**M E M O R A N D U M** DEPARTMENT OF HEALTH AND HUMAN SERVICES

Public Health Service

Food and Drug Administration

Center For Drug Evaluation and Research

**DATE:** 11 September 2003

**FROM:** Bruce V. Stadel, MD, MPH

Eric G. Colman, MD

David Orloff, MD

Division of Metabolic and Endocrine Drug Products (DMEDP)

Office of Drug Evaluation 2 (ODE 2)

Center for Drug Evaluation & Research (CDER)

Food & Drug Administration (FDA)

**TO:** Members and Consultants,

Endocrinologic & Metabolic Drugs Advisory Committee

**SUBJECT:** 7 October 2003 Advisory Committee meeting on the Women's
Health Initiative randomized clinical trial of estrogen plus progestin

in healthy postmenopausal women

**1. Type of meeting:** Open Public Hearing.

2\. Purpose

2.1 Review results from the Women's Health Initiative (WHI) randomized
clinical trial of estrogen plus progestin in healthy postmenopausal
women (hereafter, "the WHI trial").

2.2 Consider implications of results from the WHI trial for FDA
regulation of estrogen plus progestin drug products, specifically
regarding long-term use of these products for the prevention and/or
treatment of postmenopausal osteoporosis.

**3. Issues for the Committee**

The drug product used in the estrogen plus progestin arm of the WHI
trial was Prempro^TM^ \[conjugated estrogens(CEE)/medroxyprogesterone
acetate(MPA)\]. The dose was 0.625 mg CEE/2.5 mg MPA. The Prempro^TM^
Prescribing Information refers to all approved doses (0.625/5.0,
0.625/2.5, 0.45/1.5, and 0.3/1.5).

Results from the estrogen plus progestin arm of the WHI trial were first
published in July 2002. Since then, the FDA-approved Prescribing
Information for Prempro^TM^ has been revised, and the FDA has asked for
similar changes in the Prescribing Information for other estrogen plus
progestin products that are approved or pending approval for the
prevention of postmenopausal osteoporosis. This revision provides a
description of the main benefits and harms, from treatment with estrogen
plus progestin, as reported from the WHI trial.

At the Advisory Committee meeting, data and analyses from the WHI trial
will be presented and discussed by WHI investigators and FDA staff.

Considering the indication for long-term use of estrogen plus progestin
for the prevention of postmenopausal osteoporosis, DMEDP requests that
the Committee, in their deliberations:

3.1 Comment on the revisions to the Prempro^TM^ Prescribing
Information^1^ referred to above. (Attachment 1: copy of current
Prempro^TM^ Prescribing Information).

3.2 Discuss implications of the WHI trial results for the future
development, testing, and potential approval of estrogen plus progestin
drug products for the prevention and/or treatment of postmenopausal
osteoporosis.

3.3 Provide DMEDP with other comments or recommendations related to the
WHI trial, or to regulation of estrogen plus progestin products for the
prevention and/or treatment of postmenopausal osteoporosis.

**4. Background**

**4.1 Women's Health Initiative**

In the first publication from the WHI trial, in July 2002, the authors
concluded that the "overall health risks exceeded benefits from use of
combined estrogen plus progestin for an average of 5.2-year follow-up
among healthy postmenopausal US women^2^." Specifically, the rates of
coronary heart disease, stroke, breast cancer, and pulmonary embolism
were higher in women on estrogen plus progestin compared to placebo. The
benefits of estrogen plus progestin included lower rates of colon cancer
and fractures.^2^ Although the WHI did not specifically recruit
postmenopausal women with or at risk for osteoporosis, the study
confirmed decades of evidence, from observational studies and smaller
randomized trials, that estrogen plus progestin significantly reduces
risk for osteoporotic fractures, including those at the hip.^2^

In publications since the first one, detailed results regarding breast
cancer, stroke, dementia, mild cognitive impairment, & global cognitive
function, quality of life, and fractures. (add colorectal cancer if
published in time) have been presented.^2^ Of the benefits had harms
reported thus far, the benefits are a reduced risk of fractures and
colorectal cancer, and the most important harm is an increased risk of
breast cancer.^2^

(Attachment 2: NHLBI/WHI Briefing Document)

4.2 Regulatory history of estrogen and estrogen plus progestin products
used for the prevention of postmenopausal osteoporosis

**4.2.1 Approval of Premarin and Prempro^TM^**

In 1942, the Food and Drug Administration (FDA) approved the 1.25 mg
dose of Premarin \[conjugated equine estrogens (CEE)\]for the treatment
of "menopausal symptoms," based on safety considerations alone, under
the Food, Drug, and Cosmetic Act of 1938 (hereafter, "the Act.) Doses
approved since then range from 0.3 to 2.5 mg.

In 1962 the Act was amended to require that all drugs be shown to be
effective, in addition to safe, prior to marketing. In response, the FDA
contracted with the National Academy of Sciences (NAS), to evaluate the
efficacy of all drugs approved between 1938 and 1962, including
estrogens. This work was done by the NAS Drug Efficacy Study
Implementation (DESI) Group. After reviewing the DESI reports, the FDA
concluded , in 1972, that estrogens were "probably effective" in
selected cases of postmenopausal osteoporosis, and labeled the products
as such.

In 1986, the FDA concluded that estrogens at doses equivalent to 0.625
mg or higher of CEE were "effective" for postmenopausal osteoporosis.
This conclusion was based on input from two FDA Advisory Committees and
a review of published literature. The literature review included a
2-year dose-ranging study, in which doses of CEE lower than 0.625 mg per
day were found to be ineffective for the prevention of postmenopausal
bone loss. The Prescribing Information for estrogen products was changed
to include postmenopausal osteoporosis as an indication, saying: "There
is evidence that the rate of bone loss can be reduced in postmenopausal
women by taking estrogens, but substantial evidence is lacking that
estrogens decrease the incidence of osteoporotic bone fractures." Thus,
the postmenopausal osteoporosis indication for estrogens was established
on the basis of changes in bone mass, not in fracture incidence.

In 1994, DMEDP approved Prempro^TM^ 0.625/2.5 (0.625 mg CEE plus 2.5 mg
MPA) and Premphase (0.625 mg CEE for 14 days followed by 0.625 mg CEE
plus 5.0 mg MPA for 14 days) for the prevention of osteoporosis, the
treatment of moderate to severe vasomotor symptoms associated with
menopause, and the treatment of vulvar and vaginal atrophy. In 1998,
approval was expanded to include Prempro^TM^ 0.625/5.0 (0.625 mg CEE
plus 5.0 mg MPA). These approvals were based on reference to Premarin's
postmenopausal osteoporosis indication, coupled with evidence that the
doses of MPA were unlikely to attenuate the effect of the CEE dose on
bone mineral density. The approval was also contingent on the Sponsor,
Wyeth-Ayerst, agreeing to conduct a randomized, double-blind,
placebo-controlled clinical trial to evaluate the effects of lower doses
of CEE/MPA on bone mineral density, in recently postmenopausal women.
That study has since been completed,

resulting in the approval, in 2003 of Prempro^TM^ 0.45/1.5, and 0.3/1.5
for the prevention of postmenopausal osteoporosis, the treatment of
moderate to severe vasomotor symptoms associated with menopause, and the
treatment of moderate to severe symptoms of vulvar and vaginal atrophy
associated with menopause. (In 2003, a 0.45 mg dose of Premarin was also
approved.) The results of the study have been published.^3^

**4.2.2 Approval of other estrogen and estrogen plus progestin
products**

In 1994, DMEDP updated the "Guidelines for preclinical and clinical
evaluation of agents used in the prevention or treatment of
postmenopausal osteoporosis." (The current term is "Guidance.")
Significant changes included:

\(1\) a statement that: "Epidemiological studies have demonstrated that

estrogen therapy reduces the risk of vertebral and non-vertebral

(femoral neck and distal radius) fractures. Therefore, fracture
evaluation

for estrogen preparations is not required...," and

\(2\) guidance that an indication for the prevention of postmenopausal

osteoporosis could be approved, for estrogen or estrogen plus progestin

products, if randomized, double-blind, placebo-controlled clinical
trials

showed superiority, for the drug(s) tested compared to placebo,

in maintaining or increasing lumbar spine bone mineral density (BMD),

over a 2-year period, in women 45 years of age or older, and recently

(1-3 years) postmenopausal

By 2000, several other estrogen and estrogen plus progestin products
were

FDA-approved for the prevention of postmenopausal osteoporosis, in
addition to Premarin and Prempro,^TM^ (Table 1). These other approvals
were based either on designation as DESI products, or on data from
2-year clinical trials with lumbar spine BMD as the outcome, as
described above.

**5. Approval of non-estrogen products**

Since 1995, the Agency has approved 4 non-estrogen products for the
prevention of postmenopausal osteoporosis, including 3 bisphosphonates
\[Fosamax (alendronate),Actonel (risedronate), and Boniva(ibandronate)\]
and 1 selective estrogen receptor modulator \[Evista (raloxifene)\].
These approvals were based on 2-year, randomized, double-blind,
placebo-controlled clinical trials. The participants were recently
postmenopausal, non-osteoporotic women, in whom active treatment
increased lumbar spine bone mineral density by a statistically
significant amount compared to placebo. Because these drugs were also
shown to reduce the 3-year incidence of morphometric vertebral
fractures, by a statistically significant relative risk reduction of 0.3
to 0.5 compared to placebo, they were approved for the treatment of
postmenopausal osteoporosis, in addition to prevention.

Forteo (teriparatide), representing the first 34 amino acids of human
parathyroid hormone, has also demonstrated fracture efficacy and has
been approved for the treatment of postmenopausal osteoporosis, in
particular for the treatment of severe disease.

Regarding the comparative efficacy of estrogen or estrogen plus
progestin,

alendronate, risedronate, and raloxifene, for a vertebral fracture
outcome, some information is available, from a meta-analysis that was
published in by the Osteoporosis Methodology Group in 2002, before the
first publication from the WHI trial (Table 2).^4^

**REFERENCES**

1\. ATTACHMENT 1: Current Prescribing Information for Prempro^TM^ and
Premphase.

2\. ATTACHMENT 2: National Heart, Lung, and Blood Institute, and Women's
Health

Initiative Briefing document for 7 October 2003 Meeting of the
Endocrinologic and Metabolic Drugs Advisory Committee, Food and Drug
Administration.

3\. Lindsay R, et al. Effect of lower doses of conjugated equine
estrogens with and without medroxyprogesterone acetate on bone in early
postmenopausal women. JAMA. 2002;287:2668-2676.

4\. Cranney A, et al. Summary of meta-analyses of therapies for
postmenopausal osteoporosis. Endocrine Reviews. 2002;23:570-578.

**Table 1**

+-------------------+--------------------------------+-----------------+
| **FDA-Approved    |                                |                 |
| Estrogen and      |                                |                 |
| Estrogen Plus     |                                |                 |
| Progestin         |                                |                 |
| Products**        |                                |                 |
|                   |                                |                 |
| **for the         |                                |                 |
| Prevention of     |                                |                 |
| Postmenopausal    |                                |                 |
| Osteoporosis**    |                                |                 |
+-------------------+--------------------------------+-----------------+
| **Product**       | **Active Ingredients**         | **Doses (mg)**  |
+-------------------+--------------------------------+-----------------+
|                   | **Estrogen**                   |                 |
+-------------------+--------------------------------+-----------------+
| Premarin          | conjugated estrogens           | 0.3, 0.45,      |
|                   |                                | 0.625, 0.9,     |
|                   |                                | 1.25, 2.5       |
+-------------------+--------------------------------+-----------------+
| Estrace           | estradiol                      | 0.5, 1.0, 2.0   |
+-------------------+--------------------------------+-----------------+
| Climara           | estradiol                      | 0.025, 0.05,    |
| (transdermal)     |                                | 0.075, 0.1      |
+-------------------+--------------------------------+-----------------+
| Ogen              | estropipate                    | 0.75, 1.5, 3.0  |
+-------------------+--------------------------------+-----------------+
| Ortho-Est         | estropipate                    | 0.75            |
+-------------------+--------------------------------+-----------------+
| Vivelle-Dot       | estradiol                      | 0.025, 0.0375,  |
| (transdermal)     |                                | 0.05, 0.075,    |
|                   |                                | 0.1             |
+-------------------+--------------------------------+-----------------+
|                   | ### Estrogen/Progestin         |                 |
+-------------------+--------------------------------+-----------------+
| Prempro^TM^       | conjugated estrogens/          | 0.625/2.5       |
|                   | medroxyprogesterone            |                 |
| Premphase         |                                | 0.625/5.0       |
|                   |                                |                 |
|                   |                                | 0.45/1.5        |
|                   |                                |                 |
|                   |                                | 0.3/1.5         |
|                   |                                |                 |
|                   |                                | 0.625           |
|                   |                                |                 |
|                   |                                | x 14 days;      |
|                   |                                |                 |
|                   |                                | 0.625/5.0       |
|                   |                                |                 |
|                   |                                | x 14 days       |
+-------------------+--------------------------------+-----------------+
| Activella         | estradiol/norethindrone        | 1.0/0.5         |
+-------------------+--------------------------------+-----------------+
| Femhrt            | ethinyl                        | 0.005/1.0       |
|                   | estradiol/norethindrone        |                 |
+-------------------+--------------------------------+-----------------+
| Ortho-Prefest^TM^ | estradiol/norgestimate         | 1.0/0.09        |
+-------------------+--------------------------------+-----------------+

# 

**Table 2^4^**

+-----------------+-----------------+------------------+---------------+
| **Effect of     |                 |                  |               |
| various         |                 |                  |               |
| osteoporosis    |                 |                  |               |
| drugs compared  |                 |                  |               |
| to placebo, on  |                 |                  |               |
| risk of         |                 |                  |               |
| vertebral       |                 |                  |               |
| fractures       |                 |                  |               |
| (Prior to WHI   |                 |                  |               |
| trial)**        |                 |                  |               |
+-----------------+-----------------+------------------+---------------+
| **Drug**        | **Number of**   | **RR (95%        | **p-value**   |
|                 |                 | CI)\*\***        |               |
|                 | **Tr            |                  |               |
|                 | ials/Patients** |                  |               |
+-----------------+-----------------+------------------+---------------+
|                 |                 |                  |               |
+-----------------+-----------------+------------------+---------------+
| Estrogen/       | 5/3117          | 0.66 (0.41,      | 0.12          |
|                 |                 | 1.07)            |               |
| Progestin\*     |                 |                  |               |
+-----------------+-----------------+------------------+---------------+
| Alendronate     | 8/9360          | 0.52 (0.43,      | \<0.01        |
|                 |                 | 0.65)            |               |
+-----------------+-----------------+------------------+---------------+
| Risedronate     | 5/2604          | 0.64 (0.54,      | 0.01          |
|                 |                 | 0.77)            |               |
+-----------------+-----------------+------------------+---------------+
| Raloxifene      | 1/6828          | 0.60 (0.50,      | 0.01          |
|                 |                 | 0.70)            |               |
+-----------------+-----------------+------------------+---------------+

\*Includes various estrogen plus progestin products/doses

\*\*RR= relative risk, CI = confidence interval