The Comprehensive in Vitro Proarrhythmia Assay (CiPA) initiative — Update on progress

TLDR

ICH S7B/E14 guidelines have limited drug development by focusing on hERG block and QT prolongation, prompting the creation of CiPA to assess proarrhythmic risk using broader mechanisms. This article updates progress toward completing CiPA validation by December 2017. An international multidisciplinary team led by a Steering Team from FDA, EMA, and other regulators is developing and validating nonclinical assays across three pillars: human ventricular ionic channel currents, in‑silico integration, and integrated biological systems. The initiative has advanced toward its December 2017 validation target.

Abstract

The implementation of the ICH S7B and E14 guidelines has been successful in preventing the introduction of potentially torsadogenic drugs to the market, but it has also unduly constrained drug development by focusing on hERG block and QT prolongation as essential determinants of proarrhythmia risk. The Comprehensive in Vitro Proarrhythmia Assay (CiPA) initiative was established to develop a new paradigm for assessing proarrhythmic risk, building on the emergence of new technologies and an expanded understanding of torsadogenic mechanisms beyond hERG block. An international multi-disciplinary team of regulatory, industry and academic scientists are working together to develop and validate a set of predominantly nonclinical assays and methods that eliminate the need for the thorough-QT study and enable a more precise prediction of clinical proarrhythmia risk. The CiPA effort is led by a Steering Team that provides guidance, expertise and oversight to the various working groups and includes partners from US FDA, HESI, CSRC, SPS, EMA, Health Canada, Japan NIHS, and PMDA. The working groups address the three pillars of CiPA that evaluate drug effects on: 1) human ventricular ionic channel currents in heterologous expression systems, 2) in silico integration of cellular electrophysiologic effects based on ionic current effects, the ion channel effects, and 3) fully integrated biological systems (stem-cell-derived cardiac myocytes and the human ECG). This article provides an update on the progress of the initiative towards its target date of December 2017 for completing validation.