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022562S000medr.Pdf CENTER FOR DRUG EVALUATION AND RESEARCH APPLICATION NUMBER: 22-562 MEDICAL REVIEW(S) CLINICAL REVIEW Application Type NDA Application Number(s) 22-562 Priority or Standard Priority Submit Date(s) 17-June-2009 Received Date(s) 18-June-2009 PDUFA Goal Date 13-March-2010 Division / Office Gastroenterology Products/ODE 3 Reviewer Name(s) Virginia Elgin, M.D. Helen Sile, M.D. Review Completion Date February 18, 2010 Established Name carglumic acid (Proposed) Trade Name Carbaglu® Therapeutic Class not yet finalized Applicant Orphan Europe Formulation(s) oral tablet Dosing Regimen 100 - 250 mg/kg/day Indication(s) treatment of hyperammonemia due to N-acetylglutamate synthase (NAGS) deficiency Intended Population(s) pediatric and adult patients with NAGS deficiency Template Version: March 6, 2009 Clinical Review Virginia Elgin, M.D. and Helen Sile, M.D NDA 22-562/S-000 Carbaglu (carglumic acid) Table of Contents 1 RECOMMENDATIONS/RISK BENEFIT ASSESSMENT ....................................... 12 1.1 Recommendation on Regulatory Action ........................................................... 12 1.2 Risk Benefit Assessment.................................................................................. 12 1.3 Recommendations for Postmarket Risk Evaluation and Mitigation Strategies .12 1.4 Recommendations for Postmarket Requirements and Commitments .............. 12 1.5 Summary of Clinical Findings ........................................................................... 13 1.5.1 Brief Overview of Clinical Program............................................................. 13 1.5.2 Efficacy ...................................................................................................... 13 1.5.3 Safety......................................................................................................... 16 2 INTRODUCTION AND REGULATORY BACKGROUND ...................................... 18 2.1 Product Information .......................................................................................... 22 2.2 Tables of Currently Available Treatments for Proposed Indications ................. 23 2.3 Availability of Proposed Active Ingredient in the United States ........................ 25 2.4 Important Safety Issues With Consideration to Related Drugs......................... 25 2.5 Summary of Presubmission Regulatory Activity Related to Submission .......... 25 2.6 Other Relevant Background Information .......................................................... 26 3 ETHICS AND GOOD CLINICAL PRACTICES....................................................... 26 3.1 Submission Quality and Integrity ...................................................................... 26 3.2 Compliance with Good Clinical Practices ......................................................... 26 3.3 Financial Disclosures........................................................................................ 27 4 SIGNIFICANT EFFICACY/SAFETY ISSUES RELATED TO OTHER REVIEW DISCIPLINES ......................................................................................................... 27 4.1 Chemistry Manufacturing and Controls ............................................................ 27 4.2 Clinical Microbiology......................................................................................... 28 4.3 Nonclinical Pharmacology/Toxicology .............................................................. 29 4.4 Clinical Pharmacology...................................................................................... 29 4.4.1 Mechanism of Action.................................................................................. 29 4.4.2 Pharmacodynamics.................................................................................... 32 4.4.3 Pharmacokinetics....................................................................................... 32 5 SOURCES OF CLINICAL DATA............................................................................ 33 5.1 Tables of Studies.............................................................................................. 33 5.2 Review Strategy ............................................................................................... 34 5.3 Discussion of Individual Studies ....................................................................... 35 6 REVIEW OF EFFICACY....................................................................................... 133 Efficacy Summary.................................................................................................... 133 6.1 Indication ........................................................................................................ 135 6.1.1 Methods ................................................................................................... 135 3 Clinical Review Virginia Elgin, M.D. and Helen Sile, M.D NDA 22-562/S-000 Carbaglu (carglumic acid) 6.1.2 Demographics.......................................................................................... 136 6.1.3 Subject Disposition................................................................................... 139 6.1.4 Analysis of Primary Endpoint(s) ............................................................... 140 6.1.5 Analysis of Secondary Endpoints(s) ........................................................ 147 6.1.6 Other Endpoints ....................................................................................... 151 6.1.7 Subpopulations ........................................................................................ 153 6.1.8 Analysis of Clinical Information Relevant to Dosing Recommendations .. 153 6.1.9 Discussion of Persistence of Efficacy and/or Tolerance Effects............... 156 6.1.10 Additional Efficacy Issues/Analyses......................................................... 159 7 REVIEW OF SAFETY........................................................................................... 159 Safety Summary ...................................................................................................... 159 7.1 Methods.......................................................................................................... 160 7.1.1 Studies/Clinical Trials Used to Evaluate Safety ....................................... 160 7.1.2 Categorization of Adverse Events............................................................ 160 7.1.3 Pooling of Data Across Studies/Clinical Trials to Estimate and Compare Incidence.................................................................................................. 161 7.2 Adequacy of Safety Assessments .................................................................. 161 7.2.1 Overall Exposure at Appropriate Doses/Durations and Demographics of Target Populations................................................................................... 162 7.2.2 Explorations for Dose Response.............................................................. 165 7.2.3 Special Animal and/or In Vitro Testing ..................................................... 165 7.2.4 Routine Clinical Testing ........................................................................... 166 7.2.5 Metabolic, Clearance, and Interaction Workup ........................................ 166 7.2.6 Evaluation for Potential Adverse Events for Similar Drugs in Drug Class 166 7.3 Major Safety Results ...................................................................................... 166 7.3.1 Deaths...................................................................................................... 166 7.3.2 Nonfatal Serious Adverse Events ............................................................ 167 7.3.3 Dropouts and/or Discontinuations ............................................................ 168 7.3.4 Significant Adverse Events ...................................................................... 168 7.3.5 Submission Specific Primary Safety Concerns ........................................ 169 7.4 Supportive Safety Results .............................................................................. 169 7.4.1 Common Adverse Events ........................................................................ 169 7.4.2 Laboratory Findings ................................................................................. 172 7.4.3 Vital Signs ................................................................................................ 173 7.4.4 Electrocardiograms (ECGs) ..................................................................... 173 7.4.5 Special Safety Studies/Clinical Trials....................................................... 173 7.4.6 Immunogenicity........................................................................................ 173 7.5 Other Safety Explorations............................................................................... 174 7.5.1 Dose Dependency for Adverse Events .................................................... 174 7.5.2 Time Dependency for Adverse Events..................................................... 174 7.5.3 Drug-Demographic Interactions ............................................................... 174 7.5.4 Drug-Disease Interactions........................................................................ 175 7.5.5 Drug-Drug Interactions............................................................................. 175 4 Clinical Review Virginia Elgin, M.D. and Helen Sile, M.D NDA 22-562/S-000 Carbaglu (carglumic acid) 7.6 Additional Safety Evaluations ........................................................................
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