Consensus: Guidelines

Best Practices for Detection, Assessment and Management of Suspected Acute Drug-induced Liver Injury During Clinical Trials in Patients With Nonalcoholic Steatohepatitis

Arie Regev; Melissa Palmer; Mark I. Avigan; Lara Dimick-Santos; William R. Treem; John F. Marcinak; Daniel Seekins; Gopal Krishna; Frank A. Anania; James W. Freston; James H. Lewis; Arun J. Sanyal; Naga Chalasani


Aliment Pharmacol Ther. 2019;49(6):702-713. 

In This Article

Abstract and Introduction


Background: The last decade has seen a rapid growth in the number of clinical trials enrolling patients with nonalcoholic fatty liver disease and nonalcoholic steatohepatitis (NASH). Due to the underlying chronic liver disease, patients with NASH often require different approaches to the assessment and management of suspected drug-induced liver injury (DILI) compared to patients with healthy livers. However, currently no regulatory guidelines or position papers systematically address best practices pertaining to DILI in NASH clinical trials.

Aims: This publication focuses on best practices concerning the detection, monitoring, diagnosis and management of suspected acute DILI during clinical trials in patients with NASH.

Methods: This is one of several papers developed by the IQ DILI Initiative, comprised of members from 15 pharmaceutical companies, in collaboration with DILI experts from academia and regulatory agencies. This paper is based on extensive literature review, and discussions between industry members with expertise in drug safety and DILI experts from outside industry to achieve consensus on common questions related to this topic.

Results: Recommended best practices are outlined pertaining to hepatic inclusion and exclusion criteria, monitoring of liver tests, DILI detection, approach to a suspected DILI signal, causality assessment and hepatic discontinuation rules.

Conclusions: This paper provides a framework for the approach to assessment and management of suspected acute DILI during clinical trials in patients with NASH.


Nonalcoholic fatty liver disease (NAFLD) is increasingly recognized as an important public health problem and a major cause of liver disease. Nonalcoholic steatohepatitis (NASH), a subset of NAFLD with a higher likelihood of progression to advanced liver disease, is presently the most common cause of chronic liver disease (CLD) and a leading indication for liver transplantation in Western countries.[1–3] Over the last decade, there has been an acceleration in the search for new therapies for NASH and the number of clinical trials enrolling NASH and NAFLD patients is growing rapidly.[4,5] Simultaneously, the inclusion of patients with NAFLD/NASH into clinical trials in therapeutic areas other than NASH is increasing and will likely continue to increase as the obesity epidemic expands worldwide. For example, the search for new drugs for treatment of type 2 diabetes mellitus (T2DM) has led to a myriad of clinical trials enrolling T2DM patients that may have NAFLD in 60%-80% of the cases.[6,7] As in other clinical trials, drug-induced liver injury (DILI) remains a major concern for drug developers and investigators in NASH trials. The well-recognized challenges in detection, assessment and management of DILI during drug development are amplified by the fact that a significant part of the target population may have varying degrees of hepatic fibrosis. However, there are no regulatory guidelines and position papers to provide information regarding DILI-related best practices for clinical trials enrolling patients with pre-existing NASH. As a result, clinical investigators and drug developers face considerable uncertainty when identifying and managing suspected DILI in these trials, and often use diverse approaches and practices for assessment and management of liver safety signals. Given the enormous prevalence of CLD related to NASH worldwide, and the growing number of clinical trials assessing new drugs for NASH, there is a great unmet need for consistent, evidence-based recommendations for best practices pertaining to suspected DILI in such patients.

The IQ DILI Initiative was launched in June 2016 within the International Consortium for Innovation and Quality in Pharmaceutical Development (also known as the IQ consortium) to reach consensus and propose best practices on topics related to clinical DILI.[8] The IQ Consortium is a science-focused, not-for-profit organisation addressing scientific and technical aspects of drug development and is comprised of 39 pharmaceutical and biotechnology companies. The IQ-DILI Initiative is an affiliate of the IQ Consortium, comprised of 15 IQ member companies, focused on establishing best practices for monitoring, diagnosing, managing and preventing DILI. This publication is based on an extensive literature review, and the consensus achieved in carefully structured discussions between IQ DILI members and academic and regulatory experts. The recommendations are based on the opinions of the authors, and do not imply a regulatory mandate. Although this publication focuses on DILI assessment during drug development, post-approval pharmacovigilance is an important part of the safety assessment of a new drug. This is especially important for assessment of DILI, which tends to be uncommon and might be missed during drug development. Most of the recommendations and best practices included in this publication are specific to acute hepatocellular DILI. It is well recognized that some drugs may cause other types of acute DILI including cholestatic liver injury, mixed hepatocellular-cholestatic and acute steatosis with metabolic acidosis. It is also recognized that drugs may cause chronic liver injury including hepatic fibrosis, steatosis, steatohepatitis, cirrhosis, nodular regenerative hyperplasia, and vascular diseases.[9] Cholestatic DILI will be discussed in detail in another paper by the IQ DILI initiative. Due to the scarcity of data in the published literature, other types of acute DILI and chronic DILI will not be discussed in this paper. However, it is strongly recommended that drug developers and investigators remain mindful of these less common types of DILI that could arise during drug development.