DEPARTMENT OF HEALTH AND HUMAN SERVICES Food and Drug Administration Silver Spring MD 20993 NDA 208147 NDA APPROVAL Tris Pharma Attention: Yulia Pincus, Ph.D. Senior Manager, Regulatory Affairs 2033 Route 130 Monmouth Junction, NJ 08852 Dear Dr. Pincus: Please refer to your New Drug Application (NDA) dated December 18, 2014, and received December 19, 2014, submitted pursuant to section 505(b)(2) of the Federal Food, Drug, and Cosmetic Act (FDCA) for Dyanavel XR (amphetamine) extended-release oral suspension, 2.5 mg amphetamine base per ml. We acknowledge receipt of your amendments dated: January 9, 2015 February 13, 2015 March 2, 2015 March 16, 2015 March 23, 2015 March 31, 2015 April 14, 2015 April 23, 2015 May 8, 2015 May 11, 2015 June 5, 2015 June 12, 2015 July 9, 2015 July 13, 2015 August 13, 2015 August 14, 2015 August 21, 2015 August 26, 2015 August 28, 2015 September 2, 2015 September 28, 2015 October 5, 2015 October 13, 2015 October 15,2015 This new drug application provides for the use of Dyanavel XR (amphetamine) extended-release oral suspension, 2.5 mg amphetamine base per ml for the treatment of Attention Deficit Hyperactivity Disorder (ADHD). We have completed our review of this application, as amended. It is approved, effective on the date of this letter, for use as recommended in the enclosed agreed-upon labeling text. WAIVER OF HIGHLIGHTS SECTION We are waiving the requirements of 21 CFR 201.57(d)(8) regarding the length of Highlights of prescribing information. This waiver applies to all future supplements containing revised labeling unless we notify you otherwise. Reference ID: 3834955 NDA 208147 Page 2 CONTENT OF LABELING As soon as possible, but no later than 14 days from the date of this letter, submit the content of labeling [21 CFR 314.50(l)] in structured product labeling (SPL) format using the FDA automated drug registration and listing system (eLIST), as described at http://www.fda.gov/ForIndustry/DataStandards/StructuredProductLabeling/default.htm. Content of labeling must be identical to the enclosed labeling (text for the package insert, and Medication Guide). Information on submitting SPL files using eLIST may be found in the guidance for industry SPL Standard for Content of Labeling Technical Qs and As, available at http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/U CM072392.pdf. The SPL will be accessible via publicly available labeling repositories. CARTON AND IMMEDIATE CONTAINER LABELS Submit final printed carton and immediate container labels that are identical to the enclosed carton and immediate container labels as soon as they are available, but no more than 30 days after they are printed. Please submit these labels electronically according to the guidance for industry Providing Regulatory Submissions in Electronic Format – Human Pharmaceutical Product Applications and Related Submissions Using the eCTD Specifications (June 2008). Alternatively, you may submit 12 paper copies, with 6 of the copies individually mounted on heavy-weight paper or similar material. For administrative purposes, designate this submission “Final Printed Carton and Container Labels for approved NDA 208147.” Approval of this submission by FDA is not required before the labeling is used. Marketing the product with FPL that is not identical to the approved labeling text may render the product misbranded and an unapproved new drug. REQUIRED PEDIATRIC ASSESSMENTS Under the Pediatric Research Equity Act (PREA) (21 U.S.C. 355c), all applications for new active ingredients, new indications, new dosage forms, new dosing regimens, or new routes of administration are required to contain an assessment of the safety and effectiveness of the product for the claimed indication in pediatric patients unless this requirement is waived, deferred, or inapplicable. We are waiving the pediatric study requirements for ages 0 to 3 years because necessary studies are impossible or highly impracticable. This is because the diagnostic criteria and assessment measures for determining efficacy for the treatment of ADHD in children less than 4 years old are not well defined, and pharmaceutical treatment in this age group is uncommon. We are deferring submission of your pediatric study for ages 4 to 5 years for this application because pediatric studies should be delayed until additional safety or effectiveness data have been collected. At the current time, FDA has limited experience with the study of Reference ID: 3834955 NDA 208147 Page 3 ADHD in younger children (4 to less than 6 years old), so we will defer studies in this younger age group for drugs seeking a claim in ADHD. Your deferred pediatric studies required by section 505B(a) of the FDCA are required postmarketing studies. The status of these postmarketing studies must be reported annually according to 21 CFR 314.81 and section 505B(a)(3)(B) of the FDCA. These required studies are listed below. 2970-1 A single-dose, open-label, randomized pharmacokinetic study of Dyanavel XR (amphetamine extended release) oral suspension in male and female children (4 to less than 6 years of age) with ADHD in fed condition. Final Protocol Submission: Study Completion: Final Report Submission: 2970-2 A randomized, double-blind, placebo-controlled, flexible-dose titration study of Dyanavel XR (amphetamine extended-release) oral suspension in children ages 4 to 5 years diagnosed with ADHD. Final Protocol Submission: Study Completion: Final Report Submission: 2970-3 September 2016 January 2018 July 2018 September 2016 August 2019 February 2020 A one year Pediatric Open-Label Safety Study of patients age 4 to 5 years (at the time of entry into PMR 2970-1 or PMR 2970-2, or at the time of enrollment if directly enrolled into PMR 2970-3) diagnosed with ADHD treated with Dyanavel XR (amphetamine extended release) oral suspension. Final Protocol Submission: Study Completion: Report Submission: September 2016 January 2020 July 2020 Submit the protocols to your IND 116985, with a cross-reference letter to this NDA. Reports of these required pediatric postmarketing studies must be submitted as a new drug application (NDA) or as a supplement to your approved NDA with the proposed labeling changes you believe are warranted based on the data derived from these studies. When submitting the reports, please clearly mark your submission "SUBMISSION OF REQUIRED PEDIATRIC ASSESSMENTS" in large font, bolded type at the beginning of the cover letter of the submission. This product is appropriately labeled for use in ages 6 to 17 years for this indication. Therefore, no additional studies are needed in this pediatric group. Reference ID: 3834955 NDA 208147 Page 4 POSTMARKETING COMMITMENTS NOT SUBJECT TO THE REPORTING REQUIREMENTS UNDER SECTION 506B We remind you of your postmarketing commitment: 2970-4 Develop a dissolution method with enough discriminating ability using a single pH media with appropriate ionic strength. Clarify the effects of pH and ionic strength on the dissolution during the development of the dissolution method. Using the developed method test at least five commercial batches and evaluate the stability for the registration/primary batches through at least 12 months of storage under the long-term conditions. These data should be used for the setting of the final dissolution acceptance criteria. You have the option of evaluating an (b) (4) alternative discriminatory dissolution method (b) (4) in case a common dissolution method cannot be (b) (4) successfully developed for drug product The timetable you submitted on October 5, 2015, states that you will conduct this study according to the following schedule: Final Report Submission: October 2016 Submit nonclinical and chemistry, manufacturing, and controls protocols and all postmarketing final reports to this NDA. In addition, under 21 CFR 314.81(b)(2)(vii) and 314.81(b)(2)(viii) you should include a status summary of each commitment in your annual report to this NDA. The status summary should include expected summary completion and final report submission dates, any changes in plans since the last annual report, and, for clinical studies/trials, number of patients entered into each study/trial. All submissions, including supplements, relating to these postmarketing commitments should be prominently labeled “Postmarketing Commitment Protocol,” “Postmarketing Commitment Final Report,” or “Postmarketing Commitment Correspondence.” PROMOTIONAL MATERIALS You may request advisory comments on proposed introductory advertising and promotional labeling. To do so, submit, in triplicate, a cover letter requesting advisory comments, the proposed materials in draft or mock-up form with annotated references, and the package insert, Medication Guide, and patient PI (as applicable) to: OPDP Regulatory Project Manager Food and Drug Administration Center for Drug Evaluation and Research Office of Prescription Drug Promotion 5901-B Ammendale Road Beltsville, MD 20705-1266 Alternatively, you may submit a request for advisory comments electronically in eCTD format. For more information about submitting promotional materials in eCTD format, see the draft Reference ID: 3834955 NDA 208147 Page 5 Guidance for Industry (available at: http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/U CM443702.pdf ). As required under 21 CFR 314.81(b)(3)(i), you must submit final promotional materials, and the package insert, at the time of initial dissemination or publication, accompanied by a Form FDA 2253. Form FDA 2253 is available at http://www.fda.gov/downloads/AboutFDA/ReportsManualsForms/Forms/UCM083570.pdf. Information and Instructions for completing the form can be found at http://www.fda.gov/downloads/AboutFDA/ReportsManualsForms/Forms/UCM375154.pdf. For more information about submission of promotional materials to the Office of Prescription Drug Promotion (OPDP), see http://www.fda.gov/AboutFDA/CentersOffices/CDER/ucm090142.htm. REPORTING REQUIREMENTS We remind you that you must comply with reporting requirements for an approved NDA (21 CFR 314.80 and 314.81). If you have any questions, contact CDR Renmeet Grewal, Pharm.D., RAC, Team Leader/ Senior Regulatory Project Manager, at either Renmeet.Grewal@fda.hhs.gov or 301-796-1080. Sincerely, {See appended electronic signature page} Mitchell V. Mathis, M.D. Director Division of Psychiatry Products Office of Drug Evaluation I Center for Drug Evaluation and Research Enclosures: Content of Labeling Carton and Container Labeling Reference ID: 3834955 --------------------------------------------------------------------------------------------------------This is a representation of an electronic record that was signed electronically and this page is the manifestation of the electronic signature. --------------------------------------------------------------------------------------------------------/s/ ---------------------------------------------------MITCHELL V Mathis 10/19/2015 Reference ID: 3834955