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Executive Summary

DURAMED CONJUGATED ESTROGENS ARE CURRENTLY USED BY "OVER 1 MIL. WOMEN" per year and the company has distributed "almost one billion estrogen tablets" in the just under four-and-a-half years of Duramed's marketing experience with the product. In a June 15 filing with FDA, Duramed cited the usage figures as evidence of the "long and widespread safe and effective" use of its product. The Duramed filing supports its previous request for an opportunity for an administrative hearing on FDA's proposed withdrawal of generic conjugated estrogens ANDAs. The Duramed usage figures also highlight the potential increased market for the Wyeth-Ayerst brand Premarin if FDA persists with its withdrawal proceedings. The size of the generic product further indicates the incentives to the generic marketers for a protracted fight to stretch out ANDA withdrawal proceedings. Duramed has four conjugated estrogens ANDAs. Zenith joined Duramed with a separate June 15 filing on the proposed withdrawals. Both companies contend that the rate of absorption issue continues to be a matter for agency review. Objecting to the agency's interpretation of the outcomes of the two advisory committee reviews of generic conjugated estrogens during the last 18 months, Zenith argues that the "scientific dispute over the importance of rate clearly establishes a material question of fact relative to the conclusory FDA statements" in the Feb. 13 withdrawal notice. Zenith is being represented by Alan Kaplan, Robert Becker and Kinsey Reagan (Kleinfeld, Kaplan & Becker). Duramed maintains that bioequivalence data submitted by that firm to FDA in April 1988 "establishes that the extent of absorption of the Duramed product and Premarin are essentially the same, and that the Duramed product has a somewhat faster rate of absorption than Premarin." Duramed discounts the importance of the faster rate of absorption "because conjugated estrogens are a chronic use product, the difference in the rates of absorption is of no clinical significance." Duramed's filing was prepared by D.C. counsel David Weeda, Arthur Tsien and David Durkin (Olsson, Frank and Weeda). Observing that "a relatively brief exposure of the uterus to estradiol results in a long term response pattern," Duramed contends that the faster rate of absorption will not have a long-term effect on the action of the drug. "This response pattern is unlikely to be affected by differences in the rate of absorption of any estrogen since orally active estrogens do not result in pulses but sustained blood levels which will result in continuous occupancy of the estrogen receptor and sustained estrogenic responses," Duramed said. The generic firm also attempts to debunk the "natural" image of Premarin in an interesting footnote to its filing (see box below). The osteoporosis indication (added by Premarin in April 1986 via a DESI upgrade notice) may be the focal point of the continuing debate, Zenith maintained. The generic company said that the "only real issue" of the debate is FDA's allegations of a "lack of evidence of safety and efficacy data" for generic products for that indication. "If, after appropriate proceedings, it is determined that the Zenith products are not shown to be safe or effective for osteoporosis (or any other indications), Zenith will remove such indication(s) from its labeling," the comments acknowledge. Zenith maintains that it "is entitled to prior notification and opportunity to conduct a bioavailability study under conditions acceptable to the agency in order to maintain the continued approval of its ANDAs." If this opportunity is not given then Zenith is "entitled to the hearing it has requested." In noting that FDA has been developing guidance for conducting bioequivalence studies, Kleinfeld, Kaplan said "Zenith intends to support its products in accordance with such standards once the agency finally decides on the parameters it would accept." Last June, FDA issued a draft guidance setting out criteria for plasma level bioequivalence studies for conjugated estrogens. Following the May 3-4 meeting of an ad hoc subcommittee of FDA's Fertility and Maternal Health Drugs Advisory Committee, Center for Drug Evaluation and Research Director Carl Peck said that the advice and thoughts given by the panel will bring the guidance "one step" closer to being finalized ("The Pink Sheet" May 7, p. 7). In response to FDA's concern that estrogen products with faster rates or greater extents of absorption than Premarin may result in higher peak plasma concentrations that may raise the risk of endometrial cancer, the Zenith comments state: "Although the Zenith products have a faster rate of absorption and consequently a transitory higher peak concentration, there is no evidence that a transitory higher peak concentration would increase the risk of endometrial cancer where the overall extent of absorption is the same as the reference product."

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