CENTER FOR DRUG EVALUATION AND RESEARCH APPLICATION NUMBER: 22-203 MEDICAL REVIEW(S) Clinical Review, Division of Drug Oncology Products Virginia Kwitkowski NDA 22-303 /bendamustine (Treanda) CLINICAL REVIEW TEMPLATE Application Type NDA Submission Number 22303 Submission Code 000 Letter Date December 28, 2007 Stamp Date December 28, 2007 PDUFA Goal Date October 31, 2008 Reviewer Name Virginia Kwitkowski, MS, RN, ACNP-BC Review Completion Date October 21, 2008 Established Name bendamustine Trade Name Treanda ® Therapeutic Class Alkylating Agent Applicant Cephalon Priority Designation S Formulation I.V. Dosing Regimen 120 mg/m2, days 1 & 2, q 21 days Indication Rituximab-Refractory, Indolent NHL Intended Population Patients with indolent NHL 1 Clinical Review, Division of Drug Oncology Products Virginia Kwitkowski NDA 22-303 /bendamustine (Treanda) Table of Contents 1 Recommendations/Risk Benefit Analysis...................................................................... 10 1.1 Recommendation on Regulatory Action.......................................................................................10 1.2 Risk Benefit Analysis......................................................................................................................10 1.3 Recommendations for Postmarketing Risk Management Activities..........................................11 1.4 Recommendation for other Postmarketing Study Commitments..............................................12 2 Introduction and Regulatory Background...................................................................... 13 2.1 Product Information.......................................................................................................................13 2.2 Table of Currently Available Treatment for Proposed Indication ............................................13 2.3 Availability of Proposed Active Ingredient in the United States................................................14 2.4 Important Issues with Consideration to Related Drugs..............................................................15 2.5 Summary of Presubmission Regulatory Activity Related to this Submission...........................16 2.6 Other Relevant Background Information....................................................................................18 2.6.1 Development History ................................................................................................................................18 2.6.2 Marketing History .....................................................................................................................................18 3 Ethics and Good Clinical Practices................................................................................ 19 3.1 Submission Quality and Integrity .................................................................................................19 3.2 Compliance with Good Clinical Practices ....................................................................................20 3.3 Financial Disclosures......................................................................................................................21 4 Significant Efficacy or Safety Findings Related to Other Review Disciplines ............. 22 4.1 Chemistry Manufacturing and Controls......................................................................................22 4.2 Clinical Microbiology.....................................................................................................................22 4.3 Preclinical Pharmacology/Toxicology...........................................................................................22 4.4 Clinical Pharmacology ...................................................................................................................22 4.4.1 Mechanism of Action................................................................................................................................22 4.4.2 Pharmacokinetics and Pharmacodynamics................................................................................................22 5 Sources of Clinical Data and Review Strategy.............................................................. 23 5.1 Table of Clinical Studies ................................................................................................................23 5.2 Review Strategy ..............................................................................................................................25 5.3 Discussion of Individual Studies....................................................................................................26 5.3.1 Study Protocol (Primary Study) ................................................................................................................26 5.3.2 Study Protocol (Second Study) ................................................................................................................47 6. Review of Efficacy ....................................................................................................... 57 Summary of Efficacy Results and Conclusions..................................................................................57 6.1 Primary Study (SDX-105-03; N=100)...........................................................................................58 6.1.2 Methods and Study Design (Primary Study).............................................................................................59 2 Clinical Review, Division of Drug Oncology Products Virginia Kwitkowski NDA 22-303 /bendamustine (Treanda) 6.1.3 Patient Baseline Characteristics and Demographics (Primary Study).......................................................62 6.1.4 Patient Disposition (Primary Study)..........................................................................................................64 6.1.5 Analysis of Co-Primary Endpoints (Primary Study).................................................................................65 6.1.6 Secondary Endpoints (Primary Study) ......................................................................................................73 6.1.8 Subpopulations..........................................................................................................................................73 6.1.9 Analysis of Clinical Information Relevant to Dosing Recommendations (Primary Study)......................75 6.1.10 Discussion of Persistence of Efficacy and/or Tolerance Effects (Primary Study) ..................................75 6.2 Second Study (SDX-105-01; N=76) ...............................................................................................76 6.2.1 Study Methods (Second Study).................................................................................................................76 6.2.2 Patient Baseline Characteristics and Demographics (Second Study)........................................................76 6.2.3 Patient Disposition (Second Study)...........................................................................................................77 6.2.4 Study Protocol Deviation and Violations (Second Study) ........................................................................78 6.2.5 Analysis of Primary Endpoints (Second Study)........................................................................................79 6.2.6 Analysis of Secondary Efficacy Endpoints (Second Study) .....................................................................80 6.2.8 Subpopulations..........................................................................................................................................81 6.2.9 Analysis of Clinical Information Relevant to Dosing Recommendations (Second Study) .......................81 7. Integrated Review of Safety.......................................................................................... 81 Summary of Safety Results and Conclusions.....................................................................................82 7.1 Methods ...........................................................................................................................................84 7.1.1 Discussion of Clinical Studies Used to Evaluate Safety ..........................................................................85 7.1.2 Adequacy of Data......................................................................................................................................85 7.1.3 Pooling Data Across Studies to Estimate and Compare Incidence ...........................................................86 7.2 Adequacy of Safety Assessments ...................................................................................................86 7.2.1 Overall Exposure at Appropriate Doses/Durations and Demographics of Target Populations.................86 7.2.2 Explorations for Dose Response ...............................................................................................................88 7.2.3 Special Animal and/or In Vitro Testing ....................................................................................................88 7.2.4 Routine Clinical Testing ...........................................................................................................................88 7.2.5 Metabolic, Clearance, and Interaction Workup.........................................................................................88 7.2.6 Evaluation for Potential Adverse Events for Similar Drugs in Drug Class...............................................88