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