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Executive Summary

FDA SEES "NO REASON" TO CHANGE PREMARIN's ESTROGEN COMPONENT CATEGORIES as defined by FDA's Generic Drugs Advisory Committee at its February 1991 meeting, Office of Generic Drugs Director Roger Williams, MD, told a U.S. Pharmacopeial open meeting Sept. 29. Referring to Wyeth-Ayerst's proposal that the delta 8,9- dehydroestrone constituent of Premarin be recategorized as a "concomitant component," Williams said that OGD "sees no reason at this time to change any categorization, barring some special safety or efficacy documentation regarding any of these constituents." If delta 8,9 were reclassified, manufacturers of generic conjugated estrogens would have to synthesize the estrogen, which naturally occurs in equine urine-derived conjugated estrogens (Premarin) and add it to their products in amounts specified by the USP. This could further delay the availability of "AB"-rated generic conjugated estrogens. The Generic Drugs Advisory Committee recommended that generic conjugated estrogens products be required to include five estrogens: two "therapeutic moieties" -- sodium estrone sulfate and sodium equilin sulfate -- and three "concomitant components," which occur naturally in Premarin and for which therapeutic benefit is uncertain -- sodium 17 alpha-dihydroequilin sulfate, sodium 17 alpha-estradiol sulfate and 17 beta-dihydroequilin sulfate ("The Pink Sheet" March 4, 1991, p. 9). Wyeth-Ayerst had sought the classification of three estrogens as therapeutic moieties and seven as concomitant components. The recommendations of the advisory committee were enacted largely by a USP monograph change that became official in January of this year. The USP meeting was held to hear opinions on several proposed changes to the current USP bulk conjugated estrogens monograph, which has been amended at least three times since the end of 1991. The current monograph sets a limit only on the maximum amount of delta-8,9 dehydroestrone that can be present in a conjugated estrogens bulk product but does not require the inclusion of that particular estrogen. While FDA said it sees no reason why the monograph should be changed to include delta 8,9-dehydroestrone as a concomitant component, USP is ultimately responsible for the final decision. USP said it will review the scientific evidence for the inclusion of delta 8,9-dehydroestrone in the monograph and its Committee of Revision will publish the decision on the proposed changes in the form of a monograph revision announcement in Pharmacopeial Forum. Publication will occur "probably in the spring," USP said. Bulk drug maker Organics/LaGrange, a major U.S. supplier of bulk conjugated estrogens, spoke out at the USP meeting against any further changes by FDA or USP to the definition of what constitutes conjugated estrogens. Organics/LaGrange President and Technical Director Lawrence Hicks called Wyeth-Ayerst's proposed inclusion of delta 8,9- dehydroestrone a "lock-out specification" because the estrogen has not been commercially synthesized and its inclusion would bring a halt to the bulk supplier's production of the conjugated estrogens formulation as currently defined. "Don't change the monograph," Hicks urged. He said that "what is needed [by generic drug manufacturers] is a period of several years to pass without any significant change to the monograph." "Unless the target stops moving" the development of generic conjugated estrogens will stop," he added. Hicks also speculated that if the inclusion of delta 8,9-dehydroestrone were to be mandated, "two or three years from now...Ayerst will be arguing that some other stuff in Premarin is therapeutic." Wyeth-Ayerst told a press briefing following the USP meeting that it continues to study the other components of Premarin to determine the role of each estrogen in the product's efficacy and that all the estrogens found in Premarin have been shown to bind to estrogen receptors. In addition, the firm suggested that all of Premarin's actions "may not be estrogen receptor-derived." He noted that if Wyeth-Ayerst discovers that some other element in Premarin is therapeutic, the company will ask for additional monograph changes. Wyeth-Ayerst asserted that delta 8,9- dehydroestrone can be synthesized. Organics/LeGrange's conjugated estrogens product has been available to generic tablet makers since early spring. The company said it believes that only the inclusion of delta 8,9- dehydroestrone as a required ingredient in the USP monograph would force the company to modify the actual content of its conjugated estrogens. Other proposed changes to the monograph would result only in changes to the company's computer code, documentation procedures, quality assurance and quality control methods. Other potential monograph changes discussed at the meeting include changes in the method of calculation of the bulk product's composition and potency, ranges for signal impurities, reference standards for component estrogens and dissolution and labeling concerns for conjugated estrogens tablets. FDA and Wyeth-Ayerst both presented their respective proposals for monograph changes. Both parties agreed that their ideas on how to improve the monograph were similar, except for the delta 8,9-dehydroestrone question.

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