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
2
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
3
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
4
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
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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
6
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,
7
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
8
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
9
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
10
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;
11
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
12
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
13
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.
14
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
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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
16
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.
17
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
18
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
19
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?
20
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
21
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
22
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
23
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
24
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,
25
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
26
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
27
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
28
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
29
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
1
and FEV
1/FEC ratio. Clearly,
it has been
30
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
31
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
32
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
33
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
34
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
35
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
36
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
37
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
38
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
39
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
40
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
41
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
42
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
43
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
44
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
45
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
46
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
47
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
48
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.
49
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
50
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
51
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.
52
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
53
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
54
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
55
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
56
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
57
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
1,
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.
58
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
59
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
1,
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
60
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
61
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
62
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
63
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.
64
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
65
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.
66
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
67
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
68
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
69
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,
70
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
71
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.
72
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
73
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
74
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
75
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
76
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.
77
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
78
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?
79
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.
80
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
81
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.
82
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
83
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
84
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