CENTER FOR DRUG EVALUATION AND RESEARCH APPLICATION NUMBER: 208711Orig1s000 MULTI-DISCIPLINE REVIEW Summary Review Office Director Cross Discipline Team Leader Review Clinical Review Non-Clinical Review Statistical Review Clinical Pharmacology Review NDA Multi-Disciplinary Review and Evaluation – NDA NDA/BLA Multi-Disciplinary Review and Evaluation Application Type NDA Application Number(s) 208711 Priority or Standard Priority Submit Date(s) 6/14/18 Received Date(s) Rolling Review: 9/21/17; 6/14/18 PDUFA Goal Date February 14, 2019 Division/Office Division of Anti-Infective Products/Office of Antimicrobial Products Review Completion Date February 11, 2019 Established Name Triclabendazole (Proposed) Trade Name Egaten Pharmacologic Class Anthelmintic Drug Applicant Novartis Pharmaceuticals Corporation Formulation(s) Oral Dosing Regimen 10 mg/kg q12h x 2 Applicant Proposed Treatment of Fascioliasis Indication(s)/Population(s) Regulatory Action Approval Indication(s)/Population(s) WĂƚŝĞŶƚƐ ǁŝƚŚ ĨĂƐĐŝŽůŝĂƐŝƐ шϲ LJĞĂƌƐ ŽĨ ĂŐĞ 1 Reference ID: 4390563 NDA Multi-Disciplinary Review and Evaluation – NDA Table of Contents Reviewers of Multi-Disciplinary Review and Evaluation .............................................................. 11 Additional Reviewers of Application ............................................................................................. 16 Glossary ......................................................................................................................................... 17 Executive Summary Office Level Concurrence ...................................................................... 19 Product Introduction ...................................................................................................... 19 Conclusions on the Substantial Evidence of Effectiveness ............................................ 19 Benefit-Risk Assessment ................................................................................................ 21 Patient Experience Data ................................................................................................. 26 Therapeutic Context .............................................................................................................. 27 Analysis of Condition ...................................................................................................... 27 Analysis of Current Treatment Options ......................................................................... 30 Regulatory Background ......................................................................................................... 30 U.S. Regulatory Actions and Marketing History ............................................................. 30 Summary of Presubmission/Submission Regulatory Activity ........................................ 31 Significant Issues from Other Review Disciplines Pertinent to Clinical Conclusions on Efficacy and Safety................................................................................................................. 32 Office of Scientific Investigations (OSI) .......................................................................... 32 Product Quality .............................................................................................................. 33 Devices and Companion Diagnostic Issues .................................................................... 35 Nonclinical Pharmacology/Toxicology................................................................................... 36 Executive Summary ........................................................................................................ 36 Referenced NDAs, BLAs, DMFs ....................................................................................... 38 Pharmacology ................................................................................................................. 38 ADME/PK........................................................................................................................41 Toxicology ....................................................................................................................... 50 General Toxicology .................................................................................................. 50 Genetic Toxicology .................................................................................................. 56 Reproductive and Developmental Toxicology ........................................................ 58 Other Toxicology Studies ........................................................................................ 63 2 Reference ID: 4390563 NDA Multi-Disciplinary Review and Evaluation – NDA Clinical Pharmacology ............................................................................................................ 65 Executive Summary ........................................................................................................ 65 Summary of Clinical Pharmacology Assessment ............................................................ 66 Pharmacology and Clinical Pharmacokinetics ........................................................ 66 General Dosing and Therapeutic Individualization................................................. 67 Comprehensive Clinical Pharmacology Review ............................................................. 67 General Pharmacology and Pharmacokinetic Characteristics ................................ 67 Clinical Pharmacology Questions ............................................................................ 70 Statistical and Clinical Evaluation .......................................................................................... 76 Data Source and Review Strategy .................................................................................. 76 Data and Analysis Quality ....................................................................................... 82 Compliance with Good Clinical Practices ................................................................ 83 Financial Disclosure ................................................................................................. 83 Protocol Violations/Deviations ............................................................................... 83 Studies with Patient-Level Data Supporting Efficacy ..................................................... 83 Hien et al. (2008) ..................................................................................................... 83 Keiser et al. (2011) .................................................................................................. 90 Maco et al. (2015) ................................................................................................... 94 WHO/CIBA Studies .................................................................................................. 99 Supportive Information from other Studies ................................................................ 105 Integrated Review of Effectiveness .............................................................................. 109 Estimating the Historical Treatment Effect for Chronic Fascioliasis ..................... 109 Assessment of Efficacy Across Studies in Chronic Fascioliasis ..................................... 110 Summary and Conclusions - Statistics and Clinical ...................................................... 113 Clinical Microbiology Review ............................................................................................... 115 Nonclinical Microbiology .............................................................................................. 115 Mechanism of Action ............................................................................................ 115 Activity in vitro ...................................................................................................... 118 Activity in vivo ....................................................................................................... 121 Drug Resistance..................................................................................................... 123 Clinical Microbiology .................................................................................................... 128 Parasitological assessments by fecal smears ........................................................ 128 3 Reference ID: 4390563 NDA Multi-Disciplinary Review and Evaluation – NDA Parasitological assessments by serology .............................................................. 129 Interpretive Criteria .............................................................................................. 129 Review of Safety .................................................................................................................. 130 Safety Review Approach .............................................................................................. 132 Review of the Safety Database .................................................................................... 133 Adequacy of Applicant’s Clinical Safety Assessments .................................................. 134 Safety Results ............................................................................................................... 141 Deaths, SAEs, Disposition ................................................................................... 141 Treatment Emergent Adverse Events and Adverse Reactions ............................. 143 Exploration of Possible Dose-Response for Safety