Clinical Review Amir H. Shahlaee MD sNDA 22065, S-006 Ixempra® (ixabepilone) CLINICAL REVIEW Application Type Pediatric Exclusivity Determination Application Number(s) sNDA 22-065/S-006 Priority or Standard Priority Submit Date(s) 1/14/2011 Received Date(s) 1/18/2011 PDUFA Goal Date 7/14/2011 extended to 10/18/2011 Division / Office DDOP/OODP Reviewer Name(s) Amir Shahlaee, MD CDTL Ke Liu, MD, PhD Review Completion Date 9/9/2011 Established Name Ixabepilone (Proposed) Trade Name Ixempra® Therapeutic Class Microtubule inhibitor Applicant Bristol-Myers Squibb Formulation(s) Intravenous Injection Dosing Regimen Not applicable Indication(s) None Intended Population(s) None 1 Reference ID: 3020673 Clinical Review Amir H. Shahlaee MD sNDA 22065, S-006 Ixempra® (ixabepilone) Table of Contents 1 RECOMMENDATIONS/RISK BENEFIT ASSESSMENT ......................................... 6 1.1 Recommendation on Regulatory Action ............................................................. 6 1.2 Risk Benefit Assessment.................................................................................... 6 1.3 Recommendations for Postmarket Risk Evaluation and Mitigation Strategies ... 7 1.4 Recommendations for Postmarket Requirements and Commitments ................ 7 2 INTRODUCTION AND REGULATORY BACKGROUND ........................................ 8 2.1 Product Information ............................................................................................ 8 2.2 Tables of Currently Available Treatments for Proposed Indications ................... 8 2.3 Availability of Proposed Active Ingredient in the United States .......................... 8 2.4 Important Safety Issues With Consideration to Related Drugs........................... 8 2.5 Summary of Presubmission Regulatory Activity Related to Submission ............ 8 2.6 Other Relevant Background Information .......................................................... 12 3 ETHICS AND GOOD CLINICAL PRACTICES....................................................... 13 3.1 Submission Quality and Integrity ...................................................................... 13 3.2 Compliance with Good Clinical Practices ......................................................... 13 3.3 Financial Disclosures........................................................................................ 13 4 SIGNIFICANT EFFICACY/SAFETY ISSUES RELATED TO OTHER REVIEW DISCIPLINES ......................................................................................................... 14 4.1 Chemistry Manufacturing and Controls ............................................................ 14 4.2 Clinical Microbiology......................................................................................... 14 4.3 Preclinical Pharmacology/Toxicology ............................................................... 14 4.4 Clinical Pharmacology in Pediatric Patients ..................................................... 14 4.4.1 Mechanism of Action.................................................................................. 14 4.4.2 Pharmacodynamics.................................................................................... 14 4.4.3 Pharmacokinetics....................................................................................... 15 5 SOURCES OF CLINICAL DATA............................................................................ 16 5.1 Tables of Studies/Clinical Trials ....................................................................... 16 5.2 Review Strategy ............................................................................................... 17 5.3 Discussion of Individual Studies/Clinical Trials................................................. 17 5.3.1 Study CTEP-5425 ......................................................................................... 17 5.3.2 Study ADVL0524........................................................................................... 36 6 EVALUATION OF THE APPLICANT’S FULFILLMENT OF THE PEDIATRIC WRITTEN REQUEST REQUIREMENTS ............................................................... 50 7 REVIEW OF EFFICACY......................................................................................... 59 Efficacy Summary...................................................................................................... 59 7.1 Indication .......................................................................................................... 59 2 Reference ID: 3020673 Clinical Review Amir H. Shahlaee MD sNDA 22065, S-006 Ixempra® (ixabepilone) 7.1.1 Methods ..................................................................................................... 59 7.1.2 Demographics............................................................................................ 60 7.1.3 Subject Disposition..................................................................................... 61 7.1.4 Analysis of Primary Endpoint(s) ................................................................. 63 7.1.5 Analysis of Secondary Endpoints(s) .......................................................... 65 7.1.6 Other Endpoints ......................................................................................... 66 7.1.7 Subpopulations .......................................................................................... 66 7.1.8 Analysis of Clinical Information Relevant to Dosing Recommendations .... 67 7.1.9 Discussion of Persistence of Efficacy and/or Tolerance Effects................. 67 7.1.10 Additional Efficacy Issues/Analyses........................................................... 67 8 REVIEW OF SAFETY............................................................................................. 68 Safety Summary ........................................................................................................ 68 8.1 Methods............................................................................................................ 68 8.1.1 Studies/Clinical Trials Used to Evaluate Safety ......................................... 68 8.1.2 Categorization of Adverse Events.............................................................. 68 8.1.3 Pooling of Data Across Studies/Clinical Trials to Estimate and Compare Incidence.................................................................................................... 68 8.2 Adequacy of Safety Assessments .................................................................... 69 8.2.1 Overall Exposure at Appropriate Doses/Durations and Demographics of Target Populations..................................................................................... 69 8.2.2 Explorations for Dose Response................................................................ 70 8.2.3 Special Animal and/or In Vitro Testing ....................................................... 70 8.2.4 Routine Clinical Testing ............................................................................. 70 8.2.5 Metabolic, Clearance, and Interaction Workup .......................................... 71 8.2.6 Evaluation for Potential Adverse Events for Similar Drugs in Drug Class .. 71 8.3 Major Safety Results ........................................................................................ 71 8.3.1 Deaths........................................................................................................ 71 8.3.2 Nonfatal Serious Adverse Events .............................................................. 71 8.3.3 Dropouts and/or Discontinuations .............................................................. 72 8.3.4 Significant Adverse Events ........................................................................ 73 8.3.5 Submission Specific Primary Safety Concerns .......................................... 73 8.4 Supportive Safety Results ................................................................................ 73 8.4.1 Common Adverse Events .......................................................................... 73 8.4.2 Laboratory Findings ................................................................................... 76 8.4.3 Vital Signs .................................................................................................. 78 8.4.4 Electrocardiograms (ECGs) ....................................................................... 78 8.4.5 Special Safety Studies/Clinical Trials......................................................... 78 8.4.6 Immunogenicity.......................................................................................... 78 8.5 Other Safety Explorations................................................................................. 78 8.5.1 Dose Dependency for Adverse Events ...................................................... 78 8.5.2 Time Dependency for Adverse Events....................................................... 79 8.5.3 Drug-Demographic Interactions ................................................................. 80 8.5.4 Drug-Disease Interactions.......................................................................... 80 3 Reference ID: 3020673 Clinical Review Amir H. Shahlaee MD sNDA 22065, S-006 Ixempra® (ixabepilone) 8.5.5 Drug-Drug Interactions............................................................................... 80 8.6 Additional Safety Evaluations ........................................................................... 81 8.6.1 Human Carcinogenicity.............................................................................