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21882 Deferasirox Clinical PREA CLINICAL REVIEW Application Number(s) NDA 021882 S-015 Application Type Efficacy Supplement Priority or Standard Standard Submit Date(s) 12/23/2011 Received Date(s) 12/23/2011 PDUFA Goal Date 1/23/2013 Review Completed 12/12/2012 Office / Division Office of Hematology and Oncology Products / Division of Hematology Products Primary Reviewer Donna Przepiorka, MD, PhD Team Leader Albert Deisseroth, MD, PhD Established Name Deferasirox (Proposed) Trade Name Exjade® Therapeutic Class Tridentate iron chelator Applicant Novartis Formulation(s) Tablet for Oral Suspension 125 mg, 250 mg, 500 mg Dosing Regimen Initial daily dose is 10 mg/kg orally once daily for an LIC <15 mg Fe/g dw and 20 mg/kg once daily for an LIC >15 mg Fe/g dw Indication(s) Treatment of chronic iron overload Intended Population(s) Non-transfusion-dependent thalassemia patients greater than 10 years of age with an LIC >5 mg Fe/g dw Reference ID: 3242583 Clinical Review sNDA 021882 S-015 Exjade® (deferasirox) Table of Contents CLINICAL REVIEW................................................................................................................... 1 TABLE OF CONTENTS ............................................................................................................. 2 TABLE OF TABLES.................................................................................................................... 5 TABLE OF FIGURES.................................................................................................................. 7 TABLE OF ABBREVIATIONS .................................................................................................. 8 1 RECOMMENDATIONS/RISK BENEFIT ASSESSMENT.............................................. 9 1.1 Recommendation on Regulatory Action .......................................................................... 9 1.2 Risk Benefit Assessment .................................................................................................. 9 1.3 Recommendations for Labeling...................................................................................... 13 1.4 Recommendations for Postmarket Risk Evaluation and Mitigation Strategies.............. 14 1.5 Recommendations for Postmarket Requirements and Commitments ............................ 14 2 INTRODUCTION AND REGULATORY BACKGROUND.......................................... 15 2.1 Product Information........................................................................................................ 15 2.2 Currently Available Treatments for Proposed Indication............................................... 16 2.3 Availability of Proposed Active Ingredient in the United States ................................... 17 2.4 Important Issues with Consideration to Related Drugs .................................................. 17 2.5 Summary of Presubmission Regulatory Activity Related to Submission ...................... 17 2.6 Other Relevant Background Information ....................................................................... 17 2.7 Compliance with the Pediatric Research Equity Act...................................................... 19 3 ETHICS AND GOOD CLINICAL PRACTICES ............................................................ 20 3.1 Submission Quality and Integrity ................................................................................... 20 3.2 Compliance with Good Clinical Practices ...................................................................... 20 3.3 Financial Disclosures...................................................................................................... 21 4 SIGNIFICANT ISSUES RELATED TO OTHER REVIEW DISCIPLINES ............... 21 4.1 Chemistry Manufacturing and Controls ......................................................................... 21 4.2 Clinical Microbiology..................................................................................................... 21 4.3 Preclinical Pharmacology/Toxicology ........................................................................... 21 4.4 Clinical Pharmacology ................................................................................................... 21 4.5 Pharmacovigilance.......................................................................................................... 21 5 SOURCES OF CLINICAL DATA..................................................................................... 22 5.1 Tables of Studies/Clinical Trials .................................................................................... 22 5.2 Review Strategy.............................................................................................................. 22 5.3 Discussion of Individual Studies/Clinical Trials ............................................................ 23 5.3.1 Study A2209 ................................................................................................................ 23 5.3.2 Study A2202 ................................................................................................................ 27 6 REVIEW OF EFFICACY .................................................................................................. 29 6.1 Indication........................................................................................................................ 30 2 Reference ID: 3242583 Clinical Review sNDA 021882 S-015 Exjade® (deferasirox) 6.1.1 Methods ................................................................................................................... 30 6.1.2 Demographics.......................................................................................................... 30 6.1.3 Subject Disposition.................................................................................................. 32 6.1.4 Protocol Deviations ................................................................................................. 33 6.1.5 Primary Efficacy Endpoints .................................................................................... 35 6.1.5.1 Measurement of the Primary Endpoints ........................................................... 35 6.1.5.2 Relevance of the Primary Endpoints................................................................. 36 6.1.5.3 Analysis of the Primary Efficacy Endpoints..................................................... 37 6.1.6 Subpopulations ........................................................................................................ 39 6.1.7 Analysis of the Secondary Efficacy Endpoints ....................................................... 40 6.1.8 Analysis of Clinical Information Relevant to Dosing Recommendations .............. 42 6.1.8.1 Dose-Response.................................................................................................. 42 6.1.8.2 Use of Ferritin as a Surrogate for LIC .................................................................. 42 6.1.9 Discussion of Persistence of Efficacy and/or Tolerance Effects............................. 43 6.1.10 Additional Efficacy Issues/Analyses ....................................................................... 43 6.1.10.1 Error of Measurement ......................................................................................... 43 6.1.10.2 Assessment for Bias ............................................................................................ 43 6.1.11 Literature Review .................................................................................................... 44 6.1.12 Efficacy Findings from Study A2209 Extension Protocol Final Report ................. 44 6.1.12.1 Extension Protocol Demographics and Disposition ........................................... 44 6.1.12.2 Extension Protocol Efficacy Analysis ................................................................ 45 6.1.12.3 Overall Study A2209 Core plus Extension Efficacy Analysis ........................... 46 7 REVIEW OF SAFETY ....................................................................................................... 47 7.1 Methods .......................................................................................................................... 48 7.1.1 Studies/Clinical Trials Used to Evaluate Safety...................................................... 48 7.1.2 Categorization of Adverse Events........................................................................... 48 7.1.3 Pooling of Data........................................................................................................ 49 7.2 Adequacy of Safety Assessments ................................................................................... 50 7.2.1 Overall Exposure at Appropriate Doses.................................................................. 50 7.2.2 Explorations for Dose Toxicity Relationship.......................................................... 50 7.2.3 Special Animal and/or In Vitro Testing .................................................................. 52 7.2.4 Routine Clinical Testing.......................................................................................... 52 7.2.5 Metabolic, Clearance, and Interaction Workup....................................................... 52 7.2.6 Evaluation for Potential Adverse Events for Similar Drugs in Drug Class ............ 52 7.3 Major Safety Results ...................................................................................................... 53 7.3.1 Deaths.....................................................................................................................
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