In vitro cardiac new approach methodologies predict clinical cardiovascular repolarization risk comparable to non‐clinical animal studies

BACKGROUND AND PURPOSE: This study evaluated human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) as a non-animal, new approach methodology for assessing cardiovascular repolarization risk, comparing hiPSC-CM data with traditional non-clinical methods (hERG assays and animal studies) to support regulatory decisions. EXPERIMENTAL APPROACH: A pilot study of over 20 Investigational New Drug applications submitted to the FDA between 2020 and 2023 were retrospectively analysed, comparing hiPSC-CM studies using multielectrode array and voltage sensing optical platforms to traditional methods. Analysis focused on concordance between methods and their ability to predict clinical QT prolongation risk for five clinical QT positive and 18 clinical QT negative drugs. KEY RESULTS: hiPSC-CMs displayed greater overall concordance (0.71-0.82) relative to non-clinical animal studies than hERG studies (0.54-0.64). hiPSC-CMs demonstrated comparable likelihood ratios and overall accuracy (0.83) in predicting clinical QT prolongation relative to single-dose in vivo non-rodent QT (0.74) and other animal studies (0.78). Inclusion of additional animal studies had negligible impact on overall concordance, supporting the 3Rs. Approximately 50% of non-clinical in vivo QT studies tested concentrations at or below clinical Cmax, while in vitro assays generally evaluated higher exposures. CONCLUSION AND IMPLICATIONS: hiPSC-CMs offer a promising alternative to extensive animal testing for cardiovascular risk assessment. Limitations include small sample size, low prevalence of clinical QT true positives (though each non-clinical assay's higher negative predictive value versus positive predictive value provided higher confidence in negative QTc signals), early-phase data, and variability in hiPSC-CM study rigour. Examples for implementation were provided, but further research is needed to integrate hiPSC-CMs more broadly into regulatory workflows.