Rechanneling the cardiac proarrhythmia safety paradigm: A meeting report from the Cardiac Safety Research Consortium

• Published in: The American heart journal 2014-03, Vol.167 (3), p.292-300
• Main Authors: Sager, Philip T., MD, FACC, FAHA, Gintant, Gary, PhD, Turner, J. Rick, PhD, Pettit, Syril, MEM, Stockbridge, Norman, MD, PhD
• Format: Article
• Language: English
• Subjects: Arrhythmias, Cardiac - chemically induced; Arrhythmias, Cardiac - prevention & control; Cardiac arrhythmia; Cardiovascular; Conferences; Critical path; Drug Evaluation, Preclinical - methods; Drug-Related Side Effects and Adverse Reactions - prevention & control; Electrocardiography; Heart rate; Humans; Long QT Syndrome - chemically induced; Long QT Syndrome - prevention & control; Nonprofit organizations; Patch-Clamp Techniques - methods; Pharmaceuticals; Potassium; Risk Assessment; Stem cells; Studies; Torsades de Pointes - chemically induced; Torsades de Pointes - prevention & control; United States
• ISSN: 0002-8703; 1097-6744
• DOI: 10.1016/j.ahj.2013.11.004

This white paper provides a summary of a scientific proposal presented at a Cardiac Safety Research Consortium/Health and Environmental Sciences Institute/Food and Drug Administration–sponsored Think Tank, held at Food and Drug Administration's White Oak facilities, Silver Spring, MD, on July 23, 2013, with the intention of moving toward consensus on defining a new paradigm in the field of cardiac safety in which proarrhythmic risk would be primarily assessed using nonclinical in vitro human models based on solid mechanistic considerations of torsades de pointes proarrhythmia. This new paradigm would shift the emphasis from the present approach that strongly relies on QTc prolongation (a surrogate marker of proarrhythmia) and could obviate the clinical Thorough QT study during later drug development. These discussions represent current thinking and suggestions for furthering our knowledge and understanding of the public health case for adopting a new, integrated nonclinical in vitro/in silico paradigm, the Comprehensive In Vitro Proarrhythmia Assay, for the assessment of a candidate drug's proarrhythmic liability, and for developing a public-private collaborative program to characterize the data content, quality, and approaches required to assess proarrhythmic risk in the absence of a Thorough QT study. This paper seeks to encourage multistakeholder input regarding this initiative and does not represent regulatory guidance.