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Executive Summary

DEPO-PROVERA SAFETY DATA IS NOT COMPARABLE TO ORAL CONTRACEPTIVE DATA, FDA's Center for Drugs and Biologics stated in an April 25 response to Upjohn's exceptions to the Public Board of Inquiry's report on the injectable contraceptive. "The record in this proceeding establishes that no OC currently approved in the U.S. has a carcinogenic profile like that of Depo-Provera (i.e., dose-related malignant tumors in two different species)" the center asserted. The center declared: "Upjohn's worst misstatement is its allegation that carcinogenicity data on Depo-Provera and oral contraceptives are similar. The company disclaims any intention of arguing that OCs cause cancer but then goes on boldly to claim that the date on OCs and on Depo-Provera are very similar in that animal data implicate them both and that human data, although not definitive, are reassuring for both. This allegation is false." The center added that recent "good-quality, long-term controlled studies in very large populations" have demonstrated "conclusively that OCs do not cause cance." The agency said "there are no comparable data for Depo-Provera." FDA also commented on Upjohn's contention that results of animal studies are not relevant to humans. With respect to Upjohn's argument of differences between the dog model and women, the center stated that "if FDA is to dispose of the dog model, something will have to take its place." The center added that "such a revolution in drug toxicology would also have implications with respect to drugs approved on the basis of negative tests in the dog as well as those denied approval because of positive testing in that species." Regarding the monkey studies, FDA said that "by questioning the relevance of the findings of cancer in monkeys because it occurred only in high-dose animals, Upjohn implies that the tumors would not have occurred at lower contraceptive dosages used in humans." However, the agency said given the "insufficient numbers of animals and groups in the monkey study, the presence or absence of a dose response relationship could not be determined." In addition, the agency stated that "there is no evidence that Depo-Provera's potency in the rhesus monkey would be greater than in the human. On the contrary, some data suggest that progestogens may be cleared faster in monkeys than in humans and, therefore, that more of the drug would have to be given to monkeys to achieve an effect comparable to a smaller dose in humans." Discussing the World Health Organization multicenter case control studies, which Upjohn maintained provide evidence of Depo-Provera's safety, the agency said they both "suffer from a critical design problem." FDA said that "according to the study protocol, women diagnosed with cancer (be it breast or cervical) at a family planning clinic other than at an initial visit are excluded from the cases under consideration. Because women who receive Depo-Provera must necessarily attend a family planning clinic, this exclusion criterion for the cases creates a potential bias such that Depo-Provera users may be under-represented among the cases." Regardless of the design, FDA said that at this stage the numbers in both studies are extremely small and neither "contains a sufficently large number of long-term users." The agency said the data therefore "cannot be used to assess the carcinogenic potential of long-term use of the drug" or to establish its safety. The center intends to file further comments on the WHO studies by May 8. In its filing of exceptions to the Board's report, Upjohn stated that Depo-Provera labeling could direct physicians as to the appropriate patient population to receive the drug ("The Pink Sheet" Feb. 4, T&G-6). FDA responded: "Contrary to Upjohn's statements, the Board did not find that, for all women in the enumerated categories, contraceptive use of Depo-Provera would be appropriate (i.e., the risk-benefit ratio of Depo-Provera would be favorable so as to justify approval of the drug for those women). Instead, the Board expressly stated that Depo-Provera might be a reasonable and desirable 'option' for such women. That is a far cry from concluding that, for all such women, the risk/benefit ratio of Depo-Provera would be favorable." The center added that the Board "determined that only a selected few of these theoretical Depo-Provera users would be appropriate candidates for the drug and expressly declined to recommend approval of the drug for 'broad categories' of patients." The center said it opposes even a very limited approval for such individuals as women drug abusers and mentally retarded women because they are not able to give truly informed consent.

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