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Executive Summary

Barr Labs is asking for an administrative hearing on FDA's denial of its ANDA applications for five dosage strengths of generic conjugated estrogens products. Barr requested the hearing in a Nov. 10 letter to the agency, culminating a one-year cooling off period during which the company tried to resolve its disagreements with FDA over the appropriate test requirements for generic versions of the conjugated estrogens. The generic firm had indicated its intent to seek an administrative hearing in October 1988 but agreed to withhold its request to permit FDA to ask an advisory committee's opinion of test requirements and to allow FDA Commissioner Young to participate in the decision. The company had also filed a lawsuit against the agency in November 1988 seeking punitive damages. The catalysts for the hearing request are two recent letters to Barr: (1) an Oct. 11, 1989 non-approval letter from Center for Drug Evaluation and Research Director Carl Peck, and (2) a Nov. 6, 1989 letter from FDA Commissioner Young reaffirming Peck's decision. Following receipt of the Oct. 11 denial letter, Barr's outside counsel Joseph diGenova (Bishop, Cook, Purcell & Reynolds) wrote to FDA Commissioner Young to question the non-approvability decision. * Peck's decision to deny the Barr applications was based primarily on the determination that the generics were not bioequivalent to the innovator drug (Wyeth-Ayerst's Premarin) on the basis of the rate of absorption data. Barr contends that the rate of absorption criteria are a late addition by FDA to the material necessary for generic conjugated estrogens approval. "Remarkably, the importance of rate of absorption has been repudiated twice by the agency," Barr argued in its Oct. 19 letter to Young. The first time FDA denied the importance of absorption criteria, Barr said, was "in its promulgation of the urinary assay guidance in 1986." That decision, Barr contended was supported "again three years later when the FDA's Fertility and Maternal Health Drugs Advisory Committee concluded that rate of absorption is not significant in demonstrating bioequivalence." The denial of Barr's ANDAs "based on rate of absorption is clearly inconsistent with your own commitment to defer to the decision of the Fertility and Maternal Health Drugs Advisory Committee," Barr's attorneys maintained. At its Jan. 6, 1989 meeting, the advisory committee determined that the rate of absorption of estrogen moieties and/or metabolites is probably not relevant to the bioequivalence of conjugated estrogen products and that urinary excretion studies are not sufficient to establish bioequivalency for conjugated estrogens ("The Pink Sheet" Jan. 9, p. 12). However, the committee also recommended that FDA require long-term efficacy trials on the effect of generic conjugated estrogens on bone mass. Peck's Oct. 11 non-approvable letter states: "The results of [a Barr] pilot study show that even though the extent of absorption of estrone and equilin for the two treatments appears to be equivalent (on the basis of AUC (0.24), the test drug product is not bioequivalent to the reference drug product on basis of the rate of absorption of estrone and equilin" [emphasis added by "The Pink Sheet" for clarity]. The Peck letter further says: "The Division of Bioequivalence has determined that the pilot study submitted does not satisfy the confidence limits for the rate of absorption and therefore the firm has not demonstrated the in vivo bioequivalence of the test products to the reference products." The Peck denial letter also states that Barr's ANDAs are deficient because the company "has not furnished the 0 hour readings for total estrone on the first day"; "the establishment of steady state has not been documented clearly"; and "the dissolution testing data have not been submitted in this communication." Barr submitted blood level studies after FDA had denied the company's bioequivalence study based on urinary excretion levels. Barr and Able Labs had submitted urinary excretion studies for their respective estrogen products in accordance with FDA's original bioequivalency guidelines. Debate on the adequacy of that guidance arose following Wyeth-Ayerst's April 1988 petition to FDA to require only absorption rate-based blood level studies for approval of estrogens. FDA subsequently decided to require blood level studies for approval of any new conjugated estrogens and for upgrades from bioequivalence problem, "BP," ratings to therapeutically equivalent, "AB," ratings ("The Pink Sheet" July 4, 1988, T&G-11). FDA notifed Barr and Able in June 1988 that their ANDAs were being denied. Barr first submitted its blood level data in March 1989. The company later resubmitted the bioequivalence data to FDA in June, accusing the agency of misplacing the initial submission. FDA explained that the initial Barr submission was mistakenly sent by the company to Commissioner Young and during subsequent rerouting did not find its way to the Generics Division. Able is currently working on blood level studies. The generic conjugated estrogens currently on the market (Zenith, Duramed and Chelsea) do not carry "AB" ratings. Both Zenith and Duramed have applications pending for "AB" status on the basis of blood level studies. A year ago, FDA sent Zenith a non-approvable letter because the rate of absorption was not the same as Premarin. The conjugated estrogens decision is complicated by the inquisition atmosphere of the ongoing congressional hearings on manufacturing and recordkeeping problems and fraud in the regulation and compliance of the generic industry. In the Oct. 19 letter, Barr is portraying the recent denial as a retaliatory act against the company for its participation in uncovering irregularities in generic drug reviews. Barr's criticisms of FDA actions regarding its application are unusually harsh, with a decided tone of personal criticism (see excerpts from Barr's chronology of the situation, p. 9). One of Barr's attorney in the matter, diGenova, is a former prosecutor with reknown in Washington for investigating alleged corruption in the D.C. local government. "Barr must regrettably inform you of its conclusion that the Oct. 11 letter is a retaliatory act taken against Barr because of Barr's cooperation with the House Oversight Subcommittee" and because of the company's negative testimony against Peck, the Oct. 19 letter states. Barr testified at the House Commerce/Oversight Subcommittee's May 11 hearing ("The Pink Sheet" May 15, p. 12). The law firm maintained that the denial "is devoid of scientific, medical and/or legal merit." In Young's Nov. 6 response to Barr's counsel, he stated: "I have met with Dr. Peck and have discussed the Center's findings as relayed in their Oct. 11 letter to you. I am convinced that Dr. Peck's decision was based purely on the scientific and public health merits of the application." In June, FDA issued a draft guidance for conducting plasma level bioequivalence studies of conjugated estrogens ("The Pink Sheet" June 26, p. 5). The guidance did not address rate of absorption. FDA hopes to have a revised guidance out by the end of the year. Chart omitted.

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