Liver Safety Assessment in Clinical Trials of New Agents for Chronic Hepatitis B

Robert J. Fontana; Mark I. Avigan; Harry L. A. Janssen; Arie Regev; Poonam Mishra; Anuj Gaggar; Nathaniel Brown; Cynthia Wat; Patricia Mendez; Ryan T. Anderson; Bruce Given; Veronica Miller; Maria Beumont


J Viral Hepat. 2020;27(2):96-109. 

In This Article

Interpretation of Liver Safety Data in Clinical Trials

A clinical trial protocol should include a prespecified algorithm on how to adjudicate liver safety signals in studies of investigational agents for chronic HBV. In addition to frequency tables assessing the incidence and severity of liver safety biomarker laboratory data in treatment arms, treatment dose or duration effect, patient demographics, HBV parameters, liver disease parameters and other clinical factors should be considered. The timing of liver safety signal data in relationship to results from investigational assays assessing drug efficacy should also be considered.

For any patient who experiences an episode of liver injury during or after treatment with the study drug that is marked by an ALT > 5× ULN or >3× baseline, ALK >2× ULN, elevation in total bilirubin or if the study drug has been held or discontinued because of liver abnormalities, the local investigator should create a clinical narrative that includes the pertinent medical history and findings of additional diagnostic testing that were done (Table 6). If a liver biopsy was performed, available slides should be obtained and reviewed by an independent expert liver pathologist as part of the causality assessment review. In addition, the investigator will need to make a personal assessment of causality and relatedness to the study drug reporting these judgements in the patient's case record. If the episode meets regulatory criteria for a serious adverse event (SAE), the investigator must promptly notify the study sponsor and expeditiously complete a SAE report (usually with a CIOMS form) for sponsor transmission to regulatory authorities and ethics committees.[55] If a potential pattern of liver safety signals emerges in a clinical trial of an investigational agent, it is advisable that the sponsor convene an independent adjudication committee to review all available liver safety data and make recommendations regarding study discontinuation vs continuation with any needed changes in the study protocol.[21]