1 FDA Briefing Document Psychopharmacologic Drugs Advisory Committee (PDAC) Meeting December 1, 2015 2 The attached package contains background information prepared by the Food and Drug Administration (FDA) for the panel members of the advisory committee. The FDA background package often contains assessments and/or conclusions and recommendations written by individual FDA reviewers. Such conclusions and recommendations do not necessarily represent the final position of the individual reviewers, nor do they necessarily represent the final position of the Review Division or Office. We are bringing NDA 21164, gepirone hydrochloride extended-release tablets for the treatment of major depressive disorder (MDD), to the advisory committee in order to gain the Committee’s insights and opinions. The background package may not include all issues relevant to the final regulatory recommendation and instead is intended to focus on issues identified by the Agency for discussion by the advisory committee. The FDA will not issue a final determination on the issues at hand until input from the advisory committee process has been considered and all reviews have been finalized. The final determination may be affected by issues not discussed at the advisory committee meeting. All tables, figures, and graphics contained in this briefing document were created by FDA or have been electronically copied and reproduced from the sponsor's submission. 3 TABLE OF CONTENTS 1 DIVISION DIRECTOR/OND DIRECTOR MEMORANDUM ...................................................................... 5 2 CRITICAL MILESTONES ............................................................................................................................... 12 3 EFFICACY EVALUATION ............................................................................................................................. 17 3.1 SHORT-TERM STUDIES ................................................................................................................................. 17 3.1.1 Brief Summary of the Four Studies in Question – Studies Deemed to be Negative by DPP/ODE-I; Deemed to be Failed by the Sponsor ................................................................................................... 21 3.1.2 Clarifications for the Division’s Analysis of the Four Studies Whose Evidence is in Question .......... 23 3.1.3 Evaluation of Strength of Evidence for Effectiveness ......................................................................... 27 3.2 MAINTENANCE STUDY ORG28709 .............................................................................................................. 28 4 SUMMARY ......................................................................................................................................................... 33 5 APPENDICES .................................................................................................................................................... 35 5.1 MEMO – RUSSELL KATZ - NON-APPROVAL RECOMMENDATION (03/08/2002) ......................... 36 5.2 MEMO – ROBERT TEMPLE - NON-APPROVAL RECOMMENDATION (03/14/2002) .................... 44 5.3 LETTER – ROBERT TEMPLE – NOT APPROVABLE LETTER (03/15/2002) .................................... 49 5.4 MEMO – RUSSELL KATZ - NON-APPROVAL RECOMMENDATION (06/15/2004) ........................ 60 5.5 MEMO – ROBERT TEMPLE - NON-APPROVAL RECOMMENDATION (06/22/2004) .................... 68 5.6 LETTER – ROBERT TEMPLE – NOT APPROVABLE LETTER (06/23/2004) .................................... 71 5.7 MEMO – THOMAS LAUGHREN - NON-APPROVAL RECOMMENDATION (10/25/2007) ............. 79 5.8 LETTER – ROBERT TEMPLE – NOT APPROVABLE LETTER (11/02/2007) .................................... 88 5.9 MEETING MINUTES –THOMAS LAUGHREN (12/28/2011) ............................................................... 93 5.10 STATISTICS REVIEW –YEH FONG CHEN, PEILING YANG, HSIEN MING J HUNG (10/25/2013) ...................................................................................................... 143 5.11 STATISTICS REVIEW –PEILING YANG AND HSIEN MING J HUNG (10/25/2013) ...................... 175 5.12 CLINICAL REVIEW –SILVANA BORGES (04/18/2014) .................................................................... 187 5.13 ADVICE LETTER –ROBERT TEMPLE (04/18/2014) .......................................................................... 228 5.14 FORMAL DISPUTE RESOLUTION MEETING MINUTES –KHUSHBOO SHARMA (03/18/2015) 236 5.15 DISPUTE APPEAL GENERAL ADVICE –JOHN JENKINS (04/07/2015) .......................................... 287 5.16 INTERIM RESPONSE TO APPEAL –JOHN JENKINS (06/01/2015) .................................................. 291 5.17 STATISTICS MEMO –LISA LAVANGE (06/08/2015) ......................................................................... 298 5.18 REFERENCE TO ARTICLE – “REGULATORY AND SCIENTIFIC ISSUES IN STUDIES TO EVALUATE SEXUAL DYSFUNCTION IN ANTIDEPRESSANT DRUG TRIALS” (08/2015)” ....... 305 5.19 REFERENCE TO ARTICLE – “SUMMARY OF FINDINGS FROM THE FDA REGULATORY SCIENCE FORUM ON MEASURING SEXUAL DYSFUNCTION IN DEPRESSION TRIALS” (08/2015) ................................................................................................................................................... 306 5.20 REFERENCE TO ARTICLE – “VILAZODONE: CLINICAL BASIS FOR THE US FOOD AND DRUG ADMINISTRATION’S APPROVAL OF A NEW ANTIDEPRESSANT” (11/2011) ................ 307 5.21 GUIDANCE FOR INDUSTRY – PROVIDING CLINICAL EVIDENCE OF EFFECTIVENESS FOR HUMAN DRUG AND BIOLOGICAL PRODUCTS (05/1998) ..................................................... 308 4 LIST OF TABLES TABLE 1: TWELVE SHORT-TERM STUDIES WITH HAMD-17 RESULTS……………………………………………………………………….19 TABLE 2: SUMMARY OF PAIRWISE COMPARISONS FOR FOUR CONTROVERSIAL STUDIES……………………………………… 20 TABLE 3: PROBABILITIES OF FALSELY CONCLUDING EFFICACY BASED ON TWO POSITIVE TRIALS; VARIOUS NUMBERS OF NEGATIVE TRIALS………………………………………………………………………………………………………………. 27 TABLE 4: SUMMARY OF PROPORTION OF PATIENTS WITH RELAPSE……………………………………………………………………… 29 TABLE 5: SUMMARY OF PROPORTION OF PATIENTS WHO HAD RELAPSED – PRIMARY ANALYSIS AND POST-HOC ANALYSES……………………………………………………………………………………………………………………………………………….. 32 LIST OF FIGURES FIGURE 1: SPONSOR'S DIAGRAM OF WELL-CONTROLLED GEPIRONE ER STUDIES………………………………………………….. 17 FIGURE 2: SPONSOR'S CUMULATIVE PROPORTION OF PATIENTS WHO HAD RELAPSED OVER TIME……………………… 31 5 1 DIVISION DIRECTOR/OND DIRECTOR MEMORANDUM M E M O R A N D U M DEPARTMENT OF HEALTH AND HUMAN SERVICES PUBLIC HEALTH SERVICE FOOD AND DRUG ADMINISTRATION CENTER FOR DRUG EVALUATION AND RESEARCH DATE: October 13, 2015 FROM: Mitchell V. Mathis, M.D. Director Division of Psychiatry Products, HFD-130 John Jenkins, M.D. Director Office of New Drugs TO: Members of the Psychopharmacologic Drugs Advisory Committee (PDAC) SUBJECT: December 1, 2015 Meeting of the PDAC This one-day PDAC meeting will focus on issues critical to the Center for Drug Evaluation and Research (CDER) assessment of whether the sponsor has provided substantial evidence of effectiveness in the pending NDA for gepirone HCL extended-release (ER) tablets for treatment of major depressive disorder (MDD). The issues are the subject of a pending request for Formal Dispute Resolution (FDRR) in which the sponsor is appealing to the Director of the Office of New Drugs (OND) prior decisions by the Division of Psychiatry Products (DPP) and the Office of Drug Evaluation 1 (ODE-1) that the available data do not provide the substantial evidence of effectiveness required under the Food Drug and Cosmetic Act (FD&CA) to support approval. First, we will discuss the general issue of how clinical trial data should be interpreted in a development program that has accumulated a relatively large number of negative/failed trials along with the two positive, adequate and well-controlled trials normally required to meet the substantial evidence standard for approval. Although negative or failed trials are often observed in psychiatric drug development programs, at what point does the information provided by negative/failed trials undermine the evidence of effectiveness? Second, as a specific example of the first issue, we will discuss the case of gepirone ER for the treatment of MDD where the sponsor has submitted results from a relatively large number of negative/failed trials along with two positive, adequate and well-controlled trials. This application has been the subject of three review cycles and received a “not-approvable” action on each cycle, primarily due to concerns about whether the sponsor has provided substantial 6 evidence of effectiveness. We are interested in the Committee’s thoughts on how to weigh negative/failed trials in our determination of efficacy for a drug that, if approved, would be used to treat a serious, and potentially life-threatening, illness in a clinical environment where there are many effective treatment options. Background The effectiveness requirement for a drug was added to the Food Drug and Cosmetic Act (FD&CA, the Act) in 1962.1 The 1962 amendments included a provision requiring manufacturers of drug products to establish a drug’s effectiveness by “substantial evidence.” Substantial evidence was defined in section 505(d) of the Act as: “…evidence consisting of adequate and well-controlled investigations, by experts qualified by scientific training and experience to evaluate the effectiveness of the drug involved, on the basis of which it could be fairly and responsibly concluded by such