CENTER FOR DRUG EVALUATION AND RESEARCH APPLICATION NUMBER: 212379Orig1s000 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 212379 AMZEEQ (minocycline) topical foam, 4% NDA/BLA Multi-Disciplinary Review and Evaluation Application Type NDA Application Number(s) 212379 Priority or Standard Standard Submit Date(s) 12-20-2018 Received Date(s) 12-20-2018 PDUFA Goal Date 10-20-2019 Division/Office Division of Dermatology and Dental Products Review Completion Date 10-17-2019 Established/Proper Name minocycline topical foam, 4% (Proposed) Trade Name AMZEEQ Pharmacologic Class Acne Agents Code Name FMX-101 Applicant Foamix Pharmaceuticals Inc. Dosage Form foam Applicant Proposed Dosing Apply to affected areas once daily Regimen Applicant Proposed For the treatment of inflammatory lesions of non-nodular moderate Indication(s)/Population(s) to severe acne vulgaris in patients 9 years of age and older. Applicant Proposed Acne vulgaris (disorder) SNOMED CT Indication Disease Term for Each Proposed Indication Recommendation on Approval Regulatory Action Recommended AMZEEQ is a tetracycline-class drug indicated to treat inflammatory Indication(s)/Population(s) lesions of non-nodular moderate to severe acne vulgaris in patients 9 (if applicable) years of age and older. Recommended SNOMED CT 88616000 |Acne vulgaris (disorder)| Indication Disease Term for Each Indication (if applicable) Recommended Dosing Apply AMZEEQ to affected areas once daily. AMZEEQ should be Regimen gently rubbed into the skin. 1 Version date: October 12, 2018 Reference ID: 45073474580141 NDA Multi-Disciplinary Review and Evaluation: NDA 212379 AMZEEQ (minocycline) topical foam, 4% Table of Contents Table of Tables....................................................................................................................5 Table of Figures...................................................................................................................7 Reviewers of Multi-Disciplinary Review and Evaluation.....................................................8 Glossary ............................................................................................................................12 1. Executive Summary.......................................................................................................14 1.1. Product Introduction..............................................................................................14 1.2. Conclusions on the Substantial Evidence of Effectiveness.....................................14 1.3. Benefit-Risk Assessment ........................................................................................15 1.4. Patient Experience Data .........................................................................................19 2. Therapeutic Context .....................................................................................................20 2.1. Analysis of Condition..............................................................................................20 2.2. Analysis of Current Treatment Options..................................................................21 3. Regulatory Background.................................................................................................26 3.1. U.S. Regulatory Actions and Marketing History .....................................................26 3.2. Summary of Presubmission/Submission Regulatory Activity.................................26 4. Significant Issues from Other Review Disciplines Pertinent to Clinical Conclusions on Efficacy and Safety.............................................................................28 4.1. Office of Scientific Investigations (OSI) ..................................................................28 4.2. Product Quality ......................................................................................................30 4.3. Clinical Microbiology ..............................................................................................31 4.4. Devices and Companion Diagnostic Issues.............................................................32 5. Nonclinical Pharmacology/Toxicology ..........................................................................32 5.1. Executive Summary ................................................................................................32 5.2. Referenced NDAs, BLAs, DMFs...............................................................................33 5.3. Pharmacology.........................................................................................................33 5.4. ADME/PK ................................................................................................................34 5.5. Toxicology...............................................................................................................37 5.5.1. General Toxicology ..........................................................................................37 5.5.2. Genetic Toxicology...........................................................................................38 5.5.3. Carcinogenicity ................................................................................................38 5.5.4. Reproductive and Developmental Toxicology .................................................38 5.5.5. Other Toxicology Studies .................................................................................40 6. Clinical Pharmacology ...................................................................................................44 6.1. Executive Summary ................................................................................................44 6.1.1. Recommendations...........................................................................................44 2 Version date: October 12, 2018 Reference ID: 45073474580141 NDA Multi-Disciplinary Review and Evaluation: NDA 212379 AMZEEQ (minocycline) topical foam, 4% 6.1.2. Postmarketing requirement/ postmarketing commitment.............................44 6.2. Summary of Clinical Pharmacology Assessment ....................................................45 6.2.1. Pharmacology and Clinical Pharmacokinetics..................................................45 6.2.2. General Dosing and Therapeutic Individualization..........................................46 6.3. Comprehensive Clinical Pharmacology Review......................................................47 6.3.1. General Pharmacology and Pharmacokinetic Characteristics .........................47 6.3.2. Clinical Pharmacology Questions.....................................................................48 7. Sources of Clinical Data and Review Strategy...............................................................50 7.1. Table of Clinical Studies..........................................................................................50 7.2. Review Strategy......................................................................................................56 8. Statistical and Clinical and Evaluation...........................................................................56 8.1. Review of Relevant Individual Trials Used to Support Efficacy ..............................56 8.1.1. Study Design and Endpoints ............................................................................56 8.1.2. Statistical Methodologies ................................................................................57 8.1.3. Subject Disposition, Demographics, and Baseline Disease Characteristics ...............................................................................................59 8.1.4. Results of the Co-Primary Efficacy Endpoints..................................................61 8.1.5. Results of the Secondary Efficacy Endpoints ...................................................62 8.1.6. Additional Sensitivity Analysis .........................................................................64 8.1.7. Findings in Special/Subgroup Populations.......................................................65 8.2. Review of Safety.....................................................................................................72 8.2.1. Safety Review Approach ..................................................................................72 8.2.2. Review of the Safety Database ........................................................................73 8.2.3. Adequacy of Applicant’s Clinical Safety Assessments......................................74 8.2.4. Safety Results...................................................................................................76 8.2.5. Analysis of Submission-Specific Safety Issues..................................................89 8.2.6. Clinical Outcome Assessment Analyses Informing Safety/Tolerability............92 8.2.7. Safety Analyses by Demographic Subgroups...................................................92 8.2.8. Specific Safety Studies/Clinical Trials...............................................................93 8.2.9. Additional Safety Explorations.......................................................................102 8.2.10. Safety in the Postmarket Setting .................................................................103 8.2.11. Integrated Assessment of Safety .................................................................104 8.3. Statistical Issues ...................................................................................................106