Multidisciplinary Review and Evaluation NDA 211527 AKLIEF (trifarotene) Cream, 0.005% for topical use NDA Multidisciplinary Review and Evaluation Application Type NDA Application Number(s) NDA 211527/IND 111091 Priority or Standard Standard Submit Date(s) October 4, 2018 Received Date(s) October 4, 2018 PDUFA Goal Date October 4, 2019 Division/Office DDDP/ Review Completion Date See DARRTS electronic signature page Established/Proper Name Trifarotene (Proposed) Trade Name AKLIEF Pharmacologic Class Retinoid Code Name Applicant Galderma Research and Development, LLC Dosage Form Cream Dosing Regiment Once daily (b) (4) Applicant Proposed For the topical treatment of acne vulgaris (b) (4) Indication(s)/Population(s) in patients 9 years of age and older Recommendation on Regulatory Approval Action Recommended AKLIEF is indicated for the treatment of acne Indication(s)/Population(s) (if vulgaris in patients age 9 years and older applicable) Recommended Once daily in the evening Dosing Regimen 1 Version date: October 12, 2018 Reference ID: 4501464 Multidisciplinary Review and Evaluation NDA 211527 AKLIEF (trifarotene) Cream, 0.005% for topical use Table of Contents Table of Tables ................................................................................................................................ 5 Table of Figures ............................................................................................................................... 9 Reviewers of Multidisciplinary Review and Evaluation ................................................................ 11 Additional Reviewers of Application ............................................................................................. 11 Signatures ..................................................................................................................................... 13 Glossary ......................................................................................................................................... 16 1. Executive Summary ............................................................................................................... 18 Product Introduction ...................................................................................................... 18 Conclusions on Substantial Evidence of Effectiveness .................................................. 18 Benefit-Risk Assessment ................................................................................................ 19 Patient Experience Data ................................................................................................. 23 2. Therapeutic Context .............................................................................................................. 24 Analysis of Condition ...................................................................................................... 24 Analysis of Current Treatment Options ......................................................................... 25 3. Regulatory Background ......................................................................................................... 29 U.S. Regulatory Actions and Marketing History ............................................................. 29 Summary of Presubmission/Submission Regulatory Activity ........................................ 29 4. Significant Issues From Other Review Disciplines Pertinent to Clinical Conclusions on Efficacy and Safety ................................................................................................................. 32 Office of Scientific Investigations ................................................................................... 32 Product Quality .............................................................................................................. 33 5. Nonclinical Pharmacology/Toxicology................................................................................... 36 Executive Summary ........................................................................................................ 36 Referenced NDAs, BLAs, DMFs ....................................................................................... 39 Pharmacology ................................................................................................................. 39 ADME/PK ........................................................................................................................ 41 Toxicology ....................................................................................................................... 45 General Toxicology .................................................................................................. 45 General Toxicology; Additional Studies .................................................................. 46 Genetic Toxicology .................................................................................................. 47 Carcinogenicity ........................................................................................................ 48 Reproductive and Developmental Toxicology ........................................................ 49 2 Version date: October 12, 2018 Reference ID: 4501464 Multidisciplinary Review and Evaluation NDA 211527 AKLIEF (trifarotene) Cream, 0.005% for topical use Other Toxicology Studies ........................................................................................ 55 6. Clinical Pharmacology ............................................................................................................ 56 Executive Summary ........................................................................................................ 56 Summary of Clinical Pharmacology Assessment ............................................................ 56 Pharmacology and Clinical Pharmacokinetics ........................................................ 57 General Dosing and Therapeutic Individualization ................................................. 59 Comprehensive Clinical Pharmacology Review ............................................................. 59 General Pharmacology and Pharmacokinetic Characteristics ................................ 59 Clinical Pharmacology Questions ............................................................................ 62 7. Sources of Clinical Data and Review Strategy ....................................................................... 64 Clinical Studies ................................................................................................................ 64 Review Strategy (Clinical Plus Statistical) ....................................................................... 70 8. Statistical and Clinical Evaluation .......................................................................................... 71 Review of Relevant Individual Trials Used to Support Efficacy ...................................... 71 Study Design and Endpoints ................................................................................... 71 Statistical Methodologies ....................................................................................... 74 Subject Disposition, Demographics, and Baseline Disease Characteristics ............ 76 Results for Primary and Secondary Endpoints ........................................................ 79 Findings in Special/Subgroup Populations .............................................................. 84 Review of Safety ............................................................................................................. 92 Safety Review Approach ......................................................................................... 92 Review of the Safety Database ............................................................................... 93 Adequacy of Applicant’s Clinical Safety Assessments ............................................ 95 Safety Results .......................................................................................................... 97 Analysis of Submission-Specific Safety Issues ....................................................... 111 Safety Analyses by Demographic Subgroups ........................................................ 117 Specific Safety Studies/Clinical Trials .................................................................... 120 Additional Safety Explorations .............................................................................. 126 Safety in the Postmarket Setting .......................................................................... 128 Integrated Assessment of Safety ................................................................... 128 Statistical Issues ........................................................................................................... 130 Conclusions and Recommendations ............................................................................ 130 9. Advisory Committee Meeting and Other External Consultations ....................................... 131 10. Pediatrics ............................................................................................................................. 132 3 Version date: October 12, 2018 Reference ID: 4501464 Multidisciplinary Review and Evaluation NDA 211527 AKLIEF (trifarotene) Cream, 0.005% for topical use 11. Labeling Recommendations ................................................................................................ 133 Prescription Drug Labeling ......................................................................................