NDA 20380 NONPRESCRIPTION ADAPALENE 0.1% BRIEFING DOCUMENT FOR APRIL 15, 2016 TOPICAL GEL NONPRESCRIPTION DRUGS ADVISORY COMMITTEE MEETING FDA NONPRESCRIPTION DRUGS ADVISORY COMMITTEE BRIEFING DOCUMENT Differin® Gel Adapalene 0.1% Topical Gel Meeting Date: April 15, 2016 Available for Public Disclosure Without Redaction Page 1 NDA 20380 NONPRESCRIPTION ADAPALENE 0.1% BRIEFING DOCUMENT FOR APRIL 15, 2016 TOPICAL GEL NONPRESCRIPTION DRUGS ADVISORY COMMITTEE MEETING TABLE OF CONTENTS LIST OF ABBREVIATIONS ..................................................................................................................... 4 1 EXECUTIVE SUMMARY ............................................................................................................... 5 1.1 Program Overview ....................................................................................................................... 5 1.2 Acne: Prevalence and Impact on Quality of Life ...................................................................... 5 1.3 Current Self-Management of Acne ............................................................................................. 5 1.4 History of Adapalene ................................................................................................................... 6 1.5 Efficacy and Safety ....................................................................................................................... 7 1.5.1 Clinical Studies ........................................................................................................................ 7 1.5.2 Post-Marketing Surveillance .................................................................................................. 8 1.5.3 Clinical Pharmacokinetic Studies .......................................................................................... 8 1.5.4 Teratogenicity .......................................................................................................................... 9 1.5.5 Potential Off-Label Use ........................................................................................................ 12 1.5.6 Other Safety Considerations ................................................................................................ 13 1.6 Differin Gel OTC Development Program ................................................................................ 13 1.6.1 Label Comprehension Study ................................................................................................ 13 1.6.2 Actual Use Study ................................................................................................................... 14 1.6.3 Targeted Self-Selection Study .............................................................................................. 17 1.7 Benefit and Risk Considerations for Nonprescription Differin Gel ...................................... 18 1.8 Rationale for Nonprescription Access to Differin Gel ............................................................ 19 2 BACKGROUND ............................................................................................................................. 20 2.1 Overview of Acne ....................................................................................................................... 20 2.2 Current Self-Management of Acne ........................................................................................... 21 3 DEVELOPMENT OF DIFFERIN GEL ....................................................................................... 23 3.1 Properties of Adapalene and the Differin Gel Formulation ................................................... 23 3.2 Regulatory History ..................................................................................................................... 25 4 SUMMARY OF EFFICACY ......................................................................................................... 26 5 SUMMARY OF SAFETY .............................................................................................................. 27 5.1 Safety Data from Original Pivotal Clinical Studies ................................................................ 27 5.1.1 Cutaneous Tolerability ......................................................................................................... 29 5.1.2 Adverse Events ...................................................................................................................... 29 5.1.3 Serious adverse events .......................................................................................................... 32 5.2 Other Clinical Studies ................................................................................................................ 32 5.3 Post-Marketing Surveillance ..................................................................................................... 32 5.4 Clinical Pharmacokinetic Studies ............................................................................................. 33 5.4.1 Maximal Use Pharmacokinetic Study 18115 ...................................................................... 33 5.4.2 Maximal Use Pharmacokinetic Study 18097 ...................................................................... 35 5.4.3 Maximal Use Pharmacokinetic Study 18254 ...................................................................... 38 5.4.4 Conclusion of Maximal Use Clinical Pharmacokinetic Studies ........................................ 46 5.5 Teratogenicity and Fetotoxicity ................................................................................................ 46 5.5.1 Receptor-binding Properties of Adapalene ........................................................................ 47 5.5.2 Nonclinical Reproductive Toxicity Studies with Adapalene ............................................. 47 5.5.3 Calculation of Safety Margin ............................................................................................... 49 5.5.4 Exposure During Pregnancy ................................................................................................ 51 5.5.5 Evaluation of Additional Data Sources ............................................................................... 52 5.5.6 Summary of Teratogenic Risk ............................................................................................. 53 Page 2 NDA 20380 NONPRESCRIPTION ADAPALENE 0.1% BRIEFING DOCUMENT FOR APRIL 15, 2016 TOPICAL GEL NONPRESCRIPTION DRUGS ADVISORY COMMITTEE MEETING 5.6 Other Safety Considerations ..................................................................................................... 54 5.6.1 Potential Off-Label Use ........................................................................................................ 54 5.6.2 Concomitant Use with Other Acne Medications and Topical Products .......................... 55 5.6.3 Carcinogenesis and Mutagenesis ......................................................................................... 56 5.6.4 Phototoxicity .......................................................................................................................... 56 5.6.5 Lactation ................................................................................................................................ 56 6 DEVELOPMENT OF NONPRESCRIPTION DIFFERIN GEL ............................................... 57 6.1 Label Comprehension Testing .................................................................................................. 58 6.2 Actual Use Study ........................................................................................................................ 61 6.2.1 Study Design .......................................................................................................................... 61 6.2.2 Disposition of Subjects .......................................................................................................... 67 6.2.3 Actual Use Results ................................................................................................................. 67 6.3 Targeted Self-Selection Study ................................................................................................... 79 6.3.1 Study Design .......................................................................................................................... 79 6.3.2 Study Population ................................................................................................................... 80 6.3.3 Study Results ......................................................................................................................... 80 6.4 Conclusions of Differin Gel Nonprescription Development Program ................................... 81 6.5 Differin Gel Nonprescription DFL ........................................................................................... 81 7 BENEFIT AND RISK CONSIDERATIONS ............................................................................... 83 7.1 Benefits of Nonprescription Differin Gel ................................................................................. 83 7.2 Adverse Event Profile of Differin Gel ...................................................................................... 83 7.3 Teratogenicity ............................................................................................................................. 84 7.4 Potential Off-label Use ..............................................................................................................