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209521Orig1s000 CENTER FOR DRUG EVALUATION AND RESEARCH APPLICATION NUMBER: 209521Orig1s000 MULTI-DISCIPLINE REVIEW Summary Review Office Director Cross Discipline Team Leader Review Clinical Review Non-Clinical Review Statistical Review Clinical Pharmacology Review NDA 209251 Multi-disciplinary Review and Evaluation SEYSARA (sarecycline) tablets NDA/BLA Multi-Disciplinary Review and Evaluation Application Type NDA Application Number(s) 209521 Priority or Standard Standard Submit Date(s) 20-OCT-2017 Received Date(s) 20-OCT-2017 PDUFA Goal Date 20-OCT-2018 Division/Office Division of Dermatology and Dental Products/ODE3 Review Completion Date 27-Sep-18 Established Name Sarecycline (Proposed) Trade Name SEYSARA Pharmacologic Class Tetracycline antibiotic Code name WC3035 Applicant Allergan, Inc. Formulation(s) Tablets Dosing Regimen 60 mg, 100 mg, 150 mg Applicant Proposed For the treatment of inflammatory lesions of non-nodular Indication(s)/Population(s) moderate to severe acne vulgaris in patients 9 years of age and older Recommendation on Approval Regulatory Action Recommended For the treatment of inflammatory lesions of non-nodular Indication(s)/Population(s) moderate to severe acne vulgaris in patients 9 years of (if applicable) age and older 1 Version date: February 1, 2016 for initial rollout (NME/original BLA reviews) Reference ID: 4326719 NDA 209251 Multi-disciplinary Review and Evaluation SEYSARA (sarecycline) tablets Table of Contents Reviewers Team and Signature Approval Section........................................................................9 Additional Reviewers of Application ............................................................................................12 Glossary ......................................................................................................................................13 1 Executive Summary .............................................................................................................15 1.1. Product Introduction......................................................................................................15 1.2. Conclusions on the Substantial Evidence of Effectiveness ..........................................15 1.3. Benefit-Risk Assessment ..............................................................................................17 1.4. Patient Experience Data ...............................................................................................21 2 Therapeutic Context.............................................................................................................22 2.1. Analysis of Condition ....................................................................................................22 2.2. Analysis of Current Treatment Options.........................................................................22 3 Regulatory Background........................................................................................................25 3.1. U.S. Regulatory Actions and Marketing History............................................................25 3.2. Summary of Presubmission/Submission Regulatory Activity........................................25 4 Significant Issues from Other Review Disciplines Pertinent to Clinical Conclusions on Efficacy and Safety ..............................................................................................................27 4.1. Office of Scientific Investigations ..................................................................................27 4.2. Product Quality .............................................................................................................27 4.3. Devices and Companion Diagnostic Issues..................................................................33 5 Nonclinical Pharmacology/Toxicology..................................................................................34 5.1. Executive Summary ......................................................................................................34 5.2. Referenced NDAs, BLAs, and DMFs............................................................................35 5.3. Pharmacology ...............................................................................................................35 5.4. ADME/PK......................................................................................................................37 5.5. Toxicology.....................................................................................................................39 5.5.1. General Toxicology................................................................................................39 5.5.2. Genetic Toxicology ................................................................................................42 5.5.3. Carcinogenicity ......................................................................................................43 5.5.4. Reproductive and Developmental Toxicology .......................................................44 5.5.5. Other Toxicology Studies.......................................................................................48 5.5.6. Multiples of Human Exposure Calculation .............................................................50 6 Clinical Pharmacology..........................................................................................................51 2 Version date: February 1, 2016 for initial rollout (NME/original BLA reviews) Reference ID: 4326719 NDA 209251 Multi-disciplinary Review and Evaluation SEYSARA (sarecycline) tablets 6.1. Executive Summary ......................................................................................................51 6.1.1. Recommendations.................................................................................................52 6.1.2. Post-Marketing Requirement(s) and Commitment(s) ............................................52 6.2. Summary of Clinical Pharmacology Assessment .........................................................53 6.2.1. Pharmacology and Clinical Pharmacokinetics.......................................................53 6.2.2. General Dosing and Therapeutic Individualization ................................................54 6.3. Outstanding Issues .......................................................................................................55 6.4. Summary of Labeling Recommendations .....................................................................55 6.5. Comprehensive Clinical Pharmacology Review ...........................................................56 6.5.1. General Pharmacology and Pharmacokinetic Characteristics...............................56 6.5.2. Clinical Pharmacology Questions ..........................................................................58 7 Statistical and Clinical Evaluation ........................................................................................65 7.1. Sources of Clinical Data and Review Strategy .............................................................65 7.1.1. Table of Clinical Studies ........................................................................................65 7.1.2. Clinical Data...........................................................................................................68 7.2. Review of Relevant Individual Trials Used to Support Efficacy ....................................69 7.2.1. Study Design and Endpoints .................................................................................69 7.2.2. Statistical Methodologies .......................................................................................71 7.2.3. Subject Disposition, Demographics, and Baseline Disease Characteristics .........72 7.2.4. Results for the Co-Primary Efficacy Endpoints......................................................74 7.2.5. Results for the Secondary Efficacy Endpoints Related to Inflammatory Lesion Counts .............................................................................................................................75 7.2.6. Results for the Secondary Efficacy Endpoints Related to Non-Inflammatory Lesion Counts .............................................................................................................................77 7.2.7. Exploratory Analysis: IGA and Non-Inflammatory Lesions ....................................80 7.2.8. Findings in Special/Subgroup Populations ............................................................80 7.3. Review of Safety ...........................................................................................................86 7.3.1. Review of the Safety Database .............................................................................86 7.3.2. Adequacy of Applicant’s Clinical Safety Assessments ..........................................88 7.3.3. Safety Results........................................................................................................89 7.3.4. Analysis of Submission-Specific Safety Issues .....................................................94 7.3.5. Safety Analyses by Demographic Subgroups .......................................................96 7.3.6. Safety in the Postmarketing Setting.......................................................................97 7.3.7. Integrated Assessment of Safety...........................................................................97 7.4. Summary and Conclusions ...........................................................................................97 7.4.1. Statistical Issues
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