The Comprehensive in Vitro Proarrhythmia Assay (CiPA) initiative - Update on progress.
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.
US FDA, 10903 New Hampshire Ave, Silver Spring, MD 20993, United States. Electronic address: Thomas.Colatsky@fda.hhs.gov.
Thomas
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Colatsky
Pfizer, Eastern Point Road MS 4083, Groton, CT 06340, United States. Electronic address: Bernard.Fermini@pfizer.com.
Bernard
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Fermini
AbbVie, R46R AP-9, 1 North Waukegan Rd, North Chicago, IL 60064-6118, United States. Electronic address: Gary.Gintant@abbvie.com.
Gary
G
Gintant
ILSI-Health and Environmental Sciences Institute, 1156 15th Street NW, Suite 200, Washington, DC 20005, United States. Electronic address: jpierson@hesiglobal.org.
Jennifer B
JB
Pierson
Stanford University, 719 Carolina St., San Francisco, CA 94107, United States. Electronic address: psager@stanford.edu.
Philip
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Sager
NIHS Japan, Kamiyoga 1-18-1, Setagaya-ku, Tokyo 158-8501, Japan. Electronic address: yukos@nihs.go.jp.
Yuko
Y
Sekino
US FDA, 10903 New Hampshire Ave, Silver Spring, MD 20993, United States. Electronic address: David.Strauss@fda.hhs.gov.
David G
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Strauss
US FDA, 10903 New Hampshire Ave, Silver Spring, MD 20993, United States. Electronic address: Norman.Stockbridge@fda.hhs.gov.
Norman
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Stockbridge
D000818:Animals; D001145:Arrhythmias, Cardiac / Q000139:chemically induced* / Q000503:physiopathology; D003198:Computer Simulation; D004353:Drug Evaluation, Preclinical / Q000379:methods; D004562:Electrocardiography / Q000187:drug effects; D006801:Humans; D007473:Ion Channels / Q000187:drug effects; D032383:Myocytes, Cardiac / Q000187:drug effects; D013234:Stem Cells; D016171:Torsades de Pointes / Q000139:chemically induced / Q000503:physiopathology
D007473:Ion Channels
CiPA; In silico model; Ion channel; Myocyte; Proarrhythmia