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

The agency bases this estimate on

fiscal year 1995 data in which each

notice of participation filed took an

estimated 3 hours to complete.

Dated: July 31, 1997.

William K. Hubbard,

Associate Commissioner for Policy

Coordination.

[FR Doc. 97–20870 Filed 8–6–97; 8:45 am]

BILLING CODE 4160–01–F

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.

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 § 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 § 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 § 314.120, or request an

opportunity for a hearing under

§ 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

§ 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 § 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 § 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

§ 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.
Federal Register / Vol. 62, No. 152 / Thursday, August 7, 1997 / Notices 42563

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 § 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.

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.1 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 17αdihydroequilin sulfate, the third most

abundant estrogen, had little clinical

activity (Ref. 6).

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 17αdihydroequilin 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 17α-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 17αdihydroequilin 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
42564 Federal Register / Vol. 62, No. 152 / Thursday, August 7, 1997 / Notices

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.

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 § 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 § 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.2 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
Federal Register / Vol. 62, No. 152 / Thursday, August 7, 1997 / Notices 42565

3Pharmacokinetics can be defined as drug

absorption, excretion, metabolism, or distribution.

4Pharmacodynamics 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)).

equivalents’’ in § 320.1(c) is consistent

with this definition of active ingredient

in that it focuses on the therapeutic

moiety:

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 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, 3 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 4 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.

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
42566 Federal Register / Vol. 62, No. 152 / Thursday, August 7, 1997 / Notices

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 doseresponse 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

>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 17β-

>8,9-dehydroestradiol sulfate (Ref. 58).

This metabolite comprises

approximately 0.003 mg per 0.625 mg

tablet. Therefore, the total DHES plus

sodium 17β->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 17β->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) 17β->8,9-

dehydroestradiol metabolite of DHES

are the same order of magnitude as the

concentration of the 17β-diol

metabolites of the active ingredients

estrone and equilin (Refs. 59, 60, and

61). The 17β >8,9-estradiol

concentration is approximately 34

percent of the combined concentrations

of the 17β-diol metabolites of estrone

and equilin, or 26 percent of the 17βdiol 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 doseresponse 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
Federal Register / Vol. 62, No. 152 / Thursday, August 7, 1997 / Notices 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

17α-Dihydroequilin ...................... 0.102

17α-Estradiol .............................. 0.027

17β-Dihydroequilin ...................... 0.011

l7α-Dihydroequilenin ................... 0.011

17β-Dihydroequilenin .................. 0.021

Equilenin ..................................... 0.015

17β-Estradiol ............................... 0.005

∆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 ∆8,9

Dehydroestrone and 17β-∆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

17α-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 ∆8,9–DHE

Measured dose or AUC ......................................................................................................................................... .............. .............. ..................

mg per 2X 0.625mg tab ......................................................................................................................................... 0.740 0.336 0.052

Total plasma ketone (ng•hr/mL) ............................................................................................................................ 94.200 43.145 13.610

Uncon.plasma ketone (ng•hr/mL) .......................................................................................................................... 4.083 1.201 0.072

Total plasma 17βdiol (ng•hr/mL) ............................................................................................................................ 8.565 10.623 6.624

Uncon.plasma 17βdiol (ng•hr/mL) ......................................................................................................................... 0.659 1.060 0.331

The pharmacokinetics of Premarin

components are complex, as revealed in

these data. Estrone, equilin, ∆8,9-

dehydroestrone (DHE), their active 17βreduced 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

17β-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 tissuespecific differences exist. For example,

in vitro potency data for estrone and

17β-estradiol were submitted by WyethAyerst (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
42568 Federal Register / Vol. 62, No. 152 / Thursday, August 7, 1997 / Notices

5See footnote 3, supra.

(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 17β-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 17β-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

17β-dihydroequilin is about twice (1.6

times) as high as the concentration of

17β-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 17β-∆8,9-dehydroestradiol

is about half the concentration of

unconjugated 17β-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.5 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.

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
Federal Register / Vol. 62, No. 152 / Thursday, August 7, 1997 / Notices 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 doseresponse 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 17β-estradiol levels

as a surrogate marker. Comments

submitted to the docket of WyethAyerst’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 17β-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 17β-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 17β-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 17βestradiol 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 17β-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 17β-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 17β-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 crossreactivity of radio-immunoassay

reagents with other components in

Premarin. When serum 17β-estradiol is

measured by direct chemical means, the

high 17β-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 17β-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 17β-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 17β-estradiol levels do not

indicate that levels over 60 pg/mL are
42570 Federal Register / Vol. 62, No. 152 / Thursday, August 7, 1997 / Notices

attained with the dose of Premarin

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 Postmenopausal 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 doseresponse 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 WyethAyerst (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. Longterm 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
Federal Register / Vol. 62, No. 152 / Thursday, August 7, 1997 / Notices 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 ∆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, 17β-

∆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 17β-∆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 17β-∆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 17β-estradiol and is onethird the concentration of unconjugated

17β-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 17β-∆8,9-

dehydroestrodiol is present in high

concentrations depends on the potency

of 17β-∆8,9-dehydroestradiol compared

to the potency of the other circulating

estrogens. If it is assumed that the

potency of the 17β-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 17βdiol 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
42572 Federal Register / Vol. 62, No. 152 / Thursday, August 7, 1997 / Notices

6One 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

§ 314.93 has been approved. See § 314.127(a)(6)(ii).

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 17β-

>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 17β-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

§ 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 >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 § 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.6 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

§ 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 § 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.

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.
Federal Register / Vol. 62, No. 152 / Thursday, August 7, 1997 / Notices 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 ∆8,9-

dehydroestrone (∆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

17β–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 (Estratab@) 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’’
42574 Federal Register / Vol. 62, No. 152 / Thursday, August 7, 1997 / Notices

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 and

Estratab@ 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)

17β-∆8,9-dehydroestrone in Healthy

Postmenopausal Women Receiving 2×0.625

mg Premarin and 2×0.625 mg Estratab,’’

Wyeth-Ayerst draft addendum to GMR–

23669 for Protocol 713–X–108–US(17β-∆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 (2×0.625 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 ∆8,9-

dehydroestrone (∆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 ∆8,9-Dehydroestrone and

17β-∆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 ∆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 ∆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

Oestrogen,’’ Maturitas, 4:285–290, Elsevier

Biomedical Press, 1982.

80. Geola, F.L., A.M. Frumar, I.V. Tataryn,

et al., ‘‘Biological 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, ‘‘Effects of Percutaneous

Oestradiol Versus Oral Oestrogens on Bone

Density,’’ Maturitas, 20:209–213, 1995.

84. Tang, M., W. Abplanalp, S. Ayres, and

M.T.R. Subbiah, ‘‘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 ∆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.

86. Bradbury, J. T., and R. C. Long,

‘‘Equilin, an Orally Active Estrogen in

Women,’’ University of Louisville, Louisville,

KY, American Journal of Physiology, 163:700,

1950.

87. FDA, Center for Drug Evaluation and

Research, Division of Metabolism and

Endocrine Drug Products, ‘‘Guideline for

Preclinical and Clinical Evaluation of Agents

Used in the Prevention or Treatment of

Postmenopausal Osteoporosis (Draft),’’ April

1994.

88. Calvo, M. S., D. R. Eyre, and C. M.

Gundberg, ‘‘Molecular Basis and Clinical

Application of Biological Markers of Bone

Turnover,’’ Endocrine Reviews, 17:333–367,

August 1996.

89. Duramed submission to the docket

94P–0429 (C 38), October 30, 1996.

90. Reginster, J. Y., N. Sarlet, R. Deroisy,

et al., ‘‘Minimal Levels of Serum Estradiol

Prevent Postmenopausal Bone Loss,’’

Calcified Tissue International, 51:340–343,

1992.

91. Librach, S., and A. K. Nickel, ‘‘Effect

of C.E.S. and Premarin on 17β-Estradiol

Serum Levels in Postmenopausal Women,’’

Canadian Journal of Diagnosis (Suppl., May),

pp. 3–7, 1996.

92. Brennan, J. J., J. C. Nolan, J. Hui, et al.,

‘‘Plasma Concentrations of Estrogens Are

Correlated With Bone Mineral Density

Changes in Postmenopausal Women

Receiving Esterified Estrogens in an

Osteoporosis Prevention Study,’’ Abstract

PII–12, Clinical Pharmacology and

Therapeutics, Vol. 61, No. 2, p. 168, February

1997. Presented at the meeting of the

American Society for Clinical Pharmacology

and Therapeutics, San Diego, CA, March 6,

1997.

93. Thomas, G., Solvay Pharmaceuticals,

Transcript and slides from the presentation at

the United States Pharmacopeial Open

Meeting: Conjugated Estrogens, USP;

Esterified Estrogens, USP; Esterified

Estrogens Tablets, USP, Rockville, MD, pp.

62–76, September 29, 1992.

94. Stevenson, J. C., M. P. Cust, K. F.

Gangar, et al., ‘‘Effects of Transdermal Versus

Oral Hormone Replacement Therapy on Bone

Density in Spine and Proximal Femur in

Postmenopausal Women,’’ Lancet, Vol. 336,

No. 8710, ii:265–269, August 4, 1990.

95. Ettinger, B., H. K. Genant, and C. E.

Cann, ‘‘Postmenopausal Bone Loss Is

Prevented by Treatment With Low-Dosage

Estrogen With Calcium,’’ Annals of Internal

Medicine, 106:40–45, 1987.

96. The Writing Group for the PEPI Trial,

‘‘Effects of Hormone Therapy on Bone
Federal Register / Vol. 62, No. 152 / Thursday, August 7, 1997 / Notices 42575

Mineral Density: Results from the PostMenopausal Estrogens/Progestins

Intervention (PEPI) Trial,’’ Journal of the

American Medical Association, Vol 276, No.

17, pp. 1389–1396, November 6, 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.

98. United States Pharmacopeia 23,

‘‘Conjugated Estrogens Monograph,’’ p. 629,

1995.

99. Duursma, S. A., M. de Raadt, J. A.

Raymakers, and A. A. Haspels, ‘‘Is 1 mg of

Estradiol Valerate or 0.625 mg of Conjugated

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 Medicine, 97:66–77, 1994.

102. Bhavnani, B. R., ‘‘The Saga of the Ring

B Unsaturated Equine Estrogens,’’ Endocrine

Reviews, 9:396–416, 1988.

103. Wyeth-Ayerst submission to the

docket 94P–0429 (SUP 4), ‘‘Contributions of

>8,9-dehydroestrone (>8,9 DHES) 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.

105. 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 >8,9-Dehydroestrone

and 17>8,9-Dehydroestradiol,’’ October 25,

1996 (OCPB Report), Addendum 2, p. 26,

March 31, 1997.

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 § 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 § 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 § 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 § 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

§ 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

DEPARTMENT OF HEALTH AND

HUMAN SERVICES

Food and Drug Administration

[Docket No. 97N–0326]

Sterling Drug, Inc., et al.; Withdrawal of

Approval of 28 New Drug Applications,

9 Abbreviated Antibiotic Applications,

and 46 Abbreviated New Drug

Applications

AGENCY: Food and Drug Administration,

HHS.

ACTION: Notice.

SUMMARY: The Food and Drug

Administration (FDA) is withdrawing

approval of 28 new drug applications

(NDA’s), 9 abbreviated antibiotic

applications (AADA’s), and 46

abbreviated new drug applications

(ANDA’s). The holders of the

applications notified the agency in

writing that the drug products were no

longer marketed and requested that the

approval of the applications be

withdrawn.

EFFECTIVE DATE: September 8, 1997.

FOR FURTHER INFORMATION CONTACT:

Olivia A. Vieira, Center for Drug

Evaluation and Research (HFD–7), Food

and Drug Administration, 5600 Fishers

Lane, Rockville, MD 20857, 301–594–

2041.

SUPPLEMENTARY INFORMATION: The

holders of the applications listed in the

table in this document have informed

FDA that these drug products are no

longer marketed and have requested that

FDA withdraw approval of the

applications. The applicants have also,

by their request, waived their

opportunity for a hearing.

Application No. Drug Applicant

NDA 6–801 Neocurtasal Sterling Drug, Inc., 90 Park Ave., New York, NY 10016.

NDA 8–472 Cyclaine Merck & Co., Inc., P.O. Box 4, BLA–20, West Point, PA

19486.

NDA 8–656 Hydrocortone Acetate Topical Ointment Do.