NDA 211882 Multi-disciplinary Review and Evaluation Arazlo (tazarotene) lotion, 0.045% for topical use NDA Multi-Disciplinary Review and Evaluation Application Type NDA, 505(b)(2) Application Number(s) NDA 211882/IND 126277 Priority or Standard Standard Submit Date(s) February 22, 2019 Received Date(s) February 22, 2019 PDUFA Goal Date December 22, 2019 Division/Office Dermatology and Dental Products/Office of Drug Evaluation III Review Completion Date December 16, 2019 Established/Proper Name Tazarotene lotion, 0.045% (Proposed) Trade Name ArazloTM Pharmacologic Class Retinoid Code name IDP-123 Applicant Bausch Health US, LLC Dosage form Lotion Applicant proposed Dosing Once daily Regimen Applicant Proposed For the topical treatment of acne vulgaris Indication(s)/Population(s) Applicant Proposed 88616000 |Acne vulgaris (disorder)| SNOMED CT Indication Disease Term for each Proposed Indication Recommendation on Approval Regulatory Action Recommended Arazlo is indicated for the treatment of acne vulgaris in patients Indication(s)/Population(s) age 9 years and older (if applicable) Recommended SNOMED 88616000 |Acne vulgaris (disorder)| CT Indication Disease Term for each Indication (if applicable) Recommended Dosing Once daily Regimen 1 Version date: October 12, 2018 Reference ID: 4534641 NDA 211882 Multi-disciplinary Review and Evaluation Arazlo (tazarotene) lotion, 0.045% for topical use Table of Contents Table of Tables................................................................................................................................5 Table of Figures ..............................................................................................................................7 Reviewers of Multi-Disciplinary Review and Evaluation.................................................................8 Glossary ........................................................................................................................................13 1 Executive Summary...............................................................................................................14 1.1. Product Introduction......................................................................................................14 1.2. Conclusions on the Substantial Evidence of Effectiveness.............................................14 1.3. Benefit-Risk Assessment ................................................................................................16 1.4. Patient Experience Data.................................................................................................19 2 Therapeutic Context..............................................................................................................21 2.1. Analysis of Condition......................................................................................................21 2.2. Analysis of Current Treatment Options .........................................................................22 3 Regulatory Background .........................................................................................................28 3.1. U.S. Regulatory Actions and Marketing History.............................................................28 3.2. Summary of Presubmission/Submission Regulatory Activity ........................................28 4 Significant Issues From Other Review Disciplines Pertinent to Clinical Conclusions on Efficacy and Safety ................................................................................................................30 4.1. Office of Scientific Investigations...................................................................................30 4.2. Product Quality ..............................................................................................................30 4.3. Clinical Microbiology......................................................................................................32 5 Nonclinical Pharmacology/Toxicology ..................................................................................33 5.1. Executive Summary........................................................................................................33 5.2. Referenced NDAs, BLAs, DMFs ......................................................................................34 5.3. Pharmacology ................................................................................................................34 5.4. ADME/PK........................................................................................................................35 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 ...........................................................................................................42 6.1. Executive Summary........................................................................................................42 6.1.1. Recommendations..................................................................................................43 2 Version date: October 12, 2018 Reference ID: 4534641 NDA 211882 Multi-disciplinary Review and Evaluation Arazlo (tazarotene) lotion, 0.045% for topical use 6.1.2. Postmarketing Requirement(s) and Commitments(s) ............................................43 6.2. Summary of Clinical Pharmacology Assessment............................................................43 6.2.1. Pharmacology and Clinical Pharmacokinetics.........................................................43 6.2.2. General Dosing and Therapeutic Individualization.................................................45 6.2.3. Outstanding Issues..................................................................................................45 6.2.4. Summary of Labeling Recommendations ...............................................................45 6.3. Comprehensive Clinical Pharmacology Review..............................................................45 6.3.1. General Pharmacology and Pharmacokinetic Characteristics ................................45 6.3.2. Clinical Pharmacology Questions............................................................................50 7 Sources of Clinical Data and Review Strategy .......................................................................52 7.1. Table of Clinical Studies .................................................................................................52 7.2. Review Strategy .............................................................................................................55 8 Statistical and Clinical and Evaluation...................................................................................56 8.1. Review of Relevant Individual Trials Used to Support Efficacy ......................................56 8.1.1. Design of Trials 301 and 302...................................................................................56 8.1.2. Results of Trials 301 and 302 ..................................................................................58 8.1.3. Study 201................................................................................................................74 8.1.4. Assessment of Efficacy Across Trials and Integrated Assessment of Effectiveness75 8.2. Review of Safety.............................................................................................................76 8.2.1. Safety Review Approach .........................................................................................76 8.2.2. Review of the Safety Database ...............................................................................77 8.2.3. Adequacy of Applicant’s Clinical Safety Assessments.............................................79 8.2.4. Safety Results..........................................................................................................80 8.2.5. Analysis of Submission-Specific Safety Issues.........................................................88 8.2.6. Clinical Outcome Assessment Analyses Informing Safety/Tolerability...................90 8.2.7. Safety Analyses by Demographic Subgroups..........................................................90 8.2.8. Specific Safety Studies/Clinical Trials......................................................................95 8.2.9. Additional Safety Explorations................................................................................98 8.2.10. Safety in the Postmarket Setting.....................................................................99 8.2.11. Integrated Assessment of Safety.....................................................................99 8.3. Conclusions and Recommendations ............................................................................100 9 Pediatrics.............................................................................................................................102