1

DEPARTMENT OF HEALTH AND HUMAN SERVICES

FOOD AND DRUG ADMINISTRATION

CENTER FOR DRUG EVALUATION AND RESEARCH

ADVISORY COMMITTEE FOR

REPRODUCTIVE HEALTH DRUGS

Thursday, December 2, 2004

8:00 a.m.

Hilton Hotel

The Ballrooms

Gaithersburg, Maryland

P A R T I C I P A N T S

AVISORY COMMITTEE REPRODUCTIVE HEALTH DRUGS

Linda C. Giudice, M.D. - CHAIR

Arthur L Burnett, M.D.

Scott S. Emerson, M.D.

W. David Hager, M.D.

Vivian Lewis, M.D.

Larry Lipshultz, M.D.

Charles L. Lockwood, M.D.

George A. Macones, M.D.

Valerie Montgomery-Rice, M.D.

Joseph B. Stanford, M.D.

Jonathan Tobert, M.B. [Industry Representative]

Lorraine J. Tulman, R.N.. D.N.Sc.

[Consumer Representative]

Teresa A. Watkins, R.Ph., Executive Secretary

CONSULTANTS AND GUESTS

SGE Consultants (voting)

Joanne F. Dorgan, Ph.D., M.P.H.

Diane F. Merritt, M.D.

Steven Nissen, M.D.

Donald L. Patrick, Ph.D.

Martha Solonche [Patient Representative]

SGE Consultants (non-voting)

Adrian S. Dobs, M.D.

Julia r. Heiman, Ph.D.

FDA PARTICIPANTS

Julie Beitz, M.D.

Donna Griebel, M.D.

Scott Monroe, M.D.

Daniel Davis, M.D.

Lisa Soule, M.D.

C O N T E N T S

PAGE

Call to Order and Introductions 5

Linda Giudice, M.D., Chair

Conflict of Interest Statement 8

LCDR Teresa Watkins, R.Ph.,

Executive Secretary

Welcome and Comments 10

Donna Griebel, M.D., Deputy Director,

Division of Reproductive and Urologic Drugs

Assessing Risks of Hormonal Interventions 19

Judith Hsia, M.D.,Professor of Medicine,

George Washington University

Sponsor Presentation

Introduction 36

Joan M. Meyer, Ph.D., Senior Director,

New Drug Development, Procter & Gamble

Pharmaceuticals

Phase III Clinical Efficacy Data 43

Johna D. Lucas, M.D., Medical Director,

Procter & Gamble Pharmaceuticals

Clinical Relevance of Treatment Effects 57

Leonard R. DeRogatis, Ph.D.,Director,

Johns Hopkins Center for Sexual Health

and Medicine

Phase III Clinical Safety Data 68

Johna D. Lucas, M.D.

Phase III Hormone Data 86

Glenn D. Braunstein, M.D., Professor

Geffen School of Medicine, UCLA;

Chairman, Department of Medicine,

Cedars-Sinai Medical Center

Hypoactive Sexual Desire Disorder 100

Jan L. Shifren, M.D., Faculty,

Harvard Medical School; Director,

Menopause Program, Vincent OB/GYN

Service, Massachusetts General Hospital

C O N T E N T S

PAGE

Sponsor Presentation - Continued

Phase IV Long-term Safety Plan 109

Michael Steinbuch, Ph.D., Director,

Pharmacovigilance and Epidemiology,

Procter & Gamble Pharmaceuticals

Closing Remarks 119

Joan M. Meyer, Ph.D.

FDA Invited Speaker

Safety of Exogenous Testosterone in Women 123

Adrian Dobs, M.D., Professor of Medicine

Johns Hopkins University

FDA Presentation

Efficacy Findings and Issues 147

Daniel Davis, M.D., Medical Officer,

Division of Reproductive and Urologic Drugs

Safety Findings and Issues 160

Lisa Soule, M.D., Medical Officer,

Division of Reproductive and Urologic Drugs

Open Public Hearing 182

Questions from the Committee to Sponsor and FDA 245

Committee Discussion 367

P R O C E E D I N G S

Call to Order and Introductions

DR. GUIDICE: Good morning. Would everyone

take their seats, please? Thank you.

I'm Linda Giudice, and this is the

reproductive Health Drugs Advisory Committee Meting

to the FDA. And today the committee will discuss

the new drug application, the testosterone

transdermal system, Procter and Gamble, indicated

for the treatment of hypoactive sexual desire

disorder in surgically menopausal women receiving

concomitant estrogen therapy.

I'd like to first remind the audience and

committee members to please put your cell phones on

silent or vibrate so that the proceedings are not

interrupted. And I'd like to begin this morning by

going around the table so that each of our

committee members may introduce himself or herself.

Please give your name and your affiliation, and

then we will move on with the program.

So I'd like to start on this side, please.

DR. BEITZ: I'm Julie Beitz, I'm the Deputy

in Office of Drug Evaluation III.

DR. GRIEBEL: I'm Donna Griebel. I'm the

Deputy in the Division of Reproductive and Urologic

Drug Products.

DR. SOULE: I'm Lisa Soule, Medical Officer

in the Division of Reproductive and Urologic Drug

Products.

DR. MONROE: I'm Scott Monroe, Clinical

Team Leader, Division of Reproductive and Urologic

Drug Products.

DR. DAVIS: Dan Davis, a medical reviewer

in the Reproductive Drug Products Division.

DR. MACONES: George Macones, Department of

OB-GYN, University of Pennsylvania.

DR. HAGER: David Hager, Obstetrics and

Gynecology, University of Kentucky and Central

Baptist Hospital, Lexington, Kentucky.

DR. TULMAN: Lorraine Tulman, School of

Nursing, University of Pennsylvania, Philadelphia.

DR. BURNETT: Bud Burnett, Urologist on

staff at Johns Hopkins in Baltimore.

DR. DICKEY: Nancy Dickey, Family and

Community Medicine, Texas A&M University System

Health Science Center.

DR. GIUDICE: I'm Linda Giudice,

reproductive endocrinologist at Stanford

University.

DR. WATKINS: I'm Teresa Watkins. I'm the

Executive Secretary with the Advisors and

Consultants staff.

DR. LOCKWOOD: Charles Lockwood, OB-GYN,

Yale University.

DR. LEWIS: Vivian Lewis, reproductive

endocrinology, University of Rochester.

DR. LIPSHULTZ: Baylor College of Medicine,

urology.

DR. SOLONCHE: Martha Solonche, patient

representative, New York City.

DR. PATRICK: Donald Patrick, Social and

Behavioral Sciences and Health Outcomes, University

of Washington.

DR. NISSEN: I'm Steve Nissen, and I'm a

cardiologist with the Cleveland Clinic.

DR. MONTGOMERY-RICE: Valerie

Montgomery-Rice, reproductive endocrinologist,

Meharry Medical College, Nashville, Tennessee.

DR. HEIMAN: Julia Heiman, Kinsey

Institute, Indiana University.

DR. TOBERT: Jonathan Tobert, Tobert

Medical Consulting, and the University of Oxford,

England.

DR. GIUDICE: Thank you.

Ms. Teresa Watkins will now read the

conflict of interest statement.

Conflict of Interest Statement

MS. WATKINS: Thank you.

The following announcement addresses the

issue of conflict of interest, and is made as part

of the record to preclude even the appearance of

such.

Based on the submitted agenda for the

meeting, and all financial interests reported by

the committee participants, it has been determined

that all interest in firms regulated by the Center

for Drug Evaluation and Research present no

potential for an appearance of a conflict of

interest at this meeting, with the following

exceptions.

Because Drs. Adrian Dobs and Julia Heiman

has past involvements with Proctor & Gamble related

to the product under discussion, the Agency has

decided to limit their participation.

Dr. Julia Heiman may participate in the

committee's deliberations. She is, however,

excluded from voting.

Dr. Adrian Dobs is permitted to give a

presentation to the committee and to answer

questions directly related to her presentation.

We would like to note that Dr. Jonathan

Tobert has been invited to participate as a

non-voting industry representative, acting on

behalf of regulated industry. Dr. Tobert's role on

this committee is to represent industry interests

in general, and not any one particular company.

Dr. Tobert owns Tobert Medical Consulting LLC.

In the event that the discussions involve

any other products or firms not already 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 firms they may wish to comment upon.

Thank you.

DR. GIUDICE: Thank you.

Donna Griebel will now give her welcoming

statement and comments.

Welcome and Comments

DR. GRIEBEL: [Off mike.] Good morning

everybody. Can you hear me?

Now can you hear me? I'll lean.

I'm Donna Griebel. I'm the Deputy

Director--as you've already heard--of the Division

of Reproductive and Urologic Drug Products. The

Division would like to welcome you all here

today--both committee members and guests--and we

would like to express our gratitude to you all for

traveling all the way to Washington at a very busy

time of the year to consider the application that

is before us.

As you have already heard, the NDA is for

testosterone transdermal system. The proposed

indication is for the treatment of a subtype of

female sexual dysfunction called hypoactive sexual

desire disorder. And it is specifically for a

sub-group of women with this disorder, which is

surgically menopausal women who are being treated

with estrogen therapy.

This application, if approved will be the

first product that will have been approved for

female sexual dysfunction.

I'm getting tired of leaning.

And the Division did designate this review

a priority review, which means it was given a

six-month review clock. We did so because there

are no products approved for female sexual

dysfunction, and a product that successfully treats

this disorder could have a major impact on a

woman's quality of life.

In your review of the FDA's background

document--and hen you hear the FDA's presentation

today you will conclude that the FDA concurs with

the applicant, Procter & Gamble, that they have

shown a statistically significant difference

associated with treatment with TTS in the primary

efficacy endpoint of interest, which is the number

of satisfying sexual events.

However, we do have questions about

whether the statistically significant change that

was produced by TTS, and the proportion of women

who experienced this improvement relative to

placebo is a clinically meaningful difference.

Analysis of efficacy is but one piece of a

risk-benefit analysis. You also have to look at

the safety data, and you have to evaluate the

safety data base for its adequacy.

The Division factored its experience with

the impact of the outcomes from the Women's Health

Initiative studies in their approach to evaluating

the safety data in this application. The Women's

Health Initiative studies were very large,

randomized controlled trials, prospective studies,

that were powered to show important differences in

safety outcomes. They led to changes in product

labeling for products that are intended for

treatment of menopausal symptoms in

post-menopausal, and they reinforced an initiative

to be sure that the lowest effective dose of these

products has been defined.

The results of the WHI studies became

available after launch of the studies that you will

be seeing presented today.

We've invited additional experts to sit at

the table today and participate in the committee's

deliberations. They include Dr. Donald Patrick,

who has expertise in evaluating health-related

quality of life instruments and endpoints; Dr.

Julia Heiman, who's director of the Institute; Dr.

Steven Nissen is a cardiologist; and Dr. Diane

Merritt was to join us today. She's an OB-GYN from

Washington University.

The Division has invited two guest

speakers to participate. They will be making

presentations on issues relevant to assessing risk

associated with hormonal products in

post-menopausal women.

Dr. Adrian Dobs is a professor at Johns

Hopkins University in endocrinology and metabolism.

She will join us later this morning to summarize

the existing clinical evidence in the literature of

potential safety issues associated with

testosterone use in women.

Our second guest speaker, Dr. Judith Hsia,

is a cardiologist at George Washington University.

She was a lead investigator in the WHI studies.

You will hear the FDA mention WHI over and over

again this morning and clearly we do believe that

the data from these studies are relevant to today's

discussion--for a number of reasons that include:

number one, if TTS is approved, it will be approved

for the population that was studied in this

application, and that is surgically post-menopausal

women who are taking estrogen. This implies that

women who take TTS will also be taking estrogen, as

well. And, presumably, they will be taking the

products chronically.

WHI demonstrates that millions of women

can be exposed to a drug for a well-accepted

off-label use, such as estrogen for prevention of

cardio-vascular disease, and only when studied in a

large, randomized controlled trial do we find that

the drug is not effective for the presumed benefit,

and is actually associated with substantial risk.

WHI also drives home some very important

practical issues. If you want to shoot for the

ideal study design to evaluate such risks--and that

is it takes enrollment of a lot of women to get

those answers. There are also hypotheses for the

safety outcomes from the WHI studies that may be

applicable to the data that you're reviewing today.

It's important for you to remember that

the guest speakers are only available to you for

dialogue and interaction between the committee

members and the guest speakers when they're at the

podium. So we would like to remind you to be sure

and ask your questions that you would like to ask

of them while they are at the podium.

Quickly, reviewing the agenda: Dr. Hsia

will actually be our first speaker, and we'll open

the meeting today. She will be followed by Procter

& Gamble's presentation of the data. There will be

a break, followed then by Dr. Adrian Dobs.

FDA will follow Dr. Dobs, and we'll close

the morning with the open public hearing speakers.

After lunch we will return and the

committee will have an opportunity to ask

clarifying questions of the applicant, Procter &

Gamble, and the FDA. And then you'll transition

into discussion of the FDA's questions, and we'll

vote on those questions.

When you're listening to the presentations

this morning, please keep the questions in mind.

And I'll briefly run through them.

[Slide.]

The first is an efficacy question: "Do the

efficacy data represent clinically meaningful

benefit above that of placebo for surgically

menopausal women with hypoactive sexual desire

disorder who are taking concomitant estrogen?"

Uh-oh. I am now missing two of my

questions.

[Comments off mike.]

I wasn't a good Boy Scout and didn't come

prepared to the podium.

The second question is with regard to the

safety database: whether there's been an adequate

number of women exposed, and whether the duration

of exposure is adequate; whether the duration of

exposure with the placebo control is adequate--with

the bottom-line question: "Is the exposure, the

total number of women treated, and duration of

treatment adequate to demonstrate long-term

safety?"

The third question is a three-part

question. The first is: "a) Are the safety

concerns or unanswered questions associated with

use of TTS in combination with estrogen that need

to be studied; for example, questions about

cardiovascular or breast cancer outcomes, or

questions about risks and benefits in populations

who are likely to use this product off-label?"

If you answer yes to that question, we

would like you to be sure to state what your

concerns are, what questions you have.

Part c) of the question is: "Should these

concerns or questions be studied prior to approval

of the product?" If you believe that these

questions need to be answered prior to approval, we

would like to know what studies you would

recommend, what the design would be, what are the

endpoints, who's the population.

If you think that the product can be

approved and that your questions could be answered

appropriately after approval, we would like to know

what the study designs would be and, specifically,

we would like you to comment on the applicant's

proposed claims-based cohort study.

And now the question that I do

have--question number four--it's a short one but an

important one: "Are the efficacy and safety data

adequate to support approval of TTS?"

Next, I would like to introduce Dr. Judith

Hsia from George Washington University, who will

speak today about the WHI, and assessing risks of

hormonal therapies in post-menopausal women.

Assessing Risks of Hormonal Interventions

DR. HSIA: Well, it's a pleasure to be

here, and I appreciate being able to speak first,

because the Women's Health Initiative steering

committee is meeting downtown today and, as you

know, if one is not present, there's a risk of

having undesirable tasks assigned.

[Laughter.]

So I want to try to avoid that.

So I'm here to talk about approaches to

assessing risks and benefits, and what we've

learned as a consequence of the WHI.

[Slide.]

I'm really going to sort of briefly cover

four areas: biomarkers; observational studies;

randomized trials; and looking at intermediate

outcomes.

[Slide.]

So, if you think about estrogen, there are

many biomarkers. One which was studied early and

often was lipids. So if you look at LDL--the bad

cholesterol--in the lower left here, you can see

that starting two years before menopause there's a

steady increase in LDL and currently, the HDL--the

good cholesterol--is falling. And it was known

that estrogen would improve this profile.

[Slide.]

Here's data from the Women's Health

Initiative estrogen-progestin trial. What is shown

is the difference between the active E+P and the

placebo groups with regard to change in the

biomarker from baseline to year one.

So if you look at the LDL cholesterol, you

can see that falls 12 percent--which is a good

thing. The HDL increase 7 percent, which also a

good thing. Triglycerides go up, which is not good

thing. Glucose and insulin both fall, which is a

good thing. And blood pressure goes up, which is

bad. So that you end up with a mixture of

desirable and undesirable characteristics, and it's

hard to know what the overall balance is going to

be with regard to risk and benefit.

So a great many observational studies have

been undertaken to try to assess the relative risks

and benefits with hormone therapy.

[Slide.]

This is a summary from an analysis that

was published relatively recently by Joy Manson and

co-authors in the New England Journal. It sort of

summarizes the observational literature so that for

breast cancer there was thought to be an increase

in risk with E+P, which was associated with

duration of therapy. There's a 25 percent

reduction in hip fracture. There was a 45 increase

in stroke; a doubling in the rate of pulmonary

embolism; and a 39 percent reduction in the risk of

MI and coronary death.

And it was on that basis of these type of

studies that women had been being prescribed

post-menopausal hormone therapy for coronary

prevention for many years.

[Slide.]

So at the time the WHI hormone program was

designed, that was the data was available, and it

was on that basis that the design was developed.

So it was anticipated that the benefits would

include coronary prevention. And although stroke

looked like it was increased, in those

observational studies, people didn't really quite

believe that. They thought if it prevented

coronary disease it would prevent stroke as well.

So this was sort of a question mark.

It was thought it would increase breast

cancer risk, and venous thromboembolic risk. It

would reduce hip fracture and possibly overall

mortality. So that was the plan.

[Slide.]

As the trials were conducted there were

two arms. It was stratified presence of a uterus

so that women who had no uterus were randomized

either to conjugated estrogens alone or placebo;

and those who had a uterus were randomized to CEE

with daily medroxy-progesterone acetate or placebo.

These were the sample sizes that were

built into the design. And let me just point out

that in order to achieve randomization of 27,000

women, that 373,000 women were screened--which is,

you know, a significant proportion of the

age-eligible population of the country.

[Slide.]

Now, if you just look at the E+P

trial--for which the data is fully complete and has

been published--in reality there was a 24 percent

increase in the risk of coronary heart disease.

The stroke data--there was a 31 percent increased

risk in stroke; venous thromboembolism was doubled.

There was an increase in breast cancer. There was

a somewhat unexpected reduction in colorectal

cancer, which was statistically significant. Hip

fracture was reduced.

And there was ancillary study called

"WHIMS"--the Women's Health Initiative Memory

Study--in which women who were 65 or older at study

entry were invited to have annual mini mental

status exams, and if those scores fell below a

certain level, then they went on and had subsequent

testing and clinical evaluation for cognitive

impairment. And almost everybody who was offered

participation in the ancillary study did

participate. And WHIMS demonstrated a doubling in

the rate of dementia if one was assigned to active

hormones.

[Slide.]

now, there's been a lot of discussion in

looking at the WHI data about the relationship

between relative risk and absolute risk. So these

are the absolute risks with E+P. It's per 10,000

woman-years. And I think of that as 2,000 women

treated for five years, since that was the duration

of follow-up at the time the trial was stopped for

safety reasons.

So if you treat 2,000 women for five

years, there will be 30 heart attacks or coronary

deaths in the placebo group, and 37 in the active

treatment group; so an excess of seven heart

attacks or coronary deaths associated with E+P

therapy.

Now, the trial, as a sort of study policy,

does not characterize any of these differences as

large of small. You know, it's in the eye of the

beholder, and we just put the data out there so

that health care providers and women can make an

informed decision--for the first time.

If you look at stroke, there were 21

strokes in the placebo group for 2,000 women for

five years, and 29 in the active treatment group.

And you can see similar numbers across the board.

For breast cancer, there were 30 breast

cancers in the placebo group, and 38 in the active

treatment group. And you see, actually, the

dementia numbers are in some ways are the most

dramatic.

[Slide.]

So, after the results became available,

the balance had shifted from what was anticipated,

so that on the benefit side, there was a reduction

in fracture--of both hip and total fracture--and a

reduction in colorectal cancer. And the risks

included increase in dementia, coronary heart

disease, stroke, venous thromboembolism and breast

cancer. So the trial was stopped 3.3 years early,

for these reasons.

[Slide.]

Now, if you go back to the Manson, et al.,

analysis in the New England Journal--this is just a

reproduction of those numbers. And if you put the

WHI E+P numbers up alongside, you can see that

actually the observational studies were quite

predictive, as far as breast cancer was concerned.

The hip fracture numbers are relatively similar.

The stroke numbers are relatively similar. The

venous thromboembolism numbers are really

identical. And the only thing that's off is

coronary heart disease.

So the question is: why is it? And one of

the things they tried to address in their analysis

was what some possible reasons might be.

[Slide.]

Some of it might be due to the "healthy

user" effect, where women who choose to take

estrogen in those observational studies--you know,

the way they're conducted is like the Nurses Health

Study, they fill out questionnaires, "Are you

taking estrogen?" And then they follow them along

and count up how many heart attacks people have.

And women who choose to take estrogen are known to

have other healthy practices, like they exercise

more, they're leaner, they ate more servings of

spinach and so on--and that these things, although

they're adjusted for in the models, you don't know

everything that you need to adjust for, and you

don't have the data on everything that might be

relevant. So that's one problem.

Another is compliance bias. The women who

are taking their hormones might also be adherent to

other healthful behaviors like taking their blood

pressure medicine, or whatever.

It was thought--this is a relatively new

idea--that there might be outcomes identification

bias, where their health care providers thought

that if they were taking estrogen that that symptom

they had couldn't possibly have been a heart

attack, and therefore they were under diagnosed for

the outcomes that they may have had.

And there may have been incomplete capture

of early events, where women who had adverse events

while taking estrogen stopped their hormones before

they joined the study.

[Slide.]

So, now what is the potential impact of

adding progestin to estrogen, which has relevance

to the topic today?

[Slide.]

If you look at the outcomes from the

Women's Health Initiative estrogen-alone trial,

compared to the E+P trial, you can see that they

are similar in some ways and different in others.

So that if you look at coronary heart disease,

rather than a 24 percent increase in risk, actually

it's neutral: estrogen-alone is neutral with regard

to heart disease risk.

Stroke, increase is relatively similar.

There is also an increase in venous

thromboembolism, although it's not as marked.

Breast cancer actually is neutral with estrogen

alone, whereas it's increased with E+P.

The colorectal cancer benefit appears to

disappear. Hip fracture is prevented by

estrogen-alone, and there is an increase in the

rate of dementia.

So, it does appear that there are some

impacts of adding progestin to the regimen.

[Slide.]

If you compare the absolute risks of

estrogen-alone in the upper panel, with E+P in the

lower panel you can see, for one thing, that the

characteristics of women who've had a hysterectomy

differ from those of women who still have a uterus,

so that the placebo event-rate is higher. These

scales are the same.

So the placebo event-rate is higher for

women with estrogen-alone. They have more

hypertension, diabetes, greater body mass index,

and so on, and this is an issue. However, we have

done analyses to try to assess the impact of this

on the difference between the trial outcomes, and

it does not appear that this accounts for them.

But you can see, for instance, the

absolute increase in the number of strokes here was

8, and the absolute number--an increase in

strokes--here is more like 11 or 12. So there are

some differences in the absolute event-rates.

[Slide.]

So if you look at the balance of risks and

benefits with estrogen-alone--which was a 6.8-year

follow-up at the time the trial was stopped early

because of the increased risk of stroke and

dementia--the benefit is fracture reduction; it was

neutral with regard to breast cancer and coronary

heart disease, and there was an increase in

dementia, stroke and venous thromboembolism.

[Slide.]

So the impact of adding androgen to an

estrogen regimen may be difficult to predict, and

may differ among the various types of progestins or

androgens that may be studied.

Now, the alternative to carrying out a big

randomized trial that may require screening 300,000

subjects to get your enrolled population, is to do

studies of intermediate outcomes.

[Slide.]

And there are number of different measures

that can potentially be used. This is coronary

calcium, which is assessed using a fast CT scan.

It's about 500 bucks. So it's a cheaper study to

do. It's non-invasive, and may potentially have

utility.

Carotid ultrasound is another approach

that one can take to evaluating drug effects or

intervention effects without waiting for hard

clinical outcomes.

And a third possibility is coronary

angiography, or--since Dr. Nissen is in the

audience--coronary ultrasound.

And there has been some investigation

using these intermediate outcomes, which is really

summarized here.

[Slide.]

There have been a limited number of

estrogen trials with intermediate outcomes. There

have been three angiographic trials, funded by the

NIH; two used conjugated estrogen, and one used

estradiol. And they all showed no benefit or harm

with post-menopausal hormone therapy. So, on the

one hand, they didn't show protection the way the

observational studies did, but on the other hand

they did not demonstrate the harm with the

combination E+P that was observed in the randomized

trial with clinical outcomes.

For carotid ultrasound there's been one

randomized trial using estradiol that did

demonstrate benefit, and that may be considered to

be consistent, in some sense, with the

estrogen-alone coronary outcomes, but it's not

consistent with the stroke outcomes, because there

was an increase in stroke in the estrogen-alone

trial which--you know, if you think carotid

ultrasound should be more predictive of

stroke--would not be consistent.

And there actually is no estrogen trial

data with coronary calcification.

The advantages of these trials are that,

you know, they're much cheaper to do. You can do

them with a sample size of 400, rather than 16,000.

And they can be done in a shorter period of

time--maybe three years rather than six. So the

advantages are considerable--if you think that the

data are going to be predictive.

[Slide.]

So, just to summarize: the approaches that

can be taken to evaluating risk are, I think,

basically four. There are biomarkers--which I

think have very limited utility, because they're

likely to give a mixed picture, and you're not sure

how to interpret those results. There are

observational studies which, I think, have been

demonstrated to be not reliable for assessment of

coronary risk, although possibly they may be

reliable for assessment of other types of risk.

And the other thing is that, of course, suitable

cohorts may not be always available.

And then there are randomized trials, with

intermediate outcomes, which may potentially be

useful, but their predictive value is still

somewhat suspect.

And there are randomized trials which, of

course, are the gold standard, but are expensive

and take a long time to undertake.

So, I'll close with that and--am I

supposed to take questions?

DR. GIUDICE: We have time for just a few

questions.

Yes, please?

DR. NISSEN: Judy, thank you for a very

lucid presentation. I had a couple of questions.

One is: what is known about the use of

estrogen, or estrogen-progestin, in women who have

existing coronary heart disease. That's question

one.

And question two is: using something like

Framingham Risk Score, is there an interaction

between the baseline risk and the risk of

adverse--or increases in event rates in women who

receive hormonal therapy? Can you predict any of

this, using something like Framingham?

DR. HSIA: Well, let me take your first

question first.

The HERS trial randomized women--which I

was principal investigator for--randomized women

with documented coronary disease to conjugated

estrogen with medroxy-progesterone daily, or

placebo, and demonstrated an increase in coronary

events in the first year--really, the first six

months--following randomization. And thereafter,

the curves came together and there was no risk or

benefit over longer-term therapy.

And the angiographic trials of course--the

three of them--all included exclusively women with

some coronary disease, and were neutral. But they

were smaller, and there may have been a power

issue.

With regard to whether risk

characteristics at baseline can predict safety, we

have done sub-group analyses looking not at the

Framingham score because, actually, although we

have blood on everybody, we don't have laboratory

measures on everybody for cost reasons. But if you

just count up risk factors, and look at women

with--you know, with or without more or less risk

factors at baseline, it does not help you predict.

There's no interaction between that and outcome.

And if you look at the women in the

randomized estrogen-alone and E+P trials who had

prevalent coronary disease at baseline--which was

only a few percent--they had the same relative risk

as women who did not.

DR. GIUDICE: Any other questions from the

committee?

[No response.]

DR. GIUDICE: Okay, thank you very much.

DR. HSIA: Thank you.

DR. GIUDICE: We'll now proceed with the

sponsor presentation. And the first speaker is Dr.

Joan Meyer, who is Senior Director of New Drug

Development at Procter & Gamble.

Sponsor Presentation

Introduction

DR. MEYER: Good morning. In addition to

being Senior Director of Drug Development at

Procter & Gamble, I'm also the Global Project

Leader for the Testosterone Transdermal System

Project.

Today we'll present data to you on the

testosterone transdermal system. We've been

granted the trade name Intrinsa, which I will use

from now on, because it's easier to say than

testosterone transdermal system.

So what is it?

[Slide.]

Intrinsa is a patch. It delivers 300 mcg

a day of naturally occurring testosterone, and the

patch is changed twice weekly.

Our proposed indication, as you've heard,

is for the treatment of hypoactive sexual desire

disorder in surgically menopausal women on

concomitant estrogen therapy.

So what is hypoactive sexual desire

disorder?

[Slide.]

Well, this is a recognized medical

condition that affects many women. It has both ICD

and DSM codes.

There are three key elements to HSDD that

are very important to keep in mind, especially when

considering the clinical relevance of this

condition. One is: the woman has a decrease in

sexual desire. This leads to a decrease in sexual

activity, and satisfying sexual activity. This, in

turn, causes the woman personal distress. So these

three things are very important: the desire, the

decrease in satisfying sexual activity, and the

increase in distress.

It affects all aspects of a woman's life,

as we can show you today; her health, well-being

and her relationship with her partner.

So what else will we be showing you today?

[Slide.]

After I give you a brief background of the

project, Dr. Johna Lucas, the Director of Clinical

Development at Procter & Gamble, will share with us

the clinical efficacy data, and she's show you the

highly significant improvements achieved by

Intrinsa in all the endpoints that were measured,

including desire, activity and distress.

Then, Dr. Leonard DeRogatis, the Director

of the Johns Hopkins Institute for Sexual Health

and Medicine, will show us the clinical relevance

in these data to the women who participated in the

trials.

Then Dr. Lucas will return to share with

us the safety data, and show us the favorable

safety profile we saw in the clinical studies with

Intrinsa.

Then we'll hear from Dr. Glenn Braunstein,

the Chairman of Internal Medicine at the Cedars

Sinai Hospital at UCLA Medical School. He will

share with us the data from our clinical trials on

the levels of testosterone, other hormones that we

measured, and discuss their implications for

safety.

Dr. Jan Shifren is an Assistant Professor

of Reproductive Endocrinology at Harvard Medical

School. She will put these data in context for us,

and she'll show us the impact HSDD has on women's

lives, and discuss the medical need for a drug like

Intrinsa.

Then Dr. Michael Steinbuch, who is the

Director of pharmacovigilance and Epidemiology and

Procter & Gamble, will go over with you our

comprehensive Phase IV program that we've designed

to follow the long-term safety of Intrinsa.

Finally, I'll return to wrap-up and share

concluding remarks with you.

But, also available for discussion today,

we have a variety of experts, both within and

outside Procter & Gamble, to discuss any questions

or data that you'd like additional information on.

[Slide.]

I just want to go over briefly the

clinical development program for Intrinsa. And

it's important to remember that this is, indeed,

the first drug for the treatment of hypoactive

sexual desire disorder. We worked closely with the

agency, through our development program. We

followed the FDA guidance on the female sexual

function drug development, and we also did a

variety of studies to design our Phase II and Phase

III programs.

[Slide.]

As you can see from this list, we did

dermal safety studies, PK studies. From these

studies we determined the optimal site for patch

application. We did dose-ranging studies. And we

also looked at the effect of route of estrogen

administration on the data.

Our Phase III program consisted of four

large, double-blind randomized placebo-controlled

studies: two of these in surgically menopausal

women. And these are the data we'll be sharing

with you today. Two of these are in naturally

menopausal women, one of which is just completing.

We will present safety data today from

these studies to round-out the safety picture of

what we know about Intrinsa.

But we also did some additional studies to

further understand the benefits of this treatment.

Again, because it's a new therapeutic area, we had

to do some non-traditional studies. And we had

significant input and interaction with the agency

to develop these.

[Slide.]

The currently available instruments that

are out there were not considered fully appropriate

really to measure the three key aspects of

HSDD--desire, activity and distress. So we

developed three now instruments to measure these

aspects, and we validated these in four separate

clinical studies.

We also included, in our Phase III

surgical menopause program, a couple of additional

studies. One is a blinded withdrawal, that showed

that the patch is indeed having the desired

pharmacological effect. This was covered in your

briefing book, and we won't be discussing it in the

formal presentations today, but we'll be happy to

answer any questions that you might have on that.

Also, as part of the Phase III surgical

menopause program, we conducted to establish what

level of change in these instruments was meaningful

to the women in the study. And Dr. DeRogatis will

discuss this with us this morning.

We've also done a lot of safety work.

We've evaluated the safety of Intrinsa in several

different ways. We've collected adrenergic adverse

events in a very systematic way during the studies,

and we've also collected spontaneous reports.

We've continued to extend the Phase III

studies, and we are now into year three of three of

these surgically menopausal studies.

We've held two scientific advisory groups,

one to discuss what do we currently know about the

safety of long-term use of testosterone, and the

other was on breast safety and testosterone. An

outcome of the latter study was another special

study that we did in conjunction with the

Karolinska Institute. And Dr. Braunstein will

discuss these results.

Also, as you'll hear from Dr. Steinbuch

today, we've proposed a comprehensive Phase IV

safety program.

But now I'll stop telling you what we're

going to tell you, and get started on the data.

I'd like to introduce Dr. Johna Lucas,

Medical Director at Procter & Gamble.

Phase III Clinical Efficacy Data

DR. LUCAS: Good morning. I will now

present the efficacy from our Phase III surgical

menopause program, using the 300 mcg per day

testosterone patch.

[Slide.]

I will show you how the drug increased not

just our primary, and important secondary, sexual

function endpoints, but every sexual function

endpoint that we measured--and most of them in a

highly significant manner.

[Slide.]

I want to begin by talking about the

instruments we developed, and explain how the

therapeutic goals that were important to patients

became our primary efficacy endpoints. I will

describe our Phase II and Phase III surgical

menopause program, and then I"ll present the Phase

III results.

[Slide.]

Because no tools existed to measure sexual

desire and distress associated with low sexual

desire in women with HSDD, we developed three

multi-national validated instruments for the

assessment of sexual function. We consulted with

more than 100 physicians and sex therapists to get

their perspective, in addition to our validation

program with patients.

Our instruments are: the Sexual Activity

Log. It is a weekly diary that quantitates the

numbers of sexual events; the numbers of orgasms,

and the numbers of satisfying sexual events, for

both intercourse and non-intercourse activity.

The PFSF--or Profile of Female Sexual

Functioning--is a 30-day recall inventory that

evaluates seven domains of sexual function.

The PDS--or Personal Distress Scale--is

also a 30-day recall that evaluates the distress

associated with low sexual desire.

The development of these three instruments

is the subject of two publications.

[Slide.]

First, to discuss the profile of female

sexual function and the PDS. We began by speaking

to more than 250 women who reported having normal

sexual functioning prior to the removal of their

ovaries, and had experienced a substantial of

sexual desire, which they found quite distressing,

after their surgery. We used their own specific

words to generate items to be used on our

measurement tools.

These interviews generated 450 items. We

categorized the items by content; removed the items

that were, for example, redundant, slang, had

compound concepts, or were not representative of

the general reading level. We kept 83 items that

retained both content and meaning in six languages,

with both forward and backward translation.

We then tested the ability of these items

to discriminate women with HSDD from their

age-matched control women who described themselves

as well-functioning sexually, with normal sexual

desire. We tested these in three trials.

[Slide.]

This took us down to 37 items for the

PFSF, and 7 for the PDS. These items were then

tested in a fourth validation trial, comparing,

again, surgically menopausal with HSDD to

age-matched control women. Both the PDS and all

domains of the PFSF discriminated between

surgically menopausal with HSDD< and their

age-matched controls.

[Slide.]

In parallel to the development of the PFSF

and the PDS, we developed the Sexual Activity

Log--or SAL--which is a weekly diary. We developed

the instrument with further interviews, revision

and retesting to confirm that it captured all

activity; that it avoided double-counting; and that

it could be easily and universally understood by

all.

The SAL also discriminated well between

surgically menopausal women with HSDD and their

age-matched controls

[Slide.]

Our surgical menopause program for

Intrinsa consisted of two Phase II trials to

determine dose, and two Phase III therapeutic

trials. All were of similar design, with an

eight-week baseline period, and a 24 week treatment

period to measure efficacy and safety.

In all trials, patients were on

concomitant estrogen, and required to meet similar

inclusion and exclusion criteria.

In the Phase II trials, 300 mcg per day

was found to be efficacious as well as safe, and

established to be the appropriate dose to take into

Phase III.

The Phase III trials included a safety

assessment of up to 12 months.

[Slide.]

Our Phase III program included two

concurrent multinational trials of more than 500

patients each, which we refer to as SM 1, and SM 2.

These two trials had similar numbers of sites,

geography of sites, inclusion and exclusion

criteria, visits and procedures.

[Slide.]

In choosing endpoints for the Phase III

trials, desire, distress and satisfying sexual

activity were all important endpoints to understand

the treatment effect of women with HSDD. Benefits

in each of these areas are essential to achieve a

relevant treatment response. In keeping with the

FDA's draft guidance for female sexual dysfunction,

we chose "satisfying sexual activity" as our

primary endpoint. We pre-specified "desire" and

"distress" as key secondary endpoints--not only

because patients reported this as their primary

therapeutic goal, but because they comprise the

definition of hypoactive sexual desire disorder.

After showing you these key three

endpoints, I will show you additional endpoints

from the PFSF that are also relevant for a

meaningful treatment effect, since they too reflect

the other important losses that patients with HSDD

identified.

[Slide.]

Inclusion criteria were designed to ensure

that patients had HSDD associated with their

surgery; that is, patients had considered

themselves to have normal sexual functioning prior

to their surgical menopause, and had experienced as

substantial decrease in sexual desire, and

accompanying distress, after their surgery. It was

also important that patients be on estrogen, and in

a stable monogamous relations with the partner

there most of the time.

[Slide.]

Exclusion criteria were designed to rule

out other causes of low sexual desire, either

physiologic or psychologic. Exclusion criteria

were also designed to exclude patients with

conditions or medications that could confound

efficacy, or for whom testosterone might be

inappropriate.

[Slide.]

This schematic shows the number of

patients that were screened--about 1,700; who were

randomized--about 1,100; and who completed--about

870. This represents about 80 percent of patients

completing the double-blind portion of the trial.

About 96 percent chose to enter the open-label

period of the trial, and of those, 76 percent

completed the 12 months.

[Slide.]

Data will be shown in this format, with

the first two columns representing SM1, the second

two columns SM2, placebo testosterone, placebo and

testosterone.

The completion rate of 80 percent was

similar in both arms, in both trials. Of the 20

percent who discontinued, reasons for dropping out

were very similar between studies and treatment

groups. Of importance, drops for adverse events

were similar at about 8 percent, regardless of the

study, for testosterone or placebo arm.

[Slide.]

Patient characteristics were also very

similar between studies and arms. Mean age was 49,

with about 80 percent of patients being between age

40 and 59. The average length of relationship was

about 20 years, and patients on average had been

surgically menopausal about half of that.

About three-quarters of patients were on

oral estrogen, and about a quarter of patients were

on transdermal estrogen.

[Slide.]

Patients were also balanced at baseline

with regard to disease characteristics. This

baseline sexual desire score of about 20

corresponds to patients' reporting "seldom"

interested in sex. The personal distress score of

about 60 translates to patients "often" being

distressed about their lack of interest in sex.

Baseline satisfying sexual activity was about 3

episodes per four weeks.

Now, to review the results of the Phase

III trial.

[Slide.]

This graph shows the man change in total

satisfying sexual activity experienced by patients

with treatment at 24 weeks. Yellow represents

testosterone treatment; blue, placebo treatment.

Improvement seen with testosterone compared to

placebo were highly statistically significant in

both studies.

At the bottom of the slide--to help you

understand how the patients experienced their

change in satisfying sexual activity, I have

provided you with a percent change from baseline in

the respective arms. On average, in the two

trials, we see that the change experienced with

Intrinsa treatment was about double that seen with

placebo.

[Slide.]

Here, you see the changes in sexual desire

at 24 weeks for both Phase III studies. Again,

there was a highly significant increase in sexual

desire with the use of the testosterone patch

compared to placebo. Averaging over the two

studies, the increases seen in placebo were about

24 percent. AS you know, this magnitude of placebo

effect is commonly seen in behavioral studies. On

the other hand, patients who were treated with

Intrinsa experienced, on average, a little more

than 50 percent increase in sexual desire--again,

roughly double that seen with placebo.

[Slide.]

This graph shows you the changes seen in

distress. Distress associated with low sexual

desire is the hallmark HSDD. Distress

significantly decreased with Intrinsa treatment

compared to placebo in both trials.

Patients receiving testosterone treatment

reported approximately a 65 percent decline in

distress compared to their baseline.

In addition to assessing sexual desire,

distress and satisfying sexual activity, we also

pre-specific all other domains of the PFSF as

endpoints. Recall that these domains reflected the

other important losses that women with HSDD

complained of and said they would like to have

corrected.

[Slide.]

Shown here is SM1. With Intrinsa therapy,

patients experienced an improvement in every domain

of sexual functioning over placebo; that is, they

had an improvement in arousal, orgasm, improvement

in sexual pleasure, reduction of sexual concerns,

improved sexual responsiveness, and improved sexual

self image.

[Slide.]

Here are the results of SM2. Improvements

were very consistent to that seen in SM1. Again,

all PFSF domains improved significantly with

testosterone therapy compared to placebo.

[Slide.]

This graph shows increases in the other

sexual activity endpoints measured on the Sexual

Activity Log. Not only were satisfying sexual

episodes increased within Intrinsa treatment--which

I showed you previously as our primary

endpoint--but patients treated with testosterone

also experienced significant increases in numbers

of sexual episodes and in numbers of orgasms.

Note here, with the Sexual Activity Log,

we are assessing numbers of orgasms, while with the

PFSF domain of orgasm, we were assessing the ease

and reliability of orgasm.

[Slide.]

In summary, after listening to what was

important to women with HSDD, we developed and

validated instruments to measure clinically

meaningful endpoints. Both of our pivotal trials

showed strong and consistent efficacy using these

rigorously developed instruments.

Surgically menopausal women with

hypoactive sexual desire disorder experienced a

significant increase over placebo in sexual desire

and satisfying sexual activity. They also

experienced a significant decrease in distress

associated with their low sexual desire. All three

of these endpoints are critical to assessing a

relevant treatment response in this clinical

condition.

Patients further experienced benefits in

sexual arousal, orgasm, pleasure, sexual

responsiveness, sexual self image, and a decline in

sexual concerns. Patients also had increased

number of sexual events, and numbers of orgasms.

The consistent significant improvement in

all areas of sexual functioning identified by

patients as important demonstrates the clinical

meaningfulness of Intrinsa therapy to these women

with HSDD.

Dr. DeRogatis will now provide additional

perspective on the clinical relevance of these

results.

Thank you.

Clinical Relevance of Treatment Effects

DR. DeROGATIS: Good morning.

As the Director of the Johns Hopkins

Center for Sexual Health and Medicine, I see and

treat a full spectrum of patients with sexual

disorders. I also have a strong professional

interest in the methods and techniques determining

clinical relevance of the results of clinical

treatment trials.

Dr. Lucas has shared with you the efficacy

results from the Phase III trials. Now I'd like to

speak with you about the clinical relevance of

those results.

[Slide.]

To begin with, I'd like to emphasize that

the results from the Phase III clinical trails

implicitly speak to clinical relevance in a number

of ways. First, recall, as Dr. Lucas pointed out,

all of the endpoints for both the Phase II studies

and the clinical relevance study are derived

directly from conversations, interviews, etcetera,

with patients who expressed their concerns,

experiences and what was important to them.

Instruments developed in this way, by the very

nature of the process, have clinical relevance for

the patients.

Second, the decrease in personal distress

indicates in a very direct manner the impact that

the testosterone patch treatment had on the

patients' feelings about heir disorder.

Third, the fact that all of the PFSF

domains--not just desire--show improvement with

testosterone patch treatment gives us confidence

that there is a meaningful treatment benefit

associated with the patch.

In addition to this implicit evidence from

the Phase III trials, the sponsor also did a formal

Clinical Relevance Study which employed the

anchoring technique, and I'd like to tell you more

about that now.

[Slide.]

The anchoring technique for examining

clinical relevance is very well established through

broad use in numerous disciplines of medicine.

Advantages of the method are that it's readily

understood. Perhaps the most important advantage

involves the fact that it's patient-based; it

utilizes direct questions of the patient as to the

patient's perception of clinical benefit. These

patient perceptions of benefit are then tied,

through statistical analyses, to the major study

endpoints. The statistical analysis in this case

is Receiver Operating Characteristic Analysis--or

ROC analysis.

The results then define meaningful change,

in terms of what are referred to as "minimum

clinically important differences," which helps to

establish clinical relevance.

[Slide.]

What you're looking at now is a model of

the anchoring technique that was used to relate

patient perceptions of meaningful benefit to

changes in major outcomes measures in the Phase III

trials. The Clinical Relevance Study essentially

had three stages. In the first stage patients were

queried directly as to their experience, or not, of

what they perceived to be a meaningful benefit.

Those that answered "yes" were indicated as

"responders," those that answered "no" were

indicated as "non-responders."

In step to, these data were then utilized

in receiver operating characteristic analysis, with

each of the three main study endpoints: the PFSF,

the SAL and the Distress Scale.

Third, each endpoint MCID score was then

applied back to the total Phase III population to

establish proportions of responders and

non-responders in the Phase III trials.

In addition to the anchoring technique, we

also asked patients if they wanted to continue on

the treatment. This is a very telling question in

regard to patient's perceived benefits. And as

we'll see a little later, the results were quite

interesting.

[Slide.]

Let me tell you a bit more about the

details of the Clinical Relevance Study. The

Clinical Relevance Study was performed during a

two-week period immediately subsequent to the

24-week double-blind randomized trial. 132 women

from the Phase III trials were the sample for the

Clinical Relevance Study. All of the interviews

were done by a single female interviewer to reduce

variability--potential variability--across

interviewers.

The interviews began with rather

open-ended questions about experiences in the

clinical study and prior to the clinical study, and

progressed to more specific questions about

perceived benefits, if any, on the part of the

patient.

The specific question for the anchoring

analysis was: "Overall, considering everything

we've talked about today, would you say that you

experienced a meaningful benefit from the study

patches?" Patients answered either "yes" or "no."

Subsequently, when the blind was broken,

we learned that 52 percent of the patients on

testosterone, and 31 percent of the patients on

placebo indicated they had experienced a meaningful

benefit or were responders. Now, these rates of

response are actually fairly typical of a number of

areas in which clinical trials are done in

medicine. They're comparable to the rates we see

in irritable bowel studies, in incontinence

studies, in studies of depression, and so were not

unusual and really not unexpected.

Following the relevance question

concerning benefit, these data were then utilized

in the ROC analysis to essentially determine

responders and non-responders.

[Slide.]

Focusing on this distinction for a moment,

this table contents the mean change from baseline

in the responder and non-responder group in major

study outcomes.

As you can see, they're very different.

If you take satisfying sexual activity for a

moment, we see a mean change of 4.4 satisfying

sexual activities per month on the part of the

responders, and a fractional 0.5 change for the

non-responders.

In terms of sexual desire, there's a 21

point increase in sexual desire in the responder

group, which translates into moving them from

"seldom" feeling sexual desire, to "sometimes"

feeling sexual desire--which, by the way, is the

modal frequency for women in this age group.

Distress also shows a dramatic shift in

the desired direction: almost 37 point reduction in

distress in the responder group. And, again, this

translates into feeling personal distress "often"

to feeling personal distress "seldom." So, some

fairly dramatic results in our responder group.

[Slide.]

Now let me share with you an ROC

analysis--okay? And let me talk about this just

briefly for a moment. What we see in our ROC

analysis is a vertical axis which has our true

positives on it. Our horizontal axis has false

positives. And the ROC curve is actually the

entire distribution of changes from baseline on

this outcomes measure--in this case "satisfying

sexual activity"--in the sample.

Now, where the white diagonal from

upper-left to lower-right intersects the ROC curve

is the point of optimum discrimination; that is,

the value that optimally correctly assigns

responders and non-responders, and minimizes false

positive and false negative errors. This value for

satisfying sexual activity, is 1.11 satisfying

sexual activities a month.

It's a little difficult to conceptualize

fractional sexual activities. And so the sponsor

decided to modify this value a little bit to

"greater than 1," thereby retaining the accuracy of

the result, but sparing us the difficult task of

trying to conceive of fractional sexual activities.

ROC analysis has a summary statistic

associated with it that tells us, essentially, how

good the discrimination was--in this case, between

responders and non-responders. This is referred to

as the "area under the curve"--AUC

coefficient--which on this particular analysis is

.77.

Now, this is very good, since experts in

the field believe that .80 is actually an excellent

discrimination. Analogous analyses were done for

sexual desire and for personal distress. The

coefficients in those instances were .77 and .78,

respectively.

So, we wind up with excellent

discrimination in our constellation or set of

outcomes measures.

[Slide.]

Now, lets look at our anchoring model with

all the data filled in.

Over on the left we see our information on

patient perception of meaningful benefit: 52

percent of those on testosterone, and 31 percent of

those on placebo have a meaningful benefit. These

data, when integrated with ROC analysis produce

these optimum cutting scores--or MCIDs--which, when

applied to the Phase III population generate these

proportions of responders--okay?--on each of our

study outcomes measures.

Now, the three main points to be made here

are the following: first, these percentages are

approximately equal across the three major study

endpoints; second, each shows a statistically

significant advantage for the active treatment;

third, the Phase III results or rates of responders

are very analogous to the rate of responders we saw

in the Clinical Relevance Study.

[Slide.]

Now I'd like to share one final set of

results from the Clinical Relevance Study involving

interest in continuing treatment. In this graph

what we see is that 80 percent of those who

indicated they had a meaningful benefit also

indicated that they probably or definitely would

continue treatment with the patch if it were

available. Conversely, an approximately equivalent

proportion of individuals who did not experience

meaningful benefit indicated they would not wish to

continue treatment with the patch.

Now, these results are an important

measure of clinical relevance because they help

confirm that the patients' assessment of meaningful

benefit is truly valid in terms of intended

behavior, not simply perception.

[Slide.]

So, in summary, what did we learn from the

Clinical Relevance Study?

First, we learned that significantly more

testosterone patients than placebo patients

experienced meaningful benefit.

Second, anchoring, using minimum clinical

important difference values, confirms similar

proportions of responders in the Phase III studies.

Third--and perhaps most importantly--these

results are consistent across all study endpoints:

sexual desire, satisfying sexual activity, and

personal distress.

[Slide.]

So, in conclusion, I think I have to

conclude that a consistent pattern of outcomes

shows strong evidence of a clinically meaningful

benefit, which translates into observable clinical

relevance. Both as a clinical scientist and a

practicing clinician, I would conclude that these

data strongly support the sponsor's contention that

the efficacy outcomes achieved by the testosterone

patch are, in fact, clinically relevant.

Thank you.

Phase III Clinical Safety Data

DR. LUCAS: Now to turn to safety.

[Slide.]

As we started to plan the safety

evaluations to be included in the surgical

menopause program for Intrinsa, we identified these

areas of potential concerns for testosterone in

women. We reviewed the literature for known

androgen effects in animals and humans, including

hyperandrogenism in women, and adverse effects

reported with androgen treatment in men.

We also consulted with experts

knowledgeable in two areas where there was less

literature: high dose androgen used in

female-to-male transsexuals, and androgen abuse

with athletes and body builders. We then sought to

assess each one of these areas in our safety

evaluations.

[Slide.]

Recall--as I told you earlier--the SM

trials--SM1 and 2--were essentially of identical

design: six-months double-blind, followed by

open-label. Baseline health risks were balanced in

the treatment arms and across trials.

The primary safety data I will present are

from the double-blind portion of the SM1 and SM2

trials--seen here in brackets--since, as you know,

a placebo-control offers the best opportunity to

determine a drug effect. I will also show you dat

on patients who dropped from the study during the

open-label period--which you see here in white.

Finally, I will present double-blind adverse event

data from the still ongoing natural menopause

program. These data are very similar to those seen

in the surgical menopause trials, and provide the

opportunity to see double-blind data with up to 12

months of testosterone exposure.

[Slide.]

1,800 patients in the Phase II and III

treatment trials have been exposed to 300 mcg per

day testosterone or greater. Over 1,300 patients

have received at least six months of therapy, and

over 600 have received over 12 months of therapy.

This represents an exposure of more than 14,000

months, or over 1,000 patient years to the 300 mcg

per day testosterone patch in post-menopausal

women.

[Slide.]

I will show you the safety data in this

order, starting with adverse event profile, weight

and vital signs, laboratory evaluations, and,

finally, breast cancer.

[Slide.]

The numbers of patients reporting AEs

overall--in both Phase III studies--were similar

between the active and the placebo groups, and

between the two trials. About 75 to 80 percent of

patients had at least one health occurrence during

the six-month period. The small number of serious

adverse events, and dropouts due to adverse events,

were consistent between active and placebo

treatment, and between the two studies, as well.

No deaths occurred in the SM1 trial.

There was one death in the placebo group of the SM2

trial.

Looking at the most common AEs about

one-third of patients reported an application-site

skin reaction, including mild redness or itching at

some time during the six-month trial. About 75

percent of these reports were considered "mild."

Application site reactions were not higher in

patients receiving patches containing testosterone.

About 3 percent of patients dropped out because of

these site reactions in all of the arms.

[Slide.]

Now, to look at these known androgenic

effects with ADs and clinical assessments.

In the testosterone-treated arms, 94

percent of the androgenic AEs were assessed as

"mild." 78 percent of patients reporting

androgenic AEs experienced only one of them during

testosterone therapy. Further, time to even was

not different between the active and

placebo-treated groups for any of the androgenic

AEs.

[Slide.]

Acne was evaluated in two ways: clinical

assessment and AEs. Clinicians were trained in the

use of the Palatsi scale to evaluate patients for

facial acne at scheduled visits. About 98 percent

of patients in both active and placebo groups had

no positive change in their acne score.

Looking at acne AEs--which were reported

by both physicians and patients--there were no

differences between active and placebo in SM1. In

SM2 there were fewer reports of acne in the placebo

group than in the testosterone treated group.

[Slide.]

Facial hair was also evaluated in two

ways: clinical assessments and AEs. We also

trained our investigators to use a modified

Ferriman-Gallwey scale to assess facial hair

growth. With these evaluations, we again saw no

difference between active and placebo in SM1. In

SM2 we did see a mild increase in active over

placebo, primarily in chin-hair growth.

Patient-reported AEs mirrored the

objective evaluations for facial hair growth, with

no differences seen in SM1, and higher reporting

with testosterone in SM2.

[Slide.]

Now, to look at the less common androgenic

AEs--investigators specifically asked patients

about hair loss and voice deepening at regular

visits. Answering "yes," as well as spontaneous

reports, were included as AEs. Again, we saw no

differences between groups in SM1, and a slightly

higher incidence in SM2 in the active group over

placebo.

The one reported case of clitoromegaly in

SM2 was reported by phone after 12 weeks of

therapy. This was not confirmed by physical exam.

She withdrew from the study and, when contacted

five weeks later, she reported the condition had

resolved.

[Slide.]

This slide shows the withdrawals due to

androgenic AEs. Please note that some patients

reported more than one androgenic AE, so this

represents an overall withdrawal rate due to

androgenic AEs in the two trials of 1.2 percent,

and 1.8 percent in the testosterone arms.

[Slide.]

We also looked at other adverse events

that could be important to this population. We

looked at breast tenderness and hot flushes to

confirm that we were not potentiating estrogenic

adverse events, and saw no increase with

testosterone therapy.

AEs of weight gain were examined and were

minimally higher in the testosterone-treated

groups.

[Slide.]

When we looked at weight gain objectively,

we saw a similar small difference. Mean weight

gains of about 1/4 of a kilogram--or - pound,

compared to similar mean weight losses of about -

pound in the placebo arm were seen. We also

examined vital signs and saw no change from

baseline in mean systolic or mean diastolic blood

pressure in either SM trial, in either arm.

[Slide.]

We also looked at other adverse events

that were reported in the male testosterone labeled

products. We saw no difference in anxiety, edema

or aggression.

[Slide.]

Because we saw liver function testing AEs

in the testosterone arms only, we evaluated each of

these patients individually. This represents six

patients, which I would like to tell you about.

Of the six, two of the patients had

isolated bilirubin AEs--increases. Both patients

wree just at the upper limit of normal, and

increased very minimally at 24 weeks.

Four patients had transaminase increases.

Three of the four had mild increases, with less

that two times upper limit of normal. Of these

three patients, two patients remained on

testosterone therapy, and their levels returned to

normal. One patient was still mildly

elevated--just above the upper limit of

normal--after completed 52 weeks of therapy, and

when she was examined after completing the trial,

and off testosterone, remained just about the upper

limit of normal where she had been before.

The final AE--the patient with a moderate

transaminase elevation--her ALT went from 9 to 91,

her AST went from 12 to 94--she also returned to

normal while remaining on testosterone therapy

after she discontinued chetachinasol, a drug known

to be associated with elevated liver function

testing.

[Slide.]

When we examined liver function testing

overall, we saw no difference in the mean changes

from baseline in any parameter of liver function

testing--as shown here--for either placebo or

testosterone. When we looked for outliers, no

difference was seen between treatment arms for any

parameter.

[Slide.]

Now, moving on to hematology, there was a

small--very small--clinically insignificant mean

increase in hemoglobin and hematocrit, seen in both

testosterone groups. This averaged about - percent

of hematocrit, and about 1/6 gram per dL of

hemoglobin.

[Slide.]

To confirm this was of no concern to

patients at highest risk for polycythemia, we

evaluated all patients on testosterone therapy with

this scattergram. Baseline hemoglobin levels are

on the x-axis; 24-week hemoglobins are on the

y-axis. Therefore, for a patient who did not

change, her dot would fall on the 45 degree line.

Generally, we saw no large increases.

Of particular concern, though, are

patients who started off with a high hemoglobin at

baseline. These patients, like patients generally,

show no evidence of concerning increases.

[Slide.]

Now to talk about assessing changes

associated with cardiovascular risk. We've already

talked about blood pressure and weight; now to talk

about carbohydrate and lipid metabolism.

To assess carbohydrate metabolism, we

measured fasting glucose, fasting insulin, and

HbA 1c. As you can see here, mean

increases were not

different in the testosterone and placebo-treated

groups in either trial. When we looked for

outliers in each of these parameters, there was no

difference seen between the treatment groups.

[Slide.]

Additionally, no drug effect was seen on

any parameter of the lipid profile that we

measured, either: total cholesterol, HDL, LDL, or

triglycerides. Again, outliers were not different

in the two treatment groups for any of these lipids

measured.

[Slide.]

We also evaluated changes in coagulation.

Here you see mean changes in laboratory evaluations

for clotting. Again, we saw no evidence of adverse

changes with testosterone therapy.

[Slide.]

We also looked at women who were at

potentially the highest risk for cardiovascular

risk, with four adverse laboratory changes.

When we looked at 150 women who were

positive for at least three of these five criteria,

that included obesity; adverse lipid profile or on

a lipid-lowering agent; hypertensive or on an

anti-hypertensive; or had elevated fasting

glucose--our best surrogate for metabolic syndrome

in the trials.

We found no evidence of more adverse

laboratory changes in this subpopulation.

[Slide.]

Here we see the AEs reported in the

open-label period of weeks 25 through 52, and the

extension, 53 through 78. Patients who were on

placebo for the first six months, and then on

open-label the second six months are noted

"P->TTS," and as they enter the second year,

"P->TTS->TTS."

Patients who were randomized initially to

testosterone, and then went into open-label

testosterone are noted "TTS->TTS," and then, again,

"TTS->TTS->TTS."

During the open-label period, patients

with up to 12 months of exposure in the TTS->TTS

group showed only minimal differences in overal

serious AEs or withdrawals due to AEs, compared to

patients who were having up to six months of

exposure in the P->TTS group.

Incidents of AEs were similar in the week

53 to 78 extension to those seen earlier with up to

18 months of exposure.

Average withdrawal rates due to androgenic

AEs were also very similar, regardless of exposure

up to 18 months.

[Slide.]

Looking at some of the same parameters in

the natural menopause population, we see a very

similar picture to what we just saw in the surgical

menopause. NM1 is the six-months double-blind

trial. NM2 is a one-year--52-week-double-blind

trial.

This trial is still ongoing, so that this

data is interim data. You will notice that the

numbers are not equal because this reflects a

one-to-two randomization.

Like surgical menopause, about 70 to 80

percent of patients in natural

menopause--regardless of arm--experienced an

adverse event during the study. Serious adverse

events and study withdrawals were very similar for

patients with placebo and active treatment. Two

deaths occurred from motor vehicle accidents in

NM1.

Breakthrough bleeding AEs were numerically

lower with testosterone treatment in both natural

menopause trials.

[Slide.]

The natural menopause trials also give us

an opportunity to see androgenic AEs with up to 12

months of exposure in a double-blind trial

situation. Minimal differences in androgenic AEs

were seen between the active and placebo trials in

NM1--with the most differences seen in acne and

hirsutism.

Additional blinded exposure of up to 12

months in NM2 did not appear to increase the

incidence of reported androgenic AEs compared to

placebo, or compared to six months exposure in NM1.

[Slide.]

Looking specifically at withdrawals due to

androgenic AEs, minimal differences were seen

between the active and placebo arms, with similar

rates to that that we saw in the SM trials.

Additional blinded exposure of up to 12 months in

NM2 did not appear to increase withdrawals due to

androgenic AEs compared to placebo, or to six

months exposure in NM1.

[Slide.]

The final parameter that I would like to

discuss is breast cancer. We performed mammograms

in all patients over 40 years of age at entrance

and at on year, or exit, if it was greater than six

months.

In our overall program of 2,200 patients,

four patients have been diagnosed with breast

cancer; one DCIS, and three invasive cancers. All

were in the surgical menopause program, and all

were initially randomized to placebo. Remember

that in our Phase III program, patients received

testosterone therapy in the open-label second six

months, regardless of what they were randomized to

initially.

[Slide.]

We evaluated these four cases. Case 1, we

saw in Phase II, and she did not receive any

testosterone. Case 2 was a 63-year-old who

presented with an axillary mass determined to be

metastatic adenocarcinoma, after she received five

weeks of open-label testosterone therapy.

[Slide.]

Case 3 was a 56-year-old who was diagnosed

with tubolobular carcinoma after 37 weeks of

testosterone treatment. Her diagnosis was made

after findings seen in her baseline mammogram

became more prominent.

Case 4 was a 50-year-old patient who was

diagnosed with ductile carcinoma in situ after 24

weeks of testosterone therapy.

This diagnosis was made based on a new

mammographic finding.

[Slide.]

The number of breast cancers observed in

our clinical program is not unexpected and, based

on calculations of expected rates, based on our

number of women and their risk profile. Further,

detecting breast cancer only in patients who

received the least amount of testosterone because

they were initially randomized to placebo, is not

consistent with an association with testosterone.

Also, in patients who have received

open-label testosterone for up to a second year of

exposure, no additional breast cancers have been

identified.

[Slide.]

In summary, after examining safety

evaluations in more than 1,300 women for six

months, and 600 women for a year, we found overal

AEs, serious AEs, and withdrawals due to AEs were

generally similar in the active and placebo-treated

groups.

Small increases in androgenic AEs and

assessments were seen primarily in one surgically

menopausal trial. Mean weight gains over placebo of

about a pound were seen at 24 weeks. And, except

for a very small increase in red-cell mass, no

changes were seen in any mean lab parameter, or

evidence of adverse changes in outliers of any lab

parameter.

So, in conclusion, in surgically

menopausal women with HSDD, the 300 mcg per day

testosterone patch was very well tolerate. No

serious safety concerns have been identified to

date. In both Phase III surgically menopausal

trials, we continue to monitor patients receiving

open-label therapy, most now in their third year of

therapy with no further safety signal being seen.

The safety changes which have been

identified are generally mild, were rarely

associated with withdrawal, and can generally be

easily diagnosed and easily monitored by the

patient herself.

Thank you. And now, Dr. Glenn Braunstein

will address hormone delivery.

Phase III Hormone Data

DR. BRAUNSTEIN: Good morning.

I'm an endocrinologist and clinical

investigator with over 30 years of experience in

treating women with hyperandrogenic disorders, as

well as androgen insufficiency.

Dr. Lucas has shown you today that the

testosterone transdermal patch is both safe and

efficacious. But one of the concerns that we

clinicians have is the potential impact of

long-term exposure to androgens administered

therapeutically.

So my role is to examine the hormone

levels achieved with Intrinsa, and to show the

relationship between the androgen levels and the

efficacy, and especially the safety parameters.

Hopefully, my presentation will provide additional

reassurance that the transdermal testosterone

system is safe and efficacious.

[Slide.]

Here is my agenda. To put the levels of

testosterone achieved with Intrinsa into

perspective, I will first review how testosterone

circulates in the blood, because it is important to

realize that not all the testosterone that is in

the blood is available to the tissues. It is also

important to understand that one of the main

determinants of how much testosterone is available

to the tissues is the level of sex-hormone-binding

globulin--or SHBG. Therefore, I will show you the

effect of Intrinsa on the levels of SHBG, as well

as testosterone.

Then I will show how the free testosterone

levels correlate with the efficacy parameters and

the safety parameters in patients receiving

Intrinsa.

And, finally, I'll also address some

specific safety issues concerning estrogen-related

target tissues: the breast and the uterus.

You will see that the median levels of

free and bioavailable testosterone achieved fall

within a physiological reference ranges for

pre-menopausal women; that there is no accumulation

of testosterone over 12 months of therapy; that the

testosterone levels correlate with the efficacy

parameters; and that there do not appear to be any

many hormone safety issues with Intrinsa.

[Slide.]

This is a diagram of how testosterone

circulates in the blood. Approximately 98 percent

of the total testosterone in the blood is bound to

serum proteins, and the major protein is

sex-hormone-binding globulin, or SHBG, to which

approximately two-thirds of the testosterone is

bound. This binding is very tight and, basically,

the testosterone on SHBG is unavailable to the

tissues.

Approximately a third of the testosterone

is bound to albumin. And this albumin-bound

testosterone is very loosely bound and may diffuse

off of the albumin and enter target tissues.

Only about 1 to 2 percent of the total

circulating testosterone exists in the free or

biologically active state. And we refer to the

combination of the free and the albumin-bound,

weakly bound, testosterone as being bioavailable.

[Slide.]

To put the testosterone levels in

perspective for you, we have established a

reference range, shown by the dotted lines on the

right side of the screen. Note that at the present

time there are no accepted reference ranges for

androgens in women. Testosterone levels in women

vary widely. There is an age-related change, with

the levels peaking in the 20s and then declining.

There is a diurnal variation, with levels being

higher in the morning than in the evening. And

there's also changes throughout the menstrual

cycle, with levels being highest at the mid-cycle

time.

We elected to use a range based upon 161

women aged 18 to 49 years, who had multiple blood

samples attained across the menstrual cycle, and

the hormones were measured and the levels averaged.

Since this is a range that women achieve naturally

during their reproductive life, we felt that the

androgen levels within or near this physiological

range would be safe.

On the next several slides, I will show

you the free, bioavailable and total testosterone

levels, before and after Intrinsa therapy. Because

the levels achieved in both the SM1 and SM2 trials

were virtually identical, we have combined the

results for easy presentation. However, the

individual results are shown in the briefing book,

and I'll be happy to discuss the results during the

discussion period.

[Slide.]

So we will begin by looking at the free

testosterone levels as shown here. And that's

because these are the most important levels, as far

as the cells in the body are concerned.

The circles represent the median hormone

levels, while the whiskers represent the 10

th and

90 th percentiles.

The baseline free testosterone levels

were, as expected, at or below the lower limit of

the reference range in both the patients who were

assigned to placebo, and those randomized to the

testosterone system. This was what was expected,

since these are all women who had undergone

surgical oophorectomy, were receiving estrogen, and

had hypoactive sexual desire disorder.

At the end of 24 weeks, the median level

of free testosterone in the patients on Intrinsa

had increased into the reference range, while there

was no change in the placebo group. And, very

importantly, the levels were very similar at 24 and

52 weeks in the Intrinsa group, indicating no

continued accumulation of testosterone over time.

[Slide.]

Similar results were find for bioavailable

testosterone, which again represents the

combination of free testosterone as well as the

loosely bound albumin testosterone. And, again,

there was no significant accumulation of

bioavailable testosterone between 24 and 52 weeks.

[Slide.]

This slide shows the total testosterone

data. And, although the median total testosterone

levels achieved with Intrinsa were above the

reference range--in part, due to the relatively

high levels of SHBG, which I'll show shortly--it is

important to emphasize that this was not seen as a

cause for concern because the free and bioavailable

testosterone levels--the ones that are most

important as far as the tissues are concerned--were

in the reference range for a majority of the

patients.

We also found that the total testosterone

levels did not change between 24 and 52 weeks.

[Slide.]

Median levels of serum SHBG were stable

over a one-year period of time, and they were all

at the upper limit of normal for the reference

range, reflecting the fact that three-quarters of

the patients in the study were receiving oral

estrogens, while one-quarter were receiving

transdermal estrogens.

[Slide.]

Now let's look at the correlations between

testosterone levels and the efficacy parameters.

This slide shows the consistency of

results across the Intrinsa clinical studies. We

find statistically significant correlations between

the changes in free testosterone and the changes in

the efficacy parameters, including total satisfying

sexual activity, desire, and a decrease in personal

distress.

Very similar correlations were also found

for bioavailable testosterone and total

testosterone.

This finding is also consistent across all

of the trials. We have pooled the Phase II trials,

as shown initially. We have pooled the Phase III

trials, and also in the NM1 trial--the natural

menopause trial--the results show a tremendous

amount of consistency.

Now let's look at the changes in androgen

levels and safety parameters.

[Slide.]

We will examine the effect on estrogens,

either through aromatization to

testosterone--aromatization of testosterone to

estradiol, or displacement of estradiol off of SHBG

by testosterone. We will also look at the effect

of Intrinsa on estrogen-responsive tissues,

including the breast and the endometrium.

We will show the relationship between the

reported androgenic adverse events and the observed

androgenic effects to she testosterone levels, and

we'll show you the results with the free

testosterone correlations and clinical laboratory

measurements.

Although the data linking estrogen use to

breast cancer is unclear, the relationship between

unopposed estrogen use and endometrial hyperplasia

and neoplasia has been established. Therefore, it

was important to examine the effect of Intrinsa on

the serum estrogen levels and on estrogen target

tissues--including the breast and the uterus.

[Slide.]

As shown here the serum total estradiol

levels were similar in patients who received

placebo and those who received Intrinsa, and there

were no changes through 52 weeks on Intrinsa. The

levels were identical between those on placebo, and

those receiving Intrinsa.

Similar results were found for free

estradiol in the serum, as well as serum estrone.

Thus, there does not appear to be any major

increase in aromatization--at least as assessed by

levels in the serum.

Currently available data would also

indicate that aromatization does not appear to be

an issue in the tissues either, as we'll summarize

on the next slide.

[Slide.]

A study was carried out at the Karolinska

Institute in Sweden, in which women who had not

undergone hysterectomy, and who were receiving

estrogen and norenthindrone were randomized to

receive either placebo or 300 mcg ga day of

transdermal testosterone through the patch system.

They underwent mammograms and fine-needle

aspirations of the breast, both at the baseline

state and after six months of therapy. The results

showed that there were no differences between the

two groups in respect to mammographic breast

density, or in breast epithelial proliferation.

There was, however, a significant decrease

in the stromal cell proliferation in patients

receiving transdermal testosterone. And this is

important because the stromal cells are major

source of aromatase enzyme activity in breast

tissue.

In addition, preliminary analysis carried

out on paired endometrial biopsy samples--that's

approximately 300 samples--obtained from women in

the Natural Menopause Study were examined. And two

cases of endometrial hyperplasia were found. Now,

that study is still blinded, and therefore we don't

know whether the samples were obtained from women

who were receiving placebo, or receiving

transdermal testosterone. But even if we assume

that both patients were receiving transdermal

testosterone, that would give an incidence of

approximately 1 percent of endometrial hyperplasia,

which falls within the FDA guidance for

estrogen-progestin combination products.

So these results are consistent with the

lack of any estrogen-related side effects relative

to placebo observed in the safety data presented by

Dr. Lucas.

Now we'll turn to the androgenic side

effects.

[Slide.]

Although the androgenic adverse events in

each of the Phase II and Phase III studies were not

different between women on active therapy versus

placebo, we pooled the results from the Phase II

and the Phase III trials on surgically menopausal

women in order to examine the issue with a larger

group of patients.

We used a trend test to look at the

incidence of androgenic adverse events against the

highest pre-testosterone level measured in each of

the women. The only statistically significant

finding was with facial hair. This was also borne

out with the combined observations of the

investigators at the different trial sites.

Importantly, there were no specific associations

between androgen levels and acne, alopecia, voice

deepening, or clitoromegaly.

And, in a similar manner, we examined the

relationship between changes in the laboratory

parameters and the maxim free testosterone obtained

in each of the women. And these were examined

across both the Phase II and Phase III studies,

which were combined.

These laboratory parameters included tests

of liver function, lipid analysis, carbohydrate

metabolism, hematology values and clotting factors.

These parameters were chosen because they had been

associated with abnormalities with the use of

pharmacologic doses of testosterone, based on

literature studies carried out in both men and

women. And, again, the changes for patients within

the highest decile of free testosterone, compared

to placebo, were small and clinically

insignificant.

[Slide.]

So, in summary, surgically menopausal

women with hypoactive sexual desire disorder had

low testosterone levels at baseline. 300 mcg a day

of transdermal testosterone increased the

concentrations of free, bioavailable and total

testosterone, with no evidence of continued

accumulation over 12 months of dosing.

Serum concentrations of total and free

estradiol, estrone, and SHBG were not affected bu

Intrinsa administration over the year of study.

Higher exposure of free and total

testosterone was not associated with clinically

significant laboratory changes.

[Slide.]

Intrinsa raised the median free and

bioavailable testosterone levels to within the

pre-menopausal reference range that we established,

and these correlated with an increase in the number

of satisfying sexual events, the increase in sexual

desire, and a decrease in personal distress.

Based upon the currently available hormone

data, the one-year safety profile of Intrinsa shows

no cause for concern. Higher free testosterone

levels are associated with small increases in

facial hair in the pooled trials, and the

100

appearance of such androgenic effects would allow

the patient to make a personal risk versus benefit

decision.

Thank you.

It's now my pleasure to introduce Dr.

Shifren.

Hypoactive Sexual Desire Disorder Medical Need

DR. SHIFREN: Good morning.

As a gynecologist and director of the

Vincent Menopause Program at the Mass General

Hospital, I see many women with sexual concerns

after menopause.

Hypoactive sexual desire disorder is the

most common sexual problem that I see in my

practice. It's a particularly poignant problem for

our younger patients who've had their ovaries

removed. After removal of the ovaries, a woman

loses almost all of her estrogen, and approximately

half of her testosterone. We have many options

available for estrogen replacement, but currently

there are no approved testosterone products to

treat our surgically menopausal women who present

101

with sexual dysfunction post-operatively.

Today, I'll tell you about the negative

impact that HSDD has on menopausal women, and talk

also about why I'm an advocate for a low-dose

testosterone patch.

Let me begin by describing some of the

research that helps us understand HSDD.

[Slide.]

The Women's International Study of Health

and Sexuality--or the WISHeS Study--was

specifically designed to better understand HSDD in

women, as available studies didn't completely

capture all important aspects of this disorder--in

particular, distress. This was a self-report

survey of more than 4,500 women in the United

States and Europe between the ages of 20 and 70.

I'll be discussing a U.S. sub-population of 520

surgically and naturally menopausal women with

partners.

This survey used three validated

instruments: the Short Form-36, a measure of

overall health status; and the Personal Distress

102

Scale; and Profile of Female Sexual Function.

So what did these studies teach us?

[Slide.]

Well, we learned that women with HSDD do

engage in sexual activity. As these data

illustrate, partner-initiated sexual activity is

constant for women, whether they have no or normal

desire. But, importantly, women with HSDD are

significantly less likely to initiate sexual

activity. This confirms that focusing only on the

frequency of sexual activity can be misleading when

trying to understand the sexual experience of women

with HSDD.

[Slide.]

Not surprisingly, we also learned that

sexual desire correlates with a woman's overall

level of satisfaction with her sexual life. This

graph shows that women with less desire were less

satisfied with their sex lives. Women with higher

desire scores were more satisfied overall.

[Slide.]

With respect to the effect of low desire

103

on couples, for women, sexuality typically exists

within the context of the important relationships

of their lives. As you can see in this graph,

sexual satisfaction and relationship satisfaction

are intricately related for women. Women who are

less satisfied with their sex lives are

significantly less satisfied with their personal

relationships or marriage.

[Slide.]

As we see in these data from WISHeS--and

as my patients tell me often--the distress women

feel with HSDD extends beyond their loss of desire.

Compared to women with normal desire, women with

HSDD report feelings of low self-esteem, shame and

failure. My patients often are very upset

regarding the impact that their low desire has on

their relationships. And, of note, nearly 90

percent with HSDD report feelings that they're

letting their partner down.

[Slide.]

It's important to realize that HSDD not

only affects a woman's sexual health, but is

104

associated with overall diminished health status.

The WISHeS investigators used the Short Form-36--a

well known and validated measure--to measure study

participants' general health status. Compared to

women with normal desire--in green--women with HSDD

were significantly more likely to report decreased

physical function, general health and vitality.

They also reported lower levels of social

functioning, emotional and mental health.

The SF-36 scores we saw in women with HSDD

are very similar to scores seen in people with

other medical conditions, such as arthritis or

diabetes.

Now we have an understanding of HSDD and

the impact this has on a woman's life. But why

does it happen?

[Slide.]

Female sexuality is a complicated

interplay of physiology, psychology, interpersonal

relationships, and socio-cultural influences. As a

reproductive endocrinologist, my focus is on the

physiologic factors that affect a woman's sexual

105

health. When a woman presents with HSDD, the first

thing I do is rule out non-physiologic causes, as

these couples often benefit from education,

counseling, sex-therapy and lifestyle changes.

Physiologic factors, including medical,

neurologic, gynecologic and urogenital problems all

may have a negative impact on healthy sexual

functioning. For example, I've seen many

menopausal women in my practice with vaginal

atrophy and dysprunia associated with estrogen

deficiency. For these women, sexual arousal and

response often improves greatly after starting

vaginal estrogen therapy.

[Slide.]

But the most common physiologic cause of

HSDD that I see in my practice is androgen

insufficiency--often associated with oophorectomy.

As you can see in this study, removing the ovaries

of both pre- and post-menopausal women results in

an approximate 50 percent decline in testosterone

levels. Many studies over the past 20 years have

shown significant improvements in sexual desire,

106

response and intercourse frequency in surgically

menopausal women treated with testosterone. But no

testosterone product currently is available for

treating our surgically menopausal patients with

HSDD.

So what are physicians and patients doing?

[Slide.]

Unfortunately, we're using products that

have been formulated for men, putting women at risk

for receiving high doses of testosterone.

Compounded products, with limited quality control

and dosing consistency, also are being used.

As you can see, in 2003, approximately 20

percent of total prescriptions for branded male

testosterone products were actually written for

women. And in that same time period there were

over 1 million prescriptions written for compounded

or generic testosterone products, for women.

These data show the need for a quality

testosterone product specifically formulated for

menopausal women, with proven efficacy for all

aspects of HSDD.

107

[Slide.]

Before concluding, I'd like to address a

concern that some of you may have regarding the

clinical meaningfulness of the changes in sexual

function that we saw with testosterone patch

treatment.

An increase of about two satisfying sexual

events per week may not seem like a lot, but for

women whose baseline activity level is only three

events in a four-week period, this increase

represents an important change.

In addition, desire scores increased on

average by approximately 11 points, that means that

women went from "seldom" having desire closer to

"sometimes" having desire. And, most importantly,

patients' distress scores decreased 23 points with

treatment, which means went from being "often"

distressed about their lack of desire in sex, to

"sometimes" being distressed. And this represents

a clinically significant change for women.

It's also important to remember that these

are mean changes with treatment. Some women had

108

little benefit, while others had much greater

improvements in sexual activity and desire. As you

may recall from Dr. DeRogatis' presentation,

responders had greater increases in all aspects of

sexual desire, activity and distress measured in

this study. In addition, women who derive little

benefit from treatment are unlikely to continue

therapy.

[Slide.]

So what I see as a clinician, and what

we've shown you today, is that HSDD is an important

medical condition that has an important impact on

women's lives. Low-dose transdermal testosterone

treatment is a meaningful treatment option for

patients with HSDD, as it improves all aspects of

this disorder.

Intrinsa also is a much-needed option for

patients and physicians who currently have no

approved therapies with demonstrated safety and

efficacy with which to treat our patients.

Thank you.

The next speaker will be Dr. Michael

109

Steinbuch.

Phase IV Long-term Safety Plan

DR. STEINBUCH: Good morning. My name is

Michael Steinbuch, and I'm responsible for

pharmacovigilance and epidemiology at Procter &

Gamble.

Let me begin by saying that P&G is

committed to monitor the long-term safety of

Intrinsa. We believe we can best accomplish this

by conducting a prospectively designed

observational safety that will be comprehensive in

its design, and have the necessary data to detect a

possible safety signal faster than any other

method.

[Slide.]

As you've heard from Dr. Lucas, despite

extensive and systematic patient monitoring during

the Phase III program, there were no serious safety

signals that merit specific follow-up.

Nevertheless, we plan to monitor women exposed to

Intrinsa for longer periods of time.

[Slide.]

110

In addition to routine post-marking

surveillance and Phase III extension studies, we

considered three options to address the long-term

safety of Intrinsa: observational studies;

randomized controlled trials; and patient

registries. Each of these options has advantages

and disadvantages.

We carefully evaluated all options and now

believe that the best way to generate timely

long-term safety data is through a rigorous,

prospectively-designed observational study.

[Slide.]

Observational studies offer several

advantages. They provide a robust method for rapid

signal detection in a real-world setting; an

opportunity to study large numbers of patients' the

ability to adjust for potential confounding

variables; and the opportunity to evaluate all

patients that fill scrips for Intrinsa.

[Slide.]

The FDA reviewed an earlier version of our

proposed Phase IV observational study. The agency

111

raised a couple of issues regarding the potential

limitations of such a study. FDA questioned

whether data in women over 65 would be captured

when post-menopausal women treated with Intrinsa

shift to medicare; and, whether the study would

provide adequate power to detect an excess risk of

safety events of interest with women in this age

group.

However, in our clinical trials, where we

actively recruited women ages 20 to 70, the women

over 65 represented only 2 to 3 percent of the

study subjects. As you just heard from Dr.

Shifren, women are currently using various forms of

prescription testosterone. Among the 30,000 female

testosterone users in our proposed study database,

only 3 percent are over 65. Also, the

disenrollment rates are comparable, whether they

are younger or older than 65.

Partly in response to FDA's response, we

updated our study design. I'll show later that the

updated study will be powered to detect potential

safety signals.

112

Now, let's take a look at what we're

proposing.

[Slide.]

We plan to contract with Ingenix, the

research affiliate of United Healthcare, to conduct

this research. Ingenix LabRx is a large,

comprehensive insurance claims database. It

represents approximately 5 percent of the U.S.

population. It covers a range of health care

services, and includes hospital, physician,

pharmacy and laboratory data.

United Healthcare has an open formulary.

In this multi-tier system, virtually all

prescription drugs--including drugs for sexual

dysfunction--have at least partial reimbursement.

As a result, drug usage will be captured in the

database.

Upon IRB approval, Ingenix will validate

endpoints by identifying and reviewing all relevant

records. About 85 percent of those are available

for abstraction, and 90 percent of all medical

claims are processed within four months.

113

United Healthcare has a stable enrolled

population, with 85 percent per year. In addition,

Ingenix has an experienced research staff and a

proven track record with studies of this type.

[Slide.]

For example, the FDA has accepted numerous

observational studies using the Ingenix database as

a method to assess product safety. This database

has demonstrated utility across a range of drugs

and study endpoints in post-marketing safety

studies. These include allergic reactions and GI

outcomes, among others.

[Slide.]

The objective of our study is to compare

event rates in Intrinsa users versus non-users,

using a prospective cohort design with three-to-one

matching. Matching variables will be carefully

selected, and may include a propensity score, which

is a proxy for overall health status. Appropriate

matching minimizes biases between groups.

We propose the study be conducted for a

period of five years. All patients exposed to

114

Intrinsa will be included in the analyses. Of

note: there are no exclusion criteria. Endpoints

of interest will include both cardiovascular and

cancer events.

Let's take a closer look at the Ingenix

database.

[Slide.]

There are 10 million patients in the

database; of those 600,000 are menopausal, and

135,000 are menopausal women taking estrogen.

Based on estimates of HSDD disease prevalence from

the literature, we expect approximately 19,000

potential users of Intrinsa. Assuming 30 percent

of these women fill a prescription for Intrinsa,

there would be about 5,500 Intrinsa-treated

patients in the first year following launch.

[Slide.]

To provide estimates of the size of the

patient population and power to detect safety

signals over the course of the five-year

observation period, we needed to make certain

assumptions. For example, we have assumed a fixed

115

rate of 5,500 new patients per year; a .15 percent

event rate per year for cardiovascular events--as

was observed for the 50 to 59-year-olds in the WHI

study; a 50 percent discontinuation rate per year;

15 percent disenrollment per year; an alpha of .05,

and a one-sided test, which has more power to

detect a safety signal.

[Slide.]

Given these assumptions, if a major safety

signal emerged, we would be able to have 82 percent

power to detect a relative risk of 1.9 as early as

two years post-launch. AS person-years of

observation accrue over time, our ability to detect

smaller differences will increase.

[Slide.]

We recognize that observational research

encompasses a broad range of techniques, and varies

greatly in terms of their robustness. We've

proposed an approach that will maximize its value

as a signal detection method. This comprehensive

design will have a number of components not

typically found in observational research. These

116

include a collaborative protocol development with

external experts and FDA involvement and approval;

a blinded medical expert panel to adjudicate events

ascertained from medical record abstraction. And,

importantly, an independent safety review board

will be established with no P&G participation or

representation on the board. The independent board

will be responsible for identifying possible

issues, as well as analyze, interpret and report

results to FDA and P&G.

Initial data will be available at 18

months post-launch. Results and analyses will be

available for review about two years post-launch.

[Slide.]

In addition to observational studies, we

considered randomized controlled trials and patient

registries.

[Slide.]

Randomized controlled trials are idea for

testing hypotheses and determining cause and

effect. They offer the advantage of random

allocation of study subjects, which minimizes

117

confounding. However, RCTs such as large simple

trials are typically conducted in restricted

patient populations, based on a set of inclusion

and exclusion criteria.

The reality is, they may not reflect

actual use of the product in the marketplace. We

believe the major issues with a randomized safety

trial for Intrinsa are recruitment, retention and

adherence to treatment. In the WHI, for example,

the participants were presented with a potential

for a cardiovascular benefit, and yet 80 percent

refused randomization.

As you heard this morning, RCTs are very

large, and would require screening extremely large

numbers of women. In our clinical trials, we

enrolled 1,200 women from 100 sites in six months.

Based on this experience, an RCT would take several

years for patient enrollment, and five more years

for follow-up.

We believe these factors would be major

barriers to executing an RCT and detecting a signal

in a timely fashion.

118

[Slide.]

While patient registries have the

advantage of allowing the study of large numbers of

exposed patients in a real-world setting, there is

no practical method to identify a relevant

comparison group.

[Slide.]

Procter & Gamble Pharmaceuticals will

monitor the long-term safety of Intrinsa and will

continue working with the FDA and Ingenix to refine

the study plan.

Ingenix's robust infrastructure will be

instrumental in executing a successful

observational study.

Our approach is novel, in that we plan to

implement the study at launch. We will have input

from external experts to help us design the study,

and we'll have this independent safety review board

to execute, analyze and report study results to the

FDA.

We believe this is the best study design

for detecting a possible safety signal quickly, and

119

we're committed to making this happen.

Thank you for your attention, and I'll now

turn the podium over to Dr. Meyer.

Closing Remarks

DR. MEYER: For my wrap-up, what I'd like

to do with you is go over the questions that the

FDA posed to you this morning. Due to time

considerations, I'll be happy to answer any

questions on our plan to maximize the safe use of

Intrinsa with physicians and patients during the

discussion period this afternoon.

The first question: The first is an

efficacy question: "Do the efficacy data represent

clinically meaningful benefit?"

Yes. We assessed three related but

independent endpoints, all critical in HSDD.

They're concordant but they're not redundant. They

measure different aspects of the disease. These

efficacy assessments were patient-centered. The

patients told us the results were relevant. And

independent observers confirmed these results were

relevant. And the statistics told us these results

120

were relevant.

The primary endpoint and all the secondary

endpoints were highly statistically significant.

The results were consistent across studies and

across endpoints.

In addition, the randomized withdrawal

trial that we ran reinforced that the

pharmacological effect of the drug was better than

that of placebo.

Question 2: "Is the patient exposure

adequate to demonstrate long-term safety?"

Yes. As Dr. Lucas showed you our exposure

table, we have over 14,000 total patient-months of

exposure--and these data are from June, when we

were preparing our 90-day safety update for the

agency. We have an additional 180 women in the

surgical menopause program with 12 months of

exposure; an additional 100 women to include in the

18 months of exposure. We currently have 80 people

already in year three of the surgical menopause

extension.

Because of the study that we're finishing

121

up enrolling, looking at the patch in women not on

concomitant estrogen, one year from now we will

have an additional 2,500 patient years of exposure

to 300 mcg of Intrinsa.

Question 3: "Are the safety concerns or

unanswered questions that need to be studied?"

Well, as you are all aware, it is not

uncommon to have unanswered safety questions at

approval. As you think about this relative to

Intrinsa, it's important to keep in mind thus far

we have seen no significant safety signals. And

there's substantial experience already, in the real

world, with concomitant androgen and estrogen use.

Testosterone is not a new drug.

Importantly, we have committed to a

strong, independent post-marketing safety study to

be put in place at launch. Also we welcome the

opportunity to hear more ideas from the committee

and the agency about how to strengthen our labeling

to address safety issues.

Number 4--this is an easy one for you:

"Are the efficacy and safety data adequate to

122

support approval of the transdermal testosterone

system?"

Yes. We feel very strongly that the

efficacy and the safety data are adequate to

support approval of Intrinsa to provide women with

HSDD and their physicians this important treatment

option.

Thank you for your time.

DR. GIUDICE: I'd like to thank the sponsor

for their presentation this morning.

We're scheduled to take a break, but

before we do, for those who are going to

participate in the open public hearing, please be

sure that you have registered outside, and please

do this before the end of the break, otherwise you

will not be able to participate in the open public

hearing.

So we will take a break, and let us

return, please, at 10:15. Thank you.

[Off the record.]

DR. GIUDICE: Back on the record.

Please take your seats and we can continue

123

with the morning session. Thank you.

We will now continue with the FDA invited

speaker, Dr. Adrian Dobs, who's professor of

medicine from Johns Hopkins University, who will be

talking on safety of exogenous testosterone in

women.

FDA Invited Speaker

Safety of Exogenous Testosterone in Women

DR. DOBS: Good morning. My name is Adrian

Dobs, and I'm an endocrinologist at Johns Hopkins.

And when discussing the safety issues,

it's really important to think that we're not

talking only about testosterone, but also its

metabolites.

[Slide.]

Testosterone is reduced through

5-alpha-reductase to dihydrotestosterone, and it's

likely the DHT that has the effect on facial and

body hair, scalp hair loss, acne and hirsutism.

It could also act directly on muscle,

bone, causing virilization with clitoromegaly,

brain and sexual function. And then it can be

124

aromatized to estrogen, and estrogen is likely

acting directly on the breast and the uterus, and

on the bone, brain and libido.

[Slide.]

So, what I'd like to do today is go

through with you, as an outline, of what are the

safety concerns with testosterone administration.

A lot of this has been derived from a review

article we just published in the Mayo Clinic

Proceedings, which is in your packet for the

committee members.

So what I'd like to discuss is the

androgenic effects, cardiovascular

effects--particularly lipids, vascular reactivity,

glucose tolerance and hematopoietic. Then I'd like

to discuss the endometrial and breast effects, and

finally try to come up with some kinds of

recommendations.

[Slide.]

When discussing the androgenic effects,

the main three androgenic effects is that of acne,

hirsutism, and virilization. The usual clinical

125

presentation of this is acne, increased hair

growth, clitoromegaly, temple baldness and lowering

of the voice. Testosterone is involved in

thickening of the vocal chords, that's why men have

lower voices than women.

In general, one would say that at higher

doses these are extremely common. At low dose of

androgen replacement, it's probably more rare or

mild. It has been shown as a mild effect--of acne

and hirsutism--in some of the studies with

methyltestosterone.

In general, I would make the statement

that it is dose and duration dependent, and most of

these effects are reversible. The "most" would

refer to temple balding. It's unclear if that will

be fully reversible, or the clitoromegaly may take

years to see any kind of resolution. But the acne

and the hirsutism in a period of months will

probably resolve.

[Slide.]

This is a study looking at hirsutism

scores with a methyltestosterone done by Elizabeth

126

Barrett-Connor. And she looked at varying

combinations of estrogens with testosterone.

Here's androgen, a low dose. Here's androgens at a

high dose. And in the light orange color is the

percentage of subjects who claimed that they got

worse by taking a high dose of androgens.

So you see there's a trend there that

actually was not statistically significant. So

that hirsutism and acne would not be surprising

observations in women taking testosterone.

[Slide.]

Now, a large concern is obviously

cardiovascular effects, and here there really is a

great deal of question.

First, to begin with, this is an example

of a study looking at the relationship of

endogenous hormones to cardiovascular risk. And

this is looking at the odds ratio of developing a

cardiovascular event, compared to the four

quartiles of hormones. So here is testosterone in

green, adjusted for risk and the free androgen

index. And what you could see here is that

127

individuals who are in the fourth quarter--the

highest quartile--of androgens have an increased

risk of developing some kind of cardiovascular

event. And this is data from the Women's Health

Study.

So there is this interesting relationship

between endogenous hormones.

So what is the specifics of this?

[Slide.]

Well, there have been a few studies

looking at testosterone in women. Generally, with

all androgens, there's a clear significant

reduction in HDL cholesterol. It's likely neutral

on LDL, and it does result in a lower of

triglycerides. The reason for this is probably the

first pass through the liver, and the changes in

hepatic lipase.

The data from women state that it's very

dependent on the route of administration--that is

oral testosterone will have a greater effect than

transdermal, and also the type of

testosterone--whether or not its methylated or an

128

anabolic steroid.

In general, aromatizable androgens--that

is, testosterone that's converted to estrogen--have

a neutral effect.

[Slide.]

This is some of our data looking at

changes in lipids with a methyltestosterone, and as

you can see, there's a pretty impressive decline in

the HDL cholesterol, as there is a decline in the

triglycerides.

[Slide.]

However looking at Shifren's data, there

was really very little change across all the lipid

parameters when used in a transdermal preparation.

[Slide.]

Now there's also questions about vascular

reactivity. This has to do with endothelial

dysfunction. It has been found to be an earlier

marker of cardiovascular disease; that is the

stiffness may predict the development of

cardiovascular disease. This has been studied in

small non-invasive publications, looking at

129

flow-mediated vasodilatation. And it turns out

that epidemiologically, there is a decline in this

flow-mediated dilatation in women as they go

through the menopause.

The best way to study this is by looking

at brachial artery reactivity. And this has been

done by looking at endothelial independent

dilatation, which is a glyceryl trinitrate induced

kind of a procedure.

[Slide.]

So this is just one example of a study,

looking at the effects of testosterone on vascular

reactivity in women. This is flow-mediated

dilatation before and six weeks after testosterone,

to show that there was increased flow. This is the

control group, and this is women that were given a

type of nitroglycerin that would vasodilate. And

there is a statistical increase in vasoreactivity.

There's some mixed data on this. I would

probably make the statement that testosterone has a

very minimal effect on vascular reactivity, and

perhaps it could be beneficial.

130

[Slide.]

Plasma viscosity is of great concern when

discussing cardiovascular effects. We know from

epidemiological studies that increased plasma

viscosity is a risk factor for cardiovascular

disease, and does predict coronary artery disease

development. The physiology here is not very

clear. It seems to be affected by fibrinogen and

triglycerides. And the only thing I could say is

there's just been a few small studies evaluating

this, and in one study they did show that there's

actually improvement in viscosity when women were

given testosterone.

[Slide.]

When it comes to hematopoietic factors,

we've known for many years that testosterone is

involved with erythropoiesis. It, in men, can be

associated with polycythemia, and polycythemia is a

risk factor for cardiovascular disease.

In looking at some large epidemiological

studies with increasing hematocrit, there is an

increase in cardiovascular risk.

131

The mechanism for this is that

testosterone is involved in stimulating production

of erythropoietin, and also in erythroid colony

units. In men, it's very clear that testosterone

can cause erythrocytosis. This is dose-related.

It's area-under-the-curve-related, so that men who

have been given injectable testosterone are much

more likely to be found to have increase

hematocrits. In men given transdermal types of

testosterone, there's essentially very little

problem.

In women, few studies have been done. In

a study of 22 young women using a testosterone

implant there was no effect on clotting factors.

And you heard some data earlier this morning about

the new transdermal compound.

Essentially, I could not find any reports

of true polycythemia in women.

[Slide.]

Now, glucose metabolism is clearly a risk

factor for cardiovascular disease, but for

hyperglycemia and hyperinsulinism. There's very

132

little data here. There seems to be no evidence of

changes in fasting glucose or in insulin

sensitivity, although I would say there's little

data in both men and women.

I think the big caveat to this is what

we're learning more and more about, which is that

of polycystic ovarian disease and metabolic

syndrome.

[Slide.]

This is just some data from Shifren

looking at glucose and insulin across groups. And

there was no difference. This is just looking at

fasting studies.

The big problem and the big question here

is that there seems to be a fairly consistent

relationship between endogenous testosterone and

cardiovascular risk. When we're talking about

polycystic ovarian syndromes or metabolic syndrome,

metabolic syndrome is being increasingly recognized

as a risk factor for the development of

cardiovascular disease. In this situation, it's

noted to have obesity, hyperinsulinism,

133

hyperandrogenism, and hyperlipidemia.

The mechanism for the hyperandrogenism in

this complex of metabolic syndrome and PCO is not

very clear. I've just written down one postulate,

and that is the hyperinsulinism stimulates

testosterone production from the ovary, and this

works to decrease SHBG, and that works to increase

free testosterone.

So I think of challenges that are ahead is

really to determine what is the relationship here

of testosterone, metabolic syndrom, PCO, and how to

put this into context. Is it testosterone per se

that's having a cardiovascular risk, or is it its

metabolism to estradiol?

[Slide.]

I'd like to next talk about the potential

side effect of endometrial or breast effects.

Again, from endogenous hormone levels in

epidemiological studies, there seems to be a

relationship between hormones and the development

of disease. So this is looking at the odds ratio of

endometrial cancer, by quartiles of steroid

134

hormones in post-menopausal women. And the green

is estradiol, and blue is testosterone. And you

see here that women with increasing doses of

endogenous hormones will have an increased risk of

developing endometrial cancer.

[Slide.]

There's been several reports of

hyperplasia and cancer with the use of high doses

of testosterone. Most of this data comes from

women who were given high doses of testosterone for

transsexualism. This may not be applicable in this

particular discussion. But clearly in that

population when the serum testosterone level gets

into the level of a male level, that testosterone

will be aromatized to estrogen and run the risk of

unopposed estrogen and the endometrium.

With low doses there is essentially no

cancers that have been reported. There has been,

in one study, endometrial hyperplasia that was seen

in one of 107 women given methyltestosterone. But

it was also seen in one of 111 women given

estrogen. So there clearly will be this issue of

135

unopposed estrogen in women who have a uterus and

might not be taking progesterone.

In one study there was a 6 percent

incidence of cystic endometrial hyperplasia. And

in another study, though, they did study vaginal

cytologies. And these were all stable throughout

the course of the study.

[Slide.]

Breast cancer risk is something that needs

to be discussed. Epidemiologically it's similar to

the endometrial data in that there seems to be a

relationship between high endogenous testosterone

and breast cancer.

With hyperandrogenism itself, it seems to

be related to the association with metastasis. The

physiology here, it's been postulated to be due to

the fact that there is androgen receptors that are

found in 50 to 90 percent of breast tumors. This

testosterone therefore may act directly to

stimulate breast epithelium, or it may be

aromatized and therefore it's the estrogen that's

acting on the breast tissue.

136

In women there have been no reports of

breast cancer that came from exogenous testosterone

treatment. We did hear this morning some cases of

active and placebo-treated women.

[Slide.]

now, there are some other possible

effects, but these are really very mild, but I'll

just mention them in passing.

In men given alkylated androgens there's

been associated hepatotoxicity and hepatic

adenomas. This has not been the case with

transdermal testosterones. In women, there's

essentially no evidence of abnormal liver

functions, either with pellets or transdermal.

There's a theoretical risk of some fluid

retention with testosterone, but really not in the

doses used even in men, and certainly no one would

expect it in the doses for women.

[Slide.]

There's a great deal of question about

anger and hostility. This is a very difficult

parameter to measure. Some studies have asked

137

questions like "Do you have an interest in smashing

things?"

[Laughter.]

So it's really a very tough parameter to

get one's hands around.

And the physiological explanation would be

that there are certainly androgens and estrogen

receptors in the brain. In men, there's some

questionable data--I mean "questionable" because of

the study design--to say that there may be a

relationship between testosterone and violent

behaviors. I really question this data. In the

clinical trials done in men, even given high doses

of testosterone, it's been very hard to elucidate

whether or not there's any relationship here.

And in women there was one study that

showed that there was some increase in hostility

scores in women given high doses. I think, in

general, this is not a clinical problem. We

generally live in a fairly controlled society.

[Laughter.]

So, I'd like to end up with talking about

138

some recommendations.

[Slide.]

I would say there are some absolute

contraindications for the use of testosterone, and

this would certainly include pregnancy and

lactation, endometrial cancer or any unexplained

vaginal bleeding, and breast cancer.

There might be some relative

contraindications, as well. And that would be

moderate to severe acne or hirsutism, androgenic

alopecia, sever insulin resistance, and anyone with

an anger management disorder.

[Laughter.]

[Slide.]

These are some recommendations.

Obviously, there will be lots of discussions about

this if and when things go further. But these are

some monitoring that I would recommend, in that

acne and hirsutism should be evaluated at each

visit. Virulization should be evaluated at each

visit. Anger and hostility can be asked at each

visit.

139

Breast exams and serial mammograms should

be done conscientiously--likely following strictly

the recommendations, and be done annually.

It's important to ensure that women

treated with testosterone should have regular

OB/GYN exams, and if there's vaginal bleeding this

should be discontinued. Obviously, this is the

assumption that if a women has an intact uterus and

is taking testosterone.

Hematocrits should be evaluated, I think,

after the first three months and then, likely,

annually.

Serum lipids--because transdermal has very

little effect on serum lipids--can really be done

as indicated.

And measuring of serum total testosterone

I think is extremely important to ensure that the

levels do not get very high since, as I've stated

before, the side effect profile for testosterone is

related to the type of testosterone, the route of

administration, the dose used, and the length of

time that the women is being treated.

140

I might recommend that women be evaluated

at six weeks, and then I'd put question marks about

whether or not this needs to be done every six

months thereafter.

[Slide.]

So I think there are several remaining

questions about the safety of testosterone therapy.

With more women being treated for longer periods of

time there will be questions about the long-term

effects on androgenic signs and symptoms.

Conceptually, there is still a lot of

question about the overlap of endogenous

testosterone versus exogenous treatment and

cardiovascular risk, and how this relates to such

things as abdominal obesity in the metabolic

syndrome.

The other remaining questions have to do

with the use of testosterone alone versus being

done in combination with estrogen and progestins.

And really my last point that I think is of

importance is better evaluation for the risk of

breast and uterine tissue.

141

Thank you very much.

DR. GIUDICE: Thank you, Dr. Dobs.

I'd like to point out to the committee

that this is now an opportunity to ask Dr. Dobs any

questions, because there will not be an opportunity

later.

Dr. Emerson?

DR. EMERSON: Have there been any studies

that looked at the relative balance of estrogen

versus testosterone and whether that's predictive?

Or has it always just looked at testosterone levels

versus estrogen levels?

DR. DOBS: They've basically been looked at

separately, although various combinations of free

androgen index, free testosterones. And the issue

of measuring free testosterone in women is a

difficult one. It's difficult enough in men, but

the assay and the level of detection for women can

be quite problematic.

So--no, I'm not aware of ratio differences

as much as the absolute numbers.

DR. GIUDICE: Yes.

142

DR. NISSEN: I wonder how much is known

about triple therapy--that is, estrogen,

progesterone and testosterone. You know, whenever

a drug gets out on the market there tends to be

off-label use, etcetera. So we need to have some

understanding about whether anything is known about

that?

DR. DOBS: Well, triple therapy is what had

been used in the Intrinsa data, in that most--in

one of your studies--didn't you have--right--where

they did use progesterone in women that had a

uterus on board--sorry. That's a terrible way of

phrasing that.

[Laughter.]

I meant estrogen on board--then being

given progesterone. And the data was about the

same there.

So there is a small study in which there's

triple therapy--which would have to be recommended

if a woman has her uterus and is being given

estrogen and being given testosterone. She would

have to take progestin.

143

DR. GIUDICE: Dr. Rice, and then Dr.

Lockwood.

DR. MONTGOMERY-RICE: I raise a question--a

concern--about the duration effect. I think what

they share with us is that we're looking at low

doses of testosterone. However, we know that when

we look at our low-dose trials of

estrogen---particularly, I'm thinking the Hope

trial, when we looked at .3 mg of CEE, and that

first year we saw minimum cases of endometrial

hyperplasia. And in the second year we saw more

cases of endometrial hyperplasia, even though we

didn't see an increase in estrogen levels.

And so should we be concerned here about a

duration effect, even in the presence of these low

doses of testosterone?

DR. DOBS: Well, there's really no good

data for this, because the only long-term

treatments of testosterone have been with higher

doses, and mainly in transsexuals. Goren, in

Amsterdam has very nice data on uterine hyperplasia

in that population.

144

So it's really hard to say what will be

the long-term effect. There doesn't appear to be a

cumulation of testosterone in the skin, as an

example. But I think the issue of dosing is

extremely important, and monitoring of doses.

I mean, I treat a lot of men with

hypogonadism and testosterone, and their levels can

be all over the place when given any kind of

transdermal testosterone--whether it be patches or

gels, there's a great amount of variability. And I

think that might be the case here, when

testosterone is going to be used in larger numbers

of women is: what is the likelihood that the women

will get to testosterone levels above the normal

range?

So that's why I feel strongly that does

need to be monitored carefully.

But if we're talking about greater then--I

think they have two-year data--there's really very

little that's out there to suggest there would be a

problem on safety.

DR. GIUDICE: Dr. Lockwood.

145

DR. LOCKWOOD: I have a comment--and I

apologize, Dr. Dobs, for having my back to you--

DR. DOBS: Yes, where are--oh, I see.

Okay.

DR. LOCKWOOD: I can't twist my head around

180 degrees.

My comment is that we've also looked at

the endometria of women that have been exposed to

high doses of testosterone in preparation for

transsexual surgery. And the marked effect that

we've observed is decidualization, which suggests

that the predominant effect is actually more

pre-gestational than estrogenic.

So, you know, I'm not sure I would be

convinced one way or the other about the risk of

endometrial cancer--particular at very high doses

of testosterone. But there may be individual

variations in that response, depending on the level

of aromatization and so forth.

My question to you is that there is a

fairly, now, long experience with the use of

danazol in women with mastalgia and fibrocystic

146

disease, etcetera, and the question--and I don't

know whether you have the answer to this or

whether, in fact, anyone does--but since that's a

natural group to look at in terms of the risk of

androgen-induced breast cancer, is there any

evidence that such therapy is associated with a

higher rate breast cancer?

DR. DOBS: That's an interesting question,

and I've never heard of a case of breast cancer

with the use of danazol. But I don't know about

breast biopsies or any intermediate changes that

might occur. I think that's an interesting

question.

DR. GIUDICE: We have time for one more

question.

Dr. Stanford?

DR. STANFORD: I was just wondering if you

are aware of any data on androgen levels or insulin

levels in women with PCOS who have undergone

oophorectomy?

DR. DOBS: Well, I could--no, I was going

to answer that--there are certainly a few taken

147

with PCOS, and they lose weight, or be given a

medication to affect this, the insulin levels, they

will drop their testosterone levels. So this could

be modulated.

The oophorectomies wouldn't be done.

Years ago, when it used to be called

Stein-Leventhal syndrome, and there was wedge

resections performed at that time, the testosterone

levels did drop. And that's probably why they were

able to get pregnant, and why it worked, is they

were taking out a mass of the ovary, and that

resulted in normal hormones and ovulation.

DR. GIUDICE: Thank you very much.

Going on now with the FDA presentation,

our first speaker is Dr. Daniel Davis who is a

medical officer in the Division of Reproductive and

Urologic Drugs, and he will be talking on efficacy

findings and issues.

FDA Presentation

Efficacy Findings and Issues

DR. DAVIS: I'm Dan Davis, and I'm one of

two primary reviewers for this application. I

148

reviewed the efficacy data, and Dr. Lisa Soule

reviewed the safety data.

My talk this morning will focus on the

efficacy data and the efficacy issues.

[Slide.]

There are three important points that are

listed here on this slide. First is to note that

this is the first application the FDA has ever

received for a female sexual dysfunction

indication. The division did have our draft

guidance for female sexual dysfunction, which was

written in May of 2000 for helping to evaluated

this application for hypoactive sexual desire

disorder.

The second point is the issue of the

relatively small treatment effect seen with

testosterone treatment. The division agrees with

the sponsor's analyses that the endpoint changes

associated with testosterone were statistically

significant compared to the placebo effect. But

the key issue for us is really the clinical

significant of the findings.

149

The primary endpoint, as already stated,

was a change in satisfactory sexual events--noted

in my presentation as "SSE." And the two secondary

endpoints were sexual desire and personal distress.

Small mean changes were noted in all three

endpoints. And relative to the testosterone

treatment--we'll note it as the "TTS" in this

presentation--there was a strong placebo effect

that persisted throughout the two six-month blinded

trials.

The third point regards the findings of

the applicant's study for determining the minimal

meaningful clinical change in the endpoints that

will be discussed briefly a little later in the

presentation.

[Slide.]

The FDA Draft Guidance for sexual

dysfunction, and the Division's advice were very

closely followed by Procter & Gamble. As noted

earlier, in the applicant's presentation, they

developed three instruments across different

cultures and languages to assess three different

150

efficacy endpoints, namely: satisfactory sexual

events, desire and distress that was associated

with HSDD. The two placebo-controlled Phase III

trials of six months' duration were completed, and

each with over 500 subjects. And a clinical study

to determine the magnitude of change in these three

endpoints that would be clinically meaningful to

the individual woman herself was performed.

[Slide.]

The key inclusion and exclusion criteria

are summarized here. All of the women were

surgically menopausal and on stable doses of

estrogen. As noted earlier, approximately 77

percent of the women were on oral estrogen, and 23

percent on transdermal.

The diagnosis of acquired HSDD was made

primarily by answering "yes" to five questions that

are listed on the next slide.

All of the women were in good general

health, and did not have major medical or

psychiatric illnesses. And there were no specific

serum testosterone criteria for inclusion or

151

exclusion.

[Slide.]

The five questions are listed here. I'm

not going to read them, but they were used

primarily for the diagnosis of acquired HSDD. The

women themselves--as opposed to a clinician or a

sex therapist--answered the questions, so that this

was purely determined by the individual women. In

essence, the subjects has a satisfying sex life

before surgery, followed by a decrease in desire

and activity after surgery, that cause them

personal distress and a wish to have an increase in

their sexual desire and activity.

Data from the Sexual Activity Log--which

is abbreviated as SAL in some of the applicant's

presentations--and the baseline scores on the two

instruments for measuring desire and distress were

not part of the entry criteria for the study.

[Slide.]

The primary endpoint was, as noted before,

the change from baseline in satisfactory sexual

events per four weeks. The individual's sexual

152

activity was recorded retrospectively each week on

the Sexual Activity Log, and was collected at the

clinic sites every month.

The secondary endpoints were the mean

change from baseline in the Personal Distress

score, and the mean change in the sexual desire

score. The two instruments that were used to

measure these endpoints had questions about how the

individual felt over the previous 30 days. Each

instrument was completed at baseline, and weeks 4,

8, 12 and 24 of the Phase III trials.

The answers then, from both of these

instruments, were normalized to a scale of 0 to 100

points. And I think it's extremely important to

remember that. So we're talking about a scale of 0

to 100 points.

A decrease in the distress score meant

less distress, and an increase in the sexual desire

score meant an increase in sexual desire.

[Slide.]

This slide summarizes the findings for the

primary endpoint of satisfactory sexual events. On

153

average, the baseline SSEs for all subjects in the

two trials was three satisfying events--which is

shown, really, in this column: an average of about

three events. The range is noted here.

A the end of the treatment period the TTS

group increased by approximately two SSEs--that

would be change, the change of 2 in basically the

1.6, compared to the placebo group, which had a

change of the 1 and .7 events per four weeks.

The difference was shown by the applicant

to be statistically significant. The clinical

significance, however, of this mean increase from

three to five events, and the difference of one

event, placebo, compared to testosterone treatment

is not clear to the Division.

[Slide.]

The secondary endpoints, the mean change

from baseline in personal distress is summarized on

this slide for the two trials. On a scale of 0 to

100, the mean baseline score was

65--approximately--here for all participants. And

this corresponds, on average, to an answer of

154

"often" to the questions related to distress.

A decrease of 16 to 18 points was seen

with placebo--that is here, 16 and 18 points--and a

decrease of about 24 points was seen with

testosterone treatment. The difference between the

testosterone response compared to the placebo

response in both trials, with 6 to 7 points on a

scale of 100. So here's the difference of

testosterone, compared to placebo.

We are not sure of the clinical

significance of this change from baseline, and the

relative difference between the placebo effect and

testosterone effect on personal distress.

[Slide.]

The same concern is seen in the next

slide, with the other secondary endpoint, for

sexual desire.

The overall mean score was 21--mean

baseline score, yes, was approximately 21 points on

this 100-point scale. The placebo group increased

an average of 6 to 7 points, while the testosterone

group increased 11 to 12 points.

155

The difference between testosterone

treatment and placebo is approximately 5 points in

the first study, and 5.2 in the second study. And

this is on a scale of 100.

Once again, the clinical significance of

this small numeric change is the issue.

[Slide.]

The next slide simply shows a summary of

the overall events. It just shows, for SSEs, just

your change, placebo from baseline. And I really

don't need to make any more comments, except that

it's showing that there is one more satisfactory

sexual even per four weeks; five more points on the

desire scale of 100 points, and six to seven point

greater decrease in the distress scale of 100

points--when we compare the placebo effect with the

testosterone effect.

[Slide.]

To put these findings into perspective, I

will now show data collected by the applicant for

age-matched normal women with no female sexual

dysfunction, and with a normal sexual desire.

156

This slide comes from basic data collected

by Procter & Gamble early in their development

program, at the time of the initial validation of

their endpoint instruments. Data was collected

from over 300 women with HSDD, and was compared to

over 250 "normal" age-matched controls.

[Slide.]

The data presented here shows the

"normals" for 146 U.S. women, and it's shown in the

blue bars. So we have a baseline of SSEs of 12

events per four weeks; for desire, the baseline of

"normal" women is 65 for desire; and for distress,

it's 5 points on a scale of 100.

The Phase III data of the combined trials

of all the women is also shown on this slide. So,

for SSEs our baseline was 3, and with testosterone

treatment increased to 5 for the SSEs. For desire,

our baseline was 21 points and increased to 33,

with a normal of 65 and a baseline here for

distress was 65, and then that decreased to 41.

Again, the normal is at 5.

Although there was a clear treatment

157

effect with both placebo and testosterone in the

two Phase III trials, we can easily see that the

testosterone effect over the six months of

treatment did not return to the values of the

normal age-matched women, as determined by the

applicant.

[Slide.]

This entire study was covered very nicely

by Dr. DeRogatis earlier. It summarizes the study

performed by the applicant to determine a

meaningful change in the endpoints as defined by

the women themselves.

All of the 132 interviews were done within

two weeks of stopping treatment. But the subject

and the interviewer were blinded to the actual

treatment received during the treatment, and the

key question--I won't read it again, because

DeRogatis showed it to you--but "--did you have a

meaningful benefit from the study patches?"

Of the women receiving TTS treatment, 52

percent felt they had a meaningful benefit, while

31 percent of the women on placebo felt they had a

158

meaningful benefit.

The Receiver Operating Characteristics

analysis was then used to determine those changes

that best separated the group of women that felt

they had a meaningful benefit from those who felt

there was no benefit.

And the final results on that analysis

showed that these were the minimal meaningful

treatment changes, namely: greater or equal to 1.1

sexually satisfying even per four weeks; a desire

score change of 8.9 or greater on the scale of 100;

and a distress scale decrease of 20 or more in the

distress score of 0 to 100.

The main importance, however, of this

study was so that then these values could be used

to perform a series of responder analyses, as shown

on the next slide.

[Slide.]

I'm really just going to focus on the

first set of bars here, because this was the

primary endpoint for the study; that is, the

satisfactory sexual events. And the responder

159

analysis--and this is for all of the subjects in

the Phase III studies combined--so this is over

1,000 women--showed that the mean responders for

placebo was 30 percent of the placebo women,

compared to 44 percent of the testosterone women.

If the parameters are changed to greater

than 2 SSEs or 3, we see a slight lowering of the

bars. But what is important is that the difference

between placebo and testosterone treatment range

from the 12 to 14 percent; and specifically, this

is a 14 percent difference here.

[Slide.]

In summary, the clinical efficacy findings

show a small but statistically significant

testosterone treatment effect seen in the three

efficacy endpoints. There was a mean increase in

the TTS users of one more satisfactory sexual event

per four weeks, compared to the placebo response

for four weeks.

For the secondary endpoints, the distress

score decreased 6 to 7 points more with

testosterone, compared to the placebo effect, on a

160

100-point scale. And the desire score showed a

difference of 5.1 units, comparing placebo to the

testosterone treatment.

For the responder analysis of the primary

endpoint "satisfactory events," there was a 14

percent difference in the number of events per four

weeks for testosterone treatment compared to

placebo.

These changes in the testosterone

treatment do not approach the normal values seen in

the age-matched women without hypoactive sexual

desire disorder as determined by Procter & Gamble

and shown in slide number 11.

We look forward to the Advisory

Committee's input concerning the clinical

significance of these efficacy findings.

This concludes my remarks. And next we'll

hear from Dr. Soule on the safety findings.

Safety Findings and Issues

DR. SOULE: Good morning. I'm Lisa Soule.

I'd like to highlight some points raised in our

safety review of the two Phase II and two Phase III

161

studies on transdermal testosterone in surgically

menopausal women.

[Slide.]

High level concerns about safety of this

product are two-fold. The adverse effects of

long-term or chronic use of this product cannot be

characterized from the current safety database.

Events of potential concern may have a long latency

from exposure to occurrence.

Also, the addition of testosterone to

estrogen may increase risks of estrogen-associated

adverse events such as breast cancer and

cardiovascular disease--as is seen when

progesterone is combined with estrogen. And it's

worth noting again that the target

population--surgically menopausal--will be

concurrently using estrogen, a product with known

risks, and may potentially use it on a long-term

basis.

Current guidelines on the use of estrogen

products are discussed on the next slide.

[Slide.]

162

Recommendations from the FDA and

professional societies concerning the use of

hormone therapy have changed significantly since

publication of the Women's Health Initiative

findings. And you can see the FDA boxed warning

recommends that estrogen and E+P products be

prescribed at the lowest effective doses, and for

the duration, consistent with treatment goals and

risks for the individual woman. And, similarly,

the American College of OB/GYNs says the lowest

effective estrogen dose should be used for the

shortest possible time to alleviate symptoms, and

further recommends that use should be reassessed

annually.

[Slide.]

Review of the literature on testosterone

use in women suggests a spectrum of risks. Some

are documented to occur with some certainty at

doses like the TTS patch, such as androgenic

adverse effects: acne, alopecia and hirsutism.

Others are not clearly or consistently found, but

are suggested from data on women with endogenous

163

hyperandrogenism, such as changes in lipids,

hypertension. And, finally, there are very limited

data addressing the outcomes of greatest

significance, such as increased cardiovascular

morbidity and breast cancer.

[Slide.]

In evaluating the safety database from

these studies, we must consider the extent to which

results obtained from the study population can be

generalized to the target population for this

product. For example, African-Americans make up 13

percent of the U.S. population, but only 6 percent

of the study population. We do know that

African-American women are more commonly surgically

menopausal than Caucasian women, but the prevalence

of HSDD in African-American women is not known.

In addition, there were small numbers of

older women in the trial. And, finally, women who

may be at the highest risk for cardiovascular

morbidity were either under represented--such as

African-Americans and older women--or were

completely excluded from these studies, as is the

164

case for women with existing diabetes or

cardiovascular disease.

[Slide.]

In reviewing the safety database for TTS,

the following safety endpoints were of particular

interest, because they bear on specific areas that

are potentially of concern in considering chronic

use of testosterone in women. These include

adverse events related to the use of TTS and to the

duration of exposure to TTS; laboratory data that

may reflect cardiac risk; changes in blood pressure

and weight; and occurrence of breast cancer.

Before discussing safety outcome data, I

want to show you some data on testosterone levels

that were obtained in the women in these studies.

Although, as you heard earlier, mean testosterone

levels remained within the range for

reproductive-age women, a significant proportion of

the treated subjects had level of free and

bioavailable testosterone above this range.

[Slide.]

This slide shows the proportion of

165

subjects with free testosterone values outside the

upper limit of normal range, which is 7.3 pcg per

ml for reproductive-aged women, aged 18 to 49. The

percent shown here are for placebo subjects--shown

in red here--and women on TTS for varying

durations.

The green bars show subjects who were on

TTS throughout the duration of the study, and had

blood sampling done at the noted weeks here.

The purple bars are the subjects who were

initially on placebo back here in the early part of

the study and then switched to TTS. So at these

points all of these women are on TTS.

It can be seen that virtually no placebo

subjects had levels outside the reproductive-age

range. At weeks 52 and 78, there was very little

difference between groups, according to their

duration of TTS. But you can see that almost a

quarter of the women on TTS for longer than a year

developed free T levels beyond the range for

reproductive-aged women.

[Slide.]

166

And here's the similar data for

bioavailable testosterone which, as you've heard,

comprises both free and albumin-bound testosterone.

And, again, virtually no placebo subjects are

beyond the reference range.

And within subjects on testosterone,

there's not a great difference according to the

duration of testosterone. But here, up to 43

percent of women who used TTS for up to a year

developed bioavailable T beyond the reference

range.

[Slide.]

As you see, the trial design is complex,

with different arms receiving different durations

of testosterone exposure. So before I present any

more data, I'd like to try to clarify how the

subsequent data will be presented.

This figure shows the movement of subjects

through the different phases of the trials, and the

TTS exposure that each group received at the

various phases. And what these "durations" here

are. The N's in each box, shown here, are the

167

number of women who entered that phase.

The data presented from here on will

primarily compare even frequency between women on

placebo and women who received between 0 to 6, 6 to

12, and 12 to 18 months of testosterone. These

exposures to TTS did not necessarily occur in the

same phase of the trial, as the exposure of women

who were initially randomized to placebo--this line

here--and then went on to TTS always lagged six

months behind those who were initially randomized

to TTS.

The events to be reported on each slide

from here on occurred in the study phase

corresponding to the exposure interval for each

group. So, for example, events reported for TTS

subjects with up to six-months exposure occurred

here in the double-blind phase, while events for

the placebo-to-TTS subjects with the same amount of

exposure occurred over here, in the open-label

phase.

[Slide.]

Some adverse events show an increased

168

frequency in women who received TTS compared to

subjects on placebo, including androgenic adverse

events overall, as well as the individual

components: acne, hirsutism, alopecia and voice

deepening. The percents shown here are the percent

of subjects at each of the three phases of the

study who experienced androgenic events. They are

grouped by the total duration of TTS exposure that

the subjects received.

Androgenic adverse events overall occur

more frequently in TTS-exposed subjects than

placebo subjects, but don't show a steady increase

with increasing duration of exposure. Some adverse

events did occur with increased frequency, though,

as duration increased.

[Slide.]

For example, alopecia. And here you can

see, starting with placebos and no exposure, that

the rate of these events increases as the women are

on longer and long durations. And, remember, these

events are not cumulative but, rather, show the

occurrence of new cases of alopecia in each of the

169

three phases. And each phase, remember, is about

six months long.

Since the associate of androgenic adverse

events with the use of TTS seems clear, the

relationship between free T levels and the

occurrence of these adverse events was explored.

[Slide.]

The incidence of androgenic adverse events

are examined here according to quartiles of free

testosterone obtained during the double-blind

phase. And the T values used here are the maximal

values obtained at either the week-12 or the

week-24 sampling.

There appears to be an association between

higher levels of free T and greater frequency of

acne and hirsutism. And, as you hear this morning,

there was only a significant trend test here for

hirsutism.

But if you look at acne, you can see that

the women in the upper two quartiles--that is,

women above the median--do appear to have higher

rates than placebo women or women down here in the

170

lower two quartiles of free T.

In hirsutism, you can see more of an

exposure response, which may plateau up about the

third quartile. And if you look at the ranges of

the third quartile, you can see that these are

still below the reference range for

reproductive-aged women.

[Slide.]

In contrast, alopecia and voice deepening

do occur more frequently among TTS than placebo

subjects, but don't seem to increase with higher

free T levels. And it may be that these events

occur where a threshold free T level is exceeded.

[Slide.]

Getting back to our risk spectrum, I want

to review some data bearing on possible impact of

TTS on cardiac risk factors. We're concerned about

the potential impact of TTS on a number of cardiac

risk factors and, as you've heard, several of these

are believed to be linked in a common

pathophysiologic process, and form a constellation

known as the "metabolic syndrome"--which is an

171

independent risk factor for cardiovascular disease.

There are several diagnostic schemes, but

generally the components include glucose

intolerance, dyslipidemia, hypertension, and

central obesity.

A community-based study of 16,000 mean and

women found that the free androgen index was

statistically significantly higher in women with

metabolic syndrome, and also found that the

prevalence of metabolic syndrome in

African-American women was twice that in Caucasian

women.

Let's look at the lipid data first.

[Slide.]

While, on average, lipid values showed

little mean or median change, over the course of

the studies some parameters were of concern in

terms of percent of subjects who developed values

outside the normal reference range. This slide

demonstrates the proportion of subjects with

abnormal values on LDLs and triglycerides. These

labs were measured in all three phases of the

172

trials. The placebo group is in red.

Abnormal values were defined at the levels

shown here. So, for LDL, above 160 mg/dL; for

triglycerides, about 250 mg/dL--but, additionally,

required that subjects have an increase from

baseline of greater than 30 percent. So women who

entered the trial with elevated lipids may not even

be represented here. And thinking back to the

metabolic syndrome criteria that you just saw, 3 to

4 percent of these subjects may meet the

triglyceride criteria for the dyslipidemia

component.

Virtually no subjects developed abnormal

HDL levels in these trials, and the mean and median

changes were neutral, or even showed a slight

increase from baseline for HDL.

[Slide.]

Although, as you heard, mean glucose

levels were similar between treatment arms during

the double-blind phase, the change from baseline in

glucose level appears to increase with duration of

TTS exposure. And here you can follow the trend in

173

the groups, characterized by their initial

randomization. So here are women on placebo at the

beginning, and you can see that they have a slight

drop in their glucose levels. But as they go on to

six months and then 12 months of TTS, you can see

that the glucose levels are rising.

Similarly, here are subjects receiving TTS

in the beginning of the trial and, again, as their

exposure increases, so too does their glucose

level.

[Slide.]

Insulin was measured only during the

double-blind and open-label phases, and not in the

extension phase. The mean increases in the

TTS-exposed subjects at both time periods--and

again, remember, both of these, even though we have

red coloring, are on TTS in the

open-label--exceeded those down here in the placebo

subjects.

Although the changes in these markers of

carbohydrate metabolism are small, these small

trends may be magnified when the full target

174

population, including who may already be glucose

intolerant or insulin resistant, is exposed to TTS.

[Slide.]

Fibrinogen is an independent risk factor

for coronary artery disease. The lab value was

also assessed only for 12 months in the

double-blind and open-label phases. The data on

mean change from baseline is suggestive of an

increase with TTS exposure for six to 12 months.

And the median change data are similar.

The effect of TTS on blood pressure was

also of interest as a risk factor for

cardiovascular disease, as a component of metabolic

syndrome, and in regard to the occurrence of

hypertension as an outcome in itself. In the

double-blind period, hypertension was recorded as

an adverse event for 1.3 percent of placebo

subjects, and 2 percent of TTS subjects.

A 2002 meta-analysis of 61 studies

conducted by the Prospective Studies Collaboration

in the U.K. found a two-fold increase in deaths

from vascular disease and ischemic heart disease in

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40 to 69-year-olds for each increase of 20 mm in

systolic blood pressure, and 10 mm in diastolic

blood pressure.

[Slide.]

And here you can see: a rise of 10 to 19

mm occurs in 5 percent more subjects who received

TTS for 6 to 12 months, as compared to the placebo

subjects.

[Slide.]

Similarly, there are 4 percent more

subjects who had rises of diastolic blood pressure

from 10 to 19 mm in the group who received TTS for

up to six months, as compared to placebo subjects.

We don't have data that could speak to the

issue of central obesity, but we can look at the

changes in weight over the course of the studies.

[Slide.]

Although weight gain appeared to occur at

higher frequency with greater TTS exposure, so too

did the equivalent amount of weight loss.

[Slide.]

A short-term clinical trial database can

176

provide only limited information about risks with

longer latency, and a significant background

incidence; for example, no MIs occurred in these

trials.

In regard to breast cancer, epidemiologic

studies have suggested that androgen levels in

women may be linked to the risk for developing

breast cancer. And, similarly, there have been

studies suggesting that increased insulin levels

may increase breast cancer risk. Some authors have

suggested that androgen's potential role in breast

cancer risk may be through its impact on insulin

resistance.

[Slide.]

This slide describes the four cases of

breast cancer that occurred in the trails--as

you've previously heard. But given the dual

exposures to estrogen and to testosterone--all

aside from this one placebo subject--and the

relatively short duration of testosterone use--5 to

37 weeks--there are insufficient data to assess the

causal role of TTS. And this highlights the

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limited ability of short-term clinical trials to

answer questions of causality, particularly in a

population with a moderately high background

incidence of the outcome of interest.

[Slide.]

The current safety database is unable to

answer many questions about the safety of TTS for

several reasons.

First of all, placebo-controlled data is

available only for six months, and even long-term

exposure is limited to 12 months--in under 500

women, and 18 months--in 127 women. And, as you've

heard, women with diabetes and cardiac disease were

not studied.

For naturally menopausal women, our

concerns would include safety of TTS in women who

retain their uterus, and the known risks of

estrogen and progestin, which might be used for

greater duration by women using the TTS than they

would otherwise be.

[Slide.]

Procter & Gamble has a number of studies

178

in progress that will provide some additional

useful data, and these include--as you've

heard--the surgically menopausal studies: currently

321 subjects have entered this extension phase,

which is in year two of what will be, ultimately, a

three-year extension. In addition, the two

placebo-controlled studies you've heard about in

naturally menopausal women, there's a six-month

study completed, and a 12-month study close to

completion, each enrolling about 400 women. And of

these naturally menopausal studies, 281 women have

enrolled in safety extension phases.

These studies will also ultimately provide

293 paired endometrial biopsy samples.

And, finally, there's in progress a study

of the TTS patch being used alone in women who are

not taking estrogen or system

estrogen-plus-progestin--although they are allowed

to use vaginal preparations. And this study has a

projected enrollment of 750 women in three arms,

which are placebo, a dose of 150 mcg a day--half of

what we're hearing about here, as well as the 300

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mcg per day dose.

[Slide.]

As you've heard, Procter & Gamble has

proposed a post-marketing pharmacovigilance study.

And, briefly, to review, they propose to do a

prospective cohort study in a claims database, with

three-to-one matching of current and recent users

with control subjects, planned outcomes, including

cardiovascular disease and breast cancer; endpoints

to be adjudicated by a panel of medical experts

blinded to treatment exposure; and they propose

that the first analysis will be available at 24

months post-launch.

Further, they estimate that their power to

detect cardiac events occurring with a relative

risk of 1.5 will reach 85 percent by year five.

[Slide.]

We have a number of concerns about the

utility of this proposed plan, however.

First of all, to answer safety questions,

does a claims database and cohort study provide the

same level of evidence as a randomized

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placebo-controlled trial?

We're concerned that the project sample

size is inadequate. A study powered to detect a

relative risk of 1.5 for cardiovascular disease may

miss important but lower risks. And, just to

remind you, the risks seen in the WHI

estrogen-plus-progestin study were on the order of

1.2 for total cardiovascular disease, 1.3 for

breast cancer, and 1.4 for stroke. And to detect

risks of this size, a sample size of almost 17,000

was needed.

In addition, we're not given any

information on the power to detect an increased

risk of breast cancer.

We're also concerned that events with long

latency may not be detected. And, again, in the

WHI E+P study, breast cancer rates did not diverge

until year four, suggesting that the effect of

hormone exposure may not manifest above the

background incidence until that time.

In addition, we're concerned about

recruitment goals, which have not been met

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previously using this database. And we're also

concerned about turnover in plan coverage. And

although you've heard that this plan retains 85

percent per year, when you take that out to year

five you can see that you're retaining only 44

percent of the original population.

[Slide.]

The WHI had far-reaching effects on our

assessment of risks associated with long-term

hormonal treatment. We learned from this that the

data was discrepant from that we'd previously known

from observational studies, and that reinforced the

value of prospective, randomized controlled studies

of adequate duration to be able to define

attributable risk.

And, ultimately, WHI indicates the need to

give heightened scrutiny to hormonal therapy in

post-menopausal women.

[Slide.]

To summarize the issues we must consider:

the sample size and duration of treatment is

inadequate to exclude serious risks, including

182

cardiovascular disease and breast cancer, with this

treatment; and the population studied is inadequate

to identify important risks in naturally menopausal

women using estrogen and progestin, and in

sub-groups at higher risk for cardiovascular

morbidity.

We look forward to your discussion and

assistance in resolving these issues and the

efficacy issues raised earlier by Dr. Davis.

Thank you.

DR. GIUDICE: Thank you, Dr. Soule. And

the committee will have an opportunity to ask

questions of both of the FDA presenters after lunch

this afternoon.

Open Public Hearing

This is now time for the open public

hearing. And I have a statement, first, to read

regarding this.

Both the FDA and the public believe in a

transparent process for information gathering and

decision-making. To ensure such transparency at

the open public hearing session of the Advisory

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Committee meeting, FDA believes that it is

important to understand the context of an

individual's presentation.

For this reason, FDA encourages you--the

open public hearing speaker--at the beginning of

your written or oral statement to advise the

committee of any financial relationship that you

may have with the sponsor, its product and, if

known, its direct competitors. For example, this

financial information may include the sponsor's

payment of your travel, lodging, or other expenses

in connection with your attendance at the meeting.

Likewise, FDA encourages you, at the

beginning of your statement, to advise the

committee if you do not have any financial

relationships.

If you choose not to address this issue of

financial relationships at the beginning of your

statement, it will not preclude you, however, from

speaking.

So I'd like to begin with the open public

hearing speakers. I would like to advise the

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presenters to please state your name and your

organization. Presentations will be strictly

limited to three minutes--and we have a timer up

here. The light will be green for the first two

minutes and 30 seconds, then yellow for the

remaining 30 seconds--and this will be the warning

to conclude your talk. And the light will turn

red at the three minute mark, at which time the

microphone will cease to work.

[Laughter.]

So I'd like to call now--with that

proviso--Ms. Lisa Martinez, please.

MS. MARTINEZ: First, I'd like to state

that the Foundation just received a $4,000

charitable donation from Pfizer.

Now, on that point--good morning. I'm

Lisa Martinez, a nurse and an attorney, and the

executive director of the Women's Sexual Health

Foundation, an international non-profit

organization based in the U.S.

Our primary mission is to educate the

public and health care professionals in the area of

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female sexual health, including FSD.

We have heard from many women and their

partners relating to female sexual health problems.

These stories are heart-wrenching, and have a

common theme: women are devastated, suffer in

silence, feel very much alone in their journey to

find the right answers, care and treatment; and

wish that their sexual health would be taken

seriously.

For women in relationships, this impacts

not only them but their partners, who often feel

equally helpless and devastated.

Sexual problems are not an easy subject to

discuss. Women may feel embarrassed, and yet they

don't give up. Some have gone for years looking

for help from various providers, sometimes with

success and sometimes not. It's not unusual for us

to hear that women have been told by their provider

that their problems are all in their head, or that

a hysterectomy or bilateral oophorectomy could

never be he physical cause of sexual health

difficulties, and that any such problem would be

186

purely psychological.

The Foundation believes that a

multi-disciplinary approach should be used to

address sexual health problems. This would include

both physical and emotional assessments.

As part of this complete approach to

women's sexual health complaints, a serious effort

must be made to determine if there are physical

causes, such as hormone insufficiencies. Health

care providers need to follow well-recognized

workups that will leave no stone unturned, so that

treatment plans are specifically targeted at the

underlying causes of sexual dysfunction.

Consideration should be given to pharmacologic and

counseling.

Currently, there are no FDA-approved

treatments for FSD, and providers are using

off-label medications that have not been studied in

women under FDA oversight.

There is a need for such treatment,

including testosterone. But, more importantly, FSD

is a serious health issue, and not just a lifestyle

187

issue.

Thank you.

DR. GIUDICE: That you for your comments.

The next presenter, Mark Klein.

DR. KLEIN: Yes, I am a Procter & Gamble

shareholder and a physician.

If we balance Intrinsa's unimpressive

modest results from very short-term studies,

against my estimate that 50 to 80 percent of all

the Intrinsa sold will be abused by non-menopausal

girls and women--including some pregnant and

nursing--it's a no-brainer: this is too dangerous

to license for any use.

Over a decades time we could be looking at

many tens of thousands of girls, women, fetuses and

newborns permanently injured by anabolic steroids.

There is no way to avoid such abuse. Once

approved, Intrinsa will be available off the

internet, off-label and on the black market.

In my 40 years of medicine I have never,

ever seen government action prevent abuse of a hot,

popular drug.

188

As the manager of a large asset family

investment office holding Procter & Gamble, I feel

major losses--like what happened to us with Wyeth's

phyn-phen, and Merck's Vioxx. They happened

because today's very weak FDA allowed these

companies to cut scientific and ethnical corners.

Almost as certainty, Intrinsa will result in mass

tort class actions that could drive Procter &

Gamble into bankruptcy.

I suspect there are many very savvy,

seasoned long-term investors like myself unwinding

big pharma holdings. I've reduced ours over the

past two to three years from 15 percent to 6

percent.

The core problem is the big pharma's

willingness to sacrifice scientific integrity to

make their earnings numbers. And this is sure the

case with Procter & Gamble.

As an investor and trustee for family

accounts, I will sell our Procter & Gamble should

Intrinsa be approved. The potential lawsuit risks

for the company are so great that, in my opinion,

189

as a fiduciary, holding Procter & Gamble violates

the prudent-investor rule.

In conclusion, I believe Intrinsa is the

most hazardous non-narcotic drug ever presented for

FDA approval. I urge it to be rejected for any

use. And, if approved overseas, banned from sale

in this country under threat of severe criminal and

civil sanctions.

I have one word of advice to Procter &

Gamble. I am personally absolutely shocked that

you have gone into this business. We are in the

business of selling soap, we are in the business of

selling implicit promises not overt promises. And

I hope you keep in mind, "Hell hath no fury."

DR. GIUDICE: Thank you for your comments.

The next presenter is Rosalyn Washington.

MS. WASHINGTON: Good morning. My name is

Rosalyn Washington, and I have no financial

affiliation with Procter & Gamble.

I am a wife, a mother, and a woman who

suffers from low libido. Almost 10 years ago I had

a hysterectomy with removal of both of my ovaries.

190

This surgery--which, in my opinion, is performed

far too frequently on thousands of women in the

U.S. on a yearly basis--robbed me of my sexual

desire.

Unless you have experienced the lack of

sexual desire you cannot completely understand the

feeling of frustration and sense of inadequacy I

have. When I learned of this research being

conducted to help women with low libido I jumped at

the chance of being a volunteer for the clinical

trial study.

Overall, my experience in the study was an

excellent one. I did not grow a mustache or a

beard or develop large muscles. My voice did not

deepen, and I did not grow hair on my chest.

However, there was a noticeable increase

in my libido. I had first-hand experience with

the positive effects of the Intrinsa testosterone

patch, as a participant in the clinical trial

studies, and I would like to experience those

feelings again.

It is a known fact that women are much

191

more complicated than men. In a lot of cases our

libido is directly linked to our emotions and

mental state of mind. But this is not always the

case. Physical factors, like a hysterectomy can

affect libido by removing the ovaries which produce

testosterone in a woman's body.

Intrinsa is a drug therapy that I believe

the studies have shown to be effective in raising

the levels of testosterone in a woman's body with

little or no side effects.

It is my hope that Intrinsa receives FDA

approval and be made available countless women like

myself, who are seeking a solution for our sexual

dysfunction.

A healthy and satisfying sex life is

important to a woman's physical and mental

well-being. I believe Intrinsa will help restore

the level of hormones necessary for me to once

again have a healthy sex life.

Thank you.

DR. GIUDICE: Thank you.

The next presenter is Kathleen Kelly.

192

MS. KELLY: In 1982 my mother died of

ovarian cancer, setting in motion ready-made

decisions for me and my sister with ovarian cancer

familial risks.

My name is Kathy Kelly. In the summer of

1998 I had a hysterectomy and a bilateral

oophorectomy. I searched on-line and found very

little that was helpful to me, so I gathered

materials, resources and added a discussion board,

and launched a website called "Hyster-Sisters."

Now, over six years later, Hyster-Sisters

is the largest on-line hysterectomy community, with

over 55,000 members.

The Hyster-Sisters site is neither

anti-hysterectomy, nor pro-hysterectomy; rather, it

is a on-line community of women who give and

receive support for hysterectomy decisions and

recovery.

The Hyster-Sisters have sent me today to

share their stories with you.

Many members recover from their surgery

and head back into their lives without much

193

fanfare. For others, they return to our site

months or even years later, in search of additional

support for new health issues. Predominantly, they

return in search of support for hormone therapy,

many complaining of a missing libido.

And while we have thousands of personal

posts from frustrated members regarding their loss

of desire, time constrains me only to share with

you a few.

A 47-year-old woman wrote: "Since my

hysterectomy, I've tried all forms of hormone

therapy and some herbal treatments. I'm beginning

to wonder if it's simply impossible to get back my

libido."

A woman in Arkansas wrote: "I have a

check-up appointment with my OB/GYN next month, and

my husband is going with me so we can talk about my

libido. What is wrong with me? I am 24 years old.

I love my husband. Has anyone else experienced a

change in libido? How do you go about correcting

it?"

A 43-year-old woman in Southern California

194

wrote: "Prior to my surgery my libido was

tremendous. My husband and I have had 25 years of

awesome sex. My husband has been very, very

patient with me. We have tried just about

everything, but to no avail."

The Hyster-Sisters have sent me, because

it is our hope that the medical community find

better treatment so that the hysterectomy is truly

a last resort. But for those hundreds of thousands

who have had an oophorectomy, we would like hormone

options to better restore what we have lost.

Our next generation of women is depending

on us.

The Hyster-Sisters have sent me to ask

that you approve this drug--the testosterone

patch--as one option for the libido needs of the

surgically menopausal woman.

Thank you.

DR. GIUDICE: Thank you.

The next presenter is Leonore Tiefer.

DR. TIEFER: First slide, please.

My name is Leonore Tiefer--no money, no

195

way.

AS a psychologist with over 30 years of

teaching, research, awards and publications in

sexuality, I see today as a perilous moment in the

history of women's sexuality.

Next slide.

[Slide.]

A few random credentials, which I offer

because this is the first women's sexuality drug

that the FDA has ever reviewed--and there is no

sexuality drug committee. Input may be useful from

someone who has spent decades immersed in issues of

sexual nomenclature, measurement, motivation,

behavior and biology.

Third slide, please.

[Slide.]

Here are my concerns--and I have handouts

on these points, since you can only say just so

much in 180 seconds.

The Intrinsa trials are grossly inadequate

to assess the risks of extended steroid hormone

treatment. And I hope we don't have to go through

196

another HRT scandal to learn this again. That's

point one.

Point two is that assessing sexual

experience is subtle and complex and arbitrary.

Experts in sexology agree that there are numerous

ways to define and measure desire and satisfaction.

Methods chosen in every study must be closely

examined for what they leave out, as well as what

they include.

Point three: these Intrinsa trials

excluded women with medical problems, relationship

problems and life stress. It's no wonder it took

52 trial sites to find a meager 1,095 subjects.

How representative are these carefully

selected subjects of the millions P&G is hoping to

interest in it's new medicine?

Which brings me to point four: Intrinsa is

not a glass of Chardonnay, and yet we have already

seen that it may well be promoted, with a giggle

and a wink, as the female Viagra.

Not so. This is a steroid hormone women

must continuously take for weeks before getting an

197

effect. Yet P&G's promotional materials encourage

the attitude that millions of women are walking

around under-androgenized, in danger of imminent

sexual withering away. It's a revival of menopause

as a deficiency-disease, only this time it's

testosterone riding to the rescue.

Fourth slide.

[Slide.]

So here are my recommendations.

First, postpone the application until

there are longer studies on more appropriate

populations.

Second: if women with low desire are

testosterone-deficient, we must have an affordable

assay to measure that deficiency, and there is none

now.

Third: good sex research should always

have a qualitative component.

And, finally, the FDA's DDMAC needs to

carefully monitor the P&G materials for bias and

boundary violations.

Last slide.

198

[Slide.]

I am representing a large group of experts

who couldn't be here today.

Thank you very much.

DR. GIUDICE: Thank you.

Our next presenter is Wayne Shields.

MR. SHIELDS: Hi. My name is Wayne

Shields. I'm president and CEO of the Association

of Reproductive Health Professionals.

Thank you for holding this hearing and

inviting us to be here today.

We are a 501(c)(3) organization, and we do

receive support from foundations and companies, and

we have in the past received unrestricted grants

from Procter & Gamble.

It's important to know, I think, that ARHP

has been around a while, and that ARHP is a medical

organization of over 12,000 health care providers,

multi-disciplinary, mostly OB/GYN and family

practice. We have researchers and on-the-ground

practicing clinicians.

On behalf of our members I'm glad to be

199

here today.

I also have to say I realize I'm a guy,

and this conversation is about sexuality. I do

represent mostly a female constituency. But I

think the topic of sexuality is key, and it's

under-addressed in America. So this is a great

forum, and thank you for providing that

opportunity.

ARHP is an organization accredited by the

ACCME, and we provide CME for health care

providers, and other credits. And we advocate for

evidence-based research. And we support the

availability of a wide range of safe and effective

and appropriately used treatment options on women.

I'm here today to support this

application, if it's appropriately used--and I know

you'll have that discussion. And I'm here today to

let you know that we believe this medication is

appropriate for enhancing sexual desire in a very

particular subset of surgically menopausal women.

We do support--and this is important for

us in our mission at ARHP--careful clinical

200

screening to ensure that this medication is given

only to appropriate candidates. I think that

that's key.

In the past, sexual health research has

focused mostly on men's sexual health, as you know.

We feel it's important that female sexual health be

represented more prominently. And while men have

benefitted from a number of products and the

ensuing attention on their sexual disorders, this

is an important conversation and an important

product, because it allows a forum for conversation

about female sexuality, and their very unique and

very different sexual disorders.

We support focusing on the sexual health

of women. We see the introduction of a safe and

effective medication for women as a great

opportunity to be able to discuss, in an

evidence-based and appropriate manner, female

sexuality to enhance health care provider

communication with patients.

We believe that hypoactive sexual desire

disorder is a real condition, and that surgically

201

menopausal women who suffer from it deserve a range

of treatment options, whether they be behavioral or

medical. Many women with HSDD can benefit from

counseling and lifestyle adaptation and other

non-medical treatments--very true. Let's talk

about that more. But there remain some women for

whom a safe and effective medical intervention such

as this one will be of benefit.

And we think this is especially relevant

for surgically menopausal women.

The data and research we have examine

indicates that while it's not appropriate--

[Time expired. Microphone turned off.]

[Laughter.]

DR. GIUDICE: Thank you.

The next speaker is Karen Hicks.

DR. HICKS: First slide, please.

[Slide.]

I'm Dr. Karen Hicks, a sexual health

educator and founder of the Dalkon Shield

Information Network--with no financial relationship

to the company.

202

I'm here to request that approval of the

Intrinsa patch be delayed until relevant safety

issues have been fully reviewed and documented.

Drug safety issues and scrutiny of the FDA have

dominated the business news lately, due to the

Vioxx scandal and risks of antidepressants for

children. Today, as you deliberate the dawn of a

whole new class of sexual medicines for women, it's

time to consider some new precedents for

considering the safety issues relevant to a drug

like Intrinsa.

Next slide.

[Slide.]

I raise four questions: One, what is the

safe dosage for individual variations among women

who may be very different from women in the

clinical trials, particulary with regard to ages,

differing weight profiles, general health status

and possible ethnic backgrounds?

Two: what is or isn't know about the

long-term use of this drug? In the clinical

trials, subjects used Intrinsa for time ranges

203

between 14 and 24 weeks, yet it's intended to be

used continuously over the long term, and possibly

for years.

Three: what potential adverse reactions

has ben anticipated, and what might likely

unanticipated outcomes be? Experience with

testosterone in pill or injectable form, and other

reproductive hormones prescribed to women, include

cancers of the breast and other tissues, liver

ailments, excessive facial hair growth and skin

problems--to name a few.

Four: how will problems in prescribing and

dispensing be prevented or minimized. Based on the

excitement being generated in the press for this

drug already, I predict that off-label use with

soon follow.

Next slide.

[Slide.]

This week's Journal of the American

Medical Association has two relevant editorials.

The first speaks to the weaknesses of the current

post-marketing surveillance process at the FDA.

204

The second explores the potential for conflict of

interest in the evaluation of suspected adverse

drug reactions.

The journal editors recommend that an

independent entity located outside the FDA be given

primary authority for this task. The Vioxx and

Dalkon Shield IUD scandals hinge on the long

suppression of information on dangers they posed to

their users.

Next slide.

[Slide.]

I off five recommendations for setting new

precedents.

One: admit full disclosure of the clinical

trials to the public.

Two: initiate a user registry under the

purview of the FDA to all users who volunteer to be

kept informed.

Three: upload all documentation on

efficacy and safety to the FDA website and announce

the URL and telephone numbers widely on pharmacy

patient package inserts and information sheets.

205

Four: if warranted, contact all users

early through pharmacy databases about discoveries

of dangers relative to this drug's use.

Five: include label warnings about

duration of use beyond the length of the clinical

trials.

Next slide.

[Slide.]

The public perception, reflected by

substantial press coverage, already suggests that

Intrinsa is "Viagra for women." I find this notion

distorted and disturbing. This treatment is not

equivalent in manner or duration of use. It acts

on different body systems and has different

effects.

Please consider these recommendations as

you deliberate today.

Thank you.

DR. GIUDICE: Thank you.

The next presenter is Jean Koehler.

DR. KOEHLER: Hi. I'm Dr. Jean Koehler.

First of all, I want to let you know that I was a

206

paid consultant in the persistence of benefit phase

of the Intrinsa trials, and am currently a paid

regional consultant with Procter & Gamble, and a

long-term stockholder.

Additionally, I'm a paid consultant for

Ortho-MacNeill Pharmaceuticals.

It is because of my clinical experience,

and experience interviewing women on Intrinsa, that

I felt the need to take te time out of my practice

to be here today, at my own expense, to support the

approval of this product. I am a licensed marriage

and family therapist, and certified sex therapist

in private practice. Additionally, I'm a faculty

member at the University of Louisville School of

Medicine, and have held both of these positions

since 1976.

I am also the immediate past president of

the American Association of Sex Educators,

Counselors and Therapists--or AASECT. With over

2,100 members, AASECT is the oldest, largest

certifying organization of professionals in the

sexuality fields. While AASECT does not endorse

207

any particular product, I have been authorized by

the organization to support the kind of research

that is being presented here today.

In my own professional opinion, as a sex

therapist and medical educator for over 28 years, I

also see a great need for this product. Female

hypoactive sexual desire disorder is not only one

of the most common presenting complaints in

psychotherapist and physicians offices, it also has

been the most difficult of all the sexual

dysfunctions to treat successfully.

While I have successfully treated many

psycho-social causes of this disorder, my multiple

years of experience tell me that without

concomitant testosterone therapy, psychotherapy and

relationship therapy has failed with women whose

testosterone levels remain low.

I'll give you just one of many examples of

positive use of testosterone in my practice.

The nine-year marriage of my client--whom

I'll call "Laura"--was about to break up because

she had totally lost her sexual desire and

208

willingness to have sex, after a good previous sex

life with her husband. Her free testosterone

levels were very low, and her husband as so

sexually frustrated that he was becoming

emotionally abusive.

After the combination of psychotherapy and

testosterone replacement therapy restored her

drive, Laura reports two years later, on follow-up,

that she is still using her prescription, and that

her marriage has more than stabilized, and she

reports no adverse events. She now enjoys sex

again, and two little children were spared the

trauma of impending divorce.

Similar reports came from the women I

interviewed in the persistence of benefits stage.

And not only did they notice important increases in

desire and function, but improved and increased

emotional closeness with their partners.

So the importance of this product is not

just about one more sexual experience per month.

It's also about a generally improved quality of

life for these women.

209

The patch will no doubt only work for a

carefully selected group of women, but as a woman

and as an advocate for patients like Laura, I

maintain they deserve--

[Time expired. Microphone turned off.]

DR. GIUDICE: Thank you.

The next presenter is Anne Kasper, and I'm

making these remarks, prepared by Breast Cancer

Action, on behalf of both Breast Cancer Action, and

Our Bodies Ourselves.

Both organizations work in the public

interest, and do not accept funding from the

pharmaceutical industry as a matter of

principle--and neither do I.

Breast Cancer Action opposes approval of

the proposed indication for NDA-21-769. While

reduced libido and vaginal dryness are serious

concerns for women with breast cancer who are put

into menopause by chemo treatments, the solution

does not lie in the approval of this therapy, which

has only been briefly evaluated, and not in

populations of women who may be at increased risk

210

from hormonal exposures due to their cancer

history.

We recognize that the proposed indication

of this NDA is for women whose menopause is

surgically induced, but we are deeply concerned

about the enormous potential for off-label use of

the therapy in inappropriate populations.

It is now widely accepted that breast

cancer is largely a hormonally driven disease.

Most of the known risk factors for breast cancer

have to do with lifetime exposure to endogenous

hormones--particularly estrogens. The skyrocketing

incidence of breast cancer--and the Women's Health

Initiative results on hormone replacement therapy

have raised concerns about the implications of

exogenous hormonal exposures as well. While much

remains unkonw about the etiology of breast cancer

and other hormonally driven women's cancers, there

is great concern that any treatment that interferes

with the eodocrine system will ultimately stimulate

some aspect of cancer development. Breast Cancer

Action therefore urges that all women at risk for

211

breast cancer--and the agencies charged with

protecting their health--proceed with extreme

caution before pursuing hormonal treatments of

other medical conditions.

For women who have already been diagnosed

with breast cancer, this caution cannot be stated

too strongly. A very recent study published in

September in the International Journal of Cancer

indicates that high serum testosterone levels

predict a greater likelihood of breast cance

incidence.

The drug application is based on a small,

six-month trial. Yet we know from both the Women's

Health Initiative and the experience with DES that

the long-term effects of hormonal therapies may not

be known for many years. Approval of the NDA will

lead to one more instance when women become guinea

pigs in an uncontrolled experiment that may have

serious implications for their long-term health.

Thank you.

DR. GIUDICE: Thank you.

The next presenter is Sidney Wolfe.

212

DR. WOLFE: I'm Sidney Wolfe of the Public

Citizen's Health Research Group.

Is an increase in approximtely one

sexually satisfying encounter a month--not from

zero to one, but approximately from four to

five--worth the possibility of an incrased risk in

breast cancer or a coronary heart disease?

Is the FDA actually considering the

approval of this product?

I was interested to hear Dr. Davis'

skepticism--I think is the proper way of raising

it--as to what clinical significante there is in

going from four to five sexual encounters a month,

or having an increase of just 5 to 6 points more

than a placebo on a scale of 100, in terms of

sexual desire.

What is known is that there's a fairly

good consensus among epidemiologist who work in the

area of endogenous--or body-produced--hormones and

breast cancer risk, that increasing levels of the

common estrogens and adrogens such as testosterone

are associated strongly with increasing levels of

213

breast cancer risk. This is best illustrated by a

recent pooled analysis of nine high-quality

prospective studies which were published in 2002 in

the Journal of the National Cancer Institute. In

the pooled analysis, the risk of breast cancer for

post-menopausal women increased by approximately

two-fold, with a quadrupling of blood testosterone

levels.

In the data on the transdermal

patch--which you saw some of this morning--the

average blood level of testosterone in these 18 to

49-year-old women rose from a pre-treatment level

of 176 nanograms per liter, to 797 nanograms by

week 52. This is a 4.5-fold incrase in blood

testosterone levels by 52 weeks, which is slightly

higher than the four-fold increase in blood

testosterone levels in the pooled study mentioned

above that was associated with a two-fold increased

risk of breast cancer.

Other concerns about the chronic use of

testosterone, as mentioned by the FDA, is the

increased risk of coronary artery disease. A study

214

entitled "The Relationship Between Serum Sex

Hormones and Coronary Artery Disease in

Post-Menopausal Women," found "--evidence of a

positive relationship between the serum free

testosterone level and the degree of coronary

artery disease in women." And, again, in this

study there was a four-fold increase in free

testosterone with the patch.

Decreased sexual desire is a very

complicated problem, as discussed by Dr. Tiefer

today. There is little question that a large

proportion of women with this complaint respond

very well to counseling that may reveal underlying

problems, such as a history of being sexually

abused, current unstable or unhealthy

relationships, depression, or other causes better

dealt with directy rather than being glossed over

with a testosterone patch.

The journalist H.L. Mencken has said that

for every complicated problem there is a simple

solution--which is usually wrong."

I urge you and the FDA to reject the

215

application for approval of the testosterone patch.

And, in closing, I have no financial

conflict of interest.

DR. GIUDICE: Thank you.

The next presenter is John Grossman.

DR. GROSSMAN: Good afternoon. I want to

thank the FDA and the panel for allowing me to

participate in this important process that will

serve the interests and advance the health of

women.

My name is Dr. John Grossman, and I am

professor of Obstetrics and Gynecology,

Microbiology and Tropical Medicine, Prevention and

Community Health, and Health Services Management

and Leadership at the Geroge Washington Univeristy.

I'm also the Executive Vice President of the

Society for Gynecologic Investigation.

For the record, my comments do not reflect

the positions of either of these organizations. I

am here, rather, today to present my own

perspective, based on being a practicing

gynecologist in Washington, D.C. since the mid

216

1970s.

I have no personal financial relationship

with the sponsor of this product, nor with their

competitors. And I have no financial interest in

this product or any comparable products.

My 29-year practice has become what my

father, who was a founding Fellow of the American

College of Obstetricians and Gynecologists, and a

medical practitioner for 46 years, would have

called "a mture practice." As years have gone by,

I have had the good fortune to have my patients

place increasing trust in our professional

relationship. And during this period, I have

learned that many women have problems with sexual

intimacy for a variety of reasons. Perhaps one of

the most difficult problems to quantify and to

treat is diminished sexual drive.

My interest and concern about this issue

prompted me to request a copy of the product

briefing document that has been submitted to this

panel. My review of the information currently

available leads me to believe that Intrinsa is safe

217

and effective for increasing satisfying sexual

activity in these women who have had

hysterectomies, and I believe it could potentially

benefit some other groups of women, as well.

I becan my medical education during the

sexual revolution of the 1960s Even then, I would

never have envisioned a time in America when

television commercials would address what we

currently call "erectile dysfunction." Relatively

recently, health professionals have expressed

concerns about gender bias, and the public has

strongly supported gender equity in all areas of

life.

I believe that Intrinsa safety and

effectively increases sexual desire and the

frequency of satisfying sexual activity, while

reducing sexually-related personal distress. And I

urge the panel to recommend approval of this

product, not only to provide gender equity in

issues of sexuality, but also to address the needs

of my patients, and those of many other women who

might not otherwise be heard.

218

Thank you.

DR. GIUDICE: Thank you. The next

presenter is Lenore Pomerance.

MS. POMERANCE: Good morning. I have no

financial relationship with Procter & Gamble.

My name is Lenore Pomerance. I'm a

psychotherapist in Washington, D.C., and work with

mid-life women and their partners on menopause,

sexual relationships, and healthy lifestyles.

The approval of Intrinsa is premature

until long-term data have proven its safety.

What short memories some of us have. 28

months ago the Women's Health Initiative halted its

unprecedented trial of estrogen and progestin

because risks outweighed the benefits for

post-menopausal women.

The study was undertaken to test whether

the estrogen preparations that millioins of women

had already been taking for over 30 years helped or

harmed them. If we knew then what we know now,

would we have let doctors and drug companies

convince us that menopause was a disease? Would we

219

have let ourselves be fooled into believe what Dr.

Robert Wilson--who claimed in his book Feminine

Forever--that "menopause is a hormone deficiency

disease, curable and totally preventable, and that

every woman, no matter what her age, can safety

live a fully-sexed life for her entire life?"

The cure for this disease was "hormone

replacement therapy," replacing what had been lost.

And those 30 years saw efforts to make HRT reverse

the ravages of old age, from wrinkled skin and weak

hearts, to addled brains.

The results of the WHI have taken the "R"

out of HRT. Researchers and practitioners don't

talk of "replacement" anymore. The new term is

"HT," and it is to be used only for menopausal

symptoms of hot flashes and vaginal dryness, for

the shortest time, and in the lowest dose possible.

The new guidelins are not based on proven safety,

but on women's wilingness to live with the risks.

Getting rid of the "R" is a backhanded way

of admitting that menopause is a natural condiiton;

a physiological process that every woman will

220

experience if she lives long enough. Many women

are never bothered by the physiological changes.

Some even welcome them.

In my practice, women for whom menopause

is a crisis are often experiencing other

life-changing events like divorce, widowhood, dying

elderly parents, children leaving home, retirement.

Does history have to repeat itself? Will

Intrinsa become the Premarin of the 21

st century? I

don't believe for a minute that Intrinsa

prescriptions will be confined to surgically

menopausal women with low libido.

The FDA has approved off-label

prescribing, but it must foresee that, as happened

with the Viagra boom, this new drug will be

requested by many people on whom it has not been

tested. Believing that it's safe, these women may

well become the guinea pigs of the 21

st century.

Let's not let that happen.

Thank you.

DR. GIUDICE: Thank you.

The next presenter is James Simon.

221

DR. SIMON: I'm Dr. James Simon. I'm a

reproductive endocrinologist from Washington, D.C..

I'm not speaking as past president of the North

American Menopause Society, I'm speaking as a

practitioner.

My conflicts or potential conflicts are

listed for you in my handout.

Slide--could I have the next slide?

[Slide.]

This is a concerned physician's view of

the subject, and I'm representing myself and only

myself.

Next.

[Slide.]

The issue before the panel really is: is

low sexual desire really a clinically important

problem? And what about the risks.

Next.

[Slide.]

in this study from Laumann, oftentimes

brought into question, they found in a large cohort

32 percent of women experience low sexual interest.

222

And I say--this is from 1999--they have been

criticized by this high number.

Next.

[Slide.]

A recent study, published only this year,

looked at 29 countries, with 27,000 men and women,

aged 40 to 80, and defined sexual dysfunction as

"frequent or persistent problems." Those problems

studied in women were--most importantly apropos of

this application--lac of sexual interest.

Next.

[Slide.]

In this study, 65 percent of the women

were having sex. The most common dysfunction was

lack of sexual interest, found in 21 percent of the

women, similar to their previous findings. They

concluded, overall, that overall 39 percent of all

women in their study--remember, they studied 27,500

men and women--had at least one sexual dysfunction.

Next.

[Slide.]

Another study, looking at safety--and,

223

importantly, most women make the decisions about

hormones and safety of hormones based on the issue

of breast cancer. And in this study, recently

published in Menopause by the group at NIH, they

looked to see if testosterone could protect--could

protect--against the added risk of standard hormone

therapy already mentioned by previous speakers.

This was a retrospective, observational study of a

small cohort of women, average age 56 years, and

they were studied for 5.8 years. Outcomes were the

incidence of breast cancer.

Next.

[Slide.]

They found, actually, that in women on

testosterone, the risk was 238 per 100,000

women-years, lower than--not higher than--lower

than women who were in the WHI, lower than women in

the Million Women Study. And, in fact, consistent

with women who had never used hormones.

Their conclusions were: the addition of

testosterone to conventional therapy for

post-menopausal women does not increase and may

224

indeed reduce the risk of breast cancer. These

same investigators found this in pre-clinical

scientific experiments.

[Time expired. Microphone turned off.]

DR. GIUDICE: Thank you.

The next speaker is William Petok.

DR. PETOK: Good morning. I have no

financial relationships with the producers of this

product.

Good morning, members of the Advisory

Committee. Thank you for allowing me time to share

some of my thoughts about the TTS.

I'm Bill Petok, a psychologist and a sex

therapist in private practice. I'm also the Chair

of the Mental Health Professional Group of the

American Society for Reproductive Medicine. In

addition to my clinical activities, I also teach

obstetrics and gynecology residents at Baltimore's

Sinai Hospital, specifically about human sexuality.

As you are aware, sexual dysfunction in

American women occurs at a significant rate. HSDD

is the most frequent problem I see in my clinical

225

practice, and the problem most frequently seen by

the physicians that I teach. It is also one of the

most difficult problems to treat because it can

have many determinants.

In addition to the problem that HSDD

presents for an individual, this disorder can also

have an impact on relationships in which sexual

interaction is a vital aspect. Low desire on the

part of one partner can lead to frustration and

dissatisfaction for both. Some of the women that I

treat report they do not understand why they have

lost interest in sexual interaction with their

partners, especially when other aspects of their

relationship are good. The partner can be at a

loss to understand the changes in relationship, as

well.

It is important to note that not all HSDD

is hormonally related. AS I said before, it can

have many determinants that include the quality of

the relationship and other psychological factors.

It is a complicated problem that requires a careful

analysis and intervention. When hormonal factors

226

are implicated as part of the etiology, as for

surgically menopausal women, testosterone

supplementation can be an effective therapeutic

addition.

Over the years that I have treated sexual

dysfunctions, I have had many women report their

physician has prescribed testosterone in one form

or another. Frequently, the prescription is

offered as a cream that is to be applied topically.

Often the directions given to the patient are less

than adequate, and she asks me why she isn't

getting a result that increases her desire level.

She may be unclear in her understanding of

whether she is to use the product just prior to

sexual relations, daily, or with some other

frquency. A delivery system that makes sense and

has little room for misinterpretation would be

useful to these and other patients. I believe the

advantage of a product like the TTS is that it is

easier to apply and therefore less likely to be

misused.

I have two reservations--not so much about

227

TTS as about how it is reported in the press or

promoted.

One, I'm concerned that this product will

be inappropriately described as a "female Viagra"

and be viewed as a cure-all for all female sexual

dysfunction of any kind. The researchers have been

careful to describe its success with a specific

group of women: surgically menopausal women who are

on a stable dose of estrogen, and who are in

long-term established relationships.

It would be inappropriate to generalize

these findings to a wider group of women.

Second, I am concerned that women not have

expectations that are out of line with reality.

This is not a cure--

[Time expired. Microphone turned off.]

DR. GIUDICE: Thank you.

The next presenter is Raymond Rosen.

DR. ROSEN: Can I have my slides, please?

My first slides, please?

[Slide.]

Okay. Thank you.

228

I'm Raymond Rose, professor of psychiatry

at Robert Wood Johnson Medical School. I've been a

psychologist and sex researcher for approximately

30 years.

I serve as a research consultant, and have

received research support from P&G, Pfizer and

Solve Pharmaceuticals.

I'm here representing myself, and my

travel expenses wer paid by my department.

Next slide, please?

[Slide.]

I want to use my brief time to just to

comment on two important documents. One of them

has been discussed quite a bit today, and that's

the FDA Draft Guidance document on FSD from 2000.

The other document hasn't been mentioned, but I

think is quite important, which is a consensus

document that a number of people here participated

in in 2001.

Next slide, please.

[Slide.]

Just to begin with a few comments about

229

the guidance document. This is available on the

FDA website.

Next slide, please.

[Slide.]

And the guidance document , which is very

important--for people who haven't read it--covers

four areas of sexual dysfunction in women: as has

ben mentioned, inhibited or hypoactive desire is

the most common area. The guidance document

indicates how these are defined. And I think the

sponsor's done an excellent job in following those

guidelines.

Next slide, please.

[Slide.]

in terms of clinical trial endpoints,

which has been a majoar area of discussion today,

it's important for us to understand that the

satisfactory sexual events aspect of it really

comes from that guidance document. And the sponsor

has really done everything they can to meet those

guidelines.

Many of us in the field believe that,

230

particularly in the area of sexual desire

disorders, satisfactory sexual events is not

necessarily the optimal primary endpoint. And I

want to urge all of us to move beyond that. I have

spoken to members of the FDA and, hopefully, we'll

be moving past that.

Nonetheless, I think the sponsor has shown

great consistency in the effects across differenet

endpoints.

Next slide, please.

[Slide.]

Just to comment quickly on the Princeton

Consensus Conference--about 16 international

experts, many of whom are here today, participated

in this meeting in Princeton in June 2001.

Next slide, please.

[Slide.]

Of importance, we defined female androgen

insufficiency. It's discussed and defined at great

length.

Next slide, please.

[Slide.]

231

And we identified four important

etiological sub-types, the most important of which,

of course is the ovarian sub-type, including

oophorectomy or effects of radiation.

I recommend this document because it

provides very clear guidelines for diagnosis and

classification of androgen insufficiency in women.

And I hope that this document and other similar

guidelines will be used in further developing this

product if it's approved.

Thank you.

DR. GIUDICE: Thank you.

The next presenter is Amy Allina.

MS. ALLINA: Thank you. I'm here from the

National Women's Health Network, which is a

nonprofit organization that works to improve the

health of all women by influencing health policy

and supporting consumer decision-making. We accept

no financial support from pharmaceutical companies

or medical device manufacturers.

I'm going to talk primarily about my

concerns about the limitations of the data. But

232

putting those limitations aside for a minute, I do

want to acknowledge that it appears Intrinsa offers

some benefit to the women in whom it's been

studied. And the need in that group is real, so

the chance to provide real help to women with the

problem of low sex desire is hard to pass up.

As women's health advocates, however, we

can't consider this product in a vacuum, and

neither can the FDA. The world changed when the

Women's Health Initiative revealed the long-term

negative health effects of hormone therapy. And a

six-month study of a testosterone patch that would

be the first drug of its kind may have seemed

adequate before, but it's not today.

Women who might stand to get a benefit

from the testosterone patch also need to know about

its long-term effects on their healht. In the wake

of the WHI, it's appropriate and necessary to

exercise special caution about long-term hormone

use without long-term safety data.

The patch hasn't been studied for an

adequate period of time to find out whether it

233

might increase risk of breast cancer. Some early

indication might have come from a mammographic

study but, as FDA noted in its medical review,

there are several limitations that make it

difficult to determine what effect the testosterone

patch might be having on breast tissue.

The short-term that P&G has collected so

far are also not able to provide reassurance about

the effect of their product and risk of heart

disease. The events occurring in the extension

phase, which FDA noted, could reflect

cardiovascular events are potentially important.

Although there is no placebo comparison for the

extension phase, the average age of women in the

combined trials was 49. So these problems can't

simply be dismissed as expected background.

The fact that lipid profiles were similar

in the testosterone and placebo groups isn't

adequate reassurance, since lipid levels failed to

predict the the cardiovascular problems that were

eventually found to be associated with hormone

therapy in the WHI.

234

In addition to these long-term safety

concerns, I want to urge FDA and all of you to

balance the benefit that the testosterone patch

might offer to a small group of women, with the

health risks it may pose to many more.

It would be naive and irresponsible, I

think, to pretend that this drug will only be

promoted anda prescribed to women who are exactly

like those in the trials.

A cursory scan of health websites and

books that deal with sexual health issues shows

that the recommendation of testosterone for

treatment of women's sex problems is not directed

solely to those women. It includes advice to

younger women, including women in their

reproductive years--which raises a whole new set of

questions, for example, about the effect of

testosterone on future fertility.

Even the company's proposed patient

information leaflet blurs the line somewhat,

defining Intrinsa

[Time expired. Microphone turned off.]

235

DR. GIUDICE: Thank you.

The next presenter is Neil Goodman.

DR. GOODMAN: My name is Dr. Neil Goodman.

I'm speaking today representing the American

Association of Clinical Endocrinologists, where I

serve as Chairman for Reproductive Endocrinology.

The American Association of Clinical

Endocrinologists is a professional medical

organization with over 5,000 members throughout the

United States and 70 foreign countries. ACE is

devoted to the enhancement of the practice of

clinical endocrinology, and the betterment of care

for patients with endocrine diseases.

ACE supports the approval of the new drug

application for the transdermal testosterone system

from Procter & Gamble for the treatment of

hypoactive sexual desire disorder in surgically

menopausal women receiving concomitant estrogen

therapy.

As you've heard, menopausal women

frequently experience low sexual desire, which can

cause substantial distress and negatively affect

236

quality of life. Representing about a third of

post-menopausal women, surgically menopausal women,

in particular, experience a greater degree of

sexual dysfunction than any other group of

menopausal women.

For more than 20 years scientific research

has supported the use of testosterone for the

treatment of female sexual dysfunction in

surgically menopausal women. However most studies

have been limited in the number of participants and

the duration of treatment. In addition, there has

not been a form of testosterone--which should be

emphasized here--that gives women a simple and

patient-friendly means of delivering physiologic

levels of testosterone. The testosterone

transdermal system is the first such testosterone

product that has proven to be both efficacious and

safe for the treatment of the hypoactive sexual

desire disorder through randomized controlled

trials. These are statistically significant, based

on the information provided to the FDA.

It is the opinion of ACE, in reviewing the

237

study submitted to FDA by Procter & Gamble, that

the transdermal testosterone system can achieve

imporved sexual functioning at physiologic levels

of testosterone, with a minimal incidence of

adverse effects. This opinion is based, in part,

on the extremely comprehensive and well-validated

instruments for the measurement of female sexual

dysfunction that's been developed by Procter &

Gamble. These instruments, which include the

Profile of Female Sexual Functioning, the Sexual

Activity Log, and the Personal Distress Scale, are

mandatory for proving efficacy of testosterone

therapy. And I believe that these instruments have

proven their effectiveness, and have been validated

in the studies you've seen today.

The statistical analysis is highly

significant, taking into account the number of

women studied and the duration of treatment. Based

on these studies, combined treatment with estrogen

and transdermal testosterone has proven to induce

increased motivational aspects of sexual behavior,

not just frequency but, in fact, the desire and the

238

impact of orgasm in sexual intercourse.

ACE believes that the scientific data

provided to the FDA is sufficient to prove efficacy

and safety of the transdermal system, and should be

approved without further studies.

Thank you.

DR. GIUDICE: Thank you.

The next presenter is Doug Ronsheim.

REV. RONSHEIM: Thank you very much for

giving me the opportunity to speak.

I am the executive director of the

American Association of Pastoral Counselors. It is

a national counseling organization of licensed and

credentialed professionals providing clinical

services to individuals, families and couples.

The membership also attends to spiritual

and faith issues which clients might wish to

address in the context of care.

Professionally, I'm a licensed marriage

and family therapist, a Fellow in the American

Association of Pastoral Counselors, a clinical

member and approved supervisor in the American

239

Association of Marriage and Family Therapy, also a

Presbyterian minister, and have had a previous

faculty appointment at the University of Pittsburgh

Medical School Department of Psychiatry.

I initially became aware and interested in

the topic of hypoactive sexual desire disorder as

it was presented in a variety of counseling

sessions with couples. Decreased sexual desire

usually was not the presenting problem, but often

emerged during the sexual history that sexual

incompatibility post-surgery was a stressor--and

for good, understandable reasons, and not due to

any long psychiatric history.

The stress was due and exacerbated, may

time, because the couples' previous sexual

relationship had been quite satisfactory. In

addition, awareness related to this has emerged in

this past year in conversations with Dr. Larry

Nelson, who does research at NIH at the other end

of the reproductive spectrum, with premature

ovarian failure, where women often, at an early

age, for inexplicable reasons, lose the functional

240

capacity of their ovaries.

HSDD has intra- as well as inter-personal

ramifications which can be significant. Dr.

Nelson's research has shown that the loss of one's

capacity to give birth to children, in addition to

decreased sexual desire, is a double loss for them.

A high preponderance of these patients exhibit

varying degrees of depression and anxiety.

What is common here is a theme of loss.

Interpersonally, decreased sexual desire is bound

to affect a marital relationship, even though both

spouses understand that this is caused by a medical

or physiological reason, it can be experienced

personally, and can be a factor for increased

marital stress.

Having a resource for the treatment of

HSDD can be a significant benefit and assist

specifically in the improvement of a woman's sexual

response and the general improvement of one's

marital relationship which could again embrace a

natural, more responsive sexual relationship.

The importance of addressing HSDD is not

241

only to curtail an already difficult and

frustrating malady, but preventing the potential of

the further spiraling down of intra- and

inter-personal functioning, and decreasing the

chances of the co-occurring development of the

symptoms of depression and anxiety.

Thank you.

DR. GIUDICE: Thank you.

And the final presenter is Kim Wallen.

DR. WALLEN: Hi. I'm Kim Wallen from Emory

University, and the Yerkes National Primate

Research Center. I have no financial interests in

any of the drug companies involved in these

studies.

I do have an interest in female sexual

desire, and my primary research interest is in how

hormones affect female sexual desire in non-human

primates. And there, I think, are some parallels

to humans.

As a researcher who's studied this for

over 25 years, i was not surprised by the minimal

effects that Intrinsa produced in women. These are

242

not striking effects, and part of the reason, I

think, is because this is an example of a drug that

is prematurely coming to closure on something where

we don't understand the basic science.

Having looked at the literature in humans

on androgen insufficiency, I think it is quite

unconvincing that we understand what is the

hormonal basis of female sexual desire.

My concern of approval of this

drug--besides the potential health risks of this

drug--is that it will prematurely close the

investigation of understanding how female sexual

desire is influenced by hormones. There certainly

are many factors that affect female sexual desire,

but hormones are one of them, and we need to

discover what the basic mechanism is. And I think

it is quite clear from the data that Procter &

Gamble submitted for this application that they

don't know what the mechanism is. And I think from

the other published literature, it's clear we don't

know what the mechanism is.

So I would urge the committee to not

243

approve this because I think it is a premature drug

that simply does not solve what is a very important

and critical problem that we need to understand.

And it is important to resolve this issue. But

this is not the answer.

DR. GIUDICE: Thank you.

I would like to thank all of the

presenters for their thoughtful comments.

And Ms. Watkins has a statement to

make--please, before we leave for lunch.

MS. WATKINS: I'd like to remind the

committee that, in the spirit of Federal Advisory

Committee Act, and the Sunshine Amendment, that

discussions about today's topic should take place

in the forum of this meeting only, and not occur

during lunch or in private discussions.

We ask that the press honor this

obligations of the committee members as well.

We'll break for lunch now and reconvene at

1:15.

Thank you.

[Off the record.]

244

DR. GIUDICE: Back on the record.

Would everyone please sit? And would all

of the members of the committee please take their

places around the tables?

[Pause.]

This afternoon we will first begin with

questions from the committee, initially to the

sponsor, and then we will have questions to the

presenters from the FDA. And then we will address

the questions directly that were given to us by the

FDA, and give them our recommendations.

DR. GIUDICE: So I'd like to open this up

now to members of the committee. And--yes, and for

those members who came in a little late, if you

wouldn't mind introducing yourselves. This is not

to point the finger to show that you were late--

[Laughter.]

--but just to familiarize everyone with

who you are.

Dr. Emerson.

DR. EMERSON: I'm Scott Emerson. I'm a

biostatistician from the University of Washington

245

in Seattle.

DR. GIUDICE: Dr. Stanford.

DR. STANFORD: Joe Stanford, family

physician from the University of Utah, Salt Lake

City.

DR. GIUDICE: Dr. Dorgan.

DR. DORGAN: I'm Joanne Dorgan. I'm an

epidemiologist at Fox Chase Cancer Center in

Philadelphia.

DR. GIUDICE: Thank you. And Dr. Merritt

did arrive, but she's not in the room right this

minute.

Questions from the Committee to Sponsor and FDA

DR. GIUDICE: So, I would now like to open

the committee questions, and if you would just

raise your hand and--Dr. Emerson? Please.

DR. EMERSON: I guess--I don't know how you

want to interleave these, or if you want subject

matter questions, or whatever--but one of the first

questions I have is for Dr. Braunstein, who

presented reference ranges for the testosterone

levels in normal women.

246

Could you tell me what those reference

ranges represent? It was like around slide 83 of

your presentation.

DR. BRAUNSTEIN: Sure. 161 women in the

reproductive age range, having normal menstrual

cycles, not receiving any hormones at all, gave

multiple samples across the menstrual cycle. So

they weren't weighted towards mid-cycle time, or

luteal phase, or follicular phase. So they were

across the menstrual cycle.

Each individual's--the results from each

of those samples for an individual was summed, and

then the data was averaged. And these lines

represent the lower 2-1/2 percentile and the upper

97-1/2 percentile.

DR. EMERSON: Okay. Then I just want to

bring the committee's attention--slide 84, for

example--while those reference ranges are for the

central 95 percent of the data, those whiskers are

the central 80 percent of the data. And we do

have, in our materials, tables of how high the

maxima actually go.

247

But the concept of what is being presented

here is not at all comparable to the reference

range, in terms of--that the central 95 percent

would be a much, much higher range. In fact some

of those measurements go up to 100 or so.

DR. GIUDICE: Dr. Nissen. And then Dr.

Montgomery-Rice.

DR. NISSEN: Although I'm a cardiologist

and here, I think, primarily to look at the

cardiovascular issues, I did want to ask a couple

of questions about efficacy.

The main one I want to understand is:

you've gone to a lot of trouble to validate tools

for assessing this. But what I didn't see anywhere

in here--and I'd be interested in whether you can

provide us with any information--on what the effect

is of non-hormonal interventions; that is, if you

take women with this disorder, and you give them

counseling, you give them other kinds of supportive

therapies that don't involve giving a systemic

hormone, how much improvement, on the same scale,

do you get?

248

You know, we saw about a 5 percent

increase, for example, on one of your scales.

Well, I'd like to know what that is for

non-hormonal interventions. And if anybody can

answer that I think it would be very helpful to me

to put this efficacy into the context of the safety

issues.

DR. MEYER: Although we did not ever test

our scales in any other type of interventional

therapy, I think Dr. Jan Shifren can give us some

additional perspective on the efficacy of other

types of interventions.

And one thing I did want to mention--as

Dr. Shifren will reiterate--is the Intrinsa patch

is not for everyone. As she has already told us,

there are other types of therapies that are

appropriate and have worked for women prior to

androgen therapy.

DR. SHIFREN: I am not a sex therapist.

I'm a reproductive endocrinologist. And certainly,

for women with non-physiologic causes of HSDD,

other interventions, such as counseling, sex

249

therapy, education, and lifestyle changes can be

very effective.

What's important to realize is that the

women in our trial--and, again, it was a select

group of women. These are the women we would like

to see the patch used in--all had healthy sexual

functioning before surgical menopause, and reported

significant decreases in desire and activity

associated with distress, following surgical

menopause.

To be entered in the study these women

couldn't have depression or relationship conflict,

or all of the other things that the other

non-pharmacologic interventions are so effective at

treating.

DR. NISSEN: I don't think you answered my

question, though.

My question is: what do we know about

whether those therapies are effective, and what is

the magnitude of their efficacy? You have a drug

therapy here, and there are other therapies out

there. And so I need more information to

250

understand how large is this efficacy in relation

to what can be offered women via conventional,

non-drug therapies.

DR. SHIFREN: I think it really depends on

the cause of the sexual dysfunction. There are

studies that make it clear that counseling and sex

therapy are very effective therapies, and they

should be used widely. But when you select a group

of women for whom the major issue is, let's say,

surgical menopause, those are less effective.

The other thing I did want to point out is

that our placebo-treated women--it's hard to say

that was a placebo. Wearing a

non-testosterone-containing patch is a very active

intervention. And in some ways, the response in

the placebo-treated women may almost address your

question. These women were receiving active

counseling by the physicians and the nurses that

they saw regularly at the study site. They were

wearing a patch, which was a clear reminder to both

the patient and her partner that she was concerned

about her sexual activity, that it distressed her,

251

and that she was committed to making it better.

So that just being in the non-testosterone

treatment arm was an active intervention.

DR. GIUDICE: Dr. Montgomery-Rice.

DR. MONTGOMERY-RICE: I want to go back to

slide 83-84, where Dr. Braunstein compared it to

some data that Dr. Soule presented for the FDA.

Because I'm confused--and maybe, Scott, you can

help me interpret this.

When I look at slide 84, and it talks

about his median free testosterone level, and we

are still talking about a level of 7 picagrams, it

doesn't appear that there are that many subjects.

But you're saying that that is 80 percent of the

subjects had a level that was greater than that.

So would that correspondent, then to what

Dr. Soule is saying, where she points to data in

slide 8 of her presentation, that more than 35

percent of the people were beyond this median value

of 8.6

DR. EMERSON: So, if I could clarify what I

was trying to get across--in the "normals" that

252

line that is drawn at 7, only 2-1/2 percent of

normals are above that line. In the larger

study--you know, we have 500 subjects in this--they

have 10 percent of the subjects above the top

whisker there.

And so we're seeing that there's

something--and what Dr. Soule presented would be

representative numbers, suggesting that between the

dashed line and the top whisker might be 10 to 15

percent of the patients. And then another 10

percent are above that top whisker.

But the point I was trying to make is that

this graph is actually quite misleading, in trying

to give the impressing that most of the

measurements--that the difference between the

normal range and what they observed isn't that

great, when they're using two different measures

there.

DR. BRAUNSTEIN: In actuality, at any time,

the patients on testosterone, about 15 to 20

percent or so were above the upper limit of the

free testosterone level here. Again, this is a

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reference range: young, pre-menopause women--young

women. And we're using that just to show you that

the majority of women fall within that range. Some

will go above that range--but, certainly, not so

terribly above the range that one would get serious

concerns.

For instance, when Dr. Dobs was talking

about the therapeutic doses that are used in women

who are transgendered to males, they receive very

large doses, and the levels are quite a bit higher.

If you look at female athletes that are abusing

androgens, the levels are substantially higher.

DR. EMERSON: Well, but the scale--if you

went up to that 97-1/2 percentile on that--I can't

say exactly what it is, but your maximum, in the 24

week is closer to 100. Okay. So the scale of

that.

Now, again, maybe the majority of patients

aren't up there, but some patients have very, very

high levels of free--

DR. BRAUNSTEIN: Yes, there were a total of

11 patients that had a level of 21 picagrams per

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ml. And of those 11 patients, there were, I

believe, 7 who had androgenic adverse events,

primarily hirsutism. And there were no other

significant adverse events--no liver function

abnormalities, kidney function abnormalities,

etcetera. Again, they were androgenic types of

adverse events--the types of things you would

expect with very high free androgen levels.

And if we look at the highest decile--the

highest 10 percent--really, there's no statistical

difference if you look at the women who were in the

highest decile versus those who were on the

placebo.

DR. EMERSON: Where you sample size is

already down to--

DR. BRAUNSTEIN: The sample size, the upper

decile is small.

DR. EMERSON: And the other thing that I

would also like to point out on this is that you

had significant dropout in your patient population.

20 percent of your patients dropped out during the

initial six months. And then at each stage, as you

255

went from the 6 months to 12 months, 12 months to

18 months, more patients dropped out. And so

actually the highest level that you observed in

free testosterone was in an intermediate

measurement. And we can imagine that perhaps that

patient dropped out because of that high

level--perhaps not. We don't have that

information. But that's something to keep in mind.

DR. BRAUNSTEIN: Well, in actuality, there

was no relationship between when the highest level

was found--because it could have been found at any

time the bloods were sampled during the

trial--versus when the androgenic adverse event,

for instance--if one appeared--did appear.

Could I have that last slide, please?

Just to show the point in the upper

decile--this is 6-99--you can see that in the

comparison to the placebo group, the patients in

the upper decile of free testosterone, 10.3 percent

had acne, versus 7 percent in the placebo group;

3.5 alopecia, versus 2.7; 5.2 facial hair versus 5;

no voice deepening versus 1.7.

256

So, again, the reference range--and your

point is very, very well taken--but the reference

range is just to provide you sort of a baseline

sense of security. This is not being--you know, we

aren't talking about this as a replacement therapy.

This is a drug therapy--but to show you the

relative levels of androgens achieved with Intrinsa

versus the normal physiologic range in reproductive

women was the purpose for establishing this

reference range.

DR. EMERSON: Do you know whether the

patient who had a measurement at 107.7 at 24 weeks

is represented in the 52-week population where the

maximum was 63?

DR. BRAUNSTEIN: I don't know that.

DR. EMERSON: Thank you.

DR. BRAUNSTEIN: But we can find out and

come back to you on that.

DR. GIUDICE: In order: Dr. Lipshultz, Dr.

Dr. Dickey, Dr. Judice, Dr. Stanford, Dr. Hager.

And we will go around the table.

[Laughter.]

257

So--Dr. Lipshultz.

DR. LIPSHULTZ: Yes, I have a question.

We see, repeatedly, a comparison of the

TTS-treated to the placebo-treated. But I'm

interested in Dr. Davis' slide, in which he showed

the frequency of satisfactory sexual encounters

over a four-week period, comparing the placebo to

the treated to the normal. And my question is: if

these people had a normal sexual relationship prior

to the oophorectomy, and following oophorectomy

they had androgen replacement therapy, why are they

not going back to their pre- to their normal--quote

"normal"--state. If the answer is androgen

replacement, then why aren't they back to normal,

rather than back to one increased encounter in a

month?

DR. MEYER: Well, if I could have slide

252, please--although I don't know what their

normal level may be.

But what this shows you is "total

satisfying activity," "desire" and "distress."

Here's the baseline level of the women in our

258

study--in the surgical menopause study. Here's the

normal level that we got from our instrument

validation studies in total satisfying activity in

a four-week period.

The self-identified responders from our

clinical relevance study got about 50 percent of

the way back to the normal women--these are

different women--but the normal women in the

validation.

DR. LIPSHULTZ: Exactly, and my question

is: what is your hypothesis, if this is due to

something related to the oophorectomy, and you're

replacing what you think is the target hormone, why

wouldn't they go back to the validation level?

DR. MEYER: Because these are different

women. Although we did not ask them what their

normal level was. They could be back at their

normal level.

The women who are self-identified

responders in this study had a mean satisfying--an

increase in satisfying sexual activity of 4.4

activities per month. So that's one per week.

259

DR. LIPSHULTZ: Right. But I think--

DR. MEYER: So that would get them back to

seven per month, which might be their normal,

although that is lower than the women in the

validation study.

DR. LIPSHULTZ: But isn't it important for

you to have that data? I mean, as to what you

consider normal sexual activity for that group of

women? Otherwise, as was pointed out by several

people from the audience, that, you know, the

androgen may not totally explain what's going on

here, or else you would expect to see a

normalization.

DR. MEYER: And Dr. Shifren can address

this. But I think another important thing to look

at is the distress. So, again, it's not just the

activity, but--

DR. LIPSHULTZ: I'm not disagreeing that

the patients are better. My question is why aren't

they back to normal if the answer is androgens.

They should say, "I feel exactly the way I did

before because you've replaced my androgens."

260

DR. SHIFREN: I may be able to help a

little bit here. I was not involved in the U.S.

validation study. But I can tell you, from my

typical healthy sexually functioning menopausal

women, 12 events in four weeks is actually quite a

lot. That's three times a week, and that's

actually more than what we consider the typical

average for even pre-menopausal Americans.

So I can't really speak to the validation

study and normalization. But I think it's very

important to realize: this isn't blood pressure.

And there actually is no "normal." And it's

actually normative that as couples age, with both

duration of the relationship and aging, that

frequency declines, but satisfaction can remain

very high.

So there's not really a good correlation,

for most couples, between frequency and

satisfaction, and distress. The very first thing I

say to almost all of my patients when they come in

with sexual complaints is: "Let me start by saying

there is no 'normal' frequency or set of behaviors.

261

And that the typical American experience has very

little to do with Sex in the City. And if you are

comfortable in your relationship, and it's working

for you and your partner, that's all that matters.

And if it means that you're doing non-intercourse

events because your husband has erectile

dysfunction, but it's a loving, close and intimate

relationship and you have no concerns, there's

nothing to treat."

So a lot of what I do is really validating

for women that there is no "normal" for sexual

function. The most important thing is that it's

working for the woman, and that there's no

associated distress.

DR. GIUDICE: Dr. Dickey.

DR. DICKEY: I'm going to change gears a

little bit. I have a question for Dr. Steinbuch.

I think that's how you pronounce it.

I'd like a little more information about

the proposed long-term safety plan. It would

appear that you're going to collect your

262

information from claims data. And I'm a little

concerned about privacy issues, and a little

concerned about whether claims data are actually

going to give you the kinds of information that

we've heard about through the morning, in terms of

risk factors.

DR. STEINBUCH: Yes, with regard to privacy

issues, the Ingenix database--as I described

earlier--is comprised of all of these claims of

patients throughout the United Healthcare System.

And there really is no privacy issue there in

regards to the fact that every report that we get

is de-identified. So there's no--we can't identify

any individual per se. At least our company.

Ingenix, when they go after the medical

records for abstraction, it will be their company

employees who would be actually going out and

getting the information. So there really shouldn't

be an issue there.

And, as I said, we're going well beyond

claims, because we're going to be contracting with

them to actually go after medical charts for review

263

of all relevant events of interest.

DR. DICKEY: And there's no privacy issue

there?

DR. GIUDICE: This is an issue, I think,

that needs to be further discussed--the whole issue

of HIPPA. And I think what Dr. Dickey is getting

at is can you explain to us exactly what the

process is, so that patient privacy is not

violated.

DR. STEINBUCH: I think it would be best if

Dr. Alec Walker, who's here in the audience, who

represents--he's a senior vice president of

Ingenix. Perhaps he could address this issue with

regard to how it works in the United Healthcare

System.

Dr. Walker?

DR. WALKER: We have a number of

FDA-mandated post-marketing safety

studies--Alexander Walker, Senior Vice President,

Ingenix.

We have, I believe, five of these studies

going on now. They are HIPPA compliant. They are

264

done under IRB approval.

The data are manipulated in a

de-identified fashion, to the extent that they can

be. Then, at the last minute, if you have a

potential event that you want to look at from the

claims data, then it's de-identified to the extent

necessary to go to the medical record, and it comes

back.

DR. DICKEY: So, patients will give

permission to participate in the study?

DR. WALKER: No. Under HIPPA, with an IRB

approval--or, indeed, for an FDA-mandated

study--you don't need individual informed consent.

You do need the IRB or privacy board to examine the

protocol and procedures to verify that there's

adequate confidentiality in force and maintained.

DR. DICKEY: Thank you.

DR. GIUDICE: I have two questions. One

has to do with the data and the analysis. And

perhaps Dr. Meyer can answer this.

Have any of the data been analyzed with

regard to BMI, because it appears that there's one

265

dose, and women--a large range of BMI. So can you

give us any insight into that?

And the second is that there have been

several comments about potential risks g

with regard to breast cancer and cardiovascular

disease. And in our briefing documents I did not

see any pre-clinical data. And I'm wondering if

you could share with us any insight into that?

DR. MEYER: Certainly. With respect to

BMI--and we did break out these data by sub-groups,

and I think they are in your briefing book--but in

women with a BMI less than 25, between 25 and 30,

and greater than 30, the data were essentially the

same--the response on sexual desire. And for

satisfying sexual activity, the women in the

highest BMI group--that greater than 30--the

response was slightly less--the median response was

slightly less than those in the lower BMI groups.

DR. GIUDICE: And what about free

testosterone in those groups?

DR. MEYER: Let's see, I think Dr.

Braunstein--I don't know that we broke--we can

266

check. We'll look and see if we broke out free T

by BMI.

DR. GIUDICE: Okay.

DR. MEYER: And with respect to

non-clinical data in breast cancer, Dr. Mike Winrow

is our non-clinical toxicology specialist, and has

done an extensive literature review of all that's

known on the non-clinical data of testosterone.

And although-- there are lots of in vivo and in

vitro studies that he can address that have looked

at that.

DR. WINROW: Thank you. If you look at the

labeling on current testosterone products, they're

all labeled as potential carcinogens. That's based

on data generated by the International Association

for Research on Cancer, based on rodent studies

with very high doses, many of them administered to

neonates, over a period of years.

There's no doubt that at very high doses,

in rodents, that can occur.

The more interesting data--and this is

fairly recent data, and it follows from the

267

discussion that came this morning on the work being

done at NIH--if you're looking at rodent data

you're dealing with intact animals, estrus cycle

not menstrual cycle, and all the other complicating

factors--and extremely high doses.

What's being done at NIH, and published by

Dr. Demitri Kakis, is shown on slide 644--if you

could show that, please. And in this study,

they've used probably the best model that could be

used, which is an ovary-ectomized Rhesus monkey.

And what they've done ovary-ectomized Rhesus

monkeys, and then supplemented those animals with

either estrogen--in the second line down--or with

estrogen-progesterone, or

estrogen-plus-testosterone.

I realize the numbers are small, but

recognize that using Rhesus monkeys is not a

trivial event these days. Their intention was to

replace these hormones at levels that would mimic

the pre-ovary-ectomy levels. So they are within a

reasonable range of normal for both non-human

primates and primates.

268

What they were looking at was

proliferative response in breast tissue, which they

were using as a marker for potential

carcinogenicity.

It's a short-term study. But, at the same

time, the numbers are quite interesting. They used

this KI-67 antibody, which picks up an antigen that

only is produced in proliferating cells. And with

hormones, continuous cell proliferation is a

requirement for the development of cancer. And so

you normally see hormonally-induced tumors in

tissues that respond in a proliferative way to the

particular hormone under consideration. So if you

get a lot of testosterone, you'll get prostate

cancer--as an example.

And, as you can see here in these female

Rhesus monkeys, the controls had KI--that's a

percentage of cells that are proliferating--of

about 8 percent. If you--following ovary-ectomy,

if you then administered estrogen, that number shot

up to 30.

So, administering estrogen to

269

ovary-ectomized monkeys produces a very significant

increase in cellular proliferation in breast

tissue. If you added progesterone to that--very

little difference; not surprising because the

progesterone's really there to address endometrial

issues. If you added testosterone, however, that

level dropped to 16.7, which--while the number is

small, statistically it's no different from

control. But, of course, as I say, the numbers are

small.

So, adding testosterone to ovary-ectomized

monkeys, in the presence of estrogen, significantly

reduced the level of proliferation produced by

estrogen alone, and moved them back towards normal.

The other things that this group have done

along the same lines, they ran another study where

they administered flutamide to intact Rhesus

monkeys for a period of six months. So what

they're doing there is block testosterone

chemically, but leaving all the other hormones

alone.

In that case you get a doubling of

270

proliferation in breast tissue. You've removed the

testosterone, which is no longer offsetting the

proliferative response of the estrogen, and so

proliferation rate goes up--in the absence of

testosterone.

Two other studies that they've run, and

looked at other biological endpoints, they've shown

that in these testosterone-treated animals, you can

get a reduction in the expression of the oncogene

MIK, and you can also see a change in the estrogen

receptor alpha-beta ratio away from the ratio

that's considered of concern for breast cancer.

So in these small studies, using

ovary-ectomized Rhesus monkeys, all the data point

towards testosterone not having a proliferative

effect, or not raising the level of concern for

breast cancer. In fact, it's the exact opposite if

you look at the numbers.

And it was on the basis of this work that

they did the clinical study in the Australian

population which was published fairly recently.

So, you've got those two different sets of

271

data.

DR. GIUDICE: Thank you.

Now, starting over here with Dr. Stanford.

DR. STANFORD: Two questions--the first

one, back to the reference range for free

testosterone from the 161 pre-menopausal women.

You mentioned hat hey were only women with

regular cycles. Was there any other effort to

exclude those that may have indicators of metabolic

syndrome? My concern is that if you just take 100

women off the street and look at testosterone

levels, some of them may have unhealthy levels,

because some estimates are that PCOS with

hyperandrogenism may be around 10 percent of the

population.

So we may not have a healthy range,

perhaps. I wondered if any other exclusion

criteria were applied to those 161 women. That's

my first question.

DR. MEYER: And I would like--Dr.

Braunstein can address the exclusion criteria, and

then Dr. Ricardo Azziz is with us, and he's an

272

expert on PCOS and normal androgen levels in women.

And I would like him to come up and address what is

normal and not a normal androgen level in women.

DR. BRAUNSTEIN: Actually, the inclusion

criteria was that they had normal menstrual

cycles--ovulatory menstrual cycles. So if a woman

with PCOS was in there, it would be one who was

having normal ovulatory cycles.

I do think, though, since this issue of

PCOS has been raised--and that condition is

different from the model of giving back

testosterone to oophorectomized women, I think it

would be important to have Dr. Azziz address that

issue.

DR. AZZIZ: Just as a disclosure, I own no

stock and I was not a participant in these clinical

trials. I'm simply a consultant as an

androgenexist I direct the Center for Androgen

Related Disorders at Cedars-Sinai Medical Center,

and I'm faculty at UCLA.

There's a number of concerns and questions

that the committee has brought up very well, and I

273

think these need to be addressed. One was the

issue of polycystic ovary syndrome as an example of

an androgenized patient.

I need to make sure that the committee

understands that polycystic ovary syndrome has an

underlying insulin resistant syndrome etiology.

Over 70 percent of the patients with polycystic

ovary syndrome are insulin resistant, and our

research, and that of others, indicates that it's a

cell-signaling defect that actually causes--a

cell-signaling defect in the insulin-signaling

pathway that causes PCOS.

So polycystic ovary syndrome is actually

not a very good example of a hyperandrogenic

effect. And one of the things that I think is

important to not bring up is not to mix in the

insulin-resistant syndrome or PCOS in this

discussion.

In fact, androgens have very little impact

on glucose metabolism in and of themselves, which

is why they're not the etiology for the

insulin-resistance in PCOS.

274

Secondly is the issue of androgen levels

in normal women. It is important for the committee

to understand that androgens, as opposed

to--say--thyroid are not regulated very closely in

a human body. You can quadruple or actually

increase the androgen levels 10-fold in humans--and

that's males and females--and LH levels, which are

the primary responder, do nothing. They change

absolutely nothing--which is why, in humans, the

normal range of androgens in males can go from 150

nannograms per dL to 1,000 nannograms per dL. And

these are all normal males here in the audience,

and the same thing for women.

So one of the reasons that the levels of

"normal" which were presented as a normal example

are so wide. And absolutely correct--Dr.

Emerson--that, in fact there are a number of

patients that are above this--quote "normal limit"

is that, in fact, physiologic effects of androgens

do not correlate directly to the levels; and, in

fact, there's a wide variability in androgen levels

in the normal population.

275

Evolutionarily, there has been no pressure

to select people with high or low androgens,

otherwise women, of course, would be extinct, and

so on and so forth.

[Laughter.]

And it is not the case.

So it's important for the committee to

understand that this is not regulated like thyroid.

Androgens go up, LH goes down. That is not the

case in humans.

The last one is the issue of a "normal"

population. A number of issues have been brought

up related to what is a "normal sexual function,"

and why--and Dr. Lipshultz brought up very

clearly--why isn't it that these people didn't

become "normal."

I should point out that part of what we

do, of course, is look at normal sexual function.

And part of our center looks at androgen

deficiency. 49-year-old women--couples--who are in

their 50s do not, on average, have 12 intercourse

encounters a month. The vast majority of surveys

276

of sexual function in the United States today put

the number of intercourse activities--or acts--in

normal couples in their 50s at between 1-1/2 and 2

encounters per week, which is somewhere between

seven and eight per month.

In the validation study you had to recruit

people who were willing to talk about sex. And

that may have biases the--quote--"normalicy." So

it's not actually proper to actually compare the

small population of people used in the validation

study in this study to the response. We need to

look at the response of our patients here to what

is normally assumed to be normal in the U.S.

population. And in 50-year-olds, that's somewhere

between seven and eight encounters a month.

I don't know if that answers some of the

questions.

DR. STANFORD: Thank you.

My second question was for Dr. Steinbuch

about--if I gathered correctly, you're estimating

that you'd capture about 5,500 women would be

prescribed Intrinsa in the Intrinsa in the

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long-term safety monitoring plan.

What are you projecting that they would be

prescribed Intrinsa for? Would these all be

surgically menopausal, or would you be mixing

surgically menopausal and naturally menopausal

women? And how would you address that issue?

That's one of a number of issues, I think,

about this safety monitoring which are really key

to understand--whether it would be adequate.

DR. STEINBUCH: Yes, the 5,500 estimated

number of Intrinsa users per year is a combination

of both surgical and natural menopause women. And

that's actually one of the advantages of the

observational setting, in that all women who would

be prescribed this medication would be included in

the analysis, and there would be no group that

would be precluded from inclusion in the sort of

full statistical analysis at the end of each time

period.

DR. STANFORD: Okay. So maybe I could ask

just one other question.

Would chart reviews be done on all of

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those women? What's the trigger for a chart

review? You mentioned having the company from

United Healthcare go back--Ingenix, I think, go

back and do the chart reviews.

What would be the trigger for that?

DR. STEINBUCH: As I indicated, there would

be a three-to-one match, and the chart review would

be triggered by any one of the events of interest

that will be ultimately determined by the panel

would be involved, and the independent safety

review board. And then once that final decision

has been made, any of those events would trigger a

medical chart review--throughout the system.

DR. GIUDICE: So just to follow up with

regard to the patient population, it will be

surgical menopause, natural menopause, with and

without a uterus? And therefore the treatment will

be Intrinsa alone? Or also estrogen and also

progestin? I mean, what's the plan?

DR. STEINBUCH: Yes--well, the plan is to,

as I said, bring all women who receive Intrinsa

scrips--whoever they may be. In terms of the

279

matching criteria, there would be some very careful

consideration to do appropriate matching and for

perhaps stratifying by if they're estrogen only, or

estrogen-plus-progestin, that might be a reasonable

thing to match on, for example.

DR. GIUDICE: Dr. Hager, did you have a

question? And then Dr. Macones, and then Dr. Rice,

and then Dr. Lewis.

DR. HAGER: I have three fairly brief

questions.

Regarding the anchoring technique--and I'm

not an epidemiologist, and don't claim to

understand that well--but as I understand it, you

evaluated data and you had a fairly significant

dropout that increased as you progressed through

the study. You used the anchoring technique, and

you used the last available interview among those

who dropped out to go back and recapture that

information. Is that correct?

And in so doing, do you have information

from those individuals before you recaptured that

information? Do you have data up to that drop-out

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point? Because you had such large

drop-outs--without extending that to 24 weeks? If

a patient dropped out--a subject dropped out at 12

weeks, you captured that information and extended

it out to 24 weeks--is that correct?

DR. MEYER: That's correct. We used the

last observation carried forward.

DR. HAGER: Okay--so do you have the data

without that extension?

DR. MEYER: Yes, we do. And when we looked

at both ways, the very conservative LOCF method to

get the proportion of responders. And Dr.

DeRogatis showed you--what?--that was about 51, 31

percent.

When we take out the people who dropped

out and do just the protocol analysis, we get the

same--

DR. HAGER: Okay.

DR. MEYER: --effect.

DR. HAGER: Okay. And can you tell me why

the African-American and Hispanic population was

under represented in this study?

281

DR. MEYER: Yes--it's notoriously difficult

to try and recruit a sufficient number of

minorities into all clinical studies that are truly

representative of the patient population. And we

knew that going into this. And we were aware of

the data in African-American women on hysterectomy.

So we took extra care to try and recruit as many

minorities as possible. For example, we did a

patient recruitment in the media, and we would

target media that targeted various minority

populations. We talked to minority investigators.

We took as many steps as we could think of to

recruit minority populations. And 6 percent is not

representative of the U.S. population--although

better than a lot of clinical trials I've been

involved with.

But, again, we chose sites with access to

large numbers of African-Americans and Hispanic

people. We had all our instruments translated into

U.S. Spanish. We ran ads in the media--again--that

targeted minorities.

And so one of the things that we're doing

282

at P&G is we have an ongoing effort to continue to

try and increase our ability to recruit minorities

into our clinical studies.

DR. HAGER: So are you concerned about the

long-term follow-up in those sub-populations?

DR. MEYER: Well, again, with the large

observational study, if we move forward with that,

these minorities, if given a prescription, will be

able to be followed, and in larger numbers.

And the other thing that we have done is

also we have discussed our plans with a variety of,

for example, African-American clinical

researchers--OB-GYNs--to try and understand our

data in the context of these patient populations.

DR. GIUDICE: Dr. Macones?

DR. MACONES: A question for Dr. Steinbuch,

please.

I actually have two questions. First, to

follow up on Dr. Hager's point--the UHC data that

you're going to be using, can you tell us about the

ethnic background of patients that are included in

that data set? Is it a very generalizable group?

283

DR. STEINBUCH: The Ingenix database?

DR. MACONES: Yes, I'm sorry--from your

agency.

DR. STEINBUCH: Yes, it is, actually.

We've looked at some comparisons to the U.S.

Census. And demographically, they're reasonably

comparable.

DR. MACONES: My second question was about

your sample size estimate for your post-marketing

study, which you had on your slide number 120.

And my concern is that just at first

blush, I thought that a study of 5,500 patients was

going to be pretty small to look at some of the

events that you're going to be interested in.

And it made me wonder about some of your

assumptions. And the one that struck me the most

was your event-rate per year of .15 percent. And I

believe you said that that was based on WHI data

for cardiovascular events in women who were 50 to

59. Is that right?

DR. STEINBUCH: That's correct.

DR. MACONES: That's a curious choice,

284

because I think in your clinical trials about half

of the patients were less than 50.

So I wonder why you chose an estimate on

the older population, rather than being more

conservative, choosing perhaps a lower event rate,

having a bigger study, with more power and more

precision in the older patients.

I mean, I look at this now and I could

predict it's going to be a negative, under-powered

study. And that's a concern.

DR. STEINBUCH: Actually, the event rate

that we used was the lowest that was possible

within the WHI. As the FDA has indicated, they've

been using the WHI as sort of an anchor for this.

And we thought that was the best that we could do.

If you could please put up slide 691?

[Slide.]

This slide shows, broken out in the WHI,

broken out by decades here, and when we look

at--and this is for the estrogen-only arm--you

could see that this is about where the line is for

hazard ratio of 1. In the 50 to 59, most

285

of--either at or below 1 for this younger group.

Now, with regard to what the FDA has shown

and shared is I believe they've been using the E+P

for the full 50 to 79 year age group. And so,

since our mean age was about 50, this was the

closest that we could get using WHI, that would

actually be the closest estimate.

Does that make sense?

DR. MACONES: It does, but I disagree with

it. Again

DR. STEINBUCH: Okay.

DR. MACONES: I mean, the issue is that

you're going to have no power to look at events in

younger women, and that's likely to be half of the

population.

I mean, again, based on the enrollment in

your clinical trials, which the mean age was 50,

which roughly means that about half of the people

were less than that. And you're just not going to

have a lot of power to look at those patients. And

if you had a bigger study--again, power to look at

events in younger patients--you're going to have

286

lots of power to look at event rates in the older

population.

DR. LOCKWOOD: But to be fair--I mean, we

don't want to get into a debate about WHI--but if

you look at the data--and the argument's been made

that, in fact, it may be protective in that younger

age group. Look at the odds ratios--or the hazard

ratios that are presented there. They're not quite

significant, but there's certainly a strong, strong

tend toward a protective effect between 50 and 59.

So I think, to be honest, that the group

that you're thinking may have to be much larger to

detect a potential adverse event in fact might be

the opposite. It might be protective and it might

be additively protective.

DR. MACONES: I think the point is "might

be." And we don't know the "might be."

And I think for charged issues like this,

I think we're better off being conservative and

designing a bigger study rather than taking a

chance and designing a smaller study that might

miss an important effect.

287

But I appreciate the point that you make.

DR. GIUDICE: Dr. Dorgan.

DR. DORGAN: First of all, on this

question--could you tell us what the power to

detect increased breast cancer among these women

would be?

DR. STEINBUCH: Yes.

Could you please put up slide 507?

[Slide.]

And as was mentioned earlier with regard

to latency, I would direct your attention--the

event rate here was again using WHI, 50 to 59 year

age; .3 percent per year. All the other

assumptions were the same as before, with regard to

disenrollment, etcetera--discontinuation. And

getting down to the four to five year, which I

think is the most reasonable place to be looking

here, we have an 84 percent power at four years to

detect a relative risk of 1.4 with regard to breast

cancer.

DR. DORGAN: Okay. I have another question

that's based on the information in the briefing

288

book. In the briefing book it states that

"--epidemiologic studies examining the relationship

between endogenous testosterone and breast cancer

risk have yielded equivocal results." And the

reference for this is the Endogenous Hormones and

Breast Cancer Collaborative Group paper in 2002.

Now, as a co-author on that I was kind of

surprised by this interpretation of the findings.

I brought a copy of the manuscript with

me. Testosterone was very strongly, actually,

related to breast cancer risk in these women.

Women in the highest quintile of testosterone

levels--and this is within the normal range for

post-menopausal women. So it's much lower than

what we're talking about here.

Women in the highest quintile were at

two-fold--let's see exactly--2.2-fold increased

risk of developing breast cancer. This was highly

significant. And the trend was also highly

significant. With increasing levels of

testosterone, risk increased significantly, going

from the first quintile is the reference of 1, to

289

the second quintile of 1.3, to the third quintile

of 1.6--up to as high as 2.2 in the fifth quintile.

Again, I want to say that these levels are

endogenous levels in post-menopausal women. They

are much lower than the levels that we're looking

at here.

When we're talking about the concern for

the women whose levels are above the 90

percentile--based on that graph you keep looking

at, bioavailable testosterone. When we're focusing

only on the women whose levels are above the 90

percentile for pre-menopausal women, I think we're

missing the point.

The women who are even at the median, they

had levels, based on some of the data that you

provide us, that were three, four and sometimes

five-fold higher than your control placebo group.

This could translate into an increased risk of

breast cancer in this group as a whole, of maybe 70

percent going up to--it possibly could even go up

to a doubling of risk.

Could you comment on that?

290

DR. MEYER: Dr. Robert Reid, Chairman of

the OB/GYN department at Kingston will comment on

this.

DR. LOCKWOOD: On that, could I ask you a

question?

DR. DORGAN: Sure.

DR. LOCKWOOD: Did your study adjust for

potential confounding from BMI?

DR. DORGAN: We didn't adjust for BMI, but

we did actually adjust for estradiol, because of

concerns that the testosterone--this is endogenous

levels, we were concerned that there might be--the

testosterone levels might be just elevated

secondary to estradiol, and all the effect might

really be due to estradiol.

But when we did that--

[Pause.]

--sorry, I have to flip through

here--okay--and this is looking at a doubling, as

opposed to looking at quintiles.

So, if testosterone was looked at

unadjusted for estradiol, a doubling of

291

testosterone was related to a relative risk of 1.42

for breast cancer. So it's about a 40 percent

increased risk of developing breast cancer. It was

statistically significant.

Estradiol, on its own--the doubling of

estradiol--was related to--had a relative risk of

1.31--or a 31 percent increased risk.

When you include both testosterone and

estradiol together, the increased risk associated

with the doubling of testosterone was decreased a

little to 32 percent; whereas the increased risk

associated with a doubling of estradiol was

decreased to 18 percent. So it's not being

explained solely through estradiol.

DR. LOCKWOOD: I guess the big issue,

though, would be if these patients are obese

they're likely to have both elevated estradiol and

testosterone levels, and to be at higher risk,

independent of either, for breast cancer because of

the obesity. It increases aromatase activity,

potentially, in the breasts themselves.

So, you know, I hear you, but the

292

potential for confounding is so great that it does

call into question those--

DR. DORGAN: I disagree. I think that--I

don't know where you're coming--most of the

association of obesity, we have shown in subsequent

work, we can explain a lot of the association of

obesity with breast cancer risk by effects on serum

estradiol levels. And since we have adjusted for

estradiol in these analyses, I think that it's

showing that what appears to be a significant

independent effect of serum testosterone with

breast cancer in post-menopausal women.

Whether this effect is due to

aromatization of the testosterone in the breast, we

don't know. But I'm saying that these data surely

don't suggest that the results are

equivocally--epidemiologic studies that look at

associations show a very significant and strong

association of serum testosterone levels with

breast cancer risk in post-menopausal women.

We don't know if they're causal. You

would need a clinical trial to establish that.

293

DR. GIUDICE: Yes--please let's have a

response.

DR. REID: May I enter the foray?

I don't think we have a clear answer to

the question you've raised. I mean, the criticism

of studies that have looked at a single isolated

testosterone value in people who subsequently went

on to develop breast cancer have been challenged

based on problems with the assay sensitivity in the

range for women, because it's at the low end of the

assay. The fact that it's a single value, and

there may be variations due to a variety of

different life events and stresses.

The issue about aromatase activity in the

breast--and biopsy studies around breast cancer

have shown that there's often very high aromatase

activity in the quadrant where the cancer is

compared to other quadrants of the breast that

don't have a cancer. So local effects may be much

more profound than what you see in the circulation.

So it's a finding that merits

consideration and concern, but, you know, the other

294

types of data that we see, for example, in Rhesus

monkeys, showing an inhibition of proliferation, is

just the opposite. And it's very reassuring in

that context.

And I can't comment more than that on that

specific issue. I could make some comments about

relative risk and some of the other things that

affect breast cancer risk if it's of interest,

because I've heard a few things presented

about--the WHI is constantly being cited here, and

we heard a number of explanations for why the

observational data did not match the randomized

clinical trial data for cardiovascular disease.

But the one explanation we didn't hear put

forward--we heard about volunteer bias, and health

user bias and so on--there's been a lot of

discussion in the literature about the fact that

women who were involved in the WHI, many of them

were several years to many years post-menopausal.

And probably the biggest difference between

observational and randomized trial in that

circumstance that would explain, to a large degree,

295

the cardiovascular outcomes is, in fact, the

difference in age of the populations. There are

observational studies from Nurses Health Study was

in women who were 50 years of age or younger. And

WHI, as you know, two-thirds of them were over 60

in the combined arm. In the estrogen-only arm, 50

percent of them were 70 or older when the study was

closed.

So that's a very old population compared

to the younger women. I think it's a point that

maybe is lost in some of the discussion.

Would you tolerate a couple of slides? To

clarify it? Or not--it's up to you.

DR. GIUDICE: Io think we need--we have

many other questions, and we need to move on.

DR. REID: Okay.

DR. GIUDICE: So--in the queue--thank

you--is Dr. Rice, then Dr. Lewis, and then Dr.

Tulman--and others.

DR. MONTGOMERY-RICE: I have a couple of

questions.

One of the things I want to make sure I

296

understand, that in the questionnaire where you ask

about the satisfying sexual activity, that

"satisfying" was being used as an adjective,

meaning that were the women asked, well, did they

have a sexual activity? Did they have sexual

activity and maybe it wasn't satisfactory? Or did

they only have the option to check that they had a

satisfying sexual--

DR. MEYER: No, they had the option for

both.

DR. MONTGOMERY-RICE: So they did have the

option for both.

DR. MEYER: Activity and satisfying

activity--

DR. MONTGOMERY-RICE: Okay, so--

DR. MEYER: And we also, in the instrument

validation, took great pains to make sure that

these women understood what a "satisfying sexual

event" was. It's not handholding. And we

validated that in the--

DR. MONTGOMERY-RICE: Okay. So, but when

women said they had a satisfying sexual experience,

297

you took the mean--used means for your baseline and

for your increases. So this 1.9, or whatever we're

seeing, is a mean over all of--so how would an

individual have rated that if that one increase in

the number of sexual events was satisfying to them?

Was that enough for them to rate that they had

improvement?

And I ask that question because when I

look at Dr. De--ahh-

DR. MEYER: Dr. DeRogatis?

DR. MONTGOMERY-RICE: Right--in his slide

number 43, when you asked this question of interest

in continuing the treatment, if this was a

meaningful experience for them, and that a large

percentage of them got 1 point of that increase in

activity made a difference, how am I to interpret

when I see 70 percent "definitely not," or 60

percent "definitely." Tell me how I am to

interpret that, if these people really rated--they

had the option to rate whether they had sexual

activity, or whether it was satisfying? Why

weren't more people interested in continuing?

298

DR. MEYER: Oh, actually, what this shows

on this graph--in the white are the women who

reported no meaningful benefit. Now this--again,

the data were blinded to everyone when this

question was asked of them. So these are the women

who were the non-responders. So most of them--if

you look at the first "definitely not" or "probably

would not," 95 percent of these women would not use

this patch.

If you look at the women who reported

having a meaningful benefit, using the cut-off that

we used, a similar number--about 95 percent--90 to

95 percent of these women have said that they

probably or definitely would be interested in

continuing treatment.

DR. MONTGOMERY-RICE: And then the people

who are in the light blue, who would definitely

not, those were mixed--some of those on placebo,

and some of those were--or all of these are

treatment people?

DR. MEYER: All of these are women who said

they had a meaningful benefit. So some of them--

299

DR. MONTGOMERY-RICE: No, no.

DR. MEYER: --some are placebo and some

are treatment.

DR. MONTGOMERY-RICE: Okay. So what

percentage of the people who were "definitely not"

and "probably not" were the people who received the

patch?

DR. MEYER: The definitely and probably

would--this is about 51 percent of the women who

were on the patch. So it's about 49 percent are

going to be in the white bars that had no

meaningful benefit.

DR. MONTGOMERY-RICE: So 49 percent of the

people who were in this study, who were on the--49

percent of the people using the patch--

DR. MEYER: In the clinical relevance

study.

DR. MONTGOMERY-RICE: In the clinical

relevance--did not say they wanted to--they

probably would not continue treatment.

DR. MEYER: Yes. Well--no, this is placebo

also.

300

DR. MONTGOMERY-RICE: Okay. Well I'm going

to ask the question again. I want to make sure

we're clear about this.

What percentage of the people in the

"definitely not" and "probably not" were people who

used the patch?

DR. MEYER: What percent of these--

DR. MONTGOMERY-RICE: Yes.

DR. MEYER: It's about 49 percent.

[Comments off mike.]

DR. RODENBERG: 49 percent of the people on

active therapy--I have numbers to address your

question, maybe not completely, the way you're

asking it. But let me see if this addresses your

question.

49 percent of the women on active therapy

stated that they would probably not or definitely

not use the patch. 64 percent of the people on

placebo therapy stated that they would definitely

not, or probably not use the patch.

Does that answer your question?

DR. MONTGOMERY-RICE: Yes. Thank you.

301

DR. GIUDICE: Dr. Lewis?

DR. LEWIS: I have a couple of questions.

One has to do with the instrument that you

designed. And I think that certainly it helped to

make the study population very well-defined--which

I think it was well-defined in this case.

But I would like you to address a concern

that it will lead to less stringent selection of

candidates for this treatment when it reaches the

general population; that is, if it's already being

touted as a female Viagra in the general press, how

many physicians, and how will physicians be

educated to select a proper population with

hypoactive sexual desire disorder? That's one

question.

And the second question really is for our

committee consultant. Could you comment on a

correlation between testosterone levels and

hypoactive sexual--or sexual dysfunction in a

menopausal population? I'm really only aware of

the Australian study, which showed no correlation

between testosterone levels and sexual dysfunction.

302

And that was like a population-based study in

Australian women--maybe a couple thousand women,

something like that.

DR. MEYER: Okay, let me first address the

educational plans that we have to ensure that

patients and physicians understand how to maximize

the safe use of the patch.

If I could have slide 707 projected,

please?

[Slide.]

We have several plans. We have both a

package insert that we have tested with physicians

for clarity of understanding; that they understand

what this patch is indicated for, and how to use

it. And we have a patient information leaflet.

Again, it's tested which surgically and naturally

menopausal women to ensure that they understand how

to use the patch, and who it's intended for.

We're also developing tools to help both

clinicians and patients understand and recognize

HSDD, and for clinicians to diagnose HSDD and

identify appropriate patients. And these are

303

based, in part, on the five questions that we used

in our clinical study to enroll the

patients--again, to ensure they had desire, they

had the surgery, they lost desire, and they're

distressed about it.

So we have--we're targeting both the

patients and the physicians for this.

We also have a web-based educational

program in development for physicians on the

appropriate use of the product; the prevalence of

HSDD; and the clinical implications. And, for

example, one way that we are ensuring that

physicians get training in HSDD and the appropriate

use of the patch is if they would request a sample

to be sent to them they will have to fill out a

questionnaire on the disease--successfully fill out

a questionnaire, I should add--so that we can be

sure that they understand that these are for the

right people.

The other aspect of this education program

is to facilitate the dialogue between patients and

physicians, because it's not always occurring now.

304

Physicians don't have treatment options all the

time. We've done a lot of research with

physicians, and a lot of them don't discuss it with

their patients because they can't do anything

anyway. So what's the point? A lot of patients

don't really know whether or not what they're

feeling is normal, hence the Hyster-Sisters

website, which I think has helped an awful lot of

people.

So this is to facilitate dialogue between

patients and physicians so that everybody knows who

should have the patch, and who should not.

And the other thing that we're doing is a

CME program supported by unrestricted grants to

educate physicians on female sexual function.

DR. LEWIS: But your post-marketing

follow-up is with a mixed population. It's not

just with the surgical menopause patients.

DR. MEYER: Right. And we also will have

educational tools for naturally menopausal women,

contingent upon that.

DR. LEWIS: Okay. Thank you.

305

DR. GIUDICE: In the queue--

DR. MEYER: Oh, there was a second

question--

DR. GIUDICE: Oh, I'm sorry. That's

correct. Yes. Dr. Heiman.

DR. HEIMAN: Yes, I can make just a couple

of comments on the--you were talking about

endogenous levels in post-menopausal women, not

necessarily surgical menopausal?

So, these correlations typically--they're

often not significant. And there's actually going

to be a couple new studies coming out shortly that

I actually can't comment on at the moment.

But they are not significant. Typically,

DHEA, believe it or not, tends to be more

correlated with desire.

But there are subgroups of women for whom

it's--you know, that's really the problem with this

area, from our side of the fence. Number one, the

definition of sub-groups of low sexual desire, of

which there are sub-groups. There are, but they

haven't been clearly identified. And, number

306

two, the subgroups of women for whom low

testosterone actually is correlate: who are they?

How are they different?

So I'm not sure the question has been

finally answered, even with the new studies that

aren't quite out yet coming out.

DR. GIUDICE: Thank you.

DR. MEYER: Oh--Dr. Shifren would like to

comment on that.

DR. SHIFREN: One thing--if I could have

slide 500 projected, please. This will show you

some of what we're up against.

[Slide.]

Here are the levels of free testosterone

in women with low libido and women with normal

libido. And these are from our surgical menopause

population validation studies. And you can see the

extensive overlap in free testosterone between

these groups.

[Comments off mike]

The libido in oophorectomized women?

Well, as they're trying to pull that up I'll just

307

describe the study. But basically, as a

reproductive endocrinologist, I was very interested

in trying to find some data that showed us that

physiologically, testosterone is important for

libido. We clearly have treatment studies--many

before the Phase III studies you've seen today.

But what do we have as background data/

And, really, the best studies to look at are those

in which women have had their ovaries removed.

And, of course, you need to use hysterectomy,

because the majority f women who have oophorectomy

have concurrent hysterectomy.

So this is a very nice slide out of

Sweden, where they basically send questionnaires to

a group of women who had undergone hysterectomy at

one institution. They then asked the women, "Since

your hysterectomy, tell us if your libido is the

same or better or worse?"

And what you can see is that regardless of

whether women received estrogen therapy or not, if

you compare women who underwent bilateral

oophorectomy at the time of hysterectomy, to women

308

who did not undergo oophorectomy at the time of

hysterectomy, you can see that women who underwent

oophorectomy concurrently were significantly less

likely to say that libido was same or better, or

were significantly more likely to say that libido

was worse.

So I think this is one of the true more

natural experiments that does show that for

menopausal women--for surgically menopausal women,

the testosterone produced by their ovaries really

does affect libido.

DR. GIUDICE: Thank you. Dr. Tulman.

DR. TULMAN: Yes, thank you.

Do you have--and I don't know whether this

is for Dr. Shifren or for Dr. Braunstein--you've

shown us the testosterone levels for pre-menopausal

women. You've shown us testosterone levels through

the placebo group and the baseline treatment group

for women with HSDD who are, by definition,

post-menopausal.

Are there any norms you can show us for

women who are naturally menopausal, and their

309

testosterone levels, and how they might differ from

women with HSDD?

[Pause.]

And I have a part two of the question.

DR. BRAUNSTEIN: [Off mike.] I don't have a

slide for it, but--

DR. TULMAN: Well, can you tell me?

DR. BRAUNSTEIN: [Off mike.] Yes--

DR. TULMAN: I can't hear. I don't know if

anyone can hear you.

DR. BRAUNSTEIN: Yes. Levels were very

similar in the natural menopause versus surgical

menopause. They were both at sort of the lower

level of detection even with an assay that is

highly well validated by FDA standards against GC

tienna mass spec.

DR. TULMAN: And these are women both with

HSDD and women who report their sex lives as being

satisfactory?

DR. BRAUNSTEIN: No, specifically these are

the women with HSDD.

DR. TULMAN: How does that compare with

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women whose--

DR. BRAUNSTEIN: There's a lot of overlap.

So if you look at the women in the validation study

with normal sexual function, they tended to have,

on the average, about 1 picagram per ml of free

testosterone levels higher than similar women who

had been oophorectomized.

DR. TULMAN: Okay. So that--and I guess my

part two of the question goes back to some basic

theory which one of the people asking the question

at the public forum part of the meting asked: how

does the theory--or where is the theory, or what is

the mechanism for testosterone to produce the

effect of improving a woman's sex life?

DR. BRAUNSTEIN: Well, there is certainly

pre-clinical animal data that shows that if you

remove ovaries and give testosterone there's

increased sexual activity. In regards to humans,

some of the best studies on the effect are te ones

that were carried out by Dr. Cherlyn Gelfand--and

Dr. Gelfand's here--looking at women before and

after oophorectomy, and women who either received

311

placebo, estrogen, testosterone alone or estrogen

plus testosterone, and showing that those on

placebo dropped down; those who were maintained on

testosterone stayed up as far as libido.

Now, as far as the theory of where it

works, there's a couple places that testosterone

works. One, I think--if I'm not mistaken, Dr.

Heiman's group has shown that there's increased

vaginal blood flow with testosterone

administration.

But probably most importantly, there are

receptors--there are androgen and estrogen

receptors in the brain. And testosterone probably

works primarily by increasing desire. It's not a

female Viagra. Viagra works mechanically on the

erectile function in the male. This is more of

something that works centrally on desire. And I

think the desire goes up, and then sexual activity

goes up.

DR. TULMAN: And what part of the brain is

that in?

[Laughter.]

312

DR. MEYER: The highest concentration of

steroid receptors in the brain is in the area known

as HTSM--hypothalamus thalamus septum and midbrain

area--and it's long been shown that, especially in

the hypothalamic area, this is where sexuality

lies. You can lesion that area and get

Kleuver-Bussey-like syndrome and things like that.

And that's where these receptors primarily are.

DR. GIUDICE: Dr. Patrick.

DR. PATRICK: Yes, I have some questions

for Dr. DeRogatis.

The first one has to do with--I'd like to

sort of compare your slide 42 on the clinical

relevance results--the summary of the MCID with

Dr. Davis' slide 14, which is the summary of the

results, and just make sure I understand, since

it's very hard to relate the responder analysis to

the change scores.

First, in the anchoring study--if I

understood this correctly--that a single question

was asked on whether they found the change to

be--they found a change, and they found the change

313

to be meaningful.

DR. DeROGATIS: A meaningful benefit.

DR. PATRICK: And cognitively, that's a

pretty difficult task. Did you do any debriefing?

DR. DeROGATIS: I'm sorry, I didn't

understand your question.

DR. PATRICK: Did you do any debriefing of

how women thought through that question? Did the

perceive a just-noticeable difference and then call

it "important," or did they--how did they know a

change was "meaningful?"

DR. DeROGATIS: Ahh--I think it was--the

question had to do with clinical benefit: "Did you

experience a meaningful benefit?"

DR. PATRICK: Okay.

DR. DeROGATIS: I don't know that they

were--and if I'm wrong there's someone who can tell

me this--I don't know that they were debriefed

about the details of that.

DR. PATRICK: Okay.

DR. DeROGATIS: However--

DR. PATRICK: So it all sort of hinges on

314

that one question.

DR. DeROGATIS: Well--yes, that's right.

But--and that--you know, there are many approaches

to clinical relevance, and the anchoring, and all

of them--there's not a definitive approach. All of

them have strengths and weaknesses.

DR. PATRICK: Right.

DR. DeROGATIS: And perhaps, if there is a

weakness in the anchoring approach, it's the

reliability of that single question, and that

playing an important part.

However, I think it's important to

recognize for clinical relevance, I think there's a

little confusion about it, clinical relevance is

predominantly established--it's an individual

patient characteristic, and it's predominantly

established by proportions of responders--as

opposed to comparisons of means, which is the basis

for statistical significance.

And so once the MCID is established in an

optimal fashion, then the magnitude of difference

can appear small to anyone, but it's actually the

315

proportion of responders. And the significant

difference between those proportions that is the

basis for clinical relevance statement.

DR. PATRICK: Right. But the clinical

trial results, with the statistical significance

are still changes in mean group scores. And we have

to be able to interpret those, as well as a

responder analysis. And if I understand the

results, we have a change of just about one event

in four weeks from a baseline of three events to

four events.

DR. DeROGATIS: No, it's actually two

events; that is, the treatment group changed two

events, making it really a 66 percent change--

DR. PATRICK: Yes, but I'm interested in--

DR. DeROGATIS: --and the placebo group--

DR. PATRICK: --taking away the placebo

effect here.

DR. DeROGATIS: Yes, well then it's one--

DR. PATRICK: That's right.

DR. DeROGATIS: --it's one event, but still

a 33 percent change.

316

DR. PATRICK: Okay.

DR. DeROGATIS: And I--no, go ahead.

DR. PATRICK: And then with the distress,

that's 6.7 units, and with desire, that's 5.1

units. And that's what we're left with: the

difference between treatment and placebo.

And I think that the instrumentation in

this study was really well known. The validity

studies are really well done.

And our issue is interpreting those mean

group scores. And although the responder analysis

gives us a little bit of a hint there, I wonder

what you would say to: if I took that difference in

your meaningful benefit versus no meaningful

benefit and applied it to the mean differences,

which is taking the difference between two groups

and applying it to a change score--and I wasn't

quite sure about the validity of doing that,

although that's what one of the slides from Dr.

Davis does.

If that's the case--I mean, how--is that

fair to apply the MCID?

317

DR. DeROGATIS: On hundred-point

scales--and now this is a little Kentucky windage,

because I don't have actual data, although there

are some very recent reports--Guy Att and his

group, and Sloan and his colleagues have both done

reports in which they have used as example

hundred-point scales. And this technique that

they're talking about is referred to as "effect

size empirical rule checking." And I won't bore

you all with the details of that because everyone

will fall asleep.

But, in fact, they wind up with magnitudes

of change that are only slightly greater--I think

they're in the range of seven or something like

that--as opposed to the five and six here.

So it's on the edge. But, again, I'm

flying by the seat of my pants.

DR. PATRICK: Well, the Dyatt approach is

actually using the anchoring approach, but it's

using it with a 15-point scale and not a "yes/no."

So it's actually from a minimally big change to a

great deal of change.

318

DR. DeROGATIS: But in his review he

contrasts--

DR. PATRICK: Right--back to the

distributional approach. But we're not talking

about distributional approach, because that was not

presented in our briefing package.

We don't know the SEM, we don't know the

center deviation difference. So I don't want to

get into that.

But my question is: is it fair--because

this is the important thing for me--to say that the

difference between the TTS and the placebo was one

event per four weeks; your minimally clinical

important difference was one--okay. So you win on

that.

DR. DeROGATIS: I'm with you so far.

DR. PATRICK: But for distress, it was

greater than 8, and we got a difference of 7--so

that we're just on the margin there.

Is that fair to do?

DR. DeROGATIS: No, I don't think it is.

DR. PATRICK: That what I wanted to know.

319

DR. DeROGATIS: And let me tell you why.

DR. PATRICK: Because that's what's going

on in--

DR. DeROGATIS: Because we're talking about

two very different distributions here. The

distribution--the MCID is an optimal discriminator

between distributions of change from baseline,

whereas the mean scores you're referring to are a

very different distribution. I don't know that

there's necessarily a relationship between those

distributions.

And I think the important thing is that

clinical relevance here is established

through--clinical relevance obvious as a

hypothetical construct is established through some

operational paradigms that we say we're going to do

this, we're going to do that. They're logical and

we agree consistently a science.

And so this particular operational

paradigm, using the anchoring technique which is

very traditional, well established, tied back to

patient perceptions, establishes that these are, in

320

fact, these are differential proportions of

responders which significantly favor active

treatment. Now, that's a clinical relevance

statement. It's an accepted one. It's by the

book, so to speak.

I can't tell you what the relationship is

between this traditional operational definition of

clinical relevance and Dr. Davis'.

DR. PATRICK: Well, what's a little bit

confusing is this "greater than or equal to 8.9,"

because that intimates that that's change. And

it's actually a different score.

DR. DeROGATIS: That's right. It's

change--

DR. PATRICK: [Simultaneous comment

inaudible.]

DR. DeROGATIS: That's right.

DR. PATRICK: And I'd be very interested in

the statistical comment on this.

I still think, in integrating, we are left

with 50 versus 34, 44 versus 30, 51 versus 39. And

then we are left with 1, 6 and 5. And somehow,

321

putting those two things together is a big

challenge of the committee.

DR. MEYER: I have just--I have a

slide--could I have slide 705, please?

[Slide.]

DR. GIUDICE: I don't want to curb the

discussion, but I just want the committee to be

aware that we have four other people who have

questions. We have questions also for the FDA.

And then we have the list of questions that we need

to get done, and we have three committee members,

apparently, who need to leave a little early.

So--could the sponsor please be very

succinct.

DR. MEYER: Very.

Let's look at the data in a different way.

Your "satisfying sexual activity," "desire" and

"distress"--the key endpoints of HSDD. Here's our

MCID of greater than 1--8.9 for desire, and less

than 20 for distress.

Now, what did we see in the TTS patients

from baseline? Because when you're out in the real

322

world there's no placebo group. And Dr. Shifren

told us the placebo is an intervention. Women who

have HSDD who are not getting treatment are not

spontaneously necessarily going to increase their

satisfying sexual activity by one event in four

weeks.

So we have a change of almost 2 in

satisfying sexual activity in the TTS-treated

patients; 10.8--almost 11--in desire; minus 23 in

distress.

Now let's look at the women who said they

were responders. These are the ones who said they

will use the patch: 4.4 per four weeks; 21 increase

in desire; and almost 37 unit decrease in distress.

And, just for perspective, the MCID on the Western

Ontario and McMaster-Womack score for measuring

pain in arthritis is 3 or 100 mm scale.

DR. PATRICK: Thank you. I simply don't

think you can discount placebo in this. But we'll

go on.

DR. GIUDICE: I think that's an important

point that the committee, I hope, has heard.

323

In the queue--and if you've already had

your question answered, then please let me know.

Don't feel obligated to ask it.

Going through the queue--Dr. Heiman did

you have something else?

DR. HEIMAN: Yes. I'll try to be brief.

It's in regards to efficacy. What I was

curious about is if there's information on how

quickly the treatment group got up to a clinically

significant level of change. For example, did it

happen at one month, or two months or three months?

So that's one question.

And whether there was any diminution--even

in six months. I mean, I wish we had more one-year

data. But since there's older clinical information

that, for example, estratase, there's an initial

effect--could be some placebo in there, of

course--and then it quickly diminishes. And so I'm

interested in that--that question.

And related to that: any thoughts about

why--do you still feel as strongly this needs to be

used in chronic dosing, as opposed to intermittent

324

dosing.

So those things are related a little bit.

DR. MEYER: Yes--and let me take your first

question first.

If I could have slide 167, please?

[Slide.]

And this sows the time course for

satisfying activity, sexual desire, and distress.

The blue represents placebo, the yellow represents

TTS.

And we saw a difference between placebo

and TTS on sexual desire and distress that was

statistically significantly different from placebo

as early as four weeks; also in satisfying

activity.

The maximum was reached at three

months--for all three endpoints. Placebo maximized

and it pretty much stayed the same by about four

weeks. TTS continues to go up. And on the

distress it continues to go down.

DR. HEIMAN: Do you see the change in

satisfying activity as being a significant decrease

325

from the four-week mark?

DR. MEYER: No. It's not.

DR. HEIMAN: Okay. Thanks.

And chronicity--any thoughts?

DR. MEYER: What we found in the

persistence of benefit study was that if you remove

the patch the effect goes away, basically.

DR. HEIMAN: Okay.

DR. GIUDICE: Dr. Emerson?

DR. EMERSON: I have two questions. The

first was just hit upon a couple minutes ago--this

idea of ignoring the placebo group, and assuming

that the activity in the placebo group is to be an

indication of placebo effect; that there's this

concept that, no, that was just what was going to

happen over time, and it had nothing to do with a

placebo effect--as was brought out.

I notice that not only in the slide 108,

where Dr. Shifren presented the effect, she gave

the whole effect from baseline. And I also noticed

that in the package insert the only information

that's given is baseline to follow-up in the

326

testosterone group.

I'd like some comment about why you would

disregard that placebo effect so strongly, when you

don't know whether this is just a general time

course. In fact, I would actually argue that that

last slide, where you're starting to see a

diminution of effect in both groups is actually

just possibly related to the fact that you have

incident cases of patients going to the doctor for

HSDD, and they are actively trying, and during that

period they're trying to increase the frequency of

intercourse, and then after a while they give up.

DR. MEYER: I'll have Dr. Shifren comment

on the clinical consequences of that. Course

comparison to placebo is always appropriate in a

randomized clinical trial. But then in the real

world--

DR. EMERSON: And in the real world, the

question is: would this have happened anyway?

DR. SHIFREN: I think none of us are saying

disregard the placebo. That would be absurd.

What we found exciting about exciting

327

about these results is that every single aspect of

HSDD that we measured improved in a statistically

significant way compared to placebo. That, I

think, is a very appropriate comparison to placebo.

But when you're actually looking at level

of change--and I think I'm going to use hot flashes

as an example--we expect a 30 percent decrease in

hot flashes if a woman takes a placebo tablet. But

let's say with estrogen, we expect 60 to 70

percent.

When a woman walks into my office and

says, "I'm feeling better on estrogen. My hot

flashes have decreased," she doesn't say, "Well, it

was 70 percent, but I'm going to take away the 30

percent that would have been placebo, so I've only

have a 40 percent reduction in hot flashes."

When you're actually looking at treatment

effect for the patient, it is the increase from

their baseline event rate.

So I think it's very important to use

placebo when we're looking at the statistical

significance--

328

DR. EMERSON: Do you not look at trade-offs

between the benefit, relative to potential harm,

for the toxicity, that the placebo--

DR. SHIFREN: Benefits and risks are a

crucial discussion that we have with every patient.

Actually, I did want to bring out--I mean,

I think actually the exciting thing about WHI is

that it has informed all physicians and patients

that we will never take hormone therapies lightly.

I think that will actually benefit this product

because I think the likelihood of off-label use has

been significantly decreased, given both

physicians' and patients' concerns about the

long-term risks of hormone therapy.

The comments from the audience during the

open session were excellent, and I really

appreciate them. But I think we were sometimes

undermining patients' abilities to weigh and

balance risks and benefits, and to physicians'

abilities to carefully read package inserts and

patient information and advise their patients.

I see women in my practice every day with

329

debilitating hot flashes who are making very

complex decisions.

DR. EMERSON: But, to that issue, don't you

think it would be useful in the package insert to

point out what the placebo effect was?

DR. SHIFREN: Certainly placebo effect

should be in package inserts.

DR. EMERSON: Okay. I do have--

DR. SHIFREN: I completely agree.

DR. EMERSON: Okay. And I'm sorry--I'm

going to be cut off in just a second, so--

Dr. DeRogatis, I have a question about

this anchoring technique--two things. One is I'm a

little bit bothered by this idea if we just go with

where the 45 degree line intersects that ROC curve,

without really thinking through--it's possible that

whatever you're looking at is not even predictive.

And then the other question is: the way

that this question was worded to the patients, it

was post-randomization, it was just an overall

question of "How was the treatment going," which

meant the patient could have been considering in

330

these risk-to-benefit ratios.

How did this analysis proceed, in terms of

the clinical benefit, if you looked at it

treatment-group versus placebo?

DR. DeROGATIS: I'm not sure I understand

the question, to be honest.

You're having problems with the notion of

the single anchor?

DR. EMERSON: That's correct..

DR. DeROGATIS: Okay. Well--

DR. EMERSON: And basing it on an ROC

curve, no matter what. Because an ROC curve could

be just no better than flipping a coin.

DR. DeROGATIS: Ahh--

DR. EMERSON: You had an area under the

curve of .77--which you said you felt was near

excellent.

DR. DeROGATIS: Well, yes, actually it's

much better. If we had put a diagonal line going

the other way, which the line of no information on

the ROC curve, the coefficient would have been .5.

That would have been no better than flipping a

331

coin.

So the fact that we had .77--

DR. EMERSON: But this idea of choosing the

anchor that would have intersected with that 45

degree line of no-benefit, as well. And so I'm

just questioning whether there is really any

scientific rationale there. And I'm also

questioning whether this analysis shouldn't have

been done separately for the placebo group and the

treatment group--

DR. DeROGATIS: Oh, I see--I'm sorry--

DR. EMERSON: --given the generality of

your questioning of patients.

DR. DeROGATIS: Yes, I see. Yes.

This is a very traditional way of doing

anchoring methodology, because what you're

attempting to do--and so placebo and active

treatment are kept together. They're not separated

out.

And the reason for this is what you're

trying to do is establish a meaningful change, as

opposed to looking at treatment mechanism or that

332

sort of thing. And so by keeping them together,

you're not artificially separating and pulling out

separate groups, but you're establishing in a

presumably representative sample that this is the

magnitude of change that represents the minimal

clinically important difference.

They are often--in many, if not most

anchoring techniques--kept together, placebo and

treatment.

DR. RODENBERG: Can I make a quick comment,

please?

In doing the analyses--I just think it

might be important to know that whether we're

talking about those that said they had a meaningful

benefit or didn't--placebo and the active therapy

groups responded very similarly, in that whether it

was due to being in active therapy or placebo, if

you had a large change, you considered it

meaningful, and if you did not have a large change,

you did not.

The difference--this is the proportion of

people on active therapy that had a meaningful

333

benefit compared to placebo. But once a person had

a meaningful benefit, they had very similar

changes, regardless of the mechanism behind it.

DR. EMERSON: Using your anchoring

technique, would you have come up with the exact

same threshold of 1 unit for both groups?

DR. RODENBERG: I haven't done that

analysis, but I can tell you that the means and the

medians; the distribution for the placebo and the

active group--for both the responders and

non-responders--are almost identical. They're not

statistically significantly different, but there is

a sample size issue--you could bring that up.

But looking at them, for active therapy

the mean was 4.4 on the responders, and it was 4.3

on the placebo group.

So I believe--yes, I didn't do the ROC

analysis because of the low sample size. But yes,

I do believe you'd actually get a very similar

cut-off if you did this for just the active therapy

group.

Also, the 45-degree line, it's actually

334

like the inverse 45-degree line. Where that

intersects the ROC curve, that was the point that

was used as the optimal cut-off, because it

balances different types of misclassification:

misclassification of true responders and

misclassification of true non-responders. And so

we were looking for something that basically

false-positives and false-negatives were treated

equally. And that's where the ROC curve intersects

that, that was the optimal cut-off kind of

balancing misclassification rates.

DR. EMERSON: But is there any rationale

that says that where that cut-off occurs is what's

truly clinically meaningful?

DR. RODENBERG: I think you can

always--right. We get the patients that say, you

know--when we look at the two different groups,

that seems to differentiate the two, in terms of

misclassification rates.

DR. DeROGATIS: Yes, you can apply

different utility functions to false-positive,

false-negative and true-positive, true negative.

335

But in a balanced equation, as Dr. Roderberg is

pointing out, that's the optimum correct

classification--

DR. EMERSON: That's one definition of

optimum. There are many definitions of optimum.

DR. DeROGATIS: Well, it's one definition,

but it minimizes misclassification of responders

and non-responders.

DR. GIUDICE: I think we could go on all

afternoon. But thank you.

Dr. Lockwood had a question.

DR. LOCKWOOD: A quick question, and it's

for Dr. Lucas, who's thus far escaped unscathed.

[Laughter.]

And I'm sure she was relaxing there.

And it's slide 67.

I think reasonable people will

debate--probably in perpetuity--whether or not

there are cardioprotective or cardiotoxic effects

in the younger age group of the WHI study. And

some people might even still debate--I have this

debate with my ex-chair in my institution all the

336

time--about potential for there being a causative

relationship between estrogen and progesterone and

breast cancer, or estrogen not playing a role.

But everyone would agree that hormone

replacement therapy increases the risk of

thromboembolism. And there's just no doubt and no

debate and no discussion about that.

So I think if there is one single element

of safety that deserves the most scrutiny it is the

potential role of this patch in promoting

thromboembolic disease. Now, since the prevalence

is so low you would really need a very, very large

study of a WHI-type to prove this.

But a reasonable surrogate is to look at

coagulation indexes. And I would posit that the

ones you've looked at aren't particularly useful.

They're not, in fact, often affected even by oral

contraceptives, if you look at the literature; and

that the most sensitive single indices is probably

protein-S--free protein-S and protein-S activity,

which is most affected by ovarian steroids and

potentially by androgens.

337

So my question to you is: in fact, do you

have that data someplace? Were protein-S activity

levels looked at? Or, in the absence of that, were

any real indices of thrombin activation looked

at--for example, prothrombin, fragment 1.2,

thrombin, anti-thrombin complexes--something to

give us a sense of whether or not TTS actually

increased the generation of thrombin.

DR. LUCAS: We did look at prothrombin

fragments 1 and 2 in the Phase II program. We also

looked at protein-C resistance, and we looked at

plasma viscosity, platelet aggregation, and we saw

nothing. And then the values that you see here are

what we then did in Phase III. And we've not seen

anything in any of the measures.

DR. LOCKWOOD: But no protein-S.

DR. LUCAS: We did not do protein-S.

DR. GIUDICE: And a follow-up to that--not

with regard to coagulation, but if you look at the

data on Danazol, with regard to its being an

immunosuppressant, have you looked at all at any

indices of suppression of the immune system in

338

women on the Intrinsa?

DR. LUCAS: In what measures would that be?

DR. GIUDICE: One would have to--

DR. LUCAS: We looked at white counts.

DR. GIUDICE: No, one would have to do in

vitro studies--mixed lymphocyte cultures.

VOICE: [Off mike.] Measuring TH 1 and TH 2

[inaudible.]

DR. LUCAS: No, we've not looked at that.

DR. GIUDICE: There are two other

questions, and then we need to move on.

One is from Dr. Merritt, and the other

from Dr. Burnett.

DR. MERRITT: n the Phase III study design

you allowed patients to continue after 52 weeks

into a persistence of benefit arm. Are those

randomized to placebo and others were randomized to

the TTS system? And you said there was loss of

benefit. Is that only in the placebo arm?

DR. MEYER: No, not entirely. For the

persistence of benefit study, after 52 weeks there

were about--slightly over 200 women who were asked

339

if they wanted to participate in a 13-week study,

knowing that they would get either a placebo or a

testosterone patch. Now, recall, they had all been

on testosterone prior to this.

Those who agreed to participate were

randomly assigned to either placebo or the 300 mcg

testosterone patch. And no one knew what they

were getting.

Following 13 weeks on therapy they were

interviewed by a trained interviewer, with an

extensive script--and it was a script which we also

used in the clinical relevance stud. It wasn't

just a single question, it was a lot of data that

we gathered.

And we asked, in these interviews, about

the same sorts of questions that were covered in

the instruments that they were filling out: "Did

you have a decrease in desire for sexual activity,"

etcetera, etcetera.

And, again, interestingly enough, those

randomized to placebo has a statistically

significant decrease in all their sexual activity

340

indices relative to TTS. The only area where the

two groups were the same was in a noticeable

decrease in willingness for partner-initiated

activity--again, consistent with what Dr. Shifren

showed us.

So, again, it was about 60 percent of the

placebo patents showed a decrease in these indices.

And it was about a 35 to 40 percent people in the

TTS group that shoed a decrease in these indices.

All the p values were statistically significant.

DR. MERRITT: Thank you. So then your

proposal would be that this system would need to be

used chronically and long term, and at the same

time the subjects would need to be on chronic and

long-term estrogen?

DR. MEYER: We have no data on women not on

background estrogen. So, yes, they would need to

be on concomitant estrogen therapy. The patch does

need to be worn continuously, and the duration

needs to be discussed between the woman and her

physician as to what's most appropriate for her

treatment.

341

[Pause.]

And Dr. Shifren will tell us--

DR. SHIFREN: I do just want to add that as

clinicians, since we really are using much less

systemic estrogen in our menopausal

patients--clearly, the major indication is

bothersome hot flashes--we as a group of clinicians

were very concerned about the potential for

off-label use in women not on systemic estrogens,

and wanted to know whether it was truly safe and

effective in that group.

And so the sponsor was very responsive to

our needs. Very quickly we jointly designed a

trial of transdermal testosterone in surgically and

naturally menopausal women on no systemic estrogen

therapy. And that trial is currently ongoing at

the Mass General and multiple other sites.

So, hopefully, we will have answers for

that. And I think we won't know until the study is

done.

DR. GIUDICE: Dr. Burnett, and then Ms.

Solonche.

342

DR. BURNETT: Thank you. This is a safety

question--safety issue question.

I guess with many things that are good you

always--at least in America--want to up-size. And

I just wonder what the potential for--or potential

consequences may be--for somebody who may take the

patch everyday, or use it perhaps in ways it's not

intended to be.

And I guess the background for that

concern relates to some of the data presented by

Dr. Soule. I think there's a trend towards some

effects here, particularly the metabolism syndrom

indices.

So I'm just curious about--do you have any

comments or any data with regard to that sort of

concern?

DR. MEYER: For metabolic syndrome Dr.

Braunstein will address that.

With respect to abuse, we are delivering

23 to over 300 times less testosterone than these

women would need if they wanted to have steroid

abuse.

343

If I could have slide 255 projected?

[Slide.]

This is what Dr. Lucas does in her spare

time.

[Laughter.]

This is how many patches a woman would

have to wear for about six months in order to get

any significant type of abuse potential out of

these patches. And there are way cheaper ways to

do that now, if you go to the drugstore and get

DHEA or something.

So it's not very practical or cost

effective.

DR. BRAUNSTEIN: Actually, let me review a

couple of safety issues, because I think there may

have been some misconceptions during the FDA

presentation.

If we can go to slide 337.

[Slide.]

I'll start off with some of the glucose

data, and then I'm going to show one-year data in

the natural menopause study, because the surgical

344

menopause was double-blind, placebo-controlled for

six months. The natural menopause was

double-blind, placebo-controlled for one year. And

I think that gives a much more meaningful type of

evaluation of both safety and efficacy over a

longer period of time.

If we look over here, this is the glucose

data. And one can see that basically, if you look

at the exposure to testosterone over months--here's

the double-blind period, and here's the open-label

extension--that there basically is no major change

in the glucose levels in these patients versus the

baseline. There is, obviously, some scatter, but

there's no major change.

If we go to 338--

[Slide.]

--we can look at the insulin levels. And,

again, very little change over time, either in the

double-blind placebo-controlled trial, or in the

open-label extension.

And then if we go to 334--

345

[Slide.]

--the glyco-hemoglobin data is shown here.

Again, no difference in glyco-hemoglobin levels in

these patients.

So there's no evidence of really any

metabolic deterioration. Because in the

presentation that you saw, the scale of glucose

changes really was quite expanded. But the changes

were very, very small, and really non-significant.

If we go to slide 228--

[Slide.]

--which is the natural menopause study,

there are two studies--one was a 24-week

double-blind, placebo-controlled study; another was

a 52-week placebo-controlled study. And if we just

look at the 52 weeks--because the data is really

very much the same--systolic blood pressure showed

no significant change; diastolic blood pressure

showed no significant change between placebo or the

testosterone group.

There were no significant

346

differences--both lost, although the placebo group

lost a little bit more weight than the testosterone

group.

If we go to slide 330-

[Slide.]

--we'll show the lipid changes in the

52-week double-blind, placebo-controlled trial in

naturally menopausal patients. And don't forget,

these patients are also on a progestin as well as

estrogen.

And so in the placebo group we can see

there's baseline cluster of 210, going up a total

of 2 at 52 weeks, versus testosterone group,

staring off at 208, going up 6.5--again, somewhat

of a regression to the mean.

HDL levels were very similar types of

changes; both going up, same direction.

LDL--again, the levels--the final levels

were very similar; some degree of regression of the

mean; this going up, because it starts off lower;

this going down.

And triglyceride levels, again, were very

347

similar.

If we go to 344, which shows carbohydrate

levels at one year--

[Slide.]

--we can see in the placebo group the

glucose levels went up 1.1 mg/dL in both the

placebo and the testosterone patch group.

Glyco-hemoglobin levels went down to a similar

degree, and insulin levels actually went up a

little bit higher in the placebo group than in the

testosterone group.

And here's the six-month double-blind

control group--and, again, showing very similar

types of results; trying to give some degree of

confidence in the longer-term safety issues.

And then if we--

DR. GIUDICE: I need to ask you how many

more slides, because we need to move on. We still

have the questions for the FDA.

DR. BRAUNSTEIN: I will stop. But I will

summarize by saying: similarly, there are no

changes in LDL, no changes in the coagulation

348

parameters in the natural menopause study.

And, again, protein-S was not measured.

DR. GIUDICE: Thank you.

Ms. Solonche, you had a question.

MS. SOLONCHE: Yes, first, are there any

differences in your trial results related to the

reason why the subject had an oophorectomy in the

first place?

Second, how do you differentiate between

women who are distressed about HSDD, and those who

might be depressed, and therefore out of the

running?

And, third, has any work been done on the

possible negative psychological effects of using a

medication to increase libido?

DR. MEYER: Okay. Let me start with your

first one.

We did not gather any data with respect to

differences in the women as to why they had the

oophorectomy. They all had been oophorectomized

about the same amount of time, but did not do any

statistical analyses on that.

349

With respect to depression versus

distress--everyone--an entrance criteria, because

we wanted to rule out depression, all women had to

take the Back Depression Inventory, and could not

be depressed according to that inventory, to rule

that at as a possible cause of HSDD. And then they

had to score positively--or negatively, as the case

may be--on the distress scale.

And then the negative psychological

aspects of using hormonal therapy, we did not ask

any questions about that. The fact that the women

who had a positive effect remained in the trial

and/or said they would continue the patch, would

suggest there is a positive benefit, at least for

some women. It was not listed as a withdrawal

criterion. No one gave that.

DR. GIUDICE: Dr. Dorgan, the last

question.

DR. DORGAN: Two very quick questions.

For the women following bilateral

oophorectomy and hysterectomy, could there not be

any psychological component to some of these

350

problems that are being attributed to decreased

testosterone levels?

Dr. Shifren, would you like to address

this?

And also recall that by the time the women

were in this trial they were, on average, eight or

nine years post-oophorectomy. I mean, they've lost

their ovaries and their uterus has been removed. I

would think that there could be a psychological

component, but I could be wrong.

DR. SHIFREN: If you think back to the

hysterectomy study--the observational study--in

general what we see is that the majority of women

who undergo hysterectomy actually have an improved

sex-life post-operatively. And that's been shown

in many large studies.

Of course, that makes a lot of sense.

Women only have a hysterectomy if they have

underlying pathology. So typically they have

bleeding, fibroids, endometriosis. And the removal

of that problem often leads to increased sexual

activity and function.

351

What was so interesting--I thought about

that Nathorst-Buhst study that I showed you

earlier, is that within that group of women, you

were still significantly less likely to get that

increase in libido if your ovaries were removed

concurrently, and significantly more likely to have

lowered libido post-operatively.

DR. DORGAN: A second question--just to

follow up--in your 2(b) studies, I see why you

chose the 300 mcg per day dose. But you looked at

a placebo, 150 mcg dose, a 300 mcg dose and a 450

mcg dose. And of all the parameters that we're

looking in terms of efficacy, the greatest effect

was with the 300 mcg dose.

If it's the testosterone per se--I'm not a

pharmacologist--but if it's the testosterone per se

that's responsible--if testosterone replacement per

se would improve libido in these women, why aren't

we seeing a linear effect with an increased--well,

sexual increased, number of satisfying episodes of

sexual intercourse, and improved personal distress

when we go up to the 500 mcg dose.

352

I was kind of concerned that we're not

seeing--we're not even maintaining the increase.

It's no longer significant when we go up to 450.

Could somebody comment for me?

DR. MEYER: If you could project slide 181,

please?

[Slide.]

Actually, what we found in the Phase II

study is placebo and 150 were essentially the same;

450 had an effect. It was just not statistically

significantly different from placebo; 300 was

better.

But as you can, in some domains of the

PFSF--placebo's in blue, 150 in yellow, 300 in the

darker yellow, and 450 in the orange--for example,

orgasm, sexual pleasure, sexual responsiveness--450

sometimes did better than 300.

But what we were interested in was the

lowest effective dose. So it was sometimes but not

consistently. And when we did our population PK

studies, we do get dose proportionality in the

doses. So you get higher blood levels of

353

testosterone with the 450--which, again is a bit of

a conundrum. It doesn't explain the whole story

unless we're at the top of the dose-response curve

with 300.

But we chose 300 as the lowest effective

dose.

DR. DORGAN: Okay. Thank you.

DR. GIUDICE: Thank you.

Now I'd like to ask the committee for

questions to the speakers from the FDA.

Dr. Nissen.

DR. NISSEN: I had one very brief question,

and that is: there were a couple of patients that

had bilirubin elevations, and I want to know if any

of the patients in the study--as far as the FDA can

determine--met High's rule of a concomitant

transaminase elevation and bilirubin elevation?

We know that testosterone has potentially

hepatotoxicity, and I"m just looking for any signal

there. Any of the hyperbilirubinemic patients also

have elevations in liver enzymes?

DR. SOULE:: I'm unfortunately unable to

354

answer that question. It's possible that Procter &

Gamble might be able to provide you with the

answer.

DR. LUCAS: Two patients who had markedly

abnormal bilirubin--could we see the box and

whisker plots for bilirubin?

[Slide.]

DR. NISSEN: But what I need to see is

their transaminases.

DR. LUCAS: Okay.

DR. NISSEN: You're aware of High's rule,

and why it's important, I assume.

DR. LUCAS: Yes.

Could I see the bilirubin? Oh, we can't

project.

We saw no difference in outliers with

testosterone compared to placebo for any of the

transaminases or bilirubin.

DR. NISSEN: Okay, the two patients that

had elevated bilirubins, did they also have

elevated transaminases?

DR. LUCAS: No, they did not. They

355

isolated bilirubin.

DR. NISSEN: Okay. Thank you.

DR. GIUDICE: Dr. Tobert.

DR. TOBERT: Yes, I have a question for Dr.

Davis, and it refers to the FDA's first question

about clinically meaningful differences.

And I thought it might illuminate the

question a bit to consider other drugs, or other

drug classes that the FDA considers meaningful that

act on the brain, as we've heard that this product

does.

For example, if you take an SSRI for

depression, what kind of differences would you get?

I mean, if I refer to your slides 11 and 12, you're

showing that the testosterone patch sort of gets

you some way back to normal, but only about a

quarter of the way. And you have like a 52 percent

responder rate versus 31 percent.

Now, I think that 52 versus 31 would be

acceptable for something like an antidepressant.

Can you--obviously you have access to a ton of data

on this--could you comment on that, please?

356

DR. DAVIS: In our division we have not

had prior drugs that really have been evaluated on

a quality of life or patient-reported outcome

analysis.

DR. TOBERT: But the FDA looks at this

question all the time.

DR. DAVIS: Yes, but in our division we

have not handled drugs of that sort, so perhaps--

DR. TOBERT: How about the PDE-5s, the

newer PDE-5s? Did you have to deal with that?

DR. DAVIS: Let's have Dr. Griebel or Dr.

Monroe answer that.

DR. GRIEBEL: I think each one of them is

dealt with individually. And this is our first

experience with female sexual dysfunction, these

endpoints. And we're asking--that's why we brought

it to committee. We're asking for your input on

this.

DR. TOBERT: Okay. All right, I would just

state that my impression is that for other drugs,

this would be considered pretty good: 52 versus 31

percent. But if I'm wrong, please correct me.

357

DR. MACONES: This is for Dr. Soule.

Again, to go back to the post-marketing

plan--which I'm having a tough time with--on your

slide number 29, your second bullet-point says that

recruitment goals were not previously met using

this database, which seems to be a really critical

point.

Could you give us a little more

information about that?

DR. SOULE:: I don't know how directly I

can discuss a plan that involves another product at

this committee--except to say that there has been

some experience with the database and goals have

not been met, in terms of recruitment and

timeliness.

DR. MACONES: Goals with this company?

DR. WALKER: Alexander Walker.

What we can offer and promise is a number

of people. So we've got covered lives. If a

product doesn't sell, if it's displaced by other

products, a projection that's based on marketing

will fall short.

358

DR. MONROE: Dr. Walker is correct. If the

exposure to the drug is below their expectations,

they won't be able to recruit at the rate that is

predicted, so that there's two options: they'll

either miss the recruitment target, or the study

will have to run for a longer period of time.

And as Dr. Soule said, we were somewhat

skeptical of the time-lines, based on an experience

that we've had in our division. And I think we're

both in agreement, Dr. Walker.

DR. GIUDICE: Dr. Patrick, and then Dr.

Hager, and then Dr. Lipshultz.

DR. PATRICK: The sponsor faithfully

followed the 2000 draft of the female sexual

dysfunction guidance. Given the difficulties in

interpreting the number of satisfactory sexual

events--particularly, as DeRogatis pointed out, a

fractional number is not easy to interpret--has

there been a thought of trying to look at these as

combined endpoints? Or what is the relationship?

And why is satisfactory sexual event thought to be

the primary endpoint in this area?

359

DR. MONROE: Well, as everyone has heard

from the discussion that has ensued earlier today,

this is a new area, I think, for everybody. It's

an area that doesn't have clean endpoints. There's

a lot of active research that's going on.

We recognize that many of the

investigators in this area do have questions about

this being the primary endpoint. At the time that

the draft guidance was done, it reflected the best

assimilation of the available data of the people

that drafted the guidance, based on their

interactions with various investigators in the

field.

We are considering looking at this entity

of hypoactive sexual desire disorder in somewhat

different ways. But at the time this study was

started, these were the rules, and the sponsor did

follow the advice that we gave to them. And I

think it's only fair, today, to evaluate their

application primarily on the way the rules were set

up at that time.

It doesn't mean that, as we go forward and

360

gain more experience in this area, we won't give

greater or lesser weight to several of the

secondary endpoints.

DR. GIUDICE: Dr. Hager.

DR. HAGER: Granted that this is a new area

for the agency, but we do have rather long

experience with a product of combined

dequon-estrogen and testosterone that has been

available.

Are there data regarding not reaching the

primary endpoints of efficacy, but side effects, as

far as breast cancer and cardiovascular risk?

DR. MONROE: Would you like to--someone is

with us from our office of Drug Safety. And I

think she's going to show you our experience using

the adverse event reporting system--the AERS

database from the agency, the spontaneous serious

adverse event reports that the agency has received,

perhaps over the last decade.

DR. GELPERIN: I'm Kate Gelperin. I'm a

medical officer in the Office of Drug Safety. And

in the interest of time, I'll just say briefly that

361

the type of reports that are in the AERS safety

database at the FDA are generally spontaneous

reports from consumers or health professionals, and

so they are not clinical trial results.

With Estratest, we did run a search of the

AERS safety database for serious adverse event

reports--"serious" is a regulatory definition that

includes death, life-threatening, requires or

prolongs hospitalization, congenital anomaly, and

then there's a category called "other" that's other

medically important events.

And when the search was run in that way

there were a total of 226 reports in the database.

Of the raw counts, the most frequently reported

include breast cancer, depression, headache and

acne.

A review was done of the breast cancer

reports with Estratest, including any report of

breast cancer in which Estratest was a suspect or

concomitant drug. This search showed that between

the years 1992 and 2004, four unduplicated cases of

breast cancer had been received, with Estratest

362

indicated as a suspect drug--which were not from

legal sources. Patient age ranged from 31 to 56

years.

We also found a total of 69 unduplicated

cases of breast cancer that were received via legal

sources. The first legal case was received on

October 17, 2003, and all others were received

thereafter.

In each of these cases, other suspect

drugs number between three and nine, and included

other HRT therapies. Patient age ranges from 45 to

70 years.

There were also eight unduplicated cases

of breast cancer in which Estratest was considered

a concomitant drug by the reporter.

A search was done for serious events with

Estratest considered suspect, which did not include

the outcome called "other," since that was a way of

zeroing in on perhaps some of the more serious

effects that might have been required of prolonged

hospitalization. And when that search was done,

the most frequently reported events included CVA,

363

coronary artery occlusion, dizziness, headache,

breast cancer, chest discomfort, depression,

glaucoma, hypoesthesia, pain, and ovarian cancer.

The following category of events--cases

were reviewed for cardiovascular events, including

MEDRA-preferred terms, which is a way of coding

spontaneous reports. We included the MEDRA Pts,

cardiovascular disorder, coronary artery occlusion,

coronary artery re-occlusion, myocardial

infarction, chest discomfort, and chest pain.

There were a total of six cases in the

data base that were serious: two myocardial

infarction, three chest pain, one coronary

occlusion.

In the two reports of myocardial

infarction, one case occurred in a 78-year-old

female who was participating in a clinical study.

The even was considered by the investigator to be

possibly related to Estratest.

The other report was in a 57-year-old

female who was taking multiple concomitant

medications, including opiates.

364

In the three cases of chest pain, one was

attributed to cholelithiasis, and one was

attributed to hypophosphatemia. And one case of

coronary occlusion in a 58-year-old female was

treated with a stent.

With regard to cerebrovascular effects,

these included the MEDRA PT cerebrovascular

disorder, cerebrovascular accident, and headache.

There were a total of six unduplicated serious

reports, with Estratest considered a suspect drug.

There were two reports of stroke, one in a

48-year-old female, and one in a 58-year-old

female. There were three reports of serious

headache, one in a 37-year-old female who was

admitted to the hospital with depression, and was

later diagnosed with multiple sclerosis.

The other two reports were for a

49-year-old female and a 45-year-old female. There

was one report of unspecified cerebrovascular

disease in a 64-year-old female.

Now, with regard to serious reports of

depression, there were three unduplicated reports,

365

with Estratest considered a suspect drug. All

three reports included other suspect drugs.

Just in summary I would say that the sense

of these reports is that although spontaneous

reports are important for hypothesis generation,

that in this case I don't think we could regard

these as in any sense confirming a hypothesis.

DR. GIUDICE: Thank you.

Dr. Lipshultz, you had a question.

DR. LIPSHULTZ: I just had a question for

the FDA speakers, and that was: it seems to me that

you were somewhat--at least in the briefing

document--insinuating that you were not 100 percent

happy with the endpoints here, in terms of change

over placebo. And you've said that this is a new

area, and we're looking at for the first time

quality of life drug.

But that's not true. I mean, you have

looked at the PD-5 inhibitors, with three

instruments that are almost the exact same as the

three instruments here. The names have been

changed and the questions are different, but it's

366

the same thinking.

And what I'm asking is: is reviewing the

data from the two newest PD-5 inhibitors, were

those changes more robust than what we're seeing

here, in terms of quality of life changes?

DR. SHAMUS: Ben Shamus. I'm the Director

of Reproductive and Urologic drugs.

You know, we can look at this many

different ways. One way to look at this is that it

requires us to treat 100 women--expose 100 women

for 15 of them to have a sort of borderline

clinically meaningful effect attributable to the

testosterone. I mean, there's lots of ways of

looking at this, but that's basically what it boils

down to.

So that is not to say there is not a

clinically meaningful effect in some women, and

that there is a mean statistical difference. The

thing, as you know, we have to grapple with is, in

a population setting, which is what we deal with

here--in a population--is that benefit to the

population worth the risk, whatever that may be, in

367

the situation.

Of course, the PD-5s or a whole different

thing, in a sense, that we have a lot more

experience, etcetera, in terms of the risk. And if

I recall the data, actually, many of the people

returned almost to normality in terms of erectile

dysfunction--I don't have the figures in front of

me--as opposed to here, where it's not at all the

case.

But we the benefit--it is what it is, and

that's what it is. And then the risk--we have to

weigh those two things and make some kind of

decision.

DR. GIUDICE: Thank you.

Committee Discussion

DR. GIUDICE: That's an excellent segue

into question number 1, which is:"Do the efficacy

data represent a clinically meaningful benefit

above that of placebo for surgically menopausal

women with hypoactive sexual desire disorder who

are taking concomitant estrogen?"

Our task is to give our recommendations to

368

the FDA, with a yes or no answer.

Does the committee feel that it is ready

to take a vote?

[Pause.]

Dr. Emerson?

DR. EMERSON: Just one point of

clarification: you do want this question answered,

basically, with that risk-benefit trade-off that

you just spoke to--the concept--

VOICE: [Off mike.] That's the last one.

DR. EMERSON: Well, but the concept was

saying that 15--that extra 15 responses relative to

the potential risks.

So--do we want to answer the question of

whether people should want to have one extra

episode per month, or do we want to answer the

question of is this the cost of getting this one

extra episode per month is too much.

DR. GRIEBEL: The risk-benefit question,

weighing in the safety, bottom-line, is at the end.

DR. EMERSON: Okay.

DR. GRIEBEL: Four.

369

DR. EMERSON: So just comment on efficacy.

Whether the one is worth it--I mean, whether the

one is something that you'd like.

DR. GRIEBEL: Mm-hmm.

DR. EMERSON: Okay.

DR. GIUDICE: We're voting on the 1, 6 and

7--essentially.

Dr. Rice?

DR. MONTGOMERY-RICE: I want to make sure I

understand something.

On this "clinically meaningful benefit"

was that a term that you all developed? Or is that

a scientific term that I've missed in statistics?

DR. GRIEBEL: Well, there's a whole

science of clinically meaningful benefit and

minimal important difference that Dr. Patrick might

want to comment on.

DR. PATRICK: Well, you would have learned

this as clinical significance. But the term

clinical is sort of odd here, because this is

defined by the women. And so it's really the

minimum important difference. Forget the clinical.

370

But you can think of it as parallel to clinical

significance if you had a clinical anchor here.

DR. MONTGOMERY-RICE: But that's not the

same as statistical--

DR. PATRICK: No.

DR. MONTGOMERY-RICE: --difference.

DR. PATRICK: So we're got statistical

differences, and what the committee's being

asked--and while I have the mike--I didn't

understand this incorporating risk. The question

asks about clinical benefit. It doesn't say risk

in the question at all. So I'd like that clarified

before we vote, because we have all these questions

about risk later. And so I thought we were

answering this one at a time, rather than

integrating this all.

DR. MONTGOMERY-RICE: And I just want to

ask one other question to the FDA.

If the event had been five more, would

that have changed the question, versus it being 1.4

or whatever it was more? Would that have changed

the question of being a clinically meaningful

371

benefit?

DR. GRIEBEL: Well, it could work both

ways. If the study that was designed to define the

clinically meaningful difference that you had

observed was five extra events, and then the

average was one for each women, then clearly it

wasn't met.

DR. MONTGOMERY-RICE: But you didn't define

that to begin with, did you?

DR. GRIEBEL: No.

DR. MONTGOMERY-RICE: Exactly. So you just

said that it needed to be statistically different

than you chose to use from baseline, and compared

it to groups. So you didn't define that it had to

be five more events over a four-week period of time

to be clinically meaningful. Or maybe you did.

DR. MONROE: We did not, but we told the

sponsor clearly that a statistical change in and of

itself would not be sufficient; that they would

also have to provide evidence--as they've attempted

to do with this study--that the change that would

be observed would be of clinical benefit to the

372

patients; the patients would conclude that they

derived a true benefit. How they're making that

decision is up to the individual that has the

disorder. And that's what was attempted to be done

in this case in that study.

Now, the question is--that was one of the

issues we raised to the panel is there are many

ways of trying to do these studies. Was that study

done in an acceptable manner so that the numbers

that they generated from that study, do they carry

credence with you as a committee member.

In other words, we've tried to present to

you the information that the sponsor has generated,

and we're asking you for your independent

assessment and interpretation of those data.

DR. GIUDICE: Yes, Dr. Heiman.

DR. HEIMAN: I just wanted to make a

comment on this, because I do think it's tricky.

If you come from a psychotherapy side of

doing interventions as opposed to a drug side, one

of the things "clinical significance" can mean is

you jump from the dysfunctional range into the

373

functional range--somewhere into the functional

range. That's a way of quantifying, but it's not

quite statistical--"clinical significance."

I think, in this area, that's very

difficult to do, because though we have some data,

as you've seen, some data on what is the normal

range, I don't think we should, at this stage of

the development of the field, rely 100 percent on

that idea.

So what we have in this case is what

they've tried to do is look for clinical relevance.

And when you go there, it looks like the figure

comes out somewhere around 50 percent when you try

to take that table 43 apart. So that's another

piece of evidence.

And, finally, if you look at one even over

four weeks, I would just be careful as you consider

that, to not treat that casually. That could be

quite important for the women in this trial. In

some ways--it just could be quite important. It

may seen insignificant, and that's also, by the

way--all those things actually are difficult to

374

judge. We don't have a lot of objective standards

from which to do that.

So that's just, by the way, on the event

issue. It's almost as if each of these--I'm not

asking that you consider them separately, but

they're very different measures, these three

measures. It's hard to put them all into one, I

think, and really consider what it means.

DR. GIUDICE: Thank you.

So are we ready to vote?

Okay, we're going to start on this side.

Dr. Macones.

DR. MACONES: Yes.

DR. DORGAN: No.

DR. EMERSON: I'll say yes.

DR. HAGER: In light of the significant

placebo effect, and in light of apparent

discontinuation of a large number of users, and the

maintenance of benefit over time not increasing but

staying stable--in spite of those things, I do

think that there is statistically significant

benefit, and so I would vote yes, with some

375

reservation.

DR. TULMAN: I would vote no.

DR. BURNETT: Yes.

DR. DICKEY: Yes.

DR. GIUDICE: Yes.

DR. LOCKWOOD: Yes.

DR. LEWIS: Yes.

DR. LIPSHULTZ: Yes

MS. SOLONCHE: No.

DR. PATRICK: Yes.

DR. NISSEN: Let me just qualify a little

bit here--

[Laughter.]

--it's been too easy for you.

I think that the agency set a bar here for

what had to be shown with regard to efficacy, and

that bar was met. And so you can't change the

rules--in my view.

And I think that they did--they set out to

do this, they did it very carefully. They showed

efficacy. Now the efficacy, I must tell you, is

fairly marginal. And what didn't really come

376

through there--and I decided not to prolong this by

questioning--but it looks to me like about 36

percent of the placebo patients would really like

to continue the therapy, and about 50 percent of

the treated patients would really like to continue

the therapy.

And I want the sponsor to consider

marketing the placebo--

[Laughter.]

--because that's a pretty good outcome.

So my answer here is yes, but it's not a

very big effect, in my view.

DR. GIUDICE: Thank you.

DR. MERRITT: Yes.

DR. MONTGOMERY-RICE: Yes.

DR. GIUDICE: Thank you.

We are now onto safety. Question No. 2

is:

in the safety database, 494 surgically menopausal

women were treated with TTS in combination with

estrogen for 12 months. Of these 127 were treated

for 18 months. There are no long-term, placebo

377

comparative safety data beyond six months.

The expected TTS use will be chronic in

the intend population.

Is this exposure--total number of women

treated and duration of treatment--adequate to

demonstrate long-term safety?

Does the committee feel that it is ready

to vote on this, or does it need some discussion?

Dr. Tobert.

DR. TOBERT: I had to prolong this, but I

think some few--we haven't really asked any safety

questions of FDA yet--or very few. And I do have

one or two.

DR. GIUDICE: Well, now is the time.

[Laughter.]

DR. TOBERT: Well, firstly, I don't totally

follow the logic here. The WHI studies were

disappointing, but they showed what you might have

expected, considering the history of oral

contraception; you know thromboembolic effects were

no surprise. And they were only disappointing

relative to the epidemiology.

378

But the point is: does testosterone have

any biological effects that are the same as

estrogen progestin? Other than the fact, of

course, that a small amount is aromatized to

estradiol.

Just because the WHI studies were

disappointing, I don't quite see why there's an

issue with testosterone. So maybe you could

explain that.

And my second question is: with regard to

the randomized controlled trial that you are

putting on the table, then you see I'm a big fan of

randomized controlled trials. I sit on the

steering committee of two of them--both of them

about 10,000 patients. But I would question

whether it's possible to do a study that big. And

I heard the number 17,000, but I think that was

not--doesn't include evaluating the risk of breast

cancer, and would be in much older women.

So could you clarify those two points?

What, actually, if you were to study 50-year-old

women, how many you would need in a randomized

379

trial to answer the questions you want answered.

And the other is about the biology of

testosterone versus estrogen and progestin.

Thank you.

DR. SOULE:: To take your second question

first, that's really one of the questions that we

have posed to you as our advisory committee. And

we would like your thoughts and suggestions on what

sort of trial would be optimal; what design, what

duration, what sample size would be optimal.

As far as potential for risk with

testosterone--as you mentioned, there is the

concern about aromatization to estrogen, with the

following of risks that we know to be attributable

to estrogen. But I think the biggest point is that

we simply don't have enough data on women taking

testosterone on a chronic basis to be able to look

into a crystal ball and see what we may see in a

population.

DR. TOBERT: But the labels for the male

products, where you're giving 20 times as much, are

pretty benign. They talk about prostate cancer as

380

potential risk, but they're not loaded up with

warnings and black boxes.

DR. SOULE:: But women are not

physiologically exposed to the sorts of levels.

DR. TOBERT: Well, but this patch is

providing levels that would be found in a young

woman.

DR. MONROE: Well, I think you took us back

to WHI in the sense that a lot of what was being

target there was to bring levels back to what was

in young women. And you created outcomes that were

a surprise to, certainly, many people. Some of

them were apparent, as we heard from the

epidemiologic studies. Some were not.

And I think we feel that there may be some

risk in making assumptions just because something

hasn't been shown in the past in limited numbers of

women treated for short periods of time relative to

the anticipated clinical use.

DR. TOBERT: But that really goes to my

point. Because testosterone is not thrombogenic

like estrogen and progestin are. The female sex

381

hormones tilt the hemostatic balance towards

coagulation. Testosterone does not. Men don't

have to, you know--when man was evolving, women

faced major hemostatic challenge every two years.

That's not the case with men, so testosterone isn't

procoagulant. And that, I think--you know, a lot

of the findings in the WHI probably are

attributable to that.

DR. GIUDICE: My interpretation of this

question is that it is whether the exposure has

been adequate for long-term safety evaluation,

including the fact that this is a patient

population that has been studied with estrogen.

So I don't think it's just the risk of

testosterone. I think it's also the fact that the

indication that the sponsor is going for is the use

of the TTS in the setting of the surgically

menopausal woman with estrogen replacement.

DR. TOBERT: Just to clarify--

DR. GIUDICE: Is the rest of the group--

DR. TOBERT: --we're not debating the

safety of estrogen here. It's only--

382

DR. GIUDICE: I'm not so sure if we are or

are not, because this is an indication for

long-term testosterone therapy, potentially, in the

setting of an obligate long-term estrogen therapy.

And so that is something I think that the

committee needs to discuss, because this, I think,

is part of the underlying issue of the long-term

safety.

DR. HAGER: I fully agree. I think we are

evaluating the product as presented by the sponsor;

and that is in combination, in surgically

menopausal females who are using estrogen.

DR. HEIMAN: Yes, and the way I also

understood this question is in terms of long-term

safety. And so that's very crucial, I think, in

this case. Is that correct?

DR. GIUDICE: Any further discussion on

this?

Yes, Dr. Lipshultz.

DR. LIPSHULTZ: As a

non-gynecologist--getting back to the estrogen use

over a long period of time, I mean, that's already

383

been discussed, decided, published and has

become--it's a done deal.

So, I mean, we're not rediscovering the

wheel here. I don't understand this. I mean, you

know, if they're mandating these patients have to

go on long-term estrogen because it's

incorporated--and then use the patch, then

basically aren't you back to where you were with

the discussion of the safety of estrogen?

DR. LOCKWOOD: I think what Linda's

saying--if I can put words in her mouth--is that we

know that estrogens are thrombogenic. This drug is

being used with estrogen. So the question is: does

it make the estrogen more or less thrombogenic.

And there's certainly some evidence, even from the

WHI, that progesterone may actually make it more

thrombogenic. But we don't know because, 1) there

are not enough numbers and, b) I'd like to have a

few more of these--

DR. LIPSHULTZ: But then you're putting a

product on top of a base that already has warnings.

DR. LOCKWOOD: Right, but it would be like

384

using nitroglycerine and a calcium channel blocker

for angina. And the question is, all right,

nitroglycerine works, why not give another

vasodilator? That should work even better.

But what happens when you do that is--I'm

making this up. The drugs are perfectly fine.

[Laughter.]

I'm on a roll, though. But when you use

them together there's some cardiotoxic effect that

was not predicted, or you stop perfusing the brain

and something bad happens.

And so, in fact, since you're labeling it

to be used together, you have to understand the

potential for synergistic or additive effects that

are toxic.

DR. LEWIS: And it's not just that, but

it's also that there all these warnings about

"long-term"--quote-unquote--usage, because that's

what's been linked to breast cancer. And we really

don't have any data on that from the sponsor.

And--you know, do we have concerns? Obviously, the

Women's Health Initiative, if there's one thing it

385

taught us it's that estrogen is different than

estrogen plus progestin. So what is estrogen plus

androgen? We really don't know.

DR. GIUDICE: Dr. Tobert and then Dr.

Dickey.

DR. TOBERT: Well, I think this discussion

is actually very important. Ad maybe we can just

clear it up.

My understanding--and maybe I'm completely

wrong about this--is that the sponsor is

recommending that if a woman is taking estrogen

anyway--and I think they mean oral or transdermal

estrogen. The label isn't totally clear on that.

If she is taking that anyway, she can take the

patch. If she stops taken systemic estrogen, she

should stop taking the patch.

And the intent, at least, is not to

encourage any more use of estrogen than would

otherwise occur. And to that extent, it's not--the

safety or otherwise of estrogen and progestin is

not relevant.

DR. LEWIS: I don't think we can conclude

386

that. I mean, all the data we have on efficacy are

from the combine usage. So, to me, looking at that

data, if I'm going to prescribe the product, I

would assume that there's something about having

adequate estrogen on board that helps make this

product work, and I would replace the patient with

estrogen first--or I would consider it in somebody

who's already placed on estrogen.

So--

DR. TOBERT: Would you treat the patient

more or longer with estrogen? Or would you put a

patient on estrogen just so you could use the

patch? Because if you would, then it's a different

question.

DR. LEWIS: If you're a literal,

evidence-based person, you would only use it

somebody who's already on estrogen. Obviously,

they're studying it in patients who are not on

estrogen, but we don't have those data to judge

yet.

DR. TOBERT: Because if it causes more use

of estrogen, that's a whole different and important

387

question. But it's a separate question.

DR. GIUDICE: Dr. Dickey has a comment.

DR. DICKEY: I think this alludes to the

same thing we were just discussing--but this new

drug application says it's only fro the surgically

menopausal women, and yet when we talked about the

long-term safety, it was clear that we're going to

be looking at both surgically menopausal women and

naturally occurring menopausal women--I presume

without redoing any of the baseline data? So we'll

begin to look then at some of these women may be

getting three drugs: progestin, estrogen and

androgen?

DR. MONROE: Well, the sponsor has parallel

studies going on in women that are naturally

menopausal who are presently on estrogen and

progestin, and are now taking testosterone on top

of that. And that's a group that I presume that

they may eventually want to expand the claim for

use in, depending on how the data is.

Similarly, they've indicated that they're

looking at a population that's just taking

388

testosterone alone, or the drug might work equally

well without the risk of estrogen.

So those are all things that we'll learn

perhaps in the future.

DR. GIUDICE: But our charge is to look at

the data that have been presented today, in the

context of the indication.

DR. NISSEN: Folks, let's not make this any

more complicated than it already is--you know? The

question, I think, is very clearly stated. I mean,

what we know is exactly what was done in these two

trials. This is the database that we have. And

we're being asked whether, in this population,

treated in this way, whether we have an adequate

safety database in order to make a decision.

I think that couldn't be more clear. And

I don't think we have to dance around it.

VOICE: [Off mike.] And we can answer yes

or no.

DR. GIUDICE: In fact, let's do that right

now.

[Laughter.]

389

Now we'll start on this side of the table.

Dr. Montgomery-Rice.

DR. MONTGOMERY-RICE: No.

DR. STANFORD: No.

DR. MERRITT: No.

DR. NISSEN: And I must qualify again--

[Laughter.]

DR. GIUDICE: A simple yes or no will do.

DR. NISSEN: No, I really am--you know,

first of all, I have to earn my $164 salary for

coming here.

[Laughter.]

And, you know, these hormones have

widespread biological effects, affecting virtually

every tissue. And the heart is obviously one of

the target organs, which is why you have a

cardiologist sitting on the panel.

And I just have to review for a

moment--just give me two minutes--to say that we

have at least four or five pieces of data to

suggest that there is a high probability of an

excess cardiovascular risk with this product. They

390

include the evidence that endogenous testosterone

levels are associated with coronary disease. We

have the evidence from Dr. Soule's evaluation that

shows that outliers are much more likely to have

elevated lipids, elevated blood sugars, worse

insulin resistance, increasing insulin levels;

blood pressure changes of several mm/Hg, and

sometimes in the range of 10 to 19 mm--which is

highly associated with cardiovascular risk;

elevated fibrinogen.

We also have the data on the known risks

of estrogen-progesterone in the WHI study.

And so given that, the safety data base

that we have of 500 patients, in my estimation, is

at least an order of magnitude. I'm talking about

10-fold too small for us to assess a therapy that's

likely to be used in millions of patients.

And so I think this answer is very, very

clear. This is a much too small of a safety

database--

VOICE: That's a no?

[Laughter.]

391

DR. NISSEN: --that's a no--for any

reasonable assessment of cardiovascular risk.

But I do think--I want to put this on the

record, because there's a very specific reason why

it's too small. If we didn't know anything about

these biological effects of hormones, maybe it

would be okay. But we know a lot, and what we know

doesn't suggest that it's a particular safe

approach.

DR. GIUDICE: And your vote is?

[Laughter.]

DR. NISSEN: No.

DR. GIUDICE: Thank you.

DR. PATRICK: Simply no.

MS. SOLONCHE: No.

DR. LIPSHULTZ: No.

DR. LEWIS: No.

DR. LOCKWOOD: No.

DR. GIUDICE: No.

DR. DICKEY: No.

DR. BURNETT: No.

DR. TULMAN: No.

392

DR. HEIMAN: No.

DR. EMERSON: No.

DR. DORGAN: No.

DR. MACONES: No.

DR. GIUDICE: For this vote it was

completely unanimous for no.

The previous question was three no's and

14 yeses.

Thank you.

The third question has three parts. The

first part is: Are the safety concerns or

unanswered questions associated with use of TTS in

combination with estrogen that need to be studied;

for example, questions about cardiovascular or

breast cancer outcomes, or questions about risks

and benefits in populations who are likely to use

this product off-label?"

So ask the committee--I think we've

actually discussed this at quite a bit of length.

But I think the agency is asking us to state what

these particular concerns are.

So would someone like to begin the

393

articulation of these?

Dr. Lockwood.

DR. LOCKWOOD: So I guess the answers would

be: yes, there are safety concerns; and yes, they

haven't been addressed.

And the three I'll focus on--and I'm sure

other people will add--are the risk of venous

thrombotic events; pregnancy exposure--obviously,

given my concerns; and breast cancer.

And I think that in terms of venous

thrombotic events, the follow-up that would be

required--minimum follow-up--would be I'd like to

protein-S activity values assessed. You probably

have the data---you probably have the blood samples

ready to be run. And I think it would be

reasonable to follow up in the context of the

actually post-approval study, the incidence of

venous thrombotic events, a) because I am not

overly concerned if protein-S activity levels are,

in fact, normal, that there will be a strikingly

elevated occurrence of venous thrombotic events,

over that already anticipated with estrogen. So I

394

would like to see protein-S activity measure. If

it were normal, then I think it would be reasonable

to not change placebo versus treatment to do a

post-approval follow-up in the context of the

larger study proposed.

Secondly, I'm very concerned about the

potential for use in pre-menopausal women, and

concerned about the potential for exposing fetuses.

Animal studies, particular in primates; extended

virilization--levels, if possible, by labeling the

testosterone; core blood; and then, obviously, some

registry to follow up the fetuses that are exposed.

Lastly, breast cancer. And I think,

again, the evidence is, in my mind, inconsistent

toward an association. My bias is actually that

androgens are protective, to be honest with you.

But, again, I think follow-up in a broad

post-approval study, looking specifically at the

incidence of breast cancer.

DR. GIUDICE: Before we go around with

additional recommendations, we need to go around

just to answer a yes or a no question. That's part

395

a). Part b) is the actual--and I didn't make that

clear--part b) is the actual delineation of what

the recommendations are.

So I would like to start on this side of

the table.

Dr. Macones?

DR. MACONES: Yes.

DR. DORGAN: Yes

DR. EMERSON: Yes.

DR. HAGER: Yes, there are safety concerns.

DR. TULMAN: Yes.

DR. BURNETT: Yes.

DR. DICKEY: Yes.

DR. GIUDICE: Yes.

DR. LOCKWOOD: Still yes.

DR. LEWIS: Yes.

DR. LIPSHULTZ: Yes

MS. SOLONCHE: Yes.

DR. PATRICK: Yes.

DR. NISSEN: Simple yes.

DR. MERRITT: Yes.

DR. MONTGOMERY-RICE: Yes.

396

DR. GIUDICE: Yes.

That was unanimous. Thank you.

Now we'll do 3-b). In addition to Dr.

Lockwood's comments, are there other suggestions?

Yes, Dr. Nissen.

DR. NISSEN: It seems to me that we'd need

to know about the post-menopausal patient--not the

surgically menopausal patient, but the naturally

menopausal patient before approval. Because the

likelihood that those patients would be exposed is

very, very high. And keep in mind that the

naturally menopausal patient has coronary disease

risks that are now approaching that of men. And so

now you're talking about an entirely different risk

category of patients.

And so until we've studied--until the

sponsor has studied that population--you know,

we're going to end up potentially exposing very

large numbers of post-menopausal women to hormonal

therapy for which we really don't have any evidence

of whether it does or not increase cardiovascular

risk.

397

DR. GIUDICE: Yes, Dr. Lewis.

DR. LEWIS: Yes, I'd like to see greater

effort be made to enroll a larger population of

African-American women. They're disproportionately

affected by problems that engender hysterectomies

and oophorectomies. They're at high risk for

cardiovascular disease. And so I think it's going

to be crucial to have a much better representation

in the studies.

DR. GIUDICE: Thank you.

Dr. Hager.

DR. HAGER: Yes, and I would add Hispanics

to that. Only 3 percent of the population were

Hispanic. So I think minority groups need to be

enrolled.

And I would just add to the comments that

was previously made--and I'm dropping down a little

bit, I realize--but I think that in light of the

potential for off-label use of this product, we

must have information from pre-menopausal women,

and menopausal women. We must have information

from women who are not only taking estrogen, but

398

are also taking with the progestin.

DR. GIUDICE: Thank you.

Yes, Dr. Dorgan.

DR. DORGAN: I'm concerned about the

potential for breast cancer risk. Regrettably, in

animal models--in rodents, particularly--the

hormonal relationships like DHEA and breast cancer

are not the same as you see in humans. And so

using animal models might not suffice.

Also, we don't know the mechanism--we see

observational data that women with elevated

testosterone are at increased risk of breast

cancer, but I agree: we don't know if it's causal,

we don't even know a potential mechanism.

And so we don't have any really good

intermediate markers that we could suggest to you.

I would hate to see FDA approving it and

then using post-marketing drug surveillance as our

only way of evaluating potential risk for breast

cancer, because breast cancer doesn't occur

just--you know, it's a long process. And once that

process is started, stopping the testosterone is

399

not going to make the risk disappear like it's

disappearing for acne and some of the other adverse

effects. It's going to take a while before the

woman's risk is lower.

I'd love to see randomized, controlled

clinical trial, if people are interested in

pursuing this further. I think that's the only way

to really answer the question.

We'd prefer not to have any surprises like

we did with the WHI.

DR. GIUDICE: Thank you.

Dr. Patrick.

DR. PATRICK: We didn't discuss this in the

committee, but one of the exclusion criteria was

that there could be no ongoing personal

disturbances in the relationship of these couples.

And I would like to see that a little bit loosened;

meaning, how would this go down in normal life,

where there are few disturbances in menopausal

relationships--living through that.

[Laughter.]

DR. GIUDICE: Yes, Dr. Montgomery-Rice.

400

DR. MONTGOMERY-RICE: I do agree that many

of these things need to be studied. But I also

think you've got to put some of this in

perspective. And putting it in perspective is that

when you think about the indication for the

product, and the indication of the product would be

a symptomatic patient who has tried other ways to

improve her libido, etcetera. And so she then does

a risk-benefit analysis. And women do this every

day when they come in they're having hot flushes.

And they know that, based on the WHI, etcetera,

that there's a potential of an increased risk of

breast cancer if they take estrogen. But their

symptoms are bad enough that they're willing to

take that risk.

So I don't--even though there may be some

increased risk--which I don't believe there

probably is--with testosterone and breast cancer, I

don't think that patients would do any different of

an analysis than if they were coming in for

estrogen for hot flushes, because this--if you were

prescribing this correctly, and if we could control

401

how this was going to really be prescribed, then

here you would have an indication of something that

may actually give patients some--what are we

calling it?--clinical meaningful benefit, in a

patient who is actually symptomatic.

And so patients will make that same

risk-benefit analysis.

However, I do agree: we don't have enough

information for long-term safety.

DR. GIUDICE: Thank you. And that, then,

brings us to part c) which is:"Should these

concerns or questions be studied prior to approval

of the product?"

So we'll go around the room again,

starting with Dr. Rice.

[Pause.]

Yes or no.

DR. MONTGOMERY-RICE: I have to--I mean,

everybody else has had a preference, so I have to

give my little say beforehand.

I do think this drug is going to require

402

more study. I think that it should. However, I

also say that in light of the fact that in an

everyday sense, when I see patients who are coming

in already using therapies that have not been

tested in any type of market, etcetera, I was

hopeful that we would have a product that we would

be able to give patients that we know the risk and

the benefits. And this product does allow that

potential.

But I do, at the minimum believe that we

need to look at it in the natural menopausal

patient, who is going to have estrogen and

progesterone on board already, to understand the

concomitant hormone risk.

DR. GIUDICE: So your answer is--

DR. MONTGOMERY-RICE: Yes.

DR. GIUDICE: Thank you.

DR. STANFORD: And I will say yes, too, but

I think it's an interesting issue for FDA policy,

in a sense, a moving target in terms of what level

of study is required for a drug.

I think the WHI has changed what probably

403

should be that level. So that's why I say yes.

DR. MERRITT: I would say yes.

DR. NISSEN: Yes.

DR. PATRICK: Yes

MS. SOLONCHE: Yes.

DR. LIPSHULTZ: I want to say yes, but I

just want to add something here.

I mean, I understand there must be

tremendous pressure about this drug. I mean, it's

been expedited. It's the first drug available for

the treatment of sexual dysfunction in women. And

what concerns me the most--aside from what's been

stated--is that there's going to be tremendous

off-label use. And I just don't see how this can

go to market without the data that the company is

already--it looks like they're almost finished

with, on natural menopausal women, because they're

the ones who are going to be taking this drug, as

well.

So my answer is yes, and I'd like to see

that data. And I think it's to everybody's good to

wait a little bit.

404

DR. LEWIS: I agree. I would say yes, and

that's the data I want to see: the data in women

who have a uterus.

Is it going to be affected by adding a

progestin? Do you need a progestin? Maybe you

don't. Maybe if you get an androgen effect on the

uterus, maybe estrogen and androgen alone are

enough. But we don't know. We just need more

data.

DR. LOCKWOOD: Yes, I agree with my two

colleagues, plus I'd like to see the protein-S data

and the animal studies in pregnancy.

DR. GIUDICE: I vote yes.

DR. DICKEY: Yes.

DR. BURNETT: Yes.

DR. TULMAN: I vote yes. And also I don't

think 20, 24, 26-week data is "long-term data.

DR. HEIMAN: The time to gain these data

are before approval. So I do vote yes. I do think

we need adequate long-term data that demonstrate

both efficacy and safety. I do think we need it in

women who are on estrogen-testosterone, as well as

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estrogen-progestin-testosterone. And we need an

adequately powered study.

DR. EMERSON: Yes.

DR. DORGAN: Yes.

DR. MACONES: Yes.

DR. GIUDICE: Thank you.

The first part of--oh--what were the

results? Unanimous.

The first part of 3-c) is: "If yes,

what studies do you recommend? And please comment

on study populations, designs, endpoints, etcetera.

We have heard about increasing minority

populations. Perhaps one or two people from the

group could--I'm assuming you're asking for a study

design, and what kinds of studies to be done before

approval can be given. Is that correct?

DR. MONTGOMERY-RICE: Do we know what this

natural menopause study that they're doing--do we

know what the enrollment is on that? The one

that's currently going on?

DR. GIUDICE: Do we know more details about

it?

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DR. MONTGOMERY-RICE: Do we know more

details of that study?

DR. MONROE: Why don't we let the sponsor

give you those details.

DR. LUCAS: We have two trials. The first

trial was the one that I presented--the Natural

Menopause I. We had about 550 patients that were

randomized one-to-one.

The second trial, which is still ongoing

but nearing completion, is a two-to-one

randomization, and has just a little over 600

patients. So 400 patients will be on testosterone,

and about 100 will be on placebo, and those

patients have endometrial biopsies.

We are to just about 300 matched pairs.

So that would be 200 in testosterone, and 100 in

placebo.

DR. MONTGOMERY-RICE: Is it a year-long

study?

DR. LUCAS: Yes, it is.

DR. MONTGOMERY-RICE: Okay.

DR. GIUDICE: And is that with or without--

407

DR. LUCAS: It is being extended, like our

surgical menopause, so the patients are rolling

over into an extension.

DR. GIUDICE: And is this with or without

estrogen?

DR. LUCAS: It is with and progestin.

DR. MERRITT: And what dose of estrogen,

please?

DR. LUCAS: Like our surgical menopause

patients can use, you know, any approved estrogen

does. But it is with continuous progestin.

DR. LEWIS: They both have continuous

progestin?

DR. LUCAS: Both the Natural Menopause I,

and the Natural Menopause II--both have continuous

estrogen-progestin.

DR. GIUDICE: Yes, Dr. Nissen.

DR. NISSEN: Again, this is setting the bar

very high, but I think it's important that the

committee understand, and the FDA understand this

issue.

Post-menopausal women, you know the

408

leading cause of death is cardiovascular disease.

And even a hazard ratio of 1.1 or 1.2, when a

million or more women are likely to be exposed,

represents a huge burden of morbidity. And

therefore I believe that you need a prospective,

adequate sized, long-term study. I would do it in

aspirin-eligible women; in other words, women who

have enough risk that they would require aspirin

for prophylaxis.

Now, we can discuss Framingham Risk Scores

and all that, but I think you have to have a high

enough risk population to simulate what could

happen in the general population if this agent were

used in a widespread way.

And I'd be happy to work with you, and

I'll give you some thoughts from cardiovascular

side about how you do that. But it's not going to

be 600 patients. It's going to be 5,000 patients,

or 10,000 patients.

And I recognize how high I'm setting the

bar, but I must say this very clearly: the risk

that was seen with Vioxx was very modest. But when

409

you translated that to 105 million prescriptions in

20 million Americans, it represented an enormous

burden.

The potential for this agent to increase

the risk of cardiovascular morbidity and mortality

is substantial, and can only be answered--not the

post-market surveillance. We know how badly that

works. It has got to be done prospectively.

And I'm not devaluing the importance of

this symptom and its treatment. But I also don't

want to expose several million American women to

the risk of heart attack and stroke, with their

devastating consequences, in order to have one more

sexual experience per month increase.

It is not an acceptable trade-off, and we

cannot allow this to move forward until we have

such data.

DR. GIUDICE: Dr. Tobert.

DR. TOBERT: Well, I hear what Dr. Nissen

is saying. I think the committee needs to consider

the practicability of doing a randomized controlled

trial. I do have quite a bit of experience with

410

long-term, randomized trials to look at

cardiovascular outcomes. And I can tell you to do a

study that would rule out a 10 percent increase in

the risk of major vascular events would probably

require 100,000 patients--especially since the

patients--I mean, really, to make it possible,

you'd have to use elderly women, but elderly women,

we've heard, do not use this product very much.

I think it's simply undoable. You cannot

do this study. It's not practical--unfortunately.

DR. GIUDICE: I have a question for the

sponsor, and that is: since the use of estrogen in

post-menopausal women--and even peri-menopausal

women--is decreasing, with the largest use in the

peri-menopause, have you considered a trial with

just testosterone alone, as opposed to adding the

estrogen? Because, in reality, again, one is then

committing long-term use, if one is going to be an

outcomes-based type of prescriber.

DR. LUCAS: Yes, we are. We're just

finishing recruiting a study that's enrolled both

surgical and naturally menopausal women not on

411

concomitant estrogen or progestin. Vaginal

estrogen is allowed.

Part of the reason is to rule out any

other cause of sexual dysfunction.

DR. GIUDICE: And how large is that?

DR. LUCAS: About 750 women will be

enrolled in this study, and we're looking at two

doses of testosterone--the 150 mcg patch, and the

300 mcg--and placebo. And it will be one year in

duration.

Double-blind.

DR. GIUDICE: Thank you.

DR. TOBERT: May I just add to my previous

remarks the fact that--I mean, there is an

implication that if a huge trial like this is

demanded for a testosterone patch--testosterone, of

course, is a natural hormone that we all have. And

the implication of that is that any product--any

new product--that binds to a hormone receptor--an

agonist, an antagonist, not necessarily in the

reproductive area--the same sort of thing could be

demanded.

412

I don't quite see what is so hazardous, a

priori, about testosterone that one should demand

such huge and--as I say--in any case, impossible

trials.

DR. GIUDICE: Dr. Nissen.

DR. NISSEN: Well, those of us that are

male, in addition to suffering from alopecia, which

I fortunately have enough testosterone to have, we

have a cardiovascular risk which is substantially

greater than that of women. Why? And a lot of us

think that testosterone is an atherogenic

substance. And there's lots of evidence to suggest

that. And until proven otherwise, it must be

assumed to be the case.

And so when you have a therapy here that

you're going to, again, expose a lot of people to,

Jonathan, you have to know this. Because on a

population basis, this can involve tens of

thousands of myocardial infarctions and potentially

deaths.

So I just don't think we have the evidence

of the safety of giving women testosterone that we

413

need in order to know that we're not going to make

them have cardiovascular risk rates that look like

those rates of men.

And until we know that, I think we've got

a real problem here.

DR. TOBERT: Can I respond to that/ I mean,

there is no evidence that men have higher rates of

coronary disease because of their circulating

androgens. All attempts to correlate circulating

androgens--whether it's free or total--to the risk

of coronary or cardiovascular disease have failed.

I mean, there's just no correlation. It may have

something to do with the testosterone surge that

occurs perinatally, but certainly it doesn't have

anything to do with the levels that we have as

adults.

In any case, as I say, Steve--how are you

going to do this trial? It's undoable.

DR. NISSEN: I don't think it's undoable,

because what you're doing whenever you face a

situation like this is you go to a well-defined,

high-risk population, and you find out--if you can

414

show that the agent--what the hazard ratio is in

the higher-risk individuals, then you can feel very

comfortable in giving it to lower risk individuals.

And so you define a group of people that are at

relatively high risk: women's with lots of risk

factors. And you can have an enriched population.

And that's what's done in lipid-lowering trials all

the time. And you know, you're involved the SEARCH

trial. Those are not done in normal, low-risk

people. They're done in high-risk people.

DR. TOBERT: All right. They all have an

MI. And you can't do--the people who have an MI

are not going to be taking this patch. There's an

incompatibility.

DR. GIUDICE: Dr. Rice.

DR. MONTGOMERY-RICE: I mean, I think we

need to be realistic here. People who are at high

risk for cardiovascular disease are not people who

are concerned about--necessarily--increasing their

level of libido to the point where they would take

that risk--

DR. NISSEN: That--

415

DR. MONTGOMERY-RICE: --let me finish,

please--where they would take that risk of being

enrolled in a trial. And I don't even know how

realistic this is to get through the IRB.

So, while I hear what you're saying, that

there is some risk--or potential risk--I don't want

us to offer or suggest to the FDA that we should do

some trial that's unrealistic to ever have

performed.

If you think about participation in

clinical trials, there are major barriers getting

women to participate in clinical trials. So you're

talking about not only finding women who meet this

criteria of this defined sexual dysfunction, but

then on top of that we want you to also be at risk

for having a heart attack so we can make sure that

we are not increasing your risk of having the heart

attack.

I want us to be realistic here. And I

don't think you're being realistic.

DR. NISSEN: Let me reassure you that

patients that I see that have coronary heart

416

disease, that have had an angioplasty, by-pass, or

myocardial infarction frequently--one of the first

questions they ask when they come back in to see me

is when can they resume sexual activity. So the

idea that sex stops with heart disease is simply

wrong.

And I think we can--I'm convinced that we

could define for you a population, not of whom

would be post-MI. Some of them would be multi-risk

factor patients, where the risk would be high

enough that you could get a signal in a reasonable

size trial.

Now, where you set the hazard ratio has to

be discussed. But it seems to me that that's the

prudent thing to do.

DR. GIUDICE: Does the FDA feel that it has

had sufficient suggestions--

[Laughter.]

--for approaches to clinical trials?

And we would assume that you would be

working with the sponsor in this, as well.

DR. GRIEBEL: Yes.

417

DR. LEWIS: could I just bring up one more

little point along those lines?

I tend to agree with Dr. Montgomery-Rice

about the--you know, it's a different population.

But maybe just one small thing to throw in there:

women who have had a hysterectomy do tend to be at

somewhat higher risk for cardiovascular disease

already. So if there's any way to work within that

population, perhaps you could prove the point a

little bit easier.

Another surrogate that you could look at

is C-reactive protein levels.

DR. GIUDICE: Yes, Dr. Heiman.

DR. HEIMAN: I would just like to speak to

women's brains--and that would be since there were

some significant effects with cognitive change in

the WHI study, that at least some study along in

here tries to track that. It hasn't been raised.

There may be no risk, there may even be a benefit.

But somebody should tract that because if anything

that women are worried about--other than their

overall life and life span--it has to do with their

418

cognitive functioning.

DR. LIPSHULTZ: Didn't you have some data

on that? Wasn't there some data on cognitive

function in one of your slides?

DR. HEIMAN: Whatever there was, there

isn't enough, in my opinion.

DR. LOCKWOOD: I think it was aggression,

and anxiety of something.

DR. HEIMAN: That's not what I mean. I

mean in the dementia direction, as opposed to

simply mood. Mood is something else which is

interesting, but I'm talking about actual cognitive

functioning in terms of processing information.

DR. GIUDICE: Thank you.

Yes?

DR. HAGER: Could we also suggest that DHEA

be used as a marker, in addition to testosterone,

total and free?

DR. GIUDICE: We can suggest that. Okay.

DR. LIPSHULTZ: [Off mike.] [Inaudible.]

DR. HAGER: Well, we have heard today that

testosterone is the indicator of altered sexual

419

function in women. And when they have low

testosterone, they have low sexual function. And

that really is not true.

And I think that there's some information

that DHEA may be more tightly attached to altered

sexual function. And I'm just saying that we could

use that as a marker.

DR. GIUDICE: Okay.

3(c) part (ii) is if we had an answer of

"no" to question 3(c)--and it was unanimously

"yes"--however, I think there is the issue of the

claims-based cohort study, which we have discussed.

And I want to bring to the attention of the

committee, and ask you if we need to have any

further discussion about this?

Yes, Dr. Stanford.

DR. STANFORD: Well, I'd just say that

ideally a study would be done along the lines of

what Dr. Nissen is suggesting. I am not totally

clear on how feasible it is. And I guess that

would have to be a judgment call. But if it is

feasible, and you did that, I don't think you'd

420

need the post-marking study.

DR. GIUDICE: The claims-based study that

was proposed.

DR. STANFORD: The claims-based study--yes.

DR. GIUDICE: Yes, Dr. Emerson.

DR. EMERSON: I just felt--and I think this

is pretty much a moot point now--but I felt that

the level of detail that was provided about how

such a study would be done made it just completely

impossible to judge whether that would have been

adequate or not, because there would be a whole

lot, in terms of how you would match patients, and

whether you're getting comparable patients who were

on Intrinsa versus not. And without further

information I just don't think anything could be

said.

DR. GIUDICE: Okay. Thank you.

So we now reach our fourth and final

question, and that is: "Are the efficacy and safety

data adequate to support approval of TTS?"

And I will begin on this side of the

table.

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Dr. Macones.

DR. MACONES: No.

DR. DORGAN: No

DR. EMERSON: No.

DR. HAGER: No.

DR. TULMAN: No.

DR. BURNETT: No.

DR. DICKEY: No.

DR. GIUDICE: No.

DR. LOCKWOOD: No.

DR. LEWIS: No.

DR. LIPSHULTZ: No

MS. SOLONCHE: No.

DR. PATRICK: No.

DR. NISSEN: No.

DR. MERRITT: No.

DR. MONTGOMERY-RICE: No.

DR. GIUDICE: It's unanimous.

I want to thank the committee for their

hard work, and also our participants in the open

public forum.

And this now concludes our Advisory

422

Committee meeting. Thank you.

[Whereupon, at 4:22 p.m., the meeting was

adjourned.]

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