Synthetic Generic Conjugated Estrogens: Timeline
1942: The Food and Drug Administration approved Premarin for treating menopausal symptoms and related conditions.
1970: U.S. Pharmacopeia published a monograph describing conjugated estrogens as containing sodium estrone sulfate and sodium equilin sulfate.
1972: FDA published a Federal Register notice announcing that a number of estrogen products, including Premarin, had been shown to be effective in the treatment of menopausal symptoms. This evaluation was done under the Drug Efficacy Study Implementation (DESI) program designed to assess the effectiveness of drugs approved for marketing before the enactment of the 1962 amendments to the Food, Drug and Cosmetic Act. Those amendments require manufacturers to show their products are effective as well as safe.
In that same notice, FDA provided for submission and approval of ANDAs for generic conjugated estrogens.
1986: FDA announced in the Federal Register that short-acting estrogens, including Premarin, were found to be effective for preventing osteoporosis.
In the course of developing an appropriate in vitro dissolution standard for conjugated estrogens bioequivalence testing, FDA discovered that Premarin tablets are a modified release dosage form. This meant that generic copies would need to have similar modified release characteristics in order to be bioequivalent. Because of this, FDA began to require in vivo bioequivalence testing of generic conjugated estrogens products to demonstrate bioequivalence. This again raised the question of the active ingredients in Premarin, since bioequivalence testing is ordinarily performed on the active ingredients, or active metabolites, of a product.
1989: FDA's Fertility and Maternal Health Drugs Advisory Committee considered the question of active ingredients in Premarin and could not reach a consensus on whether additional components besides sodium estrone sulfate and sodium equilin sulfate should be regarded as active ingredients.
February 1990: FDA published a proposal to withdraw generic forms of conjugated estrogens tablets due to the potential for bioinequivalence and consequent concerns about safety and efficacy.
May 1990: A subcommittee of the Fertility and Maternal Health Drugs Advisory Committee could not reach a consensus on whether any of Premarin's ingredients besides estrone sulfate and equilin sulfate should be regarded as active ingredients.
February 1991: At a meeting to consider issues of pharmaceutical equivalence and bioequivalence for conjugated estrogens, FDA's Generic Drugs Advisory Committee endorsed the agency's proposal to include three additional estrogens in Premarin as concomitant components in the USP monograph for conjugated estrogens.
1991: FDA withdrew approval of all ANDAs for conjugated estrogens tablets.
1992: The USP monograph was amended to include three additional estrogens as concomitant components, as endorsed by FDA's Generic Drugs Advisory Committee.
1994: ANDA for conjugated estrogens tablets was submitted to FDA.
November 1994: Wyeth-Ayerst filed a citizen petition requesting the agency designate delta (8,9) dehydroestrone sulfate (DHES) a concomitant component of conjugated estrogens and that FDA not approve any generic versions lacking this component.
1995: Another ANDA for conjugated estrogens tablets was submitted to FDA.
July 1995: FDA's Fertility and Maternal Health Drugs Advisory Committee discussed the composition of conjugated estrogens and concluded that not enough data were available to determine whether or not components besides estrone sulfate and equilin sulfate must be present in order for Premarin to achieve its established levels of efficacy and safety.
November 1996: CDER made available for public comment its preliminary analysis of the composition of conjugated estrogens. The document summarized certain of the relevant data available to CDER regarding the composition of conjugated estrogens, provided data analyses that CDER had performed, identified areas where additional data would be needed to support definitive conclusions, and requested comment on CDER's preliminary analysis and submission of any data pertinent to the issues raised in this analysis.
May 1997: CDER's Ad Hoc Working Group on Conjugated Estrogens submitted to the CDER Director its report on the composition of conjugated estrogens and their clinical effects, including findings of the most recent studies, to the CDER director.
May 1997: CDER announced that it will not approve synthetic generic forms of Premarin at this time because they have not been shown to have the same active ingredients, and therefore to work the same, as the original drug in treating menopausal symptoms and in preventing osteoporosis.