Drug-induced liver injury (DILI) in clinical trials: Views and practical updates from DILI specialists at FDA.

Drug-induced liver injury (DILI) continues to be a significant challenge in drug development. Just 1 or 2 cases of severe hepatotoxicity in a clinical trial can be enough to raise drug approval concerns. Though great strides were made in DILI risk assessment and mitigation in clinical trials during the early 2000s, drugs continue to fail in development due to DILI, while severe cases still occur in late-phase clinical trials and post-market. Also, changes in drug development will challenge the US Food and Drug Administration's (FDA) current paradigms for DILI risk assessment. Such changes include the rise in biologic agents, which may cause hepatotoxicity distinctly different from small-molecule drugs, the increasing reliance on smaller, underpowered clinical trials for rare diseases, and the growing interest in drugs for acute and chronic liver diseases. We highlight eight key topics that may benefit from review, clarification, research, and discussion between industry, academia, and regulators as the FDA works to address these issues.