[Federal Register Volume 68, Number 71 (Monday, April 14, 2003)]
[Notices]
[Pages 17953-17957]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 03-9065]


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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

[Docket Nos. 78N-0377 and 98P-1041; DESI 7661]


Certain Estrogen-Androgen Combination Drugs; Drugs for Human Use; 
Drug Efficacy Study Implementation; Amendment and Opportunity for 
Hearing

AGENCY: Food and Drug Administration, HHS.

ACTION: Notice.

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SUMMARY: The Food and Drug Administration (FDA) is amending a previous 
Federal Register notice to reclassify certain estrogen-androgen 
combination drugs as lacking substantial evidence of effectiveness for 
the treatment of moderate to severe vasomotor symptoms associated with 
the menopause in those patients not improved by estrogen alone. The 
agency is taking this action because for this indication there is not 
substantial evidence of the contribution of each component to the 
effectiveness of these combination drugs. FDA is offering an 
opportunity for a hearing to persons affected by this action.

DATES: Requests for hearings are due on or before May 14, 2003. Data in 
support of hearing requests are due June 13, 2003.

ADDRESSES: Communications in response to this notice should be 
identified with the reference number DESI 7661 and directed to the 
attention of the appropriate office named below. A request for hearing, 
supporting data, and other comments should be identified with Docket 
No. 76N-0377 and submitted to the Dockets Management Branch (HFA-305), 
Food and Drug Administration, 5630 Fishers Lane, rm. 1061, Rockville, 
MD 20852. A request for an opinion on the applicability of this notice 
to a specific drug product should be directed to the Division of New 
Drugs and Labeling Compliance (HFD-310), Center for Drug Evaluation and 
Research, Food and Drug Administration, 5600 Fishers Lane, Rockville, 
MD 20857.

FOR FURTHER INFORMATION CONTACT: David T. Read, 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

    In a notice published in the Federal Register of September 8, 1972 
(37 FR 18225), FDA announced its evaluation of the various indications 
claimed for the following combination drugs that contain an estrogen 
and an androgen:
    1. Halodrin Tablets (NDA 11-267), containing fluoxymesterone and 
ethinyl estradiol;
    2. Tylosterone Injection (NDA 8-099), containing diethylstilbestrol 
and methyltestosterone;
    3. Tylosterone Tablets (NDA 7-661), containing diethylstilbestrol 
and methyltestosterone;
    4. Tace with Androgen Capsules (NDA 10-597), containing 
chlorotrianisene and methyltestosterone;
    5. Deladumone Injection and Deladumone OB Injection (NDA 9-545), 
containing testosterone enanthate and estradiol valerate.
    As announced in that 1972 notice, FDA found these drugs to be safe 
and effective for the ``prevention of postpartum breast engorgement and 
``for the menopausal syndrome in those patients not improved by 
estrogen alone.''
    In the Federal Register of December 17, 1998 (63 FR 69631), FDA 
withdrew approval of estrogen-containing drugs insofar as they are 
indicated for postpartum breast engorgement because estrogens have not 
been shown to be safe for this use. That Federal Register notice 
included, among others, four of the five NDAs listed above. (NDA 11-267 
was not included because the drug product covered by that application, 
Halodrin Tablets, was not labeled for use for postpartum breast 
engorgement.) Given this December 17, 1998 notice, the following 
discussion relates only to the second indication found safe and 
effective in the 1972 notice, i.e., ``for the menopausal syndrome in 
patients not improved by estrogen alone.''
    In the Federal Register of September 29, 1976 (41 FR 43112), the 
agency announced that the menopausal indication for combination drugs 
containing an estrogen and an androgen was revised to read as follows:
    Moderate to severe vasomotor symptoms associated with the 
menopause in those patients not improved by estrogen alone. (There 
is no evidence that estrogens are effective for nervous symptoms or 
depression which might occur during menopause, and they should not 
be used to treat these conditions.) 41 FR 43112 at 43113. (emphasis 
in original)
    This action was taken as one part of a large agency undertaking 
with respect to the labeling (patient-directed as well as physician-
directed) for all estrogen-containing drug products. The following 
documents were also published in the Federal Register of September 29, 
1976: (1) 41 FR 43110 (DESI 2238; Certain Preparations for Vaginal 
Use); (2) 41 FR 43114 (DESI 1543; Certain Estrogen-Containing Drugs for 
Oral or Parenteral Use); (3) 41 FR 43117 (DESI 740, 1543, 2238, and 
7661; Physician Labeling and Patient Labeling for Estrogens for General 
Use); and (4) 41 FR 43108 (a proposed rule that would require certain 
patient-directed labeling for estrogens for general use).

[[Page 17954]]

    The five applications listed below were approved on the basis of 
the 1976 notice, and their approvals are withdrawn in a notice 
published elsewhere in today's issue of the Federal Register:
    1. NDA 17-968 and ANDA 85-603 (testosterone cypionate 50 
milligrams/milliliter (mg/mL) and estradiol cypionate 2 mg/mL 
injection).
    2. ANDA 85-860 and ANDA 86-423 (testosterone enanthate 180 mg/mL 
and estradiol valerate 8 mg/mL injection).
    3. ANDA 85-865 (testosterone enanthate 90 mg/mL and estradiol 
valerate 4 mg/mL injection).
    In 1981, the Center for Drug Evaluation and Research (CDER) (then 
the Bureau of Drugs) determined in response to requests from the 
sponsors that the effectiveness finding of the 1976 DESI 7661 Federal 
Register notice could be applied to two combination drug products that 
were not listed in the 1976 notice, but were being marketed at the 
time: (1) Conjugated estrogens and methyltestosterone and (2) 
esterified estrogens and methyltestosterone. Based on this finding, FDA 
filed (i.e., accepted for review) abbreviated new drug applications 
(ANDAs) for these drug products. Wyeth-Ayerst submitted ANDA 85-515 for 
a drug product containing 0.625 mg conjugated estrogens and 5 mg 
methyltestosterone, and ANDA 87-824 for a drug product containing 1.25 
mg conjugated estrogens and 10 mg methyltestosterone. Reid-Provident 
Laboratories (subsequently acquired by Solvay Pharmaceuticals, Inc.) 
submitted ANDA 87-212 for a drug product containing 0.625 mg esterified 
estrogens and 1.25 mg methyltestosterone (Estratest H.S.), and ANDA 87-
597 for a drug product containing 1.25 mg esterified estrogens and 2.5 
mg methyltestosterone (Estratest).
    In 1996, FDA withdrew Wyeth-Ayerst's two pending applications under 
21 CFR 314.65 because the applications had been inactive for many years 
and Wyeth-Ayerst had stopped marketing the products. Solvay continues 
to market Estratest and Estratest H.S. The ANDAs for the Estratest 
products have not been approved and are still pending.
    FDA has withdrawn approval of all five new drug applications (NDAs) 
named in the 1972 and 1976 notices. The agency withdrew approval of NDA 
10-597 (Tace with Androgen Capsules containing chlorotrianisene and 
methyltestosterone) and NDA 11-267 (Halodrin Tablets containing 
fluoxymesterone and ethinyl estradiol) in Federal Register notices of 
June 25, 1993 (58 FR 34466), and March 2, 1994 (59 FR 9989), 
respectively. The agency withdrew approval of NDA 7-661 (Tylosterone 
Tablets) and NDA 8-099 (Tylosterone Injection), both containing 
diethylstilbestrol and methyltestosterone, and NDA 9-545 (Deladumone OB 
Injection and Deladumone Injection, each containing testosterone 
enanthate and estradiol valerate) in a notice published in the Federal 
Register of October 29, 1998 (63 FR 58053).
    In response to the notice of October 29, 1998, on November 24, 
1998, Solvay Pharmaceuticals submitted a citizen petition (Docket No. 
98P-1041) requesting that FDA determine that the products covered by 
the three applications withdrawn in the October 21, 1998, notice were 
not withdrawn for reasons of safety or effectiveness. As FDA is doing 
for the five estrogen-androgen combination products whose approvals are 
being withdrawn in a notice published elsewhere in today's issue of the 
Federal Register, the agency is deferring to the outcome of this 
proceeding to amend the 1976 notice the determination of whether the 
products covered by the three applications named in Solvay's petition 
were withdrawn for reasons of safety or effectiveness. If the 
proceeding to amend the 1976 notice determines that there is 
substantial evidence of effectiveness of the estrogen-androgen 
combination products for the treatment of moderate to severe vasomotor 
symptoms associated with the menopause in those patients not improved 
by estrogen alone, then the products covered by the three applications 
named in Solvay's petition, as well as the five products referred to in 
a notice published elsewhere in today's issue of the Federal Register, 
will be regarded as not withdrawn for reasons of effectiveness.
    As mentioned previously, there are two pending ANDAs for Solvay's 
Estratest and Estratest H.S., originally filed in 1981. However, as 
described in detail below, FDA no longer believes that estrogen-
androgen combination drug products are effective for the treatment of 
moderate to severe vasomotor symptoms associated with the menopause in 
those patients not improved by estrogen alone. FDA, therefore, has 
initiated this proceeding to amend the DESI finding of effectiveness 
for these products. This proceeding is limited to a determination of 
whether there is substantial evidence of the effectiveness of estrogen-
androgen combination drug products for the treatment of moderate to 
severe vasomotor symptoms associated with the menopause in those 
patients not improved by estrogen alone. The use of these combination 
drug products for any other use, including but not limited to the 
treatment of other menopausal symptoms, will not be considered in this 
proceeding. The effectiveness of estrogen-androgen combination products 
for indications not covered by this proceeding should be addressed 
through the new drug application process.

II. The Safety and Effectiveness of Estrogen-Androgen Combination Drug 
Products for the Treatment of Vasomotor Symptoms Associated With 
Menopause in Patients Not Improved by Estrogen Alone

    The agency took a renewed interest in estrogen-androgen combination 
drug products when concerns were raised about the effect of androgens 
in lowering high-density lipoproteins (Refs.
    1 and 2). It is believed that oral androgens can reverse the 
favorable impact of estrogen on lipoproteins (Ref. 3). Other safety 
concerns were virilization (Refs. 4 and 5) and possible liver toxicity 
(Refs. 6, 7, and 8).
    FDA concluded that the negative effects androgens may have on lipid 
profile may be offset by a potential positive effect on bone mineral 
density (Refs. 1, 9, and 10).
    With respect to virilization (i.e., hirsutism, acne, deepening of 
the voice, alopecia, and clitoromegaly), FDA observed that the 
incidence varied widely in clinical studies and appeared to be dose and 
duration dependent. In a 2-year trial of 33 women treated with 
methyltestosterone 2.5 mg and esterified estrogen 1.25 mg daily, 36 
percent reported a hair disorder and 30 percent reported acne (Ref. 1). 
In the same 2-year trial of 33 women treated with esterified estrogen 
1.25 mg daily, 3 percent reported a hair disorder and 6 percent 
reported acne (Ref. 1). In another trial at 24 months, 10 of the 154 
women treated with methyltestosterone and esterified estrogens and 3 of 
the 157 women treated with esterified estrogens reported hirsutism 
(Ref. 9).
    FDA does not believe there is a serious risk for possible liver 
toxicity at the relatively low doses of androgen administered in 
standard oral estrogen-androgen combination therapies (Refs. 11, 12, 
and 13).
    An agency review of the literature regarding safety concerns led to 
scrutiny of the labeled indication, that is, moderate to severe 
vasomotor symptoms associated with the menopause in those patients not 
improved by estrogen alone.

[[Page 17955]]

    Estrogen-alone drug products are approved for the treatment of 
moderate to severe vasomotor symptoms associated with the menopause. 
Vasomotor symptoms associated with the menopause are, simply put, ``hot 
flushes.'' A hot flush is a sudden feeling of heat, usually on the 
face, neck, shoulders, and chest. Hot flushes have been described as 
``recurrent, transient periods of flushing, sweating, and a sensation 
of heat, often accompanied by palpitation, feeling of anxiety, and 
sometimes followed by chills'' (Ref. 14). When hot flushes occur at 
night, they are often called night sweats.
    The indication for estrogen-androgen combination drug products is 
limited to that subset of women with ``moderate to severe vasomotor 
symptoms associated with the menopause'' that are ``not improved by 
estrogen alone'' (emphasis added). The precise wording of the 
indication quite narrowly defines the intended population. Thus, to be 
found effective for this narrow indication, there would need to be 
reliable evidence that estrogen-androgen combination products are 
effective in treating the population of menopausal women whose 
vasomotor symptoms are not relieved by estrogen alone.
    FDA believes that substantial evidence is lacking that the addition 
of an androgen can improve the effectiveness of estrogen alone in the 
treatment of vasomotor symptoms (i.e., hot flushes). An early 
randomized, placebo-controlled, five-arm, two-period crossover clinical 
trial by Sherwin and Gelfand (Ref. 15) compared the effects on 
surgically menopausal women of immediate postoperative parenteral 
administration of estrogen alone (n=11), androgen alone (n=10), 
estrogen and androgen in combination (n=12), and placebo (n=10) to 
hysterectomy controls (n=10) and found that the androgen alone, 
estrogen-androgen combination, and control hysterectomy groups had 
lower (i.e., lower frequency and severity) menopausal somatic symptoms 
scores than the estrogen alone and placebo groups. The menopausal 
somatic symptoms score evaluated a constellation of symptoms including 
hot flushes, cold sweats, weight gain, rheumatic pains, cold hands and 
feet, breast pains, headaches, numbness and tingling, and skin crawls. 
A single-center, double-blind randomized, 6-month study by Hickok, 
Toomey, and Speroff (Ref. 2) compared the effects of treating 
surgically menopausal women with esterified estrogens alone (n=13) or 
in combination with methyltestosterone (n=13) on a similar 
constellation of menopausal symptoms, but found no statistically 
significant difference between the two treatments. The 15 menopausal 
symptoms evaluated were hot flushes, cold sweats, vaginal dryness, cold 
hands and feet, breast pain or tenderness, numbness and tingling, skin 
crawls, edema, increased facial or body hair, voice deepening, acne, 
trouble sleeping, pounding of the heart, dizzy spells, and pressure or 
tightness in the head or body. A 2-year, multicenter, double-blind, 
randomized, parallel group study (Ref. 9) comparing the effects of 2 
doses of conjugated equine estrogen and 2 doses of esterified estrogen 
plus methyltestosterone in a total of 311 surgically menopausal women 
found no differences among the groups in relief of hot flashes, sweats, 
and vaginal dryness.
    Clinical studies that evaluated the effect of estrogen-androgen 
combination therapy specifically on hot flushes found that the 
combination does not reduce the frequency of vasomotor symptoms more 
than estrogen alone. Watts et al. (Ref. 1) compared treatment with 
esterified estrogens alone and treatment with esterified estrogens and 
methyltestosterone in a 2-year, multicenter, double-blind, randomized, 
parallel group study conducted in 66 surgically menopausal women. The 
authors found no significant difference in the mean reduction from 
baseline in the number of hot flushes between the two groups. Sarrel et 
al. (Ref. 17) found no meaningful differences in relief from hot 
flushes when 20 postmenopausal women were treated for 8 weeks with 
esterified estrogens or an esterified estrogens-androgen combination in 
a single-center, double-blind, randomized, parallel group study. Burger 
(Ref. 18) administered subcutaneous implants of estradiol and 
testosterone to 17 menopausal women who complained that symptoms 
persisted, particularly loss of libido, despite treatment with 
conjugated equine estrogens. There was no statistically significant 
change from baseline in hot flushes after treatment. Myers et al. (Ref. 
19) conducted a 10-week, double-blind, placebo controlled, parallel 
group study in 40 naturally menopausal women comparing 4 treatments: 
Conjugated estrogens alone, conjugated estrogens and 
medroxyprogesterone, conjugated estrogens and androgen, and placebo. 
The study found that the estrogen and estrogen/medroxyprogesterone 
groups had significantly fewer hot flashes than the estrogen/androgen 
or placebo groups. The authors concluded: ``This result is consistent 
with other studies showing no effect of androgen alone on hot flashes'' 
(Ref. 19, p. 1129).
    Other authors affirm the conclusion that estrogen-androgen 
combination drug products are not superior to estrogen in reducing 
vasomotor symptoms (Refs. 3, 20 through 23). Rosenberg summarized the 
evidence concerning the alleviation of vasomotor symptoms as follows: 
``Studies suggest that estrogen is primarily responsible for reductions 
in vasomotor symptoms and that the addition of androgen neither 
improves nor detracts from this beneficial effect'' (Ref. 24, p. 400).

III. FDA's Conclusions Concerning the Safety and Effectiveness of 
Estrogen-Androgen Combination Drug Products

    For the reasons discussed previously, FDA no longer regards 
combination drug products containing estrogen(s) and androgen(s) as 
having been shown to be effective for the treatment of moderate to 
severe vasomotor symptoms associated with the menopause in those 
patients not improved by estrogen alone. The agency has closely 
examined the data and information that formed the basis for the 1976 
finding that such combinations were effective for this indication, as 
well as the subsequent literature, and has determined that there is a 
lack of substantial evidence that this combination is effective for 
``moderate to severe vasomotor symptoms associated with the menopause 
in those patients not improved by estrogen alone.''

IV. References

    The following references have been placed on display in the Dockets 
Management Branch (HFA-305), Food and Drug Administration, 5630 Fishers 
Lane, rm. 1061, Rockville, MD 20852, and may be seen by interested 
persons between 9 a.m. and 4 p.m., Monday through Friday.
    1. Watts, N. B. et al., ``Comparison of Oral Estrogens and 
Estrogens Plus Androgen on Bone Mineral Density, Menopausal 
Symptoms, and Lipid-Lipoprotein Profiles in Surgical Menopause,'' 
Obstetrics & Gynecology, 85:529-537, 1995.
    2. Hickok, L. R., C. Toomey, and L. Speroff, ``A Comparison of 
Esterified Estrogens With and Without Methyltestosterone: Effects on 
Endometrial Histology and Serum Lipoproteins in Postmenopausal 
Women,'' Obstetrics & Gynecology, 82:919-924, 1993.
    3. Kaunitz, A. M., ``The Role of Androgens in Menopausal 
Hormonal Replacement,'' Endocrinology and Metabolism Clinics of 
North America, 26(2):391-397, 1997.
    4. ACOG Committee on Gynecologic Practice, ``Committee Opinion: 
Androgen Treatment of Decreased Libido,'' 2002 Compendium of 
Selected Publications, American College of Obstetricians and 
Gynecologists, Washington, DC, pp. 5-6, 2002.
    5. Gelfand, M. M., and B. Wiita, ``Androgen and Estrogen-
Androgen Hormone

[[Page 17956]]

Replacement Therapy: A Review of the Safety Literature, 1941 to 
1996,'' Clinical Therapeutics, 19(3):383-399, 1997.
    6. Westaby, D. et al, ``Liver Damage from Long-Term 
Methyltestosterone,'' Lancet, 2:262-263, 1977.
    7. Turani, H. et al., ``Hepatic Lesions in Patients on Anabolic 
Androgenic Therapy,'' Israel Journal of Medical Sciences, 19:332-
337, 1983.
    8. Lucey, M. R., and R. H. Moseley, ``Severe Cholestasis 
Associated With Methyltestosterone: A Case Report,'' American 
Journal of Gastroenterology, 82:461-462, 1987.
    9. Barrett-Connor, E. et al, ``A Two-Year, Double-Blind 
Comparison of Estrogen-Androgen and Conjugated Estrogens in 
Surgically Menopausal Women,'' Journal of Reproductive Medicine, 
44:1012-1020, 1999.
    10. Raisz, L. G. et al, ``Comparison of the Effects of Estrogen 
Alone and Estrogen Plus Androgen on Biochemical Markers of Bone 
Formation and Resorption in Postmenopausal Women,'' Journal of 
Clinical Endocrinology and Metabolism, 81:37-43, 1996.
    11. Gitlin, N., P. Korner, and H. Yang, ``Liver Function in 
Postmenopausal Women on Estrogen-Androgen Hormone Replacement 
Therapy: A Meta-Analysis of Eight Clinical Trials,'' Menopause, 
6(3):216-224, 1999.
    12. Ettinger, B., ``Letter: Estrogen-Androgen Hepatotoxicity,'' 
American Journal of Obstetrics and Gynecology, 178(3):627-628, 1998.
    13. Phillips, E., and C. Bauman, ``Safety Surveillance of 
Esterified Estrogens-Methyltestosterone (ESTRATEST and ESTRATEST HS) 
Replacement Therapy in the United States,'' Clinical Therapeutics, 
19(5):1070-1084, 1997.
    14. Kronenberg, F., ``Hot Flashes: Epidemiology and 
Physiology,'' Annals of the New York Academy of Sciences, 592:52-86, 
1990.
    15. Sherwin, B., and M. Gelfand, ``Differential Symptom Response 
to Parenteral Estrogen and/or Androgen Administration in the 
Surgical Menopause,'' American Journal of Obstetrics and Gynecology, 
151(2):153-160, 1985.
    16. Barrett-Connor, E., ``Efficacy and Safety of Estrogen/
Androgen Therapy,'' Journal of Reproductive Medicine, 43(8-
Suppl.):746-752, 1998.
    17. Sarrel, P. et al., ``Estrogen and Estrogen-Androgen 
Replacement in Postmenopausal Women Dissatisfied with Estrogen-Only 
Therapy,'' Journal of Reproductive Medicine, 43(10):847-856, 1998.
    18. Burger, H. et al., ``The Management of Persistent Menopausal 
Symptoms with Oestradiol-Testosterone Implants: Clinical, Lipid and 
Hormonal Results,'' Maturitas, 6:351-358, 1984.
    19. Myers, L. S. et al., ``Effects of Estrogen, Androgen and 
Progestin on Sexual Psychophysiology and Behavior in Postmenopausal 
Women,'' Journal of Clinical Endocrinology and Metabolism, 
70(4):1124-1131, 1990.
    20. Greenblatt, R. B. et al., ``Evaluation of an Estrogen, 
Androgen, Estrogen-Androgen Combination, and a Placebo in the 
Treatment of the Menopause,'' Journal of Clinical Endocrinology and 
Metabolism, 10:1547-1558, 1950.
    21. McNagny, S. E., ``Prescribing Hormone Replacement Therapy 
for Menopausal Symptoms,'' Annals of Internal Medicine, 131(8):605-
616, 1999.
    22. Barlow, D. H. et al., ``Long-Term Hormone Implant Therapy--
Hormonal and Clinical Effects,'' Obstetrics & Gynecology, 67:321-
325, 1986.
    23. Rymer, J., and E. Morris, ``Menopausal Symptoms,'' Clinical 
Evidence, 5: 1308-1310, June 2001.
    24. Rosenberg, M. J., T. D. N. King, and M. C. Timmons, 
``Estrogen-Androgen for Hormone Replacement: A Review,'' Journal of 
Reproductive Medicine, 42(7):394-404, 1997.

V. Amendment

    Based on the findings discussed in section II of this document, FDA 
is amending the Federal Register notice of September 29, 1976 (41 FR 
43112), to reclassify estrogen-androgen combination drugs as lacking 
substantial evidence of effectiveness for moderate to severe vasomotor 
symptoms associated with the menopause in those patients not improved 
by estrogen alone.
    Drug products covered by this notice (i.e., estrogen-androgen 
combination drugs) are regarded as new drugs (section 201(p) of the 
Federal Food, Drug, and Cosmetic Act (the act) 21 U.S.C. 321(p)). An 
approved NDA is required for marketing.

VI. Notice of Opportunity for a Hearing

    Any manufacturer or distributor of a drug product affected by this 
notice is hereby offered an opportunity for a hearing to show why 
estrogen-androgen combination drugs should not be reclassified as 
lacking substantial evidence of effectiveness for moderate to severe 
vasomotor symptoms associated with the menopause in those patients not 
improved by estrogen alone.
    This notice applies to the particular estrogen-androgen combination 
drugs named in this notice and to any identical, related, or similar 
drug product under Sec.  310.6 (21 CFR 310.6), whether or not it is the 
subject of an approved NDA or ANDA. Estrogen-androgen combination drugs 
subject to this notice include, but are not limited to, the following 
combination drugs: fluoxymesterone and ethinyl estradiol; 
diethylstilbestrol and methyltestosterone; chlorotrianisene and 
methyltestosterone; testosterone enanthate and estradiol valerate; 
testosterone cypionate and estradiol cypionate; and esterified 
estrogens and methyltestosterone.
    It is the responsibility of every drug manufacturer or distributor 
to review this notice to determine whether it covers any drug product 
that the person manufactures or distributes. Any person may request an 
opinion of the applicability of this notice to a specific drug product 
by writing to the Division of New Drugs and Labeling Compliance (see 
ADDRESSES).
    A request for a hearing may not rest upon mere allegations or 
denials but must set forth specific facts showing that a genuine and 
substantial issue of fact requires a hearing, together with a well-
organized and full factual analysis of the clinical and other 
investigational data that the objector is prepared to prove in a 
hearing. Any data submitted in response to this notice must be 
previously unsubmitted and include data from adequate and well-
controlled clinical investigations as described in 21 CFR 314.126.
    This notice of opportunity for hearing encompasses all issues 
relating to the legal status of the drug products subject to it 
(including identical, related, or similar drug products as defined in 
Sec.  310.6), e.g., any contention that any such drug product is not a 
new drug because it is generally recognized as safe and effective 
within the meaning of section 201(p) of the act or because it is exempt 
from part or all of the new drug provisions of the act under the 
exemption for drug products marketed before June 25, 1938, in section 
201(p) of the act, or under section 107(c)of the Drug Amendments of 
1962, or for any other reason. With respect to the issue of 
effectiveness, however, this notice is limited to whether there is 
substantial evidence of the effectiveness of estrogen-androgen 
combination drug products for the treatment of moderate to severe 
vasomotor symptoms associated with the menopause in those patients not 
improved by estrogen alone. The use of these drug products for any 
indication other than for the treatment of moderate to severe vasomotor 
symptoms associated with the menopause in those patients not improved 
by estrogen alone will not be considered in this proceeding.
    Any person subject to this notice who decides to seek a hearing 
shall file: (1) On or before May 14, 2003, a written notice of 
appearance and request for hearing, and (2) on or before June 13, 2003, 
the data, information, and analyses relied on to demonstrate that there 
is a genuine issue of material fact to justify a hearing. 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

[[Page 17957]]

appearance and request for a hearing, information and analyses to 
justify a hearing, other comments, and a grant or denial of a hearing 
are contained in Sec.  314.200 (21 CFR 314.200) and in 21 CFR part 12.
    The failure of any person subject to this notice to file a timely 
written notice of appearance and request for hearing, as required by 
Sec.  314.200, constitutes an election by that person not to use the 
opportunity for a hearing concerning the action proposed and a waiver 
of any contentions concerning the legal status of that person's drug 
product(s). Any new drug product marketed without an approved new drug 
application is subject to regulatory action at any time, but any person 
subject to this notice who files a timely written notice of appearance 
and request for hearing and who remains a party to this proceeding will 
not be subject to regulatory action for matters covered by this notice 
until the conclusion of this proceeding. If it conclusively appears 
from the face of the data, information, and factual analyses in the 
request for hearing that there is no genuine and substantial issue of 
fact to justify a hearing, or if a request for 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(s) who 
requests the hearing, making findings and conclusions, and denying a 
hearing.
    All submissions under 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 (secs. 502, 505, 21 U.S.C. 352, 355) and under authority delegated 
to the Director of the Center for Drug Evaluation and Research (21 CFR 
5.100).

    Dated: April 4, 2003.
Janet Woodcock,
Director, Center for Drug Evaluation and Research.
[FR Doc. 03-9065 Filed 4-10-03; 8:45 am]
BILLING CODE 4160-01-S