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FDA Briefing Document 1 FDA Briefing Document Psychopharmacologic Drugs Advisory Committee (PDAC) and Drug Safety and Risk Management (DSaRM) Advisory Committee Meeting February 12, 2019 Agenda Topic: The committees will discuss the efficacy, safety, and risk-benefit profile of New Drug Application (NDA) 211243, esketamine 28 mg single-use nasal spray device, submitted by Janssen Pharmaceuticals, Inc., for the treatment of treatment-resistant depression 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 have brought New Drug Application 211243, esketamine for the treatment of treatment-resistant depression to this Advisory Committee to gain the Committee’s insights and opinions, and 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. 3 Table of Contents 1. DIVISION DIRECTOR MEMORANDUM ........................................................................... 7 2. Purpose .................................................................................................................................. 11 3. Treatment of Treatment-Resistant Depression ...................................................................... 11 4. Product Under Review........................................................................................................... 14 5. Regulatory Background ......................................................................................................... 15 6. Effectiveness of Esketamine for Treatment of Treatment-Resistant Depression .................. 17 6.1. Phase 3 Study Design .................................................................................................... 17 6.2. Phase 3 Efficacy Results................................................................................................ 21 6.2.1. Study 3002 (TRANSFORM-2) ......................................................................... 22 6.2.2. Study 3003 (SUSTAIN-1) .................................................................................. 23 6.2.3. Study 3001 (TRANSFORM-1) .......................................................................... 29 6.2.4. Study 3005 (TRANSFORM-3) .......................................................................... 31 6.2.5. Secondary Efficacy Endpoints and Other Results of Note ................................. 33 6.3. Relevant Phase 2 Efficacy Results ................................................................................ 38 6.3.1. Study 2003 (SYNAPSE) .................................................................................. 38 6.3.2. Study SUI2001 ................................................................................................. 40 7. Safety of Esketamine for the Treatment of Treatment-Resistant Depression ....................... 41 7.1. Overarching Safety Issues ............................................................................................. 41 7.2. Deaths, Serious Adverse Events, Adverse Events Leading to Study Withdrawal ........ 42 7.2.1. Deaths ............................................................................................................... 42 7.2.2. Serious Adverse Events .................................................................................... 43 7.2.3 Adverse Events Leading to Study Withdrawal ................................................. 43 7.3. Adverse Events .............................................................................................................. 43 7.4. Laboratory Studies, Electrocardiograms (ECGs), and Vital Signs ............................... 47 7.4.1 Laboratory Studies ............................................................................................. 47 7.4.2 ECGs .................................................................................................................. 47 7.4.3 Vital Signs ......................................................................................................... 47 7.4.3.1. Blood Pressure ................................................................................... 47 7.4.3.2 Heart Rate .......................................................................................... 49 7.5. Other Adverse Events of Special Interest ...................................................................... 49 7.5.1. Sedation ............................................................................................................ 49 4 7.5.2. Dissociation ...................................................................................................... 53 7.5.3. Impaired Cognition ........................................................................................... 54 7.5.4. Suicidal Ideation and Behavior......................................................................... 54 7.6. Other Pertinent Safety Studies ....................................................................................... 55 7.6.1 Human Factors Validation Study ..................................................................... 55 7.6.2 Driving Studies ................................................................................................. 56 7.7. Ketamine Postmarketing Safety Concerns and Potential Relevance to Esketamine ..... 56 7.7.1. Adverse Events Related to Repeated Off-label Use of Ketamine .................... 56 7.7.2. Ketamine Abuse and Associated Harms .......................................................... 57 8. Risk Mitigation ...................................................................................................................... 58 8.1. Safety Concerns Associated with Esketamine............................................................... 58 8.2. Risk Evaluation and Mitigation Strategy (REMS) Background ................................... 59 8.3. Applicant’s REMS Proposal .......................................................................................... 60 8.4. Agency Proposed REMS ............................................................................................... 61 9. Attachments ........................................................................................................................... 63 9.1. Attachment 1 - Pharmacovigilance and Drug Utilization Review ................................. 63 9.2. Attachment 2 ‐ Drug Abuse Epidemiology Review ...................................................... 107 5 List of Tables Table 1 Summary of FDA-Approved Products for Treatment of TRD ........................................ 13 Table 2 Esketamine Phase 3 Randomized Double-Blind Active-Controlled Studies .................. 19 Table 3 Study 3002 Primary Endpoint MADRS Total Score CFB at Day 28 Using MMRM (Full Analysis Population) ..................................................................................................................... 23 Table 4 Study 3003 Primary Efficacy Endpoint of Time to Relapse in Stable Remitters ............ 25 Table 5 Study 3003 Secondary Efficacy Endpoint of Time to Relapse in Stable Responders ..... 26 Table 6 Study 3001 Primary Endpoint MADRS Total Score CFB at Day 28 Using MMRM (Full Analysis Population) ..................................................................................................................... 30 Table 7 Study 3005 Primary Endpoint MADRS Total Score Change from Baseline at Day 28 Using MMRM (Full Analysis Population) ................................................................................... 33 Table 8 Esketamine Secondary Efficacy Endpoints ..................................................................... 34 Table 9 MADRS Score Change from Baseline for Prior Approved Antidepressants .................. 38 Table 10 MADRS Total Score: Change from Baseline to End Point ANCOVA LOCF Analysis; Double-Blind Phase, Panel A, Periods 1, 2, and Combined ......................................................... 39 Table 11 Study SUI2001 MADRS Mean Total Score Change from Baseline ............................. 41 Table 12 SAEs in Esketamine and Placebo Groups in Studies 3001, 3002, and 3005 ................. 43 Table 13 Adverse Events Greater than 2% and Twice the Rate of Placebo by Treatment Group in Studies 3001 and 3002 (subjects <65 years old), n(%). ................................................................ 44 Table 14 Adverse Events Greater than 2% and Twice the Rate of Placebo by Treatment Group in Study 3005 (subjects ≥65 years old), n(%). .................................................................................. 45 Table 15 Cystitis-related Adverse Events by Treatment Group in Studies 3001, 3002, and 3005 ......................................................................................................................................................
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