CENTER FOR DRUG EVALUATION AND RESEARCH APPLICATION NUMBER: 21945Orig1s000 MEDICAL REVIEW(S) Clinical Review Barbara Wesley NDA 21-945 17-alpha hydroxyprogesterone caproate 3 February 2011 CLINICAL REVIEW Application Type NDA Application Number(s) 21-945 Priority or Standard Priority Submit Date(s) 12 July 2010 Received Date(s) 13 July 2010 PDUFA Goal Date 13 April 2011 Division / Office Division of Reproductive and Urologic Products Reviewer Name(s) Barbara Wesley, M.D., M.P.H. Review Completion Date 3 February 2011 Established Name hydroxyprogesterone caproate (Proposed) Trade Name Makena Therapeutic Class Progestin Applicant Hologic Inc. Formulation(s) Injectable (Intramuscular - IM) Dosing Regimen 250 mg (1 mL) weekly from between 16 weeks, 0 days, and 20 weeks 6 days to 37 weeks of gestation or until delivery Indication(s) Reduction of the Risk of Preterm Birth Intended Population(s) Pregnant women with a history of at least one spontaneous singleton preterm birth Reference ID: 2900781 Primary Medical Officer Review Barbara Wesley, M.D., M.P.H. NDA 21-945 17-alpha hydroxyprogesterone caproate Final 3 February 2011 Table of Contents 1 RECOMMENDATIONS/RISK BENEFIT ASSESSMENT.............................................. 5 1.1 Recommendation on Regulatory Action ..........................................................................5 1.2 Risk Benefit Assessment ..................................................................................................5 1.2.1 Efficacy .....................................................................................................................6 1.2.2 Safety.........................................................................................................................7 1.2.3 Summary ...................................................................................................................8 1.3 Recommendations for Postmarket Risk Evaluation and Mitigation Strategies................9 1.4 Recommendations for Postmarket Requirements and Commitments ..............................9 2 INTRODUCTION AND REGULATORY BACKGROUND.......................................... 10 2.1 Product Information........................................................................................................ 10 2.2 Tables of Currently Available Treatments for Proposed Indications.............................11 2.3 Availability of Proposed Active Ingredient in the United States ...................................12 2.4 Important Safety Issues with Consideration to Related Drugs.......................................12 2.4.1 Castor Oil................................................................................................................12 2.5 Summary of Previous Regulatory Activity ....................................................................13 2.5.1 Pre-NDA Activity....................................................................................................13 2.5.2 Regulatory Summary and NDA Actions.................................................................14 2.5.3 Studies to Support NDA 21-945 (Original NDA Submission April 14, 2006).......18 2.5.4 Advisory Committee (August 29, 2006) .................................................................28 2.5.5 Literature – Late Preterm Births..............................................................................30 3 ETHICS AND GOOD CLINICAL PRACTICES ............................................................ 32 3.1 Submission Quality and Integrity...................................................................................32 3.1.1 Institutional Review/Ethics/Consent Form: ............................................................32 3.2 Compliance with Good Clinical Practices......................................................................32 3.3 Financial Disclosures...................................................................................................... 33 4 SIGNIFICANT EFFICACY/SAFETY ISSUES RELATED TO OTHER REVIEW DISCIPLINES...................................................................................................................... 33 4.1 Chemistry Manufacturing and Controls .........................................................................33 4.2 Clinical Microbiology..................................................................................................... 34 4.3 Preclinical Pharmacology/Toxicology ...........................................................................34 4.4 Clinical Pharmacology ...................................................................................................34 5 SOURCES OF CLINICAL DATA..................................................................................... 36 6 REVIEW OF EFFICACY .................................................................................................. 36 6.1 Indication........................................................................................................................36 6.1.1 Methods...................................................................................................................36 6.1.2 Primary Endpoint(s) ................................................................................................36 Reference ID: 2900781 2 Primary Medical Officer Review Barbara Wesley, M.D., M.P.H. NDA 21-945 17-alpha hydroxyprogesterone caproate Final 3 February 2011 6.1.3 Secondary Endpoints(s)...........................................................................................37 6.1.4 Other Endpoints.......................................................................................................38 6.1.5 Study Design........................................................................................................... 38 7 REVIEW OF SAFETY ....................................................................................................... 47 7.7 Additional Submissions/Safety Issues............................................................................47 7.7.1 Data Safety Monitoring Board (DSMB) .................................................................47 7.7.2 Recent Safety Literature..........................................................................................48 7.7.3 Follow-up Study (17P-FU-004) ..............................................................................49 7.7.4 Safety Update.......................................................................................................... 50 8 POSTMARKET EXPERIENCE........................................................................................ 51 9 APPENDICES......................................................................................................................52 9.1 Labeling Recommendations...........................................................................................52 9.2 Bibliography ...................................................................................................................52 Reference ID: 2900781 3 Primary Medical Officer Review Barbara Wesley, M.D., M.P.H. NDA 21-945 17-alpha hydroxyprogesterone caproate Final 3 February 2011 Table of Tables Table 1 Proportion of Subjects with Delivery at <370, <350, and <320 Weeks..........................6 Table 2 Miscarriages, Stillbirths, and Neonatal Deaths..............................................................7 Table 3 Development Delay in Children from Study 17P-CT-002 *.........................................8 Table 4 Proportion of Subjects with Delivery at <370, <350, <320, and <280 Weeks ..............20 Table 5 Enrollment of Subjects by Study Center .....................................................................22 Table 6 Effect of Center on Proportion of Preterm Births at Weeks <37, <35, and <32 .........23 Table 7 Miscarriages, Stillbirths, and Neonatal Deaths............................................................25 Table 8 Selected Pregnancy Complications..............................................................................27 Table 9 Development Delay in Children from Study 17P-CT-002 *.......................................28 Table 10 Schedule of Events for the Study.................................................................................42 Table 11 Sample Size Calculation.............................................................................................. 44 Table 12 Infant Follow-up Minimum Enrollment Estimate .......................................................49 Reference ID: 2900781 4 Primary Medical Officer Review Barbara Wesley, M.D., M.P.H. NDA 21-945 17-alpha hydroxyprogesterone caproate Final 3 February 2011 1 Recommendations/Risk Benefit Assessment 1.1 Recommendation on Regulatory Action As the primary reviewing Medical Officer for this application, I recommend an approval action under the Subpart H regulation (21 CFR 314.510) [also referred to as Subpart H] for 17α- hydroxyprogesterone caproate [hereafter referred to as 17-HPC, but also known as HPC and 17P] for the reduction of the risk of preterm birth (PTB) in women with a singleton pregnancy who have a history of a singleton spontaneous preterm birth. I make this recommendation because the Applicant has fully addressed the clinical deficiencies that are listed in the January 23, 2009 Complete Response letter to my satisfaction. The Subpart H regulation states that: “FDA may grant approval for a new drug product on the basis of adequate and well-controlled clinical trials establishing that the drug product