Two or three cases of serious hepatotoxicity in a development programme can end it, so how drug-induced liver injury (DILI) is assessed in trials has consequences well beyond the trial. Two DILI specialists at the US Food and Drug Administration set out where they think the current framework is straining, and name eight topics they want industry, academia and regulators to work through.
Three pressures drive the argument. Biologic agents are causing hepatotoxicity that does not behave like small-molecule injury — different mechanisms, different time courses, and signals that the established monitoring paradigms were not built to catch. Rare disease programmes increasingly run on small trials that are underpowered to detect a rare hepatic signal at all, which shifts the burden onto post-marketing surveillance. And drugs are being developed for people who already have acute or chronic liver disease, where a rising transaminase may be the disease rather than the drug.
For a hepatologist the value is in the framing rather than in any recommendation. It is a clear statement that the rules developed in the early 2000s — Hy's law and the monitoring practices built around it — are being applied to situations they were not designed for, and that the regulator knows it. Anyone advising on a trial protocol, or reading a hepatotoxicity signal in a drug already licensed, is working inside those limits.
- Do not read a transaminase rise in a patient with existing liver disease as necessarily drug-related
- Expect biologic hepatotoxicity to present differently from small-molecule injury
- Recognise that rare-disease programmes are usually too small to exclude a rare hepatic risk
- When advising on trial protocols, raise stopping rules and rechallenge criteria explicitly
- This is a perspective, not guidance; nothing here changes current regulatory requirements
Why it matters
The regulator's own specialists are saying the framework used to judge liver safety no longer fits several of the settings it is being applied to.
Don't overread it
This is an expert perspective from two individuals, not FDA guidance or a change in regulatory requirements.
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