42562 Federal Register / Vol. 62, No. 152 / Thursday, August 7, 1997 / Notices

The agency bases this estimate on Management Branch (HFA–305), Food synthetic generic version of Premarin fiscal year 1995 data in which each and Drug Administration, 12420 should not be approved until the active notice of participation filed took an Parklawn Dr., rm. 1–23, Rockville, MD ingredients of Premarin have been estimated 3 hours to complete. 20857. sufficiently well defined to permit an Dated: July 31, 1997. FOR FURTHER INFORMATION CONTACT: ANDA applicant to show that a William K. Hubbard, Carol E. Drew, Center for Drug synthetic generic form of Premarin has Associate Commissioner for Policy Evaluation and Research (HFD–7), Food the same active ingredients. In the not Coordination. and Drug Administration, 5600 Fishers approvable letters of May 5, 1997, CDER [FR Doc. 97–20870 Filed 8–6–97; 8:45 am] Lane, Rockville, MD 20857, 301–594– notified Duramed and Barr that they 2041. BILLING CODE 4160±01±F each had the option to amend or SUPPLEMENTARY INFORMATION: withdraw their respective ANDA’s under § 314.120, or request an DEPARTMENT OF HEALTH AND I. Background opportunity for a hearing under HUMAN SERVICES Both Duramed and Barr have § 314.200 (21 CFR 314.200). submitted ANDA’s for synthetic In response to CDER’s not approvable Food and Drug Administration conjugated estrogens tablets intended letter, Duramed submitted an initial [Docket No. 97N±0325] for estrogen replacement to treat response on May 15, 1997, and under symptoms of menopause or to prevent § 314.120(a)(5), requested a 30-day Duramed Pharmaceuticals, Inc., and osteoporosis. The reference listed drug extension of time to respond pending for this product is Premarin, Barr Laboratories, Inc.; Conjugated review by its scientific and medical Estrogens Tablets; Proposal to Refuse manufactured by Wyeth-Ayerst, and personnel of the not approvable letter to Approve Two Abbreviated New Drug derived from a natural source material, and other information. Applications; Opportunity for a the urine of pregnant mares. Hearing On September 26, 1994, Duramed In a letter dated June 13, 1997, submitted ANDA 40–115 for Cenestin Duramed requested the opportunity for AGENCY: Food and Drug Administration, (conjugated estrogens tablets) under a hearing under § 314.120(a)(3) on the HHS. section 505 (j) of the Federal Food, question of whether there are grounds ACTION: Notice. Drug, and Cosmetic Act (the act) (21 for denying approval of ANDA 40–115. U.S.C. 355(j)). Duramed filed SUMMARY: The Center for Drug On June 26, 1997, CDER issued a amendments to this ANDA on March 7 response to Duramed’s May 15, 1997, Evaluation and Research (CDER) is and 25, 1996; April 2 and 3, 1996; May proposing to refuse to approve two letter documenting CDER’s decision to 9 and 14, 1996; June 28, 1996; July 12, honor Duramed’s request for an abbreviated new drug applications 1996; August 14, 15, 19, and 29, 1996; extension contingent upon Duramed’s (ANDA’s) for synthetic conjugated October 8 and 9, 1996; December 17, agreement, under § 314.120(a)(3), that estrogens tablets. Conjugated estrogens 1996; January 23 and 31, 1997; and CDER would have until August 8, 1997, tablets are intended for estrogen February 14, 1997. On May 5, 1997, in replacement to treat symptoms of accordance with § 314.120 (21 CFR to give written notice of an opportunity menopause or to prevent osteoporosis. 314.120), CDER notified Duramed by for a hearing to Duramed, under ANDA 40–115 (Cenestin, conjugated letter that Duramed’s ANDA was not § 314.200, on the question of whether estrogens tablets, 0.3 milligrams (mg), approvable under section 505 there are grounds for refusing to 0.625 mg, 0.9 mg, 1.25 mg, and 2.5 mg) (j)(2)(A)(ii)(II) and (j)(3)(C)(ii) because approve the ANDA. has been submitted by Duramed the ANDA was insufficient to show that On May 15, 1997, Barr submitted a Pharmaceuticals, Inc., 5040 Lester Rd., the active ingredients of the proposed letter to FDA requesting a 60-day Cincinnati, OH 45213 (Duramed). generic drug product were the same as extension to respond to the not ANDA 40–154 (conjugated estrogens the active ingredients of the reference approvable letter dated May 5, 1997. On tablets, 0.625 mg and 1.25 mg) has been listed drug. submitted by Barr Laboratories, Inc., 2 July 3, 1997, CDER issued a letter On July 20, 1995, Barr submitted granting Barr’s May 15, 1997, request for Quaker Rd., Pomona, NY, 10970 (Barr). ANDA 40–154 for conjugated estrogens Food and Drug Administration (FDA) is an extension contingent on Barr’s tablets under section 505(j) of the act. agreement that FDA would have 50 days offering Duramed and Barr an Barr filed amendments to this ANDA on opportunity for a hearing on the from the date of Barr’s request for the May 13, 1996, and November 14 and 18, opportunity for a hearing to provide proposal. The primary basis for CDER’s 1996. On May 5, 1997, in accordance proposed refusal to approve the ANDA’s written notice of an opportunity for a with § 314.120, CDER notified Barr by hearing. Barr submitted a letter to FDA is the agency’s conclusion that there is letter that Barr’s ANDA was not insufficient information to show that the on July 7, 1997, requesting an approvable under section 505 opportunity for a hearing on the not active ingredients of synthetic (j)(2)(A)(ii)(II) and (j)(3)(C)(ii) of the act conjugated estrogens tablets are the approvable letter and agreeing to the because the ANDA was insufficient to condition that FDA would have 50 days same as the active ingredients of the show that the active ingredients of the from July 7, 1997, to respond. reference listed drug. proposed generic drug product were the DATES: A hearing request is due on or same as the active ingredients of the This notice includes CDER’s proposed before September 8, 1997; data and reference listed drug. order to refuse to approve the Barr and information in support of the hearing CDER attached a detailed Duramed ANDA’s for synthetic request are due on or before October 6, memorandum to the not approvable conjugated estrogens drug products and 1997. letters issued to both Duramed and Barr. responds to both Duramed’s and Barr’s ADDRESSES: A request for hearing, This memo, from the CDER Director to requests for an opportunity for a hearing supporting data, and other comments the Director of the Office of Generic on the question of whether there are are to be identified with Docket No. Drugs, outlined the legal and scientific grounds for refusing to approve those 97N–0325 and submitted to the Dockets rationale for CDER’s position that a ANDA’s. Federal Register / Vol. 62, No. 152 / Thursday, August 7, 1997 / Notices 42563

II. Regulatory History of Conjugated abundant estrogen, had little clinical In 1980, FDA published the first Estrogens activity (Ref. 6). version of the document now known as With the publication of the the Approved Drug Products with FDA first permitted a new drug monographs in 1970, the rat potency Therapeutic Equivalence application for Premarin to become test was eliminated and replace by a Determinations, also known as the effective in 1942 under the new drug chemical assay for the two active ‘‘Orange Book’’ (Ref. 10). This document provisions of the act (Pub. L. 75–717, 52 ingredients. However, the traditional lists the FDA assignment of therapeutic Stat. 1040 (1938)), based on chemistry, strength assignment was maintained, equivalence among duplicate drug manufacturing, and controls even though the tablets contained fewer products based on available data information acceptable at that time and milligrams of sodium estrone sulfate pertaining to their pharmaceutical a showing, from reports of clinical and sodium equilin sulfate than the equivalence and bioequivalence. investigations, that the drug product milligram dose stated on the label. Existing conjugated estrogens tablet was safe for its intended use in the In 1972, FDA published an products were classified as ‘‘BS,’’ i.e., treatment of menopausal symptoms and assessment of the effectiveness of not considered therapeutically related conditions. The product was Premarin (Ref. 7). Drugs such as equivalent, because of concern that the known at that time to contain estrone Premarin that were approved prior to USP monograph specifications for and equilin, and it was known that 1962 were required to demonstrate estrone sulfate and equilin sulfate were additional estrogens were present in safety but not effectiveness at the time inadequate to ensure that products smaller amounts. The tablet strengths of approval. In 1962, enactment of the meeting the monograph standard would Harris-Kefauver amendments to the act and estrogenic potencies of Premarin necessarily produce equivalent created a requirement for a tablets were controlled using a therapeutic effects in patients (Ref. 11). demonstration of the effectiveness of colorimetric assay and a rat bioassay, The ‘‘BS’’ code is used by FDA to new drugs including new drugs indicate that drug products are not respectively, with estrone as the approved between 1938 and 1962 (Pub. reference standard. Thus, the 0.625 mg considered therapeutic equivalents due L. 87–781, 76 Stat. 780). FDA contracted to deficient drug standards. Premarin tablet was assigned this value with the National Academy of Sciences/ In 1986, FDA announced in the because it contained estrogenic potency National Research Council to carry out Federal Register that a 0.625 mg dose of that, in the rat model, was equivalent to the Drug Efficacy Study to assess the Premarin daily was found to be effective 0.625 mg of sodium estrone sulfate. evidence of effectiveness available for for prevention of osteoporosis in In 1970, the United States new drugs approved prior to 1962. FDA postmenopausal women (Ref. 12). Two Pharmacopeia (USP) published then implemented the results in an dose-response studies evaluating the monographs for conjugated estrogens effort known as the Drug Efficacy Study effect of Premarin on bone mineral and conjugated estrogens tablets, Implementation (DESI). The 1972 density had been published in the establishing the first compendial Federal Register notice announced literature (Refs. 13 and 14). standards for these products (Ref. 1). FDA’s conclusion that a number of In 1986, while developing an The USP described conjugated estrogens estrogen products, including Premarin, appropriate in vitro dissolution test as containing sodium estrone sulfate had been shown to be effective for standard for conjugated estrogens and sodium equilin sulfate.1 This menopausal symptoms (and several bioequivalence testing, FDA discovered description appears to have been based other conditions) based on the DESI that Premarin tablets were a modified on the known quantity, in Premarin, of Panel recommendations and other release dosage form (Ref. 15). This each of the two ingredients as well as available evidence. FDA also found that unexpected characteristic of the their demonstrated clinical estrogenic the listed estrogen products were Premarin formulation meant that effects (Refs. 2, 3, and 4). The two ‘‘probably effective’’ for prevention of generic copies were unlikely to be osteoporosis. For indications found to bioequivalent unless they also had compounds were known to be the most be ‘‘probably effective,’’ FDA required similar modified release characteristics. abundant estrogens in Premarin. sponsors to either submit substantial Because of this discovery, FDA changed Clinical data showing estrone to be an evidence of effectiveness or remove the the Orange Book code for generic active estrogen were available, and indication from the product labeling conjugated estrogens tablets from ‘‘BS’’ small-scale clinical studies of sodium within a certain period of time. to ‘‘BP’’ (Ref. 16). The code ‘‘BP’’ means equilin sulfate indicated that it was a In 1978, Ayerst Laboratories proposed that generic products so labeled are not more potent estrogen than estrone (Ref. that conjugated estrogens be required to considered therapeutically equivalent 6). Limited data from a study completed contain seven estrogenic components. due to a potential bioequivalence in 1963 and published in 1971 Ayerst subsequently modified this problem. FDA then began to require that α suggested that sodium 17 - proposal to request only that 17α- generic conjugated estrogens products dihydroequilin sulfate, the third most dihydroequilin be added to the existing demonstrate bioequivalence through in USP monograph (Ref. 8). In 1982, FDA vivo human subject bioequivalence 1 In the preamble to the final rule implementing and USP convened a public meeting to testing (Ref. 17). Because bioequivalence Title I of the Drug Price Competition and Patent discuss Ayerst Laboratories’ proposal testing is ordinarily performed on the Term Restoration Act of 1984, FDA stated that, that the monograph for conjugated active ingredients of a product, the although in most cases the agency will consider an α active ingredient to be the same as that of the estrogens include 17 -dihydroequilin question of the active ingredients of reference listed drug if it meets the standards of (Ref. 9). FDA stated at that time that the Premarin again was raised. identity described in the USP, ‘‘in some cases, FDA composition of conjugated estrogens In 1989, FDA’s Fertility and Maternal may prescribe additional standards that are material to an ingredient’s sameness.’’ (See 57 FR 17950 at should be determined by estrogenic Health Drugs Advisory Committee 17959, April 28, 1992). See also § 320.1(c) (21 CFR potency and that the proposed considered the question of the active 320.1(c)), which states that an identical active drug compound had low potency and likely ingredients in Premarin (Ref. 18). The ingredient may meet ‘‘identical compendial or other did not contribute to the clinical effect. Committee agreed that sodium estrone applicable standards’’ (emphasis added). FDA α applies current scientific knowledge in making its USP determined that 17 - sulfate and sodium equilin sulfate are regulatory decisions, even if that knowledge has not dihydroequilin should not be added to active ingredients, but could not reach yet been incorporated into the USP monograph. the monograph as an active ingredient. a consensus on whether or not other 42564 Federal Register / Vol. 62, No. 152 / Thursday, August 7, 1997 / Notices estrogens in Premarin were active of conjugated estrogens and prepared a on the scientific basis for CDER’s ingredients (Ref. 19). In 1990, an Ad background document for the Fertility conclusion that the ANDA’s fail to show Hoc Subcommittee of the Fertility and and Maternal Health Drugs Advisory that the active ingredients of the Maternal Health Drugs Advisory Committee. proposed generic drug products are the Committee met to consider Premarin On July 27 and 28, 1995, FDA’s same as those of the reference listed bioequivalence issues (Ref. 20). Again, Fertility and Maternal Health Drugs drug. the group agreed that the two named Advisory Committee, with active ingredients were correctly representation from FDA’s Generic A. Legal Requirements designated, but could not reach a Drugs Advisory Committee and FDA’s Under section 505(j)(2)(A)(ii)(II) of the consensus on whether additional Endocrinologic and Metabolic Drugs act, an ANDA for a drug product with components should be regarded as Advisory Committee, heard more than a single ingredient must active ingredients (Ref. 21). presentations and discussions on the include information to show that the In 1990, FDA published a proposal to composition of conjugated estrogens active ingredients of the drug that is the withdraw approval of the ‘‘BP’’ coded (Ref. 33). At the end of the deliberations, subject of the ANDA are the same as generic conjugated estrogens in answer to questions regarding what those in the reference listed drug, except formulations for which therapeutic additional components, if any, beyond for any different active ingredient for equivalence could not be ensured (Ref. the two recognized active ingredients which a petition was approved under 22). The proposal included withdrawing contribute to the clinical safety and section 505(j)(2)(c) of the act. all generic conjugated estrogens effectiveness of Premarin, the Furthermore, under section 505(j)(3)(J) marketed at that time. The agency Committee voted unanimously in favor of the act and § 314.127(a)(12) (21 CFR withdrew approval for these products in of the following statement: 314.127(a)(12)), FDA is required to 1991, and there are currently no The Committee feels that insufficient data refuse to approve any ANDA that fails approved generic conjugated estrogens were presented to determine whether or not to include such information. In tablets on the U.S. market (Refs. 23 and any individual component of Premarin or addition, under § 314.127(a)(3)(ii), 24). any combination of components in Premarin which implements section In February 1991, FDA’s Generic other than estrone sulfate and equilin sulfate 505(j)(3)(C)(ii) of the act, FDA is Drugs Advisory Committee met to must be present in order for Premarin to required to refuse to approve an ANDA consider issues of pharmaceutical achieve its established levels of efficacy and if ‘‘information submitted with the safety [emphasis added]. equivalence and bioequivalence for abbreviated new drug application is conjugated estrogens (Ref. 25). FDA (Ref. 34). insufficient to show that the active proposed to the committee that three of On November 1, 1996, FDA ingredients are the same as the active the additional estrogens in Premarin be completed a ‘‘Preliminary Analysis of ingredients of the reference listed drug.’’ recommended for inclusion as Scientific Data on the Composition of Under 21 CFR 314.92(a)(1), the term ‘‘concomitant components’’ in the USP Conjugated Estrogens’ (Ref. 35). ‘‘same as’’ is defined as ‘‘identical in monograph for conjugated estrogens On May 1, 1997, the Ad Hoc active ingredient(s)’’ (Ref. 40). The term (Refs. 26 and 27). These particular Conjugated Estrogens Working Group ‘‘active ingredient’’ is defined under 21 ‘‘concomitant components’’ would be completed its final report providing a CFR 60.3(b)(2) and 210.3(b)(7) as required to be in the product, but would scientific clarity background for CDER’s follows: not be considered active ingredients decision regarding the composition of and, thus, would not need to be conjugated estrogens (Ref. 36). [A]ny component that is intended to The regulatory history of conjugated furnish pharmacological activity or other included in bioequivalence testing (Ref. direct effect in the diagnosis, cure, 28). The Generic Drugs Advisory estrogens reflects the complexity of the mitigation, treatment, or prevention of Committee endorsed this proposal (Ref. scientific issues involved. FDA’s disease, or to affect the structure or any 29). Subsequently, the USP monographs positions on these issues have evolved function of the body of man or other animals. over time as new information has on conjugated estrogens were amended In the context of ANDA approvals, a become available. As with any such to include the three additional generic product with the same active ‘‘concomitant components’’ (Ref. 30). complicated scientific issue, differences ingredients as the reference listed drug On November 30, 1994, Wyeth-Ayerst in scientific opinion arose and continue that is shown to be bioequivalent is submitted a citizen petition requesting, to exist concerning how available data approved without independent among other things, that FDA not are to be interpreted and applied in the effectiveness data.2 To meet the approve any generic conjugated regulatory context. These differing definition of an active ingredient, a estrogens products that do not contain views (Refs. 37, 38, and 39) were component must be intended to furnish the compound sodium ‘‘8,9- considered prior to this proposed order sufficient pharmacological activity, or dehydroestrone sulfate (DHES) (Ref. 31). refusing to approve the two ANDA’s for other direct effect, to have some Wyeth-Ayerst also submitted a petition synthetic conjugated estrogens therapeutic effect (i.e., to diagnose, cure, for a stay of action requesting that FDA identified above. stay any decision to ‘‘receive’’ an ANDA mitigate, treat, or prevent disease, or to for a conjugated estrogens product that III. The Deficiencies in ANDA 40–115 affect the structure or function of the does not contain DHES and stay any and ANDA 40–154 body). An active ingredient performs a approval of such an application until The primary basis of this proposed drug’s therapeutic functions. The FDA responds to the petition (Ref. 32). order refusing to approve ANDA 40–115 definition of ‘‘pharmaceutical Because of the complex scientific and ANDA 40–154 is that these ANDA’s 2 In enacting the Drug Price Competition and issues associated with determining the fail to provide sufficient information to Patent Term Restoration Act of 1984, Congress active ingredients of conjugated show that the active ingredients of the intended that no safety or effectiveness data beyond estrogens, in the summer of 1995, CDER proposed generic drug products are the that developed by the innovator company be formed an Ad Hoc Conjugated Estrogens same as the active ingredients of the needed to support approval of the generic product. (See H. Rept. 857 (Part I), 98th Cong., 2d sess. 14, Working Group to consider these issues. reference listed drug. Below is a 16–17 (1984).) The interpretation of the active That group of CDER staff examined summary of the applicable legal ingredient definition in this notice is intended available data related to the composition requirements and a detailed statement solely as applied to ANDA approval. Federal Register / Vol. 62, No. 152 / Thursday, August 7, 1997 / Notices 42565 equivalents’’ in § 320.1(c) is consistent be described in terms of its total all of its active ingredients, for the with this definition of active ingredient estrogenic potency. It was believed that reasons that follow below. in that it focuses on the therapeutic the effects of different estrogens in a Emerging scientific evidence moiety: mixture were additive and that the demonstrates that all estrogens do not Pharmaceutical equivalents means drug identity of the particular estrogen exert their effects in a uniform manner products that contain identical amounts of contributing the estrogenic potency was with respect to different target tissues. the identical active drug ingredients, i.e., the not crucial. Epidemiologic data did not These differential effects may be due to same salt or ester of the same therapeutic reveal safety or effectiveness differences variable pharmacokinetics, 3 tissue moiety * * * that meet identical compendial among various estrogen preparations metabolism, tissue-specific receptor or other applicable standard of identity, used for hormone replacement therapy. factors, or additional reasons (Refs. 45, strength, quality, and purity, * ** As a result, Premarin had historically 46, 47, 48, 49, and 50). For example, disintegration times and/or dissolution rates. been defined in terms of total estrogenic clinical studies have shown that the Consequently, not all components potency rather than the sum of the potency of equilin sulfate relative to that ‘‘furnish pharmacological activity potencies of various components. In estrone sulfate varies depending on the or other direct effect’’ meet the 1970, when the first USP monograph pharmacodynamic 4 effect being studied definition of an active ingredient. A was published, little information was (Refs. 6 and 51). A dose of equilin component may be considered an active available on the effects of estrogens on sulfate that is equipotent to estrone ingredient only if it provides a clinically bone, and the estimates of estrogenic sulfate using one parameter may be meaningful contribution to the potency of Premarin components were more or less potent when evaluated therapeutic effect of the drug. A derived from clinical studies of using a different measure. For this subjective intent for a component to menopausal symptoms. Much of reason, the active ingredients of have such effect will not suffice in the Premarin’s estrogenic potency for Premarin cannot be defined solely in absence of objective evidence of a menopausal symptoms can be attributed terms of overall estrogenic potency in clinically meaningful contribution. (Cf. to the effects of estrone and equilin. any single system, but must be defined 21 CFR 201.128 (defining intended Available data on the detailed based on their contributions to use).) In most cases it will be clear what composition of Premarin and the particular estrogenic effects. components of a drug make clinically pharmacologic activity of its Put simply, the new scientific meaningful contributions to the drug’s components were limited. Much of the evidence shows that one estrogen can be therapeutic effects and, therefore, are available data indicated that many more active than another in a specific the drug’s active ingredients. However, compounds found in Premarin were tissue or organ, such as breast, uterus, where FDA has determined there is present in small amounts and had weak or bone. The most striking example of sufficient evidence that a component in estrogenic activity. this is the synthetic estrogen analog Based on the results of early studies, the reference listed drug may make a tamoxifen, which blocks estrogen including studies of Premarin, the clinically meaningful contribution to actions in breast tissue, but has effects of estrogen on bone mineral the therapeutic effect, the agency cannot estrogen-like activity on bone. These density appeared to have a very steep approve a synthetic generic version of new findings have stimulated extensive dose-response relationship, and the the drug that does not include such research into new pharmaceuticals that 0.625 mg dose of Premarin appeared to could have selective actions on specific component until it has been determined be near the top of the dose-response tissues and thus might provide whether the component makes such a curve. Therefore, it was believed that beneficial hormone replacement therapy contribution. small differences in the estrogenic As discussed below, Duramed’s without some of the undesirable side potency of conjugated estrogens ANDA 40–115 and Barr’s ANDA 40–154 effects, or could be useful in the preparations, resulting from omission of treatment of cancer or other conditions. provide insufficient information to components from generic copies, would Compositional analysis of Premarin show that the active ingredients of their not be clinically meaningful. using modern analytical techniques conjugated estrogens tablets are the In addition, the monograph ranges for demonstrates that it consists of a same as the active ingredients of the the content of sodium estrone sulfate mixture of a substantial number of reference listed drug, Premarin. and sodium equilin sulfate in compounds with potential B. Active Ingredients of Premarin Are conjugated estrogens are wide (Ref. 43). pharmacologic activity. In fact, the Not Fully Characterized Therefore, it was believed that minor steroidal content of Premarin has not differences in estrogen content between been completely defined (Ref. 52). 1. CDER’s Historical Position on the synthetic generic products and Premarin Undoubtedly, many of the compounds Active Ingredients of Premarin due to the absence in the generic copies present in Premarin do not provide a Although FDA’s Scientific Advisory of several minor Premarin constituents clinically meaningful contribution to Committees were unable to provide could not make a clinically meaningful the therapeutic effects of the drug and definitive advice on this issue, FDA difference. are best thought of as impurities. continued to support the position taken Note: the percent coefficient of However, the clinical tests, on which in the 1970 USP monograph (Ref. 41) variation of sodium estrone sulfate is the findings of the safety and efficacy of that the ingredients sodium estrone 1.98, and of sodium equilin sulfate is Premarin were based, were performed sulfate and sodium equilin sulfate are 3.01, based on percent estrogen on the entire mixture, not on individual the sole active ingredients in Premarin. composition in 500 batches of Premarin components. A basic understanding of The reasons for this position follow Tablets (Ref. 44). the chemical composition of Premarin below (Ref. 42). must be achieved as a first step in Scientific belief had been that all 2. CDER’s Current Position on estrogens were similar in their Premarin’s Active Ingredients 3 Pharmacokinetics can be defined as drug pharmacologic actions on the body, i.e., CDER’s current position on absorption, excretion, metabolism, or distribution. 4 Pharmacodynamics can be defined as a ‘‘an estrogen is an estrogen.’’ Therefore, Premarin’s active ingredients is that pharmacologic or clinical response to a given it was thought that the pharmacologic Premarin is not sufficiently concentration [of a drug] in blood or other tissue (58 activity of an estrogen preparation could characterized at this time to determine FR 39406 at 39409 (July 22, 1993)). 42566 Federal Register / Vol. 62, No. 152 / Thursday, August 7, 1997 / Notices adequately characterizing the product sulfate content of a 0.625 mg tablet is possible to define the active ingredients unless a complete understanding of about 0.03 mg or approximately 5 of a product that is adequately which components provide a percent of label claim.) Until recently characterized. meaningful clinical contribution to the little has been known about DHES or There are at least two possible ways β > effects of the product is achieved by sodium 17 - 8,9-dehydroestradiol to characterize a product. The most clinical trials alone. sulfate. straightforward method includes, first, Clinical studies have revealed that the Pharmacokinetic studies submitted by assigned potencies of Premarin tablets, Wyeth-Ayerst demonstrate that, after chemical analysis to determine what which were based on the rat bioassay, single or repeated oral dosing of components are present at significant do not correctly reflect the tablets’ Premarin in women, the plasma levels in the product. The interpretation relative potencies in human studies concentrations or areas under the curve of ‘‘significant levels’’ cannot be exact (Refs. 6, 50, 51, and 53). For example, (AUC’s) of the (conjugated plus and would depend on the specific clinical studies have shown that unconjugated) 17β->8,9- product; however, it is desirable that Premarin is between 1.4 and 2.5 times dehydroestradiol metabolite of DHES components present at the 0.1 percent more potent than estrone sulfate for are the same order of magnitude as the level or greater be identified and suppression of follicle-stimulating concentration of the 17β-diol quantified. Once the components of the hormone (FSH) and menopausal metabolites of the active ingredients product are identified, the next step in symptoms in postmenopausal women estrone and equilin (Refs. 59, 60, and characterization would be to determine (Refs. 6 and 50). Because the human 61). The 17β >8,9-estradiol which of them have potential human studies evaluating the relative potency concentration is approximately 34 pharmacologic activity. Such a of Premarin have been small, a precise percent of the combined concentrations determination may be based on the estimate of the estrogenic potency of of the 17β-diol metabolites of estrone following: The quantitative amount in Premarin relative to estrone sulfate has and equilin, or 26 percent of the 17β- the product, structure-function not been determined. Because the diol metabolites from the three relationships, in vitro tests, animal relative potencies of Premarin, estrone estrogens. The finding that a low-level studies, human studies, or a sulfate, and equilin sulfate are not (5 percent) component of the tablet combination of these. Finally, for clearly established, it is not possible to would generate a significant components that may contribute to the tell how much of the effect of Premarin concentration of a potentially active therapeutic effect based on potential can be accounted for by the effects of metabolite was completely unexpected pharmacologic activity, a study could be equilin sulfate and estrone sulfate. and illustrates the longstanding conducted comparing the effects of each Measuring these effects is further inadequate characterization of Premarin. component alone, and in combination complicated by the fact that the These pharmacokinetic data do not with additional components, to the importance or contribution of each themselves prove that the DHES in effects of the entire product, to ingredient may depend on the tissue Premarin makes a clinically meaningful demonstrate that the ‘‘candidate’’ that is being tested, e.g., bone, breast, contribution to the therapeutic effect of components achieved all of the pituitary, or uterus. Premarin. However, preliminary clinical therapeutic effects of the product. New clinical studies have clearly studies indicate that the potency of demonstrated that there is a dose- DHES may be similar to that of equilin. Alternatively, in cases where there is response relationship between estrogen (See detailed discussion below.) some confidence that the ‘‘candidate’’ administration and bone mineral Based on this new scientific active ingredients have all been density in postmenopausal women information, CDER concludes that identified, even though the product is (Refs. 54 and 55). It follows that Premarin is not adequately not fully chemically characterized, a ensuring an equivalent estrogenic characterized and that, therefore, at this head-to-head comparative dose- potency is important in the approval of time, its active ingredients cannot be response clinical trial(s) comparing the generic copies of estrogen products fully determined. Additional effects of the combined ‘‘candidate’’ intended for prevention of osteoporosis. information on both composition and active ingredients against the original In other words, it is important for the relative potencies of components will be product could, if carried out carefully, osteoporosis indication that synthetic necessary to adequately characterize demonstrate that the combination generic conjugated estrogens based on this product. This conclusion is in contributed all the clinically meaningful Premarin have estrogenic strength that agreement with the findings of FDA’s therapeutic effects of the original is identical to the Premarin tablet. Fertility and Maternal Health Advisory product. This approach might not The recent findings with regard to Committee at its July 27 and 28, 1995, clearly identify which of the >8,9-dehydroestrone sulfate (DHES) meeting on this subject (Ref. 33). ‘‘candidates’’ were actually active, but illustrate a number of the above points. could ensure that the combination This compound was first detected in 3. Unresolved Issues Concerning the Current Characterization of Premarin tested included all of the active Premarin in 1975 (Refs. 56 and 57). ingredients in the product. DHES represents only a small At the time of marketing, products percentage of the estrogenic compounds such as Premarin, that are derived from The following sections discuss the present in the product: 4.4 percent of natural source material, frequently are available scientific evidence on the the ‘‘label claim’’ (i.e., 4.4 percent of not characterized as completely as characterization of Premarin. 0.625 mg or approximately 0.0275 mg of synthetic products would be. The term a. Composition of Premarin. At least DHES per 0.625 mg tablet). (Note: ‘‘adequate characterization’’ is intended ten estrogenic compounds have been Premarin also contains a small amount to mean an amount of scientific identified and quantified in Premarin. of the DHES metabolite sodium 17β- information on a product that is The composition data for the 10 >8,9-dehydroestradiol sulfate (Ref. 58). sufficient to determine what estrogenic compounds cited in the This metabolite comprises constituents in the product are Conjugated Estrogens USP monograph, approximately 0.003 mg per 0.625 mg responsible for making clinically and listed in Table 1, were generated by tablet. Therefore, the total DHES plus meaningful contributions to its CDER’s Division of Drug Analysis from sodium 17β->8,9-dehydroestradiol therapeutic effects. In other words, it is an analysis of 2 batches of Premarin Federal Register / Vol. 62, No. 152 / Thursday, August 7, 1997 / Notices 42567

0.625 mg tablets (Ref. 62). These results basis for adequate characterization of Estrogens Including ∆8,9 agree generally with other data available the product. Obtaining this information Dehydroestrone and 17β-∆8,9 to CDER. is feasible. The constituents of Premarin Dehydroestradiol,’’ dated October 25, are small molecules that can be fully 1996 (OCPB Report) (Ref. 71), and its TABLE 1.ÐCOMPOSITION DATA FOR 10 characterized by analytical chemistry, addendum dated February 12, 1997 ESTROGENIC COMPOUNDS unlike the macromolecular constituents (Addendum) (Ref. 72), and also in of most biological products, which are information submitted to the docket of Sodium estrogen sulfate Mg/tablet difficult to fully characterize due to the Wyeth-Ayerst citizen petition (Refs. biologic variability. It is desirable that 59 and 60). The OCPB Report details Estrone ...... 0.370 the components present in Premarin at Equilin ...... 0.168 plasma concentrations of estrone 17α-Dihydroequilin ...... 0.102 or above 0.1 percent be characterized sulfate, equilin sulfate, DHES, and their 17α-Estradiol ...... 0.027 and their biological activities metabolites, as well as concentrations of β determined (Ref. 68). 17 -Dihydroequilin ...... 0.011 17α-dihydroequilin, after ingestion of l7α-Dihydroequilenin ...... 0.011 It has been argued that DHES cannot 17β-Dihydroequilenin ...... 0.021 various doses of Premarin (Ref. 72). be considered an active ingredient of Additional pharmacokinetic data on Equilenin ...... 0.015 Premarin because its presence in and 17β-Estradiol ...... 0.005 Premarin components and metabolites, ∆8,9-dehydroestrone ...... 0.026 percent composition of the formulation presented in Addendum 2, dated March are not specifically controlled during 31, 1997, to the OCPB Report (Ref. 73), the manufacturing process (Ref. 69). Additional information on the and also in information submitted to the Wyeth-Ayerst has submitted data component DHES and its metabolite are docket by Wyeth-Ayerst on March 11, demonstrating that DHES is present at discussed below. Additionally, the fact 1997 (Ref. 61), confirm the original about 4.4 percent of label claim with a that Premarin contains progestational finding discussed in the OCPB Report. agents (composition unspecified) has range of 4.0 to 5 percent (based on 10 been disclosed by Wyeth-Ayerst (Ref. lots of 0.625 mg Premarin tablets) (Ref. Table 2 is derived from 63). It is known that Premarin also 70). It is desirable that any active pharmacokinetic data submitted by contains additional steroidal ingredients, once identified, be Wyeth-Ayerst based on 7-day dosing of compounds (Ref. 52). However, precise controlled during the manufacturing women with two 0.625-mg tablets daily data on Premarin’s composition are process. (Ref. 61). The steady-state AUC data are currently very limited (Refs. 64, 65, 66, b. Pharmacokinetics. Pharmacokinetic calculated from day 7 plasma sampling. and 67). data on Premarin components are Table 2 summarizes the relationships Detailed analytical information on presented in the FDA report entitled ‘‘A among oral dose, total ketone, and total Premarin’s composition is the necessary Pharmacokinetic Analysis of Conjugated diol for three estrogens.

TABLE 2.ÐRESULTS OF PHARMACOKINETIC STUDIES

Estrogen Estrone Equilin ∆8,9±DHE

Measured dose or AUC ...... mg per 2X 0.625mg tab ...... 0.740 0.336 0.052 Total plasma ketone (ng•hr/mL) ...... 94.200 43.145 13.610 Uncon.plasma ketone (ng•hr/mL) ...... 4.083 1.201 0.072 Total plasma 17βdiol (ng•hr/mL) ...... 8.565 10.623 6.624 Uncon.plasma 17βdiol (ng•hr/mL) ...... 0.659 1.060 0.331

The pharmacokinetics of Premarin trial distributes differently into its tested by estrogen receptor binding, components are complex, as revealed in derivatives in the body. This means that estrone was shown to be much less these data. Estrone, equilin, ∆8,9- each of the three estrogens might cause potent than estradiol (about 200 times dehydroestrone (DHE), their active 17β- different effects simply as a result of less), as has been previously shown by reduced metabolites, and other these distributional differences. receptor binding and cellular assays. In estrogenic components of Premarin The actual magnitude of the contrast, when potency testing was circulate in the plasma both as the contribution of each derivative of any performed in a liver (Hep-G2) cell line conjugated (primarily sulfate ester) and component estrogen to the overall using functional activation, estrone’s unconjugated derivatives and with estrogenicity of Premarin is not well potency appeared to be of the same understood. As just stated, the various degrees of protein binding, as order of magnitude as estradiol’s pharmacokinetic data show that the discussed in the OCPB Report. There is potency. The experimenters were able to interconversion between the ketone and ratios of the concentrations of the show that this increased potency of 17β-reduced forms of each estrogen and different derivatives are distributed estrone resulted from its conversion to among the conjugated and unconjugated differently for those estrogens that have derivatives. The degree of protein been studied: Estrone, equilin, and DHE. estradiol by the cells. Therefore, in binding of each derivative may be If there are tissue-specific effects of tissues that have the capability to important to its clinical activity. derivatives, then the size of a metabolize ketone forms to diols (e.g., Put simply, this information shows derivative’s contribution could vary estrone to estradiol), circulating ketone that there is not a one-to-one depending on the tissue tested. The forms could make a large contribution to relationship between the amount of available data suggest that these tissue- observed effects in that tissue. Similarly, each estrogen in the tablet and the specific differences exist. For example, conversion of conjugated (sulfated) amount of active forms (derivatives) of in vitro potency data for estrone and forms of circulating estrogens to the that estrogen in the blood. Each of the 17β-estradiol were submitted by Wyeth- unconjugated forms has been shown to three estrogens evaluated in this clinical Ayerst (Ref. 74). When potency was occur in target tissues such as breast 42568 Federal Register / Vol. 62, No. 152 / Thursday, August 7, 1997 / Notices

(Ref. 75). In these tissues, total estrogen to definitively assign human clinical Varma et al. found Premarin to be twice concentrations (i.e., conjugated plus effects. The most confident conclusions as potent as estrone sulfate for unconjugated) may be more important can be drawn from human clinical endometrial changes (Ref. 81). Geola et than in tissues that cannot convert the testing. The following summarizes what al. evaluated the dose-response conjugated forms to the active, is known about the contribution of relationship between Premarin and unconjugated forms. Premarin components to its overall vaginal cytologies and concluded that One striking finding in the activity from in vitro or in vivo human 1.25 mg Premarin daily was necessary pharmacokinetic data is the differences testing. for achieving full replacement levels for in the proportions of the 17β-diol i. Pharmacodynamics. The term this parameter (Ref. 80). These studies concentrations resulting from the three ‘‘pharmacodynamics’’ refers to are not adequate for drawing firm estrogens (sodium estrone sulfate, pharmacologic or clinical responses to a conclusions about the relative sodium equilin sulfate, and DHES), given concentration of a drug in blood contributions of equilin and estrone to compared to the ratios of the three or other tissue.5 For example, raising or the effects of Premarin on uterine or estrogens in the tablet. It is known that lowering blood pressure, causing dry vaginal markers. the 17β-diol derivatives of equilin and mouth, or constricting the pupils are A number of studies of Premarin or its estrone are potent estrogens. The pharmacodynamic effects of various components have evaluated pharmacokinetic data as a whole show drugs. Pharmacodynamic effects can be pharmacodynamic markers of bone that, after dosing with Premarin, the beneficial, harmful, or neutral. The effects (Refs. 14, 51, 79, 80, and 83). plasma concentration of unconjugated benefits of most drugs derive from their Jones et al. estimated that Premarin was 17β-dihydroequilin is about twice (1.6 desired pharmacodynamic effects, while twice as potent as estrone sulfate for times) as high as the concentration of drug side effects often result from reduction of the urinary calcium/ 17β-estradiol, even though there is only undesirable pharmacodynamic activity. creatinine ratio. This ratio is a measure about half as much equilin as estrone in Premarin and its components, like of bone resorption. Geola et al. the tablet. The difference in the other estrogens, affect a wide variety of performed a dose-response study concentration of the active metabolite human tissues, including pituitary, evaluating the effect of Premarin on the may account for the known greater breast, uterus, bone, liver, and calcium/creatinine ratio, and found that clinical estrogenic potency of equilin. endothelium (Ref. 47). Some of these 0.3 mg Premarin was the lowest dose to As discussed above, an unexpected actions result in the beneficial effects of have a significant effect. Lobo et al. finding from the pharmacokinetic data the drug, some cause side effects, and found that Premarin was twice as potent in the Missouri study (Ref. 61), the most some (for example, cardiovascular or as both estrone sulfate and equilin reliable data generated to date, was that lipoprotein effects) have not been sulfate for reduction of the urinary the plasma concentration of definitively evaluated. There are studies calcium/creatinine ratio. The Lobo unconjugated 17β-∆8,9-dehydroestradiol in the literature of effects of estrogen on finding of a significant effect of 0.3 mg is about half the concentration of each of these tissues, especially effects Premarin was not duplicated in a larger unconjugated 17β-estradiol, even on the pituitary, uterus, and bone. This study by Lindsay et al. (Ref. 14). though there is more than 10 times more section discusses the pharmacodynamic Because of limitations in study designs estrone sulfate than DHES in Premarin. effects of Premarin and its components and because the pharmacodynamic This may account for the high oral other than the relief of menopausal markers for bone are not sufficiently potency of DHES that has been found in symptoms and prevention of quantitative, no conclusions about the limited clinical studies performed osteoporosis. comparative pharmacodynamic effects with this compound (Refs. 76 and 77). A dose-response relationship exists on bone of Premarin or its components Put simply, these data show that a between estrogen treatment and FSH can be drawn from these results. dose of DHES results in a much higher suppression (Ref. 79). Some Data on Premarin or Premarin blood level of the active metabolite than pharmacodynamic data on suppression component effects on lipoproteins and would result from the same dose of of FSH, including dose-response data, other plasma proteins, or other estrone sulfate. This finding alone exist for equilin sulfate, estrone sulfate, pharmacodynamic markers are quite suggests, but does not prove, that a low and Premarin (see also menopausal limited (Refs. 49, 50, 51, 53, and 84). dose of DHES could have a much larger symptoms, below) (Refs. 5, 6, 50, and Having information about these effects than expected effect. 80). In a study of suppression of urinary is important for several reasons. The above pharmacokinetic data gonadotrophins, equilin was found to be Stimulatory effects on liver proteins provide a basis for beginning to about twice as potent as Premarin and may affect drug safety. In addition, as understand the complex relationship five times more potent than estrone discussed in the OCPB Report (Ref. 71), between the composition of Premarin sulfate for this effect, while Premarin levels of circulating unconjugated and its clinical effects. However, this was 2.5 times more potent than estrone estrogens may be affected by binding to understanding is still incomplete. The sulfate (Ref. 6). In studies of human plasma proteins, particularly sex pharmacokinetics must be understood serum FSH levels, Premarin has been hormone binding globulin (SHBG). in the context of pharmacodynamic found to be about 1.4 to 2.0 times as Stimulation of SHBG could alter drug properties of the various components, potent as estrone sulfate (Refs. 50 and availability. Available data suggest that including their clinical effects. 81). These studies are in relative certain Premarin components differ in c. Clinical effects of Premarin. agreement. the ability to stimulate SHBG (Ref. 50). Premarin and certain Premarin The published data on the effects of Human pharmacodynamic data on components have been tested fairly Premarin and its components on uterine DHES submitted by Wyeth-Ayerst extensively in animals, particularly or vaginal markers are limited. Beck and demonstrated that 1.25 mg estrone rodents. Animal data, either in vitro or Friedrich found equilin sulfate to be two sulfate had a much greater effect on in vivo, have not proven to be to three times more potent than SHBG levels than did 0.125 mg DHES quantitatively predictive of the effects Premarin for effects on vaginal (Ref. 85); however, this result requires found in women (Ref. 78). Therefore, epithelium and endometrium (Ref. 82). confirmation. animal tests, while useful in screening Taken as a whole, the available compounds for activity, cannot be used 5 See footnote 3, supra. pharmacologic data demonstrate that Federal Register / Vol. 62, No. 152 / Thursday, August 7, 1997 / Notices 42569 estrone sulfate (as the piperazine salt), iii. Clinical effects: osteoporosis. (1) well with pharmacodynamic markers of equilin sulfate, and Premarin have Use of surrogate markers. The goal of beneficial bone effects. This correlation different pharmacodynamic effects preventive therapies for osteoporosis is suggests, but does not prove, that when potency on various tissues is the prevention of fractures and estrogen replacement therapies evaluated (Refs. 6, 50, 51, and 53). For deformity. For estrogens, FDA accepts achieving such levels of circulating example, in a single study, Premarin measurement of bone mineral density as estradiol may be effective in preventing was found to be 1.4 times more potent an adequate surrogate for preventing bone loss. than piperazine estrone sulfate these longer term clinical outcomes FDA does not currently accept 17β- (expressed as the sodium rather than (Ref. 87). A number of other markers for estradiol levels as an adequate surrogate piperazine salt) for FSH suppression, a evaluating pharmacodynamic effects on for osteoporosis prevention in women. pituitary effect (Ref. 50). In contrast, bone have been developed (Ref. 88). Trials of bone mineral density are Premarin was 3.5 times more potent None of these other markers is required. In addition, the available data than estrone sulfate for stimulation of sufficiently well understood or do not indicate that the potentially angiotensinogen and 3.2 times more quantitative to permit its use as a protective levels of 17β-estradiol are potent for stimulation of sex hormone surrogate for osteoporosis prevention attained after administration of binding globulin (SHBG). Presumably, effects. Therefore, in the absence of Premarin. this difference arises because other other validated surrogate markers, The Palacios study found that components of Premarin contribute to definitive data on bone effects must treatment with conjugated estrogens these effects in a manner different from come from human trials evaluating bone 0.625 mg resulted in a mean estradiol estrone sulfate. It is not known if these mineral density, fractures, and/or level of 40 pg/mL, which is below the differential pharmacodynamic effects deformity. 60 pg/mL minimum suggested by are completely attributable to the (2) Use of blood 17β-estradiol levels Reginster. However, the Librach and presence of equilin sulfate. as a surrogate marker. Comments Nickel study submitted to the docket, as In summary, the two Premarin submitted to the docket of Wyeth- well as the Reginster study and other components that have been carefully Ayerst’s citizen petition (Ref. 89), as data reported in the literature, found studied, equilin sulfate and estrone well as statements in the scientific that serum levels of 17β-estradiol above sulfate, differ from each other and from literature, assert that achievement of 60 pg/mL are achieved in women Premarin in phamacodynamic profile. It certain levels (e.g., 39 picograms (pg)/ treated with Premarin or a Canadian is not well understood which of the milliliter (mL) (Palacios et al.) or greater generic copy of Premarin (Refs. 89 and pharamcodynamic actions are desirable than 60 pg/mL (Reginster et al.)) of 91). In the Librach and Nickel study, and which contribute to unwanted side serum 17β-estradiol is an adequate women treated with Premarin achieved effects. Adequate characterization of surrogate for preservation of bone a 17β-estradiol level of 85.5 pg/mL Premarin will require an understanding, mineral density because there is a strong while women treated with the Canadian based on scientific data, of those correlation between the two both in product had mean serum levels of 94.9 Premarin components that contribute to clinical trials and in untreated pg/mL. These differences appear to the pharmacodynamic effects of perimenopausal women (Refs. 83 and relate to problems with analytical Premarin. 90). methodology, possibly due to cross- ii. Clinical effects: menopausal The study by Palacios et al. evaluated reactivity of radio-immunoassay symptoms. A number of clinical studies women who had undergone surgical reagents with other components in evaluating Premarin and Premarin menopause and who were randomized Premarin. When serum 17β-estradiol is components for the treatment of to percutaneous estradiol, conjugated measured by direct chemical means, the menopausal symptoms have been estrogens (source unspecified), or no high 17β-estradiol levels are not found performed (Refs. 79, 80, 82, and 86). therapy over 2 years. Untreated women in women treated daily with 0.625 mg Equilin sulfate has been found to be lost a mean of 9 percent of spine bone Premarin (Refs. 60 and 61). This latter about three times more potent than mineral density over 2 years, whereas finding is corroborated by data from a Premarin for alleviating vasomotor the estradiol treated group and the study of the effects of esterified symptoms (Ref. 82). The data submitted conjugated estrogens treated group estrogens (Estratab, USP) on bone by Wyeth-Ayerst on DHES show that gained 4.1 percent and 5.6 percent mineral density, which was recently DHES is more potent than estrone spinal bone mineral density presented in abstract (Ref. 92). In this sulfate for these effects, but the data are respectively. Women treated with study, daily dosing with 0.625 mg of not adequate to precisely assign a percutaneous estradiol were reported to esterified estrogens, which contains potency (Ref. 76). Without dose- have a mean serum estradiol level of approximately 0.518 mg sodium estrone response studies to determine the about 80 pg/mL over the course of the sulfate (Ref. 93) (0.625 mg Premarin potency of DHES for menopausal study. The conjugated estrogens treated contains about 0.370 mg sodium estrone symptoms relative to the potency of women had a mean serum estradiol sulfate) resulted in a mean plasma estrone sulfate and equilin sulfate, the level of about 40 pg/mL. It is not concentration of 17β-estradiol of 40 pg/ contribution of DHES to the activity of possible to conclude anything about a mL. In addition, in this same study, Premarin in treating menopausal protective level of 17β-estradiol from daily administration of 0.3 mg esterified symptoms cannot be determined. the conjugated estrogens arm of this estrogens, which contain about 0.248 Similarly, without a head-to-head study since conjugated estrogens also mg sodium estrone sulfate, resulted in a comparison of the dose-related effects of contain, at a minimum, equilin and mean plasma concentration of 26 pg/mL Premarin, estrone sulfate, and equilin possibly other components that of 17β-estradiol. These results are sulfate in the treatment of menopausal contribute to the effect on bone. The inconsistent with the serum level results symptoms, the extent of contribution of value of 80 pg/mL from the presented by Librach and Nickel, but the two components to the overall percutaneous estradiol arm is not generally agree with Palacios’ findings estrogenic potency of Premarin for this inconsistent with the data reported by and with Wyeth-Ayerst’s bioavailability effect also cannot be accurately Reginster et al. who found that data. Therefore, the available data on determined, although it is clear that circulating levels of 17β-estradiol serum 17β-estradiol levels do not both contribute. between 60 and 90 pg/mL correlated indicate that levels over 60 pg/mL are 42570 Federal Register / Vol. 62, No. 152 / Thursday, August 7, 1997 / Notices attained with the dose of Premarin also discussed in the section on and 1.25 mg, of esterified estrogen recommended for the prevention of estradiol blood levels). Estratab is a actually increased bone density over the osteoporosis. generic esterified estrogens product. 2-year period. This finding is consistent iv. Clinical effects: bone mineral Esterified estrogens USP contain sodium with other published data (Refs. 54 and density. The clinical effects of Premarin estrone sulfate and sodium equilin 61). In the case of the Solvay study, it on bone are well established. A number sulfate in different amounts than are in is not known whether, at the higher of clinical trials have confirmed the Premarin (Ref. 98) (based on doses, more women responded with effects of Premarin in preserving and presentations by Solvay, 0.300 mg of bone preservation than at lower doses, increasing bone mineral density in their esterified estrogens product or whether women who would have postmenopausal women (Refs. 13, 14, contains approximately 0.248 mg responded to 0.3 mg simply had a larger and 94). Ettinger et al. demonstrated in estrone sulfate and 0.038 mg equilin response to the higher doses. In either a nonrandomized trial that 0.3 mg sulfate) (Ref. 93). The study was a 2-year case, estrogenic potency has been Premarin, when administered with placebo controlled trial testing three shown to be important to the clinical calcium supplementation, was adequate doses of Estratab combined with effect on bone within this dose range. It to prevent bone mineral loss in the calcium supplementation in has been estimated that a proportion of spine and hip (Ref. 95). The recent Post- postmenopausal women evaluating women taking the recommended dose of menopausal Estrogens/Progestins bone mineral density and side effects. Premarin continue to lose bone mineral, Intervention (PEPI) trial demonstrated According to the abstract, all three doses even though mean values are sustained that the currently recommended 0.625 were effective at 12, 18, and 24 months or improved (Ref. 99). mg dose of Premarin resulted in an in preserving bone mineral density The finding that sodium equilin increase in bone mineral density in compared to placebo. The abstract sulfate and sodium estrone sulfate, at women treated for over 2 years, while reveals a dose response among the three the doses present in Estratab, preserve untreated women lost bone (Ref. 96). Estratab doses tested. Also significant is bone mineral density provides support Estrone is approved as a single the fact that the lowest dose tested, 0.3 for the proposition that equilin estrogen (marketed under the brand mg Estratab, appeared to be effective in contributes to the bone preservation name Ogen by Upjohn, generic name preserving bone mineral density when effects of Premarin. However, as estropipate), but as a different salt from given continuously in conjunction with discussed at the beginning of this the estrone in Premarin (the piperazine calcium supplementation. There are memorandum, the requirement for rather than the sodium salt of estrone lower amounts of both estrone sulfate approval of an ANDA is not that generic sulfate) for the treatment of menopausal and equilin sulfate in this dose of drugs have effects similar to the symptoms and the prevention of Estratab than are required to be in the reference listed drug but, rather, that osteoporosis. The recommended dose 0.625 mg tablet of generic conjugated they have the same active ingredients. for osteoporosis is 0.75 mg of estrogens according to the current Only if the active ingredients are the estropipate, which is equivalent to 0.625 conjugated estrogens USP monograph. same can generic copies be relied upon mg sodium estrone sulfate. A dose- Therefore, if the data in the abstract are to have the same estrogenic potency response study has shown that a dose correct, it could be concluded that a and, therefore, the same effects on bone. equivalent to 0.300 mg estrone sulfate, product containing the amounts of combined with 1 gram daily calcium Limited data on the estrone sulfate and equilin sulfate supplementation, is not effective in pharmacodynamic effects of DHES on required in the current monograph for preserving bone mineral density (Ref. bone have been submitted by Wyeth- conjugated estrogens USP would be 97). In this study, 0.625 mg of estrone Ayerst (Refs. 76 and 77). These data effective in preserving bone mineral sulfate resulted in preservation of bone show that DHES has a mineral density compared to baseline. density when given continuously with pharmacodynamic effect on bone There was no statistically significant supplemental calcium. Since the study markers, but the data do not shed light difference in bone mineral density by Harris et al. (Ref. 97) showed that 0.3 on whether the DHES component of between patients dosed with 0.625 mg mg of estrone sulfate alone is not Premarin has a meaningful clinical and those given 1.25 mg; however, only effective in preserving bone mineral effect on bone. the 1.25 mg group had bone mineral density, then it is likely that there was v. Safety. There are safety concerns densities statistically greater than the a contribution from the equilin sulfate about all estrogen preparations currently placebo group at 2-year followup. Based in the Solvay product, although firm approved for long-term administration on the data from this trial, the amount conclusions cannot be drawn from for the prevention of osteoporosis. Long- of estrone sulfate in Premarin cross-study comparisons. This term estrogen administration is (approximately 0.370 mg) is too small to information addresses to some extent associated with an increased incidence account for all of Premarin’s known one of the questions raised in FDA’s of endometrial cancer in women who effects on bone mineral density, so other ‘‘Preliminary Analysis of Scientific Data have not undergone hysterectomy, and estrogens present in the product must be on the Composition of Conjugated there is an ongoing controversy about contributing to this effect. Estrogens,’’ (Ref. 35) that is, that the the relationship of long-term estrogen Additional information on the effects contribution of equilin to preserving replacement therapy to breast cancer. of equilin on bone has recently become bone mineral density had not been No head-to-head studies have available. On October 30, 1996, demonstrated. compared the long-term safety of Duramed submitted to the docket an Despite this additional information, various estrogen preparations when abstract of a clinical study that had the question of what are the active used chronically for the prevention of recently been presented at a scientific ingredients in Premarin for the osteoporosis. The available meeting (Ref. 89). The study provided indication of maintaining bone is not epidemiologic evidence, summarized at new information germane to the clinical completely resolved. The Solvay study the July 27 and 28, 1995, Advisory effects of Premarin on bone (Ref. 55). demonstrated a dose response for bone Committee meeting, does not This study, sponsored by Solvay mineral density. The lowest dose, 0.3 definitively establish safety differences Pharmaceuticals, was a clinical trial of mg, was effective in preserving bone among various estrogens (Ref. 100). their product, Estratab (this trial was density. The two higher doses, 0.625 mg Thus, it is not known to what extent, if Federal Register / Vol. 62, No. 152 / Thursday, August 7, 1997 / Notices 42571 any, differences in the types of estrogens in the plasma is between 50 percent and potency of Premarin, depending on the used may affect safety. 125 percent (depending on what study assumptions used (Ref. 105). There are no comparative safety trials results are used) of the concentration of Just as with the animal data, it is of Premarin components available. unconjugated 17β-estradiol and is one- important to try to assess how reliably There are few pharmacodynamic third the concentration of unconjugated the in vitro data predict the actual markers available with which to assess 17β-dihydroequilin. clinical outcomes. A limitation of safety for effects such as cancer. The fact that a component is present cellular assays is that only one tissue Therefore, sufficient clinical data do not at high concentrations in the plasma type is evaluated. The results of the exist to fully characterize the does not necessarily mean that it is OCPB analysis shows that widely contributions (either positive or clinically important. The significance of differing estimates are arrived at negative) of various Premarin the finding that 17β-∆8,9- depending on the system used (Ref. components to its clinical safety. dehydroestrodiol is present in high 106). This may be due to artifacts of the vi. Other pharmacologic effects. There concentrations depends on the potency system (i.e., metabolism of estrone to is currently intense interest in the role of 17β-∆8,9-dehydroestradiol compared estradiol, etc., in the Hep-G2 cells), true of estrogen replacement therapy (ERT) to the potency of the other circulating tissue differences, or other reasons. The in the prevention of cardiovascular estrogens. If it is assumed that the best way to evaluate the in vitro potency disease and possibly other age-related potency of the 17β-diol metabolites assignments is to compare their results disorders in women (Ref. 101). No derived from estrone sulfate, equilin with known clinical outcomes. In this estrogen product is currently approved sulfate, and DHES have equal potency, case, certain comparisons are possible by FDA for such indications. If Premarin then the contribution of DHES to the because both estrone sulfate and equilin were to be found effective for overall estrogenic activity of the 17β- sulfate have been tested in women as prevention of cardiovascular disease, diol metabolites of the three estrogens single ingredients (Refs. 6 and 51). A elucidating the effects of Premarin and would be 16 percent (based on number of clinical studies have shown its components on relevant unconjugated diol AUC’s) to 26 percent that, for both FSH suppression and pharmacodynamic parameters would be (based on total diol AUC’s) (Ref. 61). treatment of menopausal symptoms, important in fully characterizing the However, there are several ways to equilin sulfate is roughly five times product. There are clinical data evaluate relative potency of estrogens. more potent than estrone sulfate when suggesting that equine estrogens may One method, testing in animal species, administered as a single ingredient. have differential effects on parameters is useful for determining estrogenicity, Comparison of this known clinical fact such as lipoprotein levels and lipid but has not proven to be quantitatively to the potency estimates in Tables 3 and peroxidation (Refs. 51 and 84); however, predictive for humans (the original rat 4 of OCPB Addendum 2 reveals that the these data are as yet very incomplete. Ishikawa cell potencies do not correctly potency test for conjugated estrogens is d. Inclusion of ∆8,9-dehydroestrone predict the oral potency of equilin a good example). This could be due to sulfate (DHES). Many of the issues relative to estrone (Ref. 73). The interspecies differences in metabolism, raised by Wyeth-Ayerst in its citizen Ishikawa cell data predict that oral some of which have been confirmed petition submitted in November 1994, equilin sulfate would be equipotent to (Ref. 102). and addressed in numerous submissions or less potent than estrone sulfate. Of to the docket, pertain to the need to If animal testing is not adequately the other in vitro estimates, the estrogen include DHES in generic copies of quantitative, in vitro studies using receptor binding assay best predicts the Premarin. The scientific issues related human cells or receptors may be known differences between equilin and to this compound are addressed below performed, or human clinical tests may estrone, predicting equilin sulfate to be insofar as they relate to the be carried out. Scientific data of both between two to four times more potent approvability of generic copies of types assessing the relative potency of than estrone sulfate depending on the Premarin, such as Duramed’s and Barr’s DHES have been submitted to the assumptions used. Because of these synthetic conjugated estrogens products. docket. Wyeth-Ayerst provided data on widely differing estimates, it must be As discussed previously at the human estrogen receptor binding as concluded that in vitro assays, even in beginning of this section (section well as functional activation data in human systems, cannot currently be III.B.2), DHES is a conjugated estrogens HEP–2 cells (Ref. 103). In addition, relied upon to provide precise component that comprises about 4.4 Duramed provided data on functional predictions of relative clinical percent of the ‘‘label claim’’ of activation of Ishikawa cells, a human potencies. Premarin. It has been recognized as a uterine cell line (Ref. 104). The results The other information available on constituent of Premarin for two decades of these studies are summarized in the the relative potency of DHES comes (Ref. 57). However, little scientific data OCPB Report of October 25, 1996 (Ref. from human studies. Wyeth-Ayerst have been available on its activity, and 71), Addendum 1 to that report dated submitted the results of two human it has been treated as an impurity. February 12, 1997 (Ref. 72), and studies to the docket (Refs. 76 and 77). Information submitted by Wyeth-Ayerst Addendum 2 to that report dated March These studies were small, unblinded, on the pharmacokinetics of DHES in 31, 1997 (Ref. 73). These OCPB Reports uncontrolled trials, and would not be of Premarin reveal that its metabolite, 17β- attempt to quantify the clinical the type relied upon for determining ∆8,9-dehydroestradiol, is present in estrogenic contribution to Premarin safety or efficacy of a drug. In addition, surprisingly large concentrations in the from equilin, estrone, DHE, and 17- they did not use a dosage form plasma, considering the composition of dihydroequilin based on the potencies equivalent to that of Premarin, and thus the tablet (Refs. 59 and 60). FDA derived from the various in vitro assays their results cannot be directly analyses support this finding (Ref. 71). in combination with the extrapolated to Premarin. However, they The 17β-∆8,9-dehydroestradiol pharmacokinetic data. are quite similar to the types of studies concentration is important because the The OCPB Report estimates that, that were originally used to evaluate the diol form of estrogen is usually the most based on the in vitro potencies and the role of estrone sulfate and equilin active in the human body. After taking known pharmacokinetics, DHE and its sulfate in Premarin and can be used to Premarin, the concentration (or AUC) of metabolite contribute approximately 2.8 assess certain comparative unconjugated 17β-∆8,9-dehydroestradiol to 6.5 percent of the overall estrogenic pharmacodynamic parameters. In these 42572 Federal Register / Vol. 62, No. 152 / Thursday, August 7, 1997 / Notices trials, 0.125 mg of DHES was provide sufficient information to show of DHES is not clinically meaningful. administered daily to postmenopausal that the active ingredients of their Duramed and Barr have failed to women. This dose of DHES is about four respective synthetic conjugated provide sufficient information in their times the amount in a 0.625 mg tablet estrogens products are the same as the ANDA’s to show that their conjugated of Premarin. In both studies, this dose active ingredients of the reference listed estrogens products contain this same of DHES caused approximately 15 to 26 drug product, Premarin. For a generic ingredient, or that the estrogenic activity percent suppression of FSH after 2 drug product with Premarin as the of DHES is not clinically meaningful. weeks of dosing. This is in the range of reference listed drug to be approved In addition to failing to provide suppression resulting from 0.625 mg of without approval of a petition under sufficient information to show that the estrone sulfate reported in the literature § 314.93 (21 CFR 314.93), the generic proposed generic drugs contain the (Ref. 50). The study performed in Brazil drug must have the same active same active ingredients as the reference included a comparison group given 1.25 ingredients as Premarin. This listed drug, ANDA 40–115 and ANDA mg estrone sulfate. This group achieved requirement, paired with a showing of 40–154 also fail to provide sufficient approximately a 40 percent reduction in bioequivalence of the generic drug to information to demonstrate that such FSH levels at 2 weeks. This effect is the reference listed drug, is meant to proposed generic drug products are somewhat greater than has been ensure that the data developed by the bioequivalent to the reference listed previously reported (Refs. 50 and 81). innovator company to demonstrate the drug. Based on these human data, the oral safety and effectiveness of the reference Under section 505(j)(3)(F) of the act potency of DHES (for pituitary listed drug will support approval of the and § 314.127(a)(6), FDA must refuse to pharmacodynamic parameters) is (very generic drug. Independent approve an ANDA for a proposed roughly) five to six times that of estrone demonstration of safety and generic drug, unless sufficient sulfate, or very similar to that of equilin effectiveness is not required for information has been submitted to show sulfate and is about what would be approval of generic drugs. Approval of that such drug is bioquivalent to the predicted on pharmacokinetic grounds generic copies of Premarin reference listed drug.6 Bioequivalence if the estrone and DHE derived diols manufactured from combined depends on the rate and extent to which were roughly equipotent. DHE, like synthesized components requires data the active ingredient or active moiety equilin, is a B ring unsaturated estrogen. sufficient to demonstrate that such becomes available at the site of action. If DHES has the same oral potency as copies contain the same active See section 505(j)(7)(B) of the act and equilin and if the contributions of ingredients as Premarin. § 320.1(e). If a drug has not been estrone sulfate, equilin sulfate, and CDER has determined that the established to contain the same active β DHES plus the small amount of 17 - reference listed drug Premarin is not ingredients or active moieties, >8,9-dehydroestradiol sulfate were to adequately characterized at this time. In bioequivalence cannot be established. be considered, then DHES and its particular, the estrogenic potency of the CDER finds that ANDA 40–115 and metabolite would contribute about 9 product is not clearly defined relative to ANDA 40–154 do not present sufficient percent of the estrogenic potency from the estrogenic potency of its information to show that the proposed these three components, at least for constituents. In addition, the generic drugs contain the same active pituitary parameters. contribution of the two most abundant ingredients or the same active moieties It can be seen from the above analysis estrogens, sodium equilin sulfate and as the reference listed drug. Therefore, that the high end of the estimate of the sodium estrone sulfate, to the overall these ANDA’s cannot be approved by contribution of DHES to the estrogenic estrogenic potency is not well FDA under section 505(j)(3)(F) of the act potency of Premarin from the in vitro understood. Furthermore, the and § 314.127(a)(6) because they fail to assays is similar to the estimate derived quantitative composition of Premarin present sufficient information to show from clinical studies, i.e., about 9 with respect to potentially that the proposed generic drugs are percent, and both of the estimates are pharmacologically active components bioequivalent to the reference listed lower than the 16 percent to 26 percent has not been defined. Without this drug. estimate based on an assumption that information it is not possible to define β Finally, in the event that each of the each 17 -diol metabolite is equally the active ingredients of Premarin. foregoing deficiencies is resolved, potent. Unfortunately, all of the Investigations designed to produce additional information may be required estimates have problems and the scientific data needed to determine to address unresolved labeling, uncertainties. A precise estimate of the the active ingredients are feasible. Such chemistry, bioequivalence, or potency of DHES relative to estrone information would allow a manufacturing issues. sulfate is not available. In addition, determination of which components of none of the data provide insight into the Premarin make a clinically meaningful IV. References contribution of these components to contribution to its overall effects. It is The following references have been estrogenic potency with respect to bone. both feasible and desirable for the placed on display in the Dockets As discussed above, preliminary constituent active ingredients in Management Branch (address above) pharmacodynamic data indicate that Premarin to be characterized to this and may be seen by interested persons DHES has an effect on bone markers. extent. between 9 a.m. and 4 p.m., Monday > The available data demonstrate that With regard to sodium 8,9- through Friday. Additional documents DHES is a potent estrogen and may dehydroestrone sulfate (DHES), the related to this notice appear in Dockets make a clinically meaningful available scientific evidence indicates 94P–0429 and 94P–0430, and are contribution to the therapeutic effects of that DHES is an active estrogen that incorporated by reference. Premarin. contributes to the estrogenic potency of Premarin. The clinical significance of 1. United States Pharmacopeia 18, pp. 242- C. Conclusions this contribution has not been 246, 1970. CDER proposes to refuse to approve determined. DHES must be included in 6 One exception to this general rule that is not Duramed’s ANDA 40–115 and Barr’s generic copies of Premarin unless applicable here relates to a drug for which a ANDA 40–154 primarily on the grounds scientific data are presented that petition under section 505(j)(2)(C) of the act and that Duramed and Barr have failed to demonstrate that the estrogenic activity § 314.93 has been approved. See § 314.127(a)(6)(ii). Federal Register / Vol. 62, No. 152 / Thursday, August 7, 1997 / Notices 42573

2. Minutes of the meeting of the Committee FDA’s Fertility and Maternal Health Drugs 42. FDA, ‘‘Conjugated Estrogens on Conjugated Estrogens of the Advisory Committee, Vols. I and II, May 3– Background Information for the Fertility and Pharmaceutical Contact Section, Washington, 4, 1990. Maternal Health Drugs Advisory Committee DC, October 23, 1962. 21. Id., Vol. II, pp. 117–135. Meeting,’’ pp. 11–13, July 27–28, 1995. 3. Minutes of the meeting of the Committee 22. FDA, ‘‘Abbreviated New Drug 43. United States Pharmacopeia 23, on Conjugated Estrogens of the Quality Applications for Conjugated Estrogens; ‘‘Conjugated Estrogens Monograph,’’ pp. Control Section, Washington, DC, April 16, Proposal to Withdraw Approval; Opportunity 627–629, 1995. 1963. for a Hearing,’’ Federal Register, Vol. 55, No. 44. Wyeth-Ayerst submission to the docket 4. Summary of Proceedings of the USP 30, pp. 5074, 5076–5078, February 13, 1990. 94P–0429 (SUP 4), ‘‘Contributions of ∆8,9- Conference on Conjugated Estrogens, 23. FDA, ‘‘Conjugated Estrogens Tablets; dehydroestrone (∆8,9 DHES) to the Biologic February 27, 1968. Withdrawal of Approval of 28 Abbreviated Activities of Conjugated Estrogens,’’ p. 13, 5. Howard, R. P., E. C. Keaty, and E. C. New Drug Applications,’’ Federal Register, September 25, 1995. Reifenstein, ‘‘Comparative Effects of Various Vol. 56, No. 57, p. 12376, March 25, 1991. 45. Yang, N.N., M. Venugopalan, S. Estrogens on Urinary Gonadotropins (FSH) in 24. FDA, ‘‘Zenith Laboratories; Conjugated Hardikar, and A. Glasebrook, ‘‘Identification Oophorectomized Women,’’ [Abstract], Estrogens Tablets; Withdrawal of Approval of of an Estrogen Response Element Activated Journal of Clinical Endocrinology and Four Abbreviated New Drug Applications,’’ by Metabolites of 17B-estrodiol and Metabolism, 16:966, 1956. Federal Register, Vol. 56, No. 87, p. 20621, Raloxifene,’’ Science, 273:1222–1225, August 6. Howard, R. P., and E. C. Keaty, May 6, 1991. 30, 1996. ‘‘Evaluation of Equilin 3-monosulfate and 25. Transcript of the meeting of FDA’s 46. Kuiper, G. G. J. M., E. Enmark, M. Other Estrogens,’’ Archives of Internal Generic Drugs Advisory Committee, Vols. I Pelto-Huikko, et al., ‘‘Cloning of a Novel Medicine, 128:229–234, August 1971. and II, February 25–26, 1991. Estrogen Receptor Expressed in Rat Prostate 7. FDA, ‘‘Certain Estrogen-Containing 26. Id., Vol. I, pp. 46–68. and Ovary,’’ Proceedings of the National Drugs for Oral or Parenteral Use,’’ Federal 27. Adams, W. P., presentation slide from Academy of Sciences of the United States of Register, Vol. 37, No. 143, pp. 14826–14828, the meeting of the FDA’s Generic Drugs America, 93:5925–5930, June 1996. July 25, 1972. Advisory Committee, February 25, 1991. 47. Barnes, R.B., and R. A. Lobo, 8. Minutes of the meeting on proposed USP 28. Transcript of the meeting of FDA’s ‘‘Pharmacology of Estrogens,’’ in Menopause: monograph for conjugated estrogens, p. 4, Generic Drugs Advisory Committee, Vol. I, Physiology and Pharmacology, edited by D. November 4, 1982. pp. 68–91, February 25–26, 1991. R. Mishell, pp. 301–315, Chicago: Year Book 9. Id. at pp. 1–4. 29. Transcript of the meeting of FDA’s Medical Publishers, 1987. 10. FDA, ‘‘Therapeutically Equivalent Generic Drugs Advisory Committee, Vol. II, 48. Von Angerer, E., ‘‘The Estrogen Drugs,’’ Federal Register, Vol. 44, No. 9, pp. pp. 16–26, February 25–26, 1991. Receptor as a Target for Rational Drug 2932–2953, January 12, 1979. Announced 30. USP, Pharmacopeial Forum, Vol. 17, Design,’’ Molecular Biology Intelligence Unit, that FDA intended to make available a list of No. 6, pp. 2–3, December 1991. pp. 5–17, Austin: RG Landes Co., August approved drug products with therapeutic 31. Wyeth-Ayerst submission to the docket 1995. evaluations of products available from more 94P–0429 (CP 1), November 30, 1994. 49. Koh, K. K., R. Mincemoyer, M. N. Bui, than one manufacturer. Originally known as 32. Wyeth-Ayerst submission to the docket Approved Prescription Drug Products with 94P–0430 (PSA 1), November 30, 1994. et al., ‘‘Effects of Hormone-Replacement Therapeutic Equivalence Evaluations, it is 33. Transcript and Summary Minutes of Therapy on Fibrinolysis in Postmenopausal now called Approved Drug Products with the meeting of FDA’s Fertility and Maternal Women,’’ New England Journal of Medicine, Therapeutic Equivalence Evaluations (the Health Drugs Advisory Committee, Vols. I 336:683–690, March 1997. Orange Book). and II, July 27–28, 1995. 50. Mashchak, C. A., R. A. Lobo, R. 11. 1980 Orange Book listing for 34. Id., Summary Minutes, p. 5, and Vol. Dozono-Takano, et al., ‘‘Comparison of conjugated estrogens, pp. 51–52. II, pp. 296–297. Pharmacodynamic Properties of Various 12. FDA, ‘‘Oral Estrogens for 35. FDA submission to the docket 94P– Estrogen Formulations,’’ American Journal of Postmenopausal Osteoporosis; Drug Efficacy 0429 (REF 1), November 4, 1996. FDA’s Obstetrics and Gynecology, 144:511–518, Study Implementation; Reevaluation,’’ ‘‘Preliminary Analysis of Scientific Data on November 1992. Federal Register, Vol. 51, No. 70, pp. 12568– the Composition of Conjugated Estrogens,’’ 51. Lobo, R. A., H. N. Nguyen, P. Eggena, 12570, April 11, 1986. November 1, 1996. and P. F. Brenner, ‘‘Biologic Effects of 13. Genant, H. K., C. E. Cann, B. Ettinger, 36. FDA, Ad Hoc Conjugated Estrogens Equilin Sulfate in Postmenopausal Women,’’ and G. S. Gordan, ‘‘Quantitative Computed Working Group, ‘‘Ad Hoc Conjugated Fertility and Sterility, 49:234–238, February Tomography of Vertebral Spongiosa: A Estrogens Working Group Final Report,’’ 1988. Sensitive Method for Detecting Early Bone [with attachments], May 1, 1997. 52. Lyman, G. W., and R. N. Johnson, Loss After Oophorectomy,’’ Annals of 37. Memorandum from the Director, Office ‘‘Assay for Conjugated Estrogens in Tablets Internal Medicine, 97:699–705, 1982. of Drug Evaluation II to the Director, Center Using Fused-Silica Capillary Gas 14. Lindsay, R., D. M. Hart, and D. M. for Drug Evaluation and Research, ‘‘Generic Chromatography,’’ Journal of Clark, ‘‘The Minimum Effective Dose of Drug Versions of Conjugated Estrogens,’’ Chromatography, 234:234–239, 1982. Estrogen for Prevention of Postmenopausal April 22, 1997. 53. Helgason, S., M–G. Damber, B. von Bone Loss,’’ Obstetrics and Gynecology, 38. Memorandum from the Associate Schoultz, and T. Stigbrand, ‘‘Estrogenic 63:759–763, 1984. Director for Medical Policy to the Director, Potency of Oral Replacement Therapy 15. FDA, ‘‘Abbreviated New Drug Center for Drug Evaluation and Research, Estimated by the Induction of Pregnancy Applications for Conjugated Estrogens; ‘‘Conjugated Estrogens; Requirements for a Zone Protein,’’ Acta Obstetrica et Proposal to Withdraw Approval; Opportunity Generic Product,’’ [with attachments], May 4, Gynecologica Scandinavica, 61:75–79, 1982. for a Hearing,’’ Federal Register, Vol. 55, No. 1997. 54. Ettinger, B., H. K. Genant, P. Steiger, 30, pp. 5074, 5076–5078, February 13, 1990. 39. Memorandum from the Director, Office and P. Madvig, ‘‘Low-dosage Micronized 16. Id. at p. 5076. of Pharmaceutical Science to the Director, 17β–estradiol Prevents Bone Loss in 17. FDA, Center for Drug Evaluation and Center for Drug Evaluation and Research, Postmenopausal Women,’’ American Journal Research, Division of Bioequivalence, ‘‘Recommendation on the Composition of of Obstetrics and Gynecology, 166:479–488, Guidance for ‘‘In-Vivo Bioequivalence Study Conjugated Estrogens Tablets, USP,’’ [with February 1992. for Conjugated Estrogens Tablets,’’ December attachments; redacted], May 3, 1997. 55. Genant, H., J. Lucas, S. Weiss, et al., ‘‘A 17, 1986. 40. FDA, ‘‘Abbreviated New Drug Clinical Study of 0.3, 0.625 and 1.25 mg 18 Transcript, Vol. II, and Summary Application Regulations; Proposed Rule,’’ Esterified Estrogens (Estratab@) for the Minutes of the meeting of FDA’s Fertility and Federal Register, Vol. 54, No. 130, pp. 28872 Prevention of Postmenopausal Osteoporosis,’’ Maternal Health Drugs Advisory Committee, (28880, 28881), July 10, 1989. States that to [Abstract PTu 577], Osteoporosis January 5–6, 1989. be ‘‘the same,’’ active ingredients must be International, 6 (Suppl. 1):S228, 1996. 19. Id. at pp. 177–193. ‘‘identical.’’ 56. Roman, R., C. H. Yates, J. F. Millar, and 20. Transcript and Summary Minutes of 41. United States Pharmacopeia 18, pp. W. J. A. Vanden Heuvel, ‘‘Identification of the meeting of the Ad Hoc Subcommittee of 242–245, 1970. Estrogens Isolated From Pregnant Mares’’ 42574 Federal Register / Vol. 62, No. 152 / Thursday, August 7, 1997 / Notices

Urine,’’ Canadian Journal of Pharmaceutical 68. The international community has Oestradiol Versus Oral Oestrogens on Bone Sciences, 10:8–11, 1974. recognized the need to characterize Density,’’ Maturitas, 20:209–213, 1995. 57. Johnson, R., R. Masserano, R. Haring, impurities present in a new drug substance 84. Tang, M., W. Abplanalp, S. Ayres, and et al., ‘‘Quantitative GLC Determination of at or above an apparent level of 0.1%. M.T.R. Subbiah, ‘‘Superior and Distinct Conjugated Estrogens in Raw Materials and Guideline for Industry, Impurities in New Antioxidant Effects of Selected Estrogen Finished Dosage Forms,’’ Journal of Drug Substances, International Conference on Metabolites on Lipid Peroxidation,’’ Pharmaceutical Sciences, 64:1007–1011, Harmonisation, Q3A, January 1996. Given Metabolism, 45:411–414, April 1996. June 1975. this international recognition of the 85. Wyeth-Ayerst submission to the docket 58. Wyeth-Ayerst submission to the docket feasability of so characterizing new drug 94P–0429 (SUP 10), May 5, 1997, ‘‘A Pilot 94P–0429 (C 96), March 26, 1997. substances, it should be possible to Study on the Clinical Effects of ∆8,9 59. Wyeth-Ayerst submission to the docket characterize conjugated estrogens at least to Dehydroestrone Sulfate Alone or in 94P–0429, (SUP 10), May 5, 1997, Doc. 1, this degree. Combination with Estrone Sulfate, Protocol Vol. 2, Protocol 713-X–108-US, Wyeth-Ayerst 69. Duramed submission to the docket CF–DHE–001 BR,’’ GMR–27679, Final Study GMR–23669, February 16, 1994, Table 46, p. 94P–0429 (RC 5), p. 5, August 22, 1996. Report, November 22, 1996 (Brazilian Study), 197; Table 52, p. 214; Table 57, p. 230. 70. Wyeth-Ayerst submission to the docket GMR–27679, p. 8. Wyeth-Ayerst submission to the docket 94P– 94P–0429 (C 96), p. 2., March 26, 1997. 86. Bradbury, J. T., and R. C. Long, 0429, (SUP 9), October 29, 1996, Doc. 1, Vol. 71. FDA, Center for Drug Evaluation and ‘‘Equilin, an Orally Active Estrogen in 5, article (Troy, S. M., D. R. Hicks, V. D. Research, Office of Clinical Pharmacology Women,’’ University of Louisville, Louisville, Parker, et al., ‘‘Differences in and Biopharmaceutics, Division of KY, American Journal of Physiology, 163:700, Pharmacokinetics and Comparative Pharmaceutical Evaluation II, ‘‘A 1950.  Bioavailability Between Premarin and Pharmacokinetic Analysis of Conjugated 87. FDA, Center for Drug Evaluation and ∆ Estratab@ in Healthy Postmenopausal Estrogens Including 8,9-Dehydroestrone and Research, Division of Metabolism and β ∆ Women,’’ Current Therapeutic Research, 17 - 8,9-Dehydroestradiol,’’ October 25, Endocrine Drug Products, ‘‘Guideline for 55:359–372, 1994); Doc. 32, GMR 21811, 1996 (OCPB Report). Preclinical and Clinical Evaluation of Agents Table 52. 72. Id., Addendum 1, February 12, 1997. Used in the Prevention or Treatment of 60. Wyeth-Ayerst submission to the docket See also Ref. 36, Attachment B–2. Postmenopausal Osteoporosis (Draft),’’ April 94P–0429 (Sup 4), Vol. 4, Tab 27, 73. Id., Addendum 2, March 31, 1997. See 1994. ‘‘Pharmacokinetic Profile of Unconjugated also Ref. 36, Attachment B–3. 88. Calvo, M. S., D. R. Eyre, and C. M. and Total (Unconjugated Plus Conjugated) 74. Wyeth-Ayerst submission to the docket β ∆ Gundberg, ‘‘Molecular Basis and Clinical 17 - 8,9-dehydroestrone in Healthy 94P–0429 (Sup 4), GTR–26521, pp. 32–34, Application of Biological Markers of Bone Postmenopausal Women Receiving 2×0.625 September 25, 1995. Turnover,’’ Endocrine Reviews, 17:333–367, mg Premarin and 2×0.625 mg Estratab,’’ 75. Barnes, R.B., and R.A. Lobo, August 1996. Wyeth-Ayerst draft addendum to GMR– ‘‘Pharmacology of Estrogens,’’ in Menopause: 89. Duramed submission to the docket 23669 for Protocol 713–X–108–US(17β-∆8,9- Physiology and Pharmacology, edited by D.R. 94P–0429 (C 38), October 30, 1996. dehydroestrone pharmacokinetic data), Mishell, p. 303, Chicago: Year Book Medical 90. Reginster, J. Y., N. Sarlet, R. Deroisy, September 20, 1995. Publishers, 1987. 61. Wyeth-Ayerst submission to the docket 76. Wyeth-Ayerst submission to the docket et al., ‘‘Minimal Levels of Serum Estradiol 94P–0429 (SUP 10), May 5, 1997, Doc. 33, ‘‘A 94P–0429 (SUP 10), May 5, 1997, ‘‘A Pilot Prevent Postmenopausal Bone Loss,’’ Steady-State Bioavailability Study of Study on the Clinical Effects of ∆8,9 Calcified Tissue International, 51:340–343, Premarin (2×0.625 mg) in Healthy Dehydroestrone Sulfate Alone or in 1992. 91. Librach, S., and A. K. Nickel, ‘‘Effect Postmenopausal Women—Final Report Combination with Estrone Sulfate, Protocol   β (Protocol Number 96–090MA),’’ GTR 29548, CF–DHE–001 BR,’’ GMR–27679, Final Study of C.E.S. and Premarin on 17 -Estradiol February 24, 1997, (Missouri Study). Report, November 22, 1996 (Brazilian Study). Serum Levels in Postmenopausal Women,’’ 62. FDA, Center for Drug Evaluation and 77. Wyeth-Ayerst submission to the docket Canadian Journal of Diagnosis (Suppl., May), Research, Division of Drug Analysis, 94P–0429 (SUP 10), May 5, 1997, ‘‘Pilot pp. 3–7, 1996. ‘‘Preliminary Assay Results from FDA’s Study on the Clinical Effects of ∆8,9- 92. Brennan, J. J., J. C. Nolan, J. Hui, et al., Division of Drug Analysis,’’ June 1995. Dehydroestrone Sulfate,’’ Summary report, ‘‘Plasma Concentrations of Estrogens Are Referenced in FDA submission to the docket (undated) (Canadian study). Correlated With Bone Mineral Density 94P–0429 (REF 1), November 4, 1996. 78. Stern, M.D., ‘‘Pharmacology of Changes in Postmenopausal Women 63. Wyeth-Ayerst submission to the docket Conjugated Oestrogens,’’ Maturitas, 4:333– Receiving Esterified Estrogens in an 94P–0429 (SUP 4), ‘‘Contributions of ∆8,9- 339, Elsevier Biomedical Press, 1982. Osteoporosis Prevention Study,’’ Abstract dehydroestrone (∆8,9 DHES) to the Biologic 79. Jones, M.M., B. Pearlman, D.H. PII–12, Clinical Pharmacology and Activities of Conjugated Estrogens,’’ p. 14, Marshall, et al., ‘‘Dose-Dependent Response Therapeutics, Vol. 61, No. 2, p. 168, February September 25, 1995. of FSH, Flushes and Urinary Calcium to 1997. Presented at the meeting of the 64. Roos, R.W., ‘‘Determination of Oestrogen,’’ Maturitas, 4:285–290, Elsevier American Society for Clinical Pharmacology Conjugated and Esterified Estrogens in Biomedical Press, 1982. and Therapeutics, San Diego, CA, March 6, Pharmaceutical Tablet Dosage Forms by 80. Geola, F.L., A.M. Frumar, I.V. Tataryn, 1997. High-Pressure, Normal-Phase Partition et al., ‘‘Biological Effects of Various Doses of 93. Thomas, G., Solvay Pharmaceuticals, Chromatography,’’ Journal of Conjugated Equine Estrogens in Transcript and slides from the presentation at Chromatographic Science, 14:505–512, Postmenopausal Women,’’ Journal of Clinical the United States Pharmacopeial Open November 1976. Endocrinology and Metabolism, 51:620–625, Meeting: Conjugated Estrogens, USP; 65. Roos, R.W., and C.A. Lau-Cain, ‘‘Liquid 1980. Esterified Estrogens, USP; Esterified Chromatographic Analysis of Conjugated and 81. Varma, T.R., D. Everard, and D. Hole, Estrogens Tablets, USP, Rockville, MD, pp. Esterified Estrogens in Tablets,’’ Journal of ‘‘Effect of Natural Estrogen on the Serum 62–76, September 29, 1992. Pharmaceutical Sciences, 74:201–204, Level of Follicle-Stimulating Hormone (FSH), 94. Stevenson, J. C., M. P. Cust, K. F. February 1985. Estradiol and Estrone in Post-Menopausal Gangar, et al., ‘‘Effects of Transdermal Versus 66. Roos, R.W., ‘‘High-pressure Liquid Women and Its Effect on Endometrium,’’ Oral Hormone Replacement Therapy on Bone Chromatographic Analysis of Estrogens in Acta Obstetrica et Gynecologica Density in Spine and Proximal Femur in Pharmaceuticals by Measurement of Their Scandinavica, 64:105–109, 1985. Postmenopausal Women,’’ Lancet, Vol. 336, Dansyl derivatives,’’ Journal of 82. Beck, V.A., and F.W. Friedrich, No. 8710, ii:265–269, August 4, 1990. Pharmaceutical Sciences, 67:1735–1739, ‘‘Equilinsulfat zur Substitution Beim 95. Ettinger, B., H. K. Genant, and C. E. December 1978. Menopause-syndrom (Equilin Sulfate in the Cann, ‘‘Postmenopausal Bone Loss Is 67. Pillai, G.K., and K.M. McErlane, Treatment of the Menopausal Syndrome),’’ Prevented by Treatment With Low-Dosage ‘‘Quantitative Determination of Conjugated Wiener Klinische Wochenschrift, 87:59–62, Estrogen With Calcium,’’ Annals of Internal Estrogens in Formulations by Capillary 1975. Medicine, 106:40–45, 1987. GLC,’’ Journal of Pharmaceutical Sciences, 83. Palacios, S., C. Menendez, A.R. Jurado, 96. The Writing Group for the PEPI Trial, 70:1072–1075, September 1981. and J.C. Vargas, ‘‘Effects of Percutaneous ‘‘Effects of Hormone Therapy on Bone Federal Register / Vol. 62, No. 152 / Thursday, August 7, 1997 / Notices 42575

Mineral Density: Results from the Post- the applicants are hereby given notice of This notice is issued under the Menopausal Estrogens/Progestins an opportunity for a hearing to show Federal Food, Drug, and Cosmetic Act Intervention (PEPI) Trial,’’ Journal of the that approval of ANDA 40–115 and (section 505) and under authority American Medical Association, Vol 276, No. 17, pp. 1389–1396, November 6, 1996. ANDA 40–154 should not be refused. delegated to the Director of the Center 97. Harris, S. T., H. K. Genant, D. J. An applicant who decides to seek a for Drug Evaluation and Research (21 Baylink, et al., ‘‘The Effects of Estrone (Ogen) hearing shall file: (1) On or before CFR 5.82). on Spinal Bone Density of Postmenopausal September 8, 1997: a written notice of Dated: July 29, 1997. Women,’’ Archives of Internal Medicine, appearance and request for hearing, and Murray M. Lumpkin, 151:1980–1984, October 1991. (2) on or before October 6, 1997, the Director, Center for Drug Evaluation and 98. United States Pharmacopeia 23, data, information, and analyses relied ‘‘Conjugated Estrogens Monograph,’’ p. 629, Research. on to demonstrate that there is a 1995. [FR Doc. 97–20792 Filed 8–6–97; 8:45 am] genuine issue of material fact to justify 99. Duursma, S. A., M. de Raadt, J. A. BILLING CODE 4160±01±P Raymakers, and A. A. Haspels, ‘‘Is 1 mg of a hearing, as specified in § 314.200(c). Estradiol Valerate or 0.625 mg of Conjugated Any other interested person may also Estrogens Sufficient for All Women to submit comments on this notice. The DEPARTMENT OF HEALTH AND Prevent Menopausal Bone Loss?’’ procedures and requirements governing HUMAN SERVICES Gynecological Endocrinology., 6:205–209, this notice of opportunity for a hearing, 1992. a notice of appearance and request for 100. Transcript and Summary Minutes of Food and Drug Administration the meeting of FDA’s Fertility and Maternal a hearing, information and analyses to Health Drugs Advisory Committee, Vol. II, justify a hearing, other comments, and [Docket No. 97N±0326] pp. 85–105, July 27–28, 1995. a grant or denial of a hearing are 101. Lafferty, F. W., and M. E. Fiske, contained in § 314.200 and in 21 CFR Sterling Drug, Inc., et al.; Withdrawal of ‘‘Postmenopausal Estrogen Replacement: A part 12. Approval of 28 New Drug Applications, Long-Term Cohort Study,’’ American Journal The failure of the applicant to file a 9 Abbreviated Antibiotic Applications, of Medicine, 97:66–77, 1994. timely written notice of appearance and and 46 Abbreviated New Drug 102. Bhavnani, B. R., ‘‘The Saga of the Ring Applications B Unsaturated Equine Estrogens,’’ Endocrine request for a hearing, as required by Reviews, 9:396–416, 1988. § 314.200, constitutes an election by that AGENCY: Food and Drug Administration, 103. Wyeth-Ayerst submission to the person not to use the opportunity for a docket 94P–0429 (SUP 4), ‘‘Contributions of hearing concerning the proposed action, HHS. >8,9-dehydroestrone (>8,9 DHES) to the and a waiver of any contentions ACTION: Notice. Biologic Activities of Conjugated Estrogens,’’ concerning the legal status of the SUMMARY: The Food and Drug GTR–26521, pp. 38–40, September 25, 1995., referenced drug products. 104. Duramed submission to the docket Administration (FDA) is withdrawing A request for a hearing may not rest 94P–0429 (C 94), January 8, 1997. approval of 28 new drug applications upon mere allegations or denials, but 105. FDA, Center for Drug Evaluation and (NDA’s), 9 abbreviated antibiotic must present specific facts showing that Research, Office of Clinical Pharmacology applications (AADA’s), and 46 and Biopharmaceutics, Division of there is a genuine and substantial issue abbreviated new drug applications Pharmaceutical Evaluation II, ‘‘A of fact that requires a hearing. If it (ANDA’s). The holders of the Pharmacokinetic Analysis of Conjugated conclusively appears from the face of > applications notified the agency in Estrogens Including 8,9-Dehydroestrone the data, information, and factual and 17>8,9-Dehydroestradiol,’’ October 25, writing that the drug products were no analyses in the request for a hearing that 1996 (OCPB Report), Addendum 2, p. 26, longer marketed and requested that the there is no genuine and substantial issue March 31, 1997. approval of the applications be of fact that precludes the refusal to 106. Id., p. 8, Table 5. withdrawn. approve the application, or when a V. Notice of Opportunity for a Hearing request for a hearing is not made in the EFFECTIVE DATE: September 8, 1997. FOR FURTHER INFORMATION CONTACT: The Director of CDER (the Director) required format or with the required has evaluated the information discussed analyses, the Commissioner of Food and Olivia A. Vieira, Center for Drug above and, on the grounds stated, is Drugs will enter summary judgment Evaluation and Research (HFD–7), Food proposing to refuse to approve ANDA against the person who requests the and Drug Administration, 5600 Fishers 40–115 and ANDA 40–154. hearing, making findings and Lane, Rockville, MD 20857, 301–594– Therefore, notice is given to Duramed conclusions, and denying a hearing. 2041. and Barr and to all other interested All submissions pursuant to this SUPPLEMENTARY INFORMATION: The persons that under section 505 notice of opportunity for a hearing are holders of the applications listed in the (j)(3)(C)(ii), (j)(3)(F), and (j)(3)(J) of the to be filed in four copies. Except for data table in this document have informed act and § 314.127 (a)(3)(ii), (a)(6), and and information prohibited from public FDA that these drug products are no (a)(12), the Director proposes to refuse disclosure under 21 U.S.C. 331(j) or 18 longer marketed and have requested that to approve ANDA 40–115 and ANDA U.S.C. 1905, the submissions may be FDA withdraw approval of the 40–154. seen in the Dockets Management Branch applications. The applicants have also, In accordance with section (address above) between 9 a.m. and 4 by their request, waived their 505(j)(4)(C) of the act and § 314.200(a), p.m., Monday through Friday. opportunity for a hearing.

Application No. Drug Applicant

NDA 6±801 Neocurtasal Sterling Drug, Inc., 90 Park Ave., New York, NY 10016. NDA 8±472 Cyclaine Merck & Co., Inc., P.O. Box 4, BLA±20, West Point, PA 19486. NDA 8±656 Hydrocortone Acetate Topical Ointment Do.