CENTER FOR DRUG EVALUATION AND RESEARCH APPLICATION NUMBER: 21-978 MEDICAL REVIEW~ CLINICAL REVIEW Application Type NDA Submission Number 21-978 Submission Code 000 Letter Date November 18, 2005 Stamp Date November 28, 2005 PDUFA Goal Date September 21,2006 Reviewer Name Denise Cook, M.D. Review Completion Date 8/28/06 Established Name Desonide (Proposed) Trade Name .. Therapeutic Class Topical corticosteroid Applicant Connectics Priority Designatiop S Formulation Foam, 0.05% Dosing Regimen bid Indication F or the treatment of mild to moderate atopic dermatitis . Intended Population Age 3 months and above Clinical Review Denise Cook, M.D. NDA 21-978/ N-OOO _ loam, 0.05%/desonide foam, 0.05% Table of Contents 1 EXECUTIVE SUMMARy................................................................................................................................5 1.1 RECOMMENDATION ON REGULATORY ACTION ...........................................................................................5 1 .2 RECOMMENDATION ON POSTMARKETING ACTIONS. .............. ...... .... .... ........... ........ ..... ... ..... ...... ......... ........5 1.2. I Risk Management Activity................ ......... ..... ............... ..... ................... ........ ........ .... ....... ... ......... ........5 1.2.2 Required Phase 4 Commitments............................................................................................................5 1.2.3 Other Phase 4 Requests..........................................................................................................................5 1.3 SUMMARY OF CLINICAL FINDINGS ..............................................................................................................5 1.3.1 Brief Overview of Clinical Program ......................................................................................................5 1.3.2 Efficacy..................................................................................................................................................6 1.3.3 Safety.......... .......... .... .......... ...... ..... ........ .... ....... ........ ......... .............. .... ...... ........ .... ..... ........ ............ .......7 1.3.4 Dosing Regimen and Administration.....................................................................................................7 1.3.5 Drug-Drug Interactions.......................................................................................................................... 7 1.3.6 Special Populations................................................................................................................................8 2 INTRODUCTION AND BACKGROUND.....................................................................................................9 2.1 PRODUCT INFORMATION .............................................................................................................................9 2.2 CURRENTLY AVAILABLE TREATMENT FOR INDICA TlONS ... ...... ... ...... ... ................ ............. ......... .......... ..... I 0 2.3 A VAILABILITY OF PROPOSED ACTIVE INGREDIENT IN THE UNITED STATES .............................................. I I 2.4 IMPORTANT ISSUES WITH PHARMACOLOGICALLY RELATED PRODUCTS................................................... I I 2.5 PRESUBMISSION REGULATORY ACTIVITY ................................................................................................. I I 2.6 OTHER RELEVANT BACKGROUND INFORMATION.. ... ............ .... .... ........... .... ............... ....... ............ ...... ...... 12 3 SIGNIFICANT FINDINGS FROM OTHER REVIEW DISCIPLINES ....................................................13 3. I CMC (AND PRODUCT MICROBIOLOGY, IF ApPLICABLE) ........................................................................... I 3 3.2 ANIMAL PHARMACOLOGy/ToXICOLOGY .................................................................................................. I 3 4 DATA SOURCES, REVIEW STRATEGY, AND DATA INTEGRITy.....................................................14 4.1 SOURCES OF CLINICAL DATA ....................................................................................................................14 4.2 TABLES OF CLINICAL STUDIES.. .... ...... ...... ............ ................ ............. .................. .......... ...... ....... .... .... ...... I 5 4.3 REVIEW STRATEGY ...................................................................................................................................16 4.4 DATA QUALITY AND INTEGRITY ...............................................................................................................16 4.5 COMPLIANCE WITH GOOD CLINICAL PRACTICES....................................................................................... I 7 4.6 FINANCIAL DISCLOSURES.......................................................................................................................... I 7 5 CLINICAL PHARMACOLOGY ...................................................................................................................18 5.1 PHARMACOKINETICS ........................................................................................:........................................ I 8 5.2 PHARMACODYNAMICS............................................................................................................................... I 8 5.3 EXPOSURE-RESPONSE RELATIONSHIPS ..................................................................................................... I 8 6 INTEGRA TED REVIEW OF EFFICACY ...................................................................................................18 6. I INDICATION. ........... .... ..... .... ......... ... ....... ...... ...... .... .... ......... ... ........... ..... ..... ..... ............. .... ..... ......... .... ...... I 8 6.1.1 Methods...............................................................................................................................................18 6. 1.2 General Discussion of Endpoints. ............. ............................................................ ............................... 19 6.1.3 Study Design........................................................................................................................................20 6. 1.4 Effcacy Findings .................................................................................................................................2 I 6. 1.5 Clinical Microbiology............... .., .... ..................................................................... ...... .........................26 6. 1.6 Effcacy Conclusions ...........................................................................................................................26 7 INTEGRA TED REVIEW OF SAFETY ........................................................................................................27 7.1 METHODS AND FINDINGS ..........................................................................................................................27 7.1.1 Deaths.................................................................................................................................................27 2 Clinical Review Denise Cook, M.D. NDA 21-978/N-000 - /oam, 0.05%/desonide foam, 0.05% 7.1.2 Other Serious Adverse Events ...........................................................................:.................................27 7.1.3 Dropouts and Other Significant Adverse Events .................................................................................28 7.1.4 Other Search Strategies........................................................................................................................29 7.1.5 Common Adverse Events ....................................................................................................................29 7.1.6 Less Common Adverse Events ............................................................................................................32 7.1.7 Laboratory Findings.............................................................................................................................32 7.1.8 Vital Signs ...........................................................................................................................................34 7.1.9 Electrocardiograms (ECGs) .................................................................................................................37 7.1.10 Immunogenicity ..............................................................................................................................38 7.1.11 Human Carcinogenicity ..................................................................................................................3 8 7.1.12 Special Safety Studies.....................................................................................................................38 7.1.13 Withdrawal Phenomena and/or Abuse Potential.............................................................................50 7.1.14 Human Reproduction and Pregnancy Data .....................................................................................51 7.1.15 Assessment of Effect on Growth.....................................................................................................51 7.1.16 Overdose Experience ............. ............... ......... .... ...... .... ........ ...... .... .................... .......... ....... ............51 7.1.17 Postmarketing