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Clinical Review Nicholas Rister, MD NDA 021572 Cubicin (Daptomycin for Injection)

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Clinical Review Nicholas Rister, MD NDA 021572 Cubicin (Daptomycin for Injection) Clinical Review Nicholas Rister, MD NDA 021572 Cubicin (Daptomycin for injection) CLINICAL REVIEW Application Type NDA supplement Application Number(s) 21572 Priority or Standard Priority Submit Date(s) March 1, 2017 Received Date(s) March 2, 2017 PDUFA Goal Date September 2, 2017 Division / Office DAIP/OAP Reviewer Name(s) Nicholas Rister, MD Review Completion Date August 4, 2017 Established Name Daptomycin (Proposed) Trade Name Cubicin Therapeutic Class Cyclic Lipopeptide Applicant Cubist Pharmaceuticals Formulation(s) Injection Dosing Regimen 7 mg/kg (12-17 years), 9 mg/kg (7-11 years), and 12 mg/kg (1-6 years) Indication(s) Bacteremia caused by Staphylococcus aureus Intended Population(s) Ages 1-17 years 1 Reference ID: 4142515 Clinical Review Nicholas Rister, MD NDA 021572 Cubicin (Daptomycin for injection) Table of Contents 1 RECOMMENDATIONS/RISK BENEFIT ASSESSMENT ......................................... 7 1.1 Recommendation on Regulatory Action ............................................................. 7 1.2 Risk Benefit Assessment .................................................................................... 7 1.3 Recommendations for Postmarket Risk Evaluation and Mitigation Strategies ... 8 1.4 Recommendations for Postmarket Requirements and Commitments ................ 8 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 .......................... 9 2.4 Important Safety Issues with Consideration to Related Drugs ............................ 9 2.5 Summary of Presubmission Regulatory Activity Related to Submission ............ 9 2.6 Other Relevant Background Information .......................................................... 10 3 ETHICS AND GOOD CLINICAL PRACTICES ....................................................... 10 3.1 Submission Quality and Integrity ...................................................................... 10 3.2 Compliance with Good Clinical Practices ......................................................... 10 3.3 Financial Disclosures ........................................................................................ 10 4 SIGNIFICANT EFFICACY/SAFETY ISSUES RELATED TO OTHER REVIEW DISCIPLINES ......................................................................................................... 10 4.1 Chemistry Manufacturing and Controls ............................................................ 10 4.2 Clinical Microbiology ......................................................................................... 11 4.3 Preclinical Pharmacology/Toxicology ............................................................... 11 4.4 Clinical Pharmacology ...................................................................................... 11 4.4.1 Mechanism of Action .................................................................................. 11 4.4.2 Pharmacodynamics.................................................................................... 11 4.4.3 Pharmacokinetics ....................................................................................... 12 5 SOURCES OF CLINICAL DATA............................................................................ 12 5.1 Tables of Studies/Clinical Trials ....................................................................... 12 5.2 Review Strategy ............................................................................................... 13 6 REVIEW OF EFFICACY ......................................................................................... 14 Efficacy Summary ...................................................................................................... 14 6.1 Indication .......................................................................................................... 14 2 Reference ID: 4142515 Clinical Review Nicholas Rister, MD NDA 021572 Cubicin (Daptomycin for injection) 6.1.1 Methods ..................................................................................................... 14 6.1.2 Demographics ............................................................................................ 15 6.1.3 Subject Disposition .................................................................................... 19 6.1.4 Analysis of Primary Endpoint(s) ................................................................. 20 6.1.5 Analysis of Secondary Endpoints(s)........................................................... 21 6.1.6 Other Endpoints ......................................................................................... 22 6.1.7 Subpopulations .......................................................................................... 22 6.1.8 Analysis of Clinical Information Relevant to Dosing Recommendations .... 24 6.1.9 Discussion of Persistence of Efficacy and/or Tolerance Effects ................. 24 6.1.10 Additional Efficacy Issues/Analyses ........................................................... 24 7 REVIEW OF SAFETY ............................................................................................. 25 Safety Summary ........................................................................................................ 25 7.1 Methods ............................................................................................................ 25 7.1.1 Studies/Clinical Trials Used to Evaluate Safety ......................................... 25 7.1.2 Categorization of Adverse Events .............................................................. 26 7.1.3 Pooling of Data Across Studies/Clinical Trials to Estimate and Compare Incidence .................................................................................................... 26 7.2 Adequacy of Safety Assessments .................................................................... 27 7.2.1 Overall Exposure at Appropriate Doses/Durations and Demographics of Target Populations ..................................................................................... 27 7.2.2 Explorations for Dose Response ................................................................ 29 7.2.3 Special Animal and/or In Vitro Testing ....................................................... 30 7.2.4 Routine Clinical Testing ............................................................................. 30 7.2.5 Metabolic, Clearance, and Interaction Workup .......................................... 31 7.2.6 Evaluation for Potential Adverse Events for Similar Drugs in Drug Class .. 31 7.3 Major Safety Results ........................................................................................ 31 7.3.1 Deaths ........................................................................................................ 31 7.3.2 Nonfatal Serious Adverse Events .............................................................. 31 7.3.3 Dropouts and/or Discontinuations .............................................................. 33 7.3.4 Significant Adverse Events ........................................................................ 34 7.3.5 Submission Specific Primary Safety Concerns .......................................... 34 7.4 Supportive Safety Results ................................................................................ 36 7.4.1 Common Adverse Events .......................................................................... 36 7.4.2 Laboratory Findings ................................................................................... 39 7.4.3 Vital Signs .................................................................................................. 42 7.4.4 Electrocardiograms (ECGs) ....................................................................... 43 7.4.5 Special Safety Studies/Clinical Trials ......................................................... 43 7.4.6 Immunogenicity .......................................................................................... 43 7.5 Other Safety Explorations ................................................................................. 43 7.5.1 Dose Dependency for Adverse Events ...................................................... 43 7.5.2 Time Dependency for Adverse Events ....................................................... 43 7.5.3 Drug-Demographic Interactions ................................................................. 44 7.5.4 Drug-Disease Interactions .......................................................................... 44 3 Reference ID: 4142515 Clinical Review Nicholas Rister, MD NDA 021572 Cubicin (Daptomycin for injection) 7.5.5 Drug-Drug Interactions ............................................................................... 44 7.6 Additional Safety Evaluations ........................................................................... 44 7.7 Additional Submissions / Safety Issues ............................................................ 44 7.8 Safety Summary ................................................................................................ 44 8 POSTMARKET EXPERIENCE ............................................................................... 45 9 APPENDICES ........................................................................................................ 46 9.1 Literature Review/References .........................................................................
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