Over the years, considerable controversy has surrounded the required composition and testing of generic conjugated estrogens. FDA's Center for Drug Evaluation and Research (CDER) announced today that it will not approve synthetic generic forms of the estrogen-replacement drug Premarin at this time because they have not been shown to contain the same active ingredients, and therefore to work the same, as the reference listed drug Premarin in treating menopausal symptoms and preventing osteoporosis.
Premarin, the brand name for currently marketed conjugated estrogens in the United States, is used to treat symptoms of menopause and to prevent osteoporosis and is the most widely-prescribed medication in the United States. Approval of a generic version of Premarin would result in significant cost savings for American women, an outcome strongly supported by the FDA. CDER finds, however, the active ingredients in Premarin have not yet been confidently defined; therefore, a generic synthetic version cannot be approved at this time.
The Federal Food, Drug, and Cosmetic (FD&C) Act requires that generic copies contain, among other things, the same active ingredients as the reference listed drug. This requirement, paired with a demonstration of bioequivalence -- a showing that the generic drug is absorbed and used by the body in the same way as the brand name drug -- provides assurance that the generic copy will be as safe and effective as the reference listed drug, whose safety and effectiveness have been demonstrated through clinical trials. Because generic drug manufacturers do not have to repeat the clinical studies used to develop the original drug, assurance that generic copies have the same active ingredients as the reference listed drug is a crucial aspect of the scientific basis for their approval for marketing.
Premarin is derived from the urine of pregnant mares and contains several different estrogens. Precisely how these various estrogens contribute to the drug=s effectiveness has not been definitively determined. The drug=s approval in 1942 predated the current requirements for such comprehensive analysis of products under review for marketing approval. At that time, Premarin's approval was based on acceptable chemistry, manufacturing, and controls information and a showing, from reports of clinical investigations, that the drug was safe for its intended use in the treatment of menopausal symptoms and related conditions.
In 1942, Premarin was known to contain two estrogens, estrone and equilin, and it was known that additional estrogens were present in smaller amounts. In 1970, the United States Pharmacopeia (USP) published in monographs the first compendial standards for conjugated estrogens and conjugated estrogens tablets, describing conjugated estrogens as containing sodium estrone sulfate and sodium equilin sulfate.
Little data were available when the first monographs were published on the detailed composition of Premarin or the pharmacologic activity of its components. The scientific belief at the time was that all estrogens were similar in their pharmacologic actions on the body and, therefore, the pharmacologic activity of an estrogen preparation could be described in terms of its total estrogenic potency. The effects of different estrogens in a mixture were believed to be additive and the identity of any particular estrogen contributing to the estrogenic potency was not considered crucial. Much of the data available at the time indicated that many compounds found in Premarin were present in small amounts and had weak estrogenic activity.
Furthermore, based on the results of early studies, including studies of Premarin, the effects of estrogen on bone mineral density appeared to have a very steep dose-response relationship, and the 0.625 mg dose of Premarin appeared to be near the top of the dose response curve. Therefore, small differences in the estrogenic potency of conjugated estrogens preparations, resulting from omission of components from generic copies, would not be clinically meaningful.
Thus, although FDA's Scientific Advisory Committees failed to provide definitive advice on the issue of Premarin's active ingredients, FDA continued to support the position taken that the ingredients sodium estrone sulfate and sodium equilin sulfate were the sole active ingredients in Premarin.
Over the past several years, emerging scientific evidence demonstrates that, for a number of reasons (e.g., variable pharmacokinetics, tissue metabolism, and tissue-specific receptor factors) all estrogens do not uniformly exert their effects on different target tissues. One estrogen can be more active than another in a specific tissue or organ, such as breast, uterus, or bone. This finding leads to the conclusion that the active ingredients in Premarin cannot be defined solely in terms of overall estrogenic potency in any single system, but must be defined based upon their contribution to particular estrogenic effects.
Compositional analysis of Premarin using modern analytical techniques demonstrates that it consists of a mixture of a substantial number of compounds with potential pharmacologic activity. In fact, the steroidal content of Premarin has not been completely defined. Undoubtedly, many of the compounds present in Premarin do not provide a clinically meaningful contribution to the therapeutic effects of the drug and are best thought of as impurities. However, the clinical tests, on which the findings of the safety and efficacy of Premarin were based, were performed on the entire mixture, not on individual components. A basic understanding of Premarin's chemical composition must be achieved as a first step in adequately characterizing the product, unless a complete understanding of which components provide a clinically meaningful contribution to the therapeutic effects of the product is achieved by clinical trials alone.
New clinical studies emphasize the importance of adequately characterizing Premarin. These studies have clearly demonstrated a dose-response relationship between estrogen administration and bone mineral density in postmenopausal women. For the osteoporosis indication, it is important that synthetic generic conjugated estrogens based on Premarin have estrogenic potency that is identical to Premarin.
Highly illustrative of the need for further characterization of Premarin are the recent findings regarding the estrogen compound delta (8,9) dehydroestrone sulfate (DHES). This compound, first detected in Premarin in 1975, represents only a small percentage (4.4%) of the estrogenic compounds present in the product. Recent pharmacokinetic studies demonstrate that, after single or repeated oral dosing of Premarin in women, the plasma concentration of the metabolite of DHES is approximately 34% of the combined concentration of the metabolites of the active ingredients estrone and equilin or 26% of the metabolites from the three estrogens. These pharmacokinetic data do not themselves prove that the DHES in Premarin makes a clinically meaningful contribution to the therapeutic effect of Premarin. However, preliminary clinical studies indicate that the potency of DHES may be similar to that of equilin. The finding that a low level (5%) component in the tablet would generate a significant concentration of a potentially active metabolite was completely unexpected and illustrates the longstanding inadequate characterization of Premarin.
CDER concludes that the reference listed drug Premarin is not adequately characterized at this time. In particular, the estrogenic potency of the product is not clearly defined relative to the estrogenic potency of its constituents. In addition, the contribution of the two most abundant estrogens, sodium equilin sulfate and sodium estrone sulfate, to the overall estrogenic potency is not well understood. Furthermore, the quantitative composition of Premarin with respect to potentially pharmacologically active components has not been defined. Without this information, it is not possible to define the active ingredients of Premarin.
Investigations designed to produce the scientific data needed to determine the active ingredients in Premarin are feasible. Such information would allow a determination of which components of Premarin make a clinically meaningful contribution to its overall effects. It is both feasible and desirable for the constituent active ingredients in Premarin to be characterized to this extent and Wyeth-Ayerst has committed to so characterize the active ingredients in Premarin.
A number of approved drug products, including piperazine estrone sulfate, micronized estradiol, and transdermal estradiol patches, are approved for the same indications as Premarin. Although the label indications of these products are very similar, they do not contain the same active ingredients as Premarin, nor could they be said to be the same as, or interchangeable with, Premarin. In fact, these products have differences in estrogenic potency and pharmacodynamic profiles. For approval of a generic product, the legal and scientific test is not whether the generic product would result in the same clinical effects as the innovator, but rather whether the active ingredients in the generic product are the same.
There are important public policy considerations behind these requirements and the manner in which generic drugs are regulated by the FDA. Health care providers are aware of and rely upon FDA's determinations of therapeutic equivalence and interchangeability. The FDA publishes in the Orange Book the therapeutic equivalence ratings for reference listed drugs and their generic copies. Drug products that are rated as AB are considered to be therapeutically equivalent and health care providers may confidently substitute the generic product for the reference listed drug relying on the fact that their safety and effectiveness should be the same. As a consequence of the purchasing arrangements of their health care plans as well as State substitution laws, consumers are often involuntarily transferred from one brand of a product to another that is AB rated. The public expects that drugs that are rated as therapeutically equivalent will provide the same amounts of the same active ingredients as the reference listed drug.
The Agency stands firmly behind the quality of its generic drugs program. Decisions on bioequivalence of generic drugs must remain supported by strong and current science. Such decisions allow the American public to maintain complete confidence in the safety and effectiveness of generic drugs.
[Last update: July 7, 2005]