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Executive Summary

Cardioprotective properties of Wyeth-Ayerst's conjugated estrogen product Premarin in women without uteruses have been demonstrated by epidemiologic studies and biological data on the activity of estrogens, FDA's Fertility and Maternal Health Drugs Advisory Committee concluded June 15. All but one member of the panel (who abstained from the vote) agreed that "the evidence provided is sufficient to conclude that estrogen replacement therapy with Premarin alone lowers the risk of cardiovascular disease in women" who have had hysterectomies. The committee unanimously agreed that "the benefits of Premarin may outweigh the risks, depending on the individual patient's risk profile for various estrogen-related diseases and conditions." The June 14-15 advisory committee discussion was unusual in both content and format. The vast majority of Wyeth-Ayerst's data package in support of a cardioprotective indication is from epidemiological studies in the literature. Instead of following the customary separation of FDA and company speakers, presentations from FDA, speakers invited by FDA, experts invited by the company, and company officials, were intermixed throughout the two-day review. Although different views on the conclusiveness of the data were expressed by the FDA and company speakers, there was a general consensus that the data indicate cardioprotective benefits. There also appeared to be agreement that the epidemiologic studies were less than ideal, but that prospective, randomized trials at this time would be difficult. * Premarin, which has been on the market in the U.S. for over 40 years, is experiencing an unusual late-product life vitality, adding several major indications recently and receiving FDA's blessing as a distinct entity from synthetically derived generic copies. The product generated sales of $285 mil. in 1989 with 20% growth over the previous year ("The Pink Sheet" May 7, p. 9). Among the concerns expressed during discussion was that the optimum dose and duration of estrogen therapy for cardioprotection was not established (most of the studies only looked at whether or not women had ever taken estrogen). Some committee members were also concerned that the exact magnitude of benefit was difficult to determine because estrogen users in the studies may have had other characteristics that would have made them less likely to get cardiovascular disease. Many of the epidemiologic studies (including the Nurses' Health study of approximately 120,000 women and the Lipid Research Clinic Program Follow-up Study on approximately 2,300 women) found that estrogen therapy was associated with a relative risk in the range of 0.5 for cardiovascular disease. Wyeth-Ayerst submitted results of a meta-analysis of 29 epidemiologic studies on the cardioprotective benefits of estrogen replacement therapy. The analysis, presented to the committee by Meir Stampfer, MD, Harvard School of Public Health, found a 0.5 relative risk of mortality from cardiovascular disease for estrogen users. A relative risk of 0.5 was also found when only the most valid studies (the prospectively controlled trials and cross-sectional studies) were analyzed together. Both analyses weighted the studies according to variance. Commenting on the data, Committee Chairman Barbara Hulka, MD, University of North Carolina School of Public Health, said: "From the standpoint of epidemiology and the many epidemiologic analytic observational studies that have been done, the findings are impressive. We rarely get such consistent findings, and this magnitude of benefit in epidemiologic studies." Referring to data on estrogen's effects on lipids, Hulka added that "there seems to be some pretty good biology supporting beneficial estrogen effects." * The committee unanimously agreed that further studies should be undertaken and specifically recommended two types of trials: a secondary intervention trial in women with severe atherosclerosis or prior myocardial infarction; and a large cohort trial evaluating subgroups of women that may be at particular risk of cardiovascular disease. The additional studies were not suggested as a prerequisite to labeling changes.

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