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FDA Briefing Document Cardiovascular and Renal Drugs FDA Briefing Document Cardiovascular and Renal Drugs Advisory Committee (CRDAC) Meeting December 10, 2019 Topic: New Drug Application 22034 Vernakalant Hydrochloride Injection for the Rapid Conversion of Recent Onset Atrial Fibrillation 1 The attached package contains background information prepared by the Food and Drug Administration (FDA) for the panel members of the advisory committee. The FDA background package often contains assessments and/or conclusions and recommendations written by individual FDA reviewers. Such conclusions and recommendations do not necessarily represent the final position of the individual reviewers, nor do they necessarily represent the final position of the Review Division or Office. We have brought New Drug Application 22034, atrial fibrillation for the treatment of recent onset atrial fibrillation, to this Advisory Committee in order to gain the Committee’s insights and opinions on key issues identified by the Agency. The background package may not include all issues relevant to the final regulatory recommendation, and the final determination may be affected by issues not discussed at the advisory committee meeting. The FDA will not issue a final determination on the issues at hand until input from the advisory committee process has been considered and all reviews have been finalized. 2 Table of Contents Glossary .......................................................................................................................................... 8 1. Introduction ........................................................................................................................... 12 2. Draft Topics for Discussion ................................................................................................... 13 3. Purpose .................................................................................................................................. 14 4. Treatment of Recent Onset Atrial Fibrillation ....................................................................... 14 5. Product Under Review........................................................................................................... 16 6. Proposed Indication ............................................................................................................... 16 7. Proposed Dosage and Administration ................................................................................... 17 8. Preclinical Pharmacology ...................................................................................................... 17 9. Regulatory Background ......................................................................................................... 17 10. Overview of Clinical Development ....................................................................................... 20 11. Conclusions on the Substantial Evidence of Effectiveness ................................................... 24 12. Overview of Safety Findings from Clinical Trials ................................................................ 25 Overall Exposure and Characteristics of the Safety Population ................................. 25 Deaths and Serious Adverse Events of Special Interest (AESI) ................................ 25 Serious Hypotension ........................................................................................ 26 Serious Ventricular Arrhythmias ..................................................................... 27 Serious Conduction Disturbances .................................................................... 28 Serious Bradycardia ......................................................................................... 28 ECG and Blood Pressure Changes .................................................................. 29 Serious Adverse Events after ECV .................................................................. 31 13. Postmarketing Safety Experience .......................................................................................... 31 Review of non-US Postmarketing Data Submitted in the NDA ................................ 31 SPECTRUM ............................................................................................................... 32 Background and Study Design ........................................................................ 32 Objectives ........................................................................................................ 32 Data Sources .................................................................................................... 33 Study Subjects ................................................................................................. 33 3 Overall Exposure ............................................................................................. 34 Safety Results .................................................................................................. 35 Summary and Limitations ............................................................................... 36 14. Safety of Available Alternative Therapies ............................................................................ 37 Overview .................................................................................................................... 37 Ibutilide ....................................................................................................................... 38 Electrical Cardioversion ............................................................................................. 38 Use of Cardiac Conversion Therapies ........................................................................ 39 Conclusions on the Safety of Alternative Therapies .................................................. 39 15. Proposed Risk Management Plan .......................................................................................... 39 16. FDA Integrated Benefit/Risk Assessment ............................................................................. 40 17. Appendices ............................................................................................................................ 43 Demographic and Baseline Characteristics of All Patients Population ...................... 43 in Integrated Analysis of Clinical Trials ................................................................................... 43 Preclinical Pharmacology ........................................................................................... 44 Potency of Vernakalant Inhibition of Cardiac Ion Channels from ............................. 54 Various Species and Cloned Cell Models (IC50s) ..................................................................... 54 Frequency- and Voltage-dependent Block of Peak Sodium Channel by ................... 55 Vernakalant ............................................................................................................................... 55 Vernakalant-related Deaths in Clinical Trials Based on Medical .............................. 56 Review ...................................................................................................................................... 56 Summaries of Serious Adverse Events of Special Interest 0-2 Hours ....................... 57 from Dosing (Clinical Trials).................................................................................................... 57 Selected Postmarketing (outside of US) Serious Adverse Event and ........................ 61 Death Cases ............................................................................................................................... 61 Selected Narratives from SPECTRUM ...................................................................... 63 ACT V Eligibility Criteria .......................................................................................... 64 Ibutilide Postmarketing Data ...................................................................................... 66 FDA Adverse Event Reporting System Data .................................................. 66 Medical Literature ........................................................................................... 66 Electrical Cardioversion Literature Review ............................................................... 71 Applicant’s Proposed Pre-Infusion Checklist ............................................................. 80 Serious Adverse Events and Number Needed to Harm (NNH) ................................. 82 4 Ventricular Arrhythmia Events from 12-lead Electrocardiograms ............................ 83 5 Table of Tables Table 1. Overview of completed clinical studies in AF/AFL patients for vernakalant Injection 21 Table 2. Conversion to Sinus Rhythm within 90 Minutes in ACT I and ACT III....................... 24 Table 3. Conversion to Sinus Rhythm within 90 Minutes, ACT I and ACT III Combined by Dose .............................................................................................................................................. 24 Table 4. Conversion to Sinus Rhythm within 90 Minutes in CRAFT ......................................... 25 Table 5. Incidence of serious hypotension-related AEs within 2 hours post-dose ...................... 26 Table 6. Incidence of serious ventricular arrhythmia AEs within 2 Hours Post-dose ................. 27 Table 7. Incidence of serious conduction disturbance AEs within 2 hours post-dose ................. 28 Table 8. Incidence of serious bradycardia AEs within 2 hours post-dose ..................................
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