CENTER FOR DRUG EVALUATION AND RESEARCH APPLICATION NUMBER: 022247Orig1s000 MEDICAL REVIEW(S) CLINICAL REVIEW Application Type NDA Application Number(s) 22247 Priority or Standard Standard Submit Date(s) September 26, 2012 Received Date(s) October 3, 2012 PDUFA Goal Date October 3, 2013 Division / Office DBRUP/ODE III/OND/CDER Reviewer Name(s) Marcea Whitaker, M.D. Stephen Bienz, M.D. Gerald Willett, M.D. Stephen Voss, M.D. Theresa Kehoe, M.D. Review Completion Date June 5, 2013 Established Name Conjugated estrogens/ bazedoxifene (Proposed) Trade Name Duavee Therapeutic Class Estrogen/SERM combination Applicant Wyeth Formulation(s) Coated Tablets Dosing Regimen One tablet daily (0.625/20mg, 0.45/20mg) Indication(s) 1) Treatment mod to severe vasomotor symptoms associated with menopause 2) Treatment mod to severe vulvar and vaginal atrophy associated with menopause 3) Prevention of postmenopausal osteoporosis Intended Population(s) Postmenopausal women with intact uterus Template Version: March 6, 2009 Reference ID: 3319796 Clinical Review Whitaker/Bienz/Willett/Voss/Kehoe NDA 022247 Conjugated estrogen/bazedoxifene Table of Contents 1 Recommendations/Risk Benefit Assessment............................................. 11 1.1 Recommendation on Regulatory Action ........................................................... 11 1.2 Risk Benefit Assessment.................................................................................. 12 1.3 Recommendations for Postmarket Risk Evaluation and Mitigation Strategies . 18 1.4 Recommendations for Postmarket Requirements and Commitments .............. 18 2 Introduction and Regulatory Background ................................................... 18 2.1 Product Information .......................................................................................... 18 2.2 Tables of Currently Available Treatments for Proposed Indications ................. 18 2.3 Availability of Proposed Active Ingredient in the United States ........................ 18 2.4 Important Safety Issues With Consideration to Related Drugs......................... 19 2.5 Summary of Presubmission Regulatory Activity Related to Submission .......... 21 2.6 Other Relevant Background Information .......................................................... 22 2.6.1 Formulation/Bioavailability Issue....................................................................... 22 3 Ethics and Good Clinical Practices ..................................................................... 23 3.1 Submission Quality and Integrity ...................................................................... 23 3.2 Compliance with Good Clinical Practices ......................................................... 24 3.3 Financial Disclosures........................................................................................ 25 4 Significant Efficacy/Safety Issues Related to Other Review Disciplines........... 26 4.1 Chemistry Manufacturing and Controls ............................................................ 26 4.2 Clinical Microbiology......................................................................................... 26 4.3 Preclinical Pharmacology/Toxicology ............................................................... 27 4.4 Clinical Pharmacology...................................................................................... 27 4.4.1 Mechanism of Action ........................................................................................ 27 4.4.2 Pharmacodynamics.......................................................................................... 28 4.4.3 Pharmacokinetics ............................................................................................. 28 5 Sources of Clinical Data............................................................................. 30 5.1 Tables of Studies/Clinical Trials ....................................................................... 30 5.2 Review Strategy ............................................................................................... 32 5.3 Discussion of Individual Studies/Clinical Trials................................................. 32 6 Review of Efficacy ............................................................................................ 58 6.1 Treatment of Moderate to Severe Vasomotor Symptoms................................. 58 6.1.1 Methods ..................................................................................................... 58 6.1.2 Demographics............................................................................................ 58 6.1.3 Subject Disposition..................................................................................... 60 6.1.4 Analysis of Primary Endpoint(s) ................................................................. 61 6.1.7 Subpopulations .......................................................................................... 68 6.1.8 Analysis of Clinical Information Relevant to Dosing Recommendations .... 69 6.1.9 Discussion of Persistence of Efficacy and/or Tolerance Effects................. 69 6.1.10 Additional Efficacy Issues/Analyses ............................................................ 69 6.2 Treatment of Moderate to Severe Vulvar and Vaginal Atrophy ........................ 71 6.2.1 Methods ..................................................................................................... 71 Demographics........................................................................................................ 71 2 Reference ID: 3319796 Clinical Review Whitaker/Bienz/Willett/Voss/Kehoe NDA 022247 Conjugated estrogen/bazedoxifene 6.2.3 Subject Disposition..................................................................................... 72 6.2.4 Analysis of Primary Endpoint(s) ................................................................. 74 6.2.5 Analysis of Secondary Endpoints(s) .......................................................... 79 6.2.6 Other Endpoints ............................................................................................ 80 6.2.7 Subpopulations .......................................................................................... 81 6.2.8 Analysis of Clinical Information Relevant to Dosing Recommendations .... 81 6.2.9 Discussion of Persistence of Efficacy and/or Tolerance Effects................. 82 6.2.10 Additional Efficacy Issues/Analyses ............................................................ 82 6.3 Prevention of Postmenopausal Osteoporosis................................................... 82 6.3.1 Methods ..................................................................................................... 82 6.3.1 Methods ..................................................................................................... 83 Demographics........................................................................................................ 83 Subject Disposition................................................................................................. 85 6.3.4 Analysis of Primary Endpoint: Bone Mineral Density ................................. 87 6.3.5 Analysis of Secondary Endpoints............................................................... 95 6.3.6 Other Endpoints .......................................................................................... 104 6.3.7 Subpopulations ........................................................................................ 114 6.3.8 Analysis of Clinical Information Relevant to Dosing Recommendations .. 114 6.3.9 Discussion of Persistence of Efficacy and/or Tolerance Effects............... 114 6.3.10 Additional Efficacy Issues/Analyses .......................................................... 114 6.4 Endometrial Safety – Endometrial Protection and Endometrial Polyps .......... 115 6.4.1 Study 303.................................................................................................... 115 6.4.2 Study 304.................................................................................................... 139 6.4.3 Study 3307.................................................................................................. 150 6.4.3 Combined Study Information for Endometrial Protection ............................ 155 6.4.4 Combined Study Information for Endometrial Polyps.................................. 156 7 Review of Safety ...................................................................................... 158 7.1 Methods.......................................................................................................... 162 7.1.1 Studies/Clinical Trials Used to Evaluate Safety ....................................... 162 7.1.2 Categorization of Adverse Events............................................................ 165 7.1.3 Pooling of Data Across Studies/Clinical Trials to Estimate and Compare Incidence.................................................................................................. 165 7.2 Adequacy of Safety Assessments .................................................................. 166 7.2.1 Overall Exposure at Appropriate Doses/Durations and Demographics of Target Populations................................................................................... 166 7.2.2 Explorations for Dose Response.............................................................. 166 7.2.3 Special Animal and/or In Vitro Testing ..................................................... 167 7.2.4 Routine Clinical Testing ..........................................................................