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AASLD-FDA-NIH-PhRMA Hepatotoxicity Steering Group Meeting, 2006 Presentations: Characterization of risk for drug-induced serious liver injury prompted by a series of spontaneously reported post-marketing cases

Mark Avigan, MD CM 
Division of Drug Risk Evaluation, Office of Drug Safety, Center for Drug Evaluation and Research,
Food and Drug Administration
Characterization of risk for drug-induced serious liver injury prompted by a series of spontaneously reported post-marketing cases [PDF]

When spontaneous case reports of drug-induced idiosyncratic liver injury linked to a particular agent are obtained by FDA during the post-marketing period, the development of a quantitatively useful risk assessment depends on multiple streams of information. It is often the case that in many reports critical information which would enable an accurate assessment of causality is not provided. Moreover, potential interactions with underlying diseases or concomitant treatments or drugs that underlie clinically significant liver injury may be difficult to interpret. As one consequence, there is a broad distribution of causality/likelihood of causal association scores among the series of liver injury cases. Finally, significant inter-individual differences between adjudicators in the causality assessment of individual reports, even when performed by a panel of experts, complicates a semi-quantitative risk evaluation. Because of these limitations, risk assessment depends on a synthetic approach that examines both the pre-marketing and post-marketing ‘weight of evidence’. In such an analysis, it is useful to ask the following questions about the post-marketing cases which have been collected:

  • In the clinical trial safety database is there a signal of liver injury detected based on imbalances between drug and placebo/comparator?
  • What relationship between drug dose, duration of exposure and patient susceptibility factors with liver injury are suggested by the pre- and post-marketing cases?
  • What is the distribution of clinical severity of liver injury among the post-marketing cases?
  • Is there a modicum of cases in which the causal link to severe idiosyncratic DILI is ‘highly likely’ based on the case report information that is provided?
  • Are the numbers of reported cases disproportionate compared to other adverse events?
  • Is there confounding by underlying disease or concomitant drugs linked to liver injury?
  • What is the distribution of probability of causality assignments (highly likely, probable, possible, unlikely, etc.) in the series?
  • What patterns of liver injury are implied in the reports? Are these different in character than those associated with the underlying diseases or concomitant drugs, suggesting that the liver injury is caused by a combinatorial effect?

Projection of the burden and incidence of cases of severe drug-induced life-threatening liver injuries into the whole population of patients treated with the drug is often crucial for evaluation of overall benefit/risk. Because AERS reports of clinically significant DILI are spontaneous, report numbers or rates cannot be readily extrapolated into an analysis of incidence. For this purpose, the clinical study safety data base should be scoured for Hy’s cases. Alternatively, epidemiologic studies using administrative linkage databases may be used. For very rare idiosyncratic severe injury events, there is an inevitable lag effect until adequate drug exposure will yield a sufficient number of cases for measurement.

Biographical Sketch

Mark Avigan obtained his B.Sc. (1972) and M.D. C.M. degrees (1977) from McGill University in Montreal, Canada. He completed residency training in Internal Medicine at the VA Medical Center/Georgetown University in Washington DC. Subsequently, he served as Chief Medical Resident and completed a clinical GI/Hepatology/Nutrition fellowship. Dr. Avigan served as a staff fellow in the Liver Unit of the National Institute of Arthritis Diabetes, and Digestive and Kidney Diseases in Bethesda Maryland and later moved to NCI where he pursued studies in molecular and cellular mechanisms governing the dysfunctional expression of oncogenes during carcinogenesis.
In 1990 he joined the faculty at the School of Medicine at Georgetown University. As an assistant and later associate professor he attended patients on the GI/Liver service at the Georgetown University Medical Center and served as a mentor in the GI clinical fellowship program. In addition, he was the principal investigator of NIH funded R-29 and R0-1 grants that supported studies to elucidate transcriptional and post-transcriptional growth regulation by cytokines.

After joining the Center for Drug Evaluation of the Food and Drug Administration in 1999 as a Medical Officer in the Division of Gastrointestinal and Coagulation Drug Products he became a Senior Medical Reviewer in 2002. He is currently serving as Director of the Division of Drug Risk Evaluation in the Office of Drug Safety.