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.
