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Assessment of the Immunotoxic Potential of Human Pharmaceuticals: A Workshop Report

The assessment of the immunotoxic potential of human pharmaceuticals has drawn considerable attention worldwide in the past few years. In Europe, the Committee for Proprietary Medicinal Products released its immunotoxicity guidance documents. The Food and Drug Administration's Center for Drug Evaluation and Research in the United States and the Japanese Ministry of Health, Labor, and Welfare are in the process of finalizing similar guidance documents. This report summarizes the discussions on drug immunotoxicity assessment held at a November 2001 DIA workshop held in Noordwijk, The Netherlands. This workshop revealed that an important issue for company attendees was the timing of the immunotoxicity studies during the drug development process. The Committee for Proprietary Medicinal Products requires that immunotoxicity endpoints be monitored for all new compounds. Industry has interpreted this requirement, and the expectation that these endpoints be studied in a 28-day repeated dose study in rats, as obligatory immunotoxicity testing for all new compounds, regardless of the stage of development. The Committee for Proprietary Medicinal Products requirements, however, are applicable only at the stage of the marketing application. Workshop participants agreed that immunotoxicity screening should preferably be carried out prior or parallel to Phase 2 development. This will substantially reduce the number of compounds that require enhanced testing for immunotoxicity (approximately 80% of the compounds are dropped from development after Phase 1) and reduce the use of animals. Presentations and discussions at the workshop also demonstrated that there is a strong scientific basis for European requirements as included in the Revised Note for Guidance on Repeated Dose Toxicity Testing. For example, not evaluating the response to a T-cell-dependent antigen would have missed the immunotoxicological effects of several compounds. This is probably due to the dynamic nature of the immune system whereby immune effects are best demonstrated using an immune function assay, as opposed to reliance on an essentially static analysis such as histopathology.