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DEPARTMENT OF HEALTH AND HUMAN SERVICES

FOOD AND DRUG ADMINISTRATION

CENTER FOR DRUG EVALUATION AND RESEARCH

ENDOCRINOLOGIC AND METABOLIC DRUGS

ADVISORY SUBCOMMITTEE

Wednesday, September 8, 2004

8:00 a.m.

Holiday Inn

Versailles Ballrooms

8120 Wisconsin Avenue

Bethesda, Maryland

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PARTICIPANTS

Glenn Braunstein, M.D., Acting Chair

LCDR Dornette Spell-LeSane, M.H.A.,

Executive Secretary

MEMBERS:

Lynne L. Levitsky, M.D.

Louis J. Aronne, M.D.

Katherine Flegal, Ph.D., M.P.H.

Melanie G. Coffin (Patient Representative)

Frank L. Greenway, M.D.

Jules Hirsch, M.D.

Jack A. Yanovski, M.D., Ph.D.

Susan Z. Yanovski, M.D.

Paul D. Woolf, M.D.

Thomas O. Carpenter, M.D.

Dean A. Follmann, Ph.D.

Steven W. Ryder, M.D.

David S. Schade, M.D.

Morris Schambelan, M.D.

Nelson B. Watts, M.D.

Margaret E. Wierman, M.D.

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C O N T E N T S

Call to Order and Introductions, Glenn Braunstein,

M.D., Cedars-Sinai Medical Center, UCLA School

of Medicine 4

Conflict of Interest Statement,

LCDR Dornette Spell-LeSane, Executive Secretary 6

Welcome and Introductory Comments, David Orloff,

M.D., Director, DMEDP 9

The Regulatory History of Weight-Loss Drugs,

Eric Colman, M.D., Medical Team Leader, DMEDP 14

The Epidemiology of Overweight and Obesity,

Katherine Flegal, Ph.D., Senior Research

Scientist, National Center for Health Statistics 38

Current Status of Weight-Loss Drugs, Frank

Greenway, M.D., Director, Pennington Biomedical

Research Center 71

Patterns of Weight-Loss Drug Use,

Laura A. Governale, Pharm.D., MBA, Drug

Utilization Specialist, Team Leader, Division of

Surveillance Research and Communications

Support, ODS 87

Role of Drugs in the Treatment of Obesity:

Current and Future, Richard L. Atkinson, M.D.,

Director, Obetech Obesity Research Center 106

Charge to the Committee, David Orloff, M.D.,

Director, DMEDP 150

Committee Discussion 186

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P R O C E E D I N G S

Call to Order and Introductions

DR. BRAUNSTEIN: We will call the meeting

to order. This is the Food and Drug

Administration, Center for Drug Evaluation and

Research, Endocrinologic and Metabolic Drugs

Advisory Committee meeting, on September 8, 2004.

The agenda today is to discuss the FDA draft

guidance document entitled, \"Guidance for the

Clinical Evaluation of Weight Control Drugs.\" The

original guidance was dated September 24, 1996.

I am Glenn Braunstein, Professor and

Chair, Department of Medicine, Cedars-Sinai Medical

Center. I am an endocrinologist. I would like to

go around the table and ask people to introduce

themselves and tell us where they are from. We

will start with Dr. Orloff.

DR. ORLOFF: I am David Orloff. I am

Director, Division of Metabolic and Endocrine Drugs

at FDA.

DR. COLMAN: I am Eric Colman, a medical

officer from Metabolic and Endocrine Drugs at FDA.

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DR. HIRSCH: Jules Hirsch, Rockefeller

University, New York.

DR. SCHAMBELAN: Morris Schambelan, from

the University of California, San Francisco.

DR. FOLLMANN: Dean Follmann, from NIH.

DR. YANOVSKI: Jack Yanovski, from NIH.

DR. LEVITSKY: Lynne Levitsky, Pediatric

Endocrinology Unit, Massachusetts General.

MS. COFFIN: I am Melanie Coffin, patient

representative.

LCDR SPELL-LESANE: Dornette Spell-LeSane,

executive secretary for the committee.

DR. GREENWAY: I am Frank Greenway, from

the Pennington Center.

DR. FLEGAL: I am Katherine Flegal, from

CDC\'s National Center for Health Statistics.

DR. YANOVSKI: Susan Yanovski, NIH.

DR. CARPENTER: Tom Carpenter, pediatric

endocrinology at Yale University.

DR. WIERMAN: I am Maggie Wierman,

endocrinologist at the University of Colorado.

DR. WOOLF: Paul Woolf, endocrinologist,

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Crozer Chester Medical Center.

DR. WATTS: Nelson Watts, endocrinology,

University of Cincinnati.

DR. SCHADE: Dave Schade, endocrinology,

University of New Mexico.

DR. ARONNE: Louis Aronne, New York City,

Weill Cornell Medical Center.

DR. RYDER: Steve Ryder, Pfizer Research

and Development. I am the industry representative.

DR. BRAUNSTEIN: Thank you. I will now

turn the meeting over to LCDR Dornette

Spell-LeSane.

Conflict of Interest Statement

LCDR SPELL-LESANE: Good morning. The

following announcement addresses the issue of

conflict of interest with respect to this meeting

and is made a part of the record to preclude even

the appearance of such at this meeting.

Based on the agenda, it has been

determined that the topic of today\'s meeting is an

issue of broad applicability, and there are no

products being approved at this meeting. Unlike

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issues before a committee in which a particular

product is discussed, issues of broader

applicability involve many industrial sponsors and

academic institutions.

All special government employees have been

screened for their financial interests as they may

apply to the general topic at hand. To determine

if any conflict of interest existed, the agency has

reviewed the agenda and all relevant financial

interests reported by the meeting participants.

The Food and Drug Administration has granted

general matters waivers to the special government

employees participating in this meeting who require

a waiver under Title 18, United States Code,

Section 208.

A copy of the waiver statements may be

obtained by submitting a written request to the

agency\'s Freedom of Information Office, Room 12A-30

of the Parklawn Building.

Because general topics impact so many

entities, it is not practical to recite all

potential conflicts of interest as they apply to

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each member, consultant and guest speaker.

FDA acknowledges that there may be

potential conflicts of interest but, because of the

general nature of the discussion before the

committee, these potential conflicts are mitigated.

With respect to FDA\'s invited industry

representative, we would like to disclose that Dr.

Steven Ryder is participating in this meeting as a

non-voting industry representative, acting on

behalf of regulated industry. Dr. Ryder is

employed by Pfizer Global Research and Development

as senior vice president and global

cardiovascular/metabolism/GI/GU development head.

And, although Pfizer conducts research in

therapeutic areas possibly covered by today\'s

discussion, Dr. Ryder\'s role on this committee is

to represent industry interests in general and not

any one particular company.

In the event that the discussions involve

any other products or firms not already on the

agenda for which FDA participants have a financial

interest, the participant\'s involvement and their

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exclusion will be noted for the record.

With respect to all other participants, we

ask in the interest of fairness, that they address

any current or previous financial involvement with

any firm whose product they may wish to comment

upon. Thank you.

DR. BRAUNSTEIN: Thank you. Dr. David

Orloff with give the welcome and introductory

comments.

Welcome and Introductory Comments

DR. ORLOFF: Good morning. The first

thing I want to say actually before I get to the

introductory comments is that I believe, Dornette,

if I am not mistaken, we do not have any speakers

for the open public hearing. Is that correct?

LCDR SPELL-LESANE: That is correct.

DR. ORLOFF: As a result of that, time

permitting, we may try to push Dr. Atkinson\'s talk

up to the morning before we break for lunch. I

leave that up to Dr. Braunstein and to the clock.

I want to wish everyone a good morning and

welcome our advisors, our guest consultants, FDA

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staff and interested public.

The purpose of today\'s meeting of the

Metabolic and Endocrine Advisory Committee is to

revisit the division\'s 1996 draft guidance on the

development of drugs for the treatment of obesity.

As everyone present knows, the FDA\'s public health

mission includes the charge to assure that safe and

effective drugs are efficiently, but without

cutting crucial corners, brought forward through

development to the marketplace in order to

diagnose, cure, treat, prevent or mitigate disease.

That, broadly speaking, explains our purpose here

today.

More specifically, in August of 2003 the

then Commissioner McClellan established the FDA

obesity working group and asked that group to

develop a plan of action to address critical

aspects of the burgeoning obesity problem in the

U.S. within the authorities of the Food and Drug

Administration.

Germane to our work here today, he charged

the so-called therapeutic subgroup, which was led

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by our division, to assess real or perceived

barriers to obesity drug development and to make

recommendations on ways to encourage the

development of new or enhanced therapeutics for

obesity.

In the face of this growing public health

problem, advances in the understanding of the

physiology and pathophysiology of obesity and the

activity within the pharmaceutical industry in this

therapeutic area, we took the opportunity to plan a

discussion of the current guidance and its

potential modification. Today\'s meeting is further

timely in light of the recent release by NIH,

announced on August 24th, of the final version of

its own strategic plan for obesity research which

includes intensification of efforts on

pharmacologic approaches to the prevention and

treatment of obesity in both children and adults.

In early 2004 we published a formal call

for comments on the guidance in the Federal

Register, with an open comment period until late

April. Today, with the help of our advisors and

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consultants, we will review what we consider to be

the salient issues raised in the comments we

received, as well as others that we believe are

critical to ensuring that FDA\'s evidentiary

standards for safety and efficacy of obesity drugs

are, to the extent possible, in line with the

science of the day.

We look forward to the formal

presentations and what we trust will be a fruitful

discussion to follow. I should make clear, as I

believe is apparent from the agenda, that this

meeting is not intended to discuss any specific

drug products, approved or in development.

Furthermore, in a manner distinct from a meeting of

that type, we will not ask the committee and guests

to vote per se on the questions we will pose.

These are intended to raise the issues that we wish

to hear discussed. We, the FDA staff, will listen

and contribute as we see fit and, of course,

respond to questions directed at us as we are able.

We intend to take the information we have gleaned

today back for consideration in drafting possible

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revisions to our guidance for industry.

It is important for those participating

and listening today to understand that by this

meeting we make no formal commitment to changes in

the guidance. We view this as an information

gathering step in a process that may lead to

changes. I know you all have the agenda and I will

not review it. I have already announced the

potential changes.

Finally, before we start, I would like to

thank Dr. Lynne Levitsky, valued advisor

particularly on pediatric matters whose term has

recently expired, for service to us over the last

term. She is here today formally speaking as a

consultant. By her agreement to stay on in that

capacity, we hope to continue to engage her in the

future and look forward to her additional input

into the work of the division and the agency.

Finally, special recognition goes to Dr.

Glenn Braunstein who has kindly agreed to serve as

the chair of today\'s meeting. Dr. Braunstein\'s

second term as a member expired in June, and having

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him here today is particularly fitting given that

he chaired the 1995 meeting that led to the

drafting of the \'96 guidance under discussion.

Glenn\'s association with the committee and the

division dates to late 1991, including two stints

as an extremely effective chair. We thank him once

again for his invaluable service. Indeed, we are

not releasing him. He too has agreed to remain a

consultant. Glenn, thank you for your generosity

with your precious time and for your contributions

over many years to this committee, to the division

and to the work of the agency. With that, I will

turn it over to you.

DR. BRAUNSTEIN: Thank you, David. I

appreciate that. The first speaker this morning as

far as presentations are concerned is Dr. Eric

Colman, who is medical team leader, and he is going

to speak about the regulatory history of weight

loss drugs.

The Regulatory History of Weight-Loss Drugs

DR. COLMAN: What I plan to do for the

next 20 minutes or so is to give you an overview of

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the FDA regulation of obesity drugs from roughly

the years 1938 through 1999. Before I get to that,

I did want to mention two milestones in the history

of drug regulatory.

These were, first, the signature in 1906

of the original Food and Drugs Act and that was

signed by President Teddy Roosevelt. Roughly

30-plus years later another Roosevelt, Franklin,

signed the Food, Drug and Cosmetic Act of 1938.

This Act has quite an influence on drug regulation.

It affected the labeling provisions, the

advertising provisions for drugs, and it was also

the first time that drug companies had to submit

evidence of a drug\'s safety before it was allowed

to go onto the market. It also marked the

beginning of the new drug application, or NDA,

process that we have all come to appreciate over

the years.

Getting started with the obesity drugs, in

1938 Myerson and colleagues reported the paper in

The New England Journal of Medicine, \"Benzedrine

sulfate as an aid in the treatment of obesity.\"

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These two colleagues treated roughly 17 obese

patients with 30 mg of amphetamine sulfate, which

is what Benzedrine is. They reported that the

patients lost anywhere from 9-54 lbs. This was

just one of a number of studies that started to

appear in the medical literature that suggested

that amphetamines may be an effective way to treat

obesity.

The following year, in 1939, the agency

approved Benzedrine for a host of different

indications, however, obesity was not one of them.

Several years later the agency approved another

amphetamine. This one was desoxyephedrine. Again,

there was a list of indications\--narcolepsy, mild

depression, alcoholism, even hay fever at one

point, but again obesity was not in the list.

Now, it took four more years before the

agency finally felt comfortable and granted an

obesity indication for desoxyephedrine. To the

best of my knowledge, this was the first drug that

the agency approved for the treatment of obesity.

I have shown you here some of the language

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from the labeling at that time to give you a flavor

of what people were thinking. For this drug the

labeling stated that the sympathomimetic amines

have been found of value, when administered under

the supervision of a physician, as an adjunct to

the dietary management of obesity. That was the

indication section.

The labeling also warned, however, against

its use in persons with cardiovascular disease,

hypertension or insomnia, and in those who were

neurotic or hyperexcitable. So, clearly, there was

an awareness that these drugs were stimulatory to

the central nervous system, to the cardiovascular

system.

On this last point regarding the

amphetamines I want to just highlight\--this is just

to remind you that I will be talking a lot about

amphetamines and I will be talking about

amphetamine-like drugs in a moment. But when I

refer to the amphetamines I am including a large

number of compounds which include amphetamine

sulfate, desoxyephedrine, also referred to as

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methamphetamine, dextroamphetamine and a number of

amphetamine-barbiturate combinations.

Soon after the amphetamines were approved

in the \'40s and early \'50s companies began to work

to try to develop compounds that, on the one hand,

maintained the anorectic properties of the

amphetamines but had less of the stimulatory

properties. They were successful to varying

degrees.

By 1960 the agency had approved five new

what I refer to as amphetamine-like drugs. These

are also referred to as the amphetamine cogeners.

These drugs were phenmetrazine, phendimetrazine,

phentermine, benzphetamine and diethylpropion.

Again to give you a sense of what people

were thinking during this time, I have shown you

some of the language from the labeling for

diethylpropion. This drug was indicated for any

obese patient, including the adolescent, the

geriatric and the gravid, as well as the special

high-risk situations of the cardiac, hypertensive

and diabetic patient. That is probably an

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indication section that most drug companies would

die for at this point.

The labeling also stated that because

tolerance, habituation or addiction did not

develop, this drug was ideal for long-term use.

Again, it is interesting to look at the labeling

language from back in the late \'50s.

Against the backdrop of the approval of

the amphetamines and amphetamine-like drugs, there

was a problem growing in this country and some

people were referring to it as an epidemic. That

was an epidemic of the abuse of amphetamines.

I have shown three figures here to give

you a sense of the amount of use of these

compounds. In 1958 there were approximately 3.5

billion tablets of amphetamines manufactured

legally in this country. Approximately a decade

later that had more than doubled to 8 billion

tablets. Expressed another way, in 1967 there were

approximately 23 million prescriptions for

amphetamines, 80 percent were for women and of all

the indications, these drugs were most commonly

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prescribed for obesity.

The government tried to intervene to slow

or stop the spread of this abuse by passing two

laws, one was the Drug Abuse Control Amendments, in

1965\. The second was the Controlled Substances Act

of 1970. This is when the scheduling of drugs was

introduced.

Moving from 1970 back to the early \'60s,

in 1962 there was a very important addition made to

the \'38 Food, Drug and Cosmetic Act. These were

the Kefauver-Harris Amendments, also known as the

Drug Efficacy Amendments. This legislation for the

first time mandated that new drug applications

contain substantial evidence of a dug\'s

effectiveness.

You recall, I mentioned that in \'38 the

law said you had to have evidence of safety. This

law now said you had to have evidence of efficacy.

So the loop had now been closed. And, this

effectiveness was to come from adequate and

well-controlled investigations.

This raised a problem however. This

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legislation took care of drugs approved in \'62

forward but there were literally thousands of drugs

that were approved between \'38 and \'62. The

question came up what do we do about the efficacy

assessment of these drugs approved before 1962?

The answer came when the Commissioner called upon

the National Research Council of the National

Academy of Sciences to take this task on. This

endeavor became known as the Drug Efficacy Study

Implementation, or the DESI review process.

The formal portion of the Drug Efficacy

Study was conducted between 1966 and 1969. There

were a host of different drug panels, depending on

expertise, and it was the psychiatric drug panel

that was charged with reviewing the available data

on the efficacy of the amphetamines and

amphetamine-like drugs. They were told after they

completed their analyses of the available data that

they should classify the efficacy using one of

these five descriptors, starting at the top with

effective; effective but; probably effective;

possibly effective; or ineffective.

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They completed their analyses in 1969 and

sent the results outcome the FDA Commissioner, and

this is what they concluded. They felt the

efficacy data supported a statement saying that the

amphetamines were possibly effective for the

treatment of obesity.

Regarding the amphetamine-like drugs, a

little bit better\--they thought that this was

effective but\... so, again, one step below

effective. The reasons they cited for not

classifying these compounds as effective were the

following: Many of the studies that they looked at

were of short duration. There was no evidence

available that the drugs altered the natural

history of obesity. There was some evidence that

the anorectic effects may have been strongly

influenced by the suggestibility of the patient.

And, there were concerns about the adequacy of the

controls in some of the clinical studies.

What were the regulatory consequences of

DESI review of the obesity drugs? In 1970 the FDA

concluded that the amphetamines were, indeed,

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possibly effective in the treatment of obesity, and

basically mimicked what the DESI review panel

recommended. However, because this was short of

the category of effective, the FDA directed

industry to submit evidence of weight-loss efficacy

from adequate and well-controlled trials and,

ideally, of more than a few weeks duration. I

would point out here that at this time the FDA made

no comment about the efficacy of the

amphetamine-like drugs. That wouldn\'t come for a

few more years.

After the DESI review process was finished

in \'69, in the early 1970s the Division of

Neuropharmacology Drug Products at the agency\--that

was a division that had the regulatory purview of

these agents\--clearly felt the need to develop a

policy whereby they could develop and regulate

obesity drugs. So, flowing from the DESI review

process, three important actions occurred in the

early \'70s. These were the Prout Consultant Group,

the Neuropharmacology Drugs Advisory Committee, and

the conduct of the Amphetamine-Anorectic Drug

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Project. Let me go through each one of those

briefly.

The Prout Consultant Group was put

together by folks in the Neuropharmacology Drug

Division at the FDA. It consisted of eight

external consultants and was headed by a physician

named Thaddeus Prout who was an endocrinologist

from Johns Hopkins. This group of eight

individuals met in April of 1071 to discuss

specific issues related to obesity drugs and

regulation and development of these compounds.

They issued these four statements back to

the Neuropharmacology Division: They felt that, in

fact, weight-loss drugs did have some potential

value. They felt that the efficacy trials for

these drugs should be at least 12 weeks in

duration; that the long-term follow-up of patients

was not the responsibility of drug companies; and

that the efficacy of the weight-loss drugs should

be defined as statistical superiority of drug to

placebo. This is an interesting point. This group

was specifically asked to define clinically

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significant weight loss. Either they could not do

it or they did not want to do it but, in any event,

they said you should consider this as efficacy. In

other words, if the weight loss on a drug is more

than the weight on the placebo and the difference

is statistically significant, then you have a drug

that works .

About five months after the Prout Group

met and made their recommendations, the

Neuropharmacology Drug Division convened its own

advisory committee, in September of \'71, and again

they wanted to get input about how to develop and

regulate the obesity drugs. They were also asked

to provide a definition of clinically significant

weight loss. They did not venture an answer.

Instead, they referred back to Prout\'s

recommendation that efficacy be defined as

statistical superiority of drug to placebo. This

was another group that could not define clinically

significant weight loss.

So, after two groups deliberated on this

the agency still had no working definition of

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clinically significant weight loss. The

Amphetamine-Anorectic Drug Project somewhat

approached this problem in a backward direction.

This was a meta-analysis conducted by members of

the Neuropharmacology Drug Division, along with

agency statisticians. The overall goal was to try

to, once and for all, quantitate the efficacy of

the amphetamine and the amphetamine-like drugs. At

this point there were data available for

fenfluramine and sanorex.

This meta-analysis was quite large. It

included 200 clinical studies. These studies

ranged in duration from one month to six months. I

would say that the average study was six to 8 weeks

in duration. There were about 10,000 patients

involved in the whole analysis. At the end of the

day, when they got done analyzing these data, they

issued two conclusions. The first one doesn\'t

sound very impressive but this is what they said:

Patients treated with active medication did, in

fact, lose some fraction of a pound a week more

than those on placebo. The second conclusion was

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that the data did not suggest that one drug was

superior to another, nor that the amphetamines as a

class were more effective than the amphetamine-like

drugs. This would have major implications, as we

will see in a few minutes.

What were the consequences of this

meta-analysis? In 1973 the agency officially

declared that the amphetamines and the

amphetamine-like drugs were effective for the

treatment of obesity. You will recall that in 1970

they said amphetamines were possibly effective and

they didn\'t say anything about the amphetamine-like

drugs. So, from doing this meta-analysis, they

felt comfortable in declaring that these two sets

of compounds were both effective for the treatment

of obesity.

The second thing that came out of this

project was class labeling. I mentioned the abuse

problem, the speed epidemic that had continued

through the \'60s and into the \'70s. So, the abuse

of the amphetamines was still very much on the

minds of the senior leadership at the FDA. So,

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people started to reason, well, if you limit the

use of these drugs just for a few weeks you can\'t

get abuse. So, if we limit their use to only a few

weeks we take care of the abuse problem and that

way we tidy up the risk/benefit profile for these

drugs. So, they made a blanket case and not only

were the amphetamines indicated for short term and

a few weeks actually shows up in the label. People

have often referred to this as a few months but the

label actually says a few weeks.

Instead of just limiting it to the

amphetamines, they threw it over to the

amphetamine-like-like drugs as well so at this

point all these drugs became indicated only for

short-term use, a few weeks use, and I would submit

that was largely driven by concerns about abuse,

street abuse.

The next notable event in this history

came in 1979 when the agency announced its plans to

remove the obesity indication from the

amphetamines. They still hadn\'t had enough; they

wanted more. They felt that they had good reason

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to propose this removal. One of the things that

backed them up, they believed, is that there was

continued evidence of abuse of amphetamines. They

knew it was largely coming from this database

referred to as DAWN, which stands for the Drug

Abuse Warning Network.

The other point has to do with, as I just

mentioned, the risk/benefit profile of the

amphetamines relative to the amphetamine-like

drugs. The FDA had clearly said that they don\'t

think the efficacy is any different for the

amphetamines than the amphetamine-like drugs but we

do believe that the abuse potential was more of a

problem for the amphetamines than the

amphetamine-like drugs. Therefore, amphetamines

have a less favorable risk/benefit profile versus

the amphetamine-like drugs. If you took the

obesity indication away from the amphetamines

people in this country would not suffer at all;

they had have the amphetamine-like drugs that

worked just as well.

The industry had a chance to respond to

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this proposal and they did so. I have listed four

of their rebuttals here. For one thing, industry

felt that the FDA analyses of the DAWN data were

incorrect. They just didn\'t believe that there was

evidence of continued abuse.

Secondly, they argued that if illicit

production and use of the amphetamines was a real

problem, that was the purview of the state medical

boards and the Department of Justice; it wasn\'t

something the FDA should get involved in.

Thirdly, they said, wait a minute, abuse

requires use beyond a few weeks and our drugs are

only approved for a few weeks. So, if this is a

problem we are talking about off-label drug use

and, once again, that is not something the FDA gets

involved in.

Finally, the risk/benefit issue\--they felt

that the risk/benefit equation should be made on

its own merits, in other words, relative to

placebo. In this case, the agency was saying that

the risk/benefit profile of the amphetamines was

less favorable than the risk/benefit profile for

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the amphetamine-like drugs. According to industry,

they didn\'t think that was a legitimate or legal or

regulatorily tenable reason to take away the

indication.

I have to say that after all this

bickering the industry won out because this planned

action never took place. The agency never removed

the obesity indication from the amphetamines and,

to this day, I know of one amphetamine that still

has in its label its use for short-term treatment

of obesity.

We now enter the 1980s, and I think the

1980s in terms of obesity drug development really

should focus on one particular happening, and that

was the start of the phen-fen studies. In the

early 1980s, a clinical pharmacologist from the

University of Rochester reasoned that the stimulant

effects of phentermine would counter the sedative

effects of fenfluramine such that the two together

would provide a very tolerable combination that

could be used over long-term use. So, he and his

colleagues started these studies in the \'80s.

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In 1992 they published a number of papers

citing the main results of these trials. They

concluded that yes, indeed, the combination was

tolerable and that people could take these drugs

over the course of years, and that it was safe and

effective.

Again, these were published in 1992. They

had a major impact on subsequent use of these

drugs, as I have shown here, in this table. These

are the estimated total number of prescriptions for

phentermine in 1992, 2 million. For fenfluarmine

there were about 70,000 prescriptions in

1992\--again, the year the papers were published.

Four years later these numbers had gone from 2

million to 11 million and from 69,000 to 7 million.

I am not saying all of this was due to these papers

but a large part of it was.

There was another event that happened

around 1992, and that was the transfer of the

regulatory responsibility of the obesity drugs from

neuropharmacology to the Division of Metabolic and

Endocrine Drugs, where they are now. When the new

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drugs arrived in the new division there was fairly

strong feeling that effective drug treatment

required long-term or indefinite treatment.

Therefore, why don\'t we have long-term pre-approval

trials? There were other thoughts within the

division. There was a strong sense that we need to

get this formulated into a guidance policy. They

convened their advisory committee in a two-day

meeting in 1995 to discuss how to develop and

regulate obesity drugs, with an eye to issuing an

obesity guidance document.

They had a successful meeting. The

obesity draft guidance was issue in 1996. I just

show you two of the more important components of

that guidance document, and these will be issues

that we will be discussing later today.

In terms of efficacy, a 5 percent

benchmark was chosen. At that time, people could

point to the fact that if people lose as little as

5 percent of weight they could get improvements in

lipids, blood pressure and cholesterol and,

therefore, this was a clinically significant weight

34

loss. So, now we finally have a definition for

clinically significant weight loss.

On the other side, in terms of the size

and duration of phase 3 trials, I think most people

felt comfortable that we had agreed that one year

of a placebo-controlled trial would be an adequate

exposure to assess efficacy and some degree of

safety. A lot of people felt though that of these

1500 patients who made it out to a year, 200-500

should be rolled over into an open-label exposure

for a following year, again, to get another sense

of safety. We will be talking about these issues

as well later today.

Just briefly, long-term treatment of

obesity, from FDA\'s perspective, came about when

dexfenfluramine was approved in 1996. We all know

it was removed from the market the following year

because of valvulopathy. A couple of months after

the removal, sibutramine, or Meridia, was approved.

I have shown you here the actual labeling for the

indication. Meridia is indicated for weight loss

and weight maintenance. Xenical, the most recently

35

approved drug, in 1999, has the same indications,

weight loss and weight maintenance, but it also has

an additional indication and that is to reduce the

risk for weight regain after prior weight loss.

These are issues that we hope committee members

will engage in a dialogue later this afternoon in

terms of what these terms mean; how they should be

defined, etc.

So, if I could provide you with a global

summary, I think it is safe to say that defining or

quantitating the efficacy of weight-loss drugs has

been problematic. It certainly has been a

challenge from a regulatory perspective. It wasn\'t

until the mid-1990s that we had a workable

definition of clinically significant weight loss,

and that is the 5 percent benchmark. We still

don\'t have a definition of clinically significant

drug-induced weight loss\--that is a different

issue.

On the other side of the coin, I also

think it is safe to say that the regulatory history

of the obesity drugs has seen its share of highly

36

publicized safety problems. Beginning with the

abuse of the amphetamines in the \'40s, \'50s, \'60s

and beyond, primary hypertension became an issue

with a drug called aminorex that was used in Europe

in the \'60s. It was never in this country.

But this condition was subsequently linked

to fenfluramine and it was a major issue at the

time that dexfenfluramine was approved. It was

well-known that this drug increased the risk of BPH

in people who took dexfenfluramine. That was

before dexfenfluramine was approved. These

concerns were only later overshadowed by the

cardiac valvulopathy that showed up a year after

their approval. These were all very, very highly

publicized events, basically so many in the

population were exposed to these drugs.

Finally, the approval of Meridia or

sibutramine, back in \'97, was accompanied by very

strong warnings, precautions and concerns regarding

the effect of that drug on blood pressure and

pulse.

Let me close. Since the topic of today\'s

37

discussion is the obesity guidance document, I

thought I would just provide a visual reminder of

the goals of not only this guidance document but I

think of all guidance documents, and that is

obviously, on the one hand, to facilitate

industry\'s development of safe and effective drugs

but, just as importantly, to provide regulators

with the best available evidence upon which to

judge a new drug\'s risk/benefit profile before the

drug is approved. Obviously, those two things

require a certain amount of compromise and juggling

but I will leave you today with that thought. Keep

that in the back of your mind as we deliberate the

various proposals to change the guidance document.

Thank you.

DR. BRAUNSTEIN: Thank you, Dr. Colman.

Are there any questions from the panel for Dr.

Colman?

\[No response\]

Thank you. We will move on then to Dr.

Katherine Flegal\'s discussion of the epidemiology

of overweight and obesity.

38

The Epidemiology of Overweight and Obesity

DR. FLEGAL: This is the outline. I am

going to give a very brief overview of trends in

obesity and overweight in the United State,; a

history of regulation of weight-loss drugs, a brief

history of definitions of overweight; some

population estimates; prevalence of overweight

categories and comorbidities; and kind of a brief

discussion of some of the aspects of possible

benefits and risks of weight change in mildly

overweight people with comorbid conditions.

Most of the data I am going to present

today come from the series of National Health and

Nutrition examination surveys in the U.S., NHANES.

Many of you are familiar with this but I know some

of you aren\'t. These are a series of

cross-sectional national representative surveys,

conducted by CDC\'s National Center for Health

Statistics, in which weight and height are measured

and many other actual measurements are taken. We

have a series of these dating back to the 1960s up

until today. So, we have a little over 40 years of

39

data on the U.S. population from these surveys.

The most recent one began in 1999 and is

continuous, representing some data from 1999 up to

2002 in that survey.

This slide shows the age-adjusted trends

in obesity, defined as a body mass index of 30 or

above in the United States. Starting back in 1960,

the prevalence was only about 10 percent for men

and today it has gone up to almost 30 percent. As

you see, the prevalence was really fairly constant

from 1960. In \'71 to \'74 and \'76 to \'80 there were

not large changes for either men or women. In the

\'89 to \'94 survey the prevalence went up sharply

and somewhat unexpectedly, and in the most recent

survey it has gone up again so we see this

continuing trend.

This is the same setup. This is for

overweight defined as a body mass index of 25 or

above so it includes the obesity data I just showed

you. Again, the prevalence was relatively stable

over the first three surveys and then increased.

One thing to note is that the prevalence of

40

overweight with these definitions has been pretty

high since 1960. Almost 50 percent of men and 40

percent of women were overweight in 1960 according

to this definition.

As you have just seen, the definitions of

overweight and obesity that I am using are based on

body mass index which is calculated as weight in

kilograms divided by height in meters squared.

There are two definitions of overweight in this

system. One is a body mass index of 25 up to 29.9

or a body mass index of 25 or above. Obesity is

then defined as a body mass index of 30 or above

and a healthy weight as a BMI of 18.5 but less than

25\.

These definitions have been a long time

getting systematized and standardized. This is a

very brief overview, but basically definitions of

overweight up to the early \'80s really were not

systematized and there were very wide international

variations. In the United States there was a lot

of use of weight-height tables like the insurance

company tables that you have probably seen. There

41

is a whole set of issues of skinfolds measurements,

different kinds of prediction equations; a lot of

different kinds of weight-height indices. There is

the Broca index, ponderal index. You can see these

used in different literature and they are used in

different metric systems as well so you never knew

whether it would be kilograms and meters or

centimeters or pounds and inches. So, if you look

at the literature back in the \'70s, say, and before

it is very difficult to make any comparisons.

There are a lot of different definitions that were

being used and there were a lot of differences

between countries as well.

I think during the 1980s epidemiologic

consensus began to form around body mass index,

which is also called Quetelet index after the great

Belgian statistician in the 19th century. So, you

can see that this index has been around for a long

time and has been used somewhat, but it began to be

really more the index of choice. An NIH consensus

conference in 1985 recommended the use of body mass

index. But at that point the cut-off values still

42

were somewhat varied.

The 1959 Metropolitan Life tables in the

U.S. had a range of desirable weights for a given

height. There was a practice that had grown up of

taking the midpoint of that range as kind of the

ideal weight and then saying if you are at or about

120 percent of that midpoint, then that was the

beginning of the definition of overweight of the

median frame weight range.

At the NIH consensus conference, in \'85,

there was data presented from NHANES, as I have

already shown you, about the 85th percentile values

for men and women age 20 to 29. Those were a value

of 27.8 for men, 27.3 for women. The consensus

conference decided to adopt those as some kind of

definition of overweight because they actually

correspond pretty closely to the Met Life, to the

120 percent definition based on Met Life. We, in

fact, used these values as recently as 10 years

ago. We would have been publishing data using

those particular cut-off points.

Meanwhile, BMI cut-points of 25 and 30

43

began to be recommended by expert committees.

These were not suggested originally by these expert

committees. I think the earliest suggestions I am

aware of were by George Bray and George Garrow,

back around 1980 probably or perhaps before. But

these were thought to be more systematized. There

was a 1995 report from an expert committee of the

World Health Organization that suggested these

cut-off points. That was followed in 1998 by the

Clinical Guidelines on the Identification,

Evaluation and Treatment of Overweight and Obesity

in Adults that NHLBI put out, which is really more

or less the basis for our current use of these

values.

Why these values? Here is what it says in

the 1995 expert committee report that they proposed

a classification with cut-off points of 25, 30 and

40\. This is based principally on the association

between BMI and mortality.

They go on to say the method used to

establish these kind of points has been largely

arbitrary. In essence, it has been based on visual

44

inspection of the relationship between BMI and

mortality: the cut-off of 30 is based on the point

of flexion of the curve.

So, in this report and in others there is

not a careful study of the criteria for using

exactly 25 or 30 as opposed to, say, using 30.5 or

27.8. These are kind of general and, as I say,

largely arbitrary. Here is kind of a typical

relation between mortality and BMI curve that would

have been available to that committee. This is

from the American Cancer Society studies.

You see a couple of things here. First of

all, the point of lowest mortality tends to hover

around a BMI of 25. You see this curvolinear,

somewhat U-shaped relationship with much higher

risk out here. Also, body mass index is not a

physiologic measure; it is just an index and you

can kind of intuit that the choice of cut points of

20, 25, 30, 35 and 40 are because these are round

numbers and they vary by 5. These are not really

physiologically based cut points. So, these are

approximations. They are very useful

45

approximations, by the way. We are very glad to

have internationally standardized definitions that

we can all use. Now you can compare one person\'s

data with another person\'s data so these are quite

valuable to have.

The 1998 NHLBI clinical guidelines also

offer the same definitions. Here overweight is 25

to 29.9 and they say the rationale was based on

epidemiological data that show increases in

mortality with BMIs above 25. This increase tends

to be modest until a BMI of 30 is reached. So, you

see that this language also is somewhat imprecise.

I think this is on the following page.

They describe quite a few studies. Very often the

point of minimum mortality is around a BMI of 25.

This is a study of NHANES I where they show the

lowest mortality in the range of 25-30, and they

found, by race and sex, the lowest mortality at

24.5 for white men, 26.5 for white women, and even

higher values for black men and women. There is

other information presented in the same NHLBI

report which also has somewhat similar analyses.

46

So, definitions of overweight have changed

quite a bit over time. We have pretty much settled

down now to using these standard definitions but

that is a little bit of the history.

Getting back to definitions, overweight is

a BMI of 25-29.9. These are slides like the ones I

showed you but now these are really just that

range. There are two things you can see from this.

One is that the prevalence of overweight by these

definitions has really changed very little over

time. It is almost constant. Another thing you

can see is that the prevalence of overweight by

these definitions is quite a bit higher in men than

it is in women, which is less true of the

prevalence of obesity. It is about 38-40 percent

for men and about 25 percent for women.

Just looking at the numbers of people, and

I am going to try to divide this by separate

categories. One is BMI to under 27 and 27 up to 30

because that is one of the cut points used in the

current guidance document. This is just to show

you the number of people in the U.S. population who

47

fall into these various categories. I also

included the next lowest category as kind of a

comparison point. In this lowest category of 23 to

less than 25 the numbers of men and women are

approximately equal, about 14 million in each. In

the range of 25 to under 27 there are a few more

men than women. There are about 16 million men and

12 million women. As you go up to the range of 27

to 30 there are more people in this category, which

is actually a broader category, of course, also.

There are 21 million men and about 17 million

women.

Looking at that by age as well, I have

divided this into 4 age groups, 29-29, 40-59, 60-79

and 80 and above. You can see that for a BMI of 25

to 27, men and women both in that BMI range are in

the age groups 20 up to 59. When you get to the

60-79 year-old age range there are fewer people but

you see that in the younger ranges there are more

men than women in these categories. When you get

up to this age range there are actually almost

equal numbers of men and women in the older ages.

48

The same is true for the next category of a BMI of

27-30. So, there is a definite age pattern with

these numbers.

Now I am going to talk about

comorbidities. There are five listed plus \"other\"

in the guidance document: hypertension,

hyperlipidemia, glucose intolerance, cardiovascular

disease, sleep apnea and other obesity-related

conditions. I don\'t really have good data to show

you on cardiovascular disease or on sleep apnea or

the other conditions so I am just going to talk

about these three from what we have, hypertension,

high cholesterol and glucose intolerance.

One thing I was asked to do is to consider

the question of the point of inflection of the

curve of the relationship of these comorbidities to

BMI. So, I have presented the data this way and I

have a whole series of slides, all laid out the

same way.

The yellow line is men\--this is for men,

20-39; the green line, 40-59; the pink line, 60-79;

and then 80 and above. This shows the body mass

49

index categories along this axis and the

prevalence. There are a couple of things you can

see from this. First of all, you don\'t see a very

clear point of inflection, for example, between

23-25, 25-27. Here you see a little increase but

in this case it was a decrease here and an increase

there so these bounce around somewhat. So, you see

a gradual increase in the prevalence of these

conditions with the BMI level in all age groups.

You don\'t visually see an obvious point of

inflection.

The other thing to notice is that although

we talk about these as obesity-related

comorbidities, this shows you pretty clearly that

they are also age-related comorbidities and, in

fact, the prevalence of any of these conditions in

people with a BMI of 30 who are young is far, far

lower than the prevalence even in people at the

lowest BMI level who are older. So, you need to

keep that in mind. Again, there are other risk

factors for these conditions and age, in

particular, is a very strong risk factor.

50

This is the same picture now for women.

Again, you see at the old age range a very high

prevalence of hypertension at all BMI levels. You

see in most age groups a slight increase in the

prevalence by BMI level and you don\'t see a strong

inflection point. By the way, I defined

hypertension as a measure of blood pressure

systolic over 140 or diastolic over 90, or using

medications for hypertension.

This is for high cholesterol, which I

defined for this purpose as total cholesterol of

above 240 mg/dl or using medication. Here you see

a somewhat similar picture. The prevalence is not

as high even in the oldest age group and our data

are somewhat sparse in the older age group. It may

be one of the reasons this curve is not estimated

that well. Again, you see some tendency for

increase in cholesterol with BMI, also a tendency

to increase with age\--not a terribly clear

inflection point.

Here is the same information for women.

Again, sort of the same comments would apply.

51

Finally diabetes\--this is just based on

diagnosed diabetes and this is self-report of

diagnosed diabetes so this is not based on

measurements of glucose tolerance or looking at

undiagnosed diabetes. This is people who say that

they have been told that they have diabetes. I

also excluded people who had age at onset below 30

and have used insulin since diagnosis,

approximately since diagnosis, to try to limit this

proximally to type 2 diabetes. Again you see the

increase with BMI. You see the age differential

and you, again, don\'t really see a strong

inflection point. The same thing for women.

This is just the prevalence of any

comorbidity. I should say any selected comorbidity

because I am only looking at three. This is by age

and body mass index group for men. This has

somewhat smoothed out the lines because there are

more comorbidities involved. Again, there is this

big age differential\--you know, fairly smooth

curves; they go up and down some but there is no

obvious inflection point between 25-27 and 27-30 or

52

23-25.

This is the same diagram for women.

Again, big age differences; increasing prevalence

of comorbidity with BMI group; fairly smooth lines.

So, how many millions of people are we

talking about? I will show you some other data but

this is when people have 2 or more comorbidities by

BMI categories. For comparison purposes, I put a

lot of BMI levels in here. In this range, which is

the range of interest for this purpose I think,

there are roughly speaking about 4 million people

in the U.S. who have a BMI at that level and have 2

or more comorbidities. That is in contrast to

about 6 million in the 27-30 range who have 2 or

more comorbidities. So, there is a ratio here.

This is about two-thirds of that. I have left out

some comorbidities so presumably these numbers

could be higher so this is just selected

comorbidities.

For comparison, even at the next lower

level there are almost 3 million people who would

fall into that category, even the lowest BMI

53

category. So, these comorbidities, again, are not

limited only to people in these overweight and

obese ranges. At the BMI level of 30-35 the

numbers are really much higher. Also, the numbers

of men and women are pretty equal in these

categories of interest in the overweight range.

There is a difference by age again. This

shows the same slide but now it is just limited to

people in the age range of 20-59. Here there is

about one and a half million people who fall into

this category, which is BMI 25-27 and one or more

comorbidities, and now the numbers of men and women

are no longer equal. There are about twice as many

men as women in this younger category.

This is for ages 60 and above. Remember,

the total here is a little under 4 million so

almost 2.5 million of those people are in the age

range of 60-70 and now we see that there are, not

unexpectedly in this case, more women than men in

this age range in this BMI category with

comorbidities. That is true along the whole

spectrum of BMI levels.

54

This is sort of changing the design here

but this shows you the number of million of people

with 1 or more, 2 or more or 3 comorbidities. This

is for BMI 25-27 so this is 1 or more, 2 or more or

3, and this shows the total with the different

components of the bar showing the age ranges. So,

what you can see is that, for example, is people

with one or more comorbidity about equal numbers of

people in the 40-59 and 60-70 age ranges and those

make up the majority of people with a smaller

contribution from people 20-39, even though many

people in the population in this 20-39 age range

don\'t fall into the comorbidity range.

So, we see about 12 million total with one

or more comorbidities as compared to 18 million in

the higher BMI range. When we get down to 2 or

more comorbidities, which is the number I just

showed you, this is approximately 4 million. The

largest group is going to be people in the 60-79

age range and people above 60 make up the majority

of this group, although not everybody in this

group. That is true also for BMI 27-29. So, the

55

age structure of these age groups is not the same

as the age structure of the population.

What about weight loss for people with BMI

25-27? I have tried to review the literature. I

have probably not reviewed everything, by a long

shot. As far as I can discern, there is not very

much information about the benefits of weight loss

in this particular BMI range. Most studies of

weight loss don\'t include that many people in this

level. Again, up to 10 years ago we would not have

considered people in this range to be overweight so

that might be one of the reasons why they were not

really going to be included. Some of them may

actually explicitly exclude people when they study

a BMI of 27 or a BMI or 28.

That is also true of studies of the

benefits of weight loss in the control of

conditions such as hypertension or hyperlipidemia.

They may explicitly exclude people who have BMIs as

low, so to speak, as 25-27 or may include few, if

any, participants.

In kind of a mirror image, I also read an

56

article which was complaining that drug trials for

hypertension are conducted in people who are

overweight but not obese so we know very little

about it. So, basically, trials of weight loss and

hypertension are conducted in obese people and in

trials of drug use and hypertension are studied in

overweight people but not the converse. So, we may

have missing information on both sides of that.

The NHLBI clinical guidelines

recommendations for a BMI of 25-29 overweight

recommend treatment only when patients have 2 or

more risk factors or a high waist circumference.

Other than that, weight maintenance is actually

recommended. So, the guidelines here for

overweight treatment do not recommend treatment for

everybody but just for people with other risk

factors. They also mention\--I didn\'t put this on

the slide\--that treatment of the other risk factors

is also just as important and should also be

considered.

You will see this statement on another

slide, but there are a lot of studies that show

57

that short-term weight loss has beneficial effects

on risk factors such as high blood pressure and

cholesterol. That is really very well established.

Most studies suggest that these are monotonic

relations but there is no obvious threshold. So,

you would infer from this that weight loss is very

likely to improve blood pressure and other risk

factors, certainly in the range of BMI of 25-27 as

well and perhaps at any weight level. We don\'t

really know but there is not that much evidence on

the specific BMI range. This is a fairly

reasonable inference.

How much benefit would that have? What

would be the net result? That is very hard to

judge in the literature. This is one very

approximate way of looking at it. You have already

seen these data but in a different format. What is

the prevalence of having 2 or more comorbidities by

age group for BMI 23-25 versus 25-27? If you think

that weight loss in the BMI group 25-27 puts you

into this next lower group, which is a very

plausible assumption, roughly speaking what would

58

the expected prevalence be?

You can see that effect\--this is an

approximation again\--by just comparing these 2 bars

which show the prevalence in the 23-25 BMI group

versus the prevalence in the 25-27 for different

age groups. In the youngest age group in which BMI

is probably a stronger risk factor, relative risk

for hypertension associated with BMI stronger are

stronger in the youngest group, you see a pretty

big potential difference of about half the number

of people in this lower BMI group. The number with

2 or more comorbidities is about half. So, that

would suggest that you get a fairly noticeable

prevalence effect by this kind of change in weight.

At the older age ranges the prevalence is high.

So, just looking at these data you would

suspect that if you had people with a BMI of 25-27

and they reduced their weight to 23-25 it is not

likely that they are going to end up down here

where the 20-39 year-olds are. They are more

likely to be approximately where people in their

same age group are. So, the prevalence of having 2

59

or more comorbidities is likely to be high even

after weight reduction. So, while there is likely

to be a beneficial effect, the net effect on

prevalence may not be that great.

Weight loss is just kind of part of the

therapeutic armamentarium for treatment of various

conditions. There is a whole non-pharmacologic

treatment or therapeutic lifestyle changes which

include weight loss, physical activity and

healthful eating habits, which may mean more fruits

and vegetables, less sodium, less saturated fat, a

whole different range of possible changes. These

are an important part of the treatment of diabetes

and cardiovascular risk factors obviously. Drug

treatment is also often used in managing these

conditions.

So, you might ask what is the relative

contribution of weight loss in this panoply of

treatments. As far as I can find out, that is not

well established. For example, what would be the

probability that non-pharmacologic treatment alone

versus drug treatment would have on management of

60

hypertension? There are review articles and

summary data on this but they tend to start at a

higher BMI level, at BMI of 27 or above or 28 or

above. So, it is somewhat difficult to assess.

Also, for example, there is one paper by

Ed Gregg using the national health interview survey

data that suggests that the intention to lose

weight is associated with improved mortality

regardless of actual weight loss, and the intention

to lose weight may be accompanied by some of these

other changes, such as increased physical activity

and changes in eating habits. So, it is hard to

judge and usually weight loss by itself is not the

only part of it. Therapeutic lifestyle changes

include more, and clinical trials will also look at

lifestyle changes. So, they include more than

weight change and try to assess where weight change

itself falls in the pictures. I couldn\'t find any

data that really spoke very clearly to this issue.

There are a couple of concerns. This is

from the Look Ahead Action for Health and Diabetes

study, I guess. This is from their website. This

61

is the sentence I already had on the other slide.

Although we know that weight loss improves risk

factors and clearly improves blood pressure and

glucose tolerance, there are these observational

studies that suggest some association of weight

loss with increased rather than decreased

mortality.

These studies do not differentiate

intentional from unintentional weight loss so they

definitely have limitations but they can\'t be

completely ignored either. Because of this, there

is actually a randomized clinical trial of

intentional weight loss going on. There are some

questions we don\'t really have the answers to about

this possibility of increased mortality with weight

loss so that is one concern, looking at weight loss

in this BMI range.

Another possible concern is, again, that a

lot of the people who are in this BMI range who

have comorbid conditions are elderly and more of

the elderly, not surprisingly, are women rather

than men and there are, you know, some possible

62

adverse effects of weight loss in this age range in

the elderly and particularly perhaps for women.

One of these is the possibility that weight loss as

adverse effects on bone health and can result in

lower bone density or greater risk of hip fracture.

This is a report from the study of

osteoporotic fractures where these women were close

to this range and the median and they had an

increased risk of hip fracture with weight loss.

In fact, this study found also an increase in thin

women as well, although the increase was not as

great. They did look at intentionality versus

unintentionality or lack of intention to lose

weight. In this study, and this is not the only

study on this topic but just something to kind of

keep in mind as a possible issue, regardless of

current weight or intention to lose weight there

was an association of weight loss with hip bone

loss and risk of hip fracture. So, they concluded

that even voluntary weight loss in overweight women

increases hip fracture risk.

Just to summarize, definitions of

63

overweight have varied a lot over time, and

epidemiologically useful consensus definitions do

not necessarily represent physiological

differences.

The prevalence of selected comorbidities

rises with BMI and doesn\'t have, at least in my

analysis, clear inflection points. There are about

12 million adults with a BMI 25-27 with at least

one selected comorbidity and about 4 million have

at least 2 selected comorbidities. So, it is a

large group of the population.

Half or more of the adults with BMI 25-27

and selected comorbidities are age 60 and above.

Weight loss, lifestyle changes and drugs are all

used to manage these and other comorbidities. So,

weight loss is part of a whole package of possible

treatment modalities.

Weight loss is associated with some

possible adverse consequences in observational

studies. So, I would conclude that the benefits

and risks of weight loss for people with BMI 25 to

under 27 have not been clearly established. Thank

64

you.

DR. BRAUNSTEIN: Thank you. Are there any

questions from the panel members? Dr. Follmann?

DR. FOLLMANN: I just had a comment. I

hadn\'t seen the relationship between BMI and

overall mortality before and I was really struck by

the nadir at 25. Many of these documents we have

been reading before this meeting were talking about

a cut point of 25-30 for definition of overweight,

and it just strikes me as maybe curious as to why

you would recommend or why people would consider

having someone who has to be above 25.1, which is

close to optimal, lose weight. So, I was wondering

if you could comment on that.

DR. FLEGAL: Well, I guess I think of this

from an epidemiological perspective. We have

prevalence estimates that use 25 and, you know,

different studies show the nadir at different

points so I don\'t think you can say that it is

exactly at 25. But the recommendations of NHLBI

are really not to lose weight at a BMI of 25.1

unless you have comorbid conditions. So, avoidance

65

of weight gain is probably more important in that

range.

DR. BRAUNSTEIN: Yes?

DR. RYDER: Yes, I just have one quick

question. On the two graphs that I you showed

earlier on the age-adjusted trends in obesity, you

used two categorical definitions, one of 25 and one

of 30 with somewhat different patterns.

I have a two-part question. One is if you

use 27 instead of 25 or 30, because I have seen

that put forward, would the display be more like 30

or more like 25?

DR. FLEGAL: I think it would be more like

30 but I haven\'t actually looked at data.

DR. RYDER: And the second part is the

average weight in the United States over this time

period I believe has been going off in somewhat of

a linear way, or maybe even more than a linear way.

Has the distribution pattern, Poissant

distribution, been maintained or is it just one arm

skewing out?

DR. FLEGAL: That I can\'t answer.

66

Basically, the whole distribution of body mass

index is shifting to the right a little bit. But

the distribution is becoming much more skewed so

there are much larger changes at the higher tail of

the distribution. The median has shifted somewhat

but the 90th percentile has shifted a lot. So, the

distribution is both shifting to the right and

becoming much more skewed.

DR. RYDER: Thank you.

DR. CARPENTER: I was struck by the large

impact of age on the comorbidities and, at the same

time, struck by the fact that in your later slides

you demonstrate that the effect on comorbidities

with weight loss is much greater at the young ages.

I wonder if anybody has looked at the duration of

carrying a certain BMI as being more important than

the current BMI as a risk factor for comorbidities.

DR. FLEGAL: There are studies like that.

I don\'t think they would explain those age

differences. I think basically a lot of people,

even at the lowest BMI in the age range of

60-79\--you know, a lot of people have hypertension

67

regardless of BMI. So, any duration or changes

can\'t affect that. You know, at every BMI level

you have like 70-80 percent of people with

hypertension so, although duration may very well

have an impact, I don\'t think that can be the

explanation for those prevalence figures.

DR. BRAUNSTEIN: Dr. Follmann?

DR. FOLLMANN: Have there been studies

done that look at the pattern of weight gain over,

say, a 10-year period and how that might affect

mortality? I am thinking of someone who, say,

weighs 200 lbs at 40 and goes up to 250 lbs in a

steady linear fashion as one kind of trajectory,

and the other where they repeatedly diet and their

weight fluctuates a lot over that 10-year period

but they end up at the same weight. So, steady

versus erratic weight velocities\--have there been

studies looking at the risk associated with those

two possible trajectories?

DR. FLEGAL: Well, there have been studies

of weight cycling. Sue Yanovski probably knows

more about that than I do. But I believe that a

68

kind of consensus is that weight cycling probably

doesn\'t have a large impact on mortality. Is that

right, Sue?

DR. S. YANOVSKI: Yes, the difficulty with

these kinds of studies is that they are all

observational studies, and weight cycling in itself

is associated with a lot of psychiatric morbidity,

a lot of other comorbidities and it is really

difficult to tease out cause and effect in those

kinds of studies.

DR. FLEGAL: Again, there are

observational studies that suggest that weight loss

is associated with increased mortality. There are

a lot of questions about intentionality; why do

people change their weight. As Sue was saying,

there are other issues. So, this whole area is a

very tangled and confused area to really sort out.

DR. BRAUNSTEIN: Dr. Hirsch?

DR. HIRSCH: I think you have just about

answered what I was going to ask. The 1997

recommendation concerning the issue that a

randomized clinical trial of intentional weight

69

loss is the only way we could prove whether there

are dangers inherent in weight loss\--no such trial

that fits any of those issues has been carried out.

Is that true?

DR. FLEGAL: Of intentional weight loss\--

DR. HIRSCH: Yes, randomized, prospective

trial. You are saying that is the only way you

could find out what the inherent harms of weight

loss might be.

DR. FLEGAL: Look Ahead is the only one I

am aware of. Is that right, Sue?

DR. S. YANOVSKI: Yes. NIDDK is

sponsoring the Look Ahead clinical trial, which is

5000 individuals with diabetes who are randomized

to intentional weight loss or a controlled

condition.

DR. HIRSCH: But no data are available?

DR. S. YANOVSKI: Not yet.

DR. BRAUNSTEIN: Why do you think the

mortality curve is J-shaped? That is, that the

mortality goes up as you start getting to a lower

BMI at a time when all the comorbid risk factors

70

seem to be lowest?

DR. FLEGAL: Well, again, there are a lot

of issues that are really unresolved. It could be

that at older ages there is some association\--at

all ages there is an association of low BMI with

mortality as well as with high BMI. It may have to

do with issues like not having adequate nutritional

reserves; people going in for surgery at age 65 and

you lose weight in the course of being in a

hospital and deplete your nutritional reserves.

You may be at a higher risk of hip fracture. The

pattern of the causes of mortality may be different

at different BMI levels at different ages. There

are also issues of smoking. Most of these studies

adjust in some way for smoking but smokers tend to

have lower body mass index and be at higher risk.

So, there are a lot of different issues. I don\'t

think it has really been sorted out very clearly in

the literature.

DR. BRAUNSTEIN: Thank you. We will move

on to Dr. Frank Greenway\'s discussion of the

current status of weight-loss drugs.

71

Current Status of Weight-Loss Drugs

DR. GREENWAY: I was asked to speak on the

safety and efficacy of the drugs that we have for

weight loss at the present time. Obesity, before

the 1985 consensus conference, was felt to be bad

habits rather than a chronic disease, which is the

way we now understand it. At least, it was my

understanding that eating habits can be retrained

over a period of a few weeks and that this at least

was another reason why the older recommendation for

obesity drugs was over a shorter period of time.

The drugs approved before 1985 were,

therefore, approved for periods up to a few weeks,

and tested over that period of time. Mazindol and

fenfluramine are no longer available; phentermine

and diethylpropion are. Dr. Colman already

reviewed the analysis of the FDA information on new

drug applications that were reviewed in the 1970s

that showed that these drugs approximately doubled

the weight loss seen with the placebo groups.

Just a few overview comments about

treating obesity as a chronic disease with

72

medications, first of all, the drugs work only when

they are taken and I will show you a slide to

demonstrate that. The average weight of the

participants in those studies is 100 kg. So, one

can look at these weight loss graphs as percent

weight losses or kilograms of weight loss since it

is 100 kg.

The placebo group in these trials has

always required some type of treatment because IRBs

feel that placebo groups need to get some form of

treatment as well. So, people in these trials are

really getting two different treatments. Weight

loss in these trials usually plateaus at about 6

months. The primary criteria for approving drugs

in Europe is a 10 percent weight loss that is

greater than placebo. A primary criterion in the

United States is a weight loss that is 5 percent

greater than placebo and is statistically

significant.

This is a slide of a study done in a

practice situation where patients were given

fenfluramine, a drug no longer approved. They were

73

seen monthly for a year. As you can see, the

weight loss plateaus at about 6 months. The

one-year people in this trial had their drug

discontinued but they would continue to be followed

for the following year. When they were followed

off the treatment the weight loss just about went

away by the time they got to the second year.

Another point I wanted to make was about

the ancillary treatment that goes on in these

clinical trials. Back in the early \'70s behavior

modification was a new treatment. There was a

trial that was done to approve mazindol and two of

the sites did it in the standard way, which is

demonstrated on this slide. Everybody got a

tear-off diet sheet and the placebo and drug groups

were given pills each week and were weighed each

week. As one can see, the placebo group really

lost no weight over 6 weeks and the mazindol group

lost 6.5 lbs over that period of time.

In another site in that trial behavior

modification was superimposed upon all groups. The

mazindol group in that site lost 8.5 lbs rather

74

than 6.5 lbs but the difference between drug and

placebo was reduced considerably, to the point

where, at least in this particular site, the

difference was no longer significant.

To sort of carry that forward, because

this is sort of the difference between the European

and U.S. kinds of criteria, here you can see that

an orlistat trial in Europe had 11 percent weight

loss but only a 2 percent difference from placebo.

This is because there was presumably a larger

ancillary program that was superimposed upon this

weight loss program.

This is a sibutramine trial that was done

in the United States where the difference was to

get a spread between the two groups. You have a 7

percent weight loss with sibutramine and a 2

percent loss with placebo, and there was,

therefore, a 5 percent difference.

In talking about the safety and efficacy

of the drugs that are presently available, the Rand

Corporation was commissioned to prepare an evidence

report on the pharmacologic treatment of obesity by

75

the agency for Health Care Policy and Research of

our federal government. Some new meta-analyses

were done during that process using the studies

that were at least 6 months in duration. Although

this hasn\'t yet been published, they have given me

permission to present some of that data.

There are several categories that one can

put the drugs available into. One would be

phentermine and diethylpropion which are approved

for obesity but for short-term use. The second

would be orlistat and sibutramine which are

approved for obesity for long-term use. Then there

are drugs that are approved for other indications,

not for obesity, things that are approved for

depression, like fluoxetine and bupropion; things

that are approved for epilepsy such as topiramate

and zonisamide which also give weight loss. Then,

there are 2 drugs that are in phase 3 clinical

trials, Axokine and rimonabant which have some

public information available on them.

The data presented here on efficacy

presents the data in the way the FDA evaluates

76

drugs, that is, the difference between the placebo

group and the drug group. In trials of phentermine

up to 6 months in duration, using 30 mg/day, the

difference between drug and placebo was about 3.5

kg. With diethylpropion, in studies that went up

to about a year, the difference was 3 kg.

One might ask how can one, in this day and

age when we understand obesity to be a chronic

disease, find a use for these medications that are

only approved over a period of a few weeks. This

is a study that was done comparing the green line,

which shows continuous use of phentermine, against

the yellow line, which showed 1 month on 1 month

off; 1 month on, 1 month off.

As you can see, the line is more jagged

but they end up at approximately the same place at

9 months compared to the red line, which is

placebo. So, there are still ways that these drugs

can be useful.

Orlistat, at 120 mg 3 times a day, gave a

2.5 kg difference compared to placebo at 6 months

in the 11 studies in this meta-analysis, and about

77

2.75 kg at 1 year in 21 studies.

Orlistat is an inhibitor of pancreatic

lipase. It causes a third of dietary fat to be

lost in the stool. The relative risks for diarrhea

were 3.4, for flatulence 3.1, and dyspepsia 1.5.

So, one can see that these side effects result from

the mechanism of action.

These trials showed a reduction in total

LDL cholesterol and in blood pressure. There was a

slight reduction in glucose and glycohemoglobin in

diabetics, and it was shown that one could prevent

diabetes in those with impaired glucose tolerance.

Sibutramine, in doses of 10-20 mg/day,

showed a 3.5 kg difference from placebo at 6 months

in 12 trials, and about a 4.5 kg difference at 1

year in 5 trials. Sibutramine is a norepinephrine

and serotonin reuptake inhibitor. It had

dose-related dry mouth, insomnia and nausea

associated with it. The heart rate went up 4

beats/minute in these trials, and there was no

consistent effect on blood pressure or lipids.

There was a slight improvement in glucose and

78

glycohemoglobin in diabetics.

One could logically ask, since we have

these two drugs that are approved for long-term use

in obesity and they work by different mechanisms,

could one combine them and get better weight loss.

This is one trial that tried to address that issue.

The yellow line shows sibutramine treatment for a

year. You can see that the weight loss plateau\'d

at 6 months and remained stable for the next 6

months. When orlistat was added to sibutramine

there was no further weight loss.

Fluoxetine is a medication that was

approved for depression, not for obesity. It was

studied for obesity, however, and at 60 mg/day, a

higher dose than is typically used for depression,

it caused about a 4.5 kg difference from placebo at

6 months. But, as you probably will notice as

something different compared to the other slides,

there is less difference at 1 year than there was

at 6 months, in this case 3 kg.

Fluoxetine is a reuptake inhibitor of

serotonin. The relative risks of nervousness,

79

sweating and tremors was 6.6; of nausea and

vomiting 2.7; fatigue and somnolence 2.4; insomnia

2.0; and diarrhea 1.7. There was regain of weight

between 6 months and a year. That is presumably

the reason that it was not approved.

This is a slide to graphically demonstrate

that fact. You can see that the weight loss came

down and plateau\'d at around 6 months, but in the

last 6 months of that year there was obvious weight

gain in the fluoxetine group and not in the placebo

group.

Bupropion is a drug that is approved for

depression and smoking cessation. At 200 mg twice

a day in 2 6-month trials there was about a 2 kg

difference from placebo. In one trial at 1 year

there was about a 5 kg difference.

Bupropion is a reuptake inhibitor of

dopamine and norepinephrine. The 6-month studies

were both in depressed patients. The 12-month

study was in obese patients that were not

depressed. So, these may represent 2 different

groups in terms of response. The relative risk for

80

dry mouth was 3. There was also an increased

incidence in insomnia, and there were no increases

in pulse or blood pressure in those studies.

Topiramate is a drug approved for

epilepsy, not for obesity. At 192 mg/day there was

a trial that showed a 6.5 kg difference between

that drug and placebo. The mechanism or weight

loss with this drug is not clear. The relative

risk of paresthesia was 4.9. Taste perversions was

9.2. There were other central nervous system and

gastrointestinal side effects with this medication.

Zonisamide is another anti-epileptic drug,

not approved for use in obesity. A 16-week trial

showed a 5 kg difference between that drug and

placebo.

Axokine is a large protein that is

injected subcutaneously and is in development in

phase 3 for the treatment of obesity. There is one

study that is in the public domain that shows a 3.5

kg difference from placebo at 1 year. Axokine

appears to activate the leptin pathway distal to

the place where leptin acts since it acts in

81

animals that don\'t have leptin. It has injection

site reactions, nausea and a dry cough associated

with its use. Over 30 percent of the people in the

trial that I mentioned developed antibodies to

Axokine. Those patients who developed these

antibodies lost less than 1 percent of their body

weight compared to placebo at a year.

Rimonabant is the other medication on

which there is public information in the phase 3

trials for the treatment of obesity. The one trial

that was reported talked about uncomplicated

obesity. It was a 16-week trial and I took the

liberty of projecting the weight loss consistent

with other weight loss curves of these types of

drugs. If one projects that out to 6 months, one

gets just slightly less than a 5 kg difference,

assuming no weight loss in the placebo group which

was not reported on that website.

There is a second trial that used

rimonabant in dyslipidemic patients. The

difference from placebo was 5 kg at 6 months and

6.5 kg at a year.

82

Rimonabant is an antagonist of

cannabinoid-1 receptor. In other words, it blocks

the receptor that is thought to be effective in

causing the munchies when people smoke marijuana.

Nausea and diarrhea were greater than 5 percent

above placebo. There was a 10 percent increase in

HDL, a 15 percent reduction in triglycerides and a

reduction in the 2-hour post glucose load insulin,

and no significant effects on pulse or blood

pressure in these dyslipidemic patients.

I put in this slide to put into context

the blue line, which is a typical drug where there

is weight loss of 10 percent, compared with the

gastric bypass which has weight loss of 30 percent

which is durable over 14 years.

In summary, there are short-term weight

loss medications that are approved for treatment of

obesity, such as phentermine and diethylpropion.

There are drugs that are approved for the long-term

use in the treatment of obesity, that is, orlistat

and sibutramine. There are other medications

approved for epilepsy or depression, i.e.,

83

bupropion, fluoxetine, topiramate and zonisamide,

which are not approved for use in treating obesity

but which seem to give weight loss. And, there are

two drugs, Axokine and rimonabant, about which

there is public information that are presently in

phase 3 trials for the treatment of obesity.

In conclusion, all these drugs give

between a 2 and 6.5 kg greater weight loss than

placebo in trials that last up to a year, and the

amount of weight loss appears to be medically

significant. The weight loss between these

different drugs is not different statistically and

the choice, therefore, revolves around side

effects. The weight loss and the difference from

placebo are two different things, which I hope I

demonstrated, and data beyond 2 years essentially

does not exist, with a couple of exceptions. Thank

you.

DR. BRAUNSTEIN: Thank you. Questions

from the panel? Yes, Dr. Woolf?

DR. WOOLF: There was a report in \"New

York Times\" on Monday, I think it was, of results

84

of a one-year or a two-year trial in Europe with a

drug that they didn\'t specify, other than saying it

was a receptor blocker of some sort that had, I

think, 19 lbs weight loss and 3.5 inch reduction in

waist and a 24 percent increase in HDL. Do you

know anything about that?

DR. GREENWAY: That was rimonabant. I saw

that article and that was about rimonabant.

DR. WOOLF: Sorry?

DR. GREENWAY: I read the article and it

was reporting on rimonabant, a new study of

rimonabant, not the one that was reported by Frank.

DR. WOOLF: Thank you.

DR. GREENWAY: Actually, those results

are on the website. I checked it yesterday, 1

year, 52 weeks, 5 and 20 mg.

DR. BRAUNSTEIN: Yes?

DR. ARONNE: Frank, can you talk a little

bit about the problem with dropouts in weight-loss

drug studies, and some of the pros and cons of the

type of analyses used, last observation carried

forward versus completers?

85

DR. GREENWAY: Well, it seems as though

people in weight-loss studies appear to have a

feeling of being stigmatized when they drop out of

studies because they don\'t want to come back. It

is very difficult to get final data on people who

drop from weight-loss studies. Weight-loss studies

that go out to a year usually have something like a

30 percent dropout rate.

The traditional way of analyzing these

studies, as Susan suggested, has been the last

observation carried forward, and what that does is

it dilutes the effect of the drug because it

assumes that the reason the people dropped out is

because they didn\'t lose weight. Actually, what

the physician treating a patient is interested in

is more what happens to the patient that I treat

who stays in treatment, rather than the more public

health perspective of this last observation carried

forward which looks at the entire group. If you

treat everybody, what does the total group gain

from this experience? So, from the way in which

these medications are used, it is much more

86

informative to me, as a clinician, to have the

analysis of completers rather than the last

observation carried forward.

DR. BRAUNSTEIN: Dr. Schambelan?

DR. SCHAMBELAN: Just a quick question

about Axokine. You said it worked distal to

leptin. Do you know if it works distal to the

leptin receptor or just distal to leptin? Is its

actual site of action known?

DR. GREENWAY: The site of action of

Axokine is in the leptin pathway. It is probably

in that signaling pathway but it is distal to the

site where leptin acts.

DR. BRAUNSTEIN: Frank, can you describe,

in the studies that were carried out for one year

with these drugs, what the effect was on the

comorbid states and whether there were any

differences among the drugs? For instance, did

some lead to lowering of blood pressure and others

didn\'t? Did some lead to lowering of cholesterol

while others didn\'t? Or were they all fairly

consistent?

87

DR. GREENWAY: You are asking me what was

the effect on comorbidities in these studies?

DR. BRAUNSTEIN: Yes.

DR. GREENWAY: Of the two drugs that are

approved for treatment of obesity in the United

States, orlistat seems to have a disproportionate

beneficial effect on lipids, probably because it

enforces a low fat diet. Sibutramine doesn\'t have

the expected beneficial effect on blood pressure

that one might expect, probably because of its

norepinephrine reuptake mechanism of action.

Otherwise, one gets the expected benefits that one

would expect with weight loss with these drugs.

DR. BRAUNSTEIN: Other questions?

\[No response\]

Thank you. Our next speaker will be Dr.

Laura Governale, who is going to speak about

patterns of weight-loss drug use.

Patterns of Weight-Loss Drug Use

DR. GOVERNALE: Good morning. To begin, I

would like to briefly state that the Division of

Surveillance Research and Communications Support in

88

the Office of Drug Safety is responsible for the

procurement, management and analysis of drug

utilization databases for the FDA\'s use. The

information contained in these slides has been

approved for this meeting.

The topics I will be discussing today are

the patterns of prescription weight-loss drug use

and the patient demographics associated with

weight-loss drug use. For this presentation

weight-loss drugs are defined as dexfenfluramine,

sibutramine and orlistat and amphetamine congeners

such as phentermine and dimetrazine diethylpropion,

phendimetrazine, diethylpropion, benzphetamine,

mazindol and fenfluramine. We did not include

amphetamines in this analysis. Also not covered in

this analysis are over-the-counter drugs and

nutritional supplements. The analysis is conducted

using proprietary databases at the agency\'s

disposal.

Two databases were used in this analysis

from IMS Health. IMS health is a pharmaceutical

marketing usage company that collects prescription

89

drug use information worldwide. The agency uses

these databases as well in order to obtain drug use

information and trends in the U.S. The two

databases from IMS Health were the National

Prescription Audit Plus and the National Disease

and Therapeutic Index.

NPA, or the National Prescription Audit

Plus, measures the retail outflow of prescriptions

from pharmacies into the hands of consumers by

formal prescriptions. The number of dispensed

prescriptions is obtained from a sample of

approximately 22,000 randomly selected pharmacies

around the country and projected nationally. The

pharmacies in the database account for

approximately 40 percent of all pharmacy stores and

represent approximately 45 percent of prescription

coverage in the U.S. The pharmacies include the

following retail channels such as chain,

independent, mass merchandisers and food stores

with pharmacies, and also include mail-order and

long-term care pharmacies.

The National Disease and Therapeutic Index

90

is a survey of roughly 3000 office-based physicians

around the country. The data gathered in NDTI are

designed to provide descriptive information on the

patterns and treatment of disease encountered in

this setting. The data are collected and projected

to provide a national estimate of use. However, in

certain instances the small sample size tend to

make these data unstable and sometimes these

results should be interpreted with caution.

Patterns for prescription weight-loss

drugs dispensed were obtained from NPA Plus. Here

I will present the trends in prescription

weight-loss drug use dispensed from 1966 to 2003

and also the method of payment for these

prescription weight-loss drugs from 1999 to 2003.

This slide, which is based on NPA data,

represents the total number of prescriptions

dispensed for prescription weight-loss products

from 1966 to 2003. The total number of

prescriptions represents new prescriptions as well

as refill prescriptions.

The yellow-shaded area here represents the

91

total added prescription weight-loss products of

all the individual weight-loss products as shown

here. The individual lines represent individual

active ingredients in some of these weight-loss

drug products. Again, this slide does not include

any amphetamine products.

As you can see, over the last 38 years

there have been fluctuations in prescription

weight-loss products. As you can see, there are

two major spikes in prescription drug use. These

fluctuations in use have been largely due to two or

three prescription drugs at any given time.

The first spike, which occurred during the

early 1970s, around the decade of the \'70s, was

most likely due to the enactment of the Controlled

Substances Act in 1970. This was also presented by

Dr. Colman in a previous presentation. This

legislation in essence restricted the production

and distribution of amphetamines which, throughout

the 1960s, were commonly prescribed for weight

loss. When these restrictions were placed on

amphetamines the amphetamine congeners were used

92

more frequently.

Also in 1973, the agency declared that

amphetamine and amphetamine-like compounds were

effective for the treatment of obesity. This led

to a large spike in use for diethylpropion and

phentermine products. The number of prescriptions

here peaked at 12.5 million in 1976.

However, we see a decline in use around

1979\. In 1979 there was a Federal Register notice

calling for the removal of the obesity indication

in amphetamines. This led to a sharp decline in

use in weight-loss drugs, namely, for phentermine

and diethylpropion. However, the proposal to

remove the obesity indication from the amphetamines

never materialized. Since then, the use of

weight-loss products had steadily declined until

the mid-1990s.

I will focus now on the last 13 years for

prescription drug trends. Looking at the last 13

years, the number of total prescriptions dispensed

for weight-loss drugs reached its lowest point

around the 1990s, early 1990s, with approximately

93

3.3 million prescriptions dispensed.

Then, in early 1995, 1996, we began to

notice an increase in usage. This was most likely

due to the result of a publication, in 1992, of a

series of papers that concluded that the

combination of phentermine and fenfluramine, or

phen-fen, was safe and effective for long-term

weight loss. In 1996 the FDA approved

dexfenfluramine for the treatment of obesity. The

number of anti-obesity prescription drugs dispensed

reached its peak in 1996 with 21 million

prescriptions. The compounds responsible for this

increase include phentermine, fenfluramine and

dexfenfluramine.

Again, dexfenfluramine was marketed under

the name of Vidoxx and fenfluramine was marketed

under the name of Pondimin. During its peak use in

1996 fenfluramine held 33 percent of the market

share with 7 million prescriptions dispensed,

whereas dexfenfluramine held 11 percent of the

market share with 2.3 million prescriptions

dispensed. Phentermine held 52 percent of the

94

market share with approximately 11 million

prescriptions dispensed.

This large spike in use was followed by a

market decline over the next two years when, in

1997, the FDA announced a voluntary withdrawal of

fenfluramine and dexfenfluramine following

increased reports of cardiac valvulopathy in

patients treated for obesity. The total number of

prescriptions dispensed went from a peak of 21

million prescriptions down to approximately 7

million prescriptions ion 1998, which represents

approximately a 67 percent decline. Since then the

number of prescriptions dispensed for weight-loss

drugs has declined to approximately 5.8 million

prescriptions in the year 2003.

Orlistat was released into the market

around 1997, and sibutramine in 1999. Currently,

or in year 2003, they hold second and third place

in the market with 1.3 million prescriptions

dispensed for orlistat or 22 percent of the market

share, and 760,000 prescriptions dispensed for

sibutramine, which represents 13 percent of the

95

market share.

Phentermine continues to predominate the

market with approximately 3 million prescriptions

dispensed, which represents over 50 percent of the

market share. Other products, such as the

amphetamine congeners, have steadily declined in

use since the mid-1990s and collectively account

for less than a million prescriptions per year.

This slide, in contrast to the previous

slides, represents only new prescriptions

dispensed. Furthermore, this analysis excludes the

mail-order and long-term care channels. Therefore,

the numbers of prescriptions reported in this

analysis are smaller than in the previous slides.

This graph is an analysis of method of

payment for prescription weight-loss drugs. As you

can see, the number of new prescriptions paid by

cash has declined steadily over the past 5 years,

from approximately 5 million in year 1999 to 2.6

million in year 2003. However, the number of

third-party payment for new prescriptions has

remained steady at approximately 1.1 to 1.6 million

96

prescriptions over the 5-year period surveyed. The

drop in cash payment, in effect, has increased the

proportion of third-party payment for these drugs

from 20 percent in year 1999 to approximately 30

percent in year 2003. So, the main message from

this slide is that cash payment remains an

important mechanism for the payment of these

weight-loss prescription drugs.

Next I will discuss the patient

demographics associated with prescription

weight-loss drugs. The data are based on IMS

Health, National Diseases and Therapeutic Index.

Again, the data are projected nationally. However,

it does not represent disease burden, nor is it

representative of all disease states in the nation.

Rather, the data reflect a population of ambulatory

patients, visiting physicians and office-based

practice settings during which a weight-loss drug

is mentioned during the visit. Again, due to the

limitations in data sampling in this database, any

perceived trends must be interpreted with caution.

The topics I will be discussing for

97

patient demographics include the principal

diagnoses associated with prescription weight-loss

drugs, the gender distribution, age distribution

and race distribution.

This table represents the principal

diagnoses associated with prescription weight-loss

products for ambulatory patients. Not

surprisingly, obesity is the diagnosis most often

mentioned with weight-loss drug products, with

approximately 89 percent or 1.8 million projected

diagnosis visits.

This slide represents the number of

mentions associated with the use of weight-loss

drugs as reported by office-based physician

practice settings. This is a measure of drug

mentions again and is not reflective of disease

burden in the nation.

As you can see, females account for a

clear majority in use for prescriptions of

weight-loss products, with an average of 2.3

million drug appearances or 85 percent over the

time period surveyed.

98

Taking a closer look at the most recent

calendar year, we see that the adult age group,

18-44, accounts for the largest majority of drug

use for prescription weight-loss products, with

approximately 1.2 million or 62 percent of total

drug appearances. This is followed next by age

45-64 category, with 624,000 mentions or 32.6

percent of total drug appearances in the year 2003.

In conclusion, the majority of weight-loss drug

products is in the young, female, adult and middle

age adults.

This graph represents the race

distribution of patients associated with the use of

prescription weight-loss drugs as reported by

office-based physician practice settings. Again,

the reporting in this database, NDTI, is reported

by the physician and not is not self-reported by

the patient. The key take-away from this graph is

that a proportion represented by each race group

has remained constant over the time period

surveyed. Approximately three-quarters of use is

from Caucasian patients.

99

Now that I have represented the data, I

will present the limitations on each of these

databases. The NDA Plus data provide only limited

demographic information on prescription use.

Therefore, we did not use this database for this

analysis. Instead, we used NDTI to obtain

demographic information which has these

limitations: As you can see, the small sample size

makes some projections unstable. Again, the data

are not generalizable to all of these patients.

And, due to the limitations, any perceived trends

must be interpreted with caution.

In conclusion, over the last 38 years

there has been a fluctuation in the total number of

prescriptions dispensed for prescription

weight-loss products. These fluctuations have been

largely due to two or three drugs at any given

time.

The second point is that cash payment

remains an important mechanism for payment for

these products. Also the primary users of these

products are Caucasian women between the ages of 18

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and 44. That is the end of the presentation.

DR. BRAUNSTEIN: Thank you. Any questions

from members of the panel? Yes?

MS. COFFIN: On your slide that talks

about the race distribution of the patients you can

see huge differences and, of course, the Caucasian

patients are shown as the largest amount. How does

that normalize to the population as a whole? Is

the population as a whole from \'98 to 2003 more

greatly Caucasian than it is Asian American or

African American?

DR. GOVERNALE: Again, this database is

not supposed to represent any epidemiology of

obesity. It represents patients visiting

office-based physicians and it could reflect just

that there are more Caucasian patients visiting

these physicians.

DR. BRAUNSTEIN: Dr. Woolf?

DR. WOOLF: Do you know if the heavy use

of cash for these drugs is because they are being

excluded by drug plans that the patients have? Are

they being excluded from the formularies that the

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patients are covered on? Is that why cash is so

prevalent?

DR. GOVERNALE: I think if I heard your

question, it is why are most of these products not

covered?

DR. WOOLF: Yes, is the reason that cash

accounts for three-quarters of the method of

payment because they are being excluded from drug

plans?

DR. GOVERNALE: Yes, that is the

limitation with these products. Most of these

products are not covered by third-party payers and,

therefore, that is why they are being paid for by

cash.

DR. BRAUNSTEIN: Dr. Watts?

DR. WATTS: I was interested in your

demographics. I may be making wrong inferences but

it seems to me if the largest use of these drugs in

the real world is by younger white women, that may

be more for cosmetic benefits of weight loss. This

is a question then for Dr. Greenway. I didn\'t get

from your presentation the demographics of the

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subjects that are studied in the typical weight

loss trial. Are they different from the people who

are using these drugs as we heard from this

presentation?

DR. GREENWAY: The patients in the regular

weight-loss trials primarily have a BMI between 30

and 40. So, they aren\'t in the trials because they

have just cosmetic concerns, but I think that what

you have observed is correct, that obesity is

stigmatized in our society, particularly

stigmatized in regards to women, and that is

probably the reason that we have 80 percent of

these obesity trials that are composed of women.

Clearly, 80 percent of the population isn\'t women.

DR. WATTS: To extend that though, is

there a particular age of the subjects in the

studies that you showed? Were they different,

older, from the use of these drugs in the real

world?

DR. GREENWAY: The average age of the

people in the trials is usually around 40. So,

they may be slightly older than this group but I

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think they are probably fairly representative.

DR. BRAUNSTEIN: Dr. Yanovski?

DR. S. YANOVSKI: These data did not

report out BMI. They might have the physician

diagnosis for obesity correct but you couldn\'t tell

how many of the patients in these studies had BMIs

above a certain range. Is that correct?

DR. GOVERNALE: Correct. There is no

linkage of BMIs to the diagnosis of obesity.

DR. S. YANOVSKI: So, in preparation for

this I pulled an article by Laura Kettle Conning

and colleagues at CDC that looked at use of

prescription weight-loss pills in U.S. adults from

1996-98 that I think addresses your question. They

used the behavioral risk factors surveillance

survey and they looked at all patients who reported

use of prescription weight-loss drugs. They then

looked at the proportion of patients who reported

using prescription weight-loss drugs who had a BMI

of less than 27, which was the lower limit for

indication with comorbidities. What they found was

that 5 million U.S. adults had used prescription

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weight-loss drugs in that 2-year period. Of that

group, 25 percent reported that they had a BMI of

less than 25. So, it looks like there is

substantial use of these medications for cosmetic

purposes.

DR. BRAUNSTEIN: Dr. Schambelan?

DR. SCHAMBELAN: I just want to pursue Dr.

Woolf\'s question about the reason that the cash

payment is decreased. Do we know that there has

been a systematic change in policy of third-party

payers as to what they will approve for weight-loss

drugs? Perhaps you don\'t know but other panelists

may know.

DR. BRAUNSTEIN: What will the effect of

the recent change in coverage of the drugs by

Medicare have on all this? I guess that is part of

the question.

DR. SCHAMBELAN: Well, Medicare or other

payers.

DR. GOVERNALE: We did not look into the

reasons for why some of these prescription drug

products are being covered or not covered by

105

third-parties, but that could be a very interesting

question to look into for future analyses.

DR. BRAUNSTEIN: Dr. Aronne?

DR. ARONNE: While there hasn\'t been a

systematic change in the number of plans which are

covering drugs, what we have seen is that

practitioners of obesity medicine where we focus on

obesity to treat someone\'s diabetes, sleep apnea or

other complications, is a steady increase in the

willingness of insurance companies to pay for drug

therapy in an appropriate setting. So, with prior

approval, if the patient is in a medically

supervised program, the insurance companies will

pay for the drugs. Right now in the New York area

it is more than 40 percent. The last number I

heard was that 44 percent of patients who have

insurance get coverage for these types of drugs.

DR. BRAUNSTEIN: Any further questions?

\[No response\]

We will take a 15-minute break. Thank

you.

\[Brief recess\]

106

DR. BRAUNSTEIN: We are changing the order

a bit. We are going to ask Dr. Richard Atkinson,

who is director of Obetech Obesity Research Center,

to speak on the role of drugs in the treatment of

obesity: current and future. Following that, we

will then move to the open public hearing, followed

by Dr. Orloff\'s talk.

Role of Drugs in the Treatment of Obesity:

Current and Future

DR. ATKINSON: Thank you, Dr. Braunstein.

Thank you, Dr. Orloff and Dr. Colman for inviting

me to speak. I am coming today wearing two hats.

One is the president of the American Obesity

Association and the second is a physician/clinician

who has literally treated thousands of obese people

over the years.

From that perspective, I have looked into

the eyes of these people and seen the pain and

heard their pain as they talk, and I have failed

them and I think we have all failed them. The

physicians and scientists have failed them. The

drug companies have failed them and the government

107

has failed them. That sounds like a negative

message and I am going to spend a little time

talking about why I think we have all failed. But

I think the promise of the future is really very

bright and I will try to end up on that.

I always like to start off with something

that is not unique to me; I probably stole it from

someone, but obesity is a chronic disease of

multiple etiologies characterized by the presence

of excess adipose tissue. Everybody has excess

adipose tissue but the critical word I think here

is \"disease.\" I think we have heard in this

discussion this morning even some questioning of

the idea of obesity as a disease. But I believe

obesity is a chronic disease and if you think of

other chronic diseases, try to think of one that is

not treated with drugs.

If obesity is a chronic disease and most

other chronic diseases are treated with drugs, why

not obesity? We know that the biochemistry of

obese individuals is different from that of lean

people. That is very well known. Bob Eckle and

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others have some data that when obese people lose

weight their biochemistry does not become the same

as lean people\'s. For example, lipoprotein lipase,

the major clearer of triglycerides out of the

bloodstream, in adipose tissue lipoprotein lipase

goes up; in muscle it goes down. So, people who

were formerly obese are poised to regain their fat.

What do we do with drugs? We change the

biochemistry. So, the rationale for using drugs is

to change the biochemistry of the bodies of obese

people.

There have been, as you have heard, a

number of barriers to the use of drugs. The first

one I am going to put up here is discrimination

against obesity. I am going to spend several

slides talking about this.

When Dr. Orloff asked me to talk, we

talked about the fact that we were going to have a

very nice bunch of scientific presentations and I

am going to come with a more emotional part with

this presentation. But as president of an

organization that is advocating for these people, I

109

want to point out some of the discrimination

against obesity. The fact of physician and

clinician ignorance of obesity, an particularly of

obesity drugs; economic factors; policy and

political barriers, and I have come much more to

appreciate that. We have had several meetings with

people from the FDA, NIH and others and I have come

to appreciate more some of the barriers. There is

a lack of advocacy about obese people and, finally,

currently there is a modest effectiveness of

obesity drugs, as we have heard.

I am going to talk a little bit about

discrimination. Obesity is the last bastion of

socially acceptable bigotry. If you are a radio

announcer or a TV announcer and you tell a joke, a

race joke or an ethnic joke, or a joke directed

against homosexuals, you will get fired. Fat jokes

are told all the time. Look in your comic pages

and virtually every day there is some slam against

fat people and nothing is done.

This discrimination against obesity is in

the people who are in our field. Stan Heshka and

110

David Allison are two very good friends, two very

bright people, good scientists, but \"labeling

obesity a disease may be expedient but it is not a

necessary step in a campaign to combat obesity and

it may be interpreted as a self-serving advocacy

without a sound scientific basis.\" Well, those are

pretty strong words for somebody who is in the

field.

There is a lack of medicalization of

obesity. Think about obesity compared with some

other chronic diseases. For example, newly

diagnosed type 2 diabetes, newly diagnosed

hypertension\--a very high percentage of those

patients will respond very well to diet and

exercise. it goes away. I did a study about 20

years ago and it goes away in 80 percent of the

people. But the first words our of the mouth of a

primary care physician are not \"I\'m going to put

you on a diet and exercise program;\" it is \"I\'m

going to put you on drugs.\"

The primary treatment for obesity is diet

and exercise and drugs are an adjunct. As we have

111

heard from Colman\'s talk, that has been true for

many, many years. Many patients must demonstrate

that they have failed diet and exercise before they

can get either drugs or surgery. There is no other

disease where that happens.

Physician and clinician

ignorance\--obesity, obviously, is not thought to be

a real disease. As many of you know, we have been

doing some work on viruses that cause obesity and I

have gotten up and had people shake their fist at

me and say, \"you\'re trying to give these fat people

an excuse.\" Wow! Physicians are uncomfortable

about counseling overweight or obese patients. I

have a talk on discrimination against obesity to

document many papers in the literature where this

has been shown.

Physicians and clinicians are not

knowledgeable about nutrition, physical activity,

and particularly about obesity drugs. This is a

disease that is killing 400,000 people per year

according to the CDC. At the University of

Wisconsin I was able to get a clinical nutrition

112

course on the curriculum and we had exactly three

lectures on obesity. Since I left, that has now

been cut to one. That is pretty much all they get

about obesity in the whole curriculum.

Physicians are unaware of referral

information. If you have a fat person, what do you

do? They feel helpless and there is a feeling that

if you refer a patient to an obesity physician you

are sort of sending them to a charlatan. There is

a bias. We have heard a little bit about that

today, that drug treatments are dangerous,

ineffective and somehow not worthy.

There are economic factors that are

barriers to obesity drugs. I was flabbergasted to

hear Lou Aronne\'s comment that in New York 40

percent of third-party payers are starting to pay

for drugs. That is super. We looked in Wisconsin

and in our population it was between 10-15 percent.

They had a very high percentage of HMOs and these

HMOs simply didn\'t cover obesity or obesity drugs.

Some of the reasons for that are that the

treatment is fairly expensive. This, after all, is

113

a chronic disease. The insurance companies and

employers are worried about breaking the bank.

There are a large number of overweight and obese

people. We heard Katherine Flegal\'s talk. Over 30

percent of the entire adult population is obese,

has a BMI of 30 or above. So, one, there is a

large population that might want to use those drugs

or use that treatment and, secondly, given a

choice, they will.

We heard from Susan Yanovski about maybe

as many as 25 percent of people that are using

these drugs are using them for cosmetic purposes.

That is a little bit of a discrimination in itself.

There is a whole industry that makes drugs for

cosmetic purposes, like skin rashes and so forth

and so on. So, what is so bad about somebody

wanting to lose some weight when, if you are

overweight, you have a harder time getting a job,

getting promoted in a job, finding a spouse. If

you are a small kid other kids don\'t want to play

with you. It is not just a cosmetic problem; this

is a socioeconomic huge discrimination problem

114

against obese people.

For many of the insurance companies and

insurance plans and HMOs savings in the future

costs are too remote compared to current expenses.

Their bottom line is a year or less. If it doesn\'t

pay for itself in a year, let\'s don\'t pay for it.

Turning to the government, honest to God,

at a Harvard CME course put on by George Blackburn,

I am happy to say a former member of the FDA, he

made the statement, \"gaining weight doesn\'t hurt

you and losing weight doesn\'t help you.\" I am

embarrassed to say I got into a shouting match with

him in front of 400 people.

Obesity drugs I think have been held to a

different standard in the past than drugs for other

diseases. I will just bring up the phen-fen

debacle versus troglitazone. Within two months of

the first unconfirmed, uncontrolled case series

that was prematurely reported by The New England

Journal\--it wasn\'t even published yet but what was

released as a press release\--within two months of

that fenfluramine and dexfenfluramine were taken

115

off the market. It was not really sure that anyone

had died from fenfluramine or dexfenfluramine.

Sixty people had died from troglitazone and it

stayed on the market two more years.

Now, the cynic in me says that is because

diabetes is a real disease and obesity is not.

That may not be fair and there are other factors,

but from my side, coming from an advocacy

organization, it looks like that is discrimination

against obesity. I am not saying that fenfluramine

and dexfenfluramine should not have been taken off

the market, but the timing was interesting.

The recent experience of obesity

drugs\--dexfenfluramine had quite a hard time

getting approved. Sibutramine was initially turned

down and only upon appeal was approved. Orlistat

had what apparently was a spurious association with

cancer so they had to go back and do a great many

more trials to look at the patients to show that

there was not a correlation with cancer.

As many of you know, and as many of you

here have participated in, the American Obesity

116

Association has sponsored a series of meetings with

people from the FDA, the NIH, other government

agencies, scientists and many representatives of

the pharmaceutical industry who have obesity drugs

or are interested in obesity drugs. And, one of

the things I have been impressed with is that the

people at FDA have a huge load on their shoulders

because if anything goes wrong, it is their

problem. We have, you know, 100 million people who

might be wanting to take these drugs and if even a

few of them start to have problems, it is the FDA\'s

fault for having not been more careful.

Fenfluramine had been on the market since

1973\. It was not until 1997 that it was found to

have cardiac valve problems. The problem with

pulmonary hypertension, as Eric noted, was there

but it was really pretty rare. So, I have a much

better understanding of the pressures, both

political and from media and from scientists, on

the FDA and why they simply have to be cautious.

From the Medicare/Medicaid perspective, we

have already heard today that until just a month or

117

so ago the language in the Medicare and Medicaid

regulations was \"obesity is not a disease\" despite

the fact that it was called a disease in 1985 by an

NIH consensus development conference. Apparently,

efficacy standards, in contrast to drugs and

treatments for most other chronic diseases, will

have to have some sort of proving that this

treatment works. Now, as I said earlier, we

have failed these people but obese people fail

themselves. The expectations and the behavior of

obese people contribute to the problem because many

do not believe they are worthy or respect. Obese

people discriminate against obese people actually

more than thin people discriminate against obese

people. They do not bind together for action.

Trying to get people to join this advocacy group

has been absolutely amazing. I thought everybody

in the world who was obese would sign up. They

don\'t. They are ashamed to be associated with the

world of obesity. They simply do not act as

advocates.

Other barriers to obesity drugs are

118

limited choices and poor efficacy. There are only

two drugs still on patent. Why haven\'t the drug

companies done more in the past? They are

certainly doing it now. There are really only

three categories of drugs, as you have heard, the

adrenergic agents, sibutramine which is in a

category by itself and orlistat which is in a

category by itself. We still have an infantile

understanding of the etiology of obesity and

mechanisms of action of drugs. We heard about

topiramate. We don\'t have a clue as to how it

works. It causes weight loss but we don\'t know how

it works.

As we have heard, typical weight-loss

agents, single agents at least, cause only about a

10 percent loss from initial body weight, and there

has been very limited use of combinations of drugs.

I will come back to that.

This is the data on dexfenfluramine, the

index study from Europe, the best study that

dexfenfluramine had, and there was about a 10

percent weight loss at a year.

119

Sibutramine, about an 8 percent or 9

percent weight loss at a year with 15 mg.

Sibutramine out over 2 years, again over in

Europe\--again, this is about a 13 percent weight

loss. This is the Storm trial.

With orlistat, about a 10 percent weight

loss at one year. This is a 2-year trial. The

2-year data was about 8 percent.

If you are a 220 lb woman and you lose 22

lbs, your physician can tell you all he or she

wishes, \"oh, you\'re healthy; your blood pressure\'s

better; your blood sugar\'s better, your lipids are

better.\" That woman or that man who is obese is

still suffering the slings and arrows of

discrimination by society. As a matter of fact,

when we showed the data from 2000, John Monroe\'s

group in BMJ and in Practitioner back a long time

ago, these were 36-week trials and the percent

weight loss was about 13 percent in each. That is

pretty much all there is with phentermine which is

the most commonly used drug.

That is sort of, if not the bad news, at

120

least the mediocre news. Let\'s look at what is

going on for the future. I apologize, I am sure

some of the companies out there have some areas

that I have left out here. But we know gut

peptides are a very fierce focus of action with CCK

analogues and enterostatin and so on; opioid

antagonists, the ones in phase 3 trials; various

neurotransmitter agonists and antagonists;

thermogenic agents, the Holy Grail\--increase your

metabolic rate, keep eating and increase your

muscle mass and reduce your fat mass. Growth

hormone and growth factors have been disappointing

to date but maybe there is something there. Things

that enhance lipid oxidation I think will be of

particular interest; and nutrient partitioning

agents will be very interesting agents for the

future. I am sure this isn\'t all. There are many

more areas in which we may be able to affect food

intake, body weight or body composition.

These are just some of the potential

agents. Again, several people and particularly

Frank have talked about bupropion, topiramate and

121

zonisamide which are already out there. There are

several in clinical trials, and then there are a

number of others here. From my understanding,

there are about 350 different drugs in the

pipeline.

This is the data on bupropion. Frank

already showed this, about a 10 percent weight loss

at a year.

Topiramate\--I put this slide up because it

shows 5-year data in epilepsy patients. As Frank

showed you, it has a pretty reasonable comparison

against placebo at 6 months.

This is the data from Gadde on zonisamide,

again showing a 32-week weight loss of about 9

percent.

However, single drugs are not likely to be

very effective or much better than about 10 percent

or 15 percent because there are so many redundant

systems regulating food intake and body weight,

something so critical to life as that. So, I think

I am not sure we are even born yet with our use of

drug combinations. I talked about the infancy of

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drubs. Obesity is a chronic disease. Most chronic

diseases are treated with drugs. Most chronic

diseases require more than one drug. How many

chronic diseases can you think of that are treated

with just one drug?

You heard about phentermine and

fenfluramine. Combinations of drugs may have

additive or synergistic effects. As Weintraub

showed with phen-fen, some of the side effects may

even be offset.

Here is the original Weintraub data

showing about a 15 percent weight loss at a year.

As you know, he took those data out to 4 years. He

had a pretty good dropout rate but still had

efficacy.

Here is another combination of ephedrine

and caffeine. Either one alone is not terribly

effective but the combination causes about a 16

percent weight loss that persisted out to a year.

That is, of course, not on the market anymore.

Here is some data that we did at the

University of Wisconsin comparing phen-fen to

123

phentermine and fluoxetine and the slope is about

the same. These are 6-month data. Again, we had a

pretty good dropout. We did not have a control

group.

This meeting is all about the guidances

and what is going to happen to the guidances. So,

let me put on my helmet, get my lance out and tilt

at this windmill for a while to talk about some of

the things that I think would be very useful to

have from an obesity advocacy point of view.

Obesity is a major public health problem.

We have an epidemic here. There have been 10 times

more people dying of obesity-related causes than

are dying of AIDS in this country alone. Why

shouldn\'t obesity drugs be fast track as they are

for many other drugs? As Dr. Greenway pointed out,

in virtually all the drugs that we see the weight

loss plateaus certainly by 6 months.

Why should we need to show efficacy? Why

should the trials go out past that? Why not have

safety? You know, safety is what is really

important. If you show efficacy, and almost all

124

the drugs show a 5 percent weight loss in 6 months

or better, virtually all the safety issues have

been seen by then, and when we have a drug on the

market\--fenfluramine\--for 20-some years and we

don\'t pick up that it has a problem, it is just a

crap shoot. Why not go ahead and allow the drug

companies to cut those massive costs of research to

get the drugs on the market earlier, and then have

a much more rigorous long-term safety evaluation as

the drugs are on the market and they can begin to

recover some of their costs?

This extended run-in period\--I see very

little usefulness for the run-in period. I am

raising some of the questions that were brought up

at the discussions that we have had, four

discussions so far. One of the things that most

people feel is really pretty useless is a run-in

period. In one of the original guidances people

were supposed to show weight loss and only those

people who showed weight loss would then be allowed

to go on to the clinical trial. That makes no

sense at all. We know that long-term diet and

125

exercise don\'t work. The question is do drugs work

long term? Trying to get people to change their

behavior is very, very difficult. If you can

change their biochemistry maybe we can get

somewhere.

Frank Greenway showed a trial on mazindol

with and without behavior modification, and when

you throw in behavior modification you reduce the

apparent efficacy of the drug but you can only lose

weight so fast. If you starve yourself you can

only lose weight so fast. So, as you have a better

diet and exercise program you wash out the effect

of the drug. Why have a run-in period at all?

Another thing that I think would be

useful\--I was quite interested in Eric\'s comments

about what used to be the acceptable standard, any

statistically significant difference from placebo.

Drugs almost certainly will have to be used in

combination. Unfortunately, sibutramine and

orlistat don\'t work in combination but phentermine

and fenfluramine did. I, and I know others in this

room, have used phentermine and topiramate together

126

and appear to get a little better weight loss than

with either one alone. That has not been studied

in any organized fashion. So, if safe, these drugs

not only cause modest weight loss, many hold

promise that they could be used in combination with

other drugs and I would love to see that in the

guidances somehow. Varied indications for use are

justified. Others have shown that rapid weight

loss initially is associated with better response

of blood pressure, blood sugar. Jim Anderson has

done two meta-analyses showing that rapid weight

loss early, no matter what the time period, no

matter what the outcome measure\--the people who

have lost a lot initially have at least as good or

better outcome variables. So, maybe drugs that

only cause a short-term weight loss might be useful

and then you switch to something else.

So, I think there are many varied

indications for use. Some for short term; some for

long term; some for use after a very low calory

diet, and perhaps the committee could consider some

of those indications.

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One of the things that David Orloff and I

spent some time talking about on the phone is how

desperate the American public for drugs to treat

obesity. So, I think rational expectations for the

media and for patients\--current drugs are only

modestly effective. Drugs in the pipeline appear

to be similar in terms of efficacy. The maximum

weight loss that I have heard is about 17 percent.

When companies over-hype the weight loss

or try to convince people that a 5 percent or 10

percent weight loss is wonderful, it is not. So, I

think over-hyping is bad on the part of the drug

companies. On the other hand, over-caution by the

FDA and scientists is detrimental. Hundreds of

thousands of people are dying of obesity-related

causes. Some drugs cause some problems. We have

to be safe but there is that tradeoff and Eric\'s

balance at the end I thought was particularly

appropriate. The media has not always been

responsible. In fact, I would say the media has

been predominantly irresponsible. I still remember

the Redux revolution\--the cover on Time magazine,

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this is going to solve all your problems, America.

The general public is desperate. They need

perspective and understanding of obesity as a

disease. Physicians have not really given them

that perspective. Unfortunately, I think long-term

lifestyle changes are needed. Trying to change

behavior is very difficult but that is what we are

stuck we right now.

For the future, I believe drugs of the

future of obesity treatment has the offer of

virtually every other chronic disease. Obesity is

due to biochemical differences. Drugs change

biochemistry. And, why am I so optimistic? Frank

Greenway showed you the data on obesity surgery is

somewhere between 25-40 percent of anethole body

weight. Surgery doesn\'t work because it makes a

little gastric pouch. It works because it changes

the biochemistry of the body. There are starting

to be lots of papers on changes in metabolic rate

and multiple different hormones. And, if surgery

can do it I have no doubt that the smart people at

the drug companies are going to figure out how they

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can reproduce that kind of weight loss with one

drug or combinations of drugs. The surgery changes

biochemistry.

At least 350 drugs are in the pipeline, I

understand, and I think that bodes very well for

the future. Combination treatment I think is going

to be necessary, and I think the future is

extremely bright.

So, I will just end up by showing the

slide for the American Obesity Association. It is

a lay advocacy group. Its mission is to improve

the quality of life of obese people. I guess you

got copies of these slides but this is my contact

information, here. Thank you very much.

DR. BRAUNSTEIN: Thank you, Richard.

Questions from the panel? Let me start off with

one. You mentioned that fenfluramine had been on

the market for some time before the valvulopathy

was uncovered. If we look at the previous

speaker\'s slides on the use of fenfluramine, it

really didn\'t pick up greatly until the Weintraub

papers had come out. So, I wonder if what we are

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talking about in terms of safety is a numbers game;

if you really do need a large number of patients to

pick up some of these potentially disastrous

complications. I would like your thoughts on that.

DR. ATKINSON: Yes, I notice there was

something like 70,000 prescriptions of fenfluramine

per year over a long period of time. That went up

to several million later. But Weintraub\'s paper

came out in 1992. By 1993 those numbers were going

up dramatically and it still took until 1997 before

it was identified, and there were millions of

people taking it obviously, and fenfluramine and

dexfenfluramine had been used in Europe.

Obviously, dexfenfluramine had been approved 10

years earlier. So, it is not just here. It was

all over the world that it was being used and it

wasn\'t picked up.

So, you know, I think drugs are going to

have consequences and obviously we need to look

very carefully at the drugs and study them, but I

would argue for shorter initial trials and more

intensive longer-term trials. I noticed in one

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slide that the FDA was not charged with showing the

safety of drugs after they have been approved.

That probably ought to change.

DR. S. YANOVSKI: I would just like to

comment on your excellent question about

dexfenfluramine and why it hadn\'t been picked up

earlier with the fenfluramine. Before the

Weintraub papers came out these drugs were used

only exclusively short term, often 30 days or less

and it was never more than 90 days. It was only

after the Weintraub paper came out that they

started getting used for months and months and, in

some cases, even years. Since there was a length

of treatment response relationship with the

valvulopathy, that is likely why it wasn\'t seen

earlier.

DR. ATKINSON: Yes, that is an interesting

point, however, there were a number of people that

were reported that had valvulopathy who used it for

a relatively short period of time. It is probably

an idiosyncratic reaction.

DR. BRAUNSTEIN: Dr. Woolf?

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DR. WOOLF: I am unclear. Are you

proposing that drugs for the treatment of obesity

be held to a different standard in terms of

evaluation of efficacy and safety than drugs in

general? At least the drugs that we discussed in

this committee before have had trials longer than 6

months, and certainly the clinical trials that I

participated in have been longer than 6 months.

So, are you proposing a different standard for

obesity drugs, or that the FDA change its modus

operandi?

DR. ATKINSON: I couldn\'t hear that very

well, but what I heard is am I proposing different

standards for obesity drugs? I think there are

different standards for different drugs. For

example, drugs for Alzheimer\'s disease, drugs for

AIDS, after relatively limited safety and efficacy

evaluations, are allowed to go on the market. The

point I am making is we have an epidemic of obesity

and a third of the population is affected. I think

it is not unreasonable to say how can we improve

the delivery of drugs, new and better drugs and

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more drugs so we can try some of those

combinations? No, I don\'t want to have different

standards but I think there are different standards

for drugs and I would like to put obesity with sort

of the ones that get handled expediently.

DR. BRAUNSTEIN: Dr. Schade?

DR. SCHADE: I have a question about

weight loss. If one assumes that the drugs overall

result in, let\'s say\--I am going to be

optimistic\--10 percent weight loss, if you look at

the mortality or morbidity curve, if somebody has a

BMI of 35 and they lose 10 percent of the weight so

they drop to a BMI of 32, is their mortality then

exactly the same as a group that doesn\'t lose

weight but has a BMI of 32?

DR. ATKINSON: Yes, that is a very good

question. I don\'t know the answer to that.

Katherine Flegal\'s data were mainly focused on the

lower BMI groups. As you start up, when you start

getting to 30 and above, those curves start going

up fairly dramatically I think, if that is right,

Katherine. But I can\'t tell you that if you have

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lost 2, 3 or 5 BMI units, do you then assume the

mortality and the morbidity of people who have

never been above that. I just don\'t know that.

DR. SCHADE: Well, the reason I ask that

is when we treat diabetes we treat hemoglobin A1C

and we assume, through our treatment, that we then

reduce the hemoglobin A1C and we can plot on the

curve the benefit. I just wondered whether the

curve for obesity is similar.

DR. ATKINSON: Yes, and I think that is

good. As you heard, there are some trials that are

ongoing to try to look at these sorts of things.

Again, this is a disease that

affects\--what?\--100-some million people in the U.S.

and we know almost nothing about it.

DR. BRAUNSTEIN: Dr. Aronne?

DR. ARONNE: Can I comment on the last

question? I think that the benefit from small

amounts of weight loss is disproportionate to the

amount of weight lost because of the initial loss

of visceral fat. When you look at the composition

of weight that is initially lost, it is the

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riskiest fat that is lost first so small amounts of

weight loss appear to have disproportionate

benefit, out of proportion of what you would expect

from that small amount. What some people have

suggested is following something like the

C-reactive protein and that in the future that

could turn out to be our version of the hemoglobin

A1C because it is a measure of the inflammatory

burden of fat, and a lot of people believe that

visceral fat is where a lot of the C-reactive

protein is coming from.

DR. BRAUNSTEIN: Dr. Orloff?

DR. ORLOFF: Can you reiterate your

position on the run-in aspect of trial designs, and

specifically address whether you are proposing that

all run-ins of any duration, of any type, be

dispensed with?

DR. ATKINSON: No, certainly not. I think

a run-in period in the trials that I have designed

and gone out and done, investigator initiated type

clinical trials, we have put in a 2-week run-in

period that was not a treatment period but we

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stretched out the initial evaluation. What that

does is get out the people who are not serious, who

don\'t want to come or it is too difficult to come,

or whatever. But in terms of requiring a weight

loss or requiring people to show that they can

adhere to a diet before they are allowed to go on

drugs, that is not true for other kinds of

diseases, for example, diabetes and hypertension,

and there may be companies that would want to do

that and would want to have a run-in, or that would

be what they think their drug is going to be useful

for\--in other words, get the weight off and then

this is going to be their weight maintenance drug.

Fine, they can have a run-in. But I think the

mandate that all companies have to have an extended

run-in I don\'t agree with.

DR. ORLOFF: Again, a bit more

clarification. Do you still advocate diet and

exercise and continued reinforcement of those

lifestyle aspects for treatment of obesity in the

context of the trial?

DR. ATKINSON: Yes, I guess it was fairly

137

dramatically shown here. Dr. Greenway showed the

difference in weight losses that are achieved in

the United States versus over in Europe. The

companies design the trial to get well over

whatever the standards are. So, I think that can

be manipulated.

I make the statement often that everybody,

whether they are skinny or fat, needs to have a

good diet and lifestyle. I think as people come in

they need to be informed of what is a healthy

lifestyle and the exercise and the vegetables, and

all those things. Again, I am speaking for myself

not for anybody else, but I think the idea of

allowing the drug companies individually to figure

out where in the spectrum they want to put that is

not unreasonable, but at least some lip service

ought to be given, if for no other reason, because

people will do things very differently. I mean,

they have to be given something because, as anybody

here who has ever taken care of obese people knows,

they get all excited about how they are going to

lose weight and they may even go on a starvation

138

diet, and all kinds of things. So, you have to

have some guidance.

DR. BRAUNSTEIN: Dr. Follmann?

DR. FOLLMANN: I guess one thread that is

running through your talk is that obesity is a

disease. So, if obesity is a disease and I am

thinking of weight loss in someone as a surrogate

for clinical endpoints\--if obesity is something

more about being concerned about your body image,

then maybe weight loss is a proper primary

endpoint. So, with your advocacy for short

duration trials where, you know, you might have

transient effects that can\'t be maintained so you

will end up with no net weight loss over a long

period of time, I don\'t see how that is really

helping combat obesity as a disease. So, I worry

about the surrogacy issue of weight loss in this

population, and particularly when you are

suggesting just to do short-term studies.

DR. ATKINSON: Again, I was having a

little trouble hearing, but the idea about obesity

as a disease and if people lose weight and then

139

can\'t keep it up, is that a negative? Well, people

have cancer and they can\'t keep that off and it

comes back. Yet we still approve drugs for cancer.

Many of you on this panel are diabetologists. I

was a diabetologist before I was an obesity doc.

None of the oral agents work for more than a few

years and then pretty much, if the patient has bad

diabetes, we put him on insulin. Again, are we

going to hold obesity to a different standard? I

don\'t think it is fair.

DR. FOLLMANN: So, basically you are

thinking even if you keep weight off over a

relatively short period of time it should have

clinical benefits. Is there evidence for that?

DR. ATKINSON: Yes, there are a few papers

looking at rapid weight loss, and even out at a

year, as compared to the slow weight loss on diet,

where the people had better glucose tolerance. The

same thing was shown with hypertension, and there

may be other studies that Lou or Susan can come up

with. People certainly feel better and their

mental outlook is improved. Lots of studies have

140

shown that weight loss is associated with that.

Yes, when they regain their weight they feel bad

again. I don\'t know how to get around that. We

need better drugs that are effective longer term.

DR. BRAUNSTEIN: Dr. Flegal?

DR. FLEGAL: I just wanted to follow up on

the question asked a while ago about change of a

BMI from 35 to 32 and its effects on mortality. I

know you can\'t hear me\--by the way, it is very hard

to hear from the podium. That is why all of us are

acting like we are deaf when we go over there.

Although the literature certainly suggests that

your blood pressure improves more rapidly or goes

down further than you would expect from the weight

loss, the observational epi. studies do show that

mortality is not necessarily decreased and may, in

fact, increase with the weight loss. So, the

changes in cardiovascular risk factors are

improvements but mortality data in the

observational studies, which have a lot of

limitations, don\'t actually show that. In fact,

your mortality may be increased.

141

DR. ATKINSON: I would just make one

comment about that. There is almost no data to

show that losing weight improves mortality. There

is a paper from 1963 of Metropolitan life tables

that showed that but I am not sure I believe that.

But Corey\'s data from surgery is the one paper that

shows that if you lose a lot of weight you have an

improved mortality. So, again, we need better

drugs and bigger weight loss.

DR. HIRSCH: I can tell you that the

people who are BMI 35 and go down to 32 are really

different from those who are 32. This is not

humorous; it is a rather subtle matter. That is,

those who come down to 32 don\'t stay there. They

go back to 35. Those who are 32 stay there. And,

that is a key difference. That is a very

interesting mixture of behavioral, biochemical,

social and I don\'t know what else. But until we

understand that we are going to be in some big

trouble in trying to figure out how to handle

weight loss.

The other thing I would comment on is the

142

phen-fen business. It is a very interesting

matter. If you look carefully, as I have a number

of times, at the Weintraub papers, please keep in

mind that this was not the great

pharmacotherapeutic trial of all time and we were

undone because of adverse effects. Not at all.

The dropout rate was enormous in that study. And,

of the few survivors remaining after four years,

even they were working their way back up to their

starting weight.

Insofar as the adverse effects were

concerned, you have to remember that we were coming

into the age of echo cardiography. This was

getting more and more commonly done with a greater

recognition of this. So, there was a sort of

cultural change in medicine that permitted a more

rapid uncovering of the valvulopathy that may or

may not have been all that significant as time has

shown but, nevertheless, occurred with these drugs.

DR. BRAUNSTEIN: Dr. Watts?

DR. WATTS: To go back to the issue of

surrogate endpoints again, I certainly can\'t argue

143

with the value of weight loss for someone who is

overweight but I am interested in knowing\--and this

has been explored a little bit\--the differences in

quality of life for people who have lost weight,

and I don\'t think any of the speakers have

addressed that, and differences in surrogate

endpoints, which was touched on. Some drugs may

have the same weight loss but different effects on

blood pressure, lipids, and so on. And, if we are

really concerned about the medical consequences of

the epidemic of obesity, evidence that short-term

interventions or any intervention will have an

impact on anything other than the scales I think is

of critical importance.

DR. ATKINSON: There is certainly a lot of

data showing short-term dramatic decreases in blood

sugar, insulin levels, blood pressure, triglyceride

levels, sleep apnea. A number of the complications

of obesity get dramatically better with weight loss

and, surprisingly, without a huge amount of weight

loss. I mean, you take somebody with a BMI of 45

and they go down to 30 or 38 and their sleep apnea

144

goes away; their diabetes has gone; their

hypertension is much better; their incontinence is

better; their arthritis is better. So, those

things certainly occur.

Yes, as they regain their weight it comes

back. Many years ago there was the wonderful paper

on glucose tolerance tests and the one who started

with 100 kg and lost down to 60 kg, she had frank

diabetes and everything got\--she was perfect; she

was normal. Then, as she gained weight her insulin

started going up and finally her glucose went back

up and she was back to having full diabetes. Did

she delay anything from her two or three years of

being normal? I don\'t know.

DR. WATTS: We have all seen dramatic

improvement in individuals who lost weight. My

question is have these changes been validated in

large-scale trials? As to the quality of life, I

would be interested in knowing if at the end of,

say, a 6-month program the people who lose weight

have an improved quality of life and then, when

they regain it, is their quality of life worse for

145

having succeeded and then failed than having not

tried at all?

DR. ATKINSON: Just to get one thing

straight about yo-yoing, for example there have

been now several meta-analyses looking at the

effect of repeated cycles of dieting and does that

make your diabetes or your hypertension, your

whatever, worse\--in other words, you would have

been better if you had never done it, and that does

not appear to be the case.

Certainly, there are many studies showing

that your quality of life improves with weight loss

and, yes, it goes back to what it was when you

regain the weight. You know, I don\'t know where to

go without saying, you know, when you have any kind

of disease and it gets better for a while and then

it gets worse, yes, it gets worse again.

DR. BRAUNSTEIN: Ms. Coffin?

MS. COFFIN: I have a couple of comments.

At one point you actually warned drug companies and

the media about over-hyping things. I want to

caution that the 400,000 people that are dying of

146

obesity-related diseases leads people to believe

that if they were to walk in any hospital all they

would see would be obese people and that is not, in

fact, the case. So, you need to be careful, again,

with how you are doing that because then an obese

person says, \"oh, I walk into a hospital and there

are lots of thin people there that are just in poor

health.\" So, be careful with that.

As far as people always gaining weight

back, I don\'t think that that is necessarily the

case. I don\'t think that we have the studies to

prove it one way or the other. Again, you have

huge dropout rates. People are very ashamed about

dealing with their obesity. I would relate it to

the mental health drugs and how we treat mental

health drugs and you wouldn\'t think of putting

someone who is severely depressed on a medication

without also putting them on behavioral changes as

well. There is value in the process of learning to

deal with lifestyle changes. I think if you use

drugs alone you are going to see 6 months and you

will bounce back because you haven\'t learned the

147

process of becoming a more healthy person. If you

go through rehabilitation if you break your leg,

you rehab and you learn how to deal with that

injury. So, you use the drugs to start out.

You suggest using the drugs, like in

diabetes, where you start with drugs and also

lifestyle changes. What that could do is that

could give a patient some initial success which

then bolsters their motivation but, without that

lifestyle change, if the lifestyle change isn\'t an

adjunct and there isn\'t a process or a protocol to

get those folks off the drugs, then, yes, you are

going to find that they bounce back. So, those

would be some of my comments as far as that goes.

DR. BRAUNSTEIN: Dr. Aronne?

DR. ARONNE: I was going to point out, as

far as the mortality issue is concerned, that the

paper that was just published in September in The

Annals of Surgery that looked at 1000 patients who

had gastric bypass and other obesity surgeries in

Canada versus 4000 controls showed striking reduced

mortality in the surgical group compared to the

148

control group. The numbers they reported were 89

percent reduction in mortality in the treated group

compared to the control group. So, it suggests

that there is a difference.

DR. BRAUNSTEIN: Dr. Woolf?

DR. WOOLF: Listening to your discussion,

there seem to be two aspects to your presentation.

One is the image of the obese person in society and

that would take, I would guess, 50 percent weight

reduction, somewhere between 30-50 percent. That

is very different than the weight reduction to

improve comorbidities, which may be 10 percent. So,

really the question is will one drug fit all sizes?

Are we going to have to have different standards

for different things? I mean, if we say that image

is something that our society needs to pay for,

that is a humongous issue. If we are talking about

improvements in comorbidities, that is still a very

large issue. In your discussion I don\'t see that

difference. I see we have to treat obesity because

we are discriminating against obese people. Yes,

that is true but it is going to be a tough issue to

149

get a handle on.

DR. ATKINSON: That is one of the

barriers. It certainly is going to be very

expensive, but expense has not kept us from

treating many other diseases that are not as common

as obesity that are also very expensive.

To give you an idea about how painful it

is and the reason that I keep pushing more than 10

percent weight loss, Coleen Rand did a study asking

obese people who had had surgery and had lost large

amounts of weight what price would they pay to stay

thin. They were asked if, \"I give you two million

dollars will you let me hook you back up and you

will regain your weight?\" A hundred percent said

no. \"If you knew the price of staying skinny was

to go deaf, would you rather be deaf and skinny or

fat again?\" A hundred percent wanted to be deaf;

89 percent wanted to be blind rather than fat

again.

So, that level of pain\--I think we in the

health professions need to address that. It is not

a cosmetic issue. All those things I said are

150

true. There are many, many studies showing that it

is harder for people to get a job, to get promoted,

to get married, and so forth. This is not simply a

cosmetic issue.

DR. BRAUNSTEIN: Richard, thank you very

much. We actually need to move on to the public

hearing to try to stay somewhat on time. We

haven\'t received any outside requests. Many

different individuals and companies have sent in

documents for the committee to review before the

meeting in response to the information in the

Federal Register. Is there anybody in the audience

who would like to address the committee? Not

hearing any, we will go on to Dr. Orloff\'s

presentation about the 1996 FDA draft guidance

document and he will also deliver the charge to the

committee.

Charge to the Committee

DR. ORLOFF: Thank you. First thing, I

want to apologize in advance. I was making some

last minute changes to these slides before the

break or during the break and the last ones outline

151

the questions for our discussion that I intend to

go over now. We will then put them up. If they

are hard to read now, I promise I will have them

fixed during lunch.

My purpose here, as Dr. Braunstein has

said, is to go over what we believe are the

important aspects of the 1996 guidance, many of

which have been touched on already but to make sure

that I have gone through the rationale behind those

aspects of the guidance, you know, from a

scientific, and clinical, and regulatory

standpoint, and then to move to a discussion of

some of the issues that were raised in the comments

that we received in response to our Federal

Register notice soliciting those direct comments,

and then from that, I will translate those into

items for discussion.

Our 1996 guidance, first of all,

identified patient populations based upon evidence

that these were populations at risk from chronic

adverse sequelae of obesity. As you can see, these

included, and still do in our drug labels, patients

152

with BMIs from 27-30 with comorbidities, for

example hypertension and diabetes, or patients who

are more obese than that, that is to say, greater

than 30 kg/m2 and they didn\'t necessarily have to

have comorbidities.

Again, the identification of patients at

significant risk goes to some overriding principles

that I will touch on probably multiply in this

presentation. The first is that, regardless of how

long these trials are and how many patients we

treat, we are always going to have limited

information at the time these drugs go to market,

and these are chronic use drugs, albeit presumably

for eventually a life-threatening condition but not

immediately life-threatening. So, we need to be

sure that we have identified patients who are at

substantial risk from the disease before we confer

risk of drug. All drugs are associated with some

risk.

I should also mention, in follow-up to

some of the conversation that was occurring

earlier, that this is a standard that is not unique

153

to the obesity drug group. This is a standard that

we apply to all chronic use drugs for what are

deemed, at least at the time that the therapies are

initiated, as non-life-threatening conditions.

Obviously, the guidance also includes as

an aspect of study design the run-in phase, which

was touched on in Dr. Atkinson\'s talk. The

rationale beyond that run-in phase for the trials

of new obesity drugs were, number one, to identify

placebo responders in order to avoid the

unnecessary treatment with drugs of patients who

were likely to do well on diet and lifestyle

changes alone. That is in keeping with what we

believed at that time and I think the committee

agreed with really a central tenet of medical

management of any chronic condition or disease,

that if you can do it with other than the most

invasive or potentially the most toxic

intervention, then that should be your approach.

With regard to the duration of phase 3

studies, again touched on a few minutes ago, we

noted, and it is really hard to toss it off to

154

bias, that there is an unavoidable fact of

historical bad luck with anti-obesity drugs. Their

mechanisms of action, perhaps the underlying risks

of the patients, the fervor with which new obesity

remedies are met by the continuously growing

population of obese patients, all lead perhaps\--I

guess in retrospect we could say\--to decisions with

regard to approval and method of use that in the

end are not necessarily advisable.

Also, it is important to point out that to

this date we have really a dearth, if not a

complete absence, of hard outcomes data from trials

of obesity drugs. With the exception of the recent

Sandoz trial which looked at an aspect of perhaps

irreversible morbidity\--probably not irreversible

but significant morbidity associated with obesity,

that is to say the development of frank diabetes,

we don\'t have much in the way of hard outcomes data

with regard to sequelae and we certainly don\'t have

mortality data.

So, in the absence of these data going

into development, we held a standard of a first

155

year placebo-controlled study in order to provide

proof of principle of efficacy and, obviously, also

to provide a comparison group for the assessment of

causality with regard to adverse outcomes observed

in the context of the study.

That was to be followed by a second

open-label year optional open label. It could also

be placebo-controlled in order to establish

durability of efficacy and tolerability, because

tolerability clearly, even if it is not toxicity

per se that leads to intolerability, does impact

the ultimate effect of the drug. And, to establish

long-term safety.

Our efficacy criteria have been mentioned

here and we actually had two efficacy criteria.

There are two efficacy criteria from which a

sponsor can choose essentially, post hoc for that

matter, in order to propose that their drug, indeed

is effective. Those criteria are, number one, a

mean placebo subtracted weight loss of greater than

or equal to 5 percent from baseline, or a

categorical analysis, as we refer to it. That is

156

to say, the proportion of subjects who lose greater

than or equal to 5 percent of baseline body weight

is greater, simply statistically significantly

greater in the drug versus placebo-treated group.

At this point, I don\'t think anyone here,

at the FDA, believes that these are too stringent

criteria for the establishment of efficacy, and we

note that the EMEA criteria that are still in place

are more stringent still with 10 percent cuts for

both of those criteria.

With regard to patient exposure, again

something that came up in the conversation just

past, the fact is that the size of patient

exposures is in the end arbitrary. There are

really no fixed constructs for how to establish the

size of a patient exposure, aside from mathematical

ones and the statistical principles that allow you

to determine that a given exposure can exclude a

certain rate of adverse events. Unfortunately, we,

or anybody else for that matter, don\'t know how

many patients you really need before you can see

that horrible adverse event that might crop up when

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it goes into the marketplace.

Our patient exposure criteria were a total

of 1500 patients completing 1 year and a placebo

control exposure, and then at least 200-500

patients completing the second year exposed to

drug. Obviously, in some cases I believe that

second year has been placebo controlled.

I note also that these standards are in

excess of the standards laid out in the ICH E1A

document which talks about safety exposures in the

development of drugs for long-term use in

non-life-threatening conditions. Specifically, the

numbers in that document are 300-600 for 6 months

and 100 for 1 year\--it is not listed here, but with

a total of 1500 patients exposed totally, including

in single dose biopharmaceutics studies.

To digress for a second but I think

important to this conversation, the ICH E1A

document goes further into discussing how to

essentially tailor the exposures in clinical

programs to a particular drug or indication.

Although those minimum numbers that I cited on the

158

last slide, 300-600 for 6 months and 100 for 1

year, are by many taken as the standard across the

board, the document clearly states that larger and

longer exposures are merited, or maybe be merited,

if the benefit of the drug is, on the one hand,

small, for example related to symptomatic

improvement or for the treatment of a less serious

disease experienced by only a fraction of treated

patients, as in perhaps a prevention type

intervention and of uncertain magnitude.

Specifically, they cite reliance on a surrogate.

Again, I point out that we don\'t have hard endpoint

data with obesity drugs generally or even, for that

matter, with any specific obesity drugs in terms of

mortality.

Our experience, again tempering our

approach to these products, as mentioned by Dr.

Atkinson, is with only modest efficacy of drugs

that we have approved and evaluated to date and, as

far as anyone around here knows, not anticipation,

frankly, that there is anything in the pipeline

that is going to be dramatically more effective

159

than what we have seen already. Anyway, I have

already made these points so I am going to move

on\--I don\'t need to say this; I don\'t need to say

that; I don\'t need to say that.

So, we put out our request for comments on

the guidance and a number of issues were raised. I

am going to walk through some of these and I have

noted what issues were not addressed in the

proposals. This should, I hope, segue into my

outlining our topics for discussion. I apologize

because I don\'t believe the order here is

necessarily going to correlate with the order of

the questions but maybe we will get lucky.

The first comments related to the

broadening of the target population. We will

include in this first one pediatrics/adolescents.

It is noted by the petitioners, if you will, that

this is a burgeoning problem, I guess in a sense

echoing the problem that was first evident in

adults, that is to say, childhood obesity long-term

population-specific risks, as well as

non-population-specific risks. One of the issues

160

that is raised as a simple statement is that the

most appropriate endpoint in growing children

should be body mass index rather than weight. I

don\'t think anybody has any quarrel with that.

I have underlined here \"no specific

criteria for selection\" were proposed. So, one of

the things that we ought to think about is what are

the entry criteria, if you will, or the eligibility

criteria for adolescents and children into trials

and, therefore, for selection for treatment.

The other one with regarding to broadening

the target population is lowering the BMI limit,

again something that was discussed by Dr. Flegal at

least with regard to the epidemiologic data. This

really, in my mind, at least in part comes down to

targeting prevention of weight gain, something that

I will mention in a second.

The petitioners talked about high risk

treatment and prevention in this lower BMI

subpopulation, although the definition of high risk

is not given, which is an issue we need to discuss.

They point out that there are observational data,

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if not controlled trial data, that drugs are

effective. That is to say, they are associated

with weight loss in excess of placebo in subgroups

of patients in larger trials who have lesser

degrees of obesity.

Finally with regard to broadening the

target population, there has been a lot of talk,

not just in the comments we received but for

several years, about essentially targeting some of

the comorbid features of obesity, for example

diabetes, metabolic syndrome, perhaps dyslipidemia,

perhaps hypertension, as primary targets for

anti-obesity therapies. One thing we want to talk

about or hear about is sort of general opinions on

that but also what would be the criteria for using

obesity drugs as primary therapies in those

diseases.

With regard to study design, we talked

about run-in, and the only thing that wasn\'t

mentioned was the means of assuring standard of

care in the context of the trial. We will want to

hear more discussion of the importance of the

162

run-in from the standpoint of inference of

efficacy, but also I think when I queried Dr.

Atkinson, whose thoughts I believe are consistent

with the petitioners on this issue, he was not

excluding diet and exercise as a standard of care

intervention in clinical trials.

The duration\--Dr. Atkinson raised this in

his presentation. The comments that we received

actually proposed one year of controlled efficacy

but safety at one year as well. There were

questions about the utility of an additional year

if there were no safety concerns raised after one

year.

There is no approach given, and I think

that is something that bears discussion, to

assessing the need for additional time or patients.

For example, there are always issues about

durability of efficacy which, in some respects, is

a simpler problem. But the necessity and

appropriateness of longer term and larger safety

exposures\--let\'s just say it is hard to come up

with any rationale for a specific fixed duration.

163

FDA always errs on the side of caution and so

larger and longer is the way we go. But if we are

going to go shorter or at least allow for shorter

and smaller, we have to be able to have some

constructs to guide us and to guide sponsors in

those instances where longer and larger exposures

might be necessary. So, for example, preclinical

findings, mechanism of action, the information that

would lead to presumptions with regard to the types

of toxicities, that is to say, acute, idiosyncratic

versus chronic, cumulative dose related, as being

two diametrically different situations which would

clearly direct different approaches in development.

Combination studies really is the next

issue and we will want to talk some about the

efficacy criteria for such studies. I will say a

bit more in just a second when we get to those

questions.

A new efficacy criterion was proposed. We

are actually at a loss to make anything of it at

this point. It was simply a total weight loss of

greater than or equal to 5 percent from baseline at

164

12 months, seemingly ignoring any placebo effect.

Other criteria proposed are in keeping

with our current criteria. Then, there was a

proposal actually to raise the bar on what would

constitute a categorical win. I am not sure

exactly where that comes from, although it would

clearly put certain drugs in a loftier or in a more

favorable position from a regulatory and marketing

standpoint.

With regard to efficacy criteria, there

were requests to define weight maintenance,

prevention of weight gain, drug-induced weight gain

and, as I talked about earlier, the efficacy

criterion with regard to BMI change in pediatric

patients. I already talked about safety exposures.

So, by way of summary, if I haven\'t lost

everybody in this rambling, let me go through what

I would like us to talk about now. With regard to

lowering the entry criterion to a BMI of greater

than or equal to 25 kg/m2 when accompanied by

comorbidities, we need to ask what evidence

supports treatment or prevention in this

165

population; what magnitude of effect would be

deemed clinically significant; and what assurance

of safety is required to treat lower risk patients.

Is this one of those instances, for example, where

you need larger numbers and longer exposures?

With regard to pediatric and adolescent

patients, what factors should be weighed or

addressed in assessing risk versus benefit, again,

in this population who, no matter how great the

problem is, I think it is agreed have a relatively

low short-term risk of at least what are deemed the

classic comorbid features of obesity or chronic

sequelae of obesity, I should say.

Then with regard to obesity associated

with metabolic derangements and cardiovascular risk

factors as primary targets of drug therapy, I think

we just need to hear some discussion there.

The run-in I have already raised. With

regard to combination drug regimens and designs, I

just want to say a few words by way of background.

The combination drug standard for the Food and Drug

Administration or approval standard is a simple

166

one. It requires that (a) and (b) together, the

two drugs in combination, be better than either one

alone. But that can be a fully additive

combinatory effect. It can be a synergistic or

less than additive effect. It can be a

multiplicative effect. I think a simple question

for approval of a combination drug regimen is what

is the incremental effect of adding one drug to

another that should be deemed clinically gainful?

As I suggested, should it be an expectation of

additivity? Should it be simply statistically

significant increased efficacy over one drug alone?

It is something we need to think about.

With regard to obesity prevention, weight

maintenance and prevention of weight gain, and Eric

Colman in his presentation actually showed you the

indication sections for sibutramine and orlistat

and those terms did find their way into those

labels. I will confess here that we did not have a

standard of evidence which we applied to the data

that were proposed to support those indications.

I guess I would begin by asking at this

167

late stage whether those, for an individual drug,

are expected to be distinct clinical effects and/or

distinct pharmacological effects. If they are

deemed to be, are studies needed to document

efficacy and safety for each of these indications?

I would propose, based on pure sort of logic,

intuition, common sense, that in fact these are not

likely to be distinct clinical and pharmacological

effects but I am interested to hear comments.

With regard to proof of treatment or

prevention of drug-induced obesity, this is

something that gets raised a lot. It is obviously

a subset of a much larger obese population due to

other causes and, yet, it is a problematic issue

for patients who take, for example, anti-diabetic

agents and who are faced with weight gain even as

they are attempting to control their diabetes. But

I think if we start to look at this from a

regulatory standpoint and, frankly, from a

standpoint of establishing a science-based clinical

rationale for these interventions, there are some

questions that come up. For example, do we know,

168

across all the drugs that are associated with

weight gain, what are the risks associated with

obesity associated with those drugs? Is it

run-of-the-mill risks associated with obesity? Are

they in some instances, because of the nature of

the drug, less prone to at least the long-term

sequelae? I think the classic example is the

diabetes drug one.

There are clearly also going to be issues

of interactions between the obesity drug, the

disease and the medications that are used to treat

the primary condition that may impact the safety

and efficacy of both agents, but let\'s just say for

the sake of discussion, talking about impacting the

safety and efficacy of the primary therapy. An

example might be weight gain associated with

neuropharmacologic intervention and the use of an

obesity drug that might work, at least in part,

through a central mechanism. What standard of

evidence is necessary to support intervention with

an obesity drug in a population of patients who

have developed obesity using neuropharm. agents?

169

With regard to the reduction in the number

of patients, again, there is no rationale based on

the magnitude or the nature of expected efficacy or

documented efficacy. There is no rationale based

on the size of the target population. Something I

didn\'t mention earlier is that it always has given

us pause, and I think a lot of our advisers, that

the population that ultimately will take obesity

drugs is absolutely massive.

As I think Richard Atkinson said, we do

live in constant fear of even a very low incidence

adverse event, but serious adverse event, rearing

its ugly head postmarketing when the drug goes from

an exposure of a few thousand to an exposure of not

just a few million but millions upon millions. It

is important for purposes of this discussion to

understand that try as we might, and with as much

money and emphasis that FDA places on postmarketing

safety surveillance of drugs, the best way to

understand drug safety still is in the context of

an adequate and well-controlled investigation.

Spontaneous adverse event reporting in

170

postmarketing has severe limitations, for obvious

reasons. I would say that as a rule the instances

in which spontaneous reports are truly useful are

when the adverse event is so wild and unexpected

and idiosyncratic that there is an unavoidable

conclusion of association. For example,

rhabdomyolysis with statins. That is not often the

case with drugs, and in a disease where many of the

drugs may confer or interact with regard to

cardiovascular risks, targeting a population whose

underlying disease puts them at risk for such, as

in the blip in the sibutramine marketing that

occurred in Europe on the basis of a couple of

cardiovascular deaths, it is really impossible to

render conclusions about causality in those cases.

With regard to the second year of an

open-label study, again I mentioned this, there is

no rationale based on the nature of drug toxicities

acute versus cumulative.

There were some other suggested changes

that we just wanted to hear comments on, which I

believe I mentioned before\--categorical weight

171

loss, absolute difference criterion; metabolic

syndrome as a therapeutic endpoint. I have

mentioned drug combinations. Then, something that

came up before, it is worth conversing a little bit

about cosmetic weight loss, under which I include

psychosocial benefits, socioeconomic benefits and

quality of life.

As I promised, I will clean those up

before the discussion because, since these do not

conform to the printed versions of the questions

that you got or the issues, we are going to plan to

just put them up on the screen as we talk. Thank

you very much. If there are any questions that I

can answer now, please go ahead.

DR. SCHAMBELAN: Dr. Orloff, with respect

to the question of the numbers of individuals in a

phase 3 study and/or the duration of the study and

the fact that relatively rare events often don\'t

emerge until postmarketing surveillance phase 4,

does the agency have any idea of what the effective

cut point is whether going from 500 to 1000, how

many detections of what ultimately turns out to be

172

a side effect that makes a drug unapproved\--how

often does that occur or one year versus two years?

You kind of alluded to that and I wonder if there

are any data.

DR. ORLOFF: I don\'t believe there are any

data. This comes down to experience and ultimately

I do think we have to look at things like drug

mechanism, preclinical toxicity, and then integrate

that information into a construct that is based

upon the severity of the disease being treated, the

magnitude of the effect observed, the size of the

population that is going to get it. Those are the

factors. We don\'t actually have the data. The

experience is, remarkably enough, that there is

something that works in our system. We do have

drugs out there for chronic life-long use, but at

the end of the day, despite having only been

studied in a relatively small number of patients,

appear to be quite safe and extremely useful

products. For example, statins I think are a huge

success and boon to the public health.

Anti-diabetic agents, troglitazone not

173

withstanding\--the number of approvals in recent

years have apparently made quite a difference in

the experience of patients and physicians who are

addressing that disease.

DR. BRAUNSTEIN: Dr. Follmann?

DR. FOLLMANN: I have two questions for

clarification. One, in the original document they

talk about 1500 being a desired number for the

initial efficacy study. Do you know how that

number came about? Secondly, you talked about two

different criteria for approval and then you

alluded to the fact that these could be chosen

after the fact and I wonder if you could amplify on

that a little.

DR. ORLOFF: Eric, 1500?

DR. COLMAN: I have to say that I don\'t

know exactly how the 1500 was derived. My sense is

that in large part it was arbitrary but I don\'t

know that for certain. The second part of your

question had to do with?

DR. FOLLMANN: Well, there are two

criteria for efficacy. Does the sponsor need to

174

prespecify which one they will be using before the

study is done, or is that left unclear and then

decided upon after all the data are in?

DR. COLMAN: I have seen companies choose

one or the other as the primary efficacy outcome.

In some cases, if a company prespecifies that they

will only use the mean difference between groups of

5 percent and they don\'t make it on that but they

have, as a secondary outcome, the categorical and

that does make it, then we would be inclined to

consider that drug efficacious.

DR. BRAUNSTEIN: In my distant cobwebs,

having sat through our original meeting, I recall a

statistical analysis that basically said that if

you have a double-blind, placebo-controlled trial

with half of the patients on placebo and half of

the patients on active drug you need a certain

number\--it may have been 750\--in order to pick up

an adverse event at a 1 percent rate and to show

that it was different from placebo. It was

something of that nature that the number came from.

Dr. Woolf?

175

DR. WOOLF: Two questions. One relates to

the current criteria that 1500 patients must be in

a randomized clinical trial for 1 year. I am

assuming that half would be on active treatment and

half would be on placebo, or is it 1500 in each

arm?

DR. ORLOFF: It is 1500 on drug, I

believe.

DR. WOOLF: Secondly, with other medical

conditions which are serious public health hazards

that don\'t kill you in the next 6 months, what are

the typical sizes of the clinical trials that

currently come into the FDA for approval?

DR. ORLOFF: What was that?

DR. WOOLF: For hypertension,

hyperlipidemia?

DR. ORLOFF: Actually, let me take

diabetes. All right? This is public information

that has been presented at the Drug Information

Association. The agency, our division

specifically, is overseeing development, if that is

the right term, of some several dozen peroxone

176

proliferator activated receptor agonists for

diabetes. Those drugs have substantial and

worrisome preclinical toxicities. For what it is

worth, they also appear in many instances to have

cumulative toxicity in animals. The two marketed

products, rosiglytazone and pyloglitazone, have

reasonable safety profiles. Although they are as

yet not well understood reasons, there are patients

who develop problems specifically related to fluid

retention and congestive heart failure. I don\'t

think there is any good evidence that either of

those drugs has a direct cardiotoxic effect per se,

which is a distinction between what is observed in

humans and what is observed in preclinical models.

Suffice it to say, the level of concern is

such with those drugs that we are asking for very

large, on the order of several thousand, patient

exposures beyond a year and a half. We are talking

about, you know, 500-plus at two years. So, this

standard for obesity drugs is actually below that.

For dyslipidemic agents, for some of these

programs, for example, the Lipitor program I

177

believe had a total of 4500 patients who were

treated with at least a single dose of drug in that

program with active treatment. They had something

approaching a thousand who were treated for a year

and a half, I believe. But going way back, our

division\--because this ICH guidance is pretty

long-standing now; I don\'t know what the date of it

is\--but we have always maintained that a higher

standard is needed specifically addressing those

conditions that ICH laid out. That is to say most

simply, if are approving based on a surrogate, you

don\'t really have a handle on what the ultimate

benefit of the drug is. So, for lack of a better

expression of it, you damned well better be sure

that it is as safe as you can know.

DR. WOOLF: As I recall, I believe when we

discussed Crestor more than a year ago, that was

defined as the single biggest statin submission and

it was several thousand.

DR. ORLOFF: I believe with Crestor there

were 4000 starts on the 10 mg dose.

DR. BRAUNSTEIN: Dr. Ryder?

178

DR. RYDER: I just wanted to add just a

couple of points. The first point is that there

have been several recent symposia on the

application of quantitative assessment tools to the

question of risk management. There was a combined

PhARMA-FDA symposium last fall. The bottom line is

that it very much depends upon what you want to

look at and what the background rates are. I mean,

I can speak a little bit more about hepatotoxicity

because we have, although still poor understanding

of background rates of hepatotoxicity\--I am not

sure about hepatotoxicity in the obese population

perhaps, but it does depend upon what you are

looking for.

Dr. Braunstein, my recollection is your

recollection as far as the ICH goes, and these go

back some time, these numbers came out of the

desire to speak with some certainty about ruling in

or out events that occur with about a percent

frequency, something akin to that.

The last point that I wanted to make is

one that I think Dr. Orloff just mentioned. I

179

think it is very important to keep in mind whether

you are talking of an absolute minimum that you

must have in terms of exposure, regardless of the

details of the preclinical toxicology or the

specific characteristics of the product that you

are investigating, as opposed to the size of a

program that ultimately you design, along with FDA

and external consultants and a number of other

agencies throughout the world today, that has to

answer a couple\--many sometimes\--key

questions\--efficacy; perhaps comparative efficacy;

and, of course, answer a number of safety issues

that have come up during preclinical testing or

early clinical testing. So, it is different when

you talk about a basic minimum versus what

ultimately happens when you get findings. Dr.

Orloff mentioned some of the findings with the

PPODs that we are all struggling with, but probably

every development program has issues like this.

DR. BRAUNSTEIN: Yes, Dr. Carpenter?

DR. CARPENTER: Given the suggested

directives for developing pediatric studies for

180

these types of drugs, what is the history and the

experience with study population size and duration

of therapy in pediatric/adolescent studies with

some of the other drugs you have mentioned as

precedents?

DR. ORLOFF: The pediatric studies, by and

large, are smaller and they are of limited

duration. In our division, for the lipid-altering

agents, LDL lowering specifically, the target

population is restricted within the pediatric age

group to those patients who have heterozygous FH

and who, therefore, have a vastly increased

lifetime risk of cardiovascular disease related to

marked hypercholesterolemia. The proof of

principle of efficacy and safety in those patients

is deemed not to take all that long, let\'s say, or

that many patients.

Our diabetes programs, likewise, are

relatively small. I guess I would offer that, you

know, once we have examined or feel comfortable

with the safety profile\--not necessarily the

absolute safety but the safety profile so we know

181

what the expected adverse events are with a

diabetes drug, for example, then it really becomes

a matter of proving or of demonstrating the extent

of its efficacy, tolerability and then safety along

those same parameters in a pediatric population.

So, again, not a big intellectual leap; not a big

scientific leap.

I should mention that I want to be careful

that I don\'t give the impression because I don\'t

believe it is the case that this relates somehow to

a bias against obesity per se, but there is broad

agreement about the importance of early

intervention in diabetes, control of hemoglobin

A1C, control of metabolic derangements to reduce

long-term sequelae.

Likewise, with marked

hypercholesterolemia, there is a very clearly

understood association between level of cholesterol

and time with extent of cardiovascular disease and,

therefore, clinical cardiovascular risk. We

believe, based upon large experience with the drugs

that we have used to target those two

182

diseases\--let\'s say we understand in most cases

very well the pharmacologic mechanisms by which

those drugs alter the metabolic profiles of the

patients being treated.

I am not sure we always have that with

obesity drugs. If we could get to a place where we

were comfortable with pharmacologic mechanisms and,

therefore, we had a greater comfort level with the

reliability of our limited observations with regard

to safety, then I think using such drugs for

prevention, if you will, or for early intervention

becomes less of a leap.

DR. BRAUNSTEIN: Thank you. Yes?

DR. SCHADE: I have one question. The

reduction in the number of the population that we

study from 1500 to, say, 500\--I can see one of the

rationales would be that studies would be

significantly less costly. There are I think

several arguments that can be made not to reduce.

The obvious one that has been made is that maybe

you would pick up more safety issues with a larger

population.

183

There are other important issues that

haven\'t been raised. One of the issues is if you

have a large enough population you can look at

subgroups. That can be important for example in a

diabetes prevention program because there were 1000

people receiving that and it was clearly shown that

it did not work well in the elderly population, at

least compared to the younger population. So, if

you have a large enough group you can actually say

something about the drug in different groups within

the larger population.

I think the argument to reduce the number,

let\'s say from 1500 to 500, may relate to the cost

of doing the trial. But what I haven\'t seen is a

slide from the FDA, or maybe FDA has some data,

that if you reduce the cost of the application and

the trial, it will really result in more or better

drugs being released. In other words, the argument

throughout all the material that you gave us to

read was that one of the problems is that it is so

expensive to put a new drug through the process.

In fact, if we do reduce the cost, does the FDA

184

feel that we will get more and better drugs or

whether we will just simply generate more profits

for the companies? That is not necessarily bad; I

am not implying that it is bad, but maybe we will

get more and better drugs. I think that is a key

issue and I haven\'t seen a slide presented showing

the cost of putting a drug through versus the

number of drugs that are actually approved.

DR. ORLOFF: I can\'t really help you

there. I don\'t believe we have such data. Agreed,

the longer, the larger the trial, the more

intensive the monitoring, the more expensive it is.

Dr. Atkinson proposed, sort of in broad terms, that

the pre-approval experience and, therefore, costs

be limited, with a commitment to investment in

better understanding of the overall profile of the

drug, risk versus benefit, in phase 4. FDA doesn\'t

have much regulatory leverage and, thus, we have

less in the way of capabilities to protect the

public health in phase 4. I think that it really

violates some central tenets of our procedures to

wing it at the time of approval.

185

DR. BRAUNSTEIN: I have two announcements,

before we break for lunch, for the committee

members. Number one, please hold on your calendars

December 13 and 14 of this year for another meeting

of the committee. Secondly, there is an area in

the hotel restaurant reserved for the committee if

you want to eat in the restaurant.

We will take a 45-minute lunch break and

convene again around 1:05 or 1:10. Thank you.

\[Whereupon, at 12:25 p.m., the proceedings

were recessed for lunch, to reconvene at 1:15 p.m.\]

186

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

Committee Discussion

DR. BRAUNSTEIN: Good afternoon. We will

open the afternoon session. Dr. Orloff, do you

want to lead us through the format?

DR. ORLOFF: This is where we start so you

can take it if you have any questions or

clarifications and I will just run up to switch

slides.

DR. BRAUNSTEIN: Terrific. Thank you.

What we will do is we will go through the questions

that have been posed by the FDA for us to discuss.

We will have sort of a general discussion where

people raise their hands to have some input or ask

questions. Then I am going to go around and ask

everybody to sort of weigh in on these issues.

Again, there is no voting but it is to give the

sense of the individual members\' of the committee

input to the FDA about what their feelings are

concerning these questions.

The first is populations. At the present

time the recommendation is for a BMI greater than

187

or equal to 27 with a comorbidity and greater than

or equal to 30 without comorbidity with be

appropriate populations to treat. One of the

queries that we have is should the recommendation

of a BMI less than 25, when accompanied by a

comorbidity, be considered? Or even should there

be exclusion of a comorbidity requirement when

considering a BMI that low?

So, let me open this up for discussion.

What evidence supports treatment or prevention in

this population? What magnitude of effect would be

clinically significant? And, what assurance of

safety is required to treat lower-risk patients?

Dr. Levitsky?

DR. LEVITSKY: Well, I will throw my voice

into the ring here. I thought about this a bit and

there clearly is no evidence to support treatment

or prevention in this population from what we have

had presented and what we know so we can\'t look at

evidence. There probably ought to be, and there

probably should be but there isn\'t.

So, what I did was to look at magnitude of

188

effect and assurance of safety, and I chose the one

treatment that we know has a huge magnitude of

effect and is not so safe, and that is surgical

bypass. Surgical bypass is the only thing that

really works in people with severe exogenous

obesity and it is associated with, I guess, a 3-5

percent risk depending on how sick someone is when

they go to bypass.

The decision there has been made, and it

is probably reasonable, that if you have very, very

severe, life-threatening obesity associated with

comorbidities that that risk is worth it.

Therefore, what I would suggest is that we need to

stratify studies based upon degree of risk, and I

would like to have assurance of much more safety

before one dropped the BMI down to the 25-27 kg/m2

range. Therefore, I would like earlier studies

done on the people who have higher risk, where the

risk is available in the literature now, and if

these agents are proved to be very, very safe in

the initial studies, then I think one could move on

to studying a population which at this point at

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least has cosmetic obesity, not obesity associated

with other risks, although I believe they probably

do have other risks that we just haven\'t defined

yet.

DR. BRAUNSTEIN: Yes, Dr. Schambelan?

DR. SCHAMBELAN: I just have a question.

Do you think the evidence is there to support

treatment for a BMI greater than 27 anymore than

there is for 25?

DR. LEVITSKY: No, I suppose you would

have to get up around 30 before we have really done

the studies.

DR. BRAUNSTEIN: Yes?

DR. ARONNE: I think that there may be

subgroups of the population who would fit into a

category of being someone worthy of treatment as a

substitute for another treatment modality. For

example, someone of Asian descent who has a BMI of

26 and has a large waist circumference and has type

2 diabetes, in my opinion, treating their obesity

would be a good idea. I think that that might be

an appropriate case of an indication for obesity

190

treatment, rather than just treating the diabetes.

So, I think that there may be situations where it

could be proven that there is health benefit.

Someone with metabolic syndrome\--mainly these would

be I guess a subpopulation who have metabolic

syndrome and a large waist circumference even

though they have a relatively low BMI. So, there

are people in that category.

One of the problems is that when we set a

guideline, then the insurance companies follow this

like it is chiselled in stone in the basement and

it is difficult to dissuade them. So, I think it

could be that companies should be encouraged to

study people in this other category so that we can

finally get data to see if there is medical benefit

from treating that part of the population.

DR. BRAUNSTEIN: Dr. Watts?

DR. WATTS: It raises an issue that Dr.

Schade brought up earlier, the value of larger

sample sizes which will allow you to do

stratification and look at subpopulations. In

terms of magnitude of effect, it is hard for me,

191

from seeing any of the data so far, to think that

weight change alone would represent a satisfactory

endpoint for me. I would like to see either

quality of life improved or improvement in

surrogate markers\--blood pressure, lipids,

C-reactive protein, and ideally some evidence that

weight reduction achieved by medication confers

some improvement in morbidity or mortality. I

think the lower you drop the level of intervention

the greater the need for safety data which, again,

requires large sample sizes to achieve.

DR. BRAUNSTEIN: Dr. Orloff?

DR. ORLOFF: I wanted to clarify something

that I forgot to mention earlier and this reminded

me. Our standard for approval or approach to the

evaluation of these drugs includes an evaluation of

the effect of drug-induced weight loss on comorbid

features\--hypertension, diabetes, dyslipidemia. As

some around the room know, the issue related to

pulse and blood pressure was salient in our

evaluation of the overall risk/benefit of

sibutramine because, indeed, there is a

192

subpopulation of patients who received that drug

who, in contrast to actually getting a benefit on

those comorbid features of obesity, seemed to have

some deterioration in those features despite

perhaps weight loss.

So, anyway, I wanted to make clear that we

do have that system in place now and that will

always be the case, that we are looking at the

weight of evidence and we approach the weight loss

criterion in light of the other aspects of the

drug\'s effect.

Finally, with regard to sibutramine lest

anyone go away thinking that sibutramine was

approved despite the fact that everybody who loses

weight gets problems with pulse and blood pressure,

in fact, the two effects are dissociated. So, we

believed that monitoring for that potential adverse

effect is sufficient to accomplish safe use of the

drug.

DR. BRAUNSTEIN: Dr. Schambelan?

DR. SCHAMBELAN: Can I get you to clarify?

If you have an enrollment criterion that includes

193

comorbidities as one of the requirements, is

comorbidity just an item of interest or is it an

endpoint as well?

DR. ORLOFF: I believe therapy are believe

they are evaluated as secondary endpoints. To the

extent that this is all based upon surrogates, if

you will, the true endpoint of interest is

long-term serious morbidity and mortality. We

don\'t have any of those data. Weight loss in

someone who is obese and at risk and has, let\'s

say, the panoply of cardiovascular risk factors

associated with classical type of obesity, it is

supposed to affect salutary changes in those risk

markers. So, we look at those as secondary

endpoints and our overall evaluation of the drug is

clearly tempered by the results of those secondary

endpoints.

DR. BRAUNSTEIN: Let\'s go around and I

will ask members of the panel to specifically

respond to question number one with the three

points here. We will start with Dr. Hirsch.

DR. HIRSCH: I will be happy to start with

194

that, but let me just say as a prelude to what I am

going to say, and I will be very brief about this,

if there were really a new and very efficacious

drug available to treat obesity we would be living

in a different time and I think the considerations

might be somewhat different. But I think people

tend to confound the issue. What has happened in

this whole obesity research scene is that it has

become evident that there is a very, very

complicated mechanism whereby body fat storage

tends to be controlled over long periods of time,

and it is controlled in a bad or deleterious way in

those people whom we designate as being obese. All

sorts of new peptides and new mechanisms are being

uncovered by the wonderful activity of molecular

genetics and cell biology, etc., etc., that fills

up our interest, and so on, but in the treatment

arena, even though these new peptides and their

agonists and antagonists are bandied about and

tried, nothing new has happened. Fundamentally,

every obesity treatment that we have, and those

that I know of in the pipeline, are sort of counter

195

forces, are techniques of making this mechanism not

work quite so well, but are not aimed at the

pathogenesis of obesity or the new understanding of

it.

So, in some respects, what we have here is

a bunch of drugs that act somewhat like jaw wiring

of years ago. I mean, no one thinks, for example,

that pancreatic lipase dysfunction is a cause of

obesity. On the other hand, its inhibition, which

ordinarily would be considered an adverse effect,

does have an effect on this body weight regulation

mechanism. So, for this reason, all the drugs we

look at and hear about all hit the 5 percent, 7

percent, 8 percent, or whatever it is, per year

weight loss as compared with placebo because they

all operate in this same counter force kind of way.

Now, I am not denying the use of these

things, but nothing new or special has happened

that makes me want to change the guidelines we

have. So, I think, in answer to your question, it

is not a good moment to lower the BMI of 27 with

comorbidity, etc., and to markedly widen this

196

population on the basis of new information. We

don\'t have any new information about the

pathogenesis of obesity that is yet relevant to its

treatment.

DR. BRAUNSTEIN: What magnitude of effect

would be clinically significant?

DR. HIRSCH: I think 5 percent over the

year is fine. I think the categorical thing, I

would worry about that. I think that is a snare

and a delusion and any statistician knows that post

hoc you can always find a category that you can

make significant. You can pick between 8-11

percent, 3 percent, whatever it is. So, if you do

categorical things, they must be stated ante hoc

and you must examine the distribution, that is, the

mathematical distribution of the weight loss.

Consider, for example, the situation in

which you want to use categorical things and

somebody\'s average weight isn\'t quite what you

wanted but the 5 percent level is met. That could

theoretically be brought about remotely because the

drug you are using actually caused some other

197

people to gain weight and balance off the mean.

So, one must be statistically extremely careful

about categorical things. I would think 5 percent

of the mean over the year is a good thing, except

in the most special of circumstances.

DR. BRAUNSTEIN: This is 5 percent below

placebo?

DR. HIRSCH: Below placebo, yes. Five

percent weight loss, that is right.

DR. SCHAMBELAN: I would concur with the

notion of not lowering the bar for enrollment.

Since I wasn\'t part of the decision to make 27 the

cut-off, I am not even sure why that is the current

cut-off. Certainly, I would continue to require

comorbidity rather than to eliminate it, as was

suggested by at least one of the submitted

documents.

I think 5 percent seems to make sense.

There is some evidence that is a health benefit.

Obviously, we want to make sure safety is assured.

I think when we get to talk about the numbers of

people in trials perhaps we will have a different

198

chance to weigh in on that.

DR. BRAUNSTEIN: Dr. Follmann?

DR. FOLLMANN: In response to the first

question, I don\'t think we have really seen

evidence to support looking at this population.

The curve that I really focused on was that

J-shaped curved of BMI and mortality, and that was

just in the overall population. So, to proceed and

try and go in this direction you would want to see,

you know, evidence that BMI greater than 25 and a

comorbidity really is where the dose-response

curves start to take off and we haven\'t really seen

that yet today.

In terms of what magnitude of effect would

be clinically significant, I would feel more

comfortable with the 5 percent benefit compared to

placebo along with some improvement in the comorbid

profile, if you could call it that.

The categorical criterion that was being

discussed earlier doesn\'t really talk about an

absolute magnitude. It just says that the

percentage of success on drug is larger than the

199

percentage of success in some control\--you know, it

is statistically significant where success is

defined as a 5 percent improvement from baseline.

So, you could have a situation where a drug, where

a company does a huge trial, wins on this \"success\"

endpoint because the trial is so large when it is a

very small actual difference between the two

groups. So, that is why I favor the first

criterion that was discussed.

Finally, in terms of safety, I think for

low risk populations, as was mentioned earlier, you

want to have more assurance about them for a couple

of reasons. One is because you are worried about

the risk/benefit relationship, but also you are

worried I think that this could be applied to a

much larger population out there, and I think our

concern about safety should be magnified if the

drug is going to be extremely widely used.

DR. BRAUNSTEIN: Dr. Yanovski?

DR. J. YANOVSKI: I concur that in general

there is no good evidence to support dropping the

criterion for routine study of such medications or

200

use of such medications at 25 kg/m2 even when

accompanied by comorbidities. In part, that is

because when we look at the lower part of the curve

the prevalence of comorbidities is not so different

below 25 as it is between 25-27. I think those

numbers are not that different. So, then it runs

the risk of people feeling that we should use

weight loss even in lower BMIs and there is the

greater probability of abuse, I think, when a

larger population is approved for use. So, for

both of those reasons I would concur that we should

not decrease routinely the criteria, and certainly

there is no evidence that would support it existing

now.

However, there may be special populations

in whom it may be appropriate to study,

particularly if we are going to consider a

criterion for prevention of weight gain. For

instance, in an individual with a BMI of 25 who is

about to undertake or is currently undertaking

psychotropic therapy with known complications of

weight gain, it might certainly be reasonable to

201

find out if any of the agents that we are studying

would be of value to prevent that weight gain and

the development of a high BMI. Maybe there will be

other criteria. So, I think there ought to be the

possibility of special populations being studied,

but it should not be a blanket statement for

anybody with a BMI of 25 even when included with

comorbidities.

The question of magnitude effect\--I think

we may be confusing two issues. One is in general

what magnitude of effect we want in obesity drugs

for obesity with a BMI over 27 or 30. Then the

question is, if you are going to consider people

who are over 25 kg/m2 who are not obviously yet

obese, then a smaller magnitude of effect or

prevention of weight gain may be appropriate as an

outcome. So, the statistics for that are going to

be different and will probably require even larger

sample sizes if we are going to look for smaller

differences. So, I think that those are going to

be population-specific statistics really. So, the

sample size questions are going to be based on what

202

is the probability of severe weight gain, for

instances, after psychotropic use.

So, I think there are unique issues when

we talk about folks who have not yet reached a

point with any elevation in mortality in general,

and we need to then look at specific populations if

we are going to use anybody under 27. And, I think

the 27 and above criteria basically comes out of

the fact that we used to define overweight at that

point. That is why the cut point came about. It

is clear. But the J-shaped curve does support the

notion that the higher the BMI, the more risk we

should take in using medication so, as a result, I

don\'t see any reason to decrease the criterion.

DR. BRAUNSTEIN: Dr. Levitsky?

DR. LEVITSKY: Well, the BMI is a

surrogate marker for obesity obviously. It is a

pretty good one but it is not a perfect one and,

therefore, I don\'t think we should reduce the BMI

criterion yet. And, I think all studies that are

done with new drugs should be done as treatment

studies initially, with prevention studies being

203

secondary after safety has been assured.

DR. BRAUNSTEIN: Ms. Coffin?

MS. COFFIN: I am actually going to go

against the curve here. I think that the 27 is in

the guidelines because that was the use back when

the draft was put together in \'96. Since then,

across the board, it has become more of a standard

out in the community, that if you have a BMI of

25-30 you are considered overweight and if you have

a BMI of 30 or higher you are considered obese. I

do think then that the consistency for the consumer

is important. So, drugs to treat people that are

overweight with comorbidities should be consistent

with the definition of being overweight, and drugs

that are consistent with treating people that are

obese, those with a BMI over 30, should be then in

there. I would not, however, suggest removing the

comorbidity from those folks who are overweight

because I believe that there are quite a few folks

out there that can be overweight but still healthy

and so only those that are having other symptoms or

other comorbidities should be considered for drug

204

treatment, and 5 percent seems to be a reasonable

magnitude. So, I would suggest lower, just for

consistency.

DR. BRAUNSTEIN: I actually am also going

to weigh in against some of my colleagues and

suggest that we do lower it to 25 or above for the

following reasons. Number one, the J-shaped curve

does seem to have the cut point at around 25. So,

above 25 the mortality goes up; below 25 the

mortality seems to go up also. But that is one

reason.

The second reason is that Dr. Flegal

showed in her summary data that there wasn\'t much

difference in the comorbidity prevalence between a

BMI of 23-25, but around 25-27 it starts to go up,

especially in men. There is more of an upswing.

It is not a clear-cut cut in the data but if you

look at her combination of any comorbidities, it

does go up between 25-27. So, I think that, in and

of itself, would be justification.

Thirdly, we are seeing increased

prevalence of obesity in the American population.

205

There is increased recognition that about 25

percent or so of the population will have the

metabolic syndrome which has been clearly

associated with cardiovascular disease and other

problems. So, I do think that lowering it to 25 is

reasonable.

Having said that, I would like to keep a

minimum of 5 percent difference between placebo and

active agent. The Europeans use 10 percent. We

have had 5 percent. There is data in the

literature, for instance in women with polycystic

ovary disease that a 7 percent reduction in weight

decreases the oligomenorrhea, increases ovulatory

rates, decreases hirsutism. So there is clearly

beneficial effect of 7 percent so I assume that

anything over 5 percent is going to be better than

less than 5 percent. But I would like to see as a

minimum 5 percent being maintained.

As far as assurances of safety, obviously

we want the drug to be ultimately extraordinarily

safe. As Dr. Ryder will probably comment\--I don\'t

mean to steal your thunder but I do want to make

206

the point that you made. Sometimes we have to look

at drugs with a risk/risk evaluation rather than a

risk/benefit evaluation. I will let you expand on

that. But, basically, my understanding of that is

that if you have a disease that has a high

mortality or morbidity rate and you have a drug

that has side effects but the risk of the side

effects, overall risk to the person\'s well being is

less than the risk of the disease then it is

worthwhile using that. As you start getting down

to a BMI of less than 27, yes, the risk/risk

probably becomes more difficult to assess and,

therefore, one would want to see a larger database

of safety in that population. Also, I do agree

that there should be a comorbidity less than a BMI

of 30. Dr. Greenway?

DR. GREENWAY: I also agree with lowering

the BMI to 25 with comorbidities. I say that for a

couple of reasons. One is that the BMI of 27 cut

point I think is mainly of historical interest, as

Dr. Flegal described. I think that the standard

across the world now is that being overweight is

207

between 25-30 and I think it would make sense to

have this standardized. Secondly, it is not just a

matter of making it standardized, there is also an

increase in risk that starts with a BMI of 25.

Clearly, with diabetes weight loss is beneficial

and even with insulin resistance it is going to

prevent diabetes. So, I think that there are

reasons to lower the BMI to 25.

I agree that a 5 percent weight loss is

what is clinically significant and that should be a

lower limit. Obviously, the lower the risks of the

population, the greater the safety of the

medication needs to be. So, anything that is used

for obesity is obviously going to have to meet a

higher level of safety than many other diseases

that are more immediately life-threatening.

DR. BRAUNSTEIN: Thank you. Dr. Flegal?

DR. FLEGAL: I guess I didn\'t realize I

was actually going to be called upon to answer

these questions. My inclination or my personal

view would be that it is not the best idea to lower

the cut point to a BMI of 25 because I think these

208

cut points are very arbitrary and, yes, I think

standardization is a good thing and it is really

helpful to us to have standardization for our

purposes, but I don\'t think they should be mistaken

for clinically significant cut points, and I think

without a lot more evidence about that range of

25-27 it would not be the best course to lower it

at this point. You know, if you read the

literature on how these cut points are determined,

it is really a very arbitrary process so I don\'t

think it should necessarily be the standard

followed to set standards for everybody else and

for other, different kinds of purposes. That would

be my only comment I think actually.

DR. S. YANOVSKI: I have mixed feelings

about this. I thought a lot about it over the

weekend and, on the one hand, more than 60 percent

of the U.S. population right now has a BMI of over

25\. That is an enormous number of people. Of

those who have that BMI between 25-30, a number

would be overweight but not really over-fat,

particularly among men. Men are not the ones,

209

however, who are going to be mostly using these

products. As we saw today, they are young white

women.

I think some of my concern stems from the

fact that lowering the BMI threshold, if one were

really going to prescribe it for those with

metabolic syndrome or diabetes it wouldn\'t worry me

as much as the fact that I know these medications

are going to be misused and taken by a number of

people who don\'t have comorbid conditions and I

think we have to be aware that that is going to

happen regardless of our best intentions.

At a minimum, I think it is not a bad

idea; it is a good idea to have these medications

studied in that population, and potentially I could

see them being approvable in, for example, someone

like Lou Aronne pointed out, someone with a BMI of

26 who is Asian and likely to have more visceral

fat who has metabolic syndrome. I think maybe

provisions could be made to come in for specific

types of indications or studies for very high risk

populations.

210

When I think about people with this BMI

between 25-30, where I really see most of the

money, would be in weight gain prevention for

people who are at really documented high risk. I

think Jack might have pointed out somebody who is

about to start an atypical anti-psychotic where we

have a good idea that they are going to be gaining

large amounts of weight, increasing the risk for

diabetes. So, I see more of the money in

prevention of weight gain in specific populations

at high risk, or perhaps a treatment indication at

very specific targeted populations at high risk,

but I have a lot of trepidation about a general

lowering of the BMI threshold to 25, both because I

think we don\'t have a lot of data on how much

benefit we are going to get there and because of my

concerns about risk of misuse.

Regarding magnitude of effect, I am going

to disagree with Dr. Hirsch, my esteemed colleague,

on not having categorical definitions. First of

all, I don\'t think any of the drugs we have

today\--I am not sure any of them would meet the 5

211

percent across the board difference from placebo.

We are going to find responders and non-responders

and I think that having the categorical variables

and allowing a drug to be approved that may have a

standard number of responders is important. Now,

the magnitude of responders versus non-responders

in the studies that I have seen is often pretty

substantial. It might be 35 percent versus 17

percent in the placebo group. There is often a

doubling of the responders. I think it would be a

good idea to actually quantify the difference

between placebo and active treatment groups in the

percentage of responders and non-responders, not

just make it statistical significance.

Regarding assurance of safety, again I

think that when you are looking at a lower risk

population you have to have even more assurances of

safety.

DR. BRAUNSTEIN: Dr. Carpenter?

DR. CARPENTER: The drama increases with

the decreasing amount of data we have to make our

decisions. I have to weigh in, after certainly

212

submitting that this is a hunch and an instinct as

opposed to a great deal of data analysis, that it

is difficult to justify dropping the BMI, primarily

for reasons that have been stated. I think the

single piece of data that sticks in the mind that I

have seen today is the J-shaped curve, and there

may be small differences between 27 and 25 but I am

hard-pressed to consider that they are clinically

significant, certainly not as significant as the

ascension between 27 and 30 in terms of

complications or mortality on that curve.

I agree also with Dr. Yanovski that I

would include the categorical proportion of

responder criteria in addition to the 5 percent

delta between placebo and treatment. It seems to

work in the way that we have been talking about the

previous data. And, I think it is absolutely clear

that safety is a primary mission of this whole

process and in a low risk patient it becomes an

even higher profile issue and we should stick with

extremely high assurance of safety in that group.

DR. BRAUNSTEIN: Dr. Wierman?

213

DR. WIERMAN: I would say that the whole

discussion today reminds me of the discussion of

what were our LDL requirements 15 years ago. Our

goal, you know, started at 120 and then went to 100

and currently is quite a bit lower than that in

different at risk populations. I think what we

have to decide now though is where are we right now

on that curve. I thought the curves looked fairly

linear, without any obvious huge cut point on many

of the curves that were shown this morning. But

because we don\'t have outcomes data related to

mortality or even morbidity, I think that I

personally would not lower the BMI cut point with

comorbidity to 25 yet until we get more outcome

data, unless there were special populations such as

have been outlined\--patients with metabolic

syndrome; patients with perhaps postpartum

hypoglycemia, etc., that could be studied in that

range. All the other comments I agree with.

DR. BRAUNSTEIN: Thank you. Dr. Woolf?

DR. WOOLF: I would like to keep the cut

point at 27. Surely there is no shortage of

214

subjects. We are not talking about an orphan drug

here. In fact, we are talking about just the

reverse. If it hadn\'t been for historical

purposes, I probably would propose increasing the

level rather than decreasing it. There is no

increase in mortality with a BMI of 25. The

J-shaped curve takes off somewhere between 25-30

and goes up. So I would much rather start where I

know it is going up rather than supposing where it

is going up. So, I really want to keep the current

guidelines where they are.

I would like also to keep both criteria.

I think it is important to know what proportion of

patients actually benefit over placebo from this

drug. It may be that the decrease in weight is

only 2 percent but, in fact, if 25 percent of the

population or, let\'s say, 30 percent of the

population really loses 5 percent and there is

another 10 percent that gains weight, we are

obviously not going to keep people who are gaining

weight on the drug; you would stop it. So, I think

that having both criteria is important. But I

215

agree with Dr. Hirsch that it ought to be

prespecified rather than post hoc. And, as

everybody else has said, where the benefits are

weak at best, you have to err on the side of

safety, and the bigger the study the better.

DR. BRAUNSTEIN: Thank you. Dr. Watts?

DR. WATTS: I am on the fence as far as

changing. I think studies certainly need to be

done looking at the effectiveness of weight-loss

strategies and for prevention of weight gain for

patients who have BMIs between 25-27. But whether

the criterion for approval should be dropped, I

have reservations about that.

Magnitude of effect\--I think there needs

to be significant weight loss and there needs to be

change in some surrogate marker, insulin resistance

or some other comorbidity, and the further you drop

the bar for initiation of therapy, the greater

assurance we need about safety.

DR. BRAUNSTEIN: Dr. Schade?

DR. SCHADE: I have a little different

opinion. I believe we should keep the BMI of 27

216

for the arguments made, but I think we should get

rid of any comorbidity stipulation. The reason for

that is if you keep a comorbidity it implies that

the treatment for the comorbidity should be weight

loss and it is very clear, I think as Dr. Orloff

stated, that the drugs that induce weight loss may

or may not affect the comorbidity. In fact, I

would make the plea that weight loss is a poor way

to treat comorbidities and, compared to five years

ago we have very good drugs to treat hypertension;

we have very good drugs to treat hyperlipidemia;

and we have very good drugs to treat diabetes.

Waiting for a clinical trial to improve

comorbidities is a huge clinical mistake.

Comorbidities need to be treated aggressively and

they need to be treated now.

So, if you design a clinical trial to look

at the effect on a comorbidity, assuming a patient

has it, I don\'t think you could ever get it through

my IRB because those patients ought to be treated

immediately for their comorbidity. You should not

wait six months or a year to see if this

217

weight-loss drug affected this comorbidity. That

would be a huge clinical mistake. I think having

comorbidities in there makes it impossible to

assess because if the trial is designed correctly

and people are treated appropriately those

comorbidities need to be treated. And, I think it

is a huge mistake to include comorbidities in any

kind of criteria for a weight-loss drug because, in

fact, it will be obscured by the treatment of those

comorbidities with much better agents. So, I will

put a strong plea in to take out the comorbidities

because I think it is a totally outdated concept

because we have much better ways to treat them.

I think the magnitude of the effect\--5

percent is okay. That would certainly be a minimum

as being clinically significant. Let me say a word

about assurance. What do we need for assurance of

safety? I can tell you what I think we need. I

think we need time. We need experience. I was a

principal investigator in a diabetes prevention

program and in that program we had 3000 patients

and we used two drugs, one was troglitazone and one

218

was metformin. The troglitazone at that time had

just been released or was just made available from

the Japanese groups, whereas with metformin we had

30 years experience in Europe. At the end of the

trial troglitazone was off the market. People had

died from it. Metformin basically was considered

an extremely safe drug.

So, if you want to know the answer to

number three about assurance, there is no

substitute for experience in use of these drugs in

large populations. So, that is basically what we

need before we start treating lower risk

populations.

DR. BRAUNSTEIN: Thank you. Dr. Aronne?

DR. ARONNE: As far as the first question

is concerned, I think the reason we don\'t have

evidence to support treatment or prevention in a

population with a BMI of 25-27 is because we

haven\'t approved drugs for that category so there

is no way to drive a company to study their drugs

unless you give them a chance to get the drugs

approved. I believe that if we include that group,

219

perhaps as a separate category to seek approval

with maybe a different set of safety standards,

that that will drive industry to study it very

carefully. I think that the criteria in that group

needs to be not just weight-based but proof of

health benefit, but my belief is that that health

benefit will be forthcoming if the weight is lost.

I think the magnitude of effect that is

clinically significant\--I think that both the 5

percent placebo subtracted weight loss and the

categorical weight loss are good measures of that.

Then, as far as what assurance of safety, I think

in the lower BMI group I would want to be sure that

this is safe using more stringent criteria. I

think the longer a drug is around, clearly that is

a good way to start. But I think that clearly you

are going to need bigger studies if you are going

to use a drug in that lower BMI group.

DR. BRAUNSTEIN: Dr. Ryder?

DR. RYDER: Yes, just two quick comments,

one just to continue on the theme that Dr.

Braunstein mentioned. I am on a one-man personal

220

crusade for replacing benefit/risk, which I think

really doesn\'t help discussions or I haven\'t found

that, with risk/risk. I know that it is somewhat

cute but it just reminds people that it is, in

fact, the risk of the illness, the risk of the

condition and the associated conditions versus the

risks of the product. I think that is important to

keep in mind. If you have the comorbidities, the

comorbidities themselves do have risks or

treatments for the comorbidities have risks. Every

treatment, whether it is surgical, pharmaceutical,

that I am aware of has at least some risk. So,

just to keep that in mind.

I don\'t have any specific comment on the

25 or the 27. The other comment that I wanted to

make was that I do think it is important, as

several committee members have mentioned, to open

up the concept of having some population-specific

development paradigms. There are some very unique

circumstances, whether it is drug-induced weight

gain or something else, there are other populations

that are somewhat unique and maybe to allow people

221

to study these would be a good thing because we

could increase our information base.

DR. BRAUNSTEIN: Thank you. Dr. Orloff?

DR. ORLOFF: Just two points. One is the

issue of enrolling patients with comorbidities with

an eye towards examining the effects of

drug-induced weight loss on those comorbidities.

Even in the day of effective treatments for the

associated metabolic derangements in obesity,

trials can clearly be designed to examine things

like drug dose, addition or subtraction of

medications in the regimen, as well as the clinical

parameters per se that are being treated, whether

it be diabetes, hypertension or dyslipidemia. So,

we don\'t actually view that as a limitation, and

that is essentially what is being done now as we

move forward in this field. And, I can\'t remember

my other point so we will move on.

DR. BRAUNSTEIN: Before going to the

second question, are there any other issues that

any members of the panel want to raise about

question number one? Dr. Carpenter?

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DR. CARPENTER: Just very quickly, talking

about using drugs for some clinical situation in

which people might gain weight, I think with the

psychotropic agents, fortunately, there are some

choices. You can use one or another kind perhaps

to minimize that. But a population that is very

vulnerable and where it is a real issue are people

who are, hopefully, stopping cigarette smoking and

that might be a kind of area to look at drug

treatment possibilities. I think that holds some

people back to not smoke because of the weight

gain.

Finally, in talking about the hazards of

different groups, there is one group that I think

is particularly vulnerable and we should be very,

very careful in all our thoughts about it, and that

is adolescent girls or women who are sensitive to

feeding disorders because the specter of bulimia

and anorectic diseases, and so on, looms high in

that group. So, that is a particularly hazardous

group I think to deal with in terms of drug

treatment. I would just like to bring up their

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particular vulnerability.

DR. ORLOFF: I know what I wanted to say.

I want to make sure that the discussants, as well

as the audience listening, the public, don\'t lose

sight of the fact that this whole

discussion\--again, this was stated in some of the

remarks earlier\--this whole discussion is taking

place in the context of a pharmacopeia that is

really inadequate. I think that is the most

accurate way of saying it. The effects of our

current crop of drugs on weight loss as well as on

comorbid features of obesity are far from ideal.

Clearly, in a risk/risk, risk/benefit sort of

construct we can\'t forget that.

Now, clearly, if a drug comes along that

preliminarily shows a huge amount of weight loss

benefit and an accompanying appropriate, graded

reduction in comorbid features, then I think that

creates a whole new arena for discussion.

DR. BRAUNSTEIN: Yes, Dr. Carpenter?

DR. CARPENTER: Another suggestion for

perhaps a minor component of this BMI cut-off,

224

given the data that was shown earlier regarding the

striking effect of age on the comorbidities, is

that it may be useful for some of the studies to

look at some parameter that would identify

interaction of age and BMI, not just segregating

out the adolescent population but through the

decades in terms of where these drugs may be most

useful and most helpful. So, it may be that BMI,

in fact, would end up being a moving target across

the decades.

DR. BRAUNSTEIN: We will move on to the

second question. I will start with Dr. Ryder this

time and go around in that direction. Actually,

before we start with Dr. Ryder, let me open it up

for general discussion and then we will go to the

specific panel members. For the

pediatric/adolescent age group what factors should

be weighed or addressed in assessing risk versus

benefit?

DR. J. YANOVSKI: This is something we

have spent a lot of time thinking about, and there

are very divergent opinions in the community about

225

what should be, for instance, the necessary

enrollment criteria for such patients.

First just to remind everybody that when

drugs are approved for adults, they are approved

down to age 16. So, this age group we are talking

about is 12-16, I guess, that we are calling

adolescents, and then pediatrics below that.

Obviously, in both populations, younger

populations, there are significant amounts of

linear growth going on and, as a result, the use of

the BMI without correction for age and sex and

maybe even race is inappropriate as the metric so

we need to use something like the body mass index

standard deviation score. So, as an entry

criterion we have promoted certainly BMI-SD over

the 2 SDs or a little less than that, 95th

percentile, as an entry criterion, following which

we have also suggested that comorbid conditions be

required to be present, besides overweight, in such

patients because they are a population that is not

making up their own minds so they need additional

protections beyond those afforded adults. So, the

226

risk of the disorder should be greater than

necessary perhaps for adults. So, we have

suggested that comorbid conditions should be

present, that high BMI be present and, indeed, the

list of comorbid conditions probably should be

prespecified as to which ones would be considered

acceptable.

The weight loss in adolescents, because of

the developmental changes in height, needs to be

interpreted carefully because, in fact, the BMI

standard deviation score can drop even while the

weight increases, depending on how the height

increases. So, measures of body fat should also be

included, but the problem being, again, that there

are no good consensus definition of what is truly

over-fat\--modern definitions, anyway. We have a

lot of things we use but no consensus on what is

over-fat for children and adolescents in terms of

the number of kilos of fat mass, for instance, or

percentage body fat. That makes it difficult but I

think those should be part of the criteria for

assessing the outcomes.

227

As a result, the physicians also have to,

of course just as in adults, make sure that they

study the patients in whom the medication will be

used and so over-sampling for a particular

population, such as Hispanics and African Americans

that are at a much greater risk, particularly

females in adolescent ages, is necessary. Then,

sufficient sample size to discern benefit among

those groups may also certainly be needed because

we expect different medications perhaps to have

different efficacy.

Then, the improvement in comorbid

conditions I think is a secondary outcome of weight

reduction in these individuals, but obviously is of

importance in deciding how beneficial it is. When

we decide to treat an adolescent we are suggesting

that they are going to be treated for the rest of

their lives or certainly for long term since, at

least in this room, I think there is a consensus

that such treatment for obesity needs to be

continued because efficacy rarely continues after

the drug is discontinued. So, we have to be doubly

228

careful that the medications we use are

sufficiently beneficial that they are worth

starting at all. So, I think large populations of

younger children should be studied before such

drugs are approved.

DR. BRAUNSTEIN: Dr. Levitsky?

DR. LEVITSKY: A question actually for

Jack, what would the comorbidities be that you

would accept for this? Hypertension, type 2

diabetes, what else?

DR. J. YANOVSKI: The list that we have

suggested includes hepatitis, diabetes,

hypertension and significant dyslipidemia. Now,

the reason why it is particularly interesting in

pediatrics is that, for instance, there is no

consensus for the treatment of dyslipidemia in the

absence of FH. So, that comorbid condition, which

we really believe is going to lead to

cardiovascular risk, is not being treated routinely

with a statin. Similarly, blood pressures that are

in the intermediate range, which we may expect to

cause trouble later on, are not being aggressively

229

treated in adolescents. So, we have suggested that

those kind of comorbid conditions should be entry

criteria. Someone suggested insulin resistance,

measured either by high fasting insulin but,

unfortunately, in adolescents almost everybody,

because of puberty, will have a higher insulin

level so that may be a less stringent criterion.

Also, obviously sleep apnea and the other disorders

that are seen would certainly be acceptable

comorbid conditions.

DR. WOOLF: I would be extremely concerned

about treating kids who have either not entered

puberty or are in puberty, rather than

post-adolescent, let\'s say, 16 year-olds. We have

no idea what these drugs will do to these kids as

they grow up or to their offspring. So, we are not

talking about a potential generational effect. So,

I would much rather have\--unless I were assured to

the contrary\--very strong data that we are treating

kids who have comorbidities. We know that fat kids

lead to fat adults but we can treat them when they

are adults.

230

Another thing that I think is important is

that we get them away from their computers and away

from the couches. There is a recent study that

exercise an hour a week leads to significant

improvement in weight. I mean, it is trivial

exercise. So, I would be much more concerned about

treating younger kids because we just don\'t know

what it is going to do.

DR. BRAUNSTEIN: Let me go around and

those of you who want to add comments, feel free to

add comments. Dr. Ryder?

DR. RYDER: My only comment would be one

that Dr. Levitsky and others have already

mentioned, that just in general as a starting

place, you expect to have a little bit more

certainty around the product specification because

we generally accept a different level of risk when

we treat pediatrics and adolescents than adults.

So, it would be just a little different starting

place typically, and this is just a general

statement across just about all products, and I

have heard a lot of people say that I think.

231

DR. BRAUNSTEIN: Dr. Schade, any other

comments?

DR. SCHADE: I just have a couple of

comments. One is that although we can wait until

they are adults to treat them, I just want to

remind everybody, and I am sure everybody knows

that atherosclerosis has been well documented in

the 21, 22 and 23 year age group from autopsies

from soldiers who have been killed. So, we are

dealing with a disease that we know starts very

early on and these people may not even live to

their 40s or 50s if they have significant risk

factors. So, we can\'t always wait.

On the other hand, I am very concerned

about treating patients with weight-loss drugs

rather than treating directly the comorbidities in

this age group, and I would actually raise the BMI

to higher than 27 for treating these children

because I am worried about these drugs causing

changes in memory and in intellectual function and

things that we don\'t know about. So, I am more

conservative about treating these adolescents with

232

weight-loss drugs, whereas I am much more

aggressive in treating the comorbidities directly

because I know atherosclerosis is a huge issue.

DR. BRAUNSTEIN: Dr. Watts, anything?

DR. WATTS: The issue about the run-in

period is going to come up later but I think it is

particularly relevant here where you are hoping to

find some change that will have long-term effects

rather than a period of pharmacologic intervention

that will then be stopped. So, I think in the

pediatric/adolescent weight-loss studies there

needs to be more attention to run-in phase behavior

modification.

For drugs that have CNS effects, I am

concerned that we need to be alert and develop

tools to measure changes in school performance,

intellectual function both during the time that the

intervention is being given and in the time after

the intervention is stopped, not just in scholastic

behavior but in personal relationships with peers

and with parents, and would hope, with the lack of

long-term data for the adult studies, there would

233

be some way to try to improve the gathering of

long-term data from these studies. I agree that a

higher BMI starting point for children would be at

least an initial step compared to the BMI starting

point used for adults.

DR. BRAUNSTEIN: Dr. Woolf, any further

comments?

DR. WOOLF: No.

DR. BRAUNSTEIN: Dr. Carpenter?

DR. CARPENTER: Just a brief comment on

the story with pediatrics here. I think that

unlike the story we heard earlier from Dr. Orloff

regarding the pediatric population perhaps being a

small subset of a study with a drug that would

expand the indication, we are really talking about

a completely different set of studies that have to

be done in this group because of the complexity of

the issues, the long-term cumulative effects of the

drugs, the developmental components both

neurologically and growth related that are going to

be part and parcel of studying this group.

I think the problem that Dr. Yanovski

234

raises of trying to assess a moving target in terms

of linear growth still going on\--it is all going to

create an environment for a completely different

design and intensity of study than what we have

previously been discussing, and I think it is going

to require a substantial discussion that perhaps

has some issues that are parallel to what we have

been talking about in the older group. But I think

it may be best to explore this in detail as a

separate issue down the pike.

DR. BRAUNSTEIN: Dr. Flegal?

DR. FLEGAL: I have just a couple of

comments. One is that, given the way the

definitions of overweight for children based on the

95th percentile are involved, it might be advisable

to have a higher standard than that to indicate

treatment, and I would not recommend using Z-scores

for that because I know how growth charts are

constructed and I know the Z-scores are not going

to work out at the tails, but maybe some absolute

amount higher than the 95th percentile.

Just one more comment, and I don\'t know

235

very much about this area but it seems to me that

the indications for treatment of high BMI as a risk

factor should be commensurate in some way with the

indications for treatment of other risk factors in

this age group, including blood pressure and high

cholesterol. I think it would be ironic if you

ended up saying that for one of these conditions we

go in and have drug treatment but for the other

ones we avoid drug treatment. There should be some

common denominator in how these are handled.

DR. BRAUNSTEIN: Dr. Greenway?

DR. GREENWAY: Well, I have just two

thoughts that I think are different about this

group. One is that I think they experience a lot

more social ostracism than people in even older age

groups and, yet, there is the whole issue of mental

growth and physical growth and development in this

population that has to be taken into consideration.

In addition, I think there are a lot of

methodologic issues that haven\'t been sorted out

with relationship to how to assess this whole area

in growing people. At least I have no idea how to

236

do a power analysis on a Z-score.

DR. BRAUNSTEIN: I basically agree with

the comments that have been made. I would like to

reemphasize what Dr. Carpenter said, that this

population of patients needs to be studied

separately from the adults so that when one designs

a study it shouldn\'t be including individuals from

ages 14 to 70. The adolescent and childhood

obesity problem needs to be treated on its own

accord with appropriate controls and studies of

growth parameters, psychological parameters, etc.

Ms. Coffin?

MS. COFFIN: I have a question for the

industry representative. I heard earlier that the

average age of the participants in the studies is

about 40 years old, which is actually even a little

on the old side for the participant users or the

end users of drugs currently. Is the industry

interested, excited, chomping at the bit to test

drugs on adolescents? Because my understanding is

that it is a terrible group to test because there

are so many complications.

237

DR. RYDER: I have never run a clinical

program so I can\'t speak for the emotional state of

the people who are running the programs. I do know

that industry is certainly interested in bringing

new treatments to people who need them, and it

sounds to me like people need new therapies for the

treatment of obesity, whether they are 12, 14, 18,

30, 40, 60, 80 or whatever. So, I am sure that the

industry supports the intervention of new

treatments.

That said, I will go back to my prior

comment\--Dr. Levitsky made it, Dr. Carpenter just

made it, many have mentioned that you have to have

a different set of certainties around you product

specifications because you are going into a

population where typically we accept a little bit

less risk. You have to perhaps notch it up in

terms of the certainty that you want in not

bringing harm, and all these considerations. Dr.

Carpenter said very nicely that it is a somewhat

different population.

MS. COFFIN: Thank you very much. I would

238

agree that this is definitely a different

population and would like to see this handled in a

separate guideline or a separate study, but I would

also say that prevention early on, as Dr. Woolf

mentioned, is important, and more education that

you can provide to adolescents. Right now we are

actually requiring a physician sign-off to get into

behavioral changes for treatment of obesity and

overweight for adolescents and pediatric

participants. So, we are looking for the medical

field to give us a little bit more direction.

DR. BRAUNSTEIN: Dr. Levitsky, any other

comments?

DR. LEVITSKY: I am going to comment on a

few different things that have been said. One is

that industry had been given encouragement to do

these studies, obviously, because they get their

drug with their patent a little longer if they do.

So, they will be done, I am sure, although they

will be more complicated.

The second thing is that I am a little bit

concerned about the level of concern about doing

239

studies in adolescents because of worries about

passage onto the next generation. I recall that

those same arguments prevented studies in women for

many years. So, I guess that we have to worry

about it but recognize, nonetheless, that these

kids do need to be studied.

The next thing is that I would categorize

pediatric studies in several groups. One of my

colleagues, a pediatrician, when he sees a patient,

a little child who is overweight and whose parents

are complaining about it, always pats the kid down

and then says, \"I can\'t feel any money in his

pockets. How is he getting the food?\" So, there

is an age at which this is not a pediatric problem;

this is a family problem and I don\'t think that we

need to look at the drugs for those kids. I have

certainly been very successful with Prader-Willi

syndrome kids as long as the parents understand it.

But there is also an age at which children become

free range and at that point testing these drugs is

important and starting at the 12-16 year range is

certainly appropriate. That is also nice because

240

it is a range that, although neuronal connections

and growth are still going on there, they are not

so intense as in the early ages. So, I think it is

feasible to conduct these studies.

The last point is one of Dr. Yanovski\'s

actually. If you use the 90th percentile for BMI

using the new fudged growth charts, which don\'t

have the weight data that are presently available

but use the old weight data because children have

gotten fatter than are on the new growth charts,

you really are working around a BMI of 30. So,

that is probably pretty reasonable, isn\'t it?

DR. BRAUNSTEIN: Thank you. Dr. Yanovski,

any other comments?

DR. J. YANOVSKI: I guess just to address

one last point to remind everyone that, indeed,

there are data suggesting that pediatric aged, or

at least adolescent aged BMI predicts additional

morbidity many years hence independent of adult

BMI, and so there really is a very good rationale

for successful treatment.

Then, to make a plea that the studies in

241

pediatric populations include long-term follow-up.

It is not enough just to show efficacy for 6 months

or even a year or maybe even 2 years if we are

going to suggest that young children, particularly

young children, take medications for 50 years.

DR. BRAUNSTEIN: Dr. Follmann, any

comments?

DR. FOLLMANN: I would just echo that in

the pediatrics and adolescents you want to study

those that have the very highest risk and they

deserve special studies.

DR. BRAUNSTEIN: Dr. Schambelan?

DR. SCHAMBELAN: I would also emphasize

the need for these being separate studies, and then

I would add that the lifestyle modification be a

major component of the approach taken in this

population, whereas that may not be as much the

case in adults.

DR. BRAUNSTEIN: Dr. Hirsch?

DR. HIRSCH: I think that the very young

women that I am most concerned about would probably

be the biggest users of such a drug, if it were

242

made available to them, because they are so

involved with food intake and worry about it, and

whether they are obese or not, and so on. I think

that the menarcheal years of young women\--they are

so susceptible to all sorts of influences and there

are all sorts of important developmental things

occurring, and this explains a lot of the feeding

disorders we have and even to consider them as

targets for the kinds of drugs that are currently

available I don\'t think is the right thing to do.

DR. BRAUNSTEIN: We will go on to the

third question. I am told this is the third out of

11 questions so what we are going to do is still

stick with sort of general discussion to begin with

and then go around, but if you don\'t have anything

to add or don\'t want to add anything, please feel

free to pass.

The third question is obesity-associated

metabolic derangements, cardiovascular risk factors

as primary targets of drug therapy, when is an

obesity drug a primary therapy for diabetes,

hypertension and dyslipidemia. Yes, Dr. Woolf?

243

DR. WOOLF: I think that is sort of a

silly question. If you are going for an indication

for a secondary problem, then go for the

indication. So, if a drug is going to treat

hypertension, then go for the hypertension

indication; and if you think it is going to treat

dyslipidemia, then go for the dyslipidemia

indication and then weight loss is a secondary

issue. So, I am going to turn it around\--

DR. ORLOFF: I am going to clarify it a

little bit. This is a thorny issue with industry.

Basically what it gets to is a question that has

been asked of us, and that is\--well, let\'s put it

this way, we have taken a position that if the

effect on the comorbidity is simply consistent with

the weight loss effect of the drug, given that for

half of these drugs we may not know what the

mechanisms of action are but we certainly don\'t

have any evidence that there are independent

effects on the comorbid features, at least for some

of the drugs, although that might be different in

the case of dyslipidemia. But just because you do

244

a study in patients who have diabetes and show that

when they lose weight with your weight-loss drug

their diabetes gets a little better, does that then

become a primary treatment for diabetes? That is

the question. How do people suggest we think about

those issues?

DR. BRAUNSTEIN: Dr. Yanovski?

DR. S. YANOVSKI: There are a couple of

issues within your issues. One is that I think if

a weight-loss drug causes improvement in the

comorbidity, even if the mechanism of that is

through weight loss, that is fabulous. We know

that weight loss improves dyslipidemia and

hypertension.

Now, there is a question as to whether you

would get a similar effect through behavioral

weight loss. I think as a physician, what I would

want to know in the PDR or anything else is that

this drug caused improvement in these risk factors

and that it was consistent with the amount of

weight loss, or that there was actually an

independent effect. So, I think you just tell the

245

physicians so that they could let their patients

know, yes, your lipids may improve; your blood

pressure may improve consistent with the amount

that it would improve if you had behavioral weight

loss treatment or non-drug treatment.

Now, if you are going for a primary

indication\--I actually saw a beautifully written

little statement in here that it should be

considered efficacious as a primary indication for

the comorbid condition if it is clinically relevant

for the disorder, in line with accepted clinical

practice, and has similar magnitude and durability.

So, I think you could go for a weight-loss

indication or a primary comorbidity indication.

But just because it is working for weight loss, I

see that as a plus not a minus.

DR. BRAUNSTEIN: Dr. Aronne?

DR. ARONNE: I strongly agree with Dr.

Yanovski\'s point, and want to point out to you one

of the absurdities right now. If you prescribe a

drug that causes weight gain and complicates

someone\'s diabetes in other arenas but it gets the

246

glucose under control, that is an approvable drug.

In fact, those drugs are approved even though they

are causing weight gain, increasing visceral fat,

increasing C-reactive protein, for example. But a

drug that causes weight loss is not approvable

because it causes weight loss as its mechanism of

action, even though it will improve other

comorbidities at the same time. That, in my

opinion, is an inherent absurdity in the rules as

they stand now. I see weight loss as a valid

method to achieve these. In fact, I look forward

to the day, 5, 10, 15, I don\'t know how many years

in the future, when one obesity drug will be used

to treat all those at the same time. So, instead

of treating all the comorbidities with 5, 6 or 10

drugs we will be using 1 or 2 or 3 obesity drugs to

treat the whole picture. So, I agree strongly with

what Dr. Yanovski says and I think that her

statement is a nice summation of it.

DR. BRAUNSTEIN: Let\'s go around and see

if anybody else has anything to add to this. Dr.

Hirsch?

247

DR. HIRSCH: If it worked it would be

great. They don\'t lose weight and they don\'t do

any other thing.

DR. SCHAMBELAN: I concur.

DR. FOLLMANN: I think it is basically

impossible to try and sort out, say, if a drug has

its entire benefit through weight loss. If a drug

has a benefit on weight loss and hypertension I

don\'t see how it is possible to describe what

percentage of the benefit, in terms of blood

pressure reduction, is due to the drug\'s

weight-loss ability or some other mechanism, and I

wouldn\'t even try to discern that or worry about

it. I would just say it reduces weight and it

reduces blood pressure.

DR. J. YANOVSKI: I just want to make an

obvious reminder to the committee that we have

approved a drug for diabetes that, in fact, causes

weight loss. It is called metformin and at least

part of its action, undoubtedly, is due to the fact

that it induces some weight loss. So, the proof of

concept has already been done. I don\'t see any

248

reason why a drug that has an indication

for\--oh\--pulmonary hypertension couldn\'t be

approved for erectile dysfunction or vice versa.

We know there is a drug that is of that nature.

Similarly, the same thing could be true for a drug

that happens to decrease body weight and might also

be very effective for hypertension or dyslipidemia.

DR. ORLOFF: I want to just clarify one

thing, Glenn. For the record and to make sure the

committee understands, what we are talking about

here really are issues around labeling because we

have criteria for approval for weight-loss drugs

and we have approved drugs using those criteria.

The question is whether the weight-loss

drug, by its reduction in weight, makes your

diabetes a little better, whether that means you

then write in the label that it is indicated for

the treatment of diabetes, essentially. We include

all this information in labeling in adherence with

the principle that our labels should convey all the

information we have on the expected benefits and

risks of the drug. So, whether it makes your

249

comorbidities better or worse, you know, the

information goes in. Likewise, for the diabetes

drug that induces weight gain the labeling, I

believe, expresses what the magnitude of weight

gain was in the clinical trials.

DR. BRAUNSTEIN: Dr. Schambelan?

DR. SCHAMBELAN: Can I ask a question?

So, are you concerned about the use of the agent in

somebody who is not obese, who doesn\'t meet that

criterion but for the treatment of diabetes alone?

That cannot be handled in the label in some way?

DR. ORLOFF: I suppose. I mean, I think

that is a potential confusion. Let me just say

that I think the best advice we got essentially

from Dr. Yanovski on this is that if an obesity

drug wants to be a diabetes drug, then it should be

taken through its paces according to the same

standards that are applied to a diabetes drug.

Likewise, for a lipid-altering drug or an

antihypertensive drug. The fact that in the trial

that was designed as a weight-loss trial in obese

diabetics, just the fact that their obesity got

250

better and their diabetes got better doesn\'t

necessarily equal a primary therapy.

DR. J. YANOVSKI: Right. So, if they want

to pursue an indication, they should do exactly the

same studies that are required for any other drug

for diabetes, any other drug for hypertension, etc.

DR. LEVITSKY: And there may be some

reasons why this would be reasonable. There may be

companies that wish to differentiate themselves

that way so I think that is a perfectly reasonable

approach.

MS. COFFIN: Just to add that the labeling

does make a difference with insurance and what they

do cover and what they don\'t cover, and you need to

keep that in mind.

DR. BRAUNSTEIN: I agree with Dr.

Yanovski\'s approach.

Design, run-in prior to randomization,

pros, stratification, etc., exclusions, responders,

limit of duration. This is the present guideline

6-week dietary, behavioral type of run-in. So, we

will open this up for general discussion first.

251

Should the run-in requirement be maintained or

deleted?

The comments received, primarily from

industry, suggested that we delete this, the

primary reason being that almost all the patients

entering this trial will have already tried diet

and exercise and have failed, and since all the

patients are being treated in a double-blind,

placebo-controlled manner with the same type of

dietary and exercise instruction, there is no need

for a pre-treatment run-in diet and exercise

period. So, that is what the basic area of the

question revolves around. It is open for comments.

Yes, Dr. Ryder?

DR. RYDER: I just have one request really

of the FDA. I do not have any empiric data

personally from my experience to bring to the

committee, but we did run into an issue like this

using an overactive bladder drug that I was

involved with. I was wondering do you have any

information where companies have had different

run-in periods in different programs, and have you

252

see selectively better results or different results

compared to, say, a placebo arm? Do you have

empiric information that would be helpful in

telling us whether using different run-in

periods\--you know, people have run different

programs in the past and I was just wondering if

you had any experience. I don\'t.

DR. ORLOFF: I can\'t speak to any

specifics. Let\'s just say that different drugs,

different diseases, different clinical trials

directed at different hypotheses will use designs

that include a run-in. Sometimes the run-in is to

establish that the patients are going to be

compliant. Sometimes it is to set the background

in the case of obesity or in the case of

dyslipidemia, with regard to standard of care

interventions.

DR. HIRSCH: It was posed originally,

years ago, as a sort of ethical issue. I am not

sure that is exactly right, the ethical issue being

the following, that there may be a subset of people

who just have to be put on a good diet and exercise

253

program and they will lose weight and they should,

therefore, not be subjected to whatever hazard

there is of a drug even in an experimental setting.

Well, as it has turned out, even under the best of

treatments with diet and exercise, and so on,

long-term results are very iffy and, therefore, one

might say that that ethical issue disappears

because what we are testing here is the issue of

even if they did lose weight by the diet and

exercise, you still want to see what the efficacy

of the drug would be in maintaining that new, lower

weight. So, this can all be explained to the

patient and then they have a choice of whether they

want to enter the study or not. So, I believe

there is probably no residual ethical issue for why

you have to give everybody a 6-week run-in period.

But now the whole experimental issue comes

up if you are going to be fooling around with

categorical things. Some people are responders and

some aren\'t. You might want to get some

information before about who is who in terms of

those responding and then rearrange the drug

254

randomization so as to randomize these factors as

well. It would be a nicer intellectual study to

still have the longer run-in but not for any

ethical purposes. So, to some degree, there is a

choice in what the investigator, company or

whatever wants to do in this, it seems to me.

DR. BRAUNSTEIN: Dr. Yanovski?

DR. S. YANOVSKI: Yes, I agree. There is

really not a lot of scientific justification

anymore for the run-in. I think whether you use

behavioral weight loss or drug weight loss people

are going to continue losing weight for the first

4-6 months regardless. People who stop losing

weight after the first few weeks are probably going

to be, as Jules said, poor responders to anything.

So, there might be advantages in having a couple of

weeks of run-in just in terms of study design and

figuring out who your responders are and

stratifying, or seeing who is actually going to be

willing to stick with your treatment. But I don\'t

see a scientific justification for a 6-week run-in

at this point.

255

DR. BRAUNSTEIN: Dr. Schade?

DR. SCHADE: The biggest problem that I

see with the studies that are submitted to the FDA

is that the populations that are studied have very

little relevance to the populations that we treat.

There are so many exclusions that are included in

the studies\--you are too big or too little, you are

too high, too wide, something\--so the fact is the

studies that are approved or are submitted for

approval are very, very select populations.

I think this is one opportunity here to

get the population that we treat as physicians

closer to what is submitted to the FDA to get rid

of the run-in period because no physician in the

real world is going to have a 6-week run-in period.

So, I am trying to get the two studies closer

together so I can believe what the FDA approves is

basically somewhat applicable to my patients. So,

I would be strongly in favor of getting rid of a

run-in period because I think in the real world it

never really happens.

DR. BRAUNSTEIN: Dr. Greenway?

256

DR. GREENWAY: In addition, I think

another disadvantage of a run-in period has to do

with interpreting the data at the end. A lot of

the microbiologics that we all think are so

important to evaluate respond to caloric deficit.

So, if you already are in caloric deficit, then you

don\'t know where to start your baseline. Do you

start your baseline before the run-in or do you

start it when you randomize the drug? And, if you

do it when you randomize the drug, then most of the

improvement in your comorbidities has already

occurred and you don\'t see that at the end of the

trial.

DR. BRAUNSTEIN: So, are you speaking in

favor of having drugs or just having behavior?

\[Laughter\]

Let\'s go around and ask if there are any

specific comments that you want to make on this.

Dr. Ryder?

DR. RYDER: Nothing,

DR. BRAUNSTEIN: Dr. Aronne:

DR. ARONNE: I just want to agree that the

257

run-in does not make sense.

DR. BRAUNSTEIN: Dr. Woolf?

DR. WOOLF: I agree that we ought to

abolish the run-in but I think that there needs to

be a sufficiently long baseline that we have some

idea of what the stability of the values are for

comorbidity, weight and things like that. So, I

would want at least a few weeks, if not a few more

than that, without treatment, a screening period.

DR. BRAUNSTEIN: Dr. Carpenter?

DR. CARPENTER: I don\'t see a reason to

justify the current practice of a run-in period. I

think some of the stratification issues that were

raised by doing this\--we don\'t even know the

quality of the stratification from data obtained in

run-in in this setting and perhaps it could be in

some way ascertained to start with. I also think,

as was mentioned earlier, that it may make a more

real-world situation for the study.

DR. BRAUNSTEIN: I also agree that I think

we can dispense with the 6-week run-in period.

MS. COFFIN: I am in favor of an

258

evaluation or a set time so you can get those

initial motivators out of the studies so that you

will have more completers. But I also agree with

the folks that have said that most of the folk that

are at the study point have tried and tried and

tried and tried, and so they have already had more

than 6 weeks run-in.

DR. BRAUNSTEIN: Dr. Levitsky?

DR. LEVITSKY: Well, it may just get study

subjects to stay with the study if they get tested

for those 6 weeks. That would be its only

advantage.

DR. BRAUNSTEIN: Dr. Yanovski?

DR. J. YANOVSKI: Just a pediatric

population comment, many severely overweight

children have yet to try a good diet with a good

behavioral program. So, in that one instance it

may be very appropriate to recommend strongly that

folks carry out a good diet program and behavior

modification program before having drug therapy in

general. If they failed previously, then there is

no reason to do it again. So, I agree, the run-in

259

with dropping out those who are responding well

seems to be the wrong approach.

DR. BRAUNSTEIN: Dr. Follmann?

DR. FOLLMANN: Yes, I don\'t see any reason

to have the current run-in design as it is

currently stated. I could see a reason to have a

short run-in to get rid of people who would be

likely non-compliers.

DR. BRAUNSTEIN: Dr. Schambelan?

DR. SCHAMBELAN: I would agree to remove

it from the guidance but I would encourage the

companies to have a period of observation baseline,

as was suggested, and that would enhance the data

at the end for their purposes.

DR. BRAUNSTEIN: Dr. Hirsch?

DR. HIRSCH: I agree.

DR. BRAUNSTEIN: The fifth question,

combination drug regimens, standards of

efficacy\--open for general discussion. David, do

you want to elaborate on this a little, the

standards of efficacy for combinations?

DR. ORLOFF: Well, I just wanted to hear

260

some thoughts from perhaps the clinical trialists

and others related to what people might suggest as

the difference between mono therapy and combo

therapy that should be deemed clinically

meaningful.

DR. BRAUNSTEIN: To rephrase then what you

said before, should it be additive, synergistic,

multicative or can it just be statistically greater

than one alone? Dr. Woolf?

DR. WOOLF: A point of clarification,

could it be just as efficacious but with fewer side

effects?

DR. ORLOFF: That is also a rationale for

combination therapy obviously. Why don\'t we skip

that one and go to weight loss efficacy? Assume

that these drugs are all perfectly safe.

DR. WATTS: Well, just to follow-up on the

point that Dr. Woolf made, I think the endpoint

would be different if you are using lower doses of

drugs in combination to get the same endpoint than

if you are using two drugs and their standard

dosing hoping that the combination gives you a

261

greater gain. It seems to me that the additional

gain needs to be at least as much as the gain that

you would get with one alone. So, if you are

requiring a 5 percent weight loss or difference

with drug A, then adding drug B, to be clinically

meaningful, you would need to get at least that

much more weight loss.

DR. BRAUNSTEIN: If I interpret that

correctly, if you have a combination and drug A

plus drug B is greater than one alone, or the

combination allows you to reduce the dose of each

of them and, therefore, potentially reduce the

toxicity.

DR. WATTS: Right, and there the goal

would be if you meet a 5 percent difference between

the intervention and placebo group for a single

drug, then that would be the goal for the

combination drug if you use it in reduced doses.

DR. BRAUNSTEIN: Dr. Aronne?

DR. ARONNE: I think that both increased

weight loss and reducing the doses of the drugs

that are used are both valid indications. I think

262

that a lot of the bad luck that we have had in the

past with these drugs has been because of

intolerable doses, and I think not understanding

how the feedback mechanisms work practitioners were

overdosing people 5, 10, 20 years ago in an effort

to induce more weight loss when, in fact, what was

going on was that a compensating system was at work

and what you wound up with was drug toxicity. If

you could use tiny doses of three or four drugs

that hit specific spots in the neuroendocrine

mechanism, you could get a superb result. Now, we

don\'t have those drugs yet but we certainly have

seen situations clinically where we have been able

to get much better weight losses than you would

expect with much lower doses of the drugs that are

currently available. So, I think that better

efficacy but lower doses of drugs would also be a

reasonable way to evaluate these.

DR. SCHAMBELAN: Could I ask for a

clarification for how the agency has looked at

combination therapy, let\'s say, for type 2 diabetes

with two agents or any hypertensive combinations?

263

I mean, what has the bar been there to help us

think about what it should be for obesity?

DR. ORLOFF: For diabetes the standard

design is maximal or just submaximal doses of the

two drugs in combination in patients who have

failed to reach hemoglobin A1C goals on a single

drug. So, it is establishment of the principle

that there is some additive effect. It presumes,

and in fact it is the observation in these trials

that there is some effect of the first drug so that

they are not completely refractory to the first

drug.

I am not sure how much we need to belabor

this. This one actually turns out to be quite a

complicated issue because it occurs to me,

listening, that there ought to be a difference

between\--one of the things I didn\'t raise as I

introduced this is the possibility of a categorical

win so that you could actually capture more

patients into a 5 percent or 10 percent category by

the addition of a second drug. But simply winning

on a categorical win does not establish that you

264

have an additive effect. It might, in fact,

indicate that you have a population that actually

just doesn\'t respond to drug A but when you add

drug B they are responders to drug B. That is not

a viable combination drug product. We want both

components to be contributory to the effect.

So, the question I guess I just want to

leave it as is if we are looking for some sort of

additive effect, so presuming an effect of drug A,

how much more do you have to get with drug B? We

heard an additional 5 percent as sort of a default

and I just want to know if anyone else has any

other thoughts.

DR. BRAUNSTEIN: With that, why don\'t we

just go around and start with Dr. Hirsch?

DR. HIRSCH: I can\'t see why there is any

a priori reason why it wouldn\'t be good to have

two. I mean, consider hypertension for example.

It is common clinical practice now to use a number

of drugs. That is a common thing to do and that is

done because it is more efficacious. What we don\'t

know is whether any combinations are going to be

265

more efficacious or not.

For example, one possibility would be not

to use two drugs simultaneously but to alternate

them, or when the weight comes down with one just

substitute another because we know that almost

inevitable failure comes in. So, it just seems to

me there has to be some experimentation with some

very carefully thought out studies of possibilities

for efficacy, but until we know that there is no

sense even talking further about it because we have

no idea whether two would work, or three, or

alternating, or whatever.

DR. BRAUNSTEIN: Dr. Schambelan?

DR. SCHAMBELAN: I find it hard to come up

with a number to answer the question. I do agree

with your principle that you want to have both of

the two drugs be effective to some degree before

you use them together. You don\'t want to just add

a drug in a drug failure situation and then

continue the other drug. But I don\'t know how to

come up with a number. I struggled enough to be

comfortable with 5 percent in the first place.

266

DR. ORLOFF: Okay, we will put that in the

guidance!

DR. BRAUNSTEIN: Dr. Follmann?

DR. FOLLMANN: I don\'t have any great

thoughts on how to change the standards of efficacy

for combination drugs, but I think it is more

exciting to think about sequential therapy, maybe

interrupted therapy, if we are going to consider

more elaborate drug regiments than just straight

two drugs for a long period of time or short period

of time.

DR. BRAUNSTEIN: Dr. Yanovski?

DR. J. YANOVSKI: To amplify on what I

think Dr. Hirsch said, since we believe obesity is

caused by so many different etiologies, each

individual drug might help a small subsegment.

Together, you might see a population effect from

combination therapy because you have now treated

successfully many people and so it is not necessary

to treat with multiple drugs simultaneously but,

rather, you know, to make the punishment fit the

crime, if you will. And, the problem is we don\'t

267

yet have good nosology so we are stuck with the

issue at hand. What would be considered a good

combination drug benefit, I am struck that it would

be hard to argue\--why should we be more strict

about this than we are for diabetes is based on the

fact that we know what we want to get for

hemoglobin A1C. We know, you know, that that is

where we want to be.

Whereas, for obesity, since none of our

drugs yet are efficacious enough to get us where we

want to be, we are figure out how lower, how much

closer to the goal we should be. If 5 percent

change is considered efficacy for a single drug it

is certainly not going to over-classify effective

combination therapy. It might miss some drugs

which together might still give some clinical

benefit. And, the idea of a clinical win might

capture those combinations which were at least of

greater benefit to the population than the single

drug alone. But, you are right, it is hard to

know. You wish you knew better how to treat the

disease properly.

268

DR. ORLOFF: Combination drugs are really

a complicated area but it is also important for

people to know that we have combination drugs that

are indicated and labeled as first-line therapy for

a target disease. But I believe probably the

majority of first-line drugs, at least for

metabolic illness like hypertension and diabetes

and dyslipidemia are sort of sequential therapies.

Avandamet is recommended for patients who have been

on metformin or Avandia but are inadequately

controlled who are then now going to go on double

therapy.

Frankly, the indications for those uses

are directed by the designs of the trials and by

their results. I am listening to this and it has

occurred to me that as a first step combination

drug trials for obesity should employ that

sequential model, again, to ensure\--to use the

aphorism that Dr. Yanovski should not have used,

the punishment fits the crime. That will be quoted

all over the place. But, no, just to assure that

you are not seeing an increase in the mean weight

269

loss not related to a true additive effect but,

again, related to a spurious effect of treating

with the second drug non-responders to the first

drug.

DR. BRAUNSTEIN: Ms. Coffin, any comments?

MS. COFFIN: Just that, like Dr. Atkinson

said, if one drug will get us 5 percent and if you

put it in combination with something that gets you

a little bit more, great; we love it if it works

better. Whether there is a number, I go back to

the statistical significance.

DR. BRAUNSTEIN: I think that I am fine

with combination drugs. I would use as the

endpoint a statistically significant increase of

the combination over either one alone. But it

needs to be carried out in a trial that has a

head-to-head comparison, a contemporaneous

head-to-head comparison with each of the agents

plus the combination in order to not rely upon

historical data from which the original agents were

approved since we do know there is a lot of

variability between results of trials.

270

DR. GREENWAY: I think that most of the

discussion is sort of centered around two approved

obesity drugs in combination. I think that there

are other types of combination drugs that have

minimal effects on their own and when combined may

do something special. That kind of synergism I

think should be another indication for a

combination drug.

DR. BRAUNSTEIN: Dr. Yanovski?

DR. S. YANOVSKI: Again, I just think that

I don\'t see a particular cut-off. I certainly

wouldn\'t hold it to a standard of having to double

the weight loss but if it adds something or reduces

side effects and gets you at least that 5 percent,

I would think that would be of benefit.

DR. BRAUNSTEIN: Dr. Carpenter?

DR. CARPENTER: I think that establishing

a guideline for percent delta with the second drug

would be premature. I think it is going to be very

interesting to see what studies come out of that

but is an exploratory outcome at present and that,

as well as other permutations such as alternating

271

months, such as some therapy we saw earlier today

versus sequential therapy versus combinations all

should be part of the experimental designs to come

but a standard for them\--we are not able to do that

yet.

DR. BRAUNSTEIN: Dr. Woolf?

DR. WOOLF: I guess the full answer to my

question is it depends. There are drugs\--and I

can\'t remember which one it is, where drug A is no

longer effective. By adding drug B the effect is

now greater than B alone. I think it is some of

the oral agents. So, just because a drug is not

effective anymore\--excuse me?

DR. J. YANOVSKI: Augmentin.

DR. WOOLF: Okay. So, there are examples

where that works and so I wouldn\'t exclude that

possibility. Adding two drugs that are known to

work, where each alone creates a 5 percent weight

loss, and having the two together statistically

different, while that may be satisfying the

statisticians it may not be clinically useful. So,

if each drug is 5 percent but the combination is

272

statistically significant at 5.5 percent, I don\'t

think that is worthwhile. I can\'t tell you what

percent above would be clinically worthwhile but it

has to be something meaningful that a group of

reasonable clinicians can at least agree about.

Finally, I would go back and say that if

the safety profiles of the two drugs are not really

terrific at maximal doses, then adding submaximal

doses to get a cumulative effect of 5 percent at a

reduced adverse event rate would be very

satisfactory to me.

DR. BRAUNSTEIN: Dr. Watts?

DR. WATTS: Just to follow-up on what Dr.

Woolf said about statistical significance, the

amount of difference that you can say is

statistically significant depends on the sample

size. If you have a large enough sample size a

tenth of a pound could be statistically

significant, and I think there really needs to be a

minimal level of additional weight loss that also

is statistically significant.

DR. BRAUNSTEIN: Dr. Schade?

273

DR. SCHADE: I just wanted to follow up on

something Dr. Greenway said and many other member

of the committee, which is to point out that

synergistic weight loss has been shown by several

groups in animal studies of combination therapies.

To my knowledge, it hasn\'t been shown in humans but

it has been shown in animal studies. So, maybe it

is at least theoretically possible that some type

of much more effective therapy can be achieved

through combination of drugs.

DR. BRAUNSTEIN: Dr. Ryder?

DR. RYDER: I would only comment that we

may be at a different place in terms of our

learning, but I do think that we should tool up and

make sure that the principles that have led us to

have successful combination drugs for

antihypertensives, diabetics, hyperlipidemics\--I

mean, this is not the first time that this

committee or the agency has been presented with

this. We should make sure that we have that

learning and use innovative designs as best as we

can, but I do think it is probably in the end going

274

to be a challenge worth facing up to.

DR. BRAUNSTEIN: We will go on to the next

question, endpoints. Define obesity prevention,

weight maintenance, prevention of weight gain. Are

these distinct clinical effects? Are these

distinct pharmacological effects? Are studies

needed to document efficacy and safety in each? I

will open this up for general discussion.

DR. ORLOFF: And we do need definitions if

people think it is relevant to distinguish all

these effects.

DR. BRAUNSTEIN: Dr. Watts?

DR. WATTS: I think there may be a

difference between prevention of weight regain and

obesity prevention/weight maintenance. That is,

the mechanisms may well be different to stop

someone from gaining weight who has never been more

overweight than in someone who has had significant

loss and preventing them from regaining. But I

think the first two, to me, sound pretty much the

same, prevention of obesity or weight maintenance.

DR. BRAUNSTEIN: Ms. Coffin?

275

MS. COFFIN: I would actually disagree. I

think that obesity prevention and weight

maintenance are different but the prevention of

weight regain\--of course, I am coming from the

perspective of folks to whom weight maintenance

means that they have already lost some weight and

are maintaining it is different. That would be

different than the prevention of the regain so I

think they are the same.

DR. BRAUNSTEIN: Dr. Follmann?

DR. FOLLMANN: I think the only difference

in these really is sort of the group that you

randomize to obesity prevention being, I guess,

people who are at risk of becoming obese.

Prevention of weight regain would be those who had

successfully lost weight and now are worried about

gaining weight again. So, the populations could,

in principle, be different but I think you would

still want to use the same endpoints, which is, you

know, does the drug compared to placebo show a

significant and 5 percent difference between the

two groups. So, to me, that is a minor distinction

276

from means and so I would just say, you know, you

can use the same designs and endpoints that we have

talked about all along. Maybe you would want to

just look at different patient populations that you

are randomizing.

DR. BRAUNSTEIN: Dr. Greenway?

DR. GREENWAY: I think that there is a

difference between weight loss and prevention of

weight regain. At least with the drugs that we

have now, if you cause weight loss with diet and

then randomize people to orlistat or placebo you

get a weight regain that is less in the orlistat

group than in the placebo group. But if you get

weight loss through dietary means and randomize

people to sibutramine versus placebo you get an

additional 7 percent weight loss. So, it appears

that there are some drugs, presumably the ones that

act centrally if that observation is correct, that

may do better at working after weight loss has

already been induced than starting from the

beginning.

DR. BRAUNSTEIN: Any other general

277

comments? Yes?

DR. HIRSCH: Except that there are special

challenge situations, like I mentioned before, like

smoking cessation or perhaps pregnancy or

menopause\--there are periods in which weight gain

so frequently occurs. I am not answering the

question as to the definition of what would be the

suitable thing. I presume that just comparison

with a placebo group under these circumstances

would be a very helpful thing.

DR. BRAUNSTEIN: Dr. Flegal?

DR. FLEGAL: Maybe I am thinking about

this a little too literally, but I see very

different issues arising from these three terms.

For example, weight maintenance\--what BMI level

would that go down to appropriately if someone had

a BMI of 23 and wanted to maintain weight? Would

that be an issue?

There is also the issue of the weight gain

that occurs with age, which is extremely common.

Would that be something where there would be an

indication for weight maintenance?

278

Also, obesity I interpret perhaps more

literally as not meaning overweight but as a BMI

over 30. So, preventing obesity would be basically

maintaining your BMI below that.

So, I see those as definitional issues

about what BMI levels these would all apply to that

would be very confusing.

DR. BRAUNSTEIN: Let\'s go around and ask

if anybody has specific comments. Oh, Dr. Schade?

DR. SCHADE: I have one other comment. I

think these are different, and they are different

in the sense that prevention of obesity can occur

in a normal weight individual where the other ones

tend to be maybe already starting with a treatment.

For example, if you treat somebody with steroids

for Graves eye disease for a 3-month period they

are all going to gain weight\--a well-known effect

of steroids. We are now treating their bone

disease to prevent them from getting osteoporosis.

In that situation I can well see we will need one

of these drugs to prevent the obesity that occurs.

So, I think these are certainly different at least

279

in different populations and I think there will be

individual studies addressing these. These are not

the same thing.

DR. ARONNE: I think as far as the issue

of are these distinct pharmacological effects, in

some cases it is going to be yes and in others no.

An example would be in the case of leptin, for

example. I think it would not prevent weight gain

but in someone who has lost weight it might prevent

weight regain. That would be an example, but that

might not be true for other drugs and other

situations so I think that there may be distinct

pharmacological effects that differentiate these

two situations.

DR. BRAUNSTEIN: Dr. Ryder, do you want to

add anything?

DR. RYDER: No.

DR. BRAUNSTEIN: Dr. Aronne, any other

comments?

DR. ARONNE: I don\'t think that you need

studies to document separate safety but I think

that efficacy is the next question obviously.

280

DR. BRAUNSTEIN: Dr. Wierman?

DR. WIERMAN: I would just say that it

seems that we know so little about the maintenance

of peak body mass and these different perturbations

in all the different systems, both centrally and

peripherally, that until we understand the

physiology better it is very hard for us to predict

if the pathophysiologic states or these different

states along the time line are the same or

different, or are going to respond similarly or

differently to different interventions. So, I

think we will just have to stratify in patient

recruitment and different types of studies and look

at that very carefully.

DR. BRAUNSTEIN: Dr. Carpenter?

DR. CARPENTER: I think clear distinctions

between these terms will emerge in a clinical

context when people start to design studies and

they will require, I think, specific applications

to the clinical context. If the harbinger is to

begin a course of steroids, to begin an

antipsychotic medication, etc., those will imply

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perhaps prevention. Changes with age may all imply

maintenance issues in the context of the study will

I think result in emergence of more specific

definitions for these terms and we will see that as

time moves on.

DR. BRAUNSTEIN: Dr. Yanovski?

DR. S. YANOVSKI: Yes, I think there are

at the very least differences between a primary

prevention of weight gain, as in the case of

smoking cessation, and prevention of weight regain

where I think some of the underlying physiology is

going to end up being different, and you are

clearly going to find weight regain in that second

year regardless of what the drug modalities are, at

least the ones we have now. I get a little bit

concerned about having arbitrarily a 5 percent

difference required for that weight regain

indication. But I can\'t pull out of thin air what

I would like to see there.

DR. BRAUNSTEIN: Dr. Greenway?

DR. GREENWAY: I think weight regain is

different from the other two, and Dr. Hirsch has

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spoken very elegantly about the fact that when

people lose weight their body is just really trying

to get back to their original weight that they

started at. So, I think you do have a different

pathophysiologic process going on there, and it may

very well be a duration effect. After you get over

a certain period of time of maintaining somebody at

a certain weight they will sort of reset all their

homeostatic mechanisms that are trying to make them

regain weight and keep the weight off. So, I do

think that is a little bit different than

prevention or maintenance.

In regards to prevention, my only issue

would be, again, a safety issue. If we define a

large group of the population who are likely to

gain weight because they are sedentary or they only

eat Big Macs or they have a strong family history

of obesity and we want to prevent that from

occurring in that group, the risk of the drugs has

to be very, very minimal because otherwise we are

going to be doing more harm than good I think in

that setting.

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MS. COFFIN: The only indicator that I

have come across for long-term maintenance of

weight is long-term lifestyle changes. So, drugs

are going to be a way to get started and at this

point we are not showing a weight maintenance so,

as I said before, I am not seeing much of a

difference there.

DR. BRAUNSTEIN: Dr. Yanovski?

DR. J. YANOVSKI: As I was thinking about

the categories here, obesity prevention and weight

maintenance could both be terms applicable to

individuals who are of normal body weight, BMI

20-25. It could also be applicable to individuals

who have lost weight to that point and now want to

prevent regain. So, all three terms could

potentially be applied to that population. For

25-30, again, all three terms could be applied. In

fact, weight maintenance is what we are

recommending for the overweight population right

now by the NHLBI guidelines. Then, for over 30 it

is conceivable that one might consider a drug for

weight maintenance or prevention of regain even in

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those people who haven\'t gotten below 30 BMI

because, as we know, the folks over BMI 30 are

clearly at risk for continued weight gain.

I think that you might conceivably wind up

studying these issues, other than obesity

prevention, in all three weight categories that we

are sort of thinking about. The changes from

placebo obviously are going to have to be defined

at some level and clinically significant weight

change of 5 percent has been proposed so that is

perfectly reasonable. Clearly, indications can be

sought that are different for prevention of weight

regain and maintaining weight. But I think there

would have to be sufficient size populations to

study these different subgroups and then document

safety and efficacy in each of those subgroups.

But I do think they are reasonable targets for

drugs to seek indications within each of these

categories.

DR. HIRSCH: These matters are so complex,

it just came to my mind that there is some evidence

that smokers in general weigh less than

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non-smokers. That is probably one reason for the

J-shaped curve of BMI versus mortality, and so on.

On the other hand, people who stop smoking seem t

have gained weight back to those who never smoked.

So, you almost have to ask yourself the question is

smoking is being used by smokers to not become

obese, then would you be concerned about trying to

prevent the obesity that occurs when you have had a

successful treatment and you stop the treatment,

and you are going to look for another drug because

of the possibility of becoming obese? Do you see

what I mean? So, the complexity of these things is

enormous and this sort of underscores the necessity

for trying to figure out how some of these agents

work on the complicated system of weight

maintenance.

DR. BRAUNSTEIN: I wonder if Dr. Greenway

can tell is if that is the reason why bupropion

which is used for smoking cessation works, that the

patients on placebo gained weight and the patients

on bupropion didn\'t change.

DR. GREENWAY: The lack of weight gain

286

with smoking cessation is certainly one of the

advantages of using that drug and the other drugs

that are used to treat that condition.

DR. WOOLF: Dr. Hirsch just reminded me

there is another group that fits in the same

category, and that is the hyperthyroid patient who,

when he becomes euthyroid, gains about 10 percent

of their body weight. Could you use a drug to keep

them from regaining their weight? I have some

patients who are 180 lbs, went to 120 and are

destined to go back to 180. Could you use a drug

like that?

DR. BRAUNSTEIN: Well, that is a good

segway into number seven, which is requirements for

approval of treatment or prevention of drug-induced

obesity; data on risk for and associated

drug-induced obesity by drug; issues of

interactions impacting safety and efficacy;

criteria for efficacy. Dr. Schade mentioned

glucocorticoids as one type of drug associated with

weight gain and there are certainly other types.

Should a weight-loss drug be indicated for

287

prevention of that type of weight gain? We will

open this up for general discussion. Yes, Dr.

Levitsky?

DR. LEVITSKY: The rather remarkable and

severe weight gain sometimes associated with type 2

diabetes that we see with some of the

psychopharmacologic agents certainly would be an

indication for these agents. The question of what

your criteria of efficacy would be, I am inclined,

because these drugs don\'t work that well, to look

to the Europeans and suggest that in a controlled

study you would have to have a 10 percent

difference between your control group and your

group that is treated with one of these drugs, but

that is just an intuitive inclination and there is

nothing to back it up.

DR. ARONNE: I think that this is a very

complex area, this is an area that we deal with

clinically all the time because of the amount of

weight that can be gained and the complications. I

think using similar criteria to the ones already

established would probably be what makes the most

288

sense but, in general, you would probably design

studies like this for when someone gains weight.

In other words, you wouldn\'t start everybody who

starts a drug on a preventative therapy but you

would set a limit and at that point the

preventative drug would be started, and from that

point on if the difference was either statistically

significant or 5 percent or 10 percent difference

evolved, then I think you could say that the drug

was effective. Our experience is that we use

drugs, other than the drugs that are approved for

obesity treatment, so the main drugs that we use

are not drugs that are used for obesity treatment;

they are drugs for diabetes and for other

indications. So, I think that the criteria for

efficacy\--you know, I just think that we don\'t have

enough data to say what that number is. I think

the 5 percent is what I would argue for or

statistical significance.

I think the issues of interactions\--you

know, in many cases they are not very material

because you are talking about, in some cases,

289

psychiatric drugs versus metabolic drugs so but in

other cases you are talking about other psychiatric

drugs or other epilepsy drugs for the same

indication and there those issues need to be

addressed. So, I think if the drug is in the same

category, then the interactions need to be

addressed. But if drug is in a completely

different category there may be no reason to be

concerned about these potential interactions.

DR. BRAUNSTEIN: Dr. Watts, any comments?

DR. WATTS: No.

DR. BRAUNSTEIN: Dr. Yanovski?

DR. S. YANOVSKI: I just want to agree

with Dr. Aronne, particularly for using these

medications for weight gain prevention, I think

that having a 10 percent difference from placebo

would be a very difficult standard to meet because

you are really starting out at a lower BMI.

DR. BRAUNSTEIN: Dr. Greenway?

DR. GREENWAY: I would tend to think that

there are certain situations, like Dr. Schade

suggested, when you start people on steroids and

290

you are almost sure they are going to gain weight I

think that you wouldn\'t wait for them to do so. I

think you would start them on the drug if you had a

drug that could potentially help them.

DR. BRAUNSTEIN: I agree. I think the

example of using bisphosphonates for glucocorticoid

therapy is an excellent example of how you could

prevent one condition while you are treating

another. But I do think that for each drug for

which this would be a labeled indication there

needs to be a study that is adequately powered,

with a placebo control, to look for drug-drug

interaction as well as to show that it does prevent

the weight gain greater than placebo alone. Dr.

Yanovski?

DR. J. YANOVSKI: I agree with the Chair.

DR. BRAUNSTEIN: Dr. Follmann?

DR. FOLLMANN: Just to agree with you too.

DR. BRAUNSTEIN: Dr. Hirsch? Dr. Schade,

any comments? No? We will move on to number nine.

We have actually covered number eight previously.

Number of patients in phase 2 and phase 3 studies;

291

rationale based on magnitude and nature of

efficacy; rationale based on size of target

population; rationale based on expectations

regarding safety. Open for general discussion.

DR. WATTS: I think the change in weight

could probably be demonstrated with a fairly small

sample size. I think a number of people have

talked about safety issues, and I think that

expectations regarding safety should be the primary

determinant of sample size and that part of that

issue relates to the size of the target population

to be treated and the vulnerability of the target

population to be treated. So pediatric/adolescents

are perhaps more vulnerable to safety issues and

older patients with established coronary disease

may be more susceptible to certain types of safety

issues. There the sample size needs to be

adequate\--you are not going to have a large enough

sample to detect something that occurs 1/10,000

people but you should certainly have a sample size

adequate to detect something that occurs more

commonly, 1/100 people.

292

DR. BRAUNSTEIN: Dr. Follmann?

DR. FOLLMANN: I would sort of broadly

agree I guess on the sample size to show the

magnitude of efficacy is going to be relatively

small; the size required to show some level of

comfort for the safety of the compound. I think we

do have to keep in mind the size of the target

population when we are worried about safety. So,

for a BMI of 25-27, 27-30, which would be a much

larger population I think we are more properly

concerned about safety. The final point, just I

guess depending on the mechanism of action for the

drug, we would be more or less concerned about

safety based on what you know about it, maybe its

history. I actually did some calculations before I

came here, speaking about the safety issue. I

guess I get some comfort to the idea of having the

larger sample size, maybe 1500 so that if the true

probability of an adverse event were, say, 1/1000

and we had 600 in each group we would have about a

50 percent chance of detecting an adverse event and

about a 25 percent chance of detecting it if we had

293

half as many, 300 per group. So, you know, more is

better and it is based partly on what you think the

underlying adverse event rate would be.

DR. BRAUNSTEIN: Dr. Schade, you are next.

DR. SCHADE: I would like to argue for a

larger sample size for efficacy because with a

small sample size you cannot look within the

population that you are studying for subgroups. I

think, for example, age and sex are two very

important subgroups, and I think the difference

between men and women ought to be able to be

evaluated within the population, and I think the

first tertile and maybe the last tertile, or

something like that, in age ought to be evaluated

because we have seen a difference in drug efficacy

in those two parameters and those are very common

parameters, and that doesn\'t even get to ethnicity

issues. So, I think a population of 1500, which

would let you look at those very straightforward,

simple questions of male versus female and young

versus old are very important in drugs that we are

going to use in all these populations. So, I

294

would argue that a larger, rather than a smaller,

efficacy population would be advantageous.

DR. BRAUNSTEIN: Dr. Watts?

DR. WATTS: Just to look at the converse,

I can\'t see a compelling reason to try to make all

possible efforts to keep the sample size small.

DR. BRAUNSTEIN: Dr. Woolf?

DR. WOOLF: I agree with Dave Schade for

all those reasons, but I would even go above 1500.

We are talking about a patient population who has

excess morbidity and mortality but it is over a

very prolonged period of time, and I think I would

like to get a very good handle on safety in this

population and in order to do that I need a bigger

N. So, 1500 to me still strikes me as very small,

particularly since certain trials are in several

thousands and that seems to be the bar. I think

1500 is below the bar. The size for phase 2 I

think is sufficient to do a dose-ranging trial and

to pick up gross toxicities.

DR. BRAUNSTEIN: Dr. Greenway?

DR. GREENWAY: I don\'t have a particular

295

number that I am trying to promote but I would like

to see it sort of driven on some sort of rationale.

If you want to detect something that occurs 1/100

or 1/1000, or whatever that might be, then kind of

figure back on your sample sizes and find out how

many you really need and what sort of degree of

safety you require to feel comfortable. What I am

getting here is sort of a feeling that more is

better, and maybe it is but I think this ought to

be driven by something other than that. With

regards to age, I think there is a real argument

that could be made that weight loss in the elderly

is not an appropriate thing, that it may well do

more harm than good.

DR. BRAUNSTEIN: Dr. Aronne, did you have

any comments on this?

DR. ARONNE? No.

DR. BRAUNSTEIN: Dr. Yanovski? Dr.

Carpenter?

DR. CARPENTER: I was just trying to

locate something I read in the handout regarding

the sample size calculation to detect a phen-fen

296

problem, and the numbers that are reported were

actually less than the requirement for the sample

size at the time that study was done. I think it

was used by one of the industry respondents to

reduce the sample size requirement. I think the

arguments for expanding the efficacy data that one

can cull from these studies is a good argument for

the 1500 figure. I have not heard or seen an

argument that would convince me to extend that

beyond 1500 for a phase 3 study for the efficacy

component. If Dr. Follmann\'s calculations are

right I would think 1500 would be about in the ball

park to detect reasonable safety incidence. For

phase 2, I would think this would actually be a

much smaller number but I would defer to

statistical help for determining that.

DR. BRAUNSTEIN: I don\'t think the set

number should be indicated on the magnitude or

nature of efficacy. I think that should be figured

out from a phase 2 trial and extrapolated to phase

3\.

In regards to the size of the target

297

population, I am less concerned about that than I

am about the safety issues. So, I really think the

numbers need to be driven by safety concerns and,

rather than have a set number, I would advocate

setting a minimal side effect profile for picking

up serious side effects, let\'s say at a level of

1/100, in some populations. In a pediatric

population I may want to go even higher than that,

depending on the population. But certainly a

minimum of 1/100\--a sample size large enough to

pick up a side effect that occurs with a frequency

of 1/100.

DR. ORLOFF: I just want to clarify the

way we think about these numbers. A 1/500 adverse

event in 1500 patients exposed, assuming that there

is no time factor, if you don\'t see a case you have

a 95 percent confidence that you have excluded the

1/500. I guess the other way of looking at it is

if it does occur in 1/500, you have a 95 percent

chance of seeing one case in 1500 patients. If you

see one case and it is sudden death, it doesn\'t get

you anywhere.

298

So, this is the problem we face over and

over and over again. That is really where we

stand. As I said in my introduction to this, we do

rely heavily on preclinical signals. We do rely

heavily on, obviously, pharmacologic mechanism. We

do rely heavily on surrogate markers, laboratory

markers, as well as on\--well, I guess those are the

big ones.

DR. BRAUNSTEIN: I think the point is

though that although the harmonization document and

several of the written comments from industry

suggested that we should lower the number to a

total of 100 at one year for safety/ efficacy, I

think that is much, much too low, and I can\'t

imagine that we will find a side effect that occurs

with a frequency of 1/100 and be pretty sure that

that is related to the drug at a level of that.

So, my gut reaction is, going back to the original

meeting where the guidance was formulated, the

statisticians at the time had figured out around

1500 in order to pick up, as I recall, a side

effect profile of 1/100 with a certain degree of

299

statistical assurance. So, that number probably is

pretty good. I would use that as a rationale

rather than just picking a number out of thin air.

DR. WOOLF: If we are talking about a drug

that is potentially going to be available to

millions of people, and if we have a severe drug

reaction of 1/1000 and we have 5 million people

being treated, that is 5000 people, which is far in

excess of what it took to get troglitazone off the

market. We are talking about a drug that is meant

to treat morbidity and mortality over the very long

haul, not for the short term. So, I would argue

vociferously that we ought to exclude the

likelihood of a severe problem with 1/1000 and do

the statistics to find out what the number would

have to be to exclude that, and it is going to be a

few thousand.

DR. BRAUNSTEIN: I think one has to weigh

the practicality with what is reasonable and

protective of the population, which is one of the

reasons why I would strongly advocate for

second-year safety data, as well as sort of

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long-term follow-up information, which is how the

troglitazone problems were picked up. They weren\'t

picked up in the original trial.

MS. COFFIN: The justification that I saw

for 1500 made sense to me. Also, a population of

that size means that you are going to get more of a

cross-section and you are going to be less likely

to have excluded all of the people who aren\'t going

to show well. So, that seems to make sense, the

1500 at a minimum.

DR. BRAUNSTEIN: Dr. Follmann?

DR. FOLLMANN: I agree that safety is

driving this and we should make our determination

about numbers based on calculations of what we want

to be able to detect. I think the 1/100 number

maybe a little too common for me. I think I would

prefer something like maybe 1/500, something

between 1/100 and 1/500.

DR. BRAUNSTEIN: Dr. Schambelan?

DR. SCHAMBELAN: I think I would agree

with the principle that the safety is the issue

that we should be using to do these calculations,

301

and I also agree with Dr. Woolf\'s comment that we

are talking about drugs that might go out into

millions of individuals so that our bar has to be

very high for making sure we are not going to

ultimately do harm. So, certainly not reducing the

number below 1500 and then using things about the

pharmacology of the drug that might predict

toxicity as a way of driving the number up. I am

curious, for example, why we ended up, Dr. Orloff,

with thousands of patients in the statin trials.

How did you get to that figure as opposed to 1500

here?

DR. ORLOFF: We were just asking ourselves

that, as a matter of fact. This is not pertaining

to statins but clinical trial programs are designed

around demonstration of efficacy primarily. That

is how trials are powered. And, the requirements

with regard to safety are ultimately arbitrary.

So, we don\'t really have a reason. I think it is

striking and I am glad it has been emphasized

here\--it is striking how relatively small the

exposure requirements have been for obesity drugs.

302

I can\'t speak to the actual numbers of patients who

were exposed but the requirements that are cited in

the comments to our guidance are actually small

compared to diabetes, lipids, osteoporosis. So, we

will take that back for consideration.

DR. BRAUNSTEIN: Dr. Hirsch?

DR. HIRSCH: We are not dealing with drugs

that we have talked about that are going to

eradicate obesity so, you know, they have fairly

low efficacy under the best of circumstances and in

an enormous potential target population. So, I

can\'t see any good rationale for reducing the

number of people studied. I would like to keep

that as high as we reasonably can.

DR. BRAUNSTEIN: Let me ask the committee

members again to try to, you know, take into

account sort of the clinical experience here, what

frequency of side effects, what sample size or what

should we be aiming at as far as being able to pick

up side effects, 1/100, 1/500, 1/000, just to give

a sense to the FDA as to what we think would be

reasonable with this group of drugs, is that fair?

303

DR. ORLOFF: Let me just say someone made

mention of the troglitazone issue, 61 cases and I

believe something over a million prescriptions, at

least from IMS. I think 31 deaths were reported,

and one never really knows what the true numerator

is from spontaneous reports\--31 deaths, I believe 2

million prescriptions, although I could be wrong.

DR. WOOLF: Glenn, define serious side

effects. Define side effects. Are we talking

about life-threatening side effects?

DR. BRAUNSTEIN: What I would call

clinically significant side effects. I don\'t mean,

you know, hemoglobin going from 40 to 39.5. I mean

significant three times elevation of liver function

tests, creatinine that goes up, rhabdomyolysis,

something like that. That is what I consider to be

clinically significant side effects.

DR. ORLOFF: Let me also say that in our

approach to adverse effects of drugs, obviously, we

worry most about the irreversible ones. When it

comes to other kinds of side effects, even if

serious, we make a judgment in our overall risk

304

management for a drug as to how effective we

believe the labeling will be, whether the side

effect is monitorable under standard or at least

readily available clinical care situations. So,

again, something like a little drop in blood count

that might merit stopping the drug, if that is

something that can be monitored and it doesn\'t

occur in a huge proportion of patients\--I mean, I

think that is one question you are asking.

The other question is perhaps the one that

we tend\--not tend to but the one that we have

nightmares about is the big unknown. You know,

1500 patients so you are pretty sure that you are

not seeing anything horrible at a rate greater than

1/500 but 1/10,000 is still pretty bad.

DR. J. YANOVSKI: Is there any thought of

developing postmarketing programs, similar to what

we do for growth hormone in kids, for obesity

agents? Given the tremendous exposure to the

population, is there a role for that sort of thing?

DR. ORLOFF: Yes, and these are cumbersome

undertakings. We actually have one in place now

305

for Forteo, which is human recombinant PTH for

osteoporosis, and based upon the preclinical

finding of osteosarcoma in rats with that drug,

really the consensus that this could not be

excluded as a potential risk to humans there are

limitations not only on the eligible treatment

population but the marketing, detailing of the

product, and then there is actually a system of

surveillance in place that involves capturing all

the incident osteosarcoma cases occurring around

the country and essentially, if a signal arises,

working towards a possible formal case controlled

study. So, those are possible.

Again, case control studies for

cardiovascular disease death in a population that

is taking all manner of drugs is a pretty

complicated, maybe fruitless, undertaking, from the

little I understand of it.

DR. WOOLF: As I recall, David, with

Crestor the committee recommended surveillance for

proteinuria and hematuria post approval. The drug

has been on the market for about a year. Do we

306

have any information?

DR. ORLOFF: It is always one step forward

and two steps back with this committee\--no, I am

kidding! To update you, I will just say, without

going into the details, that we actually have

ongoing surveillance of the incident spontaneous

reports. There is no formal postmarketing safety

study but we are looking at those reports both from

the standpoint of their numbers relative to

prescriptions compared to other statins, but also

with regard to the clinical nature of the reports

just in the event that even given the inadequacy of

that system something peculiar and remarkable comes

out about the kinds of cases that you see with

Crestor as opposed to with other statins.

So, we do have methods. None of them is

perfect. But let me just say again that I think

Dr. Braunstein\'s question is a good one and it is

worth just hearing some thoughts about it. We are

never going to have 100,000 patient pre-approval

exposures for every drug in the pharmacopeia. And,

I am a believer that the answer doesn\'t necessarily

307

lie in a total mortality trial either. The example

I always raise is that BeCalm in patients with

hypercholesterolemia and cardiovascular risk would

have won against placebo in an endpoint trial, even

as Zocor, Lipitor, and so on, do.

DR. BRAUNSTEIN: Dr. Watts?

DR. WATTS: I think there are just a

number of issues about possible side effects that

make it hard to come up with the right

number\--severity, the timing, some may occur

without a lag time some may have a lag time\--you

may get some idea from preclinical work, certain

body systems that might be more likely to be

affected; others may come out of the blue. You

have to be reasonable in the study design but also

have some type of additional\--the next question is

the need for an open-label study so if you had a

year- or 6-month even placebo-controlled study you

would have another year where potentially twice as

many subjects are on drug to being to look for

safety issues that might delay approval or put in

place a phase 4 monitoring program. DR.

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BRAUNSTEIN: Let me just try to rephrase the

question so I can get off this and go to the next

one. We have had three estimates out for what

people would be comfortable with for an initial

one-year safety trial to figure out the number

needed to treat with the drug in order to pick up

side effect incidence at different rates. So, I

said 1/100. Dr. Woolf said 1/1000. Dr. Follmann I

think said 1/500. So, we have three numbers out

there and we sort of want everybody else to sort of

weigh in with what they would be comfortable with,

and we are just defining it as a significant

clinical side effect. Dr. Aronne?

DR. ORLOFF: You know, it occurs to me we

really need somebody from Las Vegas on this

committee!

\[Laughter\]

DR. ARONNE: I would say 1/100. It is

interesting because in talking to the kind of

patients we see, BMI greater than 40, they have

1/100 or 2/100 chance of dying and, yet, they are

still willing to go for surgery they are so

309

desperate for treatment. So, in my mind, a 1/100

chance of a significant side effect would be a

reasonable one.

DR. BRAUNSTEIN: Dr. Schade?

DR. SCHADE: Yes, 1/100 sounds reasonable

if that equals 1500 people in the study.

DR. BRAUNSTEIN: Dr. Watts?

DR. WATTS: That sounds good to me.

DR. BRAUNSTEIN: Still 1/1000?

DR. WOOLF: I will hold.

DR. CARPENTER: I am in the 1/500 camp. I

think we have to be a little tighter with it.

DR. S. YANOVSKI: One in 500.

DR. FLEGAL: I would say 1/500.

DR. GREENWAY: I would say 1/100 if that

is what is being used now. We have had bad

experience with obesity drugs but it hasn\'t been

due to not picking it up in these early stages.

MS. COFFIN: I will go with the 1/500 only

because it will be extrapolated so much.

DR. LEVITSKY: Yes, 1/100 if your BMI is

40; 1/1000 if your BMI is 27. That is the problem

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with these decisions.

DR. J. YANOVSKI? I would to with 1/500

for adults and maybe a lower number for children.

DR. SCHAMBELAN: I will see 1/500 and I

will nominate Jimmy-the-Greek to serve on this

committee the next time.

DR. HIRSCH: One in 500.

DR. BRAUNSTEIN: Question number ten, need

for second year of open label study, rationale

based on nature of drug, toxicity acute versus

cumulative. Open for general discussion.

DR. ORLOFF: This question relates, as I

think I said before, to what is the utility of that

second year. It is open-label. You don\'t have

concurrent control. Does anybody have any sense

based on experience with other drugs in the

pharmacopeia as to how we should think about this?

DR. J. YANOVSKI: I think the main reason

we, in the obesity community, want to see longer

treatment studies is because of the return to

baseline phenomenon that occurs. We see plateau at

6 months, maybe maintenance over the next 6 months

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but then there is an inexorable decline the

question is how bad is it. You know, if we are

going to recommend that a drug be used for 50 years

in some individuals we would like to know that it

lasts longer than a year. So, I don\'t think it is

really the toxicity issue per se that makes us want

to see the two-year data. It is really knowing

whether there is any remaining efficacy.

DR. BRAUNSTEIN: I am also interested in

looking at toxicity over a period of time. The

issue with phen-fen, as was pointed out, may very

well have been a chronicity issue and how long the

drug was used, not just being picked up in

short-term trials\--

DR. J. YANOVSKI: I didn\'t mention this

but almost certainly these trials are going to be

with limited number of subjects. If we are talking

about detecting a 1/500 chance, there is no chance

of that with a few hundred that we are going to be

able to study for a second year.

DR. ARONNE: I think it is also valuable

having the second year to keep people in the trial

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for the first year by dangling the hope of getting

the active compound in the second year because most

of the people that come to the trial do want the

drug.

But one of the questions I have is why

can\'t the drug be submitted after one year when the

data is accumulated after one year? If we are

doing this primarily for toxicity, why can\'t the

drug be submitted sooner than having to wait until

the end of the second year?

DR. BRAUNSTEIN: I think from a practical

standpoint\--correct me if I am wrong, David, if

there is a one-year efficacy and safety trial

before the data can be submitted to the FDA the

last patient in that trial has to finish the trial

before the blind is broken, the data is analyzed by

the company, written up for submission to the FDA,

goes to the FDA, there is about a 90-day evaluation

period\--so, in all practicality, by the time it

comes before the FDA there is probably going to be

close to two years worth of data accumulated anyway

if there is a requirement for an ongoing safety

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study.

DR. ORLOFF: This is actually an issue

that comes up quite frequently as well. We have a

policy that we increasingly try to enforce that an

application should be complete at the time it is

submitted to the agency. So, even if there are

ongoing trials, the extent of the efficacy and

safety data that are included in the initial report

to the FDA should be what is deemed, on the part of

both the agency\--presumptively deemed\--and on the

part of the sponsor, based upon the sponsor\'s

analysis, sufficient to support safe and effective

use according to the proposed labeling.

So, yes, we do have lots of trials that

are ongoing. There are regulatory requirements for

safety updates 4 months after submission and then

120 days in advance of the user-feel determined

action date, should the application go past that

date in review. Anyway, the point being that we

get what we ask for and we have to ask for what we

want, and we increasingly are discouraged from

saying, well, send us one year\'s worth of data on

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day 1 but, given the fact that you have a rolling

enrollment, given the fact that trial closure and

data analyses cleaning and reporting takes a

certain amount of time, we realize that just a few

months into the application review we will be able

to get the report of the next 6 months worth of

data. If we believe we need that, we are going to

ask for it up front.

DR. BRAUNSTEIN: I guess my question was

if you have a trial that is designed for one year

of efficacy and one year of safety for

approval\--and I assume the approval would only be

for a year\'s period of time if that is all the data

you have available for use of the drug\--but you

have also requested a second year open-label

extension, but not for approval but for review by

the agency and presumably for presentation for the

advisory committee, or what data is available,

since it is open-label, that data should be

available at the time of the committee. Isn\'t that

what sort of practically happens? There have been

a number of drugs where we have had safety updates

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that were not submitted in the original

application.

DR. ORLOFF: Increasingly we don\'t like to

proceed along those lines. Our principles are

around putting our own eyes on the information.

For example, we do not want to come to an advisory

committee and have information presented at the

advisory committee by the sponsor that we have not

been privy to in advance.

DR. BRAUNSTEIN: Dr. Greenway?

DR. GREENWAY: It is my impression that

the toxicity that has been identified with the

drugs that we have studied so far has been

identified during the first year. I am not sure

that that second year really serves very much

purpose except to hold things up for another year.

I personally would sort of okay not including that.

I don\'t think it adds much in the way of safety and

doesn\'t even have the control group that you would

like to have to compare with.

DR. FOLLMANN: I think if the issue is an

issue of safety the benefit of the second year is

316

not that great. I think if you are concerned about

safety you would want to have more patients

followed initially for the first year and base your

safety decisions on that more pristine cohort

rather than what happens in the second year with

the dropouts, and so forth. So, I don\'t see a

strong rationale for that.

DR. CARPENTER: Just a question about the

nature of what happens in practice when these

longer studies break the blind and an open-label

component goes on, in practice does the degree of

monitoring change? Would we feel less comfortable

with the data obtained during the open-label phase

of the study in terms of its quality than during

the initial year, in this case, where the real meat

of the comparison with the placebo group is going

on?

DR. BRAUNSTEIN: Certainly you lose the

placebo control so any placebo effect, either

positive or negative, on the side effect profile is

going to be gone. Dave?

DR. ORLOFF: Well, just to wrap this up,

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the message that I have heard is that we ought to

give consideration possibly to increasing exposure

in the first year\--collectively, all this

discussion about sample size and exposures,

increasing the exposure and experience in the first

year while foregoing the extension into the second

year because of the minimal utility with regard to

certainly safety, and there is some disagreement

about its utility with regard to durability of

efficacy.

DR. BRAUNSTEIN: If it is one-year safety

data then I would like to go to 1/500 instead of

1/100. Dr. Hirsch?

DR. HIRSCH: I am very much for having the

second year because I am much more interested in

the dropout rate and monitoring that than the

safety issue. I think we obesity this is

particularly important. If we look at the data we

have on other drugs that have been used for more

than one year, you can see that the dropout rate

and the efficacy wanders off, and you can\'t even

get an idea of what the trajectory of that is going

318

to be if you don\'t have the second year. So, I

think that is essential.

DR. ORLOFF: So, that becomes an issue, as

both Dr. Yanovski and Dr. Hirsch have said, that

relates to sort of full labeling of the drug with

regard to expected effects in the broad population

that doctors are going to see. One consideration

that we might give in this unique instance would be

not requiring that small number of patients

extended into the second year for the initial

approval because it is not truly necessary,

perhaps, to deem the drug safe and effective for

the proposed use but certainly relevant ultimately

to completing the information in the label so that

people can understand what they can expect with the

drug. That is something we will take back.

DR. SCHADE: I want to make the same

comment I kind of made before. The second year I

think is valuable because all of a sudden the

patients know they are on the drug. Remember,

during the first year they don\'t know if they are

on the drug and their behavior may be significantly

319

different\--and we have seen this in the trials I

have done, they really know and they tend to have

different dropout rates, and they also have

different side effect rates. I am not talking

about serious side effects. I am just talking

about abdominal pain. When they know they are on a

drug you will see a whole different profile than if

they don\'t know they are on the drug. We saw that

with metformin.

So, I think the second year provides some

valuable insight into what the real world is

because when we treat a patient they know they are

on a drug. You don\'t give the patient a placebo.

The second year gives you that information. The

first year doesn\'t give you that information at

all. So, I would strongly support a second year

because, again, it gives you different types of

information that is much more real world.

MS. COFFIN: From a patient point of view,

I think that a second year provides a lot of good

information because\--I have sort of lost my train

of thought at this point. What you were saying

320

about real world makes a difference, but if we are

talking keeping patients, if this is a chronic

illness and we are going to treat it as a chronic

illness and we are going to use drugs to do that,

we are going to need to know what it does past the

first 6 months. We know people can lose weight.

People have lost weight doing a whole bunch of

things, but can they keep it off, and the second

year would give us more of that without the

requirement that drug companies have no incentive

to study it.

DR. COLMAN: Can I ask something? The

comments related to the second year, are people

suggesting that the ultimate efficacy determination

should be made at the end of the study, in other

words, at the end of the second year? When do you

make the cut for the efficacy of the drug?

DR. SCHAMBELAN: I think the discussion

has been around that being at one year but

gathering additional data in the second year,

including in essence an intent-to-treat assessment

of what happens to people over the long haul.

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DR. COLMAN: And still under double-blind

conditions?

DR. SCHAMBELAN: No, I think you would

have to break the blind at the end of the first

year, unless you rolled everybody over to active

therapy. You know, as your point was earlier to

have an incentive to patients who got placebo in

the first year of therapy, but I am not

recommending that. I think we really ought to do

it on the basis of the years.

DR. GREENWAY: Well, from an efficacy

point of view, the efficacy takes place in the

first 6 months, with the exception of fluoxetine

and that was within a year. So, I can\'t see that

one really needs more than a year to determine

efficacy of these drugs.

DR. BRAUNSTEIN: Let\'s go around and query

the panel members about how long the trial should

be and whether you think there should be a second

year of open-label study. Now, our understanding

is that if there is a requirement for a second year

of open-label study, that study must be completed

322

before it can be submitted to the FDA. Is that

correct? Yes. Dr. Aronne?

DR. ARONNE: This is too difficult. I

would say that one year based on what you are

saying because, you know, it is just taking so long

to get drugs out that I would have to say one year.

But they should send you the data on the second

year but it shouldn\'t be part of the requirement

for approval. How does that sound?

DR. SCHADE: I again vote for two years

because I think these drugs are going to be used

for the lifetime of the patient. We are not just

talking about one year. And, I think the second

year in which that curves in some drugs goes up and

sometimes stays flat is very important to see. I

think the second year would greatly influence me,

as a physician. If all the weight returned to the

base of weight by the end of the second year, I

could at least show that to the patient and say,

you know, you can use this for short term but not

for long-term kind of treatment. I think from a

physician point of view that extra year is very

323

important.

DR. WATTS: I agree that a second year

would be valuable.

DR. WOOLF: I would give up the second

year if I could get the first year to a bigger

trial in the first year.

DR. CARPENTER: I think important

information comes from the second year. I would be

in favor of keeping it. I would ask the question

though if the information related to dropout,

real-world issues, etc., that second year

open-label is intended for, if that data might be

answered in a briefer period of time than an entire

year.

DR. BRAUNSTEIN: Dr. Yanovski?

DR. S. YANOVSKI: Yes, I think that

probably the first year would give adequate data

about the safety and efficacy, but I would be in

favor of encouraging a second year and perhaps

requiring it for the weight maintenance indication

that the companies want.

DR. FLEGAL: Yes, I would say that the

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data from the second year would be fascinating and

very important but I can\'t see that it would be a

requirement for approval. I think that first year

would be enough for that.

DR. BRAUNSTEIN: Dr. Greenway?

DR. GREENWAY: Yes, I think that one year

is adequate for safety and efficacy and I can\'t

recall that other chronic diseases have

requirements for two years. I don\'t see any reason

why obesity should be different.

DR. BRAUNSTEIN: I would vote for one year

of efficacy and certainly a year of safety data. I

would prefer a second year of safety data but I

would not want to see a drug held up from approval

if it was successful at the end of one year.

Therefore, I would want to see a large N for that

one year to try to pick up some of the safety

issues.

I would also want to see that the labeling

be restricted to just one year for use if it is

efficacious over one year, and to be extended

beyond that, and if the manufacturer of the agent

325

wants it extended, they have to do the studies for

a longer period of time to show that it remains

efficacious. Ultimately, I think the patients will

vote with their feet; if they regain the weight

they will go off the drug.

MS. COFFIN: One year for efficacy and

safety. I would like the second year data so

perhaps you could start the application\--if it

takes an additional 120 days you could start the

application 120 days before the second year\'s end.

DR. LEVITSKY: As I recall the

osteoporosis decision, since the measurement was

not so accurate two years would be required. Is

that not correct, in order to really see whether

there was an effect? I think we have some of the

same thing here. We need to know the second year

outcome for several reasons, not the least of which

is that if most of these drugs to tail off after

one year we need to know that so that we can then

try other drugs at that tailing off period, and if

we don\'t encourage the manufacturers to do the

second year we will not have those data in order to

326

develop those sort of stacked continuous therapies.

DR. BRAUNSTEIN: Dr. Yanovski?

DR. J. YANOVSKI: One year for safety and

efficacy, and then a second year open-label.

DR. BRAUNSTEIN: Dr. Follmann?

DR. FOLLMANN: I go for one year safety

and efficacy. The second year of an open-label

study gives I think sort of weak evidence and

maybe, as you suggest, ten years from now we will

be doing randomized studies where we get long-term

and more global information but to try to get that

now within the context of an open-label study I

think is not doable. So, I don\'t have much

appetite for it.

DR. BRAUNSTEIN: Dr. Schambelan?

DR. SCHAMBELAN: I would agree also with

one year for safety and efficacy and, although I

think the data from the second year might be of

interest, in the studies that I have done that have

included an extended open-label period I have been

struck by the absence of a control group and the

variable dropout rates so it has been hard to

327

interpret those data scientifically. So, I think

one year would be what I would want to see.

DR. BRAUNSTEIN: I have been informed by

Dr. Orloff that the last question that he had for

us we have pretty much covered in one aspect or

another. So, this completes all the questions.

I certainly would like to thank all the

members of the panel and all the presenters for a

fascinating day, a very informative day, and ask

Dr. Orloff to make final comments.

DR. ORLOFF: I too want to thank all the

panelists. I want to thank Dr. Atkinson for

agreeing to come to talk to us even though, as

matter of the rules, he wasn\'t able to sit at the

table. It was an interesting discussion. We found

it very useful. We will take your comments and

advice back, review the transcript carefully, and

we will take it from here. So, again, thanks to

all. Thanks yet again to Drs. Braunstein and

Levitsky, and we will see everybody soon. Thank

you.

\[Whereupon, at 4:08 p.m., the proceedings

328

were adjourned.\]

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