Introduction to the 3RsC's cross-platform microphysiological systems evaluation for drug-induced liver injury in collaboration with FDA-CDER.

Drug-induced liver injury (DILI) remains a major challenge for drug development, contributing to adverse events in patients and regulatory setbacks. Traditional nonclinical approaches frequently fail to predict DILI due to interspecies differences and complex DILI mechanisms. Microphysiological systems (MPS) offer a promising alternative by recreating dynamic drug exposure, human-relevant metabolism, and organotypic features central to DILI pathogenesis. However, broader industry and regulatory adoption is limited by lack of confidence, platform variability, and lack of benchmarks. This manuscript describes the process of designing a cross-platform evaluation of eight commercially available liver MPS, conducted through a public-private partnership between the 3Rs Collaborative and FDA's Center for Drug Evaluation and Research. It ultimately focused on using liver MPS for defined Context of Use: retrospective assessment of elevated liver signals in early clinical trials. The team created a harmonized experimental strategy with blinded compounds, common endpoints, and independent data analysis to define category-level performance expectations rather than rank individual systems. This effort represents the first design of a systematic, category-level comparison of liver MPS for a regulatory application. It provides a blueprint for advancing New Approach Methodologies for regulatory use, strengthening confidence in human-relevant models for drug safety assessment.