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RODENT CARCINOGENICITY STUDY HIGH DOSE LIMIT: 1% OF DIET, NOT 5%

Executive Summary

RODENT CARCINOGENICITY STUDY HIGH DOSE LIMIT: 1% OF DIET, NOT 5% should be the limit for rodent carcinogenicity high-dose studies, Sigma-Tau told FDA in June 11 comments on the agency's proposal to harmonize animal testing standards. "The high dosage ceiling in the rodent carcinogenicity studies for relatively nontoxic drugs [should] be set at 1% of the diet instead of the current 5%, or at 1,000 mg/kg/day...in drinking water or gavage studies," Sigma-Tau suggested. "The current general scientific opinion, including that of the International Conference on Harmonization, has recognized that highly exaggerated dosage levels of exposure may, and in many cases do, alter the test-organism's homeostasis to such a degree as to produce artifacts not relevant for the actual levels of human exposure and safety," Sigma-Tau said. Examples of "questionable results" of trials using excessively high doses include saccharin, melamine, sulfamethazine and FD&C Red No. 3, the company said. Sigma-Tau added that, according to the National Toxicology Program, all known carcinogens have been detectable in rodents at levels below .1% of diet. FDA's proposed rule on new animal testing standards resulted from the International Conference on Harmonization in Brussels last year and was included in the FDA reform package from Vice President Quayle's Council on Competitiveness ("The Pink Sheet" Nov. 18, 1991, p. 7). The proposed implementing regulations were published in the April 15 Federal Register. Sigma-Tau's comments are among six submitted to the agency in response to the proposal. The American Association for Clinical Chemistry recommended to FDA that clinical pathology testing guidelines be added to the harmonized animal testing standards "for subchronic and chronic studies." AACC included a manuscript copy of its recommendations for clinical pathology testing in its June 8 comments on the proposal. Warner-Lambert's Parke-Davis division and the Association of the British Pharmaceutical Industry both asked the agency to rephrase its proposed statement on when six-month (as opposed to 12-month) dog testing would be adequate for product registration with regulatory authorities. Parke-Davis said the current wording, requiring doses "(high enough to fully characterize the toxicity profile, including induction of major (life-threatening) toxicity)...would seem to contradict the humane treatment of animals." Such testing, ABPI said, "is usually of no relevance to the risk assessment for the therapeutic use of drugs in man." Merck, in June 15 comments on the proposal, applauded the agency's decision to eliminate LD[50] studies "which is clearly in keeping with international consensus on the minimal utility of this study." Merck expressed concern that other U.S. government agencies still rely on the LD[50] test for toxicity assessments and called upon FDA to "take the lead in sharing its extensive experience in this field with other U.S. federal agencies." FDA has said since 1983 that the LD[50] test is no longer mandatory but has continued to accept the lethal-dose data for highly toxic drugs. Comments from Fisons, Merck, Parke-Davis and ABPI requested clarification of elements in the "Reproductive and Developmental Studies" section of the proposed reg. For example, Parke-Davis noted that the proposal reads: "Segment I reproductive performance and effect on fertility in the rat should be done as early as possible." The firm asked FDA to "further clarify what is meant by 'as early as possible.'"
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