Time for a Fully Integrated Nonclinical-Clinical Risk Assessment to Streamline QTc Prolongation Liability Determinations: A Pharma Perspective

The appropriate and efficient assessment of drug-induced clinical QTc prolongation (a surrogate marker of Torsades de Pointes arrhythmia) remains a concern of drug developers and regulators worldwide. Refined and validated over 15+ years, the nonclinical ICH S7B guidance describes two core assays (in vitro hERG/IKr current & in vivo QT studies) to assess the potential for delayed ventricular repolarization. Incorporating these assays early in candidate selection has lead to: i) a low prevalence of QTc prolonging drugs in clinical trials, and ii) no drugs have been removed from the marketplace due to unexpected QTc prolongation. Despite this success, nonclinical findings still minimally influence ICH E14-based strategies for interpreting clinical QTc prolongation, and defining proarrhythmic risk. In particular, the value of ICH S7B-based findings for candidates demonstrating minimal hERG/IKr block and minimal in vivo QTc prolongation at comparable clinical exposures (i.e., “double-negative nonclinical findings” are underestimated. Such reassuring nonclinical data has clear value assessing the risk of clinical QTc prolongation when clinical evaluation may be challenged by heart rate changes, exposure limitations, or safety considerations. The time has come to meaningfully merge nonclinical and clinical approaches to provide a more comprehensive and integrated proarrhythmia risk assessment strategy that complements advances described in ICH E14 amendments to enable more flexible clinical QTc risk assessments. Adoption of a truly integrative nonclinical/clinical risk assessment in the context of the low prevalence of QTc prolonging drugs would positively impact regulatory science, relieve the burden of extensive QTc monitoring, and streamline drug development