FDA's Center for Drug Evaluation & Research is planning to conduct a detailed re-examination of NDA data sets for drugs withdrawn due to post-marketing liver toxicity.

The study aims to determine if the hepatotoxic events could have been foreseen and, if so, to identify the clinical indicators for post-approval liver toxicity.

Office of Medical Policy Director Robert Temple, MD, and Office of Post-Marketing Drug Risk Assessment Senior Scientific Advisor John Senior, MD, are coordinating the effort.

Two recent drugs withdrawn due to hepatotoxic events are Pfizer's Rezulin (troglitazone) and Wyeth-Ayerst's Duract (bromfenac). In June 1999, Pfizer's Trovan (trovafloxacin) use was severely restricted following liver toxicity reports.

CDER will also undertake a cooperative project with Merck to examine the background incidence of abnormal reactions in the placebo arm of clinical studies. The project is intended to validate and determine the specificity of the abnormalities, as well as elucidate trends in clinical data as signs of potentially toxic reactions.

Additional hepatotoxicity research projects will be initiated following a Nov. 8 meeting of the Hepatotoxicity Steering Committee. Twenty-five committee members will meet at the Rockville Civic Center to discuss research initiatives in non-clinical, clinical and post-marketing hepatotoxicity.

The committee will be charged with determining funding sources, parties to get involved and specific topics for hepatotoxicity research programs. The group will also follow up on issues raised at the Feb. 12-13 workshop on liver toxicity (¹ Also see "Drug Liver Toxicity Risk Could Be Monitored In Extended Phase III - Temple" - Pink Sheet, 19 February, 2001., p. 9).

The focus of the February meeting was three "white papers" developed by FDA, the Pharmaceutical Research and Manufacturers of America and the American Association for the Study of Liver Diseases. The papers addressed pre-approval strategies for accurate detection of potential toxicity, determination of significance of toxicity in non-clinical/animal trials and post-marketing safety surveillance.

Post-Marketing Hepatotoxicity Drug Withdrawals Subject Of FDA Study

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