Time for a Fully Integrated Nonclinical–Clinical Risk Assessment to Streamline QT Prolongation Liability Determinations: A Pharma Industry Perspective
Year: 2020
Type: review
Abstract: Defining an appropriate and efficient assessment of drug-induced corrected QT interval (QTc) prolongation (a surrogate marker of torsades de pointes arrhythmia) remains a concern of drug developers and regulators worldwide. In use for over 15 years, the nonclinical International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use (ICH) S7B and clinical ICH E14 guidances describe three core assays (S7B: in vitro hERG current & in vivo QTc studies; E14: thorough QT study) that are used to assess the potential of drugs to cause delayed ventricular repolarization. Incorporating these assays during nonclinical or human testing of novel compounds has led to a low prevalence of QTc-prolonging drugs in clinical trials and no new drugs having been removed from the marketplace due to unexpected QTc prolongation. Despite this success, nonclinical evaluations of delayed repolarization still minimally influence ICH E14-based strategies for assessing clinical QTc prolongation and defining proarrhythmic risk. In particular, the value of ICH S7B-based "double-negative" nonclinical findings (low risk for hERG block and in vivo QTc prolongation at relevant clinical exposures) is underappreciated. These nonclinical data have additional value in assessing the risk of clinical QTc prolongation when clinical evaluations are limited by heart rate changes, low drug exposures, or high-dose safety considerations. The time has come to meaningfully merge nonclinical and clinical data to enable a more comprehensive, but flexible, clinical risk assessment strategy for QTc monitoring discussed in updated ICH E14 Questions and Answers. Implementing a fully integrated nonclinical/clinical risk assessment for compounds with double-negative nonclinical findings in the context of a low prevalence of clinical QTc prolongation would relieve the burden of unnecessary clinical QTc studies and streamline drug development.
DOI: 10.1002/cpt.2029
Authors: Hugo M. Vargas, Michael G. Rolf, Todd A. Wisialowski, William Achanzar, Anthony Bahinski, Alan Bass, Charles T Benson, Khuram W. Chaudhary, Nicolas Couvreur, Corina Dota, Michael J Engwall, C. Michael Foley, David Gallacher, Andrea Greiter‐Wilke, Jean‐Michel Guillon, Brian Guth, Herbert M. Himmel, Christa Hegele‐Hartung, Maki Ito, Stephen Jenkinson, Katsuyoshi Chiba, Armando Lagrutta, Paul Levesque, Eric Martel, Yoshiko Okai, Ravikumar Peri, Amy Pointon, Yusheng Qu, Ard Teisman, Martin Traebert, Takashi Yoshinaga, Gary A. Gintant, Derek J. Leishman, Jean‐Pierre Valentin
Institutions: Amgen (United States), AstraZeneca (Sweden), Pfizer (United States), Bristol-Myers Squibb (United States), GlaxoSmithKline (United States), Merck & Co., Inc., Rahway, NJ, USA (United States), Eli Lilly (United States), Institut de Recherches Internationales Servier (France), AbbVie (United States), Janssen (Belgium), F. Hoffmann-La Roche AG, Sanofi (France), Boehringer Ingelheim (Germany), Bayer (Germany), Japan Pharmaceutical Manufacturers Association, Daiichi-Sankyo (Japan), Takeda (Japan), AstraZeneca (United Kingdom), Novartis (Switzerland), Novartis Institutes for BioMedical Research, Eisai (Japan), UCB Pharma (Belgium)
Language: English
Subfield: Cardiology and Cardiovascular Medicine
Field: Medicine
Domain: Health Sciences
Open Access status: hybrid
Estimated APC paid: $3,000
OpenAlex ID: W3082864643