209353Orig1s000 - Food And Drug Administration
CENTER FOR DRUG EVALUATION ANDRESEARCHAPPLICATION NUMBER:209353Orig1s000MULTI-DISCIPLINE REVIEWSummary ReviewOffice DirectorCross Discipline Team Leader ReviewClinical ReviewNon-Clinical ReviewStatistical ReviewClinical Pharmacology Review
Multi-disciplinary Review and Evaluation NDA 209353ALTRENO (tretinoin) Lotion, 0.05% for topical useNDA 209353 Multi-disciplinary Review and EvaluationApplication TypeApplication Number(s)Priority or StandardSubmit Date(s)Received Date(s)PDUFA Goal DateDivision/OfficeReview Completion DateEstablished Name(Proposed) Trade NamePharmacologic ClassCode nameApplicantNDANDA 209353/ IND 126753StandardOctober 23, 2017October 27, 2017August 27, 2018Division of Dermatology and Dental ProductsJuly 18, 2018TretinoinALTRENORetinoidIDP-121Dow Pharmaceutical Sciences Inc c/o Valeant PharmaceuticalsNorth America LLCFormulation(s) LotionDosing Regimen Once dailyApplicant Proposed For the topical treatment of acne vulgarisIndication(s)/Population(s)Recommendation on ApprovalRegulatory ActionRecommended ALTRENO is indicated for the treatment of acne vulgaris inIndication(s)/Population(s) patients age 9 years and older(if applicable)1Version date: February 1, 2016 for initial rollout (NME/original BLA reviews)Reference ID: 4310916
Multi-disciplinary Review and Evaluation NDA 209353ALTRENO (tretinoin) Lotion, 0.05% for topical useTable of ContentsReviewers Team and Signature Approval Section . 8Additional Reviewers of Application. 11Glossary . 131Executive Summary . 14Product Introduction . 14Conclusions on the Substantial Evidence of Effectiveness . 14Benefit-Risk Assessment . 152Therapeutic Context . 18Analysis of Condition . 18Analysis of Current Treatment Options . 19Patient Experience Data . 233Regulatory Background . 24U.S. Regulatory Actions and Marketing History . 24Summary of Presubmission/Submission Regulatory Activity . 244Significant Issues from Other Review Disciplines Pertinent to Clinical Conclusions onEfficacy and Safety. 26Office of Scientific Investigations . 26Product Quality . 26Clinical Microbiology . 32Devices and Companion Diagnostic Issues . 325Nonclinical Pharmacology/Toxicology. 33Executive Summary . 33Referenced NDAs, BLAs, DMFs. 33Pharmacology . 34ALTRENO Lotion ADME/PK. 34Toxicology. 34General Toxicology. 34Genetic Toxicology . 35Carcinogenicity. 352Version date: February 1, 2016 for initial rollout (NME/original BLA reviews)Reference ID: 4310916
Multi-disciplinary Review and Evaluation NDA 209353ALTRENO (tretinoin) Lotion, 0.05% for topical useReproductive and Developmental Toxicology . 356Clinical Pharmacology. 39Executive Summary . 39Recommendations . 39Post-Marketing Requirements and Commitment(s) . 39Summary of Clinical Pharmacology Assessment. 39Pharmacology and Clinical Pharmacokinetics . 40General Dosing and Therapeutic Individualization. 42Comprehensive Clinical Pharmacology Review . 42General Pharmacology and Pharmacokinetic Characteristics . 42Clinical Pharmacology Questions . 517Statistical and Clinical and Evaluation . 53Sources of Clinical Data and Review Strategy . 53Table of Clinical Studies . 53Review Strategy . 57Review of Relevant Individual Trials Used to Support Efficacy. 57Studies 301 and 302 . 57Study Results . 60Review of Safety . 78Safety Review Approach . 78Review of the Safety Database . 78Adequacy of Applicant’s Clinical Safety Assessments . 80Safety Results . 83Analysis of Submission-Specific Safety Issues. 92Safety Analyses by Demographic Subgroups . 97Specific Safety Studies/Additional Clinical Trial Safety Data . 97Additional Safety Explorations. 99Safety in the Postmarket Setting . 101Integrated Assessment of Safety . 101SUMMARY AND CONCLUSIONS . 103Statistical Issues . 1033Version date: February 1, 2016 for initial rollout (NME/original BLA reviews)Reference ID: 4310916
Multi-disciplinary Review and Evaluation NDA 209353ALTRENO (tretinoin) Lotion, 0.05% for topical useConclusions and Recommendations . 1038Advisory Committee Meeting and Other External Consultations . 1049Pediatrics . 10410 Labeling Recommendations . 104Prescribing Information . 104Patient Labeling . 10511 Risk Evaluation and Mitigation Strategies . 10512 Postmarketing Requirements and Commitments . 10613 Appendices . 107References . 107Financial Disclosure . 107Nonclinical Pharmacology/Toxicology . 110Clinical/Biostatistics Supporting Data . 1174Version date: February 1, 2016 for initial rollout (NME/original BLA reviews)Reference ID: 4310916
Multi-disciplinary Review and Evaluation NDA 209353ALTRENO (tretinoin) Lotion, 0.05% for topical useTable of TablesTable 1: Categories of Drug Products for Acne Treatment. 19Table 2: Representative Examples of FDA Approved Topical Products . 20Table 3: Examples of Systemic Acne Products. 22Table 4: Patient Experience Data Relevant to this Application . 23Table 5: Approved Products for Reference . 24Table 6: Site Inspection Results . 26Table 7: Status of Facilities Related to Drug Substance Manufacture and Testing . 30Table 8: Status of the Facilities Related to the Drug Product Manufacture and Testing . 31Table 9: ALTRENO Lotion ADME/PK. 34Table 10: Bovine Corneal Opacity and Permeability Results of the Test Articles and the PositiveControl . 37Table 11: Summary Results of the EpiDerm Definitive Phototoxicity Assay . 38Table 12: Summary of Clinical Pharmacology Review. . 39Table 13: Summary of Pharmacokinetics of Tretinoin, Isotretinoin, and 4-Oxo-Isotretinoin . 41Table 14: Subject Disposition and Demographic Characteristics . 42Table 15: Pre-Dose (Day 1) Concentration of Tretinoin, Isotretinoin, and 4-Oxo-Isotretinoin . 44Table 16: Summary of Baseline Corrected PK Parameters of Tretinoin . 45Table 17: Summary of Baseline Corrected PK parameters of Isotretinoin . 45Table 18: Summary of Baseline Corrected PK Parameters of 4-Oxo-Isotretinoin . 46Table 19: Summary of Pharmacokinetics Parameters for Tretinoin . 47Table 20: Summary of Pharmacokinetics Parameters for Isotretinoin . 47Table 21: Summary of Pharmacokinetics Parameters for 4-Oxo-Isotretinoin . 48Table 22: Summary of Method Validation Results . 50Table 23: Clinical Trials in the NDA 209353 Development Program . 54Table 24: Evaluator’s Global Severity Score . 58Table 25: Supportive Endpoint . 59Table 26:Disposition of Subjects in Studies 301 and 302 . 61Table 27: Specified Reasons for Discontinuation in Studies 301 and 302 . 61Table 28: Per Protocol Analysis Set in Studies 301 and 302 . 62Table 29: Demographics in Studies 301 and 302 . 63Table 30: Baseline Disease Characteristics . 63Table 31: Primary Efficacy Endpoints (Studies 301 and 302) . 65Table 32: Treatment by Center Interaction P-Values . 65Table 33: Sensitivity analysis results . 69Table 34: Key Secondary Efficacy Endpoints . 72Table 35: Supportive Efficacy Endpoints . 72Table 36: Efficacy Results by Subgroup (Study 301) . 73Table 37: Efficacy Results by Subgroup (Study 302) . 74Table 38: Subject population (Trials V01-121A-301 and Trial V01-121A-302) . 79Table 39: Phase 3 Studies: Extent of Exposure (Safety Analysis Set) . 80Table 40: Cutaneous Assessment Scales . 835Version date: February 1, 2016 for initial rollout (NME/original BLA reviews)Reference ID: 4310916
Multi-disciplinary Review and Evaluation NDA 209353ALTRENO (tretinoin) Lotion, 0.05% for topical useTable 41: Treatment Emergent Serious Adverse Events . 84Table 42: Treatment-Emergent Adverse Events Leading to Discontinuation by Preferred Term 86Table 43: Most Common Treatment Emergent Adverse Events by System Organ Class. 88Table 44: Treatment Emergent Adverse Events by Preferred Term . 88Table 45: Severe Treatment Emergent Adverse Events: Pooled Phase 3 Trials . 89Table 46: Treatment Emergent Adverse Reactions . 90Table 47: Local Safety Results in the Tretinoin Group from Baseline to Week 12 . 93Table 48: Maximum Post-Baseline Local Cutaneous Safety and Tolerability Assessments (Studies301 and 302 combined) . 94Table 49: Application Site Tolerability Reactions at Any Post-Baseline Visit . 95Table 50: Location of the Labeling Discussion for Significant High Level Labeling Changes . 105Table 51: Covered Clinical Study (V01-121A-301) . 108Table 52: Covered Clinical Study (V01-121A-302) . 109Table 53: Investigators with Financial Disclosure Forms 3455 for Trials V01-121A-301 and V01121A-302 . 110Table 54: Demographics and Disposition . 117Table 55: Disposition: Reasons Given for Discontinuation . 118Table 56: Summary of Pregnancies in the Phase 3 Trials . 119Table 57: Treatment Emergent Adverse Reactions by Age . 120Table 58: Treatment Emergent Adverse Reactions by Sex. 120Table 59: Treatment Emergent Adverse Reactions by Race (White and African American) . 1216Version date: February 1, 2016 for initial rollout (NME/original BLA reviews)Reference ID: 4310916
Multi-disciplinary Review and Evaluation NDA 209353ALTRENO (tretinoin) Lotion, 0.05% for topical useTable of FiguresFigure 1 - Pre-dose Mean Plasma Concentration of Tretinoin, Isotretinoin, and 4-OxoIsotretinoin on Days 1, 12, and 14 . 49Figure 2 – Absolute Change in Non-Inflammatory Lesions by Analysis Center (Study 301) . 66Figure 3 – Absolute Change in Inflammatory Lesions by Analysis Center (Study 301) . 67Figure 4 – Absolute Change in Non-Inflammatory Lesions by Analysis Center (Study 302) . 67Figure 5 – Absolute Change in Inflammatory Lesions by Analysis Center (Study 302) . 68Figure 6 – EGSS Success (Study 301). 68Figure 7 – EGSS Success (Study 302). 69Figure 8 – Change in Non-Inflammatory Lesions by Last Available Visit Cohort . 70Figure 9 – Change in Inflammatory Lesions by Last Available Visit Cohort . 71Figure 10 – EGSS Success Rate by Last Available Visit Cohort . 71Figure 11 – Change in Non-Inflammatory Lesions by Subgroup (Study 301) . 75Figure 12 – Change in Non-Inflammatory Lesions by Subgroup (Study 302) . 75Figure 13 – Change in Inflammatory Lesions by Subgroup (Study 301) . 76Figure 14 – Change in Inflammatory Lesions by Subgroup (Study 302) . 76Figure 15 – EGSS Success by Subgroup (Study 301) . 77Figure 16 – EGSS Success by Subgroup (Study 302) . 77Figure 17 – Mean Local Cutaneous Safety and Tolerability Assessments by Visit (Studies 301 and302 combined) . 947Version date: February 1, 2016 for initial rollout (NME/original BLA reviews)Reference ID: 4310916
Multi-disciplinary Review and Evaluation NDA 209353ALTRENO (tretinoin) Lotion, 0.05% for topical useAdditional Reviewers of ApplicationOffice/DivisionODE III/DDDP – ADLODE III/DDDP – PM/CPMSODE IV/DPMHOPDP/DMPPOPDP/DAPR2OPQ/DND APIOPQ/DNDP IIOPQ/DPA OSE/PMSOSI/DCCEReviewer/Team LeaderNancy Xu, MDAngela Brown, MPH/Barbara Gould, MBAHCMCatherine Roca, MD/Miriam Dinatale, DO, LCDRMorgan Walker, PharmD,MBA, CPH/LaShawn Griffith, MSHS-pH,BSN, RNLaurie Buonaccorsi, PharmD/Walter Falter, PharmDJeffrey Medwid, PhD/Donna F. Christner, PhDZhengfang Ge, PhD/Moo-Jhong Rhee, PhDZhao Wang, PhD/Yubing Tang, PhDDaniel Schu, PhD/John W. Metcalf, PhDSandra Suarez Sharp, PhD/Vidula Kolhatkar, PhDBamidele (Florence) Aisida/Review LocationReview not requiredReview not requiredYichun Sun, PhD/Moo Jhong Rhee, PhDMadhuri R. Patel, PharmD/Sarah K. Vee, PharmDCarmen Cheng, PharmD/Vicky Chan, PharmDTri Bui-Nguyen PhD/Sue Kang, MSBei Yu, PhD/Janice Pohlman, MD, MPHIQA/PanoramaReview not requiredDARRTSDARRTSIntegrated QualityAssessment (IQA)/ noramaIQA/PanoramaDARRTSDARRTSReview not requiredDARRTSADL Associate Director of LabelingDAPR2 Division of Advertising and Promotion Review 2DB Division of BiopharmaceuticsDB III Division of Biometrics IIIDBRR I Division of Biotechnology Research and Review 1DCP 3 Division of Clinical Pharmacology 3DDDP Division of Dermatology and Dental Products11Version date: February 1, 2016 for initial rollout (NME/original BLA reviews)Reference ID: 4310916
Multi-disciplinary Review and Evaluation NDA 209353ALTRENO (tretinoin) Lotion, 0.05% for topical useDDS Deputy Director for SafetyDEPI Division of EpidemiologyDMA Division of Microbiology AssessmentDMPP Division of Medical PolicyDND API Division of New Drug APIDNDP II Division of New Drug Products IIDPA III Division of Process Assessment IIIDPM Division of PharmacometricsDPA DPMH Division of Pediatrics and Maternal HealthDARRTS Document Archiving, Reporting, and Regulatory Tracking SystemDRBM OB Office of BiostatisticsOBP Office of Biotechnology ProductsOCP Office of Clinical PharmacologyODE III Office of Drug Evaluation IIIODE IV Office of Drug Evaluation IVOPQ Office of Pharmaceutical QualityOPDP Office of Prescription Drug PromotionOPRO Office of Program and Regulatory OperationsOSE Office of Surveillance and EpidemiologyPLT Patient Labeling TeamPMS Project Management StaffRBPMBI Regulatory and Business Process Management Branch ISRPM Safety Regulatory Project Manager12Version date: February 1, 2016 for initial rollout (NME/original BLA reviews)Reference ID: 4310916
Multi-disciplinary Review and Evaluation NDA 209353ALTRENO (tretinoin) Lotion, 0.05% for topical IPIPKPPPPIPRORARREMSSAESOCTEAEabsorption, distribution, metabolism, excretionadverse eventalanine aminotransferaseaspartate aminotransferaseBurkholderia cepacia complexbovine corneal opacity and permeabilitybiologics license applicationCenter for Biologics Evaluation and ResearchCenter for Drug Evaluation and ResearchCenter for Devices and Radiological HealthCross-Discipline Team LeaderCode of Federal Regulationscreatine phosphokinase; creatine kinase (CK)case report formEvaluator’s Global Severity ScoreFood and Drug AdministrationInvestigational New Druginitial Pediatric Study Planintent to treatin vitro irritancy azolium bromidemaximum recommended human doseNew Drug ApplicationOffice of Computational ScienceOffice of Pharmaceutical QualityOffice of Surveillance and EpidemiologyOffice of Scientific Investigationprescribing informationpharmacokineticsper protocolpatient package insertpatient reported outcomeretinoic acid receptorRisk Evaluation and Mitigation Strategyserious adverse eventsystem organ classtreatment emergent adverse event13Version date: February 1, 2016 for initial rollout (NME/original BLA reviews)Reference ID: 4310916
Multi-disciplinary Review and Evaluation NDA 209353ALTRENO (tretinoin) Lotion, 0.05% for topical use1 Executive SummaryProduct IntroductionALTRENO (tretinoin) Lotion, 0.05% is a topical drug product for which the applicant seeksapproval under Section 505(b)(1) of the Federal Food, Drug and Cosmetic Act for the treatmentof acne vulgaris. This application is for a new dosage form of tretinoin. The active ingredient istretinoin, all-trans-retinoic acid, which is a member of the retinoid class of compounds and ametabolite of Vitamin A. It is currently marketed in the United States (U.S.) in various dosageforms (cream, gel, solution and capsule). The proposed indication is the topical treatment ofacne vulgaris. The proposed dose and administration is a thin layer applied to the affectedareas once daily.The Agency concluded that the proposed proprietary name, ALTRENO, was acceptable fromboth a promotional and safety perspective under NDA 209353 [Proprietary Name Review bySherly Abraham, R.Ph., Division of Medication Error Prevention and Analysis dated 1/26/2018.Conclusions on the Substantial Evidence of EffectivenessThe applicant submitted data from two adequate and well-controlled trials (V01-121A-301 andV01-121A-302) which provided evidence of the effectiveness of tretinoin lotion for the topicaltreatment of acne vulgaris in the target population. Both trials assessed the changes fromBaseline to Week 12 compared to vehicle in the co-primary endpoints:xxxAbsolute change in the mean noninflammatory lesion countAbsolute change in the mean inflammatory lesion countPercentage of subjects who achieved an Evaluator’s Global Severity Score (EGSS) of clearor almost clear and at least two-grade reductions from BaselineTretinoin lotion was statistically superior to vehicle (p-values ч 0.007) on the co-primaryendpoints in both trials. The applicant has demonstrated that tretinoin lotion is effective for itsintended use in the target population, and has met the evidentiary standard required by 21Code of Federal Regulations (CFR) 314.126(a)(b) to support approval.14Version date: February 1, 2016 for initial rollout (NME/original BLA reviews)Reference ID: 4310916
Multi-disciplinary Review and Evaluation NDA 209353ALTRENO (tretinoin) Lotion, 0.05% for topical useBenefit-Risk AssessmentBenefit-Risk Summary and AssessmentDow Pharmaceutical Sciences submitted a New Drug Application (NDA) 209353 for ALTRENO (tretinoin) Lotion, 0.05% for the treatment ofacne vulgaris under the 505(b)(1) regulatory pathway. Acne vulgaris is a common, chronic dermatological disorder of sebaceous follicles whichprimarily affects adolescents and young adults. ALTRENO is a new dosage form of tretinoin and the safety profile of the moiety is wellcharacterized. The applicant relies on data from other tretinoin product applications (right of reference for NDA 22070 (ATRALIN Gel, 0.05%),NDA 17522 (RETIN-A Cream, 0.05%), NDA 19963 (RENOVA 0.05%), NDA 20475 (RETIN-A MICRO), NDA 21108 (RENOVA 0.02%), to support thesystemic (nonclinical and clinical)) and long-term safety of their product.In two, multicenter, randomized, double-blind clinical trials enrolling 1640 subjects age 9 years and older with acne vulgaris, tretinoin lotionwas statistically superior to vehicle for the treatment of acne vulgaris. The co-primary efficacy endpoints were success on the EGSS, absolutechange in noninflammatory lesion count, and absolute change in inflammatory lesion count at Week 12. Success on the EGSS was defined asat least a 2-grade improvement from Baseline and an EGSS score of clear (0) or almost clear (1).The safety profile for tretinoin lotion was adequately characterized during the drug development program. Treatment with tretinoin lotionwas not associated with an increased risk of mortality or serious adverse events. There were no deaths or drug- related, serious adverseevents (SAEs) in the Phase 3 trials, Study V01-121A-301 and Study V01-121A-302 (referred to as Study 301 and Study 302). In the pooledsafety analysis set, SAEs occurred in 0.9% subjects in the tretinoin lotion group and 0.5% subjects in the vehicle group. Review of the datasupports including the potential for skin irritation and effects of ultraviolet light and environmental exposure in Section 5 WARNINGS ANDPRECAUTIONS of labeling. Active assessment of local tolerability indicated that the percentage of subjects who reported signs and symptoms(erythema, scaling, hypopigmentation, itching, burning, and stinging) at a post Baseline visits was greater in the tretinoin lotion group thanthe vehicle group. The most common adverse reactions occurred at the application site: dryness (4%), pain (3%), erythema (2%), irritation(1%), and exfoliation (1%).In summary, acne vulgaris is a chronic disease which may be associated with substantial impairment of quality of life. Tretinoin lotion providesan additional treatment option. The available evidence of safety and efficacy supports the approval of ALTRENO (tretinoin) Lotion, 0.05% forthe topical treatment of acne vulgaris in the population 9 years of age and older. In view of a favorable overall benefit/risk assessment, thereview team recommends approval of this product.15Version date: February 1, 2016 for initial rollout (NME/original BLA reviews)Reference ID: 4310916
Multi-disciplinary Review and Evaluation NDA 209353ALTRENO (tretinoin) Lotion, 0.05% for topical useDimens
IQA/Panorama OPQ/DPA III Zhao Wang, PhD/ Yubing Tang, PhD IQA/Panorama OPQ/DMA Daniel Schu, PhD/ John W. Metcalf, PhD IQA/Panorama OPQ/DB Sandra Suarez Sharp, PhD/ Vidula Kolhatkar, PhD IQA/Panorama OPQ/DRBM Bamidele (Florence) Aisida/ IQA/Panorama OPQ/DNDP Yichun Sun, PhD/ Moo Jhong Rh
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member requests a refill of the drug, at which time the member will receive a 60-day supply of the drug. If the Food and Drug Administration deems a drug on our formulary to be unsafe or the drug’s manufacturer removes the drug from the market, we will immediately remove the drug from our formulary and provide notice to members who take the drug.
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