A pharmaceutical consortium could create a hepatotoxin database within the next 12 to 18 months, members of the FDA/PhRMA Hepatotoxicity Steering Committee suggested during a Nov. 8 meeting.

FDA Office of Review Management Pharmacology & Toxicology Associate Director Joseph DeGeorge, PhD, described the proposed database of structure-activity relationships in human hepatoxicants as "somewhat broader than FDA's reach." The model would be the database of carcinogens.

Creating a database "would require participating companies to provide compound structure and human hepatotoxicity data to the agency," a "white paper" prepared by the FDA/Pharmaceutical Research & Manufacturers of America group suggests.

Analysis would be "done by fragment-based software, which would allow the model to be disclosed without disclosure of the proprietary information."

A key feature of the proposed database would be voluntary submissions by pharmaceutical manufacturers of compounds where development was abandoned due to liver toxicity concerns.

The database would "collect both the pharmaceutical products that come to the FDA where we have the animal outcomes and presumably human outcomes... but also products which have never been to the FDA, because the industry has clearly identified these things [as] so obviously hepatotoxic," DeGeorge said.

Aventis Head of Global Safety Assessment Intelligence Jim Sanders, PhD, suggested that manufacturers would have an incentive to participate in the consortium. "It would be available to everybody, so everybody could use it to improve their drug selections."

No formal action has been taken on the database, but the PhRMA/FDA group characterized it as a high-priority, high-feasibility and low-cost project.

DeGeorge and Sanders presented other preclinical initiatives, including a database on compounds that form reactive metabolites in humans or animals, with a timeline set at two to three years.

The group also proposed an evaluation of potential nonclinical signals for hepatotoxicity from routine toxicology tests, suggesting that PhRMA fund a post-doctoral fellow at FDA to run the project.

The committee tentatively planned a workshop to examine the progress on the nonclinical research proposals and reassess goals after 18 months.

On the clinical research side, the group reviewed a "white paper" outlining a proposed analysis of NDAs for drugs found to be hepatotoxic.

The group reviewed a "positive" list of known hepatotoxic drugs and a "negative" list of known non-hepatotoxic drugs. The steering committee decided to focus initially on two products from each list to determine the level of resources necessary to conduct a larger analysis.

"I think we're just sort of shooting in the air here and we're talking about resources and have no idea what it takes," FDA Office of Drug Evaluation I Director Robert Temple, MD, said. "I'd like to see two of them be done so we could get some idea of how much it costs, how hard it is, and know when we go begging, how much we are begging for."

The committee tentatively decided on troglitazone (Warner-Lambert's Rezulin ) and bromfenac (Wyeth-Ayerst's Duract ) for the initial analysis of "positive" hepatotoxins. The two drugs were withdrawn from the market due to toxicity concerns (Also see "Post-Marketing Hepatotoxicity Drug Withdrawals Subject Of FDA Study" - Pink Sheet, 5 November, 2001., p. 11).

The group tentatively agreed to use pharmacologically similar compounds from the negative list for comparison. For Rezulin, pioglitazone (Takeda/Lilly's Actos ) will likely be the comparison. Lilly has offered data for use by the group.

As a comparator for Duract, Temple suggested Pharmacia/Pfizer's Celebrex (celecoxib) or Merck's Vioxx (rofecoxib). Boehringer-Ingelheim/Abbott's Mobic (meloxicam) would also work, he noted.

The steering committee agreed to contact the sponsors of the products to finalize participation by Dec. 1. The group hopes to complete the analysis on the first NDAs by April. The committee is also looking at post-marketing issues like liver function monitoring (see ¹ Also see "PhRMA/FDA Hepatox Group Wants Research On Liver Monitoring" - Pink Sheet, 26 November, 2001.).

FDA/PhRMA May Create Database Of Hepatotoxins

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