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21225 Mirena Clinical PREA CLINICAL REVIEW Application Type NDA Application Number 21-225 (SE1- Applicant submission 027) Priority or Standard Priority Submit Date March 31, 2009 Received Date April 1, 2009 PDUFA Goal Date October 1, 2009 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 September 16, 2009 Established Name Levonorgestrel-releasing intrauterine system (LNG IUS) Trade Name Mirena® Therapeutic Class Progestin-containing intrauterine device Applicant Bayer HealthCare Pharmaceuticals Inc. Formulation Intrauterine device Dosing Regimen Insertion into the uterine cavity (5 year contraceptive efficacy) Indication Treatment of heavy menstrual bleeding for women who choose to use intrauterine contraception as their method of contraception Intended Population Women of childbearing age Template Version: March 6, 2009 Clinical Review Gerald Willett, M.D. NDA 21-225, SE1 Mirena® (levonorgestrel-releasing intrauterine system) Table of Contents 1 RECOMMENDATIONS/RISK BENEFIT ASSESSMENT....................................... 10 1.1 Recommendation on Regulatory Action ........................................................... 10 1.2 Risk Benefit Assessment.................................................................................. 10 1.3 Recommendations for Postmarket Risk Evaluation and Mitigation Strategies . 13 1.4 Recommendations for Postmarket Requirements and Commitments .............. 13 2 INTRODUCTION AND REGULATORY BACKGROUND ...................................... 14 2.1 Product Information .......................................................................................... 14 2.2 Currently Available Treatments for Proposed Indications................................. 15 2.3 Availability of Proposed Active Ingredient in the United States ........................ 16 2.4 Important Safety Issues with Consideration to Related Drugs.......................... 16 2.5 Summary of Presubmission Regulatory Activity Related to Submission .......... 16 2.6 Other Relevant Background Information .......................................................... 18 3 ETHICS AND GOOD CLINICAL PRACTICES....................................................... 19 3.1 Submission Quality and Integrity ...................................................................... 19 3.2 Compliance with Good Clinical Practices ......................................................... 19 3.3 Financial Disclosures........................................................................................ 19 4 SIGNIFICANT EFFICACY/SAFETY ISSUES RELATED TO OTHER REVIEW DISCIPLINES ......................................................................................................... 20 4.1 Chemistry Manufacturing and Controls ............................................................ 20 4.2 Clinical Microbiology......................................................................................... 20 4.3 Preclinical Pharmacology/Toxicology ............................................................... 20 4.4 Clinical Pharmacology...................................................................................... 20 5 SOURCES OF CLINICAL DATA............................................................................ 21 5.1 Tables of Studies/Clinical Trials ....................................................................... 21 5.2 Review Strategy ............................................................................................... 31 5.3 Discussion of Individual Studies/Clinical Trials................................................. 31 5.3.1 Pivotal Study 309849 (Report A38313)......................................................... 31 5.3.2 Study 92549 (Reports A02916 and B088) .................................................... 63 5.3.3 Study 94548 (Report A00630)....................................................................... 67 5.3.4 Study 93547 (Report A14096)....................................................................... 70 5.3.5 Study 302760 (Report A36340)..................................................................... 73 5.3.6 Study 303003 (Report A00696)..................................................................... 75 5.3.7 Study 93503 (Report BC71).......................................................................... 77 5.3.8 Study 90528 (Report B086)........................................................................... 79 5.3.9 Study 92501 (Report AY01) .......................................................................... 80 5.3.10 Study 91539 (Report AW82) ....................................................................... 81 6 REVIEW OF EFFICACY......................................................................................... 81 2 Clinical Review Gerald Willett, M.D. NDA 21-225, SE1 Mirena® (levonorgestrel-releasing intrauterine system) Efficacy Summary...................................................................................................... 81 6.1 Indication (Treatment of Heavy Menstrual Bleeding)........................................ 81 6.1.1 Methods ..................................................................................................... 81 6.1.2 Demographics............................................................................................ 86 6.1.3 Subject Disposition .................................................................................... 87 6.1.4 Analysis of Primary Endpoint(s) ................................................................. 87 6.1.5 Analysis of Secondary Endpoints............................................................... 90 6.1.6 Other Endpoints ......................................................................................... 92 6.1.7 Subpopulations .......................................................................................... 92 6.1.8 Analysis of Clinical Information Relevant to Dosing Recommendations .... 93 6.1.9 Discussion of Persistence of Efficacy and/or Tolerance Effects................. 93 6.1.10 Additional Efficacy Issues/Analyses........................................................... 93 7 REVIEW OF SAFETY............................................................................................. 93 Safety Summary ........................................................................................................ 93 7.1 Methods............................................................................................................ 93 7.1.1 Studies/Clinical Trials Used to Evaluate Safety ......................................... 93 7.1.2 Categorization of Adverse Events.............................................................. 93 7.1.3 Pooling of Data Across Studies/Clinical Trials to Estimate and Compare Incidence.................................................................................................... 94 7.2 Adequacy of Safety Assessments .................................................................... 94 7.2.1 Overall Exposure at Appropriate Doses/Durations and Demographics of Target Populations..................................................................................... 94 7.2.2 Explorations for Dose Response................................................................ 94 7.2.3 Special Animal and/or In Vitro Testing ....................................................... 94 7.2.4 Routine Clinical Testing ............................................................................. 95 7.2.5 Metabolic, Clearance, and Interaction Workup .......................................... 95 7.2.6 Evaluation for Potential Adverse Events for Similar Drugs in Drug Class .. 95 7.3 Major Safety Results ........................................................................................ 95 7.3.1 Deaths........................................................................................................ 95 7.3.2 Nonfatal Serious Adverse Events .............................................................. 95 7.3.3 Discontinuations Due to Adverse Events ................................................... 96 7.3.4 Significant Adverse Events ........................................................................ 98 7.3.5 Submission Specific Primary Safety Concerns .......................................... 98 7.4 Supportive Safety Results ................................................................................ 98 7.4.1 Common Adverse Events .......................................................................... 98 7.4.2 Laboratory Findings ................................................................................... 98 7.4.3 Vital Signs.................................................................................................. 99 7.4.4 Electrocardiograms (ECGs) ....................................................................... 99 7.4.5 Special Safety Studies/Clinical Trials......................................................... 99 7.4.6 Immunogenicity.......................................................................................... 99 7.5 Other Safety Explorations................................................................................. 99 7.5.1 Dose Dependency for Adverse Events ...................................................... 99 7.5.2 Time Dependency for Adverse Events....................................................... 99 3 Clinical Review Gerald Willett, M.D. NDA 21-225, SE1
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