REVIEW ARTICLE Liver Safety Assessment in Special Populations (Hepatitis B, C, and Oncology Trials)

Abstract The FDA guidance for industry in the premar-keting clinical evaluation of drug-induced liver injury (DILI) is the most specific regulatory guidance currently available and has been useful in setting standards for the great majority of clinical indications involving subjects with a low risk of liver disorders. However, liver safety assessment faces challenges in populations with underlying liver disease, such as viral hepatitis or metastatic cancer. This is an important issue because there are currently many promising anti-viral and oncologic therapies in clinical development, with a trend toward oral therapies with reduced side effects. Without clearer guidelines, questions regarding liver safety may become a major factor in regulatory approval and ultimately physician uptake of the new treatments. The lack of con-sensus in defining stopping rules based on serum alanine aminotransferase (ALT) levels underscores the need for precompetitive data sharing to improve our understanding of DILI in these populations and to allow evidence-based rather than empirical definition of stopping rules. A workshop was convened to discuss best practices for the assessment of drug-induced liver injury (DILI) in clinical trials. Key points There is currently a lack of consensus in defining stopping rules based on serum ALT levels in hepatitis B and C and oncology treatment regimens Both elevations of baseline ALT as well as ALT elevations during treatment should be considered when assessing the hepatotoxic potential of a candidate drug Innovative approaches that combine clinical data from registration trials with biomarker, genetic and metabolomic data in appropriate patient cohorts are urgently required to overcome the limitations of current diagnostic paradigms