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021463Orig1s000 CENTER FOR DRUG EVALUATION AND RESEARCH APPLICATION NUMBER: 021463Orig1s000 MEDICAL REVIEW(S) CLINICAL REVIEW Application Type NDA Resubmission Application Number(s) NDA 21-463 Priority or Standard Standard (Complete Response to October 16, 2009, Action Letter) Submit Date(s) 2010-06-30 Received Date(s) 2010-06-30 PDUFA Goal Date 2010-12-30 Division / Office DRUP / ODE 3 Reviewer Name(s) Guodong Fang Review Completion Date 2010-12-01 (Final draft) Established Name Testosterone 2% Gel (Proposed) Trade Name Fortesta Therapeutic Class Topical Steroid Androgen Applicant ENDO Pharmaceuticals, Inc. Formulation(s) C19H28O2 (MW 288.42) Dosing Regimen 2% Testosterone Gel Indication(s) Adult Male Hypogonadism Intended Population(s) Adult Men with Hypogonadism Reference ID: 2878718 Clinical Review Guodong Fang, MD NDA 21463 (June 2010 Re-submission) Fortesta (2% Testosterone gel) Table of Contents 1 RECOMMENDATIONS/RISK BENEFIT ASSESSMENT.............................................. 7 1.1 Recommendation on Regulatory Action..................................................................... 7 1.2 Risk Benefit Assessment ............................................................................................ 7 1.3 Recommendations for Postmarket Risk Evaluation and Mitigation Strategies........ 11 1.4 Recommendations for Postmarket Requirements and Commitments ...................... 12 2 INTRODUCTION AND REGULATORY BACKGROUND.......................................... 13 2.1 Product Information.................................................................................................. 13 2.2 Tables of Currently Available Treatments for Proposed Indications ....................... 13 2.3 Important Safety Issues With Consideration to Related Drugs ................................ 15 2.4 Summary of Presubmission Regulatory Activity Related to Submission ................ 15 3 ETHICS AND GOOD CLINICAL PRACTICES ............................................................ 17 4 SIGNIFICANT EFFICACY/SAFETY ISSUES RELATED TO OTHER REVIEW DISCIPLINES...................................................................................................................... 17 4.1 Chemistry Manufacturing and Controls ................................................................... 17 4.2 Clinical Microbiology............................................................................................... 17 4.3 Preclinical Pharmacology/Toxicology...................................................................... 17 4.4 Clinical Pharmacology.............................................................................................. 17 4.5 Biostatistics............................................................................................................... 17 4.6 Consults from Other Dvisions .................................................................................. 17 5 SOURCES OF CLINICAL DATA..................................................................................... 21 5.1 Size of the Testosterone dataset and the Number of Invalid Results........................ 21 5.2 Concordance of the Original results and the Re-assayed Results............................. 22 6 REVIEW OF EFFICACY .................................................................................................. 25 Efficacy Summary...................................................................................................................... 25 6.1 Re-analyses of Primary and Secondary Endpoints................................................... 27 6.2 Details of Day 90 Samples which were not available for re-assay........................... 27 6.3 Subjects with Cmax valuse > 1800 ng/dL on Dy 90................................................... 37 6.4 Subjects with body mass index (BMI) > 35 kg/m2 ................................................... 37 6.5 Summary and Conclusions for the Efficacy based on total serum Testosterone...... 37 6.6 Efficacy Assessment based on Other Hormones (DHT/T ratio, FSH) ..................... 37 6.7 Final Conclusion for Efficacy................................................................................... 37 7 REVIEW OF SAFETY ....................................................................................................... 38 Safety Summary......................................................................................................................... 38 7.1 No changes between this submission and the submission in 2009........................... 38 7.2 PSA issues................................................................................................................. 38 7.3 Postmarketing Safety Data........................................................................................ 39 Reference ID: 2878718 2 Clinical Review Guodong Fang, MD NDA 21463 (June 2010 Re-submission) Fortesta (2% Testosterone gel) 7.3.1 Exposure Estimates ................................................................................................. 39 7.3.2 Adverse Reactions................................................................................................... 42 7.4 Overall Safety Conclusions ...................................................................................... 44 8 POSTMARKET REQUIREMENT ................................................................................... 45 9 LABELING .......................................................................................................................... 46 10 APPENDICES...................................................................................................................... 46 Reference ID: 2878718 3 Clinical Review Guodong Fang, MD NDA 21463 (June 2010 Re-submission) Fortesta (2% Testosterone gel) Table of Tables Table 1.1 Analysis of the Original and Re-assayed Results of Total Serum Testosterone Cavg and Cmax at Day 90 for All Modified ITT (MITT) Subjects..................................... 10 Table 2.1 Currently Available Testosterone Products in the United States ....................................... 14 Table 2.2 Cmax outliers from Study T 00-03-01 in Original Submission of NDA 21463........ 15 Table 5.1 Summary of the Number of Samples by Day which Had Invalid Results (All Subjects).................................................................................................................... 21 Table 5.2 Number of Original Valid and Invalid Results Summarized by Original Assay and Re-assay on Day 90.................................................................................................... 21 Table 5.3 Summary of the Number of Samples that Were Originally Assayed, Re-assayed, and the Number of Valid and Invalid Results on Day 90Re-assay on Day 90 ................. 22 Table 5.4 Concordance Correlation Coefficients (CCC)........................................................... 23 Table 6.1 Analysis Subjects Sets ............................................................................................... 25 Table 6.2 Analysis of the Original and Re-assayed Results of Total Serum Testosterone Cavg and Cmax at Day 90 for All Modified Intent-to-Treat (MITT) Subjects ................... 26 Table 6.3 Analysis of the Original and Re-assayed Results of Total Serum Testosterone Cavg and Cmax at Day 90 for All Modified Intent-to-Treat (MITT) Subjects Analyses of the Original and Re-assayed Results of Total Serum Testosterone Cavg and Cmax at Day 90 for Subjects in the MITT Population with BMI < 35 kg/m2 ........................ 27 Table 6.4 Cavg and Cmax from the 9 subjects who did not have any Day 90 samples available for Re-assay (N = 89 Samples)....................................................................................... 28 Table 6.5 Samples with Valid original assay but no re-assayed results (N=32 samples from 22 subjects)Subjects Sets............................................................................................... 29 Table 6.6 Subjects with Day 90 samples which were not assayed in a valid bioanalytical assay and their Cavg (N=7 samples; 6 samples from MITT Population)Subjects Sets....... 30 Table 6.7 Subjects with Cmax Values > 188 ng/dL on Day 90................................................... 32 Table 6.8 Subjects in MITT Population with a BMI > 35 kg/m2 .............................................. 33 Reference ID: 2878718 4 Clinical Review Guodong Fang, MD NDA 21463 (June 2010 Re-submission) Fortesta (2% Testosterone gel) Table 6.9 Analysis of DHT, DHT/T ratio, estradiol, FSH and free T at baseline and 2 hours after FORTESTA application on Days 14, 35, 60, and 90 for the MITT population 35 Table 6.10 DHT/T ratio and change from baseline for the MITT Population ................................... 36 Table 6.11 Analysis of FSH at baseline and 2 hrs after application on Days 35 & 90 for the MITT population, and the re-assay values from runs which initially failed............. 36 Table 7.1 Summary of AE case Reports from All Sources sort by MedDRA System.............. 43 Reference ID: 2878718 5 Clinical Review Guodong Fang, MD NDA 21463 (June 2010 Re-submission) Fortesta (2% Testosterone gel) Table of Figures Figure 5.1 Scatter Plot of All of the Original Results Versus Re-assayed Results for Total Testosterone (N=3318) ............................................................................................. 24 Figure 5.2 Scatter Plot of Day 90 Results Versus Re-assayed Results for Total Testosterone (N=1253)Scatter Plot of All of the Original Results
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