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Use of Human iPSC-CMs in Nonclinical Regulatory Studies for Cardiac Safety Assessment
Xi Yang1, Alexandre J S Ribeiro2, Li Pang3
1Division 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.
Insights
Human-induced pluripotent stem cells (hiPSC)-derived cardiomyocytes (hiPSC-CMs) are increasingly used in drug safety assessments. Regulatory review shows their utility in evaluating cardiotoxicity, but context and interpretation are key for acceptance.
Area of Science:
- Cardiovascular toxicology
- Stem cell biology
- Regulatory science
Background:
- Human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) offer a human-relevant in vitro model for assessing cardiac function.
- The use of hiPSC-CMs in drug development is growing, particularly for evaluating cardiotoxicity.
- These assays are becoming important for regulatory decision-making.
Purpose of the Study:
- To provide an overview of hiPSC-CM use in regulatory applications to the U.S. Food and Drug Administration (FDA).
- To focus on the integration of human-relevant in vitro data into proarrhythmic and non-proarrhythmic risk assessment.
- To explore the utility and limitations of hiPSC-CM data for predicting human cardiac safety.
Main Methods:
- Retrospective review of regulatory submissions to the FDA.
- Identification of submissions including hiPSC-CM data.
- Analysis of the context of use and data interpretation for hiPSC-CM assays.
Main Results:
- hiPSC-CM-based in vitro assays are steadily used in nonclinical studies of drug-induced cardiotoxicity.
- Most hiPSC-CM data were from exploratory studies, submitted as supportive evidence.
- Some studies informed clinical trial design, aiding risk assessment.
Conclusions:
- Regulatory acceptance of hiPSC-CM data depends on the context of use and accurate interpretation.
- hiPSC-CMs are valuable tools for assessing drug-induced cardiotoxicity, but their limitations must be considered.
- Integration of hiPSC-CM data aids in predicting human cardiac safety in clinical trials.
Abstract:
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.
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