Consensus guidelines: best practices for detection, assessment and management of suspected acute drug‐induced liver injury occurring during clinical trials in adults with chronic cholestatic liver disease

Abstract

Summary Background Improved knowledge of the molecular pathophysiology and immunopathogenesis of cholestatic liver diseases in recent years has led to an increased interest in developing novel therapies. Patients with cholestatic liver disease often require different approaches to assessment and management of suspected drug‐induced liver injury (DILI) compared to those with healthy livers and those with parenchymal liver diseases. At present, there are no regulatory guidelines or society position papers, that systematically address best practices pertaining to detection of DILI in these patients. Aims To outline best practices for detection, assessment and management of suspected acute DILI during clinical trials in adults with the cholestatic liver diseases – Primary Biliary Cholangitis (PBC) and Primary Sclerosing Cholangitis (PSC). Methods This is one of the several papers developed by the IQ DILI Initiative, which is comprised of members from 16 pharmaceutical companies, in collaboration with DILI experts from academia and regulatory agencies. The contents are the result of an extensive literature review, as well as in‐depth discussions among industry, regulatory and academic DILI experts, to achieve consensus recommendations on DILI‐related issues occurring during clinical trials for cholestatic liver diseases. Results Recommended best practices are outlined pertaining to hepatic eligibility criteria, monitoring of liver tests, approach to a suspected DILI signal, and hepatic discontinuation rules. Conclusions This paper provides a framework for the approach to detection, assessment and management of suspected acute DILI occurring during clinical trials in adults with cholestatic liver disease.

Epidemiology of Drug- and Herb-Induced Liver Injury Assessed for Causality Using the Updated RUCAM in Two Hospitals from China

“…According to the updated RUCAM [ 9 ], the type of DILI and HILI was classified by the R value calculated from the laboratory data obtained at presentation: R value = serum [ALT/ALT ULN]/[ALP/ALP ULN], where ULN is defined as the upper limit of normal [ 11 ]. Accordingly, DILI and HILI cases were clinically divided into the following: (1) hepatocellular injury: ALT ≥ 5 × ULN and R value ≥ 5; (2) cholestatic injury: ALP ≥ 2 × ULN and R value ≤ 2; and (3) mixed injury: ALT ≥ 3 × ULN, ALP ≥ 2 × ULN, and 2 < R value < 5.…”

Systemic treatment of hepatocellular carcinoma: An EASL position paper

“…However, there is need for improvement so that outcomes through PROs are aligned with data from adverse events registration according to CTCAE [94]. At the same time, it would be worth to refine this terminology to that conventionally used and established for liver toxicity [95].…”

Overview on drug-induced liver injury in Brazil

“…Interestingly, the authors also stated that their research is expected to broaden the debate to establish a solid pharmacovigilance policy and the creation of a wide national DILI monitoring network and his integration with other DILI networks[ 1 ]. This is a very important point linked to one of the main objectives of DILI registries, which highlight the importance of working in close connection with regulatory and health authorities to strengthen both pharmacovigilance and the reporting cases of drug-induced liver reactions[ 5 ].…”