Using controlled clinical trials to learn more about acute drug-induced liver injury

✍ Scribed by Paul B. Watkins; Paul J. Seligman; John S. Pears; Mark I. Avigan; John R. Senior

• Publisher: John Wiley and Sons
• Year: 2008
• Tongue: English
• Weight: 327 KB
• Volume: 48
• Category: Article
• ISSN: 0270-9139
• DOI: 10.1002/hep.22633

✦ Synopsis

Drug-induced liver injury (DILI) is of major interest to hepatologists and clinicians in general, patients, government regulators, and the pharmaceutical industry. Understanding why this form of injury occurs only in certain individuals has major implications for the development and availability of drug therapies and in the prevention of these events. A single controlled clinical trial may be unlikely to show cases of such rare events, but in the aggregate, clinical trials offer a unique resource for learning more about individual susceptibility and developing truly predictive new biomarkers for DILI. We pose the question as to whether clinical trials could be modified or improved to provide data that would better answer some of the outstanding issues. At a recent (March 2008) public meeting, experts from academia, industry, and regulatory bodies discussed several major issues regarding liver safety in clinical trials including: what signals of liver injury should justify stopping administration of study drug or allowing it to continue; if deliberate rechallenge should be done and under what circumstances; whether patients with liver disease should be included in clinical trials; and what kinds of new biomarkers will be needed to answer these questions more clearly. Past clinical trials have not provided data to settle those issues, and reliance has defaulted to consensus of expert opinions. Modified and better clinical trials with standardized collection of data and biospecimens are probably the best source of new and potentially valuable information to supplant current rules based on consensus of expert opinions and to understand by what mechanisms and how to distinguish those individuals who are susceptible to severe DILI. (HEPATOLOGY 2008;48:1680-1689.)

D rug-induced liver injury (DILI) is the adverse event that most frequently leads to regulatory action on drugs, including failure to approve, added label warnings, and withdrawal from the market 1 and is now the leading cause of acute liver failure in the United States, exceeding all other causes combined. 2 The major form of severe liver injury of concern is idiosyncratic hepatocellular injury with loss of liver function that occurs unpredictably in only a few of the many patients treated with the drug after its approval for clinical use and marketing. In addition to the threat DILI presents to the rare susceptible patient, withdrawal of drugs from the market or limitations in their availability because of DILI in a few denies beneficial treatment to the great majority of those who are not susceptible to DILI and who could take them safely.

The recent U.S. Food and Drug Administration (FDA) draft guidance document 3 on "Drug-Induced Liver Injury: Premarketing Clinical Evaluation", represents a formal recommendation regarding consistent approaches to detecting and investigating liver safety in clinical trials. At an open public meeting in March 2008, DILI experts from academia, the pharmaceutical industry, and the FDA met to discuss aspects of the draft guidance. 4 Discussion was focused around four questions, the answers to which could improve the early detection and characterization of DILI: (1) when should the adminis-