Consensus Guidelines: Best Practices for Detection, Assessment and Management of Suspected Acute Drug-Induced Liver Injury During Clinical Trials in Adults with Chronic Viral Hepatitis and Adults with Cirrhosis Secondary to Hepatitis B, C and Nonalcoholic Steatohepatitis

Abstract

With the widespread development of new drugs to treat chronic liver diseases (CLDs), including viral hepatitis and nonalcoholic steatohepatitis (NASH), more patients are entering trials with abnormal baseline liver tests and with advanced liver injury, including cirrhosis. The current regulatory guidelines addressing the monitoring, diagnosis, and management of suspected drug-induced liver injury (DILI) during clinical trials primarily address individuals entering with normal baseline liver tests. Using the same laboratory criteria cited as signals of potential DILI in studies involving patients with no underlying liver disease and normal baseline liver tests may result in premature and unnecessary cessation of a study drug in a clinical trial population whose abnormal and fluctuating liver tests are actually due to their underlying CLD. This position paper focuses on defining best practices for the detection, monitoring, diagnosis, and management of suspected acute DILI during clinical trials in patients with CLD, including hepatitis C virus (HCV) and hepatitis B virus (HBV), both with and without cirrhosis and NASH with cirrhosis. This is one of several position papers developed by the IQ DILI Initiative, comprising members from 16 pharmaceutical companies in collaboration with DILI experts from academia and regulatory agencies. It is based on an extensive literature review and discussions between industry members and experts from outside industry to achieve consensus regarding the recommendations. Key conclusions and recommendations include (1) the importance of establishing laboratory criteria that signal potential DILI events and that fit the disease indication being studied in the clinical trial based on knowledge of the natural history of test fluctuations in that disease; (2) establishing a pretreatment value that is based on more than one screening determination, and revising that baseline during the trial if a new nadir is achieved during treatment; (3) basing rules for increased monitoring and for stopping drug for potential DILI on multiples of baseline liver test values and/or a threshold value rather than multiples of the upper limit of normal (ULN) for that test; (4) making use of more sensitive tests of liver function, including direct bilirubin (DB) or combined parameters such as aspartate transaminase:alanine transaminase (AST:ALT) ratio or model for end-stage liver disease (MELD) to signal potential DILI, especially in studies of patients with cirrhosis; and (5) being aware of potential confounders related to complications of the disease being studied that may masquerade as DILI events.

Fig. 1

Biochemical response. Early fall in serum alanine aminotransferase (ALT) during effective treatment of viral hepatitis C. The colored curves represent the ALT pattern of response from eight different patients. Reproduced from Kullak-Ublick et al. [48]

Fig. 2

Algorithm for monitoring and management of potential DILI signals in phase II–III clinical trials in patients with HCV with normal or elevated baseline ALT. ^aBaseline ALT is derived from an average of two pretreatment ALT measurements 2 weeks apart. Elevated baseline is defined as ALT ≥ 1.5 × ULN. ^bSymptoms may be liver related (e.g., severe fatigue, nausea, vomiting, right upper quadrant pain) or immunologic reaction (e.g., rash, > 5% eosinophilia). ^cFor patients with Gilbert’s syndrome or hemolysis. ^dIn patients with a sizable stable early decrease in ALT during treatment (> 50% of baseline value), a new baseline, corresponding to the ALT nadir, should be established on an individual basis for subsequent determination of a DILI signal. ^eThe specific interval between the tests should be determined based on the patient’s clinical condition. ALP alkaline phosphatase, ALT alanine aminotransferase, AST aspartate aminotransferase, DB direct bilirubin, DILI drug-induced liver injury, HBcAb+ hepatitis B core antibody positive, HBV hepatitis B virus, HCV hepatitis C virus, TBL total bilirubin, ULN upper limit of normal

Fig. 3

Algorithm for monitoring and management of potential DILI signals in phase II–III chronic HBV clinical trials in patients with HBV with normal or elevated baseline ALT who are nucleos(t)ide suppressed^f. ^fThese levels pertain to subjects who are nucleos(t)ide suppressed when entering trials, and values may differ in subjects who are not nucleos(t)ide suppressed. ^gBaseline ALT is derived from an average of two pretreatment ALT measurements 2 weeks apart. ^hFor patients with Gilbert’s syndrome or hemolysis. ⁱSymptoms may be liver related (e.g., severe fatigue, nausea, vomiting, right upper quadrant pain) or an immunologic reaction (e.g., rash, > 5% eosinophilia). ^jElevated baseline is defined as ALT ≥1.5 × ULN. ^kIn patients with a sizable stable early decrease in ALT during treatment (> 50% of baseline value), a new baseline, corresponding to the ALT nadir, should be established on an individual basis for subsequent determination of a DILI signal. ^lThe specific interval between the tests should be determined based on the patient’s clinical condition. ALP alkaline phosphatase, ALT alanine aminotransferase, AST aspartate aminotransferase, DB direct bilirubin, TBL total bilirubin, ULN upper limit of normal

Fig. 4

Algorithm for monitoring and management of potential DILI signals in phase II and III clinical trials for new agents to treat HBV in naïve or non-nucleos(t)ide-suppressed patients with normal or elevated baseline ALT. ^mBaseline ALT is derived from an average of two pretreatment ALT measurements 2 weeks apart. ⁿFor patients with Gilbert’s syndrome or hemolysis. ^oSymptoms may be liver related (e.g., severe fatigue, nausea, vomiting, right upper quadrant pain) or immunologic reaction (e.g., rash, > 5% eosinophilia). ^pElevated baseline is defined as ALT ≥1.5 × ULN. ^qIn patients with a sizable stable early decrease in ALT during treatment (> 50% of baseline value), a new baseline, corresponding to the ALT nadir, should be established on an individual basis for subsequent determination of a DILI signal. ^rThe specific interval between the tests should be determined based on the patient’s clinical condition. ALP alkaline phosphatase, ALT alanine aminotransferase, AST aspartate aminotransferase, DB direct bilirubin, TBL total bilirubin, ULN upper limit of normal