CENTER FOR DRUG EVALUATION AND RESEARCH APPLICATION NUMBER: 209570Orig1s000 CLINICAL REVIEW(S) Clinical Review Maria Allende, M.D. NDA 209570 (b) (4) CHEMO Benznidazole for Treatment of Chagas Disease CLINICAL REVIEW Application Type 505(b)(2) Application Number(s) 209570 Priority or Standard Priority Submit Date(s) December 29, 2016 Received Date(s) December 29, 2016 PDUFA Goal Date August 29, 2017 Division/Office Division of Anti-Infective Products Reviewer Name(s) Maria Allende, M.D. Review Completion Date Established Name Benznidazole (Proposed) Trade Name (b) (4) Applicant CHEMO Research SL Formulation(s) Oral tablets containing 100 mg or 12.5 mg of benznidazole Dosing Regimen Applicant Proposed Treatment of Chagas disease (American Trypanosomiasis) Indication(s)/Population(s) Recommendation on Approval Regulatory Action Recommended Treatment of Chagas disease (American Trypanosomiasis) Indication(s)/Population(s) (if applicable) 1 Reference ID: 4134724 Clinical Review Maria Allende, M.D. NDA 209570 (b) (4) CHEMO Benznidazole for Treatment of Chagas Disease Table of Contents Glossary ......................................................................................................................................... 10 1 Executive Summary ............................................................................................................... 12 1.1. Product Introduction ...................................................................................................... 12 1.2. Conclusions on the Substantial Evidence of Effectiveness ............................................ 12 1.3. Benefit-Risk Assessment ................................................................................................ 15 2 Therapeutic Context .............................................................................................................. 21 2.1. Analysis of Condition ...................................................................................................... 21 2.2. Analysis of Current Treatment Options ......................................................................... 43 3 Regulatory Background ......................................................................................................... 44 3.1. U.S. Regulatory Actions and Marketing History ............................................................. 44 3.2. Summary of Presubmission/Submission Regulatory Activity ........................................ 45 3.3. Foreign Regulatory Actions and Marketing History ....................................................... 54 4 Significant Issues from Other Review Disciplines Pertinent to Clinical Conclusions on Efficacy and Safety................................................................................................................. 55 4.1. Office of Scientific Investigations (OSI) .......................................................................... 55 4.2. Product Quality .............................................................................................................. 56 4.3. Clinical Microbiology ...................................................................................................... 57 4.4. Nonclinical Pharmacology/Toxicology ........................................................................... 64 4.5. Clinical Pharmacology .................................................................................................... 66 4.5.1. Mechanism of Action .............................................................................................. 67 4.5.2. Pharmacodynamics ................................................................................................. 68 4.5.3. Pharmacokinetics .................................................................................................... 68 4.6. Devices and Companion Diagnostic Issues .................................................................... 71 5 Sources of Clinical Data and Review Strategy ....................................................................... 71 5.1. Table of Clinical Studies .................................................................................................. 71 5.2. Review Strategy .............................................................................................................. 73 2 Reference ID: 4134724 Clinical Review Maria Allende, M.D. NDA 209570 (b) (4) CHEMO Benznidazole for Treatment of Chagas Disease 6 Review of Relevant Individual Trials Used to Support Efficacy ............................................. 74 6.1. Sosa Estani ...................................................................................................................... 74 6.1.1. Study Design............................................................................................................ 74 6.1.2. Study Results ........................................................................................................... 78 6.2. De Andrade ..................................................................................................................... 91 6.2.1. Study Design............................................................................................................ 91 6.2.2. Study Results ........................................................................................................... 94 6.3. Viotti ............................................................................................................................. 104 6.3.1. Study Design.......................................................................................................... 104 6.3.2. Study Results ......................................................................................................... 108 6.4. Efficacy data available from other published prospective, controlled trials ............... 118 6.5. Efficacy in Acute and Congenital Chagas Disease ........................................................ 130 6.6. Efficacy in the Immunosuppressed Host ...................................................................... 134 6.7. Efficacy in congenital disease transmission ................................................................. 135 7 Integrated Review of Effectiveness ..................................................................................... 137 7.1. Assessment of Efficacy Across Trials ............................................................................ 137 7.1.1. Primary Endpoints ................................................................................................. 137 7.1.2. Secondary and Other Endpoints ........................................................................... 137 7.1.3. Subpopulations ..................................................................................................... 137 7.1.4. Dose and Dose-Response...................................................................................... 137 7.1.5. Onset, Duration, and Durability of Efficacy Effects .............................................. 137 7.2. Additional Efficacy Considerations ............................................................................... 138 7.2.1. Considerations on Benefit in the Postmarket Setting .......................................... 138 7.2.2. Other Relevant Benefits ........................................................................................ 139 7.3. Integrated Assessment of Effectiveness ...................................................................... 139 8 Review of Safety .................................................................................................................. 150 8.1. Safety Review Approach .............................................................................................. 150 8.2. Review of the Safety Database .................................................................................... 151 8.2.1. Overall Exposure ................................................................................................... 151 3 Reference ID: 4134724 Clinical Review Maria Allende, M.D. NDA 209570 (b) (4) CHEMO Benznidazole for Treatment of Chagas Disease 8.2.2. Relevant characteristics of the safety population: ............................................... 153 8.2.3. Adequacy of the safety database ......................................................................... 153 8.3. Adequacy of Applicant’s Clinical Safety Assessments .................................................. 153 8.3.1. Issues Regarding Data Integrity and Submission Quality ..................................... 153 8.3.2. Categorization of Adverse Events ......................................................................... 154 8.3.3. Routine Clinical Tests ............................................................................................ 154 8.4. Safety Results ............................................................................................................... 155 8.4.1. Deaths ................................................................................................................... 155 8.4.2. Serious Adverse Events ......................................................................................... 173 8.4.3. Dropouts and/or Discontinuations Due to Adverse Effects ................................. 175 8.4.4. Significant Adverse Events .................................................................................... 180 8.4.5. Treatment Emergent Adverse Events and Adverse Reactions