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CLINICAL REVIEW(S) Clinical Review Michael C CENTER FOR DRUG EVALUATION AND RESEARCH APPLICATION NUMBER: 210655Orig1s000 CLINICAL REVIEW(S) Clinical Review Michael C. Davis, MD, PhD and Qi Chen, MD, MPH (Safety Review) NDA 210655 Perseris (RBP-7000 risperidone-ATRIGEL) CLINICAL REVIEW Application Type Initial 505(b)(2) New Drug Application (NDA) Application Number(s) 210655 Priority or Standard Standard Submit Date(s) September 28, 2017 Received Date(s) September 28, 2017 PDUFA Goal Date July 28, 2018 Division/Office Division of Psychiatry Products/Office of Drug Evaluation I Reviewer Name(s) Michael C. Davis, MD, PhD; Qi Chen, MD, MPH (Safety Review) Review Completion Date June 22, 2018 Established/Proper Name RBP-7000 (risperidone-ATRIGEL) (Proposed) Trade Name Perseris Applicant Indivior Dosage Form(s) Injectable Suspension Applicant Proposed Dosing 90 mg or 120 mg subcutaneous injection monthly Regimen(s) Applicant Proposed Schizophrenia/Adults Indication(s)/Population(s) Recommendation on Approve Regulatory Action Recommended N/A Indication(s)/Population(s) (if applicable) CDER Clinical Review Template 1 Version date: September 6, 2017 for all NDAs and BLAs Reference ID: 4288016 Clinical Review Michael C. Davis, MD, PhD and Qi Chen, MD, MPH (Safety Review) NDA 210655 Perseris (RBP-7000 risperidone-ATRIGEL) Table of Contents Glossary ........................................................................................................................................... 9 1. Executive Summary ............................................................................................................... 11 Product Introduction ...................................................................................................... 11 Conclusions on the Substantial Evidence of Effectiveness ............................................ 11 Benefit-Risk Assessment ................................................................................................ 11 Patient Experience Data ................................................................................................. 19 2. Therapeutic Context .............................................................................................................. 20 Analysis of Condition ...................................................................................................... 20 Analysis of Current Treatment Options ......................................................................... 21 3. Regulatory Background ......................................................................................................... 25 U.S. Regulatory Actions and Marketing History ............................................................. 25 Summary of Presubmission/Submission Regulatory Activity ........................................ 25 Foreign Regulatory Actions and Marketing History ....................................................... 28 4. Significant Issues from Other Review Disciplines Pertinent to Clinical Conclusions on Efficacy and Safety................................................................................................................. 28 Office of Scientific Investigations (OSI) .......................................................................... 28 Product Quality .............................................................................................................. 29 Clinical Microbiology ...................................................................................................... 29 Nonclinical Pharmacology/Toxicology ........................................................................... 29 Clinical Pharmacology .................................................................................................... 30 Devices and Companion Diagnostic Issues .................................................................... 32 Consumer Study Reviews ............................................................................................... 32 5. Sources of Clinical Data and Review Strategy ....................................................................... 33 Table of Clinical Studies .................................................................................................. 33 Review Strategy .............................................................................................................. 35 6. Review of Relevant Individual Trials Used to Support Efficacy ............................................. 36 Study RB-US-09-0010 ..................................................................................................... 36 Study Design............................................................................................................ 36 CDER Clinical Review Template 2 Version date: September 6, 2017 for all NDAs and BLAs Reference ID: 4288016 Clinical Review Michael C. Davis, MD, PhD and Qi Chen, MD, MPH (Safety Review) NDA 210655 Perseris (RBP-7000 risperidone-ATRIGEL) Study Results ........................................................................................................... 51 7. Integrated Review of Effectiveness ....................................................................................... 71 Assessment of Efficacy Across Trials .............................................................................. 71 Primary Endpoints ................................................................................................... 71 Secondary and Other Endpoints ............................................................................. 71 Subpopulations ....................................................................................................... 71 Dose and Dose-Response........................................................................................ 71 Onset, Duration, and Durability of Efficacy Effects ................................................ 72 Additional Efficacy Considerations ................................................................................. 72 Considerations on Benefit in the Postmarket Setting ............................................ 72 Other Relevant Benefits .......................................................................................... 72 Integrated Assessment of Effectiveness ........................................................................ 72 8. Review of Safety (Dr. Qi Chen) .............................................................................................. 73 Safety Review Approach ................................................................................................ 73 Review of the Safety Database ...................................................................................... 74 Overall Exposure ..................................................................................................... 74 Relevant characteristics of the safety population .................................................. 75 Adequacy of the safety database ........................................................................... 75 Adequacy of Applicant’s Clinical Safety Assessments .................................................... 75 Issues Regarding Data Integrity and Submission Quality ....................................... 75 Categorization of Adverse Events ........................................................................... 75 Routine Clinical Tests .............................................................................................. 76 Safety Results ................................................................................................................. 76 Deaths ..................................................................................................................... 76 Serious Adverse Events ........................................................................................... 77 Dropouts and/or Discontinuations Due to Adverse Effects ................................... 79 Significant Adverse Events ...................................................................................... 79 Treatment Emergent Adverse Events and Adverse Reactions ............................... 83 Laboratory Findings ................................................................................................ 87 Vital Signs .............................................................................................................. 103 CDER Clinical Review Template 3 Version date: September 6, 2017 for all NDAs and BLAs Reference ID: 4288016 Clinical Review Michael C. Davis, MD, PhD and Qi Chen, MD, MPH (Safety Review) NDA 210655 Perseris (RBP-7000 risperidone-ATRIGEL) Electrocardiograms (ECGs) .................................................................................... 108 QT .......................................................................................................................... 108 Immunogenicity ............................................................................................. 109 Analysis of Submission-Specific Safety Issues .............................................................. 109 Safety Analyses by Demographic Subgroups ............................................................... 110 Specific Safety Studies/Clinical Trials ........................................................................... 110 Additional Safety Explorations ..................................................................................... 110 Human Carcinogenicity or Tumor Development .................................................. 110
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