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
aerosol formulation, which contained
chlorofluorocarbons, has been
discontinued by GSK
as part of the phase-out of
CFC-containing products
consistent with the Montreal protocol.
Worldwide approvals by
regulatory
authorities have led to a great deal of
clinical
experience with salmeterol. Over the last 15 years
the exposure to salmeterol is the result
of the use
of salmeterol formulated as a single
agent and the
85
use of salmeterol formulated with
fluticasone
propionate in a single device. In total the
worldwide exposure is now estimated at
45.2 million
patient-years.
Based on extensive clinical
experience and
a systematic review of numerous clinical
trials,
evidence-based guidelines from the
National Heart,
Lung and Blood Institute's expert panel
report
recognize the pivotal role of
long-acting beta
agonists in the treatment of
asthma. While the
safety of long-acting beta
2 agonists is the
topic
of today's meeting, it is important to
consider the
safety of these medications in the
context of their
overall benefit/risk profile. Part of the context
is provided by current asthma treatment
guidelines
which position the use of inhaled
long-acting beta
agonists with inhaled corticosteroids as
the
preferred treatment option for patients
with
moderate to severe persistent asthma.
Asthma is a serious disease
with
significant morbidity and mortality and
salmeterol
has become a well-established pharmacological
86
therapy in the management of this
disease. As you
know, no medication is without risk and
today's
meeting provides an important
opportunity to review
safety data for inhaled long-acting beta
agonists.
We look forward to discussing the safety
of
salmeterol with the committee.
Salmeterol has been shown to
be highly
effective in the treatment of asthma and,
since its
approval 15 years ago, clinicians have
accrued
considerable experience with its
use. Based on the
extensive body of evidence in patients
with asthma,
including 64 studies in approximately
45,000
patients in the U.S. alone, GSK believes
that
salmeterol continues to exhibit a
favorable benefit
to risk profile.
Dr. Kate Knobil will now
provide a brief
overview of the efficacy of salmeterol,
followed by
a discussion of safety data. Following Dr.
Knobil's presentation, I will return to
the podium
to introduce the experts here with us
today and
then we will take questions from the
committee.
Salmeterol Review
87
DR. KNOBIL: Good morning, everyone. For
my presentation today I will first
present a brief
overview of the benefits of salmeterol
for the
treatment of asthma, followed by a
review of the
salmeterol safety data. My review of the safety
data will focus on the postmarketing
safety
surveillance studies, SNS and SMART, and
the
results from epidemiology studies of salmeterol.
In addition, I will describe the ongoing
studies
currently being conducted by GSK to
further
evaluate the efficacy and safety of
salmeterol.
Finally, I will close with an overall
assessment of
salmeterol for the treatment of patients
with
asthma.
Given time limitations, I will not be able
to cover all of the information that is
in your
briefing document. However, any questions you may
have may be addressed during the
Q&A.
For several decades beta
agonists have
been widely used to treat
bronchoconstriction.
This slide shows the structures of
albuterol and
salmeterol, and you have seen these
already today,
and highlights the long lipophilic tail
that helps
88
anchor salmeterol in the beta adrenergic
receptor.
Albuterol is highly selective for
beta
2
receptor,
thus having fewer cardiovascular effects
than
earlier less selective beta
agonists. Short-acting
beta agonists are very effective but are
limited by
their relatively short duration of
action of 4-6
hours.
This limitation was largely
overcome by
the development of selective long-acting
beta
2
agonists, such as salmeterol, which are
effective
for at least 12 hours. In addition to having a
longer duration of action, in vitro
studies have
shown salmeterol to be at least 50 times
more
selective for the airway beta
2 receptor
than
albuterol.
The benefit of the longer
duration of
action of salmeterol can be seen in the
data pooled
from the two registration studies for
salmeterol
metered dose inhaler. At the time that these
studies were conducted regular albuterol
use was a
common treatment for asthma and so was
included as
an active comparator. For salmeterol, shown in
89
green, a single dose results in a
clinically
significant improvement in FEV
1 within 30 minutes,
with maintenance of effect for at least
12 hours.
This is in contrast to albuterol, shown
in grey,
which has a more rapid onset of effect
but the
bronchodilator effect lasts only 4-6
hours.
Additionally, as shown on the right, the
bronchodilator effect of salmeterol was
maintained
after 12 weeks of treatment with no
diminution of
FEV 1 response
over time.
Studies of up to one year in
duration have
confirmed that the bronchodilator
properties of
salmeterol are maintained with long-term
use. In
this study, 12-hour FEV
1 area under the curve, or
AUC, was obtained after the first dose
and
following 8, 20 and 48 weeks of
treatment. For
salmeterol the mean FEV
1 AUC was similar at all
time points, and in all cases was
significantly
greater than placebo, demonstrating
maintenance of
bronchodilator effect. In addition to important
bronchodilator effects, salmeterol is
very
effectiveness at reducing the symptoms
of asthma.
90
The data shown here are from the same
two studies
for salmeterol MDI that I showed
previously. Over
12 weeks treatment with salmeterol resulted
in a
significant reduction in asthma symptoms
scores for
chest tightness, shortness of breath,
wheezing and
cough compared with placebo and
albuterol given 4
times daily. Although not shown here, in these and
other studies salmeterol also reduced
nocturnal
symptoms associated with asthma.
Salmeterol has also been shown
to be an
important treatment option for patients
with asthma
who are not adequately controlled on
inhaled
corticosteroids. This landmark study by Greening
and colleagues examined the effect of
adding
salmeterol to inhaled corticosteroid
therapy, in
this case beclomethasone, as compared to
increasing
the dose of inhaled steroids. The addition of
salmeterol to a low dose of inhaled
corticosteroid
was shown to result in a greater
improvement in
lung function, as shown by peak
expiratory flow,
then when compared to the higher dose of
inhaled
steroids. In addition to the improvements in lung
91
function, the use of salmeterol resulted
in greater
improvements in symptoms and rescue
albuterol use.
The addition of salmeterol to a
low to
medium dose of inhaled steroid has also
been shown
to reduce the recurrence of asthma
exacerbations.
Shown here again is the study by Matz
and
colleagues, and was of similar design to
the study
that I showed previously. When compared to
increasing the dose of fluticasone
propionate, or
FP, the addition of salmeterol to the
low dose of
FP significantly increased the time to
the first
asthma exacerbation requiring oral
corticosteroids.
Further, significantly fewer
salmeterol-treated
patients experienced one or more
exacerbations, 8.8
percent compared to the increased dose
of FP at
13.8 percent of patients.
Another means of evaluating
the patient
benefit of a medication is to assess the
impact on
quality of life. In this 12-week study that was
designed to assess asthma-specific
quality of life,
patients with asthma were randomized to
either
salmeterol or placebo, with all patients
receiving
92
albuterol as needed to use for symptoms.
Salmeterol MDI was shown to significantly
improve
quality of life compared with placebo,
and the
minimally clinically important
difference of 0.5
was achieved for each domain as well as
the global
score.
To summarize, the benefits of
salmeterol
have been well established and
salmeterol has been
accepted as having an integral role in
the
treatment of asthma.
I will now move on to the
safety portion
of the presentation, beginning first
with the
postmarketing surveillance studies for
salmeterol.
These studies are of interest because at
the time
of launch of salmeterol in both the U.K.
and in the
U.S. there was concern that the regular
use of beta
agonists may lead to deterioration of
asthma
control.
This was based primarily on studies of
short-acting beta agonists, particularly
fenoterol,
that suggested worsening of asthma with
scheduled
use.
These studies could not determine a cause and
effect relationship, however, they did
bring
93
significant attention to the appropriate
use of
this class of medications.
The first study that I will
discuss is the
Serevent Nationwide Surveillance Study,
or SNS,
which was performed in the U.K. between
1990 and
1992.
This 16-week randomized, double-blind study
evaluated over 25,000 patients with
moderate to
severe asthma. The study compared salmeterol MDI
to albuterol given 4 times daily in
patients 12
years of age and older. Both treatments were added
to the patient's current asthma therapy.
At visit 1 patients were
randomized in a
2:1 fashion to either salmeterol or
albuterol. The
primary endpoint for SNS was combined
serious
adverse events and all medical and
non-medical
withdrawals. This very broad endpoint was not
restricted to respiratory events. For this
endpoint the percentage of events was
similar for
the salmeterol and albuterol
groups. Additional
endpoints of interest included
asthma-related
deaths, hospitalizations and withdrawals. Based on
national health statistics in the U.K.
and on the
94
2:1 randomization, 10 and 5
asthma-related deaths
were predicted in the salmeterol group and
albuterol group respectively.
In this study, 14
asthma-related deaths
occurred, with 12 in the salmeterol
group and 2 in
the albuterol group, resulting in a
relative risk
of 3.
This difference was not statistically
significant but did raise concern. The results for
asthma-related deaths were not
consistent with the
data for asthma-related
hospitalizations. As you
can see here, the data for this endpoint
did not
indicate an increase in risk with
salmeterol. The
only statistically significant
difference between
the groups was seen for the percentage
of
withdrawals due to worsening asthma,
with a lower
percent observed in the salmeterol group
compared
with albuterol.
In light of the results of
SNS, including
the asthma-related deaths and
spontaneous reports,
GSK, in conjunction with the FDA,
designed the
Salmeterol Multicenter Asthma Research
Trial, or
SMART.
The study was initiated in 1996.
SMART was
95
a randomized, double-blind surveillance
study of 28
weeks duration that was conducted at
over 6,000
sites in the United States. Patients with asthma
who were 12 years of age or older, with
no previous
use of inhaled long-acting beta
agonists, were
included. All other asthma medications were
allowed during the study.
SMART consisted of a single
clinic visit
at which patients were assessed for
eligibility and
then randomized to receive either
salmeterol or
placebo which was added to their usual
asthma care.
Subjects were given a 28-week supply of
study
medication and were not required to
return for
clinic visits. Instead, patients were contacted
every 4 weeks by phone primarily to
collect
information on serious adverse events, including
respiratory-related events.
The combined endpoint of
respiratory-related deaths or
life-threatening
experiences was chosen as the primary
endpoint.
Asthma-related death was also of
interest but
because this is a rare event the sample
size
96
required for this to be the primary
endpoint was
too large to be feasible. Even with the broader
combined endpoint, it was determined
that a sample
size of 30,000 patients would be
required.
However, after 15,000 patients were
enrolled in the
study the actual rate of primary events
was found
to be approximately half of what was
expected and
the target sample size was increased to
60,000
patients.
Key secondary endpoints were
respiratory-related deaths, combined
asthma-related
deaths or life-threatening experiences,
and
asthma-related deaths, all of which were
subsets of
the primary endpoint.
Two independent review
committees were
involved with SMART. They were the mortality and
morbidity review committee, or MMRC, and
the data
safety monitoring board, or DSMB. Each serious
adverse event was adjudicated in a
blinded fashion
by the MMRC to determine if it was
respiratory
related and, if so, whether it was
asthma related.
The categories for this adjudication
were
97
unrelated, unlikely related, possibly
related or
almost certainly related. Only respiratory- and
asthma-related events considered
possibly related
or almost certainly related comprised
the primary
and secondary endpoints. The DSMB met regularly to
evaluate blinded aggregate data which
included the
cases adjudicated by the MMRC.
An interim analysis was
planned when
approximately one-half of the patients
had been
enrolled. At the interim analysis the study did
not reach predetermined stopping
criteria, however,
there was a suggestion of worse outcomes
in
salmeterol-treated patients, especially
African
Americans. For this reason, the DSMB recommended
that ideally the study should be
completed within 2
years or, if that was not possible, the
study
should be terminated and the results
disseminated.
Following discussions with the DSMB, GSK
made the
decision to stop the study due to
difficulties in
enrollment and the findings in African
Americans.
I will now move on to the
results of
SMART.
Overall, the baseline characteristics of
98
age, sex, ethnic origin and baseline
peak
expiratory flow were well matched
between the
treatment groups. Approximately 70 percent of the
population was Caucasian and 18 percent
was African
American. For reference, approximately 15 percent
of the patients with asthma in the
United States
are African American.
Asthma medications were
reported at
baseline and were similar between the
treatment
groups.
The most commonly reported asthma
medications were inhaled or oral beta
agonists
which were reported in over 90 percent
of patients.
Forty-seven of the patients reported use
of inhaled
corticosteroids at baseline.
While baseline characteristics
were
similar between the treatments for the
total
population, this was not the case when
comparing
baseline characteristics between
Caucasians and
African Americans. The baseline characteristics
indicate that African Americans had more
severe
asthma as measured by peak expiratory
flow,
nocturnal symptoms, and history of
hospitalizations
99
and intubations. For example, the proportion of
African Americans reporting a
hospitalization for
asthma during the previous 12 months was
more than
twice the percentage reported for
intubation for
asthma in their lifetime. In addition to these
markers of increased severity in African
Americans,
the reported use of an ICS at baseline
was lower
than that in Caucasians.
The results for the primary
and key
secondary endpoints will be shown on
this slide.
Due to the amount of information, I will
take a few
moments to summarize the data. These figures are
also available in your briefing document
for
reference.
First let me orient you to the
slide. The
relative risk point estimate and
corresponding 95
percent confidence intervals for the
primary and
secondary endpoints will be displayed
graphically.
The values that correspond with these
data will be
shown on the right side of the
slide. The total
population will be represented in
yellow, the
Caucasian subgroup in green, and the African
100
American subgroup in orange.
I will start by showing the
results for
the total population as this was the
primary
analysis. Then I will show the results for
Caucasians and African Americans as this
post hoc
analysis was requested by the DSMB at
the time of
the interim analysis.
The number of primary events,
combined
respiratory-related death or
life-threatening
experiences, was approximately
two-thirds of what
was expected. The primary endpoint for the total
population, as shown here on the slide,
was not
statistically significantly different
between
treatment groups as the confidence interval
includes 1. As I review the key secondary
endpoints for the total population,
which are
respiratory-related deaths, combined
asthma-related
deaths or life-threatening experiences
and
asthma-related deaths, it is important
to remember
that each is a subset of the primary
endpoint.
For the secondary endpoints,
statistically
significant differences were observed
between
101
treatment groups for the total
population,
including asthma-related death which I
will discuss
in more detail in a moment. The numbers of primary
events in the Caucasian subgroup, shown
in green,
were similar between the treatment
groups.
However, in the African American
population, shown
here in orange, a significantly greater
number of
primary events occurred in the
salmeterol treatment
group.
For the key secondary
endpoints the
relative risk of events was higher in
African
Americans compared with Caucasians. In particular,
a significantly greater number of
combined
asthma-related deaths or
life-threatening
experiences occurred in the salmeterol
group in the
African American population, while there
was no
difference between treatment groups in
the
Caucasian population.
The number of asthma deaths in
SMART was
approximately half of what was
expected. There was
a significantly higher number of
asthma-related
deaths seen in the overall population
for patients
102
receiving salmeterol compared with
placebo and the
same pattern was seen in the ethnic
subgroups.
While the relative risk of asthma deaths
appears
similar between ethnic groups, note that
there were
approximately 4 times as many Caucasians
in this
study than African Americans. Therefore, the rates
for all asthma-related endpoints were
much higher
in the African American population.
The effect of inhaled
corticosteroids was
also of particular interest to the DSMB
at the time
of the interim analysis. A post hoc analysis was
conducted to explore the association of
baseline
use of ICS with the primary and key
secondary
outcomes. As I mentioned previously, 47 percent of
the patients reported using inhaled
steroids at
baseline. The results for the total population are
shown here, again in yellow, for
reference.
Results for subjects reporting inhaled
corticosteroid use at baseline will be
shown in
blue, and those not reporting ICS use at
baseline
will be shown in white.
For subjects reporting ICSs at
baseline
103
there were not statistically significant
differences between the treatment groups
for the
primary and secondary outcomes. Patients receiving
salmeterol who did not report the use of
inhaled
corticosteroids at baseline, here in
white,
experienced significantly more combined
asthma-related events than those
receiving placebo.
The number of deaths in those patients
not
reporting inhaled corticosteroid use at
baseline
was 9 in the salmeterol group versus zero
in the
placebo group so direct calculation of
relative
risk cannot be performed. In the patients
reporting corticosteroid use at baseline
the
numbers were 4 and 3 respectively.
Although SMART was not
designed to assess
the effects on inhaled corticosteroid
use, these
data suggests that ICS may have had a
beneficial
effect on asthma outcomes in SMART.
Finally, the data were
analyzed by both
ethnicity and inhaled corticosteroid use
reported
at baseline. Caucasians are shown, again, in green
and African Americans in orange. Patients
104
receiving inhaled corticosteroids are
represented
by solid lines while dotted lines
represent
patients not reporting inhaled
corticosteroid use
at baseline. The relative risk for the primary
endpoint was higher in African Americans
than
Caucasians, and those not reporting
inhaled
corticosteroids at baseline had higher
relative
risks within those populations.
Similar to the primary
endpoint, the
relative risk for combined
asthma-related events
was higher in the groups that did not
report
inhaled corticosteroids at baseline
independent of
ethnicity.
If we focus specifically on
the number of
asthma-related deaths, shown here at the
bottom of
the slide, it is evident that these
events were
rare.
There were more asthma-related deaths in
patients receiving salmeterol who did
not report
ICS use at baseline in both Caucasians
and African
Americans.
Again, direct calculation of relative
risk cannot be performed for
asthma-related deaths
for patients not reporting inhaled
corticosteroids
105
at baseline since there were no deaths
in the
placebo group for this endpoint.
SMART was not designed to
determine the
effect of inhaled corticosteroids and
ethnicity on
these endpoints, and the number of
events in each
subgroup is quite small. Therefore, these data
should be interpreted carefully.
In summary, there were more
events,
including asthma-related deaths,
reported in the
patients receiving salmeterol. There was also a
suggestion that both African Americans
and patients
who did not report using inhaled
corticosteroids at
baseline had a higher risk of
asthma-related
events.
However, the number of events in SMART was
lower than expected, preventing
definitive
conclusions from the data.
A careful review of the data
did not
reveal any clear explanation of the
results.
Possible explanations include a direct
pharmacologic effect of salmeterol; the
presence of
polymorphisms in the beta receptor gene;
or
patient-related factors, including a
delay in
106
seeking medical care. It is well accepted that the
prevalence of patient-related risk
factors is not
equally distributed across ethnic groups
so the
differences in outcomes seen between the
ethnic
groups in SMART may be associated with
disparities
in access to medical care and asthma
management and
may not reflect biological differences
between the
groups.
Unfortunately, none of these hypotheses
can be confirmed or refuted by the data
from SMART.
While there are no clear explanations
for the data,
the findings were communicated to
physicians to
allow for informed treatment decisions.
In collaboration with the FDA,
a number of
activities were undertaken to
communicate the
results in order to inform physicians
about SMART.
On the day the study was stopped a
"dear healthcare
professional letter" was delivered
by overnight
mail to the 229,000 healthcare
professionals in the
United States who had prescribed
salmeterol or
salmeterol-containing products within
the previous
year.
Simultaneously, notices on both the FDA and
GSK web sites were posted.
107
A second letter was sent out to health
professionals when the prescribing
information for
Serevent and Advair was changed to
include the
preliminary results of the interim
analysis of
SMART.
The information was elevated to the highest
level of prominence in the form of a
boxed warning.
When the final results were obtained the
labeling
for both products was updated.
This is the boxed warning that
was added
to the prescribing information for
Serevent and
Advair.
It describes the final results of the
interim analysis of SMART. For your reference, the
full label, including the boxed warning,
is
available in your briefing package.
The results of the interim analysis were
presented at the American College of
Chest
Physicians meeting as a late-breaking
abstract.
This was the first available national
meeting with
high attendance of respiratory physicians. The
manuscript is now in press at Chest, the
journal of
the American College of Chest
Physicians.
Epidemiology studies offer an
additional
108
method to investigate associations between
drug
exposure and serious outcomes. The major advantage
of these studies is the utilization of
comprehensive medical and pharmacy
databases.
These databases allow identification of
a greater
number of events than can be achieved in
traditional randomized clinical
trials. The
primary limitation of observational
studies is the
fact that assignment of treatment is not
random and
treatment effects may be confounded by
differences
in baseline characteristics, including
co-morbid
disease, differences in asthma severity
and
selective prescribing. Since many more events can
be evaluated in an observational design,
this may
be a more informative way to assess
treatment
effects on the rare endpoint of
asthma-related
death.
This figure displays the
relative risks
from all large published cohort and
case-control
studies that evaluated whether salmeterol use
was
associated with the occurrence of severe
respiratory and asthma-related
outcomes. The
109
dotted line represents a relative risk
of 1.
The first study determine the
relative
risk of respiratory-related death among
patients
with asthma receiving salmeterol
compared with
those receiving theophylline on the left
side of
the highlighted area, or those receiving
ipratropium, which is on the right side
of the
highlighted area.
The second study, which was
conducted in
the United States, evaluated three
endpoints,
asthma-related emergency room visits,
hospitalizations and ICU admissions,
comparing
salmeterol with theophylline recipients.
The last two were separate
case-control
studies that evaluated the relative risk
of
asthma-related ICU admission or
asthma-related
death associated with salmeterol use
relative to no
use.
This last and most recent
study, shown
here on the far right, included 532
pairs of asthma
deaths and matched controls and is the
largest
case-controlled study evaluating
asthma-related
110
death ever conducted. Notably, none of these
studies showed a significant increase in
the
relative risk of these serious outcomes
for
salmeterol.
GSK is committed to a
comprehensive
research plan to further evaluate the
safety and
efficacy of salmeterol. We believe that these
currently ongoing studies will provide
valuable
information regarding the safety and
efficacy of
salmeterol in patients with either
asthma or COPD.
In order to address some of the issues
raised by
SMART, two studies are under way.
The first is a year long
clinical study
evaluating the incidence of asthma
exacerbations in
460 African American subjects. Results are
expected in 2007. The second is an epidemiology
study utilizing data from 7 Medicaid
plans to
examine racial variation and association
of
asthma-related prescription medication
use with
asthma morbidity and mortality. The results are
expected in 2006.
Studies have suggested that
response to
111
short-acting beta agonists may be
affected by
genetic polymorphisms in the beta
2 receptor.
However, there is one study that has
suggested
there is no similar association with
salmeterol and
clinical outcomes including
exacerbations. This
was the Taylor study that Dr. Sorkness
showed
earlier.
Since there were no genetic samples
collected in SMART we are conducting two
studies to
address whether clinical outcomes in
patients
receiving salmeterol are affected by
genotype.
The first study is a 38-week
clinical
trial evaluating response by beta
2
receptor
genotype in 540 subjects with
asthma. The results
are expected in 2007. The second study will
evaluate polymorphisms in beta
2
adrenergic
glucocorticoid pathways with respect to
clinical
response in approximately 1,000 subjects
from
completed GSK clinical trials.
Finally, while asthma has been
the focus
of today's discussion, there are ongoing
studies in
patients with COPD that will help
address whether
the results of SMART are relevant for
patients with
112
COPD.
The first is a 3-year study of all-cause
mortality in approximately 6,200
subjects with
COPD.
Results from this study are expected in
2006.
In addition, we are conducting 2 year-long
replicate studies examining the rate of
moderate to
severe COPD exacerbations, with results
expected in
2007.
Asthma is a serious chronic
disease with
significant morbidity and mortality. Salmeterol is
one of the most thoroughly studied
medications for
asthma and has been shown to provide
substantial
therapeutic benefit, including
improvements in lung
function, and asthma-related quality of
life, and
reduction in symptoms, rescue medication
and asthma
exacerbations.
The extensive clinical trials
have led
evidence-based asthma treatment
guidelines to
recommend long-acting beta agonists with
ICS as the
preferred option for patients with
moderate,
persistent asthma. There are conflicting data for
salmeterol. SMART and SNS suggest that salmeterol
may be associated with an increased risk
of rare
113
serious asthma-related events including
asthma-related death. But when large cohorts of
patients are evaluated in epidemiology
studies this
association is not observed. The low number of
serious asthma events in SNS and SMART
does not
allow for definitive conclusions, and
the fact that
the events of concern are also those
that are
experienced by patients with asthma, regardless
of
treatment, makes assessment of cause and
effect
relationships difficult.
Ultimately, what are the
implications of
the data for patients with asthma? Well, specific
treatment decisions for an individual
patient can
only be made by their physician. It is our
responsibility to provide the complete
information
so that the physician can make
well-informed
treatment decisions. We have done this in the
prescribing information for products
containing
salmeterol.
From the time that salmeterol
was
introduced in the United States in 1994
the
prescribing information has provided
specific and
114
appropriate guidance on its use. This includes
that salmeterol should not be used to
treat acute
symptoms. It is not a substitute for inhaled or
oral corticosteroids, and consideration should
be
given to adding anti-inflammatory
agents, for
example corticosteroids.
In 1995 further information
was added,
including a warning that salmeterol
should not be
initiated in patients with significantly
worsening
or acutely deteriorating asthma. As I have already
mentioned, detailed information on the
rare
asthma-related events seen in SNS and
SMART had
been incorporated in the prescribing
information so
that informed treatment decisions can be
made.
This includes the boxed warning, as well
as other
language to address the inconclusive
nature of the
results and the potential for a class
effect of
inhaled long-acting beta agonists.
In conclusion and based on the
weight of
evidence, we firmly believe that
salmeterol remains
a valuable medication that has improved
the level
of care for patients with asthma and
COPD.
115
Additionally, GSK is committed to
further research
that will not only help better
characterize the
efficacy and safety of salmeterol but
will also
help better understand asthma in
general. There is
a large volume of data from clinical
trials of
salmeterol, as well as extensive
clinical
experience with this medication. Taken together,
these continue to support a favorable
benefit to
risk profile and, therefore, salmeterol
should
remain available to physicians and
patients.
I thank you for your time and
I will now
turn the podium back over to Dr. Jones.
Closing Remarks
DR. JONES: I would like to introduce
three additional experts here with us
today. Prof.
Richard Beasley is the director of the
Medical
Research Institute of New Zealand. He is also an
international expert on beta agonist
safety and
asthma epidemiology. Dr. Eugene Bleecker is
professor and section head, Pulmonary,
Critical
Care, Allergy and Immunologic Diseases
at Wake
forest University Health Sciences. Dr. Bleecker is
116
also the co-director of the Center for
Human
Genomics, and was a member of the MMRC
for SMART.
Finally, Dr. George O'Connor is
professor of
medicine in the Division of Pulmonary
and Critical
Care Medicine at Boston University
School of
Medicine, and is director of the Adult
Asthma
program at Boston Medical Center. In addition, he
was the chairman of the DSMB for SMART.
We would be happy to address
any points of
clarification and questions. Thank you.
Questions by the
Committee
DR. SWENSON: Dr. Schatz?
DR. SCHATZ: I think one possible
hypothesis based on the SNS study, where
there was
increased withdrawal due to asthma in
the placebo
patients, is the possibility that there
ended up
being an imbalance in severity by the
end of the
study due to disproportionate withdrawal
of more
severe patients from the placebo
group. That is
obviously not so easy to tease out but I
would
question whether, in fact, one looked at
baseline
severity in those who withdrew versus
those who
117
didn't in both groups but particularly
in the
placebo group.
DR. KNOBIL: For SNS we don't have that
cut of the data to provide for you, but
it would
probably make a lot of sense that the
patients who
withdrew were more severe.
DR. SCHATZ: But for SMART data--
DR. KNOBIL: Oh, for SMART we saw the same
thing in that there was greater
withdrawal in the
placebo group than in the salmeterol
group but,
again, we don't have that cut of the
data for you
today.
DR. SWENSON: Dr. Gardner?
DR. GARDNER: I have two questions, one
related to measures of adherence within
or between
the groups and whether anything has been
done with
that.
The second is would you give us the status
of the ongoing studies at this
time? You have
listed four with expected results. Can you tell us
the enrollment at this time; how far
along you are?
I understand the word
"commitment" but can we see
something about progress at this time
and status?
118
DR. KNOBIL: All of the studies that I
mentioned to you are right now currently
enrolling.
As you might imagine, enrolling limited
populations
of only African Americans takes a little
bit longer
than general populations. As well, in the genetic
studies we are making sure that we have
balanced
groups with the different
genotypes. So, that does
take some time. So, what I can tell you is that
they are enrolling but I can't tell you
when they
will be done enrolling.
DR. GARDNER: And adherence?
DR. KNOBIL: Oh, I am sorry. During the
monthly telephone contacts we did ask
the
question--if you could show the slide,
please? On
a scale of 0-10, with zero meaning you
missed all
of your doses and 10 means you took all
of your
doses, what number represents how well
you followed
the study physician's instructions? In the study
the mean response, patient reported
response was 8
for each group. Again, this is patient reported
and patients did not return to the
clinic so we
cannot verify this. We did not ask them to bring
119
their cans in. We did not weigh canisters and we
didn't have a chronolog. But I think from studies
of chronolog, we know that patients
sometimes
report taking more medication than they
actually
do.
So, I can't really verify the actual
compliance of the patients.
DR. GARDNER: As far as you can tell, was
there similar adherence between the
African
American subjects and the Caucasian
subjects?
DR. KNOBIL: Yes, as far as can tell there
was no difference between any specific
group.
DR. GARDNER: Finally, on the Medicaid
study, that doesn't require
enrollment. Can you
tell me where that is being done and how
far along
that one is?
DR. KNOBIL: Yes, that one is being done
in seven states. What we are doing right now is
the first phase of the study, which is
to see if we
can identify enough patients with high
enough
proportion of African Americans to make
an analysis
feasible. So, that is where that study is right
now.
120
DR. SWENSON: Dr. Moss?
DR. MOSS: I have two separate questions.
The first one has to do with the
dissemination of
the information in your letters and the
labeling
revisions. I think the goal of this meeting is to
disseminate information properly to the
physicians
and the community. The question I have is when you
sent out those letters and put on the
box labels,
do you know if that changed the
prescription
practices for the physicians that
received those
letters or for the general community in
terms of
the prescription of your medication?
DR. KNOBIL: I don't know if that
information changed the way physicians
prescribe
the medications. We don't have any specific data
to that effect.
DR. MOSS: Did overall use of your
compound decline after those letters
were sent out?
DR. KNOBIL: The rate of use did not
change after those letters were sent
out. But, you
know, we can't guess what would have
happened; all
we saw was no change.
121
DR. MOSS: You saw no change. I think
that raises a concern about, you know,
we are
trying to disseminate information and
are we doing
that in the proper way?
The next question I have may
be answered
by you but might also be answered by
either Dr.
Bleecker or O'Connor. I think it is really hard to
figure out why someone died. Taking care of people
I see this. It is really hard to define
specifically what a cause of death
is. I was just
wondering if you can give us some
insight into how
you define respiratory versus asthma
deaths in the
SMART study.
DR. KNOBIL: Dr. Bleecker, would you like
to address that?
DR. WEAN: While Dr. Bleecker is coming
up, I want to get back to the earlier
question you
raised.
I am David WEAN, Senior Vice President of
Regulatory Affairs at
GlaxoSmithKline. I don't
think it appropriate to say that because
we can't
posit a change in prescribing habits
because of the
letters and the label that they were not
effective.
122
The important thing is that the
information was
disseminated in a very large way to prescribers
and, thereby, to patients. To expect that you
would see a drop-off in use of these
drugs that
have therapeutic benefit because of that
communication I think would be an
inappropriate
assessment about the effectiveness of
that
communication.
DR. MOSS: But I think one thing we have
learned is that publishing articles and
papers does
not get information out to the people
that need the
information to be received. In the same way, I am
not sure that sending letters out to
physicians who
get a lot of mail is an effective way of
communicating information.
DR. SWENSON: Dr. Bleecker?
DR. BLEECKER: I was asked to talk a
little bit, and George O'Connor could
complement on
how the mortality review committee in
SMART
adjudicated cases. I agree, it is often very
difficult, and as we did this we
probably all
learned.
I joined the mortality review committee
123
after about a third of the cases had
been done.
The members of the committee before that
had been
Roland Ingrham who was professor of
medicine at
Emory.
He had retired. The chairman of
the
committee was Hal Nelson who is a
professor of
medicine at Colorado, and the third
member was
Scott Weiss who is professor at Brigham
and
Williams and also head of their
pulmonary and
respiratory epidemiology program.
We had data on most patients
available
both from death certificates and from
the medical
monitors who worked with Covance. We used that to
answer questions which were related to the
cause of
death; was this respiratory related; and
you heard
before the likelihood or unlikelihood of
that
during Kate Knobil's presentation; and
then was it
asthma related. All three of us adjudicated this
independently. If we agreed on all of these
characteristics the case was not
discussed further.
All of the cases in which there was any
disagreement, ranging even between
"unrelated" and
"unlikely" were discussed in detail
in timely
124
conference calls. I think at times we did the best
we could on relating to that.
The least amount of information
was
available on deaths toward the end of
the study
that were picked up from the national
death
registry. On those deaths we had to rely on death
certificates or more limited
information.
DR. MOSS: Can I just follow-up on that?
Can you explain a little bit how you
differentiate
asthma from respiratory deaths? A respiratory
death that is not asthma, is that
pneumonia? What
were criteria to differentiate those
specific
things?
DR. BLEECKER: Well, often asthma entered
into those deaths. Let me give you an example of
respiratory death. Because someone during an auto
accident had trauma to the chest--and
this did
occur in some of the younger
individuals--and died,
and that clearly was related to an
automobile
accident and because of the nature of
the event and
other things was not related to
asthma. It was
more difficult if someone entered the
hospital with
125
pneumonia, was intubated and in an
intensive care
unit.
I think under those circumstances, some of
those deaths were adjudicated depending
on the
course on the ventilator or those
serious events as
possibly related to asthma. So, at times it is
very hard to distinguish that from the
records.
Again, I think the fact that they were
performed
independently and you needed to look for
concurrence and discussion, I think a
reasonable
approach was performed.
DR. SWENSON: Dr. Gay?
DR. GAY: Based on the appropriate
emphasis that you have begun to make on
genetic
testing, as we have seen based on the
information
that Dr. Sorkness elegantly presented
before, do
you have any preliminary estimates of
what you feel
would be the prevalence of Arg/Arg gene
presentation in patients with greater
severity of
asthma or based on ethnic differences?
DR. KNOBIL: Yes, I would not be able to
predict the different prevalences of
those genetic
subtypes and I would ask Dr. Bleecker to
comment on
126
that.
The one thing I would add is that in the one
genetic study we are making sure that
there are
equal numbers of each genetic subtype so
that we
don't have a predominance of one and
very few of
another.
Dr. Bleecker?
DR. BLEECKER: I would like to add a few
comments to that because I think there
are some
important aspects of this. First of all, we have
centered on basically one variation
within the
beta2
adrenergic gene. Looking at that
gene more
carefully--and there have been published
studies on
this, especially from the Liggett group
as well as
some work from our laboratory which has
been
presented at last year's ATS and Academy
of Allergy
meetings--there is a good deal more
variation in
that gene, and there are relationships
between the
arginine genotype and some of that other
variation.
Some of that may be very important in
trying to
sort out the hypothesis of whether
variation in
this gene affects therapeutic response
and
potentially affects outcome.
The second important issue is
there is
127
more variation, and African Americans
have a higher
prevalence of the Arg/Arg genotype,
about 22
percent, and that is what was seen
during the
screening for the ACRN BARGE trial
versus about
12-14 percent in Caucasians. The implications of
that on outcome are difficult, and I
think it is
very important that the studies that
were outlined
by Dr. Knobil on studying specifically
an African
American cohort in which they are going
to look at
outcome such as exacerbations and
genotype are
critical because those kinds of studies
are not
being done because of the limitations in
recruitment by the NIH NHLBI asthma clinical
network.
DR. SWENSON: Dr Prussin?
DR. PRUSSIN: I have a similar question
that I raised before with Dr.
Sorkness. You have
some very nice studies that are
undergoing, but do
you think they are going to address the
question at
hand in terms of asthma deaths or severe
pulmonary
endpoints? They are fairly small studies relative
to the SMART study and, when all is said
and done
128
in three or four years, it is not clear
to me at
least that you are going to have any
kind of handle
on asthma death. Could you comment on that?
DR. KNOBIL: Yes, as I mentioned, it is
very difficult to prospectively study
asthma-related death because the rate is
relatively
low and you need a very large N to get
conclusive
results.
The one study that will help us get there
though, I believe, is the Medicaid study
in that we
can get information from the 7 Medicaid
plans and
look at the different racial subgroups,
look and
see what medications they were on and
see what
contributed to those patient's deaths,
whether it
is a long-acting bronchodilator,
short-acting
bronchodilator or some other related
medication.
So, I do believe that in that
observational design
we will be able to get some more
information about
asthma-related death. The other studies are mainly
going to address asthma exacerbations
and other
responses such as lung function, rescue
albuterol
use, and we will be able to look at
those in
relationship to genetic makeup as well.
129
DR. PRUSSIN: The difficulty I have with
that though is that there is a lot of
data showing
that salmeterol improved asthma
exacerbations. You
have shown that. Clearly, the more severe
endpoints of death are tracking
differently. So,
you are thinking of it as the tip of the
iceberg,
that however exacerbations are going to
track
asthma deaths are going to track and clearly they
are behaving differently. So, just because you
have certain data on asthma
exacerbations in
certain subgroups, that may not be
proportional or
relate to asthma. We don't have any prospective
studies ongoing or planned to really
address the
endpoint that I think this committee has
been asked
to address, which is asthma death. So, it could
very well be a different phenomenon than
what is
causing asthma exacerbations.
DR. KNOBIL: That is true, and there are
other factors beyond asthma treatment
that may be
contributing to asthma-related death as
well,
including access to care or how a patient's
asthma
is managed. We don't know the answers to that
130
either.
So, that is why in order to actually even
look at asthma-related death an
observational
design is probably going to provide more
information more quickly.
I take your point that it
seems that a
prospective study would be the gold
standard. The
issue there is that if the rate of
asthma-related
death was similar to what we saw in SMART,
in order
to see an effect you might have to have
a study as
large as 800,000 patients. As you can see, that
would be very difficult to do. So, yes, it would
be nice to be able to do it
prospectively but it is
going to be more difficult than doing it
in an
observational design.
DR. JONES: Actually, I think Dr. Beasley
wanted to make a comment.
DR. BEASLEY: Yes, in response to that I
would like to caution in terms of
considering a
prospective clinical trial as being the
gold
standard when you are looking at a rare
outcome
such as mortality. I think we saw that in the
SMART study, where it was required to
study
131
approaching 30,000 subjects to obtain
around 35
respiratory-related deaths, and there
was a real
compromise in terms of design of the
study to
actually achieve that and individuals
were given 7
canisters at the beginning of the study
without any
formal clinical follow-up, which is
something which
would not be done on label in terms of
salmeterol
therapy. In terms of the other issues of the
label,
many of the subjects had asthma severity
where
salmeterol would be inappropriate as
sole therapy.
So, I think that when you try
a
prospective controlled trial to look at
a rare
outcome such as death you often have to
incorporate
a methodology that clearly is outside
the spectrum
of what is recommended clinical
practice. That
clearly happened with the SMART study so
that we
have to consider the SMART study results
not
applicable to what would be considered
good
clinical practice, and the alternative
is actually
to increase the number of deaths through
case-control methodology and that was
the method we
used in New Zealand to identify the
risks
132
associated with fenoterol.
In that regard, I think that
the Anderson
study in the BMJ is considerably more
powerful in
terms of looking at the role of
bronchodilator
therapy and the rare outcome of asthma
mortality.
They were able to look at over 500
deaths, match
them with subjects who came from the
same
proportion of the population of patients
in terms
of severity, who were subjects with a
previous
hospital admission, and then they were
able to
stratify their analysis by looking at an
even more
severe subgroup. When they did that there was
actually no increased risk associated
with the use
of salmeterol therapy.
So, I think that in terms of
the
epidemiological approach to a rare
outcome of
asthma mortality looking at the role of
medication
use, the epidemiological view is very
clearly that
the case-control methodology is more
powerful and
more accurate than a prospective
clinical trial. I
think in some respects almost the
learning point
from the experience with the SMART study
was the
133
compromise that had to be obtained in
terms of
clinical practice to achieve a study
which, even
with 30,000 people, did not have
sufficient power.
DR. SWENSON: Dr. Schoenfeld?
DR. SCHOENFELD: Do you have a tabulation
for the whole group and for each of
these subgroups
and for each of the endpoints of the absolute risk
or the attributable risk? Because from a
risk/benefit point of view the relative
risk isn't
very informative because, of course, you
can have a
3-fold relative risk of a very, very
rare event and
that may be important if you are judging
something
like an environmental pollutant that you
can remove
but is not really important when you are
judging a
very effective drug which improves
people's quality
of life.
So, I wonder if you have that tabulated.
I have done some back-of-the-envelope
calculations
but it would be helpful to have the
actual numbers
where we looked at the percent of deaths
per
patient-year or number of deaths per
1,000
patient-years, or something of that sort
that would
be attributable, assuming that there is
some
134
attributable risk to the use of the
drug, or even
just the total risk among asthma
patients per 1,000
patient-years or 10,000 patient-years,
or whatever.
DR. KNOBIL: Unfortunately, we don't have
those data. We have not done those calculations.
DR. SWENSON: Dr. Martinez?
DR. MARTINEZ: Would you please clarify
what the entry criteria were for both
studies, the
British one and the one done in the
United States?
How was asthma defined? Were any of the usual
parameters--response to beta
2 agonists or
methacholine used to define asthma in
these two
studies?
DR. KNOBIL: These studies were a little
different than normal clinical trials,
say, to
register a medication for asthma. It was the
opinion of the investigator if the
patient have
asthma.
They did not have to show reversibility.
There was no smoking criterion. In this case they
had to be 12 years of age or older. In SNS they
had to have moderate to severe asthma
and in SMART
they were not allowed to have
concomitant
135
administration of beta blockers. That is about
all.
DR. MARTINEZ: Was response to
bronchodilators measured?
DR. KNOBIL: It was not measured.
DR. SWENSON: Miss Sander?
MS. SANDER: Yes, when we are looking at
possible causes of death, are you able
to know if
patients who died were using salmeterol
as if it
was an acute bronchodilator?
DR. KNOBIL: In SMART the only question we
asked was if the patient was using the
medication
as the physician told them to. That is the data
that I showed you earlier. We do not have any data
on whether they were using it as a
rescue
medication.
DR. SWENSON: I realize that there are
more questions to be posed to GSK but we
need to
take a break at this point. We have a general
question session in the afternoon and
the rest of
these questions should be addressed at that
time.
We will be back again in 15 minutes.
136
[Brief recess]
DR. SWENSON: We will resume the meeting
with Dr. Eric Floyd, from Novartis, to
discuss
formoterol and its place in this
controversy.
Novartis Presentation
Introduction
DR. FLOYD: Good morning.
Dr. Swenson,
members of the FDA advisory committee,
Dr.
Chowdhury, members of the Food and Drug
Administration and guests, my name is
Eric Floyd.
I am Vice President and Global Head of
Drug
Regulatory Affairs for the therapeutic
areas of
dermatology, respiratory and infectious
diseases.
On behalf of Novartis Pharmaceuticals
Corporation,
I thank you for the opportunity to
review the
current safety experience today for a
long-acting
beta agonist, Foradil.
There have been numerous
safety concerns
expressed publicly regarding use of
long-acting
beta agonists. The purpose of our presentation
today is to discuss implications of
recently
available data related to the safety
profile of
137
long-acting beta agonists. This morning Novartis
would like to present to you the results
and
conclusions of our review of available
safety data
for Foradil. Based upon our review of clinical
trial data and postmarketing experience,
we would
like to demonstrate that formoterol
exhibits a
favorable risk/benefit profile.
To provide a brief regulatory
overview,
Foradil was first approved for marketing
in France
in 1990, and subsequently approved in
other
European countries. Foradil received FDA approval
to market in the United States in
2001. Foradil is
currently approved in over 80 countries
worldwide
and to date, we currently have over 13
million
person-years of exposure.
Foradil Aerolizer was marketed
as a dry
powder capsule for oral inhalation and
was approved
in 2001 for a dosage regime of 12 mcg
twice daily
for maintenance therapy for individuals
with asthma
5 years of age and above for the
following
indications, acute prevention of
exercise-induced
bronchospasm in individuals 5 years of age
and
138
older when administered on an occasional
as needed
basis, and for chronic obstructive
pulmonary
disease, including chronic bronchitis
and
emphysema.
Outside of the United States,
Foradil is
approved at 12-24 mcg twice daily and is
a highly
prescribed bronchodilator, and is also
indicated
for the maintenance therapy of asthma
specifically
in adults and children 5 years of age
and older;
for the prophylaxis and treatment of
bronchoconstriction in patients with
asthma;
prophylaxis of bronchospasm induced by
inhaled
allergens, cold air or exercise;
prophylaxis and
treatment of bronchoconstriction in
patients with
reversible or irreversible COPD,
including chronic
bronchitis and emphysema. In some countries it is
also approved as metered dose inhaler
and
multi-dose dry powder inhaler, 10 mcg,
Certihaler.
In order to provide a more
detailed review
of our current data to date, I would
like to
introduce our speakers today. Dr. Gregory Geba,
who is the Vice President and U.S. Head,
139
Respiratory, Dermatology and Infectious
Diseases,
Clinical Development and Medical Affairs
for
Novartis Pharmaceuticals, will present
the safety
profile of Foradil.
He will be followed by Dr. James
Donohue,
who is Professor of Medicine, Chief of
Pulmonary
Division, University of North Carolina,
Chapel
Hill, who will present the clinical
implications.
In addition to the key
speakers, we also
have additional advisors available to
address any
specific questions you may have. Specifically from
a statistical perspective we have Dr.
Gary Koch,
Professor of Biostatistics, School of
Public
Health, University of North Carolina,
Chapel Hill.
I would now like to turn the podium over
to Dr.
Geba.
Efficacy and Safety of
Foradil
DR. GEBA: Thank you, Dr. Floyd. Dr.
Swenson, committee members, members of
the FDA and
interested attendees from the community,
it is my
role to review with you all of the
clinical data
and postmarketing data we have available
for
140
Foradil, the other long-acting beta
agonist being
discussed today. We firmly believe that Foradil is
a drug that provides clinical benefit
with a
favorable benefit/risk profile.
As indicated in the previous
presentation
by Dr. Floyd, and later on in this
presentation by
Dr. Donohue, the clinical features of
Foradil have
led to its inclusion in both U.S. and
international
guidelines in the treatment of moderate
to severe
persistent asthma.
These are the key points of
the
presentation. We will describe pharmacologic
differences that exist between
formoterol and
salmeterol, which may or may not have
clinical
impact; a Phase 4 trial, 2307, which
examined
asthma-related serious adverse events in
adolescents and adults; our integrated
Foradil
clinical database; and postmarketing
adverse event
data.
The totality of the evidence does not
elevate concern for a safety signal for
Foradil
which continues to support its favorable
benefit/risk profile.
141
These are the chemical
structures of
formoterol on top and salmeterol on the
bottom.
Please note that at the end of the
molecule that
interacts with the beta receptor, the
catechol end
of the molecule, the molecules are
actually similar
in
having a hydroxyl group at position 5.
However,
they are different at positions 6 where
you see
different side chains. Most importantly, at
position formoterol has a much longer
allophanic
chain, as previously shown. Thus, although both
molecules bind to the beta
2 receptor, differences
in structure allow salmeterol to bind to
an
additional site within the beta
2 receptor termed
an exosite. Prolonged salmeterol activity depends
on binding with the exosite when
formoterol's
activity is independent of an
exosite. In
addition, mutation of the exosite region
could
affect the duration of action of
salmeterol. One
of the consequences of structural
differences is
that formoterol is a full agonist at the
beta
2
adrenergic receptor, whereas salmeterol
is a
partial agonist.
142
Typical experiments
illustrating this
point are performed with human bronchial
explants
which show that the bronchodilatory
effects of
isoprenaline are decreased by prior
incubation of
tissues with salmeterol but not
formoterol. The
potential clinical implication of this
difference
is that in the setting of beta
2 receptor
down-regulation the effect of rescue
bronchodilators may be greater for full
agonists
than for partial agonists.
I would like to now move on to
a
discussion of the Phase 4 trial
2307. This trial
was recently completed and is detailed
in your
briefing book. Why was this study done? Protocols
040, 041 and 049 were 3 pivotal studies
conducted
to support registration of Foradil in
the United
Sates and 040 and 041 were 12 weeks in
duration and
were conducted in adolescents and adults;
049 was
conducted for one year in children ages
5-12.
Trial participants were
randomized to
receive Foradil 12 mcg BID, 24 mcg BID
or placebo.
In 040 and 041 there was also a
comparison to
143
regular doses of albuterol 180 mcg
QID. Please
note that all groups were allowed to
take
additional doses of albuterol as needed
for
residual symptoms and all groups were allowed
anti-inflammatory agents.
Shown here are the proportion
of patients
with asthma-related serious adverse
events. These
studies showed more serious
asthma-related serious
adverse events in the higher don
formoterol arms
compared to the lower doses or the
approved
formoterol arm as well as the placebo
arm.
In light of these findings,
the agency did
not approve the higher dose of
Foradil. After
discussing this observation with the
agency and
with their guideline, we pursued a
safety study
whose primary endpoint was
asthma-related SAEs.
The inclusion and exclusion criteria for
protocol
2307 were identical to protocols 040 and
041 which
were our pivotal trials. Indeed, the resulting
population studied in protocol 2307 was
similar to
that of the pivotal trials in
adolescents and
adults, which was the population studied
and
144
requested, as shown in this slide.
Apart from the trial duration
which is
different, age differences were pretty
similar.
FEV 1 at
baseline was fairly similar.
Please note
that the proportion of black patients in
this trial
mimicked the proportion of patients in
the U.S.
population. There are some subtle differences in
terms of ICS use and reversibility. Actual
reversibility for 2307 was slightly less
than 040
and 041 but otherwise the study
populations were
very, very similar.
The design of this safety
study is shown
here.
Using identical entry criteria--again, these
are identical entry criteria to those
employed in
our pivotal studies--after a 2-week run
period,
shown here, patients were randomized to
receive, in
a double-blind fashion, one of the
following
treatments, either formoterol 12 mcg BID
formoterol
24 mcg BID--again, 12 mcg BID was the
approved
dose; 24 mcg was the higher dose. They received
either of those two doses or placebo in
another
group or, in an open-label group,
received
145
formoterol 12 mcg BID plus an additional
up to 2
rescue doses of formoterol 12 mcg BID,
which
constituted the intermediate dose arm.
Please note that to increase the rigor of
this study, after 16 weeks of treatment
we planned
to contact all patients, including those
who
discontinued, to record all adverse
events. This
assured that all patients would be
evaluated for
AEs irrespective of treatment efficacy
and trial
persistence.
Results of the study are shown
here.
Please note that there was a correction
made to the
briefing book provided by the
agency. The lower
dose arm had a somewhat higher number of
patients
who reported serious asthma-related
AEs. However,
after review of the specifics of these
cases, the
agency excluded 2 of these events in the
Foradil 12
mcg arm, reducing that number from 5 to
3. Thus,
the final event rates were 0.2 percent
in the
placebo group; 0.6 percent in the low
dose group;
0.2 percent in the intermediate dose
group; and 0.4
percent in the high dose group. Overall, there
146
were far fewer events than expected
based on the
pivotal trials.
Displayed on this slide are
the point
estimates and 95 percent confidence
intervals--which I hope you can see as
red on a
blue background--for the proportion of
patients
experiencing asthma-related SAEs in each
treatment
group.
As previously mentioned, the rates are low
for all treatment groups. The 95 percent
confidence interval for all Foradil
doses combined
overlaps the 95 percent confidence
interval for
placebo and excludes 1 percent. These data reflect
the revised rates after an FDA adjudication.
In conclusion, the observed
rate of
adverse events was far lower than we
expected from
our pivotal trials despite demographics
that were
similar to protocols 040 and 041. Absolute
differences between groups were very
small. Higher
SAE rates in the higher dose of Foradil
arm,
previously observed in adolescents and
adults in
protocols 040 and 041, were not observed
in this
larger, specifically designed safety
study.
147
Now I would like to review
with you a
comprehensive safety analysis of our
clinical trial
database. We performed an extensive review of
safety based on our clinical trial
database which
focused on deaths and asthma-related
adverse
events.
In terms of deaths, we examined all
controlled and uncontrolled trials in
the Aerolizer
and Certihaler databases. All studies irrespective
of trial duration were examined to
assure that the
very rare case of sudden paradoxical
asthma,
culminating in the demise of a patient,
was
captured.
For the analysis of
asthma-related adverse
events we focused on controlled trials
of greater
than or equal to 4 weeks duration so as
not to
dilute the denominator for adverse
events in trials
of longer duration with very short
trials,
sometimes as short as 24 hours, which
were
performed to assess short-term changes
in lung
function.
For controlled trials the
database
included nearly 6,000 patients on
Foradil, shown
148
here; for uncontrolled trials over
2,700. For
trials of 4 weeks or greater in duration
the number
was over 5,000 on Foradil, whereas the
placebo-controlled trial database was
comprised of
over 3,700 patients who had been
randomized to
Foradil.
Looking at our controlled
trials, there
were 3 deaths overall, one death in the
Foradil
group, representing over 1,600
patient-years of
experience; one death in the albuterol
group,
representing 241 patient-years of
experience; and
one death in the placebo group,
representing nearly
600 patient-years of experience. The rates of
death, therefore, was 0.41, 0.17 and
0.06 in the
albuterol, placebo and Foradil arms
respectively.
The Foradil death was asthma related,
shown here,
representing a rate of 0.06 asthma
deaths per 100
patient-years of exposure. So, here we are
expressing it as a rate per years of
exposure to
the drug, which represents less than one
asthma
death per 1,000 years of treatment.
In reviewing the uncontrolled
clinical
149
database, it is important to note that
these
studies were those that did not
incorporate
comparator arms. They were all open-label and
included trials conducted as part of
compassionate
use programs. In addition, patients tended to be
older, with a high proportion of elderly
subjects;
had more severe asthma; used more beta
agonists at
baseline; and exhibited
noon-asthma-related
mortality at a higher rate, indicating a
higher
degree of general medical morbidity
compared to the
control database. There were 5 deaths overall, 3
of which came from one study in France
which
allowed entry of severely ill patients.
Now I would like to move on to
address
significant asthma exacerbations. This term
includes asthma-related adverse events
which were
meaningful enough to prompt patient
discontinuation
whether severe or not and, to get to Dr.
Schatz'
point, included asthma-related adverse
events
reported as serious whether or not they
caused a
discontinuation. So, we are looking at patients
that dropped out of the trial due to an
150
asthma-related event that was meaningful
enough to
stop therapy.
Displayed are the
discontinuation rates
due to an asthma-related adverse event
in multiple
dose, placebo-controlled trials of
greater than or
equal to 4 weeks in
discontinuation. These are the
discontinuation rates. Please note that there were
fewer asthma-related discontinuations in
the
Foradil arms compared to the placebo arm
or to
albuterol. So, the rate overall for an formoterol
doses was 7.1; for placebo it was 10.7;
for
albuterol 8.1. Please note that this was
especially notable for the approved dose
of
Foradil, 5.6 versus 10.7.
A reverse pattern was observed
for
asthma-related serious adverse
events. Foradil
patients experienced more events than
placebo.
Here the imbalance was greater for the
higher
Foradil dose. The numbers are shown here, 3.5 for
the approved dose versus 3.1 for
albuterol, 0.9 for
placebo and a higher rate for the
albuterol 48 mcg
dose.
Again, this dose is the approved dose in the
151
U.S.
When both types of events are
taken into
consideration, the rate of significant
asthma
exacerbations, that is, asthma-related
AEs
meaningful enough to cause the patient
to
discontinue and asthma-related events that
were
labeled as serious whether or not they
caused
discontinuation, was actually lower for
Foradil at
its approved dose than the rate for
placebo or for
albuterol. Note that at the highest dose of
Foradil that rate was similar to the
placebo rate.
But for Foradil at its approved dose the
rate was
7.1 versus a placebo rate of 10.9.
In summary, based on this
analysis of our
clinical trial database for
asthma-related adverse
events, we observed a rate of
significant asthma
exacerbations for the approved Foradil
dose that
was lower than placebo rates.
I would like to now move on to
a review of
postmarketing data. In order to explore the
adverse event profile of Foradil on the
market and
to provide some estimates as to how it
might
152
compare to other drugs in its class, we
performed
an
analysis of postmarketing data based on FDA AERS
database, that is the FDA's adverse
events
reporting system.
We must recognize that this
type of
postmarketing analysis has its
limitations.
Although spontaneous reporting of ADRs
remains the
most common method used for monitoring
the safety
of marketed drugs and is useful for
detecting
safety signals, it is limited by the
fact that a
substantial percentage of ADRs are not
reported.
The reporting rate also tends to be
lower the
longer a drug is on the market. This is a
well-known phenomenon and is known as
the Weber
effect.
In addition, targeting drugs to lower or
higher risk patients may alter apparent
ADR
occurrence, and notoriety associated
with a drug or
class may alter reporting rates. A final concern
is that the ADR that is being reported
in this
instance is the disease itself, It is a
manifestation of the disease itself.
We examined FDA adverse
reports for death
153
or outcome of death and found that rates
were
highest in the first years after launch
and
declined each year thereafter. This analysis is
shown in your briefing book.
We will now review the
reporting rates for
these and other events of interest. Please note
that reporting rates are reports with
case
definition on the drug of interest
divided by the
exposure worldwide since the drug was
marketed in
the U.S. per 100,000 patient-years.
Relative rates of reporting
can also be
assessed by simply calculating the
percentage of
reports at case definition by the total
number of
adverse events reported. This does not take into
consideration the exposure to the drug
of interest
and may inflate the Weber effect if
there is a
difference of time on the market. Shown here are
the reporting proportions, on the left,
and the
reporting rates per 100,000
patient-years, on the
right, for Foradil and salmeterol.
As you can see, the reporting
proportion
for formoterol, a drug that was
established on the
154
U.S. market in 2001, compared to
salmeterol, which
was on the market since 1994, is
somewhat higher.
However, one must adjust for the
exposure to the
drug which was far greater for
salmeterol. When
adjusting for this higher number of
exposures for
salmeterol the result ratio flips. That is, when
we adjust for actual exposure to the
drug we note
that the rate for Foradil was somewhat
lower than
that of salmeterol.
In conclusion, well-described
pharmacologic differences exist between
formoterol
and salmeterol although the clinical
relevance is
not known. In pivotal trials conducted for U.S.
registration, a potential safety signal
emerged in
the Foradil high dose group, leading
only to the
approval of the 12 mcg dose, that is 12
mcg BID,
and the request for postmarketing asthma
safety
study 2307. Study 2307 examined asthma-related
serious adverse events in adolescents
and adults
and did not provide evidence of a safety
signal for
Foradil at any dose.
An analysis of the pooled
Foradil clinical
155
trial database and a review of
postmarketing
adverse event data, with its limitations,
do not
provide evidence of a safety signal for
Foradil.
The totality of the evidence, therefore,
does not
elevate concern for a safety signal and
continues
to support the favorable benefit/risk
profile of
Foradil in the treatment of asthma.
Thank you for your
attention. Dr. James
Donohue will now present the clinical
implications.
Clinical Implications
DR. DONOHUE: Thank you, Dr. Geba. Dr.
Swenson, members of the advisory
committee, Dr.
Chowdhury and Dr. Meyer and members of
the FDA,
ladies and gentlemen, I am here today as
a
clinician investigator to talk about the
clinical
implications of the long-acting beta
agonist class.
As an older physician, I can talk a
little bit
about life before the introduction of
the
long-acting beta agonist class into our
clinical
practices. While the alternatives were
short-acting beta agonists,
theophylline, various
epinephrine agents, oral beta agonists,
each of
156
these treatments had different
benefit/risk ratios
or profiles from the long-acting beta
agonist
class.
I would like to discuss a little bit the
implication of the roller-coaster effect
on our
patients with asthma's lives, the lack
of nocturnal
coverage with most of these
shorter-acting agents
and issues with compliance. There have always been
issues with the short-acting beta
agonists for the
need to frequently dose; special issues
with our
children and whether or not they could
be dosed in
the schools; the difficulty in our
blue-collar
workers, of course, who need frequent
dosing of
their medications.
The short-acting beta agonists
have, as I
say, benefits and risks. Overdosing of the
short-acting beta agonists was
associated with
tremor, particularly with the peak. There were
changes in metabolism, hypokalemia and
changes in
glucose metabolism which may or may not
be
clinically significant but could be
under certain
circumstances. There was also tachycardia
associated with people using some higher
doses or
157
people who had more co-morbidity
issues. Then
also, to inform us, we had very useful
data from
Saskatchewan looking at thee use of
short-acting
beta agonists in Canada. These are combined data
for formoterol and albuterol.
These are the deaths per
100,000 per year
and the number of canisters. We can see that as we
start getting up in the number of
canisters,
especially win formoterol, one sees an
increase in
deaths due tot he short-acting beta
agonists or
associated--not necessarily due to but
associated
with the short-acting beta agonist
class. So this
was, of course, a concern to all of us
and is part
of the recommendations presently in the
guidelines.
We also had different side
effect profiles
of
other medications available to us before the
long-acting beta agonists and drugs we
would have
to consider today as substitutes. First and
foremost, theophylline, particularly the
longer-acting forms. Their safety profile is
important to look at. There was a narrow
therapeutic window, as everyone knows,
with these
158
drugs.
There were very, very important drug
interactions. In fact, if we look at our elderly
asthmatic population, commonly these
patients would
enter the hospital with use of an
antibiotic or a
medication for reflux causing a
drug-drug
interaction and making the patient theophylline
toxic.
Furthermore, if we look at drug
interactions in the hospital, there is a
huge
safety concern about medication errors,
and
what-have-you, and theophylline were
always at the
top of the list.
Other medications we had were oral
beta
agonists, both short-acting and
long-acting and,
again, much less of an efficacy profile
as compared
to the long-acting inhaled agents and a
much
greater safety risk with tachycardia,
tremor and
reflux.
Oral corticosteroids have to be used more
and more when patients have more and
more
exacerbations and I don't have to review
the
laundry list of side effects that are
well-known to
everyone in the room.
Now, throughout the world we
have--I have
159
outlined in yellow here the G8 nations
because of
last week's meeting, but we can see the
variation
in prevalence of asthma symptoms as we
get more
industrialized societies. We see a very large
increase in the number of patients who
suffer with
airways disease.
On the other hand, there are
facts that I
find very, very consoling and
comforting. This is
the death rate due to asthma in the
United States
going back to 1960 up to 2002. These are the
deaths per 100,000 so we can sort of get
the rate
that you are asking for. Then we have the African
Americans here and the Caucasian
population here.
Short-acting beta agonists
were introduced
in the 1970s. We had the inhaled corticosteroids
introduced in the 1980s. There have been enormous
efforts in patient education, efforts by
the expert
panels of the National Institute of
Health for
guidelines and just generalized
education programs,
along with the introduction of effective
controller
medicines along with the long-acting
beta agonists
that seems to have led to a decline,
although still
160
very high, relatively higher in the
African
American population, but to the general
United
States population, from 5,400 to a
little bit above
4,000.
So, we are clearly doing something right.
What the attribution would be here to
the various
things introduced is, of course, beyond
my ability
to say but, clearly, all these things
together have
helped us to improve the lives of our
patients.
Now, what about the
long-acting beta
agonists? Just briefly, you have seen an awful lot
of
this data this morning and, at the risk of being
a little bit redundant, the first
benefit, of
course, is in patient symptoms. These are better
bronchodilators. I think we would all agree that
the data are overwhelming on this. There is a
reduction in the roller-coaster effect,
and I will
come back to that in a minute; better
control
because of the longer duration of effect
and
nocturnal symptoms. Because of the control, we
have less use of rescue
medications. We have
improved morning lung function and also
less
diurnal lung function variability. It doesn't
161
completely eradicate it but it does
minimize to
some extent some of the early morning
dipping that
leads to waking up or even worse
outcomes. Also,
equal important perhaps, it gives us
protection
against exercise-induced bronchospasm
and that is
the exercise of normal daily activities in
normal
life, and it is nice to have that kind
of
protection on board so you don't have to
continuously dose yourself.
Looking at the formoterol
data, Dr. Geba
has shown us the safety data. We saw that there
are 3 pivotal trials that you have in
your briefing
documents. There is superior improvement in the
FEV 1 over
placebo over the course of
12 hours.
This duration of action is sustained for
12 weeks
so there doesn't appear to be a signal
that there
is any tolerance or reduced
efficacy. There is a
reduced need for nighttime rescue
medicine, and the
onset of action is similar to albuterol,
as has
been outlined.
Just again showing the similar
12-hour
studies, this is the 040 and the 041
that you have
162
seen a moment ago. This is at week 12. Here we
see the 12-hour curve and this is the
mean change
in baseline FEV
1.
Here is the short-acting
albuterol and placebo, and here is the
sustained
effect of the long-acting beta agonist,
in this
case formoterol. First of all, let me draw your
attention to the pre-dose or
trough. Often we
power clinical trials on long-acting
beta agonists
and this changes well over 10 percent
here, around
12 percent, and that usually can be
transferred to
as meaningful clinical improvements such
as
symptoms in the morning and
what-have-you. Over
the course of the day you see the roller-coaster.
That in itself means nothing but what
this means
here is that as these drugs flow off
here our
patients become symptomatic and have to
disrupt
their daily activity to take rescue
albuterol.
Also one other thing I would
like to show
here is the peak effect. Patients perceive change
and when you have a nice plateau effect
a lot of
side effects such as tremor are much
less
perceptible to a patient.
163
Other outcomes besides
bronchodilator is
rescue medication. These again are from 040 and
041, the run-in for the 3 arms,
formoterol,
albuterol and placebo. We see over the course of
4, 8 and 12 weeks a nice decline in the
rescue
albuterol. These parameters are less rigorously
defined but we think the minimal
clinical
improvement in that parameter is 0.8
puffs per day
ranging to 1. So, it appears to be in the ballpark
of something that means something to a
patient and
we could quantitate that.
Simply, formoterol reduces
nocturnal
symptom scores. I am showing 040 and 041 which I
believe are the adult studies run-in and
over 12
weeks and the companion study here. We see a nice
decline from about 0.5 to 0.1 in the
nocturnal
asthma symptom score parameter.
To end up, one of the studies
that I take
consolation from as a physician is the
FACET study.
Again, points are well taken here today,
we are
talking about deaths. It is very difficult in
asthma studies though to power our
studies, as
164
everyone in the room has heard over and
over again,
on death as the outcome. Exacerbations are
extremely important and the reason that
I take a
lot of comfort from this study is that
it is a
one-year study. Also, the exacerbations are
precisely defined, as Dr. Sorkness
mentioned this
morning.
In this study we see--again in
the
mechanical function, 835 patients, 12
months--a
marked improvement after the
run-in. The patients
were in the run-in symptomatic on
inhaled
corticosteroids. But this study gives us some look
at what is the added value of adding a
long-acting
beta agonist--added clinical value--to
inhaled
corticosteroids.
Here are the two budesonide
arms. I think
there is no surprise that on the
mechanical
function we do see a change of 7 or 8
percent. But
I think one takes a better message away
from
looking at exacerbations. First of all, if
inflammation is ongoing and not being
checked the
patient is going to know that they are
going to
165
breakthrough with an exacerbation. This is our
best clinical surrogate for the
so-called masking
of inflammation, that is, the
breakthrough of
exacerbations. In a study of one-year duration we
have adequate duration to bring this
signal out.
So, in this study, as Chris
Sorkness
pointed out this morning, we have an arm
with 100
BID of budesonide and with
formoterol. Then, the
second arm is 400 BID with the addition
of
formoterol.
And, the exacerbations were described
as mild with an increase in terbutaline,
the rescue
medicine, and severe, defined by a 30
percent
change in peak flow and oral
prednisone. The
decline in mild exacerbations was about
29 percent
and 40 percent with the
combination. But with the
higher dose, high dose budesonide
reduced the
exacerbation rate by 49 percent. When one adds
formoterol to it it went to 62
percent. So, there
is
a net gain there and the actual clinical
implication of that is that it appears
to be
significant. We really haven't put a number on
that yet but that, in my mind, is a very
reassuring
166
piece of evidence that supports the use
of this
class of drug.
Using the best evidence that
one has, the
expert panels--many of the members of
which are in
the room here--have come together, and
you have
seen this before over and over again,
and have
concluded that inhaled steroids and
long-acting
beta agonists have a complementary
effect. One can
lower the dose of inhaled
corticosteroids by using
the combination, and not everyone
responds to
inhaled corticosteroids although a great
majority
do.
For more severe patients we
would be using
higher doses of inhaled corticosteroids
and
long-acting inhaled beta agonists and,
hopefully,
we will be able to avoid the use of
prednisone and
its very difficult side effect profile.
So to summarize, long-acting
beta agonists
have really become an established part
of the
current standard of asthma treatment in
the United
States and also internationally. It is an integral
part of internationally established
guidelines
167
using the best evidence that we have at our
disposal at the present time. It is well
established that long-acting beta
agonists have a
place in the treatment regimen for
asthma but must
be conjunction with inhaled corticosteroids
for
those with moderate and severe
persistent asthma.
Again, I don't think at the
present time
there is an alternative inhaled
controller
bronchodilator or one on the immediate
horizon that
is suitable for asthma. So the LABAs, the
long-acting beta agonists, have provided
documented
improvement in symptoms, airway function
and
quality of life and you have heard a
great deal
about that today. For whatever reason, since the
introduction of long-acting beta
agonists,
controllers and a national effort in
education and
guidelines, asthma hospitalizations and
mortality
have decreased, which is very reassuring
at least
to me and I think to many others. Long-acting beta
agonists in conjunction with inhaled
steroids
represent a medication category critical
for
optimal care of patients with moderate
to severe
168
asthma.
Thank you very much.
Questions by the
Committee
DR. SWENSON: The time now is open for
questions to Novartis. Dr. Schatz?
DR. SCHATZ: Some of the things we are
hearing suggest a possible disconnect
between
exacerbations, as has been studied and
defined
usually to include oral steroids and
emergency
departments or hospitalizations, and
then death or
near death. So, I guess my question has to do with
2307.
How were SAEs defined? However,
were
asthma-related SAEs defined?
DR. FLOYD: Dr. Geba?
DR. GEBA: To answer this question I would
like to bring up a slide that gives the
definition
of asthma-related and the definition of
serious.
We used predefined asthma
terms, MedDRA
terms, MedDRA preferred terms. Asthma-related AEs
were defined as asthma, dyspnea,
bronchospasm and
chest discomfort, cough, wheezing, etc.,
acute
respiratory failure and hypoxia. For the
definition of SAEs it was one of the
above plus one
169
of the following, death,
life-threatening
hospitalization, disability, congenital
abnormalities--this is regulatory
definition, and
required intervention to prevent further
impairment--standard definition.
DR. SCHATZ: Just to follow-up,
intervention could mean oral
corticosteroids?
DR. GEBA: Yes, it could be. It could be
medical intervention.
DR. SWENSON: Miss Sander?
MS. SANDER: Yes, on slide CO-10 it says
"sustained improvement in FEV
1 at 12
weeks." Was
the albuterol depicted here scheduled or
was it
based on symptoms?
DR. GEBA:
The albuterol dose in these
trials was scheduled.
MS. SANDER: I have another question on
the next slide. It says "Foradil reduces rescue
medication use." Is that albuterol use? And that
is for exacerbation? Is that right?
DR. GEBA: The presumption is it is
exacerbation. It was albuterol usage rescue
170
defined by the patient who was symptomatic
and,
therefore, referred to rescue medication
with
albuterol. Correct.
MS. SANDER: So, that phrase there,
"rescue medication" is defined
as rescue needed by
the patient.
DR. GEBA: Yes.
MS. SANDER: So, not scheduled.
DR. GEBA: No.
MS. SANDER: Thank you.
DR. SWENSON: Dr. Kercsmar?
DR. KERCSMAR: I have a question about the
049 pediatric study. The slide that shows the
serious AEs looked distinctly different
than the AE
profiles in the adult trials. Can you give us any
further insight into that, any other
data that you
might have regarding those differences
in children
in the 5-12 age range compared to the
adults?
DR. GEBA: I would like to point out that
the age range of patients in our
so-called adult
trials was actually 12 and on so it
would include
adolescents and adults. This population of
171
patients was 5-12 so it was definitely a
younger
population of patients and truly
children in 049.
There was a difference in rates of
exacerbations in
these trials and the point I guess that
I would
like to focus on, if you could bring
that slide up,
the 3 trials together, the 3 pivotal
trials, slide
CS-7, please. Thank you.
What we noticed in the 3 pivotal trials
was that for the Foradil high dose arm
there was a
higher event rate compared to the lower
don
formoterol arm. You did notice, and we did as
well, that the rate for those events was
still
higher in the lower dose of the Foradil
arm for
pediatric patients.
We were most concerned, as the
agency was,
and this was guided by conversations
that we had
with the agency to determine whether or
not there
was a dose effect going from 12 to 24
mcg. Upon
discussions with the agency, we designed
a trial to
prospectively test whether or not there
was a dose
effect between 12 mcg and 24 mcg, and we
were
requested to study the identical patient
population
172
as in 040 and 041. So, we recognize that this area
has not yet been fully analyzed and
evaluated, and
we are not certain as to why the issue
occurred in
this age group.
DR. SWENSON: Dr. Gay?
DR. GAY: Thank you.
The data of the
SMART study suggests that a predominance
of the
number of adverse outcomes began to
occur after
about 90 days. That is where the split in the
Kaplan-Meier curves begins to become
much more
significant. A number of the studies that you
performed are at 90 days or a little bit
longer. I
wonder if you have available any
post-study data of
a 3-month or 6-month follow-up that may
show any
change or any increase in the number of
adverse
events, such as asthma-related deaths or
significant numbers of exacerbations,
that go with
your most recent study or even the
earlier studies,
040 or 041?
DR. GEBA: Right, in the longer and most
recent studies there were none of those
events that
would contribute to this. We only had one death in
173
all of our clinical trials of over 6,000
patients
with 16,000 patient-years of experience.
We would like to point out
that there is a
continuity, one would argue. We analyzed this data
in terms of the event rates for serious
adverse
events to determine whether or not they
occurred
randomly during those first periods of
time during
the trial allowing us to, therefore,
pool and
express these rates as rates per 100
patient-years
of exposure. And, that is what we have done.
On the slide shown here is
depicted the
Foradil versus placebo asthma-related
serious
adverse event proportion and, as you can see,
there
is a distribution in that 3-month
window. Also, I
would point out that even in the
briefing book if
you look at the rates of events that
occurred in
SMART, you can detect already a
separation by an
earlier time point than the 3-month time
point.
So, we were fairly confident that we
could pool the
data sets that we have, limited by the
fact that we
don't have trials as long as for
salmeterol, and
come up with a reasonable estimate as to
the event
174
rates based on this type of analysis.
DR. GAY: Just in follow-up, I want to
make sure I understand this
correctly. My question
clearly is going to lead to less
rigorous data but
I am concerned about follow-up time
longer than
your study duration, longer than the 12
or 16
months, not within that specific time frame.
DR. GEBA: Right.
DR. GAY: Is this data concerning that
time up to 3 months post the end of the
study?
DR. GEBA: No, we did not routinely follow
patients beyond the time of their study
treatment,
except for a routine visit usually
performed 2
weeks post study.
DR. GAY: Thank you.
DR. GEBA: Thank you.
DR. SWENSON: Dr. Martinez?
DR. MARTINEZ: Thank you.
I am going to
talk in reference to the pooled Foradil
clinical
trial database in which you have shown,
and correct
me if I am quoting wrongly, that for
less severe
events--let's call them that way for a
175
moment--there was no difference between
formoterol
and placebo or albuterol. But for more severe
events there was a difference.
So, let me propose to you, and
I would
like to elicit your comments, that there
could be
two different ways in which the
deterioration of
asthma may occur, which may occur in
different
patients with different risk factors and
with
different asthma phenotypes. I am proposing this
to you as an interpretation of your
data. Let's
call one of them loss of asthma control,
in other
words, slow deterioration; increase in
symptoms
with more wheezing, more cough. I saw that all
those elements were present in your
definition.
For those, let me propose to you that
there is no
difference between formoterol and
placebo or
albuterol.
But it could be that there is
a different
set of patients in whom these symptoms
don't occur
every day and they have a more brisk,
brittle form
of the disease. It is in these patients that you
see that placebo is associated with 0.3
percent.
176
These patients justify the fact that in
placebo you
only see 0.3 percent and you see much
more win
formoterol. This goes to issues that have been
raised by other members of the committee
as to how
we can explain that in terms of the
everyday
symptoms, in terms of control of asthma
we see
improvement with the use of all
medicines in this
class, but we are seeing in many studies
a signal
that there could be more severe disease. Could it
be that we are in the face of two
different forms
of expression of asthma deterioration
that have
different responses to this class of
medicines?
DR. GEBA: Yes, we have not done a
sufficient enough analysis of these
events. I
would point to Dr. Cioppa from Novartis
to respond
to that question. Thank you.
DR. DELLA-CIOPPA: Thank you.
My name is
Giovanni Della-Cioppa and I am Vice
President for
Clinical Research. Dr. Martinez, your explanation
is certainly one possibility. There is also
another possible explanation that we
would to bring
to your attention, keeping in mind that
we are
177
talking here about clinical trials, and
we are
talking about clinical trials of
bronchodilators.
Despite the fact that these trials are
blinded,
many patients have a clear perception of
an
improvement of their lung function quite
rapidly.
So, one could assume that these two
kinds of events
represent very similar events in terms
of
magnitude, in terms of gravity, in terms
of impact
on the patient's well being.
But if I am a patient on
placebo, or I
think I am a patient on placebo and I
start going
down the drain--as shown this morning,
there are a
few days of unfolding of the event--then
I will
abandon the trial and experience,
therefore, a
discontinuation due to asthma. If I am a patient
on active and I know I am on active I
will be more
reluctant to get out of the trial, and
stay on the
trial, and the same event will be labeled
by the
investigators as a serious adverse
event.
It is baffling, this kind of
mirroring
situation by which people on placebo get
out from
the trial due to asthma and the people
on active
178
who stay on the trial and get serious
adverse
events.
So, the two explanations are not mutually
exclusive but I just wanted to offer an
alternative
explanation because we are seeing it
again, and
again, and again, and we are seeing it
in the
pooled database, as shown by Dr. Geba.
DR. MARTINEZ: However, as much as I can
accept your arguments, I would suggest
that either
of the two explanations, or both, are
potentially
reasonable for the data as it has been
presented.
DR. SWENSON: Dr. Meyer?
DR. MEYER: Thank you.
I just wanted to
make something explicit prior to lunch
as sort of a
summary from the agency standpoint from
these
morning's presentations. We have heard
presentations from two sponsors that
centered
around new data from studies and, of
course, we
will have our own perspective on those
after lunch.
But these are very different
studies. These are
almost apples and oranges. They were purposefully
so because they were meant to address
very
different questions.
179
The SMART study was meant to
address a
signal that was coming out from
postmarketing data
where we didn't feel like that could be
adequately
addressed by the postmarketing data or perhaps
even
by epidemiology studies but raised even,
even
pre-approval by the SNS study, a signal
of very
rare, very dire events that were not
well predicted
by the more common adverse events, even
serious
adverse events, in shorter-term
trials. Hence, a
very large, very prolonged study.
The formoterol 2307 study was
not designed
to answer that kind of question. It was designed
to answer the question of events seen in
shorter-term trials, representing more
sort of
common serious adverse events that were
detected in
the database, and really was meant to
explore a
dose effect, as was previously stated.
So, I just wanted to be very
explicit
about the fact that what we are talking
about here
in the end are two very interesting
studies but
they are addressing, and perhaps
answering to the
degree they did answer them, very
different
180
questions.
DR. SWENSON: And Miss Watkins has one
announcement, after which we will
adjourn for
lunch.
MS. WATKINS: I would like to remind the
committee that, in the spirit of the
Federal
Advisory Committee Act and the Sunshine
Amendment,
discussion about today's topic should
take place in
the form of this meeting only and not
occur during
lunch, breaks or in private
discussions. We ask
that the press honor the obligations of
the
committee members as well.
Additionally, the committee
members, once
you get lunch in Salon E, there is
reserved seating
for the committee members in Salon D,
and we ask
that you take advantage of that.
DR. SWENSON: There is one other question
here.
Dr. Newman, I apologize for leaving you out.
DR. NEWMAN:
Thank you. I just want one
clarification, if I could. You emphasized the
pharmacological differences between this
drug and
salmeterol. Are you suggesting that because of the
181
pharmacological differences the studies,
such as
SMART, are somehow not relevant to your
drug?
DR. GEBA: No, we can't go that far and I
don't want to overstate those
differences. I just
wanted to point out that the molecules
are
different; that the receptor binding
mechanism is
somewhat different; the onset of action,
those
types of things are different between
the two
molecules. Whether or not that has an implication
in terms of outcomes of the sort that we
have been
discussing this morning is
conjecture. It cannot
be ascertained. But for completeness we included a
full discussion of the molecule and
differences
from the other one that is relevant in
its class.
DR. NEWMAN: Just in follow-up on that, so
in terms of the pharmacologic action and
factors
such as desensitization of the beta
receptor, there
still is a desensitization effect, is
there not?
DR. GEBA: Well, we have some data that
distinguishes the two, and to approach
that I would
ask Dr. Trifilieff to respond to that
question.
Dr. Trifilieff is from basic research in
Novartis.
182
DR. TRIFILIEFF: So, the question was
about agonist desensitization? In theory, full
agonists will induce much more
desensitization than
partial agonists. But what you have to take into
account also is the density of the
receptors
because basically a partial agonist, by
definition,
would need more receptor in order to
achieve the
same efficacy as a full agonist. So, in a
situation where you have low density of
the
receptor a full agonist will need a 4
receptor; a
partial agonist will need 40
receptor. So, you
have a greater desensitization for
partial agonists
compared with full agonists.
DR. SWENSON: I wish to thank everyone for
their participation. We will reconvene at one
o'clock rather than 12:45 as is
presently on the
schedule.
[Whereupon, at 11:50 a.m., the
proceedings
were recessed, to reconvene at 1:00
p.m.]
183
A F T E R N O O N P R O C E E D I N G S
DR. SWENSON: Good afternoon, everyone.
We will resume the meeting with the FDA
presentation. To begin, Dr. Sally Seymour will
first speak, to be followed then by Dr.
Harry
Gunkel, after which the panel will have
the
opportunity to raise questions to the
two
presenters.
FDA Presentation
Salmeterol
DR. SEYMOUR: Good afternoon. My name is
Sally Seymour and I am a medical officer
in the
Division of Pulmonary and Allergy Drug
Products. I
am going to be speaking to you today
about the
long-acting beta agonist
salmeterol. Much of what
I will present today has been presented
this
morning but I am going to present you
the agency's
perspective.
The objectives of my
presentation today
are to discuss the regulatory history of
salmeterol, which was the first
long-acting beta
agonist approved in the United
States. In the
184
regulatory history I will emphasize the
agency's
actions in response to the safety
concerns with
salmeterol. I will then review the postmarketing
clinical studies with salmeterol which
were
conducted by the sponsor, including the
SNS study
and SMART. Following the discussion of the
postmarketing studies, I will briefly
discuss the
postmarketing spontaneous event reports
for
salmeterol. Then I will highlight the sections of
the product label which include
information about
the postmarketing studies.
Let's begin with the
regulatory history.
Serevent Inhalation Aerosol was approved
in
February, 1994 for asthma. The indication is
long-term twice daily administration in
the
maintenance treatment of asthma and the
prevention
of bronchospasm in patients 12 years of
age and
older with reversible obstructive
airways disease.
Indications for exercise-induced
bronchospasm and
for COPD were added later. However, the focus of
the discussion today, as you know, is on
asthma.
As mentioned earlier, the
sponsor chose to
185
discontinue Serevent Inhalation Aerosol
as part of
the CFC phaseout and, thus MDI is no
longer
marketed. Serevent Diskus is a dry powder
formulation of salmeterol which was
approved in
February, 1997 for similar indications
as the
Inhalation Aerosol. The Discus is approved in
children down to 4 years of age.
Finally, Advair Diskus, which
is a
combination product of the
corticosteroid
fluticasone propionate and salmeterol,
was approved
in August, 2000 for asthma, and later
the
indication for COPD with chronic
bronchitis was
added.
Let's start at the time of the
salmeterol
inhalation aerosol NDA. The NDA for salmeterol
inhalation aerosol was supported by 2
Phase 3
12-week active and placebo-controlled
clinical
trials in 556 patients with mild to
moderate
asthma.
At 12 weeks the clinical studies
demonstrated an improvement in the
salmeterol group
versus placebo in the following
endpoints, FEV
1 and
peak expiratory flow rate, mean percent
days and
186
mean percent nights with no asthma
symptoms, and
less rescue medication use.
I would like to point out that
at the time
of the NDA review the results of the SNS
study were
known and considered. The SNS study, as you know,
was a postmarketing study in the United
Kingdom and
I will discuss that shortly. An advisory committee
meeting was held in February, 1993 to
provide
advice and make recommendations
regarding the
salmeterol inhalation aerosol NDA. The advisory
committee was supportive of approval of
the
salmeterol NDA in adults and
subsequently
salmeterol inhalation aerosol was
approved in
February of 1994 for asthma.
Shortly after approval reports
of
life-threatening respiratory events and
fatalities
with salmeterol use were reported. Multiple
meetings were held with the sponsor to
discuss the
reports.
Some of the postmarketing event reports
suggest that there was possible
inappropriate use
of salmeterol. This concern led to revisions in
the label in January, 1995. The warning section
187
now included the following
statements: Serious
acute respiratory events, including
fatalities,
have been reported with salmeterol. Salmeterol is
not for acute symptoms. Salmeterol is not a
substitute for oral or inhaled
corticosteroids.
Salmeterol should not be initiated in
worsening or
acutely deteriorating asthma, and patients
should
have a short-acting beta agonist for
acute
symptoms.
The sponsor also conducted a
physician and
patient education program which included
a "dear
healthcare professional"
letter. In addition, as
you know, the sponsor committed to a
large safety
study, the Salmeterol Multicenter Asthma
Research
Trial, or SMART. SMART was initiated in July,
1996, and I think it is important to
point out in
the regulatory history what the sponsor
mentioned
earlier, that the SMART study had to be
amended in
June of 1999 to double the population
from 30,000
to 60,000 patients because of fewer than
expected
outcome events.
A planned interim analysis was
performed
188
in 2002 after approximately 26,000
patients had
been enrolled. The DSMB reviewed the interim
analysis data. The data indicated that the point
estimates suggested an excess risk with
salmeterol
and that African Americans may be at
particular
risk.
DSMB recommended to continue the study if
timely recruitment was feasible. If timely
recruitment was not feasible, the DSMB
recommended
to terminate the study and disseminate
the findings
to the clinical research communities
within 3-6
months.
Based upon the interim
analysis and
difficulty with enrollment, the sponsor
terminated
SMART in January, 2003. A "dear healthcare
professional" letter was also
issued in January,
2003.
The sponsor submitted preliminary data from
the interim analysis of SMART to the
agency and,
based upon the preliminary data the
product label
was revised in August, 2003. It is somewhat
unusual for the agency to make labeling
changes
based upon preliminary data, however,
the agency
felt the SMART information was important
to include
189
in the product label. Labeling changes included a
boxed warning and information in the
clinical trial
section of the label regarding the
findings of
SMART.
These labeling changes were applied to all
salmeterol-containing products,
including Advair.
When a safety signal is noted with a
drug substance
the agency's practice is to apply
labeling changes
to all products containing the drug
substance
unless there are data to establish the
absence of
the safety concern for a particular
product.
In August, 2003 the sponsor
submitted the
full SMART data set. The sponsor indicated at the
time that the National Death Index or
NDI search
had been performed and noted that some
of the
additional deaths were still being
adjudicated. In
February, 2004 the sponsor submitted the
full SMART
study report which included the
adjudicated NDI
data.
After review of the study report the label
was once again revised to include more
details
regarding the results of SMART. That brings us up
to date on the regulatory history.
Now let's discuss the
postmarketing
190
studies which I touched upon in the
regulatory
history, the first of which is the SNS
study. The
SNS study was a randomized,
double-blind,
active-controlled, parallel group
16-week trial in
the United Kingdom. The population was 25,000
patients with asthma who were randomized
in a 2:1
fashion to salmeterol 50 mcg BID or
salbutamol 200
mcg QID
Salbutamol is a short-acting beta agonist
known as albuterol in the United
States. Note that
this was not a placebo-controlled
study. It was an
active-controlled study in which both
arms were
treated with regularly scheduled beta
agonists.
Clinic visits were conducted at 4, 8 and
16 weeks.
Outcome measures were serious adverse
events and
reasons for withdrawals.
This table displays the key findings
in
the SNS study, and recall that the
randomization
was 2:1.
I would like you to note the following,
first, there is a numerical increase in
respiratory
and asthma-related deaths in the
salmeterol group
with a relative risk of 3. However, this was not
statistically significant. Second, there was no
191
difference in the respiratory and
asthma-related
hospitalizations or other respiratory
and
asthma-related serious events between
the
salmeterol and salbutamol group. Finally, there
were significantly fewer asthma- and
respiratory-related withdrawals in the
salmeterol
group and this was statistically
significant.
As mentioned earlier, the
results of the
SNS study, which showed a numerical
increase in
respiratory- and asthma-related deaths,
although
not statistically significant--these
were
considered at the time of approval of
salmeterol
and were discussed in the February, 1993
advisory
committee meeting. The benefit of salmeterol was
felt to outweigh the risk. Thus, salmeterol
inhalation aerosol was approved in 1994.
Following approval of
salmeterol, there
were reports of serious asthma events,
including
fatalities. In working with the agency, the
sponsor committed to a large safety
study, the
Salmeterol Multicenter Asthma Research
Trial, or
SMART, which I will discuss next.
192
SMART was a multicenter,
randomized,
double-blind, placebo-controlled,
parallel group
study of 28-week treatment
duration. The sample
size was initially planned to be 30,000
but then
was increased to 60,000 in 1999 because
of a fewer
number of events than expected. Subjects were
greater than or equal to 12 years of age
with a
clinical diagnosis of asthma. They were currently
taking prescription asthma medications
but no
long-acting beta agonists. Subjects were
randomized to salmeterol 50 mcg BID or
placebo BID
for 28 weeks treatment in addition to
usual asthma
care.
Subjects underwent one clinic visit in which
they were given a 28-week supply of
salmeterol or
placebo, and telephone contact was made
every 4
weeks.
The primary endpoint for SMART was
the
combination respiratory-related deaths
and
respiratory-related life-threatening
experiences.
Respiratory-related life-threatening
experiences
were defined as intubation and mechanical
ventilation.
193
Ideally, the endpoints for
SMART would
have been asthma-related deaths and
serious asthma
exacerbations but, based upon historical
data, the
number of events was expected to be
low. Thus, the
primary endpoint of the study was
broadened to
respiratory-related deaths and
respiratory-related
life-threatening experiences. It was thought that
a
respiratory-related life-threatening experience
was a marker of fatal asthma and
asthma-related
deaths.
As you can see in the list of
key
secondary endpoints, asthma-related
deaths was one
of the important secondary endpoints, in
addition
to all-cause death, asthma-related
deaths and
life-threatening experiences and
all-cause serious
adverse events or SAEs.
SMART was designed as a
non-inferiority
trial and was designed to show that
there was no
difference in the outcomes between
salmeterol and
placebo.
SMART was powered to rule out a 40
percent increase in the combined
respiratory-related deaths and
life-threatening
194
experiences and a 3 times increase in
asthma-related deaths. These numbers may seem high
but, again, they were based upon the
numbers of
expected events and the ability to power
and
conduct the study. As you may recall, the SNS
study with 25,000 subjects suggested a
relative
risk of 2 for respiratory- and
asthma-related
deaths for salmeterol versus salbutamol.
An interim analysis was planned after
approximately half the subjects were
enrolled.
Prespecified stopping criteria were the
following,
a relative risk of 1.4 for the primary
endpoint and
a relative risk of 3 for asthma-related
deaths,
with an alpha of 0.01.
An interim analysis was
performed in 2002
after 26,000 subjects were
enrolled. The DSMB
reviewed the interim analysis data in a
blinded
fashion.
The data suggested a potential treatment
group difference, thus, the DSMB was
unblinded.
After unblinding the DSMB, the data
suggested an
increased risk for salmeterol use. An exploratory
subgroup analysis suggested that African
Americans
195
could be at particular risk. However, the study
did not meet the prespecified stopping
criteria.
The DSMB recommended to continue the
study if
timely recruitment was feasible. If timely
recruitment was not feasible, the DSMB
recommended
to terminate the study and disseminate
the findings
within 3-6 months to the clinical and
research
community. Due to difficulties with enrollment and
the interim analysis finding, the
sponsor
terminated SMART in January, 2003.
Before discussing the results
of SMART I
would like to note the following: The results are
from a terminated study which did not
meet
prespecified stopping criteria. I think it is
important to note as I present the
results that the
non-inferiority objective was not
met. In fact,
the data I will show you suggested a
difference in
some endpoints between salmeterol and
placebo.
The results are based upon the
28-week
treatment period. The protocol specified that
investigators could report SAEs and
deaths for up
to 6 months after the 28-week treatment
period.
196
The initial SMART data submitted to the
agency
included events collected not only from
the 28-week
treatment period but also events
spontaneously
reported in a 6-month post-study
period. The
agency believes the data from the
28-week treatment
period is clinically the period of
interest. Thus,
the results I will discuss will be based
upon the
28-week treatment period.
The results also include data
from the
National Death Index search. Although this was not
specified in the protocol, the agency
determined
the NDI search data was acceptable to
capture
outcomes during the 28-week treatment
period.
Finally, the results are based upon life
table
analyses to help account for censoring
the subjects
during the study.
This table shows the subject
disposition
for SMART. As you can see, subject disposition was
similar between treatment groups and
other
categories of disposition not listed,
such as loss
to follow-up, were well matched between
the
treatment groups.
197
Similarly, subject
demographics were
similar between the treatment groups,
with the mean
age in both groups of 39 years of age;
64 percent
females and 36 percent males in both
treatment
groups.
Note that the ethnic origin was similar
and that the majority of the subjects
were
Caucasian, with 18 percent African
Americans.
The results for the primary
endpoint,
which was the combined
respiratory-related deaths
or respiratory-related life-threatening
experiences
are shown on this table. Respiratory-related and
life-threatening experiences, again,
were defined
as intubation and mechanical
ventilation. The
relative risk for the total population
is 1.4.
Note that the confidence interval does
not exclude
1 but the lower bound approaches 1. Remember that
the study was terminated early. If the study had
continued, it is possible the confidence
interval
would have tightened and excluded 1.
On post hoc subgroup analysis
Caucasians
do not appear to be at increased risk,
however,
African Americans had a relative risk of
4.1, with
198
confidence intervals that excluded
1. Thus,
African Americans appear to be at
particular risk
for the primary endpoint.
This table shows the results
for some of
the key secondary endpoints for
SMART. The
following should be noted: Note that the number of
events was low. For asthma-related deaths there
were 16 deaths in 26,000 subjects. For the total
population asthma-related deaths were
increased in
the salmeterol group with the relative
risk of 4.37
and confidence interval that excluded
1. These
results are similar to the results of
the SNS study
which showed a numerical increase in
respiratory
and asthma deaths with a relative risk
of 3 for
salmeterol versus salbutamol. Respiratory-related
deaths could include other causes of
death, such as
pneumonia, in addition to asthma-related
deaths.
For the total population
respiratory-related deaths
were also increased in the salmeterol
group with a
relative risk of 2.16 and confidence
intervals that
excluded 1.
Subgroup analyses for
asthma-related
199
deaths and respiratory-related do not
suggest a
difference in risk between Caucasians
and African
Americans. For combined asthma-related or
life-threatening experiences the
salmeterol group
was noted to have more events, with a
relative risk
of 1.7 and confidence intervals that
excluded 1.
Subgroup analyses suggest that the
African American
subgroup is driving the results for the
total
population. In the African American subgroup the
relative risk is 4.92 with confidence
intervals
that excluded 1. Although not on this slide, it is
important to note that there is no
difference in
all-cause death or all-cause
hospitalizations
between treatment groups.
What about the effect of
inhaled
corticosteroid use on the outcomes? As you heard
earlier, SMART was not designed to look
at the
effect of inhaled corticosteroid use on
outcomes.
However, because of their role in the
management of
asthma, information regarding inhaled
corticosteroid use is of interest. The
following
should be noted though, a subgroup
analysis looking
200
at the effect of inhaled corticosteroid
use was not
prespecified in the protocol. All analyses looking
at inhaled corticosteroid use are post
hoc
exploratory analyses. Inhaled corticosteroid use
was recorded at baseline only. Inhaled
corticosteroid use was not randomly
assigned.
Baseline inhaled corticosteroid use may
reflect an
imbalance in other factors that could
influence
clinical outcomes. Therefore, any difference in
outcomes between groups, defined by
baseline
inhaled corticosteroid use, may not be
attributable
to inhaled corticosteroids. Approximately half of
the total population used inhaled
corticosteroids
at baseline and 38 percent of African
Americans
used inhaled corticosteroids at
baseline.
This table shows the post hoc
analyses for
the primary endpoint by baseline inhaled
corticosteroid use. On the left side of the table
are the results for subjects using
inhaled
corticosteroids at baseline, and on the
right side
of the table are the results for
subjects who
didn't use inhaled corticosteroids at
baseline.
201
In the total population the
relative risks
are similar for subjects who used
inhaled
corticosteroids at baseline and subjects
who did
not use inhaled corticosteroids at
baseline.
Recall that in the African American
subgroup there
was a strong signal for the primary
endpoint. When
analyzed by inhaled corticosteroid use
there was an
increased number of events in the
salmeterol group
versus placebo for the primary endpoint
whether on
inhaled corticosteroids or not at
baseline. Thus,
African Americans appear to be at
increased risk
for the primary endpoint regardless of
baseline
inhaled corticosteroid used.
This table displays the key
secondary
endpoints for the post hoc exploratory
inhaled
corticosteroid use analyses. Again, the numbers
are small, making it difficult to draw
any
definitive conclusions. However, note again that
in the African American subpopulation
there was an
increased risk for salmeterol for these
secondary
endpoints regardless of baseline inhaled
corticosteroid use.
202
Although definitive
conclusions regarding
inhaled corticosteroid use cannot be
made from the
SMART data, the data suggests that the
risk for
salmeterol exists regardless of baseline
inhaled
corticosteroid use. Thus, the agency recommended a
boxed warning on Advair, the sponsor's
combination
product.
To summarize SMART, SMART was
a large,
simple safety study in 26,000 subjects, and was
stopped early due to interim analysis
findings and
difficulty with recruitment. For the total
population the relative risk for the
primary
outcome events, respiratory-related
deaths or
respiratory-related life-threatening
experiences,
was 1.4.
The confidence intervals approached 1 but
did not exclude 1. The relative risk for
asthma-related deaths was 4.37, with
confidence
intervals that excluded 1. The relative risk was
2.16 for respiratory-related deaths,
with
confidence intervals that excluded
1. The data
suggests that there was a treatment
group
difference favoring placebo for the
endpoints shown
203
on this slide.
In a Caucasian subpopulation
there were no
treatment group differences for the
primary
endpoint events, but there was an increase
in
asthma-related deaths and
respiratory-related in
the salmeterol group. In the African American
subpopulation there was a numeric
increase in the
salmeterol group for the primary
endpoint events,
asthma-related deaths and
respiratory-related
deaths, and also combined asthma-related
or
life-threatening experiences and on that
endpoint
the confidence interval actually
excluded 1. As we
discussed, no definitive conclusions
regarding
inhaled corticosteroid use can be made
in the SMART
study.
Now that I have addressed the
controlled
postmarketing studies, let's look
quickly at the
postmarketing spontaneous adverse event
reports for
salmeterol.
The Adverse Events Reporting System,
or AERS, was reviewed for deaths
reported for
salmeterol use between May, 1994 and
February, 2005
and 201 deaths were reported with
salmeterol use in
204
the United States. These cases were reviewed by
the Office of Drug Safety. Ninety-one of the
deaths were determined to be
asthma-related and 10
were possible asthma-related deaths. After a
review of the reports the determination
was that it
is difficult to draw any conclusions
regarding
salmeterol use in asthma-related deaths
and
postmarketing reports. In general, it is
challenging to analyze post reports for
events that
are associated with the underlying
disease such as
asthma-related deaths.
Next I would like to briefly
mention some
of the sections of the label that have
information
related to the SMART findings. The most
significant labeling change in response
to the
SMART results is the boxed warning shown
above, and
I think you were shown this
earlier. In addition,
a summary of SMART and results of the
primary and
key secondary endpoints were added to
the clinical
trial section, and there are copies of
the product
labels in the briefing package for
details. Note
that these labeling changes were made to
all
205
salmeterol-containing products.
To summarize what I have
discussed, I
reviewed the regulatory history for
salmeterol and
specifically focused on the agency's
handling of
the safety concerns with salmeterol
including
several labeling changes. I discussed the SNS
study which showed a numerical increase
in
respiratory and asthma deaths in the
salmeterol
group.
However, these were not statistically
significant and showed fewer withdrawals
due to
respiratory or asthma events, and this
was
statistically significant.
I discussed SMART, which was a
large,
simple safety study, stopped early due
to interim
analysis findings and difficulties with
enrollment.
The results of SMART suggest that there
is a
difference in outcomes between
salmeterol and
placebo.
In the total population there was a
relative risk of 1.4 for the primary
endpoint
although the confidence interval did not
exclude 1.
In addition, an increase in asthma- and
respiratory-related deaths, with
confidence
206
intervals that excluded 1, was also
noted for the
total population.
In the African American
population there
was an increase in primary events and an
increase
in combined asthma-related deaths or
life-threatening experiences, and both
of these
endpoints had confidence intervals that
excluded 1.
SMART was not designed to assess the
effects of
inhaled corticosteroid use on outcomes.
Because of the postmarketing
studies, the
product labels have been updated twice,
including a
boxed warning for all
salmeterol-containing
products, and I have shown you the boxed
warning
and the labels are in your packet.
So, based upon the safety concerns raised
in the postmarketing studies, we pose
the following
questions to the committee: The product labels of
salmeterol-containing products have been
modified
to include warnings related to 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
207
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?
Note that question one is slightly
different than the question in the
briefing book
and that we used the term "severe
asthma
exacerbations" in this question.
Question three, also related
to
salmeterol, which is what further
investigation, if
any, do you recommend to be performed by
GSK, the
sponsor, that can improve the
understanding of the
nature and magnitude of the risk of
salmeterol?
That concludes my presentation
and I would
like to turn the podium over to Dr.
Gunkel.
Formoterol
DR. GUNKEL: Good afternoon. My name is
Harry Gunkel. I am also a medical officer in the
Division of Pulmonary and Allergy Drug
Products. I
will be reviewing with you some data
pertaining to
the second of the drugs that we are
considering
208
today, formoterol.
In this portion of the program, after
briefly introducing the product, I will
summarize
those elements of the regulatory history
that have
brought us to this point today. As Dr. Chowdhury
stated this morning, and somewhat
differently from
the situation with salmeterol, the story
of asthma
exacerbations win formoterol was really
told in the
NDA review of the Phase 3 studies. So, we will
spend some time reviewing the results of
those
studies that are relevant to today's
topic.
Next, we will briefly review
the Phase 4
postmarketing study with Foradil; then
report the
findings from a recent review of
spontaneous
postmarketing reports, and then
summarize and offer
some concluding observations.
The only formoterol product
approved in
the United States at this time is
Foradil,
manufactured by Novartis who we heard
from this
morning.
Some of the data that I will show you
today will look familiar to you. Foradil is a dry
powder formulation for inhalation with
the
209
aerolizer device. It is a racemate of two
enantiomers of formoterol fumarate.
So, let's briefly review some
of the
relevant milestones of the regulatory
history of
Foradil.
In a few minutes I will review in more
detail the important Phase 3 studies and
the
results.
For now, I want to just point out the
findings that affected Foradil's
regulatory status.
Foradil is approved for asthma, COPD and
exercise-induced bronchospasm but, as
Dr. Chowdhury
noted earlier, our interest today is
confined to
asthma.
The new drug application for
Foradil for
use in asthma was first submitted in
June of 1997.
The clinical program that comprised the
NDA
investigated 2 different doses of
Foradil, 12 mcg
administered twice daily and 24 mcg
twice daily.
You will see as we go on that these
doses, which
were used in adolescents and adults,
were also used
in children.
The result from the Phase 3
studies that
concerns us today was the finding that
patients who
210
had received the higher dose of
formoterol
experienced more serious asthma exacerbations
than
those who received the lower dose, and
we will see
those specific results in just a
moment. At the
same time, the reviewers found no
evidence that the
higher dose consistently resulted in
greater
efficacy. Therefore, only the lower dose of
Foradil, the 12 mcg BID dose was
ultimately
approved in February, 2001. We saw in Dr.
Seymour's presentation that the events
of concern
that occurred with salmeterol did not
occur
commonly and so it was also with serious
asthma
exacerbations that were observed win
formoterol.
The Division was interested in
further
investigation of the event but believed
that
routine postmarketing surveillance would
not be
eliminating when the event of concern
was also the
underlying disease being treated. So, given these
circumstances, the Division asked
Novartis to
commit to conduct a Phase 4 study. Novartis did so
and conducted a Phase 4 study to obtain
additional
information about doses of formoterol
other than
211
the one approved.
It is important to note two
things.
First, the Division's judgment about the
relative
safety of the higher dose of formoterol
was
informed by the results of the Phase 3
studies in
the NDA and not from the results of the
Phase 4
study that followed. Second, the Phase 4
formoterol study was planned and
designed before
results of the SMART study were known.
With that regulatory
background, let's
move on to review some of the Phase 3
data. For
all practical purposes, 3 clinical
studies
comprised the pivotal evidence for the
efficacy and
safety for formoterol in asthma. Dr. Geba
introduced you to studies 040 and 041
that were
performed in adolescents and adults 12
years of age
and older. The third study was 049, a study of
children 5-11 years of age. The FDA reviewer's
conclusions about the safety of the 2
doses of
formoterol were primarily formed from
the results
of these 3 studies.
Studies 040 and 041 were
essentially
212
identical, except that 041 included some
pharmacokinetic measurements. Both studies were
randomized, double-blind, placebo- and
active-controlled 12-week studies in
asthmatics 12
years of age and older who had FEV1 40
percent or
more of predicted and 15 percent
reversibility of
their bronchoconstriction.
Patients were randomized in approximately
equal proportions to 1/4 treatments,
Foradil 12 mcg
BID, Foradil 24 mcg BID, albuterol 180
mcg QID or
placebo.
The pediatric study, 049, enrolled
children from 5-12 years of age whose
FEV
1 was
50-85 percent of predicted and who also
had 15
percent reversibility.
This study was similar to the
other
studies in using the same doses of Foradil, 12 mcg
and 24 mcg BID, but was different in not
including
an active control group. Also note that this was a
one-year study with an objective of
evaluating for
long-term safety of Foradil for
children.
Before we review the adverse
event results
of these studies, let's look at results
of the
213
bronchodilator effects of the treatments. This
graph summarizes the results. The graph displays
FEV 1 results
over the 12-hour post-dose
period at
the last study visit. Time in hours is shown
across the horizontal axis. Average FEV
1 in liters
is on the vertical axis. These results are from
study 040 and the results were
essentially the same
in study 041.
Results for the placebo group
are shown in
open circles and for the albuterol group
in open
triangles. The other 2 curves represent the
formoterol doses. The 24 mcg dose of formoterol is
shown in closed circles and the 12 mcg
dose is
shown in open squares. As you see, bon formoterol
doses were significantly better than
placebo.
Although the 24 mcg dose was
significantly better
than the 12 mcg dose at some individual time
points, there were no significant
differences at
other time points and the results were
inconsistent
between the 2 studies. There were no differences
in the areas under the curve. As mentioned
earlier, the lack of difference in
efficacy between
214
then formoterol doses was weighed in
evaluating the
adverse event findings.
This slide summarizes the
heart of the
matter.
The rates of serious asthma exacerbations
are shown in each of the 3 NDA pivotal
studies. As
you see, the absolute rates of the
events are low
but the differences between then
formoterol doses
in each study are evident
nevertheless. In each of
the 2 adult studies there were more
serious asthma
exacerbations in the 24 mcg dose group
than in the
12 mcg dose group, and more than in the
albuterol
and placebo groups as well.
Three adult patients had events of
particular severity. One patient in study 040 who
received the 24 mcg dose, a 24 year-old
male,
required intubation and mechanical
ventilation for
his exacerbation. In study 041 a 66 year-old
female experienced cardiorespiratory
arrest and
died, and a 49 year-old man had a
respiratory
arrest but survived.
Note that the overall rates
are higher in
the children in study 049, as was
pointed out this
215
morning, but also that the
proportionally greater
rate of events in the higher don
formoterol group
is maintained in this study. Recall two factors
that might contribute to the higher
incidences of
events in children. First, there was no adjustment
of doses given to children. So, these higher rates
may reflect relatively higher doses
given to
children on a body weight basis. But also, the
pediatric study duration was 1 year
versus 12 weeks
for the other 2 studies, allowing more
time for
events to be reported.
So, to summarize the relevant
issues that
arose from the Division's review of the
Foradil
NDA, as a result of more serious asthma
exacerbations occurring in the higher
dose
formoterol group and no efficacy
advantage, that
dose was not approved. Serious asthma
exacerbations were seen consistently
across the 3
pivotal studies and were more pronounced
in the
pediatric study. Finally, a commitment was made to
conduct a Phase 4 study to obtain
additional
information.
216
It is important to reiterate
here that the
Division's concern about asthma
exacerbations
associated win formoterol had been
substantiated
within the NDA itself, and it was not
the purpose
of the Phase 4 study to do that. That said, let's
examine the Phase 4 study and its
results.
This was a randomized,
parallel group,
placebo-controlled study with a 16-week
treatment
period.
There were 5 clinic visits during the
treatment phase of the study. For the study to
provide useful comparison to the Phase 3
results,
it was desired that the patients
enrolled in this
study should be as similar as possible
in
characteristics likely to affect the
outcome of
primary interest, asthma
exacerbations. Therefore,
patient entry criteria were in most
identical to
those used in the Phase 3 studies. Note that
children were not included in this
study. Indeed,
as we will see in a moment, the original
study
protocol was confined to adults and it
was only
upon amendment that adolescents down to
12 years
were allowed in the study. Events that might have
217
indicated recent exacerbations or
altered state of
the underlying disease as indicated by
changing
medications were appropriately a basis
for
exclusion from the study.
Patients were randomized in
approximately
equal proportions to receive 1/4
treatments during
the study, as shown. The 2 Foradil adult dosage
groups were treated in double-blind fashion,
while
the fourth group, who received extra on
demand
doses of Foradil, were treated in an
open-label
fashion.
Albuterol rescue was allowed during the
study, with more doses allowed for the 3
double-blind treatment groups.
The study was conducted over a
2-year
period between February, 2002 and March,
2004. All
told, 2,085 patients received
treatment. Of those,
about 86 percent completed the
study. Of the 294
patients who did not complete the study,
the most
common primary reason was occurrence of
an adverse
event.
This was the case for 103 patients overall
or 4.9 percent of the total treated
population.
Other reasons for discontinuing the
study early are
218
noted on the slide.
After this study started the
Global
Initiative fir Asthma promulgated
guidelines for
the management of asthma. The sponsor of the study
and the investigators determined that
the study
criteria were not consistent with these
guidelines,
particularly in the use of inhaled
corticosteroids,
and so the protocol was amended during
the course
of the study to, in effect, liberalize
the
concomitant use of inhaled
corticosteroids.
A third amendment about half
way through
the study was enacted in order to
accelerate
enrollment because patient accrual was
lagging
behind projections. This amendment made several
changes, including lowering the age of
eligibility
to 12 years; changing the criterion for
FEV
1
reversibility from 15 percent observed
to 12
percent historical; and shortening the
washout
periods required for other medications
for example.
The next 2 slides display the
baseline
characteristics of the 4 treatment
groups. In the
far right column of these tables the
same
219
characteristics from all patients in the
Phase 3
studies are shown to allow us to examine
whether
the populations were reasonably
comparable. For
some characteristics, for example, age
and gender,
the populations were similar. Note, however, that
the proportion of African American
patients in the
Phase 4 study was about twice that in
the Phase 3
studies.
Also note the higher FEV1 reversibility
of patients in the Phase 4 study, which
probably
reflects the amended entry criteria that
were just
described.
For characteristics indicating
acute
asthma exacerbations in recent past, the
preceding
year, the study treatment groups were
about the
same.
These data suggest a population in
relatively good control, with fewer than
10 percent
needing an ER visit or hospitalization
in the
preceding year.
On this slide is a summary of
the outcomes
of primary interest from this study,
adverse
events.
The treatment groups and the number of
patients in each are shown across the
top row. No
220
deaths at all occurred in this
study. More than 50
percent of patients experienced an
adverse event of
some kind. Between about 10-16 percent of patients
experienced asthma-related adverse
events.
Determining whether an adverse
event was
asthma-related or not was prospectively
defined by
the study protocol. It was an event with one of
the following MedDRA preferred terms,
cough,
wheezing, dyspnea, dyspnea exacerbated,
status
asthmaticus, respiratory distress,
bronchospasm,
acute respiratory failure or
hypoxia. the fourth
row down shows the number of those
asthma-related
AEs that met the regulatory definition
of serious.
There were only 9 such events in total
in this
study of more than 2,000 patients. In all 9 cases,
hospitalization was the event that
categorized the
event as serious. One patient required intubation
and mechanical ventilation for his
exacerbation.
He was a 51 year-old man who received
the 24 mcg
dose of formoterol on the study.
Serious asthma exacerbations
per se was
not a specific endpoint prospectively
named or
221
defined by the sponsor in this
study. I call your
attention to the next row in the
table. I would
like to state that no patients with
serious AEs
were excluded in this review. However, we were
interested in which patients with
serious
asthma-related AEs actually had
specifically
serious asthma exacerbations. There were 2 such
patients who had a serious
asthma-related AE which
was not an exacerbation. The 2 that were not were
both in the low formoterol dose
treatment group.
In both these patients the verbatim
event that met
the asthma-related criterion was
respiratory
distress. In one patient, however, the respiratory
distress was judged due to a myocardial
infarction
and, in the other, due to
pneumonia. Finally, the
last row in the table shows the number
and
proportion of patients in each group who
had an
asthma exacerbation of any kind or
seriousness.
This table provides more
detailed
information about the 9 patients with
serious
asthma-related AEs. There were 12 events in the 9
patients, with some patients having more
than 1
222
event.
Of these 9 patients, 2 were African
American.
This slide more succinctly
summarizes the
key results from the formoterol data we
have been
considering. It shows the number and proportions
of patients by treatment who had serious
asthma
exacerbations. The 4 studies of interest, the 3
pivotal Phase 3 studies and the Phase 4
study, are
shown in the 4 rows of the table.
To recapitulate, serious
asthma
exacerbations occurred more frequently
in the
higher don formoterol group in the Phase
3 studies
and the effect was more pronounced in
the children.
No difference was seen in the Phase 4
study, and
this slide illustrates that the rate of events
in
the 24 mcg dose group was, in fact,
quite a bit
lower overall in the Phase 4 study than
in the
Phase 3 studies.
Before concluding, let's
briefly go over
the results of a recent review of
postmarketing
spontaneous reports on formoterol. The Adverse
Event Reporting System database contains
180
223
domestic reports for formoterol as this
past June
14th. Eleven of those reports were for
bronchospasm and obstruction
events. Since the
year of marketing, 2001, there have been
4 domestic
reports of deaths in patients receiving
formoterol.
Two of those deaths were caused by myocardial
infarction and the causes for the other
2 were not
reported.
The following points are
offered in
conclusion: First, the observation made upon
review of the Foradil NDA that serious
asthma
exacerbations occurred more frequently
with 24 mcg
BID of formoterol than with 12 mcg BID
was the
basis for not approving the higher dose.
Second, the serious asthma
exacerbations
were more frequent overall in children
who received
the same nominal doses of formoterol as
adults in
children and were studied in a 1-year
study.
Finally, a Phase 4 study of
limited size
and restricted to adults and adolescents
did not
provide any additional information about
these
events.
224
With that brief review, let's
restate the
questions to the committee: 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?
And, based on the currently
available
information, do you agree that
formoterol should
continue to be marketed in the United
States?
Next, 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? Thank you.
Questions for the
Speakers
DR. SWENSON: We now have about 10 minutes
to take questions to both these speakers
for the
FDA presentation. Dr. Schoenfeld?
DR. SCHOENFELD: I guess I said this
before but I will repeat it, I think
that if we are
225
going to do a risk/benefit analysis at
some point,
then to counterbalance the benefit the
risk should
be couched in terms of the attributable
risk, which
would be the difference, I guess, in the
event rate
on the two treatments. I have calculated that,
roughly speaking but I just had to do it
on-the-back-of-an-envelope, that for
salmeterol the
risk for asthma deaths--and it is
similar for
everything else, there are about 10
events per
26,000 patient-years of follow-up. So, the risk is
1/2,600.
I just wondered, you know, do you have
any tabulation in your database of all
those risks
for the various subgroups, or at least
could you
confirm whether I am right here?
For the other compound, the
actual total
patient follow-up that is reported is
something in
the order of 260 patient-years of
follow-up. So,
it is so small an amount of follow-up
that risk at
the rate of 1 per 2,600 would be
completely
undeterminable.
But if someone in the agency
is sort of
done these calculations, I would much
prefer to see
226
those rather than what I do on the back
of an
envelope.
DR. SEYMOUR: We have not performed those
calculations based on patient years.
DR. SWENSON: Dr. Schatz?
DR. SCHATZ: I was wondering, in the SMART
study, whether the NDI surveillance
included those
who had discontinued the trial.
DR. SEYMOUR:
I have to defer that to the
sponsor; I am not quite sure.
DR. KNOBIL: The NDI database included
everyone who had been enrolled in the
study whether
or not they had discontinued study drug.
DR. SWENSON: Dr. Gay?
DR. GAY: I will restate a question that I
asked previously to the sponsor. We do see an
increase in adverse events in children
but,
clearly, that is a much longer
study. Is there any
breakdown of the timing of these events
within 90
days, within 180 days, within the final
6 months of
the study?
DR. GUNKEL: I have a little bit of
227
information, not everything that you
would like. I
was able to find that information for
the children
who received the 24 mcg dose, the dose
really of
concern.
There were 11 children who had serious
asthma exacerbations in that study
overall. Five
of those 11 occurred after day 84, which
would be
12 weeks. So, if we try to compare the children to
the adults, for example, that were in a
12-week
study, then the rates up to that 12-week
time point
are roughly comparable in children
versus
adults--with all the usual caveats about
the
studies weren't designed to do that, and
so forth.
I don't have similar information for the
12 mcg
dose group.
DR. SWENSON: Dr. Brantly?
DR. BRANTLY: This is a question for Dr.
Seymour.
Dr. Seymour, we know that socioeconomic
status plays a big role in adverse
events and
asthma medications. I was wondering if there had
been any attempt to stratify the cohort
for the
SMART trial as far as socioeconomic
status,
particularly those individuals that were
associated
228
with severe adverse events.
DR. SEYMOUR: I am not aware of any
stratification but I can ask the company
if they
have done any type of socioeconomic
stratification.
DR. KNOBIL: We did not collect much SES
data.
What we did have, we had educational level
and we had zip code. So, we only have very crude
measures. So, we did what we could with what we
had and we didn't see any impact of
income based on
zip code or educational level.
DR. SWENSON: Dr. Martinez?
DR. MARTINEZ: I have two questions for
Dr. Seymour. First, if I understand correctly from
your slide 19, discontinuations were
very similar
in
the salmeterol and the placebo group and,
therefore, in this case attributing the
results
perhaps to different rates of
discontinuation in
both groups wouldn't be fair. Am I interpreting
the data correctly?
DR. SEYMOUR: Yes, I think so. The
discontinuation rates were similar
between
treatment groups.
229
DR. MARTINEZ: The second question is that
in
the materials provided to the advisors there is
a stratification by the baseline percent
predicted
peak flow, which is the only type of
information
that I could gather with respect to
severity. If
we are going to consider that 60 percent
peak flow
or below is more severe than more than
60 percent
peak flow, you haven't commented at all
about that.
The interpretation that at least I make
is that
there appear to be different ways in which
this
behaves in this post hoc type of
analysis. For
combined respiratory-related death or
life-threatening experiences, it appears
that it is
those subjects who have more severe
disease, if
peak flow can be considered disease or
even perhaps
more related to what could be considered
COPD in
adults, who show more risk than those
with a higher
peak flow. For asthma-related deaths, it is
difficult to say anything but there
doesn't seem to
be a very clear difference between the
two groups.
Has the agency interpreted that table in
any way
similar or different to the one I just
proposed?
230
DR. SEYMOUR: I need to know what page you
are referring to.
DR. MARTINEZ: It is page 45 of the
materials provided to us, page 45 of the
section
called "salmeterol postmarketing
study review,
SMART study."
DR. SEYMOUR: Just a second. I can tell
you I don't think we have formed any
formal
conclusions based on this data.
DR. MARTINEZ: Just to propose an
interpretation, what I can see here is
that the
rates that are observed for
asthma-related deaths,
although they cannot be calculated for
the less
than 60 percent, see by the absolute
numbers don't
look very different. In other words, there appears
to be an increase in asthma-related
deaths both for
those that have more than 60 percent and
for those
that have less than 60 percent.
DR. SWENSON: Dr. Schoenfeld?
DR. SCHOENFELD: I just want to understand
whether the analysis of severe adverse
events was
intent-to-treat. That is, if a patient stopped
231
medication but then still, during the 28
weeks of
follow-up in the SMART study they had an
event,
they would count it, I assume? And, what about in
the other studies?
DR. SEYMOUR: My understanding of SMART is
that that is correct, it was on an ITT.
DR. SCHOENFELD: And the other studies?
DR. GUNKEL: The same.
DR. SWENSON: Dr. Moss?
DR. MOSS: I have a question that kind of
builds on what Dr. Schoenfeld talked
about and a
little bit about what Dr. Meyer talked
about this
morning.
It seems to me that we are being asked to
compare two studies that are different
in terms of
the size of the studies. So, it is very hard for
us in the Foradil study to draw
conclusions be the
study is a lot smaller. I was just wondering, Dr.
Meyer, if you could talk in a little bit
more depth
about why the SMART study had 26,000
people in it,
and what was the thinking of the FDA to
have the
Foradil study only have 2,000 or so in
it. I
realize you are looking for different
outcomes but
232
what was your thought process in asking
them to do
those Phase 4 studies very differently?
DR. MEYER: Sure.
I think, first off, it
would be wonderful to have such a large
outcome
study of formoterol but we don't, and
that was not
the purpose of the Phase 4 commitment. In the
Phase 4 commitment we saw a dose
response or an
apparent dose response phenomenon for
the outcome
of serious adverse events in 12-week
studies and we
wanted to reassure ourselves, since we
were not
approving the 24 mcg dose, that in fact
this was a
real finding. We also wanted further data to
relate even the 12 mcg dose to placebo
in that same
kind of setting.
So, while we, again, would
have liked to
have had a SMART-like study of
formoterol as well,
that really wasn't the question that was
being
posed in asking for the Phase 4
commitment. The
Phase 4 commitment was really to try to
better
clarify what we had seen in the Phase 3
studies in
terms of an apparent dose relationship
to adverse
events and whether that 24 mcg dose
really would
233
prove to have a clear safety signal in
relationship
to the 12 mcg dose.
Open Public Hearing
DR. SWENSON: Any further questions?
[No response]
At this point, we are moving
into the open
public hearing session. To begin this I need to
read a short statement and we will have
at least
one discussion or statement from a
public member.
Both the Food and Drug
Administration and
the public believe in a transparent
process for
information gathering and
decision-making. To
ensure such transparency at the open
public hearing
session of the advisory committee
meeting, FDA
believes it is important to understand
the context
of an individual's presentation.
For this reason, the FDA
encourages you,
the open public hearing speaker, at the
beginning
of your written or oral statement to
advise the
committee of any financial relationship
that you
may have with the sponsor, its product
and, if
known, its direct competitors. For example, this
234
financial information may include the
sponsor's
payment of your travel, lodging or other
expenses
in connection with your attendance at
the meeting.
Likewise, FDA encourages you, at the
beginning of
your statement, to advise the committee
if you do
not have any such financial relationships. If you
choose not to address this issue of
financial
relationships at the beginning of your
statement,
it will not preclude you from speaking.
At this point, I would like to
ask Mr.
Chris Ward to come to the podium. Mr. Ward, your
podium.
MR. WARD: Thank you.
Good afternoon. My
name is Chris Ward. I am an asthma and allergy
patient and current president of the
Asthma and
Allergy Foundation of America. We have not
received payment from any entity for
this testimony
or for the cost of our travel and
participation in
this meeting today.
On behalf of the almost 20
million
Americans with asthma, AAFA appreciates
the
opportunity to testify to this advisory
committee
235
concerning the safety of long-acting
beta agonist
bronchodilators. Since 1953, AAFA has been
dedicated to improving the quality of life for
people with asthma and allergies. Patients, their
families and their caregivers turn to
our
organization for education, research and
advocacy.
AAFA appreciates the heightened
vigilance
at the FDA regarding drug safety and
thanks the
advisors for reviewing the available
data and
meeting today to discuss potential
safety concerns
with this class of drugs. Asthma, of course, is a
treatment-intense condition for many
patients and
your advice to the agency today will
impact
millions of individuals who depend on
these
products as part of their regimen for
asthma
control.
There are three key messages I
would like
to convey on behalf of patients with
asthma.
First, as we understand it, there are no
concerns
with the efficacy of this class of drugs
and their
important role in asthma control, which
is
reflected in both the national and
international
236
guidelines for asthma clinical care that
use the
word "preferred" when
recommending these products
in conjunction with inhaled
corticosteroids for
moderate to severe persistent
asthma. There is
strong, consistent evidence from
clinical trials
that this approach leads to improvements
in lung
function and symptoms, and reduces the
need for
short-acting beta agonists. When we weigh this
evidence of effectiveness against the
evidence of
potential risk which is, at best, still
undefined,
we believe it would be difficult for
asthma
patients to understand why these
products would not
continue to be available to them.
Second, we believe there is an
element of
scientific and clinical progress in
asthma that may
be missing from this discussion. Mainly, there
seems to be progress in the pharmacogenomic
understanding of how beta agonists have
different
effects in different individuals. We believe the
results of the government trial,
published last
October, demonstrating different
responses to the
short-acting beta agonists based on
genotype is an
237
important step forward. We understand that a
similar clinical trial is just now
getting underway
for the long-acting beta agonists. In other words,
from the perspective of asthma patients,
there is
current and ongoing investigation into
this
important clinical question. We understand very
well that a subset of patients may be at
higher
risk than others. But we are only beginning to
understand why this is the case. At this point in
time then, it would seem advisable to
defer any
conclusive decision about the
availability of these
drugs to all patients until there are
more
definitive answers.
Third, with regard to the
consideration of
whether the labeling changes to
salmeterol should
be approached with formoterol, it is our position
that FDA's responsibility lies in
working closely
with the product sponsor to answer this
question
and to determine a product label that is
consistent
with the available medical
evidence. In fact, we
are encouraged that both product
sponsors are
working closely with the agency to
further
238
understand and clarify the nature and
magnitude of
potential risk of this class of
drugs. We believe
the safety of asthma patients should be
front and
center in this ongoing work.
In conclusion, we certainly
urge all
parties to continue this important
discussion.
however, AAFA believes that at this time
there are
too many questions to be able to draw
conclusive
decisions on medications that have been
effective
for millions of patients to be able to
control
their asthma.
Again, on behalf of these
patients, I
thank you for the opportunity to testify
on this
important issue and I am pleased to
answer any
questions you might have. Thank you.
Committee Discussion
DR. SWENSON: Thank you, Mr. Ward. At
this point the meeting schedule calls
for a break
but we are somewhat ahead of schedule so
what I
would like to do is to move into our
committee
discussion section, and we will have a
break at
some mid point there. The first part then of this
239
committee discussion would be open now I
think to
general questions to all parties
involved and
further exposition of points that may
not have been
raised earlier this morning. We will then break,
at which time we will come back to our
vote on the
specific questions that are being asked
of us by
the FDA.
So, to begin with, we had two people
earlier this morning that I had to close
out and I
will ask Dr. Kercsmar if she wishes to
pose her
question from this morning.
DR. KERCSMAR: I had a question regarding
other medication use in the SMART trial
that maybe
the sponsor can answer. During the 4-week
follow-up telephone calls, were there
any data
obtained on other medication use,
particularly the
use of short-acting beta agonists?
DR. KNOBIL: Well during each 4-week
follow-up telephone call the patients
were asked if
they were continuing on the medications
that they
had said that they had started at
baseline or at
the previous call, and if they had
started or
stopped any new medications or any of
their old
240
medications. So, if anything was stopped,
obviously, they were asked which ones
were stopped
and which ones were started.
During the course of the study
there were
some patients who did stop and start
medications
but, for the most part, throughout the
study
patients remained on their beta
2 agonists.
We
didn't ask them how much of their
short-acting beta
agonists they were taking however so we
don't have
any information on that.
DR. SWENSON: Dr. Gay, you had one
question from this morning.
DR. GAY: It was answered earlier, thank
you.
DR. SWENSON: Dr. Gardner?
DR. GARDNER: This question is for Dr.
Knobil as well. It is very impressive that you
have done such a large study and it must
be as
frustrating to you as it is to us to
hear people
periodically say, as they have today,
well, we
really can't learn anything from this
because there
were only 26,000 people there, or
something like
241
that; we can't draw any
conclusions. And, I know
how difficult these are to do. However, you have
given us data also from the SNS study
which was
conducted in England, and published, and
it is
commented that in one year of enrollment
they
enrolled 25,000 people. And, in the SMART trial
over seven years you had about the same
number of
people.
I am wondering what changed during the
intervening approximately five to six
years that
made enrollment so much more difficult
here.
Because, Dr. Castle comments in her
paper that
companies are often accused of delaying
things so
that they can stop enrollment when they
aren't
getting enough, and it is kind of an
indictment by
Dr. Castle who, by the way, was a Glaxo
employee.
So, can you help us understand why it
seemed to
have been easier to enroll that many
people in a
year in England?
DR. KNOBIL: Well, I can't really comment
on how easy it was to enroll in England
since I
wasn't involved with the initial
study. However, I
do know that for SMART one of the major
stumbling
242
blocks was the fact that patients could
not have
had any exposure to long-acting bronchodilators
to
begin with. As enrollment waned over the course of
the time, we actually held focus groups
with
physicians and patients to figure out
why we
weren't able to get more patients in the
study more
quickly.
Again, what came out was that many
patients were already taking long-acting
inhaled
beta agonists. They were not interested in the
placebo-controlled trial. There were a lot of new
medications coming out during the time
that the
study was running. So, the interest level for the
study went way down. That is the feedback we got
from our investigators and the patients
who may
have been enrolled. So, those were the major
factors.
DR. KERCSMAR: That is helpful. Thank
you.
DR. SWENSON: Dr. Schatz?
DR. SCHATZ: Well, I hate to keep going
back to the same thing but I think it is
important
to understand. Now I am confused. Intent-to-treat
243
based on people who discontinue
medication but are
still in the study is one thing but then
there are
the people who drop out. Although the percentages
are similar statistically, numerically
they are
still greater in the salmeterol
group. Do you
think the surveillance for adverse
events is
comparable in those who dropped out
versus those
who didn't drop out?
DR. KNOBIL: There is one point of
clarification. It was statistically significantly
different in the number of patients who
dropped out
of the study in the placebo group versus
the
salmeterol group. More patients on placebo did
drop out.
Now, over the course of the
study we did
follow up with the patients. Even if they dropped
out of the study and said they didn't
want to take
study medication, we still attempted to
contact
those people and get follow-up
information up to
the 28 weeks and actually even beyond
that as the
FDA has already mentioned. We would collect that
information up to 6 months after if we
could get
244
that information. But for the deaths we did look
for all patients enrolled in the study
by the NDI
database. So, at least for the deaths we were able
to
follow-up on those more than, say, patients who
refused to be contacted any further.
DR. SWENSON: Dr. Knobil, I have a
question from this morning that I wasn't
able to
ask and since you are standing I will go
ahead and
pose it to you. That is, in the SMART study--and
you just alluded to the fact that a zip
code
analysis as a proxy for socioeconomic
status and
questions unrelated to the biologic
activity of the
drug turned out negative, and you are
going to
reiterate that that was definitely a
negative
finding--
DR. KNOBIL: Yes.
DR. SWENSON: --that you found no
information by that analysis?
DR. KNOBIL:
No, and to be fair, the
analysis by zip code is quite a crude
way to look
at socioeconomic status and we really
didn't find
any differences between the groups and
nothing to
245
suggest that that was involved. However, if we had
had more detailed information that might
have been
a little bit more helpful.
DR. SWENSON: Okay, and the second part of
my question then was, given that there
was a
difference in the use of inhaled
corticosteroids
between Caucasians and the African
American
subgroup, did you make any effort to
attempt any
type of matching with the two
groups? For
instance, could you have pulled out a
cohort of
Caucasians that had the same rate of
inhaled
corticosteroid use as the African
American group,
and then did that yield any further
information?
You may not have done it but I am just
asking.
DR. KNOBIL: Well, we discussed matching
to try to get to a better understanding
of the
events, and the numbers of events are so
low that
even if you found somebody to match the
amount of
information that you would get out of that
is not
really very helpful, and I would turn to
our
statistician to see if there is anything
else that
I could add to that.
246
[Not at microphone; inaudible]
DR. KNOBIL: For those of you who didn't
hear that, he said the event rate was
still too low
to be able to do that.
DR. SWENSON: Thank you.
Miss Sander?
MS. SANDER: Am I to take it from your
presentation that kids need less
formoterol? I
think it said in one of your slides
that--no?
DR. GUNKEL: That is one possible
explanation for the difference in the
rates that we
saw.
The other is simply the duration of the
study, but one other possibility is that
they do
need, on a body weight basis, less
formoterol but
we can't say that definitively and
conclusively
from our data.
DR. SWENSON: Just a quick point here,
when we have this queue of questions it
is
difficult for anyone else to activate
their
microphone. So, if you have a question go ahead
and signify that you are ready. We will note it
and then have you in line. Thanks.
Our next
question is by Dr. Newman.
247
DR. NEWMAN: Thank you.
One question that
I have to the sponsors, and maybe the
FDA has a
comment on this as well, that is, when I
look back
at how, at the SMART study, was powered
and then,
in turn, one thing we are struggling
with is having
such a low frequency of serious adverse
events--first of all, I am glad there
are so few
serious adverse events; fundamentally
that is
good--but I wonder if I could have you
help explain
to me why that frequency of serious
adverse events
was so much lower than was
expected. Is there
something different about the kinds of
people who
were recruited into these studies that
would lead
us to have this much lower rate?
DR. KNOBIL: Well, as you can imagine,
powering the study was very difficult to
do because
when enrolling an asthma population
there are no
statistics out there that would tell you
what the
rate of events would be per asthma
patient. For
example, CDC statistics give you the rate of
events
for the total population, not just for
the patients
who have the disease in question. So, we
248
extrapolated from that. For example, the total
number of asthma deaths that occurred--I
believe it
was in 1994 at the time--divided by the
estimated
number of patients in the United States,
and
started from there.
Then, in order to get some
information
about life-threatening events, we sent
out a
questionnaire to over 100 hospitals to
tell us how
many per asthma death or per respiratory
death how
many intubations would you have? So, since there
was no information in the public domain
for this,
this was the best way that we could get
that type
of information. It turned out it was about 5
intubations per respiratory-related
death. Then,
taking into account more severe asthma
and the
higher rate in the African American
population, we
came up with the powering that we
did. If you want
anything more specific than that I will
have to
turn it over to someone who was more involved
with
the power calculations.
DR. SWENSON: Dr. Prussin?
DR. PRUSSIN: I also have a question for
249
the Glaxo team. You know, inhaled corticosteroid
and long-acting beta agonist therapy is
really the
standard of care for all mild
asthmatics, and for
the foreseeable future this is going to
be the
standard of care as far as we can tell,
for the
next ten years--five years, ten years. So, it is a
huge issue that involves huge numbers of
patients.
You mentioned a Medicaid study. Can you elaborate
on that a little? Because I think one of the
charges we have is what types of future
studies are
needed to address this and at least I am
still not
clear as to the details of that study.
DR. KNOBIL: Yes, what I will do is I will
turn it over to Courtney Davis who is an
epidemiologist with us.
DR. DAVIS: Hi. I
am Courtney Davis,
senior director of epidemiology for
GlaxoSmithKline. Our Medicaid study involves data
from 7 states in roughly the same time
period as
the SMART trial was conducted. It is 1994 through
1999 Medicaid data. For each state the Medicaid
claims data will be matched to the death
250
certificate files for all of those 7
states. So,
that is how we will obtain asthma
mortality and
respiratory-related mortality data. In addition,
of course, the claims will have the
hospitalization
data equivalent to the SMART outcomes as
well.
Because Medicaid is one of the only
available databases for epidemiology
research that
includes race, we will be able to
stratify the
analyses and look at African Americans
and
Caucasians separately so we can address
the
differences that were observed by
race. And,
because this is longitudinal data on
these
patients, including their pharmacy
records, we will
be able to look at potential effect
modification by
inhaled steroid use as well.
DR. PRUSSIN: Are you going to be able to
stratify asthma severity?
DR. DAVIS: The best we can will be using
proxies that will be available in the
claims
database. The longitudinality of the records, of
course, vary. We have data at this point that has
come in for 5 of the 7 states. On average the
251
follow-up is about 12 months, 11.7
months of data.
So, we will be able to look back as far
as we can
in terms of prior utilization that
includes serious
events like hospitalizations and, of
course,
prednisone use.
DR. SWENSON: Miss Schell?
MS. SCHELL: I guess I have some question
or clarification on the SMART survey
itself. Since
the variability of the different types
of patients
and their ability to assess themselves,
and you
just did phone follow-up calls, I wonder
what kind
of preparation you had for the patients
prior to
enrollment on how to assess themselves,
what they
considered was severe. I just don't know that they
were able to answer back consistently
over their
course.
Just clarification.
DR. KNOBIL: Yes, we had a whole telephone
script that was written in such a way as
to be as
understandable as possible to ask
patients about
whether they had been hospitalized or
whether they
had been intubated. Obviously, you are not going
to use the word "intubated"
but whether they have
252
had a breathing machine, something like that. I
will have to look over to someone who
has been
involved in the study from the beginning
but there
weren't any questions that asked them to
assess
just worsening. So, there wasn't any training on,
you know, how should they assess
worsening. There
was no diary card. There was no peak flow. There
wasn't anything like that. It was just mainly has
this happened to you? Have you changed your
medicines? Have you started any; have you stopped
any?
Have you had any averse outcomes?
DR. SWENSON: Dr. Moss?
DR. MOSS: I want to build a little bit on
what Dr. Prussin was talking about
earlier, and
this is a question for either the Glaxo
representatives or the Novartis
representatives.
It seems to me that part of the results
of this
SMART study and some of the Foradil
studies
potentially are related to the decreased
use of an
inhaled corticosteroid especially in the
African
American population. Would you guys agree with
that?
Do you think that some of these adverse
253
events would go away in the Serevent
group if 100
percent of the patients were on inhaled
corticosteroids? Do you think that is part of the
issue?
DR. KNOBIL: Obviously it is difficult to
say based on the data from SMART since
it wasn't
designed from the start to look at
inhaled
steroids. However, there is a suggestion that
inhaled steroids did have a positive
effect or
beneficial effect on these
outcomes. So, I do
believe that if more people were treated
appropriately for their asthma in
accordance with
the guidelines that we probably would
have seen
fewer events. I mean, that is just speculation.
DR. MOSS: I mean, we do these studies of
26,000 people and we still are left with
not a
definitive answer so at some point
everyone is
going to have to base things, in their
own mind, on
what they think is the right
answer. I think based
on the NHLBI guidelines in terms of
moderate and
severe persistent asthma, you could make
a very
good case that if somebody is on a
long-acting beta
254
agonist they should be on inhaled a
corticosteroid.
So, if part of the goals of this meeting
are to
disseminate information properly, then
maybe that
is something that should be
disseminated, and maybe
this would be a good network to do that
in.
DR. KNOBIL: Yes, I think it is important
to note that even from the time that
salmeterol has
been approved in the United States there
has been
language in the label that mentions that
early
consideration of anti-inflammatory therapy
should
be considered. So, this is probably not a new
thing.
Dr. Beasley?
DR. BEASLEY: I think we do have some
published data that can help answer your
question,
and that is taken from the United Kingdom
case-control study where a proportion of
asthmatics
in the control group who were taking
inhaled
corticosteroids was almost the same as
those taking
short-acting beta agonist drugs,
suggesting that
almost all patients were taking the
combination of
both an inhaled steroid and a
short-acting beta
agonist drug. In that scenario, where management
255
is very close to the recommended
guidelines, there
was no increased risk associated with
long-acting
beta agonist therapy. So, I think that we can
deduce from a study that was of high
epidemiological quality, where
management in the
control group was very close to what is
recommended
in the guidelines in terms of inhaled
steroid
therapy, that there is no risk observed
in relation
to long-acting beta agonist therapy.
DR. MOSS: I just want to say one thing in
response to that. I just want to say that I don't
think this is the entire issue, that if
everybody
was on an inhaled corticosteroid that
the effect
would go away. But I think most people in this
room I think would say that that is part
of the
issue, that people aren't being treated
in what
would now be considered the proper
manner. So, if
the goal here is to improve health of
the people in
this country, and people on NIH panels
and people
in this room feel that if someone is on
a
long-acting beta agonist they should be
on an
inhaled corticosteroid, then we should
try to
256
disseminate that information.
DR. BEASLEY: There is one other bit of
data that may be relevant to the African
Americans,
and that is that in New Zealand the
Maori
indigenous community had a far higher
rate of
mortality than the Caucasians, and it was
about the
magnitude of about three-fold or
more. With the
improvements in asthma management and in
particular
the use of inhaled corticosteroid
therapy and a
real emphasis on management within our
community,
that difference has largely resolved,
suggesting
that it is a reversible difference that
is amenable
to improvements in management.
DR. SWENSON: Dr. Newman?
DR. NEWMAN: I would like to ask both of
the sponsors a question which I asked
Dr. Sorkness
this morning but she didn't have an
answer. Based
on what we know today, and I know there
are other
studies going on but based on what we know
today,
on the benefit side of these long-acting
beta
agonists do we have reason to think that
there are
any racial differences in terms of
benefit? Do
257
African Americans benefit less from
long-acting
beta agonists? I am trying here to weigh the issue
of benefit versus risk.
DR. GEBA: Greg Geba, Novartis. In terms
of that analysis in our own data set, we
have seen
no difference in efficacy between
Caucasians and
African Americans in terms of the
endpoints that
were studies.
DR. NEWMAN: Were you powered to answer
the question do you think?
DR. GEBA: No.
The representation of
African Americans in our trials was
low. In the
most recent trial that we shared with
you before,
the 2307 study, it was actually about 8
percent and
there was no difference across treatment
groups in
terms of their response.
DR. NEWMAN: Just to make sure I
understand your answer, you didn't see a
difference
but you didn't have adequate power to
answer the
question?
DR. GEBA: No, it wasn't specifically
designed to look at that question.
258
DR. NEWMAN: So we don't know.
DR. GEBA: Right.
In terms of our usage
of
inhaled corticosteroids, it was about 70 percent
across all trials. There tended to be a slightly
lower incidence of any event in patients
that were
taking inhaled corticosteroids, as is
recommended
also in our label.
DR. KNOBIL: Similarly, we didn't have a
single trial that had enough African
American
patients to reach any conclusions, but
when we
pooled all of the data from African
Americans there
were no differences in response between
African
Americans and Caucasians.
DR. SWENSON: Dr. Kercsmar?
DR. KERCSMAR: I have another question for
GSK.
If you could clarify some of your planned
prospective trials, particularly those
that aim to
look at the influence of genotype or
some of the
polymorphisms in the beta receptor, if
you could
clarify what you hope to learn from
those trials.
I believe one of the ones that you
talked about is
using a combination product versus
salmeterol
259
alone.
The comment you made about difficulties in
enrolling patients, not wanting to be in
a
placebo-controlled trial in view of the
SMART data
that is out there, do you anticipate
being able to
fill this trial with patients not
wanting to go
into an arm that is salmeterol alone?
DR. KNOBIL: Well, I will answer the last
question first. It turns out that the genetic
trial that you have mentioned is
actually a little
bit ahead of schedule so we are doing
okay with
enrollment there. In this trial we are looking at
those two treatment groups, salmeterol
versus the
combination, with each phenotype that
has been
discussed today, the Arg/Arg, the
Arg/Gly and the
Gly/Gly.
I would ask Dr. Bleecker to stand up and
just tell us in a succinct way, I think
better than
I could, about what we can glean from
the study.
DR. BLEECKER: The trial that is ongoing
is a larger trial. There are six arms--and I could
be corrected, each with 90 individuals,
and they
are not just looking at the two
homozygote
genotypes at 16, the Arg/Arg, Arg/Gly
and Gly/Gly,
260
but also looking at the
heterozygotes. That is a
really important approach that has not
been done
for the most part until now. The kind of genetic
effect, if this is the risk genotype, is
that you
would expect or hypothesize some
intermediate
effects from the heterozygotes.
Also, the sample size in each of the arms,
90 individuals in each of the arms, I
think will
allow some better exploration of the
gene and what
we would call haplotype analysis looking
at a group
of snips across the gene to see if the
effect is
either due to that whole haplotype or
there is an
effect to variation, snips,
polymorphisms and other
parts of the gene. So, I think from the point of
view of advancing the understanding of
whether--and
this is still the question--there is a
risk
genotype that may be associated either
with varying
responses to drug or exacerbations, and
being able
to make those correlations this is a
very good
opportunity.
As I understand it as an outside
consultant, the African American study
that is
261
looking at exacerbations over a year
period will
also have the same kind of genetic
analysis. So,
again, that provides an opportunity for
the first
time in a large enough sample size to
look at
relationships, pharmacogenetic
relationships
between genotype and phenotype and
response in
African Americans.
DR. SWENSON: Dr. Brantly?
DR. BRANTLY: This is a question to both
the sponsors. In thinking about mechanisms by
which long-acting beta agonists might
have
increased morbidity and mortality, one
sort of
thinks about possibilities like, for
instance, that
these two drugs may be associated with
increased
inflammation rather than decreased
inflammation.
Sort of based on your experience with
the
preclinical animal studies in the Phase 1
and Phase
2 studies, was there any indication that
either of
these two drugs were pro-inflammatory,
particularly
for instance in bronchial biopsy studies
in the
Phase 1 and Phase 2 studies where there
may be some
increased inflammation?
262
DR. GEBA: Greg Geba, from Novartis. I
would be happy to respond on Novartis
side, if I
could ask Alex Trifilieff to come up to
respond to
this question in terms of our
preclinical studies.
DR. TRIFILIEFF If you look at all our
animal models that is something we look
at because
beta2 agonists, especially upon acute
exposure in
animal models, are
anti-inflammatory. So, we
screen in different animal models and we
always see
an anti-inflammatory effect. We never saw a
pro-inflammatory effect. These are the animal
model data for Phase 1 and Phase 2.
DR. DELLA-CIOPPA: We have conducted a
number of studies looking at
anti-inflammatory
markers with formoterol a few years ago
because
there was a rather big debate as to whether
these
agents actually had anti-inflammatory
activities,
and somehow they were used
inappropriately based on
this assumption. Rather large studies have been
published, mainly by the group in South
Hampton by
Prof. Holgate and in Sweden by Prof.
Sundstrom, and
we could confirm in several severities
that there
263
was no pro-inflammatory effect
associated win
formoterol taken alone.
There were, indeed, some
signals of a
reduction of some of the markers of
inflammation
but probably not to the extent of being
of clinical
relevance. But the few signals we did have went in
the opposite direction. These studies are
published.
DR. JOHNSON: I am Malcolm Johnson, from
GlaxoSmithKline. We had a similar experience in
the very early days of salmeterol
development. If
anything, we saw some mild
anti-inflammatory
effects in animal models. Clearly, they were not
predictive of what you might expect in
man. I
think you asked the question this
morning whether
there were any biopsy studies that have
been
carried out to address this issue, and there
are a
couple that I am aware of.
One study was conducted by
Prof. Peter
Jeffrey at the National Heart Lung
Institute, in
London.
It was a 6-week study in mild
steroid-naive asthmatics in which patients wee
264
crossed over between either salmeterol
monotherapy,
fluticasone propionate monotherapy or
placebo for 6
weeks.
Bronchial biopsies were taken and markers
of inflammation such as the numbers of
eosinophils
and T-lymphocytes and neutrophils in the
airway
tissue were assessed. I think the results were
very reassuring because in the salmeterol
monotherapy group there was no
indication of a
pro-inflammatory response and, as I
said, these
patients were steroid naive.
What was interesting in those
studies is
that there was a signal, which is to say
that there
was a reduction in neutrophils in the
tissue with
salmeterol that was not seen with
steroids. In the
steroid arm he saw a traditional
anti-inflammatory
effect of steroids whereby eosinophils
and T-cells
were reduced. So, the study was significant enough
to pick up an anti-inflammatory effect
of the
steroid that we are very well accustomed
to seeing.
There was no pro-inflammatory effect of
salmeterol
and this effect on neutrophils in
asthma, for
whatever that means.
265
DR. BRANTLY: Were any of the biopsy
studies done including blacks?
DR. JOHNSON: No, there were not. The
other thing that I think is interesting
just to
quickly add is that there are some
biopsy studies
that are being carried out that have
looked at the
impact of adding salmeterol to inhaled
steroids.
One study, again from Prof. Holgate's group,
showed
that, in fact, in patients who were
inadequately
controlled on low doses of steroids
where ongoing
inflammation was not controlled, and
that was shown
during the 3 months of the study, adding
the
long-acting beta agonist salmeterol to
that regimen
then controlled inflammation, and the
control of
inflammation was equivalent to a much
higher dose
of the steroid.
The final study, carried out
in Australia,
actually looked at an index of airway
remodeling.
They looked at angiogenesis in the
airways and,
again, a long-acting beta agonist with a
steroid
appeared to control the ongoing
vascularization of
the tissue. Now, these are limited studies but, to
266
answer your question, in all of these
together
there is no evidence of a
pro-inflammatory effect
and there may be some emerging evidence
of an
increased anti-inflammatory effect when
salmeterol
is added to steroids.
DR. SWENSON: Dr. Gardner?
DR. GARDNER: I would like to go back to
the Medicaid study. It is rare that we have a
database that is able to address so many
of our
questions. In the case of Medicaid, besides the
attributes you mentioned, we do have the
opportunity to look a bit at asthma
management. In
fact, I have done that in some Medicaid
data. So,
I would like to ask about what you have
planned, in
terms of what you can see from the
pharmacy data,
including adherence as measured by
refill patterns.
Is that planned? If not, would you plan it?
DR. DAVIS: Yes, thanks for asking that.
Persistency of use is part of our
protocol
currently. I neglected to tell you one more detail
about the study which may be of interest. Our
partner in conducting the study is
Research
267
Triangle Institute so they are actually
are linking
the data and doing the hands-on
analysis. So, GSK
is sponsoring the study and is very
actively
involved in writing the protocol as a
co-investigator but the lead
investigators are
located at RTI. In addition, we have a clinical
advisory board which is also advising us
on the
protocol and the clinical
interpretation, and that
includes Dr. Beasley who is here
today. It
includes Ann Fullbrighy[?], up at the
Channing Lab
at Harvard, and it also includes Sheryl
Winwalker[?] who is in Atlanta,
Georgia. So, we
have three outside clinicians who are
also advising
us.
But to get back to your
original question,
persistency of use is one of our
variables of
interest, including the regular use of inhaled
steroids because we know from other
observational
studies that intermittent use of inhaled
corticosteroids is often just a marker
of severity,
not necessarily associated with improved
outcomes.
DR. GARDNER: That was a good choice of
268
partner.
Can you tell us again, is it 2006 when
you expect these analyses to be
completed?
DR. DAVIS: That is right. The data from
5 of the 7 states have been obtained at
this point
so we are waiting on 2 more states, and
that
matching with the death certificates is
slower in
some states than others, as you could
imagine, so
once the additional data are received,
and we are
hopeful that it will be in the next few
months,
then the analytical portion will begin.
Also, just a final caveat, we
must have
sufficient power to conduct the study or
we will
not do a case-control study. The last thing we
would want to do is conduct another
study which
would be underpowered and raise more
questions
rather than answering them. So, we do have
criteria which must be met in order to
continue the
race-specific analyses as well as the
inhaled
steroid effect modification.
DR. GARDNER: One more thing, I can
certainly understand your position on
that about
power, but I would encourage you, from
the
269
standpoint of management, to nonetheless
complete
descriptive analyses from those data
because they
can be valuable in assisting many of the
questions
that appear here. So, even if you don't have the
power to test a hypothesis, please do
the
descriptive analyses.
DR. DAVIS: Thanks.
We will.
DR. SWENSON: Dr. Prussin?
DR. PRUSSIN: I want to follow-up on Dr.
Moss' comments about salmeterol
monotherapy. I
think the NIH guidelines support
that. We have
heard today lots of data supporting the
fact that
salmeterol monotherapy can associate
with increased
exacerbation rates. Yet, when you look at the
package insert--and I know it is a
little bit off
the mark and perhaps the FDA staff can
tell me how
much off the mark I am--one of the
issues we are
addressing is the package insert. And, if you look
at the labeling, it is "strongly
advised" and I
guess I would ask the two companies here
could that
labeling be made stronger, such as
salmeterol
monotherapy--or whatever the long-acting
beta
270
agonist--monotherapy should not be used
as chronic
monotherapy in asthma, for example? Since everyone
is in agreement on this from what I have
heard
today, yet the package labeling is a
little softer
in terms of terminology.
DR. WEAN: I noticed Bob wasn't moving--
[Laughter]
--I think one of the issues
around
labeling, and particularly around
recommending
concomitant use--if I say it wrong, Bob,
please
tell me--but there is a very fine line
between your
label that addresses your clinical data
that you
have shown in clinical studies and
labeling that
takes the guise of recommending
treatment, of being
treatment guidelines. I know that in discussions
we have had with the agency, while we
may want to
put more information into the label,
there is a
desire not to have the label be a
substitute for
treatment guidelines being issued by
NHLBI and
other appropriate groups of
experts. So, that is
sort of the fine line that we have to
walk between
strong recommendations about such
concomitant use
271
but also making appropriate reflections
in the
label.
DR. FLOYD: In follow-up, what we try to
do is base the label based upon the
outcome of the
data that we have that is generated, but
you must
maintain flexibility for physicians to
be able to
use their discretion in appropriately
prescribing
these drugs. So, we work with the agency to make
sure that the label is comparable to the
information that is generated based upon
the data
from the Phase 3 studies.
DR. SWENSON: Miss Sander?
MS. SANDER: Yes, this is to both
sponsors. Because managing asthma or achieving
good asthma control is rarely just about
taking one
drug and includes, you know,
environmental control.
It includes receiving patient education
that affect
your beliefs and, therefore, your
behaviors and
your outcomes. I am wondering in these studies do
all patients receive the same type of
education and
advice, or is it just related to the
study drug?
DR. DELLA CIOPPA: You are touching upon a
272
very important point and the short
answer is no.
We make a huge effort to do so, but
please keep in
mind that all of these studies are in
many states
in
the United States but most of these studies are
in many countries, and some very diverse
countries,
and the bigger the studies are and the
more rare
the event we are looking for, the more
countries we
go to.
It is not rare that we go to 17, 20, 25
countries, not to speak of all the
possible states
ion the United States. So, we do make a huge
effort to try to harmonize as much as we
can the
instruction to patients, the ancillary
activities
that the patients should put into place
to manage
their asthma in an appropriate way. But the
cultural differences, the background
differences,
the socioeconomic status differences
will stay
there so that is, indeed, a considerable
source of
variability in the results of the study.
On the other hand, should you
go to only
one place with perfect harmonization of
the data,
then another problem would occur, how
could you
extrapolate? How could you extend your results to
273
other states, other countries or other
cultural
situations? So, it is a balance.
MS. SANDER: So, even in one
investigator's practice would all the
patients
receive the same information?
DR. DELLA-CIOPPA: Yes, they would.
MS. SANDER: They would?
DR. DELLA-CIOPPA: They receive the same
information across the study, but the
way this
information is delivered may
change. Within one
center we are reasonably sure that they
get the
same information in the same way.
MS. SANDER: Right.
Then, I guess this is
for GSK regarding the phone calls. When you did
the follow-up phone calls with the
patients were
there any clues in the answers that they
gave you
that some of them were struggling more
than others
and were at greater risk, and was there
any kind of
discussion with the patients about
that? Was it
interactive or was it just a survey each
time?
DR. KNOBIL: You mean, was it a real
person making the telephone calls?
274
MS. SANDER: No, no, no.
The phone calls
that occurred with the patients, and you
said that
you asked them, or that they were asked
questions
about the use of the study drug. Am I
misunderstanding?
DR. KNOBIL: Well, what happened was a
real person did have a script as to what
questions
should be asked. There were specific questions and
every person got the same questions. Now, I guess
what you are asking is if the patient
said, well, I
don't know or something like that the
person on the
phone would try to clarify as much as
possible.
But also remember that the person on the
phone was
not a physician; it is a telephone
center. So,
they could only clarify what they could
and they
might not pick up on every clue that
someone who is
familiar with asthma might pick up
on. But they
did have specific questions to ask and
they got as
many answers to those questions as they
possibly
could.
MS. SANDER: So, there was no trigger.
You know, if a patient had these types
of answers,
275
then this patient is at greater risk and
the
investigator needed to be contacted?
DR. KNOBIL: I see what you are saying,
no, the information was collected but
there were no
recommendations made to the patient on
what they
should do. You know, if the patient was telling
the operator that they were having
problems, then
the operator would tell them to go see
their
physician but there was nothing else
within the
study.
DR. SWENSON: Dr. Moss?
DR. MOSS: I am going to follow-up on a
question I asked earlier to industry but
I want to
ask it to the FDA. So, you can sit down and take a
little breather. Some of the questions to our
committee deal with product labels and
boxed
warnings. I just wanted to make sure I understood
the role of boxed warnings and product
labels. Do
you have any evidence that the product
labels and
boxed warnings meet the goals that you
want them
to?
So, if we recommend that we are going to have
some change in a product label, as Dr.
Prussin was
276
talking about, or a boxed warning, does
that really
achieve what you want it to? Do you have evidence
that people change practice based on
that
information? If not, then maybe that is not the
right medium to disseminate information.
DR. TRONTELL: Anne Trontell, from FDA.
There hasn't been a systematic study of
the impact
of black box warnings. Some have looked at changes
in utilization measured by numbers of
prescriptions
but, again, that is an imperfect
surrogate for the
appropriateness of use. I believe there are some
studies forthcoming but we are not yet
privy to
those results.
DR. MOSS:
Getting back to what Dr.
Prussin was talking about, can you just
explain a
little bit in more depth what is the
goal of a
product label or a boxed warning?
DR. MEYER: That is sort of two separate
questions. The goal of the product label is to
describe the substantial evidence that
led to the
FDA's decision on the approval of the
drug. The
standard for approval is that a drug is
safe and
277
effective for use as described in the
product
labeling. So, it is to take that substantial
evidence and to put it into a format
that allows
that drug to be used in a safe and
effective manner
based on what we have found.
I agree with the comments made
earlier
about the fact that that separates it
out somewhat
from what may be very informed opinion
but
opinion-based guidelines, for instance,
and the
labeling is not meant to strictly
restrict the
practice of medicine. The FDA is not in the
business of restricting the practice of
medicine,
but it is to inform the practice of
medicine.
As far as a boxed warning
goes, it is
really to describe situations of serious
morbidity
or mortality. The standard for putting in a boxed
warning does not require certainty about
the
relationship of the drug to those
outcomes. It is
really driven much more by the outcome
itself. If
you are taking about death, and so on,
and you have
at least a reasonable suspicion--either
from animal
data or from human data be it from
studies or be it
278
from postmarketing--that the drug may be
associated, even if not certainly
causally with a
particularly bad outcome, that will
often be enough
to place a boxed warning into the
label. That is
intended to really raise to the
forefront how
serious the concern is. There are some subtleties
in terms of changing how the drug can be
marketed,
and so on, but the intent is really to
signal right
up front to anybody using that drug that
this is
something you need to consider when you
use that
drug.
DR. SWENSON: Dr. Newman?
DR. NEWMAN: Just to follow on that point,
we are being asked this afternoon what
we would
recommend to the agency in terms of
actions for you
to take to communicate. What are the other things
in your repertoire, in addition to the
things that
have been described here, when you want
to
communicate?
DR. TRONTELL: Again, depending on how
broadly you look at it, there is a
number of
so-called risk minimization
interventions that the
279
agency has worked with sponsors to
apply. In the
communication arena the agency may speak
to the
public through a public health advisory,
or some
other press release or talk paper. So, there are
ways we can make a more prominent
announcement of
concerns.
There can be additional
requirements for
patients to be specifically informed of
risks,
using patient labeling that is
specifically
oriented to the lay person in terms of
understanding. So, that includes such written
materials as medication guides which are
required
to be handed out with prescriptions, or
a patient
package insert. There is a variety of other
educational materials that could go
beyond the
print media that could be considered.
Then, obviously if you wanted
to get
beyond the communication realm such as
we have
heard--"dear healthcare
practitioner" letters and
others--you start to talk about other
ways of
making the information prominent or
actually trying
to direct care in a specific way.
280
DR. SWENSON: Dr. Martinez?
DR. MARTINEZ: I would like to follow on
Dr. Brantly's question before in
relation to the
potential for some of the observations
that have
been made to be associated with what he
generically
called changes in inflammation associated
with the
use of beta agonists.
Just a brief introduction, I
think the
issue we are talking about here is not a
global
effect, as was said before, of these
medicines on
individuals because the effects that we
are seeing
are seen in a very small number of
individuals. I
think relevant to this issue are the
data that I
would like some of the basic scientists
from both
companies to comment about, presented by
Steve
Liggett who has been one of the persons
most
assiduously working in this area, in
which
over-expression of beat adrenergic
receptors in
mice, as compared to under-expression of
beta
adrenergic receptors in mice, was
associated with a
very paradoxical effect, contrary to
what they were
really expecting. And, this is published in The
281
Journal of Clinical Investigation in
August, 2003.
Contrary to their
expectations, the mice
in which a beta adrenergic receptor was
over-expressed showed an increased
expression of
bronchoconstrictive receptors in airway
smooth
muscle, and those in which the beta
adrenergic
receptor was under-expressed showed a
decrease in
the expression of these
bronchoconstrictive
receptors for thromboxane, for
histamine, and so
forth and so on.
So, a possibility then cannot be
ruled
out, and should be seriously considered
as a
potential explanation for some of these
effects,
that there could be individuals out
there whose
genetics or phenotype of some sort that
we haven't
yet figured out could be associated with
them
becoming a little bit like the airways
of these
mice in which these beta adrenergic
receptors are
under- or over-expressed.
They didn't test in this study
if
corticosteroids affected this particular
under- or
over-expression so the issue of the
potential
282
regulation by corticosteroids was not
followed up.
So, just because this issue had been
raised by Dr.
Brantly, I just wanted to know the
opinion whether
the possibility could be that phenotypic
and
genetic characteristics of a very small
number of
subjects could make them particularly
susceptible
to effects similar to those described by
Dr.
Liggett with respect to beta adrenergic
receptors
in the mice.
DR. BEASLEY: Yes, you raise an
interesting point. I think what Steve Liggett's
experiments were attempting to address
really was
he was looking at the balance between
sympathetic
and parasympathetic pathways. I think the
prediction was if you over-express beta
receptors
you would see a corresponding decrease
in
muscarinic receptor function. In fact, what he saw
was the opposite. In fact, there was a
recompensatory rebound in muscarinic
receptor
function and, similarly, when he knocked
out the
beta receptor he got a decrease in
muscarinic
receptor. So, I think it underlines that, you
283
know, we know really little about how
the neuronal
pathways interact. Clearly, there is more work
that needs to be done there.
I do have a slight concern in
trying to
make extrapolations from animal models
that require
over-expression or knockouts to what we
can see in
the clinical scenario, and I think it is
probably
shared by everybody. But you do raise a very
interesting question that possibly in a
subtype of
patients, in a small minority, there may
be an
inappropriate balance between the two
pathways, and
were you to influence one pathway you
might get a
reaction from the other pathway. But, as I say,
the problem is that you could model
these systems
in transfected cells. You can do them in
over-expressing or knockout animal models but
that
is really all they are, they are animal
models and
making that extrapolation to man is
obviously very
difficult. And, we clearly do not yet have those
sorts of studies, but it is a very
interesting
point.
DR. MARTINEZ: I was just raising it as a
284
possible explanation but certainly I am
not saying
that this is what may be going on. It is just a
potential for explaining that in a very
small
minority of patients genetic and
phenotypic
characteristics may make this balance,
not only
with muscarinic receptors. He also studies
thromboxane receptors and histamine
receptors--
DR. BEASLEY: Yes.
DR. MARTINEZ: --maybe this balance is
altered in ways that would not be
expected for the
great majority of the population.
DR. BEASLEY: I agree, and I think today's
discussion about genotype implications
has largely
focused on polymorphisms of the beta
receptor. Of
course, we shouldn't forget there are
also
polymorphisms of the muscarinic receptor,
of the
glucocorticoid receptor, and when we are
dealing
with the body and we are dealing with
patient
response to drugs and maybe the
patient's response
to disease we are dealing with an
integration of
all these gentoypic polymorphisms. It is very
difficult then to predict what you would
see in
285
small proportions of patients.
DR. SWENSON: I would like to ask the
Novartis personnel a question regarding
the racemic
nature on formoterol. I read that I believe it is
the RR enantiomer that is the effective
moiety is
not at all blocked by the SS. But that is simply
on bronchoconstrictor aspects. Have you any data
as to whether the inactive enantiomer
might have
pro-inflammatory effects or some other
effect that
wasn't gauged in studies that I could
see? This
might bear on the problem with the
danger signal
evident in the larger doses that some
studies from
you have shown.
DR. TRIFILIEFF: I do not have any data to
show you today but we did look at this
possible
pro-inflammatory or antagonism effect of
the
inactive enantiomer for formoterol. As you said,
there was recently a clinical paper
looking at the
effect of bronchorelaxation in human
comparing the
different types of enantiomer for
formoterol and
there was basically no antagonism effect of
the
inactive enantiomer.
286
To come back to the
preclinical situation,
we had basically the same
situation. If we look in
our animal models or in vitro, we don't
see any
antagonism activity of the inactive
enantiomer.
DR. SWENSON: At this point then we will
take our break and the remainder of the
meeting,
when we return in 15 minutes, will be
focused on
the specific questions that the FDA
wishes us to
address.
[Brief recess]
DR. SWENSON: Well, we now move to the
specific questions posed by the FDA to
the panel
around warning and the potential use and
studies
necessary for these two drugs that we
have been
discussing today. We will go through the questions
in order that the panel already
has. That is, we
will jump from one drug to the other
rather than
keep all questions to one drug and then
move to the
next.
We will be moving back and forth with these
questions. Some of these will be, as you see,
recommendations that each of you will be
able to
offer, as we go around the table, to the
questions
287
that are asked. Then we will move to yes/no
questions in regards to whether we feel
that these
drugs should be continued to be marketed
with the
present database that we have.
I would ask the panel members
to make
their yes/no votes on these questions on
the basis
of the information that we have presently,
that we
have heard today. Although there are significant
studies in the pipeline that may well
answer these,
and both companies are making very
strong efforts
in this regard I believe, but your
yes/no vote
should not be based on the fact that any
of those
studies will be accomplished and will
provide
further answers. We need to vote yes/no on what we
have today.
So, with that, let first just
see if there
are any questions or general comments by
the panel.
Dr. Schoenfeld?
DR. SCHOENFELD: I have a general comment.
I made a calculation before that was
wrong, which
is one of the reasons I asked for
somebody to come
by and do a calculation with a computer
because I
288
know how often mistakes are made, and I
have made
plenty of them myself and that is why we
usually
have people repeat important
analyses. So, I
miscalculated the risk based on the
SMART study,
and I just want to give you my current
calculation,
and I think that somebody else out there
ought to
check this calculation and stop me if it
is wrong
because I think it is a very relevant
calculation.
That is, I calculate that the
attributable
risk for the treatment among the general
population
is roughly 1/700, and this is in regard
to asthma
deaths.
That is, be an extra 1 patient in 700
would suffer an asthma death on the
basis of
treatment with this drug in the general
population.
And the figure among African Americans
is roughly
1/200.
Now, I am enough of a Bayesian
that when I
see 1/700 in the general population and
1/200 in a
subgroup that was sort of chosen out of
the study
to move the 1/200 towards the
1/700. Because it
sort of caught our attention and maybe
we should
focus more on the average than on what
happens in
289
subgroups.
That being said, that is the
kind of risk
that, if we take these data on their
face, we are
facing.
What I can't really judge as a
statistician is the benefit because I
don't talk to
asthma patients every day; I don't know
how hard it
is for them. I have no real way of knowing whether
if
I was an asthma patient with a risk of 1/700 I
would take or not take. For instance, if someone
my age has a risk of 1/300 of dying from
natural
causes or from all causes--something
like that;
maybe 1/200. I keep track of this but I haven't
looked at it recently--
[Laughter]
--yes, I have gotten
older! So, I don't
really know whether this is a risk that
is too
large or not very important at all. Probably some
of the panel members who actually treat
asthma
patients would know that and it may vary
from
patient to patient.
DR. SWENSON: Dr. Meyer, I might ask if
you or any member of the agency want to
just
290
comment, even with very little
preparation, on this
question.
DR. MEYER: No, I think I would prefer not
to.
I haven't seen the calculations and I think at
this point I prefer not to.
DR. SCHOENFELD: I could go over the
calculation if someone wants me to just
say how I
did it.
Basically, I took 10. Okay, I
took
basically the data here which was 13,176
and that
is a 28-week study. That was the mistake I made
before.
I multiplied by that 28 and divided by 52.
So, that is roughly half that number I
guess you
would get roughly, which is roughly
7,000. Then,
basically, I divide 10 into that and I
get 700.
That is how I got the 1/700. Now, how I made a
mistake doing that the first time I
don't know. It
is 10 extra deaths. There were 10 extra deaths
total, 10 extra asthma deaths. I think it was 3
versus 10 I think in the data.
DR. MARTINEZ: the question I was asking
is it is 1/700 per year?
DR. SCHOENFELD: Per year of exposure. Of
291
course, every year that I am exposed I
take this
extra risk of 1/700 if I want to take
the SMART
study basically at face value. I guess one other
comment is that it is very hard in a
large, simple
trial to know what causes a mortality
difference or
a difference in any endpoint. The whole idea of a
large, simple trial is that you don't
really
control what happens to the patients
carefully so
you don't really know whether it is the
effect of
the drug or an effect of the effect of
the drug.
For instance, if a drug makes people
feel better so
they go their doctor less often they may
have
higher mortality. In a very carefully controlled
trial, like the Phase 3 trials that I am
sure were
done you are controlling all these
things. So,
there is less chance that it is some
supportive
care that is being affected by the
effect of the
drug that is causing the
difference. But in a
large, simple trial you lose that and
some people
consider that the advantages and some
people
consider that the disadvantages of a
large, simple
trial.
292
DR. WEAN: If I might just very
quickly--David Wean from GSK--respond to
that,
because I just find I can't allow a
figure such as
1/700 to be put out onto the table and
potentially
be
appearing in the press and public domain without
appropriate caveats. We, quite honestly, can't
fathom a cogent response to that
calculation but
what we do need to say is when you look
at
epidemiological data, which we presented
to you, we
don't see an attributable risk of that
sort. We
can also say that in trying to assess
the issues
that we are asking about today in a
large database
of over 25,000 patients, we had
difficulty arriving
at the intended rate for asthma- and
respiratory-related death. So, I think that
calculation, quite honestly, probably
does more
disservice to individuals that we are
wrestling
with appropriately advising around the use
of these
drugs for their asthma, and I just want
to add that
balance to that back-of-the-envelope
calculation.
DR. SWENSON: Dr. Prussin, did you have a
comment?
293
DR. PRUSSIN: This morning there was some
discussion about ongoing clinical trials
by GSK
that we heard from their
representatives, and I
just wondered if Dr. Schoenfeld might
speak a bit,
since he is an epidemiologist, on what he
sees as a
relevant clinical trial to address the
question of
increased mortality.
DR. KAMMERMAN: Before we get to that, I
am a statistician. I am Lisa Kammerman. I am a
statistical reviewer. I think just to clarify a
little bit what Dr. Schoenfeld was
doing, instead
of looking at relative risk he is a
little bit more
interested in looking at the difference
in the
rates, the proportions of people
developing
asthma-related deaths, which is where he
got the 10
from.
But in calculating any number
where you
are using person years as the
denominator there are
always issues involved. One of the major
assumptions is that there is a constant
risk for
asthma-related death over time. So, that needs to
be cautioned also.
294
DR. SWENSON: Dr. Schoenfeld, do you want
to reply to Dr. Prussin's question?
DR. SCHOENFELD: I guess not right now
because I think that the issue of what
clinical
trials should be done, or what further
we should
ask these companies for is sort of a
later issue.
The other thing, again, I am
asking the
asthma specialists here I don't know
whether this
is a large--I calculate that
number. Hopefully, it
is right, but I don't have the expertise
to know
whether this is a big number or a small
number in
regards to the benefit of these
treatments. I
mean, there are many situations in which
this would
be a very small number and there are
others where
it would be a large number.
DR. SWENSON: Dr. Schatz?
DR. SCHATZ: I was just going to say I
think it is also complicated because one
has to ask
how representative that denominator is
to the type
of patients I treat, you treat, or are
out there
and I don't think we know that
either. So, it is a
very complicated number.
295
DR. SWENSON: Dr. Martinez?
DR. MARTINEZ: Just a point of
clarification, what is it that exactly
we are
discussing? Are we opening the discussion very
generally or are we answering any of the
specific
questions? I thought that we were very generally
discussing and that is what I would like
to
intervene upon.
DR. SWENSON: The plan was to move to the
specific questions but in this time
period there
will be the chance for specific
recommendations for
each of you, if you wish to offer
those. Dr.
Meyer?
DR. MEYER: I am sorry, I just wanted to
take the opportunity to respond also to
the 1/700
figure.
I think our hope with the SMART study was
to try to get data that would either
confirm or
refute the signal that we had coming out
of the SNS
study and some of the postmarketing
experience in
the early years of Serevent being
marketed.
I think that the SMART study did go some
distance in terms of helping to answer
that. I
296
don't think it provided nearly the kind
of
precision as to what that risk might be
that would
allow for us to look at a number for
attributable
risk with any kind of confidence that
that
represents a true number. You know, these are rare
events and this was a big study but it
still
didn't, I don't think, give us a kind of
precision
around what the true difference would be
if we were
to take that out to the entire
population. So, I
just wanted to caveat that number a
little bit from
our perspective as well.
DR. LITTLE: This is Roger Little, GSK. I
am Vice President of Biostatistics for
GSK. I
agree with that very much. I like the idea of
going after absolute risk. I think that is a great
goal but I think if you think about the
way we
approach the study, we are trying to be
conservative. We have the car accident where that
is potentially related to asthma. We have been
trying very hard to go after these in a
very
conservative way. If we want to estimate the
absolute risk I think you would look to
other kinds
297
of studies. You would look to the epidemiological
study.
If there was a signal nearly as strong as
the one that has been mentioned we would
see that
in many other places. So, I don't think this is
the type of study to really address
that. This
isn't the primary efficacy endpoint. We have
picked out the one that caused the
greatest concern
perhaps, which is appropriate, in terms
of looking
at this study and thinking about the
risk but I
don't think this is the study to support
the
absolute risk and the difference between
these two
treatment groups. Thank you.
DR. SWENSON: I think we won't have any
resolution today or even in the very
near future,
particularly with issues about the
imprecision of
socioeconomic status and questions about
the
biology of various forms of asthma. I think we
will have to leave it as still
unresolved.
I would like now to move to
the specific
questions. The first question is on the screen
here.
We are being asked now to provide specific
recommendations to the FDA as to any
further
298
actions they should take to communicate
or
otherwise manage the risk of severe
asthma
exacerbations seen in the SMART
study. I will go
down our list in order and ask Dr.
Schoenfeld to
offer any recommendations you feel
strongly at this
point on this question.
DR. SCHOENFELD: I don't have any specific
recommendations there. I thought the boxed warning
seemed to--although I haven't examined
it in gory
detail, it seemed like a reasonable
warning to
include in the labeling. I am assuming that that
then gets communicated.
DR. SWENSON: Miss Sander?
MS. SANDER: I would have to agree.
DR. SWENSON: Dr. Gardner?
DR. GARDNER: I think this might lend
itself to a medication guide or other
kind of
direct patient information that is
dispensed with
the medication because it is an
opportunity to
educate people about the ancillary
issues, and also
to assist people in knowing what are the
drivers
that may signal exacerbation or other
problems that
299
would get them earlier perhaps to
care. So, I
think that I would recommend some form,
either in a
med. guide or patient package insert, of
direct
communication to the patient about these
types of
risks that includes recommendations for
what might
be done to minimize them for
individuals.
DR. SWENSON: Dr. Schatz?
DR. SCHATZ: I also don't at this point
that there is any specific change to
recommend, but
part of that is based on not having good
outcome
data as to how these communications work. So, I
would encourage answers to some of the
questions
that were brought up earlier, which is
to try to
understand what outcome occurs with a
black box
warning.
But without any of that information and
assuming that, at least on a face value,
that seems
to be an appropriate way to try to
educate people
who have to prescribe the medicines I
wouldn't
recommend any changes right now.
DR. SWENSON: Dr. Gay?
DR. NEWMAN: Excuse me, could I just ask a
point of clarification before we go
further? I am
300
sorry to interrupt.
DR. SWENSON: That is fine.
DR. NEWMAN: What warning label are we
looking at? You know, on page 34 of the materials
in that first section on the SMART study
that we
got from the FDA is what looks to me
like a
proposed modification of a warning
label. Is that
what we are commenting on or is that
what it is at
this point? Have all those deletions already been
made?
DR. SEYMOUR: There is a copy of the
product labels under separate tabs in
the back that
are the current product labels. The review may
contain different language as the
changes in the
label progressed throughout the years
but the
current labels are included in both
briefing books
at separate tabs.
DR. NEWMAN: So, I guess my question is
there is a proposed warning label change
that comes
from the FDA that is in this
packet. Are you
asking for comment on that?
DR. SEYMOUR: No, that has been resolved.
301
We are asking for comment on the current
product
label that is in the back of the
briefing books
under separate tabs.
DR. NEWMAN: Thank you.
DR. SWENSON: Dr. Gay?
DR. GAY: I would recommend a few changes.
First, I believe that we should put
greater
emphasis not only on the fact that there
does seem
to be a difference between ethnic
populations, but
also that there does seem to be some
early
difference with greater severity of
disease in
asthma for those patients with peak
expiratory
flows less than 60 percent
predicted. So, there
should be some attempt to make a warning as
well
for patients as they have greater
severity of
asthma.
In addition, we have debated
to some
extent the role of this package
insert. If it is
to clearly attempt to make the drug as
safe as
possible, the data is not quite as
strong because
from the SMART data we clearly don't
have enough
information about the use of inhaled
302
corticosteroids in that population. But much of
the other data presented to us for
combination
therapy would seem to suggest to me that
we should
in some way change the wording from
"the use of an
inhaled corticosteroid should be
considered" to
something more along the lines that the
use of an
inhaled corticosteroid should be
strongly
recommended, or the use of long-acting
beta
agonists as mono or individual therapy
in patients
with asthma should be discouraged and
should
require the use of some type of
anti-inflammatory
medication.
DR. SWENSON: Dr. Moss?
DR. MOSS: I think I am going to end up
reiterating what a few other people
said, but I
have four comments about the
warnings. Number one
is that I think the warning box should
be left on
the salmeterol. I think it is important that it
should also be kept on the Advair since
that
compound is also in Advair.
I think it is important not to
stress a
race thing, a race angle, but to state
that there
303
are subpopulations that may be at
increased risk of
adverse events from this medication
because I think
that gets back to the beta receptor
issues and
probably other snips that we are just
not aware of
yet.
As Dr. Gay said, I think it is
important
to stress the role of inhaled
corticosteroids,
reiterating what I said earlier, I don't
think that
is the whole effect but, getting back to
what Dr.
Schoenfeld said, if people are treated
properly it
might make that attributable risk more
favorable or
better by dropping the numbers in both
groups down
from 13 to 3 to maybe 6 and 2 or
something. So, I
think it important that people realize,
as Dr. Gay
stated, that this medication should be
used in
conjunction with inhaled
corticosteroids.
Again, I think the FDA needs
to re-thing
about how they are going to disseminate
information
to physicians and the public. I am not sure
changing product labels that I don't think a
lot of
people spend a lot of time reading is an
effective
way of communicating information to the
public, to
304
physicians and to the medical community.
DR. SWENSON: Dr. Newman?
DR. NEWMAN: I really have nothing more to
add beyond what Drs. Gay and Moss just
said. I
completely agree with that. I would also agree
with the idea of considering supplemental
information for patients. This gets very
complicated very quickly. I do believe that our
patients do a good job of understanding
the limits
of medical knowledge if we explain it
clearly
enough and we tell them what we know and
what we
don't know. I think a more direct reach in that
way to patients would be something worth
considering.
DR. SWENSON: Dr. Brantly?
DR. BRANTLY:
I agree with my colleagues.
I would like to make a point that I
believe is
floating around in the community--and my
hope is
that it will be picked up after this
meeting--the
impression that has been floating around
in the
community that these drugs, and
specifically
Serevent, are bad for African Americans,
and I
305
think it is critical that that message
not go
forward because it is likely that it
will be far
more harmful to the African American
community if
they avoid these types of drugs in the
future. I
think that is a real message that really
needs to
be considered strongly. I absolutely agree with
the agency taking that out of the black
box warning
area.
DR. SWENSON: Dr. Martinez?
DR. MARTINEZ: Notwithstanding my
agreement with what my colleagues have
said, I
would like to add just one more point that I
referred to before, and I think it is an
issue that
is coming up I think very clearly from
the data
that we have observed. I will briefly repeat what
I said before with respect to this
issue.
I think there may be two
dimensions to
asthma morbidity that until now were
considered as
highly correlated within
individuals. In other
words, asthma control, meaning the
everyday
presentation of symptoms, cough at
night, wheezing,
wheezing with exercise, and the
likelihood of
306
having severe asthma exacerbations. In fact, I
think that it is almost implicit in the
guidelines,
as they are stated now, that if you
adequately
consider how much a person is controlled
you in
some way, because of this implicit
supposed
correlation between this and
exacerbations, you are
also considering exacerbations, so much so
that
exacerbations are not part of the
algorithm to
determine asthma severity today, at
least in the
American guidelines.
I think that what is emerging
from this
data that we are observing here, and not only
from
this data but from several other data
that I will
not mention here, is that these two
dimensions,
although correlated, are not equivalent;
that there
are individuals in the community whose
control with
these medications, particularly with
combined
medication, is significantly improved as
compared
to treatment with only inhaled
corticosteroids or
with no medicine or with beta adrenergic
agonists
of short duration by themselves. However, there
are individuals in whom either there is
control but
307
there is still a very high risk for
severe asthma
attacks, or who don't have problems of
control, who
have something called brittle asthma,
but are at
very high risk of developing severe
asthma
exacerbations.
All that I see without yet, I
agree,
definitive proof seems to indicate to me
that
long-acting beta agonists as a group may
have a
negative effect on the control of severe
asthma
symptoms in the latter group, in what I
have called
the brittle asthma group. I don't have definitive
proof, as nobody else here has, but I
think the
data is clearly indicating that this is
what may be
going on, and the scientific community,
the FDA,
and particularly industry needs to be
very worried
about this because we are going to
discuss next
what is it that we need to do next with
this class
of medicines. And, we would not like, I think, not
to pay attention to this possibility
which could
make it difficult for these medicines to
continue
to be used in the population as a whole
because of
a small group that is at high risk when
they
308
provide significant relief of symptoms
to a very
large part of the population.
So, this idea that is
relatively new
because it is not there in the
guidelines I think
needs to be seriously considered in
evaluating
results of any clinical trials in the future. To
summarize, there may be a population of
subjects
with asthma in whom the main issue is
not
day-to-day control of symptoms for which
combination therapy is the best we have
today, but
in whom the main expression of the
disease is
severe attacks that are not only not
controlled by
these medications but may be rendered
worse by
these medications.
What are the biological bases
for this? I
propose one, which is the data that
Steve Liggett
had proposed but there may be
others. Careful
consideration to this possibility
perhaps would
allow us to understand better the
results we are
seeing.
DR. SWENSON: Dr. Kercsmar?
DR. KERCSMAR: I agree with most of the
309
statements that everyone has made
already.
Management of asthma is an incredibly
complex
problem that I think we in general tend
to
underestimate. Today we have incomplete knowledge
of asthma phenotypes, as I think
Fernando is
alluding to, and even less understanding
of the
genetic basis of asthma, which makes the
optimal
management even more difficult. Until we have
those data it makes giving a definitive
answer on
what we should do with each specific
class of
medication difficult, if not impossible.
So, I am not sure that I can
recommend any
specific changes in the way to
communicate,
although I do like the idea of perhaps
reiterating
these messages to both the medical and
the patient
community. The only caution I would have, which
was alluded to, is that virtually every
adherence
or compliance study on asthma,
particularly with
the use of inhaled corticosteroids,
would indicate
that patients under-adhere to those
medications and
any message that we send that might be
alarmist or
hinder the use of what are appropriate
medications
310
for the majority of the population would
be a
disservice to that community, while we
try to
understand for whom certain medications
are a risk
factor.
DR. SWENSON: Miss Schell?
MS. SCHELL: I agree with everyone has
said but I would just like to add that I
think it
is very important that the process
include
education not only to the caregiver but
to the
patient, and many of the patients that I
work with
at bedside haven't an idea what the
medicine is,
let alone if they read the label about
the warning.
So, I think the dilemma for me is how to
get this
information to them that they clearly
deserve, but
to put it in a message that they can
understand.
So, when you put it into fine print into
the
insert, most of them can't even read it,
and if you
put it on the box with the label, are
they going to
be educated by the caregiver? I would like a clear
understanding of the education available
to the
patient when it is dispersed to them,
with the risk
involved, also what the medication is
for, in a
311
language they understand. A lot of patients just
don't understand what they read when it
gets into
the complications of the risk. So, that is my
dilemma when I look at it, how do we get
that
information to the people that deserve
it in a
clear message?
DR. SWENSON: Dr. Prussin
DR. PRUSSIN: I would agree with Dr. Gay's
comments on trying to strengthen the
language on
monotherapy, discouraging its use. This drug is
already primarily being used in moderate
to severe
asthmatics, and those are the groups
that we talked
about being at risk. So, I am not sure if trying
to point out about subpopulations in the
package
label is going to go much beyond what
populations
are already being treated, in practical
terms.
Lastly, I was struck primarily by
the
original text, by a whole block of
text. Basically
your eyes glaze over and all the numbers
fade out.
You might consider either putting a
table or one
single figure to try to graphically
display the
relative risk data that we have been
talking about.
312
I think somebody seeing a graph or a
table, they
are going to gravitate to it much more
than to a
text box. So, you may want to consider that. I
was originally thinking of that when I
saw these
huge paragraphs of text, but maybe less
so with
what you have now.
DR. SWENSON: And my comments echo much of
what has been said but I would like to
state them
very briefly, and that is that the FDA
really
consider a much stronger sanction of
long-acting
beta agonist use in combination with
inhaled
corticosteroids, and that monotherapy be
highly
discouraged. I don't know whether this could be
done in some consensus with the
respiratory
organizations and the agencies that have
promoted
these guidelines, but to have possibly a
convergence of guidelines that are out
there by
highly respected bodies match exactly
what is in
the warning.
To the question of whether
there is a
very, very small subset of patients that
might be
adversely affected, i.e., these people
with very
313
brittle asthma, consideration being
given to
warnings that might suggest that
patients that have
had very rapid onset of asthma leading
to
respiratory arrest or need for
intubation without
warning, that this class of drugs may be
potentially considered adverse. That is obviously
something that is going to have to
evolve but at
least for agency consideration as maybe these
warnings change over time.
At this point we will move on
to the
second part of question one, which is
the vote.
Again, I will reiterate that your vote
should be
based on what we presently know and not on
what we
might know three or four years down the
road with
many of the studies that, hopefully,
will go to
completion and provide answers. I will start in
just the opposite order and ask--
MS. SANDER: Excuse me--
DR. SWENSON: Question, Miss Sander?
MS. SANDER: Excuse me.
You know before
we go to the vote, if I might just add a
little bit
from a patient perspective, I think some
really
314
wonderful insights have been shared
around the
table.
If you are considering any types of changes
in any of the labeling, I would just
encourage you
that when you are communicating with
patients or
physicians we have to be careful what we
say, and
how we say it, and when we say it
because it does
have impact on what patients will wind
up doing
about their disease with regard to this
drug. For
example, we know from within our
organization that
patients will often use Serevent to
treat acute
symptoms because they don't see
themselves in
rescue situations, warranting a rescue
use of
albuterol. And the word "rescue" has a certain
meaning to them that is very different
than what we
have talked about today around this
table. So, you
know, while I think it is good for us to
think
about what we are telling patients, it
would be
nice to have a guide. It is also very important
for us to be careful about how we
communicate. I
just wanted to echo that statement.
DR. SWENSON: Okay, if there are no
further comments, Dr. Prussin, your
vote?
315
DR. PRUSSIN: Yes, should be continued.
DR. SWENSON: Miss Schell?
MS. SCHELL: Yes.
DR. SWENSON: Dr. Kercsmar?
DR. KERCSMAR: Yes.
DR. SWENSON: Dr. Martinez?
DR. MARTINEZ: Yes.
May I justify my
yes--
DR. SWENSON: Certainly.
DR. MARTINEZ: --or is it only yes or no?
DR. SWENSON: No, be brief but you may.
DR. MARTINEZ: I will try to be as brief
as possible. I think the agency and industry--and
I thank them both--have presented very
interesting
and important information. I would like to
summarize the way I see that
information. We have
been presented with two large what I
would call
surveillance studies, both coinciding
with the same
type of result, which would indicate and
increased
risk of asthma-related deaths in
individuals who
are being treated with salmeterol
without regards
to what other medicines they are
receiving.
316
Dr. Beasley has several times
mentioned an
epidemiologic study which I think is the
strongest
study which shows that no such effect
exists in a
type of different surveillance study, in
which all
individuals who died with asthma are
compared with
matched controls. In this case, controls in that
study were matched for the hospital in
which the
subject had died or had been treated and
for age.
I would like to warn, however,
that that
study is completely different not only
in
methodology but also in many other
aspects to the
ones that were presented and are
prospective
studies.
Subjects in that study were much older;
42 percent of them had a specific
diagnosis of
COPD.
And, I would suppose that, for example, in
the SMART study any SMART doctor would
not have
included subjects with COPD because what
they were
asked to include were subjects with
asthma. So, we
may be talking about two different
things. When
you have 42 percent of subjects with
COPD in one
study and perhaps not as many in the
other study,
perhaps the results could be interpreted
317
differently.
I think we may have here a
true signal.
As Dr. Schoenfeld has many times told
us, here the
only way in which we can truly assess
the signal of
risk is in terms of benefit. My evaluation today
is with respect to the patients that I
see in my
clinic and the patients out there with
asthma in
this country in general. It is still justified to
keep this medicine in the market. However, I say
that with a conditional, which is that
there has to
be very, very accurate follow-up of the
increased
risk that has been observed in these
patients on
salmeterol in the future, and
particularly better
understanding needs to be there if this
risk is or
is not decreased by steroids. I do not think that
the data, as I see it today, justifies
saying that
this risk is decreased by steroids. I am not
saying that it is not decreased by
steroids. There
is no clear data to say either thing.
I am worried that the concept
may get out
there that there is strong data,
suggesting that if
you just give steroids this effect is
not going to
318
be there when we don't have strong and
definitive
data in that sense either. So, in that sense I
vote yes but with the strong conditional
that a
very accurate follow-up for this issue
needs to be
part of the FDA task in the future in
collaboration
with industry.
DR. SWENSON: And I think most members
would agree with that. Dr. Brantly?
DR. BRANTLY: Yes.
DR. SWENSON: Dr. Newman?
DR. NEWMAN: Yes.
DR. SWENSON: Dr. Moss?
DR. MOSS: Yes.
DR. SWENSON: Dr. Gay?
DR. GAY: Yes, and I would like to state
that these drugs do seem to have a clear
and
profound impact on morbidity and
mortality overall
in a very positive sense. We have seen the overall
declines in some of the data presented
here for the
occurrence of exacerbations and on
morbidity and
mortality. There does seem to be a true signal
present but we cannot disregard the
other things
319
that may contribute to this signal in
these
subpopulations. This does include access to
healthcare. This does include the use of inhaled
corticosteroids in these
populations. This does
include the changes in treatment and
management
patterns for certain subpopulations and
certain
under-represented populations. It is going to be
extremely important, and I do believe
that both
companies are making good efforts to
attempt to
control for those factors in the
subsequent studies
that they are beginning to perform, and
it is going
to be extremely important to analyze
this data on
the basis of those multiple factors to
see if we
can make any impact on this true signal
that does
exist. DR. SWENSON: D. Schatz?
DR. SCHATZ: Yes.
DR. SWENSON: Dr. Gardner?
DR. GARDNER: Yes, with caveats.
DR. SWENSON: Miss Sander?
MS. SANDER: Yes.
DR. SWENSON: And Dr. Schoenfeld?
DR. SCHOENFELD: Yes.
320
DR. SWENSON: My vote is yes as well. I
think that we have a unanimous vote here
but,
clearly, the warning is there that none
of us feels
100 percent yes. I think that possibly I am
stating the obvious but wish to have it
for the
record.
We will now move then to the
next question
which now turns on formoterol. Here the question
is the label for formoterol an
formoterol-containing products at this
point does
not include warnings comparable to the
warnings
that are present in the salmeterol
products and,
based on currently available
information, should
the label for formoterol-containing
products
include warnings similar to those to the
salmeterol
label?
This will be a yes/no vote,
but I think we
have enough time here if people wish to
say very
briefly why they voted one way or the
other.
DR. SCHOENFELD: May we comment first so
we can communicate with each other
before we have
to vote?
321
DR. SWENSON: That is a reasonable request
I think if we could limit to five to ten
minutes
for those that wish to make it an open
discussion
here, and I suspect you wish to lead
off.
[Laughter]
DR. SCHOENFELD: Well, first, again a
back-of the-envelope calculation and,
again, if
anybody who has better data wants to
contradict the
calculation, but as I understand it,
formoterol had
the same risk as salmeterol we would
expect, based
on the number of patient-years of
follow-up, 0.23
events--0.23, and this is based on 527,
multiplied
by 16/52 to get 162 years of follow-up,
and then
multiplying that by the event rate and
dividing
that by 700 we get 0.23. So, the chance of not
seeing any event is roughly 80 percent,
which is
good power actually for not seeing
anything. So, I
think the fact that at least in clinical
trials we
didn't see anything is not surprising
because if
the risk was exactly the same in the two
drugs the
chances of not seeing anything would be
80 percent.
That is the point I wanted to make.
322
Now, the issue as to whether a
warning
should go across the class depends upon,
I guess,
how similar with think things are in the
class,
which is beyond the level of my
expertise. They
apparently both work similarly. One drug works
faster, which may be an advantage in
terms of
preventing these problems. But if anybody has any
comment--I guess there has been a
comment by the
industrial representatives but if
anybody on the
panel would like to make a comment to
the extent
that this is a class, I would love to
hear that.
DR. SWENSON: Dr. Gardner?
DR. GARDNER: I will hold until maybe
someone can answer his question.
DR. SWENSON: Dr. Gay, do you care to
comment?
DR. GAY: Certainly.
Every other drug
that works at this receptor has shown
effects with
the arginine/arginine subtype of
receptor of
negative outcomes. We have seen it with albuterol.
We saw it with other shorter-acting
forms of beta
agonist, and we have seen it with
salmeterol as
323
well.
Because of this concern that with certain
genotypes or phenotypes of this receptor
we have
seen this effect, I have significant
concern that
it is a class effect. We have not seen a study yet
that has been powered appropriately and
designed
appropriately to look at whether or not
this is
potentially the case win
formoterol. However, with
the fact that every other beta agonist,
both
short-acting and long-acting, has
similar effects
at the receptor, I have concerns that
until proven
otherwise we have to make ourselves
believe that
formoterol may act the same way.
DR. SWENSON: Dr. Gardner?
DR,. GARDNER: I appreciate what the
question is trying to get at but I want
to raise
another one. In looking at the formoterol insert,
given the data that we saw today related
to
children, I don't think that what we saw
is very
well communicated in the insert as it
stands, and I
would like to suggest that in addition
to the
question we are addressing, which I
think probably
has mostly to do with class labeling and
black
324
boxes, I would like to suggest that more
attention
be paid to communicating what may be a
heightened
risk in children and then, of course,
update it as
more data become available.
DR. SWENSON: Dr. Schatz?
DR. SCHATZ: I guess I would like to get
some clarification from FDA people
regarding what
the standard is for class labeling. If, for
example, you have a signal from one drug
in a class
and no adequate data in the other to say
yes or no,
is that typically an indication for a
class
warning?
And, would you only not have a class
warning if that other drug had adequate
data to
show that the signal did not exist?
DR. CHOWDHURY: I want to first clarify
that the question is actually specific
to
formoterol, not necessarily all
long-acting beta
agonists. So, you can't probably use the term
class labeling. The specific question is on
formoterol.
DR. SCHATZ: Yes, but I would like to
understand the meaning of the class label,
my point
325
being that if one assumes one has to
have a class
label until you can prove the drug
doesn't do
something, then I think everyone would
agree we
have different types of studies. We don't have a
study that shows that formoterol doesn't
do this.
But I think this issue of class
labeling--what that
means, and we are talking not clinical;
we are
talking about regulatory
recommendations. So, I
think I need to understand the
regulatory
environment better.
DR. MEYER: Right.
I think that your
recommendation has to be informed by the
degree
that you do, in fact, feel, as Dr. Gay
pointed out,
that this in fact does represent a class
effect
because, as you say, we do not have data
one way or
the other. Obviously, many drugs have
idiosyncratic effects that will not be
represented
by other members of their class. On the other
hand, there are situations where we can
feel fairly
confident from the pharmacology as we
understand
it, or other mechanisms as we understand
them, that
this would extend to other members of
the class. I
326
mean, you can take certain adverse
events with ACE
inhibitors for instance where you know
it is a
direct result of its pharmacology.
So, I think we would defer to your
expertise in that regard but I think you
would need
to feel personally convinced that this
probably
does represent a class effect and,
therefore, it is
only fair to put it in formoterol's
labeling. On
the other hand, if you thought that the
observation, the signal that has been
seen in the
SNS study and the SMART study could be
due to other
considerations of the way salmeterol
itself
interacts at the beta receptor that
might not apply
to formoterol, then if that is a
significant
unknown for you, I would think your
recommendation
would be I don't think this should be
extended.
But the bottom line is we do not have
the data one
way or the other. If the SNS and the SMART study
did not exist for salmeterol, we would
be in a
situation of having really no idea at
all about
this.
We have those data for salmeterol; we don't
have them for formoterol. So, you know, it is just
327
an unknown whether formoterol would have
similar
findings or not. So, again, we are deferring to
your expertise, and I hope I gave you
enough of an
explanation there.
DR. SWENSON: I will ask Dr. Schoenfeld
then for his vote.
DR. SCHOENFELD: Again, I am sort of
voting beyond my expertise in a way
because I know
this 80 percent chance but I don't
really know the
biology of these drugs. But I think the prudent
thing would be some sort of warning,
boxed label,
on formoterol that says that this effect
has been
seen in another member of the class and
it is
unknown whether it would apply to this
member, but
at least to warn people that this could
be an
effect either of the class of drugs or
of the way
patients act when they are, in fact, on these
drugs, which is another possibility.
DR. SWENSON: Before I ask directly for
your--
DR. SCHOENFELD: So, the answer is it
shouldn't be--
328
DR. SWENSON: Wait one minute.
DR. SCHOENFELD: Sorry.
DR. SWENSON: One can abstain if you feel
so uncertain as to whether you should
vote one way
or the other. An abstention is perfectly fine.
DR. SCHOENFELD: In other words, I believe
it should be marketed but I believe it
should have
some kind of warning pointing people in
the
direction that this has been found with
other drugs
in the class.
DR. SWENSON: Miss Sander?
MS. SANDER: When I read this question, we
are talking about a similar warning
label as the
one when we are looking at
salmeterol. Is that
right?
I don't know all the similarities.
I do
know that there is information on this
in the
package insert that I do think should be
brought
forward, and there may be some other
information
that should be made more prominent as
well that we
have learned today. I don't know if I know how to
vote on this one so I think I may have
to abstain.
I think there is information that should
come
329
forward; I don't know that it needs to
be the same
information as with Serevent. So, if that is a yes
or a no, I am not sure.
DR. SWENSON: I think we will count it as
an abstention.
MS. SANDER: Okay, thank you.
DR. SWENSON: Dr. Gardner?
DR. GARDNER: I guess I would have to say,
based on what we saw today, my answer
would be no,
although I would like to comment that I
agree with
Dr. Schoenfeld that some wording pointing
at what
is known about salmeterol would be
useful until we
have more data.
DR. SWENSON: Dr. Schatz?
DR. SCHATZ: I really don't like the idea
of making such and important decision
with such
little information, and I definitely
intended to
abstain but I guess it is one of those
situations
where something has to be done. I think that in
the absence of being able to say that it
is not a
class effect, I am leaning, and I will
therefore,
vote yes, that labeling to say that it
has been
330
shown in a drug of its class; it is not
known
whether it is a class effect--I am not
even
convinced the effect--I see the
signal. There have
been mentioned other reasons for that
that may also
not even show that the drug does
it. So, I am not
even convinced there, but in the sense
of letting
people know what exists so they can made
the best
decision, I think I am in favor of
having it say
that another drug of the class has shown
this
signal and it is not clear whether it
extends to
the other class.
DR. SWENSON: Dr. Meyer?
DR. MEYER: I just wanted to perhaps point
out-- and maybe this will help Dr.
Schatz although
I guess he eventually came down on a yes
recommendation--that one of the
implications of
having one label that has these boxed
warnings and
one that does not to a patient or a
practitioner
may be, well, if this one is unsafe then
my patient
will be better off on this other one. I guess that
is the other thing you need to consider
as well.
Is that disparity something you are
comfortable
331
with?
DR. SWENSON: Dr. Gay?
DR. GAY: For the reasons I have already
stated, I will vote yes.
DR. SWENSON: Dr. Moss?
DR. MOSS: I would like to reiterate what
Dr. Meyer said because I think it is
important. If
we
sat here today and the SMART study only had
2,000 people in it, I think people would
have
totally different conclusions. We would have two
small underpowered studied that maybe
didn't show
anything. I think it would be a bad message to
send to the industry that if you
terminate studies
earlier that can be potentially
beneficial for you.
I am not saying that Novartis did that
for that
reason, but I think it is very important
that if we
don't know the information and there is
a
possibility that it is a class effect, I
think it
is very reasonable to have a warning on
formoterol
that says that a similar class of drug
has shown
adverse events. It is not implicating that drug
per se but it is just, again, relaying
the
332
information that there is the
possibility that
there are subpopulations that may have
adverse
events to this class of medication. So, I would
say yes with that reasoning.
DR. SWENSON: Dr. Newman?
DR. NEWMAN: My answer is yes. I would
just like to give you a little bit of my
basis for
it.
I think that Dr. Schatz said it very well and
I would underscore it with a little more
emphatic
yes.
We know that there are similarities in the
chemistry, the pharmacology and
mechanisms of
action.
We know that clinicians will use these two
drugs rather interchangeably. And, I think that
Dr. Schoenfeld used the key word, which
is
"prudent." Sometimes in the absence of as complete
medical information and scientific
information as
we would like, we have to recommend
something that
we think is the medically prudent thing
to do. So,
that is my basis, given all the caveats
of the
uncertainties of the data.
DR. SWENSON: Dr. Brantly?
DR. BRANTLY: Yes, I vote for a black box
333
warning for formoterol.
DR. SWENSON: Dr. Martinez?
DR. MARTINEZ: Yes.
DR. SWENSON: Dr. Kercsmar?
DR. KERCSMAR: Yes.
DR. SWENSON: Miss Schell?
MS. SCHELL: My vote is yes. I would just
like to state that I think that it is
necessary for
the patient to have that information so
they can
make an informed decision.
DR. SWENSON: Dr. Prussin?
DR. PRUSSIN: Yes, with the caveat that it
has been shown in another member of the
class but
hasn't been shown for this specific
drug.
DR. SWENSON: And my vote is yes as well,
with that same caveat in all fairness to
formoterol
that it be explicit that this has not
been
established for that drug but of its
class.
DR. GARDNER: Mr. Chairman, I want to
change my no vote to yes, given that my
colleagues
also have expressed the caveat that
caused me to
vote no.
So, I agree with what you have said as
334
long as there are caveats so yes.
DR. SWENSON: Okay, fair enough. The vote
on this then was 12 yes and 1
abstention.
We move to the vote on the
last question
on the slide, that is, based on
currently available
information, do we agree that formoterol
should
continue to be marketed in the United
States. I
will ask Dr. Prussin to start the vote.
DR. PRUSSIN: Yes.
DR. SWENSON: Miss Schell?
MS. SCHELL: My vote is yes. Again, I
would like to reiterate with patient and
physician
education as an important part of that.
DR. SWENSON: Dr. Kercsmar?
DR. KERCSMAR: Yes.
DR. SWENSON: Dr. Martinez?
DR. MARTINEZ: Yes, with the caveats and
conditions expressed before.
DR. SWENSON: Dr. Brantly?
DR. BRANTLY: Yes.
DR. SWENSON: Dr. Newman?
DR. NEWMAN: Yes.
335
DR. SWENSON: Dr. Moss?
DR. MOSS: Yes.
DR. SWENSON: Dr. Gay?
DR. GAY: Yes.
DR. SWENSON: Dr. Schatz?
DR. SCHATZ: Yes.
DR. SWENSON: Dr. Gardner?
DR. GARDNER: Yes.
DR. SWENSON: Miss Sander?
MS. SANDER: Yes.
DR. SWENSON: And Dr. Schoenfeld?
DR. SCHOENFELD: Yes.
DR. SWENSON: And my vote is yes as well.
So, that is a unanimous yes to that
question.
We now move to recommendations to the
agency with ideas and opinions and
recommendations
toward how we might further improve the
understanding of the nature and
magnitude of the
risk of salmeterol first and then we will
turn to
formoterol. I think that possibly much of what has
already been stated is contained in this
but I
think I will go down the list to give
people one
336
more opportunity to emphasize just these
points
here with specific recommendations. Dr.
Schoenfeld?
DR. SCHOENFELD: I guess I really don't
know because, clearly, if you have what
you
consider as a problem what you want to
do is figure
out how to prevent the problem. So, I am not going
to suggest that big trials or studies
would be done
to sort of determine the extent of the
problem. It
seems to me that what is necessary is to
try to
figure out how to prevent it and I don't
think with
the study we really know what the
problem is. And,
I am not really sure I know enough about
this to
suggest ways that you could study the
prevention of
this problem, whether this is an issue of
patient
education or something else.
DR. SWENSON: Miss Sander?
MS. SANDER: My feeling is that the
overall question is what we do now and
how we do
measure risks, and do we see greater
risks in
certain populations of people, whether
it is ethnic
or gender specific, or otherwise, or age
related;
337
you know, effects on children versus on
elderly
people or other groups. I think that we need to
look at things long-term. I made a few notes here
and I am trying to put them all in a
capsule here,
but the challenge is that we are always going
to
have questions about these medications,
particularly when I don't believe we are
doing
enough to study what is happening when
patients go
to the doctor in the first place to get
the
medication, what kind of information
they are being
given, and does that information empower
them to
use the product properly at home, at
school and on
the playground.
We just hear every day from
families who
get their medications, go home, and have
a zillion
questions that they don't seem to be
able to get
answered in a manner that--well, I just
think that
we could be doing a better job and I
think that
whatever studies we do approach, we do
need to make
certain that patients do have the
information
necessary to use these drugs safely so
that they do
know that Foradil and Serevent and
Advair are three
338
different drugs and the instructions for using
them
are going to be different. You know, I would hate
for patients to be left with the idea
that they are
the same and that they are used the
same.
One of my concerns is that
patients are
going to use Foradil more frequently
than they
should because of what they think when
they hear
that it treats, you know, the
breakthrough symptoms
as well as preventing symptoms. So, I think we
just need to have education included in
these
studies.
Anyway, I won't preach too much, except
to say that the language of asthma is
very
important. What we say to patients must be said
within their hearing and their ability
to follow
through whether it is a study or not.
DR. SWENSON: Well taken.
Dr. Gardner?
DR. GARDNER: I think that the studies
that GSK described to us go a long way
to helping
to answer some of our questions. The one thing I
have become concerned about is that they
be
encouraged to stay on task and get these
studies
done and reported to us in a timely
fashion. We
339
are aware that these products are moving
toward a
patent expiration and there may be
motivation not
to finish things as quickly as we would
like. If
there is a way for the agency to
encourage that
they, in fact, be completed on time and
reported in
a way that we can use the data, that
would be my
interest.
DR. SWENSON: Dr. Schatz?
DR. SCHATZ: We are trying to consider
both science and practicality in terms
of the
methodology. I think I would actually suggest
something fairly specific, which would
be a
case-control surveillance design where
one, in
fact, would involve hospitals with
linked pharmacy
databases and actively be looking for
those
patients who have these rare outcomes in
a large
enough net that it doesn't take forever
to have
those, to be able to match then sort of
real time
with other decent controls, appropriate
controls,
perhaps hospitalized and not intubated,
perhaps
emergency department. And, I think in so doing you
have a chance to get both phenotypic
information of
340
the type that we would like to have and
even
genotypic information. It is different than a
case-control study in the way I
mentioned. Without
giving this a huge amount of thought, I
would put
that on the table to be considered and,
of course,
the advantage of that is that that would
be one
study that would be essentially done for
both of
these types of medicines, as well as any
other
factors that could, in fact, be
associated with
these very severe and important but very
uncommon
outcomes.
DR. SWENSON: I am going to step in here
simply because I want to follow on with
what Dr.
Schatz had said. One recommendation I might have
is
that another system with a broad database be
considered as a source for this
particular
improvement information. That would be the VA, the
Veterans Administration. They are leading the way
in information management so this might
be another
valuable source, akin to the state
Medicare
analysis.
The other possibility would
be, if we are
341
talking about a potential class effect,
is to
consider that both companies merge
efforts here, if
possible and practical, to look at this
by
expanding numbers and resources to get
at this
issue.
Dr. Gay?
DR. GAY: I believe both companies at this
time, with a number of the studies that
they have
commented on here today, are making good
efforts
toward running the appropriate studies
to help us
evaluate some of the questions we have
brought up
as
a committee. I would be hopeful that
both
companies, with the fact that they
either have
available or have in development
combination
long-acting beta agonists and inhaled
corticosteroid formulations of their
medications,
would look to do similar studies with
those
medications to help to standardize for
the lack of
inhaled corticosteroids in a number of
these
studies, and to help us further evaluate
where we
are in terms of some of the signals that
we have
seen currently with the SMART study.
DR. SWENSON: Dr. Moss?
342
DR. MOSS: I think it is important to
remember that asthma is a heterogeneous
disease,
and I think the answer is not to just to
do an even
larger clinical trial. I think we would be sitting
here with probably having the same
discussions.
Not to sound too NIH appropriate, I
think it is
important to look at this as a
translational
research project and to take the idea
that there
are specific subsets of patients that
may not
respond properly to this long-acting
beta agonist
therapy; identifying a basic science
laboratory
with a translational approach to what
these
specific populations are, whether they
are genetic
or acquired traits, and then study those
populations to see if there are truly
harmful
outcomes in these smaller studies. I think that
would be a better way to go than just
enrolling
60,000 people, or whatever, and I think
the NIH
would like that too.
DR. SWENSON: Dr. Newman?
DR. NEWMAN:
I wish I could roll back the
clock because I guess what I really want
is for the
343
SMART study to reach its stopping point
that was
set forward and really get to that point
so we
would have something more complete. But I can't
have that now. That being said, I would underscore
the things that were said here. I don't have a
whole lot to add, except that as we go
forward with
these additional studies and we become
more
interested in both the clinical
phenotypes of
asthma, as well as the genotypes of
asthma, I would
encourage the sponsors not to ignore
something that
we all know, which is that while the
genes are
important and it is a heterogeneous
disease, there
are also major environmental factors
that are going
to affect an individual's risk of having
severe
exacerbations and I haven't heard that really
discussed here.
People look conventionally at
tobacco.
That is important. But we know that many cases of
asthma, especially in adults, have their
onset in
adulthood due to occupational and
environmental
factors other than tobacco smoke being
involved. I
think that those ought to be weighed in
when you
344
are designing studies that look at the
genetic
factors.
We have to understand the somewhat more
complex interactions and confounding
effects, as
well as true attributable risk related
to
environmental factors added to the
understanding of
the genetics.
DR. SWENSON: Dr. Brantly?
DR. BRANTLY: I would echo Dr. Moss'
belief about pursuing subgroups. But I think that
one of the keys to trying to understand
about this
small group of people who die is that we
need to
find their phenotype. One approach to doing that
is obviously pursuing exactly what that
phenotype
was at time of death, and to couple
that, for
instance, with a VA study in which we
actually are
able to forensically dissect what those
patients
were like at that time would be a very
valuable
thing.
I would encourage the sponsors to consider
partnering specifically with the VA to
approach
that and perhaps capture that death
phenotype that
we are seeing. It may open up a wide array of
possible mechanisms which we might be
able to look
345
at in the future.
DR. SWENSON: Dr. Martinez?
DR. MARTINEZ: I fully agree that at the
present time further assessment of the
potential
existence of this increased risk,
although
interesting, shouldn't be the center of
the
attention. My general assessment of the data that
has been presented to us is that there
is a signal
here, and I think the main objective
will need to
be to understand what the signal is and
in which
way it could be prevented.
I completely agree with Dr.
Brantly that
trying to define the phenotype and
perhaps the
genotype of these subjects is a great
objective
that I think needs to be pursued. This will have
an additional advantage--in Spanish
there is a
saying that not all bad things come to
harm--which
is to better understand brittle
asthma. I think
this is a good opportunity to understand
who are
the subjects who have this severe form
of the
disease who probably represent a
significant
proportion if you think about it, of
mortality for
346
this disease which is relatively low.
My recommendation also, since
I have been
doing some genetic studies for the last
ten years
in this disease, is that more than the
more common
polymorphisms expressed in any of these
potential
candidate genes, rare polymorphisms may
be the
crucial factors here. Therefore, the approach of
doing this by genotyping for common
polymorphisms
found in the general population may not
be
successful. Perhaps a better approach could be a
more profound re-sequencing of individuals
who have
this phenotype to try to determine if
rare
polymorphisms are present in them that
are not
present in the population as a
whole. I don't see
that methodological approach mentioned
and I think
it would be very important. It is more expensive
but, at the same time, it could give
very
interesting results because
polymorphisms that are
present, say, in 1/1,000 or 3 or 4/1,000
are not
going to be detected in linkage to
equilibrium--I
am sorry to give such a complicated
answer but in
linkage to equilibrium with the common
ones. They
347
will have to be found specifically in
each subject
who has these polymorphisms which perhaps
are
increasing the risk in the way we are
talking
about.
So, I strongly recommend to
the industry
to search for different approaches both
in genetic
and phenotypic studies to determine who
the
subjects are and to ensure that in that
way we can
have some sort of preventive strategy.
DR. SWENSON: Dr. Kercsmar?
DR. KERCSMAR: I agree completely with
what Dr. Moss, Dr. Brantly and what Dr.
Martinez
just stated quite elegantly, that we are
clearly
moving into an era of one size does not
fit all for
asthma therapy, and pharmacogenetics is
really
going to be what will direct us to
effective and
safe therapy, and it is only through
identifying
those high risk phenotypes that we will
be able to
do that.
So, I would agree completely with what
they said.
DR. SWENSON: Miss Schell?
MS. SCHELL: I would just like to make a
348
couple of statements. When we look at asthma, as a
practitioner at the bedside, there are
many
components and asthma is very
individualized on the
patient.
And, when you look at the components of
asthma management, clearly, medication
is one of
the components that we look at. But I also would
like to see a study that would look at
factors that
could affect how much medication you are
giving,
including the environmental factors, the
factors of
education and compliance, all those
things that
patients are not very well at doing yet
and how is
that affecting how much medication you are
going to
have to give them. So, basically looking at all
parts of asthma management on an
individual basis I
think is important to include in a
study.
DR. SWENSON: Dr. Prussin?
DR. PRUSSIN: I think it is important to
remember the public health impact of the
question
we are debating. Asthma is an incredibly common
disease.
Combination long-acting beta agonists and
inhaled corticosteroid therapy is the
primary
therapy for moderate to severe
asthma. As an
349
example of that, Advair is I believe the
number one
drug for GSK. So, these are problems that deserve
the input of some resources.
I am not an epidemiologist; I
am a
translational researcher. So, just the opposite of
Dr. Schoenfeld, I really can't think
about study
design in a way that really is going to
make sense.
But I am concerned that the small-scaled
studies
that we are looking at, these
translational
studies, are all very good for
understanding the
biology but not for answering real-world
questions.
You know, they are fine for the future
and for
projecting ourselves forward and they
are
important. It is the kind of work I do. But I
would like to step back and say, five
years from
now or three years for now, are we going
to have
answers to the questions that we are
talking about
today?
And, I am not clear that these are going to
do that.
Again, I don't know how to; that is
beyond my expertise.
I think, clearly, one of the
questions we
should be addressing is looking at
combination
350
therapy versus inhaled corticosteroid
alone. Is
the safety signal that we saw here with
salmeterol
alone still present when you have an
inhaled
steroid on board in all of the
patients? I think
that is a study that could be done.
The other concern I have, just
in terms of
long-term studies, that has not been
addressed is
the issue of monotherapy. Again, we have talked
about it but, you know, how do we get a
grasp on
it?
Both companies are selling long-acting beta
agonists and I don't think we have any
handle on
patients that are taking this as
monotherapy and
that is a public health problem that
presumably
also is a safety problem. At least we should have
a handle on the magnitude of that
problem, what
percentage of patients using these drugs
are using
them as monotherapy and that could be
addressed as
well.
So, these are some of the
issues I see as
far as what studies could be done. Again, how you
answer the specifics on those studies I
don't know
but I am hesitant just to look at
mechanistic
351
studies, thinking that those are going
to answer
real-world questions that we need
addressed that
patients and practitioners would like
addressed.
DR. SWENSON: We will move to the last
question, and I think it mirrors so much
the former
question that this may go quickly but we
should at
least allow for discussion relevant in
particular
to formoterol.
I will start just so I don't
have to have
Dr. Prussin go again initially. I think the
comments that I mentioned in regards to
salmeterol
hold equally for formoterol and they are in
the
record.
Dr. Prussin?
DR. PRUSSIN: This is in terms of question
four?
DR. SWENSON: This is in terms of
Novartis.
DR. PRUSSIN: I think really basically the
same issues are involved. I think there is a
safety signal and, obviously, the
numbers need to
be greater but I think roughly the
parallel issue
to what I mentioned for number three.
352
DR. SWENSON: Miss Schell?
MS. SCHELL: I will stand by what I said
earlier.
Thank you.
DR. SWENSON: Dr. Kercsmar?
DR. KERCSMAR: I think the same issues
apply to this drug as well.
DR. SWENSON: Dr. Martinez?
DR. MARTINEZ: The same issues.
DR. SWENSON: Dr. Brantly?
DR. BRANTLY: The same issues.
DR. SWENSON: Dr. Newman?
DR. NEWMAN: Actually I have more a
question than even a comment. Based on what we
discussed earlier about kind of a within
class
warning that we would put with this drug
based on
the SMART study and leave the question
unanswered
for Novartis' product, why wouldn't we
be saying
here today that there should be a SMART
study
equivalent, only smarter, for
formoterol? Right?
I mean, why wouldn't we be proposing
that?
Otherwise we are going to be proposing
what is
really kind of a watered down
"well, another drug
353
in the class; may have some problems and
so we put
it on this label but we don't know about
this
drug." Well, don't we need to know about this drug
and its safety profile based on what we
have heard
today?
DR. SWENSON: Dr. Moss?
DR. MOSS: I would like to build on that a
little bit. I think if Novartis thinks that there
are differences between their drug and
Serevent,
that this is not a class effect, I think
it would
be prudent for you, guys, to go and
figure that
out.
Right now, since there is not the information
and we feel that everything should be
lumped
together, it might be in your best
interest to go
and figure out, either doing the large clinical
study that Dr. Newman is talking about
if you feel
that it is worthwhile, or to come up
with smaller
translational studies that show that
there are
differences. If that was, indeed, the case then
the recommendations of a class warning
would be
changed based on that. So, that is the only thing
I would add.
354
DR. SWENSON: Dr. Gay?
DR. GAY: I have to agree with Dr. Newman
and Dr. Moss. They both stated it very eloquently.
I am sure Novartis must have some
concerns with the
potential addition of a black box
warning and I
feel that we do need to see the data that
it is
different and they will have to run some
study that
shows us the differences that exist with
their drug
in order to not have it present.
DR. SWENSON: Dr. Schatz?
DR. SCHATZ: Well, I may see it a little
differently than what has been
mentioned. I mean,
I think what we have learned from the
SMART study
is that even a study of this magnitude
doesn't
answer the question, and I understand
the concept
of doing it smarter but I am not totally
sure it is
possible to do it smarter in the way we
want and
still have it accomplished. So, I would say that
we really do need to think of another
design. Of
course, the one I suggested before I
still feel
would answer that question because, in
addition to
other drugs, it would have other
issues. So, I
355
actually don't think another SMART study
is the
right answer even though I would like to
have more
information.
But the only other thing I
would mention
is what Cal mentioned in terms of
monotherapy and
how prevalent it is. There are some data out there
that could look for that. The data like the VA and
like Kaiser where they keep track of
these sorts of
things, I think we could get a handle at
least in
those populations as to how common
monotherapy is.
I actually have seen some of that within
the Kaiser
population and it is reassuringly small
in at least
that population. So, I do think the answers to
some of those questions are there if we
look.
DR. SWENSON: Dr. Gardner?
DR. GARDNER: I agree about study design.
I think that Dr. Knobil's response to
why they
weren't able to get more than 30,000
people would
signal to us that Novartis starting the
same study
again wouldn't be able to either, and I
think a
more productive way to go would be the
combination
of the Medicaid analyses that are
planned, which
356
will address children, and possibly the
VA--encompassing all of them, the HMO
research
network or Kaiser Permanente databases
carefully
analyzed by someone who understands
their
potentials and limitations could help us
see the
real-world issues and answer some of the
questions
that we have about both of these
products about
monotherapy, about combination therapy
and so on.
So, I would encourage that if
there are
going to be more large-scale studies
done that they
be done with existing databases of
real-world data
so that we can get a better handle on
it.
The only other thing that
occurred to me
in what we saw today was the unique
signal, as I
noticed it, relative to children in the
formoterol
data and I wondered whether there should
be
pediatric dosing studies or some other
attention
paid specifically to children since that
signal
came out of there. So, I would suggest that for
this product.
DR. SWENSON: Miss Sander?
MS. SANDER: Well, I have a question first
357
and that is do black box warning make--on
drugs
that have black box warnings, are they
more likely
to wind up on the prior authorization
list of state
health programs? Does anyone know?
DR. TRONTELL: We don't have that
information. Are you talking about state Medicaid
formularies or health plans? We don't have that
information at the agency.
DR. SWENSON: Perhaps Glaxo might know
since they have been living with a black
box
warning.
DR. WEEN: Generally speaking, the black
box warning doesn't have an effect on
whether or
not your drug is listed on a formulary
or not. It
is just something that is pertinent to
prescribing
practice and what-have-you. So, the black box
warning is not an a priori reason why
you would not
be on formulary.
MS. SANDER: I just wanted to
make sure
because asthma is not a prior
authorization kind of
disease.
So, I just wanted to make certain I
clarified that. With regard to the question at
358
hand, really I think what we are talking
about here
today is trying to figure out why patients
are
dying and the data doesn't tell us. But the
parents of children with asthma who have
died and
loved ones, family members whose loved
ones have
died of asthma do tell us that asthma is
a very
deceptive disease and I think that is
one of the
reasons why we are having a hard time
getting our
hands around, you know, what the data
means in the
real world. I think that we all need to remember
that asthma is a serious condition; that
13 people
die of asthma every single day; and how
does that
fit in with this data up here? I don't really know
except that somehow in the information
that we
provide patients when we are crafting
these studies
we need to make certain that the
terminology and
the instructions that we are giving them
are
extremely clear. I would just encourage that in
your studies when you refer to albuterol
you do not
refer to it as a rescue drug because it
is not
reserved for what patients feel are
rescue
situations only. It is to prevent exercise. It is
359
to be used at the earliest point,
earliest sign of
symptoms and when we refer to it as a rescue drug
patients are waiting too long to use
it. I think
that it can also cloud some of the
answers that you
may get from them when you are asking
them about
rescue medication use. So, that is the only advice
that I have.
DR. SWENSON: Dr. Schoenfeld?
DR. SCHOENFELD: Actually, I think that
there is place for a clinical
trial. Basically, it
seems to me, there would be place for a
clinical
trial comparing the two drugs without a
placebo
control.
The advantage of this would be that the
trial could last longer because we don't
really
know the timing of these events. They may be
transitory or they may be something that
sort of
happens constant over time. So, it seems to me we
would learn that as well from a trial
that could
last longer than half a year and would
be a
comparison of the two drugs in terms of
severe
asthma or asthma-related death. I think such a
trial would be practical. I think probably that is
360
the kind of trial that NIH should
probably help
with, as they have helped with other
heads-up
trials of commonly used pharmaceuticals.
I think the only thing that
would sort of
make this less useful would be the
situation if
there is a large number of other LABAs
in the
pipeline. Then this would be less useful. But if
these are the two drugs, then they
should be
compared.
DR. SWENSON: Dr. Schatz?
DR. SCHATZ: I would just ask a question
though.
To power it for the outcomes we are
talking about, do you have any sense for
what sort
of sample sizes would be required?
DR. SCHOENFELD: You would use the
statistic of 1/700 per year--
[Laughter]
--and you could come up with a
sample size
quite easily, but I don't want to do it
on the back
of an envelope.
DR. SWENSON: You might need a big
envelope! With that, I believe we have come to the
361
end of the meeting. I wish to thank the personnel
from both Novartis and GlaxoSmithKline
for their
excellent presentations, the panel
members and the
FDA.
I think if there are no further points, then
the meeting is adjourned.
[Whereupon, at 4:45 p.m., the
proceedings
were adjourned.]
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