Workshop Report: FDA Workshop on Improving Cardiotoxicity Assessment With Human-Relevant Platforms

Abstract

Given that cardiovascular safety concerns remain the leading cause of drug attrition at the preclinical drug development stage, the National Center for Toxicological Research of the US Food and Drug Administration hosted a workshop to discuss current gaps and challenges in translating preclinical cardiovascular safety data to humans. This white paper summarizes the topics presented by speakers from academia, industry, and government intended to address the theme of improving cardiotoxicity assessment in drug development. The main conclusion is that to reduce cardiovascular safety liabilities of new therapeutic agents, there is an urgent need to integrate human-relevant platforms/approaches into drug development. Potential regulatory applications of human-derived cardiomyocytes and future directions in employing human-relevant platforms to fill the gaps and overcome barriers and challenges in preclinical cardiovascular safety assessment were discussed. This paper is intended to serve as an initial step in a public-private collaborative development program for human-relevant cardiotoxicity tools, particularly for cardiotoxicities characterized by contractile dysfunction or structural injury.

Keywords: cardiotoxicity; drug development; humans; risk assessment; stem cells.

Figure 1

Phenotypic changes that can be assessed with human cardiomyocytes in early drug screening and applications of human-relevant platforms in late preclinical and early clinical drug development process.

Figure 2

hiPSC-CMs assay can replicate the HCV-NS5B NI/Amiodarone cardiac DDIs observed in clinic and preclinical models, provide a competitive advantage for early screening/de-risking of new HCV-NI candidates, and rapidly assess the putative mechanism(s) responsible of DDIs.