Division of Pharmacology & Toxicology, Office of Cardiology, Hematology, Endocrinology, & Nephrology, Office of New Drugs, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, Maryland 20903, USA.
Division of Applied Regulatory Science, Office of Translational Science, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, Maryland 20903, USA.
Toxicol Sci. 2022 Nov 23;190(2):117-126. doi: 10.1093/toxsci/kfac095.
Human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) provide a human-relevant platform for cardiac function assessment. Alternative assays using hiPSC-CMs are increasingly being employed for regulatory decision-making. A retrospective review revealed steady use of hiPSC-CM-based in vitro assays in nonclinical studies of drug-induced cardiotoxicity in regulatory submissions to the U.S. Food and Drug Administration (FDA). Most of the hiPSC-CMs data were obtained in exploratory studies and submitted as supportive evidence in concordance with other nonclinical data. Some of those studies were used to inform clinical trial design. This article provides an overview of the use of hiPSC-CMs in regulatory applications to FDA, with a focus on the integration of human-relevant in vitro data into proarrhythmic and non-proarrhythmic risk assessment. By identifying the regulatory submissions including hiPSC-CMs data, we explore their utility and discuss their limitations for predicting human cardiac safety in clinical trials. An important take-home message is that regulatory acceptance of hiPSC-CMs data is dependent on both the context of use and accurate data interpretation.
人诱导多能干细胞衍生的心肌细胞（hiPSC-CMs）为心脏功能评估提供了一个与人类相关的平台。越来越多的替代检测方法使用 hiPSC-CMs 进行监管决策。回顾性研究显示，在向美国食品和药物管理局（FDA）提交的药物诱导心脏毒性的非临床研究中，稳定地使用了基于 hiPSC-CM 的体外检测方法。大多数 hiPSC-CMs 数据是在探索性研究中获得的，并作为支持性证据与其他非临床数据一起提交。其中一些研究用于为临床试验设计提供信息。本文概述了 hiPSC-CMs 在 FDA 监管申请中的使用情况，重点是将与人相关的体外数据整合到致心律失常和非致心律失常风险评估中。通过确定包括 hiPSC-CMs 数据在内的监管提交，我们探讨了它们在预测临床试验中的人类心脏安全性方面的效用和局限性。一个重要的信息是，监管部门对 hiPSC-CMs 数据的接受程度取决于使用的背景和准确的数据解释。
