CLINICAL REVIEW Application Type NDA Application Number 22-252 Priority or Standard Standard Submit Date July 6, 2009 PDUFA Goal Date May 6, 2010 Division / Office Division of Reproductive and Urologic Products (DRUP) / Office of Drug Evaluation III (ODE III) Reviewer Name Gerald Willett M.D. Review Completion Date April 28, 2010 Established Name Estradiol valerate / Dienogest (EV/DNG) Trade Name To be determined Therapeutic Class Combination oral contraceptive Applicant Bayer HealthCare Pharmaceuticals Inc. Formulation Oral tablets Dosing Regimen - Days 1-2 (3.0 mg EV) Cycle Days (dose) Days 3-7 (2.0 mg EV + 2.0 mg DNG) Days 8-24 (2.0 mg EV + 3.0 mg DNG) Days 25-26 (1.0 mg EV) Days 27-28 (placebo) Indication Contraception (primary) Heavy and/or prolonged menstrual bleeding (secondary) Intended Population Women of childbearing age Clinical Review Gerald Willett, M.D. NDA 22-252 (EV/DNG) Table of Contents 1 RECOMMENDATIONS/RISK BENEFIT ASSESSMENT....................................... 11 1.1 Recommendation on Regulatory Action ........................................................... 11 1.2 Risk Benefit Assessment.................................................................................. 11 1.3 Recommendations for Postmarket Risk Evaluation and Mitigation Strategies... 14 1.4 Recommendations for Postmarket Requirements and Commitments .............. 14 2 INTRODUCTION AND REGULATORY BACKGROUND ...................................... 15 2.1 Product Information .......................................................................................... 15 2.2 Currently Available Treatments for Proposed Indications................................. 15 2.3 Availability of Proposed Active Ingredients in the United States....................... 16 2.4 Important Safety Issues with Consideration to Related Drugs.......................... 17 2.5 Summary of Presubmission Regulatory Activity Related to Submission .......... 17 2.6 Other Relevant Background Information .......................................................... 20 3 ETHICS AND GOOD CLINICAL PRACTICES....................................................... 21 3.1 Submission Quality and Integrity ...................................................................... 21 3.2 Compliance with Good Clinical Practices ......................................................... 22 3.3 Financial Disclosures........................................................................................ 22 4 SIGNIFICANT EFFICACY/SAFETY ISSUES RELATED TO OTHER REVIEW DISCIPLINES ......................................................................................................... 24 4.1 Chemistry Manufacturing and Controls ............................................................ 24 4.2 Clinical Microbiology......................................................................................... 24 4.3 Preclinical Pharmacology/Toxicology ............................................................... 24 4.4 Clinical Pharmacology...................................................................................... 25 4.5 Biostatistics.......................................................................................................... 26 4.6 Interdisciplinary Review Team for QT Studies..................................................... 28 5 SOURCES OF CLINICAL DATA............................................................................ 28 5.1 Tables of Studies/Clinical Trials ....................................................................... 28 5.2 Review Strategy ............................................................................................... 37 5.3 Discussion of Individual Studies/Clinical Trials................................................. 37 5.3.1 Pivotal Study 306660 (Report A35179) for Contraception ............................ 37 5.3.2 Pivotal Study 304742 (Report A39818) for Contraception ............................ 70 5.3.3 Pivotal Study 304004 (Report A35644) for Contraception (Also Cycle Control) ................................................................................................................... 90 5.3.4 Pivotal Study 308960 (Report A29849) for DUB ......................................... 107 5.3.5 Pivotal Study 308961 (Report A42568) for DUB ......................................... 134 5.3.6 Other Studies .............................................................................................. 148 6 REVIEW OF EFFICACY....................................................................................... 186 Efficacy Summary.................................................................................................... 186 6.1 Contraceptive Indication ................................................................................. 186 2 Clinical Review Gerald Willett, M.D. NDA 22-252 (EV/DNG) 6.1.1 Methods ................................................................................................... 186 6.1.2 Demographics.......................................................................................... 187 6.1.3 Subject Disposition .................................................................................. 189 6.1.4 Analysis of Primary Endpoint ................................................................... 189 6.1.5 Analysis of Secondary Endpoints............................................................. 190 6.1.6 Other Endpoints ....................................................................................... 191 6.1.7 Subpopulations ........................................................................................ 191 6.1.8 Analysis of Clinical Information Relevant to Dosing Recommendations .. 191 6.1.9 Discussion of Persistence of Efficacy....................................................... 191 6.1.10 Additional Efficacy Issues/Analyses .......................................................... 191 6.2 Heavy and/or Prolonged Menstrual Bleeding Indication (DUB) ........................ 192 6.2.1 Methods ...................................................................................................... 192 6.2.2 Demographics and Baseline Bleeding Symptoms....................................... 192 6.2.3 Disposition................................................................................................... 193 6.2.4 Analysis of Primary Endpoint ...................................................................... 195 6.2.5 Analysis of Secondary Endpoints (Pooled Analysis) ................................... 199 6.2.6 Other Endpoints .......................................................................................... 204 6.2.7 Subpopulations ........................................................................................... 204 6.2.8 Analysis of Clinical Information Relevant to Dosing Recommendations ..... 204 6.2.9 Discussion of Persistence of Efficacy.......................................................... 204 6.2.10 Additional Efficacy Issues / Analyses ........................................................ 205 6.2.11 Summary of DUB Efficacy......................................................................... 207 7 REVIEW OF SAFETY........................................................................................... 208 Safety Summary ...................................................................................................... 208 7.1 Methods.......................................................................................................... 208 7.1.1 Components of NDA 22-252 Used to Evaluate Safety............................. 208 7.1.2 Categorization of Adverse Events............................................................ 209 7.1.3 Pooling of Data across Studies/Clinical Trials to Estimate and Compare Incidence.................................................................................................. 209 7.2 Adequacy of Safety Assessments .................................................................. 209 7.2.1 Overall Exposure at Appropriate Doses/Durations and Demographics of Target Populations................................................................................... 209 7.2.2 Explorations for Dose Response.............................................................. 210 7.2.3 Special Animal and/or In Vitro Testing ..................................................... 210 7.2.4 Routine Clinical Testing ........................................................................... 210 7.2.5 Metabolic, Clearance, and Interaction Workup ........................................ 210 7.2.6 Evaluation for Potential Adverse Events for Similar Drugs in Drug Class 210 7.3 Major Safety Results ...................................................................................... 210 7.3.1 Deaths...................................................................................................... 210 7.3.2 Nonfatal Serious Adverse Events ............................................................ 211 7.3.3 Discontinuations Due to Adverse Events ................................................. 212 7.3.4 Significant Adverse Events ...................................................................... 213 7.3.5 Submission Specific Primary Safety Concerns ........................................ 213 7.4 Supportive Safety Results .............................................................................. 214 3 Clinical Review Gerald Willett, M.D. NDA 22-252 (EV/DNG) 7.4.1 Common Adverse Events .......................................................................