CENTER FOR DRUG EVALUATION AND RESEARCH APPLICATION NUMBER: 200327 STATISTICAL REVIEW(S) Department of Health and Human Services Food and Drug Administration Center for Drug Evaluation and Research Office of Translational Sciences Office of Biostatistics S TATISTICAL R EVIEW AND E VAL UATION CLINICAL STUDIES NDA # : 200327 Drug Name: TeflaroTM (ceftaroline fosamil for injection) Indication: Acute bacterial skin and Skin Structure Infections Applicant: Cerexa (a wholly owned subsidiary of Forest Laboratories, Inc.) Stamp Date: December 30, 2009 PDUFA Goal Date: October 30, 2010 Reviewer Completion Date: October 8, 2010 Biometrics Division: Division of Biometrics IV Medical Division: Division of Anti-Infective and Ophthalmology Drug Products Documents Reviewed: \\CDSESUB1\EVSPROD\NDA200327\0000 Statistical Reviewer: Christopher Kadoorie, PhD Concurring Reviewers: Thamban Valappil, PhD Clinical Team Leader: Janice Pohlman, MD Clinical Reviewers: Neil Rellosa, MD Project Manager: Carmen DeBellas, Pharm D 1 TABLE OF CONTENTS 1. EXECUTIVE SUMMARY .......................................................................................... 5 1.1 INTRODUCTION...................................................................................................................................... 5 1.2 CONCLUSIONS AND RECOMMENDATIONS .............................................................................................. 5 1.3 BRIEF OVERVIEW OF CLINICAL STUDIES ............................................................................................... 6 1.4 MAJOR STATISTICAL ISSUES AND FINDINGS .......................................................................................... 7 2. INTRODUCTION......................................................................................................... 8 2.1 CLASS AND INDICATION ........................................................................................................................ 8 2.2 HISTORY OF DRUG DEVELOPMENT FOR ABSSSI................................................................................... 8 3. STATISTICAL EVALUATION ................................................................................. 9 3.1 EVALUATION OF EFFICACY.................................................................................................................... 9 3.1.1 Study Design and Endpoints.......................................................................................................... 9 3.1.2 Subject Disposition, Demographic and Baseline Characteristics............................................... 14 3.1.3 Statistical Methodologies ............................................................................................................ 16 3.1.4 Results of Analyses ...................................................................................................................... 19 3.1.5 Efficacy Conclusions ................................................................................................................... 28 3.2 EVALUATION OF SAFETY ..................................................................................................................... 28 4. SPECIAL/SUBGROUP POPULATIONS................................................................ 28 4.1 SUBGROUP ANALYSES......................................................................................................................... 28 4.1.1 Analyses by Infection Types......................................................................................................... 29 4.1.2 Analyses by Region...................................................................................................................... 30 4.1.3 Analyses by Baseline Fever Status .............................................................................................. 31 4.1.4 Analyses by Prior Antibiotics Use ............................................................................................... 33 4.1.5 Analyses by Concomitant Antipyretics and Anti-Inflammatory Use............................................ 34 4.2 EXPLORATORY/SENSITIVITY ANALYSES ............................................................................................. 36 4.2.1 Analyses at Days 2-5 ................................................................................................................... 36 4.2.2 Analyses for Various % Reductions............................................................................................. 38 4.2.3 Comparisons of Distributions for % Reduction in Lesion Area .................................................. 40 4.2.4 Analyses of Missing Data ............................................................................................................ 40 4.2.5 Responder Rates Using a Carry Forward Approach .................................................................. 41 4.2.6 Concordance/Discordance of Responder Rates with EOT Assessment....................................... 41 5. LIMITATIONS........................................................................................................... 42 5.1 LIMITATIONS (GENERAL) .................................................................................................................... 42 5.1.1 Uncertainties in Reliably Measuring Lesion Size........................................................................ 42 5.1.2 NI Margin Justification from Historical Studies ......................................................................... 43 5.1.3 Post-hoc Nature of Testing Hypotheses....................................................................................... 43 5.1.4 Interpretation of Responder Rates............................................................................................... 43 5.1.5 Types of Patients/Symptoms Addressed....................................................................................... 44 5.2 LIMITATIONS (SPECIFIC TO STUDIES 06 & 07)..................................................................................... 44 5.2.1 Higher Rates of Missing Data ..................................................................................................... 44 5.2.2 Investigator Errors & Biases in Measuring Lesion Size ............................................................. 44 5.2.3 Influence of Prior Antibiotics Use ............................................................................................... 45 5.2.4 Influence of Concomitant Antipyretic & Anti-inflammatory Use ................................................ 45 5.2.5 Dependence on Baseline Fever Status......................................................................................... 46 5.2.6 Discordance of Responder Rates with EOT Assessment ............................................................. 46 5.2.7 Reductions in Sample Size ........................................................................................................... 46 6. ADVISORY COMMITTEE MEETING .................................................................. 47 7. SUMMARY AND CONCLUSIONS ......................................................................... 48 REFERENCES................................................................................................................ 49 APPENDIX...................................................................................................................... 50 2 List of Tables Table 1: Applicant’s Overview of Studies 06 & 07 ........................................................................ 6 Table 2: Standard Dosing Schedule ................................................................................................ 9 Table 3: Applicant’s Study 06 & 07 Design.................................................................................. 10 Table 4: Analysis Populations, Number of Subjects ..................................................................... 11 Table 5: Clinical Response Definition .......................................................................................... 12 Table 6: Baseline Characteristics of Disease Severity in FDA-MITT Patients............................. 14 Table 7: Types of Skin Infections at Baseline............................................................................... 15 Table 8: Infection Size at Baseline................................................................................................ 16 Table 9: Applicant’s Analyses of Clinical Cure Rates at TOC ..................................................... 19 Table 10: Responder Rates............................................................................................................ 21 Table 11: Rates for Cessation/Percent Reduction of Lesion Spread ............................................. 23 Table 12: Clinical Cure Rates at EOT........................................................................................... 25 Table 13: Analyses by Baseline Pathogen in FDA-mMITT ......................................................... 26 Table 14: Rates of Absence in Erythema, Swelling and Tenderness ............................................ 27 Table 15: Responder Rates by Infection Type .............................................................................. 29 Table 16: Responder Rates by Region .......................................................................................... 30 Table 17: Responder Rates by Baseline Fever Status ..................................................................