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Executive Summary

FDA's position that generic conjugated estrogens should have the same rate of absorption as Wyeth-Ayerst's Premarin gained support from a majority of committee members and invited experts on an FDA ad hoc subcommittee of the Fertility and Maternal Health Drugs Advisory Committee. At the end of the subcommittee's May 3-4 meeting on conjugated estrogens bioequivalence, panel members were asked to answer the question: "Is there any evidence that demonstrates that rate of absorption of conjugated estrogens does not affect their safety and efficacy?" Summarizing the members' responses, subcommittee chair Arthur Haney, MD, Duke University Medical School, noted that "there was a majority opinion that there is not sufficient suggest that rate was not important." In a literal response to FDA's request that the committee attempt to prove a negative, panel member Subir Roy, MD, University of Southern California School of Medicine, explained his position, noting that there "are no studies with generic conjugated estrogens preparations that demonstrate their safety and efficacy, therefore it is impossible to state that the rate of absorption does not affect their safety and efficacy." FDA denied Barr Labs' ANDA application for conjugated estrogens last October because the product did not have the same rate of absorption as Premarin. However, Barr's plasma level studies did show that its conjugated estrogens matched the extent of absorption of Premarin. FDA also pointed to rate of absorption as a critical measurement of bioequivalence in the agency's proposal to withdraw the ANDAs of all generic conjugated estrogens on the market ("The Pink Sheet" Feb. 19, T&G-13). The Feb. 13 Federal Register notice notes that certain generic conjugated estrogens have "significantly higher rates of absorption" than Premarin and that "oral conjugated estrogens with a faster rate of absorption or a greater extent of absorption than Premarin tablets may result in instances of higher peak drug plasma concentrations...[which] may unnecessarily raise the risk of endometrial cancer." Different asborption rates could also make a conjugated estrogens product ineffective in the treatment of osteoporosis, FDA contended. The subcommittee was not asked to vote on the questions presented by FDA nor was the panel able to reach a consensus. The panel's disagreement over the rate-of-absorption issue was reflected in the minority view held by two of the experts and the chairman that rate of absorption probably is not important in determining the safety and efficacy of conjugated estrogens. "There is a minority view that rate is very unlikely to be important given the kinetics of estrogen binding and estrogen action," Haney stated. The full Fertility and Maternal Health Drugs Advisory Committee addressed the same issue of measuring the rate of absorption of conjugated estrogens in January 1989. At that time, the committee determined that the rate of absorption of estrogens moieties and/or metabolites is probably not revelant to the bioequivalence of conjugated estrogens. The subcommittee's inability to reach a consensus on the rate of absorption issue as well as several other issues raised by the FDA, including measurement of active metabolites, leaves the general question of conjugated estrogens bioequivalence requirements unresolved. The current status quo will continue to hurt generic firms seeking approval for "AB" rated generics and could lead to another advisory committee review -- possibly FDA's newly created Generic Drugs Advisory Committee. At the May 4 meeting, representatives of Barr Labs, Able Labs and Duramed made presentations to the panel. All three firms have conjugated estrogens ANDA applications based on blood level studies pending at FDA. A representative for Duramed, James Clark, MD, Baylor College of Medicine, downplayed the importance of rate of absorption. In discussing estrogen receptors, Clark maintained that "the binding interaction requires several hours to be effective. This rules out rate problems all together." He suggested that once the response begins at the receptor level, "there are many, many more hours after that that you see the response. So any considerations of rate are actually ridiculous when talking about estrogen receptors." Another representative for Duramed, Chris Rhodes, University of Rhode Island, told the subcommittee that a "major PMA company" is currently conducting a clinical study on the safety and efficacy of its conjugated estrogens product. Rhodes predicted that the study results could be available in August or September. The subcommittee also disagreed on whether estrone sulfate and equilin sulfate are the only active drug ingredients in Premarin. "The committee is split roughly 50-50," Haney said. "Half the committee feels that the active ingredients...are estrone sulfate and equilin [sulfate], and the other half believes there are at least three [other active metabolites]: 17a-Dihydroequilin, and potentially 17b-Dihydroequilin, and 17b-estradiol." The advisory group did reach a consensus on several moieties and/or metabolites that should be measured to determine bioequivalence of generic conjugated estrogens -- estrone sulfate, equilin sulfate and their unconjugated forms. However, Haney pointed out that a "substantial number of committee members suggested measuring 17a-Dihydroequilin and another group recommended measuring both 17b-Dihydroequilin, as well as 17b-estradiol." On the first day of the meeting, invited expert James Settlage, PhD, Enseco Pharmaceutical Sciences Laboratory, addressed the metabolite measuring issue. "Assuming that I can convince you that it is possible to measure all nine of these [components of Premarin tabs] if you want to...isn't there ultimately a concern that if you try to establish bioavailability based on too many compounds that ultimately, statistically [it will] catch up with you, and you simply cannot be bioequivalent nine times in a row on the same drug." The issue of which metabolites should be measured was raised at the January 1989 full committee meeting. The panel determined that blood level studies should measure the amounts of equilin, estrone, estradiol, and the sulfates of both equilin and estrone. Last June, FDA issued a draft guidance setting out the criteria for plasma level bioequivalence studies for conjugated estrogens ("The Pink Sheet" June 26, 1989, p. 5). Under the guidance, bioequivalence can be shown by a single-dose in vivo study if plasma concentrations of estrone sulfate and equilin sulfate are demonstrated at 90% confidence limits for AUC and Cmax values of 80-120%. If an estrogen product does not meet the single-dose study requirements, then it must pass multiple-dose studies that involve measuring unconjugated estrone, unconjugated equilin and unconjugated 17b-estradiol. The issue of conducting single-dose or multiple-dose studies was also addressed by the subcommittee. Haney summarized that the panel "felt fairly uniformly that a single-dose study would be the most appropriate to demonstrate bioequivalence." Invited expert Leslie Benet, PhD, University of California School of Pharmacy, San Francisco, said: "I do not expect to see a difference at steady state and therefore my answer was a single-dose study." He added: "If it is impossible to measure these things at single dose, then we would have to go to the multiple-dose studies." Regarding tablet content variability between estrogen products, the subcommittee felt that current content ranges based on USP specifications are too wide. The members determined that the range of all conjugated estrogens products, including Premarin, should be tightened. FDA Center for Drug Evaluation and Research Director Carl Peck, said that the advice and thoughts provided by the subcommittee will help bring the agency's bioequivalence testing draft guidance for conjugated estrogens "one step" closer to being finalized.

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