from pharmacies enrolled in the TIRF REMS Access program as of 02 September 2016 who had dispensed a TIRF medicine in the last 6 months. Out of the total of 561 pharmacists who accessed the survey, 333 (59.4%) pharmacists met eligibility criteria, and of those who met eligibility criteria, 318 (95.5%) completed the survey, exceeding the target of 300 completed surveys. Changes to the 60-month KAB survey for pharmacists based on the FDA feedback included the addition of 3 survey questions and a change to the recruitment strategy to limit the survey to pharmacists who had dispensed TIRF medicines in the past 6 months and attempt to recruit more closed system pharmacists and non-supervisory pharmacists. The addition of Question 12 (TIRF medicines should only be taken by patients who are opioid tolerant [True/False]) and Question 13 (Which of the following risks are associated with the use of TIRF medicines?[True/False for each of the following: misuse, abuse, addiction, overdose, hypothyroidism, and infection]) is discussed below with the key risk message results. Question 15 (How frequently do you perform the following activities when dispensing TIRF FDA_4705 60-Month FDA REMS Supplemental Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 12 of 19 medicines?) included 3 response items about pharmacist-reported activity. For each item, most respondents selected Always or Only with the first prescription; and few respondents selected Sometimes, Never, or I don’t know. Changes to recruitment efforts included a revised invitation letter addressed to the “pharmacist-in-charge” including 3 letters with unique codes; the pharmacist-in-charge was asked to distribute these letters to non-supervisory staff involved in the dispensing of TIRF medicines. This strategy was successful, with 74.8% of respondents indicating they were not the pharmacist-in-charge. The overall knowledge score of 85.7 (95% CI: 84.4 87.0) for the survey indicates most respondents demonstrated understanding of the key risk messages. The average knowledge score was t83.8 for 3 of the 4 key risk messages and was 75.4 for Key Risk Message 2 (TIRF medicines are only indicated for the management of breakthrough pain in adult cancer patients 18 years of age and older [16 years of age and older for Actiq® brand and generic equivalents] who are already receiving and who are tolerant to around-the-clock opioid therapy for their underlying persistent cancer pain); the lower average knowledge score for Key Risk Message 2 reflected 3 linked questions/items (described below) with correct response rates <65%. Of the 36 questions/items included as part of key risk messages, 27 items of the key risk messages had a correct response rate >80%, and 6 items had correct response rates from 65.1% to 79.6%. Three questions/items of Key Risk Message 2 had a correct response rate below the desired threshold of 65% (Items 6a, 6c, and 9e). The correct response rate for Item 6a (According to the product labeling, a cancer patient may start a TIRF medicine and an around-the-clock opioid at the same time) was 61.9%. The correct response rate for Item 6c (A patient must stop taking their TIRF medicine if they stop taking their around-the-clock opioid pain medicine) was 41.2%. This item was added to the 48-month survey based on feedback provided by the FDA in the 24-month and the 36-Month FDA Assessment Report Acknowledgement Letters. The correct response rate for Item 9e (Chronic non-cancer pain is not an indication for which TIRF medicines can be prescribed) was 43.4% for this 60-month survey. Item 9e has also had a low correct response rate across all previous pharmacist KAB surveys conducted (12-month, 24-month, 36-month, and 48-month surveys). The survey score for Item 9e may indicate that some respondents are dispensing TIRF medicines for non-cancer associated indications. When comparing correct response rates from the 12-month KAB survey through the 60-month KAB survey, no trend was evident for this 60-month survey in knowledge and understanding of the key risk messages. As described above, 2 new survey questions (Question 12 and Question 13 [6 separate response items]) were added as part of key risk messages for the 60-month survey. Correct response rates for the new questions/items were t95.6% for Question 12 and 4 items of Question 13 and 84.0%-89.3% for the 2 false items of Question 13 (hypothyroidism and infection). For complete data and results, see Appendix 4.3. In general, there is an overall trend over time toward maintaining, or increasing, pharmacist knowledge and understanding of the key risk messages (Appendix 4.3, Table 24). Three exceptions where pharmacists scored low included understanding that a cancer patient may not start a TIRF medicine and an around-the-clock opioid at the same time, that a patient must stop FDA_4706 60-Month FDA REMS Supplemental Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 13 of 19 taking their TIRF medicine if they stop taking their around-the-clock opioid pain medicine, and that TIRF medicines are not indicated for chronic non-cancer pain, which may indicate that some respondents are dispensing TIRF medicines for non-cancer associated indications. Overall, this 60-month survey shows a high level ( 65% for all but 3 items) of pharmacist understanding of key risk messages based on the REMS goals. TRIG acknowledges that there is room for improvement around pharmacist knowledge related to indications for TIRF medicines and safe use of TIRF medicines by patients also using around-the-clock opioid pain medicines. 2.2.3 Prescriber Report The specific goals of the TIRF medicines prescriber KAB survey were to assess prescribers’ understanding of the risks associated with TIRF medicine use, the selection of appropriate patients for treatment with TIRF medicines, preventing inappropriate conversion between TIRF medicines, and ensuring safe use of TIRF medicines while preventing exposure to children and others for whom TIRF medicines were not prescribed. The survey also included questions about whether prescribers received, read, understood, and used the product-specific educational materials, and included questions about compliance with the REMS requirements. The prescriber survey launched on 26 September 2016 and closed on 20 December 2016. Subjects were recruited from a random sample of prescribers who were enrolled in the TIRF REMS Access program and who had prescribed a TIRF medicine in the last 6 months. From the total of 524 respondents who accessed the survey, 313 prescribers (59.7%) met eligibility criteria, and of those who met eligibility criteria, 294 (93.9%) completed the survey. Changes to the 60-month KAB survey for prescribers based on the FDA feedback included the addition of 3 survey questions, the revision of 1 survey question, and a change to the recruitment strategy to limit the survey to prescribers who have prescribed TIRF medicines in the past 6 months. The change to Question 9 (Per the approved labeling for TIRF medicines, for which of the following indication(s) are TIRF medicines approved), and the addition of Question 21 (TIRF medicines should only be taken by patients who are opioid tolerant) and Question 22 (Which of the following risks are associated with the use of TIRF medicines? Please answer True, False, or I don’t know for the following statements) are discussed with the key risk message results below. Question 32 (How frequently do you perform the following activities when prescribing TIRF medicines? Please answer Always, Only with the first prescription, Sometimes, Never, or I don't know) included 3 response items about prescriber reported activity. For each item, most prescribers selected Always or Only with the first prescription; and few prescribers selected Sometimes, Never, or I don’t know. The overall knowledge score of 89.1 (95% CI: 88.0 90.2) for the survey indicates a high percentage of respondents demonstrated understanding of the key risk messages. The average knowledge score was greater than 86 for all 4 key risk messages. Of the 38 questions/items included as part of key risk messages, 28 questions/items had a correct response rate >80% and 10 questions/items had a correct response rate between 65% and 80%. None of the questions/items had a correct response rate that fell below the desired level of understanding of 65%. FDA_4707 60-Month FDA REMS Supplemental Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 14 of 19 When comparing correct response rates from the 12-month KAB survey through the 60-month KAB survey, knowledge and understanding of the key risk message questions has generally remained stable or improved over time. Correct response rates for 4 of the 5 items of the revised Question 9 were similar compared to the 48-month survey; however, the item pertaining to a response of ‘chronic non-cancer pain’ had a notably improved correct response rate. In addition, the 2 new survey questions (Question 21 and Question 22 [6 separate response items]) that were added as part of key risk messages for the 60-month survey based on the FDA feedback had a correct response rate of >96% for 5 questions/items and >78% for 2 items. For complete data and results, see Appendix 4.4. In general, there is an overall trend over time toward maintenance or improvement in prescriber knowledge and understanding of the key risk messages (Appendix 4.4, Table 26). The 60-month survey shows a high level (correct response rate greater than or equal to 65%) of prescriber understanding of key risk messages based on the REMS goals. However, TRIG acknowledges that there is room for improvement around prescriber knowledge related to conditions for use of a TIRF medicine, TIRF medicine use when stopping their around-the-clock opioid pain medicine, conversion of TIRF medicines, and definition of opioid tolerant. 3 DISCUSSION As part of the evaluation of the TIRF REMS Access program, the FDA requested that a timeline be developed to perform outreach to health professionals and pharmacies to ascertain reasons for not re-enrolling in the program. The TRIG has initiated activities to collect these data and results will be provided in the 72-Month FDA REMS Assessment Report. In addition, a protocol for phase II of the Persistency Analysis presented in the 48-Month FDA REMS Supplemental Assessment Report is included in Appendix 4.1. The consistently high level of stakeholder understanding of key risk messages in the 60-month KAB surveys indicates that the goals of the TIRF REMS are being partially met with existing tools. The TRIG acknowledges that there are areas for improvement of prescriber, pharmacist, and patient knowledge and is in the process of evaluating changes to the existing REMS tools. Specific areas of improvement include conditions for use of a TIRF medicine, TIRF medicine use when stopping an around-the-clock opioid pain medicine, conversion between TIRF medicines, and the definition of opioid tolerant. CONCLUSION Based on the KAB survey data provided in this 60-Month FDA REMS Supplemental Assessment Report, the TRIG concludes that there is no indication that the REMS is not meeting its goals. However, the TRIG acknowledges that the data are limited and that the FDA has requested further evaluation, as described in the 48-Month FDA Assessment Report Acknowledgement Letter, to determine whether the REMS is meeting its goals. The TRIG looks forward to discussing with the FDA additional data to be used to evaluate and improve upon the REMS. FDA_4708 60-Month FDA REMS Supplemental Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies 4 Page 15 of 19 APPENDICES FDA_4709 60-Month FDA REMS Supplemental Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies 4.1 Page 16 of 19 Persistency Analysis Phase II Protocol FDA_4710 Conversion between TIRF Medicines Analysis Protocol Version 1.0 09 February 2017 Title: Conversion between Transmucosal Immediate-Release Fentanyl (TIRF) Medicines Analysis Protocol Document Number: Final 1.0 Product Name: Transmucosal Immediate-Release Fentanyl Sponsor: TIRF REMS Industry Group (TRIG) of Companies: Actavis Laboratories FL, Inc. BioDelivery Sciences International, Inc. Cephalon, Inc. (a wholly-owned subsidiary of Teva Pharmaceutical Industries, Ltd.) Depomed, Inc. Insys Therapeutics Inc. Mallinckrodt Pharmaceuticals Mylan, Inc. Par Pharmaceutical, Inc. Sentynl Therapeutics, Inc. Controlled Document Copyright© United BioSource Corporation All Rights Reserved FDA_4711 Conversion between TIRF Medicines Analysis Protocol Version 1.0 09 February 2017 TABLE OF CONTENTS TABLE OF CONTENTS ......................................................................................................................2 1. GLOSSARY................................................................................................................................3 2. BACKGROUND & OBJECTIVES ................................................................................................5 3. DATA SOURCE..........................................................................................................................5 3.1. Data Variables ......................................................................................................................6 3.2. TIRF Medicines ...................................................................................................................6 4. ASSESSMENT OF CONVERSION ................................................................................................6 4.1. Patient Eligibility for Inclusion ............................................................................................6 4.2. Study Definitions & Analysis Assumptions ........................................................................7 4.2.1. Starting Dose ................................................................................................................7 4.2.2. Conversion ...................................................................................................................7 4.2.3. Appropriateness of Conversion....................................................................................9 5. STATISTICAL ANALYSIS ..........................................................................................................9 5.1. Analysis Outcomes ..............................................................................................................9 5.2. Statistical Methods ...............................................................................................................9 6. STUDY LIMITATIONS .............................................................................................................10 APPENDIX I. CASE DEMONSTRATIONS..........................................................................................11 APPENDIX II. TIRF PRODUCT LABELS.........................................................................................14 Controlled Document Copyright© United BioSource Corporation All Rights Reserved Page 2 of 18 FDA_4712 Conversion between TIRF Medicines Analysis Protocol Version 1.0 09 February 2017 1. GLOSSARY Change Regimen A change in regimen is defined as having a prescription filled for a TIRF medicine other than what composes the patient’s current TIRF regimen (excluding generic equivalents). For example, if the index TIRF regimen consists of TIRF A and TIRF B and then TIRF C is later added, this new TIRF regimen consisting of three TIRF medicines is considered the “change regimen.” Concurrent Therapy A patient can be prescribed more than one TIRF medicine. Concurrent therapy is defined as having a prescription filled for a TIRF medicine other than the index TIRF (excluding generic equivalents) prior to a gap occurring with the index TIRF, and a subsequent prescription for the index TIRF is filled to confirm its continued use. The same logic applies to concurrent therapy with a second regimen. Gap in Therapy A permissible gap in therapy is synonymous with a medicine’s grace period, both meaning that the patient has a refill for the TIRF medicine or a fill for another TIRF medicine prior to the end of the initial TIRF medicine’s grace period. There is no limit to the number of permissible gaps a patient can have during the study observation period. An impermissible gap in therapy is synonymous with a treatment discontinuation. If the patient later refills the same TIRF medicine after a treatment discontinuation, the TIRF medicine will be defined as having been re-initiated. Grace Period Based on results of the data exploration phase, the grace period for the persistency analysis is defined as 2.5 times the days’ supply of medication dispensed. Index TIRF Regimen The first prescription filled for a TIRF medicine during the study observation period is the index TIRF medicine. The index TIRF regimen may consist of one or more individual TIRF medicines (see “Concurrent Therapy”). Patient Observation Period The patient-level observation period for the persistency analysis extends from the date of the individual’s index TIRF medicine fill until October 28, 2016, the pre-defined data cut-off date (see also “Study Observation Period”). Persistence A patient is considered persistent with their TIRF regimen as long as the grace period for the regimen is not exceeded. Study Observation Period The study observation period for the persistency analysis is between March 12, 2012 and October 28, 2016. Switch Regimen A switch from a TIRF regimen is defined as having a prescription filled for a TIRF medicine other than the current TIRF regimen (excluding generic equivalents). A switch is only confirmed if the current TIRF regimen is not refilled. If the current TIRF regimen is refilled within its grace period, the patient is defined as having concurrent therapy, or if the grace period for the current TIRF has been exceeded, the regimen is considered discontinued and then re-initiated. TIRF Regimen TIRF regimens generally consist of only one TIRF medicine at a time. However, if “concurrent therapy” is observed, the TIRF regimen will include all individual TIRF medicines that make up the concurrent therapy regimen. The first TIRF regimen observed in the dataset is defined as the index TIRF regimen. Future TIRF regimens are described as second, third, fourth TIRF regimens, as appropriate. Controlled Document Copyright© United BioSource Corporation All Rights Reserved Page 3 of 18 FDA_4713 Conversion between TIRF Medicines Analysis Protocol Version 1.0 09 February 2017 Treatment Discontinuation If the time between refills of a TIRF medicine exceeds the grace period, the TIRF medicine is considered discontinued. Treatment Re-initiation If a prescription is filled for a TIRF medicine that has previously been discontinued (see “Treatment Discontinuation”), the TIRF medicine is considered re-initiated. Controlled Document Copyright© United BioSource Corporation All Rights Reserved Page 4 of 18 FDA_4714 Conversion between TIRF Medicines Analysis Protocol Version 1.0 09 February 2017 2. BACKGROUND & OBJECTIVES Following review of the 36-month Transmucosal Immediate-Release Fentanyl (TIRF) Risk Evaluation and Mitigation Strategy (REMS) Assessment Report, the US Food and Drug Administration (FDA) requested that as one of the objectives of the REMS, a persistency analysis be conducted in order to document how many patients are potentially at risk for inappropriate conversion between TIRF medicines. In response to this request, a persistency analysis was designed and conducted, and the results were submitted to the FDA with the 48-month Assessment Report. Following review of the results of the persistency analysis, 1 the FDA indicated that, “It is not possible to determine if the second objective (preventing inappropriate conversion between TIRF medicines) is being met. Though no instances of inappropriate conversions were submitted as a spontaneous report, the persistency analysis provided indicates that the number of patients who may be exposed to inappropriate conversion between TIRF medicines may be as high as 17.1-20.5% of patients receiving TIRF medicines. Further assessment of these findings is also warranted.” The FDA further commented that, “Regarding the persistency analysis submitted by the TRIG, these data indicate that the number of patients who may be exposed to ‘inappropriate conversion between TIRF medicines’ is not insignificant. Thus these TIRF product switches need to be further assessed by the TRIG and a protocol developed to assess the starting doses of the TIRF products that existing TIRF patients switch to in order to ascertain what proportion of these switches are conducted as per products’ labeling. In addition, if the data system used has outcome data, this would be informative as to whether or not any switch marked as “inappropriate” resulted in any adverse sequelae. Limitations of the databases and/or approaches used are to be included in the protocol. Please submit this protocol with the February 17, 2017, submission of the 60 month REMS assessment survey results; if additional time for protocol development is needed, please request an extension.” This protocol describes the proposed analysis approach to assess the occurrences of inappropriate conversion between TIRF medicines in patients who had a switch in their regimens. 3. DATA SOURCE The analysis of appropriateness of conversion between TIRF medicines will use the TIRF REMS database (with one additional year of data) to maintain consistency with the above-referenced persistency analysis. The TIRF REMS database consists of complete outpatient TIRF prescription activity that has been processed through the ‘switch,’ including all outpatient 1 Acknowledgement letter initially received November 10, 2016. Controlled Document Copyright© United BioSource Corporation All Rights Reserved Page 5 of 18 FDA_4715 Conversion between TIRF Medicines Analysis Protocol Version 1.0 09 February 2017 pharmacy types (independent and chain sub-stores), because all prescribers who prescribe and pharmacies that dispense TIRF medicines must enroll in the TIRF REMS Access program. All prescription data collected within the TIRF REMS database from March 12, 2012 (launch of the REMS) until October 28, 2016 2 will be used in the analysis of appropriateness of conversion. McKesson/RelayHealth will deliver the dataset with anonymized data for all patients, excluding rejected transactions and reversed claims. 3.1. DATA VARIABLES The following data elements are provided for each paid claim of TIRF medicine: x x x x x x x x x Prescription number Unique patient ID Date of birth Prescription process date Product name (brand or generic, as dispensed) National drug code (NDC) Product strength Quantity dispensed Days’ supply 3 3.2. TIRF MEDICINES TIRF medicines will be randomly assigned letter codes in presentations of data. The following TIRF medicines (and their generic equivalents) are included in the product conversion analysis: x x x x x Abstral® Actiq® (fentanyl citrate lozenge) Fentora® Lazanda® Subsys® 4. ASSESSMENT OF CONVERSION 4.1. PATIENT ELIGIBILITY FOR INCLUSION The study observation period, as defined by the data cutoff date for the 60-month REMS Assessment report, is between March 12, 2012, and October 28, 2016. Each patient’s observation window within this period is determined by his/her first and last recorded prescription fill dates. Patients who fulfilled the inclusion and none of the exclusion criteria below will be included in the analysis set: 2 October 28, 2016 was used as the cut-off date as this corresponds to the 60-month FDA Assessment Report. 3 As recorded in the TIRF REMS database; may not equal actual days’ supply since TIRF medicines are commonly used on an ‘as needed’ basis and pharmacists ascribe the days’ supply amount at the time of medication fill. Controlled Document Copyright© United BioSource Corporation All Rights Reserved Page 6 of 18 FDA_4716 Conversion between TIRF Medicines Analysis Protocol Version 1.0 09 February 2017 Inclusion x All patients who filled at least one TIRF medicine prescription during the study observation period Exclusion x x Filled a one-time prescription Exposed to only one single TIRF medicine (including its generic equivalents) 4.2. STUDY DEFINITIONS & ANALYSIS ASSUMPTIONS The analysis of the appropriateness of conversion is a continuation of the persistency analysis; therefore, it maintains the same parameter definitions (please refer to the glossary section). This section reviews some concepts from the persistency analysis that are relevant and describes new parameters that are specific to the present analysis. The first TIRF medicine(s) filled by a patient during the observation period constitutes the index regimen for that patient. TIRF regimens generally consist of only one TIRF medicine at a time. However, if “concurrent therapy” is observed, the TIRF regimen will include all individual TIRF medicines that make up the concurrent therapy. Specifically, concurrent therapy occurs when a prescription is filled for a TIRF medicine that is not in the current regimen (excluding generic equivalents) while the current regimen is being filled continuously. A gap in therapy occurs when a prescription is not filled before or on the day its days’ supply expires plus a grace period 4 of 2.5 times of its days’ supply. A switch in therapy occurs when the current regimen [or part of it] is discontinued and the patient fills a prescription for a different TIRF medicine(s). When a patient fills a prescription for a TIRF medicine that has previously been discontinued, the patients is re-initiating the medicine. 4.2.1. STARTING DOSE For each patient in the REMS claims database, the first prescription of a TIRF medicine that appears in the prescription sequence is its first fill and therefore specifies the starting dose of that TIRF medicine. 4.2.2. CONVERSION A conversion will be considered in either of the following scenarios of a switch in therapy: Scenario 1: A monotherapy regimen was discontinued and then switched to another monotherapy regimen (excluding generic equivalents) (Figure 1). Scenario 2: One or more TIRF medicines in a concurrent therapy regimen were discontinued, and one or more TIRF medicines were added to make up a new regimen (Figure 2). 4 For the purpose of this persistency analysis, a grace period of 2.5 times of the days’ supply of the filled regimen was derived based on the preliminary data exploration of the REMS claims data. Controlled Document Copyright© United BioSource Corporation All Rights Reserved Page 7 of 18 FDA_4717 Conversion between TIRF Medicines Analysis Protocol Version 1.0 09 February 2017 Figures 1 and 2 are simplified schematics where continuously filled prescriptions of TIRF medicines are represented by long solid color bars, which include grace periods between fills. The grace period of the most recent fill of a TIRF medicine is represented by a dashed horizontal line and a vertical line (i.e., vertical line denotes end date of grace period). Figure 1 describes the simplest type of conversion, which is from one monotherapy to another, with no overlaps in the grace periods of the monotherapies. In the case of Patient ID001, she started with ‘A’, then converted to ‘B’ and then converted to ‘C’. Controlled Document Copyright© United BioSource Corporation All Rights Reserved Page 8 of 18 FDA_4718 Conversion between TIRF Medicines Analysis Protocol Version 1.0 09 February 2017 The more complicated cases involving concurrent therapies are demonstrated in Figure 2. Patient ID021 converted from a concurrent therapy (‘A+B’) to a monotherapy (‘C’ only). However, since the grace periods of ‘A’ and ‘B’ ended on the same date, without prescribing instruction, the sequence of consumption of these medications cannot be determined, conversion to ‘C’ will be checked against both ‘A’ and ‘B’ (i.e., ‘A to C’ and ‘B to C’). On the other hand, Patient ID0032 started with concurrent therapy (‘A+B’) and then switched to (‘B+C’). In this case, only one conversion will be considered, which is ‘A to C’, because B continued to be filled. Demonstrations in Figure 2 also showed that conversion will NOT be considered within a concurrent therapy (i.e., for both sample patients, ‘A to B’ is not considered a conversion, whether the two medicines were filled on the same day or in sequence, as long as their grace periods overlap and the definition of concurrent therapy is satisfied). In addition, conversion will NOT be considered for re-initiations of TIRF monotherapy, as it is unknown if during gaps in therapy the patient had-received any TIRF medicine at an inpatient setting or if the patient had medication remaining from the first time period. However, the reinitiation of a TIRF medicine that was discontinued as part of a concurrent therapy will be considered for conversion on a regimen basis. Additional case examples illustrating more elaborated scenarios are provided in Appendix I. 4.2.3. APPROPRIATENESS OF CONVERSION For each eligible conversion, the appropriateness of the [initiating] dose of the new TIRF medicine will be determined based on recommendations stated in the labels of the TIRF medicines (Appendix II). A dose conversion is deemed inappropriate when the starting dose of the newly initiated TIRF medicine was higher than recommended in its product label. 5. STATISTICAL ANALYSIS 5.1. ANALYSIS OUTCOMES Characteristics of patients enrolled in the REMS during the study observation period will be summarized to describe the cohort. The primary outcomes of the analysis are the total number of inappropriate conversions that had occurred during the study observation period and the total number of patients who had at least one occurrence of inappropriate conversion. In addition, the average number of different TIRF products used per patient and total number of conversions assessed for the observation period will also be calculated. Moreover, the conversion dose of a TIRF medicine will be compared against its own starting dose where applicable. In instances where the conversion prescription [dose] is the initiating prescription [starting dose], then no comparison can be made. This occurrence will be reported as a percentage of all product conversions. 5.2. STATISTICAL METHODS Unless otherwise stated in the statistical analysis plan (SAP), descriptive statistics will be presented and will include the mean, standard deviation, median, and minimum and maximum values for continuous variables, as well as counts and percentages for categorical variables. To take into account the differences of number of patients at risk of inappropriate conversion over Controlled Document Copyright© United BioSource Corporation All Rights Reserved Page 9 of 18 FDA_4719 Conversion between TIRF Medicines Analysis Protocol Version 1.0 09 February 2017 time, four mutually-exclusive patient cohorts will be created based on duration of follow-up from the time of initiating the index TIRF: 1) 2) 3) 4) Up to 12 months of follow-up Up to 24 months of follow-up Up to 36 months of follow-up Up to 48 months of follow-up As in the persistency analysis, TIRF medicines will be randomly assigned letter codes in presentations of the assessment results for the appropriateness of conversion to avoid identification of individual products. 6. STUDY LIMITATIONS The TIRF REMS database only contains prescription claims data; no prescribing or medical information is available to inform how the TIRF medicines were instructed to be taken (e.g., in terms of multiproduct prescriptions, it is not known whether the prescriber had instructed that the patient take the medicines in a certain sequence and at what frequency). This limitation leads to the assumption that TIRF medicines were taken in the sequence as they were filled. Also, the REMS database only contains outpatient pharmacy claims data, and only data from the beginning of REMS program is available for analysis. Although the first identified TIRF claim is defined as the index claim in our analysis, patients may have had prior TIRF prescriptions. Therefore, the appropriateness of the dose of the index TIRF regimen cannot be assessed, for it is unknown whether the patient was converting from another TIRF medicine. Moreover, a gap in therapy might be explained by a hospitalization, but the fact of hospitalization is unknown. A patient could have initiated the index TIRF regimen while in the hospital and was titrated up as an outpatient. In addition, the FDA specifically requested this analysis, “…assess the starting doses of the TIRF products that existing TIRF patients switch to in order to ascertain what proportion of these switches are conducted as per products’ labeling.” Therefore, in this context, in concurrent therapies, the dose of newly initiated TIRF medicines will not be considered as a conversion, because the medicines in the current regimen were filled continuously, and there was no ‘switch’ in therapy. That is, a TIRF medicine was added and was not a switch. As was in the previous persistency analysis, a regimen’s grace period is calculated using the days’ supply. While this information is provided by the pharmacist at the time of medication fill, and the quantity for this variable in the dataset corresponds to the adjudicated claim, it does not necessarily correspond to how many days the patient will or is expected to take the TIRF medicines. The TIRF medicines are to be taken on an ‘as needed’ basis. Controlled Document Copyright© United BioSource Corporation All Rights Reserved Page 10 of 18 FDA_4720 Conversion between TIRF Medicines Analysis Protocol Version 1.0 09 February 2017 APPENDIX I. CASE DEMONSTRATIONS Case #1 Note: This is a simplified schematic where continuously filled prescriptions of TIRF medicines are represented by long solid color bars, which include grace periods between fills. The grace period of the most recent fill of a TIRF medicine is represented by a dashed horizontal line and a vertical line (i.e., vertical line denotes the end date of grace period). • • • Regimen sequence o Index regimen A + B + C o Second regimen A + B o Third regimen A + B + D o Fourth regimen A + D Number of conversion 0 Notes o There is no conversion in this patient’s regimen sequence, because the patient initiated concurrent therapy as her index regimen, and ‘D’ was initiated as the last filled TIRF of concurrent therapy in the 3rd regimen with no TIRF medicine being discontinued from the 2nd regimen. o Finally, ‘B’ was dropped from the 3rd regimen; ‘A’ and ‘D’ remained as the 4th regimen with no new TIRF medicine added. Controlled Document Copyright© United BioSource Corporation All Rights Reserved Page 11 of 18 FDA_4721 Conversion between TIRF Medicines Analysis Protocol Version 1.0 09 February 2017 Case #2 Note: This is a simplified schematic where continuously filled prescriptions of TIRF medicines are represented by long solid color bars, which include grace periods between fills. The grace period of the most recent fill of a TIRF medicine is represented by a dashed horizontal line and a vertical line (i.e., vertical line denotes the end date of grace period). • • • • Regimen sequence o Index regimen A + B o Second regimen B + C o Third regimen B + C + A o Fourth regimen A + C o Fifth regimen A + D Number of Conversion 2 Conversion assessment 1. Conversion from ‘A’ (600 mcg) to ‘C’ (200 mcg) deemed appropriate, started ‘C’ at 200 mcg as recommended by label 2. Conversion from ‘C’ (800 mcg) to ‘D’ (800 mcg) deemed inappropriate, started ‘D’ at 400 mcg instead of 100 mcg, inappropriate mcg per mcg basis conversion o 1 out of 2 conversions for this patient was deemed inappropriate Notes o ‘C’ in 2nd regimen was replacing ‘A’ in the index regimen; this was considered as a conversion. o ‘A’ was re-initiated as the last TIRF filled for the 3rd regimen as an add-on to the concurrent therapy in the 2nd regimen, thus not considered as a conversion, because no TIRF was discontinued from 2nd regimen. o ‘B’ was discontinued from the 3rd regimen, ‘A’ and ‘C’ remained in the 4th regimen. o In the 5th regimen, ‘D’ was added to ‘A’ to replace ‘C’; conversion to ‘D’ was considered against ‘C’. Controlled Document Copyright© United BioSource Corporation All Rights Reserved Page 12 of 18 FDA_4722 Conversion between TIRF Medicines Analysis Protocol Version 1.0 09 February 2017 Case #3 Note: This is a simplified schematic where continuously filled prescriptions of TIRF medicines are represented by long solid color bars, which include grace periods between fills. The grace period of the most recent fill of a TIRF medicine is represented by a dashed horizontal line and a vertical line (i.e., vertical line denotes the end date of grace period). • • • • Regimen sequence o Index regimen A + B o Second regimen B o Third regimen C o Fourth regimen A + D o Fifth regimen D o Sixth regimen E Number of Conversion 3 Conversion assessment 1. Conversion from ‘B’ (400 mcg) to ‘C’ (100 mcg) deemed appropriate, started ‘C’ at 100 mcg as recommended by label 2. Conversion from ‘C’ (400 mcg) to ‘A’ (200 mcg) deemed appropriate, started ‘A’ at 200mcg as recommended by label 3. Conversion from ‘D’ (400 mcg) to ‘E’ (400 mcg) deemed inappropriate, started ‘E’ at 400 mcg instead of 100 mcg as recommended by label; inappropriate mcg per mcg basis conversion o 1 out of 3 conversions for this patient was deemed inappropriate Notes o ‘A’ and ‘B’ were both discontinued from the index regimen and ‘B’ alone made up the 2nd regimen. o ‘B’ monotherapy was converted to ‘C’ monotherapy in the 3rd regimen. o ‘A’ was re-initiated as the first filled TIRF of the new switched 4th regimen; conversion was considered against ‘C’. o ‘A’ was discontinued from the 4th regimen, and ‘D’ remained to be the 5th regimen. o ‘D’ monotherapy was converted to ‘E’ monotherapy in the 6th regimen. Controlled Document Copyright© United BioSource Corporation All Rights Reserved Page 13 of 18 FDA_4723 Conversion between TIRF Medicines Version 1.0 Analysis Protocol 09 February 2017 APPENDIX II. TIRF PRODUCT LABELS LABEL CONVERSION INFORMATION PRODUCT CONVERSION SWITCHES BETWEEN TIRF PRODUCTS 0 Begin titration of all patients with an initial dose of Abstral of 100 meg. 0 Due to differences in the pharrnacokinetic properties and individual variability, even patients switching from other fentanyl containing products to ABSTRAL must start with the 100 dose. However, for patients converting from Actiq, see Table 1: Initial Dosing Recommendations for Patients on ACTIQ. Abstral is not equivalent on a per meg basis with all other fentanyl products, therefore, do not switch patients on a meg per basis from any other fentanyl product. Conversion from Actiq The initial dose of Abstral is always 100 with the only exception being patients already using Actiq. a. For patients being converted from Actiq, preseribers must use the Initial Dosing Recommendations for Patients on Actiq. See Table for initial dosing recommendations. Patients must be instructed to stop the use of Actiq and dispose of any remaining units. b. For patients converting from Actiq doses of 200 and 400 meg, initiate titration with 100 and 200 of Abstral, respectively and proceed using multiples of this strength. c. For patients converting from Actiq doses of 600 and 800 meg, initiate titration with 200 and 200 Abstral, respectively and proceed using multiples of this strength. (1. For patients converting from Actiq doses of 1200 and 1600 mcg, initiate titration with 200 and 400 Abstral, respectively and proceed using multiples of this strength. Table 1: Initial Dosing Recommendations for Patients on Actiq Current Actiq Dose (meg) Initial Abstral Dose (meg) 200 100 400 200 600 200 800 200 1200 200 1600 400 Controlled Document Copyright"D United BioSource Corporation All Rights Reserved Page 14 of 18 Conversion between TIRF Medicines Version 1.0 Analysis Protocol 09 February 2017 LABEL CONVERSION INFORMATION PRODUCT CONVERSION SWITCHES BETWEEN TIRF PRODUCTS 0 When prescribing, DO NOT convert a patient to Actiq from any other fentanyl product on a per meg basis as Actiq and other fentanyl products are not equivalent on a per meg basis. 0 There are no safe conversion directions available for patients on any other fentanyl products. (This includes oral, transdermal, or parenteral formulations of fentanyl). Therefore, for opioid tolerant patients, the initial dose of Actiq should always be 200 meg. Each patient should be individually titrated to provide adequate analgesia while minimizing side effects. Fentora is not bioequivalent with other fentanyl products. Do not convert patients on a meg per meg basis from other fentanyl products. 0 There are no conversion directions available for patients on any other fentanyl products other than Actiq. (This includes oral, transdermal, or parenteral formulations of fentanyl). 0 All patients should be titrated from the 100 dose. Conversion from Actiq The initial dose of Fentora is always 100 with the only exception being patients already using Actiq. a. For patients being converted from Actiq, prescribers must use the Initial Dosing Recommendations for Patient on Actiq table below (Table 1). The doses of Fentora in this table are starting doses and not intended to represent equianalgesic doses to Actiq. Patients must be instructed to stop the use of Actiq and dispose any remaining units. Table 1: Initial Dosing Recommendations for Patients on Actiq Current Actiq Dose (meg) Initial Fentora Dose (mcg)* 200 100 tablet 400 100 meg tablet 600 200 tablet 800 200 tablet 1200 2 200 meg tablets 1600 2 200 tablets From this initial dose, titrate patient to effective dose. Controlled Document Copyright"D United BioSource Corporation All Rights Reserved Page 15 of 18 Conversion between TIRF Medicines Version 1.0 Analysis Protocol 09 February 2017 LABEL CONVERSION INFORMATION PRODUCT CONVERSION SWITCHES BETWEEN TIRF PRODUCTS b. For patients converting from Actiq doses equal to or greater than 600 meg, titration should be initiated with the 200 Fentora tablet and should proceed using multiples of this tablet strength. All Other Patients 0 The initial dose of Fentora is 100 meg. AZ AND Lazanda is NOT equivalent to other fentanyl products used to treat breakthrough pain on a per meg basis. 0 When prescribing Lazanda to a patient, DO NOT convert from other fentanyl products. 0 Directions for safely converting patients to Lazanda from other fentanyl products are not currently available. (This includes oral, transdermal, or parenteral formulations of fentanyl). Therefore, for opioid-tolerant patients starting treatment for breakthrough pain, the initial dose of Lazanda is 100 meg. Individually titrate each patient?s dose to provide adequate analgesia while minimizing side effects. 0 Begin treatment of all patients (including those switching from another fentanyl product) using ONE 100 meg spray of Lazanda (l spray in one nostril). ORAL 0 When prescribing, DO NOT convert a patient to oral transmueosal fentanyl citrate from any other TRANSMUCOS AL fentanyl product on a per meg basis as oral transmueosal fentanyl citrate and other fentanyl FENTANYL products are not equivalent on a per meg basis. CITRATE 0 There are no safe conversion directions available for patients on any other fentanyl products. (This includes oral, transdermal, or parenteral formulations of fentanyl). Therefore, for opioid tolerant patients, the initial dose of oral transmueosal fentanyl should always be 200 mcg. Each patient should be individually titrated to provide adequate analgesia while minimizing side effects. Controlled Document Copyright't' United BioSource Corporation All Rights Reserved Page 16 of 18 Version 1.0 Conversion between TIRF Medicines 09 February 2017 Analysis Protocol LABEL CONVERSION INFORMATION PRODUCT CONVERSION SWITCHES BETWEEN TIRF PRODUCTS 0 SUBSYS is not bioequivalcnt with other fentanyl products. Do not convert patients on a per meg basis from other fentanyl products. 0 There are no conversion directions available for patients on any other fentanyl products other than Actiq. (This includes oral, transderrnal, or parenteral formulations of fentanyl). Conversion from Actiq The initial dose of SUBSYS is always 100 with the only exception being patients already using Actiq. a. For patients being converted from Actiq, prescribers must use the Initial Dosing Recommendations for Patient on Actiq table below (Table 1). Patients must be instructed to stop the use of Actiq and dispose any remaining units. Table 1: Initial Dosing Recommendations for Patients on Actiq Current Actiq Dose Initial SUBSYS Dose (meg) (mg) 200 100 spray 400 100 spray 600 200 spray 800 200 spray 1200 400 spray 1600 400 spray b. For patients converting from Actiq doses 400 meg and below, titration should be initiated with 100 SUBSYS and should proceed using multiples of this strength. 0. For patients converting from Aetiq doses of 600 meg and 800 meg, titration should be initiated with 200 SUBSYS and should proceed using multiples of this strength. d. For patients converting from Aetiq doses of 1200 meg and 1600 meg, titration should be initiated with 400 meg SUBSYS and should proceed using multiples of this strength. Controlled Document Copyright? United BioSource Corporation All Rights Reserved Page 17 of 18 Conversion between TIRF Medicines Version 1.0 Analysis Protocol 09 February 2017 LABEL CONVERSION INFORMATION PRODUCT CONVERSION SWITCHES BETWEEN TIRF PRODUCTS All Other Patients 0 Individually titratc SUBSYS to a dose that provides adequate analgesia and minimizes adverse reactions. 0 Initiate treatment with SUBSYS for all patients (including those switching from another fcntanyl product) using ONE 100 spray sublingually. 0 When prescribing, DO NOT patients on a per basis from any other oral transmucosal fcntanyl product to SUBSYS. Controlled Document opyright'r? United BioSource orpomtion All Rights Reserved Page 18 of 18 60-Month FDA REMS Supplemental Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies 4.2 Page 17 of 19 Patient KAB Report FDA_4729 Patient/Caregiver KAB Assessment Report Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Title: Final 10 February 2017 Page 1 of 56 Transmucosal Immediate Release Fentanyl (TIRF) REMS Assessment Quantitative Testing of Patient/Caregiver Knowledge, Attitudes, and Behavior (KAB) about TIRF Products Safety and Use Information Document Number: Wave 5, 60-Month FDA REMS Assessment Report Version 1.0 Survey Time Period: 26 September 2016 to 21 November 2016 Product Name: Transmucosal Immediate Release Fentanyl Sponsor: TIRF REMS Industry Group (TRIG) of Companies: Actavis Laboratories FL, Inc. BioDelivery Sciences International, Inc. (BDSI) Cephalon, Inc. (a wholly-owned subsidiary of Teva Pharmaceutical Industries, Ltd.) Depomed, Inc. Insys Therapeutics, Inc. Mallinckrodt Pharmaceuticals Mylan, Inc. Par Pharmaceutical, Inc. Sentynl Therapeutics, Inc. Date: 10 February 2017 Confidentiality Statement The information contained herein is confidential and the proprietary property of the TRIG of Companies and its affiliates, and any unauthorized use or disclosure of such information without the prior written authorization of the TRIG is expressly prohibited. FDA_4730 Patient/Caregiver KAB Assessment Report Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies TABLE OF CONTENTS Final 10 February 2017 Page 2 of 56 PAGE TABLE OF CONTENTS......................................................................................................... 2 LIST OF IN-TEXT TABLES .................................................................................................. 3 LIST OF APPENDICES .......................................................................................................... 4 LIST OF ABBREVIATIONS .................................................................................................. 5 EXECUTIVE SUMMARY ..................................................................................................... 6 1. PATIENT/CAREGIVER SURVEY BACKGROUND ..................................... 7 1.1 Changes to the KAB Survey for Patients/Caregivers Based on FDA Feedback............................................................................................................. 8 2. PATIENT/CAREGIVER SURVEY OBJECTIVES .......................................... 9 3. SURVEY METHODOLOGY .......................................................................... 10 3.1 Survey Sample.................................................................................................. 10 3.1.1 Eligibility .......................................................................................................... 10 3.1.2 Recruitment ...................................................................................................... 10 3.2 Questions and Statements on Key Risk Messages ........................................... 11 3.2.1 Key Risk Message 1 ......................................................................................... 11 3.2.2 Key Risk Message 2 ......................................................................................... 12 3.2.3 Key Risk Message 3 ......................................................................................... 12 3.2.4 Key Risk Message 4 ......................................................................................... 13 3.2.5 Key Risk Message 5 ......................................................................................... 13 3.2.6 Key Risk Message 6 ......................................................................................... 14 3.3 Additional Questions ........................................................................................ 14 4. STATISTICAL METHODS ............................................................................ 14 4.1 Study Population .............................................................................................. 14 4.1.1 All Respondents ............................................................................................... 14 4.1.2 Completed Surveys (Primary Population)........................................................ 14 4.1.3 General Population ........................................................................................... 15 4.2 Primary Analyses ............................................................................................. 15 4.3 Secondary Analyses ......................................................................................... 15 FDA_4731 Patient/Caregiver KAB Assessment Report Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Final 10 February 2017 Page 3 of 56 4.4 Patient Report of a Potential Adverse Event, Product Complaint, or Medical Information Request during the Survey ............................................. 16 5. RESULTS......................................................................................................... 16 5.1 Survey Participants ........................................................................................... 16 5.1.1 Survey Participant Administration Results ...................................................... 16 5.1.2 Description of Eligible Patients/Caregivers who Completed the Survey......... 21 5.1.2.1 Comparison of Survey Respondents to the General Population of TIRF Users ................................................................................................................. 24 5.1.3 TIRF Medicines Education Materials .............................................................. 27 5.1.4 Patient-Prescriber Agreement Form ................................................................. 31 5.2 Key Risk Messages .......................................................................................... 32 5.2.1 Key Risk Message 1 ......................................................................................... 32 5.2.2 Key Risk Message 2 ......................................................................................... 33 5.2.3 Key Risk Message 3 ......................................................................................... 34 5.2.4 Key Risk Message 4 ......................................................................................... 38 5.2.5 Key Risk Message 5 ......................................................................................... 39 5.2.6 Key Risk Message 6 ......................................................................................... 41 5.2.7 Key Risk Message Average Knowledge Scores .............................................. 42 5.2.8 Other Survey Questions ................................................................................... 43 5.2.8.1 Additional Questions about TIRF Medicines Safety ....................................... 43 5.3 Spontaneous Reporting of Adverse Events, Product Complaints, or Medical Information Requests ......................................................................... 45 6. DISCUSSION AND CONCLUSIONS ............................................................ 45 LIST OF IN-TEXT TABLES Table 1. Survey Administration Statistics.................................................................... 17 Table 2. Survey Participant Eligibility Results - All Respondents .............................. 18 Table 3. Time to Complete Survey - Completed Surveys ........................................... 21 Table 4. Description of Eligible Patients/Caregivers - Completed Surveys ................ 22 Table 5. Comparison of Survey Respondents to General Population of TIRF Users .............................................................................................................. 25 Table 6. Responses to Questions about TIRF Educational Materials - Completed Surveys........................................................................................................... 28 FDA_4732 Patient/Caregiver KAB Assessment Report Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Final 10 February 2017 Page 4 of 56 Table 7. Responses to Questions about the Patient-Prescriber Agreement Form Completed Surveys ........................................................................................ 31 Table 8. Primary Analysis of Responses to Questions Linked to Key Risk Message #1 - Completed Surveys .................................................................. 33 Table 9. Primary Analysis of Responses to Questions Linked to Key Risk Message #2 - Completed Surveys .................................................................. 33 Table 10. Secondary Analysis of Responses to Questions Linked to Key Risk Message #2 - Completed Surveys .................................................................. 34 Table 11. Primary Analysis of Responses to Questions Linked to Key Risk Message #3 - Completed Surveys .................................................................. 35 Table 12. Secondary Analysis of Responses to Questions Linked to Key Risk Message #3 - Completed Surveys .................................................................. 37 Table 13. Responses to Questions Linked to Key Risk Message #3 by Modality to Complete Survey - Completed Surveys (Questions/Items with Apparent Trends) ........................................................................................................... 38 Table 14. Primary Analysis of Responses to Questions Linked to Key Risk Message #4 - Completed Surveys .................................................................. 38 Table 15. Primary Analysis of Responses to Questions Linked to Key Risk Message #5 - Completed Surveys .................................................................. 39 Table 16. Secondary Analysis of Responses to Questions Linked to Key Risk Message #5 - Completed Surveys .................................................................. 40 Table 17. Primary Analysis of Responses to Questions Linked to Key Risk Message #6 - Completed Surveys .................................................................. 41 Table 18. Secondary Analysis of Responses to Questions Linked to Key Risk Message #6 - Completed Surveys .................................................................. 42 Table 19. Average Knowledge Scores - Completed Surveys ........................................ 43 Table 20. Responses to Additional Questions about the Safe Use of TIRF Medicines- Completed Surveys ..................................................................... 44 Table 21. Correct Response Rate Over Time ................................................................ 48 LIST OF APPENDICES Appendix A Patient Survey Protocol Track Change Document: Comparison of month Survey to 60-month Survey ........................................................... 55 Appendix B Survey Tables................................................................................................. 56 FDA_4733 Patient/Caregiver KAB Assessment Report Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Final 10 February 2017 Page 5 of 56 LIST OF ABBREVIATIONS BDSI BioDelivery Sciences International, Inc. CI Confidence Interval ETASU Elements to Assure Safe Use FDA Food and Drug Administration HCP Healthcare Professional KAB Knowledge, Attitudes, and Behavior KRM Key Risk Message N/A Not Applicable or Not Available PPAF Patient-Prescriber Agreement Form REMS Risk Evaluation and Mitigation Strategy SCC Survey Coordinating Center SD Standard Deviation TIRF Transmucosal Immediate Release Fentanyl TIRF medicines Transmucosal Immediate Release Fentanyl products TIRF REMS Access program REMS program for TIRF medicines TRIG TIRF REMS Industry Group UBC United BioSource Corporation US United States USPS United States Postal Service FDA_4734 Patient/Caregiver KAB Assessment Report Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Final 10 February 2017 Page 6 of 56 EXECUTIVE SUMMARY The 60-month Knowledge, Attitudes, and Behavior (KAB) survey for patients receiving Transmucosal Immediate Release Fentanyl (TIRF) medicines or their caregivers was conducted as part of the 60-Month TIRF Risk Evaluation and Mitigation Strategy (REMS) Access program assessment. On 21 July 2016, the United States (US) Food and Drug Administration (FDA) provided feedback on the patient survey. After careful review of the requested changes, the TIRF REMS Industry Group (TRIG) notified FDA that in order to incorporate all changes, an extension for report submission would be required. As proposed by FDA on 29 July 2016 and agreed to by the TRIG on 01 August 2016, the 60-month KAB survey results were planned for a separate submission from the overall assessment report on or before 17 February 2017. The 60-month KAB survey for patients or their caregivers launched on 26 September 2016 and closed on 21 November 2016. Patients who were passively enrolled in the TIRF REMS Access program and had received a TIRF medicine in the previous 4 months (120 days) were invited to participate. From the total of 394 patients/caregivers who accessed the survey, 321 (81.5%) respondents met eligibility criteria, and of those who met eligibility criteria, 310 (96.6%) completed the survey, exceeding the target of 300 completed surveys. On 21 July 2016, FDA provided feedback on the KAB survey for patients/caregivers. Changes to the 60-month KAB Survey for Patients/Caregivers based on FDA feedback included the addition of 6 survey questions and the revision of 4 survey questions. The change to Question 11 (TIRF medicines should only be taken by patients who are opioid tolerant), and the addition of Question 18 Items 18a through 18c (Please answer True, False, or I don’t know for each statement about the TIRF medicine that was most recently prescribed for you) are discussed with the key risk message results below. For questions not included as part of key risk messages, new Questions 37 through 41 showed most respondents indicated someone in the doctor’s office told them not to share the TIRF medicines with anyone else, counseled them that accidental exposure to TIRF medicines by a child may be fatal, told them to keep TIRF medicines out of reach of children to prevent accidental exposure, and told them about proper disposal of any unused or partially used TIRF medicines; and over half indicated someone in the doctor’s office asked them about the presence of children in their home. In addition, Questions 9, 15, and 16 that ask patients about prescriber activities and were revised to allow pharmacists as a potential source of information, showed most respondents indicated someone in the doctor’s office discussed the risks and possible side effects of the prescribed TIRF medicine, that someone in the doctor’s office explained how to use the prescribed TIRF medicines, and someone in the doctor’s office advised them on the proper storage of the prescribed TIRF medicines. The overall knowledge score of 84.8 (95% confidence interval [CI]: 83.5 86.0) for the survey indicates most respondents demonstrated understanding of the key risk messages. The average knowledge score for each of the key risk messages was greater than 88 for 5 of the 6 key risk messages and was 70.3 for Key Risk Message 3 (TIRF medicines should be taken exactly as prescribed by the healthcare provider). The lower average knowledge score for Key Risk Message 3 reflected the 3 items (described below) with correct response rates <65%. FDA_4735 Patient/Caregiver KAB Assessment Report Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Final 10 February 2017 Page 7 of 56 Of the 22 questions/items included as part of key risk messages, 16 items had a correct response rate >80%, and 3 items had a correct response rate between 65% and 80%. The remaining 3 items within Key Risk Message 3 had a correct response rate that fell below the desired level of understanding of 65%. These 3 items included two items from Question 10: For which of the following conditions should you use a TIRF medicine? Correct response rate for Item 10d: Pain after surgery. (Correct Response: No) was 64.2%, and correct response rate for Item 10e: Longlasting pain not from cancer, like arthritis joint pain (Correct Response: No); was 39.0%. In addition, correct response rate for Item 12b (a patient must stop taking their TIRF medicine if they stop taking their around-the-clock opioid pain medicine) was 39.7%. These items also had a low correct response rate across all patient/caregiver KAB surveys conducted (annual waves from the 12-month through the 60-month survey). When comparing correct response rates from the 12-month KAB survey through the 60-month KAB survey, knowledge and understanding of the key risk messages has generally remained stable over time, including the items mentioned above that fell below the desired level of understanding of 65% for this wave and have had lower correct response rates for all survey waves. Question 11 had a notably improved correct response rate (nearly 90%) once the question was revised back to the original 36-month survey question for this survey. In addition, over 92% of respondents correctly responded that a side effect of TIRF medicines is the chance of abuse or addiction, that TIRF medicines can be misused by people who abuse medicines or street drugs, and TIRF medicines should be kept in a safe place (new Question 18). 1. PATIENT/CAREGIVER SURVEY BACKGROUND Transmucosal Immediate Release Fentanyl (TIRF) medicines include the class of immediate release opioid analgesics indicated only for the management of breakthrough pain in cancer patients 18 years of age or older (16 or older for Actiq® [fentanyl citrate oral transmucosal lozenge] and equivalent generics) who are receiving and already tolerant to opioid therapy for their underlying persistent cancer pain. The FDA has determined that a shared system REMS is required to mitigate the risks of misuse, abuse, addiction, overdose, and serious complications due to medication errors with the use of TIRF medicines. The TIRF REMS Access program was approved by the FDA on 28 December 2011. This report describes the results from the patient/caregiver surveys conducted for the 60-month TIRF REMS Access program assessment, and reflects the REMS reporting period of 29 October 2015 to 28 October 2016. The 60-month KAB survey launched on 26 September 2016 and closed on 21 November2016. The TIRF medicines include Abstral®, Actiq®, Fentora®, Lazanda®, Subsys®, and (where applicable) their respective generic equivalents. The TRIG includes Actavis Laboratories FL, Inc.; BioDelivery Sciences International, Inc. (BDSI); Cephalon, Inc. (a wholly-owned subsidiary of Teva Pharmaceutical Industries, Ltd.); Depomed, Inc.; Insys Therapeutics, Inc.; Mallinckrodt Pharmaceuticals; Mylan, Inc.; Par Pharmaceutical, Inc.; and Sentynl Therapeutics, Inc. One company joined the TRIG during the reporting period: Sentynl Therapeutics, Inc. replaced Galena Biopharma, Inc. on 09 January 2016. FDA_4736 Patient/Caregiver KAB Assessment Report Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Final 10 February 2017 Page 8 of 56 The TIRF REMS Access program consists of a Medication Guide, Elements to Assure Safe Use (ETASU), an Implementation System, and a Timetable for Submission of Assessments. The goals of the TIRF REMS Access program are to mitigate the risks of misuse, abuse, addiction, overdose, and serious complications due to medication errors by the following: 1. Prescribing and dispensing TIRF medicines only to appropriate patients, which includes use only in opioid-tolerant patients. 2. Preventing inappropriate conversion between TIRF medicines. 3. Preventing accidental exposure to children and others for whom it was not prescribed. 4. Educating prescribers, pharmacists, and patients on the potential for misuse, abuse, addiction, and overdose of TIRF medicines. An important component of the TIRF REMS Access program assessment is the conduct of quantitative evaluation surveys to assess patients’/caregivers’ understanding and knowledge of the safe use of TIRF medicines as described in the TIRF REMS Access program educational materials. Administration of the surveys conducted among patients/caregivers enrolled in the TIRF REMS Access program is described in the protocol (See Appendix A). Note: Protocol and Survey question revisions from the 48-month assessment report are identified as tracked changes. Data from the surveys, together with other REMS evaluation metrics, will be used to determine whether changes need to be made to the REMS processes or educational materials to make them more effective in achieving the goals of the REMS. 1.1 Changes to the KAB Survey for Patients/Caregivers Based on FDA Feedback On 21 July 2016, FDA provided feedback on the KAB survey for patients or their caregivers. After careful review of the requested changes, the TRIG notified FDA that in order to incorporate all changes, an extension for report submission would be required. As proposed by FDA on 29 July 2016 and agreed to by the TRIG on 01 August 2016, the 60-month KAB survey results were planned for a separate submission from the overall assessment report on or before 17 February 2017. Specific updates made to the protocol and survey included: x Addition of the following questions: o 18a (A side effect of TIRF medicines is the chance of abuse or addiction.) o 18b (TIRF medicines can be misused by people who abuse prescription medicines or street drugs.) o 18c (TIRF medicines should be kept in a safe place to prevent it from being stolen.) FDA_4737 Patient/Caregiver KAB Assessment Report Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Final 10 February 2017 Page 9 of 56 o 37 ([PATIENT] Did a doctor, nurse, or other healthcare professional in the doctor’s office ever ask you about the presence of children in your home?) o 38 ([PATIENT] Did a doctor, nurse, or other healthcare professional in the doctor’s office ever tell you not to share the TIRF medicines with anyone else?) o 39 ([PATIENT] Did a doctor, nurse, or other healthcare professional in the doctor’s office ever counsel you that accidental exposure to TIRF medicines by a child may be fatal?) o 40 ([PATIENT] Did a doctor, nurse, or other healthcare professional in the doctor’s office ever tell you to keep TIRF medicines out of reach of children to prevent accidental exposure?) o 41 ([PATIENT] Did a doctor, nurse, or other healthcare professional in the doctor’s office ever tell you about proper disposal of any unused or partially used TIRF medicines?) x Revisions to Questions 9, 15, and 16 which ask patients about prescriber activities to allow pharmacists as a potential source of information. The 48-month survey questions that began with “Did the doctor, nurse, or other healthcare professional in the doctor’s office ever…” were revised for the 60-month survey to “Did a doctor, nurse, or other healthcare professional in the doctor’s office ever…”. x Update to Question 11 under Key Risk Message 2 to the original 36-month survey question “TIRF medicines should only be taken by patients who are opioid tolerant” instead of the revised 48-month survey question of “TIRF medicines should only be taken by cancer patients who are opioid tolerant”. All of the above requested changes were incorporated prior to survey launch on 26 September 2016. 2. PATIENT/CAREGIVER SURVEY OBJECTIVES The evaluation survey used a questionnaire to document the level of knowledge and assess the attitudes and behavior of patients and caregivers of patients regarding the following key information and risk messages communicated through the REMS: 1. TIRF medicines can cause life-threatening breathing problems that can lead to death. 2. Patients should not take TIRF medicines if they are not opioid tolerant. 3. TIRF medicines should be taken exactly as prescribed by the healthcare provider. 4. Patients should not switch from one TIRF medicine to another medicine that contains fentanyl without talking to a healthcare provider. FDA_4738 Patient/Caregiver KAB Assessment Report Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Final 10 February 2017 Page 10 of 56 5. Patients should not give TIRF medicines to anyone else even if they have the same symptoms. 6. TIRF medicines should be stored in a safe place away from children and properly disposed. 3. SURVEY METHODOLOGY This section summarizes the survey design and the questions developed to test patient understanding of the key risk messages of the REMS. Full details of the survey design are in the protocol, provided in Appendix A. 3.1 Survey Sample A sample of 300 patients or caregivers of patients who are being treated with a TIRF medicine is proposed for each survey wave. The survey sample size was determined based on both practical and statistical considerations. The survey was written to reflect wording for both methods of survey administration: Internet-based and telephone. 3.1.1 Eligibility This survey was conducted on patients identified from the TIRF REMS Access program database. All patients 18 years or older who filled 1 or more prescriptions for at least 1 of the TIRF medicines during the 120 days prior to 26 September 2016 were eligible to participate; caregivers (age 18 years or older) of eligible patients who were unable to take the survey for themselves were eligible to participate. Respondents or respondents with immediate family members who had ever worked for any of the TRIG companies, RelayHealth, McKesson Specialty Care Solutions, United BioSource Corporation (UBC), or the FDA were not eligible to participate, nor were any respondents who participated in the previous waves of the survey (annual waves from the 12-month TIRF REMS Access program assessment through the 48month TIRF REMS Access program assessment). 3.1.2 Recruitment Patients who were passively enrolled in the TIRF REMS Access program as of 02 September 2016 and had received a TIRF medicine in the previous 4 months (120 days) were invited to participate via an invitation letter sent through the United States Postal Service (USPS) (see Section 5.1.1 for more details). Address verification was required on these data due to the limited data points collected on the Patient-Prescriber Agreement Form (PPAF). In order to obtain this additional information a public records database was used and those data combined with the TIRF REMS Access program data to distribute invitations to the patient population. Through use of these sources, a list of patients who had filled a prescription for a TIRF medicine within 4 months (120 days) prior to survey launch (first prescriptions and refills) was created. Full details are provided in the protocol (Appendix A). If the required number of completed surveys was not achieved within a reasonable time frame, second and third mailings to non-respondents, as well as initial invitations to new samples of FDA_4739 Patient/Caregiver KAB Assessment Report Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Final 10 February 2017 Page 11 of 56 patients , if the data were available, were sent as necessary based on the actual rate of survey accrual relative to the proximity of the target survey close date. Each letter of invitation included a unique code needed to access the survey. The code was deactivated after the respondent had initiated the survey (whether or not the survey was completed). Respondents were given the option of taking the survey by telephone via the Survey Coordinating Center (SCC) or online via a secure website. The survey was estimated to take approximately 20 minutes to complete. All respondents who completed the survey and provided their contact information were mailed a $50 gift card for participating. The mailing included a Thank You Letter, a copy of the productspecific Medication Guide, and a copy of the correct answers to the key risk message questions. 3.2 Questions and Statements on Key Risk Messages The questions and statements comprising the knowledge survey were constructed to test the patients’/caregivers’ understanding of the key risk messages of the REMS. The questions were to be answered either by selecting options from multiple-choice lists that included statements of the specific key risk messages or by choosing “Yes” or “True,” “No” or “False,” or “I don’t know” regarding statements about TIRF medicines. For statements or questions that use “True” or “Yes” versus “False” or “No” response options, the desired response for key risk messages was generally “True” or “Yes” indicating knowledge of, or behavior in accordance with, the objectives of the REMS. However, some questions were formatted to have the respondent disagree with the statement as written by providing response options of “False” or “No” to avoid having the same affirmative answer for all desired responses. REMS statements, corresponding questions, and desired responses covering the key risk messages are identified below and can be found in the complete survey questionnaire (Appendix A). For better readability, only patient questions are presented in the key risk messages tables below. The same questions, with modified wording as appropriate for caregivers, are presented in the survey protocol (Appendix A). 3.2.1 Key Risk Message 1 Key Risk Message 1 refers to the patient’s/caregiver’s knowledge that TIRF medicines can cause life-threatening breathing problems. Key Risk Message 1: TIRF medicines can cause life-threatening breathing problems that can lead to death. Question No. Question Desired Response 13 Please answer True, False, or I don’t know for each statement about the TIRF medicine that was most recently prescribed for you. 13d TIRF medicines can cause life-threatening breathing problems that can lead to death. True FDA_4740 Patient/Caregiver KAB Assessment Report Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies 3.2.2 Final 10 February 2017 Page 12 of 56 Key Risk Message 2 Key Risk Message 2 refers to the patient’s/caregiver’s awareness that patients who are not opioid tolerant should not take TIRF medicines. Key Risk Message 2: Patients should not take TIRF medicines if they are not opioid tolerant. Question Question No. Desired Response Please answer True, False, or I don’t know for the following statement: 11 TIRF medicines should only be taken by patients who are opioid tolerant. 12 Please answer True, False, or I don’t know for each of the following statements. 12a Opioid tolerant means that a patient is already taking other opioid pain medicines around-the-clock and their body is used to these medicines. 3.2.3 True True Key Risk Message 3 Key Risk Message 3 refers to the patient’s/caregiver’s knowledge that TIRF medicines should be taken exactly as prescribed by the healthcare provider. Key Risk Message 3: TIRF medicines should be taken exactly as prescribed by the healthcare provider. Question Question No. Desired Response 10 For which of the following conditions should you use a TIRF medicine? Please answer Yes, No, or I don’t know for each statement. 10a Headache or migraine pain No 10b Breakthrough pain from cancer Yes 10c Dental pain No 10d Pain after surgery No 10e Long-lasting pain not from cancer, like arthritis joint pain No 12 Please answer True, False, or I don’t know for each of the following statements. 12b A patient must stop taking their TIRF medicine if they stop taking their around-the-clock opioid pain medicine. 13/17 13b True Please answer True, False, or I don’t know for each statement about the TIRF medicine that was most recently prescribed for you. It is OK for patients to take TIRF medicines for headache pain. False FDA_4741 Patient/Caregiver KAB Assessment Report Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Final 10 February 2017 Page 13 of 56 13c TIRF medicines should be taken exactly as prescribed by the doctor. True 17b It is OK to take TIRF medicines for short-term pain that will go away in a few days. False 3.2.4 Key Risk Message 4 Key Risk Message 4 refers to the patient’s/caregiver’s knowledge of the interchangeability of TIRF medicines. Key Risk Message 4: Patients should not switch from one TIRF medicine to another medicine that contains fentanyl without talking to a healthcare provider. Question Question No. Desired Response 12 Please answer True, False, or I don’t know for each of the following statements. 12c It is safe to switch to another medicine that contains fentanyl without talking to a healthcare provider first. 3.2.5 False Key Risk Message 5 Key Risk Message 5 refers to the patient’s/caregiver’s awareness that TIRF medicines should not be given to anyone else even if they have the same symptoms. Key Risk Message 5: Patients should never give TIRF medicines to anyone else even if they have the same symptoms. Question No. Question Desired response 12 Please answer True, False, or I don’t know for each of the following statements. 12d A patient may give TIRF medicines to another person if they have the same symptoms as the patient. 17/18 False Please answer True, False, or I don’t know for each statement about the TIRF medicine that was most recently prescribed for you. 17a Selling or giving away TIRF medicines is against the law. True 18a A side effect of TIRF medicines is the chance of abuse or addiction. True 18b TIRF medicines can be misused by people who abuse prescription medicines or street drugs. True 18c TIRF medicines should be kept in a safe place to prevent it from being stolen. True FDA_4742 Patient/Caregiver KAB Assessment Report Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies 3.2.6 Final 10 February 2017 Page 14 of 56 Key Risk Message 6 Key Risk Message 6 refers to the patient’s/caregiver’s knowledge that TIRF medicines should be stored in a safe place away from children and properly disposed. Key Risk Message 6: TIRF medicines should be stored in a safe place away from children and properly disposed. Question No. 13/17 Question Desired response Please answer True, False, or I don’t know for each statement about the TIRF medicine that was most recently prescribed for you. 13a TIRF medicines should be stored in a safe place out of the reach of children. 14 What should you do if an adult who has not been prescribed a TIRF medicine takes a TIRF medicine? (Please select one.) 17c TIRF medicines must be disposed of as described in the specific product’s Medication Guide. True 17e A TIRF medicine can cause an overdose and death in any child who takes it. True 3.3 True Get emergency help right away. Additional Questions Additional questions in the survey include inclusion/exclusion questions to confirm respondent eligibility; questions on knowledge of safe use of TIRF medicines; questions about receipt, reading and understanding the Medication Guide; questions about review and signing of the PPAF; and questions to collect demographic information. 4. STATISTICAL METHODS 4.1 Study Population 4.1.1 All Respondents The All Respondents population consisted of respondents that accessed the survey using a unique code. These respondents were used as the denominator for percentages in survey administration statistics unless otherwise specified. 4.1.2 Completed Surveys (Primary Population) The primary population for analysis was all eligible respondents who completed the survey. Eligible respondents were defined as those respondents who answered Yes to Question 1 (agree to take part in survey), Yes to Question 2 (filled a prescription for a TIRF medicine in the last 4 months) or Yes to Question 3 (caregiver for someone who had filled a prescription for a TIRF medicine in the last 4 months), and No to Question 5 (participated in past survey), and No to Question 8 (worked for a TRIG company, McKesson Specialty Care Solutions, RelayHealth, FDA_4743 Patient/Caregiver KAB Assessment Report Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Final 10 February 2017 Page 15 of 56 UBC, or FDA). Respondents also must have selected an age group of age for Question 6 (patient or caregiver). A survey was considered “completed” when an eligible patient/caregiver answered all relevant questions. 4.1.3 General Population The general population consisted of all patients who received a prescription for a TIRF medicine as shown in IMS Health data (IMS data). This population was used to compare the population represented in the survey to the general population to determine whether those completing the survey were representative of the patient population. It was assumed that the IMS data covered the majority of patients receiving TIRF medicines in the outpatient setting. The analysis included calculation of p-values by a chi-square test. 4.2 Primary Analyses Primary analyses were performed for all key risk messages. The primary analysis for a key risk message evaluated the number and percentage of correct responses for each individual question/item included in the key risk message. Confidence intervals (95% CI) were calculated using the exact binomial method around the percentage of correct responses. Primary analyses were then stratified by questions/characteristics of interest: 1) Those who indicated they both received the Medication Guide and read most of it versus those who responded they did not receive, did not have access to, or did not read the Medication Guide (Questions 19, 24, and 25). 2) Those who indicated they understood all or most of the Medication Guide versus those who understood some of it versus those understood none or did not know if they understood versus those who did not know whether they received or read the Medication Guide (Question 26). 3) Whether the survey was completed via the Internet or telephone. 4) Highest level of education (Question 43). 5) Age group of respondent (Question 6). Stratified analyses were conducted on all completed surveys. 4.3 Secondary Analyses As an indicator of the overall level of comprehension of the entire key risk message, descriptive analyses of the number and percentage of responders who answered various proportions of the key risk message questions/items correctly are presented (i.e., the proportion who answered 1 question/item in the key risk message correctly, those who answered 2 questions/items correctly, those who answered 3 questions/items correctly, etc.). A knowledge score was computed for each key risk message (KRM) and overall. The score was defined as the ratio of the number of correct responses to all KRM questions to the total number of possible correct responses to all KRM questions. The average knowledge score was calculated FDA_4744 Patient/Caregiver KAB Assessment Report Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Final 10 February 2017 Page 16 of 56 as the mean of the score across all completed surveys; 95% CIs were calculated based on the normal distribution function. 4.4 Patient Report of a Potential Adverse Event, Product Complaint, or Medical Information Request during the Survey A patient or caregiver may have reported a potential adverse event or other event experienced by a patient while taking a TIRF product either in free text fields while taking the online survey or while in conversation with the SCC Associate. If an event was mentioned to the SCC Associate, the Associate documented the event or complaint, the verbatim response, and the respondent’s contact information, if provided. The respondent was also informed that a representative from the appropriate TIRF medicine sponsor might contact him/her to obtain additional information about the event. The Internet surveys were monitored for any comments recorded in the free text field. Information on all reports (Internet or telephone) that constituted an adverse event or other event was forwarded to the appropriate TIRF medicine sponsor for processing within 1 business day of awareness of the event as outlined in the Escalating Adverse Events, Product Complaints, and Medical Information Requests Identified During Execution of the Knowledge, Attitudes, and Behavior Survey Project Specific Procedure. 5. RESULTS Unless otherwise indicated, data tables contain the question presented to the patients. Analyses were summarized by overall population, and not by type of respondent (patient vs. caregiver) since only 5 caregivers participated in the survey. Results of the patient’s/caregiver’s responses to questions in the KAB survey are summarized in this section; the full set of summary tables and listings are provided in Appendix B. 5.1 Survey Participants 5.1.1 Survey Participant Administration Results Survey recruitment was performed using the names obtained through the TIRF REMS Access program database (See Section 3.1 for survey methodology details). Based on the number of prescriptions filled or refilled during the 120 days prior to survey implementation (26 September 2016), the TIRF REMS Access program database identified 2945 potential participants. As shown in Table 1, all 2945 possible participants were sent a survey invitation letter. A total of 5397 reminder letters were sent to non-responders (some potential participants may have received more than 1 reminder letter). Successful survey recruitment through leveraging data collected by the TIRF REMS Access program (as described in Section 3.1), resulted in the patient/caregiver KAB survey closing early on 21 November 2016 once 310 surveys were collected. From the total of 394 patients/caregivers who accessed the survey, 321 (81.5%) respondents met eligibility criteria, and of those who met eligibility criteria, 310 (96.6%) completed the survey. Of the 310 respondents who completed the survey, 207 (66.8%) completed the survey online, and 103 (33.2%) completed it by telephone (Table 3). FDA_4745 Patient/Caregiver KAB Assessment Report Final 10 February 2017 Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 17 of 56 Table 1. Survey Administration Statistics Parameter, Number of invitations distributed 2945 Number of invitations remmed as undeliverable 399 Number of reminder letters distributed 5397 All Respondentsm 394 (15.5) Eligible Respondentsm 321 (81.5) Completed surveym 310 (96.6) Did not complete the surveym (3.4) Respondents not eligiblem? 73 (18.5) Source: Appendix B: Survey Tables, Table 1.1 Number of unique respondents who accessed the survey. Percentage is based on the number of invitations distributed excluding the number of invitations returned as undeliverable. Percentage is based on the number of all respondents. ?1 Percentage is based on the number of eligible respondents. [41 Number of respondents who did not meet eligibility criteria or did not complete eligibility questions. As shown in Table 2, of the 394 respondents who accessed the survey, 378 patients/caregivers answered at least 1 survey question, and 16 respondents did not answer any of the survey questions (discontinued the survey before answering Question 1). During the screening process it was determined 54 of the 378 respondents who answered at least 1 survey question were not eligible to participate in the survey because they either did not agree to participate in the survey (2 respondents), indicated that they had ?lled a prescription for a TIRF medicine within the last 4 months either for themselves or as a the caregiver of a patient (13 respondents), that they had participated in or did not know whether they participated in a survey about TIRF medicines before (38 respondents), or that they or an immediate family member had worked for a TRIG company, the FDA, or UBC (l respondent). In addition, 1 of the 378 respondents who answered at least 1 survey question discontinued the survey at Question 2, respondent discontinued at Question 5, and 1 respondent discontinued at Question 8. Thus, there were 321 eligible participants (patients/caregivers) (Table 2). For Question 4, respondents indicated prescriptions for Subsys? and Actiq? including generic versions were ?lled most frequently in the 4 months preceding the survey. Patient/Caregiver KAB Assessment Report Final 10 February 2017 Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 18 of 56 Table 2. Survey Participant Eligibility Results - All Respondents Patients/Caregivers Question ll Question 1: Do you agree to take part in this survey? Yes 376 (95.4) Now 2 (0.5) Discontinued 16 (4.1) Question 2: Within the last 4 months (120 days), have you filled a prescription for yourself for a transmucosal immediate release fentanyl medicine (known as medicines?)? TIRF medicines include Abstral?, Actiq?, Fentora?, Lazandac?, Subsys?, and the generic versions of any of these brands. Yes 357 (90.6) No 15 (3.8) I don't know 3 (0.8) Question not asked 2 (0.5) Discontinued 17 (4.3) generic versions of any of these brands. Question 3: Are you a caregiver for someone who has ?lled a prescription for a TIRF medicine within the last 4 months (120 days)? TIRF medicines include Abstral?, Actiq?, entora?, Lazanda?, Subsys? and the Yes 5 (1.3) Noll] 13 (3.3) I don't know? 0 (Answered "Yes" to Question 2) 357 (90.6) Question not asked 2 (0.5) Discontinued 17 (4.3) Please select all that apply.'3" Question 4: For which TIRF medicines have you ?lled a prescription in the last 4 months (120 days)? Abstral 15 (3.8) Actiq, including generic versions of Actiq 92 (23.4) Fentora 69 (17.5) Lazanda 17 (4.3) Subsys 162 (41.1) Other 23 (5.8) I don't know 7 (1.8) Question not asked 15 (3.8) Discontinued 17 (4.3) Patient/Caregiver KAB Assessment Report Final 10 February 2017 Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 19 of 56 Table 2. Survey Participant Eligibility Results - All Respondents Patients/Caregivers Question Question 5: Have you ever taken part in a survey about a TIRF medicine before? Yesm 26 (6.6) No 323 (82.0) I don't know? 12 (3.0) Question not asked 15 (3.8) Discontinued 18 (4.6) Question 6: Which of the following groups best describes your age? Under 18?] 0 l8 - 29 8 (2.0) 30 - 39 23 (5.8) 40 - 49 60 (15.2) 50 - 59 123 (31.2) 60 - 69 92 (23.4) 70 or older 17 (4.3) Prefer not to answerm 0 Question not asked [21 53 (13.5) Discontinued 18 (4.6) Question 7: Which of the following groups best describes the patient?s age?? Under (0-3) 50 - 59 (0.3) 60 - 69 3 (0.8) 70 or older 0 Prefer not to answerm 0 Question not asked [21 372 (94.4) Discontinued 17 (4.3) Patient/Caregiver KAB Assessment Report Final 10 February 2017 Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 20 of 56 Table 2. Survey Participant Eligibility Results - All Respondents Patients/Caregivers Question companies or agencies? Please select all that apply.? Question 8: Have you or any of your immediate family members ever worked for any of the following Actavis Laboratories FL, Incl? Anesta BioDelivery Services Intemational Cephalon, Inc. (a wholly-owned subsidiary of Teva Pharmaceutical Industries, Depomed, Incl? Galena Biopharma, [new Insys Therapeutics, Inc.[? Mall inckrodt Pharmaceuticals? McKesson Specialty Care Solutionsm Mylan [new Par Pharmaceuticals, [new RelayHealthm Therapeutics. Inc.[? Teva Pharmaceuticals, Ltd? United BioSource Corporationm b) FDA (Food and Drug 0 Now 321 (81.5) I don't known] 0 Question not asked 53 (13.5) Discontinued 19 (4.8) Source: Appendix B: Survey Tables, Table 12 Note: Respondents who discontinued the survey before completing all eligibility questions without being identi?ed as ineligible in any of the previous questions are counted as discontinued. Once a respondent is counted as discontinued, they will count as discontinued in all subsequent eligibility questions. ?1 Ineligible to participate in the survey. Question not asked due to termination response from a previous question or skip pattern. Question does not dictate eligibility for survey completion but is asked of all respondents who did not terminate prior to question presentation. Only caregivers are asked this question. More than one response can be selected, so percentages may not sum to 100%. Ineligible to participate in the survey if selected additionally to another response. Patient/Caregiver KAB Assessment Report Transmueosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Final 10 February 2017 Page 21 of 56 Those taking the survey online took a mean of 16.49 minutes to complete it, while those taking it by telephone took a mean of 22.44 minutes (Table 3). Table 3. Time to Complete Survey - Completed Surveys Telephone Internet Summary Statistic (minutes) 103 207 310 Mean (SD) 22.44 (6.012) 16.49 (7.987) 18.47 (7.895) Minimum 15.7 6.1 6.1 Median 21.10 14.65 17.66 Maximum 46.3 49.2 49.2 Category, 11 to <5 Minutes 0 0 5 to <10 Minutes 0 39 39 mm <15 Minutes 0 71 71 15 to <20 Minutes 39 47 86 20 to <25 Minutes 47 27 74 25 to <30 Minutes 10 8 18 30 Minutes or more 7 15 22 Source: Appendix B: Survey Tables, Table 1.3 Total number of eligible respondents completing the survey. 5.1.2 Description of Eligible Patients/Caregivers who Completed the Survey The demographic characteristics of respondents who completed the survey are shown in Table 4. The largest number of patients (116; 37.4%) were 50 to 59 years of age. More than half of the respondents (198; 63.9%) were females, and most respondents indicated their main language as English (305; 98.4%) and race as White (267; The majority of respondents (250; 80.6%) had at least some college education. Most participants (109; 35.2%) were from the South, followed by the West (95; Northeast (56; and Midwest (50; 16.1%) regions of the US. Patient/Caregiver KAB Assessment Report Final 10 February 2017 Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 22 of 56 Table 4. Description of Eligible Patients/Caregivers - Completed Surveys Patients/Caregivers Question Respondent's age based on Question 6: Which of the following groups best describes your age? 18 - 29 8 (2.6) 30 - 39 21 (6.8) 40 49 59 (19-0) 50-59 118 (38.1) 60 - 69 88 (28.4) 70 or older 16 (5.2) Patient's age based on Question 6/7: Which of the following groups best describes your age/the patient's age? Under 16 0 16 - 29 8 (2-6) 30 - 39 21 (6.8) 40 - 49 60 (19-4) 50 - 59 116 (37.4) 60 - 69 89 (28.7) 70 or older 16 (5.2) Question 42: What is your gender? Male 1 10 (35.5) Female 198 (63.9) Prefer not to answer 2 (0.6) Question 43: What is the highest level of education you have completed? Less than high school 1 (0.3) Some high school 4 (1.3) High school graduate/GED 52 (16.8) Some college 97 (31.3) Associate's degree 41 (13.2) Bachelor?s degree 72 (23.2) Master's degree 25 (8.1) Professional or Doctoral degree 15 (4.8) Prefer not to answer 3 (1.0) Patient/Caregiver KAB Assessment Report Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Final 10 February 2017 Page 23 of 56 Table 4. Description of Eligible Patients/Caregivers - Completed Surveys Patients/Caregivers Question 11 Question 44: What is the main language you speak at home? English 305 (98.4) French 0 Spanish 2 (0.6) Portuguese 0 Italian 0 German 0 Chinese 0 Japanase 0 Korean 0 Other 1 (0.3) Prefer not to answer 2 (0.6) Question 45: Are you Hispanic or Latino? Yes 16 (5.2) No 289 (93.2) Prefer not to answer 5 (1.6) Question 46: For infonnational purposes only, which of the following US. census categories best describes your race? American Indian or Alaska Native 5 (1.6) Asian (origins of Far East, Southeast Asia or the Indian subcontinent) (0.3) Black or African American 13 (4.2) Native Hawaiian or Other Paci?c Islander 1 (0.3) White 267 (86.1) Other 7 (2.3) Prefer not to answer 9 (2.9) Two or more races 7 (2.3) Patient/Caregiver KAB Assessment Report Final 10 February 2017 Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 24 of 56 Table 4. Description of Eligible Patients/Caregivers - Completed Surveys Patients/Caregivers Question Geographic Distribution (based on Question 47 - In which state do you Northeast 56 (18.1) Midwest 50 (16.1) South 109 (35.2) West 95 (30.6) Other 0 Prefer not to answer 0 Source: Appendix B: Survey Tables, Table 2 Total number of eligible respondents completing the survey. [21 US. Census Bureau, last revised Friday, 27-Jul-2001 12:59:43 EDT, Geography Division. Northeast includes CT, MA, ME, NH, NJ, NY, PA, RI, and VT. Midwest includes IA, IL, IN, KS, MI, MN, MO, ND, NE, OH, SD, and WI. South includes AL, AR, DC, DE, FL, GA, KY, LA, MD, MS, NC, OIQ SC, TN, TX, VA, and WV. West includes AK, AZ, CA, CO, HI, ID, MT, NM, NV, OR, UT, WA, and WY. Other includes Puerto Rico, Northern Mariana Islands, US Virgin Islands, American Samoa and Guam. 5.1.2.1 Comparison of Survey Respondents to the General Population of TIRF Users A comparison of patients who completed the survey to the general population of patients based on IMS data is provided in (Table 5). There were statistically significant differences (p<0.05) observed in the demographics between the patients completing the survey compared with the general population of patients on the questions for highest level of education and race; all other characteristics between groups were similar. It is important to note the sample size of the general population of patients (N mm) [or for race/ethnicity, language spoken in the home, and education level]) affects the power of the test, and therefore, may mean that even small differences between groups resulted in signi?cant p-values. For the questions that showed statistically signi?cant differences between the groups, it is important to review the proportional differences between the groups for each response within a question. For example, there were almost no differences between the patients completing the survey and the general population of patients for race where the response ?White? (86.1% vs. 89.3%) included the majority of responders in each group. The proportion of patients with completed college and graduate school were similar in the general population, but of those who participated in the survey, patients who completed ?some college? were overrepresented (44.4% versus 27.2% in the general population) and patients completed high school or less than high school were underrepresented (16.8 vs. 31.5% and 1.6 versus respectively. While the differences are statistically signi?cant, these differences should not have an impact on the primary objectives of the survey since a relevant uniform impact of demographic characteristics on the knowledge of the key risk messages could not be detected. Patient/Caregiver KAB Assessment Report Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Final 10 February 2017 Page 25 of 56 Table 5. Comparison of Survey Respondents to General Population of TIRF Users Patients Who Have Received a TIRF Patients Medicine Prescription Completing in the Last 4 Months Survey (120 days)Ill Question p-value TIRF Medicine Prescription(s) Filled in the last 4 Months (120 days)"' (01(4) Abstral 15 (4.8) Actiq, including generic versions of Actiq 71 (22.9) Fentora 56 (18.1) Lamnda 16 (5.2) Subsys 146 (47.1) Other 20 (6.5) I don't know 5 (1.6) Age Group'3 Under 16 0 l6 - 29 8 (2.6) 30 - 39 21 (6.8) 40 - 49 60 (19.4) 0.3579 50 - 59 116 (37.4) 60 - 69 89 (28.7) 70 or older 16 (5.2) Unknown Gender?I Male 110 (35.5) 0.2379 Female 198 (63.9) Prefer not to answer/Unknown 2 (0.6) Geographic Distribution's' (31(4) Northeast 56 (18.1) Midwest 50 (16.1) 0.4656 South 109 (35.2) West 95 (30.6) Otherm 0 Prefer not to answerl?] 0 Patient/Caregiver KAB Assessment Report Final 10 February 2017 Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 26 of 56 Table 5. Comparison of Survey Respondents to General Population of TIRF Users Patients Who Have Received a TIRF Patients Medicine Prescription Completing in the Last 4 Months Survey (120 days)Ill Question p-value (N?bm? Highest Level of Education Completed'7 (hm) Less than high school diploma 5 (1.6) High school 52 (16.8) Some college 138 (44.5) <.0001 Completed college 72 (23.2) Graduate school 40 (12.9) Prefer not to answer 3 (1.0) Main Language Spoken at Home'8 an?) English 305 (98.4) French 0 Spanish 2 (0.6) Portuguese 0 Italian 0 0.0914 German 0 Chinese 0 Japanese 0 Korean 0 Other 1 (0.3) Prefer not to answer 2 (0.6) Hispanic or Latino? mu) Yes 16 (5.2) 0.3242 No 289 (93.2) Prefer not to answer 5 (1.6) Race According to US Census Categories"0 (m4) American Indian or Alaska Nativem 5 (1.6) Asian (origins of Far East, Southeast Asia or 1 (0.3) the Indian subcontinent) <_0001 Black or African American 13 (4.2) Native Hawaiian or Other Paci?c Islandeim 1 (0.3) Patient/Caregiver KAB Assessment Report Final 10 February 2017 Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 27 of 56 Table 5. Comparison of Survey Respondents to General Population of TIRF Users Patients Who Have Received a TIRF Patients Medicine Prescription Completing in the Last 4 Months Survey (120 days)Ill Question p-value White 267 (86.1) Two or more racesl?] 7 (2.3) Otherm 7 (2.3) Prefer not to answer/Unknown 9 (2.9) Source: Appendix B: Survey Tables, Table 2a Note: Race/Ethnicity, language spoken in the home, and education level are only available for 1671 patients with a Consumer Pro?le. P-values are calculated by a chi-square test excluding prefer not to answer, other, and comparable categories. Not available. ?1 Based on data from IMS provided on 01Dec2016. Data covered period ofOSMay2016 to 02Sep2016. Based on Question 4; More than one type of TIRF medicine could be selected. Based on Question 6/7; Percentages for the IMS data are calculated based on the sum of available counts, minus the count for "Unknown." Based on Question 42. Based on Question 47; US. Census Bureau, last revised Friday, 27-Jul-2001 12:59:43 EDT., Geography Division. Northeast includes CT, MA, ME, NH, NJ, NY, PA, RI, and VT. Midwest includes IA, IL, IN, KS, MI, MN, MO, ND, NE, OH, SD, and WI. South includes AL, AR, DC, DE, FL, GA, KY, LA, MD, MS, NC, OK, SC, TN, TX, VA, and WV. West includes AK, AZ, CA, CO, HI, ID, MT, NM, NV, OR, UT, WA, and WY. Other includes Puerto Rico, Northern Mariana Islands, US Virgin Islands, American Samoa and Guam. Level not provided and/or collected by the IMS data. Based on Question 43; Less than high school diploma includes "Less than high school" and "Some high school"; Some college includes "Some college" and "Associate's degree"; Completed college includes "Bachelor's degree"; Graduate school includes "Master's degree" and "Professional or Doctoral degree." [81 Based on Question 44; "English" for the IMS data is calculated using the total of 1671 patients with a Consumer Pro?le, minus the sum of other available counts. In the IMS data, French, German, Italian, and Portuguese are reported as combined with a total of 10 patients, and individually as 5 patients for German, and l- 4 patients for French, Italian, and Portuguese. The count of 5 for German and the total of 5 for French, Italian, and Portuguese are used in the "English" calculation. Based on Question 45; "No" for the IMS data is calculated using the total of 1671 patients with a Consumer Pro?le, minus the count for "Yes." Based on Question 46; "White" for the IMS data is calculated by combining the individual categories of Caucasian (1379 patients) and Hispanic/Latino (113 patients) as reported in the IMS data. represents 1-4 patients. 5.1.3 TIRF Medicines Education Materials Respondents were asked about their awareness of educational materials for TIRF medicines, speci?cally the Medication Guide (Table 6), and the PPAF (Table 7). Of the 310 respondents, 288 reported they had received the Medication Guide for the TIRF medicine prescribed for them. Of these 288 respondents, 164 respondents reported receiving the Medication Patient/Caregiver KAB Assessment Report Transmueosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Final 10 February 2017 Page 28 of 56 Guide from their doctor or doctor?s of?ce, with 134 of these respondents receiving it at the ?rst appointment with the prescribing doctor. Of the 288 respondents who reported receiving the Medication Guide, most (265; 92.0%) reported receiving the Medication Guide from their pharmacy with 242 of these respondents stating they received the Medication Guide each time a prescription was ?lled. Of the 288 respondents who received the Medication Guide, most (278; 96.5%) indicated they had read the Medication Guide; of these 278 respondents 258 respondents read all of it or most of it, and 253 respondents indicated understanding all of it or most it. Over half of the respondents who received the Medication Guide (194; 67.4%) indicated someone offered to explain the Medication Guide to them; of these, 131 respondents indicated the doctor or someone in the doctor?s of?ce offered to explain the Medication Guide and 161 respondents indicated their pharmacist offered to explain the Medication Guide. Of the 194 respondents who indicated someone offered to explain the Medication Guide, 125 indicated they accepted the offer to have the Medication Guide explained to them, and of those 125 respondents, 120 indicated they understood all or most of the explanation. A total of 10 respondents indicated they had questions about the information in the Medication Guide (See Appendix B, Listing 3). Table 6. Responses to Questions about TIRF Educational Materials - Completed Surveys Patients/Caregivers Question '1 Question 19: Have you ever received a Medication Guide for the TIRF medicine that was prescribed for you? Yes 288 (92.9) No 5 (1.6) I don't know 17 (5.5) someone in the doctor's of?ce? Question 20: Did you receive the Medication Guide from the doctor who prescribed the TIRF medicine or Yes 164 (56.9) No 104 (36.1) I don't know 20 (6.9) (Answered ?No" or don't know" to Question I 9) 22 Question 21: When was the Medication Guide given to you? Please select all that apply?" At the ?rst appointment with the doctor who prescribed the TIRF medicine 134 (81.7) At the last appointment with the doctor who prescribed the TIRF medicine 26 (15.9) I don't remember 23 (14.0) (Answered ?No" or don 't lmow" to Question 19 or 20) 146 Patient/Caregiver KAB Assessment Report Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Final 10 February 2017 Page 29 of 56 Table 6. Responses to Questions about TIRF Educational Materials - Completed Surveys Patients/Caregivers Question Question 22: Did you receive the Medication Guide for the TIRF medicine from the pharmacy?m Yes 265 (92.0) No 16 (5.6) I don't know 7 (2.4) (Answered "No" or don 't know" to Question I 9) 22 Question 23: How frequently do you receive a Medication Guide for the TIRF medicine at the pharmacy?? Only with the ?rst ?lled prescription 10 (3.8) Each time a prescription is ?lled 242 (91.3) Other (please specify): 8 (3.0) I don't know 5 (1.9) (Answered "No" or don 't know" to Question 19 or 22) 45 Question 24: Did you read the Medication Guide?'2' Yes 278 (96.5) No 7 (2.4) I don't know 3 (1.0) (Answered "No" or don 't know" to Question I 9) 22 Question 25: How much did you read??2 All of it 168 (60.4) Most of it 90 (32.4) Some of it 20 (7.2) I don't know 0 (Answered "No" or don 't know" to Question I 9 or 24) 32 Question 26: How much of the Medication Guide did you understand?'2 All of it 144 (51.8) Most of it 109 (39.2) Some of it 25 (9.0) None of it 0 I don't know 0 (Answered "No" or don 't know" to Question 19 or 24) 32 Patient/Caregiver KAB Assessment Report Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Final 10 February 2017 Page 30 of 56 Table 6. Responses to Questions about TIRF Educational Materials - Completed Surveys Patients/Caregivers Question Question 27: Did someone offer to explain the Medication Guide to you?lzl Yes 194 (67.4) No 79 (27.4) I don't know 15 (5.2) (Answered ?No" or don 't Imow? to Question I 9) 22 Question 28: Who offered to explain the Medication Guide to you? Please select all that '51 The doctor or another healthcare professional in the doctor?s of?ce 131 (67.5) The pharmacist where the TIRF medicine prescription was ?lled 161 (83.0) Someone else 16 (8.2) (Answered ?No? or don 't know" to Question 19 or 27) 1 16 Question 29: Did you accept the offer to have the Medication Guide explained to you??I Yes 125 (64.4) No 66 (34.0) I don't know 3 (1.5) (Answered "No" or don ?t know" to Question I 9 or 2 7) 116 Question 30: How much of the explanation did you understand?'2 All of it 91 (72.8) Most of it 29 (232) Some of it 5 (4.0) None of it 0 I don't know 0 (Answered ?No or don't Imow? to Question 19, 27 or 29) 185 Patient/Caregiver KAB Assessment Report Final 10 February 2017 Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 31 of 56 Table 6. Responses to Questions about TIRF Educational Materials - Completed Surveys Patients/Caregivers Question 11 Question 31: Did you or do you have any questions about the information in the Medication Guide?"" Yes 10 (3.5) No 275 (95.5) I don't know 3 (1.0) (Answered ?No or don 't know? to Question 19) 22 Source: Appendix B: Survey Tables, Table 4 Total number of eligible respondents completing the survey. Percentages are calculated based on the sample presented with this question because of skip logic in the survey. More than one response can be selected, so percentages may not sum to 100%. Verbatim text for Question 23 (Other frequency of receiving a Medication Guide in the pharmacy) is presented in Listing 1. Verbatim text for Question 28 (Other type of person explaining Medication Guide) is presented in Listing 2. Verbatim text for question about the Medication Guide (Question 32) is presented in Listing 3. The responses to Questions 23, 28, and 31 are listed in Appendix B, Listing 1; Appendix B, Listing 2; and Appendix B, Listing 3 respectively. 5.1.4 Patient-Prescriber Agreement Form After respondents were asked questions regarding the key risk messages, they were asked if they had received, read, and understood the PPAF. A total of 239 respondents indicated that someone at the doctor?s of?ce had explained the PPAF to them, and of the 239 respondents, 200 respondents understood all of it and 36 understood most of it. Of the 310 respondents, 237 reported signing a PPAF, and of these, 182 respondents reported receiving a copy (Table 7). Table 7. Responses to Questions about the Patient-Prescriber Agreement Form - Completed Surveys Patients/Caregivers Question Question 33: Did the doctor or someone in the doctor?s of?ce explain the Patient-Prescriber Agreement Form to you? Yes 239 (77.1) No 32 (10.3) I don't know 39 12.6) Patient/Caregiver KAB Assessment Report Final 10 February 2017 Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 32 of 56 Table 7. Responses to Questions about the Patient-Prescriber Agreement Form - Completed Surveys Patients/Caregivers Question Question 34: How much of the explanation did you understand?'2 All of it 200 (83.7) Most ofit 36(15.l) Some of it 3 (1.3) None of it 0 I don't know 0 (Answered "No? or don't Imow" to Question 33) 71 Question 35: Did you sign a Patient-Prescriber Agreement Form? Yes 237 (76.5) No 15 (4.8) I don't know 58 (18.7) Question 36: Did the doctor or someone in the doctor?s o?'ice give you a copy of the signed Patient- Prescriber Agreement Form??2 Yes 182 (76.8) No 16 (6.8) I don't know 39 (16.5) (Answered ?No? or don't lmow" to Question 35) 73 Source: Appendix B: Survey Tables, Table 5 Total number of eligible respondents completing the survey. Percentages are calculated based on the sample presented with this question because of skip logic in the survey. 5.2 Key Risk Messages 5.2.1 Key Risk Message 1 Key Risk Message 1 states medicines can cause life-threatening breathing problems that can lead to death.? (Table 8). Most patients/caregivers (91 95% CI: 88.0 94.4) were aware of the risk of life-threatening breathing problems with TIRF medicines. Patient/Caregiver KAB Assessment Report Final 10 February 2017 Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 33 of 56 Table 8. Primary Analysis of Responses to Questions Linked to Key Risk Message #1 - Completed Surveys Patients/Caregivers Question [95% Question 13: Please answer True, False, or I don't know for each statement about the TIRF medicine that was most recently prescribed for you. 13d: TIRF medicines can cause life-threatening breathing problems that can lead to death. Truem 284 (91.6) [88.0 - 94.4] False 8 (2.6) I don't know 18 (5.8) Source: Appendix B: Survey Tables, Table 6.1 Total number of eligible respondents completing the survey. 95% exact two-sided con?dence intervals are calculated using the Clopper-Pearson method. Correct response. No trends were evident when the results for Key Risk Message 1 were strati?ed by whether the Medication Guide was received and read, if the Medication Guide was read and understood, modality for completing the survey (internet versus telephone), respondent highest level of education, or by the age group of the respondent (see Appendix B). 5.2.2 Key Risk Message 2 Key Risk Message 2 states ?patients should not take TIRF medicines if they are not opioid tolerant.? Two questions/items de?ned this key risk message (Table 9). The majority of respondents 95% CI: 85.4 92.6) understood that TIRF medicines should only be taken by patients who are opioid tolerant. Most respondents 95% CI: 83.9 91.5) also correctly indicated that opioid tolerant means that a patient is already taking other opioid pain medicines around-the-clock and their body is used to these medicines. Table 9. Primary Analysis of Responses to Questions Linked to Key Risk Message #2 - Completed Surveys Patients/Caregivers Question [95% Cl uestion 11: Please answer True, False, or I don't know for the followin statement: TIRF medicines should only be taken by patients who are opioid tolerant. Truem 277 (89.4) [85.4 - 92.6] False 8 (2.6) I don't know 25 (8.1) Patient/Caregiver KAB Assessment Report Final 10 February 2017 Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 34 of 56 Table 9. Primary Analysis of Responses to Questions Linked to Key Risk Message #2 - Completed Surveys Patients/Caregivers Question [95% Question 12: Please answer True, False, or I don't know for each of the following statements. 12a: Opioid tolerant means that a patient is already taking other opioid pain medicines around-the-clock and their body is used to these medicines. Truem 273 (88.1) [83.9 - 91.5] False 14 (4.5) 1 don't know 23 (7.4) Source: Appendix B: Survey Tables, Table 7.1 Total number of eligible respondents completing the survey. 95% exact two-sided con?dence intervals are calculated using the Clopper-Pearson method. Correct response. Overall, 82.9% of respondents provided correct responses for both questions/ items of Key Risk Message 2 (Table 10). Table 10. Secondary Analysis of Responses to Questions Linked to Key Risk Message #2 - Completed Surveys Patients/Caregivers Correct Responses 0 correct responses 17 (5.5) 1 correct response 36 (11.6) 2 correct responses 257 (82.9) Source: Appendix B: Survey Tables, Table 7.2 Total number of eligible respondents completing the survey. No trends were evident when the results for Key Risk Message 2 were strati?ed by whether the Medication Guide was received and read, if the Medication Guide was read and understood, modality for completing the survey (intemct versus telephone), respondent highest level of education, or by the age group of the respondent (see Appendix B). 5.2.3 Key Risk Message 3 Key Risk Message 3 states medicines should be taken exactly as prescribed by the healthcare provider.? Nine questions/items de?ned this key risk message (Table 1 1). Patient/Caregiver KAB Assessment Report Final 10 February 2017 Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 35 of 56 Almost all respondents 95% CI: 98.2 100.0) understood that TIRF medicines should be taken exactly as prescribed by the doctor. Most respondents understood that TIRF medicines should not be used for dental pain 95% CI: 82.5 90.3) or headache or migraine pain 95% CI: 73.0 82.5), and should be used for breakthrough pain from cancer 95% CI: 67.3 77.5). Over half of the respondents understood the TIRF medicines should not be used for pain after surgery 95% CI: 58.6 69.5), that it is not okay for patients to take TIRF medicines for headache pain 95% CI: 61.9 72.6), and that is not okay to take TIRF medicines for short-term pain that will go away in a few days 95% CI: 80.7 88.9). Less than half of respondents 95% CI: 33.6 44.7) indicated they were aware that TIRF medicines are not indicated for long- lasting pain not caused by cancer. Similarly, less than half of respondents 39.7%, 95% 45.4) understood that if a patient stops taking around-the-clock opioid pain medicine, they must also stop taking the TIRF medicine. Table 11. Primary Analysis of Responses to Questions Linked to Key Risk Message #3 - Completed Surveys Patients/Caregivers Question 11 195% cum Question 10: For which of the following conditions should you use a TIRF medicine? Please answer Yes, No, or I don't know for each statement. 10a: Headache or migraine pain Yes 34 (1 1.0) N091 242 (78.1) [73.0 - 82.5] I don't know 34 (l 1.0) I 0b: Breakthrough pain ?om cancer Yesm 225 (72.6) [67.3 - 77.5] No 81 (26.1) I don't know 4 (1.3) 10c: Dental pain Yes 5 (1.6) N091 269 (86.8) [82.5 - 90.3] 1 don't know 36 (11.6) I 0d: Pain after surgery Yes 69 (22.3) 199 (64.2) [58.6 - 69.5] I don't know 42 13.5) Patient/Caregiver KAB Assessment Report Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Final 10 February 2017 Page 36 of 56 Table 11. Primary Analysis of Responses to Questions Linked to Key Risk Message #3 - Completed Surveys Question Patients/Caregivers [95% cum I 0e: Long-lasting pain not from cancer, like arth ritis joint pain Yes 148 (47.7) N091 121 (39.0) [33.6 - 44.7] I don't know 41 (13.2) Question 12: Please answer True, False, or I don't know for each of the following statements. 12b: A patient must stop taking their TIRF medicine if they stop taking their around-the-clock opioid pain medicine. Truem 123 (39.7) [34.2 - 45.4] False 88 (28.4) I don't know 99 (31.9) was most recently prescribed for you. Question 13: Please answer True, False, or I don't know for each statement about the TIRF medicine that I 3b: It is OK for patients to take medicines for headache pain. True 20 (6.5) Falsem 209 (67.4) [61.9 - 72.6] I don't know 81 (26.1) I 3c: medicines should be taken exactly as prescribed by the doctor. Truem 309 (99.7) [98.2 - 100.0] False (0.3) I don't know 0 was most recently prescribed for you. Question 17: Please answer True, False, or I don't know for each statement about the TIRF medicine that I 7b: It is OK to take TIRF medicines for short-term pain that will go away in a few days. True 9 (2.9) Falsem 264 (85.2) [80.7 - 88.9] I don't know 37 (l 1.9) Source: Appendix B: Survey Tables, Table 8.1 Total number of eligible respondents completing the survey. ?195% exact two-sided con?dence intervals are calculated using the Clapper-Pearson method. Correct response. Patient/Caregiver KAB Assessment Report Final 10 February 2017 Transmueosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 37 of 56 Overall, 1 1.0% of respondents correctly answered all questions/items of Key Risk Message 3, 30.6% missed no more than 1 item, and 48.4% missed no more than 2 of the 9 items (Table 12). Table 12. Secondary Analysis of Responses to Questions Linked to Key Risk Message #3 - Completed Surveys Patients/Caregivers Correct Responses 11 0 correct responses 0 1 correct response 0 2 correct responses 9 (2.9) 3 correct responses 13 (4.2) 4 correct responses 29 (9.4) 5 correct responses 45 (14.5) 6 correct responses 64 (20.6) 7 correct responses 55 (17.7) 8 correct responses 61 (19.7) 9 correct responses 34 (1 1.0) Source: Appendix B: Survey Tables, Table 8.2 Total number of eligible respondents completing the survey. There was a signi?cant difference in the correct response rate for Question 12b when strati?ed by modality for completing the survey (Table 13). No trends were evident when the results for Key Risk Message 3 were strati?ed by whether the Medication Guide was received and read, if the Medication Guide was read and understood, respondent highest level of education, or by the age group of the respondent (see Appendix B). Patient/Caregiver KAB Assessment Report Final 10 February 2017 Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 38 of 56 Table 13. Responses to Questions Linked to Key Risk Message #3 by Modality to Complete Survey - Completed Surveys (Questions/Items with Apparent Trends) Modality to Complete Survey lntemet Telephone Question [95% cu'" [95% Question 12: Please answer True, False, or I don't know for each of the following statements. 12b: A patient must stop taking their TIRF medicine if they stop taking their around-the-clock opioid pain medicine. Truem 94 (45.4) [38.5 - 52.5] 29 (28.2) [19.7 - 37.9] False 55 (26.6) 33 (32.0) 1 don't know 58 (28.0) 41 (39.8) Source: Appendix B: Survey Tables, Table 8.1.3 95% exact two-sided con?dence intervals are calculated using the Clopper-Pearson method. Correct response. 5.2.4 Key Risk Message 4 Key Risk Message 4 states ?patients should not switch from one TIRF medicine to another medicine that contains fentanyl without talking to a healthcare provider.? (Table 14). Of the 310 respondents, 95.8% (95% CI: 92.9 97.7) understood that it is not safe to switch to another medicine that contains fentanyl without talking to a healthcare provider ?rst. Table 14. Primary Analysis of Responses to Questions Linked to Key Risk Message #4 - Completed Surveys Patients/Caregivers Question [95% culzl Question 12: Please answer True, False, or I don't know for each of the following statements. 12c: It is safe to switch to another medicine that contains fentanyl without talking to a healthcare provider first. True 6 (1.9) Falsem 297 (95.8) [92.9 - 97.7] I don't know 7 (2.3) Source: Appendix B: Survey Tables, Table 9.1 Total number of eligible respondents completing the survey. 95% exact two-sided con?dence intervals are calculated using the Clopper-Pearson method. Correct response. Patient/Caregiver KAB Assessment Report Final 10 February 2017 Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 39 of 56 No trends were evident when the results for Key Risk Message 4 were strati?ed by whether the Medication Guide was received and read, if the Medication Guide was read and understood, modality for completing the survey (intemet versus telephone), respondent highest level of education, and by the age group of the respondent (see Appendix B). 5.2.5 Key Risk Message 5 Key Risk Message 5 states ?patients should never give TIRF medicines to anyone else even if they have the same Five questions/ items de?ned this key risk message (Table 15). Almost all respondents understood that a patient may not give TIRF medicines to another person if they have the same as the patient 95% CI: 95.4 99.1), and that selling or giving away TIRF medicines is against the law 95% CI: 97.7 99.9) Similarly, most respondents correctly indicated that a side effect of TIRF medicines is the chance of abuse or addiction 95% CI: 89.1 95.2), that TIRF medicines can be misused by people who abuse prescription medicines or street drugs 95% CI: 95.0 98.9), and that TIRF medicines should be kept in a safe place to prevent it from being stolen 95% CI: 97.7 99.9). Table 15. Primary Analysis of Responses to Questions Linked to Key Risk Message #5 - Completed Surveys Patients/Caregivers Question [95% cum Question 12: Please answer True, False, or I don't know for each of the following statements. 12d: A patient may give TIRF medicines to another person if they have the same as the patient. True 6 (1.9) Falsem 303 (97.7) [95.4 - 99.1] 1 don't know 1 (0.3) Question 17: Please answer True, False, or I don't know for each statement about the TIRF medicine that was most recently prescribed for you. I 7a: Selling or giving away TIRF medicines is against the law. Truem 308 (99.4) [97.7 - 99.9] False (0.3) [don't know 1 (0.3) Question 18: Please answer True, False, or I don't know for each statement about the TIRF medicine that was most recently prescribed for you. I 8a: A side effect of TIRF medicines is the chance of abuse or addiction. Tmem 287 (92.6) [89.1 - 95.2] False 5 (1.6) 1 don't know 18 (5.8) Patient/Caregiver KAB Assessment Report Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Final 10 February 2017 Page 40 of 56 Table 15. Primary Analysis of Responses to Questions Linked to Key Risk Message #5 - Completed Surveys Patients/Caregivers Question [95% Cum I 8b: TIRF medicines can be misused by people who abuse prescription medicines or street drugs. Truem 302 (97.4) [95.0 - 98.9] False 0 I don't know 8 (2.6) 18c: TIRF medicines should be kept in a safe place to prevent it from being stolen. Truem 308 (99.4) [97.7 - 99.9] False (0.3) 1 don't know 1 (0.3) Source: Appendix B: Survey Tables, Table 10.1 Total number of eligible respondents completing the survey. 95% exact two-sided con?dence intervals are calculated using the Clopper-Pearson method. Correct response. Overall, 87.7% of respondents correctly answered all questions/items of Key Risk Message 5 (Table 16). Table 16. Secondary Analysis of Responses to Questions Linked to Completed Surveys Key Risk Message #5 - Patients/Caregivers Correct Responses 11 0 correct responses 0 1 correct response 0 2 correct responses 1 (0.3) 3 correct responses 2 (0.6) 4 correct responses 35 (1 1.3) 5 correct responses 272 (87.7) Source: Appendix B: Survey Tables, Table 10.2 Total number of eligible respondents completing the survey. No trends were evident when the results for Key Risk Message 5 were strati?ed by whether the Medication Guide was received and read, if the Medication Guide was read and understood, modality for completing the survey (internet versus telephone), respondent highest level of education, and by the age group of the respondent (see Appendix B). Patient/Caregiver KAB Assessment Report Transmucosal Immediate Release Fcntanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Final 10 February 2017 Page 41 of 56 5.2.6 Key Risk Message 6 Key Risk Message 6 states medicines should be stored in a safe place away from children and properly disposed.? Four questions/items de?ned this key risk message (Table 17). All respondents (100.0%, 95% 100.0) correctly responded that TIRF medicines should be stored in a safe place out of the reach of children. Most respondents 95% CI: 85.0 92.3) correctly indicated they should get emergency help right away if an adult who has not been prescribed a TIRF medicine takes a TIRF medicine, that TIRF medicines must be disposed of as described in the speci?c product?s Medication Guide 95% CI: 95.4 99.1), and that a TIRF medicine can cause an overdose and death in any child who takes it 95% CI: 91.0 96.5). Table 17. Primary Analysis of Responses to Questions Linked to Key Risk Message #6 - Completed Surveys Patients/Caregivers Question [95% was most recently prescribed for you. Question 13: Please answer True, False, or I don't know for each statement about the TIRF medicine that 13a: TIRF medicines should be stored in a safe place out of the reach of children. Truem 310 (100.0) [98.8 - 100.0] False 0 I don't know 0 medicine? (Please select one.) Question 14: What should you do if an adult who has not been prescribed a TIRF medicine takes a TIRF Wait an hour and see if the person is OK 10 (3.2) Get emergency help right away.[3] 276 (89.0) [85.0 - 92.3] Do nothing. 0 I don't know. 24 (7.7) was most recently prescribed for you. Question 17: Please answer True, False, or I don't know for each statement about the TIRF medicine that I 7 c: TIRF medicines must be disposed of as described in the speci?c product ?s Medication Guide. Truem 303 (97.7) [95.4 - 99.1] False 2 (0.6) I don't know 5 (1.6) Patient/Caregiver KAB Assessment Report Final 10 February 2017 Transmueosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 42 of 56 Table 17. Primary Analysis of Responses to Questions Linked to Key Risk Message #6 - Completed Surveys Patients/Caregivers av=3lo?? u%n%%cw" I 7e: A TIRF medicine can cause an overdose and death in any child who takes it. Truem 292 (94.2) [91.0 - 96.5] False 5 (1.6) I don't know 13 (4.2) Source: Appendix B: Survey Tables, Table 1.1 Total number of eligible respondents completing the survey. 95% exact two-sided con?dence intervals are calculated using the Clopper-Pearson method. Correct response. Overall, 83.9% of respondents correctly answered all questions/ items of Key Risk Message 6 (Table 18). Table 18. Secondary Analysis of Responses to Questions Linked to Key Risk Message #6 - Completed Surveys Patients/Caregivers Correct Responses 0 correct responses 0 1 correct response 1 (0.3) 2 correct responses 7 (2.3) 3 correct responses 42 (13.5) 4 correct responses 260 (83.9) Source: Appendix B: Survey Tables, Table 1.2 Total number of eligible respondents completing the survey. No trends were evident when the results for Key Risk Message 6 were strati?ed by whether the Medication Guide was received and read, if the Medication Guide was read and understood, modality for completing the survey (intemet versus telephone), respondent highest level of education, and by the age group of the respondent (see Appendix B). 5.2.7 Key Risk Message Average Knowledge Scores Table 19 presents the average knowledge score for each key risk message and an overall knowledge score for all key risk messages combined. The overall knowledge score of 84.8 (95% CI: 83.5 86.0) indicates most respondents demonstrated understanding of the key risk messages. The average knowledge score for each of the key risk messages was greater than 88 for 5 of the Patient/Caregiver KAB Assessment Report Final 10 February 2017 Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 43 of 56 6 key risk messages and was 70.3 for Key Risk Message 3 (TIRF medicines should be taken exactly as prescribed by the healthcare provider). Table 19. Average Knowledge Scores - Completed Surveys Score [95% KRM #1 91.6 [88.5, 94.7] KRM #2 88.7 [85.7, 91.7] KRM #3 70.3 [68.1, 72.5] KRM #4 95.8 [93.6, 98.1] KRM #5 97.3 [96.4, 98.2] KRM #6 95.2 [93.9, 96.6] Overall Knowledge Score 84.8 [83.5, 86.0] Source: Appendix B: Survey Tables, Table 12 95% CIs are constructed based on normal distribution function. 5.2.8 Other Survey Questions 5.2.8.1 Additional Questions about TIRF Medicines Safety Table 20 summarizes the patients?lcaregivers? responses to additional questions about the safe use of TIRF medicines beyond those associated with the key risk messages. The results generally indicate that respondents were educated by a healthcare professional (HCP) on the precautions to be taken to ensure safe use of TIRF medicines. See Section 5.2 for all key risk message question results. The majority of respondents (265; 85.5%) indicated someone in the doctor?s of?ce discussed the risks and possible side effects of the prescribed TIRF medicine. Most respondents (294, 94.8%) indicated that someone in the doctor?s of?ce explained how to use the prescribed TIRF medicines and 270 indicated someone in the doctor?s of?ce advised them on the proper storage of the prescribed TIRF medicines. The majority (238; 76.8%) were also aware that TIRF medicines are only available through the TIRF REMS Access program. Additionally, most respondents indicated someone in the doctor?s of?ce told them not to share the TIRF medicines with anyone else (268, counseled them that accidental exposure to TIRF medicines by a child may be fatal (237, told them to keep TIRF medicines out of reach of children to prevent accidental exposure (264, and told them about proper disposal of any unused or partially used TIRF medicines (237, Over half of respondents (191, 61.6%) indicated someone in the doctor?s of?ce asked them about the presence of children in their home. Patient/Caregiver KAB Assessment Report Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Final 10 February 2017 Page 44 of 56 Table 20. Responses to Additional Questions about the Safe Use of TIRF Medicines- Completed Surveys Patients/Caregivers Question Question 9: Did a doctor, nurse, or other healthcare professional in the doctor?s of?ce ever talk to you about the risks and possible side effects of the TIRF medicine that was most recently prescribed for you? TIRF medicines include Abstral?, Actiq?, entora?, Lazanda?, Subsys?, and the generic versions of these brands. Yes 265 (85.5) No 37 (11.9) I don't know 8 (2.6) use the TIRF medicine that was most recently prescribed for you? Question 15: Did a doctor, nurse, or other healthcare professional in the doctor?s office ever tell you how to Yes 294 (94.8) No 15 (4.8) 1 don't know 1 (0.3) store or keep the TIRF medicine that was most recently prescribed for you? Question 16: Did a doctor, nurse, or other healthcare professional in the doctor?s office ever tell you how to Yes 270 (87.1) No 35 (11.3) I don't know 5 (1.6) was most recently prescribed for you. Question 17: Please answer True, False, or I don't know for each statement about the TIRF medicine that the TIRF REMS Access program). 1 7d: medicines are only available to patients through a pharmacy enrolled in a special program (called Truem 238 (76.8) False 10 (3.2) I don?t know 62 (20.0) the presence of children in your home? Question 37: Did a doctor, nurse, or other healthcare professional in the doctor's of?ce ever ask you about Yes 191 (61.6) No 89 (28.7) 1 don't know 30 (9.7) share the TIRF medicines with anyone else? Question 38: Did a doctor, nurse, or other healthcare professional in the doctor's office ever tell you not to Yes 268 (86.5) No 34 (l 1.0) I don't know 8 (2.6) Patient/Caregiver KAB Assessment Report Final 10 February 2017 Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 45 of 56 Table 20. Responses to Additional Questions about the Safe Use of TIRF Medicines- Completed Surveys Patients/Caregivers Question Question 39: Did a doctor, nurse, or other healthcare professional in the doctor's office ever counsel you that accidental exposure to TIRF medicines by a child may be fatal? Yes 237 (76.5) No 48 (15.5) I don't know 25 (8.1) Question 40: Did a doctor, nurse, or other healthcare professional in the doctor's of?ce ever tell you to keep TIRF medicines out of reach of children to prevent accidental exposure? Yes 264 (85.2) No 35 (11.3) I don't know 11 (3.5) Question 41: Did a doctor, nurse, or other healthcare professional in the doctor's office ever tell you about proper disposal of any unused or partially used TIRF medicines? Yes 237 (76.5) No 48 (15.5) I don't know 25 (8.1) Source: Appendix B: Survey Tables, Table 3 Total number of eligible respondents completing the survey. Correct response. 5.3 Spontaneous Reporting of Adverse Events, Product Complaints, or Medical Information Requests Among all survey respondents (N 394; Table 1), there were 80 reports of a potential adverse event or product complaint associated with the use of TIRF medicines made during a telephone interview, while activating a gift card via telephone, or reporting a patient death via telephone (71 reports); within the survey free text ?eld during the online survey (6 reports); or Via US mail (3 reports of patient deaths). Verbatim statements are provided in Appendix B, Listing 4. 6. DISCUSSION AND CONCLUSIONS Discussion Survey invitations (and reminders) were sent to all known patients/caregivers who had ?lled a prescription within the 4 months prior to survey launch. From the total of 394 patients/caregivers Patient/Caregiver KAB Assessment Report Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Final 10 February 2017 Page 46 of 56 who accessed the survey, 321 respondents met eligibility criteria, and of those who met eligibility criteria, 310 (305 patients and 5 caregivers) completed the survey. There were statistically significant differences observed in the demographics between the patients completing the survey compared with the general population of patients on the questions for highest level of education and race; for all other questions responses were similar (Table 5). It is important to note the sample size of the general population of patients (N 3134 [or 1671 for race/ethnicity, language spoken in the home, and education level]) affects the power of the test, and therefore, may mean that even small differences between groups resulted in significant pvalues. There were almost no differences between the patients completing the survey and the general population of patients for race where the response ‘White’ (86.1% vs. 89.3%) included the majority of responders in each group. The proportion of patients with completed college and graduate school were similar in the general population, but of those who participated in the survey, patients who completed ‘some college’ were overrepresented (44.4% vs. 27.2% in the general population) and patients completed high school or less than high school were underrepresented (16.8 versus 31.5% and 1.6 versus 5.6%), respectively. While the differences are statistically significant, these differences should not have a big impact on the primary objectives of the survey since a relevant uniform correlation between demographic characteristics and the knowledge of the key risk messages could not be detected. Therefore, despite these differences, the TRIG concludes that the survey sample of 310 patients is a valid representation of the general population of TIRF patients. The overall knowledge score of 84.8 (95% CI: 83.5 86.0) for the survey indicates most respondents demonstrated understanding of the key risk messages (Table 19). The average knowledge score for each of the key risk messages was greater than 88 for 5 of the 6 key risk messages and was 70.3 for Key Risk Message 3 (TIRF medicines should be taken exactly as prescribed by the healthcare provider).The lower average knowledge score for Key Risk Message 3 reflected the 3 items (described below) with correct response rates <65%. The title of Key Risk Message 3 may also be misleading. Two of the 3 low scoring items were related to the indication for use of a TIRF medicine, and this is not really captured by the key risk message title (TIRF medicines should be taken exactly as prescribed by the HCP). There is another item in this key risk message (TIRF medicines should be taken exactly as prescribed by the doctor) that was answered correctly by 99.7% of the respondents. Of the 22 items included as part of key risk messages, 16 items had a correct response rate of greater than 80%, and 3 items had a correct response rate between 65% and 80%. The remaining 3 items within Key Risk Message 3 had a correct response rate which fell below the desired threshold of 65%. Correct response rate for Question 10: For which of the following conditions should you use a TIRF medicine? Item 10d: Pain after surgery. (Correct Response: No) was 64.2%; and correct response rate for Item 10e: Long-lasting pain not from cancer, like arthritis joint pain (Correct Response: No); was 39.0% for this 60-month survey. However, for Items 10a through 10c, most respondents understood that TIRF medicines should not be used for headache or migraine pain (78.1%) and dental pain (86.8%); and should be used for breakthrough pain from cancer FDA_4775 Patient/Caregiver KAB Assessment Report Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Final 10 February 2017 Page 47 of 56 (72.6%). In addition, the correct response rate for Item 12b (a patient must stop taking their TIRF medicine if they stop taking their around-the-clock opioid pain medicine) was 39.7% in this 60-month survey. As previously discussed, the survey was updated prior to launch based on FDA feedback received on 21 July 2016. Over 92% of respondents correctly responded that a side effect of TIRF medicines is the chance of abuse or addiction, that TIRF medicines can be misused by people who abuse medicines or street drugs, and TIRF medicines should be kept in a safe place (added Question 18). Nearly 90% of respondents correctly indicated TIRF medicines should only be taken by patients who are opioid tolerant (revised Question 11). For questions not included as part of key risk messages, new Questions 37 through 41 showed most respondents indicated someone in the doctor’s office told them not to share the TIRF medicines with anyone else, counseled them that accidental exposure to TIRF medicines by a child may be fatal, told them to keep TIRF medicines out of reach of children to prevent accidental exposure, and told them about proper disposal of any unused or partially used TIRF medicines; and over half indicated someone in the doctor’s office asked them about the presence of children in their home. In addition, Questions 9, 15, and 16 that ask patients about prescriber activities and were revised to allow pharmacists as a potential source of information, showed most respondents indicated someone in the doctor’s office discussed the risks and possible side effects of the prescribed TIRF medicine, that someone in the doctor’s office explained how to use the prescribed TIRF medicines, and someone in the doctor’s office advised them on the proper storage of the prescribed TIRF medicines. The correct response rates from the 12-month KAB survey through the 60-month KAB survey are shown in Table 21. Knowledge and understanding of the key risk messages has generally remained stable over time including Items 10d, 10e, and 12b mentioned above, which have had lower correct response rates for all survey waves.). Question 11 had a notably improved correct response rate once the question was revised back to the original 36-month survey question for this survey as detailed below. x x Question 11 as presented in the 48-month survey: TIRF medicines should only be taken by cancer patients who are opioid tolerant, correct response “True”; correct response rate 43.5%. Question 11 as presented in the 60-month survey: TIRF medicines should only be taken by patients who are opioid tolerant, correct response “True”; correct response rate 89.4%. Table 21 below includes key risk messages and questions/items within each key risk message as presented in the 60-month survey. It is important to note the question/item numbering, wording, and association with a specific key risk message may have changed across survey waves based on FDA feedback or other decisions made by the TRIG. A limitation to looking at correct response rates over time is that survey questions may have been modified. The primary focus of this table is to show general trends over time with a specific focus on changes from the 48-month survey to the 60-month survey. FDA_4776 Patient/Caregiver KAB Assessment Report Final 10 February 2017 Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 48 of 56 Table Correct Response Rate Over Time (SO-Month 12-Month Survey 24-Month Survey 36-Month Survey 48-Month Survey 60-Month Survey Survey Correct/Desired Correct/Desired Correct/Desired Correct/Desired Correct/Desired Question Questions as Presented in the Response Rate Response Rate Response Rate Response Rate Response Rate Number 60-Month Survey (95% CI) (95% Cl) (95% Cl) (95% Cl) (95% Cl) Key Risk Message 1: TIRF Medicines Can Cause Life-threatening Breathing Problems That Can Lead to Death 13 Please answer True, False, or I don?t know for each statement about the TIRF medicine that was most recently prescribed for you. TIRF medicines can cause life- 1 3 threatening breathing problems 90.1 90.1 91.3 91.9 91.6 that can lead to death. (85.0, 93.9) (86.1, 93.2) (86.8, 94.6) (88.3 - 94.7) (88.0 - 94.4) (Correct Response True) Key Risk Message 2: Patients Should Not Take TIRF Medicines if They Are Not Opioid Tolerant 1 1/12 Please answer True, False, or I don?t know for the following statement: TIRF medicines should only be 1 1 taken by patients who are 90.6 91.7 85.2 43.5 89.4 opioid tolerant (Correct (85.6, 94.3) (88.0, 94.6) (79.9, 89.5) (38.0 - 49.3) (85.4 - 92.6) Response True)m Opioid tolerant means that a patient is already taking other 12a opioid pain medicines around- 91.7 88.4 81.7 90.3 88.1 the-clock and their body is (86.8, 95.2) (84.3, 91.8) (76.0, 86.5) (86.5 - 93.4) (83.9 - 91.5) used to these medicines. (Correct Response True) Patient/Caregiver KAB Assessment Report Final 10 February 2017 Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 49 of 56 Table Correct Response Rate Over Time (SO-Month 12-Month Survey 24-Month Survey 36-Month Survey 48-Month Survey 60-Month Survey Survey Correct/Desired Correct/Desired Correct/Desired Correct/Desired Correct/Desired Question Questions as Presented in the Response Rate Response Rate Response Rate Response Rate Response Rate Number 60-Month Survey (95% CI) (95% Cl) (95% Cl) (95% Cl) (95% Cl) Key Risk Message 3: TIRF Medicines Should Be Taken Exactly as Prescribed By the Healthcare Provider 10 For which of the following conditions should you use a TIRF medicine? Please answer Yes, No, or I don?t know for each statement. 10a Headache or migraine pain. 72.9[2] 77.59] 7 8. 2[2] 80.6 78.1 (Correct Response N0) (75.8 - 84.9) (73.0 - 82.5) 10b Breakthrough pain from 69. 64. 20] 65. 90] 68.4 72.6 cancer. (Correct Response Yes) (62.9 - 73.5) (67.3 - 77.5) Dental pain. (Correct Response 2 90.3 86.8 10 89.6[ 1 87.42 87.3le No) (86.5 - 93.4) 82.5 - 90.3] 10d Pain a?er surgery. (Correct 67.7?] 6 8.591 70.39] 67.7 64.2 Response No) (62.2 - 72.9) (58.6 - 69.5) Lon -lastin ain not from We cancger likegafthritis joint pain 24 21 991 25 391 43?9 39?0 (38.3 - 49.6) (33.6 - 44.7) (Correct Response N0) 12 Please answer True, False, or I don?t know for each of the following statements. A patient must stop taking TIRF 'f 12b 3:12am 1:111:23; 51: 42.7 34.1 36.7 39.4 39.7 . g. . . . (35.6, 50.0) (28.8, 39.8) (30.4, 43.3) (33.9 - 45.0) (34.2 - 45.4) clock oprord pain (Correct Response True) 13/17 Please answer True, False, or I don?t know for each statement about the TIRF medicine that was most recently prescribed for you. Patient/Caregiver KAB Assessment Report Final 10 February 2017 Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 50 of 56 Table Correct Response Rate Over Time (SO-Month 12-Month Survey 24-Mondl Survey 36-Mon?l Survey 48-Month Survey 60-Month Survey Survey Correct/Desired Correct/Desired Correct/Desired Correct/Desired Correct/Desired Question Questions as Presented in the Response Rate Response Rate Response Rate Response Rate Response Rate Number 60-Month Survey (95% CI) (95% Cl) (95% Cl) (95% Cl) (95% Cl) It is OK for patients to take 69.4 70.8 68.2 74.8 67.4 13b TIRF 63.0, 75.3 medlcmes Or and? (63.9, 77.2) (62.6, 73.4) (69.6 - 79.6) (61.9 - 72.6) pam. (Correct Response False) TIRF medicines should be 130 taken exactly as prescribed by 100.0 99.7 99.1 100.0 99.7 the doctor. (Correct Response (98.1, 100.0) (98.2, 100.0) (96.9, 99.9) (98.8 - 100.0) (98.2 - 100.0) True) It is OK to take TIRF 17b 82.3 83.4 83.0 86.1 85.2 (76.1, 87.4) (78.8, 87.5) (77.5, 87.6) (81.8 - 89.8) (80.7 - 88.9) days. (Correct Response False) Key Risk Message 4: Patients Should Not Switch From One TIRF Medicine to Another Medicine That Contains Fentanyl Without Talking to a Healthcare Provider 12 Please answer True, False, or I don?t know for each of the following statements. It is safe to switch to another I th .2. 3.2532118: 2? 22.3.2?! 96-9 94-4 96-9 95-2 95-8 (93.3, 98.8) (91.1, 96.7) (93.8, 98.8) (92.1 - 97.3) (92.9 - 97.7) provider ?rst. (Correct Response False) Patient/Caregiver KAB Assessment Report Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Final 10 February 2017 Page 51 of56 Table Correct Response Rate Over Time (SO-Month 12-Month Survey 24-Month Survey 36-Month Survey 48-Month Survey 60-Month Survey Survey Correct/Desired Correct/Desired Correct/Desired Correct/Desired Correct/Desired Question Questions as Presented in the Response Rate Response Rate Response Rate Response Rate Response Rate Number 60-Month Survey (95% CI) (95% Cl) (95% Cl) (95% Cl) (95% Cl) Key Risk Message 5: Patients Should Never Give TIRF Medicines to Anyone Else Even if They Have the Same 12 Please answer True, False, or I don?t know for each of the following statements. A patient may give TIRF 1 2d W22: 100.0 98.0 99.1 99.4 97.7 (98.1, 100.0) (95.7, 99.3) (96.9, 99.9) (97.7 - 99.9) (95.4 - 99.1) as the patient. (Correct Response False) 17/18 Please answer True, False, or I don?t know for each statement about the TIRF medicine that was most recently prescribed for you. 11' TIRF m: (11:1: 2:11:23: 1a 97.9 98.3 99.1 98.7 99.4 1 1 w. (94.8, 99.4) (96.2, 99.5) (96.9, 99.9) (96.7 - 99.6) (97.7 - 99.9) (Correct Response True) A side effect of TIRF medicines is the chance of 92.6 18 3 abuse or addiction. (Correct (89.1 - 95.2) Response True) TIRF medicines can be misused by people who abuse 18b prescription medicines or street 97'4 (95.0 - 98.9) drugs. (Correct Response True) Patient/Caregiver KAB Assessment Report Final 10 February 2017 Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 52 of 56 Table Correct Response Rate Over Time (SO-Month 12-Month Survey 24-Mondl Survey 36-Mon?l Survey 48-Month Survey 60-Month Survey Survey Correct/Desired Correct/Desired Correct/Desired Correct/Desired Correct/Desired Question Questions as Presented in the Response Rate Response Rate Response Rate Response Rate Response Rate Number 60-Month Survey (95% CI) (95% Cl) (95% Cl) (95% Cl) (95% Cl) TIRF medicines should be kept in a safe place to prevent it 99?'om being stolen. (Correct (97.7 - 99.9) Response True) Key Risk Message 6: TIRF Medicines Should be Stored in a Safe Place Away From Children and Properly Disposed 13/17 Please answer True, False, or I don?t know for each statement about the TIRF medicine that was most recently prescribed for you. TIRF medicines should be 13a stored in a safe place out of the 100.0 100.0 99.1 99.7 100.0 reach of children. (Correct (98.1, 100.0) (98.8, 100.0) (96.9, 99.9) (98.2 - 100.0) (98.8 - 100.0) Response True) TIRF medicines must be 'b th 17.. 95-8 94-4 93-9 965 97-7 (92.0, 98.2) (91.1, 96.7) (90.0, 96.6) (93.7 - 98.2) (95.4 - 99.1) Gulde. (Correct Response True) A TIRF medicine can cause an 1 7e overdose and death in any 90.6 91.1 90.4 93.2 94.2 child who takes it. (Correct (85.6, 94.3) (87.3, 94.0) (85,8, 93,9) (89,8 - 95,8) (91.0 - 96.5) Response True) Patient/Caregiver KAB Assessment Report Final 10 February 2017 Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 53 of 56 Table 21. Correct Response Rate Over Time 60-Month lZ-Month Survey 24~Month Survey 36-Month Survey 48-Month Survey 60-Month Survey Survey Correct/Desired Correct/Desired Correct/Desired Correct/Desired Correct/Desired Question Questions as Presented in the Response Rate Response Rate Response Rate Response Rate Response Rate Number 60-Month Survey (95% Cl) (95% Cl) (95% Cl) (95% Cl) (95% Cl) What should you do if an adult who has not been prescribed a 14 TIRF medicine takes a TIRF 89.1 87.4 88.2 88.1 89.0 medicine? (Please select one.) (83.8, 93.1) (83.1, 90.9) (83.3, 92.1) (83.9 - 91.5) (85.0 - 92.3) (Correct Response: Get emergency help right away.) lQuestion was revised for the 60-month survey. 2 95% con?dence interval is not provided since the question/item was not part of a key risk message during reporting period. 3 Question was not asked during the reporting period. Patient KAB Assessment Report Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Final 10 February 2017 Page 54 of 56 Conclusions In general, knowledge and understanding of the key risk messages has remained stable over time (Table 21). Patients scored consistently low on 3 of 22 items: that TIRF medicines should not be taken for pain after surgery; that TIRF medicines should not be taken for long-lasting pain not from cancer, like arthritis joint pain; and that a patient must stop taking their TIRF medicine if they stop taking their around-the-clock opioid pain medicine. Overall, this 60-month survey shows a high level (greater than or equal to 65% for all but three items) of patient understanding of key risk messages based on the REMS goals. The TRIG acknowledges that there is room for improvement around patient knowledge related to conditions for use of a TIRF medicine and stopping a TIRF medicine when stopping their around-the-clock opioid pain medicine. FDA_4783 Patient KAB Assessment Report Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Appendix A Final 10 February 2017 Page 55 of 56 Patient Survey Protocol Track Change Document: Comparison of 48-month Survey to 60-month Survey FDA_4784 PROTOCOL TITLE: SPONSOR: VERSION: DATE: APPROVED: Quantitative Testing of Patient/Caregiver Knowledge, Attitudes, and Behavior about Transmucosal Immediate Release Fentanyl (TIRF) Products Safety and Use Information TIRF REMS Industry Group (TRIG) Actavis Laboratories FL, Inc. BioDelivery Sciences International, Inc. . . .. BDSI Cephalon, Inc. (a wholly-owned subsidiary of Teva Pharmaceutical Industries, Ltd.) Depomed, Inc. Galena-34W Therapeutics, Inc. Mallinckrodt Pharmaceuticals Mylan: Inc. Par Pharmeut?iealPharrnaceuticals, Inc. Therapeutics, Inc. +91_2.0 WHA 6 Ill?XAleinal UBC - Controlled Document Copyrighto United BioSource Corporation All Rights Reserved TIRF REMS Industry Group (TRIG) Transmucosal Immediate Release Fentanyl (TIRF) Products Patient/Caregiver KAB Survey Protocol TABLE OF CONTENTS Version 1012.0 13AUG201504AUG2016 PAGE TABLE OF CONTENTS ......................................................................................... 2 1. LIST OF ABBREVIATIONS .................................................................................. 3 2. BACKGROUND ..................................................................................................... 4 3. OBJECTIVES OF THE PATIENT EVALUATION SURVEY.............................. 5 4. METHODS .............................................................................................................. 5 4.1 Qualitative Research on the Survey ......................................................................... 5 4.2 4.2.1 4.2.2 Survey Design .......................................................................................................... 5 Questions and Statements on REMS Goals ............................................................. 6 Additional Questions.............................................................................................. 11 4.3 4.3.1 Participant Recruitment.......................................................................................... 12 Measures to Minimize Bias in the Sample............................................................. 13 5. 5.1.1 5.1.2 5.1.3 STUDY POPULATION ........................................................................................ 13 Sample Size ............................................................................................................ 13 Inclusion Criteria.................................................................................................... 14 Exclusion Criteria .................................................................................................. 14 6. SURVEY PROCESS ............................................................................................. 15 6.1 6.1.1 6.1.2 Screening and Survey Administration ................................................................... 15 Telephone ............................................................................................................... 15 Internet ................................................................................................................... 15 6.2 Measures to Minimize Bias in the Survey Process ................................................ 15 7. ANALYSIS ............................................................................................................ 16 8. SAFETY EVENT REPORTING ........................................................................... 17 9. PRIVACY PROTECTION AND CONFIDENTIALITY...................................... 17 LIST OF APPENDICES APPENDIX A Screening and Main Questionnaire........................................................... 19 APPENDIX B Recruitment Letters .................................................................................. 48 APPENDIX C Correct Answer Document ....................................................................... 54 2 of 55 FDA_4786 TIRF REMS Industry Group (TRIG) Transmucosal Immediate Release Fentanyl (TIRF) Products Patient/Caregiver KAB Survey Protocol 1. Version 1012.0 13AUG201504AUG2016 LIST OF ABBREVIATIONS BDSI CATI CI EDC ETASU FDA HIPAA IRB KAB PBM PPAF REMS SE PSP TIRF TIRF REMS TRIG UBC US BioDelivery Sciences International, Inc. Computer-Assisted Telephone Interviewing Confidence Interval Electronic Data Capture Elements to Assure Safe Use Food and Drug Administration Health Insurance Portability and Accountability Act Institutional Review Board Knowledge, Attitudes, and Behavior Pharmacy Benefits Management Patient-Prescriber Agreement Form Risk Evaluation and Mitigation Strategy Safety Event Project Specific Procedure Transmucosal Immediate Release Fentanyl TIRF REMS Access Programprogram TIRF REMS Industry Group United BioSource Corporation United States 3 of 55 FDA_4787 TIRF REMS Industry Group (TRIG) Transmucosal Immediate Release Fentanyl (TIRF) Products Patient/Caregiver KAB Survey Protocol 2. Version 1012.0 13AUG201504AUG2016 BACKGROUND Transmucosal Immediate Release Fentanyl (TIRF) medicines include the class of immediaterelease opioid analgesics, which are indicated only for the management of breakthrough pain in cancer patients 18 years of age or older (16 or older for Actiq® and equivalent generics) who are already receiving and tolerant to opioid therapy for their underlying persistent cancer pain. The TIRF medicines include Abstral®, Actiq®, Fentora®, Lazanda®, Subsys®, and generic versions of any of these brands. The TIRF REMS Industry Group (TRIG) includes Actavis Laboratories FL, Inc.; BioDelivery Sciences International, Inc. (BDSI) (replaced Meda Pharmaceuticals on March 11, 2015(BDSI); Cephalon, Inc. (a wholly-owned subsidiary of Teva Pharmaceutical Industries, Ltd.); Depomed, Inc.; Galena Biopharma, Inc.; Insys Therapeutics, Inc; Mallinckrodt Pharmaceuticals; Mylan Inc.; Par Pharmaceuticals, Inc.; and Par Pharmaceutical,Sentynl Therapeutics. Inc. The Food and Drug Administration (FDA) has determined that a class-wide Risk Evaluation and Mitigation Strategy (REMS) is required to mitigate the risks of misuse, abuse, addiction, overdose and serious complications due to medication errors with the use of TIRF medicines. The TIRF REMS Access Programprogram (hereafter referred to as TIRF REMS) was approved by the FDA on December 28, 2011. The TIRF REMS consists of a Medication Guide, Elements to Assure Safe Use (ETASU), an Implementation System, and a Timetable for Submission of Assessments of the REMS. The goals of the TIRF REMS are to mitigate the riskrisks of misuse, abuse, addiction, overdose, and serious complications due to medication errors by: 1. Prescribing and dispensing TIRF medicines only to appropriate patients, which include use only in opioid-tolerant patients 2. Preventing inappropriate conversion between TIRF medicines 3. Preventing accidental exposure to children and others for whom it was not prescribed 4. Educating prescribers, pharmacists, and patients on the potential for misuse, abuse, addiction, and overdose of TIRF medicines An important component of the TIRF REMS assessment is the conduct of quantitative evaluation surveys to assess patients’ and caregivers’ knowledge, attitudes, and behavior (KAB) regarding the safe use of TIRF medicines as described in the product-specific Medication Guide. This protocol will describe the administration of the surveys that will be conducted among patients who are treated with TIRF medicines, or their caregivers. Data from the surveys, together with other REMS evaluation metrics, will be used to determine whether changes need to be made to the REMS processes and/or educational materials to make them more effective in achieving the goals of the REMS. 4 of 55 FDA_4788 TIRF REMS Industry Group (TRIG) Transmucosal Immediate Release Fentanyl (TIRF) Products Patient/Caregiver KAB Survey Protocol Version 1012.0 13AUG201504AUG2016 The surveys will be implemented so that data will be available for inclusion in the REMS Assessment Reports that will be submitted to the FDA at 12 months after approval of the TIRF REMS and annually thereafter. 3. OBJECTIVES OF THE PATIENT EVALUATION SURVEY The evaluation survey will use a questionnaire to document the level of knowledge and assess the attitudes and behavior of patients around the following key information and risk messages communicated through the REMS: 1) TIRF medicines can cause life-threatening breathing problems that can lead to death. 2) Patients should not take TIRF medicines if they are not opioid tolerant. 3) TIRF medicines should be taken exactly as prescribed by the healthcare provider. 4) Patients should not switch from one TIRF medicine to another medicine that contains fentanyl without talking to a healthcare provider. 5) Patients should never give TIRF medicines to anyone else even if they have the same symptoms. 6) TIRF medicines should be stored in a safe place away from children and properly disposed. The survey will also include questions about whether patients received, read, and understood the product-specific Medication Guide and Patient-Prescriber Agreement Form (PPAF). 4. METHODS The survey was designed in collaboration between the TRIG and United BioSource Corporation (UBC), and will be administered by UBC. 4.1 Qualitative Research on the Survey Qualitative research to test patient comprehension was performed on the patient survey in 2012. Findings were incorporated into the survey prior to implementation of Wave 1. 4.2 Survey Design This survey will be conducted among a sample of patients or their caregivers who have filled a prescription for a TIRF medicine within the past 4 months (120 days) prior to survey launch. Respondents who have participated in a previous wave of the TIRF REMS KAB Survey will not be eligible to participate in subsequent survey waves. 5 of 55 FDA_4789 TIRF REMS Industry Group (TRIG) Transmucosal Immediate Release Fentanyl (TIRF) Products Patient/Caregiver KAB Survey Protocol Version 1012.0 13AUG201504AUG2016 The survey will be administered using the following modalities: x Self-administered, online through a secure website x Telephone surveys facilitated by a trained interviewer from the Survey Coordinating Center using a computer-assisted telephone interviewing (CATI) program The survey will begin with screening questions to confirm respondent eligibility to participate in the survey. Completion of the entire survey is expected to take approximately 20 minutes. The survey included in Appendix B A is written to reflect wording for both methods of survey administration: Internet-based and telephone administration. All respondents who complete the survey and who provide their contact information will be mailed a $50 gift card for their time. 4.2.1 Questions and Statements on REMS Goals The questionnaire is made up of multiple-choice, closed-ended statements or questions (the majority of which use true/false or yes/no dichotomous response options), and open-ended questions. These questions will evaluate current knowledge, attitudes, and behavior regarding the key risk messages noted in Section 3. The survey is written to follow principles of health literacy and readability. Questionnaire items will beQuestions are presented in several formats: x Statements or questions asking the respondent to indicate whether the statement or question is true or false, or if they do not know the answer (there is a similar set of statements and questions that use “yes,” “no,” or “I don’t know” as potential response options); x Statements or questions asking the respondent to choose from a defined list of possible statements or answers; and x Questions allowing for the respondent to provide information about when, where and from whom they obtained a Medication Guide, as well as to list questions they have about information in the Medication Guides. Questionnaires will be analyzed to determine patient understanding of each key risk message. For statements or questions that use “true” or “yes” vs. “false” or “no” response options, the desired response for the key risk messages is generally “true” or “yes” indicating knowledge of, or behavior in accordance with, the objectives of the REMS. However, some questions are formatted to have the respondent disagree with the statement as written by providing response options of “false” or “no” to avoid having the same affirmative answer for all desired responses. 6 of 55 FDA_4790 TIRF REMS Industry Group (TRIG) Transmucosal Immediate Release Fentanyl (TIRF) Products Patient/Caregiver KAB Survey Protocol Version 1012.0 13AUG201504AUG2016 REMS statements, corresponding questions, and desired responses covering the key risk messages are identified below and can be found in the complete survey questionnaire (Appendix A). For better readability, the patient questions, only, are presented in the key risk messages tables. Caregiver questions are presented in Appendix A. 7 of 55 FDA_4791 TIRF REMS Industry Group (TRIG) Transmucosal Immediate Release Fentanyl (TIRF) Products Patient/Caregiver KAB Survey Protocol Version 1012.0 13AUG201504AUG2016 Key Risk Message 1: TIRF medicines can cause life-threatening breathing problems that can lead to death. Question No. Question Desired Response 13 Please answer True, False, or I don’t know for each statement about the TIRF medicine that was most recently prescribed for you. 13d TIRF medicines can cause life-threatening breathing problems that can lead to death. TRUE Key Risk Message 2: Patients should not take TIRF medicines if they are not opioid tolerant. Question No. Question Desired Response Please answer True, False, or I don’t know for the following statement: 11 12 12a TIRF medicines should only be taken by cancer TRUE patients who are opioid tolerant. Please answer True, False, or I don’t know for each of the following statements. Opioid tolerant means that a patient is already taking other opioid pain medicines around-theTRUE clock and their body is used to these medicines. 8 of 55 FDA_4792 TIRF REMS Industry Group (TRIG) Transmucosal Immediate Release Fentanyl (TIRF) Products Patient/Caregiver KAB Survey Protocol Version 1012.0 13AUG201504AUG2016 Key Risk Message 3: TIRF medicines should be taken exactly as prescribed by the healthcare provider. Question No. Question Desired Response 10 For which of the following conditions should you use a TIRF medicine? Please answer Yes, No, or I don’t know for each statement. 10a Headache or migraine pain NO 10b Breakthrough pain from cancer YES 10c Dental pain NO 10d Pain after surgery NO 10e 12 12b 13/17 13b 13c 13b 17b Long-lasting pain not from cancer, like arthritis NO joint pain Please answer True, False, or I don’t know for each of the following statements. A patient must stop taking their TIRF medicine if they stop taking their around-the-clock opioid pain medicine. TRUE Please answer True, False, or I don’t know for each statement about the TIRF medicine that was most recently prescribed for you. It is OK for patients to take TIRF medicines for FALSE headache pain. TIRF medicines should be taken exactly as TRUE prescribed by the doctor. It is OK for patients to take TIRF medicines for FALSE headache pain. It is OK to take TIRF medicines for short-term FALSE pain that will go away in a few days. Key Risk Message 4: Patients should not switch from one TIRF medicine to another medicine that contains fentanyl without talking to a healthcare provider. Question No. 12 Question Desired Response Please answer True, False, or I don’t know for each of the following statements. 9 of 55 FDA_4793 TIRF REMS Industry Group (TRIG) Transmucosal Immediate Release Fentanyl (TIRF) Products Patient/Caregiver KAB Survey Protocol 12c It is safe to switch to another medicine that contains fentanyl without talking to a healthcare provider first. Version 1012.0 13AUG201504AUG2016 FALSE Key Risk Message 5: Patients should never give TIRF medicines to anyone else even if they have the same symptoms. Question Question No. 12 12d 17/18 17a 18a 18b 18c Desired Response Please answer True, False, or I don’t know for each of the following statements. A patient may give TIRF medicines to another person if they have the same symptoms as the FALSE patient. Please answer True, False, or I don’t know for each statement about the TIRF medicine that was most recently prescribed for you. Selling or giving away TIRF medicines is against TRUE the law. A side effect of TIRF medicines is the chance of TRUE abuse or addiction. TIRF medicines can be misused by people who TRUE abuse prescription medicines or street drugs. TIRF medicines should be kept in a safe place to TRUE prevent it from being stolen. Key Risk Message 6: TIRF medicines should be stored in a safe place away from children and properly disposed. Question Question No. 13/17 13a 14 17c 17e Desired Response Please answer True, False, or I don’t know for each statement about the TIRF medicine that was most recently prescribed for you. TIRF medicines should be stored in a safe place TRUE out of the reach of children. What should you do if an adult who has not been prescribed a TIRF medicine takes a TIRF medicine? (Please select one.) TIRF medicines must be disposed of as described in the specific product’s Medication Guide. A TIRF medicine can cause an overdose and death in any child who takes it. GET EMERGENCY HELP RIGHT AWAY. TRUE TRUE 10 of 55 FDA_4794 TIRF REMS Industry Group (TRIG) Transmucosal Immediate Release Fentanyl (TIRF) Products Patient/Caregiver KAB Survey Protocol 14 4.2.2 What should you do if an adult who has not been prescribed a TIRF medicine takes a TIRF medicine? (Please select one.) Version 1012.0 13AUG201504AUG2016 Get emergency help right away. Additional Questions Questions about the requirements of the TIRF REMS, and receipt and understanding of the Medication Guides and PPAF will be asked after the key risk message questions, and will be followed by the collection of demographic information at the completion of the survey. 11 of 55 FDA_4795 TIRF REMS Industry Group (TRIG) Transmucosal Immediate Release Fentanyl (TIRF) Products Patient/Caregiver KAB Survey Protocol 4.3 Version 1012.0 13AUG201504AUG2016 SubjectParticipant Recruitment A random sample of patients who are passively enrolled in the TIRF REMS Access Programprogram and have received a TIRF medicine in the previous 4 months (120 days) will be invited to participate via an invitation letter. Address verification is required on these data due to the limited data points collected through the PPAF. In order to obtain this additional information a public records database will be used and those data combined with the TIRF REMS Access Programprogram data will be used to distribute those invitations to the select patient population. Additional patients will be identified for participation through a pharmacy benefits management (PBM) partner, which will provide a broad demographic coverage and include patients in 49 states. Through use of these sources, a list will be created of patients who have filled a prescription for a TIRF medicine within 4 months (120 days) prior to survey launch (first prescriptions and refills). Patients in this list will be invited to participate in the survey through an invitation letter (Appendix B). The letter will be sent from the Survey Coordinating Center and mailed directly to the patients on UBC letterhead (for the patients being invited by way of the TIRF REMS Access Program database and the public record database) or the PBM’s letterhead at the corporate level (for those patients being recruited through the PBM). Both invitation letters will be mailed via the United States (US) Postal Service. via the United States (US) Postal Service. The invitation will indicate that participants will receive a $50 gift card for completing the survey. Each invitation will also include a unique code and directions for accessing the survey either via the Internet or by telephone through an interviewer at the Survey Coordinating Center. The unique code will be used to identify the manufacturer of the most recent TIRF prescription that the patient filled. A sample of patients who have filled a prescription for a TIRF medicine within the 4 months (120 days) prior to survey launch will be chosen from the TIRF REMS Access Program database and/or PBM’sprogram database. This sampling approach will be used to create several batches of survey invitations. The overall number of unique patients and the duration of the survey period will dictate the size and number of invitation batches. If the required number of completed surveys is not achieved within a reasonable time frame, a second mailing will be sent to non-respondents from the original batch mailing and initial invitations will be sent to patients in the second batch. If the required number of completed surveys is still not achieved within a reasonable time frame, reminder letters will be sent to the patients in the second batch and initial invitations will be sent to the third batch of patients. If these efforts do not result in the required number of surveys within a reasonable time frame, then a new sample of patients may be selected if available. The intervals for sending reminder invitations to non-responders and for selecting a new sample will be condensed as necessary based on the actual rate of survey accrual relative to the proximity of the target survey close date. All respondents who complete the survey and who provide their contact information will be mailed a $50 gift card to thank them for their participation. The mailing will include a thank 12 of 55 FDA_4796 TIRF REMS Industry Group (TRIG) Transmucosal Immediate Release Fentanyl (TIRF) Products Patient/Caregiver KAB Survey Protocol Version 1012.0 13AUG201504AUG2016 you letter, a copy of the product-specific Medication Guide, and a copy of the correct answers to the key risk message questions. 4.3.1 Measures to Minimize Bias in the Sample The sample of participating patients will be self-selected since respondents will voluntarily respond to the invitation to participate; however, the survey recruitment strategies are intended to recruit a heterogeneous sample of patients for participation. Respondents will be offered online or telephone options for completing the survey. Multiple modalities for survey data collection allow for wider survey access to a more heterogeneous population. Respondents will be provided a unique code during the recruitment process and will be asked to provide the unique code to gain access to the online survey or when calling the Survey Coordinating Center. The code will be deactivated after use to minimize the possibility for fraud. 5. STUDY POPULATION 5. STUDY POPULATION 5.1.1 Sample Size A sample of 300 patients treated with TIRF medicines is proposed for the survey wave. The size of the sample was determined based on both practical and statistical considerations. There is no target comprehension rate specified a priori. A sample of 300 completed surveys will allow estimation of the comprehension rate for each key risk message with a moderately high degree of precision. The table below shows the precision of the estimates for level of understanding using two-sided 95% confidence intervals (CIs) obtained with the sample size of 300 completed surveys. The noted CIs are used to indicate that for any survey-estimated rate of understanding, the true population rate of understanding is at least as high as the lower limit of the 95% CI and may be as high as the upper limit of the 95% CI. 13 of 55 FDA_4797 TIRF REMS Industry Group (TRIG) Transmucosal Immediate Release Fentanyl (TIRF) Products Patient/Caregiver KAB Survey Protocol Version 1012.0 13AUG201504AUG2016 Table 5.1: Precision of Estimated Rates of Understanding with a Sample Size of 300 Estimated Rate of Understanding 5% 10% 15% 20% 25% 30% 35% 40% 45% 50% 55% 60% 65% 70% 75% 80% 85% 90% 95% 5.1.2 Estimated Confidence Interval 2.8% 8.1% 6.8% 14.0% 11.2% 19.6% 15.6% 25.0% 20.2% 30.3% 24.9% 35.5% 29.6% 40.7% 34.4% 45.8% 39.3% 50.8% 44.2% 55.8% 49.2% 60.7% 54.2% 65.6% 59.3% 70.4% 64.5% 75.1% 69.7% 79.8% 75.0% 84.4% 80.4% 88.8% 86.0% 93.2% 91.9% 97.2% Inclusion Criteria The following respondents are eligible to participate in the survey: x Patients who are 18 years of age or older who have filled a prescription for at least one of the TIRF medicines within 4 months (120 days) prior to survey launch x Caregivers 18 years of age or older who care for patients who have filled a TIRF medicine prescription within the past 4 months (120 days) prior to survey launch and are unable to take the survey for themselves 5.1.3 Exclusion Criteria The following respondents are not eligible to participate in the surveys: x Patients who have previously participated in the TIRF REMS KAB survey (this exclusion applies to the second and subsequent waves only) x Patients or their immediate family members who have ever worked for Actavis Laboratories FL, Inc.,.; Anesta LLC,; BioDelivery Sciences International, Inc. (BDSI),); Cephalon, Inc. (a wholly-owned subsidiary of Teva Pharmaceutical Industries, Ltd.); Depomed, Inc.; Galena Biopharma; Insys Therapeutics, Inc.; Mallinckrodt Pharmaceuticals; Mylan, Inc.; Par PharmaceuticalPharmaceuticals, Inc.; Teva Pharmaceuticals, Ltd.; Sentynl Therapeutics. Inc.; UBC; McKesson Specialty Care Solutions; RelayHealth; or the FDA. 14 of 55 FDA_4798 TIRF REMS Industry Group (TRIG) Transmucosal Immediate Release Fentanyl (TIRF) Products Patient/Caregiver KAB Survey Protocol 6. SURVEY PROCESS 6. SURVEY PROCESS 6.1 Screening and Survey Administration Version 1012.0 13AUG201504AUG2016 The questionnaire will begin with a screening module with questions to confirm patient eligibility. The entire survey is expected to take approximately 20 minutes to complete. Depending on the answers to the screening questions, survey participation could either be terminated or continued. If ineligible, respondents are immediately notified with a thank you message that survey participation has ended. If eligible, respondents are allowed to continue survey participation. The electronic data capture (EDC) system that is used for both methods of survey administration has been validated and is secure for receiving and storing survey data. The system is 21 CFR Part 11 and Health Insurance Portability and Accountability Act (HIPAA) compliant. Patient-identifying information will be stored separately from survey data. The entire survey is expected to take approximately 20 minutes to complete. 6.1.1 Telephone The telephone survey is facilitated by a trained interviewer from the Survey Coordinating Center using a CATI program. The respondent will be required to provide a unique code to access the survey. Working from a CATI script, the interviewer will read questions or statements to the respondent and enter the responses into the EDC system. Screening and main elements of the questionnaire will be administered sequentially during the same telephone call. Telephone interviewing allows participation of respondents who do not have Internet access, or prefer to complete the survey in this manner. 6.1.2 Internet An Internet-based survey system will also be used for conducting the KAB surveys. If respondents select to participate in the survey online, they will be directed to a secured website and instructed to enter a unique code to access the survey. An Internet survey will be convenient for respondents to participate since they can complete the questionnaire at any convenient time and location during the specified survey time period. 6.2 Measures to Minimize Bias in the Survey Process A number of controls will be in place to ensure the survey is conducted in a controlled and professional manner and to minimize bias. For example, a unique code will be given to each survey participant and the code will be inactivated after use to minimize fraud. Telephone interviewers are highly trained and use a standardized script to administer the survey. All questions will be programmed to ensure that questions are asked in the appropriate sequence. Skip patterns will be clearly indicated. Respondents cannot go back to a question 15 of 55 FDA_4799 TIRF REMS Industry Group (TRIG) Transmucosal Immediate Release Fentanyl (TIRF) Products Patient/Caregiver KAB Survey Protocol Version 1012.0 13AUG201504AUG2016 once the question has been answered and cannot skip ahead. All questions must be answered in order to complete the survey. Response options presented in a list will be randomized to minimize positional bias. Programming will be reviewed by quality control and simulated users (User Acceptance Testing) prior to implementing the survey. 7. ANALYSIS Information obtained from the survey will be reported as descriptive statistics for the survey administration, study population, and the survey questions. Any free text fields will be grouped into applicable categories. Verbatim text from open-ended questions will be displayed when appropriate. The following will be reported as part of this analysis: x The number of invitations issued x The number of invitations returned as undeliverable x The number of reminder letters x The number of respondents screened for participation x The number of respondents eligible for participation x The number of respondents who completed all questions presented to them x Description of survey participants, including: x Type of respondent (patient/caregiver) Age (patient/caregiver) Gender (respondent) Educational level (respondent) Main language spoken at home (respondent) Ethnicity (respondent) Race (respondent) Geographic region (respondent) Data from all respondents who completed all questions presented to them in the survey (“completers”) will be analyzed, including: 16 of 55 FDA_4800 TIRF REMS Industry Group (TRIG) Transmucosal Immediate Release Fentanyl (TIRF) Products Patient/Caregiver KAB Survey Protocol Version 1012.0 13AUG201504AUG2016 Frequency distribution of responses to each key risk message question. Percent of completers selecting desired response to each question relating to each key risk message and 95% CI. Measurement of understanding will be computed for each question of the key risk message individually. A secondary analysis will be conducted to determine the number of completers who answered all items correctly for the key risk message. Behavior questions will be summarized on a question-by-question basis and are not included in the analysis by key risk message. Mean knowledge scores will be computed for each key risk message; an overall knowledge score will be computed for each respondent as well. Additional analyses may be performed as needed. 8. SAFETY EVENT REPORTING The survey will be conducted via the Internet and by telephone. It is possible that a respondent may report an adverse event or other safety event experienced while taking TIRF medicines either in free text fields of the survey or while in conversation with the Survey Coordinating Center. If an event is mentioned to a Survey Coordinating Center Associate, the Associate will document the safety event and the respondent’s contact information. The respondent will also be informed that a representative from the appropriate TIRF medicine manufacturer may contact him/her if there are questions about the survey. The Internet-based questionnaires will be monitored for any comments recorded in free text fields. Information on all comments that may constitute an adverse event or other safety event will be forwarded to the appropriate TIRF medicine manufacturer as described in the Safety Event Project Specific Procedure (SE PSP). Additional detail regarding processes for adverse event reporting will be specified in the SE PSP. 9. PRIVACY PROTECTION AND CONFIDENTIALITY All data collected during the survey will be held confidential. The EDC system used for data collection encrypts all identifiable information and respondent identifiers are stored separately from the survey responses. Respondent names and addresses are collected in order to mail a $50 gift card, a Thank You Letter, a product-specific Medication Guide, and correct survey responses to key risk message questions after the survey is completed. Respondent contact information is also requested in the event a safety event is reported and a TIRF medicine manufacturer must obtain follow-up information. A respondent may be contacted only if clarification or follow-up is needed regarding a possible safety event that was mentioned to the interviewer or recorded in free text fields of the online survey. 17 of 55 FDA_4801 TIRF REMS Industry Group (TRIG) Transmucosal Immediate Release Fentanyl (TIRF) Products Patient/Caregiver KAB Survey Protocol Version 1012.0 13AUG201504AUG2016 Respondents will be informed when they access the survey that they may be contacted if there are any questions about their survey responses. Respondents will be informed that their answers to the survey questions will not affect their ability to receive TIRF medicines. This protocol and survey will be reviewed and approved by a central Institutional Review Board (IRB) before administration of the survey. 18 of 55 FDA_4802 TIRF REMS Industry Group (TRIG) Transmucosal Immediate Release Fentanyl (TIRF) Products Patient/Caregiver KAB Survey Protocol Version 1012.0 13AUG201504AUG2016 APPENDIX A Screening and Main Questionnaire Survey Legend [PROGRAMMER] is used to indicate directions to the programmer and is set in bold, red, uppercase letters between square brackets. [PATIENT] indicates text applicable to a patient when it differs from survey text for caregivers, parents and legal guardians. [OTHER] indicates text applicable to parents, caregivers, and legal guardians when it differs from survey text for patients. (INTERVIEWER) is used to indicate directions to the telephone interviewer and is set in bold, blue, text between parentheses. This text appears when content is to be administered by telephone only (for example, spontaneous adverse event reporting). [ONLINE] indicates a question is worded specifically for administering the survey online. [PHONE] indicates a question is worded specifically to be read by a telephone interviewer and differs from the online text. [BEGIN SURVEY CONTENT] and [END SURVEY CONTENT] are used to indicate to the programmer the type of survey administration and the beginning and end of the survey or sections within the survey content, for example, [BEGIN ADVERSE EVENT/PRODUCT COMPLAINT] and [END ADVERSE EVENT/PRODUCT COMPLAINT]. [TERMINATE] is displayed next to responses that should cause the survey to end. The following termination language will be programmed into the survey or read by the interviewer unless different language is specified with the question. Thank you very much for your time today. Based on your answer, you are not eligible to take this survey. We appreciate your interest in the survey. [RANDOMIZE LIST] is inserted before questions to indicate to the programmer that the responses should be randomized. Responses such as “I don’t know,” “Prefer not to answer” or “None of the above” will always appear at the end of the randomized responses. [GO TO Qx] (Skip logic) is inserted after a response to indicate to the programmer that the survey should skip to the indicated question (for example, [GO TO Q17] skips to question 17). If no skip logic is indicated the survey continues to the next question in the sequence. Response options for questions that allow multiple responses must be indicated with check 19 of 55 FDA_4803 TIRF REMS Industry Group (TRIG) Transmucosal Immediate Release Fentanyl (TIRF) Products Patient/Caregiver KAB Survey Protocol Version 1012.0 13AUG201504AUG2016 Survey Legend e option must be selected for the question to be considered answered. If any response option requires text to be collected and does not need another question label, show [FREE TEXT] after the response option., if applicable. Response options for questions that allow only one response must be indicated with radio buttons ({). If any response option requires text to be collected and does not need another question label, show [FREE TEXT] after the response option, if applicable. [FREE TEXT] indicates to the programmer that one line should be provided for data entry. [MULTILINE INPUT] indicates to the programmer that multiple lines should be provided for data entry (for example, two address lines). [DROP-DOWN LIST INPUT WITH STATES TABLE] indicates to the programmer that the response should be a drop-down list containing the states in the table below. Alabama Georgia Massachusetts New York Tennessee Alaska Guam Michigan North Carolina Texas American Samoa Hawaii Minnesota North Dakota Idaho Mississippi Arizona Illinois Missouri Arkansas Indiana Montana Northern Mariana Islands US Virgin Islands California Iowa Nebraska Colorado Kansas Nevada Connecticut Kentucky New Hampshire Delaware Louisiana New Jersey District of Columbia Maine New Mexico Maryland Utah Vermont Ohio Virginia Oklahoma Washington Oregon West Virginia Pennsylvania Wisconsin Puerto Rico Wyoming Rhode Island South Carolina Florida South Dakota The following is used to categorize survey populations into standard geographic regions but it is not displayed in the survey. Geographic Distribution (based on address) 1: Northeast, Midwest, South, and West regions 20 of 55 FDA_4804 TIRF REMS Industry Group (TRIG) Transmucosal Immediate Release Fentanyl (TIRF) Products Patient/Caregiver KAB Survey Protocol Version 1012.0 13AUG201504AUG2016 Survey Legend Northeast Region New England Division - ME, NH, VT, MA, RI, CT Middle Atlantic Division - NY, NJ, PA Midwest Region East North Central Division - OH, IN, IL, MI, WI West North Central Division - MN, IA, MO, ND, SD, NE, KS South Region South Atlantic Division - DE, MD, DC, VA, WV, NC, SC, GA, FL East South Central Division - KY, TN, AL, MS West South Central Division - AR, LA, OK, TX West Mountain Division - MT, ID, WY, CO, NM, AZ, UT, NV Pacific Division WA, OR, CA, AK, HI The following US territories are categorized as Other: Puerto Rico, Northern Mariana Islands, US Virgin Islands, American Samoa, and Guam. 1 U.S. Census Bureau, last revised Friday, 27-Jul-2001 12:59:43 EDT. 21 of 55 FDA_4805 TIRF REMS Industry Group (TRIG) Transmucosal Immediate Release Fentanyl (TIRF) Products Patient/Caregiver KAB Survey Protocol Version 1012.0 13AUG201504AUG2016 [BEGIN SURVEY CONTENT] [BEGIN ONLINE PREAMBLE 1] Before you begin, we would like to share some important information about this survey. The survey is being conducted by UBC on behalf of the Transmucosal Immediate Release Fentanyl (TIRF) Risk Evaluation and Mitigation Strategy (REMS) Access Program (“program (TIRF REMS Access Program”program or Program), sponsors of which include the makers of Abstral®, Actiq®, Fentora®, Lazanda®, Subsys® and the generic versions of any of these brands. These TIRF Medicines are also known as rapid onset opioids (and sometimes called “fast acting fentanyls”).. Please note that references to the TIRF REMS Access Programprogram in this introduction include the sponsors of the Program, as well as its retained agents or contractors, including UBC. The information collected will help the makers of TIRF Medicines know if patients and their caregivers understand important information about taking these medicines. The survey will take about 20 minutes. There are no known risks to you in taking this survey. You may refuse to take part or withdraw at any time without penalty or loss of benefits to which you are otherwise entitled. Your answers to the questions or your decision to take part in the survey will not affect your ability to receive or take TIRF Medicines. How We Use Your Information The terms of the TIRF REMS Access Programprogram Patient-Prescriber Agreement Form (PPAF) on file and the Patient Privacy Notice contained therein, provide that the TIRF REMS Access Programprogram may receive, use, and share your health information, using a unique identifier instead of your name, in order to evaluate the proper use of TIRF Medicines and report to the Food and Drug Administration (FDA) about the effectiveness of the Program. Should you choose to participate in the survey, you agree that any information you provide during the course of the survey may be used or shared with the TIRF REMS Access Programprogram according to these terms. Your answers to the survey questions will be combined with answers given by other people taking the survey. All answers will be collected by UBC, compiled, and reported in anonymous form to the TIRF REMS Access Programprogram and the FDA. Your name will not be used in any report. If you are eligible to take the survey, complete all the questions, and provide your contact information, you will receive a $50 gift card for your time. Your name and address will be received only by UBC and will be used only to send you the gift card, a Thank You Letter, a product-specific Medication Guide, and a copy of the correct answers to key risk message questions, after you complete the survey. Providing a telephone number is optional. Your telephone number will be used only if there are any questions about your answers. 22 of 55 FDA_4806 TIRF REMS Industry Group (TRIG) Transmucosal Immediate Release Fentanyl (TIRF) Products Patient/Caregiver KAB Survey Protocol Version 1012.0 13AUG201504AUG2016 How We Protect Your Privacy We respect that the privacy of your personal information is important to you. You will not be contacted for marketing purposes based on your personal information or your answers to the survey. The TIRF REMS Access Programprogram will not sell, transfer (except in connection with reporting to the FDA), or rent your information. Your privacy will be protected; however, research survey records may be inspected by the FDA and a company called Sterling Independent Services, Inc., which is the Institutional Review Board (IRB) that looks out for the interest of survey participants. Your choice to allow the TIRF REMS Access Programprogram to use your information is entirely voluntary, but necessary to take part in this survey. Please be assured that your contact information and your individual responses will be kept strictly confidential. As noted above, however, information you provide will be combined with information and survey responses provided by others and shared or reported in anonymous form. By participating in the survey, you acknowledge and agree that such combined anonymous data may be used by the TIRF REMS Access Programprogram and disclosed to the FDA. By participating, you also acknowledge that the FDA and/or IRB, may inspect the records related to this survey which may include your individual responses. If you have questions about your rights as a research participant or related concerns, you may contact the IRB at 1-888-636-1062. Be sure to write down this telephone number; it will not be displayed again. How to Learn More About This Survey If you have questions about the survey, or have any problems with the survey, please contact the Survey Coordinating Center at 1-877-379-3297. The information in this survey should not take the place of talking with your doctor or health care professional. If you have any questions about your condition or treatment or that of the person you care for, or if you would like more information about TIRF Medicines, talk to your doctor, pharmacist, or other health care professional. Once you have answered a question and moved on, you cannot go back and change your answers. Thank you for your participation in this survey. [END ONLINE PREAMBLE 1] 23 of 55 FDA_4807 TIRF REMS Industry Group (TRIG) Transmucosal Immediate Release Fentanyl (TIRF) Products Patient/Caregiver KAB Survey Protocol Version 1012.0 13AUG201504AUG2016 [BEGIN PHONE PREAMBLE 1] Before you begin, we would like to share some important information about this survey. The survey is being conducted by UBC on behalf of the Transmucosal Immediate Release Fentanyl (TIRF) Risk Evaluation and Mitigation Strategy (REMS) Access Program (“program (TIRF REMS Access Program”program or Program) sponsors of which include the makers of Abstral®, Actiq®, Fentora®, Lazanda®, Subsys® and the generic versions of any of these brands. These TIRF (INTERVIEWER: Pronounce “TIRF,” then spell out T-I-R-F) Medicines, are also known as rapid onset opioids (INTERVIEWER: Please pause briefly) (and sometimes called “fast acting fentanyls”) or TIRF Medicines.. Please note that references to the TIRF REMS Access Programprogram in this introduction include the sponsors of the Program, as well as its retained agents or contractors, including UBC. (INTERVIEWER: Pronounce “TIRF,” then spell out T I R F). The information collected will help the makers of TIRF Medicines know if patients and their caregivers understand important information about taking these medicines. The survey will take about 20 minutes. There are no known risks to you in taking this survey. You may refuse to take part or withdraw at any time without penalty or loss of benefits to which you are otherwise entitled. Your answers to the questions or your decision to take part in the survey will not affect your ability to receive or take TIRF Medicines. Now I would like to tell you about how your contact information will be used. The terms of the TIRF REMS Access Programprogram Patient-Prescriber Agreement Form (PPAF) on file and the Patient Privacy Notice contained therein, provide that the TIRF REMS Access Programprogram may receive, use, and share your health information, using a unique identifier instead of your name, in order to evaluate the proper use of TIRF Medicines and report to the Food and Drug Administration (FDA) about the effectiveness of the Program. Should you choose to participate in the survey, you agree that any information you provide during the course of the survey may be used or shared with the TIRF REMS Access Programprogram according to these terms. Your answers to the survey questions will be combined with answers given by other people taking the survey. All answers will be collected by UBC, compiled, and reported in anonymous form to the TIRF REMS Access Programprogram and the FDA. Your name will not be used in any report. If you are eligible to take the survey, complete all the questions, and provide your contact information, you will receive a $50 gift card for your time. Your name and address will be received only by UBC and will be used only to send you the gift card, a Thank You Letter, a product-specific Medication Guide, and a copy of the correct answers to key risk message questions, after you complete the survey. 24 of 55 FDA_4808 TIRF REMS Industry Group (TRIG) Transmucosal Immediate Release Fentanyl (TIRF) Products Patient/Caregiver KAB Survey Protocol Version 1012.0 13AUG201504AUG2016 Providing a telephone number is optional. Your telephone number will be used only if there are any questions about your answers. Now I would like to tell you about how we protect your privacy. We respect that the privacy of your personal information is important to you. You will not be contacted for marketing purposes based on your personal information or your answers to the survey. The TIRF REMS Access Programprogram will not sell, transfer (except in connection with reporting to the FDA), or rent your information. Your privacy will be protected; however, research survey records may be inspected by the FDA and a company called Sterling Independent Services, Inc., which is the Institutional Review Board (IRB) that looks out for the interest of survey participants. Your choice to allow the TIRF REMS Access Programprogram to use your information is entirely voluntary, but necessary to take part in this survey. Please be assured that your contact information, and your individual responses will be kept strictly confidential. As noted above, however, information you provide will be combined with information and survey responses provided by others and shared or reported in anonymous form. By participating in the survey, you acknowledge and agree that such combined anonymous data may be used by the TIRF REMS Access Programprogram and disclosed to the FDA. By participating, you also acknowledge that the FDA and/or IRB, may inspect the records related to this survey which may include your individual responses. If you have questions about your rights as a research participant or related concerns, you may contact the IRB at 1-888-636-1062. The information in this survey should not take the place of talking with your doctor or health care professional. If you have any questions about your condition or treatment or that of the person you care for, or if you would like more information about TIRF Medicines, talk to your doctor, pharmacist, or other health care professional. Please feel free to ask me to repeat any questions or statements as we go through the survey. Once you have answered a question and moved on, you cannot go back and change your answers. Thank you for your participation in this survey. [END PHONE PREAMBLE 1] 25 of 55 FDA_4809 TIRF REMS Industry Group (TRIG) Transmucosal Immediate Release Fentanyl (TIRF) Products Patient/Caregiver KAB Survey Protocol Version 1012.0 13AUG201504AUG2016 [BEGIN INCLUSION/EXCLUSION QUESTIONS] 1. 2. 3. Do you agree to take part in this survey? Yes No [TERMINATE] Within the last 4 months (120 days), have you filled a prescription for yourself for a transmucosal immediate release fentanyl medicine (known as “TIRF medicines”)? TIRF medicines include Abstral®, Actiq®, Fentora®, Lazanda®, Subsys®, and the generic versions of any of these brands. Yes [GO TO Q4] No I don’t know Are you a caregiver for someone who has filled a prescription for a TIRF medicine within the last 4 months (120 days)? TIRF medicines include Abstral®, Actiq®, Fentora®, Lazanda®, Subsys® and the generic versions of any of these brands. Yes No [TERMINATE] I don’t know [TERMINATE] 26 of 55 FDA_4810 TIRF REMS Industry Group (TRIG) Transmucosal Immediate Release Fentanyl (TIRF) Products Patient/Caregiver KAB Survey Protocol 4. 5. Version 1012.0 13AUG201504AUG2016 [PATIENT] For which TIRF medicines have you filled a prescription in the last 4 months (120 days)? Please select all that apply. [CAREGIVER] For which TIRF medicines has the person you care for filled a prescription in the last 4 months (120 days)? Please select all that apply. Abstral Actiq, including generic versions of Actiq Fentora Lazanda Subsys Other I don’t know [CLEAR ALL OTHER SELECTIONS] Have you ever taken part in a survey about a TIRF medicine before? Yes [TERMINATE] No I don’t know [TERMINATE] 27 of 55 FDA_4811 TIRF REMS Industry Group (TRIG) Transmucosal Immediate Release Fentanyl (TIRF) Products Patient/Caregiver KAB Survey Protocol 6. 7. Version 1012.0 13AUG201504AUG2016 Which of the following groups best describes your age? Under 18 [TERMINATE] 18 29 30 39 40 49 50 59 60 69 70 or older Prefer not to answer [TERMINATE] [CAREGIVER] Which of the following groups best describes the patient’s age? Under 16 16 29 30 39 40 49 50 59 60 69 70 or older Prefer not to answer [TERMINATE] 28 of 55 FDA_4812 TIRF REMS Industry Group (TRIG) Transmucosal Immediate Release Fentanyl (TIRF) Products Patient/Caregiver KAB Survey Protocol 8. Version 1012.0 13AUG201504AUG2016 Have you or any of your immediate family members ever worked for any of the following companies or agencies? Please select all that apply. Actavis Laboratories FL, Inc. [TERMINATE] Anesta LLC [TERMINATE] BioDelivery Services International (BDSI) [TERMINATE] Cephalon, Inc. (a wholly-owned subsidiary of Teva Pharmaceutical Industries, Ltd.) [TERMINATE] Depomed, Inc. [TERMINATE] Galena Biopharma, Inc. [TERMINATE] Insys Therapeutics, Inc. [TERMINATE] Mallinckrodt Pharmaceuticals [TERMINATE] McKesson Specialty Care Solutions [TERMINATE] Mylan, Inc. [TERMINATE] Par PharmaceuticalPharmaceuticals, Inc. [TERMINATE] RelayHealth[TERMINATE] Sentynl Therapeutics. Inc. [TERMINATE] Teva Pharmaceuticals, Ltd. [TERMINATE] United BioSource Corporation [TERMINATE] FDA (Food and Drug Administration) [TERMINATE] No [IF SELECTED IN ADDITION TO OTHER RESPONSES, TERMINATE] I don’t know [TERMINATE] [END INCLUSION/EXCLUSION QUESTIONS] [BEGIN PREAMBLE 2 - DISPLAY ON SAME PAGE WITH NEXT QUESTION] [BEGIN PATIENT] Please answer the following questions based on information about the TIRF medicine that was most recently prescribed for you. TIRF medicines include 29 of 55 FDA_4813 TIRF REMS Industry Group (TRIG) Transmucosal Immediate Release Fentanyl (TIRF) Products Patient/Caregiver KAB Survey Protocol Version 1012.0 13AUG201504AUG2016 Abstral®, Actiq®, Fentora®, Lazanda®, Subsys®, and the generic versions of these brands. Please think of the information that you read or that was provided to you by a doctor, nurse, or other healthcare professional. If you don’t know the answers to any of the following questions please respond “I don’t know” instead of guessing the correct responses. [END PATIENT] [BEGIN CAREGIVER] Please answer the following questions based on information about the TIRF medicine that was most recently prescribed for the patient. TIRF medicines include Abstral®, Actiq®, Fentora®, Lazanda®, Subsys®, and the generic versions of these brands. Please think of the information that you read or that was provided to you or to the patient by a doctor, nurse, or other healthcare professional. If you don’t know the answers to any of the following questions please respond “I don’t know” instead of guessing the correct responses. [END CAREGIVER] [END PREAMBLE 2] 9. [PATIENT] Did thea doctor, nurse, or other healthcare professional in the doctor’s office ever talk to you about the risks and possible side effects of the TIRF medicine that was most recently prescribed for you? TIRF medicines include Abstral®, Actiq®, Fentora®, Lazanda®, Subsys®, and the generic versions of these brands. [CAREGIVER] Did thea doctor, nurse, or other healthcare professional in the doctor’s office ever talk to you about the risks and possible side effects of the TIRF medicine that was most recently prescribed to the patient? TIRF medicines include Abstral®, Actiq®, Fentora®, Lazanda®, Subsys®, and the generic versions of these brands. Yes No I don’t know 30 of 55 FDA_4814 TIRF REMS Industry Group (TRIG) Transmucosal Immediate Release Fentanyl (TIRF) Products Patient/Caregiver KAB Survey Protocol 10. Version 1012.0 13AUG201504AUG2016 [PATIENT] For which of the following conditions should you use a TIRF medicine? Please answer Yes, No, or I don’t know for each statement. [CAREGIVER] For which of the following conditions should the person you take care of use a TIRF medicine? Please answer Yes, No, or I don’t know for each statement. Yes No I don’t [RANDOMIZE LIST] know 10a. Headache or migraine pain 10b. Breakthrough pain from cancer 10c. Dental pain 10d. Pain after surgery 10e. Long-lasting pain not from cancer, like arthritis joint pain 11. Please answer True, False, or I don’t know for the following statement: TIRF medicines should only be taken by cancer patients who are opioid tolerant. 12. True False I don’t know Please answer True, False, or I don’t know for each of the following statements. True False I don’t [RANDOMIZE LIST] know 12a. Opioid tolerant means that a patient is already taking other opioid pain medicines around-the-clock and their body is used to these medicines. 12b. A patient must stop taking their TIRF medicine if they stop taking their around-the-clock opioid pain medicine. 12c. It is safe to switch to another medicine that contains fentanyl without talking to a healthcare provider first. 12d. A patient may give TIRF medicines to another person if 31 of 55 FDA_4815 TIRF REMS Industry Group (TRIG) Transmucosal Immediate Release Fentanyl (TIRF) Products Patient/Caregiver KAB Survey Protocol Version 1012.0 13AUG201504AUG2016 they have the same symptoms as the patient. 13. [PATIENT] Please answer True, False, or I don’t know for each statement about the TIRF medicine that was most recently prescribed for you. [CAREGIVER] Please answer True, False, or I don’t know for each statement about the TIRF medicine that was most recently prescribed for the patient. I don’t [RANDOMIZE LIST] True False know 13a. TIRF medicines should be stored in a safe place out of the reach of children. 13b. It is OK for patients to take TIRF medicines for headache pain. 13c. TIRF medicines should be taken exactly as prescribed by the doctor. 13d. TIRF medicines can cause life-threatening breathing problems that can lead to death. 14. What should you do if an adult who has not been prescribed a TIRF medicine takes a TIRF medicine? (Please select one.) [RANDOMIZE LIST] Wait an hour and see if the person is OK. Get emergency help right away. Do nothing. I don’t know. 32 of 55 FDA_4816 TIRF REMS Industry Group (TRIG) Transmucosal Immediate Release Fentanyl (TIRF) Products Patient/Caregiver KAB Survey Protocol 15. Version 1012.0 13AUG201504AUG2016 [PATIENT] Did thea doctor, nurse, or other healthcare professional in the doctor’s office ever tell you how to use the TIRF medicine that was most recently prescribed for you? [CAREGIVER] Did thea doctor, nurse, or other healthcare professional in the doctor’s office ever tell you how to use the TIRF medicine that was most recently prescribed for the patient? 16. Yes No I don’t know [PATIENT] Did thea doctor, nurse, or other healthcare professional in the doctor’s office ever tell you how to store or keep the TIRF medicine that was most recently prescribed for you? [CAREGIVER] Did thea doctor, nurse, or other healthcare professional in the doctor’s office ever tell you how to store or keep the TIRF medicine that was most recently prescribed for the patient? Yes No I don’t know 33 of 55 FDA_4817 TIRF REMS Industry Group (TRIG) Transmucosal Immediate Release Fentanyl (TIRF) Products Patient/Caregiver KAB Survey Protocol 17. Version 1012.0 13AUG201504AUG2016 [PATIENT] Please answer True, False, or I don’t know for each statement about the TIRF medicine that was most recently prescribed for you. [CAREGIVER] Please answer True, False, or I don’t know for each statement about the TIRF medicine that was most recently prescribed for the patient. [RANDOMIZE LIST] True False I don’t know 17a. Selling or giving away TIRF medicines is against the law. 17b. It is OK to take TIRF medicines for short-term pain that will go away in a few days. 17c. TIRF medicines must be disposed of as described in the specific product’s Medication Guide. 17d. TIRF medicines are only available to patients through a pharmacy enrolled in a special program (called the TIRF REMS Access Programprogram). 17e. A TIRF medicine can cause an overdose and death in any child who takes it. 18. [PATIENT] Please answer True, False, or I don’t know for each statement about the TIRF medicine that was most recently prescribed for you. [CAREGIVER] Please answer True, False, or I don’t know for each statement about the TIRF medicine that was most recently prescribed for the patient. [RANDOMIZE LIST] True False I don’t know 18a. A side effect of TIRF medicines is the chance of abuse or addiction. 18b. TIRF medicines can be misused by people who abuse prescription medicines or street drugs. 18c. TIRF medicines should be kept in a safe place to prevent it from being stolen. [BEGIN PREAMBLE 3 - DISPLAY ON SAME PAGE WITH NEXT QUESTION] [BEGIN PATIENT] The next set of questions is about the Medication Guide for the TIRF medicine that was most recently prescribed for you. 34 of 55 FDA_4818 TIRF REMS Industry Group (TRIG) Transmucosal Immediate Release Fentanyl (TIRF) Products Patient/Caregiver KAB Survey Protocol Version 1012.0 13AUG201504AUG2016 [END PATIENT] [BEGIN CAREGIVER] The next set of questions is about the Medication Guide for the TIRF medicine that was most recently prescribed for the patient. [END CAREGIVER] A Medication Guide is a paper handout that contains important information about the risks associated with the use of a TIRF medicine and how to use it safely. Medication Guides always include the title “Medication Guide” followed by the name of the medicine and its pronunciation. The Medication Guide usually has a section titled “What is the most important information I should know?” The Medication Guide is in a question-and-answer format and may be given to you by your pharmacist, doctor, or other healthcare professional. [END PREAMBLE 3] 35 of 55 FDA_4819 TIRF REMS Industry Group (TRIG) Transmucosal Immediate Release Fentanyl (TIRF) Products Patient/Caregiver KAB Survey Protocol Version 1012.0 13AUG201504AUG2016 18.19 [PATIENT] Have you ever received a Medication Guide for the TIRF medicine that was prescribed for you? [CAREGIVER] Have you or the patient ever received a Medication Guide for the TIRF medicine that was prescribed for the patient? Yes No [GO TO PREAMBLE 4] I don’t know [GO TO PREAMBLE 4] 19.20 [PATIENT] Did you receive the Medication Guide from the doctor who prescribed the TIRF medicine or someone in the doctor’s office? [CAREGIVER] Did you or the patient receive the Medication Guide from the doctor who prescribed the TIRF medicine or someone in the doctor’s office? Yes No [GO TO Q21Q22] I don’t know [GO TO Q21Q22] 20.21 [PATIENT] When was the Medication Guide given to you? Please select all that apply. [CAREGIVER] When was the Medication Guide given to you or the patient? Please select all that apply. At the first appointment with the doctor who prescribed the TIRF medicine At the last appointment with the doctor who prescribed the TIRF medicine I don’t remember [CLEAR ALL OTHER SELECTIONS] 36 of 55 FDA_4820 TIRF REMS Industry Group (TRIG) Transmucosal Immediate Release Fentanyl (TIRF) Products Patient/Caregiver KAB Survey Protocol Version 1012.0 13AUG201504AUG2016 21.22 [PATIENT] Did you receive the Medication Guide for the TIRF medicine from the pharmacy? [CAREGIVER] Did you or the patient receive the Medication Guide for the TIRF medicine from the pharmacy? Yes No [GO TO Q23Q24] I don’t know [GO TO Q23Q24] 22.23 [PATIENT] How frequently do you receive a Medication Guide for the TIRF medicine at the pharmacy? [CAREGIVER] How frequently do you or the patient receive a Medication Guide for the TIRF medicine at the pharmacy? Only with the first filled prescription Each time a prescription is filled Other (please specify): [FREE TEXT] I don’t know 23.24 Did you read the Medication Guide? Yes No [GO TO Q26Q27] I don’t know [GO TO Q26Q27] 24.25 How much did you read? All of it Most of it Some of it I don’t know 37 of 55 FDA_4821 TIRF REMS Industry Group (TRIG) Transmucosal Immediate Release Fentanyl (TIRF) Products Patient/Caregiver KAB Survey Protocol 25.26. Version 1012.0 13AUG201504AUG2016 How much of the Medication Guide did you understand? 26.27. All of it Most of it Some of it None of it I don’t know Did someone offer to explain the Medication Guide to you? 27.28. Yes No [GO TO Q30Q31] I don’t know [GO TO Q30Q31] Who offered to explain the Medication Guide to you? Please select all that apply. The doctor or another healthcare professional in the doctor’s office The pharmacist where the TIRF medicine prescription was filled Someone else [IF SELECTED, SHOW THE FOLLOWING ON THE SAME PAGE:] Specify the type of person but not his/her name: [FREE TEXT] 28.29. Did you accept the offer to have the Medication Guide explained to you? Yes No [GO TO Q30Q31] I don’t know [GO TO Q30Q31] 38 of 55 FDA_4822 TIRF REMS Industry Group (TRIG) Transmucosal Immediate Release Fentanyl (TIRF) Products Patient/Caregiver KAB Survey Protocol 29.30. 30.31. Version 1012.0 13AUG201504AUG2016 How much of the explanation did you understand? All of it Most of it Some of it None of it I don’t know Did you or do you have any questions about the information in the Medication Guide? Yes No [GO TO PREAMBLE 4] I don’t know [GO TO PREAMBLE 4] [IF QUESTION 3031 YES, DISPLAY Q31Q32 ON SAME PAGE] 31.32. What are your questions? [MULTILINE INPUT] [BEGIN PREAMBLE 4 – DISPLAY ON SAME PAGE AS NEXT QUESTION] The next set of questions is about the Patient-Prescriber Agreement Form for TIRF medicines. As a reminder, TIRF medicines include Abstral®, Actiq®, Fentora®, Lazanda®, Subsys®, and the generic versions of any of these brands. The PatientPrescriber Agreement is a form that is signed by the doctor and the patient or their caregiver. This form may also be referred to as the Prescriber-Patient Agreement. [END PREAMBLE 4] 39 of 55 FDA_4823 TIRF REMS Industry Group (TRIG) Transmucosal Immediate Release Fentanyl (TIRF) Products Patient/Caregiver KAB Survey Protocol 32.33. 33.34. Version 1012.0 13AUG201504AUG2016 Did the doctor or someone in the doctor’s office explain the Patient-Prescriber Agreement Form to you? Yes No [GO TO Q34Q35] I don’t know [GO TO Q34Q35] How much of the explanation did you understand? All of it Most of it Some of it None of it I don’t know 34.35. [PATIENT] Did you sign a Patient-Prescriber Agreement Form? [CAREGIVER] Did you or the person you are caring for sign a Patient-Prescriber Agreement Form? Yes No [GO TO DEMOGRAPHICS PREAMBLE 5] I don’t know [GO TO DEMOGRAPHICS PREAMBLE 5] 35.36. Did the doctor or someone in the doctor’s office give you a copy of the signed Patient-Prescriber Agreement Form? Yes No I don’t know 40 of 55 FDA_4824 TIRF REMS Industry Group (TRIG) Transmucosal Immediate Release Fentanyl (TIRF) Products Patient/Caregiver KAB Survey Protocol Version 1012.0 13AUG201504AUG2016 [BEGIN PREAMBLE 5 – DISPLAY ON SAME PAGE AS NEXT QUESTION] [BEGIN PATIENT] Please answer the following questions based on the conversation you had with your doctor, nurse, or other healthcare professional in your doctor’s office. If you don’t know the answers to any of the following questions please respond “I don’t know” instead of guessing the correct responses. [END PATIENT] [BEGIN CAREGIVER] Please answer the following questions based on the conversation you had with the patient’s doctor, nurse, or other healthcare professional in the doctor’s office. If you don’t know the answers to any of the following questions please respond “I don’t know” instead of guessing the correct responses. [END CAREGIVER] [END PREAMBLE 5] 37. [PATIENT] Did a doctor, nurse, or other healthcare professional in the doctor’s office ever ask you about the presence of children in your home? [CAREGIVER] Did a doctor, nurse, or other healthcare professional in the doctor’s office ever ask you about the presence of children in the patient’s home? 38. Yes No I don’t know [PATIENT] Did a doctor, nurse, or other healthcare professional in the doctor’s office ever tell you not to share the TIRF medicines with anyone else? [CAREGIVER] Did a doctor, nurse, or other healthcare professional in the doctor’s office ever tell you and the patient not to share the TIRF medicines with anyone else ? Yes No I don’t know 41 of 55 FDA_4825 TIRF REMS Industry Group (TRIG) Transmucosal Immediate Release Fentanyl (TIRF) Products Patient/Caregiver KAB Survey Protocol 39. Version 1012.0 13AUG201504AUG2016 [PATIENT] Did a doctor, nurse, or other healthcare professional in the doctor’s office ever counsel you that accidental exposure to TIRF medicines by a child may be fatal ? [CAREGIVER] Did a doctor, nurse, or other healthcare professional in the doctor’s office ever counsel you and the patient that accidental exposure to TIRF medicines by a child may be fatal ? 40. Yes No I don’t know [PATIENT] Did a doctor, nurse, or other healthcare professional in the doctor’s office ever tell you to keep TIRF medicines out of reach of children to prevent accidental exposure? [CAREGIVER] Did a doctor, nurse, or other healthcare professional in the doctor’s office ever tell you and the patient to keep TIRF medicines out of reach of children to prevent accidental exposure ? 41. Yes No I don’t know [PATIENT] Did a doctor, nurse, or other healthcare professional in the doctor’s office ever tell you about proper disposal of any unused or partially used TIRF medicines? [CAREGIVER] Did a doctor, nurse, or other healthcare professional in the doctor’s office ever tell you and the patient about proper disposal of any unused or partially used TIRF medicine? Yes No I don’t know [BEGIN DEMOGRAPHICS PREAMBLE - DISPLAY ON SAME PAGE AS NEXT QUESTION] 42 of 55 FDA_4826 TIRF REMS Industry Group (TRIG) Transmucosal Immediate Release Fentanyl (TIRF) Products Patient/Caregiver KAB Survey Protocol Version 1012.0 13AUG201504AUG2016 There are just a few more questions to help us combine your answers with other answers we have received. [END DEMOGRAPHICS PREAMBLE] 36.42. What is your gender? 37.43. Male Female Prefer not to answer What is the highest level of education you have completed? Less than high school Some high school High school graduate/GED Some college Some college/Associate’s degree Bachelor’s degree Master’s degree Professional or Doctoral degree Prefer not to answer 43 of 55 FDA_4827 TIRF REMS Industry Group (TRIG) Transmucosal Immediate Release Fentanyl (TIRF) Products Patient/Caregiver KAB Survey Protocol 38.44. Version 1012.0 13AUG201504AUG2016 What is the main language you speak at home? English French Spanish Portuguese Italian German Chinese Japanese Korean Other Prefer not to answer 39.45. Are you Hispanic or Latino? Yes No Prefer not to answer 44 of 55 FDA_4828 TIRF REMS Industry Group (TRIG) Transmucosal Immediate Release Fentanyl (TIRF) Products Patient/Caregiver KAB Survey Protocol 40.46. 41.47. Version 1012.0 13AUG201504AUG2016 For informational purposes only, which of the following U.S. census categories best describes your race? American Indian or Alaska Native Asian (origins of Far East, Southeast Asia or the Indian subcontinent) Black or African American Native Hawaiian or Other Pacific Islander White Two or more races Other Prefer not to answer In which state do you live? [DROP-DOWN LIST INPUT WITH STATES TABLE WITH “Prefer not to answer” AT END] 45 of 55 FDA_4829 TIRF REMS Industry Group (TRIG) Transmucosal Immediate Release Fentanyl (TIRF) Products Patient/Caregiver KAB Survey Protocol Version 1012.0 13AUG201504AUG2016 [PHONE - BEGIN ADVERSE EVENT/PRODUCT COMPLAINT – KEEP ON ONE PAGE] (INTERVIEWER: Please record if respondent spontaneously reported an adverse event or product complaint during the course of this interview.) Yes No [GO TO CLOSING 1] Enter Safety Adverse Event Verbatim [MULTILINE INPUT] (INTERVIEWER: Indicate to the respondent that someone may call back to ask more questions about the adverse event or product complaint that was reported.) [END ADVERSE EVENT/PRODUCT COMPLAINT] [BEGIN CLOSING 1 – KEEP ON ONE PAGE] You are eligible to receive a $50 gift card for your time completing the survey. In order to receive the gift card, we need to collect your name and address so that we can mail it to you. If you do not provide your name and address you will not receive the gift card for your time taking the survey. Do you agree to give us your name and mailing address so we can send your payment? Yes No [GO TO CLOSING 2] FIRST NAME: [FREE TEXT] LAST NAME: [FREE TEXT] ADDRESS: [MULTILINE INPUT] CITY: [FREE TEXT] STATE: [DROP-DOWN LIST INPUT WITH STATES TABLE] ZIP: [MUST BE 5 DIGIT NUMERIC-ONLY CHARACTERS] [END CLOSING 1] 46 of 55 FDA_4830 TIRF REMS Industry Group (TRIG) Transmucosal Immediate Release Fentanyl (TIRF) Products Patient/Caregiver KAB Survey Protocol Version 1012.0 13AUG201504AUG2016 [BEGIN CLOSING 2 – KEEP ON ONE PAGE] We would also like to ask for your telephone number. Providing your telephone number is optional and it will be used to contact you only if there are questions about your survey responses. Do you want to provide your telephone number? Yes No [GO TO CLOSING 3] Telephone: [MUST BE 10-DIGIT NUMERIC-ONLY CHARACTERS] [END CLOSING 2] [BEGIN CLOSING 3] This is the end of the survey. If you have questions about the survey, please contact the Survey Coordinating Center at 1-877-379-3297. Thank you again for your help. [END CLOSING 3] [END SURVEY CONTENT] 47 of 55 FDA_4831 TIRF REMS Industry Group (TRIG) Transmucosal Immediate Release Fentanyl (TIRF) Products Patient/Caregiver KAB Survey Protocol Version 1012.0 13AUG201504AUG2016 APPENDIX B SAMPLE Patient Letter of Invitation Recruitment Letters INVITATION LETTER [CURR DATE] [PAT_FIRST_NAME] [PAT_LAST_NAME ] [CURR_DATE] [PAT_STREET_ADDR] [PAT_CITY], [PAT_STATE] [PAT_ZIP] Dear [PAT_FULL_NAME]: Thank you for choosing [pharmacy partner or PBM name] for your prescription needs. The purpose of this letter is to inform you about a voluntary research survey being conducted by [COMPANY], the maker of [BRAND_GENERIC]. We are contacting you in connection with managing your participation in the Transmucosal Immediate Release Fentanyl (TIRF) Risk Evaluation and Mitigation Strategy (REMS) Access Program (TIRF REMS Access program or the Program). As you know, the TIRF REMS Access program is an FDA (Food and Drug Administration) required program designed to ensure appropriate use of TIRF medicines and to mitigate the risk of misuse, abuse, addiction, overdose and serious complications with the use of certain TIRF Medicines (Abstral®, Actiq®, Fentora®, Lazanda®, Subsys® and the generic versions of any of these brands). References in this letter to the TIRF REMS Access program (Program) include the sponsors of the Program, as well as agents or contractors retained by the Program. As part of your participation in the TIRF REMS Access program, we would like to inform you of a voluntary research survey being conducted by the Program. The survey is part of an FDA requirement to find out if patients and/or their caregivers understand important safety information about [BRAND]TIRF Medicines. Express Scripts and other medicines like it. The firstits subsidiary UBC have been retained by the Program to identify 300 people whoto complete this 20-minute survey and provide their contact information. Eligible individuals who complete the survey will receivebe sent a $50 [pharmacy partner or PBM name] gift card from [COMPANY] to thank them for their time. The terms of the TIRF REMS Access program Patient-Prescriber Agreement Form (PPAF) on file and the Patient Privacy Notice contained therein, provide that the TIRF REMS Access program may receive, use, and share your health information, using a unique identifier instead of your name, in order to evaluate the proper use of TIRF Medicines and report to the FDA about the effectiveness of the Program. Should you choose to participate in the survey, you agree that any information you provide during the course of the survey may be used by or shared with the TIRF REMS Access program according to these terms. You acknowledge, however, that should you choose to provide UBC with your name and contact information so that you may receive the $50 gift card for your time, UBC may use your name and contact 48 of 55 FDA_4832 TIRF REMS Industry Group (TRIG) Transmucosal Immediate Release Fentanyl (TIRF) Products Patient/Caregiver KAB Survey Protocol Version 1012.0 13AUG201504AUG2016 information for that purpose. Please be assured that your contact information and your individual responses will be kept strictly confidential. Any information you provide may, however, be combined with information and survey responses provided by others and shared or reported in anonymous form. By participating in the survey, you acknowledge and agree that such combined anonymous data may be used by the TIRF REMS Access program and disclosed to the FDA. By participating, you also acknowledge that the FDA as well as a company called Sterling Independent Services, Inc., which is the Institutional Review Board (IRB) that looks out for the interest of survey participants, may inspect the records related to this survey which may include your individual responses. You may be eligible to take part in the survey if you have taken [BRAND]a TIRF Medicine and are 18 years of age or older. If you are unable to take the survey yourself, a caregiver who is 18 or older may be eligible to take the survey for you. The survey asks questions about the type of information you received about [BRAND]the TIRF Medicine you have taken and where and how you getreceive your medical information. If you are interested in participating and to find out if you are eligible: x x Go online* to www.TIRFREMSsurvey.com.TIRFREMSsurvey.com any time or Call 877 379 3297, 8 a.m. to 8 p.m. Eastern Time, Monday through Friday Please have this letter with you at the time you take the survey. You will be asked to provide this code prior to starting the survey: [CODE_ID]. x *It is recommendedCall toll-free 1-877-379-3297, 8 a.m. to 8 p.m. Eastern Time, Monday through Friday Please have this letter with you at the time you take the survey. You will be asked to provide this code prior to starting the survey: [CODE ID]. *Please note that you should take the survey on a desktop or laptop computer. Taking the survey on mobile devices, such as smart phones, tablets, and e -notebooks, is not supported. (over, please) 49 of 55 FDA_4833 'l?ler' Industry Group (?l?RlG) Version I 2 .0 'l?runsmucosul Immediate Release Fenlanvl Products l?ulienl. Caregiver KAB Survey Protocol (HAU (72016 You are not required to take part. in this survey. If .you choose to take?pa??pl-ea-se?be eenhdeat-ia-lA?eu?particmatc in the survey, you will not be a-skedr cguired to identify However, if you wish to receive the $50 gift card from TIRF REMS Access program: you must provide your name and contact information for deli-very pu-bl-reatren? Neither taking the survey nor your answers to the questions will affect your ability to receive or take W73 TIRF Medicine. Sincerely: The TIRF REMS Survey Team 1-877?379-3297 bh?I-?h?y Controlled Document CopyrightO United BioSource Corporation All Rights Reserved TIRF REMS Industry Group (TRIG) Transmucosal Immediate Release Fentanyl (TIRF) Products Patient KAB Survey Protocol Version 12.0 04AUG2016 REMINDER LETTER [CURR DATE] [PAT FIRST NAME] [PAT LAST NAME] [PAT STREET ADDR] [PAT CITY], [PAT STATE] [PAT ZIP] Dear [PAT FULL NAME]: We recently sent you a letter in connection with managing your participation in the Transmucosal Immediate Release Fentanyl (TIRF) Risk Evaluation and Mitigation Strategy (REMS) Access program (TIRF REMS Access Program or the Program). As you know, the TIRF REMS Access program is an FDA (Food and Drug Administration) required program designed to ensure appropriate use of TIRF medicines and to mitigate the risk of misuse, abuse, addiction, overdose and serious complications with the use of certain TIRF Medicines (Abstral®, Actiq®, Fentora®, Lazanda®, Subsys® and the generic versions of any of these brands). References in this letter to the TIRF REMS Access program or Program include the sponsors of the Program, as well as agents or contractors retained by the Program. As part of your participation in the TIRF REMS Access program, we would like to inform you of a voluntary research survey being conducted by the Program. The survey is part of an FDA requirement to find out if patients and/or their caregivers understand important safety information about TIRF Medicines. Express Scripts and its subsidiary UBC have been retained by the Program to identify 300 people to complete this 20-minute survey. Eligible individuals who complete the survey will be sent a $50 gift card to thank them for their time. The terms of the TIRF REMS Access program Patient-Prescriber Agreement Form (PPAF) on file and the Patient Privacy Notice contained therein, provide that the TIRF REMS Access program may receive, use, and share your health information, using a unique identifier instead of your name, in order to evaluate the proper use of TIRF Medicines and report to the FDA about the effectiveness of the Program. Should you choose to participate in the survey, you agree that any information you provide during the course of the survey may be used by or shared with the TIRF REMS Access program according to these terms. You acknowledge, however, that should you choose to provide UBC with your name and contact information so that you may receive the $50 gift card for your time, UBC may use your name and contact information for that purpose. Please be assured that your contact information and your individual responses will be kept strictly confidential. Any information you provide may, however, be combined with information and survey responses provided by others and shared or reported in anonymous form. By participating in the survey, you acknowledge and agree that such combined anonymous data may be used by the TIRF REMS Access program and disclosed to the FDA. By participating, you also acknowledge that the FDA as well as a company called Sterling Independent Services, Inc., which is the Institutional Review Board 51 of 55 FDA_4835 TIRF REMS Industry Group (TRIG) Transmucosal Immediate Release Fentanyl (TIRF) Products Patient KAB Survey Protocol Version 12.0 04AUG2016 (IRB) that looks out for the interest of survey participants, may inspect the records related to this survey which may include your individual responses. You may be eligible to take part in the survey if you have taken a TIRF Medicine and are 18 years of age or older. If you are unable to take the survey yourself, a caregiver who is 18 or older may be eligible to take the survey for you. The survey asks questions about the type of information you received about the TIRF Medicine you have taken and where and how you receive your medical information. If you are interested in participating and to find out if you are eligible: x x Go online* to www.TIRFREMSsurvey.com any time or Call toll-free 1-877-379-3297, 8 a.m. to 8 p.m. Eastern Time, Monday through Friday Please have this letter with you at the time you take the survey. You will be asked to provide this code prior to starting the survey: [CODE ID]. *Please note that you should take the survey on a desktop or laptop computer. Taking the survey on mobile devices, such as smart phones, tablets, and e-notebooks, is not supported. You are not required to take part in this survey. If you choose to participate in the survey, you will not be required to identify yourself. However, if you wish to receive the $50 gift card from TIRF REMS Access program, you must provide your name and contact information for delivery. Neither taking the survey nor your answers to the questions will affect your ability to receive or take a TIRF Medicine. Sincerely, The TIRF REMS Survey Team 1-877-379-3297 www.TIRFREMSsurvey.com 52 of 55 FDA_4836 TIRF REMS Industry Group (TRIG) Transmucosal Immediate Release Fentanyl (TIRF) Products Patient KAB Survey Protocol Version 12.0 04AUG2016 THANK YOU LETTER [CURR_DATE] [PAT_FIRST_NAME] [PAT_LAST_NAME] [PAT_STREET_ADDR] [PAT_CITY], [PAT_STATE] [PAT_ZIP] Dear [PAT_FULL_NAME], On behalf of the TIRF REMS Industry Group, we would like to thank you for taking the time to complete the TIRF Medicines Survey. Your participation helps us to meet the requirements from the FDA (Food and Drug Administration). To thank you for your time and participation, we have enclosed a $50 gift card. Card Activation Instructions: To prevent loss, the enclosed card is not activated. Prior to using your card, please call the TIRF Medicines Survey Team 1-877-379-3297 between 8:00 a.m. and 8:00 p.m. Eastern Time Monday through Friday to activate your card. Please have your card available when you make the call. Also, please read the enclosed Terms and Conditions document before using your gift card as well as the privacy policy that can be found at: http://www.ctpayer.com/downloads/privacy policy.pdf Please note the enclosed gift card needs to be activated on or before XX XXX XXXX. Additionally, for your information, we have enclosed the following two documents: 1. Medication Guide for [BRAND® (generic)] 2. The correct answers to survey questions about your medicine’s key risks. Sincerely, The TIRF REMS Survey Team 1-877-379-3297 www.TIRFREMSsurvey.com Enclosures: Gift Card with Terms and Conditions Document Medication Guide for TIRF Medicines Correct Answers to Important Survey Questions 53 of 55 FDA_4837 TIRF REMS Industry Group (TRIG) Transmucosal Immediate Release Fentanyl (TIRF) Products Patient KAB Survey Protocol Version 12.0 04AUG2016 APPENDIX C Correct Answer Document Correct Responses to Select PATIENT Survey Questions about Important Safety Messages for Transmucosal Immediate Release Fentanyl (TIRF) medicines (TIRF medicines include Abstral®, Actiq®, Fentora®, Lazanda®, Subsys®, and generic versions of any of these brands) Q: Please answer True, False, or I don’t know for each statement about the TIRF medicine that was most recently prescribed for you. STATEMENT TIRF medicines can cause life-threatening breathing problems that can lead to death. It is OK for patients to take TIRF medicines for headache pain. TIRF medicines should be taken exactly as prescribed by the doctor. It is OK to take TIRF medicines for short-term pain that will go away in a few days. Selling or giving away TIRF medicines is against the law. TIRF medicines should be stored in a safe place out of the reach of children. TIRF medicines must be disposed of as described in the specific product’s Medication Guide. A TIRF medicine can cause an overdose and death in any child who takes it. Q: DESIRED RESPONSE TRUE FALSE TRUE FALSE TRUE TRUE TRUE TRUE For which of the following conditions should you use a TIRF medicine? Please answer Yes, No, or I don’t know for each statement. STATEMENT Headache or migraine pain Breakthrough pain from cancer Dental pain Pain after surgery Long-lasting pain not from cancer, like arthritis joint pain 54 of 55 DESIRED RESPONSE NO YES NO NO NO FDA_4838 TIRF REMS Industry Group (TRIG) Transmucosal Immediate Release Fentanyl (TIRF) Products Patient KAB Survey Protocol Q: What should you do if an adult who has not been prescribed a TIRF medicine takes a TIRF medicine? (Please select one.) A: Q: Version 12.0 04AUG2016 Get emergency help right away. Please answer True, False, or I don’t know for each of the following statements: STATEMENT TIRF medicines should only be taken by patients who are opioid tolerant. Opioid tolerant means that a patient is already taking other opioid pain medicines around-the-clock and their body is used to these medicines. A patient must stop taking their TIRF medicine if they stop taking their around-the-clock opioid pain medicine. It is safe to switch to another medicine that contains fentanyl without talking to a healthcare provider first. A patient may give TIRF medicines to another person if they have the same symptoms as the patient. A side effect of TIRF medicines is the chance of abuse or addiction. TIRF medicines can be misused by people who abuse prescription medicines or street drugs. TIRF medicines should be kept in a safe place to prevent it from being stolen. DESIRED RESPONSE TRUE TRUE TRUE FALSE FALSE TRUE TRUE TRUE If you have any questions about these survey responses, please discuss your questions with your healthcare provider and refer to the Medication Guide(s) for the TIRF medicine(s) that you take. 55 of 55 FDA_4839 Patient KAB Assessment Report Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Appendix B Final 10 February 2017 Page 56 of 56 Survey Tables FDA_4840 TRIG Page 1 of 1 TIRF Patient/Caregiver KAB 27DEC2016 Table 1.1: Survey Administration Statistics Parameter, Number of invitations distributed 2945 Number of invitations returned as undeliverable 399 Number of reminder letters distributed 5397 All Respondentsm 394 (15.5) Eligible Respondentsm 321 (81.5) Completed surveym 310 (96.6) Did not complete the surveym (3.4) Respondents not eligiblem? 73 (18.5) Source: Appendix B: Survey Tables, Table 1.1 Number of respondents who accessed the survey. Percentage is based on the number of invitations distributed excluding the number of invitations retumed as undeliverable. Percentage is based on the number of all respondents. [31 Percentage is based on the number of eligible respondents. Number of respondents who did not meet eligibility criteria or did not complete eligibility questions. Data Source: ADPQ Program: TSADMSAS TRIG Page 1 of 4 TIRF Patient/Caregiver KAB 27DEC2016 Table 1.2: Survey Participant Eligibility Results - All Respondents Patients/Caregivers Question Question 1: Do you agree to take part in this survey? Yes 376 (95.4) Now 2 (0.5) Discontinued 16 (4.1) Question 2: Within the last 4 months (120 days), have you ?lled a prescription for yourself for a transmucosal immediate release fentanyl medicine (known as medicines?)? TIRF medicines include Abstral?, Actiq?, entora?, Lazanda?, Subsys?, and the generic versions of any of these brands. Yes 357 (90.6) No 15 (3.8) 1 don't know 3 (0.8) Question not asked 2 (0.5) Discontinued 17 (4.3) generic versions of any of these brands. Question 3: Are you a caregiver for someone who has filled a prescription for a TIRF medicine within the last 4 months (120 days)? TIRF medicines include Abstral?, Actiq?, entora?, Lazanda?, Subsys? and the Yes 5 (1.3) No'? 13 (3.3) I don't known] 0 (Answered "Yes" to Question 2) 357 (90.6) Question not asked 2 (0.5) Discontinued 17 (4.3) Question 4: For which TIRF medicines have you filled a prescription in the last 4 months (120 days)? Please select all that Abstral 15 (33) Actiq, i"Chlding generic versions of Actiq 92 (23-4) Fentora 69 (17-5) Lazanda 17 (4.3) 8?1wa 162 (41.1) Other 23 (5.8) I don't know 7 (1.8) Data Source: ADPQ. ADTQ Program: TRIG Page 2 of 4 TIRF Patient/Caregiver KAB 27DEC2016 Table 1.2: Survey Participant Eligibility Results - All Respondents Patients/Caregivers Question Question not asked 15 (3.8) Discontinued 17 (4.3) Question 5: Have you ever taken part in a survey about a TIRF medicine before? Yes? 26 (6.6) No 323 (82.0) 1 don't known] 12 (3.0) Question not asked 15 (3.8) Discontinued 18 (4.6) Question 6: Which of the following groups best describes your age? Under 18?] 0 18 - 29 8 (2.0) 30 - 39 23 (5.8) 40 - 49 60 (15.2) 50-59 123 (31.2) 60 - 69 92 (23.4) 70 or older 17 (4.3) Prefer not to answerm 0 Question not asked 53 (13.5) Discontinued 18 (4.6) Question 7: Which of the following groups best describes the patient?s age?? Under (0.3) 50 - 59 (0.3) 60 - 69 3 (0.8) 70 or older 0 Prefer not to answerm 0 Question not asked [21 372 (94.4) Data Source: ADPQ, ADTQ Program: TRIG Page 3 of 4 TIRF Patient/Caregiver KAB 27DEC2016 Table 1.2: Survey Participant Eligibility Results - All Respondents Patients/Caregivers Question Discontinued 17 (4.3) Question 8: Have you or any of your immediate family members ever worked for any of the following companies or agencies? Please select all that apply.?I Actavis Laboratories FL, [new Anesta BioDelivery Services International Cephalon, Inc. (a wholly-owned subsidiary of Teva Pharmaceutical Industries, Depomed, [new Galena Biopharma, [new Therapeutics, [new Mallinckrodt Pharmaceuticalsm y?n A McKesson Specialty Care Solutionsm Mylan Incl? Par Pharmaceuticals, lnc.m RelayHealthm Therapeutics. Inc? Teva Pharmaceuticals, Ltd? United BioSource Corporationm DJ FDA (Food and Drug Administration)m 0 Now 321 (81.5) 1 don't known] 0 Question not asked 53 (13.5) Data Source: ADPQ, ADTQ Program: Page 4 of 4 TIRF Patient/Caregiver KAB 27DEC2016 Table 1.2: Survey Participant Eligibility Results - All Respondents Patients/Caregivers Question Discontinued 19 (4.8) Source: Appendix B: Survey Tables, Table 1.2 Note: Respondents who discontinued the survey before completing all eligibility questions without being identi?ed as ineligible in any of the previous questions are counted as discontinued. Once a respondent is counted as discontinued, they will count as discontinued in all subsequent eligibility questions. Ineligible to participate in the survey. Question not asked due to termination response from a previous question or skip pattern. Question does not dictate eligibility for survey completion but is asked of all respondents who did not terminate prior to question presentation. Only caregivers are asked this question. More than one response can be selected, so percentages may not sum to 100%. Ineligible to participate in the survey if selected additionally to another response. Data Source: ADPQ, ADTQ Program: TRIG Page 1 of 1 TIRF Patient/Caregiver KAB 27DEC2016 Table 1.3: Time to Complete Survey - Completed Surveys Telephone Internet Summary Statistic (minutes) 103 207 310 Mean (SD) 22.44 (6.012) 16.49 (7.987) 18.47 (7.895) Minimum 15.7 6.1 6.1 Median 21.10 14.65 17.66 Maximum 46.3 49.2 49.2 Category, 0 to <5 Minutes 0 0 0 5 to <10 Minutes 0 39 39 10to<15 Minutes 0 71 71 15 to <20 Minutes 39 47 86 20 to <25 Minutes 47 27 74 25 to <30 Minutes 10 8 18 30 Minutes or more 7 15 22 Source: Appendix B: Survey Tables, Table 1.3 Total number of eligible respondents completing the survey. Data Source: ADPQ Program: TRIG Page 1 of3 TIRF Patient/Caregiver KAB 27DEC2016 Table 2: Description of Eligible Patients/Caregivers - Completed Surveys Patients/Caregivers Question Respondent's age based on Question 6: Which of the following groups best describes your age? 18 - 29 8 (2.6) 30 - 39 21 (6.8) 40 - 49 59 (19-0) 50-59 118(38.1) 60 - 69 88 (28.4) 70 or older 16 (5.2) Patient's age based on Question 6/7: Which of the following groups best describes your age/the patient's age? Under 16 0 l6 - 29 8 (2.6) 30 - 39 21 (6.8) 40 - 49 60 (19.4) 50 - 59 116 (37.4) 60 - 69 89 (28.7) 70 or older 16 (5.2) Question 42: What is your gender? Male 110 (35.5) Female 198 (63.9) Prefer not to answer 2 (0.6) Question 43: What is the highest level of education you have completed? Less than high school 1 (0.3) Some high school 4 (1.3) High school graduate/GED 52 (16.8) Some college 97 (31.3) Associate's degree 41 (13.2) Bachelor's degree 72 (23.2) Master's degree 25 (8.1) Professional or Doctoral degree 15 (4.8) Data Source: ADPQ, ADTQ Program: TDESCSAS TRIG Page 2 of 3 TIRF Patient/Caregiver KAB 27DEC2016 Table 2: Description of Eligible Patients/Caregivers - Completed Surveys Patients/Caregivers Question Prefer not to answer 3 (1.0) Question 44: What is the main language you speak at home? English 305 (98.4) French 0 Spanish 2 (0.6) Portuguese 0 Italian 0 German 0 Chinese 0 Japanese 0 Korean 0 Other 1 (0.3) Prefer not to answer 2 (0.6) Question 45: Are you Hispanic or Latino? Yes 16 (5.2) No 289 (93.2) Prefer not to answer 5 (1.6) Question 46: For informational purposes only, which of the following US. census categories best describes your race? American Indian or Alaska Native 5 (1.6) Asian (origins of Far East, Southeast Asia or the Indian subcontinent) 1 (0.3) Black or African American 13 (4.2) Native Hawaiian or Other Paci?c Islander 1 (0.3) White 267 (86.1) Other 7 (2.3) Prefer not to answer 9 (2.9) Two or more races 7 (2.3) Geographic Distribution (based on Question 47 - In which state do you Northeast 56 (18.1) Data Source: ADPQ, ADTQ Program: TDESCSAS TRIG TIRF Patient/Caregiver KAB Page 3 of3 27DEC2016 Table 2: Description of Eligible Patients/Caregivers - Completed Surveys Patients/Caregivers Question Midwest 50 (16.1) South 109 (35.2) West 95 (30.6) Other 0 Prefer not to answer 0 Source: Appendix B: Survey Tables, Table 2 Total number of eligible respondents completing the survey. US. Census Bureau, last revised Friday, 27-Jul-2001 12:59:43 EDT., Geography Division. Northeast includes CT, MA, ME, NH, NJ, NY, PA, RI, and VT. Midwest includes IA, IL, IN, KS, MI, MN, MO, ND, NE, OH, SD, and WI. South includes AL, AR, DC, DE, FL, GA, KY, LA, MD, MS, NC, OK, SC, TN, TX, VA, and WV. West includes AK, AZ, CA, CO, HI, ID, MT, NM, NV, OR, UT, WA, and WY. Other includes Puerto Rico, Northern Mariana Islands, US Virgin Islands, American Samoa and Guam. Data Source: ADPQ, ADTQ Program: TDESC.SAS TRIG Page 1 of 4 TIRF Patient/Caregiver KAB 27DEC2016 Table 2a: Comparison of Survey Respondents to General Population of TIRF Users Patients Who Have Received a TIRF Patients Medicine Prescription Completing in the Last 4 Months Survey (120 days)?ll Question 11 p-value TIRF Medicine Prescription(s) Filled in the last 4 Months (120 days)"' Abstral 15 (4.8) 66 (2.1) Actiq, including generic versions of Actiq 71 (22.9) 1 125 (35.9) Fentora 56 (18.1) 606 (19.3) Lazanda 16 (5.2) 174 (5.6) Subsys 146 (47.1) 1247 (39.8) Other 20 (6.5) 1 don't know 5 (1.6) Age Group'3 Under 16 0 16 (0.5) 16 - 29 8 (2.6) 90 (2.9) 30 - 39 21 (6.8) 272 (8.8) 40 - 49 60 (19.4) 588 (18.9) 50 - 59 116 (37.4) 1127 (36.3) 60 - 69 89 (28.7) 782 (25.2) 70 or older 16 (5.2) 233 (7.5) 0.3579 Unknown 26 Gender? Male 110 (35.5) 1225 (39.1) Female 198 (63.9) 1904 (60.8) 0.2379 Prefer not to answer/Unknown 2 (0.6) 5 (0.2) Geographic DistributionIsl Northeast 56 (18.1) 527 (16.8) Midwest 50 (16.1) 449 (14.3) South 109 (35.2) 1062 (33.9) West 95 (30.6) 1096 (35.0) 0.4656 Data Source: ADPQ, ADTQ, IMFPAT Program: TDESCI MS. SAS TRIG Page 2 of 4 TIRF Patient/Caregiver KAB 27DEC2016 Table 2a: Comparison of Survey Respondents to General Population of TIRF Users Patients Who Have Received a TIRF Patients Medicine Prescription Completing in the Last 4 Months Survey (120 days)?ll Question 11 p-value Otheim 0 Prefer not to answer161 0 (N=l67l) Highest Level of Education Completedr? Less than high school diploma 5 (1.6) 93 (5.6) High school 52 (16.8) 526 (31.5) Some college 138 (44.5) 454 (27.2) Completed college 72 (23.2) 379 (22.7) Graduate school 40 (12.9) 219 (13.1) <.0001 Prefer not to answer 3 (1.0) 0 Main Language Spoken at Home'8 English 305 (98.4) 1600 (95.8) French 0 Spanish 2 (0.6) 49 (2.9) Portuguese 0 Italian 0 German 0 5 (0.3) Chinese 0 0 Japanese 0 0 Korean 0 0 Other 1 (0.3) 12 (0.7) 0.0914 Prefer not to answer 2 (0.6) 0 Hispanic or Latino? Yes 16 (5.2) 113 (6.8) No 289 (93.2) 1558 (93.2) 0.3242 Prefer not to answer 5 (1.6) 0 Race According to US Census Categoriesllol Data Source: ADPQ, ADTQ, IMFPAT Program: MS. SAS TRIG Page 3 of 4 TIRF Patient/Caregiver KAB 27DEC2016 Table 2a: Comparison of Survey Respondents to General Population of TIRF Users Patients Who Have Received a TIRF Patients Medicine Prescription Completing in the Last 4 Months Survey (120 days)?ll Question p-value American Indian or Alaska Nativel?] 5 (1.6) Asian (origins of Far East, Southeast Asia or 1 (0.3) 22 (1.3) the Indian subcontinent) Black or A?'ican American 13 (4.2) 15 (6.9) Native Hawaiian or Other Paci?c lslanderm (0.3) White 267 (86.1) 1492 (89.3) Two or more raceslq 7 (2.3) Otherm 7 (2 .3) <.0001 Data Source: ADPQ, ADTQ, IMFPAT Program: TRIG Page 4 of 4 Patient/Caregiver KAB 27DEC2016 Table 2a: Comparison of Survey Respondents to General Population of TIRF Users Patients Who Have Received a Patients Medicine Prescription Completing in the Last 4 Months Survey (120 days)Ill Question p-value Prefer not to answer/ Unknown 9 (2.9) 42 (2.5) Source: Appendix B: Survey Tables, Table 2a Note: Race/ Ethnicity, language spoken in the home, and education level are only available for 1671 patients with a Consumer Pro?le. P-values are calculated by a chi-square test excluding prefer not to answer, other, and comparable categories. Not available. ?1 Based on data from IMS provided on 01Dec2016. Data covered period of 05May2016 to 02Sep2016. Based on Question 4; More than one type of TIRF medicine could be selected. Based on Question 6/7; Percentages for the data are calculated based on the sum of available counts, minus the count for "Unknown." Based on Question 42. Based on Question 47; US. Census Bureau, last revised Friday, 27-Jul-2001 12:59:43 EDT., Geography Division. Northeast includes CT, MA, ME, NH, NJ, NY, PA, RI, and VT. Midwest includes IA, IL, IN, KS, MI, MN, MO, ND, NE, OH, SD, and WI. South includes AL, AR, DC, DE, FL, GA, KY, LA, MD, MS, NC, OK, SC, TN, TX, VA, and WV. West includes AK, AZ, CA, CO, HI, ID, MT, NM, NV, OR, UT, WA, and WY. Other includes Puerto Rico, Northem Mariana Islands, US Virgin Islands, American Samoa and Guam. Level not provided and/or collected by the IMS data. Based on Question 43; Less than high school diploma includes "Less than high school" and "Some high school"; Some college includes "Some college" and "Associate's degree"; Completed college includes "Bachelor?s degree"; Graduate school includes "Master's degree" and "Professional or Doctoral degree." Based on Question 44; "English" for the data is calculated using the total of 1671 patients with a Consumer Pro?le, minus the sum of other available counts. In the IMS data, French, German, Italian, and Portuguese are reported as combined with a total of 10 patients, and individually as 5 patients for German, and patients for French, Italian, and Portuguese. The count of 5 for German and the total of 5 for French, Italian, and Portuguese are used in the "English" calculation. Based on Question 45; "No" for the IMS data is calculated using the total of 1671 patients with a Consumer Pro?le, minus the count for "Yes." ?01 Based on Question 46; "White" for the data is calculated by combining the individual categon'es of Caucasian (1379 patients) and Hispanic/Latino(113 patients) as reported in the IMS data. represents 1-4 patients. Data Source: ADPQ, ADTQ, IMFPAT Program: TDESCI MS.SAS TRIG TIRF Patient/Caregiver KAB Page 1 of6 27DEC2016 Table 3: Responses to All Questions about the Safe Use of TIRF Medicines - Completed Surveys Question Patients/Caregivers Question 9: Did a doctor, nurse, or other healthcare professional in the doctor?s of?ce ever talk to you about the risks and possible side effects of the TIRF medicine that was most recently prescribed for you? TIRF medicines include Abstral?, Actiq?, entora?, Lazanda?, Subsys?, and the generic versions of these brands. Yes 265 (85.5) No 37 (11.9) 1 don't know 8 (2.6) No, or I don't know for each statement. Question 10: For which of the following conditions should you use a TIRF medicine? Please answer Yes, I 0a: Headache 0r migraine pain Yes 34 (l 1.0) 242 (78.1) 1 don't know 34 (l 1.0) I 0b: Breakthrough pain from cancer Yesm 225 (72.6) No 81 (26.1) 1 don't know 4 (1.3) I 0c: Dental pain Yes 5 (1.6) 269 (86.8) 1 don't know 36 (11.6) I 0d: Pain after surgery Yes 69 (22.3) 199 (64.2) 1 don't know 42 (13.5) We: Long-lasting pain not from cancer, like arthritis joint pain Yes 148 (47.7) 121 (39.0) 1 don't know 41 (13.2) Question 11: Please answer True, False, or I don't know for the following statement: Data Source: ADPQ, ADTQ Program: TEX. SAS TRIG TIRF Patient/Caregiver KAB Page 2 of 6 27DEC2016 Table 3: Responses to All Questions about the Safe Use of TIRF Medicines - Completed Surveys Patients/Caregivers Question TIRF medicines should only be taken by patients who are opioid tolerant. Truem 277 (89.4) False 8 (2.6) 1 don't know 25 (8.1) Question 12: Please answer True, False, or I don't know for each of the following statements. their body is used to these medicines. 12a: Opioid tolerant means that a patient is already taking other opioid pain medicines around-the-clock and Truem 273 (88.1) False 14 (4.5) I don't know 23 (7.4) 12b: A patient must stop taking their TIRF medicine if they stop taking their around-the-clock opioid pain medicine. Truem 123 (39.7) False 88 (28.4) I don't know 99 (31.9) 12c: It is safe to switch to another medicine that contains fentanyl without talking to a health care provider ?rst. True 6 (1.9) Falsem 297 (95.8) 1 don't know 7 (2.3) 12d: A patient may give TIRF medicines to another person if they have the same as the patient. True 6 1.9) Falsem 303 (97.7) 1 don't know 1 (0.3) was most recendy prescribed for you. Question 13: Please answer True, False, or I don't know for each statement about the TIRF medicine that l3a: TIRF medicines should be stored in a safe place out of the reach of ch ildren. Truem 310 (100.0) False 0 1 don't know 0 Data Source: ADPQ, ADTQ Program: TEX. SAS TRIG TIRF Patient/Caregiver KAB Page 3 of 6 27DEC2016 Table 3: Responses to All Questions about the Safe Use of TIRF Medicines - Completed Surveys Patients/Caregivers Question 13b: It is 0Kf0r patients to take TIRF medicines for headache pain. True 20 (6.5) Falsem 209 (67.4) 1 don't know 81 (26.1) 13c: TIRF medicines should be taken exactly as prescribed by the doctor. Truem 309 (99.7) False (0.3) 1 don't know 0 13d: TIRF medicines can cause life-threatening breathing problems that can lead to death. Truem 284 (91.6) False 8 (2.6) 1 don't know 18 (5.8) medicine? (Please select one.) Question 14: What should you do if an adult who has not been prescribed a TIRF medicine takes a TIRF Wait an hour and see if the person is OK. 10 (3.2) Get emergency help right away. 276 (89.0) Do nothing. 0 1 don't know. 24 (7.7) use the TIRF medicine that was most recently prescribed for you? Question 15: Did a doctor, nurse, or other healthcare professional in the doctor?s of?ce ever tell you how to Yes 294 (94.8) No 15 (4.8) 1 don't know 1 (0.3) store or keep the TIRF medicine that was most recently prescribed for you? Question 16: Did a doctor, nurse, or other healthcare professional in the doctor?s of?ce ever tell you how to Yes 270 (87.1) No 35 (11.3) 1 don't know 5 (1.6) was most recently prescribed for you. Question 17: Please answer True, False, or 1 don't know for each statement about the TIRF medicine that Data Source: ADPQ, ADTQ Program: TEX. SAS TRIG TIRF Patient/Caregiver KAB Page 4 of 6 27DEC2016 Table 3: Responses to All Questions about the Safe Use of TIRF Medicines - Completed Surveys Patients/Caregivers Question I 7a: Selling or giving away TIRF medicines is against the law. True'zl 308 (99.4) False (0.3) 1 don't know 1 (0.take IRF medicines for short-term pain that will go away in a few days. True 9 (2.9) Falsem 264 (85.2) I don't know 37 (11.9) I 7c: TIRF medicines must be disposed of as described in the specific product?s Medication Guide. Truem 303 (97.7) False 2 (0.6) I don't know 5 (1.6) I 7d: TIRF medicines are only available to patients through a pharmacy enrolled in the TIR REMS Access program). a special program (called Truem 238 (76.8) False 10 (3.2) 1 don't know 62 (20.0) I 7e: A TIRF medicine can cause an overdose and death in any child who takes it. Truem 292 (94.2) False 5 (1.6) 1 don't know 13 (4.2) Question 18: Please answer True, False, or I don't know for each statement about the TIRF medicine that was most recendy prescribed for you. 18a: A side effect of TIRF medicines is the chance of abuse or addiction. Truem 287 (92.6) False 5 (1.6) 1 don't know 18 (5.8) I 8b: TIRF medicines can be misused by people who abuse prescription medicines street drugs. True'z' 302 (97.4) Data Source: ADPQ, ADTQ Program: TEX. SAS TRIG TIRF Patient/Caregiver KAB Page 5 of 6 27DEC2016 Table 3: Responses to All Questions about the Safe Use of TIRF Medicines - Completed Surveys Patients/Caregivers Question False 0 1 don't know 8 (2.6) 180: TIRF medicines should be kept in a safe place to prevent it from being stolen. Truem 308 (99.4) False (0.3) [don't know 1 (0.3) the presence of children in your home? Question 37: Did a doctor, nurse, or other healthcare professional in the doctor's of?ce ever ask you about Yes 191 (61.6) No 89 (28.7) 1 don't know 30 (9.7) share the TIRF medicines with anyone elseor, nurse, oro er ea care ro essnona 0e 01?50 ce ever no 0 t'38D'ddt pf'l'thdt'f? tlly tt Yes 268 (86.5) No 34 (11.0) 1 don't know 8 (2.6) that accidental exposure to TIRF medicines by a child may be fatal? Question 39: Did a doctor, nurse, or other healthcare professional in the doctor's of?ce ever counsel you Yes 237 (76.5) No 48 (15.5) [don't know 25 (8.1) keep TIRF medicines out of reach of children to prevent accidental exposure? Question 40: Did a doctor, nurse, or other healthcare professional in the doctor's of?ce ever tell you to Yes 264 (85.2) No 35 (11.3) 1 don't know 11 (3.5) proper disposal of any unused or partially used TIRF medicines? Question 41: Did a doctor, nurse, or other healthcare professional in the doctor's of?ce ever tell you about Yes 237 (76.5) No 48 (15.5) Data Source: ADPQ, ADTQ Program: TEX. SAS TRIG Page 6 of 6 TIRF Patient/Caregiver KAB 27DEC2016 Table 3: Responses to All Questions about the Safe Use of TIRF Medicines - Completed Surveys Patients/Caregivers Question I don't know 25 (8.1) Source: Appendix B: Survey Tables, Table 3 Total number of eligible respondents completing the survey. Correct response. Data Source: ADPQ, ADTQ Program: TEXSAS TRIG TIRF Patient/Caregiver KAB Page 1 of3 27DEC2016 Table 4: Responses to Questions about TIRF Educational Materials - Completed Surveys Question Patients/Caregivers Question 19: Have you ever received a Medication Guide for the TIRF medicine that was prescribed for you? Yes 288 (92.9) No 5 (1.6) 1 don't know 17 (5.5) someone in the doctor's of?ce?'2 Question 20: Did you receive the Medication Guide from the doctor who prescribed the TIRF medicine or Yes 164 (56.9) No 104 (36.1) 1 don't know 20 (6.9) (Answered "No" or don 't know" to Question I 9) 22 Question 21: When was the Medication Guide given to you? Please select all that apply. At the ?rst appointment with the doctor who prescribed the TIRF medicine 134 (81.7) At the last appointment with the doctor who prescribed the TIRF medicine 26 (15.9) 1 don't remember 23 (14.0) (Answered or don ?t know" to Question I 9 or 20) 146 Question 22: Did you receive the Medication Guide for the TIRF medicine from the pharmacy?'2' Yes 265 (92.0) No 16 (5.6) 1 don't know 7 (2.4) (Answered "No" or don 't know" to Question I 9) 22 pharmacy?'2" Question 23: How frequently do you receive a Medication Guide for the TIRF medicine at the Only with the ?rst ?lled prescription 10 (3.8) Each time a prescription is ?lled 242 (91.3) Other (please specify): 8 (3.0) 1 don't know 5 (1.9) (Answered or don ?t know" to Question I 9 or 22) 45 Question 24: Did you read the Medication Guide?m Yes 278 (96.5) Data Source: ADPQ, ADTQ Program: TEDUC.SAS TRIG TIRF Patient/Caregiver KAB Page 2 of3 27DEC2016 Table 4: Responses to Questions about TIRF Educational Materials - Completed Surveys Patients/Caregivers Question No 7 (2.4) 1 don't know 3 (1.0) (Answered "No" or don know" to Question I 9) 22 Question 25: How much did you read?l2 All of it 168 (60.4) Most of it 90 (32.4) Some of it 20 (7.2) 1 don't know 0 (Answered "No or don 't know" to Question I 9 or 24) 32 Question 26: How much of the Medication Guide did you understand?'2 All of it 144 (51.8) Most ofit 109 (39.2) Some of it 25 (9.0) None of it 0 1 don't know 0 (Answered "No or don 't know" to Question I 9 or 24) 32 Question 27: Did someone offer to explain the Medication Guide to you??2 Yes 194 (67.4) No 79 (27.4) 1 don't know 15 (5.2) (Answered "No? or don ?t know" to Question I 9) 22 Question 28: Who offered to explain the Medication Guide to you? Please select all that apply?" The doctor or another healthcare professional in the doctor's of?ce 131 (67.5) The pharmacist where the TIRF medicine prescription was ?lled 161 (83.0) Someone else 16 (8.2) (Answered "No or don 't know" to Question I 9 or 27) 16 Question 29: Did you accept the offer to have the Medication Guide explained to you??2 Yes 125 (64.4) No 66 (34.0) Data Source: ADPQ, ADTQ Program: TEDUC.SAS TRIG TIRF Patient/Caregiver KAB Page 3 of3 27DEC2016 Table 4: Responses to Questions about TIRF Educational Materials - Completed Surveys Patients/Caregivers Question 1 don't know 3 (1.5) (Answered "No or don 't know" to Question 19 or 27) 16 Question 30: How much of the explanation did you understand??2 All of it 91 (72.8) Most of it 29 (23.2) Some of it 5 (4.0) None of it 0 1 don't know 0 (Answered "No" or don 't know" to Question 19, 27 or 29) 185 Question 31: Did you or do you have any questions about the information in the Medication Guide? Yes 10 (3.5) No 275 (95.5) 1 don't know 3 (1.0) (Answered ?No" or don 't know" to Question I 9) 22 Source: Appendix B: Survey Tables, Table 4 Total number of eligible respondents completing the survey. Percentages are calculated based on the sample presented with this question because of skip logic in the survey. More than one response can be selected, so percentages may not sum to 100%. Verbatim text for Question 23 (Other frequency of receiving a Medication Guide in the pharmacy) is presented in Listing 1. Verbatim text for Question 28 (Other type of person explaining Medication Guide) is presented in Listing 2. Verbatim text for question about the Medication Guide (Question 32) is presented in Listing 3. Data Source: ADPQ, ADTQ Program: TEDUC.SAS TRIG TIRF Patient/Caregiver KAB Page 1 of] 27DEC2016 Table 5: Responses to Questions about the Patient-Prescriber Agreement Form - Completed Surveys Patients/Care ivers (N =310) Question 11 Form to you? Question 33: Did the doctor or someone in the doctor?s of?ce explain the Patient-Prescriber Agreement Yes 239 (77.1) No 32 (10.3) 1 don't know 39 (12.6) Question 34: How much of the explanation did you understand?'2 All of it 200 (83.7) Mostofit 36(15.l) Some of it 3 (1.3) None of it 0 1 don't know 0 (Answered ?No" or don know" to Question 33) 71 Question 35: Did you sign a Patient-Prescriber Agreement Form? Yes 237 (76.5) No 15 (4.8) [don't know 58 (18.7) Patient-Prescriber Agreement Form??2 uestlon I octor or someone octorso Ice give youacopyo esngne '36D'dhd 'thd ?11" fth' Yes 182 (76.8) No 16 (6.8) I don't know 39 (16.5) (Answered ?No" or don know" to Question 35) 73 Source: Appendix B: Survey Tables, Table 5 Total number of eligible respondents completing the survey. Percentagm are calculated based on the sample presented with this question because of skip logic in the survey. Data Source: ADPQ, ADTQ Program: TPPAFSAS TRIG Page 1 of TIRF Patient/Caregiver KAB 27DEC2016 Table 6.1: Primary Analysis of Responses to Questions Linked to Key Risk Message #1 - Completed Surveys Patients/Care ivers Question [95% Cl lzl Question 13: Please answer True, False, or I don't know for each statement about the TIRF medicine that was most recently prescribed for you. I 3d: TIRF medicines can cause life-threatening breathing problems that can lead to death. Truem 284 (91.6) [88.0 94.4] False 8 (2.6) [don't know 18 (5.8) Source: Appendix B: Survey Tables, Table 6.1 Total number of eligible respondents completing the survey. 95% exact two-sided confidence intervals are calculated using the Clopper-Pearson method. Correct response. Data Source: ADPQ, ADTQ Program: TRIG TIRF Patient/Caregiver KAB Page 1 of] 27DEC2016 - Completed Surveys Table 6.1.1: Responses to Questions Linked to Key Risk Message #1 by Reading Medication Guide Question Reading Medication Guide Received and read Med Guide [95% Not received or not read Med Guide [95% cu'" Question 13: Please answer True, False, or I don't know for each statement about the TIRF medicine that was most recently prescribed for you. I 3d: TIRF medicines can cause life-threatening breathing problems that can lead to death. Truem 238 (92.2) [88.3 95.2] 46 (88.5) [76.6 95.6] False 7 (2.7) 1 (1.9) [don't know 13 (5.0) 5 (9.6) Source: Appendix B: Survey Tables, Table 6.1.1 ?195% exact two-sided confidence intervals are calculated using the Clopper-Pearson method. Correct response. Data Source: ADPQ, ADTQ Program: TK RM S. SAS TRIG Page 1 of TIRF Patient/Caregiver KAB 27DEC2016 Table 6.1.2: Responses to Questions Linked to Key Risk Message #1 by Understanding of the Medication Guide - Completed Surveys Understanding of the Medication Guide Question Understood most or all [95% Understood some [95% Did not understand [95% Did not receive or read [95% Question 13: Please answer True, False, or I don't know for each statement about the TIRF medicine that was most recently prescribed for you. I 3d: TIRF medicines can cause life-threatening breathing problems that can lead to death. Truem 234 (92.5) [88.5 - 95 22 (88.0) [68.8 - 97.5] 0 28 (87.5) [71.0 - 96.5] False 5 (2.0) 2 (8.0) 0 1 (3.1) 1 don't know 14 (5.5) 1 (4.0) 0 3 (9.4) Source: Appendix B: Survey Tables, Table 6.1.2 ?195% exact two-sided confidence intervals are calculated using the Clopper-Pearson method. Correct response. Data Source: ADPQ, ADTQ Program: TK RM S. SAS TRIG Page 1 of] TIRF Patient/Caregiver KAB 27DEC2016 Table 6.1.3: Responses to Questions Linked to Key Risk Message #1 by Modality to Complete Survey - Completed Surveys Modality to Complete Survey Internet Telephone (N=l03) Question [95% cn'" [95% cu'" Question 13: Please answer True, False, or I don't know for each statement about the TIRF medicine that was most recently prescribed for you. 13d: TIRF medicines can cause life-threatening breathing problems that can lead to death. Truem 191 (92.3) [87.8 - 95.5] 93 (90.3) [82.9 - 952] False 7 (3.4) 1 (1.0) [don?t know 9 (4.3) 9 (8.7) Source: Appendix B: Survey Tables, Table 6.1.3 95% exact two-sided con?dence intervals are calculated using the Clopper-Pearson method. Correct response. Data Source: ADPQ, ADTQ Program: TRIG Page 1 of TIRF Patient/Caregiver KAB 27DEC2016 Table 6.1.4: Responses to Questions Linked to Key Risk Message #1 by Highest Level of Education - Completed Surveys Highest Level of Education Question GED or less [95% College (N=l38) [95% or [95% Professional or Doctoral Degree [95% Question 13: Please answer True, False, or I don't know for each statement about the TIRF medicine that was most recently prescribed for you. 13d: TIRF medicines can cause life-threatening breathing problems that can lead to death. Truem 51 (85.0) [73.4 - 92.9] 133 (96.4) [91.7 - 98.8] 85 (87.6) [79.4 93.4] 15 (100.0) [78.2 - 100.0] False 4 (6.7) 1 (0.7) 3 (3.1) 0 1 don't know 5 (8.3) 4 (2.9) 9 (9.3) 0 Source: Appendix B: Survey Tables, Table 6.1.4 Note: GED or less includes "Less than high school," "Some high school," "High school graduate/GED," or "Prefer not to answer." College includes "Some college" and "Associate's degree." or includes "Bachelor's degree" and "Master's degree." Professional or Doctoral degree includes "Professional or Doctoral degree." ?195% exact two-sided con?dence intervals are calculated using the Clopper-Pearson method. Correct response. Data Source: ADPQ, ADTQ Program: TRIG Page 1 of] TIRF Patient/Caregiver KAB 27DEC2016 Table 6.1.5: Responses to Questions Linked to Key Risk Message #1 by Age Group of Respondent - Completed Surveys Age Group of Respondent older Question [95% [95% [95% [95% C1[Ill Question 13: Please answer True, False, or I don't know for each statement about the TIRF medicine that was most recently prescribed for you. I 3d: TIRF medicines can cause life-threatening breathing problems that can lead to death. Truem 27 (93.1) [77.2 - 99.2] 58 (98.3) [90.9 100.0] 108 (91.5) [85.0 95.9] 91 (87.5) [79.6 - 93 2] False 1 (3.4) 0 5 (4.2) 2 (1.9) [don't know 1 (3.4) 1 (1.7) 5 (4.2) 11 (10.6) Source: Appendix B: Survey Tables, Table 6.1.5 ?195% exact two-sided confidence intervals are calculated using the Clopper-Pearson method. Correct response. Data Source: ADPQ, ADTQ Program: TK RM S. SAS TRIG Page 1 of TIRF Patient/Caregiver KAB 27DEC2016 Table 7.1: Primary Analysis of Responses to Questions Linked to Key Risk Message #2 - Completed Surveys Patients/C are ivers Question [95% Cl lzl Question 11: Please answer True, False, or I don't know for the following statement: medicines should only be taken by patients who are opioid tolerant. Truem 277 (89.4) [85.4 - 92.6] False 8 (2.6) I don't know 25 (8.1) Question 12: Please answer True, False, or I don't know for each of the following statements. 12a: Opioid tolerant means that a patient is already taking other opioid pain medicines around-the-clock and their body is used to these medicines. Truem 273 (88.1) [83.9 - 91.5] False 14 (4.5) 1 don't know 23 (7.4) Source: Appendix B: Survey Tables, Table 7.1 Total number of eligible respondents completing the survey. 95% exact two-sided con?dence intervals are calculated using the Clopper-Pearson method. Correct response. Data Source: ADPQ, ADTQ Program: TRIG TIRF Patient/Caregiver KAB Page 1 of] 27DEC2016 - Completed Surveys Table 7.1.1: Responses to Questions Linked to Key Risk Message #2 by Reading Medication Guide Question Reading Medication Guide Received and read Med Guide [95% Not received or not read Med Guide [95% cu'" Question 11: Please answer True, False, or I don't know for the following statement: TIRF medicines should only be taken by patients who are opioid tolerant. True 234 (90.7) [86.5 - 93.9] 43 (82.7) [69.7 - 91.8] False 6 (2.3) 2 (3.8) [don't know 18 (7.0) 7 (13.5) Question 12: Please answer True, False, or I don't know for each of the following statements. 12a: Opioid tolerant means that a patient is already taking other opioid pain medicines around-the-clock and their body is used to these medicines. Truem 228 (88.4) [83.8 - 92.0] 45 (86.5) [74.2 - 94.4] False 12 (4.7) 2 (3.8) [don't know 18 (7.0) 5 (9.6) Source: Appendix B: Survey Tables, Table 7.1.1 ?195% exact two-sided con?dence intervals are calculated using the Clopper-Pearson method. Correct response. Data Source: ADPQ, ADTQ Program: TK RM S. SAS TRIG TIRF Patient/Caregiver KAB Page 1 of] 27DEC2016 Table 7.1.2: Responses to Questions Linked to Key Risk Message #2 by Understanding of the Medication Guide - Completed Surveys Question Understanding of the Medication Guide Understood most or all [95% Understood some [95% Did not understand [95% Did not receive or read [95% C1[Ill uestlon ease answer rue, ase, or ont now ort owm statement: Fl ld'k TIRF medicines should only be taken by patients who are opioid tolerant. Truem 228 (90.1) [85.8 - 93.5] 19 (76.0) [54.9 - 90.6] 0 30 (93.8) [79.2 - 992] False 6 (2.4) 2 (8.0) 0 0 1 don't know 19 (7.5) 4 (16.0) 0 2 (6.3) Question 12: Please answer True, False, or I don't know for each of the following statements. 12a: Opioid tolerant means that a patient is already taking other opioid pain medicines around-the-clock and their body is used to these medicines. Truem 225 (88.9) [84.4 - 92.5] 21 (84.0) [63.9 - 95.5] 0 27 (84.4) [67.2 - 94.7] False 12 (4.7) 1 (4.0) 0 1 (3.1) [don't know 16 (6.3) 3 (12.0) 0 4 (12.5) Source: Appendix B: Survey Tables, Table 7.1.2 ?195% exact two-sided con?dence intervals are calculated using the Clopper-Pearson method. Correct response. Data Source: ADPQ, ADTQ Program: TRIG Page 1 of] TIRF Patient/Caregiver KAB 27DEC2016 Table 7.1.3: Responses to Questions Linked to Key Risk Message #2 by Modality to Complete Survey - Completed Surveys Modality to Complete Survey Internet Telephone (N=l03) Question [95% cu"I [95% C1[Ill Question 11: Please answer True, False, or I don't know for the following statement: TIRF medicines should only be taken by patients who are opioid tolerant. Truem 189 (91.3) [86.6 - 94.8] 88 (85.4) [77.1 - 91.6] False 6 (2.9) 2 (1.9) [don't know 12 (5.8) 13 (12.6) Question 12: Please answer True, False, or I don't know for each of the following statements. 12a: Opioid tolerant means that a patient is already taking other opioid pain medicines around-the-clock and their body is used to these medicines. Truem 185 (89.4) [84.4 93.2] 88 (85.4) [77.1 - 91.6] False 7 (3.4) 7 (6.8) [don't know 15 (7.2) 8 (7.8) Source: Appendix B: Survey Tables, Table 7.1.3 95% exact two-sided con?dence intervals are calculated using the Clopper-Pearson method. Correct response. Data Source: ADPQ, ADTQ Program: TRIG Page 1 of] TIRF Patient/Caregiver KAB 27DEC2016 Table 7.1.4: Responses to Questions Linked to Key Risk Message #2 by Highest Level of Education - Completed Surveys Highest Level of Education Professional or GED or less College or Doctoral Degree Question 95% 95% 01'" 95% 95% Question 11: Please answer True, False, or I don't know for the following statement: TIRF medicines should only be taken by patients who are opioid tolerant. Truem 51 (85.0) [73.4 - 92.9] 124 (89.9) [83.6 - 94.3] 89 (91.8) [84.4 96.4] 13 (86.7) [59.5 - 98.3] False 0 4 (2.9) 2 (2.1) 2 (13.3) 1 don't know 9 (15.0) 10 (7.2) 6 (6.2) 0 Question 12: Please answer True, False, or I don't know for each of the following statements. 12a: Opioid tolerant means that a patient is already taking other opioid pain medicines around-the-clock and their body is used to these medicines. Truem 53 (88.3) [77.4 - 95.2] 121 (87.7) [81.0 - 92.7] 86 (88.7) [80.6 - 94.2] 13 (86.7) [59.5 - 98.3] False 2 (3.3) 7 (5.1) 5 (5.2) 0 1 don't know 5 (8.3) 10 (7.2) 6 (6.2) 2 (13.3) Source: Appendix B: Survey Tables, Table 7.1.4 Note: GED or less includes Less than high school," "Some high school," "High school graduate/GED," or "Prefer not to answer." College includes "Some college" and "Associate's degree." or includes "Bachelor?s degree" and "Master?s degree." Professional or Doctoral degree includes "Professional or Doctoral degree." ?195% exact two-sided confidence intervals are calculated using the Clopper-Pearson method. Correct response. Data Source: ADPQ, ADTQ Program: TRIG Page 1 of] TIRF Patient/Caregiver KAB 27DEC2016 Table 7.1.5: Responses to Questions Linked to Key Risk Message #2 by Age Group of Respondent - Completed Surveys Age Group of Respondent older Question [95% [95% [95% [95% uestlon ease answer rue, ase, or ont now ort owm statement: Fl ld'k TIRF medicines should only be taken by patients who are opioid tolerant. Truem 26 (89.7) [72.6 - 97.8] 52 (88.1) [77.1 - 95.1] 107 (90.7) [83.9 95.3] 92 (88.5) [80.7 - 93 False 2 (6.9) 5 (8.5) 1 (0.8) 0 1 don't know 1 (3.4) 2 (3.4) 10 (8.5) 12 (11.5) Question 12: Please answer True, False, or I don't know for each of the following statements. 12a: Opioid tolerant means that a patient is already taking other opioid pain medicines around-the-clock and their body is used to these medicines. Truem 28 (96.6) [82.2 - 99.9] 54 (91.5) [81.3 - 972] 106 (89.8) [82.9 - 94.6] 85 (81.7) [72.9 - 88.6] False 1 (3.4) 2 (3.4) 4 (3.4) 7 (6.7) [don't know 0 3 (5.1) 8 (6.8) 12 (11.5) Source: Appendix B: Survey Tables, Table 7.1.5 ?195% exact two-sided con?dence intervals are calculated using the Clopper-Pearson method. Correct response. Data Source: ADPQ, ADTQ Program: TK RM S. SAS TRIG Page 1 of TIRF Patient/Caregiver KAB 27DEC2016 Table 7.2: Secondary Analysis of Responses to Questions Linked to Key Risk Message #2 - Completed Surveys Patients/Care ivers Correct Responses 0 correct responses 17 (5.5) 1 correct response 36 (11.6) 2 correct responses 257 (82.9) Source: Appendix B: Survey Tables, Table 7.2 Total number of eligible respondents completing the survey. Data Source: ADPQ, ADTQ Program: TRIG TIRF Patient/Caregiver KAB Page 1 of2 27DEC2016 Completed Surveys Table 8.1: Primary Analysis of Responses to Questions Linked to Key Risk Message #3 - Question Patients/Care ivers [95% cum No, or I don't know for each statement. Question 10: For which of the following conditions should you use a TIRF medicine? Please answer Yes, I 0a: Headache or migraine pain Yes 34 (1 1.0) 242 (78.1) [73.0 - 82.5] I don't know 34 (l 1.0) I 0b: Breakthrough pain from cancer Yesm 225 (72.6) [67.3 - 77.5] No 81 (26.1) 1 don't know 4 (1.3) I 0c: Dental pain Yes 5 (1.6) Non] 269 (86.8) [82.5 - 90.3] 1 don't know 36 (11.6) I 0d: Pain after surgery Yes 69 (22.3) N091 199 (64.2) [58.6 - 69.5] I don't know 42 (13.5) I 0e: Long-lasting pain not from cancer, like arthritis joint pain Yes 148 (47.7) N001 121 (39.0) [33.6 - 44.7] 1 don't know 41 (13.2) Question 12: Please answer True, False, or I don't know for each of the following statements. I 2b: A patient must stop taking their TIRF medicine if they stop taking their around-the-clock opioid pain medicine. Truem 123 (39.7) [34.2 - 45.4] False 88 (28.4) I don't know 99 (31.9) Data Source: ADPQ, ADTQ Program: TRIG TIRF Patient/Caregiver KAB Page 2 of 2 27DEC2016 Completed Surveys Table 8.1: Primary Analysis of Responses to Questions Linked to Key Risk Message #3 - Question Patients/C are ivers [95% cu? was most recently prescribed for you. Question 13: Please answer True, False, or I don't know for each statement about the TIRF medicine that 13b: 1! is OK for patients to take TIRF medicines for headache pain. True 20 (6.5) Falsem 209 (67.4) [61.9 - 72.6] [don't know 81 (26.1) 13c: TIRF medicines should be taken exactly as prescribed by the doctor. Truem 309 (99.7) [98.2 - 100.0] False (0.3) 1 don't know 0 was most recently prescribed for you. Question 17: Please answer True, False, or I don't know for each statement about the TIRF medicine that I 7b: 1! is OK to take TIRF medicines for short-term pain that will go away in a few days. True 9 (2.9) Falsem 264 (85.2) [80.7 88.9] [don't know 37 (11.9) Source: Appendix B: Survey Tables, Table 8.1 Total number of eligible respondents completing the survey. 95% exact two-sided con?dence intervals are calculated using the Clopper-Pearson method. Correct response. Data Source: ADPQ, ADTQ Program: TIRF Patient/Caregiver KAB Page 1 of2 27DEC2016 - Completed Surveys Table 8.1.1: Responses to Questions Linked to Key Risk Message #3 by Reading Medication Guide Question Reading Medication Guide Received and read Med Guide [95% cu'? Not received or not read Med Guide [95% or I don't know for each statement. Question 10: For which of the following conditions should you use a TIRF medicine? Please answer Yes, No, I 0a: Headache or migraine pain Yes 30 (11.6) 4 (7.7) Now 202 (78.3) [72.8 - 83.2] 40 (76.9) [63.2 - 87.5] 1 don't know 26 (10.1) 8 (15.4) I 0b: Breakthrough pain ?om cancer Yesm 189 (73.3) [67.4 - 78.6] 36 (69.2) [54.9 - 81.3] No 65 (25.2) 16 (30.8) I don't know 4 (1.6) 0 10c: Dental pain Yes 4 (1.6) 1 (1.9) Now 226 (87.6) [82.9 - 91.4] 43 (82.7) [69.7 - 91.8] [don't know 28 (10.9) 8 (15.4) I 0d: Pain after surgery Yes 55 (21.3) 14 (26.9) Now 170 (65.9) [59.8 - 71.7] 29 (55.8) [41.3 - 69.5] 1 don't know 33 (12.8) 9 (17.3) We: Long-lasting pain not from cancer, like arthritis joint pain Yes 122 (47.3) 26 (50.0) Now 103 (39.9) [33.9 - 46.2] 18 (34.6) [22.0 49.1] [don't know 33 (12.8) 8 (15.4) Question 12: Please answer True, False, or I don't know for each of the following statements. 12b: A patient must stop taking their TIRF medicine if they stop taking their around-the-clock opioid pain medicine. Truem 110 (42.6) [36.5 - 48.9] 13 (25.0) [14.0 - 38.9] False 71 (27.5) 17 (32.7) Data Source: ADPQ, ADTQ Program: TK RM S. SAS TRIG TIRF Patient/Caregiver KAB Page 2 of 2 27DEC2016 - Completed Surveys Table 8.1.1: Responses to Questions Linked to Key Risk Message #3 by Reading Medication Guide Reading Medication Guide Received and read Not received or not read Med Guide Med Guide Question [95% Cll'" [95% 1 don't know 77 (29.8) 22 (42.3) was most recently prescribed for you. Question 13: Please answer True, False, or I don't know for each statement about the TIRF medicine that 13b: It is OK for patients to take TIRF medicines for headache pain. True 18 (7.0) 2 (3.8) Falsem 180 (69.8) [63.8 - 75.3] 29 (55.8) [41.3 - 69.5] 1 don't know 60 (23.3) 21 (40.4) 13c: TIRF medicines should be taken exactly as prescribed by the doctor. Truem 258 (100.0) [98.6 - 100.0] 51 (98.1) [89.7 - 100.0] False 0 1 (1.9) 1 don't know 0 0 was most recently prescribed for you. Question 17: Please answer True, False, or I don't know for each statement about the TIRF medicine that I 7b: It is OK to take TIRF medicines for short-term pain that will go away in a few days. True 6 (2.3) 3 (5.8) Falsem 229 (88.8) [84.3 - 92.3] 35 (67.3) [52.9 - 79.7] 1 don't know 23 (8.9) 14 (26.9) Source: Appendix B: Survey Tables, Table 8.1.1 ?195% exact two-sided confidence intervals are calculated using the Clopper-Pearson method. Correct response. Data Source: ADPQ, ADTQ Program: TK RM S. SAS TRIG TIRF Patient/Caregiver KAB Page 1 of3 27DEC2016 Table 8.1.2: Responses to Questions Linked to Key Risk Message #3 by Understanding of the Medication Guide - Completed Surveys Question Understanding of the Medication Guide Understood most or all [95% Understood some [95% cu"I Did not understand [95% Did not receive or read [95% uestion 10: For which of the followin conditions should ou use a TIRF medicine? Please answer Yes, No, or I don't know for each statement. I 0a: Headache 0r migraine pain Yes 30 (11.9) 3 (12.0) 0 1 (3.1) Now 198 (78.3) [72.7 - 83.2] 19 (76.0) [54.9 - 90.6] 0 25 (78.1) [60.0 - 90.7] 1 don't know 25 (9.9) 3 (12.0) 0 6 (18.8) I 0b: Breakthrough pain ?om cancer Yesm 186 (73.5) [67.6 - 78.8] 17 (68.0) [46.5 - 85.1] 0 22 (68.8) [50.0 - 83.9] No 63 (24.9) 8 (32.0) 0 10 (31.3) 1 don't know 4 (1.6) 0 0 0 I 0c: Dental pain Yes 4 (1.6) 0 0 1 (3.1) Now 223 (88.1) [83.5 - 91.9] 22 (88.0) [68.8 - 97.5] 0 24 (75.0) [56.6 - 88.5] [don't know 26 (10.3) 3 (12.0) 0 7 (21.9) I 0d: Pain after surgery Yes 54 (21.3) 5 (20.0) 0 10 (31.3) New 169 (66.8) [60.6 - 72.6] 13 (52.0) [31.3 - 722] 0 17 (53.1) [34.7 - 70.9] 1 don't know 30 (11.9) 7 (28.0) 0 5 (15.6) 10e: Long-lasting pain not from cancer, like arthritis joint pain Data Source: ADPQ, ADTQ Program: TK RM S. SAS TRIG Tl RF Patient/Caregiver KA Page 2 of3 27DEC2016 Table 8.1.2: Responses to Questions Linked to Key Risk Message #3 by Understanding of the Medication Guide - Completed Surveys Question Understanding of the Medication Guide Understood most or all [95% Understood some [95% Did not understand [95% Did not receive or read [95% cu'" Yes 1 19 (47.0) 15 (60.0) 0 14 (43.8) 98 (38.7) [32.7 - 45.0] 9 (36.0) [18.0 - 57.5] 0 14 (43.8) [26.4 - 62.3] 1 don't know 36 (14.2) 1 (4.0) 0 4 (12.5) Question 12: Please answer True, False, or I don't know for each of the following statements. 12b: A patient must stop taking their TIRF medicine if they stop taking their around-the-clock opioid pain medicine. Truem 105 (41.5) [35.4 - 47.8] 10 (40.0) [21.1 - 61.3] 0 8 (25.0) [11.5 - 43.4] False 74 (29.2) 500m 0 9 (28.1) I don't know 74 (29.2) 10 (40.0) 0 15 (46.9) Question 13: Please answer True, False, or I don't know for each statement about the TIRF medicine that was most recently prescribed for you. It is OK for patients to take TIRF medicines for headache pain. True 18(7.1) 1 (4.0) 1(3.1) alsem 178 (70.4) [64.3 - 75.9] 15 (60.0) [38.7 - 78.9] 16 (50.0) [31.9 - 68.1] 1 don't know 57 (22.5) 9 (36.0) 15 (46.9) 13c: TIR medicines should be taken exactly as prescribed by the doctor. Truem 253 (100.0) [98.6 - 100.0] 25 (100.0) [86.3 - 100.0] 31 (96.9) [83.8 - 99.9] False 0 0 1(3.1) 1 don't know 0 0 0 Question 17: Please answer True, False, or I don't know for each statement about the TIRF medicine that was most recently prescribed for you. Data Source: ADPQ, ADTQ Program: TRIG TIRF Patient/Caregiver KAB Page 3 of3 27DEC2016 Table 8.1.2: Responses to Questions Linked to Key Risk Message #3 by Understanding of the Medication Guide - Completed Surveys Question Understanding of the Medication Guide Understood most or all [95% Understood some [95% Did not understand [95% Did not receive or read [95take TIRF medicines for short-term pain that will go away in a few days. True 6 (2.4) 1 (4.0) 0 2 (6.3) Falsem 227 (89.7) [85.3 - 93.2] 18 (72.0) [50.6 - 87.9] 0 19 (59.4) [40.6 - 76.3] 1 don't know 20 (7.9) 6 (24.0) 0 11 (34.4) Source: Appendix B: Survey Tables, Table 8.1.2 ?195% exact two-sided confidence intervals are calculated using the Clopper-Pearson method. Correct rmponse. Data Source: ADPQ, ADTQ Program: TK RM S. SAS TRIG TIRF Patient/Caregiver KAB Page 1 of2 27DEC2016 Survey - Completed Surveys Table 8.1.3: Responses to Questions Linked to Key Risk Message #3 by Modality to Complete Question Modality to Complete Survey Internet [95% Telephone (N=l03) [95% or I don't know for each statement. Question 10: For which of the following conditions should you use a TIRF medicine? Please answer Yes, No, I 0a: Headache or migraine pain Yes 20 (9.7) 14 (13.6) New 164 (79.2) [73.1 - 84.5] 78 (75.7) [66.3 - 83.6] ldon?tknow 23 (11.1) 11 (10.7) I 0b: Breakthrough pain from cancer Yesm 142 (68.6) [61.8 - 74.9] 83 (80.6) [71.6 - 87.7] No 62 (30.0) 19 (18.4) [don't know 3 (1.4) (1.0) 10c: Dental pain Yes 2 (1.0) 3 (2.9) Now 181 (87.4) [82.1 - 91.6] 88 (85.4) [77.1 - 91.6] ldon'tknow 24(11.6) 12(11.7) I 0d: Pain after surgery Yes 35 (16.9) 34 (33.0) Now 141 (68.1) [61.3 - 74.4] 58 (56.3) [46.2 - 66.1] [don't know 31 (15.0) 11 (10.7) We: Long-lasting pain not from cancer, like arthritis joint pain Yes 102 (49.3) 46 (44.7) Now 78 (37.7) [31.1 - 44.7] 43 (41.7) [32.1 - 51.9] [don't know 27 (13.0) 14 (13.6) Question 12: Please answer True, False, or I don't know for each of the following statements. 12b: A patient must stop taking their TIRF medicine if they stop taking their around-the-clock opioid pain medicine. Truem 94 (45.4) [38.5 - 52.5] 29 (28.2) [19.7 - 37.9] False 55 (26.6) 33 (32.0) I don't know 58 (28.0) 41 (39.8) Data Source: ADPQ, ADTQ Program: TK RM S. SAS TRIG TIRF Patient/Caregiver KAB Page 2 of 2 27DEC2016 Survey - Completed Surveys Table 8.1.3: Responses to Questions Linked to Key Risk Message #3 by Modality to Complete Question Modality to Complete Survey Internet [95% Telephone [95% was most recently prescribed for you. Question 13: Please answer True, False, or I don't know for each statement about the TIRF medicine that 13b: It is OK for patients to take TIRF medicines for headache pain. True 14 (6.8) 6 (5.8) Falsem 141 (68.1) [61.3 - 74.4] 68 (66.0) [56.0 - 75.1] 1 don?t know 52 (25.1) 29 (28.2) 13c: TIRF medicines should be taken exactly as prescribed by the doctor. Truem 206 (99.5) [97.3 - 100.0] 103 (100.0) [96.5 - 100.0] False (0.5) 0 I don't know 0 0 was most recently prescribed for you. Question 17: Please answer True, False, or I don't know for each statement about the TIRF medicine that I 7b: It is 0K to take TIRF medicines for short-term pain that will go away in a few days. True 5 (2.4) 4 (3.9) Falsem 176 (85.0) [79.4 - 89.6] 88 (85.4) [77.1 - 91.6] 16611: know 26 (12.6) 11 (10.7) Source: Appendix B: Survey Tables, Table 8.1.3 ?195% exact two-sided confidence intervals are calculated using the Clopper-Pearson method. Correct response. Data Source: ADPQ, ADTQ Program: TK RM S. SAS TRIG TIRF Patient/Caregiver KAB Page 1 of3 27DEC2016 Table 8.1.4: Responses to Questions Linked to Key Risk Message #3 by Highest Level of Education - Completed Surveys Question Highest Level of Education GED or less [95% College (N=l38) [95% cu'" or [95% Professional or Doctoral Degree [95% Question 10: For which of the following conditions should you use a TIRF medicine? Please answer Yes, No, or 1 don't know for each statement. 10a: Headache or migraine pain Yes 4 (6.7) 18 (13.0) 11 (11.3) 1 (6.7) Now 48 (80.0) [67.7 - 89.2] 105 (76.1) [68.1 - 82.9] 77 (79.4) [70.0 86.9] 12 (80.0) [51.9 - 95.7] [don't know 8 (13.3) 15 (10.9) 9 (9.3) 2 (13.3) I 0b: Breakthrough pain from cancer Yesm 46 (76.7) [64.0 - 86.6] 95 (68.8) [60.4 - 76.4] 73 (75.3) [65.5 - 83.5] 11 (73.3) [44.9 - 922] No 13 (21.7) 43 (31.2) 22 (22.7) 3 (20.0) [don't know 1 (1.7) 2 (2.1) (6.7) 106': Dental pain Yes 0 2 (1.4) 3 (3.1) 0 Now 50 (83.3) [71.5 - 91.7] 120 (87.0) [80.2 - 92.1] 85 (87.6) [79.4 93.4] 14 (93.3) [68.1 99.8] [don?t know 10 (16.7) 16 (11.6) 9 (9.3) 1 (6.7) 10d: Pain after surgery Yes 16 (26.7) 28 (20.3) 22 (22.7) 3 (20.0) Now 35 (58.3) [44.9 - 70.9] 96 (69.6) [61.2 - 77.1] 60 (61.9) [51.4 - 71.5] 8 (53.3) [26.6 - 78.7] 1 don't know 9 (15.0) 14 (10.1) 15 (15.5) 4 (26.7) Data Source: ADPQ, ADTQ Program: TK RM S. SAS TRIG TIRF Patient/Caregiver KAB Page 2 of3 27DEC2016 Table 8.1.4: Responses to Questions Linked to Key Risk Message #3 by Highest Level of Education - Completed Surveys Question Highest Level of Education GED or less [95% College (N=l38) [95% or [95% Professional or Doctoral Degree [95% I0e: Long-lasting pain not from cancer, like arthritis joint pain Yes 34 (56.7) 74 (53.6) 36 (37.1) 4 (26.7) Now 18 (30.0) [18.8 - 43.2] 46 (33.3) [25.5 - 41.9] 47 (48.5) [38.2 58.8] 10 (66.7) [38.4 - 882] [don't know 8 (13.3) 18 (13.0) 14 (14.4) 1 (6.7) Question 12: Please answer True, False, or I don't know for each of the following statements. 12b: A patient must stop taking their TIRF medicine if they stop taking their around-the-clock opioid pain medicine. True 21 (35.0) [23.1 - 48.4] 54 (39.1) [30.9 - 47.8] 39 (40.2) [30.4 - 50.7] 9 (60.0) [32.3 - 83.7] False 17 (28.3) 44 (31.9) 24 (24.7) 3 (20.0) 1 don't know 22 (36.7) 40 (29.0) 34 (35.1) 3 (20.0) Question 13: Please answer True, False, or I don't know for each statement about the TIRF medicine that was most recently prescribed for you. 13b: It is OK for patients to take TIRF medicines for headache pain. True 3 (5.0) 11 (8.0) 6 (6.2) 0 Falsem 38 (63.3) [49.9 - 75.4] 89 (64.5) [55.9 - 72.4] 71 (73.2) [63.2 - 81.7] 11 (73.3) [44.9 - 922] [don't know 19 (31.7) 38 (27.5) 20 (20.6) 4 (26.7) 13c: TIRF medicines should be taken exactly as prescribed by the doctor. Truem 60 (100.0) [94.0 - 100.0] 138 (100.0) [97.4 - 100.0] 96 (99.0) [94.4 - 100.0] 15 (100.0) [78.2 - 100.0] False 0 0 0 1 (1.0) Data Source: ADPQ, ADTQ Program: TK RM S. SAS TRIG Page 3 of 3 TIRF Patient/Caregiver KAB 27DEC2016 Table 8.1.4: Responses to Questions Linked to Key Risk Message #3 by Highest Level of Education - Completed Surveys Highest Level of Education Professional or GED or less College or Doctoral Degree (N=l38) Question 95% 95% cu'" 95% 01'? 95% cum I don't know 0 0 0 0 uestion 17: Please answer True, False, or I don't know for each statement about the TIRF medicine that was most recently rescribed for youtake TIRF medicines for short-term pain that will go away in a few days. True 4 (6.7) 3 (2.2) 2 (2.1) 0 Falsem 48 (80.0) [67.7 - 89.2] 120 (87.0) [80.2 - 92.1] 85 (87.6) [79.4 - 93.4] 11 (73.3) [44.9 - 92 2] 1 don?t know 8 (13.3) 15 (10.9) 10 (10.3) 4 (26.7) Source: Appendix B: Survey Tables, Table 8.1.4 Note: GED or less includes "Less than high school," "Some high school," "High school graduate/GED," or "Prefer not to answer." College includes "Some college" and "Associate's degree." or includes "Bachelor?s degree" and "Master?s degree." Professional or Doctoral degree includes "Professional or Doctoral degree." 95% exact two-sided con?dence intervals are calculated using the Clapper-Pearson method. Correct response. Data Source: ADPQ, ADTQ Program: TRIG Page 1 of3 TIRF Patient/Caregiver KAB 27DEC2016 Table 8.1.5: Responses to Questions Linked to Key Risk Message #3 by Age Group of Respondent - Completed Surveys Age Group of Respondent older Question [95% [95% [95% [95% C1[Ill Question 10: For which of the following conditions should you use a TIRF medicine? Please answer Yes, No, or I don't know for each statement. I 0a: Headache 0r migraine pain Yes 5 (17.2) 9 (15.3) 10 (8.5) 10 (9.6) Now 19 (65.5) [45.7 - 82.1] 47 (79.7) [67.2 - 89.0] 93 (78.8) [70.3 85.8] 83 (79.8) [70.8 - 87.0] [don't know 5 (17.2) 3 (5.1) 15 (12.7) 11 (10.6) I 0b: Breakthrough pain ?om cancer Yesm 22 (75.9) [56.5 - 89.7] 40 (67.8) [54.4 - 79.4] 91 (77.1) [68.5 - 84.3] 72 (69.2) [59.4 - 77.9] No 6 (20.7) 18 (30.5) 25 (21.2) 32 (30.8) [don't know 1 (3.4) 1 (1.7) 2 (1.7) 0 10c: Dental pain Yes 0 0 2 (1.7) 3 (2.9) Now 24 (82.8) [64.2 - 94.2] 57 (96.6) [88.3 - 99.6] 103 (87.3) [79.9 - 92.7] 85 (81.7) [72.9 - 88.6] [don't know 5 (17.2) 2 (3.4) 13 (11.0) 16 (15.4) I 0d: Pain after surgery Yes 5 (17.2) 5 (8.5) 29 (24.6) 30 (28.8) Now 18 (62.1) [42.3 - 79.3] 49 (83.1) [71.0 - 91.6] 72 (61.0) [51.6 - 69.9] 60 (57.7) [47.6 - 67.3] 1 don't know 6 (20.7) 5 (8.5) 17 (14.4) 14 (13.5) I0e: Long-lasting pain not from cancer, like arthritis joint pain Data Source: ADPQ, ADTQ Program: TK RM S. SAS TRIG Page 2 of3 TIRF Patient/Caregiver KAB 27DEC2016 Table 8.1.5: Responses to Questions Linked to Key Risk Message #3 by Age Group of Respondent - Completed Surveys Age Group of Respondent older Question [95% [95% [95% [95% Yes 10 (34.5) 32 (54.2) 54 (45.8) 52 (50.0) Now 13 (44.8) [26.4 - 64.3] 21 (35.6) [23.6 - 49.1] 47 (39.8) [30.9 - 49.3] 40 (38.5) [29.1 - 48.5] [don?t know 6 (20.7) 6 (10.2) 17 (14.4) 12 (11.5) Question 12: Please answer True, False, or I don't know for each of the following statements. 12b: A patient must stop taking their TIRF medicine if they stop taking their around-the-clock opioid pain medicine Truem 17 (58.6) [38.9 - 76.5] 25 (42.4) [29.6 - 55.9] 45 (38.1) [29.4 - 47.5] 36 (34.6) [25.6 - 44.6] False 4 (13.8) 23 (39.0) 32 (27.1) 29 (27.9) 1 don't know 8 (27.6) 11 (18.6) 41 (34.7) 39 (37.5) Question 13: Please answer True, False, or I don't know for each statement about the TIRF medicine that was most recently prescribed for you. 13b: It is OK for patients to take TIRF medicines for headache pain. True 4 (13.8) 5 (8.5) 5 (4.2) 6 (5.8) Falsem 22 (75.9) [56.5 - 89.7] 45 (76.3) [63.4 - 86.4] 76 (64.4) [55.1 73.0] 66 (63.5) [53.4 - 72.7] [don't know 3 (10.3) 9 (15.3) 37 (31.4) 32 (30.8) 13c: TIRF medicines should be taken exactly as prescribed by the doctor. Truem 29 (100.0) [88.1 - 100.0] 59 (100.0) [93.9 - 100.0] 1 17 (99.2) [95.4 - 100.0] 104 (100.0) [96.5 - 100.0] False 0 0 (0.8) 0 I don't know 0 0 0 Question 17: Please answer True, False, or I don't know for each statement about the TIRF medicine that was most recently prescribed for you. Data Source: ADPQ, ADTQ Program: TK RM S. SAS TRIG Page 3 of3 TIRF Patient/Caregiver KAB 27DEC2016 Table 8.1.5: Responses to Questions Linked to Key Risk Message #3 by Age Group of Respondent - Completed Surveys Age Group of Respondent older Question [95% [95% [95% [95% C1[Ill 1 7b: It is OK to take TIRF medicines for short-term pain that will go away in a few days. True 1 (3.4) 2 (3.4) 2 (1.7) 4 (3.8) Falsem 26 (89.7) [72.6 - 97.8] 51 (86.4) [75.0 - 94.0] 101 (85.6) [77.9 91.4] 86 (82.7) [74.0 - 89.4] 1 don't know 2 (6.9) 6 (10.2) 15 (12.7) 14 (13.5) Source: Appendix B: Survey Tables, Table 8.1.5 ?195% exact two-sided confidence intervals are calculated using the Clopper-Pearson method. Correct response. Data Source: ADPQ, ADTQ Program: TK RM S. SAS TRIG Page 1 of TIRF Patient/Caregiver KAB 27DEC2016 Table 8.2: Secondary Analysis of Responses to Questions Linked to Key Risk Message #3 - Completed Surveys Patients/Care ivers Correct Responses 0 correct responses 0 1 correct response 0 2 correct responses 9 (2.9) 3 correct responses 13 (4.2) 4 correct responses 29 (9.4) 5 correct responses 45 (14.5) 6 correct responses 64 (20.6) 7 correct responses 55 (17.7) 8 correct responses 61 (19.7) 9 correct responses 34 (l 1.0) Source: Appendix B: Survey Tables, Table 8.2 Total number of eligible respondents completing the survey. Data Source: ADPQ, ADTQ Program: Ennis? TRIG Page 1 of TIRF Patient/Caregiver KAB 27DEC2016 Table 9.1: Primary Analysis of Responses to Questions Linked to Key Risk Message #4 - Completed Surveys Patients/Care ivers Question [95% Question 12: Please answer True, False, or I don't know for each of the following statements. 12c: It is safe to switch to another medicine that contains fentanyl without talking to a health care provider ?rst. True 6 (1.9) Falsem 297 (95.8) [92.9 - 97.7] [don't know 7 (2.3) Source: Appendix B: Survey Tables, Table 9.1 Total number of eligible respondents completing the survey. 95% exact two-sided confidence intervals are calculated using the Clopper-Pearson method. Correct response. Data Source: ADPQ. ADTQ Program: TKRM.SAS TRIG TIRF Patient/Caregiver KAB Page 1 of] 27DEC2016 - Completed Surveys Table 9.1.1: Responses to Questions Linked to Key Risk Message #4 by Reading Medication Guide Question Reading Medication Guide Received and read Med Guide [95% Not received or not read Med Guide [95% cu'" Question 12: Please answer True, False, or I don't know for each of the following statements. 12c: It is safe to switch to another medicine that contains fentanyl without talking to a healthcare provider ?rst. True 5(1.9) 1 (1.9) Falsem 247 (95.7) [92.5 - 97.9] 50 (96.2) [86.8 - 99.5] 1 don?t know 6 (2.3) 1 (1.9) Source: Appendix B: Survey Tables, Table 9.1.1 95% exact two-sided con?dence intervals are calculated using the Clopper-Pearson method. Correct response. Data Source: ADPQ, ADTQ Program: TK RM S. SAS TRIG TIRF Patient/Caregiver KAB Page 1 of] 27DEC2016 Table 9.1.2: Responses to Questions Linked to Key Risk Message #4 by Understanding of the Medication Guide - Completed Surveys Question Understanding of the Medication Guide Understood most or all [95% Understood some [95% Did not understand [95% Did not receive or read [95% C1[Ill Question 12: Please answer True, False, or I don't know for each of the following statements. 120: It is safe to switch to another medicine that contains fentanyl without talking to a healthcare provider ?rst. True 4 (1.6) 1 (4.0) 0 1 (3.1) Falsem 243 (96.0) [92.9 - 98.1] 24 (96.0) [79.6 - 99.9] 0 30 (93.8) [79.2 - 992] 1 don't know 6 (2.4) 0 0 1 (3.1) Source: Appendix B: Survey Tables, Table 9.1.2 ?195% exact two-sided confidence intervals are calculated using the Clopper-Pearson method. Correct response. Data Source: ADPQ, ADTQ Program: TK RM S. SAS TRIG Page 1 of TIRF Patient/Caregiver KAB 27DEC2016 Table 9.1.3: Responses to Questions Linked to Key Risk Message #4 by Modality to Complete Survey - Completed Surveys Modality to Complete Survey Internet Telephone Question 195% CW 11 195% Question 12: Please answer True, False, or I don't know for each of the following statements. 12c: It is safe to switch to another medicine that contains fentanyl without talking to a healthca re provider ?rst. True 2 (1.0) 4 (3.9) Falsem 201 (97.1) [93.8 - 98.9] 96 (93.2) [86.5 - 972] 1 don't know 4 (1.9) 3 (2.9) Source: Appendix B: Survey Tables, Table 9.1.3 ?195% exact two-sided con?dence intervals are calculated using the Clopper-Pearson method. Correct response. Data Source: ADPQ, ADTQ Program: TRIG Page 1 of TIRF Patient/Caregiver KAB 27DEC2016 Table 9.1.4: Responses to Questions Linked to Key Risk Message #4 by Highest Level of Education - Completed Surveys Highest Level of Education Question GED or less [95% College (N=l38) [95% cu'" or [95% Professional or Doctoral Degree [95% Question 12: Please answer True, False, or I don't know for each of the following statements. 12c: It is safe to switch to another medicine that contains fentanyl without talking to a healthcare provider ?rst. True 2 (3.3) (0.7) 3 (3.1) 0 Falsem 55 (91.7) [81.6 - 97.2] 134 (97.1) [92.7 - 99.2] 93 (95.9) [89.8 - 98.9] 15 (100.0) [78.2 - 100.0] [don't know 3 (5.0) 3 (2.2) 1 (1.0) 0 Source: Appendix B: Survey Tables, Table 9.1.4 Note: GED or less includes "Less than high school," "Some high school," "High school graduate/GED," or "Prefer not to answer." College includes "Some college" and "Associate's degree." or includes "Bachelor's degree" and "Master's degree." Professional or Doctoral degree includes "Professional or Doctoral degree." ?195% exact two-sided con?dence intervals are calculated using the Clopper-Pearson method. Correct response. Data Source: ADPQ, ADTQ Program: TRIG Page 1 of] TIRF Patient/Caregiver KAB 27DEC2016 Table 9.1.5: Responses to Questions Linked to Key Risk Message #4 by Age Group of Respondent - Completed Surveys Age Group of Respondent older Question [95% [95% [95% [95% Question 12: Please answer True, False, or I don't know for each of the following statements. 120: It is safe to switch to another medicine that contains fentanyl without talking to a healthcare provider ?rst. True 0 2 (3.4) 2 (1.7) 2 (1.9) Falsem 29 (100.0) [88.1 - 100.0] 57 (96.6) [88.3 - 99.6] 112 (94.9) [89.3 98.1] 99 (95.2) [89.1 - 98.4] I don't know 0 0 4 (3.4) 3 (2.9) Source: Appendix B: Survey Tables, Table 9.1.5 ?195% exact two-sided confidence intervals are calculated using the Clopper-Pearson method. Correct response. Data Source: ADPQ, ADTQ Program: TK RM S. SAS TRIG TIRF Patient/Caregiver KAB Page 1 of] 27DEC2016 Completed Surveys Table 10.1: Primary Analysis of Responses to Questions Linked to Key Risk Message #5 - Question Patients/Care ivers [95% cu'z' Question 12: Please answer True, False, or 1 don't know for each of the following statements. 12d: A patient may give TIRF medicines to another person if they have the same as the patient. True 6 (1.9) Falsem 303 (97.7) [95.4 - 99.1] 1 don't know 1 (0.3) was most recently prescribed for you. Question 17: Please answer True, False, or I don't know for each statement about the TIRF medicine that I 7a: Selling or giving away TIRF medicines is against the law. Truem 308 (99.4) [97.7 - 99.9] False (0.3) ldon't know 1 (0.3) was most recently prescribed for you. Question 18: Please answer True, False, or 1 don't know for each statement about the TIRF medicine that 18a: A side effect of TIRF medicines is the chance of abuse or addiction. Truem 287 (92.6) [89.1 95.2] False 5 (1.6) 1 don't know 18 (5.8) 18b: TIRF medicines can be misused by people who abuse prescription medicines street drugs. Truem 302 (97.4) [95.0 - 98.9] False 1 don't know 8 (2.6) 18c: TIRF medicines should be kept in a safe place to prevent it from being stolen. Truem 308 (99.4) [97.7 - 99.9] False (0.3) ldon't know 1 (0.3) Source: Appendix B: Survey Tables, Table 10.1 Total number of eligible respondents completing the survey. 95% exact two-sided con?dence intervals are calculated using the Clopper-Pearson method. Correct response. Data Source: ADPQ, ADTQ Program: TIRF Patient/Caregiver KAB Page 1 of] 27DEC2016 Table 10.1.1: Responses to Questions Linked to Key Risk Message #5 by Reading Medication Guide - Completed Surveys Reading Medication Guide Question Received and read Med Guide [95% Not received or not read Med Guide [95% Question 12: Please answer True, False, or I don't know for each of the following statements. 12d: A patient may give TIRF medicines to another person if they have the same as the patient. True 4 (1.6) 2 (3.8) Falsem 253 (98.1) [95.5 - 99.4] 50 (96.2) [86.8 - 99.5] [don?t know 1 (0.4) 0 Question 17: Please answer True, False, or I don't know for each statement about the TIRF medicine that was most recently prescribed for you. I 7a: Selling or giving away TIRF medicines is against the law. Truem 256 (99.2) [97.2 - 99.9] 52 (100.0) [93.2 - 100.0] False (0.4) 0 [don't know 1 (0.4) 0 Question 18: Please answer True, False, or I don't know for each statement about the TIRF medicine that was most recently prescribed for you. 18a: A side effect of TIRF medicines is the chance of abuse or addiction. Truem 240 (93.0) [89.2 - 95.8] 47 (90.4) [79.0 96.8] False 3 (12) 2 (3.8) 1 don't know 15 (5.8) 3 (5.8) 18b: TIRF medicines can be misused by people who abuse prescription medicines or street drugs. Truem 252 (97.7) [95.0 - 99.1] 50 (96.2) [86.8 - 99.5] False 0 0 I don't know 6 (2.3) 2 (3.8) 18c: TIRF medicines should be kept in a safe place to prevent it from being stolen. Truem 256 (99.2) [97.2 99.9] 52 (100.0) [93.2 - 100.0] False (0.4) 0 [don't know 1 (0.4) 0 Source: Appendix B: Survey Tables, Table [0.1.1 ?195% exact two-sided confidence intervals are calculated using the Clopper-Pearson method. Correct response. Data Source: ADPQ, ADTQ Program: TK RM S. SAS TRIG Page 1 of2 TIRF Patient/Caregiver KAB 27DEC2016 Table 10.1.2: Responses to Questions Linked to Key Risk Message #5 by Understanding of the Medication Guide - Completed Surveys Understanding of the Medication Guide Question Understood most or all [95% Understood some [95% Did not understand [95% Did not receive or read [95% Question 12: Please answer True, False, or I don't know for each of the following statements. 12d: A patient may give TIRF medicines to another person if they have the same as the patient. True 4 (1.6) 1 (4.0) 0 1 (3.1) Falsem 248 (98.0) [95.4 - 99.4] 24 (96.0) [79.6 - 99.9] 0 31 (96.9) [83.8 - 99.9] 1 don't know 1 (0.4) 0 0 0 Question 17: Please answer True, False, or I don't know for each statement about the TIRF medicine that was most recently prescribed for you. I 7a: Selling or giving away TIRF medicines is against the law. Truem 252 (99.6) [97.8 - 100.0] 24 (96.0) [79.6 - 99.9] 0 32 (100.0) [89.1 - 100.0] False 0 1 (4.0) 0 0 1 don't know 1 (0.4) 0 0 0 uestion 18: Please answer True, False, or I don't know for each statement about the TIRF medicine that was most recently rescribed for you. I 8a: A side effect of TIRF medicines is the chance of abuse or addiction. Truem 238 (94.1) [90.4 - 96.6] 19 (76.0) [54.9 - 90.6] 0 30 (93.8) [79.2 - 992] False 3 (1.2) 2 (8.0) 0 0 [don't know 12 (4.7) 4 (16.0) 0 2 (6.3) 18b: TIRF medicines can be misused by people who abuse prescription medicines or street drugs. Truem 249 (98.4) [96.0 - 99.6] 23 (92.0) [74.0 - 99.0] 0 30 (93.8) [79.2 - 992] False 0 0 0 0 Data Source: ADPQ, ADTQ Program: TK RM S. SAS TRIG Page 2 of 2 TIRF Patient/Caregiver KAB 27DEC2016 Table 10.1.2: Responses to Questions Linked to Key Risk Message #5 by Understanding of the Medication Guide - Completed Surveys Understanding of the Medication Guide Understood most or all Understood some Did not understand Did not receive or read Question 95% cu'" 95% cu'" 95% Cll'" [95% [don't know 4 (1.6) 2 (8.0) 0 2 (6.3) 180: TIRF medicines should be kept in a safe place to prevent it from being stolen. Truem 251 (992) [97.2 - 99.9] 25 (100.0) [86.3 - 100.0] 0 32 (100.0) [89.1 - 100.0] False (0.4) 0 0 0 [don?t know 1 (0.4) 0 0 Source: Appendix B: Survey Tables, Table 10.1.2 ?195% exact two-sided confidence intervals are calculated using the Clapper-Pearson method. Correct response. Data Source: ADPQ, ADTQ Program: TRIG Page 1 of] TIRF Patient/Caregiver KAB 27DEC2016 Table 10.1.3: Responses to Questions Linked to Key Risk Message #5 by Modality to Complete Survey - Completed Surveys Modality to Complete Survey Internet Telephone Question [95% cu'" [95% cu'" Question 12: Please answer True, False, or I don't know for each of the following statements. 12d: A patient may give TIRF medicines to another person if they have the same as the patient. True 1 (0.5) 5 (4.9) Falsem 206 (99.5) [97.3 - 100.0] 97 (94.2) [87.8 - 97.8] [don't know 0 1 (1.0) Question 17: Please answer True, False, or I don't know for each statement about the TIRF medicine that was most recentiy prescribed for you. 1 7a: Selling or giving away TIRF medicines is against the law. Truem 205 (99.0) [96.6 - 99.9] 103 (100.0) [96.5 - 100.0] False (0.5) 0 [don't know 1 (0.5) 0 Question 18: Please answer True, False, or I don't know for each statement about the TIRF medicine that was most recently prescribed for you. 18a: A side effect of TIRF medicines is the chance of abuse or addiction. Truem 193 (93.2) [88.9 - 96.3] 94 (91.3) [84.1 - 95.9] False 3 (1.4) 2 (1.9) [don't know 11 (5.3) 7 (6.8) 18b: TIRF medicines can be misused by people who abuse prescription medicines or street drugs. Truem 201 (97.1) [93.8 - 98.9] 101 (98.1) [93.2 - 99.8] False 0 0 I don't know 6 (2.9) 2 (1.9) 18c: TIRF medicines should be kept in a safe place to prevent it from being stolen. Truem 206 (99.5) [97.3 100.0] 102 (99.0) [94.7 100.0] False 0 (1.0) [don't know 1 (0.5) 0 Source: Appendix B: Survey Tables, Table 10.1.3 95% exact two-sided confidence intervals are calculated using the Clopper-Pearson method. Correct response. Data Source: ADPQ, ADTQ Program: TRIG TIRF Patient/Caregiver KAB Page 1 of2 27DEC2016 Table 10.1.4: Responses to Questions Linked to Key Risk Message #5 by Highest Level of Education - Completed Surveys Question Highest Level of Education GED or less [95% College (N=l38) [95% or [95% Professional or Doctoral Degree [95% Question 12: Please answer True, False, or I don't know for each of the following statements. 12d: A patient may give TIRF medicines to another person if they have the same as the patient. True 0 (0.7) 5 (5.2) 0 Falsem 59 (98.3) [91.1 - 100.0] 137 (99.3) [96.0 - 100.0] 92 (94.8) [88.4 - 98.3] 15 (100.0) [78.2 - 100.0] [don't know 1 (1.7) 0 0 Question 17: Please answer True, False, or 1 don't know for each statement about the TIRF medicine that was most recently prescribed for you. I 7a: Selling or giving away TIRF medicines is against the law. Truem 60 (100.0) [94.0 - 100.0] 137 (99.3) [96.0 - 100.0] 97 (100.0) [96.3 - 100.0] 14 (93.3) [68.1 - 99.8] False 0 (0.7) 0 0 I don't know 0 0 0 1 (6.7) Question 18: Please answer True, False, or I don't know for each statement about the TIRF medicine that was most recently prescribed for you. 18a: A side effect of TIRF medicines is the chance of abuse or addiction. Truem 51 (85.0) [73.4 - 92.9] 131 (94.9) [89.8 - 97.9] 90 (92.8) [85.7 - 97.0] 15 (100.0) [78.2 - 100.0] False 2 (3.3) 2 (1.4) 1 (1.0) 0 1 don't know 7 (11.7) 5 (3.6) 6 (6.2) 0 18b: TIRF medicines can be misused by people who abuse prescription medicines or street drugs. Truem 57 (95.0) [86.1 - 99.0] 136 (98.6) [94.9 - 99.8] 94 (96.9) [91.2 - 99.4] 15 (100.0) [78.2 - 100.0] Data Source: ADPQ, ADTQ Program: TK RM S. SAS TRIG Page 2 of 2 TIRF Patient/Caregiver KAB 27DEC2016 Table 10.1.4: Responses to Questions Linked to Key Risk Message #5 by Highest Level of Education - Completed Surveys Highest Level of Education Professional or GED or less College or Doctoral Degree (N=l38) Question 95% 95% cu'" 95% 95% cu'? False 0 0 0 0 [don't know 3 (5.0) 2 (1.4) 3 (3.1) 0 18c: TIRF medicines should be kept in a safe place to prevent it from being stolen. Truem 60 (100.0) [94.0 - 100.0] 136 (98.6) [94.9 - 99.8] 97 (100.0) [96.3 - 100.0] 15 (100.0) [78.2 - 100.0] False 0 (0.7) 0 0 [don?t know 0 (0.7) 0 0 Source: Appendix B: Survey Tables, Table 10.1.4 Note: GED or less includes "Less than high school," "Some high school," "High school graduate/GED," or "Prefer not to answer." College includes "Some college" and "Associate's degree." or includes "Bachelor?s degree" and "Master?s degree." Professional or Doctoral degree includes "Professional or Doctoral degree." 95% exact two-sided con?dence intervals are calculated using the Clapper-Pearson method. Correct response. Data Source: ADPQ, ADTQ Program: TRIG TI RF Patient/Caregiver KA Page 1 of2 27DEC2016 Table 10.1.5: Responses to Questions Linked to Key Risk Message #5 by Age Group of Respondent - Completed Surveys Age Group of Respondent 18 - 39 40 - 49 Question 11 [95% C1]Ill [95% C1['ll 50 - 59 [95% 60 or older [95% C1]Ill Question 12: Please answer True, False, or I don't know for each of the following statements. 12d: A patient may give TIRF medicines to another person if they have the same as the patient. True 0 0 3 (2.5) 3 (2.9) Falsem 29 (100.0) [88.1 - 100.0] 59 (100.0) [93.9 - 100.0] 115 (97.5) [92.7 - 99.5] 100 (962) [90.4 - 98.9] 1 don't know 0 0 0 1(1.0) Question 17: Please answer True, False, or I don't know for each statement about the TIRF medicine that was most recently prescribed for you. 1 7a: Selling or giving away TIRF medicines is against the law. Truem 29 (100.0) [88.1 - 100.0] 59 (100.0) [93.9 - 100.0] 118 (100.0) [96.9 - 100.0] 102 (98.1) [93.2 - 99.8] False 0 0 1(1.0) 1 don't know 0 0 0 1(1.0) Question 18: Please answer True, False, or I don't know for each statement about the TIRF medicine that was most recently prescribed for you. 18a: A side effect of TIRF medicines is the chance of abuse or addiction. Truem 28 (96.6) [82.2 - 99.9] 56 (94.9) [85.9 - 98.9] 108 (91.5) [85.0 - 95.9] 95 (91.3) [84.2 - 96.0] False (3.4) 0 2(1.7) 2(1.9) I don't know 0 3 (5.1) 8 (6.8) 7 (6.7) 18b: TIRF medicines can be misused by people who abuse prescription medicines or street drugs. Truem 28 (96.6) [82.2 - 99.9] 58 (98.3) [90.9 - 100.0] 114 (96.6) [91.5 - 99.1] 102 (98.1) [93.2 - 99.8] False 0 0 0 0 Data Source: ADPQ. ADTQ Program: TRIG Page 2 of 2 TIRF Patient/Caregiver KAB 27DEC2016 Table 10.1.5: Responses to Questions Linked to Key Risk Message #5 by Age Group of Respondent - Completed Surveys Age Group of Respondent older Question 95% cu'" 95% cu'" 95% Cll'" [95% [don't know 1 (3.4) 1 (1.7) 4 (3.4) 2 (1.9) 180: TIRF medicines should be kept in a safe place to prevent it from being stolen. Truem 29 (100.0) [88.1 - 100.0] 58 (98.3) [90.9 - 100.0] 118 (100.0) [96.9 - 100.0] 103 (99.0) [94.8 - 100.0] False 0 0 0 (1.0) [don?t know 0 1 (1.7) 0 0 Source: Appendix B: Survey Tables, Table 10.1.5 95% exact two-sided confidence intervals are calculated using the Clapper-Pearson method. Correct response. Data Source: ADPQ, ADTQ Program: TK RM S. SAS TRIG Page 1 of TIRF Patient/Caregiver KAB 27DEC2016 Table 10.2: Secondary Analysis of Responses to Questions Linked to Key Risk Message #5 - Completed Surveys Patients/Care ivers Correct Responses 0 correct responses 0 1 correct response 0 2 correct responses 1 (0.3) 3 correct responses 2 (0.6) 4 correct responses 35 (l 1.3) 5 correct responses 272 (87.7) Source: Appendix B: Survey Tables, Table 10.2 Total number of eligible respondents completing the survey. Data Source: ADPQ, ADTQ Program: TRIG TIRF Patient/Caregiver KAB Page 1 of] 27DEC2016 Completed Surveys Table Primary Analysis of Responses to Questions Linked to Key Risk Message #6 - Question Patients/Care ivers [95% cu? was most recently prescribed for you. Question 13: Please answer True, False, or I don't know for each statement about the TIRF medicine that 13a: medicines should be stored in a safe place out of the reach of ch ildren. True 310 (100.0) [98.8 - 100.0] False 0 I don't know 0 medicine? (Please select one.) Question 14: What should you do if an adult who has not been prescribed a TIRF medicine takes a TIRF Wait an hour and see if the person is OK. 10 (3.2) Get emergency help right away. [31 276 (89.0) [85.0 - 92.3] Do nothing. 0 I don't know. 24 (7.7) was most recently prescribed for you. Question 17: Please answer True, False, or I don't know for each statement about the TIRF medicine that I 7c: TIRF medicines must be disposed of as described in the specific product?s Meth'cation Guide. Truem 303 (97.7) [95 .4 - 99.1] False 2 (0.6) 1 don't know 5 (1.6) I 7e: A TIRF medicine can cause an overdose and death in any child who takes it. Truem 292 (94.2) [91.0 - 96.5] False 5 1.6) I don't know 13 (4.2) Source: Appendix B: Survey Tables, Table 11.1 Total number of eligible respondents completing the survey. 95% exact two-sided con?dence intervals are calculated using the lopper-Pearson method. Correct response. Data Source: ADPQ, ADTQ Program: TIRF Patient/Caregiver KAB Page 1 of] 27DEC2016 Table 11.1.1: Responses to Questions Linked to Key Risk Message #6 by Reading Medication Guide - Completed Surveys Reading Medication Guide Question Received and read Med Guide [95% Not received or not read Med Guide [95% Question 13: Please answer True, False, or I don't know for each statement about the TIRF medicine that was most recently prescribed for you. 13a: TIRF medicines should be stored in a safe place out of the reach of children. Truem 258 (100.0) [98.6 100.0] 52 (100.0) [93.2 100.0] False 0 0 1 don't know 0 0 Question 14: What should you do if an adult who has not been prescribed a TIRF medicine takes a TIRF medicine? (Please select one.) Wait an hour and see ifthe person is OK. 6 (2.3) 4 (7.7) Get emergency help right away.[2] 235 (91.1) [86.9 - 94.3] 41 (78.8) [65.3 - 88.9] Do nothing. 0 0 1 don't know. 17 (6.6) 7 (13.5) Question 17: Please answer True, False, or I don?t know for each statement about the TIRF medicine that was most recently prescribed for you. I 7c: TIRF medicines must be disposed of as described in the speci?c product?s Medication Guide. Truem 252 (97.7) [95.0 99.1] 51 (98.1) [89.7 100.0] False 2 (0.8) 0 1 don't know 4 (1.6) 1 (1.9) I 7e: A TIRF medicine can cause an overdose and death in any child who takes it. Truem 245 (95.0) [91.5 - 97.3] 47 (90.4) [79.0 - 96.8] False 4 (1.6) (1.9) I don't know 9 (3.5) 4 (7.7) Source: Appendix B: Survey Tables, Table 11.1.1 ?195% exact two-sided con?dence intervals are calculated using the Clopper-Pearson method. Correct response. Data Source: ADPQ. ADTQ Program: TK RM S. SAS 0 TRIG Page 1 of2 TIRF Patient/Caregiver KAB 27DEC2016 Table 11.1.2: Responses to Questions Linked to Key Risk Message #6 by Understanding of the Medication Guide - Completed Surveys Understanding of the Medication Guide Understood most or all Understood some Did not understand Did not receive or read Question [95% 11 [95% 11 [95% [95% Question 13: Please answer True, False, or I don't know for each statement about the TIRF medicine that was most recentiy prescribed for you. 13a: TIRF medicines should be stored in a safe place out of the reach of children. Truem 253 (100.0) [98.6 - 100.0] 25 (100.0) [86.3 - 100.0] 0 32 (100.0) [89.1 - 100.0] False 0 0 0 0 I don't know 0 0 0 0 Question 14: What should you do if an adult who has not been prescribed a TIRF medicine takes a TIRF medicine? (Please select one.) Wait an hour and see if the person is OK. 7 (2.8) (4.0) 0 2 (6.3) Get emergency help right away.[21 230 (90.9) [86.7 - 94.1] 22 (88.0) [68.8 - 97.5] 0 24 (75.0) [56.6 - 88.5] Do nothing. 0 0 0 0 I don't know. 16 (6.3) 2 (8.0) 0 6 (18.8) Question 17: Please answer True, False, or I don't know for each statement about the TIRF medicine that was most recently prescribed for you. I 7c: TIRF medicines must be diqrosed of as described in the speci?c product?s Medication Guide. Truem 247 (97.6) [94.9 - 99.1] 25 (100.0) [86.3 - 100.0] 0 31 (96.9) [83.8 - 99.9] False 2 (0.8) 0 0 0 [don't know 4 (1.6) 0 0 1 (3.1) I 7e: A TIRF medicine can cause an overdose and death in any child who takes it. Truem 241 (95.3) [91.9 - 97.5] 22 (88.0) [68.8 - 97.5] 0 29 (90.6) [75.0 - 98.0] False 4 (1.6) 0 0 1 (3.1) Data Source: ADPQ. ADTQ Program: 1 TRIG Page 2 of 2 TIRF Patient/Caregiver KAB 27DEC2016 Table 11.1.2: Responses to Questions Linked to Key Risk Message #6 by Understanding of the Medication Guide - Completed Surveys Understanding of the Medication Guide Understood most or all Understood some Did not understand Did not receive or read Question 95% cu'" 95% Cll'" 95% [95% [don't know 8 (3.2) 3 (12.0) 0 2 (6.3) Source: Appendix B: Survey Tables, Table 11.1.2 ?195% exact two-sided con?dence intervals are calculated using the Clopper-Pearson method. Correct response. Data Source: ADPQ, ADTQ Program: TK RM S. SAS 2 TRIG TIRF Patient/Caregiver KAB Page 1 of] 27DEC2016 Survey - Completed Surveys Table 11.1.3: Responses to Questions Linked to Key Risk Message #6 by Modality to Complete Modality to Complete Survey Question Internet [95% Telephone [95% was most recently prescribed for you. Question 13: Please answer True, False, or 1 don't know for each statement about the TIRF medicine that 13a: TIRF medicines should be stored in a safe place out of the reach of children. True 207 (100.0) [98.2 - 100.0] 103 (100.0) [96.5 - 100.0] False 0 0 1 don?t know 0 0 medicine? (Please select one.) Question 14: What should you do if an adult who has not been prescribed a TIRF medicine takes a TIRF Wait an hour and see if the person is OK. 5 (2.4) 5 (4.9) Get emergency help right away.[2] 188 (90.8) [86.0 - 94.4] 88 (85.4) [77.1 - 91.6] Do nothing. 0 0 1 don't know. 14 (6.8) 10 (9.7) was most recently prescribed for you. Question 17: Please answer True, False, or 1 don't know for each statement about the TIRF medicine that I 7c: TIRF medicines must be diqwsed of as described in the specific product?s Meth'cation Guide. Truem 204 (98.6) [95.8 - 99.7] 99 (96.1) [90.4 98.9] False 1 (0.5) 1 (1.0) 1 don't know 2 (1.0) 3 (2.9) I 7e: A TIRF medicine can cause an overdose and death in any child who takes it. Truem 196 (94.7) [90.7 - 97.3] 96 (93.2) [86.5 - 972] False 3 (1.4) 2 (1.9) I don't know 8 (3.9) 5 (4.9) Source: Appendix B: Survey Tables, Table 11.1.3 ?195% exact two-sided con?dence intervals are calculated using the Clopper-Pearson method. Correct response. Data Source: ADPQ. ADTQ Program: TK RM S. SAS 3 TRIG TIRF Patient/Caregiver KAB Page 1 of2 27DEC2016 Table 11.1.4: Responses to Questions Linked to Key Risk Message #6 by Highest Level of Education - Completed Surveys Question Highest Level of Education GED or less [95% College (N=l38) [95% cu'" or [95% Professional or Doctoral Degree [95% Question 13: Please answer True, False, or I don't know for each statement about the TIRF medicine that was most recently prescribed for you. 13a: medicines should be stored in a safe place out of the reach of children. Truem 60 (100.0) [94.0 - 100.0] 138 (100.0) [97.4 - 100.0] 97 (100.0) [96.3 - 100.0] 15 (100.0) [78.2 - 100.0] False 0 0 0 0 1 don't know 0 0 0 0 Question 14: What should you do if an adult who has not been prescribed a TIRF medicine takes a TIRF medicine? (Please select one.) Wait an hour and see ifthe person is OK. 1 (1.7) 5 (3.6) 4 (4.1) 0 Get emergency help right away.[2] 56 (93.3) [83.8 - 98.2] 125 (90.6) [84.4 - 94.9] 81 (83.5) [74.6 - 90.3] 14(93.3) [68.1 - 99.8] Do nothing. 0 0 0 0 [don't know. 3 (5.0) 8 (5.8) 12 (12.4) 1 (6.7) Question 17: Please answer True, False, or I don't know for each statement about the TIRF medicine that was most recently prescribed for you. I 7c: TIRF medicines must be diqwsed of as described in the specific product?s Meta'cation Guide. Truem 59 (98.3) [91.1 - 100.0] 134 (97.1) [92.7 - 99.2] 96 (99.0) [94.4 - 100.0] 14 (93.3) [68.1 - 99.8] False 0 1 (0.7) 1 (1.0) 0 [don't know 1 (1.7) 3 (2.2) 0 1 (6.7) I 7e: A TIRF medicine can cause an overdose and death in any child who takes it. True 58 (96.7) [88.5 - 99.6] 130 (94.2) [88.9 - 97.5] 90 (92.8) [85.7 - 97.0] 14 (93.3) [68.1 - 99.8] Data Source: ADPQ, ADTQ Program: TK RM S. SAS 4 TRIG Tl RF Patient/Caregiver KAB Page 2 of 2 27DEC2016 Table 11.1.4: Responses to Questions Linked to Key Risk Message #6 by Highest Level of Education - Completed Surveys Highest Level of Education Professional or GED or less College or Doctoral Degree Question 95% Cll'? 95% cu'" 95% 95% cul? False 0 3 (2.2) 2 (2.1) 0 [don't know 2 (3.3) 5 (3.6) 5 (5.2) (6.7) Source: Appendix B: Survey Tables, Table 11.1.4 Note: GED or less includes "Less than high school," "Some high school," "High school graduate/GED," or "Prefer not to answer." College includes "Some college" and "Associate's degree." or includes "Bachelor's degree" and "Master's degree." Professional or Doctoral degree includes "Professional or Doctoral degree." 95% exact two-sided con?dence intervals are calculated using the Clopper-Pearson method. Correct response. Data Source: ADPQ, ADTQ Program: TK RM S. SAS 5 TRIG Page 1 of2 TIRF Patient/Caregiver KAB 27DEC2016 Table 11.1.5: Responses to Questions Linked to Key Risk Message #6 by Age Group of Respondent - Completed Surveys Age Group of Respondent older Question 95% cu'" 95% Cll'" [95% Cll'" [95% Question 13: Please answer True, False, or I don't know for each statement about the TIRF medicine that was most recently prescribed for you. 13a: TIRF medicines should be stored in a safe place out of the reach of children. Truem 29 (100.0) [88.1 - 100.0] 59 (100.0) [93.9 - 100.0] 1 18 (100.0) [96.9 - 100.0] 104 (100.0) [96.5 - 100.0] False 0 0 0 0 1 don't know 0 0 0 0 Question 14: What should you do if an adult who has not been prescribed a TIRF medicine takes a TIRF medicine? (Please select one.) Wait an hour and see ifthe person is OK. 0 3 (5.1) 5 (4.2) 2 (1.9) Get emergency help right away.[21 27 (93.1) [77.2 - 99.2] 54 (91.5) [81.3 - 972] 110 (932) [87.1 - 97.0] 85 (81.7) [72.9 - 88.6] Do nothing. 0 0 0 0 1 don't know. 2 (6.9) 2 (3.4) 3 (2.5) 17 (16.3) Question 17: Please answer True, False, or I don't know for each statement about the TIRF medicine that was most recently prescribed for you. I 7c: TIRF medicines must be diqrosed of as described in the speci?c product?s Medication Guide. Truem 29 (100.0) [88.1 - 100.0] 58 (98.3) [90.9 - 100.0] 115 (97.5) [92.7 - 99.5] 101 (97.1) [91.8 - 99.4] False 0 0 (0.8) 1 (1.0) [don?t know 0 1 (1.7) 2 (1.7) 2 (1.9) I 7e: A TIRF medicine can cause an overdose and death in any child who takes it. Truem 29 (100.0) [88.1 - 100.0] 54 (91.5) [81.3 - 97.2] 116 (98.3) [94.0 - 99.8] 93 (89.4) [81.9 - 94.6] False 0 2 (3.4) (0.8) 2 (1.9) Data Source: ADPQ. ADTQ Program: 6 TRIG Page 2 of 2 TIRF Patient/Caregiver KAB 27DEC2016 Table 11.1.5: Responses to Questions Linked to Key Risk Message #6 by Age Group of Respondent - Completed Surveys Age Group of Respondent older Question 95% cu'" 95% cu'" 95% [95% [don't know 0 3 (5.1) (0.8) 9 (8.7) Source: Appendix B: Survey Tables, Table 11.1.5 ?195% exact two-sided con?dence intervals are calculated using the Clopper-Pearson method. Correct response. Data Source: ADPQ, ADTQ Program: TK RM S. SAS 7 TRIG Page 1 of TIRF Patient/Caregiver KAB 27DEC2016 Table 11.2: Secondary Analysis of Responses to Questions Linked to Key Risk Message #6 - Completed Surveys Patients/Care ivers Correct Responses 0 correct responses 0 1 correct response 1 (0.3) 2 correct responses 7 (2.3) 3 correct responses 42 (13.5) 4 correct responses 260 (83.9) Source: Appendix B: Survey Tables, Table 11.2 Total number of eligible respondents completing the survey. Data Source: ADPQ, ADTQ Program: 8 TRIG Page 1 of] TIRF Patient/Caregiver KAB 27DEC2016 Table 12: Average Knowledge Scores - Completed Surveys Score 95% KRM #1 91.6 [88.5, 94.7] KRM #2 88.7 [85.7, 91.7] KRM #3 70.3 [68.1, 72.5] KRM #4 95.8 [93.6, 98.1] KRM #5 97.3 [96.4, 98.2] KRM #6 95.2 [93.9, 96.6] Overall Knowledge Score 84.8 [83.5, 86.0] Source: Appendix B: Survey Tables, Table 12 ?195% Is are constructed based on normal distribution ?mction. Data Source: ADPQ, ADTQ Program: 9 TRIG Page 1 of TIRF Patient/Caregiver KAB 27DEC2016 Listing 1: Listing of Verbatim Responses to Question #23 (How frequently do you receive a Medication Guide for the TIRF medicine at the pharmacy?) - Completed Surveys Verbatim Responses each bx of medicine Each new box of TIRF (Subsys) has a new guide inside, on top after you open the box i have used actiq for over15 years now.i have seen a zillion medication guideli no longer have the pharmacy hand me the medication literature anymore,as i already know what is in the guide by heart [f I ask for it, and when they switch medicines in every box in every box Once The last time I received it at a different pharmacy upon request Data Source: ADPQ Program: LQ.SAS TRIG Page 1 of] TIRF Patient/Caregiver KAB 27DEC2016 Listing 2: Listing of Verbatim Responses to Question #28 (Who offered to explain the Medication Guide to you?) - Completed Surveys Verbatim Responses Drug Representative husband Husband/Caregiver I am a doctor manufacturer of subsys My Mom My signi?cant other is an experienced RN My wife nurse RN Pharmaceutical Rep SERVICE CENTER FOR PATIENTS AT INSYS Someone from Subsys Subsys Representative The company wife Data Source: ADPQ Program: LQ.SAS TRIG Page 1 of TIRF Patient/Caregiver KAB 27DEC2016 Listing 3: Listing of Verbatim Responses to Question #32 (Questions about the Medication Guide) - Completed Surveys Verbatim Responses Does it cause seizures? How Long can I use this medication before it is harmful to me As in How Many Years I did when I ?rst began taking Aciq,to make sure I under the information my doctor had provided to me. I had questions about what I didn't understand. have been taking the medication for some time and I don't remember. It states you can use the medication under the tongue, however it also states it is to dissolve within (1 think its 14-28 minutes) but when I put it under my tongue, I salivate alot and its dissolved within a minute or two and does not seem to work at all (it seems to only work speci?c to that intended breakdown timeframe). Then I have to wait for next dose and am miserable. I don't use under tongue anymore. So this is confusing to me as guide shows under tongue as a site for use. A doctor also said 1 could use it on lower gum/cheek but directions do not state this. I've not tried it - so again, it seems to make sense you could use it at that site, but directions only show using it between upper cheek and gum. (l have an oral cancer - tongue cancer so it has been tricky to use in mouth at times which is why it would be good to know this information- esp after surgery when swelling was worst and as mouth becomes ulcerated from radiation). The question is the disposal of it, because if it's, I'm kind of, I don't agree with how they say to dispose of the medication. The way I was told to do, what it says in the pamphlet, I don?t agree with. They tell you to fold them over and flush them in the toilet. That is polluting. 1 put it in red bag trash, like at the hospital, and I take them to a center. Like what they use in a doctors of?ce or a hospital for used needles. How did they come up with that as a viable solution to get rid of the drug that's so dangerous. What are the long-term effects of the many TIRF-REMS medications? Oral damage, organ failure, etc.. Why does it have to be in medical terminology instead of easy to understand terms? WHY IS a drug such as fentora and aqtiq, a?er over 10 years of use for patients with extreme pain for injuries. Suddenly only prescribed to people with cancer Data Source: ADPQ Program: LQ.SAS TRIG Patient/Caregiver KAB Page 1 of6 27DEC2016 Listing 4: Listing of Adverse Events and/or Product Complaints Reported by Modality Verbatim Text Modality of Report I have a hard time getting up. Even if you take it the way you are supposed to take it it's highly addictive. I need to be able to get up out the bed sometimes. I'm on hydrocodone, oxycodone, and fentanyl and the amount of pain the angioedema gives me none of those medications help. It took the doctors 6 years to diagnose they thought it was gout, arthritis, rheumatoid arthritis, bone cancer. My problem is there is no medication for it. Telephone It states you can use the medication under the tongue, however it also states it is to dissolve within (1 think its 14-28 minutes) but when I put it under my tongue, I salivate alot and its dissolved within a minute or two and does not seem to work at all (it seems to only work speci?c to that intended breakdown timeframe). Then I have to wait for next dose and am miserable. I don't use under tongue anymore. So this is confusing to me as guide shows under tongue as a site for use. A doctor also said I could use it on lower gum/cheek but directions do not state this. I've not tried it - so again, it seems to make sense you could use it at that site, but directions only show using it between upper cheek and gum. (I have an oral cancer - tongue cancer so it has been tricky to use in mouth at times which is why it would be good to know this information- esp after sm?gery when swelling was worst and as mouth becomes ulcerated ?om radiation). lntemet He has passed. He did in the hospital. Once we found the correct dosage, the drug was very bene?cial. Telephone Its chronic pain but not arthritis Telephone No, they gave it to me for chronic pain. I suffer from chronic pain, and doctors tried other medicines but they gave me bad reactions. Telephone He passed away. He was still taking the Subsys when he passed away on (m6) and I received this letter in the mail so I'm calling to let you know. Telephone What are the long-term effects of the many medications? Oral damage, organ failure, etc.. lntemet I get one sucker at a time for the procedures that I get, the injections in my back Telephone They are much weaker than you would think. Telephone I was on Abstral for almost two years, but then they told me they wouldn?t cover it anymore because it?s only for cancer patients. Telephone Arizona recently legalized marijuana but my doctor won?t prescribe it because it is not approved by the is frustrating because i was recently diagnosed with cancer Telephone He has a little trouble speaking. Yes, but it has been a awhile since his surgery. Telephone Patient, passed away on taking, if any. . Mother is unsure what product he was Telephone Data Source: Program: LQAE.SAS TRIG Page 2 of 6 TIRF Patient/Caregiver KAB 27DEC2016 Listing 4: Listing of Adverse Events and/or Product Complaints Reported by Modality Modality of Verbatim Text Report I was in a car accident in 91'. Broke my back, my whole lower back was Telephone Degenerative Bone Disease, my Sacram Sack failed and I had to have multiple surgeries, there was a 95% chance I'd end up in a wheel chair, Sciatica, Sciatica issues, I have nerve problems and nerve damage, and I have severe arthritis as well. I know there are other issues that I just don't know the name for, I just don't know what they are called. There all just technical names that, there was all stuff that was found out with a Mila gram/ spinal tape they drain all your spinal ?uid out and they ?ll it with Radioactive ?uid. There are four of five other issues I just don't know what they?re called. This was a last resort. I have a hard time concentrating Telephone Why does it have to be in medical terminology instead of easy to understand terms? lntemet I have been using the entanyl patch for some time and I also used the Subsys, now they Telephone want still using the Fentanyl the duragesic Mylan brand. I was taking the Subsys and they were working great. I suffer from chronic hepatitis its not nice to have pain. I used it for 1 year and then they took it away from me because I didn't have cancer. I?m getting a headache. Telephone My hand is gimpy. I have dialysis. Telephone This Subsys is what I was taking was not good for me- not good for me at all. Telephone I?ve been using it for almost 3 years. I am 63 years old. I know how to control my Telephone prescription. My memory is not so good. I did the chemo the worst somebody can have when I had the colon cancer, I take chemo on the nerves on my feet so I don?t feel my feet after I get up in the morning it takes 5-10 minutes I touch my feet to the ground it?s like you put nails inside of them it?s painful. The only medicine to make me feel like a normal person. Sometimes the medicine comes half ?lled, or completely empty. I already spoke with the company and gave them some of the empty containers. You?ll have to excuse me, I have a bad cold. Telephone I'm sorry, I'm hard of hearing Telephone Patient, has passed away. Telephone Patient, passed away on (bus) Telephone The patient, passed away. Telephone This would be helpful because I?m sick so it would be nice to get $50. I have a lot of actual Telephone issues with it. I don?t think it works properly that well like a lot of it doesn?t work sometimes. Data Source: Program: LQAE.SAS TRIG Page 3 of 6 Patient/Caregiver KAB 27DEC2016 Listing 4: Listing of Adverse Events and/or Product Complaints Reported by Modality Modality of Verbatim Text Report The question is the disposal of it, because if it's, I'm kind of, I don't agree with how they say Telephone to dispose of the medication. The way I was told to do, what it says in the pamphlet, I don't agree with They tell you to fold them over and ?ush them in the toilet. That is polluting. I put it in red bag trash, like at the hospital, and I take them to a center. Like what they use in a doctors office or a hospital for used needles. How did they come up with that as a viable solution to get rid of the drug that's so dangerous. how long can I use this medication before it is harmful to me? As in How Many Years? lntemet Patient, passed away on Telephone The patient, has passed away. Telephone Patient, passed away on Telephone My memory is not so good. Telephone It's breakthrough pain, but it? not from cancer. Telephone I'm going through withdraws. If I would have taken it, it would have killed me. I'll call Telephone back, I have to put my oxygen on. My husband is now deceased. Telephone I had a cancer tumor removed. My doctor is trying different medications for all of my Telephone problems: neuropathy, back, vertabrate, fractures, numerous health issues I have. I have been for 30 years. I was just hoping that by doing this survey it would show- because the people that have Telephone abused the medication that don?t need it for pain have made it very hard for those of us in pain that really need it. My goal is to answer questions so people that really need it not taken away from them, that?s what my doctors trying to do. They aren?t looking at the people that genuinely need it. I?m suffering tor it, it?s so unfair. I wish I was never put on it then I wouldn?t know there is something to get me through part of the day. In response to survey question Pain after surgery Verbatim Response: He did have it in Telephone the hospital. I know it came out for cancer, I?m not a cancer patient. Telephone Does it cause seizures? lntemet I've been taking entora for my back. The pharmacy said I can't take it anymore because 1 Telephone don't have bone cancer, but another pharmacy told me that they'd dispense it. Its for retractable back pain. Its back pain. Telephone A big old gash on my headhead. With this brain injury, I don?t want to Telephone choose wrong. I found mistake with medicine. Medicine was being radiating, and stored in UPS trucks. You're sending these letters to my my brother This is my brother. He has been Telephone deceased since July. Data Source: Program: LQAE.SAS TRIG Page 4 of 6 Patient/Caregiver KAB 27DEC2016 Listing 4: Listing of Adverse Events and/or Product Complaints Reported by Modality Modality of Verbatim Text Report This is ridiculous well getting calls every other day when you?re sick and there is a reason Telephone you are on this medicine is just wrong, very, very, wrong! I take it for a migraine. I take it to prevent my headaches. I take it if I know my headache is Telephone going south. WHY IS a drug such as fentora and aqtiq, after over 10 years of use for patients with lntemet extreme pain for SCI injuries. Suddenly only prescribed to people with cancer When I use the dose and it feels like I'm not getting anything out of it. I used to feel it going Telephone inside me. Now, I don't feel it at all. The medicine isn't working properly because I don't feel it. They increased my dose and the pharmacy won't feel it because I have to ?nish something that isn't working for me. What I?m feeling now isn?t like what I was feeling. I just had surgery and was using it Telephone I wasn't feeling well when I called before and was dealing with cancer and things. 1 have a Telephone nephew who went to jail for abusing it. I have been sick for so long on so many different medications. Patient, died in July Telephone I?m a bit hearing impaired, so I might ask you to repeat things. Telephone He passed away in August. He tried the fentanyl one time, and it sent him into a Telephone grand mal seizure, and I lost him two weeks later. I take it for chronic pain. Telephone 1 just had all my teeth pulled, so I can?t talk real clear. Telephone I've had different issues. Telephone He's in a nursing home. Telephone He was on fentanyl patches. They were worthless, they didn?t relieve the pain at all. He Telephone switched to methadone, so that gives you an idea of how worthless they were. Patient, passed away. Pt: Pt passed away as per her husband Telephone Pt: Per pt's wife is deceased. Telephone Patient, passed away at the end of August. Telephone PT: Per pt's mother, patient has passed away and he was on a fentanyl Telephone spray It?s been a lifesaver for me he?s in severe pain all the time he suffered an Telephone aneurysm at 47 and like they say once the air hits the brain its never the same the pain he suffers- and accordance with all that he can get up and move around he can have some quality of life. Data Source: Program: LQAE.SAS TRIG Page 5 of 6 TIRF Patient/Caregiver KAB 27DEC2016 Listing 4: Listing of Adverse Events and/or Product Complaints Reported by Modality Modality of Verbatim Text Report She has short term memory loss too. She?s not very copacetic. She takes two things, she Telephone takes Actiq 1200mcg, and the patch. The only thing I would potentially disagree with, in my wife?s case she has severe migraines. She has almost constant severe migraines. That?s the reason she takes it opposed to cancer. She takes it actually because she has chronic, really bad migraines. I?m so sick 1 have nausea have degenerative bone disease and 1 hurt so bad and 1 don?t Telephone feel like ?lling it out- I just let me be. I might do it later [?11 never get over this pain bones breakin and this pain and everything. I?ll get back to you when I can think clear. I?m just in so much pain. 1 was on hospice. - When 1 was on hospice they told us, but its okay because I lived. I'm Telephone alive! Hold on, I?m handicapped. I?m blind, I can hardly see. Telephone deceased Mail The passed away in July. Telephone This letter 1s to inform you that passed away on .This Mail forwarding address IS solely for informational noti?cation only. Do not send any mail this address in the ?iture. Thank you for your kind attention Sincerely, I've been doing chemo. Telephone He died in February Telephone On 11/29/2016 received a letter stating the following: passed away Telephone was in the hospital from until that day. He is not able to do your survey he hasn't had meds from you in months." This was sent to my sister, she's sick Telephone I'm not taking this for cancer, my total body was crushed 10 years ago. 1 had a 20001b wall Telephone crush me. Remove from mailing list, died Mail 1 actually slipped in my backyard and ended up breaking all kinds of bones in my foot and Telephone ankle. I've been getting these letters addressed to my husband. He passed away.. Is there any way 1 Telephone can get him taken off of this list? Data Source: Program: LQAE.SAS TRIG Page 6 of 6 Patient/Caregiver KAB 27DEC2016 Listing 4: Listing of Adverse Events and/or Product Complaints Reported by Modality Modality of Verbatim Text Report The medication worked fantastic, she?s on workers comp and it?s way too expensive we Telephone went on and on with the court. You guys price this stu?? way out of the ball park. She has had 8 back surgeries, 2 in the throat, and 6 in the lower back- its way too expensive- sorry. They cut her off. Now we have been playing. Now we have been playing around with other stuff for the last 6 months it doesn?t work quite as well- welcome to America I guess. You can tell your guys its way too expensive. Patient information removed to preserve con?dentiality. Data Source: Program: LQAE.SAS 60-Month FDA REMS Supplemental Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies 4.3 Page 18 of 19 Pharmacy KAB Report FDA_4929 Pharmac KAB Assessment Report Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Title: Final 10 February 2017 Page 1 of 62 Transmucosal Immediate Release Fentanyl (TIRF) REMS Assessment Quantitative Testing of Pharmacist Knowledge, Attitudes, and Behavior (KAB) about TIRF Products Safety and Use Information Document Number: Wave 5, 60-Month REMS Assessment Report Version 1.0 Survey Time Period: 26 September 2016 to 13 December 2016 Product Name: Transmucosal Immediate Release Fentanyl Sponsor: TIRF REMS Industry Group (TRIG) of Companies: Actavis Laboratories FL, Inc. BioDelivery Sciences International, Inc. (BDSI) Cephalon, Inc. (a wholly-owned subsidiary of Teva Pharmaceutical Industries, Ltd.) Depomed, Inc. Insys Therapeutics, Inc. Mallinckrodt Pharmaceuticals Mylan, Inc. Par Pharmaceutical, Inc. Sentynl Therapeutics, Inc. Date: 10 February 2017 Confidentiality Statement The information contained herein is confidential and the proprietary property of the TRIG of Companies and its affiliates, and any unauthorized use or disclosure of such information without the prior written authorization of the TRIG is expressly prohibited. FDA_4930 Pharmac KAB Assessment Report Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies TABLE OF CONTENTS Final 10 February 2017 Page 2 of 62 PAGE TABLE OF CONTENTS......................................................................................................... 2 LIST OF IN-TEXT TABLES .................................................................................................. 3 LIST OF APPENDICES .......................................................................................................... 5 LIST OF ABBREVIATIONS .................................................................................................. 6 EXECUTIVE SUMMARY ..................................................................................................... 7 1. PHARMACIST SURVEY BACKGROUND ......................................................... 8 1.1 Changes to the KAB Survey for Pharmacists Based on FDA Feedback ................ 9 2. PHARMACIST SURVEY OBJECTIVES............................................................ 11 3. SURVEY METHODOLOGY ............................................................................... 11 3.1 Survey Sample ....................................................................................................... 11 3.1.1 Eligibility ............................................................................................................... 12 3.1.2 Recruitment ........................................................................................................... 12 3.2 Questions and Statements on Key Risk Messages ................................................ 13 3.2.1 Key Risk Message 1 .............................................................................................. 13 3.2.2 Key Risk Message 2 .............................................................................................. 14 3.2.3 Key Risk Message 3 .............................................................................................. 15 3.2.4 Key Risk Message 4 .............................................................................................. 16 3.3 Additional Questions ............................................................................................. 17 4. STATISTICAL METHODS ................................................................................. 17 4.1 Study Population ................................................................................................... 17 4.1.1 All Respondents .................................................................................................... 17 4.1.2 Completed Surveys (Primary Population) ............................................................. 18 4.1.3 General Population ................................................................................................ 18 4.2 Primary Analyses .................................................................................................. 18 4.3 Secondary Analyses .............................................................................................. 19 4.4 Pharmacist Report of a Potential Adverse Event, Product Complaint, or Medical Information Request during the Survey .................................................. 19 5. RESULTS.............................................................................................................. 19 5.1 Survey Participants ................................................................................................ 19 FDA_4931 Pharmac KAB Assessment Report Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Final 10 February 2017 Page 3 of 62 5.1.1 Survey Participant Administration Results ........................................................... 19 5.1.2 Description of Eligible Pharmacists Who Completed the Survey ........................ 23 5.1.3 Comparison of Survey Respondents to the General Population of Pharmacists Dispensing TIRF Medicines ............................................................. 25 5.1.4 TIRF Medicines Educational Materials ................................................................ 28 5.2 Key Risk Messages ............................................................................................... 29 5.2.1 Key Risk Message 1 .............................................................................................. 29 5.2.2 Key Risk Message 2 .............................................................................................. 34 5.2.3 Key Risk Message 3 .............................................................................................. 38 5.2.4 Key Risk Message 4 .............................................................................................. 41 5.2.5 Key Risk Message Average Knowledge Scores ................................................... 44 5.2.6 Other Survey Questions......................................................................................... 44 5.2.6.1 Additional Questions about TIRF Medicines Safety ............................................ 44 5.2.6.2 Pharmacist Activities When Dispensing TIRF Medicines .................................... 46 5.3 Spontaneous Reporting of Potential Adverse Events, Product Complaints, or Medical Information Requests .......................................................................... 50 6. DISCUSSION AND CONCLUSIONS ................................................................. 50 LIST OF IN-TEXT TABLES Table 1. Survey Administration Statistics.................................................................... 20 Table 2. Survey Participant Eligibility Results - All Respondents .............................. 21 Table 3. Time to Complete Survey - Completed Surveys ........................................... 23 Table 4. Description of Eligible Pharmacists - Completed Surveys ............................ 24 Table 5. Comparison of Pharmacies Represented by the Survey Respondents to the General Population of Pharmacies That Have Dispensed TIRF Medicines in the Past Six Months (REMS Database) ................................... 27 Table 6. Responses to Questions about TIRF Medicine Educational Materials - Completed Surveys ...................................................................................... 28 Table 7. Primary Analysis of Responses to Questions Linked to Key Risk Message #1 - Completed Surveys .................................................................. 30 Table 8. Secondary Analysis of Responses to Questions Linked to Key Risk Message #1 - Completed Surveys .................................................................. 32 FDA_4932 Pharmac KAB Assessment Report Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Final 10 February 2017 Page 4 of 62 Table 9. Responses to Questions Linked to Key Risk Message #1 by Reading Full Prescribing Information or Medication Guide - Completed Surveys (Questions/Items with Apparent Trends) ......................................... 33 Table 10. Primary Analysis of Responses to Questions Linked to Key Risk Message #2 - Completed Surveys .................................................................. 35 Table 11. Secondary Analysis of Responses to Questions Linked to Key Risk Message #2 - Completed Surveys .................................................................. 36 Table 12. Responses to Questions Linked to Key Risk Message #2 by Reading Full Prescribing Information or Medication Guide - Completed Surveys (Questions/Items with Apparent Trends) ......................................... 37 Table 13. Primary Analysis of Responses to Questions Linked to Key Risk Message #3 - Completed Surveys .................................................................. 39 Table 14. Secondary Analysis of Responses to Questions Linked to Key Risk Message #3 - Completed Surveys .................................................................. 41 Table 15. Primary Analysis of Responses to Questions Linked to Key Risk Message #4 - Completed Surveys .................................................................. 42 Table 16. Secondary Analysis of Responses to Questions Linked to Key Risk Message #4 - Completed Surveys .................................................................. 43 Table 17. Responses to Questions Linked to Key Risk Message #4 by Reading Full Prescribing Information or Medication Guide - Completed Surveys (Questions/Items with Apparent Trends) ......................................... 43 Table 18. Average Knowledge Scores - Completed Surveys ........................................ 44 Table 19. Responses to Additional Questions about the Safe Use of TIRF Medicines - Completed Surveys .................................................................... 45 Table 20. Responses to Additional Questions about the Safe Use of TIRF Medicines: Question Asked of Inpatient Pharmacists Only Completed Surveys ........................................................................................ 46 Table 21. Responses to Questions about the Activities When Dispensing TIRF Medicines - Completed Surveys .................................................................... 47 Table 22. Responses to All Questions about Activities When Dispensing TIRF Medicines: Asked of Inpatient Pharmacies Only - Completed Surveys........................................................................................................... 49 Table 23. Responses to All Questions about Activities When Dispensing TIRF Medicines: Outpatient Pharmacists Only - Completed Surveys ................... 50 Table 24. Correct Response Rate Over Time ................................................................ 53 FDA_4933 Pharmac KAB Assessment Report Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Final 10 February 2017 Page 5 of 62 LIST OF APPENDICES Appendix A Pharmacy Survey Protocol Track Change Document: Comparison of 48-month Survey to 60-month Survey........................................................... 61 Appendix B Survey Tables................................................................................................. 62 FDA_4934 Pharmacist KAB Assessment Report Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Final 10 February 2017 Page 6 of 62 LIST OF ABBREVIATIONS BDSI BioDelivery Sciences International, Inc. CI Confidence Interval CSP Closed System Pharmacy ETASU Elements to Assure Safe Use FDA Food and Drug Administration ISI Important Safety Information KAB Knowledge, Attitudes, and Behavior KRM Key Risk Message N/A Not Applicable or Not Available REMS Risk Evaluation and Mitigation Strategy SCC Survey Coordinating Center SD Standard Deviation TIRF Transmucosal Immediate Release Fentanyl TIRF medicines Transmucosal Immediate Release Fentanyl products TIRF REMS Access program REMS program for TIRF medicines TRIG TIRF REMS Industry Group UBC United BioSource Corporation US United States USPS United States Postal Service FDA_4935 Pharmacist KAB Assessment Report Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Final 10 February 2017 Page 7 of 62 EXECUTIVE SUMMARY The 60-month Knowledge, Attitudes, and Behavior (KAB) survey for pharmacists who dispense Transmucosal Immediate Release Fentanyl (TIRF) medicines was conducted as part of the 60-Month TIRF Risk Evaluation and Mitigation Strategy (REMS) Access program assessment. On 21 July 2016, the Food and Drug Administration (FDA) provided feedback on the pharmacist survey. After careful review of the requested changes, the TIRF REMS Industry Group (TRIG) notified FDA that in order to incorporate all changes, an extension for report submission would be required. As proposed by the FDA on 29 July 2016 and agreed to by the TRIG on 01 August 2016, the 60-month KAB survey results were planned for a separate submission from the overall assessment report on or before 17 February 2017. The survey launched on 26 September 2016 and closed on 13 December 2016. Subjects to complete the pharmacist survey were recruited from pharmacies enrolled in the TIRF REMS Access program as of 02 September 2016 who had dispensed a TIRF medicine in the last 6 months. Out of the total of 561 pharmacists who accessed the survey, 333 (59.4%) pharmacists met eligibility criteria, and of those who met eligibility criteria, 318 (95.5%) completed the survey, exceeding the target of 300 completed surveys. On 21 July 2016, FDA provided feedback on the KAB survey for pharmacists. Changes to the 60-month KAB survey for pharmacists based on FDA feedback included the addition of 3 survey questions and a change to the recruitment strategy to limit the survey to pharmacists who had dispensed TIRF medicines in the past 6 months and attempt to recruit more closed system pharmacists and non-supervisory pharmacists. The addition of Question 12 (TIRF medicines should only be taken by patients who are opioid tolerant [True/False]) and Question 13 (Which of the following risks are associated with the use of TIRF medicines? [True/False for each of the following: misuse, abuse, addiction, overdose, hypothyroidism, and infection]) is discussed below with the key risk message results. Question 15 (How frequently do you perform the following activities when dispensing TIRF medicines?) included 3 response items about pharmacist-reported activity. For each item, most respondents selected always or only with the first prescription; and few respondents selected sometimes, never, or I don’t know. Changes to recruitment efforts included a revised invitation letter addressed to the “pharmacist-in-charge” including 3 letters with unique codes; the pharmacist-in-charge was asked to distribute these letters to non-supervisory staff involved in the dispensing of TIRF medicines. This strategy was successful, with 74.8% of respondents indicating they were not the pharmacist-in-charge. The overall knowledge score of 85.7 (95% confidence interval [CI]: 84.4 87.0) for the survey indicates most respondents demonstrated understanding of the key risk messages (KRMs). The average knowledge score was t83.8 for 3 of the 4 key risk messages and was 75.4 for Key Risk Message 2 (TIRF medicines are only indicated for the management of breakthrough pain in adult cancer patients 18 years of age and older [16 years of age and older for Actiq® brand and generic equivalents] who are already receiving and who are tolerant to around-the-clock opioid therapy for their underlying persistent cancer pain); the lower average knowledge score for Key Risk Message 2 reflected 3 linked questions/items (described below) with correct response rates <65%. Of the 36 questions/items included as part of key risk messages, 27 items of the key risk messages had a correct response rate FDA_4936 Pharmacist KAB Assessment Report Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Final 10 February 2017 Page 8 of 62 >80%, and 6 items had correct response rates from 65.1% to 79.6%. Three questions/items of Key Risk Message 2 had a correct response rate below the desired threshold of 65% (Items 6a, 6c, and 9e). The correct response rate for Item 6a (According to the product labeling, a cancer patient may start a TIRF medicine and an around-the-clock opioid at the same time) was 61.9%. The correct response rate for Item 6c (A patient must stop taking their TIRF medicine if they stop taking their around-the-clock opioid pain medicine) was 41.2%. This item was added to the 48-month survey based on feedback provided by FDA in the 24-month and the 36-month FDA REMS Acknowledgement Letter. The correct response rate for Item 9e (Chronic non-cancer pain is not an indication for which TIRF medicines can be prescribed) was 43.4% for this 60-month survey. Item 9e has also had a low correct response rate across all previous pharmacist KAB surveys conducted (12-month, 24-month, 36-month, and 48-month surveys). The survey score for Item 9e may indicate that some respondents are dispensing TIRF medicines for non-cancer associated indications. When comparing correct response rates from the 12-month KAB survey through the 60-month KAB survey, no trend was evident for this 60-month survey in knowledge and understanding of the key risk messages. As described above, 2 new survey questions (Question 12 and Question 13 [6 separate response items]) were added as part of key risk messages for the 60-month survey. Correct response rates for the new questions/items were t95.6% for Question 12 and 4 items of Question 13 and 84.0%-89.3% for the 2 false items of Question 13 (hypothyroidism and infection). 1. PHARMACIST SURVEY BACKGROUND Transmucosal Immediate Release Fentanyl (TIRF) medicines include the class of immediate release opioid analgesics indicated only for the management of breakthrough pain in cancer patients 18 years of age or older (16 or older for Actiq® [fentanyl citrate oral transmucosal lozenge] and equivalent generics) who are receiving and already tolerant to opioid therapy for their underlying persistent cancer pain. The FDA has determined that a shared system REMS is required to mitigate the risks of misuse, abuse, addiction, overdose, and serious complications due to medication errors with the use of TIRF medicines. The TIRF REMS Access program was approved by the FDA on 28 December 2011. This report describes the results from the pharmacist surveys conducted for the 60-month TIRF REMS Access program assessment, and reflects the REMS reporting period of 29 October 2015 to 28 October 2016. The 60-month KAB survey launched on 26 September 2016 and closed on 13 December 2016. The TIRF medicines include Abstral®, Actiq®, Fentora®, Lazanda®, Subsys®, and (where applicable) their respective generic equivalents. The TRIG includes Actavis Laboratories FL, Inc., BioDelivery Sciences International, Inc. (BDSI), Cephalon, Inc. (a wholly-owned subsidiary of Teva Pharmaceutical Industries, Ltd.); Depomed, Inc., Insys Therapeutics, Inc., Mallinckrodt Pharmaceuticals, Mylan, Inc., Par Pharmaceutical, Inc., and Sentynl Therapeutics, Inc. One company joined the TRIG during the reporting period: Sentynl Therapeutics, Inc. replaced Galena Biopharm, Inc. on 09 January 2016. FDA_4937 Pharmacist KAB Assessment Report Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Final 10 February 2017 Page 9 of 62 The TIRF REMS Access program consists of a Medication Guide, Elements to Assure Safe Use (ETASU), an Implementation System, and a Timetable for Submission of Assessments. The goals of the TIRF REMS Access program are to mitigate the risks of misuse, abuse, addiction, overdose, and serious complications due to medication errors by the following: 1. Prescribing and dispensing TIRF medicines only to appropriate patients, which includes use only in opioid-tolerant patients. 2. Preventing inappropriate conversion between TIRF medicines. 3. Preventing accidental exposure to children and others for whom it was not prescribed. 4. Educating prescribers, pharmacists, and patients on the potential for misuse, abuse, addiction, and overdose of TIRF medicines. An important component of the TIRF REMS Access program assessment is the conduct of quantitative evaluation surveys to assess pharmacists’ understanding and knowledge of the safe use and appropriate prescribing of TIRF medicines as described in the TIRF REMS Access program educational materials, TIRF REMS Access program Pharmacy Enrollment Form, and Prescribing Information of each product. Administration of the surveys conducted among pharmacies enrolled in the TIRF REMS Access program is described in the protocol (See Appendix A). Note: Protocol and survey question revisions from the 48-month assessment report are identified as tracked changes. Data from the surveys, together with other TIRF REMS Access program evaluation metrics, will be used to determine whether changes need to be made to the TIRF REMS Access program processes or educational materials to make them more effective in achieving the goals of the TIRF REMS Access program. 1.1 Changes to the KAB Survey for Pharmacists Based on FDA Feedback On 21 July 2016, FDA provided feedback on the pharmacist survey. After careful review of the requested changes, the TRIG notified FDA that in order to incorporate all changes, an extension for report submission would be required. As proposed by FDA on 29 July 2016 and agreed to by the TRIG on 01 August 2016, the 60-month KAB survey results were planned for a separate submission from the overall assessment report on or before 17 February 2017. Specific updates made to the protocol and survey included: x Changes to recruitment strategy to: o Limit the survey to pharmacists who had dispensed TIRF medicines in the past 6 months o Attempt to recruit more closed system pharmacists and non-supervisory pharmacists. FDA_4938 Pharmacist KAB Assessment Report Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies x Final 10 February 2017 Page 10 of 62 Addition of the following questions: o Question 15 How frequently do you perform the following activities when dispensing TIRF medicines? ƒ Item 15a Talk to the patient about the risks and possible side effects of the TIRF medicine that was most recently prescribed. ƒ Item 15b Instruct the patient on how to use the TIRF medicine that was most recently prescribed. ƒ Item 15c Instruct the patient on how to store or keep the TIRF medicine that was most recently prescribed. o Question 12 TIRF medicines should only be taken by patients who are opioid tolerant (True/False) o Question 13 Which of the following risks are associated with the use of TIRF medicines? x ƒ 13a Misuse ƒ 13b Abuse ƒ 13c Addiction ƒ 13d Overdose ƒ 13e Hypothyroidism ƒ 13f Infection Changes to the KAB survey reporting to include: o A description of how pharmacies that dispense TIRF medicines compare to the pharmacies represented by survey respondents. o The percentage of orders from outpatient versus inpatient versus closed system pharmacies (if possible) Additional information was requested as follows: x If multiple regions were represented by pharmacies represented in the survey x How many pharmacists were from the same pharmacies x How many pharmacies were represented in the survey FDA_4939 Pharmacist KAB Assessment Report Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Final 10 February 2017 Page 11 of 62 All of the above requested changes were incorporated prior to survey launch on 26 September 2016. 2. PHARMACIST SURVEY OBJECTIVES The evaluation survey used a questionnaire to document the level of knowledge and assess the attitudes and behavior of pharmacists regarding the following key information and risk messages communicated through the REMS: 1. TIRF medicines are only contraindicated in opioid non-tolerant patients. 2. TIRF medicines are indicated for the management of breakthrough pain in adult cancer patients 18 years of age and older (16 or older for Actiq® and equivalent generics) who are already receiving and who are tolerant to around-the-clock opioid therapy for their underlying persistent cancer pain. 3. TIRF medicines contain fentanyl, an opioid agonist, and a Schedule II controlled substance, with abuse liability similar to other opioid analgesics. 4. TIRF medicines are not interchangeable with each other, regardless of route of administration. 5. Patients and their caregivers must be instructed that TIRF medicines contain a medicine in an amount that can be fatal in children, in individuals for whom it is not prescribed, and in those who are not opioid tolerant. The survey will also collect data on behaviors, such as receipt and use of educational materials and compliance with REMS requirements. 3. SURVEY METHODOLOGY This section summarizes the survey design and the questions developed to test pharmacist understanding of the key risk messages of the REMS. Full details of the survey design are in the protocol, which can be found in Appendix A. 3.1 Survey Sample A sample of 300 pharmacists who were enrolled in the TIRF REMS Access program and had dispensed a TIRF medicine in the last 6 months was planned for this fifth KAB survey, which was expected to be open from 26 September 2016 to 13 December 2016. The survey sample size was determined based on both practical and statistical considerations. The survey was written to reflect wording for both methods of survey administration: Internet-based and telephone. FDA_4940 Pharmacist KAB Assessment Report Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies 3.1.1 Final 10 February 2017 Page 12 of 62 Eligibility Subjects were recruited from pharmacies enrolled in the TIRF REMS Access program as of 02 September 2016 and that had dispensed a TIRF medicine in the last 6 months. Note: The 6-month time period was at the pharmacy level as pharmacist level data was not collected by the REMS. All pharmacists who worked at the enrolled pharmacy were eligible to participate, which could have resulted in multiple completed surveys per pharmacy. Respondents or respondents with immediate family members who had ever worked for any of the TRIG companies, McKesson Specialty Care Solutions, RelayHealth, United BioSource Corporation (UBC), or the FDA were not eligible to participate nor were respondents who participated in the previous waves of the survey (the 12-month TIRF REMS Access program assessment, the 24-month TIRF REMS Access program assessment, the 36month TIRF REMS Access program assessment, or the 48-month TIRF REMS Access program assessment). 3.1.2 Recruitment Subjects were recruited via an invitation letter sent through the United States Postal Service (USPS) or via fax (see Section 5.1.1 for more detail). In an effort to ensure that a higher percentage of non-supervisory dispensing pharmacists were included for this reporting period per FDA request, the invitation letter was revised and addressed to the “pharmacist-incharge” and disseminated to those pharmacies enrolled in the TIRF REMS Access program. To increase the number of non-supervisory staff participants, a total of 3 letters with unique codes were provided to each pharmacy. The pharmacist-in-charge was asked to distribute these letters to non-supervisory staff involved in the dispensing of TIRF medicines. If the required number of completed surveys was not achieved within a reasonable time frame, second and third mailings to non-respondents, as well as initial invitations to new samples of pharmacies, if the data were available, were sent as necessary based on the actual rate of survey accrual relative to the proximity of the target survey close date. Each letter of invitation included a unique code needed to access the survey. Three categories of pharmacies were randomly sampled: Closed System Pharmacy (CSP), Inpatient Pharmacy, and Outpatient Pharmacy. Each pharmacy was provided a unique access code based on their pharmacy type because some questions in the survey were specific to only one type of pharmacy. The code was deactivated after the respondent had initiated the survey (whether or not the survey was completed). Respondents were given the option of taking the survey by telephone via the Survey Coordinating Center (SCC) or online via a secure website. The survey was estimated to take approximately 15 to 20 minutes to complete. All respondents who completed the survey and provided their contact information were mailed a $50 gift card for participating. The mailing also included a copy of the Important Safety Information (ISI) and a copy of the correct answers to the key risk message questions. FDA_4941 Pharmacist KAB Assessment Report Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies 3.2 Final 10 February 2017 Page 13 of 62 Questions and Statements on Key Risk Messages The questions and statements comprising the knowledge survey were constructed to test the pharmacists’ understanding of the key risk messages (KRMs) of the REMS. The questions were to be answered either by selecting options from multiple-choice lists that include statements of the specific key risk messages or by choosing “Yes” or “True,” “No” or “False,” or “I Don’t Know” regarding statements about TIRF medicines. For statements or questions that had “True” or “Yes” versus “False” or “No” response options, the desired response for key risk messages was generally “True” or “Yes” indicating knowledge of or behavior in accordance with the objectives of the REMS. However, some questions were formatted to have the respondent disagree with the statement as written by providing response options of “False” or “No” to avoid having the same affirmative answer for all desired responses. The REMS statements, corresponding questions, and desired responses covering the key risk messages are identified below and can be found in the survey protocol (Appendix A). 3.2.1 Key Risk Message 1 Key Risk Message 1 refers to the pharmacist’s knowledge of the specific contraindications for TIRF medicines in opioid non-tolerant patients and under what conditions a patient is considered opioid tolerant. Key Risk Message 1: TIRF medicines are contraindicated in opioid non-tolerant patients. Question No. Question Desired Response Please select True, False, or I don’t know for each of the following. 5 According to the labeling for TIRF medicines, patients with cancer who are considered opioid-tolerant are those: 5a Who are taking around-the-clock opioid therapy for underlying persistent cancer pain for one week or longer True 5b Who are not currently taking opioid therapy, but have taken opioid therapy before False 5c Who have no known contraindications to the drug fentanyl, but are not currently taking around-the-clock opioid therapy False FDA_4942 Pharmacist KAB Assessment Report Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Final 10 February 2017 Page 14 of 62 Key Risk Message 1: TIRF medicines are contraindicated in opioid non-tolerant patients. Question No. Question Desired Response 7 Please answer True, False, or I don’t know for each statement based on the labeling for TIRF medicines. 7a TIRF medicines are contraindicated in opioid non-tolerant patients because life-threatening respiratory depression could occur at any dose. True 7b Death has occurred in opioid non-tolerant patients treated with some fentanyl products. True 7c TIRF medicines may be used in opioid non-tolerant patients. False 7d Prescribers starting a patient on a TIRF medicine must begin with titration from the lowest dose available for that specific product, even if the patient has previously taken another TIRF medicine. True 11 Please select True, False, or I don’t know for each of the following. According to the labeling for TIRF medicines, patients considered opioid-tolerant are those who are taking, for one week or longer, at least: 11a 8 mg oral hydromorphone/day True 11b 60 mg oral morphine/day True 11c 30 mg oral oxycodone/day True 11d 25 mcg transdermal fentanyl/hour True 11e 25 mg oral oxymorphone/day True 11f An equianalgesic dose of another oral opioid True 12 TIRF medicines should only be taken by patients who are opioid tolerant. True 3.2.2 Key Risk Message 2 Key Risk Message 2 refers to the pharmacist’s knowledge of the indications for prescribing TIRF medicines for the management of breakthrough pain in opioid-tolerant adult cancer patients, and the timing of administration of the TIRF medicine in relation to the around-theclock opioid therapy to ensure the patient is considered opioid tolerant. FDA_4943 Pharmacist KAB Assessment Report Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Final 10 February 2017 Page 15 of 62 Key Risk Message 2: TIRF medicines are only indicated for the management of breakthrough pain in adult cancer patients 18 years of age and older (16 years of age and older for Actiq® brand and generic equivalents) who are already receiving and who are tolerant to around-theclock opioid therapy for their underlying persistent cancer pain. Question No. Question Desired Response 6 Please answer True, False, or I don’t know for each statement based on the labeling for TIRF medicines. 6a According to the product labeling, a cancer patient may start a TIRF medicine and an around-the-clock opioid at the same time. False According to the product labeling, a cancer patient who has been on an around-the-clock opioid for 1 day may start taking a TIRF medicine for breakthrough pain. False 6b 6c A patient must stop taking their TIRF medicine if they stop taking their around-the-clock opioid pain medicine. 9 Per the approved labeling for TIRF medicines, for which of the following indications can TIRF medicines be prescribed to opioid tolerant patients? Please answer Yes, No, or I don’t know for each option. 9a Acute or postoperative pain No 9b Headache or migraine pain No 9c Dental pain No 9d Breakthrough pain from cancer Yes 9e Chronic non-cancer pain No 3.2.3 True Key Risk Message 3 Key Risk Message 3 refers to the pharmacist’s knowledge of the risk factors for opioid abuse and importance in monitoring for signs of abuse in patients who take TIRF medicines. Key Risk Message 3: TIRF medicines contain fentanyl, an opioid agonist and a Schedule II controlled substance, with abuse liability similar to other opioid analgesics. Question No. Question Desired response 7 Please answer True, False, or I don’t know for each statement about TIRF medicines. 7e It is important to monitor for signs of abuse and addiction in patients who take TIRF medicines. 8 Which of the following are risk factors for opioid abuse? Please answer Yes, No, or I don’t know for each option. 8a A personal history of psychiatric illness True Yes FDA_4944 Pharmacist KAB Assessment Report Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Final 10 February 2017 Page 16 of 62 8b A personal history of past or current alcohol or drug abuse, or a family history of illicit drug use or alcohol abuse 10 Please answer True, False, or I don’t know for each statement based on the labeling for TIRF medicines. 10a TIRF medicines can be abused in a manner similar to other opioid agonists. 13 Which of the following risks are associated with the use of TIRF medicines? Please answer True, False, or I don’t know for the following statements. 13a Misuse True 13b Abuse True 13c Addiction True 13d Overdose True 13e Hypothyroidism False 13f Infection False 3.2.4 Yes True Key Risk Message 4 Key Risk Message 4 refers to the pharmacist’s knowledge of the interchangeability of TIRF medicines based on route of administration, pharmacokinetic absorption, and dosage. Key Risk Message 4: TIRF medicines are not interchangeable with each other, regardless of route of administration. Question No. Question Desired response 10 Please answer True, False, or I don’t know for each statement based on the labeling for TIRF medicines. 10b TIRF medicines are interchangeable with each other regardless of route of administration. False 10c The conversion of one TIRF medicine for another TIRF medicine may result in a fatal overdose because of differences in the pharmacokinetics of fentanyl absorption. True 10d Dosing of TIRF medicines is not equivalent on a microgram-tomicrogram basis. True 16 Please answer True, False, or I don’t know for each statement about TIRF medicines. 16c TIRF medicines with the same route of administration can be substituted with each other if the pharmacy is out of stock for one product. False FDA_4945 Pharmacist KAB Assessment Report Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies 3.3 Final 10 February 2017 Page 17 of 62 Additional Questions The survey also contained questions (Questions 14 and 15) about the requirements of the TIRF REMS Access program, receipt and understanding of the TIRF educational materials, and behaviors. The following questions about behaviors were asked after the key risk message questions: Question No. Question 14 How frequently do you perform the following activities when dispensing TIRF medicines? Please answer Always, Only with the first prescription, Sometimes, Never, or I don’t know. 14a Ask patients (or their caregivers) about the presence of children in the home 14b Instruct patients (or their caregivers) not to share TIRF medicines with anyone else 14c Counsel patients (or their caregivers) that accidental exposure to TIRF medicines by a child may be fatal 14d Instruct patients (or their caregivers) to keep TIRF medicines out of the reach of children to prevent accidental exposure 14e Instruct patients (or their caregivers) about proper disposal of any unused or partially used TIRF medicines 14f Give patients (or their caregivers) the Medication Guide for their TIRF medicine 15 How frequently do you perform the following activities when dispensing TIRF medicines? Please answer Always, Only with the first prescription, Sometimes, Never, or I don't know. 15a Talk to the patient about the risks and possible side effects of the TIRF medicine that was most recently prescribed. 15b Instruct the patient on how to use the TIRF medicine that was most recently prescribed. 15c Instruct the patient on how to store or keep the TIRF medicine that was most recently prescribed. 4. STATISTICAL METHODS 4.1 Study Population 4.1.1 All Respondents The All Respondents population consisted of respondents that accessed the survey using a unique code. These respondents were used as the denominator for percentages in survey administration statistics unless otherwise specified. FDA_4946 Pharmacist KAB Assessment Report Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies 4.1.2 Final 10 February 2017 Page 18 of 62 Completed Surveys (Primary Population) The primary population for analysis was all eligible pharmacists who completed the survey. Eligible pharmacists were defined as those respondents who answered Yes to Question 1 (agree to take part in survey) and Yes to Question 3 (work at a pharmacy that is enrolled in the TIRF REMs Access program), and No to Question 2 (participated in past survey) and No to Question 4 (worked for a TRIG company, UBC, RelayHealth, McKesson Specialty Care Solutions, or FDA). A survey was considered “completed” when an eligible pharmacist answered all relevant questions. 4.1.3 General Population The general population consists of pharmacists representing pharmacies that dispensed a TIRF medicine in the past 6 months. This population was used to compare the population represented in the survey to the general population to determine whether pharmacists completing the survey were representative of the general population. Characteristics of all pharmacies that dispensed a TIRF medicine in the last 6 months were extracted from the REMS switch provider data. Pharmacies represented in the survey were compared to the pharmacies enrolled in the TIRF REMS Access program who dispensed a TIRF medicine within the last 6 months, with the exception of inpatient pharmacies. Inpatient pharmacy REMS requirements differed from requirements of other pharmacy types and therefore data related to the timing of the last dispense were not available. Based on the difference in requirements for inpatient pharmacies, pharmacy comparisons only included data related to chain, independent, and closed-system pharmacies. Characteristics compared included geographic region, type of pharmacy, and (for outpatient pharmacies) number of orders for TIRF medicines by type of pharmacy. The analysis included calculation of p-values by a chisquare test. 4.2 Primary Analyses Primary analyses were performed for all key risk messages. The primary analysis for a key risk message evaluated the number and percentage of correct responses for each individual question/item included in the key risk message. Confidence intervals (95% CI) were calculated using the exact binomial method around the percentage of correct responses. Primary analyses were then stratified by questions/characteristics of interest: 1) Those who indicated they both received and read the Medication Guide or Full Prescribing Information versus those who did not receive/have access to or read the Full Prescribing Information or Medication Guide (Questions 21-24). 2) Whether the survey was completed via the internet or telephone 3) Time in pharmacy practice (Question 31). 4) The number of times per month they dispensed TIRF medicines within the last 6 months (Question 28). Stratified analyses were conducted on all completed surveys. FDA_4947 Pharmacist KAB Assessment Report Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies 4.3 Final 10 February 2017 Page 19 of 62 Secondary Analyses As an indicator of the overall level of comprehension of the entire key risk message, descriptive analyses of the number and percentage of responders who answered various proportions of the key risk message questions/items correctly are presented (e.g., the proportion who answered one question/item in the key risk message correctly, those who answered two questions/items correctly, those who answered 3 questions/items correctly, etc.). A knowledge score was computed for each KRM and overall. The score was defined as the rate of the number of correct responses to all KRM questions to the total number of possible correct responses to all KRM questions. The average knowledge score was calculated as the mean of the score across all completed surveys. The 95% CIs were calculated based on the normal distribution function. 4.4 Pharmacist Report of a Potential Adverse Event, Product Complaint, or Medical Information Request during the Survey A pharmacist may have reported a potential adverse event or other event experienced by a patient while taking a TIRF product either in free text fields while taking the online survey or while in conversation with the SCC Associate. If an event was mentioned to the SCC Associate, the Associate documented the event or complaint, the verbatim response, and the pharmacist’s contact information, if provided. The pharmacist was also informed that a representative from the appropriate TIRF medicine sponsor may contact him/her to obtain additional information about the event. The Internet surveys were monitored for any comments recorded in the free text field. Information on all reports (Internet or telephone) that constituted an adverse event or other event was forwarded to the appropriate TIRF medicine sponsor for processing within 1 business day of awareness of the event as outlined in the Escalating Adverse Events, Product Complaints, and Medical Information Requests Identified During Execution of the Knowledge, Attitudes, and Behavior Survey Project Specific Procedure. 5. RESULTS Results of the pharmacist’s responses to questions in the KAB survey are summarized in this section; stratified analysis tables and overall listings are provided in Appendix B. 5.1 Survey Participants 5.1.1 Survey Participant Administration Results A total of 11598 invitation letters were sent inviting pharmacists within the identified 3856 enrolled pharmacies to participate in the survey (Table 1). An additional 3772 reminder letters were sent to non-responders (See Section 3.1 for survey methodology details). Further outreach to assist in obtaining more CSPs as requested by the FDA included, outbound calling to the authorized representative identified as enrolling the pharmacy, outbound calling to additional resources, as identified by the authorized representative identified as enrolling FDA_4948 Pharmacist KAB Assessment Report Final 10 February 2017 Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 20 of 62 the pharmacy, where applicable, as well as sending the letters via Federal Express to boost participation. As noted in Section 3.1 availability of the survey was expected through 13 December 2016. The survey launch date was delayed based on FDA-requested updates received on 29 July 2016. Successful recruitment resulted in the survey closing on schedule and exceeding the targeted number of 300 completed surveys. From the total of 561 pharmacists who accessed the survey, 333 pharmacists met eligibility criteria, and of those who met eligibility criteria, 318 completed the survey. Of these 318 pharmacists, 314 completed the survey online, and 4 completed it by telephone (Table 3). Table 1. Survey Administration Statistics Parameter, Number of invitations distributed 11598 Number of invitations returned as undeliverable 139 Number of reminder letters distributed 3772 All Respondentsm 561 (4.9) Eligible Respondentsm 333 (59.4) Completed surveym 318 (95.5) Did not complete the surveym 15 (4.5) Respondents not eligiblem' 228 (40.6) Source: Appendix B: Survey Tables, Table 1.1 Number of unique respondents who accessed the survey. Percentage is based on the number of invitations distributed excluding the number of invitations retumed as undeliverable. Percentage is based on the number of all respondents. Percentage is based on the number of eligible respondents. [41 Number of respondents who did not meet eligibility criteria or did not complete eligibility questions. As shown in Table 2, of the 561 pharmacists who accessed the survey, a total of 435 pharmacists agreed to participate in this survey. During the screening process it was determined 102 respondents were not eligible to participate in the survey because they either did not agree to participate in the survey (1 respondent), indicated they had participated in or did not know whether they participated in a survey about TIRF medicines before (54 respondents), worked in pharmacies that were not enrolled or did not know whether their pharmacy was enrolled in the TIRF REMS Access program (42 respondents), or indicated they, or an immediate family member, had worked for a TRIG company, UBC, or FDA in the past or the respondent did not know if they or an immediate family member had worked for a TRIG company, UBC, or FDA in the past (5 respondents). An additional 126 respondents discontinued the survey before completing all eligibility questions without being identi?ed as ineligible. Thus, there were 333 eligible participants. Pharmacist KAB Assessment Report Final Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies 10 February 2017 Page 21 of 62 Table 2. Survey Participant Eligibility Results - All Respondents Pharmacists Question Question 1: Do you agree to participate in this survey? Yes 435 (77.5) Now 1 (0.2) Discontinued 125 (22.3) Question 2: Have you ever taken part in this survey about TIRF medicines before? TIRF medicines include Abstral?, Actiq?, entora?, Lazanda?, Subsys?, and generic versions of any of these brands. Yesm 17 (3.0) No 380 (67.7) 1 don't known] 37 (6.6) Question not asked (0.2) Discontinued 126 (22.5) Question 3: Do you work in a pharmacy that is enrolled in the TIRF REMS Access program? Yes 338 (60.2) Now 10 (1.8) 1 don't known] 32 (5.7) Question not asked 55 (9.8) Discontinued 126 (22.5) Question 4: Have you or any of your immediate family members ever worked for any of the following companies or agencies? Please select all that apply!? Actavis Laboratories FL, Inc.[? 1 (0.2) Anesta 0 BioDelivery Sciences International, Inc. 0 Cephalon, Inc. (a wholly-owned subsidiary of Teva Pharmaceutical Industries, 1 (0.2) Depomed, Inc.m Galena Biophanna, Inc.m Insys Therapeutics, Inc.[? Mallinckrodt Pharmaceuticalsm McKesson Specialty Care Solutionsm Mylan Incl? Par Pharmaceuticals, Inc.[? Therapeutics, Inem Teva Pharmaceuticals, Pharmacist KAB Assessment Report Final 10 February 2017 Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 22 of 62 Pharmacists (N=56l) Question United BioSource Corporationm 0 2 (0.4) None of these 333 (59.4) 1 don't known] 2 (0.4) Prefer not to answerm 0 Question not asked [21 97 (17.3) Discontinued 126 (22.5) Source: Appendix B: Survey Tables, Table 1.2 Note: Respondents who discontinued the survey before completing all eligibility questions without being identi?ed as ineligible in any of the previous questions are counted as discontinued. Once a respondent is counted as discontinued, they will count as discontinued in all subsequent eligibility questions. Ineligible to participate in the survey. Question not asked due to termination response from a previous question. More than one response can be selected, so percentages may not sum to 100%. Ineligible if selected in addition to another response. Pharmacists taking the survey onlinc took a mean of 15.67 minutes to complete it, while those taking it by telephone took a mean of 21.63 minutes (Table 3). Pharmacist KAB Assessment Report Final 10 February 2017 Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 23 of 62 Table 3. Time to Complete Survey - Completed Surveys Telephone Internet TotalIll Summary Statistic (minutes) 4 314 318 Mean (SD) 21.63 (4.391) 15.67 (8.557) 15.74 (8.540) Minimum 18.1 3.6 3.6 Median 20.23 13.48 13.63 Maximum 28.0 55.8 55.8 Category, 0 to <5 Minutes 0 6 6 5 to <10 Minutes 0 85 85 10 to <15 Minutes 0 95 95 15 to <20 Minutes 2 49 51 20 to <25 Minutes 1 36 37 25 to <30 Minutes 1 l6 17 30 Minutes or more 0 27 27 Source: Appendix B: Survey Tables, Table 1.3 Total number of eligible respondents completing the survey. 5.1.2 Description of Eligible Pharmacists Who Completed the Survey The characteristics of pharmacists who completed the survey are shown in Table 4. Most pharmacists (238; 74.8%) were not the pharmacist-in-charge for the TIRF REMS Access program where they work. This indicates the success of efforts to ensure that a higher percentage of non-supervisory dispensing pharmacists were included for this reporting period per FDA request. The majority of pharmacists had dispensed a TIRF medicine either not at all (60; 18.9%) or 1 to 2 times per month (149; 46.9%) within the past 6 months. The most frequently dispensed TIRF medicine within the 6 months prior to taking the survey was Actiq? or generic Actiq? (193; About half of the pharmacists who completed the survey were male (155; and 167 had been a practicing pharmacist for 1 or more years. Most participants were from the South (101; 31.8%) or Northeast (83; followed by the West (75; 23.6%) and Midwest (58; 18.2%) regions of the United States (US). Pharmacist KAB Assessment Report Final 10 February 2017 Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industrv Group (TRIG) of Companies Page 24 of 62 As per FDA request (Section 1.1), information on ?How many pharmacists were from the same pharmacies? is included as follows: . Total number of unique chain/independent pharmacies: Total number of unique chain/independent pharmacies with 1 completer 145 Total number of unique chain/independent pharmacies with 2 completers 40 Total number of unique chain/independent pharmacies with 3 completers 9 0 Total number of unique inpatient pharmacies: Total number of unique inpatient pharmacies with 1 completer 29 Total number of unique inpatient pharmacies with 2 completers l3 Total number of unique inpatient pharmacies with 3 completers 3 There was 1 completer who completed a survey from those invited from the listing of unique closed system pharmacies. Table 4. Description of Eligible Pharmacists - Completed Surveys Pharmacists (N=3l8) Question Question 27: Are you the Pharmacist in Charge for the TIRF REMS Access program where you work? Yes 77 (24.2) No 238 (74.8) I don't know 3 (0.9) Question 28: On average, how many times per month have you dispensed TIRF medicine within the last 6 months? None 60 (18.9) 1 - 2 times per month 149 (46.9) 3 - 5 times per month 38 (11.9) More than 5 times per month 47 (14.8) I don't remember 24 (7.5) Question 29: Please select the TIRF medicine(s) that you have dispensed within the last 6 months. Please select all that apply."" Abstral? 26 (10.1) Actiq? or generic Actiq? 193 (74.8) Fentora? 105 (40.7) Lazanda? 19 (7.4) Subsys? 95 (36.8) (Answered "None" to Question 25) 6O Pharmacist KAB Assessment Report Final 10 February 2017 Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industrv Group (TRIG) of Companies Page 25 of 62 Table 4. Description of Eligible Pharmacists - Completed Surveys Pharmacists (N=3l8) Question Question 30: What is your gender? Male 155 (48.7) Female 150 (47.2) Prefer not to answer 13 (4.1) Question 31: In total, how many years have you been a practicing pharmacist? Less than 3 years 37 (11.6) 3 - 5 years 51 (16.0) 6 - 10 years 56 (17.6) 11-15years 35(ll.0) More than 15 years 132 (41.5) Prefer not to answer 7 (2.2) Geographic Distribution (based on Question 32 - In which state do you Northeast 83 (26.1) Midwest 58 (18.2) South 101 (31.8) West 75 (23.6) Other 0 Prefer not to answer 1 (0.3) Source: Appendix B: Survey Tables, Table 2 Percentages are calculated based on the number of respondents to whom the question was presented. More than one response can be selected, so percentages may not sum to 100%. US. Census Bureau, last revised Friday, 27-Jul-2001 12:59:43 EDT., Geography Division. Northeast includes CT, MA, ME, NH, NJ, NY, PA, RI, and VT. Midwest includes IA, IL, IN, KS, MI, MN, MO, ND, NE, OH, SD, and WI. South includes AL, AR, DC, DE, FL, GA, KY, LA, MD, MS, NC, OK, SC, TN, TX, VA, and WV. West includes AK, AZ, CA, CO, HI, ID, MT, NM, NV, OR, UT, WA, and WY. Other includes Puerto Rico, Northern Mariana Islands, US Virgin Islands, American Samoa and Guam. 5.1.3 Comparison of Survey Respondents to the General Population of Pharmacists Dispensing TIRF Medicines The respondents completing the survey represented a total of 240 pharmacies. The pharmacies were located in all US Census Bureau regions except Other. Comparison of pharmacies represented by the survey respondents to the general population of pharmacies that had dispensed TIRF medicines in the past 6 months (based on the REMS switch provider data) showed a similar distribution by geographic region (Table 5). The distribution of types of pharmacies was signi?cantly different (p<0.05) for the 2 groups; most of the outpatient pharmacies represented by survey respondents were independent, while most of those in the Pharmacist KAB Assessment Report Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Final 10 February 2017 Page 26 of 62 general population were chains. The distribution of outpatient pharmacy orders between independent and chain pharmacies was similar for the 2 groups; however, orders in the general population included a small percentage of orders from CSPs, which could not be represented for the survey respondents’ pharmacies as the REMS Administrator can only provide aggregate data for these orders. This difference in orders from CSPs accounted for the significant p-value. FDA_4955 Pharmacist KAB Assessment Report Final 10 February 2017 Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 27 of 62 Table 5. Comparison of Pharmacies Represented by the Survey Respondents to the General Population of Pharmacies That Have Dispensed TIRF Medicines in the Past Six Months (REMS Database) Pharmacies Represented by Pharmacies Pharmacists Dispensing TIRF Completing Medicines in the Survey Past Six Months (REMS Switch (REMS Switch Provider Data) Provider Data) (N =240) Parameter p-value Geographic region of pharmacy Northeast 59 (24.6) 783 (20.3) Midwest 44 (18.3) 660 (17.1) South 78 (32.5) 1396 (36.2) 0.4924 West 59 (24.6) 1017 (26.4) Other 0 (0.0) Prefer not to answer 0 Type of pharmacy Inpatient Pharmacym 45 (18.8) 763 (19.8) Independent Outpatient Pharmacy 165 (68.8) 1311 (34.0) 0001 Chain Outpatient Pharmacy 29 (12.1) 1769 (45.9) Closed System Pharmacy 1 (0.4) 14 (0.4) Number of orders by type of Inpatient Pharmacy Independent Outpatient Pharmacy 4830 (60.0) 23417 (60.5) Chain Outpatient Pharmacy 3215 (40.0) 15139 (39.1) <.0001 Closed System Pharmacy 146 (0.4) Source: Appendix B: Survey Tables, Table 2b Note: Switch provider data was provided by McKesson on September 2016. Each pharmacy is counted only once, regardless of how many pharmacists from that pharmacy completed the survey. Percentages for the number of orders by type of pharmacy were calculated based on the total number of dispensed TIRF medicines from the pharmacies represented by pharmacists completing the survey and from pharmacies dispensing TIRF medicines in the past 6 months, respectively. P-values are calculated by a chi-square test excluding prefer not to answer. Not available. The TIRF REMS Access program database does not collect dispensing information for inpatient pharmacies. Therefore, the number of inpatient pharmacies is based on the number of all active pharmacies in the TIRF REMS. Number of orders are not available for inpatient pharmacies. Comparison is based on the number of orders from independent outpatient pharmacies, chain outpatient pharmacies and closed system pharmacies. Pharmacist KAB Assessment Report Final 10 February 2017 Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 28 of 62 5.1.4 TIRF Medicines Educational Materials Pharmacists were asked about their access to educational materials for TIRF medicines, specifically the Full Prescribing Information and the Medication Guide (Table 6). Almost all pharmacists reported they had received or had access to the Full Prescribing Information and the Medication Guide (305; 95.9% and 309; 97.2%, respectively). Of those with access to these materials, 80.7% and 88.0%, respectively, indicated that they had read the Full Prescribing Information and the Medication Guide. Table 6. Responses to Questions about TIRF Medicine Educational Materials - Completed Surveys Pharmacists Question Question 21: Did you receive or do you have access to the Full Prescribing Information for the TIRF medicine(s) that you dispense? Yes 305 (95.9) No 3 (0.9) I don't know 10 (3.1) Question 22: Did you read the Full Prescribing Information for the TIRF medicine(s) that you dispense?Ill Yes 246 (80.7) No 51 (16.7) I don't know 8 (2.6) (Answered "No" or don 't know" to Question 21) 13 Question 23: Did you receive or do you have access to the Medication Guide for the TIRF medicine(s) that you dispense? Yes 309 (97.2) No 0 I don't know 9 (2.8) Question 24: Did you read the Medication Guide for the TIRF medicine(s) that you Yes 272 (88.0) No 34 (11.0) I don't know 3 (1.0) (Answered "No" or don 't know" to Question 23) 9 Pharmacist KAB Assessment Report Final 10 February 2017 Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 29 of 62 Table 6. Responses to Questions about TIRF Medicine Educational Materials - Completed Surveys Pharmacists Question Question 25: Did you or do you have any questions about the information in the Full Prescribing Information or Medication Guide?"' Yes 6 (1.9) No 293 (92.1) 1 don't know 19 (6.0) Source: Appendix B: Survey Tables, Table 4 [11 Percentages are calculated based on the sample presented with this question because of skip logic in the survey. Verbatim text for questions about the Full Prescribing Information or Medication Guide is presented in Appendix B, Listing 1. 5.2 Key Risk Messages 5.2.1 Key Risk Message 1 Key Risk Message 1 states medicines are contraindicated in opioid non-tolerant patients.? A high percentage of pharmacists knew that patients with cancer who are considered opioid tolerant are those who are taking around-the-clock opioid therapy for cancer pain for one week or longer 95% CI: 92.7 - 97.6) and that those who are not currently taking an opioid therapy are not opioid tolerant 95% CI: 83.3 - 90.9) (Table 7). In addition, most understood that cancer patients with no known contraindications to the drug fentanyl, but who are not taking around-thc-clock opioid therapy, are not considered opioid tolerant 95% CI: 77.4 - 86.1). The majority of pharmacists knew that TIRF medicines are contraindicated in opioid non- tolerant patients because life-threatening respiratory depression could occur 95% CI: 84.3 - 91.7) and that death has occurred in opioid non-tolerant patients treated with some fentanyl products 95% CI: 92.3 - 97.3). The majority of pharmacists were aware that TIRF medicines may not be used to treat opioid non-tolerant patients 95% CI: 83.3 - 90.9) and, in response to a differently worded question on the same subject, that TIRF medicines should only be taken by patients who are opioid tolerant 95% CI: 92.7 - 97.6). Similarly, 84.0% (95% CI: 79.5 - 87.8) of pharmacists were aware that dose titration for patients starting a TIRF medicine must begin with the lowest available dose for that product. The majority of pharmacists were aware of the regimens that de?ned an opioid-tolerant patient: 8 mg oral hydromorphone/day 95% CI: 69.4 - 79.2), 60 mg oral morphine/day 95% CI: 84.0 - 91.4), 30 mg oral oxycodone/day 95% CI: 72.7 - 82.1), 25 meg transdermal fentanyl/hour 95% CI: 74.7 - 83.9), 25 mg oral Pharmacist KAB Assessment Report Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Final 10 February 2017 Page 30 of 62 oxymorphone/day 95% CI: 66.7 - 76.9), and an equianalgesic dose of another oral opioid 95% CI: 59.6 - 70.3). Table 7. Primary Analysis of Responses to Questions Linked to Key Risk Message #1 - Completed Surveys Question Pharmacists [95% Cll'? Question 5: Please select True, False, or I don't know for each of the following. According to the labeling for TIRF medicines, patients with cancer who are considered opioid-tolerant are those: 5a: Who are taking around-the-clock opioid therapy for underlying, persistent cancer pain for one week or longer Truem 304 (95.6) [92.7 - 97.6] False 10 (3.1) I don't know 4 (1.3) 5b: Who are not currently taking opioid therapy, but have taken opioid therapy before True 30 (9.4) Falsem 278 (87.4) [83.3 - 90.9] I don't know 10 (3.1) 5c: Who have no known contraindications to the drug fentanyl, but are not currently taking around-the-clock opioid therapy True 46 (14.5) Falsem 261 (82.1) [77.4 - 86.1] I don't know 11 (3.5) Question 7: Please answer True, False, or I don't know for each statement based on the labeling for TIRF medicines. 7a: TIRF medicines are contraindicated in opioid non-tolerant patients because life-threatening respiratory depression could occur at any dose. Tmem 281 (88.4) [84.3 - 91.7] False 23 (7.2) 1 don't know 14 (4.4) 7b: Death has occurred in opioid non-tolerant patients treated with some fentanyl products. Truelz] 303 (95.3) [92.3 - 97.3] False 3 (0.9) I don't know 12 (3.8) 7c: TIRF medicines may be used in opioid non-tolerant patients. True 28 (8.8) Falsem 278 (87.4) [83.3 - 90.9] I don't know 12 (3.8) Pharmacist KAB Assessment Report Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Final 10 February 2017 Page 31 of 62 Table 7. Primary Analysis of Responses to Questions Linked to Key Risk Message #1 - Completed Surveys Question Pharmacists (N=3l8) [95% 7d: Prescribers starting a patient on a TIRF medicine must begin with titration from the lowest dose available for that specific product, even if the patient has previously taken another TIRF medicine. True'zl 267 (84.0) [79.5 - 87.8] False 34 (10.7) I don't know 17 (5.3) at least: Question 11: Please select True, False, or I don't know for each of the following. According to the labeling for TIRF medicines, patients considered opioid-tolerant are those who are taking, for one week or longer, I I a: 8 mg oral hydromorphone/day Truem 237 (74.5) [69.4 - 79.2] False 38 (11.9) 1 don't know 43 (13.5) I I b: 60 mg oral morphine/da Truem 280 (88.1) [84.0 - 91.4] False 13 (4.1) I don't know 25 (7.9) I c: 30 mg oral oxycodone/day Truem 247 (77.7) [72.7 - 82.1] False 37 (11.6) I don't know 34 (10.7) I Id: 25 meg transdermalfentanyl/hour Tmem 253 (79.6) [74.7 - 83.9] False 39 (12.3) I don't know 26 (8.2) I e: 25 mg oral oxymorphone/day Truem 229 (72.0) [66.7 - 76.9] False 30 (9.4) I don't know 59 (18.6) I If: An equianalgesic dose of another oral opioid Tmem 207 (65.1) [59.6 - 70.3] False 51 (16.0) 1 don't know 60 (18.9) Pharmacist KAB Assessment Report Final 10 February 2017 Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 32 of 62 Table 7. Primary Analysis of Responses to Questions Linked to Key Risk Message #1 - Completed Surveys Question Pharmacists 8) [95% cu'? Question 12: Please answer True, False, or I don't know for the following statement about TIRF medicines: TIRF medicines should only be taken by patients who are opioid tolerant. Truelz] 304 (95.6) [92.7 - 97.6] False 12 (3.8) I don't know 2 (0.6) Source: Appendix B: Survey Tables, Table 6.1 95% exact two-sided con?dence intervals are calculated using the Clopper-Pearson method. Correct response. Overall, 30.8% of respondents answered all 14 questions/ items of Key Risk Message 1 correctly, 50.6% missed no more than one item, and 62.6% missed no more than two (Table 8). Table 8. Secondary Analysis of Responses to Questions Linked to Key Risk Message #1 - Completed Surveys Pharmacists (N =3l8) Correct Responses 11 0 correct responses 0 1 correct response 1 (0.3) 2 correct responses 1 (0.3) 3 correct responses 0 4 correct responses 2 (0.6) 5 correct responses 3 (0.9) 6 correct responses 4 (1.3) 7 correct responses 6 (1.9) 8 correct responses 25 (7.9) 9 correct responses 13 (4.1) 10 correct responses 31 (9.7) 11 correct responses 33 (10.4) 12 correct responses 38 (11.9) 13 correct responses 63 (19.8) 14 correct responses 98 (30.8) Source: Appendix B: Survey Tables, Table 6.2 Pharmacist KAB Assessment Report Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Final 10 February 2017 Page 33 of 62 The analysis strati?ed by whether the Full Prescribing Information or Medication Guide were received and read (Received and read: 279; Did not receive or read: 39) showed signi?cant differences favoring respondents who received and read the materials in Questions 11b, 11d and 11e (Table 9). A similar but non-signi?cant trend was apparent for all other items within Question 1 1. Table 9. Responses to Questions Linked to Key Risk Message #1 by Reading Full Prescribing Information or Medication Guide - Completed Surveys (Questions/Items with Apparent Trends) Reading Full Prescribing Information or Medication Guide Received and read Did not receive or read P1 or Med Guide Pl or Med Guide Question [95% [95% Question 11: Please select True, False, or I don't know for each of the following. According to the labeling for TIRF medicines, patients considered opioid-tolerant are those who are taking, for one week or longer, at least: I la: 8 mg oral hydromorphone/day Truelz] 212 (76.0) [70.5 - 80.9] 25 (64.1) [47.2 - 78.8] False 35 (12.5) 3 (7.7) I don't know 32(11.5) 11 (282) I lb: 60 mg oral morphine/day Truelz] 252 (90.3) [86.2 - 93.5] 28 (71.8) [55.1 - 85.0] False 13 (4.7) 0 I don't know 14 (5.0) 11 (282) I I c: 30 mg oral oxycodone/day Truelz] 223 (79.9) [74.7 - 84.5] 24 (61.5) [44.6 - 76.6] False 33(11.8) 4 (10.3) I don't know 23 (8.2) 11 (282) I Id: 25 transdermalfentanyI/hour Truelz] 230 (82.4) [77.5 - 86.7] 23 (59.0) [42.1 - 74.4] False 34 (12.2) 5 (12.8) I don't know 15 (5.4) 1 1 (282) I I e: 25 mg oral oxymorphone/day Truem 208 (74.6) [69.0 - 79.6] 21 (53.8) [37.2 - 69.9] False 25 (9.0) 5 (12.8) I don't know 46 (16.5) 13 (33.3) Pharmacist KAB Assessment Report Final 10 February 2017 Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 34 of 62 Table 9. Responses to Questions Linked to Key Risk Message #1 by Reading Full Prescribing Information or Medication Guide - Completed Surveys (Questions/Items with Apparent Trends) Reading Full Prescribing Information or Medication Guide Received and read Did not receive or read Pl or Med Guide Pl or Med Guide Question [95% cu'? (95% I I 1? An equianalgesic dose of another oral opioid Truelz] 189 (67.7) [61.9 - 73.2] 18 (46.2) [30.1 - 62.8] False 43 (15.4) 8 (20.5) I don't know 47 (16.8) 13 (33.3) Source: Appendix B: Survey Tables, Table 6.1.1 95% exact two-sided con?dence intervals are calculated using the lopper-Pearson method. Correct response. No meaningful comparison was possible in the analysis strati?ed by survey modality (intemet or telephone) as only 4 respondents completed the survey by telephone. Additionally, strati?cation by time in pharmacy practice (per categories in Question 31) or number of times TIRF medicines were dispensed in the last 6 months (per categories in Question 28) did not result in any uniform trends (Appendix B). 5.2.2 Key Risk Message 2 Key Risk Message 2 states medicines are only indicated for the management of breakthrough pain in adult cancer patients 18 years of age and older (16 years of age and older for Actiq? brand and generic equivalents) who are already receiving and who are tolerant to around-the-clock opioid therapy for their underlying persistent cancer pain.? A majority 95% CI: 56.4 - 67.3) of pharmacists correctly indicated that a cancer patient should not be started on a TIRF medicine and an around-the-clock opioid at the same time, and 80.5% (95% CI: 75.7 - 84.7) correctly indicated that a cancer patient who had been on an around-thc-elock opioid for one day should not start taking a TIRF medicine for breakthrough pain (Table 10). Fewer than half (41 95% CI: 35.7 - 46.8) understood that a patient must stop taking their TIRF medicine if they stop taking their around-the?clock opioid pain medicine. A majority of pharmacists were aware that TIRF medicines are indicated for opioid-tolerant patients with breakthrough pain from cancer 95% CI: 88.2 - 94.6) and not for patients with acute or postoperative pain 95% CI: 81.5 - 89.5), headache or migraine pain 95% CI: 91.2 - 96.6), or dental pain 95% CI: 93.5 - 98.0). About half of respondents 95% CI: 45.3 - 56.6) correctly responded that TIRF medicines should not be prescribed for chronic non-cancer pain. Pharmacist KAB Assessment Report Final 10 February 2017 Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 35 of 62 Table 10. Primary Analysis of Responses to Questions Linked to Key Risk Message #2 - Completed Surveys Pharmacists (N=3l8) Question [95% cu'" Question 6: Please answer True, False, or I don't know for each statement based on the labeling for TIRF medicines. 6a: According to the product labeling, a cancer patient may start a TIRF medicine and an around-the-clock opioid at the same time. True 82 (25.8) Falsem 197 (61.9) [56.4 - 67.3] 1 don't know 39 (12.3) 6b: According to the product labeling, a cancer patient who has been on an around-the-clock opioid for I day may start taking a TIRF medicine for breakthrough pain. True 34 (10.7) Falsem 256 (80.5) [75.7 - 84.7] 1 don't know 28 (8.8) 6c: A patient must stop taking their TIRF medicine if they stop taking their around-the-clock opioid pain medicine. Truelz] 131 (41.2) [35.7 - 46.8] False 151 (47.5) Idon't know 36 (11.3) Question 9: Per the approved labeling for TIRF medicines, for which of the following indications can TIRF medicines be prescribed to opioid tolerant patients? Please answer Yes, No, or I don't know for each option. 9a: Acute or postoperative pain Yes 35 (1 1.0) Now 273 (85.8) [81.5 - 89.5] [don't know 10 (3.1) 9b: Headache or migraine pain Yes 7 (2.2) Now 300 (94.3) [91.2 - 96.6] I don't know 1 1 (3.5) 9c: Dental pain Yes 2 (0.6) Now 306 (96.2) [93.5 - 98.0] Idon't know 10 (3.1) Pharmacist KAB Assessment Report Final 10 February 2017 Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 36 of 62 Table 10. Primary Analysis of Responses to Questions Linked to Key Risk Message #2 - Completed Surveys Pharmacists (N =3l8) Question [95% cu'" 9d: Breakthrough pain ?om cancer Yesm 292 (91.8) [88.2 - 94.6] No 22 (6.9) I don't know 4 (1.3) 9e: Chronic non-cancer pain Yes 138 (43.4) New 162 (50.9) [45.3 - 56.6] I don't know 18 (5.7) Source: Appendix B: Survey Tables, Table 7.1 95% exact two-sided con?dence intervals are calculated using the Clopper-Pearson method. Correct response. Overall, 22.3% of respondents correctly answered all 8 questions/items of the key risk message; 43.1% missed no more than one item. and 65.4% missed no more than two items (Table 11). Table 11. Secondary Analysis of Responses to Questions Linked to Key Risk Message #2 - Completed Surveys Pharmacists (N =3l8) Correct Responses 0 correct responses 1 (0.3) 1 correct response 3 (0.9) 2 correct responses 6 (1.9) 3 correct responses 8 (2.5) 4 correct responses 38 (l 1.9) 5 correct responses 54 (17.0) 6 correct responses 71 (22.3) 7 correct responses 66 (20.8) 8 correct responses 71 (22.3) Source: Appendix B: Survey Tables, Table 7.2 The analysis strati?ed by whether the Full Prescribing Information or Medication Guide were received and read (Received and read: 279; Did not receive or read: 39) showed a Pharmacist KAB Assessment Report Transmucosal Immediate Release Fcntanyl (TIRF) TIRF REMS Industrv Group (TRIG) of Companies Final 10 February 2017 Page 37 of 62 signi?cant difference favoring respondents who received and read the materials in Question 90 (Table 12). A similar but non-signi?cant trend was apparent for all other questions/ items linked to the key risk message. Table 12. Responses to Questions Linked to Key Risk Message #2 by Reading Full Prescribing Information or Medication Guide - Completed Surveys (Questions/Items with Apparent Trends) Question Reading Full Prescribing Information or Medication Guide Received and read Pl or Med Guide [95% Did not receive or read Pl or Med Guide [95% Cll'" Question 6: Please answer True, False, or I don't know for each statement based on the labeling for TIRF medicines. 6a: According to the product labeling, a cancer patient may start a TIRF medicine and an around-the-clock opioid at the same time. True 73 (26.2) 9 (23.1) Falsem 175 (62.7) [56.8 - 68.4] 22 (56.4) [39.6 - 72.2] Idon't know 31 (11.1) 8 (20.5) 6b: According to the product labeling, a cancer patient who has been on an around-the-clock opioid for I day may start taking a TIRF medicine for breakthrough pain. True 31 (11.1) 3 (7.7) Falsem 230 (82.4) [77.5 - 86.7] 26 (66.7) [49.8 80.9] 1 don't know 18 (6.5) 10 (25.6) 6c: A patient must stop taking their TIRF medicine if they stop taking their around-the-clock opioid pain medicine. Truelz] 118 (42.3) [36.4 - 48.3] 13 (33.3) [19.1 - 50.2] False 134 (48.0) 17 (43.6) I don't know 27 (9.7) 9 (23.1) Question 9: Per the approved labeling for TIRF medicines, for which of the following indications can TIRF medicines be prescribed to opioid tolerant patients? Please answer Yes, No, or I don't know for each option. 9a: Acute or postoperative pain Yes 29 (10.4) 6 (15.4) N691 244 (87.5) [83.0 - 91.1] 29 (74.4) [57.9 - 87.0] Idon't know 6 (2.2) 4 (10.3) 9b: Headache or migraine pain Yes 6 (2.2) 1 (2.6) N691 267 (95.7) [92.6 - 97.8] 33 (84.6) [69.5 94.1] I don't know 6 (2.2) 5 (12.8) Pharmacist KAB Assessment Report Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Final 10 February 2017 Page 38 of 62 Table 12. Responses to Questions Linked to Key Risk Message #2 by Reading Full Prescribing Information or Medication Guide - Completed Surveys (Questions/Items with Apparent Trends) Question Reading Full Prescribing Information or Medication Guide Received and read Pl or Med Guide [95% cu'" Did not receive or read P1 or Med Guide [95% 96: Dental pain Yes 2 (0.7) 0 New 272 (97.5) [94.9 - 99.0] 34 (87.2) [72.6 - 95.7] [don't know 5 (1.8) 5 (12.8) 9d: Breakthrough pain from cancer Yesm 258 (92.5) [88.7 - 95.3] 34 (87.2) [72.6 - 95.7] No 19 (6.8) 3 (7.7) [don't know 2 (0.7) 2 (5.1) 9e: Chronic non-cancer pain Yes 117 (41.9) 21 (53.8) Now 150 (53.8) [47.7 - 59.7] 12 (30.8) [17.0 - 47.6] I don't know 12 (4.3) 6 (15.4) Source: Appendix B: Survey Tables, Table 7.1.1 95% exact two-sided con?dence intervals are calculated using the lopper-Pearson method. Correct response. No meaningful comparison was possible in the analysis strati?ed by survey modality (internet or telephone) as only 4 respondents completed the survey by telephone. Strati?cation by time in pharmacy practice (per categories in Question 31) or number of times TIRF medicines were dispensed in the last 6 months (per categories in Question 28) did not result in any uniform trends (Appendix B). 5.2.3 Key Risk Message 3 Key Risk Message 3 states medicines contain fentanyl, an opioid agonist and a Schedule II controlled substance, with abuse liability similar to other opioid analgesics.? Results in Table 13 show that 98.1% (95% CI: 95.9 - 99.3) of pharmacists were aware that it is important to monitor for signs of abuse and addiction in patients who take TIRF medicines. In addition, most respondents correctly indicated that a personal history of illness is a risk factor for opioid abuse 95% CI: 72.7 - 82.1), that a personal history of past or current alcohol or drug abuse or family history of drug or alcohol abuse is a risk factor for opioid abuse 95% CI: 96.8 - 99.7), and that TIRF medicines can be abused in a manner similar to other opioid agonists 95% CI: 90.5 - 96.1). Pharmacist KAB Assessment Report Final 10 February 2017 Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 39 of 62 A majority of respondents correctly identi?ed the following as risks associated with the use of TIRF medicines: misuse 95% CI: 96.8 - 99.7), abuse 95% CI: 97.3 - 99.8), addiction 95% CI: 96.8 - 99.7), and overdose 95% CI: 97.7 - 99.9). Most respondents correctly answered that the following are not associated with the use of TIRF medicines: hypothyroidism 95% CI: 79.5 - 87.8) and infection 95% CI: 85.4 - 92.5). Table 13. Message #3 - Completed Surveys Primary Analysis of Responses to Questions Linked to Key Risk Question Pharmacists (N=3l8) [95% Question 7: Please answer True, False, or I don't know for each statement based on the labeling for TIRF medicines. 7e: It is important to monitor for signs of abuse and addiction in patients who take TIRF medicines. Truem 312 (98.1) [95.9 - 99.3] False 4 (1.3) I don't know 2 (0.6) Question 8: Which of the following are risk factors for opioid abuse? Please answer Yes, No, or I don't know for each option. 8a: A personal history of iatric illness Yesm 247 (77.7) [72.7 - 82.1] No 42 (13.2) I don't know 29 (9.1) 8b: A personal history of past or current alcohol or drug abuse, or a family history of illicit drug use or alcohol abuse Yesm 314 (98.7) [96.8 - 99.7] No 1 (0.3) 1 don't know 3 (0.9) Question 10: Please answer True, False, or I don't know for each statement based on the labeling for TIRF medicines. I 0a: TIRF medicines can be abused in a manner similar to other opioid agonists. Truelz] 298 (93.7) [90.5 - 96.1] False 12 (3.8) I don't know 8 (2.5) Pharmacist KAB Assessment Report Final 10 February 2017 Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industrv Group (TRIG) of Companies Page 40 of 62 Table 13. Primary Analysis of Responses to Questions Linked to Key Risk Message #3 - Completed Surveys Pharmacists (N=3l8) Question [95% Question 13: Which of the following risks are associated with the use of TIRF medicines? Please answer True, False, or I don't know for the following statements. 13a: Misuse Truelz] 314 (98.7) [96.8 - 99.7] False 3 (0.9) I don't know 1 (0.3) I 3b: A base Truem 315 (99.1) [97.3 - 99.8] False 2 (0.6) I don't know 1 (0.3) 13c: Addiction True-[21 314 (98.7) [96.8 - 99.7] False 3 (0.9) I don't know 1 (0.3) 13d: Overdose Truem 316 (99.4) [97.7 - 99.9] False (0.3) I don't know 1 (0.3) I 3e: Hypothyroidism True 10 (3.1) Falsem 267 (84.0) [79.5 - 87.8] I don't know 41 (12.9) I Infection True 15 (4.7) Falsem 284 (89.3) [85.4 - 92.5] 1 don't know 19 (6.0) Source: Appendix B: Survey Tables, Table 8.1 95% exact two-sided con?dence intervals are calculated using the lopper-Pearson method. Correct response. Overall, 59.4% of pharmacists correctly answered all 10 questions/ items of the key risk message, and 85.5% missed no more than one item (Table 14). Pharmacist KAB Assessment Report Final 10 February 2017 Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 41 of 62 Table 14. Secondary Analysis of Responses to Questions Linked to Key Risk Message #3 - Completed Surveys Pharmacists (N =3l8) Correct Responses 0 correct responses 0 1 correct response 0 2 correct responses 0 3 correct responses 1 (0.3) 4 correct responses 0 5 correct responses 1 (0.3) 6 correct responses 4 (1.3) 7 correct responses 8 (2.5) 8 correct responses 32 (10.1) 9 correct responses 83 (26.1) 10 correct responses 189 (59.4) Source: Appendix B: Survey Tables, Table 8.2 No meaningful comparison was possible in the analysis strati?ed by survey modality (intemet or telephone) as only 4 respondents completed the survey by telephone. Strati?cation by receipt and reading of the Full Prescribing Information or Medication Guide (received and read versus did not receive or read), time in pharmacy practice (per categories in Question 31), or number of times TIRF medicines were dispensed in the last 6 months (per categories in Question 28) did not result in any uniform trends (Appendix B). 5.2.4 Key Risk Message 4 Key Risk Message 4 states medicines are not interchangeable with each other, regardless of route of administration.? Almost all pharmacists 95% CI: 93.1 - 97.8) understood TIRF medicines are not interchangeable with each other regardless of the route of administration; 93.1% (95% CI: 89.7 - 95.6) understood the conversion of one TIRF medicine to another may result in a fatal overdose; and 89.0% (95% CI: 85.0 - 92.2) understood that dosing of TIRF medicines is not equivalent on a microgram-to-microgram basis (Table 15). Almost all pharmacists 95% CI: 92.7 - 97.6) correctly indicated that TIRF medicines with the same route of administration cannot be substituted with each other if the pharmacy is out of stock. Pharmacist KAB Assessment Report Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Final 10 February 2017 Page 42 of 62 Table 15. Primary Analysis of Responses to Questions Linked to Key Risk Message #4 - Completed Surveys Question Pharmacists [95% Question 10: Please answer True, False, or I don't know for each statement based on the labeling for TIRF medicines. I 0b: TIRF medicines are interchangeable with each other regardless of route of administration. True 6 (1.9) Falselz] 305 (95.9) [93.1 - 97.8] I don't know 7 (2.2) 10c: The conversion of one TIRF medicine for another TIRF medicine may result in a fatal overdose because of differences in the pharmacokinetics of fentanyl absorption. Truem 296 (93.1) [89.7 - 95.6] False 10 (3.1) I don't know 12 (3.8) I 0d: Dosing of TIRF medicines is not equivalent on a microgram-to-microgram basis. Truem 283 (89.0) [85.0 - 92.2] False 16 (5.0) I don't know 19 (6.0) Question 16: Please answer True, False, or I don't know for each statement about TIRF medicines. 16c: TIRF medicines with the same route of administration can be substituted with each other if the pharmacy is out of stock for one product. True 10 (3.1) Falsem 304 (95.6) [92.7 - 97.6] I don't know 4 (1.3) Source: Appendix B: Survey Tables, Table 9.1 95% exact two-sided con?dence intervals are calculated using the lopper-Pearson method. Correct response. Overall, 79.9% of pharmacists correctly answered all 4 questions/items of the key risk message, and 95.6% missed no more than one item (Table 16). Pharmacist KAB Assessment Report Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Final 10 February 2017 Page 43 of 62 Table 16. Secondary Analysis of Responses to Questions Linked to Key Risk Message #4 - Completed Surveys Pharmacists (N =3l8) Correct Responses 0 correct responses 0 1 correct response 6 (1.9) 2 correct responses 8 (2.5) 3 correct responses 50 (15.7) 4 correct responses 254 (79.9) Source: Appendix B: Survey Tables, Table 9.2 The analysis stratified by whether the Full Prescribing Information or Medication Guide were received and read (Received and read: 279; Did not receive or read: 39) showed a trend favoring respondents who received and read the materials in Question 10d (Table 17). Table 17. Responses to Questions Linked to Key Risk Message #4 by Reading Full Prescribing Information or Medication Guide - Completed Surveys (Questions/Items with Apparent Trends) Question Reading Full Prescribing Information or Medication Guide Received and read P1 or Med Guide [95% Did not receive or read Pl or Med Guide [95% cu'? Question 10: Please answer True, False, or I don't know for each statement based on the labeling for TIRF medicines. I 0d: Dosing of TIRF medicines is no! equivalent on a microgram-to-microgram basis. Truelz] 253 (90.7) [86.6 - 93.8] 30 (76.9) [60.7 - 88.9] False 15 (5.4) 1 (2.6) I don't know 11 (3.9) 8 (20.5) Source: Appendix B: Survey Tables, Table 9.1.1 95% exact two-sided con?dence intervals are calculated using the lopper-Pearson method. Correct response. No meaningful comparison was possible in the analysis strati?ed by survey modality (intemet or telephone) as only 4 respondents completed the survey by telephone. Strati?cation by time in pharmacy practice (per categories in Question 31) or number of times TIRF medicines were dispensed in the last 6 months (per categories in Question 28) did not result in any uniform trends (Appendix B). Pharmacist KAB Assessment Report Final 10 February 2017 Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 44 of 62 5.2.5 Key Risk Message Average Knowledge Scores Table 18 presents the average knowledge score for each key risk message and an overall knowledge score for all key risk messages combined. The overall knowledge score of 85.7 (95% CI: 84.4 87.0) indicates most respondents demonstrated understanding of the key risk messages. The average knowledge score for each of the key risk messages was 283.8 for 3 of the 4 key risk messages and was 75.4 for Key Risk Message 2 (TIRF medicines are only indicated for the management of breakthrough pain in adult cancer patients 18 years of age and older [16 years of age and older for Actiq? brand and generic equivalents] who are already receiving and who are tolerant to around-the-clock opioid therapy for their underlying persistent cancer pain). Table 18. Average Knowledge Scores - Completed Surveys Score [95% KRM #1 83.8 [81.8, 85.7] KRM #2 75.4 [73.1, 77.6] KRM #3 93.7 [92.7, 94.8] KRM #4 93.4 [91.7, 95.0] Overall Knowledge Score 85.7 [84.4, 87.0] Source: Appendix B: Survey Tables, Table 10 95% C15 are constructed based on normal distribution ?mction. 5.2.6 Other Survey Questions 5.2.6.1 Additional Questions about TIRF Medicines Safety Table 19 summarizes the responses of pharmacists to additional questions about the safe use of TIRF medicines beyond those associated with the key risk messages. Most pharmacists correctly indicated that use of a TIRF medicine with a CYP3A4 inhibitor may require dosage adjustment and monitoring of the patient as potentially fatal respiratory depression could occur. The majority of pharmacists correctly indicated that a family history of asthma is not a risk factor for opioid abuse In addition, majorities of pharmacists correctly indicated that TIRF medicines may not be sold, loaned, or transferred to another pharmacy and that pharmacy staff who dispense TIRF medicines must be educated on the requirements of the TIRF REMS Access program A majority of inpatient pharmacists (54/65; 83.1%) correctly indicated that it is not permissible to dispense TIRF medicines from the inpatient pharmacy inventory to an outpatient for home use (Table 20). Pharmacist KAB Assessment Report Final Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies 10 February 2017 Page 45 of 62 Table 19. Responses to Additional Questions about the Safe Use of TIRF Medicines - Completed Surveys Pharmacists (N=3l8) Question Question 6: Please answer True, False, or I don't know for each statement based on the labeling for TIRF medicines. 6d: Use of a TIRF medicine with a CYP3A4 inhibitor may require dosage adjustment and monitoring of the patient for opioid toxicity as potentially fatal respiratory depression could occur. Truem 293 (92.1) False 3 (0.9) I don't know 22 (6.9) Question 8: Which of the following are risk factors for opioid abuse? Please answer Yes, No, or I don't know for each option. 8c: A family history of asthma Yes 28 (8.8) Non] 271 (85.2) I don't know 19 (6.0) Question 16: Please answer True, False, or I don't know for each statement about TIRF medicines. I 6a: TIRF medicines may be sold, loaned, or transferred to another pharmacy. True 16 (5.0) Falsem 288 (90.6) I don't know 14 (4.4) I 6b: All pharmacy staff that dispenses medicines must be educated on the requirements of the TIRF REMS Access program. Truem 286 (89.9) False 18 (5.7) I don't know 14 (4.4) Source: Appendix B: Survey Tables, Table 3 Correct response. Pharmacist KAB Assessment Report Final 10 February 2017 Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 46 of 62 Table 20. Responses to Additional Questions about the Safe Use of TI RF Medicines: Question Asked of Inpatient Pharmacists Only - Completed Surveys Inpatient Pharmacists Question 11 Question 20: Please answer True, False, or I don't know for the following statement about TIRF medicines. (Inpatient Pharmacists, only)Ill is OK to dispense TIRF medicines ?om the inpatient pharmacy inventmy to an outpatient for use at home. True 3 (4.6) Falsem 54 (83.1) [don't know 8 (12.3) Source: Appendix B: Survey Tables, Table 5 [11 Percentages are calculated based on the sample presented with this question. Correct response. 5.2.6.2 Pharmacist Activities When Dispensing TIRF Medicines Pharmacists were asked about speci?c activities performed when dispensing TIRF medicines (Table 21). Of the 318 eligible pharmacists who completed the survey, 54.7% responded they always ask their patients (or a patient?s caregiver) about the presence of children in the home; 26.7% responded that they ask only with the ?rst prescription. Additionally, 70.1% responded they always instruct patients (or their caregivers) not to share TIRF medicines; 65.1% responded they always counsel patients (or their caregivers) that accidental exposure to TIRF medicines by a child may be fatal, 67.3% responded they always instruct patients (or their caregivers) to keep TIRF medicines out of reach of children, 61.6% responded they always instruct patients (or their caregivers) about proper disposal of any unused or partially used TIRF medicines, and 87.1% responded they always give patients (or their caregivers) the Medication Guide for TIRF medicine. Most respondents reported performing the following activities always or only with the ?rst prescription: talking to the patient about the risks and possible side effects of the TIRF medicine that was most recently prescribed (always 53.8%; only with ?rst prescription instructing the patient on how to use the TIRF medicine that was most recently prescribed (always 57.9%; only with ?rst prescription and instructing the patient on how to store or keep the TIRF medicine that was most recently prescribed (always 48.4%; only with ?rst prescription Pharmacist KAB Assessment Report Final 10 February 2017 Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industrv Group (TRIG) of Companies Page 47 of 62 Table 21. Responses to Questions about the Activities When Dispensing TIRF Medicines - Completed Surveys Pharmacists (N=3l8) Question Question 14: How frequently do you perform the following activities when dispensing TIRF medicines? Please answer Always, Only with the ?rst prescription, Sometimes, Never, or I don't know. I 4a: Ask patients (or their caregivers) about the presence of children in the home Always 174 (54.7) Only with the ?rst prescription 85 (26.7) Sometimes 33 (10.4) Never 19 (6.0) I don't know 7 (2.2) I 4b: Instruct patients (or their caregivers) not to share TIRF medicines with anyone else Always 223 (70.1) Only with the ?rst prescription 62 (19.5) Sometimes 17 (5.3) Never 13 (4.1) I don't know 3 (0.9) I 4c: Counsel patients (or their caregivers) that accidental exposure to TIRF medicines by a child may be fatal Always 207 (65.1) Only with the ?rst prescription 69 (21.7) Sometimes 24 (7.5) Never 15 (4.7) 1 don't know 3 (0.9) I 4d: Instruct patients (or their caregivers) to keep TIRF medicines out of the reach of ch ildren to prevent accidental exposure Always 214 (67.3) Only with the ?rst prescription 67 (21.1) Sometimes 22 (6.9) Never 11 (3.5) I don't know 4 (1.3) Pharmacist KAB Assessment Report Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industrv Group (TRIG) of Companies 10 February 2017 Page 48 of 62 Table 21. Responses to Questions about the Activities When Dispensing TIRF Medicines - Completed Surveys Question Pharmacists (N=3l8) I 4e: Instruct patients (or their caregivers) about proper disposal of any unused or partially used TIRF medicines Always 196 (61.6) Only with the ?rst prescription 86 (27.0) Sometimes 21 (6.6) Never 11 (3.5) I don't know 4 (1.3) I Give patients (or their caregivers) the Medication Guide for their TIRF medicine Always 277 (87.1) Only with the ?rst prescription 24 (7.5) Sometimes 6 (1.9) Never 8 (2.5) I don't know 3 (0.9) Question 15: How frequently do you perform the following activities when dispensing TIRF medicines? Please answer Always, Only with the ?rst prescription, Sometimes, Never, or I don't know. I 5a: Talk to the patient about the risks and possible side effects of the TIR medicine that was most recently prescribed. Always 171 (53.8) Only with the ?rst prescription 1 17 (36.8) Sometimes 21 (6.6) Never 8 (2.5) [don't know 1 (0.3) I 5b: Instruct the patient on how to use the TIRF medicine that was most recently prescribed. Always 184 (57.9) Only with the ?rst prescription 1 11 (34.9) Sometimes 14 (4.4) Never 8 (2.5) I don't know 1 (0.3) Pharmacist KAB Assessment Report Final 10 February 2017 Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industrv Group (TRIG) of Companies Page 49 of 62 Table 21. Responses to Questions about the Activities When Dispensing TIRF Medicines - Completed Surveys Pharmacists (N =3 8) Question 15c: Instruct the patient on how to store or keep the TIRF medicine that was most recently prescribed. Always 154 (48.4) Only with the ?rst prescription 125 (39.3) Sometimes 24 (7.5) Never 13 (4.1) I don't know 2 (0.6) Source: Appendix B: Survey Tables, Table 5 [11 Percentages are calculated based on the sample presented with this question. Correct response. Speci?c pharmacy types (inpatient, outpatient, and CSP pharmacies) were each asked a single, different question regarding pharmacy systems and processes. Question 17 was presented only to respondents from inpatient pharmacies as identified through the unique survey access code provided by the respondent to enter the survey (Table 22). Of the 65 inpatient pharmacy respondents, 61.5% reported their pharmacy has processes to ensure compliance with the TIRF REMS Access program requirements. Table 22. Responses to All Questions about Activities When Dispensing TIRF Medicines: Asked of Inpatient Pharmacies Only - Completed Surveys Inpatient Pharmacists Question :1 Question 17: Does the inpatient pharmacy where you work have an established system, order sets, protocols and/or other measures to help ensure appropriate patient selection and compliance with the requirements of the TIRF REMS Access program? (Inpatient Pharmacists, only)Ill Yes 40 (61.5) No 11 (16.9) I don't know 14 (21.5) Source: Appendix B: Survey Tables, Table 5 Percentages are calculated based on the sample presented with this question. Question 18 was presented only to pharmacy respondents from outpatient pharmacies as identi?ed through the unique survey access code provided by the respondent to enter the survey. This sub-population did not include respondents from CSPs (Table 23). Of the 252 outpatient pharmacy respondents, 81.7% reported their pharmacy processes prescriptions for TIRF medicines through their pharmacy management system regardless of the method of payment. Pharmacist KAB Assessment Report Final 10 February 2017 Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 50 of 62 Table 23. Responses to All Questions about Activities When Dispensing TIRF Medicines: Outpatient Pharmacists Only - Completed Surveys Outpatient Pharmacists (N =252) Question Question 18: Does the outpatient or retail pharmacy where you work process all TIRF medicine prescriptions, regardless of method of payment, through the pharmacy management system? (Outpatient Pharmacists, only)Ill Yes 206 (81.7) No 11 (4.4) 1 don't know 35 (13.9) Source: Appendix B: Survey Tables, Table 5 Percentages are calculated based on the sample presented with this question. Question 19 (Does the pharmacy where you work process all TIRF medicine prescriptions, regardless of method of payment, through the TIRF REMS Access Call Center?) was presented only to pharmacy respondents from CSPs. The single CSP outpatient pharmacist who participated in the survey responded that his/her pharmacy does process all TIRF medicine prescriptions through the TIRF REMS Call Center regardless of method of payment (Appendix B: Survey Tables, Table 5). 5.3 Spontaneous Reporting of Potential Adverse Events, Product Complaints, or Medical Information Requests Among all survey respondents (N 561, Table 1), there were 4 reports of a potential adverse event or product complaint associated with the use of TIRF medicines made within the survey free text ?eld during the online survey and 1 report recorded during the telephone survey. Verbatim statements are provided in Appendix B, Listing 2. 6. DISCUSSION AND CONCLUSIONS Discussion Survey invitations (and reminders) were sent to a random sample of pharmacies enrolled in the TIRF REMS Access program that had dispensed a TIRF medicine in the last 6 months, a revision to the survey recruitment strategy per FDA request. From among those who responded to the invitation, 318 pharmacists completed the survey. Thus, the required sample size of 300 was achieved within the planned survey period. The respondents completing the survey represented a total of 240 pharmacies; 175 pharmacies (145 outpatient, 29 inpatient, 1 CSP) had 1 respondent each, 53 (40 outpatient, 13 inpatient) had 2 respondents each, and 12 (9 outpatient, 3 inpatient) had 3 respondents each. The pharmacies were located in all US Census Bureau regions except Other. Comparison of pharmacies represented by the survey respondents to the general population of pharmacies that had dispensed TIRF medicines in the past 6 months based on REMS switch provider Pharmacist KAB Assessment Report Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Final 10 February 2017 Page 51 of 62 data (N 3,857) showed a similar distribution by geographic region (Table 5). The pharmacy groups differed with respect to distribution of types of pharmacies due to differing percentages of independent versus chain outpatient pharmacies. The distribution of outpatient pharmacy orders between independent and chain pharmacies was similar for the 2 groups; however, a chi-square test showed a significant difference because orders in the general population included a small percentage of orders from CSPs, which could not be represented in orders from the survey respondents’ pharmacies. The overall knowledge score of 85.7 (95% CI: 84.4 87.0) for the survey indicates most respondents demonstrated understanding of the key risk messages (Table 18). The average knowledge score for each of the key risk messages was t83.8 for 3 of the 4 key risk messages and was 75.4 for Key Risk Message 2 (TIRF medicines are only indicated for the management of breakthrough pain in adult cancer patients 18 years of age and older [16 years of age and older for Actiq® brand and generic equivalents] who are already receiving and who are tolerant to around-the-clock opioid therapy for their underlying persistent cancer pain). The lower average knowledge score for Key Risk Message 2 reflected 3 linked questions/items (described below) with correct response rates <65%. Of the 36 questions/items included as part of key risk messages, 27 items of the key risk messages had a correct response rate >80%, and 6 items had correct response rates from 65.1% to 79.6%. Three questions/items of Key Risk Message 2 had a correct response rate below the desired threshold of 65% (Items 6a, 6c, and 9e). • The correct response rate for Item 6a (According to the product labeling, a cancer patient may start a TIRF medicine and an around-the-clock opioid at the same time) was 61.9%. This is slightly lower than the correct response rates of 63.3%-69.1% observed for the previous 3 pharmacist KAB surveys conducted (24-month, 36-month, and 48-month surveys) (Table 24). • The correct response rate for Item 6c (A patient must stop taking their TIRF medicine if they stop taking their around-the-clock opioid pain medicine) was 41.2%. This item was added to the 48-month survey based on feedback provided by FDA in the 24-month and the 36-month FDA REMS Acknowledgement Letter (See Section 1.1). The item had a similar correct response rate of 41.9% in the 48-month survey. • The correct response rate for Item 9e (Chronic non-cancer pain is not an indication for which TIRF medicines can be prescribed) was 43.4%. Item 9e has also had a low correct response rate across all previous pharmacist KAB surveys conducted (annual waves from the 12-month through the 48-month surveys) (Table 24). The survey score for Item 9e may indicate that some respondents are dispensing TIRF medicines for non-cancer associated indications. As previously discussed, the survey was updated prior to launch based on FDA feedback received on 21 July 2016. Changes to the 60-month KAB survey for pharmacists based on FDA feedback included the addition of 3 survey questions and a change to the recruitment strategy to limit the survey to pharmacists who had dispensed TIRF medicines in the past 6 months and attempt to recruit more closed system pharmacists and non-supervisory FDA_4980 Pharmacist KAB Assessment Report Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Final 10 February 2017 Page 52 of 62 pharmacists. Added questions relating to key risk messages included Question 12 (TIRF medicines should only be taken by patients who are opioid tolerant [True/False]) and Question 13 (Which of the following risks are associated with the use of TIRF medicines? [True/False for each of the following: misuse, abuse, addiction, overdose, hypothyroidism, and infection]). Correct response rates for these new questions/items were t95.6% for Question 12 and 4 items of Question 13 and 84.0%-89.3% for the 2 false items of Question 13 (hypothyroidism and infection). Question 15 (How frequently do you perform the following activities when dispensing TIRF medicines?) included 3 response items about pharmacist-reported activity. For each item, most respondents selected always or only with the first prescription; and few respondents selected sometimes, never, or I don’t know. Changes to recruitment efforts included a revised invitation letter addressed to the “pharmacist-in-charge” including 3 letters with unique codes; the pharmacist-in-charge was asked to distribute these letters to non-supervisory staff involved in the dispensing of TIRF medicines. This strategy was successful, with 74.8% of respondents indicating they were not the pharmacist-in-charge. As shown in Table 24, no trend was evident for this 60-month survey in knowledge and understanding of the key risk messages. Table 24 includes key risk messages and questions/items within each key risk message as presented in the 60-month survey. It is important to note the question/item numbering, wording, and association with a specific key risk message may have changed across survey waves based on FDA feedback or other decisions made by the TRIG. A limitation to looking at correct response rates over time is that survey questions may have been modified. The primary focus of this table is to show general trends over time with a specific focus on changes from the 48-month survey to the 60-month survey. FDA_4981 Pharmacist KAB Assessment Report Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industrv Group (TRIG) of Companies Final 10 February 2017 Page 53 of 62 Table 24. Correct Response Rate Over Time 60-Month lZ-Month Survey 24?Month Survey 36-Month Survey 48-Month Survey 60-Month Survey Survey Correct/Desired Correct/Desired Correct/Desired Correct/Desired Correct/Desired Question Questions as Presented in Response Response Response Response Response Number the 60-Month Survey (95% CI) (95% Cl) (95% Cl) (95% Cl) (95% Cl) Key Risk Message 1: TIRF Medicines Are Contraindicated in Opioid Non-Tolerant Patients 5 Please select True, False, or I don?t know for each of the following. According to the labeling for TIRF medicines, patients with cancer who are considered opioid-tolerant are those: 1 5a Who are taking around-the- clock opioid therapy for underlying persistent 12 62 90.3 93.7 92.7 95.6 cancer pain for one week (86.4, 93.4) (90.3, 96.1) (89.1 - 95.4) (92.7 - 97.6) or longer (Correct Response True) 1 5b Who are not currently 31$? 80 12 80-7 87-0 87-4 87-4 before (Correct Response (75.7, 85.0) (82.7, 90.6) (83.1 - 90.9) (83.3 - 90.9) ?False 5c Who have no known contraindications to the drug fentanyl, but are not 15 62 76.0 78.7 82.4 82.1 currently taking around- (70.8, 80.7) (73.6, 83.2) (77.6 - 86.5) (77.4 - 86.1) the-clock opioid therapy (Correct Response False) 7 Please answer True, False, or 1 don?t know for each statement based on the labeling for TIRF medicine . 7a TIRF medicines are contraindicated in opioid Eggaflt?lfg?fgzging 86.1 86.0 90.7 91.0 88.4 respiratory depression (81.7, 89.8) (81.6, 89.7) (86.8, 93.7) (87.2 - 94.0) (84.3 - 91.7) could occur at any dose (Correct Response True) Pharmacist KAB Assessment Report Final 10 February 2017 Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industrv Group (TRIG) of Companies Page 54 of 62 Table 24. Correct Response Rate Over Time 60-Month lZ-Month Survey 24?Month Survey 36-Month Survey 48-Month Survey 60-Month Survey Survey Correct/Desired Correct/Desired Correct/Desired Correct/Desired Correct/Desired Question Questions as Presented in Response Response Response Response Response Number the 60-Month Survey (95% CI) (95% Cl) (95% Cl) (95% Cl) (95% Cl) 7b Death has occurred in 92.1 93.7 93.7 95.3 95.3 products (Correct (88.4, 94.8) (90.3, 96.1) (90.3, 96.1) (92.3 - 97.4) (92.3 - 97.3) Response True) 70 TIRF medicines may be used to treat opioid non- 78.5 82.0 83.7 85.4 87.4 tolerant patients (Correct (73.4, 83.0) (77.2, 86.2) (79.0, 87.7) (80.9 - 89.2) (83.3 - 90.9) Response False) 1 7d Prescribers starting a patient on a TIRF medicine must begin with titration 35:32:35: 1335233328 ?e 78.5 82.7 79.0 80.7 84.0 product, even ifthe patient (73 .4, 83.0) (77.9, 86.8) (73.9, 83.5) (75.8 - 85.0) (79.5 - 87.8) has previously taken another TIRF medicine (Correct Response True) 11 Please select True, False, or I don?t know for each of the following. According to the labeling for TIRF medicines, patients considered opioid-tolerant are those who are taking, for one week or longer, at least: 8 mg oral lla hydromorphone/day 79.02 76.32 (73 $2333 2) (69 11.79 2) (Correct Response True) 60 mg oral morphine/day 3 2 2 89.7 88.1 1 lb (Correct Response True) 85'0 84'7 (85.7 - 92.9) (84.0 - 91.4) 30 mg oral oxycodone/day 3 2 77.1 77.7 (Correct Response True) 71'3 73'3 (71.9 - 81.7) (72.7 - 82.1) Pharmacist KAB Assessment Report Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Final 10 February 2017 Page 55 of 62 Table 24. Correct Response Rate Over Time 60-Month lZ-Month Survey 24-Month Survey 36-Month Survey 48-Month Survey 60-Month Survey Survey Correct/Desired Correct/Desired Correct/Desired Correct/Desired Correct/Desired Question Questions as Presented in Response Response Response Response Response Number the 60-Month Survey (95% CI) (95% Cl) (95% Cl) (95% Cl) (95% Cl) 25 meg transdeimal 3 2 2 77.1 79.6 72.0 74.3 (71.9 81.7) (74.7 83.9) 25 mg oral 3 2 2 73.4 72.0 lle (Correct 71.0 71.0 (68.1 78.3) (66.7 76.9) An equianalgesic dose of 65.1 65.1 1 If another oral opioid 59.02 59.02 (Correct Response True) - 70.5) 696 - 703) 12 Please answer True, False, or 1 don't know for the following statement about TIRF medicines: TIRF medicines should only be taken by patients 3 3 3 3 95.6 who are opioid tolerant. (92.7 - 97.6) (Correct Response True) Key Risk Message 2: TIRF Medicines Are Only Indicated for the Management of Breakthrough Pain in Adult Cancer Patients 18 Years of Age and Older (16 Years of Age and Older for Actiq? Brand and Generic Equivalents) Who Are Already Receiving and Who Are Tolerant to Around-the-Clock Opioid Therapy for Their Underlying Persistent Cancer Pain 6 Please answer True, False, or 1 don?t know for each statement based on the labeling for TIRF medicine. According to the product labeling, a cancer patient may start a TIRF medicine 3 2 2 69.1 61.9 6" and an around-the-clock 65'3 63'3 (63.5 - 74.3) (56.4 - 67.3) opioid at the same time (Correct Response False) Pharmacist KAB Assessment Report Final 10 February 2017 Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industrv Group (TRIG) of Companies Page 56 of 62 Table 24. Correct Response Rate Over Time 60-Month lZ-Month Survey 24?Month Survey 36-Month Survey 48-Month Survey 60-Month Survey Survey Correct/Desired Correct/Desired Correct/Desired Correct/Desired Correct/Desired Question Questions as Presented in Response Response Response Response Response Number the 60-Month Survey (95% CI) (95% Cl) (95% Cl) (95% Cl) (95% Cl) According to the product labeling, a cancer patient who has been on an around-the-clock opioid for 3 2 2 82.1 80.5 6b 1 day may start taking a MA 74'7 74'0 (77.2 - 86.2) (75.7 - 84.7) TIRF medicine for breakthrough pain (Correct Response False) I A patient must stop taking their TIRF medicine if they stop taking their around- 3 3 3 41.9 41.2 6? the-clock opioid pain (36.2 - 47.7) (35.7 - 46.8) medicine (Correct Response True) 9 Per the approved labeling for TIRF medicines, for which of the following indications can TIRF medicines be prescribed to opioid tolerant patients? Please answer Yes, No, or I don?t know for each option. 9a Acute or postoperative pain 78.1 84.7 86.7 90.0 85.8 (Correct Response No) (73.1 82.7) (80.1, 88.6) (82.3, 90.3) (86.1 - 93.2) (81.5 - 89.5) 9b Headache or migraine pain 89.1 92.3 90.7 93.0 94.3 (Correct Response No) (85.0, 92.4) (88.7, 95.1) (86.8, 93.7) (89.5 - 95.6) (91.2 - 96.6) 9c Dental pain 94.7 96.7 97.0 98.3 96.2 (Correct Response No) (91.5, 96.9) (94.0, 98.4) (94.4, 98.6) (96.2 - 99.5) (93.5 - 98.0) 9? Pal? from 83.4 89.3 91.7 92.0 91.8 (Correct Response Yes) (78.8, 87.5) (85.3, 92.6) (87.9, 94.5) (88.4 - 94.8) (88.2 - 94.6) 9e Chronic non-cancer pain 29 82 47.0 43.7 50.8 50.9 (Correct Response N0) (41.2, 52.8) (38.0, 49.5) (45.0 - 56.6) (45.3 - 56.6) Pharmacist KAB Assessment Report Final 10 February 2017 Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industrv Group (TRIG) of Companies Page 57 of 62 Table 24. Correct Response Rate Over Time 60-Month lZ-Month Survey 24-Month Survey 36-Month Survey 48-Month Survey 60-Month Survey Survey Correct/Desired Correct/Desired Correct/Desired Correct/Desired Correct/Desired Question Questions as Presented in Response Response Response Response Response Number the 60-Month Survey (95% CI) (95% Cl) (95% Cl) (95% Cl) (95% Cl) Key Risk Message 3: TIRF Medicines Contain entanyl, an Opioid Agonist and a Schedule II Controlled Substance, with Abuse Liability Similar to other Opioid Analgesics 7 Please answer True, False, or I don?t know for each statement based on the labeling for TIRF medicines. 7e It is important to monitor 97.7 96.7 96.0 97.3 98.1 take TIRF medicines (95.3, 99.1) (94.0, 98.4) (93.1, 97.9) (94.8 - 98.8) (95.9 - 99.3) (Correct Response True) 8 Which of the following are risk factors for opioid abuse? Please answer Yes, No, or I don?t know for each option. 8? $53231]: 3:1th gone? 66.6 72.0 71.0 75.4 77.7 Response Yes) (60.9, 71.9) (66.6, 77.0) (65.5, 76.1) (70.1 - 80.2) (72.7 - 82.1) 8b A personal history of past or current alcohol or drug abuse, or a family history 99.7 99.0 99.3 98.7 98.7 of illicit drug use or (98 2, 100.0) (97.1, 99.8) (97.6, 99.9) (96.6 - 99.6) (96.8 - 99.7) alcohol abuse (Correct Response Yes) 10 Please answer True, False, or I don?t know for each statement based on the labeling for TIRF medicine . 10a TIRF medicines can be abused in a manner similar 90.4 94.0 94.3 95.7 93.7 to other opioid agonists (86.5, 93.5) (90.7, 96.4) (91.1, 96.7) (92.7 - 97.7) (90.5 - 96.1) (Correct Response True) 13 Which of the following risks are associated with the use of TIRF medicines? Please answer True, False, or I don't know for the following statements. 13a Misuse (Correct Response 3 3 3 3 98.7 True) (9 6.8 99.7) Pharmacist KAB Assessment Report Final 10 February 2017 Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industrv Group (TRIG) of Companies Page 58 of 62 Table 24. Correct Response Rate Over Time 60-Month lZ-Month Survey 24-Month Survey 36-Month Survey 48-Month Survey 60-Month Survey Survey Correct/Desired Correct/Desired Correct/Desired Correct/Desired Correct/Desired Question Questions as Presented in Response Response Response Response Response Number the 60-Month Survey (95% CI) (95% Cl) (95% Cl) (95% Cl) (95% Cl) 13b Abuse (Correct Response 3 3 3 3 99.1 True) (97.3 99.8) 13c Addiction (Correct 3 3 3 3 98.7 Response True) (96.8 - 99.7) 13d Overdose (Correct 3 3 3 3 99.4 Response True) (97.7 - 99.9) l3e Hypothyroidism (Correct 3 3 3 3 84.0 Response False) (79.5 - 87.8) 13f Infection (Correct 3 3 3 3 89.3 Response False) (85.4 - 92.5) Key Risk Message 4: TIRF Medicines Are Not Interchangeable with Each Other, Regardless of Route ofAdministration 10 Please answer True, False, or I don?t know for each statement based on the labeling for TIRF medicines. 10b TIRF medicines are administration (Correct (91.9, 97 2) (91.5, 96.9) (89.9, 95.9) (89.9 - 95.9) (93.1 - 97.8) Response False) 10c The conversion of one TIRF medicine for another TIRF medicine may result in a fatal overdose because 92.7 92.0 93.0 92.7 93.1 of differences in the (892, 95.4) (88.3, 94.8) (89.5, 95.6) (89.1 - 95.4) (89.7 - 95.6) pharmacokinetics of fentanyl absorption (Correct Response True) Pharmacist KAB Assessment Report Final 10 February 2017 Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industrv Group (TRIG) of Companies Page 59 of 62 Table 24. Correct Response Rate Over Time 60-Month lZ-Month Survey 24?Month Survey 36-Month Survey 48-Month Survey 60-Month Survey Survey Correct/Desired Correct/Desired Correct/Desired Correct/Desired Correct/Desired Question Questions as Presented in Response Response Response Response Response Number the (SO-Month Survey (95% CI) (95% Cl) (95% Cl) (95% Cl) (95% Cl) 10d Dosing of TIRF medicines 92.4 91.3 90.0 92.7 89.0 basis (Correct Response (88.8, 95.1) (87.6, 94.3) (86.0, 93.2) (89.1 - 95.4) (85.0 - 92.2) True) 16 Please answer True, False, or I don?t know for each statement about TIRF medicines. 16c TIRF medicines with the same route of administration can substituted with each other 95.7 96.3 97.7 if the pharmacy is out of (962 - 99.5) - 976) stock for one product (Correct Response False) lQuestion was revised for the 60-month survey. 2 95% con?dence interval is not provided since the question! item was not part of a key risk message during the reporting period. 3 Question was not asked during the reporting period Pharmacist KAB Assessment Report Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Final 10 February 2017 Page 60 of 62 The analysis stratified by whether the Full Prescribing Information or Medication Guide were received and read (received and read versus did not receive or read) showed a trend of higher correct-response rates for respondents who received and read the materials in some or all questions/items linked to Key Risk Messages 1, 2, and 4. No meaningful comparison was possible in the analysis stratified by survey modality (internet or telephone) as only 4 respondents completed the survey by telephone. Stratification by time in pharmacy practice or number of times TIRF medicines were dispensed in the last 6 months did not result in any uniform trends. Conclusions In general, there is an overall trend over time toward maintaining, or increasing, pharmacist knowledge and understanding of the key risk messages. Three exceptions where pharmacists scored low included understanding that a cancer patient may not start a TIRF medicine and an around-the-clock opioid at the same time, that a patient must stop taking their TIRF medicine if they stop taking their around-the-clock opioid pain medicine, and that TIRF medicines are not indicated for chronic non-cancer pain, which may indicate that some respondents are dispensing TIRF medicines for non-cancer associated indications. Overall, this 60-month survey shows a high level (greater than or equal to 65% for all but three items) of pharmacist understanding of key risk messages based on the REMS goals. TRIG acknowledges that there is room for improvement around pharmacist knowledge related to indications for TIRF medicines and safe use of TIRF medicines by patients also using around-the-clock opioid pain medicines. FDA_4989 Pharmacist KAB Assessment Report Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Appendix A Final 10 February 2017 Page 61 of 62 Pharmacy Survey Protocol Track Change Document: Comparison of 48-month Survey to 60-month Survey FDA_4990 PROTOCOL TITLE: Quantitative Testing of Pharmacist Knowledge, Attitudes, and Behavior about Transmucosal Immediate Release Fentanyl (TIRF) Products Safety and Use Information SPONSOR: TIRF REMS Industry Group (TRIG) Actavis Laboratories FL, Inc. BioDelivery Sciences International, Inc. . . .. Cephalon, Inc. (a wholly-owned subsidiary of Teva Pharmaceutical Industries, Ltd.) Depomed, Inc. I Galena-34W Insys Therapeutics, Inc. Mallinckrodt Pharmaceuticals Mylan: Inc. Par WPharmaceuticals, Inc. Therapeutics, Inc. VERSION: 91_ .0 DATE: WHALTGZOM APPROVED: Ill-NALFinal use use CONFIDENTIAL th?mln'? Controlled Document CopyrightO United BioSource Corporation All Rights Reserved TIRF REMS Industry Group (TRIG) Version 911.0 12AUG2015Transmucosal Immediate Release Fentanyl (TIRF) Products Pharmacist KAB Survey Protocol 04AUG2016 TABLE OF CONTENTS PAGE TABLE OF CONTENTS ......................................................................................... 2 1. LIST OF ABBREVIATIONS .................................................................................. 3 2. BACKGROUND ..................................................................................................... 4 3. OBJECTIVES OF THE PHARMACIST EVALUATION SURVEY .................... 5 4. METHODS .............................................................................................................. 5 4.1 4.1.1 4.1.2 4.1.3 Survey Design .......................................................................................................... 5 Qualitative Research on the Survey ......................................................................... 6 Questions and Statements on REMS Goals ............................................................. 6 Additional Questions.............................................................................................. 10 4.2 4.2.1 Participant Recruitment.......................................................................................... 10 Measures to Minimize Bias in the Sample............................................................. 12 5. 5.1.1 5.1.2 5.1.3 STUDY POPULATION ........................................................................................ 12 Sample Size ............................................................................................................ 12 Inclusion Criteria.................................................................................................... 13 Exclusion Criteria .................................................................................................. 13 6. SURVEY PROCESS ............................................................................................. 13 6.1 6.1.1 6.1.2 Screening and Survey Administration ................................................................... 14 Telephone ............................................................................................................... 14 Internet ................................................................................................................... 14 6.2 Measures to Minimize Bias in the Survey Process ................................................ 14 7. 7.1.1 7.1.1.1 7.1.1.2 ANALYSIS ............................................................................................................ 15 Analysis Population ............................................................................................... 15 Description of Primary Analyses ........................................................................... 15 Description of Secondary Analyses ....................................................................... 16 8. SAFETY EVENT REPORTING ........................................................................... 16 9. PRIVACY PROTECTION AND CONFIDENTIALITY...................................... 16 LIST OF APPENDICES Appendix A Pharmacist Questionnaire ......................................................................... 17 Appendix B Recruitment Materials .............................................................................. 37 Appendix C Correct Answer Document ....................................................................... 41 2 of 44 FDA_4992 TIRF REMS Industry Group (TRIG) Version 911.0 12AUG2015Transmucosal Immediate Release Fentanyl (TIRF) Products Pharmacist KAB Survey Protocol 04AUG2016 1. LIST OF ABBREVIATIONS BDSI CATI CSP CI EDC ETASU FDA HIPAA ISI KAB PI REMS SE PSP TIRF TIRF REMS TRIG UBC US BioDelivery Sciences International, Inc. Computer-Assisted Telephone Interviewing Closed System Pharmacy Confidence Interval Electronic Data Capture Elements to Assure Safe Use Food and Drug Administration Health Insurance Portability and Accountability Act Important Safety Information Knowledge, Attitudes, and Behavior Prescribing Information Risk Evaluation and Mitigation Strategy Safety Event Project Specific Procedure Transmucosal Immediate Release Fentanyl TIRF REMS Access Programprogram TIRF REMS Industry Group United BioSource Corporation United States 3 of 44 FDA_4993 TIRF REMS Industry Group (TRIG) Version 911.0 12AUG2015Transmucosal Immediate Release Fentanyl (TIRF) Products Pharmacist KAB Survey Protocol 04AUG2016 2. BACKGROUND Transmucosal Immediate Release Fentanyl (TIRF) medicines include the class of immediaterelease opioid analgesics that are indicated only for the management of breakthrough pain in cancer patients 18 years of age or older (16 or older for Actiq® and equivalent generics) who are already receiving and tolerant to opioid therapy for their underlying persistent cancer pain. The TIRF medicines include Abstral®, Actiq®, Fentora®, Lazanda®, Subsys®, and generic versions of any of these brands. The TIRF REMS Industry Group (TRIG) includes Actavis Laboratories FL, Inc.; BioDelivery Sciences International, Inc. (BDSI) (replaced Meda Pharmaceuticals on March 11, 2015(BDSI); Cephalon, Inc. (a wholly-owned subsidiary of Teva Pharmaceutical Industries, Ltd.); Depomed, Inc.; Galena Biopharma, Inc.; Insys Therapeutics, Inc.; Mallinckrodt Pharmaceuticals; Mylan Inc.; Par Pharmaceuticals, Inc.; and Par PharmaceuticalSentynl Therapeutics, Inc. The Food and Drug Administration (FDA) has determined that a class-wide Risk Evaluation and Mitigation Strategy (REMS) is required to mitigate the riskrisks of misuse, abuse, addiction, overdose, and serious complications due to medication errors with the use of TIRF medicines. The TIRF REMS Access Programprogram (hereafter referred to as TIRF REMS) was approved by the FDA on December 28, 2011. The TIRF REMS consists of a Medication Guide, Elements to Assure Safe Use (ETASU), an Implementation System, and a Timetable for Submission of Assessments of the REMS. The goals of the TIRF REMS are to mitigate the riskrisks of misuse, abuse, addiction, overdose, and serious complications due to medication errors by: 1. Prescribing and dispensing TIRF medicines only to appropriate patients, which includes use only in opioid-tolerant patients 2. Preventing inappropriate conversion between TIRF medicines 3. Preventing accidental exposure to children and others for whom it was not prescribed 4. Educating prescribers, pharmacists, and patients on the potential for misuse, abuse, addiction, and overdose of TIRF medicines An important component of the TIRF REMS is the conduct of quantitative evaluation surveys to assess pharmacists’ understanding and knowledge of the safe use and appropriate prescribing of TIRF medicines as described in the TIRF REMS educational materials, enrollment formPharmacy Enrollment Form, and Prescribing Information (PI). This protocol will describe the administration of the surveys that will be conducted among pharmacists who are enrolled in the TIRF REMS Access Programprogram. Data from the surveys, together with other REMS evaluation metrics, will be used to determine whether changes need to be made to the REMS processes or educational materials to make them more effective in achieving the goals of the REMS. 4 of 44 FDA_4994 TIRF REMS Industry Group (TRIG) Version 911.0 12AUG2015Transmucosal Immediate Release Fentanyl (TIRF) Products Pharmacist KAB Survey Protocol 04AUG2016 The surveys will be implemented so that data will be available for inclusion in the REMS Assessment Reports that will be submitted to the FDA at 12 months after approval of the TIRF REMS and annually thereafter. 3. OBJECTIVES OF THE PHARMACIST EVALUATION SURVEY The evaluation survey will use a questionnaire to document the level of knowledge and assess the attitudes and behavior of pharmacists around the following key information and risk messages communicated through REMS: 1. TIRF medicines are contraindicated in opioid non-tolerant patients. 2. TIRF medicines are only indicated for the management of breakthrough pain in adult cancer patients 18 years of age and older (16 or older for Actiq® and equivalent generics) who are already receiving and who are tolerant to around-the-clock opioid therapy for their underlying persistent cancer pain. 3. TIRF medicines contain fentanyl, an opioid agonist and a Schedule II controlled substance, with abuse liability similar to other opioid analgesics. 4. TIRF medicines are not interchangeable with each other, regardless of route of administration. 5. Patients and their caregivers must be instructed that TIRF medicines contain a medicine in an amount that can be fatal in children, in individuals for whom it is not prescribed, and in those who are not opioid tolerant. The survey will also collect data on behaviors, such as receipt and use of educational materials and compliance with REMS requirements. 4. METHODS The survey was designed in collaboration between the TRIG and United BioSource Corporation (UBC), and will be administered by UBC. 4.1 Survey Design This survey will be conducted among a sample of pharmacists who are affiliated with pharmacies enrolled in the TIRF REMS Access Programprogram that have dispensed a TIRF medicine within the last 6 months. Respondents who have participated in a previous wave of the TIRF survey will not be eligible to participate in subsequent survey waves. The survey will be administered using the following modalities: x Self-administered via the Internet through a secure website 5 of 44 FDA_4995 TIRF REMS Industry Group (TRIG) Version 911.0 12AUG2015Transmucosal Immediate Release Fentanyl (TIRF) Products Pharmacist KAB Survey Protocol 04AUG2016 x Telephone surveys facilitated by a trained interviewer from the Survey Coordinating Center using a computer-assisted telephone interviewing (CATI) program The survey will begin with screening questions to confirm respondent eligibility to participate in the survey. Completion of the entire survey is expected to take up to 20 minutes. The survey included in Appendix A is written to reflect wording for both methods of survey administration: Internet-based and telephone. All respondents who complete the survey and who provide their contact information will be mailed a $50 honorarium for their time. 4.1.1 Qualitative Research on the Survey The FDA provided feedback to the TRIG on the Knowledge, Attitudes, and Behavior (KAB) survey results for pharmacists included in the 12 month REMS Assessment results. The FDA requested that the TRIG to investigate the causes forof low correct response rates to specific questions in the survey by conductingreported in the 12-month REMS Assessment Report. Qualitative research was conducted in 2013 to determine the reasons for the poor performance on these questions and to assess proposed revised wording to select questions. Qualitative research was performed in 2013 prior to Wave 2 of the survey. Findings were incorporated into the survey and results from the revised survey were included in the 24-month REMS Assessment Report,. 4.1.2 Questions and Statements on REMS Goals The KAB questionnaire is made up of multiple-choice, close-ended statements or questions (the majority of which use true/false or yes/no dichotomous response options), and one openended question. These questions will evaluate current knowledge, attitudes, and behavior regarding the key risk messages noted in Section 3. Questions will beare presented in several formats: x Statements or questions asking the respondent to indicate whether a statement or question is true or false, or if they do not know the answer (there is a similar set of statements and questions that use “yes” or “no” as potential response options); x Statements or questions asking the respondent to choose from a defined list of possible statements or answers; and x One question allowing for the respondent to list questions or comments. Questionnaires will be analyzed to determine pharmacist understanding of each key risk message. For statements or questions that use “true” or “yes” vs. “false” or “no” response options, the desired response for the key risk messages is generally “true” or “yes” indicating knowledge of, or behavior in accordance with, the objectives of the REMS. However, some questions are formatted to have the respondent disagree with the statement as written by providing response 6 of 44 FDA_4996 TIRF REMS Industry Group (TRIG) Version 911.0 12AUG2015Transmucosal Immediate Release Fentanyl (TIRF) Products Pharmacist KAB Survey Protocol 04AUG2016 options of “false” or “no” to avoid having the same affirmative answer for all desired responses. REMS statements, corresponding questions, and desired responses covering the key risk messages are identified below and can be found in the complete survey questionnaire (Appendix A). Key Risk Message 1: TIRF medicines are contraindicated in opioid non-tolerant patients. Question No. 5 5a 5b 5c 7 7a 7b 7c 7d 11 11a 11b 11c 11d 11e 11f 12 Question Desired Response Please select True, False, or I don’t know for each of the following. According to the labeling for TIRF medicines, patients with cancer who are considered opioid-tolerant are those: Who are taking around-the-clock opioid therapy for underlying, persistent cancer pain for one week or TRUE longer Who are not currently taking opioid therapy, but FALSE have taken opioid therapy before Who have no known contraindications to the drug fentanyl, but are not currently taking around-theFALSE clock opioid therapy Please answer True, False, or I don’t know for each statement based on the labeling for TIRF medicines. TIRF medicines are contraindicated in opioid nontolerant patients because life-threatening respiratory TRUE depression could occur at any dose. Death has occurred in opioid non-tolerant patients TRUE treated with some fentanyl products. TIRF medicines may be used in opioid non-tolerant FALSE patients. Prescribers starting a patient on a TIRF medicine must begin with titration from the lowest dose TRUE available for that specific product, even if the patient has previously taken another TIRF medicine. Please select True, False, or I don’t know for each of the following. According to the labeling for TIRF medicines, patients considered opioid-tolerant are those who are taking, for one week or longer, at least: 8 mg oral hydromorphone/day TRUE 60 mg oral morphine/day TRUE 30 mg oral oxycodone/day TRUE 25 mcg transdermal fentanyl/hour TRUE 25 mg oral oxymorphone/day TRUE An equianalgesic dose of another oral opioid TRUE TIRF medicines should only be taken by patients TRUE who are opioid tolerant. 7 of 44 FDA_4997 TIRF REMS Industry Group (TRIG) Version 911.0 12AUG2015Transmucosal Immediate Release Fentanyl (TIRF) Products Pharmacist KAB Survey Protocol 04AUG2016 Key Risk Message 2: TIRF medicines are only indicated for the management of breakthrough pain in adult cancer patients 18 years of age and older (16 years of age and older for Actiq® brand and generic equivalents) who are already receiving and who are tolerant to around-theclock opioid therapy for their underlying persistent cancer pain. Question No. 6 6a 6b 6c 9 9a 9b 9c 9d 9e Question Desired Response Please answer True, False, or I don’t know for each statement based on the labeling for TIRF medicines. According to the product labeling, a cancer patient may start a TIRF medicine and an FALSE around-the-clock opioid at the same time. According to the product labeling, a cancer patient who has been on an around-theFALSE clock opioid for 1 day may start taking a TIRF medicine for breakthrough pain. A patient must stop taking their TIRF TRUE medicine if they stop taking their aroundthe-clock opioid pain medicine. Per the approved labeling for TIRF medicines, for which of the following indications can TIRF medicines be prescribed to opioid tolerant patients? Please answer Yes, No, or I don’t know for each option. Acute or postoperative pain NO Headache or migraine pain NO Dental pain NO Breakthrough pain from cancer YES Chronic non-cancer pain NO 8 of 44 FDA_4998 TIRF REMS Industry Group (TRIG) Version 911.0 12AUG2015Transmucosal Immediate Release Fentanyl (TIRF) Products Pharmacist KAB Survey Protocol 04AUG2016 Key Risk Message 3: TIRF medicines contain fentanyl, an opioid agonist and a Schedule II controlled substance with abuse liability similar to other opioid analgesics. Question No. 7 7e 8 8a 8b 10 10a 13 13a 13b 13c 13d 13e 13f Question Desired Response Please answer True, False, or I don’t know for each statement based on the labeling for TIRF medicines. It is important to monitor for signs of abuse and addiction in patients who take TIRF TRUE medicines. Which of the following are risk factors for opioid abuse? Please answer Yes, No, or I don’t know for each option. A personal history of psychiatric illness YES A personal history of past or current alcohol or drug abuse, or a family history of YES illicit drug use or alcohol abuse Please answer True, False, or I don’t know for each statement based on the labeling for TIRF medicines. TIRF medicines can be abused in a manner TRUE similar to other opioid agonists. Which of the following risks are associated with the use of TIRF medicines? Please answer True, False, or I don’t know for the following statements. Misuse TRUE Abuse TRUE Addiction TRUE Overdose TRUE Hypothyroidism FALSE Infection FALSE Key Risk Message 4: TIRF medicines are not interchangeable with each other, regardless of route of administration. Question No. 10 10b 10c 10d Question Desired Response Please answer True, False, or I don’t know for each statement based on the labeling for TIRF medicines. TIRF medicines are interchangeable with each other regardless of route of FALSE administration. The conversion of one TIRF medicine for another TIRF medicine may result in a fatal TRUE overdose because of differences in the pharmacokinetics of fentanyl absorption. Dosing of TIRF medicines is not equivalent TRUE 9 of 44 FDA_4999 TIRF REMS Industry Group (TRIG) Version 911.0 12AUG2015Transmucosal Immediate Release Fentanyl (TIRF) Products Pharmacist KAB Survey Protocol 04AUG2016 on a microgram-to-microgram basis. Please answer True, False, or I don’t know for each statement about TIRF 1316 medicines. TIRF medicines with the same route of administration can be substituted with each FALSE 13c16c other if the pharmacy is out of stock for one product. 4.1.3 Additional Questions The survey includes questions about the requirements of the TIRF REMS Access Programprogram, receipt and understanding of the TIRF educational materials, and pharmacist behaviors. in counseling patients and caregivers regarding TIRF medicines. The following question about behaviors will be asked after the key risk message questions.: Question 12: How frequently do you perform the following activities when dispensing TIRF medicines? Please answer Always, Only with the first prescription, Sometimes, Never, or I don’t know. Ask patients (or their caregivers) about the presence of children in the home Instruct patients (or their caregivers) not to share TIRF medicines with anyone else Counsel patients (or their caregivers) that accidental exposure to TIRF medicines by a child may be fatal Instruct patients (or their caregivers) to keep TIRF medicines out of the reach of children to prevent accidental exposure Instruct patients (or their caregivers) about proper disposal of any unused or partially used TIRF medicines Give patients (or their caregivers) the Medication Guide for their TIRF medicine Demographic information will be collected at the end of the survey. 4.2 Participant Recruitment A random sample of pharmacists identified from pharmacies that are enrolled in the TIRF REMS Access Programprogram and that have dispensed a TIRF medicine in the last 6 months will be invited to participate via an invitation letter to their pharmacy’s “pharmacist in charge”. The text of the sample written invitation to pharmacists can be found in Appendix B. If the required number of completed surveys is not achieved within the expected timeframe of approximately one to two weeks after the first mailing, reminder letters will be sent to non respondersthe pharmacy’s “pharmacist in charge” from the original samplewhich no responses were received with subsequent fax, e-mail, or United States (US) Mail follow-up to maximize participation. The distribution within the mailing to the second sample will be adjusted in accordance with the allocation in the original sample. If these efforts do not result in the required number of surveys within two to three weeks, then a new sample of 10 of 44 FDA_5000 TIRF REMS Industry Group (TRIG) Version 911.0 12AUG2015Transmucosal Immediate Release Fentanyl (TIRF) Products Pharmacist KAB Survey Protocol 04AUG2016 pharmacistspharmacies will be randomly selected. The distribution within the mailing to the second sample will be adjusted by completion rate for each pharmacy type. The unique code provided in the invitation letter will be linked to the type of pharmacy (inpatient, outpatient, or Closed System Pharmacy [CSP]) in which the pharmacist works, based on the information provided as part of the TIRF REMS Access Programprogram enrollment. 11 of 44 FDA_5001 TIRF REMS Industry Group (TRIG) Version 911.0 12AUG2015Transmucosal Immediate Release Fentanyl (TIRF) Products Pharmacist KAB Survey Protocol 04AUG2016 All respondents who complete the survey and who provide their contact information will be mailed a $50 honorarium to thank them for their participation. The mailing will include a Thank You Letter, a copy of the Important Safety Information (ISI), and a copy of the correct answers to key risk message questions. 4.2.1 Measures to Minimize Bias in the Sample The sample of participating pharmacistspharmacies will be self-selected since respondents will voluntarily respond to the invitation to participate; however, the survey recruitment strategies are intended to recruit a heterogeneous sample of pharmacies (e.g., inpatient, outpatient [chain and independent store] and CSP) for participation. Pharmacists will be offered Internet-based or telephone options for completing the survey. Multiple modalities for survey data collection allow for wider survey access to a more heterogeneous population. Respondents will be provided a unique code during the recruitment process and will be asked to provide the unique code to gain access to the Internet-based survey or when calling the Survey Coordinating Center. The code will be deactivated after use to minimize the possibility for fraud. 5. STUDY POPULATION 5.1.1 Sample Size A sample of 300 pharmacists whofrom pharmacies that are enrolled in the TIRF REMS Access Programprogram is proposed for each survey wave. The size of the sample was determined based on both practical and statistical considerations. There is no target comprehension rate specified a priori.. A sample of 300 completed surveys will allow estimation of the comprehension rate for each risk message with a moderately high degree of precision. The table below shows the precision of the estimates for level of understanding using two-sided 95% confidence intervals (CIs) obtained with the sample size of 300 completed surveys. The noted CIs are used to indicate that for any survey-estimated rate of understanding, the true population rate of understanding is at least as high as the lower limit of the 95% CI and may be as high as the upper limit of the 95% CI. 12 of 44 FDA_5002 TIRF REMS Industry Group (TRIG) Version 911.0 12AUG2015Transmucosal Immediate Release Fentanyl (TIRF) Products Pharmacist KAB Survey Protocol 04AUG2016 Table 5.1: Precision of Estimated Rates of Understanding with a Sample Size of 300 Estimated Rate of Understanding 5% 10% 15% 20% 25% 30% 35% 40% 45% 50% 55% 60% 65% 70% 75% 80% 85% 90% 95% 5.1.2 Estimated Confidence Interval 2.8% 6.8% 11.2% 15.6% 20.2% 24.9% 29.6% 34.4% 39.3% 44.2% 49.2% 54.2% 59.3% 64.5% 69.7% 75.0% 80.4% 86.0% 91.9% 8.1% 14.0% 19.6% 25.0% 30.3% 35.5% 40.7% 45.8% 50.8% 55.8% 60.7% 65.6% 70.4% 75.1% 79.8% 84.4% 88.8% 93.2% 97.2% Inclusion Criteria Pharmacists who work at pharmacies that are enrolled in the TIRF REMS Access Programprogram and that have dispensed a TIRF medicine in the last 6 months are eligible to participate in this survey, with the exceptions noted below. 5.1.3 Exclusion Criteria The following respondents are not eligible to participate in the surveys: 6. x Pharmacists who have previously participated in the TIRF REMS KAB survey. x Pharmacists or their immediate family members who have ever worked for Actavis Laboratories FL, Inc.; Anesta LLC; BioDelivery Sciences International, Inc. (BDSI); Cephalon, Inc. (a wholly-owned subsidiary of Teva Pharmaceutical Industries, Ltd.); Depomed, Inc.; Galena Biopharma, Inc.; Insys Therapeutics, Inc.; Mallinckrodt Pharmaceuticals; Mylan, Inc.; Par PharmaceuticalPharmaceuticals, Inc.; Teva Pharmaceuticals, Ltd.; Sentynl Therapeutics, Inc.; UBC; McKesson Specialty Care Solutions; RelayHealth; or the FDA. SURVEY PROCESS The survey will begin with screening questions to confirm respondent eligibility to participate in the survey. Completion of the entire survey is expected to take approximately 20 minutes. 13 of 44 FDA_5003 TIRF REMS Industry Group (TRIG) Version 911.0 12AUG2015Transmucosal Immediate Release Fentanyl (TIRF) Products Pharmacist KAB Survey Protocol 04AUG2016 6.1 Screening and Survey Administration The questionnaire will begin with a screening module with questions to confirm pharmacist eligibility. Depending on the answers to the screening questions, survey participation could either be terminated or continued. If ineligible, the respondent is immediately notified with a “thank you” message that survey participation has ended. If eligible, the respondent is allowed to continue survey participation. The data entry system used for both methods of survey administration has been validated and is secure for receiving and storing survey data. An Internet-based data repository will be used to store survey data and other relevant program information. The system is 21 CFR Part 11 and Health Insurance Portability and Accountability Act (HIPAA) compliant. Pharmacistidentifying information will be stored separately from survey data. Completion of the entire survey is expected to take approximately 20 minutes. 6.1.1 Telephone A trained interviewer from the Survey Coordinating Center will conduct the telephone interviews using a CATI program. The screening and main elements of the questionnaire will be administered sequentially during the same telephone call. Telephone interviewing allows participation of pharmacists who do not have Internet access or prefer taking the survey over the telephone. It will also be convenient for pharmacists to participate since they can call in and be interviewed at their convenience during the specified time period when the Survey Coordinating Center is available. 6.1.2 Internet An Internet-based survey system will also be used for conducting the KAB surveys. If the pharmacist selects to participate in the survey via the Internet, he/she will be directed to a secured website where he/she will be instructed to complete screening questions. An Internetbased survey will be convenient for respondents to participate since they can complete the questionnaire at any convenient time and location during the specified survey time period when the Survey Coordinating Center is available. 6.2 Measures to Minimize Bias in the Survey Process A number of controls will be in place to ensure the survey is conducted in a controlled and professional manner and to minimize bias. For example, a unique code will be given to each survey participant and the code will be inactivated after use to minimize fraud. Telephone interviewers are highly trained and use a standardized script to administer the survey. All questions will be programmed to ensure that questions are asked in the appropriate sequence. Skip patterns will be clearly indicated. Respondents cannot go back to a question once the question has been answered and cannot skip ahead. All questions must be answered in order to complete the survey. Response options presented in a list will be randomized to minimize positional bias. Programming will be reviewed by quality control and simulated users (User Acceptance Testing) prior to implementing the survey. 14 of 44 FDA_5004 TIRF REMS Industry Group (TRIG) Version 911.0 12AUG2015Transmucosal Immediate Release Fentanyl (TIRF) Products Pharmacist KAB Survey Protocol 04AUG2016 7. ANALYSIS Information obtained from the survey will be reported as descriptive statistics for the survey administration, study population, and the survey questions. The data from the sample population will be reported using frequency distributions of responses to all questions. The following will be reported as part of this analysis: x The number of invitations issued to pharmacists x The number of invitations returned as undeliverable x The number of reminder letters issued to pharmacists x The number of respondents screened for participation x The number of respondents eligible for participation x The number of respondents eligible for participation who answered all questions presented to them x Representativeness of pharmacists based on geography x Description of survey participants, including: o Gender o Years of professional experience o How many times per month TIRF medicines were dispensed by the pharmacist in the last 6 months Additional descriptive statistics may be reported as appropriate. 7.1.1 Analysis Population The analysis population will be based on eligible pharmacists who completed all questions presented to them in the survey (“completers”). 7.1.1.1 Description of Primary Analyses Primary analyses are done for all key risk messages using data from all completers. The primary analysis for a key risk message evaluates the rate for each correct response torate for each individual question/item defined by the key risk message. The specific correct response to each question/item is identified in the body of the risk message table. 15 of 44 FDA_5005 TIRF REMS Industry Group (TRIG) Version 911.0 12AUG2015Transmucosal Immediate Release Fentanyl (TIRF) Products Pharmacist KAB Survey Protocol 04AUG2016 7.1.1.2 Description of Secondary Analyses Secondary analyses are done only for those key risk messages that contain multiple questions/items using data from all completers. The secondary analysis entails a frequency distribution of the number of completers who got 0, 1, etc. correct responses across the total number of items for the given key risk message. Mean knowledge scores will be computed for each key risk message; an overall knowledge score will be computed for each respondent as well. Additional analyses may be performed as needed. 8. SAFETY EVENT REPORTING The term ‘Safety Event’safety event’ is defined as any information reported by a survey respondent that meets the criteria of an adverse event or product complaint. While it is not the intention of the survey to solicit the report of information that meets the criteria of a Safety Eventsafety event, it is possible that a respondent may spontaneously report information that meets this criteria in free text fields of the survey (Internet-based administration) or while in conversation with the Survey Coordinating Center (telephone-based administration). The Internet-based questionnaires will be monitored for any comments recorded in the free text fields. If an event is mentioned to a Survey Coordinating Center Associate, the Associate will document the safety event and the respondent’s contact information. Respondents will also be informed that a representative from the appropriate TIRF medicine manufacturer may contact them if they have questions about the survey. Information on all reports (Internet or telephone) that may constitute an adverse event or other safety event will be forwarded to the appropriate TIRF medicine manufacturer as described in the Safety Event Project Specific Procedure (SE PSP). Additional detail regarding processes for adverse event reporting will be specified in the SE PSP. 9. PRIVACY PROTECTION AND CONFIDENTIALITY All data collected during the survey will be held confidential. The electronic data capture (EDC) system used for data collection encrypts all identifiable information, and respondent identifiers are stored separately from the survey responses. Respondent names and addresses are collected in order to mail the $50 honorarium, a Thank You Letter, correct survey responses to key risk message questions, and the ISI after the survey is completed. Respondent contact information is also needed in the event that a safety event is reported and a TIRF medicine manufacturer must obtain follow-up information (see Section 8 above). Respondents will be informed when they access the survey that they may be contacted if there are any questions about their survey responses. Respondents will be informed that their answers to the survey questions will not affect their ability to dispense TIRF medicines. 16 of 44 FDA_5006 TIRF REMS Industry Group (TRIG) Version 911.0 12AUG2015Transmucosal Immediate Release Fentanyl (TIRF) Products Pharmacist KAB Survey Protocol 04AUG2016 Appendix A Pharmacist Questionnaire Survey Legend [PROGRAMMER] is used to indicate directions to the programmer and is set in bold, red, uppercase letters between square brackets. (INTERVIEWER) is used to indicate directions to the telephone interviewer and is set in bold, blue, text between parentheses. This text appears when content is to be administered by telephone only (for example, spontaneous adverse event reporting). [ONLINE] indicates a question is worded specifically for administering the survey online. [PHONE] indicates a question is worded specifically to be read by a telephone interviewer and differs from the online text. [BEGIN SURVEY CONTENT] and [END SURVEY CONTENT] are used to indicate to the programmer the type of survey administration and the beginning and end of the survey or sections within the survey content, for example, [BEGIN ADVERSE EVENT/PRODUCT COMPLAINT] and [END ADVERSE EVENT/PRODUCT COMPLAINT]. [TERMINATE] is displayed next to responses that should cause the survey to end. The following termination language will be programmed into the survey or read by the interviewer unless different language is specified with the question. Thank you very much for your time today. Based on your answer, you are not eligible to take this survey. We appreciate your interest in the survey. [RANDOMIZE LIST] is inserted before questions to indicate to the programmer that the responses should be randomized. Responses such as “I don’t know,” “Prefer not to answer” or “None of the above” will always appear at the end of the randomized responses. Response options for questions that allow multiple responses must be indicated with check @ \ ^ for the question to be considered answered. If any response option requires text to be collected and does not need another question label, show [FREE TEXT] after the response option, if applicable. Response options for questions that allow only one response must be indicated with radio buttons ({). If any response option requires text to be collected and does not need another question label, show [FREE TEXT] after the response option, if applicable. [GO TO Qx] (skip logic) is inserted after a response to indicate to the programmer that the survey should skip to the indicated question (for example, [GO TO Q17] skips to question 17). If no skip logic is indicated the survey continues to the next question in the sequence. 17 of 44 FDA_5007 TIRF REMS Industry Group (TRIG) Version 911.0 12AUG2015Transmucosal Immediate Release Fentanyl (TIRF) Products Pharmacist KAB Survey Protocol 04AUG2016 Survey Legend [FREE TEXT] indicates to the programmer that one line should be provided for data entry. [MULTILINE INPUT] indicates to the programmer that multiple lines should be provided for data entry (for example, two address lines). [DROP-DOWN LIST INPUT WITH STATES TABLE] indicates to the programmer that the response should be a drop-down list containing the states in the table below. Alabama Georgia Massachusetts New York Tennessee Alaska Guam Michigan North Carolina Texas American Samoa Hawaii Minnesota North Dakota Idaho Mississippi Arizona Illinois Missouri Arkansas Indiana Montana Northern Mariana Islands US Virgin Islands California Iowa Nebraska Colorado Kansas Nevada Connecticut Kentucky New Hampshire Delaware Louisiana New Jersey Maine New Mexico District of Columbia Florida Maryland Utah Vermont Ohio Virginia Oklahoma Washington Oregon West Virginia Pennsylvania Wisconsin Puerto Rico Wyoming Rhode Island South Carolina South Dakota The following is used to categorize survey populations into standard geographic regions but it is not displayed in the survey. Geographic Distribution (based on address) 1: Northeast, Midwest, South, and West regions Northeast Region New England Division - ME, NH, VT, MA, RI, CT Middle Atlantic Division - NY, NJ, PA Midwest Region East North Central Division - OH, IN, IL, MI, WI West North Central Division - MN, IA, MO, ND, SD, NE, KS South Region South Atlantic Division - DE, MD, DC, VA, WV, NC, SC, GA, FL East South Central Division - KY, TN, AL, MS West South Central Division - AR, LA, OK, TX 18 of 44 FDA_5008 TIRF REMS Industry Group (TRIG) Version 911.0 12AUG2015Transmucosal Immediate Release Fentanyl (TIRF) Products Pharmacist KAB Survey Protocol 04AUG2016 Survey Legend West Mountain Division - MT, ID, WY, CO, NM, AZ, UT, NV Pacific Division WA, OR, CA, AK, HI The following US territories are categorized as Other: Puerto Rico, Northern Mariana Islands, US Virgin Islands, American Samoa, and Guam. 1 U.S. Census Bureau, last revised Friday, 27-Jul-2001 12:59:43 EDT. 19 of 44 FDA_5009 TIRF REMS Industry Group (TRIG) Version 911.0 12AUG2015Transmucosal Immediate Release Fentanyl (TIRF) Products Pharmacist KAB Survey Protocol 04AUG2016 [BEGIN SURVEY CONTENT] [BEGIN ONLINE PREAMBLE 1] Before you begin, we would like to share some important information about this survey. The manufacturers of Transmucosal Immediate Release Fentanyl (TIRF) medicines are conducting this survey, as required by the FDA, to assess pharmacists’ understanding of the safe use and dispensing of these medicines. These medicines are known as rapid onset opioids and referred to in this survey as “TIRF medicines.” The TIRF medicines include Abstral®, Actiq®, Fentora®, Lazanda®, Subsys®, and generic versions of any of these brands. The manufacturers of these medicines include Actavis Laboratories FL, Inc.; BioDelivery Sciences International, Inc. (BDSI); Cephalon, Inc. (a wholly-owned subsidiary of Teva Pharmaceutical Industries, Ltd.); Depomed, Inc.; Galena Biopharma, Inc.; Insys Therapeutics, Inc.; Mallinckrodt Pharmaceuticals; Mylan Inc.; Par Pharmaceuticals, Inc.; and Par PharmaceuticalSentynl Therapeutics, Inc. The survey will take 15-20 minutes. There are no known risks to you in taking this survey. You may refuse to take part or withdraw at any time. Your answers to the questions or your decision to take part in the survey will not affect your ability to dispense TIRF medicines. How We Use Your Information Your answers to the survey questions will be combined with answers given by other pharmacists taking the survey. All answers will be put together and reported in anonymous form to the manufacturers of TIRF medicines. Your name will not be used in any report. If you are eligible to take the survey, complete all the questions, and provide your contact information, you will receive a $50 honorarium for your time and participation. Your name and address will be used to send you the honorarium to you after you complete the survey. Your personal information will also be used if we have questions about your survey or if we are required to use your information to comply with a federal or state law or regulation. Providing a telephone number is optional. Your telephone number will be used only if there are any questions about your survey responses. How We Protect Your Privacy We respect that the privacy of your personal information is important to you. You will not be contacted for marketing purposes based on your personal information or your answers to the survey. Neither the manufacturers of TIRF medicines nor their contractors will sell, transfer, or rent your information. Your answers will be kept strictly confidential. Your privacy will be protected; however, research survey records may be inspected by the FDA. Your choice to allow manufacturers of TIRF medicines to use your information is entirely voluntary but necessary to take part in this survey. 20 of 44 FDA_5010 TIRF REMS Industry Group (TRIG) Version 911.0 12AUG2015Transmucosal Immediate Release Fentanyl (TIRF) Products Pharmacist KAB Survey Protocol 04AUG2016 How to Learn More about This Survey If you have questions about the survey, or problems with the survey, please contact the Survey Coordinating Center at 1-877-379-3297. Be sure to write down this telephone number; it will not be displayed again. Taking the Survey Once you have answered a question and moved on, you cannot go back and change your answers. Thank you for your participation in this survey. [END ONLINE PREAMBLE 1] 21 of 44 FDA_5011 TIRF REMS Industry Group (TRIG) Version 911.0 12AUG2015Transmucosal Immediate Release Fentanyl (TIRF) Products Pharmacist KAB Survey Protocol 04AUG2016 [BEGIN PHONE PREAMBLE 1] Before you begin, we would like to share some important information about this survey. The manufacturers of Transmucosal Immediate Release Fentanyl (TIRF) medicines are conducting this survey, as required by the FDA, to assess pharmacists’ understanding of the safe use and dispensing of these medicines. These medicines are known as rapid onset opioids and referred to in this survey as “TIRF medicines.” (INTERVIEWER: Say “TIRF” then spell out T-IR-F) The TIRF medicines include Abstral®, Actiq®, Fentora®, Lazanda®, Subsys®, and generic versions of any of these brands. The manufacturers of these medicines include Actavis Laboratories FL, Inc.; BioDelivery Sciences International, Inc. (BDSI); Cephalon, Inc. (a wholly-owned subsidiary of Teva Pharmaceutical Industries, Ltd.); Depomed, Inc.; Galena Biopharma, Inc.; Insys Therapeutics, Inc.; Mallinckrodt Pharmaceuticals; Mylan Inc.; Par Pharmaceuticals, Inc.; and Par PharmaceuticalSentynl Therapeutics, Inc. The survey will take 15-20 minutes. There are no known risks to you in taking this survey. You may refuse to take part or withdraw at any time. Your answers to the questions or your decision to take part in the survey will not affect your ability to dispense TIRF medicines. Now I would like to read some information about how your contact information will be used. Your answers to the survey questions will be combined with answers given by other pharmacists taking the survey. All answers will be put together and reported in anonymous form to the manufacturers of TIRF medicines. Your name will not be used in any report. If you are eligible to take the survey, complete all the questions, and provide your contact information, you will receive a $50 honorarium for your time and participation. Your name and address will be used to send you the honorarium to you after you complete the survey. Your personal information will also be used if we have questions about your survey or if we are required to use your information to comply with a federal or state law or regulation. Providing a telephone number is optional. Your telephone number will be used only if there are any questions about your survey responses. Now I would like to tell you some information about how we protect your privacy. We respect that the privacy of your personal information is important to you. You will not be contacted for marketing purposes based on your personal information or your answers to the survey. Neither the manufacturers of TIRF medicines nor their contractors will sell, transfer, or rent your information. Your answers will be kept strictly confidential. Your privacy will be protected; however, research survey records may be inspected by the FDA. Your choice to allow manufacturers of TIRF medicines to use your information is entirely voluntary but necessary to take part in this survey. Now I will tell you how you can learn more about this survey. Please have a pen or pencil ready to write down a telephone number you can call should you have any questions about the survey. If you have questions about the survey, please ask me at any time. If you have questions at a later time, please contact the Survey Coordinating Center at 1-877-379-3297. 22 of 44 FDA_5012 TIRF REMS Industry Group (TRIG) Version 911.0 12AUG2015Transmucosal Immediate Release Fentanyl (TIRF) Products Pharmacist KAB Survey Protocol 04AUG2016 Please feel free to ask me to repeat any questions or statements as we go through the survey. Once you have answered a question and moved on, you cannot go back and change your answers. Thank you for your participation in this survey. [END PHONE PREAMBLE 1] 23 of 44 FDA_5013 TIRF REMS Industry Group (TRIG) Version 911.0 12AUG2015Transmucosal Immediate Release Fentanyl (TIRF) Products Pharmacist KAB Survey Protocol 04AUG2016 [BEGIN INCLUSION/EXCLUSION QUESTIONS] 1. Your agreement to participate in this survey confirms mutual understanding in connection with completion of the survey and the fair market value of the payment to be rendered in connection with those services. Do you agree to participate in this survey? 2. 3. 4. Yes No [TERMINATE] Have you ever taken part in this survey about TIRF medicines before? TIRF medicines include Abstral®, Actiq®, Fentora®, Lazanda®, Subsys®, and generic versions of any of these brands. Yes [TERMINATE] No I don’t know [TERMINATE] Do you work in a pharmacy that is enrolled in the TIRF REMS Access Programprogram? Yes No [TERMINATE] I don’t know [TERMINATE] Have you or any of your immediate family members ever worked for any of the following companies or agencies? Please select all that apply. Actavis Laboratories FL, Inc. [TERMINATE] Anesta LLC [TERMINATE] BioDelivery Sciences International, Inc. (BDSI) [TERMINATE] Cephalon, Inc. (a wholly-owned subsidiary of Teva Pharmaceutical Industries, Ltd.) [TERMINATE] Depomed, Inc. [TERMINATE] 24 of 44 FDA_5014 TIRF REMS Industry Group (TRIG) Version 911.0 12AUG2015Transmucosal Immediate Release Fentanyl (TIRF) Products Pharmacist KAB Survey Protocol 04AUG2016 Galena Biopharma, Inc. [TERMINATE] Insys Therapeutics, Inc. [TERMINATE] Mallinckrodt Pharmaceuticals [TERMINATE] McKesson Specialty Care Solutions [TERMINATE] Mylan, Inc. [TERMINATE] Par PharmaceuticalPharmaceuticals, Inc. [TERMINATE] RelayHealth [TERMINATE] Sentynl Therapeutics, Inc. [TERMINATE] Teva Pharmaceuticals, Ltd. [TERMINATE] United BioSource Corporation [TERMINATE] FDA [TERMINATE] None of these apply [IF SELECTED IN ADDITION TO OTHER RESPONSES, TERMINATE] I don’t know [TERMINATE] Prefer not to answer [TERMINATE] [END INCLUSION/EXCLUSION QUESTIONS] 5. Please select True, False, or I don’t know for each of the following. According to the labeling for TIRF medicines, patients with cancer who are considered opioid-tolerant are those: [RANDOMIZE LIST] Who are taking around-the-clock opioid therapy for underlying, persistent cancer pain for one week or longer Who are not currently taking opioid therapy, but have 5b. taken opioid therapy before Who have no known contraindications to the drug 5c. fentanyl, but are not currently taking around-the-clock opioid therapy 5a. 25 of 44 True False I don’t know FDA_5015 TIRF REMS Industry Group (TRIG) Version 911.0 12AUG2015Transmucosal Immediate Release Fentanyl (TIRF) Products Pharmacist KAB Survey Protocol 04AUG2016 Please answer True, False, or I don’t know for each statement based on the labeling for TIRF medicines. 6. [RANDOMIZE LIST] 6a. According to the product labeling, a cancer patient may start a TIRF medicine and an around-the-clock opioid at the same time. 6b. According to the product labeling, a cancer patient who has been on an around-the-clock opioid for 1 day may start taking a TIRF medicine for breakthrough pain. 6c. A patient must stop taking their TIRF medicine if they stop taking their around-the-clock opioid pain medicine. 6d. Use of a TIRF medicine with a CYP3A4 inhibitor may require dosage adjustment and monitoring of the patient for opioid toxicity as potentially fatal respiratory depression could occur. 7. True False I don’t know Please answer True, False, or I don’t know for each statement based on the labeling for TIRF medicines. [RANDOMIZE LIST] 7a. TIRF medicines are contraindicated in opioid nontolerant patients because life-threatening respiratory depression could occur at any dose. 7b. Death has occurred in opioid non-tolerant patients treated with some fentanyl products. 7c. TIRF medicines may be used in opioid non-tolerant patients. 7d. Prescribers starting a patient on a TIRF medicine must begin with titration from the lowest dose available for that specific product, even if the patient has previously taken another TIRF medicine. 7e. It is important to monitor for signs of abuse and addiction in patients who take TIRF medicines. 26 of 44 True False I don’t know FDA_5016 TIRF REMS Industry Group (TRIG) Version 911.0 12AUG2015Transmucosal Immediate Release Fentanyl (TIRF) Products Pharmacist KAB Survey Protocol 04AUG2016 8. 8a. 8b. 8c. 9. Which of the following are risk factors for opioid abuse? Please answer Yes, No, or I don’t know for each option. [RANDOMIZE LIST] Yes No I don’t know A personal history of psychiatric illness A personal history of past or current alcohol or drug abuse, or a family history of illicit drug use or alcohol abuse A family history of asthma Per the approved labeling for TIRF medicines, for which of the following indications can TIRF medicines be prescribed to opioid tolerant patients? Please answer Yes, No, or I don’t know for each option. [RANDOMIZE LIST] 9a. 9b. 9c. 9d. 9e. 10. Yes Acute or postoperative pain Headache or migraine pain Dental pain Breakthrough pain from cancer Chronic non-cancer pain No I don’t know Please answer True, False, or I don’t know for each statement based on the labeling for TIRF medicines. [RANDOMIZE LIST] 10a. TIRF medicines can be abused in a manner similar to other opioid agonists. 10b. TIRF medicines are interchangeable with each other regardless of route of administration. 10c. The conversion of one TIRF medicine for another TIRF medicine may result in a fatal overdose because of differences in the pharmacokinetics of fentanyl absorption. 10d. Dosing of TIRF medicines is not equivalent on a microgram-to-microgram basis. 27 of 44 True False I don’t know FDA_5017 TIRF REMS Industry Group (TRIG) Version 911.0 12AUG2015Transmucosal Immediate Release Fentanyl (TIRF) Products Pharmacist KAB Survey Protocol 04AUG2016 11. 11a. 11b. 11c. 11d. 11e. 11f. 12. Please select True, False, or I don’t know for each of the following. According to the labeling for TIRF medicines, patients considered opioid-tolerant are those who are taking, for one week or longer, at least: 8 mg oral hydromorphone/day 60 mg oral morphine/day 30 mg oral oxycodone/day 25 mcg transdermal fentanyl/hour 25 mg oral oxymorphone/day An equianalgesic dose of another oral opioid True False I don’t know Please answer True, False, or I don’t know for the following statement about TIRF medicines: TIRF medicines should only be taken by patients who are opioid tolerant. 13. True False I don’t know Which of the following risks are associated with the use of TIRF medicines? Please answer True, False, or I don’t know for the following statements. True False I don’t know 13a. Misuse 13b. Abuse 13c. Addiction 13d. Overdose 13e. Hypothyroidism 13f. Infection 28 of 44 FDA_5018 TIRF REMS Industry Group (TRIG) Version 911.0 12AUG2015Transmucosal Immediate Release Fentanyl (TIRF) Products Pharmacist KAB Survey Protocol 04AUG2016 12.14. How frequently do you perform the following activities when dispensing TIRF medicines? Please answer Always, Only with the first prescription, Sometimes, Never, or I don’t know. [RANDOMIZE LIST] 12a.14a. 12b.14b. 12c.14c. 12d.14d. 12e.14e. 12f.14f. 13.1 Always Only with the first prescription Ask patients (or their caregivers) about the presence of children in the home Instruct patients (or their caregivers) not to share TIRF medicines with anyone else Counsel patients (or their caregivers) that accidental exposure to TIRF medicines by a child may be fatal Instruct patients (or their caregivers) to keep TIRF medicines out of the reach of children to prevent accidental exposure Instruct patients (or their caregivers) about proper disposal of any unused or partially used TIRF medicines Give patients (or their caregivers) the Medication Guide for their TIRF medicine Sometimes Never I don’t know How frequently do you perform the following activities when dispensing TIRF medicines? Please answer True, FalseAlways, Only with the first prescription, Sometimes, Never, or I don’t know for each statement about TIRF medicines. [RANDOMIZE LIST] 15a Talk to the patient about the risks and possible side effects of the TIRF medicine that was most recently prescribed. 15b Instruct the patient on how to use the TIRF medicine that was most recently prescribed. TrueAlways FalseOnly with the first prescription 29 of 44 Sometimes Never I don’t know FDA_5019 TIRF REMS Industry Group (TRIG) Version 911.0 12AUG2015Transmucosal Immediate Release Fentanyl (TIRF) Products Pharmacist KAB Survey Protocol 04AUG2016 15c Instruct the patient on how to store or keep the TIRF medicine that was most recently prescribed. 16. Please answer True, False, or I don’t know for each statement about TIRF medicines. [RANDOMIZE LIST] 13a.16 TIRF medicines may be sold, loaned, or transferred to another pharmacy. 13b.16All pharmacy staff that dispenses TIRF medicines must be educated on the requirements of the TIRF REMS Access Programprogram. 13c.16 TIRF medicines with the same route of administration can be substituted with each other if the pharmacy is out of stock for one product. True False I don’t know 14.17 [INPATIENT PHARMACIST] Does the inpatient pharmacy where you work have an established system, order sets, protocols and/or other measures to help ensure appropriate patient selection and compliance with the requirements of the TIRF REMS Access Programprogram? Yes No I don’t know 15.18 [OUTPATIENT PHARMACIST] Does the outpatient or retail pharmacy where you work process all TIRF medicine prescriptions, regardless of method of payment, through the pharmacy management system? Yes No I don’t know 30 of 44 FDA_5020 TIRF REMS Industry Group (TRIG) Version 911.0 12AUG2015Transmucosal Immediate Release Fentanyl (TIRF) Products Pharmacist KAB Survey Protocol 04AUG2016 16.19. [CSP OUTPATIENT PHARMACIST] Does the pharmacy where you work process all TIRF medicine prescriptions, regardless of method of payment, through the TIRF REMS Access Call Center? Yes No I don’t know 17.20 [INPATIENT PHARMACIST] Please answer True, False, or I don’t know for the following statement about TIRF medicines. It is OK to dispense TIRF medicines from the inpatient pharmacy inventory to an outpatient for use at home. True False I don’t know [BEGIN PREAMBLE 32] The next set of questions is about the educational materials for TIRF medicines. As a reminder, the TIRF medicines include Abstral®, Actiq®, Fentora®, Lazanda®, Subsys®, and generic versions of any of these brands. [END PREAMBLE 32] 18.21 Did you receive or do you have access to the Full Prescribing Information for the TIRF medicine(s) that you dispense? Yes No [GO TO Q232023] I don’t know [GO TO Q232023] 31 of 44 FDA_5021 TIRF REMS Industry Group (TRIG) Version 911.0 12AUG2015Transmucosal Immediate Release Fentanyl (TIRF) Products Pharmacist KAB Survey Protocol 04AUG2016 19.22 Did you read the Full Prescribing Information for the TIRF medicine(s) that you dispense? Yes No I don’t know 20.23 Did you receive or do you have access to the Medication Guide for the TIRF medicine(s) that you dispense? Yes No [GO TO Q252225] I don’t know [GO TO Q252225] 21.24 Did you read the Medication Guide for the TIRF medicine(s) that you dispense? Yes No I don’t know 22.25 Did you or do you have any questions about the information in the Full Prescribing Information or Medication Guide? Yes No [GO TO DEMOGRAPHICS PREAMBLE 1] I don’t know [GO TO DEMOGRAPHICS PREAMBLE 1] [IF QUESTION 2225 YES, DISPLAY QUESTION 26 ON SAME PAGE] 23.26 What are your questions? [MULTILINE INPUT] 32 of 44 FDA_5022 TIRF REMS Industry Group (TRIG) Version 911.0 12AUG2015Transmucosal Immediate Release Fentanyl (TIRF) Products Pharmacist KAB Survey Protocol 04AUG2016 [BEGIN DEMOGRAPHICS PREAMBLE 1 - DISPLAY ON SAME PAGE WITH NEXT QUESTION] There are just a few more questions to help us combine your answers with other answers we have received. [END DEMOGRAPHICS PREAMBLE 1] 24.27 Are you the Pharmacist in Charge for the TIRF REMS Access Programprogram where you work? Yes No I don’t know 25.28 On average, how many times per month have you dispensed TIRF medicine within the last 6 months? None [Go to DEMOGRAPHICS PREAMBLE 2] 1 2 times per month 3 5 times per month More than 5 times per month I don’t remember 26.29 Please select the TIRF medicine(s) that you have dispensed within the last 6 months. Please select all that apply. Abstral® Actiq® or generic Actiq® Fentora® Lazanda® Subsys® 33 of 44 FDA_5023 TIRF REMS Industry Group (TRIG) Version 911.0 12AUG2015Transmucosal Immediate Release Fentanyl (TIRF) Products Pharmacist KAB Survey Protocol 04AUG2016 [BEGIN DEMOGRAPHICS PREAMBLE 2 - DISPLAY ON SAME PAGE WITH NEXT QUESTION] These last few questions are for demographic purposes. [END DEMOGRAPHICS PREAMBLE 2] 27.30 What is your gender? Male Female Prefer not to answer 34 of 44 FDA_5024 TIRF REMS Industry Group (TRIG) Version 911.0 12AUG2015Transmucosal Immediate Release Fentanyl (TIRF) Products Pharmacist KAB Survey Protocol 04AUG2016 28.31 In total, how many years have you been a practicing pharmacist? Less than 3 years 3 5 years 6 10 years 11 More than 15 years Prefer not to answer 15 years 29.32 In which state do you practice? [DROP-DOWN LIST INPUT WITH STATES TABLE WITH “Prefer not to answer” AT END] [PHONE - BEGIN ADVERSE EVENT/PRODUCT COMPLAINT – KEEP ON ONE PAGE] (INTERVIEWER: Please record if respondent spontaneously reported an adverse event or product complaint during the course of this interview.) Yes No [GO TO CLOSING 1] Enter Safety Adverse Event Verbatim [MULTILINE INPUT] (INTERVIEWER: Indicate to the respondent that someone may call back to ask more questions about the adverse event or product complaint that was reported.) [END ADVERSE EVENT/PRODUCT COMPLAINT] [BEGIN CLOSING 1 – KEEP ON ONE PAGE] We would like to send you a $50 honorarium within the next few weeks to thank you for your time, but we need your name and address to do so. If you do not provide your name and address you will not receive the honorarium for your time and participation in the survey. Do you agree to give us your name and mailing address so we can send you the 35 of 44 FDA_5025 TIRF REMS Industry Group (TRIG) Version 911.0 12AUG2015Transmucosal Immediate Release Fentanyl (TIRF) Products Pharmacist KAB Survey Protocol 04AUG2016 honorarium? Yes No [GO TO CLOSING 2] FIRST NAME: [FREE TEXT] LAST NAME: [FREE TEXT] ADDRESS: [MULTILINE INPUT] CITY: [FREE TEXT] STATE: [DROP-DOWN LIST INPUT WITH STATES TABLE] ZIP: [MUST BE 5 NUMERIC-ONLY CHARACTERS] [END CLOSING 1] [BEGIN CLOSING 2 – KEEP ON ONE PAGE] We would also like to ask for your telephone number. Providing your telephone number is optional and it will be used to contact you only if there are questions about your survey responses. Do you want to provide your telephone number? Yes No [GO TO CLOSING 3] Telephone: [MUST BE 10-DIGIT NUMERIC-ONLY CHARACTERS] [END CLOSING 2] [BEGIN CLOSING 3] That ends the survey. Thank you again for your help. [END CLOSING 3] [END SURVEY CONTENT] 36 of 44 FDA_5026 TIRF REMS Industry Group (TRIG) Version 911.0 12AUG2015Transmucosal Immediate Release Fentanyl (TIRF) Products Pharmacist KAB Survey Protocol 04AUG2016 Appendix B SAMPLE Pharmacist Recruitment Materials INVITATION LETTER [ CURR_DATE] [PHARMACY_NAME] [PHARMACY _STREET_ADDR] [PHARMACY_CITY], [PHARMACY _STATE] [PHARMACY _ZIP] [PHARMACY_FAX_NUMBER] Dear [PHARMACIST_ IN CHARGE] Your Pharmacypharmacy was selected to receive this letter, because of enrollment in the TIRF Transmucosal Immediate Release Fentanyl (TIRF) Risk Evaluation and Mitigation Strategy (REMS) Access Program.program and dispensing of TIRF medicines in the last 6 months. We are contacting you to inform you about a survey being conducted by the manufacturers of Transmucosal Immediate Release Fentanyl (TIRF) medicinesTIRF Medicines, as required by the Food and Drug Administration (FDA). The purpose of the survey is to assess pharmacists’ understanding of the safe and appropriate use of these medicines. The TIRF medicines include Abstral®, Actiq®, Fentora®, Lazanda®, Subsys®, and generic versions of any of these brands. The FDA has requested that non-supervisory pharmacists participate in this survey; therefore, as part of this FDA request, we are asking for your help in distributing these surveys to non-supervisory pharmacists in your pharmacy. The survey will be open through [ENTER DATE] but could be extended if the desired number of completed surveys has not been collected. The survey should take about 20 minutes to complete. You will find enclosed, [ENTER NUMBER] invitation letters to provide to [ENTER NUMBER] non-supervisory pharmacists. The manufacturers of TIRF medicines include Actavis Laboratories FL, Inc.;., BioDelivery Sciences International, Inc. (BDSI);., Cephalon, Inc. (a wholly-owned subsidiary of Teva Pharmaceutical Industries, Ltd.);.), Depomed, Inc.; Galena Biopharma, Inc.;., Insys Therapeutics, Inc.;., Mallinckrodt Pharmaceuticals;, Mylan Inc., Par Pharmaceuticals, Inc.;., and Par PharmaceuticalSentynl Therapeutics, Inc. (collectively referred to as the “TIRF REMS Industry Group”). These manufacturers are looking for 300 non-supervisory pharmacists to complete the survey. Eligible pharmacists who complete the survey will be sent a $50 honorarium to thank them for their time. The survey will take 15 20 minutes. Your answers will be kept strictly confidential and will be combined with the answers from other pharmacists who take this survey. Your name will not be used in the report of this survey and your contact information, if provided, will only be used to send you a $50 honorarium for your time to complete the survey. 37 of 44 FDA_5027 TIRF REMS Industry Group (TRIG) Version 911.0 12AUG2015Transmucosal Immediate Release Fentanyl (TIRF) Products Pharmacist KAB Survey Protocol 04AUG2016 You are under no obligation to participate in this survey. Only one pharmacist from each enrolledYour answers will be kept strictly confidential and will be combined with the answers from other pharmacists who take this survey. Your name will not be used in the report of this survey and your contact information, if provided, will only be used to send you a $50 honorarium for your time to complete the survey. Your pharmacy canis under no obligation to participate in this survey. If you areor a staff pharmacist at your pharmacy is interested in participating and to find out if you are eligible: x x Go online* to www.TIRFREMSsurvey.com any time or Call 1-877-379-3297, 8 a.m. to 8 p.m. Eastern Time, Monday through Friday Please have this letter with you at the time you take the survey. You will be asked to provide this code prior to starting the survey: [CODE_ID]. *We recommend *Please note that you should take the survey on a desktop or laptop computer. Taking the survey on mobile devices, such as smart phones, tablets, and e -notebooks, is not supported. Neither taking the survey nor your answers to the questions will affect your ability to dispense any of the TIRF medicines identified above. Sincerely, The TIRF REMS Survey Team 1-877-379-3297 www.TIRFREMSsurvey.com 38 of 44 FDA_5028 TIRF REMS Industry Group (TRIG) Version 911.0 12AUG2015Transmucosal Immediate Release Fentanyl (TIRF) Products Pharmacist KAB Survey Protocol 04AUG2016 Dear Pharmacist, The Food and Drug Administration (FDA) has requested that the sponsors of TIRF medicines conduct a survey to assess pharmacists’ understanding of the safe and appropriate use of these medicines. The TIRF medicines include Abstral®, Actiq®, Fentora®, Lazanda®, Subsys®, and generic versions of any of these brands. The FDA has requested that non-supervisory pharmacists, like yourself, participate in this survey. The manufacturers of TIRF medicines include Actavis Laboratories FL Inc., BioDelivery Sciences International, Inc., Cephalon, Inc. (a wholly-owned subsidiary of Teva Pharmaceutical Industries, Ltd.), Depomed, Inc., Insys Therapeutics, Inc., Mallinckrodt Pharmaceuticals, Mylan Inc., Par Pharmaceuticals, Inc., and Sentynl Therapeutics, Inc. (collectively referred to as the “TIRF REMS Industry Group”). These manufacturers are looking for 300 non-supervisory pharmacists to complete the survey. Eligible pharmacists who complete the survey will be sent a $50 honorarium to thank them for their time. The survey will take 20 minutes to complete. Your answers will be kept strictly confidential and will be combined with the answers from other pharmacists who take this survey. Your name will not be used in the report of this survey and your contact information, if provided, will only be used to send you a $50 honorarium for your time to complete the survey. You are under no obligation to participate in this survey. If you are interested in participating and to find out if you are eligible: x x Go online* to www.TIRFREMSsurvey.com any time or Call 1-877-379-3297, 8 a.m. to 8 p.m. Eastern Time, Monday through Friday Please have this letter with you at the time you take the survey. You will be asked to provide this code prior to starting the survey: [CODE_ID]. *Please note that you should take the survey on a desktop or laptop computer. Taking the survey on mobile devices, such as smart phones, tablets, and e-notebooks, is not supported. Neither taking the survey nor your answers to the questions will affect your ability to dispense any of the TIRF medicines identified above. Sincerely, The TIRF REMS Survey Team 1-877-379-3297 www.TIRFREMSsurvey.com 39 of 44 FDA_5029 TIRF REMS Industry Group (TRIG) Version 911.0 12AUG2015Transmucosal Immediate Release Fentanyl (TIRF) Products Pharmacist KAB Survey Protocol 04AUG2016 THANK YOU LETTER [CURR DATE] [PHARMACIST FIRST NAME] [[PHARMACIST LAST NAME], [TITLE] [PHARMACIST STREET ADDR] [PHARMACIST CITY], [PHARMACIST STATE] [PHARMACIST ZIP] Dear [PHARMACIST FULL NAME], On behalf of TIRF REMS Industry Group, we want to thank you for taking part in the TIRF REMS Survey. To express our appreciation for your valuable time, enclosed is a gift card for $50. Card Activation Instructions: To prevent loss, the enclosed card is not activated. Prior to using your card, please call the TIRF REMS Coordinating Center at 1-877-379-3297 between 8:00 a.m. and 8:00 p.m. Eastern Time, Monday through Friday, to activate your card. Please have your card available when you make the call. Also, please read the enclosed Terms and Conditions document before using your gift card as well as the privacy policy that can be found at: http://www.ctpayer.com/downloads/privacy policy.pdf Please note the enclosed card needs to be activated on or before: xx xxx xxxx Additionally, for your information and to reinforce important safety messages about TIRF Medications, we have enclosed the following two documents: 1. A copy of the correct answers to the important survey questions about the TIRF REMS key risk message questions. 2. A copy of the Important Safety Information. Additional information regarding TIRF REMS Access program can be found at www.TIRFREMSaccess.com. Thank you for your time and consideration regarding this important safety information. Sincerely, The TIRF REMS Survey Team 1-877-379-3297 www.TIRFREMSsurvey.com Enclosures: Gift Card and Terms and Conditions Correct Answers to Important Survey Questions TIRF Important Safety Information 40 of 44 FDA_5030 TIRF REMS Industry Group (TRIG) Version 911.0 12AUG2015Transmucosal Immediate Release Fentanyl (TIRF) Products Pharmacist KAB Survey Protocol 04AUG2016 Appendix C Correct Answer Document Correct Responses to Select PHARMACIST Survey Questions about Important Safety Messages for Transmucosal Immediate Release Fentanyl (TIRF) medicines (TIRF medicines include Abstral®, Actiq®, Fentora®, Lazanda®, Subsys®, and generic versions of any of these brands) Q: Please select True, False, or I don’t know for each of the following. According to the labeling for TIRF medicines, patients with cancer who are considered opioid-tolerant are those: STATEMENT Who are taking around-the-clock opioid therapy for underlying, persistent cancer pain for one week or longer Who are not currently taking opioid therapy, but have taken opioid therapy before Who have no known contraindications to the drug fentanyl, but are not currently taking around-the-clock opioid therapy Q: DESIRED RESPONSE TRUE FALSE FALSE Please answer True, False, or I don’t know for each statement based on the labeling for TIRF medicines. STATEMENT TIRF medicines are contraindicated in opioid non-tolerant patients because life-threatening respiratory depression could occur at any dose. Death has occurred in opioid non-tolerant patients treated with some fentanyl products. TIRF medicines may be used in opioid non-tolerant patients. Prescribers starting a patient on a TIRF medicine must begin with titration from the lowest dose available for that specific product, even if the patient has previously taken another TIRF medicine. According to the product labeling, a cancer patient may start a TIRF medicine and an around-the-clock opioid at the same time. According to the product labeling, a cancer patient who has been on an around-the-clock opioid for 1 day may start taking a TIRF medicine for breakthrough pain. A patient must stop taking their TIRF medicine if they stop taking their around-the-clock opioid pain medicine. 41 of 44 DESIRED RESPONSE TRUE TRUE FALSE TRUE FALSE FALSE TRUE FDA_5031 TIRF REMS Industry Group (TRIG) Version 911.0 12AUG2015Transmucosal Immediate Release Fentanyl (TIRF) Products Pharmacist KAB Survey Protocol 04AUG2016 Q: Please select True, False, or I don’t know for each of the following. According to the labeling for TIRF medicines, patients considered opioid-tolerant are those who are taking, for one week or longer, at least: STATEMENT Q: DESIRED RESPONSE 8 mg oral hydromorphone/day TRUE 60 mg oral morphine/day TRUE 30 mg oral oxycodone/day TRUE 25 mcg transdermal fentanyl/hour TRUE 25 mg oral oxymorphone/day TRUE An equianalgesic dose of another oral opioid TRUE Per the approved labeling for TIRF medicines, for which of the following indications can TIRF medicines be prescribed to opioid tolerant patients? Please answer Yes, No, or I don’t know for each option. Acute or postoperative pain DESIRED RESPONSE NO Headache or migraine pain NO Dental pain NO Breakthrough pain from cancer YES Chronic non-cancer pain NO STATEMENT 42 of 44 FDA_5032 TIRF REMS Industry Group (TRIG) Version 911.0 12AUG2015Transmucosal Immediate Release Fentanyl (TIRF) Products Pharmacist KAB Survey Protocol 04AUG2016 Q: Please answer True, False, or I don’t know for each statement based on the labeling for TIRF medicines. STATEMENT It is important to monitor for signs of abuse and addiction in patients who take TIRF medicines. TIRF medicines can be abused in a manner similar to other opioid agonists. TIRF medicines are interchangeable with each other regardless of route of administration. The conversion of one TIRF medicine for another TIRF medicine may result in a fatal overdose because of differences in the pharmacokinetics of fentanyl absorption. Dosing of TIRF medicines is not equivalent on a microgram-tomicrogram basis. Q: TIRF medicines with the same route of administration can be substituted with each other if the pharmacy is out of stock for one product. TIRF medicines should only be taken by patients who are opioid tolerant. TRUE FALSE TRUE TRUE DESIRED RESPONSE FALSE TRUE Which of the following are risk factors for opioid abuse? Please answer Yes, No, or I don’t know for each option. STATEMENT A personal history of psychiatric illness A personal history of past or current alcohol or drug abuse, or a family history of illicit drug use or alcohol abuse Q: TRUE Please answer True, False, or I don’t know for each statement about TIRF medicines. STATEMENT Q: DESIRED RESPONSE DESIRED RESPONSE YES YES Which of the following risks are associated with the use of TIRF medicines? Please answer True, False, or I don’t know for the following statements. STATEMENT Misuse Abuse Addiction 43 of 44 DESIRED RESPONSE TRUE TRUE TRUE FDA_5033 TIRF REMS Industry Group (TRIG) Version 911.0 12AUG2015Transmucosal Immediate Release Fentanyl (TIRF) Products Pharmacist KAB Survey Protocol 04AUG2016 Overdose Hypothyroidism Infection TRUE FALSE FALSE If you have questions or are unclear about any of these responses, please refer to the Full Prescribing Information, the Important Safety Information, and the Medication Guide for TIRF medicines. 44 of 44 FDA_5034 Pharmacist KAB Assessment Report Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Appendix B Final 10 February 2017 Page 62 of 62 Survey Tables FDA_5035 TRIG Page 1 of TIRF Pharmacist KAB Table 1.1: Survey Administration Statistics Parameter, Number of invitations distributed 1 1598 Number of invitations returned as undeliverable 139 Number of reminder letters distributed 3772 All Respondentsm 561 (4.9) Eligible Respondentsm 333 (59.4) Completed surveym 318 (95.5) Did not complete the surveym 15 (4.5) Respondents not eligiblem 228 (40.6) Source: Appendix B: Survey Tables, Table 1.1 Number of unique respondents who accessed the survey. Percentage is based on the number of invitations distributed excluding the number of invitations returned as undeliverable. Percentage is based on the number of all respondents. Percentage is based on the number of eligible respondents. Number of respondents who did not meet eligibility criteria or did not complete eligibility questions. Data Source: ADPQ Program: TSADMSAS TRIG Page 1 of 2 TIRF Pharmacist KAB 05JAN2017 Table 1.2: Survey Participant Eligibility Results - All Respondents Pharmacists Question Question 1: Do you agree to participate in this survey? Yes 435 (77.5) Now 1 (02) Discontinued 125 (22.3) Question 2: Have you ever taken part in this survey about TIRF medicines before? TIRF medicines include Abstral?, Actiq?, entora?, Lazanda?, Subsys?, and generic versions of any of these brands. Yesm 17 (3.0) No 380 (67.7) 1 don't know? 37 (6.6) Question not asked (0.2) Discontinued 126 (22.5) Question 3: Do you work in a pharmacy that is enrolled in the TIRF REMS Access program? Yes 338 (60.2) Now 10 (1.8) 1 don't known] 32 (5.7) Question not asked 55 (9.8) Discontinued 126 (22.5) companies or agencies? Please select all that apply.Isl Question 4: Have you or any of your immediate family members ever worked for any of the following Actavis Laboratories FL, [non] 1 (02) Anesta 0 BioDelivery Sciences lntemational, Inc. Cephalon, Inc. (a wholly-owned subsidiary of Teva Pharmaceutical Industries, 1 (02) Depomed, Inc.[? 0 Galena Biophanna, lnc.m 0 Therapeutics, lnc.m 0 Mallinckrodt Pharmaceuticalsm 0 McKesson Specialty Care Solutionsm 0 Mylan [new 0 Data Source: ADPQ. ADTQ Program: TRIG Page 2 of 2 TIRF Pharmacist KAB 05JAN2017 Table 1.2: Survey Participant Eligibility Results - All Respondents Pharmacists (N=56l) Question Par Pharmaceuticals, [new 0 Relayl?lealthm 0 Therapeutics, [new 0 Teva Pharmaceuticals, Ltd? 0 United BioSource Corporationm 0 2 (0.4) None ofthese 333 (59.4) 1 don't know? 2 (0.4) Prefer not to answerm 0 Question not asked 97 (17.3) Discontinued 126 (22.5) Source: Appendix B: Survey Tables, Table 1.2 Note: Respondents who discontinued the survey before completing all eligibility questions without being identi?ed as ineligible in any of the previous questions are counted as discontinued. Once a respondent is counted as discontinued, they will count as discontinued in all subsequent eligibility questions. ?1 Ineligible to participate in the survey. Question not asked due to termination response from a previous question. More than one response can be selected, so percentages may not sum to 100%. Ineligible if selected in addition to another response. Data Source: ADPQ, ADTQ Program: TRIG Page 1 of 1 TIRF Pharmacist KAB 05JAN2017 Table 1.3: Time to Complete Survey - Completed Surveys Telephone Internet Summary Statistic (minutes) 4 314 318 Mean (SD) 21.63 (4.391) 15.67 (8.557) 15.74 (8.540) Minimum 18.1 3.6 3.6 Median 20.23 13.48 13.63 Maximum 28.0 55.8 55.8 Category, 0 to <5 Minutes 0 6 6 5 to <10 Minutes 0 85 85 10 to <15 Minutes 0 95 95 15 to <20 Minutes 2 49 51 20 to <25 Minutes 1 36 37 25 to <30 Minutes 1 16 17 30 Minutes or more 0 27 27 Source: Appendix B: Survey Tables, Table 1.3 Total number of eligible respondents completing the survey. Data Source: ADPQ Program: TRIG Page 1 of 2 TIRF Pharmacist KAB 05JAN2017 Table 2: Description of Eligible Pharmacists - Completed Surveys Pharmacists (N=3l8) Question 11 Question 27: Are you the Pharmacist in Charge for the TIRF REMS Access program where you work? Yes 77 (24.2) No 238 (74.8) 1 don't know 3 (0.9) Question 28: On average, how many times per month have you dispensed TIRF medicine within the last 6 months? None 60 (18.9) 1 - 2 times per month 149 (46.9) 3 - 5 times per month 38 (11.9) More than 5 times per month 47 (14.8) 1 don't remember 24 (7.5) Question 29: Please select the TIRF medicine(s) that you have dispensed within the last 6 months. Please select all that apply.? Abstra1? 26 (10.1) Actiq'i' or generic Actiq? 193 (74.8) entora? 105 (40.7) Lazanda? 19 (7.4) Subsys? 95 (36.8) (Answered ?None" to Question 25) 60 Question 30: What is your gender? Male 155 (48.7) Female 150 (47.2) Prefer not to answer 13 (4.1) Question 31: In total, how many years have you been a practicing pharmacist? Less than 3 years 37 (11.6) 3-5years 51 (16.0) 6 - 10 years 56 (17.6) 11-15 years 35(11.0) More than 15 years 132 (41.5) Data Source: ADPQ, ADTQ Program: TDESCSAS TRIG Page 2 of 2 TIRF Pharmacist KAB 05JAN2017 Table 2: Description of Eligible Pharmacists - Completed Surveys Pharmacists (N=3l8) Question Prefer not to answer 7 (2.2) Geographic Distribution (based on Question 32 - In which state do you practice?)?' Northeast 83 (26.1) Midwest 58 (18.2) South 101 (31.8) West 75 (23.6) Other 0 Prefer not to answer 1 (0.3) Source: Appendix B: Survey Tables, Table 2 Percentages are calculated based on the number of respondents to whom the question was presented. More than one response can be selected, so percentages may not sum to 100%. US. Census Bureau, last revised Friday, 27-Jul-2001 12:59:43 EDT., Geography Division. Northeast includes CT, MA, ME, NH, NJ, NY, PA, RI, and VT. Midwest includes IA, IL, IN, KS, MI, MN, MO, ND, NE, OH, SD, and W1. South includes AL, AR, DC, DE, FL, GA, KY, LA, MD, MS, NC, OK, SC, TN, TX, VA, and WV. West includes AK, AZ, CA, CO, HI, ID, MT, NM, NV, OR, UT, WA, and WY. Other includes Puerto Rico, Northem Mariana Islands, US Virgin Islands, American Samoa and Guam. Data Source: ADPQ, ADTQ Program: TDESC.SAS TRIG TIRF Pharmacist KAB Page 1 of2 3IJAN2017 (REMS database) Table 2b: Comparison of Pharmacies Represented by the Survey Respondents to the General Population of Pharmacies that Have Dispensed TIRF Medicines in the Past Six Months Pharmacies Represented by Pharmacies Pharmacists Dispensing TIRF Completing Medicines in the Survey Past Six Months (REMS Sm'tch (REMS Switch Provider Data) Provider Data) (N =3857) Parameter p-value Geographic region of pharmacy Northeast 59 (24.6) 783 (20.3) Midwest 44 (18.3) 660 (17.1) South 78 (32.5) 1396 (36.2) West 59 (24.6) 1017 (26.4) Other 0 (0.0) 0.4924 Prefer not to answer 0 Type of pharmacy Inpatient Pharmacym 45 (18.8) 763 (19.8) Independent Outpatient Pharmacy 165 (68.8) 131 1 (34.0) Chain Outpatient Pharmacy 29 (12.1) 1769 (45.9) Closed System Pharmacy 1 (0.4) 14 (0.4) <.0001 Number of orders by type of pharmacy'2 Inpatient Pharmacy Independent Outpatient Pharmacy 4830 (60.0) 23417 (60.5) Chain Outpatient Pharmacy 3215 (40.0) 15139 (39.1) Data Source: ADPQ, ADTQ, PHARMCO, PHARMCS, PHARMIP Program: TRIG Page 2 of 2 TIRF Pharmacist KAB 31JAN2017 Table 2b: Comparison of Pharmacies Represented by the Survey Respondents to the General Population of Pharmacies that Have Dispensed TIRF Medicines in the Past Six Months (REMS database) Pharmacies Represented by Pharmacies Pharmacists Dispensing TIRF Completing Medicines in the Survey Past Six Months (REMS Switch (REMS Switch Provider Data) Provider Data) (N =3857) Parameter p-value Closed System Pharmacy 146 (0.4) Note: Switch provider data was provided by McKesson on September 6th, 2016. Each pharmacy is counted only once, regardless of how many pharmacists from that pharmacy complete the survey. Percentages for the number of orders by type of pharmacy were calculated based on the total number of dispensed TIRF medicines from the pharmacies represented by pharmacists completing the survey and from pharmacies dispensing TIRF medicines in the past 6 months, respectively. P-values are calculated by a chi-square test excluding prefer not to answer. Not available. The REMS database does not collect dispensing information for inpatient pharmacies. Therefore, the number of inpatient pharmacies is based on the number of all active pharmacies in the REMS. Number of orders are not available for inpatient pharmacies. Comparison is based on the number of orders from independent outpatient pharmacies, chain outpatient pharmacies and closed system pharmacies. Data Source: ADPQ, ADTQ, PHARMCO, PHARMCS, PHARMIP Program: TDESCSWISAS TRIG TIRF Pharmacist KAB Page 1 of7 05JAN2017 Table 3: Responses to All Questions about the Safe Use of TIRF Medicines - Completed Surveys Question Pharmacists (N=3l8) Question 5: Please select True, False, or I don't know for each of the following. According to the labeling for TIRF medicines, patients with cancer who are considered opioid-tolerant are those: 5a: Who are taking around-the-clock opioid therapy for underlying, persistent cancer pain for one week or longer Truem 304 (95.6) False 10 (3.1) 1 don't know 4 (1.3) 5b: Who are not currently taking opioid therapy, but have taken opioid therapy before True 30 (9.4) Falsem 278 (87.4) 1 don't know 10 (3.1) 5c: Who have no known contraindications to the drug fentanyl, but are not currently taking around-the-clock opioid therapy True 46 (14.5) Falsem 261 (82.1) 1 don't know 11 (3.5) medicines. Question 6: Please answer True, False, or I don't know for each statement based on the labeling for TIRF opioid at the same time. 6a: According to the product labeling, a cancer patient may start a TIRF medicine and an around-the-clock True 82 (25.8) Falsem 197 (61.9) 1 don't know 39 (12.3) may start taking a medicine for breakthrough pain. 6b: According to the product labeling, a cancer patient who has been on an around-the-clock opioid for I day True 34 (10.7) Falsem 256 (80.5) 1 don't know 28 (8.8) 60: A patient must stop taking their TIRF medicine if they stop taking their around-the-clock opioid pain medicine. Truem 131 (41.2) Data Source: ADPQ, ADTQ Program: TEX. SAS TRIG TIRF Pharmacist KAB Page 2 of 7 05JAN 2017 Table 3: Responses to All Questions about the Safe Use of TIRF Medicines - Completed Surveys Pharmacists (N=3l8) Question False 151 (47.5) [don't know 36 (11.3) patient for opioid toxicity as potentially fatal respiratory depression could occur. 6d: Use of a TIRF medicine with a CYP3A4 inhibitor may require dosage adjustment and monitoring of the Truem 293 (92.1) False 3 (0.9) 1 don't know 22 (6.9) medicines. Question 7: Please answer True, False, or I don't know for each statement based on the labeling for TIRF depression could occur at any dose. 7a: TIRF medicines are contraindicated in opioid non-tolerant patients because life-threatening respiratory Truem 281 (88.4) False 23 (7.2) 1 don't know 14 (4.4) 7b: Death has occurred in opioid non-tolerant patients treated with some fentanyl Truem 303 (95.3) False 3 (0.9) 1 don't know 12 (3.8) 7c: TIRF medicines may be used in opioid non-tolerant patients. True 28 (8.8) Falsem 278 (87.4) 1 don't know 12 (3.8) 7d: Prescribers starting a patient on a TIRF medicine must begin with titration from the lowest dose available for that speci?c product, even if the patient has previously taken another TIRF medicine. Truem 267 (84.0) False 34 (10.7) 1 don't know 17 (5.3) 7e: It is important to monitor for signs of abuse and addiction in patients who take TIRF medicines. Truem 312(98.l) False 4(1.3) Data Source: ADPQ, ADTQ Program: TEX. SAS TRIG TIRF Pharmacist KAB Page 3 of 7 OSJAN 2017 Table 3: Responses to All Questions about the Safe Use of TIRF Medicines - Completed Surveys Pharmacists Question I don't know 2 (0.6) know for each option. Question 8: Which of the following are risk factors for opioid abuse? Please answer Yes, 0, or I don't 8a: A personal history of illness Yesm 247 (77.7) No 42 (13.2) 1 don't know 29 (9.1) alcohol abuse 8b: A personal history of past or current alcohol or drug abuse, or a family history of illicit drug use or Yesm 314 (98.7) No (0.3) I don't know 3 (0.9) 8c: A family history of asthma Yes 28 (8.8) Now 271 (85.2) I don't know 19 (6.0) option. Question 9: Per the approved labeling for TIRF medicines, for which of the following indications can TIRF medicines be prescribed to opioid tolerant patients? Please answer Yes, No, or I don't know for each 9a: Acute or postoperative pain Yes 35 (l 1.0) Now 273 (85.8) I don't know 10 (3.1) 9b: Headache or migraine pain Yes 7 (2.2) Now 300 (94.3) I don't know 11 (3.5) 9c: Dental pain Yes 2 (0.6) Now 306 (96.2) Data Source: ADPQ, ADTQ Program: TEX. SAS TRIG TIRF Pharmacist KAB Page 4 of 7 05JAN 2017 Table 3: Responses to All Questions about the Safe Use of TIRF Medicines - Completed Surveys Pharmacists (N=3l8) Question 1 don't know 10 (3.1) 9d: Breakthrough pain from cancer Yes? 292 (91.8) No 22 (6.9) 1 don't know 4 (1.3) 9e: Chronic non-cancer pain Yes 138 (43.4) NOW 162 (50.9) 1 don't know 18 (5.7) medicines. Question 10: Please answer True, False, or I don't know for each statement based on the labeling for TIRF 10a: TIRF medicines can be abused in a manner similar to other opioid agonists. Truem 298 (93.7) False 12 (3.8) 1 don't know 8 (2.5) 10b: TIRF medicines are interchangeable with each other regardless of route of administration. True 6 1.9) Falsem 305 (95.9) 1 don't know 7 (2.2) of differences in the pharmacokinetics of fentanyl absorption. 10c: The conversion of one TIRF medicine for another TIRF medicine may result in a fatal overdose because Truem 296 (93.1) False 10 (3.1) 1 don't know 12 (3.8) 10d: Dosing of TIRF medicines is not equivalent on a microgram-to-microgram basis. Truem 283 (89.0) False 16 (5.0) 1 don't know 19 (6.0) Data Source: ADPQ, ADTQ Program: TEX. SAS TRIG TIRF Pharmacist KAB Page 5 of 7 OSJAN 2017 Table 3: Responses to All Questions about the Safe Use of TIRF Medicines - Completed Surveys Question Pharmacists at least: Question 11: Please select True, False, or I don't know for each of the following. According to the labeling for TIRF medicines, patients considered opioid-tolerant are those who are taking, for one week or longer, I I a: 8 mg oral hydromolphone/day Truem 237 (74.5) False 38 (11.9) 1 don't know 43 (13.5) I I b: 60 mg oral morphine/day Truem 280 (88.1) False 13 (4.1) I don't know 25 (7.9) I I c: 30 mg oral oxycodone/day Truem 247 (77.7) False 37 (11.6) 1 don't know 34 (10.7) I Id: 25 meg transdermalfentanyI/hour Truem 253 (79.6) False 39 (12.3) 1 don't know 26 (8.2) I I e: 25 mg oral oxymorphone/day Truem 229 (72.0) False 30 (9.4) 1 don't know 59 (18.6) I If: An equianalgesic dose of another oral opioid Truem 207 (65.1) False 51 (16.0) 1 don't know 60 (18.9) medicines: Question 12: Please answer True, False, or I don't know for the following statement about TIRF TIRF medicines should only be taken by patients who are opioid tolerant. Data Source: ADPQ, ADTQ Program: TEX. SAS TRIG Page 6 of 7 TIRF Pharmacist KAB 05JAN2017 Table 3: Responses to All Questions about the Safe Use of TIRF Medicines - Completed Surveys Pharmacists Question Truem 304 (95.6) False 12 (3.8) 1 don't know 2 (0.6) Question 13: Which of the following risks are associated with the use of TIRF medicines? Please answer True, False, or I don't know for the following statements. 13a: Misuse Truem 314 (98.7) False 3 (0.9) I don't know 1 (0.3) I 3b: A base Truem 315 (99.1) False 2 (0.6) I don't know 1 (0.3) I 3 c: Addiction Truem 314 (98.7) False 3 (0.9) 1 don't know 1 (0.3) 13d: Overdose Truem 316 (99.4) False (0.3) I don't know 1 (0.3) I 3e: )pothyroidism True 10 (3.1) Falsem 267 (84.0) 1 don't know 41 (12.9) 13f: Infection True 15 (4.7) Falsem 284 (89.3) I don't know 19 (6.0) Data Source: ADPQ, ADTQ Program: TEX. SAS TRIG TIRF Pharmacist KAB Page 7 of 7 05JAN 2017 Table 3: Responses to All Questions about the Safe Use of TIRF Medicines - Completed Surveys Question Pharmacists (N=3l8) Question 16: Please answer True, False, or I don't know for each statement about TIRF medicines. I 6a: TIR medicines may be sold, loaned, or transferred to another pharmacy. True 16 (5.0) Falsem 288 (90.6) 1 don't know 14 (44) 16b: All pharmacy staff that dispenses TIRF medicines must be educated on the requirements of the TIRF REMS Access program. Truem 286 (89.9) False 18 (5.7) I don't know 14 (4.4) 16c: TIRF medicines with the same route of administration can be substituted with each other if the pharmacy is out of stock for one product. True 10 (3.1) Falsem 304 (95.6) I don't know 4 (1.3) Source: Appendix B: Survey Tables, Table 3 Correct response. Data Source: ADPQ, ADTQ Program: TEX. SAS TRIG Page I of] TIRF Pharmacist KAB 05JAN2017 Table 4: Responses to Questions about TIRF Medicine Educational Materials - Completed Surveys Pharmacists Question Question 21: Did you receive or do you have access to the Full Prescribing Information for the TIRF medicine(s) that you dispense? Yes 305 (95.9) No 3 (0.9) [don't know 10(3.1) Question 22: Did you read the Full Prescribing Information for the TIRF medicine(s) that you dispense?Ill Yes 246 (80.7) No 51 (16.7) I don't know 8 (2.6) (Answered "No" or don't know" to Question 21) 13 Question 23: Did you receive or do you have access to the Medication Guide for the TIRF medicine(s) that you dispense? Yes 309 (97.2) No 0 I don't know 9 (2.8) Question 24: Did you read the Medication Guide for the TIRF medicine(s) that you Yes 272 (88.0) No 34 (11.0) I don't know 3 (1.0) (Answered "No" or don't know" to Question 23) 9 Question 25: Did you or do you have any questions about the information in the Full Prescribing Information or Medication Guide?"' Yes 6 (1.9) No 293 (92.1) I don't know 19 (6.0) Source: Appendix B: Survey Tables, Table 4 [11 Percentages are calculated based on the sample presented with this question because of skip logic in the survey. Verbatim text for questions about the Full Prescribing Information or Medication Guide is presented in Listing 1. Data Source: ADPQ, ADTQ Program: TEDUC.SAS TRIG Page 1 of3 TIRF Pharmacist KAB 05JAN2017 Table 5: Responses to Questions about the Activities when Dispensing TIRF Medicines - Completed Surveys Pharmacists (N=3l8) Question Question 14: How frequently do you perform the following activities when dispensing TIRF medicines? Please answer Always, Only with the first prescription, Sometimes, Never, or I don't know. 14a: Ask patients (or their caregivers) about the presence of children in the home Always 174 (54.7) Only with the ?rst prescription 85 (26.7) Sometimes 33 (10.4) Never 19 (6.0) I don't know 7 (2.2) Mb: Instruct patients (or their caregivers) not to share TIRF medicines with anyone else Always 223 (70.1) Only with the ?rst prescription 62 (19.5) Sometimes 17 (5.3) Never 13 (4.1) 1 don't know 3 (0.9) 14c: Counsel patients (or their caregivers) that accidental exposure to TIRF medicines by a child ma be fatal Always 207 (65.1) Only with the ?rst prescription 69 (21.7) Sometimes 24 (7.5) Never 15 (4.7) I don't know 3 (0.9) 14d: Instruct patients (or their caregivers) to keep IRF medicines out of the reach of children to prevent accidental exposure Always 214 (67.3) Only with the ?rst prescription 67 (21.1) Sometimes 22 (6.9) Never 11 (3.5) 1 don't know 4 (1.3) medicines I 4e: Instruct patients (or their caregivers) about proper disposal of any unused or partially used TIRF Data Source: ADPQ, ADTQ Program: TACT.SAS TRIG Page 2 of 3 TIRF Pharmacist KAB 05JAN2017 Table 5: Responses to Questions about the Activities when Dispensing TIRF Medicines - Completed Surveys Pharmacists (N=3l8) Question Always 196 (61.6) Only with the ?rst prescription 86 (27.0) Sometimes 21 (6.6) Never 11 (3.5) 1 don't know 4 (1.3) I Give patients (or their caregivers) the Medication Guide for their TIRF medicine Always 277 (87.1) Only with the ?rst prescription 24 (7.5) Sometimes 6 (1.9) Never 8 (2.5) 1 don't know 3 (0.9) Question 15: How frequently do you perform the following activities when dispensing TIRF medicines? Please answer Always, Only with the first prescription, Sometimes, Never, or 1 don't know. 15a: Talk to the patient about the risks and possible side effects of the TIRF medicine that was most recently prescribed. Always 171 (53.8) Only with the ?rst prescription 1 17 (36.8) Sometimes 21 (6.6) Never 8 (2.5) 1 don't know 1 (0.3) 15b: Instruct the patient on how to use the TIRF medicine that was most recently prescribed. Always 184 (57.9) Only with the ?rst prescription 1 1 (34.9) Sometimes 14 (4.4) Never 8 (2.5) 1 don't know 1 (0.3) 15c: Instruct the patient on how to store or keep the TIRF medicine that was most ecently prescribed. Always 154 (48.4) Only with the ?rst prescription 125 (39.3) Data Source: ADPQ, ADTQ Program: TACT.SAS TRIG Page 3 of 3 TIRF Pharmacist KAB 05JAN2017 Table 5: Responses to Questions about the Activities when Dispensing TIRF Medicines - Completed Surveys Pharmacists Question 11 Sometimes 24 (7.5) Never 13 (4.1) 1 don't know 2 (0.6) Question 17: Does the inpatient pharmacy where you work have an established system, order sets, protocols and/or other measures to help ensure appropriate patient selection and compliance with the requirements of the TIRF REMS Access program? (Inpatient Pharmacists, Yes 40 (61.5) No 11 (16.9) 1 don't know 14 (21.5) Pharmacists, only)"l Question 18: Does the outpatient or retail pharmacy where you work process all TIRF medicine prescriptions, regardless of method of payment, through the pharmacy management system? (Outpatient Yes 206 (81.7) N0 11 (4.4) 1 don't know 35 (13.9) Question 19: Does the pharmacy where you work process all TIRF medicine prescriptions, regardless of method of payment, through the TIRF REMS Access Call Center? (CSP Outpatient Pharmacists, only)Ill Yes 1 (100.0) No 0 1 don't know 0 medicines. (Inpatient Pharmacists, only)Ill Question 20: Please answer True, False, or I don't know for the following statement about TIRF It is OK to dispense TIRF medicines from the inpatient pharmacy inventory to an outpatient for use at home. True 3 (4.6) Falsem 54 (83.1) 1 don't know 8 (12.3) Source: Appendix B: Survey Tables, Table 5 [11 Percentages are calculated based on the sample presented with this question Correct response. Data Source: ADPQ, ADTQ Program: TACTSAS TRIG Page 1 of3 TIRF Pharmacist KAB 05JAN2017 Table 6.1: Primary Analysis of Responses to Questions Linked to Key Risk Message #1 - Completed Surveys Pharmacists Question [95% cu'" for TIRF medicines, patients with cancer who are considered opioid-tolerant are Question 5: Please select True, False, or I don't know for each of the following. According to the labeling those: 5a: Who are taking around-the-clock opioid therapy for underlying, persistent canc longer er pain for one week or medicines. Truem 304 (95.6) [92.7 - 97.6] False 10 (3.1) 1 don't know 4 (1.3) 5b: Who are not currently taking opioid therapy, but have taken opioid therapy before True 30 (9.4) Falsem 278 (87.4) [83.3 - 90.9] 1 don't know 10 (3.1) 5c: Who have no known contraindications to the drug fentanyl, but are not currently taking around-the-clock opioid therapy True 46 (14.5) Falsem 261 (82.1) [77.4 - 86.1] 1 don't know 11 (3.5) Question 7: Please answer True, False, or I don't know for each statement based on the labeling for TIRF depression could occur at any dose. 7a: TIRF medicines are contraindicated in opioid non-tolerant patients because life-threatening respiratory Truem 281 (88.4) [84.3 - 91.7] False 23 (7.2) I don't know 14 (44) 7b: Death has occurred in opioid non-tolerant patients treated with some fentanyl products. Truem 303 (95.3) [92.3 - 97.3] False 3 (0.9) I don't know 12 (3.8) 7c: TIRF medicines may be used in opioid non-tolerant patients. True 28 (8.8) Falsem 278 (87.4) [83.3 90.9] Data Source: ADPQ, ADTQ Program: TRIG Page 2 of3 TIRF Pharmacist KAB 05JAN2017 Table 6.1: Primary Analysis of Responses to Questions Linked to Key Risk Message #1 - Completed Surveys Pharmacists Question [95% 1 don't know 12 (3.8) 7d: Prescribers starting a patient on a IRF medicine must begin with titration from the lowest dose available for that speci?c product, even if the patient has previously taken another TIRF medicine. [21 True 267 (84.0) [79.5 - 87.8] False 34 (10.7) 1 don't know 17 (5.3) at least: Question 11: Please select True, False, or 1 don't know for each of the following. According to the labeling for TIRF medicines, patients considered opioid-tolerant are those who are taking, for one week or longer, I I a: 8 mg oral hydromorphone/day Truem 237 (74.5) [69.4 - 79.2] False 38 (11.9) 1 don't know 43 (13.5) I b: 60 mg oral morphine/day Truem 280 (88.1) [84.0 - 91.4] False 13 (4.1) 1 don't know 25 (7.9) I c: 30 mg oral oxycodone/day Truem 247 (77.7) [72.7 - 82.1] False 37 (11.6) 1 don't know 34 (10.7) 1 Id: 25 transdermalfentanyl/hour Truem 253 (79.6) [74.7 - 83.9] False 39 (12.3) 1 don't know 26 (8.2) I I e: 25 mg oral oxymorphone/day Truem 229 (72.0) [66.7 - 76.9] False 30 (9.4) 1 don't know 59 (18.6) Data Source: ADPQ, ADTQ Program: TRIG Page 3 of3 TIRF Pharmacist KAB 05JAN2017 Table 6.1: Primary Analysis of Responses to Questions Linked to Key Risk Message #1 - Completed Surveys Pharmacists (N=3l8) Question [95% I I 1? An equianalgesic dose of another oral opioid Truem 207 (65.1) [59.6 - 70.3] False 51 (16.0) 1 don't know 60 (18.9) Question 12: Please answer True, False, or I don't know for the following statement about TIRF medicines: TIRF medicines should only be taken by patients who are opioid tolerant. Truem 304 (95.6) [92.7 - 97.6] False 12 (3.8) 1 don't know 2 (0.6) Source: Appendix B: Survey Tables, Table 6.1 95% exact two-sided con?dence intervals are calculated using the Clopper-Pearson method. Correct response. Data Source: ADPQ, ADTQ Program: TIRF Pharmacist KAB Page 1 of3 05JAN2017 Table 6.1.1: Responses to Questions Linked to Key Risk Message #1 by Reading Full Prescribing Information or Medication Guide - Completed Surveys Question Reading Full Prescribing Information or Medication Guide Received and read P1 or Med Guide [95% C1[Ill Did not receive or read P1 or Med Guide [95% C1[Ill Question 5: Please select True, False, or I don't know for each of the following. According to the labeling for TIRF medicines, patients with cancer who are considered opioid-tolerant are those: 5a: Who are taking around-the-clock opioid therapy for underlying, persistent cancer pain for one week or longer Truem 268 (96.1) [93.1 98.0] 36 (92.3) [79.1 - 98.4] False 8 (2.9) 2 (5.1) [don't know 3 (1.1) (2.6) 5b: Who are not currently taking opioid therapy, but have taken opioid therapy before True 29 (10.4) 1 (2.6) Falsem 242 (86.7) [82.2 - 90.5] 36 (92.3) [79.1 - 98.4] 1 don't know 8 (2.9) 2 (5.1) 5c: Who have no known contraindications to the drug fentanyl, but are not currently taking around-the-clock opioid therapy True 40 (14.3) 6 (15.4) Falsem 232 (83.2) [78.2 87.4] 29 (74.4) [57.9 - 87.0] 1 don't know 7 (2.5) 4 (10.3) Question 7: Please answer True, False, or I don't know for each statement based on the labeling for TIRF medicines. 7a: TIRF medicines are contraindicated in opioid non-tolerant patients because life-threatening respiratory depression could occur at any dose. Truem 249 (89.2) [85.0 - 92.6] 32 (82.1) [66.5 - 92.5] False 20 (7.2) 3 (7.7) 1 don?t know 10 (3.6) 4 (10.3) 7b: Death has occurred in opioid non-tolerant patients treated with some fentanyl products. Truem 269 (96.4) [93.5 - 98.3] 34 (87.2) [72.6 - 95.7] False 2 (0.7) (2.6) I don't know 8 (2.9) 4 (10.3) 7c: TIRF medicines may be used in opioid non-tolerant patients. Data Source: ADPQ, ADTQ Program: TK RM S. SAS TIRF Pharmacist KAB Page 2 of3 OSJAN 2017 Table 6.1.1: Responses to Questions Linked to Key Risk Message #1 by Reading Full Prescribing Information or Medication Guide - Completed Surveys Reading Full Prescribing Information or Medication Guide Received and read Did not receive or read Pl or Med Guide Pl or Med Guide Question [95% [95% True 24 (8.6) 4 (10.3) Falsem 247 (88.5) [84.2 - 92.0] 31 (79.5) [63.5 - 90.7] 1 don't know 8 (2.9) 4 (10.3) 7d: Prescribers starting a patient on a TIRF medicine must begin with titration from the lowest dose available for that specific product, even if the patient has previously taken another TIRF medicine. Truem 237 (84.9) [80.2 - 88.9] 30 (76.9) [60.7 - 88.9] False 31 (11.1) 3 (7.7) [don't know 11 (3.9) 6 (15.4) Question 11: Please select True, False, or I don't know for each of the following. According to the labeling for TIRF medicines, patients considered opioid-tolerant are those who are taking, for one week or longer, at least: Ila: 8 mg oral hydromorphone/day Truem 212 (76.0) [70.5 - 80.9] 25 (64.1) [47.2 - 78.8] False 35 (12.5) 3 (7.7) 1 don't know 32 (11.5) 11 (28.2) I lb: 60 mg oral morphine/day Truem 252 (90.3) [86.2 - 93.5] 28 (71.8) [55.1 - 85.0] False 13 (4.7) 0 I don?t know 14 (5.0) 11 (28.2) I I c: 30 mg oral oxycodone/day Truem 223 (79.9) [74.7 - 84.5] 24 (61.5) [44.6 - 76.6] False 33 (11.8) 4 (10.3) [don't know 23 (8.2) 1 (28.2) I Id: 25 transdermalfentanyl/hour Truem 230 (82.4) [77.5 - 86.7] 23 (59.0) [42.1 74.4] False 34 (12.2) 5 (12.8) 1 don't know 15 (5.4) 1 1 (28.2) Data Source: ADPQ, ADTQ Program: TK RM S. SAS TRIG TIRF Pharmacist KAB Page 3 of3 05JAN 2017 Table 6.1.1: Responses to Questions Linked to Key Risk Message #1 by Reading Full Prescribing Information or Medication Guide - Completed Surveys Question Reading Full Prescribing Information or Medication Guide Received and read Pl or Med Guide [95% Did not receive or read Pl or Med Guide [95% I I e: 25 mg oral oxymorphone/day Truem 208 (74.6) [69.0 - 79.6] 21 (53.8) [37.2 - 69.9] False 25 (9.0) 5 (12.8) 1 don't know 46 (16.5) 13 (33.3) I If: An equianalgesic dose of another oral opioid Truem 189 (67.7) [61.9 - 73.2] 18 (46.2) [30.1 - 62.8] False 43 (15.4) 8 (20.5) 1 don't know 47 (16.8) 13 (33.3) Question 12: Please answer True, False, or I don't know for the following statement about TIRF medicines: TIRF medicines should only be taken by patients who are opioid tolerant. Truem 268 (96.1) [93.1 98.0] 36 (92.3) [79.1 98.4] False 10 (3.6) 2 (5.1) [don't know 1 (0.4) 1 (2.6) Source: Appendix B: Survey Tables, Table 6.1.1 ?195% exact two-sided confidence intervals are calculated using the Clopper-Pearson method. Correct response. Data Source: ADPQ, ADTQ Program: TK RM S. SAS TRIG TIRF Pharmacist KAB Page 1 of3 05JAN2017 Survey - Completed Surveys Table 6.1.2: Responses to Questions Linked to Key Risk Message #1 by Modality to Complete Question Modality to Complete Survey Internet (N=3l 4) [95% Telephone [95% Question 5: Please select True, False, or 1 don't know for each of the following. According to the labeling for TIRF medicines, patients with cancer who are considered opioid-tolerant are those: 5a: Who are taking around-the-clock opioid therapy for underlying, persistent cancer pain for one week or longer Truem 301 (95.9) [93.0 97.8] 3 (75.0) [19.4 - 99.4] False 9 (2.9) 1 (25.0) [don't know 4 (1.3) 0 5b: Who are not currently taking opioid therapy, but have taken opioid therapy before True 28 (8.9) 2 (50.0) Falsem 276 (87.9) [83.8 - 91.3] 2 (50.0) [6.8 93.2] I don't know 10 (3.2) 0 5c: Who have no known contraindications to the drug fentanyl, but are not currently taking around-the-clock opioid therapy True 45 (14.3) 1 (25.0) Falsem 258 (82.2) [77.5 86.2] 3 (75.0) [19.4 99.4] [don't know 11 (3.5) 0 medicines. Question 7: Please answer True, False, or I don't know for each statement based on the labeling for TIRF depression could occur at any dose. 7a: TIRF medicines are contraindicated in opioid non-tolerant patients because life-threatening respiratory Truem 277 (88.2) [84.1 - 91.6] 4 (100.0) [39.8 - 100.0] False 23 (7.3) 0 1 don't know 14 (4.5) 0 7b: Death has occurred in opioid non-tolerant patients treated with some fentanyl products. Truem 299 (95.2) [92.2 - 97.3] 4 (100.0) [39.8 - 100.0] False 3 (1.0) 0 I don't know 12 (3.8) 0 7c: TIRF medicines may be used in opioid non-tolerant patients. True 27 (8.6) 1 (25.0) Data Source: ADPQ, ADTQ Program: TK RM S. SAS TRIG TIRF Pharmacist KAB Page 2 of3 OSJAN 2017 Survey - Completed Surveys Table 6.1.2: Responses to Questions Linked to Key Risk Message #1 by Modality to Complete Modality to Complete Survey Internet Telephone (N=3l4) Question [95% cu'" [95% Falsem 275 (87.6) [83.4 - 91.0] 3 (75.0) [19.4 - 99.4] 1 don't know 12 (3.8) 0 7d: Prescribers starting a patient on a TIRF medicine must begin with titration ?om the lowest dose available for that speci?c product, even if the patient has previously taken another TIRF medicine. Truem 263 (83.8) [79.2 - 87.7] 4 (100.0) [39.8 - 100.0] False 34 (10.8) 0 I don't know 17 (5.4) 0 least: Question 11: Please select True, False, or I don't know for each of the following. According to the labeling for TIRF medicines, patients considered opioid-tolerant are those who are taking, for one week or longer, at Ila: 8 mg oral hydromorphone/day Truem 234 (74.5) [69.3 - 79.2] 3 (75.0) [19.4 - 99.4] False 38 (12.1) 0 [don't know 42 (13.4) 1 (25.0) I lb: 60 mg oral morphine/day Truem 276 (87.9) [83.8 - 91.3] 4 (100.0) [39.8 - 100.0] False 13 (4.1) 0 1 don't know 25 (8.0) 0 I lo: 30 mg oral oxycodone/day Truem 244 (77.7) [72.7 - 82.2] 3 (75.0) [19.4 - 99.4] False 36 (11.5) 1 (25.0) 1 don't know 34 (10.8) 0 I d: 25 meg transdermalfentanyl/hour Truem 250 (79.6) [74.7 83.9] 3 (75.0) [19.4 99.4] False 39 (12.4) 0 1 don't know 25 (8.0) 1 (25.0) I Ie: 25 mg oral oxymorphone/day Truem 225 (71.7) [66.3 - 76.6] 4 (100.0) [39.8 - 100.0] Data Source: ADPQ, ADTQ Program: TK RM S. SAS TRIG TIRF Pharmacist KAB Page 3 of3 05JAN 2017 Table 6.1.2: Responses to Questions Linked to Key Risk Message #1 by Modality to Complete Survey - Completed Surveys Modality to Complete Survey Internet Telephone (N=3l 4) Question 195% CW 195% False 30 (9.6) 0 [don?t know 59 (18.8) 0 I f: An equianalgesic dose of another oral opioid Truem 205 (65.3) [59.7 - 70.5] 2 (50.0) [6.8 - 93.2] False 51 (16.2) 0 [don't know 58 (18.5) 2 (50.0) Question 12: Please answer True, False, or I don't know for the following statement about TIRF medicines: TIRF medicines should only be taken by patients who are opioid tolerant. Truem 301 (95.9) [93.0 97.8] 3 (75.0) [19.4 99.4] False 11 (3.5) 1 (25.0) [don't know 2 (0.6) 0 Source: Appendix B: Survey Tables, Table 6.1.2 95% exact two-sided confidence intervals are calculated using the lopper-Pearson method. Correct response. Data Source: ADPQ, ADTQ Program: TK RM S. SAS TRIG TIRF Pharmacist KAB Page 1 of4 05JAN2017 Table 6.1.3: Responses to Questions Linked to Key Risk Message #1 by Time Practicing as Pharmacist - Completed Surveys Question Time Practicing as Pharmacist Less than 3 years [95% 3 to 5 years [95% 6 to 15 years [95% More than 15 years (N=l32) [95% Question 5: Please select True, False, or 1 don't know for each of the following. According to the labeling for TIRF medicines, patients with cancer who are considered opioid-tolerant are those: 5a: Who are taking around-the-clock opioid therapy for underlying, persistent cancer pain for one week or longer Truem 37 (100.0) [90.5 - 100.0] 48 (94.1) [83.8 - 98.8] 85 (93.4) [86.2 - 97.5] 127 (96.2) [91.4 - 98.8] False 0 2 (3.9) 4 (4.4) 4 (3.0) [don't know 0 (2.0) 2 (2.2) 1 (0.8) 5b: Who are not currently taking opioid therapy, but have taken opioid therapy before True 4 (10.8) 3 (5.9) 6 (6.6) 17 (12.9) Falsem 31 (83.8) [68.0 - 93.8] 47 (92.2) [81.1 - 97.8] 83 (91.2) [83.4 - 96.1] 111 (84.1) [76.7 - 89.9] I don't know 2 (5.4) (2.0) 2 (2.2) 4 (3.0) 5c: Who have no known contraindications to the drug fentanyl, but are not currently taking around-the-clock opioid therapy True 4(10.8) 6(ll.8) l4(15.4) 21 (15.9) Falsem 31 (83.8) [68.0 - 93.8] 44 (86.3) [73.7 - 94.3] 73 (80.2) [70.6 - 87.8] 108 (81.8) [74.2 - 88.0] [don't know 2 (5.4) (2.0) 4 (4.4) 3 (2.3) Question 7: Please answer True, False, or I don't know for each statement based on the labeling for TIRF medicines. 7a: TIRF medicines are contraindicated in opioid non-tolerant patients because life-threatening respiratory depression could occur at any dose. Truem 36 (97.3) [85.8 - 99.9] 51 (100.0) [93.0 - 100.0] 79 (86.8) [78.1 - 93.0] 109 (82.6) [75.0 - 88.6] False 0 0 8 (8.8) 15(11.4) Data Source: ADPQ, ADTQ Program: TK RM S. SAS TRIG TIRF Pharmacist KAB Page 2 of4 05JAN2017 Table 6.1.3: Responses to Questions Linked to Key Risk Message #1 by Time Practicing as Pharmacist - Completed Surveys Time Practicing as Pharmacist Less than 3 years 3 to 5 years 6 to 15 years More than 15 years Question 95% cu'" 95% Cll'" 95% [95% [don't know 1 (2.7) 0 4 (4.4) 8 (6.1) 7b: Death has occurred in opioid non-tolerant patients treated with some fentanyl products. Truem 37 (100.0) [90.5 - 100.0] 51 (100.0) [93.0 - 100.0] 88 (96.7) [90.7 99.3] 121 (91.7) [85.6 95.8] False 0 0 0 3 (2.3) [don't know 0 0 3 (3.3) 8 (6.1) 7c: TIRF medicines may be used in opioid non-tolerant patients. True 3 (8.1) 0 6 (6.6) 19 (14.4) Falsem 33 (89.2) [74.6 - 97.0] 51 (100.0) [93.0 - 100.0] 81 (89.0) [80.7 - 94.6] 107 (81.1) [73.3 - 87.4] [don't know 1 (2.7) 0 4 (4.4) 6 (4.5) 7d: Prescribers starting a patient on a TIRF medicine must begin with titration/ram the lowest dose available/or that speci?c product, even if the patient has previously taken another TIRF medicine. Truem 29 (78.4) [61.8 - 90.2] 43 (84.3) [71.4 - 93.0] 82 (90.1) [82.1 95.4] 107 (81.1) [73.3 87.4] False 5 (13.5) 5 (9.8) 6 (6.6) 18 (13.6) [don?t know 3 (8.1) 3 (5.9) 3 (3.3) 7 (5.3) Question 11: Please select True, False, or 1 don't know for each of the following. According to the labeling for TIRF medicines, patients considered opioid-tolerant are those who are taking, for one week or longer, at least: I I a: 8 mg oral hydromorphone/day Truem 32 (86.5) [71.2 - 95.5] 37 (72.5) [58.3 - 84.1] 66 (72.5) [62.2 - 81.4] 96 (72.7) [64.3 - 80.1] Data Source: ADPQ, ADTQ Program: TK RM S. SAS TRIG TIRF Pharmacist KAB Page 3 of4 05JAN2017 Table 6.1.3: Responses to Questions Linked to Key Risk Message #1 by Time Practicing as Pharmacist - Completed Surveys Time Practicing as Pharmacist Less than 3 years 3 to 5 years 6 to 15 years More than 15 years (N=l32) Question [95% 11 [95% 11 [95% [95% False 2 (5.4) 7 (13.7) 9 (9.9) 19 (14.4) [don't know 3 (8.1) 7 (13.7) 16 (17.6) 17 (12.9) I lb: 60 mg oral morphine/day Truem 35 (94.6) [81.8 - 99.3] 41 (80.4) [66.9 - 902] 79 (86.8) [78.1 93.0] 119 (90.2) [83.7 94.7] False 0 5 (9.8) 3 (3.3) 4 (3.0) 1 don't know 2 (5.4) 5 (9.8) 9 (9.9) 9 (6.8) I I c: 30 mg oral oxycodone/day Truem 30 (81.1) [64.8 - 92.0] 36 (70.6) [56.2 - 82.5] 73 (80.2) [70.6 - 87.8] 102 (77.3) [69.2 - 84.1] False 5 (13.5) 7 (13.7) 6 (6.6) 19(14.4) I don't know 2 (5.4) 8 (15.7) 12 (13.2) 11 (8.3) I Id: 25 transdermalfentanyl/hour Truelz] 31 (83.8) [68.0 - 93.8] 42 (82.4) [69.1 - 91.6] 77 (84.6) [75.5 91.3] 96 (72.7) [64.3 - 80.1] False 3(8.1) 5 (9.8) 6 (6.6) 25 (18.9) 1 don't know 3(8.1) 4 (7.8) 8 (8.8) 11 (8.3) I 1e: 25 mg oral oxymorphone/day Truem 30 (81.1) [64.8 - 92.0] 35 (68.6) [54.1 - 80.9] 63 (69.2) [58.7 - 78.5] 97 (73.5) [65.1 - 80.8] False 4 (10.8) 4 (7.8) 7 (7.7) 14(10.6) 1 don't know 3 (8.1) 12 (23.5) 21 (23.1) 21 (15.9) Data Source: ADPQ, ADTQ Program: TK RM S. SAS TRIG TIRF Pharmacist KAB Page 4 of4 05JAN2017 Table 6.1.3: Responses to Questions Linked to Key Risk Message #1 by Time Practicing as Pharmacist - Completed Surveys Question Time Practicing as Pharmacist Less than 3 years [95% 3 to 5 years [95% 6 to 15 years [95% More than 15 years [95% C1[Ill f: An equianalgesic dose of another oral opioid Truem 28 (75.7) [58.8 - 88.2] 35 (68.6) [54.1 - 80.9] 57 (62.6) [51.9 72.6] 83 (62.9) [54.0 71.1] False 3 (8.1) 9 (17.6) 14 (15.4) 24 (18.2) 1 don't know 6 (16.2) 7 (13.7) 20 (22.0) 25 (18.9) Question 12: Please answer True, False, or I don't know for the following statement about TIRF medicines: TIRF medicines should only be taken by patients who are opioid tolerant. Truem 37 (100.0) [90.5 - 100.0] 50 (98.0) [89.6 - 100.0] 88 (96.7) [90.7 - 99.3] 122 (92.4) [86.5 - 96.3] False 0 1 (2.0) 2 (2.2) 9 (6.8) [don't know 0 0 1 (1.1) 1 (0.8) Source: Appendix B: Survey Tables, Table 6.1.3 ?195% exact two-sided con?dence intervals are calculated using the Clopper-Peatson method. Correct response. Data Source: ADPQ, ADTQ Program: TK RM S. SAS TRIG Page 1 of4 TIRF Pharmacist KAB 05JAN2017 Table 6.1.4: Responses to Questions Linked to Key Risk Message #1 by Number of Times Dispensing TIRF Medicines per Month Within the Last 6 Months - Completed Surveys Number of Times Dispensing TIRF Medicines per Month Within the Last 6 Months 1 - 2 times 3 - 5 times More than 5 times 1 don't None per month per month per month remember Question [95% [95% cu"l [95% [95% cu'? [95% Question 5: Please select True, False, or I don't know for each of the following. According to the labeling for TIRF medicines, patients with cancer who are considered opioid-tolerant are those: 5a: Who are taking around-the-clock opioid therapy for underlying, persistent cancer pain for one week or longer Truem 55 (91.7) [81.6 - 972] 142 (95.3) [90.6 - 98.1] 37 (97.4) [86.2 - 99.9] 46 (97.9) [88.7 - 99.9] 24 (100.0) [85.8 - 100.0] False 3 (5.0) 5 (3.4) (2.6) 1 (2.1) 0 [don't know 2 (3.3) 2 (1.3) 0 0 0 5b: Who are not currently taking opioid therapy, but have taken opioid therapy before True 5 (8.3) 12 (8.1) 6 (15.8) 5 (10.6) 2 (8.3) Falsem 53 (88.3) [77.4 - 95.2] 132 (88.6) [82.4 - 93.2] 30 (78.9) [62.7 - 90.4] 42 (89.4) [76.9 - 96.5] 21 (87.5) [67.6 - 97.3] I don't know 2 (3.3) 5 (3.4) 2 (5.3) 0 (4.2) 5c: Who have no known contraindications to the drug fentanyl, but are not currently taking around-the-clock opioid therapy True 7 (11.7) 22 (14.8) 7 (18.4) 9 (19.1) 1 (4.2) Falsem 50 (83.3) [71.5 - 91.7] 121 (81.2) [74.0 - 87.1] 30 (78.9) [62.7 - 90.4] 37 (78.7) [64.3 - 89.3] 23 (95.8) [78.9 - 99.9] [don't know 3 (5.0) 6 (4.0) (2.6) 1 (2.1) 0 Question 7: Please answer True, False, or I don't know for each statement based on the labeling for TIRF medicines. 7a: TIRF medicines are contraindicated in opioid non-tolerant patients because life-threatening respiratory depression could occur at any dose. Truem l3l(87.9) [81.6-92.7] 42 22 Data Source: ADPQ. ADTQ Program: TRIG TIRF Pharmacist KAB Page 2 of4 05JAN2017 Table 6.1.4: Responses to Questions Linked to Key Risk Message #1 by Number of Times Dispensing TIRF Medicines per Month Within the Last 6 Months - Completed Surveys Number of Times Dispensing TIRF Medicines per Month Within the Last 6 Months - 2 times 3 - 5 times More than 5 times 1 don't None per month per month per month remember (N=l49) Question [95% [95% cu"l [95% c1["I [95% 11 [95% False 3 (5.0) 12 (8.1) 5 (13.2) 3 (6.4) 0 [don't know 1 (1.7) 6 (4.0) 3 (7.9) 2 (4.3) 2 (8.3) 7b: Death has occurred in opioid non-tolerant patients treated with some fentanyl products. Truem 57 (95.0) [86.1 - 99.0] 142 (95.3) [90.6 - 98.1] 37 (97.4) [86.2 - 99.9] 45 (95.7) [85.5 - 99.5] 22 (91.7) [73.0 - 99.0] False 0 3 (2.0) 0 0 0 I don't know 3 (5.0) 4 (2.7) (2.6) 2 (4.3) 2 (8.3) 7c: TIRF medicines may be used in opioid non-tolerant patients. True 2 (3.3) 16 (10.7) 4 (10.5) 6 (12.8) 0 Falsem 56 (93.3) [83.8 982] 128 (85.9) [79.3 - 91.1] 33 (86.8) [71.9 95.6] 39 (83.0) [69.2 - 92.4] 22 (91.7) [73.0 - 99.0] [don't know 2 (3.3) 5 (3.4) 1 (2.6) 2 (4.3) 2 (8.3) 7d: Prescribers starting a patient on a TIRF medicine must begin with titration from the lowest dose available for that specific product, even if the patient has previously taken another TIRF medicine. Truem 48 (80.0) [67.7 - 892] 131 (87.9) [81.6 - 92.7] 33 (86.8) [71.9 - 95.6] 38 (80.9) [66.7 - 90.9] 17 (70.8) [48.9 - 87.4] False 8 (13.3) 12 (8.1) 4 (10.5) 7 (14.9) 3 (12.5) [don't know 4 (6.7) 6 (4.0) 1 (2.6) 2 (4.3) 4 (16.7) Question 11: Please select True, False, or 1 don't know for each of the following. According to the labeling for TIRF medicines, patients considered opioid-tolerant are those who are taking, for one week or longer, at least: Data Source: ADPQ, ADTQ Program: TK RM S. SAS TRIG TIRF Pharmacist KAB Page 3 of4 05JAN2017 Table 6.1.4: Responses to Questions Linked to Key Risk Message #1 by Number of Times Dispensing TIRF Medicines per Month Within the Last 6 Months - Completed Surveys Question Number of Times Dispensing TIRF Medicines per Month Within the Last 6 Months None [95% 1 - 2 times per month (N=l49) [95% 3 - 5 times per month [95% More than 5 times per month [95% I don't remember [95% I I a: 8 mg oral hydromorphone/day Truem 48 (80.0) [67.7 - 892] 110 (73.8) [66.0 - 80.7] 26 (68.4) [51.3 - 82.5] 38 (80.9) [66.7 - 90.9] 15 (62.5) [40.6 - 81.2] False 3 (5.0) 18 (12.1) 6 (15.8) 7 (14.9) 4 (16.7) ldon?t know 9 (15.0) 21 (14.1) 6 (15.8) 2 (4.3) 5 (20.8) I lb: 60 mg oral morphine/day Truem 50 (83.3) [71.5 - 91.7] 129 (86.6) [80.0 - 91.6] 36 (94.7) [82.3 - 99.4] 44 (93.6) [82.5 - 98.7] 21 (87.5) [67.6 - 97.3] False 2 (3.3) 7 (4.7) 2 (5.3) 2 (4.3) 0 [don't know 8 (13.3) 13 (8.7) 0 1 (2.1) 3 (12.5) I I c: 30 mg oral oxycodone/day Truem 43 (71.7) [58.6 - 82.5] 115 (77.2) [69.6 - 83.7] 34 (89.5) [75.2 - 97.1] 39 (83.0) [69.2 - 92.4] 16 (66.7) [44.7 - 84.4] False 7 (11.7) 19 (12.8) 2 (5.3) 6 (12.8) 3 (12.5) [don't know 10 (16.7) 15 (10.1) 2 (5.3) 2 (4.3) 5 (20.8) I Id: 25 transdermalfentanyVhour Truem 44 (73.3) [60.3 - 83.9] 116 (77.9) [70.3 - 84.2] 33 (86.8) [71.9 - 95.6] 42 (89.4) [76.9 - 96.5] 18 (75.0) [53.3 - 90.2] False 7 (11.7) 23 (15.4) 3 (7.9) 3 (6.4) 3 (12.5) [don't know 9 (15.0) 10 (6.7) 2 (5.3) 2 (4.3) 3 (12.5) Data Source: ADPQ. ADTQ Program: TK RM S. SAS TRIG TIRF Pharmacist KAB Page 4 of4 05JAN2017 Table 6.1.4: Responses to Questions Linked to Key Risk Message #1 by Number of Times Dispensing TIRF Medicines per Month Within the Last 6 Months - Completed Surveys Question Number of Times Dispensing TIRF Medicines per Month Within the Last 6 Months None [95% - 2 times per month (N=l49) [95% 3 - 5 times per month [95% More than 5 times per month [95% I don't remember [95% I I e: 25 mg oral oxymorpll one/da Truem 38 (63.3) [49.9 - 75.4] 108 (72.5) [64.6 - 79.5] 30 (78.9) [62.7 - 90.4] 38 (80.9) [66.7 - 90.9] 15 (62.5) [40.6 81.2] False 4 (6.7) 17 (11.4) 5 (13.2) 3 (6.4) 1 (4.2) [don't know 18 (30.0) 24 (16.1) 3 (7.9) 6 (12.8) 8 (33.3) I If: An equianalgesic dose of another oral opioid Truem 38 (63.3) [49.9 - 75.4] 95 (63.8) [55.5 - 71.5] 25 (65.8) [48.6 - 80.4] 36 (76.6) [62.0 - 87.7] 13 (54.2) [32.8 - 74.4] False 7 (11.7) 20 (13.4) 7 (18.4) 9 (19.1) 8 (33.3) [don't know 15 (25.0) 34 (22.8) 6 (15.8) 2 (4.3) 3 (12.5) Question 12: Please answer True, False, or I don't know for the following statement about TIRF medicines: TIRF medicines should only be taken by patients who are opioid tolerant. Truem 57 (95.0) [86.1 - 99.0] 141 (94.6) [89.7 - 97.7] 37 (97.4) [86.2 - 99.9] 46 (97.9) [88.7 - 99.9] 23 (95.8) [78.9 - 99.9] False 2 (3.3) 7 (4.7) 1 (2.6) (2.1) 1 (4.2) [don't know 1 (1.7) 1 (0.7) 0 0 0 Source: Appendix B: Survey Tables, Table 6.1.4 ?195% exact two-sided confidence intervals are calculated using the Clopper-Pearson method. Correct response. Data Source: ADPQ, ADTQ Program: TK RM S. SAS TRIG Page 1 of 1 TIRF Pharmacist KAB 05JAN2017 Table 6.2: Secondary Analysis of Responses to Questions Linked to Key Risk Message #1 - Completed Surveys Pharmacists (N=3l8) Correct Responses 0 correct responses 0 1 correct response 1 (0.3) 2 correct responses 1 (0.3) 3 correct responses 0 4 correct responses 2 (0.6) 5 correct responses 3 (0.9) 6 correct responses 4 (1.3) 7 correct responses 6 (1.9) 8 correct responses 25 (7.9) 9 correct responses 13 (4.1) 10 correct responses 31 (9.7) 11 correct responses 33 (10.4) 12 correct responses 38 (l 1.9) 13 correct responses 63 (19.8) 14 correct responses 98 (30.8) Source: Appendix B: Survey Tables, Table 6.2 Data Source: ADPQ, ADTQ Program: ?nals? TRIG TIRF Pharmacist KAB Page 1 of2 05JAN2017 Completed Surveys Table 7.1: Primary Analysis of Responses to Questions Linked to Key Risk Message #2 - Question Pharmacists [95% cum medicines. Question 6: Please answer True, False, or I don't know for each statement based on the labeling for TIRF opioid at the same time. 6a: According to the product labeling, a cancer patient may start a TIRF medicine and an around-the-clock True 82 (25.8) Falsem 197 (61.9) [56.4 - 67.3] 1 don't know 39 (12.3) 6b: According to the product labeling, a cancer patient who has been on an around-the-clock opioid for I day may start taking a TIRF medicine for breakthrough pain. True 34 (10.7) Falsem 256 (80.5) [75.7 - 84.7] 1 don't know 28 (8.8) 6c: A patient must stop taking their TIRF medicine if they stop taking their around-the-clock opioid pain medicine. Truem 131 (41.2) [35.7 - 46.8] False 151 (47.5) ldon't know 36 (11.3) option. Question 9: Per the approved labeling for TIRF medicines, for which of the following indications can TIRF medicines be prescribed to opioid tolerant patients? Please answer Yes, No, or I don't know for each 9a: Acute or postoperative pain Yes 35 (1 1.0) New 273 (85.8) [81.5 89.5] 1 don't know 10 (3.1) 9b: Headache or migraine pain Yes 7 (2.2) Now 300 (94.3) [91.2 - 96.6] 1 don't know 11 (3.5) 9c: Dental pain Yes 2 (0.6) Data Source: ADPQ, ADTQ Program: TRIG Page 2 of 2 TIRF Pharmacist KAB 05JAN2017 Table 7.1: Primary Analysis of Responses to Questions Linked to Key Risk Message #2 - Completed Surveys Pharmacists Question [95% Cl Ill 306 (96.2) [93.5 - 98.0] 1 don't know 10 (3.1) 9d: Breakthrough pain from cancer Yesm 292 (91.8) [88.2 - 94.6] No 22 (6.9) 1 don't know 4 (1.3) 9e: Chronic non-cancer pain Yes 138 (43.4) Now 162 (50.9) [45.3 - 56.6] 1 don't know 18 (5.7) Source: Appendix B: Survey Tables, Table 7.1 95% exact two-sided con?dence intervals are calculated using the Clopper-Pearson method. Correct response. Data Source: ADPQ, ADTQ Program: TKRM.SAS TIRF Pharmacist KAB Page 1 of2 05JAN2017 Table 7.1.1: Responses to Questions Linked to Key Risk Message #2 by Reading Full Prescribing Information or Medication Guide - Completed Surveys Question Reading Full Prescribing Information or Medication Guide Received and read Pl or Med Guide [95% Did not receive or read Pl or Med Guide [95% medicines. Question 6: Please answer True, False, or I don't know for each statement based on the labeling for TIRF opioid at the same time. 6a: According to the product labeling, a cancer patient may start a TIRF medicine and an around-the-clock True 73 (26.2) 9 (23.1) Falsem 175 (62.7) [56.8 - 68.4] 22 (56.4) [39.6 - 722] [don't know 31 (11.1) 8 (20.5) 6b: According to the product labeling, a cancer patient who has been on an around-the-clock opioid for I day may start taking a TIRF medicine for breakthrough pain. True 31(ll.l) 3(7.7) Falsem 230 (82.4) [77.5 - 86.7] 26 (66.7) [49.8 - 80.9] [don't know 18 (6.5) 10 (25.6) be: A patient must stop taking their TIRF medicine if they stop taking their around-the-clock opioid pain medicine. Truem 118 (42.3) [36.4 - 48.3] 13 (33.3) [19.1 - 502] False 134 (48.0) 17 (43.6) I don't know 27 (9.7) 9 (23.1) Question 9: Per the approved labeling for TIRF medicines, for which of the following indications can TIRF medicines be prescribed to opioid tolerant patients? Please answer Yes, No, or I don't know for each option. 9a: A cute or postoperative pain Yes 29 (10.4) 6 (15.4) Now 244 (87.5) [83.0 - 91.1] 29 (74.4) [57.9 - 87.0] 1 don't know 6 (22) 4 (10.3) 9b: Headache or migraine pain Yes 6 (22) 1 (2.6) Now 267 (95.7) [92.6 - 97.8] 33 (84.6) [69.5 - 94.1] I don't know 6 (22) 5 (12.8) 9c: Dental pain Data Source: ADPQ, ADTQ Program: TK RM S. SAS TRIG TIRF Pharmacist KAB Page 2 of 2 05JAN 2017 Table 7.1.1: Responses to Questions Linked to Key Risk Message #2 by Reading Full Prescribing Information or Medication Guide - Completed Surveys Reading Full Prescribing Information or Medication Guide Received and read Did not receive or read Pl or Med Guide Pl or Med Guide Question [95% cull" [95% all" Yes 2 (0.7) 0 Now 272 (97.5) [94.9 - 99.0] 34 (87.2) [72.6 - 95.7] [don't know 5 (1.8) 5 (12.8) 9d: Breakthrough pain from cancer Yesm 258 (92.5) [88.7 - 95.3] 34 (87.2) [72.6 - 95.7] No 19 (6.8) 3 (7.7) 1 don't know 2 (0.7) 2 (5.1) 9e: Chronic non-cancer pain Yes 117 (41.9) 21 (53.8) Now 150 (53.8) [47.7 59.7] 12 (30.8) [17.0 47.6] [don?t know 12 (4.3) 6 (15.4) Source: Appendix B: Survey Tables, Table 7.1.1 ?195% exact two-sided confidence intervals are calculated using the Clopper-Pearson method. Correct response. Data Source: ADPQ, ADTQ Program: TK RM S. SAS TRIG TIRF Pharmacist KAB Page 1 of2 05JAN2017 Table 7.1.2: Responses to Questions Linked to Key Risk Message #2 by Modality to Complete Survey - Completed Surveys Question Modality to Complete Survey Internet (N=3l 4) [95% Telephone [95% medicines. Question 6: Please answer True, alse, or I don't know for each statement based on the labeling for TIRF opioid at the same time. 6a: According to the product labeling, a cancer patient may start a TIRF medicine and an around-the-clock True 80 (25.5) 2 (50.0) Falsem 196 (62.4) [56.8 - 67.8] 1 (25.0) [0.6 - 80.6] 1 don't know 38 (12.1) 1 (25.0) 6b: According to the product labeling, a cancer patient who has been on an around-the-clock opioid for I day may start taking a TIRF medicine for breakthrough pain. True 32 (10.2) 2 (50.0) Falsem 254 (80.9) [76.1 - 85.1] 2 (50.0) [6.8 - 93.2] I don't know 28 (8.9) 0 6c: A patient must stop taking their TIRF medicine if they stop taking their around-the-clock opioid pain medicine. Truem 130 (41.4) [35.9 - 47.1] 1 (25.0) [0.6 - 80.6] False 149 (47.5) 2 (50.0) [don't know 35 (11.1) 1 (25.0) Question 9: Per the approved labeling for TIRF medicines, for which of the following indications can TIRF medicines be prescribed to opioid tolerant patients? Please answer Yes, No, or I don't know for each option. 9a: A cute or postoperative pain Yes 33 (10.5) 2 (50.0) Now 272 (86.6) [82.4 - 90.2] 1 (25.0) [0.6 - 80.6] 1 don't know 9 (2.9) 1 (25.0) 9b: Headache or migraine pain Yes 5 (1.6) 2 (50.0) New 298 (94.9) [91.9 - 97.1] 2 (50.0) [6.8 - 93.2] [don't know 11 (3.5) 0 9c: Dental pain Yes 1 (0.3) 1 (25.0) Data Source: ADPQ, ADTQ Program: TK RM S. SAS TRIG TIRF Pharmacist KAB Page 2 of 2 05JAN 2017 Survey - Completed Surveys Table 7.1.2: Responses to Questions Linked to Key Risk Message #2 by Modality to Complete Modality to Complete Survey Internet Telephone (N=3l4) Question 195% Cll'? 195% Now 304 (96.8) [94.2 98.5] 2 (50.0) [6.8 - 93.2] 1 don?t know 9 (2.9) 1 (25.0) 9d: Breakthrough pain from cancer Yesp] 290 (92.4) [88.8 - 95.0] 2 (50.0) [6.8 - 93.2] No 21 (6.7) I (25.0) [don't know 3 (1.0) I (25.0) 9e: Chronic non-cancer pain Yes 136 (43.3) 2 (50.0) Now 161 (51.3) [45.6 - 56.9] 1 (25.0) [0.6 - 80.6] [don't know 17 (5.4) 1 (25.0) Source: Appendix B: Survey Tables, Table 7.1.2 ?195% exact two-sided con?dence intervals are calculated using the Clopper-Pearson method. Correct response. Data Source: ADPQ, ADTQ Program: TK RM S. SAS TRIG TIRF Pharmacist KAB Page 1 of3 05JAN2017 Table 7.1.3: Responses to Questions Linked to Key Risk Message #2 by Time Practicing as Pharmacist - Completed Surveys Question Time Practicing as Pharmacist Less than 3 years [95% 3 to 5 years [95% cu'" 6 to 15 years [95% More than 15 years (N=l32) [95% Question 6: Please answer True, False, or 1 don't know for each statement based on the labeling for TIRF medicines. 6a: According to the product labeling, a cancer patient may start a TIR medicine and an around-the-clock opioid at the same time. True 7 (18.9) 7 (13.7) 26 (28.6) 41 (31.1) Falsem 23 (62.2) [44.8 - 77.5] 36 (70.6) [56.2 - 82.5] 61 (67.0) [56.4 - 76.5] 74 (56.1) [47.2 - 64.7] [don't know 7 (18.9) 8 (15.7) 4 (4.4) 17 (12.9) 6b: According to the product labeling, a cancer patient who has been on an around-the-clock opioid for I day may Stan taking a TIRF medicine for breakthrough pain. True 4 (10.8) 5 (9.8) 10 (1 1.0) 14 (10.6) Falsem 29 (78.4) [61.8 - 90.2] 42 (82.4) [69.1 - 91.6] 75 (82.4) [73.0 - 89.6] 106 (80.3) [72.5 - 86.7] I don't know 4 (10.8) 4 (7.8) 6 (6.6) 12 (9.1) 6c: A patient must stop taking their TIRF medicine if they stop taking their around-the-clock opioid pain medicine. Truem 21 (56.8) [39.5 - 72.9] 25 (49.0) [34.8 - 63.4] 45 (49.5) [38.8 - 60.1] 37 (28.0) [20.6 - 36.5] False 13 (35.1) 23 (45.1) 38 (41.8) 74 (56.1) [don't know 3 (8.1) 3 (5.9) 8 (8.8) 21 (15.9) Question 9: Per the approved labeling for TIRF medicines, for which of the following indications can TIRF medicines be prescribed to opioid tolerant patients? Please answer Yes, No, or I don't know for each option. 9a: A cute or postoperative pain Yes 4 (10.8) 5 (9.8) 8 (8.8) 18(13.6) Data Source: ADPQ. ADTQ Program: TK RM S. SAS TRIG Page 2 of3 TIRF Pharmacist KAB 05JAN2017 Table 7.1.3: Responses to Questions Linked to Key Risk Message #2 by Time Practicing as Pharmacist - Completed Surveys Time Practicing as Pharmacist Less than 3 years 3 to 5 years 6 to 15 years More than 15 years (N=l32) Question [95% 11 95% Cll'" 95% Cll'" [95% New 30 (81.1) [64.8 - 92.0] 46 (90.2) [78.6 - 96.7] 79 (86.8) [78.1 93.0] 111 (84.1) [76.7 89.9] 1 don't know 3 (8.1) 0 4 (4.4) 3 (2.3) 9b: Headache 0r migraine pain Yes 0 0 4 (4.4) 3 (2.3) Now 36 (97.3) [85.8 - 99.9] 48 (94.1) [83.8 - 98.8] 83 (91.2) [83.4 - 96.1] 126 (95.5) [90.4 - 98.3] 1 don't know 1 (2.7) 3 (5.9) 4 (4.4) 3 (2.3) 9c: Dental pain Yes 0 0 0 2 (1.5) Now 35 (94.6) [81.8 - 99.3] 51 (100.0) [93.0 - 100.0] 85 (93.4) [86.2 - 97.5] 128 (97.0) [92.4 - 99.2] 1 don't know 2 (5.4) 0 6 (6.6) 2 (1.5) 9d: Breakthrough pain from cancer Yesm 35 (94.6) [81.8 - 99.3] 44 (86.3) [73.7 - 94.3] 87 (95.6) [89.1 98.8] 119 (90.2) [83.7 94.7] No 2 (5.4) 6 (11.8) 3 (3.3) 11 (8.3) [don't know 0 1 (2.0) 1 (1.1) 2 (1.5) 9e: Chronic non-cancer pain Yes 17 (45.9) 19 (37.3) 40 (44.0) 59 (44.7) 18 (48.6) [31.9 - 65.6] 27 (52.9) [38.5 - 67.1] 44 (48.4) [37.7 - 59.1] 69 (52.3) [43.4 - 61.0] Data Source: ADPQ. ADTQ Program: TK RM S. SAS TRIG Page 3 of 3 TIRF Pharmacist KAB 05JAN2017 Table 7.1.3: Responses to Questions Linked to Key Risk Message #2 by Time Practicing as Pharmacist - Completed Surveys Time Practicing as Pharmacist Less than 3 years 3 to 5 years 6 to 15 years More than 15 years (N=l32) Question 95% cu'" 95% Cll'" 95% 95% I don't know 2 (5.4) 5 (9.8) 7 (7.7) 4 (3.0) Source: Appendix B: Survey Tables, Table 7.1.3 ?195% exact two-sided con?dence intervals are calculated using the Clopper-Pearson method. Correct response. Data Source: ADPQ, ADTQ Program: TRIG Page 1 of3 TIRF Pharmacist KAB 05JAN2017 Table 7.1.4: Responses to Questions Linked to Key Risk Message #2 by Number of Times Dispensing TIRF Medicines per Month Within the Last 6 Months - Completed Surveys Number of Times Dispensing TIRF Medicines per Month Within the Last 6 Months 1 - 2 times 3 - 5 times More than 5 times I don't None per month per month per month remember Question 11 [95% [95% C1["l [95% 11 [95% 11 [95% cu"I Question 6: Please answer True, False, or I don't know for each statement based on the labeling for TIRF medicines. 6a: According to the product labeling, a cancer patient may start a TIR medicine and an around-the-clock opioid at the same time. True 13 (21.7) 32 (21.5) 12 (31.6) 16 (34.0) 9 (37.5) Falsem 39 (65.0) [51.6 - 76.9] 96 (64.4) [56.2 - 72.1] 24 (63.2) [46.0 - 78.2] 28 (59.6) [44.3 - 73.6] 10 (41.7) [22.1 - 63.4] [don?t know 8 (13.3) 21 (14.1) 2 (5.3) 3 (6.4) 5 (20.8) 6b: According to the product labeling, a cancer patient who has been on an around-the-clock opioid for I day may start taking a TIRF medicine for breakthrough pain. True 7(11.7) 18(12.1) 4(10.5) 2(4.3) 3(12.5) Falsem 48 (80.0) [67.7 - 89.2] 115 (77.2) [69.6 - 83.7] 31 (81.6) [65.7 - 92.3] 44 (93.6) [82.5 - 98.7] 18 (75.0) [53.3 - 90.2] [don't know 5 (8.3) 16 (10.7) 3 (7.9) (2.1) 3 (12.5) 6c: A patient must stop taking their TIRF medicine if they stop taking their around-the-clock opioid pain medicine. Truem 26 (43.3) [30.6 - 56.8] 65 (43.6) [35.5 - 52.0] 14 (36.8) [21.8 - 54.0] 18 (38.3) [24.5 - 53.6] 8 (33.3) [15.6 - 55.3] False 26 (43.3) 67 (45.0) 21 (55.3) 25 (53.2) 12 (50.0) [don't know 8 (13.3) 17 (11.4) 3 (7.9) 4 (8.5) 4 (16.7) Question 9: Per the approved labeling for TIRF medicines, for which of the following indications can TIRF medicines be prescribed to opioid tolerant patients? Please answer Yes, No, or I don't know for each option. 9a: A cute or postoperative pain Data Source: ADPQ, ADTQ Program: TRIG TIRF Pharmacist KAB Page 2 of3 05JAN2017 Table 7.1.4: Responses to Questions Linked to Key Risk Message #2 by Number of Times Dispensing TIRF Medicines per Month Within the Last 6 Months - Completed Surveys Number of Times Dispensing TIRF Medicines per Month Within the Last 6 Months 1 - 2 times 3 - 5 times More than 5 times I don't None per month per month per month remember (N=l49) Question [95% [95% cu"I [95% [95% 11 [95% Yes 11 (18.3) 12 (8.1) 3 (7.9) 6 (12.8) 3 (12.5) Now 47 (78.3) [65.8 - 87.9] 131 (87.9) [81.6 - 92.7] 34 (89.5) [75.2 - 97.1] 41 (87.2) [74.3 - 95.2] 20 (83.3) [62.6 - 95.3] [don't know 2 (3.3) 6 (4.0) (2.6) 0 (4.2) 9b: Headache 0r migraine pain Yes 0 3 (2.0) 3 (7.9) (2.1) 0 Now 56 (93.3) [83.8 - 982] 142 (95.3) [90.6 - 98.1] 35 (92.1) [78.6 - 98.3] 44 (93.6) [82.5 - 98.7] 23 (95.8) [78.9 - 99.9] [don't know 4 (6.7) 4 (2.7) 0 2 (4.3) (4.2) 9c: Dental pain Yes 0 0 (2.6) 1 (2.1) 0 Now 56 (93.3) [83.8 - 982] 145 (97.3) [93.3 - 99.3] 36 (94.7) [82.3 - 99.4] 46 (97.9) [88.7 - 99.9] 23 (95.8) [78.9 - 99.9] [don't know 4 (6.7) 4 (2.7) (2.6) 0 (4.2) 9d: Breakthrough pain from cancer Yesm 53 (88.3) [77.4 - 952] 140 (94.0) [88.8 - 97.2] 35 (92.1) [78.6 - 98.3] 41 (87.2) [74.3 - 95.2] 23 (95.8) [78.9 - 99.9] No 6 (10.0) 7 (4.7) 3 (7.9) 5 (10.6) 1 (4.2) ldon'tknow (1.7) 2 (1.3) 0 (2.1) 0 9e: Chronic non-cancer pain Data Source: ADPQ, ADTQ Program: TK RM S. SAS TRIG TIRF Pharmacist KAB Page 3 of3 05JAN2017 Table 7.1.4: Responses to Questions Linked to Key Risk Message #2 by Number of Times Dispensing TIRF Medicines per Month Within the Last 6 Months - Completed Surveys Number of Times Dispensing TIRF Medicines per Month Within the Last 6 Months - 2 times 3 - 5 times More than 5 times I don't None per month per month per month remember (N=l49) Question [95% [95% [95% C1[Ill [95% [95% cu"I Yes 20 (33.3) 67 (45.0) 21 (55.3) 18 (38.3) 12 (50.0) Now 33 (55.0) [41.6 - 67.9] 75 (50.3) [42.0 - 58.6] 16 (42.1) [26.3 - 59.2] 29 (61.7) [46.4 - 75.5] 9 (37.5) [18.8 59.4] [don't know 7 (11.7) 7 (4.7) 1 (2.6) 0 3 (12.5) Source: Appendix B: Survey Tables, Table 7.1.4 95% exact two-sided confidence intervals are calculated using the lopper-Pearson method. Correct response. Data Source: ADPQ, ADTQ Program: TK RM S. SAS TRIG TIRF Pharmacist KAB Page 1 of] 05JAN2017 Completed Surveys Table 7.2: Secondary Analysis of Responses to Questions Linked to Key Risk Message #2 - Pharmacists (N=3l8) Correct Responses 0 correct responses 1 (0.3) 1 correct response 3 (0.9) 2 correct responses 6 (1.9) 3 correct responses 8 (2.5) 4 correct responses 38 (l 1.9) 5 correct responses 54 (17.0) 6 correct responses 71 (22.3) 7 correct responses 66 (20.8) 8 correct responses 71 (22.3) Source: Appendix B: Survey Tables, Table 7.2 Data Source: ADPQ. ADTQ Program: TRIG Page 1 of2 TIRF Pharmacist KAB 05JAN2017 Table 8.1: Primary Analysis of Responses to Questions Linked to Key Risk Message #3 - Completed Surveys Pharmacists Question [95% medicines. Question 7: Please answer True, False, or I don't know for each statement based on the labeling for TIRF 7e: It is important to monitor for signs of abuse and addiction in patients who take TIRF medicines. True 312 (98.1) [95.9 - 99.3] False 4 (1.3) 1 don't know 2 (0.6) know for each option. Question 8: Which of the following are risk factors for opioid abuse? Please answer Yes, 0, or I don't 8a: A personal history of illness Yesm 247 (77.7) [72.7 - 82.1] No 42 (13.2) 1 don't know 29 (9.1) alcohol abuse 8b: A personal history of past or current alcohol or drug abuse, or a family history of illicit drug use or Yesm 314 (98.7) [96.8 - 99.7] No 1 (0.3) 1 don't know 3 (0.9) medicines. Question 10: Please answer True, False, or I don't know for each statement based on the labeling for TIRF 10a: medicines can be abused in a manner similar to other opioid agonists. Truem 298 (93.7) [90.5 - 96.1] False 12 (3.8) I don't know 8 (2.5) True, False, or I don't know for the following statements. Question 13: Which of the following risks are associated with the use of TIRF medicines? Please answer l3a: Misuse Truem 314 (98.7) [96.8 - 99.7] False 3 (0.9) 1 don't know 1 (0.3) 13b: A buse Data Source: ADPQ, ADTQ Program: TRIG Page 2 of 2 TIRF Pharmacist KAB 05JAN2017 Table 8.1: Primary Analysis of Responses to Questions Linked to Key Risk Message #3 - Completed Surveys Pharmacists Question 95% Cl Ill Truem 315 (99.1) [97.3 - 99.8] False 2 (0.6) 1 don't know 1 (0.3) 13c: Addiction Truem 314 (98.7) [96.8 - 99.7] False 3 (0.9) 1 don't know 1 (0.3) 13d: Overdose Truem 316 (99.4) [97.7 - 99.9] False (0.3) 1 don't know 1 (0.3) I 3e: Hypothyroidism True 10 (3.1) Falsem 267 (84.0) [79.5 - 87.8] I don't know 41 (12.9) 13]? Infection True 15 (4.7) Falsem 284 (89.3) [85.4 - 92.5] 1 don't know 19 (6.0) Source: Appendix B: Survey Tables, Table 8.1 95% exact two-sided con?dence intervals are calculated using the Clopper-Pearson method. Correct response. Data Source: ADPQ. ADTQ Program: TRIG TIRF Pharmacist KAB Page 1 of2 05JAN2017 Table 8.1.1: Responses to Questions Linked to Key Risk Message #3 by Reading Full Prescribing Information or Medication Guide - Completed Surveys Question Reading Full Prescribing Information or Medication Guide Received and read Pl or Med Guide [95% Did not receive or read Pl or Med Guide [95% Question 7: Please answer True, False, or I don't know for each statement based on the labeling for TIRF medicines. 7e: It is important to monitor for signs of abuse and addiction in patients who take TIRF medicines. Truem 274 (98.2) [95.9 - 99.4] 38 (97.4) [86.5 99.9] False 3 (1.1) 1 (2.6) I don't know 2 (0.7) 0 Question 8: Which of the following are risk factors for opioid abuse? Please answer Yes, No, or I don't know for each option. 8a: A personal history of illness Yesm 219 (78.5) [73.2 - 83.2] 28 (71.8) [55.1 - 85.0] No 38(13.6) 4(10.3) I don't know 22 (7.9) 7 (17.9) 8b: A personal history of past or current alcohol or drug abuse, or a family history of illicit drug use or alcohol abuse Yesm 276 (98.9) [96.9 - 99.8] 38 (97.4) [86.5 - 99.9] No (0.4) 0 [don't know 2 (0.7) (2.6) Question 10: Please answer True, False, or I don't know for each statement based on the labeling for TIRF medicines. I 0a: TIRF medicines can be abused in a manner similar to other opioid agonists. Truem 264 (94.6) [91.3 - 97.0] 34 (87.2) [72.6 - 95.7] False 9 (32) 3 (7.7) [don't know 6 (22) 2 (5.1) Question 13: Which of the following risks are associated with the use of TIRF medicines? Please answer True, False, or I don't know for the following statements. 13a: Misuse Truem 277 (99.3) [97.4 99.9] 37 (94.9) [82.7 - 99.4] False 2 (0.7) 1 (2.6) Data Source: ADPQ, ADTQ Program: TK S. SAS TRIG Page 2 of 2 TIRF Pharmacist KAB 05JAN2017 Table 8.1.1: Responses to Questions Linked to Key Risk Message #3 by Reading Full Prescribing Information or Medication Guide - Completed Surveys Reading Full Prescribing Information or Medication Guide Received and read Did not receive or read Pl or Med Guide Pl or Med Guide Question [95% Cll'" [95% all" [don't know 0 (2.6) 13b: Abuse Truem 278 (99.6) [98.0 - 100.0] 37 (94.9) [82.7 - 99.4] False (0.4) (2.6) [don?t know 0 (2.6) 13c: Addiction Truem 278 (99.6) [98.0 - 100.0] 36 (92.3) [79.1 - 98.4] False (0.4) 2 (5.1) [don't know 0 (2.6) 13d: Overdose Truem 279 (100.0) [98.7 100.0] 37 (94.9) [82.7 99.4] False 0 (2.6) [don't know 0 (2.6) Be: Hypothyroidism True 8 (2.9) 2 (5.1) Falsem 238 (85.3) [80.6 - 89.2] 29 (74.4) [57.9 - 87.0] I don't know 33 (11.8) 8 (20.5) 13f: Infection True 15 (5.4) 0 Falsem 250 (89.6) [85.4 - 92.9] 34 (87.2) [72.6 - 95.7] [don't know 14 (5.0) 5 (12.8) Source: Appendix B: Survey Tables, Table 8.1.1 ?195% exact two-sided confidence intervals are calculated using the Clopper-Pearson method. Correct response. Data Source: ADPQ. ADTQ Program: TRIG TIRF Pharmacist KAB Page 1 of2 05JAN2017 Table 8.1.2: Responses to Questions Linked to Key Risk Message #3 by Modality to Complete Survey - Completed Surveys Question Modality to Complete Survey Internet (N=3l4) [95% cu"I Telephone [95% Question 7: Please answer True, False, or I don't know for each statement based on the labeling for TIRF medicines. 7e: It is important to monitor for signs of abuse and addiction in patients who take TIRF medicines. True 308 (98.1) [95.9 - 99.3] 4 (100.0) [39.8 - 100.0] False 4 (1.3) 0 1 don't know 2 (0.6) 0 Question 8: Which of the following are risk factors for opioid abuse? Please answer Yes, No, or I don't know for each option. 8a: A personal history of illness Yesm 245 (78.0) [73.0 - 82.5] 2 (50.0) [6.8 93.2] No 41 (13.1) 1 (25.0) [don't know 28 (8.9) 1 (25.0) 8b: A personal history of past or current alcohol or drug abuse, or a family history of illicit drug use or alcohol abuse Yesm 311 (99.0) [97.2 - 99.8] 3 (75.0) [19.4 - 99.4] No (0.3) 0 1 don't know 2 (0.6) 1 (25.0) Question 10: Please answer True, False, or I don't know for each statement based on the labeling for TIRF medicines. I 0a: TIRF medicines can be abused in a manner similar to other opioid agonists. Truem 294 (93.6) [90.3 - 96.1] 4 (100.0) [39.8 - 100.0] False 12 (3.8) 0 I don't know 8 (2.5) 0 Question 13: Which of the following risks are associated with the use of TIRF medicines? Please answer True, False, or I don't know for the following statements. 13a: Misuse Truem 311 (99.0) [97.2 - 99.8] 3 (75.0) [19.4 - 99.4] False 2 (0.6) 1 (25.0) [don't know 1 (0.3) 0 Data Source: ADPQ, ADTQ Program: TK RM S. SAS TRIG TIRF Pharmacist KAB Page 2 of 2 05JAN 2017 Table 8.1.2: Responses to Questions Linked to Key Risk Message #3 by Modality to Complete Survey - Completed Surveys Modality to Complete Survey Internet Telephone (N=3l4) Question [95% Cll'" [95% cu'" 13b: Abuse Truem 312 (99.4) [97.7 - 99.9] 3 (75.0) [19.4 - 99.4] False 1 (0.3) 1 (25.0) I don't know 1 (0.3) 0 I 3 c: A ddiction Truem 310 (98.7) [96.8 - 99.7] 4 (100.0) [39.8 - 100.0] False 3 (1.0) 0 [don't know 1 (0.3) 0 13d: Overdose Truem 312 (99.4) [97.7 - 99.9] 4 (100.0) [39.8 - 100.0] False (0.3) 0 [don?t know 1 (0.3) 0 Be: ypothyroidism True 9 (2.9) 1 (25.0) Falsem 265 (84.4) [79.9 - 88.2] 2 (50.0) [6.8 - 93.2] 1 don't know 40 (12.7) 1 (25.0) 13f: Infection True 13 (4.1) 2 (50.0) Falsem 282 (89.8) [85.9 92.9] 2 (50.0) [6.8 - 93.2] [don't know 19 (6.1) 0 Source: Appendix B: Survey Tables, Table 8.1.2 ?195% exact two-sided confidence intervals are calculated using the Clopper-Pearson method. Correct response. Data Source: ADPQ, ADTQ Program: TK RM S. SAS TRIG TIRF Pharmacist KAB Page 1 of3 05JAN2017 Table 8.1.3: Responses to Questions Linked to Key Risk Message #3 by Time Practicing as Pharmacist - Completed Surveys Question Time Practicing as Pharmacist Less than 3 years [95% 3 to 5 years [95% cu"I 6 to 15 years [95% More than 15 years (N=l32) [95% Question 7: Please answer True, False, or I don't know for each statement based on the labeling for TIRF medicines. 7e: It is important to monitor for signs of abuse and addiction in patients who take TIRF medicines. Truem 37 (100.0) [90.5 - 100.0] 51 (100.0) [93.0 - 100.0] 90 (98.9) [94.0 - 100.0] 128 (97.0) [92.4 - 99.2] False 0 0 1 (1.1) 3 (2.3) 1 don't know 0 0 0 1 (0.8) Question 8: Which of the following are risk factors for opioid abuse? Please answer Yes, No, or I don't know for each option. 8a: A personal history of illness Yesm 33 (89.2) [74.6 - 97.0] 39 (76.5) [62.5 - 872] 75 (82.4) [73.0 - 89.6] 94 (71.2) [62.7 - 78.8] No 2 (5.4) 7 (13.7) 8 (8.8) 25 (18.9) 1 don't know 2 (5.4) 5 (9.8) 8 (8.8) 13 (9.8) 8b: A personal history of past or current alcohol or drug abuse, or a family history of illicit drug use or alcohol abuse Yesm 37 (100.0) [90.5 - 100.0] 51 (100.0) [93.0 - 100.0] 89 (97.8) [92.3 99.7] 130 (98.5) [94.6 99.8] No 0 0 1 (1.1) 0 ldon'tknow 0 0 1(1.1) 2 (1.5) Question 10: Please answer True, False, or I don't know for each statement based on the labeling for TIRF medicines. 10a: TIR medicines can be abused in a manner similar to other opioid agonists. Truem 36 (97.3) [85.8 - 99.9] 49 (96.1) [86.5 - 99.5] 86 (94.5) [87.6 - 98.2] 120 (90.9) [84.7 - 95.2] False 0 2 (3.9) 4 (4.4) 6 (4.5) Data Source: ADPQ, ADTQ Program: TK RM S. SAS TRIG TIRF Pharmacist KAB Page 2 of3 05JAN2017 Table 8.1.3: Responses to Questions Linked to Key Risk Message #3 by Time Practicing as Pharmacist - Completed Surveys Time Practicing as Pharmacist Less than 3 years 3 to 5 years 6 to 15 years More than 15 years (N=l32) Question 95% cu'" 95% Cll'" 95% 95% [don't know 1 (2.7) 0 1 (1.1) 6 (4.5) statements. Question 13: Which of the following risks are associated with the use of TIRF medicines? Please answer True, False, or I don't know for the following 13a: Misuse Truem 37 (100.0) [90.5 - 100.0] 51 (100.0) [93.0 - 100.0] 90 (98.9) [94.0 - 100.0] 129 (97.7) [93.5 - 99.5] False 0 0 0 3 (2.3) [don'tknow 0 0 (1.1) 0 13b: Abuse Truem 37 (100.0) [90.5 - 100.0] 51 (100.0) [93.0 - 100.0] 90 (98.9) [94.0 - 100.0] 130 (98.5) [94.6 - 99.8] False 0 0 0 2 (1.5) ldon'tknow 0 0 1 (1.1) 0 130: A ddiction Truem 37 (100.0) [90.5 - 100.0] 51 (100.0) [93.0 - 100.0] 90 (98.9) [94.0 - 100.0] 129 (97.7) [93.5 - 99.5] False 0 0 0 3 (2.3) [don?tknow 0 0 (1.1) 0 13d: Overdose Truem 37 (100.0) [90.5 - 100.0] 51 (100.0) [93.0 - 100.0] 90 (98.9) [94.0 - 100.0] 131 (99.2) [95.9 - 100.0] False 0 0 0 1 (0.8) Data Source: ADPQ, ADTQ Program: TK RM S. SAS TRIG Page 3 of3 TIRF Pharmacist KAB 05JAN2017 Table 8.1.3: Responses to Questions Linked to Key Risk Message #3 by Time Practicing as Pharmacist - Completed Surveys Time Practicing as Pharmacist Less than 3 years 3 to 5 years 6 to 15 years More than 15 years (N=l32) Question 11 95% 11 95% 11 95% 01'? [95% Idon'tknow 0 0 (1.1) 0 I 3e: Hypothyroidism True 1 (2.7) 3 (5.9) 2 (2.2) 4 (3.0) Falsem 32 (86.5) [71.2 - 95.5] 46 (90.2) [78.6 - 96.7] 76 (83.5) [74.3 90.5] 107 (81.1) [73.3 87.4] [don?t know 4 (10.8) 2 (3.9) 13 (14.3) 21 (15.9) 13f: Infection True 3 (8.1) 2 (3.9) 5 (5.5) 4 (3.0) Falsem 32 (86.5) [71.2 - 95.5] 47 (92.2) [81.1 - 97.8] 79 (86.8) [78.1 - 93.0] 121 (91.7) [85.6 - 95.8] 1 don't know 2 (5.4) 2 (3.9) 7 (7.7) 7 (5.3) Source: Appendix B: Survey Tables, Table 8.1.3 ?195% exact two-sided con?dence intervals are calculated using the Clopper-Pearson method. Correct response. Data Source: ADPQ, ADTQ Program: TK RM S. SAS TRIG TIRF Pharmacist KAB Page 1 of3 05JAN2017 Table 8.1.4: Responses to Questions Linked to Key Risk Message #3 by Number of Times Dispensing TIRF Medicines per Month Within the Last 6 Months - Completed Surveys Question Number of Times Dispensing TIRF Medicines per Month Within the Last 6 Months None [95% - 2 times per month (N=l49) [95% 3 - 5 times per month [95% More than 5 times per month [95% I don't remember [95% Question 7: Please answer True, False, or I don't know for each statement based on the labeling for TIRF medicines. 7e: It is important to monitor for signs of abuse and addiction in patients who take TIRF medicines. True 60 (100.0) [94.0 - 100.0] 145 (97.3) [93.3 - 99.3] 37 (97.4) [86.2 - 99.9] 47 (100.0) [92.5 - 100.0] 23 (95.8) [78.9 - 99.9] False 0 2 (1.3) 1 (2.6) 0 1 (4.2) 1 don't know 0 2 (1.3) 0 0 0 Question 8: Which of the following are risk factors for opioid abuse? Please answer Yes, No, or I don't know for each option. 8a: A personal history of illness Yesm 52 (86.7) [75.4 - 94.1] 116 (77.9) [70.3 - 84.2] 30 (78.9) [62.7 - 90.4] 30 (63.8) [48.5 - 77.3] 19 (79.2) [57.8 - 92.9] No 3 (5.0) 19 (12.8) 6 (15.8) 12 (25.5) 2 (8.3) [don't know 5 (8.3) 14 (9.4) 2 (5.3) 5 (10.6) 3 (12.5) 8b: A personal history of past or current alcohol or drug abuse, or a family his tory of illicit drug use or alcohol abuse Yesm 59 (98.3) [91.1-1000] 146(98.0) [94.2-99.6] No 1(1.7) 0 0 0 0 1 don't know 0 3 (2.0) 0 0 0 Question 10: Please answer True, False, or I don't know for each statement based on the labeling for TIRF medicines. I 0a: TIRF medicines can be abused in a manner similar to other opioid agonists. Data Source: ADPQ, ADTQ Program: TK RM S. SAS TRIG TIRF Pharmacist KAB Page 2 of3 05JAN2017 Table 8.1.4: Responses to Questions Linked to Key Risk Message #3 by Number of Times Dispensing TIRF Medicines per Month Within the Last 6 Months - Completed Surveys Number of Times Dispensing TIRF Medicines per Month Within the Last 6 Months - 2 times 3 - 5 times More than 5 times I don't None per month per month per month remember (N=l49) Question [95% [95% cu"l [95% [95% cu'? [95% Truem 58 (96.7) [88.5 - 99.6] 140 (94.0) [88.8 - 97.2] 36 (94.7) [82.3 - 99.4] 41 (87.2) [74.3 - 95.2] 23 (95.8) [78.9 - 99.9] False 2 (3.3) 4 (2.7) (2.6) 4 (8.5) 1 (4.2) [don't know 0 5 (3.4) (2.6) 2 (4.3) 0 statements. Question 13: Which of the following risks are associated with the use of TIRF medicines? Please answer True, False, or I don't know for the following 13a: Misuse Truem 60 (100.0) [94.0 - 100.0] 147 (98.7) [95.2 - 99.8] 37 (97.4) [86.2 - 99.9] 46 (97.9) [88.7 - 99.9] 24 (100.0) [85.8 - 100.0] False 0 (0.7) (2.6) (2.1) 0 I don't know 0 (0.7) 0 0 0 13b: Abuse Truem 60 (100.0) [94.0 - 100.0] 147 (98.7) [95.2 - 99.8] 37 (97.4) [86.2 - 99.9] 47 (100.0) [92.5 - 100.0] 24 (100.0) [85.8 - 100.0] False 0 (0.7) (2.6) 0 0 [don't know 0 (0.7) 0 0 0 I30: Addiction Truelz] 60 (100.0) [94.0 - 100.0] 146 (98.0) [94.2 - 99.6] 38 (100.0) [90.7 - 100.0] 46 (97.9) [88.7 - 99.9] 24 (100.0) [85.8 - 100.0] False 0 2 (1.3) 0 (2.1) 0 I don't know 0 (0.7) 0 0 Data Source: ADPQ, ADTQ Program: TK RM S. SAS TRIG TIRF Pharmacist KAB Page 3 of3 05JAN2017 Table 8.1.4: Responses to Questions Linked to Key Risk Message #3 by Number of Times Dispensing TIRF Medicines per Month Within the Last 6 Months - Completed Surveys Number of Times Dispensing TIRF Medicines per Month Within the Last 6 Months - 2 times 3 - 5 times More than 5 times 1 don't None per month per month per month remember (N=l49) Question [95% [95% cu"I [95% [95% cu'? [95% cu"I 13d: Overdose Truem 60 (100.0) [94.0 - 100.0] 147 (98.7) [95.2 - 99.8] 38 (100.0) [90.7 - 100.0] 47 (100.0) [92.5 - 100.0] 24 (100.0) [85.8 - 100.0] False 0 1 (0.7) 0 0 0 ldon?t know 0 (0.7) 0 0 0 Be: )pothyroidism True 0 2 (1.3) 2 (5.3) 5 (10.6) 1 (4.2) Falsem 54 (90.0) [79.5 - 96.2] 122 (81.9) [74.7 - 87.7] 32 (84.2) [68.7 - 94.0] 38 (80.9) [66.7 - 90.9] 21 (87.5) [67.6 - 97.3] I don't know 6 (10.0) 25 (16.8) 4 (10.5) 4 (8.5) 2 (8.3) 13]: Infection True 0 3 (2.0) 3 (7.9) 8 (17.0) 1 (4.2) Falsem 57 (95.0) [86.1 - 99.0] 136 (91.3) [85.5 - 95.3] 33 (86.8) [71.9 - 95.6] 37 (78.7) [64.3 - 89.3] 21 (87.5) [67.6 - 97.3] [don?t know 3 (5.0) 10 (6.7) 2 (5.3) 2 (4.3) 2 (8.3) Source: Appendix B: Survey Tables, Table 8.1.4 ?195% exact two-sided confidence intervals are calculated using the Clapper-Pearson method. Correct response. Data Source: ADPQ, ADTQ Program: TK RM S. SAS TRIG TIRF Pharmacist KAB Page 1 of] 05JAN2017 Completed Surveys Table 8.2: Secondary Analysis of Responses to Questions Linked to Key Risk Message #3 - Pharmacists (N=3l8) Correct Responses 0 correct responses 0 1 correct response 0 2 correct responses 0 3 correct responses 1 (0.3) 4 correct responses 0 5 correct responses 1 (0.3) 6 correct responses 4 (1.3) 7 correct responses 8 (2.5) 8 correct responses 32 (10.1) 9 correct responses 83 (26.1) 10 correct responses 189 (59.4) Source: Appendix B: Survey Tables, Table 8.2 Data Source: ADPQ, ADTQ Program: TRIG TIRF Pharmacist KAB Page 1 of] 05JAN2017 Completed Surveys Table 9.1: Primary Analysis of Responses to Questions Linked to Key Risk Message #4 - Question Pharmacists [95% cu'" medicines. Question 10: Please answer True, False, or 1 don't know for each statement based on the labeling for TIRF 10b: TIRF medicines are interchangeable with each other regardless of route of administration. True 6 (1.9) Falsem 305 (95.9) [93.1 - 97.8] 1 don't know 7 (2.2) of differences in the pharmacokinetics of fentanyl absorption. MC: The conversion of one TIRF medicine for another TIRF medicine may result in a fatal overdose because Truem 296 (93.1) [89.7 - 95.6] False 10 (3.1) 1 don't know 12 (3.8) 10d: Dosing of TIRF medicines is not equivalent on a microgram-to-microgram basis. Truem 283 (89.0) [85.0 - 92.2] False 16 (5.0) 1 don't know 19 (6.0) Question 16: Please answer True, False, or 1 don't know for each statement about TIRF medicines. is out of stock for one product. 16c: TIRF medicines with the same route of administration can be substituted with each other if the pharmacy True 10 (3.1) Falsem 304 (95.6) [92.7 - 97.6] 1 don't know 4 (1.3) Source: Appendix B: Survey Tables, Table 9.1 95% exact two-sided con?dence intervals are calculated using the Clopper-Pearson method. Correct response. Data Source: ADPQ, ADTQ Program: TIRF Pharmacist KAB Page 1 of] 05JAN2017 Table 9.1.1: Responses to Questions Linked to Key Risk Message #4 by Reading Full Prescribing Information or Medication Guide - Completed Surveys Question Reading Full Prescribing Information or Medication Guide Received and read Pl or Med Guide [95% cu'? Did not receive or read Pl or Med Guide [95% Question 10: Please answer True, False, or I don't know for each statement based on the labeling for TIRF medicines. 10b: TIRF medicines are interchangeable with each other regardless of route of administration. True 6 (22) 0 Falsem 269 (96.4) [93.5 - 98.3] 36 (92.3) [79.1 - 98.4] [don't know 4 (1.4) 3 (7.7) I 0c: The conversion of one TIRF medicine for another TIRF medicine may result in a fatal overdose because of differences in the pharmacokinetics of fentanyl absorption. Truem 262 (93.9) [90.4 - 96.4] 34 (87.2) [72.6 - 95.7] False 10 (3.6) 0 I don't know 7 (2.5) 5 (12.8) 10d: Dosing of TIRF medicines is not equivalent on a microgram-to-microgram basis. Truem 253 (90.7) [86.6 - 93.8] 30 (76.9) [60.7 - 88.9] False 15 (5.4) (2.6) [don't know 1 1 (3.9) 8 (20.5) Question 16: Please answer True, False, or I don't know for each statement about TIRF medicines. I 6c: TIRF medicines with the same route of administration can be substituted with each other if the pharmacy is out of stock for one product. True 10 (3.6) 0 Falsem 267 (95.7) [92.6 - 97.8] 37 (94.9) [82.7 - 99.4] I don't know 2 (0.7) 2 (5.1) Source: Appendix B: Survey Tables, Table 9.1.1 ?195% exact two-sided con?dence intervals are calculated using the Clopper-Pearson method. Correct response. Data Source: ADPQ, ADTQ Program: TK RM S. SAS 00 TRIG Page 1 of] TIRF Pharmacist KAB 05JAN2017 Table 9.1.2: Responses to Questions Linked to Key Risk Message #4 by Modality to Complete Survey - Completed Surveys Modality to Complete Survey Internet Telephone (N=3l 4) Question [95% cu"I [95% cu'" Question 10: Please answer True, False, or I don't know for each statement based on the labeling for TIRF medicines. 10b: TIRF medicines are interchangeable with each other regardless of route of administration. True 5 (1.6) 1 (25.0) Falsem 302 (96.2) [93.4 - 98.0] 3 (75.0) [19.4 - 99.4] [don?t know 7 (22) 0 10c: The conversion of one TIRF medicine for another TIRF medicine may result in a fatal overdose because of differences in the pharmacokinetics of fentanyl absorption. Truem 292 (93.0) [89.6 - 95.6] 4 (100.0) [39.8 - 100.0] False 10 (3.2) 0 I don't know 12 (3.8) 0 10d: Dosing of TIRF medicines is not equivalent on a microgram-to-microgram basis. Truem 279 (88.9) [84.8 92.1] 4 (100.0) [39.8 100.0] False 16 (5.1) 0 [don't know 19 (6.1) 0 Question 16: Please answer True, False, or I don't know for each statement about TIRF medicines. 16c: TIRF medicines with the same route of administration can be substituted with each other if the pharmacy is out of stock for one product. True 9 (2.9) 1 (25.0) Falsem 301 (95.9) [93.0 - 97.8] 3 (75.0) [19.4 - 99.4] I don't know 4 (1.3) 0 Source: Appendix B: Survey Tables, Table 9.1.2 ?195% exact two-sided con?dence intervals are calculated using the Clopper-Pearson method. Correct response. Data Source: ADPQ, ADTQ Program: TRIG TIRF Pharmacist KAB Page 1 of2 05JAN2017 Table 9.1.3: Responses to Questions Linked to Key Risk Message #4 by Time Practicing as Pharmacist - Completed Surveys Question Time Practicing as Pharmacist Less than 3 years [95% 3 to 5 years [95% 6 to 15 years [95% More than 15 years (N=l32) [95% Question 10: Please answer True, False, or I don't know for each statement based on the labeling for TIRF medicines. 10b: TIRF medicines are interchangeable with each other regardless of route of administration. True 0 0 (1.1) 4 (3.0) Falsem 36 (97.3) [85.8 - 99.9] 51 (100.0) [93.0 - 100.0] 88 (96.7) [90.7 - 99.3] 124 (93.9) [88.4 - 97.3] [don't know 1 (2.7) 0 2 (2.2) 4 (3.0) I 0c: The conversion of one TIRF medicine for another TIRF medicine may result in a fatal overdose because of differences in the pharmacokinetics of fentanyl absorption. Truelz] 37 (100.0) [90.5 - 100.0] 51 (100.0) [93.0 - 100.0] 83 (91.2) [83.4 - 96.1] 118 (89.4) [82.8 - 94.1] False 0 0 5 (5.5) 5 (3.8) 1 don't know 0 0 3 (3.3) 9 (6.8) 10d: Dosing of TIRF medicines is not equivalent on a microgram-to-microgram basis. Truelz] 36 (97.3) [85.8 - 99.9] 46 (90.2) [78.6 - 96.7] 81 (89.0) [80.7 - 94.6] 115 (87.1) [80.2 - 92.3] False 0 3 (5.9) 5 (5.5) 6 (4.5) [don't know 1 (2.7) 2 (3.9) 5 (5.5) 11 (8.3) Question 16: Please answer True, False, or I don't know for each statement about TIRF medicines. I 6c: TIRF medicines with the same route of administration can be substituted with each other if the pharmacy is out of stock for one product. True 2 (5.4) 2 (3.9) 1(1.1) 5 (3.8) alsem 34 (91.9) [78.1 - 98.3] 49 (96.1) [86.5 - 99.5] 88 (96.7) [90.7 - 99.3] 126 (95.5) [90.4 - 98.3] Data Source: ADPQ, ADTQ Program: TK RM S. SAS 02 TRIG Page 2 of 2 TIRF Pharmacist KAB 05JAN2017 Table 9.1.3: Responses to Questions Linked to Key Risk Message #4 by Time Practicing as Pharmacist - Completed Surveys Time Practicing as Pharmacist Less than 3 years 3 to 5 years 6 to 15 years More than 15 years (N=l32) Question 95% cu'" 95% Cll'" 95% 95% [don't know 1 (2.7) 0 2 (2.2) (0.8) Source: Appendix B: Survey Tables, Table 9.1.3 ?195% exact two-sided con?dence intervals are calculated using the Clopper-Pearson method. Correct response. Data Source: ADPQ, ADTQ Program: 03 TRIG TIRF Pharmacist KAB Page 1 of2 05JAN2017 Table 9.1.4: Responses to Questions Linked to Key Risk Message #4 by Number of Times Dispensing TIRF Medicines per Month Within the Last 6 Months - Completed Surveys Number of Times Dispensing TIRF Medicines per Month Within the Last 6 Months - 2 times 3 - 5 times More than 5 times 1 don't None per month per month per month remember (N=l49) Question [95% [95% cu"l [95% [95% cu'? [95% Question 10: Please answer True, False, or I don 't know for each statement based on the labeling for TIRF medicines. 10b: TIRF medicines are interchangeable with each other regardless of route of administration. True 0 2 (1.3) 3 (7.9) 1 (2.1) 0 Falsem 56 (93.3) [83.8 - 982] 14-4 (96.6) [92.3 - 98.9] 35 (92.1) [78.6 - 98.3] 46 (97.9) [88.7 - 99.9] 24 (100.0) [85.8 - 100.0] 1 don?t know 4 (6.7) 3 (2.0) 0 0 0 I 0c: The conversion of one TIRF medicine for another TIRF medicine may result in a fatal overdose because of differences in the pharmacokinetics of fentanyl absorption. Truem 53 (88.3) [77.4 - 952] 136 (91.3) [85.5 - 95.3] 38 (100.0) [90.7 - 100.0] 46 (97.9) [88.7 - 99.9] 23 (95.8) [78.9 - 99.9] False 4 (6.7) 5 (3.4) 0 (2.1) 0 I don't know 3 (5.0) 8 (5.4) 0 0 (4.2) 10d: Dosing of TIRF medicines is not equivalent on a microgram-to-microgram basis. Truem 51 (85.0) [73.4 - 92.9] 132 (88.6) [82.4 - 93.2] 37 (97.4) [86.2 - 99.9] 44 (93.6) [82.5 - 98.7] 19 (79.2) [57.8 - 92.9] False 2 (3.3) 10 (6.7) (2.6) 1 (2.1) 2 (8.3) [don't know 7 (11.7) 7 (4.7) 0 2 (4.3) 3 (12.5) Question 16: Please answer True, False, or I don't know for each statement about TIRF medicines. I 6c: TIRF medicines with the same route of administration can be substituted with each other if the pharmacy is out of stock for one product. True 1(1.7) 5 (3.4) 3 (7.9) Data Source: ADPQ, ADTQ Program: TK RM S. SAS 04 TRIG TIRF Pharmacist KAB Page 2 of 2 05JAN2017 Table 9.1.4: Responses to Questions Linked to Key Risk Message #4 by Number of Times Dispensing TIRF Medicines per Month Within the Last 6 Months - Completed Surveys Number of Times Dispensing TIRF Medicines per Month Within the Last 6 Months 1mm 0 - 2 times 3 - 5 times More than 5 times I don't None per month per month per month remember (N=l49) Falsem 58 (96.7) [88.5 - 99.6] 143 (96.0) [91.4 - 98.5] 35 (92.1) [78.6 - 98.3] 46 (97.9) [88.7 - 99.9] 22 (91.7) [73.0 - 99.0] [don't know 1 (1.7) 0 2mm Source: Appendix B: Survey Tables, Table 9.1.4 ?195% exact two-sided con?dence intervals are calculated using the Clopper-Pearson method. Correct response. Data Source: ADPQ. ADTQ Program: TK RM S. SAS 05 TRIG TIRF Pharmacist KAB Page 1 of] 05JAN2017 Completed Surveys Table 9.2: Secondary Analysis of Responses to Questions Linked to Key Risk Message #4 - Pharmacists (N=3l8) Correct Responses 0 correct responses 0 1 correct response 6 (1.9) 2 correct responses 8 (2.5) 3 correct responses 50 (15.7) 4 correct responses 254 (79.9) Source: Appendix B: Survey Tables, Table 9.2 Data Source: ADPQ. ADTQ Program: 06 TRIG Page 1 of] TIRF Pharmacist KAB 05JAN2017 Table 10: Average Knowledge Scores - Completed Surveys Score [95% KRM #1 83.8 [81.8, 85.7] KRM #2 75.4 [73.1, 77.6] KRM #3 93.7 [92.7, 94.8] KRM #4 93.4 [91.7, 95.0] Overall Knowledge Score 85.7 [84.4, 87.0] Source: Appendix B: Survey Tables, Table 10 95% C15 are constructed based on normal distribution function. Data Source: ADPQ, ADTQ Program: 07 TRIG Page 1 of] TIRF Pharmacist KAB 05JAN2017 Listing 1: Listing of Verbatim Responses to Question #26 (Questions about the Full Prescribing Information or the Medication Guide) - Completed Surveys Verbatim Responses How o?en do you have to renew the How to use Lamnda and Subsys devices Various kinetic questions We've seen prescriptions come through where the patient does not have cancer, but they are on Subsys, so that just kind of worries us. When does one have to not give the Package Insert? would like to know more about the requirements for prescribing Data Source: ADPQ Program: LQ.SAS 08 TRIG Page 1 of TIRF Pharmacist KAB 05JAN2017 Listing 2: Listing of Adverse Events and/or Product Complaints Reported by Modality Modality of Verbatim Text Report How often do you have to renew the lntemet How to use Lamnda and Subsys devices lntemet We've seen prescriptions come through where the patient does not have cancer, but they are Telephone on Subsys, so that just kind of worries us. When does one have to not give the Package Insert? lntemet would like to know more about the requirements for prescribing lntemet Data Source: Program: LQAE.SAS 09 60-Month FDA REMS Supplemental Assessment Report Transmucosal Immediate-Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies 4.4 Page 19 of 19 Prescriber KAB Report FDA_5110 Prescriber KAB Assessment Report Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Title: Final 10 February 2017 Page 1 of 70 Transmucosal Immediate Release Fentanyl (TIRF) REMS Assessment Quantitative Testing of Prescriber Knowledge, Attitudes, and Behavior (KAB) about TIRF Products Safety and Use Information Document Number: Wave 5, 60-Month REMS Assessment Report Version 1.0 Survey Time Period: 26 September 2016 to 20 December 2016 Product Name: Transmucosal Immediate Release Fentanyl Sponsor: TIRF REMS Industry Group (TRIG) of Companies: Actavis Laboratories FL, Inc. BioDelivery Sciences International, Inc. (BDSI) Cephalon, Inc. (a wholly-owned subsidiary of Teva Pharmaceutical Industries, Ltd.) Depomed, Inc. Insys Therapeutics, Inc. Mallinckrodt Pharmaceuticals Mylan, Inc. Par Pharmaceutical, Inc. Sentynl Therapeutics, Inc. Date: 10 February 2017 Confidentiality Statement The information contained herein is confidential and the proprietary property of the TRIG of Companies and its affiliates, and any unauthorized use or disclosure of such information without the prior written authorization of the TRIG is expressly prohibited. FDA_5111 Prescriber KAB Assessment Report Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies TABLE OF CONTENTS Final 10 February 2017 Page 2 of 70 PAGE TABLE OF CONTENTS......................................................................................................... 2 LIST OF IN-TEXT TABLES .................................................................................................. 3 LIST OF APPENDICES .......................................................................................................... 5 LIST OF ABBREVIATIONS .................................................................................................. 6 EXECUTIVE SUMMARY ..................................................................................................... 7 1. PRESCRIBER SURVEY BACKGROUND .......................................................... 8 1.1 Changes to the KAB Survey for Prescribers Based on FDA Feedback.................. 9 2. PRESCRIBER SURVEY OBJECTIVES ............................................................. 10 3. SURVEY METHODOLOGY............................................................................... 10 3.1 Survey Sample ...................................................................................................... 10 3.1.1 Eligibility .............................................................................................................. 11 3.1.2 Recruitment ........................................................................................................... 11 3.2 Questions and Statements on Key Risk Messages ................................................ 11 3.2.1 Key Risk Message 1 .............................................................................................. 12 3.2.2 Key Risk Message 2 .............................................................................................. 13 3.2.3 Key Risk Message 3 .............................................................................................. 15 3.2.4 Key Risk Message 4 .............................................................................................. 16 3.3 Additional Questions............................................................................................. 16 4. STATISTICAL METHODS ................................................................................. 17 4.1 Study Population ................................................................................................... 17 4.1.1 All Respondents .................................................................................................... 17 4.1.2 Completed Surveys (Primary Population) ............................................................ 17 4.1.3 General Population ................................................................................................ 18 4.2 Primary Analysis ................................................................................................... 18 4.3 Secondary Analyses .............................................................................................. 18 4.4 Prescriber Report of a Potential Adverse Event, Product Complaint, or Medical Information Request during the Survey .................................................. 19 5. RESULTS ............................................................................................................. 19 5.1 Survey Participants................................................................................................ 19 FDA_5112 Prescriber KAB Assessment Report Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Final 10 February 2017 Page 3 of 70 5.1.1 Survey Participant Administration Results ........................................................... 19 5.1.2 Description of Eligible Prescribers who Completed the Survey........................... 23 5.1.2.1 Comparison of Survey Respondents to the General Population of TIRF Prescribers ............................................................................................................. 25 5.1.3 TIRF Medicines Educational Materials ................................................................ 30 5.2 Key Risk Messages ............................................................................................... 32 5.2.1 Key Risk Message 1 .............................................................................................. 32 5.2.2 Key Risk Message 2 .............................................................................................. 40 5.2.3 Key Risk Message 3 .............................................................................................. 47 5.2.4 Key Risk Message 4 .............................................................................................. 50 5.2.5 Key Risk Message Average Knowledge Scores ................................................... 52 5.2.6 Other Survey Questions ........................................................................................ 53 5.2.6.1 Additional Questions about TIRF Medicines Safety ............................................ 53 5.2.6.2 Prescriber Activities When Prescribing TIRF Medicines ..................................... 55 5.3 Spontaneous Reporting of Adverse Events, Product Complaints, or Medical Information Requests .............................................................................. 58 6. DISCUSSION AND CONCLUSIONS ................................................................ 58 LIST OF IN-TEXT TABLES Table 1. Survey Administration Statistics.................................................................... 20 Table 2. Survey Participant Eligibility Results - All Respondents .............................. 21 Table 3. Time to Complete Survey - Completed Surveys ........................................... 22 Table 4. Description of Eligible Prescribers - Completed Surveys ............................. 23 Table 5. Comparison of Survey Respondents to General Population of Prescribers (REMS Switch Provider Data) .................................................... 26 Table 6. Comparison of Survey Respondents to General Population of Prescribers ...................................................................................................... 28 Table 7. Responses to Questions about TIRF Educational Materials Completed Surveys ........................................................................................ 31 Table 8. Responses to Questions about the Patient-Prescriber Agreement Form - Completed Surveys ............................................................................ 32 Table 9. Primary Analysis of Responses to Questions Linked to Key Risk Message #1 - Completed Surveys .................................................................. 33 FDA_5113 Prescriber KAB Assessment Report Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Final 10 February 2017 Page 4 of 70 Table 10. Secondary Analysis of Responses to Questions Linked to Key Risk Message #1 - Completed Surveys .................................................................. 36 Table 11. Responses to Questions Linked to Key Risk Message #1 by Reading Full Prescribing Information or Medication Guide - Completed Surveys (Questions/Items with Apparent Trends) ......................................... 37 Table 12. Responses to Questions Linked to Key Risk Message #1 by Time Practicing Medicine - Completed Surveys (Questions/Items with Apparent Trends) ........................................................................................... 38 Table 13. Primary Analysis of Responses to Questions Linked to Key Risk Message #2 - Completed Surveys .................................................................. 41 Table 14. Types of Chronic Pain Conditions Reported - Completed Surveys for Prescribers Who Prescribed TIRF Medicines for Chronic NonCancer Pain .................................................................................................... 43 Table 15. Reasons for Selecting a TIRF Medicine Reported - Completed Surveys for Prescribers Who Prescribed TIRF Medicines for Chronic Non-Cancer Pain ............................................................................................ 44 Table 16. Secondary Analysis of Responses to Questions Linked to Key Risk Message #2 - Completed Surveys .................................................................. 45 Table 17. Responses to Questions Linked to Key Risk Message #2 by Reading Full Prescribing Information or Medication Guide - Completed Surveys (Questions/Items with Apparent Trends) ......................................... 46 Table 18. Primary Analysis of Responses to Questions Linked to Key Risk Message #3 - Completed Surveys .................................................................. 47 Table 19. Secondary Analysis of Responses to Questions Linked to Key Risk Message #3 - Completed Surveys .................................................................. 49 Table 20. Primary Analysis of Responses to Questions Linked to Key Risk Message #4 - Completed Surveys .................................................................. 50 Table 21. Secondary Analysis of Responses to Questions Linked to Key Risk Message #4 - Completed Surveys .................................................................. 51 Table 22. Responses to Questions Linked to Key Risk Message #4 by Reading Full Prescribing Information or Medication Guide - Completed Surveys (Questions/Items with Apparent Trends) ......................................... 52 Table 23. Average Knowledge Scores - Completed Surveys ........................................ 53 Table 24. Responses to Additional Questions about the Safe Use of TIRF Medicines - Completed Surveys .................................................................... 54 Table 25. Responses to Questions about the Activities when Prescribing TIRF Medicines - Completed Surveys .................................................................... 56 Table 26. Correct Response Rate Over Time ................................................................ 61 FDA_5114 Prescriber KAB Assessment Report Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Final 10 February 2017 Page 5 of 70 LIST OF APPENDICES Appendix A Prescriber Survey Protocol Track Change Document: Comparison of 48-month Survey to 60-month Survey........................................................... 69 Appendix B Survey Tables................................................................................................. 70 FDA_5115 Prescriber KAB Assessment Report Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Final 10 February 2017 Page 6 of 70 LIST OF ABBREVIATIONS BDSI BioDelivery Sciences International, Inc. CI Confidence Interval DoD Department of Defense ETASU Elements to Assure Safe Use FDA Food and Drug Administration ISI Important Safety Information HCP Healthcare Professional KAB Knowledge, Attitudes, and Behavior KRM Key Risk Message N/A Not Applicable or Not Available NIH National Institutes of Health PI Prescribing Information PPAF Patient-Prescriber Agreement Form REMS Risk Evaluation and Mitigation Strategy SCC Survey Coordinating Center SD Standard Deviation TIRF Transmucosal Immediate Release Fentanyl TIRF medicines Transmucosal Immediate Release Fentanyl products TIRF REMS Access program REMS program for TIRF medicines TRIG TIRF REMS Industry Group UBC United BioSource Corporation US United States USPS United States Postal Service VA Department of Veterans Affairs FDA_5116 Prescriber KAB Assessment Report Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Final 10 February 2017 Page 7 of 70 EXECUTIVE SUMMARY The 60-month Knowledge, Attitudes, and Behavior (KAB) survey for prescribers who prescribe Transmucosal Immediate Release Fentanyl (TIRF) medicines was conducted as part of the 60-Month TIRF Risk Evaluation and Mitigation Strategy (REMS) Access program assessment. On 21 July 2016, the United States (US) Food and Drug Administration (FDA) provided feedback on the prescriber survey. After careful review of the requested changes, the TIRF REMS Industry Group (TRIG) notified FDA that in order to incorporate all changes, an extension for report submission would be required. As proposed by FDA on 29 July 2016 and agreed to by the TRIG on 01 August 2016, the 60-month KAB survey results were planned for a separate submission from the overall assessment report on or before 17 February 2017. The 60-month KAB survey for prescribers launched on 26 September 2016 and closed on 20 December 2016. Subjects were recruited from a random sample of prescribers who were enrolled in the TIRF REMS Access program and who had prescribed a TIRF medicine in the last 6 months. From total of 524 respondents who accessed the survey, 313 prescribers (59.7%) met eligibility criteria, and of those who met eligibility criteria, 294 (93.9%) completed the survey. On 21 July 2016, FDA provided feedback on the KAB survey for prescribers. Changes to the 60-month KAB Survey for Prescribers based on FDA feedback included the addition of 3 survey questions, the revision of 1 survey question, and a change to the recruitment strategy to limit the survey to prescribers who have prescribed TIRF medicines in the past 6 months. The change to Question 9 (Per the approved labeling for TIRF medicines, for which of the following indication(s) are TIRF medicines approved), and the addition of Question 21 (TIRF medicines should only be taken by patients who are opioid tolerant) and Question 22 (Which of the following risks are associated with the use of TIRF medicines? Please answer True, False, or I don’t know for the following statements) are discussed with the key risk message results below. Question 32 (How frequently do you perform the following activities when prescribing TIRF medicines? Please answer Always, Only with the first prescription, Sometimes, Never, or I don't know) included 3 response items about prescriber reported activity. For each item, most prescribers selected always or only with the first prescription; and few prescribers selected sometimes, never, or I don’t know. The overall knowledge score of 89.1 (95% confidence interval [CI]: 88.0 90.2) for the survey indicates a high percentage of respondents demonstrated understanding of the key risk messages. The average knowledge score was greater than 86 for all 4 key risk messages. Of the 38 questions/items included as part of key risk messages, 28 questions/items had a correct response rate >80% and 10 questions/items had a correct response rate between 65% and 80%. None of the questions/items had a correct response rate that fell below the desired level of understanding of 65%. When comparing correct response rates from the 12-month KAB survey through the 60month KAB survey, knowledge and understanding of the key risk message questions has generally remained stable or improved over time. Correct response rates for 4 of the 5 items FDA_5117 Prescriber KAB Assessment Report Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Final 10 February 2017 Page 8 of 70 of the revised Question 9 were similar compared to the 48-month survey; however, the item pertaining to a response of ‘chronic non-cancer pain’ had a notably improved correct response rate. In addition, the 2 new survey questions (Question 21 and Question 22 [6 separate response items]) that were added as part of key risk messages for the 60-month survey based on FDA feedback had a correct response rate of >96% for 5 questions/items and >78% for 2 items. 1. PRESCRIBER SURVEY BACKGROUND Transmucosal Immediate Release Fentanyl (TIRF) medicines include the class of immediate release opioid analgesics indicated only for the management of breakthrough pain in cancer patients 18 years of age or older (16 or older for Actiq® [fentanyl citrate oral transmucosal lozenge] and equivalent generics) who are receiving and already tolerant to opioid therapy for their underlying persistent cancer pain. The FDA has determined that a shared system REMS is required to mitigate the risks of misuse, abuse, addiction, overdose, and serious complications due to medication errors with the use of TIRF medicines. The TIRF REMS Access program was approved by the FDA on 28 December 2011. This report describes the results from the prescriber surveys conducted for the 60-month TIRF REMS Access program assessment, and reflects the REMS reporting period of 29 October 2016 to 28 October 2016. The 60-month KAB survey for prescribers launched on 26 September 2016 and closed on 20 December 2016. The TIRF medicines include Abstral®, Actiq®, Fentora®, Lazanda®, Subsys®, and (where applicable) their respective generic equivalents. The TRIG includes Actavis Laboratories FL, Inc.; BioDelivery Sciences International, Inc. (BDSI); Cephalon, Inc. (a wholly-owned subsidiary of Teva Pharmaceutical Industries, Ltd.); Depomed, Inc.; Insys Therapeutics, Inc.; Mallinckrodt Pharmaceuticals; Mylan, Inc.; Par Pharmaceutical, Inc.; and Sentynl Therapeutics, Inc. One company joined the TRIG during the reporting period: Sentynl Therapeutics, Inc. replaced Galena Biopharma, Inc. on 09 January 2016. The TIRF REMS Access program consists of a Medication Guide, Elements to Assure Safe Use (ETASU), an Implementation System, and a Timetable for Submission of Assessments. The goals of the TIRF REMS Access program are to mitigate the risks of misuse, abuse, addiction, overdose, and serious complications due to medication errors by the following: 1. Prescribing and dispensing TIRF medicines only to appropriate patients, which includes use only in opioid-tolerant patients. 2. Preventing inappropriate conversion between TIRF medicines. 3. Preventing accidental exposure to children and others for whom it was not prescribed. 4. Educating prescribers, pharmacists, and patients on the potential for misuse, abuse, addiction, and overdose of TIRF medicines. FDA_5118 Prescriber KAB Assessment Report Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Final 10 February 2017 Page 9 of 70 An important component of the TIRF REMS Access program assessment is the conduct of quantitative evaluation surveys to assess prescribers’ understanding and knowledge of the safe use and appropriate prescribing of TIRF medicines as described in the TIRF REMS Access program educational materials, Prescriber Enrollment Form, and Prescribing Information of each product. Administration of the surveys conducted among prescribers who are enrolled in the TIRF REMS Access program is described in the protocol (See Appendix A). Note: Protocol and survey question revisions from the 48-month assessment report are identified as tracked changes. Data from the surveys, together with other REMS evaluation metrics, will be used to determine whether changes need to be made to the REMS processes or educational materials to make them more effective in achieving the goals of the REMS. 1.1 Changes to the KAB Survey for Prescribers Based on FDA Feedback On 21 July 2016, FDA provided feedback on the KAB survey for prescribers. After careful review of the requested changes, the TRIG notified FDA that in order to incorporate all changes, an extension for report submission would be required. As proposed by FDA on 29 July 2016 and agreed to by the TRIG on 01 August 2016, the 60-month KAB survey results were planned for a separate submission from the overall assessment report on or before 17 February 2017. Specific updates made to the protocol and survey included: x x Changes to the recruitment strategy to: o Limit the survey to prescribers who have prescribed TIRF medicines in the past 6 months Addition of the following questions: o 21 (TIRF medicines should only be taken by patients who are opioid tolerant) o 32 (How frequently do you perform the following activities when prescribing TIRF medicines? ƒ 32a Talk to the patient about the risks and possible side effects of the TIRF medicine that was most recently prescribed ƒ 32b Instruct the patient on how to use the TIRF medicine that was most recently prescribed ƒ 32c Instruct the patient on how to store or keep the TIRF medicine that was most recently prescribed) o 22 (Which of the following risks are associated with the use of TIRF medicines? ƒ 22a Misuse ƒ 22b Abuse ƒ 22c Addiction ƒ 22d Overdose ƒ 22e Hypothyroidism ƒ 22f Infection) FDA_5119 Prescriber KAB Assessment Report Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies x Final 10 February 2017 Page 10 of 70 Revision to Question 9 (For which indications do you prescribe TIRF medicines to opioid tolerant patients) as it assumes that prescribers are only using TIRF medicines for opioid tolerant patients which may not be the case. Question was updated to: Per the approved labeling for TIRF medicines, for which of the following indication(s) are TIRF medicines approved? All of the above requested changes were incorporated prior to survey launch on 26 September 2016. 2. PRESCRIBER SURVEY OBJECTIVES The evaluation survey used a questionnaire to document the level of knowledge and assess the attitudes and behavior of prescribers regarding the following key information and risk messages communicated through the REMS: 1. TIRF medicines are contraindicated in opioid non-tolerant patients. 2. TIRF medicines are only indicated for the management of breakthrough pain in adult cancer patients 18 years of age and older (16 or older for Actiq® and equivalent generics) who are already receiving and who are tolerant to around-the-clock opioid therapy for their underlying persistent cancer pain. 3. TIRF medicines contain fentanyl, an opioid agonist and a Schedule II controlled substance, with abuse liability similar to other opioid analgesics. 4. TIRF medicines are not interchangeable with each other, regardless of route of administration. 5. Patients and their caregivers must be instructed that TIRF medicines contain a medicine in an amount that can be fatal in children, in individuals for whom it is not prescribed, and in those who are not opioid tolerant. 3. SURVEY METHODOLOGY This section summarizes the survey design and the questions developed to test prescriber understanding of the key risk messages of the REMS. Full details of the survey design are in the protocol, provided in Appendix A. 3.1 Survey Sample A sample of 300 healthcare professionals (HCPs) who are enrolled in the TIRF REMS Access program is proposed for each survey wave. The survey sample size was determined based on both practical and statistical considerations. The survey was written to reflect wording for both methods of survey administration: Internet-based and telephone. FDA_5120 Prescriber KAB Assessment Report Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies 3.1.1 Final 10 February 2017 Page 11 of 70 Eligibility Subjects were recruited from a random sample of prescribers who were enrolled in the TIRF REMS Access program and who had prescribed a TIRF medicine in the last 6 months. Respondents or respondents with immediate family members who had ever worked for any of the TRIG companies, RelayHealth, McKesson Specialty Care Solutions, United BioSource Corporation (UBC), or the FDA were not eligible to participate, nor were respondents who participated in the previous waves of the survey (annual waves from the 12month TIRF REMS Access program assessment through the 48-month TIRF REMS Access program assessment). 3.1.2 Recruitment Prescribers who were enrolled in the TIRF REMS Access program as of 02 September 2016 and who had prescribed a TIRF medicine in the last 6 months were recruited via an invitation letter sent via email and through the United States Postal Service (USPS) (Section 5.1.1 for more detail). If the required number of completed surveys was not achieved within the expected timeframe of approximately 1 to 2 weeks after the first mailing, reminder letters were to be sent to nonresponders from the original sample with subsequent follow-up to maximize participation. If these efforts did not result in the required number of completed surveys within 2 to 3 weeks, then a new sample of prescribers was to be randomly selected. Each letter of invitation included a unique code needed to access the survey. The code was deactivated after the respondent had initiated the survey (whether or not the survey was completed). Respondents were given the option of taking the survey by telephone via the Survey Coordinating Center (SCC) or online via a secure website. The survey was estimated to take approximately 20 minutes to complete. All respondents who completed the survey and provided their contact information were mailed a $125 gift card for participating, with the exception of prescribers who practiced in Massachusetts, Minnesota, or Vermont (due to state laws prohibiting it). The mailing also included a Thank You Letter, a copy of the Important Safety Information (ISI) and a copy of the correct answers to key risk message questions. 3.2 Questions and Statements on Key Risk Messages The questions and statements comprising the knowledge survey were constructed to test the prescribers’ understanding of the key risk messages of the REMS. The questions were to be answered either by selecting options from multiple-choice lists that included statements of the specific key risk messages or by choosing “Yes” or “True,” “No” or “False,” or “I Don’t Know” regarding statements about TIRF medicines. For statements or questions that use “True” or “Yes” versus “False” or “No” response options, the desired response for key risk messages is generally “True” or “Yes” indicating knowledge of, or behavior in accordance with, the objectives of the REMS. However, some FDA_5121 Prescriber KAB Assessment Report Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Final 10 February 2017 Page 12 of 70 questions were formatted to have the respondent disagree with the statement as written by providing response options of “False” or “No” to avoid having the same affirmative answer for all desired responses. REMS statements, corresponding questions, and desired responses covering the key risk messages are identified below and can be found in the survey protocol (Appendix A). 3.2.1 Key Risk Message 1 Key Risk Message 1 refers to the prescriber’s knowledge of the specific contraindications for TIRF medicine in opioid non-tolerant patients and under what conditions a patient is considered opioid tolerant. Key Risk Message 1: TIRF medicines are contraindicated in opioid non-tolerant patients. Question No. Question Desired Response 5 Please select True, False, or I don’t know for each of the following. According to the labeling for TIRF medicines, patients with cancer who are considered opioid-tolerant are those: 5a Who are taking around-the-clock opioid therapy for underlying, persistent cancer pain for one week or longer True 5b Who are not currently taking opioid therapy, but have taken opioid therapy before False 5c Who have no known contraindications to the drug fentanyl, but are not currently taking around-the-clock opioid therapy False 7 Please answer True, False, or I don’t know for each statement based on the labeling for TIRF medicines. 7a TIRF medicines are contraindicated in opioid non-tolerant patients because life-threatening respiratory depression could occur at any dose. True 7b Death has occurred in opioid non-tolerant patients treated with some fentanyl products. True 7c TIRF medicines may be used to treat opioid non-tolerant patients. False 7d Prescribers starting a patient on a TIRF medicine must begin with titration from the lowest dose available for that specific product, even if the patient has previously taken another TIRF medicine. True 13 Please select True, False, or I don’t know for each of the following. According to the labeling for TIRF medicines, patients considered opioid-tolerant are those who are taking, for one week or longer, at least: 13a 8 mg oral hydromorphone/day True 13b 60 mg oral morphine/day True FDA_5122 Prescriber KAB Assessment Report Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Final 10 February 2017 Page 13 of 70 Key Risk Message 1: TIRF medicines are contraindicated in opioid non-tolerant patients. Question No. Question Desired Response 13c 30 mg oral oxycodone/day True 13d 25 mcg transdermal fentanyl/hour True 13e 25 mg oral oxymorphone/day True 13f An equianalgesic dose of another oral opioid True 21 3.2.2 Please answer True, False, or I don’t know for the following statement about TIRF medicines: TIRF medicines should only be taken by patients who are opioid tolerant. True Key Risk Message 2 Key Risk Message 2 refers to the prescriber’s knowledge of the indications for prescribing TIRF medicines for the management of breakthrough pain in opioid-tolerant adult cancer patients, and the timing of administration of the TIRF medicine in relation to the around-theclock opioid therapy to ensure the patient is considered opioid tolerant. Key Risk Message 2: TIRF medicines are only indicated for the management of breakthrough pain in adult cancer patients 18 years of age and older (16 years of age and older for Actiq® brand and generic equivalents) who are already receiving and who are tolerant to around-theclock opioid therapy for their underlying persistent cancer pain. Question No. Question Desired Response 6 Please answer True, False, or I don’t know for each statement based on the labeling for TIRF medicines. 6a According to the product labeling, a cancer patient may start a TIRF medicine and an around-the-clock opioid at the same time. False 6b According to the product labeling, a cancer patient who has been on an around-the-clock opioid for 1 day may start taking a TIRF medicine for breakthrough pain False 9 Per the approved labeling for TIRF medicines, for which of the following indication(s) are TIRF medicines approved? Please answer Yes, No, or I don’t know for each option. 9a Acute or postoperative pain No 9b Headache or migraine pain No 9c Dental pain No 9d Breakthrough pain from cancer Yes FDA_5123 Prescriber KAB Assessment Report Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Final 10 February 2017 Page 14 of 70 Key Risk Message 2: TIRF medicines are only indicated for the management of breakthrough pain in adult cancer patients 18 years of age and older (16 years of age and older for Actiq® brand and generic equivalents) who are already receiving and who are tolerant to around-theclock opioid therapy for their underlying persistent cancer pain. Question No. 9e Question Chronic non-cancer pain Desired Response No 15b. Adult female with localized breast cancer; just completed a mastectomy and reconstructive surgery; persistent cancer pain managed with 30 mg oral morphine daily for the past 6 weeks. 15 The patients described are experiencing breakthrough pain. According to the labeling, a TIRF medicine is not appropriate for one of them. Which patient should not receive a TIRF medicine? Please select one option. 20 Before initiating treatment with a TIRF medicine, prescribers must review the Medication Guide with the patient. Please select True, False, or I don’t know for each of the following counseling statements. Inform patients that TIRF medicines must not be used for acute or postoperative pain, pain from injuries, headache/migraine, or any other short-term pain. True 20b Instruct patients that they can continue to take their TIRF medicine, if they stop taking their around-the-clock opioid medicine. False 20c FDA_5124 Prescriber KAB Assessment Report Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies 3.2.3 Final 10 February 2017 Page 15 of 70 Key Risk Message 3 Key Risk Message 3 refers to the prescriber’s knowledge of the risk factors for opioid abuse and importance in monitoring for signs of abuse in patients who take TIRF medicines. Key Risk Message 3: TIRF medicines contain fentanyl, an opioid agonist and a Schedule IIcontrolled substance, with abuse liability similar to other opioid analgesics. Question No. Question Desired response 7 Please answer True, False, or I don’t know for each statement based on the labeling for TIRF medicines. 7e It is important to monitor for signs of abuse and addiction in patients who take TIRF medicines. 8 Which of the following are risk factors for opioid abuse? Please answer Yes, No, or I don’t know for each option. 8a A personal history of psychiatric illness Yes 8b A personal history of past or current alcohol or drug abuse, or a family history of illicit drug use or alcohol abuse Yes 12 Please answer True, False, or I don’t know for each statement based on the labeling for TIRF medicines. 12a TIRF medicines can be abused in a manner similar to other opioid agonists. 22 Which of the following risks are associated with the use of TIRF medicines? Please answer True, False, or I don’t know for the following statements. 22a Misuse True 22b Abuse True 22c Addiction True 22d Overdose True 22e Hypothyroidism False 22f Infection False True True FDA_5125 Prescriber KAB Assessment Report Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies 3.2.4 Final 10 February 2017 Page 16 of 70 Key Risk Message 4 Key Risk Message 4 refers to the prescriber’s knowledge of the interchangeability of TIRF medicines based on route of administration, pharmacokinetic absorption, and dosage. Key Risk Message 4: TIRF medicines are not interchangeable with each other, regardless of route of administration. Question No. Question Desired response 12 Please answer True, False, or I don’t know for each statement based on the labeling for TIRF medicines. 12b TIRF medicines are interchangeable with each other regardless of route of administration. False 12c The conversion of one TIRF medicine for another TIRF medicine may result in a fatal overdose because of differences in the pharmacokinetics of fentanyl absorption. True 12d Dosing of TIRF medicines is not equivalent on a microgram-tomicrogram basis. True A patient is already taking a TIRF medicine but wants to change their medicine. His/her doctor decides to prescribe a different TIRF medicine (that is not a bioequivalent generic version of a branded product) in its place. According to the labeling, how should the prescriber proceed? Please select one option. 16b. The prescriber must not convert to another TIRF medicine on a microgram-permicrogram basis because these medicines have different absorption properties and this could result in a fentanyl overdose. 16 3.3 Additional Questions Additional questions in the survey include inclusion/exclusion questions to confirm respondent eligibility; questions on knowledge of safe use of TIRF medicines; questions about receipt/access to and reading the Full Prescribing Information and Medication Guide; questions about review and signing of the Patient-Prescriber Agreement Form (PPAF); and questions to collect demographic information. In addition, the following questions about behaviors (Question 14a-f and Question 32a-c) were asked after the key risk message questions. FDA_5126 Preseriber KAB Assessment Report Final 10 February 2017 Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 17 of 70 Question . No. Question How frequently do you perform the following activities when dispensing TIRF l4 medicines? Please answer Always, Only with the ?rst prescription, Sometimes, Never, or I don?t know.? 14a Ask patients (or their caregivers) about the presence of children in the home 14b Instruct patients (or their caregivers) not to share TIRF medicines with anyone else Counsel patients (or their caregivers) that accidental exposure to TIRF medicines by a 14? child may be fatal 14d Instruct patients (or their caregivers) to keep TIRF medicines out of the reach of children to prevent accidental exposure l4e Instruct patients (or their caregivers) about proper disposal of any unused or partially used TIRF medicines 14f Give patients (or their caregivers) the Medication Guide for their TIRF medicine How frequently do you perform the following activities when prescribing TIRF 32 medicines? Please answer Always, Only with the ?rst prescription, Sometimes, Never, or I don?t know. Talk to the patient about the risks and possible side effects of the TIRF medicine that was 32a most recently prescribed. 32b Instruct the patient on how to use the TIRF medicine that was most recently prescribed. 320 Instruct the patient on how to store or keep the TIRF medicine that was most recently prescribed. 4. STATISTICAL METHODS 4.1 Study Population 4.1.1 All Respondents The All Respondents population consisted of respondents that accessed the survey using a unique code. These respondents were used as the denominator for percentages in survey administration statistics unless otherwise speci?ed. 4.1.2 Completed Surveys (Primary Population) The primary population for analysis was all eligible prescribcrs who completed the survey. Eligible prescribcrs were de?ned as those respondents who answered Yes to Question 1 (agree to take part in survey) and Yes to Question 3 (enrolled in the TIRF REMS Access program), and No to Question 2 (participated in past survey) and No to Question 4 (worked for a TRIG company, UBC, RelayHealth, McKesson Specialty Care Solutions, or FDA). A survey was considered ?completed? when an eligible prescriber answered all relevant questions. 27 Prescriber KAB Assessment Report Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies 4.1.3 Final 10 February 2017 Page 18 of 70 General Population The general population consisted of all prescribers who prescribed a TIRF medicine in the past 6 months as shown in IMS Health data (IMS data) and REMS switch provider data. These populations were used to compare the population represented in the survey to the general population to determine whether those completing the survey were representative of the prescribing population. It was assumed that the IMS data covered the majority of HCPs prescribing TIRF medicines in the outpatient setting and REMS switch provider data included all HCPs prescribing TIRF medicines in the outpatient setting. The analysis included calculation of p-values by a chi-square test. 4.2 Primary Analysis Primary analyses were performed for all key risk messages. The primary analysis for a key risk message evaluated the number and percentage of correct responses for each individual question/item included in the key risk message. Confidence intervals (95% CI) were calculated using the exact binomial method around the percentage of correct responses. Primary analyses were then stratified by questions/characteristics of interest: 1) Those who indicated they both received/had access to and read the Medication Guide and Full Prescribing Information versus those who did not receive/have access to or read the Full Prescribing Information or Medication Guide (Questions 23-26). 2) Medical degree of respondents (Question 36). 3) Whether the survey was completed via the Internet or telephone 4) Time practicing medicine (Question 37). 5) The number of times per month they prescribed TIRF medicines within the last 6 months (Question 33). 6) Respondents practicing in a Closed Healthcare System (Question 38). Stratified analyses were conducted on all completed surveys. 4.3 Secondary Analyses As an indicator of the overall level of comprehension of the entire key risk message, descriptive analyses of the number and percentage of responders who answered various proportions of the key risk message questions/items correctly are presented (e.g., the proportion who answered 1 question/item in the key risk message correctly, those who answered 2 questions/items correctly, those who answered 3 questions/items correctly, etc.). A knowledge score was computed for each key risk message (KRM) and overall as a percentage for each respondent. The score was defined as the ratio of the number of correct responses to all KRM questions to the total number of possible correct responses to all KRM FDA_5128 Prescriber KAB Assessment Report Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Final 10 February 2017 Page 19 of 70 questions. The average knowledge score was calculated as the mean of the sore across all completed surveys; 95% CIs were calculated based on the normal distribution function. 4.4 Prescriber Report of a Potential Adverse Event, Product Complaint, or Medical Information Request during the Survey A prescriber may have reported a potential adverse event or other event experienced by a patient while taking a TIRF product either in free text fields while taking the online survey or while in conversation with the SCC Associate. If an event was mentioned to the SCC Associate, the Associate documented the event or complaint, the verbatim response, and the prescriber’s contact information, if provided. The prescriber was also informed that a representative from the appropriate TIRF medicine sponsor might contact him/her to obtain additional information about the event. The Internet surveys were monitored for any comments recorded in the free text field. Information on all reports (Internet or telephone) that constituted an adverse event or other event was forwarded to the appropriate TIRF medicine sponsor for processing within 1 business day of awareness of the event as outlined in the Escalating Adverse Events, Product Complaints, and Medical Information Requests Identified During Execution of the Knowledge, Attitudes, and Behavior Survey Project Specific Procedure. 5. RESULTS Results of the prescriber’s responses to questions in the KAB survey are summarized in this section; the full set of summary tables and listings are provided in Appendix B. 5.1 Survey Participants 5.1.1 Survey Participant Administration Results A total of 2848 prescribers were sent letters inviting them to participate in this survey (Table 1). A total of 8405 reminder letters were sent to non-responders (See Section 3.1 for survey methodology details). Most prescribers received more than 1 reminder letter. At the point of planned survey close date, the prescriber survey had still not met its goal of 300 survey completers; therefore, the survey fielding period was extended in an effort to meet the goal. The survey was closed on 20 December 2016 to allow for inclusion of results in the 17 February 2017 submission. A total of 294 prescribers completed the survey. From the total of 524 respondents who accessed the survey, 313 prescribers (59.7%) met eligibility criteria, and of those who met eligibility criteria, 294 (93.9%) completed the survey. Of these 294 prescribers, 289 (98.3%) completed the survey online, and 5 (1.7%) completed it by telephone (Table 3). Based on the TRIG Sponsors interpretation of state laws regarding prescriber reimbursement, respondents whose practices were based in Massachusetts, Vermont, and Minnesota were eligible to participate in the survey. However, they were not eligible to receive the FDA_5129 Prescriber KAB Assessment Report Final 10 February 2017 Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 20 of 70 $125 honorarium. Three respondents who practiced in Massachusetts and 1 respondent who practiced in Minnesota participated in the survey. Table 1. Survey Administration Statistics Parameter, Number of invitations distributed 2848 Number of invitations retumed as undeliverable 205 Number of reminder letters distributed 8405 All Respondentsm 524 (19.8) Eligible Respondentsm 313 (59.7) Completed surveym 294 (93.9) Did not complete the surveym 19 (6.1) Respondents not eligiblem? 211 (40.3) Source: Appendix B: Survey Tables, Table 1.1 Number of unique respondents who accessed the survey. Percentage is based on the number of invitations distributed excluding the number of invitations returned as undeliverable. Percentage is based on the number of all respondents. Percentage is based on the number of eligible respondents. Number of respondents who did not meet eligibility criteria or did not complete eligibility questions. As shown in Table 2, of the 524 prescribers who accessed the survey, 501 prescribers answered at least 1 survey question and 23 respondents did not answer any of the survey questions (discontinued the survey before answering Question 1). During the screening process it was determined that 185 of the 501 respondents who answered at least 1 survey question were not eligible to participate in the survey because they either indicated they had participated in or did not know whether they participated in a survey about TIRF medicines before (160 respondents); were not enrolled or did not know whether they were enrolled in the TIRF REMS Access program (15 respondents); or indicated they or an irmnediate family member had worked for a TRIG company, UBC, or FDA in the past or did not know if they or an immediate family member had worked for a TRIG company, UBC, or FDA in the past, or preferred not to answer the question (10 respondents). In addition, 2 of the 501 prescribers who answered at least 1 survey question discontinued the survey at Question 2, and prescriber discontinued at Question 3. Thus, there were 313 eligible participants (Table 2). 30 Preseriber KAB Assessment Report Final Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies 10 February 2017 Page 21 of 70 Table 2. Survey Participant Eligibility Results - All Respondents Prescribers Question Question 1: Do you agree to participate in this survey? Yes 501 (95.6) Now 0 Discontinued 23 (4.4) Question 2: Have you ever taken part in this survey about TIRF medicines before? TIRF medicines include Abstral?, Actiq?, entora?, Lazandac?, Subsys?, and generic versions of any of these brands. Yesm 70 (13.4) No 339 (64.7) 1 don't know?] 90 (17.2) Question not asked 0 Discontinued 25 (4.8) Question 3: Are you enrolled in the TIRF REMS Access program? Yes 323 (61.6) Now 7 (1.3) 1 don't known] 8 (1.5) Question not asked 160 (30.5) Discontinued 26 (5.0) Question 4: Have you or any of your immediate family members ever worked for any of the following companies or agencies? Please select all that apply.?3 Actavis Laboratories FL, Incl? 0 Anesta 0 BioDelivery Services International, Inc. 0 Cephalon, Inc. (a wholly-owned subsidiary of Teva Pharmaceutical Industries, Ltd.)m 3 (0.6) Depomed, Inc.[? 3 (0.6) Galena Biopharma, Inc.[? 1 (0.2) Insys Therapeutics, Inc.[? 6 (1.1) Mallinckrodt Pharmaceuticalsm (0.2) McKesson Specialty Care Solutionsm 0 Mylan Inc.?1 0 Par Pharmaceuticals, Inc.[? 0 RelayI-Iealthm 0 Therapeutics, Inc.[? 0 Preseriber KAB Assessment Report Final 10 February 2017 Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 22 of 70 Table 2. Survey Participant Eligibility Results - All Respondents Preseribers Question Teva Pharmaceuticals, (0.2) United BioSource Corporationm 0 0 None of these 313 (59.7) I don't know?] 0 Prefer not to answerm 2 (0.4) Question not asked [21 175 (33.4) Discontinued 26 (5.0) Source: Appendix B: Survey Tables, Table 1.2 Note: Respondents who discontinued the survey before completing all eligibility questions without being identi?ed as ineligible in any of the previous questions are counted as discontinued. Once a respondent is counted as discontinued, they will count as discontinued in all subsequent eligibility questions. [11 Ineligible to participate in the survey. Question not asked due to termination response from a previous question. More than one response can be selected, so percentages may not sum to 100%. Ineligible to participate in the survey if selected additionally to another response. Preseribers taking the survey online took a mean of 18.91 minutes to complete it, while those taking it by telephone took a mean of 23.90 minutes (Table 3). Table 3. Time to Complete Survey - Completed Surveys Telephone Internet TotalIll Summary Statistic (minutes) 5 289 294 Mean (SD) 23.90 (2.565) 18.91 (10.867) 18.99 (10.797) Minimum 21.0 5.6 5.6 Median 25.42 16.02 16.17 Maximum 26.4 91.2 91.2 Category, 0 to <5 Minutes 0 0 0 5to<10Minutes 0 31 31 10 to <15 Minutes 0 95 95 15 to <20 Minutes 0 74 74 20 to <25 Minutes 2 36 38 32 Preseriber KAB Assessment Report Final 10 February 2017 Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 23 of 70 Table 3. Time to Complete Survey - Completed Surveys Telephone Internet Total" 25 to <30 Minutes 3 22 25 30 Minutes or more 0 31 31 Source: Appendix B: Survey Tables, Table 1.3 Number of eligible prescribers completing the survey. 5.1.2 Description of Eligible Prescribers who Completed the Survey The demographic characteristics of prescribers who completed the survey are shown in Table 4. More males than females participated in the survey (59.5% versus 38.8%) and most respondents did not practice within a closed healthcare system. Most respondents had prescribed a TIRF medicine 1 to 2 times per month or 3 to 5 times per month within the 6 months preceding the survey, and of the TIRF medicines prescribed within the last 6 months, Aetiq? or generic Actiq? or Subsys? were most frequently prescribed. Over half of prescribers identi?ed their medical degree as MD and their medical specialty as pain management Most prescribers had practiced medicine for 1 1 years or longer Of the survey respondents, 31.6% of respondents were from the West, 30.6% from the South, 21.1% from the Northeast, and 16.3% from the Midwest regions of the US (Table 4). Table 4. Description of Eligible Prescribers - Completed Surveys Prescribers Question Question 33: On average, how many times per month have you prescribed the TIRF medicines within the last 6 months? None 15 (5.1) - 2 times per month 188 (63.9) 3 - 5 times per month 64 (21.8) More than 5 times per month 21 (7.1) I don't remember 6 (2.0) 33 Preseriber KAB Assessment Report Final 10 February 2017 Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 24 of 70 Table 4. Description of Eligible Prescribers - Completed Surveys Prescribers Question 11 Question 34: Please select the TIRF medicines that you have prescribed within the last 6 months. Please select all that apply."" Abstral? 31 (11.1) Actiq? or generic Actiq? 158 (56.6) Fentora? 93 (33.3) Lazanda? 32 (11.5) Subsys? 150 (53.8) (Answered "None" to Question 33) 15 Question 35: What is your gender? Male 175 (59.5) Female 1 14 (38.8) Prefer not to answer 5 (1.7) Question 36: What is your medical degree? MD 167 (56.8) DO 26 (8.8) Nurse Practitioner 53 (18.0) Physician Assistant 46 (15.6) Prefer not to answer 2 (0.7) Question 37: In total, how many years have you been practicing medicine, since completing your education? Less than 3 years 26 (8.8) 3 - 5 years 49 (16.7) 6 - 10 years 42 (14.3) 11 - 15 years 43 (14.6) More than 15 years 134 (45.6) Prefer not to answer 0 Question 38: Do you practice in a closed healthcare system, such as: Kaiser, VA, or Yes 4(1.4) No 290 (98.6) 34 Prescriber KAB Assessment Report Final 10 February 2017 Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industrv Group (TRIG) of Companies Page 25 of 70 Table 4. Description of Eligible Prescribers - Completed Surveys Prescribers Question Geographic Distribution (based on Question 39 - In which state do you Northeast 62 (21.1) Midwest 48 (16.3) South 90 (30.6) West 93 (31.6) Other 0 Prefer not to answer 1 (0.3) Question 40: What is your medical specialty? Oncology 45 (15.3) Primary care 29 (9.9) Pain management 173 (58.8) Other (please speeify)l?1 46 (15.6) No designated specialty (0.3) Source: Appendix B: Survey Tables, Table 2 [11 Percentages are calculated based on the sample presented with this question because of skip logic in the survey. More than one response can be selected, so percentages may not sum to 100% ?1 US. Census Bureau, last revised Friday, 27-Jul-2001 12:59:43 EDT., Geography Division. Northeast includes CT, MA, ME, NH, NJ, NY, PA, RI, and VT. Midwest includes IA, IL, IN, KS, MI, MN, MO, ND, NE, OH, SD, and W1. South includes AL, AR, DC, DE, FL, GA, KY, LA, MD, MS, NC, OK, SC, TN, TX, VA, and WV. West includes AK, AZ, CA, CO, HI, ID, MT, NM, NV, OR, UT, WA, and WY. Other includes Puerto Rico, Northem Mariana Islands, US Virgin Islands, American Samoa and Guam. Verbatim text for the question about medical specialty is presented in Listing 4. 5.1.2.1 Comparison of Survey Respondents to the General Population of TIRF Prescribers A comparison of prescribers who completed the survey to the general population of prescribers based on REMS switch provider data is provided in Table 5. There were no statistically signi?cant differences (p<0.05) observed in the demographics between the prescribers completing the survey compared with the general population of prescribers for questions on average number of times per month TIRF medicines have been prescribed, and geographic region (the only characteristics available from the switch provider data). 35 Preseriber KAB Assessment Report Final 10 February 2017 Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 26 of 70 Table 5. Comparison of Survey Respondents to General Population of Prescribers (REMS Switch Provider Data) Prescribers of Prescribers TIRF Prescribers Completing Medicines in the Completing Survey Past Six Months Survey (REMS Switch (REMS Switch (Self-Report) Provider Data) Provider Data) Question 11 p-value Average times per month TIRF medicines have been prescribed within the last 6 monthsIll None 15 (5.1) 0 0 1 - 2 times per month 188 (63.9) 163 (55.4) 1671 (54.9) 0 4088 3 - 5 times per month 64 (21.8) 98 (33.3) 951 (31.2) . More than 5 times per month 21 (7.1) 33 (11.2) 423 (13.9) I don't remember 6 (2.0) TIRF medicines prescribed within the last 6 Abstral? 31 (11.1) 18 (6.1) 199 (6.5) Actiq? or generic Actiq? 158 (56.6) 166 (56.5) 1652 (54.3) Fentora? 93 (33.3) 74 (25.2) 824 (27.1) Lazanda? 32 (11.5) 30 (10.2) 273 (9.0) Subsys? 150 (53.8) 137 (46.6) 1406 (46.2) (Answered "None" to 15 Question 33) Geographic region's' Northeast 62 (21.1) 59 (20.1) 581 (19.1) Midwest 48 (16.3) 48 (16.3) 466 (15.3) South 90 (30.6) 107 (36.4) 1116 (36.7) 0.8942 West 93 (31.6) 80 (27.2) 882 (29.0) Other 0 0 0 36 Preseriber KAB Assessment Report Final 10 February 2017 Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 27 of 70 Table 5. Comparison of Survey Respondents to General Population of Prescribers (REMS Switch Provider Data) Prescribers of Prescribers TIRF Prescribers Completing Medicines in the Completing Survey Past Six Months Survey (REMS Switch (REMS Switch (Self-Report) Provider Data) Provider Data) (N =3045) Question 11 p-value Prefer not to answer 1 (0.3) Source: Appendix B: Survey Tables, Table 2b Note: Switch provider data was provided by McKesson on September 2016. P-values are based on the REMS switch provider data comparing the survey completers vs. the prescribers of TIRF medicines in the last 6 months. Not available. Based on Question 33. Based on Question 34. Based on Question 39; US. Census Bureau, last revised Friday, 27-Jul-2001 12:59:43 EDT, Geography Division. Northeast includes CT, MA, ME, NH, NJ, NY, PA, RI, and VT. Midwest includes IA, IL, IN, KS, MI, MN, MO, ND, NE, OH, SD, and WI. South includes AL, AR, DC, DE, FL, GA, KY, LA, MD, MS, NC, OK, SC, TN, TX, VA, and WV. West includes AK, AZ, CA, CO, HI, ID, MT, NM, NV, OR, UT, WA, and WY. Other includes Puerto Rico, Northern Mariana Islands, US Virgin Islands, American Samoa and Guam. To provide a more comprehensive comparison of prescribers completing the survey and the general population of prescribers, additional data were obtained through IMS Health. This comparison of prescribers who completed the survey to the general population of prescribers based on IMS data is provided in Table 6. In this analysis there were statistically signi?cant differences (p<0.05) observed in the demographics between the prescribers completing the survey compared with the general population of prescribers on most questions with the exception of geographic distribution of practice location for which characteristics between groups were similar. It is important to note the sample size of the general population of prescribers (Nana) affects the power of the test, and therefore, may mean that even small differences between groups resulted in signi?cant p-values. Additionally, since the IMS data is compared to self-reported data, there may be reporting bias. For the questions that showed statistically signi?cant differences between the groups, it is important to review the proportional differences between the groups for each response within a question. For example, there were differences between the prescribers completing the survey and the general population of prescribers for gender (response male; 59.5% vs. medical degree (response 56.8% vs. and number of years practicing medicine (response more than 15 years; 45.6% vs. but the majority of responders in each group selected these responses. In addition, con?icting results were seen for the average prescribing frequency, indicating potential reporting bias. For differences speci?cally related to specialty, it is dif?cult to determine whether these are true differences or if this is impacted by reporting bias. 37 Prescriber KAB Assessment Report Final 10 February 2017 Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 28 of 70 While the differences are statistically signi?cant, these differences should not have a big impact on the primary objectives of the survey since a relevant uniform correlation of demographic characteristics and the knowledge of the key risk messages could not be detected. Table 6. Comparison of Survey Respondents to General Population of Prescribers Prescribers Prescribers of TIRF Completing Medicines in the Survey Past Six Months (Self-Report) Data)?ll (4) Question 11 p-value Average times per month TIRF medicines have been prescribed within the last 6 months'zl None 15 (5.1) - 2 times month 188 (63.9) pe <.0001 3 - 5 times per month 64 (21.8) More than 5 times per month 21 (7.1) I don't remember 6 (2.0) TIRF medicines prescribed within the last 6 Abstral? 31 (11.1) Actiq? or generic Actiq? 158 (56.6) Fentora? 93 (33.3) Lazanda? 32 (11.5) Subsys? 150 (53.8) (Answered "None? to Question 33) 15 Gender? Male 175 (59.5) 0.0002 Female 114 (38.8) Prefer not to answer/Unknown 5 (1.7) Medical Degree'sI MD 167 (56.8) DO 26 (8.8) Nurse Practitioner 53 (18.0) <.0001 Physician Assistant 46 (15.6) Others Prefer not to answer 2 (0.7) 38 Preseriber KAB Assessment Report Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Final 10 February 2017 Page 29 of 70 Table 6. Comparison of Survey Respondents to General Population of Prescribers Prescribers Prescribers of TIRF Completing Medicines in the Survey Past Six Months (Self-Report) (IMS Data)Ill Question 11 p-value Number of Years Practicing Medicine? (4) Less than 3 years 26 (8.8) 3 - 5 years 49 (16.7) 6 - 10 years 42 (14.3) <.0001 11 - 15 years 43 (14.6) More than 15 years 134 (45.6) Prefer not to answer/Unknown 0 Geographic Distribution of Practice Location?I Northeast 62 (21.1) Midwest 48 (16.3) South 90 (30.6) 0.4771 West 93 (31.6) Other 0 Prefer not to answer 1 (0.3) Medical Specialty's' Oncology 28 (9.5) Primary care 24 (8.2) Pain management 108 (36.7) <.0001 Other (please specify) 35 (11.9) No designated specialtym 0 39 Preseriber KAB Assessment Report Final 10 February 2017 Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 30 of 70 Table 6. Comparison of Survey Respondents to General Population of Prescribers Prescribers Prescribers of TIRF Completing Medicines in the Survey Past Six Months (Self-Report) (IMS (NW0 Question 11 p-value 99 (33.7) Source: Appendix B: Survey Tables, Table 2a Note: P-values are calculated by a chi-square test excluding prefer not to answer, other, and comparable categories. The question regarding TIRF medicine prescriptions ?lled in the last 6 months directed respondents to "select all that apply"; therefore, p-values were not calculated for the responses to this question. Not available. Based on data from provided on 07Dec2016. Data covered period of 01Mar2016 to 028ep2016. Based on Question 33. Based on Question 34. Based on Question 35. Based on Question 36. Based on Question 37. Based on Question 39; US. Census Bureau, last revised Friday, 27-Jul-2001 12:59:43 EDT., Geography Division. Northeast includes CT MA, ME, NH, NJ, NY, PA, RI, and VT. Midwest includes IA, IL, IN, KS, MI, MN, MO, ND, NE, OH, SD, and WI. South includes AL, AR, DC, DE, FL, GA, KY, LA, MD, MS, NC, OK, SC, TN, TX, VA, and WV. West includes AK, AZ, CA, CO, HI, ID, MT, NM, NV, OR, UT, WA, and WY. Other includes Puerto Rico, Northem Mariana Islands, US Virgin Islands, American Samoa and Guam. Based on Question 36/40. for the survey data is calculated as the total number of prescribers who responded "Nurse Practitioner" or "Physician Assistant" to Question 36. The other categories for the survey data are based on responses to Question 40, for prescribers who are not categorized as data includes Not Applicable, Other Specialty, and Unspeci?ed. 5.1.3 TIRF Medicines Educational Materials Prescribers were asked about their access to educational materials for TIRF medicines, speci?cally the Full Prescribing Information and the Medication Guide (Table 7). Almost all prescribers reported they had received or had access to the Full Prescribing Information and the Medication Guide Of those with access to these materials, 87.0% indicated that they had read the Full Prescribing Information and 92.2% indicated that they had read the Medication Guide. Eight prescribers indicated they had questions about the information in the Full Prescribing Information or Medication Guide (provided in Listing 3). 40 Preseriber KAB Assessment Report Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies 10 February 2017 Page 31 of 70 Table 7. Responses to Questions about TIRF Educational Materials - Completed Surveys Prescribers Question Question 23: Did you receive or do you have access to the Full Prescribing lnfonnation for the TIRF medicine(s) that you prescribe? Yes 285 (96.9) No 5 (1.7) I don't know 4 (1.4) Question 24: Did you read the Full Prescribing Information for the TIRF medicine(s) that you prescribe?Ill Yes 248 (87.0) No 31 (10.9) I don't know 6 (2.1) (Answered ?No" or don 't know? to Question 23) 9 Question 25: Did you receive or do you have access to the Medication Guide for the TIRF medicine(s) that you prescribe? Yes 282 (95.9) No 4 (1.4) [don't know 8 (2.7) Question 26: Did you read the Medication Guide for the TIRF medicine(s) that you prescribe?Ill Yes 260 (92.2) No 17 (6.0) I don?t know 5 (1.8) (Answered ?No? or don 't know" to Question 25) 12 Question 27: Did you or do you have any questions about the information in the Full Prescribing Information or Medication Guide?'2 Yes 8 (2.7) No 264 (89.8) I don't know 22 (7.5) Source: Appendix B: Survey Tables, Table 4 [11 Percentages are calculated based on the sample presented with this question because of skip logic in the survey. Verbatim text for questions about the Full Prescribing Information or Medication Guide is presented in Listing 3. Additionally, most prescribers reported reviewing the PPAF with each patient or their caregiver and of those, 97.8% indicated they and the patient/caregiver sign the 41 Preseriber KAB Assessment Report Final 10 February 2017 Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 32 of 70 PPAF and 89.9% indicated that they give a copy of the PPAF to the patient or the patient?s caregiver (Table 8). Table 8. Responses to Questions about the Patient-Prescriber Agreement Form - Completed Surveys Prescribers Question 11 Question 29: Do you review the Patient-Prescriber Agreement Form with each of your patients for whom you prescribe TIRF medicines or their caregiver? Yes 278 (94.6) No 10 (3.4) I don't know 6 (2.0) Question 30: Do you and the patient or their caregiver sign the Patient-Prescriber Agreement onn for TIRF medicines after you have reviewed it with Yes 272 (97.8) No 2 (0.7) I don't know 4 (1.4) (Answered "No" or don 't know to Question 29) 16 Question 31: Do you give a copy of the Patient-Prescriber Agreement Form for TIRF medicines to the patient or their Yes 250 (89.9) No 15 (5.4) I don't know 13 (4.7) (Answered "No" or don't know" to Question 29) 16 Source: Appendix B: Survey Tables, Table 5 [11 Percentages are calculated based on the sample presented with this question because of skip logic in the survey. 5.2 Key Risk Messages 5.2.1 Key Risk Message 1 Key Risk Message 1 states medicines are contraindicated in opioid non-tolerant patients.? Fourteen questions/ items de?ned this key risk message (Table 9). Almost all prescribers knew that patients with cancer who are considered opioid-tolerant are those who are taking around-the-clock opioid therapy for underlying, persistent cancer pain for one week or longer 95% CI: 91.7 97.1) and are those who are not currently taking opioid therapy are not opioid-tolerant 95% CI: 90.5 96.3). In addition, most understood that cancer patients with no known contraindications to the drug fentanyl, but who are not taking around-the-clock opioid therapy, are not considered opioid tolerant 42 Prescriber KAB Assessment Report Final 10 February 2017 Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 33 of 70 95% CI: 88.9 95.3). Nearly all prescribers 95% CI: 93.8 98.4) indicated TIRF medicines should only be taken by patients who are opioid tolerant. Similarly, most prescribers knew that TIRF medicines are contraindicated in opioid non- tolerant patients because life-threatening respiratory depression could occur 95% CI: 88.1 94.7), that death has occurred in opioid non-tolerant patients treated with some fentanyl products 95% CI: 92.6 97.6), and that TIRF medicines may not be used to treat opioid non-tolerant patients 95% CI: 84.2 91.9). In addition, 85.7% (95% CI: 81.2 89.5) of prescribers were aware that starting a patient on a TIRF medicine must begin with titration from the lowest dose available for that speci?c product, even if the patient has previously taken another TIRF medicine. The majority of prescribers were aware of the regimens, taken for one week or longer, that de?ned an opioid-tolerant patient based on the labeling for TIRF medicines: 8 mg oral hydromorphone/day 95% CI: 66.3 76.8), 60 mg oral morphine/day 95% CI: 92.6 97.6), 30 mg oral oxycodone/day 95% CI: 77.1 86.2), 25 meg transdermal fentanyl/hour 95% CI: 85.0 92.4), 25 mg oral oxymorphone/day (79.6 95% CI: 74.5 84.0), and an equianalgesic dose of another oral opioid 95% CI: 59.9 71.1). Table 9. Primary Analysis of Responses to Questions Linked to Key Risk Message #1 - Completed Surveys Prescribers Question [95% Question 5: Please select True, False, or I don't know for each of the following. According to the labeling for TIRF medicines, patients with cancer who are considered opioid-tolerant are those: 5a: Who are taking around-the-clock opioid th erapy for underlying, persistent cancer pain for one week or longer Tmem 279 (94.9) [91.7 - 97.1] False (3.7) I don't know 4 (1.4) 5b: Who are not currently taking opioid therapy, but have taken opioid therapy before True 16 (5.4) Falsem 276 (93.9) [90.5 - 96.3] I don't know 2 (0.7) 5c: Who have no known contraindications to the drug fentanyl, but are not currently taking around-the-clock opioid therapy True 17 (5.8) Falsem 272 (92.5) [88.9 - 95.3] I don't know 5 (1.7) 43 Preseriber KAB Assessment Report Final 10 February 2017 Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 34 of 70 Table 9. Primary Analysis of Responses to Questions Linked to Key Risk Message #1 - Completed Surveys Prescribers Question 11 [95% Question 7: Please answer True, False, or I don't know for each statement based on the labeling for TIRF medicines. 7a: TIRF medicines are contraindicated in opioid non-tolerant patients because life-threaten ing respiratory depression could occur at any dose. Truem 270 (91.8) [88.1 - 94.7] False 21 (7.1) I don't know 3 (1.0) 7b: Death has occurred in opioid non-tolerant patients treated with some fentanyl products. Truem 281 (95.6) [92.6 - 97.6] False 3 (1.0) I don't know 10 (3.4) 7c: TIRF medicines may be used to treat opioid non-tolerant patients. True 27 (9.2) Falsem 260 (88.4) [84.2 - 91.9] I don't know 7 (2.4) 7d: Prescribers starting a patient on a TIRF medicine must begin with titration from the lowest dose available for that specific product, even if the patient has previously taken another TIRF medicine. Truem 252 (85.7) [81.2 - 89.5] False 37 (12.6) I don't know 5 (1.7) Question 13: Please select True, False, or I don't know for each of the following. According to the labeling for TIRF medicines, patients considered opioid-tolerant are those who are taking, for one week or longer, at least: 13a: 8 mg oral hydromorphone/day Truem 211 (71.8) [66.3 - 76.8] False 69 (23.5) I don't know 14 (4.8) 13b: 60 mg oral morphine/day Truem 281 (95.6) [92.6 - 97.6] False 6 (2.0) I don't know 7 (2.4) 13c: 30 mg oral oxycodone/day Truem 241 (82.0) [77.1 - 86.2] 44 Prescriber KAB Assessment Report Final 10 February 2017 Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 35 of 70 Table 9. Primary Analysis of Responses to Questions Linked to Key Risk Message #1 - Completed Surveys Prescribers Question 95% l Ill False 44 (15.0) I don't know 9 (3.1) 13d: 25 meg transdermalfentanyl/hour Truem 262 (89.1) [85.0 - 92.4] False 21 (7.1) 1 don't know 11 (3.7) Be: 25 mg oral oxymorphone/day Tmem 234 (79.6) [74.5 - 84.0] False 33 (1 1.2) 1 don't know 27 (9.2) 13f: An equianalgesic dose of another oral opioid True'zl 193 (65.6) [59.9 - 71.1] False 56 (19.0) 1 don't know 45 (15.3) Question 21: Please answer True, False, or I don't know for the following statement about TIRF medicines: TIRF medicines should only be taken by patients who are opioid tolerant. Truem 284 (96.6) [93.8 - 98.4] False 8 (2.7) I don't know 2 (0.7) Source: Appendix B: Survey Tables, Table 7.1 95% exact two-sided con?dence intervals are calculated using the Clopper-Pearson method. Correct response. Overall, 32.7% of prescribers answered all questions/ items of key risk message 1 correctly, 58.5% missed no more than 1 item and 71.8% missed no more than 2 items (Table 10). 45 Prescriber KAB Assessment Report Final 10 February 2017 Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 36 of 70 Table 10. Secondary Analysis of Responses to Questions Linked to Key Risk Message #1 - Completed Surveys Prescribers Correct Responses 0 correct responses 0 I correct response 0 2 correct responses 0 3 correct responses 1 (0.3) 4 correct responses 0 5 correct responses 1 (0.3) 6 correct responses 1 (0.3) 7 correct responses 4 (1.4) 8 correct responses 9 (3.1) 9 correct responses 16 (5.4) 10 correct responses 23 (7.8) 11 correct responses 28 (9.5) 12 correct responses 39 13.3) 13 correct responses 76 (25.9) 14 correct responses 96 (32.7) Source: Appendix B: Survey Tables, Table 7.2 For Key Risk Message 1 Question 13, the analysis strati?ed by whether the Medication Guide and Full Prescribing Information was received/accessed and read showed an overall trend in favor of respondents who received and read the materials. Of note, the differences for Items 13a and 13c were signi?cant (Table 1 1). Similarly for Question 13, there was trend toward lower correct response rate for prescribcrs practicing medicine less than 3 years when strati?ed by time practicing medicine (Table 12). No other trends were evident when the results for Key Risk Message 1 were strati?ed by medical degree of respondents or number of times per month TIRF medicines were prescribed within the last 6 months. For sub-group analysis by modality used to complete the survey (intcmet versus telephone), and by those practicing in a closed healthcare system, sample sizes were too small to allow for meaningful interpretation (see Appendix B). 46 Preseriber KAB Assessment Report Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Final 10 February 2017 Page 37 of 70 Table 11. Responses to Questions Linked to Key Risk Message #1 by Reading Full Prescribing Information or Medication Guide - Completed Surveys (Questions/Items with Apparent Trends) Reading Full Prescribing Information or Medication Guide Received and read Did not receive or read Pl or Med Guide Pl or Med Guide Question [95% cu'" [95% cu'? Question 13: Please select True, False, or I don't know for each of the following. According to the labeling for TIRF medicines, patients considered opioid-tolerant are those who are taking, for one week or longer, at least: I 3a: 8 mg oral hydromorphone/day Truem 200 (74.6) [69.0 - 79.7] 11 (42.3) [23.4 - 63.1] False 57 (21.3) 12 (46.2) 1 don't know 11 (4.1) 3 (11.5) I 3b: 60 mg oral morphine/day Truem 258 (96.3) [93.2 - 98.2] 23 (88.5) [69.8 - 97.6] False 6 (2.2) 0 [don't know 4 (1.5) 3 (11.5) I 30: 30 mg oral oxycodone/day Truem 226 (84.3) [79.4 - 88.5] 15 (57.7) [36.9 - 76.6] False 36 (13.4) 8 (30.8) 1 don?t know 6 (2.2) 3 (11.5) 1311: 25 transdermalfentanyl/hour Truem 242 (90.3) [86.1 - 93.6] 20 (76.9) [56.4 - 91.0] False 19 (7.1) 2 (7.7) I don?t know 7 (2.6) 4 (15.4) I 3e: 25 mg oral oxymorphone/day Truem 218 (81.3) [76.2 - 85.8] 16 (61.5) [40.6 - 79.8] False 26 (9.7) 7 (26.9) 1 don't know 24 (9.0) 3 (11.5) I 3f: An equianalgesic dose of another oral opioid Truelz] 178 (66.4) [60.4 - 72.0] 15 (57.7) [36.9 - 76.6] False 52 (19.4) 4 (15.4) I don?t know 38 (14.2) 7 (26.9) Source: Appendix B: Survey Tables, Table 7.1.1 95% exact two-sided con?dence intervals are calculated using the Clopper-Pearson method. Correct response. 47 Preseriber KAB Assessment Report Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Final 10 February 2017 Page 38 of 70 Table 12. Responses to Questions Linked to Key Risk Message #1 by Time Practicing Medicine - Completed Surveys (Questions/Items with Apparent Trends) Time Practicing Medicine Less than 3 years 3 to 5 years 6 to 15 years More than 15 years (N =85) 134) Question [95% cu'" [95% cu'? [95% [95% Question 13: Please select True, False, or I don't know for each of the following. According to the labeling for TIRF medicines, patients considered opioid-tolerant are those who are taking, for one week or longer, at least: I 3a: 8 mg oral ydromorphone/da Truem 14 (53.8) [33.4 - 73.4] 35 (71.4) [56.7 - 83.4] 57 (67.1) [56.0 - 76.9] 105 (78.4) [70.4 - 85.0] False 8 (30.8) 13 (26.5) 22 (25.9) 26 (19.4) 1 don't know 4 (15.4) 1 (2.0) 6 (7.1) 3 (2.2) I 3b: 60 mg oral morphine/day Truem 23 (88.5) [69.8 - 97.6] 48 (98.0) [89.1 - 99.9] 79 (92.9) [85.3 - 97.4] 131 (97.8) [93.6 - 99.5] False 0 1 (2.0) 4 (4.7) 1 (0.7) [don't know 3 (11.5) 0 2 (2.4) 2 (1.5) 13c: 30 mg oral oxycodone/day Truem 17 (65.4) [44.3 - 82.8] 40 (81.6) [68.0 - 91.2] 69 (81.2) [71.2 - 88.8] 115 (85.8) [78.7 - 91.2] False 6 (23.1) 8 (16.3) 13 (15.3) 17 (12.7) 1 don't know 3 (11.5) 1 (2.0) 3 (3.5) 2 (1.5) I 3d: 25 transdermalfemanyl/hour Truem 20 (76.9) [56.4 - 91.0] 43 (87.8) [75.2 - 95.4] 79 (92.9) [85.3 - 97.4] 120 (89.6) [83.1 - 94.2] False 2 (7.7) 4 (8.2) 3 (3.5) 12 (9.0) [don't know 4 (15.4) 2 (4.1) 3 (3.5) 2 (1.5) 48 Preseriber KAB Assessment Report Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Final 10 February 2017 Page 39 of 70 Table 12. Responses to Questions Linked to Key Risk Message #1 by Time Practicing Medicine - Completed Surveys (Questions/Items with Apparent Trends) Time Practicing Medicine Less than 3 years 3 to 5 years 6 to 15 years More than 15 years 134) Question [95% 01'" [95% cu'? [95% [95% I 3e: 25 mg oral oxymorphone/day Truem 17 (65.4) [44.3 - 82.8] 39 (79.6) [65.7 - 89.8] 68 (80.0) [69.9 - 87.9] 110 (82.1) [74.5 - 88.2] False 5 (192) 8 (16.3) 7 (8.2) 13 (9.7) [don't know 4(15.4) 2(4.1) 10(ll.8) 11 (8.2) I 3 f: An eq uianalgesic dose of another oral opioid Truelz] 12 (46.2) [26.6 - 66.6] 35 (71.4) [56.7 - 83.4] 53 (62.4) [51.2 - 72.6] 93 (69.4) [60.9 - 77.1] False 6 (23.1) 5 (10.2) 20 (23.5) 25 (18.7) [don't know 8 (30.8) 9 (18.4) 12 (14.1) 16 (1 1.9) Source: Appendix B: Survey Tables, Table 7.1.4 95% exact two-sided con?dence intervals are calculated using the Clopper-Pearson method. Correct response. 49 Prescriber KAB Assessment Report Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies 5.2.2 Final 10 February 2017 Page 40 of 70 Key Risk Message 2 Key Risk Message 2 states “TIRF medicines are only indicated for the management of breakthrough pain in adult cancer patients 18 years of age and older (16 years of age and older for Actiq® brand and generic equivalents) who are already receiving and who are tolerant to around-the-clock opioid therapy for their underlying persistent cancer pain.” Ten questions/items defined this key risk message (Table 13). The majority of prescribers (77.2%, 95% CI: 72.0 81.9) correctly indicated that according to the product labeling, a cancer patient may not start a TIRF medicine and an around-the-clock opioid at the same time, and 78.2% (95% CI: 73.1 82.8) correctly indicated that according to the product labeling, a cancer patient who had been on an around-the-clock opioid for one day may not start taking a TIRF medicine for breakthrough pain. In addition, 99.3% of prescribers (95% CI:97.6 99.9) were aware that per the approved labeling, TIRF medicines are approved for use in patients with breakthrough pain from cancer, and not for patients with acute or postoperative pain (94.6%, 95% CI: 91.3 96.9), headache or migraine pain (93.9%, 95% CI: 90.5 96.3), dental pain (96.3%, 95% CI: 93.4 98.1), or chronic non-cancer pain (78.2%, 95% CI: 73.1 82.8). The 54 prescribers (18.4%) who stated that per the approved labeling for TIRF medicines, chronic non-cancer pain is an approved indication (Item 9e) were presented with 2 additional questions as requested by FDA. Question 10 addressed the type of chronic pain conditions they prescribe a TIRF medicine to treat (Table 14). The most frequently reported conditions were back pain (16.7%), chronic pain (14.8%), and cancer pain (11.1%). Question 11 addressed the reasons for selecting a TIRF medicine to treat these conditions (Table 15). The most frequently reported reasons were efficacy (24.1%), “I do not treat non-cancer patients” (13.0%), fast onset (11.1%), and that other types of treatments have failed (11.1%). Verbatim responses for Questions 10 and 11 can be found in Listing 1.1 and Listing 2.1, respectively (Appendix B). Most prescribers (72.1%, 95% CI: 66.6 77.2) correctly indicated that a TIRF medicine should not be prescribed to an adult female with localized breast cancer who just completed a mastectomy and reconstructive surgery and who has persistent cancer pain managed with 30 mg oral morphine daily for the past 6 weeks (Table 13). Regarding reviewing the Medication Guide with the patient, a high percentage of prescribers (96.3%, 95% CI: 93.4 98.1) were aware that patients need to be informed that TIRF medicines must not be used for acute or postoperative pain, pain from injuries, headache/migraine, or any other short-term pain; and most (76.5%, 95% CI: 71.3 81.3) correctly indicated that patients should be instructed that if they stop taking their around-theclock opioid medicine, they cannot continue to take their TIRF medicine. FDA_5150 Preseriber KAB Assessment Report Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Final 10 February 2017 Page 41 of 70 Table 13. Primary Analysis of Responses to Questions Linked to Key Risk Message #2 - Completed Surveys Question Prescribers [95% Question 6: Please answer True, False, or I don't know for each statement based on the labeling for TIRF medicines. 6a: According to the product labeling, a cancer patient may start a TIRF medicine and an around-the-clock opioid at the same time. True 52 (17.7) Falselz] 227 (77.2) [72.0 - 81.9] I don't know 15 (5.1) 6b: According to the product labeling, a cancer patient who has been on an around-the-clock opioid for I day may start taking a TIRF medicine for breakthrough pain. True 54 (18.4) Falsem 230 (78.2) [73.1 - 82.8] 1 don't know 10 (3.4) Question 9: Per the approved labeling for TIRF medicines, for which of the following indication(s) are TIRF medicines approved? Please answer Yes, No, or I don't know for each option. 9a: Acute or postoperative pain Yes 9 (3.1) Nom 278 (94.6) [91.3 - 96.9] I don't know 7 (2.4) 9b: Headache or migraine pain Yes 6 (2.0) Nom 276 (93.9) [90.5 - 96.3] I don't know 12 (4.1) 9c: Dental pain Yes 4 (1.4) New 283 (96.3) [93.4 - 98.1] I don't know 7 (2.4) 9d: Breakthrough pain from cancer Yesm 292 (99.3) [97.6 - 99.9] No 2 (0.7) I don't know 0 Prescriber KAB Assessment Report Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Final 10 February 2017 Page 42 of 70 Table 13. Primary Analysis of Responses to Questions Linked to Key Risk Message #2 - Completed Surveys Prescribers Question [95% Cl]Ill 9e: Chronic non-cancer pain Yes 54 (18.4) Now 230 (78.2) [73.1 - 82.8] I don't know 10 (3.4) Question 15: The patients described are experiencing breakthrough pain. According to the labeling, a TIRF medicine is not appropriate for one of them. Which patient should not receive a TIRF medicine? Please select one option. Adult male with advanced lung cancer; underlying persistent cancer pain managed with 25 meg/hour transdermal fentanyl patches for the past two months. 20 (6.8) Adult female with localized breast cancer; just completed a mastectomy and reconstructive surgery; persistent cancer pain managed with 30 mg oral morphine daily for the past 6 weeksm 212 (72.1) [66.6 - 77.2] Adult male patient with advanced prostate cancer who, over the last 2 weeks, has 18 (6.1) been prescribed 100 mg oral morphine daily for pain due to bone metastasis. Adult female with advanced sarcoma who has been taking a daily dose of 12 mg 27 (9.2) oral hydromorphone for the last 3 weeks. I don't know 17 (5.8) Question 20: Before initiating treatment with a TIRF medicine, prescribers must review the Medication Guide with the patient. Please select True, False, or I don't know for each of the following counseling statements. 20b: Inform patients that TIRF medicines must not be used for acute or postoperative pain, pain from injuries, headache/migraine, or any other short-term pain. Truem 283 (96.3) [93.4 - 98.1] False 8 (2.7) I don't know 3 (1.0) 20c: Instruct patients that they can continue to take their TIR medicine, if they stop taking their around-the- clock opioid medicine. True 58 (19.7) Falsem 225 (76.5) [71.3 - 81.3] 1 don't know 1 1 (3.7) Source: Appendix B: Survey Tables, Table 8.1 95% exact two-sided con?dence intervals are calculated using the Clopper-Pearson method. Correct response. 52 Preseriber KAB Assessment Report Final 10 February 2017 Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 43 of 70 Table 14. Types of Chronic Pain Conditions Reported - Completed Surveys for Prescribers Who Prescribed TIRF Medicines for Chronic Non-Cancer Pain Prescribers Question Question 10: For what type(s) of chronic non-cancer pain conditions do you prescribe a TIRF medicine to opioid tolerant patients? Total Number of Responsesm 80 Back Pain 9 (16.7) Chronic Pain 8 (14.8) Cancer Pain 6 (11.1) Not Applicable 6 (l 1.1) Failed Back 4 (7.4) Arachnoiditis 2 (3.7) Bone Pain 2 (3.7) Breakthrough Pain 2 (3.7) Degenerative Disc Disease 2 (3.7) Failed Spine Surgery 2 (3.7) Fibromyalgia 2 (3.7) Neck Pain 2 (3.7) Neuropathy 2 (3.7) Orthopedic Pain 2 (3.7) Post Laminectomy 2 (3.7) Re?ex Sympathetic Distrophy 2 (3.7) Spondylosis 2 (3.7) AIDS 1 (1.9) Arthritic Pain 1 (1.9) Cannot be Categorized (1.9) Cervicalgia (1.9) Chronic Regional Pain (1.9) Crohn's Disease 1 (1.9) (1.9) Facial Pain 1 (1.9) Failed Neck (1.9) Headache (1.9) Intractable Pain 1 (1.9) 53 Preseriber KAB Assessment Report Final 10 February 2017 Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 44 of 70 Table 14. Types of Chronic Pain Conditions Reported - Completed Surveys for Prescribers Who Prescribed TIRF Medicines for Chronic Non-Cancer Pain Prescribers Question Knee Pain 1 (1.9) Multiple Autoimmune Disease 1 (1.9) Multiple Sclerosis (1.9) Neuralgia (1.9) Pancreatitis (1.9) Peripheral Neuropathic Pain 1 (1.9) Phantom Limb Pain 1 (1.9) Polyneuropathy (1.9) Rheumatoid Arthritis 1 (1.9) Spinal Stenosis (1.9) Spine Pain 1 (1.9) Torticollis (1.9) Source: Appendix B: Survey Tables, Table 12 Number and percentages are based on the subset of completed surveys where prescribers responded "Yes" to prescribing TIRF medicines for chronic non-cancer pain (Question 9e: Per the approved labeling for TIRF medicines, for which of the following indication(s) are TIRF medicines approved? Chronic Non-Cancer Pain- "Yes") and were subsequently presented Question 10 and Question 1 1. Total number of responses may exceed the number of prescribers and percentages may not equal 100% as multiple responses were provided by some prescribers. Table 15. Reasons for Selecting a TIRF Medicine Reported - Completed Surveys for Prescribers Who Prescribed TIRF Medicines for Chronic Non-Cancer Pain Prescribers Question Question 11: Why do you select a TIRF medicine to treat these chronic pain conditions in patients who are opioid tolerant? Total Number of Responsesm 62 Ef?cacy 13 (24.1) I Do Not Treat Non-Cancer Patients 7 (13.0) FastOnset 6(ll.1) Other Treatments Have Failed 6 (l 1.1) Not Applicable 5 (9.3) Ease oste 3 (5.6) 54 Prescriber KAB Assessment Report Final 10 February 2017 Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 45 of 70 Table 15. Reasons for Selecting a TIRF Medicine Reported - Completed Surveys for Prescribers Who Prescribed TIRF Medicines for Chronic Non-Cancer Pain Prescribers Question Exhausted Other Options 3 (5.6) Lack of Tolerance of Other Options 3 (5.6) Medication Was Initiated by Pain Specialist 3 (5.6) No Reason Provided 3 (5-6) Dosing Options 2 (3.7) Patient Preference 2 (3.7) Convenience (1.9) Insurance Issues 1 (1.9) Long Lasting (1.9) Patient Lack of Tolerance of Other Options 1 (1.9) Safety 1 (1.9) Sustained Pain Relief 1 (1.9) Source: Appendix B: Survey Tables, Table 13 Number and percentages are based on the subset of completed surveys where prescribers responded "Yes" to prescribing TIRF medicines for chronic non-cancer pain (Question 9e: Per the approved labeling for TIRF medicines, for which of the following indication(s) are TIRF medicines approved? Chronic Non-Cancer Pain- "Yes") and were subsequently presented Question 10 and Question 1 l. Total number of responses may exceed the number of prescribers and percentages may not equal 100% as multiple responses were provided by some prescribers. Overall, 33.3% of prescribers correctly answered all questions/items of Key Risk Message 2, 64.6% missed no more than 1 item, and 80.3% missed no more than 2 of the 10 items (Table 16). Table 16. Secondary Analysis of Responses to Questions Linked to Key Risk Message #2 - Completed Surveys Prescribers Correct Responses 0 correct responses 0 1 correct response 0 2 correct responses 2 (0.7) 3 correct responses 1 (0.3) 4 correct responses 3 (1.0) 5 correct responses 6 (2.0) 55 Preseriber KAB Assessment Report Final 10 February 2017 Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 46 of 70 Table 16. Secondary Analysis of Responses to Questions Linked to Key Risk Message #2 - Completed Surveys Prescribers Correct Responses 6 correct responses 11 (3.7) 7 correct responses 35 (11.9) 8 correct responses 46 (15.6) 9 correct responses 92 (31.3) 10 correct responses 98 (33.3) Source: Appendix B: Survey Tables, Table 8.2 For Key Risk Message 2, Item 200, the analysis strati?ed by whether the Medication Guide and Full Prescribing Information was received/accessed and read showed a meaningful trend favoring respondents who received and read the materials (Table 17). No other trends were evident when the results for Key Risk Message 2 were strati?ed by medical degree of respondents, time practicing medicine, or number of times per month TIRF medicines were prescribed within the last 6 months. For sub-group analysis by modality used to complete the survey (intemet versus telephone), and by those practicing in a closed healthcare system, sample sizes were too small to allow for meaningful interpretation (see Appendix B). Table 17. Responses to Questions Linked to Key Risk Message #2 by Reading Full Prescribing Information or Medication Guide - Completed Surveys (Questions/Items with Apparent Trends) Reading Full Prescribing Information or Medication Guide Received and read Did not receive or read Pl or Med Guide Pl or Med Guide Question [95% cu'" [95% cu'" Question 20: Before initiating treatment with a TIRF medicine, prescribers must review the Medication Guide with the patient. Please select True, False, or I don't know for each of the following counseling statements. 20c: Instruct patients that they can continue to take their TIRF medicine, if th c3? stop taking their around-the- clock opioid medicine. True 51 (19.0) 7 (26.9) Falsem 210 (78.4) [72.9 - 83.1] 15 (57.7) [36.9 - 76.6] [don't know 7 (2.6) 4 (15.4) Source: Appendix B: Survey Tables, Table 8.1.1 95% exact two-sided con?dence intervals are calculated using the Clopper-Pearson method. Correct response. 56 Preseriber KAB Assessment Report Final 10 February 2017 Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 47 of 70 5.2.3 Key Risk Message 3 Key Risk Message 3 states medicines contain fentanyl, an opioid agonist and a Schedule II-controlled substance, with abuse liability similar to other opioid analgesics.? Ten questions/items de?ned this key risk message (Table 18). All prescribers (100.0%, 95% CI: 98.8 100.0) indicated that a personal history of past or current alcohol or drug abuse, or family history of drug use or alcohol abuse is a risk factor for opioid abuse. Almost all prescribers (99.0% 95% CI: 97.0 99.8) were aware that it is important to monitor for signs of abuse and addiction in patients who take TIRF medicines. In addition, most prescribers correctly indicated that a personal history of illness is a risk factor for opioid abuse 95% CI: 81.6 89.8), and that TIRF medicines can be abused in a manner similar to other opioid agonists 95% CI: 93.0 97.9). Almost all prescribers identi?ed misuse 95% CI: 96.6 99.6), abuse 95% CI: 97.0 99.8), addiction 95% CI: 97.0 99.8), and overdose 95% CI: 97.6 99.9) as risks associated with the use of TIRF medicines. Most prescribers also correctly responded that hypothyroidism 95% CI: 73.8 83.4) and infection 95% CI: 81.6 89.8) are not risks associated with the use of TIRF medicines. Table 18. Primary Analysis of Responses to Questions Linked to Key Risk Message #3 - Completed Surveys Prescribers Question [95% Question 7: Please answer True, False, or I don't know for each statement based on the labeling for TIRF medicines. 7e: It is important to monitor for signs of abuse and addiction in patients who take TIRF medicines. Truelz] 291 (99.0) [97.0 - 99.8] False 3 (1.0) I don't know 0 Question 8: Which of the following are risk factors for opioid abuse? Please answer Yes, No, or I don't know for each option. 8a: A personal history of illness Yesm 253 (86.1) [81.6 - 89.8] No 27 (9.2) I don't know 14 (4.8) 8b: A personal history of past or current alcohol or drug abuse, or a family history of illicit drug use or alcohol abuse Yesm 294 (100.0) [98.8 - 100.0] No 0 I don't know 0 57 Preseriber KAB Assessment Report Final 10 February 2017 Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 48 of 70 Table 18. Primary Analysis of Responses to Questions Linked to Key Risk Message #3 - Completed Surveys Prescribers Question [95% Cll'" Question 12: Please answer True, False, or I don't know for each statement based on the labeling for TIRF medicines. 12a: TIR medicines can be abused in a manner similar to other opioid agonists. Truelz] 282 (95.9) [93.0 - 97.9] False 10 (3.4) I don't know 2 (0.7) Question 22: Which of the following risks are associated with the use of TIRF medicines? Please answer True, False, or I don't know for the following statements. 22a: Misuse Truem 290 (98.6) [96.6 - 99.6] False 4 (1.4) I don't know 0 22b: A base Truem 291 (99.0) [97.0 - 99.8] False 2 (0-7) I don't know 1 (0.3) 22c: Addiction Truem 291 (99.0) [97.0 - 99.8] False 3 (1.0) I don't know 0 22d: Overdose Truem 292 (99.3) [97.6 - 99.9] False 2 (0.7) I don't know 0 22e: ypoth yroidism True 20 (6.8) Falsem 232 (78.9) [73.8 - 83.4] I don't know 42 (14.3) 58 Prescriber KAB Assessment Report Final 10 February 2017 Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 49 of 70 Table 18. Primary Analysis of Responses to Questions Linked to Key Risk Message #3 - Completed Surveys Prescribers Question [95% 22f: Infection True 23 (7.8) Falsem 253 (86.1) [81.6 - 89.8] I don't know 18 (6.1) Source: Appendix B: Survey Tables, Table 9.1 95% exact two-sided con?dence intervals are calculated using the lopper-Pearson method. Correct response. Overall, 61.2% of prescribers correctly answered all questions/items of Key Risk Message 3, and 85.4% missed no more than 1 of the 10 items (Table 19). Table 19. Secondary Analysis of Responses to Questions Linked to Key Risk Message #3 - Completed Surveys Prescribers Correct Responses 0 correct responses 0 1 correct response 0 2 correct responses 0 3 correct responses 0 4 correct responses 0 5 correct responses 1 (0.3) 6 correct responses 2 (0.7) 7 correct responses 7 (2.4) 8 correct responses 33 (11.2) 9 correct responses 71 (24.1) 10 correct responses 180 (61.2) Source: Appendix B: Survey Tables, Table 9.2 No trends were evident when the results for Key Risk Message 3 were strati?ed by whether the Medication Guide and Full Prescribing Information was received/accessed and read, medical degree of respondents, time practicing medicine, or number of times per month TIRF medicines were prescribed within the last 6 months. For sub-group analysis by modality used to complete the survey (intemet versus telephone), and by those practicing in a 59 Prescriber KAB Assessment Report Final 10 February 2017 Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industrv Group (TRIG) of Companies Page 50 of 70 closed healthcare system, sample sizes were too small to allow for meaningful interpretation (see Appendix B). 5.2.4 Key Risk Message 4 Key Risk Message 4 states medicines are not interchangeable with each other, regardless of route of administration.? Four questions/items de?ned this key risk message (Table 20). Almost all preseribers 95% CI: 88.5 95.0) understood TIRF medicines are not interchangeable with each other regardless of the route of administration, 96.3% (95% CI: 93.4 98.1) understood the conversion of one TIRF medicine to another may result in a fatal overdose, and 91.5% (95% CI: 87.7 94.4) understood that dosing of TIRF medicines is not equivalent on a microgram-to-microgram basis. The majority of preseribers 95% CI: 73.4 83.1) correctly indicated that, when a patient wants to change his/her TIRF medicine, the preseriber must not convert to another TIRF medicine on a microgram-per-microgram basis because these medicines have different absorption properties and this could result in a fentanyl overdose. Table 20. Primary Analysis of Responses to Questions Linked to Key Risk Message #4 - Completed Surveys Prescribers Question [95% Question 12: Please answer True, False, or I don't know for each statement based on the labeling for TIRF medicines. 12b: TIRF medicines are interchangeable with each other regardless of route of administration. True 15 (5.1) Falsem 271 (92.2) [88.5 - 95.0] I don't know 8 (2.7) 12c: The conversion of one TIRF medicine/or another TIRF medicine may result in afatal overdose because of differences in the pharmacokinetics of fentanyl absorption. Truem 283 (96.3) [93.4 - 98.1] False 5 (1.7) I don't know 6 (2.0) 12d: Dosing of TIRF medicines is not equivalent on a microgram-to-microgram basis. Truelz] 269 (91.5) [87.7 - 94.4] False 11 (3.7) I don't know 14 (4.8) 60 Preseriber KAB Assessment Report Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Final 10 February 2017 Page 51 of 70 Table 20. Primary Analysis of Responses to Questions Linked to Key Risk Message #4 - Completed Surveys Prescribers Question [95% Question 16: A patient is already taking a TIRF medicine but wants to change their medicine. His/her doctor decides to prescribe a different TIRF medicine (that is not a bioeq uivalent generic version of a branded product) in its place. According to the labeling, how should the prescriber proceed? Please select one option. The prescriber can safely convert to the equivalent dosage of the new TIRF medicine as it has the same effect as other TIRF medicines. 5(1.7) The prescriber must not convert to another TIRF medicine on a microgram-per- microgram basis because these medicines have different absorption properties and this could result in a fentanyl overdosem 231 (78.6) [73.4 - 83.1] Convert from the other TIRF medicine to the new TIRF medicine at half of the dose. 25 (8.5) The prescriber should base the starting dose of the newly-prescribed TIRF medicine 21 (7.1) on the dose of the opioid medicine used for their underlying persistent cancer pain. I don't know. 12 (4.1) Source: Appendix B: Survey Tables, Table 10.1 95% exact two-sided con?dence intervals are calculated using the Clopper-Pearson method. Correct response. Overall, 70.1% of prescribers correctly answered all questions/ items of Key Risk Message 4; 90.8% missed no more than 1 of the 4 items (Table 21). Table 21. Secondary Analysis of Responses to Questions Linked to Key Risk Message #4 - Completed Surveys Prescrihers Correct Responses 0 correct responses 2 (0.7) 1 correct response 3 (1.0) 2 correct responses 22 (7.5) 3 correct responses 61 (20.7) 4 correct responses 206 (70.1) Source: Appendix B: Survey Tables, Table 10.2 For Key Risk Message 4, for Question 16, the analysis strati?ed by whether the Medication Guide and Full Prescribing Information was received/accessed and read showed a signi?cant difference favoring respondents who received and read the materials (Table 22). No other trends were evident when the results for Key Risk Message 4 were stratified by medical 61 Prescriber KAB Assessment Report Final 10 February 2017 Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industrv Group (TRIG) of Companies Page 52 of 70 degree of respondents, time practicing medicine, or number of times per month TIRF medicines were prescribed within the last 6 months. For sub-group analysis by modality used to complete the survey (intemct versus telephone), and by those practicing in a closed healthcare system, sample sizes were too small to allow for meaningful interpretation (see Appendix B). Table 22. Responses to Questions Linked to Key Risk Message #4 by Reading Full Prescribing Information or Medication Guide - Completed Surveys (Questions/Items with Apparent Trends) Reading Full Prescribing Information or Medication Guide Received and read Did not receive or read P1 or Med Guide Pl or Med Guide Question [95% 01'" [95% cu'" Question 16: A patient is already taking a TIRF medicine but wants to change their medicine. His/her doctor decides to prescribe a different TIRF medicine (that is not a bioequivalent generic version of a branded product) in its place. According to the labeling, how should the prescriber proceed? Please select one option. The prescriber can safely convert to the 4 (1.5) (3.8) equivalent dosage of the new TIRF medicine as it has the same effect as other TIRF medicines. The prescriber must not convert to another 217 (81.0) [75.8 - 85.5] 14 (53.8) [33.4 - 73 TIRF medicine on a microgram-per-microgram basis because these medicines have different absorption properties and this could result in a fentanyl overdosem Convert from the other TIRF medicine to the 20 (7.5) 5 (19.2) new TIRF medicine at half of the dose. The prescriber should base the starting dose of 18 (6.7) 3 (11.5) the newly-prescribed TIRF medicine on the dose of the opioid medicine used for their underlying persistent cancer pain. [don't know. 9 (3.4) 3 (l 1.5) Source: Appendix B: Survey Tables, Table 10.1.1 95% exact two-sided con?dence intervals are calculated using the Clopper-Pearson method. Correct response. 5.2.5 Key Risk Message Average Knowledge Scores Table 23 presents the average knowledge score for each key risk message and an overall knowledge score for all key risk messages combined. The overall knowledge score of 89.1 (95% CI: 88.0 90.2) indicates a high percentage of respondents demonstrated understanding of the key risk messages. The average knowledge score for each of the key risk messages was greater than 86 for all key risk messages. 62 Prescriber KAB Assessment Report Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies 10 February 2017 Page 53 of 70 Table 23. Average Knowledge Scores - Completed Surveys Score [95% KRM #1 87.4 [85.8, 89.0] KRM #2 86.3 [84.6, 88.0] KRM #3 94.2 [93.2, 95.2] KRM #4 89.6 [87.5, 91.7] Overall Knowledge Score 89.1 [88.0, 90.2] Source: Appendix B: Survey Tables, Table 95% are constructed based on normal distribution function. 5.2.6 Other Survey Questions 5.2.6.1 Additional Questions about TIRF Medicines Safety Table 24 summarizes the prescribers? responses to additional questions about the safe use of TIRF medicines beyond those associated with the key risk messages. A high percentage of prescribers correctly indicated a family history of asthma is not a risk factor for opioid abuse. Most prescribers correctly indicated that for a patient starting titration with a TIRF medicine, they must start with the lowest available dose, unless the product Full Prescribing Information provides speci?c guidance. When presented with the scenario of a patient who has started titration with the lowest dose of a TIRF medicine, and for whom the breakthrough pain has not been suf?ciently relieved after 30 minutes, 70.7% of prescribers correctly responded that they should provide guidance based on the product-speci?c Medication Guide because the instructions are not the same for all TIRF medicines. In addition, a majority of prescribers correctly indicated use of a TIRF medicine with a CYP3A4 inhibitor may require a dose adjustment, and that the patient needs to be carefully monitored for opioid toxicity to minimize the risk of fatal respiratory depression. All prescribers (100.0%) understood that patients must be instructed never to share their TIRF medicine with anyone else, even if that person has the same and nearly all prescribers surveyed understood that TIRF medicines contain fcntanyl in an amount that could be fatal for children of all ages, for individuals for whom they were not prescribed, and for those who are not opioid tolerant. 63 Preseriber KAB Assessment Report Final 10 February 2017 Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 54 of 70 Table 24. Responses to Additional Questions about the Safe Use of TIRF Medicines - Completed Surveys Prescribers Question Question 8: Which of the following are risk factors for opioid abuse? Please answer Yes, No, or I don't know for each option. 86: A family history of asthma Yes 4 (1.4) Noll] 285 (96.9) I don't know 5 (1.7) Question 17: A patient is starting titration with a TIRF medicine. What dose must they start with? Please select one option. An appropriate dose based on the dose of the opioid medicine used for underlying 19 (6.5) persistent cancer pain. The dose that the prescriber believes is appropriate based on their clinical 5 (1.7) experience. The lowest available dose, unless individual product Full Prescribing Information 266 (90.5) provides product-specific guidancem The median available dose. 2 (0.7) I don't know. 2 (0.7) Question 18: A prescriber has started titrating a patient with the lowest dose of a TIRF medicine. However, after 30 minutes the breakthrough pain has not been suf?ciently relieved. What should they advise the patient to do? Please pick the best option of the scenarios described. Take another (identical) dose of the TIRF medicine immediately. 66 (22.4) Take a dose of an alternative rescue medicine. 14 (4.8) Provide guidance based on the product-speci?c Medication Guide because the 208 (70.7) instructions are not the same for all TIRF medicinesm Double the dose and take immediately. 5 (1.7) I don't know. 1 (0.3) Question 19: A patient is taking a TIRF medicine and the doctor would like to prescribe a CYP3A4 inhibitor. Please pick the best option of the scenarios described. The patient can't be prescribed because using it at the same time as a 17 (5.8) TIRF medicine could be fatal. Use of a TIRF medicine with a CYP3A4 inhibitor may require a dosage adjustment; 235 (79.9) care?rlly monitor the patient for opioid toxicity, otherwise such use may cause potentially fatal respiratory depressionm There is no possible drug interaction between CYP3A4 inhibitors and TIRF (0.3) medicines. The dose of the TIRF medicine must be reduced by one half if a CYP3A4 inhibitor 8 (2.7) is prescribed in the same patient. 64 Prescriber KAB Assessment Report Final 10 February 2017 Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 55 of 70 Table 24. Responses to Additional Questions about the Safe Use of TIRF Medicines - Completed Surveys Prescribers Question I don't know. 33 (11.2) Question 20: Before initiating treatment with a TIRF medicine, prescribers must review the Medication Guide with the patient. Please select True, False, or I don't know for each of the following counseling statements. 20a: TIRF medicines contain fentan yl in an amount that could be fatal to children of all ages, in individuals for whom they were not prescribed, and in those who are not opioid tolerant. Truel '1 293 (99.7) False 0 I don't know 1 (0.3) 20d: Instruct patients to never share their TIRF medicine with anyone else, even if that person has the same Truem 294 (100.0) False 0 I don't know 0 Source: Appendix B: Survey Tables, Table 3 Correct response. 5.2.6.2 Prescriber Activities When Prescribing TIRF Medicines Prescribers were asked about speci?c activities performed when prescribing TIRF medicines (Table 25). More than half of prescribers indicated they always ask patients (or their caregivers) about the presence of children in the home always instruct patients (or their caregivers) not to share TIRF medicines with anyone else always counsel patients (or their caregivers) that accidental exposure by a child may be fatal always instruct patients (or their caregivers) to keep TIRF medicines out of the reach of children and always instruct patients (or their caregivers) about proper disposal of TIRF medicines In addition, 44.2% of prescribers indicated they always give patients (or their caregivers) the Medication Guide for their TIRF medicine, whereas 44.6% indicated they give it only with the ?rst prescription. Similarly, over half of prescribers indicated they always talk to the patient about the risks and possible side effects of the TIRF medicine that was most recently prescribed instruct the patient on how to use the TIRF medicine that was most recently prescribed and instruct the patient on how to store or keep the TIRF medicine that was most recently prescribed 65 Preseriber KAB Assessment Report Final 10 February 2017 Transmueosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 56 of 70 Table 25. Responses to Questions about the Activities when Prescribing TIRF Medicines - Completed Surveys Prescribers Question 11 Question 14: How frequently do you perform the following activities when prescribing TIRF medicines? Please answer Always, Only with the first prescription, Sometimes, Never, or I don't know. I 4a: Ask patients (or their caregivers) about the presence of children in the home Always 182 (61.9) Only with the ?rst prescription 66 (22.4) Sometimes 35 (11.9) Never 10 (3.4) 1 don't know 1 (0.3) Mb: Instruct patients (or their caregivers) not to share TIR medicines with anyone else Always 236 (80.3) Only with the ?rst prescription 43 (14.6) Sometimes 14 (4.8) Never 1 (0.3) I don't know 0 I 4c: Counsel patients (or their caregivers) that accidental exposure to TIRF medicines by a child may be fatal Always 208 (70.7) Only with the ?rst prescription 55 (18.7) Sometimes 23 (7.8) Never 8 (2.7) I don't know 0 I 4d: Instruct patients (or their caregivers) to keep IRF medicines out of the reach of ch ildren to prevent accidental exposure Always 232 (78.9) Only with the ?rst prescription 44 (15.0) Sometimes 13 (44) Never 5 (1.7) I don't know 0 Me: Instruct patients (or their caregivers) about proper disposal of any unused or partially used TIRF medicines Always 197 (67.0) Only with the ?rst prescription 56 (19.0) Sometimes 34 (11.6) 66 Preseriber KAB Assessment Report Final 10 February 2017 Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 57 of 70 Table 25. Responses to Questions about the Activities when Prescribing TIRF Medicines - Completed Surveys Prescribers Question 11 Never 7 (2.4) I don't know 0 14/: Give patients (or their caregivers) the Medication Guide for their TIRF medicine Always 130 (44.2) Only with the ?rst prescription 131 (44.6) Sometimes 17 (5.8) Never 15 (5.1) I don't know 1 (0.3) Question 32: How frequently do you perform the following activities when prescribing TIRF medicines? Please answer Always, Only with the first prescription, Sometimes, Never, or I don't know. 32a: Talk to the patient about the risks and possible side effects of the TIR medicine that was most recently prescribed. Always 223 (75.9) Only with the ?rst prescription 53 (18.0) Sometimes 16 (5.4) Never 0 I don't know 2 (0.7) 32b: Instruct the patient on how to use the TIRF medicine that was most recently prescribed. Always 204 (69.4) Only with the ?rst prescription 67 (22.8) Sometimes 21 (7.1) Never 0 I don't know 2 (0.7) 32c: Instruct the patient on how to store or keep the TIRF medicine that was most recently prescribed Always 156 (53.1) Only with the ?rst prescription 102 (34.7) Sometimes 22 (7.5) Never 12 (4.1) I don't know 2 (0.7) Source: Appendix B: Survey Tables, Table 6 67 Prescriber KAB Assessment Report Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies 5.3 Final 10 February 2017 Page 58 of 70 Spontaneous Reporting of Adverse Events, Product Complaints, or Medical Information Requests Among all survey respondents (N 524, Table 1), there were 51 reports of a potential adverse event or product complaint associated with the use of TIRF medicines made within the survey free text field during the online survey. No reports were made during the telephone survey. Verbatim statements are provided in Appendix B, Listing 5. 6. DISCUSSION AND CONCLUSIONS Discussion Survey invitations (and reminders) were sent to a random sample of prescribers enrolled in the TIRF REMS Access program that had prescribed a TIRF medicine in the last 6 months, a revision to the survey recruitment strategy per FDA request. From the total of 524 respondents who accessed the survey, 313 prescribers met eligibility criteria, and of those who met eligibility criteria, 294 completed the survey. There were no statistically significant differences observed in the demographics between the prescribers completing the survey compared with the general population of prescribers based on REMS switch provider data (N 3045; Table 5) . There were statistically significant differences observed in the demographics between the prescribers completing the survey (b) (4) compared with the general population of prescribers based on IMS data (N on most questions with the exception of geographic distribution of practice location for which demographics between groups were similar (Table 6). It is important to note the sample size (b) (4) of the general population of prescribers (N ) affects the power of the test, and therefore, may mean that even small differences between groups resulted in significant p-values. A significant difference in gender, medical degree, and number of years practicing medicine were noted; however, the majority of responders in each group selected the same responses to these questions. In addition, conflicting results were seen for the average prescribing frequency, indicating potential reporting bias. For differences specifically related to specialty, it is difficult to determine whether these are true differences or if this is impacted by reporting bias. While the differences are statistically significant, these differences should not have a big impact on the primary objectives of the survey since a relevant uniform correlation between demographic characteristics and the knowledge of the key risk messages could not be detected. Therefore, despite these differences, the TRIG concludes that the survey sample of 294 prescribers is a valid representation of the general population of TIRF prescribers. The overall knowledge score of 89.1 (95% CI: 88.0 90.2) for the survey indicates a high percentage of respondents demonstrated understanding of the key risk messages (Table 23). The average knowledge score for each of the key risk messages was greater than 86 for all key risk messages. Of the 38 questions/items included as part of key risk messages, 28 questions/items had a correct response rate >80% and 10 questions/items had a correct response rate between 65% FDA_5168 Prescriber KAB Assessment Report Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Final 10 February 2017 Page 59 of 70 and 80%. None of the questions/items had a correct response rate that fell below the desired level of understanding of 65%. As previously discussed, the survey was updated prior to launch based on FDA feedback received on 21 July 2016. Nearly all prescribers, correctly responded that misuse, abuse, addiction, and overdose were risks associated with the use of TIRF medicines and TIRF medicines should only be taken by patients who are opioid tolerant (added Question 22 and 21). Over 90% of prescribers correctly responded that per the approved labeling, TIRF medicines are not indicated for acute or postoperative pain, headache or migraine pain, dental pain, but are indicated for breakthrough pain from cancer (revised Question 9). Fewer prescribers, but still the majority, correctly responded that chronic non-cancer pain was not an approved indication for TIRF medicines (revised Question 9). For the added Question 32 (How frequently do you perform the following activities when prescribing TIRF medicines? Please answer Always, Only with the first prescription, Sometimes, Never, or I don't know), most prescribers selected always or only with the first prescription for talking to the patient about risks and possible side effects and instructing the patient on how to use and how to store or keep for the TIRF medicine that was most recently prescribed. The correct response rates from the 12-month KAB survey through the 60-month KAB survey are shown in Table 26. Knowledge and understanding of the key risk message questions has generally remained stable or improved over time. Correct response rates for Items 9a, 9b, 9c, and 9d were similar compared with the 48-month survey; however, Item 9e had a notably improved correct response rate once the question was revised for this survey wave as detailed below: x x Question 9 as presented in the 48-month survey: In your practice, for which of the following indications do you prescribe TIRF medicines to opioid tolerant patients? Please answer Yes, No, or I don’t know for each option; Item 9e, chronic non-cancer pain, correct response “No”; correct response rate 64.8%. Question 9 as presented in the 60-month survey: Per the approved labeling for TIRF medicines, for which of the following indication(s) are TIRF medicines approved? Please answer Yes, No, or I don’t know for each option; Item 9e, chronic non-cancer pain, correct response “No”; correct response rate 78.2% There were 54 prescribers (18.4%) who responded “Yes” to Item 9e, and these prescribers were presented with 2 additional questions as requested by FDA. Question 10 addressed the type of chronic pain conditions they prescribe a TIRF medicine to treat. The most frequently reported conditions were back pain (16.7%), chronic pain (14.8%), and cancer pain (11.1%). Question 11 addressed the reasons for selecting a TIRF medicine to treat these conditions. The most frequently reported reasons were efficacy (24.1%), “I do not treat non-cancer patients” (13.0%), fast onset (11.1%), and that other types of treatments have failed (11.1%). Table 26 below includes key risk messages and questions/items within each key risk message as presented in the 60-month survey. It is important to note the question/item numbering, wording, and association with a specific key risk message may have changed across survey FDA_5169 Prescriber KAB Assessment Report Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Final 10 February 2017 Page 60 of 70 waves based on FDA feedback or other decisions made by the TRIG. A limitation to looking at correct response rates over time is that survey questions may have been modified. The primary focus of this table is to show general trends over time with a specific focus on changes from the 48-month survey to the 60-month survey. FDA_5170 Preseriber KAB Assessment Report Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Final 10 February 2017 Page 61 of 70 Table 26. Correct Response Rate Over Time 60-Month lZ-Month Survey 24?Month Survey 36-Month Survey 48-Month Survey 60-Month Survey Survey Correct/Desired Correct/Desired Correct/Desired Correct/Desired Correct/Desired Question Questions as Presented in the Response Response Response Response Response Number 60-Month Survey (95% Cl) (95% Cl) (95% Cl) (95% Cl) (95% Cl) Key Risk Message 1: TIRF Medicines Are Contraindicated in Opioid Non-Tolerant Patients 5 Please select True, False, or I don?t know for each of the following. According to the labeling for TIRF medicines, patients with cancer who are considered opioid-tolerant are those: 5a Who are taking around-the-clock opioid therapy for underlying, persistent cancer pain for one week or longer (Correct Response True) 79?] 90.4 (86.5, 93.5) 90.0 (86.0, 93.2) 95.2 (92.1 - 97.3) 94.9 (91.7 - 97.1) 5b Who are not currently taking opioid therapy, but have taken opioid therapy before (Correct Response False) 887m 88.] (83.9, 91.5) 87.0 (82.7, 90.6) 93.9 (90.6 - 96.3) 93.9 (90.5 - 96.3) 5c Who have no known contraindications to the drug fentanyl, but are not currently taking around-the-clock opioid therapy (Correct Response False) 5.6m 82.1 (77.3, 86.3) 86.3 (81.9, 90.0) 86.8 (82.5 - 90.3) 92.5 (88.9 - 95.3) Please answer True, False, or I don?t know for each statement based on the labeling for TIRF medicines. 7a TIRF medicines are contraindicated in opioid non- tolerant patients because life- threatening respiratory depression could occur at any dose (Correct Response True) 87.4 (83.1, 90.9) 87.7 (83.5, 91.2) 86.7 (82.3, 90.3) 90.3 (86.5 - 93.4) 91.8 (88.1 - 94.7) 7b Death has occurred in opioid non- tolerant patients treated with some fentanyl products (Correct Response True) 95.7 95.7 (92.8, 97.7) 93.7 (90.3, 96.2) 95.7 (92.7, 97.7) 96.1 (93.3 - 98.0) 95.6 (92.6 - 97.6) Preseriber KAB Assessment Report Final 10 February 2017 Transmueosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 62 of 70 Table 26. Correct Response Rate Over Time 60-Month lZ-Month Survey 24?Month Survey 36-Month Survey 48-Month Survey 60-Month Survey Survey Correct/Desired Correct/Desired Correct/Desired Correct/Desired Correct/Desired Question Questions as Presented in the Response Response Response Response Response Number 60-Month Survey (95% Cl) (95% Cl) (95% Cl) (95% Cl) (95% Cl) 7? 82 5 (787275 86 6) (75 232084 5) (77 $22.82 2) (80 311.38 6) (84 323.31 9) (Correct Response False) Prescribers starting a patient on a TIRF medicine must begin with 7d ml?e?fzi?et lgx??duc" 83 1 (738341 87 2) (75 f$0.885 1) (79 251488 0) (81 i589 2) (81 $5.89 5) even if the patient has previously - - taken another TIRF medicine (Correct Response True) 13 Please select True, False, or I don?t know for each of the following. According to the labeling for TIRF medicines, patients considered opioid- tolerant are those who are taking, for one week or longer, at least: 8 mg oral hydromorphone/day 72.9 71.8 13a (Correct Response True) 6852 7032 (67.6 - 77.8) (66.3 - 76.8) 60 mg oral morphine/day 94.5 95.6 13b (Correct Response True) 8912 9232 (91.4 - 96.8) (92.6 - 97.6) 30 mg oral oxycodone/day 78.7 82.0 13? (Correct Response True) 76'? 7802 (73.7 - 83.1) (77.1 - 86.2) 25 meg transdermal fentanyl/hour 85.5 89.1 13d (Correct Response True) 8032 83'72 (81.1 - 89.2) (85.0 - 92.4) 25 mg oral oxymorphone/day 72.3 79.6 ?38 (Correct Response True) 69'? 7472 (66.9 - 77.2) (74.5 - 84.0) An equianalgesic dose of another 67 7 65 6 13f oral oprord (Correct Response 65.92 59.02 (62.2 72.9) (59.9 71.1) True) 72 Preseriber KAB Assessment Report Final 10 February 2017 Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industrv Group (TRIG) of Companies Page 63 of 70 Table 26. Correct Response Rate Over Time 60-Montb lZ-Month Survey 24?Month Survey 36-Month Survey 48-Month Survey 60-Month Survey Survey Correct/Desired Correct/Desired Correct/Desired Correct/Desired Correct/Desired Question Questions as Presented in the Response Response Response Response Response Number 60-Montb Survey (95% Cl) (95% Cl) (95% Cl) (95% Cl) (95% Cl) TIRF medicines should only be 96 6 21 taken by patients who are opioid (93 8 :98 4) tolerant (Correct Response True) Key Risk Message 2: TIRF Medicines Are Only Indicated for the Management of Breakthrough Pain in Adult Cancer Patients 18 Years of Age and Older (16 Years of Age and Older for Actiq? Brand and Generic Equivalents) Who Are Already Receiving and Who Are Tolerant to Around-the- Clock Opioid Therapy for Their Underlying, Persistent Cancer Pain 6 Please answer True, False, or I don?t know for each statement based on the labeling for TIRF medicines. According to the product labeling, a cancer patient may start a TIRF 69 0 77 2 6a medicine and an around-the-clock 60.6[21 60.09opioid at the same time (Correct - - Response False) According to the product labeling, a cancer patient who has been on an around-the-clock opioid for 72.9 78.2 6b day may start taking a TIRF 64'9 70'3 (67.6 - 77.8) (73.1 - 82.8) medicine for breakthrough pain (Correct Response False) 9 Per the approved labeling for TIRF medicines, for which of the following indication(s) are TIRF medicines approved? Please answer Yes, No, or I don?t know for each option.1 9a Acute or postoperative pain 86.4 93.0 87.3 90.3 94.6 (Correct Response No) (82.0, 90.1) (89.6, 95.6) (83.0, 90.9) (86.5 - 93.4) (91.3 - 96.9) 9b Headache or migraine pain 86.8 92.4 89.7 94.8 93.9 (Correct Response No) 86.8 (82.4, 90.4) (88.8, 95.1) (85.7, 92.9) (91.8 - 97.0) (90.5 - 96.3) 9c Dental pain 96.0 96.7 97.3 98.4 96.3 (Correct Response No) (93.2, 97.9) (94.0, 98.4) (94.8, 98.8) (96.3 - 99.5) (93.4 - 98.1) 73 Preseriber KAB Assessment Report Final 10 February 2017 Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 64 of 70 Table 26. Correct Response Rate Over Time 60-Month lZ-Month Survey 24?Month Survey 36-Month Survey 48-Month Survey 60-Month Survey Survey Correct/Desired Correct/Desired Correct/Desired Correct/Desired Correct/Desired Question Questions as Presented in the Response Response Response Response Response Number 60-Month Survey (95% Cl) (95% Cl) (95% CI) (95% Cl) (95% Cl) 9d Breakthrough pain from cancer 95.4 92.4 96.0 92.9 99.3 (Correct Response Yes) (92.3, 97.4) (88.8, 95.1) (93.1, 97.9) (89.5 - 95.5) (97.6 - 99.9) 9e Chronic non-cancer pain 54 3[2] 58.9 62.0 64.8 78.2 (Correct Response No) (53.2, 64.5) (56.2, 67.5) (59.2 - 70.2) (73.1 - 82.8) 15 The patients described are experiencing breakthrough pain. According to the labeling, a TIRF medicine is not appropriate for one of them. Which patient should not receive a TIRF medicine? Adult female with localized breast cancer; just completed a mastectomy and reconstructive . . 66.3 73.2 72.1 15b surgery; cancer pain 54.30] 65.9?] managed with 30 mg oral (60.7, 71.7) (67.9 78.1) (66.6 77.2) morphine daily for the past 6 weeks (Correct Response) 20 Before initiating treatment with a TIRF medicine, prescribers must review the Medication Guide with the patient. Please select True, False, or I don?t know for each of the following counseling statements. Inform patients that TIRF medicines must not be used for acute or postoperative pain, pain 93.9 96.3 20" from injuries, headache/migraine, 9 "7 92-1 907 (90.6 - 96.3) (93.4 - 98.1) or any other short-term pain (Correct Response True) Instruct patients that they can continue to take their TIRF 20c medicme, 1fthey stop taking their 68.5 57,9 61,0 (67.6 77.8) (71.3 81.3) around-the-clock opioid medicine (Correct Response False) 74 Preseriber KAB Assessment Report Final 10 February 2017 Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 65 of 70 Table 26. Correct Response Rate Over Time 60-Month lZ-Month Survey 24?Month Survey 36-Month Survey 48-Month Survey 60-Month Survey Survey Correct/Desired Correct/Desired Correct/Desired Correct/Desired Correct/Desired Question Questions as Presented in the Response Response Response Response Response Number 60-Month Survey (95% Cl) (95% Cl) (95% CI) (95% Cl) (95% Cl) Key Risk Message 3: TIRF Medicines Contain entanyl, an Opioid Agonist and a Schedule II Controlled Substance, with Abuse Liability Similar to other Opioid Analgesics 7 Please answer True, False, or 1 don?t know for each statement based on the labeling for TIRF medicines. It is important to monitor for 7e signs of abuse and addiction in 99.7 99.0 99.7 98.7 99.0 patients who take TIRF medicines (982, 100.0) (97.1, 99.8) (98.2, 100.0) (96.7 - 99.6) (97.0 - 99.8) (Correct Response True) 8 Which of the following are risk factors for opioid abuse? Please answer Yes, No, or I don?t know for each option. 8a A personal history of 82.5 82.8 84.0 84.5 86.1 illness (Correct Response Yes) (77.7, 86.6) (78.0, 86.9) (79.4, 88.0) (80.0 - 88.4) (81.6 - 89.8) A personal history of past or 8b gau'??gta?ggloa?f $52: a (97 969.939 9) (97 919.39 8) (98 ggibo 0) (96 323.99 6) (98 8901.30 0) or alcohol abuse (Correct Response Yes) 12 Please answer True, False, or I don?t know for each statement based on the labeling for TIRF medicines. 1 2a 15:11::de 97 7 96'4 97 3 94'2 95'9 agonists (Correct Response True) (95.3, 99.1) (93.6, 98.2) (94.8, 98.8) (91.0 - 96.5) (93.0 - 97.9) 22 Which of the following risks are associated with the use of TIRF medicines? Please answer True, False, or I don?t know for the following statements. 223 - [31 [31 [31 [31 98-6 Misuse (Correct Response True) (96.6 99. 6) 22b [31 [31 [31 [31 99-0 Abuse (Correct Response True) (97.0 99.8) 75 Preseriber KAB Assessment Report Final 10 February 2017 Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 66 of 70 Table 26. Correct Response Rate Over Time 60-Month lZ-Month Survey 24?Month Survey 36-Month Survey 48-Month Survey 60-Month Survey Survey Correct/Desired Correct/Desired Correct/Desired Correct/Desired Correct/Desired Question Questions as Presented in the Response Response Response Response Response Number 60-Month Survey (95% Cl) (95% Cl) (95% CI) (95% Cl) (95% Cl) 220 Addiction (Correct Response 99.0 True) (97.0 99.8) 22d Overdose (Correct Response 99.3 True) (97.6 99.9) 228 Hypothyroidism (Correct 78.9 Response False) (73.8 - 83.4) 22f Infection (Correct Response 86.1 False) (81.6 - 89.8) Key Risk Message 4: TIRF Medicines Are Not Interchangeable with Each Other, Regardless of Route of Administration 12 Please answer True, False, or I don?t know for each statement based on the labeling for TIRF medicines. TIRF medicines are 12b Other 95.7 92.4 93.0 92.6 92.2 administration (Correct Response (92.8, 97.7) (88.8, 95.1) (89.5, 95.6) (89.1 - 95.2) (88.5 - 95.0) False) The conversion of one TIRF medicine for another TIRF 12c 94-7 94-7 96-7 95-5 96-3 in the phannacokinetics of (91.5, 96.9) (91.5, 96.9) (94.0, 98.4) (92.5 - 97.5) (93.4 - 98.1) fentanyl absorption (Correct Response True) Dosing of TIRF medicines is not 12d equivalent on a microgram-to- 90.4 90.7 90.7 90.0 91.5 microgram basis (Correct (86.5, 93.5) (86.9, 93.8) (86.8, 93.7) (86.1 - 93.1) (87.7 - 94.4) Response True) 76 Prescriber KAB Assessment Report Final 10 February 2017 Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Page 67 of 70 Table 26. Correct Response Rate Over Time 60-Month lZ-Month Survey 24?Month Survey 36-Month Survey 48-Month Survey (So-Month Survey Survey Correct/Desired Correct/Desired Correct/Desired Correct/Desired Correct/Desired Question Questions as Presented in the Response Response Response Response Number 60-Month Survey (95% Cl) (95% Cl) (95% Cl) (95% Cl) (95% CI) 1 6 A patient is already taking a TIRF medicine but wants to change their medicine. His/her doctor decides to prescribe a different TIRF medicine (that is not a bioequivalent generic version of a branded product) in its place. According to the labeling, how should the prescriber proceed? The prescriber must not convert to another TIRF medicine on a microgram-per-microgram basis 16b 75-5 (69.2, 79.3) (69.0, 79.2) (72.4 - 82.0) (73.4 - 83.1) and this could result in a fentanyl overdose (Correct Response). lQuestion was revised for the 60-month survey. 2 95% con?dence interval is not provided since the item was not part of a key risk message during the reporting period. 3 Question was not asked during the reporting period 77 Prescriber KAB Assessment Report Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Final 10 February 2017 Page 68 of 70 The analysis stratified by whether the Full Prescribing Information or Medication Guide were received and read (received and read versus did not receive or read) showed a trend of higher correct-response rates for respondents who received and read the materials in some questions/items linked to Key Risk Messages 1, 2, and 4. There was also a trend toward lower correct response rate for prescribers practicing medicine less than 3 years when stratified by time practicing medicine for one item linked to Key Risk Message 1. No trends were evident when the results were stratified by medical degree of respondents or number of times per month TIRF medicines were prescribed within the last 6 months. For sub-group analysis by modality used to complete the survey (internet versus telephone), and by those practicing in a closed healthcare system, sample sizes were too small to allow for meaningful interpretation. Conclusions In general, there is an overall trend over time toward maintenance or improvement in prescriber knowledge and understanding of the key risk messages (Table 26). The 60-month survey shows a high level (correct response rate greater than or equal to 65%) of prescriber understanding of key risk messages based on the REMS goals. However, the TRIG acknowledges that there is room for improvement around prescriber knowledge related to conditions for use of a TIRF medicine, TIRF medicine use when stopping their around-theclock opioid pain medicine, conversion of TIRF medicines, and definition of opioid tolerant. FDA_5178 Prescriber KAB Assessment Report Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Appendix A Final 10 February 2017 Page 69 of 70 Prescriber Survey Protocol Track Change Document: Comparison of 48-month Survey to 60-month Survey FDA_5179 PROTOCOL TITLE: SPONSOR: VERSION: DATE: APPROVED: All Eur-meal", CONFIDENTIAL Corporation All Rights Reserved Quantitative Testing of Prescriber Knowledge, Attitudes, and Behavior about Transmucosal Immediate Release entanyl (TIRF) Products Safety and Use Information TIRF REMS Industry Group (TRIG) Actavis Laboratories FL, Inc. BioDelivery Sciences International, Inc. - . Cephalon, Inc. (a wholly-owned subsidiary of Teva Pharmaceutical Industries, Ltd.) Depomed, Inc. Therapeutics, Inc. Mallinckrodt Pharmaceuticals Mylan: Inc. Par Wei-Pharmaceuticals, Inc. Therapeutics, Inc. mg? Whitmom Ill-.N-ArljFinal Controlled Document Copyrighto United BioSource 80 TIRF REMS Industry Group (TRIG) Transmucosal Immediate Release Fentanyl (TIRF) Products Prescriber KAB Survey Protocol TABLE OF CONTENTS Version 10.03.0 21AUG201504AUG2016 PAGE TABLE OF CONTENTS 1. LIST OF ABBREVIATIONS .................................................................................. 3 2. BACKGROUND ..................................................................................................... 4 3. OBJECTIVES OF THE PRESCRIBER EVALUATION SURVEY ...................... 5 4. METHODS .............................................................................................................. 5 4.1 4.1.1 4.1.2 4.1.3 Survey Design .......................................................................................................... 5 Qualitative Research on the Survey ......................................................................... 6 Questions and Statements on REMS Goals ............................................................. 6 Additional Questions.............................................................................................. 12 4.2 4.2.1 Participant Recruitment.......................................................................................... 12 Measures to Minimize Bias in the Sample............................................................. 13 5. STUDY POPULATION ........................................................................................ 13 5.1 5.1.1 5.1.2 Sample Size ............................................................................................................ 13 Inclusion Criteria.................................................................................................... 14 Exclusion Criteria .................................................................................................. 14 6. SURVEY PROCESS ............................................................................................. 15 6.1 6.1.1 6.1.2 Screening and Survey Administration ................................................................... 15 Telephone ............................................................................................................... 15 Internet ................................................................................................................... 15 6.2 Measures to Minimize Bias in the Survey Process ................................................ 15 7. 7.1.1 7.1.2 7.1.3 ANALYSIS ............................................................................................................ 16 Analysis Population ............................................................................................... 17 Description of Primary Analyses ........................................................................... 17 Description of Secondary Analyses ....................................................................... 17 8. SAFETY EVENT REPORTING ........................................................................... 17 9. PRIVACY PROTECTION AND CONFIDENTIALITY...................................... 17 LIST OF APPENDICES Appendix A Prescriber Questionnaire........................................................................... 19 Appendix B Prescriber Recruitment Materials ............................................................. 46 Appendix C Correct Answer Document ....................................................................... 51 2 of 54 FDA_5181 TIRF REMS Industry Group (TRIG) Transmucosal Immediate Release Fentanyl (TIRF) Products Prescriber KAB Survey Protocol 1. Version 10.03.0 21AUG201504AUG2016 LIST OF ABBREVIATIONS BDSI CATI CI EDC ETASU FDA HIPAA ISI KAB PI REMS SE PSP TIRF TIRF REMS TRIG UBC US BioDelivery Sciences International, Inc. Computer-Assisted Telephone Interviewing Confidence Interval Electronic Data Capture Elements to Assure Safe Use Food and Drug Administration Health Insurance Portability and Accountability Act Important Safety Information Knowledge, Attitudes, and Behavior Prescribing Information Risk Evaluation and Mitigation Strategy Safety Event Project Specific Procedure Transmucosal Immediate Release Fentanyl TIRF REMS Access Programprogram TIRF REMS Industry Group United BioSource Corporation United States 3 of 54 FDA_5182 TIRF REMS Industry Group (TRIG) Transmucosal Immediate Release Fentanyl (TIRF) Products Prescriber KAB Survey Protocol 2. Version 10.03.0 21AUG201504AUG2016 BACKGROUND Transmucosal Immediate Release Fentanyl (TIRF) medicines include the class of immediaterelease opioid analgesics that are indicated only for the management of breakthrough pain in cancer patients 18 years of age or older (16 or older for Actiq® and equivalent generics) who are already receiving and tolerant to opioid therapy for their underlying persistent cancer pain. The TIRF medicines include Abstral®, Actiq®, Fentora®, Lazanda®, Subsys®, and generic versions of any of these brands. The TIRF REMS Industry Group (TRIG) includes Actavis Laboratories FL, Inc.; BioDelivery Sciences International, Inc. (BDSI) (replaced Meda Pharmaceuticals on March 11, 2015(BDSI); Cephalon, Inc. (a wholly-owned subsidiary of Teva Pharmaceutical Industries, Ltd.); Depomed, Inc.; Galena Biopharma, Inc.; Insys Therapeutics, Inc.; Mallinckrodt Pharmaceuticals; Mylan Inc.; Par Pharmaceuticals, Inc.; and Par PharmaceuticalSentynl Therapeutics, Inc. The Food and Drug Administration (FDA) has determined that a class-wide Risk Evaluation and Mitigation Strategy (REMS) is required to mitigate the riskrisks of misuse, abuse, addiction, overdose, and serious complications due to medication errors with the use of TIRF medicines. The TIRF REMS Access Programprogram (hereafter referred to as TIRF REMS) was approved by the FDA on December 28, 2011. The TIRF REMS consists of a Medication Guide, Elements to Assure Safe Use (ETASU), an Implementation System, and a Timetable for Submission of Assessments of the REMS. The goals of the TIRF REMS are to mitigate the riskrisks of misuse, abuse, addiction, overdose, and serious complications due to medication errors by the following: 1. Prescribing and dispensing TIRF medicines only to appropriate patients, which includes use only in opioid-tolerant patients. 2. Preventing inappropriate conversion between TIRF medicines. 3. Preventing accidental exposure to children and others for whom it was not prescribed. 4. Educating prescribers, pharmacists, and patients on the potential for misuse, abuse, addiction, and overdose of TIRF medicines. An important component of the TIRF REMS assessment is the conduct of quantitative evaluation surveys to assess prescribers’ understanding and knowledge of the safe use and appropriate prescribing of TIRF medicines as described in the TIRF REMS educational materials, enrollment formPrescriber Enrollment Form, and Prescribing Information (PI) of each product. This protocol will describe the administration of the surveys that will be conducted among prescribers who are enrolled in the TIRF REMS Access Programprogram. Data from the surveys, together with other REMS evaluation metrics, will be used to determine whether changes need to be made to the REMS processes or educational materials to make them more effective in achieving the goals of the REMS. The surveys will be implemented so that data will be available for inclusion in the REMS Assessment Reports that will be submitted to the FDA at 12 months after approval of the TIRF REMS and annually thereafter. 4 of 54 FDA_5183 TIRF REMS Industry Group (TRIG) Transmucosal Immediate Release Fentanyl (TIRF) Products Prescriber KAB Survey Protocol 3. Version 10.03.0 21AUG201504AUG2016 OBJECTIVES OF THE PRESCRIBER EVALUATION SURVEY The evaluation survey will use a questionnaire to document the level of knowledge and assess the attitudes and behavior of prescribers around the following key information and risk messages communicated through the REMS: 1. TIRF medicines are contraindicated in opioid non-tolerant patients. 2. TIRF medicines are only indicated for the management of breakthrough pain in adult cancer patients 18 years of age and older (16 or older for Actiq® and equivalent generics) who are already receiving and who are tolerant to around-the-clock opioid therapy for their underlying persistent cancer pain. 3. TIRF medicines contain fentanyl, an opioid agonist and a Schedule II-controlled substance, with abuse liability similar to other opioid analgesics. 4. TIRF medicines are not interchangeable with each other, regardless of route of administration. 5. Patients and their caregivers must be instructed that TIRF medicines contain a medicine in an amount that can be fatal in children, in individuals for whom it is not prescribed, and in those who are not opioid tolerant. The survey will also collect data on behaviors, such as receipt and use of educational materials and compliance with REMS requirements. 4. METHODS The survey was designed in collaboration between the TRIG and United BioSource Corporation (UBC) and will be administered by UBC. 4.1 Survey Design This survey will be conducted among a sample of prescribers who are enrolled in the TIRF REMS Access Program.program and have prescribed a TIRF medicine in the last 6 months. Respondents who participate in the previous wave of the TIRF survey will not be eligible to participate in subsequent survey waves. The survey will be administered using the following modalities: x Self-administered, online through a secure website x Telephone surveys facilitated by a trained interviewer from the Survey Coordinating Center using a computer-assisted telephone interviewing (CATI) program The survey will begin with screening questions to confirm respondent eligibility to participate in the survey. Completion of the entire survey is expected to take approximately 20 minutes. The survey included in Appendix A is written to reflect wording for both methods of survey administration: Internet-based and telephone. 5 of 54 FDA_5184 TIRF REMS Industry Group (TRIG) Transmucosal Immediate Release Fentanyl (TIRF) Products Prescriber KAB Survey Protocol Version 10.03.0 21AUG201504AUG2016 All respondents who complete the survey and who provide their contact information will be mailed a $125 honorarium for their time. 4.1.1 Qualitative Research on the Survey The FDA provided feedback to the TRIG on the Knowledge, Attitudes, and Behaviors (KAB) survey results for prescribers included in the 12 month REMS Assessment results. The FDA requested that the TRIG investigate the causes for the low correct response rates to specific questions in the survey by conductingreported in the 12-month REMS Assessment Report. Qualitative research was conducted in 2013 to determine the reasons for the poor performance on these questions, and to assess proposed revised wording to select questions. Qualitative research was performed in 2013 prior to Wave 2 of the survey. Findings were incorporated into the survey and results from the revised survey were included in the 24-month REMS Assessment Report,. 4.1.2 Questions and Statements on REMS Goals The KAB questionnaire is made up of multiple-choice, close-ended statements or questions (the majority of which use true/false or yes/no dichotomous response options), and one openended question. These questions will evaluate current knowledge, attitudes, and behavior regarding the key risk messages noted in Section 3. Questions will beare presented in several formats: x Statements or questions asking the respondent to indicate whether a statement or question is true or false, or if they do not know the answer (there is a similar set of statements and questions that use “yes” or “no” as potential response options); x Statements or questions asking the respondent to choose from a defined list of possible statements or answers; and x One question allowing for the respondent to list questions about the products or comments. Questionnaires will be analyzed to determine prescriber understanding of each key risk message. For statements or questions that use “true” or “yes” vs. “false” or “no” response options, the desired response for key risk messages is generally “true” or “yes” indicating knowledge of, or behavior in accordance with, the objectives of the REMS. However, some questions are formatted to have the respondent disagree with the statement as written by providing response options of “false” or “no” to avoid having the same affirmative answer for all desired responses. REMS statements, corresponding questions, and desired responses covering the key risk messages are identified below and can be found in the complete survey questionnaire (Appendix A). 6 of 54 FDA_5185 TIRF REMS Industry Group (TRIG) Transmucosal Immediate Release Fentanyl (TIRF) Products Prescriber KAB Survey Protocol Version 10.03.0 21AUG201504AUG2016 Key Risk Message 1: TIRF medicines are contraindicated in opioid non-tolerant patients. Question No. Correct AnswerDesired Response Question 5 Please select True, False, or I don’t know for each of the following. According to the labeling for TIRF medicines, patients with cancer who are considered opioidtolerant are those: 5a Who are taking around-the-clock opioid therapy for underlying, persistent cancer pain for one week or longer TRUE 5b Who are not currently taking opioid therapy, but have taken opioid therapy before FALSE 5c Who have no known contraindications to the drug fentanyl, but are not currently taking around-theclock opioid therapy FALSE 7 Please answer True, False, or I don’t know for each statement based on the labeling for TIRF medicines. 7a TIRF medicines are contraindicated in opioid nontolerant patients because life-threatening respiratory depression could occur at any dose. TRUE 7b Death has occurred in opioid non-tolerant patients treated with some fentanyl products. TRUE 7c TIRF medicines may be used to treat opioid nontolerant patients. FALSE 7d Prescribers starting a patient on a TIRF medicine must begin with titration from the lowest dose available for that specific product, even if the patient has previously taken another TIRF medicine. TRUE 1113 Please select True, False, or I don’t know for each of the following. According to the labeling for TIRF medicines, patients considered opioid-tolerant are those who are taking, for one week or longer, at least: 11a13a 8 mg oral hydromorphone/day TRUE 11b13b 60 mg oral morphine/day TRUE 11c13c 30 mg oral oxycodone/day TRUE 11d13d 25 mcg transdermal fentanyl/hour TRUE 11e13e 25 mg oral oxymorphone/day TRUE 11f13f An equianalgesic dose of another oral opioid TRUE TIRF medicines should only be taken by patients TRUE 21 7 of 54 FDA_5186 TIRF REMS Industry Group (TRIG) Transmucosal Immediate Release Fentanyl (TIRF) Products Prescriber KAB Survey Protocol Version 10.03.0 21AUG201504AUG2016 who are opioid tolerant. Key Risk Message 2: TIRF medicines are only indicated for the management of breakthrough pain in adult cancer patients 18 years of age and older (16 years of age and older for Actiq® brand and generic equivalents) who are already receiving and who are tolerant to around-theclock opioid therapy for their underlying, persistent cancer pain. Question No. Question Desired responseResponse 6 Please answer True, False, or I don’t know for each statement based on the labeling for TIRF medicines. 6a According to the product labeling, a cancer patient may start a TIRF medicine and an around-the-clock opioid at the same time. FALSE 6b According to the product labeling, a cancer patient who has been on an around-the-clock opioid for 1 day may start taking a TIRF medicine for breakthrough pain. FALSE 9 In your practicePer the approved labeling for TIRF medicines, for which of the following indications do you prescribeindication(s) are TIRF medicines to opioid tolerant patientsapproved? Please answer Yes, No, or I don’t know for each option. 9a Acute or postoperative pain NO 9b Headache or migraine pain NO 9c Dental pain NO 9d Breakthrough pain from cancer YES 9e Chronic non-cancer pain NO 15b. Adult female with localized breast cancer; just completed a mastectomy and reconstructive surgery; persistent cancer pain managed with 30 mg oral morphine daily for the past 6 weeks. 15 The patients described are experiencing breakthrough pain. According to the labeling, a TIRF medicine is not appropriate for one of them. Which patient should not receive a TIRF medicine? Please select one option. 20 Before initiating treatment with a TIRF medicine, prescribers must review the 8 of 54 FDA_5187 TIRF REMS Industry Group (TRIG) Transmucosal Immediate Release Fentanyl (TIRF) Products Prescriber KAB Survey Protocol Version 10.03.0 21AUG201504AUG2016 Medication Guide with the patient. Please select True, False, or I don’t know for each of the following counseling statements. TRUE 20b Inform patients that TIRF medicines must not be used for acute or postoperative pain, pain from injuries, headache/migraine, or any other short-term pain. FALSE 20c Instruct patients that they can continue to take their TIRF medicine, if they stop taking their around-the-clock opioid medicine. 9 of 54 FDA_5188 TIRF REMS Industry Group (TRIG) Transmucosal Immediate Release Fentanyl (TIRF) Products Prescriber KAB Survey Protocol Version 10.03.0 21AUG201504AUG2016 Key Risk Message 3: TIRF medicines contain fentanyl, an opioid agonist and a Schedule IIcontrolled substance, with abuse liability similar to other opioid analgesics. Question No. Question Correct AnswerDesired Response 7 Please answer True, False, or I don’t know for each statement based on the labeling for TIRF medicines. 7e It is important to monitor for signs of abuse and addiction in patients who take TIRF medicines. 8 Which of the following are risk factors for opioid abuse? Please answer Yes, No, or I don’t know for each option. 8a A personal history of psychiatric illness YES 8b A personal history of past or current alcohol or drug abuse, or a family history of illicit drug use or alcohol abuse YES 12 Please answer True, False, or I don’t know for each statement based on the labeling for TIRF medicines. 12a TIRF medicines can be abused in a manner similar to other opioid agonists. 22 Which of the following risks are associated with the use of TIRF medicines? Please answer True, False, or I don’t know for the following statements. 22a Misuse TRUE 22b Abuse TRUE 22c Addiction TRUE 22d Overdose TRUE 22e Hypothyroidism FALSE 22f Infection FALSE 10 of 54 TRUE TRUE FDA_5189 TIRF REMS Industry Group (TRIG) Transmucosal Immediate Release Fentanyl (TIRF) Products Prescriber KAB Survey Protocol Version 10.03.0 21AUG201504AUG2016 Key Risk Message 4: TIRF medicines are not interchangeable with each other, regardless of route of administration. Question No. Question Desired responseResponse 12 Please answer True, False, or I don’t know for each statement based on the labeling for TIRF medicines. 12b TIRF medicines are interchangeable with each other regardless of route of administration. FALSE 12c The conversion of one TIRF medicine for another TIRF medicine may result in a fatal overdose because of differences in the pharmacokinetics of fentanyl absorption. TRUE 12d Dosing of TIRF medicines is not equivalent on a microgram-to-microgram basis. TRUE 16 A patient is already taking a TIRF medicine but wants to change their medicine. His/her doctor decides to prescribe a different TIRF medicine (that is not a bioequivalent generic version of a branded product) in its place. According to the labeling, how should the prescriber proceed? Please select one option. 11 of 54 16b. The prescriber must not convert to another TIRF medicine on a microgram-permicrogram basis because these medicines have different absorption properties and this could result in a fentanyl overdose. FDA_5190 TIRF REMS Industry Group (TRIG) Transmucosal Immediate Release Fentanyl (TIRF) Products Prescriber KAB Survey Protocol 4.1.3 Version 10.03.0 21AUG201504AUG2016 Additional Questions The survey includes questions about the requirements of the TIRF REMS Access Programprogram and receipt and understanding of the TIRF educational materials and the Patient-Prescriber Agreement Form. The following question about patient counseling behaviors will be asked after the key risk message questions: Question 14: How frequently do you perform the following activities when prescribing TIRF medicines? Please answer Always, Only with the first prescription, Sometimes, Never, or I don’t know. Ask patients (or their caregivers) about the presence of children in the home Instruct patients (or their caregivers) not to share TIRF medicines with anyone else Counsel patients (or their caregivers) that accidental exposure to TIRF medicines by a child may be fatal Instruct patients (or their caregivers) to keep TIRF medicines out of the reach of children to prevent accidental exposure Instruct patients (or their caregivers) about proper disposal of any unused or partially used TIRF medicines Give patients (or their caregivers) the Medication Guide for their TIRF medicine Demographic information will be collected at the end of the survey. 4.2 Participant Recruitment A random sample of prescribers who are enrolled in the TIRF REMS Access Programprogram will be invited to participate via an invitation letter. The text of the sample written invitation to prescribers can be found in Appendix B. If the required number of completed surveys is not achieved within the expected timeframe of approximately one to two weeks after the first mailing, reminder letters will be sent to non-responders from the original sample with subsequent fax, e-mail, or United States (US) Mail follow-up to maximize participation. The distribution within the mailing to the second sample will be adjusted in accordance with the allocation in the original sample. If these efforts do not result in the required number of completed surveys within two to three weeks, then a new sample of prescribers will be randomly selected. All respondents who complete the survey and who provide their contact information will be mailed a $125 honorarium to thank them for their participation. Prescribers who practice in Vermont, Massachusetts, or Minnesota and complete the survey will not receive compensation. Participants will be informed that prescribers from these states are eligible to participate, but they will not receive compensation for their participation. The mailing will also include a Thank You Letter, a copy of the Important Safety Information (ISI), and a copy of the correct answers to key risk message questions. 12 of 54 FDA_5191 TIRF REMS Industry Group (TRIG) Transmucosal Immediate Release Fentanyl (TIRF) Products Prescriber KAB Survey Protocol 4.2.1 Version 10.03.0 21AUG201504AUG2016 Measures to Minimize Bias in the Sample The sample of prescribers who are invited to participate will be a random sample of all enrolled prescribers. The sample of participating prescribers will be self-selected since respondents will voluntarily respond to the invitation to participate; however, the survey recruitment strategies are intended to recruit a heterogeneous sample of prescribers for participation. Prescribers will be offered online or telephone options for completing the survey. Multiple modalities for survey data collection allow for wider survey access to a more heterogeneous population. Respondents will be provided a unique code during the recruitment process and will be asked to provide the unique code to gain access to the online survey or when calling the Survey Coordinating Center. The code will be deactivated after use to minimize the possibility for fraud. 5. STUDY POPULATION 5. STUDY POPULATION 5.1 Sample Size A sample of 300 healthcare providers who are enrolled in the TIRF REMS Access Programprogram is proposed for each survey wave. The size of the sample was determined based on both practical and statistical considerations. There is no target comprehension rate specified a priori. A sample of 300 completed surveys will allow estimation of the comprehension rate for each risk message with a moderately high degree of precision. The table below shows the precision of the estimates for level of understanding using two-sided 95% confidence intervals (CIs) obtained with the sample size of 300 completed surveys. The noted CIs are used to indicate that for any survey-estimated rate of understanding, the true population rate of understanding is at least as high as the lower limit of the 95% CI and may be as high as the upper limit of the 95% CI. 13 of 54 FDA_5192 TIRF REMS Industry Group (TRIG) Transmucosal Immediate Release Fentanyl (TIRF) Products Prescriber KAB Survey Protocol Version 10.03.0 21AUG201504AUG2016 Table 5.1: Precision of Estimated Rates of Understanding with a Sample Size of 300 Estimated Rate of Understanding 5.1.1 Estimated Confidence Interval 5% 2.8% 8.1% 10% 6.8% 14.0% 15% 11.2% 19.6% 20% 15.6% 25.0% 25% 20.2% 30.3% 30% 24.9% 35.5% 35% 29.6% 40.7% 40% 34.4% 45.8% 45% 39.3% 50.8% 50% 44.2% 55.8% 55% 49.2% 60.7% 60% 54.2% 65.6% 65% 59.3% 70.4% 70% 64.5% 75.1% 75% 69.7% 79.8% 80% 75.0% 84.4% 85% 80.4% 88.8% 90% 86.0% 93.2% 95% 91.9% 97.2% Inclusion Criteria All prescribers who are enrolled in the TIRF REMS Access Programprogram and have prescribed a TIRF medicine in the last 6 months are eligible to participate in this survey, with the exceptions noted below. 5.1.2 Exclusion Criteria The following respondents are not eligible to participate in the surveys: x Prescribers who have previously participated in the TIRF REMS KAB survey. x Prescribers or their immediate family members who have ever worked for ever worked for Actavis Laboratories FL, Inc.; Anesta LLC; BioDelivery Sciences International, Inc. (BDSI); Cephalon, Inc. (a wholly-owned subsidiary of Teva Pharmaceutical Industries, Ltd); Depomed, Inc.; Galena Biopharma, Inc.; Insys Therapeutics, Inc.; Mallinckrodt Pharmaceuticals; Mylan, Inc.; Par PharmaceuticalPharmaceuticals, Inc.; 14 of 54 FDA_5193 TIRF REMS Industry Group (TRIG) Transmucosal Immediate Release Fentanyl (TIRF) Products Prescriber KAB Survey Protocol Version 10.03.0 21AUG201504AUG2016 Teva Pharmaceuticals, Ltd.; Sentynl Therapeutics, Inc.; UBC; McKesson Specialty Care Solutions; RelayHealth; or the FDA. 6. SURVEY PROCESS 6. THE SURVEY WILL BEGIN WITH SCREENING QUESTIONS TO CONFIRM RESPONDENT ELIGIBILITY TO PARTICIPATE IN THE SURVEY. SURVEY PROCESS Completion of the entire survey is expected to take approximately 20 minutes. 6.1 Screening and Survey Administration The questionnaire will begin with a screening module with questions to confirm prescriber eligibility. Depending on the answers to the screening questions, survey participation could either be terminated or continued. If ineligible, the respondent is immediately notified with a “thank you” message that survey participation has ended. If eligible, the respondent is allowed to continue survey participation. The data entry system used for both methods of survey administration has been validated and is secure for receiving and storing survey data. The system is 21 CFR Part 11 and Health Insurance Portability and Accountability Act (HIPAA) compliant. Prescriber-identifying information will be stored separately from survey data. Completion of the entire survey is expected to take approximately 20 minutes. 6.1.1 Telephone A trained interviewer from the Survey Coordinating Center will conduct the telephone interviews using a CATI program. The screening and main elements of the questionnaire will be administered sequentially during the same telephone call. Telephone interviewing allows participation of prescribers who do not have Internet access. It will also be convenient for prescribers to participate since they can call in and be interviewed at their convenience during the specified time period when the Survey Coordinating Center is available. 6.1.2 Internet An Internet-based survey system will also be used for conducting the KAB surveys. If the prescriber selects to participate in the survey online, he/she will be directed to a secured website to complete screening questions. An Internet survey will be convenient for respondents to participate since they can complete the questionnaire at any time during the survey period. 6.2 Measures to Minimize Bias in the Survey Process A number of controls will be in place to ensure the survey is conducted in a controlled and professional manner and to minimize bias. For example, a unique code will be given to each 15 of 54 FDA_5194 TIRF REMS Industry Group (TRIG) Transmucosal Immediate Release Fentanyl (TIRF) Products Prescriber KAB Survey Protocol Version 10.03.0 21AUG201504AUG2016 survey participant and the code will be inactivated after use to minimize fraud. Telephone interviewers are highly trained and use a standardized script to administer the survey. All questions will be programmed to ensure that questions are asked in the appropriate sequence. Skip patterns will be clearly indicated. Respondents cannot go back to a question once the question has been answered and cannot skip ahead. All questions must be answered in order to complete the survey. Response options presented in a list will be randomized to minimize positional bias. Programming will be reviewed by quality control and simulated users (User Acceptance Testing) prior to implementing the survey. 7. ANALYSIS Information obtained from the survey will be reported as descriptive statistics for the survey administration, study population, and the survey questions. The data from the sample population will be reported using frequency distributions of responses to all questions. The following will be reported as part of this analysis: x The number of invitations issued to prescribers x The number of invitations returned as undeliverable x The number of reminder letters x The number of respondents screened for participation x The number of respondents eligible for participation x The number of respondents eligible for participation who complete the survey x Representativeness of prescribers based on geography x Description of survey participants, including: Gender Medical degree of respondent: MD, DO, NP, PA Medical specialty Years of professional experience How many times per month TIRF medicines were prescribed by the respondent in the last 6 months Geographic region of practice Additional descriptive statistics may be reported as appropriate. 16 of 54 FDA_5195 TIRF REMS Industry Group (TRIG) Transmucosal Immediate Release Fentanyl (TIRF) Products Prescriber KAB Survey Protocol 7.1.1 Version 10.03.0 21AUG201504AUG2016 Analysis Population The analysis population will be based on eligible prescribers who completed all questions presented to them in the survey (“completers”). 7.1.2 Description of Primary Analyses Primary analyses are done for all key risk messages using data from all completers. The primary analysis for a key risk message evaluates the rate for each correct response to each individual question/item defined by the key risk message. The specific correct response to each question/item is identified in the body of the risk message table. 7.1.3 Description of Secondary Analyses Secondary analyses are done only for those key risk messages that contain multiple questions/items using data from all completers. The secondary analysis entails a frequency distribution of the number of respondents who got 0, 1, etc. correct responses across the total number of items for the given key risk message. Mean knowledge scores will be computed for each key risk message; an overall knowledge score will be computed for each respondent. Additional analyses may be performed as needed. 8. SAFETY EVENT REPORTING The term ‘Safety Event’safety event’ is defined as any information reported by a survey respondent that meets the criteria of an adverse event or product complaint. While it is not the intention of the survey to solicit the report of information that meets the criteria of a Safety Eventsafety event, it is possible that a respondent may spontaneously report information that meets this criteria in free text fields of the survey (Internet-based administration) or while in conversation with the Survey Coordinating Center (telephone-based administration). The Internet-based questionnaires will be monitored for any comments recorded in the free text fields. If an event is mentioned to a Survey Coordinating Center Associate, the Associate will document the safety event and the respondent’s contact information. Respondents will also be informed that a representative from the appropriate TIRF medicine manufacturer may contact them if there are questions about the survey. Information on all reports (Internet or telephone) that may constitute an adverse event or other safety event will be forwarded to the appropriate TIRF medicine manufacturer as described in the Safety Event Project Specific Procedure (SE PSP). Additional detail regarding processes for adverse event reporting will be specified in the SE PSP. 9. PRIVACY PROTECTION AND CONFIDENTIALITY All data collected during the survey will be held confidential. The electronic data capture (EDC) system used for data collection encrypts all identifiable information, and respondent identifiers are stored separately from the survey responses. 17 of 54 FDA_5196 TIRF REMS Industry Group (TRIG) Transmucosal Immediate Release Fentanyl (TIRF) Products Prescriber KAB Survey Protocol Version 10.03.0 21AUG201504AUG2016 Respondent names and addresses are collected in order to mail the $125 honorarium, a Thank You Letter, the correct responses to key risk messages, and the ISI after the survey is completed. Respondent contact information is also requested when necessary to comply with a federal or state law or regulation, including without limitation, reporting payments made to physicians under the federal physician payment sunshine provisions in addition to instances where a safety event is reported and a TIRF medicine manufacturer must obtain follow-up information (see Section 8 above). Respondents will be informed when they access the survey that they may be contacted if there are any questions about their survey responses. Respondents will be informed that their answers to the survey questions will not affect their ability to prescribe TIRF medicines. 18 of 54 FDA_5197 TIRF REMS Industry Group (TRIG) Transmucosal Immediate Release Fentanyl (TIRF) Products Prescriber KAB Survey Protocol Appendix A Version 10.03.0 21AUG201504AUG2016 Prescriber Questionnaire Survey Legend [PROGRAMMER] is used to indicate directions to the programmer and is set in bold, red, uppercase letters between square brackets. (INTERVIEWER) is used to indicate directions to the telephone interviewer and is set in bold, blue, text between parentheses. This text appears when content is to be administered by telephone only (for example, spontaneous adverse event reporting). [ONLINE] indicates a question is worded specifically for administering the survey online. [PHONE] indicates a question is worded specifically to be read by a telephone interviewer and differs from the online text. [BEGIN SURVEY CONTENT] and [END SURVEY CONTENT] are used to indicate to the programmer the type of survey administration and the beginning and end of the survey or sections within the survey content, for example, [BEGIN ADVERSE EVENT/PRODUCT COMPLAINT] and [END ADVERSE EVENT/PRODUCT COMPLAINT]. [TERMINATE] is displayed next to responses that should cause the survey to end. The following termination language will be programmed into the survey or read by the interviewer unless different language is specified with the question. Thank you very much for your time today. Based on your answer, you are not eligible to take this survey. We appreciate your interest in the survey. [RANDOMIZE LIST] is inserted before questions to indicate to the programmer that the responses should be randomized. Responses such as “I don’t know,” “Prefer not to answer” or “None of the above” will always appear at the end of the randomized responses. Response options for questions that allow multiple responses must be indicated with check @ cted for the question to be considered answered. If any response option requires text to be collected and does not need another question label, show [FREE TEXT] after the response option., if applicable. Response options for questions that allow only one response must be indicated with radio buttons ( ). If any response option requires text to be collected and does not need another question label, show [FREE TEXT] after the response option, if applicable. [FREE TEXT] indicates to the programmer that one line should be provided for data entry. 19 of 54 FDA_5198 TIRF REMS Industry Group (TRIG) Transmucosal Immediate Release Fentanyl (TIRF) Products Prescriber KAB Survey Protocol Version 10.03.0 21AUG201504AUG2016 Survey Legend [MULTILINE INPUT] indicates to the programmer that multiple lines should be provided for data entry (for example, two address lines). [DROP-DOWN LIST INPUT WITH STATES TABLE] indicates to the programmer that the response should be a drop-down list containing the states and US territories in the table below. Alabama Georgia Massachusetts New York Tennessee Alaska Guam Michigan North Carolina Texas American Samoa Hawaii Minnesota North Dakota Idaho Mississippi Illinois Missouri Northern Mariana Islands US Virgin Islands Indiana Montana Iowa Nebraska Kansas Nevada Kentucky New Hampshire Louisiana New Jersey Maine New Mexico Arizona Arkansas California Colorado Connecticut Delaware District of Columbia Florida Maryland Ohio Oklahoma Oregon Pennsylvania Puerto Rico Utah Vermont Virginia Washington West Virginia Wisconsin Wyoming Rhode Island South Carolina South Dakota The following is used to categorize survey populations into standard geographic regions but it is not displayed in the survey. Geographic Distribution (based on address) 1: Northeast, Midwest, South, and West regions Northeast Region New England Division - ME, NH, VT, MA, RI, CT Middle Atlantic Division - NY, NJ, PA Midwest Region East North Central Division - OH, IN, IL, MI, WI West North Central Division - MN, IA, MO, ND, SD, NE, KS South Region 20 of 54 FDA_5199 TIRF REMS Industry Group (TRIG) Transmucosal Immediate Release Fentanyl (TIRF) Products Prescriber KAB Survey Protocol Version 10.03.0 21AUG201504AUG2016 Survey Legend South Atlantic Division - DE, MD, DC, VA, WV, NC, SC, GA, FL East South Central Division - KY, TN, AL, MS West South Central Division - AR, LA, OK, TX West Mountain Division - MT, ID, WY, CO, NM, AZ, UT, NV Pacific Division WA, OR, CA, AK, HI The following US territories are categorized as Other: Puerto Rico, Northern Mariana Islands, US Virgin Islands, American Samoa, and Guam. 1 U.S. Census Bureau, last revised Friday, 27-Jul-2001 12:59:43 EDT. 21 of 54 FDA_5200 TIRF REMS Industry Group (TRIG) Transmucosal Immediate Release Fentanyl (TIRF) Products Prescriber KAB Survey Protocol Version 10.03.0 21AUG201504AUG2016 [BEGIN SURVEY CONTENT] [BEGIN ONLINE PREAMBLE 1] Before you begin, we would like to share some important information about this survey. The manufacturers of Transmucosal Immediate Release Fentanyl (TIRF) medicines are conducting this survey, as required by the FDA, to assess prescribers’ understanding of the safe use and prescribing of these medicines. These medicines are known as rapid onset opioids and referred to in this survey as “TIRF medicines.” The TIRF medicines include Abstral®, Actiq®, Fentora®, Lazanda®, Subsys®, and generic versions of any of these brands. The manufacturers of these medicines include Actavis Laboratories FL, Inc.; BioDelivery Sciences International, Inc. (BDSI); Cephalon, Inc. (a wholly-owned subsidiary of Teva Pharmaceutical Industries, Ltd.); Depomed, Inc.; Galena Biopharma, Inc.; Insys Therapeutics, Inc.; Mallinckrodt Pharmaceuticals; Mylan Inc.; Par Pharmaceuticals, Inc.; and Par PharmaceuticalSentynl Therapeutics, Inc. The survey will take approximately 20 minutes. There are no known risks to you in taking this survey. You may refuse to take part or withdraw at any time. Your answers to the questions or your decision to take part in the survey will not affect your ability to prescribe TIRF medicines. How We Use Your Information Your answers to the survey questions will be combined with answers given by other healthcare professionals taking the survey. All answers will be put together and reported in anonymous form to the manufacturers of TIRF medicines. Your name will not be used in any report. If you are eligible to take the survey, complete all the questions, and provide your contact information, you will receive a $125 honorarium for your time and participation. This compensation represents the fair value for your services in connection with completion of the survey. The amount of the compensation was not determined in any manner that takes into account the volume or value of any referrals or business otherwise generated by you. Your name and address will be used to send you the honorarium to you after you complete the survey. Your personal information will also be used if we have questions about your survey or if we are required to use your information to comply with a federal or state law or regulation, including without limitation, reporting payments made to physicians under the federal physician payment sunshine provisions. Physicians who practice in Vermont, Massachusetts, or Minnesota should be aware that they will not be permitted to receive payment for survey completion and may elect not to complete the survey. Providing a telephone number is optional. Your telephone number will be used only if there are any questions about your survey responses. How We Protect Your Privacy We respect that the privacy of your personal information is important to you. You will not be contacted for marketing purposes based on your personal information or your answers to the survey. Neither the manufacturers of TIRF medicines nor their contractors will sell, transfer, or rent your information. Your answers will be kept strictly confidential. Your personal information will not be used in a manner inconsistent with this document. Your privacy will be protected; however, research survey records may be inspected by the FDA. Your choice to 22 of 54 FDA_5201 TIRF REMS Industry Group (TRIG) Transmucosal Immediate Release Fentanyl (TIRF) Products Prescriber KAB Survey Protocol Version 10.03.0 21AUG201504AUG2016 allow manufacturers of TIRF medicines to use your information is entirely voluntary but necessary to take part in this survey. How to Learn More about This Survey If you have questions about the survey, or problems with the survey, please contact the Survey Coordinating Center at 1-877-379-3297. Be sure to write down this telephone number; it will not be displayed again. Taking the Survey Once you have answered a question and moved on, you cannot go back and change your answers. Thank you for your participation in this survey. [END ONLINE PREAMBLE 1] 23 of 54 FDA_5202 TIRF REMS Industry Group (TRIG) Transmucosal Immediate Release Fentanyl (TIRF) Products Prescriber KAB Survey Protocol Version 10.03.0 21AUG201504AUG2016 [BEGIN PHONE PREAMBLE 1] Before you begin, we would like to share some important information about this survey. The manufacturers of Transmucosal Immediate Release Fentanyl (TIRF) medicines are conducting this survey, as required by the FDA, to assess prescribers’ understanding of the safe use and prescribing of these medicines. These medicines are known as rapid onset opioids and referred to in this survey as “TIRF medicines.” (INTERVIEWER: Say “TIRF” then spell out T-IR-F) The TIRF medicines include Abstral®, Actiq®, Fentora®, Lazanda®, Subsys®, and generic versions of any of these brands. The manufacturers of these medicines include Actavis Laboratories FL, Inc.; BioDelivery Sciences International, Inc. (BDSI); Cephalon, Inc. (a wholly-owned subsidiary of Teva Pharmaceutical Industries, Ltd.); Depomed, Inc.; Galena Biopharma, Inc.; Insys Therapeutics, Inc.; Mallinckrodt Pharmaceuticals; Mylan Inc.; Par Pharmaceuticals, Inc.; and Par PharmaceuticalSentynl Therapeutics, Inc. The survey will take approximately 20 minutes. There are no known risks to you in taking this survey. You may refuse to take part or withdraw at any time. Your answers to the questions or your decision to take part in the survey will not affect your ability to prescribe TIRF medicines. Now I would like to read some information about how your contact information will be used. Your answers to the survey questions will be combined with answers given by other healthcare professionals taking the survey. All answers will be put together and reported in anonymous form to the manufacturers of TIRF medicines. Your name will not be used in any report. If you are eligible to take the survey, complete all the questions, and provide your contact information, you will receive a $125 honorarium for your time and participation. This compensation represents the fair value for your services in connection with completion of the survey. The amount of the compensation was not determined in any manner that takes into account the volume or value of any referrals or business otherwise generated by you. Your name and address will be used to send you the honorarium to you after you complete the survey. Your personal information will also be used if we have questions about your survey or if we are required to use your information to comply with a federal or state law or regulation, including without limitation, reporting payments made to physicians under the federal physician payment sunshine provisions. Physicians who practice in Vermont, Massachusetts, or Minnesota should be aware that they will not be permitted to receive payment for survey completion and may elect not to complete the survey. Providing a telephone number is optional. Your telephone number will be used only if there are any questions about your survey responses. Now I would like to tell you some information about how we protect your privacy. We respect that the privacy of your personal information is important to you. You will not be contacted for marketing purposes based on your personal information or your answers to the survey. Neither the manufacturers of TIRF medicines nor their contractors will sell, transfer, or rent your information. Your answers will be kept strictly confidential. Your personal information will not be used in a manner inconsistent with this document. Your privacy will be protected; however, research survey records may be inspected by the FDA. Your choice to 24 of 54 FDA_5203 TIRF REMS Industry Group (TRIG) Transmucosal Immediate Release Fentanyl (TIRF) Products Prescriber KAB Survey Protocol Version 10.03.0 21AUG201504AUG2016 allow manufacturers of TIRF medicines to use your information is entirely voluntary but necessary to take part in this survey. Now I will tell you how you can learn more about this survey. Please have a pen or pencil ready to write down a telephone number you can call if you have any questions about the survey. If you have questions about the survey, please ask me at any time. If you have questions at a later time, please contact the Survey Coordinating Center at 1-877-379-3297. Please feel free to ask me to repeat any questions or statements as we go through the survey. Once you have answered a question and moved on, we cannot go back and change your answers. Thank you for your participation in this survey. [END PHONE PREAMBLE 1] 25 of 54 FDA_5204 TIRF REMS Industry Group (TRIG) Transmucosal Immediate Release Fentanyl (TIRF) Products Prescriber KAB Survey Protocol Version 10.03.0 21AUG201504AUG2016 [BEGIN INCLUSION/EXCLUSION QUESTIONS] 1. Your agreement to participate in this survey confirms mutual understanding in connection with completion of the survey and the fair market value of the payment to be rendered in connection with those services. Do you agree to participate in this survey? 2. 3. Yes No [TERMINATE] Have you ever taken part in this survey about TIRF medicines before? TIRF medicines include Abstral®, Actiq®, Fentora®, Lazanda®, Subsys®, and generic versions of any of these brands. Yes [TERMINATE] No I don’t know [TERMINATE] Are you enrolled in the TIRF REMS Access Programprogram? Yes No [TERMINATE] I don’t know [TERMINATE] 26 of 54 FDA_5205 TIRF REMS Industry Group (TRIG) Transmucosal Immediate Release Fentanyl (TIRF) Products Prescriber KAB Survey Protocol 4. Version 10.03.0 21AUG201504AUG2016 Have you or any of your immediate family members ever worked for any of the following companies or agencies? Please select all that apply. Actavis Laboratories FL, Inc. [TERMINATE] Anesta LLC [TERMINATE] BioDelivery Sciences International, Inc. (BDSI) [TERMINATE] Cephalon, Inc. (a wholly-owned subsidiary of Teva Pharmaceutical Industries, Ltd.) [TERMINATE] Depomed, Inc. [TERMINATE] Galena Biopharma, Inc. [TERMINATE] Insys Therapeutics, Inc. [TERMINATE] Mallinckrodt Pharmaceuticals [TERMINATE] McKesson Specialty Care Solutions [TERMINATE] Mylan, Inc. [TERMINATE] Par PharmaceuticalPharmaceuticals, Inc. [TERMINATE] RelayHealth [TERMINATE] Sentynl Therapeutics, Inc. [TERMINATE] Teva Pharmaceuticals, Ltd. [TERMINATE] United BioSource Corporation [TERMINATE] FDA [TERMINATE] None of these apply [IF SELECTED IN ADDITION TO OTHER RESPONSES, TERMINATE] I don’t know [TERMINATE] Prefer not to answer [TERMINATE] [END INCLUSION/EXCLUSION QUESTIONS] 27 of 54 FDA_5206 TIRF REMS Industry Group (TRIG) Transmucosal Immediate Release Fentanyl (TIRF) Products Prescriber KAB Survey Protocol 5. Version 10.03.0 21AUG201504AUG2016 Please select True, False, or I don’t know for each of the following. According to the labeling for TIRF medicines, patients with cancer who are considered opioid-tolerant are those: [RANDOMIZE LIST] Who are taking around-the-clock opioid therapy for underlying, persistent cancer pain for one week or longer 5b. Who are not currently taking opioid therapy, but have taken opioid therapy before 5c. Who have no known contraindications to the drug fentanyl, but are not currently taking around-the-clock opioid therapy True False I don’t know 5a. 6. Please answer True, False, or I don’t know for each statement based on the labeling for TIRF medicines. [RANDOMIZE LIST] According to the product labeling, a cancer patient may start a TIRF medicine and an around-the-clock opioid at the same time. 6b. According to the product labeling, a cancer patient who has been on an around-the-clock opioid for 1 day may start taking a TIRF medicine for breakthrough pain. True False I don’t know 6a. 28 of 54 FDA_5207 TIRF REMS Industry Group (TRIG) Transmucosal Immediate Release Fentanyl (TIRF) Products Prescriber KAB Survey Protocol 7. Version 10.03.0 21AUG201504AUG2016 Please answer True, False, or I don’t know for each statement based on the labeling for TIRF medicines. [RANDOMIZE LIST] TIRF medicines are contraindicated in opioid nontolerant patients because life-threatening respiratory depression could occur at any dose. 7b. Death has occurred in opioid non-tolerant patients treated with some fentanyl products. 7c. TIRF medicines may be used to treat opioid non-tolerant patients. 7d. Prescribers starting a patient on a TIRF medicine must begin with titration from the lowest dose available for that specific product, even if the patient has previously taken another TIRF medicine. 7e. It is important to monitor for signs of abuse and addiction in patients who take TIRF medicines. True False I don’t know 7a. 8. Which of the following are risk factors for opioid abuse? Please answer Yes, No, or I don’t know for each option. [RANDOMIZE LIST] 8a. 8b. 8c. A personal history of psychiatric illness A personal history of past or current alcohol or drug abuse, or a family history of illicit drug use or alcohol abuse A family history of asthma 29 of 54 Yes No I don’t know FDA_5208 TIRF REMS Industry Group (TRIG) Transmucosal Immediate Release Fentanyl (TIRF) Products Prescriber KAB Survey Protocol 9. In your practicePer the approved labeling for TIRF medicines, for which of the following indications do you prescribeindication(s) are TIRF medicines to opioid tolerant patientsapproved? Please answer Yes, No, or I don’t know for each option. [RANDOMIZE LIST] 9a. 9b. 9c. 9d. 9e. Version 10.03.0 21AUG201504AUG2016 Acute or postoperative pain Headache or migraine pain Dental pain Breakthrough pain from cancer Chronic non-cancer pain Yes No I don’t know [IF 9E YES, DISPLAY Q10 and Q11 ON SUBSEQUENT PAGES] 10. For what type(s) of chronic non-cancer pain conditions do you prescribe a TIRF medicine to opioid tolerant patients? [MULTILINE INPUT] 11. Why do you select a TIRF medicine to treat these chronic pain conditions in patients who are opioid tolerant? [MULTILINE INPUT] 11. Why do you select a TIRF medicine to treat these chronic non-cancer pain conditions in patients who are opioid tolerant? [MULTILINE INPUT] 12. Please answer True, False, or I don’t know for each statement based on the labeling for TIRF medicines. [RANDOMIZE LIST] 12a. TIRF medicines can be abused in a manner similar to other opioid agonists. 12b. TIRF medicines are interchangeable with each other 30 of 54 True False I don’t know FDA_5209 TIRF REMS Industry Group (TRIG) Transmucosal Immediate Release Fentanyl (TIRF) Products Prescriber KAB Survey Protocol Version 10.03.0 21AUG201504AUG2016 regardless of route of administration. 12c. The conversion of one TIRF medicine for another TIRF medicine may result in a fatal overdose because of differences in the pharmacokinetics of fentanyl absorption. 12d. Dosing of TIRF medicines is not equivalent on a microgramto-microgram basis. 31 of 54 FDA_5210 TIRF REMS Industry Group (TRIG) Transmucosal Immediate Release Fentanyl (TIRF) Products Prescriber KAB Survey Protocol 13. Please select True, False, or I don’t know for each of the following. According to the labeling for TIRF medicines, patients considered opioid-tolerant are those who are taking, for one week or longer, at least: 13a. 8 mg oral hydromorphone/day 13b 60 mg oral morphine/day 13c. 30 mg oral oxycodone/day 13d 25 mcg transdermal fentanyl/hour 13e. 25 mg oral oxymorphone/day 13f. An equianalgesic dose of another oral opioid 14. Version 10.03.0 21AUG201504AUG2016 True False I don’t know How frequently do you perform the following activities when prescribing TIRF medicines? Please answer Always, Only with the first prescription, Sometimes, Never, or I don’t know. Always Only with the first prescription [RANDOMIZE LIST] 14a. Ask patients (or their caregivers) about the presence of children in the home 14b. Instruct patients (or their caregivers) not to share TIRF medicines with anyone else 14c. Counsel patients (or their caregivers) that accidental exposure to TIRF medicines by a child may be fatal 14d. Instruct patients (or their caregivers) to keep TIRF medicines out of the reach of children to prevent accidental exposure 14e. Instruct patients (or their caregivers) about proper disposal of any unused or partially used TIRF medicines 32 of 54 Sometimes Never I don’t know FDA_5211 TIRF REMS Industry Group (TRIG) Transmucosal Immediate Release Fentanyl (TIRF) Products Prescriber KAB Survey Protocol 14f. Give patients (or their caregivers) the Medication Guide for their TIRF medicine 15. Version 10.03.0 21AUG201504AUG2016 The patients described are experiencing breakthrough pain. According to the labeling, a TIRF medicine is not appropriate for one of them. Which patient should not receive a TIRF medicine? Please select one option. [RANDOMIZE LIST WITH I DON’T KNOW ALWAYS AT THE END] 16. Adult male with advanced lung cancer; underlying persistent cancer pain managed with 25 mcg/hour transdermal fentanyl patches for the past two months. Adult female with localized breast cancer; just completed a mastectomy and reconstructive surgery; persistent cancer pain managed with 30 mg oral morphine daily for the past 6 weeks. Adult male patient with advanced prostate cancer who, over the last 2 weeks, has been prescribed 100 mg oral morphine daily for pain due to bone metastasis. Adult female with advanced sarcoma who has been taking a daily dose of 12 mg oral hydromorphone for the last 3 weeks. I don’t know A patient is already taking a TIRF medicine but wants to change their medicine. His/her doctor decides to prescribe a different TIRF medicine (that is not a bioequivalent generic version of a branded product) in its place. According to the labeling, how should the prescriber proceed? Please select one option. [RANDOMIZE LIST WITH I DON’T KNOW ALWAYS AT THE END] The prescriber can safely convert to the equivalent dosage of the new TIRF medicine as it has the same effect as other TIRF medicines. The prescriber must not convert to another TIRF medicine on a microgram-permicrogram basis because these medicines have different absorption properties and this could result in a fentanyl overdose. Convert from the other TIRF medicine to the new TIRF medicine at half of the dose. The prescriber should base the starting dose of the newly-prescribed TIRF medicine on the dose of the opioid medicine used for their underlying persistent cancer pain. 33 of 54 FDA_5212 TIRF REMS Industry Group (TRIG) Transmucosal Immediate Release Fentanyl (TIRF) Products Prescriber KAB Survey Protocol 17. Version 10.03.0 21AUG201504AUG2016 I don’t know. A patient is starting titration with a TIRF medicine. What dose must they start with? Please select one option. [RANDOMIZE LIST WITH I DON’T KNOW ALWAYS AT THE END] 18. An appropriate dose based on the dose of the opioid medicine used for underlying persistent cancer pain. The dose that the prescriber believes is appropriate based on their clinical experience. The lowest available dose, unless individual product Full Prescribing Information provides product-specific guidance. The median available dose. I don’t know. A prescriber has started titrating a patient with the lowest dose of a TIRF medicine. However, after 30 minutes the breakthrough pain has not been sufficiently relieved. What should they advise the patient to do? Please pick the best option of the scenarios described. [RANDOMIZE LIST WITH I DON’T KNOW ALWAYS AT THE END] 19. Take another (identical) dose of the TIRF medicine immediately. Take a dose of an alternative rescue medicine. Provide guidance based on the product-specific Medication Guide because the instructions are not the same for all TIRF medicines. Double the dose and take immediately. I don’t know. A patient is taking a TIRF medicine and the doctor would like to prescribe erythromycin, a CYP3A4 inhibitor. Please pick the best option of the scenarios described. [RANDOMIZE LIST WITH I DON’T KNOW ALWAYS AT THE END] The patient can’t be prescribed erythromycin, because using it at the same time as a TIRF medicine could be fatal. Use of a TIRF medicine with a CYP3A4 inhibitor may require a dosage adjustment; carefully monitor the patient for opioid toxicity, otherwise such use 34 of 54 FDA_5213 TIRF REMS Industry Group (TRIG) Transmucosal Immediate Release Fentanyl (TIRF) Products Prescriber KAB Survey Protocol Version 10.03.0 21AUG201504AUG2016 may cause potentially fatal respiratory depression. 20. There is no possible drug interaction between CYP3A4 inhibitors and TIRF medicines. The dose of the TIRF medicine must be reduced by one half if a CYP3A4 inhibitor is prescribed in the same patient. I don’t know. Before initiating treatment with a TIRF medicine, prescribers must review the Medication Guide with the patient. Please select True, False, or I don’t know for each of the following counseling statements. [RANDOMIZE LIST] 20a. TIRF medicines contain fentanyl in an amount that could be fatal to children of all ages, in individuals for whom they were not prescribed, and in those who are not opioid tolerant. 20b. Inform patients that TIRF medicines must not be used for acute or postoperative pain, pain from injuries, headache/migraine, or any other short-term pain. 20c. Instruct patients that they can continue to take their TIRF medicine, if they stop taking their around-theclock opioid medicine. 20d. Instruct patients to never share their TIRF medicine with anyone else, even if that person has the same symptoms. 21. True False I don’t know Please answer True, False, or I don’t know for the following statement about TIRF medicines: TIRF medicines should only be taken by patients who are opioid tolerant. True False I don’t know 35 of 54 FDA_5214 TIRF REMS Industry Group (TRIG) Transmucosal Immediate Release Fentanyl (TIRF) Products Prescriber KAB Survey Protocol 22. Version 10.03.0 21AUG201504AUG2016 Which of the following risks are associated with the use of TIRF medicines? Please answer True, False, or I don’t know for the following statements. True False I don’t know 22a. Misuse 22b. Abuse 22c. Addiction 22d. Overdose 22e. Hypothyroidism 22f. Infection [RANDOMIZE LIST] 36 of 54 FDA_5215 TIRF REMS Industry Group (TRIG) Transmucosal Immediate Release Fentanyl (TIRF) Products Prescriber KAB Survey Protocol Version 10.03.0 21AUG201504AUG2016 [BEGIN PREAMBLE 2 – DISPLAY ON SAME PAGE AS NEXT QUESTION] The next set of questions is about the educational materials for TIRF medicines and the TIRF Patient-Prescriber Agreement. As a reminder, the TIRF medicines include Abstral®, Actiq®, Fentora®, Lazanda®, Subsys® and generic versions of any of these brands. [END PREAMBLE 2] 21.23 Did you receive or do you have access to the Full Prescribing Information for the TIRF medicine(s) that you prescribe? Yes No [GO TO Q23] I don’t know [GO TO Q23] No [GO TO Q25] I don’t know [GO TO Q25] 22.24 Did you read the Full Prescribing Information for the TIRF medicine(s) that you prescribe? Yes No I don’t know 23.25 Did you receive or do you have access to the Medication Guide for the TIRF medicine(s) that you prescribe? Yes No [GO TO Q27] I don’t know [GO TO Q27] No [GO TO Q25] I don’t know [GO TO Q25] 37 of 54 FDA_5216 TIRF REMS Industry Group (TRIG) Transmucosal Immediate Release Fentanyl (TIRF) Products Prescriber KAB Survey Protocol Version 10.03.0 21AUG201504AUG2016 24.26 Did you read the Medication Guide for the TIRF medicine(s) that you prescribe? Yes No I don’t know 25.27 Did you or do you have any questions about the information in the Full Prescribing Information or Medication Guide? Yes No [GO TO Q27] I don’t know [GO TO Q27] No [GO TO Q29] I don’t know [GO TO Q29] [IF QUESTION 2627 YES, DISPLAY QUESTION 28 ON SAME PAGE] 26. What are your questions? [MULTILINE INPUT] 28. What are your questions? [MULTILINE INPUT] 27.29 Do you review the Patient-Prescriber Agreement Form with each of your patients for whom you prescribe TIRF medicines or their caregiver? Yes No [GO TO DEMOGRAPHICS PREAMBLE 1QUESTION 32] I don’t know [GO TO DEMOGRAPHICS PREAMBLE 1QUESTION 32] 38 of 54 FDA_5217 TIRF REMS Industry Group (TRIG) Transmucosal Immediate Release Fentanyl (TIRF) Products Prescriber KAB Survey Protocol Version 10.03.0 21AUG201504AUG2016 28.30 Do you and the patient or their caregiver sign the Patient-Prescriber Agreement Form for TIRF medicines after you have reviewed it with him/her? Yes No I don’t know 29.31 Do you give a copy of the Patient-Prescriber Agreement Form for TIRF medicines to the patient or their caregiver? 32. Yes No I don’t know How frequently do you perform the following activities when prescribing TIRF medicines? Please answer Always, Only with the first prescription, Sometimes, Never, or I don’t know. Always Only with the first prescription [RANDOMIZE LIST] 32a. Talk to the patient about the risks and possible side effects of the TIRF medicine that was most recently prescribed. 32b. Instruct the patient on how to use the TIRF medicine that was most recently prescribed. 32c. Instruct the patient on how to store or keep the TIRF medicine that was most recently prescribed. Sometimes Never I don’t know [BEGIN DEMOGRAPHICS PREAMBLE 1 - DISPLAY ON SAME PAGE WITH NEXT QUESTION] There are just a few more questions to help us combine your answers with other answers we have received. [END DEMOGRAPHICS PREAMBLE 1] 39 of 54 FDA_5218 TIRF REMS Industry Group (TRIG) Transmucosal Immediate Release Fentanyl (TIRF) Products Prescriber KAB Survey Protocol Version 10.03.0 21AUG201504AUG2016 30.33 On average, how many times per month have you prescribed the TIRF medicines within the last 6 months? None [GO TO DEMOGRAPHICS PREAMBLE 2] 1 2 times per month 3 5 times per month More than 5 times per month I don’t remember 40 of 54 FDA_5219 TIRF REMS Industry Group (TRIG) Transmucosal Immediate Release Fentanyl (TIRF) Products Prescriber KAB Survey Protocol Version 10.03.0 21AUG201504AUG2016 31.34 Please select the TIRF medicines that you have prescribed within the last 6 months. Please select all that apply. Abstral® Actiq® or generic Actiq® Fentora® Lazanda® Subsys® 41 of 54 FDA_5220 TIRF REMS Industry Group (TRIG) Transmucosal Immediate Release Fentanyl (TIRF) Products Prescriber KAB Survey Protocol Version 10.03.0 21AUG201504AUG2016 [BEGIN DEMOGRAPHICS PREAMBLE 2 - DISPLAY ON SAME PAGE WITH NEXT QUESTION] These last few questions are for demographic purposes. [END DEMOGRAPHICS PREAMBLE 2] 32.35 What is your gender? Male Female Prefer not to answer 33.36 What is your medical degree? MD DO Nurse Practitioner Physician Assistant Prefer not to answer 34.37 In total, how many years have you been practicing medicine, since completing your education? Less than 3 years 3 5 years 6 10 years 11 More than 15 years Prefer not to answer 15 years 42 of 54 FDA_5221 TIRF REMS Industry Group (TRIG) Transmucosal Immediate Release Fentanyl (TIRF) Products Prescriber KAB Survey Protocol 35.38 Do you practice in a closed healthcare system, such as: Yes No Version 10.03.0 21AUG201504AUG2016 (b) (4) VA, DoD, or NIH? 36.39 In which state do you practice? [DROP-DOWN LIST INPUT WITH STATES TABLE WITH “Prefer not to answer” at END] 37.40 What is your medical specialty? Oncology Primary care Pain management Other (please specify): [FREE TEXT] No designated specialty [PHONE - BEGIN ADVERSE EVENT/PRODUCT COMPLAINT – KEEP ON ONE PAGE] (INTERVIEWER: Please record if respondent spontaneously reported an adverse event or product complaint during the course of this interview.) Yes No [GO TO CLOSING 1] Enter Safety Adverse Event Verbatim [MULTILINE INPUT] (INTERVIEWER: Indicate to the respondent that someone may call back to ask more questions about the adverse event or product complaint that was reported.) [END ADVERSE EVENT/PRODUCT COMPLAINT] 43 of 54 FDA_5222 TIRF REMS Industry Group (TRIG) Transmucosal Immediate Release Fentanyl (TIRF) Products Prescriber KAB Survey Protocol Version 10.03.0 21AUG201504AUG2016 [BEGIN CLOSING 1 – KEEP ON ONE PAGE] We would like to send you a $125 honorarium within the next few weeks to thank you for your time, but we need your name and address to do so. If you do not provide your name and address you will not receive the honorarium for your time and participation in the survey. As a reminder, physicians who practice in Vermont, Massachusetts, or Minnesota should be aware that they will not be permitted to receive payment for survey completion. Do you agree to give us your name and mailing address so we can send you the honorarium? Yes No [GO TO CLOSING 2] FIRST NAME: [FREE TEXT] LAST NAME: [FREE TEXT] ADDRESS: [MULTILINE INPUT] CITY: [FREE TEXT] STATE: [DROP-DOWN LIST INPUT WITH STATES TABLE] ZIP: [MUST BE 5 NUMERIC CHARACTERS ONLY] [END CLOSING 1] 44 of 54 FDA_5223 TIRF REMS Industry Group (TRIG) Transmucosal Immediate Release Fentanyl (TIRF) Products Prescriber KAB Survey Protocol Version 10.03.0 21AUG201504AUG2016 [BEGIN CLOSING 2 – KEEP ON ONE PAGE] We would also like to ask for your telephone number. Providing your telephone number is optional and it will be used to contact you only if there are questions about your survey responses. Do you want to provide your telephone number? Yes No [GO TO CLOSING 3] Telephone: [MUST BE 10-DIGIT NUMERIC-ONLY CHARACTERS] [END CLOSING 2] [BEGIN CLOSING 3] That ends the survey. Thank you again for your help. [END CLOSING 3] [END SURVEY CONTENT] 45 of 54 FDA_5224 TIRF REMS Industry Group (TRIG) Transmucosal Immediate Release Fentanyl (TIRF) Products Prescriber KAB Survey Protocol Appendix B Version 13.0 04AUG2016 SAMPLE Prescriber Invitation LetterRecruitment Materials INVITATION LETTER [CURR DATE] [PRESCRIBER FIRST NAME] [[PRESCRIBER LAST NAME], [TITLE] [PRESCRIBER STREET ADDR] [ [PRESCRIBER CITY], [PRESCRIBER STATE] [PRESCRIBER ZIP] Dear [PRESCRIBER FULL NAME]:], You were selected to receive this letter because you have enrolled in the TIRF REMS Access Programprogram and have prescribed a TIRF medicine in the last 6 months. We are contacting you to invite you to participate in a survey being conducted by the manufacturers of Transmucosal Immediate Release Fentanyl (TIRF) medicines, as required by the Food and Drug Administration (FDA). The purpose of the survey is to assess prescribers’ understanding of the safe and appropriate use of these medicines. The TIRF medicines include Abstral®, Actiq®, Fentora®, Lazanda®, Subsys®, and generic versions of any of these brands. The manufacturers of TIRF medicines (collectively referred to as the “TIRF REMS Industry Group”) include Actavis Laboratories FL, Inc.;., BioDelivery Sciences International, Inc. (BDSI);., Cephalon, Inc. (a wholly-owned subsidiary of Teva Pharmaceutical Industries, Ltd.);.), Depomed, Inc.; Galena Biopharma, Inc.;., Insys Therapeutics, Inc.;., Mallinckrodt Pharmaceuticals;, Mylan Inc., Par Pharmaceuticals, Inc., and Par PharmaceuticalSentynl Therapeutics, Inc.., (collectively referred to as the “TIRF REMS Industry Group”). These manufacturers are looking for 300 prescribers to complete the survey. Eligible prescribers who complete the survey will be sent a $125 honorarium to thank them for their time. The survey will take 15-20 minutes. You are not obligated to take part in this survey. If you are interested in participating and to find out if you are eligible: x Go online* to www.TIRFREMSsurvey.com any time, or x Call 1-877-379-3297, 8 a.m. to 8 p.m. Eastern Time, Monday through Friday Please have this letter with you at the time you take the survey. You will be asked to provide this code prior to starting the survey: [CODE ID]. *Please note that you should take the survey on a desktop or laptop computer. Taking the survey on mobile devices, such as smart phones, tablets, and e-notebooks, is not supported. Your answers will be kept strictly confidential and will be combined with the answers from other prescribers who take this survey. Your name will not be used in the report of this survey and your contact information will only be used to send you a $125 honorarium for the time you took to complete the survey and, if required, to comply with a federal or state law or regulation, including without limitation, reporting payments made to physicians under the federal physician payment sunshine provisions. PrescribersPhysicians who practice in Vermont, Massachusetts, or Minnesota should be 46 of 54 FDA_5225 TIRF REMS Industry Group (TRIG) Transmucosal Immediate Release Fentanyl (TIRF) Products Prescriber KAB Survey Protocol Version 13.0 04AUG2016 aware that they will not be permitted to receive payment for survey completion and may elect not to complete the survey. You are under no obligation to participate in this survey. If you are interested in participating, go to www.TIRFREMSsurvey.com anytime or call 1 877 379 3297, 8AM to 8PM Eastern Time Monday through Friday. You will be asked to give this unique code prior to starting the survey: [CODE ID]. * We recommend that you take the survey on a desktop or laptop computer. Taking the survey on mobile devices, such as smart phones, tablets, and e notebooks, is not supported. Please have this letter with you at the time you take the survey. Thank you in advance for your help with this important effort. Sincerely, The TIRF REMS Survey Team 1-877-379-3297 www.TIRFREMSsurvey.com 47 of 54 FDA_5226 TIRF REMS Industry Group (TRIG) Transmucosal Immediate Release Fentanyl (TIRF) Products Prescriber KAB Survey Protocol Version 13.0 04AUG2016 REMINDER LETTER [CURR DATE] [PRESCRIBER FIRST NAME] [PRESCRIBER LAST NAME], [TITLE] [PRESCRIBER STREET ADDR] [PRESCRIBER CITY], [PRESCRIBER STATE] [PRESCRIBER ZIP] Dear [PRESCRIBER FULL NAME], Recently you were sent a letter, inviting you to participate in a survey being conducted by the manufacturers of Transmucosal Immediate Release Fentanyl (TIRF) medicines, as required by the Food and Drug Administration (FDA). The purpose of the survey is to assess prescribers’ understanding of the safe and appropriate use of these medicines. The TIRF medicines include Abstral®, Actiq®, Fentora®, Lazanda®, Subsys®, and generic versions of any of these brands. The manufacturers of TIRF medicines include Actavis Laboratories FL Inc., BioDelivery Sciences International, Inc., Cephalon, Inc. (a wholly-owned subsidiary of Teva Pharmaceutical Industries, Ltd.), Depomed, Inc., Insys Therapeutics, Inc., Mallinckrodt Pharmaceuticals, Mylan Inc., Par Pharmaceuticals, Inc., and Sentynl Therapeutics, Inc., (collectively referred to as the “TIRF REMS Industry Group”). These manufacturers are looking for 300 prescribers to complete the survey. Eligible prescribers who complete the survey will be sent a $125 honorarium to thank them for their time. The survey will take 15-20 minutes. You are not obligated to take part in this survey. If you are interested in participating and to find out if you are eligible: x Go online* to www.TIRFREMSsurvey.com any time, or x Call 1-877-379-3297, 8 a.m. to 8 p.m. Eastern Time, Monday through Friday Please have this letter with you at the time you take the survey. You will be asked to give this code prior to starting the survey: [CODE ID]. *Please note that you should take the survey on a desktop or laptop computer. Taking the survey on mobile devices, such as smart phones, tablets, and e-notebooks, is not supported. Your answers will be kept strictly confidential and will be combined with the answers from other prescribers who take this survey. Your name will not be used in the report of this survey and your contact information will only be used to send you a $125 honorarium for the time you took to complete the survey and, if required, to comply with a federal or state law or regulation, including without limitation, reporting payments made to physicians under the federal physician payment sunshine provisions. Physicians who practice in Vermont, Massachusetts, or Minnesota should be aware that they will not be permitted to receive payment for survey completion and may elect not to complete the survey. Sincerely, The TIRF REMS Survey Team 1-877-379-3297 www.TIRFREMSsurvey.com 48 of 54 FDA_5227 TIRF REMS Industry Group (TRIG) Transmucosal Immediate Release Fentanyl (TIRF) Products Prescriber KAB Survey Protocol Version 13.0 04AUG2016 THANK YOU LETTER – HONORARIUM PAYMENT [CURR DATE] [PRESCRIBER FIRST NAME] [PRESCRIBER LAST NAME], [TITLE] [PRESCRIBER STREET ADDR] [PRESCRIBER CITY], [PRESCRIBER STATE] [PRESCRIBER ZIP] Dear [PRESCRIBER FULL NAME], On behalf of the TIRF REMS Industry Group, we want to thank you for taking part in the TIRF REMS Survey. To express our appreciation for your valuable time, enclosed is a gift card for $125. Card Activation Instructions: To prevent loss, the enclosed card is not activated. Prior to using your card, please call the TIRF REMS Coordinating Center at 1-877-379-3297 between 8:00 a.m. and 8:00 p.m. Eastern Time, Monday through Friday, to activate your card. Please have your card available when you make the call. Also, please read the enclosed Terms and Conditions document before using your gift card as well as the privacy policy that can be found at: http://www.ctpayer.com/downloads/privacy policy.pdf. Please note the enclosed card needs to be activated on or before: xx xxx xxxx Additionally, for your information and to reinforce important safety messages about TIRF medicines, we have enclosed the following two documents: 1. A copy of the correct answers to the important survey questions about the TIRF REMS key risk message questions. 2. A copy of the Important Safety Information. Additional information regarding TIRF REMS Access program can be found at www.TIRFREMSaccess.com. Thank you for your time and consideration regarding this important safety information. Sincerely, The TIRF REMS Survey Team 1-877-379-3297 www.TIRFREMSsurvey.com Enclosures: Gift Card and Terms and Conditions Correct Answers to Important Survey Questions TIRF Important Safety Information 49 of 54 FDA_5228 TIRF REMS Industry Group (TRIG) Transmucosal Immediate Release Fentanyl (TIRF) Products Prescriber KAB Survey Protocol Version 13.0 04AUG2016 THANK YOU LETTER – NO HONORARIUM PAYMENT [CURR DATE] [PRESCRIBER FIRST NAME] [PRESCRIBER LAST NAME], [TITLE] [PRESCRIBER STREET ADDR] [PRESCRIBER CITY], [PRESCRIBER STATE] [PRESCRIBER ZIP] Dear [PRESCRIBER FULL NAME], On behalf of the TIRF REMS Industry Group, we want to thank you for taking part in the TIRF REMS Survey. For your information and to reinforce important safety messages about TIRF medicines, we have enclosed two documents: 1. A copy of the correct answers to the important survey questions about the TIRF REMS key risk message questions. 2. A copy of the Important Safety Information. Additional information regarding TIRF REMS Access program can be found at www.TIRFREMSaccess.com. Thank you for your time and consideration regarding this important safety information. Sincerely, The TIRF REMS Survey Team 1-877-379-3297 www.TIRFREMSsurvey.com Enclosures: Correct Answers to Important Survey Questions TIRF Important Safety Information 50 of 54 FDA_5229 TIRF REMS Industry Group (TRIG) Transmucosal Immediate Release Fentanyl (TIRF) Products Prescriber KAB Survey Protocol Appendix C Version 13.0 04AUG2016 Correct Answer Document Correct Responses to Select PRESCRIBER Survey Questions about Important Safety Messages for Transmucosal Immediate Release Fentanyl (TIRF) medicines (TIRF medicines include Abstral®, Actiq®, Fentora®, Lazanda®, Subsys®, and generic versions of any of these brands) Q: Q: Please select True, False, or I don’t know for each of the following. According to the labeling for TIRF medicines, patients with cancer who are considered opioid-tolerant are those: STATEMENT DESIRED RESPONSE Who are taking around-the-clock opioid therapy for underlying, persistent cancer pain for one week or longer TRUE Who are not currently taking opioid therapy, but have taken opioid therapy before FALSE Who have no known contraindications to the drug fentanyl, but are not currently taking around-the-clock opioid therapy FALSE Please answer True, False, or I don’t know for each statement based on the labeling for TIRF medicines. STATEMENT DESIRED RESPONSE TIRF medicines are contraindicated in opioid non-tolerant patients because life-threatening respiratory depression could occur at any dose. TRUE Death has occurred in opioid non-tolerant patients treated with some fentanyl products. TRUE TIRF medicines may be used to treat opioid non-tolerant patients. FALSE Prescribers starting a patient on a TIRF medicine must begin with titration from the lowest dose available for that specific product, even if the patient has previously taken another TIRF medicine. TRUE According to the product labeling, a cancer patient may start a TIRF medicine and an around-the-clock opioid at the same time. FALSE According to the product labeling, a cancer patient who has been on an around-the-clock opioid for 1 day may start taking a FALSE 51 of 54 FDA_5230 TIRF REMS Industry Group (TRIG) Transmucosal Immediate Release Fentanyl (TIRF) Products Prescriber KAB Survey Protocol Version 13.0 04AUG2016 TIRF medicine for breakthrough pain. Q: Please select True, False, or I don’t know for each of the following. According to the labeling for TIRF medicines, patients considered opioid-tolerant are those who are taking, for one week or longer, at least: STATEMENT Q: 8 mg oral hydromorphone/day TRUE 60 mg oral morphine/day TRUE 30 mg oral oxycodone/day 25 mcg transdermal fentanyl/hour TRUE 25 mg oral oxymorphone/day TRUE An equianalgesic dose of another oral opioid TRUE TRUE Per the approved labeling for TIRF medicines, for which of the following indication(s) are TIRF medicines approved? Please answer Yes, No, or I don’t know for each option. STATEMENT Q: DESIRED RESPONSE DESIRED RESPONSE Acute or postoperative pain NO Headache or migraine pain NO Dental pain NO Breakthrough pain from cancer YES Chronic non-cancer pain NO The patients described are experiencing breakthrough pain. According to the labeling, a TIRF medicine is not appropriate for one of them. Which patient should not receive a TIRF medicine? Please select one option. A: Adult female with localized breast cancer; just completed a mastectomy and reconstructive surgery; persistent cancer pain managed with 30 mg oral morphine daily for the past 6 weeks. 52 of 54 FDA_5231 TIRF REMS Industry Group (TRIG) Transmucosal Immediate Release Fentanyl (TIRF) Products Prescriber KAB Survey Protocol Q. Before initiating treatment with a TIRF medicine, prescribers must review the Medication Guide with the patient. Please select True, False, or I don’t know for each of the following counseling statements. STATEMENT Q: Version 13.0 04AUG2016 DESIRED RESPONSE Inform patients that TIRF medicines must not be used for acute or postoperative pain, pain from injuries, headache/migraine, or any other short-term pain. TRUE Instruct patients that they can continue to take their TIRF medicine, if they stop taking their around-the-clock opioid medicine. FALSE Please answer True, False, or I don’t know for each statement based on the labeling for TIRF medicines. STATEMENT DESIRED RESPONSE It is important to monitor for signs of abuse and addiction in patients who take TIRF medicines. TRUE TIRF medicines can be abused in a manner similar to other opioid agonists. TRUE Dosing of TIRF medicines is not equivalent on a microgram-tomicrogram basis. TRUE TIRF medicines are interchangeable with each other regardless of route of administration. FALSE The conversion of one TIRF medicine for another TIRF medicine may result in a fatal overdose because of differences in the pharmacokinetics of fentanyl absorption. TRUE Q: Which of the following are risk factors for opioid abuse? Please answer Yes, No, or I don’t know for each option. STATEMENT DESIRED RESPONSE A personal history of psychiatric illness YES A personal history of past or current alcohol or drug abuse, or a family history of illicit drug use or alcohol abuse YES 53 of 54 FDA_5232 TIRF REMS Industry Group (TRIG) Transmucosal Immediate Release Fentanyl (TIRF) Products Prescriber KAB Survey Protocol Q: A patient is already taking a TIRF medicine but wants to change their medicine. His/her doctor decides to prescribe a different TIRF medicine (that is not a bioequivalent generic version of a branded product) in its place. According to the labeling, how should the prescriber proceed? Please select one option. A: Q: The prescriber must not convert to another TIRF medicine on a microgram-permicrogram basis because these medicines have different absorption properties and this could result in a fentanyl overdose. Please answer True, False, or I don’t know for the following statement about TIRF medicines: STATEMENT TIRF medicines should only be taken by patients who are opioid tolerant. Q: Version 13.0 04AUG2016 DESIRED RESPONSE TRUE Which of the following risks are associated with the use of TIRF medicines? Please answer True, False, or I don’t know for the following statements. STATEMENT DESIRED RESPONSE Misuse TRUE Abuse TRUE Addiction TRUE Overdose TRUE Hypothyroidism FALSE Infection FALSE If you have questions or are unclear about any of these responses, please refer to the Full Prescribing Information, the Important Safety Information, and the Medication Guide for TIRF medicines. 54 of 54 FDA_5233 Prescriber KAB Assessment Report Transmucosal Immediate Release Fentanyl (TIRF) TIRF REMS Industry Group (TRIG) of Companies Appendix B Final 10 February 2017 Page 70 of 70 Survey Tables Listing 1.1 and Listing 2.1 includes individual responses to Question 10 (For what type(s) of chronic pain conditions do you prescribe a TIRF medicine to opioid tolerant patients?), and Question 11 (Why do you select a TIRF medicine to treat these chronic pain conditions in patients who are opioid tolerant?), respectively. Aggregate data for Question 10 is provided in Table 14 and aggregate data for Question 11 is provided in Table 15. The verbatim responses are provided unedited as submitted by the prescriber. FDA_5234 TRIG Page 1 of TIRF Prescriber KAB 05JAN2017 Table 1.1: Survey Administration Statistics Parameter, Number of invitations distributed 2848 Number of invitations returned as undeliverable 205 Number of reminder letters distributed 8405 All Respondentsl? 524 (19.8) Eligible Respondentsm 313 (59.7) Completed surveym 294 (93.9) Did not complete the surveym 19 (6.1) Respondents not eligiblem 211 (40.3) Source: Appendix B: Survey Tables, Table 1.1 Number of unique respondents who accessed the survey. Percentage is based on the number of invitations distributed excluding the number of invitations returned as undeliverable. Percentage is based on the number of all respondents. Percentage is based on the number of eligible respondents. Number of respondents who did not meet eligibility criteria or did not complete eligibility questions. Data Source: ADPQ Program: TSADMSAS TRIG Page 1 of2 TIRF Prescriber KAB 05JAN2017 Table 1.2: Survey Participant Eligibility Results - All Respondents Prescribers Question Question 1: Do you agree to participate in this survey? Yes 501 (95.6) Now 0 Discontinued 23 (4.4) Question 2: Have you ever taken part in this survey about TIRF medicines before? TIRF medicines include Abstral?, Actiq?, entora?, Lazanda?, Subsys?, and generic versions of any of these brands. Yesm 70 (13.4) No 339 (64.7) 1 don't know? 90 (17.2) Question not asked 0 Discontinued 25 (4.8) Question 3: Are you enrolled in the TIRF REMS Access program? Yes 323 (61.6) Now 7 (1.3) 1 don't known] 8 (1.5) Question not asked 160 (30.5) Discontinued 26 (5.0) Question 4: Have you or any of your immediate family members ever worked for any of the following companies or agencies? Please select all that apply.Isl Actavis Laboratories FL, [non] 0 Anesta 0 BioDelivery Services lntemational, Inc. 0 Cephalon, Inc. (a wholly-owned subsidiary of Teva Pharmaceutical Industries, 3 (0.6) Depomed, Inc.[? 3 (0.6) Galena Biophanna, lnc.m (02) Therapeutics, lnc.m 6 (1.1) Mallinckrodt Pharmaceuticalsm (02) McKesson Specialty Care Solutionsm 0 Mylan [new 0 Data Source: ADPQ. ADTQ Program: TRIG Page 2 of 2 TIRF Prescriber KAB 05JAN2017 Table 1.2: Survey Participant Eligibility Results - All Respondents Prescribers Question Par Pharmaceuticals, [new 0 Relayl?lealthm 0 Therapeutics, [new 0 Teva Pharmaceuticals, Ltd? 1 (02) United BioSource Corporationm 0 0 None of these 313 (59.7) i don't know? 0 Prefer not to answerm 2 (0.4) Question not asked 175 (33.4) Discontinued 26 (5.0) Source: Appendix B: Survey Tables, Table 1.2 Note: Respondents who discontinued the survey before completing all eligibility questions without being identi?ed as ineligible in any of the previous questions are counted as discontinued. Once a respondent is counted as discontinued, they will count as discontinued in all subsequent eligibility questions. ?1 ineligible to participate in the survey. Question not asked due to termination response from a previous question. More than one response can be selected, so percentages may not sum to 100%. Ineligible to participate in the survey if selected additionally to another response. Data Source: ADPQ, ADTQ Program: TRIG Page 1 of 1 TIRF Prescriber KAB 05JAN2017 Table 1.3: Time to Complete Survey - Completed Surveys Telephone Internet Summary Statistic (minutes) 5 289 294 Mean (SD) 23.90 (2.565) 18.91 (10.867) 18.99 (10.797) Minimum 21.0 5.6 5.6 Median 25.42 16.02 16.17 Maximum 26.4 91.2 91.2 Category, 0 to <5 Minutes 0 0 0 5to<10 Minutes 0 31 31 10 to <15 Minutes 0 95 95 15 to <20 Minutes 0 74 74 20 to <25 Minutes 2 36 38 25 to <30 Minutes 3 22 25 30 Minutes or more 0 31 31 Source: Appendix B: Survey Tables, Table 1.3 Number of eligible prescribers completing the survey. Data Source: ADPQ Progra m: TRIG Page 1 of 2 TIRF Prescriber KAB 05JAN2017 Table 2: Description of Eligible Prescribers - Completed Surveys Prescribers Question last 6 months? Question 33: On average, how many times per month have you prescribed the TIRF medicines within the None 15 (5.1) - 2 times per month 188 (63.9) 3 - 5 times per month 64 (21.8) More than 5 times per month 21 (7.1) 1 don't remember 6 (2.0) Question 34: Please select the TIRF medicines that you have prescribed within the last 6 months. Please select all that apply."" Abstral? 31(11.1) Actiq? or generic Actiq? 158 (56.6) Fentora? 93 (33.3) Lazanda? 32 (11.5) Subsys? 150 (53.8) (Answered "None" to Question 33) 15 Question 35: What is your gender? Male 175 (59.5) Female 114 (38.8) Prefer not to answer 5 (1.7) Question 36: What is your medical degree? MD 167 (56.8) DO 26 (8.8) Nurse Practitioner 53 (18.0) Physician Assistant 46 (15.6) Prefer not to answer 2 (0.7) Question 37: In total, how many years have you been practicing medicine, since completing your education? Less than 3 years 26 (8.8) 3 - 5 years 49 (16.7) 6 - 10 years 42 (14.3) Data Source: ADPQ, ADTQ Program: TDESCSAS TRIG Page 2 of 2 TIRF Prescriber KAB 05JAN2017 Table 2: Description of Eligible Prescribers - Completed Surveys Prescribers Question 11 - 15 years 43 (14.6) More than 15 years 134 (45.6) Prefer not to answer 0 Question 38: Do you practice in a closed healthcare system, such as: Kaiser, VA, 000, or Yes 4 (1.4) No 290 (98.6) Geographic Distribution (based on Question 39 - In which state do you Northeast 62 (21.1) Midwest 48 (16.3) South 90 (30.6) West 93 (31.6) Other 0 Prefer not to answer 1 (0.3) Question 40: What is your medical specialty? Oncology 45 (15.3) Primary care 29 (9.9) Pain management 173 (58.8) Other (please specify)[4] 46 (15.6) No designated specialty (0.3) Source: Appendix B: Survey Tables, Table 2 ?1 Percentages are calculated based on the sample presented with this question because of skip logic in the survey. More than one response can be selected, so percentages may not sum to 100% US. Census Bureau, last revised Friday, 27-Jul-2001 12:59:43 EDT., Geography Division Northeast includes CT, MA, ME, NH, NJ, NY, PA, RI, and VT. Midwest includes IA, IL, IN, KS, MI, MN, MO, ND, NE, OH, SD, and South includes AL, AR, DC, DE, FL, GA, KY, LA, MD, MS, NC, OK, SC, TN, TX, VA, and WV. West includes AK, AZ, CA, CO, HI, ID, MT, NM, NV, OR, UT, WA, and WY. Other includes Puerto Rico, Northern Mariana Islands, US Virgin Islands, American Samoa and Guam. Verbatim text for the question about medical specialty is presented in Listing 4. Data Source: ADPQ, ADTQ Program: TDESCSAS TRIG Page 1 of 3 Prescriber KAB 05JAN2017 Table Za: Comparison of Survey Respondents to General Population of Prescribers Prescribers Prescribers of TIRF Completing Medicines in the Survey Past Six Months (Self-Report) (IMS Data)Ill Question p-value Average times per month TIRF medicines have been prescribed last 6 months'2 None 15 (5.1) 1 - 2 times per month 188 (63.9) 3 - 5 times per month 64 (21.8) More than 5 times per month 21 (7.1) <.0001 1 don't remember 6 (2.0) medicines prescribed within the last 6 months'3 Abstral? 31 (11.1) Actiq? or generic Actiq? 158 (56.6) Fentora? 93 (33.3) Lazanda? 32 (11.5) Subsys? 150 (53.8) (Answered "None" to Question 33) 15 Gender'4 Male 175 (59.5) Female 1 14 (38.8) 0.0002 Prefer not to answer/ Unknown 5 (1.7) Medical DegreeIsl MD 167 (56.8) DO 26 (8.8) Nurse Practitioner 53 (18.0) Physician Assistant 46 (15.6) Others <.0001 Prefer not to answer 2 (0.7) Number of Years Practicing Medicine"I Less than 3 years 26 (8.8) Data Source: ADPQ, ADTQ, IMFPRE33, 1M FPRE34, IMFPRE36, IMFPREG Program: TDESCIMSSAS Page 2 of 3 TIRF Prescriber KAB 05JAN2017 Table Za: Comparison of Survey Respondents to General Population of Prescribers Prescribers Prescribers of TIRF Completing Medicines in the Survey Past Six Months (Self-Report) (IMS Question p-value 3 - 5 years 49 (16.7) 6 - 10 years 42 (14.3) 11-15 years 43 (14.6) More than 15 years 134 (45.6) <.0001 Prefer not to answer/ Unknown 0 Geographic Distribution of Practice Locationm Northeast 62 (21.1) Midwest 48 (16.3) South 90 (30.6) West 93 (31.6) Other 0 0.4771 Prefer not to answer 1 (0.3) Medical Specialty'sl Oncology 28 (9.5) Primary care 24 (8.2) Pain management 108 (36.7) Other (please specify) 35 (11.9) No designated specialtyl9] 0 Data Source: ADPQ, ADTQ, 1M FPRE34, IMFPRE35. IMFPRE37, IMFPRE40. IMFPREG Program: TDESCIMSSAS TRIG Page 3 of 3 TIRF Prescriber KAB 05JAN2017 Table 23: Comparison of Survey Respondents to General Population of Prescribers Prescribers Prescribers of TIRF Completing Medicines in the Survey Past Six Months (Self-Report) (IMS Data)Ill (WW Question p-value 99 (33.7) <.0001 Source: Appendix B: Survey Tables, Table 2a Note: P-values are calculated by a chi-square test excluding prefer not to answer, other, and comparable categories.The question regarding TIRF medicine prescriptions ?lled in the last 6 months directed respondents to "select all that apply"; therefore, p-values were not calculated for the responses to this question. Not available. ?1 Based on data ??om provided on 07Dec2016. Data covered period ofOlMar2016 to 028ep2016. Based on Question 33. Based on Question 34. Based on Question 35. Based on Question 36. Based on Question 37. Based on Question 39; US. Census Bureau, last revised Friday, 27-Jul-2001 12:59:43 EDT., Geography Division. Northeast includes CT, MA, ME, NH, NJ, NY, PA, RI, and VT. Midwest includes IA, IL, IN, KS, MI, MN, MO, ND, NE, OH, SD, and WI. South includes AL, AR, DC, DE, FL, GA, KY, LA, MD, MS, NC, OK, SC, TN, TX, VA, and WV. West includes AK, AZ, CA, CO, HI, ID, MT, NM, NV, OR, UT, WA, and WY. Other includes Puerto Rico, Northern Mariana Islands, US Virgin Islands, American Samoa and Guam. Based on Question 36/40. for the survey data is calculated as the total number of prescribers who responded "Nurse Practitioner" or "Physician Assistant" to Question 36. The other categories for the survey data are based on responses to Question 40, for prescribers who are not categorized as data includes Not Applicable, Other Specialty, and Unspeci?ed. Data Source: ADPQ. ADTQ, IMFPRE33, 1M FPRE34, IMFPRE36, IMFPREG Program: TDESCIMSSAS TRIG Page 1 of 2 TIRF Prescriber KAB Table 2b: Comparison of Survey Respondents to General Population of Prescribers (REMS Switch Provider Data) Prescribers of Prescribers TIRF Prescribers Completing Medicines in the Completing Survey Past Six Months Survey (REMS Switch (REMS Switch (Self-Report) Provider Data) Provider Data) Question 11 p-value Average times per month TIRF medicines have been prescribed within the last 6 monthsIll None 15 (5.1) 0 0 1 - 2 times per month 188 (63.9) 163 (55.4) 1671 (54.9) 3 - 5 times per month 64 (21.8) 98 (33.3) 951 (31.2) More than 5 times per month 21 (7.1) 33 (11.2) 423 (13.9) 0.4088 1 don't remember 6 (2.0) TIRF medicines prescribed within the last 6 months'2 Abstral? 31 (11.1) 18 (6.1) 199 (6.5) Actiq? or genetic Actiq? 158 (56.6) 166 (56.5) 1652 (54.3) Fentora? 93 (33.3) 74 (25.2) 824 (27.1) Lazanda? 32 (l 1.5) 30 (10.2) 273 (9.0) Subsys? 150 (53.8) 137 (46.6) 1406 (46.2) (Answered "None" to 15 Question 33) Geographic regionm Northeast 62 (21.1) 59 (20.1) 581 (19.1) Midwest 48 (16.3) 48 (16.3) 466 (15.3) South 90 (30.6) 107 (36.4) 1 16 (36.7) West 93 (31.6) 80 (27.2) 882 (29.0) Other 0 0 0 0.8942 Data Source: ADPQ, ADTQ. PRESCBR Program: Page 2 of 2 TIRF Prescriber KAB Table 2b: Comparison of Survey Respondents to General Population of Prescribers (REMS Switch Provider Data) Prescribers of Prescribers TIRF Prescribers Completing Medicines in the Completing Survey Past Six Months Survey (REMS Switch (REMS Switch (Self-Report) Provider Data) Provider Data) Question p-value Prefer not to answer I (0.3) Source: Appendix B: Survey Tables, Table 2b Note: Switch provider data was provided by McKession on September 2016. P-values are based on the REMS switch provider data comparing the survey completers vs. the prescribers of TIRF medicines in the last 6 months. Not available. Based on Question 33. Based on Question 34. Based on Question 39; US. Census Bureau, last revised Friday, 27-Jul-2001 12:59:43 EDT., Geography Division. Northeast includes CT, MA, ME, NH, NJ, NY, PA, RI, and VT. Midwest includes IA, IL, IN, KS, MI, MN, MO, ND, NE, OH, SD, and WI. South includes AL, AR, DC, DE, FL, GA, KY, LA, MD, MS, NC, OK, SC, TN, TX, VA, and WV. West includes AK, AZ, CA, CO, HI, ID, MT, NM, NV, OR, UT, WA, and WY. Other includes Puerto Rico, Northern Mariana Islands, US Virgin Islands, American Samoa and Guam. Data Source: ADPQ, ADTQ, PRESCBR Program: TRIG Page 1 of9 TIRF Prescriber KAB 05JAN2017 Table 3: Responses to All Questions about the Safe Use of TIRF Medicines - Completed Surveys Prescribers Question Question 5: Please select True, False, or I don't know for each of the following. According to the labeling for TIRF medicines, patients with cancer who are considered opioid-tolerant are those: 5a: Who are taking around-the-clock opioid therapy for underlying, persistent cancer pain for one week or longer Truem 279 (94.9) False (3.7) 1 don't know 4 (1.4) 5b: Who are not currently taking opioid therapy, but have taken opioid therapy before True 16 (5.4) Falsem 276 (93.9) 1 don't know 2 (0.7) 5c: Who have no known contraindications to the drug fentanyl, but are not currently taking around-the-clock opioid therapy True 17 (5.8) Falsem 272 (92.5) 1 don't know 5 (1.7) Question 6: Please answer True, False, or I don't know for each statement based on the labeling for TIRF medicines. 6a: According to the product labeling, a cancer patient may start a TIRF medicine and an around-the-clock opioid at the same time. True 52 (17.7) Falsem 227 (77.2) 1 don't know 15 (5.1) 6b: According to the product labeling, a cancer patient who has been on an around-the-clock opioid for I day may start taking a medicine for breakthrough pain. True 54 (18.4) Falsem 230 (78.2) 1 don't know 10 (3.4) Question 7: Please answer True, False, or I don't know for each statement based on the labeling for TIRF medicines. Data Source: ADPQ, ADTQ Program: TEXSAS TRIG TIRF Prescriber KAB Page 2 of 9 05JAN 2017 Table 3: Responses to All Questions about the Safe Use of TIRF Medicines - Completed Surveys Question Prescribers depression could occur at any dose. 7a: TIRF medicines are contraindicated in opioid non-tolerant patients because life-threatening respiratory True? 270 (91.8) False 21 (7.1) I don't know 3 (1.0) 7b: Death has occurred in opioid non-tolerant patients treated with some fentanyl True? 281 (95.6) False 3 (1.0) 1 don't know 10 (3.4) 7c: TIRF medicines may be used to treat opioid non-tolerant patients. True 27 (9.2) False? 260 (88.4) I don't know 7 (2.4) 7d: Prescribers starting a patient on a medicine must begin with titration from the lowest dose available for that speci?c product, even if the patient has previously taken another TIRF medicine. True? 252 (85.7) False 37 (12.6) 1 don't know 5 (1.7) 7e: It is important to monitor for signs of abuse and addiction in patients who take TIRF medicines. True? 291 (99.0) False 3 (1.0) I don't know 0 know for each option. Question 8: Which of the following are risk factors for opioid abuse? Please answer Yes, 0, or I don't 8a: A personal history of illness Yes? 253 (86.1) No 27 (9.2) I don't know 14 (4.8) alcohol abuse 8b: A personal history of past or current alcohol or drug abuse, or afamily history of illicit drug use or Data Source: ADPQ, ADTQ Program: TEX. SAS TRIG TIRF Prescriber KAB Page 3 of 9 OSJAN 2017 Table 3: Responses to All Questions about the Safe Use of TIRF Medicines - Completed Surveys Prescribers Question Yes? 294 (100.0) No 0 1 don't know 0 8c: A family histon of asthma Yes 4 (1.4) Now 285 (96.9) I don't know 5 (1.7) Question 9: Per the approved labeling for TIRF medicines, for which of the following indication(s) are TIRF medicines approved? Please answer Yes, 0, or I don't know for each option. 9a: Acute or postoperative pain Yes 9 (3.1) No? 278 (94.6) I don't know 7 (2.4) 9b: Headache or migraine pain Yes 6 (2.0) Now 276 (93.9) 1 don't know 12 (4.1) 9c: Dental pain Yes 4 (1.4) Now 283 (96.3) I don't know 7 (2.4) 9d: Breakthrough pain from cancer Yes? 292 (99.3) No 2 (0.7) 1 don't know 0 9e: Chronic non-cancer pain Yesm 54 (18.4) No'? 230 (78.2) I don't know 10 (3.4) Data Source: ADPQ, ADTQ Program: TEX. SAS TRIG TIRF Prescriber KAB Page 4 of 9 OSJAN 2017 Table 3: Responses to All Questions about the Safe Use of TIRF Medicines - Completed Surveys Question Prescribers medicines. Question 12: Please answer True, False, or I don't know for each statement based on the labeling for TIRF 12a: TIRF medicines can be abused in a manner similar to other opioid agonists. True? 282 (95.9) False 10 (3.4) 1 don't know 2 (0.7) 12b: medicines are interchangeable with each other regardless of route of administration. True 15 (5.1) False? 271 (92.2) I don't know 8 (2.7) of differences in the pharmacokinetics of fentanyl absorption. 12c: The conversion of one TIRF medicine for another TIRF medicine may result in a fatal overdose because True? 283 (96.3) False 5 (1.7) I don't know 6 (2.0) 12d: Dosing 0f TIRF medicines is not equivalent on a microgram-to-microgram basis. True? 269 (91.5) False 11 (3.7) 1 don't know 14 (4.8) at least: Question 13: Please select True, False, or I don't know for each of the following. According to the labeling for TIRF medicines, patients considered opioid-tolerant are those who are taking, for one week or longer, 13a: 8 mg oral hydromorphone/day men] 211 (71.8) False 69 (23.5) I don't know 14 (4.8) 13b: 60 mg oral morphine/day True? 281 (95.6) False 6 (2.0) 1 don't know 7 (2.4) Data Source: ADPQ, ADTQ Program: TEX. SAS TRIG TIRF Prescriber KAB Page 5 of 9 05JAN 2017 Table 3: Responses to All Questions about the Safe Use of TIRF Medicines - Completed Surveys Prescribers Question I 36: 30 mg oral oxycodone/day Truem 241 (82.0) False 44 (15.0) [don't know 9 (3.1) I 3d: 25 meg transdermalfemanyl/hour Truem 262 (89.1) False 21 (7.1) 1 don't know 11 (3.7) I 3e: 25 mg oral oxymorphone/day Truem 234 (79.6) False 33 (11.2) 1 don't know 27 (9.2) I An equianalgesic dose of another oral opioid Truem 193 (65.6) False 56 (19.0) [don't know 45 (15.3) Please select one option. Question 15: The patients described are experiencing breakthrough pain. According to the labeling, a TIRF medicine is not appropriate for one of them. Which patient should not receive a TIRF medicine? Adult male with advanced lung cancer, underlying persistent cancer pain managed 20 (6.8) with 25 meg/hour transdermal fentanyl patches for the past two months. Adult female with localized breast cancer; just completed a mastectomy and 212 (72.1) reconstructive surgery, persistent cancer pain managed with 30 mg oral morphine daily for the past 6 weeksm Adult male patient with advanced prostate cancer who, over the last 2 weeks, has 18 (6.1) been prescribed 100 mg oral morphine daily for pain due to bone metastasis. Adult female with advanced sarcoma who has been taking a daily dose of 12 mg 27 (9.2) oral hydromorphone for the last 3 weeks. 1 don't know 17 (5.8) Data Source: ADPQ, ADTQ Program: TEX. SAS TRIG TIRF Prescriber KAB Page 6 of 9 05JAN 2017 Table 3: Responses to All Questions about the Safe Use of TIRF Medicines - Completed Surveys Question Prescribers one option. Question 16: A patient is already taking a TIRF medicine but wants to change their medicine. His/her doctor decides to prescribe a different TIRF medicine (that is not a bioequivalent generic version of a branded product) in its place. According to the labeling, how should the prescriber proceed? Please select The prescriber can safely convert to the equivalent dosage of the new TIRF 5 (1.7) medicine as it has the same effect as other TIRF medicines. The prescriber must not convert to another TIRF medicine on a 231 (78.6) microgram-per-microgram basis because these medicines have different absorption properties and this could result in a fentanyl overdosem Convert ?'om the other TIRF medicine to the new TIRF medicine at half of the dose. 25 (8.5) The prescriber should base the starting dose of the newly-prescribed TIRF medicine 21 (7.1) on the dose of the opioid medicine used for their underlying persistent cancer pain. 1 don't know. 12 (4.1) select one option. Question 17: A patient is starting titration with a TIRF medicine. What dose must they start with? Please An appropriate dose based on the dose of the opioid medicine used for underlying 19 (6.5) persistent cancer pain. The dose that the prescriber believes is appropriate based on their clinical 5 (1.7) experience. The lowest available dose, unless individual product Full Prescribing Information 266 (90.5) provides product-speci?c guidancem The median available dose. 2 (0.7) 1 don't know. 2 (0.7) advise the patient to do? Please pick the best option of the scenarios described. Question 18: A prescriber has started titrating a patient with the lowest dose of a TIRF medicine. However, after 30 minutes the breakthrough pain has not been suf?ciently relieved. What should they Take another (identical) dose of the TIRF medicine immediately. 66 (22.4) Take a dose of an alternative rescue medicine. 14 (4.8) Provide guidance based on the product-speci?c Medication Guide because the 208 (70.7) instructions are not the same for all TIRF medicinesm Double the dose and take immediately. 5 (1.7) 1 don't know. 1 (0.3) CYP3A4 inhibitor. Please pick the best option of the scenarios described. Question 19: A patient is taking a TIRF medicine and the doctor would like to prescribe a Data Source: ADPQ. ADTQ Program: TEX. SAS TRIG TIRF Prescriber KAB Page 7 of 9 05JAN 2017 Table 3: Responses to All Questions about the Safe Use of TIRF Medicines - Completed Surveys Prescribers Question The patient can't be prescribed because using it at the same time as a 17 (5.8) TIRF medicine could be fatal. Use of a TIRF medicine with a CYP3A4 inhibitor may require a dosage adjustment; 235 (79.9) carefully monitor the patient for opioid toxicity, otherwise such use may cause potentially fatal respiratory depression? There is no possible drug interaction between CYP3A4 inhibitors and TIRF (0.3) medicines. The dose of the TIRF medicine must be reduced by one half if a CYP3A4 inhibitor 8 (2.7) is prescribed in the same patient 1 don't know. 33 (11.2) statements. Question 20: Before initiating treatment with a TIRF medicine, prescribers must review the Medication Guide with the patient. Please select True, False, or I don't know for each of the following counseling for whom they were not prescribed, and in those who are not opioid tolerant. 20a: TIRF medicines contain fentanyl in an amount that could be fatal to children of all ages, in individuals Truem 293 (99.7) False 1 don't know 1 (0.3) headach dmigraine, or any other short-term pain. 20b: Inform patients that TIRF medicines must not be used for acute or postoperative pain, pain from injuries, Truem 283 (96.3) False 8 (2.7) 1 don't know 3 (1.0) arou nd-the-cloek opioid medicine. 20c: Instruct patients that they can continue to take their TIRF medicine, if they stop taking their True 58 (19.7) Falsem 225 (76.5) 1 don't know 11 (3.7) 20d: Instruct patients to never share their TIRF medicine with anyone else, even if that person has the same Truem 294 (100.0) False 0 1 don't know 0 Data Source: ADPQ, ADTQ Program: TEX. SAS TRIG TIRF Prescriber KAB Page 8 of 9 OSJAN 2017 Table 3: Responses to All Questions about the Safe Use of TIRF Medicines - Completed Surveys Question Prescribers medicines: Question 21: Please answer True, False, or I don't know for the following statement about TIRF TIRF medicines should only be taken by patients who are opioid tolerant. True? 284 (96.6) False 8 (2-7) 1 don't know 2 (0.7) Question 22: Which of the following risks are associated with the use of TIRF medicines? Please answer True, False, or I don't know for the following statements. 22a: Misuse True? 290 (98.6) False 4 (L4) 1 don't know 0 22b: A buse True? 291 (99.0) False 2 (0.7) I don't know 1 (0.3) 22c: Addiction True? 291 (99.0) False 3 (1.0) I don't know 0 22d: Overdose True? 292 (99.3) False 2 (0.7) I don't know 0 22c: Hypothyroidism True 20 (6.8) False? 232 (78.9) 1 don't know 42 (14.3) 22]? Infection Data Source: ADPQ, ADTQ Program: TEX. SAS TRIG Page 9 of 9 TIRF Prescriber KAB 05JAN2017 Table 3: Responses to All Questions about the Safe Use of TIRF Medicines - Completed Surveys Prescribers Question True 23 (7.8) Falsem 253 (86.1) I don't know 18 (6.1) Source: Appendix B: Survey Tables, Table 3 Correct response. Verbatim text for the type of chronic non-cancer pain and reason for selecting TIRF medicines to treat chronic non-cancer pain is presented in Listing 1 and Listing 2, respectively. Data Source: ADPQ, ADTQ Program: TEXSAS TRIG Page I of] TIRF Prescriber KAB 05JAN2017 Table 4: Responses to Questions about TIRF Educational Materials - Completed Surveys Prescribers Question Question 23: Did you receive or do you have access to the Full Prescribing Information for the TIRF medicine(s) that you prescribe? Yes 285 (96.9) No 5 (1.7) 1 don't know 4 (1.4) Question 24: Did you read the Full Prescribing Information for the TIRF medicine(s) that you Yes 248 (87.0) No 31 (10.9) [don't know 6 (2.1) (Answered "No" or don 't know" to Question 23) 9 Question 25: Did you receive or do you have access to the Medication Guide for the TIRF medicine(s) that you prescribe? Yes 282 (95.9) No 4 (1.4) I don't know 8 (2.7) Question 26: Did you read the Medication Guide for the TIRF medicine(s) that you prescribe?Ill Yes 260 (92.2) No 17 (6.0) [don't know 5 (1.8) (Answered "No" or don 't know" to Question 25) 12 Question 27: Did you or do you have any questions about the information in the Full Prescribing Information or Medication Guide?'2' Yes 8 (2.7) No 264 (89.8) I don't know 22 (7.5) Source: Appendix B: Survey Tables, Table 4 [11 Percentages are calculated based on the sample presented with this question because of skip logic in the survey. Verbatim text for questions about the Full Prescribing Information or Medication Guide is presented in Listing 3. Data Source: ADPQ, ADTQ Program: TEDUC.SAS TRIG TIRF Prescriber KAB Page 1 of] 05JAN2017 Table 5: Responses to Questions about the Patient-Prescriber Agreement Form - Completed Surveys Prescribers Question you prescribe TIRF medicines or their caregiver? Question 29: Do you review the Patient-Prescriber Agreement Form with each of your patients for whom Yes 278 (94.6) No 10 (3.4) I don't know 6 (2.0) TIRF medicines after you have reviewed it with him/her?Ill Question 30: Do you and the patient or their caregiver sign the Patient-Prescriber Agreement Form for Yes 272 (97.8) No 2 (0.7) 1 don't know 4 (1.4) (Answered "No" or don't know" to Question 29) 16 patient or their caregiver? Question 31: Do you give a copy of the Patient-Prescriber Agreement Form for TIRF medicines to the Yes 250 (89.9) No 15 (5.4) I don't know 13 (4.7) (Answered "No" or don't know" to Question 29) 16 Source: Appendix B: Survey Tables, Table 5 [11 Percentages are calculated based on the sample presented with this question because of skip logic in the survey. Data Source: ADPQ, ADTQ Program: TPPAFSAS TRIG TIRF Prescriber KAB Page 1 of3 05JAN2017 Completed Surveys Table 6: Responses to Questions about the Activities when Prescribing TIRF Medicines - Question Prescribers Question 14: How frequently do you perform the following activities when prescribing TIRF medicines? Please answer Always, Only with the first prescription, Sometimes, Never, or I don't know. 14a: Ask patients (or their caregivers) about the presence of children in the home Always 182 (61.9) Only with the ?rst prescription 66 (22.4) Sometimes 35 (l 1.9) Never 10 (3.4) I don't know 1 (0.3) Mb: Instruct patients (or their caregivers) not to share TIRF medicines with anyone else Always 236 (80.3) Only with the ?rst prescription 43 (14.6) Sometimes 14 (4.8) Never 1 (0.3) 1 don't know 0 14c: Counsel patients (or their caregivers) that accidental exposure to TIRF medicines by a child ma be fatal Always 208 (70.7) Only with the ?rst prescription 55 (18.7) Sometimes 23 (7.8) Never 8 (2.7) I don't know 0 14d: Instruct patients (or their caregivers) to keep IRF medicines out of the reach of children to prevent accidental exposure Always 232 (78.9) Only with the ?rst prescription 44 (15.0) Sometimes 13 (4.4) Never 5 (1.7) 1 don't know 0 medicines I 4e: Instruct patients (or their caregivers) about proper disposal of any unused or partially used TIRF Data Source: ADPQ, ADTQ Program: TACT.SAS TRIG Page 2 of 3 TIRF Prescriber KAB 05JAN2017 Table 6: Responses to Questions about the Activities when Prescribing TIRF Medicines - Completed Surveys Prescribers Question Always 197 (67.0) Only with the ?rst prescription 56 (19.0) Sometimes 34 (1 1.6) Never 7 (2.4) 1 don't know 0 l4]? Give patients (or their caregivers) the Medication Guide for their TIRF medicine Always 130 (44.2) Only with the ?rst prescription 131 (44.6) Sometimes 17 (5.8) Never 15 (5.1) 1 don't know 1 (0.3) Question 32: How frequently do you perform the following activities when prescribing TIRF medicines? Please answer Always, Only with the first prescription, Sometimes, Never, or I don't know. 32a: Talk to the patient about the risks and possible side effects of the TIRF medicine that was most recently prescribed. Always 223 (75.9) Only with the ?rst prescription 53 (18.0) Sometimes 16 (5.4) Never 0 1 don't know 2 (0.7) 32b: Instruct the patient on how to use the TIR medicine that was most recently prescribed. Always 204 (69.4) Only with the ?rst prescription 67 (22.8) Sometimes 21 (7.1) Never 0 1 don't know 2 (0.7) 32c: Instruct the patient on how to store or keep the TIRF medicine that was most ecently prescribed. Always 156 (53.1) Only with the ?rst prescription 102 (34.7) Data Source: ADPQ, ADTQ Program: TACT.SAS TRIG Page 3 of3 TIRF Prescriber KAB 05JAN2017 Table 6: Responses to Questions about the Activities when Prescribing TIRF Medicines - Completed Surveys Prescribers Question 11 Sometimes 22 (7.5) Never 12 (4.1) 1 don't know 2 (0.7) Source: Appendix B: Survey Tables, Table 6 Data Source: ADPQ, ADTQ Program: TACTSAS TRIG Page 1 of3 TIRF Prescriber KAB 05JAN2017 Table 7.1: Primary Analysis of Responses to Questions Linked to Key Risk Message #1 - Completed Surveys Prescribers Question [95% for TIRF medicines, patients with cancer who are considered opioid-tolerant are Question 5: Please select True, False, or I don't know for each of the following. According to the labeling those: 5a: Who are taking around-the-clock opioid therapy for underlying, persistent canc longer er pain for one week or medicines. Truem 279 (94.9) [91.7 - 97.1] False 11 (3.7) 1 don't know 4 (1.4) 5b: Who are not currently taking opioid therapy, but have taken opioid therapy before True 16 (5.4) Falsem 276 (93.9) [90.5 - 96.3] 1 don't know 2 (0.7) 5c: Who have no known contraindications to the drug fentanyl, but are not currently taking around-the-clock opioid therapy True 17 (5.8) Falsem 272 (92.5) [88.9 - 95.3] 1 don't know 5 (1.7) Question 7: Please answer True, False, or I don't know for each statement based on the labeling for TIRF depression could occur at any dose. 7a: TIRF medicines are contraindicated in opioid non-tolerant patients because life-threatening respiratory Truem 270 (91.8) [88.1 - 94.7] False 21 (7.1) 1 don't know 3 (1.0) 7b: Death has occurred in opioid non-tolerant patients treated with some fentanyl products. Truem 281 (95.6) [92.6 - 97.6] False 3 (1.0) 1 don't know 10 (3.4) 7c: TIRF medicines may be used to treat opioid non-tolerant patients. True 27 (9.2) Falsem 260 (88.4) [84.2 91.9] Data Source: ADPQ, ADTQ Program: TRIG Page 2 of 3 TIRF Prescriber KAB 05JAN2017 Table 7.1: Primary Analysis of Responses to Questions Linked to Key Risk Message #1 - Completed Surveys Prescribers Question 11 95% 1 don't know 7 (2.4) 7d: Prescribers starting a patient on a IRF medicine must begin with titration from the lowest dose available for that speci?c product, even if the patient has previously taken another TIRF medicine. True 252 (85.7) [81.2 - 89.5] False 37 (12.6) 1 don't know 5 (1-7) at least: Question 13: Please select True, False, or I don't know for each of the following. According to the labeling for TIRF medicines, patients considered opioid-tolerant are those who are taking, for one week or longer, 13a: 8 mg oral hydromorphone/day Truem 211 (71.8) [66.3 - 76.8] False 69 (23.5) 1 don't know 14 (4.8) 13b: 60 mg oral morphine/day Truem 281 (95.6) [92.6 - 97.6] False 6 (2.0) 1 don't know 7 (2.4) 13c: 30 mg oral oxycodone/day Truem 241 (82.0) [77.1 - 86.2] False 44 (15.0) 1 don't know 9 (3.1) 13d: 25 transdermalfentanyl/hour Truem 262 (89.1) [85.0 - 92.4] False 21 (7.1) 1 don't know 11 (3.7) I 3e: 25 mg oral oxymorphone/day Truem 234 (79.6) [74.5 - 84.0] False 33 (11.2) 1 don't know 27 (9.2) Data Source: ADPQ, ADTQ Program: TRIG Page 3 of3 TIRF Prescriber KAB 05JAN2017 Table 7.1: Primary Analysis of Responses to Questions Linked to Key Risk Message #1 - Completed Surveys Prescribers Question [95% 13}? An equianalgesic dose of another oral opioid Truem 193 (65.6) [59.9 - 71.1] False 56 (19.0) I don't know 45 (15.3) Question 21: Please answer True, False, or I don't know for the following statement about TIRF medicines: TIRF medicines should only be taken by patients who are opioid tolerant. Truem 284 (96.6) [93.8 - 98.4] False 8 (2.7) I don't know 2 (0.7) Source: Appendix B: Survey Tables, Table 7.1 95% exact two-sided con?dence intervals are calculated using the Clopper-Pearson method. Correct response. Data Source: ADPQ, ADTQ Program: TIRF Prescriber KAB Page 1 of3 05JAN2017 Table 7.1.1: Responses to Questions Linked to Key Risk Message #1 by Reading Full Prescribing Information or Medication Guide - Completed Surveys Question Reading Full Prescribing Information or Medication Guide Received and read Pl or Med Guide [95% C1[Ill Did not receive or read Pl or Med Guide [95% C1[Ill Question 5: Please select True, False, or I don't know for each of the following. According to the labeling for TIRF medicines, patients with cancer who are considered opioid-tolerant are those: 5a: Who are taking around-the-clock opioid therapy for underlying, persistent cancer pain for one week or longer Truem 255 (95.1) [91.8 97.4] 24 (92.3) [74.9 - 99.1] False 10 (3.7) (3.8) [don't know 3 (1.1) (3.8) 5b: Who are not currently taking opioid therapy, but have taken opioid therapy before True 15 (5.6) (3.8) Falsem 253 (94.4) [90.9 - 96.8] 23 (88.5) [69.8 - 97.6] I don't know 0 2 (7.7) 5c: Who have no known contraindications to the drug fentanyl, but are not currently taking around-the-clock opioid therapy True 16 (6.0) (3.8) Falsem 249 (92.9) [89.2 95.7] 23 (88.5) [69.8 - 97.6] [don't know 3 (1.1) 2 (7.7) Question 7: Please answer True, False, or I don't know for each statement based on the labeling for TIRF medicines. 7a: TIRF medicines are contraindicated in opioid non-tolerant patients because life-threatening respiratory depression could occur at any dose. Truem 248 (92.5) [88.7 - 95.4] 22 (84.6) [65.1 - 95.6] False 18 (6.7) 3(11.5) I don?t know 2 (0.7) 1 (3.8) 7b: Death has occurred in opioid non-tolerant patients treated with some fentanyl products. Truem 256 (95.5) [92.3 - 97.7] 25 (96.2) [80.4 - 99.9] False 3 (1.1) 0 [don't know 9 (3.4) (3.8) 7c: TIRF medicines may be used to treat opioid non-tolerant patients. Data Source: ADPQ, ADTQ Program: TK RM S. SAS TIRF Prescriber KAB Page 2 of3 OSJAN 2017 Table 7.1.1: Responses to Questions Linked to Key Risk Message #1 by Reading Full Prescribing Information or Medication Guide - Completed Surveys Reading Full Prescribing Information or Medication Guide Received and read Did not receive or read Pl or Med Guide Pl or Med Guide Question [95% Cll'" [95% True 24 (9.0) 3 (11.5) Falsem 239 (89.2) [84.8 - 92.6] 21 (80.8) [60.6 - 93.4] [don't know 5 (1.9) 2 (7.7) 7d: Prescribers starting a patient on a TIRF medicine must begin with titration from the lowest dose available for that specific product, even if the patient has previously taken another TIRF medicine. Truem 230 (85.8) [81.1 - 89.8] 22 (84.6) [65.1 - 95.6] False 34 (12.7) 3 (11.5) 1 don't know 4 (1.5) 1 (3.8) Question 13: Please select True, False, or I don't know for each of the following. According to the labeling for TIRF medicines, patients considered opioid-tolerant are those who are taking, for one week or longer, at least: 13a: 8 mg oral hydromorphone/day Truem 200 (74.6) [69.0 - 79.7] 11 (42.3) [23.4 - 63.1] False 57 (21.3) 12 (46.2) [don't know 11 (4.1) 3 (11.5) 13b: 60 mg oral morphine/day Truem 258 (96.3) [93.2 - 98.2] 23 (88.5) [69.8 - 97.6] False 6 (22) 0 I don?t know 4(1.5) 3(11.5) 13c: 30 mg oral oxycodone/day Truem 226 (84.3) [79.4 - 88.5] 15 (57.7) [36.9 - 76.6] False 36 (13.4) 8 (30.8) I don't know 6 (22) 3(11.5) I 3d: 25 transdermalfentanyl/hour Truem 242 (90.3) [86.1 - 93.6] 20 (76.9) [56.4 91.0] False 19 (7.1) 2 (7.7) [don't know 7 (2.6) 4 (15.4) Data Source: ADPQ, ADTQ Program: TK RM S. SAS TRIG TIRF Prescriber KAB Page 3 of3 05JAN 2017 Table 7.1.1: Responses to Questions Linked to Key Risk Message #1 by Reading Full Prescribing Information or Medication Guide - Completed Surveys Question Reading Full Prescribing Information or Medication Guide Received and read Pl or Med Guide [95% Did not receive or read P1 or Med Guide [95% Be: 25 mg oral oxymorphone/day Truem 218 (81.3) [76.2 - 85.8] 16 (61.5) [40.6 - 79.8] False 26 (9.7) 7 (26.9) 1 don't know 24 (9.0) 3 (1 1.5) 13]: An equianalgesic dose of another oral opioid Truem 178 (66.4) [60.4 - 72.0] 15 (57.7) [36.9 - 76.6] False 52 (19.4) 4 (15.4) [don't know 38 (14.2) 7 (26.9) Question 21: Please answer True, False, or I don't know for the following statement about TIRF medicines: TIRF medicines should only be taken by patients who are opioid tolerant. Truem 260 (97.0) [94.2 98.7] 24 (92.3) [74.9 - 99.1] False 7 (2.6) 1 (3.8) [don't know 1 (0.4) 1 (3.8) Source: Appendix B: Survey Tables, Table 7.1.1 ?195% exact two-sided confidence intervals are calculated using the Clopper-Pearson method. Correct response. Data Source: ADPQ, ADTQ Program: TK RM S. SAS TRIG Page 1 of4 TIRF Prescriber KAB 05JAN2017 Table 7.1.2: Responses to Questions Linked to Key Risk Message #1 by Medical Degree of Respondent - Completed Surveys Medical Degree of Respondent MD DO Nurse Practitioner Physician Assistant (N=l67) Question [95% C1['ll [95% [95% 11 [95% Question 5: Please select True, False, or I don't know for each of the following. According to the labeling for TIRF medicines, patients with cancer who are considered opioid-tolerant are those: 5a: Who are taking around-the-clock opioid therapy for underlying, persistent cancer pain for one week or longer Truem 157 (94.0) [89.3 - 97.1] 24 (92.3) [74.9 - 99.1] 51 (96.2) [87.0 - 99.5] 45 (97.8) [88.5 99.9] False 6 (3.6) 2 (7.7) 2 (3.8) (2.2) [don't know 4 (2.4) 0 0 5b: Who are not currently taking opioid therapy, but have taken opioid therapy before True 10 (6.0) 3 (11.5) 2 (3.8) 1 (2.2) Falsem 157 (94.0) [89.3 - 97.1] 23 (88.5) [69.8 - 97.6] 50 (94.3) [84.3 - 98.8] 44 (95.7) [85.2 - 99.5] [don't know 0 0 (1.9) (2.2) 5c: Who have no known contraindications to the drug fentanyl, but are not currently taking around-the-clock opioid therapy True 8 (4.8) 3 (11.5) 2 (3.8) 4 (8.7) Falsem 156 (93.4) [88.5 - 96.7] 23 (88.5) [69.8 - 97.6] 50 (94.3) [84.3 - 98.8] 41 (89.1) [76.4 - 96.4] [don't know 3 (1.8) 0 (1.9) 1 (2.2) Question 7: Please answer True, False, or I don't know for each statement based on the labeling for TIRF medicines. 7a: TIRF medicines are contraindicated in opioid non-tolerant patients because life-threatening respiratory depression could occur at any dose. Truem 149 (89.2) [83.5 - 93.5] 24 (92.3) [74.9 - 99.1] 50 (94.3) [84.3 - 98.8] 45 (97.8) [88.5 - 99.9] False 16 (9.6) 2 (7.7) 2 (3.8) 1 (2.2) Data Source: ADPQ, ADTQ Program: TK RM S. SAS TRIG TIRF Prescriber KAB Page 2 of4 05JAN2017 Table 7.1.2: Responses to Questions Linked to Key Risk Message #1 by Medical Degree of Respondent - Completed Surveys Medical Degree of Respondent MD DO Nurse Practitioner Physician Assistant Question [95% [95% 95% Cll'" [95% Cll'" [don't know 2 (1.2) 0 (1.9) 0 7b: Death has occurred in opioid non-tolerant patients treated with some fentanyl products. Truem 159 (95.2) [90.8 - 97.9] 25 (96.2) [80.4 - 99.9] 52 (98.1) [89.9 100.0] 43 (93.5) [82.1 98.6] False 3 (1.8) 0 0 0 [don't know 5 (3.0) (3.8) 1 (1.9) 3 (6.5) 7c: TIRF medicines may be used to treat opioid non-tolerant patients. True 19 (11.4) 2 (7.7) 3 (5.7) 3 (6.5) Falsem 146 (87.4) [81.4 - 92.0] 24 (92.3) [74.9 - 99.1] 47 (88.7) [77.0 - 95.7] 41 (89.1) [76.4 - 96.4] [don't know 2 (12) 0 3 (5.7) 2 (4.3) 7d: Prescribers starting a patient on a TIRF medicine must begin with titration/mm the lowest dose available/or that speci?c product, even if the patient has previously taken another TIRF medicine. Truelz] 144 (86.2) [80.1 - 91.1] 24 (92.3) [74.9 - 99.1] 45 (84.9) [72.4 - 93.3] 37 (80.4) [66.1 90.6] False 20 (12.0) 2 (7.7) 8 (15.1) 7 (15.2) 1 don?t know 3 (1.8) 0 0 2 (4.3) Question 13: Please select True, False, or 1 don't know for each of the following. According to the labeling for TIRF medicines, patients considered opioid-tolerant are those who are taking, for one week or longer, at least: 13a: 8 mg oral hydromorphone/day Truem 122 (73.1) [65.7 - 79.6] 20 (76.9) [56.4 - 91.0] 37 (69.8) [55.7 81.7] 30 (65.2) [49.8 - 78.6] Data Source: ADPQ, ADTQ Program: TK RM S. SAS TRIG Page 3 of4 TIRF Prescriber KAB 05JAN2017 Table 7.1.2: Responses to Questions Linked to Key Risk Message #1 by Medical Degree of Respondent - Completed Surveys Medical Degree of Respondent MD DO Nurse Practitioner Physician Assistant (N=l67) Question 95% [95% 11 95% Cll'" [95% Cll'" False 36 (21.6) 6 (23.1) 13 (24.5) 14 (30.4) [don't know 9 (5.4) 0 3 (5.7) 2 (4.3) 13b: 60 mg oral morphine/day Truem 159 (95.2) [90.8 - 97.9] 26 (100.0) [86.8 - 100.0] 50 (94.3) [84.3 - 98.8] 44 (95.7) [85.2 99.5] False 4 (2.4) 0 1 (1.9) (2.2) [don't know 4 (2.4) 0 2 (3.8) (2.2) 13c: 30 mg oral oxycodone/day Truem 135 (80.8) [74.0 - 86.5] 22 (84.6) [65.1 - 95.6] 50 (94.3) [84.3 - 98.8] 32 (69.6) [54.2 - 82.3] False 26 (15.6) 3 (11.5) 2 (3.8) 13 (28.3) [don't know 6 (3.6) 1 (3.8) 1 (1.9) 1 (2.2) 13d: 25 meg transdermalfentanyl/hour Truem 148 (88.6) [82.8 - 93.0] 22 (84.6) [65.1 - 95.6] 50 (94.3) [84.3 - 98.8] 40 (87.0) [73.7 95.1] False 15 (9.0) 2 (7.7) 1 (1.9) 3 (6.5) 166m know 4 (2.4) 2 (7.7) 2 (3.8) 3 (6.5) Be: 25 mg oral oxymorphone/day Truem 129 (77.2) [70.1 - 83.4] 21 (80.8) [60.6 - 93.4] 43 (81.1) [68.0 - 90.6] 39 (84.8) [71.1 - 93.7] False 23 (13.8) 2 (7.7) 3 (5.7) 5 (10.9) 1 don't know 15 (9.0) 3 (11.5) 7 (13.2) 2 (4.3) Data Source: ADPQ, ADTQ Program: TK RM S. SAS TRIG TIRF Prescriber KAB Page 4 of4 05JAN2017 Table 7.1.2: Responses to Questions Linked to Key Risk Message #1 by Medical Degree of Respondent - Completed Surveys Question Medical Degree of Respondent MD [95% C1[Ill D0 [95% Nurse Practitioner [95% Physician Assistant [95% 13f: An equianalgesic dose of another oral opioid Truem 113 (67.7) [60.0 - 74.7] 17 (65.4) [44.3 - 82.8] 35 (66.0) [51.7 - 78.5] 27 (58.7) [43.2 73.0] False 29 (17.4) 8 (30.8) 6 (11.3) 13 (28.3) [don?t know 25 (15.0) 1 (3.8) 12 (22.6) 6 (13.0) Question 21: Please answer True, False, or I don't know for the following statement about TIRF medicines: TIRF medicines should only be taken by patients who are opioid tolerant. Truem 160 (95.8) [91.6 - 98.3] 26 (100.0) [86.8 - 100.0] 52 (98.1) [89.9 - 100.0] 44 (95.7) [85.2 - 99.5] False 6 (3.6) 0 0 2 (4.3) [don't know 1 (0.6) 0 1 (1.9) 0 Source: Appendix B: Survey Tables, Table 7.1.2 ?195% exact two-sided con?dence intervals are calculated using the Clopper-Pearson method. Correct response. Data Source: ADPQ, ADTQ Program: TK RM S. SAS TRIG TIRF Prescriber KAB Page 1 of3 05JAN2017 Survey - Completed Surveys Table 7.1.3: Responses to Questions Linked to Key Risk Message #1 by Modality to Complete Question Modality to Complete Survey Internet [95% Telephone [95% Question 5: Please select True, False, or 1 don't know for each of the following. According to the labeling for TIRF medicines, patients with cancer who are considered opioid-tolerant are those: 5a: Who are taking around-the-clock opioid therapy for underlying, persistent cancer pain for one week or longer Truem 274 (94.8) [91.6 - 97.1] 5 (100.0) [47.8 - 100.0] False 11 (3.8) 0 [don't know 4 (1.4) 0 5b: Who are not currently taking opioid therapy, but have taken opioid therapy before True 15 (5.2) 1 (20.0) Falsem 272 (94.1) [90.7 - 96.5] 4 (80.0) [28.4 - 99.5] I don't know 2 (0.7) 0 5c: Who have no known contraindications to the drug fentanyl, but are not currently taking around-the-clock opioid therapy True 16 (5.5) 1 (20.0) Falsem 268 (92.7) [89.1 - 95.4] 4 (80.0) [28.4 - 99.5] [don't know 5 (1.7) 0 medicines. Question 7: Please answer True, False, or I don't know for each statement based on the labeling for TIRF depression could occur at any dose. 7a: TIRF medicines are contraindicated in opioid non-tolerant patients because life-threatening respiratory Truem 265 (91.7) [87.9 - 94.6] 5 (100.0) [47.8 - 100.0] False 21 (7.3) 0 [don't know 3 (1.0) 0 7b: Death has occurred in opioid non-tolerant patients treated with some fentanyl products. Truem 276 (95.5) [92.4 - 97.6] 5 (100.0) [47.8 - 100.0] False 3 (1.0) 0 1 don't know 10 (3.5) 0 7c: TIRF medicines may be used to treat opioid non-tolerant patients. True 27 (9.3) 0 Data Source: ADPQ, ADTQ Program: TK RM S. SAS TRIG TIRF Prescriber KAB Page 2 of3 OSJAN 2017 Survey - Completed Surveys Table 7.1.3: Responses to Questions Linked to Key Risk Message #1 by Modality to Complete Modality to Complete Survey Internet Telephone Question [95% cu'" [95% Falsem 255 (88.2) [83.9 - 91.7] 5 (100.0) [47.8 - 100.0] 1 don't know 7 (2.4) 0 7d: Prescribers starting a patient on a TIRF medicine must begin with titration ?om the lowest dose available for that speci?c product, even if the patient has previously taken another TIRF medicine. Truem 248 (85.8) [81.2 - 89.6] 4 (80.0) [28.4 - 99.5] False 36 (12.5) 1 (20.0) 1 don't know 5 (1.7) 0 least: Question 13: Please select True, False, or I don't know for each of the following. According to the labeling for TIRF medicines, patients considered opioid-tolerant are those who are taking, for one week or longer, at 13a: 8 mg oral hydromorphone/day Truem 206 (71.3) [65.7 - 76.4] 5 (100.0) [47.8 - 100.0] False 69 (23.9) 0 I don't know 14 (4.8) 0 13b: 60 mg oral morphine/day Truem 276 (95.5) [92.4 - 97.6] 5 (100.0) [47.8 - 100.0] False 6 (2.1) 0 1 don't know 7 (2.4) 0 13c: 30 mg oral oxycodone/day Truem 236 (81.7) [76.7 - 86.0] 5 (100.0) [47.8 - 100.0] False 44 (15.2) 0 1 don't know 9 (3.1) 0 13d: 25 transdermalfentanyl/hour Truem 257 (88.9) [84.7 92.3] 5 (100.0) [47.8 100.0] False 21 (7.3) 0 [don't know 11 (3.8) 0 Be: 25 mg oral oxymorphone/day Truem 229 (79.2) [74.1 - 83.8] 5 (100.0) [47.8 - 100.0] Data Source: ADPQ, ADTQ Program: TK RM S. SAS TRIG TIRF Prescriber KAB Page 3 of3 05JAN 2017 Table 7.1.3: Responses to Questions Linked to Key Risk Message #1 by Modality to Complete Survey - Completed Surveys Modality to Complete Survey Internet Telephone Question [95% [95% False 33 (11.4) 0 [don?t know 27 (9.3) 0 13f: An equianalgesic dose of another oral opioid Truem 188 (65.1) [59.2 - 70.5] 5 (100.0) [47.8 - 100.0] False 56 (19.4) 0 I don't know 45 (15.6) 0 Question 21: Please answer True, False, or I don't know for the following statement about TIRF medicines: TIRF medicines should only be taken by patients who are opioid tolerant. Truem 279 (96.5) [93.7 98.3] 5 (100.0) [47.8 100.0] False 8 (2.8) 0 [don't know 2 (0.7) 0 Source: Appendix B: Survey Tables, Table 7.1.3 95% exact two-sided confidence intervals are calculated using the lopper-Pearson method. Correct response. Data Source: ADPQ, ADTQ Program: TK RM S. SAS TRIG TIRF Prescriber KAB Page 1 of4 05JAN2017 Table 7.1.4: Responses to Questions Linked to Key Risk Message #1 by Time Practicing Medicine - Completed Surveys Question Time Practicing Medicine Less than 3 years [95% 3 to 5 years [95% 6 to 15 years [95% cu'" More than 15 years [95% Question 5: Please select True, False, or 1 don't know for each of the following. According to the labeling for TIRF medicines, patients with cancer who are considered opioid-tolerant are those: 5a: Who are taking around-the-clock opioid therapy for underlying, persistent cancer pain for one week or longer Truem 24 (92.3) [74.9 - 99.1] 45 (91.8) [80.4 - 97.7] 79 (92.9) [85.3 - 97.4] 131 (97.8) [93.6 - 99.5] False 2 (7.7) 3 (6.1) 4 (4.7) 2 (1.5) [don't know 0 (2.0) 2 (2.4) (0.7) 5b: Who are not currently taking opioid therapy, but have taken opioid therapy before True 1 (3.8) 0 4 (4.7) 11 (8.2) Falsem 25 (96.2) [80.4 - 99.9] 49 (100.0) [92.7 - 100.0] 80 (94.1) [86.8 - 98.1] 122 (91.0) [84.9 - 95.3] [don't know 0 0 1 (1.2) (0.7) 5c: Who have no known contraindications to the drug fentanyl, but are not currently taking around-the-clock opioid therapy True 1 (3.8) (2.0) 5 (5.9) 10 (7.5) Falsem 25 (96.2) [80.4 - 99.9] 46 (93.9) [83.1 - 98.7] 79 (92.9) [85.3 - 97.4] 122 (91.0) [84.9 - 95.3] [don't know 0 2 (4.1) (1.2) 2 (1.5) Question 7: Please answer True, False, or I don't know for each statement based on the labeling for TIRF medicines. 7a: TIRF medicines are contraindicated in opioid non-tolerant patients because life-threatening respiratory depression could occur at any dose. Truem 25 (96.2) [80.4 - 99.9] 45 (91.8) [80.4 - 97.7] 78 (91.8) [83.8 - 96.6] 122 (91.0) [84.9 - 95.3] False 1 (3.8) 4 (8.2) 6(7.1) 10 (7.5) Data Source: ADPQ, ADTQ Program: TK RM S. SAS TRIG TIRF Prescriber KAB Page 2 of4 05JAN2017 Table 7.1.4: Responses to Questions Linked to Key Risk Message #1 by Time Practicing Medicine - Completed Surveys Time Practicing Medicine Less than 3 years 3 to 5 years 6 to 15 years More than 15 years Question [95% [95% 11 95% Cll'" [95% Cll'" [don't know 0 0 (1.2) 2 (1.5) 7b: Death has occurred in opioid non-tolerant patients treated with some fentanyl products. Truem 26 (100.0) [86.8 - 100.0] 43 (87.8) [75.2 95.4] 82 (96.5) [90.0 - 99.3] 130 (97.0) [92.5 99.2] False 0 0 (1.2) 2 (1.5) [don't know 0 6 (12.2) 2 (2.4) 2 (1.5) 7c: TIRF medicines may be used to treat opioid non-tolerant patients. True 3(ll.5) 2(4.1) lO(11.8) 12(9.0) Falsem 22 (84.6) [65.1 - 95.6] 45 (91.8) [80.4 - 97.7] 73 (85.9) [76.6 - 92.5] 120 (89.6) [83.1 - 94.2] [don't know 1 (3.8) 2 (4.1) 2 (2.4) 2 (1.5) 7d: Prescribers starting a patient on a TIRF medicine must begin with titration/ram the lowest dose available/or that speci?c product, even if the patient has previously taken another TIRF medicine. Truem 23 (88.5) [69.8 - 97.6] 38 (77.6) [63.4 - 88.2] 75 (88.2) [79.4 - 94.2] 116 (86.6) [79.6 - 91.8] False 2 (7.7) 9 (18.4) 8 (9.4) 18 (13.4) 1 don?t know 1 (3.8) 2 (4.1) 2 (2.4) 0 Question 13: Please select True, False, or 1 don't know for each of the following. According to the labeling for TIRF medicines, patients considered opioid-tolerant are those who are taking, for one week or longer, at least: 13a: 8 mg oral hydromorphone/day Truem 14 (53.8) [33.4 - 73.4] 35 (71.4) [56.7 - 83.4] 57 (67.1) [56.0 76.9] 105 (78.4) [70.4 - 85.0] Data Source: ADPQ, ADTQ Program: TK RM S. SAS TRIG TIRF Prescriber KAB Page 3 of4 05JAN2017 Table 7.1.4: Responses to Questions Linked to Key Risk Message #1 by Time Practicing Medicine - Completed Surveys Time Practicing Medicine Less than 3 years 3 to 5 years 6 to 15 years More than 15 years (N=l34) Question [95% [95% 11 95% Cll'" [95% Cll'" False 8 (30.8) 13 (26.5) 22 (25.9) 26 (19.4) 1 don't know 4 (15.4) 1 (2.0) 6 (7.1) 3 (2.2) 13b: 60 mg oral morphine/day Truem 23 (88.5) [69.8 - 97.6] 48 (98.0) [89.1 - 99.9] 79 (92.9) [85.3 - 97.4] 131 (97.8) [93.6 99.5] False 1 (2.0) 4 (4.7) 1 (0.7) I don't know 3 (11.5) 0 2 (2.4) 2(1.5) 13c: 30 mg oral oxycodone/day Truem 17 (65.4) [44.3 - 82.8] 40 (81.6) [68.0 - 91.2] 69 (81.2) [71.2 - 88.8] 115 (85.8) [78.7 - 91.2] False 6 (23.1) 8 (16.3) l3(15.3) 17(12.7) I don't know 3 (11.5) 1 (2.0) 3 (3.5) 2(1.5) 13d: 25 transdermalfentanyl/hour Truem 20 (76.9) [56.4 - 91.0] 43 (87.8) [75.2 - 95.4] 79 (92.9) [85.3 - 97.4] 120 (89.6) [83.1 - 94.2] False 2 (7.7) 4 (8.2) 3 (3.5) 12 (9.0) [don't know 4 (15.4) 2 (4.1) 3 (3.5) 2 (1.5) Be: 25 mg oral oxymorphone/day Truem 17 (65.4) [44.3 - 82.8] 39 (79.6) [65.7 - 89.8] 68 (80.0) [69.9 - 87.9] 110 (82.1) [74.5 - 88.2] False 5 (19.2) 8 (16.3) 7 (8.2) 13 (9.7) 1 don't know 4 (15.4) 2 (4.1) 10 (1 1.8) 11 (8.2) Data Source: ADPQ, ADTQ Program: TK RM S. SAS TRIG TIRF Prescriber KAB Page 4 of4 05JAN2017 Table 7.1.4: Responses to Questions Linked to Key Risk Message #1 by Time Practicing Medicine - Completed Surveys Question Time Practicing Medicine Less than 3 years [95% 3 to 5 years [95% 6 to 15 years [95% More than 15 years [95% 13f: An equianalgesic dose of another oral opioid Truem 12 (46.2) [26.6 - 66.6] 35 (71.4) [56.7 - 83.4] 53 (62.4) [51.2 - 72.6] 93 (69.4) [60.9 77.1] False 6 (23.1) 5 (10.2) 20 (23.5) 25 (18.7) [don?t know 8 (30.8) 9 (18.4) 12 (14.1) 16 (1 1.9) Question 21: Please answer True, False, or I don't know for the following statement about TIRF medicines: TIRF medicines should only be taken by patients who are opioid tolerant. Truem 24 (92.3) [74.9 - 99.1] 46 (93.9) [83.1 - 98.7] 83 (97.6) [91.8 - 99.7] 131 (97.8) [93.6 - 99.5] False 2 (7.7) 3 (6.1) 2 (2.4) 1 (0.7) [don't know 0 0 0 2 (1.5) Source: Appendix B: Survey Tables, Table 7.1.4 ?195% exact two-sided con?dence intervals are calculated using the Clopper-Pearson method. Correct response. Data Source: ADPQ, ADTQ Program: TK RM S. SAS TRIG TIRF Prescriber KAB Page 1 of4 05JAN2017 Table 7.1.5: Responses to Questions Linked to Key Risk Message #1 by Number of Times Prescribing TIRF Medicines per Month Within the Last 6 Months - Completed Surveys Question Number of Times Prescribing TIRF Medicines per Month Within the Last 6 Months None [95% - 2 times per month [95% cu"l 3 - 5 times per month [95% More than 5 times per month [95% 1 don't remember [95% Question 5: Please select True, False, or I don't know for each of the following. According to the labeling for TIRF medicines, patients with cancer who are considered opioid-tolerant are those: 5a: Who are taking around-the-clock opioid therapy for underlying, persistent cancer pain for one week or longer Truem 15 (100.0) [78.2 - 100.0] 177 (94.1) [89.8 - 97.0] 61 (95.3) [86.9 - 99.0] 20 (95.2) [76.2 - 99.9] 6 (100.0) [54.1 - 100.0] False 0 9 (4.8) (1.6) 1 (4.8) 0 ldon'tknow 0 2(1.1) 2(3.l) 0 0 5b: Who are not currently taking opioid therapy, but have taken opioid therapy before True 1 (6.7) 7 (3.7) 4 (6.3) 4 (19.0) 0 Falsem 14 (93.3) [68.1 - 99.8] 179 (95.2) [91.1 - 97.8] 60 (93.8) [84.8 - 98.3] 17 (81.0) [58.1 - 94.6] 6 (100.0) [54.1 - 100.0] Idon'tknow 0 2(l.l) 0 0 0 5c: Who have no known contraindications to the drug fentanyl, but are not currently taking around-the-clock opioid therapy True 4 (26.7) 5 (2.7) 5 (7.8) 2 (9.5) 1 (16.7) Falsem 11 (73.3) [44.9 - 922] 179 (95.2) [91.1 - 97.8] 59 (92.2) [82.7 - 97.4] 18 (85.7) [63.7 - 97.0] 5 (83.3) [35.9 - 99.6] [don't know 0 4 (2.1) 0 1 (4.8) 0 Question 7: Please answer True, False, or I don't know for each statement based on the labeling for TIRF medicines. 7a: TIRF medicines are contraindicated in opioid non-tolerant patients because life-threatening respiratory depression could occur at any dose. Truem 12 (80.0) [51.9 - 95.7] 174 (92.6) [87.8 - 95.9] 61 (95.3) [86.9 - 99.0] 17 (81.0) [58.1 - 94.6] 6 (100.0) [54.1 - 100.0] Data Source: ADPQ. ADTQ Program: TK RM S. SAS TRIG Page 2 of4 TIRF Prescriber KAB 05JAN2017 Table 7.1.5: Responses to Questions Linked to Key Risk Message #1 by Number of Times Prescribing TIRF Medicines per Month Within the Last 6 Months - Completed Surveys Number of Times Prescribing TIRF Medicines per Month Within the Last 6 Months - 2 times 3 - 5 times More than 5 times 1 don't None per month per month per month remember (N=l88) Question 11 [95% [95% C1["l [95% 11 [95% 11 [95% False 2 (13.3) 13 (6.9) 2 (3.1) 4 (19.0) 0 [don't know 1 (6.7) (0.5) (1.6) 0 0 7b: Death has occurred in opioid non-tolerant patients treated with some fentanyl products. Truem 15 (100.0) [78.2 - 100.0] 180 (95.7) [91.8 - 98.1] 60 (93.8) [84.8 - 98.3] 21 (100.0) [83.9 - 100.0] 5 (83.3) [35.9 - 99.6] False 0 0 3 (4.7) 0 0 [don't know 0 8 (4.3) (1.6) 0 1 (16.7) 7c: TIRF medicines may be used to treat opioid non-tolerant patients. True 3 (20.0) 15 (8.0) 3 (4.7) 4 (19.0) 2 (33.3) Falsem 12 (80.0) [51.9 - 95.7] 168 (89.4) [84.0 - 93 60 (93.8) [84.8 - 98.3] 16 (76.2) [52.8 - 91.8] 4 (66.7) [22.3 - 95.7] [don't know 0 5 (2.7) (1.6) 1 (4.8) 0 7d: Prescribers starting a patient on a TIRF medicine must begin with titration from the lowest dose available for that specific product, even if the patient has previously taken another TIRF medicine. Truem 13 (86.7) [59.5 - 98.3] 162 (86.2) [80.4 - 90.8] 57 (89.1) [78.8 - 95.5] 14 (66.7) [43.0 - 85.4] 6 (100.0) [54.1 - 100.0] False 2 (13.3) 22 (11.7) 6 (9.4) 7 (33.3) 0 1 don?t know 0 4 (2.1) 1 (1.6) 0 Question 13: Please select True, False, or I don't know for each of the following. According to the labeling for TIRF medicines, patients considered opioid-tolerant are those who are taking, for one week or longer, at least: Data Source: ADPQ, ADTQ Program: TRIG TIRF Prescriber KAB Page 3 of4 05JAN2017 Table 7.1.5: Responses to Questions Linked to Key Risk Message #1 by Number of Times Prescribing TIRF Medicines per Month Within the Last 6 Months - Completed Surveys Number of Times Prescribing TIRF Medicines per Month Within the Last 6 Months None Question [95% - 2 times per month [95% cu"I 3 - 5 times per month [95% More than 5 times per month [95% I don't remember [95% 13a: 8 mg oral hydromorphone/day Truem 10 (66.7) [38.4 - 882] 135 (71.8) [64.8 - 78.1] 51 (79.7) [67.8 - 88.7] 13 (61.9) [38.4 - 81.9] 2 (33.3) [4.3 - 77.7] False 4 (26.7) 44 (23.4) 11 (17.2) 7 (33.3) 3 (50.0) [don't know 1 (6.7) 9 (4.8) 2 (3.1) 1 (4.8) 1 (16.7) 13b: 60 mg oral morphine/day Truem 14 (93.3) [68.1 - 99.8] 180 (95.7) [91.8 - 98.1] 61 (95.3) [86.9 - 99.0] 21 (100.0) [83.9 - 100.0] 5 (83.3) [35.9 - 99.6] False 0 5 (2.7) (1.6) 0 0 [don't know 1 (6.7) 3 (1.6) 2 (3.1) 0 1 (16.7) I 36': 30 mg oral oxycodone/day Truem 10 (66.7) [38.4 - 882] 153 (81.4) [75.1 - 86.7] 56 (87.5) [76.8 94.4] 19 (90.5) [69.6 - 98.8] 3 (50.0) [11.8 88.2] False 4 (26.7) 29 (15.4) 7 (10.9) 2 (9.5) 2 (33.3) [don't know 1 (6.7) 6 (3.2) 1 (1.6) 0 1 (16.7) 13d: 25 transdermalfentanyVhour Truem 11 (73.3) [44.9 - 922] 171 (91.0) [85.9 - 94.6] 57 (89.1) [78.8 - 95.5] 19 (90.5) [69.6 - 98.8] 4 (66.7) [22.3 - 95.7] False 3 (20.0) 11 (5.9) 5 (7.8) 1 (4.8) 1 (16.7) [don't know 1 (6.7) 6 (3.2) 2 (3.1) 1 (4.8) 1 (16.7) Data Source: ADPQ, ADTQ Program: TK RM S. SAS TRIG TIRF Prescriber KAB Page 4 of4 05JAN2017 Table 7.1.5: Responses to Questions Linked to Key Risk Message #1 by Number of Times Prescribing TIRF Medicines per Month Within the Last 6 Months - Completed Surveys Number of Times Prescribing TIRF Medicines per Month Within the Last 6 Months - 2 times 3 - 5 times More than 5 times I don't None per month per month per month remember Question [95% [95% [95% [95% [95% cu"I Be: 25 mg oral oxymorphone/day Truem 12 (80.0) [51.9 - 95.7] 152 (80.9) [74.5 - 86.2] 51 (79.7) [67.8 - 88.7] 17 (81.0) [58.1 - 94.6] 2 (33.3) [4.3 - 77.7] False 2 (13.3) 18 (9.6) 9 (14.1) 2 (9.5) 2 (33.3) 1 don?t know 1 (6.7) 18 (9.6) 4 (6.3) 2 (9.5) 2 (33.3) 13]: An equianalgesic dose of another oral opioid Truem 7 (46.7) [21.3 - 73.4] 131 (69.7) [62.6 - 76.2] 38 (59.4) [46.4 - 71.5] 14 (66.7) [43.0 - 85.4] 3 (50.0) [11.8 - 88.2] False 1 (6.7) 31 (16.5) 19 (29.7) 3 (14.3) 2 (33.3) 1 don't know 7 (46.7) 26 (13.8) 7 (10.9) 4 (19.0) 1 (16.7) Question 21: Please answer True, False, or I don't know for the following statement about TIRF medicines: TIRF medicines should only be taken by patients who are opioid tolerant. Truem 14 (93.3) [68.1 - 99.8] 183 (97.3) [93.9 - 99.1] 61 (95.3) [86.9 99.0] 20 (95.2) [76.2 - 99.9] 6 (100.0) [54.1 100.0] False 1 (6.7) 4 (2.1) 2 (3.1) 1 (4.8) 0 1 don't know 0 1 (0.5) 1 (1.6) 0 0 Source: Appendix B: Survey Tables, Table 7.1.5 ?195% exact two-sided confidence intervals are calculated using the Clopper-Pearson method. Correct response. Data Source: ADPQ, ADTQ Program: TK RM S. SAS TIRF Prescriber KAB Page 1 of3 05JAN2017 Healthcare System - Completed Surveys Table 7.1.6: Responses to Questions Linked to Key Risk Message #1 by Practicing in a Closed Question Practicing in a Closed Healthcare System Yes [95% No [95% Question 5: Please select True, False, or I don't know for each of the following. According to the labeling for TIRF medicines, patients with cancer who are considered opioid-tolerant are those: 5a: Who are taking around-the-clock opioid therapy for underlying, persistent cancer pain for one week or longer Truem 4 (100.0) [39.8 - 100.0] 275 (94.8) [91.6 97.1] False 0 11 (3.8) 1 don't know 0 4 (1.4) 5b: Who are not currently taking opioid therapy, but have taken opioid therapy before True 1 (25.0) 15 (5.2) Falsem 3 (75.0) [19.4 - 99.4] 273 (94.1) [90.8 - 96.5] I don't know 0 2 (0.7) 5c: Who have no known contraindications to the drug fentanyl, but are not currently taking around-the-clock opioid therapy True 0 17 (5.9) Falsem 4 (100.0) [39.8 - 100.0] 268 (92.4) [88.7 95.2] [don't know 0 5 (1.7) medicines. Question 7: Please answer True, False, or I don't know for each statement based on the labeling for TIRF depression could occur at any dose. 7a: TIRF medicines are contraindicated in opioid non-tolerant patients because life-threatening respiratory Truem 4 (100.0) [39.8 - 100.0] 266 (91.7) [87.9 - 94.6] False 0 21 (7.2) 1 don't know 0 3 (1.0) 7b: Death has occurred in opioid non-tolerant patients treated with some fentanyl products. Truem 4 (100.0) [39.8 - 100.0] 277 (95.5) [92.5 - 97.6] False 0 3 (1.0) 1 don't know 0 10 (3.4) 7c: TIRF medicines may be used to treat opioid non-tolerant patients. True 0 27 (9.3) Data Source: ADPQ, ADTQ Program: TK RM S. SAS TRIG TIRF Prescriber KAB Page 2 of3 OSJAN 2017 Table 7.1.6: Responses to Questions Linked to Key Risk Message #1 by Practicing in a Closed Healthcare System - Completed Surveys Practicing in a Closed Healthcare System Yes No Question [95% cu'" [95% Falsem 4 (100.0) [39.8 - 100.0] 256 (88.3) [84.0 91.7] 1 don't know 0 7 (2.4) 7d: Prescribers starting a patient on a TIRF medicine must begin with titration ?om the lowest dose available for that speci?c product, even if the patient has previously taken another TIRF medicine. Truem 4 (100.0) [39.8 - 100.0] 248 (85.5) [80.9 - 89.4] False 0 37 (12.8) 1 don't know 0 5 (1.7) Question 13: Please select True, False, or I don't know for each of the following. According to the labeling for TIRF medicines, patients considered opioid-tolerant are those who are taking, for one week or longer, at least: 13a: 8 mg oral hydromorphone/day Truem 3 (75.0) [19.4 - 99.4] 208 (71.7) [66.2 - 76.8] False 1 (25.0) 68 (23.4) I don't know 0 14 (4.8) 13b: 60 mg oral morphine/day Truem 4 (100.0) [39.8 - 100.0] 277 (95.5) [92.5 97.6] False 0 6 (2.1) 1 don't know 0 7 (2.4) 13c: 30 mg oral oxycodone/day Truem 3 (75.0) [19.4 - 99.4] 238 (82.1) [77.2 - 86.3] False 1 (25.0) 43 (14.8) 1 don't know 0 9 (3.1) 13d: 25 transdermalfentanyl/hour Truem 4 (100.0) [39.8 - 100.0] 258 (89.0) [84.8 - 92.3] False 0 21 (7.2) [don't know 0 11 (3.8) Be: 25 mg oral oxymorphone/day Truem 4 (100.0) [39.8 - 100.0] 230 (79.3) [74.2 - 83.8] Data Source: ADPQ, ADTQ Program: TK RM S. SAS TRIG TIRF Prescriber KAB Page 3 of3 05JAN 2017 Table 7.1.6: Responses to Questions Linked to Key Risk Message #1 by Practicing in a Closed Healthcare System - Completed Surveys Practicing in a Closed Healthcare System Yes No Question [95% C1[Ill cm [95% False 0 33 (11.4) [don?t know 0 27 (9.3) 13f: An equianalgesic dose of another oral opioid Truem 3 (75.0) [19.4 - 99.4] 190 (65.5) [59.7 - 71.0] False I (25.0) 55 (19.0) I don't know 0 45 (15.5) Question 21: Please answer True, False, or I don't know for the following statement about TIRF medicines: TIRF medicines should only be taken by patients who are opioid tolerant. Truem 4 (100.0) [39.8 - 100.0] 280 (96.6) [93.8 - 98.3] False 0 8 (2.8) [don't know 0 2 (0.7) Source: Appendix B: Survey Tables, Table 7.1.6 95% exact two-sided confidence intervals are calculated using the lopper-Pearson method. Correct response. Data Source: ADPQ, ADTQ Program: TK RM S. SAS TRIG Page 1 of TIRF Prescriber KAB 05JAN2017 Table 7.2: Secondary Analysis of Responses to Questions Linked to Key Risk Message #1 - Completed Surveys Prescribers Correct Responses 0 correct responses 0 1 correct response 0 2 correct responses 0 3 correct responses 1 (0.3) 4 correct responses 0 5 correct responses 1 (0.3) 6 correct responses 1 (0.3) 7 correct responses 4 (1.4) 8 correct responses 9 (3.1) 9 correct responses 16 (5.4) 10 correct responses 23 (7.8) 11 correct responses 28 (9.5) 12 correct responses 39 (13.3) 13 correct responses 76 (25.9) 14 correct responses 96 (32.7) Source: Appendix B: Survey Tables, Table 7.2 Data Source: ADPQ, ADTQ Program: TRIG TIRF Prescriber KAB Page 1 of3 05JAN2017 Table 8.1: Primary Analysis of Responses to Questions Linked to Key Risk Message #2 - Completed Surveys Question Prescribers [95% Question 6: Please answer True, False, or I don't know for each statement based on the labeling for TIRF medicines. 6a: According to the product labeling, a cancer patient may start a TIRF medicine and an around-the-clock opioid at the same time. True 52 (17.7) Falsem 227 (77.2) [72.0 - 81.9] 1 don't know 15 (5.1) 6b: According to the product labeling, a cancer patient who has been on an around-the-clock opioid for I day may start taking a TIRF medicine for breakthrough pain. True 54 (18.4) Falsem 230 (78.2) [73.1 - 82.8] 1 don't know 10 (3.4) Question 9: Per the approved labeling for TIRF medicines, for which of the following indication(s) are TIRF medicines approved? Please answer Yes, 0, or I don't know for each option. 9a: Acute or postoperative pain Yes 9 (3.1) 278 (94.6) [91.3 - 96.9] 1 don't know 7 (2.4) 9b: Headache or migraine pain Yes 6 (2.0) 276 (93.9) [90.5 - 96.3] 1 don't know 12 (4.1) 9c: Dental pain Yes 4 (1.4) N091 283 (96.3) [93 .4 - 98.1] 1 don't know 7 (2.4) 9d: Breakthrough pain from cancer Yesm 292 (99.3) [97.6 - 99.9] No 2 (0.7) Data Source: ADPQ, ADTQ Program: TRIG Page 2 of3 TIRF Prescriber KAB 05JAN2017 Table 8.1: Primary Analysis of Responses to Questions Linked to Key Risk Message #2 - Completed Surveys Prescribers Question 1] [95% cum 1 don't know 0 9e: Chronic non-cancer pain Yes 54 (18.4) Now 230 (78.2) [73.1 - 82.8] 1 don't know 10 (3.4) Question 15: The patients described are experiencing breakthrough pain. According to the labeling, a TIRF medicine is not appropriate for one of them. Which patient should not receive a TIRF medicine? Please select one option. Adult male with advanced lung cancer, underlying persistent cancer pain managed 20 (6.8) with 25 meg/hour transdermal fentanyl patches for the past two months. Adult female with localized breast cancer; just completed a mastectomy and 212 (72.1) [66.6 - 77.2] reconstructive surgery, persistent cancer pain managed with 30 mg oral morphine daily for the past 6 weeksm Adult male patient with advanced prostate cancer who, over the last 2 weeks, has 18 (6.1) been prescribed 100 mg oral morphine daily for pain due to bone metastasis. Adult female with advanced sarcoma who has been taking a daily dose of 12 mg 27 (9.2) oral hydromorphone for the last 3 weeks. 1 don't know 17 (5.8) Question 20: Before initiating treatment with a TIRF medicine, prescribers must review the Medication Guide with the patient. Please select True, False, or I don't know for each of the following counseling statements. 20b: Inform patients that TIRF medicines must not be used for acute or postoperative pain, pain from injuries, headach e/migraine, or any other short-term pain. Truem 283 (96.3) [93 .4 - 98.1] False 8 (2.7) 1 don't know 3 (1.0) 20c: Instruct patients that they can continue to take their TIRF medicine, if they stop taking their arou nd-the-clock opioid medicine. True 58 (19.7) Falsem 225 (76.5) [71.3 - 81.3] Data Source: ADPQ, ADTQ Program: TRIG Page 3 of 3 TIRF Prescriber KAB 05JAN2017 Table 8.1: Primary Analysis of Responses to Questions Linked to Key Risk Message #2 - Completed Surveys Prescribers Question [95% Cl Ill I don't know 11 (3.7) Source: Appendix B: Survey Tables, Table 8.1 95% exact two-sided con?dence intervals are calculated using the Clopper-Pearson method. Correct response. Data Source: ADPQ. ADTQ Program: TKRM.SAS TIRF Prescriber KAB Page 1 of3 05JAN2017 Table 8.1.1: Responses to Questions Linked to Key Risk Message #2 by Reading Full Prescribing Information or Medication Guide - Completed Surveys Question Reading Full Prescribing Information or Medication Guide Received and read Pl or Med Guide [95% Did not receive or read Pl or Med Guide [95% Question 6: Please answer True, False, or I don't know for each statement based on the labeling for TIRF medicines. 6a: According to the product labeling, a cancer patient may start a TIRF medicine and an around-the-clock opioid at the same time. True 47 (17.5) 5 (19.2) Falsem 209 (78.0) [72.5 - 82.8] 18 (69.2) [48.2 - 85.7] [don't know 12 (4.5) 3 (11.5) 6b: According to the product labeling, a cancer patient who has been on an around-the-clock opioid for I day may start taking a TIRF medicine for breakthrough pain. True 50 (18.7) 4 (15.4) Fa1sew 209 (78.0) [72.5 - 82.8] 21 (80.8) [60.6 - 93.4] 1 don't know 9 (3.4) 1 (3.8) Question 9: Per the approved labeling for TIRF medicines, for which of the following indication(s) are TIRF medicines approved? Please answer Yes, No, or I don't know for each option. 9a: A cute or postoperative pain Yes 5 (1.9) 4 (15.4) New 256 (95.5) [92.3 - 97.7] 22 (84.6) [65.1 - 95.6] [don't know 7 (2.6) 0 9b: Headache or migraine pain Yes 6 (22) 0 New 252 (94.0) [90.5 - 96.5] 24 (92.3) [74.9 - 99.1] 1 don't know 10 (3.7) 2 (7.7) 9c: Dental pain Yes 4 (1.5) 0 New 259 (96.6) [93.7 - 98.5] 24 (92.3) [74.9 - 99.1] [don't know 5 (1.9) 2 (7.7) 9d: Breakthrough pain from cancer Yesm 267 (99.6) [97.9 - 100.0] 25 (96.2) [80.4 - 99.9] Data Source: ADPQ, ADTQ Program: TK RM S. SAS TIRF Prescriber KAB Page 2 of3 05JAN 2017 Table 8.1.1: Responses to Questions Linked to Key Risk Message #2 by Reading Full Prescribing Information or Medication Guide - Completed Surveys Reading Full Prescribing Information or Medication Guide Received and read Did not receive or read Pl or Med Guide Pl or Med Guide Question [95% [95% N0 1 (0.4) (3.8) I don't know 0 0 9e: Irronic non-cancer pain Yes 48 (17.9) 6 (23.1) New 210 (78.4) [72.9 - 83.1] 20 (76.9) [56.4 - 91.0] I don't know 10 (3.7) 0 Question 15: The patients described are experiencing breakthrough pain. According to the labeling, a TIRF medicine is not appropriate for one of them. Which patient should not receive a TIRF medicine? Please select one option. Adult male with advanced lung cancer; underlying persistent cancer pain managed with 25 meg/hour transdermal fentanyl patches for the past two months. 20 (7.5) Adult female with localized breast cancer; just completed a mastectomy and reconstructive surgery; persistent cancer pain managed with 30 mg oral morphine daily for the past 6 weeksm 192 (71.6) [65.8 - 77.0] 20 (76.9) [56.4 - 91.0] Adult male patient with advanced prostate cancer who, over the last 2 weeks, has been prescribed 100 mg oral morphine daily for pain due to bone metastasis. 16 (6.0) 2 (7.7) Adult female with advanced sarcoma who has been taking a daily dose of 12 mg oral hydromorphone for the last 3 weeks. 24 (9.0) 3(11.5) I don't know 16 (6.0) 1 (3.8) Question 20: Before initiating treatment with a TIRF medicine, prescribers must review the Medication Guide with the patient. Please select True, False, or I don't know for each of the following counseling statements. 20b: Inform patients that TIRF medicines must not be used for acute or postoperative pain, pain from injuries, headach dmigraine, or any other short-term pain. Truem 257 (95.9) [92.8 - 97.9] 26 (100.0) [86.8 - 100.0] Data Source: ADPQ, ADTQ Program: TK RM S. SAS TIRF Prescriber KAB Page 3 of3 05JAN 2017 Table 8.1.1: Responses to Questions Linked to Key Risk Message #2 by Reading Full Prescribing Information or Medication Guide - Completed Surveys Reading Full Prescribing Information or Medication Guide Received and read Did not receive or read Pl or Med Guide Pl or Med Guide Question [95% [95% False 8 (3.0) 0 ldon'tknow 3(l.1) 0 20c: Instruct patients that they can continue to take their TIRF medicine, if they stop taking their around-the-clock opioid medicine. True 51 (19.0) 7 (26.9) Falsem 210 (78.4) [72.9 - 83.1] 15 (57.7) [36.9 - 76.6] 1 don't know 7 (2.6) 4 (15.4) Source: Appendix B: Survey Tables, Table 8.1.1 95% exact two-sided confidence intervals are calculated using the Clopper-Pearson method. Correct response. Data Source: ADPQ, ADTQ Program: TK RM S. SAS TRIG Page 1 of 4 TIRF Prescriber KAB 05JAN2017 Table 8.1.2: Responses to Questions Linked to Key Risk Message #2 by Medical Degree of Respondent - Completed Surveys Medical Degree of Respondent MD DO Nurse Practitioner Physician Assistant Question [95% C1[Ill [95% C1[Ill [95% [95% C1[Ill Question 6: Please answer True, False, or 1 don't know for each statement based on the labeling for TIRF medicines. 6a: According to the product labeling, a cancer patient may start a TIR medicine and an around-the-clock opioid at the same time. True 30 (18.0) 6 (23.1) 9 (17.0) 6 (13.0) Falsem 130 (77.8) [70.8 - 83.9] 20 (76.9) [56.4 91.0] 39 (73.6) [59.7 - 84.7] 38 (82.6) [68.6 922] [don't know 7 (42) 0 5 (9.4) 2 (4.3) 6b: According to the product labeling, a cancer patient who has been on an around-the-clock opioid for I day may start taking a TIRF medicine for breakthrough pain. True 31 (18.6) 6 (23.1) 10 (18.9) 7 (15.2) Falsem 132 (79.0) [72.1 - 84.9] 19 (73.1) [52.2 - 88.4] 39 (73.6) [59.7 - 84.7] 38 (82.6) [68.6 - 922] 1 don't know 4 (2.4) (3.8) 4 (7.5) (2.2) Question 9: Per the approved labeling for TIRF medicines, for which of the following indication(s) are TIRF medicines approved? Please answer Yes, No, or I don't know for each option. 9a: A cute or postoperative pain Yes 4 (2.4) 2 (7.7) 1 (1.9) 2 (4.3) Now 157 (94.0) [89.3 - 97.1] 24 (92.3) [74.9 - 99.1] 51 (96.2) [87.0 - 99.5] 44 (95.7) [85.2 99.5] 1 don't know 6 (3.6) 0 1 (1.9) 0 9b: Headache or migraine pain Yes 4 (2.4) 2 (7.7) 0 0 Data Source: ADPQ, ADTQ Program: TK RM S. SAS TRIG Page 2 of4 TIRF Prescriber KAB 05JAN2017 Table 8.1.2: Responses to Questions Linked to Key Risk Message #2 by Medical Degree of Respondent - Completed Surveys Medical Degree of Respondent MD DO Nurse Practitioner Physician Assistant (N=l67) Question 95% C1 'll 95% 95% 95% Cll'" Now 155 (92.8) [87.8 - 96.2] 24 (92.3) [74.9 - 99.1] 52 (98.1) [89.9 - 100.0] 43 (93.5) [82.1 - 98.6] [don't know 8 (4.8) 0 (1.9) 3 (6.5) 90: Dental pain Yes 2 (12) 2 (7.7) 0 0 Now 160 (95.8) [91.6 - 98.3] 24 (92.3) [74.9 - 99.1] 53 (100.0) [93.3 - 100.0] 44 (95.7) [85.2 - 99.5] [don't know 5 (3.0) 0 0 2 (4.3) 9d: Breakthrough pain from cancer Yesm 167 (100.0) [97.8 - 100.0] 26 (100.0) [86.8 - 100.0] 52 (98.1) [89.9 - 100.0] 45 (97.8) [88.5 - 99.9] No 0 0 1 (1.9) (2.2) I don't know 0 0 0 9e: Chronic non-cancer pain Yes 24 (14.4) 5 (19.2) 16 (30.2) 9 (19.6) Now 136 (81.4) [74.7 - 87.0] 21 (80.8) [60.6 - 93.4] 35 (66.0) [51.7 - 78.5] 36 (78.3) [63.6 - 89.1] [don't know 7 (42) 0 2 (3.8) (2.2) Question 15: The patients described are experiencing breakthrough pain. According to the labeling, a TIRF medicine is not appropriate for one of them. Which patient should not receive a TIRF medicine? Please select one option. Data Source: ADPQ, ADTQ Program: TK RM S. SAS TRIG TIRF Prescriber KAB Page 3 of4 05JAN2017 Table 8.1.2: Responses to Questions Linked to Key Risk Message #2 by Medical Degree of Respondent - Completed Surveys Medical Degree of Respondent lung cancer, underlying persistent cancer pain managed with 25 meg/hour transdermal fentanyl patches for the past two months. MD DO Nurse Practitioner Physician Assistant (N=l67) Question 95% [95% 95% cu'" [95% Adult male with advanced 7 (42) (3.8) 7 (13.2) 5 (10.9) Adult female with localized breast cancer; just completed a mastectomy and reconstructive surgery, persistent cancer pain managed with 30 mg oral morphine daily for the past 6 weeks. 128 (76.6) [69.5 - 82.8] 18 (69.2) [48.2 - 85.7] 34 (64.2) [49.8 - 76.9] 31 (67.4) [52.0 - 80.5] Adult male patient with advanced prostate cancer who, over the last 2 weeks, has been prescribed 100 mg oral morphine daily for pain due to bone metastasis. 11 (6.6) 2 (7.7) 2 (3.8) 2 (4.3) Adult female with advanced sarcoma who has been taking a daily dose of 12 mg oral hydromorphone for the last 3 weeks. 12 (7.2) 3(11.5) 6(11.3) 6 (13.0) Data Source: ADPQ, ADTQ Program: TK RM S. SAS TRIG Page 4 of4 TIRF Prescriber KAB 05JAN2017 Table 8.1.2: Responses to Questions Linked to Key Risk Message #2 by Medical Degree of Respondent - Completed Surveys Medical Degree of Respondent MD DO Nurse Practitioner Physician Assistant Question 95% cu'" 95% Cll'" 95% Cll'" 95% Cll'" [don't know 9 (5.4) 2 (7.7) 4 (7.5) 2 (4.3) Question 20: Before initiating treatment with a TIRF medicine, prescribers must review the Medication Guide with the patient. Please select True, False, or I don't know for each of the following counseling statements. 20b: Inform patients that TIRF medicines must not be used for acute or postoperative pain, pain from injuries, headache/migraine, or any other short-term pain. Truelz] 162 (97.0) [93.2 - 99.0] 25 (96.2) [80.4 - 99.9] 49 (92.5) [81.8 - 97.9] 45 (97.8) [88.5 - 99.9] False 4 (2.4) 0 3 (5.7) (2.2) [don't know 1 (0.6) (3.8) (1.9) 0 20c: Instruct patients that they can continue to take their TIRF medicine, if they stop taking their around-the-clock opioid medicine. True 37 (22.2) 6 (23.1) 5 (9.4) 10 (21.7) Falsem 126 (75.4) [68.2 - 81.8] 19 (73.1) [52.2 - 88.4] 46 (86.8) [74.7 - 94.5] 33 (71.7) [56.5 - 84.0] [don't know 4 (2.4) (3.8) 2 (3.8) 3 (6.5) Source: Appendix B: Survey Tables, Table 8.1.2 ?195% exact two-sided con?dence intervals are calculated using the Clopper-Pearson method. Correct response. Data Source: ADPQ, ADTQ Program: TRIG TIRF Prescriber KAB Page 1 of3 05JAN2017 Survey - Completed Surveys Table 8.1.3: Responses to Questions Linked to Key Risk Message #2 by Modality to Complete Question Modality to Complete Survey Internet [95% Telephone [95% medicines. Question 6: Please answer True, False, or I don't know for each statement based on the labeling for TIRF opioid at the same time. 6a: According to the product labeling, a cancer patient may start a TIRF medicine and an around-the-clock True 52 (18.0) 0 Falsem 222 (76.8) [71.5 - 81.6] 5 (100.0) [47.8 - 100.0] [don't know 15 (5.2) 0 6b: According to the product labeling, a cancer patient who has been on an around-the-clock opioid for I day may start taking a TIRF medicine for breakthrough pain. True 54 (18.7) 0 Falsem 225 (77.9) [72.6 - 82.5] 5 (100.0) [47.8 - 100.0] I don't know 10 (3.5) 0 Question 9: Per the approved labeling for TIRF medicines, for which of the following indication(s) are TIRF medicines approved? Please answer Yes, No, or I don't know for each option. 9a: A cute or postoperative pain Yes 9 (3.1) 0 Now 274 (94.8) [91.6 - 97.1] 4 (80.0) [28.4 - 99.5] 1 don't know 6 (2.1) 1 (20.0) 9b: Headache or migraine pain Yes 6 (2.1 0 Now 271 (93.8) [90.3 - 96.3] 5 (100.0) [47.8 - 100.0] I don't know 12 (4.2) 0 9c: Dental pain Yes 4 (1.4) 0 Now 278 (96.2) [93.3 - 98.1] 5 (100.0) [47.8 - 100.0] [don't know 7 (2.4) 0 9d: Breakthrough pain from cancer Yesm 287 (99.3) [97.5 - 99.9] 5 (100.0) [47.8 - 100.0] Data Source: ADPQ, ADTQ Program: TK RM S. SAS TRIG TIRF Prescriber KAB Page 2 of3 05JAN 2017 Survey - Completed Surveys Table 8.1.3: Responses to Questions Linked to Key Risk Message #2 by Modality to Complete Modality to Complete Survey Internet Telephone Question [95% cu"I [95% C1[Ill No 2 (0.7) 0 I don't know 0 0 9e: Chronic non-cancer pain Yes 54 (18.7) 0 Now 225 (77.9) [72.6 - 82.5] 5 (100.0) [47.8 - 100.0] [don't know 10 (3.5) 0 select one option. Question 15: The patients described are experiencing breakthrough pain. According to the labeling, a TIRF medicine is not appropriate for one of them. Which patient should not receive a TIRF medicine? Please Adult male with advanced lung cancer; underlying persistent cancer pain managed with 25 mcg/hour transdermal fentanyl patches for the past two months. 20 (6.9) Adult female with localized breast cancer; just completed a mastectomy and reconstructive surgery; persistent cancer pain managed with 30 mg oral morphine daily for the past 6 weeksm 209 (72.3) [66.8 - 77.4] 3 (60.0) [14.7 - 94.7] Adult male patient with advanced prostate cancer who, over the last 2 weeks, has been prescribed 100 mg oral morphine daily for pain due to bone metastasis. 18 (6.2) Adult female with advanced sarcoma who has been taking a daily dose of 12 mg oral hydromorphone for the last 3 weeks. 26 (9.0) 1 (20.0) I don't know 16 (5.5) 1 (20.0) statements. Question 20: Before initiating treatment with a TIRF medicine, prescribers must review the Medication Guide with the patient. Please select True, False, or I don't know for each of the following counseling 20b: Inform patients that TIRF medicines must not be used for acute or postoperative pain, pain from injuries, headach dmigraine, or any other short-term pain. Truem 278 (96.2) [93.3 - 98.1] 5 (100.0) [47.8 - 100.0] False 8 (2.8) 0 Data Source: ADPQ, ADTQ Program: TK RM S. SAS TRIG Page 3 of 3 TIRF Prescriber KAB 05JAN2017 Table 8.1.3: Responses to Questions Linked to Key Risk Message #2 by Modality to Complete Survey - Completed Surveys Modality to Complete Survey Internet Telephone Question [95% C1[Ill [95% [don't know 3 (1.0) 0 20c: Instruct patients that they can continue to take their TIRF medicine, if they stop taking their around-the-clock opioid medicine. True 56 (19.4) 2 (40.0) Falsem 222 (76.8) [71.5 - 81.6] 3 (60.0) [14.7 - 94.7] [don?t know 11 (3.8) 0 Source: Appendix B: Survey Tables, Table 8.1.3 95% exact two-sided con?dence intervals are calculated using the Clopper-Pearson method. Correct response. Data Source: ADPQ, ADTQ Program: TRIG TIRF Prescriber KAB Page 1 of4 05JAN2017 Table 8.1.4: Responses to Questions Linked to Key Risk Message #2 by Time Practicing Medicine - Completed Surveys Time Practicing Medicine Question Less than 3 years [95% 3 to 5 years [95% Cll'" 6 to 15 years [95% More than 15 years [95% Question 6: Please answer True, False, or 1 don't know for each statement based on the labeling for TIRF medicines. 6a: According to the product labeling, a cancer patient may start a TIR medicine and an around-the-clock opioid at the same time. True 3 (11.5) 7 (14.3) 15 (17.6) 27 (20.1) Falsem 21 (80.8) [60.6 - 93.4] 38 (77.6) [63.4 88.2] 63 (74.1) [63.5 - 83.0] 105 (78.4) [70.4 85.0] [don't know 2 (7.7) 4 (8.2) 7 (8.2) 2 (1.5) 6b: According to the product labeling, a cancer patient who has been on an around-the-clock opioid for I day may start taking a TIRF medicine for breakthrough pain. True 5 (19.2) 4 (8.2) 15 (17.6) 30 (22.4) Falsem 20 (76.9) [56.4 - 91.0] 43 (87.8) [75.2 - 95.4] 67 (78.8) [68.6 - 86.9] 100 (74.6) [66.4 - 81.7] [don't know 1 (3.8) 2 (4.1) 3 (3.5) 4 (3.0) Question 9: Per the approved labeling for TIRF medicines, for which of the following indication(s) are TIRF medicines approved? Please answer Yes, No, or I don't know for each option. 9a: A cute or postoperative pain Yes 3 (11.5) 0 0 6 (4.5) Now 22 (84.6) [65.1 - 95.6] 47 (95.9) [86.0 - 99.5] 82 (96.5) [90.0 - 99.3] 127 (94.8) [89.5 - 97.9] [don't know 1 (3.8) 2 (4.1) 3 (3.5) 1 (0.7) 9b: Headache or migraine pain Yes 0 0 0 6 (4.5) Data Source: ADPQ, ADTQ Program: TK RM S. SAS TRIG TIRF Prescriber KAB Page 2 of4 05JAN2017 Table 8.1.4: Responses to Questions Linked to Key Risk Message #2 by Time Practicing Medicine - Completed Surveys Time Practicing Medicine Less than 3 years 3 to 5 years 6 to 15 years (N =85) More than 15 years (N=l34) Question [95% 11 [95% [95% 11 [95% New 25 (96.2) [80.4 - 99.9] 48 (98.0) [89.1 - 99.9] 78 (91.8) [83.8 - 96.6] 125 (93.3) [87.6 - 96.9] [don't know 1 (3.8) 1 (2.0) 7 (8.2) 3 (2.2) 90: Dental pain Yes 0 0 0 4 (3.0) Now 25 (96.2) [80.4 - 99.9] 48 (98.0) [89.1 - 99.9] 83 (97.6) [91.8 - 99.7] 127 (94.8) [89.5 - 97.9] [don't know 1 (3.8) 1 (2.0) 2 (2.4) 3 (2.2) 9d: Breakthrough pain from cancer Yesm 26 (100.0) [86.8 - 100.0] 49 (100.0) [92.7 - 100.0] 85 (100.0) [95.8 - 100.0] 132 (98.5) [94.7 - 99.8] No 0 0 0 2 (1.5) I don't know 0 0 0 0 9e: Chronic non-cancer pain Yes 7 (26.9) 4 (8.2) 15 (17.6) 28 (20.9) Now 19 (73.1) [52.2 - 88.4] 43 (87.8) [75.2 - 95.4] 64 (75.3) [64.7 84.0] 104 (77.6) [69.6 - 84.4] [don't know 0 2 (4.1) 6 (7.1) 2 (1.5) Question 15: The patients described are experiencing breakthrough pain. According to the labeling, a TIRF medicine is not appropriate for one of them. Which patient should not receive a TIRF medicine? Please select one option. Data Source: ADPQ, ADTQ Program: TK RM S. SAS TRIG TIRF Prescriber KAB Page 3 of4 05JAN2017 Table 8.1.4: Responses to Questions Linked to Key Risk Message #2 by Time Practicing Medicine - Completed Surveys Time Practicing Medicine lung cancer, underlying persistent cancer pain managed with 25 mcg/hour transdermal fentanyl patches for the past two months. Less than 3 years 3 to 5 years 6 to 15 years More than 15 years (N=l34) Question 11 [95% cu? [95% [95% cu'" [95% Adult male with advanced 4 (15.4) 3 (6.1) 7 (8.2) 6 (4.5) Adult female with localized breast cancer; just completed a mastectomy and reconstructive surgery, persistent cancer pain managed with 30 mg oral morphine daily for the past 6 weeks. 15 (57.7) [36.9 - 76.6] 36 (73.5) [58.9 - 85.1] 63 (74.1) [63.5 - 83.0] 98 (73.1) [64.8 - 80.4] Adult male patient with advanced prostate cancer who, over the last 2 weeks, has been prescribed 100 mg oral morphine daily for pain due to bone metastasis. 2 (7.7) 4 (8.2) 3 (3.5) 9 (6.7) Adult female with advanced sarcoma who has been taking a daily dose of 12 mg oral hydromorphone for the last 3 weeks. 3 (11.5) 4 (8.2) 8 (9.4) 12 (9.0) Data Source: ADPQ, ADTQ Program: TK RM S. SAS TRIG Page 4 of4 TIRF Prescriber KAB 05JAN2017 Table 8.1.4: Responses to Questions Linked to Key Risk Message #2 by Time Practicing Medicine - Completed Surveys Time Practicing Medicine Less than 3 years 3 to 5 years 6 to 15 years More than 15 years (N=l34) Question 95% cu'" 95% Cll'" 95% Cll'" 95% Cll'" [don't know 2 (7.7) 2 (4.1) 4 (4.7) 9 (6.7) Question 20: Before initiating treatment with a TIRF medicine, prescribers must review the Medication Guide with the patient. Please select True, False, or I don't know for each of the following counseling statements. 20b: Inform patients that TIRF medicines must not be used for acute or postoperative pain, pain from injuries, headache/migraine, or any other short-term pain. Truelz] 25 (96.2) [80.4 - 99.9] 46 (93.9) [83.1 - 98.7] 80 (94.1) [86.8 - 98.1] 132 (98.5) [94.7 - 99.8] False 1 (3.8) (2.0) 4 (4.7) 2 (1.5) [don't know 0 2 (4.1) (1.2) 0 20c: Instruct patients that they can continue to take their TIRF medicine, if they stop taking their around-the-clock opioid medicine. True 2 (7.7) 10 (20.4) 17 (20.0) 29 (21.6) Falsem 21 (80.8) [60.6 - 93.4] 36 (73.5) [58.9 - 85.1] 64 (75.3) [64.7 - 84.0] 104 (77.6) [69.6 - 84.4] [don't know 3 (11.5) 3 (6.1) 4 (4.7) (0.7) Source: Appendix B: Survey Tables, Table 8.1.4 ?195% exact two-sided con?dence intervals are calculated using the Clopper-Pearson method. Correct response. Data Source: ADPQ, ADTQ Program: TK RM S. SAS TRIG TIRF Prescriber KAB Page 1 of5 05JAN2017 Table 8.1.5: Responses to Questions Linked to Key Risk Message #2 by Number of Times Prescribing TIRF Medicines per Month Within the Last 6 Months - Completed Surveys Question Number of Times Prescribing TIRF Medicines per Month Within the Last 6 Months None [95% - 2 times per month [95% C1["l 3 - 5 times per month [95% More than 5 times per month [95% 1 don't remember [95% Question 6: Please answer True, False, or I don't know for each statement based on the labeling for TIRF medicines. 6a: According to the product labeling, a cancer patient may start a TIR medicine and an around-the-clock opioid at the same time. True 3 (20.0) 32 (17.0) 1 1 (17.2) 6 (28.6) 0 Falsem 9 (60.0) [32.3 - 83.7] 147 (78.2) [71.6 - 83.9] 53 (82.8) [71.3 - 91.1] 13 (61.9) [38.4 - 81.9] 5 (83.3) [35.9 - 99.6] 1 don?t know 3 (20.0) 9 (4.8) 0 2 (9.5) 1 (16.7) 6b: According to the product labeling, a cancer patient who has been on an around-the-clock opioid for I day may start taking a TIRF medicine for breakthrough pain. True 4 (26.7) 29 (15.4) 15 (23.4) 5 (23.8) 1 (16.7) Falsem 10 (66.7) [38.4 - 88.2] 153 (81.4) [75.1 - 86.7] 46 (71.9) [59.2 - 82.4] 16 (76.2) [52.8 - 91.8] 5 (83.3) [35.9 - 99.6] I don't know 1 (6.7) 6 (3.2) 3 (4.7) 0 0 Question 9: Per the approved labeling for TIRF medicines, for which of the following indication(s) are TIRF medicines approved? Please answer Yes, No, or I don't know for each option. 9a: A cute or postoperative pain Yes 0 5 (2.7) 0 3 (14.3) 1 (16.7) Now 14 (93.3) [68.1 - 99.8] 178 (94.7) [90.4 - 97.4] 63 (98.4) [91.6 - 100.0] 18 (85.7) [63.7 - 97.0] 5 (83.3) [35.9 99.6] [don't know 1 (6.7) 5 (2.7) 1 (1.6) 0 0 9b: Headache or migraine pain Data Source: ADPQ, ADTQ Program: TK RM S. SAS TRIG Page 2 of 5 TIRF Prescriber KAB 05JAN2017 Table 8.1.5: Responses to Questions Linked to Key Risk Message #2 by Number of Times Prescribing TIRF Medicines per Month Within the Last 6 Months - Completed Surveys Number of Times Prescribing TIRF Medicines per Month Within the Last 6 Months 1 - 2 times 3 - 5 times More than 5 times 1 don't None per month per month per month remember (N=l88) Question [95% [95% cu"l [95% [95% cu'? [95% Yes 0 5 (2.7) 0 1 (4.8) 0 Now 14 (93.3) [68.1 - 99.8] 177 (94.1) [89.8 - 97.0] 63 (98.4) [91.6 - 100.0] 17 (81.0) [58.1 - 94.6] 5 (83.3) [35.9 - 99.6] [don't know 1 (6.7) 6 (3.2) (1.6) 3 (14.3) 1 (16.7) 96: Dental pain Yes 0 2 (1.1) l(4.8) 0 Now 15 (100.0) [78.2 - 100.0] 182 (96.8) [93.2 - 98.8] 63 (98.4) [91.6 - 100.0] 18 (85.7) [63.7 - 97.0] 5 (83.3) [35.9 - 99.6] I don't know 0 4 (2.1) 0 2 (9.5) 1 (16.7) 9d: Breakthrough pain from cancer Yesm 15 (100.0) [78.2 - 100.0] 187 (99.5) [97.1 - 100.0] 64 (100.0) [94.4 - 100.0] 20 (95.2) [76.2 - 99.9] 6 (100.0) [54.1 - 100.0] No 0 1 (0.5) 0 1 (4.8) 0 [don't know 0 0 0 0 0 9e: Chronic non-cancer pain Yes 3 (20.0) 36 (19.1) 4 (6.3) 8 (38.1) 3 (50.0) Now 12 (80.0) [51.9 - 95.7] 145 (77.1) [70.5 - 82.9] 58 (90.6) [80.7 - 96.5] 12 (57.1) [34.0 - 78.2] 3 (50.0) [11.8 - 88.2] [don't know 0 7 (3.7) 2 (3.1) (4.8) 0 Question 15: The patients described are experiencing breakthrough pain. According to the labeling, a TIRF medicine is not appropriate for one of them. Which patient should not receive a TIRF medicine? Please select one option. Data Source: ADPQ, ADTQ Program: TRIG TIRF Prescriber KAB Page 3 of 5 05JAN2017 Table 8.1.5: Responses to Questions Linked to Key Risk Message #2 by Number of Times Prescribing TIRF Medicines per Month Within the Last 6 Months - Completed Surveys Number of Times Prescribing TIRF Medicines per Month Within the Last 6 Months - 2 times 3 - 5 times More than 5 times I don't None per month per month per month remember Question [95% [95% cu"I [95% [95% [95% Adult male with advanced (6.7) 15 (8.0) 3 (4.7) (4.8) 0 lung cancer, underlying persistent cancer pain managed with 25 meg/hour transdermal fentanyl patches for the past two months. Adult female with localized breast cancer; just completed a mastectomy and reconstructive surgery; persistent cancer pain managed with 30 mg oral morphine daily for the past 6 weeks.[ 1 11 (73.3) [44.9 - 922] 141 (75.0) [68.2 - 81.0] 47 (73.4) [60.9 - 83.7] 11 (52.4) [29.8 - 74.3] 2 (33.3) [4.3 - 77.7] Adult male patient with advanced prostate cancer who, over the last 2 weeks, has been prescribed 100 mg oral morphine daily for pain due to bone metastasis. 2(13.3) 8 (4.3) 6 (9.4) 2 (9.5) Data Source: ADPQ, ADTQ Program: TK RM S. SAS TRIG TIRF Prescriber KAB Page 4 of 5 05JAN2017 Table 8.1.5: Responses to Questions Linked to Key Risk Message #2 by Number of Times Prescribing TIRF Medicines per Month Within the Last 6 Months - Completed Surveys Number of Times Prescribing TIRF Medicines per Month Within the Last 6 Months 1 - 2 times 3 - 5 times More than 5 times I don't None per month per month per month remember (N=l 88) Question [95% [95% cu"I [95% [95% cu'? [95% Adult female with 0 16 (8.5) 3 (4.7) 6 (28.6) 2 (33.3) advanced sarcoma who has been taking a daily dose of 12 mg oral hydromorphone for the last 3 weeks. [don't know 1 (6.7) 8 (4.3) 5 (7.8) (4.8) 2 (33.3) Question 20: Before initiating treatment with a TIRF medicine, prescribers must review the Medication Guide with the patient. Please select True, False, or I don't know for each of the following counseling statements. 20b: Inform patients that TIRF medicines must not be used for acute or postoperative pain, pain from injuries, headache/migraine, or any other short-term pam. Truem 14 (93.3) [68.1 - 99.8] 181 (96.3) [92.5 - 98.5] 62 (96.9) [89.2 - 99.6] 21 (100.0) [83.9 - 100.0] 5 (83.3) [35.9 - 99.6] False 0 6 (3.2) 2 (3.1) 0 0 [don't know 1 (6.7) (0.5) 0 0 1 (16.7) 20c: Instruct patients that they can continue to take their TIRF medicine, if they stop taking their around -the-clock opioid medicin . True 3 (20.0) 33 (17.6) 12 (18.8) 8 (38.1) 2 (33.3) Falsem 10 (66.7) [38.4 - 882] 148 (78.7) [72.2 - 84.3] 50 (78.1) [66.0 - 87.5] 13 (61.9) [38.4 - 81.9] 4 (66.7) [22.3 - 95.7] Data Source: ADPQ, ADTQ Program: TK RM S. SAS TRIG Page 5 of 5 TIRF Prescriber KAB 05JAN2017 Table 8.1.5: Responses to Questions Linked to Key Risk Message #2 by Number of Times Prescribing TIRF Medicines per Month Within the Last 6 Months - Completed Surveys Number of Times Prescribing TIRF Medicines per Month Within the Last 6 Months 1 - 2 times 3 - 5 times More than 5 times I don't None per month per month per month remember Question [95% [95% cu"I [95% [95% cu'? [95% [don't know 2 (13.3) 7 (3.7) 2 (3.1) 0 0 Source: Appendix B: Survey Tables, Table 8.1.5 ?195% exact two-sided con?dence intervals are calculated using the Clopper-Pearson method. Correct response. Data Source: ADPQ, ADTQ Program: TRIG TIRF Prescriber KAB Page 1 of3 05JAN2017 Table 8.1.6: Responses to Questions Linked to Key Risk Message #2 by Practicing in a Closed Healthcare System - Completed Surveys Question Practicing in a Closed Healthcare System Yes [95% No [95% medicines. Question 6: Please answer True, False, or I don't know for each statement based on the labeling for TIRF opioid at the same time. 6a: According to the product labeling, a cancer patient may start a TIRF medicine and an around-the-clock True 1 (25.0) 51 (17.6) Falsem 3 (75.0) [19.4 - 99.4] 224 (77.2) [72.0 - 81.9] [don't know 0 15 (5.2) 6b: According to the product labeling, a cancer patient who has been on an around-the-clock opioid for I day may start taking a TIRF medicine for breakthrough pain. True 2 (50.0) 52 (17.9) Falsem 2 (50.0) [6.8 - 93.2] 228 (78.6) [73.4 - 83.2] I don't know 0 10 (3.4) Question 9: Per the approved labeling for TIRF medicines, for which of the following indication(s) are TIRF medicines approved? Please answer Yes, No, or I don't know for each option. 9a: A cute or postoperative pain Yes 0 9 (3.1) Now 4 (100.0) [39.8 - 100.0] 274 (94.5) [91.2 - 96.8] [don't know 0 7 (2.4) 9b: Headache or migraine pain Yes 0 6 (2.1) Nom 4 (100.0) [39.8 - 100.0] 272 (93.8) [90.4 - 96.3] I don't know 0 12 (4.1) 9c: Dental pain Yes 0 4 (1.4) New 4 (100.0) [39.8 - 100.0] 279 (96.2) [93.3 - 98.1] [don't know 0 7 (2.4) 9d: Breakthrough pain from cancer Yesm 4 (100.0) [39.8 - 100.0] 288 (99.3) [97.5 - 99.9] Data Source: ADPQ, ADTQ Program: TK RM S. SAS TRIG TIRF Prescriber KAB Page 2 of3 05JAN 2017 Healthcare System - Completed Surveys Table 8.1.6: Responses to Questions Linked to Key Risk Message #2 by Practicing in a Closed Practicing in a Closed Healthcare System Yes No Question [95% cu"I [95% C1[Ill No 0 2 (0.7) I don't know 0 0 9e: Chronic non-cancer pain Yes 1 (25.0) 53 (18.3) Now 3 (75.0) [19.4 - 99.4] 227 (78.3) [73.1 - 82.9] I don't know 0 10 (3.4) select one option. Question 15: The patients described are experiencing breakthrough pain. According to the labeling, a TIRF medicine is not appropriate for one of them. Which patient should not receive a TIRF medicine? Please Adult male with advanced lung cancer; underlying persistent cancer pain managed with 25 mcg/hour transdermal fentanyl patches for the past two months. 20 (6.9) Adult female with localized breast cancer; just completed a mastectomy and reconstructive surgery; persistent cancer pain managed with 30 mg oral morphine daily for the past 6 weeksm 3 (75.0) [19.4 - 99.4] 209 (72.1) [66.5 - 77.2] Adult male patient with advanced prostate cancer who, over the last 2 weeks, has been prescribed 100 mg oral morphine daily for pain due to bone metastasis. 1 (25.0) 17 (5.9) Adult female with advanced sarcoma who has been taking a daily dose of 12 mg oral hydromorphone for the last 3 weeks. 27 (9.3) I don't know 0 17 (5.9) statements. Question 20: Before initiating treatment with a TIRF medicine, prescribers must review the Medication Guide with the patient. Please select True, False, or I don't know for each of the following counseling 20b: Inform patients that TIRF medicines must not be used for acute or postoperative pain, pain from injuries, headach dmigraine, or any other short-term pain. Truem 4 (100.0) [39.8 - 100.0] 279 (96.2) [93.3 - 98.1] False 0 8 (2.8) Data Source: ADPQ, ADTQ Program: TK RM S. SAS TRIG TIRF Prescriber KAB Page 3 of3 05JAN 2017 Table 8.1.6: Responses to Questions Linked to Key Risk Message #2 by Practicing in a Closed Healthcare System - Completed Surveys Practicing in a Closed Healthcare System Yes No Question [95% CW [95% [don't know 0 3 (1.0) 20c: Instruct patients that they can continue to take their TIRF medicine, if they stop taking their around-the-clock opioid medicine. True 1 (25.0) 57 (19.7) Falsem 3 (75.0) [19.4 - 99.4] 222 (76.6) [71.2 - 81.3] [don?t know 0 11 (3.8) Source: Appendix B: Survey Tables, Table 8.1.6 95% exact two-sided con?dence intervals are calculated using the Clopper-Pearson method. Correct response. Data Source: ADPQ, ADTQ Program: TK RM S. SAS TRIG TIRF Prescriber KAB Page 1 of] 05JAN2017 Completed Surveys Table 8.2: Secondary Analysis of Responses to Questions Linked to Key Risk Message #2 - Prescribers Correct Responses 0 correct responses 0 1 correct response 0 2 correct responses 2 (0.7) 3 correct responses 1 (0.3) 4 correct responses 3 (1.0) 5 correct responses 6 (2.0) 6 correct responses 1 (3.7) 7 correct responses 35 (l 1.9) 8 correct responses 46 (15.6) 9 correct responses 92 (31.3) 10 correct responses 98 (33.3) Source: Appendix B: Survey Tables, Table 8.2 Data Source: ADPQ. ADTQ Program: 0 TRIG Page 1 of2 TIRF Prescriber KAB 05JAN2017 Table 9.1: Primary Analysis of Responses to Questions Linked to Key Risk Message #3 - Completed Surveys Prescribers Question [95% cull" medicines. Question 7: Please answer True, False, or I don't know for each statement based on the labeling for TIRF 7e: It is important to monitor for signs of abuse and addiction in patients who take TIRF medicines. True 291 (99.0) [97.0 - 99.8] False 3 (1.0) I don't know 0 know for each option. Question 8: Which of the following are risk factors for opioid abuse? Please answer Yes, 0, or I don't 8a: A personal history of illness Yesm 253 (86.1) [81.6 - 89.8] No 27 (9.2) I don't know 14 (4.8) alcohol abuse 8b: A personal history of past or current alcohol or drug abuse, or a family history of illicit drug use or Yesm 294 (100.0) [98.8 - 100.0] No 0 1 don't know 0 medicines. Question 12: Please answer True, False, or I don't know for each statement based on the labeling for TIRF 12a: medicines can be abused in a manner similar to other opioid agonists. Truem 282 (95.9) [93.0 - 97.9] False 10 (3.4) I don't know 2 (0.7) True, False, or I don't know for the following statements. Question 22: Which of the following risks are associated with the use of TIRF medicines? Please answer 22a: Misuse Truem 290 (98.6) [96.6 - 99.6] False 4 (1.4) 1 don't know 0 22b: A buse Data Source: ADPQ, ADTQ Program: 1 TRIG Page 2 of 2 TIRF Prescriber KAB 05JAN2017 Table 9.1: Primary Analysis of Responses to Questions Linked to Key Risk Message #3 - Completed Surveys Prescribers Question 95% Cl Ill Truem 291 (99.0) [97.0 - 99.8] False 2 (0-7) 1 don't know 1 (0.3) 22c: A ddiction True 291 (99.0) [97.0 - 99.8] False 3 (1.0) 1 don't know 0 22d: Overdose Truem 292 (99.3) [97.6 - 99.9] False 2 (0.7) 1 don't know 0 22c: Hypothyroidism True 20 (6.8) Falsem 232 (78.9) [73.8 - 83.4] I don't know 42 (14.3) 22]? Infection True 23 (7.8) Falsem 253 (86.1) [81.6 - 89.8] 1 don't know 18 (6.1) Source: Appendix B: Survey Tables, Table 9.1 95% exact two-sided con?dence intervals are calculated using the Clopper-Pearson method. Correct response. Data Source: ADPQ. ADTQ Program: 2 TRIG TIRF Prescriber KAB Page 1 of2 05JAN2017 Table 9.1.1: Responses to Questions Linked to Key Risk Message #3 by Reading Full Prescribing Information or Medication Guide - Completed Surveys Question Reading Full Prescribing Information or Medication Guide Received and read Pl or Med Guide [95% Did not receive or read Pl or Med Guide [95% Question 7: Please answer True, False, or I don't know for each statement based on the labeling for TIRF medicines. 7e: It is important to monitor for signs of abuse and addiction in patients who take TIRF medicines. Truem 265 (98.9) [96.8 - 99.8] 26 (100.0) [86.8 100.0] False 3 (1.1 0 1 don't know 0 0 Question 8: Which of the following are risk factors for opioid abuse? Please answer Yes, No, or I don't know for each option. 8a: A personal history of illness Yesm 234 (87.3) [82.7 - 91.1] 19 (73.1) [52.2 - 88.4] No 23 (8.6) 4 (15.4) [don't know 11 (4.1) 3 (11.5) 8b: A personal history of past or current alcohol or drug abuse, or a family history of illicit drug use or alcohol abuse Yesm 268 (100.0) [98.6 - 100.0] 26 (100.0) [86.8 - 100.0] No 0 0 1 don?t know 0 0 Question 12: Please answer True, False, or I don't know for each statement based on the labeling for TIRF medicines. 12a: TIRF medicines can be abused in a manner similar to other opioid agonists. Truem 259 (96.6) [93.7 - 98.5] 23 (88.5) [69.8 - 97.6] False 8 (3.0) 2 (7.7) [don't know 1 (0.4) 1 (3.8) Question 22: Which of the following risks are associated with the use of TIRF medicines? Please answer True, False, or I don't know for the following statements. 22a: Misuse Truem 266 (99.3) [97.3 99.9] 24 (92.3) [74.9 - 99.1] False 2 (0.7) 2 (7.7) Data Source: ADPQ, ADTQ Program: TK S. SAS 3 TRIG TIRF Prescriber KAB Page 2 of2 05JAN2017 Table 9.1.1: Responses to Questions Linked to Key Risk Message #3 by Reading Full Prescribing Information or Medication Guide - Completed Surveys Reading Full Prescribing Information or Medication Guide Received and read Did not receive or read Pl or Med Guide Pl or Med Guide Question [95% Cll'" [95% all" I don't know 0 0 22b: Abuse Truem 268 (100.0) [98.6 100.0] 23 (88.5) [69.8 - 97.6] False 0 2 (7.7) [don?t know 0 (3.8) 220: A ddiction Truem 267 (99.6) [97.9 - 100.0] 24 (92.3) [74.9 - 99.1] False 1 (0.4) 2 (7.7) I don't know 0 0 22d: Overdose Truem 267 (99.6) [97.9 - 100.0] 25 (96.2) [80.4 99.9] False 1 (0.4) 1 (3.8) i don't know 0 0 22c: )pothyroidism True 19 (7.1) 1 (3.8) Falsem 213 (79.5) [74.1 - 84.1] 19 (73.1) [52.2 - 88.4] I don't know 36 (13.4) 6 (23.1) 22f: Infection True 20 (7.5) 3 (11.5) Falsem 233 (86.9) [82.3 - 90.7] 20 (76.9) [56.4 - 91.0] 166111 know 15 (5.6) 3 (11.5) Source: Appendix B: Survey Tables, Table 9.1.1 ?195% exact two-sided confidence intervals are calculated using the Clopper-Pearson method. Correct response. Data Source: ADPQ. ADTQ Program: TK RM S. SAS TRIG Page 1 of3 TIRF Prescriber KAB 05JAN2017 Table 9.1.2: Responses to Questions Linked to Key Risk Message #3 by Medical Degree of Respondent - Completed Surveys Medical Degree of Respondent MD DO Nurse Practitioner Physician Assistant Question 11 [95% cu'" [95% [95% 11 [95% Cll'" Question 7: Please answer True, False, or I don't know for each statement based on the labeling for TIRF medicines. 7e: It is important to monitor for signs of abuse and addiction in patients who take TIRF medicines. Truem 165 (98.8) [95.7 - 99.9] 26 (100.0) [86.8 - 100.0] 52 (98.1) [89.9 100.0] 46 (100.0) [92.3 - 100.0] False 2 (12) 0 1 (1.9) 0 1 don't know 0 0 0 0 Question 8: Which of the following are risk factors for opioid abuse? Please answer Yes, No, or I don't know for each option. 8a: A personal history of illness Yesm 145 (86.8) [80.7 - 91.6] 21 (80.8) [60.6 - 93.4] 44 (83.0) [70.2 - 91.9] 41 (89.1) [76.4 - 96.4] No 14 (8.4) 4 (15.4) 7 (13.2) 2 (4.3) 1 don't know 8 (4.8) (3.8) 2 (3.8) 3 (6.5) 8b: A personal history of past or current alcohol or drug abuse, or a family history of illicit drug use or alcohol abuse Yesm 167 (100.0) [97.8 - 100.0] 26 (100.0) [86.8 - 100.0] 53 (100.0) [93.3 - 100.0] 46 (100.0) [92.3 - 100.don't know 0 0 0 0 Question 12: Please answer True, False, or I don 't know for each statement based on the labeling for TIRF medicines. 12a: TIR medicines can be abused in a manner similar to other opioid agonists. Truem 158 (94.6) [90.0 - 97.5] 26 (100.0) [86.8 - 100.0] 51 (96.2) [87.0 - 99.5] 45 (97.8) [88.5 - 99.9] False 9 (5.4) 0 1 (1.9) 0 Data Source: ADPQ, ADTQ Program: 5 TRIG Page 2 of 3 TIRF Prescriber KAB 05JAN2017 Table 9.1.2: Responses to Questions Linked to Key Risk Message #3 by Medical Degree of Respondent - Completed Surveys Medical Degree of Respondent MD DO Nurse Practitioner Physician Assistant (N=l 67) Question 95% cu'" 95% Cll'" 95% Cll'" 95% Cll'" [don't know 0 0 (1.9) (2.2) Question 22: Which of the following risks are associated with the use of TIRF medicines? Please answer True, False, or 1 don't know for the following statements. 22a: Misuse Truelz] 165 (98.8) [95.7 - 99.9] 25 (96.2) [80.4 - 99.9] 52 (98.1) [89.9 - 100.0] 46 (100.0) [92.3 - 100.0] False 2(12) 1 (3.8) (1.9) 0 1 don't know 0 0 0 0 22b: Abuse Truem 166 (99.4) [96.7 - 100.0] 26 (100.0) [86.8 - 100.0] 51 (96.2) [87.0 - 99.5] 46 (100.0) [92.3 - 100.0] False (0.6) 0 (1.9) 0 1 don't know 0 0 (1.9) 0 220: Addiction Truelz] 167 (100.0) [97.8 - 100.0] 26 (100.0) [86.8 - 100.0] 50 (94.3) [84.3 - 98.8] 46 (100.0) [92.3 - 100.0] False 0 0 3 (5.7) 0 1 don?t know 0 0 0 0 22d: Overdose Truem 167 (100.0) [97.8 - 100.0] 25 (96.2) [80.4 - 99.9] 52 (98.1) [89.9 - 100.0] 46 (100.0) [92.3 - 100.0] False 0 (3.8) 1 (1.9) 0 Data Source: ADPQ, ADTQ Program: TK RM S. SAS 6 TRIG Page 3 of3 TIRF Prescriber KAB 05JAN2017 Table 9.1.2: Responses to Questions Linked to Key Risk Message #3 by Medical Degree of Respondent - Completed Surveys Medical Degree of Respondent MD DO Nurse Practitioner Physician Assistant (N=l67) Question 11 95% cu'? 95% cu'? 95% cu'" 95% I don't know 0 0 0 0 22c: Hypothyroidism True 9 (5.4) 4 (15.4) 6 (11.3) 1 (2.2) Falsem 135 (80.8) [74.0 - 86.5] 18 (69.2) [48.2 85.7] 41 (77.4) [63.8 - 87.7] 36 (78.3) [63.6 89.1] [don?t know 23 (13.8) 4 (15.4) 6 (11.3) 9 (19.6) 22f: Infection True 10 (6.0) 3 (11.5) 6 (11.3) 4 (8.7) Falsem 147 (88.0) [82.1 - 92.5] 21 (80.8) [60.6 - 93.4] 45 (84.9) [72.4 - 93.3] 38 (82.6) [68.6 - 922] 1 don't know 10 (6.0) 2 (7.7) 2 (3.8) 4 (8.7) Source: Appendix B: Survey Tables, Table 9.1.2 ?195% exact two-sided con?dence intervals are calculated using the Clopper-Pearson method. Correct response. Data Source: ADPQ, ADTQ Program: TK RM S. SAS 7 TRIG TIRF Prescriber KAB Page 1 of2 05JAN2017 Table 9.1.3: Responses to Questions Linked to Key Risk Message #3 by Modality to Complete Survey - Completed Surveys Question Modality to Complete Survey Internet [95% Telephone [95% Question 7: Please answer True, False, or I don't know for each statement based on the labeling for TIRF medicines. 7e: It is important to monitor for signs of abuse and addiction in patients who take TIRF medicines. True 286 (99.0) [97.0 - 99.8] 5 (100.0) [47.8 - 100.0] False 3 (1.0) 0 1 don't know 0 0 Question 8: Which of the following are risk factors for opioid abuse? Please answer Yes, No, or I don't know for each option. 8a: A personal history of illness Yesm 248 (85.8) [81.2 - 89.6] 5 (100.0) [47.8 - 100.0] N0 27 (9.3) 0 I don't know 14 (4.8) 0 8b: A personal history of past or current alcohol or drug abuse, or a family history of illicit drug use or alcohol abuse Yesm 289 (100.0) [98.7 - 100.0] 5 (100.0) [47.8 - 100.0] No 0 0 1 don't know 0 0 Question 12: Please answer True, False, or I don't know for each statement based on the labeling for TIRF medicines. 12a: TIRF medicines can be abused in a manner similar to other opioid agonists. Truem 277 (95.8) [92.9 - 97.8] 5 (100.0) [47.8 - 100.0] False 10 (3.5) 0 I don't know 2 (0.7) 0 Question 22: Which of the following risks are associated with the use of TIRF medicines? Please answer True, False, or I don't know for the following statements. 22a: Misuse Truem 285 (98.6) [96.5 - 99.6] 5 (100.0) [47.8 - 100.0] False 4 (1.4) 0 [don't know 0 0 Data Source: ADPQ, ADTQ Program: TK RM S. SAS 8 TRIG TIRF Prescriber KAB Page 2 of 2 05JAN 2017 Table 9.1.3: Responses to Questions Linked to Key Risk Message #3 by Modality to Complete Survey - Completed Surveys Modality to Complete Survey Internet Telephone Question [95% [95% cu'" 22b: Abuse Truem 286 (99.0) [97.0 - 99.8] 5 (100.0) [47.8 - 100.0] False 2 (0.7) 0 1 don't know 1 (0.3) 0 220.? A ddiction Truem 286 (99.0) [97.0 - 99.8] 5 (100.0) [47.8 - 100.0] False 3 (1.0) 0 1 don't know 0 0 22d: Overdose Truem 287 (99.3) [97.5 - 99.9] 5 (100.0) [47.8 - 100.0] False 2 (0.7) 0 1 don?t know 0 0 22e: ypothyroidism True 20 (6.9) 0 Falsem 227 (78.5) [73.4 - 83.1] 5 (100.0) [47.8 - 100.0] 1 don't know 42 (14.5) 0 22f: Infection True 23 (8.0) 0 Falsem 248 (85.8) [81.2 89.6] 5 (100.0) [47.8 100.0] 1 don't know 18 (6.2) 0 Source: Appendix B: Survey Tables, Table 9.1.3 ?195% exact two-sided confidence intervals are calculated using the Clopper-Pearson method. Correct response. Data Source: ADPQ. ADTQ Program: TK RM S. SAS TRIG TIRF Prescriber KAB Page 1 of3 05JAN2017 Table 9.1.4: Responses to Questions Linked to Key Risk Message #3 by Time Practicing Medicine - Completed Surveys Question Time Practicing Medicine Less than 3 years [95% C1[Ill 3 to 5 years [95% 6 to 15 years [95% More than 15 years (N=l34) [95% Question 7: Please answer True, False, or I don't know for each statement based on the labeling for TIRF medicines. 7e: It is important to monitor for signs of abuse and addiction in patients who take TIRF medicines. Truem 26 (100.0) [86.8 - 100.0] 49 (100.0) [92.7 - 100.0] 84 (98.8) [93.6 100.0] 132 (98.5) [94.7 99.8] False 0 0 1 (1.2) 2 (1.5) I don't know 0 0 0 0 Question 8: Which of the following are risk factors for opioid abuse? Please answer Yes, No, or I don't know for each option. 8a: A personal history of illness Yesm 21 (80.8) [60.6 - 93.4] 47 (95.9) [86.0 - 99.5] 77 (90.6) [82.3 - 95.8] 108 (80.6) [72.9 - 86.9] No 4 (15.4) 1 (2.0) 1 (1.2) 21 (15.7) [don't know 1 (3.8) 1 (2.0) 7 (8.2) 5 (3.7) 8b: A personal history of pas or current alcohol or drug abu se, or a family history of illicit drug use or alcohol abuse Yesm 26 (100.0) [86.8 - 100.0] 49 (100.0) [92.7 - 100.0] 85 (100.0) [95.8 - 100.0] 134 (100.0) [97.3 100.0] No 0 0 0 I don't know 0 0 Question 12: Please answer True, False, or I don 't know for each statement based on the labeling for TIRF medicines. 12a: TIR medicines can be abused in a manner similar to other opioid agonists. Truem 25 (96.2) [80.4 - 99.9] 47 (95.9) [86.0 - 99.5] 84 (98.8) [93.6 - 100.0] 126 (94.0) [88.6 - 97.4] False 1 (3.8) 1 (2.0) 1(1.2) 7 (5.2) Data Source: ADPQ, ADTQ Program: TK RM S. SAS TRIG TIRF Prescriber KAB Page 2 of3 05JAN2017 Table 9.1.4: Responses to Questions Linked to Key Risk Message #3 by Time Practicing Medicine - Completed Surveys Time Practicing Medicine Less than 3 years 3 to 5 years 6 to 15 years More than 15 years Question 95% cu'" 95% Cll'" 95% Cll'" 95% Cll'" [don't know 0 (2.0) 0 (0.7) Question 22: Which of the following risks are associated with the use of TIRF medicines? Please answer True, False, or I don't know for the following statements. 22a: Misuse Truelz] 26 (100.0) [86.8 - 100.0] 47 (95.9) [86.0 - 99.5] 84 (98.8) [93.6 - 100.0] 133 (99.3) [95.9 - 100.0] False 0 2 (4.1) (1.2) 1 (0.7) 1 don't know 0 0 0 0 22b: Abuse Truem 26 (100.0) [86.8 - 100.0] 47 (95.9) [86.0 - 99.5] 85 (100.0) [95.8 - 100.0] 133 (99.3) [95.9 - 100.0] False 0 2 (4.1) 0 0 1 don't know 0 0 0 (0.7) 220: Addiction Truelz] 25 (96.2) [80.4 - 99.9] 48 (98.0) [89.1 - 99.9] 85 (100.0) [95.8 - 100.0] 133 (99.3) [95.9 - 100.0] False 1 (3.8) (2.0) 0 1 (0.7) 1 don?t know 0 0 0 0 22d: Overdose Truem 26 (100.0) [86.8 - 100.0] 49 (100.0) [92.7 - 100.0] 84 (98.8) [93.6 - 100.0] 133 (99.3) [95.9 - 100.0] False 0 0 1 (1.2) 1 (0.7) Data Source: ADPQ, ADTQ Program: TK RM S. SAS TRIG TIRF Prescriber KAB Page 3 of3 05JAN2017 Table 9.1.4: Responses to Questions Linked to Key Risk Message #3 by Time Practicing Medicine - Completed Surveys Time Practicing Medicine Less than 3 years 3 to 5 years 6 to 15 years More than 15 years (N=l34) Question [95% 11 [95% [95% [95% C1[Ill I don't know 0 0 0 0 22c: Hypothyroidism True 3 (11.5) 3 (6.1) 5 (5.9) 9 (6.7) Falsem 21 (80.8) [60.6 - 93.4] 36 (73.5) [58.9 85.1] 65 (76.5) [66.0 - 85.0] 110 (82.1) [74.5 88.2] [don?t know 2 (7.7) 10 (20.4) 15 (17.6) 15 (11.2) 22f: Infection True 2 (7.7) 4 (8.2) 7 (8.2) 10 (7.5) Falsem 24 (92.3) [74.9 - 99.1] 41 (83.7) [70.3 - 92.7] 72 (84.7) [75.3 - 91.6] 116 (86.6) [79.6 - 91.8] 1 don't know 0 4 (8.2) 6 (7.1) 8 (6.0) Source: Appendix B: Survey Tables, Table 9.1.4 ?195% exact two-sided con?dence intervals are calculated using the Clopper-Pearson method. Correct response. Data Source: ADPQ, ADTQ Program: TK RM S. SAS TRIG TIRF Prescriber KAB Page 1 of3 05JAN2017 Table 9.1.5: Responses to Questions Linked to Key Risk Message #3 by Number of Times Prescribing TIRF Medicines per Month Within the Last 6 Months - Completed Surveys Question Number of Times Prescribing TIRF Medicines per Month Within the Last 6 Months None [95% - 2 times per month [95% 3 - 5 times per month [95% More than 5 times per month [95% 1 don't remember [95% Question 7: Please answer True, False, or I don't know for each statement based on the labeling for TIRF medicines. 7e: It is important to monitor for signs of abuse and addiction in patients who take TIRF medicines. True 15 (100.0) [78.2 - 100.0] 187 (99.5) [97.1 - 100.0] 62 (96.9) [89.2 - 99.6] 21 (100.0) [83.9 - 100.0] 6 (100.0) [54.1 - 100.0] False 0 (0.5) 2 (3.1) 0 0 1 don't know 0 0 0 0 0 Question 8: Which of the following are risk factors for opioid abuse? Please answer Yes, No, or I don't know for each option. 8a: A personal history of illness Yesm 11 (73.3) [44.9 - 92.2] 158 (84.0) [78.0 - 89.0] 59 (92.2) [82.7 - 97.4] 19 (90.5) [69.6 - 98.8] 6 (100.0) [54.1 - 100.0] N0 4 (26.7) 16 (8.5) 5 (7.8) 2 (9.5) 0 I don?t know 0 14 (7.4) 0 0 0 8b: A personal history of past or current alcohol or drug abuse, or a family history of illicit drug use or alcohol abuse Yesm 15 (100.0) [78.2 - 100.0] 188 (100.0) [98.1 - 64 (100.0) [94.4 - 100.0] 21 (100.0) [83.9 - 100.0] 6 (100.0) [54.1 - 100.0] 100.don't know 0 0 0 0 0 Question 12: Please answer True, False, or 1 don't know for each statement based on the labeling for TIRF medicines. 12a: TIR medicines can be abused in a manner similar to other opioid agonists. Data Source: ADPQ, ADTQ Program: TK RM S. SAS TRIG TIRF Prescriber KAB Page 2 of3 05JAN2017 Table 9.1.5: Responses to Questions Linked to Key Risk Message #3 by Number of Times Prescribing TIRF Medicines per Month Within the Last 6 Months - Completed Surveys Number of Times Prescribing TIRF Medicines per Month Within the Last 6 Months - 2 times 3 - 5 times More than 5 times I don't None per month per month per month remember Question [95% [95% cu"l [95% [95% cu'? [95% Truem 15 (100.0) [78.2 - 100.0] 179 (95.2) [91.1 - 97.8] 62 (96.9) [89.2 - 99.6] 21 (100.0) [83.9 - 100.0] 5 (83.3) [35.9 - 99.6] False 0 7 (3.7) 2 (3.1) 0 1 (16.7) ldon'tknow 0 2(1.l) 0 0 0 Question 22: Which of the following risks are associated with the use of TIRF medicines? Please answer True, False, or I don't know for the following statements. 22a: Misuse Truem 15 (100.0) [78.2 - 100.0] 185 (98.4) [95.4 - 99.7] 63 (98.4) [91.6 - 100.0] 21 (100.0) [83.9 - 100.0] 6 (100.0) [54.1 - 100.0] False 0 3 (1.6) (1.6) 0 I don't know 0 0 0 0 0 22b: Abuse Truem 15 (100.0) [78.2 - 100.0] 185 (98.4) [95.4 - 99.7] 64 (100.0) [94.4 - 100.0] 21 (100.0) [83.9 - 100.0] 6 (100.0) [54.1 - 100.0] False 0 2 (1.1) 0 0 0 [don't know 0 (0.5) 0 0 0 220: A ddiction Truem 15 (100.0) [78.2 - 100.0] 185 (98.4) [95.4 - 99.7] 64 (100.0) [94.4 - 100.0] 21 (100.0) [83.9 - 100.0] 6 (100.0) [54.1 - 100.0] False 0 3 (1.6) 0 0 0 I don't know 0 0 0 0 Data Source: ADPQ, ADTQ Program: TK RM S. SAS TRIG TIRF Prescriber KAB Page 3 of3 05JAN2017 Table 9.1.5: Responses to Questions Linked to Key Risk Message #3 by Number of Times Prescribing TIRF Medicines per Month Within the Last 6 Months - Completed Surveys Number of Times Prescribing TIRF Medicines per Month Within the Last 6 Months - 2 times 3 - 5 times More than 5 times I don't None per month per month per month remember Question [95% [95% cu"I [95% [95% cu'? [95% cu"I 22d: Overdose Truem 15 (100.0) [78.2 - 100.0] 187 (99.5) [97.1 - 100.0] 63 (98.4) [91.6 - 100.0] 21 (100.0) [83.9 - 100.0] 6 (100.0) [54.1 - 100.0] False 0 1 (0.5) 1 (1.6) 0 0 1 don?t know 0 0 0 0 0 22c: ypothyroidism True 1 (6.7) 13 (6.9) 4 (6.3) 2 (9.5) 0 Falsem 9 (60.0) [32.3 - 83.7] 148 (78.7) [72.2 - 84.3] 54 (84.4) [73.1 - 92.2] 17 (81.0) [58.1 - 94.6] 4 (66.7) [22.3 - 95.7] I don't know 5 (33.3) 27 (14.4) 6 (9.4) 2 (9.5) 2 (33.3) 22f: Infection True 1 (6.7) 15 (8.0) 3 (4.7) 4 (19.0) 0 Falsem 12 (80.0) [51.9 - 95.7] 159 (84.6) [78.6 - 89.4] 60 (93.8) [84.8 - 98.3] 17 (81.0) [58.1 - 94.6] 5 (83.3) [35.9 - 99.6] [don?t know 2 (13.3) 14 (7.4) 1 (1.6) 0 1 (16.7) Source: Appendix B: Survey Tables, Table 9.1.5 ?195% exact two-sided confidence intervals are calculated using the Clapper-Pearson method. Correct response. Data Source: ADPQ. ADTQ Program: TK RM S. SAS TRIG TIRF Prescriber KAB Page 1 of2 05JAN2017 Table 9.1.6: Responses to Questions Linked to Key Risk Message #3 by Practicing in a Closed Healthcare System - Completed Surveys Question Practicing in a Closed Healthcare System Yes [95% No [95% Question 7: Please answer True, False, or I don't know for each statement based on the labeling for TIRF medicines. 7e: It is important to monitor for signs of abuse and addiction in patients who take TIRF medicines. True 4 (100.0) [39.8 - 100.0] 287 (99.0) [97.0 - 99.8] False 0 3 (1.0) 1 don't know 0 0 Question 8: Which of the following are risk factors for opioid abuse? Please answer Yes, No, or I don't know for each option. 8a: A personal history of illness Yesm 4 (100.0) [39.8 100.0] 249 (85.9) [81.3 - 89.7] N0 0 27 (9.3) I don't know 0 14 (4.8) 8b: A personal history of past or current alcohol or drug abuse, or a family history of illicit drug use or alcohol abuse Yesm 4 (100.0) [39.8 - 100.0] 290 (100.0) [98.7 - 1000] No 0 0 1 don't know 0 0 Question 12: Please answer True, False, or I don't know for each statement based on the labeling for TIRF medicines. 12a: TIRF medicines can be abused in a manner similar to other opioid agonists. Truem 4 (100.0) [39.8 - 100.0] 278 (95.9) [92.9 - 97.8] False 0 10 (3.4) I don't know 0 2 (0.7) Question 22: Which of the following risks are associated with the use of TIRF medicines? Please answer True, False, or I don't know for the following statements. 22a: Misuse Truem 4 (100.0) [39.8 - 100.0] 286 (98.6) [96.5 - 99.6] False 0 4 (1.4) [don't know 0 0 Data Source: ADPQ, ADTQ Program: TK RM S. SAS TRIG TIRF Prescriber KAB Page 2 of 2 05JAN 2017 Table 9.1.6: Responses to Questions Linked to Key Risk Message #3 by Practicing in a Closed Healthcare System - Completed Surveys Practicing in a Closed Healthcare System Yes No Question 11 [95% Cll'" [95% cu'" 22b: Abuse Truem 4 (100.0) [39.8 - 100.0] 287 (99.0) [97.0 - 99.8] False 0 2 (0.7) [don't know 0 1 (0.3) 22c: A ddiction Truem 4 (100.0) [39.8 - 100.0] 287 (99.0) [97.0 - 99.8] False 0 3 (1.0) I don't know 0 0 22d: Overdose Truem 4 (100.0) [39.8 - 100.0] 288 (99.3) [97.5 - 99.9] False 0 2 (0.7) 1 don?t know 0 0 22e: ypoth yroidism True 0 20 (6.9) Falsem 4 (100.0) [39.8 - 100.0] 228 (78.6) [73.4 - 83.2] 1 don't know 0 42 (14.5) 22f: Infection True 0 23 (7.9) Falsem 3 (75.0) [19.4 - 99.4] 250 (86.2) [81.7 90.0] 1 don't know 1 (25.0) 17 (5.9) Source: Appendix B: Survey Tables, Table 9.1.6 ?195% exact two-sided confidence intervals are calculated using the Clopper-Pearson method. Correct response. Data Source: ADPQ, ADTQ Program: TK RM S. SAS TRIG TIRF Prescriber KAB Page 1 of] 05JAN2017 Completed Surveys Table 9.2: Secondary Analysis of Responses to Questions Linked to Key Risk Message #3 - Prescribers Correct Responses 0 correct responses 0 1 correct response 0 2 correct responses 0 3 correct responses 0 4 correct responses 0 5 correct responses 1 (0.3) 6 correct responses 2 (0.7) 7 correct responses 7 (2.4) 8 correct responses 33 (l 1.2) 9 correct responses 71 (24.1) 10 correct responses 180 (61.2) Source: Appendix B: Survey Tables, Table 9.2 Data Source: ADPQ, ADTQ Program: TRIG TIRF Prescriber KAB Page 1 of] 05JAN2017 Completed Surveys Table 10.1: Primary Analysis of Responses to Questions Linked to Key Risk Message #4 - Question Prescribers [95% medicines. Question 12: Please answer True, False, or I don't know for each statement based on the labeling for TIRF 12b: TIRF medicines are interchangeable with each other regardless of route of administration. True 15 (5.1) Falsem 271 (92.2) [88.5 - 95.0] [don't know 8 (2.7) of differences in the pharmacokinetics of fentanyl absorption. 12c: The conversion of one TIRF medicine for another TIRF medicine may result in a fatal overdose because Truem 283 (96.3) [93 .4 - 98.1] False 5 (1.7) 1 don't know 6 (2.0) 12d: Dosing of TIRF medicines is not equivalent on a microgram-to-microgram basis. Truem 269 (91.5) [87.7 - 94.4] False 11 (3.7) 1 don't know 14 (4.8) one option. Question 16: A patient is already taking a TIRF medicine but wants to change their medicine. His/her doctor decides to prescribe a different TIRF medicine (that is not a bioeq uivalent generic version of a branded product) in its place. According to the labeling, how should the prescriber proceed? Please select The prescriber can safely convert to the equivalent dosage of the new TIRF medicine as it has the same effect as other TIRF medicines. 5(1.7) The prescriber must not convert to another TIRF medicine on a microgram-per-microgram basis because these medicines have different absorption properties and this could result in a fentanyl overdose? 231 (78.6) [73.4 - 83.1] Convert ??om the other TIRF medicine to the new TIRF medicine at half of the dose. 25 (8.5) The prescriber should base the starting dose of the newly-prescribed TIRF medicine 21 (7.1) on the dose of the opioid medicine used for their underlying persistent cancer pain. 1 don't know. 12 (4.1) Source: Appendix B: Survey Tables, Table 10.1 95% exact two-sided con?dence intervals are calculated using the Clopper-Pearson method. Correct response. Data Source: ADPQ, ADTQ Program: TIRF Prescriber KAB Page 1 of2 05JAN2017 Table 10.1.1: Responses to Questions Linked to Key Risk Message #4 by Reading Full Prescribing Information or Medication Guide - Completed Surveys Question Reading Full Prescribing Information or Medication Guide Received and read Pl or Med Guide [95% C1]Ill Did not receive or read P1 or Med Guide [95% C1]Ill Question 12: Please answer True, False, or I don't know for each statement based on the labeling for TIRF medicines. 12b: TIRF medicines are interchangeable with each other regardless of route of administration. True 12 (4.5) 3 (11.5) Falsem 249 (92.9) [89.2 - 95.7] 22 (84.6) [65.1 - 95.6] [don't know 7 (2.6) 1 (3.8) 12c: The conversion of one TIRF medicine for another TIRF medicine may result in a fatal overdose because of differences in the pharmacokinetics of fentanyl absorption. Truem 259 (96.6) [93.7 - 98.5] 24 (92.3) [74.9 - 99.1] False 4 (1.5) (3.8) [don't know 5 (1.9) (3.8) 12d: Dosing of TIRF medicines is not equivalent on a microgram-to-microgram basis. Truem 246 (91.8) [87.8 - 94.8] 23 (88.5) [69.8 - 97.6] False 10 (3.7) (3.8) 1 don't know 12 (4.5) 2 (7.7) Question 16: A patient is already taking a TIRF medicine but wants to change their medicine. His/her doctor decides to prescribe a different TIRF medicine (that is not a bioeq uivalent generic version of a branded product) in its place. According to the labeling, how should the prescriber proceed? Please select one option. The prescriber can safely convert to the equivalent dosage of the new TIRF medicine as it has the same effect as other TIRF medicines. 4(1.5) 1 (3.8) The prescriber must not convert to another TIRF medicine on a microgram-per-microgram basis because these medicines have different absorption properties and this could result in a fentanyl overdoselz] 217 (81.0) [75.8 85.5] 14 (53.8) [33.4 73.4] Convert from the other TIRF medicine to the new TIRF medicine at half of the dose. 20 (7.5) 5 (19.2) Data Source: ADPQ, ADTQ Program: TK RM S. SAS TIRF Prescriber KAB Page 2 of 2 05JAN 2017 Table Responses to Questions Linked to Key Risk Message #4 by Reading Full Prescribing Information or Medication Guide - Completed Surveys Reading Full Prescribing Information or Medication Guide Received and read Did not receive or read P1 or Med Guide P1 or Med Guide Question [95% Cll'" cm [95% cu'" The prescriber should base the starting dose of 18 (6.7) 3 (1 1.5) the newly-prescribed TIRF medicine on the dose of the opioid medicine used for their underlying persistent cancer pain. [don't know. 9 (3.4) 3 (11.5) Source: Appendix B: Survey Tables, Table 10.1.1 ?195% exact two-sided con?dence intervals are calculated using the Clopper-Pearson method. Correct response. Data Source: ADPQ, ADTQ Program: TK RM S. SAS TRIG Page 1 of 3 TIRF Prescriber KAB 05JAN2017 Table 10.1.2: Responses to Questions Linked to Key Risk Message #4 by Medical Degree of Respondent - Completed Surveys Medical Degree of Respondent MD DO Nurse Practitioner Physician Assistant (N=l67) Question [95% [95% 11 [95% cu'" [95% Cll'" Question 12: Please answer True, False, or I don't know for each statement based on the labeling for TIRF medicines. 12b: TIRF medicines are interchangeable with each other regardless of route of administration. True 9 (5.4) 2 (7.7) 3 (5.7) (2.2) Falsem 156 (93.4) [88.5 - 96.7] 24 (92.3) [74.9 99.1] 49 (92.5) [81.8 - 97.9] 40 (87.0) [73.7 - 95.1] [don't know 2 (1.2) 0 1 (1.9) 5 (10.9) 12c: The conversion of one TIRF medicine for another TIRF medicine may result in a fatal overdose because of differences in the pharmacokinetics of fentanyl absorption. Truem 163 (97.6) [94.0 - 99.3] 25 (96.2) [80.4 - 99.9] 51 (96.2) [87.0 99.5] 42 (91.3) [79.2 - 97.6] False 2 (1.2) 0 2 (3.8) (2.2) I don't know 2 (1.2) (3.8) 0 3 (6.5) 12d: Dosing of TIRF medicines is not equivalent on a microgram-to-microgram basis. Truem 156 (93.4) [88.5 - 96.7] 24 (92.3) [74.9 - 99.1] 45 (84.9) [72.4 - 93.3] 42 (91.3) [79.2 - 97.6] False 3 (1.8) 2 (7.7) 5 (9.4) (2.2) [don't know 8 (4.8) 0 3 (5.7) 3 (6.5) Question 16: A patient is already taking a TIRF medicine but wants to change their medicine. His/her doctor decides to prescribe a different TIRF medicine (that is not a bioequivalent generic version of a branded product) in its place. According to the labeling, how should the prescriber proceed? Please select one option. Data Source: ADPQ. ADTQ Program: TRIG Page 2 of 3 TIRF Prescriber KAB 05JAN2017 Table 10.1.2: Responses to Questions Linked to Key Risk Message #4 by Medical Degree of Respondent - Completed Surveys Medical Degree of Respondent MD DO Nurse Practitioner Physician Assistant (N=l67) Question [95% [95% Cll'" [95% cu'" [95% The prescriber can safely 2 (l2) 0 0 3 (6.5) convert to the equivalent dosage of the new TIRF medicine as it has the same effect as other TIRF medicines. The prescriber must not convert to another TIRF medicine on a microgram-per-microgram basis because these medicines have different absorption properties and this could result in a fentanyl overdosem 135 (80.8) [74.0 - 86.5] 23 (88.5) [69.8 - 97.6] 39 (73.6) [59.7 - 84.7] 32 (69.6) [54.2 - 82.3] Convert from the other TIRF medicine to the new TIRF medicine at half of the dose. 14 (8.4) 2 (7.7) 4 (7.5) 5 (10.9) Data Source: ADPQ, ADTQ Program: TK RM S. SAS TRIG Page 3 of 3 TIRF Prescriber KAB 05JAN2017 Table 10.1.2: Responses to Questions Linked to Key Risk Message #4 by Medical Degree of Respondent - Completed Surveys Medical Degree of Respondent MD DO Nurse Practitioner Physician Assistant (N=l67) Question 95% cu'? 95% cu'? 95% cu'" 95% The should base 11 (6.6) (3.8) 6 (11.3) 3 (6.5) the starting dose of the newly-prescribed TIRF medicine on the dose of the opioid medicine used for their underlying persistent cancer pain. [don't know. 5 (3.0) 0 4 (7.5) 3 (6.5) Source: Appendix B: Survey Tables, Table 10.1.2 95% exact two-sided confidence intervals are calculated using the lopper-Pearson method. Correct response. Data Source: ADPQ, ADTQ Program: TRIG TIRF Prescriber KAB Page 1 of2 05JAN2017 Survey - Completed Surveys Table 10.1.3: Responses to Questions Linked to Key Risk Message #4 by Modality to Complete Question Modality to Complete Survey Internet [95% Telephone [95% medicines. Question 12: Please answer True, False, or I don't know for each statement based on the labeling for TIRF 12b: TIRF medicines are interchangeable with each other regardless of route of administration. True 15 (5.2) 0 Falsem 266 (92.0) [88.3 - 94.9] 5 (100.0) [47.8 - 100.0] I don?t know 8 (2.8) 0 12c: The conversion of one TIRF medicine for another TIRF medicine may result in a fatal overdose because of differences in the pharmacokinetics of fentanyl absorption. Truem 278 (96.2) [93.3 - 98.1] 5 (100.0) [47.8 - 100.0] False 5 (1.7) 0 I don't know 6 (2.1) 0 12d: Dosing of TIRF medicines is not equivalent on a microgram-to-microgram basis. Truem 264 (91.3) [87.5 94.3] 5 (100.0) [47.8 100.0] False 11 (3.8) 0 i don't know 14 (4.8) 0 Question 16: A patient is already taking a TIRF medicine but wants to change their medicine. His/her doctor decides to prescribe a different TIRF medicine (that is not a bioeq uivalent generic version of a branded product) in its place. According to the labeling, how should the prescriber proceed? Please select one option. The prescriber can safely convert to the equivalent dosage of the new TIRF medicine as it has the same effect as other TIRF medicines. 5(1.7) 0 The prescriber must not convert to another TIRF medicine on a microgram-per-microgram basis because these medicines have different absorption properties and this could result in a fentanyl overdoselzl 226 (78.2) [73.0 - 82.8] 5 (100.0) [47.8 - 100.0] Convert from the other TIRF medicine to the new TIRF medicine at half of the dose. 25 (8.7) 0 Data Source: ADPQ. ADTQ Program: TRIG Page 2 of 2 TIRF Prescriber KAB 05JAN2017 Table 10.1.3: Responses to Questions Linked to Key Risk Message #4 by Modality to Complete Survey - Completed Surveys Modality to Complete Survey Internet Telephone Question [95% Cum [95% cu'? The prescriber should base the starting dose of 21 (7.3) 0 the newly-prescribed TIRF medicine on the dose of the opioid medicine used for their underlying persistent cancer pain. [don't know. 12 (4.2) 0 Source: Appendix B: Survey Tables, Table 10.1.3 95% exact two-sided con?dence intervals are calculated using the Clopper-Pearson method. Correct response. Data Source: ADPQ, ADTQ Program: TRIG TIRF Prescriber KAB Page 1 of3 05JAN2017 Table 10.1.4: Responses to Questions Linked to Key Risk Message #4 by Time Practicing Medicine - Completed Surveys Question Time Practicing Medicine Less than 3 years [95% C1[Ill 3 to 5 years [95% 6 to 15 years [95% More than 15 years (N=l34) [95% Question 12: Please answer True, False, or I don't know for each statement based on the labeling for TIRF medicines. 12b: TIRF medicines are interchangeable with each other regardless of route of administration. True 2 (7.7) 0 6 (7.1) 7 (5.2) Falsem 24 (92.3) [74.9 - 99.1] 45 (91.8) [80.4 97.7] 77 (90.6) [82.3 - 95.8] 125 (93.3) [87.6 96.9] [don't know 0 4 (8.2) 2 (2.4) 2 (1.5) 12c: The conversion of one TIRF medicine for another TIRF medicine may result in a fatal overdose because of differences in the pharmacokinetics of fentanyl absorption. Truem 25 (96.2) [80.4 - 99.9] 47 (95.9) [86.0 - 99.5] 81 (95.3) [88.4 98.7] 130 (97.0) [92.5 - 99.2] False 1 (3.8) 0 1 (1.2) 3 (2.2) [don't know 0 2 (4.1) 3 (3.5) (0.7) 12d: Dosing of TIRF medicines is not equivalent on a microgram-to-microgram basis. Truem 20 (76.9) [56.4 - 91.0] 43 (87.8) [75.2 - 95.4] 76 (89.4) [80.8 - 95.0] 130 (97.0) [92.5 - 99.2] False 3 (11.5) 2 (4.1) 3 (3.5) 3 (2.2) [don't know 3 (11.5) 4 (8.2) 6 (7.1) 1 (0.7) Question 16: A patient is already taking a TIRF medicine but wants to change their medicine. His/her doctor decides to prescribe a different TIRF medicine (that is not a bioequivalent generic version of a branded product) in its place. According to the labeling, how should the prescriber proceed? Please select one option. Data Source: ADPQ. ADTQ Program: TK RM S. SAS TRIG TIRF Prescriber KAB Page 2 of3 05JAN2017 Table 10.1.4: Responses to Questions Linked to Key Risk Message #4 by Time Practicing Medicine - Completed Surveys Time Practicing Medicine convert to the equivalent dosage of the new TIRF medicine as it has the same effect as other TIRF medicines. Less than 3 years 3 to 5 years 6 to 15 years More than 15 years (N=l34) Question [95% [95% Cll'" [95% cu'" [95% The prescriber can safely 0 3 (6.1) 0 2 (1.5) The prescriber must not convert to another TIRF medicine on a microgram-per-microgram basis because these medicines have different absorption properties and this could result in a fentanyl overdosem 18 (69.2) [48.2 - 85.7] 39 (79.6) [65.7 - 89.8] 66 (77.6) [67.3 - 86.0] 108 (80.6) [72.9 - 86.9] Convert from the other TIRF medicine to the new TIRF medicine at half of the dose. 2 (7.7) 3(6.l) 6(7.1) 14 (10.4) Data Source: ADPQ, ADTQ Program: TK RM S. SAS TRIG Page 3 of 3 TIRF Prescriber KAB 05JAN2017 Table 10.1.4: Responses to Questions Linked to Key Risk Message #4 by Time Practicing Medicine - Completed Surveys Time Practicing Medicine Less than 3 years 3 to 5 years 6 to 15 years More than 15 years (N=l34) Question 95% cu'? 95% cu'? 95% cu'" 95% The should base 3 (11.5) 3 (6.1) 9 (10.6) 6 (4.5) the starting dose of the newly-prescribed TIRF medicine on the dose of the opioid medicine used for their underlying persistent cancer pain. [don't know. 3 (11.5) 1 (2.0) 4 (4.7) 4 (3.0) Source: Appendix B: Survey Tables, Table 10.1.4 95% exact two-sided confidence intervals are calculated using the lopper-Pearson method. Correct response. Data Source: ADPQ, ADTQ Program: TK RM S. SAS TRIG TIRF Prescriber KAB Page 1 of3 05JAN2017 Table 10.1.5: Responses to Questions Linked to Key Risk Message #4 by Number of Times Prescribing TIRF Medicines per Month Within the Last 6 Months - Completed Surveys Question Number of Times Prescribing TIRF Medicines per Month Within the Last 6 Months - 2 times 3 - 5 times More than 5 times 1 don't None per month per month per month remember [95% [95% cu"l [95% [95% [95% Question 12: Please answer True, False, or I don 't know for each statement based on the labeling for TIRF medicines. 12b: TIRF medicines are interchangeable with each other regardless of route of administration. True 1 (6.7) 5 (2.7) 6 (9.4) 3 (14.3) 0 Falsem 14 (93.3) [68.1 - 99.8] 177 (94.1) [89.8 - 97.0] 57 (89.1) [78.8 - 95.5] 17 (81.0) [58.1 - 94.6] 6 (100.0) [54.1 - 100.0] [don?t know 0 6 (3.2) (1.6) (4.8) 0 12c: The conversion of one TIRF medicine for another TIRF medicine may result in a fatal overdose because of differences in the pharmacokinetics of fentanyl absorption. Truem 14 (93.3) [68.1 - 99.8] 181 (96.3) [92.5 - 98.5] 62 (96.9) [89.2 - 99.6] 20 (95.2) [76.2 - 99.9] 6 (100.0) [54.1 - 100.0] False (6.7) 3 (1.6) (1.6) 0 0 [don't know 0 4 (2.1) (1.6) (4.8) 0 12d: Dosing of TIRF medicines is not equivalent on a microgram-to-microgram basis. Truem 13 (86.7) [59.5 - 98.3] 172 (91.5) [86.5 - 95.1] 60 (93.8) [84.8 98.3] 19 (90.5) [69.6 - 98.8] 5 (83.3) [35.9 - 99.6] False 0 7 (3.7) 2 (3.1) 2 (9.5) 0 [don't know 2 (13.3) 9 (4.8) 2 (3.1) 1 (16.7) Question 16: A patient is already taking a TIRF medicine but wants to change their medicine. His/her doctor decides to prescribe a different TIRF medicine (that is not a bioequivalent generic version of a branded product) in its place. According to the labeling, how should the prescriber proceed? Please select one option. Data Source: ADPQ. ADTQ Program: TRIG TIRF Prescriber KAB Page 2 of3 05JAN2017 Table 10.1.5: Responses to Questions Linked to Key Risk Message #4 by Number of Times Prescribing TIRF Medicines per Month Within the Last 6 Months - Completed Surveys Number of Times Prescribing TIRF Medicines per Month Within the Last 6 Months - 2 times 3 - 5 times More than 5 times I don't None per month per month per month remember Question [95% [95% [95% [95% [95% The prescriber can safely 0 3 (1.6) (1.6) (4.8) 0 convert to the equivalent dosage of the new TIRF medicine as it has the same effect as other TIRF medicines. The prescriber must not convert to another TIRF medicine on a microgram-per-microgra basis because these medicines have different absorption properties and this could result in a fentanyl overdosem 14 (93.3) [68.1 - 99.8] 145 (77.1) [70.5 - 82.9] 55 (85.9) [75.0 - 93.4] 15 (71.4) [47.8 - 88.7] 2 (33.3) [4.3 - 77.7] Convert from the other TIRF medicine to the new TIRF medicine at half of the dose. 15 (8.0) 4 (6.3) 4 (19.0) 2 (33.3) Data Source: ADPQ, ADTQ Program: TK RM S. SAS TRIG Page 3 of 3 TIRF Prescriber KAB 05JAN2017 Table 10.1.5: Responses to Questions Linked to Key Risk Message #4 by Number of Times Prescribing TIRF Medicines per Month Within the Last 6 Months - Completed Surveys Number of Times Prescribing TIRF Medicines per Month Within the Last 6 Months 1 - 2 times 3 - 5 times More than 5 times I don't None per month per month per month remember Question [95% [95% cu"I [95% [95% cu'? [95% cu"I The prescriber should 0 17 (9.0) 3 (4.7) (4.8) 0 base the starting dose of the newly-prescribed TIRF medicine on the dose of the opioid medicine used for their underlying persistent cancer pain. [don?t know. 1 (6.7) 8 (4.3) 1 (1.6) 0 2 (33.3) Source: Appendix B: Survey Tables, Table 10.1.5 95% exact two-sided confidence intervals are calculated using the lopper-Pearson method. Correct response. Data Source: ADPQ, ADTQ Program: TRIG TIRF Prescriber KAB Page 1 of2 05JAN2017 Healthcare System - Completed Surveys Table 10.1.6: Responses to Questions Linked to Key Risk Message #4 by Practicing in a Closed Question Practicing in a Closed Healthcare System Yes [95% No [95% medicines. Question 12: Please answer True, False, or I don't know for each statement based on the labeling for TIRF 12b: TIRF medicines are interchangeable with each other regardless of route of administration. True 0 15 (5.2) Falsem 4 (100.0) [39.8 - 100.0] 267 (92.1) [88.3 - 94.9] [don?t know 0 8 (2.8) 12c: The conversion of one TIRF medicine for another TIRF medicine may result in a fatal overdose because of differences in the pharmacokinetics of fentanyl absorption. Truem 4 (100.0) [39.8 - 100.0] 279 (96.2) [93.3 - 98.1] False 0 5 (1.7) I don't know 0 6 (2.1) 12d: Dosing of TIRF medicines is not equivalent on a microgram-to-microgram basis. Truem 4 (100.0) [39.8 - 100.0] 265 (91.4) [87.5 - 94.3] False 0 11 (3.8) i don't know 0 14 (4.8) one option. Question 16: A patient is already taking a TIRF medicine but wants to change their medicine. His/her doctor decides to prescribe a different TIRF medicine (that is not a bioeq uivalent generic version of a branded product) in its place. According to the labeling, how should the prescriber proceed? Please select The prescriber can safely convert to the equivalent dosage of the new TIRF medicine as it has the same effect as other TIRF medicines. 1 (25.0) 4(1.4) The prescriber must not convert to another TIRF medicine on a microgram-per-microgram basis because these medicines have different absorption properties and this could result in a fentanyl overdoselzl 3 (75.0) [19.4 - 99.4] 228 (78.6) [73.4 83.2] Convert from the other TIRF medicine to the new TIRF medicine at half of the dose. 25 (8.6) Data Source: ADPQ. ADTQ Program: TK RM S. SAS TRIG Page 2 of 2 TIRF Prescriber KAB 05JAN2017 Table 10.1.6: Responses to Questions Linked to Key Risk Message #4 by Practicing in a Closed Healthcare System - Completed Surveys Practicing in a Closed Healthcare System Yes No Question [95% Cum [95% cu'? The prescriber should base the starting dose of 0 21 (7.2) the newly-prescribed TIRF medicine on the dose of the opioid medicine used for their underlying persistent cancer pain. [don't know. 0 12 (4.1) Source: Appendix B: Survey Tables, Table 10.1.6 95% exact two-sided con?dence intervals are calculated using the Clopper-Pearson method. Correct response. Data Source: ADPQ, ADTQ Program: TRIG TIRF Prescriber KAB Page 1 of] 05JAN2017 Completed Surveys Table 10.2: Secondary Analysis of Responses to Questions Linked to Key Risk Message #4 - Prescribers Correct Responses 0 correct responses 2 (0.7) 1 correct response 3 (1.0) 2 correct responses 22 (7.5) 3 correct responses 61 (20.7) 4 correct responses 206 (70.1) Source: Appendix B: Survey Tables, Table 10.2 Data Source: ADPQ, ADTQ Program: TRIG Page 1 of] TIRF Prescriber KAB 05JAN2017 Table 11: Average Knowledge Scores - Completed Surveys Score [95% KRM #1 87.4 [85.8, 89.0] KRM #2 86.3 [84.6, 88.0] KRM #3 94.2 [93.2, 95.2] KRM #4 89.6 [87.5, 91.7] Overall Knowledge Score 89.1 [88.0, 90.2] Source: Appendix B: Survey Tables, Table 11 95% C15 are constructed based on normal distribution function. Data Source: ADPQ, ADTQ Program: TRIG TIRF Prescriber KAB Page 1 of2 31JAN2017 Table 12: Types of Chronic Pain Conditions Reported - Completed Surveys for Prescribers Who Prescribed TIRF Medicines for Chronic Non-Cancer Pain Prescribers Question Question 10: For what type(s) of chronic non-cancer pain conditions do you prescribe a TIRF medicine to opioid tolerant patients? Total Number of Response Sm 80 Back Pain 9 (16.7) Chronic Pain 8 (14.8) Cancer Pain 6 (l 1.1) Not Applicable 6 (l 1.1) Failed Back 4 (7.4) Arachnoiditis 2 (3.7) Bone Pain 2 (3.7) Breakthrough Pain 2 (3.7) Degenerative Disc Disease 2 (3.7) Failed Spine Surgery 2 (3.7) ibromyalgia 2 (3.7) Neck Pain 2 (3.7) Neuropathy 2 (3.7) Orthopedic Pain 2 (3.7) Post Laminectomy 2 (3.7) Re?ex Sympathetic Distrophy 2 (3.7) Spondylosis 2 (3.7) AIDS 1 (1.9) Arthritic Pain 1 (1.9) Cannot be Categorized 1 (1.9) Cervicalgia 1 (1.9) Chronic Regional Pain (1.9) Crohn's Disease 1 (1.9) (1.9) Facial Pain 1 (1.9) Data Source: ADPQ, _Qll Program: TCATQSAS TRIG Page 2 of 2 TIRF Prescriber KAB 31JAN2017 Table 12: Types of Chronic Pain Conditions Reported - Completed Surveys for Prescribers Who Prescribed TIRF Medicines for Chronic Non-Cancer Pain Prescribers Question Failed Neck (1.9) Headache 1 (1.9) lntractable Pain 1 (1.9) Knee Pain 1 (1.9) Multiple Autoimmune Disease 1 (1.9) Multiple Sclerosis (1.9) Neuralgia (1.9) Pancreatitis (1.9) Peripheral Neuropathic Pain 1 (1.9) Phantom Limb Pain 1 (1.9) Polyneuropathy (1.9) Rheumatoid Arthritis 1 (1.9) Spinal Stenosis 1 (1.9) Spine Pain 1 (1.9) Torticollis (1.9) Source: Appendix B: Survey Tables, Table 12 Number and percentages are based on the subset of completed surveys where prescribers responded "Yes" to prescribing TIRF medicines for chronic non-cancer pain (Question 9e: Per the approved labeling for TIRF medicines, for which of the following indication(s) are TIRF medicines approved? Chronic Non Cancer Pain "Yes") and were subsequently presented Question 10 and Question 11. Total number of responses may exceed the number of prescribers and percentages may not equal 100% as multiple responses were provided by some prescribers. Data Source: ADPQ, _Qlo, _Qll Program: TCATQSAS TRIG Page 1 of TIRF Prescriber KAB 31JAN2017 Table 13: Reasons for Selecting a TIRF Medicine Reported - Completed Surveys for Prescribers Who Prescribed TIRF Medicines for Chronic Non-Cancer Pain Prescribers Question Question 11: Why do you select a TIRF medicine to treat these chronic pain conditions in patients who are opioid tolerant? Total Number of Response Sm 62 Ef?cacy 13 (24.1) 1 Do Not Treat Non-Cancer Patients 7 (13.0) FastOnset 6(ll.l) Other Treatments Have Failed 6 (11.1) Not Applicable 5 (9.3) Ease of Use 3 (5.6) Exhausted Other Options 3 (5.6) Lack of Tolerance of Other Options 3 (5.6) Medication Was Initiated by Pain Specialist 3 (5.6) No Reason Provided 3 (5.6) Dosing Options 2 (3.7) Patient Preference 2 (3-7) Convenience 1 (1.9) Insurance Issues 1 (1.9) Long Lasting (1.9) Patient Lack of Tolerance of Other Options 1 (1.9) Safety 1 (1.9) Sustained Pain Relief 1 (1.9) Source: Appendix B: Survey Tables, Table 13 Number and percentages are based on the subset of completed surveys where prescribers responded "Yes" to prescribing TIRF medicines for chronic non-cancer pain (Question 9e: Per the approved labeling for TIRF medicines, for which of the following indication(s) are TIRF medicines approved? Chronic Non Cancer Pain "Yes") and were subsequently presented Question 10 and Question 11. Total number of responses may exceed the number of prescribers and percentages may not equal 100% as multiple responses were provided by some prescribers. Data Source: ADPQ, _Qll], _Qll Program: TCATQSAS TRIG Page 1 of 3 TI RF Prescriber KAB Listing Listing of Verbatim Responses to Question #10 (For what type(s) of chronic non-cancer pain conditions do you prescribe a medicine to opioid tolerant patients?) - Completed Surveys Survey Form Verbatim Responses 0005-000001 0005-000007 Failed back surgery torticollis, trigeminal neuralgia 0005-000011 I don't prescribe for chronic non cancer pain (outside of my scope of practice) 0005-000021 have prescribed these only to patient with chronic pain whom I have inherited and have been on these medications for several years and are stable. I do not start TIRF medications now with patients with non cancer pain. 0005-000026 Chronic back pain and neck pain 0005-000034 i don't usually 0005-000040 0005-000046 bone pain from progressive osteosarcoma 0005-000050 post-laminectomy 0005-0000 55 Severe bone pain related to fractures related to bone metastasis (stage IV cancer) 0005-000063 chronic severe pain uncontrolled by other opiates, cancer pain uncontrolled by other 0005-000072 I do not. I only treat cancer patients. 0005-000083 FAILED BACK 0005-000085 arachnoiditis, chronic LBP, chronic cervialgia 0005-000107 Fibromyalgia, rheumatoid arthritis 0005-0001 11 Failed back and orthopedic pain 0005-0001 13 chronic pain Sympathetic mediated Phantom limb pain 0005-0001 19 Severe spinal stenosis in opioid-tolerant patient 0005-000125 failed spine surgery 0005-000127 Degenerative disc disease, polyneuropathy 0005-000128 axial spine pain, chronic daily headache with execerbation, Chronic regional pain 0005-000139 I only see cancer and prescribe TIRF medications to cancer related pain 0005-000145 Patients already on along acting opioid of suf?cient dosing who require a breakthrough medication where other breakthrough medications do not work 0005-000210 Chronic knee pain due to joint degeneration, for lung metastases 0005-000228 chronic, intractable pain, mostly back pain have used for patients with GI absorption Data Source: ADPQ Program: LQCAT.SAS TRIG Page 2 of 3 TI RF Prescriber KAB Listing Listing of Verbatim Responses to Question #10 (For what type(s) of chronic non-cancer pain conditions do you prescribe a medicine to opioid tolerant patients?) - Completed Surveys Survey Form Verbatim Responses 0005-0002 55 post laminectomy 0005-000687 Patients who are narcotic dependent with pain?ll medical conditions, such as spinal tumors which are not canceror chronic orthopedic pain. 0005-000704 Chronic Pancreatitis 0005-000716 AIDS, one patient with multiple autoimmune diseases 0005-0007 53 chronic facial pain due to surgical complications 0005-0007 78 Severe back pain. 0005-000784 1 work in the oncology setting. All the patients are oncology patients. 0005-0007 89 Multiple sclerosis 0005-0008 82 I personally dont presecn'be for non cancer pain 0005-0009 89 I only prescribe to patients for cancer pain 0005-000996 0005-001005 Chronic pain not improved with alternative treatments. 0005-001042 severe neuropathy associated with HIV, chronic low back pain associated with disc disease, severe diffuse arthritic pain 0005-001044 Chronic Low back pain 0005-001053 None, only prescribe for cancer pain 0005-001081 RSD, Failed spine surgery, arachnoiditis, back pain due to degenerative discs and spondylosis 0005-001090 Failed surgical of back or neck 0005-001 107 Im a cancer specialist and have not prescribe meds for noncancer pts. Based from a rep they used it for severe debilitating chronic back pain 0005-001 121 lumbar and cervical spondylosis 0005-001 135 post chemotherapy and radiation therapy neuropathy for patients with history of cancer 0005-001 137 chronic back pain 0005-001205 Subsys. Lazanda, Fentanyl patch, Actiq, Abstral, 0005-001207 severe back or neck pain 0005-001210 A patient with chronic pain due to chronic, life-limiting illness for whom all other non-opioid pharmacologic and non-pharmacologic pain measures have been maximized for episodic breakthrough pain. 0005-001220 degenerative disc disease for which surgical intervention is not an option. Data Source: ADPQ Program: LQCAT.SAS TRIG TIRF Prescriber KAB Page 3 of3 Completed Surveys Listing Listing of Verbatim Responses to Question #10 (For what type(s) of chronic non-cancer pain conditions do you prescribe a TIRF medicine to opioid tolerant patients?) - Survey Form Verbatim Responses 0005-001243 chronic pain which is severe in nature 0005-001250 ?bromyalgia 0005-001322 Peripheral neuropathic pain 0005-001328 RSD Note: Question 10 is only asked if Question 9c is answered "Yes". Data Source: ADPQ Program: LQCAT.SAS TRIG Page 1 of] TIRF Prescriber KAB Listing 1.2: Listing of Verbatim Responses to Question #10 (For what type(s) of chronic non-cancer pain conditions do you prescribe a TIRF medicine to opioid tolerant patients?) - Incomplete Surveys Survey Form Verbatim Responses 0005-001040 Chronic pancreatitis, chronic musculoskeletal conditions. 0005-001087 Severe, chronic abdominal pain 0005-001177 central pain DOGS-001260 degenerative disc diseases of spine,stenosis, radiculopathy, hemiated disc, spondylosis, spondylolysis, and all other chronic pain in the spine. Note: Question 10 is only asked if Question 9e is answered "Yes". Data Source: ADPQ Program: LQCAT.SAS TRIG Page 1 of 3 Tl RF Prescriber KAB Listing 2.1: Listing of Verbatim Responses to Question #11 (Why do you select a medicine to treat these chronic non-cancer pain conditions in patients who are opioid tolerant?) - Completed Surveys Survey Form Verbatim Responses 0005-000001 I 0005-000007 Quick onset, selective dosing 0005-000011 I don't see this type of patient. If I did, would best be used for transient elevations in pain, due to quicker onset of the drug. 0005-000021 I do not. 0005-000026 because they offer pain relief fast 0005-000034 i don't 0005-000040 do not tolerate other therapies 0005-000046 I am an oncologist, so I would not treat non-cancer patients 0005-000050 fast onset of relief for breakthrough pain 0005-000055 works well with pain management 0005-000063 long lasting, good control less breakthrough pain 0005-000072 not applicable 0005-0000 83 EFFICACY AN CONVENIENCE 0005-0000 85 ease of use 0005-000107 They work well for the pain 0005-0001 11 Better pain control 0005-0001 13 These medications are selected after failing other conservative treatments and initial low dose opioid therapy 0005-0001 19 Severe incident (movemnt-related) pain 0005-000125 for patients who are opioid tolerant but have problematic side effects with other opioid preparations. 0005-000127 Fentanyl is very effective in reducing pain 0005-000128 episodic nature of the pain 0005-000139 n/a 0005-000145 No other medication for breakthrough has been effective and have maxed out long acting meds 0005-000210 Patient's previous use of this medication for these indications 0005-000228 fast acting controlled dosing 0005-0002 55 chronic pain condition Data Source: ADPQ Program: LQCAT.SAS TRIG Page 2 of 3 TI RF Prescriber KAB Listing 2.1: Listing of Verbatim Responses to Question #11 (Why do you select a TIRF medicine to treat these chronic non-cancer pain conditions in patients who are opioid tolerant?) - Completed Surveys Survey Form Verbatim Responses 0005-0006 87 It was started by anaesthesiologist or pain medicine specialist I only continued what had been started elsewhere. 0005-000704 Because the GI population o?en cannot tolerate or absorb traditional oral opioid meds. 0005-000716 fast onset for severe pain 0005-0007 53 was chosen by patients chronic pain doctor 0005-0007 78 Due to opioid tolerant. 0005-000784 na 0005-0007 89 patient preference or positive response with fentanyl patch who need short acting immediate relief for chronic intractable pain 0005-0008 82 1 dont prescribe TIRF meds for non cancer pain 0005-0009 89 I select products for patients receiving Radiation therapy who are imable to swallow. Fentanyl patch 0005-000996 0005-001005 No improvement with conventional therapies. 0005-001042 sometimes these patients have exhausted other options; sometimes, insurance plans do not pay for other medications 0005-001044 Patients that other opioids are not effective 0005-001053 0005-001081 excellent control of their pain which helps improve daily function 0005-001090 Long history of tried and failed therapy with both LAO and SAO 0005-001 107 I dont; i treat cancer patients 0005-001 121 steady around-the -clock relief 0005-001 135 when they are not candidates for morphine pump therapy. 0005-001 137 for break through pain 0005-001205 For more effective and sustained pain relief 0005-001207 some patients need a stronger pain medicine 0005-001210 It is a measure enacted in a patient and family with no risk factors for opioid abuse, in a setting where all other measures at ameliorating severe, episodic pain have been trailed and maximized without adequate control. I have only one patient who is on a TIRF medication and she has an incurable, life-limiting, painful medical condition. 0005-001220 safety and ease of administration Data Source: ADPQ Program: LQCAT.SAS TRIG Page 3 of3 TIRF Prescriber KAB 11JAN2017 Listing 2.1: Listing of Verbatim Responses to Question #11 (Why do you select a TIRF medicine to treat these chronic non-cancer pain conditions in patients who are opioid tolerant?) - Completed Surveys Survey Form Verbatim Responses 0005-001243 Short acting opiate with rapid onset of action 0005-001250 best effects 0005-001322 Very effective and ease of use 0005-001328 It was started by a pain specialist. have merely continued it. Note: Quation 11 is only asked if Question 9c is answered "Yes". Data Source: ADPQ Program: LQCAT.SAS TRIG Page 1 of] TIRF Prescriber KAB Listing 2.2: Listing of Verbatim Responses to Question #11 (Why do you select a TIRF medicine to treat these chronic non-cancer pain conditions in patients who are opioid tolerant?) - Incomplete Surveys Survey Form Verbatim Responses 0005-001040 If other analgesic medications are not effective. 0005-001087 Breakthrough and cannot use other options 0005-001 177 different molecule to treat pain GODS-001260 tolerance to certain short acting narcotics. Note: Question 11 is only asked if Question 9c is answered "Yes". Data Source: ADPQ Program: LQCAT.SAS Page 1 of] 05JAN2017 TRIG TIRF Prescriber KAB Listing 3: Listing of Verbatim Responses to Question #28 (Questions about the Medication Guide) - Completed Surveys Survey Form ID Verbatim Responses 0005-000079 ls entora absolutely contraindicated for opioid tolerant, NON-cancer pain. I know it is labeled for opioid tolerant cancer pain, but is it ABSOLUTELY contraindicated in all chronic, opiod tolerant NON cancer pain patients? 0005-0001 13 Information on prescribing guidelines and max dosages 0005-000154 best uses for failure of ?rst dose for BTP 0005-000160 if they can be safely taken with certain antidepressants such as gebapentin,lamictal,duloxetine 0005-000821 1 do not remember what is in it. 0005-000859 How can 1 access the information online? 0005-001042 I had questions prior to initiating prescriptions for the patients. I consulted with the ?lling pharmacist and discussed my questions with him. I do not have speci?c questions at this time. 0005-001323 What if you have a patient that has been using medications for years, the patient was prescribed back when it was used for chronic pain patients. Patient is opiod tolerant no complications and has been taking it for over 20 years? do you stop writing the rx for those patients. Data Source: ADPQ Program: LQ.SAS TRIG TIRF Prescriber KAB Listing 4: Listing of Verbatim Responses to Question #40 (What is your medical specialty?) - Completed Surveys Survey Form ID Verbatim Responses 0005-000004 Radiation Oncology 0005-000013 palliative care 0005-000025 Palliative Medicine 0005-000040 gastroenterology 0005-000046 pediatric hematology/oncology 0005-000064 Neurology 0005-000080 hosppice and palliative 0005-000087 UROLOGY 0005-000091 Palliative Medicine 0005-000094 Palliative Medicine 0005-000096 palliative care 0005-000105 Physical Medicine and Pain Medicine 0005-000106 rehab medicine 0005-000119 Palliative Medicine 0005-000140 Palliative Care 0005-000153 palliative care 0005-000154 anesthesia 0005-000168 Palliative Care 0005-000210 Palliative Care 0005-000233 0005-000261 Palliative Care 0005-000553 Palliative Medicine 0005-000569 Palliative Medicine 0005-000692 Palliative Medicine 0005-000704 Palliative Care 0005-000707 Palliative Medicine 0005-000730 Palliative Medicine 0005-000734 pain and palliative 0005-000750 Page 1 of2 05JAN2017 Data Source: ADPQ Program: LQ.SAS TRIG TIRF Prescriber KAB Listing 4: Listing of Verbatim Responses to Question #40 (What is your medical specialty?) - Completed Surveys Survey Form ID Verbatim Responses 0005-000769 Radiation Oncology 0005-000818 Palliative Care 0005-000880 Neurology 0005-001061 0005-001084 palliative medicine 0005-001137 infectious disease 0005-001 180 internal medicine. hospice, palliative care 0005-001 194 radiation oncology 0005-001205 Physical Medicine and Rehabilitation 0005-001206 Hospice and Palliative Care 0005-001209 0005-001210 Pediatric Palliative Care 0005-001222 physical medicine and rehabilitation 0005-001243 physical medicine and rehabilitation 0005-001344 PMR 0005-001345 urology 0005-001351 HOSPICE AND PALLIATIVE CARE WITH PAIN MANAGEMENT Page 2 of 2 05JAN 2017 Data Source: ADPQ Program: LQ.SAS TRIG Page 1 of 3 Tl RF Prescriber KAB 05JAN2017 Listing 5: Listing of Adverse Events and/or Product Complaints Reported by Modality Modality of Verbatim Text Report AIDS, one patient with multiple autoimmune diseases lntemet arachnoiditis, chronic LBP, chronic cervialgia depomed follow up: A phone attempt was lntemet performed today (10-Oct-2016) to obtain follow-up for this case. Due to insuf?cient patient information, the physician was unable to determine the patient or provide any new information. Since she has no recollection of a patient experiencing these events with fentanyl, she believes one of her colleagues may have reported this case. At this time, no new information is available. (bold items not in EDC) axial spine pain, chronic daily headache with execerbation, Chronic regional pain lntemet Because the G1 population often cannot tolerate or absorb traditional oral opioid meds. lntemet Chronic Pancreatitis best uses for failure of ?rst dose for BTP lntemet bone pain from progressive osteosarcoma lntemet Breakthrough and cannot use other options and Severe, chronic abdominal pain lntemet central pain different molecule to treat pain lntemet chronic back pain and for break throgh pain lntemet Chronic back pain and neck pain lntemet chronic facial pain due to surgical complications. was chosen by patient's chronic pain lntemet doctor Chronic knee pain due to joint degeneration, for 11mg metastases lntemet chronic pain Sympathetic mediated Phantom limb pain lntemet chronic pain which is severe in nature and Short acting opiate with rapid onset of action lntemet Chronic pancreatitis, chronic musculoskeletal conditions. If other analgesic medications are lntemet not effective. chronic severe pain uncontrolled by other opiates, cancer pain uncontrolled by other lntemet opiates, chronic, intractable pain, mostly back pain have used for patients with G1 absorption issues lntemet Crohn's lntemet degenerative disc disease for which surgical intervention is not an option. lntemet Degenerative disc disease, polyneuropathy lntemet degenerative disc diseases of spine,stenosis, radiculopathy, herniated disc, spondylosis, lntemet spondylolysis, and all other chronic pain in the spine. tolerance to certain short acting narcotics. Failed back and orthopedic pain lntemet Data Source: Program: LQAE.SAS TRIG Page 2 of 3 TI RF Prescriber KAB 05JAN2017 Listing 5: Listing of Adverse Events and/or Product Complaints Reported by Modality Modality of Verbatim Text Report Failed back surgery torticollis, trigeminal neuralgia lntemet FAILED BACK lntemet failed spine surgery lntemet Fibromyalgia, rheumatoid arthritis lntemet For more effective and sustained pain relief lntemet How can I access the information online? lntemet have prescribed these only to patient with chronic pain whom i have inherited lntemet and have been on these medications for several years and are stable. I do not start medications now with patients with non cancer pain. if they can be safely taken with certain antidepressants such as lntemet gebapentin,lamictal,duloxetine lnforrnation on prescribing guidelines and max dosages lntemet IS entora absolutely contraindicated for opioid tolerant, NON-cancer pain. I know it is lntemet labeled for opioid tolerant cancer pain, but is it ABSOLUTELY contraindicated in all chronic, opiod tolerant NON cancer pain patients? It is a measure enacted in a patient and family with no risk factors for opioid abuse, in a lntemet setting where all other measures at ameliorating severe, episodic pain have been trailed and maximized without adequate control. I have only one patient who is on a medication and she has an incurable, life-limiting, painful medical condition. A patient with chronic pain due to chronic, life-limiting illness for whom all other non-opioid pharmacologic and non-pharmacologic pain measures have been maximized for episodic breakthrough pain. Long history of tried and failed therapy with both LAO and SAO and Failed surgical lntemet of back or neck lumbar and cervical spondylosis and steady around-the -clock relief lntemet Multiple Sclerosis, patient preference or positive response with fentanyl patch who need lntemet short acting immediate relief for chronic intractable pain No improvement with conventional therapies. Chronic pain not improved with alternative lntemet treatments. Patients that other opioids are not effective. Chronic Low back pain. lntemet Patients who are narcotic dependent with painful medical conditions, such as spinal tumors lntemet which are not canceror chronic orthopedic pain. Peripheral neuropathic pain and very effective and ease to use lntemet post chemotherapy and radiation therapy neuropathy for patients with history of cancer and lntemet when they are not candidates for morphine pump therapy. post-laminectomy chronic pain condition lntemet Data Source: Program: LQAE.SAS TRIG Page 3 of 3 TI RF Prescriber KAB 05JAN2017 Listing 5: Listing of Adverse Events and/or Product Complaints Reported by Modality Modality of Verbatim Text Report post-laminectomy lntemet RSD lntemet RSD, Failed spine surgery, arachnoiditis, back pain due to degenerative discs and lntemet spondylosis severe back or neck pain lntemet severe back pain, due to opioid tolerant lntemet Severe bone pain related to fractures related to bone metastasis (stage IV cancer) lntemet Severe spinal stenosis in opioid-tolerant patient lntemet sometimes these patients have exhausted other options; sometimes, insurance plans do not lntemet pay for other medications. severe neuropathy associated with HIV, chronic low back pain associated with disc disease, severe diffuse arthritic pain What if you have a patient that has been using TIRF medications for years, the patient was lntemet prescribed back when it was used for chronic pain patients. Patient is opiod tolerant no complications and has been taking it for over 20 years? do you stop writing the rx for those patients. Data Source: Program: LQAE.SAS __________________________________________________________________________________ Memorandum To: Doris Auth, Associate Director Igor Cerny, REMS Assessment Reviewer Division of Risk Management, Office of Surveillance and Epidemiology (OSE) Judith Racoosin, Deputy Director for Safety Sharon Hertz, Division Director Division of Anesthesia, Analgesia, and Addiction Products, Office of New Drugs From: Tamra Meyer, Reviewer, Division of Epidemiology II (DEPI II), Office of Pharmacovigilance and Epidemiology (OPE), OSE Through: Jana McAninch, Senior Medical Epidemiologist, DEPI II, OPE, OSE Judy Staffa, Associate Director for Public Health Initiatives, OSE Date: September 21, 2017 Subject: DEPI II Responses to the Transmucosal Immediate Release Fentanyl (TIRF) Industry Group (TRIG) Responses Dated March 31, 2017 Background Transmucosal immediate-release fentanyl (TIRF) products are indicated for management of breakthrough pain in cancer patients 18 years of age and older who are already receiving and who are tolerant to around-the-clock opioid therapy for their underlying persistent cancer pain. All six brand and three generic TIRF products (Appendix A Table 1) are subject to a shared-system Risk Evaluation and Mitigation System (REMS) that was approved on 12/28/2011 and launched on 3/12/2012. The goals of the REMS are to mitigate the risk of misuse, abuse, addiction, overdose, and serious complications due to medication errors by: 1. Prescribing and dispensing TIRF medicines only to appropriate patients, which includes use only in opioid-tolerant patients; 2. Preventing inappropriate conversion between TIRF medicines; 3. Preventing accidental exposure to children and others for whom it was not prescribed; 4. Educating prescribers, pharmacists, and patients on the potential for misuse, abuse, addiction, and overdose of TIRF medicines. The TIRF REMS Industry Group (TRIG) submits annual REMS assessment reports that include descriptions of cases of accidental exposures to TIRFs in children using the Researched Abuse Diversion and Addiction-Related Surveillance System (RADARS) Poison Center Program and the FDA Adverse Event Reporting System (FAERS) data. FDA remains concerned that additional cases of accidental exposures in children may be missed. The Division of Epidemiology-II (DEPI) previously explored the possibility of using the National Electronic Injury Surveillance System-Cooperative Adverse Drug Event Surveillance (NEISS-CADES) emergency department (ED) data as a source to monitor accidental poisonings in childrena. In a sample of approximately 60 hospitals that provided ED data from 2004-2015 there were only ten accidental pediatric poisonings from fentanyl; two of them were for TIRF products, and the rest were from fentanyl patches. Distinguishing between patches and TIRFs was possible from the ED medical notes (Appendix A Table 2); however, the case counts were not high enough to generate reliable national estimates. Because the NEISS-CADES data source was determined to be insufficient for continued monitoring of accidental pediatric poisonings due to the limited coverage of EDs, FDA asked the TRIG to conduct additional monitoring of accidental poisonings from EDs and death data from a Meyer, T. Review of NEISS-CADES Data on Pediatric Emergency Department Visits Related to Accidental Exposure to Transmucosal Immediate Release Fentanyl. Dated April 14, 2017. DARRTS Reference ID: 4084489. www.fda.gov Reference ID: 4156408 FDA_7384 Interoffice Memorandum – (continued) Page 2 of 14 pages nationally-representative data sources or sources that covered multiple large geographic areas. Specifically, FDA requested that the TRIG: 1. Explore opportunities to conduct surveillance in emergency departments (EDs) from a data source that is nationally-representative or covers multiple large geographic areas, and 2. Explore opportunities to conduct surveillance using mortality data from a data source that is nationallyrepresentative or covers multiple large geographic areas. The FDA communicated this request to the TIRF industry group (TRIG) in a teleconference on March 3, 2017 and in a follow-up Information request (IR) on March 6, 2017. In addition to the request that the TRIG propose data sources to capture accidental TIRF poisonings in children, other requests were made to:  provide additional details on the accidental childhood poisoning cases identified in poison center exposure calls,  conduct a rigorous review of medical literature and lay media reports of adverse events,  identify prescribers who prescribe TIRFs to patients who are not opioid tolerant or for non-cancer pain, and  to evaluate TIRF-related adverse outcomes in patients who are not opioid tolerant (see 31MAR2017 TRIG response letter in Appendix B). The Division of Risk Management (DRISK) requested that DEPI provide responses to the TRIG proposals in their 31MAR2017 communication for ED and death data sources. The primary purpose of this memo is to evaluate and respond to the TRIG’s responses to FDA request for additional ED and mortality data for monitoring of unintentional pediatric poisonings. We also provide additional recommendations for the TRIG’s proposed study of adverse events in patients who are not opioid tolerant (Appendix B) in response to DRISK’s request to:  Evaluate TIRF-related adverse outcomes in patients who are opioid non-tolerant. For example, conduct an evaluation of events/outcomes in a population of patients using TIRFs without prior opioid exposure that would qualify them as opioid tolerant. The TRIG should develop and submit a concept paper or protocol for FDA review prior to conducting the study. DRISK will review the other TRIG responses, separately. Results The TRIG identified six possible data sources to assess accidental childhood poisonings in EDs and three data sources to assess adverse outcomes in patients who are non opioid-tolerant (Table 1). Very brief proposals for the analysis were provided. Accidental childhood poisonings: Within each data source, they will search for diagnosis codes from administrative claims for ICD-10 code T40.4X1; poisoning by other synthetic narcotics, accidental (unintentional). After identifying patients and dates of care, they will evaluate the medical notes associated with the ED visit, either using access to the electronic medical record (EMR) for the Humedica data source, or by contacting individual hospitals to abstract the ED charts for the other data sources. Text in the medical records may specify the fentanyl molecule and details that identify a TIRF product, such as noting a form like a lollipop or nasal spray. The TRIG claims that only a small percentage of hospitals will provide approval to access the charts. They estimate only 25% participation for the Premier data source, for example. In a preliminary search of HealthCore data, 11 records were found with the T40.4X1 ICD-10 code, although the search time period was not specified. It was also not specified whether the 11 records were in children or for patients of all ages. The TRIG estimated that it would take 1-2 years to review these data, and they concluded that there are no ED data sources that will provide “meaningful numbers” of accidental poisonings of children by TIRFs. They were also concerned that the ED medical records would not have enough information with which to identify a TIRF, or a specific TIRF product. The TRIG did not know of any national mortality data sources available to identify TIRF products, as was requested by FDA. Memo-TRIG Responses_final.docx Reference ID: 4156408 FDA_7385 Interoffice Memorandum – (continued) Page 3 of 14 pages Adverse outcomes in non opioid-tolerant patients: In the 31MAR2017 letter, the TRIG said that they would send a protocol for this study to FDA on or before 01AUG2017, but a protocol has not yet been received at the time of this review. The TRIG proposed to use Optum Clinformatics Data Mart, Truven Commerical/Medicare, and IMS PharMetrics as data sources, and they estimated that a study would take between 10-12 months. No other details of a proposed study were provided. Table 1. Proposed data sources to assess accidental poisonings of children related to transmucosal immediate release fentanyl products (TIRFs) as well as adverse outcomes from non opioid-tolerant patients using TIRFs Study Aim Data Source Brief Description* Premier Healthcare Database This is a large, US hospital-based database primarily from geographically diverse non-profit, nongovernmental, and community and teaching hospitals and health systems. Outpatient visits to EDs are captured for the primary diagnosis. Patients’ hospital stays and outpatient visits to the hospitals are linked. Records are not limited to specific payers. HealthCore, Inc. HealthCore Integrated Research Database is a longitudinal database of medical claims, pharmacy claims, and some electronic laboratory results from 2006 to 2016 from numerous Blue Cross and/or Blue Shield licensed plans. Inpatient and outpatient medical records can be requested from a subset of patients. Humedica (Optum) The Optum longitudinal clinical database contains EHR Accidental data across various sources including inpatient visits, childhood outpatient visits, medications, laboratory results, vital signs, poisonings and notes from physicians, pathologists, and radiologists. Text searches can be done in the EMR data source without the need for approvals and abstraction at each hospital. Practice Fusion Practice Fusion is a large, real-time, cloud-based healthcare EHR database from 30,000 physician practices (family practice and specialists) that have three or less physicians in the practice. Pharmacy and laboratory data are also available from about 90% of US pharmacies and about 600 laboratories. Optum Data Mart The Optum Clinformatics Data Mart contains administrative health claims for United Health managed care. Outpatient lab tests are available for a small subset of the population. IMS EMR Data (SDI database) No information was provided. Truven Health Analytics’ Truven Health Analytics’ MarketScan Research Databases MarketScan Research contain commercial and supplemental Medicaid and Databases Medicare claims for inpatient care, outpatient care, and prescription fills. Specialty pharmacy and mail-order Adverse prescription fills are included. Specialty databases link outcomes in non some claims to health risk assessment; dental, laboratory, opioid-tolerant and medical records. A separate hospital database allows patients for in-hospital research. Humedica (Optum) The Optum longitudinal clinical database contains EHR data across various sources including inpatient visits, Memo-TRIG Responses_final.docx Reference ID: 4156408 FDA_7386 Interoffice Memorandum – (continued) IMS Pharmetrics Plus Page 4 of 14 pages outpatient visits, medications, laboratory results, vital signs, and notes from physicians, pathologists, and radiologists. Text searches can be done in the EMR data source without the need for approvals and abstraction at each hospital. IMS RWD Adjudicated Claims contain claims for prescriptions, inpatient care, and outpatient care from 2006 to present. The database is primarily made up of commercial PPO plans. *Descriptions are from the sponsors’ submission ED, emergency departments; EHR, electronic health record; EMR, electronic medical record; RADARS, Researched Abuse Diversion and Addiction-Related Surveillance System Discussion While we agree with the TRIG that searching for accidental childhood poisonings using ED medical records may result in low numbers of cases of accidental poisonings in any one data source, the Agency does not want to rely solely on passive adverse event reports or poison center call data for case-finding, as both of these capture an unknown, and likely small proportion of actual cases. Additional data sources are needed to fully understand the effectiveness of the REMS in preventing accidental exposures in children; even small numbers of adverse outcomes related to TIRFs may indicate a need for revision of the REMS. Given that the TRIG is concerned about a low percent participation from hospitals contacted for ED records, DEPI will direct the TRIG to evaluate additional data sources that can link ED claims to EMRs. The TRIG can add integrated managed care systems, such as Kaiser Permanente, federal care systems like the system of military treatment facilities under the Department of Defense, or other large consortiums of hospitals. From our experience reviewing the NEISSCADES ED data, the medical notes available with the ED records were able to clearly differentiate between a fentanyl patch and a TIRF product (Appendix A Table 2). DEPI agrees with the TRIG that the specific product may not be identifiable, except by dosage form; however, the dosage form is unique for some of the TIRF products so we may be able to identify a specific TIRF product by dosage form (Appendix A Table 1). The sponsor could not identify any data source with the capability to capture TIRF-involved accidental deaths in children, but DEPI is aware of some possible options. First, a new de-identified data source has recently been developed by FDA and NCHS to identify specific drugs involved in death cases, based on all US death certificates.b,c This data source is publicly available and can be accessed by an analyst on-site at one of the Research Data Center locations after approval of a research proposal. The ability to identify drugs at the substance level (e.g., fentanyl), when they are mentioned on the death certificate, has already been shown.b,c The ability to identify a group of specific products in the data source, such as TIRFs, has not yet been shown, but there is access to text descriptors of the drug involved in the death that have been extracted from the raw text available in the death certificate. The extracted descriptors include any words that are immediately before or after the drug search term, helping to describe the search term (e.g., PRESCRIPTION, TABLET, PATCH) or surrounding phrases describing how the drug was involved in death (e.g., INGESTED)c. These terms could be mined to search for the dosage form of fentanyl mentioned on death certificates in a manner similar to the search of ED medical records for fentanyl dosage form. Medical examiner records are another possible source to search for accidental childhood poisonings from TIRF products, and these records may contain more details about the fentanyl products involved in death. Although there is not currently a comprehensive national database of medical examiner records, collaboration with state health departments, researchers who use medical examiner data, the National Association of Medical Examiners, and even law enforcement agencies may yield valuable information on deaths involving these products. In addition to death certificate and medical examiner data b Trinidad JP, Warner M, Bastian BA, Minino AM, Hedegaard H. Using Literal Text From the Death Certificate to Enhance Mortality Statistics: Characterizing Drug Involvement in Deaths. Natl Vital Stat Rep. 2016 Dec;65(9):1-15. c Warner M, Trinidad JP, Bastian BA, Minino AM, Hedegaard H. Drugs Most Frequently Involved in Drug Overdose Deaths: United States, 2010-2014. Natl Vital Stat Rep. 2016 Dec;65(10):1-15. Memo-TRIG Responses_final.docx Reference ID: 4156408 FDA_7387 Interoffice Memorandum – (continued) Page 5 of 14 pages sources, some, if not all states also have child death investigation programs to search for root causes, criminal child neglect, etc. The TRIG should conduct a thorough investigation of using these and other data sources. We await a protocol for the study of adverse outcomes in patients who are non opioid-tolerant. However, we have some concerns about the ability to accurately identify opioid tolerance and potential adverse outcomes of interest (e.g., overdose, death) in claims-based data sources. A study in claims data will first need to demonstrate adequate validity of any algorithms used to identify opioid tolerance and adverse outcomes. DRISK should specify which adverse outcomes are of primary interest in this study. Since death is a particular outcome of concern, the TRIG will need to select a data source that captures both in- and out-of-hospital deaths. Conclusion While the TRIG was not optimistic about finding cases of accidental childhood poisonings due to TIRFs in ED medical records or in death data, the Agency is concerned about this outcome and would like to pursue additional cases. DEPI provides recommendations for additional data sources that the TRIG can use to capture cases of accidental childhood poisoning. We will await the submission of a protocol for the proposed study of adverse outcomes in non opioid-tolerant patients, but we do have concerns about using only administrative claims databases to conduct the study. Recommendations for the TRIG: 1. To address your concerns about whether emergency department (ED) medical records will contain enough information to identify TIRFs, we were able to clearly identify the form of fentanyl involved in accidental childhood poisonings from ED records in a small study. Therefore, we continue to believe that ED medical records are a valuable source of information in estimating the scope of accidental childhood poisonings involving TIRFs. We request that you pursue the evaluation of accidental childhood poisonings in ED medical records. 2. Given the concerns about low expected hospital response rates to requests for ED records, add additional data sources with access to electronic medical records without the need for hospital-specific requests for records, such as large integrated managed care systems, government hospitals, or other large consortiums of hospitals. 3. As an interim step to your evaluation of accidental childhood poisonings, provide the following information by February 2, 2018: a. The number of unique patients ages 0-6 years with the ICD-10 code T40.4X1 (or other relevant codes to identify accidental drug poisoning or overdose related to fentanyl) during the reporting period for each study data source. b. The number of patients ages 0-6 years with the ICD10-code T40.4X (or other relevant codes) from a nationally-representative data source (e.g., Healthcare Cost and Utilization Project/National Emergency Department Sample) during the same time frame. c. A description of the IMS EMR SDI data source and any other new data sources selected. d. Clarification about whether Practice Fusion data contains any ED records. 4. Based on the proportion of synthetic opioid accidental poisoning coded claims (T40.4X1) found to be TIRF poisonings after ED medical record evaluations, estimate the number of total US ED cases of accidental childhood TIRF poisonings in the US, stratified by age. 5. We agree that the CDC Wonder data would not be helpful for identifying childhood poisonings from TIRFs. Pursue more granular sources of data on drug-involved deaths. One recently-developed source has abstracted drug names and drug characteristics (e.g., PRESCRIPTION, TABLET, PATCH) or surrounding phrases describing how the drug was involved in death (e.g., INGESTED) from all US death certificates (Warner M. Natl Vital Stat Rep. 2016;65(10):1-15 and Trinidad JP. Natl Vital Stat Rep. 2016;65(9):1-15.). Public access to these Drug Induced Mortality (DIM) data (https://www.cdc.gov/rdc/b1datatype/dt1229.html) is available through the National Center for Health Memo-TRIG Responses_final.docx Reference ID: 4156408 FDA_7388 Interoffice Memorandum – (continued) Page 6 of 14 pages Statistics (NCHS) Research Data Center (RDC) restricted access data program. The process for data access is described on the RDC website (https://www.cdc.gov/rdc/index.htm). Another option is to obtain medical examiner records from multiple states, perhaps through the National Association of Medical Examiners. Also explore whether information from state investigations of child fatalities can be searched for TIRF-related deaths (https://www.childwelfare.gov/topics/responding/fatalities/#state). We remain very concerned about the possibility of accidental childhood poisonings resulting in death, and the TRIG must provide data with which to assess the effectiveness of the REMS in preventing these childhood poisonings. 6. We await your study protocol to assess adverse events in patients using TIRFs without sufficient opioid tolerance, but we have some initial concerns about the validity of opioid tolerance and adverse event algorithms using the claims data sources noted in the 31MAR2017 communication. The rate of TIRF use in apparently non opioid-tolerant patients in the annual REMS assessment report was alarming, but does raise questions about whether administrative claims data fully and accurately reflect patients’ recent experience with opioids and their opioid tolerance status prior to receiving a TIRF. We therefore require further work to validate the opioid tolerance algorithms. Validation of non-opioid tolerance could be informed by a study of linked electronic medical records (see the 2013 Guidance for industry and FDA Staff: Best Practices for Conducting and Reporting Pharmacoepidemiologic Safety Studies Using Electronic Healthcare Data). At the time that you submit your protocol for the study of adverse events in non opioid-tolerant patients, or shortly thereafter, provide information about the validity of algorithms used to determine opioid tolerance as well as all adverse events being evaluated. As capturing TIRFinvolved deaths is of particular interest, any data sources will need to capture both in- and out-of-hospital deaths. Memo-TRIG Responses_final.docx Reference ID: 4156408 FDA_7389 Interoffice Memorandum – (continued) Page 7 of 14 pages APPENDIX A: TABLES Appendix A Table 1: Transmucosal Immediate-release Fentanyl (TIRF) Product Descriptions and Approval Dates Drug Name Dosage Forms NDA/ANDA Applicant Approval Date Abstral Sublingual Tablet NDA 022510 Sentynl Therapeutics, Inc. 1/7/2011 Actiq Oral Transmucosal Lozenge (“lollipop”) NDA 020747 Cephalon, Inc. 11/4/1998 Fentora Buccal Tablet NDA 021947 Cephalon, Inc. 9/25/2006 Lazanda Nasal Spray NDA 022569 DepoMed, Inc. 6/30/2011 Onsolis Buccal Soluble Film NDA 022266 BioDelivery Sciences International, Inc. 7/16/2009 Subsys Sublingual Spray NDA 202788 Insys Therapeutics, Inc. 1/4/2012 fentanyl citrate Oral Transmucosal Lozenge (“lollipop”) ANDA 78907 Mallinckrodt, Inc. 10/30/2009 fentanyl citrate Oral Transmucosal Lozenge (“lollipop”) ANDA 077312 Par Pharmaceuitcal, Inc. 10/30/2009 fentanyl Oral Transmucosal Lozenge ANDA 079075 Watson Laboratories, Inc. 1/7/2011 citrate (“lollipop”) *Table reproduced from Meyer, TE. Review of NEISS-CADES Data on Pediatric Emergency Department Visits Related to Accidental Exposure to Transmucosal Immediate Release Fentanyl. Dated April 14, 2017. DARRTS Reference ID: 4084489. Memo-TRIG Responses_final.docx Reference ID: 4156408 FDA_7390 Interoffice Memorandum – (continued) Page 8 of 14 pages Appendix A Table 2. Details of cases of accidental exposure to fentanyl transdermal and transmucosal immediate release fentanyl (TIRF) products in children, NEISS-CADES 2004-2014 Case Year Age Drug Role Form Disposition Comments Number Transmucosal fentanyl 2004 18 Probable/Likely Lollipop Treated/Released Ingested Mom’s migraine 1 mths medications; treated with 1mg Narcan in field 2006 2 yrs Probable/Likely Lollipop Observation Licked Grandma’s fentanyl 2 lollipop found in trash; observed Transdermal fentanyl 2005 9 3 mths Probable/Likely Patch Treated/Released 4 2006 2 yrs Probable/Likely Patch 5 2008 Probable/Likely Patch 6 2009 20 mths 10 mths 10 yrs Transferred to different hospital Treated/Released Probable/Likely Patch Admitted Probable/Likely Patch Admitted Found with multiple of Grandma’s fentanyl patches on body; treated with intubation, Ativan, Narcan, IV fluids, mannitol, and epinephrine 2011 17 Possible/Suspect Patch Admitted Possible contact with Mom’s 8 mths fentanyl patch when sitting with her, Narcan 800 mcg given 2013 19 Possible/Suspect Patch Treated/Released Grandma concerned that patient 9 mths touched pair of scissors used to cut fentanyl patch; patient asymptomatic 2015 4 Probable/Likely Patch Treated/Released Found with Grandma’s fentanyl 10 mths patch on thigh after bath; given Zofran *Table reproduced from Meyer, TE. Review of NEISS-CADES Data on Pediatric Emergency Department Visits Related to Accidental Exposure to Transmucosal Immediate Release Fentanyl. Dated April 14, 2017. DARRTS Reference ID: 4084489. NEISS-CADES collects data from a national stratified probability sample of 7 2010 Exposed to Father’s fentanyl patch via skin contact; treated with IV Narcan Ingested Dad’s fentanyl patch; treated with charcoal magcitrate Found Grandfather’s fentanyl patch in toilet and put in mouth Got into Dad’s fentanyl patches about 60 hospitals with a minimum of six beds and a 24-hour ED in the US and its territories. Trained coders at each participating hospital review clinical records of every ED visit to identify cliniciandiagnosed adverse drug-related events (ADEs), to report up to two medications implicated in each ADE, and to record narrative descriptions of the incident. The drugs for which ADEs are recorded include prescription or over-the-counter medications, vaccines, vitamins, and herbal/dietary supplements. The NEISS-CADES dataset used for this analysis contained cases from 2004-2015. We searched for ‘fentanyl’ in the two free text and two standardized drug name fields in the data source. Cases were limited to patients ages <18 years and to ADE mechanisms of ‘unintentional overdose’ We screened several free text fields for details of the case to differentiate TIRFs, patches, and other forms of fentanyl. Memo-TRIG Responses_final.docx Reference ID: 4156408 FDA_7391 Interoffice Memorandum – (continued) Page 9 of 14 pages APPENDIX B: Letter from the Transmucosal Immediate Release Fentanyl (TIRF) Industry Group (TRIG) to FDA dated 31MAR2017 Memo-TRIG Responses_final.docx Reference ID: 4156408 FDA_7392 Interoffice Memorandum – (continued) Memo-TRIG Responses_final.docx Reference ID: 4156408 Page 10 of 14 pages FDA_7393 Interoffice Memorandum – (continued) Memo-TRIG Responses_final.docx Reference ID: 4156408 Page 11 of 14 pages FDA_7394 Interoffice Memorandum – (continued) Memo-TRIG Responses_final.docx Reference ID: 4156408 Page 12 of 14 pages FDA_7395 Interoffice Memorandum – (continued) Memo-TRIG Responses_final.docx Reference ID: 4156408 Page 13 of 14 pages FDA_7396 Interoffice Memorandum – (continued) Memo-TRIG Responses_final.docx Reference ID: 4156408 Page 14 of 14 pages FDA_7397 --------------------------------------------------------------------------------------------------------This is a representation of an electronic record that was signed electronically and this page is the manifestation of the electronic signature. --------------------------------------------------------------------------------------------------------/s/ ---------------------------------------------------TAMRA E MEYER 09/21/2017 JANA K MCANINCH 09/21/2017 JUDY A STAFFA 09/21/2017 Reference ID: 4156408 FDA_7398 __________________________________________________________________________________ Memorandum To: Doris Auth, Associate Director Igor Cerny, REMS Assessment Reviewer Division of Risk Management, Office of Surveillance and Epidemiology (OSE) Judith Racoosin, Deputy Director for Safety Sharon Hertz, Division Director Division of Anesthesia, Analgesia, and Addiction Products, Office of New Drugs From: Tamra Meyer, Reviewer, Division of Epidemiology II (DEPI II), Office of Pharmacovigilance and Epidemiology (OPE), OSE Through: Jana McAninch, Senior Medical Epidemiologist, DEPI II, OPE, OSE Judy Staffa, Associate Director for Public Health Initiatives, OSE Date: November 15, 2017 Subject: DEPI II Responses to the Transmucosal Immediate Release Fentanyl (TIRF) Industry Group (TRIG) Responses Dated October 16, 2017 Background Transmucosal immediate-release fentanyl (TIRF) products are indicated for management of breakthrough pain in cancer patients 18 years of age and older who are already receiving and who are tolerant to around-the-clock opioid therapy for their underlying persistent cancer pain. All six brand and three generic TIRF products (Appendix A Table 1) are subject to a shared-system Risk Evaluation and Mitigation Strategy (REMS) that was approved on 12/28/2011 and launched on 3/12/2012. The goals of the REMS are to mitigate the risk of misuse, abuse, addiction, overdose, and serious complications due to medication errors by: 1. Prescribing and dispensing TIRF medicines only to appropriate patients, which includes use only in opioid-tolerant patients; 2. Preventing inappropriate conversion between TIRF medicines; 3. Preventing accidental exposure to children and others for whom it was not prescribed; 4. Educating prescribers, pharmacists, and patients on the potential for misuse, abuse, addiction, and overdose of TIRF medicines. The TIRF REMS Industry Group (TRIG) submits annual REMS assessment reports that include descriptions of accidental exposures to TIRFs in children, use of TIRFs by patients without appropriate opioid tolerance, and other events of interest to FDA. FDA remains very concerned about accidental childhood exposures, appropriate opioid tolerance prior to TIRF exposure, and adverse events, such as overdose, especially in patients who are not opioid-tolerant prior to exposure. The FDA and the TRIG have had several teleconferences and written communications about these concerns, and FDA has provided several recommendations for further actions to understand the extent of these safety concerns. The communications about i) accidental childhood exposures, ii) opioid non-tolerance, and iii) adverse events in opioid non-tolerant patients from the 11/1/2016-11/1/2017 period are listed here (other issues discussed in the communications are not described): 1. 11/10/2016: 48 Month REMS Assessment Acknowledgement Letter (RAAL) from FDA to TRIG communicating the need for: a. investigation of continued high levels of opioid non-tolerance in patients (42% of patients) and inappropriate conversion between TIRFs (17-21% of patients) at the individual-product level; b. additional surveillance of accidental TIRF poisonings in children; and c. other data sources to track adverse outcomes. www.fda.gov Reference ID: 4181825 FDA_7399 Interoffice Memorandum – (continued)  Page 2 of 13 pages  2. 3/1/2017: Written FDA Meeting Agenda for 3/3/2017 teleconference with TRIG requesting: a. more vigorous surveillance for accidental childhood poisonings due to TIRFs; b. exploration of prescriber-level interventions to reduce prescriptions in opioid non-tolerant patients or for pain not related to cancer; and c. evaluation of adverse events in patients receiving TIRFs who are not opioid-tolerant. 3. 3/3/2017: Teleconference to follow-up with TRIG about requests made in 11/10/2016 48-month RAAL. TRIG to provide: a. information on opioid non-tolerance by product and b. description of databases to explore accidental poisonings in children. 4. 3/7/2017: Written follow-up to the 3/3/2017 teleconference from FDA to TRIG to provide instruction on the opioid non-tolerant analysis. 5. 3/10/2017: Written communication (email only) from TRIG to FDA about the opioid non-tolerant analysis. They expressed concerns that the analysis requested for product-specific dispensing to opioid non-tolerant patients will not accurately reflect the dispensing of specific TIRF products to opioid nontolerant patients. 6. 3/21/2017: Written FDA response to 3/10/2017 communication from TRIG to provide additional requests for the opioid non-tolerant analysis. 7. 3/31/2017: Written response from TRIG to FDA’s requests from the 3/3/2017 teleconference. The response describes: a. lack of viable data sources to evaluate accidental poisonings in children, b. a plan to provide more details from poison center calls for accidental exposures to TIRFs, c. a plan to conduct review of medical literature and lay media reports/social media, and d. a general plan to conduct a study of adverse events in non opioid-tolerant compared to opioidtolerant patients using TIRFs (protocol promised by 8/1/2017). 8. 9/27/2017: Written FDA Meeting Agenda for 10/2/2017 teleconference and DEPI responses to the 3/31/2017 written TRIG communication providing additional guidance on: a. evaluation of childhood poisonings from TIRFs, b. validity of the opioid tolerance algorithm, and c. adverse events in opioid non-tolerant patients. 9. 10/2/2017: Teleconference with TRIG. We discussed: a. opioid tolerance data concerns, b. increasing trends for significant outcomes/AEs for TIRFs over time with some trends greater than those observed for other opioids, and c. that TRIG must find databases to assess accidental childhood poisonings. 10. 10/16/2017: Written communication from TRIG to FDA responding to our requests in the 10/2/2017 teleconference. The communication discussed plans for: a. validation of the opioid tolerance algorithm, b. a study to assess the risk of adverse events in non opioid-tolerant versus opioid-tolerant patients using TIRF products, and c. analyzing accidental childhood poisonings in electronic health records and mortality data. Refer to the relevant DEPI and DRISK reviews for in-depth reasoning to support the requests and recommendations in the string of communications, above: 1. DRISK review of the 48-month REMS Assessment Report (9/28/2016),a 2. DEPI Memo assessing a possible source for emergency department visits due to accidental TIRF poisonings (4/14/2017),b 3. DEPI review of the 48-month REMS Assessment Report (5/2/2017),c a Cerny I and Harris S: Review of the fifth (48 month, October 29, 2014 to October 28, 2015) Risk Evaluation and Mitigation Strategy (REMS) Assessment Report for Transmucosal Immediate Release Fentanyl (TIRF) Agents b Meyer T. Epidemiology: Review of NEISS-CADES Data on Pediatric Emergency Department Visits Related to Accidental Exposure to Transmucosal Immediate Release Fentanyl. In DARRTS c Coyle DT and Pham T. Subject: Epidemiologic Review of 48-Month TIRF Product REMS Assessment Supplemental Report. In DARRTS 5/2/2017, Ref ID: 4091934. Memo‐TRIG_Responses_16OCT2017_Final.docx  Reference ID: 4181825 FDA_7400 Interoffice Memorandum – (continued)  Page 3 of 13 pages  4. DEPI review of the 60-month REMS Assessment Report (8/4/2017),d and 5. DEPI Memo responding to the TRIG’s 3/31/2017 written communication outlining plans for assessment of opioid non-tolerance and accidental childhood poisonings (9/21/2017).e The purpose of this memo is to explain the proposed responses from DEPI to the October 16, 2017 communication from the TRIG (Appendix B) that responded to requests from an October 2, 2017 teleconference between the FDA and TRIG. During the October 2, 2017 teleconference, FDA and TRIG discussed: 1. Opioid tolerance data concerns—only 44.6% to 65.4% appear to be opioid-tolerant 2. That surveillance indicates increasing trends in significant outcomes/adverse events for TIRFs over time; some of these increases appear greater than those observed for other opioids. 3. A need to explore opportunities to conduct surveillance in emergency departments (EDs) from a data source that is nationally-representative or covers multiple large geographic areas, and 4. A need to explore opportunities to conduct surveillance using mortality data from a data source that is nationally-representative or covers multiple large geographic areas. FDA asked for TRIG to respond to the concerns discussed in the teleconference, specifically, 1. A plan for validation of the opioid tolerance algorithm, 2. A proposal for an analysis to evaluate adverse events in non-opioid tolerant patients, 3. A proposal for analyses to evaluate accidental childhood poisonings, and 4. Recommendations for REMS modifications (DRISK will review these TRIG responses, separately). Results 1. Plan for validation of the opioid tolerance algorithm: First, the TRIG proposed to explore why different versions of an algorithm to assess opioid tolerance produced different results. In an analysis previously conducted using a different algorithm from Insys, there was a higher proportion of opioid tolerance among TIRF users (77%) than in analyses conducted by the TRIG using their current opioid tolerance algorithm (44.6-65.4% opioid tolerance). The TRIG plans to investigate the difference in these algorithms before conducting the validation study. The TRIG proposed two possible data sources for the validation study; the Henry Ford Health System (HFHS) and Optum’s Clinformatics claims data and integrated claims-electronic medical record (EMR) data. As we mentioned in our call with the TRIG on October 2, FDA is currently conducting an assessment in Optum’s claims-EMR data of possible sources of opioid exposure that are not captured in claims data, alone, so we focused our review on the merits of the HFHS data source. Briefly, the HFHS is a closed healthcare system serving Detroit, Michigan and the surrounding metropolitan area. According to the TRIG communication, the HFHS has both claims data, EMR data, and a tumor registry. The TRIG commented that outpatient prescription records are available for Henry Ford Medical Group patients with Health Alliance Plan coverage. 2. Proposal for analysis to evaluate adverse events in non-opioid tolerant patients: The TRIG was asked to evaluate safety concerns in patients using TIRFs without sufficient opioid tolerance in the March 1, 2017 agenda prior to the March 3, 2017 teleconference. The TRIG responded in their March 31, 2017 communication that they would provide a protocol for this study by August 1, 2017. In the March 31 communication, they identified three possible data sources for the study, Optum Clinformatics Data Mart, Truven Commercial/Medicare, and IMS PharMetrics data. In a September 27, 2017 FDA communication to the TRIG prior to the October 2, 2017 teleconference, FDA communicated that: i. we are still waiting for their study protocol, d Meyer T. Subject: Review of Surveillance Data from the 60-month REMS Assessment Report for TIRF Products. In DARRTS 8/4/2017, Ref ID 4135176. e Meyer T. Subject: DEPI II Responses to the Transmucosal Immediate Release Fentanyl (TIRF) Industry Group (TRIG) Responses Dated March 31, 2017. Memo‐TRIG_Responses_16OCT2017_Final.docx  Reference ID: 4181825 FDA_7401 Interoffice Memorandum – (continued)  ii. iii. Page 4 of 13 pages  validation of the opioid tolerance algorithm is needed, and any data source for the study must capture both in- and out-of-hospital death. We have yet to receive a protocol for this study, and the October 16, 2017 communication from the TRIG contains only two paragraphs about the proposed study. They propose to compare the rates of abuse, misuse, overdose, death, hospitalizations, and other health care encounters in patients receiving TIRFs who did and did not have evidence of sufficient opioid tolerance. They will match patients based on propensity scores to control for confounding based on important covariates. The target data source is Optum (both Clinformatics claims data and Optum claims-Humedica data). 3. Proposal for analyses to evaluate accidental childhood poisonings: The TRIG proposes to evaluate the frequency of TIRF poisonings in children treated in the ED or inpatient hospital settings in Optum claims-Humedica data. The TRIG claims that this data source covers 20% of the US population. Initial case identification will be based on relevant ICD-9 and 10 codes indicating an accidental poisoning by a synthetic opioid product or codes identifying administration of naloxone. Subsequent searches of the EMR will be used to try to identify TIRF exposure and the clinical course of the patient. Cases will be extrapolated to national estimates. The TRIG will provide a protocol once FDA agrees to the data source and the approach. The TRIG will also attempt to evaluate accidental childhood poisonings from TIRFs that result in death from the Drug Induced Mortality (DIM) data and other data sources like Child Welfare and Medical Examiner data, per FDA request on September 27, 2017. The TRIG will pursue analysis in the DIM data by limiting the deaths to those with an underlying cause of death due to drug overdose and then using the literal text to search for TIRFs. They will submit a protocol for the DIM data analysis by February 2, 2018. Investigations of the other data streams are underway. Discussion 1. Plan for validation of the opioid tolerance algorithm: There was no description of the “Insys algorithm” or the differences between the “Insys algorithm” and the algorithm used by the TRIG for recent calculations of opioid tolerance in the 48-month REMS Assessment Report. Instead, the TRIG said that they would explore the differences in the algorithms before moving forward with a validation study. DEPI recommends that the TRIG explain the differences in the two algorithms in a subsequent communication with a short deadline for response, such as two weeks. The difference in opioid tolerance results from these two algorithms only highlights the need for algorithm validation. DEPI is concerned about holding up the validation of claims-based opioid-tolerance algorithms any longer. The TRIG must move forward with the validation study without delay, even if it means validating both algorithms. FDA has already started an investigation into sources of opioid tolerance in Optum EMR data in patients who appeared to get TIRFs but were not opioid-tolerant, as we communicated in our October 2, 2017 teleconference. Therefore, the TRIG should focus on an alternate data source for the main validation study, and they can do a smaller portability assessment of the validated algorithm in Optum if they end up using Optum data for their assessment of adverse events in non opioid-tolerant TIRF patients. The HFHS appears to be a reasonable data source to conduct the validation of opioid tolerance algorithm(s), given that the data source includes EMR data to search for other sources of opioid tolerance. The availability of a linked tumor registry could also provide valuable information on the proportion of patients getting TIRFs for non-cancer indications. However, since the validation of the algorithm can only be done among patients with evidence of a prescription fill for a TIRF, it is only the subset of patients in the Henry Ford Medical Group with Health Alliance Plan coverage and a prescription for a TIRF that will be part of the validation study. The TRIG provided a comparison of age, sex, and race Memo‐TRIG_Responses_16OCT2017_Final.docx  Reference ID: 4181825 FDA_7402 Interoffice Memorandum – (continued)  Page 5 of 13 pages  between the patients in HFHS as compared to 2012 US Census to try to show that this validation data source will be representative of the US population, but the relevant target population is US patients using TIRFs. DEPI recommends that the TRIG provide the number of patients who filled a prescription for a TIRF during the proposed validation period to estimate sample size. In addition, DEPI proposes that the TRIG provide demographic and clinical characteristics of the TIRF users in the HFHS compared to TIRF users in the US so that we can determine whether the HFHS is likely to be representative of the target population. The TRIG may want to provide the TIRF user counts and comparisons of demographic and clinical characteristics to US TIRF users for an alternate data source in case there are insufficient TIRF users in HFHS. DEPI recommends that the TRIG submit the number of TIRF users in HFHS and comparison demographic and clinical characteristics to US TIRF users by February 2, 2018. 2. Proposal for analysis to evaluate adverse events in non-opioid tolerant patients: There are insufficient details in the two paragraphs provided with which to evaluate the proposed study of adverse events in opioid non-tolerant versus opioid-tolerant TIRF users in Optum data. The TRIG needs to submit a more thorough protocol as they proposed to send by August 1, 2017. We reiterate our September 27, 2017 comment that the Optum data, alone, are unlikely to be useful because we require an assessment of both in- and out-of-hospital death from overdose. The TRIG can pursue the safety outcomes of misuse and abuse for their own purposes, but DEPI is more concerned about the overdose and death outcomes. We recommend that the TRIG focus on the outcome of fatal and nonfatal overdose, propose a data source with access to both in- and out-of-hospital death, and submit a protocol for this study with a short deadline for response. Four weeks is likely to be sufficient time to submit a protocol draft, but since the TRIG is to submit other responses by February 2, 2018, the protocol could be submitted with the February 2, 2018 responses to streamline efforts to respond to the various submissions. 3. Proposal for analyses to evaluate accidental childhood poisonings: DEPI agrees with the general outline for assessment of accidental poisonings in children, provided that there appear to be a reasonable number of patients ages 0 to 6 years with codes for accidental poisoning by a synthetic opioid. We request that the TRIG submit a protocol for this study and submit counts of patients ages 0-6 with a code for accidental poisoning by a synthetic opioid product by February 2, 2018. Recommendations to send to the TRIG: 1. Validation of opioid tolerance algorithm: i. Within two weeks from receipt of this communication, submit a detailed explanation of the differences between the “Insys algorithm” for opioid tolerance and the current TRIG algorithm for opioid tolerance. ii. The TRIG must move forward with the validation study, without delay. If necessary to avoid any further delay, validate both algorithms. iii. A full validation study in Optum data is not necessary since, as we discussed in the October 2 call, FDA has already initiated a similar investigation of opioid tolerance validation in Optum. Instead, you could do a smaller portability assessment of the algorithm in Optum if that is the data source that you plan to use for the study of adverse events in opioid non-tolerant patients. The full validation should be done in a different data source. iv. The HFHS data source appears to be reasonable. The linked tumor registry has the added advantage of facilitating an analysis of the proportion of patients prescribed TIRFs who have evidence of cancer at the time of TIRF initiation. FDA would be very interested in this information, as it would help provide additional context for the data you are submitting on TIRF use in opioid non-tolerant patients. To help us further assess the suitability of the data source, by February 2, 2018 please: Memo‐TRIG_Responses_16OCT2017_Final.docx  Reference ID: 4181825 FDA_7403 Interoffice Memorandum – (continued)  Page 6 of 13 pages  i. provide the number of patients using TIRFs during the proposed validation study period in HFHS and ii. compare the demographic and clinical characteristics of the TIRF users in HFHS to a geographically diverse sample of US patients who receive TIRFs, such as from a large nationwide claims database. v. If the number of TIRF recipients in HFHS is insufficient for a robust analysis, provide counts as well as demographic and clinical characteristics of TIRF recipients in an alternate data source. 2. Adverse events in non-opioid tolerant patients: i. Of the outcomes proposed, fatal and nonfatal overdose are of most concern to the FDA. We are unaware of any claims-based algorithms that have performed acceptably for misuse or abuse. ii. The brief outline for the study of adverse events in opioid non-tolerant vs opioid tolerant patients appears appropriate except that the data source does not appear to have both in- and out-ofhospital deaths with which to assess risk of overdose. Ensure that the data source(s) that you choose can be linked to out-of-hospital death and include this information in your protocol. iii. Submit your protocol for the study of fatal and non-fatal overdose in opioid non-tolerant versus opioid tolerant patients starting TIRFs by February 2, 2018. 3. Childhood poisonings: i. We agree with your outline for assessment of accidental poisonings in children in OptumHumedica data provided that the sample size is sufficient for estimating the incidence of accidental poisonings from TIRFs with a reasonable level of precision. Provide a protocol for this study, along with the counts of children ages 0-6 years with evidence of a claim for poisoning by a synthetic opioid, by February 2, 2018. Include in your protocol discussion of sample size and precision of estimates. ii. We agree with your plan for assessing the DIM data for cases of deaths due to accidental poisoning. We look forward to your protocol by February 2, 2018. iii. We look forward to hearing more about your outreach to assess the feasibility of other sources of data for accidental TIRF poisonings in children. Memo‐TRIG_Responses_16OCT2017_Final.docx  Reference ID: 4181825 FDA_7404 Interoffice Memorandum – (continued)  Page 7 of 13 pages  APPENDIX A: TABLES Appendix A Table 1: Transmucosal Immediate-release Fentanyl (TIRF) Product Descriptions and Approval Dates Drug Name Dosage Forms NDA/ANDA Applicant Approval Date Abstral Sublingual Tablet NDA 022510 Sentynl Therapeutics, Inc. 1/7/2011 Actiq Oral Transmucosal Lozenge (“lollipop”) NDA 020747 Cephalon, Inc. 11/4/1998 Fentora Buccal Tablet NDA 021947 Cephalon, Inc. 9/25/2006 Lazanda Nasal Spray NDA 022569 DepoMed, Inc. 6/30/2011 Onsolis Buccal Soluble Film NDA 022266 BioDelivery Sciences International, Inc. 7/16/2009 Subsys Sublingual Spray NDA 202788 Insys Therapeutics, Inc. 1/4/2012 fentanyl citrate Oral Transmucosal Lozenge (“lollipop”) ANDA 78907 Mallinckrodt, Inc. 10/30/2009 fentanyl citrate Oral Transmucosal Lozenge (“lollipop”) ANDA 077312 Par Pharmaceuitcal, Inc. 10/30/2009 fentanyl Oral Transmucosal Lozenge ANDA 079075 Watson Laboratories, Inc. 1/7/2011 citrate (“lollipop”) *Table reproduced from Meyer, TE. Review of NEISS-CADES Data on Pediatric Emergency Department Visits Related to Accidental Exposure to Transmucosal Immediate Release Fentanyl. Dated April 14, 2017. DARRTS Reference ID: 4084489. Memo‐TRIG_Responses_16OCT2017_Final.docx  Reference ID: 4181825 FDA_7405 Interoffice Memorandum – (continued)  Page 8 of 13 pages  APPENDIX B: Letter from the Transmucosal Immediate Release Fentanyl (TIRF) Industry Group (TRIG) to FDA dated 16OCT2017 Memo‐TRIG_Responses_16OCT2017_Final.docx  Reference ID: 4181825 FDA_7406 Interoffice Memorandum – (continued)  Memo‐TRIG_Responses_16OCT2017_Final.docx  Reference ID: 4181825 Page 9 of 13 pages  FDA_7407 Interoffice Memorandum – (continued)  Memo‐TRIG_Responses_16OCT2017_Final.docx  Reference ID: 4181825 Page 10 of 13 pages  FDA_7408 Interoffice Memorandum – (continued)  Memo‐TRIG_Responses_16OCT2017_Final.docx  Reference ID: 4181825 Page 11 of 13 pages  FDA_7409 Interoffice Memorandum – (continued)  Memo‐TRIG_Responses_16OCT2017_Final.docx  Reference ID: 4181825 Page 12 of 13 pages  FDA_7410 Interoffice Memorandum – (continued)  Memo‐TRIG_Responses_16OCT2017_Final.docx  Reference ID: 4181825 Page 13 of 13 pages  FDA_7411 --------------------------------------------------------------------------------------------------------This is a representation of an electronic record that was signed electronically and this page is the manifestation of the electronic signature. --------------------------------------------------------------------------------------------------------/s/ ---------------------------------------------------TAMRA E MEYER 11/15/2017 JANA K MCANINCH 11/15/2017 JUDY A STAFFA 11/15/2017 Reference ID: 4181825 FDA_7412 Department of Health and Human Services Public Health Service Food and Drug Administration Center for Drug Evaluation and Research Office of Surveillance and Epidemiology Office of Medication Error Prevention and Risk Management Review of the sixth (60 month, October 29, 2015 to October 28, 2016) Risk Evaluation and Mitigation Strategy (REMS) Assessment Report for Transmucosal Immediate Release Fentanyl (TIRF) Agents Date: December 4, 2017 Reviewers: Igor Cerny, Pharm.D. REMS Assessment Analyst Division of Risk Management Shelly Harris, Sc.D., M.P.H. Team Leader Division of Risk Management Associate Director: Doris Auth, Pharm.D. Division of Risk Management Division Director: Cynthia LaCivita, Pharm.D. Division of Risk Management Therapeutic Class: Transmucosal Immediate Release Fentanyl (TIRF) OND Review Division: Division of Anesthesia, Analgesia, and Addiction, Products (DAAAP) Drug Master File #: 27320 OSE RCM #: 2016-2999 Submission Dates: December 28, 2016 (Supporting Document #27) June 15, 2017 (Individual NDA/ANDA submissions) October 16, 2017 Reference ID: 4190326 FDA_7413 TIRF Products Drug Name Dosage and Route Abstral Sublingual Tablet Actiq Oral Transmucosal Lozenge Fentora Buccal Tablet Lazanda Nasal Spray Onsolis Subsys fentanyl citrate fentanyl citrate fentanyl citrate Reference ID: 4190326 NDA/ ANDA Applicant NDA Sentynl 022510 Therapeutics, Inc NDA 020747 NDA 021947 NDA 022569 Cephalon, Inc. Cephalon, Inc. DepoMed, Inc. BioDelivery Sciences International, Inc NDA Insys Sublingual Spray 202788 Therapeutics, Inc Oral ANDA Mallinckrodt, Inc Transmucosal 78907 Lozenge Oral Par ANDA Transmucosal Pharmaceutical, 077312 Lozenge Inc Oral ANDA Watson Transmucosal 079075 Laboratories, Inc. Lozenge Buccal Soluble Film NDA 022266 FDA_7414 Table of Contents Executive Summary ........................................................................................... 7 Introduction ........................................................................................................ 9 Background ........................................................................................................ 9 3.1.REMS Elements ............................................................................................. 10 3.2. Findings From Previous Assessment ........................................................ 11 REMS Modification .................................................................................. 12 Review Materials Reviewed ............................................................................ 12 Review of 48-month Assessment Report ......................................................... 14 Assessment Element 1: Utilization ........................................................... 14 5.1.1. Reviewer Comments: ......................................................................... 19 Assessment Element 2: Dispensing........................................................... 21 5.2.1. Reviewer Comments .......................................................................... 31 Assessment Element 3: Program Infrastructure ........................................ 33 Assessment Element 4: Program Non-Compliance .................................. 33 5.4.1. Reviewer Comments .......................................................................... 42 Assessment Element 5: Safety Surveillance ............................................. 48 5.5.1. Review of the TIRF REMS 48-Month Supplemental Report ............ 50 5.5.2. Product-Specific Assessment of Opioid Tolerance ........................... 54 5.5.2.2. Overview of the Studies ................................................................. 54 5.5.3.5. Reviewer Comments ...................................................................... 80 5.5.4. Review of TIRF REMS 60-Month Surveillance Data ....................... 81 5.6. Assessment Element 6: Knowledge, Attitudes, and Behavior (KAB) SURVEYS ........................................................................................................... 92 5.6.1. Patient Survey ........................................................................................... 92 5.6.2. Pharmacist Survey ..................................................................................... 97 5.6.3. Prescriber Survey ................................................................................... 103 5.7. Applicant's overall conclusion ................................................................ 109 6. OTHER OSE DIVISIONS INPUT ................................................................ 109 7. CONCLUSIONS............................................................................................ 110 7.1. Reference ID: 4190326 Completeness of report............................................................................ 110 FDA_7415 7.2. Achievement of the goals of the REMS .................................................. 110 7.3. Need for Assessment Plan Revision ....................................................... 111 7.4. Review team conclusion.......................................................................... 111 8. Recommendations .......................................................................................... 112 9. COMMENTS FOR THE SPONSOR ............................................................ 112 10. Appendix ..................................................................................................... 128 10.1 Assessment Plan ...................................................................................... 128 10.2 November 10, 2016 REMS Assessment Acknowledgement Letter ....... 132 10.3 Description of Surveillance Data ............................................................ 138 10.4 Surveillance Data Results........................................................................ 141 10.4.1. Spontaneous Adverse Event Reports Resultsa ............................. 141 10.5. Patient Survey Tables .............................................................................. 147 Reference ID: 4190326 FDA_7416 Table of Tables Table 1: Pharmacy Enrollments ............................................................................... 16 Table 2: Pharmacy Inactivations by Pharmacy Type .............................................. 17 Table 3: Reasons for Inactivations by Pharmacy Type ........................................... 17 Table 4: Numbers of Pharmacies Pending Enrollments for >3 – 6 months and >6 months and Reasons for Pending Enrollments ........................................................ 18 Table 5: Prescriptions from Outpatient Pharmacies That Did Not Encounter Any REMS-Related Rejections Prior to Being Authorized for Dispensing .................... 22 Table 6 Reasons for Prescriptions Not Meeting REMS Requirements .................. 23 Table 7: Prescriptions from Outpatient Pharmacies That Encountered at Least One REMS-Related Rejection Prior to Being Authorized for Dispensing ..................... 24 Table 8: Prescriptions That Encountered at Least One REMS-Related Rejection and Were Never Authorized for Dispensing .................................................................. 26 Table 9: Time to Authorization for a Prescription that Experienced at Least One Initial REMS-Related Rejection .............................................................................. 27 Table 10: Number of Prescription Authorizations per Closed System Pharmacy for the Current Reporting Period and Cumulatively ..................................................... 29 Table 11: Prescriptions Dispensed During the First 10 Days With and Without a PPAF ........................................................................................................................ 30 Table 12: Non-Compliance Activity Reports by Stakeholder in the Current Reporting Period ...................................................................................................... 36 Table 13: Results of the Closed System Pharmacy Audits ...................................... 40 Table 14: Rates of Prescriber 2 Scenario Cases Over Time .................................... 43 Table 15: Analysis 1 (first class-wide fill)—Demographics of Patients who Received an Initial Outpatient TIRF Prescription between 3/12/2012 and 10/28/2015, Class-wide and per Specific TIRF Product† ....................................... 62 Table 16: Analysis 1 (first class-wide fill)—Number and Proportion of Patients that Received an Opioid Analgesic Prescription prior to Initial Outpatient Specific TIRF Product Prescription (STP) Fill between 3/12/2012 and 10/28/2015, by year and time window............................................................................................................. 63 Table 17: Analysis 1 (first class-wide fill)—Number and Proportion of Patients who Received an Initial Outpatient TIRF Prescription in the LRx Database between 3/12/2012 and 10/28/2015, by Year and Opioid Tolerance Status .......................... 64 Table 18: Analysis 1 (first class-wide fill) sensitivity analysis —Demographics of Patients that Received an Initial Outpatient TIRF Prescription in the LRx Database between 3/12/2012 and 10/28/2015, Class-Wide and for Specific TIRF Products . 65 Reference ID: 4190326 FDA_7417 Table 19: Analysis 1 (first class-wide fill) sensitivity analysis^ —Number and Proportion of Patients who Received an Opioid Analgesic Prescription Prior to Initial Outpatient Specific TIRF Product (STP) Prescription Fill in the LRx Database between 3/12/2012 and 10/28/2015, by Year........................................... 66 Table 20 :Analysis 1 (first class-wide fill) sensitivity analysis^ —Number and Proportion of Patients who Received an Initial Outpatient Individual TIRF Prescription in the LRx Database between 3/12/2012 and 10/28/2015, by Year and Opioid Tolerance ..................................................................................................... 67 Table 21: Analysis 2 (first individual product fill)—Demographics of Patients Who Received an Initial Outpatient Specific TIRF Product Prescriptions in the LRx Database between 3/12/2012 and 10/28/2015 ......................................................... 68 Table 22: Analysis 2 (first individual product fill)—Number and Proportion of Patients who Received an Opioid Analgesic Prescription Prior to Initial Outpatient Specific TIRF Prescription (STP) Fill in the LRx Database between 3/12/2012 and 10/28/2015, by Year................................................................................................. 69 Table 23:Analysis 2 (first individual product fill)—Number and Proportion of Patients who Received an Initial Specific TIRF Product Outpatient Prescription in the LRx Database between 3/12/2012 and 10/28/2015, by Year and Opioid Tolerance.................................................................................................................. 70 Table 24:Analysis 2 (first individual product fill) sensitivity analysis^ — Demographics of Patients who Received an Initial Outpatient Specific TIRF Prescription in the LRx Database between 3/12/2012 and 10/28/2015 ................... 71 Table 25: Analysis 2 (first individual product fill) sensitivity analysis^ - Number and Proportion of Patients who Received an Outpatient Opioid Analgesic Prescription Prior to Initial outpatient Specific TIRF Product (STP) Prescription Fill in the LRx Database between 3/12/2012 and 10/28/2015, by year ......................... 72 Table 26: Analysis 2 (first individual product fill) sensitivity analysis^ —Number and Proportion of Patients who Received an Initial Outpatient Subsys Prescription in the LRx Database between 3/12/2012 and 10/28/2015, by year and Opioid Tolerance.................................................................................................................. 73 Table 27: Surveillance Study Design Characteristics .............................................. 81 Table 28: Adverse Event Rates during the 36, 48, and 60-month Reporting Periodsa,b .................................................................................................................. 84 Table 29: Percent change in adverse event rates for TIRFs and comparator opioids outcome between the pre- (7/2010-6/2012) and post-REMS (7/2012-6/2016) periods in the Poison Center Program and Other RADARS Program data ............. 85 Table 30: Average Knowledge Score by Key Risk Message ................................ 100 Table 31: Average Knowledge Scores for Each Key Risk Message ..................... 106 Reference ID: 4190326 FDA_7418 EXECUTIVE SUMMARY This review by the Division of Risk Management (DRISK) evaluates the 60-month risk evaluation and mitigation strategy (REMS) Assessment Report for the transmucosal immediate release fentanyl products (TIRF) shared system REMS, to determine if the goals of the REMS are being met. The TIRF REMS Access Program was approved in December 2011 to ensure the benefit of TIRFs outweighed the risks of misuse, abuse, addiction, overdose, and serious complications due to medication errors. All the TIRF Sponsors have formed a consortium known as the TIRF REMS Industry Group (TRIG). The assessment report was submitted on December 28, 2016. The goals of the REMS are to mitigate the risk of misuse, abuse, addiction, overdose, and serious complications due to medication errors by: 1) Prescribing and dispensing TIRF medicines only to appropriate patients, which includes use only in opioid-tolerant patients; 2) Preventing inappropriate conversion between TIRF medicines; 3) Preventing accidental exposure to children and others for whom it was not prescribed; and 4) Educating prescribers, pharmacists, and patients on the potential for misuse, abuse, addiction, and overdose of TIRF medicines. The 60-month assessment for the TIRF REMS includes data on certification/enrollment, distribution/dispensing, programmatic/infrastructure functioning and compliance, surveillance data (in the form of adverse event reports to the Sponsor and the Researched Abuse, Diversion, and Addiction Related Surveillance (RADARS)), a persistency analysis Phase II protocol assessing switches between TIRF products, as well as Patient, Prescriber, and Pharmacist knowledge and behavior (KAB) surveys. The REMS assessment report is complete, however it is not meeting its stated goal nor most of the objectives. Key observations of the 60-month REMS assessment report include: • The submitted surveillance data (spontaneously reported adverse events as well as RADARS data) contain a small number of events associated with TIRF products, especially in the RADARS Poison Center data, resulting in great variability in the data. However, the data appear to indicate that for most outcomes assessed, TIRF event rates have increased over time. In contrast, event rates for the composite comparators in most cases either decreased over time or had much smaller increases than those noted for TIRF products. A number of recommendations are provided for the TRIG such as the submittal of product-specific reports to facilitate our evaluation of any individual TIRF products that are driving the increases in adverse events over time. • In the Supplemental Report, the TRIG used the IMS Health Longitudinal Prescription Database (LRx) to capture opioid dispensations prior to a TIRF Reference ID: 4190326 FDA_7419 • • • Reference ID: 4190326 product dispensation to estimate opioid tolerance. Findings from individual NDA/ANDA submissions of opioid tolerance data generated via claims data indicate that regardless of the type of analysis, the proportion of opioid-non(b) (4) tolerant patients receiving a TIRF product ranged from %. Because the proportion of patients receiving TIRFs as calculated by these analyses remains concerning, the first objective (prescribing only to appropriate/opioid-tolerant patients) is not being achieved. The TRIG is investigating the use of an alternative algorithm for the determination of opioid tolerance, and we have asked them to move forward with validating opioid tolerance algorithms, without delay. The validation studies may identify evidence of opioid tolerance that is not apparent in claims data, or they will confirm the poor adherence by prescribers to opioid-tolerance requirements. The TRIG’s pharmacy switch database was the data source for the persistency analysis and uses outpatient TIRF prescription data. The persistency analysis examining TIRF product switches that were submitted in the 48-month REMS Assessment Addendum are difficult to interpret due to numerous methodologic concerns and thus resulted in the conclusion that it is not possible to tell if the second objective (prevention of inappropriate TIRF product interchanges) is being met. The TRIG is asked to re-submit these data using non-overlapping definitions and with numerators and denominators clarified. The data provided by the TRIG regarding the third objective (prevention of accidental exposure) are sparse and have many missing data elements. Therefore, it is not possible to determine whether this objective is being met. In multiple communications between FDA and the TRIG after the 60-month REMS Assessment Report, we have provided suggestions including the use of additional data sources for identification of unintentional pediatric exposures such as (e.g.) death certificate data as well as emergency department administrative claims data. Regarding the fourth objective, overall, patients, prescribers, and pharmacists had an adequate understanding of most of the key risk messages related to accidental exposure and the potential for misuse, abuse, addiction, and overdose of TIRF medicines; however all groups were less aware of the need to only prescribe and dispense TIRF medicines to appropriate patients (opioid-tolerant) than they were of other components of the TIRF REMS program. Although the respondents had adequate understanding of most of the key risk messages, the surveys were not based on probability random samples and had high non-response rate. Some results indicate that those who volunteered to respond to the surveys had different characteristics than those who were targeted to answer the surveys (e.g. education level). Therefore, the survey results may be biased and may not be generalizable to the general population of patients who received a TIRF prescription, TIRF prescribers, and pharmacists who dispensed a TIRF prescription. Given the FDA_7420 • • survey results, we conclude that this objective is being partially met, and request the TRIG continue to provide comparisons of the baseline characteristics between survey respondents and general population Concerns with the REMS’s compliance program are noted to the TRIG, such as: the number of patients enrolled by the prescriber without a complete PPAF on file needed to be considered a non-compliance event; the TRIG’s corrective action processes; and the passive nature of detecting noncompliance events Concerns with some of the TRIG’s administrative processes are noted to the TRIG such as the increasing median prescription processing time after at least one initial REMS-related rejection; lack of sufficient REMS process reminders in the closed governmental systems; the fact that the reason prescribers/pharmacies choose to leave the REMS is unknown; low numbers of inpatient pharmacies audited. We have determined that the TIRF REMS is not meeting its overall goal or most of the objectives. INTRODUCTION This review evaluates the 60-month REMS assessment report for the transmucosal immediate-release fentanyl (TIRF) products risk evaluation and mitigation strategy (REMS) to determine if the report is complete and if the goals of the TIRF REMS Access Program REMS are being met. The assessment period covers October 29, 2015 to October 28, 2016. This is the 6th REMS assessment for the TIRF REMS. The report was submitted to the TIRF drug master file (DMF) on December 28, 2016, with a Supplemental report submitted February 17, 2017. Data regarding opioid tolerance were submitted to 7 NDA/ANDAs on June 15, 2017, and additional data/responses were submitted by the TRIG on October 16, 2017 in response to an October 2, 2017 telecon between the FDA and the TRIG. BACKGROUND TIRFs are short-acting high-potency opioid analgesics indicated in the management of breakthrough pain in cancer patients. A primary safety concern with all the TIRFs is their use in opioid non-tolerant patients due to the potential of lifethreatening respiratory depression in patients not already taking and tolerant to chronic opioid analgesics. In addition, cases of diversion, abuse, overdose, misuse, and prescribing to opioid-non-tolerant patients have led to serious adverse events or fatalities, further demonstrating that these products can pose a serious and significant public health concern. Thus, FDA determined that a REMS was necessary to ensure the benefits outweigh the risks of misuse, abuse, addiction, Reference ID: 4190326 FDA_7421 overdose, and serious complications associated with the use of TIRF medicines. However, in 2010, the FDA also determined that, in the interest of public health and to minimize the burden on the healthcare system, a single, shared REMS should be implemented for all members of the TIRF class and on December 28, 2011, the “TIRF REMS” was approved for Abstral, Actiq, Fentora, Lazanda, Onsolis, and generic versions of these TIRF medicines. On January 4, 2012, the FDA approved Subsys, as well as its inclusion into the TIRF REMS Access program. The TIRF REMS Access program was launched on March 12, 2012, approximately 11 weeks after REMS approval. Implementation of the TIRF REMS for closed system pharmacies 1 was launched on June 30, 2012. The TIRF REMS Industry Group (TRIG) includes Actavis Laboratories FL, Inc., BioDelivery Sciences International, Inc., Cephalon, Inc. [a wholly-owned subsidiary of Teva Pharmaceutical Industries, Ltd.], Depomed, Inc., Insys Therapeutics Inc., Mallinckrodt Pharmaceuticals, Mylan, Inc. , Par Pharmaceutical, Inc., and Sentynl Therapeutics, Inc.). The TIRF REMS Access program is administered by McKesson Specialty Health and RelayHealth. The 60-month assessment report was prepared by United BioSource Corporation (UBC). The goals of the TIRF REMS Access program are to mitigate the risk of misuse, abuse, addiction, overdose, and serious complications due to medication errors by: 1. Prescribing and dispensing TIRF medicines only to appropriate patients, which includes use only in opioid-tolerant patients; 2. Preventing inappropriate conversion between TIRF medicines; 3. Preventing accidental exposure to children and others for whom it was not prescribed; 4. Educating prescribers, pharmacists, and patients on the potential for misuse, abuse, addiction, and overdose of TIRF medicines. 3.1.REMS ELEMENTS The TIRF REMS elements include: • A Medication Guide - a product-specific TIRF Medication Guide will be dispensed with each TIRF prescription. These Medication Guides are available on the TIRF REMS Access website (www.TIRFREMSaccess.com). • Elements to Assure Safe Use (ETASU) – details include:  (ETASU A) training and certifying outpatient TIRF prescribers;  (ETASU B) training and certifying pharmacies who dispense TIRFs; 1 Closed systems are defined as “integrated healthcare systems that dispense for outpatient use with pharmacy management systems unable to support the process of electronically transmitting the validation and claim information required.” Reference ID: 4190326 FDA_7422  • • (ETASU C) assurances that TIRF medicines will only be dispensed for outpatient use with evidence or other documentation of safe-use conditions; i. patients are enrolled when their first prescription is processed at a pharmacy; ii. a completed Patient-Prescriber Agreement Form (PPAF) must be sent to the TIRF REMS Access program by the prescriber within 10 working days from the processing date of the patient’s first prescription; iii. a maximum of three prescriptions are allowed within 10 working days from when the patient had their first prescription filled with no additional dispensations allowed until a completed PPAF is received; iv. upon receipt of a prescription for a TIRF medicine at an enrolled pharmacy, the pharmacist enters the prescription details in their pharmacy management system (PMS) and sends the transaction to the TIRF REMS Access program via a switch provider to ensure that all elements meet the requirements of the TIRF REMS Access program; An Implementation System involves training and enrolling wholesalers/distributors who distribute TIRFs. The TRIG is required to maintain databases of prescribers, pharmacies, patients, and distributors, as well as develop a TIRF Access System; The Timetable for submission of REMS Assessment Reports was at 6 and 12 months for the first year then annually thereafter to be submitted on or before December 28th of each year. The TIRF REMS Assessment Plan can be found in Appendix Section 10.1 of this review. 3.2. FINDINGS FROM PREVIOUS ASSESSMENT The 48-month assessment report for the TIRF REMS was finalized on September 28, 2016. On November 10, 2016, the TRIG was issued a REMS Assessment Acknowledgement Letter (RAAL) stating that the REMS Assessment was complete but that it was not possible to determine whether the overarching goal of the REMS - to mitigate the risk of misuse, abuse, addiction, overdose, and serious complications due to medication errors - was being met. The first objective (prescribing and dispensing TIRF medicines only to appropriate patients, which includes use only in opioid-tolerant patients) was not being achieved since approximately 42% of patients prescribed TIRF products were not opioid tolerant. The TRIG was told to further investigate this concerning finding and that at a minimum, further evaluation of this finding needed to include product- Reference ID: 4190326 FDA_7423 specific assessment of opioid tolerance that each member sponsor will submit only to their NDA or ANDA It was not possible to determine if the second objective (preventing inappropriate conversion between TIRF medicines) was being met, although a persistency analysis provided by the TRIG indicated that the number of patients who may be exposed to inappropriate conversion between TIRF medicines may be as high as 17.1-20.5%. It was also not possible to determine if the third objective (preventing accidental exposure to children and others for whom it was not prescribed) was being met since only a few case reports were presented and included little detail, The fourth objective (educating prescribers, pharmacists, and patients on the potential for misuse, abuse, addiction, and overdose of TIRF medicines) was partially met. Overall, while patients, prescribers, and pharmacists seemed to have an adequate understanding of most of the key risk messages, all of these stakeholders had a lower awareness of the need to only prescribe and dispense TIRF medicines to appropriate (opioid-tolerant) patients. The RAAL can be found in Appendix Section 10.2. REMS MODIFICATION On April 10, 2017, the TRIG Sponsors were issued a REMS Modification Notification Letter as a result of approval of the safety labeling changes on December 16, 2016. The REMS modification that incorporated those changes was approved in September 2017. Those labeling changes strengthened the warnings regarding the risks of misuse, abuse, addiction, overdose, death and neonatal opioid withdrawal syndrome; serotonin syndrome with concomitant use of serotonergic drugs; adrenal insufficiency; androgen deficiency; and profound sedation, respiratory depression, coma, and death associated with the concomitant use of opioid analgesics and benzodiazepines or other central nervous system depressants, including alcohol. REVIEW MATERIALS REVIEWED • August 17, 2001 Actiq Periodic Safety Update Report (PSUR)-16, Supporting Document #102 • April 15, 2008 Fentora RiskMap 5th Quarterly Report, Supporting Document #94 • May 4, 2016 48-Month REMS Supplemental Assessment Report • November 10, 2016 REMS Assessment Acknowledgement Letter from DAAAP (J. Racoosin) Reference ID: 4190326 FDA_7424 • • • • • • • • • • • • • • • • • • • • Reference ID: 4190326 December 28, 2016, 60-month TRIG Assessment Report submitted by the TRIG February 17, 2017, TRIG supplemental submission to the 60-month REMS Assessment Report. March 10, 2017 TRIG response to the March 3, 2017 TRIG-FDA teleconference March 21 FDA email to the TRIG regarding opioid tolerance March 31, 2017 TRIG response to the March 3, 2017 TRIG-FDA teleconference April 10, 2017 REMS Modification Notification Letter from DAAAP (J. Racoosin) April 10, 2017 (accessed) “What are Transmucosal Immediate-Release Fentanyl (TIRF products?” TIRF REMS webpage http://www.accessdata.fda.gov/scripts/cder/rems/index.cfm?event=RemsDet ails.page&REMS=60 April 21, 2017 DEPI II (T. Meyer) Consult Review of NEISS-CADES Data on Pediatric Emergency Department Visits Related to Accidental Exposure to Transmucosal Immediate Release Fentanyl May 2, 2017 DEPI II (D.T. Coyle and T. Pham) Consult Review of 48Month Transmucosal Immediate-Release Fentanyl (TIRF) Product REMS Assessment Data May 5, 2017 TRIG response to the April 28, 2017 FDA Information Request (IR) May 30, 2017 TRIG response to the April 28, 2017 FDA IR June 15, 2017, TIRF REMS Access Program Assessment—Use of Individual Products: NDA 22510;Name: Abstral June 15, 2017, TIRF REMS Access Program Assessment—Use of Individual Products: NDA 20747;Name: Actiq June 15, 2017, TIRF REMS Access Program Assessment—Use of Individual Products: ANDA 77312 June 15, 2017, TIRF REMS Access Program Assessment—Use of Individual Products: ANDA 79075 June 15, 2017, TIRF REMS Access Program Assessment—Use of Individual Products: NDA 21947;Name: Fentora June 15, 2017, TIRF REMS Access Program Assessment—Use of Individual Products: NDA 22569;Name: Lazanda June 15, 2017, TIRF REMS Access Program Assessment—Use of Individual Products: NDA 202788;Name: Subsys July 20, 2017 Pharmacovigilance Consult Review from DPV II (C. Patel) regarding TIRF accidental exposures and off label use August 4, 2017 DEPI II (T. Meyer) Consult Review of 60-Month Transmucosal Immediate-Release Fentanyl (TIRF) Product REMS Assessment Data FDA_7425 • • • • • • • August 24, 2017 response from TEVA to an August 10, 2017 FDA information request (IR) regarding older opioid tolerance data for Fentora August 31, 2017 response from TEVA to an August 17, 2017 FDA information request (IR) regarding older opioid tolerance data for Actiq August 31, 2017 Memo from DEPI (T. Meyer) providing responses to the TRIG’s responses Dated March 31, 2017 September 19, 2017 DB7 (R. Zhang) Statistical Review and Evaluation for TIRFs October 16, 2017 TRIG response to FDA questions from an October 2, 2017 telecon between the FDA and the TRIG November 2, 2017 TRIG response to an October 27, 2017 FDA IR November 15, 2017 Memo from DEPI (T. Meyer) providing responses to the TRIG’s responses Dated October 16, 2017. REVIEW OF 48-MONTH ASSESSMENT REPORT ASSESSMENT ELEMENT 1: UTILIZATION The first element of the Assessment Plan states: 1. The TIRF REMS Access Program Utilization Statistics (data presented per reporting period and cumulatively): a. Patient Enrollment: a. Number of unique patients enrolled b. Number of patients inactivated b. Prescriber Enrollment: a. Number of prescribers enrolled b. Number of prescribers that attempted enrollment but whose enrollment is pending for >3 months and >6 months along with the specific reasons why their enrollment is pending; c. Number of prescribers inactivated c. Pharmacy Enrollment: a. Number of pharmacies enrolled by type (inpatient, chain, independent, closed system; provide identity of closed system entities); b. Number of pharmacies that attempted enrollment but whose enrollment is pending for >3 months and >6 months along with the specific reasons why their enrollment is pending (stratified by type); c. Number of pharmacies inactivated by type (inpatient, chain, independent, closed system); d. Distributor enrollment: a. Number of distributors enrolled; Reference ID: 4190326 FDA_7426 b. Number of distributors inactivated; Patients: During the current reporting period, there were 4,225 newly enrolled patients (compared to 8,740 the previous reporting period), resulting in a cumulative total of 42,164 patients enrolled in the TIRF REMS. In a May 5, 2017 response from the TRIG to an April 28, 2017 Information Request (IR) 2 from the FDA, the TRIG verified the 4,225 newly enrolled patients total. In the assessment report the TRIG states that “…by the design of the program, a patient enrollment status will never change to inactivated.” However, in the May 5, 2017 response, the TRIG states that “Patients remain passively enrolled in the program from reporting period to reporting period as long as they continue therapy. Therefore, the number of newly enrolled patients may decrease from year to year as more patients may be continuing therapy and not initiating therapy.” Prescribers: At the end of this reporting period there were 8,151 prescribers currently enrolled (9,096 were enrolled last year). This current total includes 1,446 newly enrolled prescribers, 2,631 prescribers who re-enrolled and 4,074 who remain active from a previous period. Cumulatively there have been 16,549 prescribers who have successfully completed enrollment in the program. - Inactivations: A total of 3,635 prescribers were inactivated at some point during the current reporting period, 99.5% (3,616) were due to expiration of enrollment (prescribers are required to re-enroll every 2 years in the REMS). Of those 3,616 prescribers whose enrollment expired at some point during the current reporting period, 2,763 (76.4%) remained expired at the end of the reporting period. In total, 8,401 prescribers remained inactivated at the end of the reporting period. During the current reporting period; • 54 prescribers attempted enrollment but enrollment was pending 3 to 6 months later; • 194 prescribers had their enrollment pending for more than 6 months - Pending Enrollments The primary reasons for prescriber enrollments pending for 3-6 months were for “training not complete” (83%) and “no attestation” (82%). The primary reasons for 2 The April 28, 2017 IR asked the TRIG to verify the number of newly enrolled patients is 4225. We note that this number is less than half of the 8740 newly enrolled patients reported in the December 2015 TIRF REMS Assessment report. Reference ID: 4190326 FDA_7427 enrollments for more than 6 months were for similar reasons, “no attestation” (75%) and “training not complete” (62%). Pharmacies: The total number of pharmacies in the program (newly enrolled/re-enrolled or previously enrolled) are presented in Table 1, data taken from the TRIG’s Table 8: Table 1: Pharmacy Enrollments Curre nt Re porting Pe riod Parameter Total Number of Pharmacies Enrolled as of the End of this Reporting Period Chain Pharmacy Store s Independent Outpatient Pharmacies Inpatient Pharmacies Chain Pharmacy Headquarters Closed System Headquarters Closed System Pharmacies Total Number of Newly Enrolled Pharmacies Chain Pharmacy Store s Independent Outpatient Pharmacies Inpatient Pharmacies Chain Pharmacy Headquarters Closed System Headquarters Closed System Pharmacies Total Number of Re-Enrolled Pharmacies Chain Pharmacy Store s Independent Outpatient Pharmacies Inpatient Pharmacies Chain Pharmacy Headquarters Closed System Headquarters Closed System Pharmacies Number of Pharmacies that Remain Enrolled from the Previous Reporting Period Chain Pharmacy Store s Independent Outpatient Pharmacies Inpatient Pharmacies Chain Pharmacy Headquarters Closed System Headquarters Closed System Pharmacies Non-Clos e d Sys te m Pharmacie s N (%) Clos e d Sys te m Pharmacie s N (%) Total Pharmacie s N (%) 42,433 232 42,665 37,535 (88.5%) 4,060 (9.6%) 760 (1.8%) 78 (0.2%) N/A N/A 1,529 (5.8%) 1,026 (67.1%) 387 (25.3%) 114 (7.5%) 2 (0.1%) N/A N/A 24,787 (94.2%) 22,043 (88.9%) 2,260 (9.1%) 439 (1.8%) 45 (0.2%) N/A N/A N/A 37,535 (88.0%) N/A 4,060 (9.5%) N/A 760 (1.8%) N/A 78 (0.2%) 6 (2.6%) 6 (<0.1%) 226 (97.4%) 226 (0.5%) 8 (3.5%) N/A N/A N/A N/A 0 8 (100.0%) 1,537 (5.8%) 1,026 (66.8%) 387 (25.2%) 114 (7.4%) 2 (0.1%) 0 8 (0.5%) 219 (96.5%) 25,006 (94.2%) N/A 22,043 (88.2%) N/A 2,260 (9.0%) N/A 439 (1.8%) N/A 45 (0.2%) 5 (2.3%) 5 (<0.1%) 214 (97.7%) 214 (0.9%) 16,118 5 16,123 14,466 (89.8%) 1,414 (8.8%) 207 (1.3%) 31 (0.2%) N/A N/A N/A N/A N/A N/A 1 (20.0%) 4 (80.0%) 14,466 (89.7%) 1,414 (8.8%) 207 (1.3%) 31 (0.2%) 1 (<0.1%) 4 (<0.1%) Percentages are based on the total number (N) of pharmacies with enrollment activity in this reporting period; The number of Chain Pharmacy Headquarters and Closed System Headquarters may not be associated with the number of Chain Pharmacy Stores and Closed System Pharmacies, respectively Chain Pharmacy Stores or Closed System Pharmacies may be associated with a Headquarter enrolled in a previous reporting period As compared to 42,433 non-closed system pharmacies enrolled this reporting period, 42,968 were enrolled last reporting period. Chain pharmacies make up the vast majority (88.5%) of pharmacy types in the TIRF REMS program, while independent pharmacies comprise 9.6%. In the TRIG’s May 30, 2017 response to Reference ID: 4190326 FDA_7428 the Agency’s April 28, 2017 IR, the TRIG states that: “The TIRF REMS Access program defines independent outpatient pharmacies as “retail, mail order, or institutional outpatient pharmacies”. The vast majority of closed system pharmacies (214/232 = 92%) re-enrolled this reporting period. Tables 2 and 3 (adapted from the TRIG’s Table 9) summarizes pharmacy inactivations by pharmacy type and include the reasons for the inactivations during the current reporting period: Table 2: Pharmacy Inactivations by Pharmacy Type Curre nt Re porting Pe riod Parameter Number of Pharmacies that Became Inactivated During this Reporting Period Chain Pharmacy Stores Independent Outpatient Pharmacies Inpatient Pharmacies Chain Pharmacy Headquarters Close d Syste m Pharmacie s Numbers of Pharmacies Inactivated in This Time Period that Remain Inactivated at End of Reporting Period Chain Pharmacy Stores Independent Outpatient Pharmacies Inpatient Pharmacies Chain Pharmacy Headquarters Close d Syste m Pharmacie s Cumulative Number of Pharmacies Ever Inactivated Non-Close d Syste m Pharmacie s N (%) Close d Syste m Pharmacie s N (%) Total Pharmacie s N (%) 4,530 206 4,736 3,043 (67.2%) 1,222 (27.0%) 252 (5.6%) 13 (0.3%) N/A N/A 206 (100%) 3,043 (64.3%) 1,222 (25.8%) 252 (5.3%) 13 (0.3%) 206 (4.3%) N/A N/A N/A 2,610 39 2,649 1459 (55.9%) 942 (36.1%) 204 (7.8%) 5 (0.2%) N/A N/A 1459 (55.1%) 942 (35.6%) 204 (7.7%) 5 (0.2%) N/A 39 (100%) N/A 16,763 360 17,123 N/A N/A Table 3: Reasons for Inactivations by Pharmacy Type Reference ID: 4190326 FDA_7429 Reasons for Inactivation by Pharmacy Type Reason(s) for Chain Pharmacy Store Inactivation Enrollment Expired Program Opt-Out -----Enrollment remained expired at end of period 2,819 (92.6%) 224 (7.4%) 1,242 (44.1%) Reason(s) for Independent Outpatient Pharmacy Inactivation Enrollment Expired Program Opt-Out -----Enrollment remained expired at end of period 1,214 (99.3%) 8 (0.7%) 934 (76.9%) Reason(s) for Inpatient Pharmacy Inactivation Enrollment Expired Program Opt-Out -----Enrollment remained expired at end of period 249 (98.8%) 3 (1.2%) 201 (80.7%) Reason(s) For Closed System Pharmacy Inactivation Enrollment Expired -----Enrollment remained expired at end of period 206 (100.0%) 39 (18.9%) Reason(s) for Chain Pharmacy Headquarters Inactivation Enrollment Expired Program Opt-Out -----Enrollment remained expired at end of period 12 (92.3%) 1 (7.7%) 4 (33.3%) Of the 4,530 pharmacies inactivated this reporting period, 57.6% (2,610) remained inactivated at the end of the reporting period. The reasons for inactivation were 0.7 – 7.4% due to “program opt out” and 93-99% due to “enrollment expired.” Interestingly, while 48% of the chain stores that became inactivated this reporting period remained inactivated at the end of the reporting period, 77% of independent stores that became inactivated this reporting period remained so at the close of the period. Table 4 below (adapted from TRIG Assessment report, Table 10) presents the number and reasons for pending pharmacy enrollments for those enrollments pending for either 3-6 months or >6 months: Table 4: Numbers of Pharmacies Pending Enrollments for >3 – 6 months and >6 months and Reasons for Pending Enrollments Current Reporting Period Parameter Number of Pharmacies Who Attempted Enrollment but are Still Pending Enrollment Pharmacies Pending Pharmacies Pending Enrollment Enrollment ≥3 – 6 Months >6 Months 39 209 46% 46% 31% 10% 54% 40% 35% 4% Reasons for Pending Enrollment Pending Test Transaction Verification No Attestation Training not complete Knowledge Assessment Failures Reference ID: 4190326 FDA_7430 The TRIG states that a single pharmacy may be pending enrollment for more than one reason. The primary reason for pending enrollments is “pending test transaction verification” although “no attestation” and “training not complete” were frequent causes as well. The TRIG does not provide additional detail as to why these reasons would extend for so long a period of time. Wholesaler/Distributor Enrollment: During the current reporting period, 1 (4.8%) wholesaler/distributor was newly enrolled in the REMS program and 20 (95.2%) re-enrolled. There were 5 wholesalers/distributors inactivated during the current reporting period due to enrollment expiration and 3 had not re-enrolled by the end of the reporting period because they were acquired by other enrolled entities or were initially enrolled as the wrong stakeholder type. 5.1.1. Reviewer Comments: 1. The number of newly enrolled patients this reporting period decreased by over 50% as compared to the previous reporting period, while the number of enrolled prescribers decreased by 10% this reporting period as compared to the last. 2. Of the 3,616 prescribers whose enrollment expired at some point during the current reporting period, 2,763 (76.4%) remained expired at the end of the reporting period. Similarly, Of the 4,530 pharmacies inactivated this reporting period, 57.6% (2,610) remained inactivated at the end of the reporting period. The reasons for inactivation were 0.7 – 7.4% due to “program opt out” and 93-99% due to “enrollment expired.” In the FDA’s 36-month RAAL, the TRIG was asked to “Conduct outreach to a representative sample of those health professionals and pharmacies who did not re-enroll in the TIRF REMS Access Program so as to ascertain their reasons and report the results in your next Assessment Report. We are concerned about potential patient access issues.” In the 48 month assessment report, the TRIG responded that: “Based on…analysis, there is no barrier to patient access and further outreach is unwarranted.” The TRIG stated that 8.6% of prescribers who chose to not re-enroll had an average of no more than four prescriptions total over the course of the reporting period. However, the reasons why the remaining prescribers did not re-enroll in the program were not addressed, and the reasons why many pharmacies did not re-enroll were similarly unknown. Additionally, the reasons why 412 pharmacies chose not to re-enroll are not presented. Thus in the 48-month RAAL the TRIG was told that they should conduct an “…outreach to a representative sample of those health professionals and Reference ID: 4190326 FDA_7431 pharmacies who did not re-enroll in the TIRF REMS Access Program so as to ascertain their reasons…(w)e are concerned about potential patient access issues.” The TRIG was told to submit a timeline for the outreach plan in the February 17, 2017, submission of the supplemental 60-month REMS assessment. In the February 17, 2017 Supplement to Assessment report submission, the TRIG stated that they have “: “In response to the request from the FDA, a timeline has been developed to perform outreach to a representative sample of those health professional and pharmacies that did not re-enroll in the TIRF REMS Access program to ascertain their reasons for not re-enrolling. The TRIG has initiated activities to collect these data and results will be included in the 72-Month FDA REMS Assessment Report.” Additionally, the Agency’s April 28, 2017 IR to the TRIG requested that they “…develop an opt-out form that includes various opt-out reasons that are mutually agreed upon by the Agency and the TRIG…The TRIG would provide this form to the stakeholder to complete and submit to the REMS as written confirmation of their intention to opt-out of the program.” On May 30, 2017, the TRIG responded that their outreach activities to stakeholders who do not re-enroll “…will only include those who were deactivated for failure for re-enrollment (lapse in enrollment based on lack of action of the prescriber), not those who opt-out of the program (proactive communication to the program to have enrollment end). The TRIG can collect information via an opt-out form for stakeholders, but it is unclear whether any useful data will be obtained as collection of opt-out reasons would require proactive outreach of a stakeholder that is not interested in participating in the program.” The Agency looks forward to reviewing the data in the 72-month Assessment Report as to the reasons why those who chose not to re-enroll. As part of the data to be submitted for the 72-month report, the TRIG will be asked to investigate whether pharmacy inactivations occurred disproportionately among any particular chain or geographic region. 3. Chain pharmacies make up the vast majority (88.5%) of pharmacy types in the TIRF REMS program, and independent pharmacies comprise only 9.6%. While 48% of the chain stores that became inactivated this reporting period remained inactivated at the end of the reporting period, 77% of independent stores that became inactivated this reporting period remained so at the close of the period. During the previous reporting period, a similar pattern was shown in which a smaller proportion of inactivated chain stores remained inactive at the end of the reporting period (16.6%) as compared to independent pharmacies (78.4%). It is not clear why this large discrepancy Reference ID: 4190326 FDA_7432 exists. Also, as can be seen in Tables 5, 7, and 8, independent pharmacies appear to receive more TIRF prescriptions than chain pharmacies. The TRIG will be asked to explain why there is a lower number of reenrollments by independent pharmacies. ASSESSMENT ELEMENT 2: DISPENSING The second element of the Assessment Plan states: 2. Dispensing activity for enrolled pharmacies - metrics stratified by pharmacy type (open vs. closed system) a. Number of prescriptions/transactions authorized; for closed systems, provide the number of prescription transactions per closed system entity; b. Number of prescriptions/transactions denied and reasons for denial. Include the number of prescriptions/transactions rejected for safety issues (provide description of safety issues and any interventions or corrective actions taken); c. Number of prescriptions/transactions rejected for other reasons (e.g., prescriber not enrolled) with a description of these specific other reasons; d. Mean and median amount of time it takes for a prescription that experienced at least one initial REMS-related rejection to be authorized e. Number of patients with more than three prescriptions dispensed during the first ten days after patient passive enrollment without a PPAF; f. Number of prescriptions dispensed after ten days without a PPAF in place.” In the TRIG’s May 31, 2017 response to the FDA’s April 28, 2017 IR, 3 the TRIG states that “10,450 patients were dispensed a prescription for a TIRF during this reporting period….” However the TRIG also stated that they are further researching this number to insure it represents unique patients only. Table 5 (adapted from the TRIG’s Table 13) summarizes unique prescriptions presented for dispensing, unique prescriptions that did not encounter any REMS rejections, and dispensing by type of pharmacy: 3 The April 28, 2017 FDA IR asked the TRIG to provide us with how many patients were dispensed a prescription for a TIRF during this reporting period. Reference ID: 4190326 FDA_7433 Table 5: Prescriptions from Outpatient Pharmacies That Did Not Encounter Any REMS-Related Rejections Prior to Being Authorized for Dispensing Of the 117,708 unique prescriptions (closed and non-closed systems) submitted for REMS authorization, 89% did not encounter any REMS-related rejections (i.e., were authorized for dispensing by insurance or cash bin). Last reporting period, 152,686 prescriptions were submitted for authorization. Thus, the volume of TIRF prescriptions submitted for authorization decreased by 23% from the previous reporting period to this reporting period. Approximately 64% of the prescriptions submitted for REMS authorization that did not encounter any REMS-related rejections were filled at independent pharmacies versus 36% from chains. Recall that independent pharmacies comprise only 9.6% of pharmacies enrolled in this REMS. The TRIG presents data regarding prescriptions that either encountered at least one REMS-related rejection or were totally rejected due to REMS criteria. The TRIG has provided definitions for the reasons they cite for rejections and these are presented in Table 6 below (reproduced in its entirety from the assessment report’s Table 14): Reference ID: 4190326 FDA_7434 Table 6 Reasons for Prescriptions Not Meeting REMS Requirements Table 7 below (data extracted from the TRIG’s Table 15) presents the number of outpatient prescriptions that encountered at least one REMS-related rejection prior to being authorized for dispensing as well as the most common reasons for the REMS rejection per pharmacy type: Reference ID: 4190326 FDA_7435 Table 7: Prescriptions from Outpatient Pharmacies That Encountered at Least One REMS-Related Rejection Prior to Being Authorized for Dispensing Current Reporting Periodb 29OCT2015 to 28OCT2016 Parameter Non-Closed System Pharmacies N (%) All Closed Pharmacies System (Non-Closed Pharmacies and Closed) N (%) N (%) Cumulative b c 28DEC2011 to 28OCT2016 Non-Closed System Pharmacies N (%) Number of Unique Prescriptions Presented for Dispensing Total Number of Unique Prescriptions that encountered At Least One Initial REMSRelated Rejection Prior to being Authorized for Dispensing a Independent Pharmacies 1,212 (1.0%) 1,212 (1.0%) 15,274 (2.3%) Chain Pharmacies 1,150 (1.0%) 1,150 (1.0%) Closed System Pharmacies Closed All Pharmacies System (Non-Closed Pharmacies and Closed) N N (%) (%) 117,335 373 117,708 675,373 3,408 678,781 2,362 (2.0%) 1 (0.3%) 2,363 (2.0%) 21,733 (3.2%) 58 (1.7%) 21,791 (3.2%) 1 (0.3%) 1 (<0.1%) 15,274 (2.3%) 6,459 (1.0%) 6,459 (1.0%) 58 (1.7%) 58 (<0.1%) Independent Pharmacies: Reason(s) for Rejectiond Zip Code Missing 125 (10.3%) 6,689 (43.8%) PPAF Incomplete 319 (26.3%) 4,416 (28.9%) Prescriber last name did not 79 (6.5%) 1,925 (12.6%) match registered Prescriber ID not registered 139 (11.5%) 1,768 (11.6%) PPAF Expired 262 (22.8%) 1,102 (7.2%) PPAF terminated 0 884 (5.8%) Chain Pharmacies: Reason(s) for Rejectiond PPAF Incomplete 178 (15.5%) 2,492 (38.6%) Prescriber ID not registered 104 (9.0%) 1,190 (18.4%) Zip Code Missing 181 (15.7%) 1,043 (16.1%) Prescriber last name did not 425 (37.0%) 931 (14.4%) match registered PPAF Expired 45 (9.4%) 656 (10.2%) PPAF terminated 0 518 (8.0%) Closed System: Reason(s) for Rejectiond Zip Code Missing 0 33 (56.9%) PPAF Incomplete 0 10 (17.2%) Prescriber ID not registered 0 9 (15.5%) PPAF terminated 0 6 (10.3%) Prescriber last name did not 0 6 (10.3%) match registered PPAF Expired 0 3 (5.2%) PPAF No Activity 1 (100.0%) 1 (1.7%) a Prescription successfully adjudicated for safety (i.e., successful REMS edit).and authorized for dispensing by insurance or cash bin (bin number). b Percentages are based on the total number (N) of number of unique prescriptions that encountered at least one initial REMS-related rejection prior to being authorized for dispensing for the reporting period. c Includes authorizations from pharmacies that transitioned into the TIRF REMS Access Program from other individual REMS programs. d Prescriptions can be rejected for more than one reason. Reference ID: 4190326 FDA_7436 The TRIG also states that the percentages for all rejection reasons in the following tables may not equal 100% as a prescription may be rejected for multiple reasons A total of 2,362 of (non-closed system) prescriptions (or 2% of the overall number of prescriptions submitted for REMS authorization) received at least one REMSrelated rejection prior to dispensing. The total number of rejections was quite similar between chain and independent pharmacies although the overall volume of prescriptions submitted by independent pharmacies for authorization is higher than the overall volume for chains. The reasons for rejection between chains, independents, and closed systems were similar and involved either some form of an incomplete PPAF or a prescription written by a non-registered prescriber. Table 8 below (data extracted from the TRIG’s Table 16) presents the number of outpatient prescriptions that encountered at least one REMS-related rejection prior and were never authorized for dispensing as well as the most common reasons for the REMS rejection per pharmacy type: Reference ID: 4190326 FDA_7437 Table 8: Prescriptions That Encountered at Least One REMS-Related Rejection and Were Never Authorized for Dispensing Parameter Number of Unique Prescriptions Presented for Dispensing Total Number of Unique Prescriptions that encountered At Least One Initial REMSRelated Rejection Prior to being Authorized for Dispensing a Independent Pharmacies Chain Pharmacies Closed System Pharmacies Independent Pharmacies: Reason(s) for Rejectiond Prescriber ID not registered Prescriber last name did not match registered Zip Code Missing Prescriber is terminated PPAF Incomplete Chain Pharmacies: Reason(s) for Rejectiond Prescriber ID not registered Prescriber last name did not match registered PPAF Incomplete Prescriber is terminated Zip Code Missing Closed System: Reason(s) for Rejectiond Prescriber ID not registered Prescriber last name did not match registered PPAF Incomplete Pharmacy is terminated Prescriber is terminated Current Reporting Periodb 29OCT2015 to 28OCT2016 Non-Closed Closed All System System Pharmacies Cumulative b c 28DEC2011 to 28OCT2016 Non-Closed Closed All Pharmacies System System (Non-Closed 117,335 373 117,708 675,373 3,408 678,781 10,225 (8.7%) 44 (11.8%) 10,269 (8.7%) 51,539 (7.6%) 609 (17.9%) 52,148 (7.7%) 3,386 (2.9%) 6,839 (5.8%) 3,386 (2.9%) 23,849 (3.5%) 23,849 (3.5%) 6,839 (5.8%) 27,690 (4.1%) 27,690 (4.1%) 44 (11.8%) 44 (<0.1%) 609 (17.9%) 609 (0.1%) 1,105 (32.6%) 10,770 (45.2%) 432 (12.8%) 4,328 (18.1%) 631 (18.6%) 778 (23.0%) 168 (5.0%) 2,985 (12.5%) 2,468 (10.3%) 2,459 (10.3%) 1,298 (19.0%) 14,870 (53.7%) 3,711 (54.3%) 6,163 (22.3%) 139 (2.0%) 592 (8.7%) 1,393 (20.4%) 2,482 (9.0%) 2,019 (7.3%) 1,759 (6.4%) 23 (52.3%) 330 (54.2%) 8 (18.2%) 111 (18.2%) 0 6 (13.6%) 4 (9.1%) 55 (9.0%) 47 (7.7%) 38 (6.2%) A total of 10,225 non-closed system prescriptions (8.7% of the total amount of prescriptions submitted for REMS authorization) were never authorized for dispensing due to REMS-related rejections. Over twice as many chains as compared to independents experienced such events even though the volume of overall prescriptions submitted for authorization by chains was less than the volume submitted by independents. The primary reason for rejection for all pharmacy types was due to a prescription written by a non-registered prescriber. Reference ID: 4190326 FDA_7438 Prescription Authorization Times Table 9 below (taken in part from the TRIG’s Report Table 17) presents the mean and median times to eventual prescription authorization after the prescription experienced at least one REMS-related rejection per pharmacy type: Table 9: Time to Authorization for a Prescription that Experienced at Least One Initial REMS-Related Rejection 60 month Reporting 48 month Reporting 36 month Reporting 24 month Reporting Period 29OCT2015 Period 29OCT2014 Period 29OCT2013 Period 29OCT2012 to 28OCT2016 to 28OCT2015 to 28OCT2014 through 28 OCT2013 Total Mean Time For Prescription 6.30 6.68 4.90 -7 14 5 46 56 86 c -7 81 6 25 -- -5 10 4 82 10 04 to be Authorizeda (Days)b 2.03 1.32 1.06 Inpatient Pharmacies Chain Pharmacy Stores Independent Outpatient Pharmacies Closed System Pharmacies -2 80 1 68 56 86 c -2 17 1 03 -- -1 73 0 98 2 48 to be Authorizeda (Days)b Inpatient Pharmacies Chain Pharmacy Stores Independent Outpatient Pharmacies Closed System Pharmacies Total Median Time For Prescription 2.10 Cumulative 28DEC2011 to 28OCT2015 4.02 -4.93 3.62 7.16 0.01 0.70 -1.17 0.15 1.16 a Prescriptions included were resolved in the current reporting period. Prescriptions may have been initially rejected in a previous reporting period. b Time to authorization for a prescription that experienced at least one initial REMS-related rejection excludes prescriptions processed through the inpatient pharmacy process. c The mean and median data represent the actual time to authorization for 1 closed system pharmacy prescription.. The median prescription processing time for a prescription that experienced at least one initial REMS-related rejection appears to continue to increase over time for both chain and independent stores. In both the 36-month and the 48-Month FDA RAALs, the FDA requested that the TRIG investigate the cause of increasing delays in prescription processing since these may be potential indicators of access barriers. The TRIG did not submit the results of such an investigation. However, in the current report, the TRIG did provide data indicating that of all the prescriptions that encounter at least one REMS-related rejection over 80% are resolved within the first 10 days. The TRIG also commented that “At the current time it is not possible to distinguish between prescriptions that encounter at least one REMS-related rejection that are quickly resolved and those that are not.” Figure 1 below (reproduced from the TRIG Assessment Report’s Figure 1) shows the distribution of time to authorization for a Prescription that Experienced at Least One Initial REMS-Related Rejection during the current reporting period. Reference ID: 4190326 FDA_7439 Figure 1: Distribution of Time to Authorization for a Prescription that Experienced at Least One Initial REMS-Related Rejection for the Current Reporting Period meer ?Prescription- IMO NJ: \140 "so ?l-mlil M-?n 'Mn 11.90 91400 no. Total Tum: for Preemption (in-"mu .?iuu . Hunt?(mud Hunmm Closed Systems: The six closed-system pharmacy entities enrolled in the TIRF REMS Access program during this reporting period are listed below: . National Institutes of Health Clinical Center Pharmacy 0 0 US. Department of Veterans Affairs . m4) (m4) m4) m4) 0 DLA Troop Support . mo m4) Table 10 below (adapted from the Table 19) lists the number of prescription authorizations for each closed system entity: Reference ID: 4190326 Table 10: Number of Prescription Authorizations per Closed System Pharmacy for the Current Reporting Period and Cumulatively Current Reporting 48 month 36 month Reporting Cumulatire Period Reporting Period Period 28DEC2011 to to 290CT2014 to 290CT2013 to 280CT2016 280CT2016 280CT2015 280CTZOI-1 Total Number of Closed Pha'ma?Y 329 398 730 2,799 Prescription (bra) (m4) l?Veterarrs Affairs Ro/n) 1m (3 60/0) 4) (DH National Institutes Of 0 0 1 0.1% 4 0.1% Health I umulatively, (m4) (m4) (m4) accormt for 71% of the 2,799 closed system prescriptions authorized. The listed governmental entities accorurt for a cumulative total of 4% of the closed system prescriptions authorized. Dru'ing the previous reporting period, transitioned from being a closed-system pharmacy to a non-closed system pharmacy. Thus the prescription authorizations described in Table 18 for only represent prescriptions (4) processed prior to this transition. (4) The 36-month REMS Assessment Acknowledgement Letter requested that the TRIG ?Re-evaluate whether a novel authorization process is warranted or technically feasible at this time for the closed svstem pharmacies and report your conclusions with your next Assessment Report.? In their 48-month Assessment Report, the TRIG stated that the current prescription authorization volume for closed system pharmacies is of all TIRF prescriptions and that these types of pharmacies accormt for of all pharmacies em?olled in the REMS. Additionally, the TRIG stated that no complaints had been received from the closed system pharmacies regarding REMS processes and thus this time.? changes are warranted (N In the current Assessment Report, while the TRIG acknowledges that there have been non-compliance events identi?ed through closed system audits (where REMS Reference ID: 4190326 processes have been bypassed), the TRIG lists several challenges in working with closed system pharmacies: • the transient nature of pharmacy staff at these locations • some locations are unable to access outside websites PPAF data Table 11 below (taken directly from the Assessment Report’s Table 20) summarizes the number of prescriptions dispensed during the first 10 days with and without a PPAF: Table 11: Prescriptions Dispensed During the First 10 Days With and Without a PPAF The REMS states that the TRIG is to monitor prescribers’ compliance with the requirement to complete a PPAF with each TIRF patient, and to submit it to the REMS within ten (10) working days. A maximum of three prescriptions are allowed within 10 working days from when the patient has their first prescription filled. No Reference ID: 4190326 FDA_7442 further prescriptions will be dispensed after the 10 working day window until a completed Patient-Prescriber Agreement Form is received. The TRIG also points out that a patient could receive both prescriptions without and then with a PPAF in the first 10 days depending on when the PPAF was filled out and thus the patient numbers likely contain some duplications. For this reporting period, during the first 10 days, from ALL pharmacies, 3,270 prescriptions were dispensed during the first 10 days after patient enrollment totaling 2,828 patients. Of these patients: • The majority of patients (n=2,817) were dispensed prescriptions by nonclosed system pharmacies (3,259 prescriptions) • 56.7% of patients had one prescription filled with a PPAF • 32.7% of patients had one prescription filled without a PPAF • 1.9% of patients had either 2 or 3 prescriptions fills without a PPAF • NO patient had more than 3 fills without a PPAF • NO prescriptions were dispensed beyond 10 days after enrollment without a PPAF From the inception of the TIRF REMS through the current reporting period, 751 prescriptions from non-closed systems and 32 prescriptions from closed systems (data not presented) have been dispensed beyond the first 10 days without a PPAF (although none this reporting period). 5.2.1. Reviewer Comments 1. The volume of TIRF prescriptions submitted for authorization decreased by 23% from the previous reporting period to this reporting period. 2. Approximately 64% of the prescriptions submitted for REMS authorization that did not encounter any REMS-related rejections were filled at independent pharmacies versus 36% from chains. However, independent pharmacies comprise only 9.6% of pharmacies enrolled in this REMS. In the Agency’s April 28, 2017 IR to the TRIG, the Agency asked the TRIG to provide insight into why these independent pharmacies dispense the bulk of TIRF prescriptions. In the TRIG’s May 30, 2017 response, they state that “…the TIRF REMS Access program does not require the collection of pharmacy subtype, so the TRIG is unable to provide an evidence-based rationale for this observation.” Given the small market share that TIRF products occupy, the TRIG should be able to provide additional perspective regarding this question. In addition, the TRIG states that their “independent pharmacy” category contains “retail, mail order, and institutional outpatient pharmacies.” For subsequent assessments, the TRIG will be asked to specify what proportion of prescriptions comes from which sub-category of independent pharmacies. Reference ID: 4190326 FDA_7443 3. The median prescription processing time for a prescription that experienced at least one initial REMS-related rejection appears to continue to increase over time for both chain and independent stores. In the Agency’s April 28, 2017 information request to the TRIG, the Agency noted that our 36-month and 48month RAALs pointed out these increasing processing times for prescriptions experiencing at least one REMS-related rejection and urged the TRIG to investigate and identify the causes of these increasing delays. The Agency also pointed out that since the reasons for REMS-related rejections (PPAF incomplete, PPAF not submitted, prescriber not registered) appear to have remained the same over time, the TRIG should further explore this increase in processing times by evaluating a sample of the prescription rejections with the longest processing time to determine if there are any identifiable reasons for this that could be addressed in the REMS. In the 60-month assessment report, the TRIG provides data that shows that of all the prescriptions that encounter at least one REMS-related rejection, over 80% are resolved within the first 10 days. The TRIG also commented that “At the current time it is not possible to distinguish between prescriptions that encounter at least one REMS-related rejection that are quickly resolved and those that are not.” In the TRIG’s May 30, 2017 response to the Agency’s April 28, 2017 information request, the TRIG states only that “…data are not available to be able to determine which prescriptions…are driving the increase in time to authorization…Further, there may be variables outside of those described…that may impact the mean and median time for a prescription to be authorized.” In response to issues raised at the October 2, 2017 telecon between the FDA and TRIG, on October 16, 2017, the TRIG stated that they plan “…to conduct an analysis of prescription processing times for prescriptions that encounter at least one REMS-related rejection over the period October 29, 2014 – October 28, 2017 to evaluate trends over time. In addition to this analysis, TRIG will expand the reporting of these data to FDA to show a more holistic view of overall REMS rejections, which will put into context the overall processing time for all rejected TIRF prescriptions. The updated metrics will be included in the 02FEB2018 submission.” In such an analysis that the TRIG stated on October 16, 2017 that they plan to conduct, the TRIG needs to clarify whether their use of the term “authorization” is limited to REMS authorizations or dispensing authorizations, since the latter may reflect insurance issues. For patients who were denied a TIRF prescription due to a missing or incomplete PPAF, it is Reference ID: 4190326 FDA_7444 unclear in how many instances did the prescriber complete the PPAF versus simply prescribe an alternative therapy. The TRIG will be asked to provide any data informing this issue since this may be an indicator of a potential access issue. ASSESSMENT ELEMENT 3: PROGRAM INFRASTRUCTURE The third element of the Assessment Plan states: 3. Program Infrastructure and Performance: The following metrics on program infrastructure performance will be collected (per reporting period): a. Number of times a backup system was used to validate a prescription, with reasons for each instance (for example, pharmacy level problem, switch problem, or REMS database problem) clearly defined and described; b. Number of times unintended system interruptions occurred for each reporting period. Describe the number of stakeholders affected, how the issue was resolved, and steps put into place to minimize the impact of future interruptions; c. Call center report with: i. Overall number of contacts; ii. Summary of frequently asked questions; iii. Summary of REMS-related problems reported d. Description of corrective actions taken to address program/system problems. During this reporting period there were no instances in which a backup system was used to validate a prescription due to pharmacy level problems, switch problems, or REMS database problems. Of the 124,796 calls to the TIRF REMS Call Center received during this reporting period, the reasons reported for 82% of the calls were: enrollment status inquiry (17%); pharmacy calls for pharmacy claim rejection (16%); PPAF inquiry (10%), and general program questions (6%). The TRIG states that there were no REMSrelated barriers reported to the REMS Call Center during this reporting period. ASSESSMENT ELEMENT 4: PROGRAM NON-COMPLIANCE The fourth element of the Assessment Plan states: 4. TIRF REMS Access Non-Compliance Plan: The TIRF TRIGs should provide the following data regarding non-compliance in each assessment report (per reporting period): Reference ID: 4190326 FDA_7445 i. ii. iii. iv. v. vi. vii. viii. ix. x. xi. xii. Reference ID: 4190326 a. Report the results of yearly audits of at least 3 randomly selected closed pharmacy systems to assess the performance of the system(s) developed to assure REMS compliance. These reports are to include: Verification of training for all pharmacists dispensing TIRF products; Numbers of prescription authorizations per closed system; Reconciliation of data describing TIRF product received by the closed system pharmacy with TIRF product dispensed to patients with a valid enrollment in the TIRF REMS program period preceding the audit date. Include details on how the reconciliation is conducted (e.g., electronic vs. manual process). Describe any corrective actions taken for any non-compliance identified during the audit and corrective actions taken to address non-compliance b. Report the results of yearly audits of at least 5 randomly selected inpatient hospital pharmacies to assess the performance of the system(s) developed to assure REMS compliance. Provide the number of units of use of TIRFs ordered per inpatient hospital pharmacy audited per 12 month period. These reports are to include: Verification of training for all pharmacists dispensing TIRF products Verification that processes such as order sets/protocols are in place to assure compliance with the REMS program Describe any corrective actions taken for any non-compliance with i and ii identified above during the audit, as well as preventative measures that were developed as a result of uncovering these noncompliance events c. Description of number, specialties, and affiliations of the personnel that constitute the Non-Compliance Review Team (NCRT) as well as: Description of how the NCRT defines a non-compliance event Description of how non-compliance information is collected and tracked Criteria and processes the Team uses to make decisions Summary of decisions the Team has made during the reporting period How the Team determines when the compliance plan should be modified d. Describe each non-compliance event and the corrective action measure taken, as well as the outcome of the corrective action e. Number of TIRF prescriptions dispensed that were written by nonenrolled prescribers and include steps taken to prevent future occurrence f. Number of prescriptions dispensed by non-enrolled pharmacies and include steps taken to prevent future occurrences FDA_7446 g. Number of times a TIRF prescription was dispensed because a pharmacy (closed or open system) was able to bypass REMS edits and if any such events occurred, describe how these events were identified h. Number of times a TIRF was prescribed to an opioid non-tolerant individual. Include what was done to minimize such instances; if any such events occurred, describe how these events were identified i. Number of instances of inappropriate conversions between TIRF products, as well as any outcome of such an event. If any such events occurred, describe how these events were identified. Table 12 below (taken in its entirety from the assessment report’s Table 24) summarizes non-compliance reports by stakeholder during the current reporting period. Reference ID: 4190326 FDA_7447 Table 12: Non-Compliance Activity Reports by Stakeholder in the Current Reporting Period The TRIG states that the above table includes single noncompliance cases (as has been discussed in previous reviews, the TRIG’s definition of a “single” compliance case for a PPAF in fact requires five such cases). The TRIG states that if the cases noted in this table appear for two consecutive assessment reports, such reports will not be placed into this table but be reported in narrative fashion only. The TRIG states that a total of 62 instances of potential stakeholder non-compliance with the TIRF REMS occurred this reporting period. Fifty-eight of these reports appeared in Table 13, whereas four reports were described in narrative fashion. There were 50 cases where a prescriber failed to have a complete PPAF on file in a timely manner (each case includes 5 or more patients enrolled by the prescriber Reference ID: 4190326 FDA_7448 without a complete PPAF on file, with each patient having greater than 10 working days lapse from the initial enrollment date). Given that each case involved at least 5 PPAFs this means that a minimum of 250 PPAFs were not submitted in a timely fashion. There were seven instances in which a TIRF prescription was dispensed because a pharmacy was able to bypass the REMS. A total of three of these seven instances were due to not using the cash BIN to process a claim. In all three of these instances the pharmacy was re-educated. In the remaining four instances: • Two cases of a pharmacy the dispensed a TIRF without obtaining an authorization. The pharmacy was re-educated. • Two cases of a pharmacy dispensing a TIRF after receiving a reject message that the prescriber certification had lapsed. The prescriber completed reenrollment and the pharmacy was re-educated. In the Agency’s April 28, 2017 IR to the TRIG, the Agency asked the TRIG if, out of the 10,225 non-closed system prescriptions that were never authorized for dispensing due to REMS-related rejections, how many of these prescriptions were dispensed despite of the rejection. In the TRIG’s May 30, 2017 response, they state that “There is no way to systematically and accurately track if a pharmacy receives this rejection and still makes the decision to dispense.” In the Agency’s April 28, 2017 IR to the TRIG, the Agency also asked the TRIG, regarding the cases of the pharmacy not being aware of the need to process cash claims through the REMS or a pharmacy dispensing a TIRF without a REMS authorization, or a pharmacy receiving a reject through the REMS but dispensing the TIRF anyway, how is it that the TRIG learned of these cases. In the TRIG’s May 30, 2017 response, they state that “All of these referenced instances would only be captured through spontaneous reports to the TIRF REMS Access program.” Thus, under-reporting of events of non-compliance is quite likely. Table 12 includes a case where a prescription was dispensed by a non-enrolled pharmacy that was shipped a TIRF from an enrolled distributor. The REMS was notified of this when the non-enrolled pharmacy contacted the TIRF REMS regarding a prescription rejection for reason of “pharmacy not enrolled”. The nonenrolled pharmacy shipped the TIRF back to the distributor. The distributor was reeducated on the REMS requirements Although Table 12 contains a footnote that “There were no spontaneous reports of non-compliance from closed-system pharmacies” the TRIG reports one instance where the Call Center incorrectly provided authorization for a closed system pharmacy to dispense the TIRF even though the prescription was written by nonenrolled prescriber. The prescriber was informed of the REMS requirements and the Call Center Staff was retrained. Reference ID: 4190326 FDA_7449 The four narrative cases of non-compliance provided by the TRIG involve compliance events that occurred over a period of time. • A prescriber was identified as not submitting PPAFs for “multiple” patients on three separate occasions. After the first two incidents, formal Notices for Non-Compliance were issued to the prescriber, but after the third incident the prescriber was issued a Warning Letter requiring that a compliance action plan (CAP) be submitted. The first CAP submitted by the prescriber was not approved by the NCRT, but a revised CAP was later accepted. The prescriber was once again issued a Warning Letter requiring that a CAP be submitted for non-submittal of PPAFs. The CAP was again accepted. A year and a half later the prescriber was identified as failing to submit PPAFs. After multiple attempts to contact the prescriber failed, the prescriber was issued another Warning Letter requiring that a CAP be submitted. After two unsuccessful CPA submissions, the third CAP was accepted by the NCRT. • Another prescriber was identified as not submitting PPAFs for 6 patients on two separate occasions. After the second incident, a Warning letter was issued to the prescriber with a request for a CAP; however, the NCRT did not approve the CAP. After multiple unsuccessful attempts to reach the prescriber for a valid CAP, the prescriber was suspended from the TIRF REMS Access program. A CAP was received a month later and accepted by the NCRT and the prescriber was re-enrolled in the TIRF REMS program. • A prescriber was identified as not submitting PPAFs for 5 patients on three separate occasions. After the first two incidents, formal Notices for NonCompliance were issued to the prescriber, but after the third incident the prescriber was issued a Warning Letter requiring that a CAP be submitted. The first CAP submitted by the prescriber was not approved by the NCRT, but a revised CAP was later accepted. Closed System Audits The REMS Assessment Plan includes the following three components for closed system pharmacy audits: 1. Verification of training for all pharmacists dispensing TIRF products 2. Numbers of prescription authorizations per closed system 3. Reconciliation of data describing TIRF product prescriptions received by the closed system pharmacy with TIRF product dispensed to patients with a valid enrollment in the TIRF REMS Access program The first component of the closed system pharmacy audit requirement is accomplished through the enrollment process for the pharmacy. To become enrolled, the authorized representatives must attest that all pharmacy staff that Reference ID: 4190326 FDA_7450 participate in dispensing TIRF products will be trained on the TIRF REMS Access program requirements. The second component is done through the closed system pharmacy prescription authorization process. Closed system pharmacists are required to validate the enrollment status of the prescriber and patient prior to dispensing a TIRF product by calling or faxing the prescription details to the TIRF REMS Access program. Regarding this third component, the TRIG describes that the process of reconciliation between the closed system pharmacy’s dispensing data and the REMS program’s authorizations necessitates the TRIG requesting dispensing records from the closed system pharmacies and compares these records to the TRIG’s authorization data. After confirmation that the closed system pharmacy agrees to participate in the audit, a formal written request for data is issued upon request to the authorized representative detailing the data to be provided and the deadline for submission. Specific data requested include: • RX number for each prescription dispensed • DEA number or NPI number of the facility that dispensed each prescription • DEA number or NPI number of the prescriber that issued each prescription • Date and time of each prescription transaction • REMS Authorization code obtained for each prescription dispensed The TRIG states that due to the structure of some closed system pharmacies, their headquarters may be unable to provide data for all pharmacy locations as no central data repository is in existence (each pharmacy location maintains their own data). In these cases a random sample of pharmacy locations was selected for participation by the TRIG. Findings from each investigation are reviewed with the NCRT and actions were taken in accordance with the Non-Compliance Protocol. The TRIG states that the REMS assessment metric for closed system audits requires auditing of at least 3 randomly selected closed system pharmacies. The TRIG however included all closed-system pharmacies in the audit with a request to provide dispensing records from May 1, 2015 through April 30, 2016. Table 13 below (copied in its entirety from the assessment report’s Table 26) summarizes the reconciliation of the dispensing data from each closed system pharmacy and the authorizations received from the TIRF REMS program for the six audited closed system pharmacies: Reference ID: 4190326 FDA_7451 Table 13: Results of the Closed System Pharmacy Audits Total Dispenseszotal Date Closed System Dispenses Not Non- Audit Monitoring Request Date Dispensing Records Authorized by Compliance Number for Data Sent Received the REMS Identi?ed? 26 May 2016 08 July 2016 164.1 2 26 May 2016 15 June 20162 00 3 26 May 2016 07 September 2016 40-7 4 $10) 26 May 2016 02 September 2016 27-13 SWSII) 26 May 2016 20 June 20162 00 6 $12) 26 May 2016 02 September 2016 9959 1 The date range for dispensing records received was 01 May 2015 through 30 April 2016. 3 Pharmacy provided con?rmation that no TIRF medicines were dispensed during the reporting period (01 April 2014-30 April 2015). Initial data showed that there was one location with three instances of dispensing TIRE medications without an authorization. However. after issuance of a Notice for Non~Comp1iance. additional information was received from the phamiacy confirming that the one location only had one instance of dispensing TIRF medications without an authorization. Of the 6 audits conducted during this reporting period, 4 closed 8 stem pharmacies and $12 were found to be non-compliant with the TIRF REMS Access program requirements. A non-compliance case was opened for each of these 4 closed systems. 0 mu) (mu) - For the one unauthorized dispensation out of 164, a second formal Notice for Non-Compliance was issued requiring a CAP which was subsequently approved by the TRIG. (Veterans Administration since the VA has no central document system, REMS Access program provided 8 randomly selected and enrolled VA closed-system dispensing locations (accounting for 10% of the enrolled population for VA), out of 40 VA system authorizations, 1 location had 7 instances of dispensing TIRF medications without authorization. A third formal Notice for Non-Compliance was issued and a CAP was initiated. The system used at the pharmacies was updated to add a reminder for each TIRF NDC that authorization was required for dispensing and a Standard Operation Procedure (SOP) was developed to de?ne the need for prior authorization. This CAP was approved by the NC RT. 0 mm (m4) (m4) requested that the TIRF REMS program provided REMS authorization data for randomly selected sites and provide the information to which would then reconcile their own phannacy?s data to identify any non-compliance. The audit revealed one Reference ID: 4190326 • unauthorized dispensation out of 27 dispensations. A second formal Notice for Non-Compliance for was issued requiring a CAP. The NCRT approved the CAP. ID#CS12 (Department of Defense [DoD]) – the DoD requested that the TIRF REMS Access program provide REMS authorization data from the TIRF REMS Access program so that they could match it to their pharmacy data. The audit data showed that 11 locations had 59 instances of dispensing TIRF medications without authorization (out of 99 dispensation audited). Of the 11 locations, 3 locations were not enrolled in the TIRF REMS Access program. A third formal Notice for Non-Compliance for was issued requiring a CAP. Future plans have been made to conduct ongoing quarterly educational sessions to inform the military treatment facility on the REMS requirements until understanding, awareness, and compliance is stable. The NCRT approved the CAP. The TRIG is evaluating is quarterly review of closed system pharmacy data rather than an annual review in the current audit process. Inpatient Pharmacy Audit The inpatient hospital pharmacy audit process is conducted through an audit questionnaire invitation that is faxed to authorized inpatient pharmacists of pharmacies enrolled in the TIRF REMS Access program requesting their participation. Once the authorized inpatient pharmacist agrees to participate, they receive the audit questionnaire. If the authorized pharmacist replies that they are indeed a hospital pharmacy and have dispensed a TIRF in the previous 12 months, they are then asked the following: 1. Provide the number of units dispensed within . (See NDC list for a current listing of TIRF NDCs) ________units of use of TIRFs dispensed to inpatients. 2. Did all pharmacists who dispensed TIRF medicines complete training on the TIRF REMS Access program prior to dispensing these products? Yes/No 3. Do you have procedures in place such as order sets/protocols to assure compliance with the TIRF REMS program requirements? Yes/No. If yes, are you willing to provide examples of an order set or protocol? A total of 12 enrolled inpatient locations were solicited for participation in the audit: • 3 did not respond to the audit invitation • 4 pharmacies answered that they were either not a hospital inpatient pharmacy facility or had not dispensed TIRFs in the previous 12 months. The remaining 5 qualified to participate in the audit, and proceeded to respond to the 3 audit questions listed above. Based on responses to the 3 audit questions, 4 of Reference ID: 4190326 FDA_7453 the 5 audited inpatient hospital pharmacies were found to be compliant with the REMS program requirements. One inpatient hospital pharmacy was found to be non-compliant and a non-compliance case was opened: • The inpatient pharmacy reported dispensing 7 units of TIRFs in the previous 12 months, but also admitted that the pharmacists who dispensed these TIRFs had not completed training on the REMS program prior to dispensing these products. A Warning Letter was issued to the pharmacy requesting a CAP. The CAP was subsequently received and stated that all pharmacists would complete REMS training. The NCRT approved the CAP. The TRIG plans to invite the same pharmacy to participate in the audit in 2017. 5.4.1. Reviewer Comments 1. a. Concerns about the TRIG’s REMS overall compliance program continue and include the following issues: For the 60-month report, the TRIG continued to classify a case of PPAF non-compliance as Five or more patients enrolled by the prescriber without a complete PPAF on file (greater than 10 working days from the initial enrollment date not on file with the REMS). In the 48-month RAAL, the TRIG was told of FDA’s concern that these criteria could lead to an underreporting of PPAF non-compliance and that they should explore mechanisms to capture lower levels of non-compliance. The TRIG stated that they evaluated the occurrences of their definition of PPAF non-compliance (named “Prescriber 2 Scenario” by the TRIG) using the following denominators: • Prescribers enrolled as of the end of the reporting period; • total number of prescriptions submitted for authorization, and • total number of prescriptions that were authorized by the TIRF REMS The TRIG reported that the rates of this non-compliance scenario across all denominators have gradually decreased from the 36-month reporting period to the current reporting period (see Table 14 below, taken from the assessment report Table 23). Reference ID: 4190326 FDA_7454 Table 14: Rates of Prescriber 2 Scenario Cases Over Time Thus the TRIG determined that this established non-compliance definition is working and that they would continue to explore mechanisms to capture lower instances of non-compliance. These data do appear to indicate that occurrences of their definition of PPAF non-compliance appear to be decreasing. However, lower levels of prescriber non-compliance (<5 PPAFs not submitted to the REMS in a timely manner) are not captured. Thus the overall level of PPAF noncompliance remains unknown. It is also unknown whether or not the bulk of PPAF non-compliance is actually caused by prescribers with these lower levels of non-compliance. The TRIG was told of the FDA’s continued concerns regarding needing 5 PPAFs to establish one case of non-compliance at the October 2, 2017 telecon. In response, on October 16, 2017, the TRIG stated the following: “The TRIG will reduce the PPAF threshold to flag prescribers for non-compliance based on patients without a PPAF from 5 to 3 patients. The TRIG evaluated the incidents of non-compliance and has determined that the threshold can be lowered to 3 without a large impact to patient access.” Because the TRIG did not elaborate further how lowering the number of PPAFs needed for a case on non-compliance to less than 3 would affect Reference ID: 4190326 FDA_7455 patient access, FDA sent another IR on October 27, 2017 asking for an explanation. In the TRIG’s November 2, 2017 response, they state that: “To determine the impact of decreasing the threshold for missing PPAFs triggering a non-compliant event, the TRIG calculated estimated increases in non-compliant case volume based on current prescriber and PPAF activity. At the time of this research, the TRIG found that lowering the threshold to: • 4 missing PPAFs would result in 2 additional non-compliant cases per month (~15% increase), • 3 missing PPAFs would result in 5 additional non-compliant cases per month (~38% increase), • 2 missing PPAFs would result in 14 additional non-compliant cases per month (~107% increase), and • 1 missing PPAF would result in 42 additional non-compliant cases per month (~323% increase).” In addition, the TRIG states that they considered: “…the establishment of more strict corrective action guidelines (as proposed in the 16OCT2017 response to FDA), which will result in a higher volume of prescriber suspensions and deactivations [discussed in comment “c” directly below]. Therefore, the TRIG proposes that the increase in noncompliant cases by 38% balances the goals of making prescribers aware of the importance of compliance and patient safety without impacting patient access.” The TRIG’s arguments are about the additional work that will be placed upon them in notifying prescribers about their non-compliance as well as the fact that the implementation of criteria that will ban a prescriber for non-compliance will affect patient access. Given the concerns that the FDA has regarding the high use of TIRFs in opioid non-tolerant patients (See Section 5.5.2. of this review) as well as continued concerns with the TIRF adverse event data as compared to other opioids (See Section 5.5.4 of this review) the FDA believes that the number of PPAFs associated with a non-compliance event should be one. b. Reference ID: 4190326 In the 48 month RAAL, the FDA noted that the TRIG reported the number of instances where prescribers were either unaware of requirements to submit a PPAF or chose not to do so. The FDA stated to the TRIG that “It is important that the TRIG investigate mechanisms to reinforce to prescribers the necessity of timely completion of PPAFs.” In the current report, the TRIG states that they “…will further query noncompliant prescribers to determine more specific reasons of FDA_7456 why they were not compliant with the REMS requirements. The TRIG will assess these responses to determine appropriate actions.” The FDA looks forward to reviewing the findings of the TRIG’s query and assessment of responses in their subsequent assessment reports. c. The Assessment report continues to include cases of prescribers who receive numerous Notices of Violation, Warning Letters, and then file several CAPs before one is accepted. Yet, these prescribers are not suspended or deactivated from the program. As noted to the TRIG in the 48-month RAAL, it is unclear what types of non-compliance actions would reliably lead to prescriber suspension or deactivation. In the 48-month RAAL, the TRIG was asked to add increased specificity to their Non-Compliance Review Team (NCRT) protocol as well as to the Supporting Document of the REMS. In the current Assessment Report, the TRIG states only that they “…will consider updates to the Non-Compliance Protocol and the Supporting Document to add increased specificity around how non-compliance actions may lead to suspension or deactivation.” At the October 2, 2017 telecon between the FDA and the TRIG, the TRIG was once again urged to develop clear and specific criteria to their NCRT non-compliance protocol. In the TRIG’s October 16, 2017, response, the TRIG presented the following criteria: “The Corrective Action Guidelines within the Non-compliance Protocol will be modified to remove the second level of Notices, Warnings and Suspensions, thereby reducing the number of non-compliant events that can occur prior to deactivation of a non-compliant stakeholder, including prescribers. Once non-compliance has been confirmed, the revised non-compliant event schedule will include the following actions. • A first offense of non-compliance will result in a Notice • A second offense of non-compliance will result in a Warning • A third offense of non-compliance will result in a Suspension • A fourth offense of non-compliance will result in a Deactivation As a result of both changes, a stakeholder, including prescribers, will be deactivated from the program upon four non-compliant events.” After deliberating internally, the FDA review team decided that the TRIG should lower these 4 stages into 3 stages, and that the TRIG should eliminate their first (Notice) stage. Thus the first noncompliance event would be a Warning, the second event would results in a Suspension, and the 3rd even would result in a deactivation for a 3year period. Reference ID: 4190326 FDA_7457 d. In the 48-month RAAL, the FDA expressed concern that all three instances where a non-closed system pharmacy dispensed a TIRF product after a REMS rejection were brought to the attention of the TRIG only after the pharmacy contacted the REMS. The FDA then suggested that the “TRIG should develop a more active mechanism by which to identify and prevent such occurrences”. In the current assessment report the TRIG states that they are “…looking into a more active mechanism to identify and prevent instances where a non-closed system pharmacy dispenses a TIRF product after a TIRF REMS rejection is received.” In addition, in response to an April 28, 2017 IR to the TRIG, the TRIG verified that they have “…no way to systematically and accurately track if a pharmacy receives this rejection and still makes the decision to dispense” and that “All of these referenced instances would only be captured through spontaneous reports to the TIRF REMS Access program.” It seems likely that relying solely on spontaneous pharmacy self-reports of non-compliance will lead to an overall under-reporting in pharmacy non-compliance with the REMS. The TRIG needs to develop concrete and more active processes to address this deficiency in their compliance program and implement these processes expeditiously. e. Reference ID: 4190326 In the 36-month RAAL, FDA pointed out the poor results of both governmental entities (Veteran’s Health Administration [VA] and Department of Defense [DoD]) closed-system pharmacies. The RAAL requested that the TRIG “Re-evaluate whether a novel authorization process is warranted or technically feasible at this time for the closed system pharmacies and report your conclusions with your next Assessment Report.” In the 48-month Assessment Report the TRIG responded that “…the current prescription authorization volume for closed system pharmacies is less than 1% of all TIRF prescriptions and due to the absence of complaints with the current process, no changes are warranted at this time.” Thus in the 48-month RAAL, the FDA communicated to the TRIG that “If the TRIG does not favor a novel authorization process for all of the closed-system pharmacies solely due to the poor performance of the governmental entities, the TRIG should propose an outreach to these programs to improve compliance.” In the current Assessment Report, the TRIG reiterates that the current prescription authorization volume for closed system pharmacies is <1% of all TIRF prescriptions and closed system pharmacies account for <1% of all pharmacies enrolled in the REMS. The TRIG also reiterates that no complaints have been received from closed system pharmacies regarding the authorization process. In addition, the TRIG states that challenges to updating the REMS authorization process to include a FDA_7458 web-based modality include: the transient nature of pharmacy staff at these locations; the need for staff re-education if such a modality is implemented; and the fact that some closed pharmacy locations are unable to access the internet. In the Agency’s April 28, 2017 IR to the TRIG, the Agency asked the TRIG to provide their sources of information for the challenges listed by the TRIG since the Agency believes that some of these obstacles cited would also apply to other closed and non-closed systems. In the TRIG’s May 30, 2017 response, they state that these reasons are “anecdotal information” and that they do “…not believe that these obstacles noted apply to other non-closed systems, as by definition a non-closed system pharmacy under the REMS is able to support the process of electronically transmitting validation and claim information.” Given the small volume of prescriptions coming from closed systems as well as the overall good level of compliance with non-switch processes (by the non-governmental systems), the FDA agrees that a switch system should not be pursued. However, as stated in the 48-month RAAL, TRIG should insist that alternative approaches be taken by the two governmental entities. Examples of such alternatives could include: 1) both entities build in system alerts reminding pharmacists of the REMS requirements; and or 2) request that the two governmental entities develop a process requiring a two-person check when any TIRF is dispensed to ensure that REMS processes were followed. Likely there are additional processes that can be implemented. These alerts/revised processes should be in place and reported on starting with the December 2018 assessment report. In addition, the TRIG will be asked to provide an update is the February 28th assessment report submission regarding the TRIG’s consideration of a quarterly evaluation of closed system pharmacy data, f. Reference ID: 4190326 In the 48-month assessment report, 6 inpatient pharmacies either did not respond to the audit request or decided not to participate. In the current assessment report, 3 of 12 pharmacies (25%) did not respond to an audit request and the TRIG states that they are “…considering revisions to this (pharmacy) enrollment form to allow for process audits so as to increase the potential pool of inpatient pharmacies in the audit and will communicate any required modifications during the review of the next REMS assessment.” The FDA agrees that the TRIG should consider this revision and looks forward to learning of the TRIG’s decision regarding this enrollment form. FDA_7459 5. As the TRIG has stated in previous reports, they state in the current assessment report that there were no reports of TIRFs being prescribed to an opioid non-tolerant individual or cases of inappropriate conversions between TIRF products. The Agency has previously commented that spontaneous reports are not suitable to assess the extent of TIRF use in opioid nontolerant patient or the extent inappropriate interchanges between TIRF products. Opioid Tolerance analyses performed by the TRIG previously are discussed in this review’s section 5.5.1.1., and the individual TRIG Sponsors submitted opioid tolerance data for their applications on June 15, 2017 which remain under review by the review team. ASSESSMENT ELEMENT 5: SAFETY SURVEILLANCE The fifth element of the Assessment Plan states: Safety Surveillance (data collected per reporting period): a. TIRF TRIGs will process adverse event reports related to their specific products and report to the FDA according to current regulations outlined in 21 CFR 314.80 and the TRIG’s respective Standard Operating Procedures b. TIRF TRIGs will produce one comprehensive report that presents spontaneous adverse event data from all TRIGs of the TIRF REMS Access Program, as well as data from other databases (characteristics of which are described below). This report will focus on four categories of adverse events of interest: addiction, overdose, death, and pediatric exposures. This report should include the following: i. Line listings under each category of adverse events of interest as listed above ii. Line listings should provide at a minimum the following information (see sample table provided): 1. Identifying case number 2. Age and Gender of the patient 3. Date of the event as well as of the report 4. The Preferred Terms 5. Indication of TIRF use 6. Duration of TIRF therapy 7. Concomitant medications 8. Event Outcome iii. Other metrics of interest include: 1. Number of event reports in each event category of interest 2. Counts of adverse events related to inappropriate conversions between TIRF products Reference ID: 4190326 FDA_7460 3. Counts of adverse events related to accidental and unintentional exposures 4. Counts of adverse events that are associated with use of TIRF medicines in non‐opioid tolerant patients iv. Duplicate cases are identified and eliminated v. Case reports with adverse events in multiple categories will be listed in each category of interest, and will be noted as such vi. For each adverse event category, an overall summary analysis of the cases will be provided addressing the root cause(s) of the events. Rate of each adverse event of interest will be calculated using two distinct denominators: the number of prescriptions for TIRF products and the number of patients receiving a TIRF product throughout the reporting interval. Trends and changes in the rates of these events will be compared year‐to‐year c. Surveillance data focusing on events of addiction, overdose, death, and pediatric cases should also be drawn from the databases that are listed below. Conclusions regarding these data should be included in and inform the overall conclusions in the summary report referred to in Section 5.b. directly above: vii. Non-medical use of prescription drugs viii. Surveys conducted at substance abuse treatment programs ix. College surveys x. Poison control center data xi. Impaired health care workers xii. Drug-related hospital emergency department visits xiii. Drug-related deaths xiv. Other databases as relevant Reference ID: 4190326 FDA_7461 5.5.1. Review of the TIRF REMS 48-Month Supplemental Report 5.5.1.1. Opioid Tolerance DRISK previously reviewed the opioid tolerance data in the TIRF REMS 48-Month Supplemental Assessment Report 4; however, given both the import and complexity of these data, DRISK consulted with our colleagues in the Division of Epidemiology II (DEPI) for a review of the data in the 48-Month Supplemental Assessment Report to review: 1) TRIG’s drug utilization protocol and report regarding the TIRF REMS goal of “prescribing and dispensing TIRF products only to appropriate patients, which includes use only in opioid-tolerant patients 5, and 2) TRIG’s persistency analysis protocol and report regarding the TIRF REMS goal of “preventing inappropriate conversion between TIRF products.” DEPI was asked to assess the suitability and appropriateness of each protocol, as well as the two data reports regarding their methods, database choices, and data analyses, in accomplishing two of the objectives of the REMS goal and provided a review 6 with their findings to DRISK. In the Supplemental Report, the TRIG used the IMS Health Longitudinal Prescription Database (LRx) to capture opioid dispensations prior to a TIRF product dispensation to estimate opioid tolerance. In the outpatient retail pharmacy setting, approximately 63% of patients dispensed a TIRF had a new or refill opioid analgesic prescription dispensed in the 8-30 days prior to being dispensed a TIRF. DEPI believes that looking at opioid prescriptions 8-30 days prior to a TIRF prescription may be a reasonable proxy to evaluate opioid tolerant status. However, DEPI expressed concerns with the use of only the LRx database: “The LRx database appears to be an appropriate database for assessing U.S. outpatient retail TIRF utilization patterns, as the majority of TIRF products were sold from manufacturers to outpatient retail pharmacies. However, drug utilization data from other settings of care, such as inpatient settings and clinics, are not available. Calculating daily dose and length of therapy, especially for PRN products, based on days’ supply and product strength may not accurately reflect what is being taken by the patient, particularly for opioid products that induce drug tolerance. Specific data on directions for use (signa) are needed to establish daily dose estimates for opioids, yet this information is not included in the database used. Days’ supply of a dispensed prescription is estimated by the pharmacist, and the minimum and maximum daily dose that the patient may take depends on 4 May 4, 2016 REMS Supplemental Assessment Submission from the TRIG 5 See also section 5.5.2 for product-specific analyses of opioid tolerance May 2, 2017 DEPI II (D.T. Coyle and T. Pham) Review of 48-Month TIRF REMS Assessment Data 6 Reference ID: 4190326 FDA_7462 his/her level of pain during the day. DEPI feels strongly that opioid tolerance status cannot be inferred from utilization or claims data; as such, all analyses employing this metric in these data sources must be interpreted in the context of this significant limitation.” With regards to the finding that 63% of patients dispensed a TIRF had a new or refill opioid analgesic prescription dispensed in the 8-30 days prior to being dispensed a TIRF, DEPI also cites concerns whether this finding necessarily indicates that these patients met the definition of opioid tolerance: “The above data only show the percentage of patients who received an outpatient opioid analgesic prescription in the 30 days prior to the initial TIRF product prescription. These patients might not meet the definition of being opioid-tolerant as defined in TIRF product labeling, as daily opioid doses may vary depending on individual factors. As mentioned previously, DEPI feels strongly that daily opioid dose cannot be accurately inferred from utilization or claims data due to the phenomenon of tolerance, so using daily opioid dose as a surrogate for opioid tolerance status in this analysis is inadequate.” In addition, DEPI had concerns with the TRIG’s use of a 1-7 day pre-TIRF prescription look-back period: “ The 1-7 day pre-TIRF opioid fill metric is problematic because a patient may not be capable of being opioid-tolerant as defined by the label, as they may have only been taking an opioid for <7 days before receiving the TIRF. Stratifying by new or refill prescription status within this timeframe would be useful: a patient receiving a new opioid analgesic prescription 3 days before an index TIRF prescription is incapable of being opioid-tolerant as defined by the label. However, a patient receiving a refill opioid analgesic prescription 3 days before an index TIRF prescription has the potential to be opioid-tolerant.” The TRIG performed a sensitivity analysis which excluded individuals with no claims for any product prior to receiving a TIRF product – roughly simulating a baseline enrollment history requirement. This analysis increased the estimates of patients who received a new or refill opioid prescription 8-30 days before TIRF receipt to approximately 75%. DEPI expressed concerns with this analysis: “The original analysis did not restrict inclusion based on a pre-determined period of insurance coverage (and therefore data capture), so the sensitivity analysis is meant to exclude "new"-looking users from the pharmacies in their catchment area who look like non opioid-tolerant patients, but who may or may not have had pre-existing opioid prescriptions that were not seen with their data stream…This sensitivity analysis was not pre-specified, but rather was “implemented in the course of assessing data quality.” While its results are somewhat more reassuring than those in the main analysis, it Reference ID: 4190326 FDA_7463 is not clear how valid this sensitivity analysis is given our knowledge of the data source and its limitations.” Lastly, DEPI had concerns about the exclusion of pediatric patients from these analyses: “Pediatric patients were excluded from the analysis, but the analysis does not specify the count of these excluded patients. Accidental ingestion and inappropriate use of fentanyl products among pediatric populations is a serious public health concern. Use of TIRF products in these excluded populations may represent inappropriate prescribing, and the Agency will need additional detail on the frequency with which this occurred.” 5.5.1.2. Persistency Analysis The TRIG’s pharmacy switch database was the data source for the persistency analysis and uses outpatient TIRF prescription data collected from March 12, 2012 to October 28, 2015. The results indicate that the persistency with index regimen was 45.2% at 6 months and 30.2% at 12 months for the total cohort. Overall, 20.5% of 18,160 patients changed their index TIRF regimen, and 25.6% of those patients had a change in their second TIRF regimen. Approximately 10% of patients remained on their index or second TIRF regimen, 65-70% of patients discontinued their TIRF regimen completely, and 27 patients filled at least one prescription for all five TIRF products available during the study period. DEPI had the following concerns with how these data were calculated and presented: “The above numbers and calculations are confusing and unclear. If a patient is on a second TIRF regimen, that implies he/she switched from a first TIRF regimen. However, this does not appear to have been accounted for in a clear manner, as the numbers do not add up correctly. Further, if 20.5% of patients changed their index TIRF regimen, that implies that 79.5% did not switch their index TIRF regimen. However, the final sentence indicates that 65-70% of patients changed their TIRF regimen by discontinuing their TIRF regimen. These metrics’ lack of clarity, and the apparently-overlapping definitions employed regarding switches vs. discontinuations vs. changes, render this analysis very difficult to interpret.” “The persistency analysis and its results are very difficult to interpret. The definitions employed appear overlap [sic] with each other, and the metrics switch between describing the index, secondary, and other TIRF regimens throughout. It is not always clear to which denominator (index, secondary, Reference ID: 4190326 FDA_7464 etc.) the various percentages refer. It is unclear how the various numbers relate to each other, or what the numbers mean.” In addition, DEPI had concerns about the data source used as well as some of the assumptions made in the conduct of this study: “It is unclear why the persistency analysis excluded patients with only one prescription dispensed. These people only “persisted” through one prescription, and by excluding them, the analysis overestimates persistency. While it would be appropriate to exclude these individuals from a switching analysis, it is inappropriate to exclude them from a persistency analysis.” “By requiring follow up time in the database after cohort entry, the analysis captures only survivors and will exclude individuals who die after taking fentanyl – either from the condition the drug is treating, or from the drug itself. This approach conditions on the future, and is inappropriate because it introduces survivor bias.” DEPI also notes: “However, this analysis is most flawed in that the data source is unable to inform dose accurately due to its lack of prescriber instructions. Dose is the primary consideration for the REMS assessment of inappropriate switching…without dose data, it is not possible to determine whether a conversion between TIRF products was appropriate or inappropriate.” The overall conclusions reached by DEPI regarding both studies are as follows: “All of these studies used data sources with insufficient detail to adequately inform their analyses…Future analyses of these questions should use a data source that contains prescriber instructions to address these concerns. A chart review within an integrated healthcare system – one that captures patient encounters across inpatient and outpatient settings, as well as prescription drug data with prescriber instructions to determine dose – may provide sufficient granularity to inform the question of interest. Using data from a single integrated healthcare system may decrease external validity because patients who opt into a given integrated program may not be representative of all TIRF product users. As such, it may be necessary to use data from multiple integrated systems to enhance the generalizability of the results.” Comments to the Sponsor are included in Review Section 9. 5.5.1.3. Reviewer Comments 1. After further discussions with DEPI, it was decided that for the time being we would defer asking for the signa (instructions for use) data because: 1) few databases contain these data and 2) instructions for use for “as needed” Reference ID: 4190326 FDA_7465 (prn) prescriptions often contain a huge range of possible daily doses, and thus may not provide the specificity needed. 5.5.2. Product-Specific Assessment of Opioid Tolerance 5.5.2.1. Introduction In the November 10, 2016 REMS Assessment Acknowledgement Letter, the TRIG was told that: “The first objective (prescribing and dispensing TIRF medicines only to appropriate patients, which includes use only in opioid-tolerant patients) is not being achieved. In the TRIG’s assessment of opioid tolerance, approximately 42% of patients prescribed TIRF products were not opioid-tolerant. It is important that the TRIG further investigate this issue.” Thus, after a March 3, 2017 telecon between the FDA and the TRIG, the TRIG agreed on March 10, 2017 that each NDA/ANDA member of the TRIG would submit analyses of their product’s use in opioid-tolerant/non-tolerant patients. 5.5.2.2. Overview of the Studies Analysis #1: TIRF REMS Access Program Assessment: NDA/ANDA-Specific Utilization of TIRF Products in Opioid Non-Tolerant Patients (First ClassWide Fill) In Analysis 1, the IMS Longitudinal Prescription database (LRx) was used to identify patients who filled an initial outpatient prescription for a TIRF product (a first class-wide fill; all TIRF products included). The same data extract that was used in the original 48-Month TIRF REMS Supplemental Assessment Report was used in Analysis 1.” Results were based on the first class-wide fill and then stratified by individual TIRF product. Product-specific results were then reported for the subset of patients whose initial outpatient class-wide fill was for each product of interest. Analysis #2: NDA/ANDA-Specific Utilization of TIRF Products in Opioid NonTolerant Patients—First Product Fill (First Individual Product Fill) In Analysis 2, in contrast to Analysis 1, the initial prescription fill was the first outpatient fill for a specific TIRF Product (STP). This analysis was the “first individual product fill approach” (irrespective of prior fills for other TIRF products). In Analysis 2, the results were calculated based on the initial fill for each individual product of interest and reported separately for each product. To accurately identify prior opioid analgesic prescriptions, a new analytic dataset was compiled. This provided the opportunity to review and update National Drug Code (NDC) codes that were part of the REMS during the study period. Product-specific results were then reported for all patients with an initial outpatient fill for the product of interest. Reference ID: 4190326 FDA_7466 In both Analysis 1 and 2, previous outpatient opioid prescription fills were assessed from February 11, 2012 to October 28, 2015 (the study period). Data collected were used to identify the proportion of patients who received an opioid analgesic product, including those concordant with the TIRF REMS definition of opioid tolerance. 5.5.2.3. Objectives The objectives for the studies were to determine, for each individual TIRF product: • By year, the number of total unique patients dispensed an initial prescription for a specific TIRF product in the outpatient setting. • What proportion of those total unique patients received a prescription for an opioid analgesic product prior to the initial prescription for a specific TIRF product. • Provide data separately for patients receiving an opioid analgesic within the 7 days prior and within the 30 days prior to the initial specific TIRF product prescription. 5.5.2.4. Primary Outcomes The primary outcomes for Analysis 1 (first class-wide fill) and Analysis 2 (first individual product fill) were to: 1. Estimate the total number of unique patients dispensed an initial prescription for a TIRF product in the outpatient setting by year. 2. Estimate the proportion of unique patients who received a prescription for an opioid analgesic product within the 7 days prior to the prescription for the TIRF product (with TIRF fill on Day 0) and had days’ supply of therapy consistent with the TIRF REMS definition of opioid tolerance. 3. Estimate the proportion of unique patients who received a prescription for an opioid analgesic product within the 8-30 days prior to the prescription for the TIRF product and had days’ supply of therapy consistent with the TIRF REMS definition of opioid tolerance within the 30 days prior. 5.5.2.5. Study Data Source This study used data from the LRx database, which contains electronic dispensed records of prescription claims at the anonymized patient level collected from US retail, specialty, mail order, and long term care (LTC) pharmacies (outpatient only; prescription medications delivered during inpatient stays are not available). The database represents dispensed prescriptions for 86% of the retail pharmacy channel, 40-75% of specialty and mail-order prescriptions (depending on therapeutic area), and about 50% of LTC (across therapeutic areas). Data are available from 2003 and approximately 95% of claims are available for analyses within 12 days of being dispensed. Reference ID: 4190326 FDA_7467 The database includes de-identified patient-level longitudinal data such as age, sex, 3-digit ZIP codes, dispensed drug (through National Drug Code (NDC), molecule, form, strength, quantity, and days supply. The database flags whether a prescription fill is a first fill or refill. Other relevant data include physician specialty, method of payment, and patient out-of-pocket costs. The database contains data for over 220 million unique de-identified patients and one million physicians. All of the individual reports were prepared by QuintilesIMS. 5.5.2.6. Inclusion and Exclusion Criteria The study inclusion criteria for Analysis 1 (first class-wide fill) were: • Patients with ≥1 initial prescription fill for a TIRF product (class-wide) from an outpatient pharmacy, including retail and traditional mail order; • For individual product subanalyses: patients whose initial outpatient classwide prescription fill was for a STP The study inclusion criteria for Analysis 2 (first individual product fill) were: • Patients with ≥1 initial prescription fill for a STP from an outpatient pharmacy, including retail and traditional mail order. The study exclusion criteria for both Analysis 1 and 2 were: • Patients with age inconsistent with TIRF product labeling: younger than 16 years of age for Actiq and oral transmucosal fentanyl citrate lozenge generics; younger than 18 years of age for other products. • TIRF product prescription fills from a long-term care pharmacy. 5.5.2.7. Study Periods The study period was February 11, 2012 through October 28, 2015. The index period for both Analysis 1 (first class-wide fill) and Analysis 2 (first individual product fill) was March 12, 2012 (when the TIRF REMS began) through October 28, 2015. In Analysis 1 (first class-wide fill), an initial class-wide TIRF prescription was defined as the first outpatient prescription fill for a TIRF product during the index period (see Figure 2, copied from the submitted reports). First prescription fill was identified based on the new fill/refill flag indicating the fill was new. Pre-index period exposure to TIRF products was not assessed because this study focused on initial TIRF prescriptions once the TIRF REMS Access program had begun. Specific TIRF products are included in Analysis 1 individual product analyses. Reference ID: 4190326 FDA_7468 Figure 2: Study period and index period for Analysis 1 (first class-wide fill) In Analysis 2 (first individual product fill), initial individual product fill for a STP was defined as the first outpatient prescription fill for a STP during the index period. First prescription fill was identified based on the new fill/refill flag indicating the fill was new. As with Analysis 1, pre-index period exposure to TIRF products was not assessed. Analysis 2, provided the opportunity to review and update the NDC codes and as a result, the number of patients with an initial outpatient class-wide fill for any TIRF product may differ in the Analysis 1 and Analysis 2 datasets. (See Figure 3, copied from the submitted reports). Figure 3: Study period and index period for Analysis 2 (first individual product fill) 5.5.2.8. Prior prescriptions of opioid analgesic products Prior prescriptions of opioid analgesic products were identified as ≥1 outpatient prescription fill for opioid analgesics dispensed within 30 days prior to the initial prescription fill for a STP (not including the date of this initial fill). This approach was the same for Analysis 1 (first class-wide fill) and Analysis 2 (first individual product fill). As a change from the TRIG’s prior criteria to define opioid tolerance, prior prescriptions are restricted to patients with prescription fill dates within 30 Reference ID: 4190326 FDA_7469 days prior to the index date and do not include active supply extending from a prescription filled more than 30 days before the index date. Opioid analgesic product prescription within 8-30 days prior to the initial TIRF (depicted as Day 0 in Figure 4, copied from the submitted reports) as assessed as was opioid analgesic product prescription within 7 days prior to the initial TIRF prescription fill. Figure 4: Prior opioid analgesic use ascertainment period 5.5.2.9. Opioid Tolerance & Calculation Opioid tolerance was assessed in the same way for Analysis 1 and Analysis 2. Per the TIRF REMS, patients are considered opioid tolerant if, for one week or longer, they took at least: • 60 mg oral morphine/day • 25 mcg transdermal fentanyl/hour • 30 mg oral oxycodone/day • 8 mg oral hydromorphone/day • 25 mg oral oxymorphone/day —OR— • An equianalgesic dose of another oral opioid. Daily dose was calculated for each prescription fill as follows: Reference ID: 4190326 FDA_7470 1 The source of the conversion factors is: Centers for Medicare & Medicaid Services (CMS). Opioid conversion factors, March 2015. Available at: https://www.cms.gov/Medicare/Prescription-DrugCoverage/PrescriptionDrugCovContra/Downloads/Opioid-Morphine-EQ-Conversion-Factors-March2015.pdf The TRIG notes that the TIRF REMS-specified cutoffs equate to different morphine equivalence values. For example, the cutoff for hydromorphone is 8 mg/day, which— applying the conversion factor of 4—is equivalent to 32 mg/day of oral morphine. This is lower than the REMS-specified cutoff of 60 mg oral morphine/day, which can make specific equianalgesic dosing imprecise, especially for combination products. Patients met the criteria for opioid tolerance if they had at least 7 continuous days of sufficient daily dose immediately preceding the date of the initial TIRF prescription fill. A 1 day grace period between prescription fills was permitted to define serial prescriptions. Patients who received an opioid analgesic product prescription within 7 days prior to the initial TIRF prescription fill were only considered opioid-tolerant if the opioid prescription fill was a refill or if it was new but filled 7 days prior to the initial TIRF prescription fill. Patients with opioid analgesic product prescription fills that occurred more than 30 days prior to the initial TIRF prescription fill were still considered opioid-tolerant if all other criteria were met. For example, a patient with a 45-day continuous supply of sufficient daily dose filled 40 days before the index date would be considered opioid-tolerant. However, this patient would not be counted as having received a prior prescription of an opioid analgesic product dispensed within 30 days. Figure 5 (copied from the submitted reports) illustrates how 5 patients would be classified as opioid-tolerant or opioid non-tolerant. Because of refills and concurrent use of multiple opioid analgesic products, a patient may be counted in both the 7-day and 8 to 30-day prior opioid analgesic prescription groups (as illustrated by example Patient 3 in Figure 5 below). Reference ID: 4190326 FDA_7471 Figure 5: Examples of opioid tolerance classification for patients with opioid analgesic prescription fills prior to initial Fentora prescription fill 5.5.2.10. Independent Variables and Other Covariates The following demographic characteristics were collected: • Age • Sex • Geographical region 5.5.2.11. Statistical Analysis Descriptive statistics using frequency and percentage distributions were applied. All analyses used SAS (SAS Institute Inc., Cary, NC). 5.5.2.12. Limitations The TRIG’s reports all stated the following limitations: Reference ID: 4190326 FDA_7472 • • • Medication use estimated from claims data are still just estimates. The exact timing and quantity of use depends on actual patient behavior and can only be estimated. In particular, prescription days supply values may lead to overestimation of opioid tolerance because estimates are for maximum use possible based on the instructions for use, but the patient may in actuality use them less often for immediate-release products are dosed “as needed.” Lack of hospital data in the LRx means that inpatient opioid analgesic use is not captured, which could result in underestimation of opioid tolerance for recently hospitalized patients. Concurrent use of multiple opioid products cannot be distinguished from product switching in the LRx. This may lead to overestimation of opioid tolerance in cases where a patient was down-titrated 5.5.2.13. Results Analysis 1 Results (b) (4) A total of unique patients who received initial outpatient TIRF prescriptions between March 12, 2012 and October 28, 2015 were identified in the LRx database. LRx quality control procedures resulted in the removal of 1,815 patients (6.6%). (b) (4) Thus a total of unique patients who met Analysis 1 study inclusion and exclusion criteria received an initial outpatient prescription for a TIRF product (any class-wide product) between March 12, 2012 and October 28, 2015. Table 15 presents the demographics of patients for the 7 individual TIRF products that submitted reports as well as for TIRFs as a class: FOLLOWING THIS PAGE, FDA_7474 TO FDA_7484 WITHHELD IN FULL AS B(4)/CCI Reference ID: 4190326 FDA_7473 5.5.2.14. Review of Older Opioid Tolerance Data At an August 9, 2017, internal meeting between DRISK, DEPI, and to discuss the above opioid tolerance data, Sharon Hertz, M.D., the Director of recalled data submitted previously by two TIRF Sponsors that indicated a much higher level of opioid tolerance in patients initiating TIRFs. Dr. Hertz recalled: Reference ID: 4190326 The April 15, 2008 submission7, from the Sponsor (at that time) of Fentora, stated that of patients took at least the opioid dose required for opioid tolerance 90 days prior to Fentora Similarly, the August 17, 2001 Periodic Safety Update Report from the Sponsor (at that time) of Actiq, stated noted that mm On August 10, 2017, FDA sent an Information Request (IR) to the Sponsor of Fentora and received a response on August 24, 2017. In that response, the Sponsor stated that: The current Sponsor, Teva, bought the product from ephalon and . .most personnel who worked on the 2008 report are no longer employed by eva.? As such, the crurent Sponsor stated that they were not able to locate the original protocol for their data. The Sponsor also stated that they were to con?rm that this means that the patient had a prescription for the arozmd-the-clock medication sometime in the 90-day period and prior to the entora any time frame de?ned to indicate that the around-the-clock prescription durations were directly adjacent to or overlapping with the initial entora is possible that the around-the-clock opioid was stopped sometime prior to the initiation of entora.? The Sponsor also stated that the same patient may have been counted in more than one quarter as a new patient and that this could mask a decline in opioid tolerance The Sponsor concluded that the ?201 7 analysis is considered a much tighter time frame between the around-the?clock opioid prescription and the ?rst entora prescription.? Similarly, on August 16, 2017, FDA sent an Information Request (IR) to the Sponsor of Actiq and received a response on August 30, 2017. In that response, the Sponsor again noted that: The current Sponsor, Teva, bought the product from ephalon and . .most personnel who worked on the 2008 report are no longer employed by eva.? As such, the current Sponsor stated that they were not able to locate the original protocol for their data. 7 April 15. 2008 RiskMap 5?1 Quarterly Report. supporting Document #94 8 August 17. 2001 Periodic Safety Update Report Supporting Document #102 Reference ID: 4190326 • • • • What the Sponsor was able to gather is that this information about opioid tolerance was gathered as a result of a patient survey. Patients who received Actiq were recruited from 4 participating pharmacy chains and received follow-up calls from the Sponsor in which: o Patients were provided with reminders about safe use; and o Patients were asked: Was the patient already on a strong opioid when they received the ACTIQ prescription? The Sponsor stated that they have no information about the numbers of patients surveyed The Sponsor also offered that the question asked of patients assumed that patients understood not only what a “strong opioid” is but that patients were not confusing it with a different pain medication. Thus there is no way to determine whether the use of this “strong opioid” met the requirements for opioid tolerance (dose/duration) prior to Actiq. The Sponsor concludes that these data are “…likely to have been much less accurate than the recent 2017 estimation….” 5.5.2.15. Reviewer Comments 1. The TIRF Sponsors have provided two separate analyses, a First Class-Wide Fill analysis (Analysis 1) and a First Individual Product Fill analysis (Analysis 2), each with sensitivity sub-analyses. Sensitivity subanalyses were performed on the subset of patients who had at least one outpatient fill for any product in the 30 days prior to the initial TIRF product prescription fill with the objective of trying to minimize misclassifying patients as not opioid-tolerant simply because the LRx database did not contain any data about them previously. The reported proportions of opioid non-tolerance in patients receiving TIRFs were lower in Analysis 2 than in Analysis 1. Sensitivity sub-analyses further lowered percentages obtained from either analysis. However, regardless of the analysis, the proportion of opioid-non-tolerant patients receiving a TIRF product ranged from a low of 34.6% up to 55.4%. Thus the proportion of patients receiving TIRFs as calculated by these analyses remains concerning. However, there are limitations of the TRIG Sponsor’s analyses as follows: a. Estimating opioid tolerance from outpatient claims data has a number of potential pitfalls: i. Claims data do not typically contain instructions for use ii. Prescription days’ supply calculations (especially for prn or “as needed” instructions) may overestimate opioid tolerance since calculations of daily dose typically look at the maximum daily dosage possible (based on the instructions for use), but Reference ID: 4190326 FDA_7487 b. c. in actuality the patient may use the product much less often than the instructed daily maximum dosage. iii. Since inpatient opioid analgesic use is not captured, opioid tolerance may be underestimated especially for recently hospitalized patients. iv. Concurrent use of multiple opioid products cannot be distinguished from product switching, potentially leading to an overestimation of opioid tolerance in cases where a patient was down-titrated It is not clear to this reviewer which analysis submitted by the TRIG Sponsors is the most appropriate - First Class-Wide Fill analysis or a First Individual Product Fill. In any future submissions of such data, if the TRIG would choose to provide a similar analysis, the TRIG should include only data regarding the first class-wide fill (as opposed to the first individual product fill). The first class-wide fill likely indicates the patient’s first exposure to a TIRF, and thus these are the patients we are most concerned about should they not be opioid-tolerant at the time of initiating a TIRF. The data submitted by the TRIG Sponsors are in a format that does not permit a year by year analysis of opioid tolerance. Thus it is not possible to determine whether the use of TIRFs in opioid non-tolerant patients is increasing or decreasing. In any future submissions of such data, the TRIG should provide yearly calculations of opioid tolerance to allow for this evaluation. 2. The Sponsors’ inclusion of Figure 5 providing examples of under what circumstances a patient would or would not be considered opioid tolerant is reassuring in that the criteria applied to determine opioid tolerance look to be very logical. 3. Overall the submitted opioid tolerance data do not reveal much difference in the use of any particular TIRF product versus another TIRF product in opioid non-tolerant patients. A visual inspection of the data reveals that perhaps Abstral is very slightly less likely than other TIRFs to be used in opioid non-tolerant patients. 4. With regard to the older data on use of either Actiq or Fentora in opioid ontolerant data, despite the limitations expressed above with the 2017 analysis, this current analysis is much more reliable than the older opioid tolerance data previously reported by the Sponsor of both products. 5. The submitted data indicate that the typical TIRF patient is female, is between 35 to 64 years of age, and resides in the South. Reference ID: 4190326 FDA_7488 6. Lastly, in the TRIG’s October 16, 2017, response to the October 2, 2017, telecon between the FDA and the TRIG, the TRIG notes that: “Based on an analysis previously conducted by Insys, the proportion of patients who were opioid-tolerant was substantially higher (77%). Therefore, the TRIG will further investigate the difference between the algorithm used in the TRIG analyses and that used by Insys before proceeding with the validation study. The TRIG has investigated several data options for the validation study and has narrowed the selection to the below two choices [The Henry Ford Health System (HFHS) and Optum’s Clinformatics Claims Data and Integrated Claims-EMR Data]. Further discussions with each of these data source companies are ongoing, and TRIG will notify the FDA which option was selected following resolution of the above referenced algorithm comparison.” DEPI reviewed the proposed data sources for the opioid tolerance algorithm validation and provided some feedback about which data source would be better suited for the validation and the information that should be included with a protocol submitted by February 2, 2018. DEPI expressed concern about any further delay in the validation efforts and suggested that the TRIG validate both algorithms, if necessary, to prevent delay. The TRIG was also asked to design an assessment of adverse events among patients using TIRFs who were not opioid-tolerant. Discussions of this study continued in their October 16, 2017 responses to the October 2, 2017 teleconference, and DEPI provided more guidance on appropriate data sources for the study that are described in the RAAL. 5.5.3. Pharmacovigilance Review 5.5.3.1. Introduction To better inform whether or not one of the TIRF objectives – “Preventing accidental exposure to children and others for whom it was not prescribed” was being met, and the extent of off-label use of TIRF products, as well as whether any reports of use of TIRF products in opioid non-tolerant patients have been received, DRISK consulted the Division of Pharmacovigilance II (DPV) on March 10, 2017 to conduct an analysis of cases contained within the FDA Adverse Event Reports System (FAERS cases). DPV provided their review 9 on July 20, 2017 and their findings will be summarized here. • Reference ID: 4190326 9 July 20, 2017 Pharmacovigilance review (C. Patel) regarding TIRF accidental exposures and off label use FDA_7489 5.5.3.2. Methods DPV evaluated cases of accidental exposure and off label use with a TIRF product. The following definitions were applied: • Accidental exposures - unintended exposure to a TIRF product temporally associated with an adverse event (HLT: Accidental exposures to product) • Off label use - Cases reporting use of a TIRF product for an unlabeled indication or in an unlabeled population temporally associated with an adverse event (HLT: Off label uses) US cases from November 4, 1998 – May 9, 2017 were examined and DPV used the FBIS Quick Query. The review points out that FAERS data have limitations: • No certainty that the reported event was actually due to the product. • FDA does not receive reports for every adverse event or medication error that occurs. Therefore, FAERS data cannot be used to calculate the incidence of an adverse event in the U.S. population. 5.5.3.3. Accidental Exposures Results A total of 237 cases were identified. Of these cases: • 80% of cases were in patients <1 to 6 years of age • The TIRF products involved were as follows: o 190 – Actiq o 16 – Fentora o 10- Subsys • The following serious outcomes were reported: o Hospitalization – 26 o Death – 10 o Life-threatening – 5 o Other serious - 56 DPV then reviewed a randomly selected 25% (n=59) of the reports from the accidental exposure FAERS search and after applying certain case definitions, 19 cases were included in the in-depth look at adverse events associated with accidental exposure to a TIRF. Cases of accidental exposure to a TIRF were most frequently reported in children, including 14 cases in children 5 years of age or younger. All 14 cases reported exposure to Actiq, the majority of the events occurred in 2010 or earlier. Reference ID: 4190326 FDA_7490 5.5.3.4. Off-Label & Opioid Tolerance Results A total of 740 cases of off-label use were identified. Of these cases: • In 53% of cases, the age was unknown; in 38% the age was between 17-65 years of age • The TIRF Products involved were: o 248 (34%) – Actiq o 202 (27%) – Fentora o 107 (14%) – Subsys • The following serious outcomes were reported: o Death - 89 o Hospitalization - 116 o Life-threatening – 6 o Other serious – 185 DPV manually reviewed a randomly selected 25% (n=185) of the TIRF reports retrieved from the two off-label use FAERS searches. Approximately 30% (19/66) of the cases included a serious outcome, including nine cases of hospitalization and/or death. There were two cases with an outcome of death. When indication was reported, TIRF products were most frequently used for pain, back pain, migraine, and headaches. Thirty-six cases of off-label use reported concomitant around-the clock (ATC) opioid treatment or self-reported tolerance to opioids. Of the 36 cases, 15 were opioid-tolerant, 20 were not assessable (provided the ATC medication and, in some instances, the dosing frequency but did not report the dose), and one was opioid non-tolerant (did not meet the ATC dosing outlined in the labeling) although the opioid non-tolerance did not play a contributory role in the adverse event associated with the off-label use of the TIRF product. The review did not identify any cases of off-label use in opioid-naïve patients nor did DPV identify any cases with sufficient detail to assess appropriateness of TIRF product conversion. Figure 6 (taken from the DPV review’s Figure 1) presents the number of FAERS reports gathered yearly since 1998 for both accidental exposure and off-label use: Reference ID: 4190326 FDA_7491 Figure 6. Accidental Exposure and Off Label Use FAERS Reports (N=977)* by Initial FDA Received Year (November 4, 1998 to May 9, 2017) Especially since 2011, the numbers of reports of off-label use of TIRFs have greatly increased. 5.5.3.5. Reference ID: 4190326 Reviewer Comments 1. FAERS reports of off-label use greatly exceeded reports of accidental exposures. Also, there was a sudden increase in reports of off-label TIRF use starting after 2011. Whether the fact that the REMS was launched on December 2011 has had any impact on these reports is unknown. 2. Regarding accidental exposure reports, 80% of cases were in patients <1 to 6 years of age, with Actiq being the TIRF product most often mentioned in these reports. 3. Regarding off-label use reports, in 53% of these cases, the age of the patient was unknown whereas in 38% the age was between 17-65 years of age. Actiq remained the TIRF product most frequently cited. 4. Of the currently marketed TIRF products, Actiq is the oldest, having been approved in November 1998; therefore, the fact that this is the TIRF product most often mentioned in the reported cases is likely at least partly related to its time on the market. FDA_7492 5. The most common off-label uses of TIRF products were for pain, back pain, migraine, and headaches. 6. There was only one report of a TIRF used in an opioid non-tolerant patient. Reviews of previous assessments have discussed the limitations of searching for incidents of opioid non-tolerance in FAERS reports. 7. It should be noted that the DPV review did not look to capture opioid non-tolerant events used when TIRF are used in cancer patients. 5.5.4. Review of TIRF REMS 60-Month Surveillance Data DRISK also consulted DEPI to provide an assessment of the utility and appropriateness of the provided sruveillance data in determining whether the goals of the REMS are being met. Additionally, DRISK asked DEPI to comment on whether the data were useful for continued sru'veillance pruposes and to recommend any additional data soru'ces that may be useful in assessing whether the REMS is meeting its goals. See review10 for description of RADARS programs/data soru'ces and outcome de?nitions. As per agreement with FDA, the safety sruveillance analyses requested by FDA necessitated different time periods as noted in the relevant sections within the report. Table 27 below (reproduced from Table 2 of review) summarizes the basic study design characteristics of the sruveillance data (consisting of spontaneous adverse event reports and RADARS data): Table 27: Surveillance Study Design Characteristics Study Design Characteristic Details for This Study Time Period 60- month report observation periods Spontaneous adverse event 8/29/2015-8/28/2016 reports 0 10 August 4. 2017 DEPI II (T. Meyer) Review of 60-Month Transmucosal Immediate- Release Fentanyl (TIRF) Product REMS Assessment Data Reference ID: 4190326 RADARS® surveillance data Pre-REMS period 7/1/2010-6/30/2012 Post-REMS period 7/1/2012-6/30/2016 Study design Ecologic Exposure All TIRFs on the market during the study period combined into one category Comparators Primary comparators: 1. Schedule II immediate release opioids (oxycodone, nontransmucosal fentanyl, hydromorphone, morphine, oxymorphone, tapentadol) 2. Schedule II opioids (oxycodone, non-transmucosal fentanyl, hydromorphone, morphine, oxymorphone, methadone, tapentadol) 3. Schedule II opioids excluding methadone (oxycodone, nontransmucosal fentanyl, hydromorphone, morphine, oxymorphone, tapentadol) Since hydrocodone was not a schedule II opioid for the entire study period, it was excluded from the primary analysis and then included as a schedule II drug for the entire study period as a secondary analysis. Outcomes Reference ID: 4190326 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. Inappropriate conversion Unintentional therapeutic exposures Unintentional general exposures Non-opioid tolerant use Addiction Intentional misuse Abuse Overdose ED visits/hospitalizations Pediatric exposures Death Major medical outcomes and death FDA_7494 Denominators • • • Analysis • • Number of population extrapolated from 2000 and 2010 US Census per quarter Number of retail prescriptions from IMS Government Solutions, Inc. projected to national level retail prescriptions per quarter Number of dosage units from IMS Government Solutions, Inc. projected to national level retail dosage units per quarter Quarterly AE rates were calculated by dividing the number of events from various RADARS data sources by the sum of population, prescriptions, or dosage units for the 3-digit zip code covered by the program from US Census or IMS Health data. Poisson regression was used to compare changes in the rates of outcomes before and after the REMS was implemented. Both a comparison of means and a comparison of trends were evaluated. For the comparison of means, the mean quarterly rates of outcomes were calculated for the pre- and post-periods and the differences in means were compared across time periods. For the comparison of trends, trend lines were fit to the pre- and postperiods and slopes were compared between the periods. The report claimed that the comparisons of means provided a better fit to the data but did not provide any statistics or explanation to support that assertion. Appendix Section 10.3. summarizes the characteristics of the spontaneous adverse events data and RADARS data used in this submission. Reference ID: 4190326 FDA_7495 RESULTS: A detailed description of the results is included in Appendix Section 10.4. Spontaneous Adverse Event Data: Table 28 below (taken from the DEPI review?s Table 5) compares the adverse event rates across the three most recent reporting periods for addiction. death. overdose. and pediatric exposures: Table 28: Adverse Event Rates during the 36, 48, and 60-month Reporting Periods?:b - 60-month reporting period 48-month reporting period 36-inonth reporting period AIS of Rate per Rate per Rate per Rate per Rate per Rate per interest 100.00 Rx 100.000 100.00 Rx 100.000 1008(2)" 100.000 (4) Patieqlts (4) (4) Patients Patients (m3e Mtg? (4) (31: (4) Addiction 6 12 5 Death 344 294 400 Overdose 4 6_ 2 Pediatric 3 4 2 exposure Ali. adverse events; Rx prescriptions a Rates are the counts of the speci?c adverse event from divided by 1) the population size from US Census data 2) the water of prescription fills from 1M8 Health data. or 3) the number of dosage units from 1315 Health data. Retina-generated table based on information presented in Tables 28 and 29 of the 60-month REMS assessment report DEPI reports that of the 344 deaths this reporting period, causality for 200 deaths could not be determined; 121 were determined to be unrelated to the 4 deaths were possibly related to TIRFs and 1 death was due to the inappropriate use of a TIRF. All three pediatric events were from the intentional use of the outcomes from 2 cases were unknown While the third case had outcome of ?not recovered/resolved? . RADARS Data: DEPI states that these data include: cumulative case counts (each person cormts once per outcome) and case mentions (multiple mentions are possible per person per outcome) 0 quarterly rates per 100,000 population, 10,000 prescriptions, or 100,000 dosage tmits from the pre- to post-REMS periods, 0 percent change in the slope (95% CI) of the trend line for the quarterly abuse rates from the pre- to post-REMS periods. TRIG states that the percent mean di?erence in quarterly rates in the pre- and post- REMS periods was a better ?t to the data than the quarterly trend lines, although no data were included to substantiate this. DEPI focused mostly on the percent mean difference, but also provided the percent difference in slope in the tables. Reference ID: 4190326 DEPI also states that they focused on the prescription-based rates since the population-based rates were very low as compared to the comparator products (e.g., immediate-release [IR] opioids), given the large differences in utilization. DEPI further explains that they focused upon the prescription-adjusted rates rather than the dosage unit-adjusted rates since TIRF product dosage forms such as nasal or sublingual sprays can potentially differ from transmucosal lozenges in how these dosage forms are counted. For example, DEPI points out that there are eight sprays/dosage units per bottle of Lazanda, and pharmacies may record a quantity of one for the bottle or a quantity of eight to reflect the actual number of dosage units. Table 29 (a modification of DEPI’s Table 6) presents the percent changes in adverse event rates for TIRFs versus comparator opioids from the pre- to postREMS periods for the Poison Center and other RADARS programs: Table 29: Percent change in adverse event rates for TIRFs and comparator opioids outcome between the pre- (7/2010-6/2012) and post-REMS (7/20126/2016) periods in the Poison Center Program and Other RADARS Program data Cumulative % change in means (95% Cases CI) per 10,000 prescriptions Outcome (b) (4) % change in slope of trend lines (95% CI) per 10 000 prescriptions Poison Center Program TIRFs Abuse C2 IR opioids TIRFs Intentional Misuse C2 IR opioids Unintentional Therapeutic Error Unitentional General Exposure Emergency Department Visits and Hospitalization Major Medical Outcome and Death Treatment Center Program Abuse Rate College Survey Non-Medical Use IHCW Abuse Rate TIRFs C2 IR opioids TIRFs C2 IR opioids TIRFs C2 IR opioids TIRFs C2 IR opioids TIRFs C2 IR opioids TIRFs C2 IR opioids TIRFs C2 IR opioids Reference ID: 4190326 FDA_7497 With regards to the Poison Center data, DEPI notes the very small numbers of events throughout which likely causes the large variability in the results. Regarding the specific studied outcomes, DEPI notes the following: (b) (4) • • • • • • • • • Figure 7 (taken from the TRIG report’s Figure 8.1.1.3) compares RADARS intentional abuse mentions per 10,000 prescriptions dispensed via a comparison of means from July 2010 through June 2016 for TIRFs and comparator products: Reference ID: 4190326 FDA_7498 Figure 7: RADARS Poison Center Program Intentional Abuse Exposure Mentions per 10,000 Prescriptions Dispensed Comparison of Means from July 2010 through June 2016 for TIRFs and Comparators Figure 8 (taken from the TRIG report?s Figure 8.1.7.3) compares RADARS Treatment Center Programs combined last month use to get high mentions per 10,000 prescriptions dispensed via a comparison of means from July 2010 through June 2016 for and comparator products: Figure 8: RADARS Treatment Center Programs Combined Last Month Use to Get High Mentions per 10,000 Prescriptions Dispensed Comparison of Means from July 2010 through June 2016 for TIRFs and Comparators Figure 9 (taken from the TRIG report?s Figure 8.1.8.3) compares RADARS College Survey Program past 3 month nonmedical use mentions per 10,000 Reference ID: 4190326 prescriptions dispensed via a comparison of means from July 2010 through June 2016 for TIRFs and comparator products: Figure 9: RADARS College Survey Program Past 3 Month Nonmedical Use Mentions per 10,000 Prescriptions Dispensed Comparison of Means from July 2010 through June 2016 for TIRFs and comparator products Tl" Schmidt ll ll 0M8 Summa? of Findings: 0 ?The data suggest that the prescription-adjusted rates for past 30-day abuse or past 90-day non-medical use of IRF have increased over time even as the utilization of IRFs has decreased as a group. 0 The abuse and non-medical use rates increased most notably after the REMS was established which roughly coincides with the approval of Subsys. Product-speci?c results are needed to ascertain if certain IRF products are driving the increase. 0 The data suggest that the rates of abuse and non-medical use, after adjusting for the number of prescriptions dispensed, are substantially higher for IRFs than for the existing composite comparator groupings. 0 Although based on small numbers of cases, there appeared to be an increase in the rate for unintentional therapeutic errors; emergency department visits and hospitalizations; and major medical outcomes/deaths for TIRFs from the pre- to post-REMS periods, when adjusted for prescriptions dispensed, whereas the comparator rates decrease Reference ID: 4190326 DEPI states their concern with the above findings given that trends for most comparators were decreasing over time. DEPI emphasizes that analysis by product is needed to determine whether or not these increases are a class effect or limited to specific products. Limitations in the data that they cite are: • “small event counts for TIRF exposure, especially in PCP data • representativeness of the treatment center sources • misclassification of specific TIRF or comparator exposures • limited capture of outcomes of interest in the Poison Center data, and • voluntary reporting of exposures and outcomes across the data sources which may introduce misclassification bias.” DEPI’s Overall Conclusions/Recommendations: “We cannot assess whether the REMS was effective in mitigating the outcomes of interest with the current presentation of the data. However, these data may be useful for assessing the REMS effectiveness with respect to the overarching goals of reducing abuse, misuse, and unintentional exposures given the modifications described here. The number [sic] events may be too small, after stratifying by product, to be useful for assessing the REMS, especially for some of the Poison Center Program analyses. Although we cannot determine from the current presentation of data whether the REMS had a mitigating effect on these trends, the current presentation of the data suggests that, despite the presence of a REMS, we observed an increasing trend in prescription-adjusted rates of abuse and other significant outcomes for TIRFs over the time period.” DEPI had the following specific observations: 1. “…Currently, the Sponsors have provided data for all TIRFs, combined, and for large groups of composite comparators. Grouping multiple drugs may mask variability and trends for individual drugs…Therefore, further submissions should separate the TIRFs by product, where possible under the confines of a shared system REMS. Generics and branded products that are the same dosage forms may be combined. In addition, composite comparator groups of multiple products and molecules should not be used. Instead, we recommend oxycodone IR, oxycodone ER, hydromorphone IR, and oxymorphone IR as comparators. Please note that one document showing trends for individual TIRF products will be significantly easier to evaluate for REMS effectiveness and for surveillance purposes than having each product submitted in separate reports. 2. …To assess the effectiveness of the REMS, we have to examine patterns in AE rates before and after the REMS for the products that had no REMS implemented prior to the shared system REMS. Reporting results by TIRF product will address this need. Reference ID: 4190326 FDA_7501 3. The P-values provided are not very meaningful given the large number of tests performed and the small number of events attributed to TIRFs…With the small numbers of events it may not be possible to power the assessments appropriately, especially since we want to assess product-specific outcome rates that will split the small numbers of cases further. We will likely have to base our assessments on the descriptive data reporting the magnitude of changes in AE rates over time for TIRF and comparator products. The Sponsors should interpret the magnitude of changes instead of or in addition to statistical significance. Statistical significance of results should only be incorporated into the interpretations when sufficient a priori power was present. 4. Report case and mention counts for both the pre- and post-REMS periods. 5. Limit the TCP data to the centers that participate in the TCP for the majority of the study period as a sensitivity analysis to improve the ability to trend numbers over time. 6. Consider reporting the Poison Center results as annual rates rather than quarterly rates to help stabilize the variability due to small numbers of events. 7. Provide separate results for children under 6 years of age in the unintentional exposure AE results. 8. Remove the Impaired Healthcare Worker data as they add little value to our understanding of the trends in outcomes of interest related to these products.” DEPI also offered the following suggestions to the TRIG for “streamlining the presentation of surveillance data: • “The Sponsors need to clarify their finding that the comparison of means rather than the comparison of slopes is the best fit for the data. If we agree with their assessment, dropping the tables and figures with comparisons of slopes and intercepts will also help streamline these assessments. • DEPI can provide table shells to streamline the presentation of results further once we understand whether the slope and intercept data are essential. Reference ID: 4190326 FDA_7502 • Visual inspection of the quarterly rates over time will still be useful for identifying possible trends.” Additionally, DEPI recommended that the TRIG use the following additional surveillance data sources to assess the following outcomes: • Unintentional Pediatric Exposures: “Additional data sources for identification of unintentional pediatric exposures were proposed in a separate review. Possible data sources suggested for exploration were 1) death certificate data where fentanyl form (i.e., TIRFs) may be reported in the literal text on the death certificates and 2) emergency department administrative claims data with linkages to electronic medical records. Accidental poisonings in children could be identified via ICD-10 diagnostic codes in claims data and the specific drug and drug form could be pulled from EMR records.” [Note: DRISK consulted to DEPI as to whether the National Electronic Injury Surveillance System-Cooperative Adverse Drug Event Surveillance (NEISS-CADES) emergency department (ED) data could be a robust supplement to the TRIG’s annual reports of accidental childhood exposures to TIRFs. DEPI concluded 11 that NEISS-CADES does not appear to be a robust source of cases of accidental pediatric exposures to TIRFs since there were only two TIRF-related accidental exposure ED visits reported from about 60 sampled US hospitals from 2004-2015 (the other 8 fentanyl exposures reported were attributed to the patch). The receipt of only two cases is well below the 20 needed to generate national estimates. DEPI’s review also delves into reasons why cases were likely to be underascertained from NEISS-CADES. Thus, DEPI does not recommend adding NEISS-CADES ED cases as a routine surveillance source of accidental TIRF exposures in children.] FDA and the TRIG have had subsequent communications about these accidental poisoning analyses since DEPI finalized their review of the 60month REMS Assessment Report; the most recent communication was a written response from the TRIG on October 16, 2017 which addressed discussion between the FDA and TRIG in an October 2, 2017 teleconference. Briefly, the TRIG agreed to conduct a study of ED visits and inpatient admissions to look for evidence of TIRF poisoning in provider notes within electronic medical records. They also agreed to evaluate various sources of death records for evidence of childhood deaths due to 11 Meyer T, Kornegay C, and Staffa J. Epidemiology: Review of NEISS-CADES Data on Pediatric Emergency Department Visits Related to Accidental Exposure to Transmucosal Immediate Release Fentanyl. Filed 4/21/2017, Reference ID: 4084489 Reference ID: 4190326 FDA_7503 TIRF poisoning. DEPI provided responses to their October 16, 2017 communication that are included in section 9. • Abuse: “Further data are needed to describe abuse rates by drug in the general population. A new Survey of Non-Medical Use of Prescription Drugs Program under the RADARS system may be useful, but DEPI has not been able to fully evaluate the study methods yet. The survey began in the third quarter of 2016.” • Overdose: “Fatal overdoses may be identified in medical examiner data (by state, or possibly through requests for National Center for Health Statistics death certificate data analyses).” DEPI’s Comments to the Sponsor are in Review Section 9. 5.6. ASSESSMENT ELEMENT 6: KNOWLEDGE, ATTITUDES, AND BEHAVIOR (KAB) SURVEYS 5.6.1. PATIENT SURVEY The purpose of the patient survey was to assess patients' and caregivers' knowledge, attitudes, and behavior in terms of the safe use of TIRF medicines as described in the REMS educational materials. Patients/caregivers were eligible to participate if they were age 18 or older and had a prescription filled for a TIRF medicine within 120 days (4 months) prior to the survey launch date. Respondents were recruited through the TIRF REMS Access Program database and a Pharmacy Benefits Manager (PBM) via direct mail. The survey was conducted from September 26, 2016 to November 21, 2016. Survey invitations were sent to 2945 potential respondents with 399 returned as undeliverable. A total of 394 respondents accessed the survey, 374 answered at least one question, 321 were eligible, and 310 completed the survey. The survey closed early once 310 surveys were collected. The majority of respondents completed the survey via the internet (67%) followed by telephone (33%). According to patient reports, most respondents were between the ages of 50-69 (67%), female (64%), White (86%), and had some college/Associate's degree or higher (81%). The most commonly reported prescription was for Subsys (41%), followed by Actiq (23%), and Fentora (18%). Most respondents were from the South (35%), followed by the West (31%), Midwest (16%), and the Northeast (18%). The TRIG compared survey respondents (n=310) with the general population of patients who have received a TIRF prescription in the last four months (obtained from IMS Health data) (n=3134). The populations were compared in the areas of TIRF products used, age, gender, race, ethnicity, geographic distribution, level of education, and main language spoken at home. The Division of Biostatistics 7 (DB7) conducted a review of the comparison analysis to comment on the suitability/appropriateness of the comparison and the Reference ID: 4190326 FDA_7504 conclusions of the sponsor and suggestions for improvement or changes. DB7 noted statistically significant differences between the two groups for “highest level of education completed” (p=<.0001) and “race” (p=<.0001). In terms of education, the level of education on average was higher for survey respondents than for the general population of TIRF patients. There were more survey respondents with some college versus the general patient population (44.5% versus 27%) and fewer survey respondents with high school (17% versus 31.5%) or less than high school diploma (2% versus 6%) than the general population. In terms of race, DB7 noted that there were more race categories in the survey than provided for the general population. For common race categories, there were fewer White survey respondents as compared to the general population (86% versus 89.5%), fewer Black or African American (4% versus 7%), and fewer Asian (<1% versus 1%). DB7 did comment that although race was significantly different between the two groups, in the most common categories, survey respondents and the general patient population had comparable proportions so this difference will not likely affect the correct response rate in the survey. The survey contained questions about six key risk messages: 1) TIRF medicines can cause life-threatening breathing problems that can lead to death; 2) Patients should not take TIRF medicines if they are not opioid tolerant; 3) TIRF medicines should be taken exactly as prescribed by the healthcare provider; 4) Patients should not switch from a TIRF medicine to another medicine that contains fentanyl without talking to a healthcare provider; 5) Patients should not give the TIRF medicines to anyone else even if they have the same symptoms; 6) TIRF medicines should be stored in a safe place away from children and properly disposed. Key Risk Message 1: TIRF medicines can cause life-threatening breathing problems that can lead to death. This key risk message included questions about patients' and caregivers' knowledge of the life-threatening breathing problems that TIRF medicines can cause. The majority of respondents answered the question correctly for this key risk message (92%). Key Risk Message 2: Patients should not take TIRF medicines if they are not opioid tolerant. This key risk message included questions about patients' and caregivers' knowledge that TIRF medicines should not be taken if they are opioid tolerant and understanding of what opioid tolerance is. The majority of respondents were aware Reference ID: 4190326 FDA_7505 that opioid tolerance means that a patient is already taking other opioid pain medicines around the clock and their body is used to these medicines (88%) and TIRF medicines should only be taken by patients that are opioid tolerant (89%). Overall, 83% of respondents answered both questions correctly for this key risk message and 12% answered 1 out of 2 correctly. Key Risk Message 3: TIRF medicines should be taken exactly as prescribed by the healthcare provider. This key risk message included nine questions about patients' and caregivers' knowledge that TIRF medicines should be taken exactly as prescribed, the correct indication for TIRF medicines, knowledge that headache pain is not an appropriate indication for use of TIRF medicines, to stop taking TIRF medicines if they stop taking around-the clock opioid pain medicine, and it is not okay to take TIRF for short-term pain. All but one respondent were aware that TIRF medicines should be taken exactly as prescribed. The majority of respondents were aware that it is not okay to take TIRF medicine for short-term pain (85%) while fewer were aware that it is not okay to use TIRF medicines for headache pain (67%). Only 40% of respondents were aware that they should discontinue taking the TIRF medicine if they discontinue the around-the-clock opioid pain medicine. While most respondents were aware that TIRF medicine should not be used for headache pain (78%), dental pain (87%), respondents were unaware that TIRF medicines should not be used for long-lasting painful conditions not caused by cancer (39%) or pain after surgery (64%). In addition, only 73% of respondents reported the correct indication of breakthrough pain from cancer. Overall, 11% of respondents answered all nine questions correctly for this key risk message. Key Risk Message 4: Patients should not switch from a TIRF medicine to another medicine that contains fentanyl without talking to a healthcare provider. This key risk message included questions about patients' and caregivers' knowledge that they should not switch to another medicine that contains fentanyl without talking to a healthcare provider. The majority of respondents were aware that is not safe to switch to another medicine that contains fentanyl without discussing with a healthcare provider first (96%). Key Risk Message 5: Patients should not give the TIRF medicines to anyone else even if they have the same symptoms. This key risk message included questions about patients' and caregivers' knowledge that TIRF medicine should not be given away and selling or giving them away was against the law. The majority of respondents were aware that TIRF medicines should not be given to another person if they have the same symptoms as the patient (98%) and that selling or giving away TIRF medicines is against the law (99%). Respondents were also aware that a side effect of TIRF medicines is the chance of abuse or addiction (93%), TIRF medicines can be misused by people who abuse Reference ID: 4190326 FDA_7506 prescription medicines or street drugs (97%), and that TIRF medicines should be kept in a safe places to prevent it from being stolen (99%). Overall, 88% of respondents answered all five questions correctly for this key risk message. Key Risk Message 6: TIRF medicines should be stored in a safe place away from children and properly disposed. This key risk message included questions about patients' and caregivers' knowledge that TIRF medicines should be stored in a safe place out of reach of children, disposed of as described in the specific product's Medication Guide (MG), can cause an overdose and death in any child who takes it, and what to do if an adult takes TIRF medicines that have not been prescribed. All respondents were aware that TIRF medicines should be stored in a safe place out of the reach of children. Most respondents were aware that TIRF medication must be disposed of as described in the specific product's MG (98%), that a TIRF medicine can cause an overdose and death in any child who takes it (94%), and if an adult who has not been prescribed a TIRF medicine takes it they should get emergency help right away (89%). Overall, 84% of respondents answered all four questions correctly for this key risk message. Additional Safe Use Questions The survey included five additional questions about the safe use of TIRF medicines and patient-reported prescriber behaviors related to use of TIRF medicines. Most respondents reported that their healthcare provider talked to them about the risks and possible side effects of TIRF medicines (86%), told them how to use the TIRF medicine (95%), and told them how to store or keep the TIRF medicine (87%). Knowledge scores have been consistent across the assessment periods. Most respondents were also aware that TIRF medicines are only available through a pharmacy enrolled in the TIRF REMS Access Program (77%). Questions about REMS Educational Materials The survey included questions about patients and caregivers awareness of the TIRF educational materials including the Medication Guide (MG) and the PatientPrescriber Agreement Form. The majority of respondents reported ever receiving the Medication Guide (MG) (93%). Most respondents reported receiving it from the pharmacy (92%) each time a prescription was filled (91%). A little over half of respondents reported receiving the MG from their prescribing doctor or someone in the doctor’s office (57%), most at the first appointment (82%). The majority of respondents reported reading the MG (97%) with 92% reporting reading all or most of the MG. Most of the respondents (91%) reported understanding all or most of the MG. Most patients/caregivers reported that they did sign a Patient-Prescriber Agreement Form (77%) and received a copy of the form (77%). Respondents also Reference ID: 4190326 FDA_7507 reported that their healthcare provider offered to explain the form (77%) and they understood all or most of the explanation (99%). Summary of Findings Overall, surveyed patients had a high level of knowledge (≥80%) across most of the key risk messages as in previous assessments, including awareness of the potential side effects of TIRF medicines (breathing problems, death), that TIRF medicines should be taken as prescribed, that TIRF medicines should only be taken by patients who are opioid tolerant, that you should talk to a healthcare provider before switching medicine, that selling or giving away TIRF medicines is illegal, and that TIRF medicines should be stored in a safe place. Respondents were less aware of the correct indication for TIRF medicines with only 73% correctly selecting breakthrough pain from cancer. In addition, respondents were unaware that if a patient stops taking around-the-clock opioid pain medicine, they must also stop taking the TIRF medicine with only 40% selecting the correct answer. Knowledge rates have consistently been low with these questions across assessment periods. Most respondents reported receiving (93%) and reading (97%) the Medication Guide with 91% who reported receiving it from their pharmacy receiving it at every prescription fill. Seventy-seven percent (77%) of respondents reported signing the Patient-Prescriber Agreement Form and 77% of respondents were aware that TIRF medicines are only available through a special program, the TIRF REMS Access Program. Reviewer's Comments A. Respondents were unaware that if a patient stops taking around-the-clock opioid pain medicine, they must also stop taking the TIRF medicine, with only 40% selecting the correct answer. Knowledge rates have consistently been low with these questions across assessment periods, and ways to improve knowledge in this area should be identified and implemented. B. DB7: For the review of the comparison of the demographics of the patient survey respondents with the overall population of patients who are prescribed TIRF medicines, the survey respondents had a significantly higher “highest education level completed” than all users in the IMS database. Thus, we suspect the knowledge rate in the survey was overestimating the knowledge rate for all users. We request the following analyses from the sponsor. • Submit subgroup analyses stratified by education level, to quantify the impact of education on knowledge in the survey. Reference ID: 4190326 FDA_7508 • • Submit a sensitivity analysis predicting the knowledge rate in all users adjusting for education level in your survey (e.g. standardization) Submit the data for us to reproduce your results. 5.6.2. PHARMACIST SURVEY The purpose of the pharmacist survey was to assess pharmacists' understanding and knowledge of the safe use and appropriate prescribing of TIRF medicines. Pharmacists were eligible to participate if they dispensed TIRF products in the past six months. Respondents were recruited from a random sample of pharmacists from pharmacies that were enrolled in the TIRF REMS Access Program as of September, 2016. Any pharmacist who worked at an enrolled pharmacy was eligible to participate. The survey was conducted from September 26, 2016 to December 13, 2016. Pharmacists were recruited via mail or fax. Three categories of pharmacies were sampled: Closed System Pharmacies (CSP), Inpatient Pharmacies, and Outpatient Pharmacies. Approximately 11,598 invitation letters were sent to pharmacists from 3856 enrolled pharmacies. From these, 561 pharmacists accessed the survey, 333 (59%) met the eligibility criteria, and 318 pharmacists completed the survey and completed the survey for a response rate of 3%. The majority of respondents completed the survey via the internet (99%) followed by telephone (1%). Approximately half of respondents were male (49%) and had been practicing pharmacy for 11 or more years (53%). Nineteen percent (19%) of respondents had never dispensed a TIRF medicine while 47% had dispensed a TIRF medicine one to two times per month. Actiq was most commonly dispensed (75%) followed by Fentora (41%), and Subsys (37%). Most respondents were from the South (40%), followed by the Northeast (24%), Midwest (20%), and the West (16%). The majority of respondents (75%) were not the pharmacist-incharge. For the chain/independent pharmacies, there were 145 unique pharmacies with one completer; 40 with two completers, and nine with three completers. For the inpatient pharmacies, there were 29 unique pharmacies with one completer, 13 with two completers, and three with three completers. There was one participant from a closed system pharmacy. The TRIG compared pharmacist survey respondents (n=240) with the general population of pharmacists that have dispensed a TIRF prescription in the last six months (REMS switch provider data) (n=3875) for region, type of pharmacy, and number of orders by type of pharmacy. DB7 conducted a review of the comparison analysis to comment on the suitability/appropriateness of the comparison and the conclusions of the sponsor and suggestions for improvement or changes. DB7 noted statistically significant differences between the two groups for “type of pharmacy” (p=<.0001). In terms of Reference ID: 4190326 FDA_7509 type of pharmacy, most of the survey respondents represented independent outpatient pharmacies (69%) while the general population of TIRF pharmacists was from chain outpatient pharmacies (34%). The survey contained questions about five key risk messages: 1) TIRF medicines are contraindicated in opioid-non tolerant patients; 2) TIRF medicines are only indicated for the management of breakthrough pain in adult cancer patients 18 years of age or older (16 or older for Actiq and equivalent generics) who are already receiving and who are tolerant to around-the-clock opioid therapy for their underlying persistent cancer pain; 3) TIRF medicines contain fentanyl, an opioid agonist and a Schedule II controlled substance, with abuse liability similar to other opioid analgesics; 4) TIRF medicines are not interchangeable with each other, regardless of route of administration; 5) Patients and their caregivers must be instructed that TIRF medicines contain a medicine in an amount that can be fatal to children, in individuals for whom it is not prescribed, and in those who are not opioid tolerant. Key Risk Message 1: TIRF medicines are contraindicated in opioid nontolerant patients This key risk message included questions about pharmacists' understanding of who is considered an opioid tolerant patient and that TIRF medicines are contraindicated in opioid non-tolerant patients because of the problems that can occur such as respiratory depression and death. Most respondents knew that cancer patients who are considered opioid tolerant are those who are taking around-the clock opioid therapy for underlying persistent cancer pain for one week or longer (96%) and that patients who have no known contraindications to fentanyl, but are not currently taking around the clock opioid therapy were not considered opioid tolerant (82%). Most respondents also knew that TIRF medicines can cause life-threatening respiratory depression or death if used in opioid non-tolerant patients (88%) and that all prescribers should begin with titration from the lowest dose available for all new patients even if the patient has taken another TIRF medicine before (84%). Overall, awareness was low in terms of the specific medication/dose that a patient would need to be taken for a patient to be opioid tolerant. While most respondents were aware that patients who are taking 60 mg oral morphine/day for one week or longer (88%) or 25 mcg transdermal fentanyl/hour (80%), were considered opioidtolerant , respondents were less aware of the other regimens for opioid-tolerance (8 mg oral hydromorphone/day (75%), 30 mg oral oxycodone/day (78%), 25 mg oral oxymorphone/day (72%), and an equianalgesic dose of another oral opioid (65%)). Overall, 31% of respondents answered all thirteen questions correctly. Respondents who received and read the prescribing information or Medication Guide were more aware of the specific medication/dose for opioid tolerant patients than those that did not receive or read them. Reference ID: 4190326 FDA_7510 Key Risk Message 2: TIRF medicines are only indicated for the management of breakthrough pain in adult cancer patients 18 years of age or older (16 years of age or older for Actiq) who are already receiving and who are tolerant to around-the-clock opioid therapy for their underlying persistent cancer pain. This key risk message included questions about pharmacists' knowledge of the correct indication for TIRF medicines and understanding of timing of administration of TIRF medicines. Most respondents were aware that breakthrough pain from cancer was the correct indication for TIRF medicines (92%). In addition, most respondents were aware of incorrect indications for TIRF medicines with the exception of only 51% aware that chronic non-cancer pain was not a correct indication. While 81% of respondents were aware that a cancer patient cannot start taking a TIRF medicine after one day on an around the clock opioid, only 62% of respondents were aware that a cancer patient cannot start a TIRF medicine and an around the clock opioid at the same time. Only 41% of respondents were aware that a patient must stop taking their TIRF medicine if they stop taking their around the clock opioid pain medicine. Overall, 22% of respondents answered all eight questions correctly for this key risk message. Key Risk Message 3: TIRF medicines contain fentanyl, an opioid agonist and a schedule II controlled substance, with abuse liability similar to other opioid analgesics. This key risk message included questions about pharmacists' knowledge of the risk factors and signs and symptoms of opioid abuse in patient taking TIRF medicines. Almost all respondents were aware that a personal history of past or current alcohol or drug abuse, or a family history of illicit drug use or alcohol abuse was a risk factor for opioid abuse (99%) although only 77% were aware that a personal history of psychiatric illness was also a risk factor. Pharmacists were aware that it was important to monitor for signs of abuse and addiction in patients who take TIRF medicines (98%) and that TIRF medicines can be abused in a manner similar to other opioid agonists (94%). In addition, respondents were aware of the risks associated with TIRF medicines: misuse (99%), abuse (99%), addiction (99%), and overdose (99%). Overall, 59% of respondents answered all ten questions correctly for this key risk message. Key Risk Message 4: TIRF medicines are not interchangeable with each other, regardless of route of administration. This key risk message included questions about pharmacists' knowledge that TIRF medicines are not interchangeable regardless of the route of administration. The majority of respondents were aware that TIRF medicines are not interchangeable (96%), that conversion of one TIRF medicine to another may result in a fatal overdose (93%), the dosing of TIRF medicines is not equivalent on a microgram-to- Reference ID: 4190326 FDA_7511 microgram basis (89%), and TIRF medicines with the same route of administration cannot be substituted with each other if the pharmacy is out of stock for one product (96%). Overall, 80% of respondents answered all four questions for this key risk message. Respondents who received and read the prescribing information or Medication Guide were more aware that dosing of TIRF medicines is not equivalent on a microgram to microgram basis than those that did not receive or read them. Average Knowledge Scores by Key Risk Message Table 30 presents the average knowledge scores for each key risk message. Table 30: Average Knowledge Score by Key Risk Message Key Risk Message KRM 1 KRM 2 KRM 3 KRM 4 Overall Score [95% CI] 84% [82, 86] 75% [73, 78] 94% [93, 95] 94% [92, 95] 86% [84, 87] Additional Safe Use Questions The survey included additional questions about the safe use of TIRF medicines and pharmacist-reported activities performed related to use of TIRF medicines. Respondents were aware that TIRF medicines should not be sold, loaned, or transferred to another pharmacy (91%), that pharmacy staff must be educated about the TIRF REMS Access Program (90%), and that the use of TIRF medicines with a CYP3A4 inhibitor may require dosage adjustment and monitoring (92%). Most inpatient pharmacist respondents were aware that it is not ok to dispense TIRF medicines from the inpatient inventory to outpatients (83%) although the sample size was small (n=65). In terms of pharmacist-reported activities, most respondents reported always performing the following activities or performing them only with the first prescription: • Giving patients the MG for their TIRF medicine (87%; only with first prescription (8%)). • Instructing patients not to share TIRF medicines (70%; only with first prescription (20%)) Responses were relatively low with respondents reported always performing the following activities or performing them only with the first prescription: Reference ID: 4190326 FDA_7512 • Instructing patients on how to store or keep the TIRF medicines (62% only with first prescription (27%)) • Talk to patients about the risks and possible side effects of the TIRF medicines (48%; only with first prescription (39%)) • Asking patients about the presence of children in the home (55%; only with first prescription (27%)) • Instruct the patient on how to use the TIRF medicines (58%; only with first prescription (35%)) • Instructing patients about proper disposal of any unused or partially used TIRF medicines (62% only with first prescription (27%)) • Counseling patients that accidental exposure to TIRF medicines by a child may be fatal (65% only with first prescription (22%)) • Instructing patients to keep TIRF medicines out of reach of children (67%; only with first prescription (21%)) Only 40 (62%) of inpatient pharmacists reported having an established system, order sets, protocols and/or other measures to help ensure appropriate patient selection and compliance with the REMS program. Most outpatient pharmacists (82%) reported processing all TIRF medicine prescriptions regardless of method of payment, through the pharmacy management system. Questions about TIRF Medicine REMS Educational Materials The survey included questions about pharmacists' access to educational materials for TIRF medicines. Almost all pharmacists reported receiving or having access to the Prescribing Information (96%), and the majority of those reported reading it (81%). Most respondents reported receiving or having access to the Medication Guide (MG) (97%) and 88% of those reported reading it. In addition, 87% of respondents reported always giving patients the Medication Guide. Summary of Findings Overall, surveyed pharmacists had a high level of knowledge (≥80%) across most of the key risk messages as in previous assessments, including awareness that TIRF medicines should only be given to opioid tolerant patients, that TIRF medicines have the potential to be abused and that TIRF medicines are not interchangeable with each other. While most respondents were aware of the correct indications for TIRF medicine, only 44% correctly stated that chronic non-cancer pain was not an approved indication. Only 75% of respondents were aware that a personal history of psychiatric illness was a risk factor for opioid abuse. Overall responses were low in terms of awareness of specific medication/dose for opioid tolerant patients with Reference ID: 4190326 FDA_7513 the exception of oral morphine. Correct responses ranged from 65% to 89%. Almost all respondents reported having access to the Prescribing Information with 83% reading it. Similarly, all but one respondent reported having access to the Medication Guide with 88% reading it. While 92% of respondent reported always giving patients the MG for their TIRF medication, responses were low in terms of other behaviors including always: asking patients about the presence of children in the home (60%); counseling patients that accidental exposure to TIRF medicines by a child may be fatal (72%); and instructing patients about proper disposal of any unused or partially used TIRF medicines (69%). Only 62% of the inpatient pharmacy respondents reported having an established system, order sets, or protocols to ensure appropriate patient selection and compliance with the requirements of the TIRF REMS Access Program. The majority of outpatient pharmacies (82%) reported processing all TIRF medicine prescriptions, regardless of method of payment, through the pharmacy management system. Reviewer's Comments A. There was only one closed system pharmacy (CSP) survey respondent. The TRIG should increase efforts to get participants from additional closed systems to participate in the survey. B. Only 62% of respondents were aware that a cancer patient cannot start a TIRF medicine and an around the clock opioid at the same time. In addition, only 41% of respondents were aware that a patient must stop taking their TIRF medicine if they stop taking their around the clock opioid pain medicine. Knowledge has consistently been low in this area across assessment periods, and ways to improve knowledge in this area should be identified and implemented. C. Only 62% of the inpatient pharmacy respondents reported having an established system, order sets, or protocols to ensure appropriate patient selection and compliance with the requirements of the TIRF REMS Access Program. This should be explored further in program audits. D. DB7: For the review of the comparison of the demographics of the pharmacist survey respondents with the overall population of pharmacists who prescribed TIRF medicines, the survey respondents differed from all pharmacists in the REMS switch provider data by type of pharmacies. This may bias the results but we do not know in which direction or by how much. We request the following analyses from the sponsor. • Submit subgroup analyses stratified by type of pharmacy, to quantify the impact of type of pharmacy on knowledge in the survey. • Submit a sensitivity analysis predicting the knowledge rate in all pharmacists adjusting for type of pharmacy in your survey (e.g. standardization) • Submit the data for us to reproduce your results. Reference ID: 4190326 FDA_7514 5.6.3. PRESCRIBER SURVEY The purpose of the prescriber survey was to assess prescribers' understanding and knowledge of the safe use and appropriate prescribing of TIRF medicines. Prescribers were eligible to participate if they were enrolled in the TIRF REMS Access Program as of September 2, 2016 and had prescribed a TIRF medicine in the last six months. The survey was conducted from September 26, 2016 to December 20, 2016. Prescribers were recruited via mail. Approximately 2848 prescribers were invited to participate. A total of 8405 reminder letters were sent to non-responders. From these, 524 respondents agreed to participate and were screened and 313 prescribers were eligible with 294 completed the survey for a response rate of 10%. The majority of respondents completed the survey via the internet (98%) followed by telephone (2%). Most respondents were male (60%), were medical doctors (57%), and had been practicing medicine for 11 to more than 15 years (60%). Over half of the respondents have prescribed TIRF medicines about one to two times per month (64%) followed by 22% prescribing between three to more than five times per month. Five percent (5%) of respondents stated that they had not prescribed a TIRF medicine within the last six months. The main medical specialty was pain management (59%) followed by "Other" (16%), oncology (15%), and primary care (10%). Actiq or generic Actiq were most commonly prescribed (57%) followed by Subsys (54%), and Fentora (33%). Respondents represented all geographic regions with 32% from the West, 31% from the South, 21% from the Northeast, and 16% from the Midwest. Only 1% of respondents reported that they practiced in a closed healthcare system. The TRIG compared prescriber survey respondent self-reported data (n=294) with prescriber survey respondent data from the REMS switch provider (n=294) and the general population of prescribers that had prescribed a TIRF medicine in the last six months (REMS switch provider (n=3045)) for average times per month TIRF medicines have been prescribed within the past six months, TIRF medicines prescribed within the last six months, and geographic region. A comparison was also completed between prescriber survey respondents (n=294) and prescribers of (b) (4) TIRF medicines in the past six months (IMS data) (n= on average times per month TIRF medicines have been prescribed within the past six months, TIRF medicines prescribed within the last six months, geographic region of practice location, gender, medical profession, number of years practicing medicine, and medical specialty. DB7 conducted a review of the comparison analysis to comment on the suitability/appropriateness of the comparison and the conclusions of the sponsor and suggestions for improvement or changes. There were no significant differences between survey respondent’s data and data provided from the REMS switch provider. There were statistically significant differences between the survey respondents and the general population of prescribers from IMS data for on average Reference ID: 4190326 FDA_7515 times per month they prescribed TIRF medicines within the past six months (p=<.0001), TIRF medicines prescribed within the last six months, gender (p=0.0002), medical profession (p=<.0001), number of years practicing medicine (p=<.0001), and medical specialty (p=<.0001). Survey respondents were less likely to prescribe one to two times a month (64% versus 84%) and more likely to prescribe 3-5 times per month (22% versus 7%) as compared to prescribers from IMS data. Survey respondents were also less likely to be male (59.5% versus 71%), less likely to be MDs (57% versus 71%), more likely to have practiced medicine for a shorter timeframe (46% practiced for more than 15 years as compared to 61% IMS data), and more likely to have the specialty of pain management as compared to IMS data prescribers (37% versus 19%). The survey contained questions about five key risk messages: 1) TIRF medicines are contraindicated in opioid-non tolerant patients; 2) TIRF medicines are only indicated for the management of breakthrough pain in adult cancer patients 18 years of age or older (16 or older for Actiq and equivalent generics) who are already receiving and who are tolerant to around-the-clock opioid therapy for their underlying persistent cancer pain; 3) TIRF medicines contain fentanyl, an opioid agonist and a Schedule II controlled substance, with abuse liability similar to other opioid analgesics; 4) TIRF medicines are not interchangeable with each other, regardless of route of administration; 5) Patients and their caregivers must be instructed that TIRF medicines contain a medicine in an amount that can be fatal to children, in individuals for whom it is not prescribed, and in those who are not opioid tolerant. Key Risk Message 1: TIRF medicines are contraindicated in opioid nontolerant patients This key risk message included questions about prescribers' understanding of who is considered an opioid tolerant patient and that TIRF medicines are contraindicated in opioid non-tolerant patients because of the problems that can occur such as respiratory depression and death. The majority of respondents were aware that TIRF medicines should only be taken by patients who are opioid tolerant (97%). Most respondents knew that cancer patients who are considered opioid tolerant are those who are taking around-the clock opioid therapy for underlying persistent cancer pain for one week or longer (95%). The majority of respondents were also aware that patients were not opioid tolerant if they were not currently taking opioid therapy, but have taken opioid therapy before (94%) and if they have no known contraindications to the drug fentanyl, but are not currently taking around the clock opioids (93%). Most respondents also knew that TIRF medicines can cause lifethreatening respiratory depression (92%) and death if used in opioid non-tolerant patients (96%). Respondents were also aware that TIRF medicines should not be used to treat opioid non-tolerant patients (88%) and that all prescribers should begin with titration from the lowest dose available for all new patients even if the patient has taken another TIRF medicine before (86%). Overall, respondents were aware of Reference ID: 4190326 FDA_7516 the specific medication/dose for opioid tolerant patients: morphine (96%), 30 mg oral oxycodone/day (82%), 25 mg oral oxymorphone/day (80%) and transdermal fentanyl (89%). Respondents were less aware of the other regimens for opioidtolerance (8 mg oral hydromorphone/day (72%), and an equianalgesic dose of another oral opioid (66%).Overall, 33% of respondents answered all fourteen questions correctly. Key Risk Message 2: TIRF medicines are only indicated for the management of breakthrough pain in adult cancer patients 18 years of age or older (16 years of age or older for Actiq) who are already receiving and who are tolerant to around-the-clock opioid therapy for their underlying persistent cancer pain. This key risk message included questions about prescribers' knowledge of the correct indication for TIRF medicines and understanding of timing of administration of TIRF medicines. Most respondents were aware that breakthrough pain from cancer was the correct indication for TIRF medicines (99%) and stated that they inform patients that TIRF medicines must not be used for acute or postoperative pain, pain from injuries, headache/migraines, or any other short-term pain (96%). In addition, most respondents were aware of incorrect indications for TIRF medicines (acute or postoperative pain (95%); headache or migraine paint (94%); dental pain (96%)); with the exception of only 78% were aware that chronic non-cancer pain was not a correct indication. For respondents that indicated that chronic non-cancer pain was a correct indication, there was a follow-up question about what types of chronic pain conditions that they prescribed TIRF medicines for. Back pain was the top reported condition (17%), followed by chronic pain (15%), and cancer pain (11%). Respondents were also asked why a TIRF medicine was selected to treat these chronic pain conditions. The top responses were efficacy (24%), fast onset (11%), and other types of treatments have failed (11%). Only 72% of respondents were able to identify the patient that should not use a TIRF medicine based on the provided patient scenarios. In terms of awareness of the timing administration of TIRF medicines, 78% of respondents were aware that a cancer patient cannot start taking a TIRF medicine after one day on an around the clock opioid, 77% of respondents were aware that a cancer patient cannot start a TIRF medicine and an around the clock opioid at the same time, and 77% of respondents were aware that it is incorrect to instruct patients to continue taking their TIRF medicine if they stop taking their around the clock opioid medicine. Overall, 33% of respondents answered all ten questions correctly for this key risk message. Key Risk Message 3: TIRF medicines contain fentanyl, an opioid agonist and a schedule II controlled substance, with abuse liability similar to other opioid analgesics. Reference ID: 4190326 FDA_7517 This key risk message included questions about prescribers' knowledge of the risk factors and signs and symptoms of opioid abuse and the importance of monitoring patients taking TIRF medicines. All respondents were aware that a personal history of past or current alcohol or drug abuse, or a family history of illicit drug use or alcohol abuse was a risk factor for opioid abuse (100%) while 86% were aware that a personal history of psychiatric illness was also a risk factor. Respondents were aware that it was important to monitor for signs of abuse and addiction in patients who take TIRF medicines (99%) and that TIRF medicines can be abused in a manner similar to other opioid agonists (96%). Respondents were aware that misuse (99%), abuse (99%), addiction (99%), and overdose (99%) were all risks associated with the use of TIRF medicines. Overall, 61% of respondents answered all ten questions correctly for this key risk message. Key Risk Message 4: TIRF medicines are not interchangeable with each other, regardless of route of administration. This key risk message included questions about prescribers' knowledge that TIRF medicines are not interchangeable regardless of the route of administration. The majority of respondents were aware that TIRF medicines are not interchangeable (92%), that conversion of one TIRF medicine to another may result in a fatal overdose (96%), and the dosing of TIRF medicines is not equivalent on a microgram-to-microgram basis (92%). Only 79% of respondents selected the appropriate course of action in a proposed scenario converting a patient from one TIRF medicine to another. Overall, 70% of respondents answered all four questions for this key risk message. Average Knowledge Scores for Each Key Risk Message Table 31 presents the average knowledge score for each key risk message. Table 31: Average Knowledge Scores for Each Key Risk Message Key Risk Message Knowledge Score [95% CI] Key Risk Message 1 87% [86, 89] Key Risk Message 2 86% [85, 88] Key Risk Message 3 94% [93, 95] Key Risk Message 4 90% [88, 92] Overall Knowledge Score 89% [88, 90] Reference ID: 4190326 FDA_7518 Additional Safe Use Questions The survey included additional questions about the safe use of TIRF medicines and prescriber-reported activities performed related to use of TIRF medicines. For a scenario presented of a patient who started on the lowest dose of a TIRF medicine, and after 30 minutes breakthrough pain had not been sufficiently relieved, only 71% of respondents selected the appropriate action (to follow the guidance presented in the product-specific MG). In another scenario, a patient is taking a TIRF medicine and the doctor wants to prescribe a CYP3A4 inhibitor. Eighty percent of respondents identified the appropriate response, that use of TIRF medicine with a CYP3A4 inhibitor may require dosage adjustment, to carefully monitor the patient for opioid toxicity, and combined use can cause fatal respiratory depression. Respondents were aware that if a patient is starting titration with a TIRF medicine, they should start with the lowest available dose (91%). In addition, almost all respondents were aware that TIRF medicine contains fentanyl which can be fatal to children (99%) and all respondents knew to instruct patients never to share their TIRF medicine (100%). In terms of prescriber-reported activities, most respondents reported always instructing patients not to share TIRF medicines (80%) while 15% did this only with the first prescription: Responses were relatively low with respondents reported always performing the following activities or performing them only with the first prescription: • Asking patients about the presence of children in the home (62%; only with first prescription (22%)) • Counseling patients or caregivers that accidental exposure to TIRF medicines by a child may be fatal (71%; only with first prescription (19%)) • Instructing patients to keep TIRF medicines out of reach of children (79%; only with first prescription (15%)) • Instructing patients about proper disposal of any unused or partially used TIRF medicines (67%; only with first prescription (19%)) • Giving patients the MG for their TIRF medicine (44%; only with first prescription (45%)). • Talk to the patient about the risks and possible side effects of the TIRF medicine (76%; only with first prescription (18%)). • Instruct the patient on how to store or keep the TIRF medicine that was most recently prescribed (53%; only with first prescription (35%)). Reference ID: 4190326 FDA_7519 Questions about TIRF Medicine REMS Educational Materials The survey included questions about prescribers' access to educational materials for TIRF medicines. Almost all prescribers reported receiving or having access to the Prescribing Information (97%), and the majority of those reported reading the Prescribing Information (87%). The majority reported receiving or having access to the Medication Guide (MG) (96%) and 92% of those reported reading it. Most respondents reported reviewing the Patient-Prescriber Agreement Form with each patient prescribed TIRF medicines (95%), signing the Patient-Prescriber Agreement Form (98%), and giving a copy of the Patient-Prescriber Agreement Form to the patient (90%). Summary of Findings Overall, surveyed prescribers had a high level of knowledge (≥80%) across most of the key risk message questions as in previous assessments, including awareness that TIRF medicines are contraindicated in opioid non-tolerant patients, that TIRF medicines contain fentanyl and have the potential to be abused and that TIRF medicines are not interchangeable with each other. Responses have consistently not reached the 80% knowledge threshold for appropriate use of an around the clock opioid and a TIRF medicine. Overall, most respondents were aware of the correct indications for TIRF medicine, but 22% still reported that chronic non-cancer pain was an approved indication. Respondents that answered incorrectly stated that they prescribe TIRF medicines for conditions including back pain, chronic pain, for reasons such as efficacy, fast acting, and because other medications used have failed. Overall respondents were aware of specific medication/dose for opioid tolerant patients with the exception of 8 mg oral hydromorphone/day (72%) and an equianalgesic dose of another oral opioid (66%). Correct responses ranged from 66% to 96%. Most prescriber respondents reported reviewing the Patient-Prescriber Agreement with each patient prescribed TIRF medicines (95%), signing it after reviewing it (99%), and giving the patient a copy (90%). This was comparable to patient responses where most patients reported signing a Patient-Prescriber Agreement Form (77%) and receiving a copy of the form (77%). In general, responses were low in terms of prescriber reported behaviors about always conveying risks and how to store medicines. Most patients reported that a healthcare professional did talk about the risks and possible side effects with them (86%) and how to store the medicine (87%). Only 44% of prescriber respondents reported giving patients the Medication Guide. Most patients reported receiving the Medication Guide from their pharmacist (91%) versus their prescriber (57%). Reference ID: 4190326 FDA_7520 Reviewer's Comments A. The survey only had 294 respondents, instead of the proposed 300. The sponsor should make efforts to reach the target sample size for respondents. B. Only 77% of respondents were aware that a cancer patient cannot start a TIRF medicine and an around the clock opioid at the same time. In addition, only 77% of respondents were aware that it is incorrect to instruct patients to continue taking their TIRF medicine if they stop taking their around the clock opioid medicine. Knowledge has consistently been low in this area across assessment periods, and ways to improve knowledge in this area should be identified and implemented. C. DB7: For the review of the comparison of the demographics of the prescriber survey respondents with the overall population of prescribers who prescribed TIRF medicines provided from IMS data, the survey respondents differed from all IMS prescribers by the average times per month they prescribed TIRF medicines within the past six months, gender, medical profession, number of years practicing medicine, and medical specialty. This may bias the results but we do not know in which direction or by how much. We request the following analyses from the sponsor. • Submit subgroup analyses stratified by the average times per month they prescribed TIRF medicines within the past six months, gender, medical profession, number of years practicing medicine, and medical specialty, to quantify the impact of these characteristics on knowledge in the survey. • Submit a sensitivity analysis predicting the knowledge rate in all prescribers adjusting for these characteristics in your survey (e.g. standardization) • Submit the data for us to reproduce your results. 5.7. APPLICANT'S OVERALL CONCLUSION The TRIG concludes: “Based on the data available in this TIRF REMS Access program assessment report (program and product utilization statistics, dispensing activity, program infrastructure and performance, noncompliance reporting, and safety surveillance data) the TRIG concludes that there is no indication that the REMS is not meeting its goals. However, the TRIG acknowledges that the data are limited and that FDA has requested further evaluation, as described in the 48Month FDA Assessment Report Acknowledgement Letter, to determine whether the REMS is meeting its goals.” 6. OTHER OSE DIVISIONS INPUT The Division of Epidemiology II (DEPI) provided three reviews (see section 4) in response to three separate consults from DRISK. In addition, DPV provided an Reference ID: 4190326 FDA_7521 analysis of FAERS reports for accidental exposure, off-label, and use of TIRFs in opioid-non-tolerant patients. 7. CONCLUSIONS 7.1.COMPLETENESS OF REPORT This assessment report is technically complete and addresses all issues outlined in the approved REMS assessment plan. 7.2.ACHIEVEMENT OF THE GOALS OF THE REMS The goals of the TIRF REMS Access program are to mitigate the risk of misuse, abuse, addiction, overdose, and serious complications due to medication errors by: 1. Prescribing and dispensing TIRF medicines only to appropriate patients, which includes use only in opioid-tolerant patients; 2. Preventing inappropriate conversion between TIRF medicines; 3. Preventing accidental exposure to children and others for whom it was not prescribed; 4. Educating prescribers, pharmacists, and patients on the potential for misuse, abuse, addiction, and overdose of TIRF medicines The included surveillance data (spontaneously reported adverse events as well as RADARS data) appear to indicate that for most outcomes assessed, event rates for TIRF products have increased over time. In contrast, event rates for the comparator drugs either in most cases indicated either decreases over time or much smaller increases than those noted for TIRF products. The small number of events associated with TIRF products in the RADARS Poison Center data produce large fluctuations in the data which may affect the generalizability of this data. Findings from the June 15, 2017 individual NDA/ANDA submissions of opioid tolerance data indicate that regardless of the type of analysis, the proportion of opioid-non-tolerant patients receiving a TIRF product ranged from 34.6% to 55.4%. Since the proportion of patients receiving TIRFs as calculated by these analyses remains concerning, the first objective (prescribing only to appropriate/opioidtolerant patients) is not being achieved. The persistency analysis submitted in the May 26, 2016, 48-month REMS assessment report are difficult to interpret due to numerous data analysis issues and thus resulted in the conclusion that it is not possible to tell if the second objective (inappropriate TIRF conversions) is being met. The data provided by the TRIG regarding the third objective (prevention of accidental exposure) are limited and Reference ID: 4190326 FDA_7522 thus difficult to interpret, therefore it is not possible to determine whether this objective is being met. It appears that the 4th objective is partially being met: • Patients had a high level of knowledge (≥80%) across most of the key risk messages. Respondents were less aware of the correct indication for TIRFs, and unaware that if a patient stops taking around-the-clock opioid pain medicine, they must also stop taking the TIRF medicine. Knowledge rates have consistently been low with both of these questions across assessment periods. • Pharmacists had a high level of knowledge (≥80%) across most of the key risk messages as in previous assessments. However, fewer than 50% correctly stated that chronic non-cancer pain was not an approved indication, and pharmacist respondents were unaware that if a patient stops taking around-the-clock opioid pain medicine, they must also stop taking the TIRF medicine. Knowledge has consistently been low in this area across assessment periods. • Prescribers also had a high level of knowledge (≥80%) across most of the key risk message questions as in previous assessments. However, as in previous assessments, only 65% correctly stated that chronic noncancer pain was not an approved indication. Respondents that answered incorrectly stated that they prescribe TIRF medicines for conditions including back pain, neuropathic pain, and post-operative pain. The REMS is not meeting its overall goal or most of the objectives. 7.3.NEED FOR ASSESSMENT PLAN REVISION Our August 21, 2014 REMS assessment plan revision letter provided the REMS assessment plan for you to utilize. We have determined that your REMS assessment plan needs revision because it would help inform use of TIRF products if it was known both how many patients are dispensed a TIRF prescription during each reporting period as well as the number of mail order and institutional pharmacies dispensing TIRFs each reporting period. The revised REMS assessment plan must include, but is not limited to the items described at the very end of Section 10 “Comments to Sponsor” of this review. 7.4. REVIEW TEAM CONCLUSION DRISK, DEPI, DEPI Drug Use, DAAAP, and the Office of Compliance met several times to discuss this conclusion based on the data in the assessment report. The aim of a DRISK REMS assessment review is to determine (1) whether the report is Reference ID: 4190326 FDA_7523 complete, and (2) whether the REMS is meeting the goal(s). The review team believes the Assessment to be complete but that it is not meeting its overall goal or most of the stated objectives. 8. RECOMMENDATIONS We recommend the sponsor be sent a REMS Assessment Acknowledgment letter that includes General Comments. 9. COMMENTS FOR THE SPONSOR Please send the sponsor a REMS Assessment Acknowledgement letter (see CST template (COR-SEC901REMS-10) (COR-BLASEC901REMS-10) stating the following: We found the REMS assessment to be complete and have determined that the REMS is not meeting its overall goal and most of the objectives due to either insufficient data to inform some objectives or data indicating that other objectives are not being met or are only partially being met. General Comments: Please send the following General Comments to the sponsor. 1. Due to the short time frame between providing these comments to you and the due date for the 72 month REMS assessment, you may submit your 7th assessment report no later than February 28, 2018. 2. Regarding your submitted RADARS and spontaneous adverse event data: a. The assessment report must separate TIRFs by product. Generic products that are the same dosage form as an innovator product may be combined with the innovator product. However, the data for each individual TIRF product should be included in one document showing trends for each product in the class. It will be much easier to assess REMS effectiveness and interpret the surveillance data than when each product is submitted in a separate report. b. Use single-product or single-molecule comparators. We recommend oxycodone IR, oxycodone ER, hydromorphone IR, and oxymorphone IR as comparators. c. Clarify why the comparison of means model was a better fit to the data than a comparison of trends (page 98 of the report). d. The p-values provided are not very meaningful given the large number of tests performed and the small number of events attributed to TIRFs. Focus Reference ID: 4190326 FDA_7524 e. f. g. h. i. j. 3. interpretations on the magnitude of changes instead of statistical significance. Statistical significance of results should only be incorporated into the interpretations when sufficient power is present. Report case and mention counts for both the pre- and post-REMS periods for all outcomes for TIRF and comparator products. As a sensitivity analysis, limit the Treatment Center Program (TCP) data to the centers that participated in the TCP for the majority of the study period to improve the ability to trend numbers over time. Report the Poison Center results as annual rates rather than quarterly rates to help stabilize the variability due to small numbers of events. Remove the Impaired Health Care Worker Program data as we no longer think that they add value to our understanding of the trends in outcomes of interest. Provide separate results for unintentional exposures in children under 6 years of age to help identify unintentional pediatric exposures. Provide a separate analysis that includes counts and a description of the characteristics of pediatric patients dispensed TIRF products. Include demographic and relevant clinical information, including comorbid conditions, when available. Accidental ingestion and inappropriate use of fentanyl products among pediatric populations is a public health concern. Use of TIRF products in this population may represent inappropriate prescribing, and the Agency needs additional detail to understand this important issue. Findings from the June 15, 2017 individual NDA/ANDA submissions of opioid tolerance data indicate that regardless of the types of analysis performed, the proportion of opioid-non-tolerant patients receiving a TIRF product ranged from a 34.6% to 55.4%. Thus, the proportion of patients receiving TIRFs as calculated by these analyses continues to be of concern. For any subsequent submissions of this type of opioid tolerance analysis: a. The TRIG should include only the analysis using the first class-wide fill (as opposed to the first individual product fill). The first class-wide fill likely indicates the patient’s first exposure to a TIRF, and thus these are the patients we are most concerned about should they not be opioid-tolerant at the time of initiating a TIRF product. b. The data submitted by the TRIG Sponsors are in a format that does not permit a year by year analysis of opioid tolerance. Thus, it is not possible to determine whether the use of TIRFs in opioid non-tolerant patients is increasing or decreasing. The TRIG should provide yearly calculations of opioid tolerance to allow for this evaluation c. For both opioid tolerance and product interchange data, you should utilize a data resource that contains data on prescriber instructions, in addition to drug strength and days’ supply, to inform TIRF product dose, since dose is Reference ID: 4190326 FDA_7525 d. Reference ID: 4190326 essential to determine opioid tolerance status (as well as the appropriateness of switches between TIRF products). Lastly, we include responses to your October 16, 2017 response to the October 2, 2017, telecon between the FDA and the TRIG, with respect to opioid tolerance data. You plan to: I. “… investigate the difference between the algorithm used in the TRIG analyses and that used by Insys before proceeding with the validation study. The TRIG has investigated several data options for the validation study and has narrowed the selection to the below two choices [The Henry Ford Health System (HFHS) and Optum’s Clinformatics Claims Data and Integrated Claims-EMR Data].” 1) Within two weeks from receipt of this communication, submit a detailed explanation of the differences between the “Insys algorithm” for opioid tolerance and the TRIG algorithm used for the product-specific opioid tolerance analyses submitted in June 2017. 2) The TRIG must move forward with the validation study, without delay. If necessary to avoid any further delay, validate both algorithms. 3) A full validation study in Optum data is not necessary because, as we discussed in the October 2 call, FDA has already initiated a similar investigation of opioid tolerance algorithm validation in Optum databases through the Yale/Mayo Center for Excellence in Regulatory Science and Innovation. The full validation of the opioid tolerance algorithm should be done in a different data source. However, you could do a smaller portability assessment of the algorithm in Optum if that is the data source that you plan to use for the study of adverse events in opioid non-tolerant patients. 4) The HFHS data source appears to be reasonable. The linked tumor registry has the added advantage of facilitating an analysis of the proportion of patients prescribed TIRFs who have evidence of cancer at the time of TIRF initiation. FDA would be very interested in this information, as it would help provide additional context for the data you are submitting on TIRF use in opioid non-tolerant patients. To help us further assess the suitability of the data source, by February 28, 2018: i. provide the number of patients using TIRFs during the proposed validation study period in HFHS and FDA_7526 II. 4. ii. compare the demographic and clinical characteristics of the TIRF users in HFHS to a geographically diverse sample of US patients who receive TIRFs, such as from a large nationwide claims database. 5) If the number of TIRF recipients in HFHS is insufficient for a robust analysis, provide counts as well as demographic and clinical characteristics of TIRF recipients in an alternate data source. “…evaluate risks of adverse outcomes in a cohort of patients who initiated TIRF product but did not meet a validated definition of the labeled requirement of opioid tolerance…compared to rates in a comparator population of patients who initiated a TIRF and met a validated definition of opioid tolerance” 1) The brief outline for the study of adverse events in opioid non-tolerant vs opioid tolerant patients appears appropriate except that the data source does not appear to have both in- and out-of-hospital deaths with which to assess risk of overdose. Ensure that the data source(s) that you choose can be linked to out-of-hospital death and include this information in your protocol. 2) Of the outcomes proposed, fatal and nonfatal overdose are of most concern to the FDA. We are unaware of any claims-based algorithms that have performed acceptably for misuse or abuse. 3) Submit your draft protocol for the study of fatal and nonfatal overdose in opioid non-tolerant versus opioidtolerant patients starting TIRFs by February 28, 2018. Revise and re-submit your persistency analysis that was initially submitted as a Supplemental Assessment on May 4, 2016. This re-submission should be responsive to the necessary clarifications and explanations noted in Comments a. through d. below. Clearly note/annotate any changes in data analysis or actual data from the originally submitted report. As stated below, nonoverlapping definitions must be employed. Additionally, clarify within each table value a) which number represents the numerator, and b) which number represents the denominator. a. Many of the numbers and calculations provided in the report are uninterpretable. For example, if a patient is on a second TIRF regimen, that implies he/she switched from a first TIRF regimen. However, this does not appear to have been accounted for in a clear manner, as the numbers do not add up correctly. Further, if 20.5% of patients changed their index TIRF regimen, that implies that 79.5% did not switch their index TIRF regimen. Reference ID: 4190326 FDA_7527 However, the final sentence indicates that 65-70% of patients changed their TIRF regimen by discontinuing their TIRF regimen. These metrics’ lack of clarity, shifting denominators, and the apparently-overlapping definitions employed regarding switches vs. discontinuations vs. changes, render this analysis very difficult to interpret. b. It is unclear why the persistency analysis excluded patients with only one prescription dispensed. These people only “persisted” through one prescription, and by excluding them, the analysis overestimates persistency. While it would be appropriate to exclude these individuals from a switching analysis, it is inappropriate to exclude them from a persistency analysis. c. By requiring follow up time in the database after cohort entry, the analysis captures only survivors and will exclude individuals who die after taking fentanyl – either from the condition the drug is treating, or from the drug itself. This approach conditions on the future, and is inappropriate because it introduces survivor bias. d. As with the opioid tolerance data, utilize a data source that includes prescriber instructions since dose is the primary consideration for determining whether the REMS goal of mitigating inappropriate switching is being met. 5. In our October 2, 2017 telecon with you, we discussed your March 31, 2017 responses regarding your concerns about identifying databases that can provide ED records and accidental childhood poisoning data that are able to provide sufficient data regarding TIRFs. You responded to our discussion on October 16, 2017. We provide comments on your responses here. a. We agree with your outline for assessment of accidental poisonings in children in Optum-Humedica data provided that the sample size is sufficient for estimating the incidence of accidental poisonings from TIRFs with a reasonable level of precision. Provide a draft protocol for this study, along with the counts of children ages 0-6 years with evidence of a claim for poisoning by a synthetic opioid, by February 28, 2018. Include in your draft protocol discussion of sample size and precision of estimates. b. We agree with your plan for assessing the DIM data for cases of deaths due to accidental poisoning. We look forward to your draft protocol by February 28, 2018. c. We look forward to hearing more about your outreach to assess the feasibility of other sources of data for accidental TIRF poisonings in children. 6. Our concerns about the TRIG’s REMS compliance program and some administrative processes continue and include the following issues: a. The median prescription processing time for a prescription that experienced at least one REMS-related rejection continues to increase over time for both Reference ID: 4190326 FDA_7528 chain and independent stores. As previously conveyed in the Agency’s April 28, 2017 IR to you, as well as the 36-month and 48-month REMS Assessment Acknowledgement Letters (RAAL), we urged the TRIG to investigate and identify the causes of these increasing delays. The Agency also pointed out that because the reasons for REMS-related rejections (PPAF incomplete, PPAF not submitted, prescriber not registered) appear to have remained the same over time, you should further explore this increase in processing times by evaluating a sample of the prescription rejections with the longest processing time to determine if there are any identifiable reasons that could be addressed in the REMS about why processing times continue to increase. In response to issues raised at the October 2, 2017 telecon between the FDA and TRIG, on October 16, 2017, you stated that you plan “…to conduct an analysis of prescription processing times for prescriptions that encounter at least one REMS-related rejection over the period October 29, 2014 – October 28, 2017 to evaluate trends over time. In addition to this analysis, TRIG will expand the reporting of these data to FDA to show a more holistic view of overall REMS rejections, which will put into context the overall processing time for all rejected TIRF prescriptions. The updated metrics will be included in the 02FEB2018 submission.” In such an analysis that you stated on October 16, 2017, that you plan to conduct, clarify whether your use of the term “authorization” is limited to REMS authorizations or dispensing authorizations, because the latter may reflect insurance issues. If delays in dispensing authorization are the cause, further investigate whether such delays due to insurance issues. Lastly, for patients who were denied a TIRF prescription due to a missing or incomplete PPAF, it is unclear in how many instances did the prescriber complete the PPAF versus simply prescribe an alternative therapy. Provide any data informing this issue because this may be an indicator of a potential access issue. b. For the 60-month report, you continued to classify a case of PPAF noncompliance as five or more patients enrolled by the prescriber without a complete PPAF on file (greater than 10 working days from the initial enrollment date not on file with the REMS). In the 48-month RAAL, you were told of FDA’s concern that these criteria could lead to an underreporting of PPAF non-compliance, and that you should explore mechanisms to capture lower levels of non-compliance because it is unknown what proportion of PPAF non-compliance is caused by prescribers with these lower levels of non-compliance. Reference ID: 4190326 FDA_7529 You were again told of the FDA’s continued concerns regarding needing five PPAFs to establish one case of non-compliance at the October 2, 2017 telecon. In response, on October 16, 2017, you stated the following: “The TRIG will reduce the PPAF threshold to flag prescribers for noncompliance based on patients without a PPAF from 5 to 3 patients. The TRIG evaluated the incidents of non-compliance and has determined that the threshold can be lowered to 3 without a large impact to patient access. Because you did not elaborate further how lowering the number of PPAFs needed for a case on non-compliance to less than 3 would affect patient access, we sent another information request on October 27, 2017 asking for an explanation. In your November 2, 2017 response, you stated that: “To determine the impact of decreasing the threshold for missing PPAFs triggering a non-compliant event, the TRIG calculated estimated increases in non-compliant case volume based on current prescriber and PPAF activity. At the time of this research, the TRIG found that lowering the threshold to: • 4 missing PPAFs would result in 2 additional non-compliant cases per month (~15% increase), • 3 missing PPAFs would result in 5 additional non-compliant cases per month (~38% increase), • 2 missing PPAFs would result in 14 additional non-compliant cases per month (~107% increase), and • 1 missing PPAF would result in 42 additional non-compliant cases per month (~323% increase).” In addition, you stated that you considered: “…the establishment of more strict corrective action guidelines (as proposed in the 16OCT2017 response to FDA), which will result in a higher volume of prescriber suspensions and deactivations [discussed in comment “c” directly below]. Therefore, the TRIG proposes that the increase in noncompliant cases by 38% balances the goals of making prescribers aware of the importance of compliance and patient safety without impacting patient access.” Given our concerns regarding the high use of TIRFs in opioid non-tolerant patients, as well as continued concerns with the TIRF adverse event data as compared to other opioids, the FDA believes that the number of PPAFs associated with a non-compliance event needs to be set at “one”. Lastly, in your 48-month REMS assessment report, you reported a number of instances where prescribers were either unaware of requirements to submit a PPAF or chose not to do so. We stated to you in our November 10, 2016, REMS Assessment Acknowledgement Letter that “It is important that the TRIG investigate mechanisms to reinforce to prescribers the necessity of Reference ID: 4190326 FDA_7530 timely completion of PPAFs.” In the current REMS assessment report, you state that you “…will further query noncompliant prescribers to determine more specific reasons of why they were not compliant with the REMS requirements. The TRIG will assess these responses to determine appropriate actions.” The FDA looks forward to reviewing the findings of the TRIG’s query and assessment of responses in their subsequent assessment reports. c. Your current assessment report continues to include cases of prescribers who receive numerous Notices of Violation, Warning Letters, and then file several CAPs before one is accepted. Yet, these prescribers are rarely suspended and apparently never deactivated from the program. In our November 10, 2016, REMS Assessment Acknowledgement Letter, you were asked to add increased specificity to your Non-Compliance Review Team (NCRT) protocol as well as to the Supporting Document of the REMS. Also, at the October 2, 2017 telecon between the FDA and the TRIG you were urged to develop clear and specific criteria to your NCRT non-compliance protocol. In your October 16, 2017, response, you presented the following criteria: “The Corrective Action Guidelines within the Non-compliance Protocol will be modified to remove the second level of Notices, Warnings and Suspensions, thereby reducing the number of noncompliant events that can occur prior to deactivation of a non-compliant stakeholder, including prescribers. Once non-compliance has been confirmed, the revised non-compliant event schedule will include the following actions. • A first offense of non-compliance will result in a Notice • A second offense of non-compliance will result in a Warning • A third offense of non-compliance will result in a Suspension • A fourth offense of non-compliance will result in a Deactivation As a result of both changes, a stakeholder, including prescribers, will be deactivated from the program upon four non-compliant events.” The FDA believes that the TRIG should lower these 4 stages into 3 stages, and that the TRIG should eliminate their first (Notice) stage. Thus the first non-compliance event would be a Warning, the second event would results in a Suspension, and the third would result in a deactivation for a 3-year period. d. In our November 10, 2016, REMS Assessment Acknowledgement Letter, we expressed concern that all three instances where a non-closed system pharmacy dispensed a TIRF product after a REMS rejection were brought to the attention of the TRIG only after the pharmacy contacted the REMS. The FDA then suggested that the “TRIG should develop a more active Reference ID: 4190326 FDA_7531 mechanism by which to identify and prevent such occurrences”. In the current assessment report you state that you are “…looking into a more active mechanism to identify and prevent instances where a non-closed system pharmacy dispenses a TIRF product after a TIRF REMS rejection is received.” In addition, in response to an April 28, 2017 FDA information request to the TRIG, you verified that you have “…no way to systematically and accurately track if a pharmacy receives this rejection and still makes the decision to dispense” and that “All of these referenced instances would only be captured through spontaneous reports to the TIRF REMS Access program.” It is likely that relying solely on spontaneous pharmacy selfreports of non-compliance will lead to an overall under-reporting in pharmacy non-compliance with the REMS. Develop concrete and more active processes to address this deficiency in your compliance program and implement these processes expeditiously. For example, many pharmacy management systems are able to track when a prescription is picked up by the patient. It may be possible to link the pick-up of a TIRF prescription to earlier data about that prescription where a REMS-edit reject occurred but the pharmacist decided to make the prescription ready for pick-up nonetheless. Present your proposals in your February 2018 assessment report submission. e. We agree that it may not be practical to convert the two governmental closed pharmacies to a switch system similar to that used by non-closed system pharmacies given the low volume of TIRF prescriptions that are processed by these systems. However, as stated in our November 10, 2016, REMS Assessment Acknowledgement Letter, the TRIG should insist that alternative approaches be taken by the two governmental entities. Examples of such alternatives could include: 1) both entities build in system alerts reminding pharmacists of the REMS requirements; and or 2) request that the two governmental entities develop a process requiring a two-person check when any TIRF is dispensed to ensure that REMS processes were followed. Likely there are additional processes that can be implemented. In the February 28, 2018 assessment report submission, provide an update regarding your consideration of a quarterly evaluation of closed system pharmacy data. These alerts/revised processes should be in place and reported on starting with the December 2018 assessment report.. f. We note in your May 30, 2017 response to our April 28, 2017 information request that your “independent pharmacy” category contains a mix of retail, mail order, and institutional outpatient pharmacies (and thus this category of pharmacies dispenses the bulk of TIRF prescriptions). In order for us to better understand how TIRF products are made available to consumers, research and report what proportion of prescriptions come from each of the Reference ID: 4190326 FDA_7532 three sub-types of pharmacies contained in your independent pharmacy category and include this in your February 2018 assessment report, as well as all subsequent assessment report submissions. Additionally, while 48% of the chain stores that became inactivated this reporting period remained inactivated at the end of the reporting period, 77% of independent stores that became inactivated this reporting period remained so at the close of the period. During the previous reporting period, a similar pattern was seen in which a smaller proportion of inactivated chain stores remained inactive at the end of the reporting period (16.6%) as compared to independent pharmacies (78.4%). It is not clear why this large discrepancy exists. Similarly research why this discrepancy exists between these pharmacy types and include this in your February 2018 assessment report. g. In the 48-month assessment report, 6 inpatient pharmacies either did not respond to the audit request or decided not to participate. In the current assessment report, 3 of 12 pharmacies (25%) did not respond to an audit request and you stated that you are “…considering revisions to this (pharmacy) enrollment form to allow for process audits so as to increase the potential pool of inpatient pharmacies in the audit and will communicate any required modifications during the review of the next REMS assessment.” The FDA agrees that the TRIG should consider this revision and looks forward to learning of the TRIG’s decision regarding this enrollment form. h. In the February 17, 2017 Supplement to Assessment report submission, you stated that: “In response to the request from the FDA, a timeline has been developed to perform outreach to a representative sample of those health professional and pharmacies that did not re-enroll in the TIRF REMS Access program to ascertain their reasons for not re-enrolling. The TRIG has initiated activities to collect these data and results will be included in the 72Month FDA REMS Assessment Report.” The Agency looks forward to reviewing the data regarding the reasons why certain stakeholders chose not to re-enroll in your 72-month Assessment Report. As part of these data to be submitted for the 72-month report, detail whether pharmacy inactivations occurred disproportionately among any particular chain or geographic region. i. Many of the comments about your compliance program and administrative processes have been raised to you in previous REMS Assessment Acknowledgement Letters, and were again raised in the October 2, 2017 FDA-TRIG teleconference. We expect the above-noted changes/updates to the REMS compliance program/ administrative aspects to be made in the Supporting Document and submitted to the Agency by February 28, 2018. 7. Regarding the patient survey: Reference ID: 4190326 FDA_7533 a. Respondents were unaware that if a patient stops taking around-the-clock opioid pain medicine, they must also stop taking the TIRF medicine, with only 40% selecting the correct answer. Knowledge rates have consistently been low with these questions across assessment periods and the TRIG should consider how to strengthen the understanding of this message and propose modifications to address this by the February 2018 assessment report submission. b. For the review of the comparison of the demographics of the patient survey respondents with the overall population of patient who are prescribed TIRF medicines, the survey respondents had a significantly higher “highest education level completed” than all users in the IMS database. Thus, we suspect the knowledge rate in the survey was overestimating the knowledge rate for all users; we request the following analyses from the sponsor in the February 2018 assessment report. • Submit subgroup analyses stratified by education level, to quantify the impact of education on knowledge in the survey. • Submit a sensitivity analysis predicting the knowledge rate in all users adjusting for education level in your survey (e.g. standardization) • Submit the data for us to reproduce your results. 8. Regarding the pharmacist survey: a. There was only one closed system pharmacy (CSP) survey respondent. The TRIG should increase efforts to get additional closed systems to participate in the survey. b. Only 62% of respondents were aware that a cancer patient cannot start a TIRF medicine and an around the clock opioid at the same time. In addition, only 41% of respondents were aware that a patient must stop taking their TIRF medicine if they stop taking their around the clock opioid pain medicine. Knowledge has consistently been low in this area across assessment periods, and the TRIG should consider how to strengthen the understanding of this message and provide this in the February 2018 assessment report submission. c. Only 62% of the inpatient pharmacy respondents reported having an established system, order sets, or protocols to ensure appropriate patient selection and compliance with the requirements of the TIRF REMS Access Program. For all inpatient pharmacies that report that they do not have such established systems, conduct outreach to re-educate the authorized person. These inpatient pharmacies should be audited again within 6 months and should be de-enrolled from the program if they are unable to comply. Report on the outreach and follow-up audit in each subsequent assessment report starting with the December 2018 report. d. For the review of the comparison of the demographics of the pharmacist survey respondents with the overall population of pharmacists who Reference ID: 4190326 FDA_7534 prescribed TIRF medicines, the survey respondents differed from all pharmacists in the REMS switch provider data by type of pharmacies. This may bias the results but we do not know in which direction or by how much. We request the following analyses from the TRIG by the February 2018 assessment report submission: • Submit subgroup analyses stratified by type of pharmacy, to quantify the impact of type of pharmacy on knowledge in the survey. • Submit a sensitivity analysis predicting the knowledge rate in all pharmacists adjusting for type of pharmacy in your survey (e.g. standardization) • Submit the data for us to reproduce your results. 9. Regarding the prescriber survey: a. The survey only had 294 respondents, instead of the proposed 300. The sponsor should make efforts to reach the target sample size for respondents. a. Only 77% of respondents were aware that a cancer patient cannot start a TIRF medicine and an around the clock opioid at the same time. In addition, only 77% of respondents were aware that it is incorrect to instruct patients to continue taking their TIRF medicine if they stop taking their around the clock opioid medicine. Knowledge has consistently not met the 80% knowledge threshold in this area across assessment periods, and the TRIG should consider how to strengthen the understanding of this message and propose modifications to address this by the February 2018 assessment report submission. b. For the review of the comparison of the demographics of the prescriber survey respondents with the overall population of prescriber who prescribed TIRF medicines provided from IMS data, the survey respondents differed from all IMS prescribers by the average times per month TIRF medicines were prescribed within the past six months, gender, medical profession, number of years practicing medicine, and medical specialty. This may bias the results but we do not know in which direction or by how much. We request the following analyses from the TRIG by the February2018 assessment report submission. • Submit subgroup analyses stratified by the average times per month TIRF medicines were prescribed within the past six months, gender, medical profession, number of years practicing medicine, and medical specialty, to quantify the impact of these characteristics on knowledge in the survey. • Submit a sensitivity analysis predicting the knowledge rate in all prescribers adjusting for these characteristics in your survey (e.g. standardization) • Submit the data for us to reproduce your results. Reference ID: 4190326 FDA_7535 REMS Assessment Plan: Please send the following to communicate the REMS Assessment Plan Revision to the TRIG: Our August 21, 2014 REMS assessment plan revision letter described your REMS assessment plan. We have determined that your REMS assessment plan needs revision because it would help inform use of TIRF products if we knew both how many patients are dispensed a TIRF prescription each reporting period as well as the number of mail order and institutional pharmacies dispensing TIRFs each reporting period. The REMS assessment plan must include but is not limited to the following items. Additions are noted by bold underline and deletions are noted by strikethrough. Modified Assessment Plan for the TIRF REMS 1. 2. Reference ID: 4190326 The TIRF REMS Access Program Utilization Statistics (data presented per reporting period and cumulatively): a. Patient Enrollment: a. Number of unique patients enrolled b. Number of patients inactivated c. Number of unique patients dispensed a prescription for a TIRF during this reporting period b. Prescriber Enrollment: a. Number of prescribers enrolled b. Number of prescribers that attempted enrollment but whose enrollment is pending for >3 months and >6 months along with the specific reasons why their enrollment is pending; c. Number of prescribers inactivated c. Pharmacy Enrollment: a. Number of pharmacies enrolled by type (inpatient, chain, independent, mail order, institutional outpatient, and closed system; provide identity of closed system entities); b. Number of pharmacies that attempted enrollment but whose enrollment is pending for >3 months and >6 months along with the specific reasons why their enrollment is pending (stratified by type); c. Number of pharmacies inactivated by type (inpatient, chain, independent, closed system); d. Distributor enrollment: a. Number of distributors enrolled; b. Number of distributors inactivated; Dispensing activity for enrolled pharmacies - metrics stratified by pharmacy type (open vs. closed system) FDA_7536 a. Number of prescriptions/transactions authorized; for closed systems, provide the number of prescription transactions per closed system entity; b. Number of prescriptions/transactions denied and reasons for denial. Include the number of prescriptions/transactions rejected for safety issues (provide description of safety issues and any interventions or corrective actions taken); c. Number of prescriptions/transactions rejected for other reasons (e.g., prescriber not enrolled) with a description of these specific other reasons; d. Mean and median amount of time it takes for a prescription that experienced at least one initial REMS-related rejection to be authorized e. Number of patients with more than three prescriptions dispensed during the first ten days after patient passive enrollment without a PPAF; f. Number of prescriptions dispensed after ten days without a PPAF in place 3. a. b. c. d. 4. Reference ID: 4190326 Program Infrastructure and Performance: The following metrics on program infrastructure performance will be collected (per reporting period): Number of times a backup system was used to validate a prescription, with reasons for each instance (for example, pharmacy level problem, switch problem, or REMS database problem) clearly defined and described; Number of times unintended system interruptions occurred for each reporting period. Describe the number of stakeholders affected, how the issue was resolved, and steps put into place to minimize the impact of future interruptions; Call center report with: i. Overall number of contacts; ii. Summary of frequently asked questions; iii. Summary of REMS-related problems reported Description of corrective actions taken to address program/system problems. TIRF REMS Access Non-Compliance Plan: The TIRF TRIGs should provide the following data regarding non-compliance in each assessment report (per reporting period): a. Report the results of yearly audits of at least 3 randomly selected closed pharmacy systems to assess the performance of the system(s) developed to assure REMS compliance. These reports are to include: i. Verification of training for all pharmacists dispensing TIRF products; ii. Numbers of prescription authorizations per closed system; iii. Reconciliation of data describing TIRF product received by the closed system pharmacy with TIRF product dispensed to FDA_7537 b. c. d. e. f. g. h. i. Reference ID: 4190326 patients with a valid enrollment in the TIRF REMS program. Include details on how the reconciliation is conducted (e.g., electronic vs. manual process). iv. Describe any corrective actions taken for any non-compliance identified during the audit and corrective actions taken to address non-compliance Report the results of yearly audits of at least 5 randomly selected inpatient hospital pharmacies to assess the performance of the system(s) developed to assure REMS compliance. Provide the number of units of use of TIRFs ordered per inpatient hospital pharmacy audited per 12 month period These reports are to include: i. Verification of training for all pharmacists dispensing TIRF products ii. Verification that processes such as order sets/protocols are in place to assure compliance with the REMS program iii. Describe any corrective actions taken for any non-compliance with i and ii identified above during the audit, as well as preventative measures that were developed as a result of uncovering these non-compliance events Description of number, specialties, and affiliations of the personnel that constitute the Non-Compliance Review Team (NCRT) as well as: i. Description of how the NCRT defines a non-compliance event ii. Description of how non-compliance information is collected and tracked iii. Criteria and processes the Team uses to make decisions iv. Summary of decisions the Team has made during the reporting period v. How the Team determines when the compliance plan should be modified Describe each non-compliance event and the corrective action measure taken, as well as the outcome of the corrective action Number of TIRF prescriptions dispensed that were written by nonenrolled prescribers and include steps taken to prevent future occurrence Number of prescriptions dispensed by non-enrolled pharmacies and include steps taken to prevent future occurrences Number of times a TIRF prescription was dispensed because a pharmacy (closed or open system) was able to bypass REMS edits and if any such events occurred, describe how these events were identified Number of times a TIRF was prescribed to an opioid non-tolerant individual. Include what was done to minimize such instances; if any such events occurred, describe how these events were identified Number of instances of inappropriate conversions between TIRF products, as well as any outcome of such an event. If any such events occurred, describe how these events were identified. FDA_7538 5. Safety Surveillance (data collected per reporting period): TIRF TRIGs will process adverse event reports related to their specific products and report to the FDA according to current regulations outlined in 21 CFR 314.80 and the TRIG’s respective Standard Operating Procedures b. TIRF TRIGs will produce one comprehensive report that presents spontaneous adverse event data from all TRIGs of the TIRF REMS Access Program, as well as data from other databases (characteristics of which are described below). This report will focus on four categories of adverse events of interest: addiction, overdose, death, and pediatric exposures. This report should include the following: i. Line listings under each category of adverse events of interest as listed above ii. Line listings should provide at a minimum the following information (see sample table provided): 1. Identifying case number 2. Age and Gender of the patient 3. Date of the event as well as of the report 4. The Preferred Terms 5. Indication of TIRF use 6. Duration of TIRF therapy 7. Concomitant medications 8. Event Outcome iii. Other metrics of interest include: 1. Number of event reports in each event category of interest 2. Counts of adverse events related to inappropriate conversions between TIRF products 3. Counts of adverse events related to accidental and unintentional exposures 4. Counts of adverse events that are associated with use of TIRF medicines in non‐opioid tolerant patients iv. Duplicate cases are identified and eliminated v. Case reports with adverse events in multiple categories will be listed in each category of interest, and will be noted as such vi. For each adverse event category, an overall summary analysis of the cases will be provided addressing the root cause(s) of the events. Rate of each adverse event of interest will be calculated using two distinct denominators: the number of prescriptions for TIRF products and the number of patients receiving a TIRF product throughout the reporting interval. Trends and changes in the rates of these events will be compared year‐to‐year c. Surveillance data focusing on events of addiction, overdose, death, and pediatric cases should also be drawn from the databases that are listed a. Reference ID: 4190326 FDA_7539 below. Conclusions regarding these data should be included in and inform the overall conclusions in the summary report referred to in Section 5.b. directly above: i. Non-medical use of prescription drugs ii. Surveys conducted at substance abuse treatment programs iii. College surveys iv. Poison control center data v. Impaired health care workers vi. Drug-related hospital emergency department visits vii. Drug-related deaths viii. Other databases as relevant 6. 10. Periodic Surveys of Patients, Healthcare Providers, and Pharmacies: Prescribers’, pharmacists’, and patients’ understanding regarding the appropriate use of TIRF medicines and TIRF REMS Access Program requirements will be evaluated through knowledge, attitude, and behavior (KAB) surveys. The surveys will be administered to randomly selected prescribers, pharmacists, and patients. Surveys will assess understanding of key messages. APPENDIX 10.1 ASSESSMENT PLAN Assessment Plan for TIRF REMS (finalized 8/21/14) 1. Reference ID: 4190326 The TIRF REMS Access Program Utilization Statistics (data presented per reporting period and cumulatively): a. Patient Enrollment: a. Number of unique patients enrolled b. Number of patients inactivated b. Prescriber Enrollment: a. Number of prescribers enrolled b. Number of prescribers that attempted enrollment but whose enrollment is pending for >3 months and >6 months along with the specific reasons why their enrollment is pending; c. Number of prescribers inactivated c. Pharmacy Enrollment: a. Number of pharmacies enrolled by type (inpatient, chain, independent, closed system; provide identity of closed system entities); FDA_7540 b. d. 7. Dispensing activity for enrolled pharmacies - metrics stratified by pharmacy type (open vs. closed system) g. Number of prescriptions/transactions authorized; for closed systems, provide the number of prescription transactions per closed system entity; h. Number of prescriptions/transactions denied and reasons for denial. Include the number of prescriptions/transactions rejected for safety issues (provide description of safety issues and any interventions or corrective actions taken); i. Number of prescriptions/transactions rejected for other reasons (e.g., prescriber not enrolled) with a description of these specific other reasons; j. Mean and median amount of time it takes for a prescription that experienced at least one initial REMS-related rejection to be authorized k. Number of patients with more than three prescriptions dispensed during the first ten days after patient passive enrollment without a PPAF; l. Number of prescriptions dispensed after ten days without a PPAF in place 8. e. f. g. h. Reference ID: 4190326 Number of pharmacies that attempted enrollment but whose enrollment is pending for >3 months and >6 months along with the specific reasons why their enrollment is pending (stratified by type); c. Number of pharmacies inactivated by type (inpatient, chain, independent, closed system); Distributor enrollment: a. Number of distributors enrolled; b. Number of distributors inactivated; Program Infrastructure and Performance: The following metrics on program infrastructure performance will be collected (per reporting period): Number of times a backup system was used to validate a prescription, with reasons for each instance (for example, pharmacy level problem, switch problem, or REMS database problem) clearly defined and described; Number of times unintended system interruptions occurred for each reporting period. Describe the number of stakeholders affected, how the issue was resolved, and steps put into place to minimize the impact of future interruptions; Call center report with: iv. Overall number of contacts; v. Summary of frequently asked questions; vi. Summary of REMS-related problems reported Description of corrective actions taken to address program/system problems. FDA_7541 9. Reference ID: 4190326 TIRF REMS Access Non-Compliance Plan: The TIRF TRIGs should provide the following data regarding non-compliance in each assessment report (per reporting period): j. Report the results of yearly audits of at least 3 randomly selected closed pharmacy systems to assess the performance of the system(s) developed to assure REMS compliance. These reports are to include: v. Verification of training for all pharmacists dispensing TIRF products; vi. Numbers of prescription authorizations per closed system; vii. Reconciliation of data describing TIRF product received by the closed system pharmacy with TIRF product dispensed to patients with a valid enrollment in the TIRF REMS program. period preceding the audit date. Include details on how the reconciliation is conducted (e.g., electronic vs. manual process). viii. Describe any corrective actions taken for any non-compliance identified during the audit and corrective actions taken to address non-compliance k. Report the results of yearly audits of at least 5 randomly selected inpatient hospital pharmacies to assess the performance of the system(s) developed to assure REMS compliance. Provide the number of units of use of TIRFs ordered per inpatient hospital pharmacy audited per 12 month period These reports are to include: iv. Verification of training for all pharmacists dispensing TIRF products v. Verification that processes such as order sets/protocols are in place to assure compliance with the REMS program vi. Describe any corrective actions taken for any non-compliance with i and ii identified above during the audit, as well as preventative measures that were developed as a result of uncovering these non-compliance events l. Description of number, specialties, and affiliations of the personnel that constitute the Non-Compliance Review Team (NCRT) as well as: vi. Description of how the NCRT defines a non-compliance event vii. Description of how non-compliance information is collected and tracked viii. Criteria and processes the Team uses to make decisions ix. Summary of decisions the Team has made during the reporting period x. How the Team determines when the compliance plan should be modified m. Describe each non-compliance event and the corrective action measure taken, as well as the outcome of the corrective action FDA_7542 n. Number of TIRF prescriptions dispensed that were written by nonenrolled prescribers and include steps taken to prevent future occurrence o. Number of prescriptions dispensed by non-enrolled pharmacies and include steps taken to prevent future occurrences p. Number of times a TIRF prescription was dispensed because a pharmacy (closed or open system) was able to bypass REMS edits and if any such events occurred, describe how these events were identified q. Number of times a TIRF was prescribed to an opioid non-tolerant individual. Include what was done to minimize such instances; if any such events occurred, describe how these events were identified r. Number of instances of inappropriate conversions between TIRF products, as well as any outcome of such an event. If any such events occurred, describe how these events were identified. 10. Reference ID: 4190326 Safety Surveillance (data collected per reporting period): d. TIRF TRIGs will process adverse event reports related to their specific products and report to the FDA according to current regulations outlined in 21 CFR 314.80 and the TRIG’s respective Standard Operating Procedures e. TIRF TRIGs will produce one comprehensive report that presents spontaneous adverse event data from all TRIGs of the TIRF REMS Access Program, as well as data from other databases (characteristics of which are described below). This report will focus on four categories of adverse events of interest: addiction, overdose, death, and pediatric exposures. This report should include the following: i. Line listings under each category of adverse events of interest as listed above ii. Line listings should provide at a minimum the following information (see sample table provided): 9. Identifying case number 10. Age and Gender of the patient 11. Date of the event as well as of the report 12. The Preferred Terms 13. Indication of TIRF use 14. Duration of TIRF therapy 15. Concomitant medications 16. Event Outcome iii. Other metrics of interest include: 1. Number of event reports in each event category of interest 2. Counts of adverse events related to inappropriate conversions between TIRF products 3. Counts of adverse events related to accidental and unintentional exposures FDA_7543 4. Counts of adverse events that are associated with use of TIRF medicines in non‐opioid tolerant patients iv. Duplicate cases are identified and eliminated v. Case reports with adverse events in multiple categories will be listed in each category of interest, and will be noted as such vi. For each adverse event category, an overall summary analysis of the cases will be provided addressing the root cause(s) of the events. Rate of each adverse event of interest will be calculated using two distinct denominators: the number of prescriptions for TIRF products and the number of patients receiving a TIRF product throughout the reporting interval. Trends and changes in the rates of these events will be compared year‐to‐year f. Surveillance data focusing on events of addiction, overdose, death, and pediatric cases should also be drawn from the databases that are listed below. Conclusions regarding these data should be included in and inform the overall conclusions in the summary report referred to in Section 5.b. directly above: i. Non-medical use of prescription drugs ii. Surveys conducted at substance abuse treatment programs iii. College surveys iv. Poison control center data v. Impaired health care workers vi. Drug-related hospital emergency department visits vii. Drug-related deaths viii. Other databases as relevant 11. Periodic Surveys of Patients, Healthcare Providers, and Pharmacies: Prescribers’, pharmacists’, and patients’ understanding regarding the appropriate use of TIRF medicines and TIRF REMS Access Program requirements will be evaluated through knowledge, attitude, and behavior (KAB) surveys. The surveys will be administered to randomly selected prescribers, pharmacists, and patients. Surveys will assess understanding of key messages 10.2 NOVEMBER 10, 2016 REMS ASSESSMENT ACKNOWLEDGEMENT LETTER 1. Reference ID: 4190326 After review of the 48 month (5th overall) REMS assessment report for the Transmucosal Immediate-Release Fentanyl (TIRF) Products REMS, FDA_7544 we conclude that it is not possible to determine whether the overarching goal of the REMS - to mitigate the risk of misuse, abuse, addiction, overdose, and serious complications due to medication errors is being met. a. The first objective (prescribing and dispensing TIRF medicines only to appropriate patients, which includes use only in opioid-tolerant patients) is not being achieved. In the TIRF REMS Industry Group’s (TRIG’s) assessment of opioid tolerance, approximately 42% of patients prescribed TIRF products were not opioid tolerant. It is important that the TRIG further investigate this issue. b.It is not possible to determine if the second objective (preventing inappropriate conversion between TIRF medicines) is being met. Though no instances of inappropriate conversions were submitted as a spontaneous report, the persistency analysis provided indicates that the number of patients who may be exposed to inappropriate conversion between TIRF medicines may be as high as 17.1-20.5% of patients receiving TIRF medicines. Further assessment of these findings is also warranted. c. It is also not possible to determine if the third objective (preventing accidental exposure to children and others for whom it was not prescribed) is being met. The case reports for this metric remain quite low thus challenging the ability to assess the impact of the REMS on this objective, particularly since the case reports do not provide enough information to conduct a root cause analysis (RCA). d.The fourth objective (educating prescribers, pharmacists, and patients on the potential for misuse, abuse, addiction, and overdose of TIRF medicines) is partially being met. Overall, patients, prescribers, and pharmacists seem to have an adequate understanding of most of the key risk messages related to preventing inappropriate conversion, accidental exposure, and the potential for misuse, abuse, addiction, and overdose of TIRF medicines; however, all groups had a lower awareness of the need to only prescribe and dispense TIRF medicines to appropriate patients. 2. Reference ID: 4190326 In order to address the deficiencies outlined in 1a, b, c, and d, we have the following comments: a. Regarding the assessment of opioid tolerance submitted in the 48 month assessment, approximately 42% of patients prescribed TIRF products were not opioid tolerant. The TRIG needs to further investigate this concerning finding. A timeline for a plan to further evaluate this finding should be submitted with the February 17, 2017, submission of the 60 month REMS assessment survey results. At a minimum, further evaluation of this finding will include product-specific assessment of opioid tolerance that each member FDA_7545 sponsor will submit only to their NDA or ANDA. Additional details regarding this evaluation will be communicated in a separate letter. b.Regarding the persistency analysis submitted by the TRIG, these data indicate that the number of patients who may be exposed to “inappropriate conversion between TIRF medicines” is not insignificant. Thus these TIRF product switches need to be further assessed by the TRIG and a protocol developed to assess the starting doses of the TIRF products that existing TIRF patients switch to in order to ascertain what proportion of these switches are conducted as per products’ labeling. In addition, if the data system used has outcome data, this would be informative as to whether or not any switch marked as “inappropriate” resulted in any adverse sequelae. Limitations of the databases and/or approaches used are to be included in the protocol. Please submit this protocol with the February 17, 2017, submission of the 60 month REMS assessment survey results; if additional time for protocol development is needed, please request an extension. c. We would like to schedule a meeting to discuss opportunities for obtaining additional data on accidental exposure to children and others for whom TIRF products are not prescribed, as well as to discuss possible ways to address the low awareness of the need to prescribe and dispense TIRF medicines to appropriate patients. 3. Additional comments on the 48-month assessment: a. In the FDA’s 36-month REMS Assessment Acknowledgement Letter (date August 3, 2015), the TRIG was asked to “Conduct outreach to a representative sample of those health professionals and pharmacies who did not re-enroll in the TIRF REMS Access Program so as to ascertain their reasons and report the results in your next Assessment Report. We are concerned about potential patient access issues.” In the 48 month assessment report, the TRIG responded that: “Based on…analysis, there is no barrier to patient access and further outreach is unwarranted.” The TRIG stated that 516 prescribers (8.6%) chose to not re-enroll and that these prescribers had an average of no more than four prescriptions total over the course of the reporting period. However, the reasons why these prescribers withdrew from the program are unknown as are the reasons why 1,134 prescribers had their enrollment expire this reporting period and remain expired. Additionally, the reasons why 412 pharmacies chose not to re-enroll are not presented. It is therefore important that the TRIG proceed with conducting an “…outreach to a representative sample of those health professionals and pharmacies who did not re-enroll in the TIRF REMS Access Reference ID: 4190326 FDA_7546 Program so as to ascertain their reasons…(w)e are concerned about potential patient access issues.” Submit a timeline for the plan to conduct this outreach in the February 17, 2017, submission of the 60 month REMS assessment survey results. There continues to be a steady increase in mean and median prescription processing times during this reporting period versus the previous periods. The TRIG was previously asked to investigate this finding, but did not do so, instead stating that this finding may be due to a lower number of prescriptions with at least one initial REMS-related rejection this reporting (1,735) period as compared to the 36-month report (3,738). These differences cited by the TRIG do not appear to be so large as to account for some sort of number skewing induced by a small sample size. The TRIG needs to investigate and identify the causes of these increasing delays in prescription processing as these are potential indicators of access barriers. b.The TRIG Protocol for Corrective Actions for Instances of NonCompliance contains few concrete criteria or decision trees as to how to deal with episodes of non-compliance. Thus it is unclear to us what types of non-compliance actions would reliably lead to suspension or deactivation. The TRIG should add increased specificity to the Non-Compliance Review Team (NCRT) protocol as well as to the Supporting Document of the REMS. In addition, it is concerning that the TRIG’s criteria for an incident of an individual prescriber non-compliance with Patient-Prescriber Agreement Form (PPAF) requirements needs to involve at least “5 or more patients enrolled by the prescriber without a complete PPAF on file, with each patient having greater than 10 working days lapse from initial enrollment date.” These criteria would appear to potentially lead to an under-reporting of PPAF non-compliance. The TRIG should explore mechanisms to capture lower levels of non-compliance. c. Regarding the three instances where a non-closed system pharmacy dispensed a TIRF product after a TIRF REMS rejection, all three reports were brought to the attention of the TRIG only after the pharmacy contacted the REMS. The TRIG should develop a more active mechanism by which to identify and prevent such occurrences. d.Although results for both governmental (Veteran’s Health Administration and Department of Defense) and closed-pharmacy systems appear to have improved from the 36-month audit, they continue to be unsatisfactory. The 36-month REMS Assessment Acknowledgement Letter requested that the TRIG “Re-evaluate whether a novel authorization process is warranted or technically feasible at this time for the closed system pharmacies and report your conclusions with your next Assessment Report.” The TRIG has Reference ID: 4190326 FDA_7547 issued the following response: “The TRIG has determined that the current prescription authorization volume for closed system pharmacies is less than 1% of all TIRF prescriptions and due to the absence of complaints with the current process, no changes are warranted at this time.” An absence of complaints does not necessarily mean that a closed pharmacy system process is functioning optimally. These audits are likely one of the best sources of information regarding the performance of these closed-system pharmacies in meeting the REMS requirements. If the TRIG does not favor a novel authorization process for all of the closed-system pharmacies solely due to the poor performance of the governmental entities, the TRIG should propose an outreach to these programs to improve compliance. In addition, the TRIG should be sure to include both governmental entities in the 60-month audit so that their performance in the REMS can continue to be monitored. Lastly, the TRIG presents the process times for prescriptions that have experienced at least one REMS-related rejection. However, data on the overall processing time of a prescription that does not meet with any rejections is unclear. Given that one of the pieces of information solicited during the closed-system audits is “Date and time of each prescription transaction,” this is an excellent opportunity for the TRIG to assess prescription processing times for prescriptions that do not experience any REMS-related rejections. The TRIG should add this component to their closed-system audits. e. For the Inpatient Pharmacy audits, six inpatient pharmacies either did not respond to the audit request or decided not to participate. In the current inpatient pharmacy enrollment form, the pharmacy only agrees to have their training audited. We are considering revisions to this enrollment form to allow for process audits so as to increase the potential pool of inpatient pharmacies in the audit and will communicate any required modifications during the review of the next REMS assessment. f. The TRIG reports a number of instances where prescribers were either unaware of requirements to submit a PPAF or chose not to do so. It is important that the TRIG investigate mechanisms to reinforce to prescribers the necessity of timely completion of PPAFs. g.For subsequent submissions of Researched Abuse, Diversion and Addiction-Related Surveillance (RADARS) data that contain CII opioid comparators, expand the CII immediate-release opioid category to include oxycodone/acetaminophen, oxycodone/aspirin, and oxycodone/ibuprofen. h.The Agency has increasing concerns about the use of RADARS data to assess some of the outcomes outlined in the TIRF REMS. Given the limitations of RADARS, the Agency believes that additional data Reference ID: 4190326 FDA_7548 sources that can track adverse outcomes of interest associated with the TIRF products are necessary, and the TRIG must study intermediate objectives more closely related to the REMS intervention. The FDA proposes a meeting with the TRIG to discuss and explore new approaches to assessing this REMS with the goal of gathering useful information to better understand the impact of the REMS and to improve the program going forward. 4. Reference ID: 4190326 We refer to the July 21, 2016, FDA electronic communication in which comments on the patient, prescriber, and pharmacist surveys were conveyed based upon the 48 month REMS assessment results. We acknowledge the subsequent agreement between the Agency and the TRIG that the survey results for the 60 month TIRF REMS assessment will be submitted to the Agency on February 17, 2017. FDA_7549 10.3 DESCRIPTION OF SURVEILLANCE DATA Data Entree De-scn'ptien De?nition-s Epentnneeus AE rep-arts were cranih-ine-d TERI preducts. Line listings Pre?erre?d terms used de?ne each eutccnie are desciihed bel-aw. Adverse Event Fer cases cufaddicnc-n. m?erdnse. deaths. cur pediatric erpesures . . . . . . . . . . . . . . . . :hddl-L? lien: :Intenticunal drug misuse. diug abuse. drug at (if) Reports were provided and included ahcuut die case such as inappropriate sLte- schedule If drug adniLnistiaticn. inccurrect administered- accidenml prcuduct. dependence. drug dependence (antepartum. pesrbar'tliin]- dependence age- gender- Lndicancnn For use. preferred terms. and cc-nccniitant medical-inns. The ccuunted the number bf Lnapprepiiate cent'ersiuau bet-ween the number nf' accidental and unintentic-nal exp-esures. and the number pr-ard telerant ELE reperts. [Herd-ire: Accldental nt'erdese- intent-inanal et'eidese- cweidcnse- presc rihed m'erd-ase. accidental Death: Accrdental death. braLn death. cardiac death. death. death neenaml- sudden cardiac death. sudden death. agenal death struggle. apparent death. drug ine?'ecnre?ldeath. cardicr-iesp-iratcry attest. US- cases recen'ed by ?le manufacturer witth the study pericd were included. Nb additicunal cases ?bm pew-an centers nr literature renew were included. Each Biplane-r the . . case rep-nrts tn make a ?nal decisic-n ah-nut whether die-y were cardiac arrest. reseratery arrest. theta- dead: true cams 1.ia a pieces: that was desciihed. Pediatric Eipesures: Accrdental exposure to product by dilid. chug administered tcu patient of Lnappr-apiiate age. Failure cf child resistant mechanrsni Fer pharmaceutical preduct In additL-an tn the preferred ternis. Spenser: did a sear-m ?ar relevant cases using the fellbwing ternis: addicticun. ct?erdese- diug dependence. death. pediatric exp-asure. died. fatal. inapprc-prtate- multiple drug err-plied. passed away. infant. chle. ninther. Father- accidental. scun. daughter. grandin-ather. gandf'ather. sister. niece. intent-innal. nephew. aunt. uncle- mum. pep. dad. ccunrersiuan. nen-c-pr-ard telerant. hiest cufthe terms were an alte1nate meth-ad Fer ?nding cases m'erdc-se. death. and pediatric erbnsuie"- but these text searches were the paniary niethuad Ear ?nding cases c-Finap-p-rc-prrate cent'ersinn between and use in nc-n-npicuid tcalerant p-atLents. Reference ID: 4190326 Researched ruin-5e, Diteraien, and Addie-Hen Related. Surveillance Ejatem Pei-sen 'Center Program The PCP cemisn er infmanaticn calls ?mn the public In healthca.te prniiders tn gain in?armancn cur advice regarding p-ntentiall}: tcaic eapcnsutes. In 3915. the PCP included SCI {cf??j chsc-n centers in 43 states acrc-ss the CS- cm'enng carer nfdae US- pcpulaticun Erem the caller is entered intc- a health reccurd by traLned smff. l'wIicrc-inedea: is available tn the PC tcu identify me-dic attens based en phl'stcal desc rip-ticns provided b3? callers. Presclipticn exposures are available dcuw'n tn the prc-duct le1.'el. Fellow-up aHer an earpc-suae call is dc-ne as part pf standard tn get addtt?icanal LnFc-rmat'ican abnut clutccmes resulting ?nin the such as death. Jib-1 re: "an resulting ?nin the me-naper cur incnnect use of a where the victim was likeljr attempting to gain a high euphc-nc effect er scme ether effect" Intenliennl misu'se: "an ei?p-nsute resulting ?nin the Lntenticunal impr-aper cur an enect use cIFa substance fer leasens ether than the pursuit cf a psa?chcnepic eFfect" fnintentienal therapeutic errer: "an unintentienal deviaticn ?nin a prcaper therapeutic regimen that nesults in ?ne wrung dcuse. inchrIect reute cFaMn'ati-an. awn'aticn tn the wrung persen. cur adaninistrancun cufthe wrung substance" ['nintentinnal general emeaures: accidental unsupervised that were nc-t de?ned as "enviuanmental. cuccupat'icnnal. ?aerapeutic enicnr. misuse. latte-sting. Feed chscunLng. cur unknown" Emergent"? department iiaits'hnspitaliaatiens: cams "men at a healthc are Etcilit'y and ceded as treated. evaluated. and released: adanitted tc- critical care unit: admitted tn nencritical care unit: admitted tn care facility" Deaths: nne c-fthe inedical clutcc-nnes identi?ed 1.1a PCP Fellew-up c-f exposure calls hIajer medic .11 eulreine': and deaths: deah and patients when "exhibited as a :result efthe which were life- threatening er resulted in signi?cant residual disability er dis?gurement" rea rment Center Program The TC cf patients seeking nearment fer npinid dependence. Thu pregrana cein'pines twe treatment prcgi'aans'. the Epic-id Treatment Pregrana (DTP) that cellects dam ?'cum patients entering federahy-fnnded inedicatien-assisted ne atment centers and the Surrey cf KEV Infmanantsl Patients Pregain that celects data ?cm patients Ali-1 5e: past day nfuse bf an identi?ed prnduct tn get high Reference ID: 4190326 entering mostl}r minutely-funded substance use progianis. Both programs use the same data collection instruments to capture past month abme of speci?c opioids. Patients are of?eued the to to luntarily complete a slandaidiced. anonymous self-administeued questionnaire about The opioids that die].r wed in the past days to get high Patients 1eport plimarf opioid of abuse {by product}: other opioid: used, and route of administntion [for each dnig used in The past month to get high)- In 1015 DTP included I53 methadone treatment progiams in slates and the SKIP included 1 31 treatment programs covering 4? states. College Surrey Program The ESP collects anonymous in?ormation on past Sill-day non- medical abuse or misuse} use of prescription drugs from self-identi?ed college students at 2- or 4-year colleges. Imit'??zid?: or technical schools. Self-adminntered online questionnaire: are ?lled out at the end ofthe fall. spring: and summer semesters-'quarters. The target for number of completed sun-ego each semester is and enrollment is strati?ed into four Census regions. The selection of students is done via a nationwide panel company. No o?iet information was provided about how students are selected for participation. Students can receive prizes for completing these sln't'eys- :?ibuse: past Ell-day endorsement of non-medical use ofan identified product Impaired Health Care ?(other Program (Ell?P} The HIV-T is made up ofdatn from the dune di??erent proglanis combined into one dataset: Drug Diversion Prognm. 2} the PCP. and the 1. Health care workers that are intolt'ed in dit'etting puescription opioids are identi?ed ?'om reports from regulatory.r agencies a: well a: medical. phaimac}: nursing: and den'lal hoards ?'om the Drug Diversion Proginm. 2. Report: about exposuies to opioids inhealth care workers are identi?ed from the PCP- 3. Health care workers who abused opioids in the past davs are identi?ed from the TCP- Abuse by a health care worker was de?ned by virtue of identi?cation in the dataset. Reference ID: 4190326 Spontaneous adverse event (AB) reports 60-month report observation period 8 39 3015-3 23 2016 10.4 SURVEILLANCE DATA RESULTS Count: and rate: for mam AE: ofmterest across three reportmg penods (60-month. 48?month. and 36 month] are provided 10.4.1. Spontaneous Adverse Event Reports Results? 353 total AE: of interest ?om LIedXX'atch report: dunng 60 -month reporting penod. 344 death: which far exceeded number of overdose. or pediatric exposure cases 7 cases per AE). No inappropriate conversions. unintentional exposures. or non-opioid tolerant ca se: Detarls for case reports: Of 6 addiction cases. 1 resulted In death. 3 had unknown outcomes. and 3 had outcome of ?not recovered resolved? Of 344 deaths. 131 were determrned to be unrelated to the TM medication. ausahtjv could not be detemnned in about 200 deaths. 4 deaths related to TIRE: and 1 death from an inappropriate use ofTIRfs. Indication; other than cancer pain noted among deaths: pm (7). breakthrough pain not specrfred as cancer pain headache: use pnor to dressing change: (1). lung disea se (1). chronic pam (3). rnvertebr a] disc degeneratron (1). cell anemia (1). neck back pain (4). pam 1n unapproved indication sprain of septal car?tllage of nose (1). and Crohn': disease Indication was unknovrn for 179 cases. 4 overdose cases resulted Ln 3 deaths. 3 pediatric cases were ?om mtentronal use of TIRE: 3 cases unknown and third case had outcome of ?not recovered ?reso lved' . Outcomes for Are these data useful? If yes, are modi?cations needed? Cannot use spontaneous reports to measure or trend mcrdence prevalence of AE: hhmmal case or details provided. For example. the indication for the TIRE was unknown 11?. a majority of deaths. Llay have some for ongorng surveillance if further detail on cases. particularly fatal cases. can be provided For example. 1dent1fy1ng numerous severe outcome: that occur 11: patients using TIRE: for non-cancer pam may mdrcate a need for further regulatory action. These data do not appear to be especrallv useful for assessing whether the RELIS ts effective a Rates of adverse events discussed here encompass the counts of the speci?c adverse event from divided by l) the population size from US Census data. 2.) the nunrber of prescription ?lls from IMS Health data or 3.) the number of dosage units from IMS Health data. Reference ID: 4190326 10.4.2. Poison Center Program Data3 Data Source Main Findings Are these data useful? If yes, are modi?cations needed? Poison ("enter an (4) 0 Near?national census of 0 These data may be most Program (PCP) poison center exposure useful for monitoring Reference ID: 4190326 calls represent a tiny fraction of events of interest We don?t know what fraction or if it varies over time or across products. In many situations. particularly in the most severe cases. exposed patients may go directly to an emergency department rather than initiating a poison center pediatric -6 years of age) 60-month ?31307t 0 Misclassi?cation of unintentional exposures. observation period: exposure is thought to be but we can continue to 10 393015? an issue for manv solid momtor other outcomes 10'38'13016 dosage forms. but it may for consistency With other not be as much of an data sources. issue for TIRFs given the The unintentional unique dosage forms outcomes can be reported (Table 1) for children under 6 years 0 Numbers of events were of age separately from extremely low for TIRES cases ages 6 years and so variability in rates older . made interpretation of Rates per prescription may trends difficult. be the most useful for 0 Porson center calls comparing these products. Consider dropping the dosage unit-based rates. P-values are not needed for surveillance purposes. and they are not very meaningful given the large numbers of tests performed and the small numbers of events for Case/mention counts in the pre? and post?REMS a Rates of adverse events discussed here encompass the counts ofthe speci?c advetse event ?'om PCP data divided by l) the population size fnom US Census data, 2) the number of prescription ?lls ?'om IMS Health data, or 3) the number of dosage units from IMS Health data. Reference ID: 4190326 10.4.3. Treatment Center Program Resultsa Data Source Main Findings Are these data useful? Treatment Center Program 60-month report observation period: 1039/3015- 10"28?2016 0 Survey of Key Informants? Patients (SKIP) 0 Opioid Treatment Program (OTP) (4) These are convenience samples of people entering opioid treatment. Changes in prevalence do not account for potential changes ui the number of individuals accessing treatment. Generalizability to populations not entering treatment for opioid use disorder is unknown. Geographic distribution of sample changes over time so a sensitivity 1S needed using a set of sites that contributed data consistently of quarters). Misclassification of the specr?c product abused is an issue with these data unclear how accurately people report abuse of different products within a class. especrally generic products- whether patients might Just report fentanyl. in general- rather than a speci?c product name. or how much misclassi?cation may be introduced due to illic1t fentanyl. On the other hand. misclassi?cation of exposure may be less for TIRFs than for If yes, are modi?cations needed? 0 May be useful for comparing abuse rates by product. but generalizability Will be limited to those entering treatment for opioid use disorder. 0 P-values are not needed for surveillance purposes. and they are not very meaningful given the large numbers of tests performed and the small numbers of events for 0 Abuse rates per prescription may be the most useful for comparing these products Consider dropping the dosage unit-based rates. 0 Case-"mention counts in the pre? and post-REMS period should be provided for all evaluations. The large groupings of products Within the TIRFs and composite comparators may be masking patterns for individual drugs. Instead. single?molecule comparators like oxycodone IR. oxycodone ER hydromorphone IR. and oxymorphone IR could be used. and TIRFs should be provided by product. Reference ID: 4190326 other opioid products given the . . tuiique dosage forms . a Abuse rates discussed here encompass the counts of patients reporting abuse of the product group from TCP data divided by 1) the population size from US Census data, 2) the number of prescription ?lls from IMS Health data. or 3) the number of dosage units from IMS Health data. 10.4.4. College Survey Program Resultsa Data Source Nlain Findings Are these data useful? If yes, are modi?cations needed? College Survey 0 Opioid abuse trends in 0 Despite limitations. these data suggest that there (4) Program (CSP) 60-month report 10.2912015- 10.2812016 observation period: this survey. in general. con?ict With ?ndings in other data sources For example. these survey results suggested that trends non-medical use for all oprords were increasing. but the data suggested that only and schedule 2 opiOids increased in the pre- to post-REMS comparison. Internet survey With unclear sampling frame. survey not validated. suspect quality of these data are low may be an increasmg trend towards abuse of TIRFs among college students. The data source may still be useful for evaluating the effectiveness of the REMS and for surveillance with the recommended modifications. below P-values are not needed for surveillance purposes. and they are not very meaningful given the large numbers of tests performed and the small numbers of events for TIRFs Case "mention counts in the pre- and post- REMS period should be provided for all evaluations. The large groupings of products Within the TIRFs and composite comparators may be masking patterns for individual drugs Instead. smgle?molecule comparators like oxycodone IR. oxycodone ER. hydromorphone IR. and oxymorphone IR could be used. and TIRFs should be provided by product. a The rates discussed here encompass the counts of patients reporting non-medical use of the product group from CSP data divided by l) the population size from US Census data. 2) the number of prescription ?lls from IMS Health data. or 3) the munber of dosage units from IMS Health data. Reference ID: 4190326 10.4.5. Impaired Health Care Worker Program Resultsa Data Source hIain Findings Are these data useful? If yes, are modi?cations needed? Impaired Health 0 This type of diversron likely 0 Data are probably not useful gorng (Tare \Vorker happening through channels forward Program unrelated to prescriber education (supply chain 60-month period: diversron rather than 10 39.1301 5- diversion of dispensed 1038:3016 prescriptions) so rt?s unable to measure the effectiveness of the REMS. 1 a Rates discussed here encompass the counts of health care workers reporting abuse ofthe product group from IHWP data divided by 1 the population size from US Census data. It the number of prescription ?lls from IMS Health data. 01' 3) the number of dosage units from IMS Health data Reference ID: 4190326 10.5. PATIENT SURVEY TABLES Table 10.5.1: Patients'/Caregivers' Understanding of Key Risk Message 1 Question 12 Month Survey 24 Month Survey 36 Month Survey 48 Month Survey 60 Month Survey N=192 N=302 N=229 N=310 N=310 TIRF medicines can cause life-threatening breathing problems that can lead to death. True: 173 (90%) True: 272 (90%) True: 209 (91%) True: 285 (92%) True: 284 (92%) False: 5 (3%) False: 0 (0%) False: 1 (0.4%) False: 3 (1%) False: 8 (3%) I don't know: 14 (7%) I don't know: 30 (10%) I don't know: 19 (8%) I don't know: 22 (7%) I don't know: 18 (6%) Composite Score 90% 90% 91% 92% 92% Table 10.5.2: Patients'/Caregivers' Understanding of Key Risk Message 2 Question TIRF medicines should only be taken by patients who are opioid tolerant. 12 Month Survey 24 Month Survey 36 Month Survey 48 Month Survey 60 Month Survey N=192 N=302 N=229 N=310 N=310 True: 174 (91%) True: 277 (92%) True: 195 (85%) *True: 135 (44%) True: 277 (89%) False: 5 (3%) False: 5 (2%) False: 6 (3%) False: 122 (39%) False: 8 (3%) I don't know: 13 (7%) I don't know: 20 (7%) I don't know: 28 (12%) I don't know: 53 (17%) I don't know: 25 (8%) *Changed to TIRF medicines should only be taken by cancer patients who are opioid tolerant. (48 month) Reference ID: 4190326 FDA_7559 Opioid tolerant means that a patient is already taking other opioid pain medicines around the clock and their body is used to these medicines. True: 176 (90%) True: 267 (88%) True: 187 (82%) True: 280 (90%) True: 273 (88%) False: 7 (4%) False: 12 (4%) False: 19 (8%) False: 14 (5%) False: 14 (5%) I don't know: 9 (5%) I don't know: 23 (8%) I don't know: 23 (10%) I don't know: 16 (5%) I don't know: 23 (7%) Composite Score 61.5% 60% 54% 42% 83% Table 10.5.3: Patients'/Caregivers' Understanding of Key Risk Message 3 Question 12 Month Survey 24 Month Survey 36 Month Survey 48 Month Survey 60 Month Survey N=192 N=302 N=229 N=310 N=310 Yes: 29 (15%) Yes: 25 (8%) Yes: 25 (11%) Yes: 32 (10%) Yes: 34 (11%) No: 140 (73%) No: 234 (77.5%) No: 179 (78%) No: 250 (81%) No: 242 (78%) I don't know: 23 (12%) I don't know: 43 (14%) I don't know: 25 (11%) I don't know: 28 (9%) I don't know: 34 (11%) Yes: 134 (70%) Yes: 194 (64%) Yes: 151 (66%) Yes: 212 (68%) Yes: 225 (73%) No: 52 (27%) No: 90 (30%) No: 71 (31%) No: 80 (26%) No: 81 (26%) I don't know: 6 (9%) I don't know: 18 (6%) I don't know: 7 (3%) I don't know: 18 (6%) I don't know: 4 (1%) Yes: 3 (2%) Yes: 49 (3%) Yes: 3 (1%) Yes: 8 (3%) Yes: 5 (2%) No: 172 (90%) No: 264 (87%) No: 200 (87%) No: 280 (90%) No: 269 (87%) I don't know: 17 (9%) I don't know: 29 (10%) I don't know: 26 (11%) I don't know: 22 (7%) I don't know: 36 (12%) For which of the following conditions should you use a TIRF medicine? Headache or migraine pain Breakthrough pain from cancer Dental pain Reference ID: 4190326 FDA_7560 Pain after surgery Yes: 40 (21%) Yes: 52 (17%) Yes: 44 (19%) Yes: 65 (21%) Yes: 69 (22%) 12 month: Acute or post-operative pain No: 120 (68%) No: 207 (68.5%) No: 161 (70%) No: 210 (68%) No: 199 (64%) I don't know: 22 (11%) I don't know: 43 (14%) I don't know: 24 (11%) I don't know: 35 (11%) I don't know: 42 (14%) Yes: 136 (71%) Yes: 210 (69%) Yes: 150 (65.5%) Yes: 135 (44%) Yes: 148 (48%) No: 47 (24%) No: 66 (21%) No: 58 (25%) No: 136 (44%) No: 121 (39%) I don't know: 9 (5%) I don't know: 26 (9%) I don't know: 21 (9%) I don't know: 39 (13%) I don't know: 41 (13%) A patient must stop taking their TIRF medicine if they stop taking their around-theclock opioid pain medicine True: 82 (43%) True: 103 (34%) True: 84 (37%) True: 122 (39%) True: 123 (40%) False: 47 (24.5%) False: 87 (29%) False: 58 (25%) False: 93 (30%) False: 88 (28%) I don't know: 63 (33%) I don't know: 112 (37%) I don't know: 87 (38%) I don't know: 95 (31%) I don't know: 99 (32%) It is OK for patients to take TIRF medicines for headache pain. True: 17 (9%) True: 21 (7%) True: 16 (7%) True: 20 (7%) True: 20 (7%) False: 136 (71%) False: 206 (68%) False: 159 (69%) False: 232 (75%) False: 209 (67%) I don't know: 39 (20%) I don't know: 75 (25%) I don't know: 54 (24%) I don't know: 58 (19%) I don't know: 81 (26%) TIRF medicines should be taken exactly as prescribed by the doctor. True: 192 (100%) True: 301 (100%) True: 227 (99%) True: 310 (100%) True: 309 (100%) False: 0 (0%) False: 0 (0%) False: 2 (1%) False: 0 (0%) False: 1 (<1%) I don't know: 0 (0%) I don't know: 1 (0.3%) I don't know: 0 (0%) I don't know: 0 (0%) I don't know: 0 (0%) It is ok to take TIRF medicines for shortterm pain that will go away in a few days. True: 10 (5%) True: 15 (5%) True: 12 (5%) True: 13 (4%) True: 9 (3%) False: 158 (82%) False: 252 (83%) False: 190 (83%) False: 267 (86%) False: 264 (85%) I don't know: 24 (13%) I don't know: 35 (12%) I don't know: 27 (12%) I don't know: 30 (10%) I don't know: 37 (12%) Composite Score 39% 31% 32% 16%* 11%* Long-lasting painful conditions not caused by cancer 12 month: chronic noncancer pain *Questions added to risk message in 48-month survey Reference ID: 4190326 FDA_7561 Table 10.5.4.: Patients'/Caregivers' Understanding of Key Risk Message 4 Question 12 Month Survey 24 Month Survey 36 Month Survey 48 Month Survey 60 Month Survey N=192 N=302 N=229 N=310 N=310 It is safe to switch to another medicine that contains fentanyl without talking to a healthcare provider first. True: 1 (0.5%) True: 8 (3%) True: 2 (1%) True: 5 (2%) True: 6 (2%) False: 186 (97%) False: 285 (94%) False: 222 (97%) False: 295 (95%) False: 297 (96%) I don't know: 5 (3%) I don't know: 9 (3%) I don't know: 5 (2%) I don't know: 10 (3%) I don't know: 7 (2%) Composite Score 97% 94% 97% 95% 96% Table 10.5.5.: Patients'/Caregivers' Understanding of Key Risk Message 5 Question 12 Month Survey 24 Month Survey 36 Month Survey 48 Month Survey 60 Month Survey N=192 N=302 N=229 N=310 N=310 A patient may give TIRF medicines to another person if they have the same symptoms as the patient. True: 0 (0%) True: 5 (2%) True: 1 (0.4%) True: 0 (0%) True: 6 (2%) False: 192 (100%) False: 296 (98%) False: 227 (99%) False: 308 (99%) False: 303 (98%) I don't know: 0 (0%) I don't know: 1 (0.3%) I don't know: 1 (0.4%) I don't know: 2 (1%) I don't know: 1 (<1%) Selling or giving away TIRF medicines is against the law. True: 188 (98%) True: 297 (98%) True: 227 (99%) True: 306 (99%) True: 308 (99%) False: 3 (2%) False: 2 (1%) False: 1 (0.4%) False: 2 (1%) False: 1 (<1%) I don't know: 1 (0.5%) I don't know: 3 (1%) I don't know: 1 (0.4%) I don't know: 2 (1%) I don't know: 1 (<1%) Reference ID: 4190326 FDA_7562 A side effect of TIRF medicines is the chance of abuse or addiction. N/A N/A N/A N/A True: 287 (93%) False: 5 (2%) I don't know: 18 (6%) TIRF medicines can be misused by people who abuse prescription medicines or street drugs. N/A TIRF medicines should be kept in a safe place to prevent it from being stolen. N/A Composite Score 98% N/A N/A N/A True: 302 (97%) False: 0 (0%) I don't know: 8 (3%) N/A N/A N/A True: 308 (99%) False: 1 (<1%) I don't know: 1 (<1%) 96% 98% 98% 88% Table 10.5.6.: Patients'/Caregivers' Understanding of Key Risk Message 6 Question 12 Month Survey 24 Month Survey 36 Month Survey 48 Month Survey 60 Month Survey N=192 N=302 N=229 N=310 N=310 TIRF medicines should be stored in a safe place out of reach of children. True: 192 (100%) True: 302 (100%) True: 227 (99%) True: 309 (100%) True: 310 (100%) False: 0 (0%) False: 0 (0%) False: 1 (0.4%) False: 1 (<1%) False: 0 (0%) I don't know: 0 (0%) I don't know: 0 (0%) I don't know: 1 (0.4%) I don't know: 0 (0%) I don't know: 0 (0%) TIRF medicines must be disposed of as described in the specific product's Medication Guide True: 184 (96%) True: 285 (94%) True: 215 (94%) True: 299 (97%) True: 303 (98%) False: 2 (1%) False: 0 (0%) False: 1 (0.4%) False: 2 (1%) False: 2 (1%) I don't know: 6 (3%) I don't know: 17 (6%) I don't know: 19 (8%) I don't know: 9 (3%) I don't know: 5 (2%) Reference ID: 4190326 FDA_7563 A TIRF medicine can cause an overdose and death in any child who takes it. True: 174 (91%) True: 275 (91%) True: 209 (91%) True: 289 (93%) True: 292 (94%) False: 4 (2%) False: 2 (1%) False: 2 (1%) False: 2 (1%) False: 5 (2%) I don't know: 14 (7%) I don't know: 25 (8%) I don't know: 20 (9%) I don't know: 19 (6%) I don't know: 13 (4%) What should you do if an adult who has not been prescribed a TIRF medicine takes a TIRF medicine? Get emergency help right away: 171 (89%) Get emergency help right away: 264 (87%) Get emergency help right away: 202 (88%) Get emergency help right away: 273 (88%) Get emergency help right away: 276 (89%) Do nothing: 0 (0%) Do nothing: 17 (6%) Do nothing: 0 (0%) Do nothing: 1 (0%) Do nothing: 0 (0%) Wait an hour and see if the person is OK: 6 (3%) Wait an hour and see if the person is OK: 2 (1%) Wait an hour and see if the person is OK: 7 (3%) Wait an hour and see if the person is OK: 6 (2%) Wait an hour and see if the person is OK: 10 (3%) I don't know: 15 (8%) I don't know: 19 (6%) I don't know: 20 (9%) I don't know: 30 (10%) I don't know: 24 (8%) 79% 78.5% 77% 81% 84% Composite Score Table 10.5.7.: Patients'/Caregivers' Understanding of Safe Use Questions Question Did the doctor, nurse, or other healthcare professional in the doctor's office ever talk to you about the risks and possible side effects of the TIRF medicine that was most recently prescribed for you? Reference ID: 4190326 12 Month Survey 24 Month Survey 36 Month Survey 48 Month Survey 60 Month Survey N=192 N=302 N=229 N=310 N=310 Yes: 165 (86%) Yes: 259 (86%) Yes: 200 (87%) Yes: 259 (84%) Yes: 265 (86%) No: 23 (12%) No: 36 (12%) No: 23 (10%) No: 36 (12%) No: 37 (12%) I don't know: 4 (2%) I don't know: 7 (2%) I don't know: 6 (3%) I don't know: 15 (5%) I don't know: 3 (5%) FDA_7564 Did the doctor, nurse, or other healthcare professional in the doctor's office ever tell you how to use the TIRF medicine that was most recently prescribed for you? Yes: 180 (94%) Yes: 281 (93%) Yes: 241 (93%) Yes: 296 (96%) Yes: 294 (95%) No: 12 (6%) No: 19 (6%) No: 13 (6%) No: 9 (3%) No: 15 (5%) I don't know: 0 (0%) I don't know: 2 (1%) I don't know: 21 (9%) I don't know: 5 (2%) I don't know: 1 (<1%) Did the doctor, nurse, or other healthcare professional in the doctor's office ever tell you how to store or keep the TIRF medicine that was most recently prescribed for you? Yes: 155 (81%) Yes: 241 (80%) Yes: 185 (81%) Yes: 255 (82%) Yes: 270 (87%) No: 33 (17%) No: 52 (17%) No: 38 (17%) No: 49 (16%) No: 35 (11%) I don't know: 4 (2%) I don't know: 9 (3%) I don't know: 6 (3%) I don't know: 6 (2%) I don't know: 5 (2%) TIRF medicines are only available to patients through a special program (called the TIRF REMS Access Program). True: 97 (51%) True: 147 (49%) True: 162 (71%) True: 236 (76%) True: 238 (77%) False: 23 (12%) False: 33 (11%) False: 9 (4%) False: 8 (3%) False: 10 (3%) I don't know: 72 (37%) I don't know: 122 (40%) I don't know: 58 (25%) I don't know: 66 (21%) I don't know: 62 (20%) Reference ID: 4190326 FDA_7565 10.6. Pharmacist Survey Tables Table 10.6.1.: Pharmacists' Understanding of Key Risk Message 1 Question 12 Month Survey 24 Month Survey 36 Month Survey N=302 N=300 N=300 48 Month Survey N=301 60 Month Survey N=318 According to the labeling, patients considered opioid-tolerant are those: (12-month and 60-month) According to labeling for TIRF medicines, patients with cancer who are considered opioid-tolerant are those: (24, 36, and 48 month) Who are taking around-theclock opioid therapy for underlying persistent cancer pain for one week or longer True: 38 (13%) True: 271 (90%) True: 281 (94%) True: 279 (93%) True: 304 (96%) False: 255 (84%) False: 23 (8%) False: 11 (4%) False: 22 (7%) False: 10 (3%) I don't know: 9 (3%) I don't know: 6 (2%) I don't know: 8 (3%) I don't know: 0 (0%) I don't know: 4 (1%) Who are not currently taking opioid therapy, but have taken opioid therapy before. True: 46 (15%) True: 41 (14%) True: 29 (10%) True: 9 (27%) True: 30 (9%) False: 242 (80%) False: 242 (81%) False: 261 (87%) False: 263 (87%) False: 278 (87%) I don't know: 14 (5%) I don't know: 17 (6%) I don't know: 10 (3%) I don't know: 11 (4%) I don't know: 10 (3%) True: 242 (80%) True: 52 (17%) True: 44 (15%) True: 44 (15%) True: 46 (15%) False: 47 (16%) False: 228 (76%) False: 236 (79%) False: 248 (82%) False: 261 (82%) I don't know: 13 (4%) I don't know: 20 (7%) I don't know: 20 (7%) I don't know: 9 (3%) I don't know: 11 (4%) True: 260 (86%) True: 258 (86%) True: 271 (91%) True: 274 (91%) True: 281 (88%) False: 24 (8%) False: 27 (9%) False: 19 (6%) False: 19 (6%) False: 23 (7%) Who have no known contraindications to the drug fentanyl, but are not currently taking around-the clock opioid therapy 12 month: Who are not currently taking opioid therapy, but with no known intolerance or hypersensitivity to the drug fentanyl TIRF medicines are contraindicated in opioid nontolerant patients because life- Reference ID: 4190326 FDA_7566 threatening respiratory depression could occur at any dose. Death has occurred in opioid non-tolerant patients treated with some fentanyl products. TIRF medicines may be used in opioid non-tolerant patients. Prescribers starting a patient on a TIRF medicine must begin with titration from the lowest dose available for that specific product, even if the patient has previously taken another TIRF medicine. I don't know: 18 (6%) I don't know: 15 (5%) I don't know: 9 (3%) I don't know: 8 (3%) I don't know: 14 (4%) True: 278 (92%) True: 281 (94%) True: 281 (94%) True: 287 (95%) True: 303 (95%) False: 5 (2%) False: 2 (1%) False: 4 (1%) False: 4 (1%) False: 3 (1%) I don't know: 19 (6%) I don't know: 17 (6%) I don't know: 15 (5%) I don't know: 10 (3%) I don't know: 12 (4%) True: 48 (16%) True: 40 (13%) True: 39 (13%) True: 35 (12%) True: 28 (9%) False: 237 (78.5%) False: 246 (82%) False: 251 (84%) False: 257 (85%) False: 278 (87%) I don't know: 17 (6%) I don't know: 14 (5%) I don't know: 10 (3%) I don't know: 9 (3%) I don't know: 12 (4%) True: 237 (78.5%) True: 248 (83%) True: 237 (79%) True: 243 (81%) True: 267 (84%) False: 46 (15%) False: 38 (13%) False: 50 (17%) False: 45 (15%) False: 34 (11%) I don't know: 19 (6%) I don't know: 14 (5%) I don't know: 13 (4%) I don't know: 13 (4%) I don't know: 17 (5%) According to the labeling for TIRF medicines, patients considered opioid-tolerant are those who are taking, for one week or longer, at least: 8 mg oral hydromorphone/day 60 mg oral morphine/day Reference ID: 4190326 N/A N/A True: 237 (79%) True: 229 (76%) True: 237 (79%) True: 237 (75%) False: 29 (10%) False: 31 (10%) False: 30 (10%) False: 38 (12%) I don't know: 34 (11%) I don't know: 40 (13%) I don't know: 13 (4%) I don't know: 43 (14%) True: 255 (85%) True: 253 (85%) True: 270 (90%) True: 280 (88%) False: 14 (5%) False: 15 (5%) False: 11 (4%) False: 13 (4%) I don't know: 31 (10%) I don't know: 31 (10%) I don't know: 20 (7%) I don't know: 25 (8%) FDA_7567 30 mg oral oxycodone/day 25 mcg transdermal fentanyl/hour N/A N/A 25 mg oral oxymorphone/day An equianalgesic dose of another oral opioid N/A N/A Composite Score 57%* True: 214 (71%) True: 220 (73%) True: 232 (77%) True: 247 (78%) False: 44 (15%) False: 38 (13%) False: 41 (14%) False: 37 (12%) I don't know: 42 (14%) I don't know: 42 (14%) I don't know: 28 (9%) I don't know: 34 (11%) True: 216 (72%) True: 223 (74%) True: 232 (77%) True: 253 (80%) False: 45 (15%) False: 31 (10%) False: 42 (14%) False: 39 (12%) I don't know: 39 (13%) I don't know: 46 (15%) I don't know: 27 (9%) I don't know: 26 (8%) True: 213 (71%) True: 213 (71%) True: 221 (73%) True: 229 (72%) False: 29 (10%) False: 26 (9%) False: 36 (12%) False: 30 (9%) I don't know: 58 (19%) I don't know: 61 (20%) I don't know: 44 (15%) I don't know: 59 (19%) True: 177 (59%) True: 177 (59%) True: 196 (65%) True: 207 (65%) False: 61 (20%) False: 57 (19%) False: 49 (16%) False: 51 (16%) I don't know: 62 (21%) I don't know: 66 (22%) I don't know: 56 (19%) I don't know: 60 (19%) 43% 50% 30% 31% * Questions added to the 24 and 36 month assessment Key Risk Message that were not included for the 12-month Table 10.6.2.: Pharmacists' Understanding of Key Risk Message 2 Question Reference ID: 4190326 12 Month Survey 24 Month Survey 36 Month Survey 48 Month Survey 60 Month Survey N=302 N=300 N=300 N=301 N=318 FDA_7568 According to the product labeling, a cancer patient may start a TIRF medicine and an around-the-clock opioid at the same time. N/A According to the product labeling, a cancer patient who has been on an around the clock opioid for 1 day can start taking a TIRF medicine for breakthrough pain. N/A A patient must stop taking their TIRF medicine if they stop taking their around the clock opioid pain medicine N/A True: 80 (27%) True: 85 (28%) True: 70 (23%) True: 82 (26%) False: 196 (65%) False: 190 (63%) False: 208 (69%) False: 197 (62%) I don't know: 24 (8%) I don't know: 25 (8%) I don't know: 23 (8%) I don't know: 39 (12%) True: 50 (17%) True: 57 (19%) True: 37 (12%) True: 34 (11%) False: 224 (75%) False: 222 (74%) False: 247 (82%) False: 256 (81%) I don't know: 26 (9%) I don't know: 21 (7%) I don't know: 17 (6%) I don't know: 28 (9%) N/A N/A True: 126 (42%) True: 131 (41%) False: 136 (45%) False: 151 (48%) I don't know: 39 (13%) I don't know: 36 (11%) Per the approved labeling for TIRF medicines, for which of the following indications can TIRF medicines be prescribed to opioid tolerant patients? Acute or postoperative pain Headache or migraine pain Dental pain Reference ID: 4190326 Yes: 52 (17%) Yes: 31 (10%) Yes: 33 (11%) Yes: 22 (7%) Yes: 35 (11%) No: 236 (78%) No: 254 (85%) No: 260 (87%) No: 271 (90%) No: 273 (86%) I don't know: 14 (5%) I don't know: 15 (5%) I don't know: 7 (2%) I don't know: 8 (3%) I don't know: 10 (3%) Yes: 12 (4%) Yes: 8 (3%) Yes: 9 (3%) Yes: 12 (4%) Yes: 7 (2%) No: 269 (89%) No: 277 (92%) No: 272 (91%) No: 280 (93%) No: 300 (94%) I don't know: 21 (7%) I don't know: 15 (5%) I don't know: 19 (6%) I don't know: 9 (3%) I don't know: 11 (4%) Yes: 6 (89%) Yes: 3 (1%) Yes: 5 (2%) Yes: 2 (1%) Yes: 2 (1%) FDA_7569 Breakthrough pain from cancer Chronic non-cancer pain Composite Score No: 286 (95%) No: 290 (97%) No: 291 (97%) No: 296 (98%) No: 306 (96%) I don't know: 10 (3%) I don't know: 7 (2%) I don't know: 4 (1%) I don't know: 3 (1%) I don't know: 10 (3%) Yes: 252 (83%) Yes: 268 (89%) Yes: 275 (92%) Yes: 277 (92%) Yes: 292 (92%) No: 46 (15%) No: 27 (9%) No: 23 (8%) No: 24 (8%) No: 22 (7%) I don't know: 4 (1%) I don't know: 5 (2%) I don't know: 2 (1%) I don't know: 0 (0%) I don't know: 4 (1%) Yes: 194 (64%) Yes: 126 (42%) Yes: 146 (49%) Yes: 131 (44%) Yes: 138 (43%) No: 90 (30%) No: 141 (47%) No: 131 (44%) No: 153 (51%) No: 162 (51%) I don't know: 18 (6%) I don't know: 33 (11%) I don't know: 23 (8%) I don't know: 17 (6%) I don't know: 18 (6%) 61%* 40% 37% 22% 22% * Questions added to the 24 and 36 month assessment Key Risk Message that were not included for the 12-month Table 10.6.3.: Pharmacists' Understanding of Key Risk Message 3 Question It is important to monitor for signs of abuse and addiction in patients who take TIRF medicines. 12 Month Survey 24 Month Survey 36 Month Survey 48 Month Survey 60 Month Survey N=302 N=300 N=300 N=301 N=318 True: 295 (98%) True: 290 (97%) True: 288 (96%) True: 293 (97%) True: 312 (98%) False: 5 (2%) False: 5 (2%) False: 7 (2%) False: 7 (2%) False: 4 (1%) I don't know: 2 (1%) I don't know: 5 (2%) I don't know: 5 (2%) I don't know: 1 (<1%) I don't know: 2 (1%) Which of the following are risk factors for opioid abuse? A personal history of psychiatric illness Reference ID: 4190326 Yes: 201 (67%) Yes: 216 (72%) Yes: 213 (71%) Yes: 227 (75%) Yes: 247 (78%) No: 62 (20.5%) No: 48 (16%) No: 46 (15%) No: 43 (14%) No: 42 (13%) I don't know: 39 (13%) I don't know: 36 (12%) I don't know: 41 (14%) I don't know: 31 (10%) I don't know: 29 (9%) FDA_7570 A personal history of past or current alcohol or drug abuse, or a family history of illicit drug use or alcohol abuse Yes: 301 (100%) Yes: 297 (99%) Yes: 298 (99%) Yes: 297 (99%) Yes: 314 (99%) No: 0 (15%) No: 0 (0%) No: 0 (0%) No: 2 (1%) No: 1 (<1%) I don't know: 1 (0.3%) I don't know: 3 (1%) I don't know: 2 (1%) I don't know: 2 (1%) I don't know: 3 (1%) TIRF medicines can be abused in a manner similar to other opioid agonist. True: 273 (90%) True: 282 (94%) True: 283 (94%) True: 288 (96%) True: 298 (94%) False: 19 (6%) False: 10 (3%) False: 12 (4%) False: 8 (3%) False: 12 (4%) I don't know: 10 (3%) I don't know: 8 (3%) I don't know: 5 (2%) I don't know: 5 (2%) I don't know: 8 (3%) N/A N/A True: 314 (99%) Which of the following risks are associated with the use of TIRF medicines? Misuse N/A N/A False: 3 (1%) I don't know: 1 (<1%) Abuse N/A N/A N/A N/A True: 315 (99%) False: 2 (1%) I don't know: 1 (<1%) Addiction N/A N/A N/A N/A True: 314 (99%) False: 3 (1%) I don't know: 1 (<1%) Overdose N/A N/A N/A N/A True: 316 (99%) False: 1 (<1%) I don't know: 1 (<1%) Composite Score 60% 66% 66% 69% 59%* * Questions added to the 60 month assessment Key Risk Message that were not included for the previous months Reference ID: 4190326 FDA_7571 Table 10.6.4.: Pharmacists' Understanding of Key Risk Message 4 Question 12 Month Survey 24 Month Survey 36 Month Survey 48 Month Survey 60 Month Survey N=302 N=300 N=300 N=301 N=318 TIRF medicines are interchangeable with each other regardless of route of administration True: 9 (3%) True: 6 (2%) True: 13 (4%) True: 14 (5%) True: 6 (2%) False: 287 (95%) False: 284 (95%) False: 280 (93%) False: 281 (93%) False: 305 (96%) I don't know: 6 (2%) I don't know: 10 (3%) I don't know: 7 (2%) I don't know: 6 (2%) I don't know: 7 (2%) The conversion of one TIRF medicine for another TIRF medicine may result in a fatal overdose because of the differences in the pharmacokinetics of fentanyl absorption. True: 280 (93%) True: 276 (92%) True: 279 (93%) True: 279 (93%) True: 296 (93%) False: 10 (3%) False: 5 (2%) False: 13 (4%) False: 11 (4%) False: 10 (3%) I don't know: 12 (4%) I don't know: 19 (6%) I don't know: 8 (3%) I don't know: 11 (4%) I don't know: 12 (4%) Dosing of TIRF medicines is not equivalent on a microgram-tomicrogram basis. True: 279 (92%) True: 274 (91%) True: 270 (90%) True: 279 (93%) True: 283 (89%) False: 10 (3%) False: 10 (3%) False: 20 (7%) False: 14 (5%) False: 16 (5%) I don't know: 13 (4%) I don't know: 16 (5%) I don't know: 10 (3%) I don't know: 8 (3%) I don't know: 19 (6%) TIRF medicines with the same route of administration can be substituted with each other if the pharmacy is out of stock for one product True: 5 (2%) True: 6 (2%) True: 2 (1%) True: 3 (1%) True: 10 (3%) False: 289 (96%) False: 289 (96%) False: 293 (98%) False: 296 (98%) False: 304 (96%) I don't know: 8 (3%) I don't know: 5 (2%) I don't know: 5 (2%) I don't know: 2 (1%) I don't know: 4 (1%) Composite Score 84% 85% 81% 81% 80% Reference ID: 4190326 FDA_7572 Table 10.6.5.: Pharmacists' Understanding of Safe Use Questions Question 12 Month Survey 24 Month Survey 36 Month Survey 48 Month Survey 60 Month Survey N=302 N=300 N=300 N=301 N=318 Use of a TIRF medicine with a CYP3A4 inhibitor may require dosage adjustment and monitoring of the patient for opioid toxicity as potentially fatal respiratory depression could occur. N/A N/A N/A True: 275 (91%) True: 293 (92%) False: 8 (3%) False: 3 (1%) I don't know: 18 (6%) I don't know: 22 (7%) TIRF medicines may be sold, loaned, or transferred to another pharmacy. True: 14 (5%) True: 8 (3%) True: 11 (4%) True: 7 (2%) True: 16 (5%) False: 262 (87%) False: 274 (91%) False: 276 (92%) False: 279 (93%) False: 288 (91%) I don't know: 26 (9%) I don't know: 18 (6%) I don't know: 13 (4%) I don't know: 15 (5%) I don't know: 14 (4%) All pharmacy staff that dispenses TIRF medicines must be educated on the requirements of the TIRF REMS Access Program. True: 280 (93%) True: 282 (94%) True: 284 (95%) True: 273 (91%) True: 286 (90%) False: 12 (4%) False: 6 (2%) False: 10 (3%) False: 23 (8%) False: 18 (6%) I don't know: 10 (3%) I don't know: 12 (4%) I don't know: 6 (2%) I don't know: 5 (2%) I don't know: 14 (4%) It is ok to dispense TIRF medicines from the inpatient pharmacy inventory to an outpatient for use at home. True: 2 (12.5%) True: 0 (0%) True: 2 (13%) True: 0 (0%) True: 3 (5%) False: 14 (87.5%) False: 13 (87%) False: 13 (87%) False: 13 (87%) False: 54 (83%) I don't know: 0 (0%) I don't know: 2 (13%) I don't know: 0 (0%) I don't know: 2 (13%) I don't know: 8 (12%) Reference ID: 4190326 FDA_7573 *Inpatient pharmacists only (12 month: n=16; 24 month: n=15; 36 month: n=15; 48 month: n=15); 60 month: n=65 Table 10.6.6.: Pharmacists' Reported Activities When Dispensing TIRF Medicines Question 12 Month Survey 24 Month Survey 36 Month Survey 48 Month Survey 60 Month Survey N=302 N=300 N=300 N=301 N=318 How frequently do you perform the following activities when dispensing TIRF medicines? Ask patients about the presence of children in the home. Always: 146 (48%) Always: 167 (56%) Always: 174 (58%) Always: 180 (60%) Always: 180 (60%) Only with the first prescription: 68 (22.5%) Only with the first prescription: 54 (18%) Only with the first prescription: 68 (23%) Only with the first prescription: 67 (22%) Only with the first prescription: 67 (22%) Sometimes: 54 (18%) Sometimes: 33 (11%) Sometimes: 36 (12%) Sometimes: 36 (12%) Never: 13 (4%) Never: 14 (5%) Never: 9 (3%) Never: 9 (3%) I don't know: 12 (4%) I don't know: 11 (4%) I don't know: 9 (3%) I don't know: 9 (3%) Always: 202 (67%) Always: 208 (69%) Always: 224 (75%) Always: 235 (78%) Always: 235 (78%) Only with the first prescription: 54 (18%) Only with the first prescription: 52 (17%) Only with the first prescription: 45 (15%) Only with the first prescription: 42 (14%) Only with the first prescription: 42 (14%) Sometimes: 26 (9%) Sometimes: 26 (9%) Sometimes: 17 (6%) Sometimes: 14 (5%) Sometimes: 14 (5%) Never: 15 (5%) Never: 8 (3%) Never: 6 (2%) Never: 6 (2%) Never: 6 (2%) Sometimes: 54 (18%) Never: 28 (9%) I don't know: 6 (2%) Instruct patients not to share the TIRF medicines with anyone else. Reference ID: 4190326 FDA_7574 Counsel patients that accidental exposure to TIRF medicines by a child may be fatal Instruct patients to keep TIRF medicines out of reach of children to prevent accidental exposure. I don't know: 5 (2%) I don't know: 6 (2%) I don't know: 8 (3%) I don't know: 4 (1%) I don't know: 4 (1%) Always: 190 (63%) Always: 198 (66%) Always: 216 (72%) Always: 216 (72%) Always: 216 (72%) Only with the first prescription: 63 (21%) Only with the first prescription: 57 (19%) Only with the first prescription: 53 (18%) Only with the first prescription: 48 (16%) Only with the first prescription: 48 (16%) Sometimes: 29 (10%) Sometimes: 29 (10%) Sometimes: 16 (5%) Sometimes: 27 (9%) Sometimes: 27 (9%) Never: 13 (4%) Never: 8 (3%) Never: 6 (2%) Never: 4 (1%) Never: 4 (1%) I don't know: 7 (2%) I don't know: 8 (3%) I don't know: 9 (3%) I don't know: 6 (2%) I don't know: 6 (2%) Always: 208 (69%) Always: 223 (74%) Always: 224 (75%) Always: 238 (79%) Always: 238 (79%) Only with the first prescription: 56 (18.5%) Only with the first prescription: 44 (15%) Only with the first prescription: 48 (16%) Only with the first prescription: 39 (13%) Only with the first prescription: 39 (13%) Sometimes: 23 (8%) Sometimes: 17 (6%) Sometimes: 16 (5%) Sometimes: 16 (5%) Never: 4 (1%) Never: 3 (1%) Never: 4 (1%) Never: 4 (1%) I don't know: 5 (2%) I don't know: 8 (3%) I don't know: 4 (1%) I don't know: 4 (1%) Always: 172 (57%) Always: 198 (66%) Always: 203 (68%) Always: 209 (69%) Always: 209 (69%) Only with the first prescription: 76 (25%) Only with the first prescription: 67 (22%) Only with the first prescription: 63 (21%) Only with the first prescription: 66 (22%) Only with the first prescription: 66 (22%) Sometimes: 34 (11%) Sometimes: 26 (9%) Sometimes: 23 (8%) Sometimes: 20 (7%) Sometimes: 20 (7%) Never: 13 (4%) Never: 4 (1%) Never: 2 (1%) Never: 3 (1%) Never: 3 (1%) I don't know: 7 (2%) I don't know: 5 (2%) I don't know: 8 (3%) I don't know: 3 (1%) I don't know: 3 (1%) Always: 272 (90%) Always: 274 (91%) Always: 268 (89%) Always: 278 (92%) Always: 278 (92%) Only with the first prescription: 17 (6%) Only with the first prescription: 11 (4%) Only with the first prescription: 20 (7%) Only with the first prescription: 14 (5%) Only with the first prescription: 14 (5%) Sometimes: 5 (2%) Sometimes: 10 (3%) Sometimes: 3 (1%) Sometimes: 4 (1%) Sometimes: 4 (1%) Sometimes: 21 (7%) Never: 12 (4%) I don't know: 5 (2%) Instruct patients about proper disposal of any unused or partially used TIRF medicines. Give patients the Medication Guide for their TIRF medicine. Reference ID: 4190326 FDA_7575 Does the inpatient pharmacy where you work have an established system, order sets, protocols and/or other measures to help ensure appropriate patient selection and compliance with the requirements of the TIRF REMS Access Program? Never: 3 (1%) Never: 0 (0%) Never: 1 (0.3%) Never: 2 (1%) Never: 2 (1%) I don't know: 5 (2%) I don't know: 5 (2%) I don't know: 8 (3%) I don't know: 3 (1%) I don't know: 3 (1%) Yes: 8 (50%) Yes: 8 (53%) Yes: 7 (48%) Yes: 8 (53%) Yes: 8 (53%) No: 6 (37.5%) No: 4 (27%) No: 5 (33%) No: 7 (47%) No: 7 (47%) I don't know: 2 (12.5%) I don't know: 3 (20%) I don't know: 3 (20%) I don't know: 0 (0%) I don't know: 0 (0%) Yes: 235 (84%) Yes: 231 (82%) Yes: 254 (89%) Yes: 262 (92%) Yes: 262 (92%) No: 7 (2.5%) No: 5 (2%) No: 6 (2%) No: 10 (4%) No: 10 (4%) I don't know: 38 (14%) I don't know: 45 (16%) I don't know: 24 (8.5%) I don't know: 14 (5%) I don't know: 14 (5%) *Inpatient pharmacists only (12 month: n=16; 24 month: n=15; 36 month: n=15; 48 month: n=15) Does the outpatient or retail pharmacy where you work process all TIRF medicine prescriptions, regardless of method of payment, through the pharmacy management system? *Outpatient pharmacist only (12 month: n=280; Reference ID: 4190326 FDA_7576 24 month: 281; 36 month: n=284; 48 month: n=289) Does the pharmacy where you work process all TIRF medicine prescriptions, regardless of method of payment, through the TIRF REMS Access Call Center? Yes: 5 (83%) Yes: 2 (50%) Yes: 1 (100%) No: 0 (0%) No: 0 (0%) No: 0 (0%) I don't know: 1 (17%) I don't know: 2 (50%) I don't know: 0 (0%) N/A N/A *CSP Outpatient pharmacists only (12 month: n=6; 24 month: n=2; 36 month: n=1) Reference ID: 4190326 FDA_7577 10.7. Prescriber Survey Tables Table 10.7.1: Prescribers' Understanding of Key Risk Message 1 Question 12 Month Survey 24 Month Survey 36 Month Survey 48 Month Survey 60 Month Survey N=302 N=302 N=300 N=310 N=294 TIRF medicines should only be taken by patients who are opioid tolerant. True: 284 (97%) False: 8 (3%) I don't know: 2 (1%) 24, 48, 60 month: According to labeling for TIRF medicines, patients with cancer who are considered opioid-tolerant are those: 12 month: According to the labeling, patients considered opioid-tolerant are those: Who are taking around-theclock opioid therapy for underlying persistent cancer pain for one week or longer (T/F/DK) True: 24 (8%) True: 273 (90%) True: 270 (90%) True: 295 (95%) True: 279 (95%) False: 271 (89%) False: 24 (8%) False: 22 (7%) False: 14 (5%) False: 11 (4%) I don't know: 7 (2%) I don't know: 5 (2%) I don't know: 8 (3%) I don't know: 1 (<1%) I don't know: 4 (1%) Who are not currently taking opioid therapy, but have taken opioid therapy before. True: 25 (8%) True: 28 (9%) True: 24 (8%) True: 15 (5%) True: 65 (5%) False: 268 (89%) False: 266 (88%) False: 261 (87%) False: 291 (94%) False: 276 (94%) I don't know: 9 (3%) I don't know: 8 (3%) I don't know: 15 (5%) I don't know: 4 (1%) I don't know: 2 (1%) Who have no known contraindications to the drug fentanyl, but are not currently taking around-the clock opioid therapy True: 251 (83%) True: 39 (13%) True: 28 (9%) True: 33 (11%) True: 17 (6%) False: 47 (16%) False: 248 (82%) False: 259 (86%) False: 269 (87%) False: 272 (93%) I don't know: 4 (1%) I don't know: 15 (5%) I don't know: 13 (4%) I don't know: 8 (3%) I don't know: 5 (2%) 12 month: Who are not currently taking opioid therapy, but with no known Reference ID: 4190326 FDA_7578 intolerance or hypersensitivity to the drug fentanyl TIRF medicines are contraindicated in opioid non-tolerant patients because life-threatening respiratory depression could occur at any dose. True: 264 (87%) True: 265 (88%) True: 260 (87%) True: 280 (90%) True: 270 (92%) False: 35 (12%) False: 32 (11%) False: 32 (11%) False: 23 (7%) False: 21 (7%) I don't know: 3 (1%) I don't know: 5 (2%) I don't know: 8 (3%) I don't know: 7 (2%) I don't know: 3 (1%) Death has occurred in opioid non-tolerant patients treated with some fentanyl products. True: 289 (96%) True: 283 (94%) True: 287 (96%) True: 298 (96%) True: 281 (96%) False: 4 (1%) False: 3 (1%) False: 2 (1%) False: 2 (1%) False: 3 (1%) I don't know: 9 (3%) I don't know: 16 (5%) I don't know: 11 (4%) I don't know: 10 (3%) I don't know: 10 (3%) TIRF medicines may be used in opioid non-tolerant patients. True: 45 (15%) True: 43 (14%) True: 46 (15%) True: 38 (12%) True: 27 (9%) False: 249 (82.5%) False: 242 (80%) False: 246 (82%) False: 263 (85%) False: 260 (88%) I don't know: 8 (3%) I don't know: 17 (6%) I don't know: 8 (3%) I don't know: 9 (3%) I don't know: 7 (2%) True: 251 (83%) True: 244 (81%) True: 252 (84%) True: 265 (86%) True: 252 (86%) False: 45 (15%) False: 52 (17%) False: 42 (14%) False: 40 (13%) False: 37 (13%) I don't know: 6 (2%) I don't know: 6 (2%) I don't know: 6 (2%) I don't know: 5 (2%) I don't know: 5 (2%) Prescribers starting a patient on a TIRF medicine must begin with titration from the lowest dose available for that specific product, even if the patient has previously taken another TIRF medicine. According to the labeling for TIRF medicines, patients considered opioid-tolerant are those who are taking, for one week or longer, at least: 8 mg oral hydromorphone/day Reference ID: 4190326 N/A True: 207 (68.5%) True: 211 (70%) True: 226 (73%) True: 211 (72%) False: 64 (21%) False: 66 (22%) False: 57 (18%) False: 69 (24%) I don't know: 31 (10%) I don't know: 23 (8%) I don't know: 27 (9%) I don't know: 14 (5%) FDA_7579 60 mg oral morphine/day 30 mg oral oxycodone/day 25 mcg transdermal fentanyl/hour 25 mg oral oxymorphone/day An equianalgesic dose of another oral opioid Composite Score N/A N/A N/A N/A N/A 65%* True: 269 (89%) True: 277 (92%) True: 293 (95%) True: 281 (96%) False: 16 (5%) False: 42 (14%) False: 57 (18%) False: 6 (2%) I don't know: 17 (6%) I don't know: 12 (4%) I don't know: 27 (9%) I don't know: 7 (2%) True: 230 (76%) True: 234 (78%) True: 244 (79%) True: 241 (82%) False: 47 (16%) False: 42 (14%) False: 46 (15%) False: 44 (15%) I don't know: 25 (8%) I don't know: 24 (8%) I don't know: 20 (7%) I don't know: 9 (3%) True: 244 (81%) True: 251 (84%) True: 265 (86%) True: 262 (89%) False: 34 (11%) False: 31 (10%) False: 27 (9%) False: 21 (7%) I don't know: 24 (8%) I don't know: 18 (6%) I don't know: 18 (6%) I don't know: 11 (4%) True: 211 (70%) True: 224 (75%) True: 224 (72%) True: 234 (80%) False: 39 (13%) False: 41 (14%) False: 33 (11%) False: 33 (11%) I don't know: 52 (17%) I don't know: 34 (12%) I don't know: 53 (17%) I don't know: 27 (9%) True: 199 (66%) True: 177 (59%) True: 210 (68%) True: 193 (66%) False: 68 (22.5%) False: 66 (22%) False: 55 (18%) False: 56 (19%) I don't know: 35 (12%) I don't know: 57 (19%) I don't know: 45 (15%) I don't know: 45 (15%) 45% 50% 30% 33% * Questions added to the 24 and 36 month assessment Key Risk Message that were not included for the 12-month Table 10.7.2.: Prescribers' Understanding of Key Risk Message 2 Question Reference ID: 4190326 12 Month Survey 24 Month Survey 36 Month Survey 48 Month Survey 60 Month Survey FDA_7580 N=302 N=302 N=300 N=310 N=294 A cancer patient can be started on a TIRF medicine and an aroundthe-clock opioid at the same time. N/A True: 105 (35%) True: 101 (34%) True: 75 (24%) True: 52 (18%) False: 183 (61%) False: 180 (60%) False: 214 (69%) False: 227 (77%) I don't know: 14 (5%) I don't know: 19 (6%) I don't know: 21 (7%) I don't know: 15 (5%) A cancer patient who has been on an around the clock opioid for 1 day can start taking a TIRF medicine for breakthrough pain. N/A True: 86 (28.5%) True: 68 (23%) True: 62 (20%) True: 54 (18%) False: 196 (65%) False: 211 (70%) False: 226 (73%) False: 230 (78%) I don't know: 20 (7%) I don't know: 21 (7%) I don't know: 22 (7%) I don't know: 10 (3%) Per the approved labeling for TIRF medicines, for which of the following indications can TIRF medicines be prescribed to opioid tolerant patients? Acute or postoperative pain Headache or migraine pain Dental pain Breakthrough pain from cancer Reference ID: 4190326 Yes: 38 (13%) Yes: 17 (6%) Yes: 37 (12%) Yes: 28 (9%) Yes: 9 (3%) No: 261 (86%) No: 281 (93%) No: 262 (87%) No: 280 (90%) No: 278 (95%) I don't know: 3 (1%) I don't know: 4 (1%) I don't know: 1 (0.3%) I don't know: 2 (1%) I don't know: 7 (2%) Yes: 38 (13%) Yes: 20 (7%) Yes: 31 (10%) Yes: 16 (5%) Yes: 6 (2%) No: 262 (87%) No: 279 (92%) No: 269 (90%) No: 294 (95%) No: 276 (94%) I don't know: 2 (1%) I don't know: 3 (1%) I don't know: 0 (0%) I don't know: 0 (0%) I don't know: 12 (4%) Yes: 7 (2%) Yes: 5 (2%) Yes: 8 (3%) Yes: 5 (2%) Yes: 4 (1%) No: 290 (96%) No: 292 (97%) No: 292 (97%) No: 305 (98%) No: 283 (96%) I don't know: 5 (2%) I don't know: 5 (2%) I don't know: 0 (0%) I don't know: 0 (0%) I don't know: 7 (2%) Yes: 288 (95%) Yes: 279 (92%) Yes: 288 (96%) Yes: 288 (93%) Yes: 292 (99%) No: 14 (5%) No: 22 (7%) No: 12 (4%) No: 22 (7%) No: 2 (1%) I don't know: 0 (0%) I don't know: 1 (0.3%) I don't know: 0 (0%) I don't know: 0 (0%) I don't know: 0 (0%) FDA_7581 Chronic non-cancer pain Yes: 134 (44%) Yes: 119 (39%) Yes: 112 (37%) Yes: 106 (34%) Yes: 54 (18%) No: 164 (54%) No: 178 (59%) No: 186 (62%) No: 201 (65%) No: 230 (78%) I don't know: 4 (1%) I don't know: 5 (2%) I don't know: 2 (1%) I don't know: 3 (1%) I don't know: 10 (3%) The patients described are experiencing breakthrough pain. According to the labeling, a TIRF medicine is not appropriate for one of them. Which patient should not receive a TIRF medicine? Adult female with localized breast cancer; just completed a mastectomy and reconstructive surgery; persistent cancer pain managed with 30 mg oral morphine daily for the past 6 weeks 164 (54%) 199 (66%) 199 (66%) 227 (73%) 212 (72%) Inform patients that TIRF medicines must not be used for acute or postoperative pain, pain from injuries, headache/migraine or any other short-term pain. True: 277 (92%) True: 278 (92%) True: 272 (91%) True: 291 (94%) True: 283 (96%) False: 16 (5%) False: 16 (5%) False: 16 (5%) False: 12 (4%) False: 8 (3%) I don't know: 9 (3%) I don't know: 8 (3%) I don't know: 12 (4%) I don't know: 7 (2%) I don't know: 3 (1%) Instruct patients that, if they stop taking their around-the-clock opioid medicine, they can continue to take their TIRF medicine. True: 63 (21%) True: 95 (31.5%) True: 89 (30%) True: 64 (21%) True: 58 (20%) False: 207 (68.5%) False: 175 (58%) False: 183 (61%) False: 226 (73%) False: 225 (77%) I don't know: 32 (11%) I don't know: 32 (11%) I don't know: 28 (9%) I don't know: 20 (7%) I don't know: 11 (4%) Composite Score 61%* 39% 36% 33% 33% * Questions added to the 24 and 36 month assessment Key Risk Message that were not included for the 12-month Reference ID: 4190326 FDA_7582 Table 10.7.3.: Prescribers' Understanding of Key Risk Message 3 Question It is important to monitor for signs of abuse and addiction in patients who take TIRF medicines. 12 Month Survey 24 Month Survey 36 Month Survey 48 Month Survey 60 Month Survey N=302 N=302 N=300 N=310 N=294 True: 301 (100%) True: 299 (99%) True: 299 (100%) True: 306 (99%) True: 291 (99%) False: 1 (0.3%) False: 2 (1%) False: 1 (0.3%) False: 2 (1%) False: 3 (1%) I don't know: 0 (0%) I don't know: 1 (0.3%) I don't know: 0 (0%) I don't know: 2 (1%) I don't know: 0 (0%) Which of the following are risk factors for opioid abuse? A personal history of psychiatric illness A personal history of past or current alcohol or drug abuse, or a family history of illicit drug use or alcohol abuse TIRF medicines can be abused in a manner similar to other opioid agonist. Yes: 249 (82.5%) Yes: 250 (83%) Yes: 252 (84%) Yes: 262 (85%) Yes: 253 (86%) No: 37 (12%) No: 31 (10%) No: 23 (8%) No: 28 (9%) No: 27 (9%) I don't know: 16 (5%) I don't know: 21(7%) I don't know: 25 (8%) I don't know: 20 (7%) I don't know: 14 (5%) Yes: 300 (99%) Yes: 299 (99%) Yes: 299 (100%) Yes: 306 (99%) Yes: 294 (100%) No: 1 (0.3%) False: 2 (1%) No: 1 (0.3%) No: 4 (1%) No: 0 (0%) I don't know: 1 (0.3%) I don't know: 1 (0.3%) I don't know: 0 (0%) I don't know: 0 (0%) I don't know: 0 (0%) True: 295 (98%) True: 291 (96%) True: 292 (97%) True: 292 (94%) True: 282 (96%) False: 6 (2%) False: 9 (3%) False: 7 (2%) False: 12 (4%) False: 10 (3%) I don't know: 1 (0.3%) I don't know: 2 (1%) I don't know: 1 (0.3%) I don't know: 6 (2%) I don't know: 2 (1%) N/A N/A True: 290 (99%) Which of the following risks are associated with the use of TIRF medicines? Misuse Reference ID: 4190326 N/A N/A FDA_7583 False: 4 (1%) I don't know: 0 (0%) Abuse N/A N/A N/A N/A True: 291 (99%) False: 2 (1%) I don't know: 1 (<1%) Addiction N/A N/A N/A N/A True: 291 (99%) False: 3 (1%) I don't know: 0 (0%) Overdose N/A N/A N/A N/A True: 292 (99%) False: 2 (1%) I don't know: 0 (0%) Composite Score 80% 80% 82% 79% 61%* *Questions added for 60-month assessment Table 10.7.4.: Prescribers' Understanding of Key Risk Message 4 Question 12 Month Survey 24 Month Survey 36 Month Survey 48 Month Survey 60 Month Survey N=302 N=302 N=300 N=310 N=294 TIRF medicines are interchangeable with each other regardless of route of administration True: 9 (3%) True: 16 (5%) True: 15 (5%) True: 13 (4%) True: 15 (5%) False: 289 (96%) False: 279 (92%) False: 279 (93%) False: 287 (93%) False: 271 (92%) I don't know: 4 (1%) I don't know: 7 (2%) I don't know: 6 (2%) I don't know: 10 (3%) I don't know: 8 (3%) The conversion of one TIRF medicine for another TIRF medicine True: 286 (95%) True: 286 (95%) True: 290 (97%) True: 296 (96%) True: 283 (96%) False: 5 (2%) False: 7 (2%) False: 6 (2%) False: 6 (2%) False: 5 (2%) Reference ID: 4190326 FDA_7584 may result in a fatal overdose because of the differences in the pharmacokinetics of fentanyl absorption. I don't know: 11 (4%) I don't know: 9 (3%) I don't know: 4 (1%) I don't know: 8 (3%) I don't know: 6 (2%) Dosing of TIRF True: 273 (90%) True: 274 (91%) True: 272 (91%) True: 279 (90%) True: 269 (92%) medicines is not False: 12 (4%) False: 16 (5%) False: 18 (6%) False: 21 (7%) False: 11 (4%) equivalent on a microgram-toI don't know: 17 (6%) I don't know: 12 (4%) I don't know: 10 (3%) I don't know: 10 (3%) I don't know: 14 (5%) microgram basis. A patient is already taking a TIRF medicine but wants to change their medicine. His/her doctor decides to prescribe a different TIRF medicine (that is not a bioequivalent generic version of a branded product) in its place. His/her doctor decides to prescribe a different TIRF medicine in its place. According to the labeling, how should the prescriber proceed? The prescriber must not convert to another TIRF medicine on a microgram-permicrogram basis because these medicines have different absorption properties and this could result in a fentanyl overdose. 228 (75.5%) 225 (74.5%) 223 (74%) 240 (77%) 231 (79%) Composite Score 85%* 65% 67% 67% 70% * Questions added to the 24 and 36 month assessment Key Risk Message that were not included for the 12-month Table 10.7.5.: Prescribers' Understanding of Safe Use Questions Question Reference ID: 4190326 12 Month Survey 24 Month Survey 36 Month Survey 48 Month Survey 60 Month Survey N=302 N=302 N=300 N=310 N=294 FDA_7585 A patient is starting titration with TIRF medicine. What dose must they start with? 276 (91%) 252 (84%) 267 (89%) 267 (86%) 266 (91%) 273 (90%) 205 (68%) 199 (66%) 213 (69%) 208 (71%) 262 (87%) 225 (74.5%) 232 (77%) 235 (76%) 235 (80%) The lowest available dose, unless individual product Full Prescribing Information provides product-specific guidance. A prescriber has started titrating a patient with the lowest dose of a TIRF medicine. However, after 30 minutes the breakthrough pain has not been sufficiently relieved. What should they advise the patient to do? Provide guidance based on the product-specific MG because the instructions are not the same for all TIRF medicines. A patient is taking a TIRF medicine and the doctor would like to prescribe erythromycin, a CYP3A4 inhibitor. Please pick the best option of the scenarios described. Reference ID: 4190326 FDA_7586 Use of a TIRF medicine with a CYP2A4 inhibitor may require dosage adjustment; carefully monitor the patient for opioid toxicity, otherwise such use may cause potentially fatal respiratory depression. TIRF medicines contain fentanyl in an amount that could be fatal to children of all ages, in individuals for whom they were not prescribed, and in those who are not opioid tolerant. True: 299 (99%) True: 298 (99%) True: 298 (99%) True: 308 (99%) True: 293 (99.7%) False: 1 (0.3%) False: 1 (0.3%) False: 0 (0%) False: 1 (<1%) False: 0 (0%) I don't know: 2 (1%) I don't know: 3 (1%) I don't know: 2 (1%) I don't know: 1 (<1%) I don't know: 1 (<1%) Instruct patients never to share their TIRF medicines with anyone else, even if that person has the same symptoms. True: 300 (99%) True: 299 (99%) True: 297 (99%) True: 309 (99.7%) True: 294 (100%) False: 1 (0.3%) False: 3 (1%) False: 2 (1%) False: 0 (0%) False: 0 (0%) I don't know: 1 (0.3%) I don't know: 0 (0%) I don't know: 1 (0.3%) I don't know: 1 (<1%) I don't know: 0 (0%) Table 10.7.6.: Prescribers' Reported Activities When Dispensing TIRF Medicines Question 12 Month Survey 24 Month Survey 36 Month Survey 48 Month Survey 60 Month Survey N=302 N=302 N=300 N=310 N=294 How frequently do you perform the following activities when dispensing TIRF medicines? Reference ID: 4190326 FDA_7587 Ask patients about the presence of children in the home. Instruct patients not to share the TIRF medicines with anyone else. Counsel patients that accidental exposure to TIRF medicines by a child may be fatal Always: 175 (58%) Always: 170 (56%) Always: 169 (56%) Always: 178 (57%) Always: 182 (62%) Only with the first prescription: 76 (25%) Only with the first prescription: 70 (23%) Only with the first prescription: 81 (27%) Only with the first prescription: 75 (24%) Only with the first prescription: 66 (22%) Sometimes: 44 (15%) Sometimes: 48 (16%) Sometimes: 42 (14%) Sometimes: 42 (14%) Sometimes: 35 (12%) Never: 5 (2%) Never: 11 (4%) Never: 7 (2%) Never: 11 (4%) Never: 10 (3%) I don't know: 2 (1%) I don't know: 3 (1%) I don't know: 1 (0.3%) I don't know: 4 (1%) I don't know: 1 (<1%) Always: 239 (79%) Always: 239 (79%) Always: 235 (78%) Always: 249 (80%) Always: 236 (80%) Only with the first prescription: 36 (12%) Only with the first prescription: 37 (12%) Only with the first prescription: 41 (14%) Only with the first prescription: 43 (14%) Only with the first prescription: 43 (15%) Sometimes: 24 (8%) Sometimes: 19 (6%) Sometimes: 17 (6%) Sometimes: 13 (4%) Sometimes: 14 (5%) Never: 1 (0.3%) Never: 5 (2%) Never: 6 (2%) Never: 3 (1%) Never: 1 (<1%) I don't know: 2 (1%) I don't know: 2 (1%) I don't know: 1 (0.3%) I don't know: 2 (1%) I don't know: 0 (0%) Always: 199 (66%) Always: 197 (65%) Always: 204 (68%) Always: 203 (66%) Always: 208 (71%) Only with the first prescription: 59 (19.5%) Only with the first prescription: 63 (21%) Only with the first prescription: 66 (22%) Only with the first prescription: 66 (21%) Only with the first prescription: 55 (19%) Sometimes: 31 (10%) Sometimes: 26 (9%) Sometimes: 27 (9%) Sometimes: 23 (8%) Never: 8 (3%) Never: 3 (1%) Never: 11 (4%) Never: 8 (3%) I don't know: 3 (1%) I don't know: 1 (0.3%) I don't know: 3 (1%) I don't know: 0 (0%) Always: 220 (73%) Always: 220 (73%) Always: 223 (74%) Always: 220 (71%) Always: 232 (79%) Only with the first prescription: 51 (17%) Only with the first prescription: 46 (15%) Only with the first prescription: 52 (17%) Only with the first prescription: 61 (20%) Only with the first prescription: 44 (15%) Sometimes: 25 (8%) Sometimes: 28 (9%) Sometimes: 22 (7%) Sometimes: 19 (6%) Sometimes: 13 (4%) Never: 4 (1%) Never: 5 (2%) Never: 2 (1%) Never: 7 (2%) Never: 5 (2%) Sometimes: 24 (8%) Never: 1 (0.3%) I don't know: 2 (1%) Instruct patients to keep TIRF medicines out of reach of children to prevent accidental exposure. Reference ID: 4190326 FDA_7588 Instruct patients about proper disposal of any unused or partially used TIRF medicines. I don't know: 2 (1%) I don't know: 3 (1%) I don't know: 1 (0.3%) I don't know: 3 (1%) I don't know: 0 (0%) Always: 184 (61%) Always: 187 (62%) Always: 186 (62%) Always: 190 (61%) Always: 197 (67%) Only with the first prescription: 75 (25%) Only with the first prescription: 62 (20.5%) Only with the first prescription: 68 (23%) Only with the first prescription: 74 (24%) Only with the first prescription: 56 (19%) Sometimes: 38 (13%) Sometimes: 37 (12%) Sometimes: 34 (12%) Never: 7 (2%) Never: 6 (2%) Never: 7 (2%) I don't know: 1 (0.3%) I don't know: 3 (1%) I don't know: 0 (0%) Sometimes: 37 (12%) Never: 4 (1%) I don't know: 2 (1%) Sometimes: 37 (12%) Never: 12 (4%) I don't know: 4 (1%) Give patients the Medication Guide for their TIRF medicine. Always: 122 (40%) Always: 142 (47%) Always: 127 (42%) Always: 140 (45%) Always: 130 (44%) Only with the first prescription: 128 (42%) Only with the first prescription: 108 (36%) Only with the first prescription: 124 (41%) Only with the first prescription: 123 (40%) Only with the first prescription: 131 (45%) Sometimes: 26 (9%) Sometimes: 35 (12%) Sometimes: 23 (7%) Sometimes: 17 (6%) Never: 20 (7%) Never: 11 (4%) Never: 21 (7%) Never: 15 (5%) I don't know: 6 (2%) I don't know: 3 (1%) I don't know: 3 (1%) I don't know: 1 (<1%) N/A N/A N/A Always: 223 (76%) Sometimes: 28 (9%) Never: 20 (7%) I don't know: 4 (1%) Talk to the patient about the risks and possible side effects of the TIRF medicine that was most recently prescribed. N/A Only with the first prescription: 53 (18%) Sometimes: 16 (5%) Never: 0 (0%) I don't know: 2 (1%) Instruct the patient on how to use the TIRF medicine that was most recently prescribed. N/A N/A N/A N/A Always: 204 (69%) Only with the first prescription: 67 (23%) Sometimes: 21 (7%) Reference ID: 4190326 FDA_7589 Never: 0 (0%) I don't know: 2 (1%) Instruct the patient on how to store or keep the TIRF medicine that was most recently prescribed. N/A N/A N/A N/A Always: 156 (53%) Only with the first prescription: 102 (35%) Sometimes: 22 (8%) Never: 12 (4%) I don't know: 2 (1%) Reference ID: 4190326 FDA_7590 --------------------------------------------------------------------------------------------------------This is a representation of an electronic record that was signed electronically and this page is the manifestation of the electronic signature. --------------------------------------------------------------------------------------------------------/s/ ---------------------------------------------------IGOR CERNY 12/05/2017 REMS Assessment Review DORIS A AUTH 12/05/2017 CYNTHIA L LACIVITA 12/06/2017 Concur Reference ID: 4190326 FDA_7591