[Federal Register Volume 62, Number 152 (Thursday, August 7, 1997)]
[Notices]
[Pages 42562-42575]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 97-20792]


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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration
[Docket No. 97N-0325]


Duramed Pharmaceuticals, Inc., and Barr Laboratories, Inc.; 
Conjugated Estrogens Tablets; Proposal to Refuse to Approve Two 
Abbreviated New Drug Applications; Opportunity for a Hearing

AGENCY: Food and Drug Administration, HHS.

ACTION: Notice.

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SUMMARY: The Center for Drug Evaluation and Research (CDER) is 
proposing to refuse to approve two abbreviated new drug applications 
(ANDA's) for synthetic conjugated estrogens tablets. Conjugated 
estrogens tablets are intended for estrogen replacement to treat 
symptoms of menopause or to prevent osteoporosis. ANDA 40-115 
(Cenestin, conjugated estrogens tablets, 0.3 milligrams (mg), 0.625 mg, 
0.9 mg, 1.25 mg, and 2.5 mg) has been submitted by Duramed 
Pharmaceuticals, Inc., 5040 Lester Rd., Cincinnati, OH 45213 (Duramed). 
ANDA 40-154 (conjugated estrogens tablets, 0.625 mg and 1.25 mg) has 
been submitted by Barr Laboratories, Inc., 2 Quaker Rd., Pomona, NY, 
10970 (Barr). Food and Drug Administration (FDA) is offering Duramed 
and Barr an opportunity for a hearing on the proposal. The primary 
basis for CDER's proposed refusal to approve the ANDA's is the agency's 
conclusion that there is insufficient information to show that the 
active ingredients of synthetic conjugated estrogens tablets are the 
same as the active ingredients of the reference listed drug.

DATES: A hearing request is due on or before September 8, 1997; data 
and information in support of the hearing request are due on or before 
October 6, 1997.

ADDRESSES: A request for hearing, supporting data, and other comments 
are to be identified with Docket No. 97N-0325 and submitted to the 
Dockets Management Branch (HFA-305), Food and Drug Administration, 
12420 Parklawn Dr., rm. 1-23, Rockville, MD 20857.

FOR FURTHER INFORMATION CONTACT: Carol E. Drew, Center for Drug 
Evaluation and Research (HFD-7), Food and Drug Administration, 5600 
Fishers Lane, Rockville, MD 20857, 301-594-2041.

SUPPLEMENTARY INFORMATION:

I. Background

    Both Duramed and Barr have submitted ANDA's for synthetic 
conjugated estrogens tablets intended for estrogen replacement to treat 
symptoms of menopause or to prevent osteoporosis. The reference listed 
drug for this product is Premarin, manufactured by Wyeth-Ayerst, and 
derived from a natural source material, the urine of pregnant mares.
    On September 26, 1994, Duramed submitted ANDA 40-115 for Cenestin 
(conjugated estrogens tablets) under section 505 (j) of the Federal 
Food, Drug, and Cosmetic Act (the act) (21 U.S.C. 355(j)). Duramed 
filed amendments to this ANDA on March 7 and 25, 1996; April 2 and 3, 
1996; May 9 and 14, 1996; June 28, 1996; July 12, 1996; August 14, 15, 
19, and 29, 1996; October 8 and 9, 1996; December 17, 1996; January 23 
and 31, 1997; and February 14, 1997. On May 5, 1997, in accordance with 
Sec. 314.120 (21 CFR 314.120), CDER notified Duramed by letter that 
Duramed's ANDA was not approvable under section 505 (j)(2)(A)(ii)(II) 
and (j)(3)(C)(ii) because the ANDA was insufficient to show that the 
active ingredients of the proposed generic drug product were the same 
as the active ingredients of the reference listed drug.
    On July 20, 1995, Barr submitted ANDA 40-154 for conjugated 
estrogens tablets under section 505(j) of the act. Barr filed 
amendments to this ANDA on May 13, 1996, and November 14 and 18, 1996. 
On May 5, 1997, in accordance with Sec. 314.120, CDER notified Barr by 
letter that Barr's ANDA was not approvable under section 505 
(j)(2)(A)(ii)(II) and (j)(3)(C)(ii) of the act because the ANDA was 
insufficient to show that the active ingredients of the proposed 
generic drug product were the same as the active ingredients of the 
reference listed drug.
    CDER attached a detailed memorandum to the not approvable letters 
issued to both Duramed and Barr. This memo, from the CDER Director to 
the Director of the Office of Generic Drugs, outlined the legal and 
scientific rationale for CDER's position that a synthetic generic 
version of Premarin should not be approved until the active ingredients 
of Premarin have been sufficiently well defined to permit an ANDA 
applicant to show that a synthetic generic form of Premarin has the 
same active ingredients. In the not approvable letters of May 5, 1997, 
CDER notified Duramed and Barr that they each had the option to amend 
or withdraw their respective ANDA's under Sec. 314.120, or request an 
opportunity for a hearing under Sec. 314.200 (21 CFR 314.200).
    In response to CDER's not approvable letter, Duramed submitted an 
initial response on May 15, 1997, and under Sec. 314.120(a)(5), 
requested a 30-day extension of time to respond pending review by its 
scientific and medical personnel of the not approvable letter and other 
information.
    In a letter dated June 13, 1997, Duramed requested the opportunity 
for a hearing under Sec. 314.120(a)(3) on the question of whether there 
are grounds for denying approval of ANDA 40-115.
    On June 26, 1997, CDER issued a response to Duramed's May 15, 1997, 
letter documenting CDER's decision to honor Duramed's request for an 
extension contingent upon Duramed's agreement, under 
Sec. 314.120(a)(3), that CDER would have until August 8, 1997, to give 
written notice of an opportunity for a hearing to Duramed, under 
Sec. 314.200, on the question of whether there are grounds for refusing 
to approve the ANDA.
    On May 15, 1997, Barr submitted a letter to FDA requesting a 60-day 
extension to respond to the not approvable letter dated May 5, 1997. On 
July 3, 1997, CDER issued a letter granting Barr's May 15, 1997, 
request for an extension contingent on Barr's agreement that FDA would 
have 50 days from the date of Barr's request for the opportunity for a 
hearing to provide written notice of an opportunity for a hearing. Barr 
submitted a letter to FDA on July 7, 1997, requesting an opportunity 
for a hearing on the not approvable letter and agreeing to the 
condition that FDA would have 50 days from July 7, 1997, to respond.
    This notice includes CDER's proposed order to refuse to approve the 
Barr and Duramed ANDA's for synthetic conjugated estrogens drug 
products and responds to both Duramed's and Barr's requests for an 
opportunity for a hearing on the question of whether there are grounds 
for refusing to approve those ANDA's.

[[Page 42563]]

II. Regulatory History of Conjugated Estrogens

    FDA first permitted a new drug application for Premarin to become 
effective in 1942 under the new drug provisions of the act (Pub. L. 75-
717, 52 Stat. 1040 (1938)), based on chemistry, manufacturing, and 
controls information acceptable at that time and a showing, from 
reports of clinical investigations, that the drug product was safe for 
its intended use in the treatment of menopausal symptoms and related 
conditions. The product was known at that time to contain estrone and 
equilin, and it was known that additional estrogens were present in 
smaller amounts. The tablet strengths and estrogenic potencies of 
Premarin tablets were controlled using a colorimetric assay and a rat 
bioassay, respectively, with estrone as the reference standard. Thus, 
the 0.625 mg Premarin tablet was assigned this value because it 
contained estrogenic potency that, in the rat model, was equivalent to 
0.625 mg of sodium estrone sulfate.
    In 1970, the United States Pharmacopeia (USP) published monographs 
for conjugated estrogens and conjugated estrogens tablets, establishing 
the first compendial standards for these products (Ref. 1). The USP 
described conjugated estrogens as containing sodium estrone sulfate and 
sodium equilin sulfate.<SUP>1</SUP> This description appears to have 
been based on the known quantity, in Premarin, of each of the two 
ingredients as well as their demonstrated clinical estrogenic effects 
(Refs. 2, 3, and 4). The two compounds were known to be the most 
abundant estrogens in Premarin. Clinical data showing estrone to be an 
active estrogen were available, and small-scale clinical studies of 
sodium equilin sulfate indicated that it was a more potent estrogen 
than estrone (Ref. 6). Limited data from a study completed in 1963 and 
published in 1971 suggested that sodium 17<greek-a>-dihydroequilin 
sulfate, the third most abundant estrogen, had little clinical activity 
(Ref. 6).
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    \1\ In the preamble to the final rule implementing Title I of 
the Drug Price Competition and Patent Term Restoration Act of 1984, 
FDA stated that, although in most cases the agency will consider an 
active ingredient to be the same as that of the reference listed 
drug if it meets the standards of identity described in the USP, 
``in some cases, FDA may prescribe additional standards that are 
material to an ingredient's sameness.'' (See 57 FR 17950 at 17959, 
April 28, 1992). See also Sec. 320.1(c) (21 CFR 320.1(c)), which 
states that an identical active drug ingredient may meet ``identical 
compendial or other applicable standards'' (emphasis added). FDA 
applies current scientific knowledge in making its regulatory 
decisions, even if that knowledge has not yet been incorporated into 
the USP monograph.
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    With the publication of the monographs in 1970, the rat potency 
test was eliminated and replace by a chemical assay for the two active 
ingredients. However, the traditional strength assignment was 
maintained, even though the tablets contained fewer milligrams of 
sodium estrone sulfate and sodium equilin sulfate than the milligram 
dose stated on the label.
    In 1972, FDA published an assessment of the effectiveness of 
Premarin (Ref. 7). Drugs such as Premarin that were approved prior to 
1962 were required to demonstrate safety but not effectiveness at the 
time of approval. In 1962, enactment of the Harris-Kefauver amendments 
to the act created a requirement for a demonstration of the 
effectiveness of new drugs including new drugs approved between 1938 
and 1962 (Pub. L. 87-781, 76 Stat. 780). FDA contracted with the 
National Academy of Sciences/National Research Council to carry out the 
Drug Efficacy Study to assess the evidence of effectiveness available 
for new drugs approved prior to 1962. FDA then implemented the results 
in an effort known as the Drug Efficacy Study Implementation (DESI). 
The 1972 Federal Register notice announced FDA's conclusion that a 
number of estrogen products, including Premarin, had been shown to be 
effective for menopausal symptoms (and several other conditions) based 
on the DESI Panel recommendations and other available evidence. FDA 
also found that the listed estrogen products were ``probably 
effective'' for prevention of osteoporosis. For indications found to be 
``probably effective,'' FDA required sponsors to either submit 
substantial evidence of effectiveness or remove the indication from the 
product labeling within a certain period of time.
    In 1978, Ayerst Laboratories proposed that conjugated estrogens be 
required to contain seven estrogenic components. Ayerst subsequently 
modified this proposal to request only that 17<greek-a>-dihydroequilin 
be added to the existing USP monograph (Ref. 8). In 1982, FDA and USP 
convened a public meeting to discuss Ayerst Laboratories' proposal that 
the monograph for conjugated estrogens include 17<greek-a>-
dihydroequilin (Ref. 9). FDA stated at that time that the composition 
of conjugated estrogens should be determined by estrogenic potency and 
that the proposed compound had low potency and likely did not 
contribute to the clinical effect. USP determined that 17<greek-a>-
dihydroequilin should not be added to the monograph as an active 
ingredient.
    In 1980, FDA published the first version of the document now known 
as the Approved Drug Products with Therapeutic Equivalence 
Determinations, also known as the ``Orange Book'' (Ref. 10). This 
document lists the FDA assignment of therapeutic equivalence among 
duplicate drug products based on available data pertaining to their 
pharmaceutical equivalence and bioequivalence. Existing conjugated 
estrogens tablet products were classified as ``BS,'' i.e., not 
considered therapeutically equivalent, because of concern that the USP 
monograph specifications for estrone sulfate and equilin sulfate were 
inadequate to ensure that products meeting the monograph standard would 
necessarily produce equivalent therapeutic effects in patients (Ref. 
11). The ``BS'' code is used by FDA to indicate that drug products are 
not considered therapeutic equivalents due to deficient drug standards.
    In 1986, FDA announced in the Federal Register that a 0.625 mg dose 
of Premarin daily was found to be effective for prevention of 
osteoporosis in postmenopausal women (Ref. 12). Two dose-response 
studies evaluating the effect of Premarin on bone mineral density had 
been published in the literature (Refs. 13 and 14).
    In 1986, while developing an appropriate in vitro dissolution test 
standard for conjugated estrogens bioequivalence testing, FDA 
discovered that Premarin tablets were a modified release dosage form 
(Ref. 15). This unexpected characteristic of the Premarin formulation 
meant that generic copies were unlikely to be bioequivalent unless they 
also had similar modified release characteristics. Because of this 
discovery, FDA changed the Orange Book code for generic conjugated 
estrogens tablets from ``BS'' to ``BP'' (Ref. 16). The code ``BP'' 
means that generic products so labeled are not considered 
therapeutically equivalent due to a potential bioequivalence problem. 
FDA then began to require that generic conjugated estrogens products 
demonstrate bioequivalence through in vivo human subject bioequivalence 
testing (Ref. 17). Because bioequivalence testing is ordinarily 
performed on the active ingredients of a product, the question of the 
active ingredients of Premarin again was raised.
    In 1989, FDA's Fertility and Maternal Health Drugs Advisory 
Committee considered the question of the active ingredients in Premarin 
(Ref. 18). The Committee agreed that sodium estrone sulfate and sodium 
equilin sulfate are active ingredients, but could not reach a consensus 
on whether or not other

[[Page 42564]]

estrogens in Premarin were active ingredients (Ref. 19). In 1990, an Ad 
Hoc Subcommittee of the Fertility and Maternal Health Drugs Advisory 
Committee met to consider Premarin bioequivalence issues (Ref. 20). 
Again, the group agreed that the two named active ingredients were 
correctly designated, but could not reach a consensus on whether 
additional components should be regarded as active ingredients (Ref. 
21).
    In 1990, FDA published a proposal to withdraw approval of the 
``BP'' coded generic conjugated estrogens formulations for which 
therapeutic equivalence could not be ensured (Ref. 22). The proposal 
included withdrawing all generic conjugated estrogens marketed at that 
time. The agency withdrew approval for these products in 1991, and 
there are currently no approved generic conjugated estrogens tablets on 
the U.S. market (Refs. 23 and 24).
    In February 1991, FDA's Generic Drugs Advisory Committee met to 
consider issues of pharmaceutical equivalence and bioequivalence for 
conjugated estrogens (Ref. 25). FDA proposed to the committee that 
three of the additional estrogens in Premarin be recommended for 
inclusion as ``concomitant components'' in the USP monograph for 
conjugated estrogens (Refs. 26 and 27). These particular ``concomitant 
components'' would be required to be in the product, but would not be 
considered active ingredients and, thus, would not need to be included 
in bioequivalence testing (Ref. 28). The Generic Drugs Advisory 
Committee endorsed this proposal (Ref. 29). Subsequently, the USP 
monographs on conjugated estrogens were amended to include the three 
additional ``concomitant components'' (Ref. 30).
    On November 30, 1994, Wyeth-Ayerst submitted a citizen petition 
requesting, among other things, that FDA not approve any generic 
conjugated estrogens products that do not contain the compound sodium 
``8,9-dehydroestrone sulfate (DHES) (Ref. 31). Wyeth-Ayerst also 
submitted a petition for a stay of action requesting that FDA stay any 
decision to ``receive'' an ANDA for a conjugated estrogens product that 
does not contain DHES and stay any approval of such an application 
until FDA responds to the petition (Ref. 32).
    Because of the complex scientific issues associated with 
determining the active ingredients of conjugated estrogens, in the 
summer of 1995, CDER formed an Ad Hoc Conjugated Estrogens Working 
Group to consider these issues. That group of CDER staff examined 
available data related to the composition of conjugated estrogens and 
prepared a background document for the Fertility and Maternal Health 
Drugs Advisory Committee.
    On July 27 and 28, 1995, FDA's Fertility and Maternal Health Drugs 
Advisory Committee, with representation from FDA's Generic Drugs 
Advisory Committee and FDA's Endocrinologic and Metabolic Drugs 
Advisory Committee, heard presentations and discussions on the 
composition of conjugated estrogens (Ref. 33). At the end of the 
deliberations, in answer to questions regarding what additional 
components, if any, beyond the two recognized active ingredients 
contribute to the clinical safety and effectiveness of Premarin, the 
Committee voted unanimously in favor of the following statement:

    The Committee feels that insufficient data were presented to 
determine whether or not any individual component of Premarin or any 
combination of components in Premarin other than estrone sulfate and 
equilin sulfate must be present in order for Premarin to achieve its 
established levels of efficacy and safety [emphasis added].

(Ref. 34).
    On November 1, 1996, FDA completed a ``Preliminary Analysis of 
Scientific Data on the Composition of Conjugated Estrogens' (Ref. 35).
    On May 1, 1997, the Ad Hoc Conjugated Estrogens Working Group 
completed its final report providing a scientific clarity background 
for CDER's decision regarding the composition of conjugated estrogens 
(Ref. 36).
    The regulatory history of conjugated estrogens reflects the 
complexity of the scientific issues involved. FDA's positions on these 
issues have evolved over time as new information has become available. 
As with any such complicated scientific issue, differences in 
scientific opinion arose and continue to exist concerning how available 
data are to be interpreted and applied in the regulatory context. These 
differing views (Refs. 37, 38, and 39) were considered prior to this 
proposed order refusing to approve the two ANDA's for synthetic 
conjugated estrogens identified above.

III. The Deficiencies in ANDA 40-115 and ANDA 40-154

    The primary basis of this proposed order refusing to approve ANDA 
40-115 and ANDA 40-154 is that these ANDA's fail to provide sufficient 
information to show that the active ingredients of the proposed generic 
drug products are the same as the active ingredients of the reference 
listed drug. Below is a summary of the applicable legal requirements 
and a detailed statement on the scientific basis for CDER's conclusion 
that the ANDA's fail to show that the active ingredients of the 
proposed generic drug products are the same as those of the reference 
listed drug.

A. Legal Requirements

    Under section 505(j)(2)(A)(ii)(II) of the act, an ANDA for a drug 
product with more than a single ingredient must include information to 
show that the active ingredients of the drug that is the subject of the 
ANDA are the same as those in the reference listed drug, except for any 
different active ingredient for which a petition was approved under 
section 505(j)(2)(c) of the act. Furthermore, under section 
505(j)(3)(J) of the act and Sec. 314.127(a)(12) (21 CFR 
314.127(a)(12)), FDA is required to refuse to approve any ANDA that 
fails to include such information. In addition, under 
Sec. 314.127(a)(3)(ii), which implements section 505(j)(3)(C)(ii) of 
the act, FDA is required to refuse to approve an ANDA if ``information 
submitted with the abbreviated new drug application is insufficient to 
show that the active ingredients are the same as the active ingredients 
of the reference listed drug.''
    Under 21 CFR 314.92(a)(1), the term ``same as'' is defined as 
``identical in active ingredient(s)'' (Ref. 40). The term ``active 
ingredient'' is defined under 21 CFR 60.3(b)(2) and 210.3(b)(7) as 
follows:

    [A]ny component that is intended to furnish pharmacological 
activity or other direct effect in the diagnosis, cure, mitigation, 
treatment, or prevention of disease, or to affect the structure or 
any function of the body of man or other animals.

    In the context of ANDA approvals, a generic product with the same 
active ingredients as the reference listed drug that is shown to be 
bioequivalent is approved without independent effectiveness 
data.<SUP>2</SUP> To meet the definition of an active ingredient, a 
component must be intended to furnish sufficient pharmacological 
activity, or other direct effect, to have some therapeutic effect 
(i.e., to diagnose, cure, mitigate, treat, or prevent disease, or to 
affect the structure or function of the body). An active ingredient 
performs a drug's therapeutic functions. The definition of 
``pharmaceutical

[[Page 42565]]

equivalents'' in Sec. 320.1(c) is consistent with this definition of 
active ingredient in that it focuses on the therapeutic moiety:
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    \2\ In enacting the Drug Price Competition and Patent Term 
Restoration Act of 1984, Congress intended that no safety or 
effectiveness data beyond that developed by the innovator company be 
needed to support approval of the generic product. (See H. Rept. 857 
(Part I), 98th Cong., 2d sess. 14, 16-17 (1984).) The interpretation 
of the active ingredient definition in this notice is intended 
solely as applied to ANDA approval.

    Pharmaceutical equivalents means drug products that contain 
identical amounts of the identical active drug ingredients, i.e., 
the same salt or ester of the same therapeutic moiety * * * that 
meet identical compendial or other applicable standard of identity, 
strength, quality, and purity, * * * disintegration times and/or 
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dissolution rates.

    Consequently, not all components that ``furnish pharmacological 
activity or other direct effect'' meet the definition of an active 
ingredient. A component may be considered an active ingredient only if 
it provides a clinically meaningful contribution to the therapeutic 
effect of the drug. A subjective intent for a component to have such 
effect will not suffice in the absence of objective evidence of a 
clinically meaningful contribution. (Cf. 21 CFR 201.128 (defining 
intended use).) In most cases it will be clear what components of a 
drug make clinically meaningful contributions to the drug's therapeutic 
effects and, therefore, are the drug's active ingredients. However, 
where FDA has determined there is sufficient evidence that a component 
in the reference listed drug may make a clinically meaningful 
contribution to the therapeutic effect, the agency cannot approve a 
synthetic generic version of the drug that does not include such 
component until it has been determined whether the component makes such 
a contribution.
    As discussed below, Duramed's ANDA 40-115 and Barr's ANDA 40-154 
provide insufficient information to show that the active ingredients of 
their conjugated estrogens tablets are the same as the active 
ingredients of the reference listed drug, Premarin.

B. Active Ingredients of Premarin Are Not Fully Characterized

1. CDER's Historical Position on the Active Ingredients of Premarin
    Although FDA's Scientific Advisory Committees were unable to 
provide definitive advice on this issue, FDA continued to support the 
position taken in the 1970 USP monograph (Ref. 41) that the ingredients 
sodium estrone sulfate and sodium equilin sulfate are the sole active 
ingredients in Premarin. The reasons for this position follow below 
(Ref. 42).
    Scientific belief had been that all estrogens were similar in their 
pharmacologic actions on the body, i.e., ``an estrogen is an 
estrogen.'' Therefore, it was thought that the pharmacologic activity 
of an estrogen preparation could be described in terms of its total 
estrogenic potency. It was believed that the effects of different 
estrogens in a mixture were additive and that the identity of the 
particular estrogen contributing the estrogenic potency was not 
crucial. Epidemiologic data did not reveal safety or effectiveness 
differences among various estrogen preparations used for hormone 
replacement therapy.
    As a result, Premarin had historically been defined in terms of 
total estrogenic potency rather than the sum of the potencies of 
various components. In 1970, when the first USP monograph was 
published, little information was available on the effects of estrogens 
on bone, and the estimates of estrogenic potency of Premarin components 
were derived from clinical studies of menopausal symptoms. Much of 
Premarin's estrogenic potency for menopausal symptoms can be attributed 
to the effects of estrone and equilin.
    Available data on the detailed composition of Premarin and the 
pharmacologic activity of its components were limited. Much of the 
available data indicated that many compounds found in Premarin were 
present in small amounts and had weak estrogenic activity.
    Based on the results of early studies, including studies of 
Premarin, the effects of estrogen on bone mineral density appeared to 
have a very steep dose-response relationship, and the 0.625 mg dose of 
Premarin appeared to be near the top of the dose-response curve. 
Therefore, it was believed that small differences in the estrogenic 
potency of conjugated estrogens preparations, resulting from omission 
of components from generic copies, would not be clinically meaningful.
    In addition, the monograph ranges for the content of sodium estrone 
sulfate and sodium equilin sulfate in conjugated estrogens are wide 
(Ref. 43). Therefore, it was believed that minor differences in 
estrogen content between synthetic generic products and Premarin due to 
the absence in the generic copies of several minor Premarin 
constituents could not make a clinically meaningful difference.

    Note: the percent coefficient of variation of sodium estrone 
sulfate is 1.98, and of sodium equilin sulfate is 3.01, based on 
percent estrogen composition in 500 batches of Premarin Tablets (Ref. 
44).
2. CDER's Current Position on Premarin's Active Ingredients
    CDER's current position on Premarin's active ingredients is that 
Premarin is not sufficiently characterized at this time to determine 
all of its active ingredients, for the reasons that follow below.
    Emerging scientific evidence demonstrates that all estrogens do not 
exert their effects in a uniform manner with respect to different 
target tissues. These differential effects may be due to variable 
pharmacokinetics, <SUP>3</SUP> tissue metabolism, tissue-specific 
receptor factors, or additional reasons (Refs. 45, 46, 47, 48, 49, and 
50). For example, clinical studies have shown that the potency of 
equilin sulfate relative to estrone sulfate varies depending on the 
pharmacodynamic <SUP>4</SUP> effect being studied (Refs. 6 and 51). A 
dose of equilin sulfate that is equipotent to estrone sulfate using one 
parameter may be more or less potent when evaluated using a different 
measure. For this reason, the active ingredients of Premarin cannot be 
defined solely in terms of overall estrogenic potency in any single 
system, but must be defined based on their contributions to particular 
estrogenic effects.
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    \3\ Pharmacokinetics can be defined as drug absorption, 
excretion, metabolism, or distribution.
    \4\ Pharmacodynamics can be defined as a pharmacologic or 
clinical response to a given concentration [of a drug] in blood or 
other tissue (58 FR 39406 at 39409 (July 22, 1993)).
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    Put simply, the new scientific evidence shows that one estrogen can 
be more active than another in a specific tissue or organ, such as 
breast, uterus, or bone. The most striking example of this is the 
synthetic estrogen analog tamoxifen, which blocks estrogen actions in 
breast tissue, but has estrogen-like activity on bone. These new 
findings have stimulated extensive research into new pharmaceuticals 
that could have selective actions on specific tissues and thus might 
provide beneficial hormone replacement therapy without some of the 
undesirable side effects, or could be useful in the treatment of cancer 
or other conditions.
    Compositional analysis of Premarin using modern analytical 
techniques demonstrates that it consists of a mixture of a substantial 
number of compounds with potential pharmacologic activity. In fact, the 
steroidal content of Premarin has not been completely defined (Ref. 
52). Undoubtedly, many of the compounds present in Premarin do not 
provide a clinically meaningful contribution to the therapeutic effects 
of the drug and are best thought of as impurities. However, the 
clinical tests, on which the findings of the safety and efficacy of 
Premarin were based, were performed on the entire mixture, not on 
individual components. A basic understanding of the chemical 
composition of Premarin must be achieved as a first step in

[[Page 42566]]

adequately characterizing the product unless a complete understanding 
of which components provide a meaningful clinical contribution to the 
effects of the product is achieved by clinical trials alone.
    Clinical studies have revealed that the assigned potencies of 
Premarin tablets, which were based on the rat bioassay, do not 
correctly reflect the tablets' relative potencies in human studies 
(Refs. 6, 50, 51, and 53). For example, clinical studies have shown 
that Premarin is between 1.4 and 2.5 times more potent than estrone 
sulfate for suppression of follicle-stimulating hormone (FSH) and 
menopausal symptoms in postmenopausal women (Refs. 6 and 50). Because 
the human studies evaluating the relative potency of Premarin have been 
small, a precise estimate of the estrogenic potency of Premarin 
relative to estrone sulfate has not been determined. Because the 
relative potencies of Premarin, estrone sulfate, and equilin sulfate 
are not clearly established, it is not possible to tell how much of the 
effect of Premarin can be accounted for by the effects of equilin 
sulfate and estrone sulfate. Measuring these effects is further 
complicated by the fact that the importance or contribution of each 
ingredient may depend on the tissue that is being tested, e.g., bone, 
breast, pituitary, or uterus.
    New clinical studies have clearly demonstrated that there is a 
dose-response relationship between estrogen administration and bone 
mineral density in postmenopausal women (Refs. 54 and 55). It follows 
that ensuring an equivalent estrogenic potency is important in the 
approval of generic copies of estrogen products intended for prevention 
of osteoporosis. In other words, it is important for the osteoporosis 
indication that synthetic generic conjugated estrogens based on 
Premarin have estrogenic strength that is identical to the Premarin 
tablet.
    The recent findings with regard to <triangle>8,9-dehydroestrone 
sulfate (DHES) illustrate a number of the above points. This compound 
was first detected in Premarin in 1975 (Refs. 56 and 57). DHES 
represents only a small percentage of the estrogenic compounds present 
in the product: 4.4 percent of the ``label claim'' (i.e., 4.4 percent 
of 0.625 mg or approximately 0.0275 mg of DHES per 0.625 mg tablet). 
(Note: Premarin also contains a small amount of the DHES metabolite 
sodium 17<greek-b>-<triangle>8,9-dehydroestradiol sulfate (Ref. 58). 
This metabolite comprises approximately 0.003 mg per 0.625 mg tablet. 
Therefore, the total DHES plus sodium 17<greek-b>-<triangle>8,9-
dehydroestradiol sulfate content of a 0.625 mg tablet is about 0.03 mg 
or approximately 5 percent of label claim.) Until recently little has 
been known about DHES or sodium 17<greek-b>-<triangle>8,9-
dehydroestradiol sulfate.
    Pharmacokinetic studies submitted by Wyeth-Ayerst demonstrate that, 
after single or repeated oral dosing of Premarin in women, the plasma 
concentrations or areas under the curve (AUC's) of the (conjugated plus 
unconjugated) 17<greek-b>-<triangle>8,9-dehydroestradiol metabolite of 
DHES are the same order of magnitude as the concentration of the 
17<greek-b>-diol metabolites of the active ingredients estrone and 
equilin (Refs. 59, 60, and 61). The 17<greek-b> <triangle>8,9-estradiol 
concentration is approximately 34 percent of the combined 
concentrations of the 17<greek-b>-diol metabolites of estrone and 
equilin, or 26 percent of the 17<greek-b>-diol metabolites from the 
three estrogens. The finding that a low-level (5 percent) component of 
the tablet would generate a significant concentration of a potentially 
active metabolite was completely unexpected and illustrates the 
longstanding inadequate characterization of Premarin. These 
pharmacokinetic data do not themselves prove that the DHES in Premarin 
makes a clinically meaningful contribution to the therapeutic effect of 
Premarin. However, preliminary clinical studies indicate that the 
potency of DHES may be similar to that of equilin. (See detailed 
discussion below.)
    Based on this new scientific information, CDER concludes that 
Premarin is not adequately characterized and that, therefore, at this 
time, its active ingredients cannot be fully determined. Additional 
information on both composition and relative potencies of components 
will be necessary to adequately characterize this product. This 
conclusion is in agreement with the findings of FDA's Fertility and 
Maternal Health Advisory Committee at its July 27 and 28, 1995, meeting 
on this subject (Ref. 33).
3. Unresolved Issues Concerning the Current Characterization of 
Premarin
    At the time of marketing, products such as Premarin, that are 
derived from natural source material, frequently are not characterized 
as completely as synthetic products would be. The term ``adequate 
characterization'' is intended to mean an amount of scientific 
information on a product that is sufficient to determine what 
constituents in the product are responsible for making clinically 
meaningful contributions to its therapeutic effects. In other words, it 
is possible to define the active ingredients of a product that is 
adequately characterized.
    There are at least two possible ways to characterize a product. The 
most straightforward method includes, first, chemical analysis to 
determine what components are present at significant levels in the 
product. The interpretation of ``significant levels'' cannot be exact 
and would depend on the specific product; however, it is desirable that 
components present at the 0.1 percent level or greater be identified 
and quantified. Once the components of the product are identified, the 
next step in characterization would be to determine which of them have 
potential human pharmacologic activity. Such a determination may be 
based on the following: The quantitative amount in the product, 
structure-function relationships, in vitro tests, animal studies, human 
studies, or a combination of these. Finally, for components that may 
contribute to the therapeutic effect based on potential pharmacologic 
activity, a study could be conducted comparing the effects of each 
component alone, and in combination with additional components, to the 
effects of the entire product, to demonstrate that the ``candidate'' 
components achieved all of the therapeutic effects of the product.
    Alternatively, in cases where there is some confidence that the 
``candidate'' active ingredients have all been identified, even though 
the product is not fully chemically characterized, a head-to-head 
comparative dose-response clinical trial(s) comparing the effects of 
the combined ``candidate'' active ingredients against the original 
product could, if carried out carefully, demonstrate that the 
combination contributed all the clinically meaningful therapeutic 
effects of the original product. This approach might not clearly 
identify which of the ``candidates'' were actually active, but could 
ensure that the combination tested included all of the active 
ingredients in the product.
    The following sections discuss the available scientific evidence on 
the characterization of Premarin.
    a. Composition of Premarin. At least ten estrogenic compounds have 
been identified and quantified in Premarin. The composition data for 
the 10 estrogenic compounds cited in the Conjugated Estrogens USP 
monograph, and listed in Table 1, were generated by CDER's Division of 
Drug Analysis from an analysis of 2 batches of Premarin

[[Page 42567]]

0.625 mg tablets (Ref. 62). These results agree generally with other 
data available to CDER.

         Table 1.--Composition Data for 10 Estrogenic Compounds         
------------------------------------------------------------------------
                   Sodium estrogen sulfate                     Mg/tablet
------------------------------------------------------------------------
Estrone.....................................................       0.370
Equilin.....................................................       0.168
17<greek-a>-Dihydroequilin..................................       0.102
17<greek-a>-Estradiol.......................................       0.027
17<greek-b>-Dihydroequilin..................................       0.011
l7<greek-a>-Dihydroequilenin................................       0.011
17<greek-b>-Dihydroequilenin................................       0.021
Equilenin...................................................       0.015
17<greek-b>-Estradiol.......................................       0.005
<greek-D>8,9-dehydroestrone.................................       0.026
------------------------------------------------------------------------

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

              Table 2.--Results of Pharmacokinetic Studies              
------------------------------------------------------------------------
              Estrogen                Estrone   Equilin   <greek-D>8,9- 
---------------------------------------------------------------DHE------
Measured dose or AUC...............  ........  ........  ...............
mg per 2X 0.625mg tab..............     0.740     0.336          0.052  
Total plasma ketone (ng<bullet>hr/                                      
 mL)...............................    94.200    43.145         13.610  
Uncon.plasma ketone (ng<bullet>hr/                                      
 mL)...............................     4.083     1.201          0.072  
Total plasma 17<greek-b>diol                                            
 (ng<bullet>hr/mL).................     8.565    10.623          6.624  
Uncon.plasma 17<greek-b>diol                                            
 (ng<bullet>hr/mL).................     0.659     1.060          0.331  
------------------------------------------------------------------------

    The pharmacokinetics of Premarin components are complex, as 
revealed in these data. Estrone, equilin, <greek-D>8,9-dehydroestrone 
(DHE), their active 17<greek-b>-reduced metabolites, and other 
estrogenic components of Premarin circulate in the plasma both as the 
conjugated (primarily sulfate ester) and unconjugated derivatives and 
with various degrees of protein binding, as discussed in the OCPB 
Report. There is interconversion between the ketone and 17<greek-b>-
reduced forms of each estrogen and among the conjugated and 
unconjugated derivatives. The degree of protein binding of each 
derivative may be important to its clinical activity.
    Put simply, this information shows that there is not a one-to-one 
relationship between the amount of each estrogen in the tablet and the 
amount of active forms (derivatives) of that estrogen in the blood. 
Each of the three estrogens evaluated in this clinical trial 
distributes differently into its derivatives in the body. This means 
that each of the three estrogens might cause different effects simply 
as a result of these distributional differences.
    The actual magnitude of the contribution of each derivative of any 
component estrogen to the overall estrogenicity of Premarin is not well 
understood. As just stated, the pharmacokinetic data show that the 
ratios of the concentrations of the different derivatives are 
distributed differently for those estrogens that have been studied: 
Estrone, equilin, and DHE. If there are tissue-specific effects of 
derivatives, then the size of a derivative's contribution could vary 
depending on the tissue tested. The available data suggest that these 
tissue-specific differences exist. For example, in vitro potency data 
for estrone and 17<greek-b>-estradiol were submitted by Wyeth-Ayerst 
(Ref. 74). When potency was tested by estrogen receptor binding, 
estrone was shown to be much less potent than estradiol (about 200 
times less), as has been previously shown by receptor binding and 
cellular assays. In contrast, when potency testing was performed in a 
liver (Hep-G2) cell line using functional activation, estrone's potency 
appeared to be of the same order of magnitude as estradiol's potency. 
The experimenters were able to show that this increased potency of 
estrone resulted from its conversion to estradiol by the cells. 
Therefore, in tissues that have the capability to metabolize ketone 
forms to diols (e.g., estrone to estradiol), circulating ketone forms 
could make a large contribution to observed effects in that tissue. 
Similarly, conversion of conjugated (sulfated) forms of circulating 
estrogens to the unconjugated forms has been shown to occur in target 
tissues such as breast

[[Page 42568]]

(Ref. 75). In these tissues, total estrogen concentrations (i.e., 
conjugated plus unconjugated) may be more important than in tissues 
that cannot convert the conjugated forms to the active, unconjugated 
forms.
    One striking finding in the pharmacokinetic data is the differences 
in the proportions of the 17<greek-b>-diol concentrations resulting 
from the three estrogens (sodium estrone sulfate, sodium equilin 
sulfate, and DHES), compared to the ratios of the three estrogens in 
the tablet. It is known that the 17<greek-b>-diol derivatives of 
equilin and estrone are potent estrogens. The pharmacokinetic data as a 
whole show that, after dosing with Premarin, the plasma concentration 
of unconjugated 17<greek-b>-dihydroequilin is about twice (1.6 times) 
as high as the concentration of 17<greek-b>-estradiol, even though 
there is only about half as much equilin as estrone in the tablet. The 
difference in the concentration of the active metabolite may account 
for the known greater clinical estrogenic potency of equilin. As 
discussed above, an unexpected finding from the pharmacokinetic data in 
the Missouri study (Ref. 61), the most reliable data generated to date, 
was that the plasma concentration of unconjugated 17<greek-b>-
<greek-D>8,9-dehydroestradiol is about half the concentration of 
unconjugated 17<greek-b>-estradiol, even though there is more than 10 
times more estrone sulfate than DHES in Premarin. This may account for 
the high oral potency of DHES that has been found in the limited 
clinical studies performed with this compound (Refs. 76 and 77).
    Put simply, these data show that a dose of DHES results in a much 
higher blood level of the active metabolite than would result from the 
same dose of estrone sulfate. This finding alone suggests, but does not 
prove, that a low dose of DHES could have a much larger than expected 
effect.
    The above pharmacokinetic data provide a basis for beginning to 
understand the complex relationship between the composition of Premarin 
and its clinical effects. However, this understanding is still 
incomplete. The pharmacokinetics must be understood in the context of 
pharmacodynamic properties of the various components, including their 
clinical effects.
    c. Clinical effects of Premarin. Premarin and certain Premarin 
components have been tested fairly extensively in animals, particularly 
rodents. Animal data, either in vitro or in vivo, have not proven to be 
quantitatively predictive of the effects found in women (Ref. 78). 
Therefore, animal tests, while useful in screening compounds for 
activity, cannot be used to definitively assign human clinical effects. 
The most confident conclusions can be drawn from human clinical 
testing. The following summarizes what is known about the contribution 
of Premarin components to its overall activity from in vitro or in vivo 
human testing.
    i. Pharmacodynamics. The term ``pharmacodynamics'' refers to 
pharmacologic or clinical responses to a given concentration of a drug 
in blood or other tissue.<SUP>5</SUP> For example, raising or lowering 
blood pressure, causing dry mouth, or constricting the pupils are 
pharmacodynamic effects of various drugs. Pharmacodynamic effects can 
be beneficial, harmful, or neutral. The benefits of most drugs derive 
from their desired pharmacodynamic effects, while drug side effects 
often result from undesirable pharmacodynamic activity.
---------------------------------------------------------------------------

    \5\ See footnote 3, supra.
---------------------------------------------------------------------------

    Premarin and its components, like other estrogens, affect a wide 
variety of human tissues, including pituitary, breast, uterus, bone, 
liver, and endothelium (Ref. 47). Some of these actions result in the 
beneficial effects of the drug, some cause side effects, and some (for 
example, cardiovascular or lipoprotein effects) have not been 
definitively evaluated. There are studies in the literature of effects 
of estrogen on each of these tissues, especially effects on the 
pituitary, uterus, and bone. This section discusses the pharmacodynamic 
effects of Premarin and its components other than the relief of 
menopausal symptoms and prevention of osteoporosis.
    A dose-response relationship exists between estrogen treatment and 
FSH suppression (Ref. 79). Some pharmacodynamic data on suppression of 
FSH, including dose-response data, exist for equilin sulfate, estrone 
sulfate, and Premarin (see also menopausal symptoms, below) (Refs. 5, 
6, 50, and 80). In a study of suppression of urinary gonadotrophins, 
equilin was found to be about twice as potent as Premarin and five 
times more potent than estrone sulfate for this effect, while Premarin 
was 2.5 times more potent than estrone sulfate (Ref. 6). In studies of 
human serum FSH levels, Premarin has been found to be about 1.4 to 2.0 
times as potent as estrone sulfate (Refs. 50 and 81). These studies are 
in relative agreement.
    The published data on the effects of Premarin and its components on 
uterine or vaginal markers are limited. Beck and Friedrich found 
equilin sulfate to be two to three times more potent than Premarin for 
effects on vaginal epithelium and endometrium (Ref. 82). Varma et al. 
found Premarin to be twice as potent as estrone sulfate for endometrial 
changes (Ref. 81). Geola et al. evaluated the dose-response 
relationship between Premarin and vaginal cytologies and concluded that 
1.25 mg Premarin daily was necessary for achieving full replacement 
levels for this parameter (Ref. 80). These studies are not adequate for 
drawing firm conclusions about the relative contributions of equilin 
and estrone to the effects of Premarin on uterine or vaginal markers.
    A number of studies of Premarin or its components have evaluated 
pharmacodynamic markers of bone effects (Refs. 14, 51, 79, 80, and 83). 
Jones et al. estimated that Premarin was twice as potent as estrone 
sulfate for reduction of the urinary calcium/creatinine ratio. This 
ratio is a measure of bone resorption. Geola et al. performed a dose-
response study evaluating the effect of Premarin on the calcium/
creatinine ratio, and found that 0.3 mg Premarin was the lowest dose to 
have a significant effect. Lobo et al. found that Premarin was twice as 
potent as both estrone sulfate and equilin sulfate for reduction of the 
urinary calcium/creatinine ratio. The Lobo finding of a significant 
effect of 0.3 mg Premarin was not duplicated in a larger study by 
Lindsay et al. (Ref. 14). Because of limitations in study designs and 
because the pharmacodynamic markers for bone are not sufficiently 
quantitative, no conclusions about comparative pharmacodynamic effects 
on bone of Premarin or its components can be drawn from these results.
    Data on Premarin or Premarin component effects on lipoproteins and 
other plasma proteins, or other pharmacodynamic markers are quite 
limited (Refs. 49, 50, 51, 53, and 84). Having information about these 
effects is important for several reasons. Stimulatory effects on liver 
proteins may affect drug safety. In addition, as discussed in the OCPB 
Report (Ref. 71), levels of circulating unconjugated estrogens may be 
affected by binding to plasma proteins, particularly sex hormone 
binding globulin (SHBG). Stimulation of SHBG could alter drug 
availability. Available data suggest that certain Premarin components 
differ in the ability to stimulate SHBG (Ref. 50). Human 
pharmacodynamic data on DHES submitted by Wyeth-Ayerst demonstrated 
that 1.25 mg estrone sulfate had a much greater effect on SHBG levels 
than did 0.125 mg DHES (Ref. 85); however, this result requires 
confirmation.
    Taken as a whole, the available pharmacologic data demonstrate that

[[Page 42569]]

estrone sulfate (as the piperazine salt), equilin sulfate, and Premarin 
have different pharmacodynamic effects when potency on various tissues 
is evaluated (Refs. 6, 50, 51, and 53). For example, in a single study, 
Premarin was found to be 1.4 times more potent than piperazine estrone 
sulfate (expressed as the sodium rather than piperazine salt) for FSH 
suppression, a pituitary effect (Ref. 50). In contrast, Premarin was 
3.5 times more potent than estrone sulfate for stimulation of 
angiotensinogen and 3.2 times more potent for stimulation of sex 
hormone binding globulin (SHBG). Presumably, this difference arises 
because other components of Premarin contribute to these effects in a 
manner different from estrone sulfate. It is not known if these 
differential pharmacodynamic effects are completely attributable to the 
presence of equilin sulfate.
    In summary, the two Premarin components that have been carefully 
studied, equilin sulfate and estrone sulfate, differ from each other 
and from Premarin in phamacodynamic profile. It is not well understood 
which of the pharamcodynamic actions are desirable and which contribute 
to unwanted side effects. Adequate characterization of Premarin will 
require an understanding, based on scientific data, of those Premarin 
components that contribute to the pharmacodynamic effects of Premarin.
    ii. Clinical effects: menopausal symptoms. A number of clinical 
studies evaluating Premarin and Premarin components for the treatment 
of menopausal symptoms have been performed (Refs. 79, 80, 82, and 86). 
Equilin sulfate has been found to be about three times more potent than 
Premarin for alleviating vasomotor symptoms (Ref. 82). The data 
submitted by Wyeth-Ayerst on DHES show that DHES is more potent than 
estrone sulfate for these effects, but the data are not adequate to 
precisely assign a potency (Ref. 76). Without dose-response studies to 
determine the potency of DHES for menopausal symptoms relative to the 
potency of estrone sulfate and equilin sulfate, the contribution of 
DHES to the activity of Premarin in treating menopausal symptoms cannot 
be determined. Similarly, without a head-to-head comparison of the 
dose-related effects of Premarin, estrone sulfate, and equilin sulfate 
in the treatment of menopausal symptoms, the extent of contribution of 
the two components to the overall estrogenic potency of Premarin for 
this effect also cannot be accurately determined, although it is clear 
that both contribute.
    iii. Clinical effects: osteoporosis. (1) Use of surrogate markers. 
The goal of preventive therapies for osteoporosis is the prevention of 
fractures and deformity. For estrogens, FDA accepts measurement of bone 
mineral density as an adequate surrogate for preventing these longer 
term clinical outcomes (Ref. 87). A number of other markers for 
evaluating pharmacodynamic effects on bone have been developed (Ref. 
88). None of these other markers is sufficiently well understood or 
quantitative to permit its use as a surrogate for osteoporosis 
prevention effects. Therefore, in the absence of other validated 
surrogate markers, definitive data on bone effects must come from human 
trials evaluating bone mineral density, fractures, and/or deformity.
    (2) Use of blood 17<greek-b>-estradiol levels as a surrogate 
marker. Comments submitted to the docket of Wyeth-Ayerst's citizen 
petition (Ref. 89), as well as statements in the scientific literature, 
assert that achievement of certain levels (e.g., 39 picograms (pg)/
milliliter (mL) (Palacios et al.) or greater than 60 pg/mL (Reginster 
et al.)) of serum 17<greek-b>-estradiol is an adequate surrogate for 
preservation of bone mineral density because there is a strong 
correlation between the two both in clinical trials and in untreated 
perimenopausal women (Refs. 83 and 90).
    The study by Palacios et al. evaluated women who had undergone 
surgical menopause and who were randomized to percutaneous estradiol, 
conjugated estrogens (source unspecified), or no therapy over 2 years. 
Untreated women lost a mean of 9 percent of spine bone mineral density 
over 2 years, whereas the estradiol treated group and the conjugated 
estrogens treated group gained 4.1 percent and 5.6 percent spinal bone 
mineral density respectively. Women treated with percutaneous estradiol 
were reported to have a mean serum estradiol level of about 80 pg/mL 
over the course of the study. The conjugated estrogens treated women 
had a mean serum estradiol level of about 40 pg/mL. It is not possible 
to conclude anything about a protective level of 17<greek-b>-estradiol 
from the conjugated estrogens arm of this study since conjugated 
estrogens also contain, at a minimum, equilin and possibly other 
components that contribute to the effect on bone. The value of 80 pg/mL 
from the percutaneous estradiol arm is not inconsistent with the data 
reported by Reginster et al. who found that circulating levels of 
17<greek-b>-estradiol between 60 and 90 pg/mL correlated well with 
pharmacodynamic markers of beneficial bone effects. This correlation 
suggests, but does not prove, that estrogen replacement therapies 
achieving such levels of circulating estradiol may be effective in 
preventing bone loss.
    FDA does not currently accept 17<greek-b>-estradiol levels as an 
adequate surrogate for osteoporosis prevention in women. Trials of bone 
mineral density are required. In addition, the available data do not 
indicate that the potentially protective levels of 17<greek-b>-
estradiol are attained after administration of Premarin.
    The Palacios study found that treatment with conjugated estrogens 
0.625 mg resulted in a mean estradiol level of 40 pg/mL, which is below 
the 60 pg/mL minimum suggested by Reginster. However, the Librach and 
Nickel study submitted to the docket, as well as the Reginster study 
and other data reported in the literature, found that serum levels of 
17<greek-b>-estradiol above 60 pg/mL are achieved in women treated with 
Premarin or a Canadian generic copy of Premarin (Refs. 89 and 91). In 
the Librach and Nickel study, women treated with Premarin achieved a 
17<greek-b>-estradiol level of 85.5 pg/mL while women treated with the 
Canadian product had mean serum levels of 94.9 pg/mL. These differences 
appear to relate to problems with analytical methodology, possibly due 
to cross-reactivity of radio-immunoassay reagents with other components 
in Premarin. When serum 17<greek-b>-estradiol is measured by direct 
chemical means, the high 17<greek-b>-estradiol levels are not found in 
women treated daily with 0.625 mg Premarin (Refs. 60 and 61). This 
latter finding is corroborated by data from a study of the effects of 
esterified estrogens (Estratab, USP) on bone mineral density, which was 
recently presented in abstract (Ref. 92). In this study, daily dosing 
with 0.625 mg of esterified estrogens, which contains approximately 
0.518 mg sodium estrone sulfate (Ref. 93) (0.625 mg Premarin contains 
about 0.370 mg sodium estrone sulfate) resulted in a mean plasma 
concentration of 17<greek-b>-estradiol of 40 pg/mL. In addition, in 
this same study, daily administration of 0.3 mg esterified estrogens, 
which contain about 0.248 mg sodium estrone sulfate, resulted in a mean 
plasma concentration of 26 pg/mL of 17<greek-b>-estradiol. These 
results are inconsistent with the serum level results presented by 
Librach and Nickel, but generally agree with Palacios' findings and 
with Wyeth-Ayerst's bioavailability data. Therefore, the available data 
on serum 17<greek-b>-estradiol levels do not indicate that levels over 
60 pg/mL are

[[Page 42570]]

attained with the dose of Premarin recommended for the prevention of 
osteoporosis.
    iv. Clinical effects: bone mineral density. The clinical effects of 
Premarin on bone are well established. A number of clinical trials have 
confirmed the effects of Premarin in preserving and increasing bone 
mineral density in postmenopausal women (Refs. 13, 14, and 94). 
Ettinger et al. demonstrated in a nonrandomized trial that 0.3 mg 
Premarin, when administered with calcium supplementation, was adequate 
to prevent bone mineral loss in the spine and hip (Ref. 95). The recent 
Post-menopausal Estrogens/Progestins Intervention (PEPI) trial 
demonstrated that the currently recommended 0.625 mg dose of Premarin 
resulted in an increase in bone mineral density in women treated for 
over 2 years, while untreated women lost bone (Ref. 96).
    Estrone is approved as a single estrogen (marketed under the brand 
name Ogen by Upjohn, generic name estropipate), but as a different salt 
from the estrone in Premarin (the piperazine rather than the sodium 
salt of estrone sulfate) for the treatment of menopausal symptoms and 
the prevention of osteoporosis. The recommended dose for osteoporosis 
is 0.75 mg of estropipate, which is equivalent to 0.625 mg sodium 
estrone sulfate. A dose-response study has shown that a dose equivalent 
to 0.300 mg estrone sulfate, combined with 1 gram daily calcium 
supplementation, is not effective in preserving bone mineral density 
(Ref. 97). In this study, 0.625 mg of estrone sulfate resulted in 
preservation of bone mineral density compared to baseline. There was no 
statistically significant difference in bone mineral density between 
patients dosed with 0.625 mg and those given 1.25 mg; however, only the 
1.25 mg group had bone mineral densities statistically greater than the 
placebo group at 2-year followup. Based on the data from this trial, 
the amount of estrone sulfate in Premarin (approximately 0.370 mg) is 
too small to account for all of Premarin's known effects on bone 
mineral density, so other estrogens present in the product must be 
contributing to this effect.
    Additional information on the effects of equilin on bone has 
recently become available. On October 30, 1996, Duramed submitted to 
the docket an abstract of a clinical study that had recently been 
presented at a scientific meeting (Ref. 89). The study provided new 
information germane to the clinical effects of Premarin on bone (Ref. 
55). This study, sponsored by Solvay Pharmaceuticals, was a clinical 
trial of their product, Estratab (this trial was also discussed in the 
section on estradiol blood levels). Estratab is a generic esterified 
estrogens product. Esterified estrogens USP contain sodium estrone 
sulfate and sodium equilin sulfate in different amounts than are in 
Premarin (Ref. 98) (based on presentations by Solvay, 0.300 mg of their 
esterified estrogens product contains approximately 0.248 mg estrone 
sulfate and 0.038 mg equilin sulfate) (Ref. 93). The study was a 2-year 
placebo controlled trial testing three doses of Estratab combined with 
calcium supplementation in postmenopausal women evaluating bone mineral 
density and side effects. According to the abstract, all three doses 
were effective at 12, 18, and 24 months in preserving bone mineral 
density compared to placebo. The abstract reveals a dose response among 
the three Estratab doses tested. Also significant is the fact that the 
lowest dose tested, 0.3 mg Estratab, appeared to be effective in 
preserving bone mineral density when given continuously in conjunction 
with calcium supplementation. There are lower amounts of both estrone 
sulfate and equilin sulfate in this dose of Estratab than are required 
to be in the 0.625 mg tablet of generic conjugated estrogens according 
to the current conjugated estrogens USP monograph. Therefore, if the 
data in the abstract are correct, it could be concluded that a product 
containing the amounts of estrone sulfate and equilin sulfate required 
in the current monograph for conjugated estrogens USP would be 
effective in preserving bone mineral density when given continuously 
with supplemental calcium. Since the study by Harris et al. (Ref. 97) 
showed that 0.3 mg of estrone sulfate alone is not effective in 
preserving bone mineral density, then it is likely that there was a 
contribution from the equilin sulfate in the Solvay product, although 
firm conclusions cannot be drawn from cross-study comparisons. This 
information addresses to some extent one of the questions raised in 
FDA's ``Preliminary Analysis of Scientific Data on the Composition of 
Conjugated Estrogens,'' (Ref. 35) that is, that the contribution of 
equilin to preserving bone mineral density had not been demonstrated.
    Despite this additional information, the question of what are the 
active ingredients in Premarin for the indication of maintaining bone 
is not completely resolved. The Solvay study demonstrated a dose 
response for bone mineral density. The lowest dose, 0.3 mg, was 
effective in preserving bone density. The two higher doses, 0.625 mg 
and 1.25 mg, of esterified estrogen actually increased bone density 
over the 2-year period. This finding is consistent with other published 
data (Refs. 54 and 61). In the case of the Solvay study, it is not 
known whether, at the higher doses, more women responded with bone 
preservation than at lower doses, or whether women who would have 
responded to 0.3 mg simply had a larger response to the higher doses. 
In either case, estrogenic potency has been shown to be important to 
the clinical effect on bone within this dose range. It has been 
estimated that a proportion of women taking the recommended dose of 
Premarin continue to lose bone mineral, even though mean values are 
sustained or improved (Ref. 99).
    The finding that sodium equilin sulfate and sodium estrone sulfate, 
at the doses present in Estratab, preserve bone mineral density 
provides support for the proposition that equilin contributes to the 
bone preservation effects of Premarin. However, as discussed at the 
beginning of this memorandum, the requirement for approval of an ANDA 
is not that generic drugs have effects similar to the reference listed 
drug but, rather, that they have the same active ingredients. Only if 
the active ingredients are the same can generic copies be relied upon 
to have the same estrogenic potency and, therefore, the same effects on 
bone.
    Limited data on the pharmacodynamic effects of DHES on bone have 
been submitted by Wyeth-Ayerst (Refs. 76 and 77). These data show that 
DHES has a pharmacodynamic effect on bone markers, but the data do not 
shed light on whether the DHES component of Premarin has a meaningful 
clinical effect on bone.
    v. Safety. There are safety concerns about all estrogen 
preparations currently approved for long-term administration for the 
prevention of osteoporosis. Long-term estrogen administration is 
associated with an increased incidence of endometrial cancer in women 
who have not undergone hysterectomy, and there is an ongoing 
controversy about the relationship of long-term estrogen replacement 
therapy to breast cancer.
    No head-to-head studies have compared the long-term safety of 
various estrogen preparations when used chronically for the prevention 
of osteoporosis. The available epidemiologic evidence, summarized at 
the July 27 and 28, 1995, Advisory Committee meeting, does not 
definitively establish safety differences among various estrogens (Ref. 
100). Thus, it is not known to what extent, if

[[Page 42571]]

any, differences in the types of estrogens used may affect safety.
    There are no comparative safety trials of Premarin components 
available. There are few pharmacodynamic markers available with which 
to assess safety for effects such as cancer. Therefore, sufficient 
clinical data do not exist to fully characterize the contributions 
(either positive or negative) of various Premarin components to its 
clinical safety.
    vi. Other pharmacologic effects. There is currently intense 
interest in the role of estrogen replacement therapy (ERT) in the 
prevention of cardiovascular disease and possibly other age-related 
disorders in women (Ref. 101). No estrogen product is currently 
approved by FDA for such indications. If Premarin were to be found 
effective for prevention of cardiovascular disease, elucidating the 
effects of Premarin and its components on relevant pharmacodynamic 
parameters would be important in fully characterizing the product. 
There are clinical data suggesting that equine estrogens may have 
differential effects on parameters such as lipoprotein levels and lipid 
peroxidation (Refs. 51 and 84); however, these data are as yet very 
incomplete.
    d. Inclusion of <greek-D>8,9-dehydroestrone sulfate (DHES). Many of 
the issues raised by Wyeth-Ayerst in its citizen petition submitted in 
November 1994, and addressed in numerous submissions to the docket, 
pertain to the need to include DHES in generic copies of Premarin. The 
scientific issues related to this compound are addressed below insofar 
as they relate to the approvability of generic copies of Premarin, such 
as Duramed's and Barr's synthetic conjugated estrogens products.
    As discussed previously at the beginning of this section (section 
III.B.2), DHES is a conjugated estrogens component that comprises about 
4.4 percent of the ``label claim'' of Premarin. It has been recognized 
as a constituent of Premarin for two decades (Ref. 57). However, little 
scientific data have been available on its activity, and it has been 
treated as an impurity. Information submitted by Wyeth-Ayerst on the 
pharmacokinetics of DHES in Premarin reveal that its metabolite, 
17<greek-b>-<greek-D>8,9-dehydroestradiol, is present in surprisingly 
large concentrations in the plasma, considering the composition of the 
tablet (Refs. 59 and 60). FDA analyses support this finding (Ref. 71). 
The 17<greek-b>-<greek-D>8,9-dehydroestradiol concentration is 
important because the diol form of estrogen is usually the most active 
in the human body. After taking Premarin, the concentration (or AUC) of 
unconjugated 17<greek-b>-<greek-D>8,9-dehydroestradiol in the plasma is 
between 50 percent and 125 percent (depending on what study results are 
used) of the concentration of unconjugated 17<greek-b>-estradiol and is 
one-third the concentration of unconjugated 17<greek-b>-dihydroequilin.
    The fact that a component is present at high concentrations in the 
plasma does not necessarily mean that it is clinically important. The 
significance of the finding that 17<greek-b>-<greek-D>8,9-
dehydroestrodiol is present in high concentrations depends on the 
potency of 17<greek-b>-<greek-D>8,9-dehydroestradiol compared to the 
potency of the other circulating estrogens. If it is assumed that the 
potency of the 17<greek-b>-diol metabolites derived from estrone 
sulfate, equilin sulfate, and DHES have equal potency, then the 
contribution of DHES to the overall estrogenic activity of the 
17<greek-b>-diol metabolites of the three estrogens would be 16 percent 
(based on unconjugated diol AUC's) to 26 percent (based on total diol 
AUC's) (Ref. 61). However, there are several ways to evaluate relative 
potency of estrogens. One method, testing in animal species, is useful 
for determining estrogenicity, but has not proven to be quantitatively 
predictive for humans (the original rat potency test for conjugated 
estrogens is a good example). This could be due to interspecies 
differences in metabolism, some of which have been confirmed (Ref. 
102).
    If animal testing is not adequately quantitative, in vitro studies 
using human cells or receptors may be performed, or human clinical 
tests may be carried out. Scientific data of both types assessing the 
relative potency of DHES have been submitted to the docket. Wyeth-
Ayerst provided data on human estrogen receptor binding as well as 
functional activation data in HEP-2 cells (Ref. 103). In addition, 
Duramed provided data on functional activation of Ishikawa cells, a 
human uterine cell line (Ref. 104). The results of these studies are 
summarized in the OCPB Report of October 25, 1996 (Ref. 71), Addendum 1 
to that report dated February 12, 1997 (Ref. 72), and Addendum 2 to 
that report dated March 31, 1997 (Ref. 73). These OCPB Reports attempt 
to quantify the clinical estrogenic contribution to Premarin from 
equilin, estrone, DHE, and 17-dihydroequilin based on the potencies 
derived from the various in vitro assays in combination with the 
pharmacokinetic data.
    The OCPB Report estimates that, based on the in vitro potencies and 
the known pharmacokinetics, DHE and its metabolite contribute 
approximately 2.8 to 6.5 percent of the overall estrogenic potency of 
Premarin, depending on the assumptions used (Ref. 105).
    Just as with the animal data, it is important to try to assess how 
reliably the in vitro data predict the actual clinical outcomes. A 
limitation of cellular assays is that only one tissue type is 
evaluated. The results of the OCPB analysis shows that widely differing 
estimates are arrived at depending on the system used (Ref. 106). This 
may be due to artifacts of the system (i.e., metabolism of estrone to 
estradiol, etc., in the Hep-G2 cells), true tissue differences, or 
other reasons. The best way to evaluate the in vitro potency 
assignments is to compare their results with known clinical outcomes. 
In this case, certain comparisons are possible because both estrone 
sulfate and equilin sulfate have been tested in women as single 
ingredients (Refs. 6 and 51). A number of clinical studies have shown 
that, for both FSH suppression and treatment of menopausal symptoms, 
equilin sulfate is roughly five times more potent than estrone sulfate 
when administered as a single ingredient. Comparison of this known 
clinical fact to the potency estimates in Tables 3 and 4 of OCPB 
Addendum 2 reveals that the Ishikawa cell potencies do not correctly 
predict the oral potency of equilin relative to estrone (Ref. 73). The 
Ishikawa cell data predict that oral equilin sulfate would be 
equipotent to or less potent than estrone sulfate. Of the other in 
vitro estimates, the estrogen receptor binding assay best predicts the 
known differences between equilin and estrone, predicting equilin 
sulfate to be between two to four times more potent than estrone 
sulfate depending on the assumptions used. Because of these widely 
differing estimates, it must be concluded that in vitro assays, even in 
human systems, cannot currently be relied upon to provide precise 
predictions of relative clinical potencies.
    The other information available on the relative potency of DHES 
comes from human studies. Wyeth-Ayerst submitted the results of two 
human studies to the docket (Refs. 76 and 77). These studies were 
small, unblinded, uncontrolled trials, and would not be of the type 
relied upon for determining safety or efficacy of a drug. In addition, 
they did not use a dosage form equivalent to that of Premarin, and thus 
their results cannot be directly extrapolated to Premarin. However, 
they are quite similar to the types of studies that were originally 
used to evaluate the role of estrone sulfate and equilin sulfate in 
Premarin and can be used to assess certain comparative pharmacodynamic 
parameters. In these

[[Page 42572]]

trials, 0.125 mg of DHES was administered daily to postmenopausal 
women. This dose of DHES is about four times the amount in a 0.625 mg 
tablet of Premarin. In both studies, this dose of DHES caused 
approximately 15 to 26 percent suppression of FSH after 2 weeks of 
dosing. This is in the range of suppression resulting from 0.625 mg of 
estrone sulfate reported in the literature (Ref. 50). The study 
performed in Brazil included a comparison group given 1.25 mg estrone 
sulfate. This group achieved approximately a 40 percent reduction in 
FSH levels at 2 weeks. This effect is somewhat greater than has been 
previously reported (Refs. 50 and 81).
    Based on these human data, the oral potency of DHES (for pituitary 
pharmacodynamic parameters) is (very roughly) five to six times that of 
estrone sulfate, or very similar to that of equilin sulfate and is 
about what would be predicted on pharmacokinetic grounds if the estrone 
and DHE derived diols were roughly equipotent. DHE, like equilin, is a 
B ring unsaturated estrogen. If DHES has the same oral potency as 
equilin and if the contributions of estrone sulfate, equilin sulfate, 
and DHES plus the small amount of 17<greek-b>-<triangle>8,9-
dehydroestradiol sulfate were to be considered, then DHES and its 
metabolite would contribute about 9 percent of the estrogenic potency 
from these three components, at least for pituitary parameters.
    It can be seen from the above analysis that the high end of the 
estimate of the contribution of DHES to the estrogenic potency of 
Premarin from the in vitro assays is similar to the estimate derived 
from clinical studies, i.e., about 9 percent, and both of the estimates 
are lower than the 16 percent to 26 percent estimate based on an 
assumption that each 17<greek-b>-diol metabolite is equally potent. 
Unfortunately, all of the estimates have problems and uncertainties. A 
precise estimate of the potency of DHES relative to estrone sulfate is 
not available. In addition, none of the data provide insight into the 
contribution of these components to estrogenic potency with respect to 
bone. As discussed above, preliminary pharmacodynamic data indicate 
that DHES has an effect on bone markers. The available data demonstrate 
that DHES is a potent estrogen and may make a clinically meaningful 
contribution to the therapeutic effects of Premarin.

C. Conclusions

    CDER proposes to refuse to approve Duramed's ANDA 40-115 and Barr's 
ANDA 40-154 primarily on the grounds that Duramed and Barr have failed 
to provide sufficient information to show that the active ingredients 
of their respective synthetic conjugated estrogens products are the 
same as the active ingredients of the reference listed drug product, 
Premarin. For a generic drug product with Premarin as the reference 
listed drug to be approved without approval of a petition under 
Sec. 314.93 (21 CFR 314.93), the generic drug must have the same active 
ingredients as Premarin. This requirement, paired with a showing of 
bioequivalence of the generic drug to the reference listed drug, is 
meant to ensure that the data developed by the innovator company to 
demonstrate the safety and effectiveness of the reference listed drug 
will support approval of the generic drug. Independent demonstration of 
safety and effectiveness is not required for approval of generic drugs. 
Approval of generic copies of Premarin manufactured from combined 
synthesized components requires data sufficient to demonstrate that 
such copies contain the same active ingredients as Premarin.
    CDER has determined that the reference listed drug Premarin is not 
adequately characterized at this time. In particular, the estrogenic 
potency of the product is not clearly defined relative to the 
estrogenic potency of its constituents. In addition, the contribution 
of the two most abundant estrogens, sodium equilin sulfate and sodium 
estrone sulfate, to the overall estrogenic potency is not well 
understood. Furthermore, the quantitative composition of Premarin with 
respect to potentially pharmacologically active components has not been 
defined. Without this information it is not possible to define the 
active ingredients of Premarin.
    Investigations designed to produce the scientific data needed to 
determine the active ingredients are feasible. Such information would 
allow a determination of which components of Premarin make a clinically 
meaningful contribution to its overall effects. It is both feasible and 
desirable for the constituent active ingredients in Premarin to be 
characterized to this extent.
    With regard to sodium <triangle>8,9-dehydroestrone sulfate (DHES), 
the available scientific evidence indicates that DHES is an active 
estrogen that contributes to the estrogenic potency of Premarin. The 
clinical significance of this contribution has not been determined. 
DHES must be included in generic copies of Premarin unless scientific 
data are presented that demonstrate that the estrogenic activity of 
DHES is not clinically meaningful. Duramed and Barr have failed to 
provide sufficient information in their ANDA's to show that their 
conjugated estrogens products contain this same ingredient, or that the 
estrogenic activity of DHES is not clinically meaningful.
    In addition to failing to provide sufficient information to show 
that the proposed generic drugs contain the same active ingredients as 
the reference listed drug, ANDA 40-115 and ANDA 40-154 also fail to 
provide sufficient information to demonstrate that such proposed 
generic drug products are bioequivalent to the reference listed drug.
    Under section 505(j)(3)(F) of the act and Sec. 314.127(a)(6), FDA 
must refuse to approve an ANDA for a proposed generic drug, unless 
sufficient information has been submitted to show that such drug is 
bioquivalent to the reference listed drug.<SUP>6</SUP> Bioequivalence 
depends on the rate and extent to which the active ingredient or active 
moiety becomes available at the site of action. See section 
505(j)(7)(B) of the act and Sec. 320.1(e). If a drug has not been 
established to contain the same active ingredients or active moieties, 
bioequivalence cannot be established. CDER finds that ANDA 40-115 and 
ANDA 40-154 do not present sufficient information to show that the 
proposed generic drugs contain the same active ingredients or the same 
active moieties as the reference listed drug. Therefore, these ANDA's 
cannot be approved by FDA under section 505(j)(3)(F) of the act and 
Sec. 314.127(a)(6) because they fail to present sufficient information 
to show that the proposed generic drugs are bioequivalent to the 
reference listed drug.
---------------------------------------------------------------------------

    \6\ One exception to this general rule that is not applicable 
here relates to a drug for which a petition under section 
505(j)(2)(C) of the act and Sec. 314.93 has been approved. See 
Sec. 314.127(a)(6)(ii).
---------------------------------------------------------------------------

    Finally, in the event that each of the foregoing deficiencies is 
resolved, additional information may be required to address unresolved 
labeling, chemistry, bioequivalence, or manufacturing issues.

IV. References

    The following references have been placed on display in the Dockets 
Management Branch (address above) and may be seen by interested persons 
between 9 a.m. and 4 p.m., Monday through Friday. Additional documents 
related to this notice appear in Dockets 94P-0429 and 94P-0430, and are 
incorporated by reference.

    1. United States Pharmacopeia 18, pp. 242-246, 1970.

[[Page 42573]]

    2. Minutes of the meeting of the Committee on Conjugated 
Estrogens of the Pharmaceutical Contact Section, Washington, DC, 
October 23, 1962.
    3. Minutes of the meeting of the Committee on Conjugated 
Estrogens of the Quality Control Section, Washington, DC, April 16, 
1963.
    4. Summary of Proceedings of the USP Conference on Conjugated 
Estrogens, February 27, 1968.
    5. Howard, R. P., E. C. Keaty, and E. C. Reifenstein, 
``Comparative Effects of Various Estrogens on Urinary Gonadotropins 
(FSH) in Oophorectomized Women,'' [Abstract], Journal of Clinical 
Endocrinology and Metabolism, 16:966, 1956.
    6. Howard, R. P., and E. C. Keaty, ``Evaluation of Equilin 3-
monosulfate and Other Estrogens,'' Archives of Internal Medicine, 
128:229-234, August 1971.
    7. FDA, ``Certain Estrogen-Containing Drugs for Oral or 
Parenteral Use,'' Federal Register, Vol. 37, No. 143, pp. 14826-
14828, July 25, 1972.
    8. Minutes of the meeting on proposed USP monograph for 
conjugated estrogens, p. 4, November 4, 1982.
    9. Id. at pp. 1-4.
    10. FDA, ``Therapeutically Equivalent Drugs,'' Federal Register, 
Vol. 44, No. 9, pp. 2932-2953, January 12, 1979. Announced that FDA 
intended to make available a list of approved drug products with 
therapeutic evaluations of products available from more than one 
manufacturer. Originally known as Approved Prescription Drug 
Products with Therapeutic Equivalence Evaluations, it is now called 
Approved Drug Products with Therapeutic Equivalence Evaluations (the 
Orange Book).
    11. 1980 Orange Book listing for conjugated estrogens, pp. 51-
52.
    12. FDA, ``Oral Estrogens for Postmenopausal Osteoporosis; Drug 
Efficacy Study Implementation; Reevaluation,'' Federal Register, 
Vol. 51, No. 70, pp. 12568-12570, April 11, 1986.
    13. Genant, H. K., C. E. Cann, B. Ettinger, and G. S. Gordan, 
``Quantitative Computed Tomography of Vertebral Spongiosa: A 
Sensitive Method for Detecting Early Bone Loss After Oophorectomy,'' 
Annals of Internal Medicine, 97:699-705, 1982.
    14. Lindsay, R., D. M. Hart, and D. M. Clark, ``The Minimum 
Effective Dose of Estrogen for Prevention of Postmenopausal Bone 
Loss,'' Obstetrics and Gynecology, 63:759-763, 1984.
    15. FDA, ``Abbreviated New Drug Applications for Conjugated 
Estrogens; Proposal to Withdraw Approval; Opportunity for a 
Hearing,'' Federal Register, Vol. 55, No. 30, pp. 5074, 5076-5078, 
February 13, 1990.
    16. Id. at p. 5076.
    17. FDA, Center for Drug Evaluation and Research, Division of 
Bioequivalence, Guidance for ``In-Vivo Bioequivalence Study for 
Conjugated Estrogens Tablets,'' December 17, 1986.
    18 Transcript, Vol. II, and Summary Minutes of the meeting of 
FDA's Fertility and Maternal Health Drugs Advisory Committee, 
January 5-6, 1989.
    19. Id. at pp. 177-193.
    20. Transcript and Summary Minutes of the meeting of the Ad Hoc 
Subcommittee of FDA's Fertility and Maternal Health Drugs Advisory 
Committee, Vols. I and II, May 3-4, 1990.
    21. Id., Vol. II, pp. 117-135.
    22. FDA, ``Abbreviated New Drug Applications for Conjugated 
Estrogens; Proposal to Withdraw Approval; Opportunity for a 
Hearing,'' Federal Register, Vol. 55, No. 30, pp. 5074, 5076-5078, 
February 13, 1990.
    23. FDA, ``Conjugated Estrogens Tablets; Withdrawal of Approval 
of 28 Abbreviated New Drug Applications,'' Federal Register, Vol. 
56, No. 57, p. 12376, March 25, 1991.
    24. FDA, ``Zenith Laboratories; Conjugated Estrogens Tablets; 
Withdrawal of Approval of Four Abbreviated New Drug Applications,'' 
Federal Register, Vol. 56, No. 87, p. 20621, May 6, 1991.
    25. Transcript of the meeting of FDA's Generic Drugs Advisory 
Committee, Vols. I and II, February 25-26, 1991.
    26. Id., Vol. I, pp. 46-68.
    27. Adams, W. P., presentation slide from the meeting of the 
FDA's Generic Drugs Advisory Committee, February 25, 1991.
    28. Transcript of the meeting of FDA's Generic Drugs Advisory 
Committee, Vol. I, pp. 68-91, February 25-26, 1991.
    29. Transcript of the meeting of FDA's Generic Drugs Advisory 
Committee, Vol. II, pp. 16-26, February 25-26, 1991.
    30. USP, Pharmacopeial Forum, Vol. 17, No. 6, pp. 2-3, December 
1991.
    31. Wyeth-Ayerst submission to the docket 94P-0429 (CP 1), 
November 30, 1994.
    32. Wyeth-Ayerst submission to the docket 94P-0430 (PSA 1), 
November 30, 1994.
    33. Transcript and Summary Minutes of the meeting of FDA's 
Fertility and Maternal Health Drugs Advisory Committee, Vols. I and 
II, July 27-28, 1995.
    34. Id., Summary Minutes, p. 5, and Vol. II, pp. 296-297.
    35. FDA submission to the docket 94P-0429 (REF 1), November 4, 
1996. FDA's ``Preliminary Analysis of Scientific Data on the 
Composition of Conjugated Estrogens,'' November 1, 1996.
    36. FDA, Ad Hoc Conjugated Estrogens Working Group, ``Ad Hoc 
Conjugated Estrogens Working Group Final Report,'' [with 
attachments], May 1, 1997.
    37. Memorandum from the Director, Office of Drug Evaluation II 
to the Director, Center for Drug Evaluation and Research, ``Generic 
Drug Versions of Conjugated Estrogens,'' April 22, 1997.
    38. Memorandum from the Associate Director for Medical Policy to 
the Director, Center for Drug Evaluation and Research, ``Conjugated 
Estrogens; Requirements for a Generic Product,'' [with attachments], 
May 4, 1997.
    39. Memorandum from the Director, Office of Pharmaceutical 
Science to the Director, Center for Drug Evaluation and Research, 
``Recommendation on the Composition of Conjugated Estrogens Tablets, 
USP,'' [with attachments; redacted], May 3, 1997.
    40. FDA, ``Abbreviated New Drug Application Regulations; 
Proposed Rule,'' Federal Register, Vol. 54, No. 130, pp. 28872 
(28880, 28881), July 10, 1989. States that to be ``the same,'' 
active ingredients must be ``identical.''
    41. United States Pharmacopeia 18, pp. 242-245, 1970.
    42. FDA, ``Conjugated Estrogens Background Information for the 
Fertility and Maternal Health Drugs Advisory Committee Meeting,'' 
pp. 11-13, July 27-28, 1995.
    43. United States Pharmacopeia 23, ``Conjugated Estrogens 
Monograph,'' pp. 627-629, 1995.
    44. Wyeth-Ayerst submission to the docket 94P-0429 (SUP 4), 
``Contributions of <greek-D>8,9-dehydroestrone (<greek-D>8,9 DHES) 
to the Biologic Activities of Conjugated Estrogens,'' p. 13, 
September 25, 1995.
    45. Yang, N.N., M. Venugopalan, S. Hardikar, and A. Glasebrook, 
``Identification of an Estrogen Response Element Activated by 
Metabolites of 17B-estrodiol and Raloxifene,'' Science, 273:1222-
1225, August 30, 1996.
    46. Kuiper, G. G. J. M., E. Enmark, M. Pelto-Huikko, et al., 
``Cloning of a Novel Estrogen Receptor Expressed in Rat Prostate and 
Ovary,'' Proceedings of the National Academy of Sciences of the 
United States of America, 93:5925-5930, June 1996.
    47. Barnes, R.B., and R. A. Lobo, ``Pharmacology of Estrogens,'' 
in Menopause: Physiology and Pharmacology, edited by D. R. Mishell, 
pp. 301-315, Chicago: Year Book Medical Publishers, 1987.
    48. Von Angerer, E., ``The Estrogen Receptor as a Target for 
Rational Drug Design,'' Molecular Biology Intelligence Unit, pp. 5-
17, Austin: RG Landes Co., August 1995.
    49. Koh, K. K., R. Mincemoyer, M. N. Bui, et al., ``Effects of 
Hormone-Replacement Therapy on Fibrinolysis in Postmenopausal 
Women,'' New England Journal of Medicine, 336:683-690, March 1997.
    50. Mashchak, C. A., R. A. Lobo, R. Dozono-Takano, et al., 
``Comparison of Pharmacodynamic Properties of Various Estrogen 
Formulations,'' American Journal of Obstetrics and Gynecology, 
144:511-518, November 1992.
    51. Lobo, R. A., H. N. Nguyen, P. Eggena, and P. F. Brenner, 
``Biologic Effects of Equilin Sulfate in Postmenopausal Women,'' 
Fertility and Sterility, 49:234-238, February 1988.
    52. Lyman, G. W., and R. N. Johnson, ``Assay for Conjugated 
Estrogens in Tablets Using Fused-Silica Capillary Gas 
Chromatography,'' Journal of Chromatography, 234:234-239, 1982.
    53. Helgason, S., M-G. Damber, B. von Schoultz, and T. 
Stigbrand, ``Estrogenic Potency of Oral Replacement Therapy 
Estimated by the Induction of Pregnancy Zone Protein,'' Acta 
Obstetrica et Gynecologica Scandinavica, 61:75-79, 1982.
    54. Ettinger, B., H. K. Genant, P. Steiger, and P. Madvig, 
``Low-dosage Micronized 17<greek-b>-estradiol Prevents Bone Loss in 
Postmenopausal Women,'' American Journal of Obstetrics and 
Gynecology, 166:479-488, February 1992.
    55. Genant, H., J. Lucas, S. Weiss, et al., ``A Clinical Study 
of 0.3, 0.625 and 1.25 mg Esterified Estrogens (<a href="/cdn-cgi/l/email-protection" class="__cf_email__" data-cfemail="7c390f080e1d081d1e3c">[email protected]</a>) for the 
Prevention of Postmenopausal Osteoporosis,'' [Abstract PTu 577], 
Osteoporosis International, 6 (Suppl. 1):S228, 1996.
    56. Roman, R., C. H. Yates, J. F. Millar, and W. J. A. Vanden 
Heuvel, ``Identification of Estrogens Isolated From Pregnant Mares''

[[Page 42574]]

Urine,'' Canadian Journal of Pharmaceutical Sciences, 10:8-11, 1974.
    57. Johnson, R., R. Masserano, R. Haring, et al., ``Quantitative 
GLC Determination of Conjugated Estrogens in Raw Materials and 
Finished Dosage Forms,'' Journal of Pharmaceutical Sciences, 
64:1007-1011, June 1975.
    58. Wyeth-Ayerst submission to the docket 94P-0429 (C 96), March 
26, 1997.
    59. Wyeth-Ayerst submission to the docket 94P-0429, (SUP 10), 
May 5, 1997, Doc. 1, Vol. 2, Protocol 713-X-108-US, Wyeth-Ayerst 
GMR-23669, February 16, 1994, Table 46, p. 197; Table 52, p. 214; 
Table 57, p. 230. Wyeth-Ayerst submission to the docket 94P-0429, 
(SUP 9), October 29, 1996, Doc. 1, Vol. 5, article (Troy, S. M., D. 
R. Hicks, V. D. Parker, et al., ``Differences in Pharmacokinetics 
and Comparative Bioavailability Between Premarin<SUP></SUP> and 
<a href="/cdn-cgi/l/email-protection" class="__cf_email__" data-cfemail="397c4a4d4b584d585b79">[email protected]</a> in Healthy Postmenopausal Women,'' Current Therapeutic 
Research, 55:359-372, 1994); Doc. 32, GMR 21811, Table 52.
    60. Wyeth-Ayerst submission to the docket 94P-0429 (Sup 4), Vol. 
4, Tab 27, ``Pharmacokinetic Profile of Unconjugated and Total 
(Unconjugated Plus Conjugated) 17<greek-b>-<greek-D>8,9-
dehydroestrone in Healthy Postmenopausal Women Receiving 2 x 0.625 
mg Premarin and 2 x 0.625 mg Estratab,'' Wyeth-Ayerst draft addendum 
to GMR-23669 for Protocol 713-X-108-US(17<greek-b>-<greek-D>8,9-
dehydroestrone pharmacokinetic data), September 20, 1995.
    61. Wyeth-Ayerst submission to the docket 94P-0429 (SUP 10), May 
5, 1997, Doc. 33, ``A Steady-State Bioavailability Study of 
Premarin<SUP></SUP> (2 x 0.625 mg) in Healthy Postmenopausal 
Women--Final Report (Protocol Number 96-090MA),'' GTR 29548, 
February 24, 1997, (Missouri Study).
    62. FDA, Center for Drug Evaluation and Research, Division of 
Drug Analysis, ``Preliminary Assay Results from FDA's Division of 
Drug Analysis,'' June 1995. Referenced in FDA submission to the 
docket 94P-0429 (REF 1), November 4, 1996.
    63. Wyeth-Ayerst submission to the docket 94P-0429 (SUP 4), 
``Contributions of <greek-D>8,9-dehydroestrone (<greek-D>8,9 DHES) 
to the Biologic Activities of Conjugated Estrogens,'' p. 14, 
September 25, 1995.
    64. Roos, R.W., ``Determination of Conjugated and Esterified 
Estrogens in Pharmaceutical Tablet Dosage Forms by High-Pressure, 
Normal-Phase Partition Chromatography,'' Journal of Chromatographic 
Science, 14:505-512, November 1976.
    65. Roos, R.W., and C.A. Lau-Cain, ``Liquid Chromatographic 
Analysis of Conjugated and Esterified Estrogens in Tablets,'' 
Journal of Pharmaceutical Sciences, 74:201-204, February 1985.
    66. Roos, R.W., ``High-pressure Liquid Chromatographic Analysis 
of Estrogens in Pharmaceuticals by Measurement of Their Dansyl 
derivatives,'' Journal of Pharmaceutical Sciences, 67:1735-1739, 
December 1978.
    67. Pillai, G.K., and K.M. McErlane, ``Quantitative 
Determination of Conjugated Estrogens in Formulations by Capillary 
GLC,'' Journal of Pharmaceutical Sciences, 70:1072-1075, September 
1981.
    68. The international community has recognized the need to 
characterize impurities present in a new drug substance at or above 
an apparent level of 0.1%. Guideline for Industry, Impurities in New 
Drug Substances, International Conference on Harmonisation, Q3A, 
January 1996. Given this international recognition of the 
feasability of so characterizing new drug substances, it should be 
possible to characterize conjugated estrogens at least to this 
degree.
    69. Duramed submission to the docket 94P-0429 (RC 5), p. 5, 
August 22, 1996.
    70. Wyeth-Ayerst submission to the docket 94P-0429 (C 96), p. 
2., March 26, 1997.
    71. FDA, Center for Drug Evaluation and Research, Office of 
Clinical Pharmacology and Biopharmaceutics, Division of 
Pharmaceutical Evaluation II, ``A Pharmacokinetic Analysis of 
Conjugated Estrogens Including <greek-D>8,9-Dehydroestrone and 
17<greek-b>-<greek-D>8,9-Dehydroestradiol,'' October 25, 1996 (OCPB 
Report).
    72. Id., Addendum 1, February 12, 1997. See also Ref. 36, 
Attachment B-2.
    73. Id., Addendum 2, March 31, 1997. See also Ref. 36, 
Attachment B-3.
    74. Wyeth-Ayerst submission to the docket 94P-0429 (Sup 4), GTR-
26521, pp. 32-34, September 25, 1995.
    75. Barnes, R.B., and R.A. Lobo, ``Pharmacology of Estrogens,'' 
in Menopause: Physiology and Pharmacology, edited by D.R. Mishell, 
p. 303, Chicago: Year Book Medical Publishers, 1987.
    76. Wyeth-Ayerst submission to the docket 94P-0429 (SUP 10), May 
5, 1997, ``A Pilot Study on the Clinical Effects of <greek-D>8,9 
Dehydroestrone Sulfate Alone or in Combination with Estrone Sulfate, 
Protocol CF-DHE-001 BR,'' GMR-27679, Final Study Report, November 
22, 1996 (Brazilian Study).
    77. Wyeth-Ayerst submission to the docket 94P-0429 (SUP 10), May 
5, 1997, ``Pilot Study on the Clinical Effects of <greek-D>8,9-
Dehydroestrone Sulfate,'' Summary report, (undated) (Canadian 
study).
    78. Stern, M.D., ``Pharmacology of Conjugated Oestrogens,'' 
Maturitas, 4:333-339, Elsevier Biomedical Press, 1982.
    79. Jones, M.M., B. Pearlman, D.H. Marshall, et al., ``Dose-
Dependent Response of FSH, Flushes and Urinary Calcium to 
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Effects of Various Doses of Conjugated Equine Estrogens in 
Postmenopausal Women,'' Journal of Clinical Endocrinology and 
Metabolism, 51:620-625, 1980.
    81. Varma, T.R., D. Everard, and D. Hole, ``Effect of Natural 
Estrogen on the Serum Level of Follicle-Stimulating Hormone (FSH), 
Estradiol and Estrone in Post-Menopausal Women and Its Effect on 
Endometrium,'' Acta Obstetrica et Gynecologica Scandinavica, 64:105-
109, 1985.
    82. Beck, V.A., and F.W. Friedrich, ``Equilinsulfat zur 
Substitution Beim Menopause-syndrom (Equilin Sulfate in the 
Treatment of the Menopausal Syndrome),'' Wiener Klinische 
Wochenschrift, 87:59-62, 1975.
    83. Palacios, S., C. Menendez, A.R. Jurado, and J.C. Vargas, 
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Density,'' Maturitas, 20:209-213, 1995.
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``Superior and Distinct Antioxidant Effects of Selected Estrogen 
Metabolites on Lipid Peroxidation,'' Metabolism, 45:411-414, April 
1996.
    85. Wyeth-Ayerst submission to the docket 94P-0429 (SUP 10), May 
5, 1997, ``A Pilot Study on the Clinical Effects of <greek-D>8,9 
Dehydroestrone Sulfate Alone or in Combination with Estrone Sulfate, 
Protocol CF-DHE-001 BR,'' GMR-27679, Final Study Report, November 
22, 1996 (Brazilian Study), GMR-27679, p. 8.
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30, 1996.
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1997. Presented at the meeting of the American Society for Clinical 
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from the presentation at the United States Pharmacopeial Open 
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September 29, 1992.
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Bone Loss Is Prevented by Treatment With Low-Dosage Estrogen With 
Calcium,'' Annals of Internal Medicine, 106:40-45, 1987.
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Therapy on Bone

[[Page 42575]]

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1996.
    97. Harris, S. T., H. K. Genant, D. J. Baylink, et al., ``The 
Effects of Estrone (Ogen) on Spinal Bone Density of Postmenopausal 
Women,'' Archives of Internal Medicine, 151:1980-1984, October 1991.
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Estrogens Sufficient for All Women to Prevent Menopausal Bone 
Loss?'' Gynecological Endocrinology., 6:205-209, 1992.
    100. Transcript and Summary Minutes of the meeting of FDA's 
Fertility and Maternal Health Drugs Advisory Committee, Vol. II, pp. 
85-105, July 27-28, 1995.
    101. Lafferty, F. W., and M. E. Fiske, ``Postmenopausal Estrogen 
Replacement: A Long-Term Cohort Study,'' American Journal of 
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to the Biologic Activities of Conjugated Estrogens,'' GTR-26521, pp. 
38-40, September 25, 1995.,
    104. Duramed submission to the docket 94P-0429 (C 94), January 
8, 1997.
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Clinical Pharmacology and Biopharmaceutics, Division of 
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106. Id., p. 8, Table 5.

V. Notice of Opportunity for a Hearing

    The Director of CDER (the Director) has evaluated the information 
discussed above and, on the grounds stated, is proposing to refuse to 
approve ANDA 40-115 and ANDA 40-154.
    Therefore, notice is given to Duramed and Barr and to all other 
interested persons that under section 505 (j)(3)(C)(ii), (j)(3)(F), and 
(j)(3)(J) of the act and Sec. 314.127 (a)(3)(ii), (a)(6), and (a)(12), 
the Director proposes to refuse to approve ANDA 40-115 and ANDA 40-154.
    In accordance with section 505(j)(4)(C) of the act and 
Sec. 314.200(a), the applicants are hereby given notice of an 
opportunity for a hearing to show that approval of ANDA 40-115 and ANDA 
40-154 should not be refused.
    An applicant who decides to seek a hearing shall file: (1) On or 
before September 8, 1997: a written notice of appearance and request 
for hearing, and (2) on or before October 6, 1997, the data, 
information, and analyses relied on to demonstrate that there is a 
genuine issue of material fact to justify a hearing, as specified in 
Sec. 314.200(c). Any other interested person may also submit comments 
on this notice. The procedures and requirements governing this notice 
of opportunity for a hearing, a notice of appearance and request for a 
hearing, information and analyses to justify a hearing, other comments, 
and a grant or denial of a hearing are contained in Sec. 314.200 and in 
21 CFR part 12.
    The failure of the applicant to file a timely written notice of 
appearance and request for a hearing, as required by Sec. 314.200, 
constitutes an election by that person not to use the opportunity for a 
hearing concerning the proposed action, and a waiver of any contentions 
concerning the legal status of the referenced drug products.
    A request for a hearing may not rest upon mere allegations or 
denials, but must present specific facts showing that there is a 
genuine and substantial issue of fact that requires a hearing. If it 
conclusively appears from the face of the data, information, and 
factual analyses in the request for a hearing that there is no genuine 
and substantial issue of fact that precludes the refusal to approve the 
application, or when a request for a hearing is not made in the 
required format or with the required analyses, the Commissioner of Food 
and Drugs will enter summary judgment against the person who requests 
the hearing, making findings and conclusions, and denying a hearing.
    All submissions pursuant to this notice of opportunity for a 
hearing are to be filed in four copies. Except for data and information 
prohibited from public disclosure under 21 U.S.C. 331(j) or 18 U.S.C. 
1905, the submissions may be seen in the Dockets Management Branch 
(address above) between 9 a.m. and 4 p.m., Monday through Friday.
    This notice is issued under the Federal Food, Drug, and Cosmetic 
Act (section 505) and under authority delegated to the Director of the 
Center for Drug Evaluation and Research (21 CFR 5.82).

    Dated: July 29, 1997.
Murray M. Lumpkin,
Director, Center for Drug Evaluation and Research.
[FR Doc. 97-20792 Filed 8-6-97; 8:45 am]
BILLING CODE 4160-01-P


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