New approaches in assessing potential proarrhythmic risk and cardiovascular safety during medicines development: opportunities for 3Rs application

Cardiotoxicity, in particular arrhythmia, has historically been a leading cause of drug candidate attrition during development. Rigorous cardiac safety assessments are essential to ensure regulatory compliance, risk identification and assessment, and ultimately patient safety. Evaluation of the cardiac safety of human pharmaceuticals, particularly their proarrhythmic risk, is performed in accordance with ICH S7B/E14 guidelines and involves in vitro inhibition assays of the human ether-à-go-go-related gene (hERG) current and in vivo corrected QT interval (QTc) measurements to estimate the risk of QTc prolongation and Torsades de Pointes (TdP) in humans. While effective in preventing the marketing of proarrhythmic drugs, these guidelines are considered conservative because they rely on surrogate markers which have limited predictive value and may lead to the exclusion during development of otherwise safe and promising drug candidates. In addition, the extensive use of animal models in this context raises concerns about translatability to human cardiotoxicity. The replacement, reduction, and refinement (3Rs) principles are shaping regulatory science, and new approach methodologies (NAMs) hold the potential to replace or reduce animal use for cardiac safety assessment. Advances in 2D and 3D cell culture models, organ-on-chip and microphysiological systems, as well as in silico modelling, AI and machine learning tools are raising the potential for their use in a regulatory context. This in turn could support a paradigm shift to a more robust, accurate, and human-relevant assessment of cardiac safety, aligned with the 3Rs principles. Plain language summary Developing new medicines with cardiovascular safety in mind is essential to avoid serious side effects like arrhythmias. Traditionally, animal testing and indirect measurements have been used to assess this risk, but these methods can be imprecise and may exclude promising treatments. This article explores innovative technologies that better mimic the human heart, such as human stem cells, computer models, and organ-on-chip systems. These tools can improve the prediction of how drugs affect the heart, reduce the need for animal testing, and enhance patient safety. They also align with the ethical 3Rs principles: Replacement, Reduction, and Refinement of animal use in research. Regulatory agencies like EMA and FDA are considering these new methods to update safety guidelines. These advances could transform drug development by making it more human-relevant, efficient, and accurate.