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202067Orig1s000 CENTER FOR DRUG EVALUATION AND RESEARCH APPLICATION NUMBER: 202067Orig1s000 MEDICAL REVIEW(S) CLINICAL REVIEW Application Type NDA Application Number(s) 202067 Priority or Standard Standard Submit Date(s) December 23, 2010 Received Date(s) December 23, 2010 PDUFA Goal Date October 23, 2011 Division / Office DNP/ODE-1 Reviewer Name(s) Philip H Sheridan, M.D. Review Completion Date September 30, 2011 Established Name Clobazam (Proposed) Trade Name Onfi Therapeutic Class Anticonvulsant Applicant Lundbeck Inc. Formulation(s) Tablet 5 mg., 10 mg., 20 mg. Dosing Regimen BID Indication(s) Treatment of Lennox Gastaut Syndrome Intended Population(s) Patients > 2 years of age with Lennox Gastaut Syndrome Template Version: March 6, 2009 Reference ID: 3024687 Clinical Review Philip H. Sheridan, M.D. NDA 202067 Onfi (Clobazam) 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 (REMS)............................................................................................................... 7 1.4 Recommendations for Postmarket Requirements and Commitments ................ 7 2 INTRODUCTION AND REGULATORY BACKGROUND ........................................ 7 2.1 Product Information ............................................................................................ 7 2.2 Tables of Currently Available Treatments for Proposed Indications ................... 7 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 ............................................................ 9 3 ETHICS AND GOOD CLINICAL PRACTICES......................................................... 9 3.1 Submission Quality and Integrity ........................................................................ 9 3.2 Compliance with Good Clinical Practices ........................................................... 9 3.3 Financial Disclosures.......................................................................................... 9 4 SIGNIFICANT EFFICACY/SAFETY ISSUES RELATED TO OTHER REVIEW DISCIPLINES ......................................................................................................... 11 5 SOURCES OF CLINICAL DATA............................................................................ 12 Tables of Studies/Clinical Trials................................................................................. 12 5.2 Review Strategy ............................................................................................... 14 5.3 Discussion of Individual Studies/Clinical Trials................................................. 14 PIVOTAL STUDY FOR EFFICACY STUDY OV-1012.................................................. 14 SUPPORTIVE STUDY FOR EFFICACY OV-1002 ....................................................... 28 86 REVIEW OF EFFICACY........................................................................................ 46 Efficacy Summary...................................................................................................... 46 6.1.8 Subpopulations .......................................................................................... 48 6.1.9 Analysis of Clinical Information Relevant to Dosing Recommendations .... 49 6.1.10 Discussion of Persistence of Efficacy and/or Tolerance Effects................. 50 6.1.11 Additional Efficacy Issues/Analyses........................................................... 52 7 REVIEW OF SAFETY............................................................................................. 52 8 POSTMARKET EXPERIENCE............................................................................... 52 9 APPENDICES ........................................................................................................ 52 2 Reference ID: 3024687 Clinical Review Philip H. Sheridan, M.D. NDA 202067 Onfi (Clobazam) 9.1 Literature Review/References .......................................................................... 52 9.2 Labeling Recommendations ............................................................................. 52 9.3 Advisory Committee Meeting............................................................................ 52 3 Reference ID: 3024687 Clinical Review Philip H. Sheridan, M.D. NDA 202067 Onfi (Clobazam) Table of Tables Table 1 Alternative Therapies for LGS ........................................................................... 8 Table 2 Clinical Investigators with Financial Interests Requiring Disclosure ................. 10 Table 3 Clinical Studies and Long-Term Study Supporting Efficacy ............................ 12 Table 4 Pivotal Study OV-1012 (Sponsor's ISE Table 1) .............................................. 13 Table 5 Supportive Study OV-1002 (Sponsor's ISE Table 1)........................................ 13 Table 6 Patient Disposition for Study OV-1012 ............................................................. 20 Table 7 Percent Reduction in Average Weekly Rate of Drop Seizures in Study OV-1012 - MITT Population .......................................................................................... 21 Table 8 Sensitivity Analysis of Reduction in Average Weekly Rate of Drop Seizures in OV-1012 (Baseline to Maintenance Period) - MITT and ITT Populations ...... 23 Table 9 Percent Reduction in Average Weekly Rate of Total (Drop and Non-drop) Seizures in OV-1012 (Baseline to Maintenance Period) – MITT Population.. 24 Table 10 Percent Reduction in Average Weekly Rate of Non-drop Seizures in Study OV-1012 (Baseline to Maintenance Period) – MITT Population .................... 26 Table 11 Patient Disposition for Study OV-1002 ........................................................... 32 Table 12 Percent Reduction in Average Weekly Rate of Drop Seizures in Study OV- 1002 (Baseline to Maintenance Period) – MITT Population........................... 33 Table 13 Percent Reduction in Average Weekly Rate of Total (Drop and Non-drop) Seizures in Study OV-1002 (Baseline to Maintenance Period) – MITT Population...................................................................................................... 34 Table 14 Percent Reduction in Average Weekly Rate of Non-drop Seizures in Study OV-1002 (Baseline to Maintenance Period) – MITT Population .................... 35 Table 15 Evaluation Windows for Assigning Post-baseline Efficacy Evaluations in Study OV-1004 (Sponsor’s ISE Table 24)................................................................ 38 Table 16 Percent Reduction in Average Weekly Rate of Drop Seizures in Study OV- 1004 - Efficacy Analysis Set (Sponsor’s ISE Table 25).................................. 42 Table 17 Categories of Improvement in Average Weekly Rate of Drop Seizures in Study OV-1004 - Efficacy Analysis Set .................................................................... 43 Table 18 Percent Reduction in Average Weekly Rate of Total (Drop and Non-drop) Seizures in Study OV-1004 - Efficacy Analysis Set ....................................... 44 Table 19 Percent Reduction in Average Weekly Rate of Non-Drop Seizures by Seizure Type in Study OV-1004 - Efffcacy Analysis Set ............................................. 45 Table 20 Percent Reduction in Average Weekly Rate of Drop Seizures from Baseline to the Maintenance Period of Double blind Phase - MITT Population................ 47 Table 21 Percent Reduction in Average Weekly Rate of Total (Drop and Non-drop) Seizures from Baseline to the Maintenance Period of Double blind Phase - MITT Population............................................................................................. 48 4 Reference ID: 3024687 Clinical Review Philip H. Sheridan, M.D. NDA 202067 Onfi (Clobazam) Table of Figures Figure 1 Schematic for Study OV-1012 (Sponsor's ISE Figure 1)................................. 15 Figure 2 Schematic for Study OV-1002 (Sponsor's ISE Figure 4)................................. 29 Figure 3 Disposition of All Subjects in Study OV-1004 (Sponsor's ISE Figure 5).......... 40 5 Reference ID: 3024687 Clinical Review Philip H. Sheridan, M.D. NDA 202067 Onfi (Clobazam) 1 Recommendations/Risk Benefit Assessment 1.1 Recommendation on Regulatory Action Approval for the adjunctive treatment of seizures associated with Lennox-Gastaut syndrome (LGS) in patients age 2 years of age and above. 1.2 Risk Benefit Assessment Lennox-Gastaut syndrome (LGS) is a severe childhood epileptic encephalopathy characterized by a slow spike and wave electroencephalogram (EEG), multiple seizure types, and usually an abnormal developmental state and behavioral disturbances. Recurrent episodes of status epilepticus may occur. Onset of LGS, as determined by the appearance of the characteristic seizures, generally occurs between 3 and 8 years of age, with peak occurrence between 3 and 5 years. Most patients continue to have refractory epilepsy and continued neurocognitive impairment that persist into adulthood. Lennox-Gastaut syndrome is characterized by multiple seizure types, predominantly of the tonic, atonic,
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