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Executive Summary

WYETH-AYERST PREMARIN U.S. AND CANADIAN FORMULATION DIFFERENCES was the subject of a meeting between the company and FDA during the week of July 6. The agency reportedly has asked Wyeth-Ayerst to submit information on formulation changes that were made last year in the Canadian-produced Premarin and data on the particular version of the conjugated estrogens product used to support the drug's osteoporosis claim in the U.S. Similar requests have been made by the Canadian Health Protection Branch, which became aware of the differences between Canadian and U.S. Premarin during a November 1991 meeting of its Ad Hoc Advisory Committee on Conjugated Estrogens. The committee had been convened to evaluate safety and efficacy concerns relating to generic conjugated estrogens products. During the meeting of the Canadian advisory committee, information was presented that suggested that until about a year ago the Premarin produced by Wyeth-Ayerst in Canada had a faster rate of release than U.S. Premarin. The advisory committee issued a report recommending standards for generic Canadian conjugated estrogens and discussing the apparent differences between the Canadian and U.S. Premarin versions. The report notes that during the November 1991 meeting, data was presented by generics manufacturer ICN Canada Ltd. "claiming to show that lots of Canadian Premarin had until recently, been of a prompt-release type, but that reformulation had occurred so that a more recent lot was of a modified (delayed)-release type corresponding more closely to U.S. Premarin." Evidence also was presented by a Canadian Health Protection Branch scientist showing that "a lot of Canadian Premarin differed markedly from a lot of U.S. Premarin, again with the Canadian product releasing estrone sodium sulfate more rapidly than the U.S. product." In addition, a bioequivalence study performed by the Canadian generics firm Apotex found that Canadian and U.S. Premarin were not bioequivalent, the report states. While Wyeth-Ayerst had explained to the committee that the differences were due to minor formulation changes implemented because of HPB requirements for disintegration testing, the committee said in its report that it "is most skeptical of this explanation and considers that the formulation change is a major one and was most likely undertaken to allow Canadian Premarin tablets to meet the proposed USP drug release specifications." Release rate has been a pivotal issue in FDA's review of conjugated estrogens. In August 1991, the agency issued a revised conjugated estrogens guidance requiring that generic companies conduct studies to measure the rate and extent of absorption to demonstrate bioequivalence to Premarin ("The Pink Sheet" Sept. 2, 1991, T&G-9). FDA supported its withdrawal of generic conjugated estrogens from the market in February 1990 with the contention that faster rates of absorption could make the hormone product ineffective in the treatment of osteoporosis and may raise the risk of endometrial cancer ("The Pink Sheet" May 7, 1990, p. 7). The Canadian advisory committee noted in its report that FDA's decision to issue new standards for generic conjugated estrogens was based on Premarin's rate of release and the results of a 1984 study by Lindsay et al. that established the efficacy of Premarin for osteoporosis therapy. The report states that "it was with great concern, therefore, that the committee learned the the tablets used in the Lindsay study were of Canadian manufacture." The committee concluded that this new information leads to two possibilities: "that the lot used in the Lindsay study was of the type apparently sold in Canada until recently (the fast-release type) and thus the argument used in the U.S.A. concerning the virtue of Premarin having modified-release characteristics is flawed; or that the lot used in the Lindsay study was of the type sold recently in the U.S.A. (the slow-release type) and that, if the originator's argument concerning a steep dose-response curve is valid, Canadian Premarin formulations have been producing unsafe plasma estrogen levels in women for some years." The Canadian group recommended that "this situation be clarified before any requirements can be made of manufacturers for studies of bioequivalence." If it turns out that the Lindsay study was conducted with fast-release Premarin from Canada, Wyeth-Ayerst may face some tough questions at FDA and, in a worst-case scenario, could lose its osteoporosis indication for Premarin. The issue could also exacerbate already tense relations between the agency and some generic firms such as Barr, which was denied approval for its conjugated estrogens ANDA in October 1989 because its product had a different rate of absorption than Premarin.

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