IQ DILI Consensus Opinion: Best Practices for Rechallenge Following Suspected Drug-Induced Liver Injury in Clinical Trials

Klaudia Steplewski, Lucy Walker, Nefeteria Coffee (), Maura Fallon, Rie Yonemochi, David Alpers, Don Rockey, James Lewis, Eric Cohen, John Caminis, Judith Hey-Hadavi, Raul Jesus Andrade and Melissa Palmer
Additional contact information
Klaudia Steplewski: GSK
Lucy Walker: GSK HQ
Nefeteria Coffee: Sanofi
Maura Fallon: Daiichi Sankyo UK Ltd.
Rie Yonemochi: Daiichi Sankyo (China) Holdings Co., LTD
David Alpers: Washington University School of Medicine
Don Rockey: Digestive Disease Research Center
James Lewis: Georgetown University
Eric Cohen: AbbVie Inc.
John Caminis: Gilead Oncology, Patient Safety, US Parsippany
Judith Hey-Hadavi: Pfizer
Raul Jesus Andrade: University Hospital-IBIMA, CIBERehd
Melissa Palmer: Liver Consulting LLC New York

Drug Safety, 2025, vol. 48, issue 8, No 2, 855-874

Abstract: Abstract Rechallenge with study drug after suspected drug-induced liver injury (DILI) during drug development requires a comprehensive assessment of risks and benefits. Lack of universal consensus or societal guidelines makes this decision-making process more challenging and difficult to manage in clinical development. The sparse published literature is biased towards reporting cases of positive rechallenge (recurrent DILI), often with adverse outcomes. The heterogeneity of available data and inconsistent approaches to drug rechallenge likely lead to bias in our perception of the risks of rechallenge, ultimately leaving this topic controversial. The IQ DILI Causality Assessment Working Group, in collaboration with academic and regulatory experts, developed this manuscript with the following objectives: (1) understand and describe current practices via literature review and survey of practices and opinions among drug developers, academic experts, and regulators; (2) propose a consistent and structured approach to decision-making and managing the rechallenge process; (3) facilitate better understanding of the risks and benefits of rechallenge via a standardized approach to collecting rechallenge data, including outcomes and the importance of publishing rechallenge data; and (4) the role of obtaining a liver biopsy, guidance on when a biopsy might be considered, and what histologic findings can assist in making the rechallenge decision. Lastly, knowledge gaps in the drug rechallenge paradigm are highlighted alongside the proposal to standardize the collection and publication of rechallenge data to help address these gaps. This consensus expert opinion does not encourage rechallenge but provides guidance for drug developers to apply a consistent approach to rechallenge.

Date: 2025
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DOI: 10.1007/s40264-025-01540-x

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