I NDA/BLA Multi-Disciplinary Review and Evaluation
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NDA 021200 S015 Zelnorm (tegaserod) NDA/BLA Multi-Disciplinary Review and Evaluation Application Type sNDA Application Number(s) 021200, s015 Priority or Standard Standard Submit Date(s) 2/26/2018 Received Date(s) 2/26/2018 PDUFA Goal Date 12/26/2018 Division/Office DGIEP/ODE III Review Completion Date 3/22/2019 Established/Proper Name Tegaserod Maleate (Proposed) Trade Name Zelnorm Pharmacologic Class Serotonin (5-HT4) receptor agonist Applicant Sloan Pharma S.a.r.l, Bertrange, Cham Branch Authorized US Agent: US WorldMed, LLC Dosage form Oral tablets Applicant proposed Dosing 6 mg twice daily Regimen Applicant Proposed Treatment of women less than 65 years with irritable bowel Indication(s)/Population(s) syndrome with constipation (IBS-C). (Proposed contraindications: history of myocardial infarction, stroke, transient ischemic attack, or angina, and more than one cardiovascular risk factor: hypertension, tobacco use, diabetes, hypercholesterolemia, age ≥55 years, and obesity). Recommendation on Approval Regulatory Action Recommended Treatment of adult women less than 65 years of age with irritable Indication(s)/Population(s) bowel syndrome with constipation (if applicable) (Contraindication: history of myocardial infarction, stroke, transient ischemic attack, or angina). Recommended Dosing 6 mg twice daily Regimen i Reference ID: 4407897 NDA 021200 S015 Zelnorm (tegaserod) Table of Contents Reviewers of Multi-Disciplinary Review and Evaluation .............................................. 1 Glossary ......................................................................................................................... 3 1. Executive Summary ................................................................................................... 5 1.1. Product Introduction .......................................................................................... 6 1.2. Conclusions on the Substantial Evidence of Effectiveness ................................ 7 1.3. Benefit-Risk Assessment .................................................................................... 9 1.4. Patient Experience Data ................................................................................... 19 2. Therapeutic Context ............................................................................................... 20 2.1. Analysis of Condition ........................................................................................ 20 2.2. Analysis of Current Treatment Options ........................................................... 21 3. Relevant Regulatory History ................................................................................... 23 3.1. U.S. Regulatory Actions and Marketing History ............................................... 23 3.2. Summary of Presubmission/Submission Regulatory Activity .......................... 23 4. Significant Issues from Other Review Disciplines Pertinent to Clinical Conclusions on Efficacy and Safety ....................................................................... 27 4.1. Office of Scientific Investigations ..................................................................... 27 4.2. Product Quality................................................................................................. 27 4.3. Clinical Microbiology ........................................................................................ 28 4.4. Devices and Companion Diagnostic Issues ...................................................... 29 5. Statistical and Clinical Evaluation of Efficacy .......................................................... 29 5.1. Review Strategy for Efficacy and Overview of the Clinical Development Program for IBS-C .............................................................................................. 29 5.2. Phase 3 Trial Design .......................................................................................... 30 5.2.1. Primary Endpoint ....................................................................................... 31 5.2.2. Severely Symptomatic IBS-C Subpopulation ............................................. 35 5.3. Efficacy Conclusions ......................................................................................... 36 6. Evaluation of Overall Safety .................................................................................... 37 6.1. Safety Review Approach................................................................................... 37 6.2. Review of the Safety Database ........................................................................ 39 6.2.1. Exposure .................................................................................................... 39 6.2.2. Adequacy of the Safety Database .............................................................. 40 6.3. Safety Results ................................................................................................... 41 6.3.1. Deaths ........................................................................................................ 41 6.3.2. Serious Adverse Events .............................................................................. 41 ii Reference ID: 4407897 NDA 021200 S015 Zelnorm (tegaserod) 6.3.3. Dropouts and/or Discontinuations Due to Adverse Effects ...................... 42 6.3.4. Treatment Emergent Adverse Events and Adverse Reactions .................. 42 6.4. Safety Analyses by Demographic Subgroups ................................................... 43 6.5. Analysis of Submission-Specific Safety Issues .................................................. 43 6.6. Safety Concerns Identified Through Postmarket Experience .......................... 44 7. Cardiovascular Events of Special Interest ............................................................... 47 7.1. Nonclinical Pharmacology/Toxicology ............................................................. 47 7.1.1. Executive Summary ................................................................................... 47 7.1.2. Referenced NDAs, BLAs, DMFs .................................................................. 48 7.1.3. Serotonin Receptor Selectivity Studies...................................................... 48 7.1.4. In Vitro Cardiac Electrophysiology Studies ................................................ 49 7.1.5. Effects on Contractility of Coronary Arteries ............................................ 50 7.1.6. In Vivo Nonclinical Cardiovascular Safety Pharmacology Studies ............. 50 7.2. Clinical Pharmacology ...................................................................................... 50 7.2.1. Executive Summary ................................................................................... 50 7.2.2. Clinical Pharmacokinetics .......................................................................... 51 7.2.3. Specific Populations ................................................................................... 51 7.2.4. Drug-Drug Interactions Studies ................................................................. 52 7.2.5. Effects on Platelet Aggregation ................................................................. 54 7.3. Clinical and Statistical Evaluation ..................................................................... 57 7.3.1. Characterization of the CV Safety Signal, Including MACE ........................ 57 7.3.2. Statistical Perspective ................................................................................ 65 7.3.3. Adjudications ............................................................................................. 67 7.3.4. Other Elements of CV Safety Signal, Including Arrhythmia, Long-Term Safety, ECG (and QT Prolongation), and Blood Pressure............................... 73 7.3.4.1. Arrhythmic Events ............................................................................... 73 7.3.4.2. Long-Term (Open-label) Use ............................................................... 75 7.3.4.3. ECG Findings (Including QT) ................................................................ 76 7.3.4.4. Vital Signs Data (Including Blood Pressure) ........................................ 78 7.3.5. Patient Demographic and Baseline CV Risk Characteristics ...................... 79 7.3.6. CVI Signal by Subpopulations – Assessment of Proposed Reintroduction Populations ........................................................................... 84 7.3.7. CV Signal from Clinical Trials: Conclusions ................................................ 87 7.4. Postmarketing/Epidemiologic Study ................................................................ 88 7.4.1. Division of Epidemiology Review of Observational Study ......................... 88 iii Reference ID: 4407897 NDA 021200 S015 Zelnorm (tegaserod) 8. Neuropsychiatric Adverse Events of Interest ......................................................... 91 8.1. Clinical .............................................................................................................. 91 8.2. Postmarketing/Epidemiology ........................................................................... 95 8.2.1. Division of Pharmacovigilance Analysis of Postmarketing Suicidal Ideation and Behavior Events ............................ Error! Bookmark not defined. 8.2.2. Division of Epidemiology Review of Observational Study ......................... 95 9. Summary of Safety .................................................................................................. 96 10. Advisory