UNITED STATES OF AMERICA

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FOOD AND DRUG ADMINISTRATION

CENTER FOR DRUG EVALUATION AND RESEARCH

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ENDOCRINOLOGIC AND METABOLIC DRUGS ADVISORY COMMITTEE MEETING

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TUESDAY,

OCTOBER 7, 2003

The Advisory Committee met at 8:00 a.m. in the Versailles Ballroom of
the Holiday Inn, 8120 Wisconsin Avenue, Bethesda, Maryland, Dr. Michael
McClung, Acting Chairman, presiding.

[PRESENT]{.underline}

MICHAEL McCLUNG, M.D. Acting Chairman

HENRY BONE, M.D. Consultant (Voting)

THOMAS O. CARPENTER, M.D.Member

DEAN FOLLMAN, Ph.D. Member

BARBARA LUKERT, M.D. Consultant (Voting)

CLIFFORD ROSEN, M.D. Consultant (Voting)

DAVID SCHADE, M.D. Member

MORRIS SCHAMBELAN, M.D.Member

MARTHA N. SOLONCHE Consumer Representative (Voting)

PAUL WOOLF, M.D. Member

ROBERT ZERBE, M.D. Acting Industry Representative

DORNETTE SPELL-LeSANE, M.H.A., NP-CExecutive Secretary

[WOMEN\'S HEALTH INITIATIVE PRESENTERS]{.underline}

GARNET ANDERSON, Ph.D.

JANE CAULEY, D.Ph.

ROWAN T. CHLEBOWSKI, M.D., Ph.D.

JACQUES ROSSOUW, M.D.

MARCIA STEFANICK, Ph.D.

[WYETH PHARMACEUTICALS TEAM]{.underline}

JOSEPH S. CAMARDO, MD.

CLAUS CHRISTIANSEN, M.D.

J. CHRISTOPHER GALLAGHER, M.D

ROBERT LINDSAY, M.D., Ph.D.

JAMES H. PICKAR, M.D.

[FDA REPRESENTATIVES]{.underline}

ERIC COLMAN, M.D.

DAVID ORLOFF, M.D.

BRUCE V. STADEL, M.D., M.P.H.

[PUBLIC HEARING SPEAKERS]{.underline}

AMY ALLINA

DAVID ARCHER, M.D.

MARIE FOEGH, M.D., D.Sc.

OMEGA L. SILVA, M.D.

JAMES A. SIMON, M.D.

I-N-D-E-X

Call to Order and Introduction 3

Dr. McClung

Conflict of Interest Statement 6

Ms. Spell-LeSane

Welcome and Introductory Comments 8

Dr. Orloff

Women\'s Health Initiative Study Results: Implications for the use of
hormone therapy with

estrogen/progestin as a second-line drug for the

prevention and treatment of post menopausal

osteoporosis in women.

Open Public Hearing 18

FDA Presentation - Dr. Colman 54

WHI Presentation

Dr. Rossouw 69

Dr. Stefanick 81

Dr. Chlebowski 96

Dr. Anderson 107

Dr. Cauley 128

Dr. Anderson 143

Dr. Rossouw 149

Questions from the Committee 155

Presentation by Wyeth Pharmaceuticals 176

Dr. Camardo

FDA Presentation - Dr. Stadel 246

Charge to the Committee - Dr. Orloff 258

Committee Discussion 260

P-R-O-C-E-E-D-I-N-G-S

8:07 a.m.

CHAIRMAN McCLUNG: Good morning. I\'m Dr. Michael McClung, the acting
Chairman of the Endocrinologic and Metabolic Drugs Advisory Committee.
Let me welcome you to today\'s meeting. We have a very busy agenda that
looks like will be an interesting and enlightening day.

Let me begin by asking the members of the Advisory Committee and our
invited guests and consultants who are seated around the table to
introduce ourselves to both each other and to the audience. So, sir,
I\'m going to have you start with your end with your mouth full. Sorry.

DR. ZERBE: Sorry. I\'m Bob Zerbe, QUATRx Pharmaceuticals and I\'m the
Industry representative.

DR. SCHADE: I\'m David Schade, Endocrinology University of New Mexico,
School of Medicine.

DR. SCHAMBELAN: I\'m Morrie Schambelan, Endocrinology, University of
California in San Francisco (\"UCSF\").

DR. FOLLMAN: I\'m Dean Follman, a statistician at the National
Institutes of Allergy and Infectious Diseases.

DR. BONE: I\'m Henry Bone. I\'m an endocrinologist and the Director of
the Michigan Bone and Mineral Clinic. I guess that\'s the main thing.

DR. LUKERT: I\'m Barbara Lukert, Endocrinology, University of Kansas.

DR. CARPENTER: I\'m Thomas Carpenter, Pediatric Endocrinology, Yale
University in New Haven.

DR. WOOLF: I\'m Paul Woolf, Adult Endocrinologist, Crozer Chester
Medical Center.

SECRETARY SPELL-LeSANE: Dornette Spell-LeSane, Executive Secretary for
the Committee.

MS. SOLONCHE: And just in time, Martha Solonche, New York City, the home
of the New York Yankees, Patient Representative.

DR. STADEL: Bruce Stadel, Medical Officer, Metabolic and Endocrine
Division (FDA).

DR. COLMAN: Eric Colman, Medical Officer from Metabolic and Endocrine
(FDA).

DR. ORLOFF: David Orloff, Director, Division of Metabolic and Endocrine
Drug Products (FDA).

CHAIRMAN McCLUNG: I\'m Mike McClung, an endocrinologist at the
University of Oregon Health Sciences Center in the Oregon Osteoporosis
Center. The next item on the agenda will be to have Ms. Spell-LeSane
review the Conflict of Interest Statements regarding the Committee
members.

SECRETARY SPELL-LeSANE: The following announcement addresses the issue
of conflict of interest with respect to this meeting and is made a part
of the record to preclude even the parents of impropriety at this
meeting. The topics to be discussed today will not focus on any
particular product or company but rather may affect all companies that
make hormone therapies with estrogen-progestin that are prescribed for
the prevention and treatment of postmenopausal osteoporosis.

The Conflict of Interest statute prohibits special Government employees
from participating in matters that could affect their own or their
employers financial interests. All participants have been screened for
interest in the products and companies that could be affected by
today\'s discussions.

In accordance with 18 USC 208(b)(3), the Food and Drug Administration
(\"FDA\") has granted a full waiver to Dr. Henry Bone because the need
for his services outweighs the potential for a conflict of interest. A
copy of the waiver statement may be obtained by submitting a written
request to the Freedom of Information Office HF-135, 5600 Fisher\'s
Lane, Rockville, Maryland 20857.

We would like to note that Dr. Jacques Rossouw, Dr. Leslie Ford, Dr.
Joan McGowan and Dr. Barbara Alving were involved with the Women\'s
Health Initiative (\"WHI\") Study as part of their duties as employees
of the National Institutes of Health (\"NIH\"). We would also like to
note for the record that Dr. Robert Zerbe is participating in this
meeting as the Acting Industry Representative acting on behalf of
regulated industry.

In the even that discussions involve products or firms not on the agenda
for which an FDA participant has a financial interest, the participants
are aware of the need to exclude themselves from such involvement, and
their exclusion will be noted for the record. With respect to all other
participants, we ask in the interest of fairness that they address any
current or previous financial involvement with any firm whose products
they may wish to comment upon. Thank you.

CHAIRMAN McCLUNG: Questions or comments about that from the Committee?
Let me then invite Dr. Orloff to make his opening statements to us.

DR. ORLOFF: Thank you and good morning. I\'ll read my statement from my
seat as is my usual. Good morning. Thanks to the members of the
Committee and the consultants present for their attendance and to Dr.
McClung for agreeing to chair today\'s session. Thanks also to Drs.
Stadel and Colman for their important contributions to today\'s
proceedings.

I want to recognize in particular Dr. Stadel for a tremendous amount of
work in bringing the FDA and NIH WHI group together for this conference.
We are of course very grateful to the WHI investigators for their
willingness to be here today to present the trial results and to
participate in discussion and particularly to Dr. Rossouw whose close
contact with the FDA through Dr. Stadel has made this meeting possible.
Thanks finally to Dornette Spell-LaSane for here work in managing the
complex logistics and legalities and so on of this important conference.

This meeting represents the first public FDA meeting and the first joint
FDA and NIH public conference on the landmark Women\'s Health Initiative
Study of Premarin (medroxyprogesterone acetate, \"MPA\"), the
combination therapy, in post menopausal women. As everyone present is
well aware, the results of this study have dramatically affected the
thinking as to the role of menopausal hormone therapy in women. The
public and individual impacts of at least combination estrogen-progestin
hormone therapy and of estrogen along therapy by many patients,
researchers and practitioners are being reevaluated in light of the
overall balance of risks and benefits in Prempro in this study that was
terminated early having reached stopping criteria based on breast cancer
incidence.

Since the publication of the primary WHI trial results in July 2002, the
FDA always in collaboration and/or discussion with the NIH has taken
several steps. In its role in regulating the marketing of Prempro in
advising physicians and patients on the safe and effective use of this
and other estrogen-progestin (\"E + P\") combination products and of
estrogen only (\"E alone\") products, FDA has implemented the following:

1\. Approval of revised product labeling for Prempro, Premarin as well
as for ultimately all U.S. marketed E + P and E along products, changes
that were announced formally in early January of this year. Dr. Colman
will take you through these changes in his presentation.

2\. Issuance of revised guidances for industry on clinical development
for post menopausal uses of new estrogen and estrogen plus progestin
products and their labeling. This is with the particular goal of the
development of lowest effective doses of such products.

3\. Provision of information resources on the WHI and on the safe and
effective use of menopausal hormones on the FDA website.

4\. Finally, most recently in early September 2003, Dr. McClellan, our
Commissioner, launched a nationwide information campaign partnering with
multiple organizations across the United States to raise awareness on
the risks and benefits of menopausal hormone therapy in light of the
results of the WHI Prempro study.

Following on the results of WHI, the basic recommendations by FDA have
been consistent with those of a number of professional societies and
patient advocacy groups, including the American College of Obstetricians
and Gynecologists from which we\'ll hear a statement written today and
the North American Menopause Society. Essentially the same
recommendations have been applied to the use of E + P products,
obviously those with the use most directly informed by WHI and in the
absence of information supporting a clear difference in risk versus
benefit to E alone products. They are as follows:

1\. Estrogen and estrogen plus progestin products should not be used for
primary or secondary prevention of coronary or cardiovascular disease.
Indeed FDA had never approved labeling recommending such use though it
had become a common rationale among others for what had become known as
menopausal hormone replacement therapy, a term we hold as now clearly
inappropriate if not frankly misleading. Instead alternative
cardio-preventive intervention should be considered.

2\. Alternative therapy should be considered for the relief of
menopausal symptoms particularly as a result of vulvovaginal atrophy as
well as for the prevention of post menopausal osteoporosis (\"PMO\").

3\. If estrogens and progestins are prescribed, they should be used at
the lowest doses for the shortest duration to achieve treatment goals
and women should regularly discuss with their healthcare providers if
they need to continue treatment.

Today\'s meeting is intended to assess where we, the broad healthcare
communities engaged in areas of patient care, research and drug
development, have come thus far, that is, since July 2002, regarding
understanding of and recommendations for safe and effective use of
female menopausal hormone drug products and to engage in a public
discussion of where we ought to be going. The specific objective of this
conference is to discuss the ramifications of the WHI Prempro results
for the single chronic use, prevention directed indication for
estrogen-progestin in women. That is preservation of bone mineral
content after menopause.

As referred to earlier, the revised product labeling for Prempro as well
as the actual or intended labels for E + P and E alone products states
that if the use is solely for the prevention of PMO then alternative
approval therapies should be considered. As such, these products have
essentially been relegated to second line status in PMO prevention based
on risk versus benefit in chronic use.

Any number of complex clinical and scientific issues remain unanswered
by the WHI study or indeed are raised in its aftermath. These include
but are not restricted to the risk versus benefit of lower doses of
Prempro, the risk versus benefit of other E + P combination products,
the risk versus benefit of Premarin or other estrogen alone products,
that is to say used in the absence of progestin, the risk versus benefit
of estrogen and estrogen plus progestin products administered by
alternative routes, for example, transdermally, and the impact of
demographic factors as well as baseline risk factors, for example,
osteoporosis, atherosclerotic cardiovascular disease, breast cancer,
venous thromboembolic disease on the benefit versus risk of these
products.

The agenda for today\'s meeting is in your package. Following the open
public hearing, Dr. Eric Colman, the team leader for Osteoporosis Drugs
and Metabolic and Endocrine Division at FDA will provide background on
the historical and current regulatory approach to evaluation of
menopausal hormones and other drug products for osteoporosis prevention
and treatment. A series of presentations from the WHI group will follow
with questions and discussions afterward. After lunch, Wyeth
Pharmaceuticals will present and Dr. Stadel, Medical Officer in
Metabolic and Endocrine, will make a brief presentation based on his
review of the WHI findings.

This is not a typical FDA Advisory Committee meeting. There is no
product being considered for FDA approval today. As such, we have chosen
not to ask at least at the start explicit yes or no questions but rather
to attempt with our questions or with our laying out of issues to direct
the deliberations and discussions on three principal topics. They are
and Dr. Colman will review these as well I suspect:

1\. The accuracy, appropriateness and usefulness of the revised labeling
of Prempro after the WHI.

2\. The implications of the WHI results for the clinical development for
prevention of PMO of new estrogen plus progestin drug products, for
example, vis a vis endpoints, doses studied, among others.

3\. Broadly, further discussion and recommendations regarding FDA
regulation of estrogen plus progestin products for the prevention and
treatment of PMO.

As you will note, the issues for discussion focus on E + P drug products
as Prempro was the subject of the arm of the WHI that was terminated for
safety reasons. The Premarin alone arm continues at present as you will
hear from Dr. Rossouw and others. While we do not wish to exclude
totally any discussion of the E alone products or of other issues not
directly addressed by the WHI Prempro study, we thought it best at least
for the purposes of initial discussion within the context of the results
of this landmark clinical trial. We fully expect the discussion to
diverge and we welcome it wholeheartedly. Again, thank you to all for
your attendance and we look forward to a simulating and informative day.
I\'ll turn it back over to Dr. McClung.

CHAIRMAN McCLUNG: Thank you, Dr. Orloff. As is the custom for these
meetings, input from the community at large is invited to occur. We will
have presentations by six different speakers during the open public
hearing presentation and then a read comment from one of the major
clinical societies. Other comments are available in information that\'s
on the desk outside as well. Before inviting the first speaker though,
let me read this comment regarding the Declaration of a Conflict of
Interest from our public hearing speakers.

\"Both the FDA and the public believe in a transparent process for
information gathered in decision making. To ensure such transparency at
the open public hearing session of the Advisory Committee meeting, the
FDA believes that it is important to understand the context of an
individual\'s presentation. For this reason, the FDA encourages you, the
open public hearing speakers, at the beginning of your written or oral
statement to advise the Committee of any financial relationship that you
have with any company or any group that is likely to be impacted by the
topic of this meeting. For example, the financial information may
include a company\'s or a group\'s payment of your travel, lodging or
other expenses in connection with your attendance at this meeting.
Likewise, the FDA encourages you at the beginning of your statement to
advise the Committee if you do not have any such financial
relationships. If you choose not to address this issue of financial
relationships at the beginning of your statement, it will not preclude
you from speaking.\"

With that stated, let me invite the first of our open public hearing
speakers, Dr. Marie Foegh from Berlex Laboratories.

DR. FOEGH: Good morning and thank you for giving me the opportunity to
give a short presentation of what I think is exciting and at least to me
surprisingly positive results of a study we have conducted. Also as you
can see from my first slide, I represent Berlex Laboratories and I\'m an
employee of Berlex Laboratories. In my short presentation, I\'ll give a
short background and then present some of the data from the study, not
all, in the short timeframe, a conclusion and some slides that brings
some source that we have.

I think most of you are aware of the great importance of preventing bone
loss in post menopausal women. Certain women beyond 50 years of age have
osteopenia or osteoporosis and about 14 million women have osteoporosis
of the hip which results in many women in fracture. Fracture may sound
simple but it may heal. But we all know in older women, this may be the
beginning of the end. It\'s associated with a lot of disability and in
many instances, death will follow.

I know we all have been used to saying hormone replacement therapy and
replacement in many have been a wrong term, but if it ever were true, it
may be true for osteoporosis because increased bone loss is really a
lack of estrogen. What does it result in? You have osteoporosis,
osteopenia and you have apoptosis of the osteocytes and so forth, but
this is not a detailed scientific presentation. This is just the opening
of making the statement that estrogen certainly would be a natural
choice for treating osteoporosis.

We all know from the WHI study that the risks of using hormones seem
bigger than we original thought. It changed our thinking like the
Chairman also said and the risk/benefit, but we also have to remember
that the dose used in the WHI study may not be the lowest efficacious
dose, but it is the most common used dose today. It\'s not unreasonably
succinct that the risk may decline the lowering of dose.

What I\'m showing you today will be efficacy of a dose that\'s 75
percent below a commonly used dose. This also actually affects the
quality of life. I mean you decrease the estrogen side effects that is
not life-threatening but not pleasant. It may be feasible to have your
cake and eat it.

Berlex has sponsored a study on osteoporosis in women between the age of
60 to 80. UCSF was the coordinating center and you\'ll see some names
that are familiar to the osteoporosis field and estrogen like Dr. Grady,
Dr. Cummings and also on the investigator list, there are names familiar
in this field.

This was a double-blind, randomized trial with 417 women that were as I
said between the ages of 60 to 80 years and they all had an intact
uterus. They were more than five years post menopausal and the entrance
criteria was a z-score of more equal to 2.0. The estrogen dose was a
weekly transdermal patch which delivers 0.014 mg of estradiol. That was
tested against a placebo patch.

The goal was to increase estradiol just to 10-15 picogram per mL. This
is a low level of estradiol because you may all know that women post
menopausal have levels below 20 picogram per mL and nearly all men have
actually levels about 20 picogram per mL which may come to a surprise to
many that men have higher estradiol levels than post menopausal women.

All the women took calcium and vitamin D of reasonable doses and the
study lasted for two years with follow-ups every four months. The
primary endpoint was bone marrow density (\"BMD\") at lumbar spine.
 Another primary endpoint was endometrial safety. There was a series of
secondary endpoints which I will show you some. The hip, of course, are
bone markers and so on.

But let me focus on the lumbar spine. The blue represents the placebo
group and the red represents the active arm, the estradiol group. You
have the data at 12 and 24 months. As you can see, there\'s a 2.5
percent difference between placebo and the active arm at 24 months, a
highly significant result of a P-value less than 0.001. This is very
comparable to other estrogen and other compounds that SERMs use for
treatment of prevention of osteoporosis.

To the hip, the results were also highly statistically significantly
different both at 12 and 24 months. Again the blue is the placebo and
there is as you can see an increasing bone loss and that is counteracted
by the estrogen and again a highly significant difference of 1.5 percent
at 24 months.

We also had a secondary endpoint of fractures. Of course we were aware
that the study wasn\'t big enough to show any difference in fractures,
but as you can see numerically at least there is a difference. There is
four in the active arm and 10 fractures in the placebo arm. These are
women with fractures. Some of those women had several fractures, but
this is women with fractures at any given time.

In August, most of you are aware that a study was published on what I
would also call an ultra-low dose of estradiol. That was Dr. Prestwood
and her collaborators. And Dr. Cummings, one of the investigators,
pooled the data of these two ultra-low studies and the combined factors
were that there were six fractures for the ultra-low and sixteen for
placebo. This is statistically significantly different of a p-value of
0.4. This is really exciting because these are mainly osteopenic women
and these are fractures that we are talking about. So it\'s very
encouraging.

What were the adverse events? Here\'s adverse events we worry about
namely, breast cancer, cardiovascular events. These are what they look
like in this study which lasted for two years. We looked at all but what
I\'ve summarized here for you are the breast cancer and the
cardiovascular. It was interesting when you glance over it. There is
really no difference between the placebo and the active arm.

One interesting point is actually that we did not have any venous
thromboembolic events. If you go down to the bottomline, I thought it
might be interesting also to see there were no deaths in this age group
and the hospitalization was not statistically significantly different.
It was 22 in one group and ten in the other.

This is the conclusion. You will notice that you haven\'t seen all the
data. This is because I got my talk cut short yesterday. But of course I
am willing to give the data if you ask. What we found is the prevention
of bone loss in all the post menopausal women with this dose that is 75
percent lower than the normally used dose. It is safe for the
endometrium. The study lasted for two years so for two years you do not
need to use progestin. There was decrease in the bone markers and there
was no difference in some of the normal estrogen related side effects
like breast tenderness, headache. If you look at the bottom, there was
also no difference in lipids, sex hormone binding globin (\"SHBG\") or
C-reactive protein (\"CR-P\") between the two groups.

So we really think that this effect of this ultra-low dose is kind of a
paradigm shift in the risk-benefit of the hormone use. We showed that it
seems that you would be able to get a fracture reduction in osteopenic
patients. You can give anapost estrogen at this dose for up to two
years. We do not know what happens after two years. The adverse event
profile is similar to placebo. We have no increase in the vasomotor
symptoms. We don\'t share of course bisphosphonates effects because we
are transdermal products. Thank you so much for your attention.

CHAIRMAN McCLUNG: Thank you. Are there questions or comments? If not,
thank you very much. The second presenter will be Susan Wysocki who is
the President and CEO of National Association of Nurse Practitioners in
Women\'s Health. If she\'s not here, we\'ll come back to that point in a
moment. Next, let me invite Dr. David Archer, who will speak on behalf
of the American Society for Reproductive Medicine (\"ASRM\"). Dr.
Archer.

DR. ARCHER: Thank you very much, Dr. McClung. Good morning, ladies and
gentlemen. It\'s a pleasure to be with you this morning in Washington
although it\'s a little brisk outside. I represent the American Society
for Reproductive Medicine and myself at this meeting.

Both AMRM is composed of physicians and I am a physician. As such,
we\'ve been involved in medical education and clinical trials for many
years. Because of this, both of us have received grants, funds, clinical
research dollars from I would say every pharmaceutical company in the
United States that makes a hormone preparation for menopausal women.
That is my disclaimer in terms of our conflict of interest. I am
expecting that ASRM will reimburse me for my expenses so I am not here
as representing a pharmaceutical company.

Currently I am a professor of obstetrics and gynecology at the Eastern
Virginia Medical School. I\'m an obstetrician/gynecologist with advanced
certification in reproduction endocrinology. The ASRM is really pleased
to be a partner with the FDA in terms of its campaign for educating
women as they consider hormone therapy for post menopausal symptoms.
However, we all are concerned with the fact that media publicity has
resulted in symptomatic women who could benefit from hormone replacement
therapy by using approved and appropriate therapy for the relief of
symptoms.

We know that hormone therapy improves symptoms and the quality of life
for these women. I think we\'re all concerned that the media has
characterized hormone therapy as harmful to women, particularly in
cardiovascular disease and breast cancer. I believe the scientific
community and physicians realize that the relative risk numbers are
often high, but the attributable risks in the community is a different
issue.

Young women between the ages of 45 to 55 who are peri or post menopausal
and are symptomatic are a different class of women than those reported
in the WHI. These younger women are good health. They are not at
apparently increased risk of cardiovascular disease with the use of
hormone therapy. The current final report from the WHI in July of this
year really did not find overall an increase in coronary heart disease
in women receiving hormone therapy. We do acknowledge that there was an
increase in coronary heart disease in the first year of use but again
point out that the average age of women in this study was 63,
significantly older than the 50 year old woman that we frequently see in
our practices.

As some example for this risk, if you log on to the American Heart
Association website, www.americanheart.org and use the Framingham risk
factor for the identification of heart disease risk in a 55 year old
woman who has a mild elevation in her total cholesterol level, her
actual attributable risk are her risks of developing heart disease in
the next ten years is less than one percent. So we would submit that
there is very low risk for these women who are younger and in good
health of developing significant adverse events particularly those
related to the cardiovascular system.

We feel that this underscores the fact that consumers really apply the
results of what\'s published in the media to themselves inappropriately.
Anecdotally as I\'ve said to other people, I\'ve had a 47 year old woman
consider hormone therapy be concerned over the fact that she might
develop Alzheimer\'s disease in the next several years. So that all of
us take the sound byte from the media and apply it to our particular
lifestyle.

Now we all know that breast cancer is a significant issue for women.
However in the WHI, women who had never used hormone therapy and entered
this trial and were randomized were not found to have a significant
increase in the occurrence of breast cancer during the five years of the
clinical trial. Only in those women who had previously used hormone
therapy was there an apparent increase in the incidence of breast
cancer.

So the average age of the woman 50 to 55 who is symptomatic and requests
treatment is really not at a particularly increased incidence of breast
cancer from the use of hormone therapy using the relative hazard
published in the WHI. I might also point out that the most important
risk factor for breast cancer from numerous publications is that of age
itself.

Now as I pointed out in this anecdotal case which as I realize is
inappropriate in front of an August body such as this dealing in large
numbers that the issue of cognition in Alzheimer\'s disease really need
to be clarified for the consumer. The WHI memory study showed an
increase in the occurrence of cognitive decline in Alzheimer\'s or
probable Alzheimer\'s disease after approximately two years of hormone
therapy. However it should be pointed out which is not pointed out for
many of the consumers that this study occurred in women who were over
the age of 65. So the relevance of this finding to younger women is at
present unknown.

I\'m not cognitively impaired. I just need my helper right here in front
of me. So it\'s obvious for the younger symptomatic woman who is
complaining of hot flashes, night sweats, difficulty sleeping, mood
fluctuations and vulvo-vaginal atrophy that the message that we should
deliver as physicians to this group of patients is that hormone therapy
can relieve these symptoms without resulting in significant mortality or
morbidity in terms of its outcome.

I believe that this message is important for women who may or may not
have risk factors for bone loss. Current data from the WHI and other
publications indicate that standard and lower doses of estrogen with
progestin or estrogen alone prevent bone loss in post menopausal women.
This is based on the findings with DXA scanning and this group of
individuals are duel-energy X-ray absorptiometry.

The WHI recent publication allows us to I think unequivocally conclude
that estrogen plus progestin reduces the incidence of fracture of the
hip, spine or vertebral body and wrist in all the subgroups of post
menopausal women. We believe that these data provide a compelling reason
to initiate hormone therapy for the prevention of bone loss and
fractures in post menopausal women. The position of the ASRM therefore
is supportive of the use of hormone therapy in post menopausal women
with the understanding that this use is based on the patient\'s unique
risk/benefit profile. I want to thank you very much for allowing me to
make this presentation this morning.

CHAIRMAN McCLUNG: Thank you, Dr. Archer. Comments or questions? Thank
you very much. Our next speaker is Dr. Omega Silva, the past President
of the American Medical Women\'s Association (\"AMWA\").

DR. SILVA: I am Dr. Omega Silva, Endocrinologist and Past President of
the American Medical Women\'s Association. I appreciate the opportunity
to present AMWA\'s views on the implications of the WHI for the use of
hormone therapy with estrogen and progestin as a second line drug in the
prevention and treatment of post menopausal osteoporosis in women.

Founded in 1915, AMWA is an organization of 10,000 women physicians and
medical students dedicated to serving as the unique voice for women\'s
health and the advancement of women in medicine. AMWA supports the
current FDA approved indications for hormone therapy. Hormone therapy is
the most effective FDA approved treatment for menopausal symptoms such
as hot flashes, night sweats and vulva and vaginal atrophy. Hormone
therapy is also indicated for the prevention of post menopausal
osteoporosis. AMWA is proud to be a partner in FDA\'s menopause and
hormones information campaign which provides women with important
information about hormone therapy.

As physicians, our role is to review a patient\'s family and medical
history and assess the risks and benefits of hormone therapy for that
individual. We can help our patients by putting the risks into proper
perspective. While hormone therapy may not be appropriate for one woman,
it may be entirely appropriate for another.

With regard to osteoporosis, AMWA recognizes the enormous impact of the
disease on the health of Americans, particularly women. The disease
causes over 1.5 million fractures yearly at a cost of \$17 billion.
Following osteoporoic hip fracture, there is an excess mortality of 12
to 20 percent. Hip fracture is the second leading cause of admission to
nursing homes for women.

Osteoporosis causes severe and unrelenting bone pain. It is one of the
major debilitating disorders that contribute to the loss of functional
independence and quality of life in older women as noted in AMWA\'s
position paper on osteoporosis.

To prevent osteoporosis, AMWA members recommend weight-bearing exercise,
adequate calcium and vitamin D intake and the maintenance of a healthy
life style. In addition, medications to prevent further bone loss may be
indicated. Women who think they are at risk of developing osteoporosis
should consult their physicians. Treatment plans should be initiated as
early as possible because once bone is lost it\'s difficult to replace
as noted in AMWA\'s osteoporosis question and answer fact sheet.

The recent study in the October 1, 2003 issue of the [Journal of the
American Medical Association]{.underline} (\"JAMA\") demonstrated that
estrogen plus progestin increased bone mineral density and reduces the
risk of all fractures in healthy post menopausal women. This decreased
risk of fracture appears to be present in all subgroups of women
examined. When considering effects of hormone therapy on other important
disease outcomes in a global index developed by the WHI investigators,
the study authors concluded that there was net benefit of hormone
therapy even in women considered to be at high risk of fracture.

On this point, AMWA notes that the global index is based on selected
risks and selected benefits and not on all risks and all benefits. For
example, it includes hip fractures but not for tibial fractures or
menopausal symptoms, the primary reason women take hormone therapy. For
some women, the risk/benefit equation might change when relief from post
menopausal symptoms and prevention of tibial fractures are taken into
account.

AMWA agrees with the current FDA approved labeling for hormone therapy,
Prempro, which states that when prescribing solely for the prevention of
post menopausal osteoporosis therapy should be considered for women at
significant risk of osteoporosis and non-estrogen medications should be
carefully considered. If hormone therapy is prescribed, it should be
taken at the lowest possible dose for the shortest duration of time to
meet treatment goals.

The WHI results have reinforced what physicians have known all along.
Treatment decisions should be individualized. For this reason, it is
extremely important for FDA to preserve physician and patient choice of
therapeutic agents to prevent and treat osteoporosis. Hormone therapy
remains an important option for those women at risk of osteoporosis who
are unable to take non-estrogen medications.

On behalf of AMWA, I thank you for the opportunity to testify before the
Committee. I have no problems with getting money from this person or
that person because nobody gives me any. Now I would like to become a
patient. How much time do I have? A few minutes.

Now I would like to become a patient and give you a personal scenario.
I\'m 66 years old and follow the textbook version of peri-menopause and
menopause and post menopausal symptoms, getting those first little nasty
hot flashes at age 45, becoming a post menopausal woman at 50.5. When I
was 45, the data on the benefits and risks were very sparse, but became
better when I was about 52 or 53. So I began HRT and continued until May
30, 2003. At that point I said after the WHI results, \"Well, maybe I
can do without this HRT now.\" Within a week, those nasty little hot
flashes returned. My husband said \"For crying out loud, you\'re hot one
minute and cold the next.\" Sleeping was a ritual of getting up and
turning my pillow over on the cool side.

Now I was going on an Alaskan cruise in September. So I said \"I\'ll be
damned if I\'m going to sweat and hot flash myself through this
cruise.\" There was no breast cancer in my family. My aunts on my
mother\'s side lived to be 90 plus. One just died of pneumonia at age
100. My mother did die of cerebral hemorrhage but she had no
thromboembolic events. My father at age 94 just had colon cancer.
Therefore, I weighed by personal risks and benefits and restarted my HRT
and enjoyed my cruise and life thereafter. Many of you men may not
understand and I wouldn\'t wish prostate cancer on any of you but if you
do get it and you have to take those anti-testosterone therapies, you
may feel some of these hot flashes and then you\'ll know what the women
go through. Thank you.

CHAIRMAN McCLUNG: Thank you, Dr. Silva. Questions or comments? Great.
Thank you. Next let me invite Dr. Jim Simon who is the current President
of the North American Menopause Society to deliver his remarks. Dr.
Simon.

DR. SIMON: Dr. McClung, members and guests of the Committee, I would
like to suggest that perhaps everyone can go home early today since
today\'s [Washington Post]{.underline} seems to have published a short
article saying \"The whole issue has already been settled.\" Page F-2 in
today\'s [Washington Post]{.underline}, it\'s interesting reading.

Today I need to give the following personal introduction. I\'m a
clinical professional of obstetrics and gynecology at George Washington
University here in Washington. I am also President and CEO of a
independent investigative research site that works with literally the
entire pharmaceutical industry since its inception. So I potentially
have conflicts as mentioned by Dr. Archer. However today and
uncharacteristically of me as a person for those of you who know me
which most of the people do, I\'m going to stick closely to the script
provided to me by my colleagues at the North American Menopause Society
and will be uncharacteristically short and non-controversial.

I would like to focus attention on the estrogen and progestin use in
peri menopausal and post menopausal women position statement published
by the North American Menopause Society on September 17, 2003. All the
Committee members have a copy. This position statement represents a
significant amount of work by a smattering of true experts on this
subject from around the world including five individuals who are WHI
investigators. Many of them also HERS (\"Hysterectomy Educational
Resources and Services\") and WHIMS (\"Women\'s Health Initiative Memory
Study\") investigators, and including Dr. Stefanick who is a member of
this Committee. The information is available to you in this publication.
For those who don\'t have a copy, on the web at www.menopause.org. It is
an update of a former position statement from last year.

I want to focus attention only on a couple of major points and leave it
to the Committee to use this learned piece of work some 14 pages with
appropriate references for their own purposes. Under areas for which
there was consensus on the Committee, there is definitive evidence for
estrogen-progestin therapies efficacy in reducing the risk of post
menopausal osteoporoic fracture. There is today no comparable evidence
for estrogen therapy. Many estrogen-progestin therapies and estrogen
therapy products are Government, that is FDA, approved for prevention of
post menopausal osteoporosis through all term treatment.

Because of the potential risk associated with hormone therapy for women
who require a drug therapy for osteoporosis risk reduction including
women at high risk of fracture within the next five to ten years,
alternatives to hormone therapy should also be considered weighing the
risks and benefits of each. Recognition should be given to the fact that
there are no published data on osteoporosis drug therapies beyond seven
years.

The effects of hormone therapy on the risk of breast cancer and
osteoporoic fracture in symptomatic peri-menopausal women have not been
established in randomized clinical trials (\"RCT\"). The findings from
trials in different populations, for example, the WHI, should therefore
be extrapolated with caution. There is however no evidence that
symptomatic women differ from asymptomatic women in either cancer or
bone outcomes.

Premature menopause and premature ovarian failure are conditions
associated with earlier onset of osteoporosis and cardiovascular
disease, but there\'s no clear data as to whether estrogen therapy or
estrogen-progestin therapy will reduce morbidity or mortality from these
conditions. The benefits/risks ratio may be more favorable for younger
women.

There were also some areas where there were no consensus that could be
reached by this Committee. However there were no areas of non-consensus
vis a vis osteoporosis. I would say with my personal hat on and not my
North American Menopause Society hat on and they are paying for my
parking today that I would ask the Committee in their deliberations to
try very hard not to further limit access to therapies this and any
other so that we working in the trenches may exercise clinical judgment
in the care of our patients one patient at a time. Thank you.

CHAIRMAN McCLUNG: Thank you, Dr. Simon. Questions or comments? Let me
invite then Amy Allina who is the Program Director for the National
Women\'s Health Network who will be our next speaker.

MS. ALLINA: Thank you. I am Amy Allina, the Program Director of the
National Women\'s Health Network (\"Network\"). The Network is a
non-profit organization that works to improve the health of all women by
developing and promoting a critical analysis of health issues to
influence public policy and to support consumer decision making. We
accept no financial support from pharmaceutical or medical device
companies. We\'re supported by a national membership of about 8,000
individuals and 300 organizations.

As many of you here today are aware the Network has a long history of
advocacy and consumer education on the issue of hormone therapy for
women at menopause. We\'ve spoken at numerous FDA Advisory Committee
meetings on the topic over the last 15 years. We were leading advocates
calling on the NIH to conduct the WHI so that women would have well
founded scientific research to guide their decision making about the use
of hormone therapy. We\'ve produced extensive health education materials
for women who are considering this therapy and we are also a partner
with the FDA in the patient education campaign that was recently
announced by Dr. McClellan.

Though we understand the perspective of the many researchers and
clinicians and even some women who were disappointed with the findings
of the WHI. We are really pleased that there\'s finally data from a
large long-term RCT of hormone therapy for healthy women. Hormone
therapy has been prescribed to women for decades without this data to
back it up. Though the WHI results leaves some women with new questions
about what\'s best for their health, we believe it\'s better to know
what these questions are than to make healthcare decisions based on
unproven and false assumptions. We\'re also pleased to be able to speak
here today and thank the FDA for the opportunity to give input on the
implications of the WHI results for FDA regulation of estrogen plus
progestin drug products, specifically regarding long-term use of the
products for prevention and treatment of PMO.

We\'d like to start by commending the Agency for acting quickly to work
with sponsors on a revision of the prescribing information that
accompanies Prempro and other estrogen plus progestin products that are
approved for prevention of osteoporosis and for identifying it as a
second line option for this purpose. Although the WHI results that were
released were based only on the study of women using Prempro, FDA acted
based on its recognition that other estrogen and estrogen plus progestin
products work in similar ways and asked for revisions on other product
labels. We agree and we believe it\'s important for women using those
products to have information about the benefits and risks identified by
the WHI.

In thinking about the implications of the WHI results for future
regulatory decisions, there are a lot of important questions about study
design that the Agency is going to have to grapple with and that all of
you will have to grapple with. In considering the conduct of trials or
approval of an estrogen plus progestin drug product for the prevention
and treatment of PMO, how many women need to be studied? How long do
they have to be studied? Are there surrogate safety endpoints that the
Agency can accept?

Historically approval\'s been based on studies of three year duration or
in some cases with less, but we know that the risks of Prempro didn\'t
emerge within that timeframe, at least with respect to breast cancer.
Given the knowledge we know have about the serious health risks with
estrogen plus progestin products that emerged after six years, we
believe FDA cannot approve similar drugs for long-term use without
requiring that they studied for that length of time. An interim
exception might be made for products containing only estrogen since the
arm of WHI studying estrogen alone is on-going. Until those data are
collected and analyzed, it\'s not known whether all the same risks will
apply to those drug products.

Regarding surrogate endpoints, the WHI has shown that the surrogates
that have been used in the past for cardiovascular disease were not
predictive. Given what\'s now known about the increased risk of
cardiovascular disease associated with long-term use of estrogen plus
progestin drug products, surrogate safety points really aren\'t
acceptable.

Finally, I wanted to address some of the points that were brought up in
materials that Wyeth Pharmaceuticals prepared for today\'s meeting and
that we\'ve heard echoed in messages from a couple of other groups
speaking today regarding the factors that they believe limit the
interpretation or generalize ability of the WHI results. Wyeth wrote
that the WHI recruited women of relatively old age in comparison to the
onset of menopause and therefore that the risks associated with hormone
therapy can be expected to be substantially lower than those observed in
the WHI. We just wanted to emphasize - I\'m sure that this point will be
brought up by the presentation from the WHI - that a third of the women
in the study, the total of 5,702, were in their 50s. This is the largest
RCT ever done of women in this age group.

The company also wrote that because the WHI excluded women with severe
menopausal symptoms, it was examining a population that was not
representative of the women for whom the product is principally
indicated. In fact at the start of the trial, 12 percent of the women
enrolled reported experiencing moderate to severe hot flashes or night
sweats and more over, research conducted among women who were taking
hormones prior to the release of the WHI result has shown that only a
minority said they said taking hormones because of hot flashes.

The company also suggested that the study population wasn\'t
representative of women for whom the product is indicated because it
included a number of participants who were overweight, past or current
smokers and being treated for high cholesterol, high blood pressure and
diabetes. These conditions are common in the general population and like
most people who enroll in clinical trials designed to study disease
prevention, the women in the WHI were probably healthier than the
general population due to the healthy volunteer effect. This supposition
is supported by the fact that the rates of cardiovascular disease while
increased in the treatment arm were lower in both the estrogen plus
progestin group and the placebo group than they are in the general
population.

So in conclusion, I just want to thank the FDA again for acting promptly
and responsibly when the WHI results were released and to encourage a
similar approach as the Agency moves forward to consider future research
and product approvals. While it is important to be clear and specific
about the regimen that was studied in the WHI and the regimens for which
we will have data in the future, it\'s also important to build on the
knowledge that the trial has given us and to act based on that. Thank
you.

CHAIRMAN McCLUNG: Thank you for your comments. Let me invite again Ms.
Susan Wysocki if she\'s in the audience. If not, let me proceed and ask
Ms. Spell-LeSane if she will read into the record the comment from the
American College of Obstetrics and Gynecology.

SECRETARY SPELL-LeSANE: Statement of the American College of Obstetrics
and Gynecology (\"ACOG\") on Hormone Therapy for the Prevention and
Treatment of Post Menopausal Osteoporosis for the FDA Endocrinologic and
Metabolic Drugs Advisory Committee. The ACOG representing over 45,000
healthcare professionals dedicated to women\'s health is pleased to
offer this statement to the U.S. Food and Drug Administration
Endocrinologic and Metabolic Drugs Advisory Committee on the use of
hormone therapy for the prevention and treatment of PMO in women.

Last week Cauley, et al., published an updated final analysis of
fracture endpoints in WHI RCT.  They found that use of conjugated equine
estrogen (\"CEE\") 0.625 mg per day and MPA 2.5 mg per day reduced the
risk of hip fracture by 33 percent, hazard ratio 0.67, nominal 95
percent confidence interval 0.47 to 0.96. Subgroup analysis showed that
use of estrogen plus progestin resulted in a statistically significant
reduced risk of hip fracture in women who had experienced menopause at
least 20 years previously, who had a body mass index (\"BMI\") of less
than 25, who had at least two falls in the past year, who reported a
daily calcium intake of at least 12,000 mg per day, who had no history
of fracture, who had used hormone therapy for either less than five or
at least ten years. Similarly hormone therapy also reduced the risk of
total fractures by 24 percent, hazard ratio 0.76, confidence interval
0.69 to 0.83.

Benefits were seen in bone mineral density (\"BMD\") as well. The change
in BMD from baseline was higher in hormone users in both hip and spine
and at every interval of follow-up reported. After three years, the
percentage difference was 4.5 percent for lumbar spine and 3.6 percent
for total hip. This final analysis confirms that previously reported
data from the WHI which demonstrates that estrogen plus progestin is
protective against both fractures and loss of BMD. It is concordant as
well with a wealth of other RCT and observational studies.

The evidence is strong and consistent. Use of CEE and MPA helps prevent
osteoporosis by slowing bone loss and is valuable in treating this
condition as well. The WHI report however calculate a global index to
quantify overall benefit versus risk of estrogen-progestin therapy.
Because Cauley, et al., calculated the global index hazard ratio to
range from 1.23 to 1.03 depending on a woman\'s risk of fracture, they
concluded that there was no evidence of a net benefit and recommended
that treatment with estrogen plus progestin not be used for prevention
and treatment of osteoporosis in women without vasomotor symptoms.

We cannot agree with this global index approach because we believe it is
to be biased. In our analysis of original WHI data on BMD and fractures,
ACOG offered the following guidance:

\"1. The decision about use of hormone therapy requires evaluation of
the risks and benefits for each individual woman.

2\. For women currently using hormone therapy, it is important to assess
their reasons for using and to evaluate potential risks, benefits and
alternatives.

3\. For patients with osteoporosis, other preventive therapies such as
bisphosphonates and selective estrogen receptor modulators are
available.

4\. For women at risk of osteoporosis who have vasomotor symptoms,
hormone therapy can be of benefit.

5\. Periodic reassessment of the need for hormone therapy is recommended
at least at every annual visit or more frequently if indicated.\"

We continue to support the judicious individualized use of estrogen and
progestin for bone protection and believe that it is inappropriate to
withhold this treatment option from those who need it and would benefit
from it. While we noted that there are other agents approved for
prevention and treatment of osteoporosis, each of these agents has its
own contrary indications and side effects. Some actually increase hot
flashes and they would not be a choice of women with vasomotor symptoms.

In offering the global index hazard ratio, the WHI investigators
attempted to estimate overall benefit versus risk. Although this concept
is potentially useful from a public policy perspective, it falls short
as guidance for care of individual patients. Ultimately this weighing of
benefits and risks must be done by each individual physician with each
individual patient.

ACOG continues to educate its fellows and their patients on the current
understanding of benefits and risks of hormone therapy and participated
with the FDA in its recently launched menopausal hormone therapy
educational campaign. We look forward for continuing to work with the
FDA on this issue. Isaac Schiff, M.D., Chair, ACOG Task Force on Hormone
Therapy, Stanley Zinberg, M.D., Vice President, Practice Activities.

CHAIRMAN McCLUNG: Thank you. And I would like to thank all of the
speakers for their comments and critique this morning to help set the
stage for our subsequent discussion. I\'m going to turn and invite Dr.
Eric Colman who is the Team Leader for the Osteoporosis Drugs of the
Division of the Endocrinologic and Metabolic Drugs of the FDA to review
the criteria for the effectiveness and safety in the evaluation of
osteoporosis drug products and specifically as it applies to the
estrogen-containing compounds. Dr. Colman.

DR. COLMAN: Thank you, Mr. McClung. What I wanted to start with is just
an outline of what I\'ll be talking about for the next 15 minutes or so
beginning with some terminology that I\'ll be showing you and then move
into a brief regulatory history of the estrogens and the estrogen plus
progestin and then show you the actual products that are currently
approved for the prevention of PMO. Finally, I show you some parts of
the labeling that have been changed in response to the Prempro arm of
WHI.

You will see that estrogen is denoted as \"E\" and progestin \"P\".
Estrogen plus progestin is \"E + P\". Conjugated equine estrogens is
frequently abbreviated \"CEE\". Medroxyprogesterone acetate is \"MPA\".
Those two compounds together comprise Prempro and Premphase. The
standard post menopausal osteoporosis \"PMO\". Bone mineral density
\"BMD\". And randomized control trials \"RCT\".

The regulatory history of estrogens dates back to 1942. This was when
the Agency approved CEE or Premarin for menopausal symptoms. It was then
roughly 30 years later when the labeling for estrogen said they were
probably effective for selective cases of osteoporosis. This was a
designation that came by way of a process called \"DESI\" which stands
for Drug Efficacy Study Implementation. The National Academy of Sciences
was contracted and they put together some experts. They looked at the
available literature on estrogens and bone. The best they could come up
with was a phrase saying \"Estrogens are probably effective for select
cases of osteoporosis.\" That\'s the way that stood for years.

In 1986, that was updated to read \"Estrogens are effective therapy for
osteoporosis.\" Throughout the 1990s, the labeling for these products
used the words \"management and prevention\". There was a certain amount
of confusion over what the word \"management\" meant to a lot of people.
So we thought the best way to handle that was to take it out. Most
recently, we have taken out the word \"management\" and the labeling now
simply reads \"prevention of osteoporosis\". I\'d also mention that all
of these labeling claims are based on data related to bone density and
not to fracture data.

Prempro CEE/MPA was approved for the prevention of osteoporosis in 1994.
It was a somewhat of an usual approval in that Premarin CEE was already
approved for the prevention of PMO, the same dose 0.625. The reasoning
was we have the same dose of estrogen. We\'re adding a progestin. At
that time, some people felt that there was evidence that progestins had
their own independent positive effect on bone density. The feeling was
if we have a progestin that has a positive effect on bone, maybe we can
lower the dose of estrogen, avoid some of the known estrogen adverse
effects but still end up with a positive overall effect on bone density.

Prempro was approved in 1994 for osteoporosis. At the same time, Wyeth
agreed to do a post approval study looking at lower doses of Prempro and
Premarin with BMD as the primary outcome. That study has been published.
It\'s referred to as the \"HOPE\" trial. In fact, the data from that
trial are the basis of the recent approval of lower doses of Prempro and
Premarin, doses lower than what was used in WHI. Again those are BMD
data. I will mention that again in a second.

The other thing that happened in 1994 was the Agency updated its
osteoporosis guidance. The guidance had separated out estrogens from
non-estrogens. As far as the estrogens were concerned, there was a
statement there that said \"The epidemiologic data are sufficient to
conclude that estrogens reduce the risk for osteoporoic fracture.\"
That\'s somewhat unusual in that the Agency took a position that
epidemiologic data were sufficient to conclude a fracture benefit of
estrogens. That\'s what was in the guidance.

Subsequently no company other than one tried to get a treatment
indication which would mean a fracture indication for an estrogen or E +
P. From that day on, we have been dealing primarily with prevention of
PMO for estrogens. For a company to get a prevention of PMO indication,
they had to do a two year trial with lumbar spine BMD as a primary
endpoint and they had to compare their drug again to placebo and show
that their drug led to a statistically significant increase over
placebo.

Just briefly to recap, the E and E + P products approved for the
prevention of PMO, the approval came about in general through one of two
mechanisms. The older products were just designated as a DESI drug or
the company had to do a two-year randomized placebo controlled trial
with lumbar spine as a primary endpoint. In general, the women in these
trials had normal or osteopenic bone density at baseline. By and large,
the trial sizes were less than 500 women.

I\'d like to show you this just as a point of reference.  This outlines
the requirements for approval of the non-estrogens. This would be, for
example, alendronate (Fosamax, Actinal (risedronate) and in fact, even
SERM raloxifene. Here you will see where treatment becomes synonymous
with fracture reduction and prevention, synonymous with BMD. For a
non-estrogen to gain a treatment indication, the company had to do a
three year RCT demonstrating that their drug significantly reduced the
risk of vertebral fracture relative to placebo.

Once that was done and the company wanted a prevention of PMO indication
like with estrogens, they had to do a two year trial looking at lumbar
spine BMD. That was the same as it was with the estrogens. On top of
that, they had to have a large favorable preclinical profile for the
drug and the clinical development program for these compounds in the
last eight years have been quite large, anywhere from 5,000 to 15,000
trial subjects.

As of today, there are several E + P products approved for the
prevention of PMO again based on BMD. There are no E + P products
approved for the treatment of PMO, again treatment synonymous with
fracture efficacy which I basically said at the bottom of this slide.

The next two slides I want to show you the actual E and E + P products
that are approved for PMO. This slide shows you Prempro and Premarin.
You will notice that I have shown four doses in yellow. You recall that
the 0.625 to 2.5 dose of Prempro was what was used in WHI. Fairly
recently, the Agency has approved the lower doses of 0.45, 0.3, and 1.5
Prempro for the prevention of PMO. Again those come from BMD data from
the study that Wyeth agreed to do back in 1994. So it\'s referred to as
the HOPE trial.

The lower doses of Premarin were also studied in that trial. Again those
data form the basis for the recent approval of two lower doses of
Premarin. They are all based on BMD.

This slide shows you the other products that are approved. You will
notice that there are different estrogen compounds here. There are two
different progestin compounds. There are several different doses. You
will also notice at the bottom there are two patches to transdermal
preparations. So there are a host of different E and E + P products
currently available, all limited to BMD data in fairly small trials, but
they do offer some difference in the composition of the estrogen and the
progestin, the doses and the delivery system through two transdermal.

To summarize, there are several E + P products in addition to Prempro
that are approved for the prevention of PMO. There are no E + P products
approved for the treatment, treatment again synonymous with fracture
reduction. This is somewhat ironic. WHI now provides strong evidence
that E + P reduces the risk for osteoporoic fracture including the hip.

My last bullet is taken verbatim from last week\'s WHI Fracture paper
that was published in [JAMA]{.underline} where the authors concluded
that there was \"\...no net benefit, even in women considered to be at
high risk of fracture.\" Of course if you look at the global index, the
women who had the highest baseline risk, their global index was getting
pretty close to one. The global index does not include vertebral
fractures so those components obviously will lead to I would think some
discussions about \"Is there possibility a subgroup who might benefit
particularly with lower doses\" but that\'s more hypothetical.

Let me move on the labeling changes at this point. I want to show you
all the labeling changes. The labeling changes that I\'ll show you I\'ve
highlighted three sections, but the changes that have been made to
Prempro and Premarin. All manufacturers of E and E + P had been
requested to make the same changes. I don\'t know where we stand in
terms of getting the responses back but letters have been sent to those
individuals saying \"You need to make these changes as well even though
you\'re a transdermal, even though you\'re a different preparation.\"

Let\'s go to the black box warning. This is a little tedious because
I\'ve copied a lot here. The black box warning is the first portion of
the label on the Prempro label. The first thing it says is \"Estrogens
and progestins should not be used for the prevention of cardiovascular
disease. The Women\'s Health Initiative study reported increased risk of
myocardial infarction, stroke, invasive breast cancer, pulmonary emboli
and deep vein thrombosis in post menopausal women during five years of
treatment with CEE combined with MPA.\"

This gets to the other doses and other products. \"Other doses of
conjugated estrogens and medroxyprogesterone acetate and other
combinations of estrogens and progestins were not studied in the WHI. In
the absence of comparable data, these risks should be assumed to be
similar.\" That is the approach that the Agency has taken thus far. If
you don\'t have data to prove you\'re different, you\'re going to be
assumed to be the same.

\"Because of these risks, estrogens with or without progestin should be
prescribed at the lowest effective dose and for the shortest duration
consistent with treatment goals and risks for the individual woman.\" It
sounds very logical.

Now the indications and usage section, the first two indications, the
first has to do with vasomotor symptoms. The second has to do with
vulvovaginal atrophy. Those are two of the three continuing indications
for this product. The third indication is a prevention of PMO which now
reads \"When prescribing solely for the prevention of post menopausal
osteoporosis, therapy only should be considered for women at significant
risk of osteoporosis and non-estrogen medications should be carefully
considered.\" This is suggesting that this should be a second line agent
or you should have real good reason to use this over other products
already out there.

Finally, the dosage and administration, some more wording that we\'ve
seen before. \"Use of estrogens alone in combination with progestin
should be limited to the shortest duration consistent with treatment
goals and risks. Patients should be reevaluated periodically as
clinically necessary.\" The top portion here is more about the
osteoporosis. At the bottom, it says \"Patients should be treated with
the lowest effective dose. Generally women should be started at 0.3, 1.5
Prempro.\" Again this is a recently approved dose. \"Dosage may be
adjusted depending on the individual, clinical and bone mineral density
responses. This dose should be periodically reassessed by the healthcare
provider.\"

That concludes the basis of my presentation. I just want to leave you
with some issues we hope will be the focus of today\'s Committee
discussion. Some of these issues Dr. Orloff mentioned earlier. I just
want to reiterate those. At the end of the day when all is said and
done, we\'re going to ask the Committee to comment on the revisions made
thus far to the Prempro labeling keeping in mind that these changes have
been made to the whole class of E and E + P. It\'s not simply Prempro.
We also will ask you to discuss the implications of the WHI trial
results for the future development, testing and potential approval of
E + P drug products for the prevention and/or treatment of PMO.

Again I told you that currently it takes two years of BMD data to get
prevention indication. You can do that with well under 500 women. We now
have fairly good fracture data from WHI which if the balances were a
little bit more favorable then it\'s possible that this Prempro would
have a treatment indication now because we do have good fracture data
now. There are some things to think about. How big a trial should people
undertake? What should the endpoints be? Should they require to show
fracture?

Finally it\'s just a very open-ended question for you to provide other
comments or recommendations related to the WHI trial or to regulation of
E + P products for the prevention and/or treatment of PMO. Thank you.

CHAIRMAN McCLUNG: Thank you, Dr. Colman. We\'ll have our discussion
about that during the discussion section but let me invite the Committee
members if there are specific questions to address to Dr. Colman to
clarify issues.

DR. FOLLMAN: Yes. I had one question. You said in the early 1990s you
switched from using or thinking you should use fractures as an endpoint
in your studies to using bone mineral density and the reason for this
was given on the basis I assume strong epidemiologic data. When you went
through that, was consideration given of the minimally effective bone
mineral density difference between the two groups? I\'m thinking perhaps
that you could end up with a statistically significant change between
placebo and a hormone replacement therapy that wouldn\'t really be large
enough to reduce the fracture risk. So I just wanted to know when you
made the change, was consideration given to that issue?

DR. COLMAN: Luckily, people were still studying doses that were what we
would perhaps consider too high now, but back then they were the
standard doses. We didn\'t see a situation where after two years of
study there was a half or a one percent difference between drug and
placebo, but it was powered to the point where you could still get
statistical significance. We did not put an absolute minimum on the
difference.

DR. SCHADE: Just for clarification, you mentioned this approach using
DESI, a term that I hadn\'t heard before. Is that something that\'s
still used by the Agency or is that just historic?

DR. COLMAN: That\'s historic. It was done around 1962 because up to that
point, drugs approved by the Agency, they only had to show some kind of
rudimentary safety. People thought we have to look and see how
efficacious they are.  So the Agency actually contracted with the
National Academy of Sciences to look at hundreds of drugs. They put
together groups by discipline to review the drugs and review whatever
literature out there that was on the efficacy of the drug. That\'s how
they came up with these classifications, probably effective/ineffective.
It\'s an old classification scheme back in the 1960s.

DR. LUKERT: If I could just take advantage of gray hair to amplify Dr.
Colman\'s comment about the response to the question about why estrogens
were considered approvable for osteoporosis prevention or treatment on
the basis of bone density whereas the drugs that were in newer classes
of the time of the guidance were not, the estrogens were not at all
suspected of having any effect on bone quality that would disrupt the
relationship between bone mass and bone strength. Whereas concerns had
arisen about, for example, fluoride. So the drugs that were
unphysiologic, if you want to put it that way, were held to a higher
standard when we developed those concepts, but estrogen wasn\'t
considered to be in the same situation at all. But again, no specific
magnitude could be identified.

CHAIRMAN McCLUNG: Other comments for Dr. Colman or questions? Thank you
very much. We now turn to the presentation by representatives from the
Women\'s Health Initiative and let me first thank Dr. Rossouw and the
team of people he\'s put together to allow this to happen. There\'s an
integrated set of presentations that will happen, some before and others
after the break. Let me propose to the Committee that we listen to the
entire set of presentations and then we\'ll have time for questions,
queries and discussion with the WHI individuals after that. Let me first
introduce Dr. Jacques Rossouw to lead off the discussion from the
Women\'s Health Initiative Investigators Group.

DR. ROSSOUW: Thank you. My job is to set the scene for my colleagues who
will give us some detail.  What I want to put before the panel is the
reasons why NIH did this study, why this particular drug was chosen for
the study, why this particular population was chosen for the study and
the snapshot of the baseline characteristics of that study population to
set the scene for my colleagues who will discuss the trial design, the
results and some interpretation of the data.

The trial that we\'re going to be discussing of the WHI is part of a
larger entity. There are also in that WHI trials of dietary modification
to look at whether there\'s reduction in certain cancers and
calcium/vitamin D aimed at fracture reduction and a very large
observational study. There are two trials of hormones as was here.
We\'re going to talk about the estrogen plus progestin trial alone. The
study is conducted in 40 clinical centers across the country and a
coordinating center.

Now the issue of why did NIH do this study is best addressed by looking
at the state of knowledge in the early 1990s when this trial was
designed. I\'m going to try and illustrate that with this rather complex
slide, but I just want to point out a few details here. The blue line
represents the prescriptions in millions of estrogens over time starting
in 1960 and the black line the prescriptions of progestins over time.

As we\'ve heard the use of estrogen to treat menopausal symptoms was
approved way back in 1942, but the uptake of estrogen in the general
population wasn\'t that big until the 1960s when there was a huge
increase. It\'s interesting that the increase occurred in the face of
rather negative news on the scientific front. By that time, we knew that
oral contraceptives were associated with cardiovascular problems and
conjugate equine estrogen in men in higher doses did not prevent, in
fact, increased clots and heart attacks. But overwhelming that
apparently was a popular conception to which Dr. Wilson\'s book,
[Feminine Forever]{.underline}, appeared to contribute that hormones
were generally good for womenkind.

So the cells rose dramatically and then dipped in the mid 1970s when it
became known that estrogen alone caused endometrial cancer by some
observational data. It increased again when it became known that
progestins could prevent that increased endometrial cancer. So in the
1980s we saw a rise now concomitantly with a rise in progestin
prescriptions. In the 1980s, we also learned from observation studies
that the benefits appeared to outweigh the risks. Estrogen use was
associated with lower CHD (\"coronary heart disease\") risk and with a
lower fracture risk. However it was also associated with a higher breast
cancer risk. Because CHD is the predominant cause of mortality and
morbidity in older women, the benefits were thought to exceed the risks.
At this point, NIH became interested in doing a trial to see whether the
cardiovascular benefits indeed were real.

Now in 1991, this is when specific planning for WHI trials started. In
1991 that was also the era when evidence by medicine started dominating
thinking in the scientific community and the era of large randomized
controlled clinical trial. From the early 1990s then, a series of trials
were launched. PEPI was the forerunner of WHI. The intermediate outcomes
looked and generally found favorable results. And HERS was also planned,
a second prevention trial. As we now know, that didn\'t have positive
trials for CHD and WHI was planned. So from the early 1990s on, we
started getting into a higher standard of evidence and WHI is part of
that higher standard of evidence. That\'s what we\'re going to be
talking about.

Now at the time when this study was being planned - I must also say
there was as you see an increasing use of estrogen in that period of
planning - the interest in looking at hormones for preventing heart
disease were based on a substantial body of data including small trials
of the biological effects looking at surrogate markers such as lipids
and bone density and that all looked very positive on average on some
animal model data and on a large, growing body of epidemiological
evidence such including some of the best studies ever done including
cohort studies. But what was deficient was a large clinical trial with
disease endpoints. That was our thinking in looking at whether this
should be studies.

Now part of that background, you don\'t have to look at the details
here. I just wanted to illustrate to you how large the evidence base is
for thinking that estrogen only will prevent coronary heart disease.
This is a review done by Barrett Connor and colleagues in 1998. Some of
the cohort studies which are the higher quality studies were known at
the time when WHI was being designed. All of these were known. If you
summarize the data, there was about a 40 to 50 percent apparent
reduction in risk associated with estrogen only use. That was the
primary source of evidence driving the need for the trial.

At the time that we were designing this trial, there was very little
known about the use of combined hormones, estrogen plus progestin, and
its association with CHD. Some studies emerged during the development of
the study. Except for that one, these are all in the 90s. That was a
small clinical trial. So there\'s very little known, but when the data
came out, the relative risk was very similar on average to that which
was found for estrogen only. That was our assumption going in that. If
there was an estrogen only effect, we would probably find the same or
maybe a slightly attenuated effect based on the lipid changes for
estrogen plus progestin.

However, we were aware as you are that women who used hormone may differ
in several characteristics from those that don\'t especially those that
use over an extended period of time. Hormone users are generally less
obese, less likely to smoke and to consume a high-fact or high-salt
diet, more physically active and more highly educated. That came out in
some of these observational studies. They are also more likely to go to
doctors more regularly and have health checks done and treated and some
of our treatments actually work so that may have help prevent CHD and
have mammograms and other screening. So there\'s a surveillance bias and
a healthy user bias. They are also more compliant if women who use
hormones for a long time, maybe more compliant in other ways and
therefore have healthy lifestyle and other attributes that are not
measured typically in observational studies. Of course the long-term
hormone users, we have to remember, are the successful users.  These are
the folks who haven\'t had an adverse effect. So they are going to look
pretty good compared to non-users on average.

The question was whether these differences could explain why hormone
users appear to have a lower CHD risk. Is the CHD risk reduction real or
is part of all of it due to these various biases?

Subsequent to WHI being launched, a substantial number of second
prevention trials were published. Here are six of them. We don\'t have
to look at the detail. I just wanted to point out that the clinical
outcomes of the secondary prevention trials. None of them showed any
benefit for CHD or stroke.  They either showed no benefit or no benefit
and early harm. The secondary prevention hormone therapy whether it\'s E
or E + P doesn\'t work and maybe harmful. That emerged while we were
conducting the primary prevention trial.

The actual idea that NIH needed to do a trial of hormone therapy and CHD
started in the mid 1980s and panels were brought together. Expert advice
was sought. The outcome of that was that the PEPI trial was done as a
forerunner. Generally hormone therapy was then regarded as a promising
but unproven treatment intervention to prevent CHD. Against this
background of increasing use by millions of healthy older women, it was
of concern that the overall benefits and risks were not known. Therefore
there was this need for rigorous clinical trial. PEPI was started. HERS
was started. HERS was not an NIH supported trial and WHI for prime
prevention.

It\'s often said and we heard it today that WHI studies the wrong
population. Well, it actually studied the right population for the
question it was asking which was \"Whether hormone therapy is a suitable
treatment in older women to prevent chronic diseases\". In the mid 1995s
to illustrate that point - and it was being used increasingly for those
diseases - NHLBI did a survey and found that 85 percent of doctors -
these were non-gynecologists - were prescribing hormone therapy. All
gynecologists were prescribing hormone therapy but two percent of
non-gynecologists were prescribing hormone therapy. Of those who
prescribed hormone therapy, 93 percent did for so menopausal symptoms,
91 percent for osteoporosis, 41 percent for high blood cholesterol and
66 percent for CHD prevention.

At that time you will recall both the National Cholesterol Education
Program, AHA, ACC, all of these bodies recommended hormone therapy as a
treatment for lipid disorders and for CHD prevention. That was the
climate in which we were operating. In fact, it was quite difficult to
recruit for WHI in the early 1990s because many physicians advised their
patients they should not enroll because all women should have this
therapy. So that was the climate. There was increasing use of hormone
therapy to prevent CHD.

Now why did we choose this particular drug? Conjugate equine estrogens,
Premarin, in the U.S. was and is the most commonly prescribed hormone
therapy and in women with a uterus, MPA is the most commonly prescribed
added progestin. Initially this was cyclic. Now it\'s predominantly in a
continuous form in Prempro.

An important point from our point of view was that most epidemiologic
data on CHD risk reduction in hormone users is based on the use of
Premarin 0.625 mg. The well-known Nurses Health Study for example 66
percent of the data in those analyses are based on Premarin. Most of it
is at the dose of 0.625 mg where they looked at the dose of 0.3 mg in
their most recent publications. Their findings for CHD were similar.
They weren\'t better or worse. They were similar. Now I\'ve stated the
data on combination therapy and CHD emerged later, but when they did,
they looked similar for CHD to that for estrogen only. We didn\'t have
specific data for Prempro.

Let me move on to the study population then. Why did we choose this
study population? They were post menopausal. They were a wide age range
of 50 to 79. We wanted to make it as inclusive as possible and as
representative as possible of the greater population of post menopausal
U.S. women. So we made an effort to enroll minority women. We had this
wide age range.

We had very liberal inclusion and exclusion criteria so we included
women. We had no exclusion criteria for women with a high body mass
index (\"BMI\"). Except for very extreme levels, we did not exclude
those with CVD risk factors or with previous CVD provided it wasn\'t
recent CVD. We did not exclude those with prior hormone use.

Let me turn then to some of the characteristics of the women that we did
enroll. The mean BMI was 28.5. However when you look at that and break
that into categories of normal weight, overweight and obese, you\'ll see
that just over 30 percent were not overweight or obese. The results as
we\'ll show in subsequent presentations apply to the non-obese and the
obese generally speaking. To make a statement that the average BMI was
28.5 misses the point. We tried to make this enrollment as wide as
possible to be as representative of the population as possible. Where
feasible we do subgroup analyses. So far we haven\'t found any subgroups
that have a moderately different experience than the overall.

Similarly for the age, this is the age distribution on the left here.
5.5 thousand (5,522) of 50 to 59. Even though the average was in the 60s
we have the largest trial ever of women in their 50s. We also of course
have very important information on older women. We didn\'t have that
many women with past or current hormone use. The majority had never used
hormones before, but we are able to do some analyses by prior use.

We include women with risk factors. Here are the percentages who were
smokers, diabetic, hypertension, hyperlipidemia, used statins or ASA.
6.2 percent had prior CVD. I would point out however that these numbers
are all quite a bit lower than what you\'ll find in NHANES surveys. This
population on average was indeed healthier than the average post
menopausal population.

That\'s borne out by the fact that our CHD rates were about half of what
we had predicted when we started the study. I would also point out that
almost 2,000 of the women did have moderate to severe menopausal
symptoms at baseline and that or the body mass index or the age or the
years since menopause, any subgroup that you want to look whether they
had risk factors or not, we have not been able to identify any subgroup
that has a markedly or significantly different experience than the group
overall.

Having set the scene, I would now like to ask my colleague Dr. Marsha
Stefanick, the Chair of our Steering Committee, to show you the most
important results and updates of the study. Mr. Chair, is that okay?

DR. STEFANICK: Thank you very much. It\'s a pleasure to be here. I\'ll
try and be brief in this presentation. First of all, I would like to
state that the specific aims as you know were to test whether estrogen
plus progestin or estrogen alone reduced the risk of CHD defined as
non-fatal MI and CHD death or other CVD like stroke, increases the risk
of breast cancer and reduces the risk of hip and other fractures. But
also of equal importance to us was to determine the overall balance of
health risks and benefits of E + P and E alone.

Women were randomly assigned based on their hysterectomy status. If they
had a hysterectomy, they were assigned to either CEE at the dose 0.625
mg, essentially Premarin, or to placebo. If they still had their uterus,
they were assigned to combination therapy, the same estrogen combined
with medroxyprogesterone acetate or placebo. Initially there were a
small group of women who were assigned to a three-way randomization.
Prior to the PEPI results when the PEPI results came out, the estrogen
only arm was discontinued and women were converted to the combination
therapy.

The outcomes monitored by the Data Safety Monitoring Board (\"DSMB\")
were three cardiovascular endpoints, CHD, strokes, pulmonary emboli;
three cancer endpoints, invasive breast cancer, colorectal cancer and
endometrial cancer; hip fractures and deaths from other causes. In
addition, the global index that you\'ve heard about was defined as the
earliest occurrence of each of those events to provide the overall
balance of risks and benefits.

As you may realize, the DSMB actually requested that the investigators
inform the women after most of them had completed two years of the trial
that there was an unexpected finding relative to our hypothesis that
there was actually an increase in the number of heart attacks, strokes
and blood clots in the lungs and the legs in the women receiving active
hormones compared to women taking placebo. So all the participants in
the hormone trial were alerted to this information.

A year later, the DSMB required that we inform the women that now that
we had completed an average of four years of the trial these excess
cardiovascular events persisted in the active hormone group compared to
the placebo. All of these data were based on the combined E only and E +
P trial data. The investigators were never informed, nor were the women,
what was going on with the E only trial. As you all know last year, May
2002, the NHLBI accepted the DSMB recommendation to stop the E + P trial
after an average of 5.2 years because the risks exceeded the benefits
based on the monitoring rules which Dr. Anderson will elaborate on when
she presents her presentation.

In particular, I do want to point out that we are following these women
so they are still being monitored through the trial. They are just not
taking their hormones at this time so that we can get information about
the long term risks and benefits. Also the DSMB recommended that the E
along trial continue because the risks and benefits were not yet certain
and the balance was not clear. We were able to inform the women at that
time that there was no increased risk of breast cancer by the 5.2 year
period and we do continue to monitor these women closely. They are
continuing to take their study pills.

To just focus on the E + P trial results then, in the publication from
last July, we published both the nominal confidence intervals for the
hazard ratios for each of the primary events and very conservative
adjustments based on the sequential monitoring and the multiple
outcomes. To just point out as you see, there was a set of clear harmful
events, CHD, stroke, breast cancer and pulmonary emboli and there were a
series of benefits, colorectal cancer, hip fractures. Also shown here
are total fractures. Death was neutral.

These were all presented in the paper last year to actually focus on the
global index which was this overall balance. The main point I\'d like to
make by showing only one of our many Kaplan-Meier curves is that when we
look at the accumulated incidence as we add these up, at no point were
the E + P women better off than the placebo. The placebo were always
having a lower overall risk ratio relative to the benefit. The main
point is that the risk clearly exceeded the benefits in the active
group.

Also presented in the paper were the annualized event rates for the
primary outcomes. What you see is that the excess risk attributed to E +
P for every 10,000 women were seven more for CHD, eight more for stroke,
eight more for breast cancer and eight more for pulmonary emboli. And
the attributable benefits were six lower colorectal cancer, five fewer
hip fractures, neutral for endometrial cancer and neutral for death.

These were the events that we published last year. This basically came
out to an overall summary of 19 health problems for 10,000 women
assigned to E + P versus placebo which essentially means that over five
years there was a net per 100 women in the active treatment group who
had a harmful outcome. Our conclusion was that treatment with E + P for
up to five years is not beneficial to overall health.

Since that time, we\'ve been publishing the more extensive data. We
actually had four months more of outcomes but they had not been
adjudicated and not built into the analyses when we published the data
last year. Two of them I\'ll elaborate a bit on, the coronary heart
disease risk and stroke. You\'ll hear from Rowan Chlebowski the breast
cancer data and Jane Cauley the fracture data when I complete my
presentation.

What I\'d like to do is start out first of all with the basic principle
of these updated papers. We now have a mean of 5.6 years of follow-up.
That\'s the actual length of the overall follow-up time which means that
we have more cases for all of the events that were published last year.
In addition, all of the major events have been centrally adjudicated. In
the case of the CHD update by cardiologists, in the case of stroke by
neurologists and so forth. In addition, we have additional endpoints
relevant to the outcome in question and we have analyses on subgroups
trying to get information about many of the questions that have come our
way in terms of \"Are there groups that are better off and are there
groups that are worse off\".

With respect to the CHD, the main point that I\'d like to make from that
paper, the main issue I\'d like to summarize, is that when we looked at
all the data, first of all, I\'ll point out that the hazard ratio from
the updated centrally adjudicated data is 1.24 so 24 percent increase in
CHD. But the most important point that I\'d like make is this was
particularly elevated in the first year. The hazard ratio of 1.81
appeared in the first year.

What you see is that each year of follow-up where the first event is no
longer included in each of the next years we still have an excess risk
in Year 2, Year 3, Year 4, Year 5 in the E + P group. Not until Year 6
when the placebo group had essentially caught up at this point -
They\'ve been surviving all of this time. They now have their heart
attacks - that\'s really the explanation for this reverse of the hazard
ratio in the years after year five. At least that\'s my judgment of it.

Now I would like to point out that there had been many studies showing
benefits to lipids from E + P and E only starting before the PEPI study
but the PEPI study certainly emphasized that. We did see those in the
subsample of women for whom lipids were measured. We did see a decrease
in total cholesterol and LDL cholesterol of 12.7 percent, very similar
to data published previously. There was also an increase in HDL
cholesterol of 7.0 percent which was actually a little bit better than
the PEPI study. We also saw decreases in glucose, not significant, but
also insulin.  So the lipid benefits that we\'ve talked about were also
seen in WHI, but I think we all recognize that this is a risk factor for
a disease. The disease was not benefitted. So in this case, we have to
recognize that looking at lipid changes is not the appropriate approach
with respect to CVD and hormones.

Also just to quickly mention in all of the analyses that are coming out,
we are looking at lots of subgroup analyses. In the case of CHD, age,
years since menopause, hot flashes, with and without night sweats,
obesity status, race, ethnicity, education level, all of these have been
examined and none of them have shown any effect in terms of the
interaction. So there is no evidence that these things make a difference
with respect to the overall risk associated with E + P.

Similarly we have a large list of biomarkers and other risk factors. I
will point out that one risk factor did show up as significant. LDL
cholesterol, the higher the level the more likely you were to have a
coronary heart attack. But I also want to point out that there were so
many subgroup analyses done that we can\'t say this wasn\'t due to
chance. By the time you\'ve done 20, you have one out of 20 that could
be by chance. But at any rate, we\'ve gone to quite a bit of effort to
look for subgroups that may be better off or safe. At this point,
everything pretty much comes out to the same answer that the risks
exceed the benefits.

I also want to point out that with respect to CHD whether women had an
event in the past or whether we talked about a more comprehensive
cardiovascular package or the CHD alone, we still have a net risk
associated with that. So also history of heart disease did not make a
difference in the risk associated with E + P.

In the stroke paper, we basically elaborated on the fact that ischemic
stroke in particular was the stroke that was increased. So where we
would look at total stroke, we have a relative risk of 1.31. Ischemic
strokes, it\'s 1.44. Hemorrhagic stroke is not significant. There
weren\'t as many hemorrhagic strokes. As you see, the vast majority of
strokes were in fact ischemic strokes.

In summary from the stroke data, we now basically continue to say that
we have excess risk. Seven per 10,000 women per year are having strokes
attributable to E + P in our data. The excess risk is not explained by
blood pressure increase which I failed to point out that we did see. It
was apparent in hypertensive and normotensives and it was apparent in
all the subgroups that were examined. Also we looked at quite a few
biomarkers and there was no significant interaction on the biomarkers.

Also quickly, we now published the gynecological cancers.  Dr. Anderson
is here today. You\'ll be hearing from her. Other papers have been
submitted and are forthcoming but we do not yet have the data published.
With respect to the gynecological cancers, invasive ovarian cancer, 32
cases; hazard ratio of 1.58; confidence interval, not significant.
Endometrial cancer, 58 cases; hazard ratio. 0.81; confidence interval,
not significant. There were relatively few cases of these cancers with a
suggestion of increased risk for ovarian cancer and a suggestion of
decreased risk for endometrial. No appreciable differences in the
distributions for tumor histology, stage or grade for either of those
cancers. In the case of cervical cancer, there were 13 cases out of the
16,000 plus women and the data and the trial are really too limited to
say very much more about that.

I do want to point out that we did have relatively high discontinuation
rate for pill taking. That\'s been discussed in many settings. You see
that over the course of time an increasing number of women were coming
off the pills in both the placebo group shown in yellow and the active
group shown in orange. But also there were an increasing percent of
women going on estrogen and progestin. So that what you see below is the
women who are coming off the pills here as a substantial portion of them
were going on exactly the same medication but open label with their own
physician and twice as many women in the placebo group were falling into
that category. When we actually look at all of the data I\'ve talked
about so far and look at the data by intention to treat, we have a 24
percent increase in CHD, 31 percent increase in stroke, 24 increase in
breast cancer in the updated analyses. But when we add on to that the
compliance data looking only at women who were taking at least 80
percent of their pills and censoring the event history for six months
after they stopped taking pills, what you see is that in fact 50 percent
higher CHD, 50 percent higher stroke and 49 percent higher breast
cancer. When we actually look at the highly compliant women, the risk
attributed to these hormones is even greater.

I\'m not going to say anything about the quality of life data. I do want
to say a few things about the WHI Memory Study (\"WHIMS\"). It\'s been
pointed out and I\'ll point out again that this was an ancillary study
restricted to women who were 65 and over at baseline and included about
one-fourth of the overall study population, 4,532, with more than 90
percent of the women who were eligible to be in that trial actually
participating. So it was a fairly good representative study group.
Essentially the data that we have from that study shows that probable
dementia happened twice as often. It was diagnosed twice as often in the
E + P group relative to placebo. We actually looked at the rates per
10,000. It was 45 per 10,000 in E + P and 22 per 10,000 for the placebo
which is essentially 23 excess cases per 10,000 women per year. Dementia
twice as high. Mild cognitive impairment (\"MCI\") was actually not
different between the two groups.

So come back to our new summary, we\'re slowly improving these risk
estimates. We now can lay out that we have eight more women with breast
cancer per 10,000 per year, six more with CHD, seven more with stroke.
We have not yet published the updated data for pulmonary emboli or for
colorectal cancer in which there were six fewer, but we have published
the updated data now for hip fractures which is five fewer. So we are
still in the area of over a five year period one in 100 women are having
unhealthy events related to these hormones.

We essentially stand by the same implications that we published last
July. The overall risks of estrogen and progestin outweigh the benefits
when taken to prevent chronic disease in post menopausal women. Estrogen
and progestin should not be initiated or continued for primary
prevention of coronary heart disease and the risk for CHD, stroke,
pulmonary emboli and breast cancer must be weighed against the benefit
for fracture in selecting from available agents to prevent osteoporosis.
With that, I\'m going to turn over to my colleague, Rowan Chlebowski who
will present the breast cancer data.

CHAIRMAN McCLUNG: Actually, let me take the prerogative of suggesting
that we actually have our break at this point because we\'re come back
after the break and talk about specifics about breast cancer and about
bone disease. Plus we\'re halfway through the morning. Let me propose
that we have our 15 minute break, reconvene at 10:25 a.m. to continue
this discussion. Thanks. Off the record.

(Whereupon, the foregoing matter went off the record at 10:12 a.m. and
went back on the record at 10:31 a.m.)

CHAIRMAN McCLUNG: On the record. Let me invite Dr. Chlebowski to the
podium to continue the presentation of data from the Women\'s Health
Initiative and to specifically address the more detailed analysis of
issues related to the breast cancer risks.

DR. CHLEBOWSKI: Thank you very much. I also am delighted to be here and
to give you a little bit more detail on breast cancer in the WHI.
Menopausal hormone therapy in breast cancer as we\'ve heard about CHD
also has an extensive background. There were numerous observational
studies suggesting that longer duration usually meaning by definition, -
short duration used to be five years or less of use - would result in
increased breast cancers. There were suggestions that these cancers
would found at low stage and have favorable prognosis, the receptor
positive predominance and more lobular in histology. In essence, the
thrust was that E + P or hormones would offer an earlier diagnosis of
cancers which would otherwise anyway come forward.

When we talk about the WHI, you heard much about the characteristics of
the population. I just list here a number of the things that we captured
in terms of known and presumptive breast cancer risk factors. We won\'t
go over all these data except to say that none of these characteristics
differed significantly between treatment groups. So we have much breast
cancer risk information.

One point that\'s already been made by Dr. Rossouw that I want to point
back up again in this setting because one of the issues we\'ll be
attempting to get at is the duration issue in breast cancer is how about
prior hormone usage. As you\'ve heard before three-fourths of the women
had never prior hormone exposure. About six percent were current users.
Those users had to wash out or stop therapy for three months before
beginning their baseline evaluation.

One of the things that\'s different again from the WHI Randomized
Perspective Trial were the issues about case ascertainment and breast
safety. So baseline mammograms and clinical breast exams were required
for eligibility. Everyone was screened before entry. Annual mammograms
and clinical breast exams were required when on study and importantly
the dispensing procedures would not allow dispensing of the medications
if safety procedures were not done. So if a woman didn\'t have a report
of a mammogram within a window, at a time for dispensing she could not
be dispensed further medication until she did get those studies.

Here\'s the summary of the major results which is again updated from the
original publication. This data was published in [JAMA]{.underline} of
June of this year showing that on E + P there was a total of 245 versus
185 cases. Dr. Anderson who will follow me will go into more detail
about the statistical analyses involved. Here we have invasive breast
cancer 199 versus 150 with a hazard ratio of 1.24 and just a trend of
insight to cancers. Those were the numbers of invasive cancers that we
saw on E + P during a course of follow-up that ended after 5.6 years.

Here\'s what the Kaplan-Meier curves look like. We\'ll come back to some
of these duration issues. Again unweighted hazard ratio 1.24. You can
see actually that the curves cross at about four years and then more E +
P data. We\'ll look in more detail at the hazard ratios in the first two
to three years where there was an apparent lower incidence of breast
cancer seen on the placebo compared to the E + P arm.

Similarly to what Dr. Stefanick showed as well, we did a sensitivity
analysis to perhaps allow a better comparison to some of the existing
observational study data. Again what we did was participants were
sensored six months after becoming nonadherent. That is not taking 80
percent of their study medications or taking non-protocol hormones. What
you can see here is that our hazard ratio is now 1.49 with a earlier
departure deviation of the two curves.

We looked at many subgroups, none of which really showed a different
relationship of E + P to development of breast cancer. I\'ll just show a
couple of these. This is a breakdown by age. You can see that actually
this is a test for interaction. There is no interaction, 1.2 in the 50
to 59 year olds, 1.22 in 60 above. So basically it wasn\'t as if only
the older individuals were at breast cancer risk.

Because there\'ll be more detail gone over in the BMI portion for
fracture, we include this to look at the breakdown of hazard ratio for
development of breast cancer by BMI. The trend was actually
nonsignificant, but there was an appearance that maybe in the older
individuals there was somewhat less of an effect on E + P to increasing
breast cancer risk. Again that interaction was not statistically
significant.

Dr. Anderson will go in much more detail over issues of prior menopausal
hormone therapy exposure. I\'ll just show you this one illustration of
the overall breakdown of no prior hormone therapy versus ever prior
hormone therapy. You can see the P-value is 0.10 so the interaction
wasn\'t significant. More breast cancers on E + P in both groups, a
nonsignificant trend. Ever users were at somewhat lower risk. We have a
question which we\'ll go into more detail with at a later presentations
about cumulative exposure versus selection bias.

We\'ll point out a couple of those issues here. Here\'s the women with
no prior menopausal hormone therapy E + P/placebo. Their hazard ratios
in the first year were 0.48, 0.65. So like a 50 percent apparent
reduction in the first two years for E + P compared to placebo. You
don\'t see that in the women with prior menopausal hormone therapy. Now
the other additional issue is this will provide one possible explanation
for this because this prompted our look at the mammogram data
subsequently.

If we look at the breast cancer characteristics by group, remember there
was a suggestion from especially more recent observational studies
involving E + P that lobular cancers would be largely responsible for
most of the increase. Actually we saw nothing like that. We saw really
that all types of cancers were the same in both groups. Again the
suggestion on the predominance of the observational studies that E + P
would be associated with well differentiated cancers wasn\'t seen. We
saw the same distribution, similar histology and grade on E + P compared
to that on placebo.

How about the receptor status? What we see here is that both receptor
positive and negative breast cancers were greater on E + P. This number
tests the interaction between E + P for receptor status. You can see
more receptor positive cancers, more receptor negative cancers, more
progestin receptor positive cancers, more progestin receptor negative
cancers. The P-value suggests that there was a significant imbalance
with respect to the number of individuals having receptor status
determined. This wasn\'t based on size difference. We don\'t have an
explanation for that imbalance. It appears that both receptor positive
and negative breast cancers were greater on E + P.

Now this is an important data demonstration because very surprising
compared again to the observational study data, we saw that actually
instead of being more favorable stage, the tumors on E + P compared to
placebo were larger. This difference was statistically significant. It
was more likely to have node positive and more likely to be at regional
stage. More advanced stage was seen on E + P. I think the other thing I
can point out that this is what you get when you have a population that
has 90 percent of that population has yearly mammograms. You get an
average size on the placebo of only 1.5 cm. So the cancers were larger,
more likely to be node positive on the E + P arm.

This finding of similar grade, histology, and receptor status but more
advanced stage where ascertainment was felt to be equivalent and that
suggestion that there were apparently fewer cancers seen in the first
couple of years on hormone prompted us to look at the mammograms.
Basically it\'s our mammogram findings after one year on E + P.

As you can see, 90 percent were normal, but the abnormals were 9.4
percent versus 5.4 percent on placebo. This is a relative increase of 74
percent in abnormal mammogram frequency after one year. Most of those
abnormals were in the short interval follow-up category, Category 3, but
you can see that suspicious abnormalities usually leading to biopsy were
also higher.

This finding persisted. This is the data you saw before. This is the
mammograms abnormal, 9.4 versus 5.4 compared to the baseline of about
five percent in both groups. The cumulative after six plus years of
follow-up were 30 versus 21 percent.  This is the frequency of
mammograms by arm. You can see that after the first year 90 percent of
the women had their assigned mammograms and the cumulative goes up to 97
percent. The people that would drop off that wouldn\'t be required to
have mammograms before dispensation. That wasn\'t an issue. What we have
there in summary was that abnormal mammograms were associated with even
one year of E + P use, a four percent absolute increase in abnormal
mammograms after one year on E + P, a ten percent absolute increase in
abnormal mammograms after about five years of E + P.

Now to inform some of these results especially our finding of more
advanced stage, we can get some information from the recent results from
the United Kingdom Million Women Study. This is based on a National
Health Service Breast Cancer Screening Program trial in the United
Kingdom. What their study involved was the National Health Service there
invites all women in the United Kingdom 50 to 69 years of age of have a
screening mammography every three years by letters. A questionnaire
regarding hormone therapy use was added to the screening invitation
letter. The women showed up for their screening and then the data on
their hormone therapy use was linked to National Health Service Central
Registries for Breast Cancer and Death Outcomes. 1,084,110 million were
identified and 9,364 invasive breast cancers were seen. I should
emphasize this was a perspective cohort study. It was not randomized. It
was very large.

What did they see? Now they included if women had an abnormal mammogram
at baseline and were taking hormones one year before. They would be
considered to be on hormones for one year and that work-up would count.
So they didn\'t screen and eliminate cases. They included everyone. But
when they did this, the relative risk of developing a fatal breast
cancer by hormone therapy use at baseline had a relative risk of 1.22
which was statistically significant. They found that hormone therapy was
associated with increased breast cancers and mortality in short-term
users. By short-term users, it means they were based on deaths after
follow-up of 4.1 years.

How about the duration effect? Again it\'s really quite different than
the WHI in that there\'s a number of differences. They included the
work-ups down on baseline. Because they had mammograms done every three
years and they reported the incidence data after 2.8 years, the majority
of these cases would not be screening detected cancers, but would rather
be clinically detected cancers without mammographic screening. By this,
they get rid some of the ascertainment issues. What they saw was after
one year a relative hazard ratio of 1.45 going up over time. This is the
data for their E + P which was associated with increased breast cancer
risk in less than one year.

How about the hormone types? Without showing all their data, they saw an
increase also with E only for all types of estrogen but the risk was
substantially higher for their E + P combinations. About one-third of
the women had conjugated equine estrogens, Premarin, and they had a
relative risk of 1.29, conventionally significant. But other estradiol
was also significant and besides medroxyprogesterone acetate, other
progestins also were associated with increased breast cancer risk.

So our conclusion based on these combined findings is that combined E +
P use increases breast cancers, diagnosed in more advanced stage and
increases more abnormal mammograms. These results suggest that use of
E + P may simulate breast cancer growth and hinder breast cancer
diagnosis. Thank you. The next speaker will be Dr. Garnet Anderson who
will be going over more details of the prior E + P users.

DR. ANDERSON: Good morning. It\'s a pleasure to be here. On behalf of
colleagues, I wanted to cover the statistical methods issues, and I\'ll
try to do that in short order because I know that\'s not what most of
you get up early in the morning to hear. Then I will cover some of the
further analyses of prior hormone therapy and breast cancer risk. These
are questions that have been specifically put to us by members of the
FDA.

On the statistical methods, I wanted to point out to you that the design
and the primary analyses of all of our clinical endpoint data is based
on a weighted log rank statistic which I\'ve shown here. It can be
written in the usual observed minus expected notation. This is trying to
look at the difference in survival curves or incidence curves over time.
The only thing that\'s unique about this is the weights which is
signified here. So I wanted to describe what that means.

These weights are specified for each disease endpoint. The motivation is
not to weight different diseases because that\'s a very difficult place
to go. Rather these weights are defined by time since randomization. The
motivation is actually to increase the efficiency of the study group at
power. It was based on the idea which is common in prevention trials
that the intervention effects will not be fully manifested right away.
It will take some time for the differences in clinical endpoints to
appear.

Let me show you the actual weight we used. So any differences you see in
the early period are more likely to be due to a random occurrence than
to be a true treatment effect. We actually had very good observational
data to say that the effect of hormones on breast cancer may take a
considerable amount of time to be fully manifested.

So the weights for breast cancer were defined to be linear over a ten
year period. The differences observed in the first year or so would have
very little weight but increasing over time. Differences at year 10 and
beyond would have full weight. That was the weighting scheme for cancer
and also for mortality or global index calculations.

For CVD and fractures, the data were not so clear. In fact, the
observational data tended to suggest that it was current use of hormones
that was protective for CHD. Nevertheless a lot of the hypothesis came
through the intermediate effects of lipids which though that might be
rather immediate but its translation into a clinical impact could take
some time. After quite a bit discussion, we used a three- year weighting
period. By the time, we got to the three years any events occurring
after that would receive full weight.

That plays into both the analysis and it also played into the monitoring
plan. Dr. Rossouw gave us a nice summary trying to understand where we
were when we designed this trial. It was a prevention trial. In
developing our monitoring plan which the development has been published
back in 1996, we were thinking of the issue of benefits and risks with
CHD being a benefit that was at that time considered so obvious that the
question was \"Could we really ethically continue this trial when the
benefits might accrue by year three in the study when we knew the breast
cancer results might take a fair amount of time to see\".

The monitoring plan that we used then and continue to use now for the E
only trial was based on that general idea. We would stop for evidence of
CHD benefit using a standard procedure that looks like the upper tail of
0.05 level test with .025-level, one-sided test corrective for multiple
looks over time, the traditional O\'Brien-Fleming procedure boundary.
This is exactly the same in many trials used for a single endpoint
trial.

The only catch to this is that we did develop the global index
specifically for this monitoring purpose. That was to provide some
measure of the risks and benefits balance at that time. Though we
didn\'t require this to be as significant or as clear - we only looked
at the .05-level, one-sided test for this - it was to be clearly
weighing on the side of overall benefit to stop this trial. That was the
only way that we would stop for benefit.

Stopping for harm, there were actually two alternatives. Breast cancer
was our primary safety endpoint. There were prior data suggesting that
this might be a problem so we defined a monitoring boundary for it alone
not adjusted for multiple endpoints. Because we were interested in
proving harm to the same degree of precision as you might want for
benefit, the stopping level was a .05-level, one-sided test equivalent
to the .10 percent type one error again adjusted with O\'Brien-Fleming
procedure for multiple looks over time.

If that boundary were crossed and a global index which was supportive of
harm, that\'s a Z-statistic less than minus one. So one standard
deviation below the no-hypothesis, we would stop for harm based on
breast cancer. We also defined similar stopping boundaries for all the
other designated monitored endpoints of CHD, stroke, PE, hip fracture,
colorectal cancer, endometrial cancer and death from other causes. Death
from other causes was just to pick up anything unforeseen that was
serious in terms of the health of women. These use the same .05 level
tests but it was corrected with a conservative Bonferroni correction
because we were looking at all those multiple endpoints and didn\'t want
to inflate our type one error by looking at too many endpoints at once.
Those are our monitoring boundaries. It was the breast cancer boundary
and the global index boundary for harm that were crossed last spring.

A couple of other notes. All the analyses we present are based on
intention to treatment. That means that every women randomized is
analyzed and included the analysis in the arm in which she was
randomized regardless of whether she stayed with that arm. Even our
sensitivity analysis looking at adherents do not cross the women over.
 They just sensor her data at the time she becomes non-adherent. This is
the best in terms of preserving the ideal quality of a randomized trial.

We do provide unweighted hazard ratios which is a bit of awkwardness
given that the trials were based on the weighted design, the weights
over time. I would say that this was a compromise that we made based on
the fact that we were completely wrong about our CHD findings. The
assumptions underlying that design were wrong. We didn\'t reach the full
preventive effect by year 3.

Then what do you do with the weights? Mostly when you don\'t have an
idea of a time to effect you would do an unweighted type of statistic.
We do provide unweighted hazard ratios and then associated with those,
nominal and adjusted confidence intervals. The nominal 95 percent
confidence intervals for those hazard ratios probably need no further
comment. The adjusted however taken into account the fact that we did
look at the data every six months for monitoring purposes and we did
look at multiple endpoints. We think it\'s only fair to bring that note
of caution into the interpretation of these data.

Particularly for breast cancer, we also in some places showed the
weighted P-values, P-values from the weighted analyses, because there is
a discrepancy in the interpretation at points when you take the weights
into account and when you don\'t. To be fair, the design and the
analysis for these endpoints did always indicate that we would use
weighted analyses.

A lot of what we\'re doing today and have been doing in the papers since
last year has been looking subgroup analyses. These are much more
difficult to interpret statistically. In the process of working through
these papers, we\'ve developed our own WHI sort of policy for how we\'ll
interpret them. It is that our inference will be based primarily on the
test of interaction.

The trial was not designed to test this specific hypothesis within each
subgroup so we acknowledge that those specific subgroup tests within
themselves are low powered. That means we have a high type two error. We
also have a high type one error. We\'ve looked at many subgroup
analyses. It\'s possible to find some that are significant by chance
alone.

To minimize this as best we can, our inference is primarily based on
those tests of interaction. Then we report unadjusted P-values and we
say that these should be considered as hypothesis generating, not
testing. Then we have asked each author of each paper to report the
number of interactions they tested and to report the number that would
be expected to be significant by chance alone. We feel that it is a
reasonable approach to this area which is really very exploratory.

On that note, let me go to the specific subgroup analyses that I\'ve
been asked to address which is prior hormone use and breast cancer risk.
I feel a little embarrassed to tell you that I\'m presenting this to you
without having the WHI investigators as a whole to be able to see this
in advance nor our DSMB which will be reviewing some of these data for
the first time in a few weeks. But that said, this is an important
meeting for all of us so I will take you through these realizing that
they have not been digested by the WHI research community as they
normally would.

I\'ve been asked to look at more detailed analyses of prior hormone
exposure including type, duration and recency of use, the extent of the
disease by prior hormone use and a bit of mammography performance. This
is an amplification of what Dr. Chlebowski already showed. I\'m sorry
that some of these numbers don\'t show up very well.

Looking by prior hormone use and invasive breast cancer, the hazard
ratio is 1.09. You\'ve seen that before. In invasive cancer, the hazard
ratio is 1.86. The unweighted P-value is .04. The weighted P-value is
.10 suggesting some modest evidence of an interaction with prior hormone
use where women who have been exposed in the past if you looked at that
by itself these Z-values of -2.7 or -3.0 are clearly statistically
significant. Where you don\'t see that, it\'s just a slight trend of an
increase in the women who have not been exposed previously.

But what is rather curious about this finding and I can\'t explain it
exactly is that the rate of invasive breast cancer in women who have
been exposed previously but who then were randomized to placebo is quite
low. It\'s 0.25 here. That\'s the annualized incidence rate. Placebo who
are not previously exposed is higher. It\'s 0.36.  That\'s a little bit
curious and suggests to me some sort of selection bias probably in the
sense that these women are different, the prior hormone users versus the
no-prior exposed group.

These are the Kaplan-Meier curves in those two groups. We should
especially try to remember this one because it becomes the reference
group for many other analyses. You can see that the period in which the
E + P group has a lower incidence rate is at least for four and a half
years, but the curves do cross. The E + P group has a slightly higher
rate in the later years. Therefore the pattern is overall the same but
you see a longer duration of lower rates. Whereas in the prior exposed,
the separation of the curves does begin much earlier by about Year 2.

Now I want to break it down by type of prior exposure. Here I\'ve
categorized slightly differently than it was in the [JAMA]{.underline}
paper. Here prior E only exposure is only exposed to estrogen alone.
These women never took progestin before. Any prior E + P, some of these
women did have some episodes of E alone exposure. I wanted to keep the E
alone group pure. This group is the women who had some progestin
exposure. You can the hazard ratio. That\'s the same as before. In the
prior E alone exposure, the hazard ration is 1.47. E + P is 2.19.
Unweighted P-value for the interaction is 0.08. The weighted is 0.17. So
again there\'s some kind of suggestive trends but not very strong. The
suggested prior exposure particularly prior E + P seems to be associated
with higher risk.

Again we note that the women with prior exposure to E + P who were
randomized to placebo have a quite low rate, 0.19 percent per year
versus the other two groups with about 0.36 percent per year. So women
with prior exposure to E + P are clearly different.

Here are those curves. Prior E alone exposure, you can see that the
crossover is about three years perhaps and then the separation doesn\'t
seem to really show up until Year 5. Whereas, prior E + P exposure the
curves differ around Year 3.

This slide shows duration of use. Here we don\'t see any strong trends.
It looks like the no prior use as before but the prior year 2, 2 to 4 or
4 plus years was all in the same general area. Unweighted P and weighted
P are basically in the same region as we\'ve been seeing on those other
slides, suggesting that maybe it is just yes-or-no prior exposure. This
is one of the questions that was put to me. Is that really the case?

Here are those curves. I personally don\'t get a lot out of them. They
all show similar pattern. There\'s maybe a slight difference in where
the curves start to diverge.

Then the final one on this is recency of use. Here is at initial screen.
So women who were using hormones at the time we first encountered them
actually had to go through a three-month washout period before they
could be randomized. These are women who were using hormones before the
washout period and then within the last five years but not at the
baseline visit five to ten years ago or ten plus years ago. You can see
all of these are generally in the same region. The P-values suggest that
there\'s no interaction between those.

There are the curves. Hormone used at enrollment within the last five
years, five to ten years ago, and more than ten years ago. Maybe the
separation is coming a little bit later for older use.

One final question is the combination of prior use and BMI and I think
this motivated more by the issue of osteoporosis. Here we have
classified it by prior use and obese or not obese. You can see that
prior use in the leaner women - I\'m not sure that\'s exactly the way we
should describe it - the hazard ratio is 1.18. No prior use and the
obese women we saw no elevation there in that hazard ratio. But the
prior users both of those tend to have an elevation. The P-values again
are not very strong suggesting it\'s modest evidence for any interaction
there. There are those four curves.

In thinking about this though I was realizing that as soon as we start
to make inference about prior hormone use, we\'ve left the framework of
a randomized trial. We\'re now starting to talk about an observational
study. So we looked at the characteristics of the prior hormone users in
this trial. We noticed a lot of the same things that you all know from
observational work. Women who had used hormones before were younger,
leaner, had a lot of characteristics that make them different. Vasomotor
symptoms, parental history of fracture and had a mammogram in the last
two years, a variety of things. To what extent could those issues be
confounding our results?

The other thing is in terms of looking at the different hormone
preparations the use of E alone or combined hormones the pattern of use
is different in particular. In about 26 percent of our population, you
can see that they had used hormones previously. A little bit more had
been combined use. Here actually you can see overlap. The numbers don\'t
add up because the woman could be in either this category or that one or
both. But women who had used E alone were more likely to have a shorter
term exposure to estrogen than women who had used combined hormones.

A stronger contrast is in recency of use. E alone users 58 percent their
exposure to E only was more than 10 years ago. Whereas combined hormone
users were much more likely to be the current users. Whenever we are
looking at recency of use and we don\'t tease a power at those two, we
may be confounding that issue.

I started doing multivariate models all of these things. Controlling for
multiple confounders, this is the E + P hazard ratio. I threw in just
about everything on that first slide, listing the differences and
characteristics plus additional breast cancer risk factors. So in that
multiple variate model, the unweighted hazard ratio is 1.2. That\'s
compared to the primary result of 1.24.

Separating it out by exposure to prior hormones, you see in women with
no prior exposure the hazard ratio is now 1.02. Women with prior
exposure of any type is almost 2.0. The unweighted P-value is 0.3. The
weighted P-value is highly statistically significant. Now we\'re getting
some stronger evidence in an observational sense that there is an
interaction here.

This is separating it out in the same type multi-variate model where the
main effects now separate out the type of prior exposure. Women who are
only exposed in the past to E alone their hazard ratio for E + P is
1.36. Now don\'t confuse this as the E alone hazard ratio. That\'s not
what this is. This is the E + P hazard ratio in women who have been
exposed to E alone. I know I got confused when I put it against the
Million Women Study because their E alone hazard ratio is 1.3 or so.
That\'s not what this is. And prior exposure to combined hormones is
2.46. The P-values here are not so clear. Unweighted P is 0.05. The
weighted P is 0.64.

This is duration of use. Here you can see that it now looks a little bit
more like an orderly trend as opposed to our unadjusted analyses. Less
than five years of exposure is about 1.8. Five to ten is 2.14. Ten plus
years of exposure is 2.53. Unweighted P is 0.08. The weighted is highly
statistically significant. I would say that these tests are based on a
continuous variable not in these categories so it doesn\'t rely on us
choosing the right category perfectly.

This is recency of use. You can see that at initial screen and last five
years or five to ten years were all thereabout in the twofold increase
range. Last hormones used ten years ago it starts to fall off. Now
remember, this is any prior hormone exposure. I haven\'t teased apart
the E + P and E alone. So this is mostly reflecting an E alone prior
exposure. In fact, I couldn\'t fit them all where I teased both things
apart like this.

This is looking at the combination of prior hormone exposure and BMI.
You can see the same basic trend where it looks like women with no prior
use who are obese are not at elevated risk of breast cancer. Everyone
else is particularly those with prior hormone exposure and some clear
evidence that this may be real.

I also want to look at effective disease by prior use and randomization
assignment. You see exactly the same pattern in the size of these tumors
in the women who are unexposed before the trial and those who are. They
are not statistically significant because I\'ve divided the sample size
up here. But the same trend exists.

Percent positive nodes in advanced stage show the same pattern in both
groups but again it\'s this weird thing where the placebo group in the
women who had been exposed previously have a lower percent of positive
nodes and lower percent of advanced stage than the placebo group with no
prior exposure. So this is another very curious finding.

This is the newest data. Women received letters from us on July 8 of
last year asking them to stop taking their pills but we\'ve continued to
follow them up. This is the increment of data since that time. They have
not been taking our pills. Some of them have probably been taking their
own pills. But you can see that we\'ve had 21 new breast cancers in the
E + P trial and 18 new ones in placebo for a hazard ratio of 1.13. Our
cumulative, combining the intervention period with the post intervention
period, is 227 invasive cancers versus 170. The hazard ratio is 1.26,
again especially by our weighted statistic, very highly statistically
significant.

Let me try to summarize. We see a suggestion of greater E + P hazard
ratios in women with prior hormone exposure. I worry when I think about
this by the potential confounding of the differential characteristics of
prior users. We\'ve done a pretty good job of trying to adjust for
those. There is also the issue of the potential delay in the diagnosis
and how that\'s differential between these women with prior exposure and
those who are not. We\'ve not been able to address that. But it seems to
be creeping up in the idea that these women with prior exposure
randomized to placebo have these strangely lower rates. I think that\'s
the evidence for this that there\'s a potential delay-in-diagnosis issue
that is appearing in our data.

Our more extensive modeling does suggest that prior combined hormone use
has a stronger effect than prior E alone use. There seems to be an
increasing risk of duration of prior exposure. The recency of exposure
is an unclear factor. That\'s because in our data it\'s confounded with
type of prior hormone use. There is modest evidence for an interaction
of E + P with prior use and BMI.

As I was indicating, the data are too sparse to jointly exam type,
duration and recency at least when I\'m accounting for all of the
confounders there. There is a difference in extent of disease by
randomization status but it\'s consistent across the prior use groups.
We note that there is some hints of differential effect by prior use,
not on E + P but on the disease itself. The data on the post
intervention comparisons are still quite limited suggesting maybe in the
last 12 months that the hazard ratio has reduced a little bit but
cumulatively we\'re still looking at substantial increase very similar
to our own initial findings.

I want to briefly point out that we have also looked at the issue of
abnormal mammograms by prior hormone use. Basically what we see is it\'s
the current use here. So the solid line is no-prior-use and the dotted
lines are prior-use. Here\'s E + P and here\'s placebo. We really can\'t
distinguish those with prior-use and not-prior-use. These aren\'t
statistically significantly different, but you can see the strong E + P
effect that Dr. Chlebowski already mentioned.

E + P increased the rates of abnormal mammograms. This is slightly
different than the way it was presented to you before. Taking out the
women who had breast cancer, any kind, advanced or invasive, among those
who never had breast cancer during the study period, 32 percent of those
had an abnormal mammogram and 22 percent of the placebo women had an
abnormal mammogram. Those are the false positive rates. The role of
prior hormone use on mammography performance is quite small. That\'s all
I have to say on this. I would now like to introduce my colleague, Dr.
Jane Cauley, who will be speaking about our trial and fracture results.

DR. CAULEY: Thank you very much. As was mentioned earlier, the fracture
results were published last week. I\'m just going to go through and
summarize the results that were in the paper. The objective of the
analysis was to present the final results of the trial through the
ending of the trial on July 7^th^. That adds an additional point four
years of follow-up. We also similar to the other follow-up analysis
wanted to test the hypothesis that the effective E + P differs by risk
factors for fractures, identify a subgroup of women perhaps who are more
likely to benefit from the exposure. We measured BMD in a subgroup of
women. Finally we wanted to test whether the risk/benefit profile
summarized in a global index differs at women at higher versus lower
risk of hip fracture.

All the fracture outcomes in WHI include all fractures, including both
traumatic and non-traumatic fractures except for the fractures that are
listed here, fractures of the ribs, chest or sternum, skull, face,
fingers and toes and cervical vertebrae were in fact excluded. All the
fractures were radiographically confirmed. Hip fractures were centrally
adjudicated and we had a 94 percent agreement between central and local
adjudication of hip fractures.

BMD was measured at three of the clinical centers. The three clinical
centers were chosen to maximize the racial and ethnic diversity in women
who would have these measurements. We measured BMD at baseline, years
one and three as well as six although few of the women as yet had to
have their year six measurements. So our analysis are restricted
primarily to baseline, years one and three.

As mentioned, the global index was formed a priori during the design
phase of the trial. This wasn\'t a post hoc definition of global index.
It included life threatening conditions that were both primary and
secondary endpoints of the trial. Again the most important thing here is
that all of the analysis are intended to treat, but I just wanted to
point out that hip fractures we present the adjusted confidence
intervals. For all the other fractures, we present the nominal
confidence intervals. Why the difference? Well hip fractures were one of
eight clinical outcomes that were monitored by the DSMB. That the only
fracture outcome that we presented adjusted confidence intervals.

Now I wanted to give a little background. We tried to summarize a
woman\'s risk factor for risk of fracture. There are various different
scoring systems that have been published. Most of them have been used to
identify women who may have osteoporosis. That is they are used to
identify women who would benefit from having a bone density measurement.
There\'s really only one fracture risk scoring system that\'s been
published by Dennis Black from data from osteoporoic fractures. We
followed his model and developed it within the WHI.

Initially the first step is we took the various risk factors for
fractures and looked at the relative risk of the odds ratio of hip
fracture in age-adjusted logistic regression models. Based on those
models if the P-value is less than 0.10, they were entered into a
multi-variate analysis. Those variables that were significant in the
multi-variate analysis contributed to the calculation of the summary
score.

The four risk factors in WHI that were significant in this multi-variate
model and contributed to the scoring system are shown here. So for age,
the odds ratio was statistically significant at 1.14 and a woman was
assigned a zero to seven points for her age. For instance, a woman age
50 to 52 was assigned zero points for her age. Whereas a woman age 76 to
79 was assigned seven points for her age.

A history of a prior fracture after age 55 again is significant odds
ratio. It was assigned two points. Current smokers were assigned two
points and a low BMI was assigned one point. Essentially for each
individual woman these points were then summed and we summed for the
total fracture score for that individual woman. We then divided that
into tertiles and looked at the various risks hazard ratios across these
tertiles of the summary score. Now the area under the curve (\"AUC\")
for the summary score of predicting hip fracture was 0.79 indicating
moderate predictive strength of our summary score.

There was no difference in the summary score by randomized groups. In
this slide, we just combined the E + P and the placebo group to give you
just some descriptive characteristics of women. Who were the women that
we\'re calling at high risk of fracture? As you can see for age, the
average age of women who were considered at low risk of hip fracture was
56 compared to an average ago of 72 for women who were considered at
high risk of fracture.

BMI went in the opposite direction as expected. Women who were
considered at high risk of hip fracture had an average BMI of 27
compared to an average BMI of 30 in women at low osteoporosis low risk
of hip fracture. Percent of Caucasian increases such that 90 percent of
the women who were considered at high risk were Caucasian compared to 77
percent of women at low risk of hip fracture.

The current smoking was three percent versus 16 percent. Current hormone
therapy was 10 percent in the low risk group compared to three percent
in the high risk group. In terms of a personal fracture history since
age 55, it went from 24 percent in women who were considered at low risk
of hip fracture compared to 59 percent considered at high risk of
fracture.

In terms of the subgroup of 1,000 women that we had bone density
measurements on, we looked at the percent of women who had a T-score
less than -2.5 using the WHO (\"World Health Organization\") definition
of osteoporosis. There were about 12 percent of women considered at low
risk who had a T-score less than -2.5 compared to 41 percent in women
who were considered at high risk.

In terms of the overall prevalence of osteoporosis in the overall
population, this is looking at the WHO definition based on T-scores
using T-scores at the femoral neck. Overall the average T-score in the
hip was about -1.0 and in the spine it was about -1.3 and did not differ
by randomized group. So overall about 10 percent of women in the E + P
were considered osteoporosis based on their T-score compared to 12
percent in the placebo group. This was not statistically significant.
The majority of women, 53 percent, were considered to have low bone mass
and about one-third of the women had normal bone density measurements.

Now we\'ll get into the results. This shows the data on total fractures.
On the right, there were 733 women who experienced a fracture in the E +
P group which corresponds to about nine percent of women. There were 986
women who were randomized to placebo experienced a fracture. That\'s
about 11.1 percent. Overall the annualized incidence of fracture was 1.5
percent in women on E + P versus 1.99 in women on placebo corresponding
to a 24 percent reduction in total fractures that reached nominal
statistical significance.

In terms of hip fracture, there were 52 hip fractures in the E + P group
compared to 73 in the placebo. The overall annualized incidence of hip
fracture was 0.11 percent in the E + P group compared to 0.16 percent in
the placebo group. The overall hazard ratio was 0.65 so a 35 percent
reduction in the risk of hip fracture associated with E + P.

In terms of wrist or lower arm fractures, 189 wrist fractures compared
to 245 wrist fractures. The annualized incidence was 0.43 in women on
randomized E + P compared to 0.59 in women on placebo. The overall
hazard ratio was 28 percent reduction in the risk of wrist and lower arm
fractures in women randomized to E + P.

Now in WHI, we were limited to clinical vertebral fractures. There were
41 women who experienced a clinical vertebral fracture. That is a
vertebral fracture that comes to medical attention. In many osteoporosis
trials, they are used to looking at that data. They traditionally have
used a morphometric vertebral fractures which are identified through
serial radiographs. We did not have serial radiographs in the WHI. These
are the clinical vertebral fractures that come to clinical attention
because of pain. Overall, 0.09 annualized incident rate in E + P
compared to 0.15 in the placebo group. Overall the hazard ratio was 0.66
corresponding to a significant reduction in clinical vertebral
fractures.

Now we looked at various subgroups to see if the effect was different in
these various subgroups. On this graph, we show the effect now because
we\'re looking at five year age groups. This analysis is limited to
total fractures because the number other individual site specific
fractures would have been too low to look at five year age groups.

There was a previous meta-analysis that was published a couple of years
ago that concluded that E + P or E products may prevent fractures in
younger post menopausal women but not in older post menopausal women.
That analysis was based primarily on the conclusion of one study in the
younger women and one study in the older women. It\'s the HERS study
actually. So we wanted to look to see in WHI do we see a difference by
age of the E + P on total fractures.

Again, the yellow dotted line is the overall hazard ratio that we
observed in the overall group. The green circles here corresponds to the
point estimates for each of these five-year age groups along with their
95 percent confidence intervals. The P-value for the interaction term is
here. There was no evidence that the effect of E + P on fracture
differed across age groups.

We also looked at various other subgroups, years since menopause, by
race, ethnicity. That was limited to the total fractures and BMD was
also limited to the total fractures. All the other subgroups we looked
at hip as well as wrist and clinical vertebral fractures. It didn\'t
matter even though we looked at a number of subgroups. Dr. Anderson
mentioned that we need to report the number of subgroups that we look
at. If we looked at over 100, just five alone could be statistically
significant by chance alone. Nevertheless in our analysis, none of the
interactions were statistically significant.

The summary score data is shown here. If you focus first just on the
placebo group, the annualized incidence of fractures in the placebo
group in yellow was 1.33 in women who were considered at low risk of
fracture and it increased to 2.74 about a doubling of the rate of
fractures in women considered at high risk. But nevertheless whether a
woman was low, moderate or high risk of hip fracture, you can see that
there was no significant interaction between the summary fracture risk
score and the effect of E + P in reducing fractures. Therefore the E + P
reduced fractures equally well in women who were considered at low risk
of fracture as to women who were considered at high risk of fracture.

This just puts the WHI results in relationship of the data that were
published in the Osteoporosis Research Advisory Group (\"ORAG\") that
performed several analyses summarizing osteoporosis treatments. The
pooled estimate from this meta-analysis that was published in 2002 was
0.87 with the upper confidence interval that went up to 0.08. You can
see the WHI results are consistent with these previous studies and
clearly show us a very strong definitive result with respect to reducing
fractures.

What about the BMD results? These are the lumbar spine. We measured at
the lumbar spine the hip as well as the whole body. We found
consistently higher BMD measurements in women randomized to the E + P so
that by the end after three years of treatment, the lumbar spine
increased over 6.5 percent in the E + P group compared to about 1.2
percent in the placebo group which is overall a 4.5 difference in BMD at
year three at the lumbar spine with somewhat smaller differences at the
total hip which is consistent with other osteoporosis therapy showing
larger effects on lumbar spine than on the total hip.

Now we turn to the last goal which is try to identify a subgroup of
women who are sufficiently at high risk of fracture that indeed the
risk/benefit ratio may switch to us seeing more benefits. This is our
summary score again. If you focus on the placebo group, we know that the
high fracture risk women were much older. That explains somewhat why we
see that most of these global index events are obviously more common in
older women. But nevertheless the actual overall event rates are much
greater in women considered at high risk of fracture compared to women
at low risk of fracture.

Nevertheless the interaction term was not statistically significant. So
the hazard ratio went from 1.2 in women at low risk of fracture, 1.23 in
women at moderate risk of fracture and 1.03 in women considered at high
risk of fracture. But the overall interaction term was 0.54. So
essentially if you focus on this specific point estimate, the hazard
ratio, it\'s essentially neutral. We did not identify a net benefit in
those women.

The limitations of our analysis have been pointed out by several of the
other WHI speakers. We studied one E + P regiment. Our fracture risk
score, the ratio of highest to the lowest risk was modest at about a
twofold difference in fracture rates between women considered low versus
high. We could not incorporate BMD measurements into our fracture risk
score because we didn\'t have them measured on all of the women.

We also don\'t have any information on whether or not the women had a
prevalent vertebral fractures and it\'s well known that low BMD and
prevalent vertebral fractures are two of the strongest risk factors for
hip fracture. It\'s possible, therefore, that the benefit versus risk
profile could differ in women who had severe osteoporosis but we were
unable or limited in our ability to identify women who had severe
osteoporosis. Again we were limited to clinical vertebral fractures. I
added the global index here as a limitation but it\'s not really a
limitation because it was designed a priori and it included
life-threatening events that were basically primary and secondary
endpoints of the trial. However it did not include vertebral fractures
which are one of the most common osteoporoic fractures.

So in summary E + P increases BMD and reduces the risk of fracture in
healthy predominantly non-osteoporoic women. The decreased risk of
fracture was present in all subgroups of women examined. The effect of
E + P on fracture is consistent with recent meta-analyses. Finally, the
effect of E + P on the global index did not differ across tertiles of
fracture risk. There was no evidence of a net benefit in women at high
risk of hip fracture.

So the conclusion. Given the overall unfavorable risk/benefit ratio, the
overall global index indicating more risk events than benefit events in
the total population as well as the availability of other agents for the
prevention and treatment of osteoporosis, we believe that estrogen plus
progestin cannot be recommended for the prevention or the treatment of
osteoporosis in asymptomatic women. Before the combination of estrogen
and progestin is considered for the purpose of fracture prevention,
women should be fully informed about the potential adverse effects.
Thank you very much. Now I\'m going to turn the podium back over to Dr.
Anderson who is going to address some additional questions that were
posed by the Panel.

DR. ANDERSON: Okay. Following up with a few additional subgroup
analyses, I was asked to look at fracture rates by prior hormone use.
For this, I chose to use total fractures because in subgroup analyses
you start running out of sample size pretty quickly. Total fractures
obviously have the greatest numbers and the fracture data tend to line
up so beautifully across the fracture site. I thought this was a
reasonable way to do it.

You can see the overall results of a 24 percent reduction consistent in
both women who are not exposed to hormones before the trial and those
who took hormones at some point in the past. I didn\'t do a test for the
interaction here, but I can guarantee you that it\'s not statistically
significant.

These are the curves. They also imply no statistically significant
interactions. We did this sensitivity analysis, the per protocol thing,
where when a woman became non-adherent to her study medications we
stopped counting events that happened more than six months later. That
actually for fractures never changed the results very much which
suggests to me a certain amount of carry-over effect. The benefit
doesn\'t stop rapidly.

Then probably more interesting is the interaction between prior hormone
use and BMI. What I basically see is the same pattern. So low BMI, high
BMI here in the no-prior users and the same in the prior users. It\'s
just really the same pattern. The P-value for the interaction is 0.71.
So being obese of course protects a little bit. Having prior hormone
exposure protects a little bit. The interaction with E + P says that E +
P is protective in all of those groups.

Those are the four curves associated with that. You can see a slightly
stronger difference in BMI it looks like. I have the scale wrong so you
can\'t make the comparison there easily. Again unweighted P-value for
the interaction is not statistically significant. I didn\'t do the
weighted P-values because again for osteoporosis the difference between
weighted and unweighted is negligible.

Several comments about the global index. I wanted to spend a little bit
of time about that. This is the updated global index which is new data.
It has not been published. This is data through July 7^th^ of last year
with updated endpoints, an increase of 12 percent of E + P over placebo.
This is showing it by age group. It\'s bouncing around a little bit, but
the P-value for interactions saying are these statistically different is
0.99. Truly this is the best summary when you are looking at it by age.

This is looking at it by BMI. Women with a BMI less than 25, their
hazard ratio for the global index was 1.16. 1.12 for 25 to 29 and 1.08
for over 30. The P-value for interaction is 0.62. So you might think
that there\'s a suggestion of a trend here. I didn\'t do it as a trend
statistic. It could be that the leaner women are slightly more at risk
for one of these events. But based on this test, we don\'t have much
evidence of that.

By some of the other fracture risk endpoints, as calculated, the
P-values also suggest that the summary of the global index statistic is
a valid estimate for all those subgroups.

This is the increment of data since the intervention stopped. Again this
is new data so these are new events, 13 versus 17 hip fractures. So you
are seeing that protection is continuing in essentially the 15 months
since the trial ended. Vertebral fractures still benefit, all the
fractures. Interestingly the global index also for the incremental
events since the trial stopped remains elevated and it is highly
statistically significant. You know the nominal Z-value, the 0.5 level
test, is 1.96 or two standard deviations so this unweighted Z of -3.16
is highly statistically significant.

This is the cumulative results. Those incremental data don\'t change our
picture of benefit for fractures very much at all. These are all
pointing in the same way they did a year ago. The statistical evidence
is strong for that prevention. But so is our evidence that the overall
harm is greater than the benefit with a 14 percent increase in the
number of women who had one or more of those events. These are not
counts of events but counts of women who had one of them. It\'s highly
statistically significant.

I don\'t have a summary slide. Sorry. But I wanted to make a comment
about this. When the global index was defined, it really was for the
purpose of monitoring the trial because we knew we\'d have risks and
benefits. It was a tool to be used, but it had become more than that. We
didn\'t really envision it playing such a role in understanding how
these drugs might be used. But I think it brings to bear on the issue
that prevention work is really quite difficult to do.

We didn\'t anticipate that the trial was going to come out this way at
all. It was going to be much simpler. All we had to do was worry about
whether the breast cancer was going to show up in time for us to see it.
So this global index is pristine in the sense that it was developed
before we saw the data and it was based on diseases that we thought
might be impacted by these interventions and that had a significant
effect on the mortality of older women.

Now there\'s been some suggestion that it\'s not inclusive enough. We
would certainly acknowledge that it doesn\'t include all the potential
impacts of these medicines. It was never envisioned to. This was a
prevention trial for chronic diseases. We captured the critical chronic
diseases that we were looking at. We acknowledge some of the effects.

I think we need to be very cautious in the idea of expanding this global
index by cherrypicking particular endpoints that we like. That\'s a
great way to engineer something to come out the way you want it to do.
But because it\'s been mentioned several times, I will note that the
difference in vertebral fractures right here will not cancel out. If you
start out in these benefits, you need to go ask for a vertebral fracture
if that\'s a benefit. Define the criteria by which vertebral fractures
make it into a new global index and then let\'s start applying it to
other diseases and make sure that we have captured all the risks and
benefits that satisfy those criteria before we calculate it. So I think
with that I will end and turn it back to my colleague, Dr. Jacques
Rossouw.

DR. ROSSOUW: And don\'t worry, I\'m not going to give my talk over
again. I just wanted to summarize where WHI is going from here. Dr.
Stefanick has mentioned some of the publications that are coming out in
the next few months, but one that the investigators as a group feels is
important is to summarize, to put everything together, all the major
findings and some of the most important subgroup analyses some of which
you saw today in a final comprehensive paper much like the paper last
year in [JAMA]{.underline}, but with the updated information and the
informative subgroup analyses. That obviously has to wait until all of
the other papers on specific disease entities have been published. That
is something that we envision doing perhaps next year.

The other detailed analysis that Dr. Anderson showed you some
preliminary work on is also one I think that will be of interesting to
the community. That is on breast cancer, specifically by prior use. Now
as she\'s shown you some of the preliminary work-up of that, we haven\'t
yet found an explanation as to why in the trial there was an apparently
lesser increase in breast cancer on E + P in the women without prior
use. But she also showed you that those women appeared to have baseline
if you look at the placebo group to be of somewhat higher risk. So you
have something strange going on here.

Then if you look at the Kaplan-Meier curves and then the year-by-year
data that Dr. Chlebowski showed you, then you also get the impression
that those without prior use there\'s something strange going on in the
first three years. Why is the hazard ratio lower in the E + P group than
in the placebo group in the first three years? Is that a real effect? Do
you have a bimodal effect where the E + P in those without prior use
initially has a dampening effect on breast cancer and then later
there\'s an increase? I don\'t know what the biological explanation for
that would be. Or is it an artifact that we need to try to tease out and
explain why we could not ascertain breast cancer early on in those
without prior use? Those are two important publications that are coming
down the pipe.

Now as my colleagues have said, the trial of Premarin alone, E alone,
continues. The plan termination is 2005. Of course, it undergoes review
every six months with updated data and further analyses. But the plan
termination is 2005. So that tells you that the results do have some
differences compared to the E + P trial.

Now in trying to explain the findings that you\'ve seen today, the
investigators have also completed and have launched a number of
case-control laboratory analyses for the cardiovascular outcomes. These
have By and large been completed for the major outcomes. So we\'re
looking at whether baseline or one year lipids, coagulation,
inflammation markers, other biomarkers such as homocysteine and allelic
variations related to those intermediate factors whether they influence
the E + P effect in the trial. Some of those have been published in the
publications that have come out over the last year, but there are
others, in particular, the genomic investigations that will be published
in the future.

For fractures, there is an interest in the group in looking at whether
baseline estradiol and sex hormone binding globulin (\"SHBG\") and
markers of bone turnover and allelic variations related to estrogen
metabolism influence the results. Are the results different in subsets
of the population more or less benefit and similarly for breast cancer
again where the baseline estradiol and also testosterone SHBG and
allelic variations related to hormone metabolism influenced the results
or some of the more important lab investigations that are in the works?

Now for the E + P trial, we plan to continue surveillance. You saw a
little bit of that data of all clinical outcomes until 2007, in other
words, five years post trial follow-up. This is geared particularly to
following whether the increase in breast cancer risk persists and if so
for how long.

Now the E alone trial the investigators don\'t know the results but the
Institute has agreed to fund post-trial surveillance for two years
following that study. It\'s basically predicated upon what we were
observed in E + P. There are going to be some effects in the E alone - I
don\'t know which - that are going to be worth following up to see
whether they persist or not. They are unspecified at this point. We
don\'t know what they will be.

Then most exciting is that the Institute has also agreed to fund a
larger enterprise to ensure that the enormous amount of data and the
extraordinarily valuable biological specimen repository is exploited
fully to the benefit of the entire scientific community and of the
population. We have a cohort of over 160,000 participants in the various
trials and observational studies. We have citrated blood, EDTA plasma,
serum, DNA in the form of buffy coat and in subset urine samples that
we\'ve only barely utilized a small fraction of that.

The principle here is to invite WHI and other investigators and entities
including commercial entities that in some places have the best
expertises particularly when you think of proteomics and genomics to
exam this dataset and to participate in the further scientific
utilization of this resource. To that end, the Institute will issue a
Broad Agency Announcement towards the end of 2005 with funding for 2006
to 2010 to invite the entire community to address the scientific
questions that this resource can be useful for. There is some funding
set aside for the Broad Agency Announcement but as part of this activity
it will made clear that other sources of funding from inside NIH and
outside NIH can also be applied to this resource. Now the exact
structure of this and so forth has to be worked out but I thought it was
important to tell all of you here that we all need to start thinking
about what we can learn from WHI aside from what has been revealed so
far. Thank you very much.

CHAIRMAN McCLUNG: I thank all of you for a very careful and thoughtful
presentation to us that has I\'m sure given us all kinds of thoughts of
queries and questions to ask. We\'re a little behind schedule. What I
propose is that we still plan to have our lunch break from noon until
1:00 p.m. We have ten minutes for some questions that we can address to
the WHI panel at the moment. Then we\'ll have time if we need to reopen
that discussion when we come back from lunch. So are there questions
that the Committee members have to direct to Dr. Rossouw and to his
colleagues?

DR. CARPENTER: I was taken by the protective effect of BMI in several of
the parameters that you presented. I was wondering if this could simply
represent something like a dosage exposure effect or if it\'s even
possible to look at this data with respect to dose on a per unit weight
basis or something that would allow us to tell whether there\'s some
critical exposure level that would protect you from some of the
consequences.

DR. ROSSOUW: So the question is whether we can do further analyses to
see whether BMI modulates the effect. I guess it gets also to the issue
of what the endogenous levels are to start off with and what the
response is to the treatment. It\'s possible, for example, that women
with a higher BMI start with higher estrogen levels but also have a less
of an increment in on-treatment levels. We plan to get at some of this
by looking at the baseline levels. It may also be interesting to look at
the on-treatment levels in the mode and see whether that influences it.
Does that answer your question or were you getting at something a little
different?

DR. CARPENTER: No, I was just very simply trying to think of mechanisms
by which that could happen.

DR. ROSSOUW: Right.

DR. STEFANICK: I\'d just like to comment that when you say \"protective
effective BMI\" I\'m hoping you\'re only talking about bone and not
breast because an important thing with the breast is to realize that
we\'re comparing two groups so it may not really be protective as much
as the fact that the placebo group is at a high enough risk that adding
that little bit doesn\'t make a difference. It\'s like a dilution effect
and I don\'t know if that\'s an appropriate thing to say. Rowan could
comment on that. People have said that on other data that this BMI seems
to be protecting women against the breast cancer. It\'s really the case
that their overall risk is higher so adding one more little risk like
E + P doesn\'t make that big of a difference but that\'s my perspective.

DR. CHLEBOWSKI: As Garn points out, all these subgroups are really very
tricky. One of the other things that we did not have time to present was
we looked at the Gail model which is another way of looking at the
tertiles of Gail model risk for five years of risk. The women who were
at the absolute lowest risk again wasn\'t significant interaction but
they had suggestion of a higher effect on breast cancer than people who
had the highest risk which is a little counter intuitive to the way we
think about it and that could integrate some of these things like body
mass index.

So it gets back to the same question of \"Are these factors such as
obesity that give you a high level means that adding something on top of
it doesn\'t matter\". So the concept that we can find the low risk group
is very hazardous because if anything there seems to be in some of the
lower risk groups at least for breast cancer, a suggestion that maybe
E + P is a little higher relative risk, not absolute risk.

CHAIRMAN McCLUNG: And that underscores the problem in mixing or
confusing absolute and relative risk. When you are taking risk defined
on absolute by either the Gail model or the Black model and then looking
at relative risks among groups based on absolute risk, you have to be
really careful about our terminology and about how we interpret and
conclude from those sorts of things. Other questions? Yes.

DR. STADEL: This is a technical question. On statistical analysis, you
had outcome analyses that were both weighted and unweighted depending on
people\'s beliefs about the nature of the disease. Were any of the
interaction tests weighted based in particular on rather a known
relationship of adiposity to endogenous estrogen production which could
lead to a weighting of expectation with regard to the relationship of
body mass to outcome? I just wondered if there was any parallel
weighting of interactions testing as was done with outcome testing.

DR. ANDERSON: Yes. For the interaction test, I mostly showed you both
weighted and unweighted, but I have to say that in developing the
protocol and all that, we never talked about how we would do interaction
tests. It\'s not clear to me whether the weighting that we defined for
the primary endpoint comparisons is the right weight to use for
interactions. I put them there out of intellectual honesty but it\'s not
clear which is the right way to go.

DR. FOLLMAN: I had a comment for Dr. Stefanick. One thing that you
looked at was the hazard ratio for the CHD over time. You showed that
early on there seemed to be a harmful effect of E + P and later on it
reversed. Your explanation for that was basically the patients and the
women in the E + P group had already developed their breast cancer so it
wasn\'t a fair comparison between the two groups at that point in time.
But I was wondering if people had also looked at an alternative
explanation where maybe the benefit of E + P takes a long time to
manifest itself. I was wondering if this might explain or relate to the
epidemiological literature where you did see an beneficial effect of E +
P on CVD thinking that in the epidemiologic studies women in those
studies would have been followed up and would have a fair amount of
prior hormone therapy as they enrolled.

DR. STEFANICK: Okay. Just to clarify, you said breast cancer but you
meant CHD.

DR. FOLLMAN: Right.

DR. STEFANICK: Right. Well, the alternative hypothesis is actually the
one that we tested in a HERS follow-up study because people had that
same idea that there\'s this early harm and later benefit which they
were attributing to the one-year lipid changes. We\'ve never actually
seen the four year lipid changes from either study.

But in terms of to follow up on that question, we\'re actually doing
some very interesting analyses now within WHI on the observational study
in which we have 93,000 women, many of whom are hormone users and the
clinical trial. We\'re trying to tease that apart. Obviously I\'m not
going to say anything about what we\'re finding in that. The length of
use is an important issue. When you look at observational studies, many
of the studies are looking at women who are current users and then they
do a survey two years later.

So you have a very strange mixture of who is actually a user/non-user in
the observational studies. I\'m not really sure that we want to
completely go back to the idea that there is still benefit because we
see what I call the \"survivor\" group at the end. I\'m actually going
to ask Garnet to comment on this as well.

DR. ANDERSON: Yes. I want to sound a real note of caution for those
year-by-year analyses. The first year comparison is a randomized
comparison because everyone who is randomized goes through that first
year and has an event and is counted. The second year becomes a woman
who didn\'t have an event in the first year. That becomes the
denominator. So there are survivor issues. The farther out you go on
that timeline the worse it is.

In addition, we have lack of adherence that starts to feed into that in
a big way and later on. So looking at \"randomized comparisons\" in
those later years in a year-by-year fashion is dangerous territory and I
wouldn\'t want to make much inference about that year six data.

DR. ROSSOUW: Let me go back to the slide that prompted Dr. Follman\'s
remark. So what Garnet was saying is that this is real result. It\'s
actually quite a strong result, but we have to be cautious about the
results after these subsequent years. Nevertheless it\'s interesting if
you look at the rates in the E + P group over time. There\'s this
increase here but there\'s no convincing evidence that it decreases over
time. What\'s happening here, who knows? But it is striking that it\'s
the year in which the placebo group is highest. That explains this
apparent risk reduction there. This is very messy data.

I did want to point out that the observational data on this issue are
very messy too. It turns out that the observational studies are most of
the early events so their estimate of what happens in the first year or
so after studying hormones is very poor. But nonetheless if you look at
the conventional analyses of observational data particularly the
Nurses\' Health Study, it suggests that the benefit is greater in the
first few years and less in later years. So I don\'t think there\'s
convincing evidence from the observational studies to suggest that
longer duration is better. If anything, it may be the other way around.

DR. CHLEBOWSKI: Just another comment. When we\'re talking about duration
effects and getting back to breast cancer for a second, just reminded me
to really make this point again. If when we talk about the
time-to-events for the breast cancer, it just reminded me that the
mammograms were 74 percent more likely to be abnormal after one year,
but in that first year, there was about 30 to 40 percent less cancer
seen. So we ended up having almost twice as many abnormal mammograms, a
significantly fewer cancers seen and more advanced cancers subsequently
being delivered. Those things taken together just looking at those
numbers suggest that cancers are growing during those initial years but
we\'re not able to see them with mammograms which are mush less
effective in finding the cancers. If we\'re looking at those first two
or three years, we really don\'t know what we\'re seeing because it
appears that the E + P is making the mammographic diagnosis of those
cancers much more difficult. That\'s why they\'re being seen later. So
it\'s the same kind of question of how can we look at fairly those first
two year events when we know that there\'s two other things that are
occurring in the background.

DR. CAULEY: I just wanted to emphasize also something that Marcia said
when she showed the Kaplan-Meier of the global index. At no point was
the E + P curve lower showing more benefit than the placebo group.
That\'s during the entire duration of the follow-up.

CHAIRMAN McCLUNG: All right. Now that we\'re warmed up with that
discussion and know what the situation is going to be, let me propose
that we now break for lunch. That will give all of us a chance to
reflect on what we\'ve heard and gather our questions. Let me encourage
the panel members to refrain from working on this over lunch either with
each other or with others from outside our group so that we\'ll all come
back fresh and new at 1:00 p.m. Thanks. Off the record.

(Whereupon, at 12:02 p.m., the above-entitled matter recessed to
reconvene at 1:06 p.m. the same day.)

A-F-T-E-R-N-O-O-N S-E-S-S-I-O-N

1:06 p.m.

CHAIRMAN McCLUNG: On the record. Okay. Let\'s follow up with questions
and clarifications of the panel to the WHI investigators. So we\'ll
devote 15 minutes to that and then if we need more time, we can do that
later in the afternoon. Dr. Lukert, I know had a question.

DR. LUKERT: You know, there\'s accumulating evidence that there\'s a
connection between vascular disease and osteoporosis, that people with
osteoporosis tend to have a higher incidence of atherosclerotic change.
What I was wondering is, if there\'s a preponderance of the people who
have cardiovascular events who also were at high risk for osteoporosis.
Because that would make some difference, if one of the really high risk
populations were the people who had a greater tendency toward
osteoporosis, you\'d be more hesitant to intervene with that particular
form of treatment in that group of patients.

CHAIRMAN McCLUNG: So the question is, can they identify or did they look
at ?-

DR. LUKERT: Yes.

CHAIRMAN McCLUNG: ?- individuals based on cardiovascular risk ?-

DR. LUKERT: At risk for a fracture.

CHAIRMAN McCLUNG: Because they stratified on the risk of fracture and
looked at it the other way around.

DR. LUKERT: Right.

CHAIRMAN McCLUNG: So you are looking at the opposite way. Dr. McCauley.

DR. CAULEY: No, we didn\'t really look at that. It\'s an excellent
question. The only thing that I would point out is that the fracture
risk score was based on prediction of hip fracture. So the high risk
group they were much older than the low risk group. Just by their age
alone, they are going to be a greater risk of CVD.

DR. LUKERT: It would be interesting however to look at that age
stratified way also if you can.

DR. CAULEY: Yes, even the factors, age. Smoking was also greater in the
high risk group, but BMI went the opposite way. So some of the risk
factors of CVD would be consistent with an increase of cardiovascular
risk in the high fracture risk group and some not.

CHAIRMAN McCLUNG: Dr. Bone, you had a question.

DR. BONE: Yes, we\'ve had a very nice presentation of a lot of analyses
and subanalyses and subanalyses. One of the points that was made is that
rather than look at the individual groups in some cases, there was a
test for whether there was an interaction. We saw P-values of about 0.1
in many cases that were displayed. When we talk about a hazard ratio of
1.2 versus a hazard ratio of 1.0, was there actually testing of the
power of this test of the interaction term to detect a true difference?

DR. ANDERSON: No.

DR. BONE: So that wasn\'t tested. Thank you.

CHAIRMAN McCLUNG: Dr. Woolf.

DR. WOOLF: Several members of the public this morning indicated they
were concerned about the potential for discontinuing Prempro or
conjugated estrogens anyway for peri-menopausal women because of the
symptomatology. I thought I saw a slide briefly flashed by me that
seemed to indicate that the global index was equally poor for women in
the lowest age group as with any. Is that a true assessment?

DR. ANDERSON: Yes. I showed you global index by five year age categories
and the P-value for interaction of that was 0.99 saying that we really
have no statistical evidence for a difference by age.

DR. WOOLF: Can I follow up on Dr. Bone\'s question? Does a failure to do
a power analysis say anything about the validity of the interaction\'s
statistics?

DR. ANDERSON: A power analysis asks \"What\'s the probability of finding
an effect if there is a true one of a certain size?\" So in an
interaction test, it\'s rather challenging to ask what the power is for
something like that. We have to acknowledge that there are few women
when you cut up the data so finely. To address that, we tended to do
those interactions with a continuous variable instead of dicing it up
into little cells. We just did it continuously and still didn\'t find
anything. Yes, we don\'t have great power in some of these. I would not
want to hazard a guess of what the power would be, but this is the best
data that we\'re going to have on that. These data pretty much stand for
themselves.

DR. FOLLMAN: Just a comment on the power analysis issue, Dr. Anderson\'s
exactly right. We don\'t have good power for these tests of interaction.
That\'s just the way clinical trials are designed in a way. You design
it to ask the main question and by definition, you essentially don\'t
have good power for the interaction. So they give you some comfort if
there is not interaction, but it\'s understood that there\'s not a lot
of power for it. They did a lot of tests and they did some correction
for the multiple tests.

I\'d like to amplify on a point that Barbara made. One interesting
analyses that I thought laid everything out on the line was the global
index analysis particularly when you looked by tertiles of fracture
risk. But then on reflection, you realize that for this Committee we\'re
really just interested in the women who would be getting this probably
as a second line therapy for osteoporosis. So it would be interesting to
look at the global index as a function of tertile risk amongst those
women who would be less likely to receive hormone replacement therapy
for that indication. So, for example, eliminate those who had
hypertension at baseline or who had high risk for breast cancer or had
dyslipidemia, maybe had prior breast cancers and so on and rerun the
analysis. I was wondering if you\'ve had thought about that or had done
that kind of sensitivity analysis for the global risk index as a
function of tertiles of fracture risk.

DR. CAULEY: No, we have not done that analysis. All those risk factors
that you\'ve mentioned, the dyslipidemia the prevalence was rather low.
Hypertension about one-third of the women did report hypertension. For
all the other risk factors, the prevalence was rather low.

DR. CHLEBOWSKI: And with respect to the breast cancer, the women
self-selected against that anyway. When we looked at the Gail risk score
for the group, it was 1.5 for a 62 year old population. That\'s less
than a 60 year old with no risk factors which is 1.7 percent five year
risk. Women have to be neutral to the question and there was enough
noise about breast cancer risks that those women who were higher or had
more family histories just didn\'t enter the study.

DR. ROSSOUW: Let me just briefly respond to that. Dr. Anderson was right
and you were right that you power this to look at the overall effect and
if you do these subgroup analyses and the interaction tests and you
don\'t find anything strikingly different, then you tend to believe the
overall result is the one that probably applies to the subgroups as well
because that is the robust result that you have. In terms of looking at
clinically relevant subgroups beyond those that we\'ve done, if someone
could tell us who are the patients that are going to get this treatment
for osteoporosis prevention and what are their characteristics, we could
try to run such an analysis.

But I\'m not sure for example that a person who has a modestly elevated
blood pressure wouldn\'t still be a candidate for osteoporosis
prevention for example. But if you could give us who are the people. Is
this a targeted population? My impression in the past has been the
answer is \"No.\" Basically the gestalt was that every post menopausal
woman should basically get this if she had a low BMD. Right? If there is
a different kind of gestalt emerging now, then we could potentially run
some analyses although again our palate will be pretty low to get
informative results.

CHAIRMAN McCLUNG: Dr. Bone.

DR. BONE: Thanks. A couple of comments related to the recent discussion
of Dr. Follman\'s question in particular and it ties into subsequent
comments. The investigators did what they could with what they had as
far as this risk estimate. But I think they demonstrated pretty clearly
that there was some real limitations to the ability of the information
available to them to classify the patients according to their risk of
either developing an osteoporoic fracture or even developing
osteoporosis as we know to be defined by bone densitometry because they
didn\'t have at their disposal the basic tools that we use for doing
those things.

So a fair number of patients classified as low risk actually qualified
on their basis of their bone density as having osteoporosis amongst
those whom bone density were measured. We would ordinarily expect if we
were going to identify a high risk group to see a much higher relative
risk, say a log higher, who have a tenfold relative risk or something
like that. So some of the questions that may not be possible to model
but I don\'t know if they would be impossible to model would be to look
at what the risk/benefit ratio would be in patients who actually had
osteoporosis or try to imagine what would happen if we had the
conventional tools that we would use to assign risk.

The understanding of what\'s meant by \"prevention\" of osteoporosis
depends a lot of where you are. At the time of the U.S. guidelines were
originally formulated, it just meant that your bone density didn\'t go
down. But I think the clinical practice probably conforms a little more
closely in some cases to what the European regulatory authorities which
is basically prevention of so-called \"osteopenia\" progressing to
osteoporosis based on bone density. They actually classify early
remedial post menopausal bone loss and a few years delayed which their
delayed study would correspond more closely to what was done here except
?-

Just to take a minute. Up to five years post menopausal with osteopenia,
more than five years with post menopausal to osteopenia are classified
separately in the European guidance. Somebody correct me if I\'m
slightly off on that. It might be three years. I think it\'s five. So
most of the patients weren\'t immediately post menopausal. They weren\'t
classified on the basis of having a somewhat low bone density. But that
would be the group that probably is more thought of as the prevention
population by more doctors these days just to respond to the other
question that Dr. Woolf so raised.

DR. WOOLF: Getting back to Dr. Rossouw\'s point about who to model, I
take the reverse and say \"Who shouldn\'t be on the drug\" and that\'s
clearly the women who are hypertensive and smoke. They have a far
increased risk of stroke. I think a physician who uses estrogen in that
setting does so at his parol and the limited malpractice insurance. So
you can exclude some of those folks, certainly risk of stroke and
someone with significant hypertension and/or smokes. You should model
them out because they probably wouldn\'t be an ideal candidate for the
drug anyway.

CHAIRMAN McCLUNG: All right. Let me propose that we draw this section of
the discussion to a close and move on to the next part of the program.
Representatives from Wyeth Pharmaceuticals have prepared a presentation.
Dr. Joseph Camardo will lead off and coordinate that.

DR. CAMARDO: Thank you very much. Good afternoon. On behalf of Wyeth, I
want to thank the FDA first of all for inviting us to the Advisory
Committee Meeting and for the Committee giving us the time. Our
presentation today will focus on how we support the appropriate use of
hormone therapy based on the evidence available. That\'s evidence about
the risks and the benefits, evidence from clinical studies and evidence
from WHI as well.

My objective today is not to review a lot of data. I have some data but
not a lot of data. My objective is really to explain to you how the
medical team at Wyeth interprets the data from these studies, what data
we emphasize and why although we acknowledge certain risks we continue
to support estrogen/progestin as an option for osteoporosis. I also want
to explain how the company responds when we receive clinical study data
particularly safety data that will have an impact on the use of the
product for women and practitioners.

Now I will be presenting positive data about Prempro. I want to say in
advance that it\'s not my intention to ignore or downplay the risks
observed in WHI. You will see that we take these reports very seriously.
I will discuss them, but I did choose to reduce some of the effective
data first. I just wanted to remind you that I\'m the head of Clinical
Research at Wyeth. I\'m representing actually a medical team that\'s
been supporting our reaction to the WHI and actually our support for
estrogen/progestin over the last several years.

I have four items I would like to cover today briefly. First there\'s an
introduction. I want to explain how we come to the conclusions that E +
P, the combination Prempro, should be used for osteoporosis. I also want
to go over some clinical data about bone loss and estrogen therapy. This
probably shouldn\'t be new to any of you but I did want to review it
today. I also want to discuss the WHI data and it\'s clinical
application to practice and the risk that were reserved in this trial
and how we deal with them. The fourth thing is that I want to review the
information in the current product label. What I mean by that is the
product-prescribing information and that was I believe included in the
material that was sent to the Advisory Committee.

Let me start with this one slide. These are five points that the medical
team at Wyeth used to construct our recommendations about Prempro. These
are really the five ideas that I want to convey to you today.

1\. The first is that prevention of osteoporosis is an important aspect
of healthcare especially for women in menopause. I think we would all
agree to that.

2\. The second is that Prempro is effective for osteoporosis and it is
one of a relatively small number of medical therapies available for
osteoporosis.

3\. The third point, estrogen/progestin is the only therapy that can
reduce menopausal symptoms and prevent osteoporosis. I think we would
agree with that too.

4\. The fourth point is very important to us and I want to make sure
that it\'s emphasized properly. Practitioners really do need to
determine the use of hormone therapy for an individual based on all the
evidence available and the goal of treatment. I think that should be
clear from this morning\'s discussion and some of the questions that
came up in the afternoon because there are areas about which the
certainty is lacking.

5\. And the final thing - and this is very important from the company\'s
point of view as the sponsor of the product - is the Prempro label
provides accurate information. The point is the point number four -
practitioners need to make the decision- has to be supported by point
number five which is that sponsor provides appropriate information.

Now let\'s go into these in a little bit of detail. I think we didn\'t
talk about this very much today but there can be significant disability
and mortality related to fractures in women. It really does demand our
attention. That\'s why we\'re having a meeting today.

An interesting statistic, the National Osteoporosis Foundation
advertises that every 20 seconds there\'s a fracture related to
osteoporosis. Also I think we know this that at any given level of
trauma someone with bone loss, whatever degree, is at high risk for
fracture than someone without a decrease in bone density or quality. So
prevention of bone loss is an important aspect of healthcare for women.

Let me summarize just the four points in this slide.

1\. First, we know bone loss accompanies menopause.

2\. We know that bone loss increases the risk of hip, vertebral and
other fractures.

3\. We know that fracture risk increases before bone loss has progressed
to the level of osteoporosis.

4\. We know that hip and vertebral fractures are associated with
increased mortality and also significant disability. This was alluded to
earlier in the morning. One year mortality after hip fracture can be as
high as 20 percent. Twenty-five percent of women need nursing home care
after hip fracture. Vertebral and other osteoporoic fractures can be
disabling.

Now I said I would talk about the positive data for Prempro. Prempro is
effective for osteoporosis prevention and treatment of menopausal
symptoms. Remember this is one of the premises that the medical team at
Wyeth has based our discussion and our recommendations upon. Prempro has
been shown to reduce non-vertebral fractures especially hip fractures
now even in women who do not yet have osteoporosis. You heard that this
morning from WHI.

You\'ll also see some data from me about low dose Prempro which reduces
menopausal symptoms and also increases bone density. I want to emphasize
this is important because symptoms and bone loss may be concurrent
medical problems. We\'re not really focused on symptoms today but I
don\'t want to forget about them because that is part of the clinical
presentation in some women who also have bone loss.

We also all know that because the awareness of osteoporosis has
increased, this has encouraged the development of new medical therapy so
that in 2003 estrogen/progestin is one of a number of agents available
to protect bone health. My point here is that the availability of
different therapies is an advantage. The therapies have different
mechanisms. They had different side effects. This allows the women and
the practitioners a reasonable array of choices because each agent has
strengths and weaknesses, effectiveness, tolerability, compliance with
each therapy. They may vary with individuals. I want to emphasize this
because the medical team concluded after looking our product and looking
at the other products that the option to use estrogen/progestin is an
advantage of women and practitioners, but it\'s not the only therapy
available.

Let me show you something about how we think about the strengths and
weaknesses. First of bisphosphonates, we know that bisphosphonates
prevent fractures. There are clinical trials supporting that. But we
also know that bisphosphonates may not be suitable for all women. There
are limited data in non-osteoporoic women and bisphosphonates have
gastro-intestinal side effects.

The selective estrogens prevent vertebral fractures, raloxifene, for
example. But so far, raloxifene hasn\'t been shown to prevent hip
fracture. Moreover, hot flashes occur in about 20 percent of women so
it\'s not really an appropriate therapy for women with menopausal
symptoms.

The fourth point here we talk about E + P today. We know it prevents
vertebral and non-vertebral fractures. We\'ve also learned that E + P
may be associated with increased risk of breast cancer and CVD in
certain populations. The summary is the products have strengths and
weaknesses and the variety of agents available helps to support clinical
practice.

Now we also concluded - and this was the fourth point on my first
slide - that the decision to use estrogen/progestin or not to use
estrogen/progestin really needs to be made by the woman along with a
knowledgeable practitioner. Now it\'s very clear to everybody that the
results of the WHI study have had a major impact on the assessment of
the risk/benefit for estrogen/progestin. But still a decision to use
estrogen/progestin for osteoporosis and menopause and particularly in
the younger women cannot be based just on the WHI study.

The overall objective of the study was not necessarily to target a
therapy for every woman who may use E + P. I just remind you women with
significant symptoms were discouraged from participation in the WHI
study. There were some women in the study with symptoms but that was not
a major objective of the study. The study was designed to assess
potential benefits of long term use. We went through those, fractures,
colon cancer, CVD. We know the outcome and selected long term risks,
breast cancer, DVT. We know the outcome there too. But it really wasn\'t
designed to assess a question that physicians do face all the time which
is \"How to use estrogen/progestin in women closer to menopause who have
bone loss and menopausal symptoms.\"

Now I intend to discuss the label for Prempro as the last item on the
agenda. The premise here is that individual judgment requires knowledge.
The label for Prempro represents again what the medical team concluded
is the information to support clinical decision making. The key points
about the label are shown here. You\'ve actually seen part of this
earlier today. I\'ll discuss them briefly at the end of my presentation,
but there are four points here.

1\. First the pertinent results from numerous trials are included.

2\. The safety information is updated regularly after medical review of
evidence.

3\. The WHI data are included in the current version of the label.

4\. The information is available both to practitioners and to women.
There is a product-prescribing information which is available to the
prescriber. There\'s a patient package insert which the women will
receive when a prescription is filled. There\'s also the recent FDA
Educational Campaign which Dr. Orloff referred to in his introduction
today.

Let me go back to my first five premises. Prevention of osteoporosis is
important. Prempro is effective for osteoporosis. It\'s one of a few
agents available. Hormone therapy, that\'s estrogen/progestin for the
purpose of today is the only therapy that can reduce menopausal symptoms
and prevent osteoporosis. Fourth and fifth points very important.
Practitioners need to use the product, estrogen/progestin, for the
individual woman after making a decision based on evidence and based on
the goal of treatment. We need to support their decision with the
Prempro label providing accurate information.

I want to talk now about the clinical data for E + P. There are four
points here too.

1\. Rapid and progressive bone loss that occurs early in menopause can
be prevented with E + P. I want to show you some of that data.

2\. Most fractures occur in women who are osteopenic, not osteoporoic so
early intervention may be important.

3\. Prempro and I\'ll show this data at all doses improves bone density
in osteopenic women.

4\. Prempro in the WHI reduced fractures significantly even in women who
were not osteoporoic.

Let me review these four points in some detail. First, this slide which
I borrowed from Dr. Lindsay\'s Lancet article from 1976 shows that bone
loss follows estrogen loss and it can be prevented with early post
menopausal use of estrogen. The slide plots metacarpal bone mineral
content on the Y-axis over time on the X-axis for women who were not
treated after ovariectomy which is the blue line and women who were
treated immediately after surgery, the red squares, starting three years
after surgery, the green and starting six years after surgery, the blue
triangles.

The data from this study show that the women who started estrogen
immediately after ovariectomy preserved bone mineral content at or near
their baseline before ovariectomy. The women who started six years
later, the blue triangles, maintained bone mineral content at about the
same level it was when they started treatment but that was below their
baseline from their ovariectomy. Those who started estrogen within three
years actually fell in between the two extremes.

This is a biological effect and it suggests that early post menopausal
use of estrogen would maintain higher bone strength. It\'s one of the
pieces of evidence that has supported estrogen use in the early post
menopausal period.

Other evidence about the incidence and the number of fractures in a
large cohort study also suggests that early intervention would be
useful. This slide from Dr. Siris\' paper shows that fracture incidence
increases as bone density decreases. The density is only one of the
factors that accounts for risk. Bone quality which is a reflection of
remodeling is also very important but this does show that with lower BMD
score the number of fractures per 1,000 woman years in this cohort
increases several fold. It\'s actually highest in the women with WHO
defined osteoporosis which is to the far right of the graph.

But this slide shows that in the same cohort the actual number of
fractures is highest in the women with osteopenia because there are so
many more women who fall into the category of mild or moderate BMD loss
who are not yet osteoporoic. This is not too much different from the
population in WHI. So this is not just a theoretical benefit which I
showed you from the early intervention. There appears to be a practical
benefit as well in that more fractures can be prevented.

Based on the biologic effect of estrogen and the consideration that
prevention of further bone loss has a clinical benefit, we evaluated
Prempro at different doses specifically for osteoporosis prevention in
post menopausal women, many of whom were osteopenic. These studies
include the original studies of Prempro of more than ten years ago and
the most recent study performed as the basis for approval of the low
doses of Prempro. This recent study is the Women\'s HOPE study. That\'s
the one I\'ll discuss briefly.

The study was designed to see if doses lower than 0.625 mg estrogen and
0.625 mg progestin, the dose that was used in WHI, would be active for
symptoms and for bone loss. Two thousand, eight hundred and five women
were randomized at various doses of Prempro, Premarin or placebo. The
average age was 53. The average time since menopause was 4.7 years. The
endpoints included among numerous things most important reduction of
vasomotor symptoms and improvement in bone density and protection of the
endometrium. The bone density substudy which I\'ll show in the next
slide included 800 women who were followed for two years. Much of the
data from this study have been published.

Dr. Lindsay\'s publication in 2002 showed the Prempro improves bone
density in all doses. On the left panel is the bone density in the
spine. This declined in the placebo group which was expected. That\'s
that blue line that\'s going downward. But it increased in all the time
points starting at six months in the women who received 0.3 mg, the red
triangles, 0.45 mg, the purple squares, or 0.625 mg. That\'s the dose of
Prempro that was used in WHI shown by the green diamonds.

At the spine, the 0.45 dose, the purple, increased density about two
percent. The 0.625 dose about three percent. All the differences reached
significance compared with placebo. On the right panel are data from the
hip. It\'s the same colors. Again bone density declined in the placebo
group. In contrast, bone density was increased by all the doses of
Prempro. In this case as with the spine, all the differences reached
significance compared with placebo at the time points starting at about
one year. By 24 months, the results for all the three doses were very
close to one another. Moreover the increase in density compares
favorably with data from studies of raloxifene and bisphosphonates and I
won\'t show you that data.

Now you\'ve heard this in detail already today. Many epidemiology
studies concluded that estrogen/progestin products were associated with
a decrease in fractures in women. WHI provides evidence that fractures
are indeed prevented even in osteopenic women. I took these numbers from
the publication. All fractures were reduced by 24 percent. Hip fractures
reduced by 33 percent. Vertebral by 35. Arm and wrist fractures by 29
percent.

But the data also indicate a very reliable and robust effect. Now I
emphasize these data today because part of my job is to explain how we
responded to the WHI results. Now of us on the medical team thought that
we could or should ignore the highly favorable fracture results.

1\. It was particularly impressive that these results were achieved even
though low bone density was not a requirement for study entry. Only
about four to six percent of the women were osteoporoic. Generally we
studied bone sparing agents in osteoporoic women.  So this is a first
study to demonstrate such a benefit in osteopenic women. It\'s
consistent with what I told you in the last few slides about fractures
in osteopenic women.

2\. The fracture incidence was probably underestimated. The endpoint was
clinical fractures. I think this has been explained already. Most
studies we do for regulatory approval includes fine radiographs so we
can detect subclinical fractures. Of the women who have a
radiographically identified fracture, about 15 to 20 will develop
another fracture within a year or two.

3\. The reduction was observed within the first year of treatment. I\'m
not telling you something that you don\'t already probably know, but
what I would emphasize is these are the data that we evaluated in making
our decisions.

So there is convincing evidence that estrogen/progestin can prevent
fractures. Let me just summarize these points again. There is rapid bone
loss in early menopause. Fracture incidence increases as density
decreases. Most fractures occur in women who are osteopenic. Prempro
improves bone density in osteopenic women close to menopause. That\'s
what I showed you from the HOPE study. The WHI shows that Prempro
reduces fractures even in women who are not screened for osteoporosis.

Now of course it\'s 2003. It\'s likely that every clinical decision
includes some discussion about WHI. Practitioners need to know about it.
They read about it. It\'s featured in numerous journals. It\'s a subject
of CME. Women have learned about it through the media. The results are
featured prominently in the Wyeth Prempro Prescribing Information. The
most recent version of the label is part of that background and it\'s
also on the website.

But as I stated in the beginning, point four if you remember, applying
the results of a clinical trial really requires informed clinical
judgment. There are some limitations to the evidence that are related to
differences between a clinical trial and between clinical practice. The
investigators who spoke this morning actually alluded to some of these.

Again I want to point out the medical team at Wyeth reviewed and
discussed the WHI data at great length, internally with the
investigators, with the NIH team, with the FDA. We acted on the data
last year by amending the label and supporting dissemination of the WHI
data. You\'ll see how we did this too. But the medical team doesn\'t
agree fully with some of the broad interpretations of the data,
particularly some of the statements about the application of the data to
all clinical practice especially some of the subgroup analyses.

Now we know that the subgroup analyses are supposed to be hypothesis
generating. They are not supposed to be definitive. But one of the
problems is that in clinical practice the women whom you actually see
come from one of the subgroups or they have characteristics of one of
the subgroups and some characteristics of the other. So you have to make
an individual judgment.

These are the four points I want to make about the WHI study and about
how to apply the data from that study to clinical practice.

1\. To remind you in general, the women who receive hormone therapy than
the average age of the women in WHI. I know some younger women were
studied in WHI, but in fact the most robust effects were driven mostly
by the older women and they have menopausal symptoms, the women in
general in practice who receive hormone therapy.

2\. This one was also discussed earlier in the morning. The risk/benefit
assessment in WHI didn\'t take into account all vertebral, that includes
the clinical and morphometric fractures, and all of the nonvertebral
fractures as well as some other benefits and risks. It was defined
prospectively but it wasn\'t in fact selected.

3\. Dr. Anderson referred to this one already. The global index from WHI
is a clinical trial tool, but it cannot be used to assess the
risk/benefit in individual women.

4\. The data provide important information, being a little bit
repetitious, but clinical practice requires individual patient judgment.

Let me take these one point at a time. The first point, most women who
take estrogen/progestin are younger than women in WHI. In the Women\'s
HOPE and the other studies of estrogen/progestin in menopause, the women
in the study were within five years of menopause. In general, that\'s
because we tried to enroll women in the study in whom we can demonstrate
a benefit on vasomotor symptoms, but this age group is approximately ten
years younger than the average age of the WHI population. Again the
robust effects were driven by the average of the population. The average
age in the Women\'s HOPE study was about 53. The average age in the WHI
study was about 63. The women in Women\'s HOPE were closer to menopause.

That\'s point number two. The women less than ten years since menopause
appear to have no excess cardiac risk. Now I\'m pointing that out
because when you look at the paper for cardiac risk, it does look as
though the women less than ten years have no excess cardiac risk and
it\'s consistent actually with some common sense clinical practice, some
things that we know about age related risk of cardiovascular medicine.
 Again it\'s a subgroup analysis of the younger women, but the fact is
that if it\'s hypothesis generating, one of the hypotheses could be that
younger women have less cardiovascular risk.

In the absence of being able to make a clear demonstration of that fact,
physicians and practitioners have to be able to make a decision for the
individual woman. That\'s my point, not to have a discussion about the
pluses and minuses of a subgroup analysis. It\'s to have a discussion
about when you\'re finished with the subgroup analyses, how do the
physicians use the data that you give them. It generates a hypothesis
that the younger women closer to menopause may have a lower risk of
using the estrogen/progestin.

The final thing is that in the younger women symptoms and osteoporosis
are more likely to coexist and estrogen/progestin is the only therapy
that can concomitantly treat menopausal symptoms and prevent
osteoporosis. Remember women will come to the physician partly because
of a desire to treat a condition or a symptom or a problem, not just to
be put into a trial for a long term prevention. So there will be a
medical issue to address at the time.

I don\'t want to belabor this but the risk/benefit assessment did not
take into account all of the osteoporoic fractures. The failure to do
that when you calculate the global index may underestimate the benefit
of hormone therapy for osteoporosis in general.

That\'s not really the point about adding up the global index. The point
that I want to make and also what the medical team thinks about is that
the disability from any type of fracture may have a significant impact
on an individual woman. It may change the individual risk/benefit for
estrogen/progestin.  That\'s what actually has to be decided when
someone wants to write a prescription.

Let me talk a little bit about the WHI global index. Dr. Anderson
alluded to this. It\'s a clinical trial tool. It\'s not really a risk
management tool for individuals. It serves the purpose of a clinical
trial, but it wasn\'t designed to serve clinical practice. I just want
to point out that clinical trials evaluate the population. That\'s what
we analyze. That\'s what we look at. That\'s what we add up. But
clinical practice considers the individual risk/benefit.

I alluded to this earlier. The individual may or may not match closely.
The actual population that was evaluated in the WHI trial may not match
the subgroups. The age of the woman, the BMI, the time for menopause,
the menopausal symptoms, the degree of osteopenia, the perceived need
for osteoporosis prevention are differences that may characterize an
individual and it may be very hard to characterize actually all of those
differences in the population analysis that we do. So extending the
results beyond the trial population really again when all of the
discussion is done requires that the practitioner use judgment.

Leading to my next slide, the data provide guidance, but clinical
practice requires individual patient management. Now based on all of the
data from this study and the other studies, I think the decision making
process would be as follows:

1\. The decision to use estrogen/progestin in menopause will be
influenced by the presence, the severity of symptoms and the bone
density measurement. The potential benefit of estrogen/progestin therapy
on bone health should not be ignored in younger women in early post
menopause, but the physician and the woman have to evaluate the benefit
in light of the potential risk of vascular disease, stroke and heart
attack and breast cancer. The individual risk has to be considered.

2\. The use of estrogen/progestin in women with bone loss but no
menopausal symptoms will have to based on the need to treatment women at
high risk. We heard that the highest risk that was evaluated in WHI may
not be the highest risk that will actually be seen in practice. Still
those are the women who have to be treated. Also the consideration would
be the unsuitability of the other handful of agents that are available.
This actually isn\'t too far away from the recommendation that was made
by Dr. Cauley.

So let me summarize this section. How do you apply the data from WHI and
a lot of other clinical studies to clinical practice and the individual
woman? First, remember the women who take estrogen/progestin in general
are going to be younger than the average age of the study. The
risk/benefit assessment did not include all the fractures and a
particular kind of fracture or a concern about a fracture may be
important to a particular woman in practice. I just want to remind you
again that the global index from WHI is a clinical trial tool, but it\'s
not being advocated as some way to determine the risk/benefit for each
woman.  That still has to be done. The data provide guidance. Clinical
practice requires individual patient management. The product information
which is going to be the subject of my next section provides the
information useful for practice decisions. Finally, estrogen/progestin
in our estimation after evaluation by the medical team remains an
important therapeutic option for osteoporosis.

I want to talk about the product information specifically now. Let me
start with one very important point about the product label. The medical
team developed a label that is clear and balanced. It is the company\'s
policy to revise the label when appropriate. Now I\'m presenting the
medical team\'s point of view which is that the current label accurately
reflects the state of knowledge and the recommendations consistent with
the evidence.

I want to go through these four points.

1\. The product information strikes a balance so that the clinical
practice is guided but its use is not appropriately expanded or limited.
Those are important.

2\. The label information for prescribers includes some recent results
from a variety of clinical and epidemiological studies.  There\'s a lot
of data on the label.

3\. The balance includes statements regarding the risks that have been
reported and, with regard to safety, a conservative interpretation is
presented.

4\. New data are considered for inclusion as they become available.
That\'s exactly what happened last year when WHI became available and we
worked with FDA to make changes in the label. That\'s exactly the
process.

Now the recommendations for Prempro use are based on the evidence that
we have today. For women with menopausal symptoms, Prempro can reduce
symptoms and prevent bone loss. We say that and we cite the clinical
trial results on bone density. For women without menopausal symptoms,
Prempro is recommended only for women at significant risk for
osteoporosis and for whom non-estrogen treatments have been considered.
This change was made based on the results of WHI after consultation with
our medical team and with the medical team of the FDA.

Let me be more specific. What does the indication actually say? Prempro
or Premphase is indicated for:

1\. Treatment of moderate to severe vasomotor symptoms associated with
the menopause. That hasn\'t changed in the last year.

2\. Treatment of moderate to severe symptoms of vulvar and vaginal
atrophy associated with the menopause. This sentence in blue was added
in the labeling as a result of the WHI. It says that \"When prescribing
solely for the treatment of symptoms of vulvar and vaginal atrophy,
topical products should be considered at the same time.\"

3\. This indication about preservation of bone states \"Prempro is
indicated for mention of post menopausal osteoporosis.\" The sentence in
blue was also added after consultation and review of the WHI data and it
says \"When prescribing solely for the prevention of post menopausal
osteoporosis, therapy should only be considered for women at significant
risk of osteoporosis and non-estrogen medication should be carefully
considered.\"

We also highlight certain information to promote awareness.
Estrogen/progestin should not used for prevention of cardiovascular
disease. That\'s very prominent. The risk of myocardial infarction,
stroke, invasive breast cancer, pulmonary emboli and DVT as reported in
WHI and other studies are prominently and repeatedly noted. Specific
information on breast cancer, coronary heart disease from WHI and other
studies and information on dementia from the WHIMS study are also
included. In fact the relevant risk of the outcomes in the global index
which I discussed earlier that was published in [JAMA]{.underline} last
July is reproduced in the product information.

We also recommend therapy should be prescribed at the lowest effective
dose. We also recommend that the duration of treatment should be only as
long as required to meet objectives for the particular woman. As you saw
this morning, a boxed warning was added and that assures that actually
the prominent information is the first thing that\'s seen when the label
is read.

Now the changes in labeling were accompanied by a communications
program. The first thing was that practitioners were notified by letter
of the results of the WHI and the changes in the product information. We
did that last year. The data from WHI were distributed to practitioners
by mail and the Wyeth representatives were also asked to distribute a
copy if necessary.

Information wasn\'t given just to the prescribers. There\'s information
in the patient package insert that includes a clear assessment of the
cardiovascular disease and breast cancer and other risks that we have
determined are associated with the use of estrogen/progestin. So the
patient gets this information as well.

The question we need to answer is \"Has all this made a difference?\"
The data we have now on the pattern of use of Prempro is consistent with
the new recommendations that have been made in the last year. I just
want to address two points.

1\. About 25 percent of the new prescriptions are for low dose. We\'re
making a recommendation for low dose. The low dose was made available
only around July of this year. After about four months after the low
dose is available, 25 percent of the prescriptions are actually for the
low dose. So prescribers are following the new recommendations which is
good.

2\. The second point is 94 percent of women initiate Prempro for
menopausal symptom relief. It\'s very clear on the labeling that\'s
where the use is directed. By and large, the substantial majority of
women and prescribers are using the product now for menopausal symptom
relief so younger women constitute by far the majority treated.

I want to emphasize this. The changes in labeling had the desired
impact. This is very important. When the clinical research suggested a
change in the use of the product, the medical team at Wyeth responded.
We responded with recommendations that are consistent with the
scientific data.  The result as a pattern of prescribing indicates that
practitioners have changed in response to the new scientific data as
well.

The major conclusion I want to leave with you is that our medical team
in collaboration with the FDA has been able thus far to respond to new
data and to accomplish the objective I set out in the beginning which is
to support the appropriate use of this particular product.

My last slide is just a summary of the key points

1\. With the reminder that osteoporosis is an important medical problem,
fractures cause mortality and significant disability. We don\'t want to
forget that in our discussions.

2\. There are only a handful of treatment options currently available
for osteoporosis.

3\. Estrogen/progestin is only one of the therapies that we know can
treat both the menopausal symptoms that occur and to prevent
osteoporosis.

4\. We know now that Prempro prevents osteoporosis and reduces the
incidence of all fractures including hip fractures.

I want to thank you for your attention. If there are any questions, I or
my team will do our best to answer them. Thank you.

CHAIRMAN McCLUNG: Questions or comments? While you are gathering yours,
let me make a couple. About the HOPE trial, you\'ve emphasized that bone
loss happens early in menopause and that most of the women who take
estrogen now are younger. The average time since menopause in that trial
is 4.7 years.

DR. CAMARDO: Correct.

CHAIRMAN McCLUNG: The bone loss happens most rapidly in the first three
to five years after menopause and then slows down. You looked at lower
doses in the HOPE trial to show that it was effective in preventing bone
loss. Have you actually looked at the women who were closer to
menopause, those within the first three years for example when bone loss
we know is faster and to know whether the lower doses of Prempro or
Premarin are effective in that group of women that you are focusing our
attention on?

DR. CAMARDO: The question is did we look at a subgroup of the women even
closer to menopause than the average 4.7 years?

CHAIRMAN McCLUNG: Right.

DR. CAMARDO: I\'m going to have to ask my team to help me out on that.
Dr. Lindsay or Ginger?

DR. LINDSAY: The response to your question is that we did not look at
that because we had groups of only 80 in size and it would be an
inappropriate subgroup analysis.

CHAIRMAN McCLUNG: The other question I\'d ask has to do with the
durability of effect. One of the points that you made is that the
recommendation is that estrogen be used only as long as necessary to
achieve the treatment objective. Being treated forever is not a likely
circumstance. Then knowing how long the protective effect of estrogen
and particularly the lower doses of estrogen last becomes an important
consideration. If patients are at very low risk when they\'re begun on
therapy, treated for three years or five years and then therapy is
discontinued, it could be that the benefit then last until they are old
enough to be at risk. Or does the effect disappear? Have you followed
the women since therapy was discontinued in the HOPE trial or in other
studies?

DR. CAMARDO: Not in the HOPE study. There are actually some data that
address that. I had it in one of my slides but I won\'t show it. I think
that the conclusion that we came to is that you can assure the
preservation of bone while you\'re using the therapy. Once this
estrogen/progestin is stopped, there is a decay period. I think that\'s
actually been published. It\'s not immediate and it doesn\'t look like
it\'s accelerated. What I think will happen in general and in practice
is that if a practitioner and woman make a decision to use
estrogen/progestin for osteoporosis after a certain period of time which
is going to be hard to determine for sure, they will likely want to stop
the estrogen/progestin for symptom relief if that was part of the option
and continue something else for bone preservation. I think there would
be no disadvantage to having used estrogen/progestin.

In fact, you might argue that there would an advantage because you would
be starting from a higher baseline. I want to make sure that it\'s clear
that I\'m not advocating that if you make the decision to use the
therapy that you have to continue it forever. You can continue for as
long as a reasonable tolerance for the risk, clear benefit and then
after that you have to use another therapy which seems to make practice
sense and there wouldn\'t be disadvantage. Am I supposed to moderate the
questions? You\'re supposed to moderate the questions, aren\'t you?

DR. ROSEN: Rosen here. I have three questions, two specific and one
general. How closely tied is bone loss to menopausal symptoms? You\'ve
tied that in several occasions, especially rapid bone loss. Can you
establish for us what that connection and if you\'re trying to treat
both at the same time, can you be sure of that as a clinician?

DR. CAMARDO: I\'m going to give you part of the answer and I\'m going to
ask if maybe Dr. Gallagher could help me with this because he actually
is a clinician in practice. What we\'ve seen is that if we do a study,
we screen several thousand women on the basis of symptoms. We manage to
find a reasonable percentage of women who actually have osteopenia as
well. So they are concomitant. It\'s a very common event in practice,
but if it\'s okay, I\'d like to ask Dr. Gallagher to respond.

DR. GALLAGHER: Dr. Gallagher, Creighton University, School of Medicine.
About 50 percent of women will complain of vasomotor symptoms during the
menopause and maybe 40 percent will complain of vaginal dryness
(dyspareunia). Certainly from the HOPE study, we know that the great
majority of women actually develop bone loss so they are coincident
conditions.

DR. ROSEN: I\'m just a little concerned about the term \"rapid\" bone
loss because as you know, Chris, this comes up all the time. How many of
these people are actually losing bone rapidly and what is that
definition?

DR. GALLAGHER: I think that the common figure that goes around and Claus
has certainly pointed this out is that 25 percent of women have rapid
bone loss after the menopause. Still there\'s a considerable portion who
are having somewhere between average and that. So we\'re talking at
least 50 percent. Just a point of information for the women in the HOPE
study, the average number of years for menopause was 2.7, not 4.7.

CHAIRMAN McCLUNG: Not 4.7?

DR. GALLAGHER: No.

CHAIRMAN McCLUNG: Let me ask to follow through with Cliff\'s question.
Is there a relationship between women who are symptomatic and the rate
at which bone loss occurs? Is that question that you were asking?

DR. ROSEN: That\'s right.

CHAIRMAN McCLUNG: So we appreciate that the bone loss happens after
menopause. We appreciate that many women have symptoms. Do the women who
have symptoms lose bone more quickly than those who do not symptoms? I
think that\'s Dr. Rosen\'s question.

DR. GALLAGHER: I think I\'d like to hand the microphone over to Dr.
Christiansen.

DR. CHRISTIANSEN: There\'s a tight relation between rate of bone loss
and estradiol concentration. There\'s also a tight relation between
serum estradiol and the symptoms. None of that\'s close as to the rate
of loss but those are very significant. Therefore of course, there\'s
relation between symptoms and rate of bone loss. We have shown that many
years ago.

DR. ROSEN: Okay. I just want to finish with two very quick questions.
I\'m not sure I understand what you\'re referring to when you say \"WHI
did not address some non-vertebral fractures.\" Can you clarify for me
what you\'re talking about \"didn\'t report some non-vertebral
fractures\"?

DR. CAMARDO: Yes, what I was referring to is arm and wrist fractures. I
mean included in the index calculation. I did not see.

DR. ROSEN: In the global index.

DR. CAMARDO: In the global index.

DR. ROSEN: But it\'s very important to appreciate that they reported all
non-vertebral fractures that are standardized.

DR. CAMARDO: Yes, they did, but it wasn\'t included as part of the side
of the benefits.

DR. ROSEN: I have one philosophical question because I am a practitioner
as well. I don\'t quite understand why you make the distinction between
what we see in clinical trials and what we do in practice. Can you tell
me a little bit about that reasoning? It seems to me that we have to
base what we do in clinical practice on what the evidence is. So you
constantly make that distinction. This is what\'s in the trial. This is
what we do in practice. Can you elaborate a little bit on that?

DR. CAMARDO: I probably should have included my original slide which was
a quote about how there are consensus guidelines that are developed on
the basis of trials. Applying the guidelines to actual patients
sometimes can be difficult.

DR. ROSEN: Oh, I\'m not a fan of recommendations or guidelines but each
of the practitioners has to weigh the evidence.

DR. CAMARDO: I don\'t disagree with you at all. I think the
practitioners have to weigh the evidence. In general, when you do a
trial, you have defined a population and you have taken certain steps to
make sure that the population fits into the criteria that you\'ve set
up. Actually if you set up a trial and try to find the people that you
want to get into it and you go into a practice, you\'ll find that a lot
of the people may have the disease that you\'re trying to treat but they
don\'t actually fit in the trial.  So you have set up a situation that
requires that the results be applied with care. That\'s all I\'m really
saying.

I do not want anyone to mistake that I don\'t believe in the value of
clinical trials. Wrong. That\'s absolutely not true. But I still think
when you take the data you have to let the practitioners apply them.
That\'s what I want to tie to our product information because we feel
strongly that we need to provide the information balanced.

CHAIRMAN McCLUNG: Ms. Solonche.

MS. SOLONCHE: Yes. Early in your presentation, you showed a slide from a
1976 article in the [Lancet]{.underline}. The title of it is \"Bone Loss
Follows Estrogen Loss and Can Be Prevented With Early Use of Estrogen.\"
I see that all the participants in this seem to have had oophorectomies.

DR. CAMARDO: That was the study actually.

MS. SOLONCHE: My question is the studies that you\'ve used since then
and the WHI study, are these people who have had oophorectomies,
surgical menopause; or are these women who have what we\'ll
aphoristically call \"natural menopause\"? Do you think that makes a
difference in the results?

DR. CAMARDO: The latter, natural menopause. I think it probably does
make a difference in the results, but I really used the 1976 paper as a
model for looking at intervention at a time point when you could
determine when estrogen had disappeared rather than over time. So it was
really a way of looking at a specific question about the time point of
estrogen replacement when it was known when estrogen loss occurred. That
was a particular situation just to test the value of estrogen. In the
study participants in Women\'s HOPE in general are women who are going
through menopause, not women who ovariectomized.

MS. SOLONCHE: Thank you.

CHAIRMAN McCLUNG: Dr. Follman.

DR. FOLLMAN: You were saying that you didn\'t like the idea of using the
global index to help tradeoff the risks and benefits for an individual
patients. The reason you gave was that really this index had been
designed more for monitoring of the trial. Now it\'s being put to
another purpose. I was wondering if you had any other reasons why you
didn\'t like the global index or making this individualized risk/benefit
tradeoff and if you had thought about a different quantitative way of
making the risk/benefit tradeoff because a large part of what we hear
today is trading off risks and benefits.

DR. CAMARDO: That\'s a good question. I think actually the WHI
investigators, not just I, pointed out some of the limitations of the
global index. I found it a complicated endpoint for the trial. I think
the medical team would agree with me that it didn\'t evaluate the
benefit of the intervention the way we often evaluate the benefits of
intervention which is to see what they are, define the magnitude and
then have a discussion about whether the risks make it worth it. They
decided really on the basis of a number which you can\'t just apply to a
woman who walks into the office I think. That\'s in all cases. It\'s
just a matter that it tends to want to homogenize the results here and
it wasn\'t designed to be a tool. It\'s not like the Gail index or the
Framingham. Those things assessed cardiac risk or breast cancer risk. It
really isn\'t that. I don\'t think it was designed to do that.

DR. FOLLMAN: So I guess you\'re saying you don\'t want to use that index
and just look at all the data, look at the risks and benefits for the
different endpoints and then make some gestalt decision based on the
patient and her profile and all this information from the WHI and other
studies.

DR. CAMARDO: The recommendation we are trying to make is that the data
need to be available and that since there are some areas of gray there
is a certain point where a physician would have to make the decision. I
think that would be a fair way to say \"I don\'t know what I would do if
I were in practice.\" I\'m not in practice right now, but I believe that
there\'s some gray in that even when you look at the risks there are
some cases where either you could evaluate that the risk is lowered
because of some particular status of the individual such as low blood
pressure, low cholesterol, no history of heart disease, very young and a
lot of reasons that others have alluded to today and decide that maybe
the risk is really low.

There are other circumstances where I think for an individual woman the
risk even if you take it at face value might be worth the benefit. I
don\'t think we want to make a judgment about that. I don\'t want to
advocate for any particular position. I want to make it clear that our
mission is to make sure that the knowledge base is adequately displayed
in the labeling. I\'m telling you what I think the thought process might
be.

CHAIRMAN McCLUNG: We\'ve heard that the global index was put together at
the time the study was started. One of the important things to remember
is that the world is different now in lots of ways than it was ten years
ago. Our understanding and even the outcomes that were expected turned
out to be different than were planned and predicted. Dr. Rossouw has
already thrown a challenge to the clinical community that if we can come
up with the justification for a different set of risk factors and
benefits to be included in a different global index. My sense is that
much of that data exists in some database and in your database to allow
us to look at that. So we\'re struggling with trying to apply in
clinical practice a tool that was put together a long time ago where our
understanding about each of the diseases and the effects of estrogen has
moved on from that time. Please.

DR. CARPENTER: In addressing risk/benefit issues, you\'ve shown the
recent impact of your data demonstrating that lower doses of Prempro are
effective in preserving bone marrow density and recent increases in
prescriptions for the lower dose formulations. In that this is
potentially a very useful strategy for maintaining benefit and it
appears to be motivated by the potential for reducing risk, I wondered
to what extent there is data being collected and what plans there are to
organize or collect that data at the lower doses for these various
adverse actions.

DR. CAMARDO: At the current time, we have the database from the study
which is about 3,000 women followed for about a year. That\'s very small
but we have some assessment of the cardiovascular risk in that study
which is relatively small actually. That\'s one thing. The only other
thing at this point in time is really post marketing surveillance. We
don\'t have at this point a study designed that would answer the
particular question to the same extent that it would addressed in the
larger study that we\'re talking about today. So as you said, we have
the bone marrow density data. We have the data on vasomotor disease. We
have the side effect data which we know from the HOPE study. At this
point in time, the product\'s been out for a couple of months so we have
mostly post marketing surveillance reports. That\'s the extent of it for
right now.

CHAIRMAN McCLUNG: Dr. Woolf.

DR. WOOLF: A question and a comment. On one of your slides, you state
that the duration of treatment should be only as long as required to
meet objectives for the particular woman. You\'ve talked about
osteoporosis obviously not meant to be lifelong. But what about
flushing? Is this something that a post menopausal woman for want of a
better term outgrow or will this simply return once the estrogen
preparation has been discontinued?

DR. CAMARDO: I think those are both extremes of what can happen and
everything in between. I don\'t want to give you a flippant answer, but
in fact what we\'ve done to try to address that is to point out in the
patient information that the particular objective which is flushing
should be addressed on a regular basis. Our advisors are telling us that
in general - these are the recommendations from ACOG and others - that a
yearly reevaluation be performed and to consider to discontinue in some
women. With the discontinuation, flushing will return. We know that. In
others, it does apparently go away.

I could ask one of the clinicians in practice to talk about that, but
the way it\'s been addressed is actually in the patient information. We
advise that a discussion occur with the practitioner about whether you
still need treatment. That generally refers to flushing because that\'s
the most apparent one.  There are others. The implication is if you
don\'t need it anymore for flushing see if you don\'t. You have to try
that.

CHAIRMAN McCLUNG: Dr. Schade.

DR. WOOLF: My comment about the global index really doesn\'t pertain
specifically to Wyeth or WHI but my understanding about an index is you
develop an index from a population base and then you go and test it
against another population base. From what I can gather, this has not
been done with the global index. It was simply meant to be a tool for
deciding the severity or the risk and benefit but it really hasn\'t been
validated in another dataset. To use it as a tool to decide risk/benefit
when it hasn\'t been really tested in a new dataset to see its validity
may in fact not be appropriate.

CHAIRMAN McCLUNG: Any other comment about that?

DR. ANDERSON: I would like to comment. I think what you were talking
about in terms of developing and validating in another dataset has to do
with more a risk score such as the Gail model or the fracture risk score
that they were talking about where you\'re trying to identify risk
factors of individuals and put them together to then make a simpler
stratification of individuals.

The global index is something quite different where it\'s trying to
summarize treatment effects, not individuals. It\'s a summary of those
benefits and it\'s a valid comparison of the randomized trial endpoint.
It\'s a disease free survival statistic where the disease now is
actually the whole list of diseases that we\'re looking for. That\'s
what it is.

DR. WOOLF: But my point is that this distinction is liable to be lost on
the public and that it is becoming in fact the Gail index or some other
index of global disease. In fact from my reading of the [New York
Times]{.underline} and my local paper, the [Philadelphia
Inquirer]{.underline}, that\'s exactly what\'s happened. It\'s become
the marker of treatment that it has become a validated instrument to
decide whether to use estrogen or not. The statistical nuances are
clearly lost on the public. It\'s hard enough for me to understand. I
don\'t know if I do, but that information is not getting across.

DR. ANDERSON: Yes. I would say probably none of us here want to take
complete responsibility for what\'s in the newspapers. It\'s clearly
limited in the sense that it was designed for this trial and never meant
to go any further.

I would say that it\'s a very valuable tool for looking at the
risk/benefit profile in a philosophical sense to have some summary index
of these because we need quantitative measures of risks and benefits to
help in evidence base medicine. I would say in defense of this product
is that we lack that similar risk balance information for a lot of other
products out there. We need to move forward to have better information
like that on all these products particularly for prevention work.

Prevention work is some of the toughest. You never know with the patient
that you\'re treating for those clinicians if you give them this
medicine whether you actually prevented that disease or whether they
never would have had it in the first place. The prevention is really
population-based work. I\'m not sure that I really agree with this
individualization for prevention purposes. For treatment, it\'s a
different argument, but I\'m going beyond my scope.

CHAIRMAN McCLUNG: Okay. Great. Dr. Schade.

DR. SCHADE: I have two short questions. You showed us data on the lowest
dose of estrogens. What about a dose response curve for symptoms and the
estrogen dose? You didn\'t show us that. You showed us with the bone
mineral density. In other words, does the dose response curve look
similar to the BMD response?

DR. CAMARDO: I\'m going to ask for this specific question about the
study Dr. Pickar to just remind me of the results for the dose response
for symptoms if you could do that.

DR. PICKAR: When you look at the doses of Prempro that were studied for
menopausal symptoms, they were all very similar.

DR. SCHADE: All right. I think I asked that question because obviously
there is a push for the lowest dose. We\'re seeing reasons for that even
though right now at least the prescriptions don\'t reflect that. That
may be as you point out on your slide that the product hasn\'t been
available that long. The other question I have is on labeling. It\'s
probably my ignorance. You use a term \"should be seriously
considered.\" In other words, what does that mean? I\'m a practitioner
and basically when you have a choice of treatments in every case you
should seriously consider all the treatments and choose the optimal
treatment. So it seems to me on the label unless that\'s a term that the
FDA has utilized in many situations that I\'m not aware of but as a
practitioner that doesn\'t say very much. I just wondered about your
interpretation of that \"should be seriously considered\" statement.

DR. CAMARDO: It is just short of requiring that an alterative agent to
tried and shown to fail or be ineffective. Our medical team discussed
this a lot. There\'s a regulatory implication to some of this which I
think will be discussed later. It falls short of requiring a
demonstration of failure. We thought about it and discussed it and came
to the conclusion that there are some cases where it wouldn\'t really
make sense for us to recommend that another product be tried and fail
first when you could choose among ?- We thought it was sufficient to
recommend choosing among the options which is not something that was
ever said about the product previously and it\'s usually not said about
products. It\'s usually assumed. We explicitly state that. The reason we
were short of demonstrating is that we thought that there are some cases
where you could predict that the products might not work anyway.

Now I should tell you there is another discussion about the older women
which I would just like to mention briefly. In older women because of
the incidence of dementia in WHIMS, we\'re actually discussing the
possibility of requiring that other agents actually be used first
because in the older women, there seems to be a different risk/benefit
implied by the results of that study. We\'re discussing actually in that
case maybe we should go on the other side of that recommendation and
make it a little bit stronger. But it\'s a bit of a fine line and as
said, some of the evidence suggests that you just make the
recommendation to consider. Other evidence seems to suggest that you may
want to make the recommendation to try other products. Does that make
sense?

DR. SCHADE: Yes. Now I understand at least what you mean.

DR. CAMARDO: Okay.

CHAIRMAN McCLUNG: Dr. Stadel.

DR. STADEL: Yes, I just have a further question on the issue of summary
risk assessment. As I recall from the presentation of the fracture data
in the group that was defined as being at high risk of fracture - it got
pretty close to one - the global index was still slightly worse in the
treated group than the placebo group, but it was getting closer. My
question to you is has Wyeth proposed any further refined analyses aimed
at identifying a group within the total for whom the net would be
beneficial? That\'s what I hear you saying is that of course as a
practitioner we have to say \"How do the risk characteristics of this
patient play against the group experience that we\'re using to judge?\"
Have there ben any specific recommendations for further analyses using
more refinements of definitions coming from Wyeth back to the WHI
people?

DR. CAMARDO: Yes, the answer is that the WHI and Wyeth have actually
been working on some analyses together with the understanding that the
lead is always going to be taken by WHI in terms of publication and
everything else. So we tend to be in line after the publication results
which is appropriate I think. But we have asked to look at some of the
higher risk and we\'ve also discussed the possibility of looking at
women who may be at high risk for osteoporosis and low risk for some of
the other side effects.

I don\'t think that\'s an original idea. I think it\'s something that we
discussed. I haven\'t discussed it. Dr. Stevenson and her epidemiology
group have discussed it. The shorter answer is yes. It\'s a little
disappointing though that high risk osteoporosis doesn\'t seem to be
that high risk compared with the risk scale. So again you may not see in
that population women who you might see in practice. That\'s where the
limitation would be. The answer is yes. We\'ve actually been discussing
other possible analyses. We\'ve had some ideas. Go ahead.

DR. CAULEY: Yes, I just wanted to point out. I think we talked about the
high risk women being older and this brought to my mind when you talked
about this issue with regard to the risk of dementia in the older women.
The high risk women that we called \"high fracture risk\" were actually
in their 70s. That was the average age. That\'s the group where the
dementia finding were limited to women age 65 and over. So caution also
when we talk about including other aspects in the global index. It\'s
important to include other risks and benefits. That would be something
that would be needed to be included as well.

CHAIRMAN McCLUNG: Dr. Bone.

DR. BONE: It seems to me that many of us have been concerned that our
major target population for treatment with hormone therapy of one kind
or another would be the very early post menopausal woman within the
first year after cessation of menses who has symptoms with or without
low bone density at menopause carried forward a limited number of years,
probably something like three or five years during which time we would
have expected most of the symptoms to resolve. Perhaps the dose could be
tapered over that time. It sounds to me like one of the things that
would be extremely useful would be a prospective clinical trial actually
representing that group. WHI has done a commendable job but it didn\'t
really emphasize the very early post menopausal women particularly those
who are quite symptomatic. This very early phase of bone loss is also an
issue that\'s been brought up. My question to Wyeth and it would be a
question for sponsors of other products would be \"Do you have any plans
to look at that population specifically\".

DR. CAMARDO: We have plans to continue to evaluate the low dose.  We
don\'t at the current time have plans for a study of the size and
duration of the study we discussed this morning.

DR. BONE: I\'m not exactly sure that it would be required to obtain
quite a bit of useful information about that very specific segment.

DR. CAMARDO: It has been discussed. I don\'t have a specific proposal
that would be ready for discussion by this Committee. I think if advice
goes in that direction then it\'s something that we would work out with
the FDA medical team to actually determine how big and how long it
should be and what kind of methodologic problems we\'d have to face to
do it. I don\'t want to give an answer about anything in particular
because we\'ve really only discussed it in general terms.

DR. BONE: Having taken your point and understanding that, it\'s actually
who we\'re concerned about and that\'s actually the treatment model that
we\'re most focused on.

DR. CAMARDO: Okay.

CHAIRMAN McCLUNG: Other questions or comments? Yes.

DR. ZERBE: I have a question about total mortality. There\'s been a lot
of discussion about the global index and the pros and cons of the
various things that have been included. Total mortality does not appear
to be different. Could you discuss a little bit about strengths and
weaknesses of the use of that as a prominent feature in the evaluation
of the risk/benefit?

DR. ROSSOUW: Let me start and then Garnet can follow up and correct me
if necessary. Two points about total mortality. It\'s an extremely
insensitive index particularly when you\'re dealing with a drug entity
that has a variety of effects, some favorable and some unfavorable. By
its nature, it\'s going to be insensitive. Also in a relatively short
period of just over five years in a healthy population, the chances of
finding a significant effect on total mortality even though disease
incidence may be tending in a certain direction are slimmer.

My main point is that total mortality may be an appropriate thing when
you\'re dealing with a high risk population such as a secondary
cardiovascular prevention study where most of the subsequent deaths are
going to be due to that specific disease. As your treatment is effective
for preventing incidence, it will also prevent mortality. We\'ve seen
that in the statin trials and hypertension trials and so forth. For this
kind of drug in a prevention study with a variety of effects in a
healthy population, total mortality, you\'d have to have a huge sample
size and a very long follow-up to find an effect.

DR. CHLEBOWSKI: Maybe just an example from the breast cancer area where
we have invasive breast cancer. We had 349 cancers which will ultimately
kill 25 percent of the women even with our more effective therapies now,
but that\'s going to take a decade. We have eight deaths now. To come
back and ask that question, we\'ll have to come back ten years from now.
I think that\'s true for many of these other events as well. It\'s a
time related phenomena. It\'s like waiting for all of the events to
occur or doing a censored analysis.

DR. ZERBE: Yes. I guess the only thing I suppose emphasizes that there
really is not even the suggestion. So it isn\'t really an issue totally
of power. There\'s not even a suggestion at this point that there\'s any
increase mortality. Is that correct?

DR. CHLEBOWSKI: (Off microphone.)

CHAIRMAN McCLUNG: Dr. Camardo. Thank you very much.

DR. CAMARDO: Thank you.

CHAIRMAN McCLUNG: We are just ahead of schedule. Are there other
questions that we have for the WHI group? With Dr. Rossouw\'s permission
since we cut that short, I\'m going to make sure we have our queries and
information lined up before we deliberate later on. Yes. Dr. Woolf.

DR. WOOLF: Just a clarification. I recall a slide that has been shown a
couple of times regarding the incidence of fractures versus the number
of women who fracture in relationship to whether they are in the
osteopenic or osteoporoic category. I believe one of the slides
demonstrated that there are a greater number of fractures in the
osteopenic group. I wondered if that holds up for both placebo and
hormone treated women and if there is a discrepancy there, how one might
explain it?

DR. CAULEY: That wasn\'t WHI data.

CHAIRMAN McCLUNG: No, that was from the NORA study so it was not a
treatment study. It was just an observational study, but a number of
studies were shown that as was pointed out the total number of patients
experienced hip fractures for example who have osteoporosis is less than
half of the hip fracture of the population. That\'s because there are a
lot more younger people. So while the absolute risk is higher in the
group of patients with low bone density and osteoporosis, the proportion
of the total fracture burden falls in younger people at lower risk. If
the relative risk reduction with intervention were the same across the
spectrum of risk, then the number needed to treat to prevent fractures
would be a lot greater of course in the osteopenic population than in
the osteoporoic population. That\'s just the way risk is about that.

The other facet about that is that when you look at all fractures the
distribution of the types of fracture also changes substantially with
age. In several epidemiologic studies in women in their 60s, hip
fracture and spine fracture constitute a very small proportion of the
total fractures. In the WHI, only 15 percent of the total fractures in
either of the groups were constituted by clinical spine fracture or hip
fracture. So 85 percent of fractures were other fractures which to many
of us at least my personal view probably have less clinical import than
do hip fracture and spine fracture.

In contrast in women in their 80s, the majority of fractures that occur
are hip fracture and spine fracture. So not only does the risk of
fracture increase with age but the distribution of the types of
fractures and the severity of the types of fractures increases with age
as well. That\'s often not factored in or expressed in the sorts of data
that we see.

DR. ROSEN: Mike, can I clarify something?

CHAIRMAN McCLUNG: Yes.

DR. ROSEN: The point is that there are many more people who are
osteopenic than osteoporoic. So the number of fractures on the Y axis is
going to be greater. That\'s just when you refer to number of fractures
versus absolute risk. That\'s the difference. I do want to point out.
Jane had a slide that she took out but the number needed to treat ?-
Maybe you can talk about it, Jane, the number needed to treat because
estrogen does work across prevention populations. It is important to
emphasize that point from your data.

DR. CAULEY: The slide that Cliff is referring to is I just calculated
the number needed to treat (\"NNT\") in WHI for clinical vertebral
fractures and compared it to the numbers that were in the Osteoporosis
Research Advisory Group (\"ORAG\") report. Now the problem with doing
that is that other report included morphometric vertebral fractures and
we only had clinical vertebral fractures. And the populations varied
markedly. They define low risk in that report as BMD. They had BMD
measurements on all the women. So it\'s difficult to compare numbers
needed to treat across the different agents and across the different
trials.

But it did show that in this calculation about 800 women would be needed
to be treated for two years to prevent one clinical vertebral fracture
in the WHI population. I say that with some limitations, no inherent and
calculating NNTs and in the fact that we were limited to clinical
vertebral fractures.

CHAIRMAN McCLUNG: That\'s a good point. Let me just come back and
emphasize for the sake of what our subsequent discussion will be that
NNT is not an index of therapeutical efficacy because it\'s driven
almost entirely by the risk in the population rather than by the
effectiveness of the drug. So the WHI as a very low risk population
would be expected to have a high NNT as opposed to lots of other trials
where patients are specifically recruited and enrolled in the study.
From a cost effectiveness standpoint, that mostly reflects the
population being treated rather than the therapy being considered.

DR. ROSEN: Actually I was going to make the point that if you look at
the NNTs in the ORAG trial they are up over 2,000 for the
bisphosphonates and only 800 for estrogen. So in a low risk group of
people, actually estrogen looks like it does very well. I think it\'s
just consistent with the data and again thinking about the caveats that
we talked about already in terms of different populations.

DR. ROSSOUW: If there\'s a minute, I can\'t refrain from picking up on a
discussion that panel members had earlier and stimulated Dr. Camardo\'s
presentation which essentially says that practitioners are back to
making individual judgments based on what they think the risk profile is
of the patient. We did this trial in this population to get some real
evidence to help physicians make that judgment in an older population on
average. I think those are very useful and you\'ve seen how practice has
changed as a result of that new evidence base.

It seems to me that if we now focus in on the younger patient who is
symptomatic to fall back and say \"We don\'t really have good data in
that group and we\'re still back to seat-of-pants clinical judgment\" is
a an unsatisfactory situation. Now the data that we have in WHI is
actually the best data available at this point even for that population.
It is the best data.

Now for osteoporosis our data are perfectly consistent with smaller
studies. That\'s not the issue. The issue is the non-osteoporoic
outcomes, the cardiovascular and the cancer outcomes. Just to throw it
back on the clinician and say \"We don\'t have good data on that so make
your own judgment\" seems unsatisfactory.

Now it does seem to me that where it\'s going now with most bodies and
why the self recommending shortest period of the lowest possible base is
a perfectly sensitive clinical thing to do. As I say, it makes a lot of
sense, but can we be sure that the adverse effects are in fact less? Now
they probably are less just by virtue of the fact that this is a younger
population and a healthy population so one could make a very valid
argument that the absolute risks are low.

So even if there is a E + P associated effect, the benefit for symptom
relief and osteoporosis prevention you can assume that the benefits can
outweigh the risks. As we\'ve learned, assumptions are tricky things. So
when people say, \"We really need a large clinical trial to address this
specifically\" I must say I personally resonate to that which is not
volunteering NIH to do the trial of course.

CHAIRMAN McCLUNG: All right. Before we take our break, the final formal
presentation will be the FDA review of the WHI data and comments and Dr.
Stadel will lead that discussion.

DR. STADEL: As a clarification, my comments as a reviewer as a large of
my job here has been to work with Dr. Rossouw in communications about
the NHLBI WHI presentation here. I\'ve been intensively enrolled in
reviewing selected parts of the data. My comments now are really though
intended in a little broader sense. I just reflect for a moment on the
purpose of the trial which was to test the notion that there was
widespread cardio-protection. It was designed to do that and did that.
The purpose of this meeting is the implications with regard to the
osteoporosis indication for the drugs. Those two are related but they
are not identical.

So in going to that focus, let\'s look for a moment just as a reminder
at what is currently approved by combination estrogen/progestin drug
products. I merely put this up to emphasize that one drug product dose
was chosen for study. I don\'t disagree with that. I just want to
emphasize that the class labeling and then the considerations of future
testing apply to a diverse array of doses and formulations including
both the medroxyprogesterone and 19-nortestosterones in the various
doses of estrogen in the combination products and also in the estrogen
only products, the additional consideration of transdermal versus oral
administration for which there are various bits of evidence suggesting
that there might be some differences. One of the questions to the
Committee is their deliberations about what kinds of things should be
emphasized in the development and testing of new products. I\'ll raise
that as a global comment.

Before going ahead, the next slide I\'d like to show is just the drama
essentially of the historical event. This shows total prescriptions per
year for Prempro 2.5 and 5.0. I combined them. It\'s mostly 2.5. For the
Prempro low dose and for Premphase also and for the newer formulations
also. Now as you can see, you have this enormous increase from 1995 on
the graph and then in 1998, you have the publication of the first major
paper from the HERS trial. That\'s where I think you begin to see the
cresting of the wave.

The acceleration slows down, tops off and then in July 3, 2000 you have
the second paper from the HERS, the long term outcome paper and then on
the 17^th^, the first paper from the WHI. So you can see on the national
picture the very widespread of use of this medication. Dr. Rossouw had
referred to the diverse practitioners who were prescribing at the time.
In one area, we have been dealing with a public health issue having to
do with the widespread use of the drug in an effort to prevent
cardiovascular disease. I think the trial myself accomplished its goal
in that regard and I think the prescribing data indicate an appropriate
response on the part of the medical profession to learning that the
observation data were not sustained in a large randomized trial.

I\'d like to now comment briefly on the breast cancer data because I\'ve
been very involved in discussing this with the investigators. This is a
very simple rendition of what was presented in a far more elegant and
far more statistically rigorous fashion by Dr. Anderson. I put it up
this way for a particular reason and that is to emphasize my view that
absolute differences are the appropriate way to communicate risk in the
clinical application.

That relative risk especially when presented as percentages can easily
be misunderstood by people who do not work with them on a regular basis.
A change from 2:10 to 1:10 and a change from 2:1000 to 1:1000 have the
same relative change but a vastly different meaning. That\'s a simple
statement but it\'s one that I recurrently see a problem with in looking
at editorials and the popular and the lay press information on this
topic. I wanted to take this opportunity to stress it.

In the women who had prior use, the top group here there was an over the
trial of 1.22 percent difference in breast cancer. I\'ve done a very
simple approach to the statistics. I thought that Dr. Anderson\'s
modeling that used observational techniques was appropriate to a safety
outcome where there are unexpected things and one has to retrofit. That
did show some rigor in there being a difference between the two groups.
I think the difference is fairly apparent that in the large number of
women in this trial about 74 percent of the patient population. The
duration of exposure only on trial the net was two percent and not very
impressive as a statistical finding.

Now this doesn\'t contravene that they\'re of the notion that it\'s long
term use that matters. The prior use contributes. And it contributes
something that we don\'t fully understand. Notice that the group with
the lowest rate was the group that had the prior stimulus and then went
on placebo. One interpretation is that the prior stimulus had stimulated
cancer in susceptibles and then the remaining group when they went on
placebo were at fairly low risk. That\'s a possibility. There are other
possibilities.

The highest risk is in women who had prior use and continued on use.
That is entirely consistent with the notion that very long term use of
estrogen/progestin produces an increase in breast cancer. There\'s no
disagreement with that.

However I think it\'s important to note that in the women with no prior
use the rates are in the middle. So there\'s a message to a very large
number of women in the country who only use this product after it was
approved by the FDA and whose use would have fallen largely within the
duration of use accompanied before the trial was stopped. I thought it
was stopped at the appropriate time in that regard. There\'s a message
to those individuals that if they have incurred an increase in breast
cancer risk it is not a very large one and it is not a very clear one.

The next very important issue that comes to mind is what happens when
women stop. This is of great practical importance to women who were
taking the drug who may have revised their feelings about benefit/risk.
What happens when they stop? Now this is a slide from the Million Women
Study that was referred to earlier.  This is not a trial. It is an
observational study. I think it\'s a good observational study.

The graph here is one which shows the risk in the top for never users as
one and for past users by duration of use there is no increase of risk
except for one little blimp at five to nine years. Current users of
estrogen only there is a slight increase in risk in these data and a
much more pronounced increase with the combination. So in that regard,
it\'s quite consistent with the experience of the trial.

DR. SCHADE: Excuse me. Could you use a pointer because I can\'t read the
slide from here.

DR. STADEL: I\'m sorry. I had a lot of trouble figuring out how to make
this. This is never users. This is past users whose duration was less
than a year. One to four years. Five to nine years. And greater than ten
years. So it\'s pretty flat. This is the same sort of data for women who
used estrogen only. One to four years. And at ten year, there\'s an
increase. It doesn\'t go up much with duration sitting around 1.3ish.
1.2 here. 1.25. I tend to round them off.

Now in contrast for the estrogen/progestin group, it went up from less
than one year of 1.45 up to over 2.0 when you go up to five to nine and
greater than ten sitting out here in these data. Then of unknown HRT, I
don\'t think is entirely relevant to this discussion.

So my main reason for showing this is twofold.

1\. The current use findings are consistent with what\'s been reported
from the randomized data.

2\. The past use data are quite flat by duration of use.

I would like to also show the next slide which is from the same study.
This is never users. This is all current users. This is all past users
of less than five years, five to nine years time since last user. Less
than five years since last use, 1.04. Within this if you look at less
than one year since last year, the relevant risk is 1.15 and it\'s
statistically significant reported in the text. Again I think these
findings are consistent with what we\'re seeing. It provides some hope
for the notion that when the stimulus is renewed the increase in risk
stops. That we need very much to see more follow-up of the WHI trial
data, but that\'s the best interpretation I can give at the present
time.

Also when this was looked at separately for past use of estrogen only
and past use of estrogen/progestin, there was no increased risk. You
could not isolate that by past use of less than one year duration in the
way they presented the data. So my only reason in raising this is that
the overall results from breast cancer are rather less frightening than
one would get from reading some interpretations that I have seen.

I\'d like to go on now. I only have a couple more comments. One is a
well known element that needs to be considered in this whole issue.
After menopause, there are many papers showing that the major source of
estrogen after menopause androstenedione mostly secreted from the
adrenals and and aromatized to estrone which then equilibrates with
estradiol. It\'s in adipose tissue. I think most people believe it\'s in
the stromal cells where aromatized enzymes are located.

It is widely believed in many papers that this accounts for the positive
association between post menopausal breast cancer and obesity. Why is
this important? It\'s because the amount of estrogen that women make
after menopause depends on their amount of adipose tissue and the
functionality of their aromatizing enzymes. So if you give a specific
dose of estrogen to someone who has estrogen, you could expect
clinically that you might get a different response than if you give that
same dose of an estrogen to someone who doesn\'t have estrogen.

Now I\'m going to go to my last view here and this is something I very
much hope that I\'ll hear opinion from members of this Committee from
your endocrine backgrounds and others. These are just two references
that I pulled out that relate to this issue. In particular, Cummings, et
al. using the osteoporoic cohort study did an investigation in what\'s
called a case cohort analysis, a technique that\'s not terribly
important here. But what they said basically was points straightforward.
They measured serum estradiol levels and the really high risk of
fracture was in people who had virtually undetectable levels.

So I\'d ask a question here. We\'re talking about \"What should be done
to develop new products\". Should this include an effort to more highly
define the indication for treatment with hormones. There are various
reasons bone density may be low. One of them certainly is low estrogen
but should we be working people up with hormone measures at baseline at
least initially in more studies and potentially clinically?

The converse of course since this is a well existed literature and I\'ve
just cited one article which is compatible with the notion that the
increase in breast cancer after menopause is very related to the
increased BMI and there\'s a large literature relating this to the
increased production of endogenous estrogen. So then one would say that
giving more estrogen to someone who already has enough might not be a
wise idea. Those are really my only contributions I hope to this
meeting.

I will make a very brief comment about the WHIMS study, only to mention
that there is some indication that endogenous estradiol estrogen in
women is related to the risk of vascular dementia. Cerebrovascular
changes are recognized as contributing to Alzheimer\'s Disease (\"AD\").
This is discussed by Dr. Schumaker in the WHIMS paper and also by Dr.
Katz who might comment if needed on the specific review of the WHIMS
trial by the FDA. Lastly in an autopsy study, it was found that vascular
changes in the absence of AD were present in patients with histories of
dementia.

I put this together to say that vascular disease may be contributing
more here than immediately apparent. That\'s important because if we
tailor the doses of estrogen and the doses and types of progestin,
we\'ll more likely be able to control any contribution of exogenous
treatment to vascular disease than to other types of dementia. Thank
you.

CHAIRMAN McCLUNG: All right. Thank you. Questions or comments or
clarifications for Dr. Stadel from us? If not, let me suggest that we
take a 15 minute break and to be back at 3:05 p.m. We will embark upon
our deliberation among ourselves. Thank you. Off the record.

(Whereupon, the foregoing matter went off the record at 2:50 p.m. and
went back on the record at 3:10 p.m.)

CHAIRMAN McCLUNG: On the record. So we have completed the formal
presentations by those who were invited or who asked to be a part of the
presentation. The remainder of the meeting will be focused on a
discussion among the Committee members to share ideas with each other
and to address some of the specific issues that were posed to us by the
FDA.

We\'re happy to have the audience stay but there won\'t be the
opportunity for audience members to make comments or presentations
unless we, the Committee, have some specific issues of clarification
from either the WHI group or the group from Wyeth. To start this
session, let me invite Dr. Orloff to make comments again and to provide
us our charge.

DR. ORLOFF: First of all, I see that most of the WHI team has departed.
I want to thank the doctors who are staying and make sure that you all
thank the rest of the group for their input. I guess I should also
comment that never let it be said that we \"slow-pitch\" our advisory
committee. This is an extremely complex issue. Also let it never be said
that the FDA\'s job is an easy one. And with that, charge. No.

This has truly been a fascinating day and a unique one in bringing
together the group of investigators of a landmark trial and obviously an
extremely important and high profile public health area to present
face-to-face the results, up-to-the minute and on-going plans for their
study to our Advisory Committee and to have interested public as well as
the particular interested pharmaceutical sponsor, the most interested
perhaps be here to comment as well.

We have really two central issues that we\'d like to hear more comment
on. The first one relates to essentially your satisfaction, your
consideration of the accuracy and appropriateness and completeness of
the labeling changes that have been made to the labeling for this class
of drugs after the WHI. By and large, the discussions on both sides up
to this point, by the WHI group and by Wyeth, pretty much inform
directly your discussion on that issue. So we really need some more
direct input. That might go fairly quickly I would anticipate.

The other one is a much more complicated issue. That has to do with the
true intent of the meeting which is the implications of the WHI and its
results for the future vis \_ vis this class of drugs particularly
related to the clinical development of these drugs for use in post
menopausal women. What we\'re asking for is some comments on everything
from endpoints to inclusion criteria to duration of trials to size of
trials to whatever else you may want to speculate on. I\'ll leave it at
that. Thank you.

CHAIRMAN McCLUNG: Thank you. And I propose that we deal with those in
order. So let me ask the Committee to share with me your thoughts and
comments about the first issue which was your feelings about the
revisions and the current prescribing information for Prempro that\'s
been provided to us and has been presented today. Are there specific
comments to make about that?

DR. SCHAMBELAN: I could continue the baseball metaphor. Unfortunately
the people in the San Francisco Bay area got used to fast pitch baseball
the last weekend and so I guess I don\'t have to watch much more
television for the next couple of weeks.

The question I had about the prescribing information really focuses on a
point that was raised just before our break and actually directed to
folks at Wyeth about the subtlety of the language in point three under
indications and usage about the careful consideration of non-estrogen
medications versus a requirement that another medication be tried. I\'m
not sure that I have a specific recommendation to make, but it seems to
me of all the recommendations I\'ve seen here that\'s the one that
strikes me where we need the greatest amount of thought.

I come from the land of Grady and Cummings and Holly and Black and this
has been discussed obviously since the HERS and WHI trials have come
out. The focus of these individuals has been to recommend other
therapies before and this is in an asymptomatic patient we\'re talking
about now which would be presumably point number three for the
prevention of post menopausal osteoporosis. From my point of view in
terms of recommendations, that\'s where this discussion could best go.

CHAIRMAN McCLUNG: Dr. Bone.

DR. BONE: Thank you. We certainly want to commend the investigators for
managing an enormous amount of information. Their forthright recognition
that the osteoporosis related questions were fairly far down the list in
the considerations of the study design. We have to recognize the
challenges to the FDA in calculating things like risk/benefit balance
from a regulatory standpoint when we are dealing with information that
wouldn\'t really be considered - I don\'t mean this with any disrespect
at all for the work that was done - an adequate and well controlled
trial for the indication, prevention or treatment of osteoporosis.

The patients weren\'t selected on the basis of their risk for those
conditions. The endpoints that were measured were fracture but we don\'t
have comprehensive bone density data. We don\'t have turnover markers.
We don\'t have a lot of the information that we would want to use to
relate the risks and benefits. We have a risk scale which appears to
give a relatively shallow gradient between the highest and lowest
tertile. But with that gradient, it looks as though most of the
disadvantage to being treated is abolished in patients who have somewhat
higher risk of developing an osteoporoic fracture.

I actually think that the Agency has done a good job of incorporating
this information and the company into the current labeling. It\'s going
to be difficult to improve on this very much without having the kind of
more precise estimates of effectiveness for one thing that we would
drive in a purpose-built trial. We\'re getting to the point where we\'re
pushing it pretty hard to try to see more than has been said with some
possibility of some nuances.

The suggestion that a twofold increase in the risk of fracture is
somewhere near the breakeven point which is tantalizing as something
that might be incorporated into labeling but I think it\'s pretty soft.
I\'m not sure that I could make that recommendation. I really think that
when we start looking at the limitations of the way in which this
enormous undertaking specifically addresses the questions that we\'re
dealing with, I\'m not sure we can add a great deal.

CHAIRMAN McCLUNG: Other comments? Dr. Follman.

DR. FOLLMAN: Yes, I have a question about the labeling. It\'s more my
ignorance of this area. But there\'s this one phrase \"should be
prescribed at the lowest effective dose for the shortest possible period
to achieve treatment goals.\" I wondered what \"achieving treatment
goals\" means for osteoporosis. Does it mean that you have a target-free
BMD and you try and achieve that target and so it sounds like the
therapy could go on forever. I don\'t know what are the treatment goals
for using this for osteoporosis. I think if I understood that better
I\'d have a better handle on what the duration might be and other
points.

DR. ROSEN: Mike, can I comment?

CHAIRMAN McCLUNG: Sure.

DR. ROSEN: Yes, I think that\'s the problem in clinical practice. I
think we don\'t have good endpoints. We use bone density as a surrogate
marker but I\'m not so sure that it\'s the endpoint that we should be
looking at. We have women that fracture on estrogen whose bone density
goes up. That clearly can be misleading and that\'s a big part of the
problem.

When we\'re talking about the indication labeling here particularly for
prevention which has to be highlighted not treatment of osteoporosis
where we have endpoints such as fracture, we\'re in a real gray zone in
terms of what prevention outcomes should be. Should it just be bone
density? Well, 40 percent of women taking calcium and vitamin D will
maintain their BMD two or three years after menopause. This is a real
gray area that we haven\'t established in our \"osteopenic population\"
and that\'s what makes it very difficult for you as well as for us who
are dealing with it on a regular basis.

DR. BONE: Could I just respond to that?

CHAIRMAN McCLUNG: Yes, Dr. Bone.

DR. BONE: One of the things here is when we\'re talking about prevention
\"Do we mean stabilization of osteopenia or do we just mean prevention
of any loss whatsoever?\"  We could argue that a person whose T-scores
averaged plus one who took a drug and didn\'t drop over the next 20
years had prevention of osteoporosis. And she might have, but another
way to look at this is to identify a patient with increased risk of
developing osteoporosis and then modify that risk in some measurable
way. Maybe that\'s something that we should be clarifying.

I don\'t think that\'s something that is a response of the Agency in the
labeling of this particular medication in response to this particular
set of information but as a general approach that bears on the next
question of going forward. How we understand ourselves to be preventing
osteoporosis or preventing post menopausal bone loss and how those two
slightly different objectives interrelate is going to have tremendous
implication especially for issue like risk/benefit analysis.

CHAIRMAN McCLUNG: My personal view about the labeling and indications is
that of Dr. Bone. It\'s truly hard to get better than we are. The issue
of what the endpoint is for prevention is well taken. While we know that
bone density is a very powerful predictor of fracture risk in untreated
patients, the relationship between the magnitude of the change in bone
density in response to any therapeutic intervention and the reduction of
fracture risk is less well defined. So it is a hypothetical model in our
head as we imagine that if we preserve bone mass and prevent the loss of
bone architecture and the deterioration of bone quality that it would
make things be better. But those aren\'t measurable endpoints or
outcomes.

The issue about what to do with non-estrogen medications and whether
they should be used first or recommended first is more difficult in my
view for two reasons. One is the WHI has given us this huge set of
information with a very large clinical trial of 16,000 women followed
for five years. So we have 80,000 patient years to deal with. No other
osteoporosis alternative, non-estrogen alternative, be it a SERM or
bisphosphonates has that kind of information. While we are more
confident about the risks associated with longer term estrogen use, I
personally am less confident about the risk profile of long term use of
these other agents too. So we\'re not quite comparing apples and apples
in that regard.

Lastly if we require that somebody be treated with another drug first
and then fail, the definition of failure of therapy is an unknown issue
too. Having a fracture on bisphosphonate therapy or raloxifene therapy
or estrogen therapy isn\'t evidence of treatment failure because the
drugs don\'t cure osteoporosis. They just reduce risk. The absence of
fracture doesn\'t mean that the drugs are effective so we don\'t have a
way to decide whether a patient has failed on therapy or not which would
make it even more confusing from a clinical standpoint.

So from an indication standpoint, my personal view is that the changes
that have been made of clarifying that the use of Prempro is for the
prevention of osteoporosis, not for the treatment of osteoporosis was
helpful. That it was recommended only for women at significant risk.
Trying to define that risk more specifically in the context of a label
is really difficult and that\'s not been imposed upon any other therapy
for osteoporosis. That the reminder that there are alternatives now for
the prevention of bone loss is included in the statement already.
That\'s made great progress with the changes that have been made this
past year. Dr. Bone.

DR. BONE: Actually one comment that was made by Dr. Colman I think was
kind of provocative. That was if we were in a better position to assess
the risk/benefit relationship some of the newer data showing a reduction
in hip fracture would actually support even a specific treatment
indication.

But the problem as pointed out by a number of the WHI group is that we
don\'t have the analysis at least at the moment to look at things like
the effect on cognition in the same population that\'s at the highest
risk for fracture. So we come back to the point I was making earlier
about trying to go from an all-purpose trial to a very specific kind of
information. This is one of the places where I\'m not sure we can make
that step.

CHAIRMAN McCLUNG: Other comments about the current labeling issue? Dr.
Woolf.

DR. WOOLF: I personally like the wording on the third bullet point.
Clearly physicians need to know what their options are. While clinical
trials are meant to give us population risk, what is the appropriate
treatment for a woman with significant breast family history and
coronary artery disease clearly may be very different than somebody who
has no family history of breast cancer and no family history of coronary
artery disease and who has some vague GI problems. This gives sufficient
information to physicians to take all these individual things into
account and decide what treatment is best for the patient for
osteoporosis.

CHAIRMAN McCLUNG: There are indications for therapy but the indications
are like this. They are indications for diseases and for problems in
general. They don\'t usually define how that diagnosis is made which
gets to the point of trying to attempt to define which patient would be
the candidate for in this case estrogen/progestin therapy. This is not
what\'s usually done in the way we\'re given information as clinicians
about that. Is my assessment correct?

DR. ORLOFF: I think your assessment is correct. You know the hardest
part about labeling a drug is to ?- Put it this way. We can never expect
or even hope to fully direct the practice of medicine via a drug label
nor do we think that it\'s a good thing. As has been stated many times,
the practice of medicine although we like it to be evidence-based and as
Dr. Anderson has said particularly in the area of prevention that has to
be based upon population studies. Nevertheless when we do take care of
patients, it\'s one-on-one.

That said, the purpose of the label is to convey throughout the extent
of the label with a particular focus within the indications and usage
section that information on expected benefits and risks within the
context of use in the proposed target population.  We wind up hedging a
lot and the way we structure these indications fall short for example of
using the term \"second line therapy\" but logic directs that the intent
here is that the only primary indication for this use of this product at
this point is for the treatment of vasomotor symptoms because as has
been stated here I guess here and elsewhere that this is really the only
viable therapy for that aspect of the post menopausal condition in
women. We go on to say then as is clear that if you are treating because
you want to direct an intervention towards the other known expected
benefits of in this case estrogen plus progestin, think about what your
other options are because on balance, we cannot tell you across the
board that you can expect benefits that outweigh risks.

CHAIRMAN McCLUNG: Dr. Schade.

DR. SCHADE: I may be the only one who doesn\'t like this labeling. I\'m
convinced that everybody at this table who sees patients and I see
patients would make the right choice. What bothers me is many physicians
at least at my institution wouldn\'t have the background and knowledge
of this whole trial and hear this type of discussion.

I actually think point number three here where we\'re talking about
prevention of post menopausal osteoporosis doesn\'t really help the
physician enough. In other words, the minimum I would do is to extend
the last sentence where it says \"When prescribing solely for the
prevention of post menopausal osteoporosis, therapy should only be
considered for women at significant risk for osteoporosis and
non-estrogen medications should be carefully considered.\" I would add
something to the nature that \"particularly in patients with a family
history of breast cancer, with cardiovascular disease,\" etc. The things
that we\'re worried about.

I would simply extend that sentence to be more helpful to the general
practitioner who hasn\'t heard a day long discussion of the WHI. I think
that this is not specific or detailed enough to be very helpful.

CHAIRMAN McCLUNG: Dr. Lukert.

DR. LUKERT: But do we really know that the people who are most likely to
have these adverse effects when given estrogen were people with a family
history and the other risk factors? It was my understanding that it
really wasn\'t the case. Maybe it wouldn\'t be accurate to say that we
could limit this to worry about the people who had these particular risk
factors. It seems to me that this insert adequately \-- anyone who reads
it ?- If they don\'t read it, there\'s nothing that we can do about it.
But a physician or patient who reads this - in my experience, the
patients read them rather consistently ? the dangers are going to be
emphasized to them and they are going to understand that this is a drug
with considerable risk as well as benefits. I think it\'s fairly well
balanced in that regard. I\'m not sure that we will be giving them
accurate information if we add those risk factors. I\'m not sure that
increasing their susceptibility is the adverse effect in response to
estrogen although we would expect it to be global.

DR. ORLOFF: I want to make a quick comment if I might of clarification.

CHAIRMAN McCLUNG: Yes.

DR. ORLOFF: Because I do agree with Dr. Lukert. Unfortunately drug
labels are long and they must be read to be understood. That\'s a whole
other discussion. But as I said the label in toto addresses expected
benefits and risks when used in the proposed target population. By and
large, the indications reflect expected benefits. Elsewhere in the label
you see the risks and indeed in the sections directly following
indications, there are contraindications which are the strongest
recommendations against the use of the drug for safety reasons. Then
those are followed by warnings and by precautions.

Based upon the results of the WHI, the warnings and precautions sections
of this label have been changed to add additional information about the
overall risks of the product. And those risks need to be taken into
account when you\'re sitting across or at the bedside of the individual
patient and making the consideration about on the one hand whether their
risk for osteoporosis which isn\'t something you read from this label,
but whether they\'re at risk for any of the known potential adverse
effects of this drug that your gestalt would alter your impression of
the overall balance of risk and benefit.

CHAIRMAN McCLUNG: Mr. Follman.

DR. FOLLMAN: I\'d like to talk about the table on page 18 of the insert
which goes into the relative and absolute risks for the various events
comprising global index. I actually like this with displaying the data.
I thought it laid it out in a lot of its complexity. It showed the pros
and cons. The relative risk numbers are useful to the population and
would be appropriate here in that we usually in clinical trials think
the relative risk for the entire study is appropriate for all subgroups.
That feeling has been justified by all the analyses that were done today
where we show that the relative risk for the most part if not entirely
were consistent across the wide variety of subgroups.

When you talk about absolute risk though, the story is a little
different. The absolute risks in this table are for the entire WHI
cohort. If we\'re thinking of osteoporosis specifically, I\'m imagining
this is going to be prescribed for women who are at high risk for hip
fracture. If that\'s the case, then these absolute risks given in this
table probably are too low and don\'t quite fully reflect the benefit
you might get from hormone replacement therapy.

I did a little rough calculation based on Dr. Cauley\'s article where
she looked at the risk of hip fracture as a function of this risk score.
She showed that overall the relative risk was similar but there\'s a
huge gradient in the risk of hip fracture as a function of this risk
score. At the highest tertile, instead of expecting hip fractures in the
placebo group for 10,000 person years, it would be more like 65 and for
the estrogen replacement therapy, it would be more like 45 instead of
10. So instead of a difference of five, it would be something more like
20. This isn\'t actually an exactly correct number because I couldn\'t
do the exact calculation based on the information in the JAMA article.

But the larger point is whether we should give more specific information
regarding absolute risks in aiding the decision. We\'re trading off risk
and benefit here. We\'re thinking about absolute risk for each
individual decision and more precise estimates and more tailored to the
individual would be helpful.

CHAIRMAN McCLUNG: My comment about that is that there are ways that
people can find out what absolute risk is. There are a variety of
studies that had helped us to do and there\'s a move afoot among the
osteoporosis and bone density community to move away from expressing
bone density values in terms of T-scores and absolute values, but rather
to express them in terms of absolute risk that incorporates at least
three important dimensions, BMD, age and previous fractures. So
determining the absolute risk in an individual is an important clinical
objective. It\'s hard to figure out how to do that in the context in my
view of a specific label that is for one particular drug. That needs to
be a part of the educational process that we collectively engage in to
deal with improving the understanding of osteoporosis, its risk and
circumstances across the entire population. Dr. Bone.

DR. BONE: Just further to Dr. McClung and Dr. Follman\'s comments. If we
were truly going to try to identify a group at what for those of us who
make a large part of our effort in osteoporosis area we consider high
risk, first of all, the risk gradient would be a lot higher than even
you\'re describing. Secondly, we\'d be talking about an indication for
the treatment of osteoporosis which is not part of the label. We go
around in a circle there because once we start talking about people with
a higher risk of hip fracture, we\'re talking about a disease for which
the drug isn\'t actually approved at the moment. I\'m not disagreeing
with you. I\'m just saying it takes us to a strange place.

CHAIRMAN McCLUNG: Let me attempt to summarize then what I sense is a
prevailing comment. Let me see if I can do this in the right way. The
current label for the combination estrogen/progestin that was studied in
the WHI has been upgraded and changed substantially in two separate
steps, first on the basis of results from the HERS trial and then more
recently with the results from the WHI data.

The changes that have been made accurately reflect the information that
was provided to the academic community from those two trials and has put
the use of the medication for the prevention of bone loss and
osteoporosis in a different perspective than existed before. Changes
that have been made have been very useful and positive. Collectively, we
can\'t think of a better way to express the information than is stated
in the third indication that specifically focuses on the use of Prempro
for the prevention of osteoporosis.

We all recognize that none of this is perfect and this requires
understanding in the background that\'s in the rest of the package
insert that has to do specifically with the contraindications and the
other risks that have been described and that are outlined in subsequent
paragraphs. I personally think that it\'s not possible to incorporate
all of that information into a succinct paragraph under the indication
and usage circumstance.

With that, let me propose that we move on to the second issue which let
me restate it. We\'re asked to discuss the implications of the WHI trial
results for the future development, testing and potential approval of
estrogen plus progestin drugs products for the prevention and/or
treatment of post menopausal osteoporosis. We will expand the discussion
beyond what we\'ve worked on. Who would like to open that discussion?

DR. FOLLMAN: I guess one thing that was talked about consistent with the
labeling is lower dose, shorter duration. I can see that there will be
movement towards doing studies like that where you have low dose and
you\'ll look at probably a surrogate endpoint bone mineral density say
and see whether that differs from placebo or not.

I worry a little bit about that. This is consistent with a point that I
made earlier that you could show that there\'s a difference at a very
low dose between placebo and the treatment in terms of bone mineral
density but it might not be efficacious in terms of clinical endpoints
preventing fractures of different types. If you are doing such studies
you should probably be mindful of that and want to have a lowest dose
that still gives you what you guess is a clinically meaningful benefit.
By \"guess\" I guess I mean that you would use observational data
correlating BMD with the probability of fracture and have some comfort
that the difference in BMD would translate into a clinical benefit. I\'m
just wary of going as low as you can.

CHAIRMAN McCLUNG: Dr. Lukert.

DR. LUKERT: I think that if you could have done whatever you thought
would be most helpful it would be to look at transdermal estrogens as
opposed to oral because of the effects of the first pass through the
liver, of the effects on coagulation factors and upon the precursors of
angiotensin. Those all have such vascular implications plus the effect
on growth factors produced by the liver and the potential implications
on those. One of our areas of investigation should be other forms of
delivery.

As far as the implications are concerned, I\'m just delighted when I see
a patient come in with such profound vasomotor systems that she has to
be treated with estrogen. I know that at the same time that this will
give us some time to improve her bone metabolism while we\'re waiting
for her get over her vasomotor symptoms. Otherwise, we\'re ethically on
sort of shaky ground given the data we have with evidence based medicine
to use estrogen as a primary form of treatment or prevention of
osteoporosis.

CHAIRMAN McCLUNG: Dr. Woolf.

DR. WOOLF: I think if we learn anything from HERS and WHI it\'s that we
need hard endpoints and not surrogate endpoints. Any future estrogen
trial have hard endpoints, fracture data, current and adverse events and
we can\'t use surrogate endpoints because they led us astray for God
knows how long. They\'ll make these trials very long and make them
complex and make them expensive. But I don\'t see any alterative.

DR. BONE: Can I just respond to one point?

CHAIRMAN McCLUNG: Sure. Dr. Bone.

DR. BONE: I think if we look at the indication treatment of osteoporosis
that\'s one point. But if we\'re talking about prevention of
osteoporosis, we\'re talking about starting with a patient population at
a very low risk of having a fracture in which we hope to see that the
risk does not increase. It becomes a prohibitive problem to try to see a
difference in fracture rate in the prevention indication. That\'s the
subject of a lot of discussion and writing as you know. It\'s the reason
why the endpoints are what they are in the current guidance as to use of
bone density to show prevention of post menopausal bone loss. The
distinction there is between treatment of osteoporosis and prevention of
post menopausal bone loss.

CHAIRMAN McCLUNG: Dr. Woolf, you\'re going to respond to that.

DR. WOOLF: I agree but these other endpoints are going to take some time
and the adverse events. Typically the prevention trials have been two to
three years and these other things are going to five or six years to
develop which may give you enough time for those factors. The WHI also
showed us that these are very potent drugs to prevent fractures. The
question is can we leverage in future years to come up with a dose of
estrogen and delivery system for estrogen that gives us the bone
benefits without the cardiovascular and CNS detriments. The only way to
do that is time and obviously enough patients, but some of the
bisphosphonate trials were three or four thousand patients so they are
getting up there.

CHAIRMAN McCLUNG: Nine thousand patients.

DR. WOOLF: Even better.

CHAIRMAN McCLUNG: Right.

DR. CARPENTER: I can only echo the comments made by Barbara and others
to pursue for future investigation both dose and delivery mechanisms. I
think weighing risk and benefit in the lower doses is clearly an
important strategy and one that in fact with the data coming in through
post marketing would be highly encouraged to aggressively collect
already at this point in time. I also would being in the role of a
pediatrician having to use many drugs off-label and look at other
situations in which these medications are used perhaps on but also
off-label and that is the life-long effects of using these medications
in women with premature ovarian failure for various reasons and that
data is a smaller set but clearly everyone is applying data from studies
such as WHI and others that we\'ve heard about today extrapolating it to
long term use. I think we really don\'t have that data. It\'s an
important area to pursue.

CHAIRMAN McCLUNG: Dr. Rosen.

DR. ROSEN: Thank you. One of the areas that I feel uncomfortable about
in practice and also in research is predicting who is going to go on to
sustain rapid bone loss. This is an area although we use bone density as
a marker, we don\'t have the large scale trials to actually tell us what
the predictive factors are. So if you knew a woman who walked in at 50
with a T-score of -1 was not likely to lose a lot of bone versus
somebody who walked in and they only had a five percent bone loss as
Claus has shown that some subpopulations do have those rapid rates of
bone loss, those are clearly individuals that might be targeted for
short-term, low dose therapy.

The truth of the matter is the markers have not done a very good job
certainly not in practice of predicting that. We\'re getting to an era
now where it\'s open for the NIH and other non-commercial entities to
consider supporting this kind of investigation looking at proteomics,
trying to predict through protein markers what are the factors in post
menopausal women that might potentially predict their subsequent rate of
loss or fracture as well as genetic studies which are just starting to
do in WHI.

This is an area of investigation that we still don\'t have a real good
handle on and I\'m afraid in clinical practice we have a very poor
handle on it. We use bone density, T-scores of -1, but how that
translates into those people five years down the road still is
problematic. That\'s an area that we really would need tied to possibly
to a prevention trial with our surrogate markers. It\'s going to be
impossible to do a fracture study with young post menopausal women
because their absolute risk of fracture is so low. But we could use
another type of trial to pick up risks of rapid bone loss certainly that
is a surrogate for some aspects of changes in bone quality.

CHAIRMAN McCLUNG: Right. Just to comment, there are some data about
that. In the EPI trial for example with the large population, the only
two things that we\'ve been able to demonstrate predicated rates of bone
loss were body size and how close they were to menopause. The
distribution of the rates of loss was actually amazingly tight. There
weren\'t a big subset of fast losers and other who didn\'t lose at all.
It was tightly grouped about that.

Of course, that applies not just to this drug but to any choice of
therapeutic intervention for prevention. So defining who the person is
to initiate pharmacologic intervention is a general question that the
clinical community is still grappling with and which individual would be
candidate for estrogen as opposed to an alternative is a subquestion
under that big umbrella.

DR. ROSEN: Sorry, Mike. I just wanted to add that part of the problem
may be that we don\'t have the right markers yet to predict that.
That\'s an area of active investigation that we should consider. There
are a couple of different new markers coming out or need to be explored
and those are the kind of investigations we need to take up.

CHAIRMAN McCLUNG: Sure. Dr. Bone.

DR. BONE: One of the things that we normally do as endocrinologists is
try to achieve very consistent and precise control of the level of
whatever hormone it is that we\'re administering. I\'m not sure we\'ve
done as much about that in this area as we could have. Dr. Lukert\'s,
Dr. Rosen\'s and Dr. Stadel\'s comments all make the point that first of
all some of the earlier studies that were done looking at the serum
estradiol levels required to stabilize bone mass might be revisited with
more sensitive testing to see if much of the benefit could be achieved
at somewhat lower serum estradiol levels.

Selby\'s paper looked like something like 45 picograms per mL or
something seemed to be effective in just about everyone. There may be
some individual interactions that could be in part genetically
determined on that basis. Maybe there\'s a group that requires a lower
dose where 14 picograms per mL of estradiol is just fine depending on
what the SHBG is or something.

But this is what endocrinologists do. This is more challenging in the
case of CEE because this is a mixture of the ingredients each of which
is going to be metabolized differently. I don\'t think I can add
anything to the discussion that Dr. Woodcock gave last year at the NIH
meeting on it where she discussed this whole topic fairly thoroughly,
but the point being that it\'s more complicated with CEE. If we were
talking about serum estradiol or could pick out what it is and we really
had to be concerned with and then could thread the therapeutic needle so
to speak, we might find ourselves able to be on the right place on dose
response curve for a desirable effect with getting too far up the
adverse effect curve.

I suspect that the dose response curve is somewhat plateau-shaped as is
usually the case. And that is as often the case, the adverse event curve
may not be. We may find that really understanding the endocrinology of
post menopausal women better and what our targets are that we should be
trying to achieve in order to mitigate this rate of loss could really
put us into a more elegant, more endocrinologic approach to solving some
of these problems.

CHAIRMAN McCLUNG: Other comments? Let me add a couple of my own. The
question of what these implications are for the development of other
estrogen/progestin products for osteoporosis management, both prevention
and treatment, really is broken down into at least three discrete
categories. We met a year ago to review the guidelines again about the
prevention and treatment indications in the guidance and the types of
trials, the types of endpoints that were there.

Those guidance points have served us I think extremely well for the last
ten years or so. The distinction of preventing bone loss in low risk
populations with bone density as the primary endpoint still makes good
sense until we\'ve had some other better determinant of bone strength
and bone architecture and bone quality. As we develop new imaging
studies and new techniques, we may move away from simple bone density to
the more sophisticated endpoints. To require fracture as an endpoint in
studies where the idea is simply to prevent and stabilize the skeleton
will be beyond the scope of what anyone can do.

For the treatment indication, we all agree that surrogate endpoints
aren\'t sufficient and that documenting fracture risk is necessary to do
that. Those are already embodied and codified in the current guidelines.
Whether we are talking about estrogen/progestin drugs, estrogen only
drugs, different routes of administration, different doses,
non-estrogens, all those still fall under that same rubric.

The major issue or another issue though that makes estrogens be unique
is their risk profile and dealing with evaluating whether different
doses, different preparations, different routes of administration have
differences in risks is a different both investigative and certainly a
different clinical question to address and may take a great deal longer
time to do. It may not be practical to include in one study particularly
if we\'re talking about prevention indications the efficacy endpoints on
the one hand and the entirety of the safety endpoints that one would
like to see and to demand.

There are already in the current label for this preparation and now
expanded to the other estrogen preparations the concerns and statements
about risks that are extrapolated from the WHI. My thought is that for a
drug to be approved for the prevention of osteoporosis it could still
get there by the same route to be distinguished as being different in
terms of its risk profile could be addressed in a separate question.

For an estrogen or an estrogen/progestin preparation to be assumed to be
in the same category is maybe the most straightforward or the most sound
place to start and require that drugs do the studies to distinguish
themselves from the risks that are embodied in the WHI. That would be a
different type of study that would change the contraindications and/or
the risks but wouldn\'t change the indication.

The third piece of that is that it would be really helpful if we could
work at identifying the right people, the ones at risk and whether it\'s
estradiol levels or whether it\'s biochemical markers or new markers or
whether it\'s some other combination of risk factors. It\'s a project
probably beyond the scope of the FDA or the sponsors of studies that are
submitted to the FDA but is an NIH and/or some other global approach to
things. Dr. Lukert.

DR. LUKERT: I really like the way you sorted out the issues. But I do
wonder. It seems to me that the major question now though about
estrogen/progestin is are there risks. We know that they do work to
protect against bone loss. So I guess the thing I would question is
whether we really need any other new estrogen product if we need to just
assess its effect on bone. It seems to me that even the greater need is
to look at the risks. That would be my only difference.

CHAIRMAN McCLUNG: Yes.

DR. ORLOFF: If I might.

CHAIRMAN McCLUNG: Yes. Dr. Orloff.

DR. ORLOFF: This is a question that can\'t be resolved in the abstract.
Some day the data will have to be produced. What we would probably
conclude from this discussion is that the burden is on the proposer and
on the community involved in this field to produce a weight of evidence
that supports a favorable risk/benefit profile say for example for an
estrogen or estrogen/progestin administered by an alterative route or
for a lower dose of estrogen alone or estrogen plus progestin. That
risk/benefit profile would thereby be distinguished from the dose and
product and route of administration that was studied in the WHI.
There\'s been a lot of speculation today based upon one or another
subgroup analysis of the WHI despite cautions about inferences from
those analyses that there may be reason to believe that the risk/benefit
profile for Prempro for example might be different in one group versus
another for example by age. Those are interesting speculations but I
don\'t think we have any data from this trial to bring to bear on it.

I would say that we spent a lot of time today talking about the global
index in the WHI. I\'m not sure that there was any complete agreement on
what the role of the global index was after the fact. But for a new
product coming along, we would be hard pressed to from the start ask for
essentially the same quality of hard data, to ask for a global index
score, for a new product. We would expect sponsors to propose a data
package that would be perhaps more traditional harkening back to the
usual way in which we evaluate drugs that someone referred to here
earlier which is that we design trials to establish the benefit based
upon our hypothesis and then we look at the safety profile and we make
some judgment as to whether we think it satisfactorily safe given the
benefits. We use our heads on this.

In this particular instance, we would use our heads as Dr. Bone has
suggested that clearly there\'s every reason to believe that as you
reduce the dose the risks associated or at least some of the risks
associated with the use of such a product are also going to be reduced.
So also are the benefits, but we have to understand that the benefits of
such an intervention are monitorable.

We go into this with an assumption that particular for estrogen there is
a graded and continuous relationship albeit not perfect from patient to
patient but there is a graded and continuous relationship between bone
mineral density and fracture risk. It comes from epidemiology. It comes
from intervention. So we believe in BMD and in practice one can monitor
BMD to assess whether an individual patient has responded to the dose,
route of administration and particular molecular species with which she
is being treated.

That\'s by way of saying that ultimately we\'ll know when we know. I
don\'t think that I\'ve heard here a consensus and correct me if I\'m
wrong that we absolutely are looking towards a day when no estrogen or
estrogen/progestin could possibly come to market for the management for
post menopausal bone loss in the absence of a WHI type study.

CHAIRMAN McCLUNG: Comments about that? Dr. Bone.

DR. BONE: Yes. Broadening out a little bit from that comment from Dr.
Orloff and little bit where we are, we are basically faced with class
labeling based on CEE and medroxyprogesterone acetate. We faced with
some uncertainty about the whole issue of generalization that\'s been to
other compounds in these general categories that people have discussed a
lot about, not so much today, but at other times. These variations
include the molecular species, the dose and the route of administration
and so forth as has been mentioned.

What Dr. Orloff\'s comments lead us to is the question of how could a
sponsor proceed or how could even an independent organization proceed to
try to investigate some of these questions and have this reflected in
the labeling of the drug product. It seems to me that it would be
extremely difficult for the division to do away with the class labeling
all together in the absence of a study of at least comparable rigor. It
might not be such a big study because it could be more focused so
that\'s a fair point. But it would have to be a very large, very well
designed study to supercede with some other molecular species for
example what class labeling we seem to be developing.

On the other hand, does this make this hopeless? Could it not be the
case that to the extent that a treatment, a medication or a combination
that was proposed within the overall umbrella of the class labeling
distinguish itself in some meaningful way by well-documented data that
could be incorporated into the clinical pharmacology section of the
labeling? The sponsor then would basically be able to say \"Yes, we\'re
operating within this WHI class labeling but we\'ve been able to show
that at least one element of this is somewhat different or may well be
or something like that.\"

It seems to me that the clinical pharmacology section may be one place
for this and that could result in more nuanced warnings and precautions
if the data are there without disrupting everything. That\'s a way that
a sponsor could proceed in the development of a new product to say
\"Okay, we\'re going to concentrate on what we think are two to three
important things where we really think we can demonstrate an advantage.
Then once we have a toehold maybe we may go for the big trial.\" It\'s
just a way of thinking about that.

I have to say without wanting to open a can of worms that there\'s some
overlap of this in the SERM area because of overlapping effects that
some of these issues may arise there as well in terms of how one
distinguishes one product from another and could that be done in
clinical pharmacology?

CHAIRMAN McCLUNG: Okay. Other comments?

DR. CARPENTER: Just a brief response to the issue of the global index
and its future in potential other trials, it would be a mistake to
entirely discard this notion - and maybe I\'m speaking from the minority
point of view here - but I find that particularly in the setting where
an efficacy endpoint is very hard to establish where we\'re talking
about primarily preventive efforts in whatever endpoint we\'re looking
at. We\'re generally looking at continuous variable of reversing a
natural phenomenon with a considerable way of other side effects of this
that need to be weighed in some way against the endpoint that we\'re
looking for.

I haven\'t seen anything at least to-date that can integrate this
comparison better than what I\'ve seen today in terms of the global
index. So it may actually be a model by which at least other models
could be amplified or modified for other comparisons. I don\'t think
that it\'s something that I would discourage as an indicator of where to
go with these newer therapies.

DR. ORLOFF: I wasn\'t quarreling that for the purposes of producing or
generating definitive information, the global index didn\'t have a very
important role. All I was saying is that it would seem at this point a
very high bar to place to ask for that standard of evidence for every
new product that comes along.

CHAIRMAN McCLUNG: Dr. Follman.

DR. FOLLMAN: I\'d like to comment a little about the global index also.
I like it as a simple understandable way of coming up with a number that
traded off risks and benefits. I would also mention that I don\'t see
how we can come with a different global index for the WHI or try to
refine it in some way. We know the results of this study so it would be
like doing this study without an endpoint defined beforehand looking at
all the data and all the tests and then trying to come up with the
primary endpoint. It\'s basically impossible I think.

There\'s a potential refinement of the global health index that I think
could be done. It would be to somehow weight the different categories. A
simple way to do this would be for each of these events, say breast
cancer, hip fracture and so on, calculate the probability that you\'d be
dead say in the next five years if you had one or more of these,
separately for each of the events and then instead of summing up, you
just note whether you had one of these events or not. Then you would
calculate for each woman the probability you\'d be dead in the next five
years based on whether you had hip fractures, a stroke and so on. That
might be a way of trading off in some way what\'s worse, breast cancer
or hip fracture or stroke.

DR. ORLOFF: I understand that the WHI investigators considered that
approach and figured when all was said and done that it would just add
one more level complexity to their trial, the planning and
implementation that wasn\'t going to be worth it.

CHAIRMAN McCLUNG: Plus, it would reward events that happened late in
life. They would get a higher score because the older you are the less
likely you are to be alive five years from now. There are all kind of
nuances to that. I think we all agree that the global index was put
together again for specific purpose of this study. We\'ve learned a lot
about the disease processes that were evaluated and the outcomes that
were evaluated in the study and nothing precludes the next study if
there ever is a next large study to prospectively define a modification
of that index to include vertebral fractures or other endpoints that
we\'ve now learned are important as a part of these sorts of things. Dr.
Woolf.

DR. WOOLF: I personally would like to keep the bar high in the next
go-around because we have effective alternative therapies for
osteoporosis that have their own set of baggages. We certainly know a
lot about Premarin and its various forms. Why have a lesser standard of
evidence and a lesser standard of commitment to the next go-around? Why
pretend that we don\'t have this information? So I\'d like to keep the
bar high.

One other thing, when first I read this material about a week or so ago,
I really did not like the global index. I thought it was rather
simplistic and everything was equal. In my own mind, they weren\'t equal
and there were a whole set of things that weren\'t there that may not
have been as devastating as breast cancer but nevertheless were pretty
significant problems.

Over the course of the day, my opinion has changed because I don\'t know
of a better alternative. I certainly haven\'t heard of one. We did
discuss at lunch despite the Chairman\'s prohibition about weighting the
factors of the global index. One person\'s weight may not be someone
else\'s weight and you\'d have a whole set of disagreements about the
weighting. We can use quality-of-life years or something like that. I
don\'t know. I got away from that. I guess I came around to the global
index and liked it. Have something like that in the next go-around.

DR. ORLOFF: Mike, let me just make one more comment which is that it\'s
important for the record for everybody to understand that this is class
labeling as Dr. Bone has said. It\'s class labeling because at this
point we don\'t have sufficient not to apply in some qualitative if not
direct quantitative way the results of the WHI study to this broad class
of drugs. In the spirit of disclosure which is what we do in labeling,
we tell people what we know either specifically or broadly about the
risks and benefits.

I want to make clear that I\'m not proposing that the bar shouldn\'t be
high in order to have a drug marketed and promoted as somehow absolutely
not carrying these sorts of potential risks or this overall balance of
risk and benefit. That\'s not what I\'m saying. There\'s a very high
standard evidence and quite frankly it\'s a little bit difficult to
imagine at this point that we\'re going to get there.

That being said the way we\'ve written this label now as I said before
the only true, first line use of this product is for the treatment of
vasomotor symptoms. There is no reason not to encourage I believe the
development of lower dose, alternative routes of administration,
estrogen or estrogen/progestin drug products that would effectively
address vasomotor symptoms and then to study them in order to understand
the expected effects on other aspects of the post menopausal woman\'s
health and particularly their bone health. It doesn\'t mean that we
would alter the way we write this label. It\'s just that we would have
something else in the armamentarium to go to in lieu of higher dose
perhaps orally administrated agents for example not to pass any
judgment.

CHAIRMAN McCLUNG: Dr. Zerbe, do you have a question or comment?

DR. ZERBE: Actually all the points have been very well made and I don\'t
have a lot to add except that the whole effort is to be applauded in
terms of the data that were generated. There really does need to be
caution with regard to general application. I guess that\'s a statement
of the obvious. From an industry perspective, we need to be cautious
about the bar which certainly does need to be high, but we do need to
also balance that against bringing new products forward to actually
replace some of the products that do have the flaws. That would be the
only thing that I would say. Thanks.

CHAIRMAN McCLUNG: Dr. Woolf.

DR. WOOLF: Speaking of bars now, there is one area where the bar is
incredibly low. In fact, I think it\'s below ground. That\'s the whole
notion of phytoestrogens and natural estrogens that my patients are
coming in with. We don\'t have to worry about cancer. This is a natural
product here. It will cure my bones. It will prevent osteoporosis. I
understand the FDA\'s dilemma on this, but this has really become a
problem bordering on becoming a nightmare. Somehow or other we\'re going
to have to get a handle on this. I have no idea of what it would take,
but this notion that this is natural and no data either efficacious or
safe. We have to get a handle on that.

CHAIRMAN McCLUNG: I\'m glad that wasn\'t today\'s issue but we\'ll be
happy to have you volunteer to be the chair of that committee.

DR. ORLOFF: Let me get right back to you on that one.

CHAIRMAN McCLUNG: That\'s right. Exactly. Other comments or issues? Let
me if I can make again try to make some generality out of this. If what
I say doesn\'t resinate with what somebody else thinks the group said,
we can modify it. To address the issue that we were handed about the
implications about the WHO for the future development, testing and
approval for estrogen/progestin products for the prevention and
treatment of osteoporosis, I have heard this. The current requirements
for the approval of an estrogen/progestin product or an estrogen product
for the prevention of osteoporosis is based on sound reasoning and there
seems not to be a need or a big statement to change the guidelines or
requirements for approval for prevention of bone loss.

With that approval however comes the class labeling of the risks that
are already a part of the estrogen/progestin, estrogen labeling process.
For a new product to be able to distinguish itself as being somehow
unique and different in terms of the risk profile, a specific study that
wouldn\'t necessarily have to address all of the risks simultaneously
but could address a risk one at a time as Dr. Bone could be done. Then
were that data reviewed, then it could be incorporated somewhere in the
package labeling to reflect that the comparison had been made and that
perhaps a uniqueness for that particular product could be done. But the
absence of that, the concerns about the risks that we already have
before us with estrogen and progestin would not be able to be escaped.
Does anybody want to work on that harder?

DR. ORLOFF: With the caveat that comparative safety claims, even implied
ones, are difficult to come by.

CHAIRMAN McCLUNG: Sure.

DR. BONE: Could I just add one thing?

CHAIRMAN McCLUNG: Yes.

DR. BONE: One thing that would be extremely helpful here is if we can
obtain more informative research about the possible distinctions that
have been hinted at in a literature between for example different
progestins and how they might interact with the risk of breast cancer
and that kind of thing. This is an area not simply for large scale
clinical trials but also for really intensive and well-designed
preclinical studies that could inform us in these areas.

CHAIRMAN McCLUNG: Another point that I reflect on and would just bring
back that was made two or three times was that studying the population
of subjects for whom either the sponsor or the clinical community thinks
that a drug would be most applicable for would be helpful. We\'ve talked
about that there are different categories of risk or the different
individual patients have different risk profiles and perhaps to
encourage studies to be done where the clinical profiles are predefined
and specific groups of patients be targeted for evaluation. This would
another thing to come out of the discussions that we\'ve had today.

The third issue was the broadest of all and was a time if there were
comments beyond what we\'ve already dealt with to make to Dr. Orloff and
his team about outcomes from the WHI trial and how it relates to the
issue of approval for osteoporosis indications for estrogen and
progestin therapy. Any other comments? Now is the time to add that to
the discussion here.

DR. ORLOFF: Dr. Woolf already got his other comment in.

CHAIRMAN McCLUNG: Right.

DR. WOOLF: I expect a phone call.

CHAIRMAN McCLUNG: All right.  With that, Dr. Orloff, we have exhausted
our thoughts about this and hope that we\'ve provided some input that
you and your group can deal with over the next time here.

DR. ORLOFF: Again, thank you everybody for giving up your valuable time.
We much appreciate it and we\'ll take it from here. Thank you. Off the
record.

(Whereupon, the above-entitled matter was concluded at 4:26 p.m.)