CLINICAL REVIEW Application Type NDA Submission Number 22-310 Submission Code S-001 Letter Date June 25, 2008 Stamp Date June 25, 2008 PDUFA Goal Date December 25, 2008 Reviewer Name Dragos Roman Review Completion Date December 15, 2008 Established Name Bicalutamide (Proposed) Trade Name Casodex Therapeutic Class Antiandrogen Applicant AstraZeneca Pharmaceuticals Priority Designation P Formulation oral Dosing Regimen Indication treatment of gonadotropin- independent precocious puberty in familial male-limited precocious puberty (testotoxicosis) Intended Population boys with precocious puberty due to testotoxicosis Clinical Review {Dragos Roman} {NDA 22-310/S-001} {Casodex (bicalutamide)} Table of Contents 1 EXECUTIVE SUMMARY .....................................................................................................................................5 1.1 RECOMMENDATION ON REGULATORY ACTION ...................................................................................................5 1.2 RECOMMENDATION ON POSTMARKETING ACTIONS ............................................................................................5 1.2.1 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.........................................................................................................8 1.3.5 Drug-Drug Interactions ..............................................................................................................................8 1.3.6 Special Populations ....................................................................................................................................8 2 INTRODUCTION AND BACKGROUND............................................................................................................9 2.1 PRODUCT INFORMATION .....................................................................................................................................9 2.2 CURRENTLY AVAILABLE TREATMENT FOR INDICATIONS....................................................................................9 2.3 AVAILABILITY OF PROPOSED ACTIVE INGREDIENT IN THE UNITED STATES......................................................10 2.4 IMPORTANT ISSUES WITH PHARMACOLOGICALLY RELATED PRODUCTS ..........................................................10 2.5 PRESUBMISSION REGULATORY ACTIVITY .........................................................................................................11 2.6 OTHER RELEVANT BACKGROUND INFORMATION .............................................................................................11 3 SIGNIFICANT FINDINGS FROM OTHER REVIEW DISCIPLINES..........................................................11 3.1 CMC (AND PRODUCT MICROBIOLOGY, IF APPLICABLE) ...................................................................................11 3.2 ANIMAL PHARMACOLOGY/TOXICOLOGY ..........................................................................................................11 4 DATA SOURCES, REVIEW STRATEGY, AND DATA INTEGRITY ..........................................................11 4.1 SOURCES OF CLINICAL DATA............................................................................................................................11 4.2 TABLES OF CLINICAL STUDIES ..........................................................................................................................12 4.3 REVIEW STRATEGY ...........................................................................................................................................12 4.4 DATA QUALITY AND INTEGRITY .......................................................................................................................12 4.5 COMPLIANCE WITH GOOD CLINICAL PRACTICES ..............................................................................................12 4.6 FINANCIAL DISCLOSURES .................................................................................................................................13 5 CLINICAL PHARMACOLOGY.........................................................................................................................13 5.1 PHARMACOKINETICS.........................................................................................................................................13 5.2 PHARMACODYNAMICS ......................................................................................................................................15 5.3 EXPOSURE-RESPONSE RELATIONSHIPS .............................................................................................................16 6 INTEGRATED REVIEW OF EFFICACY.........................................................................................................16 6.1 INDICATION.......................................................................................................................................................16 6.1.1 Methods....................................................................................................................................................17 6.1.2 General Discussion of Endpoints .............................................................................................................17 6.1.3 Study Design ............................................................................................................................................17 6.1.4 Efficacy Findings .....................................................................................................................................23 6.1.5 Clinical Microbiology ..............................................................................................................................32 6.1.6 Efficacy Conclusions ...............................................................................................................................33 7 INTEGRATED REVIEW OF SAFETY..............................................................................................................34 7.1 METHODS AND FINDINGS ..................................................................................................................................34 7.1.1 Deaths ......................................................................................................................................................34 2 Clinical Review {Dragos Roman} {NDA 22-310/S-001} {Casodex (bicalutamide)} 7.1.2 Other Serious Adverse Events..................................................................................................................34 7.1.3 Dropouts and Other Significant Adverse Events......................................................................................34 7.1.4 Other Search Strategies ............................................................................................................................34 7.1.5 Common Adverse Events.........................................................................................................................35 7.1.6 Less Common Adverse Events ................................................................................................................38 7.1.7 Laboratory Findings .................................................................................................................................38 7.1.8 Vital Signs.................................................................................................................................................46 7.1.9 Electrocardiograms (ECGs) .....................................................................................................................46 7.1.10 Immunogenicity .....................................................................................................................................47 7.1.11 Human Carcinogenicity .........................................................................................................................47 7.1.12 Special Safety Studies ............................................................................................................................47 7.1.13 Withdrawal Phenomena and/or Abuse Potential....................................................................................47 7.1.14 Human Reproduction and Pregnancy Data ............................................................................................47 7.1.15 Assessment of Effect on Growth............................................................................................................47