FDA Accepts First AI-Driven Digital Liver Model Under ISTAND Program for DILI Prediction

For preclinical teams assembling nonclinical safety packages, FDA's CDER has accepted the first Letter of Intent for an in silico drug development tool (DDT) under the ISTAND DDT Qualification Program, an AI-Driven Digital Liver Model designed to predict drug-induced liver injury (DILI) in small molecule candidates.

DILI remains one of the most consequential safety liabilities in early development, accounting for a significant share of IND-stage attrition and clinical trial terminations. Current preclinical models carry well-documented limitations in translating hepatotoxicity risk to humans, leaving sponsors exposed to late-stage failures that earlier, more accurate prediction could have flagged. The accepted tool addresses this gap by using AI to compare the chemical structures of new candidates against a reference dataset of drugs with established DILI profiles, operating within a weight-of-evidence framework alongside existing nonclinical data.

The model is classified as a New Approach Methodology (NAM), consistent with CDER's sustained investment in the 3Rs, replacement, reduction, and refinement of animal testing. Acceptance of the LOI is the first of three qualification steps; the submitting company must next file a Qualification Plan, followed by a full qualification package. Qualified status would permit sponsors to incorporate the DDT into regulatory submissions within a defined context of use, potentially informing go/no-go decisions ahead of Phase I entry.

Jeffrey Siegel, MD, Director of the Office of Drug Evaluation Sciences in CDER's Office of New Drugs, noted the model's promise in assessing hepatotoxicity risk during preclinical phases. Acting CDER Director Michael Davis, MD, PhD, framed the acceptance as part of a broader effort to optimize development and evaluation of new therapies without expanding animal use.

For regulatory affairs leads, the practical read is forward-looking: qualification under ISTAND does not follow established biomarker or clinical outcome assessment pathways, making it a distinct channel for novel DDTs that lack a conventional regulatory home. Sponsors developing small molecule pipelines with hepatotoxicity exposure should monitor the qualification timeline closely, as a qualified tool would carry defined evidentiary weight in IND-stage risk assessments.

The full qualification package submission, and any subsequent context-of-use boundaries CDER sets, will determine how broadly the model can be applied across therapeutic areas and structural classes.

Source: FDA CDER via FDA.gov What's New: Drugs RSS Feed, June 3, 2026.