1

DEPARTMENT OF HEALTH AND HUMAN SERVICES

FOOD AND DRUG ADMINISTRATION

CENTER FOR DRUG EVALUATION AND RESEARCH

PULMONARY-ALLERGY DRUGS

ADVISORY COMMITTEE

Wednesday, July 13, 2005

8:00 a.m.

Gaithersburg Hilton

The Ballrooms

620 Perry Parkway

Gaithersburg Maryland

PARTICIPANTS

Erik R. Swenson, MD, Chairman

Teresa Watkins, R.Ph., Executive Secretary

MEMBERS:

Mark L. Brantly, M.D.

Steven E. Gay, M.D., M.S.

Carolyn M. Kercsmar, M.D.

Fernando D. Martinez, M.D.

I. Marc Moss, M.D.

Lee S. Newman, M.D.

Calman P. Prussin, M.D.

Michael Schatz, M.D.

David A. Schoenfeld, Ph.D.

CONSULTANTS AND GUESTS (VOTING):

Karen Schell, RRT, Consumer Representative

Jacqueline S. Gardner

Nancy J. Sander, Patient Representative

GUEST SPEAKER (NON-VOTING):

Christine Sorkness, Pharm.D.

FDA STAFF:

Robert Meyer, M.D.

Badrul Chowdhury, M.D.

Ann Trontell, M.D., M.P.H.

Sally Seymour, M.D.

J. Harry Gunkel, M.D.

Eugene J. Sullivan, M.D., FCCP

C O N T E N T S

PAGE

Call to Order

Erik R. Swenson, M.D., Chairman 5

Introductions 6

Conflict of Interest Statement

Maryanne Killian 8

FDA Introductory Remarks

Badrul Chowdhury, M.D., Division of

Pulmonary-Allergy Drug Products 14

Guest Speaker Presentation:

An Overview of Long-Acting Beta Agonists

Christine Sorkness, Pharm.D.,

University of Wisconsin 21

Questions by the Speaker 68

GlaxoSmithKline Presentation:

Opening Remarks

C. Elaine Jones, Ph.D. 82

Salmeterol Review

Katharine Knobil, M.D. 87

Closing Remarks

C. Elaine Jones, Ph.D. 115

Questions by the Committee 116

Novartis Presentation:

Introduction

Eric A. Floyd, M.S., M.B.A. 136

Efficacy and Safety of Foradil

Gregory P. Geba, M.D. 139

Clinical Implications

James F. Donohue, M.D., Chief, Pulmonary

Division, University of North Carolina 155

C O N T E N T S (Continued)

PAGE

Questions by the Committee 168

FDA Presentation:

Salmeterol

Sally Seymour, M.D., Division of

Pulmonary-Allergy Drugs 183

Formoterol

J. Harry Gunkel, M.D., Division of

Pulmonary-Allergy Drugs 207

Questions by the Speakers 224

Opening Public Hearing:

Chris Ward, Asthma and Allergy

Foundation of America 233

Committee Discussion 238

P R O C E E D I N G S

DR. SWENSON: Good morning, everyone. I

am Dr. Erik Swenson. I am the Chairman of this

Pulmonary-Allergy Drug Advisory Committee meeting,

meeting today here to discuss the implications of

recently available information and data related to

the safety of long-acting beta agonist

bronchodilators.

Before we go around and introduce the

members of the panel, I would like to ask them to

remember that we have microphones here that have

dual functions. One is to show that you wish to

raise a question. That is the "request" option

there; then to speak is on the right-hand side.

So, in raising questions, would you please first

hit the "request" button. We will be monitoring

and call you in turn. Please do remember to use

the "speak" button when you do speak since

transcribers will need to hear you on the tapes.

With that having been said, I would like

to have members of the panel here go around and

introduce themslves. We will start with Bob Meyer

and have you introduce yourself in turn.

Introductions

DR. MEYER: I am Bob Meyer. I am the

Director of the Office of Drug Evaluation II in the

Center for Drugs.

DR. CHOWDHURY: I am Badrul Chowdhury, the

Division Director, Division of Pulmonary and

Allergy Drug Products.

DR. TRONTELL: Ann Trontell, the Deputy

Director of the Office of Drug Safety.

DR. SULLIVAN: My name is Gene Sullivan.

I am the Deputy Director of the Division of

Pulmonary and Allergy Drug Products.

DR. SEYMOUR: I am Sally Seymour, medical

officer in the Division of Pulmonary and Allergy

Drug Products.

DR. GUNKEL: Harry Gunkel, medical officer

in the Division of Pulmonary and Allergy Drug

Products.

MS. SANDER: Nancy Sander, President,

Allergy and Asthma Network, Mothers of Asthmatics.

DR. GARDNER: Jacqueline Gardner,

Professor of Pharmacy at the University of

Washington, and a member of the Drug Safety and

Risk Management Advisory Committee to FDA.

DR. SCHATZ: Michael Schatz. I am an

allergist/immunologist from Kaiser Permanente San

Diego.

MS. WATKINS: I am Teresa Watkins,

executive secretary for this committee.

DR. GAY: I am Steven Gay. I am medical

director of critical care support services,

assistant professor at the University of Michigan.

DR. MOSS: Marc Moss, associate professor

of medicine, Emory University in Atlanta.

DR. NEWMAN: Lee Newman, professor of

medicine, National Jewish Medical and Research

Center and University of Colorado Denver.

DR. BRANTLY: Mark Brantly, professor of

medicine, University of Florida.

DR. MARTINEZ: I am Fernando Martinez,

professor of pediatrics at the University of

Arizona.

DR. KERCSMAR: Carolyn Kercsmar, professor

of pediatrics, Rainbow Babies and Children's

Hospital, Cleveland, Ohio.

MS. SCHELL: I am Karen Schell. I am the

consumer representative. I am a respiratory

therapist from Emporia, Kansas.

DR. PRUSSIN: Calman Prussin. I am senior

clinical investigator in the Laboratory of Allergic

Diseases, NIAID, NIH.

DR. SCHOENFELD: David Schoenfeld,

professor of medicine at the Harvard Medical School

and professor of statistics at the Harvard School

of Public Health.

DR. SWENSON: Thank you. I would like now

to call Maryanne Killian, of the FDA. She has a

statement on conflict of interest to read.

Conflict of Interest Statement

MS. KILLIAN: Good morning, everybody.

The Food and Drug Administration is convening

today's meeting of the Pulmonary-Allergy Drugs

Advisory Committee under the authority of the

Federal Advisory Committee Act. With the exception

of the industry representative, all members of this

committee are special government employees or

regular federal employees from either agencies,

subject to the conflict of interest laws and

regulations.

FDA has determined that the members of

this advisory committee are in compliance with

federal ethics and conflict of interest laws,

including but not limited to 18 USC Section 208 and

21 USC Section 355(n)(4) which applies to FDA

people. Congress has authorized FDA to grant

waivers to special government employees who have

financial conflicts when it is determined that the

agency's need for a particular individual's

services outweighs his or her potential financial

conflict of interest.

Members who are special government

employees at today's meeting, including special

government employees appointed as temporary voting

members, have been screened for potential financial

conflicts of interest of their own, as well as

those imputed to them including those of their

employers, spouse or minor child related to the

discussions on July 13, 2005 regarding implications

of recently available data related to the safety of

long-acting beta agonist bronchodilators, and on

July 14, 2005 regarding the continued need for the

essential use designation of prescription drugs for

the treatment of asthma and chronic obstructive

pulmonary disease under 21 CFR 2.125. These

interests may include investments, consulting,

expert witness testimony, contracts, grants,

CREDAs, teaching, speaking, writing, patents and

royalties and primary employment.

In accordance with 18 USC Section

208(b)(3), four waivers have been granted to the

following participants. Please note that all

interests are in firms that could be potentially

affected by the committee's deliberations. With

regard to the July 13th meeting, Dr. Carolyn

Kercsmar for activities on a speaker's bureau. She

receives less than $10,001 per year for a grant

which is valued at less than $100,000 per year, and

for a grant for which the firm supplies products

worth approximately less than $100,000 per year;

Ms. Nancy Sander for ownership of stock currently

valued at between $25,001 and $50,000, and for

unrelated advisory board activities for which she

receives less than $10,001 per year; Dr. Steven Gay

for speaker bureau activities with four firms, from

three of which he receives less than $10,001 per

firm per year, and one for which he receives from

between $10,001 to $50,000 per firm per year. We

would also like to disclose that Dr. Erik Swenson

owns stock worth less than $5,001. A waiver under

USC 208(b)(3) is not required because the de

minimis exemption under 5 CFR 2640.202 applies.

With regard to the July 14th discussions,

Dr. Carolyn Kercsmar for activities on a speakers

bureau. She receives less than $10,001 per year

for two grants which are valued at less than

$100,000 per year, and for a grant for which the

firm supplies products worth approximately less

than $100,000 per year. She also owns stock less

than $5,001. A waiver under the USC 208(b)(3) is

not required because the de minimis exemption under

5 CFR 2640.202 applies. Dr. Fernando Martinez for

his membership on a speakers bureau. He has not

lectured or received remuneration in the past 12

months, and for membership on a related advisory

board. He has not participated or received any

remuneration to date. Dr. Michael Schatz for his

activities on a speakers bureau. He receives less

than $10,001 per year, and for a grant for which

the firm supplies product worth approximately less

than $100,000 per year. Miss Nancy Sander for

ownership of stock currently valued between $25,001

and $50,000, and for unrelated advisory board

activities for which she receives less than $10,001

per year. Miss Sander also owns stock worth less

than $5,001, again a de minimis waiver is not

required because 5 CFR 2640.202 applies. Dr.

Steven Gay for speakers bureau activities with five

firms, from three of which he receives less than

$10,001 per year, and two of which he receives from

$10,001 to $50,000 per firm per year.

We would also like to disclose that Dr.

Marc Moss' spouse owns stock less than $5,001. A

waiver under 18 USC 208(b)(3) is not required

because the de minimis exemption under 5 CFR

2640.202 applies.

A copy of the written 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, 5600 Fishers Lane,

Rockville, Maryland.

In addition, Dr. Christine Sorkness is

participating as FDA's invited guest speaker on

July 13th. She would like to disclose that she is

a researcher with regards to GlaxoSmithKline's

Advair and Novartis' formoterol. She also lectures

for GlaxoSmithKline concerning Advair and receives

less than $10,000 per year.

Lastly, Dr. Theodore Reiss is the

industry representative on the committee at the

meeting. He is acting on behalf of all related

industry. He is employed by Merck. Thank you. I

am done.

DR. SWENSON: Thank you, Miss Killian. I

would like now to turn the microphone over to Dr.

Robert Meyer of the FDA.

DR. MEYER: Thank you. Prior to more

formal introduction by Dr. Chowdhury, I wanted to,

first off, thank the advisory committee in advance

for your attendance today and for what I am sure

will be a very careful deliberation.

One of the things I wanted to mention was

that there was some speculation in the trade press

yesterday that there was a very specific purpose

and outcome hoped for by the agency in holding this

meeting today. I just wanted to be clear that the

FDA looks forward to a very open discussion of the

data available on the safety experience with the

long-acting beta agonists and any potential future

regulatory actions that might be recommended coming

out of this committee. So, thank you very much for

your attendance today.

DR. SWENSON: Thank you, Dr. Meyer. Now

Dr. Chowdhury, from the FDA, is going to give us

some introductory remarks pertinent to our

discussion today.

FDA Introductory Remarks

DR. CHOWDHURY: Good morning. Honorable

Chairperson, members of the Pulmonary-Allergy Drugs

Advisory Committee, representatives from GSK and

Novartis and others in the audience, I welcome you

to this meeting.

In this brief presentation I will

introduce you to the subject matter of this

advisory committee meeting. Members of the

committee, the objective of this meeting is to

discuss the implications of the available data

related to the safety of long-acting beta agonist

bronchodilators. There are two long-acting

bronchodilators marketed in the United States that

will be discussed in this meeting. These are

salmeterol from GSK and formoterol from Novartis.

Products containing salmeterol and formoterol are

indicated for use as bronchodilators in patients

with asthma and COPD as maintenance treatments.

These are effective drugs and form

important components of the treatment options

available for patients with asthma and COPD. But

an important array of adverse effects that has been

observed with these drugs is the occurrence of

severe asthma exacerbation. The intent of this

advisory committee meeting is to discuss this

specific finding of severe asthma exacerbation

related to these two drugs. Since the available

data pertain to asthma, the focus of this meeting

is on asthma and not COPD.

Surrogates of short-acting beta agonist

bronchodilators, such as albuterol, is not a

subject of this meeting. As you discuss and

deliberate on the safety of thee two drugs, keep in

mind the well-established efficacy of these drugs

because the use of these drugs, like any other

drug, is dependent on the risk/benefit ratio.

As you can see in the agenda, the first

presentation will be by Dr. Christine Sorkness.

Dr. Sorkness is a professor of pharmacy and

medicine in the University of Wisconsin. She will

give an overview of long-acting beta agonist

bronchodilators. We are very fortunate that Dr.

Sorkness, and expert in pharmacological drugs used

in the treatment of asthma, has agreed to speak at

this meeting. I thank her on behalf of the agency.

Following Dr. Sorkness, GSK and Novartis

will make presentations on salmeterol and

formoterol respectively, followed by FDA

presentations on these two drugs. This will be

followed by an open public hearing and committee

discussion.

As you hear these presentations you will

note that the safety signal of severe asthma

exacerbation with salmeterol was seen in

postmarketing studies, specifically the recently

halted large controlled study called the salmeterol

multicenter asthma research trial, acronym SMART,

conducted by GSK. In contrast, the safety signal

of severe asthma exacerbation with formoterol was

seen in the studies conducted by Novartis to

support registration of formoterol in the United

States. Novartis also conducted a Phase 4 study

with formoterol that did not show a clear signal of

severe asthma exacerbation, but the formoterol

Phase 4 study was much smaller compared to the

SMART study.

We are choosing to have this meeting now

because all pertinent data on salmeterol and

formoterol have only become recently available. We

also decided that it would be fruitful to discuss

these two related drugs together in one meeting.

Although salmeterol has been approved for marketing

in the United States since 1994, the study relevant

to this meeting, the SMART study, was halted by GSK

in January of 2003 and the data has been recently

fully analyzed.

Formoterol was approved for marketing in

the United States in 2001. The Phase 4 study for

formoterol was completed in March, 2004 and the

data from the study also has been recently

analyzed.

The significant regulatory actions that

the FDA has taken so far pertaining to these two

drugs, based on the available data, are in

cooperation of the results of the SMART study in

all salmeterol-containing product labels, including

the addition of a boxed warning, and not approving

formoterol 25 mcg twice daily dose for marketing in

the United States. Formoterol is currently

approved at a dose of 12 mcg twice daily. Please

note that the formoterol drug label does not

currently have warnings similar to salmeterol

because of lack of specific data related to the

marketed formoterol 12 mcg twice daily dose.

In the presentations from the industry and

the FDA you will see the data that led to the

agency regulatory actions. As you hear the

presentations, I request that you keep in mind the

questions that are in the FDA briefing book and

also attached to the agenda since you will discuss

and deliberate on these questions later in the day.

Here are the four questions that you will

be asked to discuss and deliberate later in the day

today. Question one, the product labels of

salmeterol-containing products have been modified

to include warnings related outcome the SMART

study. Based on currently available information,

what further actions, if any, do you recommend that

the agency take to communicate or otherwise manage

the risks of severe asthma exacerbations seen in

the SMART study?

Based on the currently available

information, do you agree that salmeterol should

continue to be marketed in the United States?

Question two, the label of the

formoterol-containing product does not include

warnings comparable to the warnings that are

present in the salmeterol-containing products.

Based on the currently available information,

should the label of formoterol-containing products

include warnings similar to those in the salmeterol

label?

Based on the currently available

information, do you agree that formoterol should

continue to be marketed in the United States?

Question three, what further

investigation, if any, do you recommend to be

performed by GSK that can improve the understanding

of the nature and magnitude of the risk of

salmeterol?

Question four, what further investigation,

if any, do you recommend to be performed by

Novartis that can improve the understanding of the

nature and magnitude of the risk of formoterol?

These are the four questions. We look

forward to an interesting meeting and, again, I

thank you for your time, effort and commitment to

this important public health service. Thank you.

DR. SWENSON: Thank you, Dr. Chowdhury.

At this point we would like to invite Dr. Christine

Sorkness who was just introduced. She has been

kind enough to give us a broad overview of these

drugs and I would like to turn the podium over to

her.

An Overview of Long-Acting Beta Agonists

DR. SORKNESS: Good morning. I would

first like to thank Dr. Chowdhury and Dr. Sullivan

for inviting me to speak this morning, and most of

all, for gathering this group of both clinicians,

researchers, industry colleagues and the committee

to review what I believe to be an incredibly

important topic. The risk versus benefit

considerations for the long-acting beta agonists

are the topic at hand and the committee has been

asked to discuss the implications of the available

data related to the safety of long-acting beta

agonists, as Dr. Chowdhury articulated.

It is a little bit awesome to review this

topic because of its breadth and depth, and also

because I know many of the committee members and

would acknowledge that they probably know more than

I do about this particular topic. So with that

caveat, I am going to indicate that I am just going

to review and try to set a tone for the discussions

and in particular anchor some of the available

data, at least as I see it as a researcher and a

clinician, that you might use to answer the

questions that you have been charged with.

The specific objectives that I have been

asked to address are to provide an overview of the

clinical pharmacology of the long-acting beta

agonists; to discuss the selection of therapeutic

outcomes which I believe are relevant for the

assessment of risks versus benefits of the

long-acting beta agonists; to review selected

clinical trials, selected because there are so many

which provide insight into the risk/benefit of the

long-acting beta agonists; and to outline the

controversies and the remaining questions which I

believe are related to the role.

First an overview of the clinical

pharmacology of albuterol, salmeterol and

formoterol. We have come a long way from ephedra

from China and its pharmacologic properties many,

many years ago to, certainly ephedrine and

epinephrine and isoproterenol. The three major

drugs that we use in our therapeutic armamentarium

for asthma right now are albuterol, salmeterol and

formoterol. You can see in common that they all

have a simple catecholamine ring, and there has

been great novelty from the industry of adding a

variety of different side chains to these products

to affect their oral versus inhalation efficacy

and, in particular, if you look at salmeterol and

formoterol you see that there are very large side

chains that have been attached to the basic

molecule of albuterol. This has allowed these two

products to have an extended duration of action.

Both salmeterol and formoterol are highly

lipophilic products, which may explain some of

their long duration of action, salmeterol more than

formoterol. We know that salmeterol binds within

the ligand binding cleft of the receptor which

probably allows sensitivity stimulation of the

receptor and its long duration, and there are other

speculated mechanisms of action for the long

duration of formoterol. Formoterol is a raceme and

only the RR and N tumor is active.

If you were to compare very globally the

beta adrenergic agents, this table is probably

relevant. Most of the pharmacologic studies relate

molar potency of these products to isoproterenol,

which is designated as a potency of 1. You can see

that both formoterol and salmeterol are more potent

products than isoproterenol. The pharmacologic

profile of the drugs is illustrated, with

isoproterenol an formoterol classified as full

agonists and albuterol and salmeterol as partial

agonists.

You can see that in comparison to

isoproterenol as its comparator, albuterol,

formoterol and salmeterol all have the luxury or

beta2 selectivity which is acknowledged to allow

these drugs to have primarily effects on the lung

versus the cardioselective effects that we see

primarily with activation of the beta

1 receptors.

The duration of action clearly is different in

these agents and, because of the long side chains

and mechanisms of action of formoterol and

salmeterol, we have known that these are the

longest acting inhaled bronchodilators on the

market today, with durations of action of at least

12 hours after a dose, and the bronchoprotective

effects, which specifically in this slide refer to

the prevention of bronchoconstriction induced by

exercise or non-specific bronchial challenges such

as methacholine, have, indeed, a long

bronchoprotective effect.

If you were to look at a more direct

clinical comparison of formoterol and salmeterol

based specifically on information in the package

inserts, it is believed that equipotent

bronchodilating doses of formoterol and salmeterol

are listed as above, based specifically on the

dosage form by which they are delivered. So we

believe, at least in clinical practice, that 12 mcg

of Foradil aerolizer is clinically bronchodilating

equipotent to 50 mcg delivered by Serevent Diskus.

In order to deliver these equipotent doses, the

recommended inspiratory flow rate is acknowledged

to be about 60 L/min for both products over a time

course of 2-3 seconds. As you might expect,

particularly because these drugs have been FDA

approved for individuals with much more severe

broncho-obstruction such as in COPD, probably an

inspiratory flow rate much below that can get

adequate delivery of drugs.

Both of these drugs are classified as

pregnancy category C and, indeed, enjoy the same

FDA approved indications based on the package of

information submitted to the FDA, the only

distinction being that salmeterol is approved for

the treatment of asthma and prevention of

bronchospasm for children over 4 years of age and 5

years on formoterol. Both of these agents have

been approved for EIB prevention and for

maintenance treatment of COPD, which is not part of

the agenda today.

Now, the differentiation of formoterol and

salmeterol, by and large, comes down to its

acknowledged difference in onset of action. You

can find many, many studies that would classify

different pharmacologic profiles. In summary,

formoterol probably achieves 80 percent of the

maximum bronchodilation within 5-10 minutes. It is

thought to have an onset of action quite comparable

to albuterol and acts within 3 minutes. For

salmeterol most of the data suggests that 90

percent maximum bronchodilation occurs after one

hour, with a median time to significant

bronchodilation of 30-40 minutes, and an onset

certainly at a time point of about 10 minutes.

This is a simple cartoon that segues to

the issue of the long-acting beta agonists

themselves in combination with clucocorticoids.

This is a cartoon that suggests the proposed

molecular interaction between the long-acting beta

agonists and the inhaled corticosteroids. The

long-acting beta agonist, through their activation

of the beta adrenergic receptor with adenylyl

cyclase, cyclic AMP, protein kinase A and mitogen

activated protein kinase may actually prime the

glucocorticoid receptor for greater nuclear

translocation and affinity for the binding to the

glucocorticoid regulatory element, which is

designated in this slide as GRE. Therefore, it has

been speculated by a variety of pharmacologic

models--Ikleburg[?] and others who have done very

elegant work--that actually the anti-inflammatory

effect of glucocorticoids can be enhanced with the

combination of long-acting beta agonist and,

clearly, that is certainly the rationale that

brought the combination products to the

marketplace.

Now, when we talk about risks versus

benefits of any agent, it is best to talk about the

outcomes of interest. I am going to preface my

remarks by the fact that I think the medical

community and patients have all been led to hope

for a 100 percent active and effective drug with

absolutely no side effects. I quite honestly

believe that to not be realistic. Therefore, when

we talk about risk/benefits we need to put in

perspective and weigh those issues, and I think it

is important to recognize that we may have very

safe medications that really have very poor

clinical efficacy, and I would suggest that they

have a distinct risk in their own right by their

inability to treat the disease at hand.

So, I am going to try to illustrate some

issues about what I believe to be important

outcomes and talk about some of the clinical trials

to date that teach us lessons about this as

applying this drug class to asthma.

We traditionally have used lung function

measures for management of asthma, both from the

perspective of clinical decision-making and

clinical research. There are many longitudinal

studies of lung health that have been enhanced by

measurements of lung function, particularly FEV

and FEV 1/FEC ratio. Clearly,

it has been

acknowledged that the gold standard for trial entry

for the pivotal trials reviewed by the FDA have

been traditional FEV

1's of 60-80 percent predicted

with 15 percent reversibility. Therefore, there

have been very uniform population groups that have

been studied in our clinical trials. I would

actually conjecture now, and will come back to it,

that we may need to broaden that a bit to capture a

more generalizable population.

Clearly, lung function measures have been

primary outcomes to measure efficacy because we can

standardize those procedures both on site and with

home measurements, and we have grown to believe

that we can minimize variability around the

measurements and can really get a handle and our

arms around what outcomes are important. Please

recognize as I talk about different outcomes in

asthma, I am not dispelling at all the value of

lung function measurements. I think they are still

critical but I don't believe that they are enough.

Let's start talking about what I believe

to be illustrative studies. This is a study

published by the Asthma Clinical Research Network

in which I am one of the investigators, and it was

affectionately called the SOCS trial. This is a

study that was intended to ask the question that in

a patient who was well stabilized on an inhaled

steroid and representative triamcinolone, and that

had pretty stable FEV

1's and peak flow variability,

could this patient basically be transferred to

placebo and do equally well; be converted to a

salmeterol product and do equally well; or did they

need to maintain continuance on an inhaled steroid

as represented by triamcinolone?

This is a study that enrolled individuals

whose mean FEV1 was 93 percent predicted, had very

low peak variability of about 10 percent, and

during the run-in period showed very good asthma

stability. The primary outcome of this study was

morning peak flow. That was selected because of

experience that the Asthma Clinical Research

Network had with what we believe to be an effect

size that we could power our study of a difference

of about 25 L/min, and because that effect size

correlated with other more clinically robust

endpoints in a variety of trials.

I think you can see that if you look at

the primary outcome of this trial of AM peak flow

you wee in the run-in period that all of the

patients in ultimately the three arms improved

during the run-in with triamcinolone, as you would

expect. You see the placebo group, once it was

randomized at six weeks, had deterioration in that

outcome; whereas, the triamcinolone and salmeterol

groups both had maintenance and actually

improvement in the primary outcome of peak flow,

and there was not statistically significant

difference between those two arms in this

particular outcome.

Now, there was obviously a variety of

secondary outcomes in this trial. You can see that

on the basis, in particular, of some markers of

inflammation that there was both a clinically and

statistically significant difference in favor of

the inhaled corticosteroids. Because of the

multiple comparisons used by the statistician, a p

value of 0.016 was that which was deemed to be of

statistical significance.

This is important in that it translates to

another very important secondary outcome of this

trial, that being defined as treatment failure

rates, on the left, and asthma exacerbation rates,

on the right. First, asthma exacerbation rates

were defined as increases in albuterol use,

decrease in peak flow, and the need for oral

corticosteroids. You can see with this particular

outcome that triamcinolone is the only one by the

Kaplan-Meier survival curve that, in essence, did

not have significant asthma exacerbations. Very

similarly, if you looked at treatment failure

rates, which was defined as an FEV1 less than 50

percent predicted, at least one course of

prednisone, the occurrence of emergency room or

urgent care visits or hospitalization, the same

trend could be seen. The triamcinolone was very

effective in preventing treatment failure rates but

salmeterol was quite comparable to placebo.

The summary for the ACRN investigators was

that patients with persistent asthma, well

controlled by low doses of an inhaled steroid

cannot be switched to salmeterol monotherapy

without risk of clinically significant loss of

asthma control. I think this is one of the studies

that clearly the asthma community has endorsed to

support the fact that long-acting beta agonists in

asthma should not be used as monotherapy, and I

don't believe that there is particular debate on

this issue and I think there are many studies that

illustrate similar outcomes.

This study is also important in that it

shows clear disparity between lung function

measures and other outcome measures, and leads us

to the conclusion from this study that multiple

measurements and dimensions of control are needed

to adequately assess therapies.

Therefore, I think, whether we broach

studies that are industry sponsored or NIH

sponsored, we are beginning to endorse more

composite measures of asthma control. This would

include days of asthma control; treatment failure

and asthma exacerbation criteria, as I have shown

in this study and many others. I would make as a

caveat that it becomes oftentimes very difficult to

compare trials because the specific definitions for

treatment failure versus asthma exacerbations and

mild, moderate and severe exacerbations may be a

little bit different. So, it is important for us

to anchor the definitions when we evaluate.

Other composite measurements have actually

been improvements or shifts in NAEEP defined NAEEP

defined asthma severity classification; the

achievement of total control or well controlled

status, as defined by GINA and applied to the GOAL

study; and certainly a variety of more patient

specific surveys of asthma control and quality of

life that have become important secondary outcomes

in our clinical trials.

Now, in reflecting upon the issue of more

composite clinical outcomes, the question needs to

be raised in applying an appropriate risk/benefit

relationship and assessment of how much benefit can

actually be achieved by the combination of inhaled

steroids and long-acting beta agonists. I am going

to focus my remarks on the combination because I

have told you that at least my belief is that

asthma is best treated by combination and,

therefore, the relevant studies are those that use

that.

A fairly early study that began to address

the role of inhaled steroids and long-acting beta

agonists in combination is the OPTIMA trial,

entitled, low dose inhaled budesonide as a

representative inhaled steroid an formoterol as a

representative long-acting beta agonist.

This study had both a group A and a group

B. I am going to focus on group A as a

representative trial of taking patients naive to

being on inhaled steroids and ultimately, after a

one-month run-in in which they were qualified to be

in this trial, were then continued on placebo,

Pulmicort or Oxis, as formoterol is called.

Therefore, they continued on beta agonists alone

versus being randomized to Pulmicort 100 mcg BID

and Oxis placebo or Pulmicort 100 mcg BID and

active Oxis 4.5 mcg BID.

The primary outcome of this trial was

severe exacerbation, designated by the arrow. This

was defined as the need for oral corticosteroids or

admission to a hospital or an emergency room visit

or substantial decrease in peak flow. This study

group enrolled patients who were 12 years of age

and older, not on inhaled steroids, who had to have

an FEV 1 of at least 80 percent

predicted post

bronchodilator, and actually enrolled a pre

bronchodilator mean FEV

1 group of about 90 percent.

These are the two primary outcomes of this

particular study. If you look on the left-hand

side in panel A, this is the Kaplan-Meier survival

curve and you can see that both the budesonide

alone versus the budesonide in combination win

formoterol did much better in preventing the time

to the first severe asthma exacerbation as compared

to the placebo group, which is the last curve that

you see on the slide. When you plot this, on the

right-hand side of the slide you see that actually

the two active treatments were, indeed, better than

placebo but were quite comparable to each other.

However, if you look at the other important outcome

of pulmonary function test, the morning peak

expiratory flow, you see in the top curve that the

combination product is superior to both budesonide

and placebo. So, whereas by one outcome the

exacerbation rates of the two active products were

not statistically significant, when you add in

another important secondary outcome the

combination, indeed, showed better outcomes.

Now, this same issue of looking at

prevention of asthma exacerbations has been

published by many, many authors. This is just a

representative study which looked at an analysis of

asthma exacerbations, looking at available studies

of higher dose fluticasone versus the addition of

salmeterol to low dow fluticasone.

If you look at this particular slide,

which is the probability of the time to the first

exacerbation, you see that the top curve, in green,

is salmeterol and, in red, the combination, and the

combination was clearly superior in the outcome of

time to first asthma exacerbation compared to the

long-acting beta agonist alone.

The analysis in this study group culled

out the different Ns of the spectrum of pulmonary

function impairment at baseline. As I mentioned,

typically the pivotal trials enroll patients that

have baseline FEV

1's pre bronchodilator between

40-85 percent predicted. That is what you see on

the left-hand side of all-comers that enrolled in

those pivotal trials. If you, instead, break down

patients who present with less bronchoconstriction

at baseline, for example, 60-85 percent predicted

versus 40-60 percent, you see that the trends are

not different and that either way, depending upon

the severity of obstruction in these patients, the

trend of the benefit of combination certainly could

be seen.

Now, the FACET trial also showed I think a

very important lesson about looking at the outcome

of severe exacerbations and relationships of

dose-response curves with inhaled steroids, as well

as the benefit of long-acting beta agonists. This

goes back to budesonide and formoterol as the

representative drugs in this study, and in this

study severe exacerbations were defined as a need

for oral steroids or a decrease in peak flow to

more than 30 percent baseline. So, severe

exacerbations here are predominantly due to the

need for oral beta agonists.

This is a large trial that randomized

individuals to one of four arms. If you look at

the far left, in green is the budesonide 200 mcg or

low dose inhaled steroid group; the purple bar is

budesonide 200 mcg a day plus formoterol; in

yellow, a higher dose of budesonide alone versus,

in the orange bar, the addition to formoterol. I

think what you can see is the very logical

dose-response curve that 800 mcg of budesonide

fared better than 200 mcg of budesonide but, very

importantly, you can see that the prevention of

severe exacerbations in both groups could be

enhanced by the addition of formoterol. So, again,

another study that suggests to us that combination

therapy can achieve the prevention of asthma

exacerbations.

Now, in brevity, rather than showing you

the individual studies of exacerbations to date

published, I am going to take advantage of a

meta-analysis, published by Sinn and others in

JAMA, in 2004 that looked at a systematic review

and meta-analysis of a variety of pharmacologic

therapies to reduce exacerbations.

This study clearly reviewed all of the

drugs that we know that are on the marketplace but

I am specifically going to look at two of the

analyses. This is the effect of long-acting beta

agonists alone on exacerbations and the distinct

trials that the meta-analysis chose. You can see

that the majority of these studies favored a

long-acting beta agonist over placebo, and a pooled

analysis showing a relative risk and confidence

interval that favors the long-acting beta agonists.

This is the analysis that looks at many of

what I believe to be the paradigm shifting trials

that showed the addition of long-acting beta

agonists to be better than either doubling or more

than doubling the inhaled steroids, and includes

the Matz and O'Byrne studies and Pauwels studies

that I shared with you earlier. I think you can

see that we have at least somewhat mixed results

here. Certainly the majority of trials favor the

combination of inhaled steroids and long-acting

beta agonists together versus favoring the high

doses of steroids. Some of them are right on the

line. The pooled summary obviously, here by this

graph, favors the steroids and the long-acting beta

agonists.

I would suggest that certainly some of the

differences are certainly on the basis of study

design, size of study, construct, and so forth but,

again, I think the meta-analysis supports the

individual trials as far as evidence that suggests

benefit of the combination.

Now, in switching gears, besides asthma

exacerbations, I think that the issue of the

capture of asthma control, as has been defined by

GINA and the NAEEP, is a very important outcome

that we have begun to carefully think about and to

posture in our individual trials. The GOAL trial

asked a very simple but important question, is GINA

NIH guideline based control achievable, and in what

proportion of patients with a

salmeterol-fluticasone combination compared with

fluticasone alone?

So, this is going beyond the issue of just

looking at exacerbations but overall asthma control

as defined by the guidelines. You can read this.

There is both total control and well controlled,

and it basically reflects what we, as clinicians,

hope to achieve for our asthma patients. And, the

question is can this be achieved by the therapies

that we have at hand?

The GOAL study design was very complex.

It was a year study of three strata of patients

based on whether they were either corticosteroid

naive or free for six months; whether they were on

a modest dose of a baclomethasone equivalent or

higher dose of a beclomethasone equivalent. These

were individuals that had to be at least 12, not

well controlled in the run-in period, and showed

reversibility of 15 percent. They were randomized

to either the salmeterol-fluticasone combination or

fluticasone alone via diskus, with a dose based on

the stratum.

During this complex design in phase 1, the

doses were either stepped up every 12 weeks until

total control was achieved or a maximum dose was

reached. In study phase 2 a dose of total control

or a maximum study dose was continued for 52 weeks.

It is important to recognize that all the

patients in this trial deserved to be on control

therapy. Their FEV

1's were about 75-80 percent

predicted. They had very, very obvious

bronchodilator reversibility, averaging about 20

percent, and what I would call were young adults.

So, whatever the stratum, these individuals

deserved to be stepped up with the therapies that

were used.

These are the patients who achieved well

controlled status. The triangles in dark are the

combination; the open circles are fluticasone

alone. You can see the run-in phase versus phase 1

versus phase 2 on this graph. You can see that

both study groups had a fairly brisk improvement in

achievement of well-controlled status. This

continued through the 52 weeks of the trial and was

achieved by both study arms, but was achieved to a

statistically significant greater extent with the

combination therapy.

Also importantly is exacerbation rates as

were studied in this trial as a secondary outcome.

This exacerbation was defined in this study as

either a burst of steroids or an ER or

hospitalization. You can see whether it was

steroid naive, the low dose inhaled steroid or the

moderate dose inhaled steroid stratum. Clearly,

all groups showed the trend that the combination

therapy was better at achieving prevention of

exacerbation rates as defined by the GOAL

investigators.

The results of GOAL are very important in

that significantly more patients achieved control

with combination versus fluticasone in each stratum

and in each stratum the time to achieve the first

individual week of well-controlled asthma was

significantly lower with combination than

fluticasone alone. More patients achieved control

at the same or lower dose of inhaled steroid in

each stratum for combination again verifying what

had been previously published on the inhaled

steroid-sparing effect.

I think very importantly in looking at

outcomes, we know that the majority of patients who

achieved well-controlled asthma in phase 1

maintained the status when assessed in the last 8

weeks of the study. But, also, there were some

patients that, additionally, were able to gain

control with sustained therapy. So, there may be,

very importantly, subjects who initially are able

to gain control but others that require longer

exposure to achieve this particular outcome.

Now I am going to switch gears a little

bit and talk briefly about a pediatric trial. One

of the things, at least in my mind, is that most of

the data that we have in looking at inhaled

steroids and long-acting beta agonists, whether

they be as entry therapy or as add-on therapy in

preventing the addition of inhaled steroids, has

predominantly been done in adults. Even those

studies which have enrolled individuals greater

than 12 years in age and up in general have not had

a sizeable enough cohort of the 12-18 population

that really have led to what I believe is a

substantive subanalysis. So, most of what we have

I believe is in adult studies, and I think we will

see more pediatric studies in the future.

This is a study that was recently

presented at the American Thoracic Society meeting

this summer, and was conducted by the CARE network

of the NHLBI-sponsored network. It is a one-year

prospective comparison of three control or

medications for the treatment of mild or moderate

persistent asthma in children.

In brief, the study schematic is a proof

of study concept. All children were in a one- or

two-week run-in period and then were either

randomized to an inhaled steroid alone, an inhaled

steroid at half the dose in combination with a

long-acting beta agonist in comparison to a

leukotriene receptor antagonist. In order to

achieve this particular proof of concept, the ICS

group received fluticasone by morning and evening

diskus and an evening capsule placebo. The middles

group of combination, and what I am going to call

combination in the future, received an Advair

diskus in the morning, a salmeterol diskus in the

evening and a placebo capsule, and the leukotriene

regimen active arm received montelukast at night

and two placebos.

Because this study has not been published

and there are responsibilities to editors, I am not

going to be able to share with you in slide form

all of the data, but I would like to summarize it

for you as I did at the ATS.

Inclusion criteria for this study were

children 6-14 years of age who had acknowledged

mild to moderate persistent asthma, as defined by

symptoms or beta agonist rescue use of peak flows

in the yellow zone. They needed to demonstrate

asthma by a PC20 methacholine less than 12.5 mg/ml.

Bronchodilator reversibility was collected but it

was not an entry criterion because we believed it

would bias the outcomes because one of the study

arms contained a long-acting beta agonist. These

were individuals who were naive to controller

medications. The issue was to look at whether

these three arms and how asthma control was

achieved in individuals with mild or moderate

asthma.

The percent of asthma control days during

the study period of 12 months was asthma control

days defined as a day without albuterol rescue,

without the use of non-study asthma medications, no

daytime or evening asthma symptoms, unscheduled

provider visits of school absenteeism, so a day in

which a parent and a physician both would be happy

that the asthma was well controlled and that was

the defining outcome for this trial.

In summary, I am going to focus

predominantly on the two outcomes related to the

full dose inhaled steroid arm and the combination

arm of the half dose fluticasone in combination

with salmeterol. Both of those study arms achieved

improvement in the percent of asthma control days.

At baseline this group of children had about 27

percent of the days that were asthma

controlled--so, very, very few. This actually

almost doubled or tripled during the active they

and the fluticasone group gained asthma control

days of 64 percent versus the combination of 60

percent. So, both groups adequately achieved

asthma control and these were not statistically

different.

Treatment failure was also a secondary

outcome in this trial, defined by either the third

burst of prednisone or a hospitalization or ER

visit due to asthma. There were only five

treatment failures in the fluticasone arm and eight

treatment failures in the combination arm. That

was not statistically significant. Of that, there

were no hospitalizations due to asthma in the

fluticasone group and two hospitalizations with the

combination group.

Overall, the comparison of the two groups

showed in many outcomes that the inhaled steroid

alone versus the inhaled steroid at half dose in

combination with salmeterol were comparable, as I

mentioned, in asthma control days; the time to

prednisone bursts and treatment failure status.

There were some important differences in

that if you looked at secondary outcomes such as

change in PC 20, the

improvement and ENO as a marker

of inflammation, and actually changes in maximum

bronchodilator response, the full dose of inhaled

steroid was actually statistically better.

I mention this study from the point of

view of one study looking at children that will,

hopefully, soon be published and gives us some

experience, I believe, with at least efficacy and

safety in a pediatric population.

Now, let's switch gears to potential

safety concerns that have been raised by the use of

beta agonists. That is what the committee has been

asked to really put in perspective today. It has

not been just in the last few years that safety

concerns with beta agonists have been raised.

Studies in the early '90s suggested that the

regular use of a particular beta agonist,

fenoterol, might produce adverse effects. This is

the number of subjects without exacerbation as a

Kaplan-Meier curve and you can see those

individuals treated with a regular dose of

fenoterol had more asthma exacerbations than as

needed. This study, by Taylor and others, raised

the specter of regular use of short to intermediate

beta agonists producing adverse effects.

As you well know, fenoterol never made it

to the U.S. market and albuterol has become clearly

the drug of choice as the intermediate rescue beta

agonist. Therefore, Jeff Drazen and the Asthma

Clinical Research Network felt it important as one

of its missions to try to answer the question of,

given that albuterol was the primary beta agonist

used in the marketplace, did it matter whether

patients were treated with regular beta agonists

versus as needed beta agonists. To achieve this

trial, patients either received two puffs of

albuterol four times a day plus extra as needed, or

placebo inhaler two puffs four times a day and as

needed, thus, sufficing the regularly scheduled

versus as needed paradigm. The study had a run-in,

a 16-week treatment trial and then a run-out of 4

weeks.

Now, whereas this group today is not here

to debate the issues of safety of short and

intermediate beta agonists, this trial basically

has led to many of the questions that we have asked

about long-acting beta agonists, and has led to

what I believe is a series of trials that are in

construct and will build on.

The summary from this particular study,

using again peak flow as the primary outcome and

power to find a difference of 25 L/min in the two

study arms, suggested that whether you are on as

needed albuterol or regular albuterol it really

didn't make a difference in this outcome and,

therefore, there was nothing evil about the use of

regular beta agonists. But the authors

acknowledged that clearly based on the way the

asthma community was moving, PRN beta agonists was

the more rational approach.

Whereas this was a prospective trial, at

the same time that this study was in the midst of

being carried out, Steve Liggett's group at

Cincinnati and others were working on cloning the

beta receptor. This is the beta receptor as a

G-coupled protein. As you well know there has been

a lot of interest in single nucleotide

polymorphisms at both the 27 position and the 16

position in a variety of both in vitro and in vivo

studies, looking at acute bronchodilator responses

as well as a variety of other asthma outcomes.

So, when this was cloned, the Asthma

Clinical Research investigators went back to the

BAGS trial that was still ongoing and were able to

get most of the participants to come back and be

genotyped. In that regard, the analysis showed

that there was no effect in this primary outcome at

the B27 locus. There was no effect in the B16

heterozygotes. However, there was a signal. When

the B16 Arg/Arg patients were compared to the B16

Gly/Gly patients, with a difference found in the

primary outcome variable.

So, this is a retrospective look at the

BAGS data that shows that if you were a group of

patients who received regular albuterol and you

were Arg/Arg, in yellow, your AM peak flow

deteriorated during the course of the trial, in

contrast to whether you received as needed beta

agonists and were Arg/Arg, in red, or whether you

received regular albuterol and were Gly/Gly. This

retrospective analysis was believed by the ACRN to

be hypothesis generating, not definitive and,

therefore, led to another study which I will share

with you.

At the same time, Robin Taylor reported on

the influence of beta adrenergic receptor

polymorphisms in some studies he had done looking

at, again, asthma exacerbations in this context.

If you look at the far right of all-comers in this

trial, you see that albuterol and salmeterol are

comparable and superior to placebo in preventing

exacerbations. If you look at the Gly/Gly and the

Gly/Arg groups, there were really no significant

differences. However, in those individuals that

were Arg/Arg at the B16 locus, you can see that

there were more exacerbations with those treated

with albuterol but this was not seen with the

salmeterol therapy.

So, we began to see in the asthma

community some signals, some subtle signals in

retrospective data about the issue of the potential

relevance of polymorphisms at the beta receptor.

Therefore, I told you that the Drazen trial,

retrospective, was hypothesis generating to allow

us to go forward to actually create a prospective,

randomized, placebo-controlled, double-blind trial

of regular versus minimal albuterol in each

genotype. This has affectionately been called the

BARGE trial.

In this trial, in order to minimize beta

agonist use, patients were provided with

ipratropium for rescue as a primary inhaler and

then had a backup to use albuterol of symptoms were

not relieved by ipratropium.

This is a fairly complex study design but

which we believed was important to answer the

question. First, individuals between the ages of

18 and 55 years of age who had an FEV

1 of at least

70 percent predicted, and naive to inhaled

steroids, were screened and genotyped. If they

were either found to be Arg/Arg or Gly/Gly at the

B16 they were matched on the basis of FEV

enrolled in the trial, went in a 6-week run-in

period in which individuals were all on placebo

with just rescue therapy. They were then

randomized to receive 16 weeks of active treatment

or placebo; then had an 8-week run-out; were

crossed over to the opposite trial; and then a

following run-out arm.

So, a complex study design that allowed

each patient to serve as their own control of being

on scheduled albuterol versus placebo and using the

backup rescue. These are individuals who were

about 31 years of age, had fairly normal FEV1's of

about 90 percent predicted and were matched in

pairs on the basis of the genotype of interest.

This is the data as published in Lancet.

This shows the curves of either the albuterol

modeled or raw means data versus the placebo

modeled and raw means data. In particular, if you

can look at the left-hand side of the slide, this

is the Arg/Arg group. The right-hand side is the

Gly/Gly group.

Let's look at the Gly/Gly group first. If

you look at the Gly/Gly patients in the orange line

on the top, you can see that, as you would expect,

those patients on albuterol scheduled therapy

improved by their morning peak flow during the

course of the study. In contrast, during the time

they received placebo, in green, they really showed

no improvement in their peak expiratory flow. In

contrast, the Arg/Arg patients behaved differently.

In green is the placebo and you can see the Arg/Arg

patients on placebo actually improved and those

Arg/Arg patients on albuterol, in orange, failed to

improve their peak flow during the course of the

trial.

The primary analysis with this study was

to look at the treatment differences and the mean

change in AM peak flow by genotype at week 16. You

can see that the albuterol versus placebo Arg/Arg

patients had a difference in their mean peak flow

of 10 L/min; the albuterol versus placebo Gly/Gly

comparison, a difference of about 14. Therefore,

the treatment difference of the mean Arg/Arg minus

the Gly/Gly was a difference of about 25 L/min,

which is what this study was powered to find and

what we had used in other studies to power it. So,

this was determined to be statistically

significant.

There were other outcomes that paralleled

the change in peak flow. This is looking at the

difference between regular versus placebo changes

in FEV 1 over the 16 weeks. You

can see that the

Gly/Gly subjects had an improvement in their FEV

whereas the Arg/Arg patients had a deterioration in

FEV 1. The same thing could be seen with

morning

symptoms of an increase in the Arg/Arg patients

versus a decrease in the Gly/Gly patients, and a

complementary pattern of seeing a difference in

inhaler use in the different groups, whether it be

ipratropium as first-line rescue versus albuterol.

In summary, the BARGE data concluded that

morning and evening peak flow, FEV1's, symptoms and

rescue inhaler use improved significantly in

Arg/Arg patients with asthma when beta agonists

were withdrawn, and when ipratropium was

substituted, as compared with regular albuterol

used. The pattern was reversed in the Gly/Gly

patients who actually improved with regular beta

agonist use. The authors suggested that Arg/Arg

patients, who are known to be one-sixth of

asthmatics, may actually benefit from minimizing

short-acting beta agonist use.

I included this study also because of the

important caveats from the investigators and their

conclusions. They emphasized that this study was

conducted in only individuals with mild disease,

not patients with concomitant inhaled steroid doses

and, therefore, whether this data can be

extrapolated to more severe disease or to those

patients who are on concomitant inhaled steroid

doses just could not be answered by this particular

trial, suggesting that both issues need to be

studied more in the asthma community.

Obviously, the million dollar question is,

indeed, do similar effects occur with long-acting

beta2 agonists, and what is the impact of

concurrent use of inhaled steroids? Obviously, Dr.

Chowdhury addressed the committee to really

deliberate today to answer those questions. I

don't have the answers for you and, fortunately, I

am not charged to do that. That is your tough job

today.

I would have some comments on what I

believe to be future studies that may help you to

answer those questions. Much as the BAGS trial was

hypothesis generating for BARGE, the SOCS and SLIC

trial from the ACRN did retrospectively look at

their two studies of long-acting beta agonists

alone. That was the SOCS trial that I shared with

you, and the SLIC trial which looked at combination

of inhaled steroid and long-acting beta agonists

and the tapering of such.

The data from these two retrospective

studies has been presented at meetings, suggesting

that there was a signal of a same pattern of a

difference in morning peak flow based on whether

you were Arg/Arg or Gly/Gly at the 16 locus, and

that the pattern with salmeterol, with or without

the inhaled steroid, seems to be the same.

I carefully indicated that, indeed, these

are retrospective studies, very small in design

and, clearly, will be hypothesis generating for

more robust, longer-term studies that the ACRN, and

I believe the industry, will conduct. Therefore,

the ACRN now has a study called LARGE that is in

the middle of operation that is very similar to the

BARGE study but will look at an inhaled steroid,

with or without the addition of a long-acting beta

agonist, to answer the question of whether the same

patterns in a prospective, carefully designed study

can be extrapolated.

Now, we do have some data to answer the

question on a safety issue about does regular use

of long-acting beta agonists delay awareness of

asthma progression or effect from recovery? We

have been concerned that if patients are so well

controlled with symptoms with their long-acting

beta agonists will they be aware that they are

having an asthma exacerbation, or will they fail to

recover from an exacerbation in the way that they

expected to?

This is one representative study that I

think illustrates the point. This is the Matz

article I showed you earlier of an accumulation of

data from earlier published studies. At the arrow,

the day of diagnosis is the point in time at which

the patient had an asthma exacerbation as defined

by these authors. You can see that if you look at

the change in asthma symptom score about four days

or so before the actual diagnosis of an

exacerbation these individuals began to have an

increase in symptoms, were treated in completion of

an exacerbation satisfactorily, and you see that

their symptoms decreased after the exacerbation.

In this particular trial you actually see that

there is a change in the asthma symptom score that

was different in the two different study groups.

Now, one of the things that this provides

I think is some reassuring issues that on the basis

of symptoms patients are well able to detect a

difference in their symptoms, and to know whether

they are having an asthma exacerbation, and they

recover as we expect. There seems to be no adverse

effect of the addition of salmeterol. In fact,

these patients seem, by symptoms, to recover even

quicker.

We did the same analysis with the PACT

pediatric trial that I shared with you just for

interest, to do the same pattern looking at

symptoms, the issue of albuterol use and the issue

of peak flow. We plotted the three arms of the

study to look at whether the patterns were any

different. In relevance to you today, the patients

who were on combination therapy as compared to

inhaled steroid alone had no difference in their

pattern. So, all three groups were equally able to

perceive symptoms of an exacerbation and to

adequately recover in the same kind of a pattern.

So, we are beginning to, I think, have more data

that resolves this concern that has been raised.

Now, why we are here today in particular

is to discuss the evidence for increased severe

asthma exacerbations with long-acting beta

agonists. Indeed, for these studies, as Dr.

Chowdhury outlined for you, the major issue at hand

is, indeed, severe asthma exacerbations as has been

defined by these trials. I am not going to review

them for you as you clearly have received

preliminary information and I suspect you will have

other members of the audience that will provide far

better detail of these than I can do. Suffice it

to say that these are studies that have raised

questions in the asthma community about the role of

long-acting beta agonists, and my own particular

comment on these is the fact that, whereas they are

compelling for a signal and certainly warrant a

very careful review of the trials of what they can

tell us and what they cannot tell us, it is very

difficult from these trials to discern whether

these individuals were, indeed, using concurrent

inhaled steroids during the course of the trial.

Therefore, it makes it certainly somewhat difficult

to do a full analysis and, therefore, no questions

are easily answered.

In summary, I think the committee today

has a very important job of reconciling what I

believe to be a very crucial question. How do we

all reconcile the finding of these very rare

severe, life-threatening episodes that are reported

in the SMART an formoterol trials with what I hope

to have shown you is obviously the far more global

evidence that the use of long-acting beta agonists,

particularly in combination with inhaled steroids,

results in a decrease of overall asthma

exacerbations? You all are faced with the data

that I believe show that there is very strong

evidence of the ability of inhaled steroids and

long-acting beta agonists to both achieve asthma

control and to reduce overall asthma exacerbations,

as defined by the trials that I have shown you and

others. So, that piece of data needs to be kept in

context.

I would comment that there clearly is more

evidence in adults than children so most of the

decisions made are based on adult data. I believe

that the remaining concerns about safety have to

ask the question about whether, indeed, there is an

influence of genotypic predictors, as has been

picked up as the signal with the intermediate beta

agonists. I believe that we have to look at

phenotypic predictors.

I think the era of treating all patients

equally for asthma is gone and we need to gain

insight about phenotypic predictors of responses to

all our therapy. I think this needs to include

age, severity of disease, bronchodilator

reversibility status, ethnicity and a variety of

others. Clearly, we have had some signals that

there may be ethnic differences in responses to

albuterol based on whether you happen to be Puerto

Rican or Mexican-American. So, we need to get more

information.

We need to have larger and longer trials

which incorporate multiple outcomes, including the

concurrent use of inhaled steroids, and we need to

be able to ultimately answer questions of whether

this is a class effect of a dose effect.

I don't envy the committee. I know that

you will deliberate carefully. And, I appreciate

you allowing me to provide you an overview in

anchoring your thoughts for your deliberation.

Thank you very much.

DR. SWENSON: Dr. Sorkness, I want to

thank you for a very fine talk. Since you are

going to be leaving before the day is out, I wanted

to particularly leave some time for members of the

panel to ask you questions at this moment. So, we

will take questions from the panel on the talk or

issues around it.

Questions for the Speaker

DR. MARTINEZ: Thank you so much for that

very, very nice presentation. During your

presentation you said that in the PACT trial you

were the principal investigator within the CARE

network. The decision was made, you said, to use

methacholine responsiveness as a criterion for

inclusion into the trial and not reversibility. I

am trying to quote you as best as I can, because

this could have introduced bias into the results,

unquote.

DR. SORKNESS: Yes.

DR. MARTINEZ: Are you suggesting that

some of the results of the studies that you have

shown to us, including the GOAL study in which

exacerbation was shown to be less in combination

than in use of inhaled corticosteroids alone, may

be explained by bias introduced by the fact that,

for example, in the GOAL study 15 percent

reversibility was a criterion for inclusion?

Or, a second question, has anybody tried

to separate the studies in this meta-analysis that

you presented to us between those that demanded 15

percent reversibility and those which did not?

DR. SORKNESS: It is a great question,

Fernando, and I think it allows me to clarify my

intent of saying that. Clearly, because of a

variety of reasons, whether it be historical of our

belief that bronchodilator reversibility convinces

us that this is, indeed, reversibly asthma and,

therefore, the documentation of such allows

enrollment into a clinical trial, or it convinces

us that reversibility allows other drugs to show

comparability. The majority of trials, whether

they be industry sponsored or not, clearly have

used bronchodilator reversibility as entry

criteria, and clearly most of that which I shared

with you is that. That has historically been the

context.

My point in this the fact that I believe

that there are a much broader group of asthmatics

in the world today that don't have that much

bronchodilator reversibility or may have very

little and truly have asthma. So, our assumptions

of our outcomes in the therapies are predicated on

the fact that we tend to enroll a fairly defined

population.

I think, second to that, there is

certainly some data from ACRN and other groups that

bronchodilator reversibility as a phenotype clearly

may be more predictive of response to long-acting

beta agonists or for inhaled steroids, for that

matter. So, we have isolated a particular

phenotype and enrolled them in our trials.

The ACRN, because of that and I think

because of our mission of trying to more globally

answer questions in a broader asthma population, in

general have suggested that people can be in these

studies whether you have a bronchodilator response

or PC 20 as evidence of having asthma.

Both issues

are collected by entry is not predicated on having

simply a bronchodilator effect.

In the PACT trial I wanted to emphasize

that I think, because of at least some concerns

about the generalizability of the PACT results, we

felt that PC 20

predominantly was the right entry

criteria. Bronchodilator reversibility was

collected. And, clearly, the PACT data will have

the capability of looking at both genotypic and

phenotypic predictors of responses. I can say that

about the PACT data. I haven't, Fernando, really

been privy to know whether many of these other

studies teased out bronchodilator responsiveness.

So, that is my answer to the question.

DR. SWENSON: Just for the record, that

was Dr. Martinez that posed that question. Dr.

Sorkness, to what extent are the exacerbations, as

they are detected in these multiple studies, based

on the criteria of increased use of a short-acting

beta agonist or the rescue use? Because that seems

pertinent to the question of whether long-acting

beta agonists simply just, for a while, reduce the

need for short-acting and so allow whatever

underlying process toward exacerbation to go

further without recognition.

DR. SORKNESS: As a very general comment

to this, it is a difficult question to answer

simply because whether it be asthma exacerbations

or treatment failure there is clearly, in my mind,

not a uniform definition of either in the trials

that have been described. I think, in fairness,

the vast majority of at least the mild and leading

on to the use of prednisone exacerbations in

general have been anchored by asthma action plans

that have been a combination of symptoms, albuterol

use and, on some occasions, peak flows below some

safety criteria. So, many of these studies have at

least incorporated an asthma action plan of

albuterol symptoms and peak flow leading to the use

of prednisone. So, I think it becomes kind of a

composite decision that the patient makes in

concert with the physician for those studies.

Having said that, the vast majority of the

studies, at least in my mind, that have used the

term asthma exacerbation in general have been

defined by the need for prednisone, with or without

in some cases either an ER visit or a

hospitalization, but certainly the asthma

exacerbation in many of the studies could have been

achieved simply by the issue of prednisone by that

action plan. But the definitions are very variable

and I think that does make it harder to bring all

of these together to get the best insight.

DR. SWENSON: Miss Sander?

MS. SANDER: Thank you. I need a little

bit more information on what you just said.

Whenever there is the term "rescue" medications

used, that is any and all reasons not just rescue

examples?

DR. SORKNESS: I am not sure I understand,

Miss Sander.

MS. SANDER: So, rescue would imply that

they had an emergency need for that medication.

Would it include all uses such as early

intervention, prevention of exercise?

DR. SORKNESS: In my mind, most of the

studies have in their action plans specified that

the use of albuterol to relieve symptoms and/or to

treat a peak flow at a certain safety level were

used in the definition of an action plan of going

on to treat the exacerbation. Most of the action

plans in these trials, or at least the ones

certainly from the ACRN and CARE, did not

incorporate pre-exercise intended scheduled

albuterol use in that paradigm. It was strictly

albuterol use for relief of those symptoms or

relief of a drop in a peak flow to make it return

to some baseline safety level.

MS. SANDER: Thank you. Also one other

question, were there any expectant mothers in any

of these?

DR. SORKNESS: I can't say this with

absolute confidence but I would be highly suspect

that any of the trials were conducted that did not

have a safety pregnancy test at entry and did not

have some appropriate monitoring of pregnancy

status during the trial. The vast majority of

studies that have been privy to even mandate that

if a methacholine challenge procedure is being done

at a study visit a pregnancy test be done. There

is a series of questions that coordinators and

investigators ask about the chance of a pregnancy

to make decisions as far as people continuing in

trials. So, I would be very surprised if

individuals were enrolled being pregnant.

Unfortunately, life is not perfect and I think that

there are certainly trials where a woman became

pregnant during the trial. Most of the studies I

know of, that actually required a mandated

withdrawal because of the potential influence of

pregnancy on stability of asthma. So, I don't

think there is much we can gain in insight, quite

honestly, if that is some of what you are driving

at. I just don't think it exists in these trials.

DR. SWENSON: Dr. Newman?

DR. NEWMAN: Yes, thank you for what was a

very clear presentation. I wonder if you might

comment about, from the benefit side, any

differences in these trials based on race.

DR. SORKNESS: That is a tremendous

question. I think the fairness of answering the

question is that most of the trials that I am aware

of--and I say this carefully because I don't know

the literature in its extreme--probably did not

have the ability to have a satisfactory subset of a

particular racial or ethnic group to be able to

cull out to do a reasonable racial analysis. In

the beta agonist trial by Drazen, et al., I know

for a fact that because of NIH NHLBI guidelines of

enrollment of at least a third of minority

participants, that we did do a statistical analysis

in that trial and it showed that the minority

ethnic group did not do differently on any of the

outcomes versus Caucasians, negative or benefit.

They had equal responses, as did actually a gender

analysis.

I really do not know of any other trial

that could answer your question explicitly but I

think it is very important, especially given some

of what we are learning about the potential role of

ethnicity, and that mandates that we all make a far

more serious effort for doing trials big enough

with groups to answer the question.

DR. SWENSON: Dr. Brantly?

DR. BRANTLY: Dr. Sorkness, as I recall

there were a number of bronchial biopsy studies

using ICSs. I don't recall any regarding using

either long-acting beta agonists or short-acting

beta agonists. Do they exist?

DR. SORKNESS: I am not sure I can answer

that with comfort. I actually do believe that

there are bronchial biopsy studies in individuals

on long-acting beta agonists alone and certainly on

combination. That is not clearly my area of

expertise and I really think I would be remiss in

trying to answer the question of what I know about

those studies. I am a clinical researcher.

Certainly, some of my partners do those kinds of

studies but that is clearly not an expertise that I

would feel comfortable answering. And, there may

be somebody else on the committee that clearly

knows that data far more than I.

DR. SWENSON: Dr. Prussin?

DR. PRUSSIN: Chris, on your last slide

you have a note that says, "need for larger and

longer trials which incorporate multiple outcomes."

My question is, you know, clearly long-acting beta

agonists decrease exacerbations and, yet, we have

very good data that severe pulmonary events and

death are increased. So, you can't use a trial

that is looking at exacerbations to answer the

outcome that we are interested in here. Since I

work more in a smaller frame in terms of allergic

disease, not large clinical trials, can you give me

more of an idea of what you think a large clinical

trial and multiple outcomes that we should be

looking at for these endpoints of death,

intubation, severe pulmonary outcomes?

DR. SORKNESS: Cal, I think it is

difficult and I will try to answer as best I can.

I do believe we are in an era where the most

important studies are not monotherapy in asthma

with long-acting beta agonists but with

combination. So, that is the first issue.

I believe that whereas the SMART trial and

some of the formoterol pivotal trials and others

that have raised the signal of concern are helpful

and we need to take that under consideration. I

find that the way that those studies were

constructed leave me wanting more. The methods by

which patients were accrued; the issue of whether

you really knew whether people were on inhaled

steroids concurrently and were adherent with such;

that you took into account and balanced severity of

disease at the beginning; that you truly looked at

what we believe clinically as the best that we can

ask of this array of overall asthma exacerbations

and control of disease; a year long study to deal

with seasonality, especially in kids; looking at

some markers of inflammation.

I think that we are at a stage that we

would feel better and have more confidence in the

risk/benefit relationship if we had those kinds of

trials done both in adults and children, and

particularly were able to answer in our own minds

whether the combination together--adherence, people

taking them, being on them, controlling for the

issues--that we really knew what we were doing with

those particular trials. And, I think that is the

best that we can do.

DR. PRUSSIN: Let me just follow that up.

The SMART trial was stopped because of difficulties

with accrual and slow accrual. Again, we are

talking about a huge clinical trial. In your

estimation, since this is what you do, is it

possible to do that large a trial and get the

information in a much more rigorous way, as you are

proposing? I mean in terms of accrual. Is this a

feasible endeavor to go into? Because we have been

told that SMART simply became impossible to carry

forward.

DR. SORKNESS: Yes, I think the reality is

such that it is I believe, and I am investigator so

I am asked to do these things--I think it is

impossible in this day and age to recruit large

enough subjects even in a multicenter study that

are naive to either inhaled steroids or long-acting

beta agonists at entry so that you are bringing in

this naive population to answer the question. I

don't think those patients are out there anymore

because we have done such a good job with

guidelines and because all these trials showing

that when you give people good medicines, by golly,

they get better.

So, I think that if you, indeed, enroll a

far broader population of phenotypes, of patients

that have certain entry criteria, and then you

randomized them to an inhaled steroid with and

without a long-acting beta agonist, and followed

them for long enough, I think those studies can be

constructed. And, I think that is one of the

challenges to do and I suspect that they will be

done.

DR. SWENSON: Well, thank you, Dr.

Sorkness. We appreciate very much that fine talk

and discussion. At this point we will turn the

program now over to GlaxoSmithKline and, to do so

and to introduce her colleagues, Elaine Jones will

take over.

GlaxoSmithKline Presentation

Opening Remarks

DR. JONES: Good morning. My name is

Elaine Jones and I am Vice President of Regulatory

Affairs at GlaxoSmithKline. On behalf of

GlaxoSmithKline, I would like to thank the agency

and the advisory committee for this opportunity to

review data pertinent to the discussion of the

safety of long-acting beta

2 agonists in the

treatment of asthma.

Our presentation today will focus on our

data with the inhaled long-acting beta

2 agonist

salmeterol. As we begin the presentation today, I

would like to set the stage by speaking first about

the burden of asthma. As the committee members are

well aware, asthma is a chronic disease associated

with significant morbidity and mortality. In the

United States alone asthma affects approximately 20

million patients. Asthma exerts a tremendous

societal burden as evidenced by the half million

hospitalizations and over 4,000 deaths in the U.S.

in 2002.

There are many risk factors that have been

identified that put patients at risk for an

asthma-related death. Some of these include

excessive reliance on rescue medications and use of

inhaled corticosteroids, disease severity and a

delay in seeking care. Ethnic origin is also an

important risk factor, demonstrated by the fact

that the rate of asthma deaths in African Americans

is approximately 2.5-fold higher than that of

Caucasians.

The tremendous burden of asthma has fueled

a continual development of new medications to treat

this disease and GSK has a long history in the

development of respiratory medicines. Salmeterol

was the first inhaled long-acting bronchodilator,

and its approval in the United Kingdom over a

decade and a half ago represented an important

advance in the management of asthma.

To date, regulatory authorities have

granted approval to market salmeterol in over 100

countries. In the United States there are three

salmeterol-containing products that have been

approved for marketing. These are Serevent

inhalation aerosol, Serevent diskus and Advair

diskus which contain salmeterol as one of its

components. Each one of these products has been

approved for use in patients with asthma or COPD,

and each of these approvals required a full

clinical development program.

It should be noted that the inhalation

aerosol formulation, which contained

chlorofluorocarbons, has been discontinued by GSK

as part of the phase-out of CFC-containing products

consistent with the Montreal protocol.

Worldwide approvals by regulatory

authorities have led to a great deal of clinical

experience with salmeterol. Over the last 15 years

the exposure to salmeterol is the result of the use

of salmeterol formulated as a single agent and the

use of salmeterol formulated with fluticasone

propionate in a single device. In total the

worldwide exposure is now estimated at 45.2 million

patient-years.

Based on extensive clinical experience and

a systematic review of numerous clinical trials,

evidence-based guidelines from the National Heart,

Lung and Blood Institute's expert panel report

recognize the pivotal role of long-acting beta

agonists in the treatment of asthma. While the

safety of long-acting beta

2 agonists is the topic

of today's meeting, it is important to consider the

safety of these medications in the context of their

overall benefit/risk profile. Part of the context

is provided by current asthma treatment guidelines

which position the use of inhaled long-acting beta

agonists with inhaled corticosteroids as the

preferred treatment option for patients with

moderate to severe persistent asthma.

Asthma is a serious disease with

significant morbidity and mortality and salmeterol

has become a well-established pharmacological

therapy in the management of this disease. As you

know, no medication is without risk and today's

meeting provides an important opportunity to review

safety data for inhaled long-acting beta agonists.

We look forward to discussing the safety of

salmeterol with the committee.

Salmeterol has been shown to be highly

effective in the treatment of asthma and, since its

approval 15 years ago, clinicians have accrued

considerable experience with its use. Based on the

extensive body of evidence in patients with asthma,

including 64 studies in approximately 45,000

patients in the U.S. alone, GSK believes that

salmeterol continues to exhibit a favorable benefit

to risk profile.

Dr. Kate Knobil will now provide a brief

overview of the efficacy of salmeterol, followed by

a discussion of safety data. Following Dr.

Knobil's presentation, I will return to the podium

to introduce the experts here with us today and

then we will take questions from the committee.

Salmeterol Review

DR. KNOBIL: Good morning, everyone. For

my presentation today I will first present a brief

overview of the benefits of salmeterol for the

treatment of asthma, followed by a review of the

salmeterol safety data. My review of the safety

data will focus on the postmarketing safety

surveillance studies, SNS and SMART, and the

results from epidemiology studies of salmeterol.

In addition, I will describe the ongoing studies

currently being conducted by GSK to further

evaluate the efficacy and safety of salmeterol.

Finally, I will close with an overall assessment of

salmeterol for the treatment of patients with

asthma. Given time limitations, I will not be able

to cover all of the information that is in your

briefing document. However, any questions you may

have may be addressed during the Q&A.

For several decades beta agonists have

been widely used to treat bronchoconstriction.

This slide shows the structures of albuterol and

salmeterol, and you have seen these already today,

and highlights the long lipophilic tail that helps

anchor salmeterol in the beta adrenergic receptor.

Albuterol is highly selective for beta

2 receptor,

thus having fewer cardiovascular effects than

earlier less selective beta agonists. Short-acting

beta agonists are very effective but are limited by

their relatively short duration of action of 4-6

hours.

This limitation was largely overcome by

the development of selective long-acting beta

agonists, such as salmeterol, which are effective

for at least 12 hours. In addition to having a

longer duration of action, in vitro studies have

shown salmeterol to be at least 50 times more

selective for the airway beta

2 receptor than

albuterol.

The benefit of the longer duration of

action of salmeterol can be seen in the data pooled

from the two registration studies for salmeterol

metered dose inhaler. At the time that these

studies were conducted regular albuterol use was a

common treatment for asthma and so was included as

an active comparator. For salmeterol, shown in

green, a single dose results in a clinically

significant improvement in FEV

1 within 30 minutes,

with maintenance of effect for at least 12 hours.

This is in contrast to albuterol, shown in grey,

which has a more rapid onset of effect but the

bronchodilator effect lasts only 4-6 hours.

Additionally, as shown on the right, the

bronchodilator effect of salmeterol was maintained

after 12 weeks of treatment with no diminution of

FEV 1 response over time.

Studies of up to one year in duration have

confirmed that the bronchodilator properties of

salmeterol are maintained with long-term use. In

this study, 12-hour FEV

1 area under the curve, or

AUC, was obtained after the first dose and

following 8, 20 and 48 weeks of treatment. For

salmeterol the mean FEV

1 AUC was similar at all

time points, and in all cases was significantly

greater than placebo, demonstrating maintenance of

bronchodilator effect. In addition to important

bronchodilator effects, salmeterol is very

effectiveness at reducing the symptoms of asthma.

The data shown here are from the same two studies

for salmeterol MDI that I showed previously. Over

12 weeks treatment with salmeterol resulted in a

significant reduction in asthma symptoms scores for

chest tightness, shortness of breath, wheezing and

cough compared with placebo and albuterol given 4

times daily. Although not shown here, in these and

other studies salmeterol also reduced nocturnal

symptoms associated with asthma.

Salmeterol has also been shown to be an

important treatment option for patients with asthma

who are not adequately controlled on inhaled

corticosteroids. This landmark study by Greening

and colleagues examined the effect of adding

salmeterol to inhaled corticosteroid therapy, in

this case beclomethasone, as compared to increasing

the dose of inhaled steroids. The addition of

salmeterol to a low dose of inhaled corticosteroid

was shown to result in a greater improvement in

lung function, as shown by peak expiratory flow,

then when compared to the higher dose of inhaled

steroids. In addition to the improvements in lung

function, the use of salmeterol resulted in greater

improvements in symptoms and rescue albuterol use.

The addition of salmeterol to a low to

medium dose of inhaled steroid has also been shown

to reduce the recurrence of asthma exacerbations.

Shown here again is the study by Matz and

colleagues, and was of similar design to the study

that I showed previously. When compared to

increasing the dose of fluticasone propionate, or

FP, the addition of salmeterol to the low dose of

FP significantly increased the time to the first

asthma exacerbation requiring oral corticosteroids.

Further, significantly fewer salmeterol-treated

patients experienced one or more exacerbations, 8.8

percent compared to the increased dose of FP at

13.8 percent of patients.

Another means of evaluating the patient

benefit of a medication is to assess the impact on

quality of life. In this 12-week study that was

designed to assess asthma-specific quality of life,

patients with asthma were randomized to either

salmeterol or placebo, with all patients receiving

albuterol as needed to use for symptoms.

Salmeterol MDI was shown to significantly improve

quality of life compared with placebo, and the

minimally clinically important difference of 0.5

was achieved for each domain as well as the global

score.

To summarize, the benefits of salmeterol

have been well established and salmeterol has been

accepted as having an integral role in the

treatment of asthma.

I will now move on to the safety portion

of the presentation, beginning first with the

postmarketing surveillance studies for salmeterol.

These studies are of interest because at the time

of launch of salmeterol in both the U.K. and in the

U.S. there was concern that the regular use of beta

agonists may lead to deterioration of asthma

control. This was based primarily on studies of

short-acting beta agonists, particularly fenoterol,

that suggested worsening of asthma with scheduled

use. These studies could not determine a cause and

effect relationship, however, they did bring

significant attention to the appropriate use of

this class of medications.

The first study that I will discuss is the

Serevent Nationwide Surveillance Study, or SNS,

which was performed in the U.K. between 1990 and

1992. This 16-week randomized, double-blind study

evaluated over 25,000 patients with moderate to

severe asthma. The study compared salmeterol MDI

to albuterol given 4 times daily in patients 12

years of age and older. Both treatments were added

to the patient's current asthma therapy.

At visit 1 patients were randomized in a

2:1 fashion to either salmeterol or albuterol. The

primary endpoint for SNS was combined serious

adverse events and all medical and non-medical

withdrawals. This very broad endpoint was not

restricted to respiratory events. For this

endpoint the percentage of events was similar for

the salmeterol and albuterol groups. Additional

endpoints of interest included asthma-related

deaths, hospitalizations and withdrawals. Based on

national health statistics in the U.K. and on the

2:1 randomization, 10 and 5 asthma-related deaths

were predicted in the salmeterol group and

albuterol group respectively.

In this study, 14 asthma-related deaths

occurred, with 12 in the salmeterol group and 2 in

the albuterol group, resulting in a relative risk

of 3. This difference was not statistically

significant but did raise concern. The results for

asthma-related deaths were not consistent with the

data for asthma-related hospitalizations. As you

can see here, the data for this endpoint did not

indicate an increase in risk with salmeterol. The

only statistically significant difference between

the groups was seen for the percentage of

withdrawals due to worsening asthma, with a lower

percent observed in the salmeterol group compared

with albuterol.

In light of the results of SNS, including

the asthma-related deaths and spontaneous reports,

GSK, in conjunction with the FDA, designed the

Salmeterol Multicenter Asthma Research Trial, or

SMART. The study was initiated in 1996. SMART was

a randomized, double-blind surveillance study of 28

weeks duration that was conducted at over 6,000

sites in the United States. Patients with asthma

who were 12 years of age or older, with no previous

use of inhaled long-acting beta agonists, were

included. All other asthma medications were

allowed during the study.

SMART consisted of a single clinic visit

at which patients were assessed for eligibility and

then randomized to receive either salmeterol or

placebo which was added to their usual asthma care.

Subjects were given a 28-week supply of study

medication and were not required to return for

clinic visits. Instead, patients were contacted

every 4 weeks by phone primarily to collect

information on serious adverse events, including

respiratory-related events.

The combined endpoint of

respiratory-related deaths or life-threatening

experiences was chosen as the primary endpoint.

Asthma-related death was also of interest but

because this is a rare event the sample size

required for this to be the primary endpoint was

too large to be feasible. Even with the broader

combined endpoint, it was determined that a sample

size of 30,000 patients would be required.

However, after 15,000 patients were enrolled in the

study the actual rate of primary events was found

to be approximately half of what was expected and

the target sample size was increased to 60,000

patients.

Key secondary endpoints were

respiratory-related deaths, combined asthma-related

deaths or life-threatening experiences, and

asthma-related deaths, all of which were subsets of

the primary endpoint.

Two independent review committees were

involved with SMART. They were the mortality and

morbidity review committee, or MMRC, and the data

safety monitoring board, or DSMB. Each serious

adverse event was adjudicated in a blinded fashion

by the MMRC to determine if it was respiratory

related and, if so, whether it was asthma related.

The categories for this adjudication were

unrelated, unlikely related, possibly related or

almost certainly related. Only respiratory- and

asthma-related events considered possibly related

or almost certainly related comprised the primary

and secondary endpoints. The DSMB met regularly to

evaluate blinded aggregate data which included the

cases adjudicated by the MMRC.

An interim analysis was planned when

approximately one-half of the patients had been

enrolled. At the interim analysis the study did

not reach predetermined stopping criteria, however,

there was a suggestion of worse outcomes in

salmeterol-treated patients, especially African

Americans. For this reason, the DSMB recommended

that ideally the study should be completed within 2

years or, if that was not possible, the study

should be terminated and the results disseminated.

Following discussions with the DSMB, GSK made the

decision to stop the study due to difficulties in

enrollment and the findings in African Americans.

I will now move on to the results of

SMART. Overall, the baseline characteristics of

age, sex, ethnic origin and baseline peak

expiratory flow were well matched between the

treatment groups. Approximately 70 percent of the

population was Caucasian and 18 percent was African

American. For reference, approximately 15 percent

of the patients with asthma in the United States

are African American.

Asthma medications were reported at

baseline and were similar between the treatment

groups. The most commonly reported asthma

medications were inhaled or oral beta agonists

which were reported in over 90 percent of patients.

Forty-seven of the patients reported use of inhaled

corticosteroids at baseline.

While baseline characteristics were

similar between the treatments for the total

population, this was not the case when comparing

baseline characteristics between Caucasians and

African Americans. The baseline characteristics

indicate that African Americans had more severe

asthma as measured by peak expiratory flow,

nocturnal symptoms, and history of hospitalizations

and intubations. For example, the proportion of

African Americans reporting a hospitalization for

asthma during the previous 12 months was more than

twice the percentage reported for intubation for

asthma in their lifetime. In addition to these

markers of increased severity in African Americans,

the reported use of an ICS at baseline was lower

than that in Caucasians.

The results for the primary and key

secondary endpoints will be shown on this slide.

Due to the amount of information, I will take a few

moments to summarize the data. These figures are

also available in your briefing document for

reference.

First let me orient you to the slide. The

relative risk point estimate and corresponding 95

percent confidence intervals for the primary and

secondary endpoints will be displayed graphically.

The values that correspond with these data will be

shown on the right side of the slide. The total

population will be represented in yellow, the

Caucasian subgroup in green, and the African

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American subgroup in orange.

I will start by showing the results for

the total population as this was the primary

analysis. Then I will show the results for

Caucasians and African Americans as this post hoc

analysis was requested by the DSMB at the time of

the interim analysis.

The number of primary events, combined

respiratory-related death or life-threatening

experiences, was approximately two-thirds of what

was expected. The primary endpoint for the total

population, as shown here on the slide, was not

statistically significantly different between

treatment groups as the confidence interval

includes 1. As I review the key secondary

endpoints for the total population, which are

respiratory-related deaths, combined asthma-related

deaths or life-threatening experiences and

asthma-related deaths, it is important to remember

that each is a subset of the primary endpoint.

For the secondary endpoints, statistically

significant differences were observed between

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treatment groups for the total population,

including asthma-related death which I will discuss

in more detail in a moment. The numbers of primary

events in the Caucasian subgroup, shown in green,

were similar between the treatment groups.

However, in the African American population, shown

here in orange, a significantly greater number of

primary events occurred in the salmeterol treatment

group.

For the key secondary endpoints the

relative risk of events was higher in African

Americans compared with Caucasians. In particular,

a significantly greater number of combined

asthma-related deaths or life-threatening

experiences occurred in the salmeterol group in the

African American population, while there was no

difference between treatment groups in the

Caucasian population.

The number of asthma deaths in SMART was

approximately half of what was expected. There was

a significantly higher number of asthma-related

deaths seen in the overall population for patients

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receiving salmeterol compared with placebo and the

same pattern was seen in the ethnic subgroups.

While the relative risk of asthma deaths appears

similar between ethnic groups, note that there were

approximately 4 times as many Caucasians in this

study than African Americans. Therefore, the rates

for all asthma-related endpoints were much higher

in the African American population.

The effect of inhaled corticosteroids was

also of particular interest to the DSMB at the time

of the interim analysis. A post hoc analysis was

conducted to explore the association of baseline

use of ICS with the primary and key secondary

outcomes. As I mentioned previously, 47 percent of

the patients reported using inhaled steroids at

baseline. The results for the total population are

shown here, again in yellow, for reference.

Results for subjects reporting inhaled

corticosteroid use at baseline will be shown in

blue, and those not reporting ICS use at baseline

will be shown in white.

For subjects reporting ICSs at baseline

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there were not statistically significant

differences between the treatment groups for the

primary and secondary outcomes. Patients receiving

salmeterol who did not report the use of inhaled

corticosteroids at baseline, here in white,

experienced significantly more combined

asthma-related events than those receiving placebo.

The number of deaths in those patients not

reporting inhaled corticosteroid use at baseline

was 9 in the salmeterol group versus zero in the

placebo group so direct calculation of relative

risk cannot be performed. In the patients

reporting corticosteroid use at baseline the

numbers were 4 and 3 respectively.

Although SMART was not designed to assess

the effects on inhaled corticosteroid use, these

data suggests that ICS may have had a beneficial

effect on asthma outcomes in SMART.

Finally, the data were analyzed by both

ethnicity and inhaled corticosteroid use reported

at baseline. Caucasians are shown, again, in green

and African Americans in orange. Patients

104

receiving inhaled corticosteroids are represented

by solid lines while dotted lines represent

patients not reporting inhaled corticosteroid use

at baseline. The relative risk for the primary

endpoint was higher in African Americans than

Caucasians, and those not reporting inhaled

corticosteroids at baseline had higher relative

risks within those populations.

Similar to the primary endpoint, the

relative risk for combined asthma-related events

was higher in the groups that did not report

inhaled corticosteroids at baseline independent of

ethnicity.

If we focus specifically on the number of

asthma-related deaths, shown here at the bottom of

the slide, it is evident that these events were

rare. There were more asthma-related deaths in

patients receiving salmeterol who did not report

ICS use at baseline in both Caucasians and African

Americans. Again, direct calculation of relative

risk cannot be performed for asthma-related deaths

for patients not reporting inhaled corticosteroids

105

at baseline since there were no deaths in the

placebo group for this endpoint.

SMART was not designed to determine the

effect of inhaled corticosteroids and ethnicity on

these endpoints, and the number of events in each

subgroup is quite small. Therefore, these data

should be interpreted carefully.

In summary, there were more events,

including asthma-related deaths, reported in the

patients receiving salmeterol. There was also a

suggestion that both African Americans and patients

who did not report using inhaled corticosteroids at

baseline had a higher risk of asthma-related

events. However, the number of events in SMART was

lower than expected, preventing definitive

conclusions from the data.

A careful review of the data did not

reveal any clear explanation of the results.

Possible explanations include a direct

pharmacologic effect of salmeterol; the presence of

polymorphisms in the beta receptor gene; or

patient-related factors, including a delay in

106

seeking medical care. It is well accepted that the

prevalence of patient-related risk factors is not

equally distributed across ethnic groups so the

differences in outcomes seen between the ethnic

groups in SMART may be associated with disparities

in access to medical care and asthma management and

may not reflect biological differences between the

groups. Unfortunately, none of these hypotheses

can be confirmed or refuted by the data from SMART.

While there are no clear explanations for the data,

the findings were communicated to physicians to

allow for informed treatment decisions.

In collaboration with the FDA, a number of

activities were undertaken to communicate the

results in order to inform physicians about SMART.

On the day the study was stopped a "dear healthcare

professional letter" was delivered by overnight

mail to the 229,000 healthcare professionals in the

United States who had prescribed salmeterol or

salmeterol-containing products within the previous

year. Simultaneously, notices on both the FDA and

GSK web sites were posted.

107

A second letter was sent out to health

professionals when the prescribing information for

Serevent and Advair was changed to include the

preliminary results of the interim analysis of

SMART. The information was elevated to the highest

level of prominence in the form of a boxed warning.

When the final results were obtained the labeling

for both products was updated.

This is the boxed warning that was added

to the prescribing information for Serevent and

Advair. It describes the final results of the

interim analysis of SMART. For your reference, the

full label, including the boxed warning, is

available in your briefing package.

The results of the interim analysis were

presented at the American College of Chest

Physicians meeting as a late-breaking abstract.

This was the first available national meeting with

high attendance of respiratory physicians. The

manuscript is now in press at Chest, the journal of

the American College of Chest Physicians.

Epidemiology studies offer an additional

108

method to investigate associations between drug

exposure and serious outcomes. The major advantage

of these studies is the utilization of

comprehensive medical and pharmacy databases.

These databases allow identification of a greater

number of events than can be achieved in

traditional randomized clinical trials. The

primary limitation of observational studies is the

fact that assignment of treatment is not random and

treatment effects may be confounded by differences

in baseline characteristics, including co-morbid

disease, differences in asthma severity and

selective prescribing. Since many more events can

be evaluated in an observational design, this may

be a more informative way to assess treatment

effects on the rare endpoint of asthma-related

death.

This figure displays the relative risks

from all large published cohort and case-control

studies that evaluated whether salmeterol use was

associated with the occurrence of severe

respiratory and asthma-related outcomes. The

109

dotted line represents a relative risk of 1.

The first study determine the relative

risk of respiratory-related death among patients

with asthma receiving salmeterol compared with

those receiving theophylline on the left side of

the highlighted area, or those receiving

ipratropium, which is on the right side of the

highlighted area.

The second study, which was conducted in

the United States, evaluated three endpoints,

asthma-related emergency room visits,

hospitalizations and ICU admissions, comparing

salmeterol with theophylline recipients.

The last two were separate case-control

studies that evaluated the relative risk of

asthma-related ICU admission or asthma-related

death associated with salmeterol use relative to no

use.

This last and most recent study, shown

here on the far right, included 532 pairs of asthma

deaths and matched controls and is the largest

case-controlled study evaluating asthma-related

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death ever conducted. Notably, none of these

studies showed a significant increase in the

relative risk of these serious outcomes for

salmeterol.

GSK is committed to a comprehensive

research plan to further evaluate the safety and

efficacy of salmeterol. We believe that these

currently ongoing studies will provide valuable

information regarding the safety and efficacy of

salmeterol in patients with either asthma or COPD.

In order to address some of the issues raised by

SMART, two studies are under way.

The first is a year long clinical study

evaluating the incidence of asthma exacerbations in

460 African American subjects. Results are

expected in 2007. The second is an epidemiology

study utilizing data from 7 Medicaid plans to

examine racial variation and association of

asthma-related prescription medication use with

asthma morbidity and mortality. The results are

expected in 2006.

Studies have suggested that response to

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short-acting beta agonists may be affected by

genetic polymorphisms in the beta

2 receptor.

However, there is one study that has suggested

there is no similar association with salmeterol and

clinical outcomes including exacerbations. This

was the Taylor study that Dr. Sorkness showed

earlier. Since there were no genetic samples

collected in SMART we are conducting two studies to

address whether clinical outcomes in patients

receiving salmeterol are affected by genotype.

The first study is a 38-week clinical

trial evaluating response by beta

2 receptor

genotype in 540 subjects with asthma. The results

are expected in 2007. The second study will

evaluate polymorphisms in beta

2 adrenergic

glucocorticoid pathways with respect to clinical

response in approximately 1,000 subjects from

completed GSK clinical trials.

Finally, while asthma has been the focus

of today's discussion, there are ongoing studies in

patients with COPD that will help address whether

the results of SMART are relevant for patients with

112

COPD. The first is a 3-year study of all-cause

mortality in approximately 6,200 subjects with

COPD. Results from this study are expected in

2006. In addition, we are conducting 2 year-long

replicate studies examining the rate of moderate to

severe COPD exacerbations, with results expected in

2007.

Asthma is a serious chronic disease with

significant morbidity and mortality. Salmeterol is

one of the most thoroughly studied medications for

asthma and has been shown to provide substantial

therapeutic benefit, including improvements in lung

function, and asthma-related quality of life, and

reduction in symptoms, rescue medication and asthma

exacerbations.

The extensive clinical trials have led

evidence-based asthma treatment guidelines to

recommend long-acting beta agonists with ICS as the

preferred option for patients with moderate,

persistent asthma. There are conflicting data for

salmeterol. SMART and SNS suggest that salmeterol

may be associated with an increased risk of rare

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serious asthma-related events including

asthma-related death. But when large cohorts of

patients are evaluated in epidemiology studies this

association is not observed. The low number of

serious asthma events in SNS and SMART does not

allow for definitive conclusions, and the fact that

the events of concern are also those that are

experienced by patients with asthma, regardless of

treatment, makes assessment of cause and effect

relationships difficult.

Ultimately, what are the implications of

the data for patients with asthma? Well, specific

treatment decisions for an individual patient can

only be made by their physician. It is our

responsibility to provide the complete information

so that the physician can make well-informed

treatment decisions. We have done this in the

prescribing information for products containing

salmeterol.

From the time that salmeterol was

introduced in the United States in 1994 the

prescribing information has provided specific and

114

appropriate guidance on its use. This includes

that salmeterol should not be used to treat acute

symptoms. It is not a substitute for inhaled or

oral corticosteroids, and consideration should be

given to adding anti-inflammatory agents, for

example corticosteroids.

In 1995 further information was added,

including a warning that salmeterol should not be

initiated in patients with significantly worsening

or acutely deteriorating asthma. As I have already

mentioned, detailed information on the rare

asthma-related events seen in SNS and SMART had

been incorporated in the prescribing information so

that informed treatment decisions can be made.

This includes the boxed warning, as well as other

language to address the inconclusive nature of the

results and the potential for a class effect of

inhaled long-acting beta agonists.

In conclusion and based on the weight of

evidence, we firmly believe that salmeterol remains

a valuable medication that has improved the level

of care for patients with asthma and COPD.

115

Additionally, GSK is committed to further research

that will not only help better characterize the

efficacy and safety of salmeterol but will also

help better understand asthma in general. There is

a large volume of data from clinical trials of

salmeterol, as well as extensive clinical

experience with this medication. Taken together,

these continue to support a favorable benefit to

risk profile and, therefore, salmeterol should

remain available to physicians and patients.

I thank you for your time and I will now

turn the podium back over to Dr. Jones.

Closing Remarks

DR. JONES: I would like to introduce

three additional experts here with us today. Prof.

Richard Beasley is the director of the Medical

Research Institute of New Zealand. He is also an

international expert on beta agonist safety and

asthma epidemiology. Dr. Eugene Bleecker is

professor and section head, Pulmonary, Critical

Care, Allergy and Immunologic Diseases at Wake

forest University Health Sciences. Dr. Bleecker is

116

also the co-director of the Center for Human

Genomics, and was a member of the MMRC for SMART.

Finally, Dr. George O'Connor is professor of

medicine in the Division of Pulmonary and Critical

Care Medicine at Boston University School of

Medicine, and is director of the Adult Asthma

program at Boston Medical Center. In addition, he

was the chairman of the DSMB for SMART.

We would be happy to address any points of

clarification and questions. Thank you.

Questions by the Committee

DR. SWENSON: Dr. Schatz?

DR. SCHATZ: I think one possible

hypothesis based on the SNS study, where there was

increased withdrawal due to asthma in the placebo

patients, is the possibility that there ended up

being an imbalance in severity by the end of the

study due to disproportionate withdrawal of more

severe patients from the placebo group. That is

obviously not so easy to tease out but I would

question whether, in fact, one looked at baseline

severity in those who withdrew versus those who

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didn't in both groups but particularly in the

placebo group.

DR. KNOBIL: For SNS we don't have that

cut of the data to provide for you, but it would

probably make a lot of sense that the patients who

withdrew were more severe.

DR. SCHATZ: But for SMART data--

DR. KNOBIL: Oh, for SMART we saw the same

thing in that there was greater withdrawal in the

placebo group than in the salmeterol group but,

again, we don't have that cut of the data for you

today.

DR. SWENSON: Dr. Gardner?

DR. GARDNER: I have two questions, one

related to measures of adherence within or between

the groups and whether anything has been done with

that. The second is would you give us the status

of the ongoing studies at this time? You have

listed four with expected results. Can you tell us

the enrollment at this time; how far along you are?

I understand the word "commitment" but can we see

something about progress at this time and status?

118

DR. KNOBIL: All of the studies that I

mentioned to you are right now currently enrolling.

As you might imagine, enrolling limited populations

of only African Americans takes a little bit longer

than general populations. As well, in the genetic

studies we are making sure that we have balanced

groups with the different genotypes. So, that does

take some time. So, what I can tell you is that

they are enrolling but I can't tell you when they

will be done enrolling.

DR. GARDNER: And adherence?

DR. KNOBIL: Oh, I am sorry. During the

monthly telephone contacts we did ask the

question--if you could show the slide, please? On

a scale of 0-10, with zero meaning you missed all

of your doses and 10 means you took all of your

doses, what number represents how well you followed

the study physician's instructions? In the study

the mean response, patient reported response was 8

for each group. Again, this is patient reported

and patients did not return to the clinic so we

cannot verify this. We did not ask them to bring

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their cans in. We did not weigh canisters and we

didn't have a chronolog. But I think from studies

of chronolog, we know that patients sometimes

report taking more medication than they actually

do. So, I can't really verify the actual

compliance of the patients.

DR. GARDNER: As far as you can tell, was

there similar adherence between the African

American subjects and the Caucasian subjects?

DR. KNOBIL: Yes, as far as can tell there

was no difference between any specific group.

DR. GARDNER: Finally, on the Medicaid

study, that doesn't require enrollment. Can you

tell me where that is being done and how far along

that one is?

DR. KNOBIL: Yes, that one is being done

in seven states. What we are doing right now is

the first phase of the study, which is to see if we

can identify enough patients with high enough

proportion of African Americans to make an analysis

feasible. So, that is where that study is right

now.

120

DR. SWENSON: Dr. Moss?

DR. MOSS: I have two separate questions.

The first one has to do with the dissemination of

the information in your letters and the labeling

revisions. I think the goal of this meeting is to

disseminate information properly to the physicians

and the community. The question I have is when you

sent out those letters and put on the box labels,

do you know if that changed the prescription

practices for the physicians that received those

letters or for the general community in terms of

the prescription of your medication?

DR. KNOBIL: I don't know if that

information changed the way physicians prescribe

the medications. We don't have any specific data

to that effect.

DR. MOSS: Did overall use of your

compound decline after those letters were sent out?

DR. KNOBIL: The rate of use did not

change after those letters were sent out. But, you

know, we can't guess what would have happened; all

we saw was no change.

121

DR. MOSS: You saw no change. I think

that raises a concern about, you know, we are

trying to disseminate information and are we doing

that in the proper way?

The next question I have may be answered

by you but might also be answered by either Dr.

Bleecker or O'Connor. I think it is really hard to

figure out why someone died. Taking care of people

I see this. It is really hard to define

specifically what a cause of death is. I was just

wondering if you can give us some insight into how

you define respiratory versus asthma deaths in the

SMART study.

DR. KNOBIL: Dr. Bleecker, would you like

to address that?

DR. WEAN: While Dr. Bleecker is coming

up, I want to get back to the earlier question you

raised. I am David WEAN, Senior Vice President of

Regulatory Affairs at GlaxoSmithKline. I don't

think it appropriate to say that because we can't

posit a change in prescribing habits because of the

letters and the label that they were not effective.

122

The important thing is that the information was

disseminated in a very large way to prescribers

and, thereby, to patients. To expect that you

would see a drop-off in use of these drugs that

have therapeutic benefit because of that

communication I think would be an inappropriate

assessment about the effectiveness of that

communication.

DR. MOSS: But I think one thing we have

learned is that publishing articles and papers does

not get information out to the people that need the

information to be received. In the same way, I am

not sure that sending letters out to physicians who

get a lot of mail is an effective way of

communicating information.

DR. SWENSON: Dr. Bleecker?

DR. BLEECKER: I was asked to talk a

little bit, and George O'Connor could complement on

how the mortality review committee in SMART

adjudicated cases. I agree, it is often very

difficult, and as we did this we probably all

learned. I joined the mortality review committee

123

after about a third of the cases had been done.

The members of the committee before that had been

Roland Ingrham who was professor of medicine at

Emory. He had retired. The chairman of the

committee was Hal Nelson who is a professor of

medicine at Colorado, and the third member was

Scott Weiss who is professor at Brigham and

Williams and also head of their pulmonary and

respiratory epidemiology program.

We had data on most patients available

both from death certificates and from the medical

monitors who worked with Covance. We used that to

answer questions which were related to the cause of

death; was this respiratory related; and you heard

before the likelihood or unlikelihood of that

during Kate Knobil's presentation; and then was it

asthma related. All three of us adjudicated this

independently. If we agreed on all of these

characteristics the case was not discussed further.

All of the cases in which there was any

disagreement, ranging even between "unrelated" and

"unlikely" were discussed in detail in timely

124

conference calls. I think at times we did the best

we could on relating to that.

The least amount of information was

available on deaths toward the end of the study

that were picked up from the national death

registry. On those deaths we had to rely on death

certificates or more limited information.

DR. MOSS: Can I just follow-up on that?

Can you explain a little bit how you differentiate

asthma from respiratory deaths? A respiratory

death that is not asthma, is that pneumonia? What

were criteria to differentiate those specific

things?

DR. BLEECKER: Well, often asthma entered

into those deaths. Let me give you an example of

respiratory death. Because someone during an auto

accident had trauma to the chest--and this did

occur in some of the younger individuals--and died,

and that clearly was related to an automobile

accident and because of the nature of the event and

other things was not related to asthma. It was

more difficult if someone entered the hospital with

125

pneumonia, was intubated and in an intensive care

unit. I think under those circumstances, some of

those deaths were adjudicated depending on the

course on the ventilator or those serious events as

possibly related to asthma. So, at times it is

very hard to distinguish that from the records.

Again, I think the fact that they were performed

independently and you needed to look for

concurrence and discussion, I think a reasonable

approach was performed.

DR. SWENSON: Dr. Gay?

DR. GAY: Based on the appropriate

emphasis that you have begun to make on genetic

testing, as we have seen based on the information

that Dr. Sorkness elegantly presented before, do

you have any preliminary estimates of what you feel

would be the prevalence of Arg/Arg gene

presentation in patients with greater severity of

asthma or based on ethnic differences?

DR. KNOBIL: Yes, I would not be able to

predict the different prevalences of those genetic

subtypes and I would ask Dr. Bleecker to comment on

126

that. The one thing I would add is that in the one

genetic study we are making sure that there are

equal numbers of each genetic subtype so that we

don't have a predominance of one and very few of

another. Dr. Bleecker?

DR. BLEECKER: I would like to add a few

comments to that because I think there are some

important aspects of this. First of all, we have

centered on basically one variation within the

beta2 adrenergic gene. Looking at that gene more

carefully--and there have been published studies on

this, especially from the Liggett group as well as

some work from our laboratory which has been

presented at last year's ATS and Academy of Allergy

meetings--there is a good deal more variation in

that gene, and there are relationships between the

arginine genotype and some of that other variation.

Some of that may be very important in trying to

sort out the hypothesis of whether variation in

this gene affects therapeutic response and

potentially affects outcome.

The second important issue is there is

127

more variation, and African Americans have a higher

prevalence of the Arg/Arg genotype, about 22

percent, and that is what was seen during the

screening for the ACRN BARGE trial versus about

12-14 percent in Caucasians. The implications of

that on outcome are difficult, and I think it is

very important that the studies that were outlined

by Dr. Knobil on studying specifically an African

American cohort in which they are going to look at

outcome such as exacerbations and genotype are

critical because those kinds of studies are not

being done because of the limitations in

recruitment by the NIH NHLBI asthma clinical

network.

DR. SWENSON: Dr Prussin?

DR. PRUSSIN: I have a similar question

that I raised before with Dr. Sorkness. You have

some very nice studies that are undergoing, but do

you think they are going to address the question at

hand in terms of asthma deaths or severe pulmonary

endpoints? They are fairly small studies relative

to the SMART study and, when all is said and done

128

in three or four years, it is not clear to me at

least that you are going to have any kind of handle

on asthma death. Could you comment on that?

DR. KNOBIL: Yes, as I mentioned, it is

very difficult to prospectively study

asthma-related death because the rate is relatively

low and you need a very large N to get conclusive

results. The one study that will help us get there

though, I believe, is the Medicaid study in that we

can get information from the 7 Medicaid plans and

look at the different racial subgroups, look and

see what medications they were on and see what

contributed to those patient's deaths, whether it

is a long-acting bronchodilator, short-acting

bronchodilator or some other related medication.

So, I do believe that in that observational design

we will be able to get some more information about

asthma-related death. The other studies are mainly

going to address asthma exacerbations and other

responses such as lung function, rescue albuterol

use, and we will be able to look at those in

relationship to genetic makeup as well.

129

DR. PRUSSIN: The difficulty I have with

that though is that there is a lot of data showing

that salmeterol improved asthma exacerbations. You

have shown that. Clearly, the more severe

endpoints of death are tracking differently. So,

you are thinking of it as the tip of the iceberg,

that however exacerbations are going to track

asthma deaths are going to track and clearly they

are behaving differently. So, just because you

have certain data on asthma exacerbations in

certain subgroups, that may not be proportional or

relate to asthma. We don't have any prospective

studies ongoing or planned to really address the

endpoint that I think this committee has been asked

to address, which is asthma death. So, it could

very well be a different phenomenon than what is

causing asthma exacerbations.

DR. KNOBIL: That is true, and there are

other factors beyond asthma treatment that may be

contributing to asthma-related death as well,

including access to care or how a patient's asthma

is managed. We don't know the answers to that

130

either. So, that is why in order to actually even

look at asthma-related death an observational

design is probably going to provide more

information more quickly.

I take your point that it seems that a

prospective study would be the gold standard. The

issue there is that if the rate of asthma-related

death was similar to what we saw in SMART, in order

to see an effect you might have to have a study as

large as 800,000 patients. As you can see, that

would be very difficult to do. So, yes, it would

be nice to be able to do it prospectively but it is

going to be more difficult than doing it in an

observational design.

DR. JONES: Actually, I think Dr. Beasley

wanted to make a comment.

DR. BEASLEY: Yes, in response to that I

would like to caution in terms of considering a

prospective clinical trial as being the gold

standard when you are looking at a rare outcome

such as mortality. I think we saw that in the

SMART study, where it was required to study

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approaching 30,000 subjects to obtain around 35

respiratory-related deaths, and there was a real

compromise in terms of design of the study to

actually achieve that and individuals were given 7

canisters at the beginning of the study without any

formal clinical follow-up, which is something which

would not be done on label in terms of salmeterol

therapy. In terms of the other issues of the label,

many of the subjects had asthma severity where

salmeterol would be inappropriate as sole therapy.

So, I think that when you try a

prospective controlled trial to look at a rare

outcome such as death you often have to incorporate

a methodology that clearly is outside the spectrum

of what is recommended clinical practice. That

clearly happened with the SMART study so that we

have to consider the SMART study results not

applicable to what would be considered good

clinical practice, and the alternative is actually

to increase the number of deaths through

case-control methodology and that was the method we

used in New Zealand to identify the risks

132

associated with fenoterol.

In that regard, I think that the Anderson

study in the BMJ is considerably more powerful in

terms of looking at the role of bronchodilator

therapy and the rare outcome of asthma mortality.

They were able to look at over 500 deaths, match

them with subjects who came from the same

proportion of the population of patients in terms

of severity, who were subjects with a previous

hospital admission, and then they were able to

stratify their analysis by looking at an even more

severe subgroup. When they did that there was

actually no increased risk associated with the use

of salmeterol therapy.

So, I think that in terms of the

epidemiological approach to a rare outcome of

asthma mortality looking at the role of medication

use, the epidemiological view is very clearly that

the case-control methodology is more powerful and

more accurate than a prospective clinical trial. I

think in some respects almost the learning point

from the experience with the SMART study was the

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compromise that had to be obtained in terms of

clinical practice to achieve a study which, even

with 30,000 people, did not have sufficient power.

DR. SWENSON: Dr. Schoenfeld?

DR. SCHOENFELD: Do you have a tabulation

for the whole group and for each of these subgroups

and for each of the endpoints of the absolute risk

or the attributable risk? Because from a

risk/benefit point of view the relative risk isn't

very informative because, of course, you can have a

3-fold relative risk of a very, very rare event and

that may be important if you are judging something

like an environmental pollutant that you can remove

but is not really important when you are judging a

very effective drug which improves people's quality

of life. So, I wonder if you have that tabulated.

I have done some back-of-the-envelope calculations

but it would be helpful to have the actual numbers

where we looked at the percent of deaths per

patient-year or number of deaths per 1,000

patient-years, or something of that sort that would

be attributable, assuming that there is some

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attributable risk to the use of the drug, or even

just the total risk among asthma patients per 1,000

patient-years or 10,000 patient-years, or whatever.

DR. KNOBIL: Unfortunately, we don't have

those data. We have not done those calculations.

DR. SWENSON: Dr. Martinez?

DR. MARTINEZ: Would you please clarify

what the entry criteria were for both studies, the

British one and the one done in the United States?

How was asthma defined? Were any of the usual

parameters--response to beta

2 agonists or

methacholine used to define asthma in these two

studies?

DR. KNOBIL: These studies were a little

different than normal clinical trials, say, to

opinion of the investigator if the patient have

asthma. They did not have to show reversibility.

There was no smoking criterion. In this case they

had to be 12 years of age or older. In SNS they

had to have moderate to severe asthma and in SMART

they were not allowed to have concomitant

135

administration of beta blockers. That is about

all.

DR. MARTINEZ: Was response to

bronchodilators measured?

DR. KNOBIL: It was not measured.

DR. SWENSON: Miss Sander?

MS. SANDER: Yes, when we are looking at

possible causes of death, are you able to know if

patients who died were using salmeterol as if it

was an acute bronchodilator?

DR. KNOBIL: In SMART the only question we

asked was if the patient was using the medication

as the physician told them to. That is the data

that I showed you earlier. We do not have any data

on whether they were using it as a rescue

medication.

DR. SWENSON: I realize that there are

more questions to be posed to GSK but we need to

take a break at this point. We have a general

question session in the afternoon and the rest of

these questions should be addressed at that time.

We will be back again in 15 minutes.

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[Brief recess]

DR. SWENSON: We will resume the meeting

with Dr. Eric Floyd, from Novartis, to discuss

formoterol and its place in this controversy.

Novartis Presentation

Introduction

DR. FLOYD: Good morning. Dr. Swenson,

members of the FDA advisory committee, Dr.

Chowdhury, members of the Food and Drug

Administration and guests, my name is Eric Floyd.

I am Vice President and Global Head of Drug

Regulatory Affairs for the therapeutic areas of

dermatology, respiratory and infectious diseases.

On behalf of Novartis Pharmaceuticals Corporation,

I thank you for the opportunity to review the

current safety experience today for a long-acting

beta agonist, Foradil.

There have been numerous safety concerns

expressed publicly regarding use of long-acting

beta agonists. The purpose of our presentation

today is to discuss implications of recently

available data related to the safety profile of

137

long-acting beta agonists. This morning Novartis

would like to present to you the results and

conclusions of our review of available safety data

for Foradil. Based upon our review of clinical

trial data and postmarketing experience, we would

like to demonstrate that formoterol exhibits a

favorable risk/benefit profile.

To provide a brief regulatory overview,

Foradil was first approved for marketing in France

in 1990, and subsequently approved in other

European countries. Foradil received FDA approval

to market in the United States in 2001. Foradil is

currently approved in over 80 countries worldwide

and to date, we currently have over 13 million

person-years of exposure.

Foradil Aerolizer was marketed as a dry

powder capsule for oral inhalation and was approved

in 2001 for a dosage regime of 12 mcg twice daily

for maintenance therapy for individuals with asthma

5 years of age and above for the following

indications, acute prevention of exercise-induced

bronchospasm in individuals 5 years of age and

138

older when administered on an occasional as needed

basis, and for chronic obstructive pulmonary

disease, including chronic bronchitis and

emphysema.

Outside of the United States, Foradil is

approved at 12-24 mcg twice daily and is a highly

prescribed bronchodilator, and is also indicated

for the maintenance therapy of asthma specifically

in adults and children 5 years of age and older;

for the prophylaxis and treatment of

bronchoconstriction in patients with asthma;

prophylaxis of bronchospasm induced by inhaled

allergens, cold air or exercise; prophylaxis and

treatment of bronchoconstriction in patients with

reversible or irreversible COPD, including chronic

bronchitis and emphysema. In some countries it is

also approved as metered dose inhaler and

multi-dose dry powder inhaler, 10 mcg, Certihaler.

In order to provide a more detailed review

of our current data to date, I would like to

introduce our speakers today. Dr. Gregory Geba,

who is the Vice President and U.S. Head,

139

Respiratory, Dermatology and Infectious Diseases,

Clinical Development and Medical Affairs for

Novartis Pharmaceuticals, will present the safety

profile of Foradil.

He will be followed by Dr. James Donohue,

who is Professor of Medicine, Chief of Pulmonary

Division, University of North Carolina, Chapel

Hill, who will present the clinical implications.

In addition to the key speakers, we also

have additional advisors available to address any

specific questions you may have. Specifically from

a statistical perspective we have Dr. Gary Koch,

Professor of Biostatistics, School of Public

Health, University of North Carolina, Chapel Hill.

I would now like to turn the podium over to Dr.

Geba.

Efficacy and Safety of Foradil

DR. GEBA: Thank you, Dr. Floyd. Dr.

Swenson, committee members, members of the FDA and

interested attendees from the community, it is my

role to review with you all of the clinical data

and postmarketing data we have available for

140

Foradil, the other long-acting beta agonist being

discussed today. We firmly believe that Foradil is

a drug that provides clinical benefit with a

favorable benefit/risk profile.

As indicated in the previous presentation

by Dr. Floyd, and later on in this presentation by

Dr. Donohue, the clinical features of Foradil have

led to its inclusion in both U.S. and international

guidelines in the treatment of moderate to severe

persistent asthma.

These are the key points of the

presentation. We will describe pharmacologic

differences that exist between formoterol and

salmeterol, which may or may not have clinical

impact; a Phase 4 trial, 2307, which examined

asthma-related serious adverse events in

adolescents and adults; our integrated Foradil

clinical database; and postmarketing adverse event

data. The totality of the evidence does not

elevate concern for a safety signal for Foradil

which continues to support its favorable

benefit/risk profile.

141

These are the chemical structures of

formoterol on top and salmeterol on the bottom.

Please note that at the end of the molecule that

interacts with the beta receptor, the catechol end

of the molecule, the molecules are actually similar

in having a hydroxyl group at position 5. However,

they are different at positions 6 where you see

different side chains. Most importantly, at

position formoterol has a much longer allophanic

chain, as previously shown. Thus, although both

molecules bind to the beta

2 receptor, differences

in structure allow salmeterol to bind to an

additional site within the beta

2 receptor termed

an exosite. Prolonged salmeterol activity depends

on binding with the exosite when formoterol's

activity is independent of an exosite. In

addition, mutation of the exosite region could

affect the duration of action of salmeterol. One

of the consequences of structural differences is

that formoterol is a full agonist at the beta

adrenergic receptor, whereas salmeterol is a

partial agonist.

142

Typical experiments illustrating this

point are performed with human bronchial explants

which show that the bronchodilatory effects of

isoprenaline are decreased by prior incubation of

tissues with salmeterol but not formoterol. The

potential clinical implication of this difference

is that in the setting of beta

2 receptor

down-regulation the effect of rescue

bronchodilators may be greater for full agonists

than for partial agonists.

I would like to now move on to a

discussion of the Phase 4 trial 2307. This trial

was recently completed and is detailed in your

briefing book. Why was this study done? Protocols

040, 041 and 049 were 3 pivotal studies conducted

to support registration of Foradil in the United

Sates and 040 and 041 were 12 weeks in duration and

were conducted in adolescents and adults; 049 was

conducted for one year in children ages 5-12.

Trial participants were randomized to

receive Foradil 12 mcg BID, 24 mcg BID or placebo.

In 040 and 041 there was also a comparison to

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regular doses of albuterol 180 mcg QID. Please

note that all groups were allowed to take

additional doses of albuterol as needed for

residual symptoms and all groups were allowed

anti-inflammatory agents.

Shown here are the proportion of patients

with asthma-related serious adverse events. These

studies showed more serious asthma-related serious

adverse events in the higher don formoterol arms

compared to the lower doses or the approved

formoterol arm as well as the placebo arm.

In light of these findings, the agency did

not approve the higher dose of Foradil. After

discussing this observation with the agency and

with their guideline, we pursued a safety study

whose primary endpoint was asthma-related SAEs.

The inclusion and exclusion criteria for protocol

2307 were identical to protocols 040 and 041 which

were our pivotal trials. Indeed, the resulting

population studied in protocol 2307 was similar to

that of the pivotal trials in adolescents and

adults, which was the population studied and

144

requested, as shown in this slide.

Apart from the trial duration which is

different, age differences were pretty similar.

FEV 1 at baseline was fairly similar.

Please note

that the proportion of black patients in this trial

mimicked the proportion of patients in the U.S.

population. There are some subtle differences in

terms of ICS use and reversibility. Actual

reversibility for 2307 was slightly less than 040

and 041 but otherwise the study populations were

very, very similar.

The design of this safety study is shown

here. Using identical entry criteria--again, these

are identical entry criteria to those employed in

our pivotal studies--after a 2-week run period,

shown here, patients were randomized to receive, in

a double-blind fashion, one of the following

treatments, either formoterol 12 mcg BID formoterol

24 mcg BID--again, 12 mcg BID was the approved

dose; 24 mcg was the higher dose. They received

either of those two doses or placebo in another

group or, in an open-label group, received

145

formoterol 12 mcg BID plus an additional up to 2

rescue doses of formoterol 12 mcg BID, which

constituted the intermediate dose arm.

Please note that to increase the rigor of

this study, after 16 weeks of treatment we planned

to contact all patients, including those who

discontinued, to record all adverse events. This

assured that all patients would be evaluated for

AEs irrespective of treatment efficacy and trial

persistence.

Results of the study are shown here.

Please note that there was a correction made to the

briefing book provided by the agency. The lower

dose arm had a somewhat higher number of patients

who reported serious asthma-related AEs. However,

after review of the specifics of these cases, the

agency excluded 2 of these events in the Foradil 12

mcg arm, reducing that number from 5 to 3. Thus,

the final event rates were 0.2 percent in the

placebo group; 0.6 percent in the low dose group;

0.2 percent in the intermediate dose group; and 0.4

percent in the high dose group. Overall, there

146

were far fewer events than expected based on the

pivotal trials.

Displayed on this slide are the point

estimates and 95 percent confidence

intervals--which I hope you can see as red on a

blue background--for the proportion of patients

experiencing asthma-related SAEs in each treatment

group. As previously mentioned, the rates are low

for all treatment groups. The 95 percent

confidence interval for all Foradil doses combined

overlaps the 95 percent confidence interval for

placebo and excludes 1 percent. These data reflect

the revised rates after an FDA adjudication.

In conclusion, the observed rate of

adverse events was far lower than we expected from

our pivotal trials despite demographics that were

similar to protocols 040 and 041. Absolute

differences between groups were very small. Higher

SAE rates in the higher dose of Foradil arm,

previously observed in adolescents and adults in

protocols 040 and 041, were not observed in this

larger, specifically designed safety study.

147

Now I would like to review with you a

comprehensive safety analysis of our clinical trial

database. We performed an extensive review of

safety based on our clinical trial database which

focused on deaths and asthma-related adverse

events. In terms of deaths, we examined all

controlled and uncontrolled trials in the Aerolizer

and Certihaler databases. All studies irrespective

of trial duration were examined to assure that the

very rare case of sudden paradoxical asthma,

culminating in the demise of a patient, was

captured.

For the analysis of asthma-related adverse

events we focused on controlled trials of greater

than or equal to 4 weeks duration so as not to

dilute the denominator for adverse events in trials

of longer duration with very short trials,

sometimes as short as 24 hours, which were

performed to assess short-term changes in lung

function.

For controlled trials the database

included nearly 6,000 patients on Foradil, shown

148

here; for uncontrolled trials over 2,700. For

trials of 4 weeks or greater in duration the number

was over 5,000 on Foradil, whereas the

placebo-controlled trial database was comprised of

over 3,700 patients who had been randomized to

Foradil.

Looking at our controlled trials, there

were 3 deaths overall, one death in the Foradil

group, representing over 1,600 patient-years of

experience; one death in the albuterol group,

representing 241 patient-years of experience; and

one death in the placebo group, representing nearly

600 patient-years of experience. The rates of

death, therefore, was 0.41, 0.17 and 0.06 in the

albuterol, placebo and Foradil arms respectively.

The Foradil death was asthma related, shown here,

representing a rate of 0.06 asthma deaths per 100

patient-years of exposure. So, here we are

expressing it as a rate per years of exposure to

the drug, which represents less than one asthma

death per 1,000 years of treatment.

In reviewing the uncontrolled clinical

149

database, it is important to note that these

studies were those that did not incorporate

comparator arms. They were all open-label and

included trials conducted as part of compassionate

use programs. In addition, patients tended to be

older, with a high proportion of elderly subjects;

had more severe asthma; used more beta agonists at

baseline; and exhibited noon-asthma-related

mortality at a higher rate, indicating a higher

degree of general medical morbidity compared to the

control database. There were 5 deaths overall, 3

of which came from one study in France which

allowed entry of severely ill patients.

Now I would like to move on to address

significant asthma exacerbations. This term

includes asthma-related adverse events which were

meaningful enough to prompt patient discontinuation

whether severe or not and, to get to Dr. Schatz'

point, included asthma-related adverse events

reported as serious whether or not they caused a

discontinuation. So, we are looking at patients

that dropped out of the trial due to an

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asthma-related event that was meaningful enough to

stop therapy.

Displayed are the discontinuation rates

due to an asthma-related adverse event in multiple

dose, placebo-controlled trials of greater than or

equal to 4 weeks in discontinuation. These are the

discontinuation rates. Please note that there were

fewer asthma-related discontinuations in the

Foradil arms compared to the placebo arm or to

albuterol. So, the rate overall for an formoterol

doses was 7.1; for placebo it was 10.7; for

albuterol 8.1. Please note that this was

especially notable for the approved dose of

Foradil, 5.6 versus 10.7.

A reverse pattern was observed for

asthma-related serious adverse events. Foradil

patients experienced more events than placebo.

Here the imbalance was greater for the higher

Foradil dose. The numbers are shown here, 3.5 for

the approved dose versus 3.1 for albuterol, 0.9 for

placebo and a higher rate for the albuterol 48 mcg

dose. Again, this dose is the approved dose in the

151

U.S.

When both types of events are taken into

consideration, the rate of significant asthma

exacerbations, that is, asthma-related AEs

meaningful enough to cause the patient to

discontinue and asthma-related events that were

labeled as serious whether or not they caused

discontinuation, was actually lower for Foradil at

its approved dose than the rate for placebo or for

albuterol. Note that at the highest dose of

Foradil that rate was similar to the placebo rate.

But for Foradil at its approved dose the rate was

7.1 versus a placebo rate of 10.9.

In summary, based on this analysis of our

clinical trial database for asthma-related adverse

events, we observed a rate of significant asthma

exacerbations for the approved Foradil dose that

was lower than placebo rates.

I would like to now move on to a review of

postmarketing data. In order to explore the

adverse event profile of Foradil on the market and

to provide some estimates as to how it might

152

compare to other drugs in its class, we performed

an analysis of postmarketing data based on FDA AERS

database, that is the FDA's adverse events

reporting system.

We must recognize that this type of

postmarketing analysis has its limitations.

Although spontaneous reporting of ADRs remains the

most common method used for monitoring the safety

of marketed drugs and is useful for detecting

safety signals, it is limited by the fact that a

substantial percentage of ADRs are not reported.

The reporting rate also tends to be lower the

longer a drug is on the market. This is a

well-known phenomenon and is known as the Weber

effect. In addition, targeting drugs to lower or

higher risk patients may alter apparent ADR

occurrence, and notoriety associated with a drug or

class may alter reporting rates. A final concern

is that the ADR that is being reported in this

instance is the disease itself, It is a

manifestation of the disease itself.

We examined FDA adverse reports for death

153

or outcome of death and found that rates were

highest in the first years after launch and

declined each year thereafter. This analysis is

shown in your briefing book.

We will now review the reporting rates for

these and other events of interest. Please note

that reporting rates are reports with case

definition on the drug of interest divided by the

exposure worldwide since the drug was marketed in

the U.S. per 100,000 patient-years.

Relative rates of reporting can also be

assessed by simply calculating the percentage of

reports at case definition by the total number of

adverse events reported. This does not take into

consideration the exposure to the drug of interest

and may inflate the Weber effect if there is a

difference of time on the market. Shown here are

the reporting proportions, on the left, and the

reporting rates per 100,000 patient-years, on the

right, for Foradil and salmeterol.

As you can see, the reporting proportion

for formoterol, a drug that was established on the

154

U.S. market in 2001, compared to salmeterol, which

was on the market since 1994, is somewhat higher.

However, one must adjust for the exposure to the

drug which was far greater for salmeterol. When

adjusting for this higher number of exposures for

salmeterol the result ratio flips. That is, when

we adjust for actual exposure to the drug we note

that the rate for Foradil was somewhat lower than

that of salmeterol.

In conclusion, well-described

pharmacologic differences exist between formoterol

and salmeterol although the clinical relevance is

not known. In pivotal trials conducted for U.S.

registration, a potential safety signal emerged in

the Foradil high dose group, leading only to the

approval of the 12 mcg dose, that is 12 mcg BID,

and the request for postmarketing asthma safety

study 2307. Study 2307 examined asthma-related

serious adverse events in adolescents and adults

and did not provide evidence of a safety signal for

Foradil at any dose.

An analysis of the pooled Foradil clinical

155

trial database and a review of postmarketing

adverse event data, with its limitations, do not

provide evidence of a safety signal for Foradil.

The totality of the evidence, therefore, does not

elevate concern for a safety signal and continues

to support the favorable benefit/risk profile of

Foradil in the treatment of asthma.

Thank you for your attention. Dr. James

Donohue will now present the clinical implications.

Clinical Implications

DR. DONOHUE: Thank you, Dr. Geba. Dr.

Swenson, members of the advisory committee, Dr.

Chowdhury and Dr. Meyer and members of the FDA,

ladies and gentlemen, I am here today as a

clinician investigator to talk about the clinical

implications of the long-acting beta agonist class.

As an older physician, I can talk a little bit

about life before the introduction of the

long-acting beta agonist class into our clinical

practices. While the alternatives were

short-acting beta agonists, theophylline, various

epinephrine agents, oral beta agonists, each of

156

these treatments had different benefit/risk ratios

or profiles from the long-acting beta agonist

class. I would like to discuss a little bit the

implication of the roller-coaster effect on our

patients with asthma's lives, the lack of nocturnal

coverage with most of these shorter-acting agents

and issues with compliance. There have always been

issues with the short-acting beta agonists for the

need to frequently dose; special issues with our

children and whether or not they could be dosed in

the schools; the difficulty in our blue-collar

workers, of course, who need frequent dosing of

their medications.

The short-acting beta agonists have, as I

say, benefits and risks. Overdosing of the

short-acting beta agonists was associated with

tremor, particularly with the peak. There were

changes in metabolism, hypokalemia and changes in

glucose metabolism which may or may not be

clinically significant but could be under certain

circumstances. There was also tachycardia

associated with people using some higher doses or

157

people who had more co-morbidity issues. Then

also, to inform us, we had very useful data from

Saskatchewan looking at thee use of short-acting

beta agonists in Canada. These are combined data

for formoterol and albuterol.

These are the deaths per 100,000 per year

and the number of canisters. We can see that as we

start getting up in the number of canisters,

especially win formoterol, one sees an increase in

deaths due tot he short-acting beta agonists or

associated--not necessarily due to but associated

with the short-acting beta agonist class. So this

was, of course, a concern to all of us and is part

of the recommendations presently in the guidelines.

We also had different side effect profiles

of other medications available to us before the

long-acting beta agonists and drugs we would have

to consider today as substitutes. First and

foremost, theophylline, particularly the

longer-acting forms. Their safety profile is

important to look at. There was a narrow

therapeutic window, as everyone knows, with these

158

drugs. There were very, very important drug

interactions. In fact, if we look at our elderly

asthmatic population, commonly these patients would

enter the hospital with use of an antibiotic or a

medication for reflux causing a drug-drug

interaction and making the patient theophylline

toxic. Furthermore, if we look at drug

interactions in the hospital, there is a huge

safety concern about medication errors, and

what-have-you, and theophylline were always at the

top of the list.

Other medications we had were oral beta

agonists, both short-acting and long-acting and,

again, much less of an efficacy profile as compared

to the long-acting inhaled agents and a much

greater safety risk with tachycardia, tremor and

reflux. Oral corticosteroids have to be used more

and more when patients have more and more

exacerbations and I don't have to review the

laundry list of side effects that are well-known to

everyone in the room.

Now, throughout the world we have--I have

159

outlined in yellow here the G8 nations because of

last week's meeting, but we can see the variation

in prevalence of asthma symptoms as we get more

industrialized societies. We see a very large

increase in the number of patients who suffer with

airways disease.

On the other hand, there are facts that I

find very, very consoling and comforting. This is

the death rate due to asthma in the United States

going back to 1960 up to 2002. These are the

deaths per 100,000 so we can sort of get the rate

that you are asking for. Then we have the African

Americans here and the Caucasian population here.

Short-acting beta agonists were introduced

in the 1970s. We had the inhaled corticosteroids

introduced in the 1980s. There have been enormous

efforts in patient education, efforts by the expert

panels of the National Institute of Health for

guidelines and just generalized education programs,

along with the introduction of effective controller

medicines along with the long-acting beta agonists

that seems to have led to a decline, although still

160

very high, relatively higher in the African

American population, but to the general United

States population, from 5,400 to a little bit above

4,000. So, we are clearly doing something right.

What the attribution would be here to the various

things introduced is, of course, beyond my ability

to say but, clearly, all these things together have

helped us to improve the lives of our patients.

Now, what about the long-acting beta

agonists? Just briefly, you have seen an awful lot

of this data this morning and, at the risk of being

a little bit redundant, the first benefit, of

course, is in patient symptoms. These are better

bronchodilators. I think we would all agree that

the data are overwhelming on this. There is a

reduction in the roller-coaster effect, and I will

come back to that in a minute; better control

because of the longer duration of effect and

nocturnal symptoms. Because of the control, we

have less use of rescue medications. We have

improved morning lung function and also less

diurnal lung function variability. It doesn't

161

completely eradicate it but it does minimize to

some extent some of the early morning dipping that

leads to waking up or even worse outcomes. Also,

equal important perhaps, it gives us protection

against exercise-induced bronchospasm and that is

the exercise of normal daily activities in normal

life, and it is nice to have that kind of

protection on board so you don't have to

continuously dose yourself.

Looking at the formoterol data, Dr. Geba

has shown us the safety data. We saw that there

are 3 pivotal trials that you have in your briefing

documents. There is superior improvement in the

FEV 1 over placebo over the course of

12 hours.

This duration of action is sustained for 12 weeks

so there doesn't appear to be a signal that there

is any tolerance or reduced efficacy. There is a

reduced need for nighttime rescue medicine, and the

onset of action is similar to albuterol, as has

been outlined.

Just again showing the similar 12-hour

studies, this is the 040 and the 041 that you have

162

seen a moment ago. This is at week 12. Here we

see the 12-hour curve and this is the mean change

in baseline FEV 1.

Here is the short-acting

albuterol and placebo, and here is the sustained

effect of the long-acting beta agonist, in this

case formoterol. First of all, let me draw your

attention to the pre-dose or trough. Often we

power clinical trials on long-acting beta agonists

and this changes well over 10 percent here, around

12 percent, and that usually can be transferred to

as meaningful clinical improvements such as

symptoms in the morning and what-have-you. Over

the course of the day you see the roller-coaster.

That in itself means nothing but what this means

here is that as these drugs flow off here our

patients become symptomatic and have to disrupt

their daily activity to take rescue albuterol.

Also one other thing I would like to show

here is the peak effect. Patients perceive change

and when you have a nice plateau effect a lot of

side effects such as tremor are much less

perceptible to a patient.

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Other outcomes besides bronchodilator is

rescue medication. These again are from 040 and

041, the run-in for the 3 arms, formoterol,

albuterol and placebo. We see over the course of

4, 8 and 12 weeks a nice decline in the rescue

albuterol. These parameters are less rigorously

defined but we think the minimal clinical

improvement in that parameter is 0.8 puffs per day

ranging to 1. So, it appears to be in the ballpark

of something that means something to a patient and

we could quantitate that.

Simply, formoterol reduces nocturnal

symptom scores. I am showing 040 and 041 which I

believe are the adult studies run-in and over 12

weeks and the companion study here. We see a nice

decline from about 0.5 to 0.1 in the nocturnal

asthma symptom score parameter.

To end up, one of the studies that I take

consolation from as a physician is the FACET study.

Again, points are well taken here today, we are

talking about deaths. It is very difficult in

asthma studies though to power our studies, as

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everyone in the room has heard over and over again,

on death as the outcome. Exacerbations are

extremely important and the reason that I take a

lot of comfort from this study is that it is a

one-year study. Also, the exacerbations are

precisely defined, as Dr. Sorkness mentioned this

morning.

In this study we see--again in the

mechanical function, 835 patients, 12 months--a

marked improvement after the run-in. The patients

were in the run-in symptomatic on inhaled

corticosteroids. But this study gives us some look

at what is the added value of adding a long-acting

beta agonist--added clinical value--to inhaled

corticosteroids.

Here are the two budesonide arms. I think

there is no surprise that on the mechanical

function we do see a change of 7 or 8 percent. But

I think one takes a better message away from

looking at exacerbations. First of all, if

inflammation is ongoing and not being checked the

patient is going to know that they are going to

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breakthrough with an exacerbation. This is our

best clinical surrogate for the so-called masking

of inflammation, that is, the breakthrough of

exacerbations. In a study of one-year duration we

have adequate duration to bring this signal out.

So, in this study, as Chris Sorkness

pointed out this morning, we have an arm with 100

BID of budesonide and with formoterol. Then, the

second arm is 400 BID with the addition of

formoterol. And, the exacerbations were described

as mild with an increase in terbutaline, the rescue

medicine, and severe, defined by a 30 percent

change in peak flow and oral prednisone. The

decline in mild exacerbations was about 29 percent

and 40 percent with the combination. But with the

higher dose, high dose budesonide reduced the

exacerbation rate by 49 percent. When one adds

formoterol to it it went to 62 percent. So, there

is a net gain there and the actual clinical

implication of that is that it appears to be

significant. We really haven't put a number on

that yet but that, in my mind, is a very reassuring

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piece of evidence that supports the use of this

class of drug.

Using the best evidence that one has, the

expert panels--many of the members of which are in

the room here--have come together, and you have

seen this before over and over again, and have

concluded that inhaled steroids and long-acting

beta agonists have a complementary effect. One can

lower the dose of inhaled corticosteroids by using

the combination, and not everyone responds to

inhaled corticosteroids although a great majority

do.

For more severe patients we would be using

higher doses of inhaled corticosteroids and

long-acting inhaled beta agonists and, hopefully,

we will be able to avoid the use of prednisone and

its very difficult side effect profile.

So to summarize, long-acting beta agonists

have really become an established part of the

current standard of asthma treatment in the United

States and also internationally. It is an integral

part of internationally established guidelines

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using the best evidence that we have at our

disposal at the present time. It is well

established that long-acting beta agonists have a

place in the treatment regimen for asthma but must

be conjunction with inhaled corticosteroids for

those with moderate and severe persistent asthma.

Again, I don't think at the present time

there is an alternative inhaled controller

bronchodilator or one on the immediate horizon that

is suitable for asthma. So the LABAs, the

long-acting beta agonists, have provided documented

improvement in symptoms, airway function and

quality of life and you have heard a great deal

about that today. For whatever reason, since the

introduction of long-acting beta agonists,

controllers and a national effort in education and

guidelines, asthma hospitalizations and mortality

have decreased, which is very reassuring at least

to me and I think to many others. Long-acting beta

agonists in conjunction with inhaled steroids

represent a medication category critical for

optimal care of patients with moderate to severe

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asthma. Thank you very much.

Questions by the Committee

DR. SWENSON: The time now is open for

questions to Novartis. Dr. Schatz?

DR. SCHATZ: Some of the things we are

hearing suggest a possible disconnect between

exacerbations, as has been studied and defined

usually to include oral steroids and emergency

departments or hospitalizations, and then death or

near death. So, I guess my question has to do with

2307. How were SAEs defined? However, were

asthma-related SAEs defined?

DR. FLOYD: Dr. Geba?

DR. GEBA: To answer this question I would

like to bring up a slide that gives the definition

of asthma-related and the definition of serious.

We used predefined asthma terms, MedDRA

terms, MedDRA preferred terms. Asthma-related AEs

were defined as asthma, dyspnea, bronchospasm and

chest discomfort, cough, wheezing, etc., acute

respiratory failure and hypoxia. For the

definition of SAEs it was one of the above plus one

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of the following, death, life-threatening

hospitalization, disability, congenital

abnormalities--this is regulatory definition, and

required intervention to prevent further

impairment--standard definition.

DR. SCHATZ: Just to follow-up,

intervention could mean oral corticosteroids?

DR. GEBA: Yes, it could be. It could be