1 FDA Briefing Document Joint Meeting of Anesthetic and Analgesic Drug Products Advisory Committee and Drug Safety and Risk Management Advisory Committee January 15, 2020 (AM Session) 2 DISCLAIMER STATEMENT 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. The new drug application (NDA) 213426 for tramadol 44mg and celecoxib 56mg tablet, which contains a fixed dose combination of an opioid and an NSAID for the management of acute pain in adults that is severe enough to require an opioid analgesic and for which alternative treatments are inadequate, has been brought to this 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. 3 FOOD AND DRUG ADMINISTRATION Center for Drug Evaluation and Research Joint Meeting of the Anesthetic and Analgesic Drug Products Advisory Committee and Drug Safety & Risk Management Advisory Committee January 15, 2020 Table of Contents 1 Division Memorandum ........................................................................................................ 5 2 Discussion Topics ................................................................................................................ 6 3 Background ............................................................................................................................. 6 4 Benefit- Risk Integrated Assessment ..................................................................................... 9 5 Regulatory Background ..................................................................................................... 11 6 Summary of Chemistry, Manufacturing and Controls Data...................................................... 13 7 Summary of Clinical Pharmacology Data ............................................................................. 13 8 Overview of Clinical Studies ............................................................................................. 14 9 Efficacy Results: Clinical and Statistical Summary ........................................................... 19 10 Safety: Overview and Findings ................................................................................................ 26 11 Safety in the Postmarket Setting............................................................................................... 30 12 Appendices ......................................................................................................................... 32 12.1 Clinical Pharmacology Supplementary Information .................................................. 32 12.2 Clinical Supplementary Information ........................................................................... 37 12.3 Supplementary Tables Relevant to Clinical Safety Evaluation ................................... 46 13 Attachments ....................................................................................................................... 48 Epidemiology and Drug Use Review Risk Management Summary 4 List of Tables Table 1: Treatment Arms for Study ESTEVE-SUSA-301 Table 2: Dosing Scheme for Study ESTEVE-SUSA-301 Table 3: Summary of Reasons for Discontinuation of Study Medications or Withdrawal From Study Table 4: Baseline Pain Group (Full Analysis Set) Table 5: SPID48: Primary Analysis Results (BOCF Method) Table 6: SPID48: Analysis Results from the MI Method Table 7: Rescue Medication Use (Full Analysis Set) Table 8: Time (hours) to First Use of Rescue Medication: Quartiles of Distribution (Full Analysis Set) Table 9: Time to First Use of Rescue Medication: Cox Regression Analysis (Full Analysis Set) Table 10: Time to Meaningful Pain Relief (Full Analysis Set) Table 11: TEAEs in Study ESTEVE-SUSA-301 by Preferred Terms Related to CNS Depression Table 12: The mean PK parameters of tramadol, M1 and celecoxib parameters of E-58425 tablets (test drug) and Ultram tablets or Celebrex capsule (reference drugs) Table 13: Relative BA assessment of tramadol and celecoxib of E-58425 tablets versus Ultram tablets (tramadol) or Celebrex capsule (Celecoxib) Table 14: Mean PK parameters of tramadol, M1 and celecoxib of E-58425 tablets (test drug) and Adolonta or Celebrex (reference drugs) administered BID, 12 hours apart, for 15 consecutive doses Table 15: The mean PK parameters of tramadol, M1 and celecoxib parameters of E-58425 tablets under fed versus fasting conditions Table 16: Food-effect relative bioavailability assessment of E-58425 tablets (fed versus fasting conditions) Table 17: Listing of Clinical Trials Conducted by the Applicant Relevant to This NDA Table 18: Listing of Clinical Trials Performed by Mundipharma Research Ltd* Table 19: SPID (0-8 hours), Last-Observation-Carried-Forward (LOCF), PP Set Table 20: Cumulative Subject Exposure for Safety Population Table 21: Most Frequently Reported TEAEs in >5% of Subjects in Any Treatment Group by System Organ Class and Preferred Term in Study ESTEVE-SUSA-301 Table 22: Common TEAEs (>5% of Subjects) in Any Group by Severity, System Organ Class, and Preferred Term in Study ESTEVE-SUSA-301 List of Figures Figure 1: Study Design Scheme Figure 2: Disposition of Subjects for Study ESTEVE-SUSA-301 Figure 3: Mean Pain Intensity Scores Over Time (Using Observed PI Scores) Figure 4: Mean PI Scores Over Time (Pre-Rescue PI Score Was Imputed up to 4 Hours After Rescue Use Figure 5: Mean PI Scores Over Time (Pre-Rescue PI Score Was Imputed up to 4 Hours After Rescue Use and Missing PI Scores Were Imputed by the MI Method) Figure 6: Overview of Study ESTEVE-SACO4-201 Figure 7: Mean SPID (0-8 hours) With 95% CI, Last-Observation-Carried-Forward (LOCF), PP Seta 5 Division of Anesthesiology, Addiction Medicine and Pain Medicine (DAAP) Director Memorandum FDA CENTER FOR DRUG EVALUATION AND RESEARCH DIVISION OF ANESTHESIOLOGY, ADDICTION MEDICINE AND PAIN MEDICINE M E M O R A N D U M DATE: January 15, 2020 FROM: Naomi Lowy, MD Deputy Director (Acting) Division of Anesthesiology, Addiction Medicine and Pain Medicine Office of Neuroscience, CDER, FDA TO: Chair, Members and Invited Guests Anesthetic and Analgesic Drug Products Advisory Committee (AADPAC) Drug Safety and Risk Management Advisory Committee (DSaRM) RE: Overview of the January 15, 2020, AADPAC/DSaRM Meeting to Discuss NDA 213426 1 Division Memorandum At this half-day, joint meeting of AADPAC and DSaRM, we will be discussing an application from Esteve Pharmaceuticals for E-58425 (tramadol hydrochloride (HCl) 44 mg and celecoxib 56 mg), a fixed-dose combination drug product. The proposed indication is for the management of acute pain in adults that is severe enough to require an opioid analgesic and for which alternative treatments are inadequate. The Applicant’s goal was to develop a formulation of two analgesics of different classes such that the recommended dose of each component of the drug is less than the recommended dose of each component when taken individually for management of acute pain. The product contains tramadol, an opioid with abuse potential, and has not been formulated with any excipients to impart abuse-deterrent characteristics. As an opioid-containing product, the considerations described in the Agency’s draft guidance Opioid Analgesic Drugs: Considerations for Benefit‐Risk Assessment Framework, Guidance for Industry (June 2019) are relevant to the benefit-risk assessment of E-58425. 6 This Briefing Document summarizes data related to both benefit and risk of E-58425. A Phase 3 factorial study demonstrated that each component of E-58425 contributes to the efficacy of the product and provides evidence that supports a finding of analgesic efficacy for E-58425. From a safety perspective, there are no data to support a conclusion that E-58425 has any advantage or disadvantage compared to other approved analgesic drugs. During this meeting, to help inform your thinking, you will hear a review of recent epidemiologic data on use, misuse, and abuse of tramadol. If approved, E-58425 will add an alternative option to the existing armamentarium for the treatment of acute pain severe enough to require an opioid. The Comprehensive Addiction and Recovery Act of 2016, Section 106, requires FDA to refer new drug applications for opioids to an advisory committee before approval. As we review this new drug application of an opioid analgesic combined with a non-steroidal anti-inflammatory drug, we are interested in your thoughts, concerns, and recommendations. You will specifically be asked whether you have concerns about the impact of this product on public health. You will also be asked if you believe the benefits outweigh the risks for the proposed indication. Your advice and recommendations will be essential in assisting