Selected Requirements of Prescribing Information is the numerical identi?er in parenthesis at the end of each summarized statement or topic. Comment: YES 7. Section headings must be presented in the following order in HL: Section Required/Optional 0 Highlights Heading Required 0 Highlights Limitation Statement Required 0 Product Title Required 0 Initial U.S. Approval Required 0 Boxed Warning Required if a BOXED WARNING is in the FPI - Recent Major Changes Required for only certain changes to Pl* 0 Indications and Usage Required 0 Dosage and Administration Required 0 Dosage Forms and Required 0 Contraindications Required (if no contraindications must state ?None.?) 0 Warnings and Precautions Not required by regulation, but should be present 0 Adverse Reactions Required 0 Drug Interactions Optional 0 Use in Specific Populations Optional 0 Patient Counseling Information Statement Required 0 Revision Date Required RMC only applies to the BOXED WARNING. INDICATIONS AND USAGE. DOSAGE AND ADMINISTRATION. CONTRAINDICATIONS. and WARNINGS AND PRECAUTIONS sections. Comment: HIGHLIGHTS DETAILS Highlights Heading YES 8. At the beginning of HL, the following heading must be bolded and should appear in all UPPER CASE letters: OF PRESCRIBING Comment: Highlights Limitation Statement YES 9. The bolded HL Limitation Statement must include the following verbatim statement: ?These highlights do not include all the information needed to use (insert name of drug product) safely and effectively. See full prescribing information for (insert name of drug product).? The name of drug product should appear in UPPER CASE letters. Comment: Product Title in Highlights YES 10. Product title must be bolded. Comment: Initial U.S. Approval in Highlights NO 11. Initial U.S. Approval in HL must be bolded, and include the verbatim statement ?Initial U.S. Approvalz? followed by the 4-digit year. Comment: The year is missing and should state: 2014 SRPI version 3: October 2013 Page 3 0f 10 Reference ID: 3444524 Selected Requirements of Prescribing Information 20. For a product that has several dosage forms (e.g., capsules, tablets, and injection), bulleted subheadings or tabular presentations of information should be used under the Dosage Forms and Strengths heading. Comment: YES YES Contraindications in Highlights 21. All contraindications listed in the FPI must also be listed in HL or must include the statement “None” if no contraindications are known. Each contraindication should be bulleted when there is more than one contraindication. Comment: Adverse Reactions in Highlights 22. For drug products other than vaccines, the verbatim bolded statement must be present: “To report SUSPECTED ADVERSE REACTIONS, contact (insert name of manufacturer) at (insert manufacturer’s U.S. phone number) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch”. Comment: The sponsor has included a website address "www.hetlioz.com"; according to the Labeling Review Tool, "for manufacturers with a Web site for voluntary reporting of AR, the Web address of the direct link to the site may be included. NOTE: ….. a general link to a company’s website does not meet the requirement to have AR reporting contact information in HL. It would not provide a structured process for reporting AR (e.g., telephone interview, a form, or instructions for reporting). Delete this information if it appears in HL." The website does not appear to be operating so it is not possible to verify if it would be a valid site for AR reporting; recommend deleting the website from the AR statement in HL. Patient Counseling Information Statement in Highlights YES 23. The Patient Counseling Information statement must include one of the following three bolded verbatim statements that is most applicable: If a product does not have FDA-approved patient labeling:  “See 17 for PATIENT COUNSELING INFORMATION” If a product has FDA-approved patient labeling:  “See 17 for PATIENT COUNSELING INFORMATION and FDA-approved patient labeling”  “See 17 for PATIENT COUNSELING INFORMATION and Medication Guide” Comment: NO Revision Date in Highlights 24. The revision date must be at the end of HL, and should be bolded and right justified (e.g., “Revised: 9/2013”). Comment: The revision date is missing and should state: "01/2014". Also, the revision date should be fully right justified on the page and in line with the text. SRPI version 3: October 2013 Reference ID: 3444524 Page 5 of 10 Selected Requirements of Prescribing Information Contents: Table of Contents (TOC) See Appendix A for a sample tool illustrating the format for the Table of Contents. YES YES N/A YES NO NO YES 25. The TOC should be in a two-column format. Comment: 26. The following heading must appear at the beginning of the TOC: “FULL PRESCRIBING INFORMATION: CONTENTS”. This heading should be in all UPPER CASE letters and bolded. Comment: 27. The same heading for the BW that appears in HL and the FPI must also appear at the beginning of the TOC in UPPER CASE letters and bolded. Comment: 28. In the TOC, all section headings must be bolded and should be in UPPER CASE. Comment: 29. In the TOC, all subsection headings must be indented and not bolded. The headings should be in title case [first letter of all words are capitalized except first letter of prepositions (through), articles (a, an, and the), or conjunctions (for, and)]. Comment: In subsections 7.1, 7.2, 8.3, 8.4, 8.5, 12.1 and 13.1 some words in the subheadings are not capitalized and should be (e.g., in 7.1 and 7.2 the word "Inhibitors" should have the first letter capitalized; for the other subsections, see the listing in item #32 below for the correct case). These will also need to be corrected in the corresponding headings in FPI. 30. The section and subsection headings in the TOC must match the section and subsection headings in the FPI. Comment: In the TOC, there is a "." after each section heading number; these are not present in the FPI and should be removed from TOC. Also, the subsection "8.7 Smokers" is in the FPI but missing from TOC. 31. In the TOC, when a section or subsection is omitted, the numbering must not change. If a section or subsection from 201.56(d)(1) is omitted from the FPI and TOC, the heading “FULL PRESCRIBING INFORMATION: CONTENTS” must be followed by an asterisk and the following statement must appear at the end of TOC: “*Sections or subsections omitted from the full prescribing information are not listed.” Comment: SRPI version 3: October 2013 Reference ID: 3444524 Page 6 of 10 Selected Requirements of Prescribing Information N/A Comment: The cross-reference in subsection 8.7 currently reads "see Clinical pharmacology (12.3)" and should read "see Clinical Pharmacology (12.3)". 34. If RMCs are listed in HL, the corresponding new or modified text in the FPI sections or subsections must be marked with a vertical line on the left edge. Comment: FULL PRESCRIBING INFORMATION DETAILS FPI Heading YES N/A N/A YES YES 35. The following heading must be bolded and appear at the beginning of the FPI: “FULL PRESCRIBING INFORMATION”. This heading should be in UPPER CASE. Comment: BOXED WARNING Section in the FPI 36. In the BW, all text should be bolded. Comment: 37. The BW must have a heading in UPPER CASE, containing the word “WARNING” (even if more than one Warning, the term, “WARNING” and not “WARNINGS” should be used) and other words to identify the subject of the Warning (e.g., “WARNING: SERIOUS INFECTIONS and ACUTE HEPATIC FAILURE”). Comment: CONTRAINDICATIONS Section in the FPI 38. If no Contraindications are known, this section must state “None.” Comment: ADVERSE REACTIONS Section in the FPI 39. When clinical trials adverse reactions data are included (typically in the “Clinical Trials Experience” subsection of ADVERSE REACTIONS), the following verbatim statement or appropriate modification should precede the presentation of adverse reactions: “Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.” Comment: N/A 40. When postmarketing adverse reaction data are included (typically in the “Postmarketing Experience” subsection of ADVERSE REACTIONS), the following verbatim statement or appropriate modification should precede the presentation of adverse reactions: “The following adverse reactions have been identified during post-approval use of (insert drug name). Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.” Comment: PATIENT COUNSELING INFORMATION Section in the FPI N/A SRPI version 3: October 2013 Reference ID: 3444524 Page 8 of 10 --------------------------------------------------------------------------------------------------------This is a representation of an electronic record that was signed electronically and this page is the manifestation of the electronic signature. --------------------------------------------------------------------------------------------------------/s/ ---------------------------------------------------ELIZABETH A DONOHOE 01/30/2014 ERIC R BRODSKY 01/30/2014 I agree. Eric Brodsky, SEALD labeling team leader, signing for Sandra Kweder, acting SEALD Division Director. Reference ID: 3444524 1 INTRODUCTION This memorandum evaluates the revised labels for Hetlioz (Tasimelteon) Capsules, NDA 205677, submitted on January 20, 2014 (Appendix A). DMEPA previously reviewed the proposed labels under OSE Review # 2013-1436 dated September 26, 2013 and December 31, 2013. 2 MATERIAL REVIEWED DMEPA reviewed the labels submitted on January 20, 2014. We compared the revised labels against the recommendations contained in OSE Review # 2013-1436 dated September 26, 2013 and December 31, 2013. 3 CONCLUSIONS AND RECOMMENDATIONS The revised labels adequately address our concerns from a medication error perspective. We have no additional comments at this time. Please copy the Division of Medication Error Prevention and Analysis on any communication to the Applicant with regard to this review. If you have further questions or need clarifications, please contact OSE Regulatory Project Manager: Ermias Zerislassie, at 301-796-0097. 1 Page(s) of Draft Labeling have been Withheld in Full as b4 (CCI/TS) immediately following this page 2 Reference ID: 3444059 Department of Health and Human Services Public Health Service Food and Drug Administration Center for Drug Evaluation and Research Office of Surveillance and Epidemiology Office of Medication Error Prevention and Risk Management Label and Braille Label Comprehension Study Review Date: December 31, 2013 Acting Team Leader: Julie Neshiewat, PharmD, BCPS Division of Medication Error Prevention and Analysis Drug Name and Strength: Tasimelteon Capsules, 20 mg Application Type/Number: NDA 205677 Applicant: Vanda Pharmaceuticals OSE RCM #: 2013-1436 *** This document contains proprietary and confidential information that should not be released to the public.*** Reference ID: 3430085 Contents 1 Introduction ................................................................................................................. 1 1.1 Product Information......................................................................................................... 1 2 Methods and Materials Reviewed ............................................................................... 1 3 Medication Error Risk Assessment ............................................................................. 2 3.1 3.2 Revised Labels ................................................................................................................ 2 Braille Label Comprehension Study ............................................................................... 2 4 Conclusions ................................................................................................................. 3 5 Recommendations ....................................................................................................... 3 Appendices.......................................................................................................................... 4 Reference ID: 3430085 3 MEDICATION ERROR RISK ASSESSMENT The sections below discuss our label risk assessment and the results of our review of the Braille Label Comprehension Study. 3.1 REVISED LABELS Review of the revised labels show that the Applicant implemented DMEPA contained in OSE Review 2013-1436 dated September 26, 2013 and recommendations sent via e-mail to the Applicant on November 13, 2013. However, the Review Division has indicated that a Medication Guide is not needed for this product In addition, the Review Division has made revisions to the Dosage and Administration section of the insert labeling which affect the information presented on the container labels. The Usual Dosage statement on the container label should be revised for consistency with the revisions made to the Dosage and Administration section of the insert labeling. 3.2 BRAILLE LABEL COMPREHENSION STUDY Objective Intended patient population can rmderstand the information in Braille presented on the label and distinguish it from other medication bottles Study Design 0 Part 1: 22 Totally Blind Braille Readers were asked to locate a bottle on the table in front of them and asked to read the ?rst and second line of Braille 0 Part 2: 22 Totally Blind non-Braille Readers were asked if they were able to distinguish between two bottles (one bottle label with Braille and one bottle label without Braille) placed in ?'ont of them Results 0 Part 1: 100% of participants identi?ed at least 5 out of the 7 letters and 77% of participants correctly interpreted ?20 mg? 0 Part 2: 100% of participants identi?ed a difference between the two bottles and correctly identi?ed the bottle with the Braille label 0 A majority of subjective feedback referenced poor printing quality of the Braille lettering mwdid not appear more bene?cial than the Braille lettering in distinguishing the Hetlioz medication bottle ??om a similar bottle with a non-Braille label Discussion The Applicant noted the 95% con?dence interval of 59.8 to 94.8 misses the lower bound target of 60 for Braille readers to correctly read the name and strength of Hetlioz; however, given the other positive results of the study, the Applicant concludes the Hetlioz label is adequate for the target population to correctly identify their medication. Reference ID: 3430085 --------------------------------------------------------------------------------------------------------This is a representation of an electronic record that was signed electronically and this page is the manifestation of the electronic signature. --------------------------------------------------------------------------------------------------------/s/ ---------------------------------------------------JULIE V NESHIEWAT 12/31/2013 Reference ID: 3430085 --------------------------------------------------------------------------------------------------------This is a representation of an electronic record that was signed electronically and this page is the manifestation of the electronic signature. --------------------------------------------------------------------------------------------------------/s/ ---------------------------------------------------MELINDA W MCLAWHORN 12/24/2013 Reference ID: 3427917 1 INTRODUCTION On May 31, 2013, Vanda submitted for the Agency’s review a New Drug Application (NDA) for tasimelteon indicated for non-24-Hour Disorder in the totally blind. On July 3, 2013, the DNP requested that the Division of Medical Policy Programs (DMPP) review the Applicant’s proposed Medication Guide (MG) for tasimelteon. This memorandum documents the DMPP review deferral of the Applicant’s proposed Medication Guide (MG) for tasimelteon. 2 CONCLUSIONS Per discussion with DNP, there will be no patient labeling, Medication Guide or Patient Package Insert, approved for this product. Therefore, DMPP defers comment on the Applicant’s submitted patient labeling at this time. Please notify us if you have any questions. 2 Reference ID: 3426022 MEMORANDUM Department of Health and Human Services Food and Drug Administration Center for Drug Evaluation and Research Date: November 26, 2013 To: Eric Basting, M.D., Acting Director Division of Neurology Products Through: Michael Klein, Ph.D., Director Silvia Calderon, Ph.D., Team Leader Controlled Substance Staff From: Katherine Bonson, Ph.D., Pharmacologist Controlled Substance Staff Subject: Tasimelteon (Hetlioz) NDA 205,677 Indication: Treatment for Non-24-Hour Sleep-Wake Disorder in blind individuals Dosage: 20 mg/day (oral) Sponsor: Vanda Pharmaceuticals, Inc. PDUFA Goal Date: July 27, 2014 Materials reviewed: NDA (5/31/13); Pharm/Tox review (Dr. Banks-Muckenfuss, DARRTS 10/30/13) Table of Contents 1 BACKGROUND ................................................................................................................................................2 2 CONCLUSIONS: ...............................................................................................................................................2 3 RECOMMENDATIONS: .................................................................................................................................3 4 DISCUSSION:....................................................................................................................................................3 4.1 PHARMACOLOGY OF DRUG SUBSTANCE .............................................................................................................3 4.1.1 IN VITRO STUDIES ............................................................................................................................3 4.1.2 SAFETY PHARMACOLOGY STUDIES ..................................................................................................3 4.1.3 ABUSE-RELATED ANIMAL STUDIES .................................................................................................4 4.2 ABUSE-RELATED HUMAN STUDIES ...................................................................................................................8 4.2.1 ABUSE-RELATED ADVERSE EVENTS IN CLINICAL STUDIES ..............................................................8 4.2.2 HUMAN PHYSICAL DEPENDENCE STUDY ..........................................................................................8 4.2.3 HUMAN ABUSE POTENTIAL STUDY ...................................................................................................9 Tasimelteon.NDA205677.20131126.CSS Reference ID: 3413692 1 of 10 7) A human abuse potential study was not conducted because there were no abuserelated signs in animal abuse-related studies and because of the similarity between tasimelteon and the unscheduled melatonin agonist, ramelteon. 3. Recommendation: Tasimelteon is not recommended for scheduling under the Controlled Substances Act because there are no signs that the drug produces abuse potential or physical dependence in animal and human studies submitted in the NDA. 4. Discussion: 4.1 Pharmacology of drug substance 4.1.1 In vitro studies 4.1.1.1 Receptor Binding Studies (Study #52253, 52186, 1095880, AA82606, AA85237, AB04244, AB13313, AA98075, AB04243, and AB13314) Receptor binding study reports were submitted for tasimelteon and five of its metabolites (M9, M11, M12, M13 and M14). The M8 metabolite was not evaluated because it is glucuronidated. The receptor binding assays were comprehensive for 170 binding sites and included the following abuse-related CNS receptors: androgen, calcium channels, cannabinoid, dopamine, GABA, glutamate/NMDA, muscarinic, nicotinic, opioid, potassium channel, serotonin, sigma, sodium channel, and various transporters (dopamine, norepinephrine, serotonin, and GABA). Binding of tasimelteon to the abuse-related CNS sites was low (< 10 micromolar). The only sites that showed high affinity for tasimelteon were two melatonin sites (MT1 and MT2), with respective Ki values of 0.3 nM and 0.07 nM. Similarly, the tested metabolites of tasimelteon showed no significant affinity (< 10 micromolar) for any sites other than MT1 and MT2. The respective Ki values for each major metabolite at the MT1 and MT2 sites are as follows: M9 (1,180 nM and 72 nM), M11 (250 nM and 3 nM), M12 (136 nM and 11 nM), M13 (4 nM and 0.9 nM), M14 (103 nM and 4 nM). 4.1.2 Safety Pharmacology Studies 4.1.2.1 General Behavioral Studies According to the pharmacology/toxicology review by Dr. Melissa Banks-Muckenfuss (placed in DARRTS on 10/30/13), the Sponsor did not conduct the standard battery of Tasimelteon.NDA205677.20131126.CSS Reference ID: 3413692 3 of 10 Results: Midazolam produced an inverted U-shaped dose-response curve for self-administration. The highest number of injections was delivered when the dose of midazolam was 0.0125 mg/kg, with a mean injection number of 10 times per session. The dose of 0.005 mg/kg was injected an average of 6.5 times per session, while doses of 0.050 and 0.125 mg/kg were injected an average of 3-4 times per session. This rate is similar to that produced by vehicle for midazolam (4 times per session) and for tasimelteon (3 times per session). In contrast to midazolam, tasimelteon was injected an average of 3-4 times per session for each of the three doses tested (0.625, 1.25 and 2.5 mg/kg). Rats self-administering midazolam at a dose of 0.0125 mg/kg/inj (the training dose) produced significant increases in the number of injections when compared to injections of saline. In contrast, the mean number of injections for doses of 0.625, 1.25 or 2.5 mg/kg/inj tasimelteon was not significantly different relative to the mean number of saline injections self-administered. Sponsor Conclusions: “The results of this study indicate that intravenous self-administration of tasimelteon at doses less than or equal to 2.5 mg/kg/inj did not function as a reinforcer similar to midazolam self-administered at a dose of 0.0125 mg/kg/inj. Additionally, the data indicate that rats positively responded to the effects of the maintenance dose of 0.0125 mg/kg/inj midazolam.” CSS Conclusions: CSS concurs with the Sponsor conclusion that tasimelteon does not function as a reinforcer and produces self-administration levels that are indistinguishable from vehicle. 4.1.3.2 Drug Discrimination Study (Study # 8260770) Study Title: Drug Discrimination Testing in Midazolam Trained Male Sprague-Dawley Rats Administered Tasimelteon or Ramelteon (Study #8260770) Methods: Male rats (n = 13) were trained to discriminate midazolam (3.0 mg/kg, p.o.) from water, initially under an FR1 schedule of reinforcement, increasing over time to FR10. Notably, in this study, any response on the incorrect lever reset the response requirement on the correct lever. The training dose of 3.0 mg/kg was selected on the basis of its use in published drug discrimination studies in rats. A 30 minute pretreatment time was used, but no justification was provided. Tasimelteon.NDA205677.20131126.CSS Reference ID: 3413692 5 of 10 Sponsor Conclusion: “These data indicate that tasimelteon and ramelteon did not produce a discriminative cue that generalized to the training dose of 3 mg/kg midazolam. This indicates that rats did not recognize the stimulus effects of orally administered tasimelteon or ramelteon as similar to the midazolam training cue. The ability to respond on the task, as indicated by response rates on the discrimination, was not compromised at the doses that were fully assessed and did not generalize to midazolam.” CSS Conclusion: There are design flaws in the study protocol which make this study invalid: 1) The challenge sessions with midazolam, tasimelteon and ramelteon may not have been conducted at Tmax. In this study, all drugs were administered orally, which is atypical for drug discrimination because it can produce uneven drug absorption. Although a 30 minute pretreatment time was selected for all drugs, no pharmacokinetic data were provided to verify that this time corresponded to Tmax for midazolam or ramelteon following oral administration. Pharmacokinetic data for tasimelteon following oral administration to rats (provided elsewhere in the NDA) show that the Tmax for males was 4-6 hours, while the Tmax for females was 30 minutes. Since this study used male rats only, the animals were not tested at the time of peak plasma levels for tasimelteon. Thus, it is not possible to conclude that tasimelteon did not generalize to midazolam. 2) Ramelteon was not used as a training drug CSS had recommended the use of ramelteon as a control drug to determine whether tasimelteon generalized to ramelteon, since they both are melatonin agonists. However, the design of this study did not include a comparison of tasimelteon in rats trained to discriminate ramelteon from vehicle. Instead, ramelteon was only tested in midazolam-trained animals. Thus, there are no data showing whether tasimelteon produces interoceptive cues that are similar to those produced by ramelteon. It is important to note that generalization between two drugs in a drug discrimination study is highly dependent on similarity between the pharmacological mechanism of action of the drugs. Thus, even though drugs may produce similar behavioral effects (e.g., sedation), if they do not have similar mechanisms of action, they are not likely to show generalization to each other. Therefore, it is very unlikely that tasimelteon (a melatonin agonist) would have produced full generalization to midazolam (a GABA agonist), even if the study had been conducted at Tmax, since their mechanisms of action are different. This strongly suggests that the lack of a valid drug discrimination study is not a deficit in terms of whether a complete abuse potential assessment has been conducted for tasimelteon. Tasimelteon.NDA205677.20131126.CSS Reference ID: 3413692 7 of 10 by an Estimation Phase for 6 weeks. Twenty patients whose data indicated entrainment to a 24-hour clock participated in a Randomized Withdrawal Phase, in which they received either placebo or 20 mg tasimelteon (n = 10/group) for 8 weeks. During the Randomized Withdrawal Phase, patients continued to complete sleep diaries twice daily, and were contacted by telephone to collect information regarding AEs. All patients completed the Benzodiazepine Withdrawal Symptom Questionnaire (BWSQ) on Days D0, D1, D2, D7, and D14. The BWSQ consists of 20 symptoms and each symptom was rated from 0 to 2. The maximum possible score was 40 with high scores indicating presence of symptoms. Each symptom score, the total score, and the change from Day D0 score were summarized by visit for each treatment group. Results: During the withdrawal phase, there were few AEs. Those patients who continued to receive tasimelteon reported more AEs (n = 1-3 of 10 patients for liver enzyme increase, headache, somnolence/sleep disorder and twitching) compared to those who were switched to placebo and were undergoing tasimelteon discontinuation (n = 1-2 of 10 patients for unspecified AEs in categories of nervous system disorders, urinary disorders and psychiatric disorders). There were no major treatment differences were observed in the BWSQ with scores ranging from 0 to 1 for the placebo group undergoing tasimelteon discontinuation and 0 to 9 for the tasimelteon group between Days 0 and 14. Sponsor Conclusion: “With a maximum possible score of 40, the low scores indicated there were no withdrawal symptoms present in either treatment group.” Thus, the Sponsor concludes that tasimelteon does not produce physical dependence in humans. CSS Conclusion: CSS concurs with the Sponsor that tasimelteon does not produce physical dependence in humans. 4.2.3 Human Abuse Potential Study At a meeting on October 28, 2011, CSS informed the Sponsor that, “A human abuse potential study with tasimelteon will be required if the nonclinical abuse-related studies (drug discrimination and self-administration) show positive signals. However, a human abuse potential study will not be needed if the nonclinical studies were to show that tasimelteon does not maintain self-administration, does not generalize to the proposed positive control benzodiazepine, but does generalize to ramelteon.” At that time, CSS Tasimelteon.NDA205677.20131126.CSS Reference ID: 3413692 9 of 10 --------------------------------------------------------------------------------------------------------This is a representation of an electronic record that was signed electronically and this page is the manifestation of the electronic signature. --------------------------------------------------------------------------------------------------------/s/ ---------------------------------------------------KATHERINE R BONSON 11/26/2013 SILVIA N CALDERON 11/26/2013 MICHAEL KLEIN 11/26/2013 Reference ID: 3413692 Page 3 – Clinical Inspection Summary/NDA 205-677 Investigational Drug Vanda Pharmaceuticals Inc. has developed a novel product to treat subjects who are totally blind and suffer from occasional sleeplessness associated with poor quality or quantity of sleep and excessive sleepiness resulting from a Non-24 hour Sleep-Wake Disorder who are unable to synchronize their endogenous circadian clock to the 24-hour light- dark cycle. Tasimelteon, VEC-162, is a circadian regulator with specific and potent agonist activity at the MTI and MT2 melatonin receptors located primarily at the SCN. The pharmacological properties of tasimelteon and preliminary experience, suggest that tasimelteon may be an effective therapy for patients suffering from N24HSWD. The applicant conducted a study to evaluate the efficacy and safety of 20 mg of tasimelteon versus placebo in blind patients with non-entrained circadian rhythms. Although Tasimelteon is not an NME, it is currently being reviewed as part of an application to treat individuals with N24HSWD to synchronize their circadian clock and improve their physiology and behavior with the 24-hour day. Protocol VP-VEC-162-3201 The study was a multicenter, randomized, double-masked, placebo-controlled, parallel study designed to evaluate the efficacy and safety of 20 mg of tasimelteon versus placebo in patients suffering from Non-24HSWD. The study consisted of a pre-randomization phase known as a screening visit, followed by either a randomization phase or an open-label extension phase. Approximately 84 subjects were randomized in a ratio 1:1 to receive tasimelteon (20 mg/day) or placebo. Qualified subjects were administered one of the following 2 treatment groups:   Tasimelteon 20 mg/day treatment group for 26 weeks Placebo 20 mg/day treatment group for 26 weeks The primary objectives of this study were 1) to determine the efficacy of tasimelteon in patients with N24HSWD as measured by the proportion of entrainment, and 2) to determine the efficacy of tasimelteon in patients with N24HSWD as measured by the proportion of patients with a clinical response. Clinical response was defined as the coincident demonstration of:   Entrainment of the 6-sulfatoxymelatonin (aMT6s) rhythms and A score of equal or greater than 3 on the Non-24 Clinical response Scale (N24CRS). The secondary objectives of this study were: 1) to determine the efficacy of tasimelteon in patients with N24HSWD as measured by the proportion of responders with a combined sleep/wake response for nighttime sleep duration and daytime sleep duration defined as: 1. Increase of 90 minutes or greater in the lower quartile of nights of subjective nighttime total sleep time (LQ-nTST) and 2. Decrease of 90 minutes or greater in the upper quartile of the days of subjective daytime sleep duration (UQ-dTSD). I refer the field investigator to pages 19-20 of the protocol for additional objectives. Reference ID: 3402526 Page 5 – Clinical Inspection Summary/NDA 205-677 Los Angeles Daniel Norman, M.D. St. John Sleep Disorder Center 1301 Twentieth Street, Suite 360 Santa Monica, CA 90404 Site #424 VP-VEF-1623201and 3203 P3201-6pts P3202-2pts 7/24-8/2/13 NAI Key to Classifications NAI = No deviations VAI = Deviation(s) from regulations OAI = Significant deviations from regulations. Data unreliable. Pending = Preliminary classification based on e-mail communication from the field; the EIR has not been received from the field and complete review of EIR is pending. An inspection summary addendum will be generated if conclusions change upon receipt and review of the EIRs. 1. Helene Emsellem, M.D. Chevy Chase, MD 20815 a. What Was Inspected: At this site, 28 subjects were screened, 20 subjects were reported as screen failures, eight subjects were randomized into the study, and three subjects completed the study. Two subjects were terminated early, one subject completed the Open-Label Phase (OLE), and two subjects discontinued the OLE. Review of the Informed Consent Documents, for all subjects records reviewed, verified that subjects signed informed consent forms prior to enrollment. One blind subject listened to an audio version of the informed consent document in the presence of a representative and signed the informed consent document. The medical records/source documents for all subjects were reviewed. The data for primary/secondary endpoints could not be reviewed because the data for the primary efficacy endpoint of entrainment of the 6-sulfaoxymelteonin (aMT6s) present in the urine samples were not analyzed at the site in order to maintain the blind. However, the field investigator was able to confirm that the site physician ordered the collection of urine samples to send the laboratory for analyses. The site received confirmation of receiving the urine samples but not the results. The medical records/source documents for all subjects were reviewed including drug accountability records, vital signs, IRB files, laboratory results, inclusion/exclusion criteria, and use of concomitant medications, and adverse events reporting. Source documents for all subjects were compared to case report forms and data listings except for primary efficacy endpoints. b. General observations/commentary: At the conclusion of the inspection, no Form FDA 483 was issued to Dr. Amsellem. Overall, the medical records reviewed were found to be in order, organized, and the data verifiable. There were no deaths and no evidence of under-reporting of adverse events. There were limitations to the inspection only due to the fact that the primary efficacy endpoints were not available at the site. Reference ID: 3402526 Page 6 – Clinical Inspection Summary/NDA 205-677 c. Assessment of Data Integrity: The data in support of the clinical efficacy and safety at Dr. Emsellem’s site are considered reliable and acceptable in support of the application. 2. Steven Lockley, M. D. Boston, MA 02115 a. What Was Inspected: Protocol VP-VEC-162-3201: At this site, a total of 27 were screened, 20 subjects were reported as screen failures and the reasons were documented. Seven subjects were randomized into the study, and four subjects completed the study. Two subjects were enrolled into the Open-Label Phase of the study and both completed the study. For protocol VP-VEC-162-3202: At this site, a total of four subjects were screened, four subjects randomized, and two subjects completed the study. Review of the Informed Consent Documents, for all subjects reviewed, verified that subjects signed consent forms prior to enrollment. The medical records/source documents for the majority (9) of the subjects in both protocols were reviewed. The data for primary/secondary endpoints could not be reviewed because the data for the primary efficacy endpoint of entrainment of the 6sulfaoxymelteonin (aMT6s) present in the urine samples were not analyzed at the site in order to maintain the blind. However, the field investigator was able to confirm the tau data only (the screening results) that the site physician ordered the collection of urine samples to send the laboratory for analyses. The site received confirmation of receiving the urine samples but not the results. The medical records/source documents for certain subjects were reviewed including drug accountability records, vital signs, IRB files, laboratory results, inclusion/exclusion criteria, and use of concomitant medications, and adverse events reporting. Source documents for all subjects were compared to case report forms and data listings except for primary efficacy endpoints. b. General Observations/Commentary: At the conclusion of the inspection, no Form FDA 483 was issued to Dr. Lockley. The medical records reviewed were found to be in order, organized, and the data verifiable. There were limitations to the inspection only due to the fact that the primary efficacy endpoints were not available at the site. c. Assessment of Data Integrity: The data generated at Dr.Lockley’s site in support of the clinical efficacy and safety are considered acceptable and may be used in support of the pending application. Reference ID: 3402526 Page 8 – Clinical Inspection Summary/NDA 205-677 4. Daniel Norman, M.D. Santa Monica, CA 90404 a. What Was Inspected: Protocol VP-VEC-162-301: At this site, a total of 18 subjects were screened, 11 subjects were reported as screen failures, seven subjects were randomized into the study, and one subject withdrew after randomization; five subjects were randomized into the study and all completed the study. One subject completed the Open-Label Phase of the study. For protocol VP-VEC-162-3202: At this site, a total of four subjects were screened, one subject was reported as a screen failure, one subject withdrew consent, and two subjects were randomized and completed the study. Review of the Informed Consent Documents, for all subjects reviewed, verified that subjects signed consent forms prior to enrollment. The medical records/source documents for a total of 10 subjects in both protocols were reviewed. The data for primary/secondary endpoints could not be reviewed because the data for the primary efficacy endpoint of entrainment of the 6-sulfaoxymelteonin (aMT6s) present in the urine samples were not analyzed at the site in order to maintain the blind. However, the field investigator was able to confirm the tau data only (the screening results) that the site physician ordered the collection of urine samples to send the laboratory for analyses. The site received confirmation of receiving the urine samples but not the results. The medical records/source documents for 10 subjects were reviewed including drug accountability records, vital signs, IRB files, laboratory results, inclusion/exclusion criteria, financial disclosureand use of concomitant medications, and adverse events reporting. Source documents for all subjects were compared to case report forms and data listings except for primary efficacy endpoints. There were no evidence of inaccuracy of the data captured. No FDA 483 was issued. b. General Observations/Commentary: At the conclusion of the inspection, no Form FDA 483 was issued to Dr. Laman. The medical records reviewed were found to be in order, organized, and certain data were verifiable. There were no deaths and no evidence of under-reporting of adverse events. There were known limitations to the inspection due to the fact that the primary efficacy endpointe were not available during the inspection. c. Assessment of Data Integrity: The data submitted in support of the clinical efficacy and safety at Dr. Laman’s site are considered reliable and appear acceptable in support of the pending application. III. OVERALL ASSESSMENT OF FINDINGS AND GENERAL RECOMMENDATIONS Four clinical investigator sites were inspected in support of this application. The inspections of Drs. Emsellem, Lockley, Laman and Norman revealed no regulatory violations, and the final classifications for these inspections are noted above as No Action Indicated (NAI). Reference ID: 3402526 Interdisciplinary Review Team for QT Studies Consultation: Thorough QT Study Review Generic Name 205677 Tasimelteon /VEC-162 Sponsor Vanda Pharmaceuticals, Inc. Indication Non-24-Hour Disorder in the totally blind Dosage Form Capsules Drug Class Human Melatonin Receptor agonist Therapeutic Dosing Regimen 20 mg/day Duration of Therapeutic Use Chronic Maximum Tolerated Dose 300 mg/day Submission Number and Date SDN 000/31 May 2013 NDA DNP Review Division Note: Any text in the review with a light background should be inferred as copied from the sponsor’s document. 1 SUMMARY 1.1 OVERALL SUMMARY OF FINDINGS No significant QTc prolongation effects of VEC-162 (doses of 20 mg and 300 mg) were detected in this TQT study. The largest upper bounds of the 2-sided 90% CI for the mean differences between VEC-162 and placebo were below 10 ms, the threshold for regulatory concern as described in ICH E14 guidelines. The largest lower bound of the 2-sided 90% CI for the ΔΔQTcI for moxifloxacin was greater than 5 ms, and the moxifloxacin profile over time is adequately demonstrated in Figure 3, indicating that assay sensitivity was established. In this randomized, 4-period, multiple-dose, crossover study, 44 healthy subjects received VEC-162 20 mg, VEC-162 300 mg, placebo, and moxifloxacin 400 mg. Overall summary of findings is presented in Table 1. Table 1: The Point Estimates and the 90% CIs Corresponding to the Largest Upper Bounds for VEC-162 (20 mg and 300 mg) and the Largest Lower Bound for Moxifloxacin (FDA Analysis) Treatment Time (hour) ∆∆QTcI (ms) 90% CI (ms) VEC-162 20 mg 2 5.0 (1.8, 8.2) VEC-162 300 mg 2 1.6 (-1.6, 4.7) Moxifloxacin 400 mg* 2 15.7 (12.6. 18.9) * Multiple endpoint adjustment was not applied. The largest lower bound after Bonferroni adjustment for 4 timepoints is 11.4 ms The supratherapeutic dose (300 mg) produces mean Cmax values 13-fold the mean Cmax for the therapeutic dose (20 mg). These concentrations are above those for the predicted worst case scenario of tasimelteon in clinical practice when metabolic inhibitors (CYP1A2 and 2C9) are coadministered. Reference ID: 3385503 2 PROPOSED LABEL QT-IRT’s proposed labeling language is a suggestion only. We defer final labeling decisions to the Division. (b) (4) 3 BACKGROUND 3.1 PRODUCT INFORMATION Tasimelteon is a novel orally active circadian regulator that demonstrates high affinity and agonist activity for both the human melatonin MT1 and MT2 receptors and is being developed for the treatment of Non-24-Hour Disorder in the blind, other Circadian Rhythm Sleep Disorders (CRSD) and mood disorders including Major Depressive Disorder (MDD). 3.2 MARKET APPROVAL STATUS Tasimelteon is not approved for marketing in any country. 3.3 PRECLINICAL INFORMATION From IB, December 2012 Tasimelteon did not produce any statistically significant effects on action potential parameters in isolated rabbit cardiac Purkinje fibers except for a shortening of the APD90 100 μM at 1 s and 0.5 s BCL. Tasimelteon at all three concentrations did not induce statistically significant (P < 0.05) changes in resting membrane potential (RMP), action potential amplitude (APA) and the maximum rate of depolarization (Vmax) at two stimulus intervals. Tasimelteon inhibited hERG current by (Mean ± SEM; n = 3) 14.0 ± 2.2% at 100 μM versus 0.7 ± 0.4% (n = 3) in control. The hERG inhibition at 100 μM was statistically significant (P<0.05) when compared to vehicle control values. Since higher soluble concentrations were not tested, the median inhibitory concentration of tasimelteon on hERG potassium current could not be determined. Reviewer’s comments: Tasimelteon slightly blocks hERG currents with very low affinity (22% inhibition with 100 µM). 3.4 PREVIOUS CLINICAL EXPERIENCE From ISS, eCTD 2.7.4 The current safety data available and incorporated into the Integrated Summary of Safety (ISS) includes data from fourteen Phase I studies, two Phase II studies, and six Phase III studies. Two Phase III open-label safety studies of totally blind adults with a diagnosis of Non-24 are ongoing. In the overall safety database, there were 20 subjects with reported cardiac or cardiac-related adverse events that were treatment-emergent. Of these 20 subjects, 19/1346 (1.4%) occurred in tasimelteon-treated subjects and 1/306 (0.3%) occurred in placebo-treated subjects. As the total person days for the tasimelteon-treated group (N=1346, Mean Exposure = 44.6 days) is over 8 times greater than the total person days for the placebo-treated group (N=306, Mean Exposure = 22.9 days) (ISS Table 1.0.3.2), the difference in the incidence of events between treatment groups is mitigated. Reference ID: 3385503 4.2.4 Objectives Primary objective: To characterize the effect of 20 mg/day and 300 mg/day of VEC-162 on QT intervals in healthy volunteers. Secondary objective: To assess the pharmacokinetic-pharmacodynamic (PK/PD) relationship between plasma concentrations of VEC-162 and its effect, if any, on electrocardiogram (ECG) parameters. 4.2.4.1 Design This was a 4-period, randomized, double-blind (except for the use of moxifloxacin), multipledose, crossover study in healthy men and women. Each treatment period consisted of three dosing days and four washout days. 4.2.4.2 Controls The Sponsor used both placebo and positive (moxifloxacin) controls. 4.2.4.3 Blinding Moxifloxacin was administered as a positive control in an open-label manner. 4.2.5 Treatment Regimen 4.2.5.1 Treatment Arms Subjects took the following study treatments in a random order:  VEC-162, 20 mg orally once a day for three days  VEC-162, 300 mg orally once a day for three days  Moxifloxacin, 400 mg orally on Day 3 (placebo on Days 1 and 2)  Placebo for three days 4.2.5.2 Sponsor’s Justification for Doses The selection and timing of the doses were chosen to meet FDA guidance standards for a thorough ECG trial. The clinical dose of VEC-162 is 20 mg/day. The half-life of VEC-162 is less than three hours, and no accumulation is expected with once-daily dosing. Consequently, steady-state is the same as a single dose and is achieved with the first dose. Three days of dosing was considered sufficient “steady-state” exposure to meet the objectives of this study. The 300-mg supratherapeutic dose of VEC-162 mimics the exposure in healthy volunteers that might occur in the target population under the worst of circumstances, including effects related to the use of concomitant drugs and hepatic impairment. The 400-mg dose of moxifloxacin increases the QT interval in a reliable fashion, and thereby provides a measure of the “assay sensitivity” of the trial. Reviewer’s Comment: Sponsor’s dose selection appeared reasonable. 4.2.5.3 Instructions with Regard to Meals Subjects fasted for 10 hours before dosing (Baseline and Day 3), and remained fasting until four hours after dosing (except for water). Reviewer’s Comment: The sponsor’s instruction on drug administration with regard to food is reasonable because Cmax decreases with a high fat meal.. 4.2.5.4 ECG and PK Assessments ECG data were collected and assessed at 0.5, 1, 2, 3, 4, 5, 6, 8, 10, 12, 14, 18, 23.5 hours after Day 3 tasimelteon dose. The Tmax of tasimelteon is 0.5-2.5 hours and the terminal half-life of tasimelteon is about 1.3 hours. Reference ID: 3385503 Table 3: Sponsor Results ΔΔQTcI for VEC-162 20 mg, VEC-162 300 mg and Moxifloxacin 400 mg VEC-162 20 mg VEC-162 300 mg Moxifloxacin 400 mg Time (h) Estimatea Upper boundb Estimatea Upper boundb Estimatea Upper boundb 0.5 3.2 5.9 0.1 2.8 11.2 15.6 1 1.8 4.6 –0.2 2.5 13.6 18.1 2 5.1 7.9 2.1 4.9 16.0 20.4 3 1.8 4.6 –1.9 0.9 9.8 14.2 4 1.7 4.4 –0.5 2.2 13.0 17.4 5 0.7 3.5 –0.5 2.1 8.3 12.7 6 0.8 3.6 –0.1 2.6 9.3 13.7 8 0.1 2.9 0.3 3.1 6.7 11.2 10 2.3 5.0 1.0 3.7 10.2 14.6 12 0.0 2.7 1.0 3.7 9.7 14.1 14 –0.3 2.4 –1.0 1.7 5.4 9.9 18 –2.1 0.6 –0.9 1.8 7.6 12.0 –0.2 23.5 –3.4 –0.6 6.1 10.6 2.6 a Mixed-model ANOVA is fit for placebo-corrected change from Baseline and includes terms for treatment, gender, time, and a time by treatment interaction. Upper bound = upper 1-sided 95% ANOVA model based confidence limit. (Moxifloxacin is Bonferroni-corrected.) P-value for gender effect (gender main effect and treatment by gender IA) is 0.0079. Treatment*gender IA = 0.1196. Source: Clinical Study Report No., Table 9, Pg 63/652 Reviewer’s Comments: We will provide our independent analysis results in Section 5.2. 4.2.7.2.2 Assay Sensitivity The sponsor used the same mixed model to analyze the ΔQTcI effect for moxifloxacin. The analysis results were presented in Table 3. However, the sponsor did not provide lower bound result. From our independent analysis, the largest unadjusted lower bound 2-sided 90% is 12.6 was greater than 5 ms. Thus, assay sensitivity in this thorough QTcI study was established. 4.2.7.2.3 Categorical Analysis Categorical analysis was used to summarize in the categories of QTc ≤450 ms, between 450 ms and 480 ms, between 480 ms and 500 ms, and >500 ms, and changes from baseline QTc ≤30 ms, between 30 and 60 ms, and >60 ms. No subject’s absolute QTc > 480 ms and ΔQTc >60 ms. 4.2.7.3 Safety Analysis No deaths or SAEs were reported. There were no clinically relevant ECG abnormalities reported, no abnormal T-waves were reported. 4.2.7.4 Clinical Pharmacology 4.2.7.4.1 Pharmacokinetic Analysis Reference ID: 3385503 Figure 2: QT, vs. RR (Each Subject?s Data Points are Connected with a Line) 600 800 1000 1200 1400 interval (ms) 400 - 350 I 600 800 10001200 1400 RR interval (ms) 5.2 STATISTICAL ASSESSMENTS 5.2.1 Analysis 5.2.1.1 The Primary Analysis for the Study Drug The statistical reviewer used mixed model to analyze the effect. The model includes treatment as ?xed effect and baseline values as a covariate. The analysis results are listed in Table 6. The largest upper b01mds of the 2-sided 90% CI for the mean differences between VEC -162 20 mg and placebo, and between 300 mg and placebo are 8.2 ms and 4.7 ms, respectively. Table 6: Analysis Results and Moxi?oxacin 400 mg Placebo 20 mg VIC-162 3 days 300 mg VEC-162 3 days Moxi?oncin 400 mg on Day 3 Time Meal Mean 90% c1 Mean Mean 90-3.1 2.8 (0.0, 5.6) 87 -6.3 -0.4 (-32, 2.4) 84 5.1 11.0 (8.2, 13.8) (7.2, 14.9) 1 -5.5 86 4.2 1.2 (-17, 4.1) 87 -6.0 -0.6 (-34, 2.3) 84 8.0 13.5 (10.6, 16.4) (9.5, 17.4) 2 -6.3 83 -13 5.0 (1.8, 8.2) 86 4.7 1.6 4.7) 84 9.4 15.7 (12.6, 18.9) (11.4, 20.1) 3 -03 85 1.4 1.6 (-12, 4.5) 87 -22 -19 (47, 0.9) 84 9.9 10.2 (7.3, 13.0) (6.3, 14.1) 4 -1.3 85 0.2 1.4 4.5) 87 -22 -09 (40, 2.1) 84 11.3 12.6 (9.5, 15.6) (8.4, 16.8) 5 .0.7 86 -04 0.3 (-22, 2.9) 87 -1.6 -09 (-34, 1.6) 84 7.3 8.0 (5.5, 10.6) (4.6, 11.5) 6 -0.6 85 -0.6 0.1 2.7) 87 ?1.1 ?0.5 2.2) 84 8.2 8.8 (6.2, 11.5) (5.2, 12.4) 8 -0.0 85 0.5 0.5 (-23, 3.3) 85 0.3 0.3 (-25, 3.1) 84 7.1 7.1 (4.3, 9.9) (3.3, 10.9) 10 -0.9 85 0.8 1.7 (-15, 4.8) 87 -05 0.4 (-2.8, 3.5) 84 8.8 9.7 (6.6, 12.9) (5.4, 14.1) 12 -1.1 86 -1.1 0.0 (-2.8, 2.8) 86 -0.8 0.3 (-25, 3.1) 83 8.5 9.6 (6.7, 12.4) (5.7, 13.5) 14 -02 86 -1.1 -09 (-39, 2.1) 87 -1.4 -12 (42, 1.8) 84 5.4 5.6 (2.6, 8.6) (1.4, 9.7) 18 -1.4 86 40 -2.6 (-55, 0.4) 85 -3.1 -17 (47, 1.3) 84 5.8 7.2 (4.2, 10.1) (3.1, 11.2) Reference ID: 3385503 Placebo 20 mg VEC-162 3 days 300 mg VEC-162 3 days Moxi?oxacin 400 mg on Day 3 Time LS LS LS Ls LS LS Mi- (ll) LS Mean Mean Mean 90% CI Mean Mean 90% CI Mean Mean 90% CI 90% CI 23.5 .03 84 _1.2 _o.9 (-3.8, 2.0) 86 _3.7 _3.3 83 5.2 5.5 (2.6, 8.4) (1.5, 9.5) Bonferroni method was applied for multiple endpoint adjustment for 4 time points. 5.2.1.2 Assay Sensitivity Analysis The statistical reviewer used the same statistical model to analyze moxi?oxacin and placebo data. The results are presented in Table 6. The largest lmadjusted of the 2-sided 90% lower con?dence interval is 12.6 ms. By considering Bonfen?oni multiple endpoint adjustment, the largest lower confidence interval is 11.4 ms, which indicates that an at least 5 ms effect due to moxi?oxacin can be detected from the study. 5.2.1.3 Graph of Over Time Figlu'e 3 displays the time pro?le of AAQTCI for different treatment groups and moxi?oxacin 400 mg. Figure 3: Mean and 90% CI Time Course for 20 mg, 300 mg and Moxifloxacin 400 mg 20-. 20 rm 3 chy: ?m0rrgVEO-162 Sdays 18; LS Mean (90Tlme (hour) 5.2.1.4 Categorical Analysis Table 7 lists the number of subjects as well as the number of observations whose values are 450 ms, and between 450 ms and 480 m, and changes from baseline 330 ms, between subject?s is above 480 ms. No subject?s change from baseline is above 60 ms (see Table 8). Reference ID: 3385503 Table 13: Analysis Results of AQRS and AAQRS for VEC-162 20 mg, 300 mg, 5.3 CLINICAL PHARMACOLOGY ASSESSMENTS The mean concentration-time pro?le is illustrated in Figure 4. Reference ID: 3385503 and Moxi?oxacin 400 mg Placebo 20 mg 300 mg Moxi?oxacin 400 AQRS AQRS AAQRS AQRS AAQRS AQRS AAQRS Time LS LS LS LS LS LS (ll) LS Mean Mean Mean 90% CI Mean Mean 90% CI Mean Mean 90% CI 0.5 0.5 86 0.7 0.1 (-1.3, 1.5) 87 0.3 -0.2 (-1.6, 1.2) 84 ?0.7 -1.3 (-2.7, 0.2) 1 0.4 86 0.7 0.3 (-1.0, 1.6) 87 0.3 -0.1 1.2) 84 -0.5 -0.9 (-2.2, 0.4) 2 0.4 83 1.6 1.2 2.6) 86 1.0 0.6 (-0.8, 1.9) 84 0.2 -05 0.8) 3 0.8 85 0.6 _0.2 1.2) 87 0.6 -0.2 1.2) 84 03 .11 (25, 0.2) 4 0.4 85 0.5 0.1 1.5) 87 0.5 0.1 1.4) 84 ?0.3 -0.7 0.6) 5 0.6 86 0.3 03 1.1) 87 1.1 0.5 1.9) 84 07 ?1.3 0.1) 6 0.1 85 0.4 0.3 1.6) 87 0.6 0.5 1.7) 84 ?0.1 -0.3 1.0) 8 0.0 85 0.3 0.3 (-1.0, 1.6) 85 -0.1 -0.2 (-1.5, 1.1) 84 ?0.5 -0.5 0.8) 10 0.1 85 0.2 0.0 (-1.2, 1.3) 87 0.5 0.4 (-0.9, 1.6) 84 -0.2 -0.3 0.9) 12 0.2 86 1.1 0.9 2.1) 86 0.6 0.4 (09, 1.6) 83 0.5 .07 0.5) 14 ?0.6 86 0.6 1.2 2.5) 87 0.9 1.4 (0.1, 2.8) 84 04 0.1 (4.2, 1.4) 18 0.1 86 ?0.4 ?0.5 0.7) 85 0.0 -0.0 1.2) 84 -1.1 -1.1 0.1) 23.5 0.9 84 0.6 1.5 (0.2, 2.7) 86 0.2 1.1 2.3) 83 07 0.2 1.5) Table 14: Categorical Analysis for QRS Total Treatment Group QRS 110 ms QRS 110 ms 20 mg VEC-162 3 days 43 43 (100%) 0 300 mg VEC-162 3 days 44 44 (100%) 0 Moxi?oxacin 400 mg 011 Day 3 42 42 (100%) 0 Placebo 3 days 43 43 (100%) 0 Figure 5: ∆∆QTcI vs. VEC-162 concentration 5.4 CLINICAL ASSESSMENTS 5.4.1 Safety assessments None of the events identified to be of clinical importance per the ICH E 14 guidelines i.e. syncope, seizure, significant ventricular arrhythmias or sudden cardiac death occurred in this study. 5.4.2 ECG assessments Waveforms from the ECG warehouse were reviewed. According to ECG warehouse statistics 94 % of the ECGs were annotated in the primary lead II, with less than 0.5 % of ECGs reported to have significant QT bias, according to the automated algorithm. Overall ECG acquisition and interpretation in this study appears acceptable. 5.4.3 PR and QRS Interval Six subjects had PR > 200 ms without clinically meaningful increase over baseline. An additional subject had a postbaseline PR increase of 78 ms (55% increases over baseline values), postbaseline PR was 225 ms. No subject had a QRS > 110 ms. Reference ID: 3385503 6 APPENDIX 6.1 HIGHLIGHTS OF CLINICAL PHARMACOLOGY Target dose The target dose is 20 mg. (VP-VEC-162-3201 and VP-VEC-162-3203) Maximum tolerated dose 300 mg/day (CN116-001 and VP-VEC-162-1103) Principal Adverse Events The most frequent events reported in Phase 1 studies were somnolence, headache, sleep disorder, and nausea. None of these events occurred at an appreciably more frequent rate in the tasimelteon group compared to the placebo group, and did not appear to be dose-dependent. The safety profile was similar across studies regardless of the dose administered. (Module 2.7.4 Section 4.6 and ISS Table 5.0.5.1.2) Maximum dose Single Dose tested Multiple Dose Exposures Achieved at Maximum Tested Dose Single Dose Multiple Dose 300 mg (CN116-001) 150 mg QD for 28 days (CN116-002) and 300 mg QD for 3 days (VP-VEC-162-1103) Mean ± SD (CV%) Cmax: 1,011 ± 519 ng/ml (51.3%) AUC(inf): 3,230 ± 1,480 ng×hr/ml (45.8%) (CN116-001) Mean ± SD (CV%) 150 mg QD for 28 days: Cmax: 935 ± 379 ng/ml (40%); AUC(inf): 4,038 ± 1,585 ng×hr/ml (39%) (CN116-002) 300 mg QD for 3 days: Cmax: 2,492 ± 1,058 ng/ml (42.5%); AUC(inf): 10,610 ± 5,780 ng×hr/ml (54.9%) (VP-VEC-162-1103) Range of linear In studies with doses ranging from 1- to 300 mg the values of the slopes PK of log- log plots for AUC versus dose were approximately 1, indicating linearity over single doses for this range. (CN116-001, CN116-002, CN116-003, Studies VP- VEC-162-1105, -1106, -1107, -1108, -1110, 1111, and -1112; Module 2.7.2 Accumulation The pharmacokinetics of tasimelteon and its metabolites did not at steady state change with continued QD dosing of tasimelteon 20 mg for 16 days. (VP-VEC-162-1110) Reference ID: 3385503 Cardiac Effects Clinical study VP-VEC-162-1103 demonstrated that tasimelteon showed no signal of any effect on cardiac repolarization. The time-matched analysis for the QTcI endpoint revealed no subject on tasimelteon crossed the 10 msec upper bound for all time points for both the clinical and supratherapeutic doses. The moxifloxacin group met the assay sensitivity criteria as outlined in the statistical plan, and all time points for moxifloxacin were more than five msec. No clinically relevant effect of tasimelteon was noted for heart rate or for PR or QRS interval duration. No new morphologic changes were considered clinically significant. Hepatic Impairment For subjects with mild hepatic impairment, tasimelteon CL/F was reduced to 850 mL/min compared to 1128 mL/min for matched controls. For subjects with moderate hepatic impairment, CL/F was 721 mL/min compared to 1318 mL/min for matched controls. This resulted in a corresponding increase in exposure, as measured by AUC(inf), of 144% and 189% in subjects with mild and moderate hepatic impairment, respectively, less for the metabolites. The geometric mean ratios (GMR) of tasimelteon Cmax for subjects with mild or moderate hepatic impairment were 122.15% and 118.51%, respectively, as compared to healthy matched Consistent with the lack of renal excretion as a pathway of elimination for tasimelteon, there was no apparent relationship between tasimelteon CL/F and renal function as measured by either creatinine clearance (CLcr) or estimated glomerular filtration rate (eGFR). Two of tasimelteon’s metabolites, M3 and M9, could potentially accumulate in patients with severe renal impairment and/or ESRD patients. In patients with renal impairment, the clinical significance of the projected accumulation rates in Renal Impairment 19 Reference ID: 3385503 Administration of rifampin 600 mg once daily for 11 days resulted in a mean decrease in exposure of approximately 89% and Cmax of 83% after a single 20 mg dose of tasimelteon. Efficacy may be reduced when tasimelteon is used in combination with strong CYP3A4 inducers such as rifampin. A dose adjustment may be considered. (VP- VEC-1621112) Ethanol In a healthy volunteer study where 0.6 g/kg for women and 0.7 g/kg for men of ethanol (2-5 standard alcohol drinks) over 15 minutes was co-administered with 20 mg tasimelteon no additive effects were seen on psychomotor performance or memory task. (VPVEC-162-1106) Food Effects Expected High Clinical Exposure Scenario There is a 44% reduction in the Cmax of tasimelteon in healthy volunteers fed a high fat/high calorie meal compared to fasted individual. Tmax increases from 0.75 hours to 2.5 hours in fasted versus fed subjects. There is no food effect on the total AUC. (VP-VEC-162-1102) Fluvoxamine is a strong CYP1A2 and CYP2C19 inhibitor and is also classified as a weak inhibitor of CYP2C8, 2C9 and 3A4. The effect of combined inhibition of CYP1A2 and 2C19 with at least some impact on other enzymes involved in the metabolism of tasimelteon, namely CYP2C9 and 3A4 likely approximates a near worst-case scenario. At a dose of 20 mg tasimelteon, the expected AUC would be approximately 2804 h×ng/mL which is well below the mean AUC observed after supratherapeutic dosing with 300 mg tasimelteon (AUC = 3,230 ± 1,480 ng×hr/ml). (VP-VEC-162-1111 and CN116-001) 21 Reference ID: 3385503 Extrinsic Factors Renal Impairment Consistent with the lack of renal excretion as a pathway of elimination for tasimelteon, there was no apparent relationship between tasimelteon CL/F and renal function as measured by either creatinine clearance (CLcr) or estimated glomerular filtration rate (eGFR). Two of tasimelteon’s metabolites, M3 and M9, could potentially accumulate in patients with severe renal impairment and/or ESRD patients. In patients with renal impairment, the clinical significance of the projected accumulation rates in either ESRD (20% for M9 and at least 135% for M3) or severely impaired patients (120% for M3) is unknown but not expected to be a safety concern. Therefore, reducing the daily clinical recommended dose is not deemed necessary. The geometric mean ratios (GMR) of tasimelteon Cmax for subjects with end stage renal disease or severe renal impairment were 95.66% and 143.22%, respectively, as compared to healthy matched control subjects. The GMRs of tasimelteon AUC for subjects with end stage renal disease or severe renal impairment were 102.23% and 141.80%, respectively, as compared to healthy matched control subjects. (VP-VEC-1621106) DDI: Tasimelteon as a Perpetrator Repeated daily oral dosing of 20 mg tasimelteon QD for16 days did not induce CYP2C8 using rosiglitazone as a substrate. (VP-VEC-162-1110) Repeated daily oral dosing of 20 mg tasimelteon QD for 14 days did not induce CYP3A4 using midazolam as a substrate. (VP-VEC-162-1110) Consistent with the major role of CYP1A2 in the metabolism of tasimelteon, administration of fluvoxamine increased tasimelteon exposure by approximately 700%, and the Cmax by approximately 200%, compared to tasimelteon administered alone. Tasimelteon should be administered with caution in combination with fluvoxamine or other strong CYP1A2 inhibitors. (VPVEC-162-1111) Induction of CYP1A2 by cigarette smoking decreased exposure and Cmax of tasimelteon by approximately 40% as compared to the exposure in subjects that did not smoke. A dose adjustment may be considered. (VP-VEC-162-1107) DDI: Tasimelteon as a Victim 23 Reference ID: 3385503 --------------------------------------------------------------------------------------------------------This is a representation of an electronic record that was signed electronically and this page is the manifestation of the electronic signature. --------------------------------------------------------------------------------------------------------/s/ ---------------------------------------------------MOH JEE NG 10/07/2013 QIANYU DANG 10/07/2013 HONGSHAN LI 10/07/2013 KEVIN M KRUDYS 10/07/2013 MONICA L FISZMAN 10/07/2013 NORMAN L STOCKBRIDGE 10/07/2013 Reference ID: 3385503 Contents 1 Introduction ................................................................................................................. 1 1.1 Product Information ............................................................................................. 1 2 Methods and Materials Reviewed ............................................................................... 1 3 Medication Error Risk Assessment ............................................................................. 1 4 Conclusions ................................................................................................................. 2 5 Recommendations ....................................................................................................... 2 Appendices.......................................................................................................................... 4 Reference ID: 3379883 increase the prominence of important information, such as the strength. The original container is a rmit-of-use bottle and the label contains Braille for the product name and strength, which may be helpful to the patient. Therefore, we recommend including a statement to dispense the product in the original container and to affix the pharmacy label so it does not cover the Braille. Important information about M4) appears in the insert labeling and should be added to the Medication Guide. In addition, the insert labeling states to take 20 mg (4) at the same time every night. It is lurclear if there is a time frame that is acceptable. This issue was discussed with the Medical Of?cer (MO) and will be addressed at future labeling meetings. (5) (4) The Applicant submitted a Braille Comprehension Study Protocol for the container label. We recommend asking the participant to read what is presented on the container label instead of speci?cally asking for the medication name and strength on the container label. 4 CONCLUSIONS DMEPA concludes that the proposed labels and labeling can be improved to increase the readability and prominence of important information on the label to promote the safe use of the product. Additionally, the acceptability of the Braille on the container label will be a separate review issue that depends on the results of the Braille Comprehension Study. 5 RECOMMENDATIONS Based on this review, DMEPA recommends the following be implemented prior to approval of this NDA: A. to the Division 1. General At the time of the Braille Label Comprehension Study request for the container label, we were unaware the Applicant proposed (we) 2. Insert Labeling 4 . M) at the same tune a. In Section 2, it states to take 20 mg every night. It is rmclear if there is a time frame that is acceptable. If data is available, we recommend adding the acceptable time frame for takin the medication each night or removing the term 0' (4) (4) (4) Reference ID: 3379883 --------------------------------------------------------------------------------------------------------This is a representation of an electronic record that was signed electronically and this page is the manifestation of the electronic signature. --------------------------------------------------------------------------------------------------------/s/ ---------------------------------------------------JULIE V NESHIEWAT 09/26/2013 IRENE Z CHAN 09/27/2013 Reference ID: 3379883 RPM FILING REVIEW (Including Memo of Filing Meeting) To be completed for all new NDAs, BLAs, and Efficacy Supplements [except SE8 (labeling change with clinical data) and SE9 (manufacturing change with clinical data] Application Information NDA # 205677 NDA Supplement #:SEfficacy Supplement Type SEBLA# BLA Supplement # Proprietary Name: Hetlioz (pending) Established/Proper Name: tasimelteon Dosage Form: capsules, oral Strengths: 20 mg Applicant: Vanda Pharmaceuticals, Inc. Agent for Applicant (if applicable): Date of Application: May 31, 2013 Date of Receipt: May 31, 2013 Date clock started after UN: PDUFA Goal Date: January 31, 2014 Action Goal Date (if different): Filing Date: July 30, 2013 Date of Filing Meeting: July 11, 2013 Chemical Classification: (1,2,3 etc.) (original NDAs only) 1 Proposed indication(s)/Proposed change(s): Non-24 hour sleep-wake disorder in blind patients without light perception Type of Original NDA: AND (if applicable) Type of NDA Supplement: 505(b)(1) 505(b)(2) 505(b)(1) 505(b)(2) If 505(b)(2): Draft the “505(b)(2) Assessment” review found at: http://inside.fda.gov:9003/CDER/OfficeofNewDrugs/ImmediateOffice/UCM027499 and refer to Appendix A for further information. Review Classification: Standard Priority If the application includes a complete response to pediatric WR, review classification is Priority. If a tropical disease priority review voucher was submitted, review classification is Priority. Resubmission after withdrawal? Part 3 Combination Product? If yes, contact the Office of Combination Products (OCP) and copy them on all Inter-Center consults Version: 5/10/13 Reference ID: 3347295 Tropical Disease Priority Review Voucher submitted Resubmission after refuse to file? Convenience kit/Co-package Pre-filled drug delivery device/system (syringe, patch, etc.) Pre-filled biologic delivery device/system (syringe, patch, etc.) Device coated/impregnated/combined with drug Device coated/impregnated/combined with biologic Separate products requiring cross-labeling Drug/Biologic Possible combination based on cross-labeling of separate products Other (drug/device/biological product) 1 User Fee Status Payment for this application: If a user fee is required and it has not been paid (and it is not exempted or waived), the application is unacceptable for filing following a 5-day grace period. Review stops. Send Unacceptable for Filing (UN) letter and contact user fee staff. Paid X Exempt (orphan) Waived (e.g., small business, public health) Not required Payment of other user fees: If the firm is in arrears for other fees (regardless of whether a user fee has been paid for this application), the application is unacceptable for filing (5-day grace period does not apply). Review stops. Send UN letter and contact the user fee staff. Not in arrears In arrears 505(b)(2) YES NO (NDAs/NDA Efficacy Supplements only) Is the application for a duplicate of a listed drug and eligible for approval under section 505(j) as an ANDA? Is the application for a duplicate of a listed drug whose only difference is that the extent to which the active ingredient(s) is absorbed or otherwise made available to the site of action is less than that of the reference listed drug (RLD)? [see 21 CFR 314.54(b)(1)]. Is the application for a duplicate of a listed drug whose only difference is that the rate at which the proposed product’s active ingredient(s) is absorbed or made available to the site of action is unintentionally less than that of the listed drug [see 21 CFR 314.54(b)(2)]? NA Comment x If you answered yes to any of the above questions, the application may be refused for filing under 21 CFR 314.101(d)(9). Contact the 505(b)(2) review staff in the Immediate Office of New Drugs Is there unexpired exclusivity on any drug product containing the active moiety (e.g., 5-year, 3-year, orphan, or pediatric exclusivity)? Check the Electronic Orange Book at: http://www.accessdata.fda.gov/scripts/cder/ob/default.cfm If yes, please list below: Application No. Drug Name Exclusivity Code Exclusivity Expiration If there is unexpired, 5-year exclusivity remaining on the active moiety for the proposed drug product, a 505(b)(2) application cannot be submitted until the period of exclusivity expires (unless the applicant provides paragraph IV patent certification; then an application can be submitted four years after the date of approval.) Pediatric exclusivity will extend both of the timeframes in this provision by 6 months. 21 CFR 314.108(b)(2). Unexpired, 3year exclusivity may block the approval but not the submission of a 505(b)(2) application. Exclusivity Does another product (same active moiety) have orphan exclusivity for the same indication? Check the Orphan Drug Version: 5/10/13 Reference ID: 3347295 YES NO NA Comment X 3 If no, ensure that language requesting submission of the form is included in the acknowledgement letter sent to the applicant Debarment Certification YES Is a correctly worded Debarment Certification included with authorized signature? x NO NA Comment NO NA Comment NO NA Comment NO NA Comment Certification is not required for supplements if submitted in the original application; If foreign applicant, both the applicant and the U.S. Agent must sign the certification [per Guidance for Industry: Submitting Debarment Certifications]. Note: Debarment Certification should use wording in FD&C Act Section 306(k)(1) i.e.,“[Name of applicant] hereby certifies that it did not and will not use in any capacity the services of any person debarred under section 306 of the Federal Food, Drug, and Cosmetic Act in connection with this application.” Applicant may not use wording such as, “To the best of my knowledge…” Field Copy Certification (NDAs/NDA efficacy supplements only) YES For paper submissions only: Is a Field Copy Certification (that it is a true copy of the CMC technical section) included? x Field Copy Certification is not needed if there is no CMC technical section or if this is an electronic submission (the Field Office has access to the EDR) If maroon field copy jackets from foreign applicants are received, return them to CDR for delivery to the appropriate field office. Controlled Substance/Product with Abuse Potential For NMEs: Is an Abuse Liability Assessment, including a proposal for scheduling, submitted per 21 CFR 314.50(d)(5)(vii)? YES x If yes, date consult sent to the Controlled Substance Staff: 6/6/13 For non-NMEs: Date of consult sent to Controlled Substance Staff : Pediatrics PREA YES x Orphan – Prea exempt Does the application trigger PREA? If yes, notify PeRC RPM (PeRC meeting is required) 2 Note: NDAs/BLAs/efficacy supplements for new active ingredients, new indications, new dosage forms, new dosing regimens, or new routes of administration trigger PREA. All waiver & deferral requests, pediatric plans, and pediatric assessment studies must be 2 http://inside.fda.gov:9003/CDER/OfficeofNewDrugs/PediatricandMaternalHealthStaff/ucm027829.htm Version: 5/10/13 Reference ID: 3347295 6 reviewed by PeRC prior to approval of the application/supplement. If the application triggers PREA, are the required pediatric assessment studies or a full waiver of pediatric studies included? If studies or full waiver not included, is a request for full waiver of pediatric studies OR a request for partial waiver and/or deferral with a pediatric plan included? If no, request in 74-day letter If a request for full waiver/partial waiver/deferral is included, does the application contain the certification(s) required by FDCA Section 505B(a)(3) and (4)? If no, request in 74-day letter x BPCA (NDAs/NDA efficacy supplements only): Is this submission a complete response to a pediatric Written Request? If yes, notify Pediatric Exclusivity Board RPM (pediatric exclusivity determination is required) 3 Proprietary Name YES Is a proposed proprietary name submitted? x NO NA Comment Review pending If yes, ensure that the application is also coded with the supporting document category, “Proprietary Name/Request for Review.” REMS YES NO NA x Is a REMS submitted? Comment Med Guide only If yes, send consult to OSE/DRISK and notify OC/ OSI/DSC/PMSB via the CDER OSI RMP mailbox Prescription Labeling Check all types of labeling submitted. Not applicable X Package Insert (PI) Patient Package Insert (PPI) Instructions for Use (IFU) X Medication Guide (MedGuide) X Carton labels X Immediate container labels Diluent Other (specify) YES Is Electronic Content of Labeling (COL) submitted in SPL 3 NO NA Comment x http://inside.fda.gov:9003/CDER/OfficeofNewDrugs/PediatricandMaternalHealthStaff/ucm027837.htm Version: 5/10/13 Reference ID: 3347295 7 If yes, specify consult(s) and date(s) sent: Meeting Minutes/SPAs YES End-of Phase 2 meeting(s)? Date(s): 1.6.11 x NO NA Comment If yes, distribute minutes before filing meeting Pre-NDA/Pre-BLA/Pre-Supplement meeting(s)? Date(s): 2.21.13 x If yes, distribute minutes before filing meeting Any Special Protocol Assessments (SPAs)? Date(s): 10.28.11 x If yes, distribute letter and/or relevant minutes before filing meeting Version: 5/10/13 Reference ID: 3347295 9 Clinical Pharmacology TL: R. Farkas Reviewer: J. Parepally A. Bhattaram K.Riviere (biopharm) A. Men A.Dorentes (biopharm) Y Y Y Y N Reviewer: J. Luan N TL: K. Jin Y Reviewer: M. Banks-Muckenfuss Y TL: L. Freed Y K. Lin N R. Kambhampati M. Ramanadham M. Heimann B. Riley (micro CMC) R. Sood Y Y Y N Reviewer: J. Neshiewat Y TL: I.Chan N Reviewer: N/A TL: Biostatistics Nonclinical (Pharmacology/Toxicology) Statistics (carcinogenicity) Reviewer: TL: Immunogenicity (assay/assay validation) (for BLAs/BLA efficacy supplements) Reviewer: Product Quality (CMC) Reviewer: TL: TL: Quality Microbiology (for sterile products) Reviewer: TL: CMC Labeling Review Reviewer: TL: Facility Review/Inspection Reviewer: TL: OSE/DMEPA (proprietary name) OSE/DRISK (REMS) Version: 5/10/13 Reference ID: 3347295 11 REFUSE TO FILE Comments: review issues for 60 day filing letter • Clinical study site(s) inspections(s) needed? Review issues for 74-day letter X YES NO If no, explain: • Advisory Committee Meeting needed? Comments: New NME X YES Date if known: 11.14.13 NO To be determined If no, for an NME NDA or original BLA , include the reason. For example: o this drug/biologic is not the first in its class o the clinical study design was acceptable o the application did not raise significant safety or efficacy issues o the application did not raise significant public health questions on the role of the drug/biologic in the diagnosis, cure, mitigation, treatment or prevention of a disease Reason: • Not Applicable X FILE REFUSE TO FILE Abuse Liability/Potential Comments: • If the application is affected by the AIP, has the division made a recommendation regarding whether or not an exception to the AIP should be granted to permit review based on medical necessity or public health significance? Review issues for 74-day letter X Not Applicable YES NO Comments: CLINICAL MICROBIOLOGY Comments: CLINICAL PHARMACOLOGY Comments: • Clinical pharmacology study site(s) inspections(s) Version: 5/10/13 Reference ID: 3347295 Not Applicable X FILE REFUSE TO FILE Review issues for 74-day letter Not Applicable X FILE REFUSE TO FILE Review issues for 74-day letter YES 13 • Is a comprehensive and readily located list of all clinical sites included or referenced in the application? X YES NO • Is a comprehensive and readily located list of all manufacturing facilities included or referenced in the application? X YES NO REGULATORY PROJECT MANAGEMENT Signatory Authority: Ellis Unger, M.D., Director, ODE I Date of Mid-Cycle Meeting (for NME NDAs/BLAs in “the Program” PDUFA V): 9.12.13 21st Century Review Milestones (see attached) (listing review milestones in this document is optional): Comments: there are potential CMC review issues but CMC has recommended filing the application REGULATORY CONCLUSIONS/DEFICIENCIES The application is unsuitable for filing. Explain why: X The application, on its face, appears to be suitable for filing. Review Issues: No review issues have been identified for the 74-day letter. X Review issues have been identified for the 74-day letter. List (optional): 60 day letter Review Classification: Standard Review X Priority Review ACTIONS ITEMS Ensure that any updates to the review priority (S or P) and classifications/properties are entered into tracking system (e.g., chemical classification, combination product classification, 505(b)(2), orphan drug). If RTF, notify everybody who already received a consult request, OSE PM, and Product Quality PM (to cancel EER/TBP-EER). If filed, and the application is under AIP, prepare a letter either granting (for signature by Center Director) or denying (for signature by ODE Director) an exception for review. BLA/BLA supplements: If filed, send 60-day filing letter Version: 5/10/13 Reference ID: 3347295 16 If priority review: • notify sponsor in writing by day 60 (For BLAs/BLA supplements: include in 60-day filing letter; For NDAs/NDA supplements: see CST for choices) • notify OMPQ (so facility inspections can be scheduled earlier) Send review issues/no review issues by day 74 Conduct a PLR format labeling review and include labeling issues in the 74-day letter Update the PDUFA V DARRTS page (for NME NDAs in the Program) BLA/BLA supplements: Send the Product Information Sheet to the product reviewer and the Facility Information Sheet to the facility reviewer for completion. Ensure that the completed forms are forwarded to the CDER RMS-BLA Superuser for data entry into RMS-BLA one month prior to taking an action [These sheets may be found in the CST eRoom at: http://eroom.fda.gov/eRoom/CDER2/CDERStandardLettersCommittee/0 1685f ] Other Version: 5/10/13 Reference ID: 3347295 17 Selected Requirements of Prescribing Information (SRPI) Required • Product Title Required • Initial U.S. Approval Required if a Boxed Warning is in the FPI • Boxed Warning Required for only certain changes to PI* • Recent Major Changes Required • Indications and Usage Required • Dosage and Administration Required • Dosage Forms and Strengths Required (if no contraindications must state “None.”) • Contraindications Not required by regulation, but should be present • Warnings and Precautions Required • Adverse Reactions Optional • Drug Interactions Optional • Use in Specific Populations • Patient Counseling Information Statement Required Required • Revision Date * RMC only applies to the Boxed Warning, Indications and Usage, Dosage and Administration, Contraindications, and Warnings and Precautions sections. YES Comment: Specific sub-sections added. 7. A horizontal line must separate HL and Table of Contents (TOC). Comment: HIGHLIGHTS DETAILS YES YES Highlights Heading 8. At the beginning of HL, the following heading must be bolded and appear in all UPPER CASE letters: “HIGHLIGHTS OF PRESCRIBING INFORMATION”. Comment: Highlights Limitation Statement 9. The bolded HL Limitation Statement must be on the line immediately beneath the HL heading and must state: “These highlights do not include all the information needed to use (insert name of drug product in UPPER CASE) safely and effectively. See full prescribing information for (insert name of drug product in UPPER CASE).” Comment: YES Product Title 10. Product title in HL must be bolded. Comment: YES Initial U.S. Approval 11. Initial U.S. Approval in HL must be placed immediately beneath the product title, bolded, and include the verbatim statement “Initial U.S. Approval:” followed by the 4-digit year. Comment: N/A Boxed Warning 12. All text must be bolded. Comment: N/A SRPI version 2: Last Updated May 2012 Reference ID: 3328270 Page 2 of 7 Selected Requirements of Prescribing Information (SRPI) 13. Must have a centered heading in UPPER-CASE, containing the word “WARNING” (even if N/A N/A N/A N/A N/A N/A N/A YES YES more than one Warning, the term, “WARNING” and not “WARNINGS” should be used) and other words to identify the subject of the Warning (e.g., “WARNING: SERIOUS INFECTIONS”). Comment: 14. Must always have the verbatim statement “See full prescribing information for complete boxed warning.” centered immediately beneath the heading. Comment: 15. Must be limited in length to 20 lines (this does not include the heading and statement “See full prescribing information for complete boxed warning.”) Comment: 16. Use sentence case for summary (combination of uppercase and lowercase letters typical of that used in a sentence). Comment: Recent Major Changes (RMC) 17. Pertains to only the following five sections of the FPI: Boxed Warning, Indications and Usage, Dosage and Administration, Contraindications, and Warnings and Precautions. Comment: 18. Must be listed in the same order in HL as they appear in FPI. Comment: 19. Includes heading(s) and, if appropriate, subheading(s) of labeling section(s) affected by the recent major change, together with each section’s identifying number and date (month/year format) on which the change was incorporated in the PI (supplement approval date). For example, “Dosage and Administration, Coronary Stenting (2.2) --- 3/2012”. Comment: 20. Must list changes for at least one year after the supplement is approved and must be removed at the first printing subsequent to one year (e.g., no listing should be one year older than revision date). Comment: Indications and Usage 21. If a product belongs to an established pharmacologic class, the following statement is required in the Indications and Usage section of HL: [(Product) is a (name of class) indicated for (indication)].” Comment: No pharmacologic class given; TBD Dosage Forms and Strengths 22. For a product that has several dosage forms, bulleted subheadings (e.g., capsules, tablets, injection, suspension) or tabular presentations of information is used. Comment: SRPI version 2: Last Updated May 2012 Reference ID: 3328270 Page 3 of 7 Selected Requirements of Prescribing Information (SRPI) 11 DESCRIPTION 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action 12.2 Pharmacodynamics 12.3 Pharmacokinetics 12.4 Microbiology (by guidance) 12.5 Pharmacogenomics (by guidance) 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility 13.2 Animal Toxicology and/or Pharmacology 14 CLINICAL STUDIES 15 REFERENCES 16 HOW SUPPLIED/STORAGE AND HANDLING 17 PATIENT COUNSELING INFORMATION Comment: Subsections added as per product-specific. YES YES N/A N/A N/A N/A YES 39. FDA-approved patient labeling (e.g., Medication Guide, Patient Information, or Instructions for Use) must not be included as a subsection under Section 17 (Patient Counseling Information). All patient labeling must appear at the end of the PI upon approval. Comment: Missing Medication Guide (MGs are class labeling for sedative-hypnotics). 40. The preferred presentation for cross-references in the FPI is the section heading (not subsection heading) followed by the numerical identifier in italics. For example, [see Warnings and Precautions (5.2)]. Comment: 41. If RMCs are listed in HL, the corresponding new or modified text in the FPI sections or subsections must be marked with a vertical line on the left edge. Comment: FULL PRESCRIBING INFORMATION DETAILS Boxed Warning 42. All text is bolded. Comment: 43. Must have a heading in UPPER-CASE, containing the word “WARNING” (even if more than one Warning, the term, “WARNING” and not “WARNINGS” should be used) and other words to identify the subject of the Warning (e.g., “WARNING: SERIOUS INFECTIONS”). Comment: 44. Use sentence case (combination of uppercase and lowercase letters typical of that used in a sentence) for the information in the Boxed Warning. Comment: Contraindications 45. If no Contraindications are known, this section must state “None”. Comment: Will verify this labeling statement at filing meeting 6/27/13. Adverse Reactions NO SRPI version 2: Last Updated May 2012 Reference ID: 3328270 Page 6 of 7 Selected Requirements of Prescribing Information (SRPI) 46. When clinical trials adverse reactions data is included (typically in the “Clinical Trials Experience” subsection of Adverse Reactions), the following verbatim statement or appropriate modification should precede the presentation of adverse reactions: “Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.” Comment: Missing this statement. N/A 47. When postmarketing adverse reaction data is included (typically in the “Postmarketing Experience” subsection of Adverse Reactions), the following verbatim statement or appropriate modification should precede the presentation of adverse reactions: “The following adverse reactions have been identified during post-approval use of (insert drug name). Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.” Comment: NO Patient Counseling Information 48. Must reference any FDA-approved patient labeling, include the type of patient labeling, and use one of the following statements at the beginning of Section 17: • “See FDA-approved patient labeling (Medication Guide)” • “See FDA-approved patient labeling (Medication Guide and Instructions for Use)” • “See FDA-approved patient labeling (Patient Information)" • “See FDA-approved patient labeling (Instructions for Use)" • “See FDA-approved patient labeling (Patient Information and Instructions for Use)” Comment: Medication Guide (MG) missing; reference to MG missing. SRPI version 2: Last Updated May 2012 Reference ID: 3328270 Page 7 of 7 SEALD Director Sign-Off Review of the End?of?Cycle Prescribing Information: Outstanding Format De?ciencies Product Title1 (tasimelteon) capsules, for oral use Applicant Vanda Pharmaceuticals Inc. Application] Supplement Number NDA 205677 Type of Application Original Indication(s) treatment of Non-24-Hour Sleep-Wake Disorder (N on-24) Of?ce/Division ODE Division Project Manager Cathy Michaloski Date FDA Received Application May 31, 2014 Goal Date January 31, 2014 Date PI Received by SEALD January 29, 2014 SEALD Review Date January 30, 2014 SEALD Labeling Reviewer Elizabeth Donohoe I Acting SEALD Division Director I Sandra Kweder I 1 Product Title that appears in draft agreed-upon prescribing information (PI) This Study Endpoints and Labeling Development (SEALD) Director sign-off review of the end-of-cycle, prescribing information (PI) for important format items reveals outstanding format de?ciencies that should be corrected before taking an approval action. After these outstanding format de?ciencies are corrected, the SEALD Director will have no objection to the approval of this PI. The Selected Requirements of Prescribing Information (SRPI) is a checklist of 42 important format PI items based on labeling regulations [21 FR 201.56(d) and 201.57] and guidances. The word ?must? denotes that the item is a regulatory requirement, while the word ?should? denotes that the item is based on guidance. Each SRPI item is assigned with one of the following three responses: 0 NO: The PI does not meet the requirement for this item (de?ciency). 0 YES: The PI meets the requirement for this item (not a de?ciency). 0 This item does not apply to the speci?c Plunder review (not applicable). Reference ID: 3444524 Selected Requirements of Prescribing Information is the numerical identi?er in parenthesis at the end of each summarized statement or topic. Comment: YES 7. Section headings must be presented in the following order in HL: Section Required/Optional 0 Highlights Heading Required 0 Highlights Limitation Statement Required 0 Product Title Required 0 Initial U.S. Approval Required 0 Boxed Warning Required if a BOXED WARNING is in the FPI - Recent Major Changes Required for only certain changes to Pl* 0 Indications and Usage Required 0 Dosage and Administration Required 0 Dosage Forms and Required 0 Contraindications Required (if no contraindications must state ?None.?) 0 Warnings and Precautions Not required by regulation, but should be present 0 Adverse Reactions Required 0 Drug Interactions Optional 0 Use in Specific Populations Optional 0 Patient Counseling Information Statement Required 0 Revision Date Required RMC only applies to the BOXED WARNING. INDICATIONS AND USAGE. DOSAGE AND ADMINISTRATION. CONTRAINDICATIONS. and WARNINGS AND PRECAUTIONS sections. Comment: HIGHLIGHTS DETAILS Highlights Heading YES 8. At the beginning of HL, the following heading must be bolded and should appear in all UPPER CASE letters: OF PRESCRIBING Comment: Highlights Limitation Statement YES 9. The bolded HL Limitation Statement must include the following verbatim statement: ?These highlights do not include all the information needed to use (insert name of drug product) safely and effectively. See full prescribing information for (insert name of drug product).? The name of drug product should appear in UPPER CASE letters. Comment: Product Title in Highlights YES 10. Product title must be bolded. Comment: Initial U.S. Approval in Highlights NO 11. Initial U.S. Approval in HL must be bolded, and include the verbatim statement ?Initial U.S. Approvalz? followed by the 4-digit year. Comment: The year is missing and should state: 2014 SRPI version 3: October 2013 Page 3 0f 10 Reference ID: 3444524 Selected Requirements of Prescribing Information 20. For a product that has several dosage forms (e.g., capsules, tablets, and injection), bulleted subheadings or tabular presentations of information should be used under the Dosage Forms and Strengths heading. Comment: YES YES Contraindications in Highlights 21. All contraindications listed in the FPI must also be listed in HL or must include the statement “None” if no contraindications are known. Each contraindication should be bulleted when there is more than one contraindication. Comment: Adverse Reactions in Highlights 22. For drug products other than vaccines, the verbatim bolded statement must be present: “To report SUSPECTED ADVERSE REACTIONS, contact (insert name of manufacturer) at (insert manufacturer’s U.S. phone number) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch”. Comment: The sponsor has included a website address "www.hetlioz.com"; according to the Labeling Review Tool, "for manufacturers with a Web site for voluntary reporting of AR, the Web address of the direct link to the site may be included. NOTE: ….. a general link to a company’s website does not meet the requirement to have AR reporting contact information in HL. It would not provide a structured process for reporting AR (e.g., telephone interview, a form, or instructions for reporting). Delete this information if it appears in HL." The website does not appear to be operating so it is not possible to verify if it would be a valid site for AR reporting; recommend deleting the website from the AR statement in HL. Patient Counseling Information Statement in Highlights YES 23. The Patient Counseling Information statement must include one of the following three bolded verbatim statements that is most applicable: If a product does not have FDA-approved patient labeling:  “See 17 for PATIENT COUNSELING INFORMATION” If a product has FDA-approved patient labeling:  “See 17 for PATIENT COUNSELING INFORMATION and FDA-approved patient labeling”  “See 17 for PATIENT COUNSELING INFORMATION and Medication Guide” Comment: NO Revision Date in Highlights 24. The revision date must be at the end of HL, and should be bolded and right justified (e.g., “Revised: 9/2013”). Comment: The revision date is missing and should state: "01/2014". Also, the revision date should be fully right justified on the page and in line with the text. SRPI version 3: October 2013 Reference ID: 3444524 Page 5 of 10 Selected Requirements of Prescribing Information Full Prescribing Information (FPI) FULL PRESCRIBING INFORMATION: GENERAL FORMAT YES 32. The bolded section and subsection headings in the FPI must be named and numbered in accordance with 21 CFR 201.56(d)(1) as noted below (section and subsection headings should be in UPPER CASE and title case, respectively). If a section/subsection required by regulation is omitted, the numbering must not change. Additional subsection headings (i.e., those not named by regulation) must also be bolded and numbered. BOXED WARNING 1 INDICATIONS AND USAGE 2 DOSAGE AND ADMINISTRATION 3 DOSAGE FORMS AND STRENGTHS 4 CONTRAINDICATIONS 5 WARNINGS AND PRECAUTIONS 6 ADVERSE REACTIONS 7 DRUG INTERACTIONS 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy 8.2 Labor and Delivery 8.3 Nursing Mothers 8.4 Pediatric Use 8.5 Geriatric Use 9 DRUG ABUSE AND DEPENDENCE 9.1 Controlled Substance 9.2 Abuse 9.3 Dependence 10 OVERDOSAGE 11 DESCRIPTION 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action 12.2 Pharmacodynamics 12.3 Pharmacokinetics 12.4 Microbiology (by guidance) 12.5 Pharmacogenomics (by guidance) 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility 13.2 Animal Toxicology and/or Pharmacology 14 CLINICAL STUDIES 15 REFERENCES 16 HOW SUPPLIED/STORAGE AND HANDLING 17 PATIENT COUNSELING INFORMATION YES Comment: 33. The preferred presentation for cross-references in the FPI is the section (not subsection) heading followed by the numerical identifier. The entire cross-reference should be in italics and enclosed within brackets. For example, “[see Warnings and Precautions (5.2)]” or “[see Warnings and Precautions (5.2)]”. SRPI version 3: October 2013 Reference ID: 3444524 Page 7 of 10 Selected Requirements of Prescribing Information N/A 41. Must reference any FDA-approved patient labeling in Section 17 (PATIENT COUNSELING INFORMATION section). The reference should appear at the beginning of Section 17 and include the type(s) of FDA-approved patient labeling (e.g., Patient Information, Medication Guide, Instructions for Use). Comment: 42. FDA-approved patient labeling (e.g., Medication Guide, Patient Information, or Instructions for Use) must not be included as a subsection under section 17 (PATIENT COUNSELING INFORMATION). All FDA-approved patient labeling must appear at the end of the PI upon approval. Comment: SRPI version 3: October 2013 Reference ID: 3444524 Page 9 of 10 --------------------------------------------------------------------------------------------------------This is a representation of an electronic record that was signed electronically and this page is the manifestation of the electronic signature. --------------------------------------------------------------------------------------------------------/s/ ---------------------------------------------------ELIZABETH A DONOHOE 01/30/2014 ERIC R BRODSKY 01/30/2014 I agree. Eric Brodsky, SEALD labeling team leader, signing for Sandra Kweder, acting SEALD Division Director. Reference ID: 3444524 1 INTRODUCTION This memorandum evaluates the revised labels for Hetlioz (Tasimelteon) Capsules, NDA 205677, submitted on January 20, 2014 (Appendix A). DMEPA previously reviewed the proposed labels under OSE Review # 2013-1436 dated September 26, 2013 and December 31, 2013. 2 MATERIAL REVIEWED DMEPA reviewed the labels submitted on January 20, 2014. We compared the revised labels against the recommendations contained in OSE Review # 2013-1436 dated September 26, 2013 and December 31, 2013. 3 CONCLUSIONS AND RECOMMENDATIONS The revised labels adequately address our concerns from a medication error perspective. We have no additional comments at this time. Please copy the Division of Medication Error Prevention and Analysis on any communication to the Applicant with regard to this review. If you have further questions or need clarifications, please contact OSE Regulatory Project Manager: Ermias Zerislassie, at 301-796-0097. 1 Page(s) of Draft Labeling have been Withheld in Full as b4 (CCI/TS) immediately following this page 2 Reference ID: 3444059 --------------------------------------------------------------------------------------------------------This is a representation of an electronic record that was signed electronically and this page is the manifestation of the electronic signature. --------------------------------------------------------------------------------------------------------/s/ ---------------------------------------------------JULIE V NESHIEWAT 01/29/2014 Reference ID: 3444059 Contents 1 Introduction ................................................................................................................. 1 1.1 Product Information......................................................................................................... 1 2 Methods and Materials Reviewed ............................................................................... 1 3 Medication Error Risk Assessment ............................................................................. 2 3.1 3.2 Revised Labels ................................................................................................................ 2 Braille Label Comprehension Study ............................................................................... 2 4 Conclusions ................................................................................................................. 3 5 Recommendations ....................................................................................................... 3 Appendices.......................................................................................................................... 4 Reference ID: 3430085 Since the strength was the main misinterpretation of Braille, we considered if the stren in Braille is needed 'ven the ro osed roduct is sin stren received from the stud the A licant ro oses to This proposal appears reasonable and we ?nd the Braille Label Comprehension study acceptable. A certi?cate of translation will also be requested to ensure the proposed Braille is accurate. 4 CONCLUSIONS DMEPA concludes that the proposed labels can be improved to clarify information. 5 RECOMMENDATIONS Based on this review, DMEPA recommends the following be implemented prior to approval of this NDA: A. Comments to the Applicant 1. Container Label a. Since your proposed product will not have a Medication Guide, remove the statement b. For consistency with the Dosage and Administration section of the insert labelin revise the statement to read similar to ?Usual at the same . See full dosage: 20 mg per day taken before bedtime, time every night. Hetlioz should be taken wi out 00 prescribing information.? If you have further questions or need clari?cations, please contact Ermias Zerislassie, project manager, at 301-796-0097. Reference ID: 3430085 --------------------------------------------------------------------------------------------------------This is a representation of an electronic record that was signed electronically and this page is the manifestation of the electronic signature. --------------------------------------------------------------------------------------------------------/s/ ---------------------------------------------------JULIE V NESHIEWAT 12/31/2013 Reference ID: 3430085 Department of Health and Human Services Public Health Service Food and Drug Administration Center for Drug Evaluation and Research Office of Medical Policy Initiatives Division of Medical Policy Programs REVIEW DEFERRAL MEMORANDUM Date: December 20, 2013 To: Eric Bastings, M.D. Director (Acting) Division of Neurology Products (DNP) Through: LaShawn Griffiths, MSHS-PH, BSN, RN Associate Director for Patient Labeling Division of Medical Policy Programs (DMPP) Melissa Hulett, MSBA, BSN, RN Team Leader, Patient Labeling Division of Medical Policy Programs (DMPP) From: Twanda Scales, BSN MSN/Ed. Patient Labeling Reviewer Division of Medical Policy Programs (DMPP) Subject: Review Deferred: Medication Guide (MG) Drug Name (established name): tasimelteon Dosage Form and Route: Capsules Application Type/Number: 205677 Applicant: Vanda Pharmaceuticals, Inc. (Vanda) 1 Reference ID: 3426022 --------------------------------------------------------------------------------------------------------This is a representation of an electronic record that was signed electronically and this page is the manifestation of the electronic signature. --------------------------------------------------------------------------------------------------------/s/ ---------------------------------------------------TWANDA D SCALES 12/20/2013 MELISSA I HULETT 12/20/2013 Reference ID: 3426022 1. Background This memorandum responds to a consult request by the Division of Neurology Products to evaluate the abuse potential of tasimelteon, based on receptor binding data, a selfadministration study and a drug discrimination study in rats. Tasimelteon and its major metabolites have picomolar affinity at melatonin receptors (MT1 and MT2) but no significant affinity (> 10 micromolar) at other CNS relevant sites. This mechanism of action is identical to that of ramelteon, a drug approved to treat insomnia that is not scheduled under the Controlled Substances Act (CSA). The Sponsor has proposed that tasimelteon not be scheduled under the CSA, based on preclinical and clinical data in the NDA. Tasimelteon (20 mg/day) is proposed for the treatment of Non-24-Hour Disorder in blind individuals with no light perception, a circadian rhythm disorder that occurs when individuals are unable to entrain (synchronize) their endogenous master body clock to the 24-hour day-night cycle. Tasimelteon was granted an orphan drug designation for this indication. Tasimelteon was previously investigated for other indications (insomnia, Circadian Rhythm Sleep Disorders, and Jet Lag Disorder due to eastward travel) but development for these indications was discontinued. 2. Conclusions: 1) Tasimelteon and its major metabolites do not have affinity for any CNS sites other than melatonin sites in receptor binding studies. Melatonin sites are not associated with abuse potential. 2) The Sponsor did not conduct abuse-related general behavioral studies. However, the behavioral signs from toxicology studies in animals do not show abuse-related signals. 3) Tasimelteon was not self-administered and is therefore unlikely to have rewarding properties. 4) The drug discrimination study with tasimelteon is not valid because animals were tested prior to Tmax. However, given that tasimelteon is a melatonin agonist, it is unlikely that it would have generalized to midazolam, a GABA agonist used as the training drug in this study. 5) Tasimelteon did not produce any abuse-related adverse events in clinical studies. 6) Tasimelteon did not induce any signs or symptoms of withdrawal in patients with Non-24, following chronic drug administration and subsequent drug discontinuation. Thus, tasimelteon does not produce physical dependence. Tasimelteon.NDA205677.20131126.CSS Reference ID: 3413692 2 of 10 safety pharmacology studies with tasimelteon, including any studies that evaluate CNS safety pharmacology. Thus, there are no preclinical data related to general behavior induced by tasimelteon, including those that would be part of the Irwin test. In the preclinical toxicology studies conducted with tasimelteon, there were no behavioral signs in mice, rats, rabbits or monkeys at doses that produced plasma levels similar to those produced by proposed therapeutic doses in humans. In rats, behavioral signs were not present at doses that were similar to the dose ranges used in the abuse-related studies (self-administration and drug discrimination, see below). At very high doses tested for toxicological purposes, behavioral signs in rats included hypoactivity, ataxia, loss of righting reflex, tremors and ptosis. Given that tasimelteon is indicated for treatment of a sleeping disorder, these behaviors are to be expected and are not indicative of a sedative with abuse potential. 4.1.3 Abuse-Related Animal Studies 4.1.3.1 Self-Administration Study (Study # 8260771) Study Title: Potential Intravenous Self-Administration of Tasimelteon in Male SpragueDawley Rats Trained to Self-Administer Midazolam Methods: Male Sprague-Dawley rats (n = 10) were initially trained to press a lever to obtain foodreinforcement under a fixed-ratio 5 (FR5) schedule of reinforcement. Rats were then exposed to a training dose of 0.0125 mg/kg/inj midazolam (i.v.) during one-hour training sessions under an FR5 schedule. Three test doses of midazolam (0.005, 0.05 and 0.125 mg/kg/inj, i.v.) were also evaluated under an FR5 schedule to establish a dose-response curve. The midazolam training and test doses were based on scientific literature. Response to the training drug (midazolam) was considered stable when the number of injections maintained under midazolam was within 30% variability across three consecutive sessions or four out of five sessions. Response was also considered stable if the number of injections maintained under midazolam increased less than 10% over three sessions of daily availability. The effect of tasimelteon was then evaluated by substituting vehicle, escalating doses of tasimelteon (0.625, 1.25 or 2.5 mg/kg/inj, i.v.), or 0.0125 mg/kg/inj midazolam (i.v.) for self-administration. Doses of tasimelteon were selected following a pharmacokinetic study (Study #8267772). The lowest dose of 0.625 mg/kg was expected to provide tasimelteon exposure similar to the Cmax in humans at the proposed 20 mg therapeutic dose, while the highest dose of 2.5 mg/kg provides exposure several times higher than the mean human Cmax. Similarly, at the 2.5 mg/kg dose level, the exposure to the tasimelteon metabolites in humans (M9, M12, M13, and M14) are expected to be similar to or higher than the mean human Cmax. The 1.25 mg/kg dose was then chosen as the intermediate dose. Tasimelteon.NDA205677.20131126.CSS Reference ID: 3413692 4 of 10 Results: Midazolam produced an inverted U-shaped dose-response curve for self-administration. The highest number of injections was delivered when the dose of midazolam was 0.0125 mg/kg, with a mean injection number of 10 times per session. The dose of 0.005 mg/kg was injected an average of 6.5 times per session, while doses of 0.050 and 0.125 mg/kg were injected an average of 3-4 times per session. This rate is similar to that produced by vehicle for midazolam (4 times per session) and for tasimelteon (3 times per session). In contrast to midazolam, tasimelteon was injected an average of 3-4 times per session for each of the three doses tested (0.625, 1.25 and 2.5 mg/kg). Rats self-administering midazolam at a dose of 0.0125 mg/kg/inj (the training dose) produced significant increases in the number of injections when compared to injections of saline. In contrast, the mean number of injections for doses of 0.625, 1.25 or 2.5 mg/kg/inj tasimelteon was not significantly different relative to the mean number of saline injections self-administered. Sponsor Conclusions: “The results of this study indicate that intravenous self-administration of tasimelteon at doses less than or equal to 2.5 mg/kg/inj did not function as a reinforcer similar to midazolam self-administered at a dose of 0.0125 mg/kg/inj. Additionally, the data indicate that rats positively responded to the effects of the maintenance dose of 0.0125 mg/kg/inj midazolam.” CSS Conclusions: CSS concurs with the Sponsor conclusion that tasimelteon does not function as a reinforcer and produces self-administration levels that are indistinguishable from vehicle. 4.1.3.2 Drug Discrimination Study (Study # 8260770) Study Title: Drug Discrimination Testing in Midazolam Trained Male Sprague-Dawley Rats Administered Tasimelteon or Ramelteon (Study #8260770) Methods: Male rats (n = 13) were trained to discriminate midazolam (3.0 mg/kg, p.o.) from water, initially under an FR1 schedule of reinforcement, increasing over time to FR10. Notably, in this study, any response on the incorrect lever reset the response requirement on the correct lever. The training dose of 3.0 mg/kg was selected on the basis of its use in published drug discrimination studies in rats. A 30 minute pretreatment time was used, but no justification was provided. Tasimelteon.NDA205677.20131126.CSS Reference ID: 3413692 5 of 10 Sponsor Conclusion: “These data indicate that tasimelteon and ramelteon did not produce a discriminative cue that generalized to the training dose of 3 mg/kg midazolam. This indicates that rats did not recognize the stimulus effects of orally administered tasimelteon or ramelteon as similar to the midazolam training cue. The ability to respond on the task, as indicated by response rates on the discrimination, was not compromised at the doses that were fully assessed and did not generalize to midazolam.” CSS Conclusion: There are design flaws in the study protocol which make this study invalid: 1) The challenge sessions with midazolam, tasimelteon and ramelteon may not have been conducted at Tmax. In this study, all drugs were administered orally, which is atypical for drug discrimination because it can produce uneven drug absorption. Although a 30 minute pretreatment time was selected for all drugs, no pharmacokinetic data were provided to verify that this time corresponded to Tmax for midazolam or ramelteon following oral administration. Pharmacokinetic data for tasimelteon following oral administration to rats (provided elsewhere in the NDA) show that the Tmax for males was 4-6 hours, while the Tmax for females was 30 minutes. Since this study used male rats only, the animals were not tested at the time of peak plasma levels for tasimelteon. Thus, it is not possible to conclude that tasimelteon did not generalize to midazolam. 2) Ramelteon was not used as a training drug CSS had recommended the use of ramelteon as a control drug to determine whether tasimelteon generalized to ramelteon, since they both are melatonin agonists. However, the design of this study did not include a comparison of tasimelteon in rats trained to discriminate ramelteon from vehicle. Instead, ramelteon was only tested in midazolam-trained animals. Thus, there are no data showing whether tasimelteon produces interoceptive cues that are similar to those produced by ramelteon. It is important to note that generalization between two drugs in a drug discrimination study is highly dependent on similarity between the pharmacological mechanism of action of the drugs. Thus, even though drugs may produce similar behavioral effects (e.g., sedation), if they do not have similar mechanisms of action, they are not likely to show generalization to each other. Therefore, it is very unlikely that tasimelteon (a melatonin agonist) would have produced full generalization to midazolam (a GABA agonist), even if the study had been conducted at Tmax, since their mechanisms of action are different. This strongly suggests that the lack of a valid drug discrimination study is not a deficit in terms of whether a complete abuse potential assessment has been conducted for tasimelteon. Tasimelteon.NDA205677.20131126.CSS Reference ID: 3413692 7 of 10 provided feedback to the Sponsor on a protocol for a human abuse potential study, in case preclinical data showed abuse-related signals. Sponsor Conclusion: The preclinical data do not show any abuse-related signals, so a human abuse potential study was not conducted or submitted in the NDA. CSS Conclusion: CSS concurs with the Sponsor that the receptor binding, drug discrimination, and selfadministration studies do not show an abuse potential signal. Therefore, a human abuse potential study conducted with tasimelteon is not necessary. Tasimelteon.NDA205677.20131126.CSS Reference ID: 3413692 10 of 10 --------------------------------------------------------------------------------------------------------This is a representation of an electronic record that was signed electronically and this page is the manifestation of the electronic signature. --------------------------------------------------------------------------------------------------------/s/ ---------------------------------------------------KATHERINE R BONSON 11/26/2013 SILVIA N CALDERON 11/26/2013 MICHAEL KLEIN 11/26/2013 Reference ID: 3413692 Page 2 – Clinical Inspection Summary/NDA 205-677 CONSULTATION REQUEST DATE: June 20, 2013 DIVISION ACTION GOAL DATE: January 30, 2014 INSPECTION SUMMARY GOAL DATE: N/A PDUFA DATE: January 30, 2014 I. BACKGROUND: Many biological processes, including melatonin and cortisol secretion, sleep–wake patterns, alertness, performance patterns, metabolism and cardiovascular processes have a circadian component. Circadian rhythms are regulated by an endogenous circadian pacemaker that in mammals resides in the suprachiasmatic nuclei (SCN) of the hypothalamus, which spontaneously generates circadian rhythms within a period of 24 hours, and in turn regulates biological functions controlled by the clock. Circadian rhythms are precisely synchronized (entrained) to the 24-hour day by exposure to environmental time cues, the strongest of which is the daily light-dark cycle, which is detected exclusively by the eyes. In the absence of light (most blind people), the primary environmental synchronizer is lost and the circadian rhythms will follow the non-24 hour-period of the endogenous circadian pacemaker. Non-24 Hour Sleep-Wake Disorder (N24HSWD), occurs when individuals are unable to synchronize their endogenous circadian clock to the 24-hour light-dark cycle. The majority of reported cases of N24HSWD occur in blind people with conscious perception of light. The disorder is associated with significant clinical symptoms and increases risk of errors, accidents, and attention lapses which can be mistakenly diagnosed as insomnia, rather than as a result of a non-entrained circadian clock. For blind individuals, the sleeplessness and daytime fatigue that results from being blind non-entrained have profound impacts on their social and occupational lives and can be considered the most disabling aspects of their blindness. The ultimate goal in treating individuals with N24HSWD was to synchronize their circadian clock with the 24-hour day so that all of their physiology and behavior is aligned appropriately with the 24- hour social day. Two clinical trials were submitted in support of the application: Protocols VP-VEC-162-3201 and VP-VEC-162-3203. Protocols: VP-VEC-162-3201 entitled “A Multicenter, Randomized, Double-Mask, Placebo-Controlled, Parallel Study to Investigate the Efficacy and Safety of 20 mg Tasimelteon Versus Placebo in Totally Blind Subjects with N24HSWD Followed by an OLE Phase” and VP-VEC-162-3203 entitled “A Randomized, Withdrawal Study to Demonstrate the Maintenance of Effect of 20 mg Tasimelteon in the Treatment of N24HSWD’. Reference ID: 3402526 Page 5 – Clinical Inspection Summary/NDA 205-677 Los Angeles Daniel Norman, M.D. St. John Sleep Disorder Center 1301 Twentieth Street, Suite 360 Santa Monica, CA 90404 Site #424 VP-VEF-1623201and 3203 P3201-6pts P3202-2pts 7/24-8/2/13 NAI Key to Classifications NAI = No deviations VAI = Deviation(s) from regulations OAI = Significant deviations from regulations. Data unreliable. Pending = Preliminary classification based on e-mail communication from the field; the EIR has not been received from the field and complete review of EIR is pending. An inspection summary addendum will be generated if conclusions change upon receipt and review of the EIRs. 1. Helene Emsellem, M.D. Chevy Chase, MD 20815 a. What Was Inspected: At this site, 28 subjects were screened, 20 subjects were reported as screen failures, eight subjects were randomized into the study, and three subjects completed the study. Two subjects were terminated early, one subject completed the Open-Label Phase (OLE), and two subjects discontinued the OLE. Review of the Informed Consent Documents, for all subjects records reviewed, verified that subjects signed informed consent forms prior to enrollment. One blind subject listened to an audio version of the informed consent document in the presence of a representative and signed the informed consent document. The medical records/source documents for all subjects were reviewed. The data for primary/secondary endpoints could not be reviewed because the data for the primary efficacy endpoint of entrainment of the 6-sulfaoxymelteonin (aMT6s) present in the urine samples were not analyzed at the site in order to maintain the blind. However, the field investigator was able to confirm that the site physician ordered the collection of urine samples to send the laboratory for analyses. The site received confirmation of receiving the urine samples but not the results. The medical records/source documents for all subjects were reviewed including drug accountability records, vital signs, IRB files, laboratory results, inclusion/exclusion criteria, and use of concomitant medications, and adverse events reporting. Source documents for all subjects were compared to case report forms and data listings except for primary efficacy endpoints. b. General observations/commentary: At the conclusion of the inspection, no Form FDA 483 was issued to Dr. Amsellem. Overall, the medical records reviewed were found to be in order, organized, and the data verifiable. There were no deaths and no evidence of under-reporting of adverse events. There were limitations to the inspection only due to the fact that the primary efficacy endpoints were not available at the site. Reference ID: 3402526 Page 7 – Clinical Inspection Summary/NDA 205-677 3. Paul.D Laman, Jr., M.D. Pittsburg, PA 15025 a. What Was Inspected: Protocol VP-VEC-162-301: At this site, a total of 15 subjects were screened, seven subjects were reported as screen failures and the reasons were documented. Four subjects were randomized into the study, and all completed the study. Four subjects were not eligible for randomization, and three of the four subjects who were not eligible for randomization were enrolled in the Open-Label Phase of the study. For protocol VP-VEC-162-3202: At this site, a total of six subjects were screened, three were reported as screen failures, and three subjects randomized and completed the study. Review of the Informed Consent Documents, for all subjects reviewed, verified that subjects signed consent forms prior to enrollment. The medical records/source documents for a total of (11) subjects in both protocols were reviewed. The data for primary/secondary endpoints could not be reviewed because the data for the primary efficacy endpoint of entrainment of the 6-sulfaoxymelteonin (aMT6s) present in the urine samples were not analyzed at the site in order to maintain the blind. However, the field investigator was able to confirm the tau data only (the screening results) that the site physician ordered the collection of urine samples to send the laboratory for analyses. The site received confirmation of receiving the urine samples but not the results. The medical records/source documents for 11 subjects were reviewed including drug accountability records, vital signs, IRB files, laboratory results, inclusion/exclusion criteria, and use of concomitant medications, and adverse events reporting. Source documents for all subjects were compared to case report forms and data listings except for primary efficacy endpoints. There were no evidence of inaccuracy of the data captured. However, the field investigator discussed with the clinical investigator (b) (6) the failure to perform urine pregnancy test on Subject at Visits 2, 3 and 4 in (b) (6) error. Subsequent visits revealed negative pregnancy results. Subject had an abnormal EKG in which the clinical investigator decided the ECG changes were not considered as an adverse event. Thus, the impact of these errors was minor. b. General Observations/Commentary: At the conclusion of the inspection, no Form FDA 483 was issued to Dr. Laman. The medical records reviewed were found to be in order, organized, and certain data were verifiable. There were no deaths and no evidence of under-reporting of adverse events. There were known limitations to the inspection due to the fact that the primary efficacy endpoints were not available at the site for review. c. Assessment of Data Integrity: The data submitted in support of the clinical efficacy and safety at Dr. Laman’s site are considered reliable and appear acceptable in support of the pending application. Reference ID: 3402526 Page 9 – Clinical Inspection Summary/NDA 205-677 Overall, the data submitted from these four sites are considered acceptable in support of the pending application. {See appended electronic signature page} Antoine El-Hage, Ph.D. Good Clinical Practice Assessment Branch Division of Good Clinical Practice Compliance Office of Scientific Investigations CONCURRENCE: {See appended electronic signature page} Susan Thompson, M.D. Team Leader Good Clinical Practice Assessment Branch Division of Good Clinical Practice Compliance Office of Scientific Investigations {See appended electronic signature page} Kassa Ayalew, M.D., M.P.H. Acting Branch Chief Good Clinical Practice Assessment Branch Division of Good Clinical Practice Compliance Office of Scientific Investigations Reference ID: 3402526 --------------------------------------------------------------------------------------------------------This is a representation of an electronic record that was signed electronically and this page is the manifestation of the electronic signature. --------------------------------------------------------------------------------------------------------/s/ ---------------------------------------------------ANTOINE N EL HAGE 11/07/2013 SUSAN D THOMPSON 11/07/2013 KASSA AYALEW 11/07/2013 Reference ID: 3402526 2 PROPOSED LABEL QT-IRT’s proposed labeling language is a suggestion only. We defer final labeling decisions to the Division. (b) (4) 3 BACKGROUND 3.1 PRODUCT INFORMATION Tasimelteon is a novel orally active circadian regulator that demonstrates high affinity and agonist activity for both the human melatonin MT1 and MT2 receptors and is being developed for the treatment of Non-24-Hour Disorder in the blind, other Circadian Rhythm Sleep Disorders (CRSD) and mood disorders including Major Depressive Disorder (MDD). 3.2 MARKET APPROVAL STATUS Tasimelteon is not approved for marketing in any country. 3.3 PRECLINICAL INFORMATION From IB, December 2012 Tasimelteon did not produce any statistically significant effects on action potential parameters in isolated rabbit cardiac Purkinje fibers except for a shortening of the APD90 100 μM at 1 s and 0.5 s BCL. Tasimelteon at all three concentrations did not induce statistically significant (P < 0.05) changes in resting membrane potential (RMP), action potential amplitude (APA) and the maximum rate of depolarization (Vmax) at two stimulus intervals. Tasimelteon inhibited hERG current by (Mean ± SEM; n = 3) 14.0 ± 2.2% at 100 μM versus 0.7 ± 0.4% (n = 3) in control. The hERG inhibition at 100 μM was statistically significant (P<0.05) when compared to vehicle control values. Since higher soluble concentrations were not tested, the median inhibitory concentration of tasimelteon on hERG potassium current could not be determined. Reviewer’s comments: Tasimelteon slightly blocks hERG currents with very low affinity (22% inhibition with 100 µM). 3.4 PREVIOUS CLINICAL EXPERIENCE From ISS, eCTD 2.7.4 The current safety data available and incorporated into the Integrated Summary of Safety (ISS) includes data from fourteen Phase I studies, two Phase II studies, and six Phase III studies. Two Phase III open-label safety studies of totally blind adults with a diagnosis of Non-24 are ongoing. In the overall safety database, there were 20 subjects with reported cardiac or cardiac-related adverse events that were treatment-emergent. Of these 20 subjects, 19/1346 (1.4%) occurred in tasimelteon-treated subjects and 1/306 (0.3%) occurred in placebo-treated subjects. As the total person days for the tasimelteon-treated group (N=1346, Mean Exposure = 44.6 days) is over 8 times greater than the total person days for the placebo-treated group (N=306, Mean Exposure = 22.9 days) (ISS Table 1.0.3.2), the difference in the incidence of events between treatment groups is mitigated. Reference ID: 3385503 Reviewer’s Comment: The reviewer agrees with the timing of ECGs because it covers the period of tasimelteon peak exposure and potential delays over 24 hours. 4.2.5.5 Baseline The sponsor used the time-match of the individual QTc values on Day -1 as baseline. 4.2.6 ECG Collection Intensive 12-Lead Holter monitoring will be used to obtain digital ECGs. Standard 12-Lead ECGs will be obtained while subjects are recumbent. 4.2.7 Sponsor’s Results 4.2.7.1 Study Subjects A total of 44 subjects (22 female, 22 male) were enrolled and forty-two subjects (95.5%) completed the study. Mean age was 30 years (18, 44) , BMI 25 Kg/m2 (20, 30). Two subjects discontinued from the study for personal reasons. All 44 subjects were included in the ECG analysis, PK, and safety populations. 4.2.7.2 Statistical Analyses 4.2.7.2.1 Primary Analysis The primary endpoint was time-matched baseline-adjusted mean differences between VEC-162 (20 mg and 300 mg) and placebo in QTcI. The sponsor used an analysis of covariance model with gender and treatment group as factors and the results are presented in Table 3. This model included gender, time, treatment, and time-by-treatment interaction as fixed effect terms, and baseline as covariate. The upper limits of the 2-sided 90% CI for VEC-162 (20 mg and 300 mg) were below 10 ms. Reference ID: 3385503 Table 3: Sponsor Results ΔΔQTcI for VEC-162 20 mg, VEC-162 300 mg and Moxifloxacin 400 mg VEC-162 20 mg VEC-162 300 mg Moxifloxacin 400 mg Time (h) Estimatea Upper boundb Estimatea Upper boundb Estimatea Upper boundb 0.5 3.2 5.9 0.1 2.8 11.2 15.6 1 1.8 4.6 –0.2 2.5 13.6 18.1 2 5.1 7.9 2.1 4.9 16.0 20.4 3 1.8 4.6 –1.9 0.9 9.8 14.2 4 1.7 4.4 –0.5 2.2 13.0 17.4 5 0.7 3.5 –0.5 2.1 8.3 12.7 6 0.8 3.6 –0.1 2.6 9.3 13.7 8 0.1 2.9 0.3 3.1 6.7 11.2 10 2.3 5.0 1.0 3.7 10.2 14.6 12 0.0 2.7 1.0 3.7 9.7 14.1 14 –0.3 2.4 –1.0 1.7 5.4 9.9 18 –2.1 0.6 –0.9 1.8 7.6 12.0 –0.2 23.5 –3.4 –0.6 6.1 10.6 2.6 a Mixed-model ANOVA is fit for placebo-corrected change from Baseline and includes terms for treatment, gender, time, and a time by treatment interaction. Upper bound = upper 1-sided 95% ANOVA model based confidence limit. (Moxifloxacin is Bonferroni-corrected.) P-value for gender effect (gender main effect and treatment by gender IA) is 0.0079. Treatment*gender IA = 0.1196. Source: Clinical Study Report No., Table 9, Pg 63/652 Reviewer’s Comments: We will provide our independent analysis results in Section 5.2. 4.2.7.2.2 Assay Sensitivity The sponsor used the same mixed model to analyze the ΔQTcI effect for moxifloxacin. The analysis results were presented in Table 3. However, the sponsor did not provide lower bound result. From our independent analysis, the largest unadjusted lower bound 2-sided 90% is 12.6 was greater than 5 ms. Thus, assay sensitivity in this thorough QTcI study was established. 4.2.7.2.3 Categorical Analysis Categorical analysis was used to summarize in the categories of QTc ≤450 ms, between 450 ms and 480 ms, between 480 ms and 500 ms, and >500 ms, and changes from baseline QTc ≤30 ms, between 30 and 60 ms, and >60 ms. No subject’s absolute QTc > 480 ms and ΔQTc >60 ms. 4.2.7.3 Safety Analysis No deaths or SAEs were reported. There were no clinically relevant ECG abnormalities reported, no abnormal T-waves were reported. 4.2.7.4 Clinical Pharmacology 4.2.7.4.1 Pharmacokinetic Analysis Reference ID: 3385503 The model results show the slopes of the relationships for plasma concentration and the predicted change at m. The slopes for and were negative (?0.0015 for both), as were the predicted changes at max 171 and ?3.0999, respectively). These data do not support any effect of VEC -162 on cardiac repolarization. 5 ASSESSMENT 5.1 EVALUATION OF THE CORRECTION METHOD We used the criterion of Mean Sum of Squared Slopes from individual regressions of versus R. The smaller this value is, the better the correction. Based on the results listed in Table 5, it appears that is better than and To be consistent with the sponsor?s analyses, we choose to present results. Table 5: Average of Sum of Squared Slopes for Different QT-RR Correction Methods Correction Method Treatment Group 20 mg 43 0.0040 43 0.0019 43 0.0013 300 mg 44 0.0040 44 0.0009 44 0.0009 Moxi?oxacin 400 mg 42 0.0037 42 0.0012 42 0.0008 Placebo 43 0.0046 43 0.0012 43 0.0007 All 44 0.0034 44 0.0011 44 0.0004 The QT-RR interval relationship is presented in Figure 2 together with the Bazett?s Fridericia and an Individual corrections. Reference ID: 3385503 Placebo 20 mg VEC-162 3 days 300 mg VEC-162 3 days Moxi?oxacin 400 mg on Day 3 Time LS LS LS Ls LS LS Mi- (ll) LS Mean Mean Mean 90% CI Mean Mean 90% CI Mean Mean 90% CI 90% CI 23.5 .03 84 _1.2 _o.9 (-3.8, 2.0) 86 _3.7 _3.3 83 5.2 5.5 (2.6, 8.4) (1.5, 9.5) Bonferroni method was applied for multiple endpoint adjustment for 4 time points. 5.2.1.2 Assay Sensitivity Analysis The statistical reviewer used the same statistical model to analyze moxi?oxacin and placebo data. The results are presented in Table 6. The largest lmadjusted of the 2-sided 90% lower con?dence interval is 12.6 ms. By considering Bonfen?oni multiple endpoint adjustment, the largest lower confidence interval is 11.4 ms, which indicates that an at least 5 ms effect due to moxi?oxacin can be detected from the study. 5.2.1.3 Graph of Over Time Figlu'e 3 displays the time pro?le of AAQTCI for different treatment groups and moxi?oxacin 400 mg. Figure 3: Mean and 90% CI Time Course for 20 mg, 300 mg and Moxifloxacin 400 mg 20-. 20 rm 3 chy: ?m0rrgVEO-162 Sdays 18; LS Mean (90Tlme (hour) 5.2.1.4 Categorical Analysis Table 7 lists the number of subjects as well as the number of observations whose values are 450 ms, and between 450 ms and 480 m, and changes from baseline 330 ms, between subject?s is above 480 ms. No subject?s change from baseline is above 60 ms (see Table 8). Reference ID: 3385503 Table 10: Categorical Analysis for HR Total Treatment Group HR 100 ms HR >=100 ms 20 mg 43 43 (100%) 0 300 mg VEC-162 44 44 (100%) 0 Moxi?oxacin 400 mg 42 41 1 Placebo 43 42 1 5.2.3 PR Analysis The statistical reviewer used mixed model to analyze the APR effect. The model includes treatment as ?xed effect and baseline values as a covariate. The analysis results are listed in Table 11. The largest upper b01u1ds of the 2-sided 90% CI for the mean differences between VEC -162 20 mg and placebo, and between VEC-162 300 mg and placebo are 3.6 ms and 3.8 ms, respectively. Table 12 presents the categorical analysis of PR. Seven subjects who experienced PR interval greater than 200 ms are in both VEC-162 20-mg and 300-mg groups. Table 11: Analysis Results of APR and AAPR for VEC-16220 mg, VEC-162 300 mg, and Moxi?oxacin 400 mg 20 mg VEC-162 300 mg VEC-162 Moxi?oxacin 400 mg APR APR AAPR APR AAPR APR AAPR Time (ll) Mean Mean Mean 90% CI Mean Mean 90% CI Mean Mean 90% CI 0.5 -0.5 86 0.6 1.1 (-1.3, 3.5) 87 -0.1 0.4 (-2.0, 2.9) 84 0.5 1.0 (-1.5, 3.4) 1 0.6 86 1.0 0.4 2.8) 87 2.0 1.4 3.8) 84 _1.1 -1.7 (42, 0.8) 2 1.6 83 1.1 -05 2.1) 86 0.7 _1.0 1.6) 84 17 -3.4 3 1.8 85 1.6 -0.2 (-2.9, 2.5) 87 0.1 -1.7 1.1) 84 -0.3 -2.1 0.7) 4 3.3 85 1.0 ?2.4 (-4.8, 0.1) 87 2.0 ?1.4 1.1) 84 ?1.2 45 (-7.0, 5 2.7 86 1.6 -1.0 (-3.5, 1.5) 87 0.8 -l.9 0.6) 84 -1.3 -4.0 (-6.5, -1.5) 6 0.2 85 1.7 1.5 (-0.7, 3.6) 87 0.2 -0.0 (-2.2, 2.1) 84 -3.2 -3.4 (-5.6, -1.3) 8 -0.0 85 0.6 0.6 (-1.5, 2.7) 85 1.2 1.3 (-0.8, 3.4) 84 -1.3 -1.2 (-3.3, 0.9) 10 0.7 85 ?0.8 -1.6 (-3.8, 0.7) 87 0.8 0.0 2.3) 84 ?1.8 -2.6 12 -09 86 _1.1 -02 2.9) 86 3.5 4.3 (1.2, 7.5) 83 3.1 -2.2 0.9) 14 0.6 86 0.0 -0.6 (-2.5, 1.3) 87 1.4 0.8 (-1.1, 2.7) 84 -1.9 -2.5 -0.6) 18 0.3 86 ?1.2 ?1.5 (3.9, 1.0) 85 1.3 1.0 3.5) 84 00 03 (-2.8, 2.2) 23.5 0.4 84 1.2 0.8 3.1) 86 -0.4 -0.8 1.5) 83 0.8 0.4 2.7) Table 12: Categorical Analysis of PR Total Treatment Group PR 200 ms PR >=200 ms 20 mg VEC-162 Moxi?oxacin 400 mg 42 38 4 Placebo 43 38 5 5.2.4 QRS Analysis The statistical reviewer used mixed model to analyze the AQRS effect. The model includes treatment as ?xed effect and baseline values as a covariate. The analysis results are listed in Table 13. The largest upper bormds of the 2-sided 90% CI for the mean differences between 20 mg and placebo, and between VEC-162 300 mg and placebo are 2.7 ms and 2.8 ms, respectively. Table 14 presents the categorical analysis of QRS. No subject who experienced QRS interval greater than 110 ms is in VEC-162 groups. Reference ID: 3385503 Figure 5: ∆∆QTcI vs. VEC-162 concentration 5.4 CLINICAL ASSESSMENTS 5.4.1 Safety assessments None of the events identified to be of clinical importance per the ICH E 14 guidelines i.e. syncope, seizure, significant ventricular arrhythmias or sudden cardiac death occurred in this study. 5.4.2 ECG assessments Waveforms from the ECG warehouse were reviewed. According to ECG warehouse statistics 94 % of the ECGs were annotated in the primary lead II, with less than 0.5 % of ECGs reported to have significant QT bias, according to the automated algorithm. Overall ECG acquisition and interpretation in this study appears acceptable. 5.4.3 PR and QRS Interval Six subjects had PR > 200 ms without clinically meaningful increase over baseline. An additional subject had a postbaseline PR increase of 78 ms (55% increases over baseline values), postbaseline PR was 225 ms. No subject had a QRS > 110 ms. Reference ID: 3385503 Metabolism Absorption CYP1A2 and CYP3A4 are the major isozymes involved in the metabolism of tasimelteon. CYP1A1, CYP2C9/19, and CYP2D6 also minimally contribute to the metabolism of tasimelteon. (Study BMS(b) (4) 10Nov97 and Study 08639) Tasimelteon has many metabolites, 8 of which have been characterized — M1, M3, M8, M9, M11, M12, M13, and M14. All of these metabolites are present in plasma and M1, M3, M8, and M9 are also present in urine. The characterized metabolites represent greater than 72% of the total AUC. M12, M9, and M13 are the most abundant metabolites. M12 and M9 are present at higher plasma levels (180% and 130%, respectively) than the parent drug and M13 is present at about the same level. The pharmacokinetic profiles of the most abundant metabolites as well as other main metabolites (M3, M11, and M12) were studied in the clinical pharmacology program. Of the glucuronidated metabolites (M1, M3, and M8), M3 was assayed in samples from some clinical pharmacology studies because it is expressed at about the same concentration than tasimelteon in plasma, and it is the second most abundant metabolite in urine (after M9). (VP-VEC-162-1101 and VPVEC-162-1110) Absolute/Relative Bioavailability Tmax Distribution Vd/F or Vd % bound Total oral absorption of tasimelteon is at least 80.4%. (VP- VEC-162-1101) Absolute oral bioavailability has not Tasimelteon was found to have a typical median Tmax value of 0.5 hours. (Module 2.7.2, Table 4) Tmax of major metabolites range from 0.5 to 1.0 hours. (Module 2.7.2, Table 4) The apparent oral volume of distribution at steady state of tasimelteon in young healthy subjects is approximately 59 At therapeutic concentrations, tasimelteon is about 88.6 90.1% protein bound. Renal impairment does not affect the protein binding of tasimelteon. (Module 17 Reference ID: 3385503 Blood\Plasma ratio Data from the human Absorption, Metabolism and Excretion study (VP-VEC-162-1101) demonstrated that the mean Cmax and AUC values for total radioactivity in plasma were higher than those for total radioactivity in whole blood, indicating that tasimelteon is not highly associated with red blood cells. The theoretical blood-to- plasma ratio is 0.6, consistent with the observed Cmax ratio (2,385/3,987 = 0.60). Elimination Intrinsic Factors Route The main route of elimination of tasimelteon and its metabolites in humans is by way of the urine, with biliary excretion to feces contributing a minor portion. Following oral administration of radiolabeled tasimelteon, <1% of the unchanged parent was detectable in the urine, consistent with the presence of metabolites. Mean recovery of total radioactivity in urine was 80.4% and 3.72% was recovered in feces resulting in a mean recovery of 84.1%. (VP-VEC-162-1101) Terminal t½ The mean terminal elimination half-life + standard deviation of tasimelteon is 1.32 + 0.431. (Module 2.7.2, Table 4) The mean terminal elimination half-life + standard deviation of the main metabolites ranges from 1.26 +0.480 to 3.67 + 2.22. (Module 2.7.2, Table 4) CL/F or CL The apparent clearance ranged from 51 L/hour to 139 L/hour. (Module 2.7.2, Table 9) The PK characteristics of tasimelteon are highly variable amongst individuals. Intrinsic factors that might influence the PK variability of tasimelteon include age, gender, race, and body composition. Due to the overall inter-subject variability of tasimelteon, contributions to this variability by these factors, if present, are probably small and not clinically meaningful. Therefore, no dose adjustment is necessary based on age, gender, or body mass index (BMI). (Module 2.7.2 Section 5) Age, Gender, Race and BMI 18 Reference ID: 3385503 Administration of rifampin 600 mg once daily for 11 days resulted in a mean decrease in exposure of approximately 89% and Cmax of 83% after a single 20 mg dose of tasimelteon. Efficacy may be reduced when tasimelteon is used in combination with strong CYP3A4 inducers such as rifampin. A dose adjustment may be considered. (VP- VEC-1621112) Ethanol In a healthy volunteer study where 0.6 g/kg for women and 0.7 g/kg for men of ethanol (2-5 standard alcohol drinks) over 15 minutes was co-administered with 20 mg tasimelteon no additive effects were seen on psychomotor performance or memory task. (VPVEC-162-1106) Food Effects Expected High Clinical Exposure Scenario There is a 44% reduction in the Cmax of tasimelteon in healthy volunteers fed a high fat/high calorie meal compared to fasted individual. Tmax increases from 0.75 hours to 2.5 hours in fasted versus fed subjects. There is no food effect on the total AUC. (VP-VEC-162-1102) Fluvoxamine is a strong CYP1A2 and CYP2C19 inhibitor and is also classified as a weak inhibitor of CYP2C8, 2C9 and 3A4. The effect of combined inhibition of CYP1A2 and 2C19 with at least some impact on other enzymes involved in the metabolism of tasimelteon, namely CYP2C9 and 3A4 likely approximates a near worst-case scenario. At a dose of 20 mg tasimelteon, the expected AUC would be approximately 2804 h×ng/mL which is well below the mean AUC observed after supratherapeutic dosing with 300 mg tasimelteon (AUC = 3,230 ± 1,480 ng×hr/ml). (VP-VEC-162-1111 and CN116-001) 21 Reference ID: 3385503 CL/F or CL Intrinsic Factors Age, Gender, Race and BMI The apparent clearance ranged from 51 L/hour to 139 L/hour. (Module 2.7.2, Table 9) The PK characteristics of tasimelteon are highly variable amongst individuals. Intrinsic factors that might influence the PK variability of tasimelteon include age, gender, race, and body composition. Due to the overall inter-subject variability of tasimelteon, contributions to this variability by these factors, if present, are probably small and not clinically meaningful. Therefore, no dose adjustment is necessary based on age, gender, or body mass index (BMI). (Module 2.7.2 Section 5) Cardiac Effects Clinical study VP-VEC-162-1103 demonstrated that tasimelteon showed no signal of any effect on cardiac repolarization. The time-matched analysis for the QTcI endpoint revealed no subject on tasimelteon crossed the 10 msec upper bound for all time points for both the clinical and supratherapeutic doses. The moxifloxacin group met the assay sensitivity criteria as outlined in the statistical plan, and all time points for moxifloxacin were more than five msec. No clinically relevant effect of tasimelteon was noted for heart rate or for PR or QRS interval duration. No new morphologic changes were considered clinically significant. Hepatic Impairment For subjects with mild hepatic impairment, tasimelteon CL/F was reduced to 850 mL/min compared to 1128 mL/min for matched controls. For subjects with moderate hepatic impairment, CL/F was 721 mL/min compared to 1318 mL/min for matched controls. This resulted in a corresponding increase in exposure, as measured by AUC(inf), of 144% and 189% in subjects with mild and moderate hepatic impairment, respectively, less for the metabolites. The geometric mean ratios (GMR) of tasimelteon Cmax for subjects with mild or moderate hepatic impairment were 122.15% and 118.51%, respectively, as compared to healthy matched control subjects. Taking into account the therapeutic margin of tasimelteon, i.e., doses up to at least 300 mg are well tolerated; dose adjustments may not be necessary. (VP-VEC162-1105) 22 Reference ID: 3385503 --------------------------------------------------------------------------------------------------------This is a representation of an electronic record that was signed electronically and this page is the manifestation of the electronic signature. --------------------------------------------------------------------------------------------------------/s/ ---------------------------------------------------MOH JEE NG 10/07/2013 QIANYU DANG 10/07/2013 HONGSHAN LI 10/07/2013 KEVIN M KRUDYS 10/07/2013 MONICA L FISZMAN 10/07/2013 NORMAN L STOCKBRIDGE 10/07/2013 Reference ID: 3385503 Department of Health and Human Services Public Health Service Food and Drug Administration Center for Drug Evaluation and Research Office of Surveillance and Epidemiology Office of Medication Error Prevention and Risk Management Label, Labeling and Packaging Review Date: September 26, 2013 Reviewer: Julie Neshiewat, PharmD Division of Medication Error Prevention and Analysis Team Leader: Irene Z. Chan, PharmD, BCPS Division of Medication Error Prevention and Analysis Drug Name and Strength: Tasimelteon Capsules, 20 mg Application Type/Number: NDA 205677 Applicant: Vanda Pharmaceuticals OSE RCM #: 2013-1436 *** This document contains proprietary and confidential information that should not be released to the public.*** Reference ID: 3379883 increase the prominence of important information, such as the strength. The original container is a rmit-of-use bottle and the label contains Braille for the product name and strength, which may be helpful to the patient. Therefore, we recommend including a statement to dispense the product in the original container and to affix the pharmacy label so it does not cover the Braille. Important information about M4) appears in the insert labeling and should be added to the Medication Guide. In addition, the insert labeling states to take 20 mg (4) at the same time every night. It is lurclear if there is a time frame that is acceptable. This issue was discussed with the Medical Of?cer (MO) and will be addressed at future labeling meetings. (5) (4) The Applicant submitted a Braille Comprehension Study Protocol for the container label. We recommend asking the participant to read what is presented on the container label instead of speci?cally asking for the medication name and strength on the container label. 4 CONCLUSIONS DMEPA concludes that the proposed labels and labeling can be improved to increase the readability and prominence of important information on the label to promote the safe use of the product. Additionally, the acceptability of the Braille on the container label will be a separate review issue that depends on the results of the Braille Comprehension Study. 5 RECOMMENDATIONS Based on this review, DMEPA recommends the following be implemented prior to approval of this NDA: A. to the Division 1. General At the time of the Braille Label Comprehension Study request for the container label, we were unaware the Applicant proposed (we) 2. Insert Labeling 4 . M) at the same tune a. In Section 2, it states to take 20 mg every night. It is rmclear if there is a time frame that is acceptable. If data is available, we recommend adding the acceptable time frame for takin the medication each night or removing the term 0' (4) (4) (4) Reference ID: 3379883 (b) (4) B. Comments to the Applicant 1. Container Label a. Add the dosage form “capsules” following the active ingredient “Tasimelteon.” The dosage form should be presented in the same font as the active ingredient. b. Relocate the strength to underneath the established name for customary placement. Additionally, increase the prominence of the strength by bolding or other means. See example below: (Tasimelteon) Capsules 20 mg c. Relocate the NDC number to the principal display panel per 21 CFR 207.35(b)(3)(i). d. Revise the storage information from “15°C to 30°C (59°F to 86°F)” for clarity. (b) (4) to e. Decrease the size of the to the left of the proposed proprietary name or remove it since it takes attention away from important information on the label, such as the established name and strength. (b) (4) f. Add a usual dosage statement to the side panel per 21 CFR 201.100(b)(2). In order to accommodate this statement, decrease the size of the company logo. g. Since the original container is a unit-of-use bottle and contains Braille, which may be helpful to the patient, we recommend adding a statement to the principal display panel similar to “Dispense in original container. Do not cover the Braille.” (b) (4) i. Debold the net quantity and Rx only statements. 2. Braille Label Comprehension Study Protocol a. We recommend asking the patient to read the information on the bottle label aloud without clues as to what is printed in Braille instead of asking what the name and strength of the medication are. If you have further questions or need clarifications, please contact Ermias Zerislassie, project manager, at 301-796-0097. 1 Page(s) of Draft Labeling have been Withheld in Full as b4 (CCI/TS) immediately following this page 3 Reference ID: 3379883 Fast Track Designation Breakthrough Therapy Designation Rolling Review Orphan Designation Rx-to-OTC switch, Full Rx-to-OTC switch, Partial Direct-to-OTC PMC response PMR response: FDAAA [505(o)] PREA deferred pediatric studies [21 CFR 314.55(b)/21 CFR 601.27(b)] Accelerated approval confirmatory studies (21 CFR 314.510/21 CFR 601.41) Animal rule postmarketing studies to verify clinical benefit and safety (21 CFR 314.610/21 CFR 601.42) Other: Collaborative Review Division (if OTC product): List referenced IND Number(s): 54776 Goal Dates/Product Names/Classification Properties YES PDUFA and Action Goal dates correct in tracking system? X NO NA Comment NO NA Comment NA Comment X Orphan product If no, ask the document room staff to correct them immediately. These are the dates used for calculating inspection dates. Are the proprietary, established/proper, and applicant names correct in tracking system? X If no, ask the document room staff to make the corrections. Also, ask the document room staff to add the established/proper name to the supporting IND(s) if not already entered into tracking system. Is the review priority (S or P) and all appropriate classifications/properties entered into tracking system (e.g., chemical classification, combination product classification, 505(b)(2), orphan drug)? For NDAs/NDA supplements, check X the New Application and New Supplement Notification Checklists for a list of all classifications/properties at: http://inside.fda.gov:9003/CDER/OfficeofBusinessProcessSupport/ucm163969.ht m If no, ask the document room staff to make the appropriate entries. Application Integrity Policy YES X Is the application affected by the Application Integrity Policy (AIP)? Check the AIP list at: http://www.fda.gov/ICECI/EnforcementActions/ApplicationIntegrityPolicy/default .htm If yes, explain in comment column. If affected by AIP, has OC/OMPQ been notified of the submission? If yes, date notified: User Fees Is Form 3397 (User Fee Cover Sheet) included with authorized signature? Version: 5/10/13 Reference ID: 3347295 YES NO 2 User Fee Status Payment for this application: If a user fee is required and it has not been paid (and it is not exempted or waived), the application is unacceptable for filing following a 5-day grace period. Review stops. Send Unacceptable for Filing (UN) letter and contact user fee staff. Paid X Exempt (orphan) Waived (e.g., small business, public health) Not required Payment of other user fees: If the firm is in arrears for other fees (regardless of whether a user fee has been paid for this application), the application is unacceptable for filing (5-day grace period does not apply). Review stops. Send UN letter and contact the user fee staff. Not in arrears In arrears 505(b)(2) YES NO (NDAs/NDA Efficacy Supplements only) Is the application for a duplicate of a listed drug and eligible for approval under section 505(j) as an ANDA? Is the application for a duplicate of a listed drug whose only difference is that the extent to which the active ingredient(s) is absorbed or otherwise made available to the site of action is less than that of the reference listed drug (RLD)? [see 21 CFR 314.54(b)(1)]. Is the application for a duplicate of a listed drug whose only difference is that the rate at which the proposed product’s active ingredient(s) is absorbed or made available to the site of action is unintentionally less than that of the listed drug [see 21 CFR 314.54(b)(2)]? NA Comment x If you answered yes to any of the above questions, the application may be refused for filing under 21 CFR 314.101(d)(9). Contact the 505(b)(2) review staff in the Immediate Office of New Drugs Is there unexpired exclusivity on any drug product containing the active moiety (e.g., 5-year, 3-year, orphan, or pediatric exclusivity)? Check the Electronic Orange Book at: http://www.accessdata.fda.gov/scripts/cder/ob/default.cfm If yes, please list below: Application No. Drug Name Exclusivity Code Exclusivity Expiration If there is unexpired, 5-year exclusivity remaining on the active moiety for the proposed drug product, a 505(b)(2) application cannot be submitted until the period of exclusivity expires (unless the applicant provides paragraph IV patent certification; then an application can be submitted four years after the date of approval.) Pediatric exclusivity will extend both of the timeframes in this provision by 6 months. 21 CFR 314.108(b)(2). Unexpired, 3year exclusivity may block the approval but not the submission of a 505(b)(2) application. Exclusivity Does another product (same active moiety) have orphan exclusivity for the same indication? Check the Orphan Drug Version: 5/10/13 Reference ID: 3347295 YES NO NA Comment X 3 legible English (or translated into English) pagination navigable hyperlinks (electronic submissions only) If no, explain. BLAs only: Companion application received if a shared or divided manufacturing arrangement? If yes, BLA # Forms and Certifications Electronic forms and certifications with electronic signatures (scanned, digital, or electronic – similar to DARRTS, e.g., /s/) are acceptable. Otherwise, paper forms and certifications with hand-written signatures must be included. Forms include: user fee cover sheet (3397), application form (356h), patent information (3542a), financial disclosure (3454/3455), and clinical trials (3674); Certifications include: debarment certification, patent certification(s), field copy certification, and pediatric certification. Application Form YES Is form FDA 356h included with authorized signature per 21 CFR 314.50(a)? x NO NA Comment NO NA Comment NO NA Comment NO NA Comment If foreign applicant, a U.S. agent must sign the form [see 21 CFR 314.50(a)(5)]. Are all establishments and their registration numbers listed on the form/attached to the form? x Patent Information YES (NDAs/NDA efficacy supplements only) Is patent information submitted on form FDA 3542a per 21 CFR 314.53(c)? x Financial Disclosure YES Are financial disclosure forms FDA 3454 and/or 3455 included with authorized signature per 21 CFR 54.4(a)(1) and (3)? x Forms must be signed by the APPLICANT, not an Agent [see 21 CFR 54.2(g)]. Note: Financial disclosure is required for bioequivalence studies that are the basis for approval. Clinical Trials Database YES Is form FDA 3674 included with authorized signature? x If yes, ensure that the application is also coded with the supporting document category, “Form 3674.” Version: 5/10/13 Reference ID: 3347295 5 format? If no, request applicant to submit SPL before the filing date. Is the PI submitted in PLR format? 4 x If PI not submitted in PLR format, was a waiver or deferral requested before the application was received or in the submission? If requested before application was submitted, what is the status of the request? If no waiver or deferral, request applicant to submit labeling in PLR format before the filing date. All labeling (PI, PPI, MedGuide, IFU, carton and immediate container labels) consulted to OPDP? MedGuide, PPI, IFU (plus PI) consulted to OSE/DRISK? (send WORD version if available) x Carton and immediate container labels, PI, PPI sent to OSE/DMEPA and appropriate CMC review office (OBP or ONDQA)? x OTC Labeling X Not Applicable Outer carton label Immediate container label Blister card Blister backing label Consumer Information Leaflet (CIL) Physician sample Consumer sample Other (specify) Check all types of labeling submitted. x YES NO NA Comment Other Consults YES NO NA Comment Are additional consults needed? (e.g., IFU to CDRH; QT study report to QT Interdisciplinary Review Team) x Is electronic content of labeling (COL) submitted? If no, request in 74-day letter. Are annotated specifications submitted for all stock keeping units (SKUs)? If no, request in 74-day letter. If representative labeling is submitted, are all represented SKUs defined? If no, request in 74-day letter. All labeling/packaging, and current approved Rx PI (if switch) sent to OSE/DMEPA? Qt consult; nonclin carci consult sent 4 http://inside fda.gov:9003/CDER/OfficeofNewDrugs/StudyEndpointsandLabelingDevelopmentTeam/ucm0 25576.htm Version: 5/10/13 Reference ID: 3347295 8 If yes, specify consult(s) and date(s) sent: Meeting Minutes/SPAs YES End-of Phase 2 meeting(s)? Date(s): 1.6.11 x NO NA Comment If yes, distribute minutes before filing meeting Pre-NDA/Pre-BLA/Pre-Supplement meeting(s)? Date(s): 2.21.13 x If yes, distribute minutes before filing meeting Any Special Protocol Assessments (SPAs)? Date(s): 10.28.11 x If yes, distribute letter and/or relevant minutes before filing meeting Version: 5/10/13 Reference ID: 3347295 9 TL: OC/OSI/DSC/PMSB (REMS) Reviewer: N/A TL: Bioresearch Monitoring (OSI) Controlled Substance Staff (CSS) Other reviewers Other attendees Patient Labeling Reviewer: A. El Hage N TL: S. Leiberhaut N Reviewer: K. Bonson Y TL: S. Calderon A. Pariser (OND Rare Diseases) K. O’Connell (OND Rare Diseases) T.Scales M. McLawhorn Y N Y E. Zerislassie Y Safety RPM FILING MEETING DISCUSSION: GENERAL • Not Applicable 505(b)(2) filing issues: o Is the application for a duplicate of a listed drug and eligible for approval under section 505(j) as an ANDA? YES NO o Did the applicant provide a scientific “bridge” demonstrating the relationship between the proposed product and the referenced product(s)/published literature? YES NO Describe the scientific bridge (e.g., BA/BE studies): • Per reviewers, are all parts in English or English translation? X YES NO If no, explain: • Not Applicable Electronic Submission comments List comments: CLINICAL X Version: 5/10/13 Reference ID: 3347295 Not Applicable FILE 12 REFUSE TO FILE Comments: review issues for 60 day filing letter • Clinical study site(s) inspections(s) needed? Review issues for 74-day letter X YES NO If no, explain: • Advisory Committee Meeting needed? Comments: New NME X YES Date if known: 11.14.13 NO To be determined If no, for an NME NDA or original BLA , include the reason. For example: o this drug/biologic is not the first in its class o the clinical study design was acceptable o the application did not raise significant safety or efficacy issues o the application did not raise significant public health questions on the role of the drug/biologic in the diagnosis, cure, mitigation, treatment or prevention of a disease Reason: • Not Applicable X FILE REFUSE TO FILE Abuse Liability/Potential Comments: • If the application is affected by the AIP, has the division made a recommendation regarding whether or not an exception to the AIP should be granted to permit review based on medical necessity or public health significance? Review issues for 74-day letter X Not Applicable YES NO Comments: CLINICAL MICROBIOLOGY Comments: CLINICAL PHARMACOLOGY Comments: • Clinical pharmacology study site(s) inspections(s) Version: 5/10/13 Reference ID: 3347295 Not Applicable X FILE REFUSE TO FILE Review issues for 74-day letter Not Applicable X FILE REFUSE TO FILE Review issues for 74-day letter YES 13 Facility Inspection Not Applicable • Establishment(s) ready for inspection? YES NO  Establishment Evaluation Request (EER/TBP-EER) submitted to OMPQ? X YES NO Comments: Facility/Microbiology Review (BLAs only) Comments: X Not Applicable FILE REFUSE TO FILE Review issues for 74-day letter CMC Labeling Review Comments: Review issues for 74-day letter APPLICATIONS IN THE PROGRAM (PDUFA V) (NME NDAs/Original BLAs) N/A • Were there agreements made at the application’s pre-submission meeting (and documented in the minutes) regarding certain late submission components that could be submitted within 30 days after receipt of the original application? X YES NO • If so, were the late submission components all submitted within 30 days? X YES NO • What late submission components, if any, arrived after 30 days? • Was the application otherwise complete upon submission, including those applications where there were no agreements regarding late submission components? Version: 5/10/13 Reference ID: 3347295 X YES NO 15 --------------------------------------------------------------------------------------------------------This is a representation of an electronic record that was signed electronically and this page is the manifestation of the electronic signature. --------------------------------------------------------------------------------------------------------/s/ ---------------------------------------------------CATHLEEN B MICHALOSKI 07/25/2013 Reference ID: 3347295 Selected Requirements of Prescribing Information (SRPI) Highlights (HL) YES YES YES YES YES YES GENERAL FORMAT 1. Highlights (HL) must be in two-column format, with ½ inch margins on all sides and in a minimum of 8-point font. Comment: 2. The length of HL must be less than or equal to one-half page (the HL Boxed Warning does not count against the one-half page requirement) unless a waiver has been is granted in a previous submission (i.e., the application being reviewed is an efficacy supplement). Instructions to complete this item: If the length of the HL is less than or equal to one-half page then select “YES” in the drop-down menu because this item meets the requirement. However, if HL is longer than one-half page: ¾ For the Filing Period (for RPMs) ƒ For efficacy supplements: If a waiver was previously granted, select “YES” in the dropdown menu because this item meets the requirement. ƒ For NDAs/BLAs and PLR conversions: Select “NO” in the drop-down menu because this item does not meet the requirement (deficiency). The RPM notifies the CrossDiscipline Team Leader (CDTL) of the excessive HL length and the CDTL determines if this deficiency is included in the 74-day or advice letter to the applicant. ¾ For the End-of Cycle Period (for SEALD reviewers) ƒ The SEALD reviewer documents (based on information received from the RPM) that a waiver has been previously granted or will be granted by the review division in the approval letter. Comment: 3. All headings in HL must be presented in the center of a horizontal line, in UPPER-CASE letters and bolded. Comment: 4. White space must be present before each major heading in HL. Comment: 5. Each summarized statement in HL must reference the section(s) or subsection(s) of the Full Prescribing Information (FPI) that contains more detailed information. The preferred format is the numerical identifier in parenthesis [e.g., (1.1)] at the end of each information summary (e.g. end of each bullet). Comment: 6. Section headings are presented in the following order in HL: Section • Highlights Heading • Highlights Limitation Statement SRPI version 2: Last Updated May 2012 Reference ID: 3328270 Required/Optional Required Required Page 1 of 7 Selected Requirements of Prescribing Information (SRPI) YES N/A YES NO Contraindications 23. All contraindications listed in the FPI must also be listed in HL or must include the statement “None” if no contraindications are known. Comment: 24. Each contraindication is bulleted when there is more than one contraindication. Comment: Adverse Reactions 25. For drug products other than vaccines, the verbatim bolded statement must be present: “To report SUSPECTED ADVERSE REACTIONS, contact (insert name of manufacturer) at (insert manufacturer’s U.S. phone number) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch”. Comment: Patient Counseling Information Statement 26. Must include one of the following three bolded verbatim statements (without quotation marks): If a product does not have FDA-approved patient labeling: • “See 17 for PATIENT COUNSELING INFORMATION” If a product has FDA-approved patient labeling: • “See 17 for PATIENT COUNSELING INFORMATION and FDA-approved patient labeling.” • “See 17 for PATIENT COUNSELING INFORMATION and Medication Guide.” Comment: Medication Guide is missing. Will discuss at filing meeting 6/27/13. N/A Revision Date 27. Bolded revision date (i.e., “Revised: MM/YYYY or Month Year”) must be at the end of HL. Comment: Contents: Table of Contents (TOC) YES YES YES N/A GENERAL FORMAT 28. A horizontal line must separate TOC from the FPI. Comment: 29. The following bolded heading in all UPPER CASE letters must appear at the beginning of TOC: “FULL PRESCRIBING INFORMATION: CONTENTS”. Comment: 30. The section headings and subheadings (including title of the Boxed Warning) in the TOC must match the headings and subheadings in the FPI. Comment: 31. The same title for the Boxed Warning that appears in the HL and FPI must also appear at the beginning of the TOC in UPPER-CASE letters and bolded. SRPI version 2: Last Updated May 2012 Reference ID: 3328270 Page 4 of 7 Selected Requirements of Prescribing Information (SRPI) YES 32. YES 33. YES 34. YES 35. Comment: All section headings must be bolded and in UPPER CASE. Comment: All subsection headings must be indented, not bolded, and in title case. Comment: When a section or subsection is omitted, the numbering does not change. Comment: If a section or subsection from 201.56(d)(1) is omitted from the FPI and TOC, the heading “FULL PRESCRIBING INFORMATION: CONTENTS” must be followed by an asterisk and the following statement must appear at the end of TOC: “*Sections or subsections omitted from the Full Prescribing Information are not listed.” Comment: Full Prescribing Information (FPI) YES YES YES GENERAL FORMAT 36. The following heading must appear at the beginning of the FPI in UPPER CASE and bolded: “FULL PRESCRIBING INFORMATION”. Comment: font is small. 37. All section and subsection headings and numbers must be bolded. Comment: Need to remove extra periods. 38. The bolded section and subsection headings must be named and numbered in accordance with 21 CFR 201.56(d)(1) as noted below. If a section/subsection is omitted, the numbering does not change. Boxed Warning 1 INDICATIONS AND USAGE 2 DOSAGE AND ADMINISTRATION 3 DOSAGE FORMS AND STRENGTHS 4 CONTRAINDICATIONS 5 WARNINGS AND PRECAUTIONS 6 ADVERSE REACTIONS 7 DRUG INTERACTIONS 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy 8.2 Labor and Delivery 8.3 Nursing Mothers 8.4 Pediatric Use 8.5 Geriatric Use 9 DRUG ABUSE AND DEPENDENCE 9.1 Controlled Substance 9.2 Abuse 9.3 Dependence 10 OVERDOSAGE SRPI version 2: Last Updated May 2012 Reference ID: 3328270 Page 5 of 7 --------------------------------------------------------------------------------------------------------This is a representation of an electronic record that was signed electronically and this page is the manifestation of the electronic signature. --------------------------------------------------------------------------------------------------------/s/ ---------------------------------------------------CATHLEEN B MICHALOSKI 06/19/2013 Reference ID: 3328270