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209936Orig1s000 CENTER FOR DRUG EVALUATION AND RESEARCH APPLICATION NUMBER: 209936Orig1s000 MULTI-DISCIPLINE REVIEW Summary Review Office Director Cross Discipline Team Leader Review Clinical Review Non-Clinical Review Statistical Review Clinical Pharmacology Review NDA/BLA Multi-disciplinary Review and Evaluation NDA 209936 Aliqopa (copanlisib) NDA/BLA Multi-disciplinary Review and Evaluation Application Type New Drug Application (NDA) Application Number(s) 209936 Priority or Standard Priority Submit Date(s) 16 March 2017 Received Date(s) 16 March 2017 PDUFA Goal Date 16 November 2017 Division/Office DHP/OHOP Review Completion Date 13 September 2017 Established Name Copanlisib (Proposed) Trade Name Aliqopa Pharmacologic Class Kinase inhibitor Code name Phosphatidylinositol 3-kinase (PI3K) inhibitor Applicant Bayer HealthCare Pharmaceuticals Inc. Formulation(s) 60 mg intravenous infusion Dosing Regimen Days 1, 8, and 15 of a 28-day treatment cycle Applicant Proposed Indicated for the treatment of patients with relapsed (b) (4) Indication(s)/Population(s) follicular lymphoma who have received at least two prior therapies. Recommendation on Accelerated Approval Regulatory Action Recommended Indicated for the treatment of adult patients with relapsed Indication(s)/Population(s) follicular lymphoma who have received at least two prior systemic (if applicable) therapies. 1 Reference ID: 4151882 NDA/BLA Multi-disciplinary Review and Evaluation NDA 209936 Aliqopa (copanlisib) Table of Contents Reviewers of Multi-Disciplinary Review and Evaluation ................................................................ 9 Additional Reviewers of Application ............................................................................................... 9 Glossary ......................................................................................................................................... 10 1 Executive Summary ............................................................................................................... 12 1.1. Product Introduction ...................................................................................................... 12 1.2. Conclusions on the Substantial Evidence of Effectiveness ............................................ 12 1.3. Benefit-Risk Assessment ................................................................................................ 14 2 Therapeutic Context .............................................................................................................. 17 2.1. Analysis of Condition ...................................................................................................... 17 2.2. Analysis of Current Treatment Options ......................................................................... 17 3 Regulatory Background ......................................................................................................... 21 3.1. U.S. Regulatory Actions and Marketing History ............................................................. 21 3.2. Summary of Presubmission/Submission Regulatory Activity ........................................ 21 4 Significant Issues from Other Review Disciplines Pertinent to Clinical Conclusions on Efficacy and Safety................................................................................................................. 22 4.1. Office of Scientific Investigations (OSI) .......................................................................... 22 4.2. Product Quality .............................................................................................................. 22 4.3. Devices and Companion Diagnostic Issues .................................................................... 23 5 Nonclinical Pharmacology/Toxicology................................................................................... 24 5.1. Executive Summary ........................................................................................................ 24 5.2. Referenced NDAs, BLAs, DMFs ....................................................................................... 27 5.3. Pharmacology ................................................................................................................. 27 5.4. ADME/PK ........................................................................................................................ 35 5.5. Toxicology ....................................................................................................................... 37 5.5.1. General Toxicology .................................................................................................. 37 5.5.2. Genetic Toxicology .................................................................................................. 44 5.5.3. Carcinogenicity ........................................................................................................ 45 5.5.4. Reproductive and Developmental Toxicology ........................................................ 45 5.5.5. Other Toxicology Studies ........................................................................................ 49 2 Reference ID: 4151882 NDA/BLA Multi-disciplinary Review and Evaluation NDA 209936 Aliqopa (copanlisib) 6 Clinical Pharmacology ............................................................................................................ 51 6.1. Executive Summary ........................................................................................................ 51 6.2. Summary of Clinical Pharmacology Assessment ............................................................ 54 6.2.1. Pharmacology and Clinical Pharmacokinetics ........................................................ 54 6.2.2. General Dosing and Therapeutic Individualization ................................................. 55 6.3. Comprehensive Clinical Pharmacology Review ............................................................. 56 6.3.1. General Pharmacology and Pharmacokinetic Characteristics ................................ 56 6.3.2. Clinical Pharmacology Questions ............................................................................ 58 7 Statistical and Clinical Evaluation .......................................................................................... 68 7.1. Sources of Clinical Data and Review Strategy ................................................................ 68 7.1.1. Table of Clinical Studies .......................................................................................... 68 7.1.2. Review Strategy ...................................................................................................... 69 7.2. Review of Relevant Individual Trials Used to Support Efficacy ...................................... 69 7.2.1. Study 16349 Part B .................................................................................................. 69 7.2.2. Study Results ........................................................................................................... 75 7.3. Integrated Review of Effectiveness ................................................................................ 88 7.3.1. Assessment of Efficacy Across Trials ....................................................................... 88 7.3.2. Integrated Assessment of Effectiveness ................................................................. 90 7.4. Review of Safety ............................................................................................................. 90 7.4.1. Safety Review Approach ......................................................................................... 90 7.4.2. Review of the Safety Database ............................................................................... 91 7.4.3. Adequacy of Applicant’s Clinical Safety Assessments ............................................ 95 7.4.4. Safety Results .......................................................................................................... 95 7.4.5. Analysis of Submission-Specific Safety Issues ....................................................... 113 7.4.6. Safety Analyses by Demographic Subgroups ........................................................ 128 7.4.7. Specific Safety Studies/Clinical Trials .................................................................... 130 7.4.8. Additional Safety Explorations .............................................................................. 130 7.4.9. Safety in the Postmarket Setting .......................................................................... 130 7.4.10. Integrated Assessment of Safety ................................................................... 131 SUMMARY AND CONCLUSIONS .................................................................................................. 134 7.5. Statistical Issues ........................................................................................................... 134 7.6. Conclusions and Recommendations ............................................................................ 134 3 Reference ID: 4151882 NDA/BLA Multi-disciplinary Review and Evaluation NDA 209936 Aliqopa (copanlisib) 8 Advisory Committee Meeting and Other External Consultations ....................................... 136 9 Pediatrics ............................................................................................................................. 137 10 Labeling Recommendations ...............................................................................................
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